Nickel Catalyzed Regioselective Reductive Coupling Reactions

A Dissertation Submitted to the Graduate School of the University of Cincinnati in Partial Fulfillment of the Requirements for the Degree of

DOCTOR OF PHILOSOPHY (Ph. D.)

In the Department of Chemistry of McMicken College of Arts and Sciences by

Sanjeewa Kumara Rodrigo

Bachelor of Science (B. Sc.), Chemistry Faculty of Science, University of Peradeniya, Sri Lanka, 2007

Dissertation Advisor: Hairong Guan, Ph. D.

Nickel Catalyzed Regioselective Reductive Coupling Reactions

ABSTRACT

Coupling or cycloaddition of two different π-components for the construction of more complex structural motifs is commonly used in organic synthesis. Most of these systems involve a transition metal based catalyst and for reductive coupling reactions, various reducing agents are also employed. This dissertation is focused on the development and mechanistic investigation of nickel-catalyzed reductive coupling processes for useful organic transformations, specifically the coupling of aldehydes and alkynes and the cyclotrimerization of alkynes.

Ni(COD)2 combined with an N-heterocyclic carbene (NHC) ligand catalyzes the reductive coupling of ynoates and aldehydes to give 1,4-difuntioalized products. This particular catalytic system shows broad substrate scope and high regioselectivity. To accomplish this transformation, a silane has been used as the reducing agent and PPh3 has been added to extend the lifetime of the nickel catalyst. For this newly developed multicomponent coupling reactions, more than a dozen invaluable silyl-protected γ-hydroxy-α,β-enoates have been synthesized. This methodology also provides a quick entry to many other 1,4-difunctional compounds and oxygen- containing five-membered rings.

The mechanistic studies on nickel-catalyzed and silane-mediated reductive coupling of ynoates and aldehydes have been carried out. Kinetics data, deuterium-labeling studies, and kinetic isotope effect are consistent with a reaction pathway involving a rate-determining oxidative cyclization to form a metallacycle intermediate, followed by fast silane-facilitated release of the final product. Inverse first-order dependence of rate on [ynoate] indicates that the alkyne component binds to the nickel center first. An initial oxidative addition of the Si-H bond

ii to nickel followed by the sequential insertion of the substrates can be ruled out based on these data.

An effective nickel system, Ni(COD)2/PPh3 or Ni(COD)2/NHC (NHC = an N- heterocyclic carbene) has been also found to catalyze cyclotrimerization of ynoates and related alkynes. This methodology provides access to a diverse array of tri- or hexa-substituted benzene derivatives in an efficient and highly regioselective manner. This system provides several advantages. First of all, catalysts can be easily generated in situ by mixing commercially available reagents. More importantly, the catalytic process is quite efficient; turnover numbers as high as 2,000 is the highest for any transition-metal-catalyzed cyclotrimerization reaction, allowing the synthesis to be carried out on the gram scale. Moreover, the observed regioselectivity is typically high and in a number of cases only one regioisomer is formed.

iii

iv Nickel Catalyzed Regioselective Reductive Coupling Reactions

TABLE OF CONTENTS

Chapter 1: Introduction

1.1 Nickel-Catalyzed Reductive Coupling Reactions 2

1.2 Cyclotrimerization of Alkynes 6

1.3 Research Objectives 10

Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to

Access 1,4-Difunctionality

2.1 Introduction 12

2.2 Plan for the Synthesis 13

2.3 Nickel-Catalyzed Reductive Coupling of an Ynoate and an Aldehyde 15

2.4 Optimization of the Reaction Conditions 17

2.5 Control Experiments 19

2.6 Substrate Scope 19

2.7 Origin of the Regioselectivity 22

2.8 Synthetic Applications 24

2.9 Conclusions 25

2.10 Experimental 25

Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes

3.1 Introduction 44

3.2 General Mechanistic Consideration 47

3.3 Previous Mechanistic Studies on Nickel-Catalyzed Reductive Coupling of

Alkynes and Aldehydes 49

v 3.4 Mechanistic Studies of the Coupling of Ynoates and Aldehydes 56

3.4.1 Mechanistic Hypothesis 56

3.4.2 Deuterium Labeling Studies 58

3.4.3 Kinetics Studies of a Related System Reported by Montgomery 59

3.4.4 Screening Conditions for the Kinetics Study 60

3.4.5 Kinetics Experiments 64

3.4.6 Kinetic Isotope Effect 69

3.4.7 Kinetics Model 70

3.5 Conclusions 71

3.6 Experimental 71

Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes

4.1 Introduction 90

4.2 Optimization of the Reaction Conditions 92

4.3 Substrate Scope 95

4.4 Large Scale Synthesis of 1,2,4-C6H3(CO2Me)3 100

4.5 Mechanism and Regioselectivity 101

4.6 Conclusions 104

4.7 Experimental 104

Appendix 1: Asymmetric Reductive Coupling of Ynoates and Aldehydes

A1.1 Introduction 116

A1.2 Synthesis and Application of Chiral NHC Ligands 118

vi A1.3 Determination of Enatiomeric Ratios 121

A1.4 An Alternative Way for Deprotecting the Hydroxyl Group 122

A1.5 Suggested Future Work 123

A1.6 Experimental 124

Appendix 2: 1H NMR and 13C NMR Spectra (Chapter 2) 126

Appendix 3: 1H NMR and 13C NMR Spectra (Chapter 3) 177

Appendix 4: 1H NMR and 13C NMR Spectra (Chapter 4) 180

vii Nickel Catalyzed Regioselective Reductive Coupling Reactions

LIST OF FIGURES

Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to

Access 1,4-Difunctionality

Figure 1 Selected Natural Products and Medicinal Compounds Containing 1,4-

Difunctionality 12

Figure 2 X-ray Structure of [NiCl2(IMes)2] 16

Figure 3 Polarization of the Triple Bond in Ynoates 23

Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes

Figure 1 Reaction Profile 64

Figure 2 Rate Dependence on Nickel Catalyst (Low Concentrations) 65

Figure 3 Rate Dependence on Nickel Catalyst (High Concentrations) 66

Figure 4 Rate Dependence on Ynoate 67

Figure 5 Rate Dependence on Aldehyde 68

Figure 6 Rate Dependence on Silane 69

Figure 7 Calibration Plot for Ynoate 88

Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes

Figure 1 X-ray Structure of Compound 1,2,4-C6Ph3(CO2Et)3 97

Figure 2 X-ray Structure of Compound 1,2,4-C6H3(C6H4CO2Me)3 100

Figure 3 Polarization of the Triple Bond of Ynoates and Metallacycle Formation 103

Appendix 1: Asymmetric Reductive Coupling of Ynoates and Aldehydes

Figure 1 Natural Products with γ-Butyrolactone Core 118

Figure 2 Structures of Sugar Molecules in Chiralpak AD-H and OJ-H 121

viii Nickel Catalyzed Regioselective Reductive Coupling Reactions

LIST OF SCHEMES

Chapter 1: Introduction

Scheme 1 Reductive Coupling of an Alkyne an Aldehyde 3

Scheme 2 A Typical [2+2+2] Cylotrimerization of an Alkyne 6

Scheme 3 Cyclotrimerization Mechanism for Cobalt Systems 8

Scheme 4 Cyclotrimerization Mechanism for Ruthenium Systems 9

Scheme 5 Sequential Insertion Mechanism 9

Scheme 6 Iterative Enyne Metathesis Mechanism 10

Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to

Access 1,4-Difunctionality

Scheme 1 Reductive Coupling of Methyl Propiolate and Benzaldehyde 15

Scheme 2 Proposed Reaction Mechanism 22

Scheme 3 Synthetic Applications of Silyl-Protected γ-Hydroxy-α,β-Enoates 24

Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes

Scheme 1 Catalytic Coupling of Aldehydes and Alkynes 44

Scheme 2 Organozinc-Mediated Intramolecular Coupling of Alkynes and Aldehydes 45

Scheme 3 Triethylborane-Mediated Intermolecular Reductive Coupling Reaction 45

Scheme 4 Triethylsilane-Mediated Intermolecular Reductive Coupling Reaction 46

Scheme 5 Chromium (II) Chloride-Promoted Intermolecular Reductive Coupling

Reaction 47

Scheme 6 Common Mechanisms for Three-Component Coupling Reactions 48

Scheme 7 Ligand Dependent Reductive Coupling Reactions 49

ix Scheme 8 Mechanism Involving a Metallacycle 51

Scheme 9 Mechanisms without a Metallacycle Intermediate 52

Scheme 10 Intermolecular Crossover Experiment 53

Scheme 11 Intramolecular Crossover Experiment 53

Scheme 12 Generation of Nickeladihydrofuran 54

Scheme 13 Reaction of Nickeladihydrofuran with ZnMe2 54

Scheme 14 Theoretical Study on Reductive Coupling of Alkyne and Aldehyde 55

Scheme 15 Nickel-Catalyzed Coupling of Ynoates and Aldehydes 56

Scheme 16 Proposed Mechanism Based on Metallacycle Intermediates 57

Scheme 17 Alternative Mechanism without a Metallacycle Intermediate 57

Scheme 18 Deuterium-Labeling Studies 58

Scheme 19 Attempted Hydrosilylation of Methyl Propiolate 59

Scheme 20 Nickel-Catalyzed Coupling of an Ynal 59

Scheme 21 Kinetics Model 70

Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes

Scheme 1 Nickel-Catalyzed Reductive Coupling Reactions 91

Scheme 2 Benzene-1,2,4-Tricarboxylates as Branching Agents in Polymer Synthesis 92

Scheme 3 Plausible Mechanism 101

Scheme 4 Origin of Regioselectivity 103

Appendix 1: Asymmetric Reductive Coupling of Ynoates and Aldehydes

Scheme 1 Asymmetric Induction with Chiral Phosphines 116

Scheme 2 Asymmetric Induction with Chiral NHCs 117

Scheme 3 Nickel-Catalyzed Reductive Coupling of Ynoates and Aldehydes 117

x Scheme 4 Synthetic Applications of γ-Hydroxy-α,β-Enoates 117

Scheme 5 Procedure for the Synthesis of Chiral NHCs 119

Scheme 6 Attempted Synthesis of Precursor for PhSIPr 120

Scheme 7 Coupling of Methyl Propiolate and PhCHO 120

Scheme 8 Silyl-Deprotection of γ-Hydroxy-α,β-Enoates 122

Scheme 9 Silyl-Deprotection in Related Systems 122

Scheme 10 Alternative Way of Silyl-Deprotection 123

xi Nickel Catalyzed Regioselective Reductive Coupling Reactions

LIST OF TABLES

Chapter 1: Introduction

Table 1 Examples of Nickel-Catalyzed Reductive Coupling Reactions 4

Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to

Access 1,4-Difunctionality

Table 1 Optimization of the Reaction Conditions 18

Table 2 Reactions of Methyl Propiolate with Various Aldehydes 20

Table 3 Scope of Ynoates and Aldehydes 21

Table 4 Crystal Data and Structure Refinement for [NiCl2(IMes)2] 42

Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes

Table 1 Optimization of the Reaction Conditions 63

Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes

Table 1 Optimization of the Reaction Conditions 93

Table 2 Cyclotrimerization of Ynoates 96

Table 3 Cyclotrimerization of Various Alkynes 99

xii ACKNOWLEDGEMENTS

First, I want to acknowledge my indebtedness to my advisor Professor Hairong Guan, who guided and supervised me during the course of this dissertation research. Over the years I have learnt not only a great deal of chemistry from him but also how to be a good citizen. He guided me throughout all my work especially his guidance to build a project to a complete story is excellent. His encouragement and thoughtful suggestions kept me on track towards achieving the biggest milestone in my academic life. It is with appreciation I thank Hairong for being extremely patient with me, especially during the thesis-writing endeavor. I still believe I made the right decision by joining his research group.

I was privileged to have excellent committee members, Professor Allan R. Pinhas,

Professor William B. Connick and Professor James Mack. Their continuous suggestions and critical opinions helped me a lot in completing my research projects successfully. I would also like to thank all of the other faculty members of the department of chemistry that I had the pleasure of interacting with during my graduate studies.

I also like to extend my gratitude to Dr. Jeanette A. Krause for all the help with X-ray crystallography and useful suggestions during group meetings. Dr. Keyang Ding is also thanked for help with NMR experiments. My gratitude also goes to Dr. Larry Sallans and Dr. Stephen F.

Macha for help with GCMS and high-resolution mass spectrometry.

I would like to thank my labmates in the Guan group for making my experience in lab enjoyable. In particular, I would like to thank Dr. Sumit Chakraborty, the first student of our group, who helped me in numerous ways especially for persuading me to join Hairong’s group.

My gratitude also goes to Dr. Jie Zhang, our previous postdoctoral fellow, who helped me from the very beginning to get my feet wet in the lab.

xiii I had the opportunity to mentor a few fine undergraduate students (Christopher Heald,

Yogi Patel, Israel Powell, and Justin Baum). I would like to thank them for their teamwork and I wish them all the very best for their future endeavors.

Last but not least I want to thank my parents for their continuous support and affection in achieving my goals. My affection and appreciation go to my wife, Nadeesha Koralegedara and my little angel, Thinuli Rodrigo, for putting up with me for all these years and their continuous support. I couldn’t have done this without them being in my life.

xiv PREFACE

Parts of this thesis have been adapted from articles co-written by the author. The following articles were reproduced in part with permission from the American Chemical Society and the Royal Society of Chemistry:

1) Rodrigo, S.K.; Guan, H. “Quick Installation of a 1,4-Difunctionality via Regioselective Nickel-Catalyzed Reductive Coupling of Ynoates and Aldehydes” J. Org. Chem. 2012, 77, 8303-8309.

2) Rodrigo, S.K.; Powell, V. I.; Coleman, G. M.; Krause, J. A.; Guan, H. “Efficient and Regioselective Nickel-Catalyzed [2+2+2] Cyclotrimerization of Ynoates and Related Alkynes.” Org. Biomol. Chem. 2013, 11, 7653-7657.

xv

Chapter 1

Introduction

1.1 Nickel-Catalyzed Reductive Coupling Reactions

Coupling or cycloaddition of two different π-components for the construction of more complex structural motifs is commonly used in organic synthesis. Diels-Alder reaction, Prins addition reaction, and ene reaction are representative examples of selective coupling of two π- components. As a valuable addition to these classical processes, reductive coupling of two π- components offers an alternative strategy to make elaborated molecules.1 Nickel is often selected as the metal to promote reductive intermolecular/intramolecular coupling of two different unsaturated functional groups such as alkynes and aldehydes (Scheme 1).2,3,4 In the presence of a catalytic amount of a nickel species and a reducing agent, a new carbon–carbon bond forms between an electron-rich component (e.g., alkyne, 1,3-enyne, 1,3-diene and allene) and an electrophilic component (e.g., aldehyde, enone and epoxide). Some notable types of reductive coupling reactions are summarized in Table 1. Although the starting materials in a reductive coupling reaction resemble those used in thermal, non-catalytic coupling and cycloaddition reactions mentioned earlier, the products are structurally different and are in a more reduced state.

1 (a) Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (b) Ikeda, S. Angew. Chem., Int. Ed. 2003, 42, 5120. (c) Jang, H. Y.; Krische, M. J. Acc. Chem. Res., 2004, 37, 653. (d) Metal Catalyzed Reductive C-C Bond Formation- A Departure from Preformed Organometallic Reagents; Krische, M. J., ed.; Springer: Heidelberg, 2007. (e) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441. (f) Ngai, M. Y.; Kong, J. R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063 2 (a) Montgomery, J. Organometallic Complexes of Nickel. In Science of Synthesis; Trost, B. M.; Lautens, M., Eds.; Thieme: Stuttgart, Germany, 2001; Vol. 1, pp 11. (b) Modern Organonickel Chemistry; Tamaru, Y.; Ed.; Wiley-VCH: Weinheim, 2005. 3 For reviews on nickel-catalyzed reductive coupling reactions, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (b) Montgomery, J. Top. Curr. Chem. 2007, 279, 1. 4 Representative examples of nickel-catalyzed reductive coupling reactions: (a) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (b) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. (c) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156. (d) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653. (e) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076. (f) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (g) Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C. J. Am. Chem. Soc. 2004, 126, 4130. (h) Miller, K. M.; Colby, E. A.; Woodin, K. S.; Jamison, T. F. Adv. Synth. Catal. 2005, 347, 1533. (i) Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568. (j) Sato, Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito, N. Org. Lett. 2007, 9, 5597. (k) Kimura, M.; Tamaru, Y. Top Curr. Chem. 2007, 279, 173.

2 Scheme 1. Reductive coupling of an alkyne and an aldehyde

2 Ni(COD)2/L OSiR3 R O R3SiH + 3 1 R1 R R R3 H THF R2

Proposed catalytic cycle

OSiR 2 3 R O + 1 3 NiL 1 R R n R R3 H R2 oxidative reductive cyclization elimination H L R1 R1 n NiLn Ni O O SiR3 R2 R2 R3 R3

R3SiH L H 1 n R Ni SiR 3 bond metathesis O σ− R2 R3

3 Table 1. Examples of nickel-catalyzed reductive coupling reactions

electron rich electrophilic reducing agent producta referencesb component component used

Et B 4a, 4b*, 4c* 3 OR alkyne aldehyde 4d, 4i* Et3SiH Ph Ph Me CrCl2 4d

Me alkyne epoxide Et3B Ph 4e Me OH

Et2Zn 4j Ph 1,3-diene aldehyde Et3B 4j Me OH Et3SiH 4j, 4k*

OH aldehyde Et3B 4g, 4h* 1,3-enyne i-pr Ph

epoxide Et3B n-Hex 4g i-pr OH a Bond higlighted in red indicates the site for C-C bond formation, b Asterisks indicate the references for the asymmetric variants

Nickel-catalyzed reductive coupling reactions offer several synthetic advantages. For the reaction shown in Scheme 1, usually the alkyne is added directly to an aldehyde in a single operation. This process is more convenient compared to the alternative approach that involves the hydrometallation of an alkyne with a highly air and moisture sensitive metal hydride followed by the addition of the alkenyl species to an aldehyde.5 Nickel-catalyzed reductive coupling approach is also more convenient than the preparation of an alkenyl Grignard reagent followed by the addition to the electrophile. Furthermore, the use of nickel in combination with

5 A representative example on hydrometallation of alkyne for the synthesis of allylic alcohols: Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2007, 129, 16119.

4 chiral ligands provides an opportunity for the synthesis of enantiomerically enriched coupling products.4b,4c,4h-j

The intermediacy of a five-membered nickellacycle is often proposed for this type of reductive coupling reactions (Scheme 1).4 A nickellacycle is formed by the oxidative cyclization of two π-systems to a Ni(0) species.6 Although the structure shown in Scheme 1 involves two different π-components, oxidative cyclization can occur between two identical π-components.

For example, a nickellacyclopentane can be formed by the addition of two equivalents of cyclopropene.6a Cyclization of 1:1 mixture of ethylene and carbon dioxide gives a nickellalactone.6c 2-Butyne and benzaldehyde can be coupled to generate a nickelladihydrofuran.6k In addition to these well-characterized nickellacycles, such species have been involved in many other nickel-catalyzed reactions. Examples are [2+2] cycloaddition of alkenes,7 and the cyclotrimerization of alkynes.8

Following nickellacycle formation, the Ni(0) catalyst can be regenerated via the reaction of the Ni(II) nickellacycle with a reductant. This reduction process is typically accomplished through sigma-bond metathesis followed by reductive elimination. The most common reagents to promote sigma-bond metathesis in nickel-catalyzed reductive coupling are triethylborane, alkylsilanes, and diethylzinc.4 It should be mentioned that in addition to nickel catalysis there are other transition metal systems which have been developed for various reductive coupling

6 Examples of isolated nickellacycles from oxidative cyclization of two π-systems: (a) Binger, P.; Doyle, M. J.; McMeeking, J.; Krüger, C.; Tsay, Y.-H. J. Organomet. Chem. 1977, 135, 405. (b) Binger, P.; Doyle, M. J. J. Organomet. Chem. 1978, 162, 195. (c) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1982, 234, 35. (d) Eisch, J. J.; Galle, J. E.; Aradi, A. A.; Boleslawski, M. P. J. Organomet. Chem. 1986, 312, 399. (e) Buech, H. M.; Binger, P.; Benn, R.; Rufinska, A. Organometallics 1987, 6, 1130. (f) Hoberg, H.; Peres, Y.; Krüger, C.; Tsay, Y.-H. Angew. Chem., Int. Ed. 1987, 26, 771. (g) Bennett, M. A.; Hockless, D. C. R.; Wenger, E. Organometallics 1995, 14, 2091. (h) Ogoshi, S.; Oka, M.-a.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126, 11802. (i) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc. 2005, 127, 12810. (j) Ogoshi, S.; Ikeda, H.; Kurosawa, H. Angew. Chem., Int. Ed. 2007, 46, 4930. (k) Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem. Commun. 2008, 1347. 7 (a) Binger, P.; Schroth, G.; McMeeking, J. Angew. Chem., Int. Ed. 1974, 86, 518. (b) Binger, P.; McMeeking, J.; Schafer, H. Chem. Ber. 1984, 117, 1551. 8 Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.

5 reactions. Considerable advances have been made with titanium,9 iridium, 10 and rhodium- catalyzed11 processes.

1.2 Cyclotrimerization of Alkynes

Transition-metal-catalyzed [2+2+2] cyclotrimerization of alkynes is considered as a special case of reductive coupling reactions. In a typical transition metal catalyzed cyclotrimerization reaction, three alkyne molecules of 1 react via a metallacyclopentadiene intermediate 2 to give substituted benzene 3 (Scheme 2). It provides a versatile method to construct substituted aromatic compounds in a more efficient way than conventional substitution

Scheme 2. A typical [2+2+2] cylotrimerization of an alkyne R R metal R R R catalyst R R 3 + M = transition metal R R R R L = ligand(s) R M R Ln R 1 2 3 reactions of benzene derivatives because three carbon-carbon bonds can be formed in a single reaction.12 The first cyclotrimerization was reported by Berthelot in 1866 who demonstrated the production of benzene from acetylene at ~400 °C without using any metal catalyst.13 This harsh reaction conditions made thermal [2+2+2] cyclotrimerization less appealing to the organic community. 14 The discovery of transition metal catalyzed [2+2+2] cyclotrimerization of

9 (a) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787. (b) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 3182. (c) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835. (d) Ryan, J.; Micalizio, G. C. J. Am. Chem. Soc. 2006, 128, 2764. (e) Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc. 2008, 130, 15997. 10 Kim, I. S.; Ngai, M, -Y.; Komanduri, V.; Krishce, M. J. J. Am. Chem. Soc. 2008, 130, 14891. 11 Skukas, E.; Ngai, M. –Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. 12 For reviews see: (a) Schore, N. E. in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon: Oxford, 1991, Vol. 5, pp. 1129. (b) Boese, R.; Sickle, A. P. V.; Vollhardt, K. P. C. Synthesis 1994, 1374. (c) Grotjahn, D. B.; in Comprehensive Organometallic Chemistry II; Abel, E. W.; Stone, F. G. A.; Wilkinson, G.; Hegedus, L., Eds.; Pergamon: Oxford 1995, Vol. 12, pp. 741. (d) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901. (e) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (f) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209. (g) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (h) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830. 13 Berthelot, M. C. R. Acad. Sci. 1866, 62, 905. 14 Benson, S. W. In Thermochemical Kinetics; Wiley: New York, 1976.

6 acetylene by Reppe et al. in the late 1940’s was the major breakthrough in this field.15 Despite the formation of cyclooctatetraene as the major product in this process, this report opened the door for [2+2+2] cyclotrimerization reaction to become synthetically useful. Since this seminal work, many transition metal (Ni,16 Ru,17 Pd,18 Co,19 Rh,20 Ti,21 and Mo22), lanthanide (Eu and

Yb),23 actinide (U),24 and main group (Al)25 compounds have been reported to catalyze this transformation. Most of these cycloaddition reactions proceed with good chemo-, regio-, and stereoselectivities and have many useful applications in organic synthesis.

