Intramolecular -Arylation of Lithiated Carbamates

Intramolecular -Arylation of Lithiated Carbamates

A thesis submitted to the University of Manchester

for the degree of Doctor of Philosophy

in the Faculty of Engineering and Physical Sciences

2012

Anne FOURNIER

School of Chemistry

3

CONTENTS

Abstract 9

Declaration 10

Copyright Statement 10

Acknowledgements 11

Abbreviations 12

Preface 17

CChhaapptteerr II:: IINNTTRROODDUUCCTTIIOONN 18

I.1 Strategies for the Asymmetric Synthesis of Tertiary Alcohols 18

I.1.1 Asymmetric addition of carbon-based organometallic nucleophiles to

ketones 18

I.1.1.1 Catalytic enantioselective arylation, alkylation and alkenylation reactions 21

I.1.1.2 Catalytic enantioselective allylation reaction 33

I.1.1.3 Catalytic enantioselective alkynylation reactions 39

I.1.2 Catalytic asymmetric aldol reactions 43

I.1.3 Kinetic resolution of tertiary alcohols 51

I.1.4 1,2-Metallate rearrangement of boronate complexes 52

I.2 Intramolecular Electrophilic Arylation of Lithiated Ureas and

Thiocarbamates 55

I.2.1 Discovery of N to C aryl migration in lithiated N-benzyl ureas 55

I.2.2 Aryl migration in lithiated N-benzyl ureas 56

I.2.3 Aryl migration in other lithiated urea analogues 60

I.2.3.1 Aryl migration of N-benzyl-N-pyridyl ureas 60

I.2.3.2 Aryl migration of N-aryl urea derivatives of hetero- or carbocyclic

amines 61

I.2.3.3 Aryl migration of N-allyl-N-aryl ureas 63

I.2.4 Enantioselective synthesis of tertiary thiols by intramolecular arylation

of lithiated thiocarbamates 63

4

I.3 Properties and Reactivity of Lithiated Carbamates 65

I.3.1 Dipole-stabilized carbanions adjacent to oxygen 65

I.3.2 Versatile reactivity and configurational stability of lithiated

O-benzylcarbamates 66

I.3.2.1 Electrophilic substitutions of lithiated O-benzylcarbamates 67

I.3.2.2 N to C arylation migration in lithiated O-benzylcarbamates 70

I.3.3 Configurational stability of lithiated O-allylcarbamates 73

I.3.4 Configurational stability of lithiated O-propargylcarbamates 78

I.4 Carbolithiation Reactions Involving Organolithiums 80

I.4.1 Overview of carbolithiation reactions 80

I.4.1.1 General aspects of carbolithiations 80

I.4.1.2 Intermolecular carbolithiation reactions 82

I.4.1.3 Intramolecular carbolithiation reactions 85

I.4.2 Intermolecular carbolithiation reactions of vinyl carbamates 87

I.4.3 Tandem β-alkylation--arylation of amines by carbolithiation and

rearrangement of vinyl ureas 89

I.5 Aims of the project 91

CChhaapptteerr IIII:: RREESSUULLTTSS AANNDD DDIISSCCUUSSSSIIOONN 94

II.1 Synthesis of Clemastine, an Antihistaminic Agent 94

II.1.1 Total synthesis and absolute configuration of clemastine via resolution 94

II.1.1.1 Ebnöther and Weber’s pioneer work on the synthesis of

(R,R)-clemastine 94

II.1.1.2 Synthesis of optically active (R)-2-(2-chloroethyl)-1-methyl-

pyrrolidine, an intermediate in the synthesis of clemastine via resolution 95

II.1.2 Stereoselective synthesis of ()-hydroxyclemastine 97

II.1.3 Novel asymmetric synthesis of ()-(S,S)-clemastine 98

II.1.3.1 Retrosynthesis of (S,S)-clemastine 98

II.1.3.2 Synthesis of pyrrolidine fragments 99

II.1.3.3 Synthesis of tertiary alcohol by aryl migration of a lithiated

carbamate 103

5

II.1.3.4 Further evidences for stereochemically invertive

rearrangement for carbamates 104

II.1.3.5 Formation of the ether linkage and isolation of clemastine 109

II.2 Spectroscopic and Computational Studies of the Mechanism 116

II.2.1 In situ IR spectroscopy 116

II.2.2 Computational studies 124

II.3 Arylation of Lithiated Carbamates by Intramolecular N to C

Aryl Migration: Scope, Stereoselectivity and Mechanism 130

II.3.1 N to C aryl migration in lithiated N-aryl-O-allylcarbamates 130

II.3.1.1 Synthesis and aryl migration of a cinnamyl carbamate 130

II.3.1.2 Synthesis and aryl migration of -methyl cinnamyl carbamates 132

II.3.1.3 Stereospecificity in the aryl migration 135

II.3.1.4 Aryl migration of simple O-allylcarbamates 142

II.3.1.5 In situ IR spectroscopy studies 143

II.3.2 N to C aryl migration in lithiated N-aryl-O-propargylcarbamates 145

II.3.2.1 Synthesis and attempted aryl migration of primary

O-propargylcarbamates 145

II.3.2.2 Synthesis and aryl migration of -methylated propargylcarbamate 146

II.3.2.3 Stereospecificity in the aryl migration 150

II.3.3 γ-deprotonation-mediated N to C aryl migration of N-aryl-Z-enol

carbamates 153

II.3.3.1 Synthesis of Z-enol carbamates 153

II.3.3.2 -Arylation of Z-enol carbamates by γ-deprotonation and

N to C aryl migration 154

II.3.3.3 In situ IR spectroscopy studies 157

II.3.4 Limits of the N to C aryl migration 159

II.3.4.1 Attempted aryl migration in lithiated carbamates containing

the electron rich heterocycle furan 159

II.3.4.2 Attempted aryl migration in lithiated O-alkylcarbamates 160

II.4 Tertiary Alcohols by Tandem β-Carbolithiation and N to C

Aryl Migration in Enol Carbamates 162

II.4.1 Carbolithiation and aryl migration of N-methyl--aryl-O-vinylcarbamate 162

II.4.2 Carbolithiation and aryl migration of N-isopropyl--aryl-O-vinylcarbamates 163

6

II.4.2.1 Optimisation of the reaction 163

II.4.2.2 Synthesis of diarylalkylalcohols 165

II.4.2.3 Enantioselectivity in the β-carbolithiation-aryl migration 167

II.4.3 Carbolithiation and aryl migration of β-substituted

N-isopropyl--aryl-O-vinylcarbamates 169

II.4.4 Carbolithiation and aryl migration of -proparyl-O-vinylcarbamates 171

II.4.4.1 Synthesis of N-isopropyl-α-propargyl-O-vinylcarbamates 171

II.4.4.2 One-pot synthesis of multiply branched arylalkynylalcohols 172

II.4.4.3 Synthesis of enantioenriched allenes 175

II.4.5 Extension of the substrate scope of the reaction 178

II.4.5.1 Carbolithiation-aryl migration of -alkenyl-O-vinylcarbamates 178

II.4.5.2 Carbolithiation-aryl migration of -silyl-O-vinylcarbamate 180

II.4.5.3 Attempted carbolithiation-aryl migration of -heteroaryl-

O-vinylcarbamates 180

II.5 Further Extension of the Methodology 182

II.5.1 N to C vinyl migration in lithiated O-benzylcarbamates 182

II.5.2 Attempted N to C alkynyl migration in lithiated O-benzylcarbamates 187

II.5.2.1 Synthesis of ynecarbamates 188

II.5.2.2 Reactivity of lithiated ynecarbamates 190

II.5.3 Attempted N to C cyano migration in lithiated O-benzylcarbamates 193

II.5.4 Attempted N to C heteroaryl migration in lithiated O-benzylcarbamates 194

II.6 Conclusions and Future Work 197

CChhaapptteerr IIIIII:: EEXXPPEERRIIMMEENNTTAALL SSEECCTTIIOONN 203

III.1 General Information 203

III.2 General Procedures 205

III.3 Experimental Procedures and Data 217

III.4 X-Ray Crystal Data 360

7

RREEFFEERREENNCCEESS && NNOOTTEESS 364

AAPPPPEENNDDIIXX 380

Appendix 1: List of publications 380

Appendix 2: Experimental procedures for in situ React IR studies 381

Appendix 3: In situ IR spectroscopy monitoring the rearrangement

of a N-allylurea 384

8

Total Word Count : 77 989

9

ABSTRACT

Intramolecular -Arylation of Lithiated Carbamates

A submission for the degree of Doctor of Philosophy at The University of Manchester

Anne Fournier

2012

Keywords: carbamates, organolithiums, arylation/vinylation, stereospecific, carbolithiation

This thesis describes research carried out on the synthesis of tertiary alcohols or

derivatives by N to C aryl/vinyl migration in lithiated carbamates.

Section II.1 describes the first enantioselective synthesis of the antihistamine agent

clemastine, as its (S,S)-stereoisomer as an illustration of the methodology. It has been

achieved by ether formation between a proline-derived chloroethylpyrrolidine and an

enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the

carbamate derivative of -methyl-p-chlorobenzyl alcohol by invertive aryl migration on

lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the

rearrangement in contrast with related ureas.

Modelling work to establish the origin of this stereodivergent behaviour is reported in

Section II.2. This also reports in-situ IR experiments providing evidence of the mechanistic

pathway of the rearrangement of an O-benzyl-N-aryl carbamate.

The scope of the N to C aryl migration in other stabilised organolithiums is shown in

section II.3. The rearrangement is now addressed in more systematic manner, thus

allowing the -arylation of O-allyl and O-propargylcarbamates (by -deprotonation) and

O-vinylcarbamates (by -deprotonation) to be achieved in good yields but with poor

stereoselectivity.

Section II.4 goes on to show that enol carbamates derived from aromatic or ,-

unsaturated compounds and bearing an N-aryl substituent undergo carbolithiation by

nucleophilic attack at the position of the enol double bond. The resulting carbamate-

stabilised allylic, propargylic or benzylic organolithium rearranges with N to C migration

of the N-aryl substitutent, creating a quaternary carbon to O. The products may be easily

hydrolysed to generate multiply branched tertiary alcohols in good to moderate yields in a

one-pot tandem reaction.

Finally, Section II.5 proves that the rearrangement in lithiated carbamates can be

extended to N to C vinyl transfer.

10

DECLARATION

No portion of the work referred to in this thesis has been submitted in support of an

application for another degree or qualification of this or any other university or other

institute of learning

COPYRIGHT STATEMENT

i. The author of this thesis (including any appendices and/or schedules to this

thesis) owns any copyright in it (the “Copyright”) and she has given The

University of Manchester the right to use such Copyright for any administrative,

promotional, educational and/or teaching purposes.

ii. Copies of this thesis, either in full or in extracts, may be made only in

accordance with the regulations of the John Rylands University Library of

Manchester. Details of these regulations may be obtained from the Librarian.

This page must form part of any such copies made.

iii. The ownership of any patents, designs, trade marks and any and all other

intellectual property rights except for the Copyright (the “Intellectual Property

Rights”) and any reproductions of copyright works, for example graphs and

tables (“Reproductions”), which may be described in this thesis, may not be

owned by the author and may be owned by third parties. Such Intellectual

Property Rights and Reproductions cannot and must not be made available for

use without the prior written permission of the owner(s) of the relevant

Intellectual Property Rights and/or Reproductions.

iv. Further information on the conditions under which disclosure, publication and

exploitation of this thesis, the Copyright and any Intellectual Property Rights

and/or Reproductions described in it may take place is available from the Head

of School of Chemistry (or the Vice-President).

11

ACKNOWLEDGEMENTS

I would firstly like to thank Jonathan Clayden for the opportunity to work in his group and

for his support and help throughout the course of the research and during the search of my

postdoctoral. I would like to mention that it has been really pleasant to work with. I am

also grateful to the EPSRC and GlaxoSmithKline for the provision of funds.

I thank my industrial supervisor, Chris Nichols, for his continuous support in the Ph.D.

program and his patience during my three-month placement at GSK. Thanks also to Nick

Wooster (at GSK) for his assistance for React IR studies.

I am indebted to the staff at the School of Chemistry for the provision of services. I would

especially like to thank Rohana and Gareth for mass spectrometry/HPLC.

Thanks must go to all members of the Clayden group past and present – PhD, post-doc and

MChem/summer students. “Merci” to all my compatriots, Morgan, Gilles, Julien, Gaëlle,

Vincent, Thomas, Hatice, Julie, Juliette, Alexis, Alexandra and Anne-Sophie. In no

particular order thanks also to Paul, Beckii, James, Alex, Jordi, Alberto, Steve, Jemma,

Mike, Nadia, Rob, Liam, Daniele, Matteo, Tommaso, Edmund, Simon H., Rachel, Sam,

Francis and Bryden.

A special thank also to Abby, my first lab-hood neighbour, for tolerating my “horrible

English”, Simon “Sadsack” for his attention, Dan and Nicole for teaching me climbing.

Special mention goes to Sarah who is now a very good friend, with whom I laughed a lot

and spent some good times.

I am additionally grateful to Sarah, Chris and Vittorio for proof-reading.

I really enjoyed walking in the Peak District, Lake District, Snowdonia, Scotland,…with

good and bad weather, but contrary to what we think in France the weather is not that bad,

I have never been so tanned as in UK!!.

Many thanks to my family, especially my sister and my friends even though most of you

have no idea what it is that I do.

12

ABBREVIATIONS

Å angstrom(s)

[]D specific rotation [expressed without units ; the units (deg.mL)/(g.dm) are

understood]

Ac acetyl

aq. aqueous

Ar aryl

Aro aromatic

BINOL bi-2-naphthol

Bn benzyl

Boc tert-butoxycarbonyl

BOX bisoxazoline

Br broad (spectral)

Bu, n-Bu normal (primary) butyl

s-Bu sec-butyl

t-Bu tert-butyl

Bz benzoyl

c concentration

°C degrees Celsius

CAN ceric ammonium nitrate

cat. catalyst

Cb N-N-diisopropylcarbamoyl

Cbz benzyloxycarbonyl

CI chemical ionisation

CIP contact ion pair

CIPE complex induced proximity effect

Cm centimeter(s)

cm-1

wavenumber(s)

coe cyclooctene

Conds. conditions

Conv. conversion

13

COSY correlation spectroscopy

Cp cyclopentadienyl

cPr cyclopropyl

C.T. chirality transfer

Cy cyclopentyl

chemical shift in parts per million downfield from tetramethylsilane

d doublet (spectral); day(s)

DABCO 1,4-diazabicyclo[2.2.2]octane 5-(dimethylamino)-1-naphthalenesulfonyl

DBB 4,4’-di-tert-butylbiphenyl

DCE 1,2-dichloroethane

d.e. diastereoisomeric excess

DEPT distortionless enhancement by polarization transfer

DFT density functional theory

DIBAL-H diisobutylaluminium hydride

DiPEA diisopropylethylamine

DIPT ()-diisopropyltartrate

DMAP 4-(N,N-dimethylamino)pyridine

DME 1,2-dimethoxyethane

DMF dimethylformamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

DMSO dimethyl sulfoxide

dppa diphenylphosphoryl azide

d.r. diastereomeric ratio

E or EX electrophile

e.e. enantiomeric excess

EI electron impact

equiv. or eq. equivalent(s)

e.r. enantiomeric ratio

ESI or ES electrospray ionization

Et ethyl

EWG electron-withdrawing group

fum-

fumarate

g gram(s)

14

GC gas chromatography

H hour(s)

Hex hexyl

HMBC heteronuclear multiple bond correlation

HMDS hexamethyldisilazane

HMQC heteronuclear multiple quantum correlation

HPLC high-performance liquid chromatography

HRMS high-resolution mass spectrometry

HSQC heteronuclear single quantum correlation

Hz hertz

inv inversion

IPA propan-2-ol

IR infrared

J coupling constant (in NMR spectrometry)

L ligand; liter(s)

L*

chiral ligand

LDA lithium diisopropylamide

lit. literature value

LUMO lowest unoccupied molecular orbital

LiTMP lithium 2,2,6,6-tetramethylpiperidide

micro

m multiplet (spectral) or milli or meta

M molar (moles per liter) or unspecified metal or molecular mass (mass

spectrometry)

M+

parent molecular ion

Me methyl

min minute(s)

mmol millimole(s)

mol mole(s)

m.p. melting point

MS mass spectrometry; molecular sieves

MW molecular weight

m/z mass-to-charge ratio

15

N normal (equivalents per liter)

NBS N-bromosuccinimide

nm nanometer(s)

NMP N-methylpyrrolidine

NMR nuclear magnetic resonance

nOe nuclear Overhauser effect

Np naphthyl

Nu- or Nu nucleophile

n-Pent pentyl

n.d. non determined

oct octuplet

o ortho

p para

Ph phenyl

PMP p-methoxyphenyl

ppm part(s) per million

Pr propyl

i-Pr isopropyl

Py pyridine; pyridyl

q quartet (spectral)

qn quintet (spectral)

R unspecified substituent

Ret retention

Rf retention factor

RT room temperature

s singlet (spectral); second(s)

s. selectivity

SCX strong cation exchange (cartridge)

SE’ electrophilic substitution with allylic rearrangement

SE2 bimolecular electrophilic substitution

sep septet (spectral)

S.M. starting material

SN2 bimolecular nucleophilic substitution

SNAr nucleophilic aromatic substitution

16

()-sp. ()-sparteine

SSIP solvent separated ion pair

t time

t triplet (spectral)

T or Temp. temperature

TBAF tetrabutylammonium fluoride

TBDPS tert-butyldiphenylsilyl

TBHP tert-butyl hydroperoxide

TBME tert-butylmethylether

Tf trifluoromethanesulfonyl

THF tetrahydrofuran

TIPS triisopropylsilyl

TIPT tetra(isopropoxy)titanium

TLC thin layer chromatography

TMEDA N,N,N,N-tetramethyl-1,2-ethylenediamine

TMS trimethylsilyl; tetramethylsilane

Tol tolyl or toluene

tR retention time (in chromatography)

Ts p-toluenesulfonyl

UV ultraviolet

max absorption maximum

vis visible

v/v volume per unit volume

w weak

w/w weight per unit weight

17

PREFACE

The author worked for sanofi-aventis in France for two years as a Data Quality Manger

before graduating from the University of Paris XI in Orsay (France) in 2008 with a Master

of Science degree in Organic Chemistry. Her final year research project was undertaken at

the Institut de Chimie Moléculaire et des Matériaux (ICMMO) under the supervision of Dr.

Gérard Rousseau. The project investigated the reactivity of 5-phenyl-2H-pyrrol-2-one

synthesised by a 5-endo halo cyclisation of , -ethylenic hydroxamate.

In 2008, she moved to England to join the group of Prof. Jonathan Clayden working on the

lithiation of carbamates. This research is embodied in this thesis. In May 2012, the author

will take up a post-doctoral research position with Prof. James Gleason at McGill

University in Montreal, Canada.

18

CChhaapptteerr II :: IINNTTRROODDUUCCTTIIOONN

I.1 Strategies for the Asymmetric Synthesis of Tertiary Alcohols

Tertiary alcohols are common motifs in natural products and medicinally active agents

(Figure 1). As such, roughly 20 % of the top 50 pharmaceutical contain tertiary alcohols or

their derivatives.[1]

Figure 1. Examples of Tertiary Alcohols Containing Natural Products and

Pharmaceuticals.

HN

ON

N

O OH

O

O

O

O

OH

O

OH

O

O

O

OMe

N

OH

O

O

H OO

HO2C OHCO2H

O

(CH2)11CH3

OH

O

O

HO

OH OHO

NHMe

K252a (kinase inhibitor)

Integerrimine (pheromone)

Cinatrin C3

(anti-inflammatory)

Fostriecin (anti-tumor)

Erythromycin (antibiotic)

The numerous methods for asymmetric synthesis of chiral secondary alcohols (e.g.

kinetic resolution, Noyori asymmetric hydrogenation, enantioselective addition to

aldehydes and many are commercially available) are not matched by a comparable choice

of methods for the synthesis of chiral tertiary alcohols (no oxidation of C-O possible for

kinetic resolution, no hydrogenation of carbonyl possible, ketones are less reactive and

smaller steric and electron differences between prochiral carbons).

1,2-Nucleophilic addition to carbonyl compounds is probably the most straightforward

and useful manner of achieving this goal.

19

I.1.1 Asymmetric Addition of Carbon-Based Organometallic

Nucleophiles to Ketones

Tertiary alcohols are commonly obtained by addition of an organometallic reagent to

a ketone (Scheme 1, paths a and b). Although such a process can be rendered asymmetric

through the use of chiral ligands, the process requires discrimination of the enantiotopic

faces of the ketone, which can be a significant challenge when the ketone is dialkyl or

diaryl substituted.[2]

Scheme 1. Schematic Representation of the Addition of a Nucleophile on the Prochiral

Faces of a Ketone.

Nu

OHRL

RS

ORL

RS

Path a

Nu

OHRS

RL

Path b

ML*

Nu�

Nu�

a

b

ORL

RS

Nu�

Nu�

a

b

ML*

Organometallic alkylation or arylation can be classified into three processes: (a)

substrate activation using a Lewis acid catalyst, (b) reagent activation using a Lewis base

catalyst, and (c) dual activation of the substrate and reagent using a bifunctional Lewis

acid-Lewis base catalyst (Scheme 2). In recent years, a few novel methods have been

introduced, most of them based on the double activation concept.[3]

20

Scheme 2. Catalytic Synthesis of Tertiary Alcohols from Ketones and Organometallic

Reagents.

R1 R2

O

MX

Lewisacid* R1 R2

O

Lewisbase*

(a) substrate activation with a Lewis acid catalyst

(b) reagent activation witha Lewis base catalyst

R3

MXR3

R1 R2

O

Lewisacid*

Lewisbase*

(c) dual activation of the substrate and reagentwith a bifunctional Lewis acid-Lewis base catalyst

MXR3

Although several examples involving organolithium and Grignard reagents have been

reported,[4]

these usually require greater than stoichiometric amounts of chiral ligands. In

addition, the high reactivity of these reagents precludes the presence of many functional

groups in the substrates.

In contrast, organozinc reagents are mild and exhibit excellent functional group

compatibility, making them the most popular species for carbon-carbon bond-forming

reactions on carbonyl compounds.

Organoaluminium complexes are also tolerant of a wide range of functional groups

and have been applied to the asymmetric addition to ketones.

The Lewis acidic character and nucleophile activation ability (transmetallation and

deprotonation) of copper catalysts have also been utilised in asymmetric C-C bond-

formation to ketones. Lewis acidic cationic copper-catalyzed tetrasubstituted carbon-

forming reactions generally produce excellent enantioselectivity, but substrates are

restricted to activated ketones, such as pyruvate esters. The excellent enantioselectivity is

attributed to chelate coordination of the substrates to the copper centre containing a well-

21

defined geometry. On the other hand, catalytic asymmetric C-C bond formation to simple

ketones is promoted through activation of the nucleophile via transmetallation.[5]

I.1.1.1 Catalytic Enantioselective Arylation, Alkylation and Alkenylation Reactions

Dosa and Fu reported the first catalytic enantioselective addition of organozinc

reagents to ketones in 1998.[6]

Noyori’s 3-exo-dimethylaminoisoborneol ((+)-DAIB)[7]

(15

mol %) ligand 1 allowed the addition of diphenyl zinc to aromatic and aliphatic ketones in

good to high enantiomeric excesses of up to 91 % (Scheme 3).

Scheme 3. Dosa and Fu’s Breakthrough in the Asymmetric Addition of Organozinc

Reagents on Ketones.

R1 R2

O

ZnPh2

(3.5 equiv.)

(15 mol %)

PhMe, RTMeOH (1.5 equiv.)

R1 = aryl, sec-alkyl

R2 = n-alkyl

R1 R2

OHPh

60-91% e.e.

Me2N

HO

Me

N

OZn

ZnO

Ph

PhPh

Ph

R

1

An advancement in this area came in the same year when the group of Yus reported

the first addition of dialkylzinc reagents to ketones promoted by a hydroxysulfonamide-

titanium catalyst.[8]

Although an equimolar amount of titanium(IV) isopropoxide was

required, some substrates exhibited good enantioselectivities (up to 89 % e.e.) in the

presence of 20 mol % of chiral camphorsulfonamide ligand 2 (Scheme 4).

22

Scheme 4. Asymmetric Alkylation of Ketones with Diethylzinc Developed by the Groups of

Yus and Walsh.

Me

O

Et2ZnTi(O-iPr)4, L*

PhMe

* Me

HO Et

OH

O2S NH

2

OH

O2S NH HN SO2

HO

3

O2S NH HN SO2

HO

4MeO

Yus’ first generation catalyst: 20 mol % 2, CaH2, PhMe, 4 °C, 4 d, 71 % yield, 86 % e.e.

Walsh’s catalytic system: 2 mol % 3, PhMe, RT, 29 h, 71 % yield, 96 % e.e.

Yus’ second generation catalyst: 5 mol % 4, PhMe, 25 °C, 120 h, 65 % yield, 99 % e.e.

This first generation of catalytic system inspired other groups for the design of

improved ligands and the major improvement was reported in 2002 by Walsh[9]

and in

2005 by Yus[10]

. The most successful C2-symmetric disulfonamide ligand 3 was designed

in order to induce an increased constrained geometry. In most cases, it showed improved

reactivity. The ligand loading could be reduced to 2 mol % while retaining high

enantioselectivity (up to 96 % e.e.) for the addition of diorganozinc reagents to a range of

aromatic and aliphatic ketones (Scheme 4). The results of Walsh’s study are shown in

Table 1. Yus et al. published similar data.

Table 1. Conditions, Yields and e.e. for the Asymmetric Addition of Ethyl Group to

Ketones with Ligand 3.

Entry Substrate 3 (mol %) t (h) Yield (%) e.e. (%)

O

X

1 X = H 2 29 71 96 (S)

2 X = 3-Me 10

2

12

24

82

78

99

99

3 X = 4-OMe 10 111 85 94

23

Table 1. Continued.

Entry Substrate 3 (mol %) t (h) Yield (%) e.e. (%)

4 X = 3-CF3 2 14 56 98

5 X = 2-Me 10 48 24 96

6

O

10 22 35 99

7 Bu

O

10

2

47

102

83

79

87

88

8

O

Cl

10 44 82 89

9

O

2 46 56 96

10

O

2 26 80 90

11

O

10 68 68 70

This bissulfonamide structure was also used by Ramón, Yus et al. to study various

chiral ligands,[11]

which finally gave an optimised second generation catalyst 4 with perfect

enantioselectivity ( 99 % e.e.) but only in moderate yield (65 %) for the alkylation

reaction (Scheme 4). However, the scope of this catalyst remains undefined, because only

one example has been reported. This ligand has also shown to be an excellent promoter for

the catalytic enantioselective arylation of p-bromoacetophenone (96 %, 99 % e.e.) during

which the phenyl zinc intermediate was generated from triphenylboron by transmetallation

with dimethylzinc.

In the same year, the groups of Walsh and Yus reported the asymmetric arylation of

ketones catalyzed by titanium tetraisopropoxide and the chiral ligand 3 (Scheme 5).

Significant improvements, such as a low catalyst loading (10 mol %) and the use of only

1.6 equiv. of diphenylzinc, were made.[12]

The addition of commercially available

diphenylzinc to ketones gave the expected tertiary alcohols with practically quantitative

chemical yields and enantiomeric excesses as high as previously reported results for

similar aryl transfer processes (Table 2).[13]

24

Scheme 5. Asymmetric Phenylation of Ketones with Diphenylzinc.

R1 R2

O

ZnPh2

(1.6 equiv.)

Ti(O-iPr)4

(0.6 equiv.)

3 (10 mol %)

R1 R2

HO Ph

PhMe/Hexane, 6-24 h

Table 2. Yields and e.e. for the Asymmetric Phenylation of Ketones with Diphenylzinc.

Entry R1 R

2 Yield (%) e.e. (%)

1 Et 3-ClC6H4 99 92

2 Et 4-ClC6H4 99 88

3 Me 3-CF3C6H4 93 95

4 Me 2-BrC6H4 76 95

5 Me 2-naphthyl 99 96

6 Me 1-cyclohexenyl 94 93

In the study by Yus et al., a titanium catalyst of 5 mol % 3 was employed on four

examples of ZnPh2 additions to aromatic ketones, furnishing the desired products in

enantioselectivities of 80 to 96 % e.e..[14]

Extensive applications of ligand 3 were also reported by Walsh et al. for the

asymmetric addition of a variety of carbon-based nucleophiles on ketones.[15]

Some

representative examples are displayed in Scheme 6. The catalytic system using 3 is

especially reactive toward ,-unsaturated ketones and aryl alkyl ketones. The range of

nucleophiles was also widened from simple ethyl and methyl groups to functionalised alkyl,

aryl, vinyl and dienyl groups with high enantioselectivities.

Scheme 6. Walsh’s Catalytic Method for the Asymmetric Addition of Functionalised

Organometallics to Ketones.

R1 R2

OZn(R3)2

Ti(O-iPr)4

3 (0.5-10 mol %)R1 R2

HO R3

aryl alkyl ketones and -unsaturated ketones

R3 = functionalised alkyl, aryl, vinyl and dienyl groups

25

Scheme 6. Continued.

Cl

HO Ph

92 % e.e.

HO (CH2)5-Br

90 % e.e.

HO

Bu

97 % e.e.

HO

> 99 % e.e.

OTBS

Some representative examples:

So far, enantioselective organozinc addition to ketones by double activation with

bifunctional unconjugate Lewis acid-Lewis base catalysts, in which the Lewis acid and the

Lewis base are attached to each other, has been reported. Recently, Ishihara et al.

developed a highly enantioselective organozinc addition using an active and simple chiral

phosphoramide-zinc(II) complex (S)-5 as conjugate Lewis acid-Lewis base catalyst

(Scheme 7).[16]

This type of catalysis involves an electron charge transfer at the ligand

interior, thus avoiding the direct linkage between the acid and the base, and hence

enhancing the catalytic activity. The electrophile and nucleophile are doubly activated.

From aromatic and aliphatic ketones, optically active tertiary alcohols were obtained in

excellent yields and with high enantioselectivities (91-98 % e.e.) by using 10 mol % of (S)-

5. This is the first example of highly efficient ethylation of inactive ketones under mild

conditions without titanium(IV) compounds achieved by simply mixing together the

ketone substrate, diethylzinc, and the chiral ligand in a solvent.

26

Scheme 7. Catalytic Enantioselective Organozinc Addition to Ketones using Chiral

Phosphoramide 5-Zn(II) Complex.

R1 R2

O

(R1>R2)

R3Zn heptane, RT R1 R2

HO R3

HNN P

O

(10 mol %)

N P

O

N

Zn

R3

R2

OR1Zn

R3 R3

Zn: Lewis acid, O: Lewis base

(S)-5

MeO

PhHO

91 %, 96 % e.e.

Br

PhHO

93 %, 95 % e.e.

PhHO

97 %, 97 % e.e.

PhHO

88 %, 97 % e.e.

Ph

PhHO

81 %, 98 % e.e.

HO Ph

84 %, 82 % e.e.

EtHO

80 %, 93 % e.e.

EtHO

85 %, 96 % e.e.

Cl

EtHO

85 %, 96 % e.e.

S

For phenylation, 1 equiv. of Ph2Zn and 2 equiv. of Et2Zn were used.For ethylation, 3 equiv. of Et2Zn was used.


27

Walsh and Li developed a highly enantioselective addition of vinyl groups to

aromatic, alkyl and ,-unsaturated ketones in the presence titanium(IV) compounds and 3

(Scheme 8) to furnish tertiary allylic alcohols and dienols in excellent yields and with high

enantioselectivities.[17]

Following the method developed by Wipf et al.,[18]

the in situ

preparation of alkenylzinc consisted of hydrozirconation of terminal alkynes with

Schwartz’s reagent followed by transmetallation to zinc. A variety of alkynes have been

used, indicating that the reaction is compatible with functionalised substrates (Table 3).

Scheme 8. Asymmetric Vinylation of Ketones from Alkenylzirconium Reagents.

[Cp2ZrHCl]n

(1.2 equiv.)

R3 ZrClCp2

R3

Cp2ZrMeCl ZnMe2(1.2 equiv.)

MeZnR3

1) R1R2CO, RT

2) NaHCO3, H2O

R1 R3

OHR2

Ti(O-iPr)4 ZnMe2 3 *

Ti : Zn : 3 : ketone =1.2 : 0.4 : 0.1 : 1

Table 3. e.e. for the Asymmetric Vinylation of Ketones from Alkenylzirconium Reagents.

Entry Substrate Product e.e. (yield, %)

1 Ph

O

Ph Ph

OH

87 (92)

2

O

F3C

F3C

OH

OTBDPS

90 (94)

3

O

OH

Cl

90 (98)

4 Cl

O

Cl

OH

Bu

93 (93)

5 O

Bu

OH

79 (85)

6 Ph

O

Ph Bu

OH

92 (87)

28

The reaction of carbonyl compounds 6 with Grignard reagents often gives undesired

by-products, such as reduction product 7 via -H transfer and/or self-aldol product 8 via

enolisation (Scheme 9). When Grignard reagents are strongly basic, ketones are often

enolised and recovered after an acidic workup.

Scheme 9. Addition of Grignard Reagents to Ketones.

R1 R2

O

RMgCl

6

R1 R2HO R

9

6 R1 R2HO H

7

R1 R2

O

R2

HO R1

8

To overcome these problems, stoichiometric or excess amounts of inorganic additives

is usually employed.[19]

Until the method reported in 2012 by Minnaard et al., the synthesis of

enantioenriched tertiary alcohols with readily available Grignard reagents has only been

achieved with stoichiometric amounts of a chiral ligand.[4]

They developed an efficient

asymmetric catalytic alkylation reaction to aryl alkyl ketones with branched alkyl Grignard

reagents using a copper catalyst based on a chiral Josiphos-type diphosphine ligand 10

(Scheme 10).[20]

Scheme 10. Asymmetric Copper-Catalyzed Addition of Grignard Reagents to Aryl Alkyl

Ketones.

54- 98 % e.e.71-96 % yield

R1

O

X R2MgBr

(S, RFe)-10 (6 mol %)CuBrSMe2 (5 mol %)

tBuOMe, -78 °C

R1

X

HO R2

Fe

Ph2P

Cy2P

(S, RFe)-10

(1.25 equiv.)

Proposed transition state for the reaction

29


O

X

X = H, Me, CF3, F,Br, Cl, OMe, di-Cl, di-F, di-CF3

O

CF3

OO

O

S

substrate scope

MgBr

Ph

MgBr

MgBr

Et

Et

MgBr

Bu

Et

Cy

MgBr

Me3Si

MgBr

Grignard reagent scope

Good to excellent enantioselectivities and high yields of isolated products were

obtained with no significant electronic and steric effects of the substituents on the aryl ring

to the enantioselectivity. The reaction was extended to methyl-substituted ketones, phenyl-

substituted ketones and heteroaromatic ketones. However, the reaction is restricted to aryl

alkyl ketones and bulky Grignard reagents with branched alkyl groups are required for

high enantioselectivities. They proposed the transition state depicted in Scheme 10 for the

key alkyl group transfer step.

Copper-catalyzed arylation and alkenylation reactions to produce tertiary alcohols are

currently limited to using activated ketones (such as trifluoromethyl ketones or -keto

esters) as substrates.[21]

Organoaluminium compounds are excellent nucleophiles for organic reactions, due to

their high reactivity and a greater Lewis acidic nature of the aluminium centre. As such,

Gau et al. reported the first example of asymmetric aryl additions of organoaluminium

reagents to ketones.[22]

The novel asymmetric aryl transfers from [AlAr3(THF)] to a wide

variety of ketones were catalyzed by an in situ generated titanium species with (S)-BINOL

11 as the chiral ligand (Scheme 11). The reaction afforded tertiary alcohols, in general, in

high enantioselectivities of 90 % e.e. and greater for aromatic ketones bearing either an

electron-donating or an electron-withdrawing substituent at the 2-, 3-, or 4-position on

30

the aromatic ring (Table 4, entries 1 to 7), except for 2-methoxyacetophenone substrate

(entry 8). The catalytic system also tolerated ,-unsaturated ketones and 2-acetylfuran

(entries 9 and 10). Additions of different aryl compounds, such as 2-naphthyl, 4-tolyl, or 4-

(trimethylsilyl)-phenyl, to aromatic ketones also gave the desired alcohols in high yields

with excellent enantioselectivities (90-93 % e.e.).

Scheme 11. Asymmetric [AlAr3(THF)] Addition to Ketones Catalyzed by (S)-BINOL

11/[Ti(O-iPr)4].

R1 R2

O

[AlAr3(THF)]

(2.5 equiv.)

(S)-BINOL 11 (10 mol %) [Ti(O-iPr)4] (5.0 equiv.)

PhMe, 0 °C

R1 R2

HO Ar

O

OTi

O-iPr

O-iPr

n

(S)-11/[Ti(O-iPr)4]

Table 4. Conditions, Yields and e.e. for the Asymmetric [AlAr3(THF)] Addition to Ketones

Catalyzed by (S)-BINOL 11/[Ti(O-iPr)4].

Entry Substrate Ar t (h) Yield (%) e.e. (%)

1

O

Ph 12 85 93

2

OMe

Ph 12 35 90

3

O

Cl

Ph 12 92 93

4

OBr

Ph 36 50 97

5

O

O2N

Ph 12 97 93

6

O

MeO

Ph 36 97 93

3

31

Table 4. Continued.

Entry Substrate Ar t (h) Yield (%) e.e. (%)

7

O

F3C

Ph 12 98 92

8

OOMe

Ph 12 98 30

9 Ph

O

Ph 12 96 87

10 O

O

Ph 16 95 84

11

O

4-MeOC6H4 12 87 78

Later, in order to compare AlAr3(THF) and arylzinc reagents in asymmetric aryl

additions to ketones, Gau et al. probed asymmetric AlAr3(THF) additions to ketones

catalyzed by titanium catalysts of chiral ligand 3,[23]

which have been used in titanium-

catalyzed arylzinc additions to ketones (Scheme 12).[12,13]

It was demonstrated that

inorganic salts such as MgBr2 were essential in promoting the addition reactions, thus

affording similar results to (S)-BINOL 11/[Ti(O-iPr)4] system in term of enantioselectivity.

While ZnPh2 additions to ketones require lower catalyst loadings of 3 (10 mol %) and

Ti(OiPr)4 (0.6 equiv.) and use no additive, the AlAr3(THF) system gives better yields (80-

99 %), employs shorter reaction times and the reaction can be extended to additions of

different aryl groups, such as 4-tolyl or 4-(trimethylsilyl)-phenyl.

Scheme 12. Asymmetric Aryl Addition of AlAr3(THF) to Ketones Catalyzed by the

Titanium(IV) Catalytic System of 3 Promoted by MgBr2.

R1 Me

O

AlAr3(THF)

(6.0 equiv.)

3 (20 mol %)/Ti(O-iPr)4 (10 equiv.) MgBr2 (48 mol %)

PhMe, 0 °C, 12-36 h

R1 Me

Ar OH

75-98 % e.e.

To further improve the atomic-efficiency of arylaluminium reagents, they reported

the catalytic asymmetric AlArEt2(THF) addition to ketones using a titanium catalyst of (S)-

BINOL 11 (Scheme 13).[24]

The AlArEt2(THF) compounds still proved to be excellent

32

reagents for asymmetric addition to ketones in comparison to the AlAr3(THF) reagents

affording aryl tertiary alcohols in similar yields and enantioselectivities. In addition, the

amount of Ti(O-iPr)4 was decreased from 10 equiv. to 3.5 equiv..

Scheme 13. Asymmetric Addition of AlArEt2(THF) to Ketones Catalyzed by (S)-BINOL

11/Ti(O-iPr)4 Catalyst.

R1 Me

O

AlArEt2(THF)

(2.5 equiv.)

(S)-BINOL 11 (10 mol %) Ti(O-iPr)4 (3.5 equiv.)

PhMe, 0 °C, 18-36 h

R1 Me

OH

29-94 % e.e.

Ar

Interestingly, the use of stable, commercially available aryl boronic acids in place of

common organometallic reagents has been recently considered by Xu et al. (Scheme 14).[25]

The method employed a simple, chiral N-(sulfinyl)cinnamylamine ligand 12 in a rhodium-

catalyzed asymmetric 1,2 addition of aryl boronic acids to -ketoesters 13 and -diketones

14. A variety of highly enantioenriched, tertiary -hydroxy carbonyl derivatives 15 were

easily accessed at room temperature under mild conditions in moderate to excellent yields

and with e.e. values of up to 99 %.

Scheme 14. Asymmetric 1,2-Addition of Arylboric Acids to -Ketoesters and -Diketones

Catalyzed by [{Rh(coe)2Cl}2]/12.

RX

O

O

ArB(OH)2 R Ar

HO X

O

KOH (0.1 M)/THF, RT

[{Rh(coe)2Cl}]2 (3 mol %)

Ph NH

S

O13, X = O-2-Np14, X = Ph, 4-BrC6H4,4-FC6H4, 4-MeOC6H4, Me

12

15 (up to 99 % e.e.)

HOO

O-2-Nap

F

86 %, 94 % e.e.


HOO

O-2-Nap

87 %, 91 % e.e.

HOO

O-2-Nap

72 %, 93 % e.e.

OMe

(1.5 equiv.)

12 (3.3 mol %)

33


HOO

Ph

Cl

97 %, 99 % e.e.

HOO

Ph

54 %, 95 % e.e.

Me

HOO

4-Br-C6H4

Me

93 %, 98 % e.e.

Br

Me

HOO

Me

Me

45 %, 63 % e.e.

Me

HOO

Ph

Me

85 %, 80 % e.e.

Reactions involving aryl boronic acids with different electronic and steric demands

afforded -hydroxy carbonyl products 15 with similarly high levels of enantioselectivity.

13 and 14 underwent 1,2-addition with high enantioselectivities regardless of the electronic

nature of the aryl group R. However, when aliphatic -diketone (R = X = Me) was

employed, only a moderate enantioselectivity was obtained. In the case of unsymmetrical

-diketone (R = Me, X = Ph), both regio- and enantioselectivity was observed (Scheme

14).

I.1.1.2 Catalytic Enantioselective Allylation Reactions

Another classical class of carbon-based nucleophiles for addition to carbonyl

compounds is allyl metal reagents. These have been extensively employed in asymmetric

synthesis because of the ease of their preparation and the high value in synthesis of the

tertiary homoallylic alcohols resulting from such processes.[26]

In recently reported

examples, a range of nucleophilic allyl sources have been used including stannanes, silanes,

and boranes.

The first enantioselective catalyst for the asymmetric allylation reaction was

introduced by Maruoka et al..[27]

They developed a new chiral bis-BINOL-Titanium(IV)

catalyst with dibenzofuran spacer 13 which catalyzed the allylation of acetophenone and 2-

acetonaphthone using tetraallyltin as the terminal allyl source with 90 % and 92 % e.e.,

34

respectively (Scheme 15). However, the scope of this catalyst is currently limited to these

two examples.

Scheme 15. Catalytic Enantioselective Allylation of Ketones using a bis-BINOL-Ti(IV)

Complex 13.

Ar Me

OSn

4

13 (30 mol %)

CH2Cl2, 0 °CAr

(1.5 equiv.)

HO Me

ONH HN CPh3Ph3C

O

OTi

(i-PrO)2

O

OTi

(Oi-Pr)2 Ar = Ph 95 %, 90 % e.e.Ar = 2-naphthyl 98 %, 92 % e.e.

13

Later, Woodward et al. demonstrated that (S)-MTBH2 (monothiobinaphthol) 14

promoted the allylation of acetophenone derivatives with a mixture of tri- and

tetraallylstannane, employing water as a promoter and without the use of titanium (Scheme

16).[28]

. Enantiomeric excess values as high as 92 % with acetophenone were obtained.

Two procedures were introduced: one (‘dry’ method using R = Et mix) gave higher

enantioselectivities and low yields while the other (‘wet’ method using R = Bu mix) gave

lower enantioselectivities but excellent yields.

35

Scheme 16. Catalytic Enantioselective Allylation of Ketones using Chiral

Monothiobinaphthol 14 with Mixed Allyltin Reagents.

Me

O

X

14 (20 mol %)

Sn RSn

4 3

(7:3 mixture, R = Bu or Et)

Ar

SH

OH H4-Me4-NO2

89-9290-82

86

98-4332-78

98

X e.e. (%) yield (%)

HO Me

14

A significant advancement in this area came when Walsh et al. reported an

optimisation of Tagliavini’s BINOL-Titanium(IV) catalyst[29a]

for the asymmetric transfer

of tetraallyl stannane to ketones (Scheme 17).[29b-c]

They observed the beneficial effect of

isopropanol additive on the catalytic efficiency (enantioselectivity) of the chiral complex.

This procedure could be generalised to tolerate a wide range of previously unexplored

substrates, including aliphatic, aromatic, heteroaromatic, unsaturated ketones and cyclic

enones. The corresponding homoallylic alcohols were obtained in excellent yields with

high levels of enantioselectivity (up to 96 %). To date, this easily prepared catalytic system

is the most general and enantioselective catalyst for the asymmetric allylation of ketones.

Scheme 17. Catalytic Enantioselective Allylation of Ketones and ,-Unsaturated Ketones

with a BINOL-Ti(IV)-iPrOH System.

R1 R2

O

Sn4

(R)-BINOL 11 (20-30 mol %)Ti(O-iPr)4 (20-30 mol %)isopropanol (20 equiv.)

(1.5 equiv.)

catalytic system

CH2Cl2RT

R2

OH

R1

36

Scheme17. Continued.

82 %, 96 % e.e.

Me

HO HO

96 %, 95 % e.e.

Ph

HO

96 %, 80 % e.e.

Ph

HO

99 %, 96 % e.e.

O Me

HO

67 %, 84 % e.e.

n-Pen

HO

92 %, 94 % e.e.


More recently, Loh et al. reported a highly enantioselective allylation catalyzed by a

chiral indium(III) complex made from (R)-BINOL 11 and InBr3 using allyltributylstannane,

unlike other previously described asymmetric catalytic systems which demand stronger

allylation reagents such as tetraallylstannanes (Scheme 18).[30]

The allylation of aromatic,

,-unsaturated and aliphatic ketones resulted in good yields (41-82 %) and high

enantioselectivities (80-92 % e.e.).

Scheme 18. Enantioselective Allylation of Ketones Catalyzed by Chiral (R)-BINOL 11-

In(III) Complex.

R1 R2

O

SnBu3

(R)-BINOL 11-In(III) complex (20 mol %)

4Å MS / CH2Cl2

R1

OHR2

(3.0 equiv.) 80-92 % e.e.

Instead of toxic allyltin reagents with high catalyst loadings (10-30 % in most cases),

the groups of Shibasaki and Yamamoto studied the asymmetric allylation of ketones using

soft transition metal-chiral diphosphine complexes as catalysts (Scheme 19).

Shibasaki et al. used allyl boronates as nucleophiles for the allyl transfer on aliphatic

and aromatic ketones with fair to good enantioselectivities and in high yields when a chiral

copper complex was employed as a catalyst. Extensive optimisation on the catalytic system

led to the authors to select i-Pr-DuPHOS 15 (6 mol%) as a chiral ligand and La(Oi-Pr)3

(4.5 mol%) as a cocatalyst (Scheme 19).[31]

37

Yamamoto and Wadamoto later developed the silver(I)-catalyzed enantioselective

Sakurai-Hosomi allylation of ketones,[32a]

which has the advantage of using inexpensive,

non-toxic and stable allyltrialkylsilane and allyltrialkoxysilane reagents.[32b]

In the presence

of silver(I) fluoride and (R)-DIFLUOROPHOS 16 (5 mol % each) and by the addition of

methanol (1.0 equiv.), an increase in the catalyst turnover gave the highly enantioselective

allylation of a variety of ketones.(Scheme 19).

Scheme 19. Shibasaki’s and Yamamoto’s Strategies for Asymmetric Allyl Transfer on

Ketones.

R1 R2

O

Si(OMe)3

O

B O

Ag or Cuor

catalyticsystem

R1

OH

R2

P

PiPr

iPr

iPr

iPr CuF2.2H2O (3 mol %)

La(O-iPr)3 (4.5 mol %)

DMF, -40 °C

O

B O

83-99 %, 67-91% e.e.

Shibasaki et al. (2004) Yamamoto et al. (2005)

O

O

O

O

F

F

F

F

PPh2

PPh2

AgF (5 mol %)

Si(OMe)3

MeOH (1.0 equiv.)

THF, -78 °C

63-98 %, 78-96 % e.e.

(1.2 equiv.)

(2.0 equiv.)1516

(6 mol %)(5 mol %)

In the aim of improving the enantioselectivity, Shibasaki et al. designed a different

diphosphine-based ligand 17 comprising of four modules (linker, wing, chiral head, and

phosphine) (Scheme 20).[33]

In general, the enantioselectivity and catalytic activity were

significantly higher than in their previous studies using i-Pr-DuPHOS (Scheme 19).[31]

38

Scheme 20. Improved Shibasaki’s Strategy of Catalytic Asymmetric Allylation of Ketones.

R1 R2

O O

B O

CuOAc (2 mol %)17 (2.4 mol %)LiOi-Pr (0.5 equiv.)

i-PrOH (1.0 equiv.),CH2Cl2, -75 °C

R1

HO R2

O

N

O

OO

PAr2MeO

R

PAr2MeO

17, R = (S)-Ph, Ar = p-F-C6H4

phosphine

chiralhead

wing

linker


R

R = p-Me, 98 %, 92 % e.e.R = p-OMe, 90 %, 92 % e.e.

X

HO

X = CH2, 85 %, 95 % e.e. (0.1 mol% cat.)X = O, 86 %, 94 % e.e.

S

93 %, 92 % e.e. 91 %, 90 % e.e. 88 %, 83 % e.e.

HO Me

HO Me MeHO

HO Me

Another class of chiral ligand of interest for the catalytic enantioselective

allylboration of ketones and widely studied are chiral biphenols. In general, the use of

relatively high catalyst loadings is necessary. However, Schaus et al. have recently

reported an improved reaction employing 2 mol % of 18 with allyldioxaborinane and t-

BuOH (increasing enantioselectivity and the overall rate) under solvent-free reaction

conditions at room temperature to afford the products in greater than or equal to 96 % e.e.

(Scheme 21).[34]

In comparison to the reaction reported by Shibasaki,[31,33]

the

enantioselectivity was slightly superior.

39

Scheme 21. Improved Asymmetric Allylboration of Ketones Catalyzed by Chiral Biphenol

18.

R1 R2

O

BO

O

18 (2 mol %)

t-BuOH (2.0 equiv.)RT, 24 h

(1.5 equiv.)

R1

R2 OH OH

Br

OH

Br

18

> 90 % yield 96 % e.e.

I.1.1.3 Catalytic Enantioselective Alkynylation Reactions

The first general method that allowed the enantioselective addition of acetylenes to

ketones was introduced by Cozzi et al. and was based on the salen framework.[35]

An

excess of dimethylzinc was added to a mixture of the ketone substrate, a terminal alkyne

and a catalytic amount of commercially available chiral salen ligand to form the zinc

acetylide nucleophile and a zinc salen catalyst (Scheme 22). To overcome the low

reactivity of the substrates, this approach involved the concept of double activation (Lewis

acid-Lewis base) as shown in the proposed transition state (Scheme 22). For a series of

aromatic and aliphatic ketones, 20 mol % of (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-

1,2-cyclohexanediamine 19 effectively afforded the desired products with moderate

enantioselectivities.

Scheme 22. Cozzi’s Pioneering Work on Alkynylation of Ketones.

R1 Me

O

R2 H

Me2Zn (3.0 equiv.)

19 (20 mol %)

PhMe, RTR1 Me

OH R2

R1 = aryl, alkyl

R2 = Ph, TMS, CH2Cl

53-81 % e.e.

OH

N N

HO

(3.0 equiv.)

19

40

This first example was followed by many other examples which employed similar

concepts (chiral ligands such as BINOL, amino alcohols and amino alcohol derivatives in

combination with a metal source based on zinc, aluminium, and titanium). Only a few

methods are described in this thesis.

The method reported by Chan et al. was based on the concept of increasing the

reactivity of ketones by using a strong Lewis acid. Since copper(II) triflate in combination

with bis-oxazolidines is well established for the addition of nucleophiles to ketones,[36]

Chan studied Cu(OTf)2 with different ligands for the addition of phenylacetylene to

aromatic ketones. He found that ligand 2 (Scheme 4), which was first introduced by Yus[8]

was highly efficient for the addition of phenylacetylene to a variety of aromatic ketones

(Scheme 23). Substituents at the ortho-position of the substrate had a favourable effect on

the enantioselectivity, since the steric hindrance of the ortho substituents restricts the

orientation of the substrates. This method afforded higher enantioselectivity than Cozzi’s

reaction. The best enantioselectivity (97 %) was observed in the alkynylation of 2’-

chloroacetophenone.

Scheme 23. Catalytic Enantioselective Alkynylation of Aromatic Ketones using a Chiral

Camphorsulfonamide-copper(II) Complex.

Ar Me

O

Ph H

(2.6 equiv.)

Me2ZnCu(OTf)2 (10 mol %)

2 (10 mol %)

CH2Cl2, 0 °C, 48 h

Ar

Ph

HO Me

Ar = Ph 90 %, 82 % e.e.Ar = 2-ClC6H4 94 %, 97 % e.e.

(3.0 equiv.)

In both of these methods, the alkynyl zinc species are generated in situ by combining

an excess of Me2Zn with phenylacetylene. Unfortunately, Me2Zn is highly pyrophoric and

expensive so the addition of alkynides based on the use of Me2Zn has limited applicability.

Therefore, inspired by Seebach’s pioneering studies on alkynyl titanium reagents,[37a]

Cozzi developed a catalytic enantioselective addition of titanium(IV) phenylacetylides

prepared from lithium phenylacetylide and chlorotitanium(IV) isopropoxide using (R)-

BINOL 11 as the chiral ligand (Scheme 24).[37b]

Aromatic ketones provided good results

with moderate yields and good enantioselectivies.

41

Scheme 24. BINOL-Ti(IV)-Catalyzed Enantioselective Addition of Titanium(IV)

phenylacetylide to Aromatic Ketones.

Me

O

Ph Li

(1.5 equiv.)

ClTi(Oi-Pr)3

(R)-BINOL 11 (25 mol %)Ar

HO Me

PhX

X

4-Cl4-F4-Br4-Me

e.e. (%)

90868485

yield (%)

48842845

PhMe

Although advances have been achieved, high loadings of ligands (usually 20 mol %)

had to be used to obtain good to excellent enantioselectivities. Yet, Wang et al. reported an

example of a highly efficient addition of alkynylzinc to simple ketones with high e.e.

values (90 %) and good yields in low loading (1 mol %) of the ligand 20, an easily

prepared chiral Schiff base amino alcohol (Scheme 25, Table 5).[38]

Scheme 25. Catalytic Enantioselective Addition of Phenylacetylene to Aromatic Ketones

using Chiral Schiff Base Amino Alcohol 20.

Ar Me

O

Ph H

20 (1 mol %)

Et2Zn, hexaneAr

Ph

MeHO

Ph

OH

PhPh

N

20

ketone : Et2Zn : acetylene =1 : 2 : 2

42

Table 5. Yields and e.e. for the Asymmetric Addition of Phenylacetylene to Various

Ketones Promoted by 20.

Entry Substrate Yield (%) e.e. (%)

1 acetophenone 70 90

2 2-fluoroacetophenone 83 94

3 2-naphthacetophenone 77 95

4 1-naphthacetophenone 62 94

5 2-methoxyacetophenone 70 94

6 4-methylacetophenone 76 92

7 4-fluoroacetophenone 70 90

8 4-chloroacetophenone 63 90

9 3-methylacetophenone 76 90

To conclude, in comparison to aldehydes, catalytic asymmetric addition of

organometallic nucleophiles to ketones have proved to be more challenging owing to their

attenuated reactivity and lower binding affinity to metals. Furthermore, organometallic

reagents often cause aldol addition adducts/starting ketones due to competing enolisation

problems or competitive reduction via -H transfer to give undesired secondary alcohols,

this is especially the case of sterically hindered substrates. Moreover, the catalyst must

differentiate between the lone pairs of the carbonyl oxygen to achieve high

enantioselectivity. This task becomes difficult when the groups R’ and R of the ketone

R’RCO are similar in size. Nonetheless, successful catalysts for additions to ketones are

beginning to emerge, thus providing access to tertiary alcohols with high

enantioselectivities.

Ready et al. have reported in 2011 an alternative method, which relies on the use of

the toluene sulfinyl group as a chiral auxiliary controlling the asymmetric addition of

simple alkynyl, aryl and vinyl organometallic reagents to aryl ketones (Scheme 26).[39]

43

Scheme 26. Asymmetric Synthesis of Tertiary Benzylic Alcohols.

Me

O

SO

(p-Tol)

R M (2.0 equiv.)

-78 °C, THF, 3 h

R

SO

(p-Tol)

Me OH

M = MgBr or Li/CeCl3


S(O)Tol

Me OH

Si(i-Pr)3

87 %, >50:1 d.r. 83 %, >50:1 d.r.

Ph

S(O)Tol

Me OH

74 %, >50:1 d.r.

S(O)Tol

Me OH

79 %, >50:1 d.r.

4-MeO-Ph

S(O)Tol

Et OH

F

OHMe

95 %, >99 % e.e. OMe

OH

CF3

F3C

99 %, 92 % e.e.

Tertiary benzylic alcohols were generated in high yields and in diastereomerically

and enantiomerically pure form. In contrast to most previous studies, the methodology

utilised readily available Grignard reagents and lithium acetylides. Moreover, the sulfoxide

chiral auxiliary can be reductively removed in high yield or converted into useful

functional groups.

I.1.2 Catalytic Asymmetric Aldol Reactions

Catalytic asymmetric aldol addition to ketone acceptors has received growing

attention since the resulting tertiary chiral β-hydroxy carbonyl compounds are versatile

synthetic motifs for pharmaceutically attractive intermediates and biologically active

natural products.[40]

The first example of catalytic asymmetric aldol reactions of preactivated nucleophiles,

tert-butyl thioketene acetals 21 to activated ketones such as alkyl-substituted pyruvate

44

esters 22 and -diketones was reported by Evans et al. using chiral C2-symmetric cationic

bis(oxazolinyl)Cu(II) complex 23 (Scheme 27).[41]

The CuII

complex activates the

nucleophile through bidentate coordination to form the five-membered catalyst-substrate

chelate 24, which is a strict requirement for stereoselectivity.

Scheme 27. Chiral Lewis Acid Cu(II)-Catalyzed Aldol Reactions of Enolsilanes to

Pyruvate Esters.

R1OR2

O

O

St-Bu

R3

OTMS 1. 23 (1-10 mol %)THF or CH2Cl2

2. 1 N HCl, THF

R1OSt-Bu

O

O

R3

OHR2

(S)

2221 25

N

O

Me Me

O

N

Me3C CMe3

2 TfO-

Cu

2+

Cu(II)-box 23

catalyst complex:

substrate-catalyst complex :

xx IIIIXIIIIIIII24

A variety of alkyl groups were tolerated at the ester moiety of pyruvates (R1) (Table 6,

entries 1-4), high yields and enantioselectivities were obtained when the -position of

pyruvate ketone carbonyl (R2) was a methyl group (entries 1-3), whereas an -branched

substrate (R2 = i-Pr) produced less satisfactory results (entry 4). It was also demonstrated

that various -substituted silyl enolates could be used (R3), producing syn isomers as the

major product irrespective of the geometry of silyl enolates (entries 5-8).

45

Table 6. Scope of the Enantioselective Aldol Addition of Enolsilanes to Pyruvate Esters.

Entry R1 R

2 R

3 Yield (%) (syn/anti ratio) e.e. (%)

1 Me Me H 96 99

2 Bn Me H 95 99

3 tBu Me H 91 99

4 Et iPr H 36 36

5 Me Me (Z)-Me 96 (94:6) 96

6 Me Me (E)-Me 90 (95:5) 98

7 Me Me (Z)-i-Bu 88 (90:10) 93

8 Me Me (Z)-i-Pr 80 (90:10) 99

Since then, Pagenkopf et al. has used modified bis(oxazoline) ligands in copper(II)-

catalyzed reactions of dienolsilanes to aryl- and alkyl-substituted -ketoesters.[42]

A new

ligand class consisting of C1-symmetric aryl-bridged amino- and oxazolinyl sulfoximines

developed by Bolm et al. have also proved to be powerful ligands in copper(II)-catalyzed

enantioselective Mukaiyama and Mukaiyama vinylogous-type aldol reactions of

trimethylsilylenol ethers and n-alkyl-substituted -ketoesters.[43]

However, these catalytic

protocols are restricted to -ketoesters bearing sterically undemanding substituents. To

address this, Hoveyda et al. developed a method complementary in terms of substrate

range by employing a combination of AgF2 and chiral amino acid-based ligand 28

(Scheme 28).[44]

The catalytic process was highly effective (high yields and e.e. up to 96 %)

tolerating a variety of -ketoesters 26 containing sterically hindered alkyl, alkenyl and

aromatic substituents.

46

Scheme 28. Silver-Catalyzed Enantioselective Aldol Addition to -Ketoesters.

GOEt

O

OR

OTMS

HN

O

t-Bu

NHn-Bu

O

Bn

28 (10 mol%)

AgF2 (10 mol %), THF,-15 °C/-40 °C, 24 h/48 h

G = (CH2)2Ph, (CH2)2CO2Me, CH2i-Pr, i-Pr, Cy, cyclopropyl,H2C=CH(Me), Ph, 2-thienyl

GOEt

O

RO

HO

61-98 % yield72-96 % e.e.

R = Ph, t-Bu, Me

26 27 29

As shown in Scheme 27, Evans showed that the chelating ability of the -dicarbonyl

unit is essential for both activation and stereoselection. Consequently, catalytic

enantioselective aldol reactions to simple ketones face three challenges: (a) reduced

reactivity of ketones usually leads to low conversion; (b) enantioface discrimination is

difficult due to the similar steric/electronic nature between the two substituents of the

ketone carbonyl carbon and (c) retro-reaction is generally rapid. Nevertheless, the catalytic

asymmetric reaction of simple ketones has been realised based upon different approaches.

Firstly, Denmark et al. have overcome these difficulties by employing the highly

reactive trichlorosilyl enolate of methyl acetate 30 with the chiral Lewis base catalyst, bis-

N-oxide 32 (Scheme 29).[45]

Scheme 29. Lewis Base Catalyzed, Enantioselective Aldol Addition of Methyl

Trichlorosilyl Ketene Acetal to Ketones.

OMe

OSiCl3

R1 R2

O

-20 °C, CH2Cl2

R1

OMe

OOH

R2

N N

OO

t-Bu t-BuO O

32 (10 mol %)

n-Bun-Bu

30 31 33

MeMe

47

All reactions proceeded cleanly to give high yields of the aldol products 33 for a

range of ketone substrates. The enantioselectivity, however, was found to be highly

dependent on the structure of the ketones (Figure 2).

Figure 2. Substrate Scope in the Bis-N-Oxide Aldol Reactions.

Ph Me

O96 % yield83 % e.e.

Ph Et

O90 % yield81% e.e.

O

90 % yield80 % e.e.

O

89 % yield56 % e.e.

O

O

87 % yield49 % e.e.

Ph

O

Me

94 % yield35 % e.e.

Me

O

F3C

91 % yield76 % e.e.

Me

O

MeO

94 % yield68 % e.e.

O 86 % yield8 % e.e.

Et Me

O 84 % yield32 % e.e.

Ph Me


Me

O

84 % yield20 % e.e.

Me

O

91 % yield32 % e.e.

t-Bu Me


Later, Shibasaki et al. developed the first diastereo- and enantioselective catalytic

aldol reaction involving a chiral copper enolate intermediate, by using trimethylsilyl ketene

acetals 34 with chiral copper(I) fluoride-di-n-butylamine-type Taniaphos 35 (Scheme

30).[46]

Further acceleration of the rate-determining catalyst regeneration step was achieved

by using a combination of (EtO)3SiF and PhBF3K as a strong trapping reagent. As such,

this method almost completely overcame the reactivity problem of ketones in the aldol

reaction, producing high yields and good enantioselectivities from both aromatic and

aliphatic ketones. Moreover, the anti-isomer was the major product irrespective of the

geometry of the silyl enolate.

48

Scheme 30. Chiral Cu(I)-Catalyzed Aldol Reaction of Enolsilanes to Ketones.

R1 R2

O

OMe

OTMS

R3

1. CuF(PPh3)32EtOH (2.5 mol %)Taniaphos 35 (4 mol %)(EtO)3SiF (200 mol %)PhBF3K (10 mol %), DME

2. Et3N3HFR1

OMe

OOH

R2

R3

PCy2Fe

NnBu2PCy2

35

OH

MeOMe

O

93 %, 92 % e.e.

OH

OMe

O

MeO

88 %, 83 % e.e.

OMe

OOH

92 %, 90 % e.e.

OH

MeOMe

O

73 %, 84 % e.e.

OMe

OOH

MeMe

96 %, 91 % e.e.80/20 d.r., 75 % e.e.

OH

MeOMe

O

85 %, 87 % e.e.

Cl

3134 36

The above report demonstrated that copper enolates are sufficiently nucleophilic to

promote the addition to ketones once they are generated by transmetalation (Scheme 31

(1)). Conjugate addition of alkylcopper and copper hydride to ,β-unsaturated and allenic

carbonyl compounds is an alternative method for copper enolate formation (Scheme 31

(2)), thus overcoming the preactivation of the nucleophile.

49

Scheme 31. Two Strategies for Copper Enolate Generation.

(1) Si enolate formation via transmetalation

OR'

O

R

OR'

R

OTMS

preactivation

CuX transmetalation

OR'

R

OCu

OR'

O

•

OR'

O

orR-Cu

(2) conjugate addition

This strategy was realised in a catalytic asymmetric reductive aldol reaction reported

by Riant et al.[47]

and Shibasaki et al..[48]

Riant’s group utilised the

CuF•3PPh3•2MeOHTaniaphos 38 complex as a catalyst, PhSiH3 as a triggering

nucleophile, and methyl acrylate 37 as an acceptor for conjugate addition (Scheme 32 (1)).

Excellent enantioselectivity as well as diastereoselectivity were obtained using aromatic

ketone substrates. Shibasaki’s group employed allenic ester 40 as an acceptor. -Aldol

products 42 were produced as the major product with high diastereoselectivity when using

CuF•3PPh3•2EtOHTaniaphos 41 complex as the catalyst and pinacolborane as the

triggering reducing agent (Scheme 32 (2)).

50

Scheme 32. Catalytic Asymmetric Reductive Aldol Reactions of Ketones and Acrylate or

Allenic Esters.

R Me

O

OMe

O

•

OMe

O

Cu 3PPh3 2MeOH (1 mol %)38 (1 mol %)PhSiH3 (1.4 equiv.)

toluene, -50 °C, 1/2 h

PCy2Fe

NMe2PCy2

38

CuF3PPh3 2EtOH (2.5 mol %)41 (5 mol %)pinacolborane (1.6 equiv.)

THF, 20 °C, 16 h

PAr2Fe

PAr2

41

N

O

Ar = 3,5-xylyl

R OMe

O

Me

MeHO

anti/syn ratio up to 96/4anti adduct up to 95 % e.e.

CO2Me

OH

MeR

anti/syn ratio up to 10/1anti adduct up to 84 % e.e.

37

40

31

39

42

(1) Riant's strategy

(2) Shibasaki's strategy

To conclude, despite excellent progress in the field of metal-catalyzed

enantioselective nucleophilic addition to ketones, only limited success has been achieved

in catalytic enantioselective aldol reaction of ketones. The reported systems suffer from

either poor substrate scope and/or moderate enantioselectivity. Moreover, in most cases,

they involve silyl enolate derivatives as nucleophilic partners and thus require an additional

step for their preparation.

51

I.1.3 Kinetic Resolution of Tertiary Alcohols

Compared to secondary alcohols,[49]

nonenzymatic kinetic resolution of tertiary

alcohols has been much less studied, and there are only a few effective nonenzymatic

catalyst systems available to date.[50]

In this thesis, only a recent method reported by Fagnou et al. is discussed.[51]

They

employed commercially available (1S,2R)-N-methylephedrine 44 as the resolving agent for

the kinetic resolution of tertiary alcohols 43 arising from aldol reactions (Scheme 33).

Scheme 33. Kinetic Resolution with (1S,2R)-N-methylephedrine 44.

O

O OH

R1

R2

Me

OH

NMe2

PhMeO

O OH

R1

R2

43 racemic 44 43 enantioenriched

Temp.

Table 7. Conditions and Results for the Kinetic Resolution with (1S,2R)-N-

methylephedrine 44.

Entry Substrate Equiv. of 44 T (°C) Conv. (%) s e.e. (%)

1 O

O OH

MeCO2Et

2 60 51 38 88

2 O

O OH

PhCO2Et

2 80 58 21 96

3 O

O OH

CF3CO2Et

0.8 60 46 35 99

4 O

O OH

CF3Ph

1 RT 28 21 94

5 O

O OH

MeCOMe

1 60 51 10 70

A number of functionalities at the quaternary center may be present, including alkyl,

aryl, ester, trifluoromethyl and ketone substituents (Table 7). The resulting tertiary alcohols

43 were effectively resolved (up to 99 % e.e.). They proposed that hydrogen bonding of the

52

substrate alcohol 43 to the carbonyl group and the amine of 44 may be important for

reactivity and selectivity.

Although good selectivities for selected substrates are generally obtained, some of

the preparative applications of simple kinetic resolution are eventually replaced by

advances in enantioselective synthesis methodology with achiral substrates and chiral

catalysts, procedures that are not subject to the 50 % yield limit.

One of the most important and challenging features within the field of asymmetric

synthesis via chiral carbanions is the configurational stability of the metalated carbanionic

species. Several research groups have considered the possibility to use them as valuable

precursors for the synthesis of highly enantioenriched compounds. Aggarwal et al.

employed this strategy to make chiral tertiary alcohols as described below.

I.1.4 1,2-Metallate Rearrangement of Boronate Complexes

A breakthrough in the synthesis of optically active tertiary alcohols came when

Aggarwal et al. reported in 2008 a different and simple method to convert a chiral

secondary alcohol to either enantiomer of a tertiary alcohol.[52]

The method occurs via

lithiation of a benzylic carbamate 45Li (Scheme 34). Trapping with a borane or a boronic

ester forms a ate complex and a stereospecific 1,2-shift entailing departure of the

carbamoyloxy moiety afforded chiral boronate or borane intermediates 46 or 47. Oxidation

then gave the tertiary alcohols 48 or ent-48.

53

Scheme 34. Lithiation-Borylation of Chiral Secondary Carbamates Leading to Tertiary

Alcohols.

R1 R2

OCbs-BuLiEt2O

-78 °C20 min

Li

OCbR1

R2

RB(OR3)2 B(OR3)2

OCbR1

R2

RR

B(OR3)2R1

R2

R1 R2

R OH

Retention

Inversion

H2O2,NaOH

B(R3)2

OCbR1R2

RR

B(R3)2R1R2

RB(R3)2

R1 R2

R OH

H2O2,NaOH

Cb = N,N-diisopropylcarbamoyl

45 45Li

46

47

48

ent-48

This method allowed access to a broad range of tertiary alcohols, including alkyl,

cyclopropyl, vinyl, allyl, aryl and heterocyclic alcohols, in good yield (60-98 %) and very

high enantioselectivity (92-98 % e.e.) (Table 8).

Table 8. Examples of Tertiary Alcohols Obtained by Lithiation-Borylation of Chiral

Secondary Carbamates.

Entry Carbamate Migrating

group R

Borane/Boronic

ester Product

e.r., S:R

(Yield %)

1 Ph

OCb

Et BEt2 Ph

Et OH

99:1 (91)

2 Ph

OCb

cPr

O

OB

Ph

OH

3:97 (85)

3 Ph

OCb

vinyl

O

OB

Ph

OH

2:98 (75)

4 Ph

OCb

allyl

O

OB

Ph

OH

1:99 (95)

54

Table 8. Continued.

Entry Carbamate Migrating

group R

Borane/Boronic

ester Product

e.r., S:R

(Yield %)

5 OCb

pClC6H4 Ph BEt2

Ph OH

pClC6H4 4:96 (89)

6 OCb

pMeOC6H4 Et

O

OB

Et OH

pMeOC6H4 96:4 (87)

7 Ph

OCb

mCF3-C6H5

O

OB

Ph

OHmCF3C6H4

99:1 (92)

8 Ph

OCb

2-furyl

O

OB

Ph

OHO

98:2 (94)

9

OCb

Ph O

OB

OHPh

6:94 (73)

10

OCb

Et O

OB

OHEt

91:9 (98)

Interestingly, the use of the borane causes complete inversion of stereochemistry,

whereas the boronic ester results in almost complete retention of stereochemistry. Thus,

either enantiomer of a tertiary alcohol can be produced from just one enantiomer of the

starting material simply by the choice of an achiral reagent.

Later, with the aim of improving the enantioselectivity in the tertiary boronic esters

(or tertiary alcohols) resulting from carbamates and boronic esters with sterically

demanding groups and carbamates bearing electron-withdrawing aromatic groups, they

found that the use of either MgBr2/MeOH or neopentyl boronic esters in place of pinacol

esters provided essentially complete chirality transfer in the lithiation-borylation

reaction.[53]

They also showed that indanyl and tetralyl carbamates could be employed in this one-

pot lithiation/borylation/oxidation to give the corresponding tertiary alcohols in excellent

yields but the enatiomeric ratios were lower than their acyclic counterparts.[54]

Clayden et al. have extended the utility of the lithiated carbamates of secondary

benzylic alcohols by showing that they may be transformed into tertiary alcohols through a

N to C aryl transfer.[55]

Initially, this remarkable rearrangement was disclosed in lithiated

N-benzylic ureas[56]

and then later extended to thiocarbamates.[57]

55

I.2 Intramolecular Electrophilic Arylation of Lithiated Ureas

and Thiocarbamates

I.2.1 Discovery of N to C Aryl Migration in Lithiated N-Benzyl Ureas

While studying the regioselective lithiation of N-aryl ureas within the group,[58]

N-

benzyl urea 49 was treated with sec-BuLi and iodomethane with the aim of determining the

site of deprotonation (lateral lithiation (position 1), ortholithiation (position 2) or N-

benzylic lithiation (position 3)) (Scheme 35).[56]

However, instead, a rearrangement of 49

was observed, reminiscent of the Truce-Smiles rearrangement.[59]

Related rearrangements

of lithiated benzylamines and their derivatives are known.[60]

Lithiation at the benzylic

position was followed by transfer of the aryl group from the nitrogen to the -carbon of the

urea and subsequent quenching with iodomethane gave the unstable alkylated diarylamine

50 in a low yield. By replacing the methylation with an aqueous quench, the rearranged

product 51 was obtained in an improved yield of 89 %.

Scheme 35. Rearrangement of a Lithiated Urea.

N N

O

Me

Me2N N

O

Ph

MeHN N

O

Ph

1. s-BuLi, THF,-78 °C, 30 min2. MeI

1. s-BuLi, THF,-78 °C, 30 min2. NH4Cl

13 %

89 %

49

50

51

1

3

2

56

I.2.2 Aryl Migration in Lithiated N-Benzyl Ureas

Using the previous described conditions, a series of N-benzyl-N-aryl ureas 52

rearranged in a similar manner to provide ureas derivatives of diarylmethylamines 53

(Scheme 36) in good yields, regardless of the electronic or steric nature of the migrating

ring as shown in Table 9.[56]

Scheme 36. Synthesis of Secondary Diarylmethylamines.

N N

O

Me R1

1. s-BuLi (2.5 equiv.), THF, -78 °C, 30 min

2. H2O

MeHN N

O

R1 R2

52 53

R2

R1HNR2

A: 1. t-BuONO (6 equiv.), CH2Cl2, 24 h2. LiOH, H2O, THF, , 48 h

B: DIBAL-H, PhMe,

54

The amines 54 were returned either by hydrolysis of their N-nitroso derivatives (A)

or by reductive cleavage with DIBAL-H (B). Quenching the reaction with CD3OD

permitted the observation of the product which was deuterated at the doubly benzylic

position to nitrogen in 53. This suggests that 53 is deprotonated in the reaction

conditions meaning that the synthesis of secondary enantiopure diarylamines by this

method is not feasible.

57

Table 9. Aryl Migration in Lithiated N-Benzyl Ureas 52.

Interestingly, on treatment with sec-BuLi in THF and DMPU (dimethylhexahydro-2-

pyrimidinone) to increase the reactivity of the resulting organolithium,[61]

chiral N--

methylbenzylureas 55 formed a configurationally stable organolithium which underwent

rearrangement to give the ureas 56 with a new, fully substituted stereogenic centre in

generally good yields and with excellent enantioselectivities (Scheme 37). The reaction

tolerated both electron withdrawing and electron donating groups on the migrating ring

(Table 10). The reductive cleavage of ureas was carried out by hydrolysis of a nitroso

intermediate using LiOH to give ,-diarylethylamines 57 with an enantiomeric ratio up to

99:1, thus providing a route to amines bearing chiral tertiary substituents (Table 10).

Entry R1 R

2

Yield 53 (%)

(remaining 52)

Yield 54 (%)

(method)

1 Ph 2,6-diMe 89 -

2 Ph 4-Me 85 -

3 p-Tol H 85 -

4 Me H 78 (8) 84 (B)

5 Me 2-Me 76 (15) 72 (A)

6 Me 2-OMe 75 (21) 78 (A)

7 Me 2,4-di-Me 82 (14) 84 (A)

8 Me 4-Cl 69 (4) -

9 Me 4-OMe 76 (4) -

58

Scheme 37. Aryl Migration of Ureas Derived from -Methylbenzylamines.

N N Me

O

MeMe

R2

1. s-BuLi (2.5 equiv.), THF, DMPU (6 equiv.), -78 °C, 6 h

2. H2O

MeHNMe

R2

R1

1. t-BuONO (6 equiv.),CH2Cl2, 24 h

2. LiOH, H2O, THF, , 72 h

55

57

N N

O

DMPU

R1

MeHN N

O

MeMe

R2

R1

new quaternary centre

56

Retention ofconfiguration

Table 10. Stereospecific Aryl Migration.

