Palladium Catalyzed Suzuki-Miyaura Cross-Coupling of Axially Chiral Biaryls

THESIS

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

William D. Andert

Graduate Program in Chemistry

The Ohio State University

2013

Master's Examination Committee:

Professor T. V. RajanBabu, Advisor

Professor Jon R. Parquette

William D. Andert

2013

ABSTRACT

Cross-coupling reactions have been of interest to organic chemists much of the past century. It has only been in the last half century that prominent advances have been discovered, all of which take advantage of organometallic chemistry. The most widely explored reactions use palladium or nickel complexes to promote the cross-coupling of a wide variety of functionalized aryl groups. One such reaction is the Suzuki-Miyaura cross-coupling, which is a transition-metal mediated coupling of an organohalide and an organoborane. As a carbon-carbon bond forming reaction, the Suzuki-Miyaura cross- coupling has great potential in synthetic applications due to its mild conditions and functional group tolerance. An important aspect of the reaction is the ability to impart specific configurations during the formation of new carbon-carbon bonds. Such selectivity has been thoroughly explored in the Suzuki-Miyaura cross-coupling of sp2-sp2 carbon-carbon bonds with the retention of E or Z stereochemistry. However, the formation of axially chiral biaryls still presents an ongoing challenge. Biaryls containing at least three substituents ortho to the aryl-aryl bond exhibit atropisomerism, which gives rise to axial chirality. Thus, the application of asymmetric catalysis to the formation of axial chiral biaryls was of interest. The work presented in this thesis investigates the synthesis of several chiral ligands for use in cross-coupling reactions and a study of the

Suzuki-Miyaura cross-coupling of biaryls.

DEDICATION

Dedicated to my parents Tom and Sandy Andert

iii

ACKNOWLEDGMENTS

First, I would like to thank my advisor Dr. T. V. RajanBabu for giving me the opportunity to do research in his lab. His enthusiasm for teaching and research has helped me become a better chemist. I also want to thank all of the professors at Ohio

State with whom I had the opportunity to learn and teach.

I would like to thank the members of the RajanBabu group that I have had the pleasure of working with while at Ohio State. I would especially like to thank Dr.

Ramakrishna Singidi for all of his guidance when I first joined the laboratory and Dr.

Jordan Page for his help throughout my research.

Another individual I want to acknowledge is Dr. Andrew French at Albion

College, who originally fostered my interest in organic chemistry and suggested I pursue a graduate degree.

I want to thank my family for all of their support. My parents have always encouraged me in everything I have done, and their support during my time in graduate school was no exception. Lastly, I want to acknowledge my wife, Carmen. All the support she has given has helped me get through one of the biggest challenges in my life to date.

VITA

April 10, 1987 ...... Born – Kalamazoo, MI

May 2009 ...... B.A. Chemistry

Albion College

2009-2013 ...... Teaching Associate

The Ohio State University

FIELDS OF STUDY

Major Field: Chemistry

TABLE OF CONTENTS

Abstract ...... ii

Dedication ...... iii

Acknowledgments...... iv

Vita ...... v

Fields of Study ...... v

Table of Contents ...... vi

List of Schemes ...... ix

List of Tables ...... x

List of Figures ...... xi

List of Abbreviations ...... xii

Chapter 1: Development of Cross-Coupling Reactions and the Synthesis of Axially

Chiral Biaryl Compounds ...... 1

1.1 Background and Significance ...... 1

1.2 Axial Chirality in Natural Product Synthesis...... 3

1.3 Development of Coupling Reactions ...... 5

1.3.1 Ullmann Coupling ...... 7

1.3.2 Kumada Cross-Coupling ...... 9

1.3.3 Suzuki-Miyaura Cross-Coupling ...... 11

1.4 Investigation of Biaryl Synthesis by Cross-Coupling Reactions ...... 16

1.4.1 Cross-Coupling Reactions using Pd Catalysts ...... 18

1.4.2 Cross-Coupling Reactions using Ni Catalysts ...... 24

1.5 Conclusions ...... 26

Chapter 2: Palladium Catalyzed Asymmetric Suzuki-Miyaura Cross Coupling Reactions

of Biaryl Compounds ...... 27

2.1 Background and Significance ...... 27

2.2 Chiral Ligands for Cross-Coupling Reactions ...... 28

2.3 Cross-Coupling Reactions of Biaryls...... 38

2.3.1 Preparation of Cross-Coupling Precursors...... 38

2.3.2 Cross-Coupling Reactions with S-Phos Ligands ...... 41

2.3.3 Cross-Coupling Reactions with Chiral Ligands ...... 43

2.4 Conclusions ...... 45

2.5 Experimental Procedures ...... 45

2.5.1 General Methods ...... 45

2.5.2 Synthesis of Chiral Pyridinooxazoline (PyOX) Ligand...... 46

2.5.3 Synthesis of Chiral Bicyclic Sulfoxide-Alkene Ligand ...... 48

vii

2.5.4 Synthesis of Chiral Aryl Sulfoxide-Alkene Ligand ...... 54

2.5.5 Synthesis of Cross-Coupling Reagents ...... 56

Bibliography ...... 61

Appendices ...... 67

Appendix A: 1H and 13C NMR Spectra ...... 67

Appendix B: HPLC Chromatograms ...... 94

viii

LIST OF SCHEMES

Scheme 1.1. Ullmann Coupling in the Synthesis of Ellagitannins ...... 9

Scheme 1.2. Catalytic Cycle of the Kumada Coupling ...... 11

Scheme 1.3. Proposed Catalytic Cycles for Suzuki-Miyaura Cross-Coupling .... 13

Scheme 1.4. Cross-Coupling in the Synthesis of Palytoxin Carboxylic Acid ..... 16

Scheme 2.1. Synthesis of Pyridyl Oxazoline (PyOX) Ligand ...... 30

Scheme 2.2. Synthesis of Bicyclic Ketone ...... 31

Scheme 2.3. Synthesis of Bicyclic Alkene ...... 34

Scheme 2.4. Synthesis of Alkene in Aryl Sulfoxide-Alkene Ligand ...... 37

Scheme 2.5. Synthesis of Naphthalene Sulfoxide ...... 38

LIST OF TABLES

Table 1.1. History of Coupling Reactions ...... 6

Table 2.1. Preparation of Grignard Reagents for Addition to Ketones ...... 33

Table 2.2. Results of Cross-Coupling Optimization ...... 42

Table 2.3. Results of Chiral Cross-Coupling ...... 44

LIST OF FIGURES

Figure 1.1. Chirality in Naproxen and Aspartame ...... 2

Figure 1.2. Natural Products Containing Axially Chiral Biaryls ...... 4

Figure 1.3. Angiotensin II Receptor Antagonists ...... 5

Figure 1.4. Modifications for Cross-Coupling of Aryl Chlorides ...... 14

Figure 1.5. Ligands for First Asymmetric Suzuki-Miyaura Cross-Coupling ...... 19

Figure 1.6. Ligands Developed by Buchwald ...... 20

Figure 1.7. Carbene Ligand IMes ...... 25

Figure 2.1. Asymmetric Ligands for Suzuki-Miyaura Cross-Coupling ...... 29

LIST OF ABBREVIATIONS

α alpha

[α] specific rotation

Ac acetyl atm atmospheres aq aqueous

β beta

BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl br broad (NMR) n-Butyl normal-butyl t-Butyl tertiary-butyl

˚C degrees Celsius conv conversion cy cyclohexyl

δ chemical shift in parts per million d doublet (NMR) dba dibenzylideneacetone

DBDMH 1,3-dibromo-5,5-dimethylhydantoin

DCM dichloromethane dd doublet of doublets (NMR) xii

DIBAL-H diisobutyl aluminum hydride

DME dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide dt double of triplets (NMR)

η eta ee enantiomeric excess

E entgegen (trans)

Eq Equation equiv equivalent(s)

Et ethyl

EtOAc ethyl acetate g gram(s) h hour(s)

HPLC high performance liquid chromatography

Hz hertz i-Pr isopropyl

J coupling constant in hertz (NMR)

L liter(s) m milli; multiplet (NMR)

M mega; molarity

Me methyl

xiii

MeO methoxy min minute(s) mol mole(s)

ν nu; frequency in hertz (NMR)

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

OTf trifluoromethanesulfonate

Ph phenyl

Pyr pyridine

π pi q quartet (NMR) rt room temperature

σ sigma s singlet (NMR)

S-Phos 2-dicyclonexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl t triplet (NMR)

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

Ts para-toluenesulfonyl

Z zusammen (cis)

xiv

CHAPTER 1: DEVELOPMENT OF CROSS-COUPLING REACTIONS AND

THE SYNTHESIS OF AXIALLY CHIRAL BIARYL COMPOUNDS

1.1 Background and Significance

Some of the most fundamental transformations of organic chemistry involve the formation of carbon-carbon bonds. The carbon-carbon bond is incorporated in a wide range of molecules: from simple compounds to complex biological systems. Organic chemists are interested in the efficient assembly of molecules from simple building blocks, which requires reactions that often create these new carbon bonds. However, some of the most well known reactions used in organic chemistry are not atom economical and create hazardous byproducts. With a recent focus on “green” methodologies, reactions that minimize such byproducts yet still produce the desired bonds are of great interest.

Two of the key aspects regarding many synthetic routes are the regio- and stereoselectivity in the formation of the new bonds. The specific enantiomeric composition of many compounds is of upmost importance, especially with pharmaceuticals. A well known example is naproxen (Figure 1.1). The (S)-enantiomer

(1S) is a non-steroidal anti-inflammatory drug (NSAID) sold under the trade name of

Aleve®. However, the other enantiomer, (R)-naproxen (1R), is a known liver toxin.

Another interesting example showing the effect such a subtle change in configuration can

1 have is with the compound aspartame: the S,S-enantiomer (2a) tastes sweet, whereas the

R,R-enantiomer (2b) tastes bitter.

Figure 1.1. Chirality in Naproxen and Aspartame

Transition metal chemistry has proved an invaluable tool in organic synthesis.

When used in catalytic amounts, transition metals provide a quick and efficient route to carbon-carbon bonds. Some of the most prominent advancements have been in ring- closing metathesis reactions (Grubbs, Schrock) and cross-coupling reactions (Heck,

Negishi, Suzuki), both of which were recognized with Nobel Prizes. Transition metal catalysis is also used extensively in industrial applications; some of the most notable are the Ziegler-Natta process1 used in the production of long-chain polymers and the Shell

2 Higher Olefin Process for forming low molecular weight olefins of C6 to C20. Both of these processes demonstrate the significant contribution metal-catalyzed reactions have had not only in chemistry, but also in the wider realm of consumer products. Thus, the use of transition metals is a well established field that can be used to solve some current questions in organic chemistry.

1.2 Axial Chirality in Natural Product Synthesis

The sophisticated design of natural products has long intrigued chemists. It is partially the complexity of these molecules and also the specific function each of them performs that makes them so interesting. While many well established reactions exist to aid chemists in synthesizing such molecules, certain structures are harder to make than others. One such structural motif of interest is the biaryl, which is comprised of two aromatic groups linked by a sp2-sp2 carbon-carbon bond.

Often, in natural products, biaryl groups exhibit chirality in the form a atropisomerism. A prerequisite usually needed to have a stable atropisomer are the presence of three ortho substituents next to the biaryl axis.3 However, the highly congested nature of such an arrangement often makes the synthesis hard to accomplish.

Therefore, the development of a reaction that will form biaryls both efficiently and with stereoselectivity will be a positive step forward for such hard to make bonds.

Several naturally occurring compounds containing the chiral biaryl motif have been isolated. A class of compounds containing a bis-dibenzocyclooctadiene backbone, including (-)-steganone (Figure 1.2, 3), have been shown to exhibit anileukemic properties. Such compounds were first isolated from Steganotaenia araliacea in 1973 by

Kupchan.4 Several syntheses from this class of compounds have been reported.5, 6

Figure 1.2. Natural Products Containing Axially Chiral Biaryls

Another compound of synthetic interest containing a biaryl unit is vancomycin

(Figure 1.2, 4). Vancomycin is an antibiotic originally isolated by Eli Lilly in 1956.7 It has been very effective against Staphylococcus aureus, however, recent signs of bacteria becoming drug-resistant to it is of significant medical concern.8 The synthesis of vancomycin using a Suzuki-Miyaura cross-coupling has been reported by Nicolaou, among others.9

An interesting set of molecules are michellamine A (5) and korupensamine A (6)

(Figure 1.2), which are anti-HIV alkaloids. Michellamine A was synthesized by first forming the internal dinapthalene followed by a double Suzuki-Miyaura cross-coupling of the outer aromatic groups.10 The korupensamine family of molecules has been synthesized using several methods. In the first, the biaryl was formed through cross- coupling of an aryl bromide and aryl hydrogen.11 The second method of forming the korupensamine biaryls was by a Suzuki-type cross-coupling catalyzed by a chiral arene

4 chromium complex.12 The use of transition-metal catalyzed cross-couplings has been an effective route to forming the biaryls of these complex natural products.13

Two molecules that have been developed for pharmaceutical use are losartan 7

(Merck) and valsartan 8 (Novartis) (Figure 1.3).14 Both of these drugs are angiotensin II receptor antagonists, which are used to treat hypertension. These related molecules contain a biphenyl group which was shown to make the drugs deliverable orally. The synthesis of losartan was completed using a late-stage Suzuki-Miyaura cross-coupling to join the two functionalized aromatic rings in 93% yield.15 The use of cross-coupling reactions in such syntheses as these two drugs demonstrates the great potential of these reactions. Therefore, further developments of coupling reactions and their significance will be explored in more detail.

