and N, O- Containing Heterocycles by - OhioLINK ETD Center

A Dissertation

entitled

Halogen Mediated Alkene Difunctionalization for Synthesis of N, S- and N, O-

Containing Heterocycles

by

Nur-E Alom

Submitted to the Graduate Faculty as partial fulfillment of the requirements for the

Doctor of Philosophy Degree in

Chemistry

___________________________________________

Dr. Wei Li, Committee Chair

___________________________________________

Dr. Steven J. Sucheck, Committee Member

___________________________________________

Dr. Jianglong Zhu, Committee Member

___________________________________________

Dr. Ana C. Alba-Rubio, Committee Member

___________________________________________

Dr. Amanda C. Bryant-Friedrich, Dean

College of Graduate Studies

The University of Toledo

August 2020

© 2020 Nur-E Alom

This document is copyrighted material. Under copyright law, no parts of this document

may be reproduced without the expressed permission of the author.

iii

An Abstract of

Halogen Mediated Alkene Difunctionalization for Synthesis of N, S- and N, O-

Containing Heterocycles

by

Nur-E Alom

Submitted to the Graduate Faculty as partial fulfillment of the requirements for the

Doctor of Philosophy Degree in

Chemistry

The University of Toledo

August 2020

N, S- and N, O-containing heterocycles are ubiquitous structural motifs in

pharmaceuticals, agrochemicals, and bioactive natural products. These types of compounds

exhibit a broad range of bioactivities such as anti-cancer, anti-HIV, antibiotics, and

antidepressants. To gain access to those heterocycles, alkene sulfenoamination and alkene

oxyamination have been considered as powerful strategies because of its ability to rapidly

increase the molecular complexity and functional diversity. Moreover, the wide availability

of alkenes in natural products and commercial sources, in addition to the ease of synthetic

accesses make these alkene functionalization strategies more appealing in the synthetic

community for the modular synthesis of those heterocycles. Our group is interested in the

utilization of classic halonium ion as a regioselective template for the functionalization of

alkenes. The research efforts presented in this dissertation focus on the development of

simple and efficient methods for alkene sulfenoamination and alkene oxyamination by

demonstrating a series of alkene sulfenoamination protocols for accessing interesting N,

S–containing heterocycles.

iv

In Chapter 2, a simple and convenient method for the synthesis of thiazoline from

readily available chemical feedstocks such as alkenes and thioamides is described. The

reaction goes through the in-situ generation of 1,2-dibromoalkane from the bromination of

alkene, followed by the nucleophilic attack of thioamide on the 1,2-dibromoalkane

intermediate leading to thiazoline formation. The synthetic application of this method was

further demonstrated by hydrolysis of thiazoline to 1,2-amino thiol and oxidation to

thiazole, a common scaffold in drugs.

In Chapter 3, the regio- and stereoselective sulfenoamination of alkene with

thioimidazoles for the synthesis of N, S-containing heterocycle is reported. In this reaction,

Selectfluor was used as a halogen source to convert the nucleophilic sulfur reagent into an

electrophilic sulfur source through the formation of a sulfur-fluorine bond. Nucleophilic

attack of an alkene on the sulfur electrophile led to the formation of a thiiranium ion

intermediate, then intramolecular cyclization on thiiranium ion intermediate or open

carbocation resulted in the product formation. The opposite regioisomer of the product

could also be achieved by using bromine as a halogen source. This method exhibited good

functional group tolerance and a broad range of substrate scope in a highly regio- and

stereoselective manner.

In Chapter 4, an efficient approach for the synthesis of 1,4-benzothiazine via alkene

sulfenoamination is presented. This method is an improvement over our previous two

strategies, in which we can use a catalytic amount of an iodide salt, that offers an

environmentally benign and more economic strategy for alkene sulfenoamination.

Moreover, the use of unprotected aminothiophenol as a coupling partner represents another

significant advance in accessing 1,4-benzothiazine. The reaction proceeds through

v

inversion of the thiol polarity with the formation of a sulfur-iodine bond. The investigation

of the mechanism suggests that both polar thiiranium and radical pathways are plausible in

this reaction.

In Chapter 5, the development of a method for the alkylation of arene using alcohol

via carbon-carbon bond formation is disclosed. The highlighting feature of this reaction is

the utilization of an alkene as a catalyst for iodonium formation that can activate an alcohol,

leading to the generation of the product with an all-carbon quaternary centers. The method

shows a good functional group tolerance with a wide range of arene and alcohol substrate

scope. This strategy can be extended to the formation of sterically congested carbon-

heteroatom bonds. In addition, this method is chemoselective for tertiary alcohols in

preference to the primary and secondary alcohols.

In Chapter 6, an iodide-catalyzed alkene oxyamination reaction for the synthesis of

oxazolidinone is discovered. The reaction utilizes unfunctionalized carbamate as a

nucleophilic coupling partner, and Selectfluor as an oxidant to oxidize iodide to iodine.

The reaction proceeds through the generation of catalytic iodonium intermediate, followed

by nucleophilic attack of carbamate, leading to the formation of oxazolidinone product.

The complementary regioisomeric product can also be achieved utilizing NBS instead as a

halogen source.

vi

This work is dedicated to my parents Harun Moral and Basiron.

Thanks for your support and love.

vii

Acknowledgements

At first, I would like to express my sincere gratitude to my supervisor, Dr. Wei Li

for his continuous support and guidance during my PhD study. His trust and confidence in

my learning capacity as a newly minted graduate student in 2015 fostered my growth,

confidence in my organic chemistry skills, and curiosities as a scientist. I am profoundly

grateful to him for the training, encouragement and freedom that I received to explore

halogen mediated chemistry and will be a great asset for my future research endeavors.

I wish to thank my research committee members Dr. Steve Sucheck, Dr. Jianglong

Zhu, Dr. Ana C. Alba-Rubio, and Dr. Michael Young for their insightful comments and

valuable advice to my research as well as the time they have dedicated to me.

Next, I would like to thank my labmates Fan, Jeewani and Navdeep for all the fun

we had, discussions, feedbacks of the project, proofreading of my papers and thesis as well

as their collaboration for finishing my projects. I also wish to thank all the graduate students

that I have known and worked with, and Bangladeshi Communities in Toledo for always

bringing me joys. I would like to thank the Department of Chemistry and Biochemistry,

the University of Toledo for providing me facilities to conduct research.

I am greatly indebted to my parents for their love, support and sacrifice for me. My

family members and friends from home have always been there for me and have always

helped me remember my roots.

Finally, I am thankful to my wife for her relentless care, love and emotional support.

viii

Table of Contents

Abstract .............................................................................................................................. iii

Acknowledgements ........................................................................................................... vii

Table of Contents ............................................................................................................. viii

List of Tables .................................................................................................................... xii

List of Figures .................................................................................................................. xiii

List of Schemes ................................................................................................................ xiv

List of Abbreviations .........................................................................................................xv

Preface............................................................................................................................. xvii

1 Halogen Mediated Alkene Difunctionalization for the Synthesis of N, S- and N,

O-Containing Heterocycles ......................................................................................1

1.1 Introduction of Alkene Difuctionalization ...................................................1

1.1.1 Abundance and Reactivity of Alkene ..............................................1

1.1.2 Difunctionalization of Alkene..........................................................2

1.2 Significance of N, S- and N, O-Containing Heterocycles ...........................4

1.3 Our Proposed Halogen Mediated Difunctionalization of Alkene for the

Synthesis of N-Containing Heterocycles .....................................................6

2 One-Pot Strategy for Thiazoline Synthesis from Alkenes and Thioamides ..........11

2.1 Introduction ................................................................................................11

2.2 Results and Discussions for Thiazoline Synthesis .....................................14

ix

2.2.1 Reaction Design and Optimization ................................................14

2.2.2 Reaction Scope...............................................................................16

2.3 Proposed Reaction Mechanism ..................................................................19

2.4 Synthetic Application.................................................................................20

2.5 Conclusion .................................................................................................20

2.6 Experimental ..............................................................................................21

3 Intramolecular Regio- and Stereoselective Alkene Sulfenoamination With

Thioimidazoles .......................................................................................................52

3.1 Introduction ................................................................................................52

3.2 Results and Discussions for Sulfenoamination ..........................................55


3.2.2 Reaction Scope...............................................................................56

3.2.3 Regiodivergent Sulfenoamination .................................................60

3.3 Reaction Mechanism ..................................................................................61

3.3.1 Solvent Effect on Reaction ............................................................61

3.3.2 Temperature-Dependent Diastereoselectivity ................................62

3.2.3 Proposed Mechanism for Intermolecular Sulfenoamination ........63

3.4 Conclusion .................................................................................................64

3.5 Experimental ..............................................................................................64

4 Catalytic Regio- and Stereoselective Alkene Sulfenoamination and Arene

Sulfenylation for 1,4-Benzothiazine Synthesis ......................................................95

4.1 Introduction ................................................................................................95

4.2 Results and Discussions for 1,4-Benzothiazine Synthesis .........................99

x


4.2.2 Substrate Scope ............................................................................101

4.2.3 Substrate Scope for Arene Sulfenylation .....................................104

4.3 Reaction Mechanism ................................................................................106

4.4 Conclusion ...............................................................................................109

4.5 Experimental ............................................................................................109

5 Alkene Catalyzed Construction of All-Carbon Quaternary Center Via C-H

Alkylation of Arene .............................................................................................139

5.1 Introduction ..............................................................................................139

5.2 Results and Discussions for C-H Alkylation of Arene ............................144

5.2.1 Reaction Design and Optimization ..............................................144

5.2.2 Substrate Scope ............................................................................144

5.2.3 Chemoselectivity of Alcohols ......................................................148

5.3 Synthetic Exploration of Our Strategy .....................................................149


5.5 Conclusion ...............................................................................................151

5.6 Experimental ............................................................................................151

6 Iodide-Catalyzed Oxyamination of Olefins for Synthesis of Oxazolidinone from

Unfunctionalized Carbamate ...............................................................................182

6.1 Introduction ..............................................................................................182

6.2 Results and Discussions for Alkene Oxyamination .................................186

6.2.1 Reaction Design and Optimization ..............................................186

6.2.2 Substrate Scope ............................................................................186

xi

6.3 Regiodivergent Alkene Oxyamination ....................................................188


6.5 Conclusion ...............................................................................................191

6.6 Experimental ............................................................................................191

References ........................................................................................................................201

xii

List of Tables

2.1 Optimization of Reaction for Thiazoline Synthesis ...............................................15

2.2 Alkene Substrate Scope for Thiazoline Synthesis .................................................17

2.3 Thioamide Substrate Scope for Thiazoline Synthesis ...........................................18

3.1 Optimization of Reaction for Sulfenoamination ....................................................56

3.2 Alkene Substrate Scope for Sulfenoamination ......................................................58

3.3 Thioimidazole Substrate Scope for Sulfenoamination ..........................................59

4.1 Optimization for 1,4-Benzothiazine Synthesis ....................................................100

4.2 Alkene Substrate Scope for 1,4-Benzothiazine Synthesis ...................................102

4.3 Thioamine Substrate Scope for 1,4-Benzothiazine Synthesis .............................103

4.4 Substrate Scope for C-H Sulfenylation of Arene .................................................105

5.1 Optimization of Reaction Condition ...................................................................143

5.2 Arene Substrate Scope ........................................................................................145

5.3 Alcohol Substrate Scope .....................................................................................146

6.1 Optimization of Reaction Condition ...................................................................185

6.2 Substrate Scope for Alkene Oxyamination .........................................................187

xiii

List of Figures

1 – 1 Significance of Heterocycle .....................................................................................5

2 – 1 Biologically Active Compounds of Thiazoline .....................................................12

2 – 2 Validation of Hypothesis .......................................................................................14

3 – 1 Temperature-Dependent Diastereoselective Study of Cis-β-Methylstyrene .........62

3 – 2 Proposed Reaction Mechanism for Alkene Sulfenoamination ..............................63

4 – 1 Importance of 1,4-Benzothiazine Structural Motifs ..............................................96

4 – 2 Unexpected CSP2‒H Sulfenylation .......................................................................104

4 – 3 Synthesis of Thiomorpholine ...............................................................................106

5 – 1 Proposed Reaction Mechanism for Alkylation of Arene .....................................150

xiv

List of Schemes

1 – 1 Examples of Alkene Difunctionalization .................................................................3

1 – 2 Challenges of Alkene and Nucleophile Coupling ....................................................8

1 – 3 Our Proposed Halogen Mediated Coupling of Alkenes and Dinucleophile ............9

2 – 1 Literature Background of Thiazoline Synthesis ....................................................13

2 – 2 Mechanism of Thiazoline Formation .....................................................................19

2 – 3 Synthetic Exploration of Thiazoline ......................................................................20

3 – 1 Background on Sulfenoamination of Alkene .........................................................53

3 – 2 Regiodivergent of Alkene Sulfenoamination .........................................................60

3 – 3 Participation of DMF in the Sulfenoamination Reaction ......................................62

4 – 1 Alkene Sulfenoamination Background for 1,4-Benzothiazine Synthesis ..............97

4 – 2 Mechanistic Experiments for 1,4-Benzothiazine Synthesis.................................107

4 – 3 Proposed Reaction Mechanism ............................................................................108

5 – 1 Literature Background of Alcohol Activation .....................................................140

5 – 2 Chemoselectivity of Different Alcohols ..............................................................148

5 – 3 Synthetic Utilities of Our Method........................................................................149

6 – 1 Literature Background of Alkene Oxyamination ................................................183

6 – 2 Origin of Regiodivergent for Alkene Oxyamination ...........................................189

6 – 3 Proposed Reaction Mechanism for Alkene Oxyamination ..................................190

xv

List of Abbreviation

Ac ...............................acetyl

acac ............................acetylacetone

AcOH .........................acetic acid

ALS ............................amyotrophic lateral sclerosis

aq ................................aqueous

Bn ...............................benzyl

br ................................broad

CH3CN .......................acetonitrile

COD ...........................1,5-cyclooctadiene

cy-Pr ...........................cyclopropyl

δ ..................................chemical shift

d..................................doublet

DCM ..........................dichloromethane

DCE............................1,2-dichloroethane

dd................................doublet of doublet

DDQ ...........................2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DMF ...........................dimethylformamide

DMSO ........................dimethylsulfoxide

dr ................................diastereomeric ratio

equiv ...........................equivalent

EtOAc ........................ethylacetate

FTIR ...........................fourier transform infrared spectroscopy

g..................................gram

h..................................hour

HFIP ...........................hexafluoroisopropanol

HIV ............................human immunodeficiency virus

HMPA ........................hexamethylphosphoramide

HRMS ........................high resolution mass spectrometry

μL ...............................microliter

m ................................multiplet

xvi

M ................................molarity

MHz ...........................megahertz

mmol ..........................millimole

NIS .............................N-iodosuccinimide

NMR ..........................nuclear magnetic resonance

Ph ...............................phenyl

Piv ..............................pivaloyl

ppm ............................parts per million

PTH ............................phenothiazine

rr .................................regioisomeric ratio

rt .................................room temperature

s ..................................singlet

SAR ............................structure-activity relationship

t ..................................triplet

TBS ............................tert-butyldimethylsilyl

TEMPO ......................(2,2,6,6-tetramethylpiperidin-1-yl)oxyl

TFA ............................trifluoroacetic acid

Ts................................tosyl

TsOH ..........................tosylic acid

UHP............................urea hydrogen peroxide

xvii

Preface

This thesis has been adapted from the following published articles co-written by author

1. Alom, N.-E.; Wu, F.; Li, W. “One-Pot Strategy for Thiazoline Synthesis from

Alkenes and Thioamides” Org. Lett. 2017, 19, 930-933.

2. Alom, N.-E.; Rina, Y. A.; Li, W. “Intermolecular Regio- and Stereoselective

Sulfenoamination of Alkenes with Thioimidazoles” Org. Lett. 2017, 19, 6204-

6207.

3. Alom, N.-E.; Kaur, N.; Wu, F.; S. J. Saluga, S. J.; Li, W. “Catalytic Regio- and

Stereoselective Alkene Sulfenoamination for 1,4-Benzothiazine Synthesis” Chem.

Eur. J. 2019, 25, 6902-6906.

1

Chapter 1

Halogen Mediated Alkene Difunctionalization for the

Synthesis of N, S- and N, O-Containing Heterocycles

1.1 Introduction of Alkene Difunctionalization

1.1.1 Abundance and Reactivity of Alkene

Alkenes are widely used chemical feedstocks in organic transformations due to

their reactivities in synthetic processes involving acid, base, mildly oxidative, and

reductive conditions. Alkenes are regarded as attractive synthetic building blocks because

of their versatility, diversity, and abundance from petrochemicals and natural product

extracts.1 Moreover, many alkenes are commercially available, cheap, and easily

accessible. The wide availability of alkenes renders them highly appealing as reagents in

bioactive molecule syntheses in terms of structural diversity and complexity. There is a

plethora of simple and reliable procedures to synthesize alkenes, further augmenting the

synthetic utility of alkenes. Particularly, several efficient methods have been developed to

synthesize alkenes in a stereoselective manner. For example, the Wittig and the Horner-

Wadsworth-Emmons reactions provide either Z- or E-olefins under specific conditions

while the Julia olefination offers E-alkenes.2-3 The transition metal-catalyzed cross-

coupling reactions such as Suzuki, Stille, and Heck are also common methods to access

aryl olefins.4-6 The olefin metathesis, catalyzed by a variety of transition-metal complexes,

2

has been extensively used in industries.7-8 Due to the easy accessibility of alkenes, they

have been used in a broad range of classic transformations. For example, syn-selective

dihydroxylation of alkene has been achieved using OsO4 or KMnO4.

9 Moreover, alcohols

can also be synthesized in a regioselective manner from alkenes by using acid-catalyzed

hydration or hydroboration-oxidation sequence.10-11 The halogenation of alkene is another

fundamentally important reaction in organic synthesis to access dihalocompounds, which

are common synthons for a wide variety of useful compounds. The syn-selective

cyclopropanation of alkenes can be done with the Simmons-Smith reaction.12 The

Markovnikov selective ether formation can be achieved by oxymercuration and subsequent

reduction with sodium borohydride.13 More importantly, olefins play a significant role in

the petrochemical industry. The polymerization of terminal olefins, catalyzed by the

Ziegler-Natta catalyst, is an essential catalytic process in polymer synthesis.14-15

Asymmetric hydrogenation, catalyzed by the chiral ruthenium and rhodium catalysts,

developed by Noyori and Knowles, has been employed in countless pharmaceutical

syntheses.16-18

1.1.2 Difunctionalization of Alkene

The difunctionalization of alkene has received significant attention among the

synthetic communities for the rapid assembly of molecular complexity via simultaneous

construction of multiple carbon-carbon, carbon-heteroatom bonds. In this regard, metal-

catalyzed difunctionalization of alkene is one of the most powerful and widely used

strategies for the modular synthesis of complex structures from simple chemical

3

feedstocks. Significant efforts have been devoted to the direct installation of nitrogen and

oxygen functionalities for the oxyamination of alkenes. In 1996, Sharpless developed

Scheme 1-1: Examples of Alkene Difunctionalization

osmium-catalyzed asymmetric hydroxyamination of alkenes for 1,2-amino alcohol

synthesis (Scheme 1-1a).19-20 The toxicity of the catalyst and poor regioselectivity have

4

encouraged several other groups to develop alternative oxyamination protocols. The Stahl

group reported the palladium-catalyzed aminoacetoxyllation of allylic and homoallylic

ether and ester (Scheme 1-1b).21 The Yoon group discovered a series of elegant strategies

utilizing copper and iron catalyst for regiodivergent oxyamination of terminal alkenes with

oxaziridines (Scheme 1-1c).22-24 Along with the continuous success of oxyamination,

transition metal catalysis reaction has emerged as an efficient tool in many other

difunctionalization reactions. For example, the Brown, Engle, and Giri groups have

independently reported nickel-catalyzed diarylation of olefins along with other C-C bond

formation reactions from alkene (Scheme 1-1d) 25-27, and the Wolfe group reported Pd-

catalyzed intramolecular and asymmetric carboamination reaction for the synthesis of

carbocycle (Scheme 1-1e).28 Despite the advancement of above mentioned metal-catalyzed

alkene difunctionalization reactions, alkene sulfenoamination strategies for the synthesis

of N, S-containing heterocycles remains a formidable challenge due to the thiophilic nature

of the metal catalyst, which in turn can significantly alter their desired reactivity. In this

context, the development of a metal-free alkene sulfenoamination method to swiftly

construct a custom compound library of N, S-containing heterocycles is highly desirable.

1.2 Significance of N, S- and N, O-Containing Heterocycles

Sulfur is a common chemical element utilized in many important biological

processes. For example, gram-negative bacteria often rely on glutathione, whereas gram-

positive bacteria can synthesize mycothiol to neutralize oxidative stress.29 On the other

hand, nitrogen is an essential element included in many therapeutic agents. Besides, N-

containing heterocycles are common structural motifs in many biologically active

5

compounds, pharmaceuticals, and value-added products.30-31 N- and S-containing

heterocycles are also found in many natural products. For example, fully unsaturated

thiazole, is often found in natural products such as leinamycin, barakacin, and epothilone.32

Figure 1-1: Significance of Heterocycles. Reprinted with permission from reference 40

(Copyright 2014, American Chemical Society) and Reprinted by permission from Springer

Nature, Top Curr Chem (Z), Kevin A. Scott, 376:5, Copyright 2018.

Moreover, these heterocycle often exhibit a wide range of bioactivities such as anticancer,

antibiotic, anti-HIV, and neurological activities.33-34 For example, Penicillin, a class of

antibiotics containing N- and S-based thiazolidine ring, , discovered by Alexander

Flemming in 1928, have saved millions of lives from bacterial infections (Figure1-1).35

6

Pramipexole encoded with a thiazole, is a dopamine agonist, that has been used for the

treatment of Parkinson’s disorder.36 Firefly luciferin, a molecule that is responsible for

bioluminescence of fireflies, also consists of multiple S- and N-heterocycles.37 Nizatidine

is used for acid-related disorders.38 In addition, N, S-containing heterocycles can function

as photocatalysts in organic transformation. The photocatalytic activity of phenothiazine

has been shown by the Jui group39 for the reduction of aryl halide by excited photocatalyst.

Those heterocycles can also be used as a ligand in transition metal-catalyzed reactions.40

Moreover, N-containing heterocycle act can as a chiral auxiliary for the asymmetric

synthesis of active pharmaceuticals.41 The importance of those heterocycles (Figure 1-1) is

further highlighted by a recent database analysis of 1086 U.S. FDA approved small-

molecule drugs through 2012, which reveals that approximately 84% of these drugs contain

at least one nitrogen atom and 60% incorporating the nitrogen atom in a heterocycle.

Among them, there are 250 and 379 FDA approved drugs that contain five-membered and

six-membered nitrogen-containing heterocycles respectively.42 Development of new

therapeutic agents is an important solution of the global health concern on fighting against

existing and emerging diseases. Design and development of simple and reliable methods

to facilitate the synthesis of those heterocycles from simple alkenes, can improve and

expedite the discovery of new small-molecule therapeutics.40

1.3 Our Proposed Halogen Mediated Difunctionalization of

Alkene for the Synthesis of N-Containing Heterocycles

The research program proposed herein is directed towards the development of

chemical methods for the synthesis of interesting heterocycles from simple alkene

7

feedstocks and dinucleophiles. Alkenes are considered as nucleophiles whereas

heteroatoms such as nitrogen (N), oxygen (O), and sulfur (S) in any nucleophiles are also

nucleophilic atoms. The polarity mismatch between these reagents often makes these

alkene addition reactions difficult (Scheme 1-2a). Moreover, the control of regioselectivity

associated with alkene is often regarded as a prominent challenge. For example, the

addition of two heteroatoms across a simple terminal alkene can result in two regioisomeric

products (Scheme 1-2b). Chemical methods that can predictably install nitrogen, sulfur and

oxygen atoms across an alkene are of high importance and value in generating bioactive

chemical libraries. To overcome these difficulties, we will focus on enabling the concept

of halogenation for either alkene activation or thiol activation, for the synthesis of highly

functionalized N, and S- containing heterocycles. The halogenation of alkene is a viable

approach because it can reverse the polarity of an alkene to generate a dielectrophile.

However, the exact nature of the dielectrophilic intermediate can be crucial in defining the

scope and variability of both the alkenes and nucleophiles. One possibility of the

dielectrophile is dihaloalkane from halogenation of alkenes, while the second potential

dielectrophile involves the classic halonium ion.

Our group is interested in the utilization of cyclic halonium ion for the

regioselective synthesis of N, S- and N, O- containing heterocycles. The three-membered

cyclic halonium ion was first proposed by Kimball and Olah in 1937, which holds an

interest of organic chemists to account for the trans addition of halogens across alkenes.43-

45 Structural characterization of these intermediate by Nugent,46 Brown,47-49 and Kochi50

set the foundation for wide acceptance and recognition of their importance in organic

synthesis (Scheme 1-2d). Since then, halonium ion has emerged as a fundamental

8

intermediate for many organic transformations. The traditional routes to prepare cyclic

halonium ion or vicinal dihalo compounds are the addition of molecular halogens to

Scheme 1-2: Challenges of Alkene and Nucleophile Coupling.

alkenes (Scheme 1-3a). However, molecular halogens are toxic and corrosive reagents that

causes significant health concerns. To circumvent this problem, several environmentally

benign reagents have been developed. In these contexts, N-bromosuccinimide and N-

bromoacetamide are considered as safer reagents in comparison with Br2, but the cost and

low atom economy of these reagents make it less attractive to chemists.51-52 Oxidative

9

halogenation using inorganic halides has gained significant attention among the synthetic

community to preclude the use of detrimental halogens. A broad range of protocols has

been developed to achieve the bromination of alkene using bromide salts with different

oxidants such as H2O221-23, TBHP53, Oxone54-55, NaIO4, and hypervalent iodine.56-58

Another potential way to accomplish the goal of heterocycle synthesis is the

activation of sulfur-based nucleophiles into electrophilic sulfur reagents by halogenation

of thiol via the formation of a sulfur-halogen bond. Upon nucleophilic attack of an alkene

on sulfur electrophile generates thiiranium ion intermediate which can be in equilibrium

with open carbocation. Then, intramolecular attack from tethered nucleophile on the

thiiranium ion or open carbocation leads to a cyclized product (Scheme 1-3b). In addition,

a sulfur-halogen bond can undergo homolysis to generate thiyl radical, which can combine

with an alkene to form carbon-centered radical. Alternatively, the oxidation of radical into

carbocation followed by cyclization can lead to polar pathway for product formation. On

the other hand, the reversal of the alkene polarity with a simple halogenation process can

directly engage in two consecutive nucleophilic displacements to form the heterocyclic

Scheme 1-3: Our Proposed Halogen Mediated Coupling of Alkene and Dinucleophile.

10

compounds (Scheme 1-3a). A particular issue that needs to be addressed is that 1,2-

dihaloalkanes are often regarded as poor electrophiles that can undergo reversion to alkenes

or elimination in the presence of bases or hard nucleophiles. In this case, one can argue that

the careful selection of nucleophiles and fine-tuning of halogenation can be a suitable

approach to get access to various potential heterocyclic compounds. If successful,

significant diversity in structure and functionality can then be achieved with olefin

difunctionalizations.

With these nucleophile activation strategies, we hope to develop alkene

sulfenoamination and alkene oxyamination protocols for accessing valuable heterocycles

that would (i) provide regioselectivity based on the electronic and steric bias from alkene

activation and (ii) promote opposite regioisomer from thiol activation.

Aiming at achieving the aforementioned goals, the results presented herein focus

on 1) the development of a one-pot strategy for thiazoline synthesis from alkenes and

thioamides (Chapter 2) as a proof of concept on halogen activation of alkene; 2) the

demonstration of intermolecular regio- and stereoselective sulfenoamination of alkenes

with thioimidazoles (Chapter 3) as evidence of halogen activation of thiol for accessing

opposite regioisomer; (3) the discovery of catalytic regio- and stereoselective alkene

sulfenoamination for 1,4-benzothiazine synthesis (Chapter 4) as a demonstration of

catalytic utilization of iodide salt; (4) the illustration of alkene-catalyzed generation of all-

carbon quaternary centers via alkylation of arene (Chapter 5) as evidence of iodonium

activation of alcohol; (5) the development of an iodide-catalyzed alkene oxyamination for

the synthesis of oxazolidinone (Chapter 6) as an example of catalytic iodonium ion as a

regiocontrol template.

11

Chapter 2

One-Pot Strategy for Thiazoline Synthesis from Alkenes

and Thioamides

2.1 Introduction

Nitrogen- and sulfur-containing heterocycles are important structural motifs and

highly attractive synthetic targets due to their interesting biochemical properties.

Particularly, thiazoline, an important N, S-containing heterocycle, is a ubiquitous structural

unit in pharmaceuticals, bioactive compounds, and value-added molecules (Figure 2-1).

Moreover, these types of compounds show a broad range of bioactivities such as

anticancer, antibiotic, anti-HIV, and neurological activities.33-34 For example, pramipexole

encoded with a thiazole is a dopamine agonist that has been used for the treatment of

Parkinson’s disorder,20 and Ritonavir, an antiviral drug is used to treat HIV, also contains

two thiazole units. In addition, thiazoline is present in many other biologically active

natural products such as largazole, curacin A, tantazole B and pyochelin.59-62 On the other

hand, fully unsaturated thiazole structural unit is found in drugs such as abafungin,

sulfathiazole and natural product such as leinamycin, barakacin, and epothilone.32 Firefly

luciferin embedded with thiazoline and benzothiazole, is responsible for the

bioluminescence of fireflies (Figure 2-1).37 Riluzole is another important drug molecule

that is used for the treatment of anxiety disorder63 while Nizatidine is used for acid-related

12

Figure 2-1: Biologically Active Compounds of Thiazoline

disorders.42 Thiazoline rings can also act as ligands and directing groups for transition

metal-catalyzed reactions.40 Due to a broad range of bioactivities of the thiazoline scaffold

in pharmaceuticals, the synthesis of this structural motif has received significant attention

from the synthetic communities. To gain access for this heterocycle, β-aminothiols are the

most useful and convenient synthetic building blocks.64 The condensation of cysteamine

with acids, esters, and amides is the traditional way to synthesize thiazolines (Scheme 2-

1a).65-67 In this context, the coupling of aryl nitrile with cysteine provides thiazoline bearing

carboxylic acid (Scheme 2-1b).68 However, the scarcity of naturally occurring β-aminothiol

often hinders potential structure-activity relationship (SAR) studies with this interesting

bioactive scaffold. To overcome the availability problem of β-aminothiol, methods

involving the condensation of β-amino alcohols with carbonyl precursors via thionation of

amide intermediate have also been developed (Scheme 2-1c).69 Finally, intramolecular

strategies that require multistep syntheses can also be utilized to gain access to

thiazolines.69-71 In this regard, the Pierce group disclosed an intramolecular protocol for the

13

synthesis of thiazolines from thiohydroximic acids utilizing copper-catalyzed

aminobromination strategy.72 On the other hand, development of simple methods for the

synthesis of thiazolines from alkenes and thioamides can provide a significant reduction in

cost and operational complexity. Traditionally, alkenes are considered as nucleophiles. We

hypothesize that the generation of 1,2-dibromoalkanes or bromonium ion from

halogenation of alkenes can serve as dielectrophile, which in turn can couple with

thioamide dinucleophile to afford the desired thiazoline products (Scheme 2-1d).

Scheme 2-1: Literature Background of Thiazoline Synthesis

14

2.2 Results and Discussions for Thiazoline Synthesis

2.2.1 Reaction Design and Optimization

To validate our hypothesis, 1,2-dibromoethylbenzene (Figure 2-2, product 2-5) was

synthesized from the bromination of styrene in 94% yield in acetonitrile. The treatment of

1,2-dibromoethylbenzene with thiobenzamide provided thiazoline product in 63% yield in

acetonitrile at 80 ºC. This result explicitly revealed that a common solvent acetonitrile

could be used for both the 1,2-dibromoalkane formation and the subsequent nucleophilic

displacements. This experimental data suggested that we could proceed with a one-pot

strategy directly from a simple alkene.

Figure 2-2: Validation of Hypothesis

To our delight, when a one-pot reaction was carried out by adding the thioamide to the

reaction mixture after 1 h, the desired thiazoline was obtained in 39% yield (Table 2.1,

entry 1). To avoid the use of corrosive molecular bromine, oxidation of bromide salt was

carried out for in-situ generation of bromine. The combination of lithium bromide (LiBr)

and aqueous hydrogen peroxide provided the desired thiazoline in 7% yield (Table 2.1,

entry 2). The addition of trifluoroacetic acid (TFA) was realized to facilitate the oxidation

of bromide salt, increased the yield to 50% (Table 2.1, entry 3). The screening of halides,

15

Table 2.1: Optimization of Reaction for Thiazoline Synthesis

oxidants, solvents, and acids revealed the initial optimal condition to provide 56% of the

thiazoline product (Table 2.1, entries 4-13). Further testing of concentration,

stoichiometrey, and temperature didn’t provide a higher yield. We reasoned that acid

16

produced from SN2 reaction could be detrimental to subsequent nucleophilic displacement

reactions. To validate our hypothesis, LiOAc was added along with the thioamide

nucleophile, which indeed improved the yield to 60% (Table 2.1, entry 14). Further

refinement of the reaction conditions by screening different inorganic bases afforded 69%

yield with 3 equivalents of NaHCO3 (Table 2.1, entries 15-19). Finally, increasing the

oxidant to 1.5 equiv and halide source to 3.0 equiv provided the highest yield of 73% for

this reaction (Table 2.1, entry 20). However, increasing the concentration or decreasing the

temperature led to lower yields (Table 2.1, entries 21 and 22).

2.2.2 Reaction Scope

With the optimized conditions in hand, the alkene substrate scope was tested. A range of

styrene derivatives provided moderate to good yields of the desired thiazolines (Table 2.2).