15 Reppe, W.; Schweckendriek, W. J. Justus Liebigs Ann. Chem. 1948, 560, 104. 16 (a) Chiusoli, G. P.; Pallini, L.; Terenghi, G. Transition Met. Chem. 1983, 3, 189. (b) Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994, 59, 6133. (c) Saito, Y. ; Nishimata, T.; Mori, M. Heterocycles 1997, 44, 443. (d) Sato, Y.; Ohashi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5231. (e) Saito, S.; Kawasaki, T.; Tsuboya, N.; Yamamoto, Y. J. Org. Chem. 2001, 66, 796. (f) Müller, C.; Lachicotte R. J.; Jones, W. D. Organometallics 2002, 21, 1975. (g) Jeevanandam, A.; Korioi, R. P.; Huang, I-W.; Cheng, C.-H. Org. Lett. 2002, 4, 807. (h) Teske, J. A.; Deiters, A. J. Org. Chem. 2008, 73, 342. 17 (a) Peters, J. -U.; Blechert, S. Chem. Commun. 1997, 1983. (b) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2003, 125, 12143. (c) Rüba, E.; Schmid, R.; Kirchner, K.; Calhorda, M. J.; J. Organomet. Chem. 2003, 682, 204. (d) Ura, Y. Sato, Y.; Shiotsuki, M.; Kondo, T.; Mitsudo, T. J. Mol. Catal. A: Chem. 2004, 209, 35. (e) Yamamoto, Y.; Ishii, J. Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2004, 126, 3712. (f) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H. Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. (g) Cadierno, V.; García-Garrido, S. E.; Gimeno. J. J. Am. Chem. Soc. 2006, 128, 15094. 18 (a) Yamamoto, Y.; Nagata, A.; Nagata, H.; Ando, Y.; Arikawa, Y.; Tatsumi, K.; Itoh, K. Chem. Eur. J. 2003, 9, 2469. (b) Carvalho, M. F. N. N.; Almeida, F. M. T.; Galvâo, A. M.; Pombeiro, A. J. L. J. Organomet. Chem. 2003, 679, 143. (c) Cheng, J. S.; Jiang, H. F. Eur. J. Org. Chem. 2004, 643. 19 (a) Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108, 856. (b) Sigman, M. S.; Fatland, A. W.; Eaton, B. E. J. Am. Chem. Soc. 1998, 120, 5130. (c) Yong, L.; Butenschön, H. Chem. Commun. 2002, 2852. (d) Hilt, G.; Vogler, T.; Hess, W.; Galbiati, F. Chem. Commun. 2005, 1474. (e) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209. (f) Saino, N.; Amemiya, F.; Tanabe, E.; Kase, K.; Okamoto, S. Org. Lett. 2006, 8, 1439. 20 (a) Collman, J. P.; Kang, J. W.; Little, W. F.; Sullivan, M. F. Inorg. Chem. 1968, 7, 1298. (b) E. Müller, Synthesis, 1974, 761. (c) Grigg, R.; Scott, R.; Stevenson, P. Tetrahedron Lett. 1982, 23, 2691. (d) Amer, I.; Bernstein, T.; Eisen, M.; Blum, J.; Volhardt, K. P. C. J. Mol. Catal. 1990, 60, 313. (e) Ojima, I.; Vu, A. T.; McCullagh, J. V.; Kinoshita, A. J. Am. Chem. Soc. 1999, 121, 3230. (f) Sun, Q.; Zhou, X.; Islam, K.; Kyle, D. J. Tetrahedron Lett. 2001, 42, 6495. (g) Kinoshita, H.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 7784. (h) Dufková, L.; Císarová, L.; Stepnicka, P.; Kotora, M. Eur. J. Org. Chem. 2003, 2882. (i) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaki, K.; Hirano, M. Chem. Eur. J. 2005, 11, 1145. 21 (a) Johnson, E. S.; Balaich, G. J; Fanwick, P. E.; Rothwell, I. P. J. Am. Chem. Soc. 1997, 119, 11086. (b) Ozerov, O. V.; Ladipo, F. T. Patrick, B. O. J. Am. Chem. Soc. 1999, 121, 7941. (c) Ozerov, O. V.; Patrick, B. O.; Ladipo, F. T. J. Am. Chem. Soc. 2000, 122, 6423. (d) Ladipo, F. T.; Sarveswaran, V.; Kingston, J. V.; Huyck, R. A.; Bylikin, S. Y.; Carr, S. D.; Watts, R.; Parkin, S. J. Organomet. Chem. 2004, 689, 502. 22 (a) Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994, 59, 6133. (b) Kaneta, N.; Hirai, T.; Mori, M. Chem. Lett. 1995, 627. 23 Imamura, H.; Suda, E.; Konishi, T.; Sakata, Y.; Tsuchiya, S. Chem. Lett. 1995, 215. 24 Wen, T. C.; Chang, C. C.; Chuang, Y. D.; Cheng, C. P.; Chiu, J. P.; Chang, C. T. J. Am. Chem. Soc. 1981, 103, 4576. 25 Hogeveen, H.; Kingma, R. F.; Kok, D. M. J. Org. Chem. 1982, 47, 989.

7 Several mechanisms, depending on the metal catalysts used, for the alkyne cylotrimerization have been proposed in the literature.26 For cobalt-based catalysts, the most commonly proposed mechanism involves the formation of metallacyclopentadiene intermediate

5 following the coordination of two alkynes to the metal center and then oxidative cyclization

(Scheme 3).27 The third alkyne molecule is added via a Diels-Alder type [4+2] cycloaddition to give the cobaltanorbornadiene intermediate 7. The final cyclotrimerized benzene product 8 is released by reductive elimination to regenerate the catalyst.

Scheme 3. Cyclotrimerization mechanism for cobalt systems (L = ligand)

oxidative Ln-2 CoLn cyclization 2 Co-L Co-Ln-2 Co -2L n-2 4 5 6

Ln-2 reductive Co elimination + CoLn +2L 7 8

Mechanism proposed for CpRuCl based catalytic system differs from the cobalt system mainly in the insertion step for the third alkyne molecule. This step proceeds via a formal [2+2] cycloaddition between ruthenacycle 10 and the third alkyne to give the ruthenabicyclo[3.2.0]heptadiene complex 11. The metallacycle 12 is formed via retro-[2+2] cycloaddition (Scheme 4). Next, the η2-benzene complex 13 is generated by reductive elimination from 12. Replacement of the arene with two equivalents of alkyne completes the catalytic cycle.28

26 Bird, C. W. In Transition Metal Intermediates in Organic Synthesis; Logos Press: London, 1967 27 Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria, M.; Aubert, C. J. Am. Chem. Soc. 2007, 129, 8860. 28 Kirchner, K.; Calhorda, M. J.; Schmid, R.; Veiros, L. F. J. Am.Chem. Soc. 2003, 125, 11721.

8 Scheme 4. Cyclotrimerization mechanism for ruthenium systems

Oxidative Cp [2+2] CpRu(COD)Cl Cp cyclization Ru + 2 Ru -COD Cl Cl 9 10

Cp Cp Cl Ru Cl Ru Cp 2 Cp Ru + Ru Cl Cl 11 12 13 8

Transition metal hydrides and halides have also been reported to catalyze alkyne cylotrimerization via a sequential insertion mechanism.29,30 Each alkyne unit is incorporated by a cis-addition of the metal-halide (or metal-hydride) and then metal-carbon bond across the triple bond (Scheme 5). An iterative enyne metathesis mechanism has also been proposed for trimerization catalyzed by the Grubbs catalyst. In this process each alkyne is added in a series of

[2+2] and retro-[2+2]-cycloadditions (Scheme 6).31 A ring closing metathesis reaction generates the benzene product.

Scheme 5. Sequential insertion mechanism

M M M-X X M X X

x = halide or hydride M + M-X X

29 Dietl, H.; Maitlis, P. M.; Reinheim.H; Moffat, J. J. Am. Chem. Soc. 1970, 92, 2276. 30 Li, J. H.; Jiang, H. F.; Chen, M. C. J. Org. Chem. 2001, 66, 3627. 31 Peters, J. U.; Blechert, S. Chem. Commun. 1997, 1983.

9 Scheme 6. Iterative enyne metathesis mechanism

M M M M

M + M

1.3 Research Objectives

Despite the progress made in the reductive coupling reactions, poor regioselectivity, limited substrate scope, homo-coupling over cross-coupling, high catalyst loading and inadequate mechanistic details are the major challenges need to be addressed for the advancement of the field. The initial objective of my dissertation research was to develop an efficient nickel-catalyzed process for the synthesis of 1,4-difunctionality, which is a dire need for the organic community. It was discovered that Ni(COD)2 combined with an N-heterocyclic carbene (NHC) ligand catalyzes the reductive coupling of ynoates and aldehydes to give 1,4- difuntioalized products. This particular catalytic system shows broad substrate scope and high regioselectivity. Elucidation of the mechanism for this transformation became the next goal in my dissertation. Although mechanistic details of reductive coupling reactions are well understood for other metal system, ambiguities still exist for nickel-catalyzed reactions. Efforts were made to distinguish between several possible mechanisms. Cyclotrimerization of unsymmetrical alkynes with high regioselectivity and with low catalyst loading would be highly beneficial to the organic community. As the research progressed, it was also discovered that

Ni(COD)2 combined with phosphines and NHC’s can efficiently and selectively catalyze the cyclotrimerization of ynoates and related alkynes.

10

Chapter 2

Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to Access 1,4-Difunctionality

2.1 Introduction

Molecules bearing 1,4-difunctionality can be found in many natural and medicinal compounds, with some of the prominent examples shown in Figure 1.1 1,4-difunctionalized compounds, especially γ-diketones, are also important intermediates for the synthesis of heterocyclic compounds such as furans, pyrroles, thiophenes, and pyridazines.2

(−)-bursehernin ( ref 1a ) vulgamycin (ref 1b ) neosurugatoxin (ref 1c ) Antitumor activity Antibiotic activity Cytotoxic activity

Chiral 2,3-dialkyl succinates ( ref 1d ) Widespread medicinal chemistry Matrix metalloproetinase maoecrystal V (ref 1f ) intermediates inhibitor (ref 1e ) Anticancer activity

Figure 1. Selected natural products and medicinal compounds containing 1,4-difunctionality

1 (a) McDoniel, P. B.; Cole, J. R. J. Pharm. Sci. 1972, 61, 1992. (b) Seto, H.; Sato, T.; Urano, S.; Uzawa, J.; Yonehara, H. Tetrahedron Lett. 1976, 17, 4367. (c) Kosuge, T.; Tsuji, K.; Hirai, K.; Yamaguchi, K.; Okamoto, T.; Iitaka, Y. Tetrahedron Lett. 1981, 22, 3417. (d) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H. Chem. Rev. 1999, 99, 2735. (e) Fujisawa, T.; Igeta, K.; Odake, S.; Morita, Y.; Yasuda, J.; Morikawa, T. Bioorg. Med. Chem. 2002, 10, 2569. (f) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.- D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004, 6, 4327. 2 (a) Ellison, R. A. Synthesis 1973, 397. (b) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Katritsky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984, Vol. 4, pp 329. (c) Ho, T. L. Synth. Commun. 1974, 4, 265. (d) Lever, O. W. Jr. Tetrahedron 1976, 32, 1943. (e) Dean, F. M. Adv. Heterocycl. Chem. 1982, 30, 172. (f) Bossard, P.; Engster, C. H. Adv. Heterocycl. Chem. 1986, 30, 384. (g) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. (h) Hall, N. Science 1994, 266, 32.

12 Efficient construction of a 1,4-difunctionality is one of the challenges that chemists often encounter in target-directed synthesis. Disconnecting this structural moiety using a retrosynthetic analysis typically results in “unnatural” synthons such as acyl anions and homoenolates. Accordingly, most strategies for making molecules with a 1,4-difunctionality involve reactivity umpolung of heteroatom-containing carbon chains through tedious protection−deprotection sequences.3 More recent efforts, aimed at improving the efficiency of the synthesis, have focused on polarity reversal induced by N-heterocyclic carbenes (NHCs)4 or transition metals,5 homocoupling6 or heterocoupling7 of enolates by metal based oxidants, and carbonylation of carbonyl derivatives via C−H bond activation.8 Despite this progress, concise and efficient methods for the installation of a 1,4-difunctionality are still in high demand, particularly if the resulting products can be conveniently transformed into a wide variety of compounds.

2.2 Plan for the Synthesis

One conceptually different approach to access 1,4-difunctionality is to use a low-valent metal species to catalyze regioselective coupling of ynoates and aldehydes in the presence of a reducing agent such as silane (eq 1). Among various metal complexes for the reductive coupling

3 Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239. 4 (a) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326. (b) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (c) Vora, H. U.; Rovis, T. Aldrichimica Acta 2011, 44, 3. (d) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336. (e) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. 5 (a) Guan, H. Curr. Org. Chem. 2008, 12, 1406. (b) Zhang, J.; Krause, J. A.; Huang, K.-W.; Guan, H. Organometallics 2009, 28, 2938. 6 Csákÿ, A. G.; Plumet, J. Chem. Soc. Rev. 2001, 30, 313. 7 (a) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, 7083. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546. 8 (a) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (b) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378. (c) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.

13 9 , 10 of alkynes and aldehydes, catalytic systems involving Ni(COD)2/L (COD = 1,5- cyclooctadiene, L = a phosphine or an NHC), developed by Montgomery,11 Jamison,12 and others,13 have stood out due to their excellent reactivity and regioselectivity. Of the alkynes applied in these studies, however, very few of them contain functionalities that are adjacent to the C≡C bonds. In these rare cases, 1,3-difunctional products have been obtained as the major regioisomers (eqs 2 and 3).11g,13c We hypothesized that the electron-withdrawing nature of the ester group in ynoates might promote C–C bond forming reactions at the β-carbon,14 leading to the desired silyl-protected γ-hydroxy-α,β-enoates (eq 1). This specific type of 1,4-difunctional compounds has been long sought as versatile precursors to many biologically active molecules.15

9 Ni-catalyzed reactions: (a) Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (b) Ikeda, S. Angew. Chem., Int. Ed. 2003, 42, 5120. (c) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (d) Montgomery, J.; Sormunen, G. J. Top. Curr. Chem. 2007, 279, 1. (e) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441. Rh- or Ir- catalyzed reactions: (f) Rhee, J. U.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 10674. (g) Ngai, M.-Y.; Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (h) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. 10 (a) Sm-mediated stoichiometric reactions: Inanaga, J.; Katsuki, J.; Ujikawa, O.; Yamaguchi, M. Tetrahedron Lett. 1991, 32, 4921. Ti-mediated stoichiometric reactions: (b) Reichard, H. A.; McLaughlin, M.; Chen, M. Z.; Micalizio, G. C. Eur. J. Org. Chem. 2010, 391. 11 (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. (b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. (c) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (d) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441. (e) Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568. (f) Baxter, R. D.; Montgomery, J. J. Am. Chem. Soc. 2008, 130, 9662. (g) Malik, H. A.; Chaulagain, M. R.; Montgomery, J. Org. Lett. 2009, 11, 5734. (h) Malik, H. A.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2010, 132, 6304. 12 (a) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (b) Miller, K. M.; Molinaro, C.; Jamison, T. F. Tetrahedron: Asymmetry 2003, 14, 3619. (c) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156. (d) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. (e) Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130. (f) Moslin, R. M.; Jamison, T. F. Org. Lett. 2006, 8, 455. 13 (a) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653. (b) Takai, K.; Sakamoto, S.; Isshiki, T.; Kokumai, T. Tetrahedron 2006, 62, 7534. (c) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829. (d) Yang, Y.; Zhu, S.-F.; Zhou, C.-Y.; Zhou, Q.-L. J. Am. Chem. Soc. 2008, 130, 14052. (e) Saito, N.; Sugimura, Y.; Sato, Y. Org. Lett. 2010, 12, 3494. 14 Carbon-carbon bond formation in Ti-mediated coupling of ynoates and alkynes has been shown to occur at the β-carbon of ynoates, see: Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121, 7342. 15 (a) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc. 1981, 103, 1224. (b) Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386. (c) Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443. (d) Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785.

14 This work: R2 O O O cat. R3 + + R SiH 2 4 (1) 3 3 1 1 3 R1O H R R O R2 OSiR3

Montgomery: 2 Ni(COD) OTBS R OTBS O 2 NHC + (i-Pr) SiH 1 1 (2) + 3 R 2 R1 H R3 2 3 R R3 OSi(i-Pr)3 Sato: O O O Ni(COD) O 2 O 2 R NHC 3 (3) N + + Et3SiH N 1 3 R H R3 2 R2 OSiEt3

2.3 Nickel-Catalyzed Reductive Coupling of an Ynoate and an Aldehyde

In the presence of an alkyl silane, coupling of ynoates and aldehydes was examined using a catalyst generated in-situ from Ni(COD)2 and an N-heterocyclic carbene (NHC) ligand. As an initial experiment methyl propiolate (1), benzaldehyde (2a) and Et3SiH were employed as the substrates in conjunction with 10 mol % catalyst generated from Ni(COD)2 and IMes (Scheme

1). The products were analyzed by GC-MS. To our delight the desired 1,4-difunctional coupling

Scheme 1. Reductive coupling of methyl propiolate and benzaldehyde

O OMe O O Ni(COD)2 10 mol % O O IMes HCl 10 mol % O O MeO t MeO MeO OMe KO Bu 10 mol % Ph 1 MeO + MeO + + + THF, 23 oC, 12 h O OSiEt3 Ph OSiEt Et3SiH 3 O OMe O OMe Ph H 3a 3a' 4 4' 2a cyclotrimerization byproducts

product (3a) was detected along with its regioisomer, which is a 1,3-difunctional product (3aʹ).

The cyclotrimerization of methyl propiolate was also detected as a competing process to yield benzene derivatives (4 and 4ʹ). After further optimization it was established that to prevent the

15 cyclotrimerization, the solution of the ynoate in THF had to be added last and very slowly (via syringe-pump addition typically over 8h) to the reaction mixture. A similar approach has been previously developed by Saito and co-workers in related reductive coupling reactions.13c

Interestingly, during the purification of products from a stoichiometric reaction between

1, 2a, Et3SiH, Ni(COD)2 and IMes, an air and moisture stable complex [NiCl2(IMes)2] (5) was

N N

Cl Ni Cl

N N

5 isolated as a pink crystalline solid. This result made us suspect that this complex may be produced during catalytic reaction. If it does, it would be detrimental to the reaction as it diminishes the concentration of the active species. It should also be mentioned that this compound could form only after the reaction mixture was exposed to air during the work-up procedure. Nevertheless, the only available source of Cl¯ to form this compound was from the

NHC precursor, IMes•HCl.

Figure 2. X-ray structure of compound 5 (at 50 % probability level). Selected bond lengths (Å) and angles (deg): Ni-C1 or Ni-C1A 1.92 (17), Ni-Cl1 or Ni-Cl1A 2.19 (5), C1A-Ni-Cl1 89.35 (5), C1A-Ni-C1 179.91 (10), C1A-Ni-Cl1 90.65 (5), C1A-Ni-Cl1 179.37 (3)

16 2.4 Optimization of the Reaction Conditions

The aforementioned results from the coupling of methyl propiolate and benzaldehyde prompted us to further optimize the reaction conditions (Table 1). Yield of the reaction was determined by GC-MS using n-decane as the internal standard. Regioselectivity of each reaction was determined by 1H NMR of the crude reaction mixture before any separation. When IMes

(see Chart 1) was employed as the ligand, the two coupling products (3a:3aʹ = 95:5) were detected by GC; however, the combined yield was merely 14% (entry 1). Replacing IMes with other commonly used NHCs did not give satisfactory yields (entries 2-4) but SIPr was identified as our best ligand. Having observed the formation of complex 5, we wished to examine the effect of counterion by switching from Cl¯ to a weakly coordinating anion. Interestingly, when

SIPr was generated from its NHC precursor with a BF4¯ counterion, the yield was improved to

61% (entry 5). The reason behind the counterion effect is not fully understood. When Cl¯ was added externally, the yield for 3a/3bʹ would also be reduced (entry 6). In all of the experiments mentioned above, unreacted PhCHO was seen, which suggested to us that the active catalyst might already be decomposed. Gratifyingly, an attempt to extend the lifetime of catalyst16 by adding 10 mol% of PPh3 (with respect to 1) showed a quantitative conversion with a 85:15 ratio of 3a/3aʹ (entry 8). Adding more PPh3, however, had a detrimental effect on the yield (entry 9), perhaps by saturating the nickel center to inhibit the reaction. A few other NHCs were also tested (entries 10-12), but none of them promoted the coupling reaction. The choice of solvent proved to be critical; reaction in CH2Cl2, 1,4-dioxane, or DMF under otherwise the same conditions (as those described in entry 8) did not produce any of the coupling products.

16 The strategy of adding a phosphine ligand to stabilize the active catalyst has been previously used, see: Sawaki, R.; Sato, Y.; Mori, M. Org. Lett. 2004, 6, 1131.

17 Table 1. Optimization of the reaction conditions

Ni(COD)2 (10 mol%) O NHC HX (10 mol%) Ph MeO KOtBu (10 mol%) + O 3a OSiEt additive (10 mol%) O 3 + PhCHO + Et SiH 3 o MeO 2a THF, 23 C MeO 1 Ph OSiEt 3a' 3

entry NHC•HX additive yield (%)c 1 IMes•HCl – 14 2 SIMes•HCl – 15d 3 IPr•HCl – 27 4 SIPr•HCl – 38

5 SIPr•HBF4 – 61

6 SIPr•HBF4 NaCl 37 a d 7 SIPr•HBF4 – trace

8 SIPr•HBF4 PPh3 100 b 9 SIPr•HBF4 PPh3 41

10 IIPr•HBF4 PPh3 0

11 ICy•HBF4 PPh3 0

12 BAC•HBF4 PPh3 0 a o b Reaction was conducted at 50 C. 20 mol% PPh3 was added. cCombined GC yield for 3a and 3a'. dA significant amount of PhCH2OSiEt3 was detected.

iPr iPr N N N N N N

i i IMes SIMes Pr Pr IPr i i Pr Pr iPr iPr N N N N N N i N N Pr iPr Cy Cy i Pr iPr i iPr Pr IIPr ICy SIPr BAC

Chart 1. NHCs employed in this study

18 2.5 Control Experiments

A reaction performed without the catalyst mixture did not yield any of desired products, confirming the necessity of the catalyst for the occurrence of the reaction (eq 4). A control experiment with 10 mol% of PPh3 and no NHC ligand showed no reaction either, suggesting that the NHC ligand is needed and PPh3 alone cannot catalyze this reaction (eq 5).

O O THF, 23 oC + + Et3SiH no reaction (4) MeO Ph H 48 h

Ni(COD)2 10 mol% O O PPh3 10 mol% + + Et3SiH no reaction (5) MeO Ph H o THF, 23 C, 48 h

2.6 Substrate Scope

To explore the generality of the reaction, reductive coupling of 1 with various aldehydes under the optimized conditions were performed. As shown in Table 2, the methodology is amenable to aldehydes bearing functional groups such as OMe, Cl, and CO2Me (2c-e). In all cases, the 1,4-difunctional compounds were produced as the major isomers and isolated in good yields. The regioselectivity does not appear to be greatly influenced by the electronic property of the substituent at the para-position of benzaldehyde. In view of recent intense interest in the synthesis of fluorine-containing molecules,17 we also examined substrates that are fluorinated at different positions of the aromatic ring. Of particular interest is that coupling of ortho- fluorobenzaldehyde gave the 1,4-difunctional product 3h with a 95:5 regioselectivity. This high selectivity is not unique to fluorine as the reaction of ortho-tolualdehyde similarly yielded 3i as the predominant product. Other aromatic aldehydes such as 2-naphthaldehyde are also viable

17 Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470

19 substrates for the synthesis of 1,4-difunctional products. However, reactions with aliphatic aldehydes including heptaldehyde and isovaleraldehyde afforded not only 1,3-difunctional compounds as the major isomers (a 2:1 ratio favoring the 1,3-product) but also some trimerization byproducts from 1.

Table 2. Reactions of 1 with various aldehydes

Ni(COD)2 (10 mol%) O O SIPr HBF4 (10 mol%) O KOtBu (10 mol%) MeO Ar + MeO 1 PPh3 (10 mol%) MeO + THF, 23 oC 3a-j OSiEt3 Ar OSiEt3 ArCHO Et3SiH minor product 2a-j 3a'-j' R O O F MeO MeO

OSiEt3 OSiEt3 3a R = H 76% (85 : 15)a 3f p-F 61% (83 : 17) 3b R = Me 63% (82 : 18)b 3g m-F 71% (84 : 16) 3c R = OMe 58% (83 : 17) 3h o-F 85% (95 : 5) 3d R = Cl 56% (81 : 19) 3e R = CO2Me 74% (80 : 20) Me O O

MeO MeO

OSiEt3 OSiEt3 b 3i 67% (95 : 5) 3j 81% (88 : 12)

aYield of purified product; regioselectivity (in parenthesis) was determined by 1H NMR. bThe solution of 1 in THF was added over 16 h rather than 8 h.

The scope of the reaction was further investigated by varying the structures of the ynoates

(Table 3). In addition to the methyl ester 1, ethyl or 2-naphthyl propiolate can be utilized to synthesize the corresponding 1,4-regioisomer with a similar selectivity. In contrast, the coupling of tert-butyl propiolate is not selective at all, producing equal amounts of two isomeric products.

20 Ynoates bearing an internal C≡C bond are also feasible coupling partners. As a matter of fact, their reactions are generally more regioselective, and in some cases as high as a 98:2 ratio favoring the 1,4-product (e.g., 3n) was observed. More importantly, with these internal alkynes,

Table 3. Scope of ynoates and aldehydes

O Ni(COD) (10 mol%) 2 R2 O R2 SIPr HBF (10 mol%) O 4 3 R1O t R KO Bu (10 mol%) 1 R2 R1O + R O H PPh3 (10 mol%) + H OSiEt 3 R3 OSiEt3 R3CHO Et SiH THF, 23 oC 3 3k-s minor product

O H O H O H Ph Ph Ph t EtO O BuO H OSiEt3 H OSiEt3 H OSiEt3 3k 74% (88 : 12)a 3l 67% (85 : 15) 3m 46% (50 : 50)

O O O Ph Ph MeO MeO MeO H OSiEt 3 H OSiEt3 H OSiEt3 3n 91% (98 : 2) 3o 83% (97 : 3) 3p 77% (87 : 13)

O O O SiMe3 SiMe3 Ph MeO EtO EtO H OSiEt3 H OSiEt3 H OSiEt3 3q 75% (87 : 13) 3r 83% (97 : 3) 3s 81% (98 : 2)

aYield of purified product; regioselectivity (in parenthesis) was determined by 1H NMR. aliphatic aldehydes can now be successfully incorporated for the synthesis of 1,4-difunctional compounds. Trimethylsilyl (TMS)-substituted ynoates can also be coupled with both aromatic and aliphatic aldehydes to yield the 1,4-difunctional compounds (3r and 3s) with an excellent regioselectivity. It should be mentioned that syringe-pump addition of these bulky ynoates is no longer needed because under the reaction conditions their trimerization or oligomerization is

21 noncompetitive. Having the TMS groups in these molecules can be advantageous; further modification at the β position should be possible through Hiyama coupling reactions.18

2.7 Origin of the Regioselectivity

The observed regioselectivity could be rationalized by the mechanistic hypothesis outlined in Scheme 2 (using 1 and PhCHO as representative substrates). A similar mechanism has been proposed in related systems for the coupling of alkynes and aldehydes, where it has been supported by computational studies,19 kinetics,20 and even a crystal structure.21

Scheme 2. Proposed reaction mechanism

O H OSiEt3 OSiEt3 MeO O Ph 3a Ph OMe L 3a' L O Ni H Ni H OSiEt3 LNi(0) OSiEt3 MeO PhCHO O Ph Ph OMe LNi HSiEt3 Ph O HSiEt3 O L L Ni H Ni O MeO 1 1 O Ph O A Ph OMe B

18 Hiyama Cross-Coupling Reaction. In Name Reactions for Homologations, Part 1; Li, J. J., Ed; John Wiley & Sons: Hoboken, 2009; p 33. 19 (a) McCarren, P. R.; Liu, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6654. (b) Liu, P.; McCarren, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050. (c) Liu, P.; Montgomery, J.; Houk, K. N. J. Am. Chem. Soc. 2011, 133, 6956. 20 Baxter, R. D.; Montgomery, J. J. Am. Chem. Soc. 2011, 133, 5728. 21 Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem. Commun. 2008, 1347.