Entry 55 R1 R

2 Yield 56 (%) e.r. Yield 57 (%)

1 (R)-55a 4-MeO H 56a, 82 97:3 72

3 (S)-55b 3,4-OMe H 56b, 76 98:2 -

4 (S)-55c 4-F H 56c, 34 99:1 -

5 (S)-55d 4-Cl H 56d, 51 98:2 -

6 (S)-55e 3-Cl,4-F H 56e, 69 >99:1 75

7 (S)-55f 2,3-naphtyl H 56f, n.d. 95:5 68

8 (S)-55g 3,4-naphtyl H 56g, 88 >97:3 -

9 (S)-55h H 4-MeO 56h, 73 >98:2 -

10 (S)-55i 2-Me 4-MeO 56i, 64 99:1 -

11 (R)-55j 4-Me 4-MeO 56j, 79 >97:3 -

The rearrangement presumably proceeds by the mechanism displayed in Scheme

38.[62]

Deprotonation at the benzylic position of 55 generates an organolithium

configurationally stable 55aLi on the time scale of the reaction. Ipso attack of the

organolithium centre 55bLi on the aryl ring gives a dearomatised intermediate 58, which

collapses with regeneration of aromaticity to provide lithiourea 56Li and then the urea 56

59

after protonation. The structure of the intermediate 58 has been deduced by isolation of the

crystalline enone 59 by trapping with oxygen.

X-ray crystallography of 59 confirmed the absolute stereochemistry of 56 and

provides evidence for stereochemically retentive rearrangement rather than invertive

(Figure 3).[63]

Scheme 38. Proposed Mechanism and Evidence of a Dearomatised Intermediate.

N N Me

Me

O

Me

R1 s-BuLi

R2

N N Me

O

Me

Me

Li

ArN N

O

Me Me

MeLi R1

R2

MeHN N

O

MeMe

R1

R2

MeN N

OLi

MeMe

R1

R2

N N

O

OCl

aryltransfer

H+

R1 = 2,3-benzo

R2 = p-ClO2

55 55aLi 58

59

56

Retention ofconfiguration

R1

N N

O

Ar

Li

55bLi

56Li

60

Figure 3. X-Ray Crystal Structure of 59.

I.2.3 Aryl Migration of Other Lithiated Urea Analogues

I.2.3.1 Aryl Migration of N-Benzyl-N-Pyridyl Ureas

Clayden et al. reported that this novel method allowed the -pyridylation of chiral

amines 60 via urea coupling, rearrangement and deprotection to provide functionalised

aminopyridines 63 containing a fully substituted quaternary stereogenic centre adjacent to

the pyridine ring (Scheme 39).[64]

It was found that the rearrangement was optimal when

LDA was used as the lithiating reagent instead of sec-BuLi. Moreover, the addition of

DMPU to the reaction increased both the rate and stereospecificity of the reaction,

retaining the stereochemistry of the enantiomerically pure starting material. Deprotection

of 62 by the original method reported[56]

was problematic due to the electrophilicity of the

pyridine ring and the nucleophilicity of its nitrogen. However, an alternative method was

found by refluxing the compound overnight in n-butanol to give rise to the amines 63 in

good yields.

61

Scheme 39. Synthesis of Ureas by Palladium-Catalysis Coupling and Rearrangement.

NH Me

Ar1H

Me

N N

O

Me

Ar1H

Me

N Me

N

O

Me

Ar1

Me

NH

N

HN

Me

Ar1

MeN

n-BuOH,

1. LDA (2 equiv.), THF,DMPU (10:1), -78 °C1-4 h

2. NH4Cl

1. (Cl3CO)2O2. MeNH2

6063

61 62R2 R2

R2

3. Py-Br,Pd2(dba)3 (2.5 mol %),xantphos (10 mol %)PhMe, NaOt-Bu,110 °C, 14 h

Me

Using these optimised conditions the rearrangement has been shown to work on a

range of the N-pyridyl ureas 61 as outlined in Table 11.

Table 11. Ureas 62 and Aminopyridines 63 by Stereospecific Rearrangement and

Hydrolysis.

Entry 61 Ar1 Ar

2

Yield 62

(%) e.r.

Yield 63

(%)

1 (S)-61a C6H5 2-Py 65 98:2 62a 76

2 (R)-61b 4-Cl-C6H4 2-Py 73 98:2 62b 81

3 (S)-61c C6H5 4-Me-2-Py 66 >99:1 62c -

4 (R)-61d 4-Cl-C6H4 3-OMe-2-Py 80 n.d. 62d -

5 (S)-61e C6H5 3-Py 74 99:1 62e 78

6 (S)-61f C6H5 3-Quinolyl 40 n.d. 62f -

7 (S)-61g C6H5 4-Py 83 96:4 62g 65

I.2.3.2 Aryl Migration of N-Aryl Urea Derivatives of Hetero- or Carbocyclic Amines

Since then, Clayden et al. have demonstrated that some classes of cyclic amine may

be arylated by this method.[65]

62

Unlike urea derivatives of pyrrolidine, those derivatives of 2-phenylpyrrolidine 64

rearranged successfully on treatment with LDA in THF-DMPU mixture, to offer the

arylated products 65 in good yields (Scheme 40).

When treated with either sec-BuLi or LDA in a THF-DMPU mixture all ureas

derived from aminotetralin and aminoindane 66 underwent clean aryl transfer from N to C

to give the arylated products 67 in good to excellent yields. Ureas were converted into

amines by warming to 118 °C in n-butanol for 48 h. (Scheme 40).

Treatment of tetrahydroisoquinoline 68 with sec-BuLi promoted rearrangement in the

absence of DMPU and by warming to room temperature a 78 % yield was obtained,

whereas methylated tetrahydroisoquinoline gave the corresponding rearranged product 70

in the presence of DMPU in 66 % yield whilst isoindoline failed to rearrange (Scheme 40).

It was proved that the rearrangement, unlike those of acyclic N--methylbenzylureas,

is not stereospecific.

Scheme 40. -Arylation of Cyclic Amines by Aryl Transfer in Lithiated Ureas.

NH

N

RAr

3 steps

-arylation

(Ar = 4-MeOC6H4, R = -CONHMe) 89 % (Ar = 2-pyridyl, R = Me) 62 %

N Li

ON

Ar

Me

via

Arylation of the pyrrolidine ring by rearrangement

NH2

n

3 steps

n

Ar NRMe

(n = 2, Ar = Ph, R = H) 71 %(n = 1, Ar = 4-ClC6H4, R = H) 61 %(n = 1, Ar = H, R = -CONHMe) 66 %(n = 1, Ar = 2,3-benzo, R = -CONHMe) 70 %(n = 1, Ar = 2,6-dimethyl, R = -CONHMe) 78 %

Arylation of aminoindane and aminotetralin

NH

3 steps

3 steps

N

Ph O

NHMe

69, 78 %

N

O

NHMe

70, 66 %

Ph Me

Rearrangement of tetrahydroisoquinolines

64 65

66 6768

R

(R = H or Me)

63

I.2.3.3 Aryl Migration of N-Allyl-N-Aryl Ureas

This rearrangement also turned out to be applicable to N-allyl-N-aryl ureas 71

allowing the construction of enantiomerically enriched diarylallylamine derivatives 75 by

sequential double aryl migration (Scheme 41).[66]

Upon lithiation with 2 equiv. of LDA, 71

underwent rearrangement with transfer of the aryl ring from N to the allylic carbon to

form the -arylated products 72 in good yields. A further enantioselective rearrangement

of vinyl ureas 72 using chiral lithium amides 74 afforded chiral allyl urea products 75 with

selectivities lying between 84:16 and 92:8 e.r..

Scheme 41. Sequential Double Arylation of N-Allyl-N-Aryl Ureas.

N N

Me

O

PMP

1. LDA (2 eq.),THF, -78 °C, 10 min

MeHN N

O

PMP

71

(Z)-72, 53 to 95 %

R1

R1

2. DMPU,-78 °C, 3 h3. MeOH

R1 = H, p-Me, m-Tol, p-MeO,

p-Cl, m-F, p-NC, m-CF3, Ph

Ar2Br, Pd2(dba)3

xantphos, NaOt-Butoluene,

N N

O

PMP

R1

Me

R2

R1 NR2

Me

Li

R1 N R1

R2 R2

Li

or

LiCl, THF,-78 °C, 10 min

NCONHMePMP

R1

R2

R2 = p-NC, 6-MeOPy,

p-Cl, m-F, m-MeO

73

74a

74b up to 91% yieldup to 92:8 e.r.

75

I.2.4 Enantioselective Synthesis of Tertiary Thiols by Intramolecular

Arylation of Lithiated Thiocarbamates

Asymmetric tertiary thiols are a synthetically challenging class of compounds to

prepare. The few reported methods for synthesising these species require restrictive

64

functionality to be incorporated into the products or are limited to using simple carbon

electrophiles.[67]

As a result, enantiomerically pure tertiary thiols are, despite the simplicity

of their structure, a remarkably difficult class of compounds to make.

Recently, Clayden et al. reported a solution to this problem: N-aryl S--alkylbenzyl

thiocarbamates 76 proved to be suitable substrates for the N to C aryl transfer.[57]

Lithiation

of such thiocarbamates with LiTMP in THF at -78 °C led to rearrangement with invertive

migration of the N-aryl ring and returned chiral benzylic tertiary thiol derivatives 77 in

excellent yields and high enantiomeric ratios (Scheme 42).

Scheme 42. Enantioselective Synthesis of Tertiary Thiols.

Ar1 S NMe

R O

Ar2

1. LiTMP (2.5 eq.),THF, -78 °C, 15 h

2. EtCO2HAr1 S NHMe

OR Ar2

76 77

NaOEt,EtOH

20 °C,15 min

Ar1 SH

R Ar2

78

SH

Me

63 %, 96:4 e.r.

SH

Me

97 %, 91:9 e.r.

MeO

SH

Me

Cl

97 %, 96:4 e.r.

SH

Me

41 %, 96:4 e.r.

Cl

SH

Me

CN

98 %, 97:3 e.r.

SH

Me

51 %, 96:4 e.r.

SH

97 %, 98:2 e.r.

SH

Me

76 %, 67:33 e.r.

F3C

SH

Me

OMe

94 %, 50:50 e.r.

SH

Me

75 %,50:50 e.r.

MeO

SH

89 %, 74:26 e.r.

Retention of configuration

65

I.3 Properties and Reactivity of Lithiated Carbamates

I.3.1 Dipole-Stabilized Carbanions Adjacent to Oxygen

The direct formation of stable carbanions to oxygen is not a facile process.[63a,68]

In

fact, the effect of an ether oxygen on a prospective carbanion appears to be deactivating

with respect to proton removal, due to electron pair repulsion overcoming the favourable

inductive effect. Such destabilization may provide some driving force for the Wittig

rearrangement[69]

and - and -eliminations[70]

observed for reactions in which -oxo

carbanions are possible intermediates (Scheme 43).

Scheme 43. Lithiation to Oxygen and Wittig Rearrangement.

R2O R1

H H RLi

R2O R1

H Li

LiO R1

H R2Wittig

rearrangement

Following the ideas of chelate stabilization and of proximity effects[71]

as powerful

devices for directed deprotonation, Hoppe discovered the strongly activating influence of

N,N-dialkylcarbamoyloxy groups (R2) in the removal of adjacent protons of weak CH-

acids by alkyllithiums[72]

and also prevent the Wittig rearrangement (Scheme 44). 2-

alkenyl, 2-benzyl and 2-alkynyl N,N-diisopropylcarbamates are deprotonated with great

ease by n-butyllithium at low temperatures leading to five-membered chelate complexes A

(Scheme 44).

Scheme 44. Induced Dipole Stabilization.

A

..

..

..O

Li

O

NR2

R1

L

L

B

..

..

..OO

NR2

R1

L

LLi..

C

..

..

..OO

NR2

R1

L

LLi..

66

Quantitative thermodynamic stability scales of organolithium compounds derived

from tin-lithium exchange equilibria has shown that an -oxycarbanion is far better

stabilized by a carbonyl group as the O-substituent than by an alkyl or alkoxyalkyl group

(Geq is approximately 3 kcal mol-1

).[73]

The thermodynamic data and NMR studies point

to the fact that the stabilization imparted by a carbonyloxy group in “dipole-stabilized”

carbanions is at least partly derived from an electron-withdrawing effect, and not only from

the traditionally accepted effect of the chelation of the Li atom bound to the carbanionic

centre with the carbonyl oxygen as shown in Scheme 44.[74]

The favourable chelation

should contribute to the stabilization of these organolithiums since the interaction between

the cation and the oxo group increases the acceptor properties of the carbamoyloxy group

according to the resonance forms B and C.

I.3.2 Versatile Reactivity and Configurational Stability of Lithiated O-

Benzylcarbamates

Lithiation to oxygen of carbamates such as 79a generates a series of d1 reagents

79Li that may be alkylated or acylated to give 80, providing an -lithio alcohol synthetic

equivalent or homoenolate equivalent (alkenyl counterpart) (Scheme 45). Less hindered

carbamates 79b, however, are too unstable on standing at -78 °C: rearrangement by 1,2-

acyl transfer from O to C provides -hydroxyamides 81.[75]

Scheme 45. Reactivity of Lithiated O-Benzylcarbamates.

N O

R3O

R1

R2

79a, R1 = R2 = i-Pr

79b, R1 = R2 = Et

RLiN O

LiO

R1

R2 R3 R2HN O

R1O

82

R3R1 = Ar

N O

EO

R1

R2

80

R3

NR1R2O

HOR3

EX

R1 = R2 = Et

81

1,2-acyl shift

1,4-aryl transfer

79Li

R1 = R2 = i-Pr

67

I.3.2.1 Electrophilic Substitutions of Lithiated O-Benzylcarbamates

The examples of -oxy-substituted benzylic precursors leading to lithium carbanions

of considerable configurational stability are secondary carbamates,[76]

such as 83,

introduced by Hoppe et al. (Scheme 46). Deprotonation with sec-BuLi/TMEDA leads to

the chelate-stabilized lithium carbanion pair 83Li•TMEDA,[77]

configurationally stable

below -70 °C in ether or hydrocarbon solution occurring with retention of stereochemistry.

The substitution of 83Li proceeds either with retention or inversion to form the products 84

or ent-84, respectively, depending on the nature of the electrophile.[76a,b,g]

Scheme 46. Generation of a Configurationally Stable, Enantioenriched Lithiated O-

Benzylcarbamate: Stereodivergence of its Electrophilic Substitution.

i-Pr2N O

O H Me

(R)-83, 98:2 e.r.

i-Pr2N O

O Li Me

(R)-83LiTMEDA

N N

ent-84

Inversion(SE2inv)

Retention(SE2ret)

EX = MeOH (90:10 e.r.), C3H7Br (>92:8 e.r.), (MeO)2CO (97:3 e.r.), iPrCH=O (>98:2 e.r.), PhC(=O)OMe (>98:2 e.r.)

EX = HOAc (90:10 e.r.), ClCO2Me (93:7 e.r.),MeCOCl (>98:2 e.r.), MeCOCN (96:4 e.r.),PhCH2Cl (>98:2 e.r.), CO2 (92:8 e.r.),iPrNCO (>92:8 e.r.), Me3SnCl (>98:2 e.r.)

i-Pr2N O

O E Me

84

i-Pr2N O

O Me E

s-BuLi/TMEDA

hexane, -78 °C

To rationalise the stereodivergence of the electrophilic substitution, the authors

hypothesised that electrophiles, which have a high tendency to interact with the lithium

cation, such as esters, alcohols, aliphatic aldehydes and ketones, prefer to attack at the

same side as the lithium atom (retention). Electrophiles, which have an energetically low

LUMO, such as acid chlorides, heterocumulenes and trialkyltin chlorides prefer to attack

from the opposite side (inversion), which has increased electron density because of the

partially flattened nature of the carbanion 83Li.[78]

Strohmann et al. also reported that the coordination sphere of the lithium atom must

be considered to rationalise the stereochemical course of the trapping reaction.[79]

Recently,

68

Aggarwal et al. reported that the stereochemical outcome of the reaction of lithiated

alkylcarbamates with boranes depended on the steric bulk of diamine additive such as

TMEDA and sparteine, which were complexed to lithiated carbamates.[80]

On the basis of

these studies, Takeda et al. showed that the coordinating ability of electrophiles and

solvents to a lithiocarbanion generated from 1-phenylbut-2-en-1-yl diisopropylcarbamate

played a significant role in determining the stereochemical course by involving equilibrium

between a solvent-separated ion pair and contact ion pairs.[81]

The tertiary carbamoyloxy-substituted benzyllithium 83Li was also found to be

configurationally stable based on the “Hoffmann test”.[82]

Racemic benzyllithium 83Li was

generated from 83 with sec-BuLi in Et2O/TMEDA at -78 °C. Reaction with the racemic

aldehyde 85 at -78 °C furnished two diastereomeric adducts 86 and ent-86 in 30:70 ratio

(Scheme 47). Repeating the reaction with the enantiomerically pure aldehyde 85 gave the

same two products with a different ratio close to 50:50. They therefore concluded that 83Li

was configurationally stable on the time scale set by the addition to the aldehyde 85.[83]

They also proved that 83Li, trapped by tributyltin chloride and regenerated by reaction

with n-BuLi in THF, was configurationnally stable at -78 °C even in THF.

Scheme 47. Hoffmann Test on Tertiary Carbamoyloxy-substituted Benzyllithium

Compound 83Li.

i-Pr2N O

O

i-Pr2N O

O

Et2O/TMEDA,-78° C

Me

83

MeLiBu3SnCl

n-BuLi,THF, -78 °C

i-Pr2N O

O SnBu3Me

Ph

NBn2

O

H

85

Ph

O Me

OH

NBn2N

O

i-Pr2

Ph

O Me

OH

NBn2N

O

i-Pr2

86 ent-86

Et2O/TMEDA

()-85

(S)-85

(30:70)

(48:52)

93 %

86 %

()-85

(S)-85

(30:70)

(50:50)

95 %

92 %

THF

83LiTMEDA 87

s-BuLi

69

Whereas carbenoids derived from chiral secondary benzyl carbamates are

configurationally stable at -78 °C, those from primary benzyl carbamates such as 88

(Scheme 48) are not, although the same “Hoffmann test” as above demonstrated that the

enantiomerization of the complex 88Li•TMEDA is not faster than its trapping by the

aldehyde 85.[83]

Enantioselective lithiation in the presence of chiral ligands to form configurationally

labile lithiated O-benzylcarbamates and electrophiles incorporation has also been

dominated by the studies of Hoppe. The first -oxybenzyllithium compound was the

lithiated benzyl carbamate 88, but it could not be tuned to useful selectivities in the

presence of ()-sparteine 89[84]

(Scheme 48).[85]

Scheme 48. Configurationally Labile Epimeric Diamine Complexes of -Lithiated

Benzylcarbamate 88Li.

N

OO

N

i-Pr2N O

O SnBu3

i-Pr2N O

O HS HR

88

i-Pr2N O

O

(RC)-88Li90

Li90

i-Pr2N O

O

(SC)-88Li89

Li89

enantiotopic differentiation

dynamic thermodynamicresolution

Diamine, -78 °C,toluene, 2.5 h

Bu3SnCl, -78 °C, 2 h

66:34 e.r. 1:99 e.r.

8990

91 % 88 %

SEinv SEinv

91a

By changing the ligand to sterically more demanding bis(oxazoline) 90, they found

that the resulting epimeric complexes equilibrated and the RC-configured complex (RC)-

88Li•90 was strongly favored in the equilibrium (Scheme 49). After dynamic

thermodynamic resolution, the complexes could be trapped with different classes of

70

electrophiles with a similar stereodivergence in the stereochemical course to yield highly

enantioenriched secondary benzyl carbamates 91 in toluene at -78 °C.[86]

Scheme 49. Deprotonation-Substitution Sequence with O-Benzylcarbamate 88 in the

Presence of Chiral Bis(oxazoline) 90.

i-Pr2N O

O HS HR

88

i-Pr2N O

O

(RC)-8890

Li90

90, s-BuLii-Pr2N O

O

(SC)-8890

Li90

PhMe, -78 °C,2.5 h RR R

R = H, Me, OMe,2,3-benzo EX

i-Pr2N O

O

(R)-91b, 28 %, 77:23 e.r.

i-Pr2N O

OHO O

(S)-91g, 64 %, 96:4 e.r.

Et

i-Pr2N O

O

(S)-91d, 95 %, >95:5 e.r.

MeO O

i-Pr2N O

O

(S)-91e, 64 %, 96:4 e.r.

SnBu3

OMe

OH

i-Pr2N O

O

(S)-91f, 77 %, >96:4 e.r.

Me

i-Pr2N O

O

(1S,2R)-91c, 70 %, 66:34 e.r.

OHtBu

Clayden et al. reported a third mode of reactivity displayed by O-benzylcarbamates

carrying N-aryl substituents to furnish 82 with no competing 1,2-acyl shift (Scheme 45).[55]

Computational studies showed that when R1 = Ar, the calculated free energy barrier for the

attack on the aromatic ring (3.6 kJ mol-1

) is considerably lower (by 14.4 kJ mol-1

) than that

for attack on the carbonyl group (18.0 kJ mol-1

).

I.3.2.2 N to C Arylation Migration in Lithiated O-Benzylcarbamates

The novel rearrangement reaction of carbamates such as 92

(Scheme 50) allows an aromatic ring to migrate to a new

fully substituted stereogenic centre via an organolithium

intermediate in a similar way to ureas. The resulting reactions constitute (stereospecific) -

R1 H

OH

R2R1 Ar

OH

R2

71

arylations of secondary alcohols, providing a connective, “umpolung” route to (chiral)

tertiary alcohols bearing heavily substituted substituents.

Upon lithiation with LDA in a Et2O-DMPU mixture, primary O-benzylcarbamates 92

underwent the rearrangement cleanly, then by simple treatment of the rearranged

carbamates 93 with sodium ethoxide in ethanol, the secondary alcohols 94 were returned in

good yields (Scheme 50).[55]

Scheme 50. Synthesis of Diarylmethanols by Aryl Transfer.

N O

Me

OR

1. LDA (2.5 equiv.)Et2O/DMPU (4:1)-78 °C, 4 h

2. NH4ClMeHN O

O

R

92

NaOEt, EtOH

, 2 h

OH

R

94

93a R = p-Me, 62 %93b R = o-Me, 55 %93C R = p-F, 40 %

94a R = p-Me, 68 %94b R = o-Me, 83 %94c R = p-F, 67 %

A series of secondary carbamates 95 was subjected to lithiation either with sec-BuLi

in THF/DMPU (condition A) or with LDA in Et2O/DMPU (condition B) (Scheme 51).

Under either set of conditions, 1,4-aryl transfers from N to C took place, and the arylated

carbamates 96 were isolated in good to excellent yields (Table 12).[55]

Scheme 51. Aryl Transfer in Secondary Lithiated Carbamates.

N O

Me

O

MeHN O

O

R1

95 96

Me

R2

Me

R2

Conditions As-BuLi (2.5 equiv.)THF, DMPU (4:1),-78 °C, 4 h

or Conditions BLDA (2.5 equiv.),Et2O, DMPU (4:1)-78 °C, 4 h

R1

72

Table 12. Conditions and Yields for N to C Aryl Transfer in Carbamates 95.

Entry 95 R1 R

2 Conds. Yield 96 (%)

1 95a H H A 96a, 75

2 95b p-Me H B 96b, 84

3 95c o-Me H B 96c, 72

4 95d o-i-Pr H B 96d, 67

5 95e p-OMe H A 96e, 68

6 95f p-Cl H B 96f, 56

7 95g 2,3-benzo H A 96g, 85

8 95h 3,4-benzo H A 96h, 57

9 95i H p-Cl B 96i, 90

10 95j p-Me p-Cl B 96j, 82

11 95k p-OMe p-Cl A 96k, 68

12 95l 2,3-benzo p-Cl A 96l, 67

Attempts to make 96i enantioselectively by stereospecific rearrangement of (S)-95i

by using the conditions above led to a racemate. A brief look at the literature seemed to

suggest that in general organolithium species are not configurationally stable in strongly

lithium-coordinating solvents when they contain α-oxygen atoms at the benzylic

position.[76b]

This is in contrast to their nitrogen counterparts and the urea analogues have

already been shown to rearrange with minimal loss of enantiopurity. The configurational

stability of benzylic α-oxygenated organolithiums in other solvents such as hexane and

diethyl ether is greatly increased, as seen in Section I.3.2.1, a number of examples have

been shown to be stable at −78 °C in these solvents. Indeed, when (S)-95i was lithiated in

Et2O with LDA, substantial enantiomeric enrichment was preserved: (S)-96i was returned

in 85:15 e.r. (Scheme 52). Enantiomerically enriched (S)-96i was converted into alcohol

(+)-(S)-97i and allowed to conclude that unlike ureas the rearrangement proceeds with

inversion at the lithium-bearing centre by comparison with published data for optical and

chromatographic properties.[52]

73

Scheme 52. Enantioselectivity in the Rearrangement of the Carbamate 95i.

N O

O

Me

Me

Cl

(S)-95i (94:6 e.r.)

1. LDA (2.5 equiv.)Et2O, -78 °C -35 °C,24 h

2. MeOH

MeHN O

O

Me

Cl

(S)-96i (85:15 e.r.)

NaOEt,EtOH, , 2 h

(+)-(S)-97i, 77%

Cl

Me

O

NMe

(R,R)-Clemastine 98

OH

Me

Cl

Inversion ofconfiguration

(S)

(S)

(S)

,-Diaryl ethanols are valuable compounds in enantiomerically pure form.[86]

For

example, (R)-97i is an intermediate in the synthesis of the antihistamine agent (R,R)-

clemastine 98 (Scheme 52).[88]

Therefore, clemastine forms potential synthetic target of

this methodology.

Prior to this work, it was well established that not only benzylic but also allylic and

propargylic carbamates may be deprotonated to form synthetically versatile substituted

allylithiums and propargyllithiums.

I.3.3 Configurational Stability of Lithiated O-Allylcarbamates

Hoppe et al. used -lithiated 2-alkenyl N,N-diisopropylcarbamates 99Li as

homoenolate equivalents in regio and stereospecific reactions with aldehydes and ketones

after a lithium-titanium exchange (Scheme 53).[89]

74

Scheme 53. 1-Alkenyl Carbamates in Asymmetric Homoaldol Reactions.

R2

O

HR1

2. R3CH=O

3. H3O+99a R1 = R2 = Me

99b R1 = H, R2 = Me

99c R1 = H, R2 = Ph

R3

R1

OH

R2 OO

Ni-Pr2

R2

O

R1Li

O

Ni-Pr2

Ln

1. TiX4O

Ni-Pr2

10099Li

Enantioenriched (-lithio-2-alkenyl)carbamates 99Li derived from secondary

carbamates such as (E) and (Z)-2-pentenyl N,N-diisopropylcarbamates 99a, are

configurationally stable below -70 °C in nonpolar solvent. They could be generated either

by stereoretentive deprotonation of the optically active precursors by n-BuLi/TMEDA in

ether/hexane (Scheme 54) or by kinetic resolution of the racemic precursors, deprotonating

with sec-BuLi/()-sparteine in pentane (Scheme 55).[90]

The allyllithium was formed with

greater than 90:10 e.r. as estimated from trapping experiments as shown by the two

examples of stannylation depicted in Scheme 54 and 55.

Scheme 54. Configurational Stability of Lithiated (E),(Z)-2-pentenyl N,N-

diisopropylcarbamates 99aLi Generated by Deprotonation of the Optically Active

Precursors.

Me

CbO H

s-BuLi/TMEDA

hexane, -78 °C

(R,E)-99a95:5 e.r.

Me

CbO LiTMEDA

Me3SnCl Me

OCbMe3Sn

(S,Z)-101, 52 % 95:5 e.r.

Me

H OCb

(S,Z)-99a99:1 e.r.

s-BuLi/TMEDA

hexane, -78 °C

Me

CbO Li�TMEDA

Me3SnCl Me3Sn Me

OCb

(S,Z)-101, 55 % 95:5 e.r.

anti-SE'

anti-SE'

(R,E)-99aLiTMEDA

(S,Z)-99aLiTMEDA

75

Scheme 55. Configurational Stability of Lithiated (E)-2-Pentenyl N,N-

diisopropylcarbamate 99aLi Generated by Kinetic Resolution of the Racemic Precursor.

Me

OCbH

()-99a

n-BuLi/()-sparteine 89

pentane, -78 °C, 10 h

Me

OCbLi()-sparteine

OCb

MeLi()-sparteine

torsionH

OCbMe

(R)-99a41 %, 90:10 e.r.

(S)-99aLi.()-89

Me

OCbSnBu3

()-101 (R,Z)42 %, 90:10 e.r.

OCb

MeSnBu3

()-101 (S,E)6 %, 90:10 e.r.

Bu3SnCl

anti-SE'

Additional trapping experiments, in order to elucidate their stereochemical course, showed

that the lithium-titanium exchange of (S)-99aLi•TMEDA by tetra(isopropoxy)titanium

(TIPT) was accompanied by stereoretention (SEret),[91]

whereas the (S)-99aLi•()-sparteine

complex proceeded with stereoinversion (SEinv) under the same conditions.[92]

Carboxylation and methoxycarbonylation of the lithium sparteine complex (S)-99aLi•()-

89 also proceeded with stereoinversion.[93]

In contrast, (-lithio-2-alkenyl) carbamates derived from carbamate derivatives of

primary alcohols, such as (E)-2-butenyl N,N-diisopropylcarbamate 99b[94]

or (E)-cinnamyl

N,N-diisopropylcarbamate 99c,[95]

turned out to be configurationally unstable in solution

with n-BuLi/()-sparteine even at -78 °C.

In the case of (E)-2-butenyl N,N-diisopropylcarbamate 99b, however, the (S)-

configurated sparteine complex (S)-99bLi•()-89[96]

crystallised from the

pentane/cyclohexane solution with concomitant dynamic kinetic resolution,[97]

resulting in

up to 95 % d.e. in the solid (Scheme 56). Reaction of the solid with Ti(Oi-Pr)4 proceeded

76

with configurational inversion to give the allyltitanium intermediate (R)-102, which was

stable in solution up to -20 °C.[94a]

Reaction with tetrabutyltin chloride yielded

allylstannane (R)-103 with high regioselectivity and enantiomeric purity (>97:3 e.r.) via a

delithiotitanation (inversion) and detitanostannylation (anti-SE’) sequence.[94b]

Scheme 56. Configurational Stability of Lithiated (E)-2-Butenyl N,N-

diisopropylcarbamate 99bLi.

HR

OCbHS

99b

n-BuLi/pentanecyclohexane

()-sparteine,-78 °C

H

O

N(i-Pr)2

O

Li�()-sp.

(S)-99bLi89, 95 % d.e.

H

O

N(i-Pr)2

O

Li�()-sp.

(R)-99bLi89

1. epimerization2. crystallisation

HS

OCbTi(O-iPr)3

(R)-102

HR

OCbTi(O-iPr)3

(S)-102

Ti(O-iPr)4

Ti(O-iPr)4

OCb

(R)-103, 80 %, >97:3 e.r.

SEinv

SEinv

anti-SE' Bu3SnCl

Bu3Sn

Deprotonation of (E)-cinnamyl N,N-diisopropylcarbamate 99c with n-BuLi/()-

sparteine in toluene showed that the cinnamyllithium (S)-99bLi•()-89 formed upon

deprotonation epimerizes within thirty minutes at -78 °C to the thermodynamically more

stable allylithium-()-sparteine complexe (R)-99cLi•()-89 (Scheme 57). Reactions with

several electrophiles proceeded regio- and stereospecifically at the - or γ position, but at

different rates for the two diastereoisomers, leading to a decrease in enantioselectivity

compared to the diastereomeric ratio of the complexes.[95]

77

Scheme 57. Configurational Stability of Lithiated (E)-Cinnamyl N,N-

diisopropylcarbamate 99cLi.

Ph H

OCbH

99c

Ph H

OCb

Li�()-sp.toluene,-78 °C, 10 min

n-BuLi/()-sparteine Ph Li()-sp.

OCb

H30 min

Ph

OCb

SiMe3

(S)-104a88 %, 93:7 e.r.

Ph

OCb

SnMe3

(S)-104b71 %, 90:10 e.r.

Ph

OCb

(R)-104c86 %, 90:10 e.r.

t-Bu

O

Ph

OCb

CO2Me

(S)-104d69 %, 91:9 e.r.

1. CO2

2. CH2N2t-BuCOClMe3SnClMe3SiCl

(S)-99cLi()-89 (R)-99cLi()-89

It is noteworthy that lithiation of cinnamyl carbamate and 1-naphthyl derivatives in

the presence of chiral bisoxazoline (BOX) ligands results in a greater discrimination

between the diastereoisomers than with ()-sparteine, and gives enantioenriched

substitution products with e.r. values up to 97:3.[98]

In the other hand, (Z)-1-alken-1-yl N,N-diisopropylcarbamates 105 bearing an anion-

stabilizing group in the 1-position was deprotonated by n-BuLi/()-sparteine via a nine-

membered cyclic transition state with a high degree of enantiotopic differentiation in the γ

position, to form allyllithium intermediates (S)-105Li.()-89 which are configurationally

stable at -70 °C (Scheme 58).[99]

Noteworthy, the isomer (E)-105 remained unchanged.

These combined with ketones and aldehydes with high regio- (γ-position) and

stereoselectivities (up to >98:2 e.r.), allowing a simple and efficient approach to

enantiomerically enriched homoenolate reagents starting from achiral precursors.

78

Scheme 58. Enantiotopos-Differentiating γ-Deprotonation of 1-Alkenylcarbamates.

R1 R2

O HS HR

R1 = aryl, 1-alkynyl, 1-alkenyl, SiMe3

R2 = Me, Et

n-BuLi/(�)-sparteine

R1 R2

O H H

O

N

Li BuiPr2

105

R1 R2

OLi

NiPr2O

(S)-105Li()-89

()-sp.

toluene, -70 °C

O

i-Pr2N ()-sp.

I.3.4 Configurational Stability of Lithiated O-Alkynylcarbamates

Enantiomerically enriched, configurationally stable alkynylllithiums 106aLi.TMEDA

can be produced by deprotonation of enantiomerically pure secondary 2-alkynyl N,N-

diisopropylcarbamates 106a by n-BuLi or sec-BuLi/TMEDA in hexane at -78 °C (Scheme

59).[100]

It has been revealed by a high degree of chirality transfer (C.T.) in the formation of

allenyl carbinols 107.

Scheme 59. Configurational Stability of Lithiated Secondary Alkynyllithiums.

R1

OCb

Me

106a

Base/TMEDA

R1

Me LiTMEDA

OCb

• OCbMe

OH

R1• OCb

Me

OH

R1

syn-107 anti-107

106aLiTMEDA

R1

t-Bu

c-C6H11

CH3

PhMe2Si

t-BuCHO

C.T. (%) (Method)

0 (A), 84 (B)

0 (A), 88 (B)

Method A: Deprotonation with n-BuLi at -78 °CMethod B: In situ deprotonation with s-BuLi at -100 °C or -78 °C in the presence of aldehyde

Et2O, 20 min

100 (A)

73 (A)

In contrast, deprotonation of primary 2-alkynyl N,N-diisopropylcarbamates 106b by

n-BuLi/()-sparteine in toluene at -78 °C and trapping the intermediate ion pairs by

carboxylation or silylation led to slightly enantioenriched products. However, when the

79

deprotonation was performed in pentane, dynamic resolution of the lithium-()-sparteine

complexes (S)-106bLi.()-89 by selective crystallisation gave much higher levels of

enantioselectivity in the allenyl carbamates (M)-109a,b (92:8 e.r. and 94:6 e.r. respectively)

and the allenyl carbinols 110 (>96:4 e.r.) after transmetallation by rapid addition of

chlorotitanium tri(isopropoxide) from the solid state (Scheme 60).[101]

Scheme 60. Synthesis of Chiral Allenyl Carbamates and Carbinols.

(S)-106bLi()-89 (R)-106bLi()-89

R1

OCb

HR HS s-BuLi/()-sparteine

pentane, -78 °CR1

OCb

H Li�()-sp.

R1

OCb

Li H(-sp.

crystallisation

106b

R1

OCb

H Ti(O-iPr)3

R1

OCb

(Oi-Pr)3Ti H

(R)-108 (S)-108

ClTi(Oi-Pr)3, -78 °C

AcOH

i.R2CHO, -78 °Cii. AcOH

• HOCb

R2

R1

OH

110, >96:4 e.r.

R1 = t-Bu, Me3Si

R2 = i-Pr, Me, Ph

• HOCb

H

R1

(M)-109

a R1 = t-Bu, 80 %, 92:8 e.r.

b R1 = Me3Si, 86 %, 94:6 e.r.

80

I.4 Carbolithiation Reactions

Organolithium compounds are important intermediates in organic synthesis.[63a,102]

Various methods for generation of organolithium intermediates have been developed to

date. Among them, carbolithiation of unsaturated compounds such as alkenes,[103]

alkynes[104]

and enynes[105]

serves as an attractive method since carbon-carbon bond

formation leads to the formation of a second organolithium intermediate such as 111

(Scheme 61), which can be employed for subsequent reactions with different electrophiles,

thus allowing two new C-C bonds to be formed in a single pot. Commercially available n-

BuLi, sec-BuLi, and tert-BuLi are often utilised as starting organolithium compounds.[106]

Activation of the starting material by TMEDA, DABCO or ()-sparteine is also often

advantageous.

I.4.1 Overview of Carbolithiation Reactions Involving Organolithiums

1.4.1.1 General Aspects of Carbolithiation Reactions

For synthetically useful carbolithiation reactions,[107]

the formation of intermediate

111 must proceed much more rapidly than the next addition step in order to avoid the

polymerization (formation of 112) (Scheme 61). Therefore, 111 must markedly differ from

the starting one[108]

or special stabilization of 111 is required by using for example

cinnamyl derivatives 113 bearing a Lewis-basic substituent X (X = OR, NR2,…) as

demonstrated by Normant et al. (Scheme 61).[109]

The complex-induced proximity effect

(CIPE),[71]

resulting from the formation of the complex 114, causes a rapid addition

reaction to form the stabilized adduct 115, which can be trapped by various electrophiles.

Scheme 61. Conditions Required for Intermolecular Carbolithiation Reactions.

R1 R2 Li R1

Li

R2

R1

R2

R1

Li

111

112

Anionic Polymerization

E+

R1

E

R2

R1

n

81


Ph X

R1 LiPh X

R1 Li113

114

Ph

Li

R1

X

115

E+

Ph X

E

R1

X = OR, NR2, ...

Li = Li�(ligands)n

116

This drawback is diverted if the addition occurs on a triple bond, where a less

reactive sp2-C-Li bond is formed, or on an intramolecular double bond, where entropy

factors are favourable (Scheme 62). In the latter case, a new sp3 carbon is created.

Scheme 62. Carbolithiation on a Triple Bond and an Intramolecular Double Bond.

R3 LiR1 R2

R1

LiR3

R2

Li

Li

If the carbolithiation is now carried out on an ,β-disubstituted double bond, two

regioisomers can be formed and after reaction with an electrophilic reagent, two sp3

stereogenic centers are created (Scheme 63). So, in order to have a powerful reaction, it is

necessary to control the regio- and the diastereoselectivity of the carbolithiation reaction.

Regioselectivity is highly dependent on the substrate, but generally selectivity of the

addition is syn. Diastereoselectivity means that the configurational stability of sp3

organolithium derivatives towards electrophiles must be controlled. And, the sense of

diastereoselectivity, by which 116 is formed, depends on the configuration of the

intermediate 115 and the stereochemistry of the substitution step. All substrates should be

liable to an enantioselective version of carbolithiation, under the influence of either a chiral

82

ligand for lithium, which would promote a face selection on the double bond, or of a chiral

group already present on the substrate (diastereoselection). Carbolithiation is regiospecific,

for instance with the alkyl and aryl group adding exclusively to the double bond such that

the more mesomerically stabilized benzylic lithiated compound is formed.[110]

Scheme 63. Regio-, Diastereo- and Enantioselectivity of the Carbolithiation Reaction.

R3 Li

E+

R2R1

R3

R2R1

Li

HH

Regioselectivity

R3

R2R1

E

HH

Diastereoselectivity

Enantioselectivity

In this thesis, selected examples of substrates allowing such carbolithiations are

shown.

1.4.1.2 Intermolecular Carbolithiation Reactions

The first enantioselective carbolithiation of (E)-β-methylstyrene 117a and (E)-

stilbene 117b with alkyllithiums has been reported by Marek, Normant et al. utilising ()-

sparteine to induce asymmetry in the products (Scheme 64).[110e,f]

In these examples, the

chiral centre formed as a result of the C-C bond formation is configurationally stable but

the benzylic C-Li centre has low configurational stability. Protonation of the lithiated

intermediates 118aLi and 118bLi respectively afforded 2-methylhexylbenzene 118a and

1,2-biphenylhexane 118b in good yields and e.e.. Attempts to achieve diastereoselectivity

by treating 118aLi with methanol-d4 gave the deuterated product with only 60:40 d.r..

Scheme 64. Enantioselective Carbolithiation of (E)-β-Methylstyrene and (E)-Stilbene.

Ph

R

117a, R = Me117b, R = Ph

n-BuLi, ()-sparteine

hexane, -15 °C

Ph

R

118aLi, R = Me118bLi, R = Ph

Bu

Li

H3O+ Ph

R

118a, R = Me, 83 %, >92:8 e.r.118b, R = Ph, 81 %, 85:15 e.r.

Bu

83

The carbolithiation of (E)-cinnamyl alcohol 119 illustrates how stereocontrol over

both centres can be achieved (Scheme 65). Indeed, the enantioselective carbolithiation of

119 with n-BuLi/()-sparteine and subsequent trapping of the lithiated intermediate

120Li.()-89 with different electrophiles allowed the formation of two chiral centres in a

one-pot diastereospecific and enantioselective manner to provide the acyclic products 120,

121a, 121b and 121c.[110c]

Scheme 65. Enantioselective Carbolithiation with Diastereoselective Electrophile

Substitution.

Ph

HO

n-BuLi, (�)-sparteine

cumene, 0 °C

119

Ph

120Li()-89

Bu

LiO

(-)-spart

H3O+ BuPh

CH2OH

120, 85 %, 83 % e.e.

BuPh

CH2OH

BuPh

CH2OH

BuPh

CH2OHMe D PhS

121a 121b 121c

MeI DCI PhSSPh

d.r.> 98:263 % yield, 91:9 e.r.

d.r.> 98:261 % yield, > 91:9 e.r.

d.r.> 95:587 % yield, 92:8 e.r.

The presence of a free alcohol is not a necessity as similar e.e. was obtained with

dialkylamines[110e]

and improved e.r. (up to > 97:3 e.r.) with a tert-butyl ether.[111]

The

stereochemistry of the olefin is crucial for the enantioselectivity of the carbolithiation.

Employing the alkene of opposing stereochemistry ((Z)-cinnamyl alcohol) allowed access

to the opposite enantiomer of 120 from the same ()-sparteine chiral source.[110g]

Recently, O’Shea et al. have extended this methodology to the enantioselective

carbolithiation of various ortho-amino β-methylstyrenes and (E)-stilbenes initiating

cascade route to chiral heterocycles.[112]

Enynes are also reactive towards carbolithiation.[113]

Although the yields are variable,

the products are valuable allenyllithiums (Scheme 66).

84

Scheme 66 Intramolecular Carbolithiation of Enynes.

Li

•Li

60%

Carbolithiation of alkynes is recognised to be useful in the preparation of

stereochemically defined tri- and tetrasubstituted alkenes.

For example, O’Shea et al. employed an intermolecular carbolithiation of

diphenylacetylene 122 as the key synthetic step in a concice and highly stereoselective

synthesis of (Z)-tamoxifen 126, the most commonly utilised therapeutic agent for the

treatment of estrogen-dependent breast cancer (Scheme 67).[114]

Starting from

diphenylacetylene 122, syn addition of EtLi yielded the vinylic lithium species (Z)-123

which rapidly isomerises[115]

to the more thermodynamically favoured (E)-123 under the

strongly coordinating solvent conditions. Subsequent reaction of this intermediate with

triisopropylborate gave the (E)-vinyl boronic acid 124. (Z)-Tamoxifen 126 was generated

by Suzuki-Miyaura cross-coupling of 124 with the aryl iodide 125 in 38 % overall yield.

Scheme 67. Stereoselective Synthesis of (Z)-Tamoxifen.

PhPh

122

EtLi, THF

-10 °C, 2 h Ph

Li

Ph

(Z)-123

Ph

Ph

Li

(E)-123

1. B(Oi-Pr)3

2. HCl (aq.)52 %

Ph

Ph

B(OH)2

I

N

Pd(PPh3)4, Na2CO3

DME/H2O73 %

Ph

Ph

124N

126

125

Although simple alkyl groups on alkynes are prone to deprotonation, it has been

reported that carbolithiation of such alkynes is possible when the addition is accelerated

through intramolecular reaction[116]

or by a heteroatom directing group such as an alkoxy

85

or amino group on alkynes.[117]

Interestingly, as depicted in the Scheme 68, alkyl- and

aryllithium compounds underwent sterero- and regioselective carbolithiation reactions with

alkynes 127 having no heteroatoms under iron or iron-copper catalysis.[118]

Scheme 68. Iron-Catalyzed Alkyllithium of Alkynes followed by Methanolysis.

R3R2

R1 LiFeCl3 (5 mol %)TMEDA (20 mol %)PPh3 (10 mol %)

(Zn (20 mol %))Et2O, -20 °C

R2

LiR1

R3 R2

R3R1

Li R2

HR1

R3 R2

R3R1

H

MeOH

127 (E)-128 (Z)-128

R1 = Bu, R2 = Bu, R3 = 3-CF3C6H4, 82 %

R1 = Bu, R2 = Bu, R3 = 2-MeOC6H4, 82 %

R1 = Bu, R2 = Hex, R3 = Ph, 79 %, 93:7

R1 = Bu, R2 = i-Bu, R3 = Ph, 82 %, 94:6

R1 = i-Bu, R2 = Me, R3 = Ph, 72 %, > 99:1

1.4.1.3 Intramolecular Carbolithiation Reactions

The intramolecular carbolithiation of lithium carbanions onto multiple bonds is an

efficient method for the construction of carbocycles. These reactions usually proceed

rapidly only for the formation of five-membered rings.

In the field of diastereoselective intramolecular carbolithiations, a stereogenic center,

already present in the vicinity of the double bond, can induce a facial choice. For instance,

the epimerizable tertiary benzyllithium 130 of Scheme 69, underwent a 5-exo-trig

cyclisation under the influence of the neighboring chiral lithium alkoxide to give four

isomeric cyclopentanes 131 in a ratio of 82:8:7.5:2.5 in 90 % yield.[119]

Scheme 69. Synthesis of Optically Active Arylcyclopentanes by Carbocyclisation of

Alkenylbenzyllithiums Involving Diastereofacial Differentiation.

MeSePh OH

1. MeLi, LiBr

2. t-BuLi, Et2O

PhLi OLi

-20 °C, 1 h

H3O+

PhOH

131 (major isomer)129 130

86

It is also possible to start with an enantiomerically enriched secondary lithium

derivative, if cyclisation is fast enough, as compared to epimerization. An interesting

enantioselective cyclocarbolithiation has been disclosed by Hoppe et al., starting from the

carbamate 132 derived from indene (Scheme 70).[120]

Enantioselective deprotonation led to

two lithiodiastereoisomers (R,S)-132Li.()-89 and (S,S)-132Li.()-89. A kinetic resolution

takes place since the syn carbolithiation from (R,S)-132Li.()-89 maintains the carbamate

group in a pseudoequatorial position, whereas for (S,S)-132Li.()-89, this group would be

forced in an endo position. As a result the tricyclic adduct ()-133 was formed in high

purity after hydrolysis, whereas (S,S)-132Li.()-89 returned the optically active starting

material (S)-(+)-132.

Scheme 70. Enantioselective Cyclocarbolithiation via ()-Sparteine-Mediated Lithiation

of a Racemic Carbamate and Kinetic Resolution.

OCb

()-132

s-BuLi, ()-sparteineEt2O, -78 °C, 20 h

OCb

(R,S)-132(-89

HLiOCb

(S,S)-132(-89

HLi

LiH

OCbH2O

H

OCb

()-133one diastereoisomeryield 24 %>98:2 e.r.

H2O(S)-(+)-132yield 48 %

()-133Li

The same concept has been applied to the corresponding alkyne allowing the

synthesis of substituted enantiopure cyclopentanoid building blocks.[121]

Hoppe et al.

extended this application to the synthesis of chiral protected 2-alkylidene-cyclohexane 135

(as a single diastereoisomer) and -cyclobutane-1,3-diols 137 by the lithiodestannylation

87

and unsual intramolecular anti-selective 4- or 6-exo-dig carbolithiations of -lithiated ω-

carbamoyloxy-1-alkynylcarbamates (Scheme 71).[122]

Scheme 71. Synthesis of 2-Alkylidene-cycloalkane-1,3-diols via Enantioselective

Intramolecular Carbolithiation.

CbO

OCb

SnBu3O

(1S, 5RS)-134d.r. = 50:50 97:3 e.r.

TBS

O

OO

Li

Ni-Pr2

O

Ni-Pr2O

TBS

Li

n-BuLi, LiClTHF, -100 °C20 min

OCbH

OCbTBSO

MeOH,-100 °Cto RT

trans-135, 37 %98:2 e.r.

CbO

O

(1S, 3RS)-136d.r. = 50:50 97:3 e.r.

TBS

OCb

SnBu31.n-BuLi, LiClTHF, -40 °C3 h

2. HOAc, -40 °C to RT

OCbTBSO

OCbH

OCbTBSO

OCbH

trans-137, 25 % cis-137, 25 %

d.r. = 50:50, each >97:3 e.r.

I.4.2 Intermolecular Carbolithiation Reactions of Vinyl Carbamates

Hoppe[123]

and Snieckus[75b]

have also shown that -aryl-O-vinylcarbamates 138 are

highly receptive substrates for -carbolithiation, presumably owing to a CIPE of the

carbamate donor (as seen in Section I.3.3) and stability of a benzyl anion against

polymerization (Scheme 72).

Scheme 72. Carbolithiation of -Aryl-O-Vinyl Carbamates.

ArR

H

O O

NR1

R2Li

diamine (L2) ArR

H

O O

NR1

LiL2

R2

Ar

O

O

R1N

LiL2

ArR1

CbO E

RH

EX

138, R1 = i-Pr, Et

R2

RH

138R2LiL2

139LiL2 140

88

O-Vinyl carbamates 138 underwent facile syn-carbolithiation by

alkyllithium/TMEDA and delivered configurationally stable lithiated benzyl carbamates

139LiL2, which have been trapped with different electrophiles to give the products 140.

Selected examples are displayed in Table 13 (entries 1-6 for ref 123 and entries 7-11 for ref

75a).

However, when the reaction was performed in the presence of chiral diamines, such

as ()-sparteine or ()--isosparteine, moderate enantiofacial differentiation was observed.

Table 13. Yields for the Carbolithiation of -Aryl-O-Vinyl Carbamates 138.

Entry Ar R R2Li EX Yield (%)

1 C6H5 H t-BuLi CO2 75

2 C6H5 H n-BuLi Me3SnCl 62

3 -naphthyl H i-PrLi MeOH 91

4 2-(MeO)C6H5 H t-BuLi MeOH 91

5 C6H5 C6H5 n-BuLi Me3SiCl 51

6 C6H5 C(CH3)3 n-BuLi MeOH 84

7 C6H5 H n-BuLi Br 64

8 C6H5 H n-BuLi PhCH2Br 66

9 C6H5 H s-BuLi MeOD 96

10 C6H5 H t-BuLi EtI 71

11 (3-Et2NOC)C6H4 H t-BuLi MeI 50

In an other hand, Coudert et al. reported a carbolithiation approach on seven-

membered ring N-vinyl carbamate 141 to give the compounds 142 in high yields (Scheme

73).[124]

Scheme 73. Carbolithiation of Cyclic N-Vinyl Carbamate.

N Ph

Boc

RLi, THF

-78 °C to 0 °C NPh

Boc

R

LiH2O

N Ph

Boc

R

141 142

R = Me, 87 %R = n-Bu, 83 %R = s-Bu, 88 %

R = t-Bu, 84 %R= Ph, 95 %

142Li

89

Later, they explored the scope of this method to develop an efficient synthesis of

precursors of -amino acids 144 involving a carbolithiation reaction of acyclic N-vinyl

carbamates 143 followed by a spontaneous internal N to C alkyloxycarbonyl migration

(Scheme 74).[125]

Scheme 74. Carbolithiation of Acyclic N-Vinyl Carbamates.

Ar1

N Ar2

1. RLi, -78 °C to 0 °C

2. H2O, NH4Cl

143

Ar1

NH

CO2t-Bu

Ar2

R

Ot-BuO

144

PhNH

CO2t-Bu

N i-Pri-Pr

89 %

NH

CO2t-Bu

n-Bu

O

3-MeOC6H4

14 %

PhNH

CO2t-Bu

Ph

78 %

NH

CO2t-Bu

Me

2-MeC6H4

80 %

NH

CO2t-Bu

Me

3-MeOC6H4

56 %


Very recently, Clayden et al. applied this attractive method to vinyl ureas in order to

initiate N to C aryl transfer.[126]

I.4.3 Tandem β-Alkylation--Arylation of Amines by Carbolithiation and

Rearrangement of Vinyl Ureas

The Clayden group found that N-alkenyl ureas 145 exhibit umpolung reactivity,

undergoing addition of organolithiums to their nucleophilic β-carbons (Scheme 75). The

addition could be then coupled with N to C aryl transfer within the lithiated urea

intermediate to the rearranged products 146 in excellent yields. The products 146 were

converted to the amines 147, thus providing a valuable method for the construction of

multiply branched alkylamines.

90

Scheme 75. Umpolung Carbolithiation of Vinyl Ureas.

Ar2N N

O

Me Me

Ar1

-50 °C, 90 min

2. MeOH

R Lin-BuOH, 2.5 h

145

1. , THF

MeHN NR

O

Me

Ar1 Ar2

146

MeHNR

Ar1 Ar2

147

MeHN N

O

Me

Ph Ph

78 %

MeHN N

O

Me

Ph Ph

74 %

MeHN N

O

Me

Ph p-ClC6H4

72 %

MeHN NPh

O

Me

Ph p-FC6H5

78 %

MeHN N

O

Me

Tol Ph

75 %

MeHN N

O

Me

Tol Ph

96 %

O


Interestingly, β-carbolithiation and N to C aryl migration of (E)- and (Z)-alkenyl

ureas 148 turned out to be stereospecific[127]

at -40 °C either in THF or in toluene followed

by addition of DMPU to enforce the rearrangement after the carbolithiation was complete

(Scheme 76) to give 149 and epi-149 formed by syn-addition of R and Ar2. By simply

switching from the E to the Z form of vinyl ureas 148, both enantiomers of the tertiary

amines 150 could be prepared.

Scheme 76. Stereospecificity Reactions of (E)- and (Z)-Alkenyl Ureas.

Ar2N N

O

Me Me

Ar1 n-BuOH, 2.5 h

E-148

E

Ar2N N

O

Me Me

Ar1

Z-148

Z

1. RLi, THF,-40 °C (3-6 h)2. MeOH or

1. RLi, Tol,-40 °C, 1 h2. DMPU, 16 h3. MeOH

MeHN NMe

O

Me R

Ar2 Ar1

149, 54-85 %

MeHN NR

O

Me

Ar2 Ar1

epi-149, 44-75 %

Me

Ar1 R

Me

Ar2MeHN

150, 66-75 %

Ar1R

Me

Ar2MeHN

epi-150, 67-70 %

Ar1 = C6H5, p-ClC6H4, p-FC6H4, pMeC6H4, p-MeOC6H4

Ar2 = C6H5, p-MeOC6H4, m-MeOC6H4

R = i-Pr, n-Bu, t-Bu

91

I.5 Aims of the project

As discussed in Section I.2 and I.3.3, we have uncovered a unnoticed facet of the

reactivity of organolithiums stabilized by N-arylcarbamoyl groups, namely their tendency

to undergo migration of the N-aryl ring to the carbanion centre in what amounts to an

intramolecular nucleophilic substitution on an electron-rich aromatic ring.[56,64,65]

In the

case of N-aryl-O-benzylic carbamates, lithiation at the benzylic carbon induces a

stereochemically invertive intramolecular N to C aryl transfer, and provides a route to -

arylated tertiary alcohols in enantiomerically enriched form.[55]

Tertiary diarylated alcohol 97i is an intermediate in the synthesis of clemastine 98

(Scheme 77). Clemastine is a selective H1 antagonist with anticholinergic and sedative

effects. The synthesis of all four possible stereoisomers of clemastine was reported by

Ebnöther and Weber in 1976 (see Section II.1.1.1).[128]

The most active isomer was

identified as the (+)-(R,R)-isomer, with the stereochemistry of the quaternary center to

oxygen determining activity to a greater extent than the center in the pyrrolidine ring.

Published routes to clemastine all employ resolution,[129]

and no asymmetric synthesis of

clemastine has been described, although a synthesis of ()-hydroxyclemastine was reported

in 2007 (See Section II.1.3).[130]

Therefore, it was the first aim of the project to accomplish

the first enantioselective synthesis of clemastine as its (S,S)-enantiomer as an application

of this rearrangement. The strategy consists of the coupling of enantiomerically pure

chloroethylpyrrolidine (S)-151 derived from commercially available (S)-proline and the

enantiomerically enriched tertiary alcohol (S)-97i arising from invertive N to C aryl

migration in a lithiated carbamate.

Scheme 77. Retrosynthesis of (S,S)-clemastine.

N O

MeMe

Cl

s s

N

Me

s

Cl HOMe

Cl

s

(S,S)-clemastine 98 (S)-151 (S)-97i

92

As described in Section I.3.4 and I.3.5, the lithiated allylic and propargylic

carbamates 99 and 106 have proved their worth in stereoselective synthesis where the

organolithium is trapped by an electrophile such as a carbonyl compound or alkylating

agent (Figure 4).

Figure 4. Lithiated Allyl- and alkynylcarbamates.

Me LiR

O

NiPr2

O

N

NLi

Me

O

NiPr2

O

N

N

99LiTMEDA 106LiTMEDA

However, there are currently no methods allowing the stereoselective arylation of

lithiated allyl or propargyl carbamates. These particular nucleophiles have the potential to

react in the same manner as a benzylic organolithium species ( to the oxygen). The

second aim of the project was therefore to explore the potential of aryl migration within

these lithiated carbamates as a means to achieve this aim and thereby showing that these

arylation reactions are not confined in scope to benzyllithiums. Moreover, these substrates

are of value because the resulting alcohol products may be oxidized through to hydroxyl

acid derivatives.

One of the challenges to the extension of this mechanistically remarkable method

into a more general synthesis of hindered and/or electron rich alcohols is the fact that the

deprotonation step needed to generate the intermediate benzyllithium is relatively slow.

However, Hoppe[123]

and Snieckus[75b]

have shown that -aryl-O-alkenylcarbamates are

receptive substrates for -carbolithiation (see Section I.4.2), presumably owing to a

complex induced proximity effect arising from coordination of the organolithium to the

carbamate donor (see Section I.3.1), and the stability of benzylic anion preventing

polymerization. Judging that the carbolithiation would require some degree of stabilization

of the product anion, -aryl, alkynyl, alkenyl, and silyl-O-vinylcarbamates were prepared

93

as substrates (Scheme 78). Such a reaction would provide a remarkable connective route to

tertiary alcohols involving two new C-C bond-forming reactions in a single pot.

Scheme 78. Umpolung Carbolithiation of Vinyl Carbamates.

XR

H

O O

NR Ar1

O Li

ON

R1

R

Ar1

R

X

O Ar1

OHN

R1

R

carbolithiation

aryl migrationR1 Li R

X

X = aryl, alkynyl, alkenyl, silyl

Vinylic electrophiles cannot normally be coupled directly with organolithiums and

transmetallation is usually required to form new vinylic C-C bonds using

organolithiums.[131]

This methodology can therefore be used to provide a new approach to

the vinylation of organolithium nucleophiles that would permit the construction of

functionalised quaternary centres by vinylation of tertiary carbanions (Scheme 79).

Scheme 79. Intramolecular Vinylation of Lithiated Carbamates.

N O

Me

O Me

MeHN O

O Me

RR

vinylmigration

94

CChhaapptteerr IIII :: RREESSUULLTTSS AANNDD DDIISSCCUUSSSSIIOONN

II.1 Synthesis of Clemastine, an Antihistaminic Agent

II.1.1 Total Synthesis and Absolute Configuration of Clemastine via

Resolution

II.1.1.1 Ebnöther and Weber’s Pioneer Work on the Synthesis of (R,R)-Clemastine

The total synthesis of clemastine 98 by an optical resolution method was pioneered in

1976 by Ebnöther et al. and was followed by the determination of its absolute

configuration.[128]

Clemastine was prepared by coupling of 2-(2-chloroethyl)-1-

methylpyrrolidine 151 with -methyl-p-chlorobenzyl alcohol 97i to give an isomeric

mixture of 98 and 152. The minor structural isomer 152 is likely to be a result of an initial

intramolecular cyclisation within the pyrrolidine moiety followed by the nucleophilic ring

opening by the corresponding alcohol 97i. The corresponding diastereoisomers of 98 were

separated as hydrogenfumarate salts, and the corresponding enantiomers were resolved as

hydrogenmaleinate salts by crystallisation (Scheme 81).

Scheme 81. Ebnöther and Weber’s Synthesis of Clemastine.

NaNH2

xylene, 100 °C,16 h

Major (86 %)

Minor (14 %)

97i151

98

152

N O

MeMe

Cl

N

Me

Cl HOMe

Cl

OMe

Cl

NMe

95

The absolute configuration of clemastine has been determined by X-ray-

crystallography and also by acid catalysed hydrolysis of products 98 and 152 as illustrated

below (Scheme 82).

Scheme 82. Acid Catalysed Hydrolysis of 98 and 152.

97i 15498

152

N O

MeMe

Cl

N

Me

OHHOMe

Cl

OMe

Cl

NMe

153Cl

H+

H2O

H+

H2O

97i

HOMe

Cl153

Cl

NMe

OH

155

The ether-linkage hydrolysis of each product afforded the tertiary alcohol 97i, alkene

fragment 153, primary and secondary alcohols (154 and 155), from which the absolute

configuration of clemastine was confirmed.

II.1.1.2 Synthesis of Optically Active (R)-2-(2-Chloroethyl)-1-Methylpyrrolidine, an

Intermediate in the Synthesis of Clemastine via Resolution

Nikiforov et al. developed a new approach to synthesise the chiral pyrrolidine

fragment 151 via resolution in 1990 (Scheme 83).[129b]

96

Scheme 83. Synthesis of (R)-2-(2-Chloroethyl)-1-methylpyrrolidine 151 via Resolution.

N S

Me

N S

Me

COOCH2Ph

Br

N

Me

COOCH2Ph

N

Me

COOCH2Ph

N

Me

COOCH2PhH

N

Me

H

OHN

Me

H

Cl

BrCH2COOCH2C6H5

CH3CN

Ph3P, NEt3

CH2Cl2

96 %

NaCNBH3

MeOH

di-p-toluoyl-D-tartaric acid

EtOH

67 %

LiAlH4SOCl2

(R)-151

156 157

158 159

(R)-160 (R)-154

The synthesis began with the coupling of 1-methyl-2-thiopyrrolidinone 156 and

benzyl bromo acetate to yield the corresponding salt 157. This was followed by a sulfide

contraction reaction in the presence of triphenylphosphine and triethylamine to give the

enaminoester 158 in 96 %. The resulting product 158 was then reduced using sodium

cyanoborohydride in acidic conditions to yield the compound 159. The resolution was then

performed using di-p-toluoyl-D-tartaric acid. Several chiral acids such as tartaric, mandelic

and di-benzoyl-tartaric acids have also been investigated as alternatives but resolution

could not be achieved. The resolution involves the formation of the corresponding

diastereoisomeric salts. The diastereoisomeric salt of compound (R)-160 crystallised

selectively from 70 % ethanol and was then basified using conc. ammonia solution. The

reduction to a primary alcohol (R)-154 was carried out using lithium aluminium hydride

followed by the conversion to the chloride derivative (R)-151 to complete the synthesis.

Although this synthetic route is chemically appealing in a sense that the resolution

reagents are reusable, it suffers from the relative large number of steps. In addition, the

use of a resolution method has limited the maximum yield of the corresponding step to

50 % and results in poor overall yield.

97

II.1.2 Stereoselective Synthesis of ()-Hydroxyclemastine

Hydroxyclemastine was targeted as a versatile analogue of clemastine with H1

receptor antagonist activity.

Recently, the synthesis of ()-hydroxyclemastine 168 outlined in Scheme 84 was

achieved from the chiral auxiliary 162 via the chelation-controlled diastereoselective 1,2-

addition reaction to build the challenging quaternary centre to the oxygen, following by

O-alkylation with (R)-2-(2-chloroethyl)-1-methylpyrrolidine 151.

Scheme 84. Synthetic Route to ()-Hydroxyclemastine 168.

H

O

OO

MgBrMeO

CuI, THF/Me2S80 %

syn 99 % OMe

OH

OO

Br

NaH, DME83 %

162163

OMe

O

OO

164

O3, MeOH

CH2Cl284 %

OMe

O

OO

165

O

Ph2Zn, CH2Cl2

4-Cl-PhMgCl

87 %, 90 % d.e.

OMe

O

OO

166

PhOH

Cl

NCl2.

1. NaH, xylene

OMe

O

OO

167

O

Ph

Cl

N

Me

H CAN

aq. HCl, CH3CN45 %

HO

168

O

Ph

Cl

N

Me

H

(R)-151 Me

98

The organocopper compound, prepared from 4-methoxyphenylmagnesium bromide

and CuI in THF/Me2S, reacted with the aldehyde 162 highly stereoselectively ( 99 %)

affording syn-addition product 163 in an excellent yield of 80 %.[132]

Then, the auxiliary

163 underwent an O-alkylation with 3-bromo-2-phenylpropene in 83 % yield, followed by

ozonolysis of the alkene obtained to give the ketone 165 in 84 % yield. The key step

involves the coordination of 165 with Ph2Zn in CH2Cl2, followed by addition of 4-

chlorophenyl magnesium bromide to produce the alcohol 166 with 90 % d.e. in 87 %

yield.[133]

As previously described, the skeleton was obtained from O-alkylation of 166

with (R)-2-(2-chloroethyl)-1-methylpyrrolidine (R)-151 in 78 % yield. Finally,

deprotection of chiral auxiliary in 167 with ceric ammonium nitrate gave the desired ()-

hydroxyclemastine 168 in 45 % yield. Thus, the chiral auxiliary plays a dual role as a

chiral inducer as well as a protecting group.

Since no asymmetric synthesis of clemastine has been reported, we envisaged to

explore the potential of the rearrangement to achieve this goal.

II.1.3 Novel Asymmetric Synthesis of ()-(S,S)-Clemastine

II.1.3.1 Retrosynthesis of (S,S)-Clemastine

As revealed from the retrosynthesis (Scheme 85), clemastine 98 could be generated

by the coupling of enantiomerically pure chloropyrrolidine (S)-151 and enantiomerically

enriched tertiary alcohol (S)-97i, the key intermediate arising from the invertive N to C

aryl migration in the lithiated carbamate 95i.

The commercially available ()-(S)-N-Cbz-proline 169, as a source for one of two

chiral centres would give access to the compound (S)-174 by an Arndt-Eistert

homologation, followed by reduction of the ester (S)-174 to give alcohol (S)-175, which in

turn would be converted into chloro derivative (S)-151.

99

Scheme 85. Retrosynthesis of (S,S)-Clemastine.

N

Me

OMe

Cl

s s

N Cl

Me

s

N OMe

Cbz

sO

N CO2H

Cbz

s

HOMe

Cl

ss

MeN O

Me

Cl

O

s

Me

Cl

HO

Invertive arylmigration

Arndt-Eistert

(S,S)-clemastine 98

(S)-151

(S)-97i

(S)-169(S)-174

(S)-95i

(S)-183a

II.1.3.2 Synthesis of Pyrrolidine Fragments

II.1.3.2.1 Synthesis of the Chloroethylpyrrolidine Fragment (S)-151HCl

Construction of the fragment (S)-151 began with ()-(S)-Cbz-proline (S)-169, which

was commercially available in 99 % e.e. (Scheme 86). One-carbon homologation of (S)-

169 was achieved via the Arndt-Eistert protocol.[134]

The first step involved the formation

of acyl chloride (S)-170 with oxalyl chloride plus catalytic DMF in CH2Cl2 at 0 °C for 2 h,

which subsequently reacted with trimethylsilyldiazomethane (TMSCHN2) in the presence

of triethylamine in THF-CH3CN at 0 °C for 5 h following by an aqueous work-up to give

-diazoketone (S)-171 in 80 % yield. A small amount of (S)-172 was isolated which is the

result of the nucleophilic attack by HCl just produced on -diazoketone as observed by

Shioiri et al.[135]

. In place of the hazardous diazomethane, stable and safe TMSCHN2 was

employed.

100

Scheme 86. Synthesis of -Diazoketone (S)-171 by the Arndt-Eistert Reaction.

N COOH

Cbz

(COCl)2, DMF, CH2Cl2

0 °C, 2 hN

Cbz O

ClN

Cbz O

N2

TMSCHN2, NEt3THF/CH3CN

0 °C, 5 hN

Cbz O

(S)-169 (S)-172(S)-171, 80 %(S)-170

Cl

The key step of the Arndt-Eistert homologation is the Wolff rearrangement of

diazoketone (S)-171 to give ketene (S)-173, which was accomplished by silver(I) catalysis

(Scheme 87).[136]

The reaction was conducted in the presence of methanol as a nucleophile

to capture the ketene intermediate (S)-173 and returned the chain-extented methyl ester (S)-

174[137]

in 78 % yield. The Wolff rearrangement of the diazo-ketone was proved to proceed

with retention of configuration by [α]D values.[135]

Scheme 87. Synthesis of Ester (S)-174 by the Wolff Rearrangement.

N

Cbz O

N2

(S)-171

N

Cbz

CO

HN

Cbz

O

OMeAgObz MeOH

NEt3

(S)-174, 78 %(S)-173

RT, 3 h

Lithium aluminium hydride in THF at 45 °C reduced both the ester and the

carbamate protecting group,[138]

giving the hydroxyethylpyrrolidine derivative (S)-175[139]

in 60 % yield (Scheme 88). The alcohol was converted to the chloroethylpyrrolidine

coupling partner with thionyl chloride in chloroform at 60 °C for 2 h,[140]

which returned

the amine hydrochloride (S)-151•HCl[141]

in 92 % yield.

Scheme 88. Completion of the Synthesis of Chloroethylpyrrolidine Fragment (S)-151•HCl.

N OMe

Cbz

O

N OH

Me

N Cl

Me

·HCl

LiAlH4, THF

45 °C, 45 min

(S)-175, 60 %

SOCl2, CHCl3

60 °C, 2h

(S)-151HCl, 92 %(S)-174

http://www.organic-chemistry.org/namedreactions/wolff-rearrangement.shtm

101

II.1.3.2.2 Toward the Synthesis of Chloroethylpyrrolidine Fragment (R)-151•HCl

An analogous strategy could be employed for making the (R)-isomer from (+)-D-

proline. However, although the synthetic route is relatively short and attractive, (+)-D-

proline, a non-natural product is an expensive starting material and therefore not suitable

for large-scale synthesis.

Therefore, (R)-151•HCl was made previously within the group by an alternative

method. Starting with inexpensive starting material N-Boc pyrrolidine 176, which was

lithiated with sec-BuLi in the presence of ()-sparteine. The resulting complex was

quenched with dry CO2[142]

to yield N-Boc-(R)-proline (R)-177 in 55 % yield and 99:1 e.r.

after crystallisation (Scheme 89). Due to the incompatibility of the Boc group with the

conditions used for diazoketone formation, a protecting group swap was necessary, which

was achieved using 2 M HCl followed by addition of benzyl chloroformate.[143]

The

product (R)-169 was taken through the same series of transformations to yield (R)-151•HCl.

Scheme 89. Preparation of Chloroethylpyrrolidine Fragment (R)-151•HCl.

N

Boc

N

Boc

CO2H N

Cbz

CO2H

1. s-BuLi/89, Et2O

2. CO2

1. HCl (2 M),Et2O, , 2 h

2. ClCO2Bn,NaOH

(R)-177, 55 % (R)-169, 77 %

(R)-151HCl

176

A small amount of (S)-151•HCl was converted to its free base 151 by elution through

an SCX cartridge.[144]

However, we found that prolonged storage of 151 either neat or in

solution led to the formation of significant quantities of the bicyclic ammonium salt

178+

•Cl- (Scheme 90). The same cyclisation was observed in good yield on attempted

purification of 151 by distillation.[140a]

Cyclisation to 178+

•TsO- was likewise observed on attempted formation of the

tosylate derivative of 175. In general therefore we chose to store and use 151 as its stable

hydrochloride salt.

102

Scheme 90. Intramolecular Cyclisation of 151 and 175.

N

Me

Cldistillation

N

Me

X N

Me

OH

TsCl, py, DMAP

151178+

175

X = Cl- X = TsO-

In view of this instability, an alternative coupling partner lacking a basic nitrogen

atom, the Cbz-protected iodide 180 was made. This compound would avoid the unwanted

azepane ring formation and consequently the formation of the side product 152 observed in

the final O-alkylation reaction (Scheme 81). Moreover, the iodo group would favour the

SN2 substitution.

II.1.3.2.3 Synthesis of Cbz-Protected Iodoethylpyrrolidine Fragment (S)-180.

Selective reduction of (S)-174 with lithium borohydride in THF at room temperature

for 96 h gave the alcohol (S)-179 in 80 % yield (Scheme 91).[145]

Scheme 91. Synthesis of Alcohol (S)-179 by Reduction of the Ester Group.

N

Cbz

O

OMe

(S)-174

N

Cbz

OHLiBH4, THF

96 h, RT

(S)-179, 80 %

Finally, the combination of triphenylphosphine, imidazole and iodine was employed

to convert the alcohol (S)-179 into iodide derivative (S)-180 (Scheme 92). Subsequent

optimisation led to (S)-180 in 74 % yield (Table 14).

Scheme 92. Conversion of Alcohol (S)-179 into its Corresponding Iodide (S)-180.

N

Cbz

OH

(S)-179

N

Cbz

I

(S)-180

(Table 14)

PPh3, Imidazole,I2, solvent, T(°C)

103

Firstly, the conditions used commonly within the group (Table 14, entry 1) gave (S)-

180 in low yield (27 %). Treatment with the portion-wise addition of iodine at 0 °C until a

yellow colour persisted and only 2 equiv. of imidazole (entry 2) gave (S)-180 in an

increased yield of 48 %. Finally, the yield was improved greatly to 74 % when the reaction

time and the amount of PPh3 and imidazole were decreased and the reaction was carried

out in a mixture of Et2O and CH3CN (entry 3).

Table 14. Optimal Reaction Conditions.

Entry PPh3

(equiv.)

Imidazole

(equiv.) I2 Solvent T (°C) t (h)

Yield

(%)

1 2 4 4 equiv. THF/CH3CN RT 21 27

2 2 2 elemental THF/CH3CN 0 5 48

3 1.75 1.85 elemental Et2O/CH3CN 0 1 74

II.1.3.3 Synthesis of Tertiary Alcohol by Aryl Migration of a Lithiated carbamate

The tertiary alcohol (S)-97i was made from p-chloroacetophenone 181a, which was

reduced by the method of Noyori[146]

using formic acid in the presence of the ruthenium

complex (S,S)-182 to provide the alcohol (S)-183a[52]

in 91% yield and 99:1 e.r. (Scheme

93). This alcohol was converted to its carbamate derivative (S)-95i by reaction with phenyl

isocyanate in CH2Cl2 at room temperature for 15 h and methylation with sodium hydride

and methyl iodide in DMF at room temperature for 15 h in 74 % yield over 2 steps.

A previous optimisation within the group[55]

has shown that the stereospecificity of

the aryl migration in the lithiated carbamate (S)-95i is maximal if the reaction is carried out

with LDA at -78 °C, followed by slowly warming to -35 °C and quenching with MeOH

after 24 h. Accordingly, the rearranged product (S)-96i was formed in moderate yield with

84:16 e.r.. We have previously noted that the lithium-coordinating cosolvent DMPU

markedly increases the reactivity of hindered organolithiums towards nucleophilic attack

on arenes,[61]

probably by favouring the formation of solvent-separated ions pairs.[147]

Indeed, addition of DMPU to the reaction gave considerably higher yield (90 %), but

returned racemic product.

Alcoholysis of the carbamate product 96i was achieved by heating to reflux with

sodium ethoxide in ethanol for 2 h, which gave alcohol (S)-97i in 87 % yield. The

stereochemistry of the product was confirmed as (S) by comparison with literature data.[52]

104

Scheme 93. Synthesis of Tertiary Alcohol (S)-97i.

(S,S)-182 cat. HCO2H-NEt3

91%, 99:1 e.r.

1. PhNCO, NEt3, CH2Cl2,RT, 15 h

2. NaH, DMF0 °C, 30 minMeI, RT, 15 h

74 % over 2 steps, >99:1 e.r.

RT, 48 h

NH2

Ru

NPh

Ph

Ts

Cl

(S,S)-182 cat.

(S)-95i(S)-183a

1. LDA (2.5 eq.), Et2O,-78 °C-35 °C, 24 h

2. MeOH

(S)-96i, 51 %, 84:16 e.r.

NaOEt, EtOH,, 2 h

HOMe

Cl

(S)-97i, 87 %, 84:16 e.r.

Inversion of configuration

181a

N O

Me

O

Cl

Me

MeHN O

O

Me

Cl

[]D29 = +5.3 (c 0.9, CHCl3)

[lit.52 +14.8 (c 6.5, CHCl3)]

HO

Cl

Me

O

Cl

Me

II.1.3.4 Further Evidence for Stereochemically Invertive Rearrangement for

Carbamates

For the purpose of stereochemical confirmation, further rearrangement substrates (R)-

95e, (S)-95m, (S)-95n and (R)-95o (Scheme 94) were made in a similar way as (S)-95i

(Scheme 94). The chiral secondary alcohols (S)-183b and (S)-183c were prepared by

Noyori’s asymmetric reduction[146]

of the corresponding ketones 181b and 181c in 78 %

and 94 % yield with 99:1 e.r. and 97:3 e.r., respectively and subsequently converted into

the required carbamates (S)-95m and (S)-95n (Scheme 94).

Scheme 94. Preparation of enantiopure carbamates (R)-95e, (S)-95m, (S)-95n and (R)-

95o.

(S,S)-182 cat. HCO2H-NEt3

1. PhNCO, NEt3, CH2Cl2,RT, 15 h

2. NaH, DMF0 °C, 30 minMeI, RT, 15 h

RT, 48 h

(S)-183b, R1 = p-OMe,

78%, > 99:1 e.r.

(S)-183c, R1 = m-CF3,

94%, 97:3 e.r.

