Efforts Toward Improved Allylic Substitution Via Pd-Catalyzed C-H Activation

Efforts Toward Improved Allylic Substitution via Pd-Catalyzed C-H Activation

Thesis

Presented in Partial Fulfillment of the Requirement for the Master of Science in the Graduate School of The Ohio State University

Chi H. Le. B.S.

Graduate Program in Chemistry

The Ohio State University

2014

Thesis Committee

Professor Christopher M. Hadad, Advisor

Professor James P. Stambuli

Professor Jonathan Parquette

Chi H. Le

2014

Abstract

Studies toward Pd-catalyzed allylic substitution via C-H activation are described for two reactions: allylic acetoxylation and allylic fluorination.

Through a systematic screen of different thioether ligands, a better catalytic condition for Palladium-catalyzed allylic acetoxylation was discovered. Using simple ligand such as tetrahydrothiophene, this protocol was able to produce higher yield and selectivity for the linear allylic acetate product than previously reported procedures.

Vinylsilanes were shown previously to effectively produce “pseudo-branch” allylic acetoxylation product. In attempts to take advantage of this finding, we set out to develop conditions for allylic fluorination of vinylsilanes. Screening conditions revealed

NFSI was competent in producing the desired allylic fluorine product. However, the allylic sulfonamide was also produced in equimolar amount in all cases. Discussion regarding the mechanism of the reaction and our solutions to induce the desired selectivity is shared.

Dedication

This document is dedicated to my family, my friends and my chemistry heroes.

iii

Acknowledgments

I believe that everything happens for a reason. When I ponder the journey I took to get to where I am today, the “everything” that happened to me was the incredible people I was blessed with.

Professor James Patrick Stambuli is my chemistry hero. I have never met a professor who loves chemistry as much as James. I really believe the reason why James is critical about research results is because he loves this field, he wants to protect the integrity of it, and he wants to advance it the right way. When you love chemistry as much as I do, it is impossible not to be inspired by James. It is also impossible not to see him as a true leader. He always leads by example, from the hours he puts in, the way he conducts research, to the way he presents his work. Some might say he is too tough but I would strongly disagree. I believe I can join any lab and be a productive member right away. I would not be who I am today without James’ guidance and “tough” training.

James also cares for his students. James cares for me. I still remember the night he came in the office to make sure I didn’t work through the night. I also remember the days when he just popped into lab to encourage me to keep going when research wasn’t going so well. James is my chemistry hero. When I join the Stambuli lab, I didn’t want James to be my friend, I wanted him to be my PI. That did not happen. James trained me to be a better graduate student, a better chemist, and a better teacher. But he did not stop there. He inspires me to be a better human being. For that, I am forever thankful.

I would like to thank Professor Christopher Hadad for all the opportunities he has given me. I have always thought of Chris as another advisor that I can always go to. His love for everything in chemistry has made all our conversation so enjoyable. Like James,

I can always tell that he cares for me. Just the fact that he always takes time out of his extremely busy schedule for me is incredible and touching. I can’t thank Chris enough for what he has done during my time at OSU. James and Chris, they are who I will always thrive to be when I become a professor.

I would like to thank Prof Anita Mattson, Prof Jon Parquette, Prof Craig Forsyth,

Prof Jovica Badjic, and Prof Christopher Callam for the impact they have made on my career path and my research interest.

My time at OSU wouldn’t be the same without my fellow graduate students. First,

I would like to thank Sean Whittemore for an awesome friendship and mentorship. Our love for organometallic chemistry has always made our discussions so enjoyable and productive. Sean was always available to listen to my struggles (mainly with trying to dehydrogenate fatty acids), my ideas (good and bad) and he was never afraid to tell me what I needed to hear. I always believe that a good labmate is someone who is not only critical of my ideas when I believe in it too much but also hopeful when I don’t believe in my ideas at all. Sean is an incredible labmate. I’m thankful to have him as a mentor and a friend.

Will Henderson, Chris Check, Matt Lauer, Mathieu Chellat, Matt Vanden

Eynden, Brenda Wray and Kamala Kunchithapatham will always be my older brothers and sister. I’m thankful for their patience and guidance during our time in the Stambuli

v lab. They were always very honest about what is expected of me and that, to me, is invaluable.

Kelsey Miles and I never seemed to be able to get along but she has always challenged me to be a better chemist every day. She has shown me that it is important to understand our differences in order to work together to achieve a common goal. That is one the most important lessons I have learned during my time here. I am thankful for our time together.

I would like to thank Amneh Awad, Luke Baldwin, Jon Crowe, Ryan McKenney,

Tom Corrigan and Ben Garrett for their patience while working with me. I always think of our lab as a family and this family would definitely not be the same without each and every single one of you.

I would like to thank Sonia So, Josh Wieting, Krista Cunningham, Andrew

Schafer, Tyler Auvil, and Erica Couch for the support they have always generously given. I can easily write a book on why everyone (not just graduate students) needs people like you in their lives. I am blessed to know you all.

I am lucky to have a big family (too big to list) who has always encouraged me to be the best that I can be. More importantly, they love me for who I am and not my achievements. Somehow, that drives me to work harder and care deeper about what I do.

Most importantly, I am thankful for my Heavenly Father. The people I am given in my life are the biggest blessings any son could ask for.

Vita

June 29, 1988 ...... Born – Ho Chi Minh City, Vietnam

2006...... Greater Atlanta Christian School

2010...... B.S. Chemistry, Harding University

2010 to 2011 ...... Graduate Teaching Assistant, Organic

Division, Department of Chemistry

The Ohio State University

2011 to present ...... Graduate Teaching Assistant, NMR Facility

Department of Chemistry

2010 to present ...... Graduate Research Assistant, Department of

Chemistry, The Ohio State University

Publications

Le, C.; Kunchithapatham, K.; Henderson, W. H.; Check, C. T.; Stambuli, J. P. Chem.

Eur. J. 2013, 19, 11153.

Fields of Study

Major Field: Chemistry

vii

Table of Contents

Abstract ...... ii

Dedication ...... iii

Acknowledgments...... iv

Vita ...... vii

Table of Contents ...... viii

List of Schemes ...... x

List of Tables ...... xii

List of Figures ...... xiv

List of Abbreviations ...... xv

Chapter 1: Overview of Allylic Substitution ...... 1

1.1. Introduction ...... 1

1.2. Metal-catalyzed allylic substitution via leaving group approach ...... 3

1.3. Metal-catalyzed allylic substitution via C-H activation approach ...... 5

1.4. Focus of this thesis ...... 7

Chapter 2: Pd-catalyzed Allylic Acetoxylation of Terminal Alkenes ...... 9

2.1. Introduction ...... 9

2.2. Results and Discussion ...... 13

viii

2.3. Conclusions and Future Work ...... 23

2.4. Experimental ...... 24

2.4.1. Materials and Methods ...... 24

2.4.2. Experimental Procedures for The Synthesis of New Ligands ...... 25

2.4.3. General Procedure for The Ligand Screens ...... 28

2.4.4. Substrate Scope for Allylic Acetoxylation of Terminal Olefins ...... 29

Chapter 3: Allylic Fluorination of Vinylsilanes...... 35

3.1. Introduction ...... 35

3.2. Method Development...... 40

3.3. Understand the Mechanism...... 51

3.4. Progress Toward Synthesis of NFSI Derivatives...... 55

3.5. Conclusions and Future Work ...... 58

3.6. Experimental ...... 59

3.6.1. Materials and Methods ...... 59

3.6.2. Independent Synthesis of Isolated Products ...... 60

3.6.2.-3.6.7 General Procedure for Screening Conditions ...... 62

3.6.8. Procedure for Isolation of Major Products ...... 64

References ...... 65

Appendix A: NMR Spectra of Selected Compounds ...... 70

Appendix B: Results of Conditions Screened for Vinylsilanes Allylic Fluorination ...... 97

List of Schemes

Scheme 1.1. Possible convergent transformation from allylic substitution motifs ...... 2

Scheme 1.2. Common routes to access allylic alcohols...... 3

Scheme 1.3. General mechanism for allylic substitution via LG approach ...... 4

Scheme 1.4. Examples of reported allylic substitution via LG approach ...... 5

Scheme 1.5. Proposed mechanism for allylic substitution via C-H activation ...... 6

Scheme 1.6. Examples of reported allylic substitution via C-H activation ...... 7

Scheme 2.1. Early example of Pd-catalyzed allylic acetoxylation ...... 10

Scheme 2.2. Recent reported examples of Pd-catalyzed allylic acetoxylation ...... 11

Scheme 2.3. Example of thioether ligand in promoting allylic acetoxylation ...... 12

Scheme 2.4. General mechanism of Pd-catalyzed allylic acetoxylation ...... 12

Scheme 3.1. Examples of selective sp2 C-H fluorination ...... 36

Scheme 3.2. Examples of selective sp3 C-H fluorination ...... 37

Scheme 3.3. Allylic fluorination of terminal alkene via Pd-catalyzed C-H activation...... 38

Scheme 3.4. Selectivity of π-allyl complex with silane groups ...... 39

Scheme 3.5. Desired transformation for allylic fluorination of vinylsilanes ...... 40

Scheme 3.6. Synthesis of desired product via reported methodology ...... 41

Scheme 3.7. Different selectivity for nucleophilic Pd-π-allyl system ...... 42

Scheme 3.8. Isolation of major products ...... 51

Scheme 3.9. Mechanism via nucleophilic allyl system ...... 52

Scheme 3.10. Mechanism via Pd(II)/Pd(IV) catalytic system ...... 53

Scheme 3.11. Attempt at changing substituents of Pd(IV) complex ...... 54

Scheme 3.12. Studies on effect of sulfonamide on rate of C-F reductive elimination ...... 55

Scheme 3.13. Reported synthesis of NFSI derivatives ...... 56

Scheme 3.14. Previously reported fluorination of primary and secondary amines ...... 56