Figure 1.3. Angiotensin II Receptor Antagonists

1.3 Development of Coupling Reactions

Organometallic chemistry has received much attention in recent decades, and many interesting and useful advances have been discovered. In particular, the formation

5 of carbon-carbon bonds through coupling reactions has been demonstrated to have a broad scope16 and has found numerous uses in the synthesis of complex natural products.

In general, a coupling reaction is the process of forming a carbon-carbon bond through the use of a metal catalyst. A wide variety of reactions have been developed (Table 1.1), and many new developments are being discovered.

Name First Publication Type Catalyst Reactant Aa Reactant Ba Wurtz Reaction17 1855 Homo Na R-X R-X Glaser Coupling18 1869 Homo Cu R-C≡C-H R-C≡C-H Ullmann Coupling19 1901 Homo Cu Ar-X Ar-X

20 Gomberg-Bachmann 1924 Cross - Ar-H Ar-N2X Cadiot-Chodkiewicz21 1957 Cross Cu R-C≡C-H R-C≡C-Br Castro-Stephens22 1963 Cross Cu R-C≡C-H Ar-X

23 Gilman Reagent 1967 Cross - R2CuLi R-X Kumada Coupling24, 25 1972 Cross Pd or Ni R-MgX R-X Heck Reaction26 1972 Cross Pd Alkene R-X Sonogashira Reaction27 1975 Cross Pd and Cu R-C≡C-H R-X Negishi Coupling28 1977 Cross Pd or Ni R-ZnX R-X

29 Stille Coupling 1978 Cross Pd R’-SnR3 R-X

30, 31 Suzuki-Miyaura 1979 Cross Pd or Ni R’-B(OR)2 R-X

32 Hiyama Coupling 1988 Cross Pd R-SiR3 R-X

33, 34 Buckwald-Hartwig 1994 Cross Pd R-NR2 Ar-X Fukuyama Coupling35 1998 Cross Pd R-ZnI RCO(SEt)

36 Liebeskind-Srogl 2000 Cross Pd R-B(OR)2 RCO(SEt) a R = alkyl; R’ = alkenyl; X = halide

Table 1.1. History of Coupling Reactions 6

One of the earliest reports of a coupling reaction was published by Adolphe

Wurtz in 1855.17 Wurtz reacted sodium metal with an alkyl halide via metal-halogen exchange followed by nucleophilic substitution of a second equivalent of the alkyl halide.

This marked the beginning of a rich area of chemical research. Subsequent work (Table

1.1) began to explore the use of other metals in coupling reactions; copper was extensively researched through the first half of the twentieth century, and since then other transition metals including palladium and nickel have gained widespread use. The remarkable diversity of carbon-carbon bond formations possible by these reactions is a strong indication of the impact couplings have had in organic chemistry.

1.3.1 Ullmann Coupling

Several coupling reactions are well suited for use in the formation of biaryl compounds, one of which is the Ullmann coupling. A useful homocoupling reaction, the

Ullmann coupling was first published in 1901 by Fritz Ullmann.19 The reaction joins two aryl halides 9 with a stoichiometric amount of copper to form biaryl compound 10 (Eq.

1.1). The original conditions required for the coupling are harsh, needing high temperatures (200˚C or above) to achieve the transformation. Several modifications developed to circumvent the high temperature include using DMF as the solvent and using an activated copper powder.37 Another aspect of the substrate that enhances the reactivity is the presence of electron-withdrawing groups on the aromatic ring. Such groups as nitro and carboxymethyl help activate the halogen for reaction with the copper,

7 while sterically hindered groups significantly slow the reactivity. One limitation of the

Ullmann coupling is a consequence of being a homocoupling, only symmetrical biaryls can be synthesized. However, it has been used with good results in several syntheses.

A novel use of the Ullmann coupling to form a biaryl molecular framework was done by Meyers in the synthesis of ellagitannin (Scheme 1.1, 13).38 Compounds in the ellagitannin family were of synthetic interest due to their ability to inhibit biological processes in HIV and their antioxidant properties. Structurally, the ellagitannins contain a glucose unit with galloyl ester bonds and a chiral biaryl unit. The synthesis of the chiral biaryl unit began by forming a chiral oxazoline 11.39 The oxazoline moiety functioned as a chiral auxiliary during the Ullmann coupling to produce biaryl 12 in 60% yield of the major diastereomer after separation by silica gel chromatography. A study of the selectivity of the coupling using the chiral oxazoline revealed the reaction could proceed in up to 96:4 S/R diastereoselectivity.40 Further reactions led to the desired ellagitannin.

The synthesis demonstrated the remarkable ability of the coupling reaction to quickly combine key fragments in a complex molecule. Additionally, the use of the chiral oxazoline is a novel way to control the outcome of the stereochemistry. However, the success of the synthesis depended upon installing and later removing the oxazoline ring,

8 which extends the length of the synthesis and ultimately diminishes the applicability of the method to other complex syntheses.

Scheme 1.1. Ullmann Coupling in the Synthesis of Ellagitannins

1.3.2 Kumada Cross-Coupling

The cross-coupling reaction of a Grignard reagent with an organic halide is known as the Kumada coupling. The reaction was independently discovered in 1972 by

Makoto Kumada and Robert Corriu.37 As one of the earliest catalytic cross-coupling reactions, the Kumada coupling uses either a palladium or nickel catalyst. In the original publication by Kumada,24 the cross-coupling was accomplished using a dihalophosphinenickel complex as the catalyst. Substrates tested in the cross-coupling included aromatic and alkyl Grignard reagents with aromatic and alkenyl halides.

Kumada also established that bidentate phosphine ligands gave strong catalytic activity in the reaction.41 Lastly, a publication by Corriu25 reported satisfactory results with

9 nickel(II) acetylacetonate as the catalyst for the coupling of aromatic Grignard reagents with alkenyl and aryl halides.

A general procedure42 for the Kumada cross-coupling is to first generate a

Grignard reagent 15 (Eq. 1.2) from the desired alkyl or aryl halide 14 with magnesium and diethylether. Next, the Grignard reagent is directly added to a mixture of a second organohalide 16 and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) (Eq. 1.3).

The reaction is then refluxed and subsequently quenched with a dilute acid to give the coupled product 17.

As a catalytic process, the nickel complex is used in a sub-stoichiometric amount, with typical loading of 0.5-5 mol %.37 The reaction is proposed to proceed with an electron-rich palladium starting in the Pd(0) oxidation state (Scheme 1.2).43 The first step is the oxidative addition of the organohalide, which changes the palladium to Pd(II) and adds the organohalide in a cis orientation. The second step of the catalytic cycle is the transmetalation; the Grignard reagent transfers the organic group to the palladium while a halogen is transferred to the magnesium. Once the Pd(II) complex has the two organic groups attached, they will undergo a rapid trans to cis isomerization44 in order to obtain 10 the correct geometry for the final reductive elimination. With the formation of the new carbon-carbon bond, the palladium returns to a Pd(0) state for further use in the catalytic cycle. The catalytic cycle for the Kumada coupling is also generally applicable for most of the cross-coupling reactions involving the use of a palladium catalyst (Kumada,

Sonogashira, Negishi, Stille, Suzuki), with the main difference between each being the choice of metal for transmetalation.

Scheme 1.2. Catalytic Cycle of the Kumada Coupling

1.3.3 Suzuki-Miyaura Cross-Coupling

The cross-coupling of alkyl boronic acids with alkyl halides, known as the

Suzuki-Miyaura reaction, has found use as an efficient and less toxic method to form carbon-carbon bonds. The reaction can be used with a large range of functional groups and the presence of water usually does not adversely affect it. Seminal studies published in 1979 by Suzuki and Miyaura showed the cross-coupling of 1-alkenylboranes with both

1-alkenyl and 1-alkynyl halides30 and with aryl halides31. One of the requirements of the 11 reaction was the need of a base to facilitate the activation of the boronic acid during transmetallation. The use of NaOH, NaOMe, NaOEt, and NaOAc were found to give successful cross-coupling while lewis bases such as triethyl amine did not work.

Additionally, the articles by Suzuki and Miyaura noted a high degree of stereo- and regioselectivy not previously obtainable by catalytic methods at that time; the coupling- reaction consistently proceeded with retention of the alkene stereochemistry found in the alkenylboranes. These findings opened a new pathway for the synthesis of sp2-sp2 and sp2-sp carbon-carbon bonds in a highly selective manner.

The mechanistic pathway of the Suzuki-Miyaura cross-coupling is similar to that of the Kumada coupling, however, the exact transmetalation process is unclear. The transmetalation under the Suzuki-Miyaura conditions concerns the transfer of an organic group from a borane, boronic acid, or boronic ester. The main concern revolves around how the required base takes part in the catalytic cycle and causes the transmetalation to occur. Two methods for the transmetalation have been examined. It was postulated by

Smith et al.45 that due to the basic conditions, a hydroxide adds to the boronic acid 18 to form tetrahedral anion 19 (Eq. 1.4), which is known to be more reactive than the neutral boron. They also completed kinetic studies on the use of water and base and found that both were required to activate the boronic acid to the salt. Additional evidence from electrospray ionization mass spectroscopy46 supports the use of the activated boronic acid as the key intermediate for successful transmetalation (Scheme 1.3, Pathway A). Another method of activation using the base was put forth by Suzuki47 (Scheme 1.3, Pathway B).

He theorized that prior to the transmetalation, the replacement of the halogen with a base

12 on the palladium was the key intermediate that promoted the addition of the organo boronic acid. Overall, the mechanistic cycle requires a base to perform the transmetalation, regardless of the pathway taken.

Scheme 1.3. Proposed Catalytic Cycles for Suzuki-Miyaura Cross-Coupling 13

Another aspect regarding the catalytic cycle is the rate of turnover. It is well understood that the oxidative addition typically acts as the rate determining step. A study on the effects of the halide has shown that the rate of reaction increases with leaving group ability (chlorine < bromine < iodine).48 For instance, the oxidative addition of iodobenzene with Pd(0)[PPh3]4 occurred at room temperature, while bromobenzene required heating to 80C to react and chlorobenzene did not react. An interesting result found however, was the use of an aryl iodide caused the transmetalation to be rate determining instead of the oxidative addition.45 The usefulness of aryl chlorides is of interest to many chemists due to their wider availability and lower cost compared to other halogens, but their low reactivity poses a problem. One solution discovered by Fu to improve upon the reactivity of aryl chlorides is to use a sterically bulky, electron rich

49 phosphine such as P(t-Bu)3 with the base Cs2CO3. Another modification to promote the coupling of aryl chloride presented by Buchwald uses phosphine 20 (Figure 1.4) with the

50, 51 base K3PO4. Lastly, Herrmann demonstrated the use of palladacycle 21 in the cross- coupling with moderate yields.52

Figure 1.4. Modifications for Cross-Coupling of Aryl Chlorides

Many of the early examples of the Suzuki-Miyaura cross-coupling used various phosphine ligands, the most common being triphenylphosphine (PPh3). An advance came in 1994 when Novak53 developed a method for using phosphine-free palladium

3 . sources. He used palladium acetate, [( -C3H5)PdCl]2, and Pd2(dba)3 C6H6 and found that all three showed higher reactivity than Pd(PPh3)4. It was also found that the addition of excess PPh3 to the catalyst system slowed the rate of reaction. One final observation made by Novak was the influence the pH had on the rate. When K2CO3 was used as the base rather than KHCO3, the reaction rate and yield increased.

The application of a new, novel reaction to the synthesis of complex molecules is often a true test to the significance of a reaction. One such application of the Suzuki-

Miyaura cross-coupling was in the synthesis of palytoxin carboxylic acid and palytoxin amide, toxins isolated in a marine natural product, by Kishi in 198954. As part of the synthetic strategy employed, a late stage coupling (Scheme 1.4) of cis-iodide 23 and trans-vinylboronic acid from alcohol 22 provided cis,trans-diene 24 in 70% yield.