181b, R1 = p-OMe

181c, R1 = m-CF3

N O

Me

O Me

(R)-95e, R1 = H, R2 = p-OMe, 76 %

(S)-95m, R1 = p-OMe, R2 = H, 92 %

(S)-95n, R1 = m-CF3, R2 = H, 86 %

(R)-95o, R1 = H, R2 = m-CF3, 85 %

R1

R2

HO

Me

R1O

Me

R1

105

Under the standard lithiation conditions, LDA (2.5 equiv.) in a mixture of THF and

DMPU at -78 °C, (S)-95m failed to rearrange (Scheme 95; Table 15, entry 1). However,

the rearrangement was promoted by warming the reaction to -40 °C to give the rearranged

product 96e in low yield as a racemate (entry 2). An attempt to make the arylated

carbamate product enantioselectively, using the same successful conditions employed for

the carbamate bearing a choro group 95i, was unsuccessful (entry 3). In addition to the

starting material, only isolated products 184 and 183b resulting from nucleophilic attack

on the carbamate C=O group were identified by 1H NMR.

Scheme 95. Attempted Stereospecific Rearrangement of (S)-95m and (R)-95e.

N O

Me

O Me

R1

R2

MeHN O

O

Me

(S)-95m, R1 = p-OMe, R2 = H > 99:1 e.r.

(R)-95e, R1 = H, R2 = p-OMe, 99:1 e.r.

(Table 15)

96e

OMe

Table 15. Conditions and Yields for the Attempted Stereospecific Rearrangement of (S)-

95m and (R)-95e.

Entry S.M. Base Solvent Additive T(°C) t (h) Results

1 (S)-95m LDA THF DMPU -78 19 95m

2 (S)-95m LDA THF DMPU -78 to -40 24 96e, 19 %

3 (S)-95m LDA Et2O - -78 to -35 21 184 and 183b

4 (R)-95e s-BuLi THF DMPU -78 4 96e, 65

5 (R)-95e LDA Et2O - -78 to -35 17 -

6 (R)-95e s-BuLi Et2O - -78 to -35 24 -

NHHO

Me

OMe184 183bMe

Introduction of a p-methoxy group on the aryl group presumably leads to a decrease

in kinetic acidity of the proton adjacent to oxygen. The next attempt was therefore to

interchange the two aryl rings. The carbamate (R)-95e now rearranged successfully on

106

treatment with sec-BuLi (2.5 equiv.) in a mixture of THF and DMPU at -78 °C (Table 15,

entry 4). However, when this carbamate was subjected to lithiation, under the conditions

developed to avoid racemization, it failed to rearrange or only traces of rearranged product

96e were observed (entries 5 and 6). Indeed, the arylation involves nucleophilic attack of

the organolithium centre on the N-aryl ring, and given the nucleophilicity of the p-methoxy

aryl group it is not surprising that the rearrangement of (R)-95e was sluggish without

DMPU and THF.

We therefore turned our attention towards investigating the stereospecific aryl

migration in lithiated carbamate (S)-95n (Scheme 96).

Scheme 96. Attempted Stereospecific Rearrangement of (S)-95n.

(S)-95n, 97:3 e.r.

N O

Me

O Me

MeHN O

O

Me

CF3CF3

(Table 16)

96n

Table 16. Conditions and Yields for the Attempted Stereospecific Rearrangement of (S)-

95n.

Entry Base Solvent Additive T (°C) t (h) 96n, Yield (%) e.r.

1 LDA THF DMPU -78 4 81 50:50

2 LDA Et2O - -78 22 60 43:57

3a LDA Et2O - -78→-35 2 - -

4 LDA Et2O - -78→-35 18 64 45:55

Firstly, in order to ascertain that the rearrangement of (S)-95n occurs, the standard

lithiation conditions were used to yield the desired rearranged carbamate 96n in excellent

yield (Table 16, entry 1). Then, treatment of (S)-95n with LDA (2.5 equiv.) in Et2O at -

78 °C for 22 h allowed the rearranged product 96n to be isolated in a decreased yield of

60 %, due to the nucleophilic attack on the carbamate C=O group and with loss of

enantiomeric purity (entry 2). In order to make the rearrangement faster than the

a unintentional quench of the reaction : 95n and 96n (very low yield) = 76:24 e.r.

107

racemization of the organolithium intermediate, the temperature was raised to -35 °C

(entry 4). However, the stereochemistry was not retained.

Therefore, the rearrangement of (S)-95n competes poorly against racemization of the

organolithium intermediate, probably due to the strongly electron-withdrawing

trifluoromethyl group promoting delocalisation of the charge in the organolithium

intermediate.

As a note regarding the entry 3: a quench of the reaction occurred during the

monitoring. Nevertheless, the enantiomeric ratios of the starting material 95n and the

rearranged product 96n were determined and proved to be similar, which means that the

possibility of having a mixture of inversion and retention of configuration might be ruled

out.

The way to overcome the problem of racemization of the organolithium intermediate

would be to interchange the two aryl rings (Scheme 97).

Scheme 97. Stereospecific Rearrangement of (R)-95o.

85% over 2 steps, 98:2 e.r.

(R)-95o

N O

Me

O Me

MeHN O

O

Me

CF3(Table 17)F3C (R)

(S)-96n

Table 17. Conditions and Yields for the Stereospecific Rearrangement of (R)-95o.

Entry Base Solvent Additive T (°C) t (h) 96n, Yield (%) e.r.

1 LDA THF DMPU -78 6 46 52:48

2 LDA Et2O - -78→-35 22 - -

3 LiTMP Et2O - -78→-35 24 38 90:10

N

Li

LiTMP

N

Li

LDA

Empirical structures are shown without aggregation

108

When enantiomerically enriched carbamate (R)-95o was treated with LDA (2.5

equiv.) in THF/DMPU (Table 17, entry 1), a moderate yield of the rearranged carbamate

96n was obtained, and in essentially racemic form. Under the conditions for avoidance of

racemization, LDA in Et2O at -78 °C to -35 °C (entry 2), no sign of rearranged product 96n

was observed, only the starting material 95o and products arising from nucleophilic attack

on the carbamate C=O group were recovered. A change of the base to LiTMP (lithium

tetramethylpiperidine) led to the formation of the rearranged product 96n with a

considerable increased in enantioselectivity: 90:10 e.r and in moderate yield (entry 3).

The higher e.r. obtained with LiTMP[148]

is presumably a consequence of slower

lithiation coupled with higher configurational stability resulting from increased steric

bulk,[149]

and the electron deficient aryl ring migrates faster than the benzyllithium

intermediate racemises.

Deprotection of the rearranged carbamate 96n was achieved by refluxing with

sodium ethoxide in ethanol to yield the tertiary alcohol 97n in 75 % yield. Following

deprotection, the []D of the alcohol 97n was measured and gave a positive []D,

confirming after comparison with the literature,[52]

that the (S)-enantiomer of alcohol 97n

had been synthesised. This in turn confirmed that the (S)-rearranged carbamate 96n has

been formed and that the rearrangement proceeded with inversion of stereochemistry

(Scheme 98).

Scheme 98. Deprotection of (S)-96n.

(S)-96n, 38 %, 90:10 er

MeHN O

O

Me

CF3HO

Me

CF3(S) (S)NaOEt, EtOH,

, 3 h

(S)-97n, 75 %, 90:10 er

[]D31 = +19.2 (c 3.5, CHCl3)

[lit.52 +29.3 (c 5.5, CHCl3)]

109

II.1.3.5 Formation of the Ether Linkage and Isolation of Clemastine

II.1.3.5.1 Attempts at Formation of the Ether Linkage from Cbz-protected

Iodoethylpyrrolidine (S)-180

In an initial study, the coupling reaction via a Williamson ether reaction using

commercially available 1,1-diphenylethanol 185 was examined (Scheme 99).

Scheme 99. Coupling Reaction between (S)-180 and 1,1-Diphenylethanol 185.

N

Cbz

I

(S)-180

HO N

Cbz

OBase, Solvent

T(°C)

(S)-98185

Me Me

First of all, the conditions used by Ebnöther and Weber[128]

(Table 18, entry 1) turned

out to be unsuitable: the iodide derivative (S)-180 was prone to elimination leading to 186.

For nucleophilic substitution reactions, a wide range of solvents can be used but it should

be noted that apolar solvents tend to slow the reaction rate strongly. Therefore, the next

attempt was accomplished in a polar solvent, N-methyl-2-pyrrolidone (NMP) (entry 2), but

also resulted in the elimination product 186. Then, the use of a less basic base, KOH, was

tested in DMF and DMSO, affording the formate 187 and the elimination product 186

respectively (entries 3 and 4).

Table 18. Attempted Coupling Reaction with (S)-180.

Entry Base Solvent Temp (°C) t (h) Result

1 NaH Toluene 110 17

2 NaH NMP 100 13 186

3 KOH DMF 80 17 NCbz

O H

O

187

4 KOH DMSO 80 15 186

NCbz

186

110

Another strategy was attempted involving O-H insertion reaction of -diazo ketone

171 with tertiary alcohol 185 in the presence of indium triflate as a catalyst (Scheme

100).[140]

However, In(OTf)3 acted as an Lewis acid on the alcohol to give 189. The use of

milder Lewis acids such as ZnBr2, CuCl2 and FeCl3 led to similar results.

Scheme 100. Attempted O-H Insertion of Diazoketone 171 to Alcohol 185 Using Various

Lewis Acids.

N N2

OHO

Cbz

cat. Lewis acid

PhMe, RT

N

OCbz

O

(S)-171 185

189

188

Me Me

The last attempt was the formation of the hindered ether from the pyrrolidine

derivative 172 by using Ebnöther’s conditions (Scheme 101). Indeed, as shown by the

relative rates,[151]

the stabilization of the SN2 transition state with a carbonyl group is much

more effective than with a simple alkane or a benzene ring. However, after 16 h at reflux in

toluene in the presence of sodium hydride, 172 was returned.

Scheme 101. Attempted Coupling Reaction from 172.

Cl

O

ClMe Cl

Relative rate of SN2 reactions of alkyl

chlorides with the iodide ion

200200 100 000

N Cl

O

HO

Cbz

NaH,PhMe

110 °C, 16 hN

OCbz

O

(S)-172 185 188

Me Me

111

Since the coupling of the unstable chloroethylpyrrolidine 151 with a tertiary alcohol

is reported to lead to good yields,[128,130]

we decided to optimise this route.

II.1.3.5.2 Formation of the Ether Linkage from Chloroethylpyrrolidine (S)-151 and

Isolation of Clemastine

Enantiopure chloroethylpyrrolidine hydrochloride (S)-151HCl and enantiomerically

enriched tertiary alcohol (S)-97i (84:16 e.r.) were prepared for the challenging formation of

the hindered ether by deprotonating by free-basing (S)-151 with KOH[152]

(used

immediately) and deprotecting (S)-97i with sodium hydride (Scheme 102). Heating (S)-151

and the resulting sodium alkoxide of (S)-97i together at reflux in toluene for a period of 16

h returned a mixture of isomers: 15 % of the azepanes 190 and 48 % of the

diastereoisomers of 98.

Scheme 102. Formation of the Ether Linkage Resulting in the Synthesis of Clemastine as a

Diastereoisomeric Mixture.

PhMe, 110 °C,16 h

NCl

. HClMe

Converted to its free base form

N

Me

,NaH

Ph

Cl

ONa

98

190

N

Me

O

Cl

NO

Me

Cl

190, 15 %

Cl

HOMe

Cl

Me

s s

N

Me

O

Cl

Me

s R

48 % (ca 84:16)

(S,S)-98 (S,R)-98

(S)-151�HCl

(S)-97i

Me

[]D31 = -37.4 (c 2.04, EtOH)

[lit.128 []D20 = -33.7 for (S,S)-isomer and

-58.8 for (S,R)-isomer (c 2.00, EtOH)]

178+

112

The formation of 190 presumably arises through participation of the amine N in the

substitution to form 178+, followed by expansion of the resulting bicyclic cation. However,

as shown previously when N participation was discouraged by use of the Cbz-protected

iodopyrrolidine (S)-180 we observed no coupling of any sort, suggesting that participation

of the amine N is involved in the pathways to both products and that anchimeric assistance

to departure of Cl- is essential to the method.

The presumed ca. 84:16 mixture of diastereoisomers resulting from coupling

enantiopure (S)-151 with (S)-97i of 84:16 e.r. gave an []D of 37.4, confirming after

comparison with literature data ([α]D20

33.7 (c 2.00, EtOH) for (S,S)-isomer) [128]

that

(S,S)-clemastine has been synthesised as major isomer. The (S,S)-stereochemistry of the

product furthermore confirms the invertive nature of the rearrangement.

II.1.3.5.3 Isolation of Clemastine Fumarate

The mixture of diastereoisomers of 98 displayed a single set of peaks by 1H and

13C

NMR in both CDCl3 and CD3OH (Figure 5), and no separation into diastereoisomers was

observed by HPLC on a variety of chiral and achiral stationary phases. However, on

addition of 1 equiv. fumaric acid (Scheme 103), an 87:13 mixture of diastereoisomeric

fumarate salts 98H+

•fum- was evident by

1H NMR in CDCl3 for the set of peaks relating to

the -CH2 to the oxygen (Figure 6). This mixture was recrystallised to constant melting

point and []D, resulting in crystals which contained, by NMR, 10 % of the minor

diastereoisomer. The filtrate, by contrast, was a ca. 1:1.5 mixture of the two

diastereoisomers by 1H NMR (Figure 7).

Scheme 103. Isolation of Clemastine Fumarate 98H+

•fum-.

N

Me

O

Cl

Me

s s

N

Me

O

Cl

Me

s R

(S,S)-98

(S,R)-98

1. Fumaric acid, EtOH

2. Recrystallisation

N O

Cl

Me

s s

H Me

O2CCO2H

(S,S)-98H+fum-

113

Figure 5. 1H NMR and

13C NMR in CDCl3 of the Mixture of Diastereoisomers of

Clemastine 98.

N

Me

O

Cl

H H

MeN

Me

O

Cl

H H

Me

(S,S)-98 (S,R)-98

114

Figure 6. Sets of Peaks Assigned to –CH2 to the Oxygen of the Mixture of

Diastereoisomeric Fumarate Salts 98H+

•fum-.

Figure 7. Sets of Peaks Assigned to –CH2 to the Oxygen of Clemastine Fumarate

98H+

•fum- and the Filtrate after Recrystallisation.

After recrystallisation

crystalline powder of (S,S)-

clemastine fumarate

98H+

•fum-

powder remaining

in solution

115

The polarimetric and melting point data for the fumarate salts, and corresponding

literature values,[128]

are shown in Table 19. These are fully consistent with the hypothesis

that the initial coupling produces principally (S,S)-clemastine contamined with (S,R)-

clemastine, but that recrystallisation removes the minor diastereoisomer and returns a pure

sample of (S,S)-clemastine.

Table 19. Physical Data for Clemastine Fumarate 98H+

•fum-.

Compound m.p./°C m.p. (lit)/°C []D28c

[]D20

(lit.)c

(S,S)+(S,R)-98H+fum

- a 170-172

177-178 (S,S)

159-160 (S,R) 17.3

16.9 (S,S)

32.8 (S,R)

(S,S)-98H+fum

- b 176-177 177-178 17.1 16.9

Therefore, the first enantioselective synthesis of the antihistamine agent clemastine

98, as its (S,S)-stereoisomer, has been achieved by ether formation between a proline-

derived chloroethylpyrrolidine (S)-151 and an enantiomerically enriched tertiary alcohol

(S)-97i resulting from the carbamate (S)-95i by invertive aryl migration on lithiation. The

(S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement.

This is in contrast to the retentive rearrangement of ureas.

In situ IR spectroscopy and modelling work have been performed to establish the

origin of this stereodivergent behaviour.

aFumarate salt of this mixture, which

1H NMR indicates contains an 87:13

diastereoisomeric ratio; bRecrystallised fumarate salt with 10% minor diastereoisomer

by 1H NMR.

c c = 2.0 (MeOH).

116

II.2 Spectroscopic and Computational Studies of the Mechanism

II.2.1 In Situ IR Spectroscopy

The presence of the carbonyl group makes carbamates particulary suitable for

mechanistic studies by in situ IR spectroscopy.[62,153]

Recently, for example, O’Brien

showed that the course of the lithiation of N-Boc piperidine (νC=O = 1695 cm-1

) with sec-

BuLi/TMEDA, ()-sparteine or (+)-sparteine could be followed by in situ infrared

spectroscopy. They observed directly the “pre-lithiated complex” (νC=O = 1675 cm-1

)

between the substrate and lithiating agent in TBME at -78 °C and the lithiated complex

(νC=O = 1644 cm-1

).[153d]

The existence of a prelithiation complex had previously been

deduced by kinetic studies on a related compound.[154]

Beak also monitored the lithiation of

an N-Boc allylamine through in situ IR with n-BuLi/()-sparteine in toluene at -73 °C.[153b]

They observed a similar reaction pathway involving a “prelithiated complex” at 1675 cm-1

and a lithiated complex at 1640 cm-1

. They also showed that addition of n-BuLi to N-Boc

allylamine generated a stable carbamate-n-BuLi complex at 1675 cm-1

and upon addition

of ()-sparteine deprotonation occured as evidenced by the appearance of the peak at 1640

cm-1

.

Previous studies in this area, of the rearrangements of ureas, had failed to find

evidence of either a pre-lithiation complex or of the presence of the postulated

dearomatised intermediate 58 with a benzenoid ring migrating (see Section I.2.2).[62]

We

therefore undertook detailed studies of the rearrangement of 95i by in situ IR spectroscopy.

A mixture of 95i and THF in a three-necked flask equipped with a ReactIR probe was

cooled to -60 °C. Once the temperature has stabilized, spectroscopic analysis was

commenced at a rate of one scan every 30 s: 95i showed a C=O absorbance at 1698 cm-1

(Scheme 104; Figure 8). Treatment with sec-BuLi (1.1 equiv.) transformed this signal

directly into one at 1642 cm-1

and one at 1333 cm-1

arising from C-O and C-N stretches

within the lithio carbamate function of the rearranged product 96iLi and addition of MeOH

returned the rearranged carbamate 96i with a C=O stretch of 1735 cm-1

. A similar peak at

1646 cm-1

for the intermediate 96iLi was observed with LDA (1.5 equiv.).

117

Scheme 104. Intermediate Detected in the Rearrangement of 95i.

N O

Me

O Me

Cl

1. s-BuLi (1.1 equiv.),

95i

MeHN O

O

Cl

MeMeN O

OLi

Cl

Me

2. MeOH

THF,-60 °C 96i96iLi

1698 cm-1 1735 cm-1

1642 cm-1

+ 1333 cm-1

Figure 8. In situ React IR Monitoring the Rearrangement of Benzylcarbamate 95i in THF

with sec-BuLi at -60 °C. (a) Three-dimensional plot of absorbance versus wavenumber

versus time. (b) Several sequential two-dimensional infrared spectra at various stages of

the reaction.

Arylcarbamate

95i in THF

sec-BuLi added

Quenched 1698cm

-1: 95i

1735cm-1

: 96i 1642cm-1

: 96iLi

(a)

(b)

1333cm-1

: 96iLi

1642cm-1

: 96iLi

Arylcarbamate in THF

sec-BuLi added

Quenched

118

Evidence that the absorption at 1642 cm-1

assigned to the product anion 96iLi was

obtained by treating 96i with sec-BuLi in THF: the spectrum assigned to 96iLi reappeared

(Scheme 105; Figure 9).

Scheme 105. Intermediate Detected in the Retreatment of 96i.

s-BuLi (1.1 equiv.),

MeHN O

O

Cl

Me

96i

MeN O

OLi

Cl

Me

96iLi

THF,-60 °C

Figure 9. In situ React IR Monitoring the Retreatment of Rearranged Carbamate 96i in

THF with sec-BuLi at -60°C.

Rearranged

carbamate 96i

in THF

sec-BuLi

added

Quenched 1735cm

-1: 96i

1642cm-1

: 96iLi

119

In the absence of THF, the rearrangement was much slower. Treatment of 95i in

TBME at -60 °C with sec-BuLi (2.0 equiv.) gave transiently an absorbance at 1686 cm-1

,

which then gave way over a period of minutes to a band at 1649 cm-1

(Scheme 106; Figure

10). Quenching the reaction with MeOH regenerated starting material 95i, we therefore

assigned the absorbance at 1649 cm-1

to 95iLi, and proposed that the transient absorption

at 1686 cm-1

is the “prelithiated complex” 95i•RLi.

Scheme 106. Intermediates Detected in the Lithiation of 95i.

N O

Me

O Me

Cl


95i

N O

Me

O Me

Cl

LiR

N O

Me

O Li

Cl95iRLi 95iLi

TBME, -60 °C

R1698 cm-1 1649 cm-11686 cm-1

Figure 10. In situ React IR Monitoring the Lithiation of Benzylcarbamate 95i with sec-

BuLi in TBME at -60 °C.

Arylcarbamate

95i in TBME

Addition of

sec-BuLi

Quenched

1686cm-1

: 95i•RLi 1649cm-1

: 95iLi

1698cm-1

: 95i

120

When 95i was treated with sec-BuLi (2.0 equiv.) in toluene at -60 °C, only the absorbance

at 1686 cm-1

was formed, indicating that under these conditions, complexation may take

place, but not deprotonation (Scheme 107; Figure 11). After a reaction time of 30 min,

addition of TMEDA (1.0 equiv.) returned the starting material 95i, probably by

decomplexation of the species 95i•RLi.


N O

Me

O Me

Cl


PhMe,-60 °C

95i

N O

Me

O Me

Cl

LiR

95iRLi2. TMEDA

1698 cm-11686 cm-1

Figure 11. In situ React IR Monitoring the Lithiation of Benzylcarbamate 95i with sec-

BuLi in Toluene at -60 °C.

Arylcarbamate

95i in toluene

Addition of

sec-BuLi

TMEDA

added

1698cm-1

: 95i

1686cm-1

: 95i•RLi 1649cm

-1

121

A similar outcome was obtained using LDA (3.5 equiv.) in TBME at -60 °C

displaying a band at 1690 cm-1

. After stirring for 1 h, addition of CD3OD to the reaction

mixture resulted in the recovery of starting material 95i with no deuterium incorporation

(Scheme 108; Figure 12).


1698 cm-1

1690 cm-1

N O

Me

O Me

Cl95i

LDA (3.5 eq.),TBME, -60 °C

N O

Me

O Me

Cl

LiNN

Li iPr

iPrPri

Pri

S

95iRLi

Figure 12. In situ React IR Monitoring the Lithiation of Benzylcarbamate 95i with LDA in

TBME at -60 °C.

Arylcarbamate

95i in TBME LDA

added

Quenched

with CD3OD

1690cm-1

: 95i•RLi

122

Conversion of the solution of 95iLi formed from 95i with sec-BuLi in TBME to

96iLi was achieved by adding 4.0 equiv. of THF to the reaction mixture in order to

promote the rearrangement. Little change in the IR spectrum was observed, but adding

MeOH after 90 min generated a new peak at 1735 cm-1

corresponding to the rearranged

product 96i. The entire course of the reaction is illustrated in Scheme 109 and Figure 13a,

with the intermediates highlighted more clearly in Figure 13b, which shows a different

spectrum, subtracting the initial spectrum of 95i.

Scheme 109. Intermediates Detected in the Rearrangement of 95i.

N O

Me

O Me

Cl


95i

N O

Me

O Me

Cl

LiR

N O

Me

O Li

Cl

Me

95iRLi 95iLi

2. THF(4.0 equiv.)

MeHN O

O

Cl

Me

96i

MeN O

OLi

Cl

Me

96iLi

3. MeOH

TBME, -60 °C

R1698 cm-1 1649 cm-1

1686cm-1

1642cm-1

+ 1333 cm-1 1735 cm-1

Figure 13. In situ React IR Monitoring the Rearrangement of Benzylcarbamate 95i with

sec-BuLi in TBME at -60 °C Followed by Addition of THF.

Arylcarbamate

95i in TBME

sec-BuLi added

THF added

Quench with

MeOH

1698cm-1

: 95i

1735cm-1

: 96i

1649cm-1

: 96iLi

1686cm-1

: 95i•RLi

(a)

123

It is notable that νC=O for lithiated carbamate 95iLi and the product carbamate 96iLi

are very similar. However, the spectrum of 96iLi also showed a significant peak at 1333

cm-1

(Figure 8b) which is absent from the spectrum of 95iLi. As shown in Figure 13c,

indeed this peak grew progressively as time progressed allowing us to monitor the progress

of the rearrangement pathway. No other intermediates were observed along the reaction

pathway.

Arylcarbamate in TBME

2eq sBuLi added

2eq THF added

4eq THF added

1h30 after THF added

Quenched

(c) 1333 cm

-1 : 96iLi

1649cm-1: 96iLi 1686cm-1: 95i•RLi

1735cm-1: 96i

1698cm-1: 95i

(b)

124

II.2.2 Computational Studies

In order to understand the experimental observation of the 1,4-aryl transfer, Mark Vincent

and Ian Hillier at the University of Manchester have achieved some computational studies.

Appropriate models were constructed involving the benzylic carbamate 95a in its

metallated form 95aLi and the base LDA, with THF as solvent. The potential energy

surface for the reaction was obtained using electronic structure calculations employing

DFT. Properly characterised minima and transition structures (TS) were located at the

B3LYP/6-31G level, giving both vibrational frequencies and starting structures for

optimisation at the B3LYP/6-31++G** level. The model (Scheme 110) involves one

explicit LDA dimer coordinated to the carbonyl oxygen of the carbamate 95a•RLi (A).

They assume that deprotonation to 95aLi gives the reactant structure (B) in which the

carbanion has a solvated lithium ion bound to it.

Their strategy was to search for the transition structures, and to follow these back to the

reactants, and forward to the products.

They found three different reactant configurations, R2 leading to retention of configuration

and R3 and R4 leading to inversion, which were higher in energy than the lowest energy

reactant R1 (Scheme 110). In this latter structure (Fig. 14 (a)), the Li+ is clearly bound to

the carbanion centre (at a distance of 2.20 Å). In the three reactant configurations this

distance is increased considerably in order to free up the carbanion lone pair for

nucleophilic attack.

125

Scheme 110. Schematic Representation of the Structures Along the Computed Reaction

Pathways.

MeN O Me

O H

95aRLi (A) 95aLi (B)

Base

THF

LiR2N

NR2

Li

THF

MeN O Me

O Li

Base (THF)3

MeN O

O

Base

R1

MeN

Li

Me

O

O

(THF)3

Base

MeN O

Base

Li (THF)3

O

MeN O

BaseO

Li (THF)3

R2 R3 R4

MeN O

O

Me

Base

Li

(THF)3 P2 P4

TS2TS3 TS4

Rotation

Movement of

Li+(THF)x off C-

inversionretention inversion

MeN O

O

Me

Base

Li

Me

(THF)n

Me Me

(THF)n-Li

Both transition structures TS2 and TS3, leading to retention and inversion respectively

involve the interaction of the solvated Li+ species with the benzyl ring. Structure TS3

(Figure 14 (c)) differs from TS2 (Figure 14 (b)) in that the lithium ion is on the other side

of the phenyl group, and thus is unavailable for stabilising the developing charge on the

attacked ring. In structure TS3 the average distance of the Li to the benzyl ring is 3.32 Å,

while the length of the forming CC bond is 1.93 Å. This latter distance is shorter than in

126

transition structure (TS2) which leads to retention of stereochemistry. The transition

structure TS3 leads to inversion of stereochemistry (Figure 14 (c)) as the forming CC

bond is in the opposite direction to the original Li-carbanion bond. This is in contrast to

transition structure TS2 where the Li-phenyl interaction is in the same direction as the

original Li-carbanion bond and leads to retention of configuration.

In the third transition structure TS4 and corresponding reactant R4 (Figure 14 (d)) the

Li(THF)3+ is bonded to and in the plane of the carbamate group which requires a 1,2 shift

of the Li+. This Li

+ shift from the carbon to the in-plane oxygen lone pair requires

conformational changes in the minimum energy reactant structure so that the Li+ is now in

the plane of the carbamate and adjacent to the oxygen lone pair. We note that the other lone

pair on oxygen is not available, being conjugated with the carbonyl. This conformation has

the carbanion and the remote phenyl group neatly arranged for reaction. Indeed, the

carbanion is slightly pyramidal as is the phenyl carbon that is attacked and thus the bond

has started to form. This mechanism gives rise to inversion as moving the lithium into the

plane of the carbamate, prior to its transfer to the oxygen atom results in the Li-C bond

pointing away from the remote phenyl group.

Figure 14. Optimal structures along the reaction pathways. For clarity LDA has been

omitted.

(a) Lowest energy reactant (R1)

127

(b) Reactant (R2) and transition structure (TS2) leading to retention of stereochemistry

(c) Reactant (R3) and transition structure (TS3) leading to inversion of stereochemistry

128

(d) Reactant (R4) and transition structure (TS4) leading to inversion of stereochemistry

If we now consider the energetics of the three reactions, the transition structures for

retention (TS2), inversion via O (TS4) and inversion via phenyl (TS3), lie respectively 81,

62 and 71 kJ mol-1

, above the lowest energy reactant structure (R1) (Table 20). However,

the corresponding three reactant structures (R2, R3 and R4) are of considerable higher

energy than this lowest energy structure (R1) so that the barriers for reaction from these

structures are considerably lower, all being below 35 kJ mol-1

. Thus, the calculations

clearly predict that inversion via carbamate oxygen is the lowest energy route. However,

we note that the transition structure for inversion via benzyl ring is only 8 kJ mol-1

higher

in energy, so that inversion by both mechanisms is clearly feasible.

129

Table 20. Relative Energies (kJ mol-1

) of Stationary structures.

Stereochemistry Structure Free Energy

Lowest energy minimum R1 0.0

Retention (via Ph)

R2 81.5

TS2 81.3

P2 -66.0

Inversion (via O)

R4 45.7

TS4 62.4

P4 -67.7

Inversion (via Ph)

R3 36.0

TS3 70.7

P3 -48.3

They also determined the harmonic frequencies for the various minimum energy species

which the computations have identified along the reaction pathway of the benzyl

carbamate. In the neutral reactant, the C=O stretch is computed to occur at 1693 cm-1

, close

to the experimental band at 1698 cm-1

. The addition of base leads to a peak at 1686 cm-1

,

which correlates with the peak computed at 1672 cm-1

for structure A (Scheme 14),

corresponding to a “pre-lithiated complex” having the LDA dimer coordinated to the

carbonyl oxygen. The structure R1 is predicted to have strong peaks at 1638, 1642 and

1650 cm-1

, which are mixtures of C=O and C-H ring modes. Experimentally, a peak at

1646 cm-1

is seen to grow following the addition of LDA to the benzyl carbamate 95i

which we thus assume corresponds to the computed structure R1. For the product anion in

which the solvated THF is coordinated to the nitrogen atom of the carbamate, we predict

intense adsorptions at 1335 and 1652 cm-1

, values which are in excellent agreement with

the peaks observed experimentally at 1333 and 1642 cm-1

. After protonation of the anion,

the computed carbonyl stretch is 1745 cm-1

, close to the experimental value of 1735 cm-1

.

130

II.3 Arylation of Lithiated Carbamates by Intramolecular Aryl

N to C Aryl Migration: Scope, Stereoselectivity and Mechanism

II.3.1 N to C Aryl Migration in Lithiated N-aryl-O-Allylcarbamates

As mentioned in Section I.2.3, recent studies within the group have shown that N-allyl-

N’-aryl ureas may be lithiated to nitrogen and undergo a related rearrangement with

transfer of the aryl ring from N to the allylic carbon.[66]

We therefore considered the

possibility of extending the scope of the rearangement to lithiated N-aryl-O-allyl

carbamates.

II.3.1.1 Synthesis and Aryl Migration of a Cinnamyl Carbamate

In a preliminary experiment to assess the reactivity of lithiated N-aryl-O-

allylcarbamates towards rearrangement, the cinnamyl derivative 193 was made by standard

methods used within the group.[55]

The cinnamyl alcohol 191 was combined with phenyl

isocyanate, followed by methylation to give the desired carbamate 193 in 89 % yield over

two steps (Scheme 111).

Scheme 111. Synthesis of Cinnamyl Carbamate 193.

HO Ph

191

PhNCO,NEt3,CH2Cl2

RT, 15 hO Ph

192

NH

O1. NaH,DMF, 0 °C,30 min

2. MeI, RT,15 h

O Ph

193

N

O

Me

The rearrangement of 193 was then attempted under different conditions. Firstly, in

the presence of sec-BuLi in a mixture of THF and DMPU at -78 °C, a significant amount

of starting material remained and the cinnamyl alcohol 191 was recovered resulting from

nucleophilic attack on C=O after quenching the reaction mixture with MeOH. Under these

conditions, it appeared that sec-BuLi was acting as a nucleophile rather than lithiating at

the required centre. Addition of DMPU has been shown previously to accelerate related

rearrangements and cyclisations.[61]

131

Deprotonation of carbamate 193 by a less nucleophilic base, LDA (pKa ≈ 36),[155]

was therefore attempted. However, the TLC and 1H NMR showed a complex mixture of

products with negligible desired product.

Finally, the cinnamyl carbamate 193 was treated with sec-BuLi (2.5 equiv.) in THF

at -78 °C for 1 h. The principal product of the reaction (41 % yield) was the aryl ketone

197, a compound which can arise only by migration of the N-phenyl ring from N to C.

Evidence that N to C migration of an aryl ring is involved in the formation of 197 is

supported by the identification of a by-product 196 (9 %) from which 197 can be derived

by hydrolysis (Scheme 112).

Scheme 112. Nto C Aryl Migration of Cinnamyl Carbamate 193.

N O

O

Ph

Me

Ph

O1. s-BuLi (2.5 eq.), THF, -78 °C,1 h

2. MeOH

193 197, 41 %(Z)-196, 9 %

Ph

O O

NHMe

A plausible route to 197 is shown in Scheme 113: deprotonation to give the

allyllithium 193Li, followed by aryl migration to form 195, which undergoes a second

deprotonation to give a cinnamyllithium species 196Li, and -reprotonation on work-up to

yield the (Z)-vinyl carbamate 196. The fact that 196 was formed with Z-selectivity suggests

that 196Li exists as an endo, exo-3-allyl complex.

[66,156]

Scheme 113. Proposed Mechanism for the Formation of 197.

N O

O

Me

Phbase

193

H Ph

O

O

N

LiLn

Me

rearranges

NO

OMe

HPh

LiLn

194

H Ph

O OLi

NMe

195

Ph

O

O

N

LiLn

Me Li

MeOHPh

O O

NHMe

(Z)-196

Ph

O

197

baseMeOH

193Li

196Li

endo

exo

132

The second deprotonation could be avoided by increasing the substitution at the

position, thus creating a quaternary centre devoid of any labile protons after migration.

Therefore, we replaced the cinnamyl derivative 193 with an -methylated compound 201.

II.3.1.2 Synthesis and Aryl Migration of -Methyl Cinnamyl Carbamates

The -methyl cinnamyl carbamate 201 was prepared in 72 % over three steps using

the same method previously described, from -methyl cinnamyl alcohol 199 prepared by

addition of methyllithium to cinnamyl aldehyde 198 (Scheme 114).

Scheme 114. Synthesis of -Methyl Cinnamyl Carbamate 201.

HO Ph

NH

O

O

Ph N O

O

Ph

Me

PhNCO, NEt3, CH2Cl2

RT, 15 h

1. NaH, DMF,0 °C, 30 min

2. MeI, RT, 15 h

199

200

201, 72 % over 3 steps

Me

Me

Ph

198

H

O

1. MeLi, Et2O,-78° C, 2 h

2. NH4Cl

Me

Under the conditions previously used for deprotonation of cinnamyl carbamate 193,

sec-BuLi (2.5 equiv.) in THF at -78 °C, the resulting rearranged product underwent a

carbolithiationof the conjugated alkene[106d]

by sec-BuLi to give 202 in 23 % yield as a 1:1

diastereomeric mixture. The tertiary alcohol 203 was also isolated in poor yield (6 %)

resulting from N to C aryl migration followed by an in-situ carbamate function

deprotection (Scheme 115).

Scheme 115. Nto C Aryl Migration of -Methyl Cinnamyl Carbamate 201 upon Lithiation

with sec-BuLi.

N O

O

Ph

Me201

1. s-BuLi (2.5 eq.), THF,-78 °C, 1 h

2. MeOH

MeHN O

O

Ph

202, 23 %

Me Me

HO Ph

Me

203, 6 %

133

Instead, deprotonation with LDA (2.0 equiv.) in THF at -78 °C gave after 1 h a

compound identified as 204 in the NMR spectrum of the crude reaction mixture (Scheme

116). However, this material proved extremely unstable to purification on silica and

alumina, presumably due to the ready formation of a highly stabilized cation.

Scheme 116. N to C Aryl Migration of -Methyl Cinnamyl Carbamate 201 upon Lithiation

with LDA.

N O

O

Ph

Me 201

1. LDA (2.0 eq.), THF,-78 °C, 1 h

2. MeOH

MeHN O

O

Ph

204

Me Me

It was anticipated that deprotection of the crude carbamate 204 would result in a

product with greater stability.

It was reported that using DIBAL-H a carbamate could be reduced to give the desired

alcohol product.[157]

However, using this method, a side product 206 was isolated shown to

be an elimination product. It is likely that formation of the product was promoted by the

Lewis acidic aluminium in the DIBAL-H (Scheme 117).

Scheme 117. Attempted Deprotection of 204 by DIBAL-H.

MeHN O

O

Ph

MeDIBAL-H, THF

reflux or RT, 2 h

AlO Ph

Me

PhPh

204206205

-H2O

i-Bu2

An alternative method for the cleavage of the carbamate function would be to reflux

the product 204 in an alcohol in the presence of sodium carbonate.[64]

However, attempt to

deprotect the carbamate employing n-butanol or methanol at reflux or at room temperature

gave, in addition to the elimination product 206 in very low yield, the two isomers 207/208

and 209/210 respectively, resulting from the incorporation of the alcohol and expulsion of

the carbamate moiety (Scheme 118).

134

Scheme 118. Attempted Deprotection of 204 by Refluxing in Alcohol.

MeHN O Ph

O Me

204

Ph Ph

BuO Me

Ph Ph

Me OBu

Ph Ph

Me OMe

Ph Ph

MeO Me

207 208

209 210

40 % over 2 steps (1/1.3)

71 % over 2 steps (1.5/1)

n-BuOH,Na2CO3,reflux, 2 h

MeOH,Na2CO3,50 °Cor RT, 2 h

As an alternative, hydrolysis of the carbamate’s N-nitroso derivative 211 was

envisaged using the same method previously described in the group for ureas.[56]

However,

treatment of the rearranged product 204 with tert-butyl nitrite to make the N-nitroso

derivative 211 was unsuccessful: only the starting material 204 was recovered (Scheme

119).

Scheme 119. Attempted Deprotection of 204 by Hydrolysis of Carbamate’s N-nitroso

derivative.

MeHN O

O

Ph

Me

204

N O

O

Ph

Me

NO

HO Ph

Me1. t-BuONO

2. LiOH, H2O,THF

211 203

Me

, 48 hCH2Cl2, 24 h

As outlined in the mechanism in the Scheme 113, the rearrangement would generate

a lithiocarbamate species. Therefore, the nitrogen being more nucleophilic, N-nitrosation

could be carried out simply by terminating the rearrangement with an excess of tert-butyl

nitrite. Pleasingly, adding 6.0 equiv. of tert-butyl nitrite at the end of the reaction and

stirring the resulting basic reaction mixture at room temperature for 24 h afforded the

desired alcohol 203 in 68 % yield in a one pot reaction (Scheme 120).

135

Scheme 120. Synthesis of Tertiary Alcohol 203 by Adding t-BuONO at the End of the

Rearrangement Reaction.

N O Ph

O Me

Me

1. LDA (2.0 eq.), THF, -78 °C, 1 h

2. t-BuONO (6.0 eq.), 24 h, RT

HO Ph

Me

201 203, 68 %

II.3.1.3 Stereospecificity in the Aryl Migration

By starting with enantiomerically pure 201, we hoped to be able to form the

allyllithium intermediate as a single enantiomer which would rearrange faster than it could

racemise. Enantiomerically enriched benzylcarbamates may be lithiated and rearranged

stereospecifically, provided the conditions are carefully chosen, and carbamates closely

related to 201 have some degree of configurational stability (see Section I.3.4).

The first task was the preparation of (R)--methyl cinnamyl alcohol 199. Sharpless

Kinetic Resolution (SKR)[158]

allowed to access to the enantiopure alcohol (R)-199 in 40 %

yield and with 99:1 e.r..1 Subsequent conversion into the corresponding carbamate (R)-201,

using the same method previously described, was achieved in 89 % yield over 2 steps

(Scheme 121).

Scheme 121. Preparation of Enantiopure -Methyl Cinnamyl Carbamate (R)-201.

Ti(O-i-Pr)4 (1.0 eq.),(L)-(+)-DIPT (1.2 eq.),TBHP (0.6 eq.)

CH2Cl2, 4Å MS-20 °C, 3.5 h

HO Ph

Me

199

HO Ph

Me

(R)-199, 40 %, 99:1 e.r.

O Ph

Me

(R)-201, 89 %, 99:1 e.r.

N

O

Me

The successful reaction conditions used on the racemic material were tried on the

enantiopure starting material (R)-201 (Scheme 122; Table 21, entry 1). However, not

surprisingly, these conditions caused racemization. Interestingly, the deep red colour of the

reaction mixture indicates the high degree of ion separation (SSIP), thus decreasing the

1 Chiralcel OD-H was used as stationary chiral phase to determine the []D. The absolute stereochemistry

was confirmed by comparison with literature data[159]

136

configurational stability of the allyllithium. Rearrangements in less coordinating solvents

tend to return higher enantiomeric excesses.[160]

Therefore, the reaction was repeated in

Et2O (THF with a dipole moment of = 1.75 [D] has a stronger donor capacity compared

to that of Et2O ( = 1.15 [D])[161]

) at -78 °C which led to a yellow solution presumably

arising from the formation of a closer contact ion pair (CIP) (entries 2). However, it did not

reach completion in 2 h and gave a product with a low enantiomeric excess. Tellingly, the

recovered starting material was partially racemised too, suggesting that the lithiated

intermediate is not configurationally stable under the conditions of the reaction. Slowly

raising the temperature to -40 °C allowed the reaction to reach completion but still gave

essentially racemic product (entry 3). The challenge was therefore to find conditions under

which rearrangement is accelerated while racemization is decelerated. Diamines such as

()-sparteine, (+)-sparteine surrogate,[162]

or TMEDA are known to slow down the rate at

which organolithiums racemise.[163]

Indeed adding either ()-sparteine or TMEDA (1.0

equiv.) to the rearrangement reaction in Et2O resulted in a product retaining some degree

of enantiomeric enrichment (entries 4 to 6) but as a racemate with 2.0 equiv. of ()-

sparteine (entry 7) or in the presence of (+)-sparteine surrogate (entry 8). However, the

maximum achievable was little more than 60:40, suggesting that 80 % of the material is

racemic.

Scheme 122. Stereospecificity in the Aryl Migration of (R)-201.

O Ph

Me

(R)-201, 89 %, 99:1 e.r.

N

O

Me

1. LDA (2.0 eq.) (Table 21)

2. MeOHO Ph

(S)-204

MeHN

O Me

137

Table 21. Conditions for the Stereospecificity in the Aryl Migration of (R)-201.

Entry Solvent/Additive Temp. (°C) Time (h) e.r.a

1 THF -78 1 50:50

2 Et2O -78 2 46:54b

3 Et2O -78 to -40 3 46:54

4c Et2O + ()-sparteine (1 eq.) -45 2 37:63

5 Et2O + ()-sparteine (1 eq.) -60 3 39:61

6 Et2O + TMEDA (1 eq.) -45 2 38:62

7 Et2O + ()-sparteine (2 eq.) -60 3 48:52d

8 Et2O + (+)-sparteine

surrogate (1 eq.) -45 2 48:52

d

()-sparteine

N

HN

H

N

HN

Me

(+)-sparteine surrogate

These results point to the importance of the incorporation of the lithium cation into a

dense chelate complex which hampers the cation from changing the enantiotopic faces of

the anion.

An alternative approach for the enantioselective rearrangement could make use of a

chiral base or an alkyllithium/()-sparteine complex, the aim being to induce kinetic

resolution of the chiral starting material or dynamic kinetic or thermodynamic resolution of

the intermediate organolithium.[175]

However, racemic products were also formed when

racemic starting materials were deprotonated in the presence of chiral lithium amide 212Li

in THF or Et2O (Table 22, entries 1 and 2),[66]

or in the presence of sec-BuLi/()-sparteine

complex in Et2O at -78 °C (entry 3) or at -60 °C (entry 4) or in the presence of n-BuLi/()-

sparteine in toluene at -78 °C followed by the addition of THF (4.0 equiv.) to promote the

rearrangement (entry 5).

a e.r. determined from crude reaction.

b Remaining starting material: 77:23 e.r.

c LDA added

to a solution of carbamate and ()-sparteine. d Remaining starting material: 48:52 e.r.

138

Table 22. Enantioselectivity in the Aryl Migration of 201.

Entry Base or Additive Solvent T (°C) t (h) e.r.

1 Ph NH

Ph .n-BuLi

212

THF -78 1 50:50

2 Ph NH

Ph .n-BuLi

212

Et2O -78 1 50:50

3 ()-sparteine/s-BuLi (2.0 eq.) Et2O -78 15 49:51

4 ()-sparteine/s-BuLi (2.0 eq.) Et2O -60 15 49:51

5 ()-sparteine/n-BuLi (1.5 eq.)

then THF (4.0 eq.) PhMe -78 3 45:55

Recently, Takeda et al. examined the chirality transfer in a [2,3]-Wittig

rearrangement of 213 as a new tool for evaluation of the effect of conjugative electron-

withdrawing groups and -anion-stabilising heteroatom substitutents X on the

configurational stability of a chiral carbanion through a double bond (Scheme 123).[160]

Scheme 123. [2,3]-Wittig Rearrangement of 213 as a Tool for Estimation of the Effect of

Group X on the Configurational Stability of Chiral Carbanions.

X Ph

O

n-C5H11 X Ph

HOn-C5H11

base

solventRT

X = Me, Ph, SiMe3, CN,SO2Ph, P(O)(OEt)2, P(O)Ph2

213 214

He suggested that in the case of conjugating groups, such as a phenyl group,

racemization occurs depending on the solvent (Table 23, entries 4 to 9). In contrast, when

X is an anion-unstabilizing group such as a methyl group, little racemization was observed

regardless of the solvent used (entries 1 to 3).

139

Table 23. [2,3]-Wittig Rearrangement of 213.

Entry X Solvent Base 214, Yield

(%)

e.e. (%)

214 ent-214

1 Me 1,4-dioxane n-BuLi 77 94 98

2 Me Et2O n-BuLi 79 95 100

3 Me THF n-BuLi 87 93 96

4 Ph 1,4-dioxane n-BuLi 70 84 92

5 Ph Et2O n-BuLi 64 60 71

6 Ph THF LDA 61 3 4

7 CN 1,4-dioxane LDA 31 8 9

8 CN Et2O LDA 31 8 6

9 CN THF LDA 40 2 3

Consequently, it was worth examining the stereospecific rearrangement of -methyl

cinnamyl carbamates 217 bearing an electron-donating group (-OMe) on the phenyl group

which would increase the configurational stability of the chiral carbanion intermediate by

minimizing its delocalisation through the double bond.

(R)--Methyl cinnamyl alcohol 216 was made by Sharpless Kinetic Resolution

(SKR)[158]

in 37 % yield and with 97:3 e.r., which was converted to its carbamate

derivative (R)-217 by reaction with phenyl isocyanate and methylation with sodium

hydride and methyl iodide in 63 % yield over two steps (Scheme 124).

Scheme 124. Preparation of Enantiomerically Enriched -Methyl Cinnamyl Carbamate

(R)-217.

HO

N O

O1. PhNCO, NEt3, CH2Cl2, RT, 15 h

2. (i) NaH, DMF,0 °C, 30 min(ii) MeI, RT, 15 h

216, 87 %

(R)-217, 63 % over 2 steps, 97:3 e.r.

Me

Me

215

H

O

1. MeLi, Et2O,-78 °C, 2 h

2. NH4ClOMe OMe

OMe

HO

(R)-216, 37 %, 97:3 e.r.

Me

OMe

Ti(O-i-Pr)4 (1.0 eq.),(L)-(+)-DIPT (1.2 eq.),TBHP (0.6 eq.)

CH2Cl2, 4Å MS-20 °C, 3 days

Me

140

Scheme 125. Stereospecificity in the Aryl Migration of (R)-217.

N O

O

(R)-217, 97:3 e.r.

Me

OMeMe

O

O

MeHN

Me

OMe218

Table 24

Table 24. Conditions for the Stereospecificity in the Aryl Migration of (R)-217.

Entry Base Solvent Temp. (°C) Time (h) e.r.a

1 LDA THF -78 1 50:50

2b LDA Et2O -78 18 -

3b LDA Et2O -78 to -35 17 -

4 LDA Et2O/THF (2 eq.) -78 to -35 15 55:45

5 LDA Et2O -45 19 53:47

Firstly, in order to ascertain that the rearrangement of the carbamate 217 occurs, the

standard lithiation conditions were used yielding the desired rearranged carbamate 218

cleanly (Scheme 125; Table 24, entry 1). However, in Et2O at -78 °C, the carbamate failed

to rearrange (entry 2) as well as at higher temperature (entry 3) contrary to carbamate 201.

Two equivalents of THF (as lithium-coordinating additive) were required to promote the

aryl transfer (entry 4) but the stereochemistry is not retained under these conditions. In

order to make the rearrangement faster than the racemization of the organolithium

intermediate, the reaction was repeated at -45 °C, the rearranged product 218 was, however,

returned with a poor enantiomeric ratio (entry 5). Therefore, N to C aryl migration of the p-

methoxy analogue of 201 made no change to the previous results.

We conclude that the rearrangement of allylic carbamates cannot therefore be used to

make them in enantiomerically pure form. However, conversion of the material (S)-204

with low enantiomeric enrichment (Table 21, entry 4) to the allylic alcohol 203 by

nitrosation and base-promoted cleavage returned material whose optical rotation has been

compared with a reported value[164]

(Scheme 126). Both sign and magnitude is consistent

with the alcohol product of the reaction being of about 20 % optical purity and having (S)

a Determine from crude reaction.

b Starting material recovered.

141

absolute configuration. It appears therefore that the rearrangement of allylic carbamates,

like that of benzylic carbamates, proceeds with inversion of configuration.

Scheme 126. Confirmation of the Invertive Nature of the Aryl Migration in Allylic

Carbamates.

MeHN O

O

(S)-204, 37:63 e.r.

HO

(S)-203, 65 % over 2 steps, 37:63 e.r.

1. n-BuLi (2.0 eq.),THF, -78 °C, 30 min

2. t-BuONO (6.0 eq.),RT, 24 h

[]D25 - 1.5 (c 1.0, CHCl3)

[lit [164] []D20 - 5.33 (c 0.6, Et2O)]

Me Me

The use of ()-sparteine as a means of reducing the rate of racemization was explored

as a way of improving the results obtainable from the rearrangements of benzylic

carbamates described previously. Addition of ()-sparteine to the rearrangement of 95o

improved the e.r. of the product from 90:10 to 97:3, but at the expense of yield, while

addition of ()-sparteine to the less reactive 95i induced a remarkable change in the

mechanism of the reaction, which produced the 2-hydroxyamide 219, by a 1,2-acyl shift, in

80:20 e.r. (Scheme 127). The absolute configuration of 219 has not been determined but

Nakai et al. reported that alkyl N,N-diisopropylcarbamates underwent the 1,2-carbamoyl

migration with complete retention of configuration at the Li-bearing carbanion

terminus.[75c]

We can therefore assume that the configuration of 219 is (S).

142

Scheme 127. Effect of ()-Sparteine on the Rearrangement of Lithiated Benzylcarbamates.

N O

O Me

Me

MeHN O

O

1. LiTMP (2.5 eq.), Et2O, -78 °C to -35 °C,24 h

(R)-95o, 98:2 e.r.

F3CMe

CF3

without ()-sparteine (S)-96o, 38 %, 90:10 e.r.with ()-sparteine: (S)-96o, 18 %, 97:03 e.r.

2. MeOH

1. LDA (2.5 eq.),Et2O, -78 °C to-35 °C, 24 h2. MeOH

O

O

Cl

MeHN

(S)-96i, 51 %, 84:16 e.r.

N

Me

O

OH

Cl

(S)-219, 85 %, 80:20 e.r.

1,2-acyl shift

1,4-aryl transfer

(S)-95i, 99:1 e.r.

N O

O Me

MeCl

Me

1. LDA (2.5 eq.),Et2O, ()-sparteine,-78 °C to -35 °C, 24 h2. MeOH

Me

II.3.1.4 Aryl Migration of Simple O-Allylcarbamates

The rearrangement of simple O-allylcarbamate (N-Alloc aniline) 220 was also

attempted, with the aim of following the reaction pathway depicted in Scheme 128.

Assuming that the rearrangement of carbamate 220 occurs in the same manner as the

cinnamyl carbamate 201 previously studied, the free NH-group of the rearranged

carbamate 221 offers the possibility to couple an aryl group on the carbamate. A second

deprotonation-rearrangement sequence would lead to carbamate 223 with an interesting

diarylvinyl substituent, a possible precursor of diarylhydroxy acids.

143

Scheme 128. Proposed Route Towards Diarylvinylcarbamates 223 from a Simple Allyl

carbamate 220.

Ar1

N O

O

Me

MeHN O

O Ar1aryl migration

N O

O Ar1

Ar2

Me

MeHN O

O Ar1Ar2

N-arylation

aryl migration

221220

222 223

Upon treatment with LDA in THF at -78 °C, the less hindered N-methylated

compound 220a gave only N-methylaniline as a product (Scheme 129). While the N-

isopropyl analogue 220b was less prone to direct cleavage to the aniline, it failed to

undergo aryl migration, generating instead the 2-hydroxyamide product 226 of a 1,2-acyl

shift in 28 % yield.

Scheme 129. Attempted Aryl Migration of Simple Allylcarbamates.

N O

O

R

1. LDA (2.0 eq.), THF, -78 °C, 1 h

1,2-acyl shift

R = i-Pr

OH

226

N

O

220a, R = Me220b, R = i-Pr

2. MeOH

O

LiLnO

N

O

O

N

LiLn

28 %

224 225

144

II.3.1.5 In Situ IR Spectroscopy Studies

We also undertook detailed studies of the rearrangement of 201 (Scheme 130). A

mixture of 201 and THF in a three-necked flask equipped with a ReactIR probe was cooled

to -60 °C. Once the temperature has stabilized, spectroscopic analysis was commenced at a

rate of one scan every 1 min. The initial spectrum was recorded, before LDA (1.5 equiv.)

was added. Immediately on addition of LDA, the C=O stretching frequency of 1709 cm-1

corresponding to the starting carbamate was replaced by a peak at 1329 cm-1

and a double

peak centred approximately at 1656 cm-1

which persisted until after 45 min the reaction

was quenched with MeOH (Figure 15). At this point a peak at 1768 cm-1

appeared

corresponding to the product carbamate 204. In this reaction, under these conditions, we

saw no evidence for any other intermediates. We assume that the strong signals in the

region of 1329 and 1656 cm-1

arise from C-O and C-N stretches within the lithio carbamate

function of rearranged compound 204 which is formed by instantaneous rearrangement of

deprotonated 201.

Scheme 130. Intermediates Detected in the Rearrangement of 201.

N O

O

Me

PhLDA (1.5 eq.)

201 Me Ph

O

O

N

LiLn

Me

rearranges

Me

THF, -60 °C

MeHN O

O

Ph

204

Me

MeN O

O

Ph

MeLi MeOH

not observed

201Li

204Li

1709 cm-1

1768 cm-11656 cm-1

+ 1329 cm-1

145

Figure 15. In Situ React IR Monitoring of the Rearrangement of 201 Using LDA in THF at

-60 °C (Three-dimensional plot of absorbance versus wavenumber versus time in the 1800-

1600 cm-1

region of the IR spectrum).

Allylcarbamate 201

in THF at -60 °C

LDA added

Quench with

MeOH 1709cm

-1 : 201

1768cm-1

: 204 1664 & 1649cm

-1 : 204Li

146

II.3.2 N to C Aryl Migration in Lithiated N-Aryl-O-Propargylcarbamates

In order to broaden the scope of substrates, other stabilized organolithiums with

versatile propargylic structures was used for the rearrangement, something not studied

previously within the group.

II.3.2.1 Synthesis and Attempted Aryl Migration of Primary O-Propargylcarbamates

Primary propargyl carbamate 230a was synthesised, by the method developed within

the group, from the corresponding alcohol 227a which was converted to its carbamate

derivative by reaction with phenyl isocyanate and methylation with sodium hydride and

methyl iodide in 52 % yield over 2 steps (Scheme 131).

In contrast, the preparation of 230b by the usual method led to the formation of (E)-

4-alkylidene-2-oxazolidinone 231 as single isomer[165]

in 31 % yield and 4-

benzyloxazolone 232 in 24 % yield, arising from the deprotonation of –NH and subsequent

5-exo-dig ring closure of the intermediate sodium carbamate[166]

(Scheme 131). The base

promoted cyclisation of O-propargyl carbamates to give 4-alkylidene-2-oxazolidinones has

long been established[167]

and developed these recent years.[168]

Accordingly, 230b was

alternatively synthesised from the propargyl chloroformate 229 and N-methylaniline in

64 % yield over 2 steps.[168f]

Scheme 131. Preparation of O-Propargylcarbamates 230a and 230b.

HO

R

O

R

NH

O

PhPhNCO, NEt3

CH2Cl2, RT, 15 h227a, R = Me

227b, R = Ph

1. NaH, DMF,0 °C, 30 min2. MeI, RT, 15 h

R = Me

R = Ph

R = Ph

PhNHMe

NEt3, CH2Cl2

230a, R = Me, 52 % over 2 steps230b, R = Ph, 64 % over 2 steps

228a, R = Me228b, R = Ph

231, 31 %(E-isomer)

232, 24 %

Et2O, RT

(Cl3CO)2CO

O

Ph

Cl

O

O

R

N

O

Ph

Me229

ON

O

Ph

Ph

ON

O

Ph

Ph

147

However, as with the simple O-allylcarbamate 220a, O-propargylcarbamates 230a

and 230b, on treatment with LDA in THF at -78 °C, produced products resulting from

attack directly on the carbamate C=O group. Therefore, we turned our attention towards

investigating the rearrangement of -methylated O-propargylcarbamates.

II.3.2.2 Synthesis and Aryl Migration of -Methylated O-Propargylcarbamates

As expected, the synthesis of 237a using the initial method, returned oxazolone 235

in 52 % yield as single product (Scheme 132). Therefore, 237a and 237b were made via

chloroformate 236 in 57 % and 55 % yield over 2 steps, respectively.

Scheme 132. Preparation of -Methylated O-Propargylcarbamates 237a and 237b.

(Cl3CO)2CO,Et2O, RT

HO

Me

O

Me

NH

O

O

Me

Cl

O

O

Me

N

O

R

PhNCO, NEt3

CH2Cl2, RT233 234

236

CH2Cl2, RT

237a, R = Me 57 % over 2 steps237b, R = i-Pr 55 % over 2 steps

1. NaH, DMF,0 °C, 30 min

2. MeI, RT, 15 h

235, 52 % over 2 stepsPhNHMe, NEt3

or PhNHiPr, Na2CO3

ON

O

Me

Treatment with base led to migration of the aryl ring from N to C but was followed

by cyclisation of the resulting carbamate anion onto the triple bond to yield the

benzylidene oxazolidinones (E)-238a and (Z)-238a in a ratio highly dependent upon the

base used in the cyclisation (Scheme 133). N to C aryl migration in the presence of LDA

(2.0 equiv.) in THF at -78 °C afforded (E)-substituted 4-alkylidene-2-oxazolidinone 238a

in a 13:1 diastereoisomeric ratio in a moderate yield of 43 % due to the carbamate cleavage.

X-ray crystallography confirmed the structure of the cyclised product (E)-238a (Figure 16).

In contrast, the use of LiHMDS gave the (Z)-isomer 238a as major product (0.5:1 ratio by

1H NMR). Surprisingly, when propargyl carbamate 237a was treated with KHMDS in THF

148

at 0 °C a mixture of (E)- and (Z)-substituted 4-alkylidene-2-oxazolidinone 238a, easily

separable by column chromatography, was obtained in both 16 % yield (1.3:1 ratio by 1H

NMR). The (Z)-stereochemistry was confirmed by a nOe experiment which showed

coupling through space between the C-methyl group and the vinylic proton. The use of

NaHMDS led to the formation of (E)-substituted 4-alkylidene-2-oxazolidinone 238a in

44 % yield as major isomer (1:5 ratio by 1H NMR).Therefore, these compounds indicate

that the rearrangement can be initiated by organometallic intermediates of potassium and

sodium, which has not been observed previously.

Scheme 133. Aryl Migration of -Methylated O-Propargylcarbamate 237a.

N O

O

Me

Me

ON

O

Me

Me

ON

O

Me

Me

1. Base (2.0 equiv.)

Base: LDA, THF, -78 °C, 15 min

45 % 0 % (13:1 by 1H NMR)

KHMDS, THF, 0 °C, 15 min

NaHMDS, THF, 0 °C, 15 min

16 % 16 % (1.3:1 by 1HNMR)

7 % 44 % (1:5 by 1HNMR)

LiHMDS, THF, 0 °C, 15 min

14 % 31 % (0.5:1 by 1H NMR)

237a

(E)-238a (Z)-238a

2. MeOH

Me

O NHMe

OLi

149

Figure 16. X-Ray Crystal Structure of (E)-238a.

A number of procedures to synthesise 4-methylene-1,3-oxazolidinones have been

reported,[167,168]

while few processes to produce 5-tetrasubstituted ones have been

published.[167g,168c,b,e,g]

In addition to intramolecular nucleophilic cyclisations of propargyl

carbamates,[168f]

Schmalz et al. reported that 4-alkylidene-1,3-oxazolidin-2-ones could be

prepared from O-propargyl carbamates using catalytic AuCl in CH3CN.[168d]

In addition,

various approaches to oxazolidinones via cycloaddition reactions of carbon dioxide with

propargylic alcohols and amines have also been reported,[167f,168b,c]

which suffer from

drawbacks such as the need for toxic and noble-metal catalysts, the involvement of volatile

organic chemicals (VOCs), and harsh reaction conditions.

The cyclisation, while interesting, detracts from the possible utility of the

rearrangement. We reasoned that a triisopropylsilyl group as an acetylenic substituent

might compromise the reactivity of the acetylenic bond by decreasing its electrophilicity.

O-propargylcarbamate 241 was therefore made from 4-(trimethylsilyl)but-3-yn-2-ol 239 by

reaction with phenyl isocyanate and methylation with sodium hydride and methyl iodide to

give terminal O-propargylcarbamate 240 in 51 % yield over 2 steps. This in turn was

deprotonated with n-BuLi in THF at -78 °C and treated with i-Pr3SiCl to afford 241 in

65 % yield (Scheme 134).

150

Scheme 134. Preparation of O-Propargylcarbamate 241.

N O

O Me

H

N O

O Me

TIPS

HO

Me

TMS

1. PhNCO, Et3N,DCM, 15 h

2. NaH, DMF,0 °C, 1 h Me

1. n-BuLi, THF,-78 °C, 1 h

2. i-Pr3SiCl, RT, 5 h

Me

239 240, 51 % over 2 steps

241, 65 %

Treatment of 241 with 2.0 equiv. of LDA in THF/DMPU for 1 h gave the desired

rearranged product 242 in a promising 40 % yield accompanied with 30 % of the starting

material (Scheme 135; Table 25, entry 1). The use of 2.5 equiv. of LDA led to a further

increase in yield (66 %) with 20 % of recovered starting material (entry 2). The reaction

was completed over a longer reaction time (3 h) but in a lower yield of 54 % which could

be accounted for the formation of by-products (entry 3).

Scheme 135. Aryl Migration of O-Propargylcarbamate 241.

1. LDA, THF/DMPU,-78 °C

2. MeOHN O

O Me

TIPSMe

O

O

TIPS

MeHN

Me

241 242

Table 25. Conditions and Yields for the Aryl Migration of O-Propargylcarbamate 241.

Entry Equiv. of LDA Time (h) 242, Yield (%)

1 2.0 1 40a

2 2.5 1 66a

3 2.0 3 54

a Remaining starting material

151

II.3.2.3 Stereospecificity in the Aryl Migration

Enantiomerically enriched O-propargyl carbamate (E)-237a (Scheme 136) was made

from 4-phenylbut-3-yn-2-one, which was reduced by the method of Noyori[169]

using a

solution of KOH in 2-propanol in the presence of the ruthenium complex (S,S)-182. As

expected, in THF at -78 °C, the rearrangement/cyclisation reaction with LDA (2.0 equiv.)

gave only racemic product (Table 26, entry 1) as observed with benzylcarbamate 95i.

Replacing THF with Et2O diverted the course of the reaction towards attack directly on the

carbamate C=O group, with N-methylaniline being formed (entry 2). Attempts to reduce

the susceptibility of the carbonyl group to nucleophilic attack by replacing the N-methyl

with an N-isopropyl group ameliorated the yield in THF (70 %) (entry 3), but shut down

completely any reaction in Et2O. At various temperatures, with or without addition of ()-

sparteine, slow decay of the e.r. of the starting material, by racemization of its lithium

derivative, was also observed (entries 4 to 6).

Scheme 136. Stereospecificity in the Aryl Migration of 237a and 237b.

N O

O

R

Me ON

O

RPh

Me

(S)-237a, R = Me(S)-237b, R = i-Pr

(E)-238a, R = Me(E)-238b, R = i-Pr

(Table 26)

Table 26. Conditions and Yields for the Attempted Stereospecific Aryl Migration of 137.

Entry R Base Solvent Temp. (°C) Time Yield (%) e.r.

1 Me LDA THF -78 15 min 238a, 43 50:50

2 Me LDA Et2O -78 30 min - -

3 i-Pr LDA THF -78 15 min 238b, 70 50:50

4 i-Pr LDA Et2O -78 1 h 237b (15:85 e.r.)

5 i-Pr LDA Et2O -60 1 h 237b (27:73 e.r.)

6 i-Pr LDA + ()-

sparteine

Et2O then

THF (2 eq.) -78 1h + 4 h 237b (34:66 e.r.)

152

Again it seems likely that racemization competes with rearrangement, and no further

enantioselective reactions were pursued with these compounds.

N- or O-substituted allyllithiums may be formed either by -deprotonation of either

an allylamine/allyl alcohol derivative or alternatively by γ-deprotonation of an

enamine/enol derivative as mentioned in Section I.3.3. The advantage of the latter is the

lack of chirality in the starting material, which opens yet another mechanistic possibility

for carrying out an enantioselective rearrangement via asymmetric deprotonation.

Previously, it has been shown within the group that asymmetric deprotonation works well

in the vinyl urea series.[66]

We therefore embarked on -deprotonation-mediated N to C

aryl migration of N-aryl-Z-enol carbamates.

153

II.3.3 γ-Deprotonation-Mediated N to C Aryl Migration of N-Aryl-Z-enol

carbamates

II.3.3.1 Synthesis of Z-Enol Carbamates

The efficient method depicted below was employed to make N-aryl-Z-enol

carbamates (Scheme 137).[170]

Scheme 137. General Synthesis of (Z)-Enol Carbamates.

N O

O

R4 R3

(Z)-248

O O

DMSO, 15 h, RT

R3 R3

247

70 °C, 45 min

246

Na+N

O

R4

245

Cl

R1 R1

R1

R2R2

NH2

Me Me

O"NaBH(OAc)3"

AcOH, DCERT, 4 h

R2

HN

243

244c, R2 = p-Cl, 72 %

244d, R2 = p-Me, 86 %

244e, R2 = m-CF3, 87 %

244f, R2 = p-OMe, 90 %

Cl3CO OCCl3

OPy, CH2Cl2

RT, 2 h

248a, R1 = R2 = H, R3 = R4 = Me, 57 %

248b, R1 = R2 = H, R3 = Et, R4 = Me, 65 %

248c, R2 = H, R1 = R3 = R4 = Me, 48 %

248d, R1 = H, R2 = Cl, R3 = Et, R4 = Me, 52 %

248e, R1 = R2 = R3 = H, R4 = Me, 46 %

DMSO,NaH

248f, R1 = R2 = R3 = H, R4 = i-Pr, 62 %

248g, R2 = R3 = H, R1 = Cl, R4 = i-Pr, 60 %

248h, R1 = R3 = H, R2 = Cl, R4 = i-Pr, 50 %

248i, R1 = OMe, R3 = R2 = H, R4 = i-Pr, 37 %

248j, R1 = R2 = H, R3 = Ph, R4 = i-Pr, 55 %

248k, R1 = H, R2 = Cl, R3 = Ph, R4 = i-Pr, 46 %

R2

245a, R2 = p-Cl, R4 = Me, 87 %

245b, R2 = H, R4 = i-Pr, 60 %

245c, R2 = p-Cl, R4 = i-Pr, 74 %

245d, R2 = p-Me, R4 = i-Pr, 79 %

245e, R2 = m-CF3, R4 = i-Pr, 97 %

245f, R2 = p-OMe, R4 = i-Pr, 65 %

244

DMSO was used both as reagent and as solvent. The methyl sulfinyl carbanion

(“dimsyl anion”) was formed by reaction of the solvent with NaH at 70 °C. Corey et al.

first reported the versatility and reactivity of this base in organic synthesis.[171]

It should be

noted that the temperature should not exceed 70 °C, otherwise decomposition occurs. This

is also induced by prolonged reaction times. Upon addition of the appropriate ketone 246,

the conjugated base of DMSO afforded the corresponding sodium enolate derivative 247,

which was trapped with the desired carbamoyl chloride 245 affording the (Z)-O-

154

vinylcarbamates 248 in moderate yields. The moderate yield could be attributed to the

competing C-acylation, but also to the formation of a β-hydroxy sulfoxide adduct and a

symmetrical urea resulting from the decomposition of carbamoyl chloride. Carbamoyl

chlorides 245 were prepared by treating the amines 244 with triphosgene (safe equivalent

of phosgene) in the presence of pyridine as an HCl scavenger in good yields.[172]

The

amines 244 were obtained by direct reductive amination in excellent yields with sodium

triacetoxyborohydride, generated in situ in DCE and in the presence of acetic acid for

accelerating the reaction. This is very effective with weakly and non basic amines.[173]

The (Z)-configuration of the double bond in 248b, 248c and 248d was confirmed by

nOe experiments which did not show coupling through space between the vinylic proton

and the N-methyl protons and for 248j through a single-crystal X-ray analysis (Figure 17).

Figure 17. X-ray Crystal Structure of 248j.

II.3.3.2 -Arylation of Z-Enol Carbamates by γ-Deprotonation and N to C Aryl

Migration

(Z)-Enol carbamate 248a was firstly synthesised by the method depicted in Scheme

137 in 57 % yield. Hoppe et al. have noticed that the prerequisites for ()-sparteine-

mediated intramolecular γ-deprotonation are met only in the isomer (Z), since isomer (E)

remained unchanged.[99a]

Treatment of 248a with LDA (2.0 equiv.) in THF at -78 °C for 1

h gave the rearranged carbamate derivative of tertiary doubly benzylic alcohol 249a in

excellent yield (Scheme 138). Under the same conditions, enol carbamate (Z)-248b

underwent the rearrangement cleanly. However, when subjected to flash column

chromatography on basified silica, the resulting allylic carbamate 249b was prone to a

[3,3]-sigmatropic rearrangement to give 250 as reported by Overman.[174]

Consequently,

155

the rearranged product 249b was isolated by trituration in a mixture of hexane and Et2O in

80 % yield (Scheme 138).

Scheme 138. γ-Deprotonation-Mediated N to C Aryl Migration in Lithioallyl Carbamates.

1. LDA (2.5 eq.), THF, -78 °C, 1 hN O

O

MeO

NHMe

O

(Z)-248a, R = H

(Z)-248b, R = Me

2. MeOH R

249a, 86 %, R = H249b, 83 %, R = Me

R = Me

silica MeHN O

O Me

250

R

Z-enol carbamate 248c was then made (in 48 % yield) to examine the aryl transfer

under the influence of chiral lithium amides. Stereochemically, two extreme mechanistic

possibilities could present themselves:[175]

either the stereochemistry of the product is

determined by stereospecific rearrangement of a configurationally stable planar chiral

allyllithium or it is the result of a stereoselective reaction of a configurationally unstable

allyllithium under the kinetic or thermodynamic control of the associated chiral amine.

Vinyl carbamate (Z)-248c rearranged successfully on treatment with LDA (2.5 equiv.)

in THF at -78 °C to provide allyl carbamate 249c in 80 % yield (Scheme 139; Table 27,

entry 1). Replacing LDA with the monodentate homochiral lithium amide 252Li as its

hydrochloride salt[176]

(2.5 equiv.) led to a slower reaction, and a longer time was needed to

reach completion but the level of enantiomeric enrichment was poor (entry 2). It is

reasonable to assume that chiral lithium amides having two chiral carbons on the amide

nitrogen would be more effective as chiral bases. Based on this consideration, the

deprotonation was carried out with the bis-phenylethylamide 212 which offers the

advantage of C2-symmetry. In THF at -78 °C, the rearranged product 249c was indeed

returned with a slightly increased enantiomeric ratio of 68:32 (entry 3). The reaction was

then carried out at -60 °C (entry 4) but this led to 249c in very low enantioselectivity.

Likewise, when (Z)-248d was treated with LDA in THF at -78 °C, the rearranged product

249d was isolated in excellent yield (entry 5). However, in the presence of chiral lithium

amide 212Li, partially racemic 249d in lower yields was obtained using the conditions

attempted in entries 6 and 7.

156

Scheme 139. Enantioselectivity in the γ-Deprotonation and Aryl Migration of 248c and

248d.

N O

O

MeO

NHMe

O

R = H, R1 = Me, R2 = H, (Z)-248c

R = Me, R1 = H, R2 = Cl, (Z)-248d

R1 R1

1. chiral base, n-BuLi

2. MeOHR

R2R2

R= H, R1 = Me, R2 = H, 249c

R = Me, R1 = H, R2 = Cl, 249d

R

Table 27. Conditions, Yields and e.r. for the Asymmetric γ-Deprotonation and Aryl

Migration of 248c and 248d.

Entry S.M. Base Solvent T (°C) t (h) Yield (%) e.r.

1 (Z)-248c LDA THF -78 1 249c, 80 -

2 (Z)-248c

HN Ph

.HCl

252

THF -78 5 249c, 72 56:44

3 (Z)-248c Ph NH

Ph

212

THF -78 3 249c, 28a 68:32

4 (Z)-248c Ph NH

Ph

212

THF -60 3 249c, 50b 54:46

5 (Z)-248d LDA THF -78 1 249d, 80 -

6 (Z)-248d Ph NH

Ph

212

THF -78 5 249d, 18a 52:48

7 (Z)-248d Ph NH

Ph

212

THF -60 3 249d, 62 52:48

a Remaining starting material;

b Formation of a side-product

157

II.3.3.3 In Situ IR Spectroscopy Studies

Rearrangement of 248d gave a little more detail about the mechanistic pathway,

presumably because the allyl anion generated by deprotonation is a little more stable than

that formed from 201. Immediately on addition of LDA, a new band at 1578 cm-1

appeared

which lasted for only a few minutes before giving way to a band at 1649 cm-1

(Scheme 140;

Figure 18). This band, which corresponds to the band at 1656 cm-1

in Figure 15, persisted

until the quench, which generated the product peak at 1735 cm-1

. The band at 1649 cm-1

is

again presumably that corresponding to the product anion 251dLi, with the band at 1578

cm-1

being a precursor, probably the lithiated starting material 248dLi. A cinnamyllithium

species such as 248dLi was identified in the region of 1552 cm-1

during in situ IR studies

on the rearrangement in an N-allylurea (see Appendice 3), which suggests that the peak at

1578 cm-1

is more likely the intermediate 248dLi. Moreover, a prelithiated complex has

not been observed in THF previously.

Scheme 140. Intermediates Detected in the Rearrangement of 248d.

LDA (1.1 eq.)

THF, -60 °C

O

NMe

LiO

Cl

O

NHMe

O

Cl

O

N

OMe LiLn

Aryl migration

248dLi

Cl248d

251dLi 251d

MeOH

1731 cm-1

1735 cm-11649 cm-1

1578 cm-1

N O

O

Me

Cl

158

Figure 18. Three-Dimensional Infrared Profile for the Aryl Migration of 248d Using LDA

in THF at -60 °C.

Enolcarbamate 248d

in THF at -60°C

at -60°C

LDA added

Quench with

MeOH

1649 cm-1

: 251Li 1578 cm-1

: 248Li

1731 cm-1

: 248d

1735 cm-1

: 251d

159

II.3.4 Limits of the N to C Aryl Migration

II.3.4.1 Attempted Aryl Migration in Lithiated Carbamates Containing the Electron

Rich Heterocycle Furan

Furanyl carbamate 255a was synthesised from (furan-3-yl)methanol 254a by

standard methods in 69 % yield over 2 steps (Scheme 141). 255a failed to rearrange upon

treatment with LDA or sec-BuLi in the presence of DMPU, only the starting material was

recovered. Indeed, the deprotonation could occur on the furanyl group in the 2 or 5

position. In order to test this hypothesis, the reaction was quenched with iodomethane and

the NMR analysis showed that the methylation took place on the furanyl group.

Scheme 141. Preparation of Furanyl Carbamates.

N O

Me

O

OR

R

R = H, 255a, 69 % over 2 stepsR = Me, 255b, 71 % over 3 steps

O

HO

OR

RHO

O

253 R = H, 254aR = Me, 254b

1. LiAlH4, Et2O0 °C, 16 h, RT

2. EtOH,Rochelle's salt

1. PhNCO,NEt3, CH2Cl215 h, RT

2. NaH, DMF,MeI, 15 h, RT

Consequently, 255b with additional methyl groups on the furan ring was prepared

from dimethyl furoic acid 253 using the standard methods in 71 % yield over 3 steps. Next,

with the aim of promoting the rearrangement, a number of experiments were performed by

changing the base, the temperature and the reaction time (Scheme 142; Table 28).

However, none of these experiments resulted in the formation of the rearranged product

256b. In all cases, the starting material was recovered and in some cases, N-methylaniline

arising from nucleophilic attack on the carbamate C=O group, was also observed in the

crude 1H NMR. After quenching the reaction with MeI, no evidence of methylation was

present, suggesting that lithiation to oxygen had not occurred.

160

Scheme 142. Attempted Aryl Migration of Furanyl Carbamate 255b.

N O

Me

O

O255b

O

O

O256b

MeHN

(Table 28)

Table 28. Conditions and Results for the Attempted Aryl Migration of Furanyl Carbamate

255b.