Scheme 3.15. Attempt at synthesis of NFSI derivatives ...... 57

Scheme 3.16. Attempt at in-situ generation of NFSI derivatives ...... 57

Scheme 3.17. Synthesis of N-fluorosulfonamide 3.41 ...... 58

Scheme 3.18. Attempt at allylic fluorination with 3.41 ...... 58

Scheme 3.19. Best up-to-date conditions for allylic fluorination of vinylsilanes ...... 59

Scheme 3.20. Independent synthesis of 3.30 ...... 61

List of Tables

Table 2.1. Yields of common substrates in Pd-catalyzed allylic acetoxylation ...... 13

Table 2.2. Akyl-aryl sulfides as ligands in allylic acetoxylation of terminal olefins ...... 15

Table 2.3. Aryl-aryl sulfides as ligands in allylic acetoxylation of terminal olefins ...... 17

Table 2.4. Bidentate sulfides as ligands in allylic acetoxylation of terminal olefins...... 19

Table 2.5. Dialkyl sulfides as ligands in allylic acetoxylation of terminal olefins ...... 21

Table 2.6. Substrate scope of allylic acetoxylation reactions with THT as ligand ...... 22

Table 2.7. New benchmark in Pd-catalyzed allylic acetoxylation of terminal olefins ...... 23

Table 3.1. Screen of nucleophilic fluorine source in Pd-catalyzed allylic fluorination .....42

Table 3.2. Screen of electrophilic fluorine source in Pd-catalyzed allylic fluorination ....44

Table 3.3. Solvents screen of Pd-catalyzed allylic fluorination with NFSI ...... 45

Table 3.4. Screen of sulfide ligands in allylic fluorination with NFSI and BQ ...... 46

Table 3.5. Screen of sulfoxide ligands in allylic fluorination with NFSI and BQ ...... 47

Table 3.6. Screen of BQ equivalent in allylic fluorination with NFSI ...... 48

Table 3.7. Screen of ligands in allylic fluorination without BQ ...... 49

Table B.1. Screen of oxidants in allylic fluorination ...... 98

Table B.2. Screen of in situ-generated fluorine sources in allylic fluorination ...... 99

Table B.3. Screen of in situ-generated fluorine sources w/ bases in allylic fluorination 100

Table B.4. Screen of NFSI derivatives in allylic fluorination ...... 101

Table B.5. Screen of NFSI derivatives with bases in allylic fluorination...... 102

xii

Table B.6. Screen of anionic NFSI derivatives in allylic fluorination...... 103

Table B.7. Screen of potassium anionic NFSI derivatives in allylic fluorination ...... 104

Table B.8. Screen of silver salts in [Pd(allyl)Cl]2-catalyzed allylic fluorination ...... 105

Table B.9. Screen of ligands in [Pd(allyl)Cl]2-catalyzed allylic fluorination ...... 106

xiii

List of Figures

Figure 1.1. Allylic substituted scaffold found in important drug/imaging molecules ...... 2

Figure 2.1. Plot of percent yield of linear allylic acetate vs. Hammett δ values ...... 18

Figure 3.1. Selectivity of π-allyl complex to give branch or linear product ...... 38

xiv

List of Abbreviations

⁰C degrees Celsius

α alpha

Å angstrom

β beta

γ gamma

Δ heat (reflux)

δ chemical shift in parts per million

μ micro

1H NMR proton nuclear magnetic resonance

13C NMR carbon 13 nuclear magnetic resonance

Ac acetyl

AcOH acetic acid aq aqueous atm atmosphere(s)

Bn benzyl

Bt benzotriazole

BQ 1,4-benzoquinone br broad nBu normal-butyl

xv sBu sec-butyl tBu tert-butyl

Bz benzoyl c centi c concentration calcd calculated

CAM ceric ammonium molybdate cat catalytic

COSY correlation spectroscopy

CSA camphorsulfonic acid

D dextrorotatory d day(s); doublet dba dibenzylideneacetone

DCM dichloromethane dd doublet of doublets

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

(DHQ)2PHAL dihydroquinine 1,4-phthalazinediyl diether

(DHQD)2PHAL dihydroquinidine 1,4-phthalazinediyl diether

DIAD diisopropyl azodicarboxylate

DIBAL diisobutylaluminum hydride

DIPEA diisopropylethylamine

DMAP N,N-dimethylaminopyridine

DME 1,2-dimethoxymethane

DMF N,N-dimethylformamide

xvi

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide dppe 1,2-bis(diphenylphosphino)ethane dt doublet of triplets

E entgegen ee enantiomeric excess equiv equivalent(s)

ESI electrospray ionization

Et ethyl

FTIR Fourier transform infrared spectroscopy g gram(s)

GC gas chromatography h hour(s)

HMPA hexamethylphosphoramide

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

HWE Horner-Wadsworth-Emmons

Hz hertz

IR infrared iPr iso-propyl

J coupling constant in Hertz

L liter(s)

L levorotatory

LDA lithium diisopropylamide

xvii

LiHMDS lithium hexamethyldisilazide lut 2,6-lutidine m meta m milli; multiplet

M molarity m-CPBA meta-chloroperoxybenzoic acid

Me methyl

MeCN acetonitrile

MeOH methanol min minute(s) mol mole(s)

MOM methoxymethyl

MS mass spectrometry; molecular sieves

Ms mesyl/methanesulfonyl

MTBE methyltert-butyl ether

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NMP N-methyl-2-pyrrolidone

NOESY nuclear Overhauser effect spectroscopy

NR no reaction o ortho p para p pentet

Pd(OAc)2 palladium (II) acetate

xviii pdt product

PEG polyethylene glycol

Ph phenyl

PIDA phenyliodine diacetate

PMB para-methoxybenzyl ppm parts per million iPr iso-propyl p-TSA para-toluenesulfonic acid pyr pyridine q quartet

R rectus rt room temperature s sec/secondary s singlet

S sinister sat. saturated sep septet sext sextet

SM starting material t/tert tertiary t triplet

TBAB tetrabutylammonium bromide

TBAC tetrabutylammonium chloride

TBAF tetrabutylammonium fluoride

xix

TBAI tetrabutylammonium iodide

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TES triethylsilyl

TEA triethylamine

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

Tf triflyl/(trifluoromethanesulfonyl)

THF tetrahydrofuran

TFA trifluoroacetic acid

TLC thin layer chromatography

TMEDA tetramethylethylenediamine

TMS trimethylsilyl

TMSE 2-(trimethylsilyl)ethyl

Ts tosyl/(p-toluenesulfonyl)

UV ultraviolet

Z zusammen

Chapter 1: Overview of Allylic Substitution

1.1 Introduction

Nature has long been an inspirational source of biologically-active molecules.1

Organic compounds extracted from living organisms are often found to be active against numerous illnesses and diseases that are considered untreatable or incurable.2 Careful structural studies and modifications of biologically active molecules can lead to more selective and effective drug candidates.2 The drug design process can be hampered by two factors: (1) Low efficiency in isolation and synthesis; (2) Limited modifications due to lack of converging points or available methodology. Understanding these shortcomings, organic transformation methodology development continues to be the foundation of multiple drug discovery disciplines. As part of this community, our group is particularly interested in finding new protocols that can lead to more efficient and selective allylic substitutions.

Figure 1.1. Allylic substituted scaffold found in important drug/imaging molecules

Motifs including substitution at the allylic position are ubiquitous in many important molecules (Figure 1.1).2 They are also important building blocks that can serve as a converging point in synthesis (Scheme 1.1).3

Scheme 1.1. Possible convergent transformations from allylic substitution motifs

Popular methods in constructing these motifs often require an allylic alcohol as the starting point, which is commonly synthesized by utilizing selenium dioxide or by addition of a nucleophilic vinyl group to the appropriate carbonyl (Scheme 1.2).4

Although reliable, the aforementioned methodologies can suffer from functional group compatibility. Moreover, they can create excess waste and lengthy protocols, making the overall synthesis unattractive.4

Scheme 1.2. Common routes to access allylic alcohols

Metal-catalyzed methodologies have become a major force in establishing new reactivity patterns. These protocols also offer attractive upside in both efficiency and selectivity. Allylic substitution has benefited tremendously from the advances of this field due to the presence of a nearby olefin, which serves as an excellent directing group. In constructing allylic substitution motifs, there are two major approaches that are commonly employed: (1) Leaving group (LG) approach and (2) C-H activation approach.

1.2. Metal-catalyzed allylic substitution via LG approach

In the LG approach, the reaction takes advantage of the ease of insertion of the metal center into the allylic C-LG bond following the metal-olefin coordination (Scheme

1.3).3c, 3h, i This can lead to a metal-π-allyl complex that can be further functionalized with

3 the appropriate nucleophile to furnish allylic substituted product. LG is often a halide or pseudo-halide such as acetate, trichloroacetimidate and other alcohol-derived groups.

Scheme 1.3. General mechanism for allylic substitution via LG approach

Multiple transition metals have been shown to be effective in forming C-C, C-N, and C-F bonds.3a-d, 3h-k Representative examples of these transformations are shown in

Scheme 1.4. All starting materials require a leaving group, which is often synthesized from an allylic alcohol. While convenient and well-established, the approach using a leaving group still depends on the ability to construct allylic alcohols, which can suffer from functional group tolerance and synthetic inefficiency. The C-H activation approach has recently become more popular as it aims to alleviate these setbacks.

Scheme 1.4. Examples of reported allylic substitution via LG approach.3b, 3j, 5

1.3. Metal-catalyzed allylic substitution via C-H activation approach

The ubiquitous nature of the C-H bond creates difficulty in designing selective functionalization. Taking advantage of the olefin as a directing group and also the difference in bond dissociation energy, allylic C-H can be exclusively functionalized.

Among reported conditions, palladium acetate complexes have been found to be popular catalysts due to a broad tolerance of substrates and reliable reactivity patterns.3e-g, 6

Following the initial olefin coordination, acetate-assisted deprotonation occurs at the allylic position to yield a π-allyl Pd complex.3f Similar to the leaving group approach,

5 multiple allylic substitution motifs can be synthesized with the appropriate nucleophile

(Scheme 1.5).

