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Photochemical asymmetric synthesis and novel photoreactions in the solid state Kang, Ting 2001

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PHOTOCHEMICAL ASYMMETRIC SYNTHESIS AND NOVEL PHOTORJEACTIONS IN THE SOLID STATE by T I N G K A N G B.Sc, Nankai University, P.R.China, 1993 M.Sc., Nankai University, P.R.China, 1996 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE D E G R E E OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (DEPARTMENT OF CHEMISTRY) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH C O L U M B I A M A Y 2001 ©Ting Kang, 2001 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department The University of British Columbia Vancouver, Canada DE-6 (2/88) Abstract The photochemistry of several cis- and fra«5-9-decalyl aryl ketones was studied in solution and the solid-state. Norrish/Yang type II photocyclization was found to be the major process in both media, and the e«<io-aryl cyclobutanols were obtained exclusively. No type II photoelimination products were observed. The reactions in the solid state were regiospecific and only one of two possible cyclobutanols was formed. The results were rationalized by means of crystal structure-reactivity correlation studies. The crystal structures of six starting ketones showed that the disposition of the carbonyl chromophore favored the abstraction of only one y-hydrogen in each case, resulting in only one cyclobutanol. The poor orbital overlap calculated from these structures eliminated the possibility of photocleavage. The least motion character of the solid-state reaction suppressed the formation of the exo-cyclobutanols, leading to very high diastereoselectivity. In both the cis- and trans- systems, some novel products were obtained. The rarely seen P-hydrogen abstraction products were observed in the czs-ketones, presumably initiated by favorable stereoelectronic factors. However, the product formed in the solid state was different from those in solution and could not be obtained in the latter medium, reflecting a "latent reactivity". Unprecedented decarbonylation products were formed in the case of the trans-ketones with a possible mechanism proposed. The "ionic chiral auxiliary" approach was applied to both the cis- and fraws-ketones and poor to excellent enantiomeric excess (ee) values were observed. From the crystal structures of three salts, it was found that the presence of a single conformation of the salt in the unit cell resulted in high ee's, and that "conformational enantiomerism", i.e., the co-existence of both ii enantiomeric conformations of the anion portion of the salt in the same unit cell, led to poor ee's. Two novel solid-state photochemical reactions were investigated. The first involved the formation of oxetanes from photolysis of crystals of 1-phenylcyclopentyl aryl ketones, while solution-state reactions of the same compounds afforded only typical Norrish type I products. Oxetane formation was rationalized by type I cleavage followed by hydrogen abstraction and a subsequent Paternd-Blichi reaction. Asymmetric induction in this reaction through formation of chiral salts gave poor to fair ee's. The extension of this reaction to acyclic as well as other cyclic systems met with failure. The second reaction was concerned with photochemical 1,3-phenyl migration in the cc-phenyl substituted aromatic ketones. Although the reaction has been studied before in solution, the solid-state version was never investigated. The crystals of the starting ketones showed very high selectivity, yielding the migration products exclusively, while the solution reactions afforded both migration and type I cleavage products,. i i i Table of Contents Abstract ii Table of Contents iv List of Figures ix List of Schemes xii List of Tables xiv List of Symbols and Abbreviations xv Acknowledgements xvii Dedications • • xix Part I Asymmetric Yang Photocyclization in the Solid State CHAPTER 1. INTRODUCTION 2 1.1 The Norrish/Yang Type II Reaction 2 1.1.1 General Aspects 2 1.1.2 Electronic Aspects 4 1.1.3 Extension of the Norrish/Yang Type. II Reaction 5 1.2 Orientational Requirements for the Norrish/Yang Type II Reaction 8 1.3 The Topochemical Postulate 11 1.4 The "Ionic Chiral Auxiliary" Approach 19 1.5 Solid-State X-ray Structure-Reactivity Correlations '. 25 1.6 Thesis Goals 26 CHAPTER 2. PREPARATION OF SUBSTRATES 28 2.1 Preparation of the cz's-9-Decalyl Aryl Ketones 28 2.2 Preparation of trans-9-Decalyl Aryl Ketones 32 2.3 Preparation of Chiral Salts of Keto Acids 46 and 53 35 CHAPTER 3. ISOLATION AND IDENTIFICATION OF THE PHOTOPRODUCTS OF THE cw-KETONES 38 iv 3.1 Photochemical Reactions of the cw-Ketones 38 3.2 Identification of the Cyclobutanols 75-78 41 3.3 Identification of Cyclobutanols 79-82 49 3.4 Identification of the 1-Indanone Derivatives 83-86 55 3.5 Identification of Cyclopropanol 87 59 3.6 Photolysis of the cz's-Chiral Salts and the Enantiomeric Excess Determination of the Photoproducts 62 CHAPTER 4. STRUCTURE-REACTIVITY CORRELATION A N D KINETIC STUDIES FOR THE cw-KETONES 64 4.1 Regio- and Diastereoselectivity of Cyclobutanol Formation 65 4.2 Cleavage vs Cyclization 69 4.3 Enantioselectivity in the Solid State 71 4.4 Kinetic Studies of the Photochemical Process of Ketone 43 78 4.5 Competition between (5- and y-Hydrogen Abstractions 82 4.6 Summary 85 CHAPTER 5. ISOLATION AND IDENTIFICATION OF THE PHOTOPRODUCTS OF THE fra/w-KETONES 87 5.1 Photochemical Reactions of the tran^-Ketones 87 5.2 Identification of Cyclobutanols 94-97 89 5.3 Identification of a-Tetralone Derivatives 98 and 99 96 5.4 Identification of Decarbonylation Products 100 and 101 100 5.5 Photolysis of Chiral Salts and Enantiomeric Excess Determinations 106 CHAPTER 6. STRUCTURE-REACTIVITY CORRELATION STUDIES FOR THE fraws-KETONES 108 6.1 Reactivity and Selectivity in the Photoreactions of Ketones 50-54 109 6.2 Proposed Mechanisms for the Formation of Products 98-101 113 6.3 Asymmetric Induction in the Solid State 116 6.4 Summary 117 Part II Novel Photochemical Reactions in the Solid State CHAPTER 7. PATERNO-BUCHI REACTION IN THE SOLID STATE 120 7.1 Introduction 120 7.2 Synthesis of the Starting Materials 124 7.3 Photochemical Reactions of Ketones 126,128 and 130 126 7.4 Characterization of Oxetanes 136-141 128 7.5 Mechanistic Studies of the Formation of the Oxetanes in the Solid State 133 7.6 Asymmetric Induction in the Solid-State Formation of the Oxetanes 137 7.7 Attempted Extension of the Solid-State Paterno-Biichi Reaction 139 7.8 Summary 141 CHAPTER 8. A NOVEL 1,3-ARYL MIGRATION REACTION IN THE SOLID STATE 142 8.1 Introduction 142 8.1.1 1,5-Aryl Migration 142 8.1.2 1,3-Aryl Migration 145 8.1.3 Research Goals 149 8.2 Preparation of the Substrates and Photochemical Studies 149 8.3 Discussion 154 8.3.1 Formation of Some Novel Products 154 8.3.2 1,3-Phenyl Migration Reaction 156 8.4 Summary and Outlook 159 Part III Experimental CHAPTER 9. SYNTHESES OF STARTING MATERIALS 162 9.1 General Considerations 162 9.2 Synthesis of the cis-Ketones 43-47 167 9.2.1 Synthesis of cw-9-Decalyl Phenyl Ketone (43) 167 vi 9.2.2 Synthesis of cz's-9-Decalyl p-Fluorophenyl Ketone (44) 169 9.2.3 Synthesis ofp-Cyanophenyl cz's-9-Decalyl Ketone (45) 170 9.2.4 Synthesis ofp-Carbohydroxyphenyl czs-9-Decalyl Ketone (46) 172 9.2.5 Synthesis of jo-Carbomethoxyphenyl cw-9-Decalyl Ketone (47) 174 9.3 Synthesis of the zrans-Ketones 50-54 175 9.3.1 Synthesis of trans-9-Deca\yl Phenyl Ketone (50) 175 9.3.2 Synthesis of trans-9-Decalylp-Fluorophenyl Ketone (51) 177 9.3.3 Synthesis ofp-Cyanophenyl zra/is-9-Decalyl Ketone (52) 178 9.3.4 Synthesis of/?-Carbohydroxyphenyl zrarcs-9-Decalyl Ketone (53) 180 9.3.5 Synthesis of/7-Carbomethoxyphenyl zr<ms-9-Decalyl Ketone (54) 181 9.4 Synthesis of cis- and trans-CYma\ salts 55-74 182 9.4.1 General Procedure 182 9.4.2 Synthesis of cis-Chiral salts 55-66 183 9.4.3 Synthesis of trans-Chiral Salts 67-74 197 9.5 Synthesis of Cyclopentyl Ketones 126-130 and Cyclohexyl Ketone 145 206 9.5.1 Synthesis of Phenyl 1-Phenylcyclopentyl Ketone 126 206 9.5.2 Synthesis ofp-Fluorophenyl 1-Phenylcyclopentyl Ketone 127 208 9.5.3 Synthesis ofp-Cyanophenyl 1-Phenylcyclopentyl Ketone (128) 209 9.5.4 Synthesis ofp-Carbohydoxyphenyl 1-Phenylcyclopentyl Ketone (129) 211 9.5.5 Synthesis ofp-Carbomethoxyphenyl 1-Phenylcyclopentyl Ketone (130) 212 9.5.6 Synthesis of Phenyl 1-Phenylcyclohexyl Ketone (145) 213 9.6 Synthesis of the Chiral Salts of Acid 129 (131-134) 214 9.7 Synthesis of Ketones 162 and 164 219 9.8 Independent Synthesis of Ketones 173,174 and 179 221 CHAPTER 10. PHOTOCHEMICAL STUDIES AND QUANTUM YIELDS 225 10.1 General Considerations 225 10.2 Photochemical Studies of cz's-Ketones 43-47 226 10.2.1 Photolysis of Ketone 43 226 10.2.2 Photolysis of Ketone 44 230 vn 10.2.3 Photolysis of Ketone 45 234 10.2.4 Photolysis of Ketone 47 238 10.3 Photochemical Studies of trans-Ketones 50-54 243 10.3.1 Photolysis of Ketone 50 243 10.3.2 Photolysis of Ketone 51 246 10.3.3 Photolysis of Ketone 52 249 10.3.4 Photolysis of Ketone 54 252 10.4 Photochemical Studies of Ketones 126, 128,130 and 145 255 10.4.1 Photolysis of Ketone 126 255 10.4.2 Photolysis of Ketone 128 258 10.4.3 Photolysis of Ketone 130 261 10.4.4 Photolysis of Ketone 145 264 10.5 Photochemical Studies of Ketones 162,146,163 and 164 266 10.5.1 Photolysis of Ketone 162 266 10.5.2 Photolysis of Ketone 146 267 10.5.3 Photolysis of Ketone 163 270 10.5.4 Photolysis of Ketone 164 274 10.6 Quantum Yields and Quenching Studies of Ketone 43 277 References 280 V l l l List of Figures Figure 1.1 Electronic configurations of the carbonyl group 4 Figure 1.2 . Geometric requirements for hydrogen abstraction as suggested by Turro et al 8 Figure 1.3 Geometric requirements for the Norrish/Yang type II reaction 9 Figure 1.4 Conformations of a 1,4-biradical 10 Figure 1.5 Schematic presentation of the "reaction cavity" concept 16 Figure 1.6 Steric compression inhibition of solid-state photodimerization along the "center-to-center" mechanism 18 Figure 1.7 Schematic presentation of the "ionic chiral auxiliary" approach 23 Figure 1.8 Objective compounds 39 and 40 26 Figure 2.1 The ' H N M R (400 MHz) spectra of ketones 43-47 30 Figure 2.2 Partial 1 3 C N M R (75 MHz, CDC13) spectra of ketone 44 at variable temperature 31 Figure 2.3 Conformational isomerization of cw-9-decalyl aryl ketones 31 Figure 2.4 The *H N M R (400 MHz) spectra of ketones 50-54 34 Figure 3.1 Typical ! H N M R spectra of the cyclobutanols 75-78 42 Figure 3.2 The ] H N M R spectrum (500 MHz in C 6 D 6 ) of cyclobutanol 78 43 Figure 3.3 Partial COSY spectrum (500 MHz in C 6 D 6 ) of cyclobutanol 78 44 Figure 3.4 Partial H M Q C spectrum (500 MHz for *H and"l25 M H z for 1 3 C in C 6 D 6 ) of cyclobutanol 78 45 Figure 3.5 The NOE difference spectra (400 MHz in C 6 D 6 ) of 78 46 Figure 3.6 The NOE interactions of the cyclobutanol 78 48 Figure 3.7 The ORTEP drawing of cyclobutanol 78 48 Figure 3.8 Typical ! H N M R spectra of cyclobutanols 79-82 50 Figure 3.9 The *H N M R spectrum (500 MHz in C 6 D 6 ) of cyclobutanol 82 51 Figure 3.10 Partial COSY spectrum (500 M H z in C 6 D 6 ) of cyclobutanol 82 52 Figure 3.11 Partial H M Q C spectrum (500 M H z for ] H and 125 M H z for 1 3 C) of cyclobutanol 82 53 IX Figure 3.12 The NOE difference spectra (400 MHz in C 6 D 6 ) of cyclobutanol 82 54 Figure 3.13 The NOE interactions in cyclobutanol 82 55 Figure 3.14 Typical ' H N M R spectra of 1-indanone derivatives 83-86 56 Figure 3.15 Partial 1 3 C N M R spectrum (75 M H z in C 6 D 6 ) of 86 58 Figure 3.16 The ORTEP drawing of compound 86 58 Figure 3.17 The full 1 H N M R (a, 400 MHz in C 6 D 6 ) and partial 1 3 C N M R (b, 100 MHz in C 6 D 6 ) of cyclopropanol 87 .....61 Figure 3.18 The HPLC traces for the resolution of racemic 78 63 Figure 4.1 The ORTEP drawings of ketones 43 (a), 44 (b), 45 (c) and 47 (d) 66 Figure 4.2 Cleavage conformation 71 Figure 4.3 Anion part of the crystal structures of salts 56 (a), 59 (b) and 60 (c) 74 Figure 4.4 The chirality-matched view of molecules I and II for salt 59 77 Figure 4.5 Stern-Volmer plots for the formation of cyclobutanols 75 and 79 79 Figure 5.1 *H N M R spectra of cyclobutanols 94-97 90 Figure 5.2 ' H N M R spectrum (500 MHz in CD 2C1 2) of cyclobutanol 94 91 Figure 5.3 Partial COSY spectrum (500 M H z in CD 2C1 2) of cyclobutanol 94 92 Figure 5.4 Partial H M Q C spectrum (500 MHz in CD 2C1 2) of cyclobutanol 94 93 Figure 5.5 The NOE difference spectra (400 MHz in CD 2C1 2) of cyclobutanol 94 94 Figure 5.6 The NOE interactions of cyclobutanol 94 95 Figure 5.7 Typical *H N M R spectra of a-tetralone derivatives 98 and 99 97 Figure 5.8 Partial COSY spectrum (500 MHz in CDC13) of 99 98 Figure 5.9 Partial H M Q C spectrum (500 M H z for ] H and 125 M H z for 1 3 C) of 99 99 Figure 5.10 Typical ! H N M R spectra of 100 and 101 100 Figure 5.11 Partial COSY spectrum (500 M H z in CDC13) of 100 101 Figure 5.12 Partial H M Q C spectrum (500 M H z for ' H and 125 M H z for 1 3 C) of 100 102 Figure 5.13 The NOE difference spectra (400 M H z in CDC13) of 100 103 Figure 5.14 Conformational analysis result for photoproduct 100 (HyperChem MM+).... 105 Figure 5.15 The NOE interactions in photoproduct 100 -105 Figure 5.16 The HPLC traces for the resolution of racemic 97 107 Figure 6.1 The ORTEP drawings of ketones 51 (a) and 52 (b) 110 Figure 7.1 Electronic configuration of the n-Tt* excited state of the carbonyl group 122 x Figure 7.2 General structure of the target molecule 124 Figure 7.3 COSY spectrum (400 MHz, C 6 D 6 ) of product 136 130 Figure 7.4 H M Q C spectrum (500 MHz, C 6 D 6 ) of product 136 131 Figure 7.5 The NOE difference spectra (400 MHz, C 6 D 6 ) of oxetane 136 132 Figure 7.6 NOE interactions in oxetane 136 133 Figure 7.7 (a) The GC trace of the solution-state photoreaction of compounds 90 and 144 after 25 h of irradiation; (b) The GC trace of the solid-state photolysis of ketone 126 after 2 h of irradiation at -20 °C 136 Figure 7.8 GC trace of the resolution of oxetane 138 138 Figure 7.9 Model compounds for the extension of the solid-state Paterno-Biichi reaction 140 Figure 8.1 Candidate compounds for 1,3-phenyl migration studies 150 Figure 8.2 The GC traces of the solution (a) and solid-state (b) photoreaction of ketone 163 158 xi List of Schemes Scheme 1.1 The Norrish/Yang type II photoreaction 2 Scheme 1.2 Photoreaction of cyclobutylphenyl ketone 1 3 Scheme 1.3 Photochemical preparation of cyclobutanol 5 3 Scheme 1.4 P-Hydrogen abstraction reaction of benzoquinone-diene Diels-Alder adduct 6 5 Scheme 1.5 8-Hydrogen abstraction of 8 6 Scheme 1.6 s-Hydrogen abstraction of 10 6 Scheme 1.7 t^-Hydrogen abstraction of ketone 13 6 Scheme 1.8 Lon-range hydrogen abstraction of steroidal benzophenone ester 16 7 Scheme 1.9 Photoreaction of ?ran^-cinnamic acid 12 Scheme 1.10 Template control of [2+2] photocycloaddition of 22 13 Scheme 1.11 Photolysis of compound 24 14 Scheme 1.12 Conformational control of the photoreaction of diazo compound 24 15 Scheme 1.13 Photoreaction of a,p-unsaturated ketone 28 18 Scheme 1.14 Absolute asymmetric synthesis 20 Scheme 1.15 Photoreaction of 32 in an inclusion crystal with chiral host 34 21 Scheme 1.16 Covalent chiral auxiliary: solid-state photoreaction of chiral ester 35 22 Scheme 1.17 "Ionic chiral auxiliary"-induced solid-state photolysis of salt 37 24 Scheme 2.1 Syntheses of ketones 43-47 28 Scheme 2.2 Synthesis of ketones 50-54 33 Scheme 3.1 Photochemical reactions of the cz's-ketones 38 Scheme 4.1 Formation of photoproducts 75-87 68 Scheme 4.2 Simplified schematic presentation of the formation of products 75 and 79 80 Scheme 4.3 Photochemical studies of compound 88 by Lewis and co-workers 81 Scheme 4.4 Photochemical studies of compound 91 by Wagner 82 Scheme 4.5 Mechanism for the formation of compounds 83-86 83 Scheme 5.1 Photochemical reactions of the trans-ketones 87 Scheme 6.1 Postulated mechanism for the formation of compounds 98 and 99 113 Scheme 6.2 Postulated mechanism for the formation of photoproducts 100 and 101 114 Scheme 7.1 Paterno-Biichi reaction 120 Scheme 7.2 Total synthesis of compounds 115 and 116 121 Scheme 7.3 Inherent stereoselectivity for the Paterno-Biichi reaction 123 Scheme 7.4 Diastereoselective formation of an oxetane using a chiral auxiliary 123 Scheme 7.5 Synthesis of ketones 126-130 125 Scheme 7.6 Photoreactions of ketones 126, 128 and 130 127 Scheme 7.7 Proposed mechanism for the formation of the oxetanes 134 Scheme 7.8 Photoreactions of ketone 145 140 Scheme 8.1 1,5-Phenyl shift of compound 149 143 Scheme 8.2 Photoreaction of compound 152 144 Scheme 8.3 Proposed mechanism for the formation of compound 153 144 Scheme 8.4 Solid-state 1,5-phenyl migration 145 Scheme 8.5 Photochemical reaction of tritylphenones 157 146 Scheme 8.6 Proposed mechanism for 1,3-aryl migration 148 Scheme 8.7 Photoreaction of ketone 160 149 Scheme 8.8 Preparation of ketones 162 and 164 150 Scheme 8.9 Photoreaction of ketone 162 151 Scheme 8.10 Photoreaction of ketone 146 152 Scheme 8.11 Photoreaction of ketones 163 and 164 153 Scheme 8.12 Mechanism for the formation of compound 177 155 Scheme 8.13 Proposed mechanism for the formation of ketone 173 156 xiii List of Tables Table 2.1 Preparation of chiral salts of keto acid 46 36 Table 2.2 Preparation of chiral salts of keto acid 53 36 Table 3.1 Photolyses of ketones 43-47 in solution and the solid state 39 Table 3.2 The HPLC conditions for the resolution of racemic 78 63 Table 4.1 Geometric parameters derived from the crystal structures of ketones 43-45 and 47 67 Table 4.2 Geometric data of A and B from HyperChem M M + calculations 68 Table 4.3 Cleavage and cyclization parameters for ketones 43-45 and 47 70 Table 4.4 Asymmetric induction in the photolyses of chiral salts 55-66 72 Table 4.5 Hydrogen abstraction parameters for salts 56, 59 and 60 75 Table 4.6 Cleavage and cyclization parameters for salts 56, 59 and 60 75 Table 4.7 Quantum yields and kinetic parameters for solution-state photolysis of 43 79 Table 4.8 X-ray derived P-H abstaction parameters for ketones 44, 45 and 47 84 Table 4.9 Hydrogen abstraction parameters 86 Table 5.1 Photochemical results of the trans-ketones 88 Table 5.2 The HPLC conditions for the resolution of racemic 97 106 Table 6.1 X-ray derived geometric parameters for ketones 51 and 52 I l l Table 6.2 Cleavage and cyclization parameters for ketones 51 and 52 112 Table 6.3 Asymmetric induction of the trans-chirdX salts 116 Table 7.1 Preparation of the chiral salts of keto acid 129 126 Table 7.2 Photochemical results of ketones 126,128 and 130 127 Table 7.3 Asymmetric induction for the solid-state formation of the oxetanes 138 xiv List of Symbols and Abbreviations A angstrom A heat to reflux 8 chemical shift (ppm) O quantum yield anal. analysis APT attached proton test BB broad band br broad Bu butyl l BuOH tertiary-butanol CeD(, benzene-^ calcd calculated CDCI3 chloroform-^ CD3OD methanol-^ CI chemical ionization COSY ' I I - ' H correlation spectroscopy d doublet de diastereomeric excess DEPT distortionless enhancement by polarization transfer ee enantiomeric excess EI electron impact EtOH ethanol GC gas chromatography h hour(s) hv light H M B C heteronuclear multiple bond connectivity H M Q C heteronuclear multiple quantum coherence xv HPLC high performance liquid chromatography HRMS high resolution mass spectrometry ER. infrared M P A C International Union of Pure and Applied Chemistry J coupling constant (Hz) L R M S low resolution mass spectrometry m multiplet M molarity Me methyl MeOH methanol M e C N acetonitrile mp melting point N M R nuclear magnetic resonance NOE nuclear Overhauser effect ORTEP Oak Ridge Thermal Ellipsoid Program ppm parts per million Ph phenyl 'Pr isopropyl q quartet s singlet t triplet THF tetrahydrofuran U V / VIS ultraviolet / visible xvi Acknowledgements First of all, I would like to express my deepest gratitude to my research supervisor, Dr. John R. Scheffer, for giving me the chance to work in his group. His patience, encouragement and wise guidance throughout the past five years were essential to the success of my education in Canada, and will benefit my future life. I would also like to thank all the past and present members of Scheffer group. They endured me on a daily basis and made me feel at home here in U B C . Thank you Heiko Dimels, Joe Wu, Brian Patrick, Matt Netherton, Eugene Cheung, Kristin Janz and Mardy Leibovitch; you were the very first persons I worked with in the Chemistry Department. I will never forget those good times I spent with Jeff Raymond, Carl Scott, Letian Wang, Clair Cheer, Alia Zenova, Ken Chong, Katja Rademacher, Sherman Hon, Wayne Chou, Vishnu Kodumuru, Matt Moran, Shuang Chen, Keyan Wang and Kathrin Wissel. Special thanks go to some of the people above, including Jeff Raymond for doing some pioneering work in Part I of this thesis, Matt Netherton for providing some smart ideas during the course of my research, Eugene Cheung for solving all the crystal structures in this thesis, Eugene Cheung and Carl Scott for very careful reading of this work and putting forward some very good suggestions, and Ken Chong for constant encouragement and caring during the preparation of this thesis. This work would not be possible without the help from other members of the U B C chemistry department. I am grateful to the staff of N M R laboratory, Mass Spectrometry and Mr. Peter Borda in microanalysis laboratory. I would also like to thank Drs. Larry Weiler, David Dolphin, Robert Thompson and Les Burtnick for allowing me to use their instruments. xvn Special thanks also go to Dr. Bi l l Champion of Chiral Technologies, Inc. for determining the optical rotation signs of some of the chiral products. I am grateful to everyone in my family. M y parents, brothers and sisters mentally and economically supported me to come to Canada, and constantly encouraged me to complete my education. I am in debt to them forever. Particularly I would express my deepest thanks and love to my wife, Susan Xuan Gui. She accompanied me and supported me through all the ups and downs during the past five years in every aspect of my study, research and life. Without her, this thesis would be unimaginable. Finally, I would like to thank all the old and new friends. No matter where you are, you shared a piece of my happiness and bitterness, a piece of my success and failure. You will be in my heart forever. xvm Dedications To M y Parents, Brothers and Sisters Nephews and Nieces and M y Lovely Wife Susan with Love Parti Asymmetric Yang Photocyclization in the Solid State Chapter 1. Introduction Chapter 1. Introduction 1.1 The Norrish/Yang Type II Reaction 1.1.1 General Aspects The Norrish/Yang type II reaction1 is probably the most well-studied photoreaction of ketones. It describes a process whereby, upon irradiation, a ketone with a C - H bond at the gamma position undergoes a 1,5-hydrogen transfer to form a 1,4-biradical. This intermediate can partition itself between three major pathways: a) direct radical combination to yield a cyclobutanol, which is called Yang photocyclization;2 b) cleavage of the original a-(3 sigma bond to form an alkene and an enol, which will ketonize very rapidly3 (known as the Norrish type II photoelimination4); c) reverse hydrogen transfer to reform the starting ketone (Scheme 1.1). Scheme 1.2 shows the photoreaction of cyclobutylphenyl ketone 1 as an example of processes (a) and (b).5 R' reverse H-transfer hv cyclization Norrish type II elimination O OH R' + Scheme 1.1 The Norrish/Yang type II photoreaction 2 Chapter 1. Introduction O O P h O H Ph benzene hv + Ph 1 2 (25%) 3 (38%) Scheme 1.2 Photoreaction of cyclobutylphenyl ketone 1 The biradical nature of this reaction has been well established. Early attempts consisted of trapping studies with thiols6 and the observation that ketones with chiral y-carbons racemize.7 Very recently, the reaction was retested using Nobel prize-winning femtosecond spectroscopic techniques.8 These studies clearly indicate that the Norrish/Yang type II reaction is non-concerted. The time scales for hydrogen atom transfer and biradical closure or cleavage are 70-90 fs and 400-700 fs, respectively. This reaction is of widespread interest because it not only can be induced under other conditions such as electronic impact (McLafferty rearrangement9 in mass spectroscopy), but provides enormous synthetic potential as well. The synthetically difficult formation of cyclobutanol derivatives has become very simple now (Scheme 1.3). 