Indoles and Indolines – Palladium-Catalyzed Synthesis and ...

Indoles and Indolines – Palladium-Catalyzed Synthesis and Functionalizations

by Aromatization and Dearomatization

by

Nicolas Zeidan

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy

Department of Chemistry University of Toronto

© Copyright by Nicolas Zeidan 2020

ii

Indoles and Indolines –

Palladium-Catalyzed Synthesis and Functionalizations

by Aromatization and Dearomatization

Nicolas Zeidan

Doctor of Philosophy

Department of Chemistry

University of Toronto

2020

Abstract

The Lautens group has developed many late transition-metal catalyzed protocols for the synthesis

of various heterocycles. The focus of this work is palladium-catalysis for the synthesis and

functionalization of indoles and indolines. This thesis is divided into three chapters concerning the

synthesis of indoles using the Fang-Lautens indole synthesis, the dearomatization of indole by a

migratory insertion strategy, and an electrophilic dearomatization of indoles with N-

fluorobenzenesulfonimide.

Chapter 1 describes the synthesis of 2-cyanoindoles using the Fang-Lautens indole synthesis. The

reaction utilizes vinyl gem-dibromo anilines to access diverse free- and N-capped 2-cyanoindoles

in good yield. An investigation of the mechanism and a one-pot procedure to access the 2-tetrazole

containing indole is presented.

Chapter 2 focuses on the palladium-catalyzed dearomatization of indoles by migratory insertion

to access chiral 2,3-functionalized indolines in good to excellent yields. Two research goals are

presented. First, a protocol for a diastereoselective arylation/direct arylation of indoles is

described, producing complex indolines from benzoyl-indoles and activated C–H bond containing

iii

aryl and heteroaryl compounds. The role of a copper additive is explored in preserving dr in the

products. Secondly, an asymmetric arylation/borylation of indoles is presented. The synthesis of

privileged 3,3’-diaryl phosphoramidite ligands as well as a preactivated mixed-boron reagent

containing an sp2-“sp3” bond is described.

Chapter 3 focuses on an electrophilic dearomatization of indoles using an electrophilic source of

fluoride in a “push-pull mechanism”. The scalable reaction produces activated indolines bearing

an exocyclic double bond on the 2-position. The amphoteric nature of these indolines is explored

and various palladium, rhodium, and copper reactions are described for the formation of new C–

H, C–B, C–C (sp3 and sp2), C–N, C–O, C–P, and C–S bonds.

iv

Acknowledgments

When I started graduate school in 2015, I did not expect to make so many great friends and

connections. Now that I have finished, I can truly say that this degree would not have been possible

without the support and guidance of so many great mentors, friends, colleagues, and comrades.

Mark Lautens, thank you for your thoughtful guidance over the years. I really appreciate that you

accepted me into your group when I came with a minimal organic chemistry background. The

more I progressed and learnt, the more I appreciated just how vast your knowledge in the field is.

I hope one day I can be as meticulous with my chemistry and management as you. To my

supervisor in Germany, Armido Studer, thank you for letting me join your group. I appreciated

expanding my knowledge in a different research pursuit. Mark Taylor, I really appreciated all the

thoughtful questions and comments at our annual meetings. Sophie Rousseaux, j’aimerais

sincèrement vous remercier pour tout votre appui et vos conseils. Merci pour m’avoir encourager

à poursuivre les études supérieures. J’apprécie infiniment que tu étais toujours disponible pour

converser durant mes années comme étudiant et je vais chérir nos discussions intellectuelles

ensemble.

To my lab colleagues, there are just too many to thank. If your name is not mentioned, I hope you

know that there are just too many memories to recall on a single page. Thank you to the original

mentors in the group. Dave Petrone, thank you for yelling just enough. Christine Le, thank you for

the Boss way you got us into the Bruker party. Zafar Qureshi, thank you for the great snowboarding

memories. Hyung Yoon, I could always count on getting your honest advice. Alvin Jang, thank

you for the friendship amidst the chemistry. Andy Yen, thank you for taking the bullet on so many

things, seeing as though we were so close in time. Thank you Heather Lam and Andrew Whyte

for your fierce and friendly competition and motivation. There is something special about being in

the same year as someone, and I will always cherish that. Thank you to all the students afterwards

for being excellent and continuing the Lautens ways. I will never forget our camping trips,

snowboarding trips, and interesting spring formals.

Many thanks to all the students whom I worked with over the years, there are just too many to

name. I am very grateful to have met so many international students and look forward to visiting

v

the Europeans when I make it across the pond. Christian Breuers, thanks for letting me crash on

your couch. Randy Sanichar, thanks for the great fishing and rum. Christian Dank, zaufst du dich

heute weider so an? Veil ich mochte. Tamara Beisel, for encouraging me to do so much, I hope

one day I can be as good of a chemist (and person) as you.

Thank you to my mother Katia Zeidan, and Father Joseph Zeidan for all your support over the

years. Thank you for all the late-night drives back home. Thank you to all my siblings (all of them,

Salam), for the late-night drinks and shiii. Finally, thank you to the boneyard boys, and sometimes

the gulag girls for all the great drops and George Dubyas.

Last and most importantly, to my partner, Milena Aitken, we made it :) Thank you very much for

your patience, every day, and every night. Being in school at the same time was not ideal but it

was fun. I am so proud that you are now a successful PA. I look forward to getting married,

spending time in Europe with you, and the rest of our lives together. Thank you for always pushing

me to do my best and holding down the fort.

vi

Table of Contents

Acknowledgments.......................................................................................................................... iv

Table of Contents ........................................................................................................................... vi

List of Tables ................................................................................................................................. ix

List of Schemes ................................................................................................................................x

List of Appendices ....................................................................................................................... xvi

List of Publications ..................................................................................................................... xvii

Abbreviations ............................................................................................................................. xviii

Chapter 1 ........................................................................................................................................1

Palladium-Catalyzed Synthesis of 2-Substituted Indoles from Vinyl gem-Dibromo

Containing Anilines ....................................................................................................................1

1.1 Introduction ..........................................................................................................................1

1.1.1 Ubiquity of Indoles ..................................................................................................1

1.1.2 Nucleophilicity of Indoles........................................................................................3

1.1.3 Synthesis of Indoles .................................................................................................3

1.1.4 Fang-Lautens Indole Synthesis ..............................................................................11

1.2 Research Goal ....................................................................................................................18

1.2.1 Motivation ..............................................................................................................18

1.2.2 Contributions..........................................................................................................20

1.2.3 Results and Discussion ..........................................................................................20

1.3 Chapter Summary ..............................................................................................................28

1.4 Experimental ......................................................................................................................29

1.4.1 General Considerations ..........................................................................................29

1.4.2 Synthesis of Starting Materials ..............................................................................29

1.4.3 Palladium-Catalyzed Synthesis of 2-Cyanoindoles ...............................................31

vii

1.4.4 Derivatization of 2-Cyanoindole............................................................................38

1.4.5 Substrates of Mechanistic Studies .........................................................................39

Chapter 2 ......................................................................................................................................39

Migratory Insertion Strategy for Indole Dearomatization ........................................................40

2.1 Introduction ........................................................................................................................40

2.1.1 Elementary View on Aromatization ......................................................................40

2.1.2 Strategies for Benzene Dearomatization ................................................................41

2.1.3 Strategies for Indole Dearomatization ...................................................................44

2.2 Research Goal 1 – Palladium-Catalyzed Dearomative Arylation/Heteroarylation of

Indoles ................................................................................................................................59

2.2.1 Motivation ..............................................................................................................59

2.2.2 Contributions..........................................................................................................59


2.3 Research Goal 2 – Arylation/Borylation of Indoles ..........................................................69

2.3.1 Motivation ..............................................................................................................69

2.3.2 Contributions..........................................................................................................70


2.3.4 Section Conclusion ................................................................................................82

2.4 Chapter Summary ..............................................................................................................83

2.5 Experimental ......................................................................................................................83

2.5.1 General Considerations ..........................................................................................83

2.5.2 Synthesis of Starting Materials ..............................................................................84

2.5.3 Research Goal 1 – Dearomative Palladium-Catalyzed

Arylation/Heteroarylation ......................................................................................89

2.5.4 Research Goal 2 – Dearomative Palladium-Catalyzed Arylation/Borylation .....102

Chapter 3 ....................................................................................................................................117

Dearomatization of Indoles with NFSI and Further Aromative Functionalizations ...............117

viii

3.1 Introduction ......................................................................................................................117

3.1.1 Importance of Fluorine in Biology, Medicine, Materials ....................................117

3.1.2 Strategies of Fluorine Incorporation ....................................................................118

3.1.3 Electrophilic Dearomatization of Indoles – Push-Pull Mechanism .....................124

3.2 Research Goal 3 – Synthesis and Reactions of 3,3-Difluoro-2-exo-Methylidene

Indolines ...........................................................................................................................127

3.2.1 Motivation ............................................................................................................127

3.2.2 Contributions........................................................................................................128

3.2.3 Results and Discussion ........................................................................................129

3.3 Chapter Summary ............................................................................................................136

3.4 Experimental ....................................................................................................................136

3.4.1 General Considerations ........................................................................................136

3.4.2 Synthesis of Starting Materials ............................................................................137

3.4.3 Synthesis of 3,3-Difluoro-2-exo-Methylidene Indolines .....................................138

3.4.4 Reactions of 3,3-Difluoro-2-exo-Methylidene Indolines .....................................142

General Conclusions and Outlook ..........................................................................................149

Appendix A – NMRs from Chapter 1 ..........................................................................................150

Appendix B – NMRs from Chapter 2 ..........................................................................................190

Appendix C – HPLC Chromatograms from Chapter 2 ................................................................281

Appendix D – NMRs from Chapter 3 ..........................................................................................288

Appendix E – X-Ray Crystallographic data ................................................................................330

ix

List of Tables

Table 1 Various coupling partners investigated for the synthesis of 2-substituted indoles .......... 13

Table 2 Optimized reaction conditions and effects of reaction parameters .................................. 22

Table 3 Substrate scope for the synthesis of 2-cyanoindoles ....................................................... 25

Table 4 Effects of reaction parameters in the dearomative arylation/heteroarylation of indolesa 61

Table 5 Investigating the substrate scope with respect to the indolea ........................................... 63

Table 6 Investigating the substrate scope with respect to the activated arenesa ........................... 66

Table 7 Epimerization studies and probing of the effects of CuII chloridea ................................. 68

Table 8 Optimization for the enantioselective aryl/borylationa .................................................... 76

Table 9 Ligand screen with the optimized conditionsa ................................................................. 78

Table 10 Examining the scope of the aryl/borylation of indoles .................................................. 81

Table 11 Effects of the reaction parameters in the dearomative fluorination of indolesa ........... 130

Table 12 Examining the scope of the indole fluorination with NFSIa ........................................ 132

x

List of Schemes

Scheme 1 Abundant indoles in biology, pharmaceuticals, and clandestine sources. ..................... 2

Scheme 2 General reactivity of indoles towards electrophiles (SEAr) ........................................... 3

Scheme 3 General reactivity of 3-substituted indoles towards electrophiles (SEAr) ...................... 3

Scheme 4 General reaction scheme for the Fischer indole synthesis ............................................. 4

Scheme 5 Three classic methods for the synthesis of indoles from nitroarenes. Leimgruber–

Batcho, Bartoli, and Reissert indole syntheses. .............................................................................. 5

Scheme 6 Buchwald modification of the Fischer indole synthesis................................................. 7

Scheme 7 Mori-Ban indole synthesis using Pd0 and Hegedus indole synthesis using PdII ............ 7

Scheme 8 Larock indole synthesis and important features of the reaction ..................................... 8

Scheme 9 Intramolecular -arylation of arylimines for the synthesis of 2,3-disubstituted ............ 9

Scheme 10 Synthesis of indoles by an unexpected interception by nucleopalladation ................ 10

Scheme 11 An aqueous Pd0-catalyzed arylation cyclization to 2-arylindoles .............................. 10

Scheme 12 Enantioselective variation of the Cacchi reaction by the use of privileged ligands ... 11

Scheme 13 General scheme for the Fang-Lautens indole synthesis ............................................. 11

Scheme 14 Initial report of indole synthesis using vinylic-gem-dibromides ................................ 12

Scheme 15 The first general method for the Fang-Lautens indole synthesis ............................... 13

Scheme 16 Two possible pathways. (top) kinetically favored E–selective oxidative addition,

arylation, amination. (bottom) Z–selective oxidative addition, amination, arylation ................... 14

Scheme 17 Reaction of proposed intermediates from both pathways to study second step ......... 15

Scheme 18 Proposal for a directed- Z-selective oxidative addition .............................................. 15

xi

Scheme 19 Vinylidene intermediate allowing for an E- to Z- isomerization of the correct oxidative

addition metal-complex. (top) Negatively charged complex. (bottom) Positively charged complex

....................................................................................................................................................... 16

Scheme 20 Transition-state for the Pd-facilitated E- to Z- isomerization .................................... 16

Scheme 21 Productive use of the reversible oxidative addition for the synthesis of 2-bromoindoles

....................................................................................................................................................... 17

Scheme 22 Proposed reaction: Fang-Lautens indole synthesis for the synthesis of 2-cyanoindoles

....................................................................................................................................................... 18

Scheme 23 General Pd-catalyzed cyanation of aryl-(pseudo)halides ........................................... 18

Scheme 24 Examples of biologically interesting compounds which feature 2-cyanoindole derived

core ................................................................................................................................................ 19

Scheme 25 Synthesis of 2-cyanoindoles by C–H activation ........................................................ 19

Scheme 26 Ramirez Olefination for the synthesis of gem-dibromides ......................................... 20

Scheme 27 Ramirez Olefination for the synthesis of gem-dichlorides ......................................... 21

Scheme 28 Selective tin reduction of the nitro moiety to the aniline ........................................... 21

Scheme 29 Reactivity of chloro- and bromo- containing substrates ............................................ 26

Scheme 30 Single-pot transformation of the gem-dibromides to indoles containing a tetrazole

moiety at the 2-position by amination/cyanation/azide-cyclization ............................................. 26

Scheme 31 Subjecting 1.48, a potential intermediate, to the standard reaction conditions .......... 27

Scheme 32 Subjecting 1.62, a potential intermediate, to the standard reaction conditions .......... 27

Scheme 33 Proposed mechanism for the synthesis of 2-cyanoindoles ......................................... 28

Scheme 34 Example of aromatic system vs. anti-aromatic system .............................................. 40

Scheme 35 Simple method for drawing the MO-diagram of benzene -bonds ........................... 40

xii

Scheme 36 Benefits of dearomatization. After dearomatization, -bonds react as simple olefins in

future functionalizations ............................................................................................................... 41

Scheme 37 Birch Reduction products for EDG and EWG substituted aryl-rings ........................ 41

Scheme 38 Mechanism of the Birch Reduction ............................................................................ 42

Scheme 39 Trapping of the final anion intermediate of the Birch Reduction and its use in

Palladium-chemistry as a formal source of HCN ......................................................................... 42

Scheme 40 Modern methods of dearomatization with metal catalysts or oxidants ...................... 43

Scheme 41 Cycloaddition of arenophile, MTAD, with arenes ..................................................... 43

Scheme 42 Typical functionalizations carried out on dearomatized intermediates 2.9 ................ 44

Scheme 43 Palladium-catalyzed Tsuji-Trost type reactivity of intermediate 2.8 ......................... 44

Scheme 44 Push-pull dearomatization of indoles ......................................................................... 45

Scheme 45 Mizoroki-Heck and Interrupted-Heck reactivity ........................................................ 46

Scheme 46 Migratory insertion strategy and interrupted-Heck reactivity .................................... 46

Scheme 47 Intramolecular Mizoroki-Heck Reaction for an efficient route to fused indolines .... 47

Scheme 48 Mechanism proposed for the intramolecular Mizoroki-Heck reaction of N-(2-

halobenzoyl)indoles ...................................................................................................................... 48

Scheme 49 Domino Larock annulation/dearomative Heck reaction of N-(2-iodoaryl)benzamides

....................................................................................................................................................... 49

Scheme 50 Total synthesis of (+)-Hinckdentine A using a key enantioselective dearomative Heck

reaction .......................................................................................................................................... 50

Scheme 51 Reaction conditions reported by Jia for the enantioselective dearomative Heck reaction

of pyrroles ..................................................................................................................................... 50

Scheme 52 Enantioselective reductive Heck-reaction of indoles ................................................. 51

xiii

Scheme 53 Palladium-catalyzed dearomatization of indoles by arylation/borylation then

protodeborylation, or arylation/hydride reduction ........................................................................ 52

Scheme 54 (a) Pd-catalyzed dearomative Heck reaction of indoles by a C-2 tethered arylamide.

(b) Extended chain benzamide dearomatization for dihydrobenzoquinolone formation .............. 53

Scheme 55 Palladium-catalyzed dearomative bisfunctionalization of indoles ............................. 54

Scheme 56 Pd-catalyzed diastereoselective indole 1,2-difunctionalization by a dearomatization

strategy .......................................................................................................................................... 55

Scheme 57 Palladium-catalyzed dearomative bisfunctionalization of indoles. All three examples

are highly diastereoselective ......................................................................................................... 56

Scheme 58 First Pd-catalyzed enantioselective dearomatization by difunctionalization of indoles

via arylation/alkynylation sequence .............................................................................................. 57

Scheme 59 Palladium-catalyzed diastereoselective trapping of the dearomatized benzylic

intermediate with various nucleophiles ........................................................................................ 58

Scheme 60 General reaction studied in research goal 1 ............................................................... 59

Scheme 61 Synthesis of N-benzoyl indoles .................................................................................. 60

Scheme 62 Convergence of diastereomers by the alkylation of 2.63 ........................................... 67

Scheme 63 Dearomative aryl/borylation with palladium ............................................................. 69

Scheme 64 There is a plethora of precedence for the chemical transformation of the C–B bond to

various other atoms ....................................................................................................................... 69

Scheme 65 Miyaura-Borylation of aryl-halides and domino methods ......................................... 70

Scheme 66 Initial racemic aryl/borylation of indoles ................................................................... 71

Scheme 67 Protodeborylation of 2.65a in the presence of inorganic base ................................... 71

Scheme 68 Phosphoramidite ligands and their reaction condition requirements ......................... 72

xiv

Scheme 69 B2Pin2 pre-activation for transmetallation with CsOPiv ............................................ 72

Scheme 70 Copper-catalyzed borylation developed by Santos and coworkers ............................ 73

Scheme 71 Mixed-boron transmetallation and expected byproduct neutralization ...................... 73

Scheme 72 Synthesis of mixed-boron reagent .............................................................................. 74

Scheme 73 General strategy for the synthesis of 3,3’-substituted BINOLs ................................. 74

Scheme 74 O-P-N coupling for the synthesis of phosphoramidite ligands .................................. 75

Scheme 75 Oxidation of the boron-containing product 2.65a ...................................................... 82

Scheme 76 Further oxidation with PCC to the benzylic ketone ................................................... 82

Scheme 77 Fluoro-derivative of cortisone .................................................................................. 117

Scheme 78 The synthesis of anhydrous TBAF by SNAr ............................................................ 119

Scheme 79 The fluorination of chloro- and nitro-arenes with anhydrous NFSI at room temperature

..................................................................................................................................................... 119

Scheme 80 Common N–F reagents............................................................................................. 120

Scheme 81 The synthesis of aromatic and heteroaromatic fluorides by the reaction of Grignard

reagents with NFSI ..................................................................................................................... 121

Scheme 82 Fluorination of aryl-BF3K salts with KF and an internal oxidant ............................ 121

Scheme 83 Palladium-catalyzed C–F bond formation via Pd0/PdII and PdII/PdIV cycles ........... 122

Scheme 84 In situ active catalyst formation by arylation of the charged ligand ........................ 123

Scheme 85 Palladium(II)-catalyzed direct fluorination of C–H bonds ...................................... 123

Scheme 86 Dearomatization of indoles by a push-pull mechanism ........................................... 124

Scheme 87 Dearomative allylation of indoles ............................................................................ 125

xv

Scheme 88 Intramolecular palladium-catalyzed dearomatization of indoles using 3-tethered aryl-

halides as internal electrophiles .................................................................................................. 125

Scheme 89 Fluorine or nitrogen transfer using NFSI ................................................................. 126

Scheme 90 The use of Selectfluor for fluorination and trapping with oxygen nucleophiles ...... 126

Scheme 91 Enantioselective fluorination with NFSI, and trapping with O/N-based nucleophiles

tethered at the 3-position, forming multi-cyclic products ........................................................... 127

Scheme 92 Dearomative fluorination of 2-methylindole ............................................................ 128

Scheme 93 Asymmetric allylic fluoroalkylation/trifluoromethylation ....................................... 128

Scheme 94 Medium-scale synthesis of 3.38a ............................................................................. 131

Scheme 95 Amphoteric properties of 3.38a ................................................................................ 133

Scheme 96 Palladium-catalyzed allylic functionalizationsa ....................................................... 134

Scheme 97 Cu- and Rh- addition/-fluoride elimination ........................................................... 136

xvi

List of Appendices

Appendix A – NMRs from Chapter 1 ..........................................................................................150

Appendix B – NMRs from Chapter 2 ..........................................................................................190

Appendix C – HPLC Chromatograms from Chapter 2 ................................................................281

Appendix D – NMRs from Chapter 3 ..........................................................................................288

Appendix E – X-Ray Crystallographic data ................................................................................330

List of Publications

1. “Synthesis and Reactions of 3,3-Difluoro-2-exo-Methylidene Indolines” Zeidan, N.;

Zambri, M.; Unger, S.; Dank, C.; Torelli, A.; Mirabi, B.; Lautens. M. Org. Lett. 2020, 22,

3688.

2. “Migratory Insertion Strategies for Dearomatization” Zeidan, N.; Lautens, M. Synthesis

2019, 51, 4137.

3. “Pd-catalyzed dearomative arylborylation of indoles” Shen, C.*; Zeidan, N.*; Wu, Q.;

Breuers, C. B. J.; Liu, R.-R.; Jia, Y.-X.; Lautens, M. Chem. Sci. 2019, 10, 3118.

4. “Palladium-Catalyzed Arylation/Heteroarylation of Indoles: Access to 2,3-Functionalized

Indolines” Zeidan, N.; Beisel, T.; Ross, R.; Lautens, M. Org. Lett. 2018, 20, 7332.

5. “Palladium-Catalyzed Synthesis of 2-Cyanoindoles from 2-gem-Dihalovinylanilines”

Zeidan, N.; Bognar, S.; Lee, S.; Lautens, M. Org. Lett. 2017, 19, 5058.

6. “Pd(0)-Catalyzed Dearomative Diarylation of Indoles” Petrone, D. A.; Kondo, M.;

Zeidan, N.; Lautens, M. Chem. Eur. J. 2016, 22, 5684.

7. “Dearomative Indole Bisfunctionalization via a Diastereoselective Palladium-Catalyzed

Arylcyanation” Petrone, D. A.; Yen, A.; Zeidan, N.; Lautens, M. Org. Lett. 2015, 17, 4838.

Abbreviations

Ac acetyl

aq aqueous

Ar aryl

atm atmosphere

ATR attenuated total reflectance

BINAP 1,1-binaphthalene-2,2-diyl)bis(diphenylphosphine)

bipy 2,2’-bipyridyl

Bn benzyl

Boc tert-butoxycarbonyl

BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl

i-Bu isobutyl

n-Bu n-butyl

t-Bu tert-butyl

Bz benzoyl

°C degree Celsius

Cat catechol

cat. catalyst

Cbz carboxybenzoyl

xix

COD 1,5-cyclooctadiene

Conc. concentrated

Conv. conversion

Cy cyclohexyl

d day

DART Direct analysis in real time

DCE 1,2-dichloroethane

DCM dichloromethane

dba dibenzylideneacetone

DG directing group

DMA dimethylacetamide

DMF dimethylformamide

DMSO dimethyl sulfoxide

dppe 1,2-bis(diphenylphosphino)ethane

DTBPF 1,1-bis(di-tert-butylphosphino)ferrocene

DTPF 1,1’-bis(di-o-tolylphosphino)ferrocene

dr diastereomeric ratio

EDG electron donating group

ee enantiomeric excess

equiv molar equivalent

xx

er enantiomeric ratio

ESI electrospray ionization

Et ethyl

EtOAc ethyl acetate

EWG electron withdrawing group

g gram

h hour

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

IR infrared

L generic ligand

LG leaving group

Me methyl

MeCN acetonitrile

min minute

mg milligram

mL milliliter

mmol millimole

mp melting point

MOM methoxymethyl

xxi

MS molecular sieves

MTAD N-methyl-1,2,4-triazoline-3,5-dione

ND not determined

NFSI N-fluorobenzenesulfonimide

MO molecular orbital

Nu nucleophile

NMR nuclear magnetic resonance

OA oxidative addition

OTf trifluoromethanesulfonate

PDC pyridinium dichromate

Ph Phenyl

Pin pinacolato

Piv pivaloyl

PMP para-methoxyphenyl

i-Pr isopropyl

Pyr pyridine

quant. quantitative

R alkyl chain

RE reductive elimination

Rf retardation factor

xxii

rt room temperature

sat. saturated

SEAr electrophilic aromatic substitution

SM starting material

SNAr nucleophilic aromatic substitution

TBAF tetrabutylammonium fluoride

Temp temperature

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

Tol para-tolyl

Ts para-toluenesulfonyl

X halide

Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

1

Chapter 1

Palladium-Catalyzed Synthesis of 2-Substituted Indoles from Vinyl gem-Dibromo Containing Anilines

1.1 Introduction

1.1.1 Ubiquity of Indoles

To describe indoles (1.1) as an important class of heterocycle would be insufficient. Indoles are

ubiquitous; they appear in elementary undergraduate courses teaching the Fischer indole synthesis

as well as advanced topics in modern chemistry describing the various methods by which to

prepare indoles from metal-catalyzed transformations. It is no surprise that the Wikipedia page for

the simple term “indole” features 8 subgroups of detailed information,1 or that a search for the

term “indole” yields 1850 results of related topics.2

The structure of the essential amino acid tryptophan (1.2) features an indole core (Scheme 1). This

amino acid is linked to essential growth in children, as a precursor to serotonin (1.3), as well as a

precursor to many of the alkaloids in bacteria and plants.3 Due to its high bioactivity, the indole

core has been featured in the structures of many pharmaceuticals such as rizatriptan (Maxalt 1.4

by Merck), a medication for treating migraines, and tadalafil (Cialis 1.5 by Eli Lilly), a medication

used to treat erectile disfunction.4

1 https://en.wikipedia.org/wiki/Indole [cited 2019/10/30]

2 https://en.wikipedia.org/w/index.php?search=indole&title=Special%3ASearch&fulltext=1&ns0=1 [cited

2019/10/30] 3 Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.

4 CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2016 [cited 2019/10/30]. Available from:

http://www.e-cps.ca or http://www.myrxtx.ca.

2

Scheme 1 Abundant indoles in biology, pharmaceuticals, and clandestine sources.

The capacity of indolic compounds to stimulate central nervous activity has led to the

popularization of many illicit drugs, as well as spiritual medicines with diverse hallucinogenic

effects. In recent times, many Canadians will travel to South America to experience the effects of

“Ayahuasca”, a traditional brew containing a cocktail of active indoles such as N,N-

dimethyltryptamine (1.6, DMT), providing an intense and relatively short period of

hallucinations.5 Another popular chemical enjoyed by a segment of the population has been those

of psilocybin, 1.7, an active ingredient in certain fungi which users have reported euphoric changes

in their perspective of space and time.6

5 O’Brien, C. CTVNEWS [cited 2019/10/30] Montreal conference will put spotlight on hallucinogenic ayahuasca.

Available from: https://www.ctvnews.ca/health/montreal-conference-will-put-spotlight-on-hallucinogenic-

ayahuasca-1.4633061 6 Passie, T.; Seifert, J.; Schneider, U.; Emrich, H. M. Addict. Biol. 2002, 7, 357.

3

1.1.2 Nucleophilicity of Indoles

Indoles are electron rich heteroaromatics due to the contribution of the nitrogen lone pair into the

aromatic system and hence react by SEAr. Most importantly, indoles react nucleophilically at the

C3–carbon, as opposed to the C2–carbon to avoid dearomatizing the backbone 6-membered ring

(Scheme 2).

Scheme 2 General reactivity of indoles towards electrophiles (SEAr)

This reactivity is so pronounced that even C3-substituted indoles will react in the same way, and

thereafter shift the more stabilized group to the C2 position to rearomatize the system (Scheme 3).

Scheme 3 General reactivity of 3-substituted indoles towards electrophiles (SEAr)

1.1.3 Synthesis of Indoles

1.1.3.1 Classic Synthesis

Of all the methods for indole synthesis, the best understood and extensively utilized is the Fischer

indole synthesis, discovered by Professor Emil Fischer.7 The reaction utilizes cheap and accessible

arylhydrazines 1.8, and aliphatic aldehydes and ketones 1.9, in a condensation in the presence of

an acid catalyst (Scheme 4). The intermediate shown undergoes a [3,3]-sigmatropic rearrangement

to furnish 2,3-difunctionalized indoles 1.10. This method quickly provides access to a library of

7(a) Fischer, E.; Jourdan, F. Berichte der deutschen chemischen Gesellschaft 1883, 16, 2241. (b) Fischer, E.; Hess, O.

Berichte der deutschen chemischen Gesellschaft 1884, 17, 559.

4

indoles quickly however, it is typically limited to ketones which have only one type of -protons.

In most cases, the reaction suffers when sterically congested arylhydrazines are used.

Scheme 4 General reaction scheme for the Fischer indole synthesis

An alternate approach for the synthesis of indoles has been from nitroarenes 1.11 since they contain

many of the atoms necessary for indoles, including the nitrogen atom masked in a higher oxidation

state. Additionally, the activated nature of such arenes allows for simple manipulations (Scheme

5, top). The Leimgruber–Batcho synthesis exploits the reduced pKa of the benzylic protons of an

ortho substituent to deprotonate and subsequently condense the benzyl-anion onto the

dimethylacetal of DMF, thus incorporating all atoms necessary for an indole (1.12).8 A general

reduction of the nitro substituent to the aniline allows for a condensation and aromatization of the

system.

8 Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214.

5

Scheme 5 Three classic methods for the synthesis of indoles from nitroarenes. Leimgruber–

Batcho, Bartoli, and Reissert indole syntheses.

Similarly, the Reissert indole synthesis also traps a benzylic anion but instead with dialkyl oxalate

(1.13). Following reduction of the nitro group, indole-2-carboxylates (1.14) are obtained in good

yield (Scheme 5, middle).9 The Bartoli Indole synthesis utilizes vinyl Grignard reagents to partially

reduce nitroarenes to the O-vinylhydroxylamines which undergo a [3,3]-sigmatropic

rearrangement to the corresponding 7-substituted indoles (Scheme 5, bottom, 1.16).10 There are

many other classic indole synthesis in the literature including: Bischler–Möhlau indole synthesis

9 Reissert, A. Berichte der deutschen chemischen Gesellschaft 1897, 30, 1030.

10 Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tet. Lett. 1989, 30, 2129.

6

(reaction of -bromoarylketones and anilines),11 Cadogan-Sundberg indole synthesis (phosphine

reduction of nitroarenes, cyclization onto adjacent vinyl groups),12 Fukuyama indole synthesis

(AIBN/Bu3SnH mediated radical cyclization of o-isocyanostyrenes),13 Gassman indole synthesis

(reaction of anilines with -thioether ketones),14 Hemetsberger-Knittel indole synthesis (the use

of nitrenes from azide decomposition for indole synthesis),15 Madelung indole synthesis (similar

benzylic deprotonation however on N-acetylanilines then cyclization onto the acetyl group),16

Nenitzescu indole synthesis (reaction of benzoquinone and -aminocrotonicesters, delivers 5-

hydroxyindole derivatives).17

1.1.3.2 Palladium-Catalyzed Indole Synthesis

The past half-century of novel indole synthesis reported in the literature has been dominated by

metal-catalyzed methods, largely due to the discovery of palladium catalyzed approaches.18 One

strategy published by the Buchwald group involved the synthesis of an arylhydrazine surrogate for

a Fischer indole synthesis using a Buchwald-Hartwig amination (

Scheme 6).19

11

(a) Möhlau, R. Ber. 1881, 14, 171. (b) Bischler, A.; Fireman, P. Ber. 1893, 26, 1346. 12

(a) Bunyan, P.J.; Cadogan, J.I.G. Proc. Chem. Soc, 1962, 78. (b) Sundberg, R.J. J. Org. Chem. 1965, 30, 3604. 13

Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791. 14

Gassman, P. G.; Van Bergen, T. J.; Gruetzmacher, G. J. Am. Chem. Soc. 1973, 95, 6508. 15

Hemetsberger, H.; Knittel, D. Monatshefte für Chemie. 1972, 103, 194. 16

Madelung, W. Berichte der deutschen chemischen Gesellschaft 1912, 45, 1128. 17

Nenitzescu, C. Bull. Soc. Chim. Romania 1929, 11, 37. 18

(a) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469. (b) Mancuso, R.; Dalpozzo, R. Catalysts 2018, 8, 458. (c)

Molnar, A. Chem. Rev. 2011, 111, 2251. 19

(a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6621. (b) Wagaw, S.; Yang, B. H.;

Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251.

7

Scheme 6 Buchwald modification of the Fischer indole synthesis

The diarylhydrazine 1.18 is hydrolyzed, condenses onto a ketone, then undergoes the [3,3]-

sigmatropic rearrangement to deliver the desired indole product (1.19).

Other notable methods of palladium catalyzed indole synthesis involve the use of olefin reactivity

with Pd0 (Mizoroki-Heck-like-reactivity) or PdII (Wacker-like-reactivity), popularized by Mori

and Ban,20 and Hegedus21 respectively (Scheme 7).

Scheme 7 Mori-Ban indole synthesis using Pd0 and Hegedus indole synthesis using PdII

20

(a) Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1803. (b) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977,

18, 1037. (c) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711. 21

Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674.

8

In the Mori-Ban indole synthesis, ortho-halo substrates 1.23 are used as an entry point for Pd0

oxidative addition (1.24), 5-exo-trig migratory insertion (1.25), -hydride elimination, and

rearomatization generates indole products 1.1 (for an in-depth view at the Mizoroki Heck Reaction,

see section 2.1.3.2 on page 45). The Hegedus approach involves the use of PdII activation of the

olefin 1.21 towards nucleophilic attack of the aniline nitrogen, -hydride elimination, and

isomerization generates the indole products 1.1. Reoxidation of the Pd0 catalyst is necessary for

turnover (typically achieved with CuII or benzoquinone).

One of the most widely used methods is the Larock indole synthesis discovered in 1991 by Richard

C. Larock (Scheme 8).22 The power of the reaction comes from its generality and use of simple

starting materials. An anionic palladium mechanism is proposed since the use of chloride is

required (potentially generating [Pd0-Cl]– species). The reaction tolerates a number of chloride

sources, bases, and internal alkyne coupling partners.

Scheme 8 Larock indole synthesis and important features of the reaction

Ortho-haloanilines, 1.26, are used in a reaction that involves the oxidative insertion of a Pd0

catalyst into the C–X bond, and a regioselective migratory insertion into internal alkynes

generating the 6-membered palladacycle 1.27. The regioselectivity is steric driven; the larger

22

Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.

9

group is placed at the carbon destined to become the C–2 position due to the clashing of the new

C-C bond during the carbopalladation step.23

The area of palladium-catalyzed indole synthesis continues to grow and shown below are some

highlights of the recent literature of such reactions. Nolan and coworkers reported a convenient

synthesis of free indoles and diverse azaindoles using an -arylation strategy of arylimines 1.29

(Scheme 9).24

Scheme 9 Intramolecular -arylation of arylimines for the synthesis of 2,3-disubstituted

The authors use an electron-rich and sterically hindered NHC-palladium catalyst to access various

heterocycles in good to excellent yields. The ability of the catalyst to tolerate azaindoles is

interesting and unusual, demonstrating the power of this reaction.

In their attempt to explore an intramolecular Heck reaction of 1.31 to generate large-ring

benzo[1,4]heterocycles, Gharpure observed a competitive nucleopalladation/retro-oxa-Michael

generating N-alkylindoles (Scheme 10).25

23

Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652. 24

Marelli, E.; Corpet, M.; Minenkov, Y.; Neyyappadath, R. M.; Bismuto, A.; Buccolini, G.; Curcio, M.; Cavallo, L.;

Nolan, S. P. ACS catalysis 2016, 6, 2930. 25

Gharpure, S. J.; Anuradha, D. Org. Lett. 2017, 19, 6136.

10

Scheme 10 Synthesis of indoles by an unexpected interception by nucleopalladation

Rather than undergoing a 7-exo-trig carbopalladation, the PdII oxidative addition complex 1.32

undergoes a nucleopalladation/reductive elimination. The oxazole intermediate formed then

undergoes a ring opening by retro-oxa-Michael.

Scheme 11 An aqueous Pd0-catalyzed arylation cyclization to 2-arylindoles

An interesting aqueous PdII-catalyzed synthesis of indoles is reported by Cheng and Chen (Scheme

11).26 The utility of the reaction come from its use of a reliable arylation of simple aryl

acetonitriles, providing the atom-blueprint for a cyclization of the adjacent aniline to deliver 2-

arylindoles (1.36).

26

Yu, S.; Hu, K.; Gong, J.; Qi, L.; Zhu, J.; Zhang, Y.; Cheng, T.; Chen, J. Org. Biomol. Chem. 2017, 15, 4300.

11

In a 2019 report by Zhu, axially chiral indoles are synthesized using an enantioselective PdII

variation of the Cacchi Reaction (Scheme 12).27

Scheme 12 Enantioselective variation of the Cacchi reaction by the use of privileged ligands

The authors screened privileged ligands and found that QuinoxP* promotes the reaction in good

yields and enantioselectivity. Due to the anti-nature of the nucleopalladation suggested for this

reaction, it is likely that the enantiodetermining step might be the pre-coordination of the metal-

complex to the alkyne, before cyclization (similarly to intermediate 1.21).