22 As illustrated in Scheme 2, regioselectivity in metallacycle formation is influenced by polarization of the triple bonds. Hoffmann et al. reported that the large lobes of polarized π* orbital of the starting alkyne would orient at the β-positions of the forming metallacycle.22 In other words, during the metallacycle formation nickel would form the bond with the carbon that is adjacent to the electron-withdrawing group (Figure 3). Therefore the formation of metallacycle A is favored over that of metallacycle B, leading to high selectivity for the 1,4- difunctionalized product.

RO R1 O R1 = H, alkyl group, TMS π∗ orbital of an ynoate

Figure 3. Polarization of the triple bond in ynoates

The regioselection in this type of chemistry is not determined by the electronic factors only. For example, the metallacycle intermediate A would be destabilized when the methyl ester is replaced by a tert-butyl ester, possibly due to the increased steric clash between the ester moiety and the ancillary ligand on nickel. This analysis is in agreement with the non- regioselectivity observed for 3m (Table 3). For internal alkynes, the formation of A is expected to be more favorable on the basis of both electronic (polarization of the ynoate) and steric arguments, resulting in enhanced selectivity for the 1,4-difunctional products. In the case of benzaldehyde bearing an ortho-substituent (2h and 2i), the intermediate B should be even less favorable owing to the unfavorable steric interaction between the ester group and the aryl ring.

22 (a) Stockis, A.; Hoffmann, R. J. Am. Chem. Soc. 1980, 102, 2952; (b) Mori, N.; Ikeda, S.; Sato, Y.; J. Am. Chem. Soc. 1999, 121, 2722.

23 2.8 Synthetic Applications

As mentioned earlier, silyl-protected γ-hydroxy-α,β-enoates are important building blocks for a diverse array of compounds. To demonstrate their synthetic utility, compound 3h was subjected to saturation of the C=C bond followed by lactonization to furnish 7 (Scheme 3).

Given the fact that γ-butyrolactones are present in about 10% of all natural products,23 we anticipate that the method described here may open a new synthetic path to these molecules.

Another important class of compounds is the substituted tetrahydrofurans,24 as illustrated in

Scheme 3, they are readily accessible from silyl-protected γ-hydroxy-α,β-enoates following deprotection of the silyl group, reduction of the carbonyls, and cyclodehydration of the resulting diols.

Scheme 3. Synthetic applications of silyl-protected γ-hydroxy-α,β-enoates

IPrCuOtBu O F F O (1 mol%) O PMHS TBAF O MeO o toluene, 23 C MeO THF, 23 oC OSiEt 95% yield 3h 3 6 OSiEt3 85% yield F

TBAF 7 THF, 23 oC 76% yield F F O O LiAlH4 ZnCl2 o THF, 23 C o MeO HO ClCH2CH2Cl, 80 C F 95% yield 72% yield O OH 8 9 10

23 Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94. 24 Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504.

24 2.9 Conclusions

In summary, we have developed a nickel-based catalytic system for regioselective multicomponent coupling of ynoates, aldehydes, and a silane. The reactions are applicable to a broad range of substrates and enable regioselective synthesis of a wide variety of silyl-protected

γ-hydroxy-α,β-enoates. Further manipulations of these 1,4-difunctional compounds allow for convenient access to oxygen-containing five-membered rings, which are important cores of natural products.

2.10 Experimental

General Experimental Methods

All the reactions were carried out in flame-dried glassware under an argon atmosphere using standard glove box and Schlenk techniques. Dry and oxygen-free solvents (THF and

CH2Cl2) were collected from an Innovative Technology solvent purification system and used throughout the experiments. DMF was dried over molecular sieves (4 Å) and then degassed by three freeze-pump-thaw cycles. Anhydrous 1,4-dioxane was obtained from Sigma-Aldrich in a

Sure/SealTM bottle. Aldehydes were purchased from commercial sources and freshly distilled

25 prior to use. BAC•HBF4 was prepared as described in the literature.

General Procedure for Nickel-Catalyzed Reductive Coupling of an Ynoate and an

Aldehyde

To a flame-dried Schlenk flask was added Ni(COD)2 (13.8 mg, 0.050 mmol), SIPr·HBF4

t (23.9 mg, 0.050 mmol ), PPh3 (13.1 mg, 0.050 mmol), and KO Bu (5.6 mg, 0.050 mmol). THF

(4.0 mL) was then added to this flask at 0 °C and the resulting mixture was stirred at the same temperature for 15 min, followed by a successive addition of Et3SiH (88 µL, 0.55 mmol) and an

25 Lavallo, V.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Science 2006, 312, 722.

25 aldehyde (0.55 mmol). After stirring the mixture at 0 °C for 5 min, a solution of an ynoate (0.50 mmol) in 4.0 mL of THF was added at room temperature (23 °C) over a period of 8 h (or 16 h for the synthesis of 3b and 3i) using a syringe pump. Upon completion of the addition, the reaction mixture was stirred at room temperature for another hour before concentrated under the vacuum. The ratio for the two isomers was determined from 1H NMR spectrum of the crude products. The desired 1,4-difunctional compound was separated from the isomeric mixture using column chromatography (eluted with diethyl ether/hexanes). For the synthesis of 3r and 3s, the ynoate solution was added over a period of 1 h and the resulting solution was stirred at room temperature for 36 h prior to work-up. Characterization data of the isolated products are listed below.

1 Compound 3a: H NMR (400 MHz, CDCl3, δ): 7.33-7.24 (m, ArH, 5H),

3 3 4 6.99 (dd, JH-H = 15.4 and 4.5 Hz, CH=CHCH, 1H), 6.14 (dd, JH-H = 15.4 Hz, JH-H = 1.7 Hz,

3 4 CH=CHCH, 1H), 5.31 (dd, JH-H = 4.5 Hz, JH-H = 1.9 Hz, CH=CHCH, 1H), 3.71 (s, OCH3, 3H),

3 13 1 0.90 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.60-0.54 (m, SiCH2CH3, 6H). C{ H} NMR (101

MHz, CDCl3, δ): 167.31, 150.79, 141.90, 128.70, 127.95, 126.44, 118.65, 74.05, 51.74, 6.91,

-1 4.96. IR (neat, cm ): 2953, 2911, 2876, 1722 (νCO), 1657, 1493, 1454, 1435, 1414, 1295, 1276,

1240, 1191, 1163, 1118, 1084, 1064, 1003, 973, 838, 817, 726, 697. HRMS-ESI (m/z): [M +

+ Na] calcd for C17H26O3SiNa, 329.1549; found, 329.1539.

26 1 Compound 3aʹ: H NMR (400 MHz, CDCl3, δ): 7.37-7.20 (m, ArH,

5H), 6.26-6.25 (m, C=CH2, 1H), 6.10-6.09 (m, C=CH2, 1H), 5.61 (br s, CH2=CCH, 1H), 3.67 (s,

3 13 1 OCH3, 3H), 0.86 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.57-0.51 (m, SiCH2CH3, 6H). C{ H}

NMR (101 MHz, CDCl3, δ): 166.61, 144.13, 142.92, 128.25, 127.59, 127.25, 124.07, 72.60,

-1 51.84, 6.91, 4.95. IR (neat, cm ): 2953, 2911, 2876, 1720 (νCO), 1630, 1493, 1454, 1438, 1413,

1358, 1292, 1256, 1192, 1147, 1084, 1003, 953, 912, 875, 835, 815, 726, 697, 603, 540. HRMS-

+ ESI (m/z): [M + Na] calcd for C17H26O3SiNa, 329.15434; found, 329.15435.

1 Compound 3b: H NMR (400 MHz, CDCl3, δ): 7.20 and 7.13

3 3 (AB pattern, JAB = 8.0 Hz, ArH, 4H), 6.98 (dd, JH-H = 15.2 and 4.4 Hz, CH=CHCH, 1H), 6.12

3 4 3 4 (dd, JH-H = 15.2 Hz, JH-H = 1.6 Hz, CH=CHCH, 1H), 5.28 (dd, JH-H = 4.4 Hz, JH-H = 1.6 Hz,

3 CH=CHCH, 1H), 3.71 (s, OCH3, 3H), 2.33 (s, ArCH3, 3H), 0.90 (t, JH-H = 7.6 Hz, SiCH2CH3,

13 1 9H), 0.60-0.53 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ): 167.36, 151.01,

138.93, 137.62, 129.37, 126.38, 118.44, 73.89, 51.70, 21.33, 6.92, 4.93. IR (neat, cm-1): 2953,

2912, 2876, 1724 (νCO), 1657, 1512, 1458, 1435, 1413, 1276, 1239, 1192, 1162, 1118, 1104,

+ 1072, 1004, 974, 843, 815, 720. HRMS-ESI (m/z): [M + Na] calcd for C18H28O3SiNa,

343.16999; found, 343.17007.

27 OMe O

MeO

3c OSiEt3 1 3 Compound 3c: H NMR (400 MHz, CDCl3, δ): 7.22 (d, JH-

3 3 H = 8.8 Hz, ArH, 2H), 6.97 (dd, JH-H = 15.4 and 4.5 Hz, CH=CHCH, 1H), 6.86 (d, JH-H = 8.8

3 4 3 Hz, ArH, 2H), 6.11 (dd, JH-H = 15.4 Hz, JH-H = 1.8 Hz, CH=CHCH, 1H), 5.26 (dd, JH-H = 4.5

4 3 Hz, JH-H = 1.8 Hz, CH=CHCH, 1H), 3.80 (s, OCH3, 3H), 3.71 (s, OCH3, 3H), 0.89 (t, JH-H = 7.9

13 1 Hz, SiCH2CH3, 9H), 0.59-0.52 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ):

167.34, 159.32, 150.95, 133.99, 127.68, 118.31, 114.01, 73.57, 55.41, 51.68, 6.88, 4.91. IR

-1 (neat, cm ): 2953, 2911, 2876, 1722 (νCO), 1657, 1610, 1510, 1244, 1193, 974, 818, 724.

+ HRMS-ESI (m/z): [M + Na] calcd for C18H28O4SiNa, 359.16491; found, 359.16487.

1 Compound 3d: H NMR (400 MHz, CDCl3, δ): 7.30 and 7.25

3 3 (AB pattern, JAB = 8.4 Hz, ArH, 4H), 6.93 (dd, JH-H = 15.4 and 4.6 Hz, CH=CHCH, 1H), 6.11

3 4 3 (dd, JH-H = 15.4 Hz, JH-H = 1.6 Hz, CH=CHCH, 1H), 5.28 (d, JH-H = 4.6 Hz, CH=CHCH, 1H),

3 3.72 (s, OCH3, 3H), 0.90 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.60-0.54 (m, SiCH2CH3, 6H).

13 1 C{ H} NMR (101 MHz, CDCl3, δ): 167.14, 150.14, 140.51, 133.70, 128.90, 127.76, 119.04,

-1 73.38, 51.82, 6.89, 4.93. IR (neat, cm ): 2953, 2911, 2876, 1722 (νCO), 1658, 1488, 1458, 1435,

1409, 1297, 1275, 1240, 1191, 1163, 1120, 1088, 1014, 973, 819, 725. HRMS-ESI (m/z): [M +

+ Na] calcd for C17H25O3SiClNa, 363.11537; found, 363.11541.

28 1 3 Compound 3e: H NMR (400 MHz, CDCl3, δ): 8.01 (d, JH-

3 3 H = 7.9 Hz, ArH, 2H), 7.40 (d, JH-H = 7.9 Hz, ArH, 2H), 6.96 (dd, JH-H = 15.4 Hz and 4.5 Hz,

3 4 3 CH=CHCH, 1H), 6.15 (dd, JH-H = 15.4 Hz, JH-H = 1.8 Hz, CH=CHCH, 1H), 5.36 (dd, JH-H =

4 3 4.5 Hz, JH-H = 1.8 Hz, CH=CHCH, 1H), 3.91 (s, OCH3, 3H), 3.72 (s, OCH3, 3H), 0.90 (t, JH-H =

13 1 7.9 Hz, SiCH2CH3, 9H), 0.63-0.53 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ):

166.99, 166.92, 149.69, 146.94, 130.03, 129.74, 126.25, 119.25, 73.61, 52.22, 51.75, 6.80, 4.85.

-1 IR (neat, cm ): 2953, 2912, 2876, 1721 (νCO), 1658, 1610, 1458, 1435, 1413, 1242, 1191, 1164,

1108, 1018, 971, 888, 857, 825, 807, 769, 725, 566. HRMS-ESI (m/z): [M + Na]+ calcd for

C19H28O5SiNa, 387.1604; found, 387.1595.

1 Compound 3f: H NMR (400 MHz, CDCl3, δ): 7.28-7.25 (m,

3 ArH, 2H), 7.02-6.97 (m, ArH, 2H), 6.93 (dd, JH-H = 15.4 and 4.6 Hz, CH=CHCH, 1H), 6.10 (dd,

3 4 3 4 JH-H = 15.4 Hz, JH-H = 1.7 Hz, CH=CHCH, 1H), 5.27 (d, JH-H = 4.6 Hz, JH-H = 1.7 Hz,

3 CH=CHCH, 1H), 3.72 (s, OCH3, 3H), 0.90 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.58-0.52 (m,

13 1 1 SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ): 167.23, 162.50 (d, JC-F = 246.4 Hz, CF),

4 3 2 150.45, 137.76 (d, JC-F = 2.7 Hz), 128.10 (d, JC-F = 7.1 Hz), 118.85, 115.59 (d, JC-F = 21.4 Hz),

-1 73.39, 51.81, 6.89, 4.94. IR (neat, cm ): 2954, 2912, 2877, 1722 (νCO), 1658, 1604, 1507, 1458,

1435, 1414, 1297, 1277, 1222, 1191, 1164, 1156, 1116, 1092, 1072, 1004, 974, 886, 872, 834,

+ 821, 721. HRMS-ESI (m/z): [M + Na] calcd for C17H25O3FSiNa, 347.14492; found, 347.14498.

29 F

O

MeO OSiEt 3g 3 1 Compound 3g: H NMR (400 MHz, CDCl3, δ): 7.31-7.26 (m,

3 ArH, 1H), 7.13-7.01 (m, ArH, 2H), 7.01-6.92 (m, ArH + CH=CHCH, 2H), 6.13 (dd, JH-H = 15.4

4 3 4 Hz, JH-H = 1.7 Hz, CH=CHCH, 1H), 5.30 (dd, JH-H = 4.5 Hz, JH-H = 1.7 Hz, CH=CHCH, 1H),

3 3.72 (s, OCH3, 3H), 0.91 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.63-0.53 (m, SiCH2CH3, 6H).

13 1 1 C{ H} NMR (101 MHz, CDCl3, δ): 167.06, 163.11 (d, JC-F = 247.1 Hz, CF), 149.92, 144.59

3 3 4 2 (d, JC-F = 6.7 Hz), 130.15 (d, JC-F = 8.3 Hz), 121.83 (d, JC-F = 2.7 Hz), 119.11, 114.78 (d, JC-F

2 -1 = 22.1 Hz), 113.24 (d, JC-F = 22.1 Hz), 73.35, 51.76, 6.82, 4.87. IR (neat, cm ): 2954, 2912,

2877, 1722 (νCO), 1679, 1659, 1614, 1591, 1483, 1448, 1436, 1414, 1348, 1268, 1192, 1166,

1136, 1116, 1004, 977, 945, 911, 870, 825, 789, 770, 727, 690. HRMS-ESI (m/z): [M + Na]+ calcd for C17H25O3FSiNa, 347.1455; found, 347.1458.

1 Compound 3h: H NMR (400 MHz, CDCl3, δ): 7.48-7.43 (m,

ArH, 1H), 7.27-7.23 (m, ArH, 1H), 7.16-7.10 (m, ArH, 1H), 7.03-6.97 (m, ArH + CH=CHCH,

3 4 3 4 2H), 6.16 (dd, JH-H = 15.4 Hz, JH-H = 1.7 Hz, CH=CHCH, 1H), 5.69 (d, JH-H = 4.6 Hz, JH-H =

3 1.7 Hz, CH=CHCH, 1H), 3.72 (s, OCH3, 3H), 0.90 (t, JH-H = 7.6 Hz, SiCH2CH3, 9H), 0.63-0.55

13 1 1 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ): 167.21, 159.19 (d, JC-F = 246.4 Hz,

3 2 CF), 149.21, 129.37 (d, JC-F = 9.1 Hz), 129.01 (d, JC-F = 14.1 Hz), 127.99 (d, JC-F = 4.0 Hz),

2 124.60 (d, JC-F = 4.0 Hz), 119.04, 115.27 (d, JC-F = 22.2 Hz), 67.02, 51.72, 6.80, 4.76. IR (neat,

-1 cm ): 2954, 2912, 2877, 1725 (νCO), 1659, 1573, 1458, 1456, 1435, 1296, 1271, 1242, 1223,

30 1164, 1130, 1087, 1004, 974, 819, 796, 725. HRMS-ESI (m/z): [M + Na]+ calcd for

C17H25O3FSiNa, 347.14492; found, 347.14492.

1 Compound 3i: H NMR (400 MHz, CDCl3, δ): 7.41-7.38 (m, ArH,

3 3 1H), 7.20-7.08 (m, ArH, 3H), 6.96 (dd, JH-H = 15.6 and 4.4 Hz, CH=CHCH, 1H), 6.10 (dd, JH-H

4 3 4 = 15.6 Hz, JH-H = 1.6 Hz, CH=CHCH, 1H), 5.49 (dd, JH-H = 4.4 Hz, JH-H = 1.6 Hz,

3 CH=CHCH, 1H), 3.70 (s, OCH3, 3H), 2.33 (s, ArCH3, 3H), 0.89 (t, JH-H = 8.0 Hz, SiCH2CH3,

13 1 9H), 0.60-0.52 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ): 167.38, 149.75,

139.81, 134.44, 130.65, 127.76, 126.98, 126.51, 118.71, 71.41, 51.73, 19.38, 6.89, 4.94. IR

-1 (neat, cm ): 2952, 2911, 2876, 1723 (νCO), 1656, 1459, 1435, 1413, 1276, 1239, 1164, 1114,

+ 1091, 1068, 1004, 970, 820, 722. HRMS-ESI (m/z): [M + Na] calcd for C18H28O3SiNa,

343.16999; found, 343.17002.

1 Compound 3j: H NMR (400 MHz, CDCl3, δ): 7.82-7.76 (m,

3 ArH, 4H), 7.48-7.42 (m, ArH, 3H), 7.06 (dd, JH-H = 15.4 and 4.5 Hz, CH=CHCH, 1H), 6.19 (dd,

3 4 3 4 JH-H = 15.4 Hz, JH-H = 1.6 Hz, CH=CHCH, 1H), 5.48 (dd, JH-H = 4.5 Hz, JH-H = 1.6 Hz,

3 CH=CHCH, 1H), 3.71 (s, OCH3, 3H), 0.91 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.63-0.56 (m,

13 1 SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ): 167.28, 150.64, 139.33, 133.48, 133.26,

128.59, 128.15, 127.93, 126.38, 126.19, 125.13, 124.52, 118.88, 74.19, 51.76, 6.95, 4.99. IR

-1 (neat, cm ): 3056, 2952, 2910, 2875, 1721 (νCO), 1656, 1601, 1508, 1457, 1434, 1413, 1366,

31 1338, 1298, 1270, 1238, 1191, 1162, 1124, 1108, 1073, 1004, 975, 954, 896, 856, 816, 727.

+ HRMS-ESI (m/z): [M + Na] calcd for C21H28O3SiNa, 379.16999; found, 379.17005.

1 Compound 3k: H NMR (400 MHz, CDCl3, δ): 7.33-7.24 (m, ArH,

3 3 4 5H), 6.97 (dd, JH-H = 15.4 and 4.5 Hz, CH=CHCH, 1H), 6.11 (dd, JH-H = 15.4 Hz, JH-H = 1.6

3 4 Hz, CH=CHCH, 1H), 5.31 (dd, JH-H = 4.5 Hz, JH-H = 1.6 Hz, CH=CHCH, 1H), 4.20-4.14 (m,

3 3 OCH2CH3, 2H), 1.27 (t, JH-H = 7.1 Hz, OCH2CH3, 3H), 0.90 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H),

13 1 0.60-0.54 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ): 167.42, 159.39, 151.03,

134.07, 127.75, 118.39, 114.08, 73.63, 55.48, 51.74, 6.94, 4.98. IR (neat, cm-1): 2955, 2911,

2876, 1718 (νCO), 1656, 1454, 1413, 1367, 1276, 1238, 1161, 1114, 1064, 1038, 1002, 975, 846,

+ 819, 742, 726, 697. HRMS-ESI (m/z): [M + Na] calcd for C18H28O3SiNa, 343.16999; found,

343.17003.

1 Compound 3l: H NMR (400 MHz, CDCl3, δ): 7.85-7.78

3 (m, ArH, 3H), 7.58-7.56 (m, ArH, 1H), 7.50-7.21 (m, ArH + CH=CHCH, 9H), 6.39 (dd, JH-H =

4 3 4 15.3 Hz, JH-H = 1.8 Hz, CH=CHCH, 1H), 5.41 (dd, JH-H = 4.3 Hz, JH-H = 1.8 Hz, CH=CHCH,

3 13 1 1H), 0.94 (t, JH-H = 8.0 Hz, SiCH2CH3, 9H), 0.65-0.58 (m, SiCH2CH3, 6H). C{ H} NMR (101

MHz, CDCl3, δ): 165.39, 152.75, 148.50, 141.61, 133.90, 131.58, 129.49, 128.76, 128.07,

127.89, 127.80, 126.64, 126.49, 125.78, 121.34, 118.69, 118.17, 74.11, 6.90, 4.93. IR (neat, cm-

1 ): 3060, 3029, 2954, 2910, 2874, 1733 (νCO), 1653, 1630, 1600, 1493, 1463, 1356, 1269, 1237,

32 1208, 1154, 1122, 1078, 969, 808, 736, 697. HRMS-ESI (m/z): [M + Na]+ calcd for

C26H30O3SiNa, 441.18564; found, 441.18569.

1 Compound 3m: H NMR (400 MHz, CDCl3, δ): 7.33-7.24 (m,

3 3 4 ArH, 5H), 6.86 (dd, JH-H = 15.2 and 4.8 Hz, CH=CHCH, 1H), 5.99 (dd, JH-H = 15.4 Hz, JH-H =

3 4 1.6 Hz, CH=CHCH, 1H), 5.28 (dd, JH-H = 4.8 Hz, JH-H = 1.6 Hz, CH=CHCH, 1H), 1.46 (s,

3 13 1 C(CH3)3, 9H), 0.90 (t, JH-H = 8.0 Hz, SiCH2CH3, 9H), 0.60-0.53 (m, SiCH2CH3, 6H). C{ H}

NMR (101 MHz, CDCl3, δ): 165.99, 148.96, 142.03, 128.41, 127.61, 126.25, 120.83, 80.32,

-1 73.92, 28.09, 6.70, 4.75. IR (neat, cm ): 2955, 2912, 2876, 1712 (νCO), 1654, 1493, 1454, 1413,

1392, 1367, 1297, 1281, 1246, 1148, 1120, 1064, 1001, 976, 847, 818, 740, 726, 697. HRMS-

+ ESI (m/z): [M + Na] calcd for C20H32O3SiNa, 371.20129; found, 371.20135.

1 Compound 3n: H NMR (400 MHz, CDCl3, δ): 7.32-7.23 (m,

ArH, 5H), 6.26 (s, CH=C(Hex)CH, 1H), 5.10 (s, CH=C(Hex)CH, 1H), 3.70 (s, OCH3, 3H), 2.67-

2.61 (m, CH=CCH2, 1H), 2.06-2.01 (m, CH=CCH2, 1H), 1.29-1.18 (m, CH=CCH2(CH2)4, 8H),

13 1 0.89-0.83 (m, CH3, 12H), 0.57-0.51 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ):

167.38, 164.90, 141.98, 128.33, 127.86, 127.21, 113.69, 77.75, 51.05, 31.61, 29.90, 29.55, 29.45,

-1 22.69, 14.17, 6.84, 4.89. IR (neat, cm ): 2953, 2875, 1720 (νCO), 1649, 1493, 1454, 1433, 1413,

1377, 1312, 1209, 1145, 1102, 1062, 1004, 974, 938, 915, 884, 849, 825, 725, 698. HRMS-ESI

+ (m/z): [M + Na] calcd for C23H38O3SiNa, 413.2488; found, 413.2492.

33 1 Compound 3o: H NMR (400 MHz, CDCl3, δ): 7.32-7.24 (m,

ArH, 5H), 6.28 (s, CH=C(Pr)CH, 1H), 5.10 (s, Et3SiOCH, 1H), 3.70 (s, OCH3, 3H), 2.67-2.60

(m, CH=CCH2, 1H), 2.04-2.01 (m, CH=CCH2, 1H), 1.33-1.28 (m, CH=CCH2CH2, 2H), 0.90-

13 1 0.85 (m, CH2CH2CH3 + SiCH2CH3, 12H), 0.58-0.50 (m, SiCH2CH3, 6H). C{ H} NMR (101

MHz, CDCl3, δ): 167.36, 164.68, 141.92, 128.32, 127.85, 127.19, 113.81, 77.72, 51.03, 31.51,

-1 22.90, 14.67, 6.82, 4.85. IR (neat, cm ): 2956, 2912, 2875, 1720 (νCO), 1649, 1454, 1433, 1377,

1313, 1278, 1240, 1196, 1145, 1099, 1057, 1004, 883, 845, 726, 698. HRMS-ESI (m/z): [M +

+ Na] calcd for C20H32O3SiNa, 371.20129; found, 371.20134.