4 5 (85%) Scheme 1.3 Photochemical preparation of cyclobutanol 5 10 3 Chapter 1. Introduction 1.1.2 Electronic Aspects For ketones, the carbonyl group is the chromophore which will absorb a photon upon irradiation. Hence its electronic properties are important and must be understood. The ground state electronic configuration of the carbonyl group is shown as (a) in Figure 1.1. a * o~* a * (a) 71* 71 hv 7t* n intersystem 71 CT (b) crossing (c) 71* 7t Figure 1.1 Electronic configurations of the carbonyl group (a) ground state (b) singlet n-7i* excited state (c) triplet n-7t* excited state When a ground state ketone absorbs a photon, one electron in a non-bonding or a bonding orbital will be excited to an anti-bonding orbital. Among the several possible excitations, n-7t* and Ti-71* transitions require the lowest energy and thus take place. It is found that, for hydrogen atom abstraction processes, ketones with lowest n-7i* triplet excited states are much more reactive than those with lowest 71-71* triplets." In other words, hydrogen atom abstraction reaction is preferred from n-71* excited states. The multiplicity of the n-7t* excited states has also been thoroughly studied and the different roles of singlet and triplet excited states in the reaction have been made clear. For aliphatic ketones, the type II photoelemination 4 Chapter 1. Introduction reaction occurs from both singlet and triplet n-n* excited states, which is evidenced by partial quenching of the reaction by a triplet quencher. Yang photocyclization takes place mainly from the triplet n-n* state, based on the finding that the cyclization to elimination ratio decreases significantly with increasing concentration of the triplet quencher. 1 2 a " c On the other hand, for aromatic ketones, only triplet states are found to be responsible for both elimination and cyclization.1 3 The simple reason is the much more rapid intersystem crossing for aromatic ketones. In Part I of this thesis, all the photoexcitable starting materials we investigated are aromatic ketones. Their photochemical behavior is derived from their corresponding n-7i* triplet excited states and the resulting biradicals. 1.1.3 Extension of the Norrish/Yang Type II Reaction It is noteworthy that 1,5-hydrogen transfer in Norrish/Yang type II reaction is only one of many possible hydrogen abstraction reactions. Similar processes can also occur over shorter or longer distances with the same mechanism. The reactions shown in Scheme 1.4-8 represent examples of P-, 5-, s-, C,- and long-range hydrogen transfer reactions. 6 7 (50%) Scheme 1.4 P-Hydrogen abstraction reaction of benzoquinone-diene Diels-Alder adduct 6 5 Chapter 1. Introduction O M e O O M e O H M e O H O B u ' Ph Scheme 1.5 5-Hydrogen abstraction of 8 O 10 hv H H O H O H 11 (31%) O H 12(10%) Scheme 1.6 s-Hydrogen abstraction of 10 16 P h P h O hv O ^ Ph 13 O H O ^ P h P\ X H Ph ?..iOH Ph^ .H O H A . iPh Scheme 1.7 t^-Hydrogen abstraction of ketone 13 17 6 Chapter 1. Introduction O OH OH 16 17 (55%) Scheme 1.8 Long-range hydrogen abstraction of steroidal benzophenone ester 16 18 These reactions are not as common as typical Norrish type II reactions because they are comparatively slow processes. They often occur when there is no geometrically favorable y-H present (or no y-H at all) and the more remote hydrogen atom lies in close proximity to the carbonyl oxygen. Sometimes, even though there is a y-H in a favorable abstraction geometry, certain stereoelectronic factors enable non-type II hydrogen transfer to compete with type II abstraction. In this situation, products from both processes will be observed. The detailed discussion of this competition will be available in Chapter 4. To conclude, although non-type II reactions are relatively rare, they make an important contribution to hydrogen abstraction 18 reactions and organic synthesis. 7 Chapter 1. Introduction 1.2 Orientation al Requirements for the Norrish/Y ang Type II Reaction Not long after the discovery of Yang cyclization, people realized the importance of conformation for this reaction and started to study its orientational requirements. Since n-7i* excited states are involved, the relative orientation between the singly-occupied n orbital on the oxygen atom and the y-hydrogen atom becomes important. In 1968, Turro and co-workers made the first attempt in this area and suggested that the gamma C - H bond axis should be directed towards the n orbital of the oxygen atom for reaction to take place (Figure 1.2).19 Scheffer and co-workers studied a variety of ketones that undergo intramolecular hydrogen abstraction in the crystalline state, and have proposed several ground state geometric parameters that describe the excited state reactivity.2 0'2 1 This comparison is considered valid because the n orbital is orthogonal to the n orbital and is highly localized. The excitation of the carbonyl group will not cause a significant geometric change on the rest of the molecule, especially for aromatic ketones in the solid state. The parameters Scheffer suggested are shown in Figure 1.3. •C o Figure 1.2 Geometric requirements for hydrogen abstraction as suggested by Turro et al. 19 8 Chapter 1. Introduction Figure 1.3 Geometric requirements for the Norrish/Yang type II reaction The first parameter is d, the distance between the carbonyl oxygen and the y-H. The ideal value of d is thought to be 2.72 A, which is the sum of van der Waals radii of a carbon atom and a hydrogen atom. The second parameter A describes the C=0—HY angle, whose optimum value should be between 90° and 120°, depending on the hybridization of the oxygen atom.21 The 0 - H Y - C Y angle 6 is the third parameter and the best situation for the reaction is when 9 = 180°, i.e., atoms O, H Y and C Y lie on the same straight line. 2 2 The fourth parameter co is the out of plane angle of the y-H with respect to the carbonyl plane. Since the n orbital of the oxygen atom lies in the carbonyl plane, the optimum value of co is zero. These four parameters determine whether the first step of the Norrish/Yang type II reaction, i.e., the hydrogen abstraction to yield a 1,4-biradical, will be successful. As mentioned in the last section, this biradical can partition itself among various pathways. The factors affecting this partitioning have been reviewed.23 It is found that photocleavage is favored by good overlap of the breaking C2-C3 bond with both singly-occupied p orbitals at the radical centers,24'25 and factors preventing this overlap will suppress cleavage. Cyclization products have been found to be obtained more readily from ketones with ct-substituents.26 Figure 1.4 summarizes the different conformations of a 1,4-biradical. 9 Chapter 1. Introduction 7 / 0 H cisoid gauche transoid cyclization and c leavage c leavage Figure 1.4 Conformations of a 1,4-biradical In the cisoid and transoid conformers, all four carbon atoms (C1-C4) are coplanar, while in the gauche conformation, the radical centers C l and C4 are separated by a torsion angle of 60°. In terms of steric hindrance, the transoid conformation is the most stable and the cisoid conformation is the least stable because it suffers from eclipsing interactions. Owing to orbital and bond overlap considerations, the transoid conformation will undergo cleavage exclusively and the cisoid and the gauche arrangement can either cyclize or cleave. In Part I of this thesis, only the gauche conformation can be adopted for all the 1,4-biradical intermediates studied because of skeletal restrictions in the starting materials. For these compounds, three other parameters are used to describe the behavior of biradicals. In Figure 1.4, assuming the hybridization of the radical centers is sp2, we define (pi as the dihedral angle between the C 2 -C3 sigma bond and the p-orbital lobe on C l with which it most nearly overlaps; and q>4 is defined as the dihedral angle of involving the C2-C3 bond and the most favorably oriented p-orbital lobe on C4. For cleavage, the optimum values of cpl and cp4 are 0°. " The parameter D is defined as the distance between C l and C4. It partly reflects the possibility of C1-C4 10 Chapter 1. Introduction bond formation for cyclization. The ideal value of D should be <3.4 A, which is the sum of the van der Waals radii of two carbon atoms. 1.3 The Topochemical Postulate During the last few decades, there has been a growing trend to study photoreactions in organized media. The reason is that chemists have realized the important role of the reaction medium in controlling rates, product distributions and stereochemistry. Photoreactions in organized media have repeatedly shown unique reactivity and selectivity compared to those in isotropic liquids. Among many ordered or constrained systems utilized to organize the reactants, the notable ones are micelles, microemulsions, liquid crystals, inclusion complexes, 97 98 monolayers, adsorbed surfaces such as zeolites and organic crystals. ' Owing to the development of the powerful techniques of X-ray crystallography, the crystalline state has become the most well-studied medium for organic photoreactions.29,30 As early as 1918, Kohschutter stated that reactions in crystals proceed with a minimum of atomic and molecular movement.31 This rule was later termed the "topochemical postulate" by Schmidt and co-workers in the early 1960s in connection with their pioneering work on the • 32 solid-state photoreaction of aromatically-substitured trans-cirmamic acids (Scheme 1.9). In solution, all of the cinnamic acid variations undergo only trans-cis isomerization. In the solid state, some of these acids crystallize in three polymorphic forms, namely, a, p and y. Their solid-state reactivity varies with the polymorphic form adopted. The a and P forms, with intermolecular double bond-to-double bond distances between 3.5 A and 4.2 A, afford ct-truxillic acids and P-truxinic acids, respectively. The y form has a longer distance (>4.7 A) 11 Chapter 1. Introduction between the double bonds and is photostable. After extensive studies of the [2+2] photodimerization of <?ra«.s-cinnamic acids, Schmidt concluded: (a) The nature of the crystal structures determines whether or not reaction will occur and the structures of the products; (b) The reaction involves dimerization of nearest neighbor molecules in a stack and occurs with a minimum of atomic and molecular movement. At the same time, he also emphasized that the double bonds of the reactants must be not only within 4.2 A, but also must be aligned in a parallel fashion for cycloaddition to occur. Ph hv C O O H s o l u t i o n Ph C O O H \ = / 18 19 H O O C . Ph Ph / C O O H hv HOOC- ) — 7 \ : /3.6-4 .1A a-form v — ( 1 Ph Ph Ph \ — 1 /3.9-4.1 C O O H hv A (3-form C O O H Ph \= C O O H Ph 20 a-truxillic acid Ph Ph \ C O O H C O O H 21 (3-truxinic acid H O O C / C O O H n v ». n o r e a c t i 0 n /4.7-5 .1A y-form n o r e a c t l o n Ph Scheme 1.9 Photoreaction of trans-cirmamic acid 12 Chapter 1. Introduction Schmidt's topochemical postulate has been supported by numerous examples and is now used as a rule to understand a variety of [2+2] photodimerization reactions of varying types. Recently, chemists have started to grow multi-component crystals in order to try and direct molecules to obey this rule. 3 3 By forming crystalline supermolecules, the chemo-, regio- and stereoselectivity of particular solid-state photoreactions can be forcibly changed in a desired direction, and new photoreactions can possibly be discovered. The systems people have tried include mixed crystals, hydrogen-bonded co-crystals, donor-acceptor crystals, inclusion crystals, crystalline organic salts and solid mixtures. One of the latest examples is from MacGillivary and co-workers.34 O H - - - N O H - - - N o N - - - H O 22 hv crystal OH---ISL O H - - N jCZXN--- HO X Z X N — H O 23 (100%) Scheme 1.10 Template control of [2+2] photocycloaddition of 22 13 Chapter 1. Introduction trans-1,2-Bis(4-pyridyl)ethylene (the guest molecule in complex 22) crystallizes to form a layered structure where the neighboring double bonds are separated by 6.52 A and are orthogonal to each other. As predicted from the Schmidt's rules, this compound is photostable. However, co-crystallization of this compound with resorcinol results in a four-component assembly (22) formed by means of O-H—N hydrogen bonding, with the olefins aligned in a parallel fashion and separated by only 3.65 A. Irradiation of complex 22 stereospecifically gives complex 23 in 100% yield. Although the topochemical rules are derived from studies of bimolecular reactions, they are equally valid for unimolecular reactions. But here the intramolecular geometric arrangements, instead of intermolecular geometric considerations, play a decisive role in determining the reactivity. The conformation of the reactants in the solid state often controls the course of the reaction. N 5 P h - P h Ph hv -N-^ P h - P h ' ^ Y ' P h C H , solid state^ C H , 24 25 P h - P h Ph X H C H 3 (Z)-26 solution P h - P h Ph X H C H 3 P h - P h H X P K C H 3 (27E)-26 (27E)-27 Scheme 1.11 Photolysis of compound 24 14 Chapter 1. Introduction Garcia-Garibay and co-workers35 recently reported the photolysis of diazo compound 24 to form carbene 25 (Scheme 1.11). Subsequent 1,2-H or 1,2-Ph shifts afforded the corresponding alkenes 26 and 27. In solution, both Z and E configurations of alkenes 26 and 27 were observed due to the fast interconversions between different conformations of the starting material 24. In the solid state, however, (Z)-26 is the sole product. X-ray crystallographic studies revealed that 24 adopts a pre-(Z) conformation in the solid state, which places the migrating hydrogen atom in a good overlap position with the empty p-orbital of the carbene carbon in the transition state. As a result, the 1,2-H shift stereoselectively yielded the observed (Z)-26 exclusively. p h - P h - Q = N 2 h v » P h Ph^7y T V P h - P h H H pre-(Z)-24 (Z)-26 Scheme 1.12 Conformational control of the photoreaction of diazo compound 24 Nowadays, there can be no doubt about the general validity of the original topochemical postulate. But it has limitations, and some solid-state photoreactions occur with apparent violations of this rule. 3 6 ' 3 7 To refine this principle and extend its generality, people have suggested some new concepts. 38 One of these is the "reaction cavity" concept which was put forward by Cohen. Under this concept, molecules that participate in solid-state reactions exist in cavities formed by their nearest neighbors. As reaction occurs, the geometry change of the reacting molecule will 15 Chapter 1. Introduction cause "pressure" on the cavity wall and tend to distort it. This distortion may involve a large decrease in attractive forces or an increase in repulsive ones. Any of these distortions will be opposed by the closely packed environment, and only those reactions involving minimal geometric changes will be energetically feasible. Therefore, the topochemical postulate can be reinterpreted so that "reactions proceeding under lattice control do so with minimal distortion of the surface of the reaction cavity". In Figure 1.5, product B would be produced rather than C because the transition state of B better fits the reaction cavity. This concept was extended by Gavezzotti in the 1980's/ y He developed a computer program to calculate the volume of a molecule and determine the size and the location of empty and filled spaces in the crystal lattice. On the basis of detailed studies, he concluded that "a prerequisite for crystal reactivity is the availability of free space around the reaction site". cavity before reaction transition states (dashed line) products Figure 1.5 Schematic presentation of the "reaction cavity" concept 16 Chapter 1. Introduction Later, Weiss, Ramamurthy and Hammond4 0 further expanded the "reaction cavity" concept by setting up a model to include a number of other organized and constraining media besides just crystals. As far as the crystalline medium in this model is concerned, the walls of reaction cavities within crystals are considered to be either stiff or hard, and the free volume needed to accommodate shape changes during the reaction must be intrinsic. One elegant example of this "reaction cavity" theory in explaining a solid-state photochemical result comes from Scheffer and co-workers' studies of a,(3-unsaturated ketone 28.41 (Scheme 1.13) This compound does not undergo intermolecular [2+2] photodimerization in the solid state, even though the potentially reactive enone double bonds of adjacent molecules are arranged in an almost perfect intermolecular [2+2] fashion (parallel with a center-to-center distance of 3.79 A) from X-ray crystallographic studies. This photostability is not an intrinsic property of compound 28 because its solution state photolysis affords an essentially quantitative yield of intramolecular [2+2] cylcoadduct 29. By computer simulation of the solid-state [2+2] photocycloaddition through two different mechanisms (center-to-center mechanism and twist mechanism), it was found that, as reaction takes place, regardless of which mechanism is followed, there always exist short H—H interactions between the methyl groups of the reacting molecules and their neighbors. There are eight methyl groups involved in the center-to-center dimerization (Figure 1.6) and four in the twist mechanism. This "steric compression", as Scheffer called it, inhibits the photocycloaddition. 17 Chapter 1. Introduction no reaction 29 28 E = C 0 2 M e Scheme 1.13 Photoreaction of oc,|3-unsaturated ketone 28 neighboring molecule molecule Figure 1.6 Steric compression inhibition of solid-state photodimerization along the "center-to-center" mechanism Another concept called "dynamic preformation" was proposed by Craig and co-workers.42 Based on theoretical calculations, they postulated that photoexcitation can cause short-term lattice instability which may drive one molecule close to a neighbor and result in a photochemical reaction. If a reaction occurs during this short period before lattice relaxation back to the ground state structure, it can be said to be dynamically promoted or preformed. 18 Chapter 1. Introduction The photodimerization of 7-methoxycoumarin, which has two neighboring olefins rotated by about 65° to one another, can be explained in terms of this concept.29 In explaining the solid-state photobehavior of diacyl peroxides, McBride developed the concept of "local stress".43 When a molecule undergoes homolysis, it must expand to allow the bond cleavage. This in turn produces stress or pressure in the lattice, which will influence the behavior of the radicals and also the reactions of the surrounding molecules. Convincing evidence has been obtained to support the hypothesis that local stress rather than topochemical factors control these reactions. In addition to the concepts mentioned above, some subtle factors affecting solid-state reactivity have also been identified. Among them are: molecular shape and size, 3 0 ' 4 4 the presence of impurities,30 crystal defects45 and polymorphism.46 1.4 The "Ionic Chiral Auxiliary" Approach Since Pasteur's pioneering work in separating (+)- and (-)-tartaric acid from the racemic mixture about 150 years ago,47 our understanding of molecular chirality has increased tremendously, and the challenge of synthesizing chiral compounds in high optical purity is enticing.48 Historically, much more effort has been put into ground state than excited state asymmetric synthesis. Nevertheless, some notable advances have been achieved in the field of photochemical asymmetric synthesis in recent years.49 Several approaches have been utilized and they include: photolysis with circularly polarized light, 4 9 a" c ' 5 0 application of chiral solvents,49b the use of optically active photosensitizers,49a"c'51 photolysis in the presence of 19 Chapter 1. Introduction chiral additives,49f attachment of chiral substituents,47 photolysis in the cavities of chiral host molecules52 and the photochemistry of crystals in chiral space groups.53 For solid-state photoreactions, enantioselectivity comes from two key steps: (a) successful development of chiral crystals with suitable molecular packing and proper orientation of reactive groups, and (b) performing topochemical reactions in such a way that the chirality of the crystals is transferred to the products. Several different methods have been used to obtain chiral crystals: (a) Achiral compounds that spontaneously crystallize in chiral space groups.5 2 3'5 4 The reaction of these crystals to yield chiral products is known as "absolute asymmetric synthesis"55 because there is no external asymmetric source present. The first example of a reaction of this type was reported by Schmidt and co-workers56 over three decades ago on the gas-solid bromination of jt?,/»-dimethylchalcone. The first photochemical examples on 57 58 bimolecular and unimolecular reactions are from Green and Scheffer , respectively. A recent example from Sakamoto and co-workers59 is illustrated in Scheme 1.14. Despite the fact that "absolute asymmetric synthesis" is such a nice process, it is not very useful in organic synthesis. The reason is that this spontaneous chiral crystal formation is rare and unpredictable. C H 2 P h i N " C H 2 P h 30 hv crystal H Ph •N S ' C H 2 P h 31 chiral s p a c e group P 2 1 8 1 - 9 7 % ee Scheme 1.14 Absolute asymmetric synthesis 20 Chapter 1. Introduction (b) Achiral molecules that form chiral inclusion complexes with optically pure host compounds.33'52 A variety of host molecules has been studied and many of them control the enantioselectivity of the photoreactions and give satisfactory enantiomeric excesses. For example, Miyamoto and co-workers60 studied the photoreaction of compound 32 (Scheme 1.15) in inclusion crystals with chiral host 34. Optically active product 33 was obtained in 42% yield with 97% ee. Scheme 1.15 Photoreaction of 32 in an inclusion crystal with chiral host 34 (c) Molecules with covalent chiral auxiliaries that crystallize in chiral space groups. Subsequent photoreactions should give diastereomerically enriched products. The solution version of this type of reaction has been reviewed several times4 9 and is widely utilized in organic synthesis. In contrast, the same type of reaction in the solid state is comparatively new and not many examples are available. One of the instances is from Scheffer and co-workers.61 (-)-Bornyl P-keto ester 35 crystallizes in chiral space group P212121 and the ketone carbonyl oxygen atom is oriented closer to one of the enantiotopic gamma hydrogens H x (2.50 A) than the other one H y (3.38 A). Upon irradiation, Yang photocyclization followed by retro-aldol ring opening yielded 5-keto ester 36 in >95% diastereomeric excess. 