Further functionalization of the diene followed by a Wittig reaction provided the desired palytoxin carboxylic acid product. The use of the cross-coupling procedure showed the ease with which a boronic acid could be prepared and employed in a strategic carbon- carbon bond formation.

Scheme 1.4. Cross-Coupling in the Synthesis of Palytoxin Carboxylic Acid

1.4 Investigation of Biaryl Synthesis by Cross-Coupling Reactions

The synthesis of biaryl compounds presents a unique challenge to chemists. In the traditional reactions of organic chemistry no methods exist for the efficient coupling of two different aromatic groups in a single reaction. There are possible synthetic routes to make biaryls, but the ability to complete such a transformation quickly and efficiently

16 could be a potentially powerful tool for organic synthesis. Many developments utilizing homocoupling and cross-coupling reactions have been presented in the past few decades.37, 55 The following section highlights some of the most important contributions to this field in recent years.

The synthesis of biaryls has been of interest to Al Meyers since he first published work on them in 1975. In that paper,56 Meyers introduced a method to do a nucleophilic aromatic substitution of methoxy-substituted aryls with Grignard reagents. Eventually, this method was applied toward the synthesis of a class of natural products with the structural motif of dibenzocyclooctadiene lignans.5, 40, 57 An interesting aspect of the reaction is that the method does not require a transition metal catalyst to complete a biaryl coupling. The coupling (Eq. 1.5) occurs by generation of an aromatic Grignard reagent from the corresponding halide 26, followed by addition of an aryl oxazoline 25 containing an o-methoxy functional group. Asymmetric control over the reaction is provided by a chiral functionality on the oxazoline substituent and gives high diastereoselectivity (S,S : S,R 98:2) for the desired biaryl 27. Related work using chiral auxiliaries to direct the stereochemistry of coupling products has been shown by Cram.58

While this method successfully created the carbon-carbon biaryl bond with the desired selectivity, it required several additional steps to introduce the oxazoline and protected alcohol and to later remove them. Therefore, a more general method applicable to any synthesis is of interest.

1.4.1 Cross-Coupling Reactions using Pd Catalysts

Palladium catalysts have seen the most widespread use in the Suzuki-Miyaura cross-coupling due to the high selectivity and wide versatility they exhibit. Many modifications from Suzuki’s original procedure have attempted to expand the scope of the reaction. Extensions have included the use of traditionally unreactive aryl halides, the use of ligands other than phosphines, and the formation of axially chiral products. It is the last of these extensions that is poised to have the largest impact toward the synthesis of complex organic compounds, but the successful development of an asymmetric reaction is often the most difficult. Recent research toward they synthesis of biaryl compounds using palladium catalysts is presented below.

A procedure for the cross-coupling of symmetric biaryls was published in 1996 by

Brian Keay.59 The unique aspect of the process was the in situ formation of an aryl boronic ester and consecutive use in a cross-coupling (Eq. 1.6). An aryl halide 28 (bromo or iodo) was reacted with 0.5 equivalents of n-butyllithium followed by addition of trimethylborate, which converted half of the starting aryl halide to a boronic ester. The addition of a palladium catalyst, base (Na2CO3 or Ba(OH)2), and solvent initiated the cross-coupling reaction. The reaction gave yields up to 96% of symmetric biaryls. This

18 method of preparing the cross-coupling avoids the need to isolate the aryl boronic ester and allows symmetrical biaryls to be easily produced.

The earliest report of an asymmetric Suzuki-Miyaura cross-coupling came in

2000 by Andrew Cammidge.60 First, a study of the conditions necessary for the coupling of napthalenes was explored including the combination of bases and solvents, boronic ester derivatives, and halides. The best conditions were then used along with chiral ligands (Figure 1.5). The highest selectivity was observed with the ferrocene-based ligand (S)-(R)-PFNMe 32, giving 50% yield and 85% ee. Later studies61 using these ligands also achieved moderate yields and selectivities.

Figure 1.5. Ligands for First Asymmetric Suzuki-Miyaura Cross-Coupling

Extensive research in the area of cross-coupling reactions has been done by

Stephen Buchwald. He is best known for the Buchwald-Hartwig reaction33, 50 for the formation of aryl amines, but he has also developed modifications to the Suzuki-Miyaura coupling. In 2000, Buchwald reported (shortly after Cammidge) an asymmetric Suzuki

62 coupling of biaryls. The reaction used Pd2(dba)3 as the catalysts and a bulky phosphine ligand with a biphenyl scaffold (see Figure 1.4, 20). The best selectivity reported was

95% yield with 86% ee. Also, the procedure presented the preparation of functionalized biaryls, which had not previously been demonstrated.

A variety of phosphine ligands (Figure 1.6) based on the biphenyl phosphine motif have been developed by Buchwald.63 The coupling of hindered biaryls was demonstrated in 2001 using these ligands.64 Formation of tetra-ortho substitution is difficult due to the high steric hindrance, and previous attempts were not generally applicable methods.65 Buchwald showed yields as high as 91% using ligand 35 for these substrates (Eq. 1.7). Another related use of ligands 37 and 38 was in the Negishi cross- coupling of biaryls, which gave high yields with similarly hindered substrates.66

Figure 1.6. Ligands Developed by Buchwald

Another modification of the Suzuki coupling is the use of aryl trifluoroborate salts

(ArBF3K) instead of a boronic acid or ester. The use of ArBF3K compounds was first shown by Molander67 in 2001 reacting with aryl sulfonates. Further work by Molander68 demonstrated the reaction of the borate salts with aryl halides and triflates with a ligandless catalyst system of Pd(OAc)2 and K2CO3 in water or methanol. Lastly,

Buchwald69 has shown the use of aryl trifluoroborates with aryl chlorides in the presence of ligand 37 (Figure 1.6). The main benefits of using the borate salts are their increased air stability compared to boronic esters and the enhanced nucleophilicity of the boron

(which benefits the transmetalation step of the catalytic cycle).

Recently, in an attempt to broaden the scope of substrates for the Suzuki-Miyaura cross-coupling, Buchwald70 investigated a variety of ester, phosphonate, and protected amides. The reaction used Pd(OAc)2 with the chiral ligand (S)-KenPhos 45 and gave yields of 80-92% and enantioselectivities of 88-94% ee. A representative example (Eq.

1.8) is the coupling of boronic acid 42 and the amide-substituted aryl bromide 43 to give biaryl 44 in 83% yield and 94% ee. One of the current shortcomings of the Suzuki-

Miyaura coupling is the challenge of using functionalized substrates, especially heteroaryls which could find use in many syntheses.

A topic of growing interest over the past few years is the use of carbenes as ligands. The most famous examples of carbene containing catalysts are those used in metathesis reactions, namely the Grubbs and Schrock catalysts. A report of the Suzuki coupling using chiral, acyclic diamino carbenes attached to a palladium was published in

2009 by Hong.71 The reaction was shown to give moderately high yields, but the selectivity was poor. With the carbene ligands, the catalyst was capable of forming tri- and tetrasubstituted biaryls, but yields decreased with increased steric demand. Another use of a palladium complex with a carbene ligand by Labonde72 in 2010 showed cross- coupling (Eq. 1.9) yields up to 95%, but low selectivity (23-40% ee). The ligand (47) evaluated is similar to Cammidge’s ferrocenyl phosphines (Figure 1.5), but has the addition of an N-heterocyclic carbene (NHC) which creates a chiral environment around the palladium. As a key component of a catalyst system, ligands help define the reactivity and selectivity of a catalyst. These variations from the standard ligand choice of phosphines have shown promise.

Chiral dienes have also been researched as ligands for the Suzuki coupling.

Alkenes are known to weakly coordinate with transition metals, which makes them attractive as hemilabile groups. In 2010, Lin73 showed chiral diene 48 could be used to form a Pd(II)-diene complex (Eq. 1.10). When reacted with an aryl halide and aryl boronic acid, biaryls could be formed in moderate to high yields of 72-99% and enantioselectivities up to 90% ee. Lin has also shown the use of the chiral diene ligand in conjugate additions of aryl boronic acids to nitroalkenes74 and N-tosylimines.75

A wide variety of modifications have been attempted to increase the reactivity and selectivity of palladium catalysts in the Suzuki-Miyaura cross-coupling. The most notable improvements are the ability to use traditionally difficult aryl halides and aryl sulfonates, and the control over stereoselectivity via ligands. There is still room for improvement in regard to functional group tolerability and sterically hindered substrates,

23 but the advancements noted above show promise in this area. Finally, even with the many attempts to use a viable chiral catalyst, a general method toward achieving high axial chirality is yet to be developed.

1.4.2 Cross-Coupling Reactions using Ni Catalysts

Several factors important to the practical, large-scale use of a reaction are the availability and cost associated with reagents. The use of palladium is beneficial since it often gives higher selectivity, but the tradeoff is lower reactivity and a higher cost of the metal. As an alternative, nickel shows remarkable reactivity as a catalyst and is much cheaper. It has also been found that the reaction of challenging substrates (i.e. chlorides, sulfonates, amines) is easier to accomplish with a nickel catalyst. The only drawback is the lower selectivity associated with nickel’s use. Several examples of nickel’s application in the Suzuki-Miyaura cross-coupling reaction have been reported in recent years.

A series of studies in 1995 by Percec looked at homocoupling and cross-coupling reactions using aryl mesylates catalyzed by nickel. It was found that the homocoupling of aryl mesylates (and most other aryl sulfonates) was an effective way to make symmetrical biaryls (Eq. 1.11).76 The Ni catalyst was generated in situ by Zn reduction and proposed to follow a Ni(I)/Ni(III) mechanistic pathway. The cross-coupling of simple aryl mesylates and phenyl boronic acids gave moderate yields with the same catalyst system.77 A later extension in 2011 by Yang78 showed aryl triflates could react with aryl boronic acids in the presence of a Ni(0) catalyst. Yields were reported to be

99% for sterically unhindered biaryls. These studies showed that aryl sulfonates, which had been found relatively unreactive in standard coupling conditions with palladium, can be used for a variety of biaryl synthesis methodologies.79

The use of aryltrimethylammonium salts (ArNMe3X) as a cross-coupling substrate has been explored by David MacMillan.80 These salts had been previously shown in cross-coupling with the Kumada coupling. The Suzuki coupling of these salts was tried using Ni(dppp)Cl2 and (2,4,6-trimethylphenyl)imidazole carbene (IMes, 51), but low yields were observed. Upon changing the catalyst to phosphine-free Ni(COD)2 with IMes, the reaction gave cross-coupling in yields between 79-98%. It was also noted that palladium catalysts were not successful in obtaining the cross-coupled biaryls. The challenge associated with using the ArNMe3X salts is having a catalyst active enough to insert into the carbon-nitrogen bond, which is less reactive than aryl halides. Thus, the use of the Ni(0) catalyst under phosphine-free conditions showed the potential of using nickel and a carbene ligand.

Figure 1.7. Carbene Ligand IMes 25

1.5 Conclusions

The Suzuki-Miyaura cross-coupling reaction is a valuable tool for the formation of new carbon-carbon bonds between aromatic groups. One of the largest hurdles to overcome is the development of a general route to highly efficient coupling and excellent stereoselectivity. Many advances have been made in the past several decades toward a general method, including a broader substrate scope and more selective catalysts.

However, there are still limitations to the current methods in these two areas. For the

Suzuki coupling to be of synthetic value for the formation of biaryls, functional group incompatibilities must be overcome and the asymmetric transfer of chirality needs to be improved. It should be exciting to see what further developments occur in the coming years.

CHAPTER 2: PALLADIUM CATALYZED ASYMMETRIC SUZUKI-MIYAURA

CROSS COUPLING REACTIONS OF BIARYL COMPOUNDS

2.1 Background and Significance

A growing area of research has been organometallic chemistry. Many significant reactions have been discovered which allow high yields and selectivities at every level, including enantioselectivity. In reactions involving transition metal catalysts, important aspects of the catalytic system include the metal, ligand, possible use of additives such as promoters and bases, solvent, and temperature. Each of these aspects has an important role in the outcome of a catalytic process. The choice of transition metal is often the first consideration due to the key role it plays in the reaction. Following the choice of a transition metal one must consider the ligand(s) attached to the metal center since the ligand will affect the reactivity of the metal, and can be used to control the selectivity aspects including stereochemical outcomes of the reaction.