For example, substituents at the para position of the benzene ring with electron-donating

or -neutral properties worked well, providing acceptable yields (Table 2.2, products 2-8 to

2-10, 2-13, 2-19). On the other hand, electron-withdrawing group at the para position

afforded the product in moderate yield (Table 2.2, product 2-11). Moreover, halogen

substituents at either the para or ortho position delivered good yields of thiazoline products

(Table 2.2, products 2-12, 2-14 to 2-16). Aliphatic alkenes comprised of alkyl, alcohol,

ether, ester, and imides were also compatible with the reaction conditions (Table 2.2,

products 2-17, 2-18, 2-20 to 2-25). In the case of regioselectivity for aliphatic alkenes, the

initial nucleophilic attack from the sulfur atom was reversed compared to styrene

derivatives because the primary C-Br bond was the more electrophilic site due to steric

hinderance whereas secondary benzylic C-Br bond for styrene derivatives is more

electrophilic due to electronic reason.

17

Table 2.2: Alkene Substrate Scope for Thiazoline Synthesis

18

Table 2.3: Thioamide Substrate Scope for Thiazoline Synthesis

For the thioamide substrate scope, the methyl group at either the para or ortho position

provided the products in good yields (Table 2.3, products 2-26 and 2-27). For electron-

donating substituents such as alcohol, ether, and amine, the thiazolines were obtained in

moderate

19

yields (Table 2.3, products 2-28, 2-37 to 2-39). The different halogen-substituted

thioamides proceeded to generate the products efficiently (Table 2.3, products 2-29 to 2-

35). Alkylthioamide could also accomplish the corresponding thiazoline product (Table

2.3, products 2-36). Moreover, thioamides containing electron-deficient aromatics such as

pyridines and pyrimidine could also furnish the desired thiazoline products with high

regioselectivities albeit in lower yields (Table 2.3, products 2-40 to 2-43). The thiazoline

from 2-pyridinethioamide could function as potential ligand in metal-catalyzed reactions.

(Table 2.3, product 2-40). The ability of our strategy to incorporate these heteroaromatic

structures further highlights the versatility and utility of the method.

2.3 Proposed Reaction Mechanism

At first, bromine is generated from the oxidation of LiBr by urea hydrogen peroxide

(UHP). The bromination of alkene leads to the formation of 1,2-dibromoalkanene A which

can act as a dielectrophile. Then, the reaction goes through a double nucleophilic attack

from thioamide onto the 1,2-dibromoalkane or bromonium ion intermediate, leading to the

formation of thiazoline.

Scheme 2-2: Mechanism of Thiazoline Formation

20

2.4 Synthetic Application

After demonstrating a broad substrate scope, the synthetic utility of thiazoline was

explored. The gram-scale synthesis of thiazoline 2-8 was achieved in 61% yield using the

standard reaction conditions. Under oxidation of thiazoline 2-8 by DDQ in

dichloromethane afforded thiazole in 95% yield, one of the most attractive structural units

in sulfur-containing FDA approved drugs (Scheme 2-3, product 2-44). On the other hand,

hydrolysis of thiazoline by using 5 M HCl provided a single β-aminothiol in 92% yield

(Scheme 2-3, product 2-45) which could overcome the β-aminothiol availability problem.

Scheme 2-3: Synthetic Exploration of Thiazoline.

2.5 Conclusion

We have developed a simple and reliable method for the synthesis of thiazoline

from the coupling of alkenes with thioamides. The method offers a wide variety of

thiazolines with structural diversities and good functional group compatibility. The

derivatization of the thiazoline to thiazole and β-aminothiol via oxidation and hydrolysis

respectively further demonstrates the synthetic utility of our method. We have also

21

compiled a small library of thiazoline compounds suitable for biochemical evaluations. We

hope that this method will be beneficial for synthetic communities in the synthesis of

potentially bioactive compounds bearing thiazoline structural motifs.

2.6 Experimental

General Information. Commercial reagents and solvents were purchased from Sigma

Aldrich, Oakwood Chemicals, Alfa Aesar, Matrix Scientific, Acros Organic, and were used

as received. The substrates for the products 2-20,73 2-24,74 2-25,75 were synthesized

according to the reported procedure. Organic solutions were concentrated under reduced

pressure on a Büchi rotary evaporator using an acetone-dry ice bath. Chromatographic

purification of products was accomplished using flash chromatography on 230-400 mesh

silica gel. Thin-layer chromatography (TLC) was performed on Analtech 250 mm silica

gel HLF UV-254 plates. Visualization of the developed plates was performed by

fluorescence quenching, potassium permanganate and iodine-silica gel system. 1H and 13C

NMR spectra were recorded on a Bruker 600 instrument (600 and 150 MHz) or INOVA

600 (600 and 150 MHz) and are internally referenced to residual protio solvent signals (for

CDCl3, 7.26 and 77.0 ppm, respectively). Data for 1H NMR are reported as follows:

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

heptet, m = multiplet, br = broad), integration, coupling constant (Hz). 13C spectra were

reported as chemical shifts in ppm and multiplicity where appropriate. IR spectra were

recorded on a Perkin Elmer FT-IR spectrophotometer and are reported in terms of

wavenumber of absorption (cm-1). High resolution mass spectra were obtained on Waters

Synapt High Definition Mass Spectrometer (HDMS) by electrospray ionization at

22

University of Toledo, OH, USA.

General Procedure A: Urea hydrogen peroxide (71 mg, 0.75 mmol) was added to a

mixture of LiBr (130 mg, 1.5 mmol), TFA (77 L, 1.0 mmol) and alkene (0.5 mmol) in

acetonitrile (0.5 mL, 1.0 M). Then, the reaction mixture was stirred at 80 °C for 1 h. After

the reaction mixture was cooled to room temperature, NaHCO3 (126 mg, 1.5 mmol) and

thioamide (1.5 mmol) were added sequentially to the reaction mixture and stirred at 80 °C

for 15 h. The reaction mixture was cooled to room temperature, followed by dilution with

water (3 mL), extraction with EtOAc (3 x 4 mL). The combined organic layer was

concentrated in vacuo and purified by flash chromatography on SiO2 (5-50% EtOAc in

hexanes) to provide the desired product. The regioisomeric ratio was determined by crude

NMR.

General Procedure B: Urea hydrogen peroxide (71 mg, 0.75 mmol) was added to a

mixture of LiBr (130 mg, 1.5 mmol), TFA (77 L, 1.0 mmol) and alkene (0.5 mmol) in

propionitrile (0.5 mL, 1.0 M). Then, the reaction mixture was stirred at 100 °C for 1 h.

After the reaction mixture was cooled to room temperature, NaHCO3 (126 mg, 1.5 mmol)

and thioamide (1.5 mmol) were added sequentially to the reaction mixture and stirred at

100 °C for 15 h. The reaction mixture was cooled to room temperature, followed by dilution

with water (3 mL), extraction with EtOAc (3 x 4 mL). The combined organic layer was

concentrated in vacuo and purified by flash chromatography on SiO2 (5-50% EtOAc in

hexanes) to provide the desired product. The regioisomeric ratio was determined by crude

NMR.

Spectral Characterization of the Products

23

2,5-diphenyl-4,5-dihydrothiazole (2-8): This compound was prepared according to the

General Procedure A using styrene (52 mg, 0.5 mmol), thiobenzamide (206 mg, 1.5 mmol).

After purification by column chromatography on SiO2 (5% EtOAc in hexanes, Rf = 0.3),

the title compound was isolated as a light yellow oil (85 mg, 71% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 7.90 (d, J = 7.6 Hz, 2 H), 7.54-7.40 (m, 3 H), 7.40-

7.24 (m, 5 H), 5.09 (dd, J = 5.6, 9.0 Hz, 1 H), 4.80 (dd, J = 9.0, 16.1 Hz, 1 H), 4.64 (dd, J

= 5.6, 16.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 168.1, 141.9, 132.8, 131.3, 128.8, 128.5, 128.4, 127.8,

127.0, 73.0, 54.4;

IR (neat): 3059, 3027, 2846, 1648, 1600, 1489, 1447, 1311, 1236, 1007, 944, 763 cm-1;

HRMS (ESI) m/z calcd for C15H14NS [(M+H)+] 240.0847, found 240.0850.

5-(1,1'-biphenyl]-4-yl)-2-phenyl-4,5-dihydrothiazole (2-9): This compound was

prepared according to the General Procedure A using 4-vinylbiphenyl (90 mg, 0.5 mmol),

thiobenzamide (206 mg, 1.5 mmol). After purification by column chromatography on SiO2

(5% EtOAc in hexanes, Rf = 0.2), the title compound was isolated as a light yellow solid

(79 mg, 50% yield, >95:5).

24

1H NMR (600 MHz, CDCl3): = 7.90 (d, J = 7.3 Hz, 2 H), 7.56 (d, J = 8.3 Hz, 2 H),

7.58 (d, J = 7.8 Hz, 2 H), 7.52-7.48 (m, 1 H), 7.48-7.40 (m, 6 H), 7.39-7.32 (m, 1 H),

5.13 (dd, J = 5.5, 8.8 Hz, 1 H), 4.82 (dd, J = 8.8, 16.1 Hz, 1 H), 4.69 (dd, J = 5.5, 16.1

Hz, 1 H);

13C NMR (150MHz, CDCl3): = 167.6, 141.2, 140.7, 140.5, 133.1, 131.3, 128.8, 128.5,

128.4, 127.6, 127.5, 127.4, 127.0, 73.3, 54.2;

IR (neat): 2921, 1610, 1484, 1308, 1006, 823, 761, 601, 558 cm-1;


5-(4-(tert-butyl)phenyl)-2-phenyl-4,5-dihydrothiazole (2-10): This compound was

prepared according to the General Procedure A using 4-tert-butylstyrene (86 mg, 93%

purity, 0.5 mmol), thiobenzamide (206 mg, 1.5 mmol). After purification by column

chromatography on SiO2 (5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated

as a light yellow solid (95 mg, 64% yield, >95:5);


7.34 (m, 2 H), 7.34-7.28 (m, 2 H), 5.09 (dd, J = 5.9, 8.8 Hz, 1 H), 4.78 (dd, J = 8.8, 16.1

Hz, 1 H), 4.64 (dd, J = 5.9, 16.1 Hz, 1 H), 1.33 (s, 9 H).

13C NMR (150MHz, CDCl3): = 167.7, 150.7, 138.8, 133.1, 131.1, 128.4, 128.3, 126.7,

125.7, 73.1, 54.3, 34.4, 31.2;

IR (neat): 3057, 2959, 1660, 1602, 1490, 1445, 1310, 1225cm–1;

25


2-phenyl-5-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (2-11): This compound

was prepared according to the General Procedure A using 4-(trifluoromethyl)styrene (86

mg, 0.5 mmol), thiobenzamide (206 mg, 1.5 mmol). After purification by column


as a light yellow solid (63 mg, 41% yield, 92:8).

1H NMR (600 MHz, CDCl3): = 7.87 (d, J = 7.6 Hz, 2 H), 7.58 (d, J = 8.1 Hz, 2 H), 7.54-


= 4.9, 16.2 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 167.4, 146.3, 132.8, 131.5, 128.6, 128.4, 127.4, 125.9,

125.8, 77.2, 76.8, 73.1, 53.7;

IR (neat): 2983, 1607, 1324, 1158, 1068, 953, 767, 666, 525 cm-1;

HRMS (ESI) m/z calcd for C16H13F3NS [(M+H)+] 308.0721, found 308.0720.

5-(2-bromophenyl)-2-phenyl-4,5-dihydrothiazole (2-12): This compound was prepared

according to the General Procedure A using 2-bromostyrene (92 mg, 0.5 mmol),


26

(5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a colorless liquid (118

mg, 74% yield, >95:5).


7.44 (m, 2 H), 7.44-7.38 (m, 2 H), 7.29-7.23 (m, 1 H), 7.14-7.07 (m, 1 H), 5.46 (dd, J =

3.8, 8.7 Hz, 1 H), 4.74 (dd, J = 8.7, 16.2 Hz, 1 H), 4.66 (dd, J = 3.8, 16.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 167.5, 141.3, 133.0, 132.9, 132.9, 132.7, 131.5,

131.2, 129.3, 128.9, 128.7, 128.4, 128.2, 128.0, 127.9, 123.2, 71.4, 71.3, 71.2, 53.1, 53.0;

IR (neat): 2897, 1595,1575, 1483, 1445, 1236, 1005, 943, 771, 676, 503 cm-1;

HRMS (ESI) m/z calcd for C15H13BrNS [(M+H)+] 317.9952, found 317.9963.

4-(2-phenyl-4,5-dihydrothiazol-5-yl)phenyl acetate (2-13): This compound was

prepared according to the General Procedure A using 4-acetoxystyrene (81 mg, 0.5 mmol),


(10% to 20% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a light yellow

solid (89 mg, 60% yield, >95:5).


7.41 (m, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 5.06 (dd, J = 5.4, 8.8

Hz, 1 H), 4.74 (dd, J = 8.8, 16.1 Hz, 1 H), 4.61 (dd, J = 5.4, 16.1 Hz, 1 H), 2.29 (s, 3 H);

13C NMR (150MHz, CDCl3): = 169.4, 167.5, 149.9, 139.6, 132.9, 131.3, 128.5, 128.3,

128.1, 121.9, 73.2, 53.8, 21.0;

27

IR (neat): 3024, 2929, 1753, 1604, 1504, 1490, 1369, 1308 cm–1;

HRMS (ESI) m/z calcd for C17H16NO2S [(M+H)+] 298.0902, found 298.0900.

5-(4-fluorophenyl)-2-phenyl-4,5-dihydrothiazole (2-14): This compound was prepared

according to the General Procedure A using 4-fluorostyrene (61 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a gummy liquid (78

mg, 61% yield, >95:5).


7.40 (m, 2 H), 7.35-7.28 (m, 2 H), 7.04-6.96 (m, 2 H), 5.05 (dd, J = 5.2, 8.9 Hz, 1 H), 4.77

(dd, J = 8.9, 16.1 Hz, 1 H), 4.59 (dd, J = 5.2, 16.1 Hz, 1 H);

13C NMR (151MHz, CDCl3): = 167.5, 162.9, 161.3, 138.0, 138.0, 132.9, 131.3, 128.7,

128.6, 128.5, 128.4, 115.7, 115.6, 73.3, 53.7;

IR (neat): 3060, 2846, 1601, 1577, 1505, 1311, 1223, 1006, 763, 604, 525 cm-1;

HRMS (ESI) m/z calcd for C15H13FN S[(M+H)+] 258.0753, found 258.0755.


28

according to the General Procedure A using 4-bromostyrene (92 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a yellow solid (86 mg,

54% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 7.87 (d, J = 7.8 Hz, 2 H), 7.52-7.46 (m, 1 H), 7.46-7.40

(m, 4 H), 7.22 (d, J = 8.3 Hz, 2 H), 5.01 (dd, J = 5.1, 9.0 Hz, 1 H), 4.77 (dd, J = 9.0, 16.1

Hz, 1 H), 4.59 (dd, J = 5.1, 16.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 167.5, 141.3, 132.8, 131.9, 131.4, 128.7, 128.6, 128.4,

121.6, 73.1, 53.7;

IR (neat): 2897, 1595, 1575, 1483, 1445, 1236, 1005, 943, 771, 676, 503 cm-1;


5-(4-chlorophenyl)-2-phenyl-4,5-dihydrothiazole (2-16): This compound was prepared

according to the General Procedure A using 4-chlorostyrene (69 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a yellow solid (84 mg,

61% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 7.90-7.83 (m, 2 H), 7.52-7.46 (m, 1 H), 7.46-7.40 (m, 2

H), 7.31-7.24 (m, 4 H), 5.02 (dd, J = 5.2, 8.9 Hz, 1 H), 4.77 (dd, J = 8.9, 16.1 Hz, 1 H),

4.59 (dd, J = 5.2, 16.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 167.5, 140.7, 133.5, 132.8, 131.4, 128.9, 128.6, 128.4,

29

128.4, 77.2, 76.8, 73.2, 53.7;

IR (neat): 2897, 1595, 1574, 1486, 1398, 1235, 1086, 944, 771, 603, 577, 506 cm-1;

HRMS (ESI) m/z calcd for C15H13ClNS [(M+H)+] 274.0457, found 274.0467.

Methyl-2-phenyl-4,5-dihydrothiazole-4-carboxylate (2-17): This compound was

prepared according to the General Procedure A using methyl acrylate (43 mg, 0.5 mmol),


(20% EtOAc in hexanes, Rf = 0.4), the inseparable mixture of both regioisomers were

isolated as a colorless liquid (75 mg, 68% yield, 59:41).

1H NMR (600 MHz, CDCl3): = 7.87 (d, J = 7.8 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.48

(q, J = 7.6 Hz, 2 H), 7.44-7.37 (m, 3 H), 5.29 (t, J = 9.2 Hz, 1 H), 4.94 (d, J = 11.5 Hz, 1

H), 4.61-4.53 (m, 1 H), 3.84 (s, 3 H), 3.77 (s, 2 H), 3.72 (dd, J = 9.2, 10.9 Hz, 1 H), 3.64

(t, J = 10.3 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 171.7, 171.2, 170.9, 165.7, 132.5, 132.3, 131.6, 131.3,

128.5, 128.5, 128.4, 128.3, 78.4, 67.6, 52.9, 52.7, 50.1, 35.3;

IR (neat): 2951, 1733, 1596, 1434, 1315, 1197, 991, 764, 603 cm-1;


2-phenyl-4,5-dihydrothiazol-4-yl)methanol (2-18): This compound was prepared

30

according to the General Procedure B using allyl alcohol (29 mg, 0.5 mmol),


(50% EtOAc in hexanes, Rf = 0.4), the inseparable mixture of both regioisomers were

isolated as a white solid (43 mg, 45% yield, 78:22).


H), 4.83-4.74 (m, 1 H), 4.10-3.98 (m, 1 H), 3.78 (dd, J = 5.6, 11.2 Hz, 1 H), 3.46-3.39 (m,

1 H), 3.34-3.26 (m, 1 H), 2.75 (br. s., 1 H);

13C NMR (150MHz, CDCl3): = 169.7, 132.8, 131.4, 131.3, 128.5, 128.4, 128.3, 128.3,

79.3, 77.2, 76.8, 66.9, 64.9, 64.4, 52.4, 34.3;

IR (neat): 3239, 3064, 2924, 1603, 1576, 1440, 1324, 1228, 1069, 947, 766, 687 cm-1;

HRMS (ESI) m/z calcd for C10H12NOS [(M+H)+] 194.0640, found 194.0638.

N-(4-(2-phenyl-4,5-dihydrothiazol-5-yl)phenyl)acetamide (2-19): This compound was

prepared according to the General Procedure A using 2-vinylacetanilide (81 mg, 0.5

mmol), thiobenzamide (206 mg, 1.5 mmol) and Br2 (79 mg, 0.5 mmol) instead of urea

hydrogen peroxide, LiBr, and TFA. After purification by column chromatography on SiO2

(50% EtOAc in hexanes, Rf = 0.2), the title compound was isolated as a yellow solid (95

mg, 64% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 7.92-7.83 (m, 3 H), 7.50-7.38 (m, 5 H), 7.25 (d, J = 8.5

Hz, 1 H), 5.02 (dd, J = 5.4, 8.8 Hz, 1 H), 4.73 (dd, J = 8.8, 16.1 Hz, 1 H), 4.56 (dd, J = 5.4,

16.1 Hz, 1 H), 2.13 (s, 3 H);

31

13C NMR (150MHz, CDCl3): = 168.6, 167.9, 137.8, 137.5, 133.0, 131.3, 128.5, 128.3,

127.6, 120.2, 73.1, 54.0, 24.4;

IR (neat): 3322, 2926, 1660, 1596, 1365, 1010, 763, 647, 524 cm-1;

HRMS (ESI) m/z calcd for C17H17N2OS [(M+H)+] 297.1062, found 297.1068.

4-((benzyloxy)methyl)-2-phenyl-4,5-dihydrothiazole (2-20): This compound was

prepared according to the General Procedure B using ((allyloxy)methyl)benzene (74 mg,

0.5 mmol), thiobenzamide (206 mg, 1.5 mmol). After purification by column

chromatography on SiO2 (10% EtOAc in hexanes, Rf = 0.4), the title compound (major

regioisomer) was isolated as a yellow liquid (75 mg, 53% yield).


(m, 6 H), 7.34-7.28 (m, 1 H), 4.92 (dd, J = 4.4, 7.8 Hz, 1 H), 4.63 (s, 2 H), 3.87 (dd, J =

4.4, 9.0 Hz, 1 H), 3.68-3.58 (m, 1 H), 3.55-3.47 (m, 1 H), 3.44-3.36 (m, 1 H);

13C NMR (150MHz, CDCl3): = 168.8, 138.0, 133.1, 131.2, 128.4, 128.3, 127.7, 127.7,

77.2, 73.3, 70.8, 35.8;

IR (neat): 3028, 2855, 1601, 1576, 1447, 1360,1251, 1093, 940, 687, 607 cm-1;


4-hexyl-2-phenyl-4,5-dihydrothiazole (2-21): This compound was prepared according to

32

the General Procedure B using 1-octene (56 mg, 0.5 mmol), thiobenzamide (206 mg, 1.5

mmol). After purification by column chromatography on SiO2 (2% to 5% EtOAc in

hexanes, Rf = 0.4), the title compound (major regioisomer) was isolated as a colorless liquid

(71 mg, 57% yield).


4.60 (m, 1 H), 3.48 (dd, J = 8.4, 10.5 Hz, 1 H), 3.08 (dd, J = 8.4, 10.5 Hz, 1 H), 1.96-1.84

(m, 1 H), 1.71-1.62 (m, 1 H), 1.61-1.42 (m, 2 H), 1.42-1.22 (m, 6 H), 0.89 (t, J = 6.6 Hz,

3 H);

13C NMR (150MHz, CDCl3): = 166.2, 133.4, 131.0, 128.4, 128.3, 77.9, 38.1, 35.1,

31.8, 29.3, 26.7, 22.6, 14.1;

IR (neat): 2924, 2854, 1598, 1490, 1447, 1252, 764 cm–1;

HRMS (ESI) m/zcalcd for C15H22NS [(M+H)+] 248.1473, found 248.1475.

5-hexyl-2-phenyl-4,5-dihydrothiazole (2-21’): This compound was prepared according

to the General Procedure B using 1-octene (56 mg, 0.5 mmol), thiobenzamide (206 mg, 1.5

mmol). After purification by column chromatography on SiO2 (2% to 5% EtOAc in

hexanes, Rf = 0.2), the title compound (minor regioisomer) was isolated as a colorless liquid

(13 mg, 11% yield).

1H NMR (600 MHz, CDCl3): = 7.83 (d, J = 7.3 Hz, 2 H), 7.48-7.37 (m, 3 H), 4.39 (dd,

J = 8.2, 15.7 Hz, 1 H), 4.24 (dd, J = 4.8, 15.7 Hz, 1 H), 3.98-3.89 (m, 1 H), 1.71-1.63 (m,

33

2 H), 1.44-1.35 (m, 2 H), 1.35-1.19 (m, 6 H), 0.88 (t, J = 6.7 Hz, 3 H).

13C NMR (150MHz, CDCl3): = 168.1, 133.7, 131.2, 128.7, 128.4, 70.6, 52.1, 36.7, 31.9,

29.2, 28.3, 22.8, 14.3;

IR (neat): 2924, 2853, 1598, 1446, 1252, 688 cm–1;


4-phenethyl-2-phenyl-4,5-dihydrothiazole (2-22): This compound was prepared

according to the General Procedure B using 4-phenyl-1-butene (66 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.4), the title compound (major regioisomer) was isolated as

a yellow liquid (87 mg, 65% yield).


(m, 4 H), 7.24-7.17 (m, 1 H), 4.65 (t, J = 7.4 Hz, 1 H), 3.51 (t, J = 9.5 Hz, 1 H), 3.17-3.07

(m, 1 H), 2.97-2.82 (m, 2 H), 2.29-2.16 (m, 1 H), 2.06-1.94 (m, 1 H);

13C NMR (150MHz, CDCl3): = 166.5, 141.7, 133.4, 131.1, 128.5, 128.4, 128.4, 128.4,

125.9, 77.1, 38.1, 36.8, 33.1;

IR (neat): 3025, 2921, 1602, 1576, 1490, 1447, 1312, 938, 764 cm-1;


5-phenethyl-2-phenyl-4,5-dihydrothiazole (2-22’): This compound was prepared

34

according to the General Procedure B using 4-phenyl-1-butene (66 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.2), the title compound (minor regioisomer) was isolated as

a yellow liquid (15 mg, 11% yield).


(m, 2 H), 7.23-7.16 (m, 3 H), 4.39 (dd, J = 8.3, 15.9 Hz, 1 H), 4.30 (dd, J = 4.4, 15.9 Hz, 1

H), 3.95-3.88 (m, 1 H), 2.82-2.66 (m, 2 H), 2.03-1.93 (m, 2 H);

13C NMR (150MHz, CDCl3): = 167.9, 141.1, 133.6, 131.3, 128.7, 128.7, 128.5, 126.3,

70.5, 51.1, 38.4, 34.3 167.6, 140.9, 133.3, 131.1, 128.5, 128.4, 128.2, 126.1, 70.3, 50.8,

38.1, 34.0;

IR (neat): 3026, 2923, 1603, 1578, 1491, 1447, 1313, 944, 765, 690 cm-1;


4-cyclohexyl-2-phenyl-4,5-dihydrothiazole (2-23): This compound was prepared

according to the General Procedure B using Vinylcyclohexane (55 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.4), the title compound (major regioisomer) was isolated as

a white solid (67 mg, 55% yield).


(m, 1 H), 3.40 (dd, J = 8.7, 10.6 Hz, 1 H), 3.17 (t, J = 10.6 Hz, 1 H), 2.07 (d, J = 12.7 Hz,

1 H), 1.84-1.64 (m, 5 H), 1.34-1.14 (m, 5H);

35

13C NMR (150MHz, CDCl3): = 165.9, 133.5, 130.9, 128.3, 128.3, 83.2, 43.1, 35.7,

30.5, 29.5, 26.5, 26.2;

IR (neat): 2921, 2850, 1602, 1575, 1490, 1446, 1308, 1253, 933, 763, 682 cm-1;


5-cyclohexyl-2-phenyl-4,5-dihydrothiazole (2-23’): This compound was prepared

according to the General Procedure B using Vinylcyclohexane (55 mg, 0.5 mmol),


(5% EtOAc in hexanes, Rf = 0.4), the title compound (minor regioisomer) was isolated as

a white solid (6 mg, 5% yield.

1H NMR (600 MHz, CDCl3): = 7.86-7.80 (m, 2 H), 7.48-7.37 (m, 3 H), 4.38 (dd, J =

8.5, 15.9 Hz, 1 H), 4.30 (dd, J = 5.6, 15.9 Hz, 1 H), 3.88-3.82 (m, 1 H), 1.83-1.69 (m, 5 H),

1.66 (d, J = 12.7 Hz, 1 H), 1.54-1.45 (m, 1 H), 1.29-1.18 (m, 3 H), 1.05-0.96 (m, 1 H);

13C NMR (150MHz, CDCl3): = 168.1, 133.4, 131.0, 128.4, 128.2, 67.9, 58.1, 43.1,

30.8, 30.6, 26.2, 26.0;

IR (neat): 2922, 2850, 1605, 1578, 1447, 1310, 1013, 765, 607 cm-1;


2-(2-phenyl-4,5-dihydrothiazol-4-yl)ethyl pivalate (2-24): This compound was prepared

36

according to the General Procedure B using but-3-en-1-yl pivalate (78 mg, 0.5 mmol),


(5% to 10% EtOAc in hexanes, Rf = 0.3), the title compound (major regioisomer) was

isolated as a light yellow oil (87 mg, 59% yield).

1H NMR (600 MHz, CDCl3): = 7.82 (d, J = 7.3 Hz, 2 H), 7.44 (t, J = 7.3 Hz, 1 H), 7.39

(t, J = 7.3 Hz, 2 H), 4.72 (t, J = 7.6 Hz, 1 H), 4.34-4.28 (m, 2 H), 3.52 (dd, J = 8.3, 10.7

Hz, 1 H), 3.13 (dd, J = 8.1, 10.7 Hz, 1 H), 2.23-2.17 (m, 1 H), 2.03-1.98 (m, 1 H), 1.21 (s,

9 H);

13C NMR (150MHz, CDCl3): = 178.5, 167.1, 133.1, 131.1, 128.4, 128.3, 74.5, 62.1,

38.7, 38.1, 34.0, 27.2;

IR (neat): 3061, 2969, 1723, 1603, 1479, 1447, 1147, 765 cm–1;


2-(2-phenyl-4,5-dihydrothiazol-5-yl)ethyl pivalate (2-24’): This compound was

prepared according to the General Procedure B using but-3-en-1-yl pivalate (78 mg, 0.5

mmol), thiobenzamide (206 mg, 1.5 mmol). After purification by column chromatography

on SiO2 (10% to 20% EtOAc in hexanes, Rf = 0.2), the title compound (minor regioisomer)

was isolated as a light yellow oil (3 mg, 2% yield).


(m, 2 H), 4.43 (dd, J = 8.1,15.6 Hz, 1 H), 4.33 (dd, J = 4.3, 15.7 Hz, 1 H), 4.23-4.12 (m, 2

H), 4.05 - 3.97 (m, 1 H), 2.11-2.02 (m, 1 H), 2.00-1.91 (m, 1 H), 1.22 (s, 9 H);

37

13C NMR (125 MHz, CDCl3): = 178.7, 167.9, 133.4, 131.5, 128.7, 128.5, 70.6, 62.6,

48.4, 39.0, 35.5, 27.4;

IR (neat): 2970, 1727, 1479, 1284, 1156, 691 cm–1;


2-(2-(2-phenyl-4,5-dihydrothiazol-4-yl)ethyl)isoindoline-1,3-dione (2-25): This

compound was prepared according to the General Procedure B using N-(3-buten-1-yl)

phthalimide (101 mg, 0.5 mmol), thiobenzamide (206 mg, 1.5 mmol). After purification

by column chromatography on SiO2 (30% EtOAc in hexanes, Rf = 0.4), the title compound

(major regioisomer) was isolated as a yellow liquid (84 mg, 50% yield, 75:25). The minor

regioisomer was not isolable.


Hz, 2 H), 7.43-7.37 (m, 1 H), 7.33-7.27 (m, 2 H), 4.71-4.61 (m, 1 H), 4.08-3.99 (m, 1 H),

3.98-3.89 (m, 1 H), 3.58 (dd, J = 8.4, 10.9 Hz, 1 H), 3.13 (dd, J = 8.4, 10.9 Hz, 1 H), 2.31-

2.21 (m, 1 H), 2.06 (m, 1 H);

13C NMR (150MHz, CDCl3): = 168.4, 167.0, 133.9, 133.1, 132.2, 131.0, 128.3, 123.2,

75.6, 38.2, 35.9, 33.7;

IR (neat): 3059, 2935, 1769, 1704, 1597, 1576, 1490, 1395, 1368, 1026, 766, 718 cm-1;

HRMS (ESI) m/z calcd for C19H17N2O2S [(M+H)+] 337.1011, found 337.1012.

38

5-phenyl-2-(p-tolyl)-4,5-dihydrothiazole (2-26): This compound was prepared according

to the General Procedure A using styrene (52 mg, 0.5 mmol), 4-methylthiobenzamide (227

mg, 1.5 mmol). After purification by column chromatography on SiO2 (5% EtOAc in

hexanes, Rf = 0.3), the title compound was isolated as a light yellow solid (67 mg, 53%

yield, >95:5).


(m, 3 H), 5.06 (dd, J = 5.4, 8.8 Hz, 1 H), 4.78 (dd, J = 8.8, 16.1 Hz, 1 H), 4.61 (dd, J = 5.4,

16.1 Hz, 1 H), 2.41 (s, 3 H);

13C NMR (150MHz, CDCl3): = 167.5, 142.1, 141.6, 130.4, 129.2, 128.8, 128.3, 127.7,

127.0, 77.2, 76.8, 73.2, 54.4, 21.5;

IR (neat): 2920, 1601, 1452, 1180, 1077, 959, 823, 759, 704, 602 cm-1;


5-phenyl-2-(o-tolyl)-4,5-dihydrothiazole (2-27): This compound was prepared according

to the General Procedure A using styrene (52 mg, 0.5 mmol), 2-methylthiobenzamide (227

mg, 1.5 mmol.). After purification by column chromatography on SiO2 (5% EtOAc in

hexanes, Rf = 0.2), the title compound was isolated as a colorless liquid (83 mg, 65% yield,

>95:5).

39


J = 5.4, 9.0 Hz, 1 H), 4.83 (dd, J = 9.0, 16.0 Hz, 1 H), 4.70 (dd, J = 5.4, 16.0 Hz, 1 H), 2.59

(s, 3 H).

13C NMR (150MHz, CDCl3): = 167.6, 142.3, 137.0, 132.8, 131.1, 129.9, 129.6, 128.8,

127.6, 126.9, 125.6, 73.8, 54.6, 21.0;

IR (neat): 3025, 1610, 1598, 1489, 1453, 1224, 933, 757 cm–1;


4-(5-phenyl-4,5-dihydrothiazol-2-yl)phenol (2-28): This compound was prepared

according to the General Procedure A using styrene (52 mg, 0.5 mmol), 4-

hydroxythiobenzamide (230 mg, 1.5 mmol). After purification by column chromatography

on SiO2 (30% EtOAc in hexanes, Rf = 0.2), the title compound was isolated as a light yellow

solid (78 mg, 61% yield, >95:5).



Hz, 1 H), 4.57 (dd, J = 5.9, 15.9 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 159.1, 141.8, 130.4, 128.9, 127.8, 127.0, 125.1, 115.5,

72.5, 54.3

IR (neat): 2921, 2849, 1598, 1507, 1289, 1243, 1018, 834, 697, 608 cm-1;


40

5-phenyl-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (2-29): This compound

was prepared according to the General Procedure A using styrene (52 mg, 0.5 mmol), 4-

(trifrluoromethyl)thiobenzamide (308 mg, 1.5 mmol). After purification by column


as a white solid (93 mg, 60% yield, 94:6).



= 5.6, 16.5 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.4, 141.7, 136.2, 132.9, 132.6, 128.9, 128.7, 127.9,

127.0, 125.5, 73.4, 55.0;

IR (neat): 3032, 2915, 1596, 1574, 1408, 1322, 1224, 1109, 845 cm–1;


2-(4-fluorophenyl)-5-phenyl-4,5-dihydrothiazole (2-30): This compound was prepared


fluorothiobenzamide (233 mg, 1.5 mmol). After purification by column chromatography


41

oil (80 mg, 62% yield, >95:5).


