Synthesis and Ring-Opening Reactions of Bicyclic Alkene-Fused Isoxazolines by Jaipal Reddy Nagireddy A Thesis Presented to The University of Guelph In partial fulfillment of requirements for the degree of Doctor of Philosophy in Chemistry Guelph, Ontario, Canada  Jaipal Reddy Nagireddy, December, 2014 ABSTRACT Synthesis and Ring-Opening Reactions of Bicyclic Alkene-Fused Isoxazolines Jaipal Reddy Nagireddy Advisor: University of Guelph, 2014 Prof. William Tam This thesis is an investigation of 1,3-dipolar cycloaddition reactions of nitrile oxides with symmetrical and unsymmetrical bicyclic alkenes, and their subsequent isoxazoline ring opening reactions. Although a large number of 1,3-dipolar cycloaddition reactions between nitrile oxides and bicyclic alkenes have been reported, most of these are currently limited to carbobicyclic alkenes. Introduction of a heteroatom in the bicyclic ring offers differences in the reactivity and selectivity of cycloaddition reactions. Introduction of a substituent at the bridgehead carbon of the bicycloalkene makes the molecule unsymmetrical. The implications of the reduction of symmetry in C1-substituted heterobicyclic rings open the door to regioselectivity studies for these cycloaddition reactions. The stereo- and regiochemical aspects of 1,3-dipolar cycloaddition reactions with acetonitrile oxide and benzonitrile oxide were examined on a wide variety of symmetrical and unsymmetrical oxabicyclic and azabicyclic alkenes. The cycloadditions were found to be completely stereoselective producing only the exo adducts in moderate to excellent yields. In the majority of the cycloaddition reactions, both of the possible regioisomers were produced in varying ratios that depended on electronic and steric effects of the C1 substituent. After having generated numerous isoxazoline derivatives, various metal-catalyzed (Mo, Pd, Zn, Fe and Ni) cleavage conditions were investigated, with successful N-O bond cleavage of isoxazoline rings achieved using Raney-Ni/AlCl An N-O bond 3. cleavage, followed by an imine hydrolysis led to the formation of a variety of novel β- hydroxyketone products with moderate to excellent yields. In the early part of this project, a simple and scalable procedure for the preparation of 2-bromofuran was developed. 2-Bromofuran was found to be useful for preparing a series of 2-aryl furans using the Suzuki cross coupling reaction with arylboronic acids. Similarly 2-alkyl furans were prepared using an iron catalyzed cross coupling reaction between 2-bromofuran and alkyl Grignard reagents. The 2-substituted furans were used for the preparation of various C1-substituted oxabicyclic alkenes via the Diels-Alder cycloaddition strategy. Acknowledgements First and foremost, I would like to thank my supervisor, Prof. William Tam, who has provided me with the opportunity to pursue my goals. I am highly grateful to Prof. Tam for his encouragement, motivation and guidance for all these years. I owe special thanks to Prof. Tam for his numerous meeting appointments on weekends. I would like to express my gratitude to my advisory committee members Prof. Mike Chong of University of Waterloo, Prof. Adrian Schwan, Prof. Michael Denk and Prof. France-Isabelle Auzanneau, of University of Guelph for their contributions to my experiences as a Ph.D. candidate. I would like to thank my external examiner Dr. Malik Slassi, President & Chief Scientific Officer of Fluorinov Pharma Inc. for agreeing to participate in my dissertation. I would also like to thank Prof. Wojciech Gabryelski, the chair of the examination committee and Prof. Richard Manderville of University of Guelph for being on my defense examination committee. I would like to express my sincere thanks to Mr. Darren Hall, Mr. Jason Fischer, Dr. Steve Horne, and Dr. Gamini Weeratunga for their encouragement at Apotex Pharmachem Inc. I would like