32 33 (42% yield, 9 7 % ee) (R,R)-(-)-34 21 Chapter 1. Introduction r^iT^OOR* P212 l2* H x °VPh JLHy J hv C O O R * R*=(-)-bornyl 35 36 (>95% de) Scheme 1.16 Covalent chiral auxiliary: solid-state photoreaction of chiral ester 35 (d) With the aid of "ionic chiral auxiliaries", achiral compounds form chiral crystals. This approach was pioneered by Scheffer and co-workers62 and has turned out to be one of the most successful methods for solid-state photochemical asymmetric induction. By attaching a carboxylic acid functional group to a prochiral photoreactive substrate and reacting it with an enantiomerically-pure amine, an optically-active organic salt can be prepared using acid-base chemistry. The opposite approach, in which an achiral photoreactive substrate bearing an amine functionality forms a salt with an optically-active carboxylic acid, is also valid. 6 3 The presence of the chiral auxiliary enables the salts to crystallize in chiral space groups, which carry the asymmetric information and provide the medium in which photoreaction occurs. Figure 1.7 shows a schematic representation of the mechanism for this method. Two diastereomeric transition states with unequal energy are responsible for the overall enantioselectivity of the reaction. As an example, Scheme 1.17 illustrates the photoreaction of (-)-norephedrine salt 37, which affords final product 38 in 95.8% ee.64 22 Chapter 1. Introduction C O O M e (-)-chiral product C H 2 N 2 workup rme© COO NH. C O O M e (+)-chiral product C H 2 N 2 workup c o o N h U hv crystalline state / COO- NH + chiral crystal A . C O O H acid-base reaction N H , achiral acid photoreactive substrate optically pure amine auxiliary Figure 1.7 Schematic presentation of the "ionic chiral auxiliary" approach. In the example shown, formation of the (-)-product is kinetically favored 23 Chapter 1. Introduction O H C O O M e Scheme 1.17 "Ionic chiral auxiliary" induced solid-state photolysis of salt 37 There are numerous advantages62"64 of the ionic chiral auxiliary method: (a) Formation of the salts is straightforward and the yield of this acid-base reaction is usually very high; (b) The ionic character of the salts furnishes them with melting points and lattice forces that are higher and stronger than those of molecular crystals, resulting in topochemical control that is well maintained at higher conversions during irradiation. Also, the high melting points suggest that there is a better chance of obtaining crystals of salts whose photochemical behavior can be monitored by crystallographic techniques; (c) By simply using the opposite optical antipodes of the chiral auxiliaries, both enantiomers of the products are accessible63"65; (d) Unlike achiral compounds that spontaneously crystallize in chiral space groups, which is rare and unpredictable and give both "right-handed" and "left-handed" enantiomorphs, the process of recrystallization of the salts into homochiral crystals is reproducible and can be done on a gram scale. Thus, with high enantiomeric excesses obtainable at high conversion and with reasonable yields, the synthetic potential is quite promising. 24 Chapter 1. Introduction Many types of reactions have been studied using the "ionic chiral auxiliary" approach. Among them are: the Norrish/Yang photocyclization reaction,6 1'6 3"6 6 the di-7i-methane rearrangement reaction,6 2'6 7 the 8-hydrogen atom abstraction reaction,68 photoreaction of benzocyclohexadienone derivatives,69 photoreaction of tropolone derivatives,70 cis-trans isomerization of 1,2-diphenylcyclopropane derivatives71. The most widely studied reaction, however, is the Norrish/Yang photocyclization reaction. 1.5 Solid-state X-ray Structure-Reactivity Correlations In Section 1.3, it was pointed out that reactions in the solid state are different from those in fluid media because atomic and molecular freedom of movement is restricted, i.e., solid-state reactions occur with a minimum motion of atoms or molecules. This simple, yet profound, topochemical rule leads to the idea that the transition states and intermediates in solid-state reactions will resemble the structure of the starting materials. This is the basis of the solid-state structure-reactivity correlation concept. With structural data for the starting material from X-ray crystallography, valuable information about the corresponding transition states and intermediates may be inferred and used to account for the chemo-, regio- and stereoselectivities of the reactions being studied. The Norrish/Yang type II reaction of aryl ketones, which will be investigated in this thesis, is especially appropriate for this method because of two widely accepted assumptions: (a) As mentioned in Section 1.2, unlike 7i-7t* excited states, the n-Tt* excited states are highly localized. The geometry change caused by excitation of the starting material is negligible; (b) From the starting ketone to the 1,4-biradical intermediate, only one hydrogen atom moves and the heavy atoms remain essentially 25 Chapter 1. Introduction immobile. Thus by correlating the X-ray data with the observed solid-state reactivity for a series of compounds, it is possible to deduce the general geometric requirements for the reaction. 1.6 Thesis Goals The present work is an extension of our previous studies on solid-state Norrish/Yang type II photoreactions. In general, we are aiming at: (a) obtaining the geometric requirements for general Norrish type II hydrogen abstraction reaction by using solid-state X-ray structure-reactivity correlation studies on a series of structurally related compounds; (b) applying the "ionic chiral auxiliary" approach and extending its generality in solid-state photochemical asymmetric induction, and (c) correlating the experimental results with the calculated ones from molecular modeling programs and testing the validity of these programs in predicting the photochemical behavior of the starting materials. Specifically, cis- and fra/w-9-decalyl aryl ketones were chosen with general structures 39 and 40 shown in Figure 1.8. 0 © X=H, F, C N , C O O H , COOMe, C O O N H 3 R Figure 1.8 Target compounds 39 and 40 26 Chapter 1. Introduction Both systems have Cs symmetry and four potentially abstractable y-hydrogens, with two pairs enantiotopically related (H2/H7 and H4/H5). The first goal was to determine the regioselectivity, i.e., which hydrogen will be abstracted (H2/H7 vs H4/H5). We expect that it will be closely related to the conformations adopted by the starting material, especially in the solid state. After the formation of the 1,4-biradicals, the intermediates can undergo either Yang photocyclization or Norrish photoelimination. We hope the crystal structures of the starting ketones will reveal information about the geometry of the biradicals. For the Yang cyclization, both endo- and exo-aryl cyclobutanols are possible. Therefore, the diastereoselectivity of the reaction can be investigated. We are interested in using potential information about the transition states and intermediates from the X-ray crystallographic data of the starting materials to account for the above photochemical behavior, and we expect to observe the topochemically-favored products in the solid state. When X=COOH, we can react the prochiral acids 39 and 40 with a number of optically pure amines by acid-base chemistry and apply the "ionic chiral auxiliary" approach. Specifically, in these two systems, the competition will be between the abstraction of H2 vs H7 or H4 vs H5. The achiral to chiral transformation is one of our major objectives, and solid-state X-ray structure-reactivity correlation studies will be performed to rationalize the enantioselectivity. MacroModel M M 3 * , 7 2 HyperChem M M + 7 3 and some higher level calculations will also be performed throughout the work. These computational results will be correlated with the experimental data and used as predictive tools for product formation. 27 Chapter 2. Preparation of Substrates Chapter 2. Preparation of Substrates 2.1 Preparation of the c/s-9-Decalyl Aryl Ketones The cw-9-decalyl aryl ketones were synthesized according to Scheme 2.1 below. C O O H C O C I C O P h Scheme 2.1 Syntheses of ketones 43-47 Chapter 2. Preparation of Substrates cz's-9-Decalyl carboxylic acid 41 is a known compound and was prepared from a commercially available cis/trans mixture of P-decalol.74 Using standard synthetic methods, ketones 43 to 47 were synthesized from acid 41. A l l these ketones are new and they were fully characterized by ' H and 1 3 C N M R , FT-IR, L R M S , HRMS, U V and elemental analysis. Their spectroscopic and analytical data can be found in Chapter 9 and the ' H N M R spectra of ketones 43-47 are shown in Figure 2.1. The X-ray crystallographic studies of ketones 43-45 and 47 completely confirmed their structures. For simplicity and clarity of discussion, the trivial names of these compounds are used throughout Part I of this thesis. Their corresponding rUPAC names are presented in Part III (Experimental). A n interesting property of these c/.s-9-decalyl aryl ketones is revealed by interpretation of 13 the data acquired from variable-temperature C N M R studies. The fluoro-substituted ketone i o 44 is used here as an example and its partial C N M R spectrum in the region of 15-35 ppm at room temperature, as well as its spectra at higher (50 °C) and lower (0 °C) temperatures, are shown in Figure 2.2. At 25 °C (Figure 2.2b), besides two distinct signals due to C9 and CIO, there are only two broad methylene peaks at 28.02 and 22.70 ppm. Scrutiny of the spectrum allows the identification of two more broad peaks with very low signal-to-noise ratio (S/N) at around 32 and 23 ppm, respectively. By recording the 1 3 C N M R spectrum at higher temperature (50 °C), the expected four methylene peaks are observed (Figure 2.2a). Cooling the sample to 0 °C, however, produces two very broad peaks located between 20-30 ppm (Figure 2.2c). In terms of conformational arguments, the overall Cs symmetry of cis-9-substituted decalins is obtained through an equilibrium of two enantiomeric conformations (Figure 2.3). The above observations reflect the slow interconversion between these two conformations. 29 Chapter 2. Preparation of Substrates 30 Chapter 2. Preparation of Substrates (a) 50 °C ppm 30 25 20 Figure 2.2 Partial 1 3 C N M R (75 MHz, CDC13) spectra of ketone 44 at variable temperature Figure 2.3 Conformational isomerization of c/s-9-decalyl aryl ketones 31 Chapter 2. Preparation of Substrates 2.2 Preparation of /rans-9-Decalyl Aryl Ketones The /ra«5-9-decalyl aryl ketones were synthesized in almost the same way as the cis-ketones. The synthetic scheme is outlined in Scheme 2.2. The zra«.s-9-decalyl carboxylic acid 48 was also synthesized from a commercially available cis/trans mixture of (5-decalol.74 Ketones 50-54 are all new compounds and they were fully characterized by ' H and 1 3 C NMR, FT-IR, L R M S , HRMS, U V and elemental analysis. Their zra/w-9-decalyl structures are also confirmed by the single crystal X-ray crystallographic determinations of 51-53. A l l their relevant analytical data are detailed in Chapter 9. As in the case of the c.s-ketones, the trivial names for these trans-ketones will be used throughout Part I of the thesis and their M P A C names are presented in the Experimental Section. The characteristic ] H N M R spectra of ketones 50-54 are shown in Figure 2.4. Unlike the czs-ketones in the previous section, the zra«s-decalin structure is very rigid and symmetric, and conformational interconversion is not involved in obtaining the Cs symmetry. Thus in the 1 3 C N M R spectra, this intrinsic symmetry results in four sharp methylene peaks at room temperature. 32 Chapter 2. Preparation of Substrates C O O H C O C I C O P h /F-O-MgBr / T H F (75%) Scheme 2.2 Synthesis of ketones 50-54 33 Chapter 2. Preparation of Substrates 34 Chapter 2. Preparation of Substrates 2.3 Preparation of Chiral Salts of Keto Acids 46 and 53 One of the major objectives of this research was to apply the "ionic chiral auxiliary" approach and transform achiral compounds into enantiomerically-enriched products. A l l of the chiral auxiliaries were selected randomly from commercially available amines on the basis of two criteria. The first one is the pKa consideration. It has been concluded that, to ensure complete proton transfer from acid to base instead of forming a neutral hydrogen bonded complex, the pKa of the reacting acid should be lower than that of the protonated base by about 3 units. 7 5 ' 7 6 From the proper forms of the Hammett and Taft equations,77 the pKa's were calculated for keto acids 46 and 53, as well as for the protonated chiral amines we are going to use. It was found that the keto acids 46 and 53 have similar pKa's of about 3.87 and that those of the protonated chiral amines vary from 8.88 to 10.62. With ApKa's much greater than 3, salt formation should present no problem. The second criterion which must be followed is that when a certain amine is selected, it does not interfere with the ketone absorption upon photolysis. In other words, the amine should not have chromophores with strong absorptions at 320-330 nm which is required for n-7i* excitation of the ketones. Based on the above rules, a variety of chiral salts were prepared. The amines and the solvents we used along with the morphology and the melting points of the resulting salts are summarized in Tables 2.1 and 2.2. 35 Chapter 2. Preparation of Substrates Table 2.1 Preparation of chiral salts of keto acid 46 salt amine recryst solvent cryst morphol mp(°C) 55 (i?)-(+)-a-methylbenzylamine EtOH thin needles 216.5-218 56 (.S)-(-)-a-methylbenzylamine EtOH thin needles3 217-218 57 (li?,25)-(-)-ephedrine MeOH thin needles 170-172 58 (15,2/?)-(+)-ephedrine CH 3 CN/MeOH thin needles 170-172 59 (li?,2S)-(-)-norephedrine CH 3 CN/MeOH plates3 173.5-175 60 (15',2i?)-(+)-norephedrine CH 3 CN/MeOH plates3 173-174 61 (li?,2i?)-(-)-pseudoephedrine CH 3 CN/MeOH thin needles 163-165 62 (5)-2-(+)-prolinol CH 3 CN/MeOH plates 178-181 63 L-prolinamide CH 3 CN/MeOH small plates 176-179 64 (1 R,2S)-(+)-cis-1 -amino-2-indanol CH 3 CN/MeOH needles 204(decomp) 65 (/?)-(+)- P -methylphenethylamine CH 3 CN/MeOH needles 177-179 66 (7?)-(+)-bornylamine CH 3 CN/MeOH plates 186-189 X-ray crystal structure obtained. Table 2.2 Preparation of chiral salts of keto acid 53 salt amine recryst solvent cryst morphol mp(°C) 67 (5)-(-)-a-methylbenzylamine MeOH needles 248-250 68 (i?)-(+)-a-methylbenzylamine CH 3 CN/MeOH needles 250-251 69 (lJR,2.S)-(-)-ephedrine CH 3 CN/MeOH needles 191-193 70 (li?,25)-(-)-norephedrine CH 3 CN/MeOH thin needles 186-188 71 (li?,2i?)-(-)-pseudoephedrine CH 3 CN/MeOH needles 193-195 72 (li?,25f)-(+)-c.'5-l-amino-2-indanol CH 3 CN/MeOH plates 208-210 73 (i?)-(+)-p-methylphenethylamine CH 3 CN/MeOH prisms 160-162 74 (7?)-(+)-bornylamine CH 3 CN/MeOH prisms 192-195 Salt formation is evidenced by the melting points and FT-IR spectra. The melting points of the salts are different from both the keto acids and the corresponding amines. In the FT-IR 36 Chapter 2. Preparation of Substrates spectra, the most diagnostic information is that the signals due to the acid carbonyl group in acids 46 and 53 are replaced by two intense bands from 1300-1650 cm"1 in the salts, which 78 1 result from symmetric and asymmetric stretching of the carboxylate anion. '° The ' H N M R and F A B mass spectra along with the elemental analyses indicate a 1:1 acid/base stoichiometry for all of the salts. The single crystal X-ray studies of salts 56, 59 and 60 unambiguously confirmed the above conclusions. 37 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones 3.1 Photochemical Reactions of the cw-Ketones The photochemical studies of c/s-ketones 43-47 were performed in both solution and the solid state. The details of the experiments as well as the apparatus used are given in the Experimental section. Scheme 3.1 and Table 3.1 summarizes the photochemical results in both media. R=H 75 79 83 87 ( R = C 0 2 M e ) R=F 76 80 84 R = C N 77 81 85 R = C 0 2 M e 78 82 86 Scheme 3.1 Photochemical reactions of the cz's-ketones 38 Chapter 3. Isolation and Identification of the Photoproducts of the cis-Ketones Table 3.1 Photolyses of ketones 43-47 in solution and the solid state ketone R temp. medium time(h) conv(%)a products (%)b 43 H 75 79 83 RT C C H 3 C N 20 100 59.2 39.3 1.5 --20°C crystald 1 8.1 0 100 0 -2 23.5 7.2 76.6 7.0 -3 36.6 13.0 78.5 8.4 -6 72.5 21.3 67.5 4 -44 F 76 80 84 RT C C H 3 C N 20 100 54.6 40.0 4.0 --20°C crystald 2.5 8.6 100 0 0 -6 16.3 100 0 0 -9 28.0 77.5 11.3 0 -22 72.3 68.7 11.9 2.5 -45 C N 77 81 85 RT C C H 3 C N 28 100 38.9 49.6 7.1 -RT° crystald 1 1.4 100 0 0 -1.5 7.1 50.9 10.3 e -3 10.6 45.0 10.9 e -16 72.5 31.5 19.8 e -47 C 0 2 M e 78 82 86 87 RT C C H 3 C N 23 100 46.7 47.1 6.2 0 -20°C crystald 6 100 81.1 0 0 18.9 a Percentage of total GC integral due to the disappearance of the corresponding starting material. b Percentage of total GC integral due to the corresponding product. 0 RT, room temperature. d For the photolysis in the crystalline state at higher conversion, the combined percentage of the reported compounds is less than unity because of some unidentified GC peaks.e GC peak was overlapped by side product peaks. 39 Chapter 3. Isolation and Identification of the Photoproducts of the cz's-Ketones A l l the solution photolyses were performed at room temperature with acetonitrile as the solvent. The low temperature of -20 °C was applied to the solid-state photolyses of ketones 43, 44 and 47 to minimize melting due to product formation. The photolysis of the crystals of ketone 45 was carried out at room temperature for two reasons: (a) solid-state photoreaction of 45 at low temperatures is very slow, and (b) ketone 45 possesses a comparatively high melting point (110.5-111.5 °C) and the irradiation of the crystals at room temperature does not result in observable melting. From Table 3.1 it can be seen that all the cz's-ketones show similar photochemical behavior in solution, yielding two typical Yang cyclization products (cyclobutanols 75-78 and 79-82) and a novel 1-indanone derivative (83-86). However, the solid-state photolyses of these ketones are different from each other. Ketone 43 yields cyclobutanol 79 as the major product, which is derived from the abstraction of H2/H7. The other ketones (44, 45 and 47) afford the cyclobutanols (76, 77 and 78) from H4/H5 abstraction as the dominant product. In the case of ketone 47, a rarely observed cyclopropanol, 87, was also isolated as a minor product. The structure-reactivity correlation studies accounting for the different reactivities are discussed in Chapter 4. Most of the products were isolated from the reaction mixture by chromatography. The separation of two cyclobutanols (75-78 and 79-82) was quite challenging, requiring repetitive chromatography on silica gel. TLC development on alumina did not give improved separation. In the case of keto-nitrile 45, attempted chromatographic separation of cyclobutanols 77 and 81 failed. However, repetitive fractional crystallization of the mixture from diethyl ether was found to be effective, and both cyclobutanols were isolated in >95% purity. A l l the products were characterized by melting points (for the solids only), ID ! H and 1 3 C (BB and APT) 40 Chapter 3. Isolation and Identification of the Photoproducts of the c/5-Ketones N M R , 2D ' H - H (COSY) and ! H - 1 3 C (HMQC and HMBC) N M R , NOE difference, FT-IR, LR and HR MS as well as elemental analyses. Some structures were also confirmed by X-ray single-crystal studies (cyclobutanol 78 and 1-indanone derivative 86). The details of the separation conditions along with the analytical data of the products are given in the Experimental section. 3.2 Identification of the Cyclobutanols 75-78 The closely related structures of the cyclobutanols 75-78 cause them to have similar ] H and 1 3 C N M R spectra, as can be seen in Figure 3.1. With compound 78 as representative, Figure 3.2-5 shows its ! H NMR, COSY, H M Q C and NOE difference spectra, respectively, as well as the peak assignments. It should be noted that the numbering of the structure is different from that of the starting ketone 47 and the IUPAC numbering rules are followed. These numbers are based on the carbon skeleton and each number is shared by both the carbon atom and the hydrogen atoms attached to it. Different hydrogen signals on the same carbon in the ! H N M R spectrum are differentiated by primes. The primed numbers indicate a hydrogen atom below the corresponding cyclohexane ring, and the hydrogens above the cyclohexane ring are numbered without primes. 41 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones — j — i — i — i — | — i — i — i — | — i — i — i — | — i — i — i — | — i — i — i — | — i — i — i — | — i — i — i — i — i — i — i — i B 7 6 5 A 3 2 1 ( Figure 3.1 Typical ' H N M R spectra of the cyclobutanols 75-78 42 Chapter 3. Isolation and Identification of the Photoproducts of the czs-Ketones Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones Chapter 3. Isolation and Identification of the Photoproducts of the czs-Ketones Chapter 3. Isolation and Identification of the Photoproducts of the cis-Ketones Figure 3.5 The NOE difference spectra (400 MHz in C 6 D 6 ) of 78 with irradiations at (a) nil; (b) 2.01; (c) 2.64; (d) 3.53; (e) 7.06 and (f) 8.11 ppm 46 Chapter 3. Isolation and Identification of the Photoproducts of the cis-Ketones The L R M S gives the parent peak of 78 at m/z 300, which is the same as the starting ketone 47. The HRMS confirmed that the product had the same chemical formula as the starting material and the elemental analysis further supported this conclusion. The COSY spectrum clearly indicates that the two doublets at 8.10 (J= 8.4 Hz) and 7.05 (/= 8.4 Hz) ppm in the *H N M R are coupled to each other, which leads to the conclusion that the aromatic ring is para di-substituted and remains intact during the reaction. A sharp absorption at 3483 cm"1 in the FT-IR spectrum indicates a non-hydrogen bonded O - H stretch, and the disappearance of the ketone carbonyl absorption in the product 78 reveals that the reaction involves loss of the C=0 double bond. The B B and APT 1 3 C N M R not only show 12 distinct peaks (including one methyl carbon from the ester functionality) between 10-90 ppm, reflecting the asymmetric structure of the aliphatic moiety of the compound, but also reveal that the ketone carbonyl carbon in the starting material is replaced by a quaternary carbon at 84.06 ppm in 78. From its chemical shift, this carbon is probably attached to an oxygen atom. A l l the above information leads us to assign a cyclobutanol structure. Further analysis of the COSY (Figure 3.3) and the H M Q C spectrum (Figure 3.4) results in the assignment of cyclobutanol structure 78 from the original H4/H5 abstraction in the starting material 47. The relative stereochemistry at C l l could not be determined until the NOE difference spectrum was recorded (Figure 3.5). The most important information is that HI3 and HI7 are close to H2' , H7, H8 and H10, and the hydroxyl group is close to H6. A better view of these interactions is shown in Figure 3.6. A l l the above data lead to an assignment of the endo-ary\ cyclobutanol structure 78. This conclusion was confirmed by an X-ray single crystal study of photoproduct 78 (Figure 3.7), and the pertinent crystallographic parameters are given in the Experimental section. 