H), 7.12 (t, J = 8.7 Hz, 2 H), 5.09 (dd, J = 5.5, 9.0 Hz, 1 H), 4.77 (dd, J = 9.0, 16.1 Hz, 1

H), 4.61 (dd, J = 5.5, 16.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.5, 165.3, 163.7, 141.8, 130.5, 130.4, 129.3, 129.3,

128.9, 127.8, 127.0, 115.7, 115.5, 73.2, 54.9;

IR (neat): 3028, 2912, 1599, 1503, 1401, 1231, 1154, 999, 842, 698, 617 cm-1;

HRMS (ESI) m/z calcd for C15H13FNS [(M+H)+] 258.0753, found 258.0765.



bromothiobenzamide (324 mg, 1.5 mmol). After purification by column chromatography

on SiO2 (5% EtOAc in hexanes, Rf = 0.4), the title compound was isolated as a white solid

(102 mg, 64% yield, >95:5).


7.30 (m, 4 H), 7.30-7.24 (m, 1 H), 5.10 (dd, J = 5.6, 8.8 Hz, 1 H), 4.77 (dd, J = 8.8, 16.1

Hz, 1 H), 4.60 (dd, J = 5.6, 16.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.6, 141.8, 132.0, 131.7, 129.8, 128.9, 127.9, 127.0,

125.8, 73.3, 54.9;

IR (neat): 2971, 1598, 1585, 1482, 1394, 1074, 926, 825, 754, 699, 594 cm-1;

42


2-(4-chlorophenyl)-5-phenyl-4,5-dihydrothiazole (2-32): This compound was prepared


chlorothiobenzamide (258 mg, 1.5 mmol). After purification by column chromatography

on SiO2 (5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a yellow solid

(85 mg, 62% yield, >95:5).


7.31 (m, 4 H), 7.31-7.25 (m, 1 H), 5.10 (dd, J = 5.6, 8.8 Hz, 1 H), 4.78 (dd, J = 8.8, 16.1

Hz, 1 H), 4.62 (dd, J = 5.6, 16.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.5, 141.8, 137.3, 131.5, 129.6, 128.9, 128.7, 127.8,

127.0, 73.2, 54.9;

IR (neat): 3063, 2918, 1599, 1486, 1398, 1090, 830, 754, 693, 596 cm-1;


2-(2,4-difluorophenyl)-5-phenyl-4,5-dihydrothiazole (2-33): This compound was

43

prepared according to the General Procedure A using styrene (52 mg, 0.5 mmol), 2,4-

difluorothiobenzamide (260 mg, 1.5 mmol). After purification by column chromatography

on SiO2 (5% EtOAc in hexanes, Rf = 0.3), the title compound was isolated as a white solid

(80 mg, 58% yield, >95:5).



4.58 (dd, J = 5.7, 16.4 Hz, 1 H);

13C NMR (151MHz, CDCl3): = 165.2, 165.2, 163.6, 163.5, 161.8, 141.7, 132.1, 132.0,

132.0, 132.0, 128.9, 127.8, 127.0, 111.9, 111.8, 111.7, 111.7, 104.9, 104.7, 104.6, 72.3,

54.4, 54.4;

IR (neat): 2916, 2851, 1614, 160 0, 1494, 1314, 1250, 1139, 1097, 971, 851, 763, 670,

542 cm-1;






oil (55 mg, 35% yield, 94:6).

1H NMR (600 MHz, CDCl3): = 8.07 (s, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.61 (d, J = 7.9

44

Hz, 1 H), 7.37-7.24 (m, 7 H), 5.10 (dd, J = 5.6, 9.0 Hz, 1 H), 4.78 (dd, J = 9.0, 16.2 Hz, 1

H), 4.63 (dd, J = 5.6, 16.2 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.2, 141.8, 134.9, 134.1, 131.1, 130.0, 128.9, 127.9,

127.0, 127.0, 122.6, 73.2, 54.8;

IR (neat): 3026, 2938, 1602, 1560, 1419, 1226, 1008, 696 cm–1;





on SiO2 (5% EtOAc in hexanes, Rf = 0.2), the title compound was isolated as a yellow

liquid (100 mg, 63% yield, 93:7).

1H NMR (600 MHz, CDCl3): = 7.65 (d, J = 8.1 Hz, 1 H), 7.61-7.55 (m, 1 H), 7.41 (d, J

= 7.1 Hz, 2 H), 7.39-7.32 (m, 3 H), 7.32-7.24 (m, 2 H), 5.13 (dd, J = 5.4, 9.0 Hz, 1 H), 4.81

(dd, J = 9.0, 16.2 Hz, 1 H), 4.66 (dd, J = 5.4, 16.2 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.4, 142.0, 134.8, 133.6, 131.1, 130.5, 128.8, 127.8,

127.2, 127.0, 121.2, 73.2, 55.8;

IR (neat): 3026, 2937, 2845, 1620, 1466, 1224, 995, 752, 643 cm-1;


45

2-isopropyl-5-phenyl-4,5-dihydrothiazole (2-36): This compound was prepared

according to the General Procedure A using styrene (52 mg, 0.5 mmol), thioisobutyramide

(155 mg, 1.5 mmol). After purification by column chromatography on SiO2 (10% EtOAc

in hexanes, Rf = 0.3), the title compound was isolated as a yellow solid (31mg, 30% yield,

>95:5);

1H NMR (600 MHz, CDCl3): = 7.41-7.21 (m, 5 H), 4.91 (dd, J = 5.5, 9.0 Hz, 1 H), 4.54

(dd, J = 9.0, 15.6 Hz, 1 H), 4.36 (dd, J = 5.5, 15.6 Hz, 1 H), 2.92-2.77 (m, 1 H), 1.28 (s, 6

H);

13C NMR (150MHz, CDCl3): = 176.7, 142.5, 128.8, 127.6, 126.9, 72.6, 54.1, 34.0, 21.1,

21.1;

IR (neat): 2965, 1625, 1454,1324,984,760,696 cm-1;


2-(4-methoxyphenyl)-5-phenyl-4,5-dihydrothiazole (2-37)66: This compound was

prepared according to the General Procedure A using styrene (52 mg, 0.5 mmol), 4-

methoxythiobenzamide (251 mg, 1.5 mmol). After purification by column chromatography


solid (70 mg, 52% yield, >95:5).


46


Hz, 1 H), 4.58 (dd, J = 5.4, 16.0 Hz, 1 H), 3.86 (s, 3 H).

2-(3,4-dimethoxyphenyl)-5-phenyl-4,5-dihydrothiazole (2-38): This compound was

prepared according to the General Procedure A using styrene (52 mg, 0.5 mmol), 3,4-

dimethoxythiobenzamide (296 mg, 1.5 mmol). After purification by column

chromatography on SiO2 (10% to 20% EtOAc in hexanes, Rf = 0.3), the title compound

was isolated as a white solid (72 mg, 48% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 7.49 (s, 1 H), 7.40-7.21 (m, 6 H), 6.86 (d, J = 8.3 Hz, 1

H), 5.04 (dd, J = 5.3, 8.5 Hz, 1 H), 4.74 (dd, J = 8.5, 16.0Hz, 1 H), 4.58 (dd, J = 5.3, 16.0

Hz, 1 H), 3.91 (s, 3 H), 3.93 (s, 3 H);

13C NMR (150MHz, CDCl3): = 167.1, 151.6, 148.7, 142.0, 128.8, 127.7, 127.0, 125.9,

122.5, 110.2, 109.9, 73.0, 55.9, 55.9, 54.5;

IR (neat): 3051, 2925, 1605, 1581, 1507, 1412, 1262 cm–1;

HRMS (ESI) m/zcalcd for C17H18NO2S [(M+H)+] 300.1058, found 300.1060.

4-(5-phenyl-4,5-dihydrothiazol-2-yl)aniline (2-39): This compound was prepared

47


aminothiobenzamide (254 mg, 1.5 mmol). After purification by column chromatography


solid (41 mg, 32% yield, >95:5).


= 8.5 Hz, 2 H), 5.01 (dd, J = 5.4, 8.8 Hz, 1 H), 4.72 (dd, J = 8.8, 15.9 Hz, 1 H), 4.56 (dd,

J= 5.4, 15.9 Hz, 1 H), 3.98 (br. s., 2 H);

13C NMR (150MHz, CDCl3): = 167.1, 149.3, 142.3, 130.1, 128.7, 127.6, 127.0, 123.3,

114.2, 73.0, 54.3;

IR (neat): 3446, 3184, 2852, 1634, 1592, 1513, 1304, 1171, 1009, 930, 930, 763 cm-1;

HRMS (ESI) m/z calcd for C15H15N2S [(M+H)+] 255.0956, found 255.0956.

5-phenyl-2-(pyridin-2-yl)-4,5-dihydrothiazole (2-40): This compound was prepared

according to the General Procedure A using styrene (52 mg, 0.5 mmol), pyridine-2-

carbothioic acid amide (207 mg, 1.5 mmol). After purification by column chromatography

on SiO2 (DCM to 40% EtOAc in DCM, Rf = 0.3), the title compound was isolated as a

white solid (64 mg, 53% yield, >95:5).


(t, J = 7.7 Hz, 1 H), 7.40-7.33 (m, 3 H), 7.31 (t, J = 7.2 Hz, 2 H), 7.28-7.22 (m, 1 H), 5.05

(dd, J = 5.8, 9.1 Hz, 1 H), 4.88 (dd, J = 9.1, 16.6 Hz, 1 H), 4.67 (dd, J = 5.8, 16.6 Hz, 1 H).

48

13C NMR (150MHz, CDCl3: = 170.0, 151.0, 149.2, 142.1, 136.5, 128.7, 127.5, 127.0,

125.3, 121.4, 73.7, 53.2;

IR (neat): 3054, 2903, 1599, 1466, 1434, 1321, 961, 700 cm–1;

HRMS (ESI) m/zcalcd for C14H13N2S [(M+H)+] 241.0799, found 241.0798.

5-phenyl-2-(pyridin-3-yl)-4,5-dihydrothiazole (2-41)66: This compound was prepared




liquid (40 mg, 33% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 9.10-9.05 (m, 1 H), 8.71 (d, J= 4.6 Hz, 1 H), 8.14 (d, J

= 8.1 Hz, 1 H), 7.41-7.23 (m, 6 H), 5.13 (dd, J = 5.6, 9.0 Hz, 1 H), 4.80 (dd, J = 9.0, 16.4

Hz, 1 H), 4.64 (dd, J = 5.6, 16.4 Hz, 1 H).

5-phenyl-2-(pyridin-4-yl)-4,5-dihydrothiazole (2-42): This compound was prepared




solid (21 mg, 18% yield, >95:5).

49



= 5.6, 16.7 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 166.1, 150.4, 141.4, 139.9, 129.0, 128.0, 127.0, 122.1,

73.4, 54.9;

IR (neat): 3027, 2920, 2847,1591, 1550, 1406, 1321, 1243, 1006, 822,696.54, 611 cm-1;


5-phenyl-2-(pyrimidin-2-yl)-4,5-dihydrothiazole (2-43): This compound was prepared

according to the General Procedure A using styrene (52 mg, 0.5 mmol), Pyrimidine-2-

carbothioamide (209 mg, 1.5 mmol). After purification by column chromatography on

SiO2 (5% MeOH in DCM, Rf = 0.3), the title compound was isolated as a light yellow oil

(38 mg, 31% yield, >95:5).

1H NMR (600 MHz, CDCl3): = 8.87 (d, J = 4.9 Hz, 2 H), 7.39-7.34 (m, 3 H), 7.31 (t, J

= 7.4 Hz, 2 H), 7.28-7.22 (m, 1 H), 5.12 (dd, J = 5.9, 9.3 Hz, 1 H), 4.95 (dd, J = 9.3, 17.1

Hz, 1 H), 4.76 (dd, J = 5.9, 17.1 Hz, 1 H);

13C NMR (150MHz, CDCl3): = 168.2, 159.1, 157.5, 141.8, 128.8, 127.7, 127.1, 121.7,

73.9, 54.1;

IR (neat): 3029, 2928, 1611, 1559, 1416, 1007, 698 cm–1;


50

Procedure for oxidation of thiazoline76:

2,5-diphenylthiazole (2-44): The molecular sieve (4Å MS, 400 mg/ mmol, 100 mg) was

added to solution of thiazoline 2-8 (60 mg, 0.25 mmol) in CH2Cl2 (1.5 mL, 0.17 M); After

10 min, DDQ (86 mg, 0.38 mmol) was added to the reaction mixture and stirred at 50 °C.

After 16 h, the reaction mixture was cooled to room temperature and quenched with 10%

NaOH (4 mL) and extracted with CH2Cl2 (3 x 2 mL). The combined organic layer was

concentrated in vacuo. Purification by flash chromatography on SiO2 (5% EtOAc in

hexanes, Rf = 0.4) provided the title compound as a white solid (56 mg, 95% yield)77.

1H NMR (600 MHz, CDCl3): = 8.03 (s, 1 H), 8.01-7.95 (m, 2 H), 7.61 (d, J = 7.8 Hz, 2

H), 7.51-7.39 (m, 5 H), 7.38-7.32 (m, 1 H).

Procedure for hydrolysis of thiazoline71:

2-amino-1-phenylethane-1-thiol hydrochloride (2-45): The thiazoline 2-8 (120 mg, 0.5

mmol) was added to the solution of HCl 5N (2.5 mL) and heated under reflux for 16 h.

After 16 h, the reaction mixture was cooled to room temperature and extracted with EtOAc

(2 x 2 mL), aqueous layer was concentrated in vacuo to provide the desired product as a

white solid (87 mg, 92% yield).

1H NMR (600MHz, D2O): = 7.46-7.38 (m, 4 H), 7.36 (d, J = 5.9 Hz, 1 H), 4.22 (t, J =

7.9 Hz, 1 H), 3.52-3.38 (m, 2 H);

51

13C NMR (150 MHz, D2O): =139.6, 129.6, 128.8, 127.2, 46.2, 40.5;

IR (neat): 3313.62, 3029, 2142, 1451, 1159, 692 cm-1;


52

Chapter 3

Intermolecular Regio- and Stereoselective Alkene

Sulfenoamination With Thioimidazoles

3.1 Introduction

Nitrogen and sulfur-containing heterocycles are common structural motifs in

natural products, bioactive compounds, and agrochemicals.42 Expedient incorporation of

nitrogen and sulfur heteroatoms into simple chemical feedstocks like alkenes, represents

an important and attractive strategy for the direct synthesis of pharmaceuticals. However,

the absolute control of regio- and stereoselectivity associated with alkene is often

considered as a prominent challenge. Therefore, chemical methods that can selectively

install nitrogen and sulfur atoms at the desired carbon position of the alkenes are of high

importance and value for accessing biomedically-relevant chemical libraries. In this

context, electrophilic activation has been representing a powerful tool for alkene

functionalization reactions.78 Typically, the electrophilic activating group converts alkene

into -onium intermediate, followed by nucleophilic displacement to give the desired

product. The utilization of such a strategy for the development of vicinal sulfenoamination

of the alkene in a regioselective manner has drawn significant attention from the synthetic

and medicinal communities due to the frequent appearances of nitrogen (N) and sulfur (S)

atoms in pharmaceuticals and natural products. In addition, the abundant, versatile, and

53

Scheme 3-1: Background on Sulfenoamination of Alkene

diverse nature of the alkene substrate make the method even more attractive to gain access

to valuable heterocycles with diverse functionalities. In this regard, several methods have

been well documented for intramolecular alkene sulfenoamination utilizing electrophilic

sulfur precursors.79-80 The pioneering work from Denmark group has demonstrated the

enantioselective sulfenoamination of N-alkenyl sulfonamide with phenylthiophthalimide

(PhthSPh) for the synthesis of N-containing heterocycles in intramolecular settings

54

(Scheme 3-1a).79, 81-82 Similarly, Shi and coworkers also reported intramolecular

thioamination using benzenesulfenate (MeOSPh) (Scheme 3-1a).83 The origin and extent

of regioselectivity, in these cases, are dependent on the competing endo vs. exo trapping

of the thiiranium intermediate (compound 3-1) by a pendant nucleophile. Later, Wirth

group developed hypervalent iodine-catalyzed thioamination of alkenes with sodium

thiophenolate via activation of the alkene by iodine (III) reagents.80 However, in contrast

to intramolecular sulfenoamination, the development of intermolecular thioamination

which is thermodynamically and kinetically disfavored, is more challenging and highly

desirable.84 In a demonstration of this strategy, sulfenoamination for the synthesis of β-

acetamido sulfide have been reported using nitrile as solvent and nitrogen source, and thiol

as a sulfur source via Ritter type reaction (Scheme 3-1b).85-87 However, this approach is

only limited to nitrile while intermolecular protocols with a broad range of alkenes and

thioamine structures can provide a modular approach for increasing structural complexity

and functional group diversity of the molecules.88 Direct intermolecular sulfenoamination

of alkene using unadorned thioamine as a nucleophile has not been realized. In addition,

the utilization of stable sulfur precursor instead of pre-generated electrophilic sulfur

reagents can further enhance the practicality of the alkene sulfenoamination strategy.89-91

As part of our interest in heterocycles synthesis, we aim to develop an

intermolecular alkene sulfenoamination strategy for accessing structurally diverse N- and

S-containing heterocycles. As a proof of concept for our halogen activation, we have

previously developed an intermolecular and regioselective sulfenoamination of terminal

olefins for the synthesis of thiazoline, utilizing thioamide as a stable sulfur and nitrogen

precursor, in a one-pot process (Scheme 3-1c).92 The regioselectivity for thiazoline

55

synthesis originates from the initial nucleophilic displacement of a 1,2-dibromoalkane,

generated from the halogenation of alkenes, with which the more nucleophilic sulfur atom

preferentially attacks the more electrophilic carbon of the 1,2-dibromoalkane.

In contrast to this previous halogenation approach, we hypothesize that

halogenation of thiol can lead to an in-situ generation of electrophilic sulfur reagent instead

of formation of 1,2-dihaloalkane.93-95 Attack of the resulting thiiranium ion (compound 3-

6) by a pendant nitrogen nucleophile, can then afford the desired N- and S-containing

heterocycle.96-100 With this hypothesis in mind, we report herein an intermolecular regio-

and stereoselective alkene sulfenoamination reaction with thioimidazoles (Scheme 3-1d).

3.2 Results and Discussions for Sulfenoamination


We commenced our study with the evaluation of a range of sulfur- and nitrogen-

containing structures with different halogen source for exploration of the compatibility of

the nucleophile with halogen. To our delight, our screenings revealed that Selectfluor was

a suitable halogen source that could enable 2-mercaptobenzimidazole to readily couple

with styrene. The reaction provided desired heterocyclic product 3-10 with high

regioselectivity albeit in low yield (7%) using acetonitrile as solvent (Table 3.1, entry 1).101

The validation of the hypothesis inspired us to perform further optimization, and testing of

different solvents revealed that N, N-dimethylformamide (DMF) was a superior solvent,

affording the product in 53% yield (Table 3.1, entries 2 and 3). The screening of the

concentration and stoichiometry of Selectfluor improved the yield of the product to 77%

(Table 3.1, entries 4-7). Additional time studies confirmed that 16 he was needed for the

56

Table 3.1: Optimization of Reaction for Sulfenoamination

reaction to proceed to completion (Table 3.1, entries 8 and 9). Further evaluation of the

stoichiometry of alkene and thiobenzimidazole demonstrated that the optimal condition

was achieved by increasing the stoichiometry of styrene to 1.5 equiv, providing the

expected product in 87% yield in a single regioisomer (Table 3.1, entries 10-12).

3.2.2 Reaction Scope

With the optimized condition in hand, we were excited to explore the scope of the

57

alkene substrate for our sulfenoamination strategy. We were pleased to find that a wide

range of alkenes with different functionalities was tolerable in our reaction condition,

providing good to excellent yields of the products. The styrene derivatives with different

halogen substituents at para - position provided the products with good yields and high

regioselectivities (Table 3.2, products 3-11 to 3-13). Moreover, the styrene derivatives with

electron-donating substituents such as methoxy, acetoxy, and electron-withdrawing groups

such as ester and trifluoromethyl groups were compatible with the reaction conditions,

affording the products in excellent regioselectivities with high efficiencies (Table 3.2,

products 3-14 to 3-17, 3-22, 3-23). The regioisomers observed in these reactions are shown

in Table 3.2 with a sulfur atom attached to the terminal position and nitrogen atom to the

benzylic position. To our delight, sterically hindered 1,1-disubstituted styrene derivatives

provided the desired products with the formation of highly steric congested quaternary

carbon centers (Table 3.2, products 3-18 to 3-21). The regioselectivities, in these cases,

were also consistent with the standard substrate. In addition, 1,2-disubstituted alkenes such

as trans-β-methyl styrene, Indene, and trans-4-octene were participated in the reaction,

affording the products in good yields with excellent diastereoselectivities (Table 3.2,

products 3-24 to 3-26). Interestingly, aliphatic disubstituted alkenes are also viable

substrates, providing exotic tetracyclic structures 3-27 and 3-28 further highlighting the

synthetic utility of this sulfenoamination strategy (Table 3.2, products 3-27, 3-28). In

general, the regioselectivity of the aliphatic alkenes is predominately governed by steric

factors. In our strategy, the regioselectivity with sulfur being in terminal carbon, was

decreased with increasing steric bulkiness in alkene and completely reversing the normally

observed regioselectivity for product 3-32 (Table 3.2, products 3-29 to 3-32).

58

Table 3.2: Alkene Substrate Scope for Sulfenoamination

Excited by the comprehensive alkene substrate scope, we focused on extending our

protocol to the incorporation of thioimidazole structure in this reaction. We were pleased

to find that our strategy could be extended to a wide range of functionalities. A number of

59

Table 3.3: Thioimidazole Substrate Scope for Sulfenoamination

useful functional groups including electron-donating and -withdrawing groups such as

alkyl, halogen, ether, nitro, and difluoromethyl ether provided the thioaminated products

efficiently (Table 3.3, Products 3-33 to 3-39). In each of these cases, regioselectivity shown

in Table 3.3, were obtained from the aspect that both nitrogen atoms in the benzimidazole

ring were capable of nucleophilic additions. However, regioselectivity with respect to N-

and S- additions to the alkene structure, remained intact with only nitrogen addition to the

benzylic position and sulfur to the terminal carbon. Moreover, 2-thioimidazoles were also

viable substrates providing the corresponding products in moderate yields with excellent

regioselectivities (Table 3.3, products 3-40 and 3-41).

60

3.2.3 Regiodivergent Sulfenoamination

In our previous sulfenoamination study for thiazoline synthesis with thioamides,

we observed the opposite regioselectivity for styrene derivatives, in which sulfur was added

to the benzylic positions and nitrogen was attached to the terminal carbons. We wondered

if we could develop potential regiodivergent sulfenoamination processes on both the

halogenation and electrophilic sulfur activation strategies. In this regard, utilization of

Scheme 3-2: Regiodivergent of Alkene Sulfenoamination

Selectfluor as a halogen source resulted in the formation of 3-10, 3-14, and 3-22 as the only

regioisomeric products with sulfur being in terminal position and nitrogen is attached to

benzylic carbon. On the other hand, the opposite regioisomers 3-42 to 3-44 were obtained

when bromine was used as the halogen source via 1,2-dibromoethylarene, from alkene and

thiobenzimidazole coupling (Scheme 3.2).102 Moreover, the electronic nature of the styrene

substrates did not have any impact on the regioisomeric outcome of the product,

highlighting the robustness of regiocontrol in these reactions.

61

3.3 Reaction Mechanism

To get insight into the mechanism of the reaction, we considered several

experiments for intermolecular sulfenoamination reaction. The formation of product 3-21

proceeds with cyclopropane ring remaining intact. This data suggests that pathways leading

to the formation of radical at the benzylic position are less likely, as such pathways

generally will lead to cyclopropane ring opening.103 In addition, the regioselectivity of the

product 3-32, obtained from 3,3-dimethylbutene is not characteristic of thiyl radical

addition. In radical addition, we would expect a product with sulfur being attached to the

terminal carbon of alkene. Instead, the ability of steric factors to influence regioselectivity,

suggested the thiiranium ion pathway. Furthermore, NMR studies by mixing

thiobenzimidazole and Selectfluor in deuterated DMF revealed a new set of fluorine peaks

showing up at 38 ppm, in agreement with literature data of a sulfur-fluorine bond.

3.3.1 Solvent Effect on Reaction

To further understand the mechanism, we also considered the effect of DMF, only

solvent that works efficiently for the reaction. DMF can act as a nucleophile and can

participate in opening up the thiiraniun ion intermediate A to form intermediate B which

can undergo nucleophile attack from the nitrogen of thiobenzimidazole, resulting in

cyclized product 3-10 (Scheme 3-3). To test the effect of the solvent, the reaction was

carried out in acetonitrile (CH3CN). The increasing the equivalent of DMF increased the

yield to 32% for 5 equiv of DMF. That yield is not comparable to the yield in standard

reaction conditions, suggesting that DMF can act as a Lewis base, with having little effect

in sulfenoamination reaction.

62

Scheme 3-3: Participation of DMF in the Sulfenoamination Reaction

3.3.2 Temperature-Dependent Diastereoselectivity

To further probe the mechanism of this transformation, several control experiments

were performed as shown in Figure 3-1. When the reaction was conducted with cis-β-

methylstyrene as an alkene substrate, the cis diastereomeric product 3-45 was observed as

Figure 3-1: Temperature-Dependent Diastereoselective Study of Cis-β-Methylstyrene

63

the major product in 15% yield and 85:15 dr at 0 ˚C. On the other hand, increasing

temperatures favoring the formation of trans product and at 50 ˚C, the trans isomer is

obtained in >98:2 ratio. This temperature-dependent behavior is consistent with previous

studies on the configurational stability of the thiiranium ions conducted by Smit and

Denmark.104-106

3.3.3 Proposed Mechanism for Intermolecular Sulfenoamination

After considering the above-mentioned experiments, our proposed mechanism for

this reaction is depicted in Figure 3-2. Fluorination of thioimidazole 3-46 by Selectfluor

results in the formation of the active sulfur electrophile 3-47. Alkene attack on this

Figure 3-2: Proposed Reaction Mechanism for Alkene Sulfenoamination

sulfur electrophile leads to the formation of thiiranium ion 3-48. Generally, the thiiranium

ion is unstable, equilibration to the open carbocation 3-49 can occur, and subsequent

nucleophile trapping results in the product formation 3-50. Alternatively, DMF can act as

a nucleophile and participate in thiiranium ring opening. The ensuing intramolecular

64

cyclization then preserves the stereochemistry in the product, as evidence in the cis-β-

methyl styrene case at low temperature.

3.4 Conclusion

We have developed a highly regio- and stereoselective sulfenoamination reaction

of alkenes. The method exhibits good functional group tolerance and broad substrate scope.

The mechanistic studies suggest the reaction pathway involving an in-situ generation of

the sulfur electrophile. Moreover, we have observed an interesting temperature-dependent

equilibrium between the thiiranium ion and the open carbocation species. In addition, we

have also developed a highly regiodivergent protocol to access both regioisomeric products

utilizing two different halogen sources. Finally, this modular and practical synthetic

approach will enable the generation of exotic heterocyclic motifs for potentially useful

biological studies.

3.5 Experimental



as were used as received. The alkene substrates for products 3-21,107 3-23,108 3-25,75 were

synthesized according to reported procedure. Organic solutions were concentrated under

reduced pressure on a Büchi rotary evaporator using an acetone-dry ice bath.

Chromatographic purification of products was accomplished using flash chromatography

on 230-400 mesh silica gel. Thin-layer chromatography (TLC) was performed on Analtech

65

250 mm silica gel HLF UV-254 plates. Visualization of the developed plates was

performed by fluorescence quenching, potassium permanganate and iodine-silica gel

system. 1H and 13C NMR spectra were recorded on a Bruker 600 instrument (600 and 150

MHz) or INOVA 600 (600 and 150 MHz) and are internally referenced to residual protio

solvent signals (for CDCl3, 7.26 and 77.0 ppm, respectively). Data for 1H NMR are

reported as follows: chemical shift ( ppm), multiplicity (s = singlet, d = doublet, t = triplet,

q = quartet, h = heptet, m = multiplet, br = broad), integration, coupling constant (Hz). 13C

spectra were reported as chemical shifts in ppm and multiplicity where appropriate. IR

spectra were recorded on a PerkinElmer FT-IR spectrophotometer and are reported in terms

of wavenumber of absorption (cm-1). High resolution mass spectra were obtained on

Waters Synapt High Definition Mass Spectrometer (HDMS) by electrospray ionization at

University of Toledo, OH, USA.

Experimental Procedures

General Procedure A: Alkene (0.75 mmol) was added to a solution of 2-

mercaptoimidazole (0.5 mmol) in DMF (1 mL, 0.5 M). After adding Selectfluor (213 mg,

0.6 mmol), the reaction mixture was stirred at room temperature for 16 h. After completion,

the reaction mixture was quenched with 1 M NaOH (2 mL). The aqueous layer was

extracted with DCM (2 x 4 mL) and combined organic layers were washed with water (3

mL) three times. The organic solution was dried with anhydrous Na2SO4, filtered,

concentrated in vacuo by rotavapor and purified by flash chromatography on SiO2 (30-70%

EtOAc in hexanes) to provide the desired product. The regioisomeric ratio was determined

by crude NMR.

66

General Procedure B: Alkene (0.75 mmol) was added to a solution of 2-

mercaptoimidazole (0.5 mmol) in DMF (1 mL, 0.5 M). After adding Selectfluor (213 mg,

0.6 mmol), the reaction mixture was stirred at 50 ºC for 16 h. After completion, the reaction

mixture was cooled to room temperature and quenched with 1 M NaOH (2 mL). The

aqueous layer was extracted with DCM (2 x 4 mL) and combined organic layers were

washed with water (3 mL) three times. The organic solution was dried with anhydrous

Na2SO4, filtered, concentrated in vacuo by rotavapor and purified by flash chromatography

on SiO2 (30-70% EtOAc in hexanes) to provide the desired product. The regioisomeric

ratio was determined by crude NMR.

General Procedure C: Alkene (0.75 mmol) was added to a solution of bromine (0.5

mmol) in DMF (1 mL, 0.5 M) and stirred at room temperature for 1 h. After adding 2-

mercaptobenzimidazole (113 mg, 0.75 mmol), the reaction mixture was stirred at 50 ºC for

16 h. Then, the reaction mixture was cooled to room temperature and quenched with 1 M

NaOH (2 mL) and 20% aq Na2S2O3 (1 mL). The aqueous layer was extracted with DCM

(2 x 4 mL) and combined organic layers were washed with water (3 mL) three times. The

organic solution was dried with anhydrous Na2SO4, filtered, concentrated in vacuo by

rotavapor and purified by flash chromatography on SiO2 (30-50% EtOAc in hexanes) to

provide the desired product. The regioisomeric ratio was determined by crude NMR.

3. Spectral Characterization of the Products

67

3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-10): This compound was

prepared according to the General Procedure A using styrene (78 mg, 0.75 mmol), 2-

mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by column chromatography

on SiO2 (30-50% EtOAc in hexanes), the title compound was isolated as a white solid (110

mg, 87% yield, >98:2 rr).


(m, 2 H), 7.13 (t, J = 7.7 Hz, 1 H), 6.94 (t, J = 7.7 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 5.49

(t, J = 7.6 Hz, 1 H), 4.14 (dd, J = 7.6, 11.2 Hz, 1 H), 3.76 (dd, J = 7.6, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 158.5, 149.5, 136.8, 133.4, 129.2, 129.1, 126.5,

121.8, 121.5, 118.6, 109.2, 77.2, 76.8, 61.0, 43.2;

IR (neat): 3027, 1612, 1469, 1448, 1248, 733 cm-1;


3-(4-fluorophenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-11): This

compound was prepared according to the General Procedure A using 4-fluorostyrene (92

mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by

column chromatography on SiO2 (30-50% EtOAc in hexanes), the title compound was

isolated as a white solid (106 mg, 78% yield, >98:2 rr).

1H NMR (600 MHz, CDCl3): = 7.61 (d, J = 8.1 Hz, 1 H), 7.25 (dd, J = 5.2, 8.1 Hz, 2

68

H), 7.14 (t, J = 7.7 Hz, 1 H), 7.08 (t, J = 8.1 Hz, 2 H), 6.97 (t, J = 7.7 Hz, 1 H), 6.57 (d, J

= 8.1 Hz, 1 H), 5.49 (t, J = 7.3 Hz, 1 H), 4.15 (dd, J = 7.3, 11.2 Hz, 1 H), 3.72 (dd, J = 7.3,

11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 163.7, 162.1, 158.4, 149.5, 133.3, 132.7, 132.6,

128.4, 128.3, 122.0, 121.6, 118.7, 116.3, 116.2, 109.1, 60.3, 43.2;

IR (neat): 3070, 1677, 1603, 1582, 1469, 1275, 928 cm-1;

HRMS (ESI) m/z calcd for C15H12FN2S [(M+H)+] 271.0705, found 271.0711.

3-(4-chlorophenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-12): This

compound was prepared according to the General Procedure A using 4-chlorostyrene (104





(d, J = 8.1 Hz, 2 H), 7.15 (t, J = 7.7 Hz, 1 H), 6.98 (t, J = 7.7 Hz, 1 H), 6.60 (d, J = 8.1 Hz,

1 H), 5.49 (t, J = 7.3 Hz, 1 H), 4.17 (dd, J = 7.3, 11.4 Hz, 1 H), 3.71 (dd, J = 7.3, 11.4 Hz,

1 H);

13C NMR (150 MHz, CDCl3): = 158.4, 149.5, 135.4, 135.0, 133.2, 129.4, 127.8,

122.0, 121.7, 118.7, 109.1, 60.2, 43.1;

IR (neat): 3054, 1609, 1472, 1219, 926, 737 cm-1;

69

HRMS (ESI) m/z calcd for C15H12ClN2S [(M+H)+] 287.0410, found 287.0412.