The main aspect of the following research is the ligand for chiral catalysis. A wide variety of ligands have been developed and studied. Some of the best known ligands are phosphines, which are strongly coordinating groups. Chiral phosphine ligands, such as BINAP (Figure 1.5, 30), have been shown to be highly selective when used in various reactions. In an effort to explore other classes of ligands, chemists have used other atoms including carbon, oxygen, nitrogen, and sulfur as σ-bond donating

27 groups as well as electron rich groups like alkenes and conjugated compounds (i.e. η5- cyclopentadienyl).37 Of particular interest are bidentate ligands, which contain two groups able to form bonds with the metal center. If the two groups on the bidentate ligand are different, it is possible to have one strongly coordinating group and one weakly coordinating group, making the ligand hemilabile. A benefit of such an arrangement allows for easily opening a coordination site for the reactants, yet still having a coordinating site nearby to promote reductive elimination of the substrates. One weakly coordinating group that can fill the hemilabile role is the olefin bond. Several notable applications of olefins in chiral ligands have been shown including chiral dienes,73 olefin- phosphine ligands,81 olefin-nitrogen ligands,82 and olefin-sulfoxide ligands.83-86 The synthesis of such ligands for use in the Suzuki-Miyaura cross-coupling reaction was thought to be an effective method of introducing axial chirality to biaryl compounds.

2.2 Chiral Ligands for Cross-Coupling Reactions

For the study of the Suzuki-Miyaura cross-coupling of biaryl compounds, two classes of ligands were explored (Figure 2.1). The first class of ligands uses a bidentate binding site consisting of two nitrogen atoms. The ligand of choice was a pyridyl oxazoline (PyOX) (52) motif first introduced by Brunner87 and later adapted by Stoltz88.

The second class of ligands uses a bidentate, hemilabile sulfoxide-alkene binding site.

For these ligands, a combination of a chiral sulfoxide and molecular shape influence the stereochemistry while the alkene acts as a hemilabile group to the metal center. Two ligands of this class were explored: a bicyclic ligand (53) demonstrated by Knochel83 and

28 an aryl ligand (54) shown by Wan,84, 85 both incorporating the chiral sulfoxide and alkene functional groups. These three compounds were expected to have potential as asymmetric ligands in the Suzuki-Miyaura cross-coupling, so their syntheses and subsequent use were attempted.

Figure 2.1. Asymmetric Ligands for Suzuki-Miyaura Cross-Coupling

The first ligand synthesized was a pyridyl oxazoline (PyOX) based compound.

Brian Stoltz has shown the ligand provides effective chirality transfer in asymmetric conjugate additions to ,-unsaturated carbonyls.88 The chirality of the ligand originates from L-valine. Reduction of the carboxylic acid of L-valine (55) to alcohol 56 provided a convenient route to introducing the chirality (Scheme 2.1, Eq. 2.1). The synthesis (Eq.

2.2) started with conversion of 2-cyanopyridine 57 to carboxyimidate 58 upon addition of sodium methoxide to form a stable, clear oil. The reaction of this intermediate compound with (S)-valinol (56) under refluxing conditions promoted the formation of the cyclic oxazoline ring (52) in 91% yield over the two steps. With a quick and convenient route to the oxazoline functionality, the PyOX-type ligands can be easily synthesized for use.

Scheme 2.1. Synthesis of Pyridyl Oxazoline (PyOX) Ligand

The second ligand attempted was a chiral sulfoxide-alkene (Figure 2.1, 53). The ligand was originally shown to be useful in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to ,-unsaturated carbonyls by Paul Knochel.83 Inspiration for sulfoxide-alkene ligands came from the phosphorous-alkene ligands studied by Tamao

Hayashi.81 Preparation of the ligand was intended to follow the procedure given by

Knochel, however several challenges presented themselves along the way.

The initial functionalization of norbornene (59) (Scheme 2.2) included a simultaneous addition of a bromine and an alcohol to the bicyclic ring. An early report89 of this reaction used N-bromosuccinimide (NBS) in the presence of a strong acid (sulfuric acid) and t-butanol. However, the substrate was found to react with NBS in water to produce the desired product 60 as a mixture of constitutional isomers in moderate yields

(40-51%) after separation. Oxidation of the alcohol with the Swern protocol formed ketone 61 in quantitative conversion.

Scheme 2.2. Synthesis of Bicyclic Ketone

The next step of the synthetic scheme involved the addition of an aromatic group to ketone 61 followed by dehydration to alkene 62. Due to the higher substitution around the ketone, the use of a standard Grignard addition would not work; instead, the reaction was shown by Knochel to require activation with a Lewis acid.83 The first method attempted used a lanthanum mediated Grignard addition. The lanthanum compound used

. was LaCl3 2LiCl, which was first prepared as a 0.33M solution and later obtained commercially as a 0.6M solution.90 In the addition reaction (Eq. 2.3), a solution of the lanthanum Lewis acid was added to ketone 61 followed by addition of the aryl Grignard reagent. Once the addition was complete, dehydration of the alcohol was effected under acidic conditions. It was found that the reaction did not proceed as desired and only the aromatic compound (from the Grignard reagent) was isolated.

In the first trials of the addition reaction above the intermediate alcohol product was not isolated. In an attempt to optimized the reaction, the in situ dehydration was omitted to isolate the alcohol product (Eq. 2.4). It was found that addition reaction did not occur when no Lewis acid was used (Table 2.1, entry 1). A series of trials using

. LaCl3 LiCl to activate the ketone were tried (Table 2.1, entries 2-7). The choice of aromatic halide (iodine and bromine) for the preparation of the Grignard reagent was examined, and the aryl bromide was found to form the reagent easier. Changes in the solvent from THF to diethylether also did not appear to affect the outcome. Since the

Grignard reagent was thought to be the problem in the reaction, the method of activation of the magnesium when forming the Grignard reagent was explored (Table 2.1, entries 3,

7, and 8). In entries 3 and 7, addition of the lithium chloride salt91 was expected to help mediate the halogen/magnesium exchange, but was unsuccessful in the addition reactions.

Entry Aryl Halide Activating Reagent Temperaturea Solvent Addition Yield 1b 4-iodoanisole 1,2-dibromoethane 80˚C THF 0% 2 4-iodoanisole 1,2-dibromoethane 80˚C THF 0% 3 4-iodoanisole 1,2-dibromoethane, LiCl 80˚C THF 0% 4 4-bromoanisole 1,2-dibromoethane 80˚C THF 0% 5 4-bromoanisole 1,2-dibromoethane 40˚C Ether 0% 6 4-bromoanisole 1,2-dibromoethane 0˚C Ether 0% 7 4-bromoanisole i-PrI, LiCl 0˚C THF 0%

b,c 8 4-bromoanisole ZnCl2, LiCl 25˚C THF 62%

a b . Temperature of Grignard reagent formation. Reaction did not use Lewis acid LaCl3 2LiCl. c Formed organozinc reagent

Table 2.1. Preparation of Grignard Reagents for Addition to Ketones

A successful route to the alcohol was finally found with entry 8 (Table 2.1). The reagent was prepared as diorganozinc compound 65 (Scheme 2.3).92 In the preparation of the reagent, aryl bromide 64 was reacted at room temperature with ZnCl2, magnesium turnings, and lithium chloride using THF as the solvent. The organozinc reagent underwent addition to ketone 61 without the need of an additional Lewis acid. This route formed the desired alcohol 63 as two diastereomers in up to 62% yield. With the alcohol formed, dehydration using methanesulfonic acid was easily accomplished in 92% conversion to alkene 62 (Scheme 2.3).

Scheme 2.3. Synthesis of Bicyclic Alkene

As a key aspect of the sulfoxide-alkene type ligand, the chiral sulfoxide needed to be prepared before incorporation into the alkene scaffold (62). Sulfur is known to have a valence electron shell containing 10 or 12 electrons. These possible configurations are present when sulfur is tetra- and hexacoordinated respectively. For the purposes of forming a chiral sulfoxide, sulfur will have 10 electrons with a sulfur-oxygen double bond and two other sigma bonded substituents. Due to the extra lone pair sulfur possesses, the geometry will effectively be tetrahedral. A high energy barrier to inversion of the stereocenter makes a chiral sulfoxide energetically stable.

A route to accessing a specific enantiomer of a chiral sulfoxide was first shown by

Sharpless in 1987.93 Using a chiral auxillary, the sulfur stereocenter can be set. A convenient source of that chirality is menthol, which can be directly attached to the sulfur and easily replaced.94 For the synthesis of chiral sulfoxide 68 (Eq. 2.5), (-)-menthol (66) was reacted with p-toluenesulfonyl chloride (TsCl) (67) in the presence of triphenylphosphine (Ph3P) and triethylamine (Et3N). The sulfonyl chloride is thought to undergo a selective reduction to a sulfinyl chloride followed by substitution of the 34 alcohol. After a workup of the reaction solution, a mixture of sulfoxide diastereomers was isolated. The major diastereomer could be separated by successive recrystallizations from acetone. The main problem with the route was a low level of product isolation, with a maximum of 14% yield of the diastereomeric mixture and 7% yield of the single, pure isomer being isolated.

The final step to synthesize sulfoxide-alkene ligand 53 was to install chiral sulfoxide 68 at the C7-position of the bicyclic ring. To accomplish this, bromide 62 would first react by lithium-halogen exchange, followed by addition addition of the sulfoxide to form the desired carbon-sulfur bond (Eq. 2.6). The chirality of the sulfoxide is known to invert when reacted with organometallic reagents, which is consistent with a

95 nucleophilic substitution (SN2) mechanism. When the reaction was attempted, a mixture of two constitutional diastereomers (53a and 53b) was isolated in 42% yield.

The two diastereomers could be separated by column chromatography and the compounds were isolated in yields of 15% and 6%. Due to the low yields of these compounds, only small amounts were isolated (25 mg and 11 mg, respectively). Upon comparison of melting point data, the major isolated product corresponded well to the known melting point of structure 53a. However, the minor product isolated was

35 significantly different than the reported values of both structures leading to the conclusion that this product was something else. NMR data of the major product corresponded well to previously published data on these compounds. Analysis by HPLC

(see Appendix B) indicated several impurities in both isolated products. Due to the low yields obtained and the impurities encountered, this ligand was not studied in the cross- coupling reaction.

Since difficulties were encountered in obtaining a useable amount of ligand 53a, the synthesis of a related sulfoxide-alkene ligand (Figure 2.1, 54) was undertaken. This ligand was developed by Wan84, 85 for the rhodium-catalyzed asymmetric conjugate addition of aryl boronic acids to nitroalkenes. The ligand was constructed around a central aromatic ring starting with dibromide 69 (Scheme 2.4). Following the procedure for the Arbuzov reaction,96 the primary bromide (69) was converted to the diethyl phosphonate 70 in excellent yield. The phosphonate was then reacted with aldehyde 71 to form (E)-alkene 72 using the Horner-Wadsworth-Emmons modification of the Wittig

36 reaction. The alkene was synthesized in quantitative yield with high selectivity for the

(E)-isomer.

Scheme 2.4. Synthesis of Alkene in Aryl Sulfoxide-Alkene Ligand

For sulfoxide-alkene ligand 54, the sulfoxide functional group was to be constructed with a naphthalene ring attached. As a source of the naphthalene group, alcohol 73 (2-naphthol) was converted to ether 74 (2-methoxynaphthalene) by the

Williamson ether synthesis (Scheme 2.5). In order to introduce the sulfoxide functional group a two step reaction sequence was followed: first addition of thionyl chloride

97 98 (SOCl2), then introduction of (-)-menthol to set the sulfoxide stereochemistry. It was found that the intermediate product after the reaction of SOCl2 could not be isolated; instead, the intermediate product was dried under vacuum to remove excess thionyl chloride and immediately reacted with (-)-menthol. The sulfoxide compound (75) was isolated as a mixture of diastereomers after separation by column chromatography.

However, attempts to recrystallize the mixture, where a single diastereomer would crystallize while the other remained in the solution, was not successful. Since the separation of the diastereomers failed, the sulfoxide could not be used to form the ligand

37 since a high degree of enantiopurity is required in a chiral ligand. Thus, the second attempt to synthesis a chiral sulfoxide ligand was unsuccessful and no cross-coupling reactions were done utilizing this ligand.

Scheme 2.5. Synthesis of Naphthalene Sulfoxide

2.3 Cross-Coupling Reactions of Biaryls

2.3.1 Preparation of Cross-Coupling Precursors

To study the cross-coupling reaction between an aryl halide and an aryl boronic acid, these two coupling partners needed to be prepared. A major structural concern when choosing compounds for the coupling was their ortho-substitution pattern. Since at least three ortho groups are required to form a stable atropisomer, one of the compounds would need at least two ortho groups while the other contained at least one group in the ortho-position. The use of naphthalene based compounds provides steric bulk in the ortho-position when the halide or boronic acid is at C1 of the aromatic ring.