Scheme 1.5. Proposed mechanism for allylic substitution via C-H activation approach

The C-H activation approach can be seen as not only a complement, but also a progressive alternative to the LG approach. Protocols have been developed to prepare allylic acetates, which can be used as starting materials for numerous well-known metal- catalyzed allylic substitutions. Moreover, conditions have also been found to be effective in constructing C-C, C-N and C-F bonds (Scheme 1.6).3e-g, 3l, 6a, b, 7

Scheme 1.6. Examples of reported allylic substitution via LG approach.3e, 3g, 3l, 6a

1.4. Focus of this thesis

Recognizing the benefits of the C-H activation approach, we became interested in finding new methodologies that can be added to the growing library of established protocols. Allylic acetate continues to serve as an important functional group due to its converging versatility in synthesis. In order to improve current catalysts for palladium-

7 catalyzed allylic acetoxylation, we performed an extensive ligands study, focusing on thioether ligands. The results, discussion, and future work are shared in chapter 2.

During the course of our studies, we became aware of the ability of vinylsilanes to serve as excellent analogs for terminal olefins. Understanding the importance of allylic fluorine installation, we set out to apply our findings in vinylsilanes to establish an optimal palladium-catalyzed allylic fluorination protocol. Our effort in this area is discussed in chapter 3.

Chapter 2: Pd-catalyzed allylic acetoxylation of terminal alkenes

2.1 Introduction

Selective functionalization of a C-H bond in complex molecules has long been considered the “holy grail” of organic chemistry.8 Following the success in traditional cross coupling chemistry (Suzuki9, Neigishi10, Stille11, Hartwig-Buchwald12), transition metal complexes have shown promising reactivity toward C-H activation. The majority of research efforts have been focusing on functionalizing aromatic sp2 C-H bonds by taking advantage of the relatively lower bond dissociation energy and high stability of metal-arene species. In addition, high regioselectivity can be achieved by installing directing group tethered to the aromatic system. Work done by Ellman13, Sanford14, and

Yu15 have shown this is an excellent strategy.

The same approach can be used to selectively substitute allylic C-H bonds.

Similar to aromatic C-H bonds, allylic C-H bonds have relatively low bond dissociation energy. Comparable to metal-arene systems, metal-π-allyl complexes are stable, which lead to a low activation energy barrier during the C-H activation step. Since olefins can be transformed further to expand the complexity of the molecule, the ability to substitute allylic C-H is of high importance.4 Among different transformations one can think of for allylic C-H activation, efficient allylic acetoxylation stands out as one of the major goals in this arena. Since allylic acetate is a common starting material for well-established

9 allylic substitution (see chapter 1 for examples), an effective and selective preparation of this motif can serve as the bridge between the traditional allylic substitution methodology and allylic C-H activation. Moreover, as demonstrated by White and coworkers7, allylic acetoxylation can be expanded to allylic macrolactonization, which continues to be a key step in many synthesis efforts of complex molecules.

In 1966, Rappoport and Young reported the first example of allylic C-H

16 activation of terminal alkenes by Pd(OAc)2. When stoichiometric palladium was used in acetic acid, vinylic acetate was observed the major product with a small amount of linear allylic acetate. Interestingly, with DMSO as a co-solvent, the linear allylic acetate became the major product, isolated in 73% yield (Scheme 2.1). Although considered a weakly-coordinating ligand, DMSO was shown to be competent in controlling the reactivity of the metal complex.

Scheme 2.1. Early example of Pd-catalyzed allylic acetoxylation reported by Rappoport

Guided by this promising result, several groups have performed extensive research toward catalytic conditions with different classes of ligands (Scheme 2.2).3e, f, 6c,

Scheme 2.2. Recent reported examples of Pd-catalyzed allylic acetoxylation.3e, f, 6c, 17

Despite the widespread usage of sulfoxide as ligands in metal-catalyzed methodology, sulfide ligands are typically avoided due to the common belief in their inhibition tendency toward metal complexes.18 Our group was pleased to discover a novel thioether-ligated palladium complex that is competent in promoting allylic acetoxylation

(Scheme 2.3).3e

Scheme 2.3. Example of thioether ligand in promoting allylic acetoxylation.3e

The proposed mechanism of allylic acetoxylation (Scheme 2.4) begins with coordination of a terminal alkene to yield complex II. From here, acetate-assisted C-H activation occurs at the allylic position to yield π-allyl complex III. Reductive elimination can proceed at the terminal position to yield Pd(0) complex IV. In some cases, elimination can also occur at the internal position (not shown) to yield the branch product as the major product (example 2, scheme 2.2). Following dissociation of the olefin, Pd(0) complex is oxidized by benzoquinone and acetic acid to regenerate complex

I in the catalytic cycle..3f, 6c, 17a

Scheme 2.4. General mechanism of Pd-catalyzed allylic acetoxylation 12

A quick glance at the three most promising allylic acetoxylation conditions (Table

2.1) reveals the need for a much more general and reliable system before this type of methodology can be considered a daily synthetic protocol. Building off previous success we had with sulfide ligands, we set out to screen a variety of thioether ligand families to better understand the behavior of the palladium-sulfide catalyst in allylic acetoxylation of terminal alkenes. The results of this study can also be used to develop a better catalytic system.

Table 2.1. Yields of common substrates in Pd-catalyzed allylic acetoxylation. 3e, f, 6c

2.2. Results and Discussion

The ligand screens were carried out using 1-dodecene (2.1) as the test substrate.

In order to examine the efficiency of the catalyst, conversion of starting material and 13 yield of desired product (E)-2.2 were measured for each condition. Ratios between 2.2,

2.3 and 2.4 as well as linear E/Z were used to evaluate the level of selectivity.

The study began with determining the importance of the oxygen atom on ligand

2.5, which gave 52% yield with good selectivity of linear over branch and vinylic product

(Table 2.2, entry 1). When oxygen was replaced by the methylene group (2.6), there was no change in conversion and the yield was slightly higher. Using ligand 2.6, 2.7, and 2.8 also showed that the oxygen atom does not affect the catalyst’s reactivity. The outcome of the reaction changed dramatically when a strong electron-withdrawing group was added to the alkyl portion (2.9, entry 5). The decrease in conversion and linear selectivity can be explained by the weaker coordination of the less basic sulfur ligand. This can lead to greater catalyst decomposition through precipitation of Pd(0), which results in low turnover. Weak coordination allows “naked” Pd(OAc)2 to interact with alkenes to yield vinylic products, which was shown in the original report by Rappoport. Simple sulfide

2.10 proved to be efficient in promoting better conversion, but with comparable yield to

2.5 due to a decrease in selectivity. Modification of the aromatic scaffold of 2.10 (entry 7 to 10) revealed that an electron-rich system (2.11, 2.12 & 2.14) provides better yield.

Unfortunately, when a more electron-donating group was used (2.12), the yield was comparable to when 2.11 was employed. Conversion and selectivity stayed the same when the alkyl portion was replaced with benzyl (2.14). The use of ortho-acetyl thioanisole and ethylnaphthyl sulfide did not give improved results.

Table 2.2. Alkyl-aryl sulfides as ligands in allylic acetoxylation of terminal olefins

Next, we exploited the tunability of diaryl sulfides to assess the necessary basicity of sulfide ligands in allylic acetoxylation. Diphenyl sulfide (2.17) provided good turnover but poor selectivity, yielding linear 2.2 and vinyl acetate 2.4 in comparable amounts.

Tweaking the electronics of the one aromatic scaffold did not suppress the formation of the vinyl product. The addition of electron-donating groups (2.18 – 2.25) or electron- withdrawing groups (2.26 – 2.31) gave low to poor yield of desired product. Placing activating groups on both aromatic rings (2.32, 2.33) did not provide promising results.

Using 2.33, the yield obtained was comparable to when simple aryl-alkyl sulfide such as

2.10 was used. Incorporation of the indolyl group (2.29) proved unfruitful in improving yield and selectivity.

Further examination of the relationship between Hammett δ value and yield of linear allylic acetate product (Figure 2.1) lent further support to our hypothesis of strong correlation between the ligand’s basicity and the system’s efficiency toward the desired product. In general, electron-rich aromatic systems provided higher yield and selectivity then electron-withdrawing ones. The para-cyano group, although known as a deactivator, showed higher yield than expected. This perhaps comes from the coordinating ability of the nitrile functionality. Since 2.27 and 2.28, our most electron-rich systems, failed to give high-yielding amount of linear acetate product, it was clear that diaryl sulfides are not the solutions to a better allylic acetoxylation condition.

Table 2.3. Aryl-aryl sulfides as ligands in allylic acetoxylation of terminal olefins

45.00

p-OCH3 40.00

35.00

30.00 H

25.00 m-OCH3 Yield(%) p-F 20.00 p-CN

15.00

10.00

m-CO2CH3 p-CF3

5.00

p-NO2

0.00 -0.3 -0.1 0.1 0.3 0.5 0.7 0.9 δ

Figure 2.1. Plot of percent yield of linear allylic acetate versus Hammett δ values

using ligands 2.17-2.19, 2.21-2.25 and yields from Table 2.3

Since basicity and coordinating strength seemed to correlate strongly with the yield and also selectivity for linear acetate product 2.1, we next investigated the effect of bidentate sulfide ligands (Table 2.4). Unfortunately, comparable yields were only achieved when catalyst loading was increased to 10 mol%. 1,2-bis(phenylthio)ethane

(2.30) gave linear acetate (E)-2.2 in good yield. Installing an electron-donating group resulted in diminished yield (2.31). Although electron-withdrawing group (2.32) provided high conversion, low linear/branch/vinyl selectivity led to similar yield as with 2.30. The naphthyl group was tested, but showed inferior activity (2.33, entry 4).

Table 2.4. Bidentate sulfide as ligands in allylic acetoxylation of terminal olefins

Changing the ligand linker’s length yielded interesting results. One-carbon linker

(2.34) showed high turnover; however, low E/Z selectivity gave a poor yield of (E)-2.2.