1.1.4 Fang-Lautens Indole Synthesis

The general scheme for the Fang-Lautens indole synthesis is shown below (Scheme 13). Various

nucleophiles have been used and will be discussed within this section.

Scheme 13 General scheme for the Fang-Lautens indole synthesis

27

He, Y. P.; Wu, H.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2019.

12

1.1.4.1 The Discovery of the Reaction

Near the turn of the century, the usefulness of gem-dibromo compounds was already becoming

apparent,28 though it wasn’t until 2004 that Bisseret and coworkers reported two examples of a

palladium-catalyzed tandem reaction of ortho-vinylic-gem-dibromoanilines with nucleophiles,

generating substituted indoles (Scheme 14).29

Scheme 14 Initial report of indole synthesis using vinylic-gem-dibromides

The first reported reaction used diethylphosphite for the synthesis of diethyl indole-2-phosphonate

(top) and the second uses para-methoxyphenylboronic acid for a Suzuki-Miyaura trap, forming 2-

arylindole (bottom). Lautens and Fang independently reported a general version of the indole

synthesis, capable of tolerating various electronic and steric perturbations on the anilines, as well

as any aryl, heteroaryl, vinyl, and alkyl boronic acids (Scheme 15).30 The authors attribute the

excellent reactivity of the catalyst system to SPhos, a bulky and electron rich ligand novel at the

time.31

28

(a) Zapata, A. J.; Rúiz, J. J. Organomet. Chem. 1994, 479, c6. (b) Shen, W.; Thomas, S. A. Org. Lett. 2000, 2,

2857. 29

Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907. 30

(a) Fang, Y. Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538. 31

Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871.

13

Scheme 15 The first general method for the Fang-Lautens indole synthesis

Over the next decade, many groups investigated other possible coupling partners for the modular

synthesis of 2-substituted indoles using these substrates (Table 1). Intermolecular and

intramolecular Heck and Sonogashira traps were developed shortly after the first report.32 Alper

and coworkers as well as Pontikis and Florent developed protocols for the carbonylation and

trapping of indoles.33 Lan and coworkers developed an interesting direct heteroarylation using

activated heterocycles, generating bi-heteroaryl products.34

Table 1 Various coupling partners investigated for the synthesis of 2-substituted indoles

Coupling partner Product Group

Lautens (2006)

Lautens (2007)

Alper (2008)

32

Fayol, A.; Fang, Y. Q.; Lautens, M. Org. Lett. 2006, 8, 4203. (b) Nagamochi, M.; Fang, Y. Q.; Lautens, M. Org.

Lett. 2007, 9, 2955. 33

(a) Vieira, T. O.; Meaney, L. A.; Shi, Y. L.; Alper, H. Org. Lett. 2008, 10, 4899. (b) Arthuis, M.; Pontikis, R.;

Florent, J. C. Org. Lett. 2009, 11, 4608. 34

Qin, X.; Cong, X.; Zhao, D.; You, J.; Lan, J. Chem. Commun. 2011, 47, 5611.

14

Pontikis and Florent (2009)

Lan (2011)

1.1.4.2 The Mechanistic Conundrum

Bisseret and coworkers made an important remark about the mechanism of the reaction; the

oxidative addition of the E- C–Br bond is kinetically favored (1.45).29 This selective oxidative

addition has also been explored by others.35 This leads to their proposed mechanism that the

arylation should occur first, generating intermediate 1.46, which then undergoes a cycloamination,

generating 2-aryl indoles (Scheme 16, top, 1.36).

Scheme 16 Two possible pathways. (top) kinetically favored E–selective oxidative addition,

arylation, amination. (bottom) Z–selective oxidative addition, amination, arylation

Lautens and coworkers synthesized the two possible intermediates 1.46 and 1.48, and subjected

them to the reaction conditions to assess their role in the reaction (Scheme 17).30 It was found that

substrate 1.46 produced small amounts of double arylated product 1.49, which was never observed

35

Zapata, A. J.; Rúiz, J. J. Organomet. Chem. 1994, 479, c6.

15

in any other studies, casting doubt on the possibility of the arylation/amination mechanism.

Intermediate 1.48 however produced exclusively the desired indole 1.36 in excellent yield.

Scheme 17 Reaction of proposed intermediates from both pathways to study second step

Various mechanisms have been proposed for this apparent formal Z-selective oxidative addition.

It is possible the selectivity of the oxidative addition is influenced by the ortho-heteroatom in a

directed oxidative addition however, in this case, it is unlikely the soft, electron-rich Pd0–complex

would coordinate to the hard-donor (Scheme 18).36

Scheme 18 Proposal for a directed- Z-selective oxidative addition

Other possibilities discussed include a charge-separated metal vinyl carbene intermediate (Scheme

19), by either donation of the aniline (top) or a stabilized benzylic anion (bottom).37

36

(a) Pearson, R. G. J. Chem. Ed. 1987, 64, 561. (b) Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 113.

(c) Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748. (d) Tudor, R.; Ashley, M. Platin. Met. Rev. 2007, 51, 116.

(e) Deangelis, A.; Colacot, T. J. in RSC Catalysis Series, Vol. 2015 (ed. T. J. Colacot), The Royal Society of Chemistry,

Cambridge, 2015, pp. 20–90. 37

(a) Brady, K. A.; Nile, T. A. J. Organomet. Chem. 1991, 206, 299. (b) Zargarian, D.; Alper, H.

16

Scheme 19 Metal vinyl carbene intermediate allowing for an E- to Z- isomerization of the

correct oxidative addition metal-complex. (top) Negatively charged complex. (bottom) Positively

charged complex

Recent computational work on Pd-assisted E- to Z- isomerization on vinyl-iodides, supported by

experimental evidence, suggest that the isomerization may not be via a defined metal carbene

intermediate (Scheme 20).38

Scheme 20 Transition-state for the Pd-facilitated E- to Z- isomerization

The transition state is described by three important characteristics: the Pd–C bond is twisted

slightly out of plane, the Pd–C bond is shortened slightly, the C=C bond is lengthened slightly.

The changes in bond lengths however were very minute. The authors concluded, both

computationally and experimentally, that the sequence of E-selective oxidative

Organometallics, 1991, 10, 2914. (c) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A. Organometallics 2004,

689, 4642. (d) Tanke, R. S.; Crabtree, R. H. J. Am. Chem. Soc. 1990, 112, 7984. (e) Chung, L. W.; Wu, Y.-D.; Trost,

B. M.; Ball, Z. T. J. Am. Chem. Soc. 2003, 125, 11578. 38

Petrone, D. A.; Franzoni, I.; Ye, J.; Rodriguez, J. F.; Poblador-Bahamonde, A. I.; Lautens, M. J. Am. Chem. Soc.

2017, 139, 3546.

17

addition/isomerization was kinetically favoured compared to Z-selective oxidative addition. In a

separate computational study by Lautens and Schoenebeck, a palladium-facilitated Cis to Trans

isomerization was found to have only minor charge build up in the transition state. The lack of

bond length change as well as charge build up suggest that a long-lived metal vinyl carbene species

is not an intermediate in these isomerizations.39

1.1.4.3 Reversible Oxidative Addition

Oxidative addition has historically been considered an irreversible process when it comes to aryl-

halides and palladium catalysts. Hartwig and coworkers published a series of mechanistic

investigations into this process, and it was found that the use of excess bulky ligand favoured a

reductive elimination of the C–X bond.40 From this observation, a practical use of the reversible

oxidative addition was demonstrated by Lautens and Newman in the synthesis of 2-bromoindoles

by means of the Fang-Lautens indole synthesis using bulky phosphine ligands (Scheme 21)002E41

Scheme 21 Productive use of the reversible oxidative addition for the synthesis of

2-bromoindoles

39

Sperger, T.; Le, C. M.; Lautens, M.; Schoenebeck, F. Chem. Sci. 2017, 8, 2914. 40

(a) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232. (b) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc.

2003, 125, 13944. (c) Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 1533. 41

(a) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M. Chem. Commun. 2009, 5236. (b) Newman, S. G.;

Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416.

18

The authors were able to run an intramolecular Buchwald-Hartwig amination even in the presence

of a C–I bond, as well as in the presence of product 1.51 which could sequester the catalyst as 1.52

or 1.53.

1.2 Research Goal

1.2.1 Motivation

The first research goal of this thesis was to develop a protocol for the synthesis of 2-cyanoindoles

using the Fang-Lautens indole synthesis,42 as the products would possess a versatile handle for

future transformations (Scheme 22).

Scheme 22 Proposed reaction: Fang-Lautens indole synthesis for the synthesis of 2-cyanoindoles

Metal-catalyzed cyanation of aromatic and heteroaromatic compounds has been an important

research objective, as the nitrile functionality serves as a versatile synthetic handles for functional

group manipulation.43 The d10 transition-metals have been the most commonly used catalysts for

cyanation by cross-coupling; C–X bonds could be transformed to C–CN bonds by means of

oxidative addition and trapping with a source of [CN]– (Scheme 23).

Scheme 23 General Pd-catalyzed cyanation of aryl-(pseudo)halides

Ionic sources of cyanide such as NaCN, KCN, and Zn(CN)2 require polar aprotic solvents. The

biggest challenge faced with palladium-catalyzed cyanation reactions is catalyst poisoning by the

irreversible formation of inactive complexes. This is typically the result of binding an excess

42

Zeidan, N.; Bognar, S.; Lee, S.; Lautens, M. Org. Lett. 2017, 19, 5058. 43

(a) Cohen, D. T.; Buchwald, S. L. Org. Lett. 2015, 17, 202. (b) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009,

351, 3027. (c) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049.

19

amount of cyanide on the metal-center. This is further discussed in the context of the Fang-Lautens

indoles synthesis below.

Derivatives of 2-cyanoindoles exhibit high bioactivity and can be identified in many natural

products and pharmaceutical agents (Scheme 24).44

Scheme 24 Examples of biologically interesting compounds which feature 2-cyanoindole

derived core

Some recent methods for the synthesis of 2-cyanoindoles have utilized Rh,45 Pd,46 Cu,47 Co,48 or

Mn/Zn49 as catalysts to activate the C–H bond in the 2-position of indoles for cyanation (Scheme

25). These methods allow the direct functionalization of indoles however, the use of specific

directing groups, usually pyrimidine, are removed under harsh basic reflux.

Scheme 25 Synthesis of 2-cyanoindoles by C–H activation

44

(a) Almagro, L.; Fernandez-Perez, F.; Pedreno, M. A. Molecules 2015, 20, 2973. (b) Borza, I.; Kolok, S.; Galgoczy,

K.; Gere, A.; Horvath, C.; Farkas, S.; Greiner, I.; Domany, G. Bioorg. Med. Chem. Lett. 2007, 17, 406. 45

(a) Mishra, N. K.; Jeong, T.; Sharma, S.; Shin, Y.; Han, S.; Park, J.; Oh, J. S.; Kwak, J. H.; Jung, Y. H.; Kim, I. S.

Adv. Synth. Catal. 2015, 357, 1293. (b) Chaitanya, M.; Anbarasan, P. J. Org. Chem. 2015, 80, 3695. 46

Xu, S.; Huang, X.; Hong, X.; Xu, B. Org. Lett. 2012, 14, 4614. 47

Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Chem. - Eur. J. 2013, 19, 16880. 48

Li, J.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 3635. 49

Liu, W.; Richter, S. C.; Mei, R.; Feldt, M.; Ackermann, L. Chem. - Eur. J. 2016, 22, 17958.

20

The extension of the Fang-Lautens indole synthesis for cyanation would be a valuable addition to

the literature as it can both generate the indole core and add functionality in a single step without

the need for a directing group.

1.2.2 Contributions

The results presented were obtained in collaboration with Sabine Bognar (visiting master’s student

from Germany) and Sophia Lee (undergraduate students from the University of Toronto). I

conceived the idea, directed the project, and executed most of the experiments. Sophia Lee assisted

in the optimization of the reaction and substrate synthesis. Sabine Bognar focused on synthesizing

substrates and assisted on exploring the scope of the reaction. Specific contributions are listed

within the text as well as within the experimental section.

1.2.3 Results and Discussion

1.2.3.1 Starting Material Synthesis

The synthesis of the gem-dihaloanilines is straightforward and is typically achieved in high yields

using the Ramirez Olefination (Scheme 26).50 The gem-dichlorides are also accessed in the same

way using chloroform as the surrogate of CCl2 (Scheme 27).

Scheme 26 Ramirez Olefination for the synthesis of gem-dibromides

50

Desai, N. B.; McKelvie, N.; Ramirez, F. J. Am. Chem. Soc. 1962, 84, 1745.

21

Scheme 27 Ramirez Olefination for the synthesis of gem-dichlorides

One improvement to the Ramirez-olefination was published by the Lautens group, which applies

the Horner-Wadsworth-Emmons modification by using P(Oi-Pr)3.51 This allows for a simplified

purification of the products by aqueous workup, and avoiding the tedious purification step from

the usual triphenylphosphine oxide byproduct.

The aniline is then accessed by reduction of the nitro group, most commonly achieved on large-

scale by SnCl2 in EtOH (Scheme 28). Other important methods used for the nitro-selective

reduction (leaving the gem-dibromide intact), have been Fe0–reductions, with FeCl3 catalyst, and

vanadium-doped platinum-catalyzed hydrogenation.

Scheme 28 Selective tin reduction of the nitro moiety to the aniline

1.2.3.2 Optimization

We began our studies with conditions similar to those previously reported41b and the use of

Zn(CN)2 as the cyanide source. The use of the bulky ligand allows both the monitoring of the 2-

bromoindole intermediate (since this ligand allows for reversible oxidative addition into 1.48) as

well as minimizing over coordination of cyanide ion (vide infra). After screening reaction

parameters, we found Pd(t-Bu3P)2 (5 mol %), Zn(CN)2 (0.55 equiv), Zn(TFA)2 (10 mol %) and

K3PO4 (2 equiv) in PhMe–DMA (3:1) at 110 °C for 18 h at 0.5 mmol scale to be our optimal

conditions for the preparation of 1.61 in 74% yield (Table 2, entry 1).

51

Lautens, M.; Fang, Y.-Q.; Lifchits, O. Synlett 2008, 2008, 413.

22

Table 2 Optimized reaction conditions and effects of reaction parameters

Entry Change to standard condition Conv (%) 1.61 (%) 1.48 (%)

1 None Full 74 –

2 Double the scale Full 73 –

3 Dichloride instead of dibromide Full 78 –

4 No Zn(TFA)2 92 55 5

5 Zn dust instead of Zn(TFA)2 85a 58a –

6b Zn(OAc)2 instead of Zn(TFA)2 Fullc 42 –

7b No DMA Full 15 70

8b PhMe–DMA (1:1) 46 11 –

aAverage for 3 runs, 40–70% yield. bYield determined by 1H NMR from crude using 1,3,5-trimethoxybenzene as

internal standard. cLarge amounts of 3 isolated (42%).

The reaction was run on 1 mmol scale with no change in yield (Table 2, entry 2). The use of the

gem-dichloride is possible, delivering the product in comparable yield (Table 2, entry 3). When no

additive was used, the reaction was irreproducible and failed to fully consume all of the starting

material (Table 2, entry 4). Grushin and Macgregor have recently described the modes of

23

Pd-catalyst deactivation during cyanation by presence of air, water, amines, and excess cyanide.52

Limited reports on the use of Zn(0) and Zn(OAc)2 to improve catalytic turnover are available.53

When Zn(0) was used, improved conversion was observed but the reaction remained

irreproducible with variance in yields up to 30% in parallel reactions (Table 2, entry 5). The use

of Zn(OAc)2 was detrimental to the reaction, and large amounts of a bromoalkyne 1.62 was

produced presumably by base-promoted hydrodebromination (Table 2, entry 6). The

trifluoroacetate variant was used to reduce the basicity of the acetate counter-ion to prevent the

elimination from occurring. Zn(TFA)2 led to full consumption of the starting material and the

highest yield consistently. Although the role of the additive is unclear, it may facilitate

transmetallation, thus partially regulating the amount of free cyanide in solution.

The solvent ratio was carefully selected to accommodate the opposing polarity requirements for

cyclization and cyanation as they necessitate the use of non-polar and polar conditions,

respectively. In the absence of DMA as a co-solvent, full consumption of the starting material is

achieved however, cyanation is retarded and 1.48 is the major product (Table 2, entry 7). The

bromoindole is a likely intermediate in the reaction (vide infra) suggesting the cyanation is slower.

We reason the lower reactivity to be the result of poor Zn(CN)2 solubility in PhMe.52 In contrast,

poor conversions were observed in a 1:1 solvent ratio (Table 2, entry 8). Only 1.61 was observed

suggesting cyanation of 1.48 occurred rapidly but with poor catalytic turnover. A 3:1 solvent ratio

was found to be ideal for a consecutive cyclization/cyanation. We believe this may also moderate

the amount of Zn(CN)2 present in solution throughout the reaction, hence slowing the formation

of catalytically inert, coordinatively saturated palladium complexes. DMA proved better than other

polar solvents such as THF or MeCN due to its high boiling point. Reactions with DMF yielded

greater amounts of 1.62 as a byproduct, presumably by solvent decomposition at high

temperatures.54

52

Erhardt, S.; Grushin, V. V.; Kilpatrick, A. H.; Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc.

2008, 130, 4828. 53

(a) Ramnauth, J.; Bhardwaj, N.; Renton, P.; Rakhit, S.; Maddaford, S. P. Synlett 2003, 2237. (b) Chidambaram, R.

Tetrahedron Lett. 2004, 45, 1441. 54

Petrone, D. A.; Yen, A.; Zeidan, N.; Lautens, M. Org. Lett. 2015, 17, 4838.

24

1.2.3.3 Exploring the Substrate Scope

With optimized conditions in hand, we proceeded to investigate the scope of the transformation

(Scheme 3). Extending the aromatic system to the naphthyl ring delivered product 1.61b with no

change in yield (74%). Alkyl substitution adjacent to the aniline or the vinyl dibromide delivered

products 1.61c and 1.61d in 71% and 69% yield respectively. Alkyl and benzyl groups on the

aniline nitrogen provided the N-caped indoles in similar yield (1.61e-g, 72%, 72%, 77%), even

when a sterically demanding isopropyl group was used. Placing an electron-donating OMe at the

para position relative to the aniline gave an improved yield (1.61h, 77%), presumably by

increasing the nucleophilicity of the nitrogen.

In contrast, an electron-withdrawing substituent para to the aniline, as in 1.61i and 1.61j bearing

CO2Me and F necessitated slightly higher catalyst loading and higher temperature to achieve full

consumption, delivering products in 48% and 67%, respectively. An opposite trend was found

when studying electronic-effects at the position para relative to the olefin. While the methoxy

substituent required forcing conditions to deliver product 1.61k in 68% yield, the methyl ester

proceeded smoothly to afford product 1.61l in 75%. Fluorine substitution led to the desired product

1.61m albeit in reduced yield (61%). Having similar electronic properties to 1.41h, reaction of

1.41n proceeded smoothly to 1.61n in slightly improved yield (77%). Interestingly, the highly

electron-rich nature of the scaffold bearing the dioxolane ring was more challenging and provided

1.61o albeit in reduced yields (53%). The reaction selectively underwent the desired reaction with

a chlorine substituent para- to the nitrogen (1.61p), leaving a tangible, heteroaryl C–X bond for

future derivatization (Scheme 29, top).

25

Table 3 Substrate scope for the synthesis of 2-cyanoindoles

1.61b (74%)

1.61c (71%)a

1.61d (69%)

1.61e (72%)a

1.61f (72%)

1.61g (77%)

1.61h (77%)

1.61i (48%)a,b

1.61j (67%)a,b

1.61k (68%)

1.61l (75%)a

1.61m (61%)

1.61n (77%)

1.61o (53%)b

1.61p (70%)

1.61q (61%)b,c

aReaction, workup, and/or purification was run by Sabine Bognar. bPd(t-Bu3P)2 (7.5 mol%), Zn(TFA)2 (15 mol%),

120 °C. cFrom 4-bromo-2-(2,2-dibromovinyl)-aniline using Zn(CN)2 (2.2 equiv).

26

Scheme 29 Reactivity of chloro- and bromo- containing substrates

Contrarily, Br-containing scaffold 1.41q led to a complex mixture, possibly due to a competing

cyanation of the aryl ring. Increasing the Zn(CN)2 loading to 2.2 equivalents afforded 1.61q in

satisfactory yield (Scheme 29, bottom).

1.2.3.4 Derivatization of the Product

To show the synthetic versatility of these products, a one-pot derivatization has been demonstrated

(Scheme 30). Upon completion of the Pd-catalyzed cyclization/cyanation, NaN3 and NH4Cl were

added into the vial and upon heating for 14 h, 1.63 was isolated in 65% yield.

Scheme 30 Single-pot transformation of the gem-dibromides to indoles containing a tetrazole

moiety at the 2-position by amination/cyanation/azide-cyclization

27

1.2.3.5 Mechanistic Investigation

To further evaluate the mechanism of the transformation and gain insight on the roles of the

observed species, 1.48 and 1.62 were synthesized. Subjecting 1.48 to the standard conditions

delivered the desired product in 93% yield (Scheme 31).

Scheme 31 Subjecting 1.48, a potential intermediate, to the standard reaction conditions

This result supports the proposal that the reaction proceeds via the formation of 1.48. In contrast,

when 1.62 was subjected to the same conditions, 60% of unreacted material was recovered with

no other compounds identified (Scheme 32). This result suggests 1.62 is part of a non-productive

decomposition pathway leading to loss in mass-balance under these conditions.

Scheme 32 Subjecting 1.62, a potential intermediate, to the standard reaction conditions

We sought to investigate the order of events; the possibility of cyanation occurring prior to

cyclization. Although we have never observed these products in reactions carried out to partial

conversions, this sequence remains a plausible pathway since oxidative addition of a catalyst

across the C–(E)-Br bond would give the kinetically favored product. Selective coupling of the C–

(E)-Br with boronic acids is known,30 however, any attempts55 to cyanate by selective cross-

coupling led to full recovery of unreacted starting material. The difficulty of the cyanation using

55

Catalyst such as Pd, Ni and Cu were used with varying ligands and Zn(CN)2 or KCN as the cyanide source. Along

with 1a, gem-vinyldihalides with ortho-nitro functionality and dimethyl-protected aniline was used. All reactions led

to recovery of starting material.

28

metal-catalyzed methods raises doubt about cyanation occurring prior to cyclization however, the

oxidative addition and isomerization mechanism remains the most likely.

1.2.3.6 Proposed Mechanism

A plausible mechanism for the reaction is shown in Scheme 33. Oxidative addition into the E-C–

Br bond of 1.41, and isomerization provides the stabilized palladacycle. Deprotonation of the

aniline and reductive elimination provides 1.48. Oxidative addition into the C2–Br bond,

transmetallation from a zinc species and reductive elimination delivers 1.61a and regenerates the

catalyst. Aside from the transmetallation step, the evidence discussed in this chapter suggests that

all steps of the cycle are reversible.

Scheme 33 Proposed mechanism for the synthesis of 2-cyanoindoles

1.3 Chapter Summary

In conclusion, we have developed a convenient method for the synthesis of 2-cyanoindoles from

easily accessible aniline precursors. This reaction utilizes an additive which maintains catalytic

activity, and a solvent mixture which limits the cyanide concentration in the reaction phase to

29

prevent catalyst poisoning. Finally, the versatility of the products was demonstrated by extending

the protocol to a one-pot transformation of the nitrile to the tetrazole.

1.4 Experimental

1.4.1 General Considerations

Unless otherwise stated all reactions were run under an atmosphere of argon in oven or flame dried

glassware. Catalytic reactions were run in 3-dram vials with open-top caps fitted with a Teflon

septum. Reactions were monitored by thin-layer chromatography (TLC) on EMD Silica Gel 60

F254 plates and visualized under UV light or by immersion in potassium permanganate (KMnO4)

stain. Flash column chromatography was performed on Silicycle 40-60 m silica gel and in the

case of 2-cyanoindoles, the silica was suspended in 5% NEt3 in hexanes before loading the column.

PhMe was distilled over CaH. DMA was purchased from Sigma-Aldrich in a Sure/Seal bottle and

used without further purification. Pd(t-Bu3P)2 was purchased from Johnson Matthey. All reagents

and organic building blocks were purchased from commercial supplier (Sigma Aldrich, Strem,

Alfa Aesar, TCI, Combi-blocks) and used without further purification.

1H and 13C NMR spectra were obtained on the Agilent DD2 500 equipped with a 5mm Xsens Cold

Probe. The spectra were internally referenced to the solvent peak. 19F NMR spectra were obtained

on the Varian Mercury 400 or 500 operating at 470 or 564 MHz. Measurements were taken at 296

K and chemical shifts are reported in parts per million (ppm). Data is reported in the following

format: chemical shift ( ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet), coupling constant (Hz), integration. Melting points were measured on a Fischer-Johns

Melting Point Apparatus and are uncorrected. High resolution mass spectra (HRMS) were obtained

on a Micromass 70S-250 spectrometer (EI) or an ABI/Sciex QStar Mass Spectrometer (ESI) or a

JEOL AccuTOF model JMS-T1000LC mass spectrometer equipped with an IONICS® Direct

Analysis in real Time (DART) ion source.

1.4.2 Synthesis of Starting Materials

1.4.2.1 Synthetic Remarks

Compounds 1.41a–1.41d, 1.41f, 1.41g, 1.41i, 1.41j, 1.41l, and 1.41m were synthesized according

to literature procedure.30 Compound 1.41e was synthesized according to literature procedure.32b

30

Compound 1.41p and 1.41o were synthesized according to literature procedure.56 Compound

1.41n was synthesized according to literature procedure.57 Compound 1.41q was synthesized

according to literature procedure.41b

1.4.2.2 General Procedure for the Synthesis of 2-gem-Dihaloanilines

To a solution of nitrobenzaldehyde (9.07 g, 60 mmol, 1 equiv) and CBr4 (29.85 g, 90 mmol, 1.5

equiv) in DCM (300 ml, 0.2 M with respect to the aldehyde) at 0 °C was added a solution of PPh3

(47.21 g, 180 mmol, 3 equiv) in DCM (200 ml, 0.9 M) dropwise over a 30-minute period,

maintaining the temperature under 5 °C. The reaction was stirred for 30 min before warming to r.t.

and stirred for an additional 30 min. Consumption of the starting material was monitored by TLC.

The reaction was filtered through a short pad of silica gel, eluting with 10% EtOAc in hexanes

until all product was collected as monitored by TLC to reduce the amount of triphenylphosphine

oxide present. The crude was concentrated to an oil, taken up into EtOH (200 ml, 0.3 M) and was

added SnCl2⸳H2O (67.7 g, 300 mmol, 5 equiv). The reaction was refluxed at 90 °C for 45 min,

cooled, and was basified using K2CO3 to pH 10. The aqueous layer was extracted 5 times with

EtOAc, and the organic layer was washed with H2O, brine and dried over Na2SO4. The product

was purified by silica gel flash chromatography.

1.4.2.3 Characterization Data for New Compounds

2-(2,2-dibromovinyl)-4-methoxyaniline (1.41h) – The compound was

synthesized according to General Procedure 1.4.2.2 using 5.4 mmol of the

aldehyde. The product was purified by flash chromatography using hexanes–

EtOAc (5:1, v:v) as the mobile phase and was isolated as an off-white solid

(901.1 mg, 2.935 mmol, 76%, mp = 66–67 °C). 1H NMR (500 MHz, CDCl3) δ 7.35 (s, 1H), 6.91

(d, J = 2.9 Hz, 1H), 6.78 (dd, J = 8.7, 2.9 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 3.76 (s, 3H). 13C NMR

56

Gupta, S.; Koley, D.; Ravikumar, K.; Kundu, B. J. Org. Chem. 2013, 78, 8624. 57

Yuen, J.; Fang, Y. -Q.; Lautens, M. Org. Lett. 2006, 8, 653.

31

(125 MHz, CDCl3) δ 152.4, 137.1, 133.9, 122.8, 117.4, 116.2, 113.8, 92.7, 55.8. IR (thin film, cm-

1) 3439, 3360, 2996, 2947, 2907, 2830, 1609, 1497, 1464, 1427. HRMS (DART, M+1) Calculated

for C9H10Br2NO 305.9129, found 305.9126.

2-(2,2-dibromovinyl)-5-methoxyaniline (1.41k) – The compound was

synthesized according to General Procedure 1.4.2.2 using 3.84 mmol of the

aldehyde. The product was purified by flash chromatography using hexanes–

EtOAc (9:1, v:v) as the mobile phase and was isolated as an off-white solid

(949 mg, 3.09 mmol, 58%, mp = 59–60 °C). 1H NMR (500 MHz, CDCl3) δ 7.44 – 6.99 (m, 2H),

6.37 (d, J = 8.7 Hz, 1H), 6.21 (s, 1H), 3.97 – 3.55 (m, 5H). 13C NMR (125 MHz, CDCl3) δ 160.6,

145.1, 133.3, 130.1, 114.4, 104.1, 100.6, 91.0, 54.9. IR (thin film, cm-1) 3464, 3377, 3207, 2997,

2959, 2936, 2835, 1612, 1566, 1462. HRMS (DART, M+1) Calculated for C9H10Br2NO 305.9129,

found 305.9127.

1.4.3 Palladium-Catalyzed Synthesis of 2-Cyanoindoles

1.4.3.1 General Procedure for the Substrate Scope

To an oven dried 3-dram vial, substrate (0.5 mmol, 1 equiv), Zn(CN)2 (32.3 mg, 0.275 mmol, 0.55

equiv), Zn(TFA)2 (14.6 mg, 0.05 mmol, 10 mol %), and K3PO4 (212.3 mg, 1 mmol, 2 equiv) were

added. After the vial was purged with Ar for 5 min, 1 ml of PhMe and 1 ml of DMA was added.

To a second oven dried vial, Pd(t-Bu3P)2 (12.8 mg, 0.025 mmol, 5 mol %) was added and purged

with Ar for 5 min. The catalyst was dissolved in 2 ml of PhMe and the solution was transferred to

the substrate mixture. The reaction was stirred at 1000 rpm and 110 °C for 18 h. The reaction

contents were transferred into a separatory funnel, diluted in EtOAc, and the organic phase was

washed multiple times with water and brine. The organic layer was concentrated, and the product

was purified by silica gel flash chromatography. It was necessary to let the silica stand in 5% NEt3

in hexanes before loading the column to achieve better separation and prevent minor

decomposition.

32

1.4.3.2 Procedure for 1 mmol Scale Reaction

To an oven dried vial, substrate (1 mmol, 1 equiv), Zn(CN)2 (64.6 mg, 0.55 mmol, 0.55 equiv),

Zn(TFA)2 (29.1 mg, 0.1 mmol, 10 mol %), and K3PO4 (424.5 mg, 2 mmol, 2 equiv) were added.

After the vial was purged with Ar for 5 min, 2 ml of PhMe and 2 ml of DMA was added. To a

second oven dried vial, Pd(t-Bu3P)2 (25.6 mg, 0.05 mmol, 5 mol %) was added and purged with

Ar for 5 min. The catalyst was dissolved in 4 ml of PhMe and the solution was transferred to the

substrate mixture. The reaction was stirred at 1000 rpm and 110 °C for 18 h. The reaction contents

were transferred into a separatory funnel, diluted in EtOAc, and the organic phase was washed

multiple times with water and brine. The organic layer was concentrated, and the product was

purified by silica gel flash chromatography. It was necessary to let the silica stand in 5% NEt3 in

hexanes before loading the column to achieve better separation and prevent minor decomposition.


1H-indole-2-carbonitrile (1.61a) – The compound was synthesized according

to General Procedure 1.4.3.1. The product was purified by flash

chromatography using hexanes–EtOAc–DCM (17:2:1, v:v:v) as the mobile

phase and was isolated as a white solid (0.5 mmol scale: 52.6 mg, 0.37 mmol, 74%, 1 mmol scale:

103.8 mg, 0.73 mmol 73%, mp = 94–95 °C). 1H NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 7.68 (dd,

J = 8.2, 1.0 Hz, 1H), 7.50 – 7.34 (m, 2H), 7.25 – 7.16 (m, 2H). 13C NMR (125 MHz, CDCl3) δ

137.1, 126.4, 126.3, 122.2, 121.8, 114.6, 114.5, 111.9, 106.2. IR (thin film, cm-1) 3131, 3078,

3051, 2974, 2926, 2236, 1653, 1558, 1522, 1410, 1348. HRMS (DART, M+1) Calculated for

C9H7N2 143.0609, found 143.0607.

1H-benzo[g]indole-2-carbonitrile (1.61b) – The compound was

synthesized according to General Procedure 1.4.3.1. The product was

purified by flash column chromatography using hexanes–EtOAc–DCM

(17:2:1, v:v:v) as the mobile phase and was isolated as an off-white solid (71.0 mg, 0.37 mmol,

74%, mp = 237–240 °C). 1H NMR (500 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.39 (ddt, J = 8.2, 1.4,

0.8 Hz, 1H), 7.98 (ddt, J = 8.0, 1.3, 0.5 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.64 (ddd, J = 8.2, 7.0,

1.3 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.48 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 133.0, 131.4,

128.6, 126.3, 125.9, 122.3, 122.2, 121.5, 121.2, 120.5, 114.9, 114.4, 103.8. 3316, 3080, 3051,

33

3001, 2214, 1535, 1450. IR (thin film, cm-1) 3316, 3080, 3051, 3001, 2214, 1535, 1450. HRMS

(DART, M+1) Calculated for C13H9N2 193.0766, found 193.0770.

7-methyl-1H-indole-2-carbonitrile (1.61c) – The compound was synthesized

according to General Procedure 1.4.3.1. The data for this compound was

acquired and organized with the assistance of Sabine Bognar. The product was

purified by flash column chromatography using hexanes–EtOAc–DCM (18:1:1, v:v:v) as the

mobile phase and was isolated as an off-white solid (55.3 mg, 0.354 mmol, 71%, mp = 151–152

°C). 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 7.53 (ddt, J = 8.0, 1.5, 0.7 Hz, 1H), 7.22 (d, J =

2.1 Hz, 1H), 7.19 (dt, J = 7.1, 1.0 Hz, 1H), 7.14 (dd, J = 7.9, 7.1 Hz, 1H), 2.52 (s, 3H). 13C NMR

(125 MHz, CDCl3) δ 136.9, 126.6, 126.0, 122.2, 121.2, 119.9, 115.0, 114.6, 106.0, 16.7. IR (thin

film, cm-1) 3288, 3063, 2964, 2915, 2857, 2227, 1617, 1526, 1432, 1363. HRMS (DART, M+18)

Calculated for C10H12N3 174.1031, found 174.1031.

4-methyl-1H-indole-2-carbonitrile (1.61d) – The compound was synthesized

according to General Procedure 1.4.3.1. The product was purified by flash

column chromatography using hexanes–EtOAc–DCM (18:1:1, v:v:v) as the

mobile phase and was isolated as an off-white solid (54.0 mg, 0.346 mmol,

69%, mp = 83–84 °C). 1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 7.35 – 7.20 (m, 3H), 7.01 (dt,

J = 6.8, 1.1 Hz, 1H), 2.56 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 136.8, 131.8, 126.4, 126.4,

121.5, 114.5, 113.0, 109.3, 105.4, 18.6. IR (thin film, cm-1) 3480, 3326, 3131, 3063, 2918, 2854,

2226, 1615, 1518, 1473. HRMS (DART, M+1) Calculated for C10H9N2 157.0766, found

157.0771.

1-methyl-1H-indole-2-carbonitrile (1.61e) – The compound was synthesized

according to General Procedure 1.4.3.1. The data for this compound was

acquired and organized with the assistance of Sabine Bognar. The product was


mobile phase and was isolated as an off-white solid (55.8 mg, 0.36 mmol, 72%). Spectral data

match literature reports.58 1H NMR (500 MHz, CDCl3) δ 7.67 (dt, J = 8.1, 1.0 Hz, 1H), 7.41 (ddd,

J = 8.5, 6.8, 1.1 Hz, 1H), 7.36 (dq, J = 8.5, 1.0 Hz, 1H), 7.21 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.16

58

Ushijima, S.; Moriyama, K. Tetrahedron, 2011, 67, 958.

34

(d, J = 0.9 Hz, 1H), 3.91 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 138.0, 126.1, 125.8, 122.3, 121.3,

113.6, 112.6, 110.2, 110.1, 31.5.

1-isopropyl-1H-indole-2-carbonitrile (1.61f) – The compound was

synthesized according to General Procedure 1.4.3.1. The product was purified

by flash column chromatography using hexanes–EtOAc–DCM (40:1:1, v:v:v)

as the mobile phase and was isolated as a colorless oil (66.3 mg, 0.36 mmol, 72 %). 1H NMR (500

MHz, CDCl3) δ 7.66 (ddd, J = 8.1, 0.9 Hz, 1H), 7.52 – 7.45 (m, 1H), 7.37 (ddd, J = 8.6, 7.0, 1.2

Hz, 1H), 7.22 – 7.15 (m, 2H), 4.92 (m, J = 7.0 Hz, 1H), 1.71 (d, J = 7.0 Hz, 6H). 13C NMR (125

MHz, CDCl3) δ 136.5, 126.5, 125.4, 122.4, 121.1, 114.5, 114.2, 111.0, 107.8, 49.4, 22.0. IR (thin

film, cm-1) 3117, 3053, 2980, 2936, 2882, 2222, 1612, 1514, 1447. HRMS (DART, M+1)

Calculated for C12H13N2 185.1079, found 185.1076.