The aryl halide (77) was synthesized from 2-methylnapthalene (76), which provided the two required ortho-substituents. Due to its known ease of reactivity, the 38 halide of choice was bromine. The first procedure followed61 for the bromination (Eq.

2.7) used NBS in acetonitrile; however, the reaction would not go to completion and

99 resulted in unpure product. An alternative procedure (Eq. 2.8) using Br2 in acetic acid produced the brominated naphthalene (77) as a clear oil in up to 77% yield.

Synthesis of the aryl boronic acid took several attempts to be successfully accomplished. As with the aryl bromide, the aryl structure for the boronic acid came from a naphthalene compound. The typical procedure for installing the boron functional group includes preparing an organometallic reagent (Grignard or organolithium) from a halide, followed by addition of a boronic ester.100 Quenching the resulting boronic ester with water will produce a boronic acid. In the first synthesis61 (Eq. 2.9), the Grignard reagent was prepared from 1-bromonaphtalene (78), reacted with trimethylborate, and quenched with dilute hydrochloric acid. The product, 1-naphthaleneboronic acid (79), is known to form as a white crystalline solid, but was not observed in the preceding reaction. Upon repetition of the reaction with 2-methyl-1-bromonaphthalene (77), no conversion of the product was again observed. A different preparation62 of the

39 organometallic reagent was tried next (Eq. 2.10); the reaction of aryl bromide 77 with n- butyllithium via lithium-halogen exchange, and addition of trimethylborate with acidic workup was tried. Unfortunately, the reaction failed to form the desired aryl boronic acid. The final unsuccessful attempt to the boron functionality (Eq. 2.11) first involved preparation of the Grignard reagent and addition of trimethyl borate. Following the formation of the methyl boronic ester, the product was concentrated then refluxed with pinacol to form the pinacol protected boronic ester (81).101 Alas, the boronic ester was not successfully isolated.

Another route utilized for the synthesis of the boron functional group was the preparation of trifluoroborate salts. Following the procedure by Molander,67 aryl bromides 78 was made into a Grignard reagent and reacted with trimethyl borate, then

40 potassium bifluoride (KHF2) was added to form the borate salt 82 (Eq. 2.12). The resulting white solids were air stable and could be used in the cross-coupling procedure.

Lastly, a variation recently published102 proved to be a highly successful route to aryl boronic acids. In this procedure (Eq. 2.13), the formation of the Grignard reagent was mediated by the presence of lithium chloride with activation of the magnesium occurring by the addition of a substoichiometric amount of DIBAL-H. Also noteworthy was that the Grignard reagent could be formed at room temperature, instead of refluxing temperatures typically needed. The boronic acid (79) formed was easily recrystallized from water as a white solid. The use of this procedure proved a straightforward way to access the boronic acid functionality.

2.3.2 Cross-Coupling Reactions with S-Phos Ligands

To optimize the Suzuki-Miyaura cross-coupling reaction, two achiral ligands were employed. The first ligand is known as S-Phos (Figure 1.6, 37). The second ligand is a

41 modified version of S-Phos containing a sodium sulfonato group, S-Phos-SO3Na (84), to increase its water solubility. Both ligands were developed by Buchwald63 and are commercially available. In the cross-coupling reaction (Eq. 2.14), the initial optimization was carried out using Pd(OAc)2 as the metal source. The palladium undergoes an initial reduction with the ligand from Pd(II) to Pd(0) to form the reactive catalyst. Other variables looked at were the choice of base, solvent, and boron functional group. The results are summarized in Table 2.2.

Entry R-Groupa Metal Ligand Base Yield

1 -BF3K 1% Pd(OAc)2 2% S-Phos-SO3Na K2CO3 0%

2 -BF3K 2% Pd(OAc)2 4% S-Phos-SO3Na K2CO3 0%

3 -BF3K 2% Pd(OAc)2 4% S-Phos-SO3Na K3PO4 0%

4 -BF3K 2% Pd(OAc)2 4% S-Phos K2CO3 0%

b 5 -BF3K 2% Pd(OAc)2 4% S-Phos K2CO3 0%

6 -B(OH)2 2% Pd(OAc)2 4% S-Phos K2CO3 93%

7 -B(OH)2 2% Pd(OAc)2 4% S-Phos-SO3Na K2CO3 >99%

a b Boron group attached to C1 of naphthalene Solvent was 5% H2O/MeOH

Table 2.2. Results of Cross-Coupling Optimization

It was found that using the trifluoroborate salt would not give the cross-coupling product. One possible reason this result was obtained is that the borate salt substrate that was prepared had decomposed prior to its use. With the successful couplings, the ligand choice did not have a profound effect on the yield; both S-Phos and S-Phos-SO3Na gave high yields of the cross-coupled product. The biaryl product (83) was found to agree with published 1H and 13C NMR data.73 The products of entries 6 and 7 (Table 2.2) were analyzed by HPLC and found to have two major peaks corresponding to the two expected atropisomers. Further exploration of the achiral cross-coupling could look at the use of a different base such as K3PO4 or CsF in the reaction of the aryl bromide and aryl boronic acid.

2.3.3 Cross-Coupling Reactions with Chiral Ligands

In the study of the Suzuki-Miyaura cross-coupling reaction of axially chiral biaryls, the prepared ligand PyOX (52) was utilized. Due to difficulties encountered during the synthesis of the two sulfoxide-alkene ligands (53 and 54), they were not tried in the cross-coupling. A series of trials using PyOX as the ligand was completed (Table

2.3). The use of different palladium sources was explored to determine if that would impact the reaction. Palladium acetate (Table 2.3, entries 1 and 2) produced the cross- coupled product 83, but the yield in both trials was low. The reaction also gave low yields when bis(dibenzylideneacetone)palladium(0) was used (entry 3). Lastly, with bis(benzonitrile)palladium chloride (entries 4 and 5), the reaction did not produce any product when the solvent was only methanol; interestingly, when the solvent was

43 changed to a combination of methanol and water the reaction proceeded in slightly higher yield than the previous trials.

Entry Metal Ligand Base Yield

1 2% Pd(OAc)2 2.5% PyOX K2CO3 11%

2 5% Pd(OAc)2 6% PyOX K2CO3 7%

. 3 2.5% Pd2(dba)3 CHCl3 6% PyOX K2CO3 15%

4 5% Pd(PhCN)2Cl2 6% PyOX K2CO3 0%

a 5 5% Pd(PhCN)2Cl2 6% PyOX K2CO3 34%

a Solvent was MeOH/H2O

Table 2.3. Results of Chiral Cross-Coupling

As a key component of the study, the outcome of the axial chirality was examined in each of the cross-coupling trials (Table 2.3). The product mixture from each reaction was filtered through a plug of silica gel to remove the metal catalyst, then subjected to analysis by HPLC (see Appendix B). In all of the reactions, a mixture of compounds was isolated including the product biaryls, unreacted starting materials (aryl bromide and aryl boronic acid). Thus, the determination of the reaction selectivity was unable to be accomplished.

2.4 Conclusions

Due to the promising future of the Suzuki-Miyaura cross-coupling reaction for the synthesis of sterically demanding biaryls, further study for the optimization of the synthesis of biaryls using chiral ligands is of interest. In the current project, the goal was to synthesize several chiral ligands and apply them to the cross-coupling reaction. The synthesis of three ligands was attempted [bidentate dinitrogen compound PyOX (52) and two bidentate sulfoxide-alkene compounds (53 and 54)]. However, the syntheses of the two sulfoxide-alkene ligands were not completed because of technical difficulties, and thus the study of the chiral cross-coupling reaction was done with only PyOX. Also completed during the study was the optimization of cross-coupling conditions using two commercially available, non-chiral ligands (S-Phos and S-Phos-SO3Na). The authentic samples of the intended products were prepared and the chiral stationary phase HPLC separation of the enantiomers was accomplished. These studies of the cross-coupling showed that the reaction using a chiral ligand is viable, but improvements on the yields will need to be addressed before further study of the ligand selectivity is done. Further work would involve completion of the syntheses of the sulfoxide-alkene ligands and further optimization of the structure of the PyOX ligands.

2.5 Experimental Procedures

2.5.1 General Methods

Air-sensitive reactions were performed under an inert atmosphere of nitrogen using Schenk techniques or a Vacuum Atmospheres glovebox. Dichloromethane was distilled from calcium hydride and stored over molecular sieves. Tetrahydrofuran was distilled from sodium/benzophenone ketyl under nitrogen. Analytical TLC was done on

Sorbent Technologies precoated (0.25 mm) silica gel XHL plates with UV254. Flash column chromatography was performed using silica gel 40 (Microns Flash).

Enantiomeric excess of chiral compounds were determined by chiral high performance liquid chromatography using Chiralcel OJ-H or Chiralpak AD columns on a Shimadzu

HPLC equipped with a SPD-20A UV/VIS detector. NMR spectra were obtained using a

Bruker DPX 250, Bruker Avance III 400, and Bruker DRX 500.

2.5.2 Synthesis of Chiral Pyridinooxazoline (PyOX) Ligand

(S)-valinol (56): To a round bottom flask equipped with a reflux condener was added

NaBH4 (3.56 g, 94 mmol) in 100 mL of dry THF. S-valine (5.00 g, 42.7 mmol) was added and the mixture was cooled to 0˚C. A solution of I2 (11.17 g, 44 mmol) in 25 mL of THF was added over 30 minutes. The flask was heated to reflux for 18 hours, then cooled to room temperature and quenched with 25 mL of methanol. The solvent was removed to leave a white solid to which was added 125 mL of 20% (w/v) KOH and stirred overnight. The solution was extracted with CH2Cl2 (3 x 50 mL), then the combined organic layers were dried with Na2SO4, filtered, and concentrated. The crude alcohol was purified by Kugelrohr distillation to afford 3.31 g (75%) of a clear oil. 1H 46

NMR (250 MHz; CDCl3) δ 3.55 (1H, dd, J=4.0, 10.5Hz), 3.24 (1H, dd, J= 9.0, 10.5Hz),

2.49 (1H, ddd, J=4.0, 6.5, 9.0Hz), 2.36 (3H, br. s), 1.53 (1H, m, J=6.5, 6.7), 0.90 (6H, d,

J=6.7).

Methyl pyridine-2-carboxyimidate (58): A round bottom flask with methanol (10 mL) was cooled to 0˚C. Sodium metal (0.044 g, 1.9 mmol) was slowly added to the flask until it was consumed. In a second round bottom flask was added 2-cyanopyridine (2.00 g,

19.2 mmol) and 20 mL of methanol. This was cooled to 0˚C, the NaOMe solution was added, and allowed to stir at room temperature overnight. The reaction was quenched with acetic acid, the solvent was evaporated, and the resulting product was dissolved in

50 mL CH2Cl2. The organic layer was washed with brine (2 x 25 mL), dried with

MgSO4, filtered, and the solvent was removed to get 2.53 g (96%) of a clear oil which

1 was used without further purification. H NMR (250 MHz; CDCl3) δ 9.52 (1H, br. s),

8.63 (1H, d, J=5.0Hz), 7.80 (2H, m), 7.34 (1H, t, J=6.2Hz), 3.98 (3H, s).

(S)-4-(isopropyl)-2-(pyridine-2-yl)-4,5-dihydrooxazole (52): To a three-neck round bottom flask equipped with a reflux condenser was added methyl pyridine-2- carboxyimidate (0.93 g, 6.8 mmol), (S)-valinol (0.704 g, 6.8 mmol), and 34 mL of 47

. toluene. While stirring, p-TsOH H2O (0.065 g, 0.34 mmol) in 1 mL toluene was added.

The solution was heated to 80˚C and stirred for 24 hours. A saturated solution of

NaHCO3 was added and the mixture was then washed with ethyl acetate, dried with

MgSO4, filtered, and the solvent was removed. The product was obtained as an orange

1 oil (1.24 g, 95%). H NMR (250 MHz; CDCl3) δ 8.69 (1H, d, J=5.0Hz), 8.04 (1H, d,

J=7.5Hz), 7.75 (1H, t, J=7.5Hz), 7.37 (1H, dd, J=5.0, 7.5Hz), 4.47 (1H, m), 4.15 (2H, m),

1.87 (1H, m), 1.04 (3H, d, J=7.5Hz), 0.92 (3H, d, J=7.5Hz); 13C NMR (62.9 MHz;

CDCl3) δ 149.71, 136.57, 125.44, 123.88, 72.93, 70.73, 32.74, 19.06, 18.17. The data is consistent with what is reported in the literature.