1 Compound 3p: H NMR (400 MHz, CDCl3, δ): 5.92 (s,

3 CH=C(Pr)CH, 1H), 4.10 (t, JH-H = 5.4 Hz, CH=C(Pr)CH, 1H), 3.69 (s, OCH3, 3H), 2.84-2.76

(m, CH=CCH2, 1H), 2.17-2.08 (m, CH=CCH2, 1H) 1.54-1.26 (m, CH=CCH2CH2 +

13 1 CH=CCH(CH2)5, 12H), 1.00-0.86 (m, CH3, 15H), 0.61-0.55 (m, SiCH2CH3, 6H). C{ H} NMR

(101 MHz, CDCl3, δ): 167.36, 166.21, 140.29, 114.19, 75.61, 51.00, 36.74, 31.92, 29.45, 25.21,

-1 23.14, 22.78, 14.93, 14.22, 7.01, 4.96. IR (neat, cm ): 2954, 2933, 2875, 1721 (νCO), 1649,

1458, 1433, 1414, 1379, 1329, 1242, 1152, 1126, 1094, 1005, 978, 889, 820, 724. HRMS-ESI

+ (m/z): [M + Na] calcd for C20H40O3SiNa, 379.2644; found, 379.2646.

34 1 Compound 3q: H NMR (400 MHz, CDCl3, δ): 5.91 (s,

CH=C(Pr)CH, 1H), 4.15-4.12 (m, Et3SiOCH, 1H), 3.69 (s, OCH3, 3H), 2.83-2.76 (m,

CH=CCH2, 1H), 2.15-2.08 (m, CH=CCH2, 1H), 1.76-1.66 (m, CH(CH3)2, 1H), 1.57-1.29 (m,

CH=CCH2CH2 + CH2CH(CH3)2, 4H), 1.01-0.89 (m, CH3, 18H), 0.61-0.55 (m, SiCH2CH3, 6H).

13 1 C{ H} NMR (101 MHz, CDCl3, δ): 167.32, 166.80, 114.17, 74.47, 51.03, 46.59, 31.84, 24.52,

-1 23.73, 23.27, 22.27, 15.00, 7.03, 5.01. IR (neat, cm ): 2955, 2875, 1720 (νCO), 1650, 1463,

1434, 1414, 1384, 1367, 1329, 1305, 1240, 1155, 1131, 1085, 1002, 961, 900, 724. HRMS-ESI

+ (m/z): [M + Na] calcd for C18H36O3SiNa, 351.2332; found, 351.2326.

O SiMe3 MeO OSiEt 3r 3 1 Compound 3r: H NMR (400 MHz, CDCl3, δ): 7.31-7.23 (m,

4 4 ArH, 5H), 6.85 (d, JH-H = 1.3 Hz, CH=C(SiMe3)CH, 1H), 5.40 (d, JH-H = 1.3 Hz,

3 CH=C(SiMe3)CH, 1H), 4.24-4.18 (m, OCH2CH3, 2H), 1.32 (t, JH-H = 7.1 Hz, OCH2CH3, 3H),

3 3 0.90 (t, JH-H = 7.9 Hz, SiCH2CH3, 9H), 0.58 (q, JH-H = 7.9 Hz, SiCH2CH3, 6H), 0.00 (s,

13 1 Si(CH3)3, 9H). C{ H} NMR (101 MHz, CDCl3, δ): 167.57, 164.94, 141.79, 129.59, 128.36,

127.99, 127.77, 78.48, 60.49, 14.51, 7.04, 5.12, 0.10. IR (neat, cm-1): 2954, 2910, 2876, 1718

(νCO), 1598, 1454, 1413, 1368, 1307, 1244, 1185, 1085, 1039, 1004, 841, 726, 698. HRMS-ESI

+ (m/z): [M + Na] calcd for C21H36O3Si2Na, 415.20952; found, 415.20951.

35 1 Compound 3s: H NMR (400 MHz, CDCl3, δ): 6.61 (s,

3 CH=C(SiMe3), 1H), 4.39-4.37 (m, CH=C(SiMe3)CH, 1H), 4.17 (q, JH-H = 7.1 Hz, OCH2CH3,

3 2H), 1.32-1.25 (m, CH2 of the hexyl group + OCH2CH3, 13H), 0.95 (t, JH-H = 7.9 Hz,

3 SiCH2CH3, 9H), 0.92-0.86 (m, CH2CH2CH3, 3H), 0.57 (q, JH-H = 7.9 Hz, SiCH2CH3, 6H), 0.21

13 1 (s, SiCH3, 9H). C{ H} NMR (101 MHz, CDCl3, δ): 167.80, 167.58, 128.11, 75.12, 60.18,

38.68, 31.97, 29.42, 25.95, 22.78, 14.44, 14.23, 7.04, 5.00, –0.17. IR (neat, cm-1): 2955, 2933,

2876, 1719 (νCO), 1603, 1460, 1413, 1378, 1312, 1247, 1139, 1089, 1048, 1005, 843, 740, 681.

+ HRMS-ESI (m/z): [M + Na] calcd for C21H44O3Si2Na, 423.2727; found, 423.2723.

Procedure for the Conjugate Reduction of 3h

Following a similar procedure established for the conjugate reduction of α,β-unsaturated carbonyl compounds,26 1,3-bis(2,6-di-i-propylphenyl)imidazolium copper (I) chloride (8.0 mg,

0.020 mmol, 1 mol%) and NaOtBu (2.0 mg, 0.020 mmol, 1 mol%) were mixed in an oven dried flask under an argon atmosphere. About 1.0 mL of toluene was added and the mixture was stirred at room temperature for 10 min, followed by the addition of poly(methoxyhydrosiloxane)

(PMHS) (0.015 mL, 0.20 mmol, 1.0 equiv). After stirring the yellow solution at room temperature for 5 min, more toluene (2.0 mL) and PMHS (0.045 mL, 0.60 mmol, 3.0 equiv) were added. A solution of 3h (65 mg, 0.20 mmol, 1.0 equiv) and tBuOH (0.06 mL, 0.80 mmol,

4.0 equiv) in 1 mL of toluene was then added via a cannula. The reaction mixture was stirred at room temperature until all the starting material was fully converted. The reaction was quenched by water and treated with ethyl acetate. The organic layer was separated while the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with

26 Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003, 5, 2417.

36 brine, dried over anhydrous MgSO4, and concentrated under the vacuum. The crude product was purified by column chromatography and compound 6 was isolated as a yellow oil (57 mg, 95% yield).

F O

MeO

6 OSiEt3 1 H NMR (400 MHz, CDCl3, δ): 7.51-7.47 (m, ArH, 1H), 7.23-7.18 (m,

3 ArH, 1H), 7.14-7.09 (m, ArH, 1H), 7.00-6.95 (m, ArH, 1H), 5.12 (t, JH-H = 5.8 Hz, CHOSiEt3,

3 1H), 3.63 (s, OCH3, 3H), 2.44-2.29 (m, CH2CH2, 2H), 2.06-2.00 (m, CH2CH2, 2H), 0.88 (t, JH-H

13 1 = 7.9 Hz, SiCH2CH3, 9H), 0.57-0.50 (m, SiCH2CH3, 6H). C{ H} NMR (101 MHz, CDCl3, δ):

1 2 3 174.04, 159.22 (d, JC-F = 245.4 Hz, CF), 131.71 (d, JC-F = 14.1 Hz), 128.67 (d, JC-F = 7.1 Hz),

2 127.94 (d, JC-F = 4.0 Hz), 124.15 (d, JC-F = 5.1 Hz), 115.03 (d, JC-F = 22.2 Hz), 66.78, 51.61,

-1 34.25, 29.81, 6.83, 4.78. IR (neat, cm ): 2954, 2912, 2877, 1740 (νCO), 1616, 1587, 1487, 1456,

1437, 1415, 1366, 1270, 1224, 1159, 1107, 1087, 1067, 1003, 889, 841, 799, 756, 725, 568, 528.

+ HRMS-ESI (m/z): [M + Na] calcd for C17H27O3FSiNa, 349.1611; found, 349.1611.

Procedure for the Deprotection of Silyl Group

A similar procedure has been described in the literature.11e To a solution of 6 (or 3h for the synthesis of 8) in 3 mL of THF was added 1M solution of tetrabutylammonium fluoride in

THF (2 equiv). The reaction mixture was stirred at room temperature until all the starting material was fully converted. The reaction was then diluted with diethyl ether (10 mL/mmol) and washed with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under the vacuum. The crude product was purified on silica by column chromatography. Compounds 7 and 8 were isolated in 85 % and 76

% yield, respectively.

37 O O

F 7 1 Compound 7: H NMR (400 MHz, CDCl3, δ): 7.43-7.39 (m, ArH, 1H),

3 7.37-7.31 (m, ArH, 1H), 7.20-7.16 (m, ArH, 1H), 7.12-7.06 (m, ArH, 1H), 5.75 (t, JH-H = 7.2

13 1 Hz, OCHAr, 1H), 2.79-2.65 (m, CH2, 3H), 2.25-2.15 (m, CH2, 1H). C{ H} NMR (101 MHz,

1 3 2 CDCl3, δ): 176.83, 159.74 (d, JC-F = 248.5 Hz, CF), 130.11 (d, JC-F = 8.1 Hz), 127.07 (d, JC-F =

2 12.1 Hz), 126.63 (d, JC-F = 4.0 Hz), 124.60 (d, JC-F = 4.0 Hz), 115.79 (d, JC-F = 21.2 Hz), 76.38

3 -1 (d, JC-F = 3.0 Hz), 29.91, 28.63. IR (neat, cm ): 2950 (br), 1770 (νCO), 1618, 1589, 1490, 1457,

1420, 1375, 1328, 1297, 1236, 1212, 1189, 1171, 1138, 1101, 1038, 1021, 989, 941, 891, 833,

+ 811, 798, 755, 666, 601, 635, 602, 525. HRMS-ESI (m/z): [M + Na] calcd for C10H9O2FNa,

203.0484; found, 203.0480.

F O

MeO 8 O 1 Compound 8: H NMR (400 MHz, CDCl3, δ): 7.92-7.88 (m, ArH,

1H), 7.56-7.50 (m, ArH, 1H), 7.27-7.21 (m, ArH, 1H), 7.17-7.12 (m, ArH, 1H), 3.71 (s, OCH3,

3 13 1 3H), 3.35-3.31 (m, CH2, 2H), 2.76 (t, JH-H = 6.4 Hz, CH2, 2H). C{ H} NMR (101 MHz,

3 1 3 CDCl3, δ): 196.44 (d, JC-F = 5.1 Hz), 173.37, 162.32 (d, JC-F = 255.5 Hz, CF), 134.89 (d, JC-F =

4 2 3 9.1 Hz), 130.78 (d, JC-F = 2.0 Hz), 125.20 (d, JC-F = 13.1 Hz), 124.60 (d, JC-F = 3.0 Hz), 116.83

2 4 -1 (d, JC-F = 24.2 Hz), 51.93, 38.39 (d, JC-F = 8.1 Hz), 28.19. IR (neat, cm ): 2953, 1737 (νCO),

1688 (νCO), 1610, 1582, 1481, 1452, 1438, 1411, 1358, 1323, 1274, 1214, 1169, 1153, 1105,

+ 1069, 1026, 991, 950, 829, 765, 538. HRMS-ESI (m/z): [M + Na] calcd for C11H11O3FNa,

233.0590; found, 233.0588.

Procedure for the Reduction of 8, At 0 ºC under an inert atmosphere, a solution of 8

(200 mg, 0.95 mmol) in 2 mL of THF was added dropwise to a suspension of LiAlH4 (144.0 mg,

38 3.80 mmol, 4 equiv) in THF (3 mL). The reaction mixture was stirred at room temperature until all the starting material was fully converted. The excess LiAlH4 was carefully quenched at 0 ºC with 5 mL of EtOAc followed by 5 mL of water, at which point a white precipitate formed. The mixture was then acidified with 15 % HCl (ca. 4 mL) until it became a clear solution, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated under the vacuum. The crude product was purified by column chromatography to give compound 9 (167 mg, 95 % yield).

F

HO 9 OH 1 H NMR (400 MHz, CDCl3, δ): 7.42-7.38 (m, ArH, 1H), 7.19-7.14

3 (m, ArH, 1H), 7.08-7.04 (m, ArH, 1H), 6.96-6.92 (m, ArH, 1H), 4.94 (t, JH-H = 6.0 Hz, OCHAr,

1H), 4.29 (br s, OH, 2H), 3.57-3.46 (m, HOCH2, 2H), 1.78-1.73 (m, CH2, 2H), 1.65-1.50 (m,

13 1 1 CH2, 2H). C{ H} NMR (101 MHz, CDCl3, δ): 159.63 (d, JC-F = 246.4 Hz, CF), 131.74 (d,

2 3 3 4 JC-F = 13.1 Hz), 128.65 (d, JC-F = 8.1 Hz), 127.36 (d, JC-F = 4.0 Hz), 124.26 (d, JC-F = 3.0 Hz),

2 -1 115.15 (d, JC-F = 22.2 Hz), 67.65, 62.34, 35.03, 28.79. IR (neat, cm ): 3311 (br, νOH), 2941,

2361, 2338, 1717, 1616, 1586, 1487, 1454, 1269, 1221, 1178, 1042, 824, 754, 619. HRMS-ESI

+ (m/z): [M + Na] calcd for C10H13O2FNa, 207.0797; found, 207.0792.

Procedure for the synthesis of 10, A similar procedure has been described in the

27 literature. Compound 9 (48 mg, 0.26 mmol) and ZnCl2 (53 mg, 0.39 mmol, 1.5 equiv) were mixed with 5 mL of 1,2-dichloroethane in an oven-dried flask. The reaction mixture was stirred at 80 ºC until all the starting material was fully converted. The solution was diluted with 3 mL of CH2Cl2, and then washed with water and brine. The organic layer was separated and dried

27 Kim, S.; Chung, K. N.; Yang, S. J. Org. Chem. 1987, 52, 3917.

39 over anhydrous MgSO4. The crude product was purified by column chromatography to yield compound 10 (31 mg, 72 % yield).

O

10 F 1 H NMR (400 MHz, CDCl3, δ): 7.47-7.43 (m, ArH, 1H), 7.24-7.19 (m,

3 ArH, 1H), 7.14-7.10 (m, ArH, 1H), 7.03-6.98 (m, ArH, 1H), 5.14 (t, JH-H = 7.1 Hz, OCHAr,

1H), 4.13-4.08 (m, CHCH2O, 1H), 3.97-3.91 (m, CHCH2O, 1H), 2.44-2.36 (m, CH2CHArO,

13 1 1H), 2.04-1.97 (m, OCH2CH2, 2H), 1.83-1.74 (m, CH2CHArO, 1H). C{ H} NMR (101 MHz,

1 2 3 CDCl3, δ): 160.00 (d, JC-F = 246.4 Hz, CF), 131.03 (d, JC-F = 13.1 Hz), 128.59 (d, JC-F = 8.1

2 Hz), 126.99 (d, JC-F = 4.0 Hz), 124.17 (d, JC-F = 3.0 Hz), 115.25 (d, JC-F = 21.2 Hz), 75.25 (d,

3 -1 JC-F = 2.0 Hz, OCHAr), 68.82, 33.69, 26.15. IR (neat, cm ): 2977, 2870, 1617, 1588, 1485,

1455, 1364, 1273, 1229, 1185, 1151, 1103, 1059, 939, 923, 821, 753, 516, 493, 461. HRMS-ESI

+ (m/z): [M + Na] calcd for C10H11OFNa, 189.06861; found, 189.06857.

X-ray Structure Determination

Pale pink plate-like crystals of 5 were grown from hexane-ether. For X-ray examination and data collection, a suitable crystal, approximate dimensions 0.07 x 0.05 x 0.02 mm, was mounted in a loop with paratone-N and transferred immediately to the goniostat bathed in a cold stream. Intensity data were collected at 150 K on a Bruker APEX2 CCD detector at Beamline

11.3.1 at the Advanced Light Source (Lawrence Berkeley National Laboratory) using synchrotron radiation tuned to λ=0.77490 Å. A series of 4-s data frames measured at 0.2o increments of were collected to calculate a unit cell. For data collection frames were measured for a duration of 4-s at 0.3o intervals of ω with a maximum 2θ value of ~60o. The data frames were collected using the program APEX2 and processed using the program SAINT routine

40 within APEX2. The data were corrected for absorption and beam corrections based on the multi- scan technique as implemented in SADABS. The structure was solved by a combination of direct methods SHELXTL v6.14 and the difference Fourier technique and refined by full-matrix least squares on F2. Non-hydrogen atoms were refined with anisotropic displacement parameters. The H-atom positions were calculated and treated with a riding model in subsequent refinements. The isotropic displacement parameters for the H-atoms were defined as a*Ueq of the adjacent atom (a-1.5 for methyl and 1.2 for all others). The refinement converged with crystallographic agreement factors of R1=3.73%, wR2=8.88% for 7375 reflections with I>2σ(I)

(R1=5.24%, wR2=9.55% for all data) and 456 variable parameters.

41 Table 4. Crystal data and structure refinement for 5

42

Chapter 3

Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes

3.1 Introduction

Nickel-catalyzed coupling of alkyne and aldehyde was first reported in 1997,1 and since then many variants have been developed and they are usually categorized as either alkylative

(transferring a carbon substituent) or reductive (transferring a hydrogen atom) coupling reactions

(Scheme 1). Catalyst systems used in these reactions are generated from low valent nickel species stabilized by various ligands such as cyclooctadiene (COD), phosphines, and N- heterocyclic carbenes (NHCs). The most commonly used reducing agents (MR4) include silanes, organozinc, organoborane and vinylzirconium reagents.2

Scheme 1. Catalytic coupling of aldehydes and alkynes

R4 OH R2 O Ni(0) + + 4 M-R R1 R3 R1 R3 H R2

reductive coupling, R4 = H alkylative coupling, R4 = alkyl

The first report on nickel-catalyzed coupling of alkynes and aldehydes utilized ZnRʹ2 as the reducing agent to promote the alkylative cyclization of 5-hexynal derivatives for the synthesis of allylic alcohols (Scheme 2).1 It was also shown in this study that pre-treatment of

Ni(COD)2 with PBu3 caused the incorporation of hydrogen rather than an alkyl group during the reductive cyclization. However, hydrogen atom transfer was not observed for the analogues intermolecular three-component coupling reaction.

1 Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. 2 Montgomery, J.; Sormunen, J. Nickel-Catalyzed Reductive Couplings of Aldehyde and Alkynes. In Metal Catalyzed Reductive C-C Bond Formation-A Departure from Preformed Organometallic Reagents; Krische, M. J., ed.; Springer: Heidelberg, 2007; pp 3

44 Scheme 2. Organozinc-mediated intramolecular coupling of alkynes and aldehydes

R' Ni(COD)2 (2-20 mol%) O R HO R

' H ZnR 2 (2.5-3.0 eq), THF

Ph H3C Ph Et HO H HO H HO Me HO Ph

72% 70% 64% 67%

More efficient intermolecular reductive coupling of alkyne and aldehyde was later reported by Jamison and co-workers using organoboranes as reducing agents (Scheme 3).3

Scheme 3. Triethylborane-mediated intermolecular reductive coupling reaction

Ni(COD)2 10 mol% OH 2 R O PBu3 20 mol% + R1 R3 R1 R3 H Et B ( 2.0 eq), THF 3 R2

OH OH OH OH Me Ph Ph Ph Ph Ph nBu nHep Me TMS TMS Me

77% (92:8) 49% (98:2) 58%(98:2) 83% (93:7)

A more regioselective catalytic system for the intermolecular coupling of aldehydes and alkynes involves Ni(COD)2 in combination with NHC ligands and uses Et3SiH as the reducing

3 Huang, W. S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221.

45 agent. Under this catalytic system a broad range of alkynes and aldehydes are shown to undergo desired reductive coupling reaction (Scheme 4).4

Scheme 4. Triethylsilane-mediated intermolecular reductive coupling reaction

Ni(COD)210 mol% IMes HCl 10 mol% OH N N O R3 KOtBu 10 mol% Mes Mes + + Et3SiH Cl- R1 R3 R1 H R2 THF 2 eq. R2 IMes HCl

OH OH OH OH

n Ph Ph Ph Ph Hex Ph Ph nHex Me Me Me

84% (98:2) 72% (98:2) 82% (98:2) 71% (98:2)

Related catalytic systems have been developed for highly regioselective and enantioselecetive reductive coupling reactions.5 The reaction catalyzed by the combination of

NiCl2 and PPh3 in the presence of CrCl2 as the reducing agent is complementary to the reductive

6,7 coupling processes described above. In contrast to the method involving Et3B and Et3SiH the coupling of terminal alkynes promoted by CrCl2 gives the more branched regioisomers (Scheme

5).

4 Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. 5 Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568. 6 Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653 7 Takai, K.; Sakamoto, S.; Isshiki, T.; Kokumai, T. Tetrahedron 2006, 62, 7534

46 Scheme 5. Chromium (II) chloride-promoted intermolecular reductive coupling reaction

CrCl OH R2 O 2 + R1 H R1 H NiCl2, PPh3 R2 H2O, DMF

OH OH OH

Ph n-C8H17 n-C10H21 n-C10H21 Ph

80% (96:4) 79% (90:10) 82% (95:5)

During the past few years, nickel-catalyzed reductive coupling reactions have become an increasingly useful method for the construction of complex molecules. The advantage of this methodology offers the opportunity to build elaborate molecules from simple π-components and main group organometallic reagents. Despite the emergence of various reductive coupling reactions many mechanistic questions remain to be answered. A better understanding of the mechanistic details would provide important guidelines for further catalyst development. The following section summarizes our current mechanistic understanding of nickel-catalyzed reductive coupling reactions.

3.2 General Mechanistic Consideration

Various pathways have been proposed to account for the reductive coupling reactions.

Three main mechanisms are illustrated in Scheme 6, and they differ by how Ni(0) is converted to

Ni(II) species.8 In mechanism (a) the coupling process is initiated by the oxidative cyclization of nickel (0) with two general π-components, E=F and G=J, to generate metallacycle 4. This step is followed by the transmetallation of a metal alkyl species MR to give 5. Finally, a reductive

47 elimination step affords the final product 6. Oxidative addition of the reducing agent MR to

Ni(0) to form a reactive metal hydride or alkyl 7 initiates the process in mechanism (b). The two

π-components E=F and G=J undergo sequential migratory insertion to yield 8 followed by reductive elimination to give product 6. In mechanism (c) oxidative addition of one of the π- components E=F to nickel (0) is facilitated by a Lewis acid (M´X). The resulting nickel alkyl 9

(often a π-allyl complex) reacts with the second π-component G=J, followed by transmetallation of MR and reductive elimination to generate the final product 6. These three mechanisms are oversimplified illustrations and obviously many variations are possible. Coordination number for nickel, association of reactive components, and changes in the hapticity of unsaturated reactive ligands are not specified in the mechanisms summarized in Scheme 6. Furthermore, mechanisms involving cyclizations of free radicals, radical anions, or paramagnetic nickel intermediates are also possible.8

Scheme 6. Common mechanisms for three-component coupling reactions

Ni(0) M E J R E=F + G=J + MR F G (MR = reducing agent)

(a) Oxidative cyclization of two π−components

Ln Ln Ni NiL Ni E J E=F + G=J n E J F G F G 4

L MR n M E J R M E J Ni F G F G R 5 6

48 (b) Oxidative addition of the reducing agent and susbsequent insertions of π-components

M M NiLn G=J MR LnNi LnNi R R G J 7

M E=F M E J R LnNi G J E F R F G 8 6 (c) Oxidation of Ni(0) promoted by a Lewis acid

G J NiL LnNi X G=J E=F + M'X n M' M' E F E F LnNi X (M'X = Lewis acid) 9

MR G J M' M' E J R E F LnNi R F G MX 6

3.3 Previous Mechanistic Studies on Nickel-Catalyzed Reductive Coupling of Alkynes and

Aldehydes

The first report on nickel-catalyzed coupling of alkynes and aldehydes showed interesting

8 mechanistic features (Scheme 7). When Ni(COD)2 was employed as the catalyst and ZnEt2 was utilized as the reducing agent, ynals were cyclized to produce allylic alcohols 12 with alkyl transfer at the terminal position of the exocyclic double bond. A reductive coupling pathway to Scheme 7. Ligand dependent reductive coupling reactions β-hydride H elimination HO R H3C L = PBu3 O R Ni(COD) (2-20 mol%), L Ni 2 L EtZnO n R 11 H reductive ZnEt2 (2.5-3.0 eq), THF Et elimination HO R 10 L = THF or COD

12

8 Hasnain, A. M.; Baxter, R. D.; Montgomery, J. In Catalysis Without Precious Metals; Bullock, R. M, Ed.; Wiley: 2010; pp 200.

49 install a hydrogen atom at the distal carbon of the newly formed double bond in 11 was achieved with the combination of Ni(COD)2 and PBu3. This change in reaction mechanism is exclusive to intramolecular version of the reaction. This phenomenon of changing from alkylative to reductive coupling suggests that changing electronic or steric environment at the nickel center can alter the reactivity drastically. β-hydride elimination is enabled at the nickel center by the σ- donation of the phosphine ligands, leading to the formation of reductive coupling product 11.