Entry Base Equiv. Temp. (°C) Time (h) Results

1 s-BuLi 2 -78 4 255b + 184b

2a LDA 2 -78 4 255b

3 LDA 2.5 -40 6 255b

II.3.4.2 Attempted Aryl Migration in Lithiated O-Alkylcarbamates

We have shown that benzyl, alkenyl and alkynyl carbamates are deprotonated with

great ease by LDA at low temperature leading to stable five-membered chelate complexes,

which smoothly undergo N to C aryl transfer. Hoppe et al. reported that even primary alkyl

carbamates, which lack further carbanion-stabilising groups, are deprotonated by sec-

BuLi/TMEDA.[177]

Therefore, rearrangement of O-alkylcarbamate 257 was attempted,

firstly under the usual conditions for deprotonation (Scheme 143; Table 29, entry 1: LDA

in THF/DMPU at -78 °C). However, only the starting material was recovered and the same

was observed at -45 °C (entry 2). A quench with MeI indicated that lithiation to oxygen

did not occur. Repeating the reaction with a stronger base, sec-BuLi, returned 257 (entry 3).

Under the conditions used by Hoppe for lithiation, sec-BuLi in Et2O/TMEDA at -78 °C

followed by warming the reaction slowly to -15 °C to promote the rearrangement, 257 was

also isolated after a quench with MeOH (entry 4). Quenching the reaction with acetic acid

d4 after 2 h at -78 °C showed no evidence of deuterium incorporation.

a Further experiment : quenching with MeI

b Arising from nucleophilic attack on the carbamate C=O group

161

Scheme 143. Attempted Aryl Migration of Alkyl Carbamate 257.

N O

Me

O

MeHN O

O(Table 29)

257 258

Table 29. Conditions and Results for the Attempted Aryl Migration of Alkyl Carbamate

257.

Entry Base Solvent/Additive Temp. (°C) Time (h) Results

1 LDA THF/DMPU -78 2 257

2a LDA THF/DMPU -45 2 257

3 s-BuLi THF/DMPU -78 2 257

4b s-BuLi Et2O/TMEDA -78 to -15 2 + 17 257 + 258

In summary, it is clear that while enantiomeric enrichment in the product cannot be

controlled due to racemization of the intermediate organolithiums, nonetheless the

reactivity of lithiated O-benzyl, O-allyl, O-propargyl and O-vinyl carbamates, bearing N-

aryl groups, towards migration of the aryl ring from N to C provides a valuable method for

arylating an organolithium centre adjacent to oxygen in very easily made substrates.

Furthemore, enol carbamates could be attractive substrates for generation of

organolithium intermediates by β-carbolithiation. We therefore made -aryl, alkynyl,

alkenyl and silyl-O-vinylcarbamates as substrates in order to examine if the resulting

stabilized organolithiums could undergo N-aryl migration.

a Quenching with MeI: no methylation

b Quenching with acetic acid d4 at -78 °C: no deuterium incorporation

162

II.4 Tertiary Alcohols by Tandem β-Carbolithiation and N to C

Aryl Migration in Enol Carbamates

II.4.1 Carbolithiation and Aryl Migration of N-Methyl--aryl-O-

vinylcarbamate

In an initial study, N-methyl--aryl-O-vinylcarbamate 248e was treated with i-PrLi

(2.5 equiv.) in THF at -78 °C for 1 h (Scheme 144). β-Carbolithiation occurred, followed

by N to C migration of the N-phenyl ring, to return the product 259a in moderate yield

(36 %) (Table 30, entry 1). Similar yields were obtained with n-BuLi (entry 2) and sec-

BuLi (entry 3). The rearranged product 259c was obtained as a 1:1 mixture of rotamers.

This can be explained by a slow rotation due to the steric hindrance of the sec-butyl group.

The principal by-product was enamine 260 presumably resulting from a pathway initiated

by carbamate cleavage. This was highlighted by the attempted carbolithiation with MeLi

which formed only 260 (entry 4). Evidently, regioselective carbolithiation of 248e occurs

readily under these conditions, presumably yielding initially a benzylic organolithium.

Scheme 144. Carbolithiation-Aryl Migration of N-Methyl--aryl-O-vinylcarbamate 248e.

N O

Me

O

1. R-Li, THF,-78 °C, 1 h

2. MeOH

248e

O

O

259

R

Ph Ph

HN

Me

Ph

NPhMe

260

Table 30. Organolithiums and Yields for the Carbolithiation-Aryl Migration of N-Methyl-

-aryl-O-vinylcarbamate 248e.

Entry R 259, Yield (%)

1 i-Pr 259a, 36

2 n-Bu 259b, 33

3 sec-Bu 259c, 35

4 Me 259d, 80

163

The investigation was pursued by the replacement of the N-methyl group with a

bulky N-isopropyl substituent for shielding the carbonyl moiety which would lead to better

yields.

II.4.2 Carbolithiation and Aryl Migration of N-Isopropyl--aryl-O-

vinylcarbamates

II.4.2.1 Optimisation of the Reaction

The optimisation of the alkylation/arylation reactions of 248f and 248g (Scheme 145)

is displayed in Table 31.

Scheme 145. Carbolithiation-Aryl Migration of 248f and 248g.

1. R-Li

2. MeOH

248f, R1 = H

248g, R1 = Cl

262

N O

O

i-Pr

R1

PhN O

O

i-Pr

Ar

R

HN O

O

R

ArPh

i-Pr

261(Table 31)

Table 31. Optimisation of the Carbolithiation-Aryl Migration of 248f and 248g.

Entry S.M. R Solvent/Additive T (°C) t Yield (%)

1 248f i-Pr THF -78 1 h. 261a, 28 + 262a, 10

2 248f i-Pr THF -78 3 h 262a, 21

3 248f i-Pr THF -45 2 h -

4 248f i-Pr THF then DMPU -78 1 h + 2 h 262a, 62

5 248f i-Pr THF/DMPU -78 15 min 262a, 80

6 248f n-Bu THF/DMPU -78 15 min 262b, 73

7 248f sec-Bu THF/DMPU -78 5 min 262c, 80

8 248f tert-Bu THF/DMPU -78 15 min 262d, 83

9 248f Ph THF/DMPU -78 3 h 248f 10 248f Ph THF/DMPU -45 1 h 248f 11 248f Ph PhMe/TMEDA -78 5 h 248f + 261b

12 248f Me THF/DMPU -45 2 h 248f

13 248f Me THF/DMPU -20 3 h 248f

14 248f Me PhMe/TMEDA -78 3 h 248f

15 248f OEt

Li

THF/DMPU -45 3 h 248f

16 248f Li THF/DMPU -45 3 h 248f

164

Table 31. Continued.

17 248g i-Pr THF/DMPU -78 15 min 262e, 81

18 248g n-Bu THF/DMPU -78 15 min 262f, 74

19 248g sec-Bu THF/DMPU -78 15 min 262g, 75

20 248g tert-Bu THF/DMPU -78 15 min 262h, 81

Addition of i-PrLi to 248f in THF at -78 °C for 1 h and quenching with methanol led

to a mixture of a simple addition product 261a and the desired product 262a (Table 31,

entry 1). The isolation of the addition product implied a slow rearrangement, and 3 h was

required for complete migration (entry 2). However 262a was returned in low yield (21 %).

When the reaction was carried out at a higher temperature (-45 °C), the TLC and 1H NMR

showed a complex mixture of products with negligible desired product 262a (entry 3).

Adding DMPU to enforce rearrangement after the carbolithiation was complete increased

the yield to 62 % (entry 4). The best yields (73 % to 83 %) were obtained by carrying out

the reaction in a mixture of THF and DMPU (25 % v/v) at -78 °C. By following the

reaction carefully by TLC and 1H NMR, it was shown that the compounds 262 were

formed by instantaneous carbolithiation-rearrangement of 248f (entries 5 to 8). Therefore,

it is clear that replacement of the N-methyl group with an N-isopropyl substituent

improved the yield significantly.

Whatever the experimental conditions used, phenyllithium, methyllithium,

ethylvinyllithium ether[178]

and vinyllithium[179]

failed to add to 248f (entries 9 to 16). By

using TMEDA as a lithium-coordinating additive, which enhances the reactivity of

organolithium intermediate by reducing its aggregation[180]

in toluene, a single addition

product 261b was obtained with PhLi as reagent in poor yield with a significant amount of

recovered starting material (entry 11).

Likewise, the addition of iso-propyllithium, n, sec- and tert-butyllithiums coupled

with N to C aryl migration could be successfully added to O-vinylcarbamate 248g in

THF/DMPU at -78 °C for 15 min (entries 17 to 20).

In an attempt to extend the scope of the reaction by adding less reactive

organolithiums to O-vinylcarbamates, Meyers’ strategy was considered. In 1991, Meyers

et al. showed that organolithium reagents derived from lithium 4,4-di-tert-butylbiphenyl

263 (LiDBB) (Freeman’s Reagent) are uniformly superior to all other methods used for

additions to naphthalene oxazolines such as 264 (Scheme 146).[181]

Not only are the

165

reaction conditions milder and of shorter duration, but the yields are comparable in some

cases as shown by the examples in Scheme 146.

Scheme 146. Addition of LiDBB 263 to Naphthalene Oxazoline 264.

t-But-Bu2 Li+

LiDBB 263

RXRLi t-Bu

2

LiCl

NO

Ph OMe

a) RLi

b) MeI

ROXZMe

264

H2C CHSnBu3 MeLi

t-BuLi

LiDBB

Br LiDBB

RLi Preparation Temp (°C) Time (h) 265,Yield (%)

-78-0

-78- -30

-10

-30

12

10

24

12

0

78

82

70

265

Br

Br

However, attempted β-carbolithiations of 248f with 1-bromo-2-methylpropen-1-ene

and 1-bromobenzene treated with LiDBB, in THF at -20 °C for 15 h returned only the

starting material.

II.4.2.2 Synthesis of Diarylalkylalcohols

The next step was the challenging deprotection of the N-isopropyl carbamate group.

Cleavage of the carbamate group of 248f under standard conditions[55,56]

(EtONa/EtOH at

reflux, DIBAL-H/THF at room temperature and at reflux and N-nitrosation) was

accompanied by dehydration, but by quenching the carbolithiation-rearrangement reactions

with tert-butylnitrite (to form an N-nitroso carbamate in situ) and stirring the resulting

basic reaction mixture for 24 h at room temperature, diarylalkylalcohol 266a could be

obtained from 248f in a one-pot reaction (Scheme 147).

166

Scheme 147. Synthesis of Diarylalkylalcohols.

1. RLi (2.0 eq.), THF/DMPU,-78 °C, 15 min

2. t-BuONO (6.0 eq.),RT, 24 h

N O

O

i-Pr

R2

R1248f-i 266

HOR

R2

R1

The next challenge was therefore to extend the scope of the reaction by varying the

substituents on both the migrating ring and the aryl ring to oxygen.

Table 32. Yields for the Carbolithiation-Aryl Migration of 248f-i to Give 266.

Entry S.M. R1 R

2 R Product 266, Yield (%)

1 248f H H

n-Bu

HO

R2

R1

266a, 57

2 248g Cl H 266b, 55

3

4

248h

248i

H

OMe

Cl

H

266b, 77

266c, 68

5 248f H H Benzyla

HO

266d, 53b

6 248f H H

i-Pr

HO

R2

R1

266e, 73

7 248g Cl H 266f, 51

8

9

248h

248i

H

OMe

Cl

H

266f, 65

266g, 81

10 248f H H

sec-Bu

HO

R2

R1

266h, 64

11 248g Cl H 266i, 51c

12

13

248h

248i

H

OMe

Cl

H

266i, 67c

266j, 64c

14 248f H H

tert-Bu

HO

R2

R1

266k, 71

15 248g Cl H 266l, 36

16

17

248h

248i

H

OMe

Cl

H

266l, 27

266m, 67

a Obtained by metalation of toluene at RT in the presence of sparteine.

b After deprotection of the

crude rearranged product by treatment with n-BuLi in THF followed by tert-butyl nitrite quench. c 1:1 mixture of diastereoisomers.

167

Addition reactions worked best with primary and secondary alkyllithiums and gave

266 in good to excellent yields (Table 32, entries 1-13) while tert-butyllithium (entries 14-

17) gave lower yields in some cases. N to C aryl migration proceeded smoothly regardless

of the electronic nature of aryl rings Ar1 and Ar

2. Accordingly, a product could be made in

two ways by exchanging Ar1 and Ar

2.

If an efficient method would be available to render such a process asymmetric, it

would acquire utility as a method for the creation of enantioenriched tertiary multiply

branched alcohols.

II.4.2.3 Enantioselectivity in the β-Carbolithiation-Aryl Migration

The complexed conformers A/B-267, formed by the coordination of organolithium

RLi and a chiral ligand L2*, will react with the C=C bond in an intramolecular syn-addition

to form the benzyllithium derivatives (R)-268•L2* and (S)-268•L2*, which are

configurational stable and can be trapped (Scheme 148). Overall, the sequence provides

enantiofacial attack at the styrene double bond. We can note that the carbanionic centre in

the reagent is not stereogenic. Any differentiation is due to the chiral ligand L2*. A few

efficient examples for such a strategy are known.[110e,f,111,182]

Scheme 148. Enantioinduction in the Carbolithiation.

ArH

O O

NR1R2

H

ArH

O

NR1R2

H

O LiL2*

R

RLiL2*

ArH

O

NR1R2

H

O LiL2*

R

O LiL2*

O

2R1RN

Ar R

A-267 B-267

O LiL2*

O

2R1RN

Ar R

Si Re

(R)-268 L2* (S)-268 L2*

168

Normant and Marek reported that the readily available lupine alkaloid ()-sparteine

89 could serve as promoter for the enantioselective carbolithiation of cinnamyl derivatives

by addition of organolithium compounds.[107,110f,112d]

These observations led us to consider

the enantioinduction in the ()-sparteine-mediated carbolithiation reaction onto O-

vinylcarbamate 248g (Scheme 149). The data are collected in Table 33.

Scheme 149. Enantioinduction in the ()-Sparteine-Mediated Carbolithiation Reaction.

1. R-Li-sparteine

2. MeOH

262

N O

O

i-Pr

Cl

PhN O

O

i-Pr

Ar

R

HN O

O

R

PhAr

i-Pr

261(Table 33)

248g

Table 33. Conditions, Yields and e.r. for the Enantioselective Carbolithiation of 248g.

Entry RLi Solvent T (°C) t (h) Yield (%), e.r.

1 n-BuLi Toluene -78 3 248g

2 n-BuLi Toluene -50 3 261c 55, 68:38 e.r.

3 n-BuLi Cumene -50 2 261c 42, 65:35 e.r.

4 i-PrLi Cumene -50 2 248g + 261d 18, 72:28 e.r.

5 n-BuLi Toluene then

DMPU (4.0 eq.) -50 3 + 1 262f 61, 57:43 e.r.

Treating vinylcarbamate 248g with 2.0 equiv. of n-BuLi and ()-sparteine in toluene

at -78 °C for 3 h returned the starting material (Table 33, entry 1). When the reaction was

performed at higher temperature (-50 °C), a single addition product 261c was isolated in

55 % yield and a poor enantiofacial discrimination (68:38 e.r.) was revealed in the product

(entry 2). It was shown that cumene as a solvent gave high e.r. values for the

carbolithiation reaction.[110f]

However, the use of cumene in the reaction provided similar

results in terms of yield and e.r. (entry 3). The best result was obtained with i-PrLi (72:28

e.r.) returning the addition product 261d in poor yield (entry 4). However, the migration

did not take place under these conditions, and the isolation of the rearranged product 262f

was only possible by adding 4.0 equiv. of DMPU to enforce rearrangement after the

carbolithiation was complete (entry 5) but this tampered with the enantioselectivity.

169

The enantiomeric ratio obtained in entry 6 is of a similar order of magnitude as

observed by Hoppe[123]

and Snieckus.[75b]

Hoppe et al. even examined different chiral

ligands but none of them provided high enantioselectivities. They suggested that the

induction is established in the intermediate complexes A-267 and B-267 (Scheme 148).

Both complexes are in slow equilibrium and react with similar activation energies.

II.4.3 Carbolithiation and Aryl Migration of β-Substituted N-Isopropyl-

-aryl-O-vinylcarbamates

Evidently, the tandem β-carbolithiation-N to C aryl transfer of β-prostereogenic O-

vinylcarbamates can lead to two diastereoisomeric products. Therefore, it will be

interesting to examine the diastereoselectivity of the reaction.

Attempted β-carbolithiation of the β-substituted O-vinylcarbamate 248a with i-PrLi

(2.5 equiv.) in THF at -78 °C gave the alkene 269 in 57 % yield, presumably resulting

from N to C aryl migration initiated by a γ-deprotonation followed by γ-carbolithiation of

i-PrLi and subsequent β-elimination of the lithium carbamate (Scheme 150). To test this

hypothesis, the reaction was repeated with only 2.0 equiv. of i-PrLi, and indeed, in addition

to the alkene 269, the rearranged product 249a was isolated in 7 % yield.

Scheme 150. Attempted β-Carbolithiation of β-Substituted O-Vinylcarbamate 248a.

1. i-PrLi, THF, -78 °C, 3 h

2. MeOH

N O

O

Me

O

NHMe

O

2.0 eq. of i-PrLi

2.5 eq. of i-PrLi 0 % 57 %

7 % 29 %

248a

249a 269

As a note, O-vinylcarbamate 248d also failed to react upon β-carbolithiation with i-

PrLi in THF at -78 °C and -45 °C or with n-BuLi in toluene/TMEDA at -45 °C.

170

β-Carbolithiation was successful however when γ-deprotonation was blocked by a

phenyl group (Scheme 151).

Scheme 151. Stereospecificity in the Carbolithiation of 248j and 248k.

N O

O

Ar

i-Pr

Ph

Ph

(Z)-248j, Ar = Ph(Z)-248k, Ar = p-ClC6H4

HPh

PhO

BuLiO

N

i-Pr

HAr

PhO

BuPh

N

OLi

i-Pr

270

273b, Ar = p-ClC6H4

Ar

syncarbolithiation

invertivemigration

ArN O

O

i-Pr

Ph

Bu

Ph

i-PrHN O

O Ph

Bu

Ph

Ar

HO

Ph

Bu

Ph

Ar

1. n-BuLi, PhMe/TMEDA,-78 to -30 °C, 2 h

2. MeOH

2. DMPU

2. -15 °C, 15 h

3. MeOH

271a, 70 %, Ar = Ph271b, 80 %, Ar = p-ClC6H4

272a, 60 %272b, 54 %

274b, 22 % + 271b, 40 %

3. MeOH

migration +in situ carbamate

deprotection

Under the conditions used for the carbolithiation and rearrangement of β-non-

prostereogenic vinylcarbamates or at higher temperature, the starting material 248j was

returned.

A single diastereoisomer of the addition products 271 was isolated in good yields

when 248j or 248k was treated with n-BuLi/TMEDA in toluene, quenching with methanol

at -30 °C. The relative configuration of 271a was proved by an X-ray crystal structure

(Figure 19). The stereochemistry with syn-addition of the organolithium followed by

retentive protonation is in agreement with Hoppe’s related observations.[123]

This result

suggests that the substituted benzyllithium intermediate 270 is configurationally stable[183]

in toluene/TMEDA on the time scale of the reaction.

171

Figure 19. X-ray Crystal Structure of 271a.

Coordinating solvents accelerate both the aryl migration step and inversion at the

lithium center,[55]

and accordingly adding DMPU to enforce rearrangement after the

carbolithiation was complete led to the formation of the alcohol 272b but as a mixture of

diastereoisomers.[184]

Avoiding DMPU and instead warming the reaction slowly to -15 °C

and stirring for 15 h gave a 35:65 mixture of the single addition product 271b and the

rearranged product 274b in a 95:5 diastereoisomeric ratio. The relative stereochemistry of

274b was not determined because 271b and 274b were not separable by flash column

chromatography, but previous aryl migrations in lithiated carbamates have been shown to

be invertive.[55]

Having showed that β-carbolithiation-aryl migration of O-vinylcarbamates is a

straightforward method to access tertiary alcohols, we decided to investigate the scope of

the reaction by varying the migrating ring and the group at the α-position to oxygen.

II.4.4 Carbolithiation and Aryl Migration of -Alkynyl-O-

vinylcarbamates

II.4.4.1 Synthesis of N-Isopropyl-α-alkynyl-O-vinylcarbamates

The versatile method depicted in the Scheme 152 was used to prepare -alkynyl,

alkenyl, and silyl-O-vinylcarbamates.

172

Scheme 152. Synthesis of -alkynyl-O-vinylcarbamates.

O

n-BuLi

RT, 15 h

OLiDMPU, 5 h,RT

N O

i-Pr

O

R1

R2

N

i-Pr

OR2

Cl

N O

i-Pr

OR2

N O

i-Pr

O LiR2

275 276

245

277, 57-75 %

278280, 70-87 %

t-BuLi,THF

-78 °C, 1 h

I2, THF, -78 °C

C CHR1

NEt3, CuI Pd(PPh3)4,RT, 15 h

N O

i-Pr

O IR2

279

R2 = H, p-Cl, p-Me, m-CF3, p-OMe

R1 = t-Bu, Si(i-Pr)3, SiMe3, Ph

The lithium enolate 276 of acetaldehyde was generated by cleavage of THF 275

using n-BuLi,[185]

and O-carbamoylation[186]

gave simple O-vinylcarbamates 277 in good

yields (57-75 %). Under standard metalation conditions (t-BuLi, THF, -78 °C),[187]

277

underwent -lithiation and the resulting -lithio species 278 were trapped with I2 to form

vinyl iodides 279 with perfect control of regiochemistry. The alkynyl groups of 280 were

introduced by a Sonogashira reaction in excellent yields (70-87 %).[188]

II.4.4.2 One-pot Synthesis of Multiply Branched Arylalkynylalcohols

The series of -alkynyl-O-vinylcarbamates 280 were subjected to the conditions

shown to induce β-carbolithiation and N to C aryl migration in -aryl-O-vinylcarbamates

248f-i (Scheme 153).

Scheme 153. Carbolithiation-Aryl Migration of 280.

N O

i-Pr

O

R1

R2

280

Conditions A:1. RLi (2.0 eq.), THF, DMPU,-78 °C, 15 min2. t-BuONO, RT, 24 h

Conditions B:1. RLi (2.0 eq.), THF, DMPU,-45 °C, 15 min2. MeOH

R1

HO R

R2

281

173

The alkyllithium was added either in THF in the presence of DMPU at -78 °C for 15

min, followed by a tert-butyl nitrite quench, or at -45 °C, with an in situ carbamate

deprotection. The resulting alcohols 281 were isolated from this one-pot reaction in

moderate to good yields (Table 34).

Table 34. Yields for the Carbolithiation-Aryl Migration of 280.

Entry S.M. Product 281, R, Yield (%),

(conditions)

1

N O

i-Pr

O

t-Bu280a

t-Bu

HO R

281a, n-Bu, 71 (A)

281b, i-Pr, 74 (A)

281c, t-Bu, 67 (A)

2

N O

i-Pr

O

t-Bu280b

Cl

t-Bu

HO R

Cl

281d, n-Bu, 40 (A)

281e, i-Pr, 43 (A)

281f, t-Bu, 47 (A)

3

N O

i-Pr

O

t-Bu280c

Me

t-Bu

HO R

Me

281g, n-Bu, 34 (A)

281h, i-Pr, 44 (A)

4

N O

i-Pr

O

t-Bu280d

F3C

t-Bu

HO R

F3C

281i, n-Bu, 37 (A)

281j, i-Pr, 55 (A)

281k, t-Bu, 26 (A)

5

N O

i-Pr

O

t-Bu280e

MeO

t-Bu

HO R

MeO

281l, n-Bu, 40 (B)

281m, i-Pr, 47 (B)

6

N O

i-Pr

O

Si(i-Pr)3280f

Si(i-Pr)3

HO R

281n, n-Bu, 76 (A)

281o, s-Bu, 58 (A)

281p, t-Bu, 63 (A)

174

Table 34. Continued.

Entry S.M. Product 282, R, Yield (%)

7a

N O

i-Pr

O

SiMe3280g

H

CbO R

282a, n-Bu, 72

282b, i-Pr, 51

8a

SiMe3

CbO t-Bu

283, 41

H

CbO t-Bu

282c, 13

9a

N O

i-Pr

O

Ph280h

Ph

CbO i-Pr

284, 30

NO

Oi-Pr

Ph Ph

i-Pr

285, 28

As highlighted in Table 34, the migration of both electron-rich and -poor migrating

rings took place cleanly (entries 1 to 5). The reaction tolerated tert-butyl and

triisopropylsilyl groups as acetylenic substituents, but trimethylsilyl and phenyl groups

were prone to subsequent reactions. Treating O-vinylcarbamate 280g with either n-BuLi or

i-PrLi in THF at -78 °C gave the products 282a and 282b of carbolithation, N to C aryl

migration, and loss of the TMS group (entry 7). Tert-BuLi gave a mixture of 283 and

desilylated product 282c (entry 8). Treating O-vinylcarbamate 280h with i-PrLi in THF at -

78 °C led to carbolithiation, N to C aryl migration, and cyclisation of the resulting

carbamate anion of 284 onto the triple bond to yield the benzylidene oxazolidinone 285

(entry 9). These results are compatible with previous observations that a terminal phenyl

substituent accelerates the insertion of a carbon-carbon triple bond into a nitrogen-lithium

bond. In contrast, the activity of alkynes bearing an alkyl or silyl group in the terminal

position toward nucleophilic attack is significantly lowered.

It should be noted that the result of the entry 6 fulfilled our expectation: the

carbolithiation of O-enolcarbamates is a more efficient method of initiating aryl migration

than deprotonation of -methylated carbamates as seen in Section II.2.2.2.

a Cb = C(=O)NHi-Pr. Conditions : (1) RLi, THF/DMPU, -78°C, 15min. (2) MeOH.

175

The in situ carbamate deprotection at -45 °C could occur either in the presence of

excess alkyllithium or by the extrusion of the lithium alkoxide via the lithiocarbamate as

observed by Hoppe with lithiothiocarbamate (Scheme 154).[190]

Scheme 154. Rearrangement of lithiothiocarbamate on Warming.

N S

Li

O

Li

SLi

Li O

C

N

SLi

LiN

O

1. 10 min, -78 °C2. 15 min, 0 °C

3. 15 min, -78 °C

II.4.4.3 Formation of Enantioenriched Allenes

As observed before with -aryl-O-vinylcarbamate 248f, avoiding DMPU resulted in

products of carbolithiation only. Indeed, treatment of the alkynyl-O-vinylcarbamates 280a

and 280g with n-BuLi in THF at -78 °C gave allenes 286a and 286b (Scheme 155) on

protonation.[190]

Scheme 155. Formation of Enantioenriched Allenes.a

PhN O

i-Pr

O

R1

1. n-BuLi, ()-sparteine,PhMe, 4 h

2. MeOH R1•

O

H

n-Bu

N OPh

i-Pr

280a, R1 = t-Bu

280g, R1 = SiMe3

286a, R1 = t-Bu

286b, R1 = SiMe3 a Absolute stereochemistry not determined

When 280g was treated with n-BuLi in the presence of ()-sparteine (2.0 equiv.) in

toluene at -78 °C or -50 °C for 4 h, 286b was returned as a racemate (Table 35, entries 1

and 2), presumably because the silyl group stabilizes a negative charge which facilitates

racemization.[191]

In contrast, under the same conditions, 280a afforded 286a in 89:11 e.r. but in a low

yield (8 %) due to an incomplete conversion (entry 3). Raising the temperature to -50 °C

176

increased the yield to 20 % with a slight erosion in the e.r. (84:16) (entry 4). A longer

reaction time (18 h) lowered the enantioselectivity to 75:25 e.r with no improvement in the

yield (entry 5), presumably due to the epimerization of the lithiated intermediate.[191,192]

Yoshida et al. showed that a slight excess of ()-sparteine increased the e.r. in the

enantioselective carbolithiation of enynes[192]

but a similar e.r. was observed when using

2.5 equiv. of ()-sparteine at -50 °C (enty 6). The complete conversion to 286a was

observed by concentrating the reaction mixture or by employing an excess of n-BuLi/()-

sparteine (3.0 equiv.), thus increasing the yield but with poor e.r. (entries 7 and 8). When

the reaction was performed in Et2O at -50 °C for 4 h, 286a was returned as a racemate in

moderate yield (entry 9).

Table 35. Conditions, Yields and e.r. for the Asymmetric Carbolithiation of 280g and 280a.

Entry S.M. Solvent Temp. (°C) Time (h) Yield (%) e.r.

1 280g PhMe -78 4 14 51:49

2 280g PhMe -50 4 64 46:54

3 280a PhMe -78 4 8a 89:11

4 280a PhMe -50 4 20a 84:16

5 280a PhMe -50 18 25a 75:25

6b 280a PhMe -50 4 28

a 83:17

7c 280a PhMe -50 4 43

d 75:25

8e 280a PhMe -50 4 35

d 78:22

9 280a Et2O -50 4 32d 51:49

Aside from the work using a flow microreactor system reported recently by Yoshida

et al.,[192]

to the best of my knowledge, this is the first example of the synthesis of

enantioenriched allenes via asymmetric carbolithiation of conjugated enynes.

a Remaining starting material

b 2.5 eq. ()-sparteine, 2eq n-BuLi

c Concentration of the reaction mixture

d Carbamate cleavage

e 3 eq. ()-sparteine, 3 eq. n-BuLi

177

Axial chirality transfer in enantioenriched allene 286a could offer a valuable

opportunity to form the rearranged product 287 enantiomerically enriched (Scheme 156).

However, as expected, 286a lost completely its chiral information upon treatment with sec-

BuLi in THF/DMPU at -78 °C since the rearranged product 287 was returned as a

racemate.

Scheme 156. Attempted Axial Chirality Transfer in the Allene 286a.

t-Bu•

O

H

n-Bu

N OPh

i-Pr

t-Bu

OPh

n-Bu

i-PrHN

O1. sec-BuLi, THF,DMPU, -78 °C, 1 h

2. MeOH

286a, 84:16 e.r.

287, 89 %, 50:50 e.r.

As mentioned above, quenching the carbolithiation reaction with MeOH formed the

allenic adduct over the propargylic one. It therefore seemed to be interesting to examine

the regioselectivity of the electrophilic substitution of lithiocarbamate 288 with different

electrophiles (Scheme 157). The carbolithiation of 280a proceeded smoothly within 15 min

by adding a slight excess of n-BuLi to the THF solution at -78 °C. Next, addition of MeI

and CO2 gave the γ-adducts 289 and 290 while the -adduct 291 was isolated on addition

of Me3SiCl.

Lithiated propargylic derivatives exists in two tautomeric forms in equilibrium, as a

propargyl or allenyllithium reagent.[193]

Yet, we can here suspect that propargyllithium

288b should be stabilized at the cost of 288a by a chelating ligand at the 1-oxygen

atom.[193d]

Thereby, the γ-adducts was probably formed via a SE2’ process.

178

Scheme 157. Divergent Regioselectivity in the Electrophilic Substitution of

Lithiocarbamate 288.

2. Me3SiCl3. MeOH

291, 67 %

1. n-BuLi, THF,

-78°C, 1h

280a

2. CO2

3. MeOH

t-Bu•

CO2H

290, 34 %

O

n-Bu

NPh

i-Pr

O

t-Bu•

Li288b

O

n-Bu

N

O

Ph

i-Pr

Li

ON

O

Ph

i-Prt-Bu

n-Bu

SiMe3

ON

O

Ph

i-Prt-Bu

n-Bu

288a

t-Bu•

Me

289, 66 %

O

n-Bu

NPh

i-Pr

O

2. MeI

PhN O

i-Pr

O

t-Bu

To further evaluate the substrate scope, the carbolithiation-aryl migration of -

alkenyl-O-vinylcarbamates, -silyl-O-vinylcarbamate and -heteroaryl-O-vinylcarbamates

was investigated.

II.4.5 Extension of the Substrate Scope of the Reaction

II.4.5.1 Carbolithiation-Aryl Migration of -Alkenyl-O-vinylcarbamates

The carbamates 292 and 293 were prepared by the strategy used for -alkynyl-O-

vinylcarbamates 280 (Scheme 158). The alkenyl groups of 292 and 293 were introduced by

a Stille reaction in 35 % yield.[194]

and by the in situ conversion of 278 into the

corresponding zinc species (ZnCl2) and subsequent Pd-catalyzed cross-coupling with

bromostyrene in 70 % yield.

179

Scheme 158. Synthesis of -Alkenyl-O-vinylcarbamates 292 and 293.

O

n-BuLi

RT, 15 h

OLiDMPU, 5 h,RT

N

i-Pr

O

Cl

N O

i-Pr

O

N O

i-Pr

O Li

275 276

245b

277a, 75 %

278

t-BuLi,THF

-78 °C, 1 h

1. ZnCl2, 0 °C

2. PhCH=CHBr,Pd(PPh3)4, RT

N O

i-Pr

O

293, 70 %

N O

i-Pr

O

292, 35 %

1. I2, THF,-78 °C

2. Pd(PPh3)2Cl2, 100 °C,20 h,

SnBu3

Under the conditions used previously for carbolithiation-N to C aryl migration of -

aryl and -alkynyl-O-vinylcarbamates (THF/DMPU, -78 °C), -alkenyl-O-

vinylcarbamates 292 and 293 failed to react, returning only degradation products and

starting material, respectively. However, the corresponding alcohol 294 was obtained in

54 % yield by carrying out the carbolithiation in toluene at -78 °C in the presence of

TMEDA, thus increasing the reactivity of the organolithium by deaggregation,[180]

then

adding DMPU and increasing the temperature to -15 °C to enforce N to C aryl migration

after the carbolithiation was complete (Scheme 159). Notably, carbolithiation was

regioselective for the enol double bond rather than the styrene double bond.[106d]

Scheme 159. Carbolithiation-Aryl Migration of -Alkenyl-O-vinylcarbamate 293.

N O

i-Pr

O

293

1. n-BuLi,PhMe, TMEDA,-78 °C, 2 h

2. DMPU, -15 °C,15 h

HO n-Bu

294, 54 %

180

II.4.5.2 Carbolithiation-Aryl Migration of -Silyl-O-vinylcarbamate

The carbamate 295 was prepared in 52 % yield from O-vinylcarbamate 277a, which

underwent an -lithiation followed by trapping with PhMe2SiCl (Scheme 160).

Scheme 160. Synthesis of -Silyl-O-vinylcarbamate 295.

N O

i-Pr

O

277a

N O

i-Pr

O

SiMe2Ph

295, 52 %

1. t-BuLi, THF,1 h

2. PhMe2SiCl,RT, 2 h

Carbolithiation of -silyl-O-vinylcarbamate 295 gave only the addition product 296

in 70 % yield upon treatment with n-BuLi in THF/DMPU at -45 °C (Scheme 161). We

were unable to induce N to C aryl migration of the intermediate, perhaps because of its

inability to form a solvent separated ion pair under the conditions of the reaction since

carbanionic centers are stabilized by -silyl groups.[195]

Scheme 161. Addition of n-BuLi to -Silyl-O-vinylcarbamate 295.

N O

i-Pr

O

SiMe2Ph

295

N O

i-Pr

O

SiMe2Ph

296, 70%

n-Bu1. n-BuLi, THF, DMPU,-45 °C, 2 h

2. MeOH

II.4.5.3 Attempted Carbolithiation-Aryl Migration of -Heteroaryl-O-

vinylcarbamates

The carbamates 299 and 300 were prepared by the method used for enolcarbamates

248 in 48 and 19 % yield, respectively (Scheme 162).

181

Scheme 162. Synthesis of -Furanyl-O-vinylcarbamates 299 and 300.

N O

i-Pr

O

O

N O

i-Pr

O

O

299, 48 %

300, 19 %

Me

O

O

O

OMe

N

i-Pr

Cl

O

DMSO, NaH

245b

297

298

Attempted carbolithiation-aryl migration of 299 with n-BuLi (2.0 equiv.) in

THF/DMPU at -78 °C for 1 h failed, only degradation products were observed by 1H-NMR.

The reaction with 300 either in THF/DMPU or in PhMe/TMEDA at -78 °C for 1 h

was unsuccessful. Only the starting material was recovered, perhaps due to the electron-

rich enol double bond or the steric hindrance of the dimethylfuranyl group.

In summary, the β-carbolithiation of a range of N-aryl-N-isopropyl-O-

vinylcarbamates, coupled with tandem N to C aryl migration, nitrosation and deprotection,

provides a method for the construction of branched tertiary benzylic, propargylic, and

allylic alcohols in a single pot from simple precursors.

182

II.5 Further Extension of the Methodology

We have showed that when carbamates bearing N’-aryl groups are lithiated, a

remarkably fast nucleophilic substitution at the ispo position of the aryl group leads to

intramolecular transfer of the aryl substituent to the carbanion centre. Given that this

intramolecular nucleophilic aromatic substitution is successful even with electron rich

rings, it seems plausible that the migration of electron-rich alkenyl groups might also be

feasible. We therefore investigated the migration of styrenyl and vinyl groups and

compared with the above methods.

II.5.1 N to C Vinyl Migration in Lithiated O-Benzylcarbamates

In a preliminary experiment, the most obvious activated styrenyl migrating group

was studied. O-benzyl-N-styrenyl carbamate 305 was made in 49 % over three steps from

-methylbenzylalcohol 183d by reaction with the alkenyl isocyanate 302 available via a

Curtius rearrangement of cinnamic acid 301 in the presence of diphenylphosphoryl azide

(dppa)[196]

followed by methylation with sodium hydride and methyl iodide (Scheme 163).

Scheme 163. Preparation of O-Benzyl-N-styrenyl carbamate 305.

OH

O

NH

O

O MeNCO

HO

Me

NEt3, CH2Cl2RT, 1 h

1. NaH, DMF, 20 min, 0 °C2. MeI, RT, 1 h

1. DPPA, NEt3,benzene2. PhMe,

301

302

183d


N O

Me

O Me

304

When 305 was treated with LDA (2.5 equiv.) in THF/DMPU (4/1 v/v) at -78 °C for 1

h, only the starting material was recovered. On repeating the rearrangement of 305 at -

183

60 °C for 1 h, a compound identified as 307 in the 1H NMR spectrum of the crude reaction

mixture was observed (Scheme 164). We presume that the reaction occurs via the

organolithium intermediates 305Li and 306 by analogy with N to C aryl migration.

Therefore, it is an alternative way to make -aryl, -alkenyl tertiary alcohols.

Scheme 164. Rearrangement of a Styrenyl Group in Lithiated Carbamate 305.

N O

Me

O Me

MeHN O

O

N O

O

Me

LiLnMeN O

OLiN O

Me

O LiLn

Me

1. LDA (2.5 equiv.),THF/DMPU,-60 °C, 1 h

2. MeOH307305

306

deprotonation

migration

protonation

Me

MeMe

305Li

307Li

More remarkably, even the simple unactivated vinyl carbamates 308 underwent

rearrangement, allowing vinylation of the organolithium (Scheme 165). Vinyl carbamates

308 were made in two steps from commercially available starting materials, employing the

usual methods. As observed for the styrenyl group, vinyl migration seems slower than aryl

migration since at -78 °C after 2 h in THF/DMPU, the rearranged product 309 was

obtained along with a significant amount of starting material. In most cases, complete vinyl

migration was observed by performing the reaction at -45 °C in THF/DMPU for 1-4 h

affording the rearranged derivatives 309 in good to moderate yields or the in-situ

deprotected rearranged product 310a in 22 % yield (Table 36).

184

Scheme 165. Vinylation of O-Benzylcarbamates 308 from -methylbenzyl alcohols 183.

N O

Me

O Me

MeHN O

O

309308

Me

NCO

HO

Me1.

NEt3, CH2Cl2RT, 1 h

2. (i) NaH, DMF,0°C, 20 min(ii) MeI, RT, 1h

183

R

R = H, Cl, CF3,Me, OMe

R

1. LDA (2.5 eq.),THF/DMPU,-45 °C

R2. MeOH

Table 36. Yields for the Vinyl Migration of O-Benzylcarbamates 308.

Entry S.M. Yield

a

(%) Product

Time

(h)

Yield

(%)

1 N O

Me

O Me

308a

69 MeHN O

O Me

309a

1 70

2 N O

Me

O Me

308b Cl

52 MeHN O

O Me

309bCl

1 54

3 N O

Me

O Me

308c

CF3

32 MeHN O

O Me

309c

CF3

1 32

4 N O

Me

O Me

308d

Me

65 MeHN O

O Me

309d

Me

4 48

5 N O

Me

O Me

308e OMe

62 HO

Me

310a OMe

4 22b

Conversion of the crude product 309a to the -tertiary allylic alcohol 310b was

achieved simply by solvolysis in mild base. Treatment of the carbamate with EtONa in

refluxing EtOH[55]

gave 310b in 48 % over two steps in a single reaction vessel (Scheme

166).

a yields over two steps

b starting material remaining

185

Scheme 166. Conversion to -Tertiary Allylic Alcohol 310b.

N O

Me

O Me

308a

HO

310b, 48 % over 2 steps

1. (i) LDA, THF, DMPU,-45 °C, 1 h(ii) MeOH

2. EtONa, EtOH,, 3 h

The low configurational stability of benzylic organolithiums bearing -oxygen

substituents under the conditions to promote rearrangement as observed previously meant

that the product 309a was not obtained enantiomerically pure from enantiomerically pure

starting material 308a. Essentially racemic 309a or returned racemic or partially racemic

starting material 308a were obtained under all conditions attempted.

Further details of the migration of the vinyl group in carbamate 308a were provided

by in-situ IR spectroscopy (Scheme 167; Figure 20). In THF at -45 °C, the carbamate 308a

displayed two absorptions at 1716 and 1625 cm-1

which disappeared over a period of 25

min on treatment with LDA being replaced by two new intermediates with absorptions at

1660 and 1616 cm-1

. Quenching the reaction at this stage returned the starting material and

the rearranged product, so we assume that the transient absorptions arise from the lithiated

carbamate 308aLi and the lithiocarbamate 309aLi. Slowly warming the reaction to room

temperature promoted the rearrangement. At 5 °C the absorption at 1660 cm-1

began to

decrease in intensity to give, about 10 min later, only the absorption at 1616 cm-1

.

Quenching the reaction with MeOH generated a peak at 1735 cm-1

assigned to the

rearranged product 309. The lag between the disappearance of 308Li and the complete

formation of 309Li hints at the intermediacy of a cyclic structure 311, but we were unable

to identify clearly absorptions corresponding to this proposed structure.

186

Scheme 167. Intermediates Detected in the Rearrangement of 308a.

N O

Me

O Me

MeHN O

O

N O

O

Me

MeN O

OLi

N O

Me

O [Li]

Me

1. LDA (1.5 eq.),THF, -45 °C

2. MeOH

309a

308a 308aLi

311

309aLi

MeMe

Me

[Li]

-45 °C to RT

H

1716 cm-1 1656 cm-1

1735 cm-11621 cm-1

Figure 20. In Situ React IR Monitoring of the Rearrangement of 308a Using LDA at -

45 °C. (a) Three-dimensional plot of absorbance versus wavenumber versus time. (b)

Several sequential two-dimensional infrared spectra at various stages of the reaction.

Carbamate 308a in

THF at -45 °C

LDA added

at -45 °C

Warmed to RT

Quenched

1716cm-1

: 308a

1735cm-1

: 309a

1664 &

1649cm-1

: 308aLi

1627 &

1616cm-1

: 309aLi

(a)

187

II.5.2 Attempted N to C Alkynyl Migration in Lithiated O-

Benzylcarbamates

Alkynyl migration seems plausible given the reactivity of ynamides as shown in

Figure 21. The electron-donating ability of the nitrogen atom (tempered by the electron-

withdrawing group) polarizes the triple bond, which allows for a high level of reactivity

with a strong differentiation of the two sp-hybridized carbon atoms.

Figure 21. General Reactivity of Ynamides.

R N

R'

EWG

R

N•R'

EWG

NucleophilesElectrophiles

(b)

Carbamate in THF at -45 °C

LDA added at -45 °C

Warmed up to RT

At RT

Quenched

188

II.5.1 Synthesis of Ynecarbamates[197]

The use of hypervalent alkynyliodonium salts as alkynylating agents[198]

and the

copper-catalyzed coupling of amides with alkynyl halides,[199]

alkynyltrifluoroborotes,[200]

terminal alkynes,[201]

1,1-dihalo-1-alkenes,[202]

or propiolic acids[203]

have emerged as

efficient strategies for the preparation of ynamides.

In most cases, oxazolidinones are the most tolerated amide substrates for the

transformation. Other classes of amides such as acyclic carbamates were all poor coupling

partners, probably because of their increased steric hindrance compared to their cyclic

homologues and their lower acidity. Gratefully, Hsung et al. communicated an efficient

and general method for the synthesis of acyclic ynecarbamates featuring a copper sulphate-

pentahydrate-1,10-phenanthroline driven catalytic system.[199c]

The synthesis of N-methyl ynecarbamate 316a was therefore achieved in 43 % yield

by coupling N-methyl-O-benzylcarbamate 314a and phenyl alkynyl bromide 315

employing CuSO4.5H2O and 1,10-phenanthroline with K3PO4 as the base in toluene at

100 °C (Scheme 168, Strategy 1). However, when N-isopropyl-O-benzylcarbamate 316b

was engaged in the reaction under the same conditions, only a poor yield was obtained,

presumably due to the lower acidity of 314b.

Tetraisopropylsilyl alkynyl bromides were showed to be a better partner,[199d]

which

would be more versatile given the readily removable TIPS group. Pleasingly, repeating the

reaction with alkynyl bromide 318 and N-isopropyl-O-benzylcarbamate 314b or -

methylated N-isopropyl-O-benzylcarbamate 314c allowed the isolation of 319a and 319b

in good yields (Scheme 168, Strategy 2). The TIPS group was then removed with TBAF in

THF at 0 °C to give ynecarbamates 320a and 320b in excellent yields.[199b]

These products

can be further transformed to aryl-substituted ynecarbamates 316b and 316c in excellent

yields by a Sonogashira cross-coupling reaction with iodobenzene using 10 mol % of

Pd(PPh3)4 and 7 mol % of CuI in DiPEA/toluene at room temperature.[204]

O-

Benzylcarbamate 314 were made in reasonable yields from either commercially available

O-benzyl chloroformate 312a or 312b formed in-situ with triphosgene, which subsequently

reacted with isopropylamine in the presence of pyridine in CH2Cl2. Bromoalkynes 315 and

318 were readily formed in good yields by bromination of the corresponding terminal

alkynes 313 and 317 upon treatment with NBS and AgNO3 in acetone.[205]

A more direct

way of making 316c would have been the deprotonation of 316b with sec-BuLi/TMEDA

in toluene at -78 °C followed by methylation with MeI, but the reaction failed.

189

Scheme 168. Synthesis of Ynecarbamates.

N O

Ph

R1

O

ONH

O

R1 Ph

Br

Ph

H

O

O

Cl

312a

R1 NH2, Py,

CH2Cl2, RT

314a, R1 = Me, 65 %

314b, R1 = i-Pr, 78 %

313

NBS, AgNO3,acetone, RT

315, 82 %

K3PO4, CuSO4.5H2O,1,10 phenanthroline

PhMe, 100 °C, 45 h

316a, R1 = Me, 43 %

316b, R1 = i-Pr, 10 %

(a) Strategy 1: Copper-catalyzed amidation of phenyl alkynyl bromide

ONH

O

i-Pr

R2

HO

Me

1. (Cl3CO)2CO, THF,NEt3, RT2. i-PrNH2, Py,CH2Cl2, RT

183d

314b, R2 = H

314c, R2 = Me, 45 %

TIPS

Br

318, 83 %

TIPS

H317

NBS, AgNO3,acetone, RT

N O

TIPS

i-Pr

OK3PO4, CuSO4.5H2O,1,10 phenanthroline

PhMe, 100 °C, 45 h

R2

319a, R2 = H 61 %

319b, R2 = Me, 65 %

TBAF, THF,0 °C, 1 h

N O

H

i-Pr

O R2

320a, R2 = H, 88 %

320b, R2 = Me, 82 %

PhI, Pd(PPh3)4,CuI, DiPEA

PhMe, RT, 15 hN O

Ph

i-Pr

O R2

316b, R2 = H, 84 %

316c, R2 = Me, 68 %

(b) Strategy 2: TIPS group as a key in the synthesis of N-isopropyl ynecarbamates

190

II.5.2 Reactivity of Lithiated Ynecarbamates

First of all, TIPS-substituted ynecarbamates 319a and 319b turned out not to be

suitable substrates for alkynyl migration (Scheme 169). The lithiated ynecarbamate 319a

generated with 2.5 equiv. of LDA was unreactive in THF/DMPU either at -78 °C or -45 °C

(Table 37, entries 1 and 2). By concentrating the reaction and using LiCl[206]

to enhance

the reactivity of the intermediate lithium species (entries 3 and 4), the lithiated product of

319a was prone to 1,2-acyl shift giving 321a. Likewise, the product 321b was formed from

319b under the same conditions (entry 5). From these results, it can be concluded that the

excess of lithium cation might complex the carbonyl oxygen atom of the carbamate group

and facilitated the attack on the carbonyl group.

Scheme 169. Attempted Alkynyl Migration in Lithiated 319a and 319b.

N O

TIPS

i-Pr

O OH

N

O

i-Pr

TIPS

LDA (2.5 eq.),THF/DMPU

319a, R2 = H

319b, R2 = Me

(Table 37)

R2

R2

321a, R2 = H

321b, R2 = Me

Table 37. Conditions for 1,2-Acyl Shift in 319a and 319b.

Entry S.M. Temp. (°C) Time (h) Additive Result

1 319a -78 2 - 319a

2 319a -45 2 - 319a

3a 319a -45 2 LiCl 319a

4b 319a -45 2 LiCl 321a, 24 %

5b 319b -45 2 LiCl 321b, 20 % + 319b

The isolation of 321a and 321b implied that the 1,2-acyl shift competed against the

1,4-alkynyl migration. We reasoned that the replacement of the TIPS group by a phenyl

group might compromise the reactivity of the acetylenic bond and thereby its increased

electrophilicity could favour 1,4-alkynyl migration.

a c = 0.13 M;

b c = 0.22 M

191

Attempted migration of the alkynyl group in 316a upon treatment with LDA in the

presence of LiCl was unsuccessful: either starting material was recovered at -78 °C in

THF/DMPU or nucleophilic attack on the carbamate C=O group was observed at -45 °C.

Attempts to reduce the susceptibility of the carbonyl group to nucleophilic attack by

replacing the N-methyl with an N-isopropyl group enabled three oxazolidinones 322, (Z)-

323 and 324 to be isolated after quenching with MeOH (Scheme 170).

Scheme 170. Cyclisation of Ynecarbamate 316b.

N O

Ph

i-Pr

O

N O

Ph

i-Pr

O LiLnN

O

Oi-Pr

Ph

LnLi

cyclisation

NO

Oi-Pr

Ph

NO

Oi-Pr

Ph

NO

Oi-Pr

Ph

OH

1. LDA (2.5 eq.),THF/DMPU, LiCl

2. MeOH

316b

324322 (Z)-323

316aLi

oxidation-protonationdeprotonation -protonation

NO

Oi-Pr

Ph

LiLn

protonshift

322Li

Oxazolidinone 322 was produced as a major product accompanied by its isomer 323

with Z-configuration (confirmed by a nOe experiment) and an unexpected cyclised product

324, regardless of the temperature (-45 °C or -20 °C) and the time used (Table 38). X-ray

crystallography confirmed the structure of 324 (Figure 21). We presumed that the reaction

proceeds through deprotonation of the carbamate to O to give benzyllithium 316aLi,

followed by attack on the acetylenic bond to give the intermediate exo,exo-3-lithiumallyl

complex 322Li, which is protonated at its γ or position giving 322 or (Z)-323, or

oxidized at its γ position forming 324. Migration of the alkynylic substituent is therefore

interrupted by the stability of the vinylic intermediate anion 322Li. The triple bond acts as

an internal electrophile toward the organolithium intermediate and it is therefore

reasonable to say that this reaction corresponds to an intramolecular carbolithiation.

192

Table 38. Conditions and Yields for Cyclisation of Ynecarbamate 316b.

Entry Temp. (°C) Time (h) Yield (%)

1 -45 5 322, 20 + 323, 8 + 324, 18

2 -45 15 322, 30 + 323, 10 + 324, 12

3 -20 2 322, 36 + 323, 6 + 324, 20

Figure 21. X-ray Crystal Structure of 324.

Despite the failure of the alkynyl group to migrate in 316b, we examined the

behaviour of -methylated ynecarbamate 316c, which in fact cyclised in the predicted

manner as illustrated in Scheme 171. Upon treatment with LDA in THF/DMPU in the

presence of LiCl at -20 °C, three oxazolidinones were isolated in poor yields: (Z)-325

might be the result of 1,2-acyl shift followed by an anti-stereoselective 5-exo-dig

cyclisation of the oxygen nucleophile onto the triple bond (Scheme 171).[207]

However, a

syn-addition and isomerization of the double bond in the more stable vinyllithium 325aLi

cannot be excluded completely. (Z)-238, isolated in poor yield, perhaps, arises from the

vinyllithium 238bLi, which was expected to be primarily formed in the intramolecular syn-

addition of the corresponding lithiated ynecarbamate 316bLi to the triple bond.[208]

In

contrast, the product (E)-238, formed in 18 % yield, probably emerged from the

thermodynamically more stable vinyllithium species 238aLi, being in equilibrium with

238bLi.

193

Scheme 171. Proposed Pathways for the Cyclisation of -Methylated Ynecarbamate 316c.

N O

Ph

i-Pr

O

316c

Me NO

Oi-Pr

Ph

NO

Oi-Pr

Ph

NO

i-Pr

O

Ph

MePh

Me PhMe Ph

1. LDA (2 eq.)THF/DMPU,LiCl, -20 °C, 2 h

2. MeOH

(E)-238, 18 %(Z)-238(Z)-325

16 % (1:0.7) (unseparable)

316cLi

N O

O

i-Pr

Ph

LiPh

NO

Oi-Pr

Ph MePh

NO

Oi-Pr

Ph

Me Ph

238bLi 238aLi

Li

NO

i-Pr

O

Ph

Me Ph325aLi

1,2-acyl shift

Li

Li

Li

NO

i-Pr

OMe Ph

Ph

Li NO

i-Pr

OMe Ph

325bLi

LiPh

II.5.3 Attempted N to C Cyano Migration in Lithiated O-

Benzylcarbamates

N-Cyanocarbamate 326 was easily made in 50 % yield in two steps in a single

reaction vessel from O-benzyl chloroformate 312a (Scheme 172).[209]

This latter compound

was treated with an excess of monosodium cyanamide, freshly prepared by reaction with

cyanamide and sodium hydroxide in 2-propanol,[210]

to give the intermediate N-

cyanocarbamate. Given its instability at room temperature[211]

it was immediately

methylated with NaH and MeI to yield N-cyanocarbamate 326.

194

Scheme 172. Preparation of N-Cyanocarbamate 326 and Attempted Migration or

Cyclisation.

N O

O

NC

Me

OCl

O1. NaNHCN,THF, RT, 15 h

2. NaH, DMF,MeI, RT, 15 h

MeHN O

O CNN

O

OMe

HNor/and

LDA (2 eq.),THF/DMPU,LiCl, -78 °C, 3 h

HO

312a


327 328

329

In the hope of promoting the rearrangement of the cyano group or the cyclisation

affording 327 or 328, N-cyanocarbamate 326 was treated with LDA (2.0 equiv.) in

THF/DMPU at -78 °C. However, 1H NMR showed only benzylic alcohol 329 resulting

from nucleophilic attack on the carbamate C=O group. No further studies were pursued

with this compound suspecting that the strong electron-withdrawing cyano group renders

the carbonyl group extremely sensitive to nucleophilic attack under any conditions.

II.5.4 Attempted N to C Heteroaryl Migration in Lithiated O-

Benzylcarbamates

As demonstrated previously, the formation of tertiary alcohols bearing an aryl and a

heteroaryl rings failed either by -deprotonation-aryl migration of O-heteroarylcarbamates

(see Section II.2.4.1) or by β-carbolithiation-aryl migration of -heteroaryl-O-

vinylcarbamates (see Section II.4.5.3). Another alternative to access to these alcohols

would be the migration of heteroaryl groups. We therefore embarked on the migration of

the benzothiazole group.

As reported by the group, Pd-catalyzed amidation of bromopyridines proved to be an

efficient method for the synthesis of N-pyridyl-ureas.[64]

Pleasingly, this procedure could

be successfully applied to the preparation of N-benzothiazol-O-benzylcarbamate 328 in

moderate yield (34 %) with Pd2(dba)3, Xantphos, NaOt-Bu in toluene at 100 °C (Scheme

173). O-Benzylcarbamates 314 were made by the usual method as described previously

195

and bromobenzothiazole 327 was synthesised by treatment of aminobenzothiazole 326

with t-BuONO and CuBr2 in acetonitrile in 87 % yield.[212]

Scheme 173. Preparation of N-Benzothiazol-O-benzylcarbamate 328.

ON

O

Me

N

S

S

NBr

S

NNH2

t-BuONO, CuBr2,CH3CN, 60 °C

327, 87%

ONH

O

R

O

O

Cl

312a

R1 NH2, Py,

CH2Cl2, RT

314a, R = Me, 65 %314b, R = i-Pr, 78 %

326

Pd2(dba)3, Xantphos,NaOt-Bu

PhMe,100 °C, 16 h

328, 34 %

R = Me

R = i-Pr

NH

N

Si-Pr

329

N

S

N

330

i-Pr

N

S

However, upon treatment with LDA (2.0 equiv.) in THF/DMPU at -78 °C for 1 h, N-

benzothiazol-O-benzylcarbamate 328 was cleaved. Pd-catalyzed amidation with N-

isopropylcarbamate 314b was not successful: only two side products 329 and 330 were

isolated, which nonetheless indicates that the amidation had occurred.

In summary, deprotonation of benzylic carbamates bearing N’-alkenyl substitutents

generated -O-stabilized tertiary carbanions which underwent intramolecular migration of

a styrenyl group and simple vinyl groups to the carbanionic centre. This provides an

alternative route to the synthesis of -arylated, -alkenylated tertiary alcohols, which was

unsuccessful by N to C aryl migration of simple O-allylcarbamates (see Section II.3.1.4).

However, migration of alkynyl substituents failed. Terminal substituent such as a TIPS

group is too electron-rich for being nucleophilically attacked, thereby promoting the

competing 1,2-acyl shift. In contrast, a phenyl-substituted alkyne facilitated the insertion of

196

the carbon-carbon triple bond into the carbon-lithium bond but the stability of the resulting

vinylic intermediate anion interrupted the alkynyl migration.[213]

197

II.6 Conclusions and Future Work

Many classes of electrophiles, including alkylating and acylating agents, carbonyl

compounds and halogenating agents, are compatible with organolithium chemistry.

However, competing reactions such as elimination or halogen metal exchange limit the use

of some substrates, and the direct arylation or vinylation of organolithiums is a particular

challenge typically overcome by transmetallation with copper or zinc. And, the use of

organolithiums to form C-C bonds is generally limited to quenches with alkylating agents

and carbonyl compounds, with coupling to sp2 carbon atoms to conjugate additions and

substitutions with electrophiles carrying anion stabilizing groups. The intramolecular aryl

and vinyl transfers we have described overcome these limitations.

We have successfully completed the first enantioselective synthesis of the

antihistaminic agent (S,S)-clemastine 98.[214]

The synthesis featured an application of our N

to C aryl migration in lithiated carbamate 95i, which provided the enantiomerically

enriched tertiary alcohol (S)-97i, setting one of the two chiral centres. Commercially

available (S)-N-Cbz-proline 169 was used to construct the second fragment,

enantiomerically pure chloroethylpyrrolidine (S)-151. (S,S)-Clemastine was finally made

by the challenging ether formation between these two fragments, followed by

recrystallisation from fumaric acid. Moreover, this synthesis has permitted us to bring

further evidence for the invertive nature of the rearrangement of carbamates.

198

Scheme 174. Synthesis of ()-(S,S)-Clemastine.

(S)-151

(S)-97i

(S)-169 (S)-174

(S)-95i(S)-183a

N

Me

OMe

Cl

s s

N Cl

Me

s

N OMe

Cbz

sO

N CO2H

Cbz

s

HOMe

Cl

ss

MeN O

Me

Cl

O

s

Me

Cl

HO

Arndt-Eistert

(S,S)-clemastine

invertive arylmigration

The scope of N to C aryl migration has been extended to a wide range of stabilized

lithiated carbamates. One the one hand, -deprotonation of -methylated O-allyl and O-

propargylcarbamates led to arylated allylic and propargylic alcohol derivatives 204, 218

and 242 or benzylidene oxazolidinones 238 (Scheme 175 (a)). In the other hand, -

deprotonation of O-vinylcarbamates 248 allowed the formation of diarylated allylic alcohol

derivatives 251 in excellent yield (Scheme 175 (b)). However, competition between

racemization and rearrangement of these lithiated carbamates hampered to make the

rearranged products enantioselectively by stereospecific N to C aryl migration.

Nonetheless, the reactivity of lithiated O-allyl, O-propargyl and O-vinyl carbamates

bearing N-aryl groups towards migration of the aryl ring from N to C provides a valuable

method for arylating an organolithium centre adjacent to O from very easily made

substrates.

199

Scheme 175. -Arylation of Lithiated Carbamates.

N O

O

Me

Me

R1

MeHN O

O

R1

Me

R1 = C6H5, p-OMeC6H4, TIPS

MeHN O

O Me

TIPS

ON

O

Me

Me

N O

O

Me

R1

Li

Me

MeN O

O

R1

MeLi

base

204, R1 = C6H5

218, R1 = p-OMeC6H4238, 45 to 51 %

242, 66 %

aryl migration

(a) -Deprotonation of O-allyl and O-propargylcarbamates

R1 = C6H5

R1 = TIPS

N O

O

Me O

NHMe

O

R3 R3

R1

R2R2

R1

base

(b) -Deprotonation of O-vinylcarbamates

248

251, 80 to 86 %

-Carbolithiation with simple alkyllithiums followed by N to C aryl migration of -

aryl, alkenyl, and alkynyl-O-vinylcarabamates has been accomplished to obtain multiply

branched alkylalcohols in a one pot reaction in moderate to good yields (Scheme 176).[215]

200

Scheme 176. Tertiary Alcohols by Tandem -Carbolithiation and N to C Aryl Migration in

Enol Carbamates.

N O

i-Pr

OR1

X

HO

R3

R2

R1

HO

Bu

R1

R2HO

R3

R1 R2

294, 54 %281, 40 to 76 %

R3Li

R3Li

X =

X =

X =

R2

266, 27 to 81 %

R2R2

n-BuLi

So far, we have shown that the organolithium intermediate in carbamates, generated

either by deprotonation or -carbolithiation could be stabilized by an aryl, alkenyl,

propargyl and silyl group. It would be interesting to investigate the possibility of stabilising

the intermediate by a cyano, ester or acid carboxylic group, which would provide a direct

route to hydroxyl acids 335 (Scheme 177).

Scheme 177. Aryl Reaction of Hydroxyacid Derivatives.

N O CN

Me

O

MeHN O CN

O

Me

Me

N O

Me

O Me

OR2

O

MeHN O CO2R

O

Me

332, R2 = H or t-Bu

331333

334

HO CO2HMe

335R1

R1

R1

R1

R1

Tandem -carbolithiation and N to C aryl migration could be also applied in the

synthesis of (Z)-Tamoxifen 126, a therapeutic agent for the treatment of estrogen-

201

dependent breast cancer and other emerging clinical applications,[114]

as revealed from the

proposed retrosynthesis in Scheme 179. The key would be to exploite the -elimination of

the carbamate moiety as observed in Section II.3.1.2 when attempted to deprotect

carbamates 204, 96i and 96m by DIBAL-H (Scheme 178).

Scheme 178. -Elimination of Carbamate Moiety.

MeHN O

O

Ph

Me

DIBAL-H, THF, RT

Ph

204 206

MeHN O

O

Me

R96i, R = Cl96m, R = OMe

R

336, R = Cl337, R = OMe

The intermediate 338 in the proposed synthesis of (Z)-Tamoxifen 126 could therefore

be generated by -elimination of the carbamate moiety in 339, which could be obtained by

-carbolithiation of O-vinylcarbamate 340 with EtLi followed by N to C aryl migration

(Scheme 179).

Scheme 179. Proposed Retrosynthesis of (Z)-Tamoxifen.

(Z)-Tamoxifen 126

N O

O

i-Pr

MeO

O

O

i-PrHN

MeOON

-elimination

-carbolithiation

NC aryl migration

338

339340

OMe

202

Interestingly, N to C aryl migration has been extended to the vinyl migration in

carbamates 308, easily made from commercially available secondary alcohols 303 and

vinyl isocyanate (Scheme 180), leading to the -vinylation (and -alkenylation) of

alcohols. The synthesis of quaternary centres bearing heteroatoms is in many cases

challenging, and the ability to deliver alkenyl substituents to such centres is useful.

Scheme 180. Intramolecular vinylation in lithiated tertiary carbamates.

HO Ar

Me

NCO1.

2. NaH, MeI

N O

Me

O

Ar

Me

2. MeOH MeHN O Ar

O Me

HO Ar

Me

NaOEt,EtOH,

303

308 309, 32 to 70 %

310

1.LDA, THF,DMPU,-45 °C, 1 h

vinylation

Several difficulties have been encountered: (a) deprotection of rearranged carbamate

products by usual methods returned only unwanted products. However, conversion to -

tertiary alcohols was found to be feasible in a one-pot reaction with t-BuONO; (b)

instability of some N-methyl-N-aryl carbamates under basic conditions led to carbamate

cleavage, which was solved by the introduction of an N-isopropyl group instead of the N-

methyl group; (c) the competing 1,2-acyl shift of some N-aryl carbamates hampered the

rearrangement to take place; (d) in the asymmetric version, competition between

racemization and rearrangement has not allowed the synthesis of enantiomerically enriched

tertiary alcohols. Nevertheless, this was overcome to some degree by the use of ()-

sparteine or TMEDA.

203

CChhaapptteerr IIIIII :: EEXXPPEERRIIMMEENNTTAALL SSEECCTTIIOONN

III.1 General Information

All non-aqueous reactions were conducted under an atmosphere of dry nitrogen in

oven dried glassware. The temperatures quoted are those of an external bath. Cooling baths

used are acetone/dry ice for -78 °C and acetonitrile/dry ice for -42 °C.

Reagents and solvents were used as received except where stated below. All solvents

and reagents requiring purification were done so using standard laboratory techniques.[216]

Tetrahydrofuran was distilled from sodium wire and using benzophenone as a radical

indicator under nitrogen atmosphere. The Solvent Purification System (SPS) was used for

diethyl ether and toluene. Dichloromethane and diisopropylamine were obtained by

distillation from calcium hydride under nitrogen. Petrol refers to the fraction of light

petroleum ether boiling between 40 and 65 °C. Acetonitrile and DMPU were distilled,

under reduced pressure, from calcium hydride, and stored over molecular sieves. TMEDA

was distilled over KOH. ()-Sparteine was purified by Küglerhor distillation.

Triethylamine and pyridine were stored over KOH.

n-Butyllithium was obtained from Acros as a solution in hexanes (2.5 M), sec-

butyllithium in cyclohexane/hexane (92/8) (1.3 M), isopropyllithium in pentane (0.7 M),

tert-butyllithium in pentane (1.9 M), phenyllithium in n-butylether (2.0 M), methyllithium

in diethylether (1.6 M). All the above organolithium solutions were titrated prior to use

against a solution of N-benzylbenzamide.

Analytical thin layer chromatography (TLC) was carried out on pre-coated UV254

plates (Macherey-Nagel alugram. Sil G/UV254 or Machery-Nagel polygram. Alox N/UV254),

with visualisation by UV light at 254 nm, phosphomolybdic acid dip or potassium

permanganate dip. Flash column chromatography was carried out using Fluorochem

Davisil 40 – 63 µm 60 Å silica, under a positive pressure by means of compressed air,

followed by removal of the solvent under reduced pressure after purification.

Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Varian XL

300 (300 MHz), Bruker Ultrashield 400 (400 MHz) or 500 (500 MHz) spectrometer with

204

residual non-deuterated solvent as the internal standard. Carbon nuclear magnetic

resonance (13

C NMR) spectra were recorded on a Varian XL 300 (75 MHz), Bruker

Ultrashield 400 (100 MHz) or 500 (125 MHz) spectrometer. NMR data are presented as

follows: chemical shift δ (in parts per million (ppm) downfield of trimethylsilane),

multiplicity, coupling constant J (in Hz), integration, and assignment (based on chemical

shift, integration, coupling pattern and COSY, DEPT, HMQC and HMBC NMR

experiments when necessary). Splitting patterns are abbreviated as follows: singlet (s),

doublet (d), triplet (t), quartet (q), quintet (qn), septet (sep), octet (oct), nonet (non),

multiplet (m), broad (br), or a combination of these. The solvent used was deuterated

chloroform (δH: CDCl3 7.26 ppm; δC: CDCl3 77.0 ppm; δH: CD3OD 3.31 ppm; δC: CD3OD

49.0 ppm).

Low and high resolution mass spectra were recorded by staff at the University of

Manchester. EI and CI spectra were recorded on a Fisons VG Trio 2000 and high

resolution mass spectra (HRMS) were recorded on a Kratos Concept-IS mass spectrometer,

and are accurate to 0.001 Da. For the mass spectra of chlorine and bromine containing

compounds, only 35

Cl and 80

Br isotopes are reported.

Infrared spectra were recorded on an ATi Matson Genesis Series FTIR spectrometer.

Absorptions reported are sharp and strong unless otherwise stated as broad (br) or weak

(w), only absorption maxima (max) of interest are reported and quoted as wavenumbers

(cm–1

).

Melting points (m.p.) were determined on a ‘GallenKamp Melting Point’ apparatus

or a Kofler microscope melting point machine and are uncorrected.

Optical rotations [α]DT were measured on an Optical Activity AA-100 using a cell

with a pathlength of 0.25 dm. Concentrations (c) are given in grams per 100 cm3.

Chiral HPLC measurements were carried out on a Hewlett Packard Series 1050

instrument with a Diode Array Detector, using Daicel Chiralcel OD-H, Daicel Chiralpack

AD-H or (R,R)-Whelk-O1 chiral stationary phases using a mixture of hexane and

isopropanol (IPA) as eluent. Absorption was measured at 254 or 214 nm.

205

III.2 General Procedures

General Procedure A – Preparation of racemic secondary alcohols by addition of MeLi

to aldehydes.

To a solution of aldehyde (1.0 mmol) in anhydrous Et2O (c 0.20 M) was added dropwise a

solution of methyllithium (1.5 mmol) at -78 °C under nitrogen atmosphere. The resulting

reaction mixture was stirred for 2 h after which a saturated aqueous solution of NH4Cl was

added. The organic layer was washed with brine, dried over MgSO4, filtered and

concentrated under reduced pressure. The residue was purified by flash column

chromatography.

General Procedure B – Preparation of racemic secondary alcohols by reduction with

LiAlH4.

To a suspension of lithium aluminium hydride (1.5 mmol) in anhydrous Et2O (c 0.20 M) at

0 °C under nitrogen atmosphere was slowly added a solution of ketone (1.0 mmol) in

anhydrous Et2O (c 0.50 M). The mixture reaction was stirred at room temperature for 3 h

and then slowly quenched with EtOH and a saturated aqueous solution of Rochelle’s salt at

0 °C. The organic layer was washed with brine three times, dried over MgSO4, filtered and

concentrated under reduced pressure.

General Procedure C – Preparation of enantiomerically enriched secondary alcohols via

Sharpless Kinetic Resolution.

By the method reported by Sharpless et al.:[158]

To a stirred suspension of 4 Å molecular sieves (pellets) in anhydrous CH2Cl2 (c 0.20 M),

titanium isopropoxide (1.0 mmol) was added under nitrogen atmosphere. The reaction

mixture was cooled to -20 °C and ()-diisopropyltartrate (1.2 mmol) was added and stirred

for 10 min, after which alcohol (1.0 mmol) dissolved in anhydrous CH2Cl2 (c 0.20 M) was

added and stirred at -20 °C for 30 min To the above solution tert-butyl hydroperoxide (5.5

M in decane, 0.6 mmol) was added and stirred at -20 °C for 3.5 h (for 199) or 3 days (for

206

216). After completion of half of the reaction, the reaction mixture was quenched with

10 % aqueous solution of DL-tartaric acid, after which was continued for 30 min at -20 °C

and 15 h at room temperature. The organic layer was separated, washed with water, dried

over MgSO4, filtered and concentrated under reduced pressure. The residue was diluted

with Et2O (c 0.07 M) and stirred with 1.0 M NaOH (5.0 mmol) for 1 h at 0 °C. The organic

layer was then separated, washed with brine, dried over MgSO4, filtered and concentrated

under reduced pressure. The crude compound was purified by flash column

chromatography.

General Procedure D – Preparation of enantiomerically enriched secondary alcohols via

Noyori’s asymmetric transfer hydrogenation.

By the method reported by Noyori et al.:[146]

Catalyst preparation :[146]

A mixture of [RuCl2(η6-mesitylene)]2 (80 mg, 0.13 mmol), (1S,2S)-N-p-toluenesulfonyl-

1,2-diphenylethylenediamine (TsDPEN) (100 mg, 0.26 mmol), and triethylamine (0.08

cm3, 0.52 mmol) (Ru atom:TsDPEN:NEt3 molar ratio = 1:1:2) in 2-propanol (2 cm

3) was

heated at 80 °C under nitrogen atmosphere for 1 h. The orange solution was concentrated

under reduced pressure and the solid Ru complex was collected by filtration. The crude

material was washed with a small amount of water and dried under reduced pressure for 10

h to afford (R)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-p-cymene) 182 as an

orange solid.

Reaction :[52,146]

To triethylamine (2.4 mmol) stirred at 0 °C was added dropwise formic acid (6.0 mmol)

(5:2 formic acid-NEt3 azeotropic mixture). Upon warming to room temperature, ketone

(1.0 mmol) and (R)-RuCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2](η6-p-cymene) 182 (0.5

mol %) were successively added, and the reaction mixture was stirred at room temperature

under nitrogen atmosphere for 48 h. Then it was diluted with water and extracted with

EtOAc three times. The combined organic layers were washed with a saturated aqueous

solution of NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced

pressure.

207

General Procedure E – Preparation of carbamates from isocyanates.

By the method reported by Clayden et al.:[55]

To a solution of alcohol (1.0 mmol) in anhydrous CH2Cl2 (c 0.20 M) were added aryl

isocyanate (1.2 mmol) and triethylamine (2.0 mmol). The solution was stirred at room

temperature for 15 h (or as stated) under nitrogen atmosphere. The mixture was

concentrated under reduced pressure and the product was reacted without purification.

General Procedure F – Preparation of methylated or isopropylated carbamates from

carbamates.


To a solution of carbamate (1.0 mmol) in anhydrous DMF (c 0.25 M) was slowly added

sodium hydride (60 % in mineral oil, 2.0 mmol) at 0 °C under nitrogen atmosphere.

Hydrogen gas was evolved. The mixture was stirred for 30 min at 0 °C and methyl iodide

or isopropyl iodide (2.5 mmol) was added and the solution stirred for 15 h (or as stated) at

room temperature. Water was added carefully and the reaction mixture was extracted with

Et2O. The organic layer was washed with water twice, dried over MgSO4, filtered and

concentrated under reduced pressure. The crude product was purified by flash column

chromatography on silica.

General Procedure G – Preparation of propargyl chloroformates.

O

O R1

ClHO

R1

Cl3CO OCCl3

O

Et2O, C, RT

By a modified method reported by Chandrasekaran et al.:[168f]

To a stirred solution of triphosgene (0.50 mmol) in anhydrous Et2O (c 0.50 M), activated

charcoal was added and stirred for 1 h at room temperature. The solution was cooled to

208

0 °C and propargyl alcohol (1.0 mmol) in anhydrous Et2O (c 1.5 M) was added dropwise.

The resultant solution was stirred for 15 h and filtered through a Celite path. The ether

layer was concentrated under reduced pressure and the resulting oil was used for the

reactions without further purification.

General Procedure H – Preparation of propargyl carbamates from propargyl

chloroformates.

N O

R2

O R1

O

O R1

ClNH

, Na2CO3

CH2Cl2, 0 °C

or

NH

, NEt3

then RT, 15 h

To a solution of propargyl chloroformate (1.0 mmol) and amine (1.0 mmol) in anhydrous

CH2Cl2 (c 0.55 M) was added triethylamine (with N-methylaniline) or sodium carbonate

(with N-isopropylaniline) (1.5 mmol) at 0 °C. The mixture was stirred at room temperature

for 15 h, concentrated under reduced pressure and purified by flash column

chromatography.

General Procedure I – Preparation of N-isopropyl-N-aryl amines by reductive amination.

NH2 O"NaBH(OAc)3"

AcOH, DCERT, 4 h

HN

RR

By the method reported by Abdel-Magid et al.:[173]

A two-necked round bottomed flame-dried flask was equipped with a magnetic stirring bar,

a nitrogen inlet, and a digital thermometer probe and was purged with nitrogen. The flask

was then charged with sodium borohydride (1.5 mmol) and 1,2-dichloroethane (c 0.30 M),

209

then was cooled to 0 °C. Glacial acetic acid (4.5 mmol) was added dropwise maintaining

the internal temperature of the flask below 5 °C and upon completion of acid addition was

allowed to further react at 0 °C for 45 min to ensure completion of formation of sodium

triacetoxyborohydride. The flask was then brought to room temperature over the course of

30 min. Amine (1.0 mmol) and glacial acetic acid (1.5 mmol) were added to the flask and

allowed to stir for 5 min, then distilled acetone (1.0 mmol) was added to the flask dropwise.

The reaction mixture was further agitated at room temperature for a period of 4 h. The

reaction was quenched by the slow addition of a saturated aqueous solution of NaHCO3

and extracted with EtOAc three times. The resulting organic layers were combined, dried

over MgSO4, filtered and concentrated under reduced pressure and the resulting crude was

purified by flash column chromatography.

General Procedure J – Preparation of carbamoyl chlorides.

HN

R4Cl3CO OCCl3

O

Py, CH2Cl2RT., 2 h

N Cl

O

R4

R R

By the method reported by Rouden et al.:[172]

To triphosgene (1.0 mmol) in anhydrous CH2Cl2 (c 0.30 M) at -78 °C were added pyridine

(2.8 mmol) then amine (2.8 mmol) slowly under nitrogen atmosphere. The reaction

mixture was warmed to room temperature, stirred for 2 h then hydrolyzed with 1 N HCl.