2.5.3 Synthesis of Chiral Bicyclic Sulfoxide-Alkene Ligand

(exo, syn)-7-Bromobicyclo[2.2.1]heptan-2-ol (60): In a round bottom flask was added norbornene (10.0 g, 106.2 mmol) and 140 mL of water. To this mixture was added NBS

(19.85 g, 111.5 mmol) and the mixture was stirred at room temperature for 48 hours. The product was extracted with ether, dried with MgSO4, filtered, and the solution concentrated. Purification by column chromatography (hexanes-ethyl acetate, 10:1)

1 produced 9.87 g (48%) of the desired compound. H NMR (250 MHz; CDCl3) δ 3.93

(1H, s), 3.78 (1H, br. s), 2.45 (3H, m), 2.02 (2H, m), 1.57 (2H, m), 1.15 (2H, m); 13C

NMR (62.9 MHz; CDCl3) δ 56.40, 49.15, 42.87, 41.58, 25.40, 24.72.

7-Bromobicyclo[2.2.1]heptan-2-one (61): In a flame dried round bottom flask was added oxalyl chloride (0.99 mL, 11.5 mmol) and 20 mL dry CH2Cl2 under nitrogen gas.

The temperature was lowered to -78˚C, distilled DMSO (1.65 mL, 23.0 mmol) was slowly added, and the mixture was allowed to stir for 20 minutes. The starting alcohol

(2.00 g, 10.5 mmol) in 20 mL of CH2Cl2 was slowly added to the mixture and stirring was continued for 2 hours. To the flask was added dry triethylamine (7.3 mL, 52.5 mmol) and the solution was allowed to warm to room temperature. The solution was washed with saturated NH4Cl solution (50 mL), water (3 x 50 mL), dried with MgSO4, filtered, and the solvent was removed to get 1.98 g (>99%) of the ketone. 1H NMR (250

MHz; CDCl3) δ 4.12 (1H, s), 2.64-2.76 (3H, m), 1.87-1.95 (3H, m), 1.54-1.63 (3H, m);

13 C NMR (62.9 MHz; CDCl3) δ 213.76, 56.45, 54.38, 41.74, 41.50, 25.68, 22.67.

Preparation of diaryl zinc reagent (65): In a dried round bottom flask was placed anhydrous LiCl (0.33 g, 7.9 mmol), anhydrous ZnCl2 (0.78 g, 5.7 mmol), and Mg turnings (0.64 g, 26.2 mmol). The flask was evacuated and refilled with nitrogen gas three times. Dry THF (20.0 mL) was added to the flask, then 4-bromoanisole (1.96 g,

10.5 mmol) in 1.0 mL of dry THF was introduced. The reaction mixture was stirred for 4

49 hours. The resulting grey colored solution was transferred via cannula to another dry flask to remove excess magnesium.

7-Bromo-2-(4-methoxyphenyl)bicyclo[2.2.1]hept-2-ol (63): In a dry round bottom flask was added the ketone (1.00 g, 5.25 mmol) in 10 mL of dry THF. The earlier prepared diaryl zinc reagent was added via cannula and the reaction was allowed to stir at room temperature for 22 hours. The reaction mixture was washed with saturated NH4Cl solution and the organic layer was dried with MgSO4, filtered, and concentrated. Two products formed, which were separated with column chromatography (hexane-ether,

1 20:1) to get 0.74 g (47%) of the major alcohol. H NMR (250MHz, CDCl3) δ 7.39 (2H, d, J=10.0 Hz), 6.86 (2H, d, J=10.0 Hz), 4.17 (1H, s), 3.79 (3H, s), 3.53 (1H, s), 2.43-2.75

(5H, m), 1.94 (1H, m), 1.57-1.62 (2H, m), 1.23-1.27 (3H, m), 0.86-0.95 (2H, m); 13C

NMR (62.5MHz, CDCl3) δ 158.7, 135.8, 127.7, 116.0, 114.6, 113.4, 82.8, 58.4, 56.5,

55.3, 54.4, 53.8, 44.3, 43.6, 41.8, 41.5, 25.7, 24.3, 23.1, 22.7.

7-Bromo-2-(4-methoxyphenyl)bicyclo[2.2.1]hept-2-ene (62): The starting material

(0.736 g, 2.47 mmol) was placed in a dry round bottom flask with 10 mL of dry THF.

The flask was cooled to -78˚C, then methanesulfonic acid (0.64 mL, 9.88 mmol) was added dropwise. The solution was allowed to warm to room temperature, then quenched with triethyl amine (1.37 mL, 9.88 mmol). The organic layer was washed with saturated

NH4Cl solution, H2O, dried over MgSO4, filtered, and concentrated to afford 0.636 g

1 (92%) of the alkene product. H NMR (250MHz, CDCl3) δ 7.36 (2H, d, J=7.5 Hz), 6.86

(2H, d, J=10.0 Hz), 6.13 (1H, d, J=2.5 Hz), 3.98 (1H, d, J=2.5 Hz), 3.79 (3H, s), 3.40

13 (1H, s), 3.13 (1H, s), 1.88-1.90 (3H, m), 1.24-1.30 (3H, m); C NMR (62.5MHz, CDCl3)

δ 159, 145, 127, 126.5, 124.1, 114.0, 65.3, 55.3, 50.9, 50.5, 25.1, 23.0.

(S)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-methylbenzenesulfinate (68): To a round bottom flask was added (-)-menthol (3.00 g, 19.2 mmol), p-toluene sulfonyl chloride (5.49 g, 28.8 mmol), and 40 mL of distilled CH2Cl2. The mixture was cooled to

0˚C, then triphenylphosphine (7.55 g, 38.8 mmol) and triethylamine (13.3 mL, 96 mmol) were slowly introduced in 30 mL of CH2Cl2 over 1 hour. When the addition was complete, the reaction was finished. The mixture was washed with 3M HCl (2 x 100 mL), saturated NaHCO3 solution (100 mL), brine (100 mL), dried with MgSO4, filtered, and concentrated. The product mixture was dissolved in 1:2 ether-petroleum ether, and then filtered to remove byproducts. The product was separated by column 51 chromatography (hexanes-ethyl acetate, 20:1) to get 0.817 g (14%) of a diastereomeric mixture of the products. Recrystallization from acetone at 0˚C precipitated a single diastereomer. Subsequent addition of a drop of concentrated HCl to the mother liquor and repeated recrystallization allowed additional product to be isolated. The combined recrystallizations yielded 0.287 g (5%) of a single diastereomer. 1H NMR (250MHz,

CDCl3) δ 7.58 (2H, d, J=10.0 Hz), 7.30 (2H, d, J=10.0 Hz), 4.10 (1H, td, J=7.5, 5 Hz),

2.40 (3H, s), 1.65 (2H, m), 1.17-1.33 (3H, m), 0.94 (3H, d, J=5.0 Hz), 0.83 (3H, d, J=7.5

Hz), 0.69 (3H, d, J=7.5 Hz).

(1S,4R,7S)-2-(4-methoxyphenyl)-7-((R)-p-tolylsulfinyl)bicyclo[2.2.1]hept-2-ene (53a) and (1R,4S,7R)-2-(4-methoxyphenyl)-7-((R)-p-tolylsulfinyl)bicyclo[2.2.1]hept-2-ene

(53b): A dry, nitrogen flushed round bottom flask was primed with the starting alkene

(62) (0.140 g, 0.50 mmol) in 1 mL of dry THF, and the solution was cooled to -78˚C. To the solution was slowly added 0.65 mL (1.10 mmol) of t-butyllithium (1.7M solution in pentane), which was subsequently stirred for 2 hours. A prepared solution of magnesium chloride (0.052 g, 0.55 mmol) in 2 mL of THF was added to the reaction flask and allowed to stir for 30 minutes. The sulfinate (0.162 g, 0.55 mmol) in 0.5 mL of THF was then introduced to the reaction flask. The temperate was maintained at -78˚C and stirred

52 for 4 hours, at which time the flask was brought to room temperature and slowly quenched with H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried with

MgSO4, filtered, and concentrated. Column chromatography separation (hexanes- acetone, 4:1) gave a mixture of diastereomeric products. A second separation

(dichloromethane-ethyl acetate, 2:1) allowed for the collection of two products: 53a –

0.0255 g (15%); 53b – 0.0113 g (6%). A comparison of melting point, NMR, and HPLC data of compound 53a to the reported literature values83 showed similarities, but several deviations in chemicals shifts (NMR) and the presence of several impurities (HPLC) did not allow the confirmation of this product. The melting point for compound 53b does not agree with the reported literature value, leading to the conclusion that the isolated product

1 was not the desired compound. 53a: H NMR (250MHz, CDCl3) δ 7.50 (2H, d, J=7.5

Hz), 7.43 (2H, d, J=10.0 Hz), 7.30 (2H, d, J=7.5 Hz), 6.87 (2H, d, J=10.0 Hz), 6.17 (1H, d, 2.5 Hz), 3.93 (1H, s), 3.80 (3H, s), 2.79 (1H, s), 2.58 (1H, s), 2.39 (3H, s), 1.95-1.68

13 (2H, m), 1.37-1.15 (3H, m); C NMR (62.5MHz, CDCl3) δ 159.6, 145.4, 141.8, 141.7,

129.9, 127.0, 126.8, 124.4, 124.3, 114.0, 87.2, 55.3, 45.8, 44.9, 27.1, 24.8, 21.7; mp 176-

180˚C (lit. 173-174˚C); HPLC (Chiralpak AD, 20% isopropanol:hexane, flow: 0.3

1 mL/min, 40˚C), retention time: 41.804 min (74.08%). 53b: H NMR (250MHz, CDCl3) δ

7.41 (2H, d, 10.0 Hz), 7.29 (4H, m), 6.88 (2H, d, J=10.0 Hz), 6.31 (1H, d, J=5.0 Hz), 3.81

(3H, s), 3.62 (1H, br. s), 2.84 (1H, d, J=2.5 Hz), 2.79 (1H, s), 2.39 (3H, s), 2.00-1.86 (1H, m), 1.80-1.63 (2H, m), 1.49-1.32 (2H, m), 1.20-1.10 (1H, m); 13C NMR (62.5MHz,

CDCl3) δ 141.7, 130.0, 126.9, 126.4, 124.6, 114.3, 55.1, 25.0, 21.6; mp 154-156˚C (lit.

213-214˚C).

2.5.4 Synthesis of Chiral Aryl Sulfoxide-Alkene Ligand

Diethyl 2-bromobenzylphosphonate (70): In a dry round-bottomed flask with attached reflux condenser was added 2-bromobenzyl bromide (2.00 g, 8.0 mmol). The flask was successively dried under vacuum and flushed with nitrogen gas. To the flask was added

CH2Cl2 (16 mL), then triethyl phosphite (1.51 mL, 8.8 mmol) and stirred at 50˚C overnight. The reaction was quenched with 3M HCl (25 mL), extracted with CH2Cl2 (50 mL), dried over MgSO4, filtered, and concentrated to afford 2.4 g (>99%) of

1 phosphonate. H NMR (400MHz, CDCl3) δ 7.49 (1H, d, J=8.0 Hz), 7.39 (1H, d, J=7.6

Hz), 7.19 (1H, t, J=7.6 Hz), 7.03 (1H, t, J=7.6 Hz), 3.98 (4H, m, J=6.4, 7.2 Hz), 3.36 (1H, s), 3.31 (1H, s), 1.18 (6H, t, J=6.8 Hz).

(E)-1-bromo-2-(4-methoxystyryl)benzene (72): To a dry, round bottom flask was added NaH (0.088 g, 2.2 mmol) and dimethyoxyethane (1 mL). The flask was cooled to

0 C, then diethyl 2-bromobenzylphosphonate (0.368 g, 1.0 mmol) in 1 mL of DME was 54 added. The solution was allowed to warm to room temperature and stirred for 1 hour.

The flask was again cooled to 0˚C and p-anisaldehyde (0.136 g, 1.0 mmol) in 1 mL of

DME was introduced. The reaction was warmed to room temperature and stirred overnight. Upon quenching the reaction with water (25 mL), the product was extracted with Et2O (2 x 25 mL). The combined organic layers were washed with brine, dried with

MgSO4, filtered, and concentrated to give 0.28 g of the desired alkene, which was

84 1 consistent with reported literature data. H NMR (400MHz, CDCl3) δ 7.52 (1H, dd,

J=2.0, 8.0 Hz), 7.45 (1H, dd, J=1.2, 8.0 Hz), 7.36 (2H, d, 8.8 Hz), 7.22 (1H, d, J=16.0

Hz), 7.16 (1H, t, J=8.0 Hz), 6.95 (1H, td, J=8.0, 1.6 Hz), 6.86 (1H, d, J=16.4 Hz), 6.79

13 (2H, d, J=8.8 Hz), 3.69 (3H, s); C NMR (100 MHz; CDCl3) δ 158.6, 136.3, 132.0,

129.9, 128.8, 127.3, 127.0, 126.4, 125.4, 124.2, 122.9, 113.1, 54.2.