It has been postulated that oxametallacycles 13 are involved in this transformation as shown in Scheme 8. Buchwald and Crowe have proposed analogous titanacycles in reductive cyclization of enones and enals respectively.9,10 Nickel-oxygen bond is cleaved in a σ-bond metathesis type process to generate a nickel-intermediate 14. This intermediate is a nickel

4 hydride (R = H) when Et3SiH is used as the reductant. Subsequent reductive elimination regenerates the catalyst while releasing product 17. When organoboranes, organozincs or alkenylzirconium reagents are used, the intermediate 14 becomes an alkyl or alkenyl nickel species. Direct C-C reductive elimination from 14 would generate alkylative coupling product

16. However, β-hydride elimination of the R group would afford the reductive coupling product

15.

9 Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 118, 6785 10 Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787

50 Scheme 8. Mechanism involving a metallacycle

Ln R2 O 1 Ni Ni(COD) , L R O + 2 R1 H R3 R2 R3 13

MR4

R4 H OH R4 = alkyl 4 NiL OM R4 = alkyl or aryl R OH with β−Η n R1 R3 L = THF 1 3 L = PR3 R1 R3 R R R2 2 R2 R 15 14 16

H OSiEt3 (MR4 = Et SiH) R1 R3 3 R2 17

In addition to the mechanism involving a metallacycle, sequential insertion pathways are also possible (Scheme 9).9 To begin the process, silane undergoes oxidative addition to Ni(0) form intermediate 18. Next, 18 could be converted to the final product 17 by hydrometallation of the alkyne (leading to intermediate 19) or by silylmetallation of the aldehyde (leading to intermediate 20).

51 Scheme 9. Mechanisms without a metallacycle intermediate

SiEt3 L Ni Ni(COD)2 + L + Et3SiH n H 18

R1 R2 R3CHO

R2 R1 R3 O SiEt3 LnNi H LnNi 19 20 SiEt3 H

O R1 R2 H R3

O O R2 2 3 1 2 Et3SiO H R R1 3 R R R 3 R1 H R H R L Ni H L Ni SiEt3 O 1 n n SiEt R3 R LnNi 3 Et3SiH LnNi H 22 17 R2 21

Nickel(I) hydride species 21 or nickel silyl species 22 could also be involved in a similar sequential insertion pathway (Scheme 9). To differentiate these mechanisms from those in

4 Scheme 9, crossover experiments had been developed using both Et3SiD and Pr3SiH. In this study, reductive coupling of benzaldehyde and 1-phenylpropyne was examined in the presence of 1 equiv of Et3SiD and 1 equiv Pr3SiH using a catalyst generated from Ni(COD)2 and IMes

(Scheme 10). Products 24 and 25 were cleanly produced in comparable amounts, and only <1% of crossover products 23 and 26 were observed.

52 Scheme 10. Intermolecular crossover experiment

X OSiR3 O Ph Et SiD Ni(COD) + + 3 2 + Ph Ph Ph H H C 3 Pr SiH IMes 3 CH3

H OSiEt3 D OSiEt3 H OSiPr3 D OSiPr3

Ph Ph Ph Ph Ph Ph Ph Ph CH3 CH3 CH3 CH3 23 24 25 26 <1 % 48 % 50 % <1 %

In the same report, intramolecular couplings of ynal 27 was examined using Ni(COD)2 in combination with IMes (Scheme 11). The results were similar to those in intermolecular coupling reaction, as not much of crossover products were observed. However, when PBu3 was used in place of IMes, a significant amount of crossover products were observed (Scheme 11).

These crossover experiments demonstrate that the mechanisms for the two catalytic systems are

Scheme 11. Intramolecular crossover experiment X Ni(COD)2 O Ph Et SiD (1 eq) Ph OSiR3 + 3

H Pr3SiH (1 eq) L 27

H D H D Ph OSiEt3 Ph OSiEt3 Ph OSiPr3 Ph OSiPr3

28 29 30 31 L = IMes <2 % 55 % 41 % <2 %

L = PBu3 25 % 34 % 23 % 18 % fundamentally different. The mechanism outlined in Scheme 8 or the top part of Scheme 9 would be consistent with no crossover product formation. On the other hand, crossover products

53 are expected if intermediate 21 or 22 is involved in the coupling reaction.

Ogoshi and co-workers have shown direct evidence for the existence of a nickel- metallacycle intermediate in alkyne aldehyde coupling reactions.11 They were able to obtain the crystal structure of a dimeric oxametallacycle 32 from a Ni(COD)2/PCy3 mediated reaction between benzaldehyde and 2-butyne (Scheme 12).

Scheme 12. Generation of nickeladihydrofuran

Ph 1. Ni(COD) / PCy O 2 3 toluene, RT, 1 hr O PCy3 + Ni Ni Ph H 2. toluene/n-hexane Cy3P O -20 oC, 24 hr Ph 32

In the presence of ZnMe2, PCy3 and excess PhCHO, complex 32 undergoes slow conversion to product 33 (Scheme 13). These results support that the three-component coupling of alkyne, aldehyde and organozinc proceeds via a nickeladihydrofuran followed by reductive elimination.

Scheme 13. Reaction of nickeladihydrofuran 32 with ZnMe2

Ph 1. PhCHO (20 eq) O PCy 3 PCy3 (2 eq) Ph Ni Ni + ZnMe2 Cy3P O THF, -20 oC to RT OH 30 min Ph 2. H+ 32 33

Ph H+ Ph OZnMe Ni OZnMe Cy3P Me

11 Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem. Commun. 2008, 1347.

54 Houk and Jamison have carried out a computational study on the mechanism of nickel- catalyzed reductive coupling of alkyne and aldehyde with PMe3 as the supporting ligand and

12 Et3B as the reducing agent (Scheme 14). Mechanistic pathway A involving rate-determining formation of metallacycle 37 was found to be favored. An alternative pathway B in which Et3B is bonded to nickel was found to be energetically less accessible than pathway A. Another possible pathway would be the oxidative addition of the reductant Et3B followed by sequential addition of π-components (Scheme 9). However, the transition states were not located and it was found that the reactant complexes (21 and 22) of that mechanism are higher in energy than that of path A.

Scheme 14. Theoretical study on reductive coupling of aldehyde and alkyne

Et3B L L R1 Ni BEt 1 Ni O 3 R O

R2 38 R3 2 3 Transmetalation L Oxidative R R Oxidative R1 37 (alkyl migration) Ni cyclization cyclization L 34 Path A

R2 L R1 BEt3 Et3B Ni O L L L Et R R1 1 Ni O Ni R3 1 Ni O Path B R2 R O BEt2 R3 36 R R3 R2 H 2 R2 R3 35 39

OBEt2 hydride + H L β− R1 R3 elimination and R1 Ni 41 R2 reductive elimination R2 O R2 OBEt2 + R R 3 1 H R3 40

12 McCarren, P. R.; Liu, P.; Cheong, P., H-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6654.

55 Recently, Montgomery and co-workers have reported kinetics study of intramolecular reductive coupling of ynal.13 Their data are also consistent with a metallacycle mediated reaction pathway. This will be discussed in detail in the following section.

3.4 Mechanistic Studies of the Coupling of Ynoates and Aldehydes

Despite many mechanistic studies on reductive coupling reactions, ambiguities still exist, particularly for nickel-catalyzed reactions. Having developed a new class of nickel-catalyzed reductive coupling reaction of ynoates and aldehydes (Scheme 15, also see Chapter 2) we became interested in elucidating the mechanism of this reaction. Efforts were made to distinguish between possible mechanistic pathways for this transformation.

Scheme 15. Nickel-catalyzed coupling of ynoates and aldehydes

Ni(COD)2 (10 mol%) SIPr HBF (10 mol%) O O 4 Ph KOtBu (10 mol%) MeO MeO O PPh (10 mol%) + 3 OSiEt + PhCHO + Et3SiH 3 Ph OSiEt MeO THF, 23 oC 3a 3 1 2a 3a' minor product

3.4.1 Mechanistic Hypothesis

One of our mechanistic hypotheses for the aforementioned coupling reaction is outlined in Scheme 16 using 1 and PhCHO as representative substrates. Oxidative cyclization of 1 and

PhCHO would generate oxanickellacycles 42 and 43 depending on the orientation of the ynoates during the metallacycle formation. Metallacycle 42 leads to the formation of the major product

3a, while 43 yields the minor product 3aʹ.

13 Baxter, R. D.; Montgomery, J. J. Am. Chem. Soc. 2011, 133, 5728.

56 Scheme 16. Proposed mechanism based on metallacycle intermediates

O H OSiEt OSiEt3 MeO 3 O 3a Ph Ph OMe 3a' L O L H Ni H Ni OSiEt LNi(0) OSiEt3 MeO 3 PhCHO O Ph Ph OMe LNi Ph Et SiH Et SiH 3 O 3 H O O L L Ni MeO Ni O O MeO

Ph O Ph 42 OMe 43

An alternative mechanism can be proposed based on oxidative addition of Si-H to nickel center followed by sequential insertion of 1 and PhCHO as outlined in Scheme 17.

Scheme 17. Alternative mechanism without a metallacycle intermediate

Et3SiO H Et3SiO H

Ph H Ph CO2Me L CO2Me H Ni Ni L Et3Si O H Et3Si O H LNi(0) Ph H Ph CO2Me Et3SiH CO2Me H HC CCO2Me CO Me H 2

Et3Si Ni 44 L H H H L L H PhCHO CO2Me Et3Si Ni Et3Si Ni H CO Me H H O 2 O Ph Ph 45 46

57 3.4.2 Deuterium Labeling Studies

To gain an initial insight into the mechanism of this reaction, we first conducted two deuterium-labeling studies. Consistent with the mechanism proposed in Scheme 16, selectively labeling the silane hydrogen with deuterium gave rise to 3a-D with deuterium exclusively at the

α-position (Scheme 18). This result does not necessarily rule out the mechanism involving the

Scheme 18. Deuterium-labeling studies O optimized O conditions Ph + PhCHO + Et3SiD MeO MeO 1 D OSiEt3 3a-D O O optimized conditions Ph + PhCDO + Et3SiH MeO MeO 1 H D OSiEt3 3a-D activation of silane first, followed by sequential insertions of ynoate and aldehyde (Scheme 17).

However, transition-metal-catalyzed hydrosilylation of ynoates with analogous silane activation and alkyne insertion typically leads to the addition of silane hydrogen to the β-carbon (via intermediate 45).14,15 If this mechanism is operating, we should have seen high selectivity for

3aʹ. An experiment was further conducted using the standard conditions but in the absence of an aldehyde to see the selectivity for silylated product if ynoates ever undergo hydrosilylation

(Scheme 19). Analysis of reaction products by GC-MS and NMR confirmed no hydrosilylation products; instead the products from the cyclotrimerization of ynoates were detected. A similar experiment (Scheme 18) using PhCDO yielded 3a-D with deuterium at the carbon center originating from the aldehyde, suggesting that activation of aldehyde hydrogen is unlikely.

14 Rooke, D. A.; Ferreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3225. 15 Tsipis, C. A.; J. Organomet. Chem. 1980, 187, 427.

58 Scheme 19. Attempted hydrosilylation of ynoate 1

Ni(COD)2 10 mol% O O O SIPr HBF4 10 mol% KOtBu 10 mol% MeO + Et3SiH MeO + MeO SiEt3 1 THF, 23 oC SiEt 1.1 eq 3 Expected products

3.4.3 Kinetics Studies of a Related System Reported by Montgomery

To further distinguish between the mechanism involving initial silane activation and the metallacycle mechanism, kinetics studies were conducted. Montgomery and co-workers have reported the first kinetics study of intramolecular coupling of alkyne and aldehyde catalyzed by nickel in combination with trialkyl phosphines.14 They have evaluated specifically the mechanism of nickel-catalyzed and silane mediated coupling of ynal 47 (Scheme 20). Their study revealed that the cyclization reaction is first order with respect to both the catalyst and the ynal, and zeroth order with respect to the silane. These results are consistent with a mechanism Scheme 20. Nickel-catalyzed coupling of ynal 47

O H Ni(COD)2 10 mol% Ph OSiEt3 PCy3 20 mol% H Ph + Et3SiH THF , RT

47 48 involving a metallacycle intermediate and suggest that oxidative cyclization of the ynal is the rate-determining step. The fact that the rate is independent of [Et3SiH] rules out mechanistic scenarios involving initial oxidative addition of silane to nickel. While informative, the disadvantage of studying intramolecular coupling of alkyne and aldehyde is that it provides no information on which substrate gets activated first at the nickel center. Furthermore, their system uses a phosphine as the only supporting ligand and our study presents a good opportunity to

59 evaluate NHC’s role in mechanistic aspects of these reductive coupling reactions, especially in an intermolecular reaction.

3.4.4 Screening Conditions for the Kinetics Study

The main challenge for the kinetics study of our intermolecular reductive coupling reaction is the slow addition of ynoate over a long period of time to prevent its cyclotrimerization

(see Chapter 2). This operational procedure would complicate the kinetics studies. Therefore the first step would be to identify an ynoate substrate that does not need to be added slowly.

Fortunately, during our study of substrate scope, we were able to identify ynoate 1r as a suitable substrate for this purpose.

O

EtO TMS 1r

The initial plan was to study the progress of the reaction of 1r, PhCHO and Et3SiH by monitoring the disappearance of 2a with in situ IR spectroscopy (eq 1). Unfortunately, the C=O

Ni(COD) 10 mol% 2 O TMS O O SIPr HBF4 10 mol% t Ph KO Bu 10 mol% + TMS + EtO EtO (1) EtO PhCHO + Et3SiH THF, 23 oC OSiEt3 1r TMS 2a 3r Ph OSiEt3 3r' stretch band of the aldehyde (1707 cm-1) and that of the ester 1r (1715 cm-1) are overlapped, making the combination of these two substrates not viable for the kinetics data collection.

Efforts were made to screen different aldehydes that would have C=O absorption well separated from that of 1r. Benzaldehyde with a different ortho and para substituent and two aliphatic aldehydes were found to be reactive with 1r but their C=O IR absorption band remain

60 2-Me H O 2-Cl 2-F O H R' = 4-Me H 4-OMe R' 4-tBu O Chart 1 overlapped with that of the ester (Chart 1). In contrast, aldehydes shown in Chart 2 have well separated absorption from the ester group of 1r, but unfortunately they do not react with 1r.

O O O H H O H H O O Me N 2 CHO Chart 2

Fortunately, aldehyde 2k was shown to be a reactive substrate and having an IR absorption (1733 cm-1) well separated from the carbonyl band of 1r. Monitoring the disappearance of 2k in the presence of 10 mol% catalyst (eq 2) was conducted by measuring IR absorption at 1715 cm-1 continuously. The trend line setup to track the changes of [2k] was

O

H

MeO2C 2k decreasing in the beginning of the reaction, indicating the disappearance of the reactant being monitored. Surprisingly, after some time the trend line started growing, possibly due to the overlap of IR absorptions of 2k with absorptions from the products. It was later found out that the main product 3t has an absorption at 1720 cm-1 for the ester group.

61 O Ni(COD)2 10 mol% CO Me O CHO 2 EtO TMS SIPr HBF4 10 mol% O TMS KOtBu 10 mol% EtO + + Et SiH + OSiEt3 (2) 3 EtO TMS o 1r THF, 25 C OSiEt3 MeO2C CO2Me 3t 3t' 2k

However, in the same reaction an IR absorption at 1233 cm-1 attributed to the C-O stretch of the ester group in 1r, showed a decay over the reaction time without any interference. It was then decided to use this absorption to monitor the kinetics for the reaction given in eq 2.

After determining the conditions to collect kinetics data, the next goal was to examine the dependence of the rate of the reaction (eq 2) on the concentrations of substrates and the nickel- catalyst. We commenced our study with determining initial rates by varying the concentration of the 1r. After several runs, it was obvious that the data collected with the catalytic system

t generated in situ from Ni(COD)2, SIPr•HBF4 and KO Bu were not reproducible. This could be due to high air/moisture sensitivity of the catalyst mixture, resulting in change in the concentration of the active catalyst between different runs. Another possibility would be errors associated with weighing of all three components in the catalyst mixture. As a solution to this issue, we turned to an alternative catalytic system, which could be used as a pre-catalyst to avoid the need of having to weigh several components to generate the catalyst in situ. Using a more stable catalyst would be ideal, as it would increase the reproducibility of the catalyst concentration in the reaction mixture. We had identified (1,5-hexadiene)Ni(SIPr) (Ni-SIPr) 16

Ni SIPr

Ni-SIPr

16 Wu, J.; Faller, J.; Hazari, N.; Schmeier, T. Organometallics 2012, 31, 806.

62 complex, previously developed by Hazari and co-workers for alkene hydrogenation, as a viable catalyst for the coupling of ynoates and aldehydes.

The reaction conditions were optimized for the coupling between 1a and 2a using the Ni-

SIPr pre-catalyst (Table 1). Combined yield of 3a and 3aʹ (90:10) was determined using GC-MS by varying the catalyst loading and concentration.

Table 1. Optimization of the reaction conditions

O O O Ni-SIPr Ph MeO + MeO + PhCHO + Et3SiH MeO THF, 23 oC OSiEt3 1a 2a 3a Ph OSiEt3 3a'

Entry Ni-SIPr (mol %) [Ni-SIPr] (M) Yield (%) 1 10 0.02 98 2 5 0.005 40 3 2.5 0.0025 12 4 5 0.025 93

Ni-SIPr pre-catalyst appeared to be more active (entry1, Table 1) than the in situ

t generated catalyst from Ni(COD)2, SIPr•HBF4 and KO Bu (see Table 1 in Chapter 2). Since this complex is more active and air and thermally more stable than the aforementioned catalyst mixture, we decided to use this pre-catalyst in our kinetics studies. This would eliminate the difficulties associated with defining the active catalytic species in the reaction using in situ generated catalysts. Interestingly, the reaction between 1r and 2k catalyzed by Ni-SIPr is shown to be highly selective, producing only the 1,4-difuntionalized product 3t.

O CHO CO2Me 5 mol % Ni-SIPr O TMS (3) EtO + + Et SiH 1r 3 EtO TMS THF, 25 oC 1 eq 3t OSiEt3 1 eq 2k CO2Me 1 eq

63 3.4.5 Kinetics Experiments

Monitoring the disappearance of 1r in the presence of 5 mol% of Ni-SIPr catalyst in real time via in situ IR spectroscopy and converting the absorbance values to concentrations using a calibration plot gave the reaction profile as shown in Figure 1. Initial rates were calculated by considering data points up to 30% conversion of the 1r. In order to determine the order with respect to each component (ynoate 1r, aldehyde 2k, Et3SiH and Ni-catalyst Ni-SIPr) in the reaction, initial rates were determined by changing their initial concentrations. The value of the order for a given reaction component was determined by plotting the natural log of the initial rates versus to the natural log of the component initial concentrations.

0.12

0.1

0.08

0.06 [1r] (mol/L) [1r] 0.04

0.02

0 0 2000 4000 6000 8000 Time (Seconds)

Figure 1. Reaction profile

64 Under the reaction conditions illustrated in eq 4, measuring initial rates against systematic variation of the concentration of nickel-catalyst, Ni-SIPr (5-12.5 mol%, 0.005-0.0125

M) generated Figure 2.

O CHO CO2Me 5 -12.5 mol % Ni-SIPr O TMS (4) EtO + + Et3SiH 1r TMS THF , 25 oC EtO 1 eq 3t OSiEt3 1 eq 2k CO2Me 1 eq

30 25 (M/s) (M/s)

-6 20

t x 10 15 Δ 10 [1r]/ Δ 5 0 0.000 0.005 0.010 0.015 0.020 [Ni-SIPr] (M)

Figure 2. Rate dependence on [Ni-SIPr]

When calculating the reaction order using the data from Figure 2, it turned out to be 1.56 with respect to nickel catalyst. Close inspection of the data revealed that the initial rate at 5 mol% (0.005 M) catalyst loading is exceptionally low. If we were to consider only the higher concentrations (0.0075, 0.01 and 0.0125 M) the reaction order would become 1.10. This suggests that the initial rate value obtained at the lowest catalyst loading causes a significant change in the calculated order for Ni-SIPr. The reason for obtaining an inconsistent rate at 0.005

M catalyst concentration could be due to substantial decomposition of catalyst at this diluted

65 catalyst level. Intrigued by this analysis, we decided to conduct another series of experiments with 0.015 M catalyst concentration (Figure 3). Reaction order in Ni-SIPr calculated using initial rates at 0.0075-0.015 M nickel catalyst was 1.04. According to Figure 3 reaction rate shows a linear dependence on [Ni-SIPr].

30 25 (M/s) (M/s)

-6 20

t x 10 15 Δ 10 [1r]/ Δ 5 0 0.000 0.005 0.010 0.015 0.020 [Ni-SIPr] (M)

Figure 3. Rate dependence on [Ni-SIPr] Under the reaction conditions given in eq 5 the reaction rate shows an inverse linear dependence on [1r] in the concentration range of 0.05 M-0.125 M of 1r (Figure 4).

O CHO CO2Me TMS 5 mol % Ni-SIPr O (5) EtO + + Et SiH 3 o 1r TMS THF , 25 C EtO 1 eq 3t OSiEt3 0.75- 0.25 eq 2k CO2Me 1 eq

66 12

10 (M/s) (M/s)

-6 8

6 t x 10 Δ 4 [1r]/ Δ 2

0 0 0.04 0.08 0.12 0.16 [1r] (M)

Figure 4. Rate dependence on [1r]

Under the optimized reaction conditions described in eq 6 the reaction rate shows a linear dependence on [2k] in the concentration range 0.1 M-0.25 M of 2k (Figure 5).

O CHO O TMS 5 mol % Ni-SIPr Ph EtO (6) EtO + + Et3SiH 1s o TMS THF , 25 C OSiEt3 1 eq 3t 1 eq 2k CO2Me 1-2.5 eq

67 16 14 12 (M/s) (M/s)

-6 10 8 t x 10

Δ 6

[1r]/ 4 Δ 2 0 0 0.1 0.2 0.3 [2k] (M)

Figure 5. Rate dependence on [2k]

Under the optimized reaction conditions in eq 7 the reaction rate shows a zero-order dependence on [Et3SiH] in the concentration range 0.1 M-0.4 M of Et3SiH (Figure 6).

O CHO CO2Me TMS 5 mol% Ni-SIPr O EtO + + Et SiH (7) 3 o EtO 1s TMS THF , 25 C 1-4 eq 3t OSiEt3 1 eq 2k CO2Me 1 eq

68 10

8 (M/s) (M/s) -6 6 t x 10 Δ 4 [1r]/ Δ 2

0 0.0 0.1 0.2 0.3 0.4 0.5

[Et3SiH] (M)

Figure 6. Rate dependency on [Et3SiH]

3.4.6 Kinetic Isotope Effect

To further distinguish the mechanisms shown in Schemes 16 and 17 a competition kinetic isotopic study was performed to gain an insight into the Si-H bond cleavage (eq 8). No competition kinetic isotopic effect was observed (kH/kD = 1.0) for the reaction between 1r and 2k in the presence of 5 mol% of [Ni-SIPr] (eq 8). This result suggests that it is unlikely for oxidative addition of Si-H to nickel to be involved in the rate-limiting step.

CO2Me O CHO O TMS Ni-SIPr 5 mol% (8) EtO + + Et3SiH EtO 1s THF (0.1 M), 25 oC TMS + H/D OSiEt Et SiD 3 1 eq 3 2k 3t/3t-D CO2Me 1 eq each 1 eq H/D = 50:50 KIE = 1.0

69 3.4.7 Kinetics Model

Considering the kinetics data, deuterium labeling studies and kinetic isotope effect, we have developed the following kinetics model for the Ni-SIPr catalyzed reductive coupling of ynoates 1r and aldehyde 2k in the presence of Et3SiH. One of the main objectives of the kinetics analysis was to examine which substrate gets activated first at the metal center. The inverse first-order dependence on [1r] suggests that there is a pre-equilibrium process occurring before the rate-determining metallacycle formation (Scheme 21). The final product is generated via σ- bond metathesis type reaction mediated by Et3SiH, which is a faster process. The rate law for this reaction can be derived as shown in Scheme 21.

Scheme 21. Kinetics model

O

EtO TMS EtOC Y TMS [I] [Y] Keq Keq = (1) (SIPr) Ni + [M] TMS EtO O EtO2C [Ni] = [I] + [M] (2) M (SIPr)Ni I [I] [Y] [I] ([Y] + Keq) TMS [Ni] = [I] + = (3) Keq Keq

OHC CO2Me k2 rate = k2 [I] [RCHO] (4)

solving [I] from eq 3 and substituting it in eq 4 EtOC TMS k2 Keq [Ni] [RCHO] rate = (5) (SIPr) Ni [Y] + K O eq

if [Y] >> Keq CO2Me Et3SiH

k2 Keq [Ni] [RCHO] rate = CO Me [Y] O TMS 2

EtO H OSiEt3

70 3.5 Conclusions

In summary, the kinetics of nickel-catalyzed and Et3SiH mediated intermolecular reductive coupling of ynoate and aldehyde have been studied. This is the first such study performed for an intermolecular reductive coupling reaction using a nickel-NHC based catalytic system. Data gathered from initial rates, deuterium-labeling studies, and kinetic isotope effect are consistent with a reaction pathway involving a rate-determining oxidative cyclization to form a metallacycle intermediate, followed by fast silane-mediated generation of the final product.

Inverse dependence of rate on [ynoate] indicates that the alkyne component binds to the nickel center first. An initial oxidative addition of the Si-H to nickel followed by the sequential insertion of the substrates can be ruled out based on these data.

3.6 Experimental

General Experimental Methods

All the reactions were carried out in flame-dried glassware under an argon atmosphere using standard glove box and Schlenk techniques. Dry and oxygen-free THF were collected from an Innovative Technology solvent purification system and used throughout the experiments. The ynoate 1r was purchased from Acros Organics and used without further

17 purification. Ni-SIPr was synthesized according to a literature procedure. Et3SiH and aldehyde

2k were purchased from Aldrich and used without further purification. In situ FTIR data were acquired using a Remspec Reactor-IRTM module equipped with a ZnS-tipped probe.