3-(4-bromophenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-13): This

compound was prepared according to the General Procedure A using 4-bromostyrene (137





-7.10 (m, 3 H), 6.98 (t, J = 7.6 Hz, 1 H), 6.60 (d, J = 7.6 Hz, 1 H), 5.48 (t, J = 7.4 Hz, 1 H),

4.16 (dd, J = 7.4, 11.2 Hz, 1 H), 3.71 (dd, J = 7.4, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 158.4, 149.4, 135.9, 133.2, 132.4, 128.1, 123.1, 122.0,

121.7, 118.7, 109.1, 60.2, 43.1;

IR (neat): 3051, 1595, 1472, 1219, 820, 737 cm-1;

HRMS (ESI) m/z calcd for C15H12BrN2S [(M+H)+] 330.9904, found 330.9906.

3-(4-(tert-butyl)phenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-14): This

70

compound was prepared according to the General Procedure A using 4-tert-butylstyrene

(120 mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by




7.19 (d, J = 8.1 Hz, 2 H), 7.15 (t, J = 7.6 Hz, 1 H), 6.96 (t, J = 7.6 Hz, 1 H), 6.62 (d, J =

8.1 Hz, 1 H), 5.48 (t, J = 7.4 Hz, 1 H), 4.13 (dd, J = 7.4, 11.1 Hz, 1 H), 3.75 (dd, J = 7.4,

11.1 Hz, 1 H), 1.32 (s, 9 H);

13C NMR (150 MHz, CDCl3): = 158.6, 152.2, 149.5, 133.7, 133.5, 126.2, 126.1, 121.7,

121.4, 118.5, 109.3, 60.7, 43.3, 34.6, 31.2;

IR (neat): 3051, 1596, 1472, 1276, 737 cm-1;


4-(2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazol-3-yl)phenyl acetate (3-15): This

compound was prepared according to the General Procedure A using 4-acetoxystyrene



isolated as a white gummy solid (114 mg, 73% yield, >98:2 rr).


7.08 (m, 3 H), 6.95 (t, J = 7.6 Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 5.50 (t, J = 7.3 Hz, 1 H),

71

4.14 (dd, J = 7.3, 11.2 Hz, 1 H), 3.72 (dd, J = 7.3, 11.2 Hz, 1 H), 2.29 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 169.1, 158.4, 151.0, 149.4, 134.3, 133.3, 127.6, 122.4,

121.9, 121.6, 118.6, 109.2, 60.3, 43.2, 21.0;

IR (neat): 3053, 1757, 1608, 1472, 1187, 738 cm-1;


3-(4-methoxyphenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-16): This

compound was prepared according to the General Procedure A using 4-methoxystyrene





(t, J = 7.7 Hz, 1 H), 6.98-6.87 (m, 3 H), 6.57 (d, J = 8.1 Hz, 1 H), 5.46 (t, J = 7.7 Hz, 1 H),

4.09 (dd, J = 7.7, 11.2 Hz, 1 H), 3.81 (s, 3 H), 3.76 (dd, J = 7.7, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 160.0, 158.3, 149.3, 133.4, 128.5, 127.8, 121.7,

121.4, 118.4, 114.4, 109.2, 60.7, 55.2, 43.2;

IR (neat): 3012, 1607, 1474, 1226, 768 cm-1;


72

3-(2-methoxyphenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-17): This

compound was prepared according to the General Procedure A using 2-methoxystyrene



isolated as a white gummy solid (121mg, 86% yield, >98:2 rr).


= 7.7 Hz, 1 H), 7.04-6.93 (m, 2 H), 6.86-6.77 (m, 2 H), 6.68 (d, J = 6.8 Hz, 1 H), 5.99 (dd,

J = 5.6, 7.6 Hz, 1 H), 4.28 (dd, J = 7.6, 11.0 Hz, 1 H), 3.90 (s, 3 H), 3.74- 3.67 (m, 1 H);

13C NMR (150 MHz, CDCl3): = 159.1, 156.2, 149.4, 133.4, 129.8, 126.5, 124.7, 121.7,

121.5, 120.7, 118.5, 110.6, 109.3, 55.4, 54.9, 42.1;

IR (neat): 3053, 1601, 1449, 1242, 737 cm-1;


3-methyl-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-18): This

compound was prepared according to the General Procedure A using α-methylstyrene (89



73

isolated as a white gummy solid (90 mg, 68% yield, >98:2 rr).

1H NMR (600 MHz, CDCl3): =7.64 (d, J = 8.1 Hz, 1 H), 7.42-7.35 (m, 3 H), 7.28 (d, J

= 8.1 Hz, 2 H), 7.16 (t, J = 7.7 Hz, 1 H), 6.98 (t, J = 7.7 Hz, 1 H), 6.69 (d, J = 8.1 Hz, 1 H),

3.98 (d, J = 11.2 Hz, 1 H), 3.84 (d, J = 11.2 Hz, 1 H), 2.05 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 158.0, 149.7, 140.9, 132.8, 129.1, 128.5, 125.6, 121.9,

121.5, 118.8, 109.3, 66.4, 50.3, 23.1;

IR (neat): 3056, 1610, 1443, 1219, 738 cm-1;


3-isopropyl-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-19): This

compound was prepared according to the General Procedure A using α-isopropylstyrene





7.25 (m, 3 H), 7.18-7.11 (m, 2 H), 7.06 (t, J = 7.7 Hz, 1 H), 4.10 (d, J = 11.7 Hz, 1 H), 3.99

(d, J = 11.7 Hz, 1 H), 3.24-3.15 (m, 1 H), 1.17-1.03 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 158.3, 149.4, 140.9, 133.8, 128.8, 128.1, 126.0,

121.7, 121.3, 118.7, 110.5, 73.3, 43.1, 35.8, 19.1, 17.7;

IR (neat): 2959, 1607, 1473, 1221, 738 cm-1;

74


3,3-diphenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-20): This compound was

prepared according to the General Procedure A using α-phenylstyrene (135 mg, 0.75

mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by column

chromatography on SiO2 (30-50% EtOAc in hexanes), the title compound was isolated as

a white solid (110 mg, 67% yield, >98:2 rr).


(m, 4 H), 7.14 (s, 1 H), 6.90 (s, 1 H), 6.33 (d, J = 8.1 Hz, 1 H), 4.43 (s, 2 H);

13C NMR (150 MHz, CDCl3): = 157.5, 149.0, 138.9, 133.9, 128.7, 128.6, 127.8, 121.8,

121.7, 118.9, 109.8, 73.1, 51.5;

IR (neat): 3028, 1611, 1475, 1227, 733 cm-1;


3-cyclopropyl-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-21): This

compound was prepared according to the General Procedure A using α-cyclopropylstyrene


75




= 7.7 Hz, 1 H), 6.96 (t, J = 7.7 Hz, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 3.89 (d, J = 11.2 Hz, 1

H), 3.75 (d, J = 11.2 Hz, 1 H), 1.87-1.80 (m, 1 H), 0.96-0.88 (m, 1 H), 0.68-0.61 (m, 1 H),

0.57 (dd, J = 5.7, 9.6 Hz, 1 H), 0.45 (dd, J = 5.5, 9.6 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 158.1, 149.2, 141.2, 133.4, 128.8, 128.4, 126.4,

121.7, 121.5, 118.8, 109.8, 69.3, 47.0, 18.2, 3.6, 1.2;

IR (neat): 3016, 1610, 1473, 1216, 744 cm-1;


3-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-22):

This compound was prepared according to the General Procedure A using 4-

(trifluoromethyl)styrene (129 mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5

mmol). After purification by column chromatography on SiO2 (30-50% EtOAc in

hexanes), the title compound was isolated as a white solid (79 mg, 49% yield, >98:2 rr).

1H NMR (600 MHz, CDCl3): = 7.70-7.62 (m, 3 H), 7.38 (d, J = 8.1 Hz, 2 H), 7.18 (t, J

= 7.8 Hz, 1 H), 7.01 (t, J = 7.7 Hz, 1 H), 6.63 (d, J = 8.1 Hz, 1 H), 5.64 (t, J = 7.1 Hz, 1 H),

4.28 (dd, J = 7.6, 11.2 Hz, 1 H), 3.75 (dd, J = 6.7, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 158.5, 149.6, 141.0, 133.2, 131.6, 131.3, 126.9,

76

126.3, 122.3, 122.0, 118.9, 109.1, 77.2, 76.8, 60.2, 43.2;

IR (neat): 2924, 1611, 1470, 1320, 741 cm-1;

HRMS (ESI) m/z calcd for C16H12F3N2S [(M+H)+] 321.0670, found 321.0674.

methyl 4-(2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazol-3-yl)benzoate (3-23): This

compound was prepared according to the General Procedure A using methyl 4-

vinylbenzoate (122 mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol). After

purification by column chromatography on SiO2 (30-70% EtOAc in hexanes), the title

compound was isolated as a white solid (65 mg, 42% yield, >98:2 rr).



1 H), 5.60 (t, J = 7.3 Hz, 1 H), 4.23 (dd, J = 7.3, 11.2 Hz, 1 H), 3.92 (s, 3 H), 3.77 (dd, J =

7.3, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 166.2, 158.5, 149.5, 141.8, 133.3, 131.0, 130.5,

126.6, 122.1, 121.8, 118.8, 109.1, 60.6, 52.3, 43.1;

IR (neat): 2947, 1725, 1477, 1276, 737 cm-1;


77

6a,11b-dihydro-7H-benzo[4,5]imidazo[2,1-b]indeno[1,2-d]thiazole (3-24): This

compound was prepared according to the General Procedure A using indene (87 mg, 0.75



a yellow solid (108 mg, 82% yield, >98:2 rr, >98:2 dr).

1H NMR (600 MHz, CDCl3): =7.60 (d, J = 8.1 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 2 H), 7.34-

7.27 (m, 2 H), 7.27-7.17 (m, 3 H), 5.95 (d, J = 7.1 Hz, 1 H), 5.21 (dt, J = 2.9, 7.1 Hz, 1 H),

3.58 (dd, J = 7.1, 17.0 Hz, 1 H), 3.35 (dd, J = 2.9, 17.0 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 157.7, 149.5, 140.7, 137.9, 133.7, 129.8, 128.0, 125.7,

125.7, 122.2, 122.1, 119.1, 109.3, 65.8, 55.5, 39.2;

IR (neat): 3025, 1613, 1467, 1230, 727 cm-1;



compound was prepared according to the General Procedure A using trans-β-

methylstyrene (89 mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol). After

purification by column chromatography on SiO2 (30-50% EtOAc in hexanes), the title

78

compound was isolated as a white solid (107 mg, 80% yield, >98:2 rr, >98:2 dr).


7.28 (m, 2 H), 7.12 (t, J = 7.7 Hz, 1 H), 6.91 (t, J = 7.7 Hz, 1 H), 6.43 (d, J = 8.1 Hz, 1 H),

4.98 (d, J = 8.5 Hz, 1 H), 4.37-4.28 (m, 1 H), 1.61 (d, J = 6.8 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 158.0, 149.2, 135.9, 133.8, 129.7, 129.5, 127.5, 122.1,

121.7, 118.9, 109.6, 69.3, 56.3, 18.6;

IR (neat): 2914, 1612, 1466, 1249, 735 cm-1;


2,3-dipropyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-26): This compound was

prepared according to the General Procedure B using trans-4-octene (84 mg, 0.75 mmol),

2-mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by column


a colorless oil (94 mg, 72% yield, >98:2 dr).

1H NMR (600 MHz, CDCl3): =7.59 (d, J = 8.3 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 4.33-4.27 (m,

1 H), 4.00-3.92 (m, 1 H), 1.88-1.76 (m, 4 H), 1.54-1.36 (m, 4 H), 0.99-0.89 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 157.6, 149.5, 133.6, 121.8, 121.7, 118.9, 109.0, 62.4,

58.2, 39.5, 35.1, 20.5, 19.0, 14.2, 13.8;

IR (neat): 2957, 1613, 1447, 1252, 737 cm-1;


79

2,3,3a,10a-tetrahydrobenzo[4,5]imidazo[2,1-b]furo[2,3-d]thiazole (3-27): This

compound was prepared according to the General Procedure A using 2,3-dihydrofuran (53



isolated as a white solid (74 mg, 68% yield, >98:2 rr, >98:2 dr).


7.14 (m, 2 H), 6.35 (d, J = 6.3 Hz, 1 H), 4.94 (t, J = 7.0 Hz, 1 H), 4.15 (t, J = 8.2 Hz, 1 H),

3.89 (ddd, J = 4.8, 9.2, 11.2 Hz, 1 H), 2.49-2.37 (m, 1 H), 2.27 (dd, J = 4.8, 13.4 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 157.1, 150.1, 133.1, 122.7, 122.4, 118.8, 109.4, 88.7,

67.1, 54.3, 35.6;

IR (neat): 2965, 1613,1468, 1251, 753 cm-1;


2H-spiro[benzo[4,5]imidazo[2,1-b]thiazole-3,1'-cyclopentane] (3-28): This compound

was prepared according to the General Procedure A using methylenecyclopentane (62mg,

0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by column




80

7.10 (m, 2 H), 3.70 (s, 2 H), 2.40-2.30 (m, 2 H), 2.10-1.97 (m, 4 H), 1.87-1.76 (m, 2 H);

13C NMR (150 MHz, CDCl3): = 158.1, 150.1, 132.5, 121.9, 121.6, 119.2, 108.8, 71.4,

48.1, 36.1, 25.1;

IR (neat): 3047, 1610, 1475, 1229, 743 cm-1;


3-hexyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-29): This compound was

prepared according to the General Procedure B using 1-octene (84 mg, 0.75 mmol), 2-

mercaptobenzimidazole (75 mg, 0.5 mmol). After purification by column chromatography

on SiO2 (30-50% EtOAc in hexanes), the inseparable mixture of both regioisomers was

isolated as a colorless oil (103 mg, 79% yield, 75:25 rr).

1H NMR (600 MHz, CDCl3): = 7.58 (d, J = 7.8 Hz, 1 Hmajor + 1 Hminor), 7.23-7.08 (m, 3

Hmajor + 3 Hminor), 4.58 (tt, J = 3.5, 7.6 Hz, 1 Hmajor), 4.41 (d, J = 7.3 Hz, 1 Hminor), 4.31 (dd,

J = 7.3, 9.8 Hz, 1 Hminor), 3.99 (dd, J = 7.6, 11.1 Hz, 1 Hmajor), 3.86 (dd, J = 7.3, 9.8 Hz, 1

Hminor), 3.53 (dd, J = 3.5, 11.1 Hz, 1 Hmajor), 1.99 (ddd, J = 4.5, 9.5, 13.8 Hz, 1 Hmajor), 1.95-

1.78 (m, 1 Hmajor + 2 Hminor), 1.44-1.39 (m, 1 Hmajor), 1.39-1.23 (m, 7 Hmajor + 8 Hminor),

0.92-0.79 (m, 3 Hmajor + 3 Hminor);

13C NMR (150 MHz, CDCl3): = 158.2, 149.7, 133.6, 121.9, 121.9, 121.8, 118.9, 118.8,

109.1, 108.9, 57.3, 53.9, 49.7, 39.8, 35.5, 32.7, 31.8, 31.8, 29.3, 29.1, 28.1, 25.6, 22.8, 14.3;

IR (neat): 2925, 1614, 1448, 1248, 736 cm-1;


81

2-(2-(2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazol-3-yl)ethyl)isoindoline-1,3-dione (3-

30): This compound was prepared according to the General Procedure B using N-(3-buten-

1-yl)phthalimide (151 mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol).

After purification by column chromatography on SiO2 (30-70% EtOAc in hexanes), the

inseparable mixture of both regioisomers was isolated as a white solid (149 mg, 85% yield,

76:24 rr).

1H NMR (600 MHz, CDCl3): = 7.87-7.78 (m, 2 Hmajor + 2 Hminor), 7.75-7.68 (m, 2 Hmajor

+ 2 Hminor), 7.57-7.54 (m, 1 Hminor), 7.51 (d, J = 7.6 Hz, 1 Hmajor), 7.19 (d, J = 7.6 Hz, 1

Hmajor), 7.17-7.04 (m, 2 Hmajor + 3 Hminor ), 4.73-4.58 (m, 1 Hmajor), 4.42-4.31(m, 2 Hminor),

4.13 (dd, J = 7.4, 11.4 Hz, 1 Hmajor), 4.02 (dd, J = 4.9, 9.8 Hz, 1 Hminor), 3.92-3.78 (m, 2

Hmajor + 2 Hminor), 3.74 (dd, J = 4.2, 11.4 Hz, 1 Hmajor), 2.49 - 2.39 (m, 1 Hmajor), 2.25 (d, J =

6.8 Hz, 2 Hminor), 2.31-2.15 (m, 1 Hmajor);

13C NMR (150 MHz, CDCl3): = 168.3, 158.1, 149.7, 134.5, 133.2, 132.0, 131.9,

123.7, 122.2, 122.1, 122.0, 119.0, 118.9, 109.0, 109.0, 55.0, 50.5, 49.4, 39.4, 35.8, 34.9,

34.4, 31.1;

IR (neat): 2937, 1768, 1701, 1248, 715 cm-1;


82

3-cyclohexyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-31): This compound was

prepared according to the General Procedure B using vinylcyclohexane (83 mg, 0.75


chromatography on SiO2 (30-50% EtOAc in hexanes), the inseparable mixture of both

regioisomers were isolated as a white solid (80 mg, 62% yield, 50:50 rr).

1H NMR (600 MHz, CDCl3): = 7.59 (d, J = 7.6 Hz, 1 Hmajor + 1 Hminor), 7.23 (d, J = 7.6

Hz, 1 Hmajor), 7.19-7.10 (m, 2 Hmajor + 3 Hminor), 4.53-4.47 (m, 1 Hmajor), 4.36-4.27 (m, 2

Hminor), 3.97-3.90 (m, 1 Hmajor + 1 Hminor), 3.68 (dd, J = 3.7, 11.2 Hz, 1 Hmajor), 2.25-2.15

(m, 1 Hmajor), 1.84-1.64 (m, 4 Hmajor + 5 Hminor), 1.49 (d, J = 11.7 Hz, 1 Hmajor), 1.34-1.10

(m, 5 Hmajor + 6 Hminor);

13C NMR (150 MHz, CDCl3): = 158.7, 158.5, 149.5, 148.9, 134.0, 133.8, 122.2, 122.0,

121.9, 121.8, 118.9, 118.8, 109.5, 108.9, 61.7, 60.0, 47.8, 42.8, 40.9, 36.7, 31.4, 31.1, 29.9,

27.3, 26.3, 26.3, 26.2, 26.0, 25.9;

IR (neat): 2922, 1614, 1471, 1245, 738 cm-1;


2-(tert-butyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-32): This compound was

prepared according to the General Procedure B using 3,3-dimethylbut-1-ene (63 mg, 0.75




83


= 8.1 Hz, 1 H), 4.21 (dd, J = 8.1, 10.3 Hz, 1 H), 4.02 (dd, J = 8.1, 10.3 Hz, 1 H), 1.07 (s, 9

H);

13C NMR (150 MHz, CDCl3): = 158.5, 149.0, 133.9, 122.0, 121.8, 118.7, 108.8, 65.0,

45.3, 34.5, 27.4;

IR (neat): 2949, 1614, 1445, 1250, 738 cm-1;



compound was prepared according to the General Procedure A using styrene (78 mg, 0.75

mmol), 2-mercapto-5-methylbenzimidazole (82 mg, 0.5 mmol). After purification by

column chromatography on SiO2 (30-50% EtOAc in hexanes), the inseparable mixture of

both nitrogen addition products was isolated as a yellow solid (117 mg, 88% yield, >98:2

rr, 54:46 N1:N2).

1H NMR (600 MHz, CDCl3): = 7.49 (d, J = 8.1 Hz, 1 Hminor), 7.42-7.36 (m, 4 Hmajor + 3

Hminor), 7.29-7.23 (m, 2 Hmajor + 2 Hminor), 6.96 (d, J = 8.1 Hz, 1 Hminor), 6.77 (d, J = 8.3 Hz,

1 Hmajor), 6.46 (d, J = 8.3 Hz, 1 Hmajor), 6.40 (s, 1 Hminor), 5.49 (t, J = 7.4 Hz, 1 Hmajor + 1

Hminor), 4.15 (ddd, J = 7.4, 11.4, 13.2 Hz, 1 Hmajor + 1 Hminor), 3.79-3.70 (m, 1 Hmajor + 1

Hminor), 2.39 (s, 3 Hmajor), 2.24 (s, 3 Hminor);

13C NMR (150 MHz, CDCl3): = 158.4, 157.8, 149.8, 147.5, 137.0, 136.9, 133.6, 131.5,

131.5, 129.2, 129.2, 129.1, 129.0, 126.5, 126.4, 123.2, 122.7, 118.6, 118.1, 109.3, 108.7,

84

61.0, 60.7, 43.3, 43.3, 21.5, 21.4;

IR (neat): 2917, 1615, 1472, 1112, 746 cm-1;


7-methoxy-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-34): This


mmol), 2-mercapto-5-methoxybenzimidazole (90 mg, 0.5 mmol). After purification by


both nitrogen addition products was isolated as a white solid (100 mg, 71% yield, >98:2 rr,

60:40 N1:N2).

1H NMR (600 MHz, CDCl3): = 7.49 (d, J = 8.8 Hz, 1 Hminor), 7.44 - 7.36 (m, 3 Hmajor +

3 Hminor), 7.31-7.25 (m, 2 Hmajor + 2 Hminor), 7.14 (d, J = 2.4 Hz, 1 Hmajor), 6.76 (dd, J = 2.4,

8.8 Hz, 1 Hminor), 6.59 (dd, J = 2.4, 8.8 Hz, 1 Hmajor), 6.45 (d, J = 8.8 Hz, 1 Hmajor), 6.08 (d,

J = 2.4 Hz, 1 Hminor), 5.53-5.45 (m, 1 Hmajor + 1 Hminor), 4.20-4.09 (m, 1 Hmajor + 1 Hminor),

3.84-3.73 (m, 4 Hmajor + 1 Hminor), 3.61 (s, 3 Hminor);

13C NMR (150 MHz, CDCl3): = 158.7, 157.1, 155.8, 155.4, 150.4, 143.9, 136.9, 136.7,

134.0, 129.2, 129.2, 128.1, 126.6, 126.6, 118.9, 110.5, 109.6, 109.4, 102.0, 94.3, 77.2, 76.8,

61.4, 60.9, 55.7, 55.6, 43.3, 43.3;

IR (neat): 2993, 1619, 1437, 1225, 695 cm-1;


85

7-nitro-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-35): This compound

was prepared according to the General Procedure A using styrene (78 mg, 0.75 mmol), 2-

mercapto-5-nitrobenzimidazole (98 mg, 0.5 mmol). After purification by column

chromatography on SiO2 (30-70% EtOAc in hexanes), the inseparable mixture of both

nitrogen addition products was isolated as a yellow gummy solid (95 mg, 64% yield, >98:2

rr, 55:45 N1:N2).

1H NMR (600 MHz, CDCl3): = 8.45-8.41 (m, 1 Hminor), 8.05 (dd, J = 2.0, 9.0 Hz, 1

Hmajor), 7.87 (dd, J = 1.7, 8.8 Hz, 1 Hminor), 7.60 (d, J = 9.0 Hz, 1 Hmajor), 7.50-7.47 (m, 1

Hmajor), 7.47-7.39 (m, 3 Hmajor + 3 Hminor), 7.33-7.26 (m, 2 Hmajor + 2 Hminor), 6.57 (d, J = 9.0

Hz, 1 Hminor), 5.72-5.62 (m, 1 Hmajor + 1 Hminor), 4.34-4.22 (m, 1 Hmajor + 1 Hminor), 3.88 (td,

J = 6.7, 11.4 Hz, 1 Hmajor + 1 Hminor);

13C NMR (150 MHz, CDCl3): = 164.4, 162.5, 154.0, 148.8, 143.2, 142.3, 137.4, 135.7,

132.5, 129.8, 129.7, 129.6, 129.6, 129.4, 126.5, 126.3, 118.2, 118.2, 117.7, 114.7, 108.7,

105.5, 61.3, 61.3, 43.4, 43.4;

IR (neat): 2922, 1616, 1438, 1315, 1054, 696 cm-1;


7-chloro-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-36): This


86

mmol), 5-chloro-2-mercaptobenzimidazole (92 mg, 0.5 mmol). After purification by


both nitrogen addition products was isolated as a white solid (109 mg, 76% yield, >98:2 rr,

55:45 N1:N2).

1H NMR (600 MHz, CDCl3): = 7.59-7.56 (m, 1 Hminor), 7.49 (d, J = 8.5 Hz, 1 Hmajor),

7.45-7.37 (m, 3 Hmajor + 3 Hminor), 7.27 (d, J = 5.1 Hz, 2 Hmajor + 2 Hminor), 7.09 (dd, J = 1.7,

8.5 Hz, 1 Hmajor), 6.90 (dd, J = 1.7, 8.3 Hz, 1 Hminor), 6.57-6.53 (m, 1 Hmajor), 6.45 (d, J =

8.3 Hz, 1 Hminor), 5.51 (q, J = 7.6 Hz, 1 Hmajor + 1 Hminor), 4.17 (ddd, J = 4.5, 7.3, 11.4 Hz, 1

Hmajor + 1 Hminor), 3.83-3.75 (m, 1 Hmajor + 1 Hminor);

13C NMR (150 MHz, CDCl3): = 160.1, 159.5, 150.2, 148.1, 136.4, 136.3, 133.9, 132.0,

129.5, 129.4, 129.4, 129.4, 127.6, 127.2, 126.5, 126.5, 122.5, 121.8, 119.3, 118.5, 109.8,

109.4, 61.3, 61.1, 43.3, 43.3;

IR (neat): 2919, 1618, 1437, 1027, 696 cm-1;

HRMS (ESI) m/z calcd for C15H12ClN2S [(M+H)+] 287.0410, found 287.0396.

7-(difluoromethoxy)-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-37):

This compound was prepared according to the General Procedure A using styrene (78 mg,

0.75 mmol), 5-(difluoromethoxy)-2-mercaptobenzimidazole (108 mg, 0.5 mmol). After

purification by column chromatography on SiO2 (30-70% EtOAc in hexanes), the

inseparable mixture of both nitrogen addition products was isolated as a colorless oil (107

mg, 67% yield, >98:2 rr, 53:47 N1:N2).

87

1H NMR (600 MHz, CDCl3): = 7.53 (d, J = 8.8 Hz, 1 Hmajor), 7.43-7.39 (m, 3 Hmajor + 3

Hminor), 7.38-7.36 (m, 1 Hminor), 7.31-7.23 (m, 2 Hmajor + 2 Hminor), 6.92 (dd, J = 2.1, 8.7 Hz,

1 Hmajor), 6.75 (dd, J = 1.8, 8.7 Hz, 1 Hminor), 6.49 (d, J = 8.8 Hz, 1 Hminor), 6.44 (t, J = 72

Hz, 1 Hminor), 6.33 (d, J = 2.0 Hz, 1 Hmajor), 6.32-6.30 (m, 1 Hmajor), 5.52 (dt, J = 2.9, 7.6

Hz, 1 Hmajor + 1 Hminor), 4.17 (ddd, J = 3.5, 7.5, 11.2 Hz, 1 Hmajor + 1 Hminor), 3.83-3.76 (m,

1 Hmajor + 1 Hminor);

13C NMR (150 MHz, CDCl3): = 160.3, 159.5, 149.9, 147.1, 146.5, 145.9, 136.4, 136.2,

133.4, 131.2, 129.4, 129.4, 129.3, 126.5, 126.5, 119.0, 118.1, 117.9, 116.4, 116.2, 114.6,

114.4, 114.4, 114.4, 110.1, 109.4, 101.5, 61.3, 61.1, 43.3, 43.3;

IR (neat): 2988, 1621, 1470, 1111, 697 cm-1;

HRMS (ESI) m/z calcd for C16H13F2N2OS [(M+H)+] 319.0716, found 319.0717.

6-chloro-7-fluoro-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-38): This


mmol), 6-chloro-5-fluoro-2-mercaptobenzimidazole (101 mg, 0.5 mmol). After

purification by column chromatography on SiO2 (30-50% EtOAc in hexanes), the

inseparable mixture of both nitrogen addition products was isolated as a white solid (101

mg, 66% yield, >98:2 rr, 51:49 N1:N2).

1H NMR (600 MHz, CDCl3): = 7.59 (d, J = 6.6 Hz, 1 Hminor), 7.47-7.40 (m, 3 Hmajor + 3

Hminor), 7.36 (d, J = 9.5 Hz, 1 Hmajor), 7.31-7.24 (m, 2 Hmajor + 2 Hminor), 6.55 (d, J = 6.6 Hz,

1 Hmajor), 6.32 (d, J = 8.8 Hz, 1 Hminor), 5.55-5.48 (m, 1 Hmajor + 1 Hminor), 4.19 (dt, J = 7.6,

88

10.5 Hz, 1 Hmajor + 1 Hminor), 3.86-3.78 (m, 1 Hmajor + 1 Hminor);

13C NMR (150 MHz, CDCl3): = 160.8, 160.1, 155.1, 154.4, 153.5, 152.8, 148.4,148.3,

145.7, 136.0, 135.9, 131.9, 131.8, 130.0, 129.7, 129.6, 129.5, 126.6, 126.5, 119.4, 115.4,

115.3, 114.9, 114.8, 109.9, 106.0, 105.8, 97.4, 97.2, 61.5, 61.4, 43.4, 43.3;

IR (neat): 2923, 1618, 1515, 1444, 1335, 696 cm-1;

HRMS (ESI) m/z calcd for C15H11ClFN2S [(M+H)+] 305.0320, found 305.0316.

6,7-dichloro-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-39): This


mmol), 5,6-dichloro-2-mercaptobenzimidazole (110 mg, 0.5 mmol). After purification by


isolated as a yellow solid (108 mg, 67% yield, >98:2 rr).


Hz, 2 H), 6.63 (s, 1 H), 5.52 (t, J = 7.6 Hz, 1 H), 4.20 (dd, J = 7.6, 11.2 Hz, 1 H), 3.81 (dd,

J = 7.6, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 161.0, 148.7, 135.9, 132.5, 129.6, 129.5, 126.4, 126.1,

125.4, 119.7, 110.4, 61.3, 43.4;

IR (neat): 3058, 1614, 1445, 1252, 740, 693 cm-1;

HRMS (ESI) m/z calcd for C15H11Cl2N2S [(M+H)+] 321.0013, found 321.0020.

89

3-phenyl-2,3-dihydroimidazo[2,1-b]thiazole (3-40): This compound was prepared

according to the General Procedure B using styrene (104 mg, 1.0 mmol), 2-

mercaptoimidazole (50 mg, 0.5 mmol), Selectfluor (266 mg, 0.75 mmol). After purification

by column chromatography on SiO2 (30-50% EtOAc in hexanes), the title compound was

isolated as a yellow oil (37 mg, 37% yield, >98:2 rr).

1H NMR (600 MHz, CDCl3): = 7.44-7.37 (m, 3 H), 7.25-7.20 (m, 2 H), 7.03 (s, 1 H),

6.72 (s, 1 H), 5.34 (t, J = 7.6 Hz, 1 H), 4.07 (dd, J = 7.2, 11.2 Hz, 1 H), 3.70 (dd, J = 8.1,

11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 149.6, 137.7, 134.3, 129.2, 129.1, 126.5, 116.5, 62.1,

43.7;

IR (neat): 2935, 1465, 1234, 696 cm-1;


3,5,6-triphenyl-2,3-dihydroimidazo[2,1-b]thiazole (3-41): This compound was prepared

according to the General Procedure B using styrene (78 mg, 0.75 mmol), 4,5-diphenyl-2-

imidazolethiol (126 mg, 0.5 mmol). After purification by column chromatography on SiO2

(30-50% EtOAc in hexanes), the title compound was isolated as a yellow solid (90 mg,

51% yield, >98:2 rr).

90



3.55 (dd, J = 2.1, 11.2 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 149.1, 143.0, 138.7, 134.4, 130.4, 129.7, 128.8,128.5,

128.5, 128.1, 128.1, 127.5, 126.6, 126.5, 125.8, 60.5, 43.6;

IR (neat): 3031, 1601, 1440, 1317, 1137, 695 cm-1;


2-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-42): This compound was

prepared according to the General Procedure C using styrene (78 mg, 0.75 mmol), 2-

mercaptobenzimidazole (113 mg, 0.75 mmol). After purification by column


a white solid (96 mg, 76% yield, 94:6 rr).


7.34 (m, 3 H), 7.24-7.15 (m, 3 H), 5.58 (t, J = 7.9 Hz, 1 H), 4.61 (dd, J = 7.9, 10.3 Hz, 1

H), 4.26 (dd, J = 7.9, 10.3 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 158.0, 148.9, 137.5, 133.5, 129.1, 129.0, 127.7, 121.9,

121.9, 118.8, 108.8, 56.0, 51.7;

IR (neat): 2927, 1612, 1473, 1249, 742 cm-1;


91

2-(4-(tert-butyl)phenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-43): This

compound was prepared according to the General Procedure C using 4-tert-butylstyrene

(120 mg, 0.75 mmol), 2-mercaptobenzimidazole (113 mg, 0.75 mmol). After purification

by column chromatography on SiO2 (30-50% EtOAc in hexanes), the title compound was

isolated as a white solid (101 mg, 65% yield, 95:5 rr).


(m, 3 H), 5.53 (t, J = 7.9 Hz, 1 H), 4.53 (dd, J = 7.9, 10.3 Hz, 1 H), 4.22 (dd, J = 7.9, 10.3

Hz, 1 H), 1.33 (s, 9 H);

13C NMR (150 MHz, CDCl3): = 158.1, 152.1, 148.8, 134.2, 133.5, 127.3, 126.0, 121.8,

121.8, 118.6, 108.8, 55.7, 51.5, 34.6, 31.1;

IR (neat): 2957, 1612, 1465, 1229, 734 cm-1;


2-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3-44):

This compound was prepared according to the General Procedure C using 4-

(trifluoromethyl)styrene (129 mg, 0.75 mmol), 2-mercaptobenzimidazole (113 mg, 0.75

mmol). After purification by column chromatography on SiO2 (30-50% EtOAc in

hexanes), the title compound was isolated as a yellow solid (91 mg, 57% yield, >98:2).