47 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones 3.3 Identification of Cyclobutanols 79-82 Similar analyses were followed as in the previous section to assign the structures of cyclobutanols 79-82. Figure 3.8 shows their similar ' H N M R spectra. Compound 82 is used as an example to deduce the structure, and its ' H N M R , COSY, H M Q C and NOE difference spectra are illustrated in Figures 3.9-12, respectively. The numbering of the carbon skeleton is different from that of the starting ketone 47 and the IUPAC numbering rules are followed. The hydrogen atoms attached to the same carbon atom share the number of that carbon, and their distinct signals in the ] H N M R spectrum are differentiated with primes in the same way as in the previous section. The LR and HRMS clearly indicate that product 82, like product 78, is an isomer of the starting ketone 47, which is confirmed by elemental analysis. Its l H N M R spectrum gives two doublets at 8.11 (J= 8.4 Hz) and 7.16 (J= 8.4 Hz), respectively, which are coupled to each other from the COSY spectrum. Thus, the aromatic ring is para di-substituted and remains intact during the reaction. The FT-IR spectrum shows a strong, sharp absorption at 3591 cm"1 and a single ester carbonyl group at 1718 cm"1, reflecting that the reaction occurs on the ketone carbonyl group and a hydroxyl group is generated. The B B and APT 1 3 C N M R indicate the asymmetric structure of the compound and the replacement of the ketone carbonyl carbon from the staring ketone by a quaternary carbon attached to an oxygen atom. The detailed analysis of the COSY (Figure 3.10) and the H M Q C (Figure 3.11) spectra results in the assignment of cyclobutanol structure 82 from H2/H7 abstraction in the starting ketone 47. The O H 49 Chapter 3. Isolation and Identification of the Photoproducts of the czs-Ketones endo-aryl configuration at CIO is determined from the NOE difference spectra (Figure 3.12), and the important interactions are summarized in Figure 3.13. Our attempts to obtain single crystals of cyclobutanols79-82 failed. i • • • 1 • • • 1 • • • 1 • ' • i • • • i • • ^ A J 8 7 6 5 1 3 2 1 Figure 3.8 Typical ' H N M R spectra of cyclobutanols 79-82 50 Chapter 3. Isolation and Identification of the Photoproducts of the czs-Ketones Chapter 3. Isolation and Identification of the Photoproducts of the czs-Ketones 1 '—>—i— i—'— 1 — 1 — i 1 1 1 1 i 1 1 1 1 i ppm 2.5 2.0 1.5 1.0 Figure 3.10 Partial COSY spectrum (500 M H z in C 6 D 6 ) of cyclobutanol 82 Chapter 3. Isolation and Identification of the Photoproducts of the cis-Ketones 53 Chapter 3. Isolation and Identification of the Photoproducts of the cz's-Ketones — | i i r—r—i Figure 3.12 The NOE difference spectra (400 MHz in C 6 D 6 ) of cyclobutanol 82 with irradiations at: (a)nil; (b) 1.87; (c) 2.19; (d) 2.48; (e) 7.16 and (f) 8.11 ppm. 54 Chapter 3. Isolation and Identification of the Photoproducts of the m-Ketones Figure 3.13 The NOE interactions in cyclobutanol 82 3.4 Identification of the 1-Indanone Derivatives 83-86 In each solution photolysis of ketones 43-47, a minor product was isolated in addition to two cyclobutanols. Figure 3.14 shows the typical ' H N M R spectra of these compounds (83-86). We use compound 86 as an example to show how their structures were elucidated. 55 Chapter 3. Isolation and Identification of the Photoproducts of the cz's-Ketones 83 in CDC13 (400 MHz) Figure 3.14 Typical ' H N M R spectra of 1-indanone derivatives 83-86 56 Chapter 3. Isolation and Identification of the Photoproducts of the czs-Ketones The FT-IR spectrum of photoproduct 86 shows two very closely located carbonyl groups between 1725-1715 cm"1, and no other functional groups can be observed. The ' H N M R spectrum indicates that the aromatic ring of the product becomes tri-substituted and the hydrogen signals in the aliphatic region are not well resolved. The B B and APT 1 3 C N M R reveal a significant amount of information about the structure: (a) There are two carbonyl groups in the molecule with one being an ester and the other being a ketone; (b) The aromatic ring is tri-substituted with the appearance of three CH's and three C's between 165-120 ppm; (c) The molecule contains symmetry in the aliphatic moiety (Figure 3.15). Besides the methyl group from the ester functionality, there are two quaternary carbons and only four methylene peaks. The intensities of these methylene peaks are even higher than that of the methyl peak, reflecting that each peak represents more than one carbon atom; (d) Other than the ketone, ester and the aromatic ring, there is no other unsaturated carbon atom. Since the L R M S , HRMS and the elemental analysis reveal that product 86 has two less hydrogens than the starting material 47, it becomes obvious that 86 must have one more degree of unsaturation than 47. Owing to fact (d) from the 1 3 C N M R spectrum, there must be another ring structure in 86. A l l the above information results in the assignment of a 1-indanone strucuture for 86, which was confirmed by an X-ray single crystal study (Figure 3.16). The crystallographic parameters are given in the Experimental section. 57 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones CH3 i—!—1—1—1—r~ 40 35 - 1 T~ 30 I 1 1 1 1 <— 2S 20 PPM Figure 3.15 Partial 1 3 C N M R spectrum (75 M H z in QDe) of 86 Figure 3.16 The ORTEP drawing of compound 86 58 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones 3.5 Identification of Cyclopropanol 87 Compound 87 was isolated from solid-state photolysis of ketone 47 and its structural assignment was made in a similar way as in the previous section. The L R M S , HRMS and elemental analysis show that 87 has the same chemical composition as the starting ketone 47. The FT-IR shows a sharp O - H stretch at 3489 cm"1 and only the ester carbonyl group at 1708 cm"1 is present in the molecule, indicating that the ketone is converted to an alcohol. The ] H N M R spectrum (Figure 3.17a) reveals the para di-substitution on the aromatic ring by showing two doublets at 8.15 and 7.15 ppm, respectively, with the same coupling constant of 8.4 Hz. This is confirmed from the B B and APT C N M R that give two aromatic CH's and two aromatic C's along with the carbonyl and methyl from 1 "\ the ester. As in section 3.4, these C N M R sepctra expose rich information about the structure of the aliphatic moiety in 87. The ketone carbonyl of the starting material 47 is replaced by a quaternary carbon at 65.34 ppm in 87, which, based on chemical shift considerations, is probably attached to an oxygen atom. Besides the methyl carbon from the ester group, there are four methylene peaks and one quaternary carbon peak, indicating that the structure is highly symmetric (Figure 3.17b). An important observation concerns the chemical shifts of 59 Chapter 3. Isolation and Identification of the Photoproducts of the c/5-Ketones two quaternary carbons (23.50 and 65.34 ppm). They are substantially upfield compared to similar quaternary (47-51 ppm) and hydroxy-substituted quaternary carbons (81-85 ppm) in cyclobutanols 75-82. The most probable reason is the presence of a three-membered ring, because it is well known that carbons and hydrogens on cyclopropane ring are highly shielded. 7 9 , 8 0 This leads us to assign the cyclopropanol structure 87. Attempts to grow the single crystals of 87 met with failure. 60 Chapter 3. Isolation and Identification of the Photoproducts of the cz's-Ketones (a) ~ i 1 * 1 1 1 * 1 * ' i * * 1 1 1 1 1 1 1 f 5.* 3.1 ' S ' « 6 'i S i i.l i S ! . « 2.5 M 1 5 ' . J (b) CH3 CH2 - T — | — I — I — I — I — | — I — r — ! — T — ) — I — I — I — I — | — I S5 G0 55 50 ~ i — i — [ — i — i — i — i — | — i — i — i — i — [ — i — i — i — i — | — r ~ i — i — r "1—1—'—'—1—I—*" 45 40 PPM 35 30 25 20 Figure 3.17 The full ' H N M R (a, 400 MHz in C 6 D 6 ) and partial 1 3 C N M R (b, 100 MHz in CeD6) of cyclopropanol 87 61 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones 3.6 Photolysis of the c/s-Chiral Salts and the Enantiomeric Excess Determination of the Photoproducts The cz's-chiral salts 55-66 were photolyzed both in solution and the solid state. The same procedures as in the photolyses of ketones 43-47 were followed, except that a mixture of actonitrile and water was used as the solvent for solution reactions and all solid-state photolyses were performed at room temperature because of the high melting points of the salts. The starting salts in solution were irradiated until the reactions were complete. The time of photolysis for each solid-state reaction was controlled to different lengths so that the enantiomeric excess could be determined at various conversions. A l l the solution and solid-state photolysis reaction mixtures were treated directly with ethereal diazomethane solution to convert the ammonium salts to the corresponding methyl esters. After the appropriate workup as detailed in the Experimental section, the percentage conversion as well as the product composition was determined by GC. A l l the solution state reactions afforded the same distribution of cyclobutanols 78, 82 and 1-indanone derivative 86 as from the solution photolysis of keto-ester 47. Photoproducts 78 and 82 were later determined to be racemic. Irradiation of the chiral salts in the crystalline state always yielded cyclobutanol 78 as the major product. The details of the photochemical results at different conversions are given in Chapter 4. Our attempts to resolve racemic 78 on chiral GC columns met with failure. However, chiral HPLC with a Chiralcel OD™ column gave baseline separation. The HPLC conditions as well as the column specifications are listed in Table 3.2. Figure 3.18a shows the HPLC trace of the racemic mixture of cyclobutannol 78. The HPLC trace recorded by Dr. Bi l l 62 Chapter 3. Isolation and Identification of the Photoproducts of the c/s-Ketones Champion from Chiral Technologies, Inc., as well as the optical rotation determination trace, is illustrated in Figure 3.18b. Table 3.2 The HPLC conditions for the resolution of racemic 78 Column Chiralcel OD™ Column specifications 250 mm x 4.6 mm ID Solvent 98/2 (hexane/2-propanol) Flow rate 1 mL/min Detector U V at 230 nm (b) normal HPLC trace optical rotation trace -JL— Figure 3.18 The HPLC traces for the resolution of racemic 78 (a) the experimental HPLC trace; (b) the HPLC and optical rotation trace recorded by Dr. B i l l Champion (Chiralcel OD™ column (250 mm x 4.6mm), 98/2 hexane/ethanol) 63 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the c^-Ketones Chapter 4. Structure-Reactivity Correlation and Kinetic Studies for the c/s-Ketones . . A r T H 1 0 T 44 (R=F) H 5 H 4 45 (R=CN) 47 ( R = C 0 2 M e ) hv R=H R=F R = C N R = C 0 2 M e A r ^ ^ O H 87 ( R = C 0 2 M e ) As described in the previous chapter, photolysis of ketones 43-47 in solution led to very similar results, yielding two cyclobutanols (75-78 and 79-82) and a 1-indanone derivative (83-86). These compounds originate from the hydrogen abstraction of H4/H5, H2/H7 or H10, respectively. The cyclobutanols are formed through typical Yang photocyclization pathways, while the formation of compounds 83-86 occurs via abstraction of H10 followed by a series of rearrangements. In the solid state, however, the photoreactivity of the ketones depends heavily on the conformation they adopt within the crystal lattice. Based on the crystal-structure data of ketones 43-45 and 47, it was possible to perform structure-reactivity correlation studies, thereby rationalizing their photochemical behavior. 64 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones 4.1 Regio- and Diastereoselectivity of Cyclobutanol Formation In each ketone (43-47) there are four y-hydrogen atoms which could, in theory, be abstracted. Figure 4.1 shows the crystal structures of ketones 43-45 and 47, and the relevant geometric data are summarized in Table 4.1. From the crystallographic data, it is observed that the ketones adopt two different conformations. Ketone 43 (Figure 4.1a) adopts a conformation in which the phenyl ring is lying on top of the decalin system, positioning the carbonyl oxygen atom closer to H2 (2.65 A) than to H4 (3.52 A). For ketones 44, 45 and 47 (Figure 4.1b-d), however, the carbonyl group lies above the decalin structure and the oxygen atom is proximal to H4 (2.55-2.67 A) and H10 (2.36-2.42 A), and distant from H2 (3.41-3.50 A). Table 4.1 reveals that the closely located y-hydrogens (H2 for 43 and H4 for the other ketones) also have favorable abstraction angles in comparison to the corresponding ideal values. Although angles 0 and co deviate significantly from 180° and 0°, it is known that hydrogen abstraction still occurs even when angle 0 deviates considerably from its ideal value, and the abstraction reactivity is suggested to have a cos2co dependence.13 With an average value of 48° for m, ketones 43-47 should still maintain 45% of their maximum reactivity in the solid state. On the basis of this information, it is expected that, upon irradiation, crystals of ketone 43 will undergo H2 abstraction while the other ketones will abstract H4 preferentially. The experimental results shown in Table 3.1 conform to this conclusion, where cyclobutanol 79 was found as the major photoproduct of 43 and cyclobutanols 76-78 predominated for the other ketones. Although products resulting from abstraction of the unfavorable y-hydrogens (H4 for 43 and H2 for 44 and 45) were observed, this may be due to the lattice defects caused by product formation, which may break down the crystal lattice and allow more atomic and molecular motion. 65 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the c/s-Ketones Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the m-Ketones Table 4.1 Geometric parameters derived from the crystal structures of ketones 43-45 and 47 ketone Y-H d ( A ) a A ( ° ) a 9 ( ° ) a c o ( ° ) a 43 H4 3.52 44 106 44 H2 2.65 84 113 56 44 H4 2.67 85 111 55 H2 3.50 47 105 46 45 H4 2.59 89 115 40 H2 3.41 51 109 48 47 H4 2.55 85 116 56 H2 3.47 45 107 45 Ideal values <2.72 90-120 180 0 For definitions, see section 1.2. As expected, the observed solid-state regioselectivity is lost in solution, where rotation of the aryl group is not prevented by the crystal lattice, and H2/H7 abstraction becomes possible. An approximately 1:1 mixture of two cyclobutanols was obtained for all the ketones (Table 3.1). The HyperChem MM+ conformational analysis of the starting materials gave two lowest energy conformations as A and B in Scheme 4.1, and they are almost isoenergetic, differentiated by only 0.1 kcal/mol. The detailed geometric analysis in terms of distances and angles (Table 4.2) shows that these two conformations are the same as the corresponding crystal structures in Figure 4.1. Therefore, conformer A will afford cyclobutanols 75-78 and conformer B accounts for photoproducts 79-82. Since A and B are isoenergetic and can interconvert by simply rotating around the C9-C(0) sigma bond, the 1:1 ratio of two cyclobutanols in solution photolyses is not surprising. 67 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the cis-Ketones Table 4.2 Geometric data of A and B from HyperChem M M + calculations Parameters d(A) 6 ( ° ) A ( ° ) co(°) H4 (A) 2.38 111 102 44 H2(A) 3.18 106 58 57 H2 (B) 2.40 110 103 43 H4 (B) 3.22 106 60 58 Ideal Values <2.7 180 90-120 0 H hv 4 / \n-io H Q Ar A V O H H O A r H C V A r R B hv - H 2 A \ , x x O H A \ , A O H H O sSAr Ar« , v O H H T H Q Ar exo- endo-75-78 75-78 87 83-86 endo- exo-79-82 79-82 Scheme 4.1 Formation of photoproducts 75-87 68 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the c^-Ketones A n interesting observation is that, no matter whether in solution or the solid state, all the cyclobutanols are formed with endo-ary\ stereochemistry and no exo-aryl isomers are obtained. This high diastereoselectivity is presumably the result of kinetic control in solution and topochemical control in the solid state. Scheme 4.1 summarizes the formation of all possible products, where biradicals C, D and F are primary intermediates after hydrogen abstraction. The direct radical recombination of biradicals C and F with retention of configuration at the protonated ketyl radical center will afford the observed endo-ary\ cyclobutanols. To yield the corresponding exoaryl cyclobutanols, intermediates C and F have to rotate around the C9-C(OH) sigma bond to form biradicals G and H, and then cyclize, which is evidently a comparatively slow process. Since products derived from biradicals G and H are not observed, the selectivity in solution must be kinetically controlled. This is in contrast to the solid state, where neighboring molecules in the unit cell physically prevent bond rotation and biradicals G and H are not accessible, which accounts for the selectivity. 4.2 Cleavage vs Cyclization The biradicals derived from czs-ketones 43-47 adopt gauche conformations exclusively and, as pointed out in the Introduction section, can in principle undergo either cleavage or cyclization reactions. The geometry of these intermediates dictates which direction the reactions proceed. However, in the course of this research, no cleavage product was observed, regardless of reaction medium. The most important information to explain the absence of any cleavage products comes from structure-reactivity correlation studies. 69 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones From the crystal structures of the starting ketones (Figure 4.1), torsion angles q>\ and (p$ were calculated (the definitions of these parameters are given in section 1.2). The overlap between the singly occupied p orbitals and the potentially breaking bond is described as a cosine function of these torsion angles, and Table 4.3 summarizes <p\, q>\, and their cosine values along with D, the distance between the radical centers, for ketones 43-47. Table 4.3 Cleavage and cyclization parameters for ketones 43-45 and 47 ketone y-H a cos <p\ <P4(°) COS (p4 D ( A ) 43 H2 67 0.39 36 0.81 3.08 44 H4 -69 0.36 -35 0.82 3.07 45 H4 87 0.05 37 0.80 3.12 47 H4 -68 0.37 -35 0.82 3.05 Ideal values 0 1 0 1 <3.40 Only the geometrically favored y-H's are listed. The results summarized in Table 4.3 show that the p orbitals on the y-carbons have good overlap with the C a -Cp bond, averaging 81±1% (cos<p4), while the overlap of the p orbitals at the hydroxy radical centers is poor. For ketones 43, 44 and 47, cosc^i is 37±2% and for ketone 45, cost?i shows only 5% overlap. Since the cleavage reaction requires good overlap on both radical centers, the poor q>\ angles at the hydroxy radical center suppress the bond breaking. On the other hand, the favorable distance between the two radical centers (3.08±0.04 A) helps cyclization to become the dominant process. In solution, rotation around C9-C(OH) sigma bond is free, which, in theory, could align the singly occupied p orbitals at good geometry to form the cleavage products. The failure to 70 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the cz's-Ketones observe these products indicates that the conformation responsible for cleavage is not kinetically favorable. Take biradical C in Scheme 4.1 as an example. Its Newman projection is shown in Figure 4.2 looking along the C(OH)-C9 sigma bond. In biradical J where the perfect cleavage orbital-bond overlap is adopted, the aryl group is in a near-eclipsed position with the C8-C9 bond, which is not favored in solution. Figure 4.2 Cleavage conformation 4.3 Enantioselectivity in the Solid State One of the major objectives of the present research was the application of the "ionic chiral auxiliary" approach. A series of chiral salts was thus made as stated in section 2.3. Solid-state photolysis of all the salts yielded cyclobutanol 78 as the major product after the diazomethane workup. The ee's of photoproduct 78 at different percentage conversions are summarized in Table 4.4. 71 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones Table 4.4 Asymmetric induction in the photolyses of chiral salts 55-66 salt amine rxn time(h) conv%a 78%b ee%c 55 (i?)-(+)-a-methylbenzylamine 1 22.9 80.2 (-)-95.0 2 90.0 58.4 >98 3 94.4 63.4 >98 56 (iS)-(-)-a-methylbenzylamine 1 17.1 74.0 (+)->98 2 35.2 69.2 >98 4 55.7 66.5 >98 8 84.7 63.2 97.6 57 (li?,25)-(-)-ephedrine 0.25 12.0 73.1 (+)->98 0.5 36.9 56.7 >98 1 85.9 46.9 >98 4 97.7 46.4 >98 5 100 45.7 96.0 58 (l£2tf)-(+)-ephedrine 0.5 43.4 52.7 (-)->98 0.75 68.4 50.9 >98 59 (li?,2,S)-(-)-norephedrine 0.5 10.3 94.3 (-)-30.4 2 23.5 93.3 23.0 4 55.3 94.8 29.8 60 (1 ,S',2ic)-(+)-norephedrine 2 29.4 94.9 (+)-24.6 61 (l/?,2i?)-(-)-pseudoephedrine 0.5 38.4 74.4 (+)->98 1 58.8 69.9 >98 2 86.7 65.4 95.6 62 (5)-2-(+)-prolinol 0.5 12.3 100 (+)-31.8 1 43.4 89.5 15.8 64 (lR,2S)-(+ycis-1 -amino 0.25 12.8 84.2 (+)->98 -2-indanol 0.5 36.6 73.0 >98 1 59.1 72.6 >98 4 96.6 71.6 95.0 72 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the c/s-Ketones 65 CR)-(+)-p-mefhyl 0.5 31.0 57.7 (+)-97.4 Phenethylamine 1 45.8 56.6 96.6 2 89.0 48.2 87.6 66 (i?)-(+)-bornylamine 0.5 9.3 100 (-)->98 1 18.2 100 >98 3 77.9 100 >98 a Percentage of total GC integral due to the disappearance of compound 47. Percentage of total GC integral due to compound 78. Yield reduced at higher conversion is due to presence of unidentified GC peaks.0 Enantiomeric excess (ee) values were measured on a Chiracel OD™ column using a U V detector. Sign of rotation in front of the numbers was obtained at 675nm. Table 4.4 shows that many salts (55-58, 61 and 64-66) gave excellent ee's (>98%) even at very high conversions (almost 100%) while others (59, 60 and 62) only yielded around 30% ee. This difference is explained on the basis of the crystal structures of salts 56, 59 and 60 (Figure 4.3). In the unit cells, all of the molecules present adopt conformation A (Scheme 4.1) exclusively. The geometric parameters summarized in Tables 4.5 and 4.6 reflect their high similarity to the crystals of ketones 44, 45 and 47, which accounts for their photochemical regioselectivity, diastereoselectivity and lack of cleavage reaction. 73 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the cfc-Ketones Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the crs-Ketones Table 4.5 Hydrogen abstraction parameters for salts 56, 59 and 60 salt y-H d ( A ) A ( ° ) e ( ° ) c o ( ° ) 56 H5 2.62 84 115 55 H7 3.43 45 109 45 59 (I) H4 2.70 80 114 56 H2 3.58 41 107 41 59 (II) H5 2.65 83 114 55 H7 3.54 . 