General procedure for Ni-SIPr-catalyzed reductive coupling of ynoates and aldehydes

In a Schlenk flask Ni-SIPr (14 mg, 0.025 mmol, 0.05 equiv) was weighed and dissolved in 4 mL of THF at room temperature (23 oC). 1r (95 µL, 0.5 mmol, 1.0 equiv), 2k (82 mg, 0.5

71 mmol, 1.0 equiv) and triethylsilane (80 µL, 0.5 mmol, 1.0 equiv) were combined in 1 mL of THF and added to the catalyst mixture all at once via a syringe. The reaction mixture was stirred at room temperature until all the starting materials were consumed. Upon completion, the reaction mixture was concentrated under vacuum. The desired 1,4-difunctional compound was purified using column chromatography (eluted with diethyl ether/hexanes) to yield 3t (218 mg, 97%) as a colorless oil. Characterization data for 3t are listed below.

CO2Me O TMS

EtO 3t OSiEt3 1 Compound 3t HNMR (400 MHz, CDCl3, δ): 7.98 (d, J = 8.0

Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.83 (s, 1H), 5.42 (s, 1H), 4.21 (q, J = 6.8 Hz, 2H), 3.89 (s,

3H), 1.32 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.9 Hz, 9H), 0.62-0.56 (m, 6H), 0.00 (s, 9H); 13C{1H}

NMR (101 MHz, CDCl3, δ), 167.17, 166.99, 164.08, 147.08, 130.44, 129.64, 129.42, 127.56,

-1 78.42, 60.50, 52.16, 14.39, 6.91, 4.98, 0.09; IR (neat cm ) 2953, 2877, 1720 (νCO), 1610, 1458,

1435, 1411, 1369, 1304, 1275, 1244, 1186, 1083, 1037, 1004, 971, 905, 838, 811, 728, 707, 616,

+ 579, 535, 494; HRMS-ESI (m/z) [M + Na] calcd for C23H38O5Si2Na 473.2155, found 473.2154.

General procedure for determining initial rates: In-situ monitoring of reductive coupling of ynoates and aldehydes

Under an inert atmosphere Ni-SIPr (14 mg, 0.025 mmol, 0.05 equiv) was weighed in a 10 mL scintillation vial equipped with a Teflon septum and dissolved in 4 mL of THF at room temperature (23 oC). The IR probe of the reactor IR was inserted through the center neck of a 25 mL three-necked flask via argon purged Teflon adapter under a positive argon pressure. The flask with the probe was immersed in a constant temperature bath, which was set at 25 oC. A background spectrum was acquired after temperature was equilibrated (at least 15 min). The

72 catalyst mixture was transferred into the flask by a cannula and it was allowed to equilibrate for at least 15 min. Solvent subtracted spectra were acquired at 60 second intervals for approximately 15 min until the baseline of the IR spectrum at 1233 cm-1 (ynoates C-O stretch band) and solution temperature had stabilized. 1r (95 µL, 0.5 mmol, 1.0 equiv), 2k (82 mg, 0.5 mmol, 1.0 equiv) and Et3SiH (88µL, 0.5 mmol, 1.0 equiv) were combined in 1 mL of THF in a

10 mL scintillation vial equipped with a Teflon septum and added to the catalyst solution all at once via a cannula. The progress of the reaction was monitored by observing absorbance of the ynoate C-O stretch as a function of time. Absolute absorbance values were determined by the peak height at 1233 cm-1 relative to a baseline zeroed value at 1345 cm-1. Absorbance values were converted to concentration values via a calibration curve. Initial rates are expressed as a change in molar concentration with respect to time. Reactions were monitored up to 30% conversion to ensure data was collected beyond at least one catalytic turnover.

Initial rates as a function of [1r]

General procedure for kinetic analysis was followed to react ynoate 1r (0.25 mmol-0.625 mmol, 0.05 M-0.125 M) with aldehyde 2k (0.5 mmol, 0.1 M) and Et3SiH (0.5 mmol, 0.1 M) in the presence of Ni-SIPr (0.025 mmol, 0.005 M) in 5 mL THF at 25 oC. Reported values are average of three runs.

73 -6 [1r]initial (mol/L) Δ1r/Δt (M/s) x 10 Average Δ1r/Δt Std. Dev

0.05 10.3 9.7 9.8 0.4 9.5

0.075 6.8 7.4 7.3 0.5 7.8

0.10 5.4 5.7 5.5 0.2 5.5

0.125 3.5 4.1 3.8 0.3 3.9

0.05 mol/L 1r: initial rate = 10.3 x 10-6 M/s, R = 0.992

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 -500 0 500 1000 1500 2000 2500 3000

Time (seconds)

74 0.075 mol/L 1r: initial rate = 6.8 x 10-6 M/sec, R = 0.987

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 0 1000 2000 3000 4000 5000 Time (seconds)

0.10 mol/L 1r: initial rate = 5.5 x 10-6 M/s, R = 0.979

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

75

0.125 mol/L 1r: initial rate = 3.9 x 10-6 M/s, R = 0.977 0.14

0.12

0.1

0.08

[1r] (M) 0.06

0.04

0.02

0 0 2000 4000 6000 8000 Time (seconds)

Initial rates as a function of [2k]

General procedure for kinetic analysis was followed to react ynoate 1r (0.5 mmol, 0.05

M) with aldehyde 2k (0.5 mmol-1.25 mmol, 0.1 M – 0.25 M) and Et3SiH (0.5 mmol, 0.1 M) in the presence of Ni-SIPr (0.025 mmol, 0.005 M) in 5 mL THF at 25 oC. Reported values are average of three runs.

76 -6 [2k]initial (mol/L) Δ1r/Δt (M/s) x 10 Average Δ1r/Δt Std. Dev

0.10 5.4 5.7 5.5 0.2 5.5

0.15 7.8 7.5 7.5 0.3 7.3

0.20 10.3 10.6 10.4 0.2 10.2

0.25 12.5 12.9 12.7 0.2 12.8

0.10 mol/L 2k: initial rate = 5.5 x 10-6 M/s, R = 0.981

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

77 0.15 mol/L 2k: initial rate = 7.8 x 10-6 M/s, R = 0.987

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

0.2 mol/L 2k: initial rate = 10.3 x 10-6 M/s, R = 0.989

0.12

0.1

0.08

0.06 [1r] [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

78

0.25 mol/L 2k: initial rate = 12.9 x 10-6 M/sec, R = 0.992

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

Initial rates as a function of [Ni-SIPr]

General procedure for kinetic analysis was followed to react ynoate 1r (0.5 mmol, 0.05

M) with aldehyde 2k (0.5 mmol, 0.1 M) and Et3SiH (0.5 mmol, 0.1 M) in the presence of Ni-

SIPr complex (0.025 mmol-0.075 mmol, 0.005 M – 0.015 M) in 5 mL THF at 25 oC. Reported values are average of three runs.

79 [Ni-SIPr] (mol/L) Δ1r/Δt (M/s) x 10-6 Average Δ1r/Δt Std. Dev

0.005 5.4 5.7 5.5 0.2 5.5

0.0075 13.3 12.8 13.2 0.4 13.5

0.01 19.4 18.9 19.1 0.3 19.1

0.0125 22.8 22.6 22.8 0.2 22.9

0.0150 27.5 26.7 27.1 0.4 27.2

0.005 mol/L Ni: initial rate = 5.5 x 10-6 M/s, R = 0.979 0.15

0.1 [1r] (M)

0.05

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

80

0.0075 mol/L Ni: initial rate = 13.2 x 10-6 M/s, R = 0.994 0.15

0.1 [1r] (M)

0.05

0 -500 0 500 1000 1500 2000 2500 3000

Time (Seconds)

0.01 mol/L Ni: initial rate = 19.4 x 10-6 M/s, R = 0.987 0.15

0.1 [1r] (M)

0.05

0 -500 0 500 1000 1500 2000 2500 3000 Time (Seconds)

81

0.0125 mol/L Ni: initial rate = 22.8 x 10-6 M/s, R = 0.985 0.15

0.1 [1r] (M)

0.05

0 -500 0 500 1000 1500 2000 Time (Seconds)

0.0150 mol/L Ni: initial rate = 27.5 x 10-6 M/s, R = 0.987

0.15

0.1 [1r] (M)

0.05

0 -500 0 500 1000 1500 2000 Time (Seconds)

82 Initial rates as a function of [Et3SiH]

General procedure for kinetic analysis was followed to react ynoate 1r (0.5 mmol, 0.05

M) with aldehyde 2k (0.5 mmol) and Et3SiH (0.5 mmol-2 mmol, 0.1-0.4 M) in the presence of

Ni-SIPr (0.025 mmol, 0.005 M) in 5 mL THF at 25 oC. Reported values are average of three runs.

-6 [Et3SiH]initial (mol/L) Δ1r/Δt (M/s) x 10 Average Δ1r/Δt Std. Dev

0.1 5.4 5.7 5.5 0.2 5.5

0.2 5.5 5.6 5.6 0.2 5.8

0.3 6.2 5.8 5.9 0.3 5.7

0.4 6.1 5.5 5.6 0.4 5.3

83 -6 0.10 mol/L Et3SiH: initial rate = 5.5 x 10 M/s, R = 0.979 0.14

0.12

0.1

0.08

[1r] (M) 0.06

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (seconds)

-6 0.20 mol/L Et3SiH: initial rate = 5.6 x 10 M/s, R = 0.976 0.14

0.12

0.1

0.08

[1r] (M) 0.06

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (Seconds)

84 -6 0.30 mol/L Et3SiH: initial rate = 6.2 x 10 M/s, R = 0.979

0.12

0.1

0.08

0.06 [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (Seconds)

-6 0.40 mol/L Et3SiH: initial rate = 6.1 x 10 M/s, R = 0.993

0.12

0.1

0.08

0.06 [1r] [1r] (M)

0.04

0.02

0 -1000 0 1000 2000 3000 4000 5000 6000 7000 Time (Seconds)

85 NMR Determination of the Kinetic Isotope Effect with Respect to Triethylsilane

CO2Me O CHO O TMS 5 mol% Ni-SIPr EtO + + Et3SiH EtO 1r THF , 25 oC TMS H/D OSiEt Et SiD 3 1 eq 3 2k 3t/3t-D CO2Me 1 eq each 1 eq H/D = 50:50 KIE = 1.0

Under an inert atmosphere Ni-SIPr (14 mg, 0.025 mmol, 0.05 equiv) was weighed in

Schlenk flask and dissolved in 4 mL of THF at room temperature (23 oC). 1r (95 µL, 0.5 mmol,

1.0 equiv), 2k (82 mg, 0.5 mmol, 1.0 equiv), Et3SiH (80 µL, 0.5 mmol, 1.0 equiv), and Et3SiD

(80 µL, 0.5 mmol, 1.0 equiv) were combined in 1 mL of THF and added to the catalyst mixture as a single portion via syringe. The reaction mixture was stirred at room temperature until 1r and 2k were consumed. Upon completion, the reaction mixture was flushed through a plug of silica using diethyl ether/hexane (1:5). The mixture was analyzed by NMR, and the integration of the vinylic proton was diagnostic for the percentage of hydrogen incorporated in the product.

CO2Me O TMS

EtO OSiEt H/D H 3

CO2Me O TMS

EtO H/D OSiEt3

86 Deuterium- labeling experiments

(1) The general procedure (Chapter 2) was followed except that Et3SiD was used in

1 2 place of Et3SiH. The isolated 1,4-difuncational product was analyzed by H and H NMR as shown below.

Hb Ha Hc

1 HNMR (CDCl3)

c Hb H

2 HNMR (CHCl3)

(2) The general procedure was followed except that PhCDO was used in place of

PhCHO. The isolated 1,4-difuncational product was analyzed by 1H and 2H NMR as shown below.

a c b H H a H H OSiEt3 MeO Ph Hc O Hb

b H a H 1 HNMR (in CDCl3)

a H OSiEt3 2 MeO Ph HNMR (in CHCl3) D O Hb

87 Calibration plot for ynoate 1r

Reaction rates are usually expressed as change in concentration per unit time. According to Beer-Lambert law infrared absorbance of an organic compound is directly proportional to its concentration. Therefore, absorbance values can be converted to concentration values easily using a calibration plot. To make sure there is a linear relationship between ynoate 1r concentration and its IR absorbance, a calibration plot was created using stock solutions of 1r of known concentrations (Figure 7).

0.12

0.1

0.08 y = 0.7649x - 0.0007 R = 0.9995 0.06

Absorbance 0.04

0.02

0 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 [1r] (M)

Figure 7. Calibration plot for ynoate 1r

88

Chapter 4

Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes

4.1 Introduction

Transition-metal-catalyzed [2 + 2 + 2] cycloaddition of alkynes represents a versatile method for the construction of benzene rings.1 It is especially useful when the desired substitution pattern is not easily built via conventional aromatic substitution reactions. The challenge of implementing this cyclization strategy, however, arises in performing the reactions of unsymmetrical alkynes due to the formation of different regioisomers. Typically, [2 + 2 + 2] cycloaddition of a diyne and an alkyne2 or intramolecular cycloaddition of a triyne3 is more regioselective, and therefore it has been more widely utilized in organic synthesis.1

Nevertheless, over the past two decades, a plethora of transition metal systems (e.g., Ti, Co, Ni,

Ru, Rh, Pd ; see Chapter 1) have been developed specifically to catalyze intermolecular [2 + 2 +

2] cycloaddition of three individual alkyne molecules. Despite the progress, many challenges remain, particularly to increase catalytic efficiency and improve regioselectivity. While the majority of known protocols employ 5-10 mol% of metal catalysts (with respect to the total alkynes), there are a few cases where a catalyst loading as low as 1 mol% is sufficient to convert alkynes to substituted benzenes in high yields with high regioselectivity.4 One notable example

1 For representative reviews and book chapters, see: (a) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901. (b) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (c) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209. (d) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (e) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830. (f) Grotjahn, D. B. In Comprehensive Organometallic Chemistry II; Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Elsevier: Oxford, 1995; Vol. 12, ch. 7.3, pp. 741. (g) Schore, N. E. in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; vol. 5, ch. 9.4, pp 1129. 2 For recent representative examples of [2 + 2 + 2] cycloaddition of a diyne and an alkyne, see: (a) Yamamoto, Y.; Nagata, A.; Nagata, H.; Ando, Y.; Arikawa, Y.; Tatsumi, K.; Itoh, K. Chem. Eur. J. 2003, 9, 2469. (b) Saino, N.; Amemiya, F.; Tanabe, E.; Kase, K.; Okamoto, S.; Org. Lett. 2006, 8, 1439. (c) Teske, J. A.; Deiters, A. J. Org. Chem. 2008, 73, 342. (d) Teske, J. A.; Deiters, A. Org. Lett. 2008, 10, 2195. 3 For recent representative examples of intramolecular cyclotrimerization of a triyne, see: (a) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem., Int. Ed. 2004, 43, 1998. (b) Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M. Org. Lett. 2004, 6, 1519. (c) Saino, N.; Kogure, D.; Okamoto, S. Org. Lett. 2005, 7, 3065. (d) Tanaka, K.; Sagae, H.; Toyoda, K.; Noguchi, K.; Hirano, M. J. Am. Chem. Soc. 2007, 129, 1522. (e) Nicolaus, N.; Strauss, S.; Neudörfl, J.-M.; Prokop, A.; Schmalz, H.-G. Org. Lett. 2009, 11, 341. (f) Welsch, T.; Tran, H.-A.; Witulski, B. Org. Lett. 2010, 12, 5644. 4 (a) Ozerov, O. V.; Patrick, B. O.; Ladipo, F. T. J. Am. Chem. Soc. 2000, 122, 6423. (b) Takeuchi, R.; Nakya, Y. Org. Lett. 2003, 5, 3659. (c) Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697. (d) Dutta, B.; Curchod, B. F. E.; Campomanes, P.; Solari, E.; Scopelliti, R.; Rothlisberger, U.; Severin, K. Chem. Eur. J. 2010, 16, 8400.

90 and arguably the most active catalytic system reported to date involves cyclopentadienyl- ruthenium-based complexes,4d which promote cyclotrimerization of alkynes with turnover numbers (TONs) up to 196 and isomeric ratios at least 90:10 (eq 1).

CO2R

RO2C RO2C CO2R [RuCl2(Cp^)] 1 mol % CH CCO2R + (1) CH Cl , rt, 30 min 2 2 H O CO R CO R 2 2 Ru q r Cl Cl

R = Me, q/r = 92:8 [RuCl2(Cp^)] R = Et, q/r = 90:10

During the course of developing the nickel-based catalytic system for regioselective reductive coupling of ynoates and aldehydes (Chapter 2), we found that in order to achieve high yields for the desired silyl-protected γ-hydroxy-α,β-enoates, the ynoate substrate must be added very slowly to the reaction mixture. Close inspection of the byproducts revealed that one of the competing pathways was the cyclotrimerization of ynoates to generate benzene-1,2,4- tricarboxylates as the major isomers (Scheme 1).

Scheme 1. Nickel-catalyzed reductive coupling reactions

CO2R OSiEt R' CO2R 3 [Ni] [Ni] R' CO2R + Et3SiH + R"CHO R" CO2R R' R' R' CO2R

Nickel-catalyzed oligomerization of ynoates is known in the literature, but in most cases tetra-substituted cyclooctatetraenes are the cycloaddition products.5 A study done in the early sixties using Ni(PPh3)2(CO)2 as the catalyst showed that oligomerization of ethyl propiolate

5 (a) Leto, J. R.; Leto, M. F. J. Am. Chem. Soc. 1961, 83, 2944. (b) Diercks, R.; Dieck, H. T. Chem. Ber. 1985, 118, 428.

91 produced 1,2,4- and 1,3,5-substituted aromatic compounds in 89% and 6% yields, respectively.6

These benzene derivatives could be used as new branching or cross-linking agents for polymers7

(Scheme 2) and as precursors to synthesizing organic light-emitting diode materials.8

Scheme 2. Benzene-1,2,4-tricarboxylates as branching agents in polymer synthesis

O OMe O

O O MeO HO CH2CH2 OH + + H3CO OCH3

ethylene glycol dimethyl terephthalate (DMT) O OMe branching agent 1.5 mol % with respect to DMT

O O O O

C C OCH2CH3 O O CH2CH2O C C

O O O O O O CH2CH2O C C

4.2 Optimization of the Reaction Conditions

We commenced our study with the identification of optimal conditions for the cyclotrimerization reaction using ethyl propiolate 1a as the substrate. The results are summarized in Table 1. In alignment with our previous procedures for reductive coupling of ynoates and aldehydes, the first set of experiments (entries 1-3) was to test catalytic performance

6 Meriwether, L. S.; Colthup, E. C.; Kennerly, G. W.; Reusch, R. N. J. Org. Chem. 1961, 26, 5155. 7 McKee, M. G.; Wilkes, G. L.; Colby, R. H.; Long, T. E. Macromolecules 2004, 37, 1760. 8 Yang, J.-S.; Huang, H.-H.; Lin, S.-H.; J. Org. Chem. 2009, 74, 3974.

92 Table 1. Optimization of the reaction conditionsa

CO2Et CO2Et CO2Et catalyst + CO2Et 23 oC, 1 h 1a EtO2C CO2Et 3a CO2Et 2a

cat. entry catalyst solvent yield (%)b 2a : 3ac (mol%) n 1 Ni(COD)2 : P Bu3 (1:1) 10 Toluene 2 n.d.

2 Ni(COD)2 : PCy3 (1:1) 10 Toluene 20 n.d. 3 Ni(COD)2 : PPh3 (1:1) 10 Toluene 82 n.d.

4 Ni(PPh3)4 1 Toluene 100 97 : 3 5 Ni(COD)2 : PPh3 (1:4) 1 Toluene 100 97 : 3

6 Ni(COD)2 : PPh3 (1:3) 1 Toluene 100 97 : 3 7 Ni(COD)2 : PPh3 (1:2) 1 Toluene 57 n.d.

8 Ni(COD)2 : PPh3 (1:1) 1 Toluene 36 n.d. 9 Ni(COD)2 : PPh3 (1:3) 1 THF 42 n.d. 10 Ni(COD)2 : PPh3 (1:3) 1 CH3CN 72 n.d. aconditions: 1a (0.25 mmol), nickel catalyst and n-decane (internal standard, 0.04 mmol) in 2 mL of solvent. bcombined (2a + 3a) yield determined by GC- MS. cratio determined by 1H NMR (n.d. = not determined).

of Ni(COD)2 (10 mol%) combined with an equimolar amount of a phosphine ligand. In the

n presence of Ni(COD)2/P Bu3, only a negligible amount of product formed after 1 h at room

n temperature, as determined by GC-MS (entry 1). While replacing P Bu3 with PCy3 increased the yield to 20% (entry 2), the use of PPh3 led to a more significant improvement with GC yield reaching 82% (entry 3). Encouraged by this result, we were curious to see if the commercially available Ni(PPh3)4 would catalyze the same reaction. With 1 mol% of Ni(PPh3)4 (entry 4), a quantitative conversion of 1a to aromatic compounds 2a and 3a (with a ratio of 97:3; determined

1 by H NMR) was observed within 1 h. Although Ni(PPh3)4 proved to be an effective catalyst, it is a relatively expensive reagent. We thus decided to replace it with the much cheaper Ni(COD)2

93 9 along with 4 quivalents of PPh3. The in situ generated catalyst turned out to be as efficient as pure Ni(PPh3)4 in promoting the cyclotrimerization reaction without compromising the level of regioselectivity (entry 5). Additional optimization studies suggested that the amount of PPh3 could be reduced to 3 equivalents relative to Ni(COD)2 (entry 6). However, reducing the

PPh3/Ni(COD)2 ratio further resulted in diminished yields (entries 7 and 8). We also examined different solvents for the cyclotrimerization reaction. Among the solvents tested, toluene was found to be a much better medium to carry out the reaction than the more polar solvents such as

THF and CH3CN (entries 9 and 10).

It should be mentioned that there are literature precedents for Ni(COD)2/PPh3-catalyzed

[2 + 2 + 2] cycloaddition of alkynes. The Mori group has reported cocyclization of diynes and

10a acetylene catalyzed by 30 or 40 mol% of Ni(COD)2/PPh3 (1:4). Saito, Yamamoto, and co- workers have used the same catalytic mixture (10 mol%) for regioselective cyclotrimerization of

10b 1-perfluoroalkylenynes. Ikeda et al. have employed 5 mol% of Ni(COD)2/PPh3 (1:2) for cross-cyclotrimerization of two different alkynes.10c A more recent study by the Baran group has demonstrated that 10 mol% Ni(COD)2/PPh3 (1:1) is an effective catalyst for co-oligomerization of 1,3-dienes and akynes, but for some alkyne substrates, benzene derivatives are the main products.10d One common feature of aforementioned catalytic processes as well as other

Ni(COD)2-catalyzed reactions is the high catalyst loading, which is, in part, due to the low thermal stability of the Ni(0) species.11 In that regard, the relatively low catalyst loading needed in our system is quite unusual. As a matter of fact, even with 0.05 mol% of nickel catalyst,

9 Prices listed by Sigma-Aldrich: Ni(PPh3)4, $87/mmol; Ni(COD)2, $8.4/mmol; PPh3, $0.046/mmol. 10 (a) Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994, 59, 6133. (b) Saito, S.; Kawasaki, T.; Tsuboya, N.; Yamamoto, Y. J. Org. Chem. 2001, 66, 796. (c) Mori, N.; Ikeda, S.; Odashima, K. Chem. Commun. 2001, 181. (d) Holte, D.; Götz, D. C. G.; Baran, P. S. J. Org. Chem. 2012, 77, 825. 11 Wender, P. A.; Smith, T. E.; bis(1,5-cyclooctadiene)nickel (0), in Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.; Crich, D.; Fuchs, P. L.; Molander, G. A., Eds.; Wiley: Chichester, UK, 2009; 2nd edn, Vol. 2, pp 906.

94 cyclotrimerization of 1a was found to be complete within 2 h (eq 2). The calculated TON of

2,000, to the best of our knowledge, is the highest for any transition-metal-catalyzed cyclotrimerization reaction.