1-benzyl-1H-indole-2-carbonitrile (1.61g) – The compound was synthesized

according to General Procedure 1.4.3.1. The product was purified by flash

column chromatography using hexanes–MTBE (40:1, v:v:v to 20:1, v:v:v) as

the mobile phase and was isolated as a colorless oil (89.7 mg, 0.386 mmol, 77 %). 1H NMR (500

MHz, CDCl3) δ 7.70 (dt, J = 8.1, 1.0 Hz, 1H), 7.39 – 7.27 (m, 5H), 7.25 – 7.16 (m, 4H), 5.48 (s,

2H). 13C NMR (125 MHz, CDCl3) δ 137.6, 136.1, 129.0, 128.2, 126.9, 126.5, 126.1, 122.5, 121.7,

113.8, 113.6, 110.8, 110.1, 49.1. IR (thin film, cm-1) 3119, 3063, 3032, 2926, 2220, 1616, 1603,

1518, 1452. HRMS (DART, M+1) Calculated for C16H13N2 233.1079, found 233.1078.

5-methoxy-1H-indole-2-carbonitrile (1.61h) – The compound was


purified by flash column chromatography using hexanes–EtOAc–NEt3

(17:2:1, v:v:v) as the mobile phase and was isolated as a white solid (65.9 mg, 0.38 mmol, 77%,

mp = 146–147 °C). 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 7.34 – 7.28 (m, 1H), 7.11 (d, J =

1.0 Hz, 1H), 7.08 – 7.03 (m, 2H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 155.4, 132.1, 126.7,

118.0, 114.2, 113.9, 112.6, 106.4, 101.9, 55.7. IR (thin film, cm-1) 3287, 3121, 2955, 2940, 2835,

2241, 1450, 1362, 1173. HRMS (DART, M+1) Calculated for C10H9N2O 173.0715, found

173.0717.

35

methyl 2-cyano-1H-indole-5-carboxylate (1.61i) – The compound was synthesized with the

following modification to General Procedure 1.4.3.1: Pd(t-Bu3P)2

(19.2 mg, 0.0376 mmol, 7.5 mol %), Zn(TFA)2 (21.9 mg, 0.075, 15

mol %), at 120 °C. The data for this compound was acquired and

organized with the assistance of Sabine Bognar. The product was purified by flash column

chromatography using hexanes–EtOAc–DCM (17:2:1, v:v:v) as the mobile phase and was isolated

as a white solid (48 mg, 0.240 mmol, 48%, decomp at 230 °C). 1H NMR (500 MHz, DMSO-d6)

δ 12.74 (s, 1H), 8.38 (dd, J = 1.6, 0.7 Hz, 1H), 7.91 (dd, J = 8.7, 1.7 Hz, 1H), 7.55 (dt, J = 8.8, 0.9

Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 3.86 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 166.5, 139.2,

125.7, 125.5, 124.6, 122.5, 114.7, 114.0, 112.5, 107.7, 52.0. IR (thin film, cm-1) 3234, 3161, 2958,

2926, 2854, 2228, 1683, 1614, 1428. HRMS (DART, M+1) Calculated for C11H9N2O2 201.0664,

found 201.0666.

5-fluoro-1H-indole-2-carbonitrile (1.61j) – The compound was

synthesized with the following modification to General Procedure 1.4.3.1:

Pd(t-Bu3P)2 (19.2 mg, 0.0376 mmol, 7.5 mol %), Zn(TFA)2 (21.9 mg, 0.075,

15 mol %), at 120 °C. The data for this compound was acquired and organized with the assistance

of Sabine Bognar. The product was purified by flash column chromatography using hexanes–

EtOAc–DCM (18:1:1, v:v:v) as the mobile phase and was isolated as an off-white solid (53.6 mg,

0.335 mmol, 67%, mp = 111–112 °C). 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 7.37 (ddt, J =

9.0, 4.3, 0.8 Hz, 1H), 7.31 (ddd, J = 9.0, 2.5, 0.6 Hz, 1H), 7.19 – 7.11 (m, 2H). 13C NMR (125

MHz, CDCl3) δ 158.7 (d, J = 238.2 Hz), 133.6, 126.6 (d, J = 10.8 Hz), 115.6 (d, J = 27.1 Hz),

114.3 (d, J = 5.4 Hz), 114.1, 113.0 (d, J = 9.5 Hz), 107.7, 106.5 (d, J = 23.9 Hz). 19F NMR (564

MHz, CDCl3) δ -121.44 (m). IR (thin film, cm-1) 3295, 3090, 2991, 2917, 2227, 1635, 1578, 1520,

1492. HRMS (DART, M+1) Calculated for C9H6FN2 161.0515, found 161.0518.

6-methoxy-1H-indole-2-carbonitrile (1.61k) – The compound was



mobile phase and was isolated as a white solid (58.7 mg, 0.34 mmol, 68%, mp = 98–99 °C). 1H

NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 6.88 (dd, J = 8.8,

2.2 Hz, 1H), 6.82 (s, 1H), 3.86 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 159.5, 138.0, 122.8, 120.4,

114.7, 114.7, 113.3, 104.6, 93.6, 55.5. IR (thin film, cm-1) 3358, 3011, 2965, 2932, 2218, 1628,

36

1582, 1510, 1448, 1400. HRMS (DART, M+1) Calculated for C10H9N2O 173.0715, found

173.0713.

methyl 2-cyano-1H-indole-6-carboxylate (1.61l) – The compound

was synthesized according to General Procedure 1.4.3.1. The data for

this compound was acquired and organized with the assistance of

Sabine Bognar. The product was purified by flash column chromatography using hexanes–EtOAc–

DCM (17:2:1, v:v:v) as the mobile phase and was isolated as an off-white solid (75.2 mg, 0.376

mmol, 75%, decomp at 216 °C). 1H NMR (500 MHz, DMSO-d6) δ 8.07 (dt, J = 1.6, 0.9 Hz, 1H),

7.78 (dd, J = 8.5, 0.8 Hz, 1H), 7.71 (dd, J = 8.5, 1.5 Hz, 1H), 7.44 (d, J = 0.9 Hz, 1H), 3.87 (s,

3H). 13C NMR (125 MHz, DMSO-d6) δ 166.5, 136.2, 129.1, 126.4, 121.9, 121.0, 114.2, 114.0,

113.0, 109.1, 52.2. IR (thin film, cm-1) 3279, 2361, 2330, 2226, 1692, 1559, 1534, 1560, 1441.

HRMS (DART, M+1) Calculated for C11H9N2O2 201.0664, found 201.0666.

6-fluoro-1H-indole-2-carbonitrile (1.61m) – The compound was


purified by flash column chromatography using hexanes–PhMe (3:1, v:v) as

the mobile phase and was isolated as a white solid (48.6 mg, 0.303 mmol, 61%, mp = 139–140

°C). 1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 7.62 (ddt, J = 8.8, 5.3, 0.7 Hz, 1H), 7.19 (dd, J

= 2.2, 1.0 Hz, 1H), 7.10 (dddd, J = 9.1, 2.3, 1.0, 0.6 Hz, 1H), 7.00 (ddd, J = 9.4, 8.8, 2.2 Hz, 1H).

13C NMR (125 MHz, CDCl3) δ 162.3 (d, J = 244.4 Hz), 137.0 (d, J = 13.0 Hz), 123.3 (d, J = 10.4

Hz), 122.8, 114.6 (d, J = 1.2 Hz), 113.9 (d, J = 2.4 Hz), 111.5 (d, J = 25.3 Hz), 106.7, 97.9 (d, J =

26.7 Hz). 19F NMR (470 MHz, CDCl3) δ -114.31 (m). IR (thin film, cm-1) 3277, 3140, 3072, 2928,

2857, 2229, 1627, 1590, 1522, 1450. HRMS (DART, M+1) Calculated for C9H6FN2 161.0515,

found 161.0516.

7-methoxy-1H-indole-2-carbonitrile (1.61n) – The compound was

synthesized according to General Procedure 1.4.3.1. The product was purified

by flash column chromatography using hexanes–EtOAc–DCM (17:2:1, v:v:v)

as the mobile phase and was isolated as a white solid (66.6 mg, 0.39 mmol, 77%, mp = 125–126

°C). 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H),

7.13 (dd, J = 8.1, 7.7 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 3.98 (s, 3H). 13C NMR (125 MHz, CDCl3)

δ 146.1, 128.2, 127.3, 122.2, 114.4, 114.1, 114.1, 105.9, 104.8, 55.5. IR (thin film, cm-1) 3343,

37

3080, 3007, 2963, 2938, 2911, 2839, 2228 1628, 1584, 1530, 1447. HRMS (DART, M+1)

Calculated for C10H9N2O 173.0715, found 173.0716.

5H-[1,3]dioxolo[4,5-f]indole-6-carbonitrile (1.61o) – The compound

was synthesized with the following modification to General Procedure

1.4.3.1: Pd(t-Bu3P)2 (19.2 mg, 0.0376 mmol, 7.5 mol %), Zn(TFA)2 (21.9

mg, 0.075, 15 mol %), at 120 °C. The product was purified by flash column chromatography using

hexanes–EtOAc–DCM (40:5:2, v:v:v) as the mobile phase and was isolated as a white solid (48.9

mg, 0.26 mmol, 53%, mp = 210–211 °C). 1H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.16

(s, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 6.02 (s, 2H). 13C NMR (125 MHz, DMSO-d6) δ 147.9, 144.1,

132.9, 120.1, 114.9, 113.3, 103.7, 101.1, 98.8, 92.0. IR (thin film, cm-1) 3311, 3125, 3009, 2917,

2209, 1528, 1499, 1475. HRMS (DART, M+18) Calculated for C10H10N3O2 204.0773, found

204.0772.

5-chloro-1H-indole-2-carbonitrile (1.61p) – The compound was


purified by flash column chromatography using hexanes–EtOAc–DCM

(18:1:1, v:v:v) as the mobile phase and was isolated as an off-white solid (61.5 mg, 0.35 mmol,

70%, decomp at 144 °C). 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.66 (dt, J = 1.7, 0.9 Hz,

1H), 7.36 – 7.34 (m, 2H), 7.14 (dd, J = 2.1, 0.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 135.1,

127.7, 127.1, 126.9, 121.3, 113.8, 113.5, 112.8, 107.6. IR (thin film, cm-1) 3310, 3115, 3069,

2963, 2924, 2232, 1518, 1483, 1414, 1346. HRMS (DART, M+1) Calculated for C9H6ClN2

177.0220, found 177.0219.

1H-indole-2,5-dicarbonitrile (1.61q) – The compound was synthesized

with the following modification to General Procedure 1.4.3.1: Zn(CN)2

(129.2 mg, 1.1 mmol, 2.2 equiv), Pd(t-Bu3P)2 (19.2 mg, 0.0376 mmol,

7.5 mol %), Zn(TFA)2 (21.9 mg, 0.075, 15 mol %), at 120 °C. The product was purified by flash

column chromatography using hexanes–EtOAc–DCM (8:1:1, v:v:v) as the mobile phase and was

isolated as a white solid (51.0 mg, 0.305 mmol, 61%, mp = 227–228 °C). 1H NMR (500 MHz,

DMSO-d6) δ 8.26 (dd, J = 1.5, 0.9 Hz, 1H), 7.71 – 7.57 (m, 2H), 7.50 (d, J = 0.8 Hz, 1H). 13C

NMR (125 MHz, DMSO-d6) δ 138.4, 128.1, 127.5, 125.5, 119.7, 113.9, 113.8, 113.7, 113.7,

38

108.6, 103.4. IR (thin film, cm-1) 3250, 3130, 3054, 2991, 2928, 2857, 2227, 1618, 1476. HRMS

(DART, M+H) Calculated for C10H6N3 168.0562, found 168.0564.

1.4.4 Derivatization of 2-Cyanoindole

2-(1H-tetrazol-5-yl)-1H-indole (1.63) – To an oven dried 3-dram vial, 1.41 (138.5 mg, 0.5 mmol,

1 equiv), Zn(CN)2 (32.3 mg, 0.275 mmol, 0.55 equiv), Zn(TFA)2 (14.6 mg, 0.05 mmol, 10 mol

%), and K3PO4 (212.3 mg, 1 mmol, 2 equiv) were added. After the vial was purged with Ar for 5

min, 1 ml of PhMe and 1 ml of DMA was added. To a second oven dried vial, Pd(t-Bu3P)2 (12.8

mg, 0.025 mmol, 5 mol %) was added and purged with Ar for 5 min. The catalyst was dissolved

in 2 ml of PhMe and the solution was transferred to the substrate mixture. The reaction was stirred

at 1000 rpm and 110 °C for 18 h. Once the vial had cooled to rt, NaN3 (65 mg, 1 mmol, 2 equiv)

and NH4Cl (53.5 mg, 1 mmol, 2 equiv) were added and the reaction was reheated to 110 ºC and

stirred at 1000 rpm for 14 h. The reaction contents were transferred into a separatory funnel, diluted

in EtOAc, and the organic phase was washed multiple times with water and brine. The organic

layer was concentrated, and the product was purified by silica gel flash chromatography

using DCM–MeOH–AcOH (100:1:1, v:v:v) as the mobile phase and was isolated as a white solid

(60.2 mg, 0.325 mmol, 65%). Spectral data was in accordance to reported data.59 1H NMR (500

MHz, DMSO-d6) δ 12.16 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.0 Hz, 1H), 7.22

(ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.19 (dd, J = 2.2, 0.9 Hz, 1H), 7.08 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H).

13C NMR (125 MHz, DMSO-d6) δ 150.3, 137.5, 127.5, 123.6, 122.1, 121.2, 120.2, 112.3, 103.7.

59

Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z. Chem. - Eur. J. 2013, 19, 16880.

39

1.4.5 Substrates of Mechanistic Studies

2-bromo-1H-indole (1.48) – was synthesized according to literature procedure

and the spectral data matched reported value.41b 1H NMR (500 MHz, CDCl3) δ

8.03 (s, 1H), 7.56 (ddt, J = 7.8, 1.5, 0.8 Hz, 1H), 7.29 (dq, J = 8.1, 0.9 Hz, 1H),

7.20 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 7.15 (ddd, J = 7.8, 7.1, 1.1 Hz, 1H), 6.56 (dd, J = 2.1, 0.9 Hz,

1H). 13C NMR (125 MHz, CDCl3) δ 136.4, 128.7, 122.2, 120.5, 119.6, 110.3, 108.7, 104.8.

Upon treatment of 1.48 to general procedure 1.4.3.1, 1.61 was isolated (66.1 mg, 0.465 mmol,

93%) by flash column chromatography using hexanes–EtOAc–DCM (17:2:1, v:v:v). as the mobile

phase.

2-(bromoethynyl)aniline (1.62) – was synthesized according to literature

procedure and the spectral data matched reported value.60 1H NMR (500 MHz,

DMSO-d6) δ 7.15 (ddd, J = 7.7, 1.6, 0.5 Hz, 1H), 7.06 (ddd, J = 8.2, 7.2, 1.6 Hz,

1H), 6.69 (ddd, J = 8.2, 1.2, 0.5 Hz, 1H), 6.48 (ddd, J = 7.7, 7.2, 1.2 Hz, 1H), 5.42 (s, 2H). 13C

NMR (125 MHz, DMSO-d6) δ 150.3, 132.2, 129.9, 115.7, 114.0, 105.1, 77.4, 55.8.

Upon treatment of 1.62 to general procedure 1.4.3.1, 60% of 1.62 was recovered.

Chapter 2

60

Kunzer, A. R.; Wendt, M. D. Tetrahedron Lett. 2011, 52, 1815.

40

Migratory Insertion Strategy for Indole Dearomatization

2.1 Introduction

2.1.1 Elementary View on Aromatization

Aromaticity refers to the extra level of stability that planar rings with conjugated -bonds exhibit

when they obey Huckel’s rule of 4n+2 electrons (Scheme 34, left).61 Importantly, unsaturated rings

which contain 4n electrons have reduced stability. They are said to be anti-aromatic when planar,

and will twist to avoid overlap between their -bond (Scheme 34, right).

Scheme 34 Example of aromatic system vs. anti-aromatic system

The increase in stability could be described by molecular orbital theory; aromatic compounds have

all bonding orbitals filled with paired electrons. For simple rings, drawing MO-diagrams could be

done by placing the apex of a ring towards the bottom and considering all points of the ring as

energy levels (Scheme 35).

Scheme 35 Simple method for drawing the MO-diagram of benzene -bonds

61

(a) E, Hückel, “Grundzüge der Theorie ungesáttigter und aroma tischer Verbindungen,” Verlag Chemie, Berlin,

1938, 71. (b) von E. Doering, W.; Detert, F. L. J. Am. Chem. Soc. 2002, 73, 876.

41

2.1.2 Strategies for Benzene Dearomatization

The dearomatization of aromatic compounds has been of long-standing interest as a way to access

otherwise inaccessible products. The appeal of this strategy in retrosynthesis lies in the possibility

of a difunctionalization as well as further manipulations of the remaining -systems, which now

lack resonance stabilization energy (Scheme 36).

Scheme 36 Benefits of dearomatization. After dearomatization, -bonds react as simple olefins

in future functionalizations

2.1.2.1 Classic Reactions: Birch Reduction

In the mid 1940’s, Arthur Birch reported on arguably the simplest method for the reduction of

benzene to the cyclohexadiene (Scheme 37).62 The reaction only requires cheap alkali-metals

dissolved in liquid ammonia, and alcohol, and has predictable selectivity.

Scheme 37 Birch Reduction products for EDG and EWG substituted aryl-rings

The selectivity for arenes with EDG typically proceeds to give the most substituted 1,4-diene

whilst arenes with electron-withdrawing substituents typically give the unsubstituted 1,4-diene.

The reaction proceeds by a single-electron reduction by the solvated electride [Na(NH3)6]+[e-]

62

(a) Birch, A. J. J. Chem. Soc. 1944, 430. For a collection of the work of A. J. Birch, see Tetrahedron 1988, 44, V.

42

formed in situ as a strong reducing agent capable of dearomatizing the system and is characterized

by a bright blue color (Scheme 38).63

Scheme 38 Mechanism of the Birch Reduction

Additionally, the final anion formed in the reaction can be trapped with electrophiles, providing

functionalized dienes. The Studer group has dubbed these dienes “pro-aromatic”; upon releasing

an equivalent of HCN, they gain 33–36 kcal of energy (Scheme 39, 2.5).64

Scheme 39 Trapping of the final anion intermediate of the Birch Reduction and its use in

Palladium-chemistry as a formal source of HCN

2.1.2.2 Modern Reactions: MTAD

For many years, the development of new benzene dearomatization chemistry has been largely

dominated by phenol/aniline dearomatization (Scheme 40). The dearomatization of phenols and

63

For a case of isolated electrides, see: (a) Dye, J. L. Science 1990, 247, 663. For reports examining the mechanism

of the Birch Reduction, see: (b) Krapcho, A. P.; Bothner, A. A. J. Am. Chem. Soc. 1959, 81, 3658. (c) Wooster, C. B.;

Godfrey, K. L. J. Am. Chem. Soc. 1937, 59, 596. (d) Birch, A. J. Q. Rev., Chem. Soc. 1950, 4, 69. 64

Bhunia, A.; Bergander, K.; Studer, A. J. Am. Chem. Soc. 2018, 140, 16353.

43

anilines fall within two categories; nucleophilic dearomatizations with external electrophilic

species (such as metal-allyl complexes or aryl halides) or oxidative electrophilic dearomatizations

with external nucleophiles and oxidants (such as hypervalent iodine species).65

Scheme 40 Modern methods of dearomatization with metal catalysts or oxidants

Recent research on arene dearomatization led by the Sarlah group has focused on the development

of reagents which rapidly undergo cycloadditions with arenes, labeled arenophiles.66 Reagents

such as N-methyl-1,2,4-triazoline-3,5-dione (MTAD, 2.7) participate in photochemically induced

cycloadditions, forming dearomatized intermediates (2.8) bearing isolated olefins capable of future

functionalizations (Scheme 41).67

Scheme 41 Cycloaddition of arenophile, MTAD, with arenes

Their method offers an expediated route to densely substituted unsaturated ring systems. Once the

olefin has undergone functionalization, the authors have demonstrated methods for removing the

MTAD moiety. For example, a retro-[4+2] yields the conjugated diene, or reduction to access the

65

Wu, W. T.; Zhang, L.; You, S. L. Chem. Soc. Rev. 2016, 45, 1570. 66

Wertjes, W. C.; Southgate, E. H.; Sarlah, D. Chem. Soc. Rev. 2018, 47, 7996. 67

Southgate, E. H.; Pospech, J.; Fu, J.; Holycross, D. R.; Sarlah, D. Nat. Chem. 2016, 8, 922.

44

diamine products is possible (Scheme 42).68 The utility of this transformation was demonstrated

using a dihydroxylation of cycloadduct 2.8 in the total synthesis of natural products and drug

molecules.69

Scheme 42 Typical functionalizations carried out on dearomatized intermediates 2.9

In line with the research described in this thesis, cycloadduct 2.8 undergoes a variety of base-

metal,70 and palladium-catalyzed Tsuji-Trost type reactivity, by forming a metal-allyl intermediate

(2.12) which then reacts with nucleophiles (Scheme 43).71

Scheme 43 Palladium-catalyzed Tsuji-Trost type reactivity of intermediate 2.8

2.1.3 Strategies for Indole Dearomatization

Indoles and other simple heterocycles are typically more prone to dearomatization as compared to

benzene since they typically have reduced aromatic stabilization energy.72 The five membered ring

68

Okumura, M.; Nakamata Huynh, S. M.; Pospech, J.; Sarlah, D. Angew. Chem. Int. Ed. 2016, 55, 15910. 69

Southgate, E. H.; Holycross, D. R.; Sarlah, D. Angew. Chem. Int. Ed. 2017, 56, 15049. 70

Hernandez, L. W.; Klockner, U.; Pospech, J.; Hauss, L.; Sarlah, D. J. Am. Chem. Soc. 2018, 140, 4503. 71

Okumura, M.; Shved, A. S.; Sarlah, D. J. Am. Chem. Soc. 2017, 139, 17787. 72

Zhuo, C. X.; Zhang, W.; You, S. L. Angew. Chem. Int. Ed. 2012, 51, 12662.

45

of the indole can be dearomatized relatively easily since the 6-membered ring remains intact (vide

supra, Scheme 3, page 3). This strategy offers two important benefits: milder reaction conditions

allows for stereoselective methods, and 2,3-substituted indolines are of particular interest as they

are present in countless natural products.73

2.1.3.1 Push-Pull Dearomatization

Indole dearomatization has been largely dominated by a push-pull approach; a nucleophilic attack

of the C3–position forms an intermediate iminium ion (2.15) which is trapped by a nucleophile

(Scheme 44, 2.16).74 This topic will be the main focus of chapter 3 (see section 3.1.3 on page 124).

Scheme 44 Push-pull dearomatization of indoles

2.1.3.2 Migratory Insertion Strategy – An Umpolung Approach

One strategy for chemical dearomatization, which has been explored in recent years, is transition-

metal-catalyzed reactions which feature a migratory insertion as the dearomative step.75 The key-

step leading to dearomatized products relies on an interrupted-Heck reaction (Scheme 45).76 The

mechanism of the Mizoroki-Heck Reaction involves oxidative addition of C–X bond, syn 1,2-

migratory insertion into an alkene, and -hydride elimination (Scheme 45, Prod A). The

Interrupted Heck Reaction involves trapping of the -bound palladium intermediate with a

nucleophile by reductive elimination (Scheme 45, Prod B).

73

Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458. 74

Roche, S. P.; Youte Tendoung, J.-J.; Tréguier, B. Tetrahedron 2015, 71, 3549. 75

Zeidan, N.; Lautens, M. Synthesis 2019, 51, 4137. 76

Thornbury, R. T.; Saini, V.; Fernandes, T. A.; Santiago, C. B.; Talbot, E. P. A.; Sigman, M. S.; McKenna, J. M.;

Toste, F. D. Chem. Sci. 2017, 8, 2890.

46

Scheme 45 Mizoroki-Heck and Interrupted-Heck reactivity

Primarily in intramolecular systems, migratory insertion into the 2,3-carbon bond of indoles can

be achieved, and if -hydrides are not available, trapping with exogenous nucleophiles can follow

(Scheme 46). The advantage of this method of dearomatization is the high regio- and

stereoselectivity achieved. These reactions undergo a syn migratory insertion, which could be

catalyzed by a chiral ligand, delivering products with excellent diastereo- and enantioselectivity.

Additionally, the reactions have typically produced products with the opposite regioselectivity as

compared to the push-pull mechanism of indoles; the nucleophilic coupling partner is incorporated

at the C3-position (vide supra, Scheme 44).

Scheme 46 Migratory insertion strategy and interrupted-Heck reactivity

47

2.1.3.2.1 Dearomative Monofunctionalization of Indoles

The first report of a Pd-catalyzed dearomative Heck-reaction on indoles was by Yao and Wu in

2012 (Scheme 47).77 The authors used 2,3-disubstituted-N-(2-halobenzoyl)indoles (2.20) to

accomplish the intramolecular dearomatization, delivering indolines (selected examples: 2.21–

2.23) bearing an exo-cyclic double bond in excellent yields. These substrates had been used

previously by Grigg78 and coworkers (vide infra, Scheme 55).

Scheme 47 Intramolecular Mizoroki-Heck Reaction for an efficient route to fused indolines

The reaction was found to be very efficient, utilizing only 2 mol% Pd(OAc)2 and in nearly all

cases, very high yields were achieved. A Pd0-PdII mechanism was proposed, and the active catalyst

is likely formed by the reduction of PdII by DMF (Scheme 48).79

77

Zhao, L.; Li, Z.; Chang, L.; Xu, J.; Yao, H.; Wu, X. Org. Lett. 2012, 14, 2066. 78

Brown, S.; Clarkson, S.; Grigg, R.; Thomas, W. A.; Sridharan, V.; Wilson, D. M. Tetrahedron 2001, 57, 1347. 79

Molina de la Torre, J. A.; Espinet, P.; Albéniz, A. C. Organometallics 2013, 32, 5428.

48

Scheme 48 Mechanism proposed for the intramolecular Mizoroki-Heck reaction of N-(2-

halobenzoyl)indoles

Oxidative addition into the substrate C–X bond results in a PdII complex (2.24). Following a Ag-

mediated ligand exchange (2.25), carbopalladation across the C2-C3 bond of the indole furnishes

the dearomatized intermediate with a chiral -bound benzylic Pd species (2.26). A -hydride

elimination furnishes the indoline product (2.21), and the catalyst is regenerated by reductive

elimination.

A domino approach was discovered by Jia by taking aryl-amides 2.27 and subjecting them to a

Larock indole synthesis/dearomatization sequence (Scheme 49).80 The N-(2-

bromobenzoyl)indoles 2.20 are formed in situ by Larock annulation and thereby undergo a

dearomative Heck reaction using dppf as the bidentate phosphine ligand.

80

Liang, R. X.; Xu, D. Y.; Yang, F. M.; Jia, Y. X. Chem. Commun. 2019, 55, 7711.

49

Scheme 49 Domino Larock annulation/dearomative Heck reaction of N-(2-iodoaryl)benzamides

A target-focused example of this reaction was demonstrated by Kitamura and Fukuyama who

reported a total synthesis of (+)-Hinckdentine A (2.31), utilizing an enantioselective dearomative

Heck reaction as the key step (Scheme 50).81 Until then, studies on the biological activity of this

compound were hindered due to a shortage in supply. The catalytic dearomatization of 2.29 could

be scaled up to 10 g, delivering 2.30 in near quantitative yield and excellent er, which could be

recrystallized to >99:1 er. Importantly, the authors utilized a chiral and bulky monodentate

phosphoramidite ligand L1 which would set the stage for future enantioselective

difunctionalizations (vide infra, section 2.1.3.2.2).

81

Douki, K.; Ono, H.; Taniguchi, T.; Shimokawa, J.; Kitamura, M.; Fukuyama, T. J. Am. Chem. Soc. 2016, 138,

14578.

50

Scheme 50 Total synthesis of (+)-Hinckdentine A using a key enantioselective dearomative

Heck reaction

A reliable highly enantioselective variation of the reaction was reported by Yao and Wu, shown

in Scheme 47, as well as the enantioselective dearomatization of pyrrole was achieved

simultaneously by Jia82 and You83 in 2018, using (S)-SEGPHOS as the ligand (Scheme 51).

Scheme 51 Reaction conditions reported by Jia for the enantioselective dearomative Heck

reaction of pyrroles

82

Li, X.; Zhou, B.; Yang, R. Z.; Yang, F. M.; Liang, R. X.; Liu, R. R.; Jia, Y. X. J. Am. Chem. Soc. 2018, 140, 13945. 83

Yang, P.; You, S. L. Org. Lett. 2018, 20, 7684.

51

The authors report a broad scope for both the indolines and dihydropyrrole products (2.33).

Notably, the aryl-triflate analogue of 2.20 was necessary to access the indoline products; possibly

allowing bidentate ligation via a cationic palladium mechanism with the non-coordinating

counterion.

In 2015, Jia reported the first enantioselective dearomative reductive Heck-reaction on this class

of substrates (Scheme 52).84

Scheme 52 Enantioselective reductive Heck-reaction of indoles

Excellent yields and enantioselectivity were observed, and the reaction conditions were quite

flexible in that a wide range of solvents, and bases were tolerated. Notably, a simple chiral

bidentate phosphine like BINAP was sufficient to deliver products (2.35) with high

enantioenrichment. The scope of the reaction was later extended to tolerate vinyl-halides by using

indoles bearing N-(2-bromocyclohexene) moieties.85

A second class of substrates worth mentioning arises by tethering the aryl-halide to the C-2 or C-

3 position of the heterocycle. This was first demonstrated by Ma and Xu in 2016 by tethering a

halo-aniline via an amide bond at the C-2 position of indoles (Scheme 53).86

84

Shen, C.; Liu, R. R.; Fan, R. J.; Li, Y. L.; Xu, T. F.; Gao, J. R.; Jia, Y. X. J. Am. Chem. Soc. 2015, 137, 4936. 85

Liang, R.-X.; Yang, R.-Z.; Liu, R.-R.; Jia, Y.-X. Org. Chem. Front. 2018, 5, 1840. 86

Wei, F.; Wei, L.; Zhou, L.; Tung, C.-H.; Ma, Y.; Xu, Z. Asian J. Org. Chem. 2016, 5, 971.

52

Scheme 53 Palladium-catalyzed dearomatization of indoles by arylation/borylation then

protodeborylation, or arylation/hydride reduction

Complex spirocyclic indolines/oxindoles (2.37) are accessed in high yield by means of

intramolecular arylation by migratory insertion, generating intermediate 2.38. The benzylic-

palladium intermediate is then either trapped with B2Pin2 and further protodeborylated, or directly

trapped with a strong hydridic source.

The enantioselective variant, as well as an extended scope was later developed in 2018 by Jia and

coworkers (Scheme 54).87

87

(a) Li, X.; Zhou, B.; Yang, R. Z.; Yang, F. M.; Liang, R. X.; Liu, R. R.; Jia, Y. X. J. Am. Chem. Soc. 2018, 140,

13945. (b) Douki, K.; Shimokawa, J.; Kitamura, M. Org. Biomol. Chem. 2019, 17, 1727.

53

Scheme 54 (a) Pd-catalyzed dearomative Heck reaction of indoles by a C-2 tethered arylamide.

(b) Extended chain benzamide dearomatization for dihydrobenzoquinolone formation

The reported reactions utilized a variety of phosphoramidite ligands. Some successful examples

bore saturated BINOL backbones and 3,3’-substitution (L2) which was key for high

enantioselectivities. The reaction delivered many spirocyclic heterocycles (2.40), incorporating

indoles, benzofurans, pyrroles, and furans. Additionally, the amide tether could be reversed to the

benzamide (2.41), accessing spirocyclic dihydrobenzoquinolones (2.42) in good yields and

enantioselectivity.

54

2.1.3.2.2 Dearomative Difunctionalizations – Interrupted Heck Reaction

The seminal work on the palladium-catalyzed dearomative difunctionalization of indoles via an

interrupted Heck mechanism by Grigg was reported in 2001 (Scheme 55).78 The N-benzoyl indoles

(2.43) reported were previously explored in radical cyclizations.88 Grigg describes the “queuing

process” for what is now commonly referred to as a domino process. Furthermore, the authors

describe the idea of “relay switch” species such as carbon monoxide which switches the cascade

between intramolecular to intermolecular.

Scheme 55 Palladium-catalyzed dearomative bisfunctionalization of indoles

Only one example was reported, and it arose by a sequence of arylation and

carbonylation/heteroarylation (2.44), with the major byproduct being from the direct

carbonylation/heteroarylation (2.45). Grigg concluded that the low yield was due to the poor

reactivity of the secondary alkyl-Pd-intermediate which is sterically encumbered within the bowl

shape of the molecule (intermediate 2.46).

This reactivity wasn’t further investigated until studies by the Lautens group in 2015, where we

reported a Pd-catalyzed diastereoselective bisfunctionalization of these types of indoles with

Zn(CN)2 as the trapping nucleophile (Scheme 56).54

88

Zhang, W.; Pugh, G. Tetrahedron Lett. 1999, 40, 7591.

55

Scheme 56 Pd-catalyzed diastereoselective indole 1,2-difunctionalization by a dearomatization

strategy

The reaction utilizes DtBPF as the ligand and proceeds to give exclusively the product of syn-

addition (2.47) in excellent yields. Some control studies confirmed the hypothesis by Grigg,

namely that the product of syn-migratory insertion is the kinetic product. The nitrile nucleophile

reacts on the concave face and only epimerizes when subjected to base.

Following this report, several groups expanded the capacity of the benzylic Pd-intermediate to be

intercepted with various nucleophiles (Scheme 57). The following examples were all published

within 2016. In the first example, the benzylic-Pd intermediate is trapped with boroxines in a

Suzuki-like mechanism (2.48).89 Jing and Liang90 as well as Jia91 reported a decarboxylative

alkynylation (2.49), and Jia described the direct alkynylation (2.50).92

89

(a) Petrone, D. A.; Kondo, M.; Zeidan, N.; Lautens, M. Chem. Eur. J. 2016, 22, 5684. 90

(b) Chen, S.; Wu, X. X.; Wang, J.; Hao, X. H.; Xia, Y.; Shen, Y.; Jing, H.; Liang, Y. M. Org. Lett. 2016, 18, 4016. 91

(c) Wang, Y.; Liu, R.; Gao, J.; Jia, Y. Chin. J. Org. Chem. 2017, 37, 691-697. 92

(d) Liu, R. R.; Xu, T. F.; Wang, Y. G.; Xiang, B.; Gao, J. R.; Jia, Y. X. Chem. Commun. 2016, 52, 13664.

56

Scheme 57 Palladium-catalyzed dearomative bisfunctionalization of indoles. All three examples

are highly diastereoselective

All three of the examples were highly diastereoselective but racemic when using bulky

monodentate phosphine ligands. Although the reductive Heck published by Jia one year earlier

was enantioselective using BINAP, and tolerated a wide variety of bases and solvents (vide supra,

Scheme 52), these three reactions were reported to give poor or no enantioselectivities. There is

currently no consensus on the reasons for the lack of induction, particularly since the

enantiodetermining step is proposed to precede trapping of the nucleophile. One possibility is that

transmetallation might occur prior to addition to the aryl -bond, and thus the ligands on the metal

center are different.

57

It was not until 2017 that Jia published the first diastereo- and enantioselective dearomative

bisfunctionalization of these N-tethered indoles via an arylation/alkynylation sequence (Scheme

58).93

Scheme 58 First Pd-catalyzed enantioselective dearomatization by difunctionalization of indoles

via arylation/alkynylation sequence

The authors solved the enantioselectivity issue by utilizing a chiral, monodentate, yet bulky ligand

(L4). The ligand is similar to the phosphoramidite used by Kitamura and Fukuyama (vide supra,

Scheme 50) however it was made bulkier by installing 3,3’-aryl rings on the BINOL backbone.

An MTBE–THF mixture was found to be the optimal solvent mixture; MTBE was necessary for

high enantioselectivity and THF was necessary for improved reactivity.

In recent years, many palladium-catalyzed difunctionalization-dearomatization of indoles have

been published and although they are typically diastereoselective, it remains a challenge to access

these scaffolds in high enantioselectivities (Scheme 59).

93

Liu, R. R.; Wang, Y. G.; Li, Y. L.; Huang, B. B.; Liang, R. X.; Jia, Y. X. Angew. Chem. Int. Ed. 2017, 56, 7475.

58

Scheme 59 Palladium-catalyzed diastereoselective trapping of the dearomatized benzylic

intermediate with various nucleophiles

These reactions include the arylation-phosphorylation94 (2.52) and arylation-vinylation95 (2.54)

by Jia, and the arylation-carbonylation96 (2.53) by Wu. In all cases, the products are highly

functionalized indolines, and most are equipped with readily modifiable groups. Jia could access

the vinyl products 2.54 with modest enantioselectivity. The limitation of the enantioselective

conditions for the anion-capture chemistry is that MTBE and Et2O are currently the only two

94

Weng, J.-Q.; Xing, L.-L.; Hou, W.-R.; Liang, R.-X.; Jia, Y.-X. Org. Chem. Front. 2019, 6, 1577. 95

Liang, R.-X.; Wang, K.; Wu, Q.; Sheng, W.-J.; Jia, Y.-X. Organometallics 2019, 38, 3927. 96

Wang, H.; Wu, X.-F. Org. Lett. 2019, 21, 5264.

59

solvents which provide high ee using the phosphoramidite ligands. In the 4 cases above, MTBE

was not a suitable solvent for reactivity. This incompatibility seems to be the biggest restriction

and hence it would be desirable to develop ligands which could tolerate a broader range of solvents

for the enantioselective dearomative bisfunctionalization of indoles.