44 107 44 60 (III) H4 2.65 83 114 55 H2 3.54 44 106 44 60 (IV) H5 2.70 80 114 57 H7 3.58 42 106 42 Ideal values <2.72 90-120 180 0 Table 4.6 Cleavage and cyclization parameters for salts 56, 59 and 60 salt y-H cos <p\ cos cp4 D ( A ) 56 H5 -68 0.37 -36 0.81 3.07 59(1) H4 65 0.42 34 0.83 3.08 59 (II) H5 -69 0.36 -36 0.81 3.08 60 (III) H4 69 0.36 34 0.83 3.09 60 (IV) H5 -65 0.42 -36 0.81 3.08 Ideal values 0 1 0 1 <3.40 For salt 56, there is only one molecule present in the unit cell (Figure 4.3a) and it has a geometrically favorable Y-H (H5, d = 2.62 A). Since the optically pure (SM-)-a-methylbenzylamine, whose absolute configuration is known, was used as a chiral handle, the Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones structure shown in Figure 4.3a is the absolute conformation. Therefore, after hydrogen abstraction, only a single enantiomer of cyclobutanol 78 wil l be formed (the (+)-product as later determined by HPLC), and the >98% ee is not surprising. On the other hand, for (-)-norephedrine salt 59, equal amount of two independent molecules (molecules I and II in Figure 4.3b) were found in the same unit cell. For each molecule there is a geometrically favored y-H (H4 in molecule I and H5 in molecule II). So both molecules should be photoreactive upon irradiation. Moreover, without considering the chiral auxiliary in the crystal lattice, the anion conformations of I and II are almost enantiomerically related. Superimposition of the mirror image of molecule II on top of molecule I using the HyperChem program provides the view given in Figure 4.4, where the blue atoms represent molecule I and the pink ones correspond to molecule II. The calculated root-mean-square error (RMSE) of only 0.08 A implies a near-perfect overlap of these two molecules. With all other factors being equal, irradiation of crystals with same amount of I and II should give racemic photoproducts because molecules I and II yield opposite enantiomers of the same cyclobutanol. We propose that the observed (-)-30.4% ee at 10.3% conversion reflects the different rates of ring closure of the 1,4-hydroxybiradicals relative to their corresponding reverse hydrogen transfer. This difference is caused by the presence of (-)-norephedrine which makes the competition between the (+)- and (-)-cyclobutanol formations diastereomeric in nature, yielding the (-)-product as the major component. (+)-Norephedrine salt 60 is the opposite antipode of salt 59 and it gave a very similar crystal structure (Figure 4.3c). Photolysis of these crystals yielded the (+)-product as the major component with the same photoreactivity as salt 59, showing that these salts behave as expected in the crystalline state. 76 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the cfr-Ketones O Figure 4.4 The chirality-matched view of molecules I and II for salt 59 The presence of two enantiomeric conformations co-existing in the same unit cell is termed "conformational enantiomerism" and has been observed previously in our photochemical studies of chiral organic salts. Similar situations were also observed in other systems and low ee's were obtained in these cases as well. In general, the low ee's can be understood in the following way. Each of the conformational enantiomers resides in its own unique reaction cavity which determines its reactivity. Without the chiral auxiliary, the influence of the crystal lattice on both enantiomeric conformers is the same and racemic product is the overall outcome. When a chiral auxiliary is involved, this environmental influence changes to act on different diastereomers and results in a differentiated reactivity. The enantiomeric excess observed in these cases is a direct measure of the environmental effect. However, how this environmental effect influences the reactivity cannot be visualized by simple inspection of crystal structures and needs careful computational analysis. 77 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones 4.4 Kinetic Studies of the Photochemical Process of Ketone 43 In order to have a better understanding of this reaction, a quantum yield kinetic study of ketone 43 was performed by using a merry-go-round apparatus. The concentration of ketone 43 was determined by its absorbance at 313 nm so that the solution is opaque at that wavelength. Valerophenone was chosen as the actinometer and the quantum yields of product formation were measured in benzene (O) and 67% (w/w) tert-butanol/benzene (O m a x ) . Linear Stern-Volmer plots based on Equation 4.1 were obtained for cyclobutanols 75 and 79 by determining their quantum yields with varying amounts of triplet quencher 2,5-dimethyl-2,4-hexadiene (Figure 4.5). In this equation, [Q] is the concentration of the quencher, O 0 represents the quantum yield without quencher and O is the quantum yield at different concentrations of quencher. When Oo/O is plotted against [Q], the slope of the plots will be kqr, where r is the triplet excited state lifetime and kq is the quenching rate constant. Quenching is normally considered to be diffusion controlled and the value of kq is dependent on solvent. For benzene, kq = 5x l0 9 MT'-s"1. Therefore, the triplet lifetime can be estimated. The results are tabulated in Table 4.7. O q Equation 4.1 Stern-Volmer quenching equation85 78 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the c/s-Ketones Table 4.7 Quantum yields and kinetic parameters for solution state photolysis of 43 parameters cyclobutanol 75 cyclobutanol 79 [43] (M) 0.039±0.002 O 0.0336±0.003 0.019±0.001 'I'max 0.108+0.001 0.083±0.003 kqr(MA) 6.83±0.05 8.46±0.28 r(10"9s) 1.37 1.69 O 75 • 79 0 0.2 0.4 0.6 0.8 1 [Q] (M) Figure 4.5 Stern-Volmer plots for the formation of cyclobutanols 75 and 79 As shown in Table 4.7, the quantum yields (O) for cyclobutanol formation are low, less than 5%, indicating the low efficiency of the reaction. This explains the requirement of long irradiation times. A very interesting observation in the kinetic studies is that two excited states 79 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the cz's-Ketones were found for the formation of cyclobutanols 75 and 79, and their lifetimes were determined to be 1.37 and 1.69 ns, respectively. The highly linear plots in Figure 4.5 with near-unity regression coefficients ( r ) of 0.9999 and 0.9983 indicate that the observation of two excited states is not due to experimental errors. The difference in triplet lifetimes can be accounted for by examining the mechanism of cyclobutanol formation. A simplified version of Scheme 4.1 is shown below as Scheme 4.2. A il B hv A* • C 75 k-i hv k1 • B* • 79 Scheme 4.2 Simplified schematic presentation of the formation of products 75 and 79 Cyclobutanols 75 and 79 are formed from different conformations A and B of the starting material, which can equilibrate in both the ground and excited states. The rate constants for their interconversion in the excited state are symbolized by ki and k_i. Hydrogen abstractions of A* and B* form biradicals C and F with rate constants of k c and k F , respectively. In the situation of k i , k.i » kc, kp, where the Curtin-Hammett principle applies,86 the ratio of 75 and 79 depends on the activation energy difference for A* and B* to form biradicals C and F; the lifetimes of both exicted conformers will be the same. However, i f the activation energy for the excited state conformational isomerization is greater than that for hydrogen abstraction, i.e., k c , k F » ki , k_i, then the ratio of products will depend on the population of A* and B* and their efficiencies to form products. Since electron excitation is much faster than nuclear 80 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones movement, the population of A and B in the ground state will determine the population of A* and B*. In this situation, A* and B* might have different lifetimes. It is believed that the quenching studies of ketone 43 were an example of the latter case, i.e., hydrogen abstraction occurs faster than conformational isomerization, which causes the observation of two excited states. This argument is not unprecedented and has been applied to other systems. Lewis and co-workers87 have studied the photochemistry of 1-methylcyclohexyl phenyl ketone (88) (Scheme 4.3) and found that type II product cyclobutanol (89) and type I product benzaldehyde (90) were formed from two different excited state conformational isomers. The result was attributed to the slow conformational interconversion between the isomers compared to the fast a-cleavage and y-hydrogen abstraction processes. Scheme 4.3 Photochemical studies of compound 88 by Lewis and co-workers 81 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones Similar observations were also reported by Wagner in 1977 (Scheme 4.4). In the photochemical studies of o-methyl valerophenone (91), enol (92) and type II product (93) were formed from different excited states because of very fast hydrogen abstraction from the o-methyl group. 91 93 Scheme 4.4 Photochemical studies of compound 91 by Wagner 4.5 Competition between P- and y-Hydrogen Abstractions8* In addition to the typical y-hydrogen abstraction products (cyclobutanols 75-82) obtained in the photolyses of ketones 43-47, rarely observed P-hydrogen abstraction products (1-indanone derivatives 83-86 and cyclopropanols 87) were also obtained both in solution and the 82 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the c/s-Ketones solid state. The formation of cyclopropanol 87 presumably occurs through abstraction of H10, forming 1,3-biradical D, followed by direct ring closure (Scheme 4.1). 1-Indanone derivatives 83-86 were believed to be from the hydrogen abstraction followed by a series of processes90 which are presented in Scheme 4.5. 83-86 Scheme 4.5 Mechanism for the formation of compounds 83-86 In general, y-H abstraction is much faster than the (3- version because of the favorability of the cyclic six-membered transition state over its five-membered counterpart.91 Therefore, 1,5-hydrogen transfer is the most often seen process. However, from the existing examples of P-H abstraction,89'92 two factors seem to be quite crucial in deciding its occurrence. First, the p-hydrogen must be geometrically available for abstraction. This is especially critical in the solid state where the motion of each atom and molecule is greatly restricted. Most importantly, the distance d between the carbonyl oxygen and the P-H, should be less than 2.72 A. Second, the 83 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones beta C - H bond must be activated by its substituents. In other words, the resultant radical must be electronically stabilized. Analysis of the crystal structures of ketones 44, 45 and 47 reveals the very favorable P-H abstraction geometry, especially for the distance d (2.36-2.42 A) and the out-of-plane angle co (0-6°) compared to their ideal values (Table 4.8). Therefore, P-H abstraction is geometrically available. Electronically, after H10 abstraction, the resultant biradical D (Scheme 4.1) has a hydroxy radical center and a tertiary radical center, whereas biradical C, formed from H4 (y-H) abstraction, contains the same hydroxy radical and a secondary radical. It has been found that 1,5-hydrogen transfer from a tertiary carbon can be four times faster than from a secondary carbon.10 This electronic effect offsets the unfavorable transition state for H10 abstraction and enables the P-H abstraction process to become competitive. Table 4.8 X-ray derived P-H abstaction parameters for ketones 44,45 and 47 ketone d (A) 0(°) A ( ° ) co(°) D (A) 44 2.36 101 85 0 2.52 45 2.42 99 83 6 2.52 47 2.38 99 85 1 2.51 Ideal Values <2.72 180 90-120 0 <3.40 At the same time, product formation is medium-dependent. 1-Indanones were formed only in solution while cyclopropanols were formed only in the crystalline state. Presumbably this difference is again due to the kinetic and topochemical control in different media. Referring to Scheme 4.1, since bond rotation is restricted in the crystalline state, the formation 84 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the czs-Ketones of 1,3-biradical E from D is impossible and products 83-86 cannot be formed. Direct radical recombination of D, which is geometrically allowed with a very short distance D (2.51 A), yielded the very rarely observed cyclopropanol 87. (We were not able to isolate its analogues from the solid-state reaction mixtures of ketones 44 and 45.) Cyclopropanols were not formed in solution probably owing to the large strain associated with the three membered ring, which would lead to a higher energy transition state and make it unable to compete with the bond rotation and rearrangements that are responsible for 1-indanone derivatives 83-86. The formation of cyclopropanol 87 in the solid state reflects the "latent reactivity" of ketone 47.93 In solution, the atoms and molecules are relatively free to move and rotate. As a result, the formation of photoproduct 87 is not favored and cannot be seen. When the medium is changed to the solid state, strong crystal-lattice forces suppress the indanone formation, and the "latent reactivity" to form cyclopropanol 87 is stimulated because it is topochemically allowed. Hence, compound 87 can be obtained in significant amounts. 4.6 Summary The stereoselective photochemical reactions of the cw-9-decalyl aryl ketones that have been discussed in this present work are excellent illustrations of the advantages of solid-state organic photochemistry. These compounds yielded a mixture of products in solution, but their reactions were much more stereoselective in the crystalline state and also afforded a novel product that is not available in solution. Moreover, the X-ray structure - solid-state reactivity correlation method not only enabled the rationalization of the formation of the products from 85 Chapter 4. Structure-Reactivity Correlation and Kinetic Studies of the cw-Ketones their starting materials, including the novel P-hydrogen atom abstraction products, but also allowed the explanation of both high and low enantioselectivities in the crystalline state chiral salt photolyses. The geometric parameters for y-hydrogen abstraction derived from these correlations conform very well to other ketone systems previously studied (Table 4.8), indicating a general rule for this reaction. These data, in addition to those already collected, can serve as a reference source for predicting the reactivity of future systems. Table 4.9 Hydrogen abstraction parameters Systems d ( A ) 0 ( ° ) A ( ° ) co(°) 21 a-cycloalkyacetophenones 2.74+0.16 N / A 84+8 43+9 Medium/large ring aliphatic diketones94 2.73+0.03 115+2 83+4 52+5 Rigid cylcohexyl aryl ketones64 2.61±0.07 115+2 84±7 53+11 Spirobenzoyladmantane95 2.63+0.03 114+1 81±4 58+3 oc-Mesitylacetophenone68 2.77±0.04 123±3 80±7 59±2 Present work 2.62+0.08 113±3 85+5 48+8 MM+ 2.39±0.01 110±1 102+1 44±1 PM3 2.82+0.04 109±1 79+1 58+1 Conformational searches using the HyperChem package were conducted for all the starting materials at the MM+ level and refined at the PM3 level. These data, summarized in Table 4.9 along with the data obtained from previous work, show reasonable agreement with the experimental values, demonstrating its applicability in predicting chemical reactivity for future systems. As the data pool is increased with ongoing work, these predictions will become increasingly reliable. 86 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones Chapter 5. Isolation and Identification of the Photoproducts of the fra/is-Ketones 5.1 Photochemical Reactions of the fiwis-Ketones Photolysis of the trans-ketones 50-54 was performed both in solution and in the solid state. The same photochemical procedures were followed as described in Chapter 3, and the details are presented in Chapter 10. Scheme 5.1 and Table 5.1 summarizes the photochemical results in both media. O 50 (R 51 (R 52 (R: 54 (R H) F) C N ) hv R=H R=F R = C N 94 95 96 97 98 99 100 101 R = C 0 2 M e Scheme 5.1 Photochemical reactions of the trans-ketones 87 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones Table 5.1 Photochemical results of the trans-ketones* ketone R medium time(h) conv(%)b products (%)c 50 H 94 98 t BuOH/PhH d 57 100 42.8 10.0 crystal 50 16.6 100 0 51 F 95 99 t BuOH/PhH d 57.5 84.3 63.6 23.2 crystal 44.5 2.0 70.0 0 52 C N 96 100 l BuOH/PhH d 71 100 32.6 25.1 crystal 44.5 6.7 100 0 54 C 0 2 M e 97 101 t BuOH/PhH d 76 100 30.1 47.1 crystal 50 3.8 41.6 0 a A l l the photolyses (solution and the solid state) were performed at room temperature; b Percentage of total GC integral due to the disapperance of the corresponding starting material; c Percentage of total GC integral due to the corresponding product; d The solvent combination is 4/1 (v/v). The photoreactions of all four ketones were found to be very slow, especially in the solid state. Even after extended irradiation at room temperature, only a very small amount of the crystals of the starting ketone react. Possible reasons for their inertness are discussed in Chapter 6. For solution state photolyses, a 4/1 (v/v) mixture of terr-butanol and benzene was chosen as the solvent to speed up the reactions. It has been found that the quantum yield of the Norrish/Yang type II photoreaction can be greatly enhanced in polar solvents such as alcohols.96 The increase is attributed to hydrogen bonding between the hydroxy 1,4-biradical intermediate and the solvent, which suppresses reverse hydrogen transfer and enhances product formation. This explanation is supported by separate studies showing that the low quantum yields in non-polar solvents are due mainly to reverse hydrogen transfer of the 88 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones hydroxy 1,4-biradical.7 tert-Butanol is the solvent of choice because it does not contain any abstractable a-H's which could interfere with type II process under investigation. Since tert-butanol has a rather high melting point (25-26 °C), a small amount of benzene is added to make it a liquid at room temperature. The application of this solvent system turned out to be very effective, and the complete conversion of the starting ketones in solution became possible within a reasonable time period. From Table 5.1, it is apparent that the solution state photoreactions of the trans-ketones are not as clean as those of the c/s-ketones described in the previous chapter. The total GC integral of the identified products in each case does not add up to unity because of the presence of some unidentified products. Cyclobutanols 94-97 are always one of the major products, and the other major product varies depending on the R group on the aromatic ring. In the solid state, the cyclobutanols can always be observed when the starting ketone reacts. Detailed discussions concerning the photoreactivities in different media are presented in Chapter 6. 5.2 Identification of Cyclobutanols 94-97 Typical *H N M R spectra of cyclobutanols 94-97 are shown in Figure 5.1. With compound 94 as an example to deduce the structure, its ' H , COSY, H M Q C and NOE difference spectra, as well as the peak assignments, are presented in Figures 5.2-5, respectively. As in Chapter 3, the numbering of the carbon atoms follows the IUPAC rules and each number is shared by HO, A r 89 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones both the carbon and the hydrogens attached to it. Different hydrogens on the same carbon are distinguished by primes. I i i i i ! i , . i | i i i i ! i i i i | . . . i | i i i i | | i i i i | i i i i | i i i i | i i i i | i i i i | i • i i | i i i i .5 B.B 7.5 7.a 6 .S E . i 5 .5 5,1 «.S >.I J . 5 i . t 2 .5 2.8 1.5 1.1 .5 t. Figure 5.1 ' H N M R spectra of cyclobutanols 94-97 90 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones 91 Chapter 5. Isolation and Identification of the Photoproducts of the fra«s-Ketones H7 H8\10,5',8&3 \ H4&10' OH&3 ' H9 '&2 ' ppm 2 . 0 1.5 1.0 Figure 5.3 Partial COSY spectrum (500 M H z in CD 2C1 2) of cyclobutanol 94 Ok % »* * I * » f % dkf. • • 4 * / t i f tt 1 1 0 £ ft \ •00 k * 1.0 •1.5 - 2 .0 ppm 92 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones H13&17 H 5 & 5 ' Figure 5.5 The NOE difference spectra (400 MHz in CD 2C1 2) of cyclobutanol 94 with irradiations at (a) nil; (b) 0.70; (c) 2.27; (d) 2.42 and (e) 7.30 ppm. 94 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones Compound 94 is an alcohol, which is evidenced by a strong, sharp peak at 3590 cm"1 in the FT-IR. The L R and HRMS indicate that it is a constitutional isomer of the starting ketone 50, and this is confirmed by its elemental analysis. The disappearance of the ketone carbonyl group in the product as evidenced from the FT-IR and the 1 3 C N M R spectra indicates that the reacting site is the C=0 double bond. The phenyl group from the starting material remains intact during the reaction because the l H and 1 3 C (BB and DEPT) N M R spectra show the mono-substitution of the aromatic ring in product 94. The 1 3 C N M R spectrum shows 11 distinct aliphatic peaks, with two of them being methine groups, reflecting the asymmetry of the structure. A quaternary peak at 83.76 ppm hints that the carbon responsible for this signal is connected to an oxygen atom. A l l this information indicates that this compound is probably a cyclobutanol, a typical type II reaction product. The observation of the coupling between the two methine groups in the COSY spectrum (Figure 5.3) precludes the H2/H7 abstraction in the starting ketone 50. Combined with the studies of the H M Q C spectrum (Figure 5.4), the cyclobutanol structure 94 was assigned. The enJo-aryl configuration at C l l was determined from the NOE difference spectra (Figure 5.5). Hydrogens HI3 and HI7 on the phenyl ring are found to lie in proximity to H2, H7, H8, H10 and OH. The important interactions are summarized in Figure 5.6. Attempts to grow single crystals of cyclobutanol 94 were unsuccessful. Figure 5.6 The NOE interactions of cyclobutanol 94 95 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones 5.3 Identification of a-Tetralone Derivatives 98 and 99 Compounds 98 and 99 are minor products in the solution photolyses of ketones 50 and 51, and their ! H N M R spectra are shown in Figure 5.7. Compound 99 is chosen as the representative to illustrate the structural deduction, and its COSY and H M Q C spectra as well as the peak assignments are shown in Figures 5.8 and 5.9, respectively. Like the previous cases, the IUPAC rules are followed to number the carbon skeleton. Hydrogens attached to the same carbon share the number of that carbon and their distinct signals in the *H N M R are differentiated by primes. The hydrogens lying above the cyclohexane ring are numbered with primes, and those without primes indicate a below-the-ring position. The L R M S implies that the mass of compound 99 is less than that of the starting ketone 51 by two atomic mass units. The HRMS and elemental analysis confirmed that this is due to the loss of two hydrogen atoms. The ] H N M R spectrum in the aromatic region shows three groups of peaks at 8.02 (IH, dd, J= 8.6 & 6.0 Hz), 6.96 (IH, td, J = 2.6 & 8.6 Hz) and 6.85 (IH, dd, J = 2.6 & 9.0 Hz) ppm, respectively, reflecting the tri-substitution on the aromatic ring. This conclusion is supported by the C N M R (BB and APT) spectra, which show six different carbons with three of them being methines and the others being quaternary carbons. This indicates the involvement of the aromatic ring during the reaction. A strong ketone carbonyl absorption is found at 1675 cm"1 in FT-IR spectrum and the 1 3 C N M R spectrum 96 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones confirms the carbonyl's presence. The 1 3 C N M R spectrum of compound 99 also shows seven methylenes, two methines and one quaternary carbon between 10-50 ppm, indicating that the structure is unsymmetrical and that one of the methylene groups in the starting material has been converted to a methine group. Since the two methine hydrogens are coupled to each other in the COSY spectrum (Figure 5.8), the newly formed methine group should be at the C4/C5 position of the starting material. Study of the 2D N M R spectra (COSY and HMQC) leads to the assignment of the a-tetralone structure 99. Attempts to grow single crystals of this compound were not successful. 