CO2Et 0.05 mol% Ni(COD) 2 CO2Et 0.15 mol% PPh3 CO Et 2 toluene (2 mL) (2) 1a 23 oC, 2 h 1.5 mmol TON = 2,000 CO2Et 2a 92% isolated yield

4.3 Substrate Scope

To explore the scope of the cyclotrimerization reaction, we applied the optimized conditions to a variety of ynoates. As shown in Table 2, methyl, ethyl, or tert-butyl propiolate

(entries 1-3) underwent facile cyclotrimerization to afford the corresponding benzene-1,2,4- tricarboxylate as the major product. The observed regioselectivity (97:3) appeared unaffected by the size of the alkyl groups. However, the reaction of 2-naphthyl propiolate was less selective, resulting in a 88:12 mixture of 1,2,4- and 1,3,5-isomers (entry 4). Attempts to improve the regioselectivity by replacing 3 equiv of PPh3 with 1 equiv of an NHC ligand (Chart 1) were unsuccessful (entries 5 and 6). Ynoates with an internal C≡C bond also proved to be viable substrates, although a longer reaction time or a higher temperature was necessary. For example, cyclotrimerization of diethyl acetylenedicarboxylate 1e took 5 h to complete, providing a hexa- substituted benzene in nearly quantitative yield upon isolation (entry 7). In contrast, no reaction was observed for 1f after 24 h at room temperature. Yang and co-workers had encountered a similar challenge8 when using Hilt’s cobalt diimine catalyst12 to effect the cyclotrimerization of

12 Hilt, G.; Vogler, T.; Hess, W.; Galbiati, F. Chem. Commun. 2005, 1474.

95 Table 2. Cyclotrimerization of ynoatesa

R1 R1 R2 R1 R2 R2 Ni catalyst + R1 R2 toluene, 23 or 80 oC 1a-j R2 R2 R1 R1 R1 R2 2a-j 3a-j entry ynoate cat. time (h) temp (oC) yield (%)b 2 : 3d

1 CO2Et A 1 23 90 97 : 3 (1a) 2 CO2Me A 1 23 91 97 : 3 (1b) t 3 CO2 Bu A 1 23 88 97 : 3 (1c) c 4 CO2(2-Np) A 1 23 86 88 : 12 (1d) 5 B 1 23 n.d. 75 : 25 6 C 1 23 n.d. 75 : 25

7 EtO2C CO2Et A 5 23 96 - (1e) c 8 EtO2C Ph A 12 80 94 80 : 20 (1f) 9 B 24 23 92 97 : 3

10 EtO2C Me A 24 23 74 80 : 20 (1g) 11 B 24 23 n.d. 85 : 15 12 C 24 23 84 90 : 10 n 13 MeO2C Pr A 24 23 71 80 : 20 (1h) 14 B 24 23 94 >99 : 1

n 15 MeO2C Hex B 24 23 89 >99 : 1 (1i)

16 EtO2C TMS B 24 23 92 >99 : 1 (1j)

aabbreviations: 2-Np = 2-naphthyl, nPr = n-propyl, nHex = n-hexyl; reaction conditions: 1.5 mmol of 1 in 2 mL of toluene (for cat. A) or THF (for cat. B and C), cat. A = 1 mol% Ni(COD)2/PPh3 (1 : 3), cat. B = 1 mol% Ni(COD)2/SIPr (1 : 1), cat. C = 1 mol% b c d Ni(COD)2/SIMes (1 : 1). isolated yield for 2. combined isolated yield for 2 and 3. ratio determined by 1H NMR or GC-MS. iPr iPr

N N N N

iPr iPr SIPr SIMes

Chart 1. NHC’s employed in this study

96 1f. Fortuately, at 80 °C, nikel-catalyzed cyclotrimerization proceeded smoothly to yield the unsymmetrical cyclotrimer 2f as the major isomer, albeit with a modest selectivity of 80:20

(entry 8). The regioselectivity was, however, substantially higher when SIPr was used in place of PPh3 (entry 9). The substitution pattern of 2f was further established by X-ray crystallography

(Figure 1). Of particular note is that 2f has been previously sought after as a precursor to

Figure 1. X-ray structure of compound 2f (at 50% probability level) isotruxene,8 a potential building block for synthesizing various π-conjugated systems.13 Thus, the method developed here could be a convenient synthetic route to these types of molecules.

Interestingly, Ni(COD)2/PPh3-catalyzed cyclotrimerization of 1g (entry 10) and 1h (entry 13) took place at room temperature, but displayed modest regioselectivity (80:20). These results were somewhat surprising; in our previous study of reductive coupling of ynoates and aldehydes

(Chapter 2), the reaction of 1h was found to be much more regioselective than that of 1a or 1b.

For related reactions including the cyclotrimerization of alkynes, metallacyclopentadiene

13 (a) Yang, J.-S.; Lee, Y.-R.; Yan, J.-L.; Lu, M.-C. Org. Lett. 2006, 8, 5813. (b) Diring, S.; Ziessel, R.; Tetrahedron Lett. 2009, 50, 1203. (c) Huang, H.-H.; Prabhakar, C.; Tang, K.-C.; Chou, P.-T.; Huang, G.-J.; Yang, J.-S. J. Am. Chem. Soc. 2011, 133, 8028.

97 intermediates are usually generated via reductive coupling of alkynes,1 and the regioselectivity in metallacycle formation is often influenced by polarization of the triple bonds.14 Given the disparity of electronic property between an ester group and an alkyl group, we had anticipated high regioselectivity for 1g and 1h. Perhaps in these cases, steric effects are also important. We then decided to switch to NHC ligands with the objective to improve the regioselectivity. In the presence of a 1:1 catalytic mixture of Ni(COD)2 and SIPr, the ratio of 2g to 3g was increased slightly to 85:15 (entry 11). The use of SIMes resulted in a further improvement of selectivity to

90:10, and 2g could be separated from the mixture in 84% yield (entry 12). In the case of 1h, the employment of SIPr as an ancillary ligand led to the exclusive formation of 2h (entry 14). The sterically more demanding ynoates 1i and 1j did not react at room temperature or 80 °C using

Ni(COD)2/PPh3 as the catalytst. On the other hand, cyclotrimerization of both substrates was smoothly catalyzed by Ni(COD)2/SIPr, giving 2i and 2j as the predominant products (entries 15 and 16).

The success of ynoate cyclotrimerization prompted us to examine the reactivity of alkynes without the ester functionality (Table 3). At room temperature in the presence of 1 mol% of Ni(COD)2 and 3 mol% of PPh3, phenylacetylene 1k was regioselectively converted to

1,2,4-triphenyl benzene 2k in 90% yield (entry 1). Similarly high yields and regioselectivity were obtained for the cyclotrimerization of 1l and 1m (entries 2 and 3), and one of the products

2m was also crystallographically characterized (Figure 2). The reaction of 1n, an internal alkyne, required an elevated temperature; no reactivity was observed at room temperature (entry

4). Compounds 1o and 1p have been rarely tested for cyclotrimerization reaction. The pyridyl group in 1o may potentially poison the catalyst by binding to nickel, while the cyclopropyl group

14 (a) Stockis, A.; Hoffmann, R. J. Am. Chem. Soc. 1980, 102, 2952. (b) Mori, N.; Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 2722.

98 in 1p may undergo ring-opening reaction. We were pleased to find that neither process was operating under our catalytic conditions. Analogous to the reaction of other terminal alkynes,

1,2,4-trisubstituted benzene derivatives formed as the major isomers (entries 5 and 6).

Table 3. Cyclotrimerization of various alkynesa

R1 R1 1 mol% Ni(COD)2 R2 R1 R2 R2 3 mol% PPh3 R1 R2 + toluene, 23 or 80 oC 1k-p R2 R2 R1 R1 R1 R2 2k-p 3k-p entry alkyne time (h) temp (oC) yield (%)b 2 : 3d

1 Ph 12 23 90 >99 : 1 (1k) 2 F 12 23 92 >99 : 1 (1l)

3 MeO2C 12 23 90 >99 : 1 (1m) 4 Ph Ph 24 80 76 - (1n) N 5 12 23 95 >99 : 1 (1o) 6 12 23 88c 86 : 14 (1p)

a conditions: 1 (1.5 mmol), Ni(COD)2 (0.015 mmol) and PPh3 (0.045mmol) in 2 mL of toluene. bisolated yield for 2. ccombined isolated yield for 2p and 3p. dratio determined by 1H NMR.

99

Figure 2. X-ray structure of compound 2m (at 50% probability level)

4.4 Large Scale Synthesis of 2b

To further demonstrate the synthetic utility of the cyclotrimerization reaction, we conducted a gram-scale synthesis of 2b using 0.05 mol% of nickel catalyst (eq 3). The regioselectivity remained high (97:3) favoring the unsymmetrical isomer 2b, which was isolated in high yield.

100 CO2Me

0.05 mol% Ni(COD)2 CO2Me 0.15 mol% PPh3 CO2Me (3) 1b toluene (5.6 mL) 23 oC, 5 h 1.22 g CO2Me 2b 1.05 g isolated (86%)

4.5 Mechanism and Regioselectivity

Many mechanistic studies have implicated the intermediacy of metallacyclopentadiene 4, which is formed by coordination of two alkyne molecules to the metal center followed by oxidative cyclization.15 Two pathways have been proposed in the literature to account for the reaction of third alkyne with the 4 to generate the free aromatic product 8 (Scheme 3): (1) the two new C-C bonds are formed in a stepwise manner via a metallacycloheptatriene intermediate

6, and (2) the two new C-C bonds are formed in a concerted fashion (as in the Diels-Alder reaction) via a metallanorbornadiene intermediate 7.

Scheme 3. Plausible mechanism

Ln+1M LnM LnM -L Ln+2M -L 4

LnM

6 -MLn+2 LnM LnM

4 5 Ln 8 M

7

15 See for example: (a) Trost, B. M. Angew. Chem., Int. Ed. 1986, 25, 1. (b) Schore, N. E. Chem. Rev. 1988, 88, 1081. (c) Negishi, E. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Permagon: Oxford, 1991; Vol. 5, pp 1163-1184. (d) Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 539. (e) Ojima, I.; Tzamarioudaki, M.; Zhaoyang, L.; Donovan, R. J. Chem. Rev. 1996, 96, 635.

101 Most of the mechanistic studies have focused on the nature of the intermediates in the [2

+ 2 + 2] cyclotrimerization reaction. Rothwell et al. extensively studied the reactions of aryloxide-based titanacyclopentadienes with alkynes and olefins,16 and their results support a concerted pathway. Studies conducted by Wigley et al. also suggested a concerted addition pathway for the reactions of tantalacyclopentadiene and tantalanorbornadiene complexes supported by aryloxide ligands.17 Bianchini and Caulton et al.18 also proposed a concerted pathway for the [2 + 2 + 2] cycloaddition of acetylene at iridium centers. A Recent computational mechanistic study of the cyclotrimerization of acetylene catalyzed by CpCoL2 (L

= CO, PR3, alkenes) concluded that the intermediacy of a cobaltocycloheptatriene 6 is energetically prohibitive and a concerted addition pathway is favored.19

Regardless of which mechanism is operating, cyclotrimerization of unsymmetrical alkynes leads to arenes with either 1,2,4- or 1,3,5-substitution pattern (Scheme 4). The regioselectivity is determined at two stages, first at the formation of the metallacyclopentadiene and then during its subsequent reaction with the third alkyne. The preference for the formation of any of the metallacyclopentadienes A-C (Scheme 4) depends on catalyst, substitution pattern on the alkyne, and reaction conditions. Complexes A and C lead exclusively to the 1,2,4- product, independent of the orientation of the third alkyne during its C-C bond formation. The formation of the 1,3,5-compound would require the involvement of the metallacycle B.

16 (a) Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc. 1993, 115, 1581. (b) Warantuke, S. A.; Johnson, E. S.; Thorn, M. G.; Fanwick, P. E.; Rothwell, I. P. J. Chem. Soc. Chem. Commun. 1996, 2617. (c) Johnson, E. S.; Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc. 1997, 119, 7685. (d) Warantuke, S. A.; Thorn, M. G.; Fanwick, P. E.; Rothwell, A. P.; Rothwell, I. P. J. Am. Chem. Soc. 1999, 121, 9111. 17 (a) Strickler, J. R.; Bruck, M. A.; Wigley, D. E. J. Am. Chem. Soc. 1990, 112, 2814. (b) Smith, D. P.; Strickler, J. R.; Gray, S. D.; Bruck, M. A.; Holmes, R. S.; Wigley, D. E. Organometallics 1992, 11, 1275. 18 Bianchini, C.; Caulton, K. G.; Chardon, C.; Eisenstein, O.; Folting, K.; Johnson, T. J.; Meli, A.; Peruzzini, M.; Rauscher, D. J.; Streib, W. E.; Vizza, F. J. Am. Chem. Soc. 1991, 113, 5127. 19 Agenet, N.; Grandon, V.; Volhardt, P. C.; Malacria, M.; Aubert, C. J. Am. Chem. Soc. 2007, 129, 8860.

102 Scheme 4. Origin of regioselectivity

OR O O OR O O OR RO LnNi

O OMe O OR A

O O O O O O -2 L OR OR RO OR OR L Ni [NiLn+2] + OR n + RO 1eq 2 eq O O OMe O OR O OR B

O RO O O OR OR LnNi OR OR

C O O RO O

To rationalize the observed regioselectivity for the cyclotrimerization of ynoates in this study, we have considered the regiochemistry for the formation of nickelacyclopentadienes

(Figure 3). This step is controlled by both electronic and steric factors. Hoffmann et al. proposed that in the coupling reaction of two alkynes to form a metallacycle intermediate, the

RO α M α R1 O β R1 = H, alkyl group, TMS β π* orbital of an ynoate orientation of alkynes in the metallacycle Figure 3. Polarization of the triple bond of ynoates and metallacycle formation

controlling orbital is the HOMO of the complex, the ligand part of which is dominated by π* orbitals. Therefore, regioselectivity originates from the polarity in the π* orbital of the unsymmetrical alkyne. In other words the carbon attached to the electron-withdrawing substituent will end up as the α-carbon of the metallacycle while the carbon attached to the electron-donating substituent is transformed into the β-carbon of the metallacycle.14a According

103 to this argument metallacycle A would be more preferred over B and C, (Figure 3) hence we obtain high selectivity for arenes with the 1,2,4-susbstituition pattern.

4.6 Conclusions

In summary, we have developed an effective nickel system, Ni(COD)2/PPh3 or

Ni(COD)2/NHC (NHC = an N-heterocyclic carbene), for catalytic cyclotrimerization of ynoates and related alkynes. This methodology provides access to a diverse array of tri- or hexa- substituted benzene derivatives in an efficient and highly regioselective manner. The ester- containing products 2a-j may find various applications in materials chemistry. Preliminary studies have also shown that compounds 2d/3d, 2l, 2m and 2o display interesting photoluminescent properties. This system provides several advantages. First of all, catalysts can be easily generated in situ by mixing commercially available reagents. More importantly, the catalytic process is quite efficient; TONs as high as 2,000 is the highest for any transition-metal- catalyzed cyclotrimerization reaction, allowing the synthesis to be carried out on the gram scale.

Moreover, the observed regioselectivity is typically high and in a number of cases only one regioisomer is formed.

4.7 Experimental

General Experimental Methods

All reactions were carried out in flame-dried glassware under an argon atmosphere using standard glove box techniques. Dry and oxygen-free solvents for carrying out synthesis (THF and toluene) were collected from an Innovative Technology solvent purification system. CH3CN was dried over CaH2 and then degassed by freeze-pump-thaw cycles. Alkynes were purchased

104 from Sigma-Aldrich and used without further purification except for phenylacetylene, which was freshly distilled prior to use. Ni(COD)2 was purchased from Acros Organics, stored in a –30 °C freezer of a glove box, and used without further purification. All other reagents were obtained from Sigma-Aldrich and used as received. NHC ligands were generated in situ by mixing equimolar amounts of imidazolidinium tetrafluoroborate and KOtBu in THF. 1H and 13C{1H}

NMR spectra were recorded on a Bruker Avance-400 MHz spectrometer. Chemical shift values were referenced internally to the residual solvent resonances. Infrared spectra were recorded on a Thermo Scientific Nicolet 6700 FT-IR spectrometer equipped with smart orbit diamond attenuated total reflectance (ATR) accessory. High-resolution ESI-MS data for all the new compounds were obtained from either a Micromass Q-TOF-2TM or a ThermoFinnigan LTQ

Linear Ion-Trap FTMS instrument.

General Procedures for Catalytic [2+2+2] Cyclotrimerization of Alkynes (1 mol% Catalyst

Loading).

To a 10 mL scintillation vial under an argon atmosphere was added Ni(COD)2 (4.1 mg,

0.015 mmol, 1 mol%), PPh3 (11.8 mg, 0.045 mmol, 3 mol%) and 2 mL of toluene at 23 °C. The resulting mixture was stirred at the same temperature for 5 min, followed by the addition of the alkyne substrate (1.5 mmol). The reaction mixture was then stirred at appropriate temperature

(see Tables 2 and 3 for details) until the starting material was fully converted. Upon completion of the reaction, the volatiles were removed under vacuum, and the residue was extracted by diethyl ether and filtered through a short plug of silica. The isomeric ratio was determined by analyzing either 1H NMR (reactions of 1a-f and 1k-p) or GC/MS (reactions of 1g-j) of the crude product. The desired 1,2,4-isomer was separated from the isomeric mixture using column chromatography (eluted with diethyl ether/hexanes). Reactions catalyzed by Ni(COD)2/NHC

105 were carried out in the same fashion except that 0.045 mmol of PPh3 was replaced with 0.015 mmol of NHC ligand and the solvent was switched to THF.

Compounds 2a,20 2b,21 2c,22 2e,23 2f,24 2g,24 2j,25 2k,26 2l,27 2m,28 2n29 and 2p +

3p30 have been reported in the literature, and the NMR data are consistent with the reported values. New compounds 2d + 3d, 2h, 2i and 2o were further characterized using IR and high- resolution ESI-MS.

Procedure for Catalytic [2+2+2] Cyclotrimerization of Ethyl Propiolate (0.05 mol%

Catalyst Loading)

Under an argon atmosphere, Ni(COD)2 (5.5 mg , 0.020 mmol) and PPh3 (15.6 mg, 0.060 mmol) were mixed in 10 mL of toluene at 23 °C. The resulting mixture was stirred at this temperature for 5 min to produce a stock solution of the catalyst. A portion of the stock solution

(375 µL) was added to a 10 mL scintillation vial under an argon atmosphere and the volume was brought up to 2 mL with toluene, followed by the addition of ethyl propiolate (152 µL, 1.5 mmol). The reaction was complete within 2 h, and the product was isolated in 92% yield.

Procedure for the Large-Scale Reaction of Methyl Propiolate

Under an argon atmosphere, 3.6 mL of the catalyst stock solution (as prepared above) was added to a 50 mL Schlenk flask. A solution of methyl propiolate (1.22 g, 1.29 mL, 14.5 mmol) in 2 mL of THF was then added to this flask at 23°C over a period of 30 min (best carried

20 Yong, L.; Kirleis, K.; Butenschön, H. Adv. Synth. Catal. 2006, 348, 883. 21 Mayhoub, A. S.; Talukdar, A.; Cushman, M. J. Org. Chem. 2010, 75, 3507. 22 Rohbogner, C. J.; Wunderlich, S. H.; Clososki, G. C.; Knochel, P. Eur. J. Org. Chem. 2009, 1781. 23 Cadierno, V.; García-Garrido, S. E.; Gimeno, J. J. Am. Chem. Soc. 2006, 128, 15094. 24 Yoshida, K.; Morimoto, I.; Mitsudo, K.; Tanaka, H. Tetrahedron 2008, 64, 5800. 25 Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552. 26 Hill, J. E.; Balaich, G. P.; Fanwick, E.; Rothwell, I. P. Organometallics 1993, 12, 2911. 27 Liu, Y.; Yan, X.; Yang, N.; Xi, C. Catal. Commun. 2011, 12, 489. 28 Xu, L.; Yu, R.; Wang, Y.; Chen, J.; Yang, Z. J. Org. Chem. 2013, 78, 5744. 29 Tu, T.; Sun, Z.; Fang, W.; Xu, M.; Zhou, Y. Org. Lett. 2012, 14, 4250. 30 Dzhemilev, U. M.; Khusnutdinov, R. I.; Shchadneva, N. A.; Nefedov, O. M.; Tolstikov, G. A. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1989, 10, 2360.

106 out using a syringe pump to avoid the evaporation of the alkyne due to high exothermicity of the reaction). The reaction mixture was stirred for additional 3 h before work up as described as above. The product 2b was isolated in 86% yield.

Characterization Data for Compounds 2a-p, 3d and 3p

O OEt O

EtO

O OEt Compound 2a (colorless oil, 133 mg, 90%): 1H NMR (400 MHz,

4 3 4 CDCl3, δ) 8.41 (1H, d, JH-H = 1.7 Hz, ArH), 8.20 (1H, dd, JH-H = 7.9 Hz, JH-H = 1.7 Hz, ArH),

3 13 1 7.76 (1H, d, JH-H = 7.9 Hz, ArH), 4.50-4.35 (6H, m, CH2), 1.50-1.35 (9H, m, CH3); C{ H}

NMR (101 MHz, CDCl3, δ) 167.24, 166.70, 165.07, 136.36, 132.77, 132.17, 132.10, 130.19,

128.95, 62.09, 62.03, 61.78, 14.36, 14.20, 14.15.

O OMe O

MeO

O OMe Compound 2b (colorless oil, 115 mg, 91%): 1H NMR (400 MHz,

4 3 4 CDCl3, δ) 8.43 (1H, d, JH-H = 1.7 Hz, ArH), 8.21 (1H, dd, JH-H = 8.2 Hz, JH-H = 1.7 Hz, ArH),

3 13 1 7.75 (1H, d, JH-H = 8.2 Hz, ArH), 3.96 (3H, s, CH3), 3.94 (6H, s, CH3); C{ H} NMR (101

MHz, CDCl3, δ) 167.76, 166.98, 165.52, 136.38, 132.59, 132.44, 131.75, 130.43, 129.03, 53.07,

53.00, 52.78.

107 O OtBu O

tBuO

O OtBu Compound 2c (white solid, 167 mg, 88%): 1H NMR (400 MHz,

4 3 4 CDCl3, δ) 8.23 (1H, d, JH-H = 1.8 Hz, ArH), 8.05 (1H, dd, JH-H = 8.1 Hz, JH-H = 1.8 Hz, ArH),

3 13 1 7.64 (1H, d, JH-H = 8.1 Hz, ArH), 1.60 (27H, s, CH3); C{ H} NMR (101 MHz, CDCl3, δ)

166.54, 166.14, 164.48, 137.50, 133.78, 133.73, 131.39, 129.94, 128.76, 82.57, 82.43, 82.11,

28.27, 28.19, 28.17.

O ONp O O O

NpO NpO ONp +

O ONp O ONp Compounds 2d + 3d (6.5: 1 ratio, white solid,

1 253 mg, 86% combined yield): H NMR (400 MHz, CDCl3, δ) 9.36 (0.5H, s, ArH of 3d), 8.97

4 3 4 (1H, d, JH-H = 1.7 Hz, ArH of 2d), 8.60 (1H, dd, JH-H = 8.0 Hz, JH-H = 1.7 Hz, ArH of 2d), 8.19

3 (1H, d, JH-H = 8.0 Hz, ArH of 2d), 7.97-7.74 (14H, m, ArH of 2d and 3d), 7.57-7.41 (10.5H, m,

13 1 ArH of 2d and 3d); C{ H} NMR (101 MHz, CDCl3, δ) of 2d + 3d: 165.71, 165.09, 163.73,

148.34, 136.73, 136.35, 133.91, 133.88, 133.66, 132.80, 131.99, 131.87, 131.51, 129.99, 129.88,

128.03, 127.95, 126.97, 126.85, 126.19, 126.14, 120.96, 120.89, 118.84; IR (neat, cm-1) 3058,

1730 (νCO), 1630, 1600, 1582, 1511, 1463, 1442, 1356, 1297, 1277, 1256, 1236, 1204, 1148,

1136, 1120, 1073, 1038, 960, 928, 897, 853, 803, 780, 753, 725, 699, 631, 620; HRMS-ESI

+ (m/z) [M+Na] calcd for C39H24O6Na 611.1470, found 611.1478.

108 CO2Et EtO2C CO2Et

EtO2C CO2Et CO2Et Compound 2e (yellow solid, 245 mg, 96%): 1H NMR (400 MHz,

3 3 13 1 CDCl3, δ) 4.34 (12H, q, JH-H = 7.2 Hz, CH2), 1.34 (18H, t, JH-H = 7.2 Hz, CH3); C{ H} NMR

(101 MHz, CDCl3, δ) 164.77, 133.77, 62.64, 13.74.

CO2Et EtO2C Ph

Ph Ph CO2Et Compound 2f (white solid, 240 mg, 92%): 1H NMR (400 MHz,

CDCl3, δ) 7.35 (5H, s, ArH), 7.14-7.11 (6H, m, ArH), 7.04-7.00 (4H, m, ArH), 4.01-3.92 (4H, m,

3 3 CH2), 3.65 (2H, q, JH-H = 7.1 Hz, CH2), 0.92-0.85 (6H, m, CH3), 0.67 (3H, t, JH-H = 7.1 Hz,

13 1 CH3); C{ H} NMR (101 MHz, CDCl3, δ) 167.84, 167.49, 167.45, 16, 140.89, 139.32, 137.72,

137.59, 137.45, 137.37, 134.24, 132.15, 130.00, 129.92, 129.22, 129.02, 128.15, 128.06, 127.61,

127.44, 127.30, 61.67, 61.06, 13.58, 13.46.

CO2Et EtO2C Me

Me Me CO2Et Compound 2g (colorless oil, 141 mg, 84%): 1H NMR (400 MHz,

3 CDCl3, δ) 4.41 (2H, q, JH-H = 7.2 Hz, CH2), 4.36-4.29 (4H, m, CH2), 2.30 (3H, s, ArCH3), 2.26

13 1 (3H, s, ArCH3), 2.23 (3H, s, ArCH3), 1.40-1.33 (9H, m, CH2CH3); C{ H} NMR (101 MHz,

CDCl3, δ) 169.48, 168.55, 167.86, 137.59, 135.90, 133.81, 132.68, 130.37, 129.97, 61.57, 61.54,

61.46, 17.38, 17.09, 16.63, 14.27, 14.13.

109 O OMe O nPr MeO

nPr nPr

O OMe Compound 2h (colorless oil, 178 mg, 94%): 1H NMR (400 MHz,

CDCl3, δ) 3.91 (3H, s, CO2CH3), 3.86 (3H, s, CO2CH3), 3.84 (3H, s, CO2CH3), 2.64-2.47 (6H,

13 1 m, ArCH2), 1.56-1.48 (6H, m, ArCH2CH2), 1.00-0.88 (9H, m, CH3); C{ H} NMR (101 MHz,

CDCl3, δ) 170.12, 169.23, 168.50, 140.56, 137.60, 137.43, 135.90, 134.10, 130.04, 52.56, 52.23,

-1 33.81, 33.60, 32.10, 24.99, 24.74, 14.97, 14.83, 14.70; IR (neat, cm ) 2959, 2873, 1729 (νCO),

1438, 1305, 1267, 1240, 1200, 1146, 1114, 1087, 1014, 977, 743; HRMS-ESI (m/z) [M+Na]+ calcd for C21H30O6Na 401.19346, found 401.19357.