2.2 Research Goal 1 – Palladium-Catalyzed Dearomative Arylation/Heteroarylation of Indoles

2.2.1 Motivation

The first research goal related to this topic was to develop a palladium-catalyzed dearomative

bisfunctionalization of indoles by means of a migratory insertion, and direct C–H arylation with

activated heterocycles (Scheme 60).97

Scheme 60 General reaction studied in research goal 1

This method would allow for the rapid construction of a large library of complex chiral

heterocycles from simple starting materials. Additionally, direct C–H arylation would be

advantageous as it would remove the need for pre-functionalized coupling partners.

2.2.2 Contributions

The results presented were obtained in collaboration with Dr. Tamara Beisel (postdoc from

Germany) and Rachel Ross (graduate student in the Lautens group). I conceived the idea, directed

the project, and executed most of the experiments. Dr. Tamara Beisel assisted in the optimization

of the reaction and the scope of the heteroaryl coupling partner. Rachel Ross focused on exploring

97

Zeidan, N.; Beisel, T.; Ross, R.; Lautens, M. Org. Lett. 2018, 20, 7332.

60

the scope of the reaction with respect to the indoles. Specific contributions are listed within the

text as well as within the experimental section.



Starting materials are synthesized by benzoylation of the corresponding 2-functionalized indoles

(Scheme 61). The indoles which are not commercially available could be synthesized by the Fang-

Lautens indole synthesis (See section 1.1.4 on page 11).30

Scheme 61 Synthesis of N-benzoyl indoles

Starting materials (2.34) were synthesized by deprotonating 2-functionalzied indoles (2.57), and

reacting them with derivatives of 2-halobenzoyl chlorides (see section 2.5.2). Although the yields

of this method are generally low, the cheap cost of materials and scalability of the reaction make

it ideal for scope studies.


We began our studies with benzothiazole (BTA) as the coupling partner based on the reactivity of

the C–H bond and for its potentially useful therapeutic effects.98 After screening the reaction

parameters, we found that 0.2 mmol of 2.34-Br with 5 mol % Pd(t-Bu3P)2, 8 equiv of BTA, 2

equiv of Cs2CO3, 40 mol % CuCl2 in toluene at 120 °C for 15 h provided the dearomatized product

2.58a in quantitative yield as a single diastereomer, as confirmed by single-crystal X-ray

analysis.99 To assess the importance of the reaction parameters, we altered the conditions and

evaluated the impact (Table 4).

98

Kamal, A.; Syed, M. A. H.; Mohammed, S. M. Expert Opin. Ther. Pat. 2015, 25, 335. 99

CCDC deposition number: 1858836.

61

Table 4 Effects of reaction parameters in the dearomative arylation/heteroarylation of indolesa

Entry Change to standard condition 2.58a (%)b drc

1 None >99 >20:1

2 1.2 equiv of Cs2CO3 67 >20:1

3 4 equiv of BTA 83 >20:1

4 No CuCl2 60 3.2:1

5 CuCl instead of CuCl2 62 5.6:1

6b PivOH instead of CuCl2 74 4.6:1

7b Added 10 L H2O (2.8 equiv) 97 >20:1

8 1 g scale instead of 0.2 mmol scale 88 >20:1

aReactions run on 0.2 mmol scale. bYield of 2.58a determined by NMR using trimethoxybenzene as an internal

standard. cDiastereomeric ratio determined by NMR. BTA = benzothiazole

Importantly, other aryl phosphine, alkyl phosphine, and Buchwald ligands were not efficient in

catalyzing this reaction. Lowering the number equivalents of base (Table 4, entry 2) or BTA (Table

4,entry 3) resulted in a slightly diminished yield, with no impact on dr. Omitting CuCl2 from the

reaction (Table 4, entry 4) resulted in diminished yields as well as lower dr, suggesting that the

additive influences the rate or longevity of the catalyst as well as affects epimerization. Notably,

CuCl (Table 4, entry 5) as well as various Cu(I or II), Zn(II), Fe(III), and Yb(III) salts did not

62

improve the yield or dr. Pivalic acid, a common additive in C–H activation,100 improves the yield,

but at the expense of poor diastereoselectivity (Table 4, entry 6). Finally, we found that the reaction

tolerates a modest amount of water without catalyst deactivation (Table 4, entry 7). Gratifyingly,

we were able to scale the reaction up to 1 g with minimal loss in yield (Table 4, entry 8).

2.2.3.3 Exploring the Scope of the Reaction

With the optimized conditions in hand, we investigated the scope with respect to the indole (Table

5). Product 2.58a could be accessed on a 1 g scale, or by using the aryl-iodide or aryl-chloride

variants of 2.34 in good yield with excellent dr.

Relative stereochemistry was assigned by analogy to 2.58a. An EWG para- to the benzoyl linker

(2.58b) or an EDG para- to the halide (2.58c) were tolerated; however, the opposite electronic

pattern provided products 2.58d and 2.58e with diminished yields. Substitution at the 5-position

of the indole provided products 2.58f and 2.58g, albeit in reduced stereoselectivity. However,

excellent dr was observed for the difluoro product 2.58h. A longer alkyl chain at the 2-position, as

in the case of 2.58i or protected amine 2.58j, was tolerated. Additionally, Weinreb amide 2.58k,

and a variety of 2-aryl indoles (2.58l –2.58o), all participated in the reaction. Finally, vinyl halide

2.34p was a compatible substrate in the diarylation reaction providing product 2.58p in good yield.

Slow hydrolysis was observed for electron deficient starting materials providing 2-methylindole

as a side product. In all other cases, only product was observed by crude NMR suggesting other

decomposition pathways are operative.

100

Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.

63

Table 5 Investigating the substrate scope with respect to the indolea

2.58a

from 2.34-Br

(>99%, >20:1 dr)

2.58a

from 2.34-I

(65%, >20:1 dr)

2.58a

from 2.34-Cl

(48%, >20:1 dr)b

2.58b

(94%, >20:1 dr)c

2.58c

(77%, >20:1 dr)b,d

2.58d

(46%, >20:1 dr)d

2.58e

(90%, >20:1 dr)d

64

2.58f

(95%, 9.6:1 dr)

2.58g

(71%, 10.8:1 dr)d

2.58h

(52%, >20:1 dr)

2.58i

(90%, >20:1 dr)d

2.58j

(78%, >20:1 dr)d

2.58k

(63%, >20:1 dr)b,d

2.58l

(90%, >20:1 dr)d

2.58m

(73%, >20:1 dr)e,d

2.58n

(88%, >20:1 dr)d

2.58o

(87%, >20:1 dr)d

65

2.58p

(78%, >20:1 dr)d

aUnless otherwise noted, reactions run on a 0.2 mmol scale. bReaction run using 10 mol % catalyst cReaction run at

100 °C. dReactions were run by Rachel Ross. eReaction run on 0.1 mmol scale.

Next, we examined the scope with respect to the C–H partner (Table 6). Pyridine-N-oxide was an

excellent coupling partner, providing product 2.59 in excellent yield and selectivity as compared

to the standard reaction. Although not a heterocycle, pentafluorobenzene was sufficiently electron

deficient towards C-H activation to undergo the reaction and delivered product 2.60, in good yield

and excellent selectivity albeit requiring a slight increase in catalyst loading. No regioselectivity

was observed with 4-methylthiazole, providing both C-2 and C-5 arylation products in 62% (2.61)

and 31% (2.62) yields, respectively, however, they could be easily separated by column

chromatography. Indole and benzofuran did not have sufficiently low energy of activation to

undergo the desired reaction.101

101

Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848.

66

Table 6 Investigating the substrate scope with respect to the activated arenesa

2.59

(94%, >20:1 dr)

2.60

(77%, >20:1 dr)b

2.61

(62%, >20:1 dr)

2.62

(31%, >20:1 dr)

2.63

(99%, 1:1.2 dr)

aReactions run on 0.2 mmol scale. Reactions were run by Dr. Tamara Beisel. bReactions run using 10 mol % catalyst.

67

Under the standard conditions, benzoxazole provided the dearomatized product (2.63) in

quantitative yield, albeit with poor selectivity. The diastereomers converged to a single

diastereomer by alkylating the acidic position to give two fully substituted contiguous centers

(Scheme 62, 2.64).102

Scheme 62 Convergence of diastereomers by the alkylation of 2.63

Indoles, benzofurans, and benzothiophenes were not tolerated in the reaction and only trace

product could be observed.

2.2.3.4 Investigation of the Role of Copper in the Reaction

We also investigated the role of copperII chloride on the reaction as both the yield and the dr of the

product increased when used (vide supra, section 2.2.3.2 on page 60). We subjected a sample of

the product to Cs2CO3 in toluene at 120 °C for 15 hours (Table 7, entry 1). Although full recovery

of the product was seen, the dr eroded to 2.4:1. The addition of 40 mol% copper gave a similar

outcome (Table 7, entry 2). However, in the presence of 2 equiv of copper, full recovery of the

material was achieved with no erosion in dr (Table 7, entry 3). We attribute the need for 2 equiv

to the relative concentrations of copper and the product relative to base during the progress of the

reaction. That is, during the standard reaction, as the concentration of product increases, the

concentration of base decreases, and hence, a smaller amount of copper is sufficient to maintain

high dr values. The possibility of a diastereromeric resolution by copper was investigated (Table

102

Only one isomer was observed under these reaction conditions. Alkylation proposed to occur stereoselectively

from the convex face due to the rigid structure of the molecule (see ref Error! Bookmark not defined. on page 76).

68

7, entry 4), but no clarity was achieved. However, there was no change in dr suggesting

epimerization is suppressed in both diastereomers.

Table 7 Epimerization studies and probing of the effects of CuII chloridea

Entry Change to standard condition 2.58a+2.58a’ (%)b drc

1 None 98 2.4:1

2 CuCl2 (40 mol%) 79 2.3:1

3 CuCl2 (2 equiv) 97 >20:1

4 CuCl2 (2 equiv) and

sample of 2.58a used was 4:1 dr 89 4:1

aReactions run on 0.1 mmol scale. bYield of 2.58a determined by NMR using trimethoxybenzene as an internal

standard. cDiastereomeric ratio determined by NMR.

2.2.3.5 Conclusion of Research Goal 1

In conclusion, we have developed a palladium-catalyzed diastereoselective dearomatization of

indoles by a 1,2-arylation/direct heteroarylation sequence. Functionalized indolines are accessed

in good to excellent yields and selectivity. The role of copperII chloride was investigated and was

found to prevent epimerization of the easily epimerizable dibenzylic center, as well as improve

conversions.

69

2.3 Research Goal 2 – Arylation/Borylation of Indoles

2.3.1 Motivation

The second research goal of the chapter was to develop a palladium-catalyzed dearomative

aryl/borylation of indoles. Enantioenriched indolines which possess chiral C–B bonds are useful

for future transformations (Scheme 63).103

Scheme 63 Dearomative aryl/borylation with palladium

Boron containing molecules serve as important building blocks: the C–B bond can be used as a

handle for forging new carbon−carbon or carbon−heteroatom bonds (Scheme 64).104 This can been

achieved by metal-catalyzed, radical, oxidative, and reductive methods.

Scheme 64 There is a plethora of precedence for the chemical transformation of the C–B bond to

various other atoms

Palladium-catalysis has been used as a reliable method of borylation of aryl-halides (Scheme 65,

top).105 The domino Heck-borylation reaction, employing boron reagents as nucleophiles, is an

103 Shen, C.; Zeidan, N.; Wu, Q.; Breuers, C. B. J.; Liu, R.-R.; Jia, Y.-X.; Lautens, M. Chem. Sci. 2019, 10, 3118.

104 (a) Pelter, A.; Smith K.; Brown, H. C. Borane Reagents; Academic Press: London, 1988; (b) Miyaura, N.; Suzuki,

A. Chem. Rev. 1995, 95, 2457. (c) Davison, M.; Hughes, A. K.; Marder T. B.; Wade, K. Contemporary Boron

Chemistry; RSC: Cambridge, U.K., 2000. (d) Boronic Acids: Preparation and Applications in Organic Synthesis

Medicine and Materials, 2nd edn., (Ed.: Hall, D. G.), Wiley-VCH, Weinheim, 2011. 105 (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (b) Takagi, J.; Takahashi, K.; Ishiyama,

T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 8001.

70

efficient method to synthesize Csp3-based organoboron compounds (Scheme 65, middle and

bottom).106

Scheme 65 Miyaura-Borylation of aryl-halides and domino methods

It is worthwhile to extend this methodology for the synthesis of structurally diverse, chiral

organoboron heterocycles by dearomatization. At the time of project planning, there had been

numerous studies on forming C–H and C–C bond by dearomative migratory insertion strategy

however, no C–heteroatom bond forming reactions had been explored.

2.3.2 Contributions

The results presented were obtained in collaboration with Christian Breuers (visiting master’s

student from Germany). I conceived the idea, directed the project, and executed most of the

experiments. Christian Breuers synthesized many of the ligands and assisted in the optimization.

Specific contributions are listed within the text as well as within the experimental section.

106 (a) Vachhani, D. D.; Butani, H. H.; Sharma, N.; Bhoya, U. C.; Shah, A. K.; Van der Eycken, E. V. Chem. Commun.

2015, 51, 14862. (b) Lautens, M.; Yoon, H.; Jang, Y. Synthesis 2016, 48, 1483.

71


2.3.3.1 Starting Material Synthesis and Initial Screening

Starting materials were accessed by the same chemical sequence as described in Research Goal 1

(see section 2.2.3.1) however, the aryl-chlorides were used as they produced higher er in the

enantioselective variant, as described below. In our initial screening using previously encountered

conditions for borylation, we were able to achieve a good yield of 2.65a with the presence of

protodeborylated product 2.66 (Scheme 66). At this point, we joined a collaborative effort for the

development of this protocol with the group of Yi-Xia Jia and they took lead in optimizing the

racemic protocol.103

Scheme 66 Initial racemic aryl/borylation of indoles

We continued our studies with the development of the enantioselective variant. Our chief concern

was that 2.65a underwent protodeborylation when subjected to inorganic bases for prolonged

reaction times at high temperatures (Scheme 67).

Scheme 67 Protodeborylation of 2.65a in the presence of inorganic base

72

Furthermore, the only class of ligands which was successful in delivering enantioenriched products

was phosphoramidites107 however, the reaction conditions needed for their success were

incompatible with our optimized conditions thus far (Scheme 68).93

Scheme 68 Phosphoramidite ligands and their reaction condition requirements

The conditions for borylation, protodeborylation, and ligand compatibility conflicted. It was clear

that the development of an enantioselective protocol would rely on the elimination of the inorganic

base in the reaction.

2.3.3.2 Mixed–Boron Reagent

Classic borylation methods rely on the use of B2Pin2 (2.67) and an inorganic base, typically

CsOPiv, KOAc, NaOt-Bu, etc. for transmetallation to a PdII complex formed in situ from oxidative

addition (Scheme 69).108

Scheme 69 B2Pin2 pre-activation for transmetallation with CsOPiv

The coordination of the base to a boron atom allows for an activated sp2-sp3 bond, where the sp2-

boron center could be transferred onto a palladium complex. The Santos group reported a copper-

107 Teichert, J. F.; Feringa, B. L. Angew. Chem. Int. Ed. 2010, 49, 2486. 108 Chow, W. K.; Yuen, O. Y.; Choy, P. Y.; So, C. M.; Lau, C. P.; Wong, W. T.; Kwong, F. Y. RSC Advances 2013,

3, 12518.

73

catalyzed hydroboration of ,-unsaturated conjugated compounds using a pre-activated mixed-

sp2-sp3 boron reagent (Scheme 70, 2.69).109

Scheme 70 Copper-catalyzed borylation developed by Santos and coworkers

The reagent allows the reaction to occur without the need of exogenous inorganic base. The

transmetallation could be explained by a coordination of the amine (Scheme 71).

Scheme 71 Mixed-boron transmetallation and expected byproduct neutralization

To our knowledge, this reagent had not been used with palladium catalysis. The acidic byproduct

produced did not affect the published copper reaction109 however, we suspected this might inhibit

the palladium catalysts as a H-PdII-Cl species. We could however neutralize the reaction with

organic base to avoid protodeborylation of the oxyphilic borylated products. The synthesis of this

mixed-boron reagent, 2.69, is simple and can be done by mixing commercially available

diolamine (2.70) with B2Pin2 (2.67) under conditions which precipitate the polar product, as it is

formed (Scheme 72).

109 (a) Gao, M.; Thorpe, S. B.; Santos, W. L. Org. Lett. 2009, 11, 3478. (b) Thorpe, S. B.; Guo, X.; Santos, W. L.

Chem. Commun. 2011, 47, 424. (c) Gao, M.; Thorpe, S. B.; Kleeberg, C.; Slebodnick, C.; Marder, T. B.; Santos, W.

L. J. Org. Chem. 2011, 76, 3997.

74

Scheme 72 Synthesis of mixed-boron reagent

2.3.3.3 Ligand Synthesis

Phosphoramidites are a class of privileged ligands discovered and popularized by Feringa and

Alexakis.110 Many ortho-functionalized BINOL derivatives have been synthesized in the

literature, mainly by ortho-lithiation/bromination, Suzuki-Miyaura coupling (Scheme 73).111

Scheme 73 General strategy for the synthesis of 3,3’-substituted BINOLs

This divergent protocol allowed for a large library of ligands to be synthesized rapidly. The

commonly employed method for O-P-N coupling requires the use of PCl3 as an electrophile with

various amines (Scheme 74).112 A work-up with DCM and pentanes allows for the isolation of the

ligands in high yields without the need for column chromatography (see section 2.5.4.2.5).

110 (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem. Int. Ed. 1996, 35, 2374. (b) Alexakis, A.; Rosset,

S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 9, 1375. 111 Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701. 112 Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 1657.

75

Scheme 74 O-P-N coupling for the synthesis of phosphoramidite ligands

2.3.3.4 Optimization of the Enantioselective Reaction

The enantioselective Heck/borylation reaction of 2.34 was then investigated using

phosphoramidite L5 as the chiral ligand (Table 8). It was necessary to change solvents from DCE

the MTBE since the former was not efficient in the enantioselective variant (Table 8, entry 1 and

2). Although the bromo- and iodo- variations of the substrates delivered product in higher yields

than the aryl-chloride, it was evident that the smaller halide improved the enantioselectivities

(Table 8, entries 3–4). In the case of the aryl-chloride, there was no reaction using B2Pin2 (Table

8, entry 5). We employed an organic base to neutralize the by-product of the boron-reagent and

the conversion improved to 50% while maintaining the ee (Table 8, entry 6).

Preliminary screening suggested that increasing the steric bulk of the ligand improved the yield of

the reaction (Table 8, entry 7) and therefore further optimization studies were carried out with

ligand L6 (Table 8, entries 8–11). Other amines (Table 8, entry 8) or lowering the temperature

(Table 8, entry 9) were not effective. By increasing ligand and reagent loading, the product was

delivered in 74% yield and 94% ee (Table 8, entry 10 and 11). The absolute stereochemistry of

2.65a was assigned by single-crystal X-ray analysis.113

113 CCDC deposition number: 1855293

76

Table 8 Optimization for the enantioselective aryl/borylationa

Entry X Additive Changes to condition yield (%) er (%)

1 Br None None 73 82:18

2 Br None DCE as solvent 34 60:40

3 I None None 40 75:25

4 Cl None None 15 94:6

5 Cl K2CO3 (2 equiv) B2Pin2 (2 equiv) NR –

6 Cl NEt3 (3 equiv) None 50 94:6

7 Cl NEt3 (3 equiv) Using L6 65 94:6

––––––––––Entries 8–11 using ligand L.6 (N-Cy, p-OMe) ––––––––––

8 Cl i-Pr2NEt (3 equiv) None 27 –

9 Cl NEt3 (3 equiv) 80 °C NR –

10 Cl NEt3 (3 equiv) 10 mol% ligand 68 95.5:4.5

11 Cl NEt3 (5 equiv) 10 mol% ligand

3 equiv 2.69 74 97:3

aIsolated yield. er was determined by chiral HPLC. NR = no reaction.

77

With optimized conditions in hand, we studied the effect of ligand substitution on the reaction

using the conditions in Table 8, entry 11 (Table 9). Many ligands, including BINAP, Prophos,

Binapine, and the parent Josiphos or Walphos produced trace or no product in the reaction.

To our surprise, 3,3’-unsubstituted ligands produced trace or no product (Table 9, L7–L9). We

confirmed that the cyclohexylamine ligand L6 was superior to the initially used ligand (Table 9,

L5–L6). Sterically smaller alkyl groups on the nitrogen were worse in catalyzing the reaction

(Table 9, L10). However, attempting to add steric bulk, while maintaining the electronic properties

of the 3,3’-anisole did not improve the reaction (Table 9, L11–L12). Increasing the electron

density in the aryl rings did not improve the reaction (Table 9, L13). We examined the effects of

increasing the steric bulk at the para position while slightly reducing the electronic perturbations,

and although the yield improved, the enantioselectivity slightly diminished (Table 9, L14).

Investigating electron-withdrawing substitutions also did not further improve the selectivity

however, the sterically congested 3,5-CF3-aryl substituted ligand increased the yield as compared

to the anisole ligand (Table 9, L15–L17).

78

Table 9 Ligand screen with the optimized conditionsa

(R)-BINAP

Trace, ND

L7

Trace, ND

L8

Trace, ND

L9

Trace, ND

L5

74%, 96:4 er

L6

74%, 97:3 er

L10

12%, ND

L11

70%, 95.5:4.5 er

79

L12

71%, 90.5:9.5

er

L13

34%, 93:7 er

L14

80%, 93.5:6.5

er

L15

52%, 89:11 er

L16

23%, 92.5:7.5

er

L17

80%, 81.5:18.5

er

aYields determined by NMR using trimethoxybenzene as an internal standard. The er was determined by chiral HPLC.

80


We then examined the scope of the dearomative Heck/borylation on various aryl-chloride

substrates (Table 10). Absolute stereochemistry was assigned by analogy to 2.65a. Sterically

hindered aryl-halide (2.65b), as well as substrates with functionalities para to the amide tether

(2.65c, 2.65d) provided products in diminished enantioselectivities. In contrast, substitution para

to the chloride (2.65e) or on the indole moiety provided 2.65f -2.65g in moderate yields and

excellent enantioselectivities. Aryl functionality at the C2-position of the indole provided 2.65h

and 2.65i in moderate and good yields with excellent enantioselectivities. Finally, a heterocycle

containing scaffold 2.65j was accessed in good yield albeit in a diminished enantioselectivity.

81

Table 10 Examining the scope of the aryl/borylation of indoles

2.65a

74%, 97:3

2.65b

59%, 89.5:10.5

2.65c

88%, 84:16

2.65d

65%, 84:16

2.65e

66%, 95.5:4.5

2.65f

59%, 95.5:4.5

2.65g

65%, 96.5:3.5

2.65h

73%, 97:3

2.65i

40%, 97:3

2.65j

81%, 91:9

82

2.3.3.6 Derivatization of the Products

We investigated the modular versatility of the C–B bond. Oxidation of compound 2.65a with

perborate provided the chiral alcohol 2.77 (Scheme 75).114

Scheme 75 Oxidation of the boron-containing product 2.65a

Additionally, the alcohol could be further oxidized to the ketone 2.78 with no loss in enantiomeric

excess (Scheme 76).115

Scheme 76 Further oxidation with PCC to the benzylic ketone

2.3.4 Section Conclusion

In conclusion, we have developed a dearomative difunctionalization of indoles through a

palladium-catalyzed intramolecular aryl/borylation reaction. Indolines possessing vicinal

borylated tertiary and tetrasubstituted stereocenters were accessed in good yields and excellent

diastereoselectivities. The asymmetric variant of this reaction was explored with a new BINOL-

based chiral phosphoramidite ligand and moderate to excellent enantioselectivities were obtained

114

Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Angew. Chem. Int. Ed. 2015, 54, 8809. 115

For more derivatizations of the C–B bond, see work by Jia in ref 103.

83

(up to 94% ee). Transformations of the benzylic boron to the alcohol and ketone were presented

to show the synthetic versatility of the products.

2.4 Chapter Summary

This chapter has explored the developments of dearomative reactions of indoles by migratory

insertion and nucleophilic trapping. The regioselectivity of the reaction is complementary to

typical indole dearomatization by electrophiles. Currently, these nucleophilic trapping reactions

are known asymmetrically with phosphoramidite ligands, which are typically expensive. I expect

that future research would aim to find cheaper routes to the enantioenriched products by the

development of new catalysts.

2.5 Experimental


Reactions were monitored by thin-layer chromatography (TLC) on EMD Silica Gel 60 F254 plates

and visualized under UV light or by immersion in iodine on silica stain. Flash column

chromatography was performed on Silicycle 40-60 m silica gel. PhMe was distilled over CaH.

Pd(t-Bu3P)2 was purchased from Johnson Matthey. All reagents and organic building blocks were

purchased from commercial supplier (Sigma Aldrich, Strem, Alfa Aesar, TCI, Combi-blocks) and

used without further purification.


Probe. The spectra were internally referenced to the solvent peak. 19F NMR spectra were obtained

on the Varian Mercury 400 or 500 operating at 470 or 564 MHz. Measurements were taken at 296

K and chemical shifts are reported in parts per million (ppm). Data is reported in the following

format: chemical shift ( ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet), coupling constant (Hz), integration. Melting points were measured on a Fisher-Johns

Melting Point Apparatus and are uncorrected. High resolution mass spectra (HRMS) were obtained

on a Micromass 70S-250 spectrometer (EI) or an ABI/Sciex QStar Mass Spectrometer (ESI) or a

JEOL AccuTOF model JMS-T1000LC mass spectrometer equipped with an IONICS® Direct

Analysis in real Time (DART) ion source. Chiral HPLC analysis was performed on an Agilent HP

1100 or HP 1200 series modular system, operated by ChemStation LC 3D software. Column

specification and conditions described when used.

84



Starting materials 2.34 were synthesized according to literature procedure.54,89 All other starting

materials were synthesized by a slight variation shown below.

2.5.2.2 General Procedure for the Synthesis of N-(2-halobenzoyl)indoles

To a suspension of benzoic acid derivatives (1.2 –2 equiv) in DCM (1 M) and a few drops of DMF

at 0 °C, was added oxalyl chloride (1.2–2 equiv). Stirring ceased when the reaction stopped

evolving gas and a homogeneous solution was observed. The solvent was evaporated, and the acyl-

chloride formed was redissolved in THF (1 M). In a second flask, a solution of indole (1–50 mmol,

1 equiv) in THF (1 M), using an ice water bath as a heat sink, was added NaH (60% dispersion in

mineral oil, 1.2 equiv) and was stirred at room temperature for 10–30 minutes (noticeable dark

colour change upon deprotonation). The solution of acyl-chloride was added to the deprotonated

indole over 1 minute and the reaction was stirred for 2 hours (noticeable light color change). The

reaction was quenched with NH4Cl(aq) (Caution: exothermic and vigorous reaction with left over

NaH). The aqueous layer was extracted with EtOAc, and the organic layer was washed with

NaHCO3(aq) and brine. After evaporation, the crude mixture was columned on silica gel using

relatively non-polar conditions containing triethylamine to remove all traces of indole which

typically elute rapidly (typically seen as a pink–red color upon standing of pure material).

85


(2-iodophenyl)(2-methyl-1H-indol-1-yl)methanone – The compound

was synthesized according to General Procedure 2.5.2.2. The product was

purified by flash column chromatography using pentanes–EtOAc (100:1,

v:v) as the mobile phase and was isolated as a white solid (1.7 g, 4.6 mmol,

46%). 1H NMR (300 MHz, CDCl3) δ 2.26 (d, J = 1.2 Hz, 3H), 6.42 (p, J = 1.1 Hz, 1H), 7.10 (ddd,

J = 8.5, 7.3, 1.4 Hz, 1H), 7.16 – 7.31 (m, 3H), 7.42 – 7.55 (m, 3H), 7.93 (dd, J = 8.0, 1.1 Hz, 1H).

13C NMR (125 MHz, CDCl3) δ 16.6, 93.2, 110.5, 115.1, 119.9, 123.7, 123.8, 128.7, 129.2, 130.1,

132.0, 137.0, 137.5, 140.0, 142.3, 169.2. IR (thin film, cm-1) 3053, 2964, 2924, 2856, 1682, 1595,

1574, 1455, 1308. HRMS (DART, M+H) Calc’d for C16H13INO 362.0042, found 362.0030.

(2-bromo-4-methoxyphenyl)(2-methyl-1H-indol-1-yl)methanone

– The compound was synthesized according to General Procedure

2.5.2.2. The product was purified by flash column chromatography

using pentanes–toluene–DCM (2:2:1, v:v:v) as the mobile phase and

was isolated as a white solid (1.04 g, 3.0 mmol, 60%, mp = 57–62 °C). 1H NMR (500 MHz,

CDCl3) δ 2.30 (d, J = 1.2 Hz, 3H), 3.89 (s, 3H), 6.40 (p, J = 1.1 Hz, 1H), 6.96 (dd, J = 8.6, 2.5 Hz,

1H), 7.09 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.16 – 7.20 (m, 2H), 7.24 – 7.29 (m, 1H), 7.40 – 7.46

(m, 2H). 13C NMR (125 MHz, CDCl3) δ 16.1, 55.8, 109.7, 113.8, 114.5, 118.8, 119.7, 121.6,

123.2, 123.4, 129.8, 130.4, 131.0, 136.8, 137.4, 161.9, 167.6. IR (thin film, cm-1) 3074, 2970,

2929, 2841, 1702, 1610, 1594, 1482, 1466, 1375, 1289, 1321, 1217, 1133, 1025, 752, 732, 696.

HRMS (DART, M+H) Calc’d for C24H19N2O2S 399.11672, found 399.11646.

1-(2-bromobenzoyl)-N-methoxy-N-methyl-1H-indole-2-

carboxamide – The compound was synthesized according to General

Procedure 2.5.2.2. The product was purified by flash column

chromatography using pentanes–EtOAc (5:1, v:v) as the mobile phase

and was isolated as a white solid (658.3 mg, 1.7 mmol, 85%, mp = 72–

76 °C). 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 4H), 3.50 (s, 3H), 7.01 (s, 1H), 7.24 – 7.32 (m,

2H), 7.36 – 7.46 (m, 3H), 7.50 – 7.56 (m, 1H), 7.59 – 7.65 (m, 1H), 7.65 – 7.70 (m, 1H). 13C NMR

(125 MHz, CDCl3) δ 33.4, 61.4, 113.1, 114.8, 121.3, 122.0, 124.0, 126.4, 127.4, 128.7, 130.8,

132.5, 132.5, 133.7, 136.6, 136.6, 163.1, 166.7. IR (thin film, cm-1) 3060, 2985, 2947, 1694, 1653,

86

1457, 1420, 1366, 1332, 1312, 958, 754, 692, 625. HRMS (DART, M+H) Calc’d for

C18H15BrN2O3 387.0344, found 387.0343.

(2-chlorophenyl)(2-methyl-1H-indol-1-yl)methanone – The compound

was synthesized according to General Procedure 2.5.2.2. The product was

purified on silica by flash chromatography, eluting with pentanes to

pentanes–NEt3 (40:1, v:v). The product was isolated as a white solid (60% yield, mp = 58–59 °C).

1H NMR (500 MHz, CDCl3) δ 7.52–7.46 (m, 4H), 7.45–7.39 (m, 2H), 7.23 (td, J = 7.5, 1.0 Hz,

1H), 7.14 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 6.42 (p, J = 1.1 Hz, 1H), 2.27 (d, J = 1.3 Hz, 3H); 13C

NMR (125 MHz, CDCl3) δ 166.9, 137.2, 136.8, 136.4, 132.0, 131.7, 130.3, 129.9, 129.2, 127.4,

123.7, 123.6, 119.8, 114.9, 110.4, 16.2. HRMS (DART, M+H) calculated for C16H13ClNO

270.0686, found 270.0685.

(2-chloro-3-methylphenyl)(2-methyl-1H-indol-1-yl)methanone –

The compound was synthesized according to General Procedure 2.5.2.2.

The crude reaction mixture was purified on silica by flash

chromatography, eluting with pentanes to pentanes–EtOAc (50:1, v:v). The product was isolated

as a white solid (47% yield, mp = 85–86 °C). 1H NMR (500 MHz, CDCl3) δ 7.46–7.38 (m, 3H),

7.32–7.30 (m, 2H), 7.20 (td, J = 7.5, 1.0 Hz, 1H), 7.11 (ddd, J = 8.5, 7.3, 1.3 Hz, 1H), 6.40 (t, J =

1.0 Hz, 1H), 2.45 (d, J = 0.7 Hz, 3H), 2.24 (d, J = 1.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ

167.3, 137.8, 137.3, 136.8, 136.8, 133.0, 131.4, 129.9, 127.0, 126.5, 123.7, 123.5, 119.7, 115.0,

110.3, 20.2, 16.2. HRMS (DART, M+H) calculated for C17H15ClNO 284.0842, found 284.0849.

(2-chloro-4-methoxyphenyl)(2-methyl-1H-indol-1-yl)methanone


2.5.2.2. The crude reaction mixture was purified on silica by flash

chromatography. Two columns were required, first eluting with pentanes–EtOAc (10:1, v:v), then

pentanes–DCM–toluene (2:2:1, v:v:v). The product was isolated as a white solid (31% yield, mp

= 105–106 °C). 1H NMR (500 MHz, CDCl3) δ 7.46–7.42 (m, 2H), 7.30–7.24 (m, 1H), 7.20–7.16

(m, 1H), 7.09 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 8.6, 2.5 Hz,

1H), 6.41–6.39 (m, 1H), 3.88 (s, 3H), 2.31 (d, J = 1.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ

166.9, 162.2, 137.4, 136.8, 133.5, 131.1, 129.8, 128.3, 123.4, 123.2, 119.7, 115.7, 114.4, 113.3,

109.7, 55.8, 16.0. HRMS (DART, M+H) calculated for C17H15ClNO2 300.0791, found 300.0790.

87

(2-chloro-4-fluorophenyl)(2-methyl-1H-indol-1-yl)methanone – The compound was

synthesized according to General Procedure 2.5.2.2. The crude reaction

mixture was purified on silica by flash chromatography, eluting with

pentanes to pentanes–Et2O (100:1, v:v). The product was isolated as a

white solid (35% yield, mp = 51–52 °C). 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J = 8.6, 5.8 Hz,

1H), 7.46 (ddd, J = 7.7, 1.3, 0.7 Hz, 1H), 7.32 (dq, J = 8.3, 0.9 Hz, 1H), 7.27–7.19 (m, 2H), 7.17–

7.11 (m, 2H), 6.42 (t, J = 1.1 Hz, 1H), 2.28 (d, J = 1.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ

166.2, 163.8 (d, J = 255.6 Hz), 137.2, 136.8, 133.5 (d, J = 10.8 Hz), 132.8 (d, J = 3.8 Hz), 131.2

(d, J = 9.4 Hz), 130.0, 123.8, 123.8, 120.0, 118.1 (d, J = 24.9 Hz), 115.1 (d, J = 21.8 Hz), 114.7,

110.5, 16.3. 19F NMR (377 MHz, CDCl3) δ -105.88 (q, J = 7.9 Hz). HRMS (DART, M+H)

calculated for C16H12ClFNO 288.0591, found 288.0590.

(2-chloro-5-fluorophenyl)(2-methyl-1H-indol-1-yl)methanone – The

compound was synthesized according to General Procedure 2.5.2.2. The

crude reaction mixture was purified on silica by flash chromatography,

eluting with pentanes to pentanes–Et2O, (100:1, v:v). The product was

isolated as a white solid (36% yield, mp = 73–75 °C). 1H NMR (500 MHz, CDCl3) δ 7.48–7.43

(m, 2H), 7.42–7.39 (m, 1H), 7.25–7.19 (m, 3H), 7.14 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 6.43 (t, J =

1.2 Hz, 1H), 2.28 (d, J = 1.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.4 (d, J = 2.0 Hz), 161.2

(d, J = 250.3 Hz), 137.7 (d, J = 7.2 Hz), 136.9, 136.6, 131.9 (d, J = 8.0 Hz), 129.9, 126.7 (d, J =

3.6 Hz), 123.9, 123.8, 119.9, 119.1 (d, J = 22.8 Hz), 116.3 (d, J = 24.7 Hz), 114.7, 110.8, 16.2. 19F

NMR (377 MHz, CDCl3) δ -112.96 (td, J = 8.0, 4.6 Hz). HRMS (DART, M+H) calculated for

C16H12ClFNO 288.0591, found 288.0584.

(2-chlorophenyl)(5-fluoro-2-methyl-1H-indol-1-yl)methanone –

The compound was synthesized according to General Procedure


chromatography, eluting with pentanes to pentanes–Et2O (100:1, v:v). The product was isolated

as a white solid (47% yield, mp = 84–85 °C). 1H NMR (500 MHz, CDCl3) δ 7.56–7.38 (m, 5H),

7.10 (dd, J = 8.6, 2.6 Hz, 1H), 6.85 (td, J = 9.1, 2.6 Hz, 1H), 6.36 (p, J = 1.2 Hz, 1H), 2.19 (d, J =

1.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.8, 159.8 (d, J = 240.0 Hz), 138.9, 136.3, 133.2

(d, J = 1.4 Hz), 132.2, 131.8, 131.1 (d, J = 10.0 Hz), 130.5, 129.3, 127.6, 116.1 (d, J = 9.1 Hz),

111.3 (d, J = 24.7 Hz), 110.2 (d, J = 3.7 Hz), 105.6 (d, J = 23.8 Hz), 16.3. 19F NMR (377 MHz,

88

CDCl3) δ -119.68 (td, J = 8.6, 8.2, 4.6 Hz). HRMS (DART, M+H) calculated for C16H12ClFNO

288.0591, found 288.0596.