The product was extracted with CH2Cl2 and the organic extract was washed with a

saturated aqueous solution of NaHCO3, dried over MgSO4, filtered and concentrated under

reduced pressure. The resulted product was reacted on without purification.

210

General Procedure K – Preparation of -aryl-O-vinylcarbamates.

N Cl

O

R4

DMSO, NaH,RT, 15 h

O N O

R4

OR1

R3

R3

R2

R2

R1

By the method reported by Feringa et al.:[170]

A two-necked round bottomed flame-dried flask was equipped with a magnetic stirring bar,

a nitrogen inlet, and a digital thermometer probe and was purged with nitrogen. The flask

was then charged with sodium hydride (60 % in mineral oil, 1.5 mmol) and anhydrous

DMSO (c 2.5 M) was slowly added under nitrogen atmosphere and under vigorous stirring.

The mixture was heated at 75 °C for 45 min and cooled to room temperature. The

completion of the reaction is shown by the disappearance of sodium hydride and the

cessation of hydrogen evolution. The final solution was milky and grey-olive in colour.

Ketone (1.0 mmol) in anhydrous DMSO (c 4.0 M) was added slowly to dimsyl anion

solution, the addition being slightly exothermic and changing the color of the solution. The

solution was stirred for 15 min at room temperature and then cooled to 10 °C. The addition

of the corresponding carbamoyl chloride (1.1 mmol) in anhydrous DMSO (c 0.10 M) was

carried out while maintaining the temperature at 10 °C. After stirring 15 h at room

temperature, the solution was carefully quenched with water, extracted with n-hexane five

times and dried over MgSO4. The solvent was removed under reduced pressure and the

residue was purified by flash column chromatography or crystallisation.

General Procedure L – Preparation of simple O-vinylcarbamates.

N Cl

O

O

n-BuLi

RT, 15 h

OLi

R2

DMPU, RT, 4 h

N O

OR2

211

By a modified method reported by Snieckus et al.:[186]

A solution of n-BuLi (1.5 mmol) in anhydrous THF (c 1.3 M) was stirred at room

temperature for 15 h. The solution was then cooled to 0 °C and the corresponding N-

isopropyl-N-aryl carbamoyl chloride (1.0 mmol) in anhydrous DMPU (c 1.7 M) was added.

The solution was allowed to stir at room temperature for 4 h, which caused the color to

change to red. The reaction was quenched with a saturated aqueous solution of NH4Cl and

after extraction with Et2O, the organic layer was washed with water twice and dried over

MgSO4. After removal of the solvent under reduced pressure, the residue was purified by

flash column chromatography.

General Procedure M – -iodonisation of simple O-vinylcarbamates.

N O

OR2

1. t-BuLi, THF, -78 °C, 1 h

2. I2, THF,RT, 30 min

N O

OR2

I

To a solution of O-vinylcarbamate (1.0 mmol) in anhydrous THF (c 0.25 M) was added

tert-BuLi (1.1 mmol) at -78 °C under nitrogen atmosphere. The yellow solution was stirred

for 1 h. A solution of iodide (3.0 mmol) in anhydrous THF (c 0.15 M) was added dropwise

at -78 °C and the resulting solution was allowed to warm up to room temperature for 30

min, then diluted with EtOAc and quenched with a 25 % aqueous solution of sodium

metabisulfite. The organic layer was washed with brine, dried over MgSO4, filtered and


chromatography.

General Procedure N – Preparation of -propargyl-O-vinylcarbamates.

N O

OR2

I

H

R1 , NEt3

CuI, Pd(PPh3)4, RT

N O

OR2

R1

212

By a method reported by Hoppe et al.:[188]

To iodovinylcarbamate (1.0 mmol) in triethylamine (c 0.25 M) were added the

corresponding acetylene (1.2 mmol), copper(I) iodide (2 mol %) and tetrakis

(triphenylphosphine) palladium(0) (1 mol %) under nitrogen atmosphere. The reaction

mixture was stirred for 15 h at room temperature after which a saturated aqueous solution

of NH4Cl was added. The aqueous layer was extracted with Et2O. The organic layer was

washed with water twice, dried over MgSO4, filtered and concentrated under reduced

pressure. The residue was purified by flash column chromatography.

General Procedure O – Organolithiums mediated rearrangement or alkylation/arylation

of carbamates.

A solution of freshly prepared LDA solution in anhydrous THF (c 0.35 M) or

organolithium (equiv. as stated) was added dropwise to a precooled (-78 °C or as stated)

solution of carbamate (1.0 mmol) in anhydrous THF or Et2O (c 0.07 M) with or without

anhydrous DMPU (4:1 v/v). The resulting reaction mixture was stirred under nitrogen

atmosphere after which MeOH (10 mmol) and a saturated aqueous solution of NH4Cl were

added and the reaction mixture stirred for a further 30 min while warming to room

temperature. The reaction mixture was diluted with Et2O and the organic layer was washed

with water twice. The combined organic layers were dried over MgSO4, filtered and

concentrated under reduced pressure to give a residue which was purified by flash column

chromatography.

LDA: n-BuLi (1.0 mmol) was added dropwise to a stirred solution of distilled

diisopropylamine (1.0 mmol) in distilled THF or Et2O (c 0.35 M) at 0 °C under nitrogen

atmosphere and allowed to stir for 20 min.

General Procedure P – Organolithiums mediated rearrangement or alkylation/arylation

of carbamates and quenching with t-BuONO.

Freshly prepared LDA solution in anhydrous THF (c 0.35 M) or organolithium (equiv. as

stated) was added dropwise to a precooled (-78 °C) solution of carbamate (1.0 mmol) in

anhydrous THF (c 0.15 M). The resulting reaction mixture was stirred under nitrogen

213

atmosphere after which tert-butyl nitrite (6.0 mmol) was added and the reaction mixture

was stirred at room temperature for 24 h. The mixture was diluted with Et2O and the

organic layer was washed with saturated aqueous K2CO3 three times, dried over MgSO4,

filtered and concentrated under reduced pressure to give a residue which was purified by


General Procedure Q – The LiTMP or LDA mediated rearrangement of carbamates in

Et2O (for avoidance of racemisation).

A solution of LiTMP or LDA (2.5 mmol) in anhydrous Et2O (c 0.25 M) was added to a

solution of carbamate (1.0 mmol) in anhydrous Et2O (c 0.10 M) with or without freshly

distilled ()-sparteine (1.0 mmol) at -78 ºC under nitrogen atmosphere. The reaction was

allowed to stir at -78 ºC for 45 min and was then warmed slowly to -35 ºC. The reaction

was maintained at this temperature for 24 h. The reaction was quenched with MeOH (10

mmol) and a saturated aqueous solution of NH4Cl, diluted with Et2O and washed with

water twice. The combined organic layers were dried over MgSO4, filtered and


chromatography.

General Procedure R – Deprotection of rearranged carbamate products with NaOEt


Rearranged product (1.0 mmol) was dissolved in EtOH (c 0.10 M) and NaOEt (21 % w/w

in EtOH, 10 mmol) was added. The solution was heated at 78 °C for 2 h. The solution was

cooled to room temperature and neutralised with glacial acetic acid. The residue was

washed with water three times. The crude product was purified by flash chromatography

on silica.

General Procedure S – Carbolithiation reactions in toluene/TMEDA.

A solution of n-BuLi (2.5 mmol) was added dropwise to a precooled solution (-78 °C) of

carbamate (1.0 mmol) in a mixture of anhydrous toluene (c 0.14 M) and distilled TMEDA

214

(2.5 mmol) under nitrogen atmosphere. The resulting reaction mixture was warmed up to -

30 °C for 2 h after which MeOH (10 mmol) and a saturated aqueous solution of NH4Cl

were added and the reaction mixture stirred for a further 30 min while warming to room

temperature. The mixture was diluted with Et2O. The organic layer was washed with water

twice and the combined organic layers were dried over MgSO4, filtered and concentrated

under reduced pressure. The residue was purified by flash column chromatography.

General Procedure T – Alkylation/arylation reactions in toluene/TMEDA followed by

addition of DMPU.

A solution of n-BuLi (2.5 mmol) was added dropwise to a precooled solution (-78 °C) of

carbamate (1.0 mmol) in a mixture of anhydrous toluene (c 0.14 M) and distilled TMEDA

(2.5 mmol) under nitrogen atmosphere. The resulting reaction mixture was warmed up to -

30 °C for 2 h after which anhydrous DMPU (4.0 mmol) was added and stirred for 15 h.

The reaction was quenched with MeOH (10 mmol) and a saturated aqueous solution of

NH4Cl and stirred for a further 30 min while warming to room temperature. The mixture

was diluted with Et2O. The organic layer was washed with water twice and the combined

organic layers were dried over MgSO4, filtered and concentrated under reduced pressure.

The residue was purified by flash column chromatography.

General Procedure U – Alkylation reactions followed by quenching with an electrophile.

To a solution of 5,5-dimethylhex-1-en-3-yn-2-yl isopropylphenylcarbamate 280a (1.0

mmol) in anhydrous THF (0.17 M) was added n-BuLi (2.0 mmol) at -78 °C under nitrogen

atmosphere. The pale yellow solution was stirred for 15 min and the electrophile (4.0

mmol) was added at -78 °C. The reaction mixture was warmed to room temperature and

stirred for 30 min. The reaction was quenched with a saturated aqueous solution of NH4Cl

and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and


chromatography.

215

General Procedure V – Preparation of O-benzylcarbamates.

ONH

O

R1

O

O

ClMeNH2 or i-PrNH2

CH2Cl2, Py., 0 °C then RT, 15 h

To a solution of commercially available O-benzyl chloroformate (1.0 mmol) in anhydrous

CH2Cl2 (c 0.20 M) were added methylamine (2 M in THF, 2.0 mmol) or isopropylamine

(2.0 mmol) and pyridine (2.0 mmol) at 0 °C under nitrogen atmosphere. The reaction

mixture was stirred at room temperarure for 15 h and concentrated under reduced pressure.

The residue was purified by flash column chromatography.

General Procedure W – Preparation of bromoalkynes.

R

Br

R

H

NBS, AgNO3

acetone, RT, 2 h

By the method reported by Hofmeister et al.:[205]

To a solution of acetylene (1.0 mmol) in acetone (c 0.15 M) were added N-

bromosuccinimide (1.1 mmol) and silver(I) nitrate (5 mol %). The reaction mixture was

stirred at room temperature for 2 h (cloudy solution), concentrated under reduced pressure

and the residue was purified by flash column chromatography.

General Procedure X – Preparation of ynecarbamates.

N O

R

R1

O

ONH

O

R1R

Br

K3PO4, CuSO4.5H2O,1,10 phenanthroline

PhMe, 100 °C, 45 h

By the method reported by Hsung et al.:[199c]

To a mixture of benzylcarbamate (1.0 mmol), potassium phosphate (2.0 mmol), copper(II)

sulfate pentahydrate (0.1 mmol), and 1,10-phenanthroline (0.2 mmol) in a sealed tube was

216

added a solution of bromoalkyne (1.1 mmol) in toluene (c 0.10 M). The tube was sealed

and the mixture was stirred vigourously at 100 °C for 45 h. The mixture was cooled to

room temperature, diluted with EtOAc, filtered through Celite and concentrated under

reduced pressure. The residue was purified by flash column chromatography.

General Procedure Y – Deprotection of TIPS group in ynecarbamates.

N O

TIPS O R2TBAF, THF,0 °C, 1 h

N O

H O R2

By the method reported by Hsung et al.:[199b]

To a solution of ynecarbamate (1.0 mmol) in anhydrous THF (c 0.10 M) was added

tetrabutylammonium fluoride (1.0 M in THF, 2.0 mmol) at 0 °C. The reaction mixture was

stirred at 0 °C for 1 h after quenching with a saturated aqueous solution of NH4Cl. The

mixture was diluted with Et2O and washed with brine. The organic layer was dried over

MgSO4, filtered and concentrated under reduced pressure. The residue was purified by


General Procedure Z – Sonogashira coupling reaction with ynecarbamates.

N O

H O R2PhI, Pd(PPh3)4,CuI, DiPEA

PhMe, RT, 15 h

N O

Ph O R2

By the method reported by Hsung et al.:[204]

To ynecarbamate (1.0 mmol), phenyl iodide (1.3 mmol), copper(I) iodide (7 mol %),

tetrakis(triphenylphosphine) palladium(0) (10 mol %) were added toluene (c 0.13 M) and

diisopropylamine (c 0.07 M). The reaction mixture was stirred at room temperature under

nitrogen atmosphere in the dark for 15 h. The mixture was filtered through Celite and


chromatography.

217

III.3 Experimental Procedures and Data

1-Phenylethyl 4-methoxyphenylmethylcarbamate 95e.

N O

OO

1

23

45

6

7

8

9

10

1112

13

General procedures E and F were followed. 1-Phenylethanol 183d (1.0 g, 8.2 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound ()-95e

(1.7 g, 74 % over 2 steps) as a colourless oil.

Rf 0.38 (Petrol:EtOAc 8:2); IR max (neat/cm-1

) 1703 (C=O), 1512 (C=C), 1246 (C-O-C);

1H NMR (400MHz, CDCl3) 7.31-7.14 (m, 7H, aryl), 6.88 (d, J = 8.8 Hz, 2H, H-11), 5.84

(q, J = 6.2 Hz, 1H, H-5), 3.82 (s, 3H, H-13), 3.27 (s, 3H, H-8), 1.48 (br d, 3H, H-6); 13

C

NMR (100MHz, CDCl3) 157.6 (C-12), 155.1 (C-7), 142.3 (C-4), 136.2 (C-9), 128.3,

127.4, 127.2, 125.7 (CH aryl), 113.9 (C-11), 73.5 (C-5), 55.4 (C-13), 37.9 (C-8), 22.9 (C-

6); MS m/z (ES+) 308 (100 %, M+Na+); HMRS (ES+) calcd for C17H19O3N1Na1 (M+Na

+):

308.1257, found: 308.1258.

The same procedure was used to produce the equivalent enantiopure (99:1 e.r.) carbamate,

()-(R)-1-phenylethyl 4-methoxyphenylmethylcarbamate 95e (1.8 g, 76 % over 2 steps)

from (+)-(R)-1-phenylethanol 183d (1.0 g, 8.2 mmol).

[]D31

-47.2 (c 1.00, CH2Cl2); HPLC separation conditions: Chiralcel OD-H column,

hexane:2-propanol (90:10), flow rate: 1.0 mL/min; tR 10.2 min for (R)-enantiomer (major)

and 12.0 min for (S)-enantiomer (minor).

218

1-(4-Chlorophenyl)ethyl methylphenylcarbamate 95i.

N O

O

Cl

1

2

34

5

6

7

8

9

1011

12

General procedures E and F were followed. 1-(4-Chlorophenyl)ethanol 183a (300 mg, 1.95

mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title

compound ()-95i (310 mg, 55 % over 2 steps) as a colourless oil.


) 1707 (C=O); 1H-NMR (500MHz, CDCl3)

δ 7.37-7.18 (m, 9H, aryl), 5.81 (q, J = 6.2 Hz, 1H, H-5), 3.31 (s, 3H, H-8), 1.47 (d, J = 6.2

Hz, 3H, H-6); 13

C-NMR (125MHz, CDCl3) δ 154.8 (C-7), 143.1 (C-9), 140.8 (C-4), 133.3

(C-1), 128.8, 128.5, 127.2, 126.1, 125.8 (CH aryl), 73.0 (C-5), 37.6 (C-8), 22.7 (C-6); MS

m/z (ES+) 312 (100 %, M+Na+); HRMS (ES+) calcd for C16H16N1O2

35Cl1Na1 (M+Na

+):

312.0783, found: 312.0773.


(S)-1-(4-chlorophenyl)ethyl methylphenylcarbamate 95i (682 mg, 74 % over 2 steps) from

()-(S)-1-(4-chlorophenyl)ethanol 183a (1.0 g).

HPLC separation conditions: Chiralcel OD-H column, hexane:2-propanol (98:2), flow rate:

1.0 mL/min; tR 14.9 min for (S)-enantiomer (major) and 15.6 min for (R)-enantiomer

(minor).

219

1-(4-Methoxyphenyl)ethyl methylphenylcarbamate 95m.

N O

O

O12

3

45

6

7

8

9

10

11

12

13

General procedures E and F were followed. 1-(4-Methoxyphenyl)ethanol 183b (2.0 g, 13


compound ()-95m (3.9 g, 96 % over 2 steps) as a colourless oil.


) 1698 (C=O), 1597, 1515 (C=C), 1247 (C-

O-C); 1H NMR (400MHz, CDCl3) 7.39-7.22 (m, 7H, aryl), 6.88 (d, J = 8.8 Hz, 2H, H-3),

5.84 (q, J = 6.2 Hz, 1H, H-6), 3.82 (s, 3H, H-1), 3.33 (s, 3H, H-9), 1.51 (d, J = 6.2 Hz, 3H,

H-7); 13

C NMR (100MHz, CDCl3) 159.0 (C-2), 155.0 (C-8), 143.4 (C-10), 134.4 (C-5),

128.9, 128.7, 127.3, 125.8 (CH aryl), 113.7 (C-3), 73.5 (C-6), 55.3 (C-1), 37.6 (C-9), 22.7

(C-7); MS m/z (ES+) 308 (100 %, M+Na+); HMRS (ES+) calcd for C17H19O3N1Na1

(M+Na+): 308.1257, found: 308.1266.

The same procedure was used to produce the equivalent enantiopure (99:1 e.r.)

carbamate, (+)-(S)-1-(4-methoxyphenyl)ethyl methylphenylcarbamate 95m (661 mg, 98 %

over 2 steps) from ()-(S)-1-(4-methoxyphenyl)ethanol 183b (385 mg, 2.53 mmol).

[]D37

+30.4 (c 1.09, CH2Cl2); HPLC separation conditions: Chiralcel OD-H column,

hexane:2-propanol (90:10), flow rate: 1.0 mL/min; tR 6.7 min for (S)-enantiomer (major)

and 7.1 min for (R)-enantiomer (minor).

220

1-(3-Trifluoromethyl)phenyl)ethyl methylphenylcarbamate 95n.

N O

O

CF3

1

2

3

4

56

78

9

10

11

12

13

14

15

General procedures E and F were followed. 1-(3-Trifluoromethyl)phenyl)ethanol 183c

(439 mg, 2.31 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 5 %)

the title compound ()-95n (557 mg, 74 % over 2 steps) as a colourless oil.


) 1706 (C=O), 1336 (C-F); 1H NMR

(400MHz, CDCl3) 7.52-7.23 (m, 9H, aryl), 5.89 (q, J = 6.4 Hz, 1H, H-8), 3.32 (s, 3H, H-

11), 1.49 (br d, J = 6.4 Hz, 3H, H-9); 13

C NMR (100MHz, CDCl3) 154.6 (C-10), 143.4

(C-7), 143.0 (C-12), 130.7 (q, 2JC-F = 32 Hz, C-4), 129.1, 128.9, 128.8, 126.3, 125.9 (CH

aryl), 124.3 (q, 3JC-F = 3.6 Hz, C-3), 124.0 (q,

1JC-F = 270 Hz, C-5), 122.4 (q,

3JC-F = 3.6 Hz,

C-6), 72.9 (C-8), 37.7 (C-11), 22.9 (C-9); MS m/z (ES+) 346 (100 %, M+Na+); HMRS

(ES+) calcd for C17H16O2N1F3Na1 (M+Na+): 346.1025, found: 346.1029.


(+)-(S)-1-(3-trifluoromethyl)phenyl)ethyl methylphenylcarbamate 95n (657 mg, 86 % over

2 steps) from ()-(S)-1-(3-(trifluoromethyl)phenyl)ethanol 183c (470 mg, 2.47 mmol).

[]D29

+36.2 (c 0.95, CH2Cl2); HPLC separation conditions: Chiralpack AD-H column,

hexane:2-propanol (98:2), flow rate: 1.0 mL/min; tR 12.4 min for (R)-enantiomer (minor)

and 16.6 min for (S)-enantiomer (major).

221

1-Phenylethyl 3-(trifluoromethyl)phenylmethylcarbamate 95o.

N O

O

F3C

1

2

34

5

6

7

8

9

10

1112

13

1415

General procedures E and F were followed. 1-Phenylethanol 183d (1.0 g, 8.2 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound ()-95o



) 1710 (C=O), 1328 (C-F); 1H NMR

(400MHz, CDCl3) 7.55 (s, 1H, H-15), 7.47 (br, 3H, aryl), 7.36-7.26 (m, 5H, aryl), 5.88 (q,

J = 6.8 Hz, 1H, H-5), 3.36 (s, 3H, H-8), 1.53 (d, J = 6.8 Hz, 3H, H-6); 13

C NMR (100MHz,

CDCl3) 154.5 (C-7), 143.7 (C-9), 141.8 (C-4), 131.1 (q, 2JC-F = 32 Hz, C-13), 129.2,

128.5, 128.4, 127.8, 125.8 (CH aryl), 124.0 (q, 1JC-F = 270 Hz, C-14), 122.3 (q,

3JC-F = 3.6

Hz, C-12 and C-15), 74.3 (C-5), 37.3 (C-8), 22.7 (C-6); MS m/z (ES+) 346 (100 %,

M+Na+); HMRS (ES+) calcd for C17H16O2N1F3Na1 (M+Na

+): 346.1025, found: 346.1029.


()-(R)-1-phenylethyl 3-(trifluoromethyl)phenylmethylcarbamate 95o (2.2 g, 85 % over 2

steps) from (+)-(R)-1-phenylethanol 183d (1.0 g, 8.2 mmol).

[]D31

-22.6 (c 1.22, CH2Cl2); HPLC separation conditions: Chiralcel OD-H column,



222

1-(4-Methoxyphenyl)-1-phenylethyl methylcarbamate 96e.

O

O

O

NH 12

34

56

7

89

10

11

1213

General procedure O was followed with LDA (2.5 equiv.) or sec-BuLi (2.5 equiv.) and

DMPU. 1-Phenylethyl 4-methoxyphenylmethylcarbamate 95e and 1-(4-

methoxyphenyl)ethyl methylphenylcarbamate 95m (100 mg, 0.35 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 20 %) the title compound 96e (19 mg, 19 %

and 65 mg, 65 %) as a colourless oil.


) 3364 (br, N-H), 1700 (C=O), 1520 (Amide

II)2, 1511 (C=C), 1266 (Amide III), 1251 (C-O-C);

1H NMR (400MHz, CDCl3) 7.30-

7.22 (m, 7H, aryl), 6.83 (d, J = 8.8 Hz, 2H, H-3), 4.76 (br, 1H, -NH), 3.78 (s, 3H, H-1), 2.72

(d, J = 4.8 Hz, 3H, H-13), 2.21 (s, 3H, H-7); 13

C NMR (100MHz, CDCl3) 158.4 (C-2),

155.4 (C-12), 146.5, 138.1, 128.0, 127.3, 126.9, 125.7 (aryl), 113.3 (C-3), 83.6 (C-6), 55.1

(C-1), 27.6, 27.2 (C-7 and C-13); MS m/z (ES+) 308 (100 %, M+Na+); HMRS (ES+)

calcd for C17H19O3N1Na1 (M+Na+): 308.1257, found: 308.1263.

1-(4-Chlorophenyl)-1-phenylethyl methylcarbamate 96i.

O

O

Cl

NH 1

2

34

5

6

78

9

10

1112

General procedure O was followed with LDA (2.5 equiv.) and DMPU. 1-(4-

Chlorophenyl)ethyl methylphenylcarbamate 95i (100 mg, 0.35 mmol) gave after flash

2 For carbamate (like for amide), vibration assignement is as follows: (NH) = Amide A, (C=O) = Amide I,

(C-N) contraction + (NH) opening = Amide II, (C-N) elongation+ (NH) opening = Amide III.

223

column chromatography (SiO2, Petrol:EtOAc 10 %) the title compound ()-96i (90 mg,

90 %) as a colourless oil.


) 3353 (br, N-H), 1704 (C=O), 1526 (Amide

II), 1266 (Amide III); 1H-NMR (400MHz, CDCl3) δ 7.34-7.23 (m, 9H, aryl), 4.89 (br, 1H,

-NH), 2.71 (d, J = 4.8 Hz, 3H, H-12), 2.22 (s, 3H, H-6); 13

C-NMR (100MHz, CDCl3) δ

155.2 (C-11), 145.6, 144.6, 132.8, 128.2, 128.1, 127.4, 127.1, 125.7 (aryl), 83.1 (C-5), 27.3,

27.2 (C-6 and C-12); MS m/z (ES+) 312 (M+Na+) (100 %); HRMS (ES+) calcd for

C16H16N1O235

Cl1Na1 (M+Na+): 312.0762, found: 312.0762.

General procedure Q with LDA (2.5 equiv.) was used to produce the equivalent

enantiomerically enriched (84:16 e.r.) carbamate, (S)-1-(4-chlorophenyl)-1-phenylethyl

methylcarbamate 96i (51 mg, 51 %) from (S)-1-(4-chlorophenyl)ethyl

methylphenylcarbamate 95i (100 mg).



(minor).

1-(3-(Trifluoromethyl)phenyl)-1-phenylethyl methylcarbamate 96n.

NH

O

O

CF3

1

2

345

6

78

9

1011

12

13

14

15

General procedure O was followed with LDA (2.5 equiv.) and DMPU. 1-(3-

Trifluoromethyl)phenyl)ethyl methylphenylcarbamate 95n (100 mg, 0.31 mmol) and 1-

phenylethyl 3-(trifluoromethyl)phenylmethylcarbamate 95o gave after flash column

chromatography (SiO2, Petrol:EtOAc 20 %) the title compound ()-96n (81 mg, 81 % and

46 mg, 46 %) as a colourless oil.


) 3352 (br, N-H), 1703 (C=O), 1520 (Amide

II), 1330 (C-F), 1267 (Amide III); 1H NMR (400MHz, CDCl3) 7.65 (s, 1H, H-8), 7.51-

7.49 (m, 1H, H-11), 7.41-7.39 (m, 2H, aryl), 7.32-7.25 (m, 5H, aryl), 4.85 (br, 1H, -NH),

224

2.73 (d, J = 4.8 Hz, 3H, H-15), 2.24 (s, 3H, H-6); 13

C NMR (100MHz, CDCl3) 155.0 (C-

14), 147.2 (C-7), 145.2 (C-4), 130.3 (q, 2JC-F = 32 Hz, C-9), 129.4, 128.5, 127.3, 125.8,

125.5 (CH aryl), 123.9 (q, 3JC-F = 3.6 Hz, C-11), 122.8 (q,

1JC-F = 270 Hz, C-10), 122.4 (q,

3JC-F = 3.6 Hz, C-8), 83.1 (C-5), 27.3, 27.2 (C-6, C-15); MS m/z (ES+) 346 (100 %,

M+Na+); HMRS (ES+) calcd for C17H16O2N1F3Na1 (M+Na

+): 346.1025, found: 346.1036.

General procedure Q with LiTMP (2.5 equiv.) was used to produce the equivalent

enantiomerically enriched (90:10 e.r. or 97:3 e.r. in the presence of ()-sparteine)

carbamate, (S)-1-(3-(trifluoromethyl)phenyl)-1-phenylethyl methylcarbamate 96n (76 mg,

38 % or 36 mg, 18 %) from (R)-1-phenylethyl 3-(trifluoromethyl)phenylmethylcarbamate

95o (200 mg, 0.62 mmol).

HPLC separation conditions: Chiralcel OD-H column, hexane:2-propanol (90:10), flow

rate: 1.0 mL/min; tR 7.3 min for (S)-enantiomer (major) and 8.4 min for (R)-enantiomer

(minor).

1-(4-Chlorophenyl)-1-phenylethanol 97i.[52]

HO

Cl

1

2

34

5

6

78

9

10

General procedure R was followed. 1-(4-Chlorophenyl)-1-phenylethyl methylcarbamate

96i (50 mg, 0.17 mmol) gave after flash chromatography (SiO2, Petrol:EtOAc 2 %) the

title compound ()-97i (36 mg, 90 %) as a colourless oil.


) 3411 (br, O-H); 1H-NMR (400MHz,

CDCl3) δ 7.38-7.21 (m, 9H, aryl), 2.11 (br, 1H, -OH), 1.91 (s, 3H, H-6); 13

C-NMR

(100MHz, CDCl3) δ 147.4, 146.5, 132.7, 128.3, 128.2, 127.3, 127.2, 125.7 (aryl), 75.8 (C-

5), 30.8 (C-6); MS m/z (ES+) 215 (100 %, M-H2O+H+); HRMS (ES+) calcd for

C14H13O135

Cl1 (M+): 232.0646, found: 232.0649. Spectral data matched the published

values.[52]

225

The same procedure was used to produce the equivalent enantiomerically enriched (84:16

e.r.) alcohol, (+)-(S)-1-(4-chlorophenyl)-1-phenylethanol 97i (70 mg, 87 %) from (S)-1-(4-

chlorophenyl)-1-phenylethyl methylcarbamate 96i (100 mg).

[]D29

+5.3 (c 0.9, CHCl3) [lit.[52]

[]D22

+14.8 (c 6.5, CHCl3, 98:2 e.r. (S):(R))]; HPLC

separation conditions: Chiralpack AD-H column, hexane:2-propanol (97:3), flow rate: 1.0

mL/min; tR 12.9 min for (R)-enantiomer (minor) and 14.1 min for (S)-enantiomer (major).

1-Phenyl-1-(3-trifluoromethylphenyl) ethanol 97n.[52]

HO

CF3

1

2

34

5

6

78

9

1011

12

13

General procedure R was followed. 1-(3-(Trifluoromethyl)phenyl)-1-phenylethyl

methylcarbamate 96n (35 mg, 0.11 mmol) gave after flash chromatography (SiO2,

Petrol:EtOAc 2 %) gave the title compound ()-97n (22 mg, 78 %) as a colourless oil.


) 3400 (br, O-H), 1329 (C-F); 1H NMR

(400MHz, CDCl3) 7.69 (br, 1H, H-8), 7.47-7.41 (m, 2H, aryl), 7.35-7.18 (m, 6H, aryl),

2.16 (s, 1H, -OH), 1.90 (s, 3H, H-6); 13

C NMR (100MHz, CDCl3) 149.0, 147.1 (C aryl),

130.6 (q, 2JC-F = 32 Hz, C-9), 129.4, 128.6, 128.4, 127.4, 125.8 (CH aryl), 123.7 (q,

3JC-F =

3.6 Hz, C-11), 122.8 (q, 1JC-F = 270 Hz, C-10), 122.3 (q,

3JC-F = 3.6 Hz, C-8), 76.0 (C-5),

30.8 (C-6); MS m/z (ES-) 265 (100 %, M-H+); HRMS (ES-) calcd for C15H13O1F3 (M

+):

266.0907, found: 266.0911. Spectral data matched the published values.[52]

The same procedure was used to produce the equivalent enantiomerically enriched (90:10

e.r.) alcohol, (+)-(S)-1-phenyl-1-(3-trifluoromethylphenyl) ethanol 97n (21 mg, 75 %)

from (S)-1-(3-(trifluoromethyl)phenyl)-1-phenylethyl methylcarbamate 96n (34 mg, 0.10

mmol).

[]D31

+19.2 (c 3.50, CHCl3) [lit.[52]

+29.3 (c 5.50, CHCl3, 99:1 e.r. (S):(R))]; HPLC

separation conditions: Chiralcel OD-H column, hexane:2-propanol (90:10), flow rate: 1.0

mL/min; tR 5.8 min for (S)-enantiomer (major) and 6.5 min for (R)-enantiomer (minor).

226

Assignment of stereochemistry of (S)-97n.

The absolute stereochemistry of ()-(S)-97n was deduced by comparison with literature

data of (a) the optical rotation and (b) relative retention times of the two enantiomers on

the chiral stationary phase Chiralcel OD-H.

Thus:

• Material obtained from the rearrangement is dextrorotatory, with []D31

= +19.2 (c

3.50, CHCl3). Aggarwal[52]

reported that (S)-97n is dextrorotatory and (R)-97n is

laevorotatory.

• The major enantiomer from the rearrangement is the faster eluting on Chiralcel OD-

H. Aggarwal[52]

reported that (S)-97n is faster eluting on Chiralcel OD-H.

()-2-{2-[1-(4-Chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrroline (Clemastine)

98.[128]

16

15 8

9

10

11

12

13

14

1

2

34

5

6

7

N O

Cl17

1-(4-Chlorophenyl)-1-phenylethanol (S)-97i (118 mg, 0.42 mmol) and NaH (60 % in

mineral oil, 28 mg, 0.56 mmol) were dissolved in anhydrous toluene (3 cm3) and refluxed

under nitrogen atmosphere for 3 h. The solution was allowed to cool to room temperature

and 2-(2-chloroethyl)-1-methylpyrrolidine (S)-151 (45 mg, 0.28 mmol) in anhydrous

toluene (1.3 cm3) was added. The reaction mixture was stirred at reflux for 20 h. The

reaction mixture was quenched with water and diluted with EtOAc. The aqueous layer was

separated and extrated with EtOAc (2 10 cm3). The combined organic layers were dried

over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified

by flash column chromatography (SiO2, Petrol:EtOAc:NEt3 80:20:1) to provide the title

compound 98 (50 mg, 48 %) as a colourless oil.

Rf 0.14 (Petrol:EtOAc:NEt3 60:40:1); []D31

37.4 (c 2.04, EtOH) [lit.[128]

[α]D20

33.7 (c

2.00, EtOH) for (S,S)-isomer]; 1H-NMR (400MHz, CDCl3) δ 7.35-7.20 (m, 9H, aryl), 3.34-

3.20 (m, 2H, H-11), 3.08-3.03 (m, 1H, H-16), 2.32 (s, 3H, H-17), 2.20-2.09 (m, 2H, H-16,

H-13), 2.07-1.99 (m, 1H, H-12), 1.93-1.81 (m, 1H, H-14), 1.84 (s, 3H, H-6), 1.79-1.61 (m,

227

2H, H-15), 1.51-1.37 (m, 2H, H-12, H-14); 13

C-NMR (100MHz, CDCl3) δ 146.1, 145.7,

132.4, 128.1, 128.0, 126.9, 126.7, 126.6 (aryl), 80.0 (C-5), 63.8 (C-13), 60.4 (C-11), 57.1

(C-16), 40.4 (C-17), 34.4 (C-12), 30.9 (C-14), 25.5 (C-6), 21.9 (C-15); MS m/z (ES+) 344

(100 %, M+H+); HRMS (ES+) calcd for C21H27N1O1

35Cl1 (M+H

+): 344.1776, found:

344.1787.

()-(2S)-2-{2-[(1S)-1-(4-Chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrroline

monofumarate 98H+ (Clemastine Fumarate).

[128]

N O

ClH

O2CCO2H

2-{2-[1-(4-Chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrroline 98 (50 mg, 0.15 mmol)

and fumaric acid (20 mg) were dissolved by heating in EtOH (0.5 cm3), then the mixture

was allowed to cool to room temperature slowly to afford 98H+

•fum- (47 mg, 66 %) as a

white powder. []D28

17.3 (c 2.08, MeOH) [lit.[128]

[α]D20

16.9 (c 2.00, MeOH) for (S,S)-

isomer]; m.p. 170-172 °C, [lit.[128]

177-178 °C]. The salt was recrystallised from EtOH to

give (S,S)-98H+

•fum- as a white powder with an []D

28 17.1 and a melting point of 176-

178 °C.

()-(S)-2-(2-Chloroethyl)-1-methylpyrrolidine Hydrochloride 151.[140]

N

Me

1

2

3

45

6

7

Cl

�HCl

To a solution of 2-(1-methylpyrrolidin-2-yl)ethanol (S)-175 (100 mg, 0.93 mmol) in

chloroform (1.5 cm3), a solution of thionyl chloride (0.16 cm

3, 2.6 mmol) in chloroform

(0.5 cm3) was added dropwise at 0 °C, and the resulting mixture was refluxed for 2 h and

concentrated under reduced pressure. The brown residue was triturated with MeOH, and a

228

small amount of decolorizing charcoal was added. The mixture was refluxed for 30 min,

filtered through Celite, and the filtrate was concentrated under reduced pressure to provide

the title compound (S)-151HCl as a yellow solid. Recrystallisation from

ethanol:diethylether provided 130 mg (92 %) of (S)-151HCl as a white solid.

Rf 0.41 (CH2Cl2:MeOH:NH4OH 95:5:1); []D31

49.8 (c 1.10, CHCl3); m.p. 119-121 °C

(EtOH/Et2O); IR max (neat/cm-1

) 3420 (br); 1H-NMR (400MHz, CDCl3) δ 12.5 (br, 1H,

N+H), 3.92-3.90 (m, 2H, H-1), 3.38-3.30 (m, 1H, H-3), 2.89-2.82 (m, 1H, H-6), 2.85-2.81

(m, 4H, H-6 and H-7), 2.58-2.39 (m, 1H, H-5), 2.48-2.39 (m, 1H, H-5), 2.36-2.23 (m, 2H,

H-2 and H-4), 2.09-1.93 (m, 2H, H-2 and H-4); 13

C-NMR (100MHz, CDCl3) δ 66.1 (C-3),

55.9 (C-1), 41.2 (C-6), 39.2 (C-7), 32.3 (C-2), 29.1 (C-4), 21.3 (C-5); MS m/z (ES+) 148

(100 %, M+H+); HRMS (ES+) calcd for C7H15N1

35Cl1 (M+H

+): 148.0885, found:

148.0888.

The free base of (S)-151 was obtained as a colourless oil by treatment with aqueous KOH,

extraction with CH2Cl2, drying over MgSO4, and concentrated under reduced pressure. The

free base is used immediately without storage.

(S)-N-Carboxylbenzyldiazoketone intermediate 171.[134,137]

N

O OO

N2

123

45

6

7

8 910

11

12

To a solution of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (S)-169 (5.0 g, 20

mmol) in anhydrous DMF (35 drops) and anhydrous CH2Cl2 (65 cm3) at 0

oC, oxallyl

chloride (2.3 cm3, 27 mmol) was added dropwise under nitrogen atmosphere. The reaction

mixture was allowed to rise to room temperature and stirred for 2 h, resulting in a pale

yellow solution. The solvent was evaporated under reduced pressure to yield a pale yellow

oil. The crude product was immediately dissolved in a mixture of THF (80 cm3) and

CH3CN (80 cm3) and cooled to 0

oC under nitrogen atmosphere. Anhydrous triethylamine

229

(5.6 cm3, 40 mmol) and 2 M trimethylsilyldiazomethane solution (22 cm

3, 44 mmol) were

added, in turn, and the reaction mixture stirred for 5 h at 0 oC. The solution was quenched

with glacial acetic acid (20 cm3) and concentrated under reduced pressure to afford a dark

brown oil. The residue was purified by flash column chromatography (SiO2, Petrol:EtOAc

30 %) to provide the title compound (S)-171 (4.4 g, 80 %) as a yellow solid.

Rf 0.35 (Petrol:EtOAc 5:5); m.p. 58-60 °C (CH2Cl2); IR max (neat/cm-1

) 2105 (C=N),

1702 (C=O, carbamate), 1698 (C=O, ketone); 1H-NMR (400MHz, CDCl3) (mixture of

rotamers) δ 7.37-7.33 (m, 5H, aryl), 5.48 (br, 0.5H, H-1, rotamer 1), 5.25 (br, 0.5H, H-1,

rotamer 2), 5.20-5.06 (m, 2H, H-8), 4.35-4.33 (m, 0.5H, H-3, rotamer 1), 4.29-4.27 (m,

0.5H, H-3, rotamer 2), 3.60-3.45 (m, 2H, H-6), 2.15-2.02 (m, 2H, H-4), 1.99-1.85 (m, 2H,

H-5); 13

C-NMR (100MHz, CDCl3) (mixture of rotamers) δ 195.2, 194.4 (C-2), 155.2,

154.5 (C-7), 136.4, 136.3 (C-9), 128.5, 128.4, 128.0, 127.9, 127.8 (CH aryl), 67.2 (C-8),

64.0, 63.9 (C-1), 53.3, 52.6 (C-3), 47.3, 46.9 (C-6), 31.2, 29.6 (C-4), 24.3, 23.5 (C-5); MS

m/z (ES+) 296 (100 %, M+Na+); HRMS (ES+) calcd for C14H16N3O3 (M+H

+): 274.1113,

found: 274.1186. Spectral data matched published values.[137]

()-(S)-2-Methoxycarbonylmethylpyrrolidine-1-carboxylic acid benzyl ester

174.[137,217]

N

O O

1

2

3

4

56

7

8

910

11

12

O

O

13

To a solution of N-Cbz-diazoketone (S)-171 (4.3 g, 16 mmol) in anhydrous MeOH (50 cm3)

at room temperature under nitrogen atmosphere, a solution of silver benzoate (0.36 g, 1.6

mmol) in anhydrous triethylamine (6.6 cm3) was added dropwise. The mixture was stirred

at room temperature for 3 h, changing colour from yellow to black as an exothermic

reaction took place, generating N2 gas. A solution of sodium metabisulfite 20 % (50 cm3)

was added and the mixture filtered to remove silver residue. The solution was extracted

with EtOAc (2 30 cm3) and the combined organic layers washed with brine (30 cm

3),

dried over MgSO4, filtered and concentrated under reduced pressure. The crude oil was

230

purified by flash column chromatography (SiO2, Petrol:EtOAc 20 %) to provide the title

compound (S)-174 (3.4 g, 78 %) as a colourless oil.

Rf 0.58 (Petrol:EtOAc 5:5); []D31

42.7 (c 1.02, CHCl3) [lit.[217]

[]D25

36.6 (c 1.33,

CHCl3, >99:1 e.r. (S):(R))]; IR max (neat/cm-1

) 1734 (C=O, ester), 1700 (C=O, carbamate);

1H-NMR (400MHz, CDCl3) (mixture of rotamers) δ 7.38-7.30 (m, 5H, aryl), 5.15 (s, 1H,

H-9, rotamer 1), 5.12 (s, 1H, H-9, rotamer 2), 4.27-4.21 (m, 1H, H-4), 3.66 (s, 1.5H, H-1,

rotamer 1), 3.63 (s, 1.5H, H-1, rotamer 2), 3.35-3.40 (m, 2H, H-7), 3.00 (dd, J = 16.0 and

4.0 Hz, 0.5H, H-3, rotamer 1), 2.82-2.77 (dd, J = 16.0 and 4.0 Hz, 0.5H, H-3, rotamer 2),

2.38-2.31 (m, 1H, H-3), 2.13-2.04 (m, 1H, H-5), 1.90-1.82 (m, 2H, H-6), 1.80-1.73 (m, 1H,

H-5); 13

C-NMR (100MHz, CDCl3) (mixture of rotamers) δ 171.9, 171.7 (C-2), 154.6 (C-8),

136.9, 136.8 (C-10), 128.4, 127.9, 127.8 (CH aryl), 66.8, 66.6 (C-9), 54.5, 53.9 (C-4), 51.5

(C-1), 46.7, 46.4 (C-7), 39.07, 38.1 (C-3), 31.3, 30.6 (C-5), 23.5, 22.7 (C-6); MS m/z (ES+)

300 (100 %, M+Na+); HRMS (ES+) calcd for C15H20N1O4 (M+H

+): 278.1314, found:

278.1387. Spectral data matched published values.[137]

()-2-((S)-1-Methylpyrrolidin-2-yl)ethanol 175.[138,139]

N

Me

1

2

3

45

6

7

OH

To a solution of 2-methoxycarbonylmethylpyrrolidine-1-carboxylic acid benzyl ester (S)-

174 (1.50 g, 5.41 mmol) in anhydrous THF (30 cm3) at 0 °C under nitrogen atmosphere,

lithium aluminium hydride (1 M in THF, 16 cm3, 16 mmol) was added dropwise. The

resulting mixture was warmed at 45 °C for 45 min. The reaction mixture was diluted with

Et2O (15 cm3) at 0 °C and quenched with water (4 cm

3). An aqueous solution of 15 %

NaOH (4 cm3) was added followed by addition of further water (2 cm

3). The resulting

mixture was stirred for 15 min and anhydrous MgSO4 was added into the mixture. Further

stirred for 15 min and the solid residue was filtered by suction. The filtrate was

concentrated under reduced pressure to afford an amber oil as a crude. The crude product

was purified by Isolute® SCX (Strong Cation Exchange) cartridge (manufactured by

231

Biotage) using CH2Cl2:MeOH:NH4OH 7 N in MeOH (90:10:1) to provide the title

compound (S)-175 (0.42 g, 60 %) as a colourless oil.

Rf 0.24 (MeOH/NH4OH 1 %); []D31

–78.9 (c 1.03, EtOH) [lit.[139]

[α]D20

58.4 (c 1.00,

acetone]; IR max (neat/cm-1

) 3287 (br, O-H), 1055 (C-O); 1H-NMR (400MHz, CDCl3) δ

5.61 (br, 1H, O-H), 4.00 (td, J = 10.9 and 2.8 Hz, 1H, H-1), 3.68 (dt, J = 10.9 and 4.4 Hz,

1H, H-1), 3.08-3.03 (m, 1H, H-6), 2.62-2.56 (m, 1H, H-3), 2.36 (s, 3H, H-7), 2.18-2.12 (m,

1H, H-6), 2.05-1.96 (ddt, J = 14.7, 10.9 and 4.4 Hz, 1H, H-2), 1.93-1.73 (m, 4H, H-4 and H-

5), 1.46 (dq, J = 12.0 and 4.4 Hz, 1H, H-2); 13

C-NMR (100MHz, CDCl3) δ 65.2 (C-1),

60.3 (C-3), 57.0 (C-6), 40.9 (C-7), 31.1 (C-2), 28.1 (C-4), 23.2 (C-5); MS m/z (ES+) 130

(100 %, M+H+); HRMS (ES+) calcd for C7H15N1O1 (M

+): 129.1152, found: 129.1148.

()-(S)-2-(2-Hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester 179.[145,218]

N

O O

1

2

3

45

6

7

8 910

11

12

OH

2-Methoxycarbonylmethylpyrrolidine-1-carboxylic acid benzyl ester (S)-174 (3.3 g, 12

mmol) was dissolved in anhydrous THF (60 cm3) and cooled to 0

oC under nitrogen

atmosphere. Lithium borohydride (0.91 g, 42 mmol) was added and the reaction mixture

stirred for 96 h at room temperature. The solution was quenched to pH 7 with glacial acetic

acid. It was diluted with H2O (30 cm3) and extracted with EtOAc (2 30 cm

3). The

combined organic layers were dried over MgSO4, filtered and concentrated under reduced

pressure to afford a colourless oil, which was purified by flash column chromatography

(SiO2, Petrol:EtOAc 30 %) to provide the title compound (S)-179 (2.1 g, 71 %) as a

colourless oil.


7.6 (c 1.10, CHCl3) [lit.[218]

[]D25

+7.2 (c 1.00,

CHCl3), >97:3 e.r. (R):(S))]; IR max (neat/cm-1

) 3435 (O-H), 1677 (C=O); 1H-NMR

(400MHz, CDCl3) δ 7.36-7.29 (m, 5H, aryl), 5.14 (s, 2H, H-8), 4.25-4.20 (m, 1H, H-3),

232

4.14-4.11 (m, 1H, -OH), 3.60-3.57 (m, 2H, H-1), 3.44-3.38 (m, 2H, H-6), 2.05-1.95 (m, 1H,

H-4), 1.93-1.88 (m, 2H, H-5), 1.76-1.63 (m, 2H, H-4 and H-2), 1.54-1.47 (m, 1H, H-2); 13

C-

NMR (100MHz, CDCl3) δ 156.7 (C-7), 136.6 (C-9), 128.5, 128.0, 127.8 (CH aryl), 67.1

(C-8), 59.0 (C-1), 54.3 (C-3), 46.3 (C-6), 38.2 (C-2), 31.1 (C-4), 23.5 (C-5); MS m/z (ES+)

272 (100 %, M+Na+); HRMS (ES+) calcd for C14H19N1O3Na1 (M+Na

+): 272.1257, found:

272.1259. Spectral data matched published values.[218]

(S)-2-(2-Iodoethyl)pyrrolidine-1-carboxylic acid benzyl ester 180.[219]

N

O O

1

2

3

45

6

7

8 910

11

12

I

2-(2-Hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (S)-179 (300 mg, 1.20 mmol)

was dissolved in a mixture of anhydrous Et2O and anhydrous CH3CN (3:2, 30 cm3) under

nitrogen atmosphere and cooled to 0 °C. Imidazole (120 mg, 1.68 mmol) and

triphenylphosphine (410 mg, 1.56 mmol) were added and the mixture was treated portion-

wise with iodine, until an orange colour persisted and a white solid appeared. After stirring

for 1 h at 0 °C, the reaction was completed (TLC control). The reaction mixture was

quenched with a saturated aqueous solution of sodium metabisulfite (25 %). It was

extracted with Et2O (3 20 cm3) and the combined organic layers were washed with brine

(20 cm3), dried over MgSO4, filtered and concentrated to give a pale yellow oil. The

residue was purified by flash column chromatography (SiO2, Petrol:EtOAc 5 % + NEt3

1 %) to give the title compound (S)-180 (320 mg, 74 %) as a yellow oil.


) 1686 (C=O); 1H-NMR (400MHz, CDCl3)

(mixture of rotamers) δ 7.36-7.30 (m, 5H, aryl), 5.13-5.10 (m, 2H, H-8), 3.96-3.90 (m, 1H,

H-3), 3.50-3.35 (m, 2H, H-1), 3.19-3.01 (m, 2H, H-6), 2.38-2.22 (m, 1H, H-4), 1.99-1.85 (m,

4H, H-2 and H-5), 1.68-1.62 (m, 1H, H-4); 13

C-NMR (100MHz, CDCl3) (mixture of

rotamers) δ 155.1, 154.9 (C-7), 136.8 (C-9), 128.4, 128.1, 127.9, 127.8 (CH aryl), 66.9,

66.6 (C-8), 58.6, 57.8 (C-3), 46.5, 46.3 (C-6), 39.0, 38.7 (C-2), 30.4, 29.9 (C-4), 23.8, 23.0

233

(C-5), 1.47 (C-1); MS m/z (ES+) 382 (100 %, M+Na+); HRMS (ES+) calcd for

C14H18N1O2Na1 (M+Na+): 382.0384, found: 382.0274.

()-(S)-1-(4-Chlorophenyl)ethanol 183a.[52]

1

2

34

5

6

HO

Cl

General procedure D was followed. 1-(4-chlorophenyl)ethanone 181a (500 mg, 3.25 mmol)

gave after flash column chromatography (SiO2, Petrol:EtOAc 15 %) the title compound

(S)-183a (450 mg, 91 %, 99:1 e.r.) as a colourless oil.


36.6 (c 1.08, CH2Cl2) [lit.[52]

[]D24

45.3 (c 2.00,

CH2Cl2, 98:2 e.r. (S):(R))]; IR max (neat/cm-1

) 3364 (br, O-H), 1088 (C-O); 1H-NMR

(400MHz, CDCl3) δ 7.31 (br, 4H, aryl), 4.88 (q, J = 6.4 Hz, 1H, H-5), 1.83 (br, 1H, -OH),

1.47 (d, J = 6.4 Hz, 3H, H-6); 13

C-NMR (100MHz, CDCl3) δ 144.2 (C-4), 133.0 (C-1),

128.6, 126.8 (CH aryl), 69.7 (C-5), 25.3 (C-6). Spectral data matched the published

values.[52]



(minor).

()-(S)-1-(4-Methoxyphenyl)ethanol 183b.[52]

12

3

456HO

O

7

General procedure D was followed. 1-(4-Methoxyphenyl)ethanone 181b (500 mg, 3.33


compound (S)-183b (385 mg, 76 %, 99:1 e.r.) as a colourless oil.

234


-45.4 (c 1.03, CH2Cl2). [lit.[52]

[α]D24

-50.5 (c 1.02,

CH2Cl2, 98:2 e.r. (S):(R))]; IR max (neat/cm-1

) 3364 (br, O-H), 1615, 1514 (C=C), 1246

(C-O-C), 1035 (C-O); 1H NMR (400MHz, CDCl3) 7.31 (d, J = 8.4 Hz, 2H, H-4), 6.90 (d,

J = 8.4 Hz, 2H, H-3), 4.85 (q, J = 6.4 Hz, 1H, H-6), 3.82 (s, 3H, H-1), 2.09 (br, 1H, -OH),

1.49 (d, J = 6.4 Hz, 3H, H-7); 13

C NMR (100MHz, CDCl3) 158.9 (C-2), 138.0 (C-5),

126.7 (C-4), 113.8 (C-3), 69.9 (C-6), 55.3 (C-1), 25.0 (C-7); MS m/z (ES+) 175 (100 %,

M+Na+); HMRS (ES+) calcd for C9H12O2Na1 (M+Na

+): 175.1797, found: 175.0730.

Spectral data matched the published values.[52]


1.0 mL/min; tR 32.0 min for (R)-enantiomer (minor) and 37.4 min for (S)-enantiomer

(major).

1-(3-(Trifluoromethyl)phenyl)ethanol 183c.[52,220]

HOCF3

1

2

3

4

56

78

9

General procedure B was followed. 1-[3-(Trifluoromethyl)phenyl]ethanone 181c (500 mg,

2.65 mmol) gave the title compound ()-183c (491 mg) as a colourless oil which was

reacted without purification.


) 3338 (br, O-H), 1328 (C-F); 1H NMR

(400MHz, CDCl3) 7.65 (s, 1H, H-6), 7.57-7.45 (m, 3H, aryl), 4.97 (qd, J = 6.4 and 3.6 Hz,

1H, H-8), 1.91 (d, J = 3.6 Hz, 1H, -OH), 1.51 (d, J = 6.4 Hz, 3H, H-9); 13

C NMR (100MHz,

CDCl3) 146.7 (C-7), 130.9 (q, 2JC-F = 32 Hz, C-4), 128.9, 128.7 (C-1, C-2), 124.2 (q,

3JC-

F = 3.6 Hz, C-3), 124.1 (q, 1JC-F = 270 Hz, C-5), 122.2 (q,

3JC-F = 3.6 Hz, C-6), 69.8 (C-8),

25.4 (C-9); MS m/z (ES+) 173 (100 %, M-H2O+H+); HMRS (ES+) calcd for C9H8F3 (M-

H2O+H+): 173.1547, found: 173.0573. Spectral data matched published values.

[220]

General procedure D was used to produce the equivalent enantiopure (99:1 e.r.) alcohol,

()-(S)-1-(3-trifluoromethyl)phenyl)ethanol 183c (470 mg, 94 %) as a colourless oil from

235

1- (3-(trifluoromethyl)phenyl)hanone 181c (500 mg, 2.66 mmol) after flash column

chromatography (SiO2, Petrol:EtOAc 15 %).

[]D25

-27.0 (c 1.03, CH2Cl2) [lit.[52]

[α]D24

-21.9 (c 1.40, CH3OH, 92:8 e.r. (S):(R))]. HPLC


mL/min; tR 17.2 min for (S)-enantiomer (major) and 18.6 min for (R)-enantiomer (minor).

2-Vinyl pyrrolidine-1-carboxylic acid benzyl ester 186.[221]

N

O O

1

2

3

45

6

7

8 910

11

12


) 1686 (C=O); 1H NMR (300MHz, CDCl3)

(mixture of rotamers) 7.46-7.24 (m, 5H, aryl), 5.86-5.75 (m, 1H, H-2), 5.14 (s, 2H, H-8),

5.11-5.02 (m, 2H, H-1), 4.42 (m, 1H, H-3), 3.52-3.48 (m, 2H, H-6), 2.07-1.74 (m, 4H, H-4,

H-5); 13

C NMR (100MHz, CDCl3) (mixture of rotamers) 155.0, 154.7 (C-7), 138.4,

137.8 (C-9), 136.9 (C-2), 128.3, 128.1, 127.7 (CH aryl), 114.2 114.0 (C-1), 66.5 (C-8),

59.3, 58.9 (C-3), 46.6, 46.3 (C-6), 31.9, 31.1 (C-4), 23.3, 22.5 (C-5); MS m/z (ES+) 254

(100 %, M+Na+). Spectral data matched the published values.

[221]

2-(2-Formyloxyethyl) pyrrolidine-1-carboxylic acid benzyl ester 187.

N

O O

12

3

4

5

67

8

9

10 1112

OH

O

13

14

2-(2-Iodoethyl)pyrrolidine-1-carboxylic acid benzyl ester (S)-xx (50 mg, 0.14 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 5 % + NEt3 1 %) gave the title

compound 187 (20 mg, 52 %) as a colourless oil.

236


) 1723 (C=O), 1698 (C=O); 1H NMR

(400MHz, CDCl3) (mixture of rotamers) 7.90 (s, 0.6 H, H-1, rotamer 1), 7.38 (s, 0.4 H,

H-1, rotamer 2), 7.37-7.28 (m, 5H, aryl), 5.13 (s, 2H, H-10), 4.24-4.12 (m, 2H, H-3), 3.99

(m, 1H, H-5), 3.53-3.37 (m, 2H, H-8), 2.21-1.70 (m, 6H, H-4, H-6 and H-7); 13

C NMR

(100MHz, CDCl3) (mixture of rotamers) 161.1, 160.9 (C-2), 155.0 (C-9), 114.1 (C-11),

128.4, 128.0, 127.9, 127.8 (CH aryl), 66.9, 66.6 (C-10), 61.7, 61.5 (C-3), 55.3, 54.5 (C-5),

46.5, 46.2 (C-8), 33.7, 33.1 (C-4), 30.9, 30.3 (C-6), 23.8 23.0 (C-7); MS m/z (ES+) 300

(100 %, M+Na+).

4-(1,1-Diphenylethoxy)-1-methylperhydroazepine 190.

1615

8

9

10

11

1213

14

1

2

34

5

6

7

NO

Cl17

Rf 0.11 (Petrol:EtOAc:NEt3 60:40:1); 1H-NMR (400MHz, CDCl3) δ 7.33-7.19 (m, 9H),

3.63 (qn, J = 6.0 Hz, 1H, H-11), 2.71-2.64 (m, 1H, H-16), 2.58-2.55 (m, 2H, H-14), 2.43-

2.38 (m, 1H, H-16), 2.33 (s, 3H, H-15), 1.81 (s, 3H, H-6), 1.83-1.66 (m, 4H, H-12 and H-

17), 1.56-1.43 (m, 2H, H-13); MS m/z (ES+) 344 (100 %, M+H+); HRMS (ES+) calcd for

C21H27N1O135

Cl1 (M+H+): 344.1776, found: 344.1787.

(E)-Cinnamyl methylphenylcarbamate 193.

N O

O

1

2

34

5

6

7

8

9

10

11

12

13

General procedures E and F were followed. (2E)-3-Phenyl-2-propen-1-ol 191 (1.0 g, 7.5


compound 193 (1.7 g, 90 % over 2 steps) as a colourless oil.

237


) 1707 (C=O), 1597 (C=C); 1H NMR

(300MHz, CDCl3) 7.43-7.24 (m, 10H, aryl), 6.60 (d, J = 16.5 Hz, 1H, H-5), 6.30 (dt, J =

16.5 and 5.7 Hz, 1H, H-6), 4.81 (d, J = 5.7 Hz, 2H, H-7), 3.37 (s, 3H, H-9); 13

C NMR

(100MHz, CDCl3) 154.9 (C-8), 142.9 (C-10), 136.0 (C-4), 132.9 (C-5), 128.5, 128.2,

127.5, 126.2, 125.7, 125.4, 123.5 (C-6 and CH aryl), 65.8 (C-7), 37.3 (C-9); MS m/z (ES+)

290 (100 %, M+Na+); HMRS (ES+) calcd for C17H17O2N1Na1 (M+Na

+): 290.1152, found:

290.1153.

(Z)-1,3-Diphenylprop-1-enyl methylcarbamate 196.

O O

NH

1

2

34

5

67

8

9

11

12

13

10

General procedure O was followed with sec-BuLi (2.5 equiv.). (E)-Cinnamyl

methylphenylcarbamate 193 (100 mg, 0.37 mmol) gave after flash column chromatography

(SiO2, Petrol:EtOAc 5 %) the title compound 196 (9 mg, 9 %) as a yellow solid.

Rf 0.26 (Petrol:EtOAc 8:2); m.p. 74-76 °C (CH2Cl2); IR max (neat/cm-1

) 3351 (br, N-H),

1715 (C=O), 1537 (Amide II), 1237 (Amide III); 1H NMR (400MHz, CDCl3) 7.38 (d, J

= 7.8 Hz, 2H, aryl), 7.28-7.11 (m, 8H, aryl), 5.89 (t, J = 7.6 Hz, 1H, H-6), 4.96 (br, 1H, -

NH), 3.47 (d, J = 7.6 Hz, 2H, H-5), 2.79 (d, J = 4.8 Hz, 3H, H-9); MS m/z (ES+) 290

(100 %, M+Na+); HMRS (ES+) calcd for C17H17O2N1Na1 (M+Na

+): 290.1145, found:

290.1145.

The (Z)-stereochemistry was deduced by a nOe experiment: irradiation at 5.89 ppm (CH=C)

enhanced peak at 7.38 ppm (aryl) from 2.16 %.

238

1,3-Diphenylpropan-1-one 197.[222]

O

1

2

34

56

78

9

10

11

General procedure O was followed with sec-BuLi (2.5 equiv.). (E)-Cinnamyl


(SiO2, Petrol:EtOAc 5 %) the title compound 197 (32 mg, 41 %) as a yellow solid.

Rf 0.70 (Petrol:EtOAc 8:2); m.p. 66-68 °C (MeOH); 1H NMR (300MHz, CDCl3) 7.87

(d, J = 9.0 Hz, 2H, H-3), 7.49-7.10 (m, 8H, aryl), 3.22 (t, J = 7.8 Hz, 2H, H-6), 2.98 (t, J =

7.8 Hz, 2H, H-7); 13

C NMR (100MHz, CDCl3) 199.1 (C-5), 141.3 (C-8), 136.8 (C-4),

133.0, 128.5, 128.4, 128.2, 128.0, 126.1 (CH aryl), 40.4 (C-6), 30.1 (C-7); MS m/z (ES+)

233 (100 %, M+Na+). Spectral data matched the published values.

[222]

(E)-4-Phenylbut-3-en-2-ol 199.[159,223]

HO

1

2

34

5

67

8

General procedure A was followed. trans-Cinnamaldehyde 198 (1.00 g, 7.57 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 10 %) the title compound ()-199

(0.76 g, 68 %) as a yellow oil.


) 3350 (br, O-H); 1H NMR (400MHz,

CDCl3) 7.24-7.07 (m, 5H, aryl), 6.41 (d, J = 16.0 Hz, 1H, H-5), 6.11 (dd, J = 16.0 Hz and

6.4 Hz, 1H, H-6), 4.34 (qn, J = 6.4 Hz, 1H, H-7), 1.45 (br, 1H, -OH), 1.22 (d, J = 6.4 Hz,

3H, H-8); 13

C NMR (100MHz, CDCl3) 136.7 (C-4), 133.5 (C-5), 129.4 (C-6), 128.6,

127.7, 126.4 (CH aryl), 69.0 (C-7), 23.4 (C-8). Spectral data matched the published

values.[223]

239

General procedure C was used to produce the equivalent enantiopure (99:1 e.r.) alcohol,

(+)-(R)-(E)-4-phenylbut-3-en-2-ol 199 (120 mg, 40 %) as a white solid from (E)-4-

phenylbut-3-ene-2-ol 199 (300 mg, 2.03 mmol).

[]D28

+26.3 (c 0.85, CHCl3) [lit.[159]

[α]D20

+33.2 (c 1.02, CHCl3, >99:1 e.r. (R):(S))];


rate: 1.0 mL/min, tR 15.9 min for (R)-enantiomer (major) and 10.7 min for (S)-enantiomer

(minor).

(E)-4-Phenylbut-3-en-2-yl methylphenylcarbamate 201.

N O

O

1

2

34

5

67

8

9

10

11

12

13

14

General procedures E and F were followed. (E)-4-Phenylbut-3-en-2-ol 199 (560 mg, 3.78


compound ()-201 (940 mg, 89 % over 2 steps) as a colourless oil.


) 1699 (C=O), 1597 (C=C); 1H NMR

(500MHz, CDCl3) 7.30-7.12 (m, 10H, aryl), 6.44 (d, J = 15.5 Hz, 1H, H-5), 6.09 (dd, J =

15.5 and 5.5 Hz, 1H, H-6), 5.42 (qn, J = 5.5 Hz, 1H, H-7), 3.25 (s, 3H, H-10), 1.32 (d, J =

5.5 Hz, 3H, H-8); 13

C NMR (125MHz, CDCl3) 155.0 (C-9), 143.3 (C-11), 136.5 (C-4),

130.9 (C-5), 129.3 (C-6), 128.7, 128.5, 127.7, 126.5, 125.9, 125.7 (CH aryl), 72.4 (C-7),

37.6 (C-10), 20.7 (C-8); MS m/z (ES+) 304 (100 %, M+Na+); HMRS (ES+) calcd for

C18H19O2N1Na1 (M+Na+): 304.1308, found: 304.1307.


()-(R)-(E)-4-phenylbut-3-en-2-yl methylphenylcarbamate 201 (202 mg, 89 % over 2 steps)

from ()-(R)-(E)-4-phenylbut-3-en-2-ol 199 (120 mg, 0.81 mmol).

[]D30

-49.9 (c 1.05, CHCl3); HPLC separation conditions: Chiralcel OD-H column,



240

3-sec-Butyl-2,4-diphenylbutan-2-yl methylcarbamate 202.

NH

O

O

1

2

34

56

78

9

10

11

12

13

14 15

16

1718

General procedure O was followed with sec-BuLi (2.5 equiv.). (E)-4-Phenylbut-3-en-2-yl


(SiO2, Petrol: EtOAc 5 % to 10 %) the title compound 202 (28 mg, 23 %) as a white solid.


) 3360 (br, N-H), 1701 (C=O), 1517 (Amide

II), 1258 (Amide III); 1H NMR (400MHz, CDCl3) (mixture of diastereoisomers) 7.31-

7.11 (m, 10H, aryl), 4.06 (br, 0.5H, -NH), 3.98 (br, 0.5H, -NH), 2.90 (dt, J = 14.6 and 5.9

Hz, 1H, H-6), 2.72 (d, J = 5.9 Hz, 0.5H, H-5), 2.68 (d, J = 5.9 Hz, 0.5H, H-5), 2.53 (d, J =

5.6 Hz, 1.5H, H-18), 2.59 (d, J = 5.6 Hz, 1.5H, H-18), 2.34 (t, J = 5.9 Hz, 0.5H, H-5), 2.29

(t, J = 5.9 Hz, 0.5H, H-5), 1.98 (s, 1.5H, H-16), 1.97 (s, 1.5H, H-16), 1.50-1.41 (m, 1H, H-

8), 1.32-1.25 (m, 1H, H-7), 1.03-0.92 (m, 1H, H-8), 0.86 (d, J = 76.9 Hz, 1.5H, H-16), 0.75

(t, J = 7.3 Hz, 1.5H, H-9), 0.61 (d, J = 6.9 Hz, 1.5H, H-10), 0.50 (t, J = 7.3 Hz, 1.5H, H-9);

MS m/z (ES+) 362 (100 %, M+Na+); HMRS (ES+) calcd for C22H29O2N1Na1 (M+Na

+):

362.2079, found: 362.2091.

(E)-2,4-Diphenyl-but-3-en-2-ol 203.[164,224]

HO

1

2

34

5

6

7

8

910

11

12

General procedure P was followed. (E)-4-phenylbut-3-en-2-yl methylphenylcarbamate

201 (100 mg, 0.35 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc

5 %) the title compound 203 (27 mg, 68 % over 2 steps) as a colourless oil.

241


) 3397 (br, O-H); 1H NMR (400MHz,

CDCl3) 7.45 (d, J = 8.4 Hz, 2H, aryl), 7.28-7.14 (m, 8H, aryl), 6.57 (d, J = 16.0 Hz, 1H,

H-6), 6.43 (d, J = 16.0 Hz, 1H, H-5), 1.94 (s, 1H, -OH), 1.69 (s, 3H, H-8); 13

C NMR

(100MHz, CDCl3) 146.5 (C-9), 136.6 (C-4), 136.3 (C-5), 128.8, 128.5, 128.3, 127.6,

127.1, 126.5, 125.2 (C-6 and CH aryl), 74.6 (C-7), 29.7 (C-8); MS m/z (ES+) 207 (100 %,

M-H2O+H+), HRMS (ES+) calcd for C16H15 (M-H2O+H

+): 207.1168, found: 207.1173.


The enantiomerically enriched alcohol ()-(S)-203 was made by following the procedure

below:

A solution of LDA (0.72 mmol) in anhydrous Et2O (2.0 cm3) was added to a solution of

carbamate (100 mg, 0.36 mmol) in anhydrous Et2O (2.5 cm3) and freshly distilled ()-

sparteine (0.08 cm3, 0.36 mmol) at -45 ºC under nitrogen atmosphere. The reaction was

stirred for 2 h was quenched slowly with MeOH (0.1 cm3) at -45 °C. The mixture was

diluted with Et2O and washed with water twice. The combined organic layers were dried

over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved

in THF (2.0 cm3) and cooled at -78 °C under nitrogen atmosphere. n-BuLi (0.28 cm

3, 0.72

mmol) was added and the yellow solution was stirred at -78 °C for 30 min after which tert-

butyl nitrite (0.25 cm3, 2.16 mmol) was added and the reaction mixture was stirred at room

temperature for 24 h. The mixture was diluted with Et2O and the organic layer was washed

with saturated aqueous K2CO3 three times, dried over MgSO4, filtered and concentrated

under reduced pressure to give a residue which was purified by flash column

chromatography (SiO2, Petrol:EtOAc 5 %) the title compound ()-(S)-203 (26 mg, 65 %

over 2 steps, 37:63 e.r.) as a colourless oil.

[]D25

1.5 (c 1.00, CHCl3) [lit.[164]

[α]D20

5.33 (c 0.60, Et2O, 95:5 e.r. (S):(R))]; HPLC


mL/min, tR 17.0 min for (R)-enantiomer (minor) and 20.9 min for (S)-enantiomer (major).

242

(E)-2,4-Diphenylbut-3-en-2-yl methylcarbamate 204.

NH

O

O

1

2

34

5

6

7

8

910

1112

1314

General procedure O was followed with LDA (2.0 equiv.) from (E)-4-phenylbut-3-en-2-yl

methylphenylcarbamate 201 (100 mg, 0.35 mmol).

1H NMR (400MHz, CD3OD) (crude) 7.28-7.13 (m, 10H, aryl), 6.63 (d, J = 16.4 Hz, 1H,

H-6), 6.47 (d, J = 16.4 Hz, 1H, H-5), 4.70 (br, 1H, -NH), 2.63 (d, J = 4.8 Hz, 3H, H-14),

1.91 (s, 3H, H-8); MS m/z (ES+) 226 (100 %, M-CONHCH3+) 207 (90 %, M-

OCONHCH3+); HMRS (ES+) calcd for C22H29O2N1Na1 (M+Na

+): 304.1308, found:

304.1301.

(E)-1,3-Diphenylbuta-1,3-diene 206.[225]

1

23

45

67

8

910

11

12

To a solution of crude (E)-2,4-diphenylbut-3-en-2-yl methylcarbamate 204 (~100 mg, 0.35

mmol) in THF (5 cm3) was added DIBAL-H (1 M in toluene, 0.70 cm

3, 0.70 mmol) at 0 °C

under nitrogen atmosphere. The mixture was refluxed for 2 h The reaction was then

allowed to cool and quenched with a saturated aqueous solution of Rochelle’s salt (sodium

potassium tartrate) (5 cm3). The reaction mixture was extracted with EtOAc (20 cm

3),

washed with water (2 20 cm3), dried over MgSO4, filtered and concentrated under

reduced pressure.

Rf 0.95 (Petrol:EtOAc 8:2); 1H NMR (300MHz, CDCl3) 7.32-7.11 (m, 10H, aryl), 6.95

(d, J = 16.0 Hz, 1H, H-6), 6.40 (d, J = 16.0 Hz, 1H, H-5), 5.31 (s, 1H, H-8), 5.14 (s, 1H, H-8).


243

(E)-3-Butoxy-1,3-diphenylbut-1-ene 207. (E)-1-Butoxy-1,3-diphenylbut-2-ene 208.

O O

1

2

34

5

67

8

9

10

11

12

1314

15

16 1'

2'

3'4'

5'6'

7'

8' 9'

10' 11'

12'

13'14'

15'

16'


mmol) in n-butanol (5 cm3, 1 cm

3 per 10 mg) was added sodium carbonate (20 mg, 0.19

mmol) and the mixture was heated under reflux at 117 °C for 2 h. The solution was cooled

to room temperature and the solvent was evaporated under reduced pressure. The residue

was purified by flash column chromatography (SiO2, Petrol:EtOAc 5 %) to yield the two

title compounds 207 and 208 (20 mg, 40 %).

Rf 0.65 (Petrol:EtOAc 9.5:0.5); 1H NMR (300MHz, CDCl3) 7.34-7.15 (m, 20H, aryl),

6.53 (d, J = 16.4 Hz, 0.6H, H-6), 6.31 (d, J = 16.4 Hz, 0.6H, H-5), 5.88 (d, J = 8.7 Hz, 0.4H,

H-6’), 5.11 (d, J = 8.7 Hz, 0.4H, H-5’), 3.48-3.23 (m, 4H, H-9 and H-9’), 1.11 (s, 1.8H, H-

8), 1.63 (s, 1.2H, H-8’), 1.59-1.47 (m, 4H, H-10 and H-10’), 1.39-1.26 (m, 4H, H-11, H-

11’), 0.86-0.77 (m, 6H, H-12 and H-12’); 13

C NMR (100MHz, CDCl3) 145.8, 142.8 (C-

13 and C-13’), 137.0, 136.9 (C-4 and C-4’), 135.2 (C-7’), 130.7, 129.4, 128.9, 128.3, 128.1,

127.9, 127.5, 127.4, 127.0, 126.5, 126.2, 126.1, 126.0, 125.8, 125.1 (C-6, C-5, C-6’ and

CH aryl), 78.6, 78.4 (C-7 and C-5’), 68.2, 62.5 (C-9 and C-9’), 32.6, 32.0 (C-10 and C-10’),

24.9, 22.3 (C-8 and C-8’), 19.5, 16.5 (C-11 and C-11’), 14.0, 13.9 (C-12 and C-12’); MS

m/z (ES+) 207 (100 %, M-BuOH), 303 (65 %, M+Na+).

244

(E)-3-Methoxy-1,3-diphenylbut-1-ene 209. (E)-1-methoxy-1,3-diphenylbut-2-ene 210.

O O

1

2

34

5

67

89

1011

12

13 1'

2'

3'4'

5'6'

7'

8'9'

10'11'

12'

13'


mmol) in methanol (5 cm3, 1 cm

3 per 10 mg) was added sodium carbonate (20 mg, 0.19

mmol) and the reaction mixture was heated at 50 °C for 1 h. The solution was cooled to

room temperature and the solvent was evaporated under reduced pressure. The residue was

purified by flash column chromatography (SiO2, Petrol:EtOAc 95:5) to yield the 2 title

compounds 209 and 210 (30 mg, 71 %).

Rf 0.50-0.42 (Petrol:EtOAc 9.5:0.5); 1H NMR (300MHz, CDCl3) 7.40-7.15 (m, 20H,

aryl), 6.54 (d, J = 16.4 Hz, 0.6H, H-6), 6.30 (d, J = 16.4 Hz, 0.6H, H-5), 5.87 (d, J = 8.0 Hz,

0.4H, H-6’), 5.0 (d, J = 8.0 Hz, 0.4H, H-5’), 3.29 (s, 1.2H, H-8’), 3.16 (s, 1.8H, H-8), 2.11 (s,

1.2H, H-9’), 1.63 (s, 1.8H, H-9); 13

C NMR (100MHz, CDCl3) 144.7, 142.8 (C-10 and C-

10’), 137.7, 136.9 (C-4 and C-4’), 134.5 (C-7’), 129.4, 128.9, 128.6, 128.5, 128.3, 127.9,

127.6, 127.3, 127.1, 126.7, 126.6, 126.4, 125.9 (C-5, C-6, C-6’ and CH aryl), 80.2, 79.2

(C-7 and C-5’), 50.9, 56.2 (C-8 and C-8’), 24.5, 16.6 (C-9 and C-9’); MS m/z (ES+) 173

(100 %, M-MeOH), 261 (75 %, M+Na+).

(E)-4-(4-methoxyphenyl)but-3-en-2-ol 216.[226]

HO

O12

3

45

6

78

9

General procedure A was followed. trans-p-Methoxycinnamaldehyde 215 (1.00 g, 6.17


compound ()-216 (0.95 g, 87 %) as a white solid.

245

Rf 0.19 (Petrol:EtOAc 8:2); m.p. 67-68 °C (MeOH); IR max (neat/cm-1

) 3312 (br, O-H),

1608, 1512 (C=C), 1251 (C-O-C); 1H NMR (400MHz, CDCl3) 7.31 (d, J = 8.8 Hz, 2H,

H-4), 6.85 (d, J = 8.8 Hz, 2H, H-3), 6.51 (d, J = 16.0 Hz, 1H, H-6), 6.12 (dd, J = 16.0 and

6.8 Hz, 1H, H-7), 4.51-4.43 (m, 1H, H-8), 3.81 (s, 3H, H-1), 1.52 (d, J = 3.6 Hz, 1H, -OH)

1.36 (d, J = 6.4 Hz, 1H, H-9); 13

C NMR (100MHz, CDCl3) 159.2 (C-2), 131.3 (C-6),

129.3 (C-5), 129.0 (C-7), 127.6 (C-4), 114.0 (C-3), 69.1 (C-8), 55.3 (C-1), 23.4 (C-9).


General procedure C was used to produce the equivalent enantiopure (93:7 e.r.) alcohol,

(+)-(E)-(R)-4-(4-methoxyphenyl)but-3-en-2-ol 216 (151 mg, 39 %) from (E)-4-(4-

methoxyphenyl)but-3-en-2-ol 216 (384 mg, 2.16 mmol).

[]D28

+28.3 (c 1.03, CHCl3) [lit.[227]

[α]D25

+9.4 (c 1.10, CHCl3, >99:1 e.r. (R):(S)]. HPLC


mL/min, tR 13.1 min for (R)-enantiomer (major) and 14.0 min for (S)-enantiomer (minor).

(E)-4-(4-Methoxyphenyl)but-3-en-2-yl methylphenylcarbamate 217.

N O

O

O12

3

45

6

78

9

10

11

12

13

14

15

General procedures E and F were followed. 4-(4-Methoxyphenyl)but-3-en-2-ol 216 (750

mg, 4.21 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the

title compound ()-217 (837 mg, 64 % over 2 steps) as a colourless oil.