O OMe O nHex MeO

nHex nHex

O OMe Compound 2i (colorless oil, 224 mg, 89%): 1H NMR (400 MHz,

CDCl3, δ) 3.90 (3H, s, CO2CH3), 3.85 (3H, s, CO2CH3), 3.84 (3H, s, CO2CH3), 2.64-2.48 (6H,

13 1 m, ArCH2), 1.53-1.26 (24H, m, CH2), 0.91-0.86 (9H, m, CH3); C{ H} NMR (101 MHz,

CDCl3, δ) 170.11, 169.22, 168.50, 140.68, 137.49, 136.07, 134.08, 129.92, 52.54, 52.20, 31.79,

31.66, 31.60, 31.58, 31.51, 31.41, 31.27, 30.06, 30.02, 29.95, 29.83, 22.70, 22.65, 14.20; IR

-1 (neat, cm ) 2954, 2927, 2857, 2361, 2338, 1733 (νCO), 1437, 1210, 1146, 1099, 668; HRMS-ESI

+ (m/z) [M+Na] calcd for C30H48O6Na 527.3348, found 527.3342.

110 CO2Et EtO2C TMS

TMS TMS CO2Et Compound 2j (colorless oil, 234 mg, 92%): 1H NMR (400 MHz,

CDCl3, δ) 4.35-4.25 (6H, m, CH2), 1.40-1.32 (9H, m, CH2CH3), 0.37 (9H, s, Si(CH3)3), 0.33

13 1 (9H, s, Si(CH3)3), 0.28 (9H, s, Si(CH3)3); C{ H} NMR (101 MHz, CDCl3, δ) 170.45, 169.71,

153.15, 151.02, 147.10, 139.05, 138.77, 138.54, 61.93, 61.88, 61.80, 14.09, 14.04, 4.32, 3.77,

1.72.

Ph Ph

1 Ph Compound 2k (white solid, 138 mg, 90%): H NMR (400 MHz, CDCl3, δ)

13 1 7.79-7.17 (18H, m, ArH); C{ H} NMR (101 MHz, CDCl3, δ) 141.61, 141.24, 141.11, 140.72,

140.50, 139.67, 131.25, 130.05, 130.01, 129.57, 128.98, 128.07, 128.04, 127.58, 127.28, 126.74,

126.67, 126.27.

F

F

F Compound 2l (yellow solid, 165 mg, 92%): 1H NMR (400 MHz,

CDCl3, δ) 7.65-7.55 (4H, m, ArH), 7.45-7.43 (1H, m, ArH), 7.15-7.08 (6H, m, ArH), 6.95-6.90

13 1 1 (4H, m, ArH); C{ H} NMR (101 MHz, CDCl3, δ) 162.74 (d, JC-F = 247.4 Hz, CF), 162.00 (d,

1 1 4 JC-F = 247.4 Hz, CF), 161.94 (d, JC-F = 247.4 Hz, CF), 140.14, 139.74, 138.62, 137.24 (d, JC-F

4 4 3 = 3.0 Hz), 136.88 (d, JC-F = 3.0 Hz), 136.58 (d, JC-F = 3.0 Hz), 131.50 (d, JC-F = 9.1 Hz),

111 3 3 2 131.46 (d, JC-F = 7.1 Hz), 131.22, 129.30, 128.80 (d, JC-F = 8.1 Hz), 126.30, 115.90 (d, JC-F =

2 2 20.2 Hz), 115.19 (d, JC-F = 22.2 Hz), 115.15 (d, JC-F = 24.2 Hz).

CO2Me

MeO2C

CO2Me Compound 2m (pale yellow solid, 216 mg, 90%): 1H NMR

(400 MHz, CDCl3, δ) 8.16-8.12 (2H, m, ArH), 7.92-7.89 (4H, m, ArH), 7.76-7.68 (4H, m, ArH),

13 1 7.55-7.52 (1H, m, ArH), 7.24-7.20 (4H, m, ArH), 3.94 (3H, s, CH3), 3.89 (6H, s, CH3); C{ H}

NMR (101 MHz, CDCl3, δ) 166.82, 145.53, 145.20, 144.43, 140.26, 139.90, 139.36, 131.22,

130.26, 129.87, 129.81, 129.49, 129.44, 129.36, 128.72, 128.64, 127.05, 126.97, 52.22, 52.15.

Ph Ph Ph

Ph Ph 1 Ph Compound 2n (white solid, 203 mg, 76%): H NMR (400 MHz, CDCl3,

13 1 δ) 6.87-6.82 (30H, m, ArH); C{ H} NMR (101 MHz, CDCl3, δ) 140.75, 140.44, 131.56,

126.71, 125.32.

112 N N

N Compound 2o (pale yellow solid, 146 mg, 95%): 1H NMR (400 MHz,

3 3 CDCl3, δ) 8.72 (1H, d, JH-H = 8.0 Hz, ArH), 8.62 (2H, d, JH-H = 8.0 Hz, ArH ), 8.32 (1H, s,

3 ArH), 8.19 (1H, d, JH-H = 8.0 Hz, ArH), 7.88-7.75 (3H, m, ArH), 7.51-7.45 (2H, m, ArH), 7.27-

13 1 7.24 (1H, m, ArH), 7.17-7.03 (4H, m, ArH); C{ H} NMR (101 MHz, CDCl3, δ) 159.26,

158.85, 156.67, 149.79, 149.56, 149.54, 140.21, 140.17, 139.58, 136.83, 135.69, 135.63, 131.05,

129.08, 127.02, 125.12, 122.46, 121.70, 120.82; IR (neat, cm-1) 3005, 1583, 1562, 1466, 1458,

1442, 1423, 1386, 1306, 1288, 1249, 1141, 1096, 1047, 1030, 1019, 988, 962, 929, 900, 857,

847, 802, 793, 781, 773, 753, 718, 646, 634, 622, 612, 579, 541, 524, 498, 445; HRMS-ESI

+ (m/z) [M+H] calcd for C21H16N3 310.1344, found 310.1341.

+

Compounds 2p + 3p (6:1 ratio, colorless oil, 87 mg, 88%

1 3 combined yield): H NMR (400 MHz, CDCl3, δ) 6.86 (1H, d, JH-H = 8.0 Hz, ArH of 2p), 6.79

3 (1H, d, JH-H = 8.0 Hz, ArH of 2p), 6.70 (1H, s, ArH of 2p), 6.57 (0.5H, s, ArH of 3p), 2.26-2.05

(2H, m, CH of 2p), 1.85-1.78 (1.5H, m, CH of 2p and 3p), 1.02-0.78 (7H, m, CH2 of 2p and 3p),

13 1 0.75-0.53 (7H, m, CH2 of 2p and 3p); C{ H} NMR (101 MHz, CDCl3, δ) of 2p: 142.43,

141.28, 139.74, 125.37, 122.91, 122.69, 15.22, 13.22, 12.92, 9.04, 7.33, 7.21; 13C{1H} NMR

-1 (101 MHz, CDCl3, δ) of 3p: 143.98, 120.39, 15.47, 9.09; IR (neat, cm ) 3080, 3002, 1612, 1565,

113 1502, 1461, 1426, 1348, 1217, 1173, 1099, 1045, 1015, 945, 895, 812, 743, 702, 660, 626, 518,

+ 455; HRMS-ESI (m/z) [M+H] calcd for C15H19 199.1487, found 199.1483.

114

Appendix 1

Asymmetric Reductive Coupling of Ynoates and Aldehydes

A1.1 Introduction

There are two general methods available in the literature for nickel-catalyzed asymmetric reductive coupling of alkynes and aldehydes.1 One protocol uses (+)-NMDP as a chiral monodentate phosphine ligand. In this work it has been shown that internal aromatic alkynes undergo reductive coupling in good yields and moderate to good enantioselectivities varying from 42% ee to 96% ee (Scheme 1).2 The substrate scope is limited to aryl-substituted alkynes.

Highest asymmetric induction has been achieved with α-branched aldehydes.

Scheme 1. Asymmetric induction with chiral phosphines

Ni(COD)2 10 mol% O R3 OH Me + (+)-NMDPP 20 mol% Me PPh R1 H R2 R1 R3 2 Et3B (2.0 eq), DMI/EtOAc (1:1) R2 (+)-NMDPP

OH OH OH OH Me Me Ph i-Pr Ph Ph Ph n-Pr n-Pr Me Et Me n-Pr Me

95% (90% ee) 79% (73% ee) 74% (92% ee) 35% (42% ee)

Chiral N-heterocyclic carbenes (NHCs) have been employed for asymmetric nickel- catalyzed reductive coupling (Scheme 2).3 Broad substrate scopes have been observed for both aldehydes and alkynes. Enantioselectivities ranging from 65% to 85% have been achieved with this catalytic system. Aliphatic alkynes are as effective as aromatic alkynes. For aldehydes, both aliphatic and aromatic ones are viable substrates for this reaction.

1 Hasnain, A. M.; Baxter, R. D.; Montgomery, J. In Catalysis without precious metals; Bullock, R. M, Ed.; Wiley: 2010; pp199 2 Miller, K. M.; Huang, W, -S, Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. 3 Chalugain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568.

116 Scheme 2. Asymmetric induction using a chiral NHC ligand

Ph Ph Cy Cy BF - Ni(COD)2 10 mol% 4 N N 10 mol% O R3 (R,R)-L OH t + KO Bu 10 mol% Cy Me Me Cy 1 3 R H R2 Et SiH (2 eq), THF R1 R 3 (R,R)-L R2

OSiEt3 OSiEt3 OSiEt3 OSiEt3

Ph Ph Et C-Hex n-Hex C-Hex Ph C-Hex Me Et HO

98% (78% ee) 84% (85% ee) 64% (>19:1 rs, 65% ee) 35% (42% ee)

We have demonstrated that γ-hydroxy-α,β-enoates, produced from coupling of ynoates and aldehydes, (Scheme 3, see Chapter 2) are important building blocks for a diverse array of

Scheme 3. Nickel-catalyzed reductive coupling of ynoates and aldehydes

O Ni(COD) (10 mol%) 2 R2 O R2 SIPr HBF (10 mol%) O 4 3 R1O t R KO Bu (10 mol%) 1 R2 R1O + R O H PPh3 (10 mol%) + H OSiEt 3 R3 OSiEt3 R3CHO Et SiH THF, 23 oC 3 minor product compounds. In particular, we have shown silyl-protected γ-hydroxy-α,β-enoates can be converted cyclic molecules such as γ-butyrolactones and tetrahydrofurans (Scheme 4).

Scheme 4. Synthetic applications of silyl-protected γ-hydroxy-α,β-enoates O

O O R2 O R2 R3 R3 R1O [Ni] + R1O R2 H OSiEt R3CHO Et3SiH 3 γ-hydroxy-α-β-enoates O

R2 R3

117 Given the fact that γ-butyrolactones are present in about 10% of all natural products,4 we anticipate that this method may open up a new synthetic path to these molecules. We envisioned as most of the natural products with a γ-butyrolactone core posses stereo centers5 (Figure 1) enantioselective coupling of ynoates and aldehydes would be more useful.

Figure 1. Natural products with γ-butyrolactone core

A1.2 Synthesis and Application of Chiral NHC Ligands

Considering the optimized conditions for the reductive coupling of ynoates and aldehydes, we wished to develop chiral NHC ligands for the asymmetric reaction. Since SIPr was found to be the best ligand for the coupling reaction we decided first to synthesize new NHC ligand 1, which is closely related to SIPr.

iPr iPr Ph Ph iPr iPr N N N N

iPr iPr iPr iPr SIPr PhSIPr

4 Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. 1985, 24, 94. 5 (a) Seitz, M.; Reiser, O. Curr. Opin. Chem. Bio. 2005, 9, 285. (b) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem. 2005, 243, 43.

118 The common approach is first to synthesize N-aryl substituted diamine via palladium-catalyzed cross coupling reaction, followed by the cyclization with (EtO)3CH to yield the desired NHC precursors (Scheme 5)

Scheme 5. Procedure for the synthesis of chiral NHCs

Ph Ph R R Br Ph Ph R R N N + H2N NH2 R R

Ph Ph R R

Br t Ph Ph Pd2(dba)3 , BINAP, BuOK NHHN R R + toluene, 100 oC H2N NH2 R R

Ph Ph R R (EtO)3CH , formic acid N N - BF4 H4NBF4 R R

When the reaction between 4 and (1R, 2R)-(+)-1,2-diphenylmethylenediamine was attempted, the expected product 5 was not observed (Scheme 6). Apparently, palladium- catalyzed C-N cross coupling is not operating for aryl groups bearing large ortho substituents.

119 Scheme 6. Attempted synthesis of precursor for PhSIPr

NH2 Ph Ph 1 eq NH2 Ph Ph Ph Ph i i i i Pr Pr Pr Pr - Br Pd2(dba)3, CHCl3 0.05 eq BF NH BF 4 BINAP 0.12 eq NHHN 4 4 N N HCO2H t 3 eq Na OBu iPr iPr HC(OEt)3 iPr iPr o 4 o 120 C, 12 h Toluene, 90 C, 48 h 5 6 2.4 eq did not form

Next, a procedure similar to the one shown in Scheme 5 was used to synthesize chiral

NHC precursors 7 and 8 with aryl groups containing smaller ortho substituents.

Ph Ph Ph Ph

N N N N

7 8

The coupling of ynoate 1 and PhCHO was attempted using standard conditions in the presence of 7 and 8 separately. Only ligand generated from 7 gave desired products at about

15% yield while a similar reaction using 8 did not yield any product.

Scheme 7. Coupling of ynoate 1 and PhCHO

O Ni(COD)2 10 mol % L 10 mol % O O MeO t KO Bu 10 mol % Ph 1 MeO + MeO + THF, 23 oC O OSiEt3 Ph OSiEt Et3SiH 3 Ph H 3a 3a' 2a

120 A1.3 Determination of Enantiomeric Ratios

Separation of the enantiomers was attempted using HPLC equipped with a chiral column

Chiralpak AD-H or Chiralpak OJ-H (Figure 2).

OR OR

O O RO RO OR OR O n O n

Silica-gel Silica-gel

H CH3 R= N CH3 O R= O CH3 Chiralpak AD-H Chiralpak OJ-H

Figure 2. Structures of sugar molecules in chiralpak AD-H and OJ-H

Unfortunately, no separation of the silyl-protected products was observed. This could be due to the weak interaction of silyl-protected compounds with the column materials. Next, it was decided to use unprotected compounds for the HPLC separation. When these silyl- protected γ-hydroxy-α,β-enoates were subjected to deprotection procedure (see Chapter 2) they underwent isomerization to yield 1,4-dicarbonyl compounds as shown in Scheme 8. This process results in the loss of the chiral center. In contrast, related silyl-protected allylic alcohols

121 were reported in the literature to undergo silyl-deprotection without isomerization (Scheme 9).6

It is likely that the ester group in our compounds might have some role in this rearrangement.

Scheme 8. Silyl-deprotection of γ-hydroxy-α,β-enoates

O TBAF O Ph THF, 23 oC Ph RO RO

OSiEt3 OH expected product

O Ph RO O observed product

Scheme 9. Silyl-deprotection in related systems

OSiEt3 TBAF OH THF, 23 oC Ph Ph Ph Ph Me Me

A1.4 An Alternative Way for Deprotecting the Hydroxyl Group

As an attempt to prevent the aforementioned isomerization, it was decided to first reduce the ester group of silyl-protected γ-hydroxy-α,β-enoates and then attempt the silyl-deprotection as shown in Scheme10. First step of this scheme was successful and reduced product 9 was isolated.

6 Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568

122 Scheme 10. An alternative way of conducting silyl-deprotection

O OH OH TBAF Ph DIBAL Ph Ph MeO

OSiEt3 OSiEt3 OH 3a 9 10

A1.5 Suggested Future Work

Moving forward this project, the silyl-deprotection step in Scheme 10 should be performed and the expected product 10 should be subjected to HPLC separation of the enantiomers. In addition, the chiral NHC precursors shown in Chart 1 should be synthesized and utilized in nickel-catalytic asymmetric reductive coupling reaction.

Ph Ph - BF4 N N

Cp Cp Cp Cp

Ph Ph Ph Ph - BF - BF4 4 N N N N

Cy Cy Cy Cy

Chart 1

123 A1.6 Experimental

Procedure for the synthesis of 7

Ph Ph

NHHN

7' A similar procedure has been described in the literature.7

Under an inert atmosphere, Pd(OAc)2 (8 mg, 0.035 mmol), BINAP (44 mg, 0.07 mmol) and

NaOtBu (205 mg, 2.1 mmol) were weighed in a Schlenk flask and stirred in toluene (10 mL) for

20 min. A solution of (1R,2R)-(+)-1,2-diphenylmethylenediamine (0.71 mmol, 150 mg), and 2- bromo-1,3,5-trimethylbenzene (293 mg, 1.49 mmol) in toluene (3 mL) was then added to the mixture and heated at 100 °C for 16 h. The crude reaction mixture was filtered through Celite

(washed with methylene chloride), concentrated under the vacuum and purified by column chromatography. The product was isolated as a pale yellow solid (270 mg, 85% yield) with spectral data consistent with reported values in the literature.

Ph Ph - BF4 N N

7 The diamine 7ʹ (157 mg, 0.35 mmol) and ammonium tetrafluoroborate (45 mg, 0.42 mmol) were dissolved in triethyl orthoformate (10.0 equiv, 2 mL based on the starting diamine) followed by the addition of a catalytic amount of formic acid (1 drop). The mixture was heated under an inert atmosphere at 120 °C for 5 h. The solution was then allowed to cool to room temperature. The crude reaction mixture was purified by column chromatography (SiO2, 1:10 methanol/CH2Cl2) to afford 7 as off-white solids with spectral data

7 Seiders, T. J.; Ward, d. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225

124 consistent with reported values in the literature.

Procedure for the reduction of compound 3a

OH Ph

OSiEt3 9 A similar procedure has been described in the literature.8 The solution of

o ester 3a (153 mg, 0.5 mmol) in Et2O (10 mL) was cooled to -78 C and 1 M DIBAL-H solution in hexane (350 µl, 2.2 equiv) was added dropwise. The reaction mixture was allowed to stir at -

78 oC for 2 h and then warmed up to room temperature. A brine solution (15 mL) was added and stirred until the phases were seen. The aqueous phase was separated and extracted with Et2O

(3x15 mL). The combined organic phases were washed with brine, dried over Na2SO4 and purified on silica gel using ether and hexane (128 mg, 92% yield). The spectral data are consistent with literature values.

8 Jaunzeme, I.; Jirgensons, A. Tetrahedron 2008, 64, 5794

125

Appendix 2

1H NMR and 13C NMR Spectra (Chapter 2)

3 l C D C n i 3 t E i S O a 3 O O e M R M N H 1

127 3 l C D C n i 3 t E i S O a 3 O O e M R M N } H 1 { C 3 1

128 3 l C D C n i 3 t E i S O ' a 3 h O P O e M R M N H 1

129 3 l C D C n i 3 t E i S O ' a 3 h O P O e M R M N } H 1 { C 3 1

130 3 l C D C n i e M 3 t E i S O b 3 O O e M R M N H 1

131 3 l C D C n i e M 3 t E i S O b 3 O O e M R M N } H 1 { C 3 1

132 3 l C D C e n i M O 3 t E i S O c 3 O O e M R M N H 1

133 3 l C D C e n i M O 3 t E i S O c 3 O O e M R M N } H 1 { C 3 1

134 3 l C D C n i l C 3 t E i S O d 3 O O e M R M N H 1

135 3 l C D C n i l C 3 t E i S O d 3 O O e M R M N } H 1 { C 3 1

136 3 l C D C e n O i M O 3 t E i S O e 3 O O e M R M N H 1

137 3 l C D C e n O i M O 3 t E i S O e 3 O O e M R M N H 1

138 3 l C D C n i F 3 t E i S O f 3 O O e M R M N H 1

139 3 l C D C n i F 3 t E i S O f 3 O O e M R M N } H 1 { C 3 1

140 3 l C D C n i 3 F t E i S O g 3 O O e M R M N H 1

141 3 l C D C n i 3 F t E i S O g 3 O O e M R M N } H 1 { C 3 1

142 3 l C D C n i 3 t E i S F O h 3 O O e M R M N H 1

143 3 l C D C n i 3 t E i S F O h 3 O O e M R M N } H 1 { C 3 1

144 3 l C D C n i 3 t E i S e O M i 3 O O e M R M N H 1

145 3 l C D C n i 3 t E i S e O M i 3 O O e M R M N } H 1 { C 3 1

146 3 l C D C n i 3 t E i S O j 3 O O e M R M N H 1

147 3 l C D C n i 3 t E i S O j 3 O O e M R M N } H 1 { C 3 1

148 3 l C D C n i 3 t E i S O k 3 O O t E R M N H 1

149 3 l C D C n i 3 t E i S O k 3 O O t E R M N } H 1 { C 3 1

150 3 l C D C n i 3 t E i S O l 3 O O R M N H 1

151 3 l C D C n i 3 t E i S O l 3 O O R M N } H 1 { C 3 1

152 3 l C D C n i 3 t E i S O m 3 O O R M N H 1

153 3 l C D C n i 3 t E i S O m 3 O O R M N } H 1 { C 3 1

154 3 l C D C n i 3 t E i S O n 3 O O e M R M N H 1

155 3 l C D C n i 3 t E i S O n 3 O O e M R M N } H 1 { C 3 1

156 3 l C D C n i 3 t E i S O o 3 O O e M R M N H 1

157 3 l C D C n i 3 t E i S O o 3 O O e M R M N } H 1 { C 3 1

158 3 l C D C n i 3 t E i S O p 3 O O e M R M N H 1

159 3 l C D C n i 3 t E i S O p 3 O O e M R M N } H 1 { C 3 1

160 3 l C D C n i 3 t E i S O q 3 O O e M R M N H 1

161 3 l C D C n i 3 t E i S O q 3 O O e M R M N } H 1 { C 3 1

162 3 l C D C n i 3 t E i S S O M T r 3 O O t E R M N H 1

163 3 l C D C n i 3 t E i S S O M T r 3 O O t E R M N } H 1 { C 3 1

164 3 l C D C n i 3 t E i S S O M T s 3 O O t E R M N H 1

165 3 l C D C n i 3 t E i S S O M T s 3 O O t E R M N } H 1 { C 3 1

166 3 CDCl in 3 OSiEt F 6 O MeO HNMR 1

167 3 CDCl in 3 OSiEt F 6 O MeO H}NMR 1 { C 13

168 3 CDCl in F 7 O O HNMR 1

169 3 CDCl in F 7 O O H}NMR 1 { C 13

170 3 CDCl in O F 8 O MeO HNMR 1

171 3 CDCl in O F 8 O MeO H}NMR 1 { C 13

172 3 CDCl in OH F 9 HO HNMR 1

173 3 CDCl in OH F 9 HO H}NMR 1 { C 13

174 3 CDCl in F 10 O HNMR 1

175 3 CDCl in F 10 O H}NMR 1 { C 13

176

Appendix 3

1H NMR and 13C NMR Spectra (Chapter 3)

3

CDCl in

Me 2

CO

3

OSiEt TMS

3t

O EtO

HNMR

1

178

3 CDCl in Me 2

CO

3

OSiEt

TMS

3t

O EtO H}NMR 1 C{ 13

179

Appendix 4

1H NMR and 13C NMR

Spectra (Chapter 4)

3

CDCl in OMe O O O MeO MeO HNMR 1

181

3 CDCl in OMe O O O MeO MeO NMR H}

1

{

C

13

182

3 CDCl in

OEt

O

O O

EtO EtO HNMR 1

183

3 CDCl

in

OEt

O

O O

EtO EtO NMR H} 1 { C 13

184

3 CDCl in Bu t O O O O BuO BuO t t HNMR 1

185

3 CDCl in

Bu

t

O

O O O BuO BuO t t NMR H} 1 { C

13

186

CDCl3 in O O O O O O + O O O O O O HNMR 1

187

CDCl3 in O O O O O O + O O O O O O H]NMR 1 C{ 13

188

3

CDCl

in Et Et 2 2 CO CO Et Et 2 2 CO CO C C 2 2 EtO EtO HNMR 1

189

3 CDCl in Et Et 2 2 CO CO Et Et 2 2 CO CO C C

2 2

EtO EtO NMR H} 1 {

C

13

190

3 CDCl in Et 2 Ph CO Et Et 2 2 CO CO Ph Ph HNMR 1

191

3 CDCl in Et 2 Ph CO Et Et 2 2 CO CO Ph Ph NMR H} 1 { C 13

192

3 l C D

C

n

i

t E 2 e O t t C M E E 2 2 O O C C e e

M M

R

M

N

H

1

193

3 l C D

C

n

i

t E 2 e O

t t C

M

E E

2 2

O O C C e e M M R M N } H 1 { C 3 1

194

3

CDCl

in

Me

2

CO

Me Me

2 2

CO CO

HNMR

1

195

3

CDCl

in

Me

2

CO Me Me 2 2

CO CO

NMR

H}

1 { C 13

196

3

CDCl

in

Me

2

CO

Me Me

2 2

CO CO

HNMR 1

197

3

CDCl

in

Me

2

CO

Me Me

2 2

CO CO

NMR H} 1 { C

13

198

3

CDCl

in

Et

2

TMS CO

Et Et

2 2

CO CO

TMS TMS HNMR 1

199

3

CDCl

in

Et 2 TMS CO Et Et 2 2 CO CO

TMS TMS

NMR

H}

1

{

C

13

200

3 CDCl in HNMR 1

201

3 CDCl in NMR H} 1 { C 13

202

3 CDCl in F F F HNMR 1

203

3 CDCl in F F F

NMR

H}

1 {

C

13

204

3 CDCl Me in 2 CO Me Me 2 2 CO CO

HNMR

1

205

3 CDCl Me in 2 CO

Me Me

2 2 CO CO NMR H} 1 { C 13

206

3 CDCl in HNMR 1

207

3 CDCl in

NMR H} 1 { C 13

208

3 CDCl in N N N HNMR 1

209

3 CDCl in N N N NMR H} 1 { C 13

210

3

CDCl

in

+ HNMR 1

211

3 CDCl in +

NMR H} 1 { C 13

212