(2-chlorophenyl)(5-methoxy-2-methyl-1H-indol-1-yl)methanone



chromatography, eluting with pentanes to pentanes–NEt3 (20:1, v:v). The product was isolated as

a white solid (41% yield, mp = 54–55 °C). 1H NMR (500 MHz, CDCl3) δ 7.51–7.46 (m, 3H),

7.43–7.39 (m, 1H), 7.31 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 9.0, 2.6 Hz,

1H), 6.33 (dt, J = 1.9, 0.9 Hz, 1H), 3.82 (s, 3H), 2.20 (d, J = 1.2 Hz, 3H). 13C NMR (125 MHz,

CDCl3) δ 166.5, 156.4, 137.9, 136.4, 131.8, 131.6, 131.4, 130.9, 130.2, 129.1, 127.3, 115.7, 111.6,

110.4, 102.9, 55.6, 16.2. HRMS (DART, M+H) calculated for C17H15ClNO2 300.0791, found

300.0784.

(2-chlorophenyl)(2-phenyl-1H-indol-1-yl)methanone – The compound

was synthesized according to General Procedure 2.5.2.2. The crude

reaction mixture was purified on silica by flash chromatography, eluting

with pentanes to pentanes–Et2O (100:1, v:v). The product was isolated as

a white solid (46% yield, mp = 86–87 °C). 1H NMR (500 MHz, CDCl3) δ 8.14 (ddt, J = 8.1, 1.4,

0.8 Hz, 1H), 7.61 (ddd, J = 7.3, 1.6, 0.7 Hz, 1H), 7.40–7.29 (m, 2H), 7.28–7.25 (m, 2H), 7.21 (ddd,

J = 7.6, 1.6, 0.6 Hz, 1H), 7.16–7.08 (m, 5H), 7.03 (ddd, J = 7.7, 6.7, 1.9 Hz, 1H), 6.66 (d, J = 0.7

Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 167.4, 140.5, 137.8, 135.6, 132.8, 132.5, 131.8, 130.6,

129.9, 129.5, 128.8, 127.7, 127.7, 126.3, 125.0, 124.0, 120.6, 115.2, 111.4. HRMS (DART, M+H)

calculated for C21H15ClNO 332.0842, found 332.0844.

(2-chlorophenyl)(2-(4-fluorophenyl)-1H-indol-1-yl)methanone – The



eluting with pentanes to pentanes–MTBE (50:1, v:v). The product was

isolated as a white solid (21% yield, mp = 94–96 °C). 1H NMR (500 MHz,

CDCl3) δ 8.11 (ddt, J = 8.2, 1.4, 0.8 Hz, 1H), 7.60 (ddd, J = 7.2, 1.7, 0.7

Hz, 1H), 7.39–7.31 (m, 2H), 7.25–7.21 (m, 3H), 7.18 (ddd, J = 8.1, 7.2, 1.7 Hz, 1H), 7.13 (ddd, J

= 8.2, 1.4, 0.5 Hz, 1H), 7.08 (td, J = 7.5, 1.3 Hz, 1H), 6.85–6.80 (m, 2H), 6.64 (d, J = 0.8 Hz, 1H).

89

13C NMR (125 MHz, CDCl3) δ 167.3, 162.1 (d, J = 248.2 Hz), 139.3, 137.6, 135.5, 132.3, 131.9,

130.6 (d, J = 7.6 Hz), 130.5, 130.0, 129.3, 128.9 (d, J = 3.6 Hz), 126.5, 125.2, 124.1, 120.6, 115.2,

114.8 (d, J = 21.9 Hz), 111.6. 19F NMR (377 MHz, CDCl3) δ -113.45 (ddd, J = 13.9, 9.0, 5.6 Hz).

HRMS (DART, M+H) calculated for C21H14ClFNO 350.0748, found 350.0743.

(2-chloropyridin-3-yl)(2-methyl-1H-indol-1-yl)methanone – The



eluting with pentanes–EtOAc (10:1 to 5:1, v:v). The product was isolated as a white solid (38%

yield, mp = 66–67 °C). 1H NMR (500 MHz, CDCl3) δ 8.60 (dd, J = 4.9, 2.0 Hz, 1H), 7.85 (dd, J

= 7.6, 2.0 Hz, 1H), 7.48–7.41 (m, 3H), 7.23 (td, J = 7.5, 1.0 Hz, 1H), 7.15 (ddd, J = 8.6, 7.3, 1.3

Hz, 1H), 6.44 (p, J = 1.2 Hz, 1H), 2.23 (d, J = 1.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.2,

151.5, 148.0, 138.0, 136.7, 136.6, 132.9, 130.0, 124.1, 124.0, 122.7, 120.0, 114.8, 111.1, 16.5.

HRMS (DART, M+H) calculated for C15H12ClN2O 271.0638, found 271.0630.

2.5.3 Research Goal 1 – Dearomative Palladium-Catalyzed Arylation/Heteroarylation

2.5.3.1 General Procedure for the Arylation/Heteroarylation

In an oven-dried 2-dram vial equipped with an open-top septum cap purging with an argon balloon

was added substrate 2.34 (0.2 mmol), Pd(t-Bu3P)2 (5 mol %), Cs2CO3 (2 equiv), CuCl2 (40 mol

%), and the heterocycle (8 equiv) if it is a solid at room temperature. After a 10-minute purge,

PhMe (2 mL, 0.1 M) and, in the cases where a liquid heterocycle was used, the heterocycle (8

equiv), in that order. The balloon was removed, and the reaction was heated to 120 °C, for 15 h. It

was necessary to stir the reaction at 1000–1400 rpm to avoid clumping of the base. Upon

completion, the reaction was filtered through a silica plug, concentrated, and columned via silica

gel chromatography.

90


(±)-11-(benzo[d]thiazol-2-yl)-10b-methyl-10b,11-dihydro-6H-

isoindolo[2,1-a]indol-6-one (2.58a) – Was synthesized according to

General Procedure 2.5.3.1. The product was purified by flash column

chromatography using pentanes–EtOAc (9:1 to 7:3, v:v) as the mobile phase

and was isolated as an off-white (73.7 mg, 0.2 mmol, >99%, mp = 223–226

°C). 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.45 (m, 2H), 7.38 (dt, J = 7.6,

1.0 Hz, 1H), 7.34 (ddd, J = 8.3, 7.1, 1.2 Hz, 2H), 7.29 (td, J = 7.5, 1.3 Hz, 1H), 7.24 (td, J = 7.5,

1.1 Hz, 1H), 7.18 (td, J = 7.7, 1.2 Hz, 2H), 5.02 (d, J = 0.6 Hz, 1H), 1.85 (s, 3H). 13C NMR (125

MHz, CDCl3) δ 171.0, 168.4, 152.3, 147.3, 139.3, 136.3, 135.5, 133.0, 132.5, 130.2, 128.9, 127.2,

126.0, 125.3, 125.0, 124.6, 123.6, 122.9, 121.8, 117.8, 75.7, 55.5, 28.3. IR (thin film, cm-1) 3080,

3051, 2980, 2926, 1694, 1603, 1486, 1466, 1357, 1312, 904, 758. HRMS (DART, M+H) Calc’d

for C23H17N2OS 369.1062, found 369.1067.

Syn-diastereomer: 1H NMR (500 MHz, CDCl3) δ 8.16 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H), 7.97 (ddd,

J = 8.0, 1.3, 0.6 Hz, 1H), 7.92 (dt, J = 7.6, 1.0 Hz, 1H), 7.81 (dt, J = 7.7, 0.9 Hz, 1H), 7.76 (dt, J =

7.9, 0.8 Hz, 1H), 7.69 (td, J = 7.5, 1.2 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.51 – 7.42 (m, 3H), 7.21 (td,

J = 7.6, 1.1 Hz, 1H), 5.22 (t, J = 1.2 Hz, 1H), 1.46 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.8,

167.7, 153.6, 150.6, 140.0, 135.8, 135.1, 133.4, 132.5, 129.6, 129.2, 126.6, 126.5, 125.7, 125.2,

125.1, 123.4, 123.2, 121.8, 117.8, 75.3, 55.0, 23.6. HRMS (DART, M+H) Calc’d for C23H17N2OS

369.1062, found 369.1062.

Gram-scale: Reaction was run according to General Procedure 2.5.3.1 however, on a scale of 1 g

(3.2 mmol of 1a) in a 100 mL Schlenk bomb (producing 1.04 g of product).

(±)-11-(benzo[d]thiazol-2-yl)-9-fluoro-10b-methyl-10b,11-dihydro-

6H-isoindolo[2,1-a]indol-6-one (2.58b) – Was synthesized according to

General Procedure 2.5.3.1 however using 100 °C reaction temperature.

The product was purified by flash column chromatography using

pentanes–EtOAc (20:1 to 7:3, v:v) as the mobile phase and was isolated

as an off-white (72.65 mg, 0.188 mmol, 94%, mp = 210–214 °C). 1H NMR (500 MHz, CDCl3) δ

7.93 – 7.88 (m, 1H), 7.86 (dd, J = 7.9, 1.1 Hz, 1H), 7.69 (dd, J = 8.4, 5.0 Hz, 1H), 7.51 (td, J = 7.8,

1.1 Hz, 2H), 7.40 – 7.33 (m, 2H), 7.24 – 7.17 (m, 2H), 7.10 (dd, J = 8.2, 2.3 Hz, 1H), 6.94 (td, J =

91

8.7, 2.1 Hz, 1H), 5.01 (s, 1H), 1.84 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 170.6, 167.3, 165.5

(d, J = 254.0 Hz), 152.5, 150.0 (d, J = 9.8 Hz), 139.3, 135.9, 135.4, 130.3, 129.1 (d, J = 2.0 Hz),

127.2, 126.7 (d, J = 9.8 Hz), 126.2, 125.4, 125.2, 123.1, 121.8, 117.8, 116.8 (d, J = 23.6 Hz), 111.2

(d, J = 24.2 Hz), 75.3 (d, J = 2.5 Hz), 55.4, 28.2. 19F NMR (377 MHz, CDCl3) δ -104.95 (td, J =

8.8, 5.1 Hz). IR (thin film, cm-1) 3064, 2972, 2928, 2856, 1713, 1628, 1602, 1479, 1354, 1192.

HRMS (DART, M+H) Calc’d for C23H16FN2OS 387.0967, found 387.0976.

(±)-11-(benzo[d]thiazol-2-yl)-9-methoxy-10b-methyl-10b,11-

dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58c) – The compound

was synthesized according to General Procedure 2.5.3.1 using 10 mol

% catalyst loading. This reaction was run by Rachel Ross. The product

was purified by flash column chromatography using pentanes–EtOAc

(9:1 to 7:3, v:v) as the mobile phase and was isolated as an orange

solid (61.1 mg, 0.15 mmol, 77%, mp = 57–62 °C). 1H NMR (500 MHz, CDCl3) δ 1.84 (s, 3H),

3.69 (s, 3H), 4.99 – 5.02 (m, 1H), 6.75 (dd, J = 8.4, 2.2 Hz, 1H), 6.84 (dd, J = 2.2, 0.5 Hz, 1H),

7.16 (td, J = 7.5, 1.1 Hz, 1H), 7.21 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.32 – 7.40 (m, 2H), 7.46 – 7.52

(m, 2H), 7.61 (dd, J = 8.4, 0.5 Hz, 1H), 7.85 (ddt, J = 7.9, 1.1, 0.5 Hz, 1H), 7.90 (ddd, J = 8.2, 1.1,

0.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 171.3, 168.4, 163.4, 152.3, 150.1, 139.8, 135.7, 130.2,

127.1, 126.1, 126.0, 125.4, 125.0, 122.8, 121.9, 117.6, 116.4, 107.8, 75.2, 55.8, 55.5, 28.7. IR

(thin film, cm-1) 3074, 2970, 2929, 2841, 1702, 1610, 1594, 1482, 1466, 1375, 1289, 1321, 1217,

1133, 1025, 752, 732, 696. HRMS (DART, M+H) Calc’d for C24H19N2O2S 399.1167, found

399.1165.

(±)-11-(benzo[d]thiazol-2-yl)-10b-methyl-8-(trifluoromethyl)-

10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58d) – The

compound was synthesized according to General Procedure 2.5.3.1. This

reaction was run by Rachel Ross. The product was purified by flash

column chromatography using pentanes–EtOAc (9:1 to 7:3, v:v) as the

mobile phase and was isolated as a brown solid (40.0 mg, 0.09 mmol,

46%, mp = 123–128 °C). 1H NMR (500 MHz, CDCl3) δ 1.86 (s, 3H), 5.06 (d, J = 0.6 Hz, 1H),

7.19 – 7.24 (m, 2H), 7.37 (ddd, J = 8.4, 7.3, 1.2 Hz, 2H), 7.49 – 7.58 (m, 4H), 7.88 (tt, J = 8.2, 0.8

Hz, 2H), 7.99 (dt, J = 1.6, 0.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 28.3, 55.3, 75.9, 117.9,

121.9, 122.0 (q, J = 3.9 Hz), 123.0, 123.6 (q, J = 272.7 Hz), 124.3, 125.3, 125.8, 126.3, 127.3,

92

129.2 (q, J = 3.6 Hz), 130.4, 131.6 (q, J = 33.1 Hz), 134.0, 135.3, 136.0, 138.9, 150.2 – 151.0 (m),

152.4, 166.6, 170.3. 19F NMR (376 MHz, CDCl3) δ -62.53. IR (thin film, cm-1) 3064, 2972, 2926,

2852, 1706, 1630, 1605, 1479, 1435, 1322, 1117, 753. HRMS (DART, M+H) Calc’d for

C24H16F3N2OS 437.0935, found 437.0934.


dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58e) – The compound was

synthesized according to General Procedure 2.5.3.1. This reaction was

run by Rachel Ross. The product was purified by flash column

chromatography using pentanes–EtOAc (9:1 to 7:3, v:v) as the mobile

phase and was isolated as an orange solid (67.4 mg, 0.17 mmol, 85%

(+5% diastereomer), mp = 150–155 °C). 1H NMR (500 MHz, CDCl3) δ 1.82 (s, 3H), 3.73 (s, 3H),

4.98 – 5.00 (m, 1H), 6.85 (dd, J = 8.4, 2.5 Hz, 1H), 7.15 – 7.23 (m, 3H), 7.25 – 7.29 (m, 1H), 7.33

– 7.38 (m, 2H), 7.46 – 7.53 (m, 2H), 7.88 (ddt, J = 10.0, 7.9, 0.8 Hz, 2H). 13C NMR (125 MHz,

CDCl3) δ 28.4, 55.5, 55.7, 75.4, 107.1, 117.8, 120.9, 121.8, 123.0, 124.4, 125.0, 125.3, 126.0,

127.2, 130.2, 134.5, 135.6, 136.5, 139.3, 139.7, 152.4, 160.3, 168.3, 171.3. IR (thin film, cm-1)

2929, 1702, 1610, 1478, 1434, 1357, 1321, 1285, 1145, 1053, 1013, 832, 776, 760, 732. HRMS

(DART, M+H) Calc’d for C24H19N2O2S 399.1167, found 399.1153.


dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58f) – The compound was


purified by flash column chromatography using pentanes–EtOAc (9:1

to 7:3, v:v) as the mobile phase and was isolated as a white solid (68.54

mg, 0.172 mmol, 86% (+9% diastereomer), mp = 171–175 °C). 1H

NMR (500 MHz, CDCl3) δ 7.88 (ddd, J = 8.3, 1.2, 0.6 Hz, 1H), 7.78 (dd, J = 8.7, 0.5 Hz, 1H),

7.70 (ddd, J = 7.4, 1.3, 0.7 Hz, 1H), 7.48 (ddd, J = 8.0, 1.2, 0.7 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.28

(td, J = 7.5, 1.3 Hz, 1H), 7.24 (td, J = 7.4, 1.2 Hz, 1H), 7.19 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.02

(ddd, J = 8.7, 2.6, 0.4 Hz, 1H), 6.90 (dt, J = 2.6, 0.5 Hz, 1H), 4.97 (d, J = 0.6 Hz, 1H), 3.77 (s, 3H),

1.84 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 170.8, 168.3, 157.7, 152.3, 147.2, 137.7, 135.5, 133.3,

132.8, 132.3, 128.9, 126.0, 125.0, 124.5, 123.5, 122.9, 121.8, 118.5, 115.5, 112.8, 76.1, 55.8, 55.8,

28.1. IR (thin film, cm-1) 3004, 2966, 2943, 2836, 1718, 1700, 1489, 1362, 1279. HRMS (DART,

M+H) Calc’d for C24H19N2O2S 399.1167, found 399.1160.

93

(±)-11-(benzo[d]thiazol-2-yl)-2-fluoro-10b-methyl-10b,11-dihydro-6H-isoindolo[2,1-

a]indol-6-one (2.58g) – The compound was synthesized according to

General Procedure 2.5.3.1. This reaction was run by Rachel Ross. The

product was purified by flash column chromatography using pentanes–

EtOAc (9:1 to 7:3, v:v) as the mobile phase and was isolated as a white

solid (50.2 mg, 0.13 mmol, 65% (+6% diastereomer), mp = 224–228 °C).

1H NMR (500 MHz, CDCl3) δ 1.85 (s, 3H), 5.00 (s, 1H), 7.07 (dd, J = 7.9,

2.6 Hz, 1H), 7.17 – 7.22 (m, 2H), 7.23 – 7.27 (m, 1H), 7.30 (td, J = 7.5, 1.3 Hz, 1H), 7.34 – 7.38

(m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.72 (ddd, J = 7.4, 1.3, 0.7 Hz, 1H), 7.82 (dd, J = 8.7, 4.6 Hz,

1H), 7.88 (d, J = 8.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 28.2, 55.6 (d, J = 1.9 Hz), 76.2,

114.5 (d, J = 24.4 Hz), 117.0 (d, J = 23.6 Hz), 118.7 (d, J = 8.6 Hz), 121.8, 123.0, 123.5, 124.7,

125.2, 126.2, 129.0, 132.6, 132.8, 135.4, 135.6 (d, J = 2.3 Hz), 137.9 (d, J = 8.4 Hz), 147.2, 152.3,

160.4 (d, J = 244.5 Hz), 168.5, 169.9. 19F NMR (376 MHz, CDCl3) δ -116.68 – -116.59 (m). IR

(thin film, cm-1) 2921, 1694, 1614, 1490, 1361, 1333, 1309, 1229, 1137, 1109, 1085, 1065, 896,

824, 768, 732. HRMS (DART, M+H) Calc’d for C23H16FN2OS 387.0967, found 387.0968.

94

(±)-11-(benzo[d]thiazol-2-yl)-2,9-difluoro-10b-methyl-10b,11-

dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58h) – The compound

was synthesized according to General Procedure 2.5.3.1. The product

was purified by flash column chromatography using pentanes–EtOAc

(20:1 to 7:3, v:v) as the mobile phase and was isolated as a white solid

(42.06 mg, 0.104 mmol, 52%, mp = 178–182 °C). 1H NMR (500 MHz,

CDCl3) δ 7.94 (s, 1H), 7.80 (dd, J = 8.7, 4.6 Hz, 1H), 7.69 (dd, J = 8.4, 4.9 Hz, 1H), 7.60 (d, J =

34.1 Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.14 – 7.02 (m, 2H), 6.94 (t, J = 8.6

Hz, 1H), 5.01 (s, 1H), 1.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.4, 166.5114., 164.5, 161.4,

159.5, 149.8 (d, J = 9.7 Hz), 135.5 (d, J = 2.3 Hz), 128.9 (d, J = 2.1 Hz), 126.8 (d, J = 10.0 Hz),

126.3, 125.4, 121.9, 118.7 (d, J = 8.6 Hz), 117.2, 117.1 (d, J = 2.6 Hz), 116.9, 114.6 (d, J = 24.4

Hz), 111.2 (d, J = 24.3 Hz), 55.5. IR (thin film, cm-1) 3069, 2971, 2854, 1714, 1623, 1598, 1485,

1191. HRMS (DART, M+H) Calc’d for C23H15F2N2OS 405.0873, found 405.0872.

(±)-11-(benzo[d]thiazol-2-yl)-10b-ethyl-10b,11-dihydro-6H-

isoindolo[2,1-a]indol-6-one (2.58i) – The compound was synthesized

according to General Procedure 2.5.3.1. This reaction was run by Rachel

Ross. The product was purified by flash column chromatography using

pentanes–EtOAc (9:1 to 7:3, v:v) as the mobile phase and was isolated as a

white solid (68.6 mg, 0.18 mmol, 90%, mp = 229–231 °C). 1H NMR (500

MHz, CDCl3) δ 0.69 (t, J = 7.3 Hz, 3H), 2.25 (qd, J = 7.1, 3.3 Hz, 2H), 5.04 (s, 1H), 7.14 – 7.21

(m, 2H), 7.22 – 7.30 (m, 2H), 7.30 – 7.37 (m, 3H), 7.48 (td, J = 7.7, 1.1 Hz, 2H), 7.72 (dd, J = 7.3,

1.3 Hz, 1H), 7.82 – 7.93 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 8.0, 33.5, 55.1, 79.2, 117.7,

121.8, 122.9, 123.6, 124.4, 125.0, 125.2, 126.0, 127.0, 128.9, 130.1, 132.4, 134.0, 135.6, 136.7,

139.7, 145.7, 152.4, 169.0, 171.2. IR (thin film, cm-1) 3051, 3037, 2984, 2973, 2934, 2876, 1689,

1600, 1516, 1480, 1459, 1365, 1106, 753. HRMS (DART, M+H) Calc’d for C24H19N2OS

383.1218, found 383.1227.

95

(±)-2-(3-(11-(benzo[d]thiazol-2-yl)-6-oxo-6H-isoindolo[2,1-

a]indol-10b(11H)-yl)propyl)isoindoline-1,3-dione (2.58j) –

The compound was synthesized according to General Procedure

2.5.3.1. This reaction was run by Rachel Ross. The product was

purified by flash column chromatography using pentanes–EtOAc

(9:1 to 1:1, v:v) as the mobile phase and was isolated as an orange

solid (84.6 mg, 0.16 mmol, 78%, mp = 205–208 °C). 1H NMR (500 MHz, CDCl3) δ 1.18 – 1.31

(m, 1H), 1.66 (ddtd, J = 13.5, 11.6, 6.8, 4.9 Hz, 1H), 2.21 – 2.35 (m, 2H), 3.56 (t, J = 7.0 Hz, 2H),

5.02 (s, 1H), 7.17 (tdd, J = 7.6, 4.8, 1.1 Hz, 2H), 7.19 – 7.24 (m, 2H), 7.24 – 7.28 (m, 1H), 7.30 –

7.35 (m, 2H), 7.44 – 7.49 (m, 2H), 7.67 – 7.72 (m, 3H), 7.79 – 7.81 (m, 2H), 7.85 (ddt, J = 9.6,

8.0, 0.8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 23.0, 37.7, 37.7, 55.3, 78.3, 117.8, 121.7, 122.9,

123.4, 123.6, 124.6, 125.0, 125.4, 126.0, 127.1, 129.1, 130.2, 132.1, 132.7, 133.6, 134.1, 135.6,

136.3, 139.7, 145.5, 152.3, 168.3, 169.1, 170.9. IR (thin film, cm-1) 3061, 2929, 2857, 1710, 1606,

1486, 1466, 1405, 1362, 1301, 1125, 760, 720, 692, 672. HRMS (DART, M+H) Calc’d for

C33H24N3O3S 542.1538, found 542.1530.

(±)-11-(benzo[d]thiazol-2-yl)-N-methoxy-N-methyl-6-oxo-6H-

isoindolo[2,1-a]indole-10b(11H)-carboxamide (2.58k) – The

compound was synthesized according to General Procedure 2.5.3.1 using

10 mol % catalyst loading. This reaction was run by Rachel Ross. The


EtOAc (9:1 to 7:3, v:v) as the mobile phase and was isolated as a yellow

solid (56.0 mg, 0.13 mmol, 63%, mp = 194–198 °C). 1H NMR (400 MHz, CDCl3) δ 3.10 (s, 3H),

3.42 (s, 3H), 6.40 (s, 1H), 7.17 (tt, J = 7.6, 1.4 Hz, 2H), 7.23 – 7.34 (m, 3H), 7.35 (dd, J = 7.6, 1.1

Hz, 1H), 7.40 – 7.52 (m, 3H), 7.69 – 7.73 (m, 1H), 7.85 (dd, J = 8.1, 5.9 Hz, 2H). 13C NMR (125

MHz, CDCl3) δ 34.5, 51.7, 61.3, 81.5, 117.0, 121.6, 123.2, 124.1, 124.2, 124.9, 125.6, 125.9,

126.8, 129.5, 130.0, 132.6, 134.2, 135.4, 136.5, 139.9, 141.5, 152.8, 168.9, 169.6, 170.0. IR (thin

film, cm-1) 3068, 2976, 2935, 1715, 1653, 1486, 1470, 1357, 1307, 758, 733. HRMS (DART,

M+H) Calc’d for C25H20N3O3S 442.1225, found 442.1219.

96

(±)-11-(benzo[d]thiazol-2-yl)-10b-phenyl-10b,11-dihydro-6H-

isoindolo[2,1-a]indol-6-one (2.58l) – The compound was synthesized





MHz, CDCl3) δ 5.66 (s, 1H), 7.12 – 7.30 (m, 6H), 7.38 (qd, J = 6.6, 1.3 Hz, 3H), 7.50 (td, J = 7.7,

1.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.67 – 7.69 (m, 1H), 7.84 – 7.88 (m, 2H), 7.97 (d, J = 8.1

Hz, 1H), 8.00 (dd, J = 8.0, 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 57.4, 80.8, 117.6, 121.8,

123.1, 124.6, 124.6, 125.1, 125.3, 125.6, 126.1, 126.9, 128.4, 128.8, 129.2, 130.3, 132.3, 132.6,

135.8, 136.0, 140.0, 142.8, 146.8, 152.7, 169.0, 171.0. IR (thin film, cm-1) 3070, 3046, 3029, 1734,

1709, 1604, 1479, 1459, 1348, 1304, 1140, 748. HRMS (DART, M+H) Calc’d for C28H19N2OS

431.1218, found 431.1227.

(±)-11-(benzo[d]thiazol-2-yl)-10b-(4-methoxyphenyl)-10b,11-

dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58m) – The compound

was synthesized according to General Procedure 2.5.3.1 on 0.1 mmol

scale. This reaction was run by Rachel Ross. The product was purified

by flash column chromatography using pentanes–EtOAc (9:1 to 8:2,

v:v) as the mobile phase and was isolated as a white solid (33.7 mg,

0.07 mmol, 73%, mp = 240–245 °C). 1H NMR (500 MHz, CDCl3) δ 3.75 (s, 3H), 5.61 (d, J = 0.6

Hz, 1H), 6.85 – 6.92 (m, 2H), 7.15 (dtd, J = 8.6, 7.5, 1.1 Hz, 2H), 7.18 – 7.23 (m, 2H), 7.25 – 7.28

(m, 1H), 7.38 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 7.46 – 7.53 (m, 3H), 7.67 (ddd, J = 7.4, 1.3, 0.7 Hz,

1H), 7.71 – 7.78 (m, 2H), 7.95 (ddd, J = 8.2, 1.2, 0.7 Hz, 1H), 7.98 (ddt, J = 7.9, 1.1, 0.5 Hz, 1H).

13C NMR (125 MHz, CDCl3) δ 55.4, 57.3, 80.5, 114.5, 117.6, 121.8, 123.0, 124.5, 124.5, 125.1,

125.6, 126.1, 126.5, 126.9, 128.7, 130.2, 132.3, 132.6, 134.6, 135.6, 136.2, 139.9, 147.2, 152.5,

159.6, 169.0, 171.0. IR (thin film, cm-1) 3072, 2935, 2839, 1715, 1607, 1511, 1478, 1466, 1306,

1258, 1183, 1037, 754, 729. HRMS (DART, M+H) Calc’d for C29H21N2OS 461.1324, found

461.1324.

97

(±)-11-(benzo[d]thiazol-2-yl)-10b-(4-(trifluoromethyl)phenyl)-

10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (2.58n) – The

compound was synthesized according to General Procedure 2.5.3.1.

This reaction was run by Rachel Ross. The product was purified by flash

column chromatography using pentanes–EtOAc (9:1 to 8:2, v:v) as the

mobile phase and was isolated as a white solid (87.5 mg, 0.18 mmol,

88%, mp = 210–214 °C). 1H NMR (500 MHz, CDCl3) δ 5.62 (s, 1H), 7.14 – 7.29 (m, 5H), 7.40

(t, J = 7.4 Hz, 1H), 7.48 – 7.56 (m, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 7.4, 1.4 Hz, 1H),

7.95 – 8.03 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 57.30, 80.51, 117.68, 121.87, 123.12, 123.91

(q, J = 272.2 Hz), 124.56, 124.80, 125.23, 125.79, 125.87, 126.22 (q, J = 3.8 Hz), 126.96, 127.21,

129.21, 130.51, 130.71 (q, J = 32.7 Hz), 132.27, 132.84, 135.45, 135.86, 139.81, 145.89, 146.90,

152.74, 168.87, 170.54. 19F NMR (376 MHz, CDCl3) δ -62.70. IR (thin film, cm-1) 3078, 2925,

1723, 1606, 1486, 1470, 1325, 1305, 1161, 1117, 1069, 1025, 844, 824, 752, 732, 692, 612. HRMS

(DART, M+H) Calc’d for C29H18F3N2OS 499.1092, found 499.1090.

(±)-11-(benzo[d]thiazol-2-yl)-8-methyl-10b-phenyl-10b,11-dihydro-

6H-isoindolo[2,1-a]indol-6-one (2.58o) – The compound was synthesized





MHz, CDCl3) δ 2.19 (s, 3H), 5.63 (s, 1H), 7.01 (ddd, J = 8.0, 1.6, 0.7 Hz, 1H), 7.13 (td, J = 7.5,

1.1 Hz, 1H), 7.21 – 7.29 (m, 3H), 7.33 – 7.42 (m, 4H), 7.46 – 7.51 (m, 2H), 7.54 (ddd, J = 7.9, 1.2,

0.6 Hz, 1H), 7.81 – 7.85 (m, 2H), 7.96 – 8.01 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 21.3, 57.3,

80.6, 117.5, 121.9, 123.1, 124.2, 124.8, 125.0, 125.2, 125.5, 126.1, 126.9, 128.2, 129.1, 130.2,

132.5, 133.8, 135.8, 136.2, 139.0, 140.0, 143.2, 144.2, 152.6, 169.1, 171.1. IR (thin film, cm-1)

3066, 2925, 2853, 1710, 1602, 1486, 1466, 1357, 1309, 1241, 1137, 760, 732, 708, 628. HRMS

(DART, M+H) Calc’d for C29H21N2OS 445.1375, found 445.1379.

98

(±)-11-(benzo[d]thiazol-2-yl)-10b-methyl-7,8,9,10,10b,11-hexahydro-

6H-isoindolo[2,1-a]indol-6-one (2.58p) – The compound was synthesized



pentanes–EtOAc (9:1, v:v) as the mobile phase and was isolated as an orange

solid (57.9 mg, 0.16 mmol, 78%, mp = 206–209 °C). 1H NMR (500 MHz,

CDCl3) δ 1.06 (ddtt, J = 12.7, 9.2, 6.4, 3.6 Hz, 1H), 1.19 – 1.28 (m, 1H), 1.41 – 1.48 (m, 1H), 1.52

(dtdd, J = 13.2, 7.8, 5.3, 2.6 Hz, 1H), 1.64 (s, 3H), 1.93 (dddt, J = 17.7, 8.0, 5.3, 2.4 Hz, 1H), 2.08

– 2.22 (m, 3H), 4.76 (s, 1H), 7.12 (td, J = 7.5, 1.1 Hz, 1H), 7.25 – 7.33 (m, 2H), 7.44 (tt, J = 7.7,

1.4 Hz, 2H), 7.69 (dt, J = 8.1, 2.1 Hz, 2H), 7.97 (d, J = 8.2 Hz, 1H). 13C NMR (125 MHz, CDCl3)

δ 20.4, 21.5, 21.8, 23.2, 25.0, 54.7, 77.1, 117.7, 121.9, 123.0, 124.9, 125.2, 126.2, 127.1, 130.1,

133.8, 135.8, 136.0, 139.9, 152.5, 158.9, 171.5, 172.4. IR (thin film, cm-1) 3067, 3037, 2958, 2931,

2859, 1688, 1601, 1511 1479, 1459, 1432, 1332, 1306, 1127, 1101, 772. HRMS (DART, M+H)

Calc’d for C23H21N2OS 373.1375, found 373.1376.

(±)-2-(10b-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indol-11-

yl)pyridine 1-oxide (2.59) – The compound was synthesized according to

General Procedure 2.5.3.1. This reaction was run by Dr. Tamara Beisel. The

product was purified by flash column chromatography using DCM–MeOH

(200:1 to 50:1, v:v) as the mobile phase and was isolated as a white solid

(47.94 mg, 0.146 mmol, 73%, mp = 164–166 °C). 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J =

6.5, 1.2 Hz, 1H), 7.91 (dt, J = 7.7, 0.9 Hz, 1H), 7.83 (dt, J = 8.1, 0.7 Hz, 1H), 7.66 (ddd, J = 7.5,

1.2, 0.7 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 7.29 (td, J = 7.5, 1.0 Hz, 1H),

7.21 – 7.18 (m, 2H), 6.85 (ddd, J = 7.6, 6.4, 2.0 Hz, 1H), 6.72 (td, J = 7.8, 1.2 Hz, 1H), 6.00 (dd, J

= 7.9, 2.1 Hz, 1H), 5.58 (s, 1H), 1.91 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.7, 151.6, 147.9,

140.4, 139.0, 135.5, 132.8, 132.4, 129.7, 129.0, 126.8, 125.5, 125.5, 125.5, 124.2, 123.9, 123.3,

117.8, 117.5, 49.2, 28.1. IR (thin film, cm-1) 3083, 2971, 2925, 2245, 1722, 1694, 1486, 1430,

1361, 906. HRMS (DART, M+H) Calc’d for C21H17N2O2 329.1290, found 329.1287.

99

(±)-10b-methyl-11-(perfluorophenyl)-10b,11-dihydro-6H-

isoindolo[2,1-a]indol-6-one (2.60) – The compound was synthesized

according to General Procedure 2.5.3.1 using 10 mol % catalyst loading.

This reaction was run by Dr. Tamara Beisel. The product was purified by

flash column chromatography using pentanes–EtOAc (20:1, v:v) as the

mobile phase and was isolated as a white solid (61.7 mg, 0.15 mmol, 77%,

mp = 191–196 °C). 1H NMR (400 MHz, CDCl3) δ 1.80 (s, 3H), 4.78 (s, 1H), 7.06 – 7.10 (m, 1H),

7.11 – 7.18 (m, 2H), 7.39 – 7.46 (m, 3H), 7.79 (d, J = 7.9 Hz, 1H), 7.82 – 7.87 (m, 1H). 13C NMR

(125 MHz, CDCl3) δ 29.2, 45.7, 74.8, 115.0, 117.4, 121.8, 125.1, 125.4, 125.9, 129.3, 129.6, 132.8,

132.9, 132.9, 134.2, 140.7, 140.7, 147.8, 168.6, 168.7. 19F NMR (376 MHz, CDCl3) δ -162.12 (td,

J = 21.6, 8.1 Hz), -160.76 (td, J = 21.7, 8.0 Hz), -154.31 (t, J = 21.1 Hz), -144.58 (ddd, J = 22.6,

7.9, 3.6 Hz), -139.78 (dd, J = 22.4, 8.3 Hz). IR (thin film, cm-1) 3047, 2972, 2930, 2868, 1707,

1528, 1503, 1488, 1466, 1357, 1337, 1308, 1133, 1000, 979, 762, 683. HRMS (DART, M+H)

Calc’d for C22H13F5NO 402.0917, found 402.0922.

(±)-10b-methyl-11-(4-methylthiazol-2-yl)-10b,11-dihydro-6H-


according to General Procedure 2.5.3.1. This reaction was run by Dr. Tamara

Beisel. The product was purified by flash column chromatography using


white solid (41.22 mg, 0.124 mmol, 62%, mp = 144–149°C). 1H NMR (500

MHz, CDCl3) δ 7.83 (ddd, J = 7.9, 1.1, 0.5 Hz, 1H), 7.71 (dt, J = 7.6, 1.0 Hz, 1H), 7.47 (td, J =

7.8, 1.3 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.36 – 7.31 (m, 2H), 7.17 (td, J = 7.5, 1.1 Hz, 1H), 6.40 (p,

J = 1.0 Hz, 1H), 4.89 (s, 1H), 2.25 (d, J = 1.1 Hz, 3H), 1.79 (s, 3H). 13C NMR (125 MHz, CDCl3)

δ 169.7, 168.5, 152.0, 147.7, 139.4, 136.7, 133.0, 132.1, 130.0, 128.7, 127.0, 125.2, 124.4, 123.9,

117.7, 114.6, 75.8, 54.8, 27.9, 17.0. IR (thin film, cm-1) 3098, 3039, 2968, 2924, 2858, 1721, 1699,

1529, 1483, 1361, 1131. HRMS (DART, M+H) Calc’d for C20H16N2OS 333.1062, found

333.1055.