) 1697 (C=O), 1607, 1512 (C=C), 1248 (C-

O-C); 1H NMR (400MHz, CDCl3) 7.37-7.19 (m, 7H, aryl), 6.83 (d, J = 8.8 Hz, 2H, H-3),

6.48 (d, J = 15.6 Hz, 1H, H-6), 6.03 (dd, J = 15.6 and 6.4 Hz, 1H, H-7), 5.47 (qn, J = 6.4 Hz,

1H, H-8), 3.80 (s, 3H, H-1), 3.31 (s, 3H, H-11), 1.38 (d, J = 6.4 Hz, 3H, H-9); 13

C NMR

(100MHz, CDCl3) 159.3 (C-2), 155.0 (C-10), 143.4 (C-12), 130.5 (C-6), 129.2 (C-7),

128.7, 127.7, 125.8, 125.7 (CH aryl), 113.9 (C-3), 72.6 (C-8), 55.2 (C-1), 37.6 (C-11), 20.8

246


(M+Na+): 334.1414, found: 334.1409.


(S)-(E)-4-(4-methoxyphenyl)but-3-en-2-yl methylphenylcarbamate 217 (218 mg, 63 %

over 2 steps) from (R)-4-(4-methoxyphenyl)but-3-en-2-ol 216 (197 mg, 1.11 mmol).

HPLC separation conditions: Chiralpack AD-H column, hexane:2-propanol (97:3), flow

rate: 1.0 mL/min, tR 13.2 min for (S)-enantiomer (major) and 15.6 min for (R)-enantiomer

(minor).

(E)-4-(4-Methoxyphenyl)-2-phenylbut-3-en-2-yl methylcarbamate 218.

NH

O

O

12

3

45

6

7

8

9

12

13

14

O

1110

15

General procedure O was followed with LDA (2.0 equiv.) from (E)-4-(4-

Methoxyphenyl)but-3-en-2-yl methylphenylcarbamate 217 (100 mg, 0.32 mmol).

1H NMR (300MHz, CD3OD) 7.36-7.16 (m, 7H, aryl), 6.77 (d, J = 8.7 Hz, 2H, H-3), 6.53

(d, J = 16.2 Hz, 1H, H-7), 6.42 (d, J = 16.2 Hz, 1H, H-6), 4.63 (br, 1H, -NH), 3.73 (s, 3H,

H-1), 2.67 (d, J = 4.8 Hz, 3H, H-15), 1.91 (s, 3H, H-9).

(S)-2-(4-Chlorophenyl)-2-hydroxy-N-methyl-N-phenylpropanamide 219.

N

O

OH

Cl1

2

34

5

6

7

8

9

10

11

12

General procedure Q was followed with LDA (2.5 equiv.) in the presence of ()-sparteine

(1.0 equiv.). (S)-1-(4-Chlorophenyl)ethyl methylphenylcarbamate 95i (50 mg, 0.17 mmol)

247

gave after trituration in hexane the title compound 219 (42 mg, 85 %, 80:20 e.r.) as a

white solid.

Rf 0.20 (Petrol:EtOAc 8:2); 1H-NMR (400MHz, CDCl3) δ 7.22-6.92 (m, 9H, aryl), 5.24

(br, 1H, -OH), 3.23 (br, 3H, H-8), 1.62 (br, 3H, H-6); 13

C-NMR (100MHz, CDCl3) δ 174.9

(C-7), 141.9, 133.2, 128.9, 128.4 (br), 128.2, 127.9, 127.3 (aryl), 74.9 (C-5), 40.8 (C-8),

25.6 (C-6); MS m/z (ES+) 312 (M+Na+) (100 %).


1.0 mL/min; tR 10.5 min for (R)-enantiomer (minor) and 11.4 min for (S)-enantiomer

(major). The absolute configuration of (S)-219 remains unassigned.

Allyl methylphenylcarbamate 220a.

N O

O1

2

3

4

5

6

7

8

9

General procedures E and F were followed. 2-Propen-1-ol (1.0 g, 1.7 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 220a (2.9 g,

89 % over 2 steps) as a colourless oil.


) 1706 (C=O); 1H NMR (400MHz, CDCl3)

7.40-7.36 (m, 2H, aryl), 7.28-7.22 (m, 3H, aryl), 5.96-5.89 (m, 1H, H-2), 5.24 (d, J = 17.6

Hz, 1H, H-1), 5.19 (d, J = 10.4 Hz, 1H, H-1), 4.64 (d, J = 5.2 Hz, 2H, H-3), 3.34 (s, 3H, H-

5); 13

C NMR (100MHz, CDCl3) 155.2 (C-4), 143.1 (C-6), 132.7 (C-2), 128.8, 126.0,

125.7 (CH aryl), 117.1 (C-1), 66.1 (C-3), 37.7 (C-5); MS m/z (ES+) 214 (100 %, M+Na+);

HMRS (ES+) calcd for C11H13O2N1Na1 (M+Na+): 214.0838, found: 214.0847.

248

Allyl isopropylphenylcarbamate 220b.

N O

O1

2

3

4

56

7

8

9

10

6

General procedures E and F were followed. 2-Propen-1-ol (1.0 g, 1.7 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 220b (2.8 g,



) 1703 (C=O); 1H NMR (400MHz, CDCl3)

7.37-7.29 (m, 3H, aryl), 7.11 (d, J = 8.0 Hz, 2H, aryl), 5.86-5.78 (m, 1H, H-2), 5.07 (br, J

= 10.8 Hz, 2H, H-1), 4.60 (sep, J = 6.8 Hz, 1H, H-5), 4.54 (d, J = 4.8 Hz, 2H, H-3), 1.11 (d,

J = 6.8 Hz, 6H, H-6); 13

C NMR (100MHz, CDCl3) 155.2 (C-4), 138.3 (C-7), 133.0 (C-2),

129.9, 128.7, 127.4 (CH aryl), 116.4 (C-1), 65.7 (C-3), 49.0 (C-5), 21.4 (C-6); MS m/z

(ES+) 242 (100 %, M+Na+); HMRS (ES+) calcd for C13H17O2N1Na1 (M+Na

+): 242.1152,

found: 242.1152.

2-hydroxy-N-isopropyl-N-phenylbut-3-enamide 226.

OH

N

O

1

23

4

566

78

9

10

General procedure O was followed with LDA (2.0 equiv.). Allyl

isopropylphenylcarbamate 220b (50 mg, 0.23 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 15 %) the title compound 226 (14 mg, 28 %) as an

orange solid.

Rf 0.25 (Petrol:EtOAc 8:2); m.p. 48-50 °C (MeOH/Et2O); IR max (neat/cm-1

) 3409 (br, N-

H), 1648 (C=O); 1H NMR (400MHz, CDCl3) 7.42 (m, 3H, aryl), 7.15-7.10 (m, 2H, aryl),

5.58 (ddd, J = 16.8, 10.4 and 6.4 Hz, 1H, H-2), 5.02-4.92 (m, 3H, H-1, H-3), 4.31 (sep, J =

249

6.8 Hz, 1H, H-5), 3.82 (d, J = 8.0 Hz, 1H, -OH), 1.12 (d, J = 6.8 Hz, 3H, H-6), 1.04 (d, J =

6.8 Hz, 3H, H-6) 13

C NMR (100MHz, CDCl3) 171.9 (C-4), 136.2 (C-7), 135.2 (C-2),

131.5, 129.4, 128.9 (CH aryl), 117.4 (C-1), 70.2 (C-3), 47.7 (C-5), 21.1 (C-6), 20.2 (C-6);


+):

242.1152, found: 242.1153.

3-Phenylprop-2-ynyl phenylcarbamate 228b.

ONH

O

1

23

45

67

8

9

1011

12

General procedure E was followed. 3-Phenylprop-2-yn-1-ol 227b (500 mg, 3.79 mmol)


228b (605 mg, 64 %) as a yellow solid.

Rf 0.40 (Petrol:EtOAc 8:2); 1H NMR (400MHz, CDCl3) 7.48-7.45 (m, 2H, aryl), 7.41-

7.39 (m, 2H, aryl), 7.34-7.29 (m, 5H, aryl), 7.11-7.07 (m, 1H, aryl), 6.71 (br, 1H, -NH), 5.02

(s, 2H, H-7); 13

C NMR (100MHz, CDCl3) 171.3 (C-8), 137.4 (C-9), 131.9, 129.1, 128.8,

128.3, 123.7 (CH aryl), 122.0 (C-4), 118.6 (C-10), 86.6 (C-5), 82.9 (C-6), 53.6 (C-7).

But-2-ynyl methylphenylcarbamate 230a.

N O

O

1

23

4

5

6

7

8

9

10

General procedures E and F were followed. But-2-yn-1-ol 227a (500 mg, 7.14 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 230a

(745 mg, 52 % over 2 steps) as a colourless oil.

250


) 2237 (w, CC), 1702 (C=O); 1H NMR

(400MHz, CDCl3) 7.38-7.19 (m, 5H, aryl), 4.68 (br, 2H, H-4), 3.32 (s, 3H, H-6), 1.84 (t, J

= 2.8 Hz, 3H, H-1); 13

C NMR (100MHz, CDCl3) 155.0 (C-5), 143.1 (C-7), 128.8, 126.1,

125.7 (CH aryl), 82.6 (C-2), 73.8 (C-3), 53.9 (C-4), 37.8 (C-6), 3.72 (C-1); MS m/z (ES+)


+): 226.0838, found:

226.0831.

3-Phenylprop-2-ynyl methylphenylcarbamate 230b.

N O

O

1

2

34

56

7

8

9

10

11

12

13

General procedures G and H were followed. 3-Phenylprop-2-yn-1-ol 227b (500 mg, 3.79


compound 230b (640 mg, 64 % over 2 steps) as a white solid.

Rf 0.42 (Petrol:EtOAc 8:2); m.p. 46-48 °C (Et2O/Petrol); IR max (neat/cm-1

) 1711 (C=O);

1H NMR (400MHz, CDCl3) 7.46-7.22 (m, 10H, aryl), 4.96 (s, 2H, H-7), 3.35 (s, 3H, H-

9); 13

C NMR (100MHz, CDCl3) 154.8 (C-8), 142.9 (C-10), 131.9, 128.9, 128.6, 128.2,

126.2, 125.7 (CH aryl), 122.3 (C-4), 85.9 (C-5), 83.7 (C-6), 53.9 (C-7), 38.0 (C-9); MS m/z


+): 288.0995,

found: 288.1004.

251

(E)-4-benzylidene-3-phenyloxazolidin-2-one 231.[168f]

ON

O

12

3

4

5

67

8 9

10 11

12

General procedure F was followed. 3-Phenylprop-2-ynyl phenylcarbamate 228b (605 mg,

2.41 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 10 %) the title

compound 231 (188 mg, 31 %) as a slightly yellow solid.


) 1751

(C=O); 1H NMR (400MHz, CDCl3) 7.57-7.44 (m, 5H, aryl), 7.42-7.16 (m, 3H, aryl), 6.98

(d, J = 7.2 Hz, 2H, aryl), 5.65 (t, J = 2.4 Hz, 1H, H-5), 5.40 (d, J = 2.4 Hz, 2H, H-7); 13

C

NMR (100MHz, CDCl3) 155.6 (C-8), 136.9 (C-6), 135.0, 133.5, 129.9, 128.8, 127.6,

127.0, 126.1 (aryl), 101.5 (C-5), 67.4 (C-7); MS m/z (ES+) 274 (100 %, M+Na+); HMRS

(ES+) calcd for C16H13O2N1Na1 (M+Na+): 274.0838, found: 274.0833. Spectral data

matched the published values.[168f]

4-Benzyl-3-phenyloxazol-2(3H)-one 232.

ON

O

12

3

4

5

67

8 9

10 11

12

General procedure F was followed. 3-Phenylprop-2-ynyl phenylcarbamate 228b (605 mg,


compound 232 (143 mg, 24 %) as a yellow oil.

252


) 1748 (C=O); 1H NMR (400MHz, CDCl3)

7.43-7.38 (m, 3H, aryl), 7.24-7.18 (m, 5H, aryl), 7.02-7.00 (m, 2H, aryl), 6.55 (t, J = 1.4

Hz, 1H, H-7), 3.55 (d, J = 1.4 Hz, 2H, H-5); 13

C NMR (400MHz, CDCl3) 155.2 (C-8),

134.8 (C-9), 133.2 (C-4), 129.4, 128.7, 128.6, 128.5 (CH aryl), 128.4 (C-6), 127.4, 127.1

(CH aryl), 125.0 (C-7), 30.3 (C-5); MS m/z (ES+) 274 (100 %, M+Na+); HMRS (ES+)


()-(S)-4-Phenylbut-3-yn-2-ol 233.[169]

HO

1

23

45

67

8

By a modified method reported by Noyori et al.:[169]

A solution of [RuCl2(6-p-cymene)]2 (15 mg, 3 mol %) and (S,S)-TsDPEN (17 mg, 6

mol %) in deaerated 2-propanol (2 cm3) was stirred at 28 °C for 15 min under nitrogen

atmosphere. A 1.5 M solution of KOH in 2-propanol (0.18 cm3) and a solution of 4-

phenylbut-3-yn-2-one (1.00 g, 6.94 mmol) in deaerated 2-propanol (8 cm3) were added

sequentially and stirred at 28 °C for 5 days. The mixture was then concentrated under

reduced pressure and the residue was purified by flash column chromatography (SiO2,

Petrol:EtOAc 5 %) to give the title compound (S)-233 (0.65 g, 65 %, 97:3 e.r.) as a

colourless oil.


28 (c 1.60, CHCl3) [lit.[169]

[]D23

35.0 (c 1.00,

CHCl3, 99:1 e.r. (S):(R)]. 1H NMR (400MHz, CDCl3) 7.58-7.27 (m, 5H, aryl), 4.76 (q, J

= 6.6 Hz, 1H, H-7), 2.71 (br, 1H, -OH), 1.55 (d, J = 6.6 Hz, 3H, H-8); 13

C NMR (100MHz,

CDCl3) 132.5, 128.6, 128.3 (CH aryl), 122.5 (C-4), 90.9 (C-6), 83.9 (C-5), 58.8 (C-7),

24.3 (C-8). Spectral data matched the published values.[228]


rate: 1.0 mL/min; tR 7.21 min for (S)-enantiomer (major) and 16.3 min for (R)-enantiomer

(minor).

253

4-Phenylbut-3-yn-2-yl phenylcarbamate 234.

ONH

O

1

2

34

56

7

8

9

10

11

12

13

General procedure E was followed. 3-Phenylprop-2-yn-1-ol 233 (500 mg, 3.42 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 234 (605

mg, 64 %) as a yellow solid.


) 3343 (br, N-

H), 1702 (C=O), 1599 (C=C), 1527 (Amide II), 1224 (Amide III); 1H NMR (400MHz,

CDCl3) 7.47-7.41 (m, 4H, aryl), 7.34-7.29 (m, 5H, aryl), 7.08 (t, J = 7.4 Hz, 1H, aryl),

6.78 (br, 1H, -NH), 5.77 (q, J = 6.7 Hz, 1H, H-7), 1.66 (d, J = 6.7 Hz, 3H, H-8); 13

C NMR

(100MHz, CDCl3) 152.3 (C-9), 137.6 (C-10), 131.8, 129.0, 128.6, 128.2, 123.5 (CH aryl),

122.1 (C-4), 118.7 (C-11), 87.4 (C-6), 84.8 (C-5), 61.8 (C-7), 21.8 (C-8).

4-Benzyl-5-methyl-3-phenyloxazol-2(3H)-one 235.

ON

O

12

3

4

5

678

9 10

11 12

13

General procedure F was followed. 4-Phenylbut-3-yn-2-yl phenylcarbamate 234 (100 mg,


compound 235 (52 mg, 52 %) as a yellow oil.


) 1750 (C=O); 1H NMR (400MHz, CDCl3)

7.33-7.31 (m, 3H, aryl), 7.19-7.17 (m, 3H, aryl), 7.07-7.04 (m, 2H, aryl), 6.87-6.84 (m, 2H,

aryl), 3.58 (s, 2H, H-5), 2.16 (s, 3H, H-8); 13

C NMR (100MHz, CDCl3) 154.6 (C-9),

254

136.4 (C-10), 133.7 (C-4), 133.6, 129.2, 128.5, 128.4, 128.0, 127.5 (CH aryl), 126.8 (C-6),

121.0 (C-7), 28.9 (C-5), 10.2 (C-8); MS m/z (ES+) 288 (100 %, M+Na+); HMRS (ES+)


4-Phenylbut-3-yn-2-yl methylphenylcarbamate 237a.

ON

O

1

23

45

67

8

9

10

11

12

13

14

General procedures G and H were followed. 4-Phenylbut-3-yn-2-ol 233 (500 mg, 3.42


compound ()-237a (544 mg, 57 % over 2 steps) as a yellow oil.


) 1702 (C=O), 2233 (w, C≡C); 1H NMR

(500MHz, CDCl3) 7.44-7.20 (10H, aryl), 5.70 (q, J = 5.3 Hz, 1H, H-7), 3.34 (s, 3H, H-10),

1.55 (br d, J = 5.3 Hz, 3H, H-8); 13

C NMR (125MHz, CDCl3) 154.5 (C-9), 143.1 (C-11),

131.8, 128.7, 128.4, 128.1, 125.9, 125.5 (CH aryl), 122.4 (C-4), 87.9 (C-6), 84.3 (C-5),


calcd for C18H18O2N1 (M+H+): 280.1332, found: 280.1325.


(S)-4-phenylbut-3-yn-2-yl methylphenylcarbamate 237a (296 mg, 54 % over 2 steps) from

()-(S)- 4-phenylbut-3-yn-2-ol 233 (300 mg, 2.05 mmol).


rate: 1.0 mL/min; tR 6.06 min for (R)-enantiomer (minor) and 7.27 min for (S)-enantiomer

(major).

255

4-Phenylbut-3-yn-2-yl isopropylphenylcarbamate 237b.

N O

O

1

2

34

56

7

8

9

101111

13

14

15

16

General procedures G and H were followed. 4-Phenylbut-3-yn-2-ol 233 (140 mg, 0.96


compound ()-237b (163 mg, 55 % over 2 steps) as a white solid.

Rf 0.53 (Petrol:EtOAc 8:2); m.p. 70-72 °C (Petrol/Et2O); IR max (neat/cm-1

) 1685 (C=O),

2235 (w, CC); 1H NMR (400MHz, CDCl3) 7.38-7.28 (m, 8H, aryl), 7.12 (d, J = 7.2 Hz,

2H, aryl), 5.66 (q, J = 6.2 Hz, 1H, H-7), 4.60 (sep, J = 6.8 Hz, 1H, H-10), 1.46 (br d, J = 6.2

Hz, 3H, H-8), 1.14 (d, J = 6.8 Hz, 3H, H-11), 1.13 (d, J = 6.8 Hz, 3H, H-11) 13

C NMR

(100MHz, CDCl3) 154.6 (C-9), 138.2 (C-13), 131.8, 129.9, 128.6, 128.3, 128.2, 127.3 (CH

aryl), 122.6 (C-4), 88.2 (C-6), 84.0 (C-5), 61.7 (C-7), 49.2 (C-10), 21.6 (C-8), 21.4 (C-11);


+):

330.1465, found: 330.1460.


(S)-isopropyl phenyl carbamic acid 1-methyl-3-phenylprop-2-ynyl ester 237b (188 mg,

54 % over 2 steps) from ()-(S)- 4-phenylbut-3-yn-2-ol 233 (350 mg, 2.40 mmol).


rate: 1.0 mL/min; tR 5.19 min for (R)-enantiomer (minor) and 6.25 min for (S)-enantiomer

(major).

256

(E)-4-Benzylidene-3,5-dimethyl-5-phenyloxazolidin-2-one 238a.

ON

O

12

3

4

5

6

78

9

10

11

1213

14

General procedure O was followed with LDA (2.0 equiv.). 4-Phenylbut-3-yn-2-yl

methylphenylcarbamate 237a (58 mg, 0.21 mmol) gave after flash column chromatography

(SiO2, Petrol:EtOAc 4 %) the title compound (E)-238a (25 mg, 43 %) as a yellow solid.


) 1751

(C=O), 1661 (C=C); 1H NMR (400MHz, CDCl3) 7.36-7.31 (m, 5H, aryl), 7.09-7.04 (m,

3H, aryl), 6.75 (dd, J = 7.2 and 1.2 Hz, 2H, aryl), 5.75 (s, 1H, H-5), 3.22 (s, 3H, H-7), 1.87

(s, 3H, H-10); 13

C NMR (100MHz, CDCl3) 155.3 (C-8), 144.2 (C-6), 140.1 (C-11), 134.0

(C-4), 129.0, 128.9, 128.7, 127.9, 126.4, 126.2 (aryl), 101.2 (C-5), 85.1 (C-9), 28.3 (C-7),

22.9 (C-10); MS m/z (ES+) 302 (100 %, M+Na+); HMRS (ES+) calcd for C18H17O2N1Na1

(M+Na+): 302.1152, found: 302.1151.


enhanced peak at 3.22 ppm (N-CH3) from 3.10 %. The structure of the compound was

confirmed by an X-ray crystal structure.

(Z)-4-Benzylidene-3,5-dimethyl-5-phenyloxazolidin-2-one 238a.

ON

O

1

23

45

6

78

9

10

11

1213

14



(SiO2, Petrol:EtOAc 3 %) the title compound (Z)-238a (22 mg, 44 %) as a yellow oil.

257


) 1765 (C=O), 1675 (C=C); 1H NMR

(400MHz, CDCl3) 7.47-7.07 (m, 10H, aryl), 5.56 (s, 1H, H-5), 2.73 (s, 3H, H-7), 1.90 (s,

3H, H-10); 13

C NMR (125MHz, CDCl3) 156.8 (C-8), 143.6 (C-6), 141.5 (C-11), 134.2

(C-4), 129.6, 128.6, 128.5, 127.8, 126.8, 125.0 (aryl), 100.8 (C-5), 84.8 (C-9), 32.3 (C-7),


(M+Na+): 302.1152, found: 302.1156.


enhanced peak at 1.90 ppm (N-CH3) from 1.44 %.

(E)-4-Benzylidene-3-isopropyl-5-methyl-5-phenyloxazolidin-2-one 238b.

ON

O

12

3

4

5

6

7

8

910

11

12

1314

815


isopropylphenylcarbamate 237b (50 mg, 0.16 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 3 %) the title compound (E)-238b (35 mg, 70 %) as a

white solid.


) 1744

(C=O), 1661 (C=C); 1H NMR (400MHz, CDCl3) 7.34-7.25 (m, 5H, aryl), 7.10-7.02 (m,

3H, aryl), 6.71 (dd, J = 6.8 and 0.8 Hz, 2H, aryl), 5.94 (s, 1H, H-5), 4.29 (sep, J = 6.8 Hz,

1H, H-7), 1.80 (s, 3H, H-11), 1.59 (d, J = 6.8 Hz, 3H, H-8), 1.58 (d, J = 6.8 Hz, 3H, H-

8)13


129.2, 128.7, 128.5, 127.8, 126.3, 126.0 (aryl), 101.3 (C-5), 83.6 (C-10), 45.7 (C-7), 23.1

(C-11), 19.1, 18.7 (C-8)MS m/z (ES+) 330 (100 %, M+Na+); HMRS (ES+) calcd for

C20H22O2N1 (M+H+): 308.1646, found: 308.1656.

258

But-3-yn-2-methylphenylcarbamate 240.

ON

O

23

4

5

6

7

8

9

10

1

General procedures E and F were followed. 4-(Trimethylsilyl)-3-butyn-2-ol 239 (500 mg,


compound 240 (364 mg, 51 % over 2 steps) as a colourless oil.


) 1692 (C=O); 1H NMR (400MHz, CDCl3)

7.20-7.03 (m, 5H, aryl), 5.27 (qd, J = 6.8 and 2.0 Hz, 1H, H-3), 3.15 (s, 3H, H-6), 2.27 (d,

J = 2.0 Hz, 1H, H-1), 1.30 (br d, J = 6.8 Hz, 3H, H-4); 13

C NMR (100MHz, CDCl3)

154.5 (C-5), 143.0 (C-7), 128.8, 126.0, 125.6 (CH aryl), 82.6 (C-2), 72.7 (C-1), 61.4 (C-3),


C12H14O2N1 (M+H+): 204.1020, found: 204.1022.

4-(Triisopropylsilyl)but-3-yn-2-yl methylphenylcarbamate 241.

ON

O

1

2

34

5

6

7

8

9

10

11

12

2

Si

To a solution of but-3-yn-2-methylphenylcarbamate 240 (228 mg, 1.12 mmol) in

anhydrous THF (10 cm3) was added n-BuLi (1.6 M in hexanes, 0.90 cm

3, 1.45 mmol) at -

78 °C. After stirring the solution for 1 h, triisopropylsilylchloride (0.30 cm3, 1.45 mmol)

was added at -78 °C and the reaction mixture was warmed to room temperature and stirred

for 5 h. The reaction was quenched with water (10 cm3) and diluted with Et2O (15 cm

3).

The organic layer was washed with H2O (20 cm3), dried over MgSO4, filtered and


chromatography (SiO2, Petrol:EtOAc 3 %) to give the title compound 241 (260 mg, 65 %)

as a pale yellow oil.

259


) 1709 (C=O); 1H NMR (400MHz, CDCl3)

7.28-7.10 (m, 5H, aryl), 5.42 (q, J = 6.8 Hz, 1H, H-5), 3.24 (s, 3H, H-8), 1.39 (d, J = 6.8

Hz, 3H, H-6), 0.99 (s, 21H, H-1 and H-2); 13

C NMR (100MHz, CDCl3) 154.5 (C-7),

143.1 (C-9), 128.7, 125.8, 125.6 (CH aryl), 106.3 (C-4), 85.4 (C-3), 62.3 (C-5), 37.7 (C-8),


calcd for C21H33O2N1Na1Si1 (M+Na+): 382.2173, found: 382.2179.

4-(Triisopropylsilyl)-2-phenylbut-3-yn-2-yl methylcarbamate 242.

ONH

O

1

2

345

6

78

9

10

1112 2

Si

General procedure O was followed with LDA (2.5 equiv.) and DMPU. 4-

(Triisopropylsilyl)but-3-yn-2-yl methylphenylcarbamate 241 (50 mg, 0.14 mmol) gave


mg, 66 %) as a white solid.


) 3307 (N-H),

2177 (w, CC), 1703 (C=O), 1540 (Amide II), 1272 (Amide III); 1H NMR (400MHz,

CDCl3) 7.54 (d, J = 7.4 Hz, 2H, aryl), 7.29-7.18 (m, 3H, aryl), 4.58 (br, 1H, -NH), 2.63

(br d, J = 4.3 Hz, 3H, H-12), 1.82 (s, 3H, H-6), 1.03 (s, 21H, H-1 and H-2); 13

C NMR

(100MHz, CDCl3) 154.5 (C-11), 143.2 (C-7), 128.1, 127.6, 125.0 (CH aryl), 106.9 (C-4),

88.0 (C-3), 75.8 (C-5), 32.5 (C-12), 27.3 (C-6), 18.6 (C-2), 11.2 (C-1): MS m/z (ES+) 377

(60 %, M+NH4+), 360 (40 %, M+H

+), 382 (10 %, M+Na

+); HMRS (ES+) calcd for

C21H33O2N1Na1Si1 (M+Na+): 382.2173, found: 382.2162.

260

4-Chloro-N-isopropylbenzenamine 244c.[229]

HN

Cl

1

234

5

62

General procedure I was followed. 4-Chloroaniline 243c (1.00 g, 7.87 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 2 %) the title compound 244c (0.95 g,


Rf 0.38 (Petrol:EtOAc 8:2); 1H-NMR (400MHz, CDCl3) δ 7.10 (d, J = 8.8 Hz, 2H, H-5),

6.49 (d, J = 8.8 Hz, 2H, H-4), 3.58 (sep, J = 6.3 Hz, 1H, H-1), 3.44 (br, 1H, -NH), 1.20 (d, J

= 6.3 Hz, 6H, H-2) ; 13

C-NMR (125MHz, CDCl3) δ 146.1 (C-3), 129.0 (C-6), 121.4 (C-5),

114.2 (C-4), 44.4 (C-1), 22.9 (C-2); MS m/z (ES+) 170 (100 %, M+H+); HMRS (ES+)

calcd for C9H13N1Cl1 (M+H+): 170.0731, found: 170.0727. Spectral data matched the

published values.[229]

N-Isopropyl-4-methylbenzenamine 244d.[230]

HN

1

2

34

5

6

7

2

General procedure I was followed. p-Toluidine 243d (3.0 g, 28 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 244d (3.6 g, 86 %)

as an orange oil.

Rf 0.48 (Petrol:EtOAc 8:2); 1

H-NMR (400MHz, CDCl3) δ 6.98 (d, J = 8.2 Hz, 2H, H-5),

6.52 (d, J = 8.2 Hz, 2H, H-4), 3.60 (sep, J = 6.3 Hz, 1H, H-1), 3.31 (br, 1H, -NH), 2.24 (s,

3H, H-7), 1.20 (d, J = 6.3 Hz, 6H, H-2) ; 13

C-NMR (100MHz, CDCl3) δ 145.2 (C-3), 129.7

(C-5), 126.2 (C-6), 113.5 (C-4), 44.5 (C-1), 23.0 (C-7), 20.3 (C-2); MS m/z (ES+) 150

(100 %, M+H+); HMRS (ES+) calcd for C10H16N1 (M+H

+): 150.1277, found: 150.1274.


261

(3-Trifluoromethyl)-N-isopropylbenzenamine 244e.[230]

HNF3C

1

2

34

5

62

78

9

General procedure I was followed. 3-(Trifluoromethyl)aniline 243e (1.0 g, 6.2 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 244e (1.1

g, 87 %) as a colourless oil.

Rf 0.68 (Petrol:EtOAc 8:2); IR max (neat/cm

-1) 3417 (br, N-H), 1115 (C-F);

1H-NMR

(400MHz, CDCl3) δ 7.28 (t, J = 7.8 Hz, 1H, H-8), 6.93 (d, J = 7.8 Hz, 1H, H-7), 6.81 (s, 1H,

H-4), 6.75 (d, J = 7.8 Hz, 1H, H-9), 3.72-3.65 (m, 2H, H-1, -NH), 1.27 (d, J = 6.3 Hz, 6H,

H-2) ; 13

C-NMR (100MHz, CDCl3) δ 147.6 (C-3), 131.5 (q, 2JC-F = 32 Hz, C-5), 129.6 (C-

8), 124.0 (q, 1JC-F = 270 Hz, C-6), 116.0 (C-9), 113.1 (q,

3JC-F = 3.6 Hz, C-4), 109.1 (q,

3JC-

F = 3.6 Hz, C-7), 44.1 (C-1), 22.7 (C-2); MS m/z (ES+) 204 (100 %, M+H+), (ES-) 202

(100 %, M-H+). Spectral data matched the published values.

[230]

N-Isopropyl-4-methoxybenzenamine 244f.[229]

HN

O

1

234

5

672

General procedure I was followed. p-Anisidine 243f (3.0 g, 24 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 244f (3.6 g, 90 %)

as a yellow oil.

Rf 0.25 (Petrol:EtOAc 8:2); IR max (neat/cm

-1) 3381 (br, N-H), 1507 (C=C), 1229 (C-O-C);

1H-NMR (400MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H, H-5), 6.57 (d, J = 8.9 Hz, 2H, H-4),

3.75 (s, 3H, H-7), 3.54 (sep, J = 6.3 Hz, 1H, H-1), 3.11 (br, 1H, -NH), 1.19 (d, J = 6.3 Hz,

6H, H-2) ; 13

C-NMR (100MHz, CDCl3) δ 151.8 (C-3), 141.7 (C-6), 114.8 (CH aryl), 55.7

(C-7), 45.1 (C-1), 23.0 (C-2); MS m/z (ES+) 166 (100 %, M+H+); HMRS (ES+) calcd for

262

C10H16N1O1 (M+H+): 166.1227, found: 166.1228. Spectral data matched the published

values.[229]

N-Methyl-N-4-chlorophenylcarbamoyl chloride 245a.

N Cl

O

1

34

5

6

2

Cl

General procedure J was followed. 4-Chloroaniline 243c (1.0 g, 7.1 mmol) gave the title

compound 245a (1.2 g, 87 %) as an orange solid.

Rf 0.36 (Petrol:EtOAc 8:2); m.p. 74-76 °C (CH2Cl2); IR max (neat/cm

-1) 1728 (C=O);

1H

NMR (400MHz, CDCl3) 7.40 (d, J = 8.0 Hz, 2H, H-4), 7.19 (d, J = 8.0 Hz, 2H, H-5),

3.35 (br, 3H, H-1); 13

C NMR (400MHz, CDCl3) 148.9 (C-2), 141.7 (C-3), 134.4 (C-6),

129.8, 128.8 (CH aryl), 40.3 (C-1); MS m/z (ES+) 225 (100 %, M+Na+). Spectral data

matched the published values.

Isopropyl(phenyl) carbamic chloride 245b.

N Cl

O

12

345

6

7

2

General procedure J was followed. N-isopropylaniline 244b (1.5 g, 11 mmol) gave the title

compound 245b (1.1 g, 60 %) as a white solid.


) 1736 (C=O); 1H NMR (400MHz, CDCl3)

7.44-7.40 (m, 3H, aryl), 7.17-7.14 (m, 2H, aryl), 4.69 (sep, J = 6.8 Hz, 1H, H-1), 1.16 (d,

J = 6.8 Hz, 6H, H-2); 13

C NMR (400MHz, CDCl3) 148.9 (C-3), 138.3 (C-4), 130.0,

129.1, 128.8 (CH aryl), 52.3 (C-1), 20.9 (C-2); MS m/z (ES+) 220 (100 %, M+Na+).

263

(4-Chlorophenyl)(isopropyl) carbamic chloride 245c.

N Cl

OCl

12

345

6

7

2

General procedure J was followed. 4-Chloro-N-isopropylbenzenamine 244c (920 mg, 5.44

mmol) gave the title compound 245c (929 mg, 74 %) as a white solid.


-1) 1734 (C=O);

1H-

NMR (400MHz, CDCl3) δ 7.41 (d, J = 8.8 Hz, 2H, H-5), 7.09 (d, J = 8.8 Hz, 2H, H-6),

4.68 (sep, J = 6.8 Hz, 1H, H-1), 1.15 (d, J = 6.8 Hz, 6H, H-2) ; 13

C-NMR (100MHz, CDCl3)

δ 148.7 (C-3), 136.7 (C-4), 134.9 (C-7), 131.4, 129.4 (CH aryl), 52.3 (C-1), 20.9 (C-2);

MS m/z (ES+) 254 (60 %, M+Na+).

Isopropyl(p-tolyl) carbamic chloride 245d.

N Cl

O

12 2

345

6

7

8

General procedure J was followed. N-Isopropyl-4-methylbenzenamine 244d (3.5 g, 23

mmol) gave the title compound 245d (3.9 mg, 79 %) as a white solid.


-1) 1716 (C=O);

1H-


4.66 (sep, J = 6.8 Hz, 1H, H-1), 2.39 (s, 1H, H-8), 1.15 (d, J = 6.8 Hz, 6H, H-2) ; 13

C-NMR

(100MHz, CDCl3) δ 149.1 (C-3), 138.8 (C-4), 135.5 (C-7), 129.7 (CH aryl), 52.1 (C-1),

21.1 (C-8), 20.8 (C-2); MS m/z (ES+) 234 (100 %, M+Na+).

264

(3-Trifluoromethyl)phenyl)(isopropyl) carbamic chloride 245e.

N Cl

O

F3C

12 2

345

6

7

8

9

10

General procedure J was followed. (3-Trifluoromethyl)-N-isopropylbenzenamine 244e (1.0

g, 4.9 mmol) gave the title compound 245e (1.2 g, 97 %) as a white solid.

m.p. 68-70 °C (CH2Cl2); IR max (neat/cm-1

) 1753 (C=O), 1323 (C-F); 1H-NMR (400MHz,

CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H, H-8), 7.57 (t, J = 7.8 Hz, 1H, H-9), 7.42 (s, 1H, H-5), 7.36

(d, J = 7.8 Hz, 1H, H-10), 4.68 (sep, J = 6.8 Hz, 1H, H-1), 1.16 (d, J = 6.8 Hz, 6H, H-2) ;

13C-NMR (100MHz, CDCl3) δ 148.2 (C-3), 138.8 (C-4), 131.9 (C-10), 130.8 (q,

2JC-F = 32

Hz, C-6), 129.8 (C-9), 126.8 (q, 3JC-F = 3.6 Hz, C-5), 125.6 (q,

3JC-F = 3.6 Hz, C-8), 123.0

(q, 1JC-F = 270 Hz, C-7), 52.5 (C-1), 20.7 (C-2); MS m/z (ES+) 288 (30 %, M+Na

+).

Isopropyl(4-methoxyphenyl) carbamic chloride 245f.

N Cl

OO

12

345

6

78

2

General procedure J was followed. N-Isopropyl-4-methoxybenzenamine 244f (3.5 g, 21

mmol) gave the title compound 245f (3.1 g, 65 %) as a pale yellow solid.

m.p. 81-83 °C (CH2Cl2); IR max (neat/cm

-1) 1731 (C=O), 1505 (C=C), 1211 (C-O-C);

1H-


4.66 (sep, J = 6.8 Hz, 1H, H-1), 3.83 (s, 1H, H-8), 1.14 (d, J = 6.8 Hz, 6H, H-2) ; 13

C-NMR

(100MHz, CDCl3) δ 159.5 (C-7), 149.4 (C-3), 131.0 (C-4), 130.8 (C-5), 114.1 (C-6), 55.4

(C-8), 52.0 (C-1), 20.9 (C-2); MS m/z (ES+) 250 (100 %, M+Na+).

265

(Z)-1-Phenylprop-1-enyl methylphenylcarbamate 248a.

N O

O

1

2

3

45

6

7

8

9

1011

12

13

General procedure K was followed. Propiophenone 246a (500 mg, 3.73 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound (Z)-248a (568



) 1710 (C=O);

1H NMR (400MHz, CDCl3) 7.44-7.22 (m, 10H, aryl), 5.83 (q, J = 6.8 Hz, 1H, H-6), 3.40

(br, 3H, H-9), 1.75 (d, J = 6.8 Hz, 3H, H-7); 13

C NMR (100MHz, CDCl3) 153.2 (C-8),

147.3 (C-5), 143.0 (C-10), 135.6 (C-4), 129.1, 128.4, 127.8, 126.3, 126.0, 124.3 (CH aryl),



(Z)-1-Phenylbut-1-enyl 4-chlorophenylmethylcarbamate 248b.

14

N O

O

1

2

3

45

6

78

9

10

1112

13

General procedure K was followed. Butyrophenone 246b (500 mg, 3.38 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound (Z)-248b (615



) 1711 (C=O);

1H NMR (400MHz, CDCl3) 7.43-7.22 (m, 10H, aryl), 5.75 (t, J = 7.2 Hz, 1H, H-6), 3.39

(br, 3H, H-10), 2.23-2.15 (m, 2H, H-7), 1.05 (t, J = 7.6 Hz, 3H, H-8); 13

C NMR (100MHz,

266

CDCl3) 153.1 (C-9), 145.9 (C-5), 142.9 (C-11), 135.5 (C-4), 129.0, 128.2, 127.7, 126.6,

126.1, 124.2 (CH aryl), 119.7 (C-6), 38.1 (C-10), 19.4 (C-7), 13.5 (C-8); MS m/z (ES+)


+): 304.1308, found:

304.1309.


enhanced the aromatic peaks (CHaro) from 3.16 % and did not enhance peak at 3.39 ppm

(N-CH3).

(Z)-1-p-Tolylprop-1-enyl methylphenylcarbamate 248c.

N O

O

1

23

4

56

7

8

9

10

111213

14

General procedure K was followed. 4-Methylpropiophenone 246c (500 mg, 3.38 mmol)

gave after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound (Z)-

248c (455 mg, 48 %) as a white solid.


) 1712 (C=O);

1H NMR (400MHz, CDCl3) 7.43-7.25 (m, 7H, aryl), 7.10 (d, J = 8.0 Hz, 2H, aryl), 5.76

(q, J = 6.8 Hz, 1H, H-7), 3.38 (br, 3H, H-10), 2.31 (s, 3H, H-1), 1.73 (d, J = 6.8 Hz, 3H, H-

8); 13

C NMR (100MHz, CDCl3) 153.2 (C-9), 147.4 (C-6), 143.1, 137.6, 132.9, 129.1,

126.6, 126.3, 126.2, 124.3 (aryl), 111.8 (C-7), 38.2 (C-10), 21.1 (C-1), 11.5 (C-8); MS m/z


+): 304.1308,

found: 304.1295.



(N-CH3).

267

(Z)-1-Phenylbut-1-enyl 4-chlorophenylmethylcarbamate 248d.

14

N O

O

1

2

3

45

6

78

9

10

1112

13

Cl

General procedure K was followed. Butyrophenone 246b (500 mg, 3.38 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound (Z)-248d (548

mg, 52 %) as a yellow oil.


) 1719 (C=O); 1H NMR (400MHz, CDCl3)

7.32-7.17 (m, 9H, aryl), 5.70 (t, J = 7.6 Hz, 1H, H-6), 3.32 (br, 3H, H-10), 2.12 (qn, J =

7.6 Hz, 2H, H-7), 1.00 (t, J = 7.6 Hz, 3H, H-8); 13

C NMR (100MHz, CDCl3) 153.0 (C-9),

145.8 (C-5), 141.5, 135.4, 129.2, 128.3, 127.9 (br), 127.3, 124.3 (aryl), 119.9 (C-6), 38.0

(C-10), 19.5 (C-7), 13.5 (C-8); MS m/z (ES+) 338 (100 %, M+Na+); HMRS (ES+) calcd

for C18H18O2N135

Cl1Na1 (M+Na+): 338.0918, found: 338.0911.



(N-CH3).

1-Phenylvinyl methylphenylcarbamate 248e.[231]

7

8

910

11

12

1

2

34

5

6N O

O

General procedure K was followed. Acetophenone 246e (300 mg, 2.50 mmol) gave after

crystallisation from Et2O/n-hexane (2/4) the title compound 248e (288 mg, 46 %) as a

white solid.

268

Rf 0.36 (Petrol:EtOAc 8:2); m.p. 57-60 °C (Et2O/hexane); IR max (neat/cm-1

) 1706 (C=O),

1642 (C=C); 1H-NMR (400MHz, CDCl3) δ 7.43-7.29 (m, 10H, aryl), 5.41 (br, 1H, H-6),

5.08 (br, 1H, H-6), 3.39 (br, 3H, H-8); 13

C-NMR (100MHz, CDCl3) δ 153.5, 153.2 (C-5

and C-7), 142.8, 134.8, 129.1, 128.7, 128.4, 126.4 (br), 124.9 (aryl), 101.6 (C-6), 38.2 (C-

8); MS m/z (ES+) 276 (100 %, M+Na+); HMRS (ES+) calcd for C16H15O2N1Na1 (M+Na

+):

276.0995, found: 276.1003. Spectral data matched the published values.[231]

1-Phenylvinyl isopropylphenylcarbamate 248f.

7

8

1011

12

1

2

34

5

6N O

O

9 9

13


flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 248f (722 mg,

62 %) as a white solid.


) 1698 (C=O);

1H NMR (400MHz, CDCl3) 7.45-7.23 (m, 10H, aryl), 5.35 (s, 1H, H-6), 5.03 (s, 1H, H-6),

4.63 (sep, J = 6.8 Hz, 1H, H-8), 1.16 (d, J = 6.8 Hz, 6H, H-9); 13


153.2 (C-5 and C-7), 137.9, 135.1, 129.9, 128.9, 128.5, 128.3, 127.8, 124.8 (aryl), 101.1

(C-6), 49.3 (C-8), 21.2 (C-9); MS m/z (ES+) 304 (100 %, M+Na+); HMRS (ES+) calcd for

C18H19O2N1Na1 (M+Na+): 304.1308, found: 304.1297.

269

1-(4-Chlorophenyl)vinyl isopropylphenylcarbamate 248g.

7

8

1011

12

1

2

34

5

6N O

O

9 9

13

Cl

General procedure K was followed. 4-Chloroacetophenone 246g (500 mg, 3.25 mmol)


248g (611 mg, 60 %) as a yellow solid.


) 1717 (C=O);

1H NMR (400MHz, CDCl3) 7.46-7.36 (m, 3H, aryl), 7.26-7.21 (m, 6H, aryl), 5.31 (s, 1H,

H-6), 5.06 (s, 1H, H-6), 4.61 (sep, J = 6.8 Hz, 1H, H-8), 1.15 (d, J = 6.8 Hz, 6H, H-9); 13

C

NMR (100MHz, CDCl3) 152.2 (C-5 and C-7), 137.8, 134.4, 133.7, 129.8, 129.0, 128.5,

127.9, 126.2 (aryl), 101.5 (C-6), 49.4 (C-8), 21.2 (C-9); MS m/z (ES+) 338 (100 %,

M+Na+); HMRS (ES+) calcd for C18H18O2N1

35Cl1Na1 (M+Na

+): 338.0918, found:

338.0908.

1-Phenylvinyl 4-chlorophenylisopropylcarbamate 248h.

7

8

1011

12

1

2

34

5

6N O

O

9 9

13

Cl


flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 248h (529


270


) 1698 (C=O);

1H NMR (400MHz, CDCl3) 7.41 (d, J = 8.5 Hz, 2H, aryl), 7.31-7.29 (m, 5H, aryl), 7.18 (d,

J = 8.5 Hz, 2H, aryl), 5.36 (br, 1H, H-6), 5.02 (br, 1H, H-6), 4.63 (sep, J = 6.8 Hz, 1H, H-8),

1.15 (d, J = 6.8 Hz, 6H, H-9); NMR (100MHz, CDCl3) 153.2, 153.0 (C-5 and C-7), 136.4,

134.9, 133.7, 131.1, 129.2, 128.7, 128.3, 124.8 (aryl), 101.4 (C-6), 49.3 (C-8), 21.2 (C-9);

MS m/z (ES+) 338 (100 %, M+Na+); HMRS (ES+) calcd for C18H18O2N1

35Cl1Na1

(M+Na+): 338.0919, found: 338.0905.

1-(4-Methoxyphenyl)vinyl isopropylphenylcarbamate 248i.

78

10

1112

1

23

45

6

N O

O

109

13

O

14

General procedure K was followed. p-Methoxyacetophenone 246i (500 mg, 3.33 mmol)


248i (370 mg, 37 %) as a white solid.


) 1702 (C=O),

1245 (C-O-C); 1H NMR (400MHz, CDCl3) 7.43-7.22 (m, 7H, aryl), 6.81 (d, J = 8.4 Hz,

2H, H-3), 5.22 (s, 1H, H-7), 4.93 (s, 1H, H-7), 4.63 (sep, J = 6.8 Hz, 1H, H-9), 3.79 (s, 3H,

H-1), 1.15 (d, J = 6.8 Hz, 6H, H-10); 13

C NMR (100MHz, CDCl3) 159.8 (C-2), 153.1 (C-

6 and C-8), 142.5, 138.0, 129.9, 128.9, 127.8, 127.7, 126.2 (aryl), 113.7 (C-3), 99.3 (C-7),

55.3 (C-1), 49.2 (C-9), 21.2 (C-10)MS m/z (ES+) 334 (100 %, M+Na+); HMRS (ES+)


271

(Z)-1,2-Diphenylvinyl isopropylphenylcarbamate 248j.

1

2

34

56

78

910

11

1213

1415

16

17

13

N O

O

General procedure K was followed. Deoxybenzoin 246j (500 mg, 2.55 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound (Z)-248j (485



) 1716 (C=O);

1H NMR (400MHz, CDCl3) 7.51-7.23 (m, 15H, aryl), 6.56 (s, 1H, H-6), 4.57 (sep, J = 6.8

Hz, 1H, H-12), 1.11 (d, J = 6.8 Hz, 6H, H-13); 13

C NMR (100MHz, CDCl3) 152.1 (C-11),

147.0 (C-5), 137.6, 136.5, 134.5, 129.9, 128.9, 128.8, 128.5, 128.2, 128.1, 128.0, 127.2,

124.7 (aryl), 116.6 (C-6), 49.3 (C-12), 21.1 (C-13); MS m/z (ES+) 380 (100 %, M+Na+);


The Z-stereochemistry was deduced by an X-ray crystal structure.

(Z)-1,2-diphenylvinyl 4-chlorophenylisopropylcarbamate 248k.

1

2

34

56

78

910

11

1213

1415

16

17

13

N O

OCl

General procedure K was followed. Deoxybenzoin 246j (1.1 g, 5.6 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound (Z)-248k (1.1 g,


272


) 1718 (C=O);


Hz, 1H, H-12), 1.09 (d, J = 6.8 Hz, 6H, H-13); 13

C NMR (100MHz, CDCl3) 152.1 (C-11),

146.9 (C-5), 136.3, 136.2, 134.5, 131.3, 129.3, 128.8, 128.6, 128.4, 128.2, 127.3, 124.7

(aryl), 116.8 (C-6), 49.3 (C-12), 21.1 (C-13); MS m/z (ES+) 414 (100 %, M+Na+); HMRS

(ES+) calcd for C24H22O2N1Na1 (M+Na+): 414.1231, found: 414.1231.

1-1-Diphenylallyl methylcarbamate 249a.

O

NH

O123

45

6

7

8

9

General procedure O was followed with LDA (2.5 equiv.). (Z)-1-Phenylprop-1-enyl


(SiO2, Petrol:EtOAc 5 % + NEt3 1 %) the title compound 249a (43 mg, 86 %) as a white

solid.


) 3349 (br,

N-H), 1700 (C=O), 1522 (Amide II), 1262 (Amide III); 1H NMR (400MHz, CDCl3)

7.32-7.23 (m, 10H, aryl), 7.13 (dd, J = 17.4 Hz, J = 10.8 Hz, 1H, H-2), 5.42 (d, J = 10.8

Hz, 1H, H-1), 4.82 (br, 1H, -NH), 4.80 (d, J = 17.4 Hz, 1H, H-1), 2.74 (d, J = 4.8 Hz, 3H, H-

9); 13

C NMR (100MHz, CDCl3) 155.1 (C-8), 143.4 (C-4), 140.3 (C-2), 127.8, 127.3,



273

(E)-1,1-Diphenylbut-2-enyl methylcarbamate 249b.

O

NH

O

1

23

4

9

10

56

7

8

General procedure O was followed with LDA (2.5 equiv.). (Z)-1-Phenylbut-1-enyl 4-

chlorophenylmethylcarbamate 248b (50 mg, 0.18 mmol) gave after crystallisation from

hexane:Et2O 1 % the title compound 249b (39 mg, 78 %) as a white solid.


) 3329 (br, N-

H), 1703 (C=O), 1517 (Amide II), 1251 (Amide III); 1H NMR (400MHz, CDCl3) 7.29-

7.20 (m, 10H, aryl), 6.83 (d, J = 15.6 Hz, 1H, H-3), 5.13 (dq, J = 15.6 and 6.5 Hz, 1H, H-2),

4.80 (br, -NH), 2.70 (d, J = 4.8 Hz, 3H, H-10), 1.72 (dd, J = 6.5 and 1.6 Hz, 3H, H-1); 13

C

NMR (100MHz, CDCl3) 155.2 (C-9), 144.2 (C-5), 133.6 (C-3), 131.6 (C-2), 127.7,

127.1, 127.0 (CH aryl), 86.5 (C-4), 27.3 (C-10), 18.0 (C-1); MS m/z (ES+) 304 (100%,

M+Na+); HMRS (ES+) calcd for C18H19O2N1Na1 (M+Na

+): 304.1302, found: 304.1321.

1-Phenyl-1-p-tolylallyl methylcarbamate 249c.

O

NH

O123

45

6

7

8

910

11

12

13

14

General procedure O was followed with LDA (2.5 equiv.). (Z)-1-p-Tolylprop-1-enyl

methylphenylcarbamate 248c (50 mg, 0.18 mmol) gave after flash column chromatography

on silica (Petrol:EtOAc 10 % + NEt3 1%) the title compound 249c (40 mg, 80 %) as a

white solid.

274


) 3353 (br, N-


7.09 (m, 10H, aryl and H-2), 5.41 (d, J = 10.8 Hz, 1H, H-1), 4.84 (br, 1H, -NH), 4.81 (d, J =

17.4 Hz, 1H, H-1), 2.73 (d, J = 4.8 Hz, 3H, H-14), 2.33 (s, 3H, H-8); 13

C NMR (100MHz,

CDCl3) 155.1 (C-13), 143.5, 140.5, 140.4, 136.9, 128.6, 127.8, 127.2, 127.0, 126.9 (aryl

and C-2), 119.0 (C-1), 86.5 (C-3), 27.3 (C-14), 21.0 (C-8); MS m/z (ES+) 304 (100 %,


+): 304.1308, found: 304.1299.

HPLC separation conditions: Chiralpack AD-H column, hexane:2-propanol (95:5), flow

rate: 1.0 mL/min, tR 13.3 min for the major enantiomer and 13.9 min for the minor

enantiomer.

(E)-1-(4-Chlorophenyl)-1-phenylbut-2-enyl methylcarbamate 249d.

O

NH

O

Cl

1

234

5 6

7

8

910

11

12

13

14


chlorophenylmethylcarbamate 248d (50 mg, 0.16 mmol) gave after crystallisation from

hexane:Et2O 1 % the title compound 249d (40 mg, 80 %) as a white solid.


) 3309 (br,


7.24-7.13 (m, 9H, aryl), 6.73 (d, J = 15.6 Hz, 1H, H-3), 5.11-5.02 (m, 1H, H-2), 4.73 (br,

1H, -NH), 2.66 (d, J = 4.8 Hz, 3H, H-14), 1.68 (dd, J = 5.2 and 1.6 Hz, 3H, H-1); 13

C NMR

(100MHz, CDCl3) 155.1 (C-13), 143.7, 142.9 (C-5 and C-9), 133.2 (C-3), 133.0 (C-12),

132.0 (C-2), 128.5, 128.0, 127.9, 127.3, 127.0 (CH aryl), 86.1 (C-4), 27.4 (C-14), 18.1 (C-

1); MS m/z (ES+) 338 (20 %, M+Na+), (ES-) 350 (100 %, M+Cl

-); HMRS (ES+) calcd for

C18H19O2N135

Cl1 (M+H+): 316.1099, found: 316.1112.


1.0 mL/min, tR 15.1 min for the minor enantiomer and 16.5 min for the major enantiomer.

275

4,4-Diphenylbut-3-en-2-yl methylcarbamate 250.

NH

O

O

5

67

8

9

10

1

23

411

12

1314


chlorophenylmethylcarbamate 248b (50 mg, 0.18 mmol) gave after flash column

chromatography on silica (Petrol:EtOAc 5 %) the title compound 250 (37 mg, 75 %) as a

colourless oil.


) 3338 (br, N-H), 1694 (C=O), 1519 (Amide

II), 1248 (Amide III); 1H NMR (400MHz, CDCl3) 7.41-7.22 (m, 10H, aryl), 6.03 (d, J =

8.8 Hz, 1H, H-10), 5.33-5.27 (m, 1H, H-11), 4.53 (br, 1H, -NH), 2.76 (d, J = 5.2 Hz, 3H, H-

14), 1.31 (d, J = 6.4 Hz, 3H, H-12); 13

C NMR (100MHz, CDCl3) 156.4 (C-13), 143.0,

141.6, 139.0 (C-4, C-5 and C-6), 129.5, 128.7, 128.3, 128.1, 127.5, 127.4, 127.3 (C-10 and

aryl), 69.8 (C-11), 27.4 (C-14), 21.4 (C-12); MS m/z (ES+) 304 (100 %, M+Na+); HMRS


(2,5-Dimethylfuran-3-yl)methanol 254b.[232]

O1

2

3

45

6

1HO

Procedure B was followed. 2,5-Dimethyl-3-furoic acid 253 (500 mg, 3.57 mmol) gave the

title compound 254b (331 mg) as a yellow oil which was reacted without purification.

Rf 0.57 (Petrol:EtOAc 5:5); 1H NMR (300MHz, CDCl3) 5.94 (s, 1H, H-4), 4.40 (s, 2H,

H-6), 2.23 (s, 6H, H-1). Spectral data matched the published values.[232]

276

(Furan-3-yl)methyl methylphenylcarbamate 255a.

N O

O

O1

2

34

5

6

7

8

910

11

General procedures E and F were followed. 2-Furylmethanol 254a (1.0 g, 0.01 mmol) gave




) 1703 (C=O); 1H NMR (400MHz, CDCl3)

7.39 (s, 1H, H-1), 7.34-7.30 (m, 3H, aryl, H-2), 7.23-7.16 (m, 3H, aryl), 6.39 (s, 1H, H-3),

5.02 (s, 2H, H-5), 3.31 (s, 3H, H-7); 13

C NMR (100MHz, CDCl3) 155.5 (C-6), 143.5 (C-

8), 143.2 (C-2), 141.2 (C-1), 128.9, 126.1, 125.8 (CH aryl), 121.0 (C-4), 110.5 (C-3), 59.0

(C-5), 29.7 (C-7); MS m/z (ES+) 254 (100%, M+Na+); HMRS (ES+) calcd for

C13H13O3N1Na1 (M+Na+): 254.0788, found: 254.0790.

(2,5-Dimethylfuran-3-yl)methyl methylphenylcarbamate 255b.

N O

O

O1

2

3

45

6

7

8

9

1011

12

1

General procedures E and F were followed. (2,5-Dimethylfuran-3-yl)methanol 254b (331


title compound 255b (573 mg, 62 % over 3 steps) as a yellow oil.


) 1698 (C=O); 1H NMR (400MHz, CDCl3)

7.28-7.11 (m, 5H, aryl), 5.82 (br, 1H, H-4), 4.82 (s, 2H, H-6), 3.22 (s, 3H, H-8) 2.14 (s, 6H,

H-1); 13


128.8, 125.9, 125.7 (CH aryl), 115.5 (C-5), 107.3 (C-4), 59.5 (C-6), 37.7 (C-8), 13.4, 11.6

277


(M+Na+): 282.1101, found: 282.1101.

Propyl methylphenylcarbamate 257.

N O

O1

2

3

4

5

6

7

8

9

General procedures E and F were followed. 1-Propanol (0.5 g, 8.3 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 4 %) the title compound 257 (1.2 g, 74 %

over 2 steps) as a pale yellow oil.


) 1699 (C=O); 1H NMR (400MHz, CDCl3)

7.36-7.18 (m, 5H, aryl), 4.06 (t, J = 6.8 Hz, 2H, H-3), 3.30 (s, 3H, H-5), 1.64-1.57 (m, 2H,

H-2), 0.88 (t, J = 7.6 Hz, 3H, H-1); 13

C NMR (100MHz, CDCl3) 155.7 (C-4), 143.3 (C-

6), 128.7, 125.8, 125.6 (CH aryl), 67.2 (C-3), 37.5 (C-5), 22.2 (C-2), 10.3 (C-1); MS m/z

(ES+) 194 (100 %, M+H+); HMRS (ES+) calcd for C11H15O2N1Na1 (M+Na

+): 216.0995,

found: 216.0989.

3-Methyl-1,1-diphenylbutyl methylcarbamate 259a.

NH

O

O

1

2

34

5

6 8

7

8

910

2

3

1

General procedure O was followed with i-PrLi (2.5 equiv.). 1-Phenylvinyl

methylphenylcarbamate 248e (50 mg, 0.20 mmol) gave after flash column chromatography

(SiO2, Petrol:EtOAc 2 %) the title compound 259a (21 mg, 36 %) as a colourless oil.

278


) 3390 (br, N-H), 1627 (C=O), 1592 (Amide

II), 1354 (Amide III); 1H NMR (400MHz, CDCl3) 7.41-7.03 (m, 10H, aryl), 5.11 (br, 1H,

-NH), 3.20 (br, 3H, H-10), 2.09-1.83 (m, 3H, H-6 and H-7), 1.04 (d, J = 5.9 Hz, 3H, H-8),

0.98 (d, J = 5.9 Hz, 3H, H-8) ; 13

C NMR (100MHz, CDCl3) 174.8 (C-9), 143.9 (C-4),

128.8, 128.1, 127.6, 127.3, 125.8 (CH aryl), 78.0 (C-5), 44.6 (C-6), 40.8 (C-10), 24.4 (C-7),

24.1 (C-8); MS m/z (ES+) 298 (100 %, M+H+); HMRS (ES+) calcd for C19H24O2N1

(M+H+): 298.1802, found: 298.1806.

1,1-Diphenylhexyl methylcarbamate 259b.

2

3

1

NH

O

O

1

2

34

5

6 7

8 9

10

1112

General procedure O was followed with n-BuLi (2.5 equiv.). 1-Phenylvinyl


(SiO2, Petrol:EtOAc 2 %) the title compound 259b (22 mg, 33 %) as a colourless oil.


) 3411 (br, N-H), 1634 (C=O), 1593 (amide

II), 1356 (Amide III); 1H NMR (400MHz, CDCl3) 7.30-7.00 (m, 10H, aryl), 5.28 (br, 1H,

-NH), 3.22 (br, 3H, H-12), 1.86 (br, 2H, H-6), 1.67-1.58 (m, 1H, H-7), 1.39-1.19 (m, 5H, H-

7, H-8 and H-9), 0.92 (t, J = 7.2 Hz, 3H, H-10) ; 13

C NMR (100MHz, CDCl3) 174.5 (C-

11), 143.4 (C-4), 128.8, 128.4, 128.1, 127.8, 127.4, 126.0 (CH aryl), 77.8 (C-5), 39.1 (C-6),

36.3 (C-12), 32.1, 23.2, 22.7 (C-7, C-8 and C-9), 14.1 (C-10); MS m/z (ES+) 334 (100 %,


+): 334.1778, found: 334.1768.

279

3-Methyl-1,1-diphenylpentyl methylcarbamate 259c.

NH

O

O

1

2

34

5

67

8

910

1112

12

3

General procedure O was followed with sec-BuLi (2.5 equiv.). 1-Phenylvinyl


(SiO2, Petrol:EtOAc 2 %) the title compound 259c (23 mg, 35 %) as a colourless oil.


) 3400 (br, N-H), 1628 (C=O), 1594 (Amide

II), 1369 (Amide III); 1H NMR (400MHz, CDCl3) (mixture of rotamers) 7.18-6.99 (br,

10H, aryl), 5.07 (br, 0.5H, -NH, rotamer 1), 4.97 (br, 0.5H, -NH, rotamer 1), 3.18 (br, 3H,

H-12), 2.15-1.79 (2 br, 2H, H-6), 1.74-1.60 (m, 1H, H-7), 1.53-1.42 (m, 1H, H-9), 1.31-1.20

(m, 1H, H-9), 1.00 (d, J = 6.8 Hz, 1.5H, H-8, rotamer 1), 0.98 (d, J = 6.8 Hz, 1.5H, H-8,

rotamer 2), 0.93 (t, J = 7.6 Hz, 1.5H, H-10, rotamer 1), 0.86 (t, J = 7.6 Hz, 1.5H, H-10,

rotamer 2); 13

C NMR (100MHz, CDCl3) (mixture of rotamers) 174.9, 174.8 (C-11),

143.8 (C-4), 128.9, 128.1, 127.5, 127.2, 125.9, 125.8 (CH aryl), 77.8 (C-5), 43.0 (C-6),

31.0, 30.9 (C-9), 29.8 (C-12), 20.3 (C-7), 11.4 (C-8), 11.0 (C-10); MS m/z (ES+) 334


+): 334.1778, found:

334.1771.

280

3-Methyl-1-phenylbutyl isopropylphenylcarbamate 261a.

N O

O

1

2

34

5

67

8

9

1011

12

13

14

8

11

15

General procedure O was followed with i-PrLi (2.5 equiv.). 1-Phenylvinyl

isopropylphenylcarbamate 248f (50 mg, 0.18 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 261a as a colourless oil.


) 1703 (C=O); 1H NMR (400MHz, CDCl3)

7.33-7.00 (m, 10H, aryl), 5.64 (dd, J = 8.8 and 5.6 Hz, 1H, H-5), 4.50 (sep, J = 6.8 Hz, 1H,

H-10), 1.62-1.51 (m, 1H, H-6), 1.44-1.25 (m, 2H, H-6 and H-7), 1.03 (d, J = 6.8 Hz, 3H, H-

11), 0.98 (d, J = 6.8 Hz, 3H, H-11), 0.80 (d, J = 6.0 Hz, 3H, H-8), 0.77 (d, J = 6.0 Hz, 3H,

H-8); 13

C NMR (100MHz, CDCl3) 154.9 (C-9), 142.1 (C-12), 138.3 (C-4), 130.1, 128.5,

128.2, 127.3, 127.2, 126.0 (CH aryl), 75.5 (C-5), 48.6 (C-10), 46.1 (C-6), 24.7 (C-7), 22.8,

22.4 (C-8), 21.4, 21.3 (C-11); MS m/z (ES+) 348 (100 %, M+Na+); HMRS (ES+) calcd for

C21H27O2N1Na1 (M+Na+): 348.1934, found: 348.1940.

1-(4-Chlorophenyl)hexyl isopropylphenylcarbamate 261c.

N O

O

Cl1

2

34

5

67

8 9

10

11

1213

14

1516

17

13

General procedure S was followed. 1-(4-Chlorophenyl)vinyl isopropylphenylcarbamate

248g (50 mg, 0.16 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc

1 %) the title compound 261b as a colourless oil.

281


) 1699 (C=O); 1H NMR (500MHz, CDCl3)

7.40-7.03 (m, 9H, aryl), 5.59 (t, J = 6.5 Hz, 1H, H-5), 4.56 (sep, J = 6.8 Hz, 1H, H-12),

1.69-1.45 (m, 2H, H-6), 1.22-1.10 (m, 6H, H-7, H-8 and H-9), 1.07 (d, J = 6.8 Hz, 6H, H-

13), (t, J = 6.5 Hz, 3H, H-10); 13

C NMR (125MHz, CDCl3) 154.7 (C-11), 140.3 (C-14),

138.2 (C-4), 133.0 (C-1), 130.0, 128.6, 128.3, 127.5, 127.4 (CH aryl), 76.1 (C-5), 48.7 (C-

12), 36.6 (C-6), 31.3, 24.7, 22.4 (C-7, C-8 and C-9), 21.3 (C-13), 13.9 (C-10); MS m/z

(ES+) 396 (100 %, M+Na+); HMRS (ES+) calcd for C22H28O2N1

35Cl1Na1 (M+Na

+):

396.1701, found: 396.1714.

3-Methyl-1,1-diphenylbutyl isopropylcarbamate 262a.

NH

O

O

1

2

34

5

67

8

8

9

10

11

11

General procedure O was followed with i-PrLi (2.0 equiv.) and DMPU. 1-Phenylvinyl

isopropylphenylcarbamate 248f (50 mg, 0.18 mmol) gave after recrystallisation from

hexane:Et2O 1 % the title compound 262a (46 mg, 80 %) as a white solid.

Rf 0.58 (Petrol:EtOAc 8:2); m.p. 154-156 °C (Hexane/Et2O); 1H NMR (400MHz, CDCl3)

7.34 (d, J = 7.4 Hz, 4H, aryl), 7.26 (t, J = 7.4 Hz, 4H, aryl), 7.17 (t, J = 7.4 Hz, 2H, aryl),

4.68 (br d, J = 6.6 Hz, 1H, -NH), 3.70 (oct, J = 6.6 Hz, 1H, H-10), 2.74 (d, J = 5.6 Hz, 2H,

H-6), 1.56-1.48 (m, 1H, H-7), 1.11 (d, J = 6.6 Hz, 6H, H-11), 0.81 (d, J = 6.4 Hz, 6H, H-8);

13C NMR (100MHz, CDCl3) 153.5 (C-9), 146.0 (C-4), 127.9, 126.5, 125.8 (CH aryl),

85.3 (C-5), 44.7 (C-6), 42.6 (C-10), 24.0 (C-8), 23.8 (C-11), 23.0 (C-7); MS m/z (ES+) 298


+): 298.1802, found:

298.1806.

282

1,1-Diphenylhexyl isopropylcarbamate 262b.

NH

O

O

1

2

34

5

67

8 9

10

11

12

13

13

General procedure O was followed with n-BuLi (2.0 equiv.) and DMPU. 1-Phenylvinyl


hexane:Et2O 1 % the title compound 262b (44 mg, 73 %) as a white solid.

Rf 0.50 (Petrol:EtOAc 8:2); m.p. 126-128 °C (Hexane/Et2O); IR max (neat/cm-1

) 3280 (br,


7.34-7.17 (m, 10H, aryl), 4.68 (br d, J = 6.6 Hz, -NH), 3.71 (oct, J = 6.6 Hz, 1H, H-12),

2.75 (t, J = 7.6 Hz, 2H, H-6), 1.24-1.21 (m, 6H, H-7, H-8 and H-9), 1.11 (d, J = 6.6 Hz, 6H,

H-13), 0.81 (t, J = 6.8 Hz, 6H, H-10); 13

C NMR (100MHz, CDCl3) 153.6 (C-11), 145.7

(C-4), 127.9, 126.6, 125.9 (CH aryl), 85.3 (C-5), 42.7 (C-12), 37.4 (C-6), 31.9, 23.0 (C-13),

22.8, 22.5 (C-7, C-8 and C-9), 13.9 (C-10); MS m/z (ES+) 362 (100 %, M+Na+); HMRS


3-Methyl-1,1-diphenylpentyl isopropylcarbamate 262c.

2

3

1

4NH

O

O

1

23

45

67

8

9

10

11

12

13

13

General procedure O was followed with sec-PrLi (2.0 equiv.) and DMPU. 1-Phenylvinyl


hexane:Et2O 1 % the title compound 262c (48 mg, 80 %) as a white solid.

283


7.35-7.24 (m, 8H, aryl), 7.16 (t, J = 7.2 Hz, 2H, aryl), 4.67 (br d, J = 6.6 Hz, -NH), 3.68

(oct, J = 6.6 Hz, 1H, H-12), 2.77 (dd, J = 14.0 and 3.2 Hz, 1H, H-6), 2.69 (dd, J = 14.0 and

6.8 Hz, 1H, H-6), 1.27-1.16 (m, 3H, H-7 and H-9), 1.13 (d, J = 6.6 Hz, 3H, H-13), 1.11 (d, J

= 6.6 Hz, 3H, H-13), 0.74-0.70 (m, 6H, H-8 and H-10); 13


153.5 (C-11), 146.1, 146.0 (C-4), 127.8, 126.5, 126.4, 125.9, 125.8 (CH aryl), 85.2 (C-5),

42.9 (C-6), 42.6 (C-12), 30.8 (C-9) 29.8 (C-7), 22.9 (C-13), 20.2 (C-8), 11.1 (C-10); MS

m/z (ES+) 362 (100 %, M+Na+); HMRS (ES+) calcd for C22H29O2N1Na1 (M+Na

+):

362.2091, found: 362.2103.

3,3-Dimethyl-1,1-diphenylbutyl isopropylcarbamate 262d.

NH

O

O

1

2

34

5

67

8

9

10

11

11

General procedure O was followed with tert-BuLi (2.0 equiv.) and DMPU. 1-Phenylvinyl


hexane:Et2O 1 % the title compound 262d (40 mg, 83 %) as a white solid.


) 3333 (br,

N-H), 1688 (C=O), 1521 (Amide II), 1253 (Amide III); 1H NMR (400MHz, CDCl3) 7.35

(d, J = 7.6 Hz, 4H, aryl), 7.24 (t, J = 7.6 Hz, 4H, aryl), 7.15 (t, J = 7.6 Hz, 2H, aryl), 4.69 (br

d, J = 6.6 Hz, -NH), 3.70 (oct, J = 6.6 Hz, 1H, H-10), 2.90 (s, 2H, H-6), 1.11 (d, J = 6.6 Hz,

6H, H-11), 0.77 (s, 9H, H-8) ; 13

C NMR (100MHz, CDCl3) 153.5 (C-9), 147.0 (C-4),

127.9, 126.3, 125.6 (CH aryl), 84.7 (C-5), 47.2 (C-6), 42.6 (C-10), 31.5 (C-7), 31.0 (C-8),


(M+Na+): 362.2091, found: 362.2092.

284

1-(4-Chlorophenyl)-3-methyl-1-phenylbutyl isopropylcarbamate 262e.

NH

O

O

Cl1

2

34

5

67

8

8

910

11

12

13

14

15

15

General procedure O was followed with i-PrLi (2.0 equiv.) and DMPU. 1-(4-

Chlorophenyl)vinyl isopropylphenylcarbamate 248g (50 mg, 0.16 mmol) gave after

recrystallisation from hexane:Et2O 1 % the title compound 262e (43 mg, 81 %) as a white

solid.



2.71 (dd, J = 14.0 and 6.1 Hz, 1H, H-6), 2.65 (dd, J = 14.0 and 5.6 Hz, 1H, H-6), 1.53-1.46

(m, 1H, H-7), 1.10 (d, J = 6.6 Hz, 6H, H-15), 0.81 (d, J = 6.7 Hz, 3H, H-8), 0.77 (d, J = 6.7

Hz, 3H, H-8); 13

C NMR (100MHz, CDCl3) 153.4 (C-13), 145.4, 144.7, 132.3, 128.1,

128.0, 127.3, 126.7, 125.7 (aryl), 84.8 (C-5), 44.7 (C-6), 42.7 (C-14), 24.0, 23.9 (C-8),


C22H26O2N135

Cl1Na1 (M+Na+): 382.1544, found: 382.1539.

1-(4-Chlorophenyl)-1-phenylhexyl isopropylcarbamate 262f.

NH

O

O

Cl

1

2

345

67

8 9

10

1112

13

14

1516

17

17

General procedure O was followed with n-BuLi (2.0 equiv.) and DMPU. 1-(4-


285

recrystallisation from hexane:Et2O 1 % the title compound 262f (44 mg, 74 %) as a white

solid.


) 3330 (br,



2.79-2.65 (m, 2H, H-6), 1.27-1.23 (m, 6H, H-7, H-8 and H-9), 1.12 (d, J = 6.6 Hz, 6H, H-

17), 0.81 (t, J = 6.9 Hz, 3H, H-10); 13

C NMR (100MHz, CDCl3) 153.4 (C-15), 145.1,

144.3, 132.5, 128.1, 128.0, 127.4, 126.8, 125.8 (aryl), 84.9 (C-5), 42.7 (C-16), 37.4 (C-6),

31.8, 23.0 (C-17), 22.7, 22.5 (C-7, C-8 and C-9), 13.9 (C-10); MS m/z (ES+) 396 (100 %,


35Cl1Na1 (M+Na

+): 396.1701, found:

396.1686.

1-(4-Chlorophenyl)-3-methyl-1-phenylpentyl isopropylcarbamate 262g.

NH

O

O

Cl1

2

34

5

6

7

8

9

10

1112

13

14

1516

17

17

General procedure O was followed with sec-BuLi (2.0 equiv.) and DMPU. 1-(4-


recrystallisation from hexane:Et2O 1 % the title compound 262g (44 mg, 75 %) as a white

solid.

Rf 0.48 (Petrol:EtOAc 8:2); m.p. 138-140°C (Hexane/Et2O); IR max (neat/cm-1

) 3304 (br,


(mixture of diastereoisomers) 7.28-7.14 (m, 9H, aryl), 4.64 (br d, J = 6.6 Hz, -NH), 3.67

(oct, J = 6.6 Hz, 1H, H-16), 2.74 (dd, J = 14.0 and 3.6 Hz, 0.5H, H-6), 2.66 (d, J = 5.2 Hz,

1H, H-6), 2.59 (dd, J = 14.0 and 6.8 Hz, 0.5H, H-6), 1.32-1.07 (m, 3H, H-7, H-9), 1.08 (br,

6H, H-17), 0.73-0.65 (m, 6H, H-8 and H-10); 13

C NMR (100MHz, CDCl3) (mixture of

diastereoisomers) 153.3 (C-15), 145.5, 145.4, 144.8, 144.7, 132.4, 132.3, 128.0, 127.9,

286

127.5, 127.3, 126.8, 126.7, 125.8, 125.7 (aryl), 84.8 (C-5), 42.8, 42.7 (C-6), 42.6 (C-16),

30.8, 30.7 (C-9), 29.8 (C-7), 23.0 (C-17), 20.3 (C-8), 11.1 (C-10); MS m/z (ES+) 396

(100 %, M+Na+); HMRS (ES+) calcd for C22H28O2N1

35Cl1Na1 (M+Na

+): 396.1701, found:

396.1698.

1-(4-Chlorophenyl)-3,3-dimethyl-1-phenylbutyl isopropylcarbamate 262h.

NH

O

O

Cl1

2

34

5

67

8

910

11

12

13

14

15

15

General procedure O was followed with tert-BuLi (2.0 equiv.) and DMPU. 1-(4-


recrystallisation from hexane:Et2O 1 % the title compound 262h (48 mg, 81 %) as a white

solid.


) 3323 (br,



2.91 (d, J = 14.5 Hz, 1H, H-6), 2.81 (d, J = 14.5 Hz, 1H, H-6), 1.12 (d, J = 6.6 Hz, 6H, H-

15), 0.76 (s, 9H, H-8) ; 13

C NMR (125MHz, CDCl3) 153.4 (C-13), 146.4, 145.8, 132.1,

128.1, 128.0, 127.1, 126.5, 125.5 (aryl), 84.3 (C-5), 47.2 (C-6), 42.8 (C-14), 31.5 (C-7),

31.0 (C-8), 23.0, 22.8 (C-15); MS m/z (ES+) 396 (100 %, M+Na+); HMRS (ES+) calcd for

C22H29O2N135

Cl1 (M+H+): 374.1881, found: 374.1874.

287

1,1-Diphenylhexan-1-ol 266a.

OH

1

2

34

5

6

78

910

General procedure P was followed with n-BuLi (2.0 equiv.). 1-Phenylvinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266a (25 mg, 57 %) as a

colourless oil.


2.25 (m, 2H, H-6), 2.09 (s, 1H, -OH), 1.30-1.27 (m, 6H, H-7, H-8 and H-9), 0.85 (t, J = 6.8

Hz, 3H, H-10); 13

C NMR (125MHz, CDCl3) 147.2 (C-4), 128.1, 126.7, 126.0 (CH aryl),

78.3 (C-5), 41.9 (C-6), 32.2, 23.4, 22.2 (C-7, C-8 and C-9), 14.0 (C-10); MS m/z (ES+)

254 (100 %, M+); HMRS (ES+) calcd for C18H22O1 (M

+): 254.1665, found: 254.1665.

1-(4-Chlorophenyl)-1-phenylhexan-1-ol 266b.

OH

1

2

34

5

6

78

910

1112

13

14Cl

General procedure P was followed with n-BuLi (2.0 equiv.). 1-(4-Chlorophenyl)vinyl

isopropylphenylcarbamate 248g and 1-phenylvinyl 4-chlorophenylisopropylcarbamate

248h (50 mg, 0.16 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc

1 %) the title compounds 266b (35 mg, 77 % and 25 mg, 55 %) as a colourless oil.