Four-carbon linker (2.35) gave excellent results in both conversion and yield of the desired product. Lastly, exchanging phenyl with a benzyl group (2.36) proved detrimental since the catalyst failed to give appreciable amount of any products. Although ligand 2.35 was able to provide the best conditions for allylic acetoxylation so far, the requirement for high catalyst loading diminishes its value. The bidentate nature of the ligand most 19 likely inhibits catalyst activity, and despite good selectivity, more palladium salt is required to compensate to give comparable yields with respect to the aryl-alkyl sulfides that were previously screened.

From the results we have obtained so far, it seems that there is a small range of ligand basicity/coordination strength that must be met in order to produce an efficient system with high selectivity. The ligand should bind to the metal center stronger than aryl-alkyl sulfide to induce more activity and prolong catalyst lifetime. However, if the binding strength surpasses that of bidentate nature, it becomes an inhibitor. Among common thioether molecules, dialkyl sulfide was envisaged to provide the right balance for this intricate system.

Dimethyl sulfide (2.37, Table 2.5), when combined with Pd(OAc)2 gave (E)-2.2 in 62% yield. A small increase in alkyl size resulted in small improvement (2.38).

However, when di-isobutyl sulfide (2.39) was used, selectivity decreased greatly which led to poor yield. Employing the tert-butyl scaffold (2.40), resulted in low conversion and inappreciable amount of the desired product. From these results, dialkyl sulfides seemed to provide the right amount of basicity. However, steric hindrance appeared to be an important factor. With that in mind, we tried to decrease the steric bulk of 2.38 by employing tetrahydrothiophene as a ligand. To our surprise, combination of 2.41 with

Pd(OAc)2 yielded superior results in conversion, selectivity and yield. At only 5 mol% catalyst loading, this simple ligand was able to promote 95% conversion while providing linear acetate (E)-2.2 in 88% yield.

Table 2.5. Dialkyl sulfides as ligands in allylic acetoxylation of terminal olefins

Encouraged by this result, we set out to test the substrate scope of this new catalytic system. We were pleased to find commercially available tetrahydrothiophene

(THT) promoted many of the highest yields reported to date with high selectivity for (E)- linear allylic acetate product. In addition to 1-dodecene (2.1), allylbenzene and 1-allyl-4- fluorobenzene also provided the corresponding acetoxylated product in good yield (Table

2.6, entry 2-3). Silyl ether or benzyl ether appended substrates gave decent yields (entry

5-6). Esters and amide functional group are tolerated to provide the desired product in good yields (entry 7-10).

Table 2.6. Substrate scope of allylic acetoxylation reactions with THT as ligand

2.3. Conclusions and Future Work

Multiple families of sulfide ligands were screened in attempt to improve Pd- catalyzed allylic acetoxylation of terminal alkenes. Generally, aryl-alkyl sulfides give good yield and selectivity for the linear acetoxylated products while diaryl sulfides tend to favor the vinyl acetoxylated product. Although bidentate sulfides were able to give decent turnover and yield, the required high catalyst loading diminished the value of the catalytic system. Dialkyl sulfides provided the most active and selective catalytic system, especially tetrahydrothiophene. With this new system, a new benchmark for Pd-catalyzed allylic acetoxylation reactions was established (Table 2.7).

Table 2.7. New benchmark in Pd-catalyzed allylic acetoxylation of terminal olefins

The results of this study can be used to develop the next generation of catalyst.

Although encouraged by the high activity of tetrahydrothiophene, the substrate scope can still be improved with regards to acid-sensitive functional groups. Reducing the amount of acetic acid can help to expand the functional group tolerance. Moreover, thioethers as ligands have the tendency to form complex multinuclear complexes, making catalyst design more challenging. Isolation and determination of the active catalyst’s structure will further the effort in allylic acetoxylation. The results of those studies can potentially enhance the understanding of fundamental organometallic chemistry of metal-sulfide complexes.

2.4. Experimental

2.4.1 Materials and Methods

Allylic oxidations were conducted in a 2 mL or 4 mL borosilicate glass vials in an air atmosphere. Palladium acetate was used as received from Pressure Chemicals. 1,4-

Benzoquinone was sublimed before use. All solvents were reagent grade, predried, or distilled. All other commercially obtained reagents were used as received. Ligands phenyl(2-(p-tolyloxy)ethyl)sulfane (2.5),3e phenyl(3-phenylpropyl)sulfane (2.6),19 benzyl(phenyl)sulfane (2.7),20 phenyl(2,2,2-trifluoroethyl)sulfane (2.9),21 methyl(p- tolyl)sulfane (2.11),22 (4-methoxyphenyl)(methyl)sulfane (2.12),22 (4- fluorophenyl)(methyl)sulfane (2.13),22 benzyl(p-tolyl)sulfane (2.14),20 1-(2- methylthio)phenylethanone (2.15),23 (4-methoxyphenyl)(phenyl)sulfane (2.18), 24 (3- methoxyphenyl)(phenyl)sulfane (2.19),24 (2,6-dimethylphenyl)(phenyl)sulfane (2.20),24

(4-fluorophenyl)(phenyl)sulfane (2.21),24 (4-nitrophenyl)(phenyl)sulfane (2.22),24 4-

(phenylthio)benzonitrile (2.23),24 3-(phenylthio)benzoic acid,24 phenyl(4-

(trifluoromethyl)phenyl)sulfane (2.25),24 phenyl(2-(trifluoromethyl)phenyl)sulfane

(2.26),24 (4-methoxyphenyl)(p-tolyl)sulfane (2.27),24 (2-methoxyphenyl)(p-tolyl)sulfane

(2.28),24 5-(p-tolylthio)-1H-indole (2.29),24 bis(phenylthio)methane (2.34),25 1,4- bis(phenylthio)butane (2.35),26 1,2-bis(benzylthio)ethane (2.36),27 were synthesized according to literature procedures. Substrates 1-allyl-4-fluorobenzene (2.42),28 tert- butyl(hex-5-en-1-yloxy)diphenylsilane (2.45),29 ((hex-5-en-1-yloxy)methyl)benzene

(2.46),30 4-methoxybenzyl pent-4-enoate (2.47),3e but-3-en-1-yl benzoate (2.48),31 1-(but-

3-en-1-yl)pyrrolidine-2,5-dione (2.49),32 1-(1-phenylbut-3-en-1-yl)pyrrolidine-2,5-dione

(2.50)33 were prepared according to literature procedures.

GC analysis was performed on an instrument equipped with FID detectors using a

HP-5 (5%-Phenyl)-methylpolysiloxane column. 1H and 13C NMR spectra are reported relative to tetramethylsilane. IR spectra were recorded on a Perkin Elmer 1600 FT-IR spectrometer. High resolution mass spectra were obtained from the mass spectrometry facility at The Ohio State University.

2.4.2 Experimental Procedures for the synthesis of new ligands

Methyl 3-(phenylthio)benzoate (2.24). 3-(Phenylthio)benzoic acid (113 mg, 0.50 mmol) was dissolved in acetone (0.5 mL). To the solution K2CO3 (108 mg, 0.78 mmol)

25 and iodomethane (0.5 mL, 0.80 mmol) were added. The reaction was stirred for 16 h at ambient temperature. The reaction was quenched with H2O and extracted with CH2Cl2 (3

X 5 mL). The combined organic layers were dried with Na2SO4 and the solvent removed in vacuo. The crude material was purified by column chromatography (5% Ethyl Acetate/

95% hexanes) to yield 65% (77.8 mg, 0.32 mmol) of the product as a pale yellow oil. 1H

NMR (CDCl3, 400 MHz): δ 3.88 (s, 3H), 7.27 to 7.38 (m, 6H), 7.44 to 7.47 (m, 1H) 7.88

13 (dt, J= 7.7, 1.2 Hz, 1H), 8.01 (t, J= 1.6, Hz); C NMR (CDCl3, 100 MHz): 52.2, 127.7,

127.9, 129.2, 129.4, 131.2, 131.4, 131.7, 134.6, 134.7, 137.13, 166.44; IR (thin film):

-1 + 3058, 2949, 1718, 1570, 1261 cm ; HRMS (ESI): calcd for C14H12O2S [M+Na] :

267.0450, found 267.0455.

1,2-bis((4-methoxyphenyl)thio)ethane (2.31). 4-methoxybenzenethiol (3.42 g, 24.4 mmol) was added to a stirring solution of KOH (1.63 g, 29.0 mmol) in MeOH (23 mL) at

0 °C. After stirring for 10 min 1,2-dibromoethane (1.00 mL, 11.6 mmol) was added and the reaction was stirred at 23 °C for 16 h. MeOH was removed under vacuum, H2O (20 mL) was added and the aqueous layer extracted with EtOAc (3 x 40 mL). The organic layers were combined, dried over MgSO4, and the solvent removed under vacuum. The off-white solid was purified by recrystallization from hot hexanes to give 1,2-bis((4- methoxyphenyl)thio)ethane (2.35 g, 7.66 mmol, 66% yield) as a white crystalline solid.

1 H NMR (CDCl3, 400 MHz): δ 7.29-7.27 (m, 4H), 6.83-6.80 (m, 4H), 3.79 (s, 6H), 2.92

13 (s, 4H); C NMR (CDCl3, 100 MHz): δ 159.2, 133.7, 125.2, 114.7, 55.3, 35.3; IR (thin film): 3006, 2959, 2940, 2837, 1592, 1493, 1285, 1245 cm-1; HRMS (ESI): calcd for

+ C16H18O2S2 [M+Na] : 329.0640, found 329.0645.

1,2-bis((4-fluorophenyl)thio)ethane (2.32). 4-fluorobenzenethiol (732 mg, 5.69 mmol) was added to a stirring solution of KOH (271 mg, 6.77 mmol) in MeOH (5 mL) at 0 °C.