1H NMR (600 MHz, CDCl3): = 7.65 (t, J = 7.9 Hz, 3 H), 7.58 (d, J = 8.1 Hz, 2 H), 7.28-

92

7.15 (m, 3 H), 5.63-5.55 (m, 1 H), 4.64 (dd, J = 7.7, 10.4 Hz, 1 H), 4.31-4.22 (m, 1 H);

13C NMR (150 MHz, CDCl3): = 157.4, 149.0, 141.9, 133.5, 131.2, 131.0, 128.0, 126.2

(q, JC-F = 3.5 Hz), 124.5, 122.2, 118.9, 108.9, 55.0, 51.4;

IR (neat): 2950, 1615, 1473, 1113, 746 cm-1;

HRMS (ESI) m/z calcd for C16H12F3N2S [(M+H)+] 321.0673, found 321.0665.

Temperature dependent diastereoselectivity:

The study of diastereoselctivity was carried out according to the General Procedure A using

cis-β-methylstyrene (89 mg, 0.75 mmol), 2-mercaptobenzimidazole (75 mg, 0.5 mmol) for

8 h. The temperature 50 ºC, rt, 0 ºC and -20 ºC provided 69% (cis:trans <2:98), 42%

(cis:trans 69:31), 15% (cis:trans 85:15), and <5% based on crude NMR yield, and ratio

respectively. After purification of the rt reaction by column chromatography on SiO2 (25%

EtOAc in hexanes), the inseparable mixture of two diastereomers was isolated as a white

solid (53 mg, 40% yield).

1H NMR (600 MHz, CDCl3): = 7.60 (d, J = 8.3 Hz, 1 Htrans), 7.51-7.47 (m, 2 Hcis), 7.47

-7.39 (m, 3 Htrans + 2 Hcis), 7.35-7.29 (m, 2 Htrans + 2 Hcis), 7.29-7.23 (m, 1 Hcis), 7.20-7.15

(m, 2 Hcis), 7.13 (t, J = 7.6 Hz, 1 Htrans), 6.94 (t, J = 7.6 Hz, 1 Htrans), 6.45 (d, J = 8.1 Hz, 1

Htrans), 4.99 (d, J = 8.5 Hz, 1 Htrans), 4.85 (d, J = 7.3 Hz, 1 Hcis), 4.34 (dd, J = 6.8, 8.5 Hz,

1 Htrans), 3.71 (t, J = 7.2 Hz, 1 Hcis), 1.60 (d, J = 6.8 Hz, 3 Htrans), 1.32 (d, J = 7.3 Hz, 3

Hcis);

13C NMR (150 MHz, CDCl3): = 157.7, 149.9, 148.4, 143.1, 135.4, 133.4, 129.4, 129.3,

128.2, 127.6, 127.2, 126.6, 122.2, 122.0, 121.6, 118.3, 109.4, 79.1, 69.1, 56.2, 50.8, 18.7,

18.2;

93

IR (neat): 2916, 1615, 1470, 1247, 737 cm-1;


NMR Study for Sulfur-Fluorine Bond:

The Selectfluor (213 mg, 0.6 mmol) was added to the deuterated dimethylformamide in

NMR tube and 19F NMR was taken for Selectfluor. Then, 2-mercaptobenzimidazole (75

mg, 0.5 mmol) was added to the solution of Selectfluor in NMR tube and 19F NMR was

taken after 5 min, 30 min, 2 h, 6 h, 7 days. The intensity of new peak (38 ppm) was

increasing with time. The peak at 38 ppm indicates the S-F bond, and peak at -182 ppm is

responsible for BF4-.

94

5 mmol scale reaction:

The large-scale reaction was carried out according to the General Procedure A using

styrene (781 mg, 7.5 mmol), 2-mercaptobenzimidazole (750 mg, 5 mmol) and Selectfluor

(2125 mg, 6 mmol). After purification by column chromatography on SiO2 (30-50%

EtOAc in hexanes), the title compound was isolated as a white solid (828 mg, 66% yield,

>98:2 rr).

95

Chapter 4

Catalytic Regio- and Stereoselective Alkene

Sulfenoamination and Arene Sulfenylation for 1,4-

Benzothiazine Synthesis

4.1 Introduction

Alkene functionalization is an important strategy for the rapid construction of carbon-

carbon, carbon-heteroatom bond across the alkene, enabling the molecular complexity and

functional diversity of the molecule.25, 78, 109-113 In this regard, alkene difunctionalizations

such as oxyamination21, 24, diamination114, diarylation25, and carboamination28 have widely

been studied and well documented in the literature. On the other hand, alkene

sulfenoamination is a difficult process to achieve, hold significant potential for the

construction of N, S-containing molecule.42 A major challenge for this functionalization is

that the thiophilic nature of many metal catalysts often precludes the use of transition metal

for alkene sulfenoaminations.72, 115-116 Therefore, stable electrophilic sulfur reagents need

to be used for alkene activation and subsequent nucleophilic attack from another

heteroatom on the alkene can afford vicinal thioamine product.93-95 In this context,

Denmark and Shi groups have independently reported intramolecular and enantioselective

alkene thioamination for the synthesis of N-containing heterocycles.79, 81, 83, 117-118 In

addition, intermolecular sulfenoamination was achieved using nitriles as nucleophile.85-87

Despite their success on sulfenoamination of alkene, the construction of N, S-containing

96

Figure 4-1: Importance of 1,4-Benzothiazine Structural Motifs

heterocycles via alkene sulfenoamination from readily available feedstock chemicals like

alkene and unfunctionalized thiol-amine is still very rare, but highly desirable due to their

easy synthetic elaborations.

N- and S- containing heterocycles are ubiquitous structural motifs in natural

products and agrochemicals. Particularly, benzothiazine bearing N, S atoms, and its

derivatives are important scaffolds in commercially approved drugs (Figure 4-1).

Moreover, benzothiazine also plays a significant role in biological and pharmaceutical

processes.119-121 These compounds exhibit a wide variety of bioactivities such as

anticancer, antitumor, antimicrobial, antifungal, and neurodegenerative diseases, and KATP

channel openers.122 For example, Rufloxacin, a worldwide drug embedding benzothiazine

ring, has been used for bacterial infection.123 DHBT-NE-1 has been known to be relevant

in neurodegenerative diseases,124-125 and Promethazine, a first-generation antihistamine of

97

Scheme 4-1: Alkene Sulfenoamination Background for 1,4-Benzothiazine Synthesis

phenothiazine family, is used as a sedative and antiallergic medication.126 Additionally,

these structural units can also serve as photosensitizers for many organic transformations,

and ligands in metal-catalyzed reactions.127 Due to their significance in pharmaceuticals

and organic transformation, the syntheses of 1,4-benzothiazine have garnered enormous

98

attention among the medicinal and synthetic communities.128-131 Several methods have

been developed for the syntheses of benzothiazine.132-135 The traditional method involves

condensation of 2-aminothiophenol/its sodium salt with α-bromoacetophenone, followed

by reduction to get access 1,4-benzothiazine (Scheme 4-1a).134, 136-137 Alternatively, the o-

aminobenzenethiols can couple with various ketones in a radical pathway to afford the

unsaturated 1,4-benzothiazine.138 Moreover, Kumar group reported a two-step strategy

utilizing sulfenoacetoxylation of alkene, followed by TFA mediated cyclization to afford

1,4-benzothiazine (Scheme 4-1b).139 Jiang group developed an interesting strategy of

accessing benzothiazine, engaging Pd-catalyzed coupling of presynthesized diiodo

compound bearing tosyl protected amine with sodium thiosulfate as sulfurating agent.140

Gao group disclosed a one-pot protocol for the construction of benzothiazine from the

alkene, involving sufenoamination using N-sulfanylsuccinimides and sulfonamide,

followed by stoichiometric copper-mediated intramolecular cyclization (Scheme 4-1c).84

Nevertheless, most of the methods suffer from certain limitations, such as limited substrate

scope, Ts- or Ac-protected amine functionalities, strong acid, and stoichiometric transition

metal.141 The requirement of multistep syntheses and tedious procedure to get access

starting materials, make the methods less attractive to medicinal chemists for potential SAR

studies, and screening for various bioactivities.142-144 The development of an efficient and

convenient method utilizing unadorned 2-aminothiophenols and alkenes for accessing

structurally diverse 1,4-benzothiazine is in great demand.

As a part of our program to access bioactive heterocycles from the simple chemical

feedstock, we are interested in the utilization of alkene as building blocks for 1,4 -

benzothiazine synthesis. In our previous studies, we realized that halogen could activate a

99

thiol into an electrophilic sulfur reagent, enabling the alkene to thiiranium ion formation,

and then a subsequent nucleophilic attack of tethered amine on thiiranium intermediate or

carbocation would lead to cyclized product (Scheme 4-1d). We wondered whether in-situ

generated catalytic halogen source would be capable of thiol polarity inversion. Herein, we

report an iodide-catalyzed regioselective synthesis of 1,4-benzothiazine using simple

feedstock alkene and free thioamine (Scheme 4-1e). In addition, we also extend our

coupling protocol to achieve a highly versatile Csp2‒H sulfenylation of aniline derivatives,

to afford 1,4-benzothiazine structure that is complementary to the alkene coupling protocol.

4.2 Results and Discussions for 1,4-Benzothiazine Synthesis


With the aforementioned hypothesis in mind, our study was commenced with α-

methylstyrene as alkene partner, 2-aminothiophenol, sodium iodide (NaI), potassium

persulfate (K2S2O8) as an oxidant in 1,2-dichloroethane (DCE) at 80 ˚C. To our delight,

the reaction provided 1,4-benzothiazine in 10% yield with excellent regioselectivity (Table

4.1, entry 1). Further evaluation of reaction solvents revealed that acetonitrile (CH3CN)

was the superior solvent affording product 4-16 in 65% yield (Table 4.1, entries 2 and 3).

However, other oxidants were less effective to deliver the product (Table 4.1, entries 4 and

5). Interestingly, increasing stoichiometry of the alkene to 2.5 equiv provided the optimal

condition, affording the desired product in 98% yield (Table 4.1 entries 6 and 7). Screening

of different halides demonstrated that all halides could afford the product with comparable

yields (Table 4.1, entries 7-10). Further, increasing or decreasing the concentration resulted

in lower yields (Table 4.1, entries 11 and 12). Decreasing the halide loading or lowering

100

Table 4.1: Optimization for 1,4-Benzothiazine Synthesis

the temperature provided the product in diminished yields (Table 4.1, entries 13 and 14).

The control experiment demonstrated that only oxidant without halide could furnish the

101

product in a very low yield of 12%, and no product was observed in the absence of oxidant

in optimized condition (Table 4.1, entries 15 and16).

4.2.2 Substrate Scope

With optimized conditions in hand, we sought to explore the alkene substrate scope.

A range of 1,1-disubstituted styrene derivatives provided highly steric congested 1,4-

benzothiazines in excellent yields (Table 4.2, products 4-16 to 4-21). The regioselectivity

outcomes in these cases were identical to our previous sulfenoamination chemistry

involving thiiranium ion intermediate, in which sulfur attached to terminal carbon and

nitrogen added on benzylic carbon. Moreover, cross-coupling ready functional groups

such as bromo, fluoro, and methoxy were tolerated, affording the products in excellent

yields. The styrene with different functionalities and vinyl naphthalene proceeded

smoothly to afford desired products with high regioselectivities (Table 4.2, products 4-22

to 4-26). Both cis-, trans-1,2-disubstituted styrene participated in the reaction smoothly and

delivered the 1,4-benzothiazines with high diastereoselectivities (Table 4.2, products 4-27

to 4-29). Interestingly, trisubstituted alkene which is usually ineffective for most of the

alkene functionalization reactions, furnished products in good yields with excellent

diastereoselectivities (Table 4.2, products 4-30 and 4-31). The aliphatic monosubstituted

alkenes were also viable substrates to deliver the product with moderate regioselectivities

(Table 4.2, products 4-32 and 4-33). Finally, the complex steroid derived alkene resulted

in the product formation in good yield (Table 4.2, products 4-34).

Encouraged by these promising substrate scope of alkenes, we, then, turned our

attention to explore the thioamine substrate scope. A range of 2-aminothiophenol

102

Table 4.2: Alkene Substrate Scope for 1,4-Benzothiazine Synthesis

103

possessing different halogen substituents such as fluoro, chloro, and bromo performed well

and afforded the corresponding 1,4-benzothiazine products in nearly quantitative yields

(Table 4.3, products 4-35 to 4-38). In addition, pharmaceutically relevant trifluoromethyl

was tolerated and provided the product in excellent yield (Table 4.3, product 4-39). The 2-

aminothiophenol bearing electron-donating substituents were also viable substrates to

furnish the products in good yields (Table 4.3, products 4-40 and 4-41). Gratifyingly,

unprotected carboxylic acid substituent was tolerable in this reaction and furnished the 1,4-

benzothiazine in high yield with excellent regioselectivity (Table 4.3, product 4-42).

Furthermore, we could also synthesis 1,4-benzooxathiine when 2-hydroxythiophenol was

used as a substrate (Table 4.3, product 4-43). Finally, these substrates all uniformly

afforded a single regioisomeric product in good yields.

Table 4.3: Thioamine Substrate Scope for 1,4-Benzothiazine Synthesis

104

4.2.3 Substrate Scope for Arene Sulfenylation

While we were satisfied with the scope for alkene sulfenoamination reaction, we

were concerned by the modest regioselectivity of the aliphatic olefins in the reaction.

Fortuitously, during our studies toward thiomorpholine synthesis with the 2-

(phenylamino)ethane-1-thiol substrate shown in figure 4-2, we instead observed the 1,4-

benzothiazine product, in which the thiol cyclized intramolecularly via Csp2‒H

sulfenylation of the arene. Intrigued by this finding, we were delighted that this strategy

could provide complementary products comparable to the alkene sulfenoamination

protocol of aliphatic olefins. In the case of 4-44, the structure is equivalent to the product

derived from the coupling of ethylene with 2-aminothiophenol in the alkene

Figure 4-2: Unexpected Csp2‒H Sulfenylation

105

sulfenoamination. Excited by this result, we decided to examine the preliminary scope of

this method. Simply removing the olefin from the reaction and with a slight increase in

catalyst loading resulted in the formation of product 4-44 in high yield. With this modified

procedure, we screened a number of thioamine structures. This sulfenylation protocol

impressively tolerated highly substituted carbon centers and tertiary aniline structure

(Table 4.4, products 4-45 to 4-48). In addition, different functional groups with varying

electronic nature all proceeded smoothly (Table 4.4, products 4-49 to 4-52). Notably,

diastereoselectivity could be completely transferred from the thioamine starting material

to the 1,4-benzothiazine as demonstrated in the case of product 4-46. Interestingly, when

the ortho-positions of the benzene ring were blocked, the thioamine substrate 4-53 could

Table 4.4: Substrate Scope for C-H Sulfenylation of Arene

106

then participate in the alkene sulfenoamintion reaction (Figure 4-3). In this case, a

sterically encumbered product 4-54 was formed as a single regioisomer. Further studies

of this thiomorpholine synthesis protocol are currently underway in our laboratory.

Figure 4-3: Synthesis of Thiomorpholine


In order to gain insight into the reaction mechanism, first, we considered the

regiochemical outcome of the reaction. For the styrene derived substrates, nitrogen was

attached to the benzylic position whereas the sulfur was attached to the terminal carbon.

This regiochemical feature is distinct from the previously developed alkene

sulfenoamination based on halogenation of alkene in which more nucleophilic sulfur was

added to the benzylic position. This regioselectivity suggests that reaction can go through

either radical or thiiranium pathway. To further understand the mechanism, several control

experiments were performed as shown in scheme 4-2. When the standard reaction was

carried out with α-cycloproylstyrene, cyclopropane ring intact product 4-55 was obtained

in 12% suggesting the polar pathway was operative (Scheme 4-2a). We also observed a

complex mixture of ring-opening adducts from the product isolation. Moreover, when the

107

Scheme 4-2: Mechanistic Experiments for 1,4-Benzothiazine Synthesis

reaction was performed using disulfide as a thioamine structure 4-56, the desired product

4-16 was observed in a comparable 70% yield, which indicates that active catalytic halogen

source is capable of cleaving the S-S bond to form sulfur electrophile (Scheme 4-2b). Our

control experiments revealed that in the absence of the oxidant, the iodide salt could also

promote disulfide 4-56 for product formation to 12 % yield, and in the absence of NaI, less

than 2% product was observed. Moreover, when TEMPO was added to the standard

reaction as a free radical scavenger, the percentage of yield for product formation was

decreasing with the increasing amount of TEMPO (Scheme 4-2c). These results further

support the radical pathways for product formation. It is noteworthy that only oxidant could

afford benzothiazine in 12% (Table 4.1, entry 15) which again confirmed the radical

108

Scheme 4-3: Proposed Reaction Mechanism

process might be involved in the reaction. Hence, the radical trapping experiment could

not completely inhibit the formation of 1,4-benzothiazine, we cannot rule out the ionic

thiiranium ion intermediate for product formation.

Based on the experimental results and literature reports, two potential mechanisms are

proposed in the Scheme 4-3. Initially, sodium iodide is oxidized by potassium persulfate to

generate iodine which can react with thioamine to generate sulfur electrophile A. The

intermediate A then undergoes electrophilic attack on alkene to form the thiiranium ion B.

The thiiranium ion can be in equilibrium with the open carbocation C which can then be

trapped by the tethered nucleophile to provide the final heterocyclic product. Alternatively,

pathway B from intermediate A involves homolytic cleavage of sulfur iodine bond to thiyl

109

radical D. The radical intermediate D combines with the alkene to generate more stable

benzylic radical E which can undergo single electron transfer from oxidant to produce

carbocation C. Finally, the intramolecular cyclization on the carbocation leads to desired

product 4-22.

4.4 Conclusion

We have developed an iodide-catalyzed regioselective alkene sulfenoamination for

1,4-benzothiazine synthesis from free thioamine. A wide range of alkenes and thioamine

with a variety of functional groups are tolerable with the reaction conditions. We have also

demonstrated that disulfide is a viable substrate for this protocol. We have discovered an

arene ortho sulfenylation reaction to afford 1,4-benzothiazine. The feasibility of this

catalytic strategy towards thiomorpholine synthesis is also validated. Finally, the

mechanistic experiment demonstrates that both thiiraniun and radical pathways are

operative in our reaction protocol.

4.5 Experimental



as received. The thioamine substrates for products 4-35 to 4-37, 4-40 to 4-42 were

synthesized according to reported procedure.145 The alkene substrates for products 4-30

and 4-31 were synthesized according to reported procedure.146 Organic solutions were

concentrated under reduced pressure on a Büchi rotary evaporator using an acetone-dry ice

bath. Chromatographic purification of products was accomplished using flash

110

chromatography on 230-400 mesh silica gel. Thin-layer chromatography (TLC) was

performed on Analtech 250 mm silica gel HLF UV-254 plates. Visualization of the

developed plates was performed by fluorescence quenching, potassium permanganate and

iodine-silica gel system. 1H and 13C NMR spectra were recorded on a Bruker 600

instrument (600 and 150 MHz) or INOVA 600 (600 and 150 MHz) and are internally

referenced to residual protio solvent signals (for CDCl3, 7.26 and 77.0 ppm, respectively).

Data for 1H NMR are reported as follows: chemical shift ( ppm), multiplicity (s = singlet,

d = doublet, t = triplet, q = quartet, h = heptet, m = multiplet, br = broad), integration,

coupling constant (Hz). 13C spectra were reported as chemical shifts in ppm and

multiplicity where appropriate. IR spectra were recorded on a PerkinElmer FT-IR

spectrophotometer and are reported in terms of wavenumber of absorption (cm-1). High

resolution mass spectra were obtained on Waters Synapt High Definition Mass

Spectrometer (HDMS) by electrospray ionization at The University of Toledo, OH, USA

and University of Cincinnati, OH, USA.


General Procedure A: The alkene (0.625 mmol) and 2-aminothiophenol (0.375 mmol)

were added to the solution of NaI (10 mol%, 3.7 mg) in acetonitrile (4 mL). Then, the

K2S2O8 (0.25 mmol, 67.6 mg) was added to the reaction mixture and stirred at 80 ºC for 16

h. The reaction was quenched with saturated NaHCO3 (1 mL), 20% Na2S2O3 (1 mL) and

EtOAc (2 mL) was added. The organic layer was separated, and aqueous layer was

extracted with EtOAc (2 x 2 mL). The combined organic solution was dried with anhydrous

Na2SO4, filtered, concentrated in vacuo by rotavapor and purified by flash Chromatography

111

on SiO2 (5%-10% EtOAc in hexanes or 10%-30% DCM in hexanes) to provide the desired

product. The regioisomeric ratio was determined by crude NMR.

General Procedure B for Arene Sulfenylation: The thioamine (0.325 mmol) were added

to the solution of NaI (20 mol%, 7.5 mg) in acetonitrile (2.5 mL). Then, the K2S2O8 (0.25

mmol, 67.6 mg) was added to the reaction mixture and stirred at 80 ºC for 16 h. The reaction

was quenched with saturated NaHCO3 (1 mL), 20% Na2S2O3 (1 mL) and EtOAc (2 mL)

was added. The organic layer was separated, and aqueous layer was extracted with EtOAc

(2 x 2 mL). The combined organic solution was dried with anhydrous Na2SO4, filtered,

concentrated in vacuo by rotavapor and purified by flash chromatography on SiO2 (5%-

10% EtOAc in hexanes or 10%-30% DCM in hexanes) to provide the desired product. The

regioisomeric ratio was determined by crude NMR.

Procedure for synthesis of N-arylthioamine substrates:

The aniline (25 mmol) was added to the solution of sulfide (20 mmol) in ethanol (0.5 M,

40 mL) stirred at 35 ºC for 16 h. The ethanol was concentrated in vacuo by rotavapor and

product was purified by flash chromatography on SiO2 (5%-10% EtOAc in hexanes) to

provide the desired product. For cyclohexane sulfide, the reaction was run at 50 ºC for 36

h. The purified products were characterized by NMR techniques.

112

Spectral Characterization of the Products

3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-16): This compound was

prepared according to the General Procedure A using α-methylstyrene (74 mg, 0.625

mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol). After purification by column

chromatography on SiO2 (10% DCM in hexanes), the title compound was isolated as a


1H NMR (600 MHz, CDCl3): = 7.45-7.40 (m, 2 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.30-7.25

(m, 1 H), 7.03-6.94 (m, 2 H), 6.67-6.58 (m, 2 H), 4.19 (br. s., 1 H), 3.14 (d, J = 12.7 Hz, 1

H), 2.94 (d, J = 12.7 Hz, 1 H), 1.70 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 146.8, 141.1, 128.5, 127.6, 127.1, 125.7, 125.4, 117.7,

115.1, 114.6, 54.6, 37.8, 29.3;

IR (neat): IR (neat): 3413, 2930, 1588, 1442, 750 cm-1;


3-isopropyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-17): This compound

was prepared according to the General Procedure A using α-isopropylstyrene (91 mg, 0.625



113


1H NMR (600 MHz, CDCl3): = 7.32-7.19 (m, 5 H), 6.95 (t, J = 7.6 Hz, 1 H), 6.90 (d, J

= 7.6 Hz, 1 H), 6.67 (d, J = 8.1 Hz, 1 H), 6.57 (t, J = 7.4 Hz, 1 H), 4.32 (br. s., 1 H), 3.30

(d, J = 12.7 Hz, 1 H), 3.08 (d, J = 12.7 Hz, 1 H), 2.31-2.21 (m, 1 H), 1.03 (d, J = 6.8 Hz, 3

H), 0.81 (d, J = 7.1 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 145.2, 141.3, 128.2, 127.6, 126.6, 126.2, 125.6, 117.5,

115.3, 115.0, 60.8, 38.4, 33.7, 17.6, 16.7;

IR (neat): 3407, 2947, 1590, 1473, 747 cm-1 ,


3,3-diphenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-18): This compound was

prepared according to the General Procedure A using α-phenylstyrene (113 mg, 0.625




1H NMR (600 MHz, CDCl3): = 7.37-7.25 (m, 10 H), 6.99-6.92 (m, 2 H), 6.66-6.59 (m,

2 H), 4.58 (s, 1 H), 3.55 (s, 2 H);

13C NMR (150 MHz, CDCl3): = 145.4, 141.0, 128.4, 127.5, 127.4, 127.1, 125.5, 118.0,

115.3, 114.8, 61.3, 35.8;

IR (neat): 3402, 2937, 1589, 1474, 695 cm-1;


114

3-(4-fluorophenyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-19): This

compound was prepared according to the General Procedure A using 4-fluoro-α-

methylstyrene (85 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol). After

purification by column chromatography on SiO2 (10% DCM in hexanes), the title

compound was isolated as a white solid (53 mg, 81% yield).


H), 4.16 (br. s., 1 H), 3.10 (d, J = 12.7 Hz, 1 H), 2.94 (d, J = 12.7 Hz, 1 H), 1.70 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 162.6, 160.9, 142.6, 140.9, 127.6, 127.2, 127.2, 125.8,

117.9, 115.3, 115.2, 115.1, 114.5, 54.4, 37.8, 29.6;

IR (neat): 3406, 2976,1589, 1475, 740 cm-1;


3-(4-bromophenyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-20): This

compound was prepared according to the General Procedure A using 4-bromo-α-

methylstyrene (123 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol). After




6.93 (m, 2 H), 6.67-6.57 (m, 2 H), 4.15 (br. s., 1 H), 3.07 (d, J = 12.7 Hz, 1 H), 2.93 (d, J

115

= 12.7 Hz, 1 H), 1.66 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 145.9, 140.7, 131.5, 127.6, 127.3, 125.8, 121.0, 117.9,

115.2, 114.4, 54.6, 37.4, 29.7;

IR (neat): 3400, 2912, 1588, 1473, 748 cm-1


3-(4-methoxyphenyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-21): This

compound was prepared according to the General Procedure A using 4-methoxy-α-

methylstyrene (93 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol) and

benzoyl peroxide (75% pure, 81 mg, 0.25 mmol). After purification by column

chromatography on SiO2 (5% EtOAc in hexanes), the title compound was isolated as a

yellow gummy solid (44 mg, 65% yield).

1H NMR (600 MHz, CDCl3): = 7.37-7.31 (m, J = 8.8 Hz, 2 H), 7.02 (d, J = 7.6 Hz, 1

H), 6.99-6.94 (m, 1 H), 6.90-6.84 (m, J = 8.5 Hz, 2 H), 6.64 (t, J = 7.4 Hz, 1 H), 6.59 (d, J

= 8.1 Hz, 1 H), 4.16 (br. s., 1 H), 3.80 (s, 3 H), 3.11 (d, J = 12.7 Hz, 1 H), 2.91 (d, J = 12.7

Hz, 1 H), 1.69 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 158.5, 141.2, 138.9, 127.5, 126.6, 125.6, 117.7, 115.2,

114.5, 113.7, 55.2, 54.0, 38.0, 29.2;

IR (neat): 3373, 2929, 1588, 1509, 742 cm-1;


116

3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-22): This compound was prepared


aminobenzenethiol (40 μL, 0.375 mmol), NaI (20 mol%, 7.5 mg) for 16 h. After


compound was isolated as a colorless liquid (29 mg, 51% yield). The spectral data match

with literature134.

1H NMR (600 MHz, CDCl3): = 7.45-7.31 (m, 5 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.98-6.90

(m, 1 H), 6.71-6.64 (m, 1 H), 6.57-6.50 (m, 1 H), 4.68 (dd, J = 2.2, 9.0 Hz, 1 H), 4.13 (br.

s., 1 H), 3.18 (dd, J = 9.0, 12.5 Hz, 1 H), 3.04-2.98 (m, 1 H);

13C NMR (150 MHz, CDCl3): = 142.8, 142.2, 128.9, 128.2, 127.4, 126.7, 125.6, 118.3,

115.4, 115.3, 56.1, 33.1;

IR (neat): 3384, 2921, 1590, 1476, 697 cm-1;


3-(4-fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-23): This compound was

prepared according to the General Procedure A using 4-fluorostyrene (76 mg, 0.625 mmol),

2-aminobenzenethiol (40 μL, 0.375 mmol), NaI (20 mol%, 7.5 mg) for 16 h. After


117

compound was isolated as a yellow solid (29 mg, 47% yield). The spectral data match with

literature.136

1H NMR (600 MHz, CDCl3): = 7.34 (dd, J = 6.1, 7.3 Hz, 2 H), 7.10-7.04 (m, 3 H), 6.94

(t, J = 7.6 Hz, 1 H), 6.68 (t, J = 7.6 Hz, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 4.68 (d, J = 8.5 Hz,

1 H), 4.10 (br. s., 1 H), 3.17-3.08 (m, 1 H), 2.98 (d, J = 12.5 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 163.3, 161.7, 142.0, 138.6, 138.6, 128.3, 128.3, 127.5,

125.7, 118.5, 115.8, 115.7, 115.4, 115.3, 55.4, 33.1.

3-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-24): This compound

was prepared according to the General Procedure A using 4-methoxystyrene (84 mg, 0.625

mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol), benzoyl peroxide (75% pure, 81 mg,

0.25 mmol), NaI (20 mol%, 7.5 mg) for 16 h. After purification by column chromatography

on SiO2 (5% EtOAc in hexanes), the title compound was isolated as a yellow solid (32 mg,

50% yield). The spectral data match with literature.134


- 6.90 (m, 3 H), 6.67 (t, J = 7.6 Hz, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 4.62 (dd, J = 2.0, 9.3

Hz, 1 H), 4.08 (br. s., 1 H), 3.83 (s, 3 H), 3.15 (dd, J = 9.3, 12.5 Hz, 1 H), 3.01-2.93 (m, 1

H);

13C NMR (150 MHz, CDCl3): = 159.4, 142.3, 134.9, 127.8, 127.4, 125.5, 118.2, 115.3,

115.3, 114.2, 55.5, 55.3, 33.1.

118

4-(3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)phenyl acetate (4-25): This compound

was prepared according to the General Procedure A using 4-acetoxystyrene (101 mg, 0.625

mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol), NaI (20 mol%, 7.5 mg) for 16 h. After

purification by column chromatography on SiO2 (5% EtOAc in hexanes), the title

compound was isolated as a yellow solid (41 mg, 57% yield).

1H NMR (600 MHz, CDCl3): = 7.39 (d, J = 8.3 Hz, 2 H), 7.14 - 7.03 (m, 3 H), 6.94 (t,

J = 7.6 Hz, 1 H), 6.68 (t, J = 7.4 Hz, 1 H), 6.52 (d, J = 7.8 Hz, 1 H), 4.68 (d, J = 8.5 Hz, 1

H), 4.13 (br. s., 1 H), 3.15 (dd, J = 8.5, 12.3 Hz, 1 H), 3.00 (d, J = 12.3 Hz, 1 H), 2.32 (s,

3 H);

13C NMR (150 MHz, CDCl3): = 169.5, 150.4, 142.0, 140.3, 127.8, 127.4, 125.6, 122.0,

118.4, 115.3, 115.3, 55.5, 33.0, 21.1;

IR (neat): 3393, 2924, 1760, 1588, 1477, 743 cm-1;


3-(naphthalen-1-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-26): This compound was

prepared according to the General Procedure A using 2-vinylnaphthalene (96 mg, 0.625



119

compound was isolated as a yellow gummy solid (47 mg, 68% yield). The spectral data

match with literature.136


Hz, 1 H), 7.01-6.95 (m, 1 H), 6.71 (t, J = 7.6 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 4.85 (dd,

J = 2.0, 9.0 Hz, 1 H), 4.24 (s, 1 H), 3.27 (dd, J = 9.0, 12.5 Hz, 1 H), 3.07 (d, J = 12.5 Hz,

1 H);

13C NMR (150 MHz, CDCl3): = 142.2, 140.1, 133.3, 133.2, 128.7, 127.9, 127.7, 127.5,

126.4, 126.2, 125.7, 125.6, 124.5, 118.3, 115.4, 115.4, 56.2, 33.0.

Trans-2-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-27): This

compound was prepared according to the General Procedure A using trans-β-

methylstyrene (74 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol), NaI (20

mol%, 7.5 mg) for 16 h. After purification by column chromatography on SiO2 (10% DCM

in hexanes), the title compound was isolated as a white solid (13 mg, 22% yield, >95:5 dr).

1H NMR (600 MHz, CDCl3): = 7.42-7.30 (m, 5 H), 7.06 (d, J = 7.8 Hz, 1 H), 6.92 (t, J


H), 4.12 (br. s., 1 H), 3.33 (quin, J = 7.1 Hz, 1 H), 1.08 (d, J = 6.8 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 142.0, 141.4, 128.8, 128.4, 127.6, 126.9, 125.4, 118.3,

116.8, 114.7, 63.1, 39.4, 18.0;

IR (neat): 3371, 2923, 1590, 1480,739 cm-1;


120

Trans-(4-methoxyphenyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-28):

This compound was prepared according to the General Procedure A using 4-methoxy-

trans-β-methylstyrene (93 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol),

NaI (20 mol%, 7.5 mg) for 16 h. After purification by column chromatography on SiO2

(5% EtOAc in hexanes), the title compound was isolated as a white solid (27 mg, 40%

yield, >95:5 dr).


6.85 (m, 3 H), 6.64 (t, J = 7.4 Hz, 1 H), 6.48 (d, J = 7.8 Hz, 1 H), 4.10 (d, J = 8.3 Hz, 1 H),

4.05 (br. s., 1 H), 3.81 (s, 3 H), 3.30-3.23 (m, 1 H), 1.04 (d, J = 6.8 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 159.5, 142.1, 133.4, 128.6, 126.8, 125.3, 118.2, 116.9,

114.7, 114.1, 62.5, 55.3, 39.5, 17.9;

IR (neat): 3344, 2961, 1589, 1455, 1242, 743 cm-1;


Cis-4b,5,10a,11-tetrahydrobenzo[b]indeno[1,2-e][1,4]thiazine (4-29): This compound

was prepared according to the General Procedure A using indene (73 mg, 0.625 mmol), 2-



121

compound was isolated as a brown solid (30 mg, 50% yield, >95:5 dr).