2-methoxynaphthalene (74): In a dry round bottom flask was added sodium hydride

(2.40 g, 60.0 mmol) and 15 mL of DMSO. To this solution was added 2-naphthol (4.32 g, 30.0 mmol) in 15 mL DMSO. The flask was brought to reflux for 1 hour, and then methyl iodide (2.05 mL, 33.0 mmol) was added. The reaction was quenched with water, then the organic portion was extracted with CH2Cl2, dried with MgSO4, filtered, and concentrated. Separation by column chromatography (hexanes-ethyl acetate, 10:1)

1 allowed for the isolation of 4.44g (93%) of product. H NMR (400MHz, CDCl3) δ 7.70

(1H, s), 7.66 (2H, d, J=9.2 Hz). 7.38 (1H, t, J=7.2 Hz), 7.26 (1H, t, J=7.2 Hz), 7.07 (2H,

13 d, J=7.6 Hz), 3.85 (3H, s); C NMR (100 MHz; CDCl3) δ 157.6, 134.6, 129.4, 129.0,

127.6, 126.7, 126.4, 123.6, 118.7, 125.8, 55.3.

(S)-(L)-menthyl 2-methoxy-1-naphthalenesulfinate (75): To a dry round bottom flask was added 2-methoxynaphthalene (1.00 g, 6.3 mmol), and then in one portion was added thionyl chloride (0.92 mL, 12.6 mmol). The mixture was stirred at room temperature until a solid was formed. Next, the flask was placed under high vacuum with an in-line liquid nitrogen trap to remove excess thionyl chloride. To the remaining solid was added

(-)-menthol (1.08 g, 6.9 mmol) in 20 mL CH2Cl2. The solution was stirred for 10 minutes, then added 5 mL dry pyridine. The precipitate that formed was filtered off, and the remaining solution was washed with 3M HCl, dried with MgSO4, filtered, and concentrated. The crude product was separated by column chromatography (hexanes- ethyl acetate, 20:1) and isolated 0.059 g (2%) of a diastereomeric mixture of products (Rf

= 0.55; hexanes-ethyl acetate, 10:1). Recrystallization from acetone at 0˚C was unsuccessful.

2.5.5 Synthesis of Cross-Coupling Reagents

1-bromo-2-methylnaphthalene (77): To a round bottom flask was added 2- methylnapthalene (1.00 g, 7.0 mmol) and 2 mL acetic acid. A solution of Br2 (1.23 g,

0.40 mL, 7.7 mmol) in 2 mL of acetic acid was added dropwise to the flask to allow dissipation of the bromine before the next drop. The mixture was stirred at room temperature overnight. The reaction was extracted with CH2Cl2 (50 mL) and the organic layer was washed with NaHCO3, water, dried with MgSO4, filtered, and concentrated.

Purification by column chromatography (hexanes-ethyl acetate, 20:1) afforded 1.19 g

1 (76%) of a clear oil. H NMR (250MHz, CDCl3) δ 8.27 (1H, d, J=7.5 Hz), 7.77 (1H, d,

J=7.5 Hz), 7.69 (1H, d, J=10.0 Hz), 7.58 (1H, t, J=7.5 Hz), 7.52 (1H, t, J=7.5 Hz), 7.33

(1H, d, J=7.5 Hz), 2.61 (3H, s).

1-naphthaleneboronic acid (79): In a dry round bottom flask was placed magnesium turning (0.301 g, 12.5 mmol) and anhydrous LiCl (0.265 g, 6.25 mmol) in 12.5 mL THF.

While stirring, DIBAL-H (0.05 mL, 0.05 mmol) was slowly added followed by 1- bromonaphthalene (1.00 g, 5.0 mmol). The reaction was allowed to stir overnight. The flask was next cooled to 0C and trimethylborate (1.12 mL, 10.0 mmol) was added. The reaction was quenched with 0.1M HCl solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried with MgSO4, filtered, and concentrated.

The resulting product was recrystallized from water (dissolved at reflux). Obtained 1.09 g of the boronic acid.

Cross-Coupling General Procedure (83): To a dry flask was added 5% Pd source and

6% ligand with 1 mL MeOH. The mixture was stirred for 1 hour at room temperature, and then K2CO3 (3.0 equiv.) was added. The flask was heated to reflux followed by the addition of 1-naphthalene boronic acid (1.5 equiv.). The mixture was stirred for 15 minutes, and then 1-bromo-2-methylnaphthalene (1 equiv.) was added to the reaction.

The reaction was allowed to stir at reflux for 22 hours. The product was diluted with

EtOAc, filtered through silica to remove the metal, and concentrated. Purification was done by column chromatography (ether-hexanes, 1%-5%). Analysis of the biaryl products by HPLC showed less than 1% ee (nearly racemic mixture) in all trials (see

Appendix B). Variations of the reaction conditions are shown in Table 2.2 and Table 2.3,

1 and details of the analysis are given in Section 2.3. H NMR (250MHz, CDCl3) δ 8.03-

7.93 (4H, m), 7.67 (1H, t, J=7.5 Hz), 7.58-7.42 (4H, m), 7.32 (2H, d), 7.27 (2H, d), 2.19

13 (3H, s); C NMR (125 MHz; CDCl3) δ 137.6, 136.2, 134.5, 133.9, 133.6, 132.7, 132.1,

128.7, 128.4, 127.9, 127.8, 127.7, 126.4, 126.2, 126.1, 126.0, 126.0, 125.8, 124.9, 20.6.

Cross-Coupling using S-Phos (Table 2.2, entry 6): Followed the general procedure using

1-naphthalene boronic acid (0.129 g, 0.75 mmol) and 1-bromo-2-methylnaphthalene

(0.110 g, 0.5 mmol) with Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.02 equiv), S-Phos (8.2 mg,

0.02 mmol, 0.04 equiv), K2CO3 (0.207 g, 1.5 mmol), and 2 mL of methanol. The product mixture was separated by column chromatography (ether-hexanes, 1%-5%) to get 0.124 g

(93%) of a racemic mixture of biaryls. HPLC (Chiralcel OJ-J, 5% isopropanol/hexane, flow: 1.0 mL/min, 40˚C) retention time [min (area)] = 4.765 (1.782%), 5.030 (3.550%),

5.462 (43.700%), 6.205 (4.711%), 7.275 (46.257%).

Cross-Coupling using S-Phos-SO3Na (Table 2.2, entry 7): Followed the general procedure using 1-naphthalene boronic acid (0.129 g, 0.75 mmol) and 1-bromo-2- methylnaphthalene (0.110 g, 0.5 mmol) with Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.02 equiv),

S-Phos-SO3Na (10.3 mg, 0.02 mmol, 0.04 equiv), K2CO3 (0.207 g, 1.5 mmol), and 2 mL of methanol. The product mixture was separated by column chromatography (ether- hexanes, 1%-5%) to get 0.235 g (>99%) of a racemic mixture of biaryls. HPLC

(Chiralcel OJ-J, 5% isopropanol/hexane, flow: 1.0 mL/min, 40˚C) retention time [min

(area)] = 4.757 (1.388%), 5.457 (36.005%), 6.355 (15.385%), 7.276 (47.221%).

Cross-Coupling using PyOX and Pd(OAc)2 (Table 2.3, entry 1): Followed the general procedure using 1-naphthalene boronic acid (0.129 g, 0.75 mmol) and 1-bromo-2- methylnaphthalene (0.110 g, 0.5 mmol) with Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.02 equiv),

PyOX (2.4 mg, 0.0125 mmol, 0.025 equiv), K2CO3 (0.207 g, 1.5 mmol), and 2 mL of methanol. The product mixture was separated by column chromatography (ether- hexanes, 1%-5%) to get 0.0148 g (11%) of a racemic mixture of biaryls. HPLC

(Chiralcel OJ-J, 5% isopropanol/hexane, flow: 1.0 mL/min, 40˚C) retention time [min

(area)] = 4.744 (2.581%), 5.455 (4.692%), 6.121 (41.878%), 7.184 (41.396%), 10.669

(9.453%).

. Cross-Coupling using PyOX and Pd2(dba)3 CHCl3 (Table 2.3, entry 3): Followed the general procedure using 1-naphthalene boronic acid (0.129 g, 0.75 mmol) and 1-bromo-

. 2-methylnaphthalene (0.110 g, 0.5 mmol) with Pd2(dba)3 CHCl3 (12.9 mg, 0.0125 mmol,

0.025 equiv), PyOX (5.7 mg, 0.03 mmol, 0.06 equiv), K2CO3 (0.207 g, 1.5 mmol), and 2 mL of methanol. The product mixture was separated by column chromatography (ether- hexanes, 1%-5%) to get 0.0107 g (15%) of a racemic mixture of biaryls. HPLC

(Chiralcel OJ-J, 5% isopropanol/hexane, flow: 1.0 mL/min, 40˚C) retention time [min

(area)] = 4.760 (3.378%), 5.061 (0.703%), 5.471 (8.913%), 6.137 (39.798%), 7.193

(40.740%), 10.723 (6.469%).

Cross-Coupling using PyOX and Pd(PhCN)2Cl2 (Table 2.3, entry 5): Followed the general procedure using 1-naphthalene boronic acid (0.129 g, 0.75 mmol) and 1-bromo-

2-methylnaphthalene (0.110 g, 0.5 mmol) with Pd(PhCN)2Cl2 (9.6 mg, 0.025 mmol, 0.05 equiv), PyOX (5.7 mg, 0.03 mmol, 0.06 equiv), K2CO3 (0.207 g, 1.5 mmol), 2 mL of methanol and 0.05 mL of water. The product mixture was separated by column chromatography (ether-hexanes, 1%-5%) to get 0.0456 g (34%) of a racemic mixture of biaryls. HPLC (Chiralcel OJ-J, 5% isopropanol/hexane, flow: 1.0 mL/min, 40˚C) retention time [min (area)] = 4.758 (4.076%), 5.466 (10.916%), 6.137 (36.795%), 7.199

(35.841%), 10.692 (10.946%), 11.560 (1.427%).

BIBLIOGRAPHY

1. Eisch, J. J., Organomet. 2012, 31 (14), 4917.

2. Lutz, E. F., J. Chem. Educ. 1986, 63 (3), 202.

3. Eliel, E. L.; Wilen, S. H., Stereochemistry of Organic Compounds. John Wiley and Sons: New York, 1994.

4. Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Cilmore, C. J.; Restivo, R. J.; Bryan, R. F., J. Am. Chem. Soc. 1973, 95 (4), 1335.

5. Meyers, A. I.; Flisak, J. R.; Aitken, R. A., J. Am. Chem. Soc. 1987, 109 (18), 5446.

6. Joncour, A.; Decor, A.; Thoret, S.; Chiaroni, A.; Baudoin, O., Angew. Chem. Int. Ed. 2006, 45, 4149; Singidi, R. R.; RajanBabu, T. V., Org. Lett. 2008, 10 (15), 3351; Gong, W.; Singidi, R. R.; Gallucci, J. C.; RajanBabu, T. V., Chem. Sci. 2012, 3, 1221.

7. Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N., Angew. Chem. Int. Ed. 1999, 38, 2096.

8. Hubbard, B. K.; Walsh, C. T., Angew. Chem. Int. Ed. 2003, 42 (7), 730; Williams, D. H.; Bardsley, B., Angew. Chem. Int. Ed. 1999, 38, 1172.

9. Nicolaou, K. C.; Ramanjulu, J. M.; Natarajan, S.; Brase, S.; Li, H.; Boddy, C. N. C.; Rubsam, F., J. Chem. Soc., Chem. Commun. 1997, 1899; Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.; Hughes, R., Chem. Eur. J. 1999, 5 (9), 2622.

10. Bringmann, G.; Gotz, R.; Keller, P. A.; Walter, R.; Boyd, M. R.; Lang, F.; Garcia, A.; Walsh, J. J.; Tellitu, I.; Bhaskar, V.; Kelly, T. R., J. Org. Chem. 1998, 63, 1090; Hoye, T.; Chen, M., J. Org. Chem. 1996, 61, 7940.

11. Bringmann, G.; Ochse, M.; Gotz, R., J. Org. Chem. 2000, 65, 2069.

12. Watanabe, T.; Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura, M., J. Org. Chem. 2004, 69, 4158.

13. Suzuki, A., Nobel Lecture December 8, 2010. 61

14. Aulakh, G. K.; Sodhi, R. K.; Singh, M., Life Sci. 2007, 81, 615.

15. Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J., J. Org. Chem. 1994, 59, 6391.