100

(±)-10b-methyl-11-(4-methylthiazol-5-yl)-10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one

(2.62) – The compound was synthesized according to General Procedure

2.5.3.1. This reaction was run by Dr. Tamara Beisel. The product was purified

by flash column chromatography using pentanes–EtOAc (4:1 to 7:3, v:v) as

the mobile phase and was isolated as a white solid (20.61 mg, 0.062 mmol,

31%, mp = 171-175 °C). 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.83 –

7.79 (m, 1H), 7.76 (dt, J = 7.5, 1.0 Hz, 1H), 7.42 (dtd, J = 13.5, 7.6, 1.3 Hz, 2H), 7.35 (td, J = 7.5,

1.1 Hz, 1H), 7.21 (ddt, J = 7.7, 1.4, 0.7 Hz, 1H), 7.17 – 7.12 (m, 2H), 4.68 (s, 1H), 2.54 (s, 3H),

1.78 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.4, 151.5, 147.8, 147.7, 138.8, 138.4, 133.2, 132.9,

132.7, 129.6, 128.9, 126.5, 125.3, 124.8, 122.3, 117.7, 75.9, 48.9, 27.9, 15.8. IR (thin film, cm-1)

3079, 2969, 2925, 2856, 1702. 1603, 1478, 1463, 1357, 1308, 756. HRMS (DART, M+H) Calc’d

for C20H16N2OS 333.1062, found 333.1058.

(±)-11-(benzo[d]oxazol-2-yl)-10b-methyl-10b,11-dihydro-6H-


according to General Procedure 2.5.3.1. This reaction was run by Dr.

Tamara Beisel. The product was purified by flash column chromatography

using pentanes–EtOAc (9:1, v:v) as the mobile phase and two white solids

were isolated corresponding to the anti-isomer and syn-isomer.

Anti-diastereomer: 31.72 mg, 0.09, 45%, mp = 239-244 °C. 1H NMR (500 MHz, CDCl3) δ 7.86

(dt, J = 7.9, 0.8 Hz, 1H), 7.81 – 7.76 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (td, J = 7.8, 1.2 Hz,

1H), 7.33 – 7.26 (m, 4H), 7.14 (tdd, J = 7.9, 3.4, 1.2 Hz, 2H), 7.08 (ddd, J = 8.3, 7.2, 1.1 Hz, 1H),

7.02 (d, J = 8.2 Hz, 1H), 4.82 (s, 1H), 1.84 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.6, 163.4,

150.7, 147.4, 140.3, 140.0, 133.7, 132.9, 132.7, 130.0, 129.0, 126.5, 125.1, 125.0, 124.8, 124.2,

122.4, 119.9, 118.0, 110.5, 74.8, 51.0, 28.2. IR (thin film, cm-1) 3053, 2970, 2931, 2922, 2854,

1708, 1615, 1570, 1480, 1353, 755. HRMS (DART, M+H) Calc’d for C23H17N2O2 353.1290,

found 353.1285.

Syn-diastereomer: 38.44 mg, 0.109 mmol, 54%, mp = 194-196 °C. 1H NMR (500 MHz, CDCl3)

δ 7.93 (d, J = 7.6 Hz, 1H), 7.87 – 7.84 (m, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H),

7.71 (td, J = 7.5, 1.1 Hz, 1H), 7.68 – 7.65 (m, 1H), 7.59 – 7.53 (m, 2H), 7.48 – 7.40 (m, 3H), 7.25

– 7.21 (m, 1H), 5.00 (s, 1H), 1.47 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.6, 163.2, 151.0,

101

150.1, 141.2, 139.6, 133.6, 133.4, 132.6, 129.4, 129.4, 127.0, 125.7, 125.3, 125.2, 124.9, 123.0,

120.6, 117.7, 110.8, 75.0, 50.6, 23.3. IR (thin film, cm-1) 3080, 3050, 2974, 2929, 2856, 1706,

1606, 1569, 1479, 1354, 750. HRMS (DART, M+H) Calc’d for C23H17N2O2 353.1290, found

353.1296.

2.5.3.3 Alkylation of 2.63

(±)-tert-butyl 2-(11-(benzo[d]oxazol-2-yl)-10b-methyl-6-oxo-10b,11-dihydro-6H-

isoindolo[2,1-a]indol-11-yl)acetate (2.64) – I designed the experiment and the reaction was run

by Rachel Ross. In a dried vial under argon was added 2.63 (70.5 mg, 0.2 mmol, 1 equiv, 1:1.2 dr)

and DMF (2 mL, 0.1 M) and cooled in an ice bath. In the following order, NaH (4.8 mg, 0.24

mmol, 1.2 equiv), and TBAI (7.4 mg, 0.04 mmol, 20 mol %) were added. The alkyl bromide (30

µL, 0.4 mmol, 2 equiv) was added quickly. The reaction was stirred for 4 hours, quenched with

NH4Cl, and extracted with EtOAc. The organic layer was washed thoroughly with water, brine,

and dried over MgSO4, before pumping off the solvent and purification by flash column

chromatography using pentanes–EtOAc (9:1 to 5:1, v:v) as the mobile phase and was isolated as

a white solid (60.7 mg, 0.13 mmol, 65%, mp = 179-184 °C). 1H NMR (400 MHz, CDCl3) δ 1.12

(s, 9H), 1.28 (s, 3H), 1.82 (d, J = 15.5 Hz, 1H), 2.95 (d, J = 15.5 Hz, 1H), 7.23 – 7.29 (m, 1H),

7.38 – 7.44 (m, 2H), 7.47 (td, J = 7.7, 1.3 Hz, 1H), 7.61 (td, J = 7.5, 1.0 Hz, 1H), 7.64 – 7.70 (m,

1H), 7.74 (td, J = 7.5, 1.2 Hz, 1H), 7.77 – 7.81 (m, 1H), 7.82 – 7.87 (m, 2H), 7.90 (dt, J = 7.7, 0.9

Hz, 1H), 7.96 (dt, J = 7.6, 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 23.8, 27.9, 43.9, 54.6, 77.8,

81.5, 110.9, 117.5, 120.6, 123.8, 124.8, 124.9, 125.1, 125.3, 128.9, 129.7, 129.9, 133.1, 133.7,

136.0, 137.8, 141.4, 146.8, 150.8, 165.6, 166.6, 168.3. IR (thin film, cm-1) 3072, 2980, 2931, 2872,

1736, 1707, 1482, 1457, 1370, 1341, 1154, 1137, 758, 737. HRMS (DART, M+H) Calc’d for

C29H27N2O4 467.1971, found 467.1976.

102

2.5.3.4 Epimerization Studies

Epimerization studies were conducted in dried 2-dram vials under argon on 0.1 mmol scale. 2.58a

(36.8 mg, 0.1 mmol, 1 equiv), Cs2CO3 (65.8 mg, 0.2 mmol, 2 equiv), the additive studied, and

toluene were sealed and heated to 120 °C for 15 h. The reaction was filtered through a silica plug

in a vial containing a known amount of trimethoxybenzene (5–10 mg). The crude mixture was

analyzed by NMR for the ratio of the diastereomers and yield of each. In the case of Table 7, entry

4, a sample of 2.58a having a dr of 4:1 was used.

2.5.4 Research Goal 2 – Dearomative Palladium-Catalyzed Arylation/Borylation

2.5.4.1 Synthesis of Mixed-Boron

Note: If a commercial source of 2.67 is used, it was necessary to add 10 mol% of the N-methylated

analogue (1,1'-(methylazanediyl)bis(propan-2-ol)) to sequester B2Pin2 impurities from the final

product, eliminating the need for recrystallization.

To a solution of B2Pin2 (1 equiv) in Et2O (4 ml/mmol) was added 2.70 (1.1 equiv) in DCM (0.5

ml/mmol). After 5 minutes, a white precipitate formed, and the reaction was stirred for 48 h. The

product was filtered and washed with Et2O to provide product 2.69 (60% yield)

103

2.5.4.2 Synthesis of Phosphoramidite Ligands

Synthesis of Phosphoramidite ligands was performed by first building 3,3’-substitued BINOL

derivatives according to literature procedure (summarized below),111 then coupling to PCl3 using

a slight variation to literature protocols.112 Spectral data for known compounds could be obtained

free of charge by following the citation above.

2.5.4.2.1 MOM-Protection of BINOL

To NaH (60% in mineral oil, 2.2 equiv) in THF (0.5 M) at 0 °C was slowly added a solution of

BINOL (2.79, 1 equiv) in THF (0.67 M). The reaction was stirred for 1 h, then was warmed to

room temperature for 15 minutes. The reaction was cooled back down to 0 °C, and chloromethyl

methyl ether (2.2 equiv) was added dropwise. The reaction was stirred at room temperature for 5

hours, after which was quenched with aqueous ammonium chloride, extracted with ethyl acetate

and the organic layer was concentrated. The product was columned in hexanes–ethyl acetate

(10:1).

2.5.4.2.2 Ortho-Bromination of BINOL

To a solution of mom-protected BINOL (2.71) in Et2O (17 mL/mmol) was added n-BuLi (3 equiv)

dropwise. The reaction was stirred for 3 h, then THF (11 mL/mmol) was added and the reaction

104

mixture was further stirred for an additional hour. After cooling the flask in an ice water bath,

dibromotetrachloroethane (3 equiv) was added quickly in one portion. The reaction was stirred at

room temperature for 5 hours, after which was quenched with aqueous ammonium chloride,

extracted with Et2O and the organic layer was concentrated. The product was columned in

hexanes–ethyl acetate (10:1).

2.5.4.2.3 Suzuki-Miyaura Cross-Coupling

To 3,3’-dibromo binaphthyl 2.72 (1 equiv), Pd(PPh3)4 (10 mol%) in DME (6.7 mL/mmol) in a

round bottom flask at room temperature under argon was added an arylboronic acid (3.5 equiv)

and 2 M aqueous Na2CO3 (5 equiv). The mixture was stirred at reflux for 10 h, cooled, passed

through a Celite pad, and concentrate. The residue was redissolved in DCM, washed with NH4Cl,

water, brine and concentrated. The products were purified typically by column chromatography

using hexanes–ethyl acetate (10:1).

2.5.4.2.4 Acidic Solid Support Deprotection of MOM-Protecting Group

A mixture of mom-protected BINOL derivatives (2.80, 1 equiv) and Amberlyst 15 resin (100 w%)

in THF–MeOH (1:1) was heated to reflux for 15 h. The reaction was cooled to room temperature,

filtered through a Celite pad, and concentrated. The products were purified typically by column

chromatography using hexanes–ethyl acetate (10:1).

105

2.5.4.2.5 General Procedure for the Synthesis of Phosphoramidite Ligands

To a flame dried round bottom flask cooled under a flow of argon was added DCM (0.1 M with

respect to BINOL derivative), and PCl3 (1 equiv). The flask was cooled to 0 °C, and NEt3 (5 equiv)

was added slowly. The reaction was warmed to room temperature. The dialkylamine of choice

(2.74, 1 equiv) was added dropwise, and the reaction was stirred for 5 h. The BINOL derivative

(2.73, 1 equiv) was added in one portion through the top and the reaction was stirred for an

additional 12 h. The reaction was filtered through a silica pad carefully, eluting with a mixture of

hexanes–DCM (20% to 60%). It is crucial that the ligand is not purified using EtOAc since there

are byproducts that coelute.

2.5.4.2.6 Characterization Data for Ligands

N,N-diisopropyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-

amine – The ligand was synthesized according to General Procedure

2.5.4.2.5 and was isolated as a white foam which could be crushed into

a crystalline solid. The reaction was run by Christian Breuers. 1H NMR

(600 MHz, CDCl3) δ 7.98 (d, J = 8.7 Hz, 1H), 7.95 – 7.91 (m, 3H), 7.54

(dd, J = 8.7, 0.9 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.44 (dd, J = 8.7, 1.0 Hz, 1H), 7.43 – 7.40 (m,

2H), 7.35 (dd, J = 8.6, 1.1 Hz, 1H), 7.28 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 7.26 – 7.23 (m, 1H), 3.42

(dhept, J = 10.7, 6.8 Hz, 2H), 1.26 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H). 13C NMR (125

106

MHz, CDCl3) δ 150.6, 150.5, 150.3, 133.0, 132.9, 132.9, 132.8, 131.4, 131.4, 130.6, 130.6, 130.4,

130.3, 130.3, 129.5, 129.5, 128.4, 128.3, 128.3, 127.3, 127.2, 126.0, 126.0, 125.9, 124.7, 124.4,

124.2, 124.1, 122.6, 122.5, 122.5, 122.0, 122.0, 45.0, 44.9, 24.7, 24.6. 31P NMR (243 MHz,

CDCl3) δ 151.73.

N,N-dicyclohexyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-


2.5.4.2.5 and was isolated as a white foam which could be crushed into a

crystalline solid. The reaction was run by Christian Breuers. 1H NMR

(500 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 1H), 7.93 – 7.87 (m, 3H), 7.52 (dd, J = 8.7, 0.9 Hz, 1H),

7.45 (d, J = 8.8 Hz, 1H), 7.44 – 7.38 (m, 4H), 7.33 (dd, J = 8.6, 1.1 Hz, 1H), 7.29 – 7.21 (m, 2H),

2.82 (dtt, J = 15.3, 11.9, 3.6 Hz, 2H), 1.98 – 1.42 (m, 14H), 1.08 – 0.81 (m, 6H). 13C NMR (126

MHz, CDCl3) δ 150.6, 150.5, 150.3, 133.0, 133.0, 132.8, 132.8, 131.4, 131.4, 130.6, 130.4, 130.3,

130.2, 130.2, 129.4, 129.4, 128.4, 128.2, 127.2, 127.1, 127.0, 126.0, 125.9, 124.7, 124.4, 124.2,

124.2, 122.6, 122.5, 122.3, 122.0, 122.0, 54.3, 54.2, 35.3, 26.6, 26.5, 25.6. 31P NMR (243 MHz,

CDCl3) δ 151.92.

5-(dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)-5H-

dibenzo[b,f]azepine – The ligand was synthesized according to

General Procedure 2.5.4.2.5 and was isolated as a white foam which

could be crushed into a crystalline solid. 1H NMR (600 MHz, CDCl3)

δ 8.02 (d, J = 8.8 Hz, 1H), 7.95 – 7.92 (m, 1H), 7.82 – 7.77 (m, 1H),

7.67 (dd, J = 8.7, 0.8 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.42 (ddd, J = 8.1, 6.6, 1.3 Hz, 1H), 7.39 (ddd,

J = 8.0, 6.6, 1.2 Hz, 1H), 7.34 (dd, J = 8.5, 1.1 Hz, 1H), 7.28 (ddd, J = 6.9, 6.0, 1.7 Hz, 2H), 7.25

– 7.20 (m, 6H), 7.16 (dd, J = 7.2, 2.0 Hz, 1H), 7.02 (d, J = 11.5 Hz, 1H), 6.99 – 6.94 (m, 2H), 6.91

(d, J = 8.7 Hz, 1H), 6.57 (td, J = 7.6, 1.6 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 150.1, 150.0,

148.8, 148.8, 143.1, 143.0, 142.6, 136.6, 136.5, 135.3, 133.0, 133.0, 132.3, 132.3, 131.6, 131.5,

131.5, 130.4, 130.3, 129.3, 129.2, 129.2, 129.1, 129.1, 129.0, 128.7, 128.5, 128.4, 128.0, 127.2,

126.9, 126.8, 126.8, 126.3, 126.2, 125.8, 125.0, 124.4, 124.4, 124.3, 122.3, 122.2, 121.6, 121.3,

121.2. 31P NMR (243 MHz, CDCl3) δ 137.93.

107

N,N-diisopropyl-2,6-bis(4-methoxyphenyl)dinaphtho[2,1-d:1',2'-

f][1,3,2]dioxaphosphepin-4-amine – The ligand was synthesized

according to General Procedure 2.5.4.2.5 and was isolated as a white

foam which could be crushed into a crystalline solid. 1H NMR (600

MHz, CDCl3) δ 8.08 – 8.01 (m, 2H), 7.98 – 7.93 (m, 2H), 7.89 – 7.83

(m, 2H), 7.72 – 7.68 (m, 2H), 7.43 (dddd, J = 6.7, 5.8, 2.9, 1.2 Hz, 3H),

7.30 (dd, J = 8.5, 1.1 Hz, 1H), 7.28 – 7.26 (m, 1H), 7.23 (ddd, J = 8.6,

6.7, 1.3 Hz, 1H), 7.03 – 6.94 (m, 4H), 3.86 (d, J = 6.0 Hz, 6H), 3.16 (dp, J = 10.6, 6.7 Hz, 2H),

0.88 (d, J = 6.7 Hz, 6H), 0.66 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 159.2, 159.2,

148.4, 148.3, 148.1, 134.7, 133.8, 132.5, 132.4, 131.7, 131.4, 131.4, 131.4, 130.8, 130.6, 130.5,

129.8, 129.3, 128.4, 128.3, 127.2, 127.1, 125.8, 125.6, 125.3, 125.3, 125.0, 124.6, 123.5, 113.5,

113.5, 55.5, 55.5, 44.8, 44.8, 24.6, 24.5, 23.6. 31P NMR (243 MHz, CDCl3) δ 148.32.

N,N-dicyclohexyl-2,6-bis(4-methoxyphenyl)dinaphtho[2,1-d:1',2'-




MHz, CDCl3) δ 8.02 (d, J = 16.3 Hz, 2H), 7.97 – 7.90 (m, 2H), 7.86 –

7.79 (m, 2H), 7.73 – 7.66 (m, 2H), 7.39 (dddd, J = 8.8, 7.6, 5.6, 1.4 Hz,

3H), 7.26 – 7.18 (m, 3H), 7.00 – 6.96 (m, 2H), 6.96 – 6.93 (m, 2H),

3.85 (d, J = 8.9 Hz, 6H), 2.56 (s, 2H), 1.52 – 0.54 (m, 20H). 13C NMR (126 MHz, CDCl3) δ 159.2,

159.1, 148.4, 148.3, 148.2, 134.7, 134.7, 133.5, 132.6, 132.6, 132.5, 132.4, 131.5, 131.5, 131.4,

131.4, 131.3, 131.2, 130.8, 130.6, 130.6, 129.8, 129.0, 128.4, 128.1, 127.1, 127.0, 125.7, 125.6,

125.3, 125.3, 124.9, 124.6, 123.5, 123.5, 113.5, 113.4, 55.5, 55.5, 54.3, 26.6, 25.5. 31P NMR (243

MHz, CDCl3) δ 148.79. HRMS (ESI, M+H) calculated for C46H46NO4P 708.3221, found

708.3231.

108





MHz, CDCl3) δ 8.13 (s, 1H), 8.00 (s, 1H), 7.98 – 7.91 (m, 2H), 7.67 (dd,

J = 7.6, 1.8 Hz, 1H), 7.57 – 7.50 (m, 1H), 7.51 – 7.23 (m, 10H), 7.11 –

6.95 (m, 5H), 3.77 (d, J = 25.2 Hz, 6H), 3.16 (dp, J = 10.6, 6.7 Hz, 2H),

0.74 (d, J = 6.7 Hz, 6H), 0.65 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 157.5, 157.4,

149.4, 149.3, 148.9, 133.2, 133.0, 133.0, 132.8, 132.2, 131.4, 131.3, 131.1, 130.6, 129.9, 129.2,

129.0, 128.7, 128.4, 128.3, 127.5, 127.4, 127.4, 125.6, 125.4, 125.1, 124.7, 124.7, 124.6, 124.1,

121.9, 120.2, 120.1, 120.0, 111.1, 110.4, 55.8, 55.6, 55.5, 44.7, 44.6, 24.3, 24.3, 23.5, 23.5, 18.5,

13.7, 1.2. 31P NMR (162 MHz, CDCl3) δ 147.10. HRMS (ESI, M+1) calculated for C40H39NO4P

628.2611, found 628.2611.





MHz, CDCl3) δ 8.13 (d, J = 0.7 Hz, 1H), 8.07 (s, 1H), 8.02 – 7.92 (m,

2H), 7.53 (dd, J = 2.6, 1.6 Hz, 1H), 7.49 (ddd, J = 7.7, 1.6, 1.0 Hz, 1H),

7.48 – 7.43 (m, 3H), 7.39 – 7.25 (m, 8H), 6.95 (ddd, J = 7.8, 2.6, 1.5

Hz, 1H), 6.92 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.85 (d, J = 15.8 Hz, 6H), 3.16 (dp, J = 10.8, 6.8 Hz,

2H), 0.87 (d, J = 6.7 Hz, 6H), 0.66 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 159.4,

159.3, 148.3, 148.3, 148.0, 139.5, 139.4, 135.2, 135.2, 134.0, 132.7, 132.7, 131.2, 130.5, 130.3,

130.0, 128.9, 128.9, 128.5, 128.5, 127.2, 127.1, 126.0, 125.9, 125.3, 125.1, 124.7, 123.4, 123.4,

123.0, 122.9, 122.9, 115.8, 115.7, 115.7, 113.8, 113.3, 55.5, 55.4, 44.9, 44.8, 24.5, 24.4, 23.6. 31P

NMR (162 MHz, CDCl3) δ 148.96. HRMS (ESI, M+1) calculated for C40H39NO4P 628.2611,

found 628.2609.

109

2,6-bis(4-(tert-butyl)phenyl)-N,N-diisopropyldinaphtho[2,1-

d:1',2'-f][1,3,2]dioxaphosphepin-4-amine – The ligand was

synthesized according to General Procedure 2.5.4.2.5 and was isolated

as a white foam which could be crushed into a crystalline solid. The

reaction was run by Christian Breuers. 1H NMR (500 MHz, CDCl3) δ

8.13 – 8.07 (m, 2H), 7.97 (dq, J = 8.3, 1.1 Hz, 2H), 7.86 – 7.80 (m, 2H),

7.72 – 7.64 (m, 2H), 7.50 – 7.42 (m, 7H), 7.35 (dd, J = 8.5, 1.1 Hz, 1H),

7.29 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.25 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H),

3.12 (dp, J = 10.7, 6.7 Hz, 2H), 1.38 (d, J = 5.8 Hz, 18H), 0.83 (d, J = 6.7 Hz, 6H), 0.58 (d, J =

6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 150.4, 150.3, 148.6, 148.5, 148.2, 135.3, 135.2, 135.2,

135.0, 134.2, 132.7, 132.6, 132.6, 132.6, 131.4, 131.4, 130.5, 130.3, 130.0, 130.0, 129.8, 129.5,

128.5, 128.4, 127.3, 127.2, 125.8, 125.7, 125.3, 125.2, 124.9, 124.8, 124.8, 124.6, 123.3, 123.3,

44.8, 44.7, 34.7, 34.7, 31.5, 24.4, 24.3, 23.4, 23.4. 31P NMR (243 MHz, CDCl3) δ 148.05. HRMS

(ESI, M+1) calculated for C46H51NO2P 680.3652, found 680.3656.

N,N-diisopropyl-2,6-bis(4-nitrophenyl)dinaphtho[2,1-d:1',2'-


according to General Procedure 2.5.4.2.5 and was isolated as a bright

yellow foam which could be crushed into a crystalline solid. 1H NMR

(600 MHz, CDCl3) δ 8.34 – 8.26 (m, 4H), 8.11 (d, J = 28.9 Hz, 2H),

8.08 – 8.04 (m, 2H), 8.02 – 7.97 (m, 2H), 7.94 – 7.88 (m, 2H), 7.49

(dtd, J = 7.9, 6.4, 1.4 Hz, 2H), 7.42 (dd, J = 8.5, 1.1 Hz, 1H), 7.35 (ddd,

J = 8.4, 6.7, 1.3 Hz, 1H), 7.33 – 7.27 (m, 2H), 3.13 (dq, J = 11.0, 6.6 Hz, 2H), 0.83 (d, J = 6.8 Hz,

6H), 0.60 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 147.5, 147.4, 147.2, 147.1, 146.8,

144.8, 144.7, 133.1, 133.1, 133.1, 132.7, 132.7, 131.7, 131.1, 131.1, 131.0, 131.0, 130.8, 130.8,

130.6, 130.3, 128.8, 127.0, 127.0, 127.0, 126.9, 125.6, 125.3, 125.2, 125.2, 123.5, 123.5, 123.2,

123.2, 45.0, 44.9, 24.4, 24.3, 23.6. 31P NMR (243 MHz, CDCl3) δ 150.39.

110

dimethyl 4,4'-(4-(dicyclohexylamino)dinaphtho[2,1-d:1',2'-

f][1,3,2]dioxaphosphepine-2,6-diyl)dibenzoate – The ligand was

synthesized according to General Procedure 2.5.4.2.5 and was

isolated as a white foam which could be crushed into a crystalline

solid. The reaction was run by Christian Breuers. 1H NMR (400

MHz, CDCl3) δ 8.12 – 8.02 (m, 6H), 7.98 – 7.92 (m, 4H), 7.83 –

7.74 (m, 2H), 7.48 – 7.36 (m, 3H), 7.33 – 7.20 (m, 3H), 3.93 (dd, J

= 2.7, 0.7 Hz, 6H), 3.08 (ddt, J = 13.5, 10.1, 6.7 Hz, 2H), 0.79 (d, J = 6.6 Hz, 6H), 0.56 (d, J = 6.8


133.9, 133.0, 132.9, 132.9, 131.1, 130.4, 130.3, 130.3, 130.2, 130.1, 129.2, 129.2, 128.9, 128.7,

128.6, 128.5, 127.0, 126.9, 126.4, 126.3, 125.2, 125.2, 125.1, 124.9, 123.4, 123.4, 52.1, 52.1, 44.9,

44.7, 24.4, 24.3, 23.5. 31P NMR (162 MHz, CDCl3) δ 149.67. HRMS (ESI, M+1) calculated for

C42H39NO6P 684.2510, found 684.2506.

2,6-bis(3,5-bis(trifluoromethyl)phenyl)-N,N-

diisopropyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-


2.5.4.2.5 and was isolated as a white foam which could be crushed into

a crystalline solid. 1H NMR (600 MHz, CDCl3) δ 8.37 (d, J = 1.7 Hz,

2H), 8.23 – 8.21 (m, 2H), 8.13 (d, J = 26.3 Hz, 2H), 8.04 (ddt, J = 12.3,

8.5, 0.9 Hz, 2H), 7.93 – 7.86 (m, 2H), 7.52 (dddd, J = 9.3, 8.1, 6.4, 1.5

Hz, 2H), 7.47 (dd, J = 8.6, 1.0 Hz, 1H), 7.38 (ddd, J = 8.4, 6.7, 1.3 Hz,

1H), 7.36 – 7.29 (m, 2H), 3.10 (dq, J = 10.8, 6.7 Hz, 2H), 0.80 (d, J = 6.7 Hz, 7H), 0.53 (d, J = 6.8


132.2, 132.2, 132.2, 132.1, 131.8, 131.8, 131.5, 131.5, 131.3, 131.2, 131.1, 130.9, 130.7, 130.7,

130.6, 130.5, 130.4, 130.4, 128.9, 128.8, 127.7, 127.2, 127.2, 127.0, 125.9, 125.6, 125.6, 125.5,

124.9, 123.5, 123.5, 122.2, 121.4, 121.3, 121.3, 121.0, 120.9, 120.9, 119.5, 45.1, 45.0, 24.1, 24.0,

23.5. 31P NMR (243 MHz, CDCl3) δ 150.31. 19F NMR (564 MHz, CDCl3) δ -62.68, -62.91.

111

2.5.4.3 General Procedure for the Aryl/Borylation

In a dry and purged 1D vial, Pd(dba)2 (5 mol%) and L6 (10 mol%) were pre-stirred in 2 mL of

MTBE at 40 °C for 15 minutes. The catalyst solution was transferred (washing with 2 mL of

MTBE, total 4 mL) into a Schlenk tube containing the corresponding aryl-chloride (0.2 mmol) and

Mixed-Boron (3 equiv). NEt3 (5 equiv) was added and the reaction was sealed and heated to 100

°C for 18 h. The reaction was filtered through silica and purified by column chromatography.


10b-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10b,11-

dihydro-6H-isoindolo[2,1-a]indol-6-one (2.65a) – The compound was

synthesized according to General Procedure 2.5.4.3 and was purified by silica

flash chromatography, eluting with pentanes–EtOAc–DCM (10:1:1, v:v:v).

Product isolated as a white solid (53.5 mg, 0.148 mmol, 74%, 97:3 er, mp = 193-195 °C). 1H NMR

(500 MHz, CDCl3) δ 7.86 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.56 (td, J = 7.5, 1.0 Hz,

1H), 7.51 – 7.44 (m, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.0 Hz, 1H), 7.06 (td, J = 7.5, 1.0

Hz, 1H), 2.92 (s, 1H), 1.66 (s, 3H), 0.84 (s, 6H), 0.68 (s, 6H). 13C NMR (125 MHz, CDCl3) δ

168.1, 150.0, 138.8, 138.6, 133.6, 132.0, 128.4, 127.1, 124.58, 124.56, 124.4, 122.6, 117.4, 83.4,

73.9, 28.6, 24.3, 23.8. HRMS (ESI, M+1) Calculated for C22H25BNO3 362.1922, found 362.1921.

[α]D20 = +90.7 (c 1.0, CHCl3). HPLC [Daicel Chiralpak IA column (25 cm × 0.46 cm), n-hexane–

i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 9.9 min, tR(minor) = 7.8 min].

10,10b-dimethyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (2.65b) – The compound

was synthesized according to General Procedure 2.5.4.3 and was purified by

silica flash chromatography, eluting with pentanes–EtOAc–DCM (10:1:1,

112

v:v:v). Product isolated as a white solid (44.4 mg, 0.118 mmol, 59%, 89.5:10.5 er, mp = 161–162

°C). 1H NMR (500 MHz, CDCl3) δ 7.71–7.66 (m, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.30 (dt, J = 7.5,

1.0 Hz, 1H), 7.25 (td, J = 7.7, 1.4 Hz, 1H), 7.14 (ddt, J = 7.5, 1.3, 0.7 Hz, 1H), 7.04 (td, J = 7.5,

1.1 Hz, 1H), 2.98 (s, 1H), 2.49 (s, 3H), 1.68 (s, 3H), 0.82 (s, 6H), 0.67 (s, 6H). 13C NMR (125

MHz, CDCl3) δ 167.5, 148.0, 138.6, 138.1, 134.1, 133.8, 132.6, 128.6, 127.2, 124.5, 124.3, 122.3,

117.2, 83.4, 74.2, 26.4, 24.3, 23.8, 18.7. HRMS (DART, M+1) Calculated for C23H27BNO3

376.2079, found 376.2046. [α]D20 = +125.2 (c 1.0, CHCl3). HPLC [Daicel Chiralpak IA column

(25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 8.7 min, tR(minor) = 7.6

min.

9-methoxy-10b-methyl-11-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-

one (2.65c) – The compound was synthesized according to General

Procedure 2.5.4.3 and was purified by silica flash chromatography,

eluting with pentanes–EtOAc–DCM (10:1:1, v:v:v). Product isolated as a white solid (69.2 mg,

0.177 mmol, 88%, 84:16 er, mp = 243-245 °C). 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.5

Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.26 (td, J = 7.5, 1.0 Hz, 1H), 7.15 –

7.11 (m, 2H), 7.06 (td, J = 7.5, 1.0 Hz, 1H), 3.88 (s, 3H), 2.89 (s, 1H), 1.64 (s, 3H), 0.86 (s, 6H),

0.72 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 168.0, 160.4, 142.4, 139.0, 138.6, 135.0, 127.1, 124.6,

124.4, 123.5, 120.2, 117.3, 107.2, 83.4, 73.7, 55.8, 28.7, 24.5, 23.9. HRMS (ESI, M+1) Calculated

for C23H27BNO4 392.2028, found 392.2044. [α]D20 = +172.4 (c 1.0, CHCl3). HPLC [Daicel

Chiralpak IA column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) =

13.5 min, tR(minor) = 10.8 min.

(10bR,11S)-9-fluoro-10b-methyl-11-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one

(2.65d) – The compound was synthesized according to General



0.129 mmol, 65%, 84:16 er, mp = 152–154 °C). 1H NMR (500 MHz, CDCl3) δ 7.82 (ddd, J = 8.0,

5.1, 0.8 Hz, 1H), 7.64 (dd, J = 7.8, 1.0 Hz, 1H), 7.25 (td, J = 7.6, 1.3 Hz, 1H), 7.17–7.12 (m, 3H),

7.05 (td, J = 7.5, 1.1 Hz, 1H), 2.90 (s, 1H), 1.64 (s, 3H), 0.86 (s, 6H), 0.73 (s, 6H). 13C NMR (125

MHz, CDCl3) δ 167.1, 165.5 (d, J = 252.5 Hz), 152.8 (d, J = 9.3 Hz), 138.6, 138.1, 129.5 (d, J =

113

2.2 Hz), 127.2, 126.7 (d, J = 9.6 Hz), 124.7, 124.5, 117.3, 115.9 (d, J = 23.4 Hz), 110.1 (d, J =

23.8 Hz), 83.6, 73.5 (d, J = 2.6 Hz), 28.6, 24.4, 23.9. 19F NMR (377 MHz, CDCl3) δ -106.75 (dt,

J = 9.0, 4.5 Hz). HRMS (DART, M+1) Calculated for C22H24BFNO3 380.1833, found 380.1832.

[α]D20 = +87.3 (c 1.0, CHCl3). HPLC [Daicel Chiralpak IA column (25 cm × 0.46 cm), n-hexane–

i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 10.7 min, tR(minor) = 8.5 min.



(2.65e) – The compound was synthesized according to General Procedure

2.5.4.3 and was purified by silica flash chromatography, eluting with

pentanes–EtOAc–DCM (10:1:1, v:v:v). Product isolated as a white solid

(50.3 mg, 0.133 mmol, 66%, 95.5:4.5 er, mp = 170–172 °C). 1H NMR (500 MHz, CDCl3) δ 7.67–

7.63 (m, 1H), 7.51 (dd, J = 7.7, 2.5 Hz, 1H), 7.43 (dd, J = 8.3, 4.4 Hz, 1H), 7.28–7.23 (m, 3H),

7.14 (ddt, J = 7.4, 1.3, 0.7 Hz, 1H), 7.06 (td, J = 7.5, 1.1 Hz, 1H), 2.90 (s, 1H), 1.64 (s, 3H), 0.85

(s, 6H), 0.72 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 166.7 (d, J = 3.3 Hz), 163.1 (d, J = 247.7

Hz), 145.6 (d, J = 2.6 Hz), 138.6, 138.34, 135.8 (d, J = 8.4 Hz), 127.2, 124.7, 124.7, 124.0 (d, J =

8.4 Hz), 119.2 (d, J = 23.5 Hz), 117.4, 111.2 (d, J = 23.2 Hz), 83.5, 73.7, 28.6, 24.4, 23.9. 19F

NMR (377 MHz, CDCl3) δ -112.89 – -113.09 (m). HRMS (DART, M+1) Calculated for

C22H24BFNO3 380.1833, found 380.1836. [α]D20 = +72.7 (c 1.0, CHCl3). HPLC [Daicel Chiralpak

IA column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 8.6 min,

tR(minor) = 6.8 min.



(2.65f) – The compound was synthesized according to General Procedure


pentanes–EtOAc–DCM (10:1:1, v:v:v). Product isolated as a white solid (44.6 mg, 0.118 mmol,

59%, 95.5:4.5 er, mp = 193–194 °C). 1H NMR (500 MHz, CDCl3) δ 7.84 (dt, J = 7.5, 1.0 Hz, 1H),

7.61–7.53 (m, 2H), 7.49–7.43 (m, 2H), 6.97–6.91 (m, 1H), 6.85 (ddd, J = 8.3, 2.5, 0.8 Hz, 1H),

2.89 (s, 1H), 1.65 (s, 3H), 0.83 (s, 6H), 0.67 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 168.1, 160.2

(d, J = 242.2 Hz), 149.7, 140.9 (d, J = 8.5 Hz), 134.8 (d, J = 2.2 Hz), 133.4, 132.1, 128.6, 124.7,

122.7, 117.9 (d, J = 9.0 Hz), 113.5 (d, J = 23.5 Hz), 112.2 (d, J = 24.3 Hz), 83.7, 74.5, 28.5, 24.4,

23.9. 19F NMR (377 MHz, CDCl3) δ -118.53 – -118.71 (m). HRMS (DART, M+1) Calculated for

114

C22H24BFNO3 380.1833, found 380.1837. [α]D20 = +86.0 (c 1.0, CHCl3). HPLC [Daicel Chiralpak

IA column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 10.1 min,


(10bR,11S)-2-methoxy-10b-methyl-11-(4,4,5,5-tetramethyl-1,3,2-


(2.65g) – The compound was synthesized according to General



0.129 mmol, 65%, 96.5:3.5 er, mp = 189–191 °C). 1H NMR (500 MHz, CDCl3) δ 7.83 (dt, J =

7.5, 1.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.53 (td, J = 7.4, 1.2 Hz, 1H), 7.48–7.42 (m, 2H), 6.77

(ddd, J = 8.5, 2.6, 0.5 Hz, 1H), 6.71 s(dd, J = 2.6, 0.8 Hz, 1H), 3.78 (s, 3H), 2.86 (s, 1H), 1.64 (s,

3H), 0.83 (s, 6H), 0.66 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 168.0, 157.0, 149.9, 140.5, 133.8,

132.4, 131.8, 128.4, 124.5, 122.5, 117.7, 111.6, 111.3, 83.5, 74.3, 55.6, 28.5, 24.4, 23.9. HRMS

(DART, M+1) Calculated for C23H27BNO4 392.2033, found 392.2028. [α]D20 = +28.6 (c 1.0,

CHCl3). HPLC [Daicel Chiralpak IA column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v),

0.75 mL/min, tR(major) = 16.2 min, tR(minor) = 10.8 min.

10b-phenyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10b,11-

dihydro-6H-isoindolo[2,1-a]indol-6-one (2.65h) – The compound was

synthesized according to General Procedure 2.5.4.3 and was purified by silica

flash chromatography, eluting with pentanes–EtOAc–DCM (10:1:1, v:v:v).