98 in CD2C12 (500 M H z ) Figure 5.7 Typical ' H N M R spectra of a-tetralone derivatives 98 and 99 97 Chapter 5. Isolation and Identification of the Photoproducts of the fraws-Ketones Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones 99 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones 5.4 Identification of Decarbonylation Products 100 and 101 R In the solution photolyses of ketones 52 and 54, the other major products in addition to cyclobutanols 96 and 97, were found to be decalin derivatives 100 and 101, respectively. These compounds were not isolated in pure form, and each of them contains around 15% of another isomer as determined from GC-MS. We will use compound 100 as an example to illustrate how the structures of these compounds were assigned. The ! H , COSY, H M Q C and NOE difference spectra of compound 100 are shown in Figures 5.10-13, respectively. 100 in CDC13 (500 MHz) ~i—i—r-101 in CDC13 (400 MHz) i-t i i i i 1 1 1 1 i 1 1 1 ' i M II | I ' I 1 | I I I I | I I I I | I I I I | I I I T * | I T I I | I I I I | I I M | 7.5 7.0 6.5 5.1 5.5 5.1 t.5 U 5.5 3.1 2.5 2.1 1.5 1.1 .5 Figure 5.10 Typical ! H N M R spectra of 100 and 101 100 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Kctones / Figure 5.12 Partial H M Q C spectrum (500 MHz for *H and 125 M H z for 1 3 C) of 100 102 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones H13&15 PPM Figure 5.13 The NOE difference spectra (400 MHz in CDC13) of 100 with irradiations at (a) nil; (b) 0.72; (c) 2.23 and (d) 7.22 ppm 103 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones The FT-IR spectrum indicates the disappearance of the carbonyl group in photoproduct 100 and does not show any other functionality except the cyano group. The L R M S gives a parent mass of 239, which is lower than that of the starting ketone 54 by 28 atomic mass units. The HRMS confirms that this difference is due to the loss of carbon monoxide. The 1 3 C N M R spectrum shows nine aliphatic carbon peaks, one of which corresponds to two carbon atoms that coincidentally overlap each other. Thus the structure of this compound must be unsymmetrical, which means that the decarbonylation does not occur at the bridge-head position (C9) of the starting material. The coupling correlations in the C O S Y spectrum (Figure 5.11), especially between HI and H2, indicates that the aryl group has shifted to the C4/C5 position of the starting ketone 54. Study of the 2D N M R spectra and the N O E difference spectra (Figure 5.13) leads to the assignment of structure 100. It should be pointed out that, owing to the 1,3-diaxial interactions, the trans-decalin system does not retain the chair conformations on the two cyclohexane rings. The HyperChem M M + conformational analysis of 100 provides a single conformation in which the unsubstituted ring adopts a twist-boat conformation and the other ring a boat form (Figure 5.14). This conformation nicely explains the NOE experimental results, which are summarized in Figure 5.15. Attempts to grow single crystals of compounds 100 and 101 met with failure. 104 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketoms Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones 5.5 Photolysis of Chiral Salts and Enantiomeric Excess Determinations The rrans-chiral salts 67-74 were photolyzed in the solid state in the same way as outlined in section 3.6. After diazomethane workup, the percentage conversion was determined by GC. Cyclobutanol 97 was isolated as the major product for all the salts and its optical purity at different conversions is summarized in Chapter 6. Like cyclobutanol 78 in Chapter 3, racemic cyclobutanol 97 could not be separated on chiral GC columns. However, a Chiralcel OD™ HPLC column gave a baseline separation. The HPLC conditions as well as the column specifications are listed in Table 5.2. Figure 5.16a shows the experimental HPLC trace for racemic cylcobutanol 97. The H P L C trace of the same compound along with the optical rotation trace recorded by Dr. B i l l Champion from Chiral Technologies, Inc. is illustrated in Figure 5.16b. Table 5.2 The HPLC conditions for the resolution of racemic 97 Column Chiralcel OD™ Column specifications 250 mm x 4.6 mm ID Solvent 99/1 (hexane/2-propanol) Flow rate 1 mL/min Detector U V at 230 nm 106 Chapter 5. Isolation and Identification of the Photoproducts of the trans-Ketones » 3 .OO (a) ac IO Mi nil t as > a. CM I S « r in (b) normal H P L C trace optical rotation trace \ 1 1 V 1 i 1 i i i i i i i i i i i r i i 1 1 i r — i 1 1 0.0 25.0 Figure 5.16 The HPLC traces for the resolution of racemic 97 (a) the experimental HPLC trace; (b) the HPLC and optical rotation traces recorded by Dr. B i l l Champion (Chiralcel OD™ column (250 mm x 4.6 mm), 98/2 hexane/ethanol) 107 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones Chapter 6. Structure-Reactivity Correlation Studies for the fraws-Ketones ° * - . A r hv 50(R=H) 51 (R=F) 52 (R=CN) 54 ( R = C 0 2 M e ) H C L N A r + R=H R=F R = C N R = C 0 2 M e 94 95 96 97 O 98 99 100 101 As in the previous chapter, photolysis of ketones 50-54 gave the corresponding Yang photocyclization products, cyclobutanols 94-97, as one of the major products both in solution and the solid state. The other major products in the solution photolyses varied with the different R groups on the aromatic ring. oc-Tetralone derivatives 98 and 99 were formed for the phenyl (50) and p-fluorophenyl (51) ketones, whereas ketones 52 (cyano) and 54 (methyl ester) yielded trans-decalin derivatives 100 and 101. A l l products, 94-101, are believed to be from H4/H5 abstraction. The formation of cyclobutanols 94-97 occurs through typical Yang photocyclization pathways, while those of products 98-99 and 100-101 are not as 108 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones straightforward and proceed with hydrogen abstractions followed by a series of rearrangements which are discussed later in this chapter. 6.1 Reactivity and Selectivity in the Photoreactions of Ketones 50-54 Like cw-ketones 43-47, /rans-ketones 50-54 also possess four potentially available y-H's and could, theoretically, yield different products. The actual photochemical results in Table 5.1 indicate that only H4/H5 were abstracted. The regioselectivity was rationalized from the crystal structures of ketones 51 and 52 shown in Figure 6.1. The molecules within the unit cell of these crystals adopt the same conformation, in which the carbonyl group lies on top of the trans-decalin system and the carbonyl plane almost bisects the decalin rings. The carbonyl oxygen atom was found to be in a position proximal to both H4 and H5, with one slightly favored over the other one (Table 6.1). Since these two hydrogens are enantiotopically related, their abstraction yields the same cyclobutanol 95 in the fluoro-substituted case and cyclobutanol 96 in the cyano-substituted case. For the other two y-hydrogens, H2 and H7, their poor geometry with respect to the carbonyl oxygen atom prevents their abstraction from occurring. It was not possible to obtain the crystal structures of ketones 50 and 54. However, from their solid-state photochemical results, they probably adopt structures similar to ketones 51 and 52, yielding cyclobutanols 94 and 97, respectively. 109 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones Chapter 6. Structure-Reactivity Correlation Studies of the frans-Ketones Table 6.1 X-ray derived geometric parameters for ketones 51 and 52: ketone y-H d ( A ) A ( ° ) 6 ( ° ) c o ( ° ) 51 H4 2.40 105 118 13 H5 2.56 89 117 50 H2 2.87 73 111 61 H7 3.38 51 103 50 52 H4 2.41 97 124 ' 30 H5 2.48 95 117 35 H2 3.07 64 30 60 H7 3.23 57 69 56 Ideal values <2.72 90-120 180 0 a For definitions of d, A, 8 and co, see Chapter 1 of this thesis. Unlike cw-ketones 43-47, the solid-state regioselectivity observed in the photochemistry of rra«s-ketones 50-54 was not lost in solution, and only the products from H4/H5 abstraction were observed. It is likely that the same conformations were adopted in solution as in the solid state. This assumption was supported by the results from a HyperChem M M + conformational analysis of ketones 50-54. The calculations indicated that the structures in Figure 6.1 are the most stable conformations for the corresponding starting ketones. No conformation was found to favor H2/H7 abstraction, indicating that this process is likely to be energetically unfavorable in solution. Compared to that of the cw-ketones, the abstraction geometry for the trans-ketones is more favorable, especially the distance d and the angle co. The average 0 - H Y distance of 2.48±0.08 A for the ^ raws-ketones is over 0.1 A shorter than 2.62±0.08 A for the cw-ketones. As well, the out-of-plane angles co for the trans-ketones are 31+18 °, closer to the ideal value 111 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones of 0° than 48±8° for the cz's-ketones. As mentioned in Chapter 4, the abstraction reactivity has been suggested to have a cos2co dependence. Hence, the angle co contributes about 73 % of maximum reactivity for the ^rans-ketones and only around 45 % for the cw-ketones. Therefore, the hydrogen abstraction process for the trans-ketones should be more favored than for the c«-ketones, which seemingly contradicts the observed slow reactions (at least two days of continuous irradiation is required, see Table 5.1). It is very likely that the favorable abstraction geometry also favors reverse hydrogen transfer, regenerating the starting ketone and slowing down the product formation. Table 6.2 lists the cleavage and cyclization parameters for ketones 51 and 52. They show the same tendency as those for the cw-ketones, with only the p orbital of the y-C radical center favoring cleavage. Hence, cleavage products were not observed. Table 6.2 Cleavage and cyclization parameters for ketones 51 and 52a ketone y-H a COS <f>\ COS C04 D ( A ) 51 H4 71 0.35 37 0.80 3.19 H5 71 0.35 37 0.80 3.11 52 H4 90 0 35 0.82 3.16 H5 90 0 36 0.81 3.14 Ideal values 0 1 0 1 <3.40 a For definitions of q>\, q>4 and D, see Chapter 1 of this thesis. 112 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones 6.2 Proposed Mechanisms for the Formation of Products 98-101 While all the ketones form cyclobutanols as major products in solution, the nature of the minor products varies among them. For ketones 50 and 51, oc-tetralone derivatives 98 and 99 were obtained. Their formation is quite similar to that of 1-indanones 83-86 in Chapter 4 and is presented in Scheme 6.1. R. R - O H H O . 102 50-51 H O tautomerization 98-99 103 R = H, F Scheme 6.1 Postulated mechanism for the formation of compounds 98 and 99 For ketones 52 and 54, however, the novel decarbonylation products 100 and 101 were formed. Both compounds were not isolated in pure form and contain around 15% of another isomer. GC-MS analysis indicates that both isomers have the same molecular mass and show 113 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones very similar mass spectra, reflecting their structural similarity. The mechanism for the formation of products 100 and 101 is not clear yet. One of the possibilities is presented in Scheme 6.2. 100-101 110 110 108 109 R = C N , C 0 2 M e Scheme 6.2 Postulated mechanism for the formation of photoproducts 100 and 101 114 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones In this proposed mechanism, following H4/H5 abstraction, the resulting 1,4-biradical rearranges to another biradical intermediate, 104, in which both radical centers are well stabilized, one by a hydroxy group and the other by the conjugation effect of the R group. Rearomatization of 104 affords a hydroxy carbene (105), which undergoes an insertion reaction to form aldehyde 106. This compound is able to absorb a second photon yielding radical 107 through a Norrish type I pathway.97 Subsequent intermolecular hydrogen abstraction of 107 from aldehyde 106 affords the observed products 100-101. Radical 107 can also isomerize to its cis-form 108 and finally yield product 109 which is assumed to be the minor component in the product mixture. The acyl radical 110 from intermolecular hydrogen transfer extrudes carbon monoxide and propagates the chain reaction. This mechanism is supported by two facts: first, the photodecarbonylation reaction for • O R aldehydes, especially tertiary alkyl aldehydes, is known; and second, the trans-cis isomerization of 9-decalyl radical has been studied and the zra/w-isomer was found to make up 85% in the mixture,9 9 which is consistent with our observations. It is likely that the formation of different products 98-99 and 100-101 is the result of the electronic effect of the R group on the aromatic ring. The conjugation effect of the cyano and ester groups makes biradical 104 relatively stable. When R is H or F, its stability is diminished, and the formation of neutral enol 103 (Scheme 6.1) predominates instead. 115 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones 6.3 Asymmetric Induction in the Solid State A series of chiral salts of trans-keto acid 53 was prepared as in Chapter 2 and cyclobutanol 97 was obtained as the major product after irradiation and diazomethane workup. The optical purity of 97 at various conversions is listed in Table 6.3. Table 6.3 Asymmetric induction of the trans-chiral salts salt amine rxn time(h) conv%a 97% b ee%c 67 (5)-(-)-a-methylbenzylamine 39 19.0 86.3 (-)-12.2 48.5 19.3 83.4 12.0 68 (i?)-(+)-a-methylbenzylamine 20 14.2 79.6 (+)-H-2 42 26.5 78.9 11.6 66 27.9 77.8 11.4 69 (li?,25)-(-)-ephedrine 16 3.1 64.5 (0-86.0 49 6.6 72.7 85.0 88.5 17.3 72.8 84.4 70 (lic,25)-(-)-norephedrine 20 1.1 100 (+)-26.6 41.5 1-2 100 29.8 63 1.7 100 38.8 71 (l/?,2i?)-(-)-pseudoephedrine 24 4.2 78.6 (0-87.4 48 5.3 69.8 86.2 72 13.7 72.3 82.8 72 (\R,2S)-(+)-cis-1 -amino-2-indanol 5 12.2 57.4 (+)-38.8 6 17.4 50.6 39.2 24 43.7 64.1 25.6 48 45.9 61.7 26.2 64 46.0 58.5 27.8 73 (i?)-(+)-P-methyl-phenethylamine 24 7.3 60.3 (+)-8.8 116 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones 49 10.5 47.6 28.2 72 18.5 56.2 21.8 74 (i?)-(+)-bornylamine 24 16.9 45.6 (+)-44.0 49 47.3 50.7 31.4 72 54.1 61.2 27.0 a Percentage of total GC integral due to the disappearance of ketone 54. Percentage of total GC integral due to compound 97. c Enantiomeric excess (ee) values were measured on Chiracel OD™ column. Sign of rotation in front of the numbers was obtained at 675nm. From Table 6.3, it is evident that most salts show poor enantioselectivity, with enantiomeric excess varying from 11-44%. Only the (-)-ephedrine salt 69 and the (-)-pseudoephedrine salt 71 gave higher ee's (>80%). Unfortunately, we were not able to obtain quality crystals for X-ray diffraction analysis, and structure-reactivity correlation studies could not be performed. Presumably most salts adopt the same conformation as ketones 51 and 52, in which both enantiotopic y-H's H4 and H5 are abstractable. Different rates of product formation from H4 and H5 abstraction result in the observation of low ee's. 6.4 Summary As in the case of cw-ketones 43-47, the solid-state photolyses of trans-ketones 50-54 occur with high regio- and stereoselectivity. Using structure-reactivity correlation studies, it was possible to explain the observed reactivities based on the crystal structures of ketones 51 and 52. In solution, ketones 50-54 showed diverse reactivities, yielding some novel products in addition to the expected type II cyclobutanols. The chiral salts of keto acid 53 afforded poor to good enantioselectivity in the crystalline state upon irradiation. Along with the examples 117 Chapter 6. Structure-Reactivity Correlation Studies of the trans-Ketones from Chapter 4 and previous studies, the results reflect the generality of using a chiral crystal lattice as the medium to transfer asymmetric information. Molecular modeling again showed its usefulness in predicting and explaining photochemical behavior for the present system. 118 Part II Novel Photochemical Reactions in the Solid State Chapter 7. Paterno-Biichi Reaction in the Solid State Chapter 7. Paterno-Biichi Reaction in the Solid State 7.1 Introduction In 1909, Paterno and Chieffi reported the results of a long-term experiment which lasted 104 days from December 5, 1907 to March 20, 1908. 1 0 0 In this experiment, they irradiated benzaldehyde (90) in the presence of 2-methyl-2-butene (111) with sunlight and obtained a product which was suggested to have a four-membered ring structure. It was not until 1954, when Biichi and co-workers101 reinvestigated this reaction, that the oxetane structure of product 112 was unambiguously confirmed as shown in Scheme 7.1. O A + Pin H 90 C H , C H , hv o-Ph — ( -H C H 3 O-P h --H • C H 3 H C H 3 111 H C H 3 112 Scheme 7.1 Paterno-Biichi reaction 102 Since 1964, this reaction has been known as the Paterno-Biichi reaction and its usefulness in organic synthesis has been widely recognized, with numerous reviews having been published concerning various aspects of the reaction 49b,49d,103 The photocycloaddition can occur both inter- and intramolecularly, and the substrates of the reaction cover a variety of organic compounds, from ketones and aldehydes to esters and nitriles, and from alkenes and 120 Chapter 7. Paterno-Biichi Reaction in the Solid State alkynes to allenes and heterocycles. A recent example reported by Rawal and co-workers104 is illustrated in Scheme 7.2, in which a Paterno-Biichi reaction was used as a key step to construct the skeleton of (±)-5-oxosilphiperfol-6-ene (115) and (±)-silphiperfol-6-ene (116). 116 115 Scheme 7.2 Total synthesis of compounds 115 and 116 Mechanistically, Paterno-Biichi reactions occur from the excited states of the carbonyl compound, which react with the ground state alkene to yield oxetanes. For aromatic ketones and aldehydes, the n-n* triplet states are responsible for this reactivity. It has been well accepted that the immediate precursors of the oxetane products are biradicals, whose existence has been confirmed by trapping experiments,105 the application of laser flash photolysis1 0 6 and independent generation.107 121 Chapter 7. Paterno-Biichi Reaction in the Solid State Figure 7.1 Electronic configuration of the n-7i* excited state of the carbonyl group The n-7i* excited state of the carbonyl group, whose electronic configuration is shown in Figure 7.1, has an amphoteric nature: an electrophilic region due to the half-vacant n orbital on the oxygen atom and a nucleophilic region above or below the carbonyl plane because of the presence of a 7i* electron. Therefore, when a Paterno-Biichi reaction occurs, two mechanisms108 can be proposed for the formation of the intermediates. In the "parallel approach", the electron-deficient alkenes interact preferentially with the nucleophilic n* orbital. On the other hand, electron-rich alkenes prefer to interact with the electrophilic n orbital that is perpendicular to the 7i-plane, which is called the "perpendicular approach". Although analyses of the product stereochemistry cannot distinguish between these apporach geometries, this model is strongly supported by fluorescence quenching studies.1080 In the conversion from starting materials (carbonyl compounds and alkenes) to photoproducts (oxetanes), the Paterno-Biichi reaction can generate three new stereogenic centers. Therefore, the stereoselectivity of oxetane formation is one of the core topics of interest to chemists. 4 9 b ' 4 9 d ' 1 0 3 c It is generally accepted that triplet n-7i* carbonyl compounds react less stereoselectively than their singlet counterparts because long-lived triplet biradicals are generated in the former case, thus allowing for increased bond rotation.1 0 9 High stereoselectivity can be obtained either as a result of inherent stereoelectronic factors between the substrates or by attaching asymmetric auxiliaries. 122 Chapter 7. Paterno-Biichi Reaction in the Solid State C O M e + M e , C O M e 117 118 119 a: R = H b: R = l B u c: R = O H > 24 : 1 < 1 : 30 > 30 : 1 Scheme 7.3 Inherent stereoselectivity for the Paterno-Biichi reaction no In the example shown in Scheme 7.3, biacetyl (117) reacts with norbornene (118a) with high exo-selectivity (> 24 : 1), whereas the reaction with syrc-7-t-butyl derivative 118b inverts the selectivity, yielding endo-adduct 119b as the major product. Clearly, steric effects contribute to the inverted results. When R = OH, hydrogen bonding between the substrates overcomes the steric unfavorability and directs excited ketone 117 to the exoface of alkene 118c, affording exo-oxetane 119c stereoselectively. Scheme 7.4 demonstrates the utilization of (-)-8-phenylmenthol as a built-in chiral auxiliary to induce the diastereoselective formation of oxetane 122 (de > 96 % ) . U 1 O H P h H 120 121 122 (de > 96 %, 99 % yield) Scheme 7.4 Diastereoselective formation of an oxetane using a chiral auxiliary 123 Chapter 7. Paterno-Biichi Reaction in the Solid State Apparently, the phenyl group of the chiral auxiliary in glyoxylate 120 blocks the si-face of the carbonyl group, accounting for the observed diastereoselectivity. Due to the topochemical restrictions in solid-state photochemistry, bimolecular reactions like the Paterno-Biichi reaction are difficult to study because of the necessity of co-crystallization in packing arrangements favorable for reaction. Prior to the current research, there had been no documented case of a solid-state Paterno-Biichi reaction. The initial objective in studying the photochemistry of ketone 123 (Figure 7.2) was to observe the formation of chiral cyclobutanols through a typical Norrish/Yang type II pathway. Hence, the "ionic chiral auxiliary" approach could be applied to study the enantioselectivity of the process. Unexpectedly, the actual photolysis of ketone 123 showed different reactivity, yielding Paterno-Biichi reaction products in the crystalline state. 7.2 Synthesis of the Starting Materials Ketones 126-130 were prepared from commercially available 1-phenylcyclopentyl carboxylic acid (124) using the same strategy as in Chapter 2. The synthetic route is illustrated 123 Figure 7.2 General structure of the target molecule 124 Chapter 7. Paterno-Biichi Reaction in the Solid State in Scheme 7.5. The structures of these compounds were determined on the basis of spectroscopic data (IR, ' H N M R , 1 3 C NMR, L R M S and HRMS) and elemental analyses. r - " \ / C O O H SOCI US P h (93%) ^ ^ C O C I 124 Ph 127 P h P h M g B r , T H F ^ (89%) ^ A ^ C O P h P h 125 126 F - ^ M g B r T H F (74%) K C N , D M S O A (55%) Q > 0 -P h C N P h 128 K O H , E t O H H 2 0 (55%) rVMT]^CQ*Me « C H 2 N 2 rVW^VcO .H L - V P h (quantit.) L ^ / \ p h h 130 P h 129 Scheme 7.5 Synthesis of ketones 126-130 Four chiral salts (131-134) of keto acid 129 were obtained by crystallizing a mixture of 1 equivalent of acid 129 and 1.1-1.4 equivalents of the corresponding optically pure amine in the proper solvent. Salt formation was evidenced by melting point and IR spectroscopy. The melting points of salts 131-134 are different from those of acid 129 and the amines, and in the IR spectra, the carbonyl absorption of acid 129 is replaced by two strong absorptions between 1650 and 1300 cm"1 due to the symmetric and asymmetric stretching of the carboxylate 125 Chapter 7. Paterno-Biichi Reaction in the Solid State anion. A l l the salts were determined to have a 1:1 acid/base stoichiometry. Table 7.1 lists their morphologies and melting points along with the solvents used for recrystallization. Table 7.1 Preparation of the chiral salts of keto acid 129 Salt Amine Cryst. Solvent Morphol. Mp (°C) 131 (i?)