After stirring for 10 min 1,2-dibromoethane (233 μL, 2.70 mmol) was added and the reaction stirred was at 23 °C for 16 h. MeOH was removed under vacuum, H2O (50 mL) was added, and the aqueous layer extracted with EtOAc (3 x 40 mL). The organic layers were combined, dried over MgSO4, and the solvent removed under vacuum. The off- white solid was purified by recrystallization from hot hexanes to give 1,2-bis((4- fluorophenyl)thio)ethane (543 mg, 1.92 mmol, 71% yield) as a white crystalline solid. 1H

13 NMR (CDCl3, 400 MHz): δ 7.33-7.28 (m, 4H), 7.01-6.95 (m, 4H), 2.98 (s, 4H); C

NMR (CDCl3, 100 MHz): δ 163.6, 161.1, 133.4, 133.3, 130.1, 130.0, 116.5, 116.3, 34.8;

-1 IR (thin film): 3057, 1590, 1490, 1230, 1156 cm ; HRMS (ESI): calcd for C14H12F2S2

[M+Na]+: 305.0241, found 305.0230.

1,2-bis(naphthalen-1-ylthio)ethane (2.33). Naphthalen-1-thiol (0.91 mg, 5.67 mmol) was added to a stirring solution of KOH (480 mg, 8.6 mmol) in MeOH (12 mL) at 0 °C.

After stirring for 10 min, 1,2-dibromoethane (0.23 mL, 2.66 mmol) was added and the reaction was stirred at 23 °C for 16 h. MeOH was removed under vacuum, H2O (20 mL) was added, and the aqueous layer extracted with EtOAc (3 x 40 mL). The organic layers were combined, dried over MgSO4, and the solvent removed under vacuum. The off- white solid was purified by recrystallization from hot hexanes to give 1,2- bis(naphthalene-1-ylthio)ethane (701 mg, 2.02 mmol, 76% yield) as a white crystalline

1 solid. H NMR (CDCl3, 400 MHz): δ 8.37-8.36 (m, 2H), 7.84-7.82 (m, 2H), 7.73 (d, J=

13 8.4 Hz, 2H), 7.54-7.43 (m, 6H), 7.29 (t, J=7.6 Hz, 2H); C NMR (CDCl3, 100 MHz): δ

134.2, 133.5, 132.2, 129.6, 128.8, 128.1,126.8, 126.5, 125.7, 125.4, 34.0; IR (thin film):

-1 + 3057, 1792, 1558, 1505, 1381 cm ; HRMS (ESI): calcd for C22H18S2 [M+Na] :

369.0742, found 369.0761.

2.4.3. General procedure for the ligand screens

To a mixture of Pd(OAc)2 (X mol %), ligand (X mol %), and benzoquinone (0.5 mmol, 2.0 equiv) in AcOH (0.25 mL) was added 1-dodecene (56 μL, 0.25 mmol, 1 equiv). The reaction was stirred at 40 °C for 13 to 48 h.

2.4.4. Substrate scope for allylic acetoxylation of terminal olefins

General procedure: Under air, a 4 mL borosilicate glass vial was charged with tetrahydrothiophene (4.4 mg, 0.05 mmol, 0.050 equiv), Pd(OAc)2 (11.2 mg, 0.050 mmol,

0.050 equiv), benzoquinone (216 mg, 2.00 mmol, 2.0 equiv), and AcOH (0.75 mL) in that specific order. Alkene substrate (1.00 mmol) was added and the resultant mixture was stirred at 40 °C for 12 to 48 h. The final mixture was quenched with saturated

NaHSO3 (15 mL) at ambient temperature and extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered before

CH2Cl2 was evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel to afford allylic acetate product.

(E)-dodec-2-en-1-yl acetate ((E)-2.2): This reaction was performed according to the general procedure using dodec-1-ene (224 μL, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to give 87% of the product (196 mg, 0.867 mmol) as a pale yellow oil. 1H NMR matches previously reported

3e 1 data. H NMR (CDCl3, 400 MHz): δ 5.80-5.74 (m, 1H), 5.59-5.52 (m, 1H), 4.50 (dd, J

= 6.5, 0.9 Hz, 2H), 2.06 (s, 3H), 1.27 (br s, 16H), 0.88 (t, J = 6.7 Hz, 3H).

(E)-3-(4-fluorophenyl)prop-2-en-1-yl acetate (2.51): This reaction was performed according to the general procedure using 1-allyl-4-fluorobenzene (136 mg, 1.00 mmol).

The crude product was purified by column chromatography (silica gel, 2%

EtOAc/hexanes) to give 77% of the product (149 mg, 0.767 mmol) as a pale yellow oil.

1 3e 1 H NMR matches previously reported data. H NMR (CDCl3, 400 MHz): δ 7.37-7.34

(m, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.61 (d, J = 15.9 Hz, 1H), 6.20 (dt, J = 15.9, 6.5 Hz,

1H), 4.71 (dd, J = 6.5, 1.2 Hz, 2H), 2.09 (s, 3H).

(E)-3-phenylprop-2-en-1-yl acetate (2.52): This reaction was performed according to the general procedure using allylbenzene (132 μL, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 2% EtOAc/hexanes) to give 80% of the product (141 mg, 0.800 mmol) as a pale yellow oil. 1H NMR matches previously reported

3e 1 data. H NMR (CDCl3, 400 MHz): δ 7.40-7.37 (m, 2H), 7.34-7.30 (m, 2H), 7.28-7.23

(m, 1H), 6.65 (d, J = 15.9 Hz, 1H), 6.28 (dt, J = 15.9, 6.5 Hz, 1H), 4.73 (dd, J = 6.4, 1.3

Hz, 1H), 2.09 (s, 3H).

(E)-4-phenylbut-2-en-1-yl acetate (2.53): This reaction was performed according to the general procedure using but-3-en-1-ylbenzene (150 μL, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 50 to 75% DCM/hexanes) to give

79% of the product (150 mg, 0.790 mmol) as a pale yellow oil. 1H NMR matches

3e 1 previously reported data. H NMR (CDCl3, 400 MHz): δ 7.35-7.28 (m, 2H), 7.22-7.17

(m, 3H), 5.96-5.89 (m, 1H), 5.66-5.59 (m, 1H), 4.54 (dm, J = 6.4 Hz, 2H), 3.39 (d, J =

6.7 Hz, 2H), 2.05 (s, 3H).

(E)-6-((tert-butyldiphenylsilyl)oxy)hex-2-en-1-yl acetate (2.54): This reaction was performed according to the general procedure using tert-butyl(hex-5-en-1- yloxy)diphenylsilane (338 mg, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 50% DCM/hexanes) to give 61% of the product (242 mg,

0.610 mmol) as a pale yellow oil. 1H NMR matches previously reported data.3e 1H NMR

(CDCl3, 400 MHz): δ 7.67-7.65 (m, 4H), 7.44-7.35 (m, 6H), 5.78-5.71 (m, 1H), 5.59-5.51

(m, 1H), 4.48 (dd, J = 6.4, 0.8 Hz, 2H), 3.66 (t, J = 6.3 Hz, 2H), 2.16 (q, J = 7.2 Hz, 2H),

2.05 (s, 3H), 1.65 (m, 2H), 1.04 (s, 9H).

(E)-6-(benzyloxy)hex-2-en-1-yl acetate (2.55): This reaction was performed according to the general procedure using ((hex-5-en-1-yloxy)methyl)benzene (190 mg, 1.00 mmol).

The crude product was purified by column chromatography (silica gel, 3 to 5%

EtOAc/hexanes) to give 82% of the product (203 mg, 0.817 mmol) as a clear oil. 1H

NMR (CDCl3, 400 MHz): δ 7.35-7.27 (m, 5H), 5.80-5.73 (m, 1H), 5.61-5.53 (m, 1H),

4.50-4.48 (m, 4H), 3.47 (t, J = 6.4 Hz, 2H), 2.2-2.14 (m, 2H), 2.05 (s, 3H), 1.74-1.67 (m,

13 2H); C NMR (CDCl3, 100 MHz): δ 170.8, 138.5, 135.7, 128.4, 127.6, 127.5, 124.3,

72.9, 69.5, 65.2, 28.9, 28.8, 21.0; IR (thin film): 3087, 3063, 3029, 2939, 2855, 2793,

1952, 1738, 1667, 1495, 1453, 1366, 1231, 1102, 1025, 968, 736, 698 cm-1; HRMS (ESI)

+ calcd for [C15H21O3 + Na] 271.1305, found 271.1309.

(E)-4-methoxybenzyl 5-acetoxypent-3-enoate (2.56): This reaction was performed according to the general procedure using 4-methoxybenzyl pent-4-enoate (220 mg, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 20%

EtOAc/hexanes) to give 48% of the product (133 mg, 0.477 mmol) as a pale yellow oil.

1 3e 1 H NMR matches previously reported data. H NMR (CDCl3, 400 MHz): δ 7.30-7.26

(m, 2H), 6.90-6.88 (m, 2H), 5.93-5.85 (m, 1H), 5.73-5.66 (m, 1H), 5.06 (s, 2H), 4.54 (dd,

J = 6.2, 1.1 Hz, 2H), 3.81 (s, 3H), 3.12 (dd, J = 6.9, 1.2 Hz, 2H), 2.06 (s, 3H).

(E)-4-acetoxybut-2-en-1-yl benzoate (2.57): This reaction was performed according to the general procedure using but-3-en-1-yl benzoate (176 mg, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 10% EtOAc/hexanes) to give

1 85% of the product (198 mg, 0.845 mmol) as a pale yellow oil.; H NMR (CDCl3, 400

MHz): δ 8.07-8.04 (m, 2H), 7.58-7.54 (m, 2H), 7.46-7.42 (m, 2H), 6.02-5.91 (m, 2H),

13 4.84 (d, J = 4.1 Hz, 2H), 4.61 (d, J = 4.2 Hz, 2H), 2.08 (s, 3H); C NMR (CDCl3, 100

MHz): δ 170.6, 166.2, 133.0, 130.0, 129.6, 128.4, 128.2, 128.0, 64.3, 63.9, 20.8. IR (thin film): 3063, 3032, 2943, 2883, 1971, 1916, 1761, 1681, 1601, 1584, 1491, 1453, 1377,

1314, 1270, 1176, 1111, 1070, 1025, 968, 832, 806, 711 cm-1; HRMS (ESI) calcd for

+ [C13H14O4 + Na] 257.0784, found 257.0782.