Product isolated as a white solid (61.8 mg, 0.146 mmol, 73%, 97:3 er, mp = 180–183 °C). 1H

NMR (500 MHz, CDCl3) δ 7.85 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66–7.63 (m, 2H),

7.57 (d, J = 7.5 Hz, 1H), 7.49 (td, J = 7.5, 1.0 Hz, 1H), 7.41 (td, J = 7.5, 1.0 Hz, 1H), 7.31 – 7.28

(m, 2H), 7.27–7.23 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.02 (td, J = 7.5,

1.0 Hz, 1H), 3.62 (s, 1H), 0.89 (s, 6H), 0.73 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 168.7, 149.3,

144.2, 139.1, 138.6, 133.1, 132.3, 128.6, 128.4, 127.6, 127.2, 124.8, 124.7, 124.6, 124.2, 123.7,

117.3, 83.7, 79.0, 24.4, 23.9. HRMS (ESI, M+1) Calculated for C27H27BNO3 424.2079, found

424.2049. [α]D20 = +219.1 (c 1.0, CHCl3). HPLC [Daicel Chiralpak IA column (25 cm × 0.46 cm),

n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 11.1 min, tR(minor) = 12.9 min.

115

(10bS,11S)-10b-(4-fluorophenyl)-11-(4,4,5,5-tetramethyl-1,3,2-


(2.65i) – The compound was synthesized according to General Procedure


pentanes–EtOAc–DCM (10:1:1, v:v:v). Product isolated as a white solid

(35.0 mg, 0.0793 mmol, 40%, 97:3, mp = 163–165 °C). 1H NMR (500 MHz, CDCl3) δ 7.84 (dt, J

= 7.5, 1.0 Hz, 1H), 7.75 (dd, J = 7.8, 1.0 Hz, 1H), 7.61–7.56 (m, 2H), 7.53–7.45 (m, 2H), 7.40 (td,

J = 7.3, 1.3 Hz, 1H), 7.23 (td, J = 7.6, 1.4 Hz, 1H), 7.08–7.04 (m, 1H), 7.01 (td, J = 7.5, 1.1 Hz,

1H), 6.97–6.91 (m, 2H), 3.56 (s, 1H), 0.86 (s, 6H), 0.71 (s, 6H). 13C NMR (125 MHz, CDCl3) δ

168.6, 162.1 (d, J = 246.6 Hz), 149.2, 139.9 (d, J = 3.1 Hz), 139.0, 138.4, 133.0, 132.4, 128.5,

127.3, 126.6 (d, J = 8.1 Hz), 124.9, 124.7, 124.2, 123.6, 117.4, 115.5 (d, J = 21.6 Hz), 83.7, 78.6,

24.4, 23.9. 19F NMR (376 MHz, CDCl3) δ -114.95 – -115.03 (m). HRMS (DART, M+1)

Calculated for C27H26BFNO3 442.1990, found 442.1994. [α]D20 = +183.2 (c 1.0, CHCl3). HPLC

[Daicel Chiralpak IA column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min,

tR(major) = 10.5 min, tR(minor) = 13.1 min.

(11S,11aR)-11a-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)-11,11a-dihydro-5H-pyrido[2',3':3,4]pyrrolo[1,2-a]indol-5-one (2.65j)

– The compound was synthesized according to General Procedure 2.5.4.3 and

was purified by silica flash chromatography, eluting with pentanes–EtOAc–

DCM (10:1:1, v:v:v). Product isolated as a white solid (58.7mg, 0.162 mmol, 81%, 91:9 er, mp =

120–122 °C). 1H NMR (500 MHz, CDCl3) δ 8.72 (dd, J = 4.9, 1.6 Hz, 1H), 8.12 (dd, J = 7.7, 1.6

Hz, 1H), 7.68 (ddt, J = 7.7, 1.0, 0.5 Hz, 1H), 7.39 (dd, J = 7.7, 4.9 Hz, 1H), 7.27 (tdd, J = 7.6, 1.3,

0.6 Hz, 1H), 7.20 (ddt, J = 7.6, 1.4, 0.7 Hz, 1H), 7.08 (td, J = 7.5, 1.2 Hz, 1H), 3.01 (s, 1H), 1.71

(s, 3H), 0.86 (s, 6H), 0.71 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 169.7, 166.5, 152.5, 138.4,

137.9, 132.6, 127.4, 127.3, 124.9, 124.8, 123.1, 117.5, 83.4, 74.7, 27.0, 24.5, 23.7. HRMS (DART,

M+1) Calculated for C21H24BN2O3 363.1880, found 363.1878. [α]D20 = +105.6 (c 1.0, CHCl3).

HPLC [Daicel Chiralpak IA column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75

mL/min, tR(major) = 12.4 min, tR(minor) = 8.5 min.

116

2.5.4.5 Synthetic Transformation of Products

Oxidation of 3a to 11-hydroxy-10b-methyl-10b,11-dihydro-6H-

isoindolo[2,1-a]indol-6-one (2.77) – The oxidation was performed

according to the literature procedure.116 In a reaction vial, 2.65a (72.2 mg,

0.2 mmol) was dissolved in THF/H2O (1:1, 2 mL). NaBO3•4H2O (153.9 mg,

1.0 mmol) was then added at room temperature. After stirred for 2 h, the reaction mixture was

extracted three times with EtOAc, dried over MgSO4, and filtered. The crude mixture was purified

by flash column chromatography eluting with pentanes–EtOAc, (1:1, v:v) to afford the product

2.77 as a white solid (50.2 mg, 0.2 mmol, >99%, 96.5:3.5 er, mp = 99–101 °C). 1H NMR (500

MHz, CDCl3) δ 7.62 (td, J = 7.5, 1.0 Hz, 1H), 7.58 – 7.50 (m, 4H), 7.46 (td, J = 7.5, 1.0 Hz, 1H),

7.36 (td, J = 7.5, 1.0 Hz, 1H), 7.23 (td, J = 7.5, 1.0 Hz, 1H), 4.86 (s, 1H), 2.62 (s, 1H), 1.49 (s,

3H). 13C NMR (125 MHz, CDCl3) δ 168.6, 147.0, 139.2, 137.0, 133.1, 132.5, 130.4, 128.8, 126.7,

124.8, 124.4, 123.2, 117.8, 76.2, 76.0, 24.5. HRMS (DART, M+1) Calculated for C16H14NO2

252.1019, found 252.1022. [α]D20 = +178.4 (c 1.0, CHCl3). HPLC [Daicel Chiralpak IA column

(25 cm × 0.46 cm), n-hexane–i-PrOH (70:30, v:v), 0.8 mL/min, tR(major) = 11.1 min, tR(minor) = 6.4

min.

Oxidation of 4 to10b-methyl-6H-isoindolo[2,1-a]indole-6,11(10bH)-

dione (2.78) – In a reaction vial, alcohol 2.77 (50.3 mg, 0.2 mmol) was

dissolved in CHCl3 (2 mL). Pyridinium chlorochromate (64.7 mg, 0.6 mmol)

was then added at room temperature. And the reaction mixture was heated to

35 °C and stirred overnight. The solvent was then removed under vacuum and the residue was

purified by chromatography on silica gel, eluting with pentanes–EtOAc (5:1, v:v) to afford the

product 2.78 as a white solid (42.4 mg, 0.17 mmol, 85%, 96:4 er). Spectral data matched those

reported in the literature117: 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 1H), 7.87–7.82 (m,

2H), 7.80 – 7.75 (m, 2H), 7.72 (td, J = 7.5, 1.0 Hz, 1H), 7.54 (td, J = 7.5, 1.0 Hz, 1H), 7.30 (td, J

= 7.5, 1.0 Hz, 1H), 1.82 (s, 3H). [α]D20 = +578.9 (c 1.0, CHCl3). HPLC [Daicel Chiralpak IA

column (25 cm × 0.46 cm), n-hexane–i-PrOH (90:10, v:v), 0.75 mL/min, tR(major) = 11.0 min,


116

Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Angew. Chem. Int. Ed. 2015, 54, 8809. 117

Liu, R.-R.; Wang, Y.-G.; Li, Y.-L.; Huang, B.-B.; Liang, R.-X.; Jia, Y.-X. Angew. Chem. Int. Ed. 2017, 56, 7475.

117

Chapter 3

Dearomatization of Indoles with NFSI and Further Aromative Functionalizations

3.1 Introduction

3.1.1 Importance of Fluorine in Biology, Medicine, Materials

Fluorine-containing molecules continue to account for a large portion of pharmaceutical and

agrochemical compounds due to an increase in solubility, lipophilicity, and biological stability

against oxidation as compared to the C–H bond containing analogues.118 In 1955, the first fluorine-

containing drug was approved in the United-States and by 2016, 30% of drugs contained at least

one fluorine atom.119 This drug was a derivative of cortisone with one H to F substitution, and it

was found to have a significant increase in glucocorticoid activity compared to the non-fluorinated

counterpart (Scheme 77, 3.1).120

Scheme 77 Fluoro-derivative of cortisone

Of the 31 recently approved active ingredients in fungicides, herbicides, and insecticides, 19

contain at least one fluorine atom (over 60%).121 The benefits of incorporating a fluorine extends

to other stages of active pharmaceutical ingredients (API) development. For example, the nuclei

118

(a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H., Chem.

Rev. 2016, 116, 422. (b) Fujiwara, T.; O'Hagan, D., J. Fluorine Chem. 2014, 167, 16. 119

O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071. 120

Fried, J.; Sabo, E. F. J. Am. Chem. Soc. 1954, 76, 1455. 121

Beer, A. Agrow-Agribusiness Intelligence Annual Review. 2018,

https://agrow.agribusinessintelligence.infoma.com/-/media/agri/agrow/ag-market-reviews-

pdfs/supplements/agrowannualreview2018.pdf (accessed January 15, 2020).

118

can be used to track compounds in vitro or in vivo by NMR or MRI respectively.122 The 18F

radionuclide is the most commonly used radioisotope in positron emitting tomography due to its

convenient half-life (110 minutes) and favorable resolution (attributed to its low positron energy

of 635 keV).123

3.1.2 Strategies of Fluorine Incorporation

Diverse strategies have been employed for fluorine incorporation into small molecules, including

the use of catalysts, nucleophilic reagents, electrophilic reagents, and radical additions.124

3.1.2.1 Nucleophilic Fluorine Reagents

Alkali-metal fluorides are commonly used as a source of F- however, one must consider their

hygroscopicity as there are competing reactions with hydroxides. Other common reagents include

alkylammonium fluorides such as tetrabutylammonium fluoride (TBAF)125 since there is a weaker

ionic bonding energy to overcome as well as an increased solubility in organic solvents.126

Similarly, TBAF suffers from being hygroscopic and thus there is an interest in sources of “naked”

fluoride anion. Contrary to typical displacement reactions, it was found that the nucleophilicity of

alkali-metal fluorides and TBAF in tert-butyl alcohol is significantly increased.127 It is proposed

that while the solvent is capable of hydrogen bonding sufficiently to solvate fluoride anion, there

is limited coordination due to the bulkiness of the tert-butyl groups.127 DiMagno and coworkers

reported the synthesis of dry TBAF by the SNAr reaction of hexafluorobenzene (3.1) with

tetrabutylammonium cyanide (Scheme 78, 3.3).128

122

Ruiz-Cabello, J.; Barnett, B. P.; Bottomley, P. A.; Bulte, J. W., NMR Biomed. 2011, 24, 114. 123

Jacobson, O.; Kiesewetter, D. O.; Chen, X., Bioconjugate Chem. 2015, 26, 1. 124

(a) Szpera, R.; Moseley, D. F. J.; Smith, L. B.; Sterling, A. J.; Gouverneur, V., Angew. Chem. Int. Ed. 2019, 58,

14824. (b) Champagne, P. A.; Desroches, J.; Hamel, J. D.; Vandamme, M.; Paquin, J. F., Chem. Rev. 2015, 115, 9073.

(c) Campbell, M. G.; Ritter, T., Chem. Rev. 2015, 115, 612. (d) Studer, A., Angew. Chem. Int. Ed. 2012, 51, 8950. 125

Yoshida, Y.; Kimura, Y. Chem. Lett. 1988, 17, 1355. 126

Clark, J. H. Chem. Rev. 1980, 80, 429. 127

Kim, D. W.; Jeong, H. J.; Lim, S. T.; Sohn, M. H.; Katzenellenbogen, J. A.; Chi, D. Y. J. Org. Chem. 2008, 73,

957. 128

Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050.

119

Scheme 78 The synthesis of anhydrous TBAF by SNAr

Anhydrous TBAF displayed remarkable nucleophilicity compared to commercial sources of

TBAF, and electron-deficient chloro- and nitroarenes could be fluorinated at room temperature

in short reaction times (Scheme 79).129

Scheme 79 The fluorination of chloro- and nitro-arenes with anhydrous NFSI at room

temperature

Finally, nucleophilic fluorination has been explored using palladium catalysis. The challenges and

mechanistic peculiarities are described in section 3.1.2.3 on page 121.

3.1.2.2 Electrophilic Fluorine Reagents

For decades, various electrophilic fluorinating reagents have been well developed and widely

used.130 Due to fluorine being the most electronegative atom on the periodic table, the only obvious

electrophilic source of fluorine is F2. Since it is an extremely toxic and reactive gas, it is used in

the synthesis of many reagents with properties better suited for laboratory use.131 The most

common family of reagents are those which contain N–F bonds (Scheme 80).

129

Sun, H.; DiMagno, S. G. Angew. Chem. Int. Ed. 2006, 45, 2720. 130

Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431. 131

Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737.

120

Scheme 80 Common N–F reagents

One of the most commonly used electrophilic sources of fluorine is N-fluorobenzenesulfonimide

(3.10, NFSI) due to its shelf-stability, controlled reactivity, modest cost, ability to vary its

electronic properties, and the availability of a 18F variant.132 Although the N–F bond is polarized

towards fluorine due to the difference in electronegativity, formal F+ transfer occurs by two

mechanisms. The first mechanism is proposed to occur by SN2 at the fluorine atom since the *N–

F orbital is more sterically accessible.133 The second mechanism proposed occurs by single

electron transfer. There is evidence that both pathways take place simultaneously depending on

reaction conditions.134

One of the most reliable methods for the fluorination of simple aromatic and heteroaromatic

compounds (3.12) is the reaction of Grignard reagents (3.13) with electrophilic N–F reagents

(Scheme 81).135

132

(a) Teare, H.; Robins, E. G.; Arstad, E.; Luthra, S. K.; Gouverneur, V., Chem. Commun. 2007, 2330. (b)

Buckingham, F.; Kirjavainen, A. K.; Forsback, S.; Krzyczmonik, A.; Keller, T.; Newington, I. M.; Glaser, M.; Luthra,

S. K.; Solin, O.; Gouverneur, V., Angew. Chem. Int. Ed. 2015, 54, 13366. (c) Meyer, D.; Jangra, H.; Walther, F.;

Zipse, H.; Renaud, P., Nat. Commun. 2018, 9, 4888. 133

Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P. P.; ́ Wong, C.-H. Angew. Chem. Int. Ed. 2005, 44,

192. 134

(a) Lee, K. Y.; Kochi, J. K. J. Chem. Soc., Perkin Trans. 2 1992, 1011. (b) Bockman, T. M.; Lee, K. Y.; Kochi, J.

K. J. Chem. Soc., Perkin Trans. 2 1992, 1581. (c) Vincent, S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.; Wong, C.-

H. J. Org. Chem. 1999, 64, 5264. (c) Brandt, J. R.; Lee, E.; Boursalian, G. B.; Ritter, T. Chem. Sci. 2014, 5, 169. 135

Yamada, S.; Gavryushin, A.; Knochel, P. Angew. Chem. Int. Ed. 2010, 49, 2215.

121

Scheme 81 The synthesis of aromatic and heteroaromatic fluorides by the reaction of Grignard

reagents with NFSI

The Sanford group developed an interesting fluorination with a relatively cheap source of fluoride,

KF, with a large excess of Cu(OTf)2, which served two roles (Scheme 82).136 The copper was the

mediator for the reaction between the aryl-BF3K reagents (3.15) and the fluoride anion, and

subsequently, as the internal oxidant for a productive reductive elimination.

Scheme 82 Fluorination of aryl-BF3K salts with KF and an internal oxidant

Electrophilic fluorination reactions involving palladium as a catalyst have also been explored. The

strategy for such reactions as well as the mechanistic uniqueness are described in the next section.

3.1.2.3 Pd-Catalyzed C–F Bond Formation (nucleophilic & electrophilic)

There are two strategies for fluorine incorporation using palladium-catalysts: low valent Pd0-PdII

mechanism and high valent PdII-PdIV mechanism (Scheme 83).

136

Ye, Y.; Schimler, S. D.; Hanley, P. S.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 16292.

122

Scheme 83 Palladium-catalyzed C–F bond formation via Pd0/PdII and PdII/PdIV cycles

The transformation of aryl-halides/triflates to aryl fluorides via a Pd0-mechanism was successfully

accomplished by the Buchwald group in 2009 (Scheme 83, left).137 Until then, the reductive

elimination of Caryl–F was underexplored due to the formation of unproductive species such as

dimers as well as the competing kinetics for the reductive elimination of phosphine ligands.138 The

authors utilized a bulky monodentate phosphine ligand to force a T-shaped three-coordinate

complex (3.17), facilitating reductive elimination. Interestingly, it was found that the ligand was

functionalized in situ to form the active catalyst (Scheme 84, 3.18).137

137

(a) Lee, H. G.; Milner, P. J.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 3792. (b) Watson, D. A.; Su, M.;

Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661. (c) Sather, A.

C.; Buchwald, S. L. Acc. Chem. Res. 2016, 49, 2146. 138

Grushin, V. V. Chem. - Eur. J. 2002, 8, 1006.

123

Scheme 84 In situ active catalyst formation by arylation of the charged ligand

The second approach features a kinetically favored reductive elimination by a mechanism which

invokes a palladium(IV) species (Scheme 83, right).139 Sanford and coworkers reported the first

example of this type of reactivity in the fluorination of 2-arylpyridines (3.19) (Scheme 85).139a The

use of an electrophilic source of fluorine as an oxidant led to two possible mechanisms being

proposed: a direct substitution (nucleophilic attack of Pd–C on F+) or the oxidative addition to

high-valent palladium-complexes with a reduced barrier to reductive elimination. Future studies

involving the isolations and characterization of key PdIV-complexes supported the mechanism

which features a PdIV reductive elimination complex.139b,c

Scheme 85 Palladium(II)-catalyzed direct fluorination of C–H bonds

139

(a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. (b) Ball, N. D.; Sanford, M. S.

J. Am. Chem. Soc. 2009, 131, 3796. (c) Racowski, J. M.; Gary, J. B.; Sanford, M. S. Angew. Chem. Int. Ed. 2012, 51,

3414.

124

3.1.3 Electrophilic Dearomatization of Indoles – Push-Pull Mechanism

One may take advantage of indole nucleophilicity for dearomatization. When substituted at the 3-

position, indoles typically participate in substitution reactions with electrophiles to form the 3,3-

disubstituted iminium, which in many cases can be isolated (Scheme 86, 3.22).140 These iminiums

can then be trapped with nucleophiles (hence push-pull), before (3.23a) or after migration (3.23b)

of a group to the 2-position (path a or path b).

Scheme 86 Dearomatization of indoles by a push-pull mechanism

Arguably some of the best understood electrophilic metal-complexes, allyl-palladium species,

have been used in a wide variety of reactions concerning indoles.141 Trost and coworkers reported

an asymmetric dearomative allylation of indoles (Scheme 87).142 Interestingly, the boron-based

Lewis acid was found to both increase reactivity, and influence the enantioselectivity. 3,3-

Disubstituted indoles (3.25) are isolated in good to excellent yield and selectivity.

140

Roche, S. P.; Youte Tendoung, J.-J.; Tréguier, B. Tetrahedron 2015, 71, 3549. 141

Trost, B. M. Tetrahedron 2015, 71, 5708. 142

Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.

125

Scheme 87 Dearomative allylation of indoles

Similarly, the oxidative addition complexes of palladium and aryl-halides are considered

electrophilic as they can be trapped by various nucleophiles. By this logic, You and coworkers

developed a simple intramolecular dearomatization of indoles with aryl-bromides tethered at the

3-position (Scheme 88, 3.26).143 The authors found large amounts of 1,2-migration when the 5-

membered ring was generated however, they were able to trap the imines with a hydride source,

generating the indoline products in good yields (3.28).

Scheme 88 Intramolecular palladium-catalyzed dearomatization of indoles using 3-tethered aryl-

halides as internal electrophiles

NFSI (3.10) has been shown to be a versatile reagent, capable of fluorine or sulfonamide transfer

to heterocycles, typically by modifying the solvent (Scheme 89).144 The incorporation of fluorine

143

Wu, K. J.; Dai, L. X.; You, S. L. Org. Lett. 2012, 14, 3772. 144

(a) Sakurai, F.; Yukawa, T.; Taniguchi, T., Org. Lett. 2019, 21, 7254. (b) Wang, X. J.; Lei, B. W.; Ma, L. F.; Jiao,

H. X.; Xing, W. H.; Chen, J. M.; Li, Z. Y., Adv. Synth. Catal. 2017, 359, 4284. (c) Meanwell, M.; Nodwell, M. B.;

Martin, R. E.; Britton, R., Angew. Chem. Int. Ed. 2016, 55, 13244. (d) Liu, H. H.; Wang, Y.; Deng, G. J.; Yang, L.,

Adv. Synth. Catal. 2013, 355, 3369. (e) Lim, Y. H.; Ong, Q.; Duong, H. A.; Nguyen, T. M.; Johannes, C. W., Org.

Lett. 2012, 14, 5676. (f) Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson, A. L.; Giuffredi, G. T.; Bettati,

M.; Walker, M.; Borman, R.; Gouverneur, V., Angew. Chem. Int. Ed. 2011, 50, 8105.

126

proved to be a useful method to rapidly access functionalized isatin-analogues (Scheme 89,

right).145

Scheme 89 Fluorine or nitrogen transfer using NFSI

The electrophilic dearomatization of indoles has been explored with various N–F reagents such as

NFSI and Selectfluor. The most common strategy involves the fluorination and subsequent

trapping of the iminium formed. Jiao and coworkers used Selectfluor and oxygen nucleophiles to

access highly substituted indolines (Scheme 90).146 Water (3.30), alcohols (3.31), and N-tethered

alcohols (3.32) were tolerated well in the reaction.

Scheme 90 The use of Selectfluor for fluorination and trapping with oxygen nucleophiles

Simultaneously and independently, the Gouverneur group developed an enantioselective

fluorination of indoles, trapping with 3-tethered alkyl alcohols, phenol, and various N-nucleophiles

145

(a) Lim, Y. H.; Ong, Q.; Duong, H. A.; Nguyen, T. M.; Johannes, C. W., Org. Lett. 2012, 14, 5676. (b) Bhrigu,

B.; Pathak, D.; Siddiqui, N.; Alam, M.; Ahsan, W., Int. J. Pharm. Sci. Drug Res. 2010, 2, 229. 146

Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2011, 13, 4498.

127

(Scheme 91).147 2,3-Cis-fused indolines (3.34) bearing a fluorine atom at one of the two

stereogenic centers are isolated in good yield and selectivity. The chirality stems from the use of a

hydroquinidine derived organocatalyst ((DHQ)2PHAL).

Scheme 91 Enantioselective fluorination with NFSI, and trapping with O/N-based nucleophiles

tethered at the 3-position, forming multi-cyclic products

3.2 Research Goal 3 – Synthesis and Reactions of 3,3-Difluoro-2-exo-Methylidene Indolines

3.2.1 Motivation

The focus of this project was to develop a dearomative fluorination of 2-methylindoles, generating

3,3-difluoroindolines bearing an exocyclic double bond (Scheme 92).148 The reactivity of these

indolines was studied, mainly in reactions concerning allylic-fluorides.

147

Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.;

Borman, R.; Gouverneur, V. Angew. Chem. Int. Ed. 2011, 50, 8105. 148

Zeidan, N.; Zambri, M.; Unger, S.; Dank, C.; Torelli, A.; Mirabi, B.; Lautens, M. Org. Lett. 2020, 22, 3688.

128

Scheme 92 Dearomative fluorination of 2-methylindole

The products generated possess allylic fluorides capable of undergoing a variety of future

derivatizations. Allylic fluorides have been long studied, and continue to be of interest due to their

greater reactivity towards certain Tsuji-Trost type reactions.149 For example, the Trost group

recently developed an asymmetric palladium-catalyzed trifluoromethylation of allylic fluorides

using chiral Trost ligands (Scheme 93).150

Scheme 93 Asymmetric allylic fluoroalkylation/trifluoromethylation

3.2.2 Contributions

The results presented were obtained in collaboration with Matthew Zambri (an undergraduate

student at the University of Toronto), Sven Unger (a visiting student from Germany), Dr. Christian

Dank (a postdoc from Austria), Bijan Mirabi (a PhD student in the Lautens group), and Alexa

Torelli (a PhD student in the Lautens group). I conceived the idea, directed the project, and

executed most of the experiments. Matthew Zambri investigated the scope of the reaction and

optimized some derivatizations. Sven Unger optimized and ran palladium-allylation reactions. The

149

Hazari, A.; Gouverneur, V.; Brown, J. M. Angew. Chem. Int. Ed. 2009, 48, 1296. 150

Trost, B. M.; Gholami, H.; Zell, D. J. Am. Chem. Soc. 2019, 141, 11446.

129

other collaborators contributed specific derivatizations based on their expertise. All contributions

are specified within the text as well as within the experimental section.



The starting materials were synthesized by the same chemical transformation as Chapter 2 (see

section 2.5.2.2). NFSI is a commercially available and bench stable reagent.


We began our studies with 2.2 equivalents of NFSI in MTBE at 60 °C. The reaction parameters

were varied to study their effects (Table 11). Other solvents were tolerated (Table 11, entry 1–3)

however, the reaction was best in THF (Table 11, entry 4). Notably, DCM gave no product,

possibly due to the background amidation reaction reported by Yang.151 Dropping the temperature

resulted in diminished yield (Table 11, entry 5). Concentrating the reaction increased the yield

(Table 11, entry 6) however, further increasing the concentration to 0.5 M resulted in the

immediate appearance of a black colour and decomposition ensued (Table 11, entry 7). A wide

range of additives, organic bases, inorganic bases, and acids were screened, in hopes of activating

either the substrate or NFSI, and we found that the addition of NH4Cl increased the yield to 60%

(Table 11, entry 8).

151

Liu, H. H.; Wang, Y.; Deng, G. J.; Yang, L., Adv. Synth. Catal. 2013, 355, 3369.

130

Table 11 Effects of the reaction parameters in the dearomative fluorination of indolesa

Entry Solvent Variation 3.38a (%) 3.39 (%)

1 MTBE none 32 –

2 DCM none – –

3 MeCN none 26 –

4 THF none 47 <5

5 THF 40 °C 37 15

6 THF 0.2 M 48 15

7 THF 0.5 M decomp –

8 THF 0.2 M and 1 equiv NH4Cl 60 –

aReactions run on 0.2 mmol scale and yields were determined by NMR using trifluorotoluene as an internal standard.

The fluorination of 2-methylindole (3.37a) with NFSI according to the conditions in Table 11,

entry 8 delivered exomethylidene containing indoline 3.38a as a crystalline, bench stable

product.152

3.2.3.3 Decomposition Studies and Scale-up

It was found that upon increasing the concentration or the scale of the reaction past 1 mmol, the

reaction immediately turned black and only decomposition of the starting material was observed.

For this reason, we added NFSI via a syringe pump.This allowed us to increase the initial

concentration with respect to the substrate (0.5 M) while decreasing the decomposition pathway

152

CCDC deposition number 1956222.

131

involving NFSI. The reaction mixture was filtered through a silica plug to remove the polar by-

products of NFSI. Importantly, the product was recrystalized in pentanes, removing the need for

relatively wasteful column chromatographic purification on a larger scale.

Scheme 94 Medium-scale synthesis of 3.38a


Next, we investigated the impact of the protecting group on nitrogen as well as a few substituents

on the indole backbone (Table 12). The substrate bearing an electron-rich benzoyl group delivered

product 3.38b in comparable yield. However, electron-withdrawing groups had a negative effect

on yield, with the strong -withdrawing nitro group having the greatest impact (3.38c and 3.38d).

The opposite trend was found when introducing electronic perturbations at the 5-position of the

indole; MeO- functionalized indole (3.38e) provided the product in slightly diminished yield and

F- containing indole (3.38f) was accessed in good yield. Dimethoxy containing indoline 3.38g was

isolated in low yield, however an interesting restrictive rotation around the C–N bond was

elucidated by NMR, suggesting meta-functionalized benzoyl groups are too sterically bulky for

the reaction. Azaindole derivative produced product 3.38h in modest yield however, the product

was found to be unstable and decomposed shortly following isolation. A carbonyl moiety on the

nitrogen was necessary as only acetyl and Boc protected indoles gave the desired product (1H

NMR and 19F NMR), accompanied by inseparable byproducts. Benzyl and tosyl protected indoles

decomposed upon reaction with NFSI. Extending the carbon chain at the 2-position led to no

reactivity.

132

Table 12 Examining the scope of the indole fluorination with NFSIa

3.38a

60%

3.38b

57%b

3.38c

39%c

3.38d

37%b

3.38e

44%b

3.38f

57%b

3.38g

33%c

3.38h

33%c

aReactions were run on 0.2 mmol scale. bReaction, workup, and/or purification was run by Matthew Zambri. cReaction,

workup, and/or purification was run by Sven Unger

3.2.3.5 Derivatization of the Products

With an efficient medium-scale synthesis of indoline 3.38a, we sought to evaluate the reactivity

of these interesting exomethylidene containing fluorinated scaffolds. First we aimed to study the

electronic properties of the olefin as it appears there is potential for amphoteric reactivity since

133

there are -bond withdrawing fluorine atoms as well as weak -donation from the nitrogen atom

(Scheme 95).

Scheme 95 Amphoteric properties of 3.38a

Gratifyingly, we found that the olefin could participate in an SN2’ reaction with morpholine acting

as the nucleophile (3.40). The reaction required DMA as a solvent and no product was isolated in

toluene, in contrast with the outcome when using palladium (vide infra). Rapid and quantitative

epoxidation with DMDO was also achieved with preservation of the fluorine moiety (3.41, reaction

run by Dr. Christian Dank).

Functionalization of allylic and propargylic fluorides has been studied with various nucleophiles,

metal-catalysts, and organocatalysts.153,149 Reactions catalyzed by palladium and platinum have

been investigated in detail and the reactivity is found to be superior compared to many commonly

used oxygen-based leaving groups.153b, 153c We aimed to further elucidate the electrophilic nature

of these indolines as potential substrates in palladium-allylation chemistry (Scheme 96).

Phenylsilane, as a hydride source, delivered 3-fluoroindole 3.43 in quantitative yield.154 When 1.5

equivalents of morpholine were reacted in toluene, a mixture of mono- and di-addition products

were formed. However, upon increasing the loading of morpholine (5 equivalents), we could

153

(a) Nishimine, T.; Fukushi, K.; Shibata, N.; Taira, H.; Tokunaga, E.; Yamano, A.; Shiro, M.; Shibata, N., Angew.

Chem. Int. Ed. 2014, 53, 517. (b) Benedetto, E.; Keita, M.; Tredwell, M.; Hollingworth, C.; Brown, J. M.; Gouverneur,

V., Organometallics 2012, 31, 1408. (c) Pacheco, M. C.; Purser, S.; Gouverneur, V., Chem. Rev. 2008, 108, 1943. 154

Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N., Org. Lett. 2007, 9, 3465.

134

isolate the double addition product 3.44 in 80% yield. The second addition may occur via an

oxidative addition into the heteroaryl-fluoride bond.155

Scheme 96 Palladium-catalyzed allylic functionalizationsa

aUnless otherwise stated, reactions run on a 0.1 mmol scale using [(C3H5)PdCl]2 (2.5–5 mol%) and xantphos (5–10

mol%). Reaction conditions: (a) XPhos (5 mol%) instead of xantphos, PhSiH3 (2 equiv), Et3N (1 equiv), EtOH, 50

°C, 6h. (b) morpholine (5 equiv), PhMe, 100 °C, 6 h. (c) Sodium phenylsulfinate (5 equiv), PhMe, 100 °C, 18 h, then

LiOH (2 M), 2h. (d) HP(O)(OEt)2 (2 equiv), CsF (1 equiv), PhMe, 70 °C, 18 h. (e) sodium dimethylmalonate (5 equiv),

15-crown-5 (5 equiv), DCM, r.t., 2h.

155

Amii, H.; Uneyama, K., Chem. Rev. 2009, 109, 2119.

135

In a similar manner, sulfonylation of 3.38a led to the product of double addition (3.45), which

upon treatment with LiOH led to cleavage of the labile benzoyl moiety.156 A clean phosphorylation

reaction was observed using dialkylphosphite as a nucleophile, producing 3.46 in good yield.157

Finally, using sodium dimethylmalonate as a nucleophile, according to the literature procedure,

produced 3.47 in excellent yield.153C

We also explored the viability of metal-catalyzed addition to the olefin, through a sterically

congested metal-complex 3.48 which could undergo a -fluoride elimination (Scheme 97).158 The

rhodium-catalyzed arylation/-fluoride elimination of 3.38a provided the mono-arylated product

3.49 in good yield and maintained a fluoride atom within the product [reaction run by Bijan

Mirabi]. Similarly, the copper-catalyzed borylation/-fluoride elimination provided product 3.50,

which possesses two handles for future transformations [reaction run by Alexa Torelli].

156

Eichelmann, H.; Gais, H.-J., Tetrahedron: Asymmetry 1995, 6, 643. 157

(a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T., Synthesis 1981, 1981, 56. (b) Hong, Y.; Liu, W.; Dong, M.;

Chen, X.; Xu, T.; Tian, P.; Tong, X., Org. Lett. 2019, 21, 5742. 158

(a) Jang, Y. J.; Rose, D.; Mirabi, B.; Lautens, M., Angew. Chem. Int. Ed. 2018, 57, 16147. (b) Huang, Y.; Hayashi,

T., J. Am. Chem. Soc. 2016, 138, 12340. (c) Gao, P.; Yuan, C.; Zhao, Y.; Shi, Z., Chem 2018, 4, 2201.

136

Scheme 97 Cu- and Rh- addition/-fluoride elimination

3.3 Chapter Summary

In conclusion, we have developed an efficient and scalable protocol for the synthesis of a gem-

difluoroindoline bearing an exocyclic and allylic olefin without the need for column

chromatography. These scaffolds are versatile building blocks capable of acting in an amphoteric

sense as well as with various Pd/Cu/Rh reactions forming new C–H, C–B, C–C, C–N, C–O, C–P,

and C–S bonds.

3.4 Experimental


Metal catalyzed reactions were run under an atmosphere of argon in oven or flame dried 2-dram

vials with open-top caps fitted with a Teflon septum. Reactions were monitored by thin-layer

chromatography (TLC) on EMD Silica Gel 60 F254 plates and visualized under UV light or by

immersion in iodine on silica stain. Flash column chromatography was performed on Silicycle 40-

60 m silica gel. PhMe was distilled over CaH. All reagents and organic building blocks were

purchased from commercial supplier (Sigma Aldrich, Strem, Alfa Aesar, TCI, Combi-blocks) and

used without further purification.


Probe. The spectra were internally referenced to the solvent peak. 19F and 31P NMR spectra were

obtained on the Varian Mercury 400 or 500 operating at 470 or 564 MHz. Measurements were

taken at 296 K and chemical shifts are reported in parts per million (ppm). Data is reported in the

following format: chemical shift ( ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =

quartet, m = multiplet), coupling constant (Hz), integration. High resolution mass spectra (HRMS)

were obtained on a Micromass 70S-250 spectrometer (EI) or an ABI/Sciex QStar Mass

Spectrometer (ESI) or a JEOL AccuTOF model JMS-T1000LC mass spectrometer equipped with

an IONICS® Direct Analysis in real Time (DART) ion source.

137



Starting materials were synthesized according to the previous protocol with using non-halogenated

benzoyl chlorides (see section 2.5.2.2 on page 84). Characterization data for known compounds

matched the literature data.159


(2-methyl-1H-indol-1-yl)(4-nitrophenyl)methanone (3.37d) – The

compound was synthesized according to general procedure 2.5.2.2. The


EtOAc–NEt3 (100:1:1 v:v) as the mobile phase and was isolated as a

yellow solid (203.6 mg, 0.7264 mmol, 14.5%). 1H NMR (400 MHz, CDCl3) δ 8.39 – 8.31 (m,

2H), 7.91 – 7.84 (m, 2H), 7.48 (dt, J = 7.8, 1.0 Hz, 1H), 7.18 (ddd, J = 7.9, 7.2, 1.0 Hz, 1H), 7.05

(ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 6.95 (dq, J = 8.4, 0.9 Hz, 1H), 6.47 (p, J = 1.1 Hz, 1H), 2.41 (d, J

= 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.8, 150.2, 141.3, 137.7, 136.9, 130.6, 129.9,

124.1, 123.5, 123.4, 120.3, 114.4, 110.0, 16.2. IR (thin film, cm-1) 3399, 3113, 3070, 3052, 2926,

2858, 1686, 1602, 1454, 1525, 1193, 804, 708. HRMS (DART, M+H) Calculated for C16H13N2O3

281.0926, found 281.0928.

(2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone

(3.37g) – The compound was synthesized according to general

procedure 2.5.2.2. The product was purified by flash column

chromatography using pentanes–EtOAc–NEt3 (30:1:1 v:v) as the

mobile phase and was isolated as a white solid (2.34 g, 7.92 mmol, 72%). 1H NMR (400 MHz,

CDCl3) δ 7.45 – 7.40 (m, 1H), 7.38 (dq, J = 8.3, 0.9 Hz, 1H), 7.20 – 7.12 (m, 2H), 7.11 – 7.04 (m,

2H), 6.96 (dd, J = 7.5, 1.7 Hz, 1H), 6.36 (t, J = 1.0 Hz, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 2.28 (d, J

= 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.7, 153.2, 146.8, 137.9, 137.2, 132.1, 129.9,

124.7, 123.5, 123.3, 120.2, 119.7, 115.1, 115.1, 109.7, 61.8, 56.1, 16.3. IR (thin film, cm-1) 2981,

2927, 2840, 1668, 1592, 1574, 1456, 1441, 1361, 984, 749. HRMS (DART, M+H) Calculated for

C18H18NO3 296.1281, found 296.1282.