) 3464 (br, O-H); 1H NMR (400MHz,

CDCl3) 7.40-7.21 (m, 9H, aryl), 2.24 (t, J = 7.6 Hz, 2H, H-6), 2.08 (s, 1H, -OH), 1.30-

1.18 (m, 6H, H-7, H-8 and H-9), 0.85 (t, J = 6.9 Hz, 3H, H-10); 13

C NMR (100MHz,

288

CDCl3) 146.8 (C-11), 145.7 (C-4), 132.5 (C-1), 128.2, 128.2, 127.5, 127.0, 125.9 (CH

aryl), 77.9 (C-5), 41.8 (C-6), 32.1, 23.3, 22.5 (C-7, C-8 and C-9), 14.0 (C-10); MS m/z

(ES-) 287 (100 %, M-H+); HMRS (ES+) calcd for C18H21O1

35Cl1 (M

+): 288.1275, found:

288.1276.

1-(4-Methoxyphenyl)-1-phenylhexan-1-ol 266c.

OH

12

3

45

6

7

89

10

11

1213

14

15O

General procedure P was followed with n-BuLi (2.0 equiv.). 1-(4-Methoxyphenyl)vinyl

isopropylphenylcarbamate 248i (50 mg, 0.16 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266c (31 mg, 68 %) as a

colourless oil.


) 3492 (br, O-H), 1610, 1510 (C=C), 1245

(C-O-C); 1H NMR (500MHz, CDCl3) 7.39 (d, J = 5.9 Hz, 2H, aryl), 7.33-7.20 (m, 5H,

aryl), 6.84 (d, J = 8.8 Hz, 2H, H-3), 3.79 (s, 3H, H-1), 2.24 (t, J = 6.1 Hz, 2H, H-7), 2.06 (s,

1H, -OH), 1.29-1.24 (m, 6H, H-7, H-9 and H-10), 0.85 (t, J = 5.4 Hz, 3H, H-11); 13

C NMR

(125MHz, CDCl3) 158.3 (C-2), 147.3 (C-12), 139.5 (C-5), 128.0, 127.3, 126.6, 125.9

(CH aryl), 113.4 (C-3), 78.0 (C-6), 55.2 (C-1), 42.0, 32.2, 23.5 (C-7, C-8 and C-9), 22.5

(C-10), 14.0 (C-11); MS m/z (ES+) 267 (100 %, M-H2O+H+), (ES-) 283 (30 %, M-H

+);

HMRS (ES+) calcd for C19H23O1 (M-H2O+H+): 267.1744, found: 267.1754.

289

1,1,3-Triphenylpropan-1-ol 266d.

OH

1

23

45

6

7

8

910

11

To a mixture of anhydrous toluene (0.10 cm3) and distilled ()-sparteine (0.10 cm

3, 0.45

mmol) was added sec-BuLi (1.20 M, 0.35 cm3, 0.43 mmol) at -45 °C under nitrogen

atmosphere, then the mixture reaction was stirred at room temperature for 1 h. To a

solution of 1-phenylvinyl isopropylphenylcarbamate 248f (50 mg, 0.18 mmol) in

anhydrous THF (1 cm3) and DMPU (0.25 cm

3) was added the above yellow solution

dropwise at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred

at -78 °C under nitrogen atmosphere after which MeOH (0.1 cm3) and a saturated aqueous

solution of NH4Cl were added and the reaction mixture stirred for a further 30 min while

warming to room temperature. The mixture was partitioned between Et2O (10 cm3) and

water. The organic layer was washed with water (3 30 cm3), dried over MgSO4, filtered

and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (1

cm3), and n-BuLi (0.14 cm

3, 0.27 mmol) was added, followed by tert-butylnitrite (0.11 cm

3,

1.44 mmol) under nitrogen atmosphere. The reaction was stirred 24 h. The mixture was

partitioned between Et2O (10 cm3) and a saturated aqueous solution of K2CO3. The organic

layer was washed with saturated aqueous K2CO3 (3 20 cm3), dried over MgSO4, filtered

and concentrated under reduced pressure to give a residue which was purified by flash

column chromatography (SiO2, Petrol:EtOAc 2 %) to give the title compound 266d (27 mg,



) 3444 (br, O-H); 1H NMR (400MHz,

CDCl3) 7.49 (d, J = 7.3 Hz, 4H, aryl), 7.38-7.19 (m, 11H, aryl), 2.65 (s, 4H, H-6 and H-7),

2.20 (s, 1H, -OH), 13

C NMR (100MHz, CDCl3) 146.8 (C-4), 142.3 (C-8), 128.4, 128.3,

128.2, 126.9, 126.0, 125.8 (CH aryl), 78.2 (C-5), 44.0 (C-6), 30.2 (C-7); MS m/z (ES+)

311 (100 %, M+Na+); HMRS (ES+) calcd for C21H20O1Na1 (M+Na

+): 311.1404, found:

311.1405.

290

3-Methyl-1,1-diphenylbutan-1-ol 266e.

OH

1

2

34

5

6

78 8

General procedure P was followed with i-PrLi (2.0 equiv.). 1-Phenylvinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266e (28 mg, 73 %) as a

colourless oil.


) 3472 (br, O-H); 1H NMR (500MHz,

CDCl3) 7.43 (d, J = 7.7 Hz, 4H, aryl), 7.32-7.20 (m, 6H, aryl), 2.25 (d, J = 6.6 Hz, 2H, H-

6), 2.04 (s, 1H, -OH), 1.71 (non, J = 6.6 Hz, 1H, H-7), 0.88 (d, J = 6.6 Hz, 6H, H-8); 13

C

NMR (125MHz, CDCl3) 147.6 (C-4), 128.0, 126.7, 126.0 (CH aryl), 78.8 (C-5), 50.3 (C-

6), 24.6 (C-8), 24.3 (C-7); EI GC/MS 183 (M+-C4H9).

1-(4-Chlorophenyl)-3-methyl-1-phenylbutan-1-ol 266f.

OH

1

23

45

6

78

910

11

12

8

Cl

General procedure P was followed with i-PrLi (2.0 equiv.). 1-(4-Chlorophenyl)vinyl



1 %) the title compound 266f (28 mg, 65 % and 22 mg, 51 %) as a colourless oil.


) 3464 (br, O-H); 1H NMR (400MHz,

CDCl3) 7.42-7.22 (m, 9H, aryl), 2.22 (d, J = 6.2 Hz, 2H, H-6), 2.01 (s, 1H, -OH), 1.69

(non, J = 6.2 Hz, 1H, H-7), 0.89 (d, J = 6.2 Hz, 3H, H-8), 0.87 (d, J = 6.2 Hz, 3H, H-8); 13

C

291

NMR (100MHz, CDCl3) 147.2 (C-9), 146.0 (C-4), 132.4 (C-1), 128.2, 128.1, 127.5,

127.0, 125.9 (CH aryl), 78.4 (C-5), 50.2 (C-6), 24.6, 24.5 (C-8), 24.2 (C-7); MS m/z (ES-)

273 (100 %, M-H+); HMRS (ES+) calcd for C17H19O1

35Cl1 (M

+): 274.1107, found:

274.1119.

1-(4-Methoxyphenyl)-3-methyl-1-phenylbutan-1-ol 266g.

OH

12

3

45

6

7

89

1011

12

13

9

O

General procedure P was followed with i-PrLi (2.0 equiv.). 1-(4-Methoxyphenyl)vinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266g (35 mg, 81 %) as a

colourless oil.


) 3473 (br, O-H), 1610, 1509 (C=C), 1245

(C-O-C); 1H NMR (400MHz, CDCl3) 7.41 (d, J = 7.3 Hz, 2H, aryl), 7.34-7.19 (m, 5H,

aryl), 6.83 (d, J = 8.8 Hz, 2H, H-3), 3.78 (s, 3H, H-1), 2.21 (d, J = 6.2 Hz, 2H, H-7), 2.00 (s,

1H, -OH), 1.69 (non, J = 6.2 Hz, 1H, H-8), 0.89 (d, J = 6.2 Hz, 3H, H-9), 0.85 (d, J = 6.2 Hz,

3H, H-9); 13

C NMR (100MHz, CDCl3) 158.2 (C-2), 147.7 (C-10), 140.0 (C-5), 128.0,

127.2, 126.5, 126.0 (CH aryl), 113.3 (C-3), 78.5 (C-6), 55.2 (C-1), 50.4 (C-7), 24.6 (C-9),

24.3 (C-8); MS m/z (ES+) 253 (100 %, M-H2O+H+), (ES-) 269 (40 %, M-H

+); HMRS

(ES+) calcd for C18H21O1 (M-H2O+H+): 253.1587, found: 253.1592.

292

3-Methyl-1,1-diphenylpentan-1-ol 266h.

OH

1

2

34

5

6

7 89

10

General procedure P was followed with sec-BuLi (2.0 equiv.). 1-Phenylvinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266h (29 mg, 64 %) as a

colourless oil.

Rf 0.29 (Petrol:EtOAc 9:1); 1H NMR (400MHz, CDCl3) 7.44 (d, J = 8.0 Hz, 4H, aryl),

7.33-7.20 (m, 6H, aryl), 2.36 (dd, J = 14.3 and 4.1 Hz, 1H, H-6), 2.15 (dd, J = 14.3 and 6.8

Hz, 1H, H-6), 2.03 (s, 1H, -OH), 1.54-1.45 (m, 1H, H-7), 1.38-1.28 (m, 1H, H-9), 1.22-1.12

(m, 1H, H-9), 0.83-0.77 (m, 6H, H-8 and H-10); 13

C NMR (100MHz, CDCl3) 147.8,

147.4 (C-4), 128.0, 126.7, 126.6, 126.1, 126.0 (CH aryl), 78.7 (C-5), 48.3 (C-6), 31.2 (C-9),

30.2 (C-7), 21.2 (C-8), 11.2 (C-10); MS m/z (ES-) 253 (100 %, M-H+).

1-(4-Chlorophenyl)-3-methyl-1-phenylpentan-1-ol 266i.

OH

1

2

34

5

6

789

10

1112

13

14Cl

General procedure P was followed with sec-BuLi (2.0 equiv.). 1-(4-Chlorophenyl)vinyl



1 %) the title compound 266i (30 mg, 67 % and 23 mg, 51 %) as a yellow oil.

Rf 0.55 (Petrol:EtOAc 8:2); 1H NMR (500MHz, CDCl3) (mixture of diastereoisomers)

7.42-7.22 (9H, aryl), 2.33 (dd, J = 14.2 and 4.0 Hz, 1H, H-6), 2.12 (dd, J = 14.2 and 5.6 Hz,

293

1H, H-6), 2.00 (s, 1H, -OH), 1.56-1.44 (m, 1H, H-7), 1.39-1.27 (m, 1H, H-9), 1.23-1.12 (m,

1H, H-9), 0.85-0.78 (m, 6H, H-8 and H-10); 13


diastereoisomers) 147.5, 147.1 (C-11), 146.3, 145.9 (C-4), 132.5, 132.4 (C-1), 128.2,

128.1, 127.6, 127.5, 127.0, 126.9, 126.0, 125.9 (CH aryl), 78.5, 78.4 (C-5), 48.2, 48.1 (C-

6), 31.2, 31.1 (C-9), 30.3, 30.2 (C-7), 21.1, 21.0 (C-8), 11.1 (C-10); MS m/z (ES-) 287

(100 %, M-H+); HMRS (ES+) calcd for C18H21O1

35Cl1 (M

+): 288.1275, found: 288.1276.

1-(4-Methoxyphenyl)-3-methyl-1-phenylpentan-1-ol 266j.

OH

12

34

56

7

8910

11

1213

14

15O

General procedure P was followed with sec-BuLi (2.0 equiv.). 1-(4-Methoxyphenyl)vinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266j (29 mg, 64 %) as a

colourless oil.


) 3475 (br, O-H), 1682, 1510 (C=C), 1245

(C-O-C); 1H NMR (500MHz, CDCl3) (mixture of diastereoisomers) 7.41 (d, J = 7.3 Hz,

2H, aryl), 7.28-7.19 (m, 5H, aryl), 6.83 (d, J = 8.8 Hz, 2H, H-3), 3.79 (s, 1.5H, H-1), 3.78 (s,

1.5H, H-1), 2.32 (dd, J = 14.3 and 4.0 Hz, 1H, H-7), 2.11 (dd, J = 14.3 and 6.7 Hz, 1H, H-7),

1.98 (s, 1H, -OH), 1.53-1.44 (m, 1H, H-8), 1.38-1.21 (m, 1H, H-10), 1.21-1.10 (m, 1H, H-

10), 0.84-0.75 (m, 6H, H-9 and H-11); 13


diastereoisomers) 158.3, 158.2 (C-2), 147.9, 147.6 (C-12), 140.2, 139.8 (C-5), 128.0,

127.3, 127.2, 126.6, 126.5, 126.0, 125.9 (CH aryl), 113.3 (C-3), 78.5, 78.4 (C-6), 55.2 (C-

1), 48.4, 48.3 (C-7), 31.2, 31.1 (C-10), 30.3, 30.2 (C-8), 21.1, 21.0 (C-9), 11.2, 11.1 (C-11);

MS m/z (ES+) 267 (100 %, M-H2O+H+), (ES-) 283 (20 %, M-H


C19H23O1 (M-H2O+H+): 267.1744, found: 267.1747.

294

3,3-Dimetyl-1,1-diphenylbutan-1-ol 266k.

OH

1

2

34

5

6

7

8

General procedure P was followed with tert-BuLi (2.0 equiv.). 1-Phenylvinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266k (32 mg, 71 %) as a

white solid.

Rf 0.29 (Petrol:EtOAc 9:1); m.p. 70-72 °C (MeOH/Et2O); 1H NMR (400MHz, CDCl3)

7.49 (d, J = 7.2 Hz, 4H, aryl), 7.31-7.18 (m, 6H, aryl), 2.43 (s, 2H, H-6), 2.05 (s, 1H, -OH),

0.86 (s, 9H, H-8); 13

C NMR (100MHz, CDCl3) 148.5 (C-4), 127.9, 126.4, 125.8 (CH

aryl), 78.5 (C-5), 53.0 (C-6), 31.9 (C-7), 31.7 (C-8); MS m/z (ES-) 253 (100 %, M-H+).

1-(4-Chlorophenyl)-3,3-dimethyl-1-phenylbutan-1-ol 266l.

OH

1

23

4

6

5

7

8

910

11

12Cl

General procedure P was followed with tert-BuLi (2.0 equiv.). 1-(4-Chlorophenyl)vinyl



1 %) the title compound 266l (12 mg, 27 % and 16 mg, 36 %) as a yellow oil.


7.19 (m, 5H, aryl), 2.40 (s, 2H, H-6), 2.03 (s, 1H, -OH), 0.86 (s, 9H, H-8); 13

C NMR

(125MHz, CDCl3) 148.3 (C-9), 146.9 (C-4), 132.2 (C-1), 128.1, 128.0, 127.3, 126.7,

295

125.6 (CH aryl), 78.2 (C-5), 53.0 (C-6), 31.9 (C-7), 31.7 (C-8); MS m/z (ES-) 287 (60 %,

M-H+).

1-(4-Methoxyphenyl)-3,3-dimethyl-1-phenylbutan-1-ol 266m.

OH

12

3

45

6

7

8

1011

12

13

9

O

General procedure P was followed with tert-BuLi (2.0 equiv.). 1-(4-Methoxyphenyl)vinyl


chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 266m (30 mg, 67 %) as a

yellow oil.


) 3494 (br, O-H), 1608, 1510 (C=C), 1244

(C-O-C); 1H NMR (400MHz, CDCl3) 7.45 (d, J = 7.3 Hz, 2H, H-11), 7.37 (d, J = 8.8 Hz,

2H, H-4), 7.28 (t, J = 7.3 Hz, 2H, H-12), 7.18 (t, J = 7.3 Hz, 1H, H-13), 6.81 (d, J = 8.8 Hz,

2H, H-3), 3.77 (s, 3H, H-1), 2.38 (s, 2H, H-7), 2.00 (s, 1H, -OH), 0.85 (s, 9H, H-9); 13

C

NMR (100MHz, CDCl3) 158.1 (C-2), 148.6 (C-10), 141.0 (C-5), 127.9, 127.0, 126.3,

125.8 (CH aryl), 113.2 (C-3), 78.3 (C-9), 55.1 (C-1), 53.1 (C-7), 31.9 (C-9), 31.7 (C-8);

MS m/z (ES+) 267 (100 %, M-H2O+H+), (ES-) 283 (50 %, M-H


C19H23O1 (M-H2O+H+): 267.1744, found: 267.1745.

296

(1S*,2S*)-1,2-Diphenylhexyl isopropylphenylcarbamate 271a.

N O

O

1

2

34

5

67

8 9

10

1112

13

14

15

1617

18

1920

21

17

General procedure S was followed. (Z)-1,2-Diphenylvinyl isopropylphenylcarbamate 248j

(50 mg, 0.14 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 1 %) the

title compound 271a (40 mg, 70 %) as a white solid.

Rf 0.50 (Petrol:EtOAc 8:2); m.p. 80-82°C (Petrol/Et2O); IR max (neat/cm-1

) 1688 (C=O);

1H NMR (400MHz, CDCl3) 7.41-7.38 (m, 3H, aryl), 7.18-6.91 (m, 10H, aryl), 6.60 (m,

2H, aryl), 5.81 (d, J = 6.4 Hz, 1H, H-5), 4.48 (sep, J = 6.8 Hz, 1H, H-16), 2.70 (br, 1H, H-6),

1.53-1.41 (m, 2H, H-7), 1.24-1.07 (m, 4H, H-8, H-9), 1.02 (d, J = 6.8 Hz, 3H, H-17), 0.96

(d, J = 6.8 Hz, 3H, H-17), 0.74 (t, J = 7.2 Hz, 3H, H-10); 13


154.4 (C-15), 140.7 (C-4), 140.3 (C-11), 138.0 (C-18), 130.3, 128.9, 128.6, 127.8, 127.5,

127.3, 127.2, 126.5, 125.9 (aryl), 79.8 (C-5), 52.0 (C-6), 48.3 (C-16), 31.7, 29.4, 22.5 (C-7,

C-8 and C-9), 21.2 (C-17), 13.8 (C-10); MS m/z (ES+) 438 (100 %, M+Na+), (ES-) 414

(100 %, M-H+); HMRS (ES+) calcd for C28H33O2N1Na1 (M+Na

+): 438.2404, found:

438.2387.

The syn-stereochemistry was proved by an X-ray crystal structure.

297

(1S*,2S*)-1,2-Diphenylhexyl 4-chlorophenylisopropylcarbamate 271b.

N O

O

1

2

34

5

67

8 9

10

1112

13

14

15

1617

18

1920

21

17

Cl

General procedure S was followed. (Z)-1,2-diphenylvinyl 4-

chlorophenylisopropylcarbamate 248k (50 mg, 0.13 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 271b (44 mg, 80 %) as a

white solid.


) 1687 (C=O);

1H NMR (400MHz, CDCl3) 7.35 (d, J = 8.5 Hz, 2H, aryl), 7.23-7.09 (m, 6H, aryl), 6.98

(m, 2H, aryl), 6.80 (d, J = 8.5 Hz, 2H, aryl), 6.71 (m, 2H, aryl), 5.82 (d, J = 7.2 Hz, 1H, H-5),

4.46 (sep, J = 6.8 Hz, 1H, H-16), 2.73 (br, 1H, H-6), 1.55-1.38 (m, 2H, H-7), 1.21-0.96 (m,

4H, H-8 and H-9), 0.99 (d, J = 6.8 Hz, 3H, H-17), 0.93 (d, J = 6.8 Hz, 3H, H-17), 0.74 (t, J

= 7.2 Hz, 3H, H-10); 13

C NMR (100MHz, CDCl3) 154.2 (C-15), 140.8 (C-4), 140.2 (C-

11), 136.5 (C-18), 133.2 (C-21), 131.5, 128.8, 128.7, 127.9, 127.7, 127.4, 126.6, 126.1

(aryl), 80.1 (C-5), 52.0 (C-6), 48.3 (C-16), 31.8, 29.3, 22.4 (C-7, C-8 and C-9), 21.1 (C-17),

13.8 (C-10); MS m/z (ES+) 472 (100 %, M+Na+); HMRS (ES+) calcd for

C28H33O2N135

Cl1 (M+H+): 450.2194, found: 450.2205.

298

1,1,2-Triphenylhexan-1-ol 272a.

1

2

34

5

6

7

8

9

10

11

1213

14

1516

18

19

17

OH

General procedure T was followed. (Z)-1,2-Diphenylvinyl isopropylphenylcarbamate 248j

(50 mg, 0.14 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 1 %) the

title compound 272a (28 mg, 60 %) as a white solid.

Rf 0.61 (Petrol:EtOAc 8:2); m.p. 99-101°C (MeOH/Et2O); 1H NMR (400MHz, CDCl3)

8.61-8.00 (m, 15H, aryl), 4.71 (dd, J = 11.6 and 2.8 Hz, 1H, H-6), 3.45 (s, 1H, -OH),

2.91-2.72 (m, 2H, H-7), 2.35-2.03 (m, 4H, H-8, H-9), 1.78 (t, J = 7.2 Hz, 3H, H-10); 13

C

NMR (400MHz, CDCl3) 146.4, 146.0 (C-4 and C-15), 140.0 (C-11), 130.0, 128.2, 127.7,

127.5, 126.7, 126.3, 126.2, 126.1, 125.6 (aryl), 80.9 (C-5), 54.1 (C-6), 30.2, 29.8, 22.6 (C-

7, C-8 and C-9), 13.9 (C-10); MS m/z (ES+) 353 (100 %, M+Na+); HMRS (ES+) calcd for

C24H26O1Na1 (M+Na+): found: 353.1876.

1-(4-Chlorophenyl)-1,2-diphenylhexan-1-ol 272b.

1

2

34

5

6

7

8

9

10

11

1213

14

1516

18

19

17

OH

Cl

General procedure T was followed. (Z)-1,2-diphenylvinyl 4-

chlorophenylisopropylcarbamate 248k (50 mg, 0.13 mmol) gave after flash column


colourless oil.

299

Rf 0.34 (Petrol:EtOAc 8:2); 1H NMR (400MHz, CDCl3) (mixture of diastereoisomers)

7.50-6.93 (m, 14H, aryl), 3.59 (t, J = 12.0 Hz, 0.5H, H-6), 3.58 (t, J = 12.0 Hz, 0.5H, H-

6), 2.37 (s, 0.5H, -OH), 2.35 (s, 0.5H, -OH), 1.80-1.56 (m, 2H, H-7), 1.24-0.94 (m, 4H, H-8,

H-9), 0.68 (t, J = 7.0 Hz, 3H, H-10); 13


diastereoisomers) 145.9, 145.8, 145.0, 144.5 (C-4 and C-15), 139.8, 139.6 (C-11), 132.5,

131.8 (C-18), 130.0, 129.9, 128.4, 128.2, 127.8, 127.7, 127.6, 127.1, 126.9, 126.5, 126.4,

126.3, 126.1, 125.6 (aryl), 80.7, 80.6 (C-5), 54.0, 54.0 (C-6), 30.1, 29.8, 29.7, 22.6, 22.5

(C-7, C-8 and C-9), 13.9 (C-10); MS m/z (ES+) 363 (100 %, M+H+); HMRS (ES+) calcd

for C28H33N1O2Na135

Cl1 (M+Na+): 438.2404, found: 438.2387.

Vinyl isopropylphenylcarbamate 277a.

N O

O

1

2

3

45

67

8

9

5

General procedure L was followed. Isopropyl(phenyl) carbamic chloride 245b (1.00 g,


compound 277a (0.80 g, 75 %) as a white solid.

Rf 0.41 (Petrol:EtOAc 8:2); m.p. 33-35°C (Petrol); IR max (neat/cm-1

) 1719 (C=O), 1645

(C=C); 1H-NMR (400MHz, CDCl3) δ 7.42-7.26 (m, 4H, aryl and H-2), 7.12 (d, J = 7.0 Hz,

2H, aryl), 5.70 (br, 1H, H-1), 5.39 (br, 1H, H-1), 4.58 (sep, J = 6.8 Hz, 1H, H-4), 1.15 (d, J =

6.8 Hz, 6H, H-5); 13

C-NMR (100MHz, CDCl3)3 δ 142.3 (C-2), 129.7, 128.7, 127.7 (CH

aryl), 95.4 (C-1), 49.4 (C-4), 21.1 (C-5); MS m/z (ES+) 228 (100 %, M+Na+); HMRS


3 Quaternary carbons were not clearly detectable in the

13C NMR spectrum.

300

Vinyl 4-chlorophenylisopropylcarbamate 277b.

N O

OCl

1

2

3

45

6

5

7

8

9

General procedure L was followed. (4-Chlorophenyl)(isopropyl) carbamic chloride 245c

(1.20 g, 5.19 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 1 %) the

title compound 277b (0.85 g, 67 %) as a pale yellow oil.


) 1715 (C=O), 1645 (C=C); 1H-NMR

(400MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, 2H, H-7), 7.17 (dd, J = 14.0 and 6.0 Hz, 1H, H-2),

7.05 (d, J = 8.5 Hz, 2H, H-8), 4.59 (sep, J = 6.8 Hz, 1H, H-4), 4.51 (br, 1H, H-1), 4.38 (br,

1H, H-1), 1.13 (d, J = 6.8 Hz, 6H, H-5); 13


§ δ 142.2 (C-2), 133.6,

131.0, 129.0 (CH aryl), 95.7 (C-1), 49.4 (C-4), 21.2 (C-5); MS m/z (ES+) 262 (100 %,

M+Na+); HMRS (ES+) calcd for C12H14O2N1Na1

35Cl1 (M+Na

+): 262.0606, found:

262.0598.

Vinyl isopropyl-p-tolylcarbamate 277c.

N O

O

1

2

3

45

67

5

8

9

10

General procedure L was followed. Isopropyl(p-tolyl) carbamic chloride 245d (250 mg,


compound 277c (148 mg, 57 %) as a colourless oil.


) 1713 (C=O), 1646 (C=C); 1H-NMR

(400MHz, CDCl3) δ 7.18-7.16 (m, 3H, H-7 and H-2), 6.99 (d, J = 7.8 Hz, 2H, H-8), 4.58

(sep, J = 6.8 Hz, 1H, H-4), 4.48 (br, 1H, H-1), 4.34 (br, 1H, H-1), 2.38 (s, 3H, H-10), 1.12 (d,

J = 6.8 Hz, 6H, H-5) ; 13

C-NMR (100MHz, CDCl3) § δ 142.4 (C-2), 137.5, 129.4 (CH aryl),

301

95.4 (C-1), 49.2 (C-4), 24.3 (C-10), 21.1 (C-5); MS m/z (ES+) 242 (100 %, M+Na+);


Vinyl 3-(trifluoromethyl)phenylisopropylcarbamate 277d.

NF3C O

O

1

2

3

45

67

89

1011

12

5

General procedure L was followed. (3-Trifluoromethyl)phenyl)(isopropyl) carbamic

chloride 245e (1.00 g, 3.77 mmol) gave after flash column chromatography (SiO2,

Petrol:EtOAc 2 %) the title compound 277d (0.68 g, 63 %) as a colourless oil.


) 1717 (C=O), 1648 (C=C), 1317 (C-F); 1H-

NMR (400MHz, CDCl3) δ 7.62 (d, J = 7.9 Hz, 1H, H-10), 7.52 (t, J = 7.9 Hz, 1H, H-11),

7.39 (s, 1H, H-7), 7.32 (d, J = 7.9 Hz, 1H, H-12), 7.18 (dd, J = 14.0 and 6.2 Hz, 1H, H-2),

4.61 (sep, 3J = 6.8 Hz, 1H, H-4), 5.56 (br, 1H, H-1), 4.40 (br, 1H, H-1), 1.15 (d,

3J = 6.8 Hz,

6H, H-5) ; 13

C-NMR (100MHz, CDCl3) δ 152.3 (C-3), 142.1 (C-2), 138.3 (C-6), 133.2 (C-

12), 131.4 (q, 2JC-F = 32 Hz, C-8), 129.4 (C-11), 126.5 (q,

3JC-F = 3.6 Hz, C-7), 125.5 (q,

1JC-F = 270 Hz, C-9), 124.6 (q,

3JC-F = 3.6 Hz, C-10), 95.9 (C-1), 49.7 (C-4), 21.2 (C-5);

MS m/z (ES+) 296 (100 %, M+Na+); HMRS (ES+) calcd for C13H15O2N1F3 (M+H

+):

274.1050, found: 274.1051.

Vinyl isopropyl-4-methoxyphenylcarbamate 277e.

N O

OO

1

2

3

455

678

910

General procedure L was followed. Isopropyl(4-methoxyphenyl) carbamic chloride 245f


title compound 277e (0.71 g, 69 %) as a colourless oil.

302


) 1712 (C=O), 1645, 1509 (C=C), 1245 (C-

O-C); 1H-NMR (400MHz, CDCl3) δ 7.16 (br dd, J = 13.0 and 4.9 Hz, 1H, H-2), 7.00 (d, J

= 8.8 Hz, 2H, H-7), 6.87 (d, J = 8.8 Hz, 2H, H-8), 4.58 (sep, J = 6.8 Hz, 1H, H-4), 4.46 (d, J

= 13.0 Hz, 1H, H-1), 4.30 (br, 1H, H-1), 3.80 (s, 3H, H-10), 1.09 (d, J = 6.8 Hz, 6H, H-5) ;

13C-NMR (100MHz, CDCl3) δ 158.7 (C-9), 152.7 (C-3), 142.3 (C-2), 130.6 (C-7), 129.7

(C-6), 113.7 (C-8), 95.2 (C-1), 55.2 (C-10), 49.0 (C-4), 20.9 (C-5); MS m/z (ES+) 258

(100 %, M+Na+); HMRS (ES+) calcd for C13H18O3N1 (M+H

+): 236.1282, found: 236.1288.

1-Iodovinyl isopropylphenylcarbamate 279a.

N O

O I

123

45

67

8

9

5

General procedure M was followed. Vinyl isopropylphenylcarbamate 277a (500 mg, 2.44


compound 279a (715 mg, 88 %) as a white solid.


) 1719 (C=O), 1624

(C=C), 1H-NMR (400MHz, CDCl3) δ 7.42-7.26 (m, 3H, aryl), 7.12 (d, J = 7.0 Hz, 2H, aryl),

5.70 (br, 1H, H-1), 5.39 (br, 1H, H-1), 4.58 (sep, J = 6.8 Hz, 1H, H-4), 1.15 (d, J = 6.8 Hz,

6H, H-5) ; 13

C-NMR (100MHz, CDCl3) δ 150.3 (C-3), 135.0 (C-6), 129.7, 128.9, 128.0

(CH aryl), 118.0 (C-1), 102.0 (C-2), 50.1 (C-4), 21.0 (C-5); MS m/z (ES+) 354 (100 %,

M+Na+); HMRS (ES+) calcd for C12H14O2N1Na1I1 (M+Na

+): 353.9961, found: 353.9958.

303

1-Iodovinyl 4-chlorophenylisopropylcarbamate 279b.

N O

O ICl

123

45

6

5

7

8

9

General procedure M was followed. Vinyl 4-chlorophenylisopropylcarbamate 277b (606


title compound 279b (470 mg, 51 %) as a white solid.


) 1715 (C=O),

1618 (C=C); 1

H-NMR (400MHz, CDCl3) δ 7.37 (d, J = 8.5 Hz, 2H, H-7), 7.06 (d, J = 8.5

Hz, 2H, H-8), 5.71 (br, 1H, H-1), 5.41(br, 1H, H-1), 4.56 (sep, J = 6.8 Hz, 1H, H-4), 1.14 (d,

J = 6.8 Hz, 6H, H-5) ; 13

C-NMR (100MHz, CDCl3) δ 150.1 (C-3), 135.5, 133.9, 131.0,

129.2 (aryl), 118.2 (C-1), 101.6 (C-2), 50.0 (C-4), 21.1 (C-5); MS m/z (ES+) 388 (100 %,


35Cl1Na1I1 (M+Na

+): 387.9577, found:

387.9572.

1-Iodovinyl isopropyl-p-tolylcarbamate 279c.

N O

O I

123

45

67

8

9

10

5

General procedure M was followed. Vinyl isopropyl-p-tolylcarbamate 277c (332 mg, 1.52


compound 279c (191 mg, 37 %) as a yellow solid.


) 1729 (C=O), 1623

(C=C); 1

H-NMR (400MHz, CDCl3) δ 7.19 (d, J = 7.8 Hz, 2H, H-7), 6.99 (d, J = 7.8 Hz,

2H, H-8), 5.69 (br, 1H, H-1), 5.38 (br, 1H, H-1), 4.57 (sep, J = 6.8 Hz, 1H, H-4), 2.38 (s, 3H,

304

H-10), 1.14 (d, J = 6.8 Hz, 6H, H-5) ; MS m/z (ES+) 368 (100 %, M+Na+); HMRS (ES+)

calcd for C13H16O2N1Na1I1 (M+Na+): 368.0119, found: 368.0117.

1-Iodovinyl 3-(trifluoromethyl)phenylisopropylcarbamate 279d.

N O

O I

F3C 123

455

67

89

10

11

12

General procedure M was followed. Vinyl 3-(trifluoromethyl)phenylisopropylcarbamate

277d (668 mg, 2.45 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc

3 %) the title compound 279d (390 mg, 40 %) as a white solid.

Rf 0.50 (Petrol:EtOAc 8:2); m.p. 58-60 °C (Petrol); IR max (neat/cm-1

) 1722 (C=O), 1620

(C=C), 1309 (C-F); 1

H-NMR (400MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 1H, H-10), 7.54 (t,

J = 7.9 Hz, 1H, H-11), 7.39 (s, 1H, H-7), 7.33 (d, J = 7.9 Hz, 1H, H-12), 5.74 (br, 1H, H-1),

5.43 (br, 1H, H-1), 4.58 (sep, J = 6.8 Hz, 1H, H-4), 1.17 (d, J = 6.8 Hz, 6H, H-5) ; 13

C-

NMR (100MHz, CDCl3) δ 150.8 (C-3), 137.9 (C-6), 132.1 (C-12), 131.2 (q, 2JC-F = 32 Hz,

C-8), 129.6 (C-11), 126.5 (q, 3JC-F = 3.6 Hz, C-7), 125.2 (q,

1JC-F = 270 Hz, C-9), 124.9 (q,

3JC-F = 3.6 Hz, C-10), 118.4 (C-1), 101.2 (C-2), 50.3 (C-4), 21.1 (C-5); MS m/z (ES+) 422

(100 %, M+Na+); HMRS (ES+) calcd for C13H13N1O2F3Na1I1 (M+Na

+): 421.9835, found:

421.9824.

1-Iodovinyl isopropyl-4-methoxyphenylcarbamate 279e.

N O

OO

I

123

45

67

8

910

5

General procedure M was followed. Vinyl isopropyl-4-methoxyphenylcarbamate 277e


title compound 279e (0.71 g, 69 %) as a colourless oil.

305


) 1719 (C=O), 1618, 1512 (C=C), 1245 (C-

O-C); 1

H-NMR (400MHz, CDCl3) δ 7.02 (d, J = 8.8 Hz, 2H, H-7), 6.89 (d, J = 8.8 Hz, 2H,

H-8), 5.69 (br, 1H, H-1), 5.38 (br, 1H, H-1), 4.58 (sep, J = 6.8 Hz, 1H, H-4), 3.83 (s, 3H, H-

10), 1.12 (d, J = 6.8 Hz, 6H, H-5) ; 13

C-NMR (100MHz, CDCl3) δ 159.0 (C-9), 151.5 (C-

3), 130.7 (C-6), 129.4 (C-7), 118.0 (C-8), 114.0 (C-1), 102.3 (C-2), 55.4 (C-10), 49.8 (C-4),

21.0 (C-5); MS m/z (ES+) 384 (100 %, M+Na+); HMRS (ES+) calcd for C13H16N1O3Na1I1

(M+Na+): 384.0068, found: 384.0057.

5,5-Dimethylhex-1-en-3-yn-2-yl isopropylphenylcarbamate 280a.

N O

O

1

2

3

4

5

67

89 9

1011

12

13

General procedure N was followed. 1-Iodovinyl isopropylphenylcarbamate 279a (710 mg,

2.15 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 2 % then 4 %)

the title compound 280a (533 mg, 87 %) as a white solid.


) 2211 (w,

C≡C), 1712 (C=O); 1H-NMR (400MHz, CDCl3) δ 7.39-7.30 (m, 3H, aryl), 7.13 (d, J = 7.0

Hz, 2H, H-11), 5.04 (br, 1H, H-6), 4.99 (br, 1H, H-6), 4.59 (sep, J = 6.8 Hz, 1H, H-8), 1.24

(s, 9H, H-1), 1.14 (d, J = 6.8 Hz, 6H, H-9); 13

C-NMR (100MHz, CDCl3) δ 152.8 (C-7),

138.0 (C-10), 137.1 (C-5), 129.7, 128.7, 127.5 (CH aryl), 109.2 (C-6), 98.4 (C-3), 73.8 (C-

4), 49.6 (C-8), 30.5 (C-1), 27.7 (C-2), 21.2 (C-9); MS m/z (ES+) 308 (100 %, M+Na+);


306

5,5-Dimethylhex-1-en-3-yn-2-yl 4-chlorophenylisopropylcarbamate 280b.

N O

O

1

2

3

4

5

67

89 9

1011

12

13

Cl

General procedure N was followed. 1-Iodovinyl 4-chlorophenylisopropylcarbamate 279b

(470 mg, 1.29 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 2 %

then 3 %) the title compound 280b (302 mg, 74 %) as a white solid.


) 2209 (w,

C≡C), 1702 (C=O); 1H-NMR (400MHz, CDCl3) δ 7.34 (d, J = 8.5 Hz, 2H, H-12), 7.07 (d,

J = 8.5 Hz, 2H, H-11), 5.06 (br, 1H, H-6), 4.99 (br, 1H, H-6), 4.58 (sep, J = 6.8 Hz, 1H, H-

8), 1.24 (s, 9H, H-1), 1.38 (d, J = 6.8 Hz, 6H, H-9); 13


(C-7), 137.0 (C-10), 136.5 (C-5), 133.4 (C-13), 131.0, 129.0 (CH aryl), 109.3 (C-6), 98.6

(C-3), 73.6 (C-4), 49.5 (C-8), 30.5 (C-1), 27.7 (C-2), 21.2 (C-9); MS m/z (ES+) 342

(100 %, M+Na+); HMRS (ES+) calcd for C18H22O2N1Na1

35Cl1 (M+Na

+): 342.1232, found:

342.1233.

5,5-Dimethyl-1-en-3-yn-2-yl isopropyl-p-tolylcarbamate 280c.

N O

O

1

2

3

4

5

67

89 9

1011

12

13

14

General procedure N was followed. 1-Iodovinyl isopropyl-p-tolylcarbamate 279c (184 mg,


compound 280c (112 mg, 70 %) as a white solid.

307


) 2215 (w,

C≡C), 1720 (C=O); 1H-NMR (400MHz, CDCl3) δ 7.17 (d, J = 7.8 Hz, 2H, H-11), 7.00 (d,

J = 7.8 Hz, 2H, H-12), 5.04 (br, 1H, H-6), 4.98 (br, 1H, H-6), 4.58 (sep, J = 6.8 Hz, 1H, H-

8), 2.37 (s, 3H, H-14), 1.24 (s, 9H, H-1), 1.12 (d, J = 6.8 Hz, 6H, H-9); 13

C-NMR (100MHz,

CDCl3) δ 153.2 (C-7), 137.3, 137.2 (C-5 and C-10), 135.0 (C-13), 129.4, 129.3 (CH aryl),

109.2 (C-6), 98.3 (C-3), 73.9 (C-4), 49.4 (C-8), 30.5 (C-1), 27.7 (C-2), 21.2 (C-14),


(M+Na+): 322.1778, found: 322.1772.

5,5-Dimethyl-1-en-3-yn-2-yl 3-(trifluoromethyl)phenylisopropylcarbamate 280d.

N O

O

1

2

3

4

5

67

89 9

10

11

1213

14

1516

F3C

General procedure N was followed. 1-Iodovinyl 3-

(trifluoromethyl)phenylisopropylcarbamate 279d (369 mg, 0.92 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 2 % then 4 %) the title compound 280d (245

mg, 75 %) as a yellow oil.


) 2216 (w, C≡C), 1725 (C=O), 1322 (C-F);

1H-NMR (400MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 1H, H-13), 7.52 (t, J = 7.9 Hz, 1H, H-

12), 7.40 (s, H, H-16), 7.33 (d, J = 7.9 Hz, 1H, H-11), 5.07 (br, 1H, H-6), 5.01 (br, 1H, H-6),

4.60 (sep, J = 6.8 Hz, 1H, H-8), 1.24 (s, 9H, H-1), 1.16 (d, J = 6.8 Hz, 6H, H-9); 13

C-NMR

(100MHz, CDCl3) δ 152.4 (C-7), 138.8 (C-10), 136.9 (C-5), 133.1 (C-11), 131.4 (q, 2JC-F =

32 Hz, C-14), 129.4 (C-12), 126.5 (q, 3JC-F = 3.6 Hz, C-16), 127.0 (q,

1JC-F = 270 Hz, C-15),

124.4 (q, 3JC-F = 3.6 Hz, C-13), 109.4 (C-6), 98.8 (C-3), 73.5 (C-4), 49.9 (C-8), 30.4 (C-1),


C19H22O2N1F3Na1 (M+Na+): 376.1495, found: 376.1487.

308

5,5-Dimethylhex-1-en-3-yn-2-yl isopropyl-4-methoxyphenylcarbamate 280e.

N O

O

1

2

3

4

5

67

89 9

1011

12

13

O14

General procedure N was followed. 1-Iodovinyl isopropyl-4-methoxyphenylcarbamate

279e (506 mg, 1.40 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc

5 %) the title compound 280e (325 mg, 74 %) as an orange oil.


) 2215 (w, C≡C), 1719 (C=O), 1632, 1510

(C=C), 1245 (C-O-C); 1H-NMR (400MHz, CDCl3) δ 7.01 (d, J = 8.8 Hz, 2H, H-11), 6.88

(d, J = 8.8 Hz, 2H, H-12), 5.03 (br, 1H, H-6), 4.96 (br, 1H, H-6), 4.58 (sep, J = 6.8 Hz, 1H,

H-8), 3.82 (s, 3H, H-14), 1.24 (s, 9H, H-1), 1.11 (d, J = 6.8 Hz, 6H, H-9); 13

C-NMR

(100MHz, CDCl3) δ 158.7 (C-13), 152.9 (C-7), 137.2 (C-5 and C-10), 130.7 (C-11), 113.9

(C-12), 109.2 (C-6), 98.3 (C-3), 73.9 (C-4), 55.3 (C-14), 49.2 (C-8), 30.5 (C-1), 27.7 (C-2),


(M+Na+): 338.1727, found: 338.1729.

4-(Triisopropylsilyl)but-1-en-3-yn-2-yl isopropylphenylcarbamate 280f.

112

N O

O

3

4

5

67

89 9

1011

12

13

Si



compound 280f (363 mg, 75 %) as a colourless oil.

309

Rf 0.63 (Petrol:EtOAc 8:2) ; IR max (neat/cm-1

) 1725 (C=O); 1H-NMR (400MHz, CDCl3)

δ 7.37-7.30 (m, 3H, aryl), 7.12 (d, J = 7.6 Hz, 2H, H-10), 5.17 (br, 1H, H-6), 5.10 (br, 1H,

H-6), 4.58 (sep, J = 6.8 Hz, 1H, H-8), 1.13 (d, J = 6.8 Hz, 6H, H-9), 1.09 (s, 21H, H-1 and

H-2); 13

C-NMR (100MHz, CDCl3) δ 152.5 (C-7), 138.0 (C-10), 136.6 (C-5), 129.7, 128.7,

127.6 (CH aryl), 110.6 (C-6), 100.6 (C-4), 91.6 (C-3), 49.7 (C-8), 21.1 (C-9), 18.5 (C-1),

11.1 (C-2); MS m/z (ES+) 408 (100%, M+Na+); HMRS (ES+) calcd for C23H36O2N1Si1

(M+H+): 386.2510, found: 386.2506.

4-(Trimethylsilyl)but-1-en-3-yn-2-yl isopropylphenylcarbamate 280g.

N O

O

Si1

2

34

56

78 8

910

11

12


1.80 mmol) gave after flash column chromatography (SiO2, Petrol:EtOAc 2%) the title

compound 280g (402 mg, 74 %) as a white solid.


) 2166 (w,


Hz, 2H, H-10), 5.20 (br, 1H, H-5), 5.10 (br, s, 1H, H-5), 4.59 (sep, J = 6.8 Hz, 1H, H-7),

1.14 (d, J = 6.8 Hz, 6H, H-8), 0.20 (s, 9H, H-1); 13

C-NMR (100MHz, CDCl3) δ 152.6 (C-6),

137.8 (C-9), 136.6 (C-4), 129.7, 128.7, 127.6 (CH aryl), 111.5 (C-5), 98.5 (C-3), 95.0 (C-

2), 49.7 (C-7), 21.2 (C-8), -0.40 (C-1); MS m/z (ES+) 324 (80 %, M+Na+), 302 (20 %,

M+H+); HMRS (ES+) calcd for C17H24O2N1 (M+H

+): 302.1571, found: 302.1573.

310

4-Phenylbut-1-en-3-yn-2-yl isopropylphenylcarbamate 280h.

N O

O

1

2

34

5

6

7

89

101111

1213

14

15



compound 280h (293 mg, 81 %) as a white solid.


) 2207 (w,


Hz, 2H, aryl), 5.27 (br, 1H, H-8), 5.17 (br, 1H, H-8), 4.63 (sep, J = 6.8 Hz, 1H, H-10), 1.16

(d, J = 6.8 Hz, 6H, H-11); 13

C-NMR (100MHz, CDCl3) δ 152.7 (C-9), 137.8 (C-12), 136.8

(C-7), 131.8, 129.7, 128.9, 128.8, 128.2, 127.7 (CH aryl), 122.0 (C-4), 111.2 (C-8), 89.0

(C-5), 83.6 (C-6), 49.6 (C-10), 21.2 (C-11); MS m/z (ES+) 328 (100 %, M+Na+); HMRS


2,2-Dimethyl-5-phenyldec-3-yn-5-ol 281a.

23

45

6

78

910

1112

13

14

HO

1

General procedure P was followed with n-BuLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-yn-

2-yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave after flash column


colourless oil.

311


) 3424 (br, O-H), 2220 (w, CC); 1H-NMR

(400MHz, CDCl3) δ 7.62 (d, J = 7.1 Hz, 2H, aryl), 7.37-7.25 (m, 3H, aryl), 2.29 (s, 1H, -

OH), 1.94-1.86 (m, 1H, H-6), 1.83-1.76 (m, 1H, H-6), 1.52-1.40 (m, 1H, H-7), 1.34-1.22 (m,

5H, H-7, H-8 and H-9), 1.29 (s, 9H, H-1), 0.86 (t, J = 6.8 Hz, 3H, H-10); 13

C-NMR

(100MHz, CDCl3) δ 145.5 (C-11), 127.9, 127.3, 125.5 (CH aryl), 95.1 (C-3), 81.0 (C-4),

73.3 (C-5), 45.6 (C-6), 31.6 (C-7), 31.0 (C-1), 27.5 (C-2), 24.4 (C-8), 22.4 (C-9), 13.9 (C-

10); MS m/z (ES+) 281 (100 %, M+Na+); HMRS (ES+) calcd for C18H26O1Na1 (M+Na

+):

281.1876, found: 281.1866.

2,7,7-Trimethyl-4-phenyloct-5-yn-4-ol 281b.

23

45

6

788

910

11

12

HO

1

General procedure P was followed with i-PrLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-yn-2-

yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave after flash column


colourless oil.


) 3436 (br, O-H), 2200 (w, CC); 1H-NMR


OH), 1.88-1.75 (m, 3H, H-6 and H-7), 1.30 (s, 9H, H-1), 0.98 (d, J = 6.4 Hz, 3H, H-8), 0.84

(d, J = 6.4 Hz, 3H, H-8) ; 13

C-NMR (100MHz, CDCl3) δ 145.9 (C-9), 128.0, 127.3, 125.5

(CH aryl), 95.1 (C-3), 81.4 (C-4), 73.0 (C-5), 53.9 (C-6), 30.9 (C-1), 27.5 (C-2), 25.1 (C-7),


C17H24O1Na1 (M+Na+): 267.1719, found: 267.1727.

312

2,2,7,7-Tetramethyl-4-phenyloct-5-yn-4-ol 281c.

23

45

6

7

8

910

11

12

HO

1

General procedure P was followed with tert-BuLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-

yn-2-yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281c (30 mg, 67 %) as a

colourless oil.


) 3443 (br, O-H), 2220 (w, CC); 1H-NMR


OH), 1.94 (d, J = 14.4 Hz, 1H, H-6), 1.83 (d, J = 14.4 Hz, 1H, H-6), 1.28 (s, 9H, H-1), 0.98

(s, 9H, H-8) ; 13

C-NMR (100MHz, CDCl3) δ 147.2 (C-9), 127.9, 127.2, 125.6 (CH aryl),

95.6 (C-3), 82.1 (C-4), 72.5 (C-5), 57.2 (C-6), 31.4 (C-2), 30.9 (C-1), 30.7 (C-8), 27.5 (C-

7); MS m/z (ES+) 281 (100 %, M+Na+); HMRS (ES+) calcd for C18H26O1Na1 (M+Na

+):

281.1876, found: 281.1877.

5-(4-Chlorophenyl)-2,2-dimethyldec-3-yn-5-ol 281d.

23

45

6

78

910

1112

13

14

HO

1

Cl

General procedure P was followed with n-BuLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-yn-

2-yl 4-chlorophenylisopropylcarbamate 280b (50 mg, 0.16 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281d (20 mg, 40 %) as a

colourless oil.

313


) 3393 (br, O-H), 2240 (w, C≡C); 1H-NMR

(400MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 2H, H-12), 7.30 (d, J = 8.8 Hz, 2H, H-13), 2.27 (s,

1H, -OH), 1.90-1.82 (m, 1H, H-6), 1.79-1.72 (m, 1H, H-6), 1.48-1.21 (m, 6H, H-7, H-8 and

H-9), 1.27 (s, 9H, H-1), 0.85 (t, J = 6.8 Hz, 3H, H-10); 13


δ 144.1, 133.1, 128.0, 127.0 (aryl), 95.4 (C-3), 80.7 (C-4), 72.8 (C-5), 45.6 (C-6), 31.6,

30.9 (C-1), 27.4 (C-2), 24.3, 22.4 (C-7, C-8 and C-9), 13.9 (C-10); MS m/z (ES+) 275

(100 %, M-H2O+H+); HMRS (ES+) calcd for C18H24

35Cl1 (M-H2O+H

+): 275.1561, found:

275.1563.

4-(4-Chlorophenyl)-2,7,7-trimethyloct-5-yn-4-ol 281e.

23

45

6

788

910

11

12

HO

1

Cl

General procedure P was followed with i-PrLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-yn-2-

yl 4-chlorophenylisopropylcarbamate 280b (50 mg, 0.16 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281e (12 mg, 43 %) as a

colourless oil.


) 3409 (br, O-H), 2240 (w, C≡C); 1H-NMR


1H, -OH), 1.82-1.70 (m, 3H, H-6 and H-7), 1.27 (s, 9H, H-1), 0.96 (d, J = 6.4 Hz, 3H, H-8),

0.83 (d, J = 6.4 Hz, 3H, H-8) ; 13

C-NMR (100MHz, CDCl3) δ 144.5, 133.1, 128.1, 127.0

(aryl), 95.5 (C-3), 81.0 (C-4), 72.6 (C-5), 53.9 (C-6), 30.8 (C-1), 27.5 (C-2), 25.1 (C-7),

24.1 (C-8), 23.9 (C-8); MS m/z (ES+) 261 (100 %, M-H2O+H+); HMRS (ES+) calcd for

C17H2235

Cl1 (M-H2O+H+): 261.1405, found: 261.1401.

314

4-(4-Chlorophenyl)-2,2,7,7-tetramethyloct-5-yn-4-ol 281f.

23

45

6

7

8

910

11

12

HO

1

Cl

General procedure P was followed with tert-BuLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-

yn-2-yl 4-chlorophenylisopropylcarbamate 280b (50 mg, 0.16 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281f (21 mg, 47 %)

as a colourless oil.


) 3434 (br, O-H), 2240 (w, CC); 1H-NMR


1H, -OH), 1.89 (d, J = 14.4 Hz, 1H, H-6), 1.78 (d, J = 14.4 Hz, 1H, H-6), 1.26 (s, 9H, H-1),

0.97 (s, 9H, H-8) ; 13

C-NMR (100MHz, CDCl3) δ 145.8, 133.0, 128.0, 127.1 (aryl), 95.9

(C-3), 81.7 (C-4), 72.1 (C-5), 57.2 (C-6), 31.4 (C-2), 31.0 (C-1), 30.6 (C-8), 27.5 (C-7);

MS m/z (ES+) 275 (100 %, M-H2O+H+); HMRS (ES+) calcd for C18H24

35Cl1 (M-H2O+H

+):

275.1561, found: 275.1550.

2,2-Dimethyl-5-p-tolyldec-3-yn-5-ol 281g.

15

23

45

6

78

910

1112

13

14

HO

1

General procedure P was followed with n-BuLi (2.0 equiv.). 5,5-Dimethyl-1-en-3-yn-2-yl

isopropyl-p-tolylcarbamate 280c (50 mg, 0.17 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281g (17 mg, 34 %) as a

colourless oil.

315


) 3426 (br, O-H), 2242 (w, C≡C); 1H-NMR


3H, H-15), 2.22 (s, 1H, -OH), 1.92-1.85 (m, 1H, H-6), 1.82-1.74 (m, 1H, H-6), 1.51-1.26 (m,

6H, H-7, H-8 and H-9), 1.28 (s, 9H, H-1), 0.85 (t, J = 6.8 Hz, 3H, H-10); 13

C-NMR

(100MHz, CDCl3) δ 142.7, 137.0, 128.6, 125.4 (aryl), 94.9 (C-3), 81.1 (C-4), 73.2 (C-5),

45.5 (C-6), 31.6, 31.0 (C-1), 27.4 (C-2), 24.4, 22.4 (C-7, C-8 and C-9), 21.0 (C-15),

13.9 (C-10); MS m/z (ES+) 255 (90 %, M-H2O+H+), 295 (60 %, M+Na

+); HMRS (ES+)

calcd for C19H27 (M-H2O+H+): 255.2108, found: 255.2151.

2,7,7-Trimethyl-4-p-tolyloct-5-yn-4-ol 281h.

13

23

45

6

788

910

11

12

HO

1

General procedure P was followed with i-PrLi (2.0 equiv.). 5,5-Dimethyl-1-en-3-yn-2-yl

isopropyl-p-tolylcarbamate 280c (50 mg, 0.17 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281h (18 mg, 44 %) as a

colourless oil.


) 3429 (br, O-H), 2239 (w, C≡C); 1H-NMR

(400MHz, CDCl3) δ 7.51 (δ, Ξ = 8.1 Ηζ, 2Η, Η-10), 7.15 (δ, Ξ = 8.1 Ηζ, 2Η, Η-11), 2.34 (σ,

3Η, Η-13), 2.17 (σ, 1Η, -ΟΗ), 1.85-1.73 (μ, 3Η, Η-6 ανδ Η-7), 1.27 (σ, 9Η, Η-1), 0.97 (δ, Ξ

= 6.4 Ηζ, 3Η, Η-8), 0.83 (δ, Ξ = 6.4 Ηζ, 3Η, Η-8); 13

C-NMR (100MHz, CDCl3) δ 143.1,

137.0, 128.6, 125.4 (aryl), 95.0 (C-3), 81.5 (C-4), 72.9 (C-5), 53.8 (C-6), 30.9 (C-1), 27.4

(C-2), 25.2 (C-7), 24.1, 24.0 (C-8), 21.0 (C-13); MS m/z (ES+) 281 (100 %, M+Na+), 241

(70 %, M-H2O+H+); HMRS (ES+) calcd for C18H25 (M-H2O+H

+): 241.1951, found:

241.1962.

316

5-(3-(Trifluoromethyl)phenyl)-2,2-dimethyldec-3-yn-5-ol 281i.

1314

15

23

45

6

78

9

16

10

1112

HO

1

F3C

17

General procedure P was followed with n-BuLi (2.0 equiv.). 5,5-Dimethyl-1-en-3-yn-2-yl

3-(trifluoromethyl)phenylisopropylcarbamate 280d (50 mg, 0.14 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281i (17 mg, 37 %)



) 3426 (br, O-H), 2242 (w, CC), 1327 (C-

F); 1H-NMR (400MHz, CDCl3) δ 7.91 (s, 1H, H-12), 7.80 (d, J = 7.8 Hz, 1H, H-17), 7.52

(d, J = 7.8 Hz, 1H, H-15), 7.45 (t, J = 7.8 Hz, 1H, H-16), 2.31 (s, 1H, -OH), 1.92-1.84 (m,

1H, H-6), 1.81-1.74 (m, 1H, H-6), 1.49-1.21 (m, 6H, H-7, H-8, H-9), 1.28 (s, 9H, H-1),

0.85 (t, J = 6.8 Hz, 3H, H-10); 13

C-NMR (100MHz, CDCl3) δ 146.7 (C-11), 130.2 (q, 2JC-F

= 32 Hz, C-13), 129.0 (C-17), 128.4 (C-16), 124.2 (q, 1JC-F = 270 Hz, C-14), 124.2 (q,

3JC-F

= 3.6 Hz, C-15), 122.5 (q, 3JC-F = 3.6 Hz, C-12), 95.8 (C-3), 80.4 (C-5), 73.0 (C-4), 45.6

(C-6), 31.5, 30.9 (C-1), 27.5 (C-2), 24.3, 22.4 (C-7, C-8 and C-9), 13.9 (C-10); MS m/z

(ES+) 309 (100 %, M-H2O+H+).

4-(3-(Trifluoromethyl)phenyl)-2,7,7-trimethyloct-5-yn-4-ol 281j.

1314

152

34

5

6

788

910

11

12 HO

1

F3C

General procedure P was followed with i-PrLi (2.0 equiv.). 5,5-Dimethyl-1-en-3-yn-2-yl 3-

(trifluoromethyl)phenylisopropylcarbamate 280d (50 mg, 0.14 mmol) gave after flash

317

column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281j (24 mg, 55 %)

as a orange oil.


) 3307 (br, O-H), 2240 (w, C≡C), 1325 (C-


(d, J = 7.8 Hz, 1H, H-13), 7.45 (t, J = 7.8 Hz, 1H, H-14), 2.28 (s, 1H, -OH), 1.84-1.71 (m,

3H, H-6 and H-7), 1.28 (s, 9H, H-1), 0.98 (d, J = 6.4 Hz, 3H, H-8), 0.86 (d, J = 6.4 Hz, 3H,

H-8) ; 13

C-NMR (100MHz, CDCl3) δ 147.2 (C-9), 130.3 (q, 2JC-F = 32 Hz, C-11), 129.0

(C-15), 128.5 (C-14), 124.2 (q, 1JC-F = 270 Hz, C-12), 124.2 (q,

3JC-F = 3.6 Hz, C-13),

122.5 (q, 3JC-F = 3.6 Hz, C-10), 95.9 (C-3), 80.8 (C-4), 72.8 (C-5), 53.9 (C-6), 30.8 (C-1),

27.5 (C-2), 25.2 (C-7), 24.1, 23.9 (C-8); MS m/z (ES+) 295 (100 %, M-H2O+H+); HMRS

(ES+) calcd for C18H22F3 (M-H2O+H+): 295.1668, found: 295.1659.

4-(3-(Trifluoroethyl)phenyl)-2,2,7,7-tetramethyloct-5-yn-4-ol 281k.

1314

152

34

5

6

7

8

910

1112 HO

1

F3C

General procedure P was followed with tert-BuLi (2.0 equiv.). 5,5-Dimethyl-1-en-3-yn-2-

yl 3-(trifluoromethyl)phenylisopropylcarbamate 280d (50 mg, 0.14 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281k (12 mg, 26 %)

as a yellow oil.


) 3446 (br, O-H), 2239 (w, C≡C), 1326 (C-


(d, J = 7.8 Hz, 1H, H-13), 7.45 (t, J = 7.8 Hz, 1H, H-14), 2.24 (s, 1H, -OH), 1.90 (d, J =

14.5 Hz, 1H, H-6), 1.78 (d, J = 14.5 Hz, 1H, H-6), 1.27 (s, 9H, H-1), 1.00 (s, 9H, H-8); 13

C-

NMR (100MHz, CDCl3) δ 148.5 (C-9), 130.4 (q, 2JC-F = 32 Hz, C-11), 129.0 (C-15),

128.4 (C-14), 124.2 (q, 1JC-F = 270 Hz, C-12), 124.1 (q,

3JC-F = 3.6 Hz, C-13), 122.6 (q,

3JC-F = 3.6 Hz, C-10), 96.4 (C-3), 81.5 (C-4), 72.2 (C-5), 57.2 (C-6), 31.6 (C-2), 31.0 (C-1),

30.6 (C-8), 27.5 (C-7); MS m/z (ES+) 309 (60 %, M-H2O+H+).

318

5-(4-Methoxyphenyl)-2,2-dimethyldec-3-yn-5-ol 281l.

152

34

5

6

78

910

1112

13

14

HO

1

O

General procedure O was followed with n-BuLi (2.0 equiv.) at -45°C. 5,5-Dimethylhex-1-

en-3-yn-2-yl isopropyl-4-methoxyphenylcarbamate 280e (50 mg, 0.16 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281l (12 mg,



) 3334 (br, O-H), 2239 (w, C≡C), 1611,

1511 (C=C), 1251 (C-O-C); 1H-NMR (400MHz, CDCl3) δ 7.46 (d, J = 8.8 Hz, 2H, H-12),

6.80 (d, J = 8.8 Hz, 2H, H-13), 3.74 (s, 3H, H-15), 2.13 (s, 1H, -OH), 1.92-1.85 (m, 1H, H-

6), 1.81-1.74 (m, 1H, H-6), 1.42-1.31 (m, 1H, H-7), 1.21-1.17 (m, 5H, H-7, H-8 and H-9),

1.19 (s, 9H, H-1), 0.78 (t, J = 6.8 Hz, 3H, H-10); 13

C-NMR (100MHz, CDCl3) δ 158.9 (C-

14), 137.7 (C-11), 126.8 (C-12), 113.2 (C-13), 95.0 (C-3), 81.1 (C-4), 73.0 (C-5), 55.2 (C-

15), 45.5 (C-6), 31.6, 31.0 (C-1), 27.5 (C-2), 24.5, 22.4 (C-7, C-8 and C-9), 13.9 (C-10);

MS m/z (ES+) 271 (100 %, M-H2O+H+); HMRS (ES+) calcd for C19H27O1 (M-H2O+H

+):

271.2057, found: 271.2065.

4-(4-Methoxyphenyl)-2,7,7-trimethyloct-5-yn-4-ol 281m.

23

45

6

788

910

11

1213

HO

1

O

General procedure O was followed with i-PrLi (2.0 equiv.) at -45°C. 5,5-Dimethylhex-1-

en-3-yn-2-yl isopropyl-4-methoxyphenylcarbamate 280e (50 mg, 0.16 mmol) gave after

319

flash column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281m (20 mg,



) 3331 (br, O-H), 2232 (w, C≡C), 1611,

1511 (C=C), 1251 (C-O-C); 1H-NMR (400MHz, CDCl3) δ 7.54 (d, J = 8.8 Hz, 2H, H-10),

6.87 (d, J = 8.8 Hz, 2H, H-11), 3.81 (s, 3H, H-13), 2.17 (s, 1H, -OH), 1.86-1.69 (m, 3H, H-6

and H-7), 1.28 (s, 9H, H-1), 0.97 (d, J = 6.4 Hz, 3H, H-8), 0.81 (d, J = 6.4 Hz, 3H, H-8) ;

13C-NMR (100MHz, CDCl3) δ 158.8 (C-12), 138.1 (C-9), 126.8 (C-10), 113.2 (C-11),

95.1 (C-3), 81.5 (C-4), 72.7 (C-5), 55.2 (C-13), 53.9 (C-6), 30.9 (C-1), 27.5 (C-2), 25.2 (C-

7), 24.1, 23.9 (C-8); MS m/z (ES+) 257 (100 %, M-H2O+H+); HMRS (ES+) calcd for

C18H25O1 (M-H2O+H+): 257.1900, found: 257.1906.

1-(Triisopropylsilyl)-3-phenyloct-1-yn-3-ol 281n.

2

34

2

5

6

78

9

1112

13

14

10

1Si

HO

General procedure P was followed with n-BuLi (2.0 equiv.). 4-(Triisopropylsilyl)but-1-en-

3-yn-2-yl isopropylphenylcarbamate 280f (50 mg, 0.13 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281n (36 mg, 76 %) as a

colourless oil.


) 3425 (br, O-H), 2161 (w, C≡C); 1H-NMR

(400MHz, CDCl3) δ 7.66 (d, J = 7.1 Hz, 2H, H-12), 7.38-7.26 (m, 3H, aryl), 2.36 (s, 1H, -

OH), 1.99-1.91 (m, 1H, H-6), 1.88-1.80 (m, 1H, H-6), 1.48-1.42 (m, 1H, H-7), 1.42-1.33 (m,

1H, H-7), 1.34-1.23 (m, 4H, H-8, H-9), 1.12 (s, 21H, H-1, H-2), 0.85 (t, J = 6.8 Hz, 3H, H-

10) ; 13

C-NMR (100MHz, CDCl3) δ 144.8 (C-11), 128.0, 127.5, 125.5 (CH aryl), 109.8

(C-4), 86.8 (C-3), 73.9 (C-5), 45.6 (C-6), 31.6, 24.5, 22.5 (C-7, C-8 and C-9), 18.6 (C-2),


C23H42O1N1Si1 (M+NH4+): 376.3030, found: 376.3034.

320

1-(Triisopropylsilyl)-5-methyl-3-phenylhept-1-yn-3-ol 281o.

2

34

2

5

6

7

8

9

1112

13

14

10

1Si

HO

General procedure P was followed with sec-BuLi (2.0 equiv.). 4-(Triisopropylsilyl)but-1-

en-3-yn-2-yl isopropylphenylcarbamate 280f (50 mg, 0.13 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281o (27 mg, 58 %) as a

colourless oil.


) 3442 (br, O-H), 2163 (w, C≡C); 1H-NMR

(400MHz, CDCl3) (mixture of diastereoisomers) δ 7.61 (d, J = 7.4 Hz, 2H, H-12), 7.29-

7.18 (m, 3H, aryl), 2.23 (s, 0.5H, -OH), 2.22 (s, 0.5H, -OH), 1.92-1.68 (m, 2H, H-6), 1.64-

156 (m, 1H, H-7), 1.47-0.98 (m, 2H, H-8), 1.04 (s, 21H, H-1, H-2), 0.93 (d, J = 6.6 Hz,

1.5H, H-10), 0.76 (t, J = 7.4 Hz, 1.5H, H-9), 0.69 (t, J = 7.4 Hz, 1.5H, H-9), 0.65 (d, J

= 6.6 Hz, 1.5H, H-10); 13

C-NMR (100MHz, CDCl3) (mixture of diastereoisomers)

δ 145.5, 145.3 (C-11), 128.0, 127.6, 127.5, 125.6, 125.5 (CH aryl), 110.1, 110.0 (C-4),

87.2, 87.1 (C-3), 74.1, 73.8 (C-5), 51.9, 51.8 (C-6), 31.7, 31.3 (C-7), 30.7, 30.6 (C-8), 20.6,

20.4 (C-9, C-10), 18.6 (C-2), 11.2 (C-1); MS m/z (ES+) 381 (100 %, M+Na+); HMRS

(ES+) calcd for C23H42O1N1Si1 (M+NH4+): 376.3030, found: 376.3028.

321

1-(Triisopropylsilyl)-5,5-dimethyl-3-phenylhex-1-yn-3-ol 281p.

2

34

88

2

5

6

7

8

111213

141

Si

HO

General procedure P was followed with tert-BuLi (2.0 equiv.). 4-(Triisopropylsilyl)but-1-

en-3-yn-2-yl isopropylphenylcarbamate 280f (50 mg, 0.13 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 281p (29 mg, 63 %) as a

colourless oil.


) 3440 (br, O-H), 2160 (w, C≡C); 1H-NMR

(400MHz, CDCl3) δ 7.62 (d, J = 7.1 Hz, 2H, H-12), 7.28-7.17 (m, 3H, aryl), 2.20 (s, 1H, -

OH), 1.89 (d, J = 14.5 Hz, 1H, H-6), 1.79 (d, J = 14.5 Hz, 1H, H-6), 1.03 (s, 21H, H-1, H-2),

0.93 (s, 9H, H-8) ; 13

C-NMR (100MHz, CDCl3) δ 146.6 (C-11), 128.0, 127.4, 125.6 (CH

aryl), 110.7 (C-4), 88.3 (C-3), 73.1 (C-5), 56.9 (C-6), 31.5 (C-7), 31.0 (C-8), 18.6 (C-2),

11.2 (C-1); MS m/z (ES+) 381 (100 %, M+Na+); HMRS (ES+) calcd for C23H42O1N1Si1

(M+NH4+): 376.3030, found: 376.3027.

3-Phenyloct-1-yn-3-yl isopropylcarbamate 282a.

23

4

13

14

15

12

5

67

8

11

11

9

10

1NH

O

O

H

General procedure O was followed with n-BuLi (2.0 equiv.) and DMPU. 4

(Trimethylsilyl)but-1-en-3-yn-2-yl isopropylphenylcarbamate 280g (50 mg, 0.17 mmol)

322


282a (34 mg, 72 %) as a white solid.


) 3308 (C-H),

3285 (br, N-H), 1698 (C=O), 1532 (Amide II), 1256 (Amide III); 1H-NMR (400MHz,

CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H, H-13), 7.35-7.24 (m, 3H, aryl), 4.59 (br, 1H, -NH), 3.73

(br, 1H, H-10), 2.81 (s, 1H, H-1), 2.08 (t, J = 11.8 Hz, 1H, H-4), 1.89 (t, J = 11.8 Hz, 1H, H-

4), 1.56-1.43 (m, 1H, H-5), 1.25-1.22 (m, 5H, H-5, H-6 and H-7), 1.13 (d, J = 6.0 Hz, 3H,

H-11), 1.08 (d, J = 6.0 Hz, 3H, H-11), 0.83 (t, J = 6.8 Hz, 3H, H-8) ; 13

C-NMR (100MHz,

CDCl3) δ 153.3 (C-9), 141.9 (C-12), 128.1, 127.5, 125.0 (CH aryl), 82.5 (C-2), 78.3 (C-3),

75.9 (C-1), 44.6 (C-4), 42.8 (C-10), 31.5, 23.8, 23.0 (C-11), 22.4 (C-5, C-6 and C-7),

13.9 (C-8); MS m/z (ES+) 310 (10 0%, M+Na+), (ES-) 286 (100 %, M-H

+); HMRS (ES+)


5-Methyl-3-phenylhex-1-yn-3-yl isopropylcarbamate 282b.

23

4

13

7

12

5

6

6

8

9

11

9

10 1NH

O

O

H

General procedure O was followed with i-PrLi (2.0 equiv.) and DMPU. 4-



282b (23 mg, 51 %) as a colourless oil.


) 3308 (C-H and br N-H), 1691 (C=O),

1531 (Amide II), 1248 (Amide III); 1H-NMR (400MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 2H,

H-11), 7.35-7.24 (m, 3H, aryl), 4.55 (br, 1H, -NH), 3.74 (br, 1H, H-8), 2.83 (s, 1H, H-1),

2.05-1.99 (m, 1H, H-4), 1.88-1.85 (m, 2H, H-4 and H-5), 1.13 (d, J = 6.0 Hz, 3H, H-9), 1.08

(d, J = 6.0 Hz, 3H, H-9), 0.97 (d, J = 6.4 Hz, 3H, H-6), 0.76 (d, J = 6.4 Hz, 3H, H-6) ; 13

C-


323

(C-2), 78.3 (C-3), 76.2 (C-1), 52.7 (C-4), 42.8 (C-8), 24.9 (C-5), 24.0, 23.9 (C-6), 23.0 (C-

9); MS m/z (ES+) 296 (100 %, M+Na+), (ES-) 272 (100 %, M-H


C17H23O2N1Na1 (M+Na+): 296.1621, found: 296.1610.

5,5-Dimethyl-3-phenylhex-1-yn-3-yl isopropylcarbamate 282c.

23

4

13

7

12

5

6

8

9

11

9

10 1NH

O

O

H

General procedure O was followed with tert-BuLi (2.0 equiv.) and DMPU. 4-



282c (6 mg, 13 %) as a white solid.


) 3309 (C-

H), 3286 (br, N-H), 1698 (C=O), 1534 (Amide II), 1258 (Amide III); 1H-NMR (400MHz,

CDCl3) δ 7.57 (d, J = 7.6 Hz, 2H, H-11), 7.35-7.24 (m, 3H, aryl), 4.52 (br, 1H, -NH), 3.75

(br, 1H, H-8), 2.87 (s, 1H, H-1), 2.13 (d, J = 14.5 Hz, 1H, H-4), 1.94 (d, J = 14.5 Hz, 1H, H-

4), 1.15 (d, J = 6.0 Hz, 3H, H-9), 1.09 (d, J = 6.0 Hz, 3H, H-9), 0.96 (s, 9H, H-6) ; 13

C-


(C-2), 78.9 (C-3), 76.8 (C-1), 56.3 (C-4), 42.8 (C-8), 31.6 (C-5), 31.0 (C-6), 23.0 (C-9);

MS m/z (ES+) 310 (100 %, M+Na+), (ES-) 286 (100 %, M-H


C18H25O2N1Na1 (M+Na+): 310.1778, found: 310.1771.

324

5,5-Dimethyl-1-(trimethylsilyl)-3-phenylhex-1-yn-3-yl isopropylcarbamate 283.

234

13

12

5

6

811

9

10

1

14

NH

O

O

Si

10

7

General procedure O was followed with tert-BuLi (2.0 equiv.) and DMPU. 4-


gave after flash column chromatography (SiO2, Petrol:EtOAc 4 %) the title compound 283

(24 mg, 41 %) as a white solid.


) 3303 (br, N-

H), 1696 (C=O), 1531 (Amide II), 1248 (Amide III); 1H-NMR (400MHz, CDCl3) δ 7.57

(d, J = 8.8 Hz, 2H, H-12), 7.36-7.24 (m, 3H, aryl), 4.53 (br, 1H, -NH), 3.72 (br, 1H, H-9),

2.16 (d, J = 14.5 Hz, 1H, H-5), 1.90 (d, J = 14.5 Hz, 1H, H-5), 1.11 (br d, 6H, H-10), 0.98

(s, 9H, H-7), 0.24 (s, 9H, H-1) ; 13

C-NMR (100MHz, CDCl3) δ 152.9 (C-8), 143.6 (C-11),

128.0, 127.3, 125.2 (CH aryl), 104.6 (C-3), 94.1 (C-2), 78.2 (C-4), 56.4 (C-5), 42.9 (C-9),

31.5 (C-6), 31.0 (C-7), 22.9 (C-10), -0.34 (C-1); MS m/z (ES+) 382 (100 %, M+Na+);

HMRS (ES+) calcd for C21H33O2N1Na1Si1 (M+Na+): 382.2173, found: 382.2177.

5-Methyl-1,3-diphenylhex-1-yn-3-yl isopropylcarbamate 284.

17

2

34

13

712

5

8

11

9

10

6

1

NH

O

O

10

13 1415

16

General procedure O was followed with i-PrLi (2.0 equiv.) and DMPU. 4-Phenylbut-1-en-

3-yn-2-yl isopropylphenylcarbamate 280h (50 mg, 0.16 mmol) gave after flash column

325

chromatography (SiO2, Petrol:EtOAc 2 %) the title compound 284 (15 mg, 30 %) as a

colourless oil.


) 3279 (br, N-H), 1712 (C=O); 1H-NMR

(400MHz, CDCl3) δ 7.62-7.27 (m, 10H, aryl), 4.55 (br, 1H, -NH), 3.74 (br, 1H, H-12),

2.16-2.10 (m, 1H, H-8), 1.96-1.93 (m, 2H, H-8 and H-9), 1.13 (d, J = 5.5 Hz, 3H, H-13),

1.10 (d, J = 5.5 Hz, 3H, H-13), 1.02 (d, J = 6.4 Hz, 3H, H-10), 0.83 (d, J = 6.4 Hz, 3H, H-

10) ; 13

C-NMR (100MHz, CDCl3) δ 153.2 (C-11), 142.9, 131.9, 128.4, 128.2, 128.1, 127.5,

125.2, 122.8 (aryl), 87.9, 79.0 (C-5 and C-6), 77.7 (C-7), 52.9 (C-8), 42.8 (C-12), 25.0 (C-

9), 24.1, 23.9 (C-10), 23.0 (C-13); MS m/z (ES+) 372 (50 %, M+Na+).

(E)-4-Benzylidene-5-isobutyl-3-isopropyl-5-phenyloxazolidin-2-one 285.

2

34

13

7

1712

58

11

9

102

6

1

7

14 15

16

NO

O

General procedure O was followed with i-PrLi (2.0 equiv.) and DMPU. 4-Phenylbut-1-en-

3-yn-2-yl isopropylphenylcarbamate 280h (50 mg, 0.16 mmol) gave after flash column


white solid.

Rf 0.26 (Petrol:EtOAc 8:2); 1H-NMR (400MHz, CDCl3) δ 7.32-7.25 (m, 5H, aryl), 7.12-

7.03 (m, 3H, aryl), 6.70 (d, J = 7.0 Hz, 2H, aryl), 5.98 (s, 1H, H-9), 4.32 (sep, J = 6.8 Hz,

1H, H-6), 2.08 (dd, J = 14.7 and 8.0 Hz, 1H, H-3), 1.97 (dd, J = 14.7 and 3.8 Hz, 1H, H-3),

1.87-1.77 (m, 1H, H-1), 1.56 (d, J = 6.8 Hz, 3H, H-7), 1.55 (d, J = 6.8 Hz, 3H, H-7), 0.96

(d, J = 6.6 Hz, 3H, H-2), 0.78 (d, J = 6.6 Hz, 3H, H-2) ; 13

C-NMR (100MHz, CDCl3) δ

154.9 (C-5), 141.9 (C-8), 141.4 (C-14), 134.5 (C-10), 129.1, 128.6, 128.5, 127.8, 126.4,

126.1 (CH aryl), 101.5 (C-9), 86.6 (C-4), 45.7 (C-6), 42.2 (C-3), 24.5 (C-1), 23.6 (C-7),

19.1, 18.7 (C-2); MS m/z (ES+) 330 (100 %, M+Na+); HMRS (ES+) calcd for C20H22O2N1

(M+H+): 308.1646, found: 308.1656.