16. Tamao, K.; Miyaura, N., Top. Curr. Chem. 2002, 219, 1-9.

17. Wurtz, A., Annales de Chimie et de Physique 1855, 44, 275.

18. Glaser, C., Berichte der Deutschen Chemischen Gesellschaft 1869, 2 (1), 422.

19. Ullmann, F.; Bielecke, J., Chemische Berichte 1901, 34 (2), 2174.

20. Gomberg, M.; Bachmann, W., J. Am. Chem. Soc. 1924, 46 (10), 2339.

21. Chodkiewicz, W., Ann. Chim. Paris 1957, 2, 819.

22. Stephens, R.; Castro, C., J. Org. Chem. 1963, 28 (12), 3313.

23. Gilman, H.; Jones, R. G.; Woods, L. A., J. Org. Chem. 1952, 17, 1630; Corey, E. J.; Posner, G. H., J. Am. Chem. Soc. 1967, 89, 3911.

24. Tamao, K.; Sumitani, K.; Kumada, M., J. Am. Chem. Soc. 1972, 94 (12), 4374.

25. Corriu, R. J. P.; Masse, J. P., J. Chem. Soc., Chem. Commun. 1972, (3), 144a.

26. Mizoroki, T.; Mori, K.; Ozaki, A., Bull. Chem. Soc. Jap. 1971, 44 (2), 581; Heck, R. F.; Nolley, J. P., J. Org. Chem. 1972, 37 (14), 2320.

27. Sonogashira, K.; Tohda, Y.; Hagihara, N., Tetrahedron Lett. 1975, 16, 4467.

28. King, A.; Okukado, N.; Negishi, E.-i., J. Chem. Soc., Chem. Commun. 1977, (19), 683.

29. Milstein, D.; Stille, J. K., J. Am. Chem. Soc. 1978, 100 (11), 3636.

30. Miyaura, N.; Yamada, K.; Suzuki, A., Tetrahedron Letters 1979, 36, 3437.

31. Miyaura, N.; Suzuki, A., J. Chem. Soc., Chem. Commun. 1979, 866.

32. Hatanaka, Y.; Hiyama, T., J. Org. Chem. 1988, 53 (4), 918.

33. Guram, A. S.; Buchwald, S. L., J. Am. Chem. Soc. 1994, 116 (17), 7901.

34. Paul, F.; Patt, J.; Hartwig, J. F., J. Am. Chem. Soc. 1994, 116 (13), 5969.

35. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T., Tetrahedron Lett. 1998, 39 (20), 3189.

36. Liebeskind, L.; Srogl, J., J. Am. Chem. Soc. 2000, 122 (45), 11260.

37. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M., Chem. Rev. 2002, 102 (5), 1359.

38. Nelson, T. D.; Meyers, A. I., J. Org. Chem. 1994, 59, 2577.

39. Nelson, T. D.; Meyers, A. I., Tetrahedron Lett. 1993, 34 (19), 3061.

40. Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A., Tetrahedron 2004, 60, 4459.

41. Kumada, M., Pure Appl. Chem. 1980, 52 (3), 669.

42. Kumada, M.; Tamao, K.; Sumitani, K., Org. Synth. 1978, 58, 127.

43. Knappke, C. E. I.; von Wangelin, A. J., Chem. Soc. Rev. 2011, 40, 4948.

44. Casado, A. L.; Espinet, P., Organometallics 1998, 17, 954.

45. Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; O., K. A.; Verhoeven, T. R., J. Org. Chem. 1994, 59, 8151.

46. Aliprantis, A. O.; Canary, J. W., J. Am. Chem. Soc. 1994, 116, 6985.

47. Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A., J. Am. Chem. Soc. 1985, 107 (4), 972.

48. Fitton, P.; Rick, E. A., J. Organomet. Chem. 1971, 28, 287.

49. Littke, A. F.; Fu, G. C., Angew. Chem. Int. Ed. 1998, 37, 3387; Littke, A. F.; Dai, C.; Fu, G. C., J. Am. Chem. Soc. 2000, 122, 4020; Littke, A.; Fu, G., Angew. Chem. Int. Ed. 2002, 41, 4176.

50. Old, D. W.; Wolfe, J. P.; Buchwald, S. L., J. Am. Chem. Soc. 1998, 120, 9722.

51. Wolfe, J. P.; Buchwald, S. L., Angew. Chem. Int. Ed. 1999, 38 (16), 2413; Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L., J. Am. Chem. Soc. 1999, 121, 9550.

52. Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.; Brossmer, C., Angew. Chem. Int. Ed. 1995, 34 (17), 1848; Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C.-P., J. Organomet. Chem. 1999, 576, 23. 63

53. Wallow, T. I.; Novak, B. M., J. Org. Chem. 1994, 59, 5034.

54. Armstrong, R.; Beau, J.-M.; Cheon, S. H.; Christ, W.; Fujioka, H.; Ham, W.-H.; Hawkins, L.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M.; McWhorter, W. J.; Mizuno, M.; Nakata, M.; Stutz, A.; Talamas, F.; Taniguchi, M.; Tino, J.; Ueda, K.; Uenishi, J.-i.; White, J.; Yonaga, M., J. Am. Chem. Soc. 1989, 111, 7525; Armstrong, R.; Beau, J.-M.; Cheon, S. H.; Christ, W.; Fujioka, H.; Ham, W.-H.; Hawkins, L.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M.; McWhorter, W. J.; Mizuno, M.; Nakata, M.; Stutz, A.; Talamas, F.; Taniguchi, M.; Tino, J.; Ueda, K.; Uenishi, J.-i.; White, J.; Yonaga, M., J. Am. Chem. Soc. 1989, 111, 7530.

55. Spessard, G. O.; Miessler, G. L., Organometallic Chemistry. 2nd ed.; Oxford University Press, Inc.: New York, 2010.

56. Meyers, A. I.; Mihelich, E. D., J. Am. Chem. Soc. 1975, 97 (25), 7383.

57. Warshawsky, A. M.; Meyers, A. I., J. Am. Chem. Soc. 1990, 112, 8090.

58. Wilson, J. M.; Cram, D. J., J. Org. Chem. 1984, 49 (25), 4930.

59. Andersen, N. G.; Maddaford, S. P.; Keay, B. A., J. Org. Chem. 1996, 61, 9556.

60. Cammidge, A. N.; Crepy, K. V. L., J. Chem. Soc., Chem. Commun. 2000, 1723.

61. Cammidge, A. N.; Crepy, K. V. L., Tetrahedron 2004, 60, 4377.

62. Yin, J.; Buchwald, S. L., J. Am. Chem. Soc. 2000, 122, 12051.

63. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L., J. Am. Chem. Soc. 2005, 127, 4685.

64. Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L., J. Am. Chem. Soc. 2001, 124 (7), 1162.

65. Johnson, M. G.; Foglesong, R. J., Tetrahedron Lett. 1997, 38 (40), 7001.

66. Milne, J. E.; Buchwald, S. L., J. Am. Chem. Soc. 2004, 126, 13028.

67. Molander, G. A.; Ito, T., Org. Lett. 2001, 3 (3), 393.

68. Molander, G. A.; Biolatto, B., Org. Lett. 2002, 4 (11), 1867; Molander, G. A.; Biolatto, B., J. Org. Chem. 2003, 68, 4302.

69. Barder, T. E.; Buchwald, S. L., Org. Lett. 2004, 6 (16), 2649.

70. Shen, X.; Jones, G. O.; Watson, D. A.; Brijesh, B.; Buchwald, S. L., J. Am. Chem. Soc. 2010, 132, 11278.

71. Snead, D. R.; Inagaki, S.; Abboud, K. A.; Hong, S., Organomet. 2010, 29, 1729.

72. Debono, N.; Labande, A.; Manoury, E.; Daran, J.-C.; Poli, R., Organomet. 2010, 29, 1879.

73. Zhang, S.-S.; Wang, Z.-Q.; Xu, M.-H.; Lin, G.-Q., Org. Lett. 2010, 12 (23), 5546.

74. Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q., Angew. Chem. Int. Ed. 2010, 49, 5780.

75. Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q., J. Am. Chem. Soc. 2007, 129, 5336; Cui, Z.; Yu, H.-J.; Yang, R.-F.; Gao, W.-Y.; Feng, C.-G.; Lin, G.-Q., J. Am. Chem. Soc. 2011, 133, 12394.

76. Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H., J. Org. Chem. 1995, 60, 176; Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H., J. Org. Chem. 1995, 60, 1066.

77. Percec, V.; Bae, J.-Y.; Hill, D., H., J. Org. Chem. 1995, 60, 1060.

78. Fan, X.-H.; Yang, L.-M., Eur. J. Org. Chem. 2011, 1467.

79. Percec, V.; Bae, J.-Y.; Hill, D. H., J. Org. Chem. 1995, 60, 6895.

80. Blakey, S. B.; MacMillan, D. W. C., J. Am. Chem. Soc. 2003, 125, 6046.

81. Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T., Angew. Chem. Int. Ed. 2005, 44, 4611; Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T., J. Am. Chem. Soc. 2007, 129, 2130.

82. Hahn, B. T.; Tewes, F.; Frohlich, R.; Glorius, F., Angew. Chem. Int. Ed. 2010, 49, 1143.

83. Thaler, T.; Guo, L.-N.; Steib, A. K.; Raducan, M.; Karaghiosoff, K.; Mayer, P.; Knochel, P., Org. Lett. 2011, 13 (12), 3182.

84. Xue, F.; Li, X.; Wan, B., J. Org. Chem. 2011, 76, 7256.

85. Xue, F.; Wang, D.; Li, X.; Wan, B., J. Org. Chem. 2012, 77, 3071.

86. Lang, F.; Chen, G.; Li, L.; Xing, J.; Han, F.; Cun, L.; Liao, J., Chem. Eur. J. 2011, 17, 5242; Jin, S.-S.; Wang, H.; Zhu, T.-S.; Xu, M.-H., Org. Biomol. Chem. 2012, 10, 1764; Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Chen, J.-R.; Xiao, W.-J., Chem. Commum. 2012, 48, 5596. 65

87. Brunner, H.; Obermann, U., Chem. Ber. 1989, 122, 499.

88. Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M., J. Am. Chem. Soc. 2011, 133, 6902.

89. Zalkow, L. H.; Oehlschlager, A. C., J. Org. Chem. 1964, 29, 1625.

90. Krasovskiy, A.; Kopp, F.; Knochel, P., Angew. Chem. Int. Ed. 2006, 45, 497; Metzger, A.; Gavryushin, A.; Knochel, P., Synlett 2009, 9, 1433.

91. Krasovskiy, A.; Knochel, P., Angew. Chem. Int. Ed. 2004, 43, 3333.

92. Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P., Chem. Eur. J. 2009, 15, 7192; Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P., Angew. Chem. Int. Ed. 2010, 49, 4665.

93. Klunder, J. M.; Sharpless, K. B., J. Org. Chem. 1987, 52, 2598.

94. Watanabe, Y.; Mase, N.; Tateyama, M.-a.; Toru, T., Tetrahedron: Asymmetry 1999, 10, 737.

95. Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I., J. Am. Chem. Soc. 1964, 86, 5637.

96. Blake, A. J.; Harding, M.; Sharp, J. T., Perkin Trans. 1 1994, 3149.

97. Bell, K. H., Aust. J. Chem. 1985, 38, 1209.

98. Pyne, S. G.; Hajipour, A. R.; Prabakaran, K., Tetrahedron Lett. 1994, 35 (4), 645.

99. Pathak, R.; Nhlapo, J. M.; Govender, S.; Michael, J. P.; van Otterlo, W. A. L.; de Koning, C. B., Tetrahedron 2006, 62, 2820.

100. Matteson, D. S., Tetrahedron 1989, 45 (7), 1859.

101. Wong, K.-T.; Chien, Y.-Y.; Liao, Y.-L.; Lin, C.-C.; Chou, M.-Y.; Leung, M.-k., J. Org. Chem. 2002, 67, 1041.

102. Leermann, T.; Leroux, F. R.; Colobert, F., Org. Lett. 2011, 13 (17), 4479.

APPENDICES

APPENDIX A: 1H AND 13C NMR SPECTRA

Isolated as a mixture of diastereomeric products.

The product contains a mixture of diastereomers and several impurities.

The product is a mixture of diastereomers: δ 4.24 (1.5H, dt) and δ 4.15 (1.6H, dt).

APPENDIX B: HPLC CHROMATOGRAMS

20% isopropanol/hexane; 0.3 mL/min; 40˚C; Chiralpak AD column