J = 1.2, 7.6 Hz, 1 H), 6.98-6.91 (m, 1 H), 6.70-6.60 (m, 2 H), 4.92 (d, J = 5.1 Hz, 1 H),

4.38 (br. s., 1 H), 3.91-3.81 (m, 1 H), 3.34 (dd, J = 6.3, 16.0 Hz, 1 H), 3.02 (dd, J = 4.3,

16.0 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 144.2, 142.4, 140.6, 128.1, 128.1, 127.1, 126.0, 125.4,

123.8, 118.6, 117.8, 115.5, 60.8, 42.9, 38.3;

IR (neat): 3340, 2922, 1590, 1479, 744 cm-1;


Trans-2,3-dimethyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-30) This

compound was prepared according to the General Procedure A using trans-but-2-en-2-

ylbenzene (83 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol). After


compounds were isolated as white gummy solid (48 mg, 75% yield, >95:5 dr).

1H NMR (600 MHz, CDCl3): =7.47 (d, J = 7.8 Hz, 2 H), 7.37 (t, J = 7.6 Hz, 2 H), 7.32-

7.27 (m, 1 H), 7.02 (d, J = 7.6 Hz, 1 H), 6.98-6.92 (m, 1 H), 6.67 (t, J = 7.4 Hz, 1 H), 6.57

(d, J = 8.1 Hz, 1 H), 4.14 (br. s., 1 H), 3.43 (q, J = 6.8 Hz, 1 H), 1.61 (s, 3 H), 1.11 (d, J =

6.8 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 146.3, 141.0, 128.5, 127.3, 127.1, 126.0, 125.3, 117.8,

115.7, 115.1, 57.2, 43.1, 22.5, 16.5;

122

IR (neat): 3403, 2934, 1590, 1474, 739 cm-1;

HRMS (ESI) for m/z calcd for C16H18NS [(M+H)+] 256.1160, found 256.1152.

Trans-3-methyl-3-phenyl-2-propyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-31): This

compound was prepared according to the General Procedure A using trans-hex-2-en-2-

ylbenzene (100 mg, 0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol). After


compounds were isolated as white solid (47 mg, 66% yield, >95:5 dr).


(m, 1 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.98-6.91 (m, 1 H), 6.69-6.63 (m, 1 H), 6.55 (d, J = 8.1

Hz, 1 H), 4.12 (s, 1 H), 3.29 (dd, J = 2.6, 10.9 Hz, 1 H), 1.63 (s, 3 H), 1.60-1.51 (m, 1 H),

1.43-1.34 (m, 1 H), 1.34-1.16 (m, 2 H), 0.80 (t, J = 7.3 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 146.5, 141.1, 128.4, 127.3, 127.3, 126.1, 125.3, 117.7,

115.5, 115.0, 57.3, 49.0, 32.2, 23.0, 20.7, 13.7;

IR (neat): 3423, 2950, 1592, 1478, 968 cm-1;


2-hexyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-32): This compound was prepared

according to the General Procedure A using octene (70 mg, 0.625 mmol), 2-

123


purification by column chromatography on SiO2 (10% DCM in hexanes), the inseparable

mixture of two regioisomers was isolated as a red gummy solid (21 mg, 36% yield, 2.5:1

rr).

1H NMR (600 MHz, CDCl3): = 7.02-6.96 (m, 1 Hmajor + 1 Hminor ), 6.91-6.85 (m, 1 Hmajor

+ 1 Hminor), 6.64-6.58 (m, 1 Hmajor + 1 Hminor), 6.50-6.44 (m, 1 Hmajor + 1 Hminor), 3.95 (br.

s., 1 Hmajor + 1 Hminor), 3.66-3.57 (m, 1 Hmajor), 3.56-3.47 (m, 1 Hminor), 3.31-3.18 (m, 2

Hmajor), 2.95 (dd, J = 2.4, 12.5 Hz, 1 Hminor), 2.82 (dd, J = 8.1, 12.2 Hz, 1 Hminor), 1.69-1.55

(m, 2 Hmajor + 2 Hminor), 1.54-1.38 (m, 2 Hmajor + 2 Hminor), 1.38-1.28 (m, 5 Hmajor + 4 Hminor),

1.28-1.15 (m, 1 Hmajor + 2 Hminor), 0.95-0.78 (m, 3 Hmajor + 3 Hminor);

13C NMR (150 MHz, CDCl3): = 141.5, 127.5, 127.4, 125.5, 125.2, 118.2, 117.9, 116.5,

115.2, 115.0, 51.3, 47.7, 39.6, 36.4, 33.6, 31.7, 31.7, 30.7, 29.2, 29.1, 26.8, 25.5, 22.6, 14.1;

IR (neat): 3406, 2924, 1591, 1484, 740 cm-1;


2-phenethyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-33): This compound was

prepared according to the General Procedure A using 4-phenyl-1-butene (83 mg, 0.625



compound was isolated as a colorless liquid (28 mg, 44% yield, 2.5:1 rr).

124

1H NMR (600 MHz, CDCl3) for major: = 7.33-7.27 (m, 2 H), 7.25-7.18 (m, 3 H), 7.01


1 H), 3.96 (br. s., 1 H), 3.63 (d, J = 11.7 Hz, 1 H), 3.31 (dd, J = 7.3, 11.7 Hz, 1 H), 3.25-

3.17 (m, 1 H), 2.87 (td, J = 7.1, 13.9 Hz, 1 H), 2.83-2.73 (m, 1 H), 2.04-1.92 (m, 2 H);

13C NMR (150 MHz, CDCl3) for major: = 141.4, 141.2, 128.5, 128.4, 127.6, 126.0,

125.3, 118.2, 116.0, 115.0, 47.6, 38.7, 35.3, 32.9;

IR (neat) for major: 3390, 2925, 1587, 1492, 742 cm-1;

HRMS (ESI) for major m/z calcd for C16H18NS [(M+H)+] 256.1160, found 256.1158.

1H NMR (600 MHz, CDCl3) for minor: = 7.33-7.28 (m, 2 H), 7.24-7.20 (m, 3 H), 6.99


1 H), 3.87 (br. s., 1 H), 3.59 (d, J = 6.1 Hz, 1 H), 2.99 (dd, J = 2.6, 12.3 Hz, 1 H), 2.86 (dd,

J = 7.4, 12.3 Hz, 1 H), 2.82-2.71 (m, 2 H), 2.01-1.88 (m, 2 H);

13C NMR (150 MHz, CDCl3) for minor: = 141.4, 141.1, 128.6, 128.3, 127.4, 126.2,

125.5, 118.0, 115.7, 115.4, 50.7, 37.7, 32.0, 30.6;

IR (neat) for minor: 3400, 2921, 1589, 1498, 750 cm-1;

HRMS (ESI) for minor m/z calcd for C16H18NS [(M+H)+] 256.1160, found 256.1158.

(8R,9S,13S,14S,17S)-2-(3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-13-methyl-

7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl pivalate

(4-34): This compound was prepared according to the General Procedure A using

125

(8R,9S,13S,14S,17S)-13-methyl-2-vinyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-

cyclopenta[a]phenanthren-17-yl pivalate (229 mg, 0.625 mmol), 2-aminobenzenethiol (40

μL, 0.375 mmol), NaI (20 mol%, 7.5 mg) for 16 h. After purification by column


white solid (61 mg, 50% yield, 1:1 dr).


(s, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.95-6.89 (m, 1 H), 6.66 (t, J = 7.4 Hz, 1 H), 6.50 (d, J

= 8.1 Hz, 1 H), 4.67 (t, J = 8.4 Hz, 1 H), 4.60 (dd, J = 2.0, 9.0 Hz, 1 H), 4.08 (br. s., 1 H),

3.21-3.13 (m, 1 H), 2.98 (d, J = 12.5 Hz, 1 H), 2.92-2.85 (m, 2 H), 2.37-2.17 (m, 3 H),

1.96-1.84 (m, 2 H), 1.81-1.71 (m, 1 H), 1.56-1.45 (m, 3 H), 1.45-1.36 (m, 3 H), 1.35-1.27

(m, 1 H), 1.21 (s, 9 H), 0.88-0.81 (m, 3 H);

13C NMR (150 MHz, CDCl3): = 178.6, 142.3, 140.4, 140.0, 140.0, 137.3, 127.4, 127.2,

125.9, 125.5, 124.0, 123.9, 118.2, 118.2, 115.4, 115.3, 115.2, 82.2, 55.9, 55.8, 49.8, 44.2,

44.2, 43.0, 38.9, 38.3, 38.3, 36.9, 33.1, 29.6, 29.5, 27.5, 27.2, 27.1, 26.0, 26.0, 23.3, 12.1;

IR (neat): 3344, 2922, 1722, 1590, 1478, 743 cm-1;


7-fluoro-3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-35): This


mg, 0.625 mmol), 2-amino-5-fluorobenzenethiol (54 mg, 0.375 mmol). After purification

by column chromatography on SiO2 (10% DCM in hexanes), the title compound was

126

isolated as a purple solid (64 mg, 99% yield).


(m, 1 H), 6.76 (dd, J = 2.7, 8.8 Hz, 1 H), 6.70 (dt, J = 2.7, 8.4 Hz, 1 H), 6.55 (dd, J = 4.8,

8.8 Hz, 1 H), 4.11 (br. s., 1 H), 3.17 (d, J = 12.7 Hz, 1 H), 2.96 (d, J = 12.7 Hz, 1 H), 1.70

(s, 3 H);

13C NMR (150 MHz, CDCl3): = 156.1, 154.5, 146.5, 137.3, 128.5, 127.2, 125.3, 116.0,

115.8, 115.7, 113.6, 113.4, 112.6, 112.4, 54.3, 37.6, 29.2;

IR (neat): 3398, 2925, 1577,1476, 799, 698 cm-1;


7-chloro-3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-36): This


mg, 0.625 mmol), 2-amino-5-chlorobenzenethiol (60 mg, 0.375 mmol). After purification


isolated as a white solid (65 mg, 94% yield).


Hz, 1 H), 6.92 (dd, J = 2.2, 8.5 Hz, 1 H), 6.54 (d, J = 8.5 Hz, 1 H), 4.22 (s, 1 H), 3.14 (d, J

= 12.7 Hz, 1 H), 2.94 (d, J = 12.7 Hz, 1 H), 1.71 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 146.3, 139.7, 128.6, 127.2, 126.7, 125.5, 125.3, 122.0,

116.3, 116.0, 54.6, 37.5, 29.4;

IR (neat): 3407, 2928, 1580,1475,797, 698 cm-1;

127


7-bromo-3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-37): This


mg, 0.625 mmol), 2-amino-5-bromobenzenethiol (77 mg, 0.375 mmol). After purification



1H NMR (600 MHz, CDCl3): =7.42-7.33 (m, 4 H), 7.32-7.27 (m, 1 H), 7.13 (s, 1 H),

7.05 (dd, J = 2.0, 8.5 Hz, 1 H), 6.49 (d, J = 8.5 Hz, 1 H), 4.23 (br. s., 1 H), 3.13 (d, J = 12.7

Hz, 1 H), 2.93 (d, J = 12.7 Hz, 1 H), 1.71 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 146.3, 140.1, 129.5, 128.6, 128.3, 127.2, 125.2, 116.8,

116.4, 108.9, 54.6, 37.5, 29.4;

IR (neat): 3400, 2968, 1576, 1474, 799 cm-1;


6-chloro-3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-38): This


mg, 0.625 mmol), 2-amino-4-chlorobenzenethiol (60 mg, 0.375 mmol). After purification

128




H), 6.64-6.59 (m, 2 H), 4.27 (s, 1 H), 3.13 (d, J = 12.7 Hz, 1 H), 2.93 (d, J = 12.7 Hz, 1 H),

1.72 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 146.3, 142.0, 130.8, 128.6, 128.5, 127.2, 125.3, 117.6,

114.5, 113.0, 54.7, 37.6, 29.4;

IR (neat): 3402, 2920, 1577, 1474, 792, 698 cm-1;


3-methyl-3-phenyl-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-39):

This compound was prepared according to the General Procedure A using α-methylstyrene

(74 mg, 0.625 mmol), 2-amino-4-(trifluoromethyl)benzenethiol hydrochloride (86 mg,

0.375 mmol). After purification by column chromatography on SiO2 (10% DCM in

hexanes), the title compound was isolated as a white solid (76 mg, 98% yield).


Hz, 1 H), 6.90-6.83 (m, 2 H), 4.40 (s, 1 H), 3.19 (d, J = 12.7 Hz, 1 H), 2.97 (d, J = 12.7 Hz,

1 H), 1.74 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 146.1, 141.0, 128.6, 127.9, 127.8, 127.7, 127.3, 125.2,

125.1, 123.3, 119.2, 114.0, 114.0, 113.9, 113.9, 111.4, 111.4, 111.4, 111.4, 54.7, 37.5, 29.4;

IR (neat): 3406, 2927, 1600, 1482, 1071, 864, 701 cm-1;

129


7-methoxy-3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-40): This


mg, 0.625 mmol), 2-amino-5-methoxybenzenethiol (58 mg, 0.375 mmol). After


compound was isolated as a yellow gummy solid (47 mg, 69% yield).


(d, J = 7.3 Hz, 1 H), 6.63 - 6.54 (m, 3 H), 3.96 (s, 1 H), 3.72 (s, 3 H), 3.18 (d, J = 12.7 Hz,

1 H), 2.96 (d, J = 12.7 Hz, 1 H), 1.68 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 151.9, 146.8, 135.1, 128.5, 127.0, 125.4, 116.4, 115.6,

112.8, 111.7, 55.7, 54.2, 37.9, 29.2;

IR (neat): 3375, 2924, 1600, 1491, 697 cm-1;


3,6,7-trimethyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-41): This


mg, 0.625 mmol), 2-amino-4,5-dimethylbenzenethiol (57 mg, 0.375 mmol). After


130

compound was isolated as a yellow gummy solid (65 mg, 97% yield).


(d, J = 7.3 Hz, 1 H), 6.81 (s, 1 H), 6.47 (s, 1 H), 4.05 (br. s., 1 H), 3.14 (d, J = 12.7 Hz, 1

H), 2.93 (d, J = 12.7 Hz, 1 H), 2.20 (s, 3 H), 2.15 (s, 3 H), 1.71 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 147.0, 138.9, 134.1, 128.4, 128.2, 127.0, 126.0, 125.4,

116.6, 111.2, 54.4, 38.0, 29.2, 19.4, 18.6;

IR (neat): 3281, 2920, 1600, 1481, 744 cm-1;


3-methyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (4-42):

This compound was prepared according to the General Procedure A using α-methylstyrene

(74 mg, 0.625 mmol), 4-amino-3-mercaptobenzoic (63 mg, 0.375 mmol). After


compound was isolated as a yellow solid (60 mg, 84% yield).

1H NMR (600 MHz, CDCl3): = 7.82 (s, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 7.40-7.33 (m, 4

H), 7.32-7.27 (m, 1 H), 6.61 (d, J = 8.5 Hz, 1 H), 4.77 (br. s., 1 H), 3.12 (d, J = 12.7 Hz, 1

H), 2.95 (d, J = 12.7 Hz, 1 H), 1.79-1.72 (m, 3 H);

13C NMR (150 MHz, CDCl3): = 171.6, 146.0, 145.8, 130.6, 128.7, 128.5, 127.4, 125.2,

118.1, 114.1, 114.0, 55.6, 37.5, 29.5;

IR (neat): 3371, 2924, 1656, 1560, 1251, 697 cm-1;


131

2-methyl-6-nitro-2-phenyl-2,3-dihydrobenzo[b][1,4]oxathiine (4-43): This compound

was prepared according to the General Procedure A using α-methylstyrene (74 mg, 0.625

mmol), 2-mercapto-4-nitrophenol (64 mg, 0.375 mmol). After purification by column


yellow gummy solid (57 mg, 79% yield).

1H NMR (600 MHz, CDCl3): = 7.98 (d, J = 2.4 Hz, 1 H), 7.94 (dd, J = 2.4, 9.0 Hz, 1

H), 7.37 (d, J = 4.2 Hz, 4 H), 7.32 (dd, J = 4.2, 8.3 Hz, 1 H), 7.08 (d, J = 9.0 Hz, 1 H), 3.33

(d, J = 13.7 Hz, 1 H), 3.20 (d, J = 13.7 Hz, 1 H), 1.79 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 155.9, 143.2, 141.5, 128.7, 127.8, 124.5, 123.5, 121.6,

119.2, 118.3, 77.7, 34.7, 28.5;

IR (neat): 2927, 1510, 1337, 1066, 698 cm-1;


3,4-dihydro-2H-benzo[b][1,4]thiazine (4-44): This compound was prepared according to

the General Procedure B using 2-(phenylamino)ethane-1-thiol (50 mg, 0.325 mmol). After


compound was isolated as a yellow liquid (30 mg, 79% yield).

1H NMR (600 MHz, CDCl3): = 7.02-6.97 (m, 1 H), 6.92-6.86 (m, 1 H), 6.62 (t, J = 7.6

Hz, 1 H), 6.46 (d, J = 8.1 Hz, 1 H), 3.97 (br. s., 1 H), 3.67-3.58 (m, 2 H), 3.10-3.01 (m, 2

132

H);

13C NMR (150 MHz, CDCl3): = 141.7, 127.7, 125.4, 118.1, 115.9, 115.3, 42.2, 26.0;

IR (neat): 3400, 2926, 1587, 1483, 739 cm-1;


4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-45): This compound was prepared

according to the General Procedure B using 2-(methyl(phenyl)amino)ethane-1-thiol (54

mg, 0.325 mmol). After purification by column chromatography on SiO2 (20% DCM in

hexanes), the title compound was isolated as a yellow liquid (39 mg, 94% yield).


H), 3.12-3.06 (m, 2 H), 2.96 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 144.6, 127.4, 125.9, 118.6, 117.6, 112.5, 51.6, 40.1,

26.3;

IR (neat): 2924, 1585, 1489, 738 cm-1;

HRMS (ESI) m/z calcd for C9H12NS [(M+H)+] 166.0690, found 166.0681

Trans-2,3,4,4a,10,10a-hexahydro-1H-phenothiazine (4-46): This compound was

prepared according to the General Procedure B using 2-(phenylamino)cyclohexane-1-thiol

133

(67 mg, 0.325 mmol). After purification by column chromatography on SiO2 (20% DCM

in hexanes), the title compound was isolated as a white solid (47 mg, 92% yield, >95:5 dr).

1H NMR (600 MHz, CDCl3): = 7.02-6.94 (m, 1 H), 6.91-6.83 (m, 1 H), 6.61 (t, J = 7.1

Hz, 1 H), 6.47 (d, J = 7.8 Hz, 1 H), 3.85-3.65 (m, 1 H), 3.19-3.07 (m, 1 H), 2.94 (ddd, J =

3.5, 8.8, 11.8 Hz, 1 H), 2.02 (d, J = 12.9 Hz, 1 H), 1.98-1.92 (m, 1 H), 1.88-1.79 (m, 2 H),

1.51-1.27 (m, 4 H);

13C NMR (150 MHz, CDCl3): = 141.4, 126.8, 125.2, 118.0, 117.0, 114.7, 56.1, 42.8,

33.4, 30.5, 25.6, 24.4;

IR (neat): 3353, 2922, 1588, 1482, 1305, 736 cm-1;


2-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-47): This compound was prepared

according to the General Procedure B using 1-(phenylamino)propane-2-thiol (54 mg, 0.325

mmol). After purification by column chromatography on SiO2 (20% DCM in hexanes), the

title compound was isolated as a yellow solid (35 mg, 85% yield).


(t, J = 7.6 Hz, 1 H), 6.49 (d, J = 8.1 Hz, 1 H), 4.01 (br. s., 1 H), 3.59 (dd, J = 2.2, 11.7 Hz,

1 H), 3.41-3.32 (m, 1 H), 3.22 (dd, J = 8.3, 11.7 Hz, 1 H), 1.36 (d, J = 6.8 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 141.1, 127.4, 125.2, 118.1, 116.5, 115.0, 49.2, 34.0,

19.1;

IR (neat): 3403, 2921, 1490, 1484, 739 cm-1;

134


2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-48): This compound was

prepared according to the General Procedure B using 2-methyl-1-(phenylamino)propane-

2-thiol (59 mg, 0.325 mmol). After purification by column chromatography on SiO2 (20%

DCM in hexanes), the title compound was isolated as a colorless liquid (32 mg, 71% yield).


(t, J = 7.4 Hz, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 4.12 (br. s., 1 H), 3.25 (s, 2 H), 1.42 (s, 6 H);

13C NMR (150 MHz, CDCl3): = 140.1, 127.6, 125.2, 118.0, 116.4, 114.7, 54.5, 39.5,

27.9;

IR (neat): 3409, 2959, 1590, 1484, 739 cm-1;


5-fluoro-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-49): This compound was prepared

according to the General Procedure B using 2-((2-fluorophenyl)amino)ethane-1-thiol (56

mg, 0.325 mmol). After purification by column chromatography on SiO2 (20% DCM in

hexanes), the title compound was isolated as a yellow liquid (40 mg, 95% yield).

1H NMR (600 MHz, CDCl3): = 6.81-6.69 (m, 2 H), 6.52 (dt, J = 5.5, 8.0 Hz, 1 H), 4.24

135

(br. s., 1 H), 3.67 (td, J = 2.7, 7.3 Hz, 2 H), 3.11-3.03 (m, 2 H);

13C NMR (150 MHz, CDCl3): = 151.6, 150.1, 130.4, 130.3, 122.8, 122.8, 117.5, 117.5,

116.5, 116.4, 111.1, 110.9, 41.4, 25.7;

IR (neat): 3419, 2929, 1608, 1496, 757 cm-1;


8-chloro-3,4-dihydro-2H-benzo[b][1,4]thiazine and 6-chloro-3,4-dihydro-2H-

benzo[b][1,4]thiazine (4-50): This compound was prepared according to the General

Procedure B using 2-((3-chlorophenyl)amino)ethane-1-thiol (61 mg, 0.325 mmol). After


compounds were isolated as clear liquid (major) and white solid (minor) (44 mg, 95%

yield, 1.5:1 rr).

1H NMR (600 MHz, CDCl3) for major: = 6.81 (t, J = 7.9 Hz, 1 H), 6.72 (d, J = 7.9 Hz,

1 H), 6.37 (d, J = 8.1 Hz, 1 H), 4.11 (br. s., 1 H), 3.63-3.54 (m, 2 H), 3.12-3.04 (m, 2 H);

13C NMR (150 MHz, CDCl3) for major: = 143.1, 131.6, 125.2, 118.6, 115.6, 113.2,

41.5, 26.3;

IR (neat) for major: 3403, 2925, 1580, 1304, 750 cm-1

HRMS (ESI) for major m/z calcd for C8H9ClNS [(M+H)+] 186.0144, found 186.0145.

1H NMR (600 MHz, CDCl3) for minor: = 6.89 (d, J = 8.2 Hz, 1 H), 6.57 (dd, J = 1.8,

8.2 Hz, 1 H), 6.45 (d, J = 1.8 Hz, 1 H), 4.05 (br. s., 1 H), 3.66-3.58 (m, 2 H), 3.05-2.97 (m,

136

2 H);

13C NMR (150 MHz, CDCl3) for minor: = 142.4, 130.7, 128.6, 117.8, 114.5, 114.1,

42.1, 25.5;

IR (neat) for minor: 3408, 2928, 1581, 1307, 759 cm-1;

HRMS (ESI) for minor m/z calcd for C8H9ClNS [(M+H)+] 186.0144, found 186.0143.

5,7-difluoro-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-51): This compound was

prepared according to the General Procedure B using 2-((2,4-

difluorophenyl)amino)ethane-1-thiol (61 mg, 0.325 mmol). After purification by column


clear liquid (45 mg, 96% yield).

1H NMR (600 MHz, CDCl3): = 6.60-6.49 (m, 2 H), 4.05 (br. s., 1 H), 3.62 (dt, J = 2.7,

4.8 Hz, 2 H), 3.12-3.06 (m, 2 H);

13C NMR (150 MHz, CDCl3): = 154.6, 154.5, 153.0, 152.9, 151.1, 151.0, 149.5, 149.4,

126.8, 126.8, 118.7, 118.7, 118.6, 118.6, 109.0, 108.9, 108.8, 108.8, 100.1, 100.0, 99.9,

99.8, 41.1, 26.2;

IR (neat): 3424, 1621, 1494, 1103, 994, 585 cm-1;


137

8-fluoro-5-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-52): This compound was

prepared according to the General Procedure B using 2-((5-fluoro-2-

methoxyphenyl)amino)ethane-1-thiol (65 mg, 0.325 mmol). After purification by column


yellow liquid (49 mg, 98% yield).

1H NMR (600 MHz, CDCl3): = 6.44 (dd, J = 4.9, 8.8 Hz, 1 H), 6.33 (t, J = 8.9 Hz, 1 H),

4.65 (br. s., 1 H), 3.80 (s, 3 H), 3.69-3.60 (m, 2 H), 3.06-2.99 (m, 2 H);

13C NMR (150 MHz, CDCl3): = 154.5, 153.0, 142.1, 142.1, 132.5, 132.4, 105.5, 105.4,

103.6, 103.5, 101.1, 100.9, 55.8, 41.1, 24.5;

IR (neat): 3418, 2931, 1609, 1498, 775 cm-1;

HRMS (ESI) m/z calcd for C9H11FNOS [(M+H)+] 200.0545, found 200.0538.

4-(2,6-dimethylphenyl)-3-phenylthiomorpholine (4-54): This compound was prepared

according to the General Procedure A using styrene (65 mg, 0.625 mmol), 2-((2,6-

dimethylphenyl)amino)ethane-1-thiol (68 mg, 0.375 mmol), NaI (20 mol%, 7.5 mg) for 16

h. After purification by column chromatography on SiO2 (10% DCM in hexanes), the title


138



H), 3.58 (t, J = 12.2 Hz, 1 H), 3.30 (d, J = 12.9 Hz, 1 H), 3.18-3.09 (m, 1 H), 2.99-2.90 (m,

1 H), 2.58-2.50 (m, 2 H), 2.43 (s, 3 H), 2.31 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 147.8, 142.2, 137.0, 136.0, 129.4, 128.2, 127.8, 127.1,

126.9, 125.1, 66.9, 53.4, 37.5, 28.4, 20.3, 19.4;

IR (neat): 2897, 1583, 1450, 771, 518 cm-1;


3-cyclopropyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine (4-55): This compound

was prepared according to the General Procedure A using α-cycloopropylstyrene (90 mg,

0.625 mmol), 2-aminobenzenethiol (40 μL, 0.375 mmol). After purification by column


clear liquid (8 mg, 12% yield).

1H NMR (600 MHz, CDCl3): = 7.38 (d, J = 7.8 Hz, 2 H), 7.31 (t, J = 7.8 Hz, 2 H), 7.28-

7.21 (m, 1 H), 6.97-6.91 (m, 2 H), 6.64-6.56 (m, 2 H), 4.27 (br. s., 1 H), 3.27 (d, J = 12.7

Hz, 1 H), 3.12 (d, J = 12.7 Hz, 1 H), 1.38-1.30 (m, 1 H), 0.58-0.44 (m, 2 H), 0.34-0.21 (m,

2 H);

13C NMR (150 MHz, CDCl3): = 143.9, 141.1, 128.2, 127.7, 127.1, 126.8, 125.7, 117.6,

115.1, 114.9, 57.6, 36.1, 22.6, 1.5, 0.6;

IR (neat): 3328, 2956, 1587, 1478, 740 cm-1;

HRMS (ESI) m/z calcd for C17H20NS [(M+H)+] 268.1160, found 268.1159

139

Chapter 5

Alkene Catalyzed Construction of All-Carbon Quaternary

Center Via C-H Alkylation of Arene

5.1 Introduction

Alcohols are prevalent in many natural products and biologically active

compounds. Alcohols are considered as important chemical feedstocks for many organic

transformations because of easy accessibility, versatility, commercial availability, and

efficient synthetic procedures, and can be modified into other functional groups via

nucleophilic substitution.147-149 Direct nucleophilic substitution of alcohol is quite

challenging because of their thermodynamic and kinetic barrier for removal of hydroxide

anion, other chemical activators are required.150 Traditionally, protonation, using strong

acids, conversion of alcohol to sulfonate, phosphite ester are the widely used strategies to

achieve the goal of substitution of alcohol.151-152 Conventionally, the Mitsunobu reaction

is one of the most frequently used strategy, despite fact that it involves the use of hazardous

and mass intensive stoichiometric reagents.153-154 In addition, several catalytic strategies

using Lewis acids, transition metals have been developed for the conversion of alcohols to

the various useful compounds.155-156 The Shenvi group developed an elegant strategy for

Lewis acid-catalyzed stereoinversion of tertiary alcohols to tertiary alkyl isonitrile via

conversion of alcohol to their corresponding trifluoroacetate (Scheme 5-1a).157

140

Scheme 5-1: Literature Background of Alcohol Activation

141

Moreover, the Lambert group has made a significant contribution to the nucleophilic

substitution of alcohols into various valuable compounds by utilizing the Breslow-type

cyclopropenium cation (Scheme 5-1e).158-162 Similarly, the Nguyen group demonstrated

catalytic activity of the organic Lewis acid tropylium for the activation of hetero atom

containing compounds (Scheme 5-1e).163-167 Recently, the Denton group reported an

organic phosphine oxide catalyzed Mitsunobu reaction of alcohol for C-O, C-N, C-S bond

formations (Scheme 5-1b).168 Despite the significant advancement of primary and

secondary alcohol functionalizations, tertiary alcohol functionalization remains significant

challenges due to their competing elimination reaction.169 Moreover, the functionalization

of tertiary alcohol for the construction of all-carbon quaternary center is difficult due to

strong steric hindrance.150

Our group is interested in the utilization of halogen a widely used synthetic reagent

in many organic transformations that garnered enormous attention from synthetic and

medicinal chemists. A significant effort has been devoted to identifying the reactive

intermediates and their reaction mechanism. In 1937, Kimball first proposed the cyclic

three-membered halonium ion as an intermediate for the halogenation of ethylene.43 Later,

the syntheses of the retively more stable bromonium, chloronium, and iodonium of

adamantylideneadamantane and their characterization has been done by Olah,44-45

Nugent,46 Brown47 followed by the elucidation of X-ray structure of bridged 2,2’-

bis(adamant-2-ylidene) chloronium cation by Kochi lab (Scheme 5-1c).50 With such

success, synthetic utilities of those halonium intermediates have been demonstrated by

halocyclization of alkenols and alkenoic acids, which often proceeded via halonium

transfer from adamantylideneadamantane to the acceptor alkene.48-49 Later, the Denmark

142

lab studied the absolute configurational stability of bromonium and chloronium ions by

examining the retention of enantiospecificity of nucleophilic substituted products.170 In

some cases, bromonium ion transfer has been observed between substrate and alkene,

similar to the previously reported alkene to alkene transfer processes for thiiranium and

seleniranium (Scheme 5-1d).105 Recently, the Matsubara group further expanded this

promising strategy by demonstrating the sterically hindered alkene-catalyzed

bromolactonization of alkenoic acids by utilizing the alkene to alkene transfer phenomenon

of an in-situ generated bromonium ion.171 Besides, halogen or halonium ion has been

extensively used in the activation of alkene for halofunctionalization and

difunctionalization reactions. The Denmark lab has been a pioneer, that has made

significant contribution in the halofunctionalization of alkene.78 Muniz lab developed a

bromonium-catalyzed intramolecular diamination of the alkene.114 Moreover, our group

and a few others have been focusing on halogen activation of alkene for heterocycle

syntheses.172-174 Despite these advances, halonium activation of heteroatom has been

underdeveloped, represents significant potential in organic chemistry. To the best of our

knowledge, iodonium transfer from alkene to alcohol has not been realized so far.

As a part of our general program in halogen activation, we propose here an alkene

catalyzed C-H alkylation of arene for the construction of quaternary carbon center via

iodonium transfer from an alkene to an alcohol (Scheme 5-1f). We envision that

electrophilic iodinating reagent could generate iodonium with an alkene, which would

transfer to alcohol due to nucleophilicity of alcohol, resulting in carbocation formation with

the elimination of HOI. The newly generated carbocation could be attacked by arene,

leading to the formation of an alkylated quaternary carbon center.

143

Table 5.1: Optimization of Reaction Condition

144

5.2 Results and Discussions for C-H Alkylation of Arene


With this hypothesis in mind, the reaction was commenced with adamantanol, NIS as the

halogen source, 1-methylcyclohexene as the catalyst, and Ts-protected pyrrole as a

nucleophile in hexafluoroisopropanol (HFIP) at rt for 16 h. To our delight, the reaction

provided 47% yield of the expected product as a single regioisomer (Table 5.1, entry 1).

Surprisingly, other solvents were unable to afford any product (Table 5.1 entries 2 and 3).

After the screening of stoichiometry of nucleophile and concentration revealed that 1.5

equiv of arene and 1.5 mL of HFIP was the best combination, providing the product in 94%

yield (Table 5.1, entries 4-7). Other alkene catalysts did not improve the yield of the

product (Table 5.1, entries 8-11). As expected, reactions in absence of either the alkene or

NIS did not generate any product, demonstrating that both NIS and alkene catalyst were

required for alkylation of arene (Table 5.1, entries 12 and 13).


With optimized conditions in hand, we focused on the exploration of the arene

substrate scope for the alkylation of arenes. Different indole derivatives including electron-

withdrawing substituent afforded the products in very good yields with excellent

regioselectivities (Table 5.2, products 5-10 to 5-12). In these cases, the regioselectivity

favoring the alkylation at C-3 position of indoles and pyrrole. Surprisingly, the reaction

occurred when the C-3 position was blocked with ethyl group, delivering the product with

adamantyl group attached to C-2 and C-5 position of indole in almost equal

regioselectivities (Table 5.2, product 5-13). Moreover, 2-oxindole was a compatible

145

Table 5.2: Arene Substrate Scope

146

Table 5.3: Alcohol Substrate Scope

substrate, providing the product with excellent regioselectivity albeit in low yield (Table

147

5.2, product 5-14). The sulfur-containing heterocycles such as benzothiophene, thiophene

afforded products in good yields (Table 5.2, products 5-15 and 5-16). The aniline

derivatives delivered the products with excellent regioselectivities (Table 5.2, products 5-

17 to 5-19. Interestingly, the adamantyl group was added chemoselectively to 4-position

of aniline in the presence of a methoxy group in another aromatic ring (Table 5.2, product

5-19). Different nucleophilic functional groups such as sulfur, ether, and alcohol were well

tolerated and provided the products in good yields with high regioselectivities (Table 5.2,

products 5-20 to 5-24). To our surprise, electron neutral ring toluene furnished the product

in good yield (Table 5.2, product 5-25). A natural product such as estradiol provided

product with demonstrating the chemoselectivity for the aromatic ring instead of a

secondary alcohol (5.2, product 5-26). The late-stage functionalization of Tyrosine,

Gemifibrozil, Naproxen further highlights the synthetic utility of our method (Table 5.2,

product 5-27 to 5-29).