326

2,2-Dimethyldeca-3,4-dien-5-yl isopropylphenylcarbamate 286a.

23

4

13

7

13

5

8

11

9

10

6

14

15

16

1

12

O •

H

N

O17

General procedure O was followed with n-BuLi (2.0 equiv.). 5,5-Dimethylhex-1-en-3-yn-

2-yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave after flash column


colourless oil.


) 1977 (w, C=C=C), 1715 (C=O); 1H-NMR

(400MHz, CDCl3) δ 7.37-7.28 (m, 3H, aryl), 7.10 (d, J = 7.0 Hz, 2H, H-15), 5.61 (t, J =

3.1 Hz, 1H, H-3), 4.58 (sep, J = 6.8 Hz, 1H, H-12), 2.14 (br, 2H, H-6), 1.33-1.12 (m, 6H,

H-7, H-8, H-9), 1.12 (d, J = 6.8 Hz, 3H, H-13), 1.11 (d, J = 6.8 Hz, 3H, H-13), 1.05 (s, 9H,

H-1), 0.84 (t, J = 6.8 Hz, 3H, H-10) ; 13

C-NMR (100MHz, CDCl3) δ 192.1 (C-4), 153.6

(C-11), 138.3 (C-14), 129.8, 128.6, 127.3 (CH aryl), 126.3 (C-5), 113.9 (C-3), 49.1 (C-12),

33.4 (C-2), 31.8 (C-6), 31.1, 29.7 (C-1), 26.0, 22.4 (C-7, C-8 and C-9), 21.3, 21.2 (C-13),


(M+Na+): 366.2404, found: 366.2418.

The equivalent enantioenriched (84:16 e.r.) allene 286a (12 mg, 20 %) was made by

following the procedure below:

To a solution of distilled ()-sparteine (0.08 cm3, 0.34 mmol) in anhydrous toluene (2.0

cm3) was added n-BuLi (2.5 M, 0.14 cm

3, 0.34 mmol) at -50 °C. The resulting yellow

solution was stirred for 15 min after which a solution of 5,5-dimethylhex-1-en-3-yn-2-yl

isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) in anhydrous toluene (0.50 cm3) was

added and stirred at -50 °C for 4 h. The reaction was quenched with MeOH (0.10 cm3) and

a saturated aqueous solution of NH4Cl (1 cm3) and the reaction mixture stirred for a further

30 min while warming to room temperature. The mixture was diluted with Et2O (5 cm3)

and the organic layer was washed with an aqueous solution of CuSO4 (10 cm3) and water

327

(2 x 10 cm3), dried over MgSO4, filtered and concentrated under reduced pressure. The

residue was purified by flash column chromatography (SiO2, Petrol:EtOAc 1 %) to give

the enantioenriched allene 286a as a colourless oil.

HPLC separation conditions: (R,R)-Whelk-O1 column, hexane:2-propanol (98:2), flow rate:

1.0 mL/min; tR 6.3 min for major enantiomer and 8.0 min for minor enantiomer.

1-(Trimethylsilyl)octa-1,2-dien-3-yl isopropylphenylcarbamate 286b.

23413

7

12

5

8

11

9

10

614

15

16

O •

H

SiN

O

1

12

General procedure O was followed with n-BuLi (2.0 equiv.). 4-(Trimethylsilyl)but-1-en-3-

yn-2-yl isopropylphenylcarbamate 280g (50 mg, 0.17 mmol) gave after flash column


colourless oil.


) 1694 (C=O); 1H-NMR (400MHz, CDCl3)

δ 7.37-7.26 (m, 3H, aryl), 7.10 (d, J = 7.0 Hz, 2H, H-14), 5.68 (t, J = 4.0 Hz, 1H, H-2),

4.58 (sep, J = 6.8 Hz, 1H, H-11), 2.15 (br, 2H, H-5), 1.25-1.21 (m, 6H, H-6, H-7 and H-8),

1.11 (d, J = 6.8 Hz, 3H, H-12), 1.10 (d, J = 6.8 Hz, 3H, H-12), 0.84 (t, J = 6.8 Hz, 3H, H-

9), 0.11 (s, 9H, H-1); 13

C-NMR (125MHz, CDCl3) δ 205.6 (C-3), 153.7 (C-10), 138.4 (C-

13), 129.8, 128.5, 127.3 (CH aryl), 123.4 (C-4), 98.0 (C-2), 49.2 (C-11), 31.2 (C-5), 31.0,

26.0, 22.4 (C-6, C-7 and C-8), 21.3, 21.2 (C-12), 14.0 (C-9), -1.07 (C-1); MS m/z (ES+)

382 (100 %, M+Na+); HMRS (ES+) calcd for C21H33O2N1Si1Na1 (M+Na

+): 382.2173,

found: 382.2178.

328

2,2-Dimethyl-5-phenyldec-3-yn-5-yl isopropylcarbamate 287.

ONH

O

23

45

67

89

10

11

12

13

14

15

16

171

13

General procedure O was followed with sec-BuLi (2.0 equiv.) and DMPU. 2,2-

Dimethyldeca-3,4-dien-5-yl isopropylphenylcarbamate 286a (45 mg, 0.13 mmol) gave




) 3307 (br,

N-H), 2241 (w, CC), 1698 (C=O), 1528 (Amide II), 1254 (Amide III); 1H-NMR

(400MHz, CDCl3) δ 7.52 (d, J = 7.2 Hz, 2H, H-15), 7.34-7.22 (m, 3H, aryl), 4.57 (br, 1H, -

NH), 3.71 (sep, J = 6.6 Hz, 1H, H-12), 2.10-2.03 (m, 1H, H-6), 1.86-1.79 (m, 1H, H-6),

1.49-1.43 (m, 1H, H-7), 1.30 (s, 9H, H-1), 1.13-1.10 (m, 5H, H-7, H-8 and H-9), 1.06 (d, J

= 6.6 Hz, 6H, H-13), 0.84 (t, J = 6.8 Hz, 3H, H-10); 13


(C-11), 143.0 (C-14), 127.9, 127.2, 125.2 (CH aryl), 96.9 (C-3), 79.1 (C-4), 77.5 (C-5),

44.9 (C-6), 42.8 (C-12), 31.5, 30.9 (C-1), 27.6 (C-2), 23.9, 22.9 (C-13), 22.3 (C-7, C-8 and

C-9), 13.9 (C-10); MS m/z (ES+) 366 (100 %, M+Na+); HMRS (ES+) calcd for

C22H25O2N1Na1 (M+Na+): 366.2404, found: 366.2418.

329

2,2,3-Trimethyldeca-3,4-dien-5-yl isopropylphenylcarbamate 289.

234

18 7

13

5

8

11

910

6

14

15

16

1

12 O •N

O

17

14

General procedure U was followed with iodomethane as electrophile. 5,5-Dimethylhex-1-

en-3-yn-2-yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave after flash column


colourless oil.


) 1972 (w, C=C=C), 1711 (C=O); 1H-NMR

(400MHz, CDCl3) δ 7.37-7.27 (m, 3H, aryl), 7.10 (d, J = 7.0 Hz, 2H, H-16), 4.59 (sep, J =

6.8 Hz, 1H, H-13), 2.19-2.07 (m, 2H, H-7), 1.76 (s, 3H, H-1), 1.31-1.12 (m, 6H, H-8, H-9

and H-10), 1.11 (d, J = 6.8 Hz, 3H, H-14), 1.10 (d, J = 6.8 Hz, 3H, H-14), 1.06 (s, 9H, H-

2), 0.85 (t, J = 6.8 Hz, 3H, H-11); 13

C-NMR (100MHz, CDCl3) δ 190.5 (C-5), 153.9 (C-

12), 138.5 (C-15), 129.8, 128.5, 127.2 (CH aryl), 123.9 (C-4), 120.5 (C-6), 49.0 (C-13),

35.0 (C-3), 31.9 (C-7), 31.2, 28.9 (C-2), 26.0, 22.5 (C-8, C-9 and C-10), 21.4, 21.3 (C-14),

16.0 (C-1), 14.0 (C-11); MS m/z (ES+) 358 (100 %, M+H+); HMRS (ES+) calcd for

C23H36O2N1 (M+H+): 358.2741, found: 358.2741.

2-tert-Butyl-4-(isopropyl(phenyl)carbamoyl)nona-2,3-dienoic acid 290.

234

18 7

13

5

8

11

910

6

14

15

16

1

12 O •

CO2H

N

O

17

14

General procedure U was followed with dry ice as electrophile. 5,5-Dimethylhex-1-en-3-

yn-2-yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave after flash column

330


white solid.


) 3087 (br, O-

H), 1712 (C=O, acid), 1687 (C=O, carbamate); 1H-NMR (400MHz, CDCl3) δ 11.4 (br, 1H,

-OH), 7.44-7.10 (m, 5H, aryl), 4.61 (sep, J = 6.8 Hz, 1H, H-13), 2.06-2.04 (m, 2H, H-7),

1.25-1.07 (m, 21H, H-1, H-8, H-9, H-10 and H-14), 0.83 (t, J = 6.8 Hz, 3H, H-11); 13

C-

NMR (100MHz, CDCl3) δ 199.4 (C-5), 165.0 (C-1), 153.9 (C-12), 141.9 (C-15), 136.9 (C-

4), 129.4, 129.0, 128.2 (CH aryl), 121.2 (C-6), 50.1 (C-13), 35.0 (C-3), 31.6 (C-7), 29.1

(C-2), 25.2, 24.0, 22.2 (C-8, C-9 and C-10), 21.0, 20.9 (C-14), 13.8 (C-11); MS m/z (ES+)

410 (30 %, M+Na+), (ES-) 386 (100 %, M-H

+); HMRS (ES+) calcd for C23H34O4N1

(M+H+): 388.2483, found: 388.2486.

2,2-Dimethyl-5-(trimethylsilyl)dec-3-yn-5-yl isopropylphenylcarbamate 291.

6

23

4

18 7

13

5

8

11

910

14

15

16

12 ON

O

17

141

Si

General procedure U was followed with trimethylsilylchoride as electrophile. 5,5-

Dimethylhex-1-en-3-yn-2-yl isopropylphenylcarbamate 280a (50 mg, 0.17 mmol) gave


mg, 67 %) as a colourless oil.


) 1702 (C=O); 1H-NMR (400MHz, CDCl3)

δ 7.39-7.28 (m, 3H, aryl), 7.11 (d, J = 7.0 Hz, 2H, H-16), 4.60 (sep, J = 6.8 Hz, 1H, H-13),

1.92-1.74 (m, 2H, H-7), 1.35-1.19 (m, 6H, H-8, H-9 and H-10), 1.25 (s, 9H, H-1), 1.15 (d,

J = 6.8 Hz, 3H, H-14), 1.13 (d, J = 6.8 Hz, 3H, H-14), 0.89 (t, J = 6.8 Hz, 3H, H-11), 0.00

(s, 9H, H-6); 13

C-NMR (100MHz, CDCl3) δ 154.4 (C-12), 138.8 (C-15), 130.2, 128.4,

126.9 (CH aryl), 96.8 (C-3), 78.6 (C-4), 72.9 (C-5), 48.2 (C-13), 36.5 (C-7), 32.0, 31.1 (C-

1), 27.6 (C-2), 24.5, 22.4 (C-8, C-9 and C-10), 21.5, 21.3 (C-14), 14.0 (C-11), -2.53 (C-6);

331

MS m/z (ES+) 438 (100 %, M+Na+) 416 (85 %, M+H


C25H42O2Si1 (M+H+): 416.2980, found: 416.2965.

Buta-1,3-dien-2-yl isopropylphenylcarbamate 292.

N O

O1

23

4

5

67 7

8

9

10

11

By the method reported by Duchêne et al.:[194]

Dichlorobis(triphenylphosphine)palladium(II) (5 mol %, 44 mg) was added to an

anhydrous DMF (1.5 cm3) solution of 1-iodovinyl isopropylphenylcarbamate 278a (370

mg, 1.12 mmol) in a sealed tube under nitrogen atmosphere, and tributylvinyltin (0.75 cm3,

1.23 mmol) was added after stirring for 15 min at room temperature. The mixture was

stirred at 100 °C for 20 h. After cooling, the reaction mixture was filtered through a Celite

path and then treated with a 1.0 M solution of potassium fluoride and EtOAc. The aqueous

layer was extracted with Et2O. The organic layer was washed with brine, dried over

MgSO4, filtered and concentrated under reduced pressure. The residue was purified by

flash column chromatography (SiO2, Petrol:EtOAc 3 %) to give the title compound 292

(65 mg, 35 %) as a pale orange oil.


) 1714 (C=O); 1H-NMR (400MHz, CDCl3)

δ 7.42-7.17 (m, 5H, aryl), 6.17 (dd, J = 17.0 and 11.2 Hz, 1H, H-2), 5.03 (br, 2H, H-1), 5.00

(br, 1H, H-4), 4.89 (br, 1H, H-4), 4.63 (sep, J = 6.8 Hz, 1H, H-6), 1.15 (d, J = 6.8 Hz, 6H,

H-7); 13

C-NMR (100MHz, CDCl3) δ 152.9 (C-5), 152.0 (C-3), 137.8 (C-8), 131.7 (C-2),

129.8, 128.8, 127.7 (CH aryl), 114.8 (C-1), 105.0 (C-4), 49.2 (C-6), 21.2 (C-7); MS m/z


+): 254.1152,

found: 254.1152.

332

(E)-4-Phenylbuta-1,3-dien-2-yl isopropylphenylcarbamate 293.

N O

O

1

2

34

5

67

8

9

101111

12

1314

15

To a solution of vinyl isopropylphenylcarbamate 277a (200 mg, 0.98 mmol) in anhydrous

THF (4 cm3) was added t-BuLi (1.9 M, 0.56 cm

3, 1.08 mmol) at -78 °C. After 1 h, a

solution of ZnCl2 (1.0 M in Et2O, 1.1 cm3, 1.08 mmol) was added dropwise. The mixture

was stirred for an additional 30 min at -78 °C then at 0 °C for 45 min. The resulting

solution was transferred to a flask containing bromostyrene (0.14 cm3, 1.08 mmol) and

tetrakis(triphenyl)palladium(0) (60 mg, 5 mol %) in THF (4 cm3) and it was stirred at room

temperature for 4 h. The reaction was then quenched with a saturated aqueous solution of

NH4Cl, extracted with Et2O twice and the combined organic layers were washed with

water, brine and dried over MgSO4, filtered and concentrated under reduced pressure. The

residue was purified by flash column chromatography (SiO2, Petrol:EtOAc 5 %) to afford

the title compound 293 (210 mg, 70 %) as a pale yellow solid.


) 1720 (C=O);

1H-NMR (400MHz, CDCl3) δ 7.48-7.22 (m, 10H, aryl), 6.51 (d, J = 15.8 Hz, 1H, H-5),

6.27 (br, 1H, H-6), 5.13 (s, 1H, H-8), 4.97 (s, 1H, H-8), 4.68 (sep, J = 6.8 Hz, 1H, H-10),

1.18 (d, J = 6.8 Hz, 6H, H-11); 13

C-NMR (100MHz, CDCl3) δ 152.6 (C-9), 151.8 (C-7),

137.8 (C-12), 136.1 (C-4), 129.8, 129.3, 128.9, 128.5, 127.9, 127.8, 126.6 (C-6 and aryl),

123.4 (C-5), 104.5 (C-8), 49.1 (C-10), 21.1 (C-11); MS m/z (ES+) 330 (100 %, M+Na+);


333

(E)-1,3-Diphenyloct-1-en-3-ol 294.

2

34

713

58

11

9 10

1

6

14

15

16

12

HO

A solution of n-BuLi (1.8 M, 0.18 cm3, 0.32 mmol) was added dropwise to a precooled

solution (-78 °C) of (E)-4-phenylbuta-1,3-dien-2-yl isopropylphenylcarbamate 293 (50 mg,

0.16 mmol) in a mixture of anhydrous toluene (1.0 cm3) and distilled TMEDA (0.05 cm

3,

0.32 mmol) under nitrogen atmosphere. The resulting reaction mixture was stirred at -

78 °C for 2 h after which anhydrous DMPU (0.10 cm3, 0.64 mmol) was added, warmed up

to -15 °C and stirred for 15 h. The reaction was quenched with MeOH (0.1 cm3) and a

saturated aqueous solution of NH4Cl (1 cm3) and stirred for a further 30 min while

warming to room temperature. The mixture was diluted with Et2O (5 cm3). The organic

layer was washed with an aqueous solution of CuSO4 (10 cm3) and water (2 x 10 cm

3),

dried over MgSO4 and concentrated under reduced pressure. The residue was purified by


(24 mg, 54 %) as a colourless oil.


) 3410 (br, O-H); 1H-NMR (400MHz,

CDCl3) δ 7.47 (d, J = 7.2 Hz, 2H, aryl), 7.38-7.18 (m, 8H, aryl), 6.62 (d, J = 16.0 Hz, 1H,

H-6), 6.51 (d, J = 16.0 Hz, 1H, H-5), 2.04-1.90 (m, 2H, H-8), 1.93 (s, 1H, -OH), 1.32-1.20

(m, 6H, H-9, H-10 and H-11), 0.83 (t, J = 6.8 Hz, 3H, H-12); 13


δ 145.8 (C-13), 136.8 (C-4), 136.0 (C-5), 128.5, 128.2, 127.8, 127.5, 126.8, 126.5, 125.4

(C-6 and CH aryl), 76.9 (C-7), 42.5 (C-8), 32.1, 23.3, 22.5 (C-9, C-10, C-11), 14.0 (C-12);

MS m/z (ES+) 263 (80 %, M+H2O-H+); HMRS (ES+) calcd for C20H23 (M+H2O-H

+):

263.1795, found: 263.1800.

334

1-(Dimethyl(phenyl)silyl)vinyl isopropylphenylcarbamate 295.

N O Si

O

2

5

348 6

10

7

11

12

10 1

5

9

1314

To a solution of vinyl isopropylphenylcarbamate 277a (170 mg, 0.83 mmol) in dry THF (3

cm3) was added t-BuLi (1.9 M, 0.48 cm

3, 0.91 mmol) at -78 °C under nitrogen atmosphere.

The mixture was stirred for 1 h at -78 °C after which chloro(dimethyl)phenylsilane (0.17

cm3, 1.0 mmol) was added. The reaction was stirred at -78 °C for 15 min and then at room

temperature for 2 h. A saturated aqueous solution of NH4Cl was added and the mixture was

diluted with Et2O. The organic layer was washed with water and dried over MgSO4,

filtered and concentrated under reduced pressure to give a residue which was purified by


(145 mg, 52 %) as a colourless oil.


) 1716 (C=O); 1H-NMR (400MHz, CDCl3)

δ 7.50 (d, J = 7.2 Hz, 2H, aryl), 7.35-7.29 (m, 6H, aryl), 6.90 (d, J = 7.2 Hz, 2H, aryl), 5.44

(br, 1H, H-7), 5.01 (br, 1H, H-7), 4.47 (sep, J = 6.8 Hz, 1H, H-9), 1.01 (d, J = 6.8 Hz, 6H,

H-10), 0.41 (s, 6H, H-5); 13

C-NMR (100MHz, CDCl3) δ 162.0 (C-8), 138.0 (C-11), 136.9

(C-6), 134.1, 129.8, 129.1, 128.6, 127.6, 127.4 (CH aryl), 115.0 (C-7), 48.9 (C-9), 21.1 (C-

10), -2.30 (C-5); MS m/z (ES+) 362 (100 %, M+Na+); HMRS (ES+) calcd for

C20H25O2N1Na1Si1 (M+Na+): 362.1552, found: 362.1554.

335

1-(Dimethyl(phenyl)silyl)hexyl isopropylphenylcarbamate 296.

2

34

7

13

5

8

11

910

1

6

14

15

16

12

17

N O Si

O

5

14

18

General procedure O was followed with n-BuLi (2.0 equiv.) and DMPU. 1-

(Dimethyl(phenyl)silyl)vinyl isopropylphenylcarbamate 295 (50 mg, 0.15 mmol) gave


mg, 70 %) as a colourless oil.


) 1694 (C=O); 1H-NMR (400MHz, CDCl3)

δ 7.17-7.05 (m, 8H, aryl), 6.81, (d, J = 8.0 Hz, 2H, aryl), 4.59 (t, J = 6.8 Hz, 1H, H-6), 4.38

(sep, J = 6.8 Hz, 1H, H-13), 1.19 (m, 2H, H-7), 1.08-0.93 (m, 6H, H-8, H-9 and H-10),

0.89 (d, J = 6.8 Hz, 3H, H-14), 0.86 (d, J = 6.8 Hz, 3H, H-14), 0.63 (t, J = 6.8 Hz, 3H, H-

11), 0.00 (s, 3H, H-5), -0.05 (s, 3H, H-5); 13

C-NMR (100MHz, CDCl3) δ 156.0 (C-12),

136.5, 134.0, 130.2, 129.0, 128.5, 127.5, 127.1 (aryl), 69.1 (C-6), 48.5 (C-13), 31.6 (C-7),

31.2, 26.4, 22.4 (C-8, C-9 and C-10), 21.4, 21.3 (C-14), 14.0 (C-11), -4.69, -5.11 (C-5);

MS m/z (ES+) 398 (100 %, M+H+), (ES-) 396 (100 %, M-H


C24H35O2N1Si1Na1 (M+Na+): 420.2330, found: 420.2322.

1-(Furan-2-yl)vinyl isopropylphenylcarbamate 299.

N O

O

O

12

3

45

6

7

89 9

10

1112

13

General procedure K was followed. 2-Acetylfuran 297 (250 mg, 2.27 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 299 (298 mg,


336


) 1706 (C=O);

1H NMR (400MHz, CDCl3) 7.44-7.34 (m, 3H, aryl), 7.32 (br, 1H, H-3), 7.21 (d,

3J = 7.2

Hz, 2H, H-11), 6.32 (br, 1H, H-2), 6.05 (br, 1H, H-1), 5.35 (br, 1H, H-6), 5.01 (br, 1H, H-

6), 4.63 (sep, J = 6.8 Hz, 1H, H-8), 1.17 (d, J = 6.8 Hz, 6H, H-9); 13

C NMR (100MHz,

CDCl3) 152.8 (C-7), 149.2 (C-5), 144.6 (C-4), 142.6 (C-3), 137.7 (C-10), 129.7, 128.9,

127.8 (CH aryl), 111.1 (C-2), 107.0 (C-1), 99.3 (C-6), 49.4 (C-8), 21.2 (C-9); MS m/z


+): 294.1101,

found: 294.1099.

1-(2,5-Dimethylfuran-3-yl)vinyl isopropylphenylcarbamate 300.

N O

O

O1

2

3

45

6

7

8

109

10

11

1213

314

General procedure K was followed. 3-Acetyl-2,5-dimethylfuran 298 (250 mg, 1.81 mmol)


(100 mg, 19 %) as a pale yellow oil.


) 1714 (C=O); 1H NMR (400MHz, CDCl3)

7.41-7.32 (m, 3H, aryl), 7.17 (d, J = 7.2 Hz, 2H, H-12), 5.82 (br, 1H, H-1), 4.87 (br, 1H,

H-7), 4.83 (br, 1H, H-7), 4.62 (sep, J = 6.8 Hz, 1H, H-9), 2.18 (s, 6H, H-3), 1.14 (d, J = 6.8

Hz, 6H, H-10); 13

C NMR (100MHz, CDCl3) 149.5 (C-8), 148.5 (C-6), 147.4 (C-5),

137.8 (C-11), 129.8, 128.8, 127.7 (CH aryl), 117.0 (C-2), 113.2 (C-4), 105.3 (C-1), 100.5

(C-7), 49.3 (C-9), 21.2 (C-10), 13.2 (C-3), 13.0 (C-3); MS m/z (ES+) 322 (100 %, M+Na+);


337

1-Phenylethyl methylstyrylcarbamate 305.

2

34

7 5

8

9

10

1

6

N O

O11

12

13

14

A suspension of trans-cinnamic acid 301 (500 mg, 3.38 mmol) in dry benzene (5.0 cm3)

was stirred in the presence of triethylamine (0.47 cm3, 3.38 mmol) at 0 °C under nitrogen

atmosphere. Diphenylphosphoryl azide (0.73 cm3, 3.38 mmol) was added slowly and the

reaction was stirred at room temperature for 3 h. The reaction was quenched with a

saturated aqueous solution of NH4Cl (5 cm3) and then washed with a 1 N aqueous solution

of KHSO4 (20 cm3), water (20 cm

3), a saturated aqueous solution of NaHCO3 (20 cm

3) and

brine (20 cm3). The organic phase was concentrated under reduced pressure at room

temperature.[196]

The resulting isocyanate 302 was solubilised directly in anhydrous

CH2Cl2 (12 cm3) and 1-phenylethanol 183d (300 mg, 2.70 mmol) and triethylamine (0.70

cm3, 6.08 mmol) were added. The reaction mixture was stirred at room temperature for 15

h under nitrogen atmosphere and the solvent was evaporated under reduced pressure. The

crude mixture was solubilised in anhydrous DMF (10 cm3), NaH (60 % in mineral oil, 180

mg, 6.76 mmol) was added slowly at 0 °C and the mixture was stirred for 30 min under

nitrogen atmosphere. Methyl iodide (0.35 cm3, 8.45 mmol) was added and the reaction was

stirred at room temperature for 15 h. Water (10 cm3) was added and the reaction mixture

was extracted with Et2O (20 cm3). The organic layer was then washed with water (2 x 30

cm3), dried over MgSO4, filtered and evaporated under reduced pressure. The crude

product was purified by flash column chromatography on silica (SiO2, Petrol:EtOAc 3 %)

to give the title compound 305 (465 mg, 49 % overall yield) as a colourless oil.


) 1703 (C=O), 1643 (C=C); 1H NMR

(300MHz, CDCl3) 7.75 (d, J = 14.7 Hz, 1H, H-9), 7.39-7.16 (m, 10H, aryl), 5.91 (q, J =

6.6 Hz, 1H, H-5), 5.83 (d, J = 14.7 Hz, 1H, H-10), 3.20 (s, 3H, H-8), 1.62 (d, J = 6.6 Hz,

3H, H-6); 13

C NMR (100MHz, CD3OD) 141.7 (C-7), 140.8, 137.0, 129.6, 128.6, 128.5,

128.0, 126.1, 126.0, 125.4 (C-9 and aryl), 109.4 (C-10), 74.7 (C-5), 31.2 (C-8), 22.6 (C-6);


+):

304.1308, found: 304.1302.

338

1-Phenylethyl methylvinylcarbamate 308a.

2

34

7 5

8

9

10

1

6

N O

O

General procedures E and F were followed (stirred at room temperature for 1 h). 1-

phenylethanol 183d (100 mg, 0.82 mmol) gave after flash column chromatography (SiO2,

Petrol:EtOAc 4%) the title compound 308a (100 mg, 69 % over 2 steps) as a colourless oil.


) 1705 (C=O), 1625 (C=C); 1H NMR

(500MHz, CDCl3) (mixture of rotamers) 7.29-7.20 (m, 5H, aryl), 7.16 (dd, J = 15.8 and

9.2 Hz, 1H, H-9), 5.80 (q, J = 6.6 Hz, 1H, H-5), 4.23 (d, J = 15.8 Hz, 1H, H-10), 4.16 (d, J

= 9.2 Hz, 1H, H-10), 3.00 (s, 1.2H, H-8, rotamer 1), 2.97 (s, 1.8H, H-8, rotamer 2), 1.51 (d,

J = 6.6 Hz, 3H, H-6); 13

C NMR (125MHz, CDCl3) (mixture of rotamers) 153.7, 153.1

(C-7), 141.7 (C-4), 133.5 (C-9), 128.5, 127.8, 125.9 (CH aryl), 91.6 (C-10), 74.3, 74.1 (C-

5), 30.1 (C-8), 22.5 (C-6); MS m/z (ES+) 228 (100 %, M+Na+); HMRS (ES+) calcd for

C12H15O2N1Na1 (M+Na+): 228.0995, found: 228.0993.

1-(4-Chlorophenyl)ethyl methylvinylcarbamate 308b.

2

34

7 5

8

9

101

6

N O

O

Cl

General procedures E and F were followed (stirred at room temperature for 1 h). 1-(4-

Chlorophenyl)ethanol 183a (200 mg, 1.28 mmol) gave after flash column chromatography

(SiO2, Petrol:EtOAc 2 %) the title compound 308b (158 mg, 52 % over 2 steps) as a

colourless oil.


) 1705 (C=O), 1625 (C=C); 1H NMR

(500MHz, CDCl3) (mixture of rotamers) 7.33-7.28 (m, 4H, aryl), 7.19 (dd, J = 15.8 and

8.8 Hz, 1H, H-9), 5.83 (q, J = 6.6 Hz, 1H, H-5), 4.32 (d, J = 15.8 Hz, 1H, H-10), 4.16 (d, J

339

= 8.8 Hz, 1H, H-10), 3.07 (s, 1.2H, H-8, rotamer 1), 3.04 (s, 1.8H, H-8, rotamer 2), 1.56 (d,

J = 6.6 Hz, 3H, H-6); 13

C NMR (125MHz, CDCl3) (mixture of rotamers) 153.1 (C-7),

140.3 (C-4), 133.6 (C-1), 133.4 (C-9), 128.7, 127.3 (CH aryl), 91.9 (C-10), 73.7, 73.5 (C-

5), 30.1 (C-8), 22.4 (C-6); MS m/z (ES+) 262 (100 %, M+Na+); HMRS (ES+) calcd for

C12H14O2N135

Cl1Na1 (M+Na+): 262,0606, found: 262.0612.

1-(3-(Trifluoromethyl)phenyl)ethyl methylvinylcarbamate 308c.

2

3

4

75

8

11

9

10

1

6

N O

O

CF313

12


Trifluoromethylphenyl)ethanol 183c (224 mg, 1.18 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 2 %) the title compound 308c (102 mg, 32 % over 2

steps) as a colourless oil.


) 1709 (C=O), 1628 (C=C), 1317 (C-F); 1H

NMR (500MHz, CDCl3) (mixture of rotamers) 7.55 (s, 1H, H-6), 7.54-7.46 (m, 3H, aryl),

7.21 (dd, J = 15.8 and 9.2 Hz, 1H, H-12), 5.92 (q, J = 6.6 Hz, 1H, H-8), 4.34 (d, J = 15.8

Hz, 1H, H-13), 4.29 (d, J = 9.2 Hz, 1H, H-13), 3.10 (s, 1.3H, H-11, rotamer 1), 3.06 (s,

1.7H, H-11, rotamer 2), 1.60 (d, J = 6.6 Hz, 3H, H-9); 13


(mixture of rotamers) 153.5, 153.0 (C-10), 142.8 (C-7), 134.0, 133.8 (C-12), 130.6 (q,

2JCF = 32 Hz, C-4), 129.3, 129.1 (CH aryl), 124.0 (q,

1JCF = 270 Hz, C-5), 124.7 (q,

3JCF =

3.6 Hz, C-3), 122.6 (q, 3JCF = 3.6 Hz, C-6), 92.2 (C-13), 73.6, 73.4 (C-8), 30.2, 30.1 (C-11),

22.5 (C-9); MS m/z (ES+) 296 (100 %, M+Na+); HMRS (ES+) calcd for

C13H14O2N1F3Na1 (M+Na+): 296.0869, found: 296.0862.

340

1-m-Tolylethyl methylvinylcarbamate 308d.

13

12

23

4

7 58

11

9

10

1

6

N O

O


Methylphenyl)ethanol 183e (203 mg, 1.49 mmol) gave after flash column chromatography

(SiO2, Petrol:EtOAc 2 %) the title compound 308d (209 mg, 65 % over 2 steps) as a

colourless oil.


) 1707 (C=O), 1625 (C=C); 1H NMR

(400MHz, CDCl3) (mixture of rotamers) 7.32-7.15 (m, 5H, aryl and H-12), 5.89 (q, J =

6.6 Hz, 1H, H-8), 4.35 (d, J = 15.8 Hz, 1H, H-13), 4.29 (d, J = 9.0 Hz, 1H, H-13), 3.13 (s,

1.2H, H-11, rotamer 1), 3.10 (s, 1.8H, H-11, rotamer 2), 1.62 (d, J = 6.6 Hz, 3H, H-9); 13

C

NMR (100MHz, CDCl3) (mixture of rotamers) 153.2 (C-10), 141.7 (C-7), 138.1 (C-4),

134.2, 133.6 (C-12), 128.7, 128.4, 126.6, 122.9 (CH aryl), 91.5 (C-13), 74.2, 74.4 (C-8),



1-(4-Methoxyphenyl)ethyl methylvinylcarbamate 308e.

2

34

7

58

11

9

10

1

6N O

O

O


Methoxyphenyl)ethanol 183b (229 mg, 1.51 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 308e (220 mg, 62 % over 2

steps) as a colourless oil.


) 1707 (C=O), 1625, 1513 (C=C), 1246 (C-

O-C); 1H NMR (300MHz, CDCl3) 7.31 (d, J = 8.8 Hz, 2H, H-4), 7.20 (dd, J = 15.8 and

341

8.8 Hz, 1H, H-10), 6.89 (d, J = 8.8 Hz, 2H, H-3), 5.84 (q, J = 6.6 Hz, 1H, H-6), 4.28 (d, J =

15.8 Hz, 1H, H-11), 4.22 (d, J = 8.8 Hz, 1H, H-11), 3.80 (s, 3H, H-1), 3.04 (s, 3H, H-9),

1.57 (d, J = 6.6 Hz, 3H, H-7); 13

C NMR (75MHz, CDCl3) 159.2 (C-2), 153.2 (C-8),

134.2 (C-5), 133.8 (C-10), 127.4 (C-4), 113.8 (C-3), 91.4 (C-11), 74.0 (C-6), 55.2 (C-1),

30.0 (C-9), 22.2 (C-7); MS m/z (ES+) 258 (100 %, M+Na+).

2-Phenylbut-3-en-2-yl methylcarbamate 309a.

2

34

7

5

8

910

1

6

NH

O

O

General procedure O was followed with LDA (2.0 equiv.) and DMPU at -45°C. 1-

Phenylethyl methylvinylcarbamate 308a (43 mg, 0.21 mmol) gave after flash column


colourless oil.


) 3355 (br, N-H), 1698 (C=O), 1618 (C=C),

1520 (Amide II), 1262 (Amide III); 1H NMR (400MHz, CDCl3) 7.39-7.23 (m, 5H, aryl),

6.30 (dd, J = 17.4 and 10.8 Hz, 1H, H-7), 5.25 (d, J = 17.4 Hz, 1H, H-8), 5.23 (d, J = 10.8,

1H, H-8), 4.70 (br, 1H, -NH), 2.74 (d, J = 4.8 Hz, 3H, H-10), 1.89 (s, 3H, H-6); 13

C NMR

(100MHz, CDCl3) 155.5 (C-9), 144.3 (C-4), 142.1 (C-7), 128.1, 127.1, 125.1 (CH aryl),

114.0 (C-8), 82.2 (C-5), 27.2 (C-10), 25.8 (C-6); MS m/z (ES+) 228 (100 %, M+Na+);


2-(4-Chlorophenyl)but-3-en-2-yl methylcarbamate 309b.

2

34

7

5

8

910

1

6

NH

O

O

Cl

General procedure O was followed with LDA (2.0 equiv.) and DMPU at -45°C. 1-(4-

Chlorophenyl)ethyl methylvinylcarbamate 308b (50 mg, 0.21 mmol) gave after flash

342

column chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 309b (27 mg, 54 %)



) 3352 (br, N-H), 1697 (C=O), 1620 (C=C),


6.26 (dd, J = 17.4 and 10.8 Hz, 1H, H-7), 5.24 (d, J = 17.4 Hz, 1H, H-8), 5.23 (d, J = 10.8

Hz, 1H, H-8), 4.69 (br, 1H, -NH), 2.73 (d, J = 4.8 Hz, 3H, H-10), 1.89 (s, 3H, H-6); 13

C

NMR (100MHz, CDCl3) 155.3 (C-9), 142.9 (C-4), 141.7 (C-7), 133.0 (C-1), 128.3,

126.7 (CH aryl), 114.5 (C-8), 81.7 (C-5), 27.3 (C-10), 25.8 (C-6); MS m/z (ES+) 262

(100 %, M+Na+); HMRS (ES+) calcd for C12H14O2N1Na1

35Cl1 (M+Na

+): 262.0606, found:

262.0604.

2-(3-(Trifluoromethyl)phenyl)but-3-en-2-yl methylcarbamate 309c.

1213

2

3

47

5

8

910

1

6

11

NH

O

O

CF3


(Trifluoromethyl)phenyl)ethyl methylvinylcarbamate 308c (50 mg, 0.18 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 309c (16 mg,



) 3353 (br, N-H), 1699 (C=O), 1625 (C=C),

1521 (Amide II), 1328 (C-F), 1263 (Amide III); 1H NMR (500MHz, CDCl3) 7.62 (s, 1H,

H-6), 7.52-7.43 (m, 3H, aryl), 6.28 (dd, J = 17.4 and 10.8 Hz, 1H, H-10), 5.28 (d, J = 17.4

Hz, 1H, H-11), 5.27 (d, J = 10.8 Hz, 1H, H-11), 4.75 (br, 1H, -NH), 2.74 (d, J = 4.8 Hz,

3H, H-13), 1.89 (s, 3H, H-9); 13

C NMR (125MHz, CDCl3) 155.2 (C-12), 145.5 (C-7),

141.3 (C-10), 130.5 (q, 2JCF = 32 Hz, C-4), 128.6, 128.7 (CH aryl), 124.1 (q,

1JCF = 270 Hz,

C-5), 124.0 (q, 3JCF = 3.6 Hz, C-3), 122.0 (q,

3JCF = 3.6 Hz, C-6), 114.9 (C-11), 81.6 (C-8),

27.2 (C-13), 25.9 (C-9); MS m/z (ES+) 296 (100 %, M+Na+), (ES-) 272 (50 %, M-H

+);


343

2-m-Tolylbut-3-en-2-yl methylcarbamate 309d.

1312

2

3

4

75

8

910

1

6

11

NH

O

O

General procedure O was followed with LDA (2.0 equiv.) and DMPU at -45°C. 1-m-

Tolylethyl methylvinylcarbamate 308d (50 mg, 0.23 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 309d (24 mg, 48 %) as a

colourless oil.


) 3355 (br, N-H), 1698 (C=O), 1619 (C=C),


6.29 (dd, J = 17.4 and 10.8 Hz, 1H, H-10), 5.25 (d, J = 17.4 Hz, 1H, H-11), 5.22 (d, J =

10.8 Hz, 1H, H-11), 4.75 (br, 1H, -NH), 2.73 (d, J = 4.8 Hz, 3H, H-13), 2.35 (s, 3H, H-5),

1.88 (s, 3H, H-9); 13

C NMR (100MHz, CDCl3) 155.5 (C-12), 144.2 (C-7), 142.1 (C-10),

137.6 (C-4), 128.8, 128.0, 125.7, 122.1 (CH aryl), 113.8 (C-11), 82.1 (C-8), 27.2 (C-13),


C13H17O2N1Na1 (M+Na+): 242.1152, found: 242.1143.

2-(4-Methoxyphenyl)but-3-en-2-ol 310a.

2

3

4

7

5

89

1

6HO

O


Methoxyphenyl)ethyl methylvinylcarbamate 308e (50 mg, 024 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 3 %) the title compound 310a (10 mg, 22 %)


344


) 3414 (br, O-H), 1610, 1509 (C=C), 1244

(C-O-C); 1H NMR (400MHz, CDCl3) 7.39 (d, J = 9.0 Hz, 2H, H-4), 6.87 (d, J = 9.0 Hz,

2H, H-3), 6.15 (dd, J = 17.2 and 10.6 Hz, 1H, H-8), 5.28 (dd, J = 17.2 and 1.1 Hz, 1H, H-

9), 5.13 (dd, J = 10.6 and 1.1 Hz, 1H, H-9), 3.80 (s, 3H, H-1), 1.82 (br, 1H, -OH), 1.64 (s,

3H, H-7); 13

C NMR (100MHz, CDCl3) 158.5 (C-2), 145.0 (C-8), 138.5 (C-5), 126.4 (C-

4), 113.5 (C-3), 112.0 (C-9), 74.4 (C-6), 55.3 (C-1), 29.3 (C-7); MS m/z (ES+) 161 (100 %,

M-H2O+H+); HMRS (ES+) calcd for C11H13O1 (M-H2O+H

+): 161.0961, found: 161.0961.

2-Phenylbut-3-en-2-ol 310b.[52]

2

34

7

5

8

1

6

HO

General procedures O and R were followed. 1-Phenylethyl methylvinylcarbamate 308a

(200 mg) gave after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title

compound 310b (96 mg, 48 % over 2 steps) as a yellow oil.


) 3395 (br, O-H); 1H NMR (400MHz,

CDCl3) 7.38 (d, J = 8.0 Hz, 2H, H-3), 7.26 (t, J = 8.0 Hz, 2H, H-2), 7.17 (t, J = 8.0 Hz,

1H, H-1), 6.08 (dd, J = 17.2 and 10.8 Hz, 1H, H-7), 5.21 (dd, J = 17.2 and 1.2 Hz, 1H, H-

8), 5.06 (dd, J = 10.8 and 1.2 Hz, 1H, H-8), 1.92 (s, 1H, -OH), 1.57 (s, 3H, H-6); 13

C NMR

(100MHz, CDCl3) 146.3 (C-4), 144.8 (C-7), 128.2, 126.9, 125.1 (CH aryl), 112.3 (C-8),

74.7 (C-5), 29.3 (C-6); GC/MS 148.1 (M+). Spectral data matched the published data.

[52]

345

Benzyl methylcarbamate 314a.[233]

NH

O

O

1

2

34

5

67

General procedure V was followed. Benzyl chloroformate 312a (1.00 g, 5.88 mmol) gave


(0.63 g, 65 %) as a colourless oil.


) 3339 (br, N-H), 1697 (C=O), 1529 (Amide

II), 1254 (Amide III); 1H NMR (400MHz, CDCl3) 7.38-7.28 (m, 5H, aryl), 5.10 (s, 2H,

H-5), 4.10 (br, 1H, -NH), 2.81 (d, J = 4.8 Hz, 3H, H-7); 13


157.0 (C-6), 136.6 (C-4), 128.5, 128.1, 126.9 (CH aryl), 66.0 (C-5), 27.5 (C-7); MS m/z

(ES+) 188 (100 %, M+Na+); HMRS (ES+) calcd for C9H12O2N1 (M+H

+): 166.0863, found:

166.0864. Spectral data matched the published values.[233]

Benzyl isopropylcarbamate 314b. [234]

NH

O

O

1

2

34

5

6

7

8

8

General procedure V was followed. Benzyl chloroformate 312a (500 mg, 2.94 mmol) gave

after flash column chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 314b

(439 mg, 78 %) as a white solid.

Rf 0.48 (Petrol:EtOAc 8:2); m.p 58-60 °C (Et2O/Petrol); IR max (neat/cm-1

) 3326 (br, N-


7.29 (m, 5H, aryl), 5.08 (s, 2H, H-5), 4.59 (br d, J = 6.6 Hz, 1H, -NH), 3.84 (oct, J = 6.6

Hz, 1H, H-7), 1.16 (d, J = 6.6 Hz, 6H, H-8); 13

C NMR (100MHz, CDCl3) 155.5 (C-6),

136.6 (C-4), 128.4, 128.1, 128.0 (CH aryl), 66.4 (C-5), 43.1 (C-7), 23.0 (C-8); MS m/z

346

(ES+) 216 (100 %, M+Na+); HMRS (ES+) calcd for C11H16O2N1 (M+H

+): 194.1176,

found: 194.1170. Spectral data matched the published values.[234]

1-Phenylethyl isopropylcarbamate 314c.

NH

O

O

1

2

34

5

6

78

9

9

To a solution of 1-phenylethanol 183d (1.00 g, 8.20 mmol) in anhydrous THF (130 cm3)

were added triethylamine (1.1 cm3, 8.20 mmol) and a solution of triphosgene (2.40 g, 9.02

mmol) in anhydrous THF (30 cm3) dropwise at 0 °C. The reaction mixture was stirred at

room temperature for 15 h under nitrogen atmosphere. The solvent was evaporated under

reduced pressure and the residue was dissolved in anhydrous CH2Cl2 (40 cm3).

Isopropylamine (1.4 cm3, 16.4 mmol) and pyridine (1.2 cm

3, 16.4 mmol) were added

dropwise at 0 °C. The reaction mixture was stirred at room temperature and concentrated

after 15 h. The residue was purified by flash column chromatography (SiO2, Petrol:EtOAc

5 %) to give the title compound 314c (0.76 g, 45 % over 2 steps) as a white solid.


) 3327 (br, N-


7.17 (m, 5H, aryl), 5.71 (q, J = 6.8 Hz, 1H, H-5), 4.53 (br d, J = 6.6 Hz, 1H, -NH), 3.73

(oct, J = 6.6 Hz, 1H, H-8), 1.45 (d, J = 6.8, 3H, H-6), 1.07 (d, J = 6.6 Hz, 3H, H-9), 1.03 (d,

J = 6.6 Hz, 3H, H-9); 13

C NMR (100MHz, CDCl3) 155.0 (C-7), 142.2 (C-4), 128.4,

127.6, 125.9 (CH aryl), 72.2 (C-5), 42.9 (C-8), 22.9 (C-9), 22.4 (C-6); MS m/z (ES+) 230


+): 230.1152, found:

230.1158.

347

1-(2-Bromoethynyl)benzene 315.[235]

1

23

4

5

6

Br

General procedure W was followed. Phenylactetylene 313 (1.0 g, 9.8 mmol) gave after

flash column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 315 (1.5 g,

82 %) as a yellow oil.


) 2196 (CC); 1H NMR (400MHz, CDCl3)

7.47-7.44 (m, 2H, aryl), 7.35-7.29 (m, 3H, aryl); 13

C NMR (100MHz, CDCl3) 132.0,

128.7, 128.3 (CH aryl), 122.6 (C-3), 80.0 (C-2), 49.7 (C-1). MS m/z (ES+) 180 (100 %,

M+). Spectral data matched the published values.

[235]

Benzyl methyl-2-phenylethynylcarbamate 316a.

1

23

45

6N O

O

7

89

10

11

12

13

General procedure X was followed. Benzyl methylcarbamate 314a (300 mg, 1.82 mmol)


316a (207 mg, 43 %) as a yellow solid.


) 2249 (CC),

1722 (C=O); 1H NMR (400MHz, CDCl3) 7.33-7.15 (m, 10H, aryl), 5.16 (s, 2H, H-5),

3.16 (s, 3H, H-7); 13

C NMR (100MHz, CDCl3) 155.2 (C-6), 135.6 (C-4), 130.9, 128.4,

128.2, 128.2, 127.6, 127.4 (CH aryl), 123.1 (C-10), 85.1 (C-8), 83.8 (C-9), 68.4 (C-5), 37.7

(C-7); MS m/z (ES+) 283 (70 %, M+Na+), 266 (20 %, M+H


C17H16O2N1 (M+H+): 266.1176, found: 266.1172.

348

Benzyl isopropyl-2-phenylethynylcarbamate 316b.

1

23

45

6N O

O

8

910

11

1213

7

14

8

General Procedure Z was followed. Benzyl ethynylisopropylcarbamate 320a (195 mg, 0.90


compound 316b (222 mg, 84 %) as a colourless oil.


) 2247 (CC), 1716 (C=O); 1H NMR

(500MHz, CDCl3) 7.34-7.14 (m, 10H, aryl), 5.17 (s, 2H, H-5), 4.34 (sep, J = 6.8 Hz, 1H,

H-7), 1.21 (d, J = 6.8 Hz, 6H, H-8); 13

C NMR (125MHz, CDCl3) 154.7 (C-6), 135.8 (C-

4), 130.8, 128.5, 128.2, 128.1, 127.6, 127.2 (CH aryl), 123.5 (C-11), 79.8 (C-9), 73.0 (C-

10), 68.2 (C-5), 49.3 (C-7), 20.3 (C-8); MS m/z (ES+) 316 (100 %, M+Na+); HMRS (ES+)

calcd for C19H20O2N1 (M+H+): 294.1489, found: 294.1482.

1-Phenylethyl isopropyl-2-phenylethynylcarbamate 316c.

15

1

23

45

6

N O

O

9 9

1011

12

13

7

14

8

General Procedure Z was followed. 1-Phenylethyl ethynylisopropylcarbamate 320b (336


title compound 316c (304 mg, 68 %) as a colourless oil.


) 2245 (CC), 1715 (C=O); 1H NMR

(400MHz, CDCl3) 7.43-7.27 (m, 10H, aryl), 5.88 (q, J = 6.4 Hz, 1H, H-5), 4.40 (sep, J =

6.8 Hz, 1H, H-8), 1.62 (d, J = 6.4 Hz, 3H, H-6), 1.32 (d, J = 6.8 Hz, 3H, H-9), 1.28 (d, J =

349

6.8 Hz, 3H, H-9); 13

C NMR (100MHz, CDCl3) 154.2 (C-7), 141.7 (C-4), 130.6, 128.4,

128.2, 127.8, 127.1, 125.7 (CH aryl), 123.7 (C-12), 80.1 (C-10), 75.1 (C-5), 73.0 (C-11),



(2-Bromoethynyl)triisopropylsilane 318. [235]

12

3 44

Si

Br

General procedure W was followed. (Triisopropylsilyl)acetylene 317 (2.0 g, 11 mmol)


(2.4 g, 83 %) as a colourless oil.

Rf 0.81 (Petrol); IR max (neat/cm-1

) 2120 (CC); 1H NMR (400MHz, CDCl3) 1.07 (s,

21H, H-3 and H-4); 13

C NMR (100MHz, CDCl3) 83.4 (C-2), 61.7 (C-1), 18.5 (C-4), 11.2

(C-3); MS m/z (ES+) 260 (100 %, M+). Spectral data matched the published values.

[235]

Benzyl isopropyl-2-(triisopropylsilyl)ethynylcarbamate 319a.

1

23

45

6N O

OSi

8

910

1112

12

78

General procedure X was followed. Benzyl methylcarbamate 314b (522 mg, 2.70 mmol)


319a (615 mg, 61 %) as a colourless oil.


) 2171 (CC), 1722 (C=O); 1H NMR

(400MHz, CDCl3) 7.41-7.31 (m, 5H, aryl), 5.20 (s, 2H, H-5), 4.34 (sep, J = 6.8 Hz, 1H,

350

H-7), 1.26 (d, J = 6.8 Hz, 6H, H-8), 1.06 (s, 21H, H-11 and H-12); 13

C NMR (100MHz,

CDCl3) 155.0 (C-6), 135.6 (C-4), 128.4, 128.1, 127.9 (CH aryl), 93.4 (C-9), 70.9 (C-10),

68.2 (C-5), 48.7 (C-7), 20.2 (C-8), 18.6 (C-12), 11.4 (C-11); MS m/z (ES+) 374 (100 %,

M+H+); HMRS (ES+) calcd for C22H36O2N1Si1 (M+H

+): 374.2510, found: 374.2495.

1-Phenylethyl isopropyl-2-(triisopropylsilyl)ethynylcarbamate 319b.

1

23

45

6

N O

OSi

9 9

1011

12

13

7

13

8

General procedure X was followed. 1-Phenylethyl isopropylcarbamate 314c (738 mg, 3.56


compound 319b (890 mg, 65 %) as a colourless oil.


) 2172 (CC), 1721 (C=O); 1H NMR

(400MHz, CDCl3) 7.40-7.27 (m, 5H, aryl), 5.84 (q, J = 6.4 Hz, 1H, H-5), 4.29 (sep, J =

6.8 Hz, 1H, H-8), 1.57 (d, J = 6.4 Hz, 3H, H-6), 1.26 (d, J = 6.8 Hz, 3H, H-9), 1.20 (d, J =

6.8 Hz, 3H, H-9), 1.11 (s, 21H, H-12 and H-13); 13

C NMR (100MHz, CDCl3) 154.5 (C-

7), 141.7 (C-4), 128.4, 127.7, 125.8 (CH aryl), 93.7 (C-10), 74.9 (C-5), 70.7 (C-11), 48.5

(C-8), 23.0 (C-6), 20.2 (C-9), 18.7 (C-13), 11.4 (C-12); MS m/z (ES+) 410 (100 %,

M+Na+); HMRS (ES+) calcd for C23H38O2N1Si1 (M+H

+): 388.2667, found: 388.2673.

Benzyl ethynylisopropylcarbamate 320a.

1

23

45

6N O

O9

8

10

78

H

General procedure Y was followed. Benzyl isopropyl-2-

(triisopropylsilyl)ethynylcarbamate 319a (667 mg, 1.90 mmol) gave after flash column

351


pale yellow oil.


) 3291 (C-H), 2135 (CC), 1719 (C=O);


Hz, 1H, H-7), 2.85 (s, 1H, H-10), 1.24 (d, J = 6.8 Hz, 6H, H-8); 13

C NMR (125MHz,

CDCl3) 155.0 (C-6), 135.7 (C-4), 128.5, 128.2, 127.8 (CH aryl), 73.1 (C-9), 68.3 (C-5),



1-Phenylethyl ethynylisopropylcarbamate 320b.

1

23

45

6

N O

O

9 9

1011

7

8

H

General procedure Y was followed. 1-Phenylethyl isopropyl-2-

(triisopropylsilyl)ethynylcarbamate 319b (890 mg, 2.30 mmol) gave after flash column


colourless oil.


) 3297 (C-H), 2138 (CC), 1716 (C=O);

1H NMR (400MHz, CDCl3) 7.40-7.27 (m, 5H, aryl), 5.86 (q, J = 6.4 Hz, 1H, H-5), 4.29

(sep, J = 6.8 Hz, 1H, H-8), 2.87 (s, 1H, H-11), 1.59 (d, J = 6.4 Hz, 3H, H-6), 1.24 (d, J =

6.8 Hz, 3H, H-9), 1.21 (d, J = 6.8 Hz, 3H, H-9); 13

C NMR (100MHz, CDCl3) 154.5 (C-

7), 141.5 (C-4), 128.5, 127.8, 125.7 (CH aryl), 94.8 (C-10), 75.1 (C-5), 60.8 (C-11), 48.6

(C-8), 22.8 (C-6), 20.0 (C-9); MS m/z (ES+) 254 (100 %, M+Na+); HMRS (ES+) calcd for

C14H17O2N1Na1 (M+Na+): 254.1152, found: 254.1154.

352

2-Hydroxy-N-isopropyl-N-(2-(triisopropylsilyl)ethynyl)-2-phenylacetamide 321a.

1

2

34

56

8

91011

12

12

78

N

OH

OSi

General Procedure O was followed with LDA (2.5 equiv.), LiCl and DMPU. Benzyl

isopropyl-2-(triisopropylsilyl)ethynylcarbamate 319a (50 mg, 0.13 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 2 %) the title compound 321a (12 mg, 0.03

mmol, 24 %) as a colourless oil.


) 3469 (br, O-H), 2164 (CC), 1680 (C=O);

1H NMR (400MHz, CDCl3) 7.40-7.29 (m, 5H, aryl), 5.73 (d, J = 8.4 Hz, 1H, -OH), 4.69

(sep, J = 6.8 Hz, 1H, H-7), 3.82 (d, J = 8.4 Hz, 1H, H-5), 1.26 (d, J = 6.8 Hz, 3H, H-8),

1.14 (d, J = 6.8 Hz, 3H, H-8), 1.04, 1.00 (m, 21H, H-11, H-12); 13

C NMR (100MHz,

CDCl3) 174.4 (C-6), 138.5 (C-4), 128.6, 128.4, 127.1 (CH aryl), 92.7 (C-9), 76.0 (C-10),

72.3 (C-5), 47.5 (C-7), 19.8, 19.7 (C-8), 18.6 (C-12), 11.2 (C-11); MS m/z (ES+) 396

(100 %, M+Na+), (ES-) 372 (100 %, M-H

+).

2-Hydroxy-N-isopropyl-N-(2-(triisopropylsilyl)ethynyl)-2-phenylpropanamide 321b.

1

2

34

5

6

9 9

101112

13

7

8

N

OH

OSi

13

General Procedure O was followed with LDA (2.5 equiv.), LiCl and DMPU. 1-Phenylethyl

isopropyl-2-(triisopropylsilyl)ethynylcarbamate 319b (50 mg, 0.13 mmol) gave after flash

column chromatography (SiO2, Petrol:EtOAc 1 %) the title compound 321b (10 mg, 0.03

mmol, 20 %) as a colourless oil.

353


) 2174 (CC), 1632 (C=O); 1H NMR

(400MHz, CDCl3) 7.54 (d, J = 7.2 Hz, 2H, H-3), 7.39-7.27 (m, 3H, aryl), 4.21 (sep, J =

6.8 Hz, 1H, H-8), 3.41 (s, 1H, -OH), 1.74 (s, 3H, H-6), 1.44 (d, J = 6.8 Hz, 6H, H-9), 1.10-

1.07 (m, 21H, H-12 and H-13); 13

C NMR (100MHz, CDCl3) 172.3 (C-7), 139.4 (C-4),

128.3, 128.0, 124.7 (CH aryl), 92.8 (C-10), 82.3 (C-5), 76.4 (C-11), 45.2 (C-8), 25.0 (C-6),

18.9 (C-9), 18.8 (C-13), 11.7 (C-12); MS m/z (ES+) 388 (100 %, M+H+).

4-Benzyl-3-isopropyl-5-phenyloxazol-2(3H)-one 322.

1

2

345

6

9

10

7

8

14

13 1112

NO

O

8


isopropyl-2-phenylethynylcarbamate 316b (100 mg, 0.26 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 322 (36 mg, 0.12 mmol,

36 %) as a yellow oil.


) 1743 (C=O); 1H NMR (400MHz, CDCl3)

7.41-7.17 (m, 10H, aryl), 3.97 (s, 2H, H-10), 3.70 (sep, J = 6.8 Hz, 1H, H-7), 1.24 (d, J =

6.8 Hz, 6H, H-8); 13

C NMR (100MHz, CDCl3) 153.8 (C-6), 135.9, 135.8, 129.1, 128.8

(aryl), 128.1 (C-5), 127.9, 127.6, 127.3, 125.0 (CH aryl), 120.6 (C-9), 46.5 (C-7), 29.3 (C-

10), 19.5 (C-8); MS m/z (ES+) 316 (100 %, M+Na+).

354

(Z)-4-Benzylidene-3-isopropyl-5-phenyloxazolidin-2-one 323.

1

2

345

69

7

8

NO

O

10

8

14

1311

12



chromatography (SiO2, Petrol:EtOAc 5 %) the title compound 323 (6 mg, 0.02 mmol, 6 %)

as a yellow oil.


(s, 1H, H-10), 5.07 (s, 1H, H-5), 4.32 (sep, J = 6.8 Hz, 1H, H-7), 1.53 (d, J = 6.8 Hz, 3H,

H-8), 1.51 (d, J = 6.8 Hz, 3H, H-8); MS m/z (ES+) 316 (100 %, M+Na+).


did not enhance peak at 4.32 ppm (N-CH).

4-(Hydroxy(phenyl)methyl)-3-isopropyl-5-phenyloxazol-2(3H)-one 324.

1

2

34

5

68

9

10

7

8

14

13

11

12

NO

O

HO



chromatography (SiO2, Petrol:EtOAc 10 %) the title compound 324 (21 mg, 0.07 mmol,

20 %) as white solid.

355


) 3369 (br,

O-H), 1722 (C=O); 1H NMR (400MHz, CDCl3) 7.47-7.32 (m, 10H, aryl), 6.20 (d, J =

3.6 Hz, 1H, H-10), 3.92 (sep, J = 6.8 Hz, 1H, H-7), 2.51 (d, J = 3.6 Hz, 1H, -OH), 1.40 (d,

J = 6.8 Hz, 3H, H-8), 0.94 (d, J = 6.8 Hz, 3H, H-8); 13

C NMR (100MHz, CDCl3) 153.8

(C-6), 139.0, 136.6, 128.8, 128.7, 128.6 (aryl), 127.9 (C-5), 126.3, 125.4 (aryl), 123.8 (C-

9), 65.6 (C-10), 47.7 (C-7), 19.0 (C-8), 18.2 (C-8); MS m/z (ES+) 310 (100 %, M+H+), 332


+): 332.1258, found:

332.1269.

The structure was confirmed by an X-ray crystal structure.

(Z)-2-Benzylidene-3-isopropyl-4-methyl-4-phenyloxazolidin-5-one 325. and (Z)-4-

Benzylidene-3-isopropyl-5-methyl-5-phenyloxazolidin-2-one 238.

1

23

45

6

9

71413

11

12

10

8

11

15

NO

O

7'

8'

15'

ON

O

1'

2'3'

4'5'

6'8'

9'10'

11'

12'

13'14'

General Procedure O was followed with LDA (2.0 equiv.), LiCl and DMPU. 1-Phenylethyl

isopropyl-2-phenylethynylcarbamate 316c (100 mg, 0.34 mmol) gave after flash column

chromatography (SiO2, Petrol:EtOAc 2 %) the title compounds 325 and 238 (16 mg, 16 %).


(s, 0.4H, H-5’), 4.97 (s, 0.6H, H-5), 4.19 (sep, J = 6.8 Hz, 0.6H, H-10), 3.60 (sep, J = 6.8

Hz, 0.4H, H-7’), 1.87 (s, 1.2H, H-11’), 1.81 (s, 1.8H, H-9), 1.40 (d, J = 6.8 Hz, 3.6H, H-

11), 1.26 (d, J = 6.8 Hz, 1.2H, H-8’), 1.12 (d, J = 6.8 Hz, 1.2H, H-8’); 13

C NMR (125MHz,

CDCl3) 171.5 (C-7), 155.7 (C-9’), 149.0 (C-6), 143.6 (C-6’), 141.8, 139.2, 135.5, 134.9,

128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 127.0, 126.9, 125.1, 124.6 (aryl), 100.8 (C-5’),

84.6, 83.6 (C-8 and C-10’), 82.4 (C-5), 47.6, 45.4 (C-7’ and C-10), 27.3, 25.1 (C-9 and C-

11’), 19.2, 19.0 (C-8’), 18.7 (C-11).

The (Z)-stereochemistry of xx was deduced by a nOe experiment: irradiation at 4.95 ppm

(CH=C) enhanced peak at 4.19 ppm (N-CH) from 3.47 %.

356

Benzyl cyanomethylcarbamate 326.[209]

10

1

2

34

5

6

9

CN O

ON

To a suspension of NaNHCN[210]

(1.13 g, 17.6 mmol) in anhydrous THF (30 cm3) was

added a solution of benzyl chloroformate 312a (1.00 g, 5.88 mmol) in anhydrous THF (15

cm3) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at

room temperature for 15 h, quenched with water (20 cm3) and extracted with EtOAc (20

cm3). The aqueous phase was acidified with 1 N HCl until pH 1 and extracted with EtOAc

(2 × 10 cm3). The combined organic phases were dried over MgSO4 and concentrated

under reduced pressure. The crude residue (0.96 g, 5.47 mmol) was dissolved in anhydrous

DMF (27 cm3) and NaH (60 % in mineral oil, 0.44 g, 10.9 mmol) was added slowly at 0°C

under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min and methyl

iodide (0.85 cm3, 13.7 mmol) was added. The reaction was stirred at 16 °C for 21 h. Water

was added and the reaction mixture was extracted with Et2O (30 cm3). The organic layer

was then washed with water (3 × 20 cm3), dried over MgSO4, filtered and concentrated

under reduced pressure. The crude product was purified by flash column chromatography

(SiO2, Petrol: EtOAc 5 % then 7 %) to give the title compound 326 (0.55 g, 50 % over 2

steps) as a white solid.


) 2245 (CN),

1748 (C=O); 1H NMR (400MHz, CDCl3) 7.40-7.36 (m, 5H, aryl), 5.28 (s, 2H, H-5),

3.22 (s, 3H, H-9); 13

C NMR (100MHz, CDCl3) 152.6 (C-6), 134.1 (C-4), 128.9, 128.7,



357

2-Bromobenzo[d]thiazole 327. [236]

75

6

23

41

S

NBr

By the modified method reported by Dehaen et al.[212]

:

To a solution of 2-amino-benzothiazole 326 (250 mg, 1.67 mmol) and copper(II) bromide

(575 mg, 2.50 mmol) in anhydrous MeCN (15 cm3) was added tert-butyl nitrite (0.30 cm

3,

2.50 mmol). The mixture was stirred at 80 °C in a sealed tube for 18 h. After cooling to

room temperature, the mixture was taken up in EtOAc (15 cm3) and washed with a 3 N

aqueous HCl solution (15 cm3), a saturated aqueous solution of NaHCO3 (15 cm

3) and

brine (15 cm3). The organic layer was dried over MgSO4, filtered and concentrated under

reduced pressure. The residue was purified by flash column chromatography (SiO2,

Petrol:EtOAc 1 %) to give the title compound 327 (310 mg, 87 %) as a pale yellow solid.

Rf 0.66 (Petrol:EtOAc 8:2); m.p. 44-46 °C (EtOH); 1H NMR (400MHz, CDCl3) 7.99 (d,

J = 7.8 Hz, 1H, H-6), 7.80 (d, J = 7.8 Hz, 1H, H-3), 7.49-7.39 (m, 2H, H-4 and H-5); 13

C

NMR (100MHz, CDCl3) 152.3 (C-2), 138.9 (C-1), 137.3 (C-7), 126.6 (C-3), 125.7 (C-6),

122.8, 120.9 (C-4 and C-5); MS m/z (ES+) 214 (100 %, M+H+); HMRS (ES+) calcd for

C7H5N2S280

Br1 (M+H+): 213.9321, found: 213.9324. Spectra data matched the published

values.[236]

Benzyl benzo[d]thiazol-2-ylmethylcarbamate 328.

13 145

6

7

8

9

1011

12

34

2

1

ON

ON

S


O-Benzylcarbamate 314a (258 mg, 1.56 mmol), 2-bromobenzo[d]thiazole 327 (516 mg,

2.34 mmol), sodium tert-butoxide (300 mg, 3.12 mmol), 4,5-bis(diphenylphosphino)-9,9-

358

dimethylxanthenene (XantPhos) (93 mg, 0.156 mmol, 10 mol %) and tris-

(benzylideneacetone)dipalladium(0) (37 mg, 0.039 mmol, 2.5 mol %) were dissolved in

toluene (18 cm3) in a sealed tube. The solution was degassed for 30 min and heated under

reflux (110 °C) for 16 h under nitogen atmosphere. The mixture was cooled to room

temperature and a saturated aqueous solution of NH4Cl (10 cm3) was added. The mixture

was extracted with Et2O (2 10 cm3), the combined organic phases were washed with

brine and dried over MgSO4, filtered and concentrated under reduced pressure. The residue

was purified by flash column chromatography (SiO2, Petrol:EtOAc 5 %) to give the title

compound 328 (157 mg, 34 %) as a white solid.


) 1713

(C=O); 1H NMR (400MHz, CDCl3) 7.86 (d, J = 7.8 Hz, 1H, H-13), 7.78 (d, J = 7.8 Hz,

1H, H-10), 7.47-7.27 (m, 7H, aryl), 5.36 (s, 2H, H-5), 3.73 (s, 3H, H-7); 13

C NMR

(100MHz, CDCl3) 161.2 (C-8), 150.0 (C-9), 149.1 (C-6), 135.0 (C-4), 132.1 (C-14),

128.7, 128.4, 126.3, 125.8, 123.3, 121.1, 120.9 (CH aryl), 68.9 (C-5), 38.9 (C-7); MS m/z

(ES+) 321 (100 %, M+Na+); HMRS (ES+) calcd for C16H15O2N2S1 (M+H

+): 299.0849,

found: 299.0835.

N-Isopropylbenzo[d]thiazol-2-amine 329.

56

7

89

1

34 2

1

S

NNH


H NMR (400MHz, CDCl3) 7.47 (dd, J = 7.8 and 0.6 Hz, 1H,

H-8), 7.42 (dd, J = 7.8 and 0.6 Hz, 1H, H-5), 7.18 (t, J = 7.8 Hz, 1H, H-6), 6.96 (t, J = 7.8

Hz, H-7), 5.31 (br, 1H, -NH), 3.81 (br, 1H, H-2), 1.21 (d, J = 6.8 Hz, 6H, H-1) ; 13

C NMR

(100MHz, CDCl3) 166.6 (C-3), 152.5 (C-4), 130.4 (C-9), 125.9, 121.4, 120.8, 118.8 (CH

aryl), 47.6 (C-2), 23.0 (C-1).

359

N-(Benzo[d]thiazol-2-yl)-N-isopropylbenzo[d]thiazol-2-amine 330.

N

S

N N

S

5

6

78

9

1

34

21


H NMR (300MHz, CDCl3) 7.77 (d, J = 7.8 Hz, 2H, H-8),

7.70 (d, J = 7.8 Hz, 2H, H-5), 7.35 (t, J = 7.8 Hz, 2H, H-6), 7.20 (t, J = 7.8 Hz, 2H, H-7),

5.01 (sep, J = 6.8 Hz, 1H, H-2), 1.68 (d, J = 6.8 Hz, 6H, H-1); 13


162 (C-3), 150.0 (C-4), 132.3 (C-9), 129.0, 126.1, 123.5, 121.1 (CH aryl), 57.2 (C-2),

20.0 (C-1) ; MS m/z (ES+) 348 (100 %, M+Na+).

III.4 X-Ray Crystal Data

360

III.4.1 X-Ray Crystal Data and Structure Refinement for 238a.

ON

O

Identification code s3385m

Empirical formula C18 H17 N O2

Formula weight 279.33

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system, space group Monoclinic, P2(1) /c

Unit cell dimensions a = 6.2019(5) A alpha = 90 deg.

b = 30.774(3) A beta = 92.856(2) deg.

c = 7.4657(6) A gamma = 90 deg.

Volume 1423.1 (2) A^3

Z, Calculated density 4, 1.304 Mg/m^3

Absorption coefficient 0.085 mm^-1

F(000) 592

Crystal size 0.30 x 0.25 x 0.20 mm

Theta range for data collection 1.32 to 28.28 deg.

Limiting indices -8<=h<=7, -40<=k<=40, -9<=1<=9

Reflections collected / unique 12137 / 3372 [R(int) = 0.0396]

Completeness to theta = 25.03 100.0 %

Absorption correction None

Max. and min. transmission 0.9832 and 0.9750

Refinement method Full-matrix least-squares on F^2

Data / restraints / parameters 3372 / 0 / 192

Goodness-of-fit in F^2 1.048

Final R indices [I>2sigma(I)] R1 = 0.0502, wR2 = 0.1097

R indices (all data) R1 = 0.0674, wR2 = 0.1264

Largest diff. peak and hole 0.37 and -0.226 e.A^-3

361

III.4.2 X-Ray Crystal Data and Structure Refinement for 248j.

N O

O






Crystal system, space group Triclinic, P-1

Unit cell dimensions a = 9.9252(18) A alpha = 67.709(3) deg.

b = 10.0516(18) A beta = 69.292(3) deg.

c = 11.659(2) A gamma = 66.289(3) deg.

Volume 957.3 (3) A^3



F(000) 380














362

III.4.3 X-Ray Crystal Data and Structure Refinement for 271j.

N O

O

Identification code s3418





Crystal system, space group Monoclinic, P2(1) /n


b = 23.295(10) A beta = 90.032(9) deg.

c = 21.312(9) A gamma = 90 deg.

Volume 4869 (4) A^3



F(000) 1792













363

III.4.4 X-Ray Crystal Data and Structure Refinement for 324.

NO

O

HO






Crystal system, space group Monoclinic, P2(1) /c


b = 8.5645(7) A beta = 97.5880(10) deg.

c = 14.3329(11) A gamma = 90 deg.

Volume 1618.7 (2) A^3



F(000) 656














364

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380

AAPPPPEENNDDIIXX

APPENDIX 1: List of Publications

1. Fournier, A. M.; Brown, R. A.; Farnaby, W.; Miyatake-Ondozadal, H.; Clayden, J.

P. Synthesis of ()-(S,S)-Clemastine by Invertive Aryl Migration in a Lithiated

Carbamate, Org. Lett. 2010, 12, 2222.

2. Fournier, A.; Clayden, J. Tertiary Alcohols by Tandem β-Carbolithiation and N→C

Aryl Migration in Enol Carbamates, Org. Lett. 2012, 14, 142.

3. Lefranc, J.; Fournier, A.; Mingat, G.; Herbert, S.; Marcelli, T.; Clayden, J.

Intramolecular Vinylation of Secondary and Tertiary Organolithiums, J. Am. Chem.

Soc. Communication, accepted.

4. Fournier, A. M.; Nichols, C.; Vincent, M. A.; Hillier, I. H.; Clayden, J. P. Lithium

Choreography:Intramolecular Arylations of Carbamate-Stabilized Carbanions and

their Mechanisms Probed by in-situ IR and DFT, J. Am. Chem. Soc., Article,

submitted.

381

APPENDIX 2: Experimental Procedures for the in situ React IR Studies.

An FTIR analyzer, ReactIRTM

iC10 with a DiComp (Diamond) probe connected to an

MCT detector with a DS Series 9.5mm AgXFiberConduitTM

from Mettler Toledo was used

for all experiments. The iC IRTM

software was used to control the spectrometer and collect

spectra. Nitrogen purge on the IR system was maintained throughout any experiments and

nitrogen background was used in computing the absorbance spectra. Each spectrum

represent 30 co-added scans measured at a spectral resolution of 8 cm-1

in the 2000 to 650

cm-1

range with the Happ-Genzel apodization.

II.1 In situ React IR monitoring the rearrangement of benzylcarbamate 95i with sec-

BuLi in THF.

Anhydrous THF (4 cm3, 0.26 M) was added to benzylcarbamate 95i (300 mg) in a 25 cm

3

three-neck flask equipped with a stirrer bar, thermometer and React IR probe under N2.

The solution was cooled in an acetone/CO2 bath and aged for 15 min (for stability of

readout on React IR). Then, sec-BuLi (0.81 cm3, 1.1 equiv., 1.4 M in cyclohexane) was

added dropwise. The reaction was aged for 1 h at -60 °C before quenching with MeOH.

II.2 In situ React IR monitoring the retreatment of rearranged carbamate 96i.

Anhydrous THF (4 cm3, 0.26 M) was added to rearranged product 96i (300 mg) in a 25

cm3 three-neck flask equipped with a stirrer bar, thermometer and React IR probe under

N2. The solution was cooled in an acetone/CO2 bath and aged for 15 min (for stability of


added dropwise. The reaction was aged for 15 min at -60 °C before quenching with MeOH.

382


BuLi in TBME.

Anhydrous TBME (4 cm3, 0.26 M) was added to benzylcarbamate 95i (300 mg) in a 25

cm3 three-neck flask equipped with a stirrer bar, thermometer and React IR probe under N2.


readout on React IR). Then, sec-BuLi (1.40 cm3, 2.0 equiv., 1.4M in cyclohexane) was

added dropwise. The reaction was aged for 1 h at -60 °C before quenching with MeOH OR

anhydrous THF (0.34 cm3, 4.0 equiv.) was added and the reaction was stirred for further 1

h 30 before quenching with MeOH.


BuLi in toluene.

Anhydrous toluene (4 cm3, 0.26 M) was added to benzylcarbamate 95i (300 mg) in a 25




added dropwise. The reaction was aged for 1 h at -60 °C before adding TMEDA (0.15 cm3,

1.1 equiv.). The reaction mixture was stirred for 30 min before quenching with MeOH.

II.5 In situ React IR monitoring the rearrangement of benzylcarbamate 95i with LDA

in TBME.

Anhydrous TBME (4 cm3, 0.26 M) was added to benzylcarbamate 95i (300 mg) in a 25



readout on React IR). Then, LDA (1.80 cm3, 3.5 equiv., 2 M in THF/heptane/ethylbenzene)

was added dropwise. The reaction was aged for 1 h at -60 °C before quenching with

MeOH.

II.6 In situ React IR monitoring the rearrangement of allylcarbamate 201 with LDA

in THF.

Anhydrous THF (4 cm3, 0.27 M) was added to allylcarbamate 201 (300 mg) in a 25 cm

3




383

was added dropwise. The reaction was aged for 1 h at -60 °C before quenching with

MeOH.

II.7 In situ React IR monitoring the rearrangement of benzylcarbamate 308 with

LDA in THF.

Anhydrous THF (5 cm3, 0.26 M) was added to benzylcarbamate 308 (400 mg) in a 25 cm

3




was added dropwise. The reaction was aged for 45 min at -60 °C and then warmed slowly

to room temperature and stirred at room temperature for 30 min before quenching with

MeOH.

384

APPENDIX 3: In Situ IR Spectroscopy Monitoring the Rearrangement

of a N-allylurea

Anhydrous THF (4 cm3, 0.25M) was added to allylurea 341 (300 mg) in a 25 mL three-

neck flask equipped with a stirrer bar, thermometer and React IR probe under N2. The

solution was cooled in an acetone/CO2 bath and aged for 15 min (for stability of readout on

React IR). Then, LDA (1.0 cm2, 2.0 equiv., 2 M in THF/heptane/ethylbenzene) was added

dropwise. The reaction was aged for 1 h at -60 °C before quenching with MeOH and

warming up to room temperature.

Scheme 181. Intermediates Detected in the Rearrangement of 341.

PhN N

Me

O

PMP LDA (1eq.),THF, -60 °C

NN

O LiLnMe

PhPMP

N

OLi

PMPPh

MeN

N

O LiLn

PMPPh

MeN

Li

MeHN N

O

PMP

Ph

LDA (1eq.),THF, -60 °C

341

343

MeOH

341Li

343Li

342Li

385

Figure 22. Characteristic changes in the 1800-1400 cm-1

region of the IR spectrum during

the rearrangement of 341. Five spectra taken at different stages in the experiment are

overlaid. Dark blue: urea prior to lithiation; green: after addition of 1 eq. of LDA at -60 °C;

red: after addition of a further equivalent of LDA; light blue: after addition of MeOH at -

60 °C; pink: after warming to 25 °C.

Figure 23. Perspective view of the changes in the IR spectrum during the rearrangement.

LDA added

Quench with

MeOH Allylurea 341

in THF at -60 °C

Warming up

to 25 °C

1657 cm-1

: 341

1683 cm-1

: 343

1552 cm-1

: 343Li

1605 cm-1

: 342Li

1595 cm-1

: 343Li

Intramolecular -Arylation of Lithiated Carbamates

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