(E)-4-(2,5-dioxopyrrolidin-1-yl)but-2-en-1-yl acetate (2.58): This reaction was performed according to the general procedure using 1-(but-3-en-1-yl)pyrrolidine-2,5-

33 dione (153 mg, 1.00 mmol). The crude product was purified by column chromatography

(silica gel, 25 to 50% EtOAc/hexanes) to give 71% of the product (150 mg, 0.710 mmol)

1 as a yellow oil. H NMR (CDCl3, 400 MHz): δ 5.83-5.69 (m, 2H), 4.53-4.52 (m, 2H),

13 4.12 (d, J = 5.4 Hz, 2H), 2.72 (s, 4H), 2.06 (s, 3H); C NMR (CDCl3, 100 MHz): δ

176.6, 170.6, 128.5, 126.5, 63.7, 39.7, 28.2, 20.8. IR (thin film): 3460, 2942, 1770, 1731,

1694, 1427, 1401, 1366, 1335, 1230, 1173, 1127, 1026, 969, 904, 821, 665 cm-1; HRMS

+ (ESI) calcd for [C10H13NO4 + Na] 234.0737, found 234.0735.

(E)-4-(2,5-dioxopyrrolidin-1-yl)-4-phenylbut-2-en-1-yl acetate (2.59): This reaction was performed according to the general procedure using 1-(1-phenylbut-3-en-1- yl)pyrrolidine-2,5-dione (229 mg, 1.00 mmol). The crude product was purified by column chromatography (silica gel, 25 to 50% EtOAc/hexanes) to give 76% of the

1 product (220 mg, 0.766) as a yellow oil. H NMR (CDCl3, 400 MHz): δ 7.39-7.27 (m,

5H), 6.61-6.54 (m, 1H), 5.87-5.80 (m, 2H), 4.66-4.56 (m, 2H), 2.70 (s, 4H), 2.074 (s,

13 3H); C NMR (CDCl3, 100 MHz): δ 176.4, 170.6, 137.8, 129.2, 129.1, 128.6, 128.0,

127.7, 63.8, 56.5, 28.1, 20.9; IR (thin film): 3057, 3030, 2940, 1773, 1738, 1703, 1602,

1495, 1451, 1432, 1383, 1365, 1239, 1176, 1131, 1076, 1029, 974, 864, 819, 730, 699

-1 + cm ; HRMS (ESI) calcd for [C16H18NO4 + Na] 310.1050, found 310.1052.

Chapter 3: Allylic fluorination of vinylsilanes

3.1 Introduction

The ability to selectively introduce a fluorine atom into a molecule of interest has long been a must-have tool for organic chemists.34 Due to its strong electronegative characteristic, fluorine has served as a source of unusually productive behavior not only in drug discovery but also in materials chemistry.35 Up until recently, installation of fluorine can be carried out by (1) coupling with fluorine-containing materials that are commercially available or (2) classical fluorination methods that are often low in efficiency and selectivity.36 Moreover, traditional fluorination can be carried out from only a limited library of functional groups.34a Due to these major setbacks, tremendous efforts have been put forth into developing methodology that allows selective fluorination of organic molecules with milder conditions, broader substrate scope, and flexible starting materials.34b

The C-H bond is certainly the most popular “functional group” in nature. Hence, the ability to substitute fluorine for hydrogen at a given carbon is a powerful synthetic tool. The last decade has seen tremendous progress and success in such transformation of sp2 C-H bonds of aromatic systems. Works done by Sanford14, Yu37 and Daugulis38 have demonstrated the feasibility of selective C-H activation fluorination by employing

35 appropriate metal catalysts with directing group-embedded starting materials. (Scheme

3.1)

Scheme 3.1. Examples of selective sp2 C-H fluorination14, 37a, 38

More recently, methodologies have also been found to selectively fluorinate sp3

C-H at the benzylic position by taking advantage of pre-installed directing groups and also by exploiting the stability of the benzylic radical (Scheme 3.2).39 The Lectka group also showed the ability to transform aliphatic sp3 C-H to C-F bond, although the methodology is limited to highly symmetrical starting materials to ensure good selectivity.39c

Scheme 3.2. Examples of selective sp2 and sp3 C-H fluorination. 14b, 39b, 39d

Allylic C-H substitution is an area of research that has received considerable interest in the C-H activation arena. Due to the presence of allylic fluorine motif in multiple important building blocks in drug-discovery and imaging agents,34 a versatile methodology for allylic fluorination via C-H activation is high on all synthetic chemists’ wish list. To our knowledge, only one example of such transformation has been reported by Doyle and coworkers (Scheme 3.3).3l The reaction requires relatively high catalyst loading while producing only an average yield. Moreover, low selectivity between branch and linear allylic fluorination diminishes the overall efficiency.

Scheme 3.3. Allylic fluorination of terminal alkene via Pd-catalyzed C-H activation

Branch/linear selectivity has always been an important criteria in allylic substitution.3e, f, 6c, 17a, 40 The branch product is considered more attractive because of the possible stereocenter at the substituted position.41 In addition, starting with terminal alkenes, the branch product is also more difficult to obtain via metal-catalyzed C-H- activated methodology due to the nature of the metal π-allyl system from both an electronic and steric standpoint (Figure 3.1).3f, 17a Since the terminal carbon is more accessible and also relatively more electropositive, the linear product is more likely to form in most systems.

Figure 3.1. Selectivity of π-allyl complex to give branch or linear product 38

Recently, our group has shown that by introducing a silane group, the selectivity can be reversed.41 As shown in Scheme 3.4, the silane group potentially balances the difference in steric hindrance around the π-allyl system. Moreover, its ability to donate electrons to the neighboring carbon makes that position less likely to undergo reductive elimination via nucleophilic attack. As the result, substitution was only observed at the non-silane carbon. The product formed can be protodesilylated to yield the branch product.42 Vinylsilanes are also important building blocks, and complexity can be built quickly through well-established methodology.43 Eager to take advantage of this finding, we set out to develop conditions to efficiently prepare allylic fluorines from vinylsilanes.

After a large number of experiments, this project is still in progress as we are working toward optimizing the conditions. We disclose here our findings and the interesting proposed mechanism. Challenges in this reaction will also be discussed.

Scheme 3.4. Selectivity of π-allyl complex with silane groups

3.2. Method Development

cis-Vinyl triethylsilanes were previously reported to be the most efficient in Pd- catalyzed allylic acetoxylation so 3.1 was chosen as the starting material for optimization.

Ideally, the optimized conditions would convert 3.1 to the desired product 3.2 with high efficiency and selectivity.

Scheme 3.5. Desired transformation for allylic fluorination of vinyl silanes

Allylic fluorine 3.2 was synthesized in 4 steps with 32% overall yield using reported methodology (Scheme 3.6). Clearly, a straight conversion from 3.1 to 3.2 is advantageous. With the desired product in hand, we set out to design the first set of screening conditions.

Scheme 3.6. Synthesis of desired product via reported methodology

Palladium acetate was chosen as our catalyst due to its success in catalyzing allylic substitution. Similar to other reported allylic substitution methodology, we hypothesized that once the π-allyl system is formed; nucleophilic fluorine can enter the system to furnish the desired product. Because of the silane group, we realized there was a potential for both starting material and product decomposition. A quick screen of nucleophilic fluorine showed zero conversion. Addition of acids such as acetic acid or trifluoroacetic acid did result in high conversion, but formation of the desired product was not observed.

Table 3.1. Screen of nucleophilic fluorine source in Pd-catalyzed allylic fluorination

We next turned out attention toward electrophilic fluorine sources. Although the

π-allyl system has been shown to exhibit nucleophilic characteristic under certain conditions,44 the silane group might not give clear selectivity between the pseudo-branch and pseudo-linear products (Scheme 3.7).

Scheme 3.7. Different selectivities for nucleophilic Pd π-allyl system

From an electronic standpoint, the silane-carbon contains higher electron density and is the better nucleophile. From a steric standpoint, the non-silane-carbon might be the better nucleophile. With these questions in mind, we carried out the next screen using available electrophilic fluorine sources. SelectFluor (3.9) exhibits minimal activity with only trace amount of desired product observed (Table 3.2, entry 1). Increasing the temperature only improved the conversion, while the yield remained the same. Well- known pyridinium-fluorine compounds did not give promising results. When tetrafluoroborate salts were used (entry 3-8), all starting material was recovered for each reaction. Interestingly, triflate salts (entry 9-14) generated great conversion, but 3.2 was not observed. We hypothesized that our starting vinyl silanes might be decomposing in the presence of triflate anion. This was confirmed by reacting 3.14 with 3.1 in dioxane at

50 °C. The reaction produced a mixture of multiple products. When N- fluorobenzenesulfonimide (NFSI, 3.16) was employed as the fluorine source, we were pleased to record good conversion and (E)-3.2 was produced in 17% yield. Formation of

(Z)-3.2 was not observed in any amount, interestingly. Increasing the temperature with

NFSI did not give better result. Hypervalent iodine 3.17 was recently reported to be an efficient electrophilic fluorine source.45 Unfortunately, it failed to produce any product

(entry 16-17).

Table 3.2. Screen of nucleophilic fluorine source in Pd-catalyzed allylic fluorination

Table 3.3. Solvents screen for Pd-catalyzed allylic fluorination with NFSI

Dioxane was chosen as the solvent choice at first due to its ability to solubilize a wide range of organic and organometallic compounds. After screening a variety of different solvents (table 3.3), dioxane was indeed the optimal solvent for this condition.

THF provided low conversion and minimal yield; while other common solvents seem to shut down the reaction.

With the optimized solvent in hand, we next wanted to examine whether a ligand could increase the efficiency of the reaction. Extensive ligand screens revealed that common phosphine ligands completely shut down the reaction. Sulfide ether ligands

(table 3.4, entry 1) gave lower conversion but similar yield to when no ligand was present in the reaction. Placing an electron-withdrawing group on the phenoxide scaffold (entry

2) showed no improvement. An electron-donating group such as tert-butyl (entry 3) produced high conversion and 30% yield of the desired product. Interestingly, installing a methoxy group was detrimental to the reaction (entry 4). Sampling different aryl-alkyl

45 sulfides revealed simple thioanisole produced similar conversion and yield of (E)-3.2

(entry 5). Diaryl sulfides such as 3.22 diminished the efficiency of the reaction while bisulfide 3.23 inhibits all catalytic activity.