After satisfied with the arene substrate scope, we then turned our attention to

discover alcohol substrate scope. Different six-membered cyclic alcohols provided the

products in very good yields with exceptional regioselectivities (Table 5.3, products 5-30

to 5-34). The methyl, tert-butyl substituted alcohols furnished the products with good

diastereoselectivities (Table 5.3, products 5-33 and 5-34). Four-, five-, eight-, twelve-

membered cyclic alcohols were also excellent substrates in product formation with a good

regioselective manner (Table 5.3, products 5-35 to 5-38). O- and N-containing heterocyclic

alcohols were compatible and delivered the products without loss of efficiency (Table 5.3,

products 5-39 and 5-40). The benzylic alcohols with different substituents provided the

sterically encumbered products in a highly regioselective manner (Table 5.3, products 5-

148

41 to 5-45). Tert-butanol and tert-amyl alcohol also provided products with good

regioisomers (Table 5.3, products 5-46 and 5-47). The complex alcohol, derived from

lithocholic acid afforded the product with a quaternary carbon center, demonstrating

chemoselectivity for tertiary alcohol over secondary alcohol (Table 5.3, product 5-48).

5.2.3 Chemoselectivity of Alcohols

The synthetic applicability of our protocol was further demonstrated by the

chemoselectivity of different alcohols for C-C bond formation via alkylation of arene

(Scheme 5-2). Surprisingly, the aliphatic tertiary alcohol showed preference over benzylic

tertiary alcohol for the alkylation of pyrrole, providing the product in high yield (Scheme

5-2a). Moreover, pyrrole was added selectively to Adamantanol in the presence of primary

and secondary alcohol, highlighting the utility of our method (Scheme 5-2b,c).

Scheme 5-2: Chemoselectivity of Different Alcohols

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5.3 Synthetic Exploration of Our Strategy

Encouraged by the comprehensive substrate scope, we decided to explore other

nucleophiles for the construction of various carbon-heteroatom bonds. To our delight, p-

toluenesulfonamide, azide, benzylcarbamate, and hexafluoroisopropanol delivered the

corresponding products in very good yields (Scheme 5-3, products 5-53 to 5-56).

Interestingly, our method could activate the silyl protected alcohol and acetoxy functional

groups which are difficult to activate by other protocols, provided the respective products

in excellent yields (Scheme 5-3b, c). The observed regioselectivity of the product in these

cases is identical to the regioselectivity obtained from the arylation of alcohol.

Scheme 5-3: Synthetic Utilities of Our Method

150


To understand the reaction mechanism, we considered several experiments. In the

absence of alkene, the reaction did not provide any product, suggesting that alkene is

participating in the reaction as a catalyst (Table 5.1, entry 12). Moreover, the reaction

without NIS did not afford the product, indicates that the electrophilic iodonium source is

required in the reaction. Based on experimental data and literature precedents, we propose

a mechanism for the alkylation of arene depicted in figure 5-1. First, NIS can activate

alkene A to form iodonium intermediate B and then the transfer of iodonium to alcohol

leading to the formation of intermediate C. The intermediate C undergoes the formation of

carbocation D with loss of HOI and subsequent nucleophilic attack from arene on

carbocation results in the generation of carbon-carbon bond-forming product.

Figure 5-1: Proposed Reaction Mechanism for Alkylation of Arene

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5.5 Conclusion

We have developed a simple and highly efficient method for carbon-carbon bond

formation via alkylation of the arene. The reaction utilizes an alkene as a catalyst for the

in-situ generation of iodonium and subsequent activation of alcohol. The method shows

good functional group compatibility and a broad range of substrate scope. The reaction is

chemoselective for tertiary alcohol in preference to secondary or primary alcohols. We

have also demonstrated that various other nucleophiles could also couple with alcohol to

provide the products in a highly efficient manner. Moreover, we have shown that our

reaction protocol could apply to activate ether and ester to generate their corresponding

products which will enable the expansion of this chemistry to the related systems. We

expect that this reaction will lead to the development of other alkene catalyzed reactions

and further advances the carbocation chemistry.

5.6 Experimental


Aldrich, Oakwood Chemicals, Alfa Aesar, Matrix Scientific, Acros Organic, and were

used as received. The alcohol substrates were synthesized according to the reported

procedure. Organic solutions were concentrated under reduced pressure on a Büchi rotary

evaporator using an acetone-dry ice bath. Chromatographic purification of products was

accomplished using flash chromatography on 230-400 mesh silica gel. Thin-layer

chromatography (TLC) was performed on Analtech 250 mm silica gel HLF UV-254 plates.

Visualization of the developed plates was performed by fluorescence quenching, potassium

152

permanganate, and iodine-silica gel system. 1H and 13C NMR spectra were recorded on a

Bruker 600 instrument (600 and 150 MHz) or INOVA 600 (600 and 150 MHz) and are

internally referenced to residual protio solvent signals (for CDCl3, 7.26 and 77.0 ppm,

MeOH-d4 3.31, 4.90 and 49.0 ppm, DMSO-d6 2.50 and 39.53 respectively). Data for 1H

NMR are reported as follows: chemical shift ( ppm), multiplicity (s = singlet, d = doublet,

t = triplet, q = quartet, h = heptet, m = multiplet, br = broad), integration, coupling constant

(Hz). 13C spectra were reported as chemical shifts in ppm and multiplicity where

appropriate.


General Procedure A: The alcohol (0.25 mmol) and arene (0.375 mmol), 1-methyl-1-

cyclohexene (10 mol%, 3 µL), NIS (10 mol%, 6 mg) were added to 8 mL vial. Then, HFIP

(1.5 mL) was added to the reaction mixture and stirred at room temperature for 16 h. After

the reaction, HFIP was removed by rotavapor. The reaction was quenched with 20%

Na2S2O3 (1 mL) and EtOAc (2 mL) was added. The organic layer was separated, and

aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic solution was

dried with anhydrous Na2SO4, filtered, concentrated in vacuo by rotavapor and purified by

flash chromatography on SiO2 (2%-20% EtOAc in hexanes) to provide the desired product.

General Procedure B: The alcohol (0.25 mmol) and arene (0.375 mmol), 1-methyl-1-

cyclohexene (20 mol%, 6 µL), NIS (20 mol%, 11 mg) were added to 8 mL vial. Then, DCE

(0.5 mL) was added to the reaction mixture and stirred at 50 ºC for 16 h. The reaction was

quenched with 20% Na2S2O3 (1 mL) and EtOAc (2 mL) was added. The organic layer was

separated, and aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic

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solution was dried with anhydrous Na2SO4, filtered, concentrated in vacuo by rotavapor

and purified by flash chromatography on SiO2 (2%-5% EtOAc in hexanes) to provide the

desired product.

3. Spectral Characterization of the Products

3-adamantan-1-yl-1-tosyl-1H-pyrrole (5-9): This compound was prepared according to

the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 1-tosyl-1H-pyrrole (83




(t, J = 2.2 Hz, 1 H), 6.85 (s, 1 H), 6.27-6.22 (m, 1 H), 2.40 (s, 3 H), 2.00 (br. s., 3 H), 1.78-

1.67 (m, 12 H);

13C NMR (150 MHz, CDCl3): = 144.6, 140.9, 136.4, 129.9, 126.7, 120.6, 114.8, 111.7,

43.2, 36.7, 32.6, 28.6, 21.6.

154

3-(adamantan-1-yl)-1-tosyl-1H-indole (5-10): This compound was prepared according to

the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 1-tosyl-1H-indole (102




7.73 (d, J = 8.3 Hz, 2 H), 7.27-7.22 (m, 2 H), 7.22-7.14 (m, 3 H), 2.32 (s, 3 H), 2.08 (br.

s., 3 H), 2.03 (br. s., 6 H), 1.85-1.76 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 144.6, 135.9, 135.3, 132.8, 129.7, 129.3, 126.7,

123.9, 122.3, 122.0, 121.0, 113.9, 42.1, 36.9, 34.0, 28.5, 21.5.

3-(adamantan-1-yl)-5-bromo-1-tosyl-1H-indole (5-11): This compound was prepared

according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 5-bromo-

1-tosyl-1H-indole (131 mg, 0.375 mmol). After purification by column chromatography

on SiO2 (2% EtOAc in hexanes), the title compound was isolated as a white solid (83 mg,

69% yield).


Hz, 2 H), 7.37-7.33 (m, 1 H), 7.25-7.20 (m, 3 H), 2.35 (s, 3 H), 2.10 (br. s., 3 H), 2.00 (br.

s., 6 H), 1.86-1.74 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 145.0, 135.0, 134.6, 132.3, 131.0, 129.9, 126.8, 126.7,

155

124.6, 122.3, 115.9, 115.2, 42.1, 36.8, 34.0, 28.4, 21.6.

3-(adamantan-1-yl)-5-nitro-1-tosyl-1H-indole (5-12): This compound was prepared

according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 5-nitro-

1-tosyl-1H-indole (119 mg, 0.375 mmol) at 80 ˚C. After purification by column




Hz, 1 H), 7.82-7.74 (m, J = 8.1 Hz, 2 H), 7.41 (s, 1 H), 7.32-7.24 (m, J = 8.1 Hz, 2 H), 2.37

(s, 3 H), 2.12 (br. s., 3 H), 2.04 (br. s., 6 H), 1.83 (br. s., 6 H);

13C NMR (150 MHz, CDCl3): = 145.6, 143.2, 138.8, 134.7, 133.4, 130.1, 128.9, 126.8,

123.8, 119.2, 118.3, 113.8, 42.2, 36.7, 34.1, 28.4, 21.6.

5-(adamantan-1-yl)-3-ethyl-1-tosyl-1H-indole (5-13): This compound was prepared

according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 3-ethyl-

156

1-tosyl-1H-indole (112 mg, 0.375 mmol) 50 ˚C. After purification by column

chromatography on SiO2 (2% EtOAc in hexanes), the inseparable mixture of two

regioisomers was isolated as a white solid (82 mg, 76% yield, 59:41 rr).

1H NMR (600 MHz, CDCl3): = 7.99 (s, 1 H major), 7.90 (d, J = 8.5 Hz, 1 H minor),

7.79- 7.72 (m, 2 H major + 2 H minor), 7.40 (d, J = 8.5 Hz, 1 H major + 1 H minor), 7.36

(d, J = 8.8 Hz, 1 H minor), 7.29-7.26 (m, 2 H major + 1 H minor), 7.19 (d, J = 8.3 Hz, 2 H

major + 2 H minor), 2.73-2.59 (m, 2 H major + 2 H minor), 2.32 (s, 3 H major + 3 H

minor), 2.14 (br. s., 3 H major), 2.10 (br. s., 3 H minor), 2.02-1.90 (m, 6 H major + 6 H

minor), 1.87-1.71 (m, 6 H major + 6 H minor), 1.37-1.23 (m, 3 H major + 3 H minor);

13C NMR (150 MHz, CDCl3): = 148.5, 146.3, 144.5, 144.4, 135.8, 135.5, 135.3, 133.4,

130.8, 129.7, 129.6, 128.8, 126.7, 126.7, 125.4, 125.1, 122.1, 121.8, 121.7, 120.3, 118.7,

115.1, 113.1, 110.1, 43.5, 36.7, 36.5, 36.1, 29.0, 29.0, 21.5, 18.2, 18.1, 13.3, 13.2.

5-(-adamantan-1-yl)indolin-2-one (5-14): This compound was prepared according to the

General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), indolin-2-one (50 mg,

0.375 mmol) at 80 ºC. After purification by column chromatography on SiO2 (10% EtOAc

in hexanes), the title compound was isolated as a white solid (14 mg, 21% yield).

1H NMR (600MHz, DMSO-d6): = 10.21 (s, 1 H), 7.17 (s, 1 H), 7.08 (d, J = 8.1 Hz, 1

H), 6.69 (d, J = 8.1 Hz, 1 H), 3.39 (s, 2 H), 1.99 (br. s., 3 H), 1.78 (br. s., 6 H), 1.72-1.62

157

(m, 6 H);

13C NMR (150 MHz, DMSO-d6): = 176.5, 144.0, 141.3, 125.5, 123.4, 121.0, 108.5,

42.9, 36.2, 36.0, 35.4, 28.4.

3-(adamantan-1-yl)benzo[b]thiophene (5-15): This compound was prepared according

to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), benzothiophene (50

mg, 0.375 mmol). After purification by column chromatography on SiO2 (hexanes), the

title compound was isolated as a white solid (53 mg, 79% yield).


(t, J = 7.3 Hz, 1 H), 7.29 (t, J = 7.3 Hz, 1 H), 7.07 (s, 1 H), 2.18 (s, 6 H), 2.14 (br. s., 3 H),

1.85 (br. s., 6 H);

13C NMR (150 MHz, CDCl3): = 146.1, 141.7, 137.5, 124.6, 123.4, 123.3, 123.0, 119.7,

42.0, 37.0, 36.9, 28.8.

2-(adamantan-1-yl)-3-iodothiophene (5-16): This compound was prepared according to

the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 3-iodothiophene (79

mg, 0.375 mmol). After purification by column chromatography on SiO2 (hexanes), the

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title compound was isolated as a colorless liquid (72 mg, 84% yield, 78:15:7).

1H NMR (600 MHz, CDCl3): = 7.22-7.19 (m, 1 H minor1), 7.05 (d, J = 5.1 Hz, 1 H major),

7.02 (d, J = 5.1 Hz, 1 H major), 6.80-6.77 (m, 1 H minor1), 6.72 (s, 1 H minor2), 2.28-2.24 (m, 6

H major), 2.24-2.21 (m, 6 H minor1 + 6 H minor2), 2.10 (br. s., 3 H major + 6 H minor2), 1.95-1.88

(m, 3 H minor1 + 6 H minor2), 1.82-1.68 (m, 6 H major + 6 H minor1 + 12 H minor2);

13C NMR (150 MHz, CDCl3): = 150.6, 138.2, 123.1, 71.3, 41.1, 36.5, 36.4, 28.7.

N-(4-adamantan-1-yl)phenyl)acetamide (5-17): This compound was prepared according

to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), N-phenylacetamide

(51 mg, 0.375 mmol) at 80 ºC. After purification by column chromatography on SiO2 (10%

EtOAc in hexanes), the title compound was isolated as a white solid (53 mg, 79% yield).


(s, 3 H), 2.08 (br. s., 3 H), 1.88 (br. s., 6 H), 1.82-1.70 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 168.3, 147.5, 135.2, 125.3, 119.8, 43.1, 36.7, 35.8, 28.9,

24.5.

159

N-(4-((1s,3s)-adamantan-1-yl)phenyl)benzamide (5-18): This compound was prepared

according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), N-

phenylbenzamide (74 mg, 0.375 mmol) at 50 ºC. After purification by column



1H NMR (600 MHz, CDCl3): = 7.94 (br. s., 1 H), 7.85 (d, J = 7.6 Hz, 2 H), 7.62-7.56

(m, J = 8.3 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.39-7.31 (m, J =

8.8 Hz, 2 H), 2.10 (br. s., 3 H), 1.91 (br. s., 6 H), 1.84-1.71 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 165.7, 147.8, 135.3, 135.0, 131.7, 128.7, 127.0, 125.4,

120.1, 43.2, 36.7, 35.9, 28.9.

N-(4-adamantan-1-yl)phenyl)-4-methoxybenzamide (5-19): This compound was

prepared according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol),

4-methoxy-N-phenylbenzamide (85 mg, 0.375 mmol) at 50 ºC. After purification by

column chromatography on SiO2 (20% EtOAc in hexanes), the title compound was isolated

as a white solid (58 mg, 64% yield).

1H NMR (600 MHz, CDCl3): = 7.94 (s, 1 H), 7.82 (d, J = 8.8 Hz, 2 H), 7.60-7.53 (m, J

= 8.5 Hz, 2 H), 7.36-7.29 (m, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 2.10

(br. s., 3 H), 1.90 (br. s., 6 H), 1.83-1.69 (m, 6 H);

160

13C NMR (150 MHz, CDCl3): = 165.2, 162.2, 147.5, 135.5, 128.9, 127.2, 125.4, 120.1,

113.8, 55.4, 43.1, 36.7, 35.8, 28.9.

1-(4-methoxyphenyl)adamantane (5-20): This compound was prepared according to the

General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), anisole (41 mg, 0.375

mmol). After purification by column chromatography on SiO2 (2% EtOAc in hexanes), the

title compound was isolated as a colorless liquid (60 mg, 99% yield).

1H NMR (600 MHz, CDCl3): = 7.33-7.28 (d, J = 8.5 Hz, 2 H), 6.91-6.85 (d, J = 8.5 Hz,

2 H), 3.81 (s, 3 H), 2.10 (br. s., 3 H), 1.91 (br. s., 6 H), 1.83-1.71 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 157.3, 143.7, 125.8, 113.4, 55.2, 43.4, 36.8, 35.5, 29.0.

3-(3-adamantan-1-yl)-4-methoxyphenyl)propan-1-ol (5-21): This compound was


3-(4-methoxyphenyl)propan-1-ol (62 mg, 0.375 mmol). After purification by column



161


Hz, 1 H), 3.81 (s, 3 H), 3.69 (t, J = 6.3 Hz, 2 H), 2.64 (t, J = 7.8 Hz, 2 H), 2.09 (br. s., 6

H), 2.06 (br. s., 3 H), 1.93-1.84 (m, 2 H), 1.77 (br. s., 6 H);

13C NMR (150 MHz, CDCl3): = 157.0, 138.4, 133.4, 126.7, 126.2, 111.7, 62.5, 55.1,

40.6, 37.1, 36.9, 34.6, 31.6, 29.1.

(4-adamantan-1-yl)phenyl)(phenyl)sulfane (5-22): This compound was prepared

according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol),

diphenylsulfane (70 mg, 0.375 mmol). After purification by column chromatography on

SiO2 (1% EtOAc in hexanes), the title compound was isolated as a white solid (52 mg, 65%

yield).

1H NMR (600 MHz, CDCl3): = 7.39-7.25 (m, 8 H), 7.25-7.18 (m, 1 H), 2.10 (br. s., 3

H), 1.90 (br. s., 6 H), 1.83-1.71 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 150.8, 136.7, 131.5, 131.5, 130.2, 129.0, 126.5, 125.9,

43.0, 36.7, 36.1, 28.9;

162

4-(adamantan-1-yl)-2-ethylphenol (5-23): This compound was prepared according to the

General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 2-ethylphenol (46 mg,

0.375 mmol). After purification by column chromatography on SiO2 (5% EtOAc in


1H NMR (600 MHz, CDCl3): = 7.14 (br. s., 1 H), 7.08 (d, J = 8.3 Hz, 1 H), 6.72 (d, J =

8.3 Hz, 1 H), 4.56 (s, 1 H), 2.65 (q, J = 7.5 Hz, 2 H), 2.09 (br. s., 3 H), 1.90 (br. s., 6 H),

1.77 (q, J = 12.1 Hz, 6 H), 1.25 (t, J = 7.5 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 151.0, 144.0, 129.1, 125.9, 123.3, 114.7, 43.4, 36.8,

35.6, 29.0, 23.4, 14.2.

5-(adamantan-1-yl)-2-hydroxybenzoic acid (5-24): This compound was prepared

according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol), 2-

acetoxybenzoic acid (68 mg, 0.375 mmol) 80 ºC. After purification by column



163

1H NMR (600 MHz, Methanol-d4): = 7.81 (d, J = 2.4 Hz, 1 H), 7.52 (dd, J = 2.4, 8.5

Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 2.09 (br. s., 3 H), 1.95-1.88 (m, 6 H), 1.86-1.76 (m, 6

H);

13C NMR (150 MHz, Methanol-d4): = 173.8, 161.0, 143.3, 133.6, 127.3, 117.8, 113.2,

44.4, 37.8, 36.6, 30.4.

1-(p-tolyl)adamantane (5-25): This compound was prepared according to the General

Procedure A using 1-adamantanol (38 mg, 0.25 mmol), toluene (35 mg, 0.375 mmol) at 80

ºC. After purification by column chromatography on SiO2 (hexanes), the title compound

was isolated as a colorless liquid (38 mg, 67% yield).

1H NMR (600 MHz, CDCl3): = 7.31-7.27 (m, J = 8.1 Hz, 2 H), 7.18-7.13 (m, J = 8.1

Hz, 2 H), 2.34 (s, 3 H), 2.11 (br. s., 3 H), 1.92 (br. s., 6 H), 1.78-1.72 (m, 6 H) ;

13C NMR (150 MHz, CDCl3): = 148.4, 134.9, 128.8, 124.7, 43.2, 36.8, 35.8, 29.0, 20.9.

(8R,9S,13S,14S,17S)-2-((1s,3R)-adamantan-1-yl)-13-methyl 7,8,9,11,12,13,14,15,16,

17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol (5-26): This compound was

164


estradiol (102 mg, 0.375 mmol). After purification by column chromatography on SiO2

(20% EtOAc-10% DCM in hexanes), the title compound was isolated as a white solid (81

mg, 80% yield).

1H NMR (600 MHz, CDCl3): = 7.16 (s, 1 H), 6.40 (s, 1 H), 4.87 (s, 1 H), 3.75 (t, J = 8.2

Hz, 1 H), 2.85-2.71 (m, 2 H), 2.42-2.33 (m, 1 H), 2.26-2.17 (m, 1 H), 2.15-2.10 (m, 6 H),

2.10-2.05 (m, 3 H), 2.00-1.92 (m, 1 H), 1.90-1.82 (m, 1 H), 1.78 (br. s., 6 H), 1.74-1.65 (m,

1 H), 1.56-1.41 (m, 4 H), 1.41-1.24 (m, 4 H), 1.24-1.16 (m, 1 H), 0.79 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 152.2, 135.1, 133.7, 131.9, 124.0, 116.7, 82.0, 50.0,

44.3, 43.2, 40.7, 38.9, 37.1, 36.7, 36.6, 30.6, 29.0, 28.9, 27.2, 26.4, 23.1, 11.1.

Methyl 3-(3-(adamantan-1-yl)-4-hydroxyphenyl)-2-(1,3-dioxoisoindolin-2-yl)

Propanoate (5-27): This compound was prepared according to the General Procedure A

using 1-adamantanol (38 mg, 0.25 mmol), methyl 2-(1,3-dioxoisoindolin-2-yl)-3-(4-

hydroxyphenyl)propanoate (122 mg, 0.375 mmol) 50 ºC. After purification by column




Hz, 1 H), 6.70 (s, 1 H), 6.48 (d, J = 8.1 Hz, 1 H), 5.26 (s, 1 H), 5.01 (dd, J = 4.9, 11.5 Hz,

1 H), 3.79 (s, 3 H), 3.50-3.32 (m, 2 H), 1.89 (br. s., 3 H), 1.79-1.69 (m, 6 H), 1.64 (d, J =

165

12.5 Hz, 3 H), 1.55 (d, J = 11.7 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 169.4, 167.4, 153.4, 136.1, 134.1, 131.6, 128.1, 127.5,

127.0, 123.5, 117.0, 53.8, 52.8, 40.1, 36.9, 36.2, 34.0, 28.8.

N-(4-(adamantan-1-yl)phenyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide

(5-28): This compound was prepared according to the General Procedure A using 1-

adamantanol (38 mg, 0.25 mmol), 5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-

phenylpentanamide (122 mg, 0.375 mmol) 80 ºC. After purification by column




= 7.6 Hz, 1 H), 6.67 (d, J = 7.6 Hz, 1 H), 6.61 (s, 1 H), 3.94 (t, J = 5.1 Hz, 2 H), 2.30 (s, 3

H), 2.18 (s, 3 H), 2.09 (br. s., 3 H), 1.90 (br. s., 6 H), 1.84-1.72 (m, 10 H), 1.34 (s, 6 H);

13C NMR (150 MHz, CDCl3): = 175.5, 156.8, 147.5, 136.5, 135.3, 130.3, 125.3, 123.5,

120.7, 119.8, 112.0, 67.8, 43.2, 42.7, 37.7, 36.7, 35.8, 28.9, 25.6, 25.1, 21.4, 15.8.

166

(2S)-N-(4-(adamantan-1-yl)phenyl)-2-(6-methoxynaphthalen-2-yl)propenamide (5-

29): This compound was prepared according to the General Procedure A using 1-

adamantanol (38 mg, 0.25 mmol), (S)-2-(6-methoxynaphthalen-2-yl)-N-

phenylpropanamide (115 mg, 0.375 mmol) at 80 ˚C. After purification by column



1H NMR (600 MHz, CDCl3): = 7.77-7.69 (m, 3 H), 7.46-7.40 (m, 1 H), 7.38-7.32 (m, J

= 8.8 Hz, 2 H), 7.25-7.21 (m, J = 8.8 Hz, 2 H), 7.20-7.15 (m, 2 H), 7.15-7.12 (m, 1 H),

3.93 (s, 3 H), 3.85 (d, J = 7.1 Hz, 1 H), 2.06 (br. s., 3 H), 1.84 (br. s., 6 H), 1.80-1.69 (m, 6

H), 1.66 (d, J = 7.1 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 172.3, 157.8, 147.4, 136.1, 135.2, 133.8, 129.2, 129.0,

127.8, 126.2, 126.2, 125.2, 119.4, 119.2, 105.6, 55.3, 47.9, 43.1, 36.7, 35.8, 28.8, 18.5.

3-(1-methylcyclohexyl)-1-tosyl-1H-pyrrole (5-30): This compound was prepared

according to the General Procedure A using 1-methylcyclohexan-1-ol (29 mg, 0.25 mmol),

1-tosyl-1H-pyrrole (83 mg, 0.375 mmol). After purification by column chromatography on

SiO2 (2% EtOAc in hexanes), the title compound was isolated as a colorless liquid (57 mg,

72% yield).


= 2.7 Hz, 1 H), 6.87 (s, 1 H), 6.19 (dd, J = 1.6, 3.1 Hz, 1 H), 2.37 (s, 3 H), 1.72-1.62 (m, 2

167

H), 1.47-1.38 (m, 4 H), 1.38-1.29 (m, 4 H), 1.06 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 144.6, 139.5, 136.4, 129.8, 126.6, 120.8, 116.1, 112.7,

38.1, 34.1, 29.7, 26.2, 22.4, 21.6.

3-(1-phenylcyclohexyl)-1-tosyl-1H-indole (5-31): This compound was prepared

according to the General Procedure B using 1-phenylcyclohexan-1-ol (44 mg, 0.25 mmol),

1-tosyl-1H-indole (102 mg, 0.375 mmol). After purification by column chromatography


90% yield).


(s, 1 H), 7.30-7.24 (m, 2 H), 7.24-7.15 (m, 5 H), 7.15-7.10 (m, 2 H), 6.97 (t, J = 7.6 Hz, 1

H), 2.39-2.31 (m, 5 H), 2.24-2.16 (m, 2 H), 1.66-1.45 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 147.3, 144.7, 136.1, 135.0, 130.0, 129.8, 129.7, 128.1,

126.8, 126.7, 125.8, 124.2, 124.1, 122.7, 121.9, 113.9, 43.1, 36.8, 26.3, 22.9, 21.6.

1-tosyl-3-(1,3,3-trimethylcyclohexyl)-1H-pyrrole (5-32): This compound was prepared

according to the General Procedure A using 1,3,3-trimethylcyclohexan-1-ol (36 mg, 0.25

168

mmol), 1-tosyl-1H-pyrrole (83 mg, 0.375 mmol), NIS (20 mol%), catalyst (20 mol%).

After purification by column chromatography on SiO2 (2% EtOAc in hexanes), the title



(br. s., 1 H), 6.87 (s, 1 H), 6.23-6.18 (m, 1 H), 2.38 (s, 3 H), 1.92 (d, J = 13.4 Hz, 1 H),

1.65 (d, J = 13.9 Hz, 1 H), 1.56-1.45 (m, 2 H), 1.28-1.19 (m, 3 H), 1.15-1.07 (m, 1 H), 1.04

(s, 3 H), 0.84 (s, 3 H), 0.35 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 144.5, 139.3, 136.5, 129.7, 126.5, 120.8, 115.9, 113.6,

50.9, 39.6, 37.1, 34.4, 34.0, 33.1, 31.2, 27.6, 21.6, 19.6.

3-(1,2-dimethylcyclohexyl)-1-tosyl-1H-pyrrole (5-33): This compound was prepared

according to the General Procedure A using 1,2-dimethylcyclohexan-1-ol (32 mg, 0.25

mmol), 1-tosyl-1H-pyrrole (83 mg, 0.375 mmol), NIS (20 mol%), catalyst (20 mol%).


compound was isolated as a colorless liquid (41 mg, 49% yield).


7.02 (m, 1 H), 6.93-6.87 (m, 1 H), 6.24 (dd, J = 1.5, 2.9 Hz, 1 H), 2.39 (s, 3 H), 1.70 (d, J

= 12.7 Hz, 1 H), 1.60 (ddd, J = 3.9, 6.8, 10.9 Hz, 1 H), 1.54-1.41 (m, 5 H), 1.33-1.17 (m,

2 H), 1.09-1.04 (m, 3 H), 0.56 (d, J = 6.8 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 144.5, 140.6, 136.4, 129.8, 126.6, 120.8, 116.5, 112.7,

169

41.3, 39.7, 37.4, 30.3, 26.4, 22.1, 21.6, 16.8, 16.4.

3-(4-(tert-butyl)-1-methylcyclohexyl)-1-tosyl-1H-pyrrole (5-34): This compound was

prepared according to the General Procedure A using 4-(tert-butyl)-1-methylcyclohexan-

1-ol (43 mg, 0.25 mmol), 1-tosyl-1H-pyrrole (83 mg, 0.375 mmol). After purification by


as a colorless liquid (69 mg, 63%, 4:1 dr yield).

1H NMR (600 MHz, CDCl3): = 7.71 (d, J = 8.3 Hz, 2 H major), 7.66 (d, J = 8.3 Hz, 2

H minor), 7.27 (d, J = 8.1 Hz, 2 H major), 7.23 (d, J = 8.1 Hz, 2 H minor), 7.08-7.04 (m, 1

H major + 1 H minor), 6.91-6.87 (m, 1 H major + 1 H minor), 6.25 (br. s., 1 H major), 6.18

(br. s., 1 H minor), 2.39 (s, 3 H major), 2.36 (s, 3 H minor), 1.99 (d, J = 13.4 Hz, 2 H

minor), 1.67 (s, 1 H major), 1.65 (s, 1 H major), 1.61 (s, 1 H major), 1.59 (s, 1 H major),

1.47 (dt, J = 3.2, 13.1 Hz, 2 H major + 2 H minor), 1.34-1.18 (m, 2 H major + 2 H minor),

1.13 (s, 3 H major), 1.04 (s, 3 H minor), 1.00 - 0.91 (m, 1 H major + 3 H minor), 0.90 -

0.79 (m, 9 H major), 0.68 (s, 9 H minor);

13C NMR (150 MHz, CDCl3) major: = 144.6, 142.2, 136.4, 129.9, 126.7, 120.6, 114.9,

112.2, 48.0, 38.6, 33.0, 32.4, 27.5, 23.3, 22.7, 21.6;

13C NMR (150 MHz, CDCl3) minor: = 144.5, 142.2, 136.9, 129.8, 126.4, 121.2, 117.4,

113.4, 48.0, 38.4, 34.4, 34.1, 32.2, 27.4, 23.5, 21.5.

170

1-methoxy-4-(1-phenylcyclobutyl)benzene (5-35): This compound was prepared

according to the General Procedure B using 1-phenylcyclobutan-1-ol (37 mg, 0.25 mmol),

anisole (41 mg, 0.375 mmol) in HFIP (0.5 mL). After purification by column


colorless liquid (45 mg, 76% yield).


Hz, 2 H), 3.77 (s, 3 H), 2.76-2.69 (m, 4 H), 2.02-1.91 (m, 2 H);

13C NMR (150 MHz, CDCl3): = 157.3, 150.2, 141.8, 128.2, 127.2, 126.0, 125.3, 113.5,

55.2, 50.5, 35.1, 16.6.

3-(1-methyl-2,3-dihydro-1H-inden-1-yl)-1-tosyl-1H-indole (5-36): This compound was

prepared according to the General Procedure B using 1-methyl-2,3-dihydro-1H-inden-1-

ol (37 mg, 0.25 mmol), 1-tosyl-1H-indole (102 mg, 0.375 mmol). After purification by




(d, J = 7.6 Hz, 1 H), 7.25-7.19 (m, 5 H), 7.11 (t, J = 7.4 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H),

171

6.97 (d, J = 8.1 Hz, 1 H), 6.87 (d, J = 7.6 Hz, 1 H), 3.05 (td, J = 7.8, 15.8 Hz, 1 H), 2.98-

2.88 (m, 1 H), 2.58 (td, J = 8.2, 12.7 Hz, 1 H), 2.39-2.31 (m, 3 H), 2.10 (ddd, J = 4.5, 8.2,

12.7 Hz, 1 H), 1.67 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 149.6, 144.7, 142.7, 136.1, 135.2, 130.3, 129.8, 129.4,

126.9, 126.8, 126.7, 124.7, 124.1, 123.5, 123.0, 122.6, 121.5, 113.8, 47.4, 40.4, 30.4, 26.8,

21.6.

3-(1-methylcyclooctyl)-1-tosyl-1H-pyrrole (5-37): This compound was prepared

according to the General Procedure A using 1-methylcyclooctan-1-ol (36 mg, 0.25 mmol),

1-tosyl-1H-pyrrole (83 mg, 0.375 mmol). After purification by column chromatography on


yield).


(t, J = 2.3 Hz, 1 H), 6.89 (s, 1 H), 6.24-6.20 (m, 1 H), 2.39 (s, 3 H), 1.78-1.70 (m, 2 H),

1.66-1.58 (m, 2 H), 1.56-1.43 (m, 8 H), 1.42-1.34 (m, 2 H), 1.08 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 144.5, 139.9, 136.3, 129.8, 126.6, 120.8, 116.2, 113.1,

37.1, 35.6, 29.9, 28.6, 25.2, 23.1, 21.6.