-(+)-Bornylamine MeOH Thin needles 191-193 132 (li?,2i?)-(-)-Pseudoephedrine CH 3 CN/MeOH Thin needles 144-146 133 (lS,2i?)-(-)-Norephedrine CH 3 CN/MeOH Powder 168-170 134 (5)-(-)-a-Methylbenzylamine CH 3 CN/MeOH Thin needles 165-167 7.3 Photochemical Reactions of Ketones 126,128 and 130 Photochemical studies were performed for ketones 126, 128 and 130 both in solution and the solid state. Fluoro-substituted ketone 127 proved to be an oil and its solid-state photoreactivity could not be studied. A l l of the solid-state photolyses were conducted at room temperature without observable melting except for ketone 126, where low temperatures were required. The photochemical results of ketones 126, 128 and 130 are summarized in Scheme 7.6 and Table 7.2. 126 Chapter 7. Paterno-Biichi Reaction in the Solid State Scheme 7.6 Photoreactions of ketones 126,128 and 130 Table 7.2 Photochemical results of ketones 126,128 and 130 Ketone Reaction Temp. Time Conv. Products medium (°C) (h) (%)a (%)b 126 135 136 139 C H 3 C N RT C 15 100 43 0 0 Crystal -20 2 38 0 91 6 10 95 0 59 13 22.5 100 0 63 12 -30 2 39 0 92 4 7 53 0 83 8 128 135 137 140 C H 3 C N RT C 5.5 100 60 0 0 Crystal RT C 46 100 0 13 28 130 135 138 141 C H 3 C N RT C 3 100 47 0 0 Crystal RT° 24 48 0 19 12 RT C 51.5 73 0 20 11 a Percentage of total GC integral due to the disappearance of the corresponding starting material; b Percentage of total GC integral due to the corresponding product in product mixture; c Room temperature. 127 Chapter 7. Paterno-Biichi Reaction in the Solid State Solution-state photolyses of all the ketones afforded the Norrish type I a-cleavage product, compound 135, as the only isolable product. In the solid state, however, the Paterno-Biichi reaction products, oxetanes 136-141, were obtained. The yields of the products in Table 7.2 do not add up to unity because of the presence of non-isolable side products. A detailed discussion concerning the formation of the oxetanes is presented later in this chapter. 7.4 Characterization of Oxetanes 136-141 The determination of the structures of oxetanes 136-141 was based on spectroscopic information {lU NMR, 1 3 C N M R (BB and APT), COSY, H M Q C , L R M S , HRMS and NOE difference) and elemental analyses. IUPAC numbering rules were used to number the structures. Each carbon atom and the hydrogen atoms attached to it share the same number. Different geminal hydrogens on ] H N M R spectra are differentiated by a prime. The COSY, H M Q C and NOE difference spectra of compound 136 are shown in Figures 7.3-7.5, respectively. L R and HRMS spectra and elemental analysis of oxetane 136 indicates that it is a constitutional isomer of the starting material 126. The FTIR spectrum shows no evidence of an obvious functional group, suggesting that the carbonyl group in starting ketone 126 has been converted to an ether. The ] H , 1 3 C and H M Q C N M R spectra show that there are two methine groups present at fairly low field (5.43 and 5.40 ppm in ! H N M R , and 90.05 and 88.12 ppm in 1 3 C NMR). So it is likely that these two groups are connected to the oxygen atom. Compared to the presence of four methylene groups in starting ketone 126, product 136 has only three methylenes along with two more methines, indicating that at least one of the original 128 Chapter 7. Paterno-Biichi Reaction in the Solid State methylene groups is converted to a methine group. Hence, an oxetane structure was assigned. This assignment is strongly supported by the spectroscopic data for similar compounds in the 112 • literature. The regiochemistry of compound 136 was deduced on the basis of its COSY spectrum, which shows that the two methine hydrogens are not coupled, thus precluding the possibility of the other regioisomer. The exo-stereochemistry for this oxetane was not determined until the NOE difference spectra were recorded (Figure 7.5). The most important interactions are summarized in Figure 7.6. 129 Chapter 7. Paterno-Biichi Reaction in the Solid State Figure 7.3 COSY spectrum (400 MHz, C 6 D 6 ) of product 136 130 Chapter 7. Paterno-Biichi Reaction in the Solid State Figure 7.4 H M Q C spectrum (500 MHz, C 6 D 6 ) of product 136 131 Chapter 7. Paterno-Btlchi Reaction in the Solid State H16&18 Figure 7.5 The NOE difference spectra (400 MHz, C 6 D 6 ) of oxetane 136 with irradiations at: (a) nil; (b) 2.38; (c) 5.40; (d) 5.43; (e) 6.81; (f) 7.14 ppm. 132 Chapter 7. Paterno-Biichi Reaction in the Solid State Figure 7.6 NOE interactions in oxetane 136 Similarly, compounds 139-141 were assigned as endo-aryl oxetanes. 7.5 Mechanistic Studies of the Formation of the Oxetanes in the Solid State The photochemical results summarized in Table 7.2 show that starting ketones 126, 128 and 130 have completely different reactivities depending on the medium used. In solution, 97 they form compound 135 as the major product through a typical Norrish type I pathway. The formation of oxetanes 136-141 in the solid state is very unusual and a possible mechanism is presented in Scheme 7.7 with ketone 126 as an example. 133 Chapter 7. Paterno-Biichi Reaction in the Solid State P h hv f 143 126 crystal cage hydrogen abstract ion 136 and 1 3 9 - * Paterno-Bi ich i reaction hv crystal cage Scheme 7.7 Proposed mechanism for the formation of the oxetanes In this mechanism, irradiation of the crystals of ketone 126 results in a Norrish type I cleavage of the a C - C bond to form a radical pair, a 1-phenylcyclopentyl radical 142 and a benzoyl radical 143. Hydrogen abstraction by the benzoyl radical 143 from the C2 position of radical 142 affords two neutral molecules, benzaldehyde (90) and 1-phenylcyclopentene (144). Under the reaction conditions, benzaldehyde is able to absorb a second photon and undergo a Paterno-Biichi reaction, presumably through its n-n* triplet excited state, with ground state alkene 144 to form the observed oxetanes 136 and 139. Strong support for this mechanism comes from GC-MS analysis of the product mixture, where trace ammounts of compounds 90 and 144 were detected. In order to confirm that the oxetanes were formed from compounds 90 and 144, their solution state photolysis was performed in benzene. The reaction was very slow and produced a number of products as evidenced from the GC trace of the reaction mixture (Figure 7.6a). 134 Chapter 7. Paterno-Biichi Reaction in the Solid State After 69 h of irradiation, benzaldehyde 90 was almost consumed but in the product mixture, there was only 6 % of oxetane 136 and 13 % of oxetane 139. The other products were not isolated or identified. Presumably they are the other regioisomeric oxetanes and the products from side reactions. This result is not very surprising since benzaldehyde 90 has a higher triplet energy (E T = 298-301 kJ/mol) than that of the conjugated alkene 144 (E T = 248 kJ/mol)." 3 Therefore, triplet-triplet energy transfer becomes a very important process, which not only slows down oxetane formation, but also causes other reactions. The above observations are consistent with studies of other similar systems. 1 1 4 , 1 1 5 It has been found that when the triplet energy of a conjugated alkene is lower than that of an aromatic carbonyl compound, solution-state oxetane formation is inefficient, either being excluded 1 1 4 or becoming a side reaction to other processes such as cis-trans isomerization of the alkene, alkene dimerization or carbonyl hydrogen abstraction.115 The corresponding reactions with aliphatic ketones and aldehydes have been shown to be more effective owing to the involvement of the singlet excited states of the carbonyl compounds.116 In contrast to the photochemical results in solution, solid-state photolysis of ketone 126 proceeds cleanly and efficiently, yielding exo-axy\ oxetane 136 with a small amount of endo-aryl oxetane 139 (Figure 7.6b). This result can be considered another instance of "latent reactivity" as discussed in Chapter 4, because the reaction of ketone 126 in solution did not form oxetanes, but rather compound 135. It is believed that the crystal cage plays a key role in the success of this reaction in the solid state. Upon irradiation, radical pair [142+143] are forced to reside within the reaction cavity and intermediates 90 and 144 are generated in situ, with the relative geometry between 90 and 144 resembling starting ketone 126 owing to the least motion character of the solid-state reactions.31'32 Thus, the C=0 double bond of 135 Chapter 7. Paterno-Biichi Reaction in the Solid State benzaldehyde and the C=C double bond of alkene 144 are pre-oriented in a favorable fashion, allowing oxetane formation not only to compete with the normally rapid triplet-triplet energy transfer, but also to take place regiospecifically, precluding the formation of other regioisomeric oxetanes. Moreover, the crystal cage suppresses other processes that would otherwise occur in fluid media and yields oxetanes 136 and 139 efficiently. 139-(a) 144 90 \ 136, AW (b) 90 r 144 X 136 126 / 139 Figure 7.7 (a) The GC trace of the solution state photoreaction of compounds 90 and 144 after 25 h of irradiation; (b) The GC trace of the solid-state photolysis of ketone 126 after 2 h of irradiation at -20 °C. The numbers in both diagrams represent the corresponding compounds.3 ' The retention times of the same compound in two diagrams do not match due to different temperature programs used. 136 Chapter 7. Paterno-Biichi Reaction in the Solid State When ketone 126 is photolyzed in solution, the radical pair [142+143] formed from oc-cleavage are quickly segregated by the solvent molecules, thus greatly diminishing the probability of hydrogen abstraction to form intermediates 90 and 144, and their further addition to yield oxetanes 136 and 139. 7.6 Asymmetric Induction in the Solid-State Formation of the Oxetanes Two characteristics of this reaction enable the application of the "ionic chiral auxiliary" concept to the present system: first, the reaction takes place in the solid state; and second, chiral oxetanes are formed from achiral starting ketones. Chiral salts of keto acid 129 were prepared as in section 7.2 and their solid-state photobehavior was studied. The photoproduct mixtures were treated directly with an ethereal diazomethane solution to convert all carboxylates to the corresponding methyl esters, so that gas chromatography could be used to examine the percentage conversions and the product composition. Both exo- (138) and endo- (141) aryl oxetanes were formed for all of the salts, reflecting the generality of this reaction, but the major component varies from case to case (Table 7.3). Racemic exo-oxetane 138 was successfully resolved on a custom chiral GC column (50% 6-TBDMS-2,3-dimethyl-P-cyclodextrin dissolved in OV-1701, 20 m x 0.25 mm ID), with the GC trace shown in Figure 7.8. A l l attempts to resolve racemic endo-oxetane 141 met with failure. Therefore, the enantiomeric excess (ee) is only reported for those cases in which exo-oxetane 138 was formed as the major product. 137 Chapter 7. Paterno-Biichi Reaction in the Solid State Table 7.3 Asymmetric induction for the solid-state formation of the oxetanes3 Salt Conv. % b 138 % c 141 % c ee%of l38 d 131 17 57 10 6.8 (B) 56 44 8 9.9 (B) 61 41 9 9.1 (B) 132 29 3 42 -65 2 57 -96 2 25 -133 16 3 28 -29 5 38 -35 4 30 -134 23 31 11 52 (B) 41 28 9 45(B) 67 17 5 42 (B) 3 A l l the photolyses were performed at room temperature. Pertentage of total GC integral due to the disappearance of the starting material. 0 Percentage of total GC integral due to the corresponding compound in product mixture. d The letter in parenthesis represents the major peak in Figure 7.8. Figure 7.8 GC trace of the resolution of oxetane 138 138 Chapter 7. Paterno-Biichi Reaction in the Solid State Because it was not possible to obtain a crystal structure for any of the salts, structure-reactivity correlation studies could not be performed and the enantioselectivity of the reaction could not be easily understood. However, previous studies6 3"6 5'6 8 on crystals exhibiting low to mediocre ee's have shown that conformational enantiomerism may be responsible for the observed results.81 It is likely that a similar effect occurs in this system. On the other hand, the dual function of the chiral crystal lattice in this reaction is clearly seen. It not only serves as the medium for the reaction (the ability to form oxetanes is lost in solution), but also carries the asymmetric information, and transfers this to the reactive intermediates (compounds 90 and 144 in the present work), which then react enantioselectively. 7.7 Attempted Extension of the Solid-State Paterno-Biichi Reaction The success of the selective solid-state oxetane formation in the aryl 1-phenylcyclopentyl ketone system encouraged us to extend this reaction to other systems. Thus, a cyclic ketone (145) and an acyclic ketone (146) were tested (Figure 7.9). Both ketones were chosen on the basis of two factors: a) they contain phenyl group(s) at the a-positions so that the Norrish type I cleavage should be favored upon irradiation; b) both ketones have P-hydrogens, which could possibly be abstracted by the benzoyl radical to form the intermediates for the subsequent Paterno-Biichi reaction. 139 Chapter 7. Paterno-Biichi Reaction in the Solid State J P h P h O 145 146 Figure 7.9 Model compounds for the extension of the solid-state Paterno-Biichi reaction Ketone 145 was prepared from commercially available 1-phenylcyclohexane carboxylic acid through successive reactions with thionyl chloride and phenylmagnesium bromide. Ketone 146 was made by following the literature procedures.117 However, oxetanes were not obtained from the photolysis of either ketone. Instead, ketone 145 afforded the typical Norrish type I and type II products 147 and 148, which is summarized in Scheme 7.8. Irradiation of ketone 146 produced novel 1,3-phenyl migration products in addition to the products from Norrish type I cleavage. The photochemical studies of ketone 146 are discussed in the next chapter. J Ph 145 C H 3 C N _ hv solid w state " P h P h — 147 (28 %) P h / , . O H 148 (48 %) 148 (12 % convers ion , 75 % yield) Scheme 7.8 Photoreactions of ketone 145 These results indicate that oxetane formation is not favored in the reactions of compounds 145 and 146, and that the solid-state Paterno-Biichi reaction is not a general process for these ketones. Since there is no crystallographic data available for either aryl 1-phenylcyclopentyl 140 Chapter 7. Paterno-Biichi Reaction in the Solid State ketones (126-130) or compounds 145 and 146, the geometrical factors influencing the success or failure of solid-state oxetane formation are not clear. 7.8 Summary Another example of "latent reactivity" was found in the present research. The solution-state photolyses of ketones 126-130 yielded a typical Norrish type I product, while reaction in the solid state afforded the novel oxetanes regio- and stereoselectively. The formation of these oxetanes is believed to occur through Norrish type I oc-cleavage and hydrogen abstraction followed by a Paterno-Biichi reaction within the crystal cage. The proposed mechanism was supported by the detection of the intermediates by GC-MS analysis. This result represents the first example of a solid-state Paterno-Biichi reaction and indicates the superior selectivity and efficiency possible in solid-state reactions over their solution counterparts. The enantioselectivity of the reaction was also studied by applying the "ionic chiral auxiliary" approach, but only low to mediocre enantiomeric excesses were observed. The present enantioselectivity studies also extend the generality of using crystals as chiral "messengers" in the induction of asymmetry in organic photochemistry. 141 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State 8.1 Introduction The migration of an aryl group is a very general process in organic chemistry, occurring under appropriate conditions in both the ground and excited states. The migrating aryl group can shift to an adjacent atom or a more distant one, and the migration terminus can be either a carbon or a heteroatom. There have been many reports of this process in various systems, but this introduction will concentrate exclusively on photochemical aryl migrations from a carbon atom to a carbonyl oxygen atom. 8.1.1 1,5-Aryl Migration In 1962, research groups from Yale University 1 1 8 and the University of Wisconsin at Madison 1 1 9 independently reported very similar results regarding photochemical studies of cis-1,2-dibenzoylethylene (149, Scheme 8.1). In this reaction, one of the phenyl groups migrated from the carbonyl carbon atom to the oxygen atom of the other carbonyl group upon irradiation, with ketene 150 being suggested as the intermediate responsible for the formation of enol ether 151. This reaction was later found to occur >90% through the singlet n-7i* 120 121 excited state of the starting material. ' 142 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State 151 150 Scheme 8.1 1,5-Phenyl shift of compound 149 This 1,5- phenyl migration is a general photochemical process and has been observed in a variety of organic systems containing the cw-dibenzoylethylene moiety. 1 2 1 ' 1 2 2 The intermediate ketene in the reaction has been detected 1 2 2 8 ' 1 2 3 and even isolated.1 2 4 It should be pointed out that the first photochemical investigations of similar compounds were attempted by the Swiss chemist von Halban and co-workers during the period 1920-1948.1 2 5 They studied the photochemistry of tetrabenzoylethylene (152) but could not establish the structure of the photoproduct. This system was reinvestigated later by Australian scientists126 and the structure of product 153 was determined by X-ray crystallography (Scheme 8.2). 143 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State 152 153 Scheme 8.2 Photoreaction of compound 152 Nine years later, a mechanism was proposed for this reaction and the formation of product 123 153 was suggested to be initiated by a 1,5-phenyl migration (Scheme 8.3). 153 Scheme 8.3 Proposed mechanism for the formation of compound 153 Given a favorable geometry, this 1,5-phenyl migration can also take place in the solid state. 1 2 2 g ' 1 2 4" 1 2 6 Compound 154 crystallizes in an anti-syn conformation as shown in Scheme 8.4, with the distance between the ipso carbon of the migrating phenyl and the receiving oxygen atom being 3.24 A . This distance is almost equal to the sum of the van der Waals radii 144 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State of carbon and oxygen (3.22 A), thus explaining the phenyl migration to form ketene 155. The presence of intermediate 155 was evidenced by its unique absorption in the FT-IR spectrum of the reaction mixture, and subsequent treatment with methanol to afford product 156. Scheme 8.4 Solid-state 1,5-phenyl migration 8.1.2 1,3-Aryl Migration Unlike the 1,5-aryl shift process, the 1,3-version of carbon-to-oxygen aryl migration is less well known and only a few compounds have shown this type of reactivity. The first example of this reaction was reported by Heine in 1971, 1 2 7 where the photochemical behavior of tritylphenones 157 was investigated (Scheme 8.5). 145 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State A r ' O Ar" A r A O C A r ' 3 hv Ar 'O Ar ' Ar ' + R R' 157 158 159 A r = Ar ' = a : R = H, R' = H b: R = H, R' = C H 3 c: R = C H 3 , R' = H Scheme 8.5 Photochemical reaction of tritylphenones 157 Upon irradiation of tritylphenone 157 in benzene, the aryl migrated compounds 158 and 159 were obtained as the major products along with small amounts of the expected Norrish type I a-cleavage products. Undoubtedly, phenanthrene derivatives 159 are secondary photoproducts in these reactions, formed from the corresponding enol ethers 158 through a known photoelectrocyclization/oxidation process.128 Quenching studies with piperylene revealed that only the a-cleavage processes were inhibited, indicating that the migration reaction occurred through a singlet excited state. In fact, the photochemical study of compound 157a had been attempted over a decade before Heine's results with sunlight used as the light source.1 2 9 Unfortunately, the chemists who performed this study reported the compound to be photoinert. Later, a few more examples130 were discovered showing similar 1,3-aryl migration reactivity. A l l of these compounds are sterically congested aromatic ketones with aryl substitution at the a-position. Based on previous and their own systematic studies, Wagner and co-workers summarized some features of this reaction in a 1991 paper.131 146 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State (a) The 1,3-aryl migration process takes place through the triplet n-7t* excited state, not the singlet state as reported by Heine 1 2 7 and Hart. 1 3 0 a ' b The triplet lifetimes of these ketones are very short and the triplets cannot be quenched by modest concentrations of quenchers. Hence, relatively high concentrations are required for significant quenching. (b) Owing to the congestion of the molecule, bond rotation is restricted and is slower than triplet decay. Therefore, the ground state conformation of the starting material controls the reactivity. (c) The mechanism of the 1,3-aryl shift is suggested to be initiated by charge-transfer (CT) complexation of the donor a-aryl group to the n-n* triplet of the carbonyl chromophore (Scheme 8.6). When the oc-carbon is significantly crowded, i.e., when Ri and R2 are large groups such as phenyl and mesityl, the donor aryl group is likely to migrate to the oxygen atom to relieve this congestion. On the other hand, i f Ri and R2 are small groups such as hydrogen or methyl, CT simply leads to quenching and no migration will be observed. 147 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State Scheme 8.6 Proposed mechanism for 1,3-aryl migration This model nicely explains many experimental observations, one of which is shown in Scheme 8.7. In this example, compound 160 has two a-aryl groups (phenyl and mesityl), and both of them could possibly migrate to the carbonyl oxygen based on independent conformational studies.132 However, only the mesityl group migrates as shown by experiment. This preference is not only because mesityl is a better donor compared to the phenyl group, but also because the migration of mesityl leads to a greater relief of steric strain at the op-position. 148 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State hv M e s O M e s P h H 160 161 Scheme 8.7 Photoreaction of ketone 160 8.1.3 Research Goals Organic compounds often crystallize as their most stable conformations, and in many cases these conformations control the reactivity of the substrates in the solid state, as was discussed in Chapter 1, Chapter 4 and Chapter 6 of this thesis. This feature of conformational control resembles the solution photochemical properties of the congested systems mentioned in the previous section, and suggests the study of the same and similar systems in the solid state, which remains an unexplored area to date. This thesis describes some initial work on this project. 