Table 3.4. Screen of different sulfide ligands

Sulfoxide analogs of previously-screened sulfide ligands were also included in our studies (table 3.5). Overall, they allowed high conversion but there was no improvement in yield compared to when 3.19 was used.

Table 3.5. Screen of different sulfoxide ligands

Benzoquinone, besides being a common oxidant, was reported to promote reductive elimination in Pd-π-allyl system.17a Although in our system, the allyl group seemed to act as a nucleophile attacking the electrophilic fluorine source, we hypothesized that it was very possible for benzoquinone to induce the π-allyl system to be more nucleophilic by crowding the Pd center. Despite being a weak-coordinating ligand, too much or too little equivalent of BQ can alter the reaction pathways. Intrigued by this hypothesis, we investigated the effect of different equivalents of BQ on the outcome of the reaction. We chose to employ 3.19 as our ligand since it generated the best efficiency so far.

Table 3.6. Screen of optimal equivalent of BQ for allylic fluorination

When one equivalent of BQ was used, conversion and yield both decreased (table

3.6, entry 1). However, to our surprise, as the equivalent was decreased, yields started to increase. From entry 6, the reaction clearly does not require benzoquinone. This finding indicates that Pd(0) complexes might not be a part of the typical catalytic cycle. Absence of Pd(0) can also be supported by the lack of precipitation of black Pd(0) during the course of the reaction, which has always been observed for other allylic C-H activation with Pd(OAc)2 in our lab. At this point, we decided to rescreen our ligands since BQ might have had negative impact on the reaction.

Table 3.7. Ligand screen without BQ in allylic fluorination

Without ligand, mixing NFSI (3.16) with vinyl silane 3.1 in the presence of catalytic Pd(OAc)2 gave high conversion but only 17% yield of the desired product (table

3.7, entry 1). As mentioned before, when ligand 3.19 was employed, conversion was high and yield almost double (entry 3). Interestingly, when an electron-donating or – withdrawing group was installed, this resulted in both low conversion and yield (entry 2 and 4). Simple ligands such as thioanisole (entry 5) and tetrahydrothiophene (entry 6) gave the same efficiency in comparison with 3.19. Similar to when BQ was still present, bisulfide ligand was detrimental to the reaction (entry 7). Sulfoxide ligands were also explored. As shown in entries 8-11, they often give high conversion but inferior yield with respect to sulfide ligands.

Intrigued by the fact that most of the reaction provided high conversion but low yield, while the GC analysis did not show other significant signals, we scaled up the reaction with the best ligand in attempt to isolate the desired product and also other possible side products. To our surprise, the other side product, isolated in almost identical yield with 3.2, was allylic sulfonamide 3.30 (Scheme 3.8). The identity of this product was confirmed by another independent synthesis in our lab. The reason why this product was not detected completely by GC was due to its low stability under GC analysis conditions. Fortunately, yield of 3.30 can be quantitatively measured by combining the area of two signals that the product “decomposed” to. Unlucky for us, in all reactions that we tried, allylic fluorine and allylic sulfonamide were produced in about 1 to 1 ratio, giving no selectivity despite the use of different ligands. In order to develop a good strategy to induce the right selectivity, understanding the mechanism plays a crucial role in this process.

Scheme 3.8. Isolation of major products

3.3 Understanding the mechanism

One can think of a simple nucleophilic addition mechanism (Scheme 3.9) as the starting point. In this catalytic cycle, Pd(II) does not have to change its oxidation state.

Given the lack of Pd(0) precipitation, this seems plausible. However, to our knowledge, this type of mechanism is unprecedented in recent Pd-catalysis literature. Scheme 3.10 depicts a much more commonly proposed mechanism for the involvement of NFSI in Pd- catalyzed reaction.

Scheme 3.9. Mechanism via nucleophilic allyl system

Similar to other electrophilic fluorine sources, NFSI has been shown to oxidize certain Pd(II) complexes to Pd(IV) complexes.46 As shown, Pd-π-allyl III (Scheme 3.8) can be converted to Pd(IV) complex IV via oxidative addition of NFSI. From here, reductive elimination quickly occurs to give either V or VI due to the stability of Pd(II) relative to Pd(IV). Based on the identity of isolated products, we were pleased to find that reductive elimination of the π-allyl system only occurs at the non-silane carbon. Within complex IV, three possible reductive eliminations can occur: C-O, C-N, or C-F. In our case, C-O bond formation did not occur. This was confirmed by the lack of formation of allylic acetoxylation product (not shown). Selectivity between C-N vs. C-F bond has been reported to be possible. 46

Scheme 3.10. Mechanism via Pd(II)/Pd(IV) catalytic system

Despite exhaustive screening effort with different additives, the ratio between the allylic fluorine and allylic sulfonamide was consistently at 1 to 1. At this point, it seems that ligands and additives do not play a role in determining the selectivity of reductive elimination regardless of whether they are a part of the Pd(IV) complex or not. The only important factors we can potentially change are the different components of this high oxidation state complex. Given the desire to construct a C-F bond, F fluorine is unchangeable. We considered changing the structure of the vinyl silanes drastically by employing substrates derived from allylbenzene but this substrate provided a mixture of product based on GC analysis. When different silane groups were employed, a mixture of product was also observed (Scheme 3.11). Pd(TFA)2 was also used as our catalyst in

53 several screens, but it did not give any improvements in both yield and selectivity with respect to when Pd(OAc)2 was used.

Scheme 3.11. Attempts at changing substituent of Pd(IV) complex

At this point, we hypothesized that changing the structure of sulfonamide can potentially limit C-N bond formation and ultimately increase the formation of the desired allylic fluorination product. As shown by Ritter and coworkers, the more electron-rich benzenesulfonamide does induce faster C-F bond formation (Scheme 3.12).47

Scheme 3.12. Studies on effect of sulfonamide on rate of C-F reductive elimination

This change in rate can be explained by the trans-effect. It should be noted that this is conflicting with what was previously reported by Hartwig and coworkers in that more electron-rich nitrogens have the higher tendency toward reductive elimination.48

Given that, reductive elimination around a Pd(II) center might be drastically different compared to Pd(IV) center. Moreover, the proposed structure of our Pd(IV) complex is very different from the reported system. Unsettled on one trend, we set out to attempt to change the electronic properties of the benzenesulfonimide scaffold in both directions.

3.4 Progress toward synthesis of NFSI derivatives

To our knowledge, only one procedure existed regarding the synthesis of NFSI derivatives (Scheme 3.13). As reported by Yang and coworkers, sodium benzenesulfonamides were reacted with a fluorine/nitrogen gas mixture to furnish the desired N-fluoro-products.46a Although we were able to synthesize the starting sulfonamides, we were not equipped to carry out reactions involving the use of fluorine gas. Due to this limitation, we began looking at alternative routes to introduce different sulfonamides into our proposed Pd(IV) complex.

Scheme 3.13. Reported synthesis of NFSI-derivatives

The Shreeve group reported an elegant synthesis of different N-F moieties using

SelectFluor as the fluorinating agent (Scheme 3.14).49 Although reported examples were limited to alkyl primary and secondary amines, we hypothesized that if our sulfonamides are nucleophilic enough, the desired transformation might occur.

Scheme 3.14. Previously reported fluorination of primary and secondary amines

Sulfonamide 3.36 was chosen as the test substrate since it is equipped with the most number of electron-donating groups. Despite numerous attempts (Scheme 3.15), we have not been to synthesize and isolate N-fluorosulfonamide 3.37. Other attempts have been carried out using sodium or potassium salts of 3.36. However, the formation of 3.37 was not observed.

Scheme 3.15. Attempts at synthesis of NFSI-derivatives

We also attempted to generate 3.37 in situ under our best allylic fluorination condition. Despite exhaustive search for the right protocol, starting material 3.1 was never converted and was always recovered. (Scheme 3.16)

Scheme 3.16. Attempts at in-situ generation of NFSI-derivatives

Recently, we were able to synthesize N-fluorosulfonamide 3.41 following procedures reported by Meier and coworkers (Scheme 3.17). Currently, this protocol is being applied to synthesize 3.37.

Scheme 3.17. Synthesis of N-fluorosulfonamide 3.41

Our allylic fluorination protocol was carried out in the presence of 3.41 (Scheme

3.18). Unfortunately, this did not give desired product 3.2 and all starting material was recovered. Screening of different conditions is being carried out before a conclusion can be made about whether 3.41 is a competent fluorinating agent.

Scheme 3.18. Attempt at allylic fluorination with 3.41

In addition, it has been shown that the structure around the nitrogen atom greatly affect the reduction potential across the N-F bond.50 Comparing the drastic differences in electronic properties between NFSI (3.16) and 3.41, we suspect that 3.41 might not be a competent oxidant for our Pd complex. Because of this hypothesis, two sulfonyl groups might be crucial in allowing the right reduction potential. Attempt to synthesize NFSI- derivatives are ongoing in our lab.

3.5 Conclusions

We have developed preliminary conditions toward Pd-catalyzed allylic fluorination of vinyl silanes. Allylic fluorine and sulfonamide are being generated in 1 to

1 ratio under our best conditions (Scheme 3.19). Despite exhaustive search in conditions, the ratio of the two major products remained the same.

Scheme 3.19. Best up-to-date conditions for allylic fluorination of vinyl silanes

Studies carried out in our group and literature data suggest that changing the electronic properties of NFSI’s sulfonamide scaffold might result in different selectivity.

Currently, efforts are being focused on synthesizing NFSI derivatives and also developing other competent fluorinating agent to be used in our reaction. If allylic fluorine formation can indeed be selectively favored, chirality may be introduced to the fluorinating agent to allow enantioselective allylic fluonation of vinyl silanes.