172

3-(1-methylcyclododecyl)-1-tosyl-1H-pyrrole (5-38): This compound was prepared

according to the General Procedure A using 1-methylcyclododecan-1-ol (50 mg, 0.25

mmol), 1-tosyl-1H-pyrrole (83 mg, 0.375 mmol). After purification by column




7.02 (m, 1 H), 6.89-6.84 (m, 1 H), 6.22 (dd, J = 1.6, 3.1 Hz, 1 H), 2.42-2.37 (m, 3 H), 1.54-

1.43 (m, 4 H), 1.35-1.14 (m, 17 H), 1.08-1.00 (m, 4 H);

13C NMR (150 MHz, CDCl3): = 144.5, 139.5, 136.3, 129.8, 126.6, 120.7, 116.1, 113.0,

36.2, 34.2, 28.2, 26.6, 26.1, 22.6, 22.1, 21.6, 19.5.

3-(4-phenyltetrahydro-2H-pyran-4-yl)-1-tosyl-1H-indole (5-39): This compound was

prepared according to the General Procedure A using 4-phenyltetrahydro-2H-pyran-4-ol

(45 mg, 0.25 mmol), 1-tosyl-1H-indole (102 mg, 0.375 mmol). After purification by



173


(s, 1 H), 7.30-7.22 (m, 6 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.18-7.13 (m, 1 H), 7.10 (d, J = 8.1

Hz, 1 H), 6.99 (t, J = 7.7 Hz, 1 H), 3.87-3.79 (m, 2 H), 3.76-3.66 (m, 2 H), 2.49-2.38 (m, 4

H), 2.36 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 145.9, 144.9, 136.1, 134.9, 129.8, 129.3, 128.4, 128.2,

126.7, 126.6, 126.3, 124.4, 124.1, 122.9, 121.6, 114.0, 64.6, 40.8, 36.3, 21.6.

3-(4-phenyl-1-tosylpiperidin-4-yl)-1-tosyl-1H-indole (5-40): This compound was

prepared according to the General Procedure A using 4-phenyl-1-tosylpiperidin-4-ol (76

mg, 0.23 mmol), 1-tosyl-1H-indole (102 mg, 0.375 mmol) at 50 ˚C. After purification by




(s, 1 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.21-7.15 (m, 5 H), 7.15-7.11 (m, 3 H), 7.04 (d, J = 8.1

Hz, 1 H), 6.97 (t, J = 7.6 Hz, 1 H), 3.43-3.34 (m, 2 H), 3.03 (td, J = 6.0, 12.1 Hz, 2 H), 2.50

(t, J = 5.4 Hz, 4 H), 2.43 (s, 3 H), 2.35 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 44.9, 144.8, 143.5, 135.8, 134.7, 133.9, 129.8, 129.7,

128.9, 128.5, 127.5, 127.4, 126.6, 126.5, 124.5, 123.9, 122.9, 121.5, 113.8, 43.0, 41.1, 35.2,

21.5.

174

3-(2-phenylpropan-2-yl)-1-tosyl-1H-indole (5-41): This compound was prepared

according to the General Procedure B using 2-phenylpropan-2-ol (36 mg, 0.25 mmol), 1-

tosyl-1H-indole (102 mg, 0.375 mmol). After purification by column chromatography on


yield).


7.56 (s, 1 H), 7.29-7.14 (m, 8 H), 6.97 (t, J = 7.4 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 2.37

(s, 3 H), 1.73 (s, 6 H);

13C NMR (150 MHz, CDCl3): = 147.9, 144.7, 136.0, 135.2, 132.2, 129.8, 129.5,

128.2, 126.7, 126.0, 125.9, 124.1, 122.6, 122.3, 121.9, 113.7, 39.0, 30.0, 21.5.

3-(2-phenylbutan-2-yl)-1-tosyl-1H-indole (5-42): This compound was prepared

according to the General Procedure B using 2-phenylbutan-2-ol (38 mg, 0.25 mmol), 1-

tosyl-1H-indole (102 mg, 0.375 mmol). After purification by column chromatography on


yield).


175

(s, 1 H), 7.25-7.11 (m, 8 H), 6.93 (t, J = 7.6 Hz, 1 H), 6.79 (d, J = 8.1 Hz, 1 H), 2.36 (s, 3

H), 2.26-2.08 (m, 2 H), 1.62 (s, 3 H), 0.66 (t, J = 7.4 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 147.1, 144.7, 136.1, 135.1, 131.0, 129.7, 128.1, 126.7,

126.7, 125.9, 124.2, 123.4, 122.7, 121.9, 113.8, 42.7, 32.8, 26.4, 21.6, 8.8.

3-(2-(4-methoxyphenyl)butan-2-yl)-1-tosyl-1H-indole (5-43): This compound was

prepared according to the General Procedure B using 2-(4-methoxyphenyl)butan-2-ol (45

mg, 0.25 mmol), 1-tosyl-1H-indole (102 mg, 0.375 mmol). After purification by column



1H NMR (600 MHz, CDCl3): = 7.96 (d, J = 8.3 Hz, 1 H), 7.80-7.73 (m, J = 8.1 Hz, 2

H), 7.50 (s, 1 H), 7.25-7.21 (m, J = 8.1 Hz, 2 H), 7.19 (t, J = 7.7 Hz, 1 H), 7.10-7.04 (m, J

= 8.5 Hz, 2 H), 6.95 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 6.78-6.72 (m, J = 8.5

Hz, 2 H), 3.76 (s, 3 H), 2.36 (s, 3 H), 2.23-2.15 (m, 1 H), 2.15-2.06 (m, 1 H), 1.60 (s, 3 H),

0.66 (t, J = 7.2 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 157.5, 144.7, 139.2, 136.0, 135.1, 131.2, 129.7, 129.7,

127.7, 126.7, 124.1, 123.2, 122.6, 122.0, 113.7, 113.3, 55.1, 42.0, 33.0, 26.5, 21.5, 8.8.

176

3-(3-methyl-2-phenylbutan-2-yl)-1-tosyl-1H-indole (5-44): This compound was

prepared according to the General Procedure B using 3-methyl-2-phenylbutan-2-ol (41 mg,

0.25 mmol), 1-tosyl-1H-indole (102 mg, 0.375 mmol). After purification by column




(s, 1 H), 7.23 (d, J = 8.3 Hz, 2 H), 7.21-7.12 (m, 6 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.82 (d, J

= 8.1 Hz, 1 H), 2.67-2.58 (m, 1 H), 2.36 (s, 3 H), 1.63 (s, 3 H), 0.94 (d, J = 6.8 Hz, 3 H),

0.83 (d, J = 6.6 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 145.2, 144.7, 135.9, 135.1, 130.8, 130.3, 129.7, 127.7,

126.7, 125.8, 124.0, 123.3, 122.6, 122.4, 113.7, 46.0, 34.6, 22.7, 21.5, 18.9, 18.7.

3-(1-phenylpentyl)-1-tosyl-1H-indole (5-45): This compound was prepared according to

the General Procedure B using -1-phenylpentan-1-ol (41 mg, 0.25 mmol), 1-tosyl-1H-

indole (102 mg, 0.375 mmol). After purification by column chromatography on SiO2 (2%

EtOAc in hexanes), the title compound was isolated as a white solid (74 mg, 71% yield).


177

(s, 1 H), 7.25-7.13 (m, 9 H), 7.08 (t, J = 7.6 Hz, 1 H), 3.99 (t, J = 7.4 Hz, 1 H), 2.34 (s, 3

H), 2.15-2.06 (m, 1 H), 2.00-1.92 (m, 1 H), 1.39-1.19 (m, 4 H), 0.87 (t, J = 7.1 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 144.7, 143.6, 135.6, 135.2, 130.7, 129.7, 128.4, 127.8,

127.0, 126.7, 126.3, 124.6, 123.0, 122.7, 120.1, 113.7, 42.6, 35.3, 30.0, 22.7, 21.5, 14.0.

3-(tert-butyl)-1-tosyl-1H-pyrrole (5-46): This compound was prepared according to the

General Procedure A using tert-butanol (19 mg, 0.25 mmol), 1-tosyl-1H-pyrrole (83 mg,

0.375 mmol) at 50 ˚C. After purification by column chromatography on SiO2 (2% EtOAc

in hexanes), the title compound was isolated as a colorless liquid (55 mg, 79%, 93:7 rr

yield).

1H NMR (600 MHz, CDCl3): = 7.74-7.70 (m, J = 8.1 Hz, 2 H), 7.31-7.27 (m, J = 8.1

Hz, 2 H), 7.06 (t, J = 2.6 Hz, 1 H), 6.88 (s, 1 H), 6.25-6.22 (m, 1 H), 2.40 (s, 3 H), 1.17 (s,

9 H);

13C NMR (150 MHz, CDCl3): = 144.6, 140.4, 136.3, 129.9, 126.7, 120.7, 114.9, 112.5,

30.9, 30.7, 21.6.

3-(tert-pentyl)-1-tosyl-1H-pyrrole (5-47): This compound was prepared according to the

178

General Procedure A 50 ˚C using 2-methylbutan-2-ol (22 mg, 0.25 mmol), 1-tosyl-1H-

pyrrole (83 mg, 0.375 mmol). After purification by column chromatography on SiO2 (2%

EtOAc in hexanes), the title compound was isolated as a colorless liquid (50 mg, 69%

yield).


(t, J = 2.6 Hz, 1 H), 6.86 (s, 1 H), 6.21-6.15 (m, 1 H), 2.40 (s, 3 H), 1.45 (q, J = 7.4 Hz, 2

H), 1.13 (s, 6 H), 0.64 (t, J = 7.4 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 144.6, 138.8, 136.4, 129.8, 126.6, 120.9, 116.2, 112.9,

36.1, 34.0, 27.9, 21.6, 9.0.

(3R,5R,8R,9S,10S,13R,14S)-10,13-dimethyl-17-((R)-5-methyl-5-(1-tosyl-1H-indol-3-

yl)hexan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (5-48): This

compound was prepared according to the General Procedure A using

(3R,5R,8R,9S,10S,13R,14S)-17-((R)-5-hydroxy-5-methylhexan-2-yl)-10,13-dimethyl

hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (98 mg, 0.25 mmol), 1-tosyl-1H-indole



1H NMR (600 MHz, CDCl3): = 7.99 (dd, J = 2.4, 8.3 Hz, 1 H major), 7.74-7.63 (m, 3 H

major + 3 H minor), 7.51 (d, J = 7.8 Hz, 1 H minor), 7.31-7.13 (m, , 5 H major + 5 H minor), 3.86

179

(br. s., 1 H minor), 3.62 (d, J = 4.2 Hz, 1 H major), 2.38-2.27 (m, 3 H major + 3 H minor), 2.10 (m,

2 H minor), 1.92-1.53 (m, 9 H major + 7 H minor), 1.52-1.41 (m, 3 H major + 3 H minor), 1.41-1.21

(m, 9 H major + 9 H minor), 1.14 -0.63 (m, 10 H major + 4 H minor), 0.55-0.48 (3 H major, dr1 + 6

H minor), 0.35 (d, J = 6.6 Hz, 3 H major, dr2);

13C NMR (150 MHz, CDCl3): = 144.5, 143.4, 136.9, 136.2, 136.1, 135.8, 135.2, 131.5,

131.4, 129.8, 129.7, 129.7, 129.6, 126.7, 126.6, 126.5, 124.5, 124.1, 124.0, 123.0, 122.6,

122.6, 122.5, 122.4, 122.3, 121.7, 119.8, 114.0, 113.9, 71.9, 71.9, 56.4, 55.6, 52.7, 48.9,

43.4, 42.5, 42.3, 42.0, 41.7, 41.7, 41.6, 40.4, 40.1, 39.3, 39.1, 38.7, 37.7, 37.6, 37.1, 36.9,

36.5, 36.4, 36.2, 36.1, 35.8, 35.8, 35.3, 35.2, 35.1, 34.9, 34.9, 34.6, 34.5, 34.5, 34.4, 31.6,

31.1, 30.6, 30.5, 30.5, 29.1, 28.4, 28.4, 28.2, 28.2, 28.2, 27.9, 27.6, 27.2, 27.1, 26.9, 26.6,

26.4, 25.5, 25.3, 25.3, 25.1, 25.1, 24.1, 23.4, 23.3, 23.1, 23.1, 22.6, 22.6, 22.3, 21.6, 21.5,

20.7, 20.7, 19.3, 18.7, 14.9, 14.1, 12.0, 11.9.

N-(adamantan-1-yl)-4-methylbenzenesulfonamide (5-53): This compound was


p-toluene sulfonamide (65 mg, 0.375 mmol). After purification by column chromatography




(s, 1 H), 2.40 (s, 3 H), 1.97 (br. s., 3 H), 1.76 (br. s., 6 H), 1.61-1.48 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 142.6, 141.1, 129.4, 126.9, 55.0, 43.0, 35.8, 29.4, 21.5.

180

1-azidoadamantane (5-54): This compound was prepared according to the General

Procedure B using 1-adamantanol (38 mg, 0.25 mmol), trimethylsilyl azide (49 µL, 0.375

mmol) in MeNO2 (0.5 mL) at 80 ̊ C. After purification by column chromatography on SiO2


yield). The spectral data match with literature.176

1H NMR (600 MHz, CDCl3): = 2.15 (br. s., 3 H), 1.80 (br. s., 6 H), 1.73-1.59 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 59.0, 41.5, 35.9, 29.8.

benzyl (adamantan-1-yl)carbamate (5-55): This compound was prepared according to

the General Procedure B using 1-adamantanol (38 mg, 0.25 mmol), benzyl carbamate (57

mg, 0.375 mmol) in HFIP (0.5 mL) at 80 ̊ C. After purification by column chromatography



1H NMR (600 MHz, CDCl3): = 7.39 - 7.33 (m, 4 H), 7.33 - 7.28 (m, 1 H), 5.03 (br. s.,

2 H), 4.63 (br. s., 1 H), 2.08 (br. s., 3 H), 1.94 (br. s., 6 H), 1.67 (br. s., 6 H);

13C NMR (150 MHz, CDCl3): = 154.2, 136.8, 128.5, 128.1, 128.0, 65.9, 50.7, 41.8, 36.3,

29.4.

181

1-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)adamantane (5-56): This compound was

prepared according to the General Procedure A using 1-adamantanol (38 mg, 0.25 mmol).


compound was isolated as a colorless liquid (41 mg, 54% yield).

1H NMR (600 MHz, CDCl3): = 4.45-4.35 (m, 1 H), 2.21 (br. s., 3 H), 1.79 (br. s., 6 H),

1.57-1.69 (m, 6 H);

13C NMR (150 MHz, CDCl3): = 121.6 (J = 283.5 Hz), 78.5, 67.8 (J = 31.5 Hz), 41.6,

35.8, 30.8, 30.7.

182

Chapter 6

Iodide-Catalyzed Oxyamination of Olefins for Synthesis of

Oxazolidinone from Unfunctionalized Carbamate

6.1 Introduction

Alkene difunctionalization has emerged as a powerful tool to rapidly construct

molecular complexity via simultaneous construction of multiple carbon-carbon, carbon-

heteroatom bonds across alkenes.113, 178 In this regard, oxyamination of alkene is one of the

most attractive and widely used transformations for the modular synthesis of vicinal amino

alcohol which is a common motif in natural products, bioactive compounds, and ligand

frameworks.109 In this context, absolute control of regio- and stereoselectivity in alkene

oxyamination is highly appealing but difficult to achieve in the alkene difunctionalization

field. Sharpless osmium-catalyzed hydroxyamination reaction became prominent after its

discovery in 1996 and remains as a benchmark for the asymmetric synthesis of 1,2-amino

alcohol (Scheme 6-1a).19-20 The toxicity of the catalyst and poor regioselectivity have

encouraged several other groups to develop alternative oxyamination protocols. Significant

efforts have been devoted to broader substrate scope and address the regio- and

enantioselectivity issues via intramolecular oxyamination of alkenes, achieved by

Palladium,179-184 Copper,185-187 Gold,188 and non-metal catalysis.189-193 However, catalytic

and regioselective intermolecular oxyamination of alkene remains significant challenges.

183

Scheme 6-1: Literature Background of Alkene Oxyamination

184

In this regard, Stahl group reported palladium-catalyzed aminoacetoxylation of allylic and

homoallylic ether and ester (Scheme 6-1b).21 Yoon group discovered elegant strategies

utilizing copper and iron catalyst for regiodivergent oxyamination of terminal alkenes with

oxaziridines (Scheme 6-1c).22-24 Despite the advancement of the above-mentioned

reactions, direct intermolecular oxyamination of alkene for the synthesis of oxazolidinone

is underdeveloped due to the poor nucleophilicity of carbamate substrate. To address this

issue, Xu group disclosed an iron-catalyzed strategy for oxazolidinone synthesis,

proceeded via iron-nitrenoid species generated by the cleavage of N-O bond of

functionalized hydroxylamine.194 In addition, the significance of oxazolidinones as

bioactive compounds and chiral auxiliary in asymmetric synthesis has greatly inspired

many synthetic chemists to develop different strategies to afford the oxazolidinones from

other useful precursors.30, 41 The common methods to access to this oxazolidinone

structures involves the coupling of carbon dioxide with aziridine, amino alcohol or

epoxide.195-198 Moreover, Beller group developed a ruthenium-catalyzed synthesis of

oxazolidinone from diol and urea via hydrogen atom transfer.199 However, most of the

methods are limited to presynthesized starting materials, functionalized nucleophile, and

often poor regioselectivity, make the methods unattractive to medicinal chemists.

Therefore, development of a simple intermolecular oxyamination method for swift

construction of a custom compound library of oxazolidinone heterocycles is highly

desirable.

Our group has previously discovered an iodide-catalyzed formal [3+2]

cycloaddition of ureas with alkenes.173 From mechanistic studies, it revealed that reaction

went through an in-situ generation of iodonium intermediate with alkenes, followed by the

185

Table 6.1: Optimization of Reaction Condition

nucleophilic attack of urea on iodonium ion, leading to the formation of 2-aminooxazoline.

We wonder whether we could utilize the unfunctionalized carbamate as a nucleophilic

coupling partner and achieve the same iodonium intermediate as a regioselective template

186

for the synthesis of oxazolidinone. Herein, we disclose an iodide-catalyzed oxyamination

of alkenes for oxazolidinones synthesis from carbamates.

6.2 Results and Discussions for Alkene Oxyamination


To validate our hypothesis, we commenced our reaction with styrene, methylcarbamate,

TBAI, and Selectfluor as an oxidant in DCE at 90 ˚C for 16 h. To our delight, the reaction

provided 47% yield of our expected oxazolidinone product in a single regioisomer (Table

6.1, entry 1). After the screening of solvents revealed that hexane was the superior solvent

in this oxyamination reaction (Table 6.1, entries 2-4). The other iodide sources did not

improve the yield of products (Table 6.1, entries 5-7). The testing of Lewis acids further

demonstrated that Fe(OTf)2 was the best Lewis acid to provide the product in 73% yield

(Table 6.1, entries 8-10). The optimal yield of the product was achieved by the evaluation

of the stoichiometry of carbamate and Fe(OTf)2, affording oxazolidinone in 76% (Table

6.1, entries 11-14). In the absence of Selectfluor, the reaction did not furnish any product,

suggested that Selectfluor was essential in this reaction (Table 6.1, entry 16).


Based on the optimized conditions, we sought to explore the alkene substrate scope

for this oxyamination reaction. Different halogen-substituted styrenes provided the

products in high yields (Table 6.2, products 6-9 to 6-11). The electron-donating and

electron-withdrawing substituents were compatible, affording the products in good yields

with high regioselectivities (Table 6.2, products 6-12 to 6-14). The regioselectivity

187

Table 6.2: Substrate Scope for Alkene Oxyamination

obtained from styrene derivatives was nitrogen added on benzylic carbon and oxygen was

attached to the terminal carbon. Moreover, 1,1-disubstituted alkenes also furnished the

sterically congested products in excellent yields (Table 6.2, products 6-16 to 6-18). 1,2-

188

Disubstituted alkene such as trans-β-methyl styrene delivered the product with high

diastereoselectivity (Table 6.2, product 6-19). With satisfied with the alkene substrate

scope, we then focused on the carbamate substrate scope. Different substituents on the

nitrogen of carbamate were capable of providing the oxazolidinones in moderate to high

yields (Table 6.2, products 6-20 to 6-23).

6.3 Regiodivergent Alkene Oxyamination

The actual regioisomer of oxazolidinone product was with nitrogen on benzylic

carbon and oxygen on the homobenzylic position. We wondered whether we could oppose

the regioselectivity by controlling the halonium intermediate, generated from the alkene.

To our delight, when we used N-bromo succinimide (NBS) instead of iodonium condition,

the reaction provided opposite regioisomer of oxazolidinone (Scheme 6-2, product 6-24).

The regioselectivity of these reactions is governed by the relative rate of nucleophilic attack

on the halonium ion vs equilibrium between two resonance forms of carbamate. If the

reaction generates more electrophilic halonium, more nucleophilic nitrogen of carbamate

attack preferentially on the benzylic position whereas nucleophilic attack is slower,

equilibrium predominates the negative charge on the oxygen of carbamate. For example,

Lewis acid condition, the reaction goes through the formation of more electrophilic

iodonium and nitrogen attacks on iodonium before carbamate equilibrates to its resonance

form. The resulted intermediate 6-27 undergo cyclization to afford product 6-9. On the

other hand, in NBS condition, generated bromonium ion is less electrophilic than iodonium

ion and carbamate can equilibrate faster to its resonance form 6-26 where oxygen is

negatively charged, and nucleophilic attack occur from the more nucleophilic oxygen of

189

Scheme 6-2: Origin of Regiodivergent for Alkene Oxyamination

carbamate on bromonium, leading to the generation of complementary regioisomer of

oxazolidinone 6-24.


In order to shed light on the reaction mechanism, several experiments were

conducted. The control experiments in the absence of either TBAI or Selectfluor did not

190

Scheme 6-3: Proposed Reaction Mechanism for Alkene Oxyamination.

provide any oxazolidinone product which suggested the generation of iodonium in the

reaction (Table1, entry 16). To better understand the reaction intermediate, we ran reaction

using the iodo intermediate 6-29, which delivered the product in 50% yield, suggesting the

feasibility of 6-29 as catalytic intermediate (Scheme 6-3a). Based on experimental

observation and literature, we propose a mechanism for this alkene oxyamination in

Scheme 6-3b. The iodide salt is oxidized by Selectfluor and generates iodo intermediate 6-

29. This intermediate can activate alkene to form iodonium intermediate 6-30, which then

undergoes nucleophilic ring-opening with carbamate and followed by cyclization leading

to the product formation and generation of iodide catalyst. The regioselectivity, in this case,

191

is achieved by the nucleophilic attack from the nitrogen of carbamate on more electrophilic

benzylic carbon of iodonium intermediate.

6.5 Conclusion

We have developed an iodide-catalyzed alkene oxyamination protocol for the

synthesis of oxazolidinone. A broad range of alkenes and thioamides with various

functionalities are capable of affording products. The halide exchange of Selectfluor with

TBAI is the viable pathway for the reaction to occur. We have also demonstrated the

regiodivergent synthesis of oxazolidinone by utilizing two different halogen sources. The

exploration of this protocol with expanding substrate scope and achieving different

heterocycles is underway in our laboratory.

6.6 Experimental


Aldrich, Oakwood Chemicals, Alfa Aesar, Matrix Scientific, Acros Organic, and were

used as received. The carbamate substrates were synthesized according to the reported

procedure. Organic solutions were concentrated under reduced pressure on a Büchi rotary

evaporator using an acetone-dry ice bath. Chromatographic purification of products was

accomplished using flash chromatography on 230-400 mesh silica gel. Thin-layer

chromatography (TLC) was performed on Analtech 250 mm silica gel HLF UV-254 plates.

Visualization of the developed plates was performed by fluorescence quenching, potassium

192

permanganate, and iodine-silica gel system. 1H and 13C NMR spectra were recorded on a

Bruker 600 instrument (600 and 150 MHz) or INOVA 600 (600 and 150 MHz) and are

internally referenced to residual protio solvent signals (for CDCl3, 7.26 and 77.0 ppm,

MeOH-d4 3.31, 4.90 and 49.0 ppm, DMSO-d6 2.50 and 39.53 respectively). Data for 1H

NMR are reported as follows: chemical shift ( ppm), multiplicity (s = singlet, d = doublet,

t = triplet, q = quartet, h = heptet, m = multiplet, br = broad), integration, coupling constant

(Hz). 13C NMR spectra were reported as chemical shifts in ppm and multiplicity where

appropriate.


General Procedure: To a 8 mL vial equipped with a stir bar was added Fe(OTf)2 (9 mg,

5 mol% ), TBAI (20 mol%, 37 mg), F-TEDA-BF4 (266 mg, 0.75 mmol) and carbamate

substrate (1.5 mmol). Then hexane (1 mL) was added via syringe, followed by alkene

substrate (0.5 mmol). The reaction mixture was then heated to 90 ˚C and stirred for 16 h.

After cooling to room temperature, the reaction mixture was diluted with EtOAc (3 mL)

and quenched with 20% aq. Na2S2O3 (1 mL) and saturated NaHCO3 solution (1 mL). The

organic layer was separated and the aqueous layer was extracted with EtOAc (2×2 mL).

The combined organic layer was dried over Na2SO4 and concentrated under reduced

pressure to give the crude product, which was purified by column chromatography on silica

gel to afford the pure product.

193

Spectral Characterization of the Product

4-phenyloxazolidin-2-one (6-9): This compound was prepared according to the General

Procedure using styrene (58 µL, 0.5 mmol), methyl carbamate (113 mg, 1.5 mmol). After



1H NMR (600 MHz, CDCl3): = 7.43-7.29 (m, 5 H), 6.65 (br. s., 1 H), 4.94 (t, J = 7.8

Hz, 1 H), 4.74-4.67 (m, 1 H), 4.18-4.12 (m, 1 H);

13C NMR (150 MHz, CDCl3): = 160.1, 139.5, 129.0, 128.6, 125.9, 72.4, 56.3.

4-(4-bromophenyl)oxazolidin-2-one (6-10): This compound was prepared according to

the General Procedure using 4-bromostyrene (65 µL, 0.5 mmol), methyl carbamate (113




(br. s., 1 H), 4.91 (t, J = 7.8 Hz, 1 H), 4.69 (t, J = 8.7 Hz, 1 H), 4.10 (dd, J = 7.1, 8.3 Hz, 1

H);

194

13C NMR (150 MHz, CDCl3): = 160.0, 138.6, 132.2, 127.6, 122.6, 77.2, 76.8, 72.2,

55.7.

4-(4-chlorophenyl)oxazolidin-2-one (6-11): This compound was prepared according to

the General Procedure using 4-chlorostyrene (60 µL, 0.5 mmol), methyl carbamate (113




6.66 (br. s., 1 H), 4.94 (t, J = 7.9 Hz, 1 H), 4.71 (t, J = 8.8 Hz, 1 H), 4.12 (dd, J = 7.2, 8.2

Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 159.9, 138.0, 134.5, 129.3, 127.4, 72.3, 55.7.

4-(4-(tert-butyl)phenyl)oxazolidin-2-one (6-12): This compound was prepared

according to the General Procedure using 4-tert-butylstyrene (98 µL, 0.5 mmol), methyl

195

carbamate (113 mg, 1.5 mmol). After purification by column chromatography on SiO2


yield).


(br. s., 1 H), 4.93 (t, J = 7.8 Hz, 1 H), 4.70 (t, J = 8.7 Hz, 1 H), 4.17 (t, J = 7.8 Hz, 1 H),

1.35-1.28 (m, 9 H);

13C NMR (150 MHz, CDCl3): = 159.9, 151.8, 136.3, 126.0, 125.8, 72.5, 56.1, 34.6, 31.2.

4-(2-oxooxazolidin-4-yl)phenyl acetate (6-13): This compound was prepared according

to the General Procedure using 4-acetoxystyrene (77 µL, 0.5 mmol), methyl carbamate

(113 mg, 1.5 mmol) without Lewis acid. After purification by column chromatography on

SiO2 (50% EtOAc in hexanes), the title compound was isolated as a white solid (69 mg,

62% yield).


(s, 1 H), 4.93 (t, J = 7.8 Hz, 1 H), 4.68 (t, J = 8.6 Hz, 1 H), 4.13 (dd, J = 7.0, 8.6 Hz, 1 H),

2.29 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 169.4, 159.8, 150.7, 137.1, 127.2, 122.3, 72.3, 55.8,

21.0.

196

4-(4-(trifluoromethyl)phenyl)oxazolidin-2-one (6-14): This compound was prepared

according to the General Procedure using 1-(trifluoromethyl)-4-vinylbenzene (74 µL, 0.5

mmol), methyl carbamate (113 mg, 1.5 mmol). After purification by column




7.02 (br. s., 1 H), 5.03 (t, J = 7.8 Hz, 1 H), 4.74 (t, J = 8.8 Hz, 1 H), 4.15-4.08 (m, 1 H);

13C NMR (150 MHz, CDCl3): = 160.1, 143.5, 130.9 (q, 2JC-F = 33 Hz), 126.4,126.1(q,

3JC-F = 4.5 Hz), 125.5, 123.8 (q, 1JC-F = 271.5 Hz), 72.1, 55.8.

4-(naphthalen-1-yl)oxazolidin-2-one (6-15): This compound was prepared according to

the General Procedure using 2-vinylnaphthalene (77 mg, 0.5 mmol), methyl carbamate



197

1H NMR (600 MHz, CDCl3): = 7.96-7.80 (m, 3 H), 7.77 (s, 1 H), 7.59-7.47 (m, 2 H),

7.43 (dd, J = 1.8, 8.4 Hz, 1 H), 6.22 (br. s., 1 H), 5.09 (t, J = 7.9 Hz, 1 H), 4.77 (t, J = 8.8

Hz, 1 H), 4.25 (dd, J = 7.0, 8.4 Hz, 1 H);

13C NMR (150 MHz, CDCl3): = 159.8, 136.6, 133.3, 133.1, 129.4, 127.9, 127.7, 126.7,

126.6, 125.4, 123.2, 72.3, 56.4.

4-methyl-4-phenyloxazolidin-2-one (6-16): This compound was prepared according to

the General Procedure using α-methylstyrene (65 µL, 0.5 mmol), benzyl carbamate (227



1H NMR (600 MHz, CDCl3): = 7.43-7.34 (m, 4 H), 7.31 (t, J = 7.0 Hz, 1 H), 6.78 (br.

s., 1 H), 4.43-4.31 (m, 2 H), 1.75 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 159.4, 143.5, 128.9, 127.8, 124.5, 78.0, 60.5, 27.8.

4-(4-bromophenyl)-4-methyloxazolidin-2-one (6-17): This compound was prepared

according to the General Procedure using 4-bromo-α-methylstyrene (99 mg, 0.5 mmol),

198

benzyl carbamate (227 mg, 1.5 mmol). After purification by column chromatography on


73% yield).

1H NMR (600 MHz, CDCl3): = 7.49 (d, J = 8.5 Hz, 2 H), 7.39 (s, 1 H), 7.23 (d, J = 8.5

Hz, 2 H), 4.36 (d, J = 8.5 Hz, 1 H), 4.30 (d, J = 8.5 Hz, 1 H), 1.70 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 159.6, 142.7, 132.0, 126.4, 121.8, 77.7, 60.3, 27.8.

4-(4-fluorophenyl)-4-methyloxazolidin-2-one (6-18): This compound was prepared

according to the General Procedure using 4-fluoro-α-methylstyrene (68 mg, 0.5 mmol),

benzyl carbamate (227 mg, 1.5 mmol). After purification by column chromatography on


76% yield).

1H NMR (600 MHz, CDCl3): = 7.33 (dd, J = 5.1, 8.8 Hz, 2 H), 7.28 (br. s., 1 H), 7.05

(t, J = 8.7 Hz, 2 H), 4.37 (d, J = 8.3 Hz, 1 H), 4.31 (d, J = 8.3 Hz, 1 H), 1.72 (s, 3 H);

13C NMR (150 MHz, CDCl3): = 162.1 (d, J = 244.5 Hz), 159.6, 139.4 (d, J = 3 Hz),

126.4 (d, J = 7.5 Hz), 115.8, 115.7 (d, J = 21.0 Hz), 78.0, 60.2, 27.9.

199

5-methyl-4-phenyloxazolidin-2-one (6-19): This compound was prepared according to

the General Procedure using trans-β-methylstyrene (65 µL, 0.5 mmol), benzyl carbamate



1H NMR (600 MHz, CDCl3): = 7.41-7.36 (m, 2 H), 7.36-7.30 (m, 3 H), 6.50 (br. s., 1

H), 4.45 (d, J = 7.3 Hz, 1 H), 4.42-4.36 (m, 1 H), 1.48 (d, J = 6.2 Hz, 3 H);

13C NMR (150 MHz, CDCl3): = 159.4, 138.7, 129.0, 128.7, 126.1, 81.6, 64.0, 19.2.

3-phenethyl-4-phenyloxazolidin-2-one (6-22): This compound was prepared according

to the General Procedure using styrene (58 µL, 0.5 mmol), benzyl phenethylcarbamate



1H NMR (600 MHz, CDCl3): = 7.43-7.33 (m, 3 H), 7.28 (t, J = 7.3 Hz, 2 H), 7.23 (t, J

= 7.3 Hz, 1 H), 7.20-7.15 (m, 2 H), 7.12 (d, J = 7.1 Hz, 2 H), 4.55-4.45 (m, 2 H), 4.06

(dd, J = 6.3, 8.1 Hz, 1 H), 3.71 (ddd, J = 5.7, 8.4, 14.2 Hz, 1 H), 3.01-2.93 (m, 1 H), 2.92-

2.82 (m, 1 H), 2.75 (ddd, J = 5.9, 7.9, 13.6 Hz, 1 H);

200

13C NMR (150 MHz, CDCl3): = 158.0, 138.4, 137.6, 129.2, 129.0, 128.6, 128.5,

127.0, 126.5, 69.7, 60.2, 43.2, 33.5.

201

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