to offer my special thanks to Dr. Bhaskar Guntoori and Dr. Keshava Murthy for inspiring me to pursue PhD studies. I would like to thank Dr. Farzad Mirzaei for his encouragement and support at Vibrant Pharma Inc. I would also like to thank all the past and present members of the Tam group. I would like to thank my friend Raheem for always being there in each and every step of my graduate studies and making this fabulous task possible. I would also like to thank Karine, Gavin, Nicole and Woo for their support and enlightening conversations. I would also like to thank Michelle, Jordon, Neil, Ben, Paul and Jamie for their friendly discussions and help during my research. I owe a special thanks to Paula Estey and Emily Carlson for not only proofreading my thesis but also providing very valuable suggestions for improvement. I sincerely appreciate their time and efforts in shaping my thesis. I would like to thank my parents, all my friends and family members who have tolerated my absence during studies. Most significantly, I appreciate and thank my wife Nalini and my daughter Harika for their support, understanding and sacrifices during the course of my graduate studies. Table of Contents vi List of Schemes x List of Figures xiv List of Tables xv Abbreviations and Acronyms xvi Appendix List xx Table of Contents Chapter 1 Introduction and Background 1 1.1 Cycloaddition Reactions 2 1.2 Cycloadditions with Bicyclic Alkenes 3 1.3 1,3-Dipolar Cycloadditions 5 1.3.1 Basic Aspects 5 1.3.2 1,3-Dipolar Cycloadditions of Nitrile Oxides 12 Regio- and Stereochemical Aspects of Nitrile Oxide 1,3-Dipolar 1.3.3 15 Cycloadditions 1.3.4 Nitrile Oxide Cycloadditions of Bicyclic Alkenes 20 Tam Group’s Research on Cycloaddition Reactions of Bicyclic 1.4 27 Alkenes 1.4.1 [2+2] Cycloaddition 27 1.4.2 Rhodium Catalyzed Cyclodimerization 33 1.4.3 1,3-Dipolar Cycloaddition 34 1.4.4 Rhodium Catalyzed Cyclopropanation 37 1.5 Ring-Opening Reactions of Isoxazolines 37 1.5.1 β-Hydroxycarbonyls Through N-O Bond Cleavage of Isoxazolines 38 1.5.1.1 Nickel Catalyzed Cleavage 38 1.5.1.2 Palladium Catalyzed Cleavage 39 1.5.1.3 Titanium Catalyzed Cleavage 40 1.5.1.4 Samarium Iodide Catalyzed Cleavage 41 1.5.1.5 Iron Catalyzed Cleavage 41 1.5.1.6 Oxidative Cleavage 42 1.5.1.7 Metal Carbonyl Catalyzed Cleavage 43 1.5.2 Retro-aldol Products from Metal Carbonyl Induced Cleavage 44 1.5.3 γ-Aminoalcohols Through N-O Bond Cleavage 44 1.5.4 Oximes Through C-O Bond Cleavage with Inorganic Bases 45 1.5.5 β-Hydroxynitriles Through N-O Bond Cleavage with Organic Bases 45 vi Synthetic Applications of Nitrile Oxide Cycloadditions Followed 1.6 46 by Ring-Opening Reactions of Isoxazolines 1.7 Research Goals 49 Chapter 2 Synthesis of Substituted Furans and Bicyclic Alkenes 52 2.1 Introduction 53 2.2 Synthesis of 2-Substituted Furans 53 2.2.1 Preparation of 2-Bromofuran 53 2.2.2 Background 54 2.2.3 Results and Discussion 55 2.3 Synthesis of 2-Aryl Furans 55 2.3.1 Background 55 2.3.2 Pd Catalyzed Suzuki Cross Coupling Reactions 56 2.3.3 General Mechanism of Suzuki Cross Coupling Reaction 57 2.3.4 Results and Discussions 58 2.3.5 Pd Catalyst Screening Study 63 2.3.6 Results and Discussions 64 2.4 Synthesis of 2-Alkyl Furans 67 2.4.1 Background 67 2.4.2 Alkyl-Aryl Cross Coupling 68 2.4.3 Iron Catalyzed Cross Coupling 69 2.4.4 Mechanism of the Iron Catalyzed Cross Coupling 69 2.4.5 The Tam Group’s Previous Work on Iron Catalyzed Cross Coupling 72 2.4.6 Results and Discussions 73 2.5 Synthesis of C1-Substituted Oxanorbornenes 79 2.5.1 Background 79 Results of Reactions Between 2-Substituted Furans with Maleic 2.5.2 80 Anhydride Results of Reactions Between 2-Substituted Furans with N- 2.5.3 82 Phenylmaleimide 2.6 Synthesis of C1-Substituted Oxabenzonorbornadienes 85 2.6.1 Background 85 2.6.2 Results and Discussions 86 Chapter 3 1,3-Dipolar Cycloadditions between Bicyclic Alkenes and Nitrile Oxides 94 3.1 Introduction 95 3.2 Proposed Methodology 98 3.3 Stereochemical Considerations 99 3.4 Results and Discussion 101 3.4.1 Cycloadditions with Symmetrical Bicyclic Alkenes 101 1,3-Dipolar Cycloadditions of Symmetrical 7- 3.4.1.1 101 Oxabenzonorbornadienes vii 1,3-Dipolar Cycloadditions of Symmetrical 7- 3.4.1.2 106 Azabenzonorbornadienes 1,3-Dipolar Cycloaddition of 5,6-Bis-methoxymethyl-7-oxa- 3.4.1.3 109 bicyclo[2.2.1]hept-2-ene 3.4.2 Cycloadditions with Unsymmetrical Bicyclic Alkenes 110 1,3-Dipolar Cycloaddition of C1-Substituted-7- 3.4.2.1 110 oxabenzonorbornadienes 1,3-Dipolar Cycloadditions of C1-Substituted N- 3.4.2.2 117 Phenylmaleimide Fused Oxanorbornenes 1,3-Dipolar Cycloaddition of N-Acyl-2-oxa-3-azanorborn- 3.4.2.3 120 5-enes 3.5 Conclusions 128 Chapter 4 Cleavage of Bicyclic Alkene-fused 2-Isoxazolines 130 4.1 Introduction 131 4.2 Development of Cleavage Methodology for 2-Isoxazolines 132 4.3 Molybdenum-Mediated Cleavage of 2-Isoxazolines 134 Tam Group Research on Molybdenum-Mediated Cleavage 4.3.1 134 Reactions of 2-isoxazolines 4.3.2 Results and Discussion on Molybdenum-Mediated Cleavage 137 4.4 Palladium-Mediated Cleavage of 2-Isoxazolines 139 4.5 Zinc-Mediated Cleavage Reactions of 2-Isoxazolines 140 4.6 Fe-NH Cl -Mediated Cleavage of 2-Isoxazolines 140 4 4.7 Nickel-Mediated Cleavage of 2-Isoxazolines 141 4.7.1 Results and Discussion on Nickel-Mediated Cleavage 142 Cleavage of 2-Isoxazolines Derived from Symmetrical 7- 4.7.2 143 Oxabenzonorbornadienes Cleavage of 3-Methyl-2-isoxazolines Derived from C1-Substituted 4.7.3 146 7-Oxabenzonorbornadienes Cleavage of 3-Methyl-2-isoxazolines Derived from C1-Substituted 4.7.4 148 7-Oxanorbornenes Cleavage of 3-Methyl-2-isoxazolines Derived from Symmetrical 4.7.5 149 7-Azabenzonorbornadienes viii 4.8 Conclusions 150 Chapter 5 Epilogue 152 5.1 Synopsis 153 5.2 Future Perspective 159 Chapter 6 162 6.1 Experimental Sections 163 6.2 Appendix 215 6.3 References 241 ix List of Schemes Selected examples of norbornadiene/norbornene cycloaddition Scheme 1.1 4 reactions. Scheme 1.2 Representation of allyl/propargyl type 1,3-dipoles. 6 Scheme 1.3 Examples of common allyl/propargyl type 1,3-dipoles. 7 Huisgen-proposed concerted mechanism for 1,3-dipolar Scheme 1.4 8 cycloaddition. Firestone-proposed step-wise mechanism for 1,3-dipolar Scheme 1.5 8 cycloaddition. Regiochemical considerations based on orbital coefficient Scheme 1.6 11 magnitudes. Scheme 1.7 1,3-Dipolar cycloaddition of nitrile oxide with alkenes/alkynes. 13 Scheme 1.8 Resonance structures of nitrile oxides. 13 Scheme 1.9 Preparation of nitrile oxides from aldehydes. 14 Preparation of nitrile oxides from nitroalkanes using Mukaiyama Scheme 1.10 14 method. Preparation of nitrile oxides from nitroalkanes using Hassner’s Scheme 1.11 15 method. Possible regioisomers from 1,3-DCA of nitrile oxides with Scheme 1.12 16 monosubstituted olefins. Possible regioisomers from 1,3-DCA of nitrile oxides with 1,2- Scheme 1.13 16 disubstituted olefins. Possible regio- and stereoisomers from 1,3-DCA of nitrile oxides Scheme 1.14 17 with 1,2-disubstituted is and trans olefins. 1,3-DCA of chiral nitrile oxide 1-64 with cis 1,2-disubstituted Scheme 1.15 18 olefin. 1,3-DCA of chiral nitrile oxide 1-67 with cis 1,2-disubstituted Scheme 1.16 18 olefin. Scheme 1.17 1,3-DCA of nitrile oxides with chiral olefin 1-71. 19 Scheme 1.18 1,3-DCA of nitrile oxide 1-75 with chiral olefin 1-74. 19 Scheme 1.19 1,3-DCA of olefins with chiral auxiliary. 20 Scheme 1.20 Nitrile oxide 1,3-DCA of norbornadienes 1-86. 21 Scheme 1.21 Nitrile oxide 1,3-DCA of bicyclic alkenes 1-89 to 1-91. 22 Scheme 1.22 Nitrile oxide 1,3-DCA of bicyclic alkene 1-98. 23 Scheme 1.23 Nitrile oxide 1,3-DCA of bicyclic alkenes 1-102. 24 Scheme 1.24 Nitrile oxide 1,3-DCA of bicyclic alkenes 1-106. 25 Scheme 1.25 Nitrile oxide 1,3-DCA of bicyclic alkenes 1-109. 25 x