3.6. Experimental

3.6.1. Materials and Methods

Allylic fluorinations were conducted in a 2 mL or 4 mL borosilicate glass vials in an air atmosphere. Palladium acetate, palladium trifluoroacetate and Grubbs catalyst (2nd

59 generation) were used as received from Pressure Chemicals. 1,4-Benzoquinone was sublimed before use. All solvents were reagent grade, predried, or distilled. All other commercially obtained reagents were used as received. 5-phenylpent-1-en-3-ol (3.4)51, 5- phenylpent-1-en-3-yl 2,2,2-trichloroacetimidate (3.5)52, (3-fluoropent-4-en-1-yl)benzene

(3.6)3i, triethyl(vinyl)silane (3.7)53, phenyl(2-(p-tolyloxy)ethyl)sulfane (3.8)3e, 1-methyl-

4-(2-(phenylsulfinyl)ethoxy)benzene (3.24)3e, dibenzo[b,d]thiophene 5-oxide (3.26)54,

1,2-bis(phenylsulfinyl)ethane (3.28)55, 4-methoxy-N-((4- methoxyphenyl)sulfonyl)benzenesulfonamide (3.36)56, N-fluoro-N-isopropyl-4- methylbenzenesulfonamide (3.41)57 were prepared according to literature procedures.

GC analysis was performed on an instrument equipped with FID detectors using a

HP-5 (5%-Phenyl)-methylpolysiloxane column. 1H and 13C NMR spectra are reported relative to tetramethylsilane. High resolution mass spectra were obtained from the mass spectrometry facility at The Ohio State University.

3.6.2. Independent synthesis of isolated products

(E)-triethyl(3-fluoro-5-phenylpent-1-en-1-yl)silane ((E)-3.2): Preparation using synthesis from scheme 3.6. Under Argon, a round-bottom flask was charged with a solution of Grubbs Catalyst - 2nd Gen (60.0 mg, 0.07 mmol, 0.2 equiv) in benzene. To the flask were added (3-fluoropent-4-en-1-yl)benzene (3.6) (50.0 mg, 0.30 mmol, 1.0 equiv.)

60 and triethyl(vinyl)silane (3.7) (125.0 mg, 0.90 mmol, 3.0 equiv.). The solution was heated to reflux for 24 hours. Solvent was removed via rotovap and the product was isolated via column chromatography (silica gel, 5% EtOAc/Hexanes, Rf = 0.7). The product isolated

1 13 1 from allylic fluorination condition has identical H and C spectrum. H NMR (CDCl3,

400 MHz): δ 7.30-7.27 (m, 2H), 7.21-7.18 (m, 3H), 6.07 (ddd, J = 13.76, 12.16, 5.2 Hz,

1H), 5.89 (ddd, J = 19.04, 2.78, 1.26 Hz, 1H), 4.87 (dm, JH-F = 49.2 Hz, 1H), 2.81-2.66

(m, 2H), 2.09-1.84 (m, 2H), 0.94 (t, J = 7.9 Hz, 9H), 0.58 (q, J = 7.9 Hz, 9H). 13C NMR

(CDCl3, 100 MHz): δ 144.9, 144.7, 141.4, 128.7, 128.6, 128.5, 126.0, 94.9, 93.3, 37.1,

19 36.9, 31.0, 30.9, 7.3, 3.3 F NMR (CDCl3, 100 MHz): δ -178.5 (decoupled). HRMS

+ (ESI): calcd for C17H27FSi [M+Na] : 301.1758, found 301.1756.

Scheme 3.20. Independent synthesis of 3.30

(E)-N-(5-phenyl-1-(triethylsilyl)pent-1-en-3-yl)-N-

(phenylsulfonyl)benzenesulfonamide ((E)-3.30): Under an atmosphere of air, a round- bottom flask was charged with (E)-5-phenyl-1-(triethylsilyl)pent-1-en-3-yl acetate

41 (3.42) (160 mg, 0.5 mmol, 1 equiv), K2CO3 (100 mg, 0.75 mmol, 1.5 equiv) and MeOH

(1 mL). The mixture was stirred at 23 °C for 12 hours. Final mixture was diluted with

EtOAc, washed with NH4Cl (aq, sat) and brine. Organic layer was dried with Na2SO4 then solvent was removed via rotovap to yield (E)-5-phenyl-1-(triethylsilyl)pent-1-en-3- ol (3.43). This compound was used for the next reaction without further purification.

Conversion from alcohol to sulfonamide was done according to reported procedure.58

Under air, a vial was charged with (E)-5-phenyl-1-(triethylsilyl)pent-1-en-3-ol (3.43) (60 mg, 0.21 mmol, 1 equiv), NFSI (230 mg, 0.73 mmol, 3 equiv) and DCM. PPh3 (190 mg,

0.73 mmol, 3 equiv) was added in one portion then the solution was heated at 50 °C for

6h. The solvent was removed then the mixture was subjected to column chromatography to yield (E)-3.30 (silica gel, 20% EtOAc/Hexanes, Rf = 0.5).

The product isolated from allylic fluorination condition has identical spectrum.

1 H NMR (CDCl3, 400 MHz): δ 7.92 (d, J = 4.2, 4H), 7.61 (t, J = 7.4, 2H), 7.49 (t, J = 7.9,

2H), 7.29-7.18 (m, 3H), 7.02 (d, J = 6.9, 2H), 6.32 (dd, J = 18.8, 7.5 Hz, 1H), 5.48 (d, J =

18.8, 1H), 4.46-4.40 (m, 1H), 2.61-2.34 (m, 3H), 2.11-2.02 (m, 3H), 0.91 (t, J = 7.9 Hz,

13 9H), 0.54 (q, J = 7.9 Hz, 9H). C NMR (CDCl3, 100 MHz): δ 143.7, 140.5, 133.6, 133.5,

128.9, 128.5, 128.4, 128.3, 126.1, 67.5, 35.0, 33.0, 7.3, 3.3. We were unable to obtain

HRMS for this compound.

3.6.3. General Procedure for Table 3.1

To a mixture of Pd(OAc)2 (10 mol %), ligand (10 mol %), fluorine source (0.15 mmol,

1.5 equiv) and benzoquinone (0.15 mmol, 1.5 equiv) in dioxane (0.50 mL) was added 3.1

(0.1 mmol, 1 equiv). The reaction was stirred at 50 to 90 °C for 24 h.

3.6.3. General Procedure for Table 3.2

To a mixture of Pd(OAc)2 (10 mol %), fluorine source (0.15 mmol, 1.5 equiv) and benzoquinone (0.15 mmol, 1.5 equiv) in dioxane (0.50 mL) was added 3.1 (0.1 mmol, 1 equiv). The reaction was stirred at 50 to 90 °C for 24 h.

3.6.4. General Procedure for Table 3.3

To a mixture of Pd(OAc)2 (10 mol %), NFSI (0.15 mmol, 1.5 equiv) and benzoquinone

(0.15 mmol, 1.5 equiv) in solvent (0.50 mL) was added 3.1 (0.1 mmol, 1 equiv). The reaction was stirred at 50 to 90 °C for 24 h.

3.6.5. General Procedure for Table 3.4 and 3.5

To a mixture of Pd(OAc)2 (10 mol %), ligand (10 mol %), NFSI (0.15 mmol, 1.5 equiv) and benzoquinone (0.15 mmol, 1.5 equiv) in dioxane (0.50 mL) was added 3.1 (0.1 mmol, 1 equiv). The reaction was stirred at 50 to °C for 24 h.

3.6.6. General Procedure for Table 3.6

To a mixture of Pd(OAc)2 (10 mol %), ligand (10 mol %), NFSI (0.15 mmol, 1.5 equiv) and benzoquinone in dioxane (0.50 mL) was added 3.1 (0.1 mmol, 1 equiv). The reaction was stirred at 50 to °C for 24 h.

3.6.7. General Procedure for Table 3.7

To a mixture of Pd(OAc)2 (10 mol %), ligand (10 mol %), and NFSI (0.15 mmol, 1.5 equiv) in dioxane (0.50 mL) was added 3.1 (0.1 mmol, 1 equiv). The reaction was stirred at 50 to °C for 24 h.

3.6.8. Procedure for Isolation of Major Products (Scheme 3.8)

To a mixture of Pd(OAc)2 (22 mg, 0.1 mmol, 0.1 equiv), thioanisole (12 mg, 0.1 mmol,

0.1 equiv), and NFSI (470 mg, 1.5 mmol, 1.5 equiv) in dioxane (2.5 mL) was added 3.1

(260 mg, 1.0 mmol, 1 equiv). The reaction was stirred at 50 to °C for 48 h. Upon cooling to ambient temperature, the red orange solution was diluted with EtOAc. Organic solution was washed with water and brine. It was then dried with Na2SO4 before all solvent was evaporated via rotovap. Crude mixture was subjected to column chromatography (silica gel, gradient hexanes to 20% EtOAc/hexanes) to yield ((E)-3.2)

(30% yield) and ((E)-3.30) (30% yield). The identity of these compounds was confirmed by comparing their NMR spectra with spectra of independently-synthesized compounds.

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Appendix A: NMR Spectroscopy Data for Selected Compound

Appendix B: Screened Conditions for Allylic Fluorination of Vinylsilanes

Table B.1. Screen of oxidants in allylic fluorination

Table B.2. Screen of in situ-generated fluorine sources in allylic fluorination

Table B.3. Screen of in situ-generated fluorine sources with bases in allylic fluorination

100

Table B.4. Screen of NFSI derivatives in allylic fluorination

101

Table B.5. Screen of NFSI derivatives with bases in allylic fluorination

102

Table B.6. Screen of sodium anionic NFSI derivatives in allylic fluorination

103

Table B.7. Screen of potassium anionic NFSI derivatives in allylic fluorination

104

Table B.8. Screen of silver salts in [Pd(allyl)Cl]2-catalyzed allylic fluorination

105

Table B.9. Screen of ligands in [Pd(allyl)Cl]2-catalyzed allylic fluorination

106