159

Ramella, V.; He, Z.; Daniliuc, C. G.; Studer, A., Org. Lett. 2015, 17, 664.

138

(3,4-dimethoxyphenyl)(2-methyl-1H-indol-1-yl)methanone (3.37h) – The

compound was synthesized according to general procedure 2.5.2.2. The

product was purified by flash column chromatography using hexanes–

EtOAc–DCM (20:1:1 v:v) as the mobile phase and was isolated as a white

solid (590.7 mg, 2.5 mmol, 74%).1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J = 4.8, 1.6 Hz, 1H),

7.80 – 7.74 (m, 3H), 7.65 – 7.59 (m, 1H), 7.48 – 7.42 (m, 2H), 7.05 (dd, J = 7.7, 4.8 Hz, 1H), 6.39

(q, J = 1.1 Hz, 1H), 2.59 (d, J = 1.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.7, 149.7, 142.8,

139.1, 135.0, 133.4, 130.9, 128.4, 127.6, 121.6, 118.3, 104.8, 15.3. IR (thin film, cm-1) 3013, 2960,

2931, 1686, 1596, 1560, 1402, 1305, 1251, 904, 812. HRMS (DART, M+H) Calculated for

C15H13N2O 237.1022, found 237.1026.

3.4.3 Synthesis of 3,3-Difluoro-2-exo-Methylidene Indolines

3.4.3.1 General Procedure

In an oven-dried 2-dram vial equipped with a open-top septum cap purging with an argon balloon

was added substrate 3.37 (0.2 mmol), NFSI (0.44.mmol), and NH4Cl (0.2 mmol). After a 10-

minute purge, THF (1 mL, 0.2 M) was added. The balloon was removed, and the reaction was

heated to 60 °C, for 12–24 h. Upon completion, the reaction was diluted with pentanes to crash

out the polar byproducts and filtered through a silica plug, eluting with a 2:1 solvent mixture of

pentanes–Et2O. The reaction was concentrated and purified via silica gel chromatography. When

required, analytically pure material was obtained by recrystallization in pentanes.

3.4.3.2 Procedure for the 20 mmol-Scale Reaction

(3,3-difluoro-2-methyleneindolin-1-yl)(phenyl)methanone (3.38) – In a flame dried round

bottom flask equipped with an argon balloon was added substrate 3.37a (11 or 20 mmol, 1 equiv),

NH4Cl (1 equiv), and THF (0.5 M) and was stirred at 60 °C. NFSI (2.2 equiv) in THF (1 M) was

added using a syringe pump over 2 h and the reaction was further stirred for 24 h. Upon completion,

polar materials were crashed out using pentanes and the suspension was filtered over a silica plug

139

eluting with pentanes–Et2O (2:1). The product was recrystalized using pentanes and small amounts

of Et2O to afford analytically pure 3.38a (44% yield for 11 mmol and 20 mmol scales).


(3,3-difluoro-2-methyleneindolin-1-yl)(phenyl)methanone (3.38a) – Was

synthesized according to general procedure 3.4.3.1. The product was purified

by flash column chromatography using pentanes–Et2O (50:1 to 30:1, v:v) as

the mobile phase and was isolated as a white solid (32.6 mg, 0.12 mmol,

60%). 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.60 (m, 3H), 7.60 – 7.54 (m, 1H), 7.53 – 7.44 (m,

2H), 7.41 – 7.35 (m, 2H), 7.22 (ddd, J = 7.7, 4.7, 3.7 Hz, 1H), 5.43 (td, J = 3.0 Hz, 1H), 5.18 (td,

J = 3.6, 2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 168.8, 142.8 (t, J = 5.8 Hz), 142.6 (t, J = 26.9

Hz), 135.2, 132.9 (t, J = 1.5 Hz), 132.2, 129.0, 128.5, 124.8 (t, J = 1.7 Hz), 124.1, 122.9 (t, J =

24.8 Hz), 118.2 (t, J = 240.6 Hz), 116.4, 102.0 (t, J = 3.3 Hz). 19F NMR (377 MHz, CDCl3) δ -

85.13. IR (thin film, cm-1) 3338, 3151, 3129, 3061, 3029, 1673, 1616, 1600, 1462, 1355, 1152,

1047, 767. HRMS (DART, M+H) Calculated for C16H12F2NO 272.0887, found 272.0892.

(3,3-difluoro-2-methyleneindolin-1-yl)(4-

methoxyphenyl)methanone (3.38b) – Was synthesized according to

general procedure 3.4.3.1. The product was purified by flash column

chromatography using pentanes–Et2O (30:1, v:v) as the mobile phase

and was isolated as a white solid (34.6 mg, 0.1148 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ

7.67 – 7.58 (m, 3H), 7.42 – 7.33 (m, 2H), 7.22 – 7.16 (m, 1H), 6.99 – 6.92 (m, 2H), 5.41 (td, J =

3.2, 2.5 Hz, 1H), 5.20 (td, J = 3.6, 2.5 Hz, 1H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3 δ 168.4,

163.0, 143.2 (t, J = 6.0 Hz), 143.0 (t, J = 26.6 Hz), 132.9 (t, J = 1.5 Hz), 131.1, 127.0, 124.4 (t, J

= 1.7 Hz), 124.0, 122.7 (t, J = 24.8 Hz), 118.3 (t, J = 239.9 Hz), 116.1, 114.2, 101.1 (t, J = 3.3 Hz),

55.6. 19F NMR (377 MHz, CDCl3) δ -85.04. IR (thin film, cm-1) 3130, 3012, 2937, 2842, 1736,

1671, 1604, 1578, 1469, 1252, 756. HRMS (DART, M+H) Calculated for C17H14NO2F2 302.0987,

found 302.0991.

(3,3-difluoro-2-methyleneindolin-1-yl)(4-fluorophenyl)methanone

(3.38c) – Was synthesized according to general procedure 3.4.3.1 with the

following variations. The reaction was run on 0.5 mmol scale. The product

contained two unknown inseparable byproducts. The yield was measured

140

by proton NMR using 10.6 mg of TMB as an internal standard (0.197 mmol, 39%). 1H NMR (400

MHz, CDCl3) δ 7.74 – 7.65 (m, 3H), 7.50 – 7.39 (m, 2H), 7.28 – 7.23 (m, 1H), 7.23 – 7.17 (m,

2H), 5.49 (td, J = 3.0 Hz, 1H), 5.21 (td, J = 3.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 167.4,

164.9 (d, J = 253.8 Hz), 143.0 – 142.3 (m), 132.8 (t, J = 1.5 Hz), 131.2 (d, J = 8.9 Hz), 131.0 (d,

J = 3.5 Hz), 124.8 (t, J = 1.7 Hz), 124.0, 122.7 (t, J = 24.8 Hz), 118.1 (t, J = 240.1 Hz), 116.1 (d,

J = 8.1 Hz), 116.0, 101.7 (t, J = 3.3 Hz). 19F NMR (377 MHz, CDCl3) δ -85.39, -105.72 (td, J =

8.4, 7.9, 4.2 Hz). IR (thin film, cm-1) 3125, 3068, 3015, 2969, 3927, 1664, 1615, 1602, 1482, 1350,

1270, 1196, 1048. HRMS (DART, M+H) Calculated for C16H11NOF3 290.0787, found 290.0783.

(3,3-difluoro-2-methyleneindolin-1-yl)(4-nitrophenyl)methanone

(3.38d) – Was synthesized according to general procedure 3.4.3.1. The


Et2O (50:1 to 30:1, v:v) as the mobile phase and was isolated as a

yellow solid (23.4 mg, 0.074 mmol, 37%). 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.31 (m, 2H),

7.84 – 7.77 (m, 2H), 7.72 – 7.63 (m, 1H), 7.43 (d, J = 4.2 Hz, 2H), 7.28 (dd, J = 8.5, 4.8 Hz, 1H),

5.50 (td, J = 2.9 Hz, 1H), 5.14 (td, J = 3.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 166.2, 149.7,

142.4 (t, J = 27.3 Hz), 142.1 (t, J = 5.8 Hz), 140.7, 133.2 (t, J = 1.5 Hz), 129.6, 125.6 (t, J = 1.7

Hz), 124.3, 123.1 (t, J = 24.8 Hz), 117.9 (t, J = 240.5 Hz), 116.4, 103.0 (t, J = 3.1 Hz). 19F NMR

(377 MHz, CDCl3) δ -86.03. IR (thin film, cm-1) 3111, 2981, 1674, 1615, 1601, 1526, 1472, 1346,

1294, 762. HRMS (DART, M+H) Calculated for C16H11F2N2O3 317.0738, found 317.0743.

(3,3-difluoro-5-methoxy-2-methyleneindolin-1-

yl)(phenyl)methanone (3.38e) – Was synthesized according to general

procedure 3.4.3.1. The product was purified by flash column

chromatography using pentanes–Et2O (50:1 to 30:1, v:v) as the mobile

phase and was isolated as a white solid (26.5 mg, 0.088 mmol, 44%). 1H NMR (400 MHz, CDCl3)

δ 7.63 – 7.52 (m, 3H), 7.50 – 7.43 (m, 2H), 7.34 (dt, J = 9.1, 1.5 Hz, 1H), 7.14 (dt, J = 2.8, 1.4 Hz,

1H), 6.93 (ddt, J = 9.1, 2.6, 1.1 Hz, 1H), 5.41 (td, J = 2.9 Hz, 1H), 5.14 (td, J = 3.3 Hz, 1H), 3.83

(s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.2, 149.7, 142.4 (t, J = 27.3 Hz), 142.1 (t, J = 5.8 Hz),

140.7, 133.2 (t, J = 1.5 Hz), 129.6, 125.6 (t, J = 1.7 Hz), 124.3, 123.1 (t, J = 24.8 Hz), 117.9 (t, J

= 240.5 Hz), 116.4, 103.0 (t, J = 3.1 Hz). 19F NMR (377 MHz, CDCl3) δ -85.45. IR (thin film,

cm-1) 3137, 3068, 3028, 3012, 2967, 2921, 2851, 2835, 1655, 1486, 1361, 1220, 1047. HRMS

(DART, M+H) Calculated for C17H14F2NO2 302.0993, found 302.0995.

141

phenyl(3,3,5-trifluoro-2-methyleneindolin-1-yl)methanone (3.38f) –

Was synthesized according to general procedure 3.4.3.1. The product was

purified by flash column chromatography using pentanes–Et2O (50:1, v:v)

as the mobile phase and was isolated as a white solid (32.98 mg, 0.114

mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.52 (m, 3H), 7.52 –

7.43 (m, 2H), 7.37 – 7.30 (m, 1H), 7.13 (td, J = 8.9, 2.8 Hz, 1H), 5.41 (td, J = 3.1 Hz, 1H), 5.01

(td, J = 3.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) ) δ 168.3, 157.1 (t, J = 1.8 Hz), 142.8 (t, J =

26.8 Hz), 136.4 (t, J = 6.0 Hz), 135.4, 131.9, 128.9, 128.3, 123.8 (t, J = 24.4 Hz), 119.5 (t, J = 1.6

Hz), 118.2 (t, J = 240.4 Hz), 117.7, 107.9, 102.1 (t, J = 3.3 Hz), 55.9. 19F NMR (377 MHz, CDCl3)

δ -85.57, -116.44 (dd, J = 7.3 Hz). IR (thin film, cm-1) 3141, 3065, 3017, 2926, 2855, 1666, 1482,

1268, 1188. HRMS (DART, M+H) Calculated for C16H11F3NO 290.0793, found 290.0790.

(3,3-difluoro-2-methyleneindolin-1-yl)(3,4-

dimethoxyphenyl)methanone (3.38g) – Was synthesized according to

general procedure 3.4.3.1. The product was purified by flash column

chromatography using pentanes–Et2O (50:1 to 30:1, v:v) as the mobile

phase and was isolated as a white solid (39.7 mg, 0.12 mmol, 33%). 1H NMR (400 MHz, CDCl3)

δ 7.62 (dt, J = 7.6, 1.0 Hz, 1H), 7.41 – 7.28 (m, 2H), 7.24 – 7.18 (m, 1H), 7.17 – 7.13 (m, 1H),

7.07 (dd, J = 8.3, 1.5 Hz, 1H), 6.95 (dd, J = 7.6, 1.5 Hz, 1H), 5.43 (d, J = 2.3 Hz, 1H), 5.34 (s,

1H), 3.90 (s, 3H), 3.80 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.4, 153.1, 146.0, 142.4 (t, J =

5.9 Hz), 142.1 (t, J = 26.9 Hz), 133.0 (t, J = 1.5 Hz), 131.0, 125.1 (t, J = 1.9 Hz), 125.0, 124.0,

123.2 (t, J = 24.8 Hz), 119.5, 118.1 (t, J = 239.7 Hz), 116.4, 114.9, 102.3, 61.7, 56.1. 19F NMR

(377 MHz, CDCl3) δ -82.94 (d, J = 270.8 Hz), -86.23 (d, J = 271.5 Hz). IR (thin film, cm-1) 3012,

2938, 2839, 1680, 1615, 1398, 1582, 1471, 1358, 1290, 1270, 1048, 751. HRMS (DART, M+H)

Calculated for C18H16F2NO3 332.1093, found 332.1088.

(3,3-difluoro-2-methylene-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-

yl)(phenyl)methanone (3.38h) – Was synthesized according to general

procedure 3.4.3.1. The product was purified by flash column chromatography

using pentanes–EtOAc (30:1, v:v) as the mobile phase and was isolated as a

white solid (18.1 mg, 0.066 mmol, 33%). 1H NMR (400 MHz, CDCl3) δ 8.14 (ddt, J = 5.0, 1.9,

1.0 Hz, 1H), 7.93 (dq, J = 7.6, 1.5 Hz, 1H), 7.68 – 7.59 (m, 2H), 7.55 (ddt, J = 7.9, 7.0, 1.3 Hz,

1H), 7.47 – 7.37 (m, 2H), 7.06 (dd, J = 7.6, 5.0 Hz, 1H), 6.27 (td, J = 4.1, 2.2 Hz, 1H), 5.63 (td, J

142

= 3.4, 2.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 168.8, 155.4 (t, J = 6.0 Hz), 152.0 (t, J = 1.7

Hz), 141.2 (t, J = 26.6 Hz), 135.5, 133.3, 132.2, 129.1, 128.2, 119.6 (t, J = 1.4 Hz), 116.3 (t, J =

241.0 Hz), 115.8 (t, J = 25.7 Hz), 102.2 (t, J = 3.2 Hz). 19F NMR (377 MHz, CDCl3) δ -84.64. IR

(thin film, cm-1) 3029, 2961, 2924, 2856, 1684, 1594, 1473, 1449, 1420, 1272, 1059, 902. HRMS

(DART, M+H) Calculated for C19H11F2N2O 273.0834, found 273.0835.

3.4.4 Reactions of 3,3-Difluoro-2-exo-Methylidene Indolines

3.4.4.1 Allylic Substitution with Morpholine Nucleophile (SN2’)

(3-fluoro-2-(morpholinomethyl)-1H-indol-1-yl)(phenyl)methanone (3.40) – In an oven-dried

2-dram vial equipped with an open-top cap with septum and an argon balloon was added substrate

3.38a (0.1 mmol), DMA (1 mL), and morpholine (10 equiv) in that order. The balloon was

removed, the reaction was sealed tightly, and was heated to 70 °C for 18 h. The reaction was

filtered over silica, concentrated, and columned using a pentanes–EtOAc (10:1, v:v) eluting phase

to isolated 3.40 as a white solid (28.76 mg, 0.85 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ 7.77

– 7.69 (m, 2H), 7.65 – 7.54 (m, 2H), 7.54 – 7.41 (m, 3H), 7.29 – 7.19 (m, 2H), 3.54 – 3.43 (m,

6H), 2.15 – 2.06 (m, 4H). 13C NMR (101 MHz, CDCl3 δ 169.7, 147.8 (d, J = 251.8 Hz), 135.7,

134.2 (d, J = 5.3 Hz), 132.8, 129.8, 128.6, 125.3, 122.9, 119.0 (d, J = 18.3 Hz), 118.8 (d, J = 22.4

Hz), 116.9 (d, J = 2.6 Hz), 114.3 (d, J = 1.8 Hz), 67.0, 52.7, 50.6 (d, J = 2.7 Hz). 19F NMR (377

MHz, CDCl3) δ -168.89. IR (thin film, cm-1) 3058, 2962, 2854, 2814, 1694, 1454, 1411, 1343,

1320, 1116, 747. HRMS (DART, M+H) Calculated for C20H20N2O2F 339.1503, found 339.1507.

3.4.4.2 DMDO epoxidation

143

(3,3-difluorospiro[indoline-2,2'-oxiran]-1-yl)(phenyl)methanone (3.41) – This experiment was

devised by Nicolas Zeidan and executed by Dr. Christian Dank. DMDO was synthesized according

the literature procedure.160 3.3 mL of DMDO in acetone (0.066 M, 1.1 equiv) was added to 3.38a

(54.25 mg, 0.2 mmol, 1 equiv) at 0 °C. The reaction was gradually warmed to r.t. and stirred for

20 h. The clear solution was concentrated under reduced pressure to give 3.41 as a slightly yellow

oil (57.45, 0.2 mmol, >99%).1H NMR (400 MHz, CDCl3) δ 7.70 – 7.53 (m, 4H), 7.53 – 7.43 (m,

2H), 7.38 (tq, J = 7.5, 1.2 Hz, 1H), 7.24 (dd, J = 8.0, 7.1 Hz, 1H), 7.13 – 7.02 (m, 1H), 3.75 (ddd,

J = 4.6, 2.7, 2.0 Hz, 1H), 3.31 (dd, J = 4.5, 0.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 169.1,

143.8 (dd, J = 6.7, 5.4 Hz), 134.8, 132.8, 132.1, 128.6, 128.3, 124.6 (t, J = 1.8 Hz), 123.7, 121.3

(dd, J = 25.2, 24.7 Hz), 119.4 (dd, J = 249.9, 243.5 Hz), 117.2, 76.1 (dd, J = 41.6, 25.3 Hz), 48.2

(d, J = 4.2 Hz). 19F NMR (377 MHz, CDCl3) δ -93.82 (d, J = 259.7 Hz), -109.25 (d, J = 259.7

Hz). IR (thin film, cm-1) 3060.2, 3004.7, 2920.1, 1971.9, 1674.0, 1615.2, 1600.9, 1472.8, 1405.8,

1341.7, 1293.8, 1195.1, 1158.2, 1140.2, 1115.7, 1076.3, 948.59, 759.96, 699.23. HRMS (DART,

M+H) Calculated for C16H12NO2F2 288.0831, found 288.0830.

3.4.4.3 Pd-Catalyzed Hydro-Defluorination

(3-fluoro-2-methyl-1H-indol-1-yl)(phenyl)methanone (3.43) – In an oven-dried 2-dram vial

equipped with an open-top cap with septum and an argon balloon was added substrate 3.38a (0.1

mmol), [(C3H5)PdCl]2 (2.5 mol%), and xphos (5 mol%). The vial was purged for 10 minutes and

thereafter, EtOH (1 mL), PhSiH3 (2 equiv), and NEt3 (1 equiv) were added successively. The

balloon was removed, the reaction was sealed tightly and was heated to 50 °C for 6 h. The reaction

was filtered over silica, concentrated, and columned using a pentanes–Et2O (100:1, v:v) eluting

phase to isolated 3.43 as a white solid (25.3 mg, 0.999 mmol, >99%). 1H NMR (600 MHz, CDCl3)

δ 7.73 – 7.68 (m, 2H), 7.67 – 7.61 (m, 1H), 7.55 – 7.47 (m, 3H), 7.21 (ddd, J = 7.9, 6.8, 1.2 Hz,

1H), 7.15 – 7.07 (m, 2H), 2.31 (d, J = 2.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 169.6, 147.0

160

Organic Syntheses 2013, 90, 350.

144

(d, J = 248.3 Hz), 135.7, 133.5 (d, J = 5.2 Hz), 133.0, 129.7, 129.0, 124.3, 123.1, 120.4 (d, J =

18.6 Hz), 119.6 (d, J = 25.2 Hz), 116.3 (d, J = 2.6 Hz), 114.8 (d, J = 1.9 Hz), 11.1 (d, J = 1.5 Hz).

19F NMR (564 MHz, CDCl3) δ -171.22. IR (thin film, cm-1) 3058, 2964, 2927, 2854, 1687, 1645,

1600, 1456, 1347, 1316, 743. HRMS (DART, M+H) Calculated for C16H13NOF 254.0976, found

254.0977.

3.4.4.4 Pd-Catalyzed Double Amination

(3-morpholino-2-(morpholinomethyl)-1H-indol-1-yl)(phenyl)methanone (3.44) – In an oven-

dried 2-dram vial equipped with an open-top cap with septum and an argon balloon was added

substrate 3.38a (0.1 mmol), [(C3H5)PdCl]2 (2.5 mol%), and Xantphos (5 mol%). The vial was

purged for 10 minutes and thereafter, PhMe (1 mL), and morpholine (5 equiv) were added

successively. The balloon was removed, the reaction was sealed tightly, and it was heated to 100

°C for 6 h. The reaction was filtered over silica, concentrated, and columned using a pentanes–

EtOAc (10:1, v:v) eluting phase to isolate 3.44 as a white solid (32.3 mg, 0.0796 mmol, 80%). 1H

NMR (400 MHz, CDCl3) δ 7.78 – 7.70 (m, 3H), 7.63 – 7.54 (m, 1H), 7.51 – 7.43 (m, 3H), 7.21 –

7.13 (m, 2H), 3.89 – 3.83 (m, 4H), 3.51 (s, 2H), 3.46 (t, J = 4.7 Hz, 4H), 3.28 – 3.21 (m, 4H), 2.09

– 2.02 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 170.0, 136.3, 135.9, 133.2, 132.7, 130.8, 129.9,

128.5, 125.7, 123.9, 122.0, 119.8, 114.1, 68.0, 67.0, 52.9, 52.8, 51.9. IR (thin film, cm-1) 2958,

2852, 1688, 1454, 1344, 1327, 1261, 1115, 748. HRMS (DART, M+H) Calculated for

C24H28N3O3 406.2125, found 406.2127.

3.4.4.5 Pd-Catalyzed Double sulfonylation

145

3-(phenylsulfonyl)-2-((phenylsulfonyl)methyl)-1H-indole (3.45) – In an oven-dried 2-dram vial


mmol), [(C3H5)PdCl]2 (5 mol%), Xantphos (10 mol%), and sodium benzene sulfinate (5 equiv).

The vial was purged for 10 minutes and thereafter, PhMe (1 mL) was added. The balloon was

removed, the reaction was sealed tightly, and it was heated to 100 °C for 18 h. The reaction was

filtered over silica, concentrated, and columned using a pentanes–EtOAc (5:1 to 2:1, v:v) eluting

phase to isolate 3.45 as a white solid (40.3 mg, 0.098 mmol, 49%). 1H NMR (400 MHz, CDCl3)

δ 9.72 (s, 1H), 7.86 – 7.77 (m, 3H), 7.77 – 7.70 (m, 2H), 7.70 – 7.61 (m, 1H), 7.59 – 7.41 (m, 4H),

7.41 – 7.33 (m, 2H), 7.33 – 7.28 (m, 1H), 7.22 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 5.25 (s, 2H). 13C

NMR (126 MHz, CDCl3) δ 142.9, 137.6, 135.5, 134.7, 132.9, 129.6, 129.6, 129.2, 128.5, 126.5,

125.0, 124.3, 123.0, 120.2, 115.4, 112.1, 52.7. IR (thin film, cm-1) 3317, 3069, 3011, 2918, 1534,

1447, 1426, 1302, 1131, 908, 733. HRMS (DART, M+H) Calculated for C21H21N2O4S2

429.09372, found 429.09327.

3.4.4.6 Pd-Catalyzed Allylic Phosphorylation

diethyl ((1-benzoyl-3-fluoro-1H-indol-2-yl)methyl)phosphonate (3.46) – In an oven-dried 2-

dram vial equipped with an open-top cap with septum and an argon balloon was added substrate

3.38a (0.1 mmol), [(C3H5)PdCl]2 (2.5 mol%), and Xantphos (5 mol%), and CsF (1 equiv). The vial

was purged for 10 minutes and thereafter, PhMe (1 mL), and diethyl phosphite (2 equiv) were

added successively. The balloon was removed, the reaction was sealed tightly, and it was heated

to 70 °C for 18 h. The reaction was filtered over silica, concentrated, and columned using a

pentanes–EtOAc (3:1 to 2:1, v:v) eluting phase to isolate 3.46 as a white solid (26.1 mg, 0.067 mmol,

67%). 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.76 (m, 2H), 7.69 – 7.60 (m, 1H), 7.52 (dddd, J =

13.8, 7.7, 6.9, 1.4 Hz, 3H), 7.17 (ddd, J = 8.0, 7.2, 0.9 Hz, 1H), 7.01 (ddt, J = 8.5, 7.2, 1.3 Hz, 1H),

6.63 (dd, J = 8.6, 2.2 Hz, 1H), 4.01 (dqd, J = 8.3, 7.1, 2.5 Hz, 4H), 3.74 (dd, J = 21.0, 1.5 Hz, 2H),

1.17 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 169.7 (d, J = 1.1 Hz), 147.8 (dd, J = 252.0,

11.2 Hz), 135.1, 134.0 (dd, J = 5.4, 1.9 Hz), 133.3, 130.3, 128.9, 124.5 (d, J = 2.1 Hz), 122.7 (d, J

146

= 1.6 Hz), 119.3 (dd, J = 17.9, 4.0 Hz), 116.7 (dd, J = 2.3 Hz), 114.6 (dd, J = 24.5, 14.7 Hz), 114.2

(dd, J = 1.8 Hz), 62.4 (d, J = 6.5 Hz), 22.2 (dd, J = 141.0, 2.2 Hz), 16.3 (d, J = 5.9 Hz). 19F NMR

(377 MHz, CDCl3) δ -168.38 (d, J = 12.1 Hz). 31P NMR (162 MHz, CDCl3) δ 23.03 (d, J = 11.9

Hz). IR (thin film, cm-1) 3062, 2983, 2931, 3909, 1692, 1638, 1453, 1349, 1019, 853. HRMS

(DART, M+H) Calculated for C20H22FNO4P 390.1265, found 390.1266.

3.4.4.7 Pd-Catalyzed Double Alkylation

dimethyl 2-(1-benzoyl-2-(3-methoxy-2-(methoxycarbonyl)-3-oxopropyl)-1H-indol-3-

yl)malonate (3.47) – In an oven-dried 2-dram vial equipped with an open-top cap with septum

and an argon balloon was added substrate 3.38a (0.1 mmol), [(C3H5)PdCl]2 (2.5 mol%), and

Xantphos (5 mol%), sodium dimethylmalonate (5 equiv), and 15-crown-5 (5 equiv). The vial was

purged for 10 minutes and thereafter, DCM (1 mL) was added. The balloon was removed, the

reaction was sealed tightly, and it was stirred at r.t. for 2 h. The reaction was filtered over silica,

concentrated, and columned using a pentanes–EtOAc (10:1 to 5:1, v:v) eluting phase to isolate

3.47 as a white solid (46.4 mg, 0.09364 mmol, 94%). 1H NMR (500 MHz, CDCl3) δ 7.75 – 7.69

(m, 2H), 7.66 (ddt, J = 8.8, 7.3, 1.3 Hz, 1H), 7.61 (ddd, J = 8.0, 1.3, 0.7 Hz, 1H), 7.54 – 7.46 (m,

2H), 7.12 (ddd, J = 8.0, 7.2, 1.0 Hz, 1H), 6.94 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 6.48 (dt, J = 8.5, 0.9

Hz, 1H), 5.16 (s, 1H), 4.07 (t, J = 7.6 Hz, 1H), 3.78 (s, 7H), 3.69 – 3.64 (m, 8H). 13C NMR (126

MHz, CDCl3) δ 170.0, 169.2, 168.5, 136.7, 136.0, 134.9, 133.6, 130.1, 129.0, 128.1, 123.6, 122.8,

121.3, 114.4, 114.2, 52.9, 52.9, 51.6, 49.0, 25.2. IR (thin film, cm-1) 3655, 2981, 2973, 2889, 1755,

1737, 1458, 1311, 1154. HRMS (DART, M+H) Calculated for C26H26NO9 496.1602, found 496.1597.

147

3.4.4.8 Rhodium-Catalyzed Arylation

(3-fluoro-2-(4-methoxybenzyl)-1H-indol-1-yl)(phenyl)methanone (3.49) – This experiment

was devised by Nicolas Zeidan and executed by Bijan Mirabi. In an oven-dried 2-dram vial


mmol), aryl boronic acid (2.5 equiv), [Rh(COD)OH]2 (2.5 mol%), and rac-BINAP (5 mol%). The

vial was purged for 10 minutes and thereafter, dioxane (1 mL) and distilled H2O (0.1 mL) was

added. The balloon was removed, the reaction was sealed tightly, and it was stirred at 120 °C for

24 h. The reaction was cooled to room temperature and quenched with an aqueous solution of

saturated NaHCO3. The mixture was diluted with EtOAc, washed once with an aqueous solution

of NaHCO3, once with H2O, and once with brine. The organic layer was dried over magnesium

sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash column

chromatography pentanes–EtOAc (9:1, v:v) to obtain product 3.49 as a yellow film (40.25 mg,

0.112 mmol, 56%). 1H NMR (500 MHz, CDCl3) δ 7.63 – 7.57 (m, 2H), 7.55 – 7.50 (m, 2H), 7.46

– 7.40 (m, 2H), 7.22 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 7.07 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.00 –

6.93 (m, 2H), 6.84 (ddt, J = 8.5, 2.3, 0.8 Hz, 1H), 6.75 – 6.71 (m, 2H), 4.24 (d, J = 1.9 Hz, 2H),

3.73 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.4 (d, J = 1.2 Hz), 158.3, 147.3 (d, J = 250.0 Hz),

135.3, 133.9 (d, J = 5.4 Hz), 133.0, 130.3 (d, J = 2.0 Hz), 129.8, 129.4, 128.8, 124.5, 122.9, 122.9

(d, J = 24.0 Hz), 119.9 (d, J = 18.6 Hz), 116.7 (d, J = 2.6 Hz), 114.5 (d, J = 1.8 Hz), 113.9, 55.3,

29.2 (d, J = 1.8 Hz). 19F NMR (377 MHz, CDCl3) δ -170.14. IR (neat) 3063, 2913, 2988, 2843,

1693, 1639, 1607, 1511, 1458, 1355, 1313, 1235, 1174, 1110, 1047, 894, 755, 720, 699, 663, 638.

HRMS (DART, M+H) Calculated for C23H19NO2F 360.1394, found 360.1396.

148

3.4.4.9 Copper-Catalyzed Borylation

(3-fluoro-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-1H-indol-1-

yl)(phenyl)methanone (3.50) – This experiment was devised by Nicolas Zeidan and executed by

Alexa Torelli. In an oven-dried 2-dram vial equipped with an open-top cap with septum and an

argon balloon was added Tetrakisacetonitrile copper hexafluorophosphate (4 mol%), bppp (6

mol%), and sodium tert-butoxide (1.5 equiv). Anhydrous MTBE (1 mL) was added to the vial and

the catalyst solution was stirred for 5 minutes. Bis(pinacolato)diboron (1.5 equiv) was added in 1

mL of anhydrous MTBE and the suspension was stirred for 5 minutes. Substrate 3.38a (0.2 mmol,

1 equiv) was dissolved in anhydrous MTBE (2 mL) and charged to the reaction vial. The reaction

was stirred for 10 h then filtered through a celite pad and concentrated. A crude NMR with TMB

as an internal standard suggested the yield is around 89%. The product was purified by flash

column chromatography using pentanes–EtOAc (6% to 10%) to isolate 3.50 as a white solid (60.6

mg, 0.1598, 80%). 1H NMR (500 MHz, Chloroform-d) δ 7.79 – 7.71 (m, 2H), 7.67 – 7.60 (m,

1H), 7.55 – 7.45 (m, 3H), 7.18 – 7.11 (m, 1H), 6.92 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 6.47 (dd, J =

8.5, 2.2 Hz, 1H), 2.66 (d, J = 1.9 Hz, 2H), 1.13 (s, 12H). 13C NMR (126 MHz, CDCl3) δ 170.0 (d,

J = 1.3 Hz), 146.2 (d, J = 245.9 Hz), 135.7, 132.9 (d, J = 5.3 Hz), 132.8, 130.0, 128.7, 123.2, 122.6,

122.1 (d, J = 25.4 Hz), 120.6 (d, J = 18.7 Hz), 116.1 (d, J = 2.6 Hz), 114.3 (d, J = 1.8 Hz), 83.9,

24.8, 9.6. 19F NMR (377 MHz, Chloroform-d) δ -172.70. IR (thin film, cm-1) 2936, 1692, 1631,

1448, 1323, 1238, 1204, 1143, 970, 845, 767, 713, 658. HRMS (DART, M+H) Calculated for

C22H24BNO3F 380.1834, found 380.1828.

149

General Conclusions and Outlook

The synthesis of indoles and their reactivity is a flourishing field, even after many years of

important discoveries. Research in metal-catalyzed synthesis of indoles will continue to grow as

complementary methods are required for the rapid synthesis of functionalized indoles. In this

regard, base-metal catalysts will be crucial in the development of inexpensive alternatives.

Students looking to pursue methodologies for the synthesis of indoles should focus on modular

methods which yield diversified indoles at the non-traditional positions (such as 2-, 4-, 7-).

Likewise, the dearomatization of indoles, and related heterocycles, will continue to be relevant as

they allow an atom-economic route to otherwise difficult to access saturated chiral cycles.

Indolines show high bioactivity and therefore will remain to be important targets of small-molecule

API development in the foreseeable future. It is advisable for those pursuing this field to develop

new catalysts for dearomatization reactions. Additionally, research into the dearomatization of

non-heterocycles by migratory insertion is lagging, and therefore I would expect this will be the

focus of research in the nearby future. The use of custom boron regents is very underdeveloped as

well. Students looking to pursue any palladium-catalyzed functionalizations are encouraged to use

the mixed boron reagent presented in chapter 2.

Finally, the need for new C–F bond forming reactions, especially those involving interesting

molecules, is crucial. Combining the ideas of dearomatization and electrophilic fluorination is a

steppingstone towards cheaper alternatives. The use of base-metals such as cobalt and nickel for

radical incorporation of these N–F reagents will likely be an interesting avenue for chemists to

come. The stable difluoroindoline presented in chapter 3 shows a remarkable stability as well as

olefin reactivity. Students pursuing related work are encouraged to attempt enantioselective

desymmetrisation reactions using palladium, rhodium, or other metals as they have been shown to

work well.

150

Appendix A – NMRs from Chapter 1

190

Appendix B – NMRs from Chapter 2

281

Appendix C – HPLC Chromatograms from Chapter 2

288

Appendix D – NMRs from Chapter 3

330

Appendix E – X-Ray Crystallographic data

Experiments were run by Dr. Alan Lough

331

Compound 2.58 =

332

Table 1. Crystal data and structure refinement for d1847a_a.

Identification code d1847a_a

Empirical formula C23 H16 N2 O S

Formula weight 368.44

Temperature 150(2) K

Wavelength 0.71073 Å

Crystal system Orthorhombic

Space group Pna21

Unit cell dimensions a = 15.0523(7) Å = 90°.

b = 11.1701(6) Å = 90°.

c = 10.6235(5) Å = 90°.

Volume 1786.19(15) Å3

Z 4

Density (calculated) 1.370 Mg/m3

Absorption coefficient 0.197 mm-1

F(000) 768

Crystal size 0.180 x 0.150 x 0.060 mm3

Theta range for data collection 2.270 to 27.500°.

Index ranges -19<=h<=18, -14<=k<=14, -13<=l<=13

Reflections collected 11663

Independent reflections 4064 [R(int) = 0.0436]

Completeness to theta = 25.242° 99.6 %

333

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7456 and 0.7051

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4064 / 1 / 245

Goodness-of-fit on F2 1.021

Final R indices [I>2sigma(I)] R1 = 0.0404, wR2 = 0.0855

R indices (all data) R1 = 0.0537, wR2 = 0.0911

Absolute structure parameter -0.02(4)

Extinction coefficient n/a

Largest diff. peak and hole 0.304 and -0.240 e.Å-3

334

Compound 2.65a =

335

Table 1. Crystal data and structure refinement for d1866a_a.

Identification code d1866a_a

Empirical formula C22 H24 B N O3




Crystal system Monoclinic

Space group P21


b = 10.4616(2) Å = 90.9230(10)°.

c = 18.5419(3) Å = 90°.

Volume 1932.33(6) Å3

Z 4



F(000) 768



Index ranges -11<=h<=11, -12<=k<=11, -22<=l<=22



336









Absolute structure parameter 0.01(5)

Extinction coefficient n/a

Largest diff. peak and hole 0.364 and -0.248 e.Å-3

337

Compound 3.38a

338

Table 1. Crystal data and structure refinement for d19161_a.

Identification code d19161_a

Empirical formula C16 H11 F2 N O




Crystal system Monoclinic

Space group P21/n


b = 5.7406(6) Å = 102.044(6)°.

c = 15.530(2) Å = 90°.

Volume 1268.6(3) Å3

Z 4



F(000) 560



Index ranges -17<=h<=17, -6<=k<=6, -18<=l<=18




339








Extinction coefficient 0.0106(16)

Largest diff. peak and hole 0.173 and -0.194 e.Å

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