8.2 Preparation of the Substrates and Photochemical Studies Compounds 146, 162 and 163 (Figure 8.1) were chosen as candidates to study the solid-state 1,3-phenyl migration reaction. By varying the number of phenyl groups at the a-position, the influence of steric effects on the reaction could be tested. Compound 164 was also photolyzed because, unlike the other phenyl ketones that have lowest energy n-n* triplet 149 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State states, /?ara-mefhoxy substituted phenyl ketones are well-known to possess lowest energy TC-7i* triplet excited states.133 The different excited state nature of ketone 164 makes it an interesting target to study and allows for a comparison of the reactivities of different excited states. P h P h > y P h p f f O O Ph P h . . P h Ph . O M e 146 162 O 163 P h P h . . P h Ph O 164 Figure 8.1 Candidate compounds for 1,3-phenyl migration studies Compounds 146117 and 163134 were synthesized in good yields by following literature procedures. a-Dimethylation of deoxybenzoin (165) under basic conditions afforded compound 162, and compound 164 was obtained by reacting triphenylmethyl lithium 1 3 5 with anisoyl chloride (Scheme 8.8).1 3 6 The synthetic details for compounds 162 and 164 are given in the Experimental section. P h P h O N a H , C H 3 I T H F P h P h O 165 P h 3 C H 166 162 1 ) n B u L i , T H F O 2) M e O - < Q ^ C O C I P h , C 164 s O M e Scheme 8.8 Preparation of ketones 162 and 164 150 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State Photochemical studies were performed for compounds 146 and 162-164 both in solution and the solid state, and are summarized in Schemes 8.9-8.11, respectively. Ph Ph hv O 162 b e n Z 6 n e > P h > V P h + PhCHO 100%conv. P n 167 (55%) + Ph' H 168 (2%) 90 (10%) Ph 169 (3%) solid state. • trace amount of 90 and 169 -20°C, 9h Scheme 8.9 Photoreaction of ketone 162 As shown in Scheme 8.9, solution photolysis of ketone 162 yielded mainly Norrish type I products 90 and 167-169. No phenyl migration product could be detected from GC-MS analysis of the reaction mixture. This result is consistent with what Heine had previously 1 17 discovered, except that compounds 168 and 169 were not reported in his paper. When the medium was changed to the solid state, which had not been investigated before, the reaction was slow and only trace amounts of type I cleavage products 90 and 169 could be observed. 151 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State CH 3 CN \ Ph Ph / } = \ + X + PhCHO 97%conv.~ Ph oPh Ph H 170(27E,22%) 171(24%) 9 0 ( 4 % ) Ph Ph Ph hv O 146 P h P h \ / \ / P h Ph ^ Ph O 172 (23%) 173(5%) solid state -10°C 35% conv • 170 (Z/E, 88%) + 172(9%)+ 90 (trace) Scheme 8.10 Photoreaction of ketone 146 For compound 146 (Scheme 8.10), which was originally used as a candidate for the solid-state Paterno-Biichi reaction (see Chapter 7), its photochemical behavior had not been investigated before our present study . In solution, photolysis afforded phenyl migrated enol ether 170 and ketone 173 in addition to the typical a-cleavage products 90, 171 and 172. The structure of product 170 was determined on the basis of spectroscopic information (IR, LRMS, HRMS, ! H and 1 3 C N M R spectroscopy), elemental analysis and hydrolysis studies. By refluxing the Z/E mixture of enol ether 170 in concentrated hydrochloric acid for 5 hours, phenol and 2-phenyl propiophenone (174) were obtained. The structures of phenol, compound 174 and photoproduct 173 were determined by comparison with commercial phenol and independently synthesized authentic samples, respectively. The synthetic details are available in the Experimental section. In the solid state, phenyl migration product 170 was obtained as the major product, with a small amount of alkene 172 and benzaldehyde from a-cleavage processes. 152 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State O P h , C - C - A r A r = hv R 163 (R=H) 164 (R=OMe) benzene . P h x _ 7 0 P h Ph A r 175 a : R=H, 53% conv. 441% b: R=OMe,95% conv. 1 0 % + A r C H O + 90 a: R=H 4 % b: R = O M e 6% 1 6 % 2 1 % 177 3% 6% solid state.. r.t. 175 + 176 + P h 3 C H 166 2 4 % 39% 178 6% 1 2 % a: R=H, 6 7 % conv. 9 3 % b: R = O M e , 9% conv. 6 0 % 7% 4 0 % Scheme 8.11 Photoreaction of ketones 163 and 164 For ketones 163 and 164, the solution and solid-state photolyses revealed similar results, reflecting their similar reactivity. In solution, the results are consistent with what Heine reported,127 except that ketone 178 was not reported. In addition to spectroscopic information (IR, L R M S , HRMS, *H and 1 3 C NMR) and elemental analysis, the structure of enol ether 175a was further confirmed by hydrolysis studies. Phenol and diphenylacetophenone (179) were obtained after refluxing compound 175a in concentrated hydrochloric acid. Commercial phenol and independently synthesized ketone 179 were used to confirm the structural 153 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State assignments. In the solid state, the reactions are far cleaner, yielding only phenyl migration product 175 and secondary photoproduct 176. 8.3 Discussion 8.3.1 Formation of Some Novel Products From the results of photolysis of ketones 146 and 162-164, it is observed that most products are formed from a typical Norrish type I or a 1,3-phenyl migration pathway. Phenanthrine derivatives 176 arise via secondary photochemical electrocylclization and oxidation reactions of enol ether 175, which was confirmed by independent irradiation studies of compound 175. However, there are still some products, specifically compounds 173, 177 and 178, whose formation is not obvious. The observation of 9-phenyl-9//-fluorene 177 and aryl 9-phenyl-9-fluorenyl ketone 178 seems to be a general process in the photolysis of trityl aryl ketones such as 163 and 164. Compound 177 is believed to form from the trityl radical generated via a-cleavage of the starting ketone. The mechanism for the formation of this compound is summarized in Scheme 8.12. Photolysis of ketone 163 or 164 leads to an intermediate, the trityl radical, which can cyclize to yield a new radical 179. Hydrogen abstraction by one of the other radicals present in the system forms compound 180 which undergoes a 1,3-hydrogen shift to produce product 177. It should be mentioned that compound 177 could also be formed via the Scholl reaction in which triphenylmethane (166) in the ground state is treated with a Lewis acid. This is almost certainly not the case under our photochemical conditions. 154 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State Ph H H H 177 180 179 Scheme 8.12 Mechanism for the formation of compound 177 The formation of compound 178 is not very clear. The most straightforward mechanism seems to be the combination of the aroyl and 9-phenyl-9-fluorenyl radicals. However, studies have shown that the 9-phenyl-9-fluorenyl radical cannot be formed from the trityl radical, 1 3 8 ' 1 4 0 although a perchlorotrityl radical does form the corresponding perchloro 9-phenyl-9-fluorenyl radical. 1 4 1 It is possible that 9-phenyl-9-fluorenyl radical was formed from the reaction between other radicals present in the reaction mixture and 9-phenyl-9//-fluorene 177. The observation of ketone 173 in the photoreaction of ketone 146 is unexpected, but its formation is not hard to rationalize. A possible mechanism is presented in Scheme 8.13, in which the benzoyl radical reacts with 1,1-diphenylethylene 172 to form radical 181. Subsequent hydrogen abstraction produces ketone 173. 155 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State P h P h P h O 146 P h hv P h P h . P h + I f O R* - R H P h P h 172 P h R H P h O 173 P h ^ ^ ^ P h P h O 181 Scheme 8.13 Proposed mechanism for the formation of ketone 173 8.3.2 1,3-Phenyl Migration Reaction As the number of phenyl groups at the a-position of acetophenone increases in ketones 162, 146 and 163, the steric congestion is also increased. Correspondingly, phenyl migrations were observed in the more congested ketones 146 and 163, but not in the less hindered ketone 162, indicating that steric effects play a key role in the success of the migration process. This is consistent with literature results 1 3 0 ' 1 3 1 and can be explained by Wagner's model as was discussed in the introduction section of this chapter. Ketone 164 possesses a lowest energy n-7 i* triplet excited state, which is expected to be less reactive than the other ketones owing to the n-rc* nature of the phenyl migration reaction. However, it shows similar reactivity to 156 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State ketone 163. This conforms to Wagner's studies on similar compounds, where it was suggested that the reaction still occurs from the n-Tt* excited state131 even though it is only - 1 % populated.142 The novelty of the present work lies in the fact that, for the first time, the 1,3-phenyl migration process was investigated in the solid state. From the photochemical results in Schemes 8.10 and 8.11, it is very clear that these reactions are much more selective in the solid state than in solution, yielding migration products as the major or the only products. A typical example is the case of ketone 163. While solution photolysis yields several products, namely compounds 90, 166 and 175-178, the reaction in the solid state affords only compounds 175a and a small amount of 176a (Figure 8.2). 157 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State Figure 8.2 The GC traces of the solution (a) and solid-state (b) photoreaction of ketone 163 These results are not hard to understand and may be rationalized as follows: (a) In the solid state, the radicals generated from the competing Norrish type I process are forced to reside in the crystal cavity. Any interactions between the radicals that could result in the type I products observed in solution are greatly suppressed owing to the least motion character of solid-state reactions. It is very likely that the dominating process for this radical pair is to regenerate the starting material. This is evidenced in the solid-state photolysis of 158 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State ketone 162. Even though there is no competing phenyl migration, presumably because of the unfavorable conformation and a less hindered oc-center, the starting ketone 162 still showed its inertness in the solid state, yielding only trace amounts of benzaldehyde and alkene 169. (b) Unlike the formation of type I products, which requires inter-radical interactions, the 1,3-phenyl migration is an intramolecular process. It requires less molecular motion and thus is favored in the solid state. Evidently the space required for the phenyl group to migrate from carbon to oxygen can be accommodated by the crystal cavity. (c) In solution, molecules are free to move and the interactions between radicals are increased, enhancing the formation of type I products. Comparing the results from the photolyses of ketones 162, 146, 163 and 164, it can be observed that phenyl migration either happens in both media (solution and solid state) or does not occur at all. Assuming molecules adopt their most stable conformations in the solid state, which is often the case, the above results support Wagner's conclusion that migratory aptitude is controlled by the ground state conformation of the sterieally congested ketones. Unfortunately, no X-ray quality crystals of any of the starting ketones were obtained, and structure-reactivity correlation studies could not be performed. 8.4 Summary and Outlook The photochemical 1,3-phenyl migration reaction was observed in the cases of ketones 146, 163 and 164, with the results from the solution-state photolyses being consistent with previous examples. The same reactions in the solid state were investigated for the first time and showed superior selectivity over their solution counterparts. 159 Chapter 8. A Novel 1,3-Aryl Migration Reaction in the Solid State Investigations on the migratory aptitudes of three different aryl groups at the a-position of acetophenone are currently under way. By varying the substituents on the aromatic rings, steric and electronic effect on the reaction will be studied. 160 Part III Experimental 161 Chapter 9. Synthesis of Starting Materials Chapter 9. Syntheses of Starting Materials 9.1 General Considerations Infrared Spectra (IR) Infrared spectra were recorded on a Perkin-Elmer 1710 Fourier-transform spectrometer. Solid samples (2-5 mg) were ground with IR grade K B r (100-200 mg) in an agate mortar and pelleted in an evacuated die (Perkin-Elmer 186-0002) with a laboratory press (Carver, model B) at 17,000 psi. Liquid samples were analyzed either neat as thin films between two sodium chloride plates or as chloroform or deuterated chloroform solutions in a sodium chloride cell. The positions of selected absorption maxima (v m a x ) are reported in units of cm"1. Melting Points (mp) Melting points were determined on a Fisher-Johns hot stage apparatus and are uncorrected. Nuclear Magnetic Resonance (NMR) Spectra Proton nuclear magnetic resonance ( 'H N M R ) spectra were recorded in deuterated solvents as noted. Data were collected on the following instruments: Bruker AC-200 (200.0 MHz), Bruker AV-300 (300.1 MHz), Bruker WH-400 (400.0 MHz), Bruker AV-400 (400.1MHz), and Bruker AMX-500 (500.2 MHz). Chemical shifts (5) are reported in parts per million (ppm) and are referenced to the residual ] H solvent signals with tetramethylsilane (5 162 Chapter 9. Synthesis of Starting Materials 0.00 ppm) as an external standard: chloroform (7.24 ppm), benzene (7.16 ppm), dichloromethane (5.32 ppm), methanol (3.30 ppm), and dimethylsulfoxide (2.49 ppm). The signal multiplicity, coupling constants, number of hydrogen atoms, and assignments are given in the parentheses. Multiplicities are abbreviated as follows: multiplet (m), singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), and broad (br). Nuclear Overhauser Effect Difference (NOED) spectra were recorded on the Bruker WH-400 spectrometer. ' H- 'H correlation spectroscopy (COSY) was conducted on the Bruker WH-400, Bruker AV-400 or Bruker AMX-500 instruments. Carbon nuclear magnetic resonance ( 1 3 C N M R ) spectra were recorded on Bruker AC-200 (50.3 MHz), Varian XL-300 (75.4 MHz), Bruker AV-300 (75.5 MHz), Bruker AV-400 (100.5 MHz), Bruker AM-400 (100.5 MHz) and Bruker AMX-500 (125.6 MHz) spectrometers. A l l experiment were conducted using broadband ' H decoupling. Chemical shifts (5) are reported in ppm and are referenced to the center of the solvent multiplet with tetramethylsilane (8 0.0 ppm) as an external standard: chloroform (77.0 ppm), benzene (128.0 ppm), dichloromethane (54.0 ppm), methanol (49.0 ppm), and dimethylsulfoxide (39.5 ppm). Some spectra are supported by data from the Attached Proton Test (APT) or the Distortionless Enhancement by Polarization Transfer (DEPT) experiment. The phase of each signal is given in parenthesis after the signal position. Two dimensional 1 3 C - ' H correlation spectra were obtained on Bruker AV-400 and Bruker AMX-500 spectrometers using the Heteronuclear Multiple Quantum Coherence (HMQC) experiment for one-bond correlations and the Heteronuclear Multiple Bond Connectivity (HMBC) experiment for long-range connectivities. 163 Chapter 9. Synthesis of Starting Materials Mass Spectra (MS) Low and high resolution mass spectra (LRMS and HRMS) were recorded on a Kratos MS 50 instrument using electron impact (EI) ionization at 70 eV or on a Kratos MS 80 spectrometer using desorption chemical ionization (DCI) with the ionization gas noted. The masses of organic salts were determined on a Kratos IIHQ hybrid mass spectrometer by recording liquid secondary ionization mass spectra (LSIMS) with the various matrices noted. Ultraviolet-Visible Spectra (UV/VIS) UV/VIS spectra were recorded on a Perkin-Elmer Lambda-4B UV/VIS spectrometer in the spectral grade solvents indicated. Absorption maxima (X m a x ) are reported in nanometers (nm), with molar extinction coefficients (E) reported in parentheses in units of M^cm" 1 . Microanalysis (Anal.) Elemental analyses were obtained for most new compounds. These were performed by Mr. P. Borda on a Carlo Erba C H N Model 1106 analyzer. Crystallography Single crystal X-ray analysis was performed on either a Rigaku AFC6S four-circle diffractometer (Cu-Ka or M o - K a radiation) or a Rigaku AFC7 four-circle diffractometer equipped with a DSC Quautum CCD detector (Mo-Ka radiation). Structures were determined by Dr. Eugene Cheung under the supervision of Dr. James Trotter. Structures are presented as ORTEP drawings at the 50% probability level. 164 Chapter 9. Synthesis of Starting Materials Gas Chromatography (GC) Gas chromatographic analyses in a helium carrier gas were performed on a Hewlett-Packard 5890A or a 5890 series II Plus gas chromatograph fitted with a flame ionization detector and a Hewlett-Packard 3 3 92A or 3 3 93 A integrator. The Hewlett-Packard fused-silica capillary columns HP-5MS (30 m x 0.25 mm x 0.25 um film thickness), HP-5 (30 m x 0.25 mm x 0.25 um film thickness), Supelco beta-DEX 390 column (30 m x 0.25 mm x 0.25 um film thickness) and a custom chiral column (50% 6-TBDMS-2,3-dimethyl-P-cyclodextrin dissolved in OV-1701, 20 m x 0.25 mm ID) were used. Analyses were run with a split injection port (split ratios between 25:1 and 100:1). Gas Chromatographv-Mass Spectrometry (GC-MS) GC-MS data were recorded on an Agilent 6890 plus GC system connected to an Agilent 5973 network mass selective detector with an HP-5MS (30mxO.25mmxO.25um film thickness) column. The samples were run with a split injection port with split ratio of 100:1 and an electronic impact ionization source of 70 eV was employed. High Performance Liquid Chromatography (HPLC) High performance liquid chromatography (HPLC) was performed on a Waters 600E system controller connected to a tunable U V detector (Waters 486). For the determination of enantiomeric excesses, a Chrialcel OD™ column (250mmx4.6mm) from Chiral Technologies, Inc. was used. The solvent combination was employed as noted. 165 Chapter 9. Synthesis of Starting Materials Optical Rotations The sign of optical rotation for each separated enantiomer was determined by Dr. Bi l l Champion from Chiral Technologies, Inc. at 675 nm. Silica Gel Chromatography Analytical thin layer chromatography (TLC) was carried out on commercial pre-coated silica gel plates (E. Merck, type 5554). Column chromatography was performed using 230-400 mesh silica gel (Merck 9385) slurry packed with the eluting solvent. Radial chromatography was carried out on a Harrison Research Chromatotron (Model 7924T) with self-coated silica gel plates (1mm or 2mm thickness with E M Science silica gel 60 PF254 containing gypsum 7749-3). Solvents and Reagents Tetrahydrofuran (THF) and diethyl ether were refluxed over the sodium ketyl of benzophenone under an argon atmosphere and distilled before use. Anhydrous dichoromethane and benzene were obtained by refluxing over calcium hydride and distilling prior to use. DMSO was dried over calcium hydride at room temperature over days and vacuum distilled before use. Anhydrous methanol was obtained by refluxing the commercial solvent (Fisher Scientific) over magnesium and distilling prior to use. Unless otherwise noted, all the commercially available chemicals were used without further treatment and all the reactions were conducted under a dry argon atmosphere in oven-dried glassware. A l l of the solvents used for reaction workup and product separation, including diethyl ether, 35-60 °C petroleum ether, ethyl acetate and hexanes, were not purified prior to use. 166 Chapter 9. Synthesis of Starting Materials 9.2 Synthesis of the c/s-Ketones 43-47 9.2.1 Synthesis of c/s-9-Decalyl Phenyl Ketone (43) To 14.5 g (79.7 mmol) of cw-9-decalyl carboxylic acid 41 was added 70 mL (960 mmol) of thionyl chloride. The solution was stirred at room temperature for 30 min and then refluxed for another 2 h. After cooling to room temperature, the excess thionyl chloride was removed by applying vacuum to the reaction mixture with a water aspirator. At the final stage of the evacuation, gentle heating was applied. The residue was put under vacuum to remove the last traces of thionyl chloride. The resulting acid chloride 42 was used either without further purification as a brown oil or vacuum-distilled with a Kugelrohr oven at 175-180 °C/8 mmHg as a colorless oil in nearly quantitative yield. A solution of 3.00 g (15.0 mmol) of the above acid chloride 42 in 28 mL of dry THF was cooled to 0-5 °C in an ice-water bath. Then 9.7 mL of 1.7 M phenyllithium (16.5 mmol) in cyclohexane-diethyl ether was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to quench the reaction. The aqueous layer was extracted with diethyl ether and the combined organic layer 167 Chapter 9. Synthesis of Starting Materials was washed successively with 10% sodium bicarbonate solution, water, brine and then dried over magnesium sulfate. After filtration, the filtrate was concentrated and subjected to flash chromatography on silica gel with 1/100 (v/v) diethyl ether/petroleum ether as the eluent to afford 2.03 g (58 %) of white solid. Recrystallization from methanol gave 43 as colorless cubes. mp 61.5-62.5 °C; ! H N M R (CDC1 3, 400 MHz): 5 7.60-7.58 (m, 2H, ArH), 7.43-7.33 (m, 3H, ArH), 2.41 (m, IH, R 3 CH), 1.89-1.79 (m, 4H), 1.55-1.29 (m, 12H) ppm; 1 3 C N M R (CDCI3, 75 MHz, 55 °C, APT: C, C H 2 : +; C H , C H 3 : -) 5 210.46 (+, C=0), 140.71 (+), 129.95 (-), 127.76 (-), 127.32 (-), 52.96 (+), 35.78 (-), 31.46 (+), 28.20 (+), 23.19 (+), 22.79 (+) ppm; IR(KBr) 3049, 2930, 2867,1665 (C=0), 1594, 1574, 1446, 1348,1303, 1285, 1268, 1231, 1213, 1182, 1156, 1085, 1037, 1021, 1008, 959, 936, 903, 870, 857, 841, 799, 784, 772, 715, 698, 676, 626, 591,564 cm"1; UV (hexane) 203.4 (16,000), 234.8 (8,600), 270.6 (500), 322.4 (126) nm; L R M S (EI) m/z 242 (M + ) , 137, 136(100), 105, 95, 81, 77; H R M S (EI) m/z 242.1674 (Calcd for C 1 7 H 2 2 0 , 242.1671). Anal. Calcd for C i 7 H 2 2 0 : C, 84.24; H , 9.16. Found: C, 84.41; H , 9.09. X-ray crystallographic data: space group, P2\lc; a = 7.3068(6) A, b = 19.757(2) A, c = 9.958(1) A; a =90 °, /?= 108.452(7) °, y= 90 °; V= 1363.7(3) A 3 ; Z = 4; radiation, Cu-Koc; R = 0.049. 168 Chapter 9. Synthesis of Starting Materials 9.2.2 Synthesis of cis-9-Decalyl />-Fluorophenyl Ketone (44) F H 44 cz's-9-Decalyl carbonyl chloride 42 was prepared in the same way as previously described. A solution of 15.57 g (77.65 mmol) of acid chloride 42 in 50 mL of dry THF was cooled to 0-5 °C in an ice-water bath and 41.5 mL of 2.0 M 4-fluorophenyl magnesium bromide (84 mmol) in diethyl ether was slowly added. The solution was allowed to warm to room temperature and stirred overnight. After quenching with water, the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. After removal of the solvent, the resulting yellow solid was subjected to flash chromatography on silica gel with 1/100 (v/v) diethyl ether/petroleum ether as the eluent. A pale yellow solid (16.4 g, 82.4 %) was obtained, and recrystallization from methanol gave 14.12 g of ketone 44 as colorless prisms. nip 75.0-75.5 °C; ! H N M R (CDCI3, 400 MHz) 5 7.70-7.62 (m, 2H, ArH), 7.10-7.00 (m, 2H, ArH), 2.39 (m, 1H,R 3 CH), 1.89-1.81 (m, 4H), 1.65-1.27 (m, 12H) ppm; 169 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CDCI3, 100 MHz, 55 °C, DEPT: C: nil; C H 2 : -; C H , C H 3 : +) 5 209.23 (nil, C=0), 165.01, 162.52 (nil, VC-F =251 Hz), 136.27, 136.24 (nil, VC-F= 3 Hz), 130.00, 129.92 (+, VC-F= 9 Hz), 114.97, 114.75 (+, V C - F = 22 Hz), 52.83 (nil), 35.80 (+), 31.62 (-), 28.23 (-), 23.25 (-), 22.83 (-) ppm; IR (KBr) 3070, 2922, 2857, 1665 (C=0), 1596, 1504, 1468, 1445, 1401, 1289, 1231, 1157, 1103, 1025, 1006, 980, 958, 931, 903, 846, 794, 750, 702„653, 631, 595, 543, 517, 506, 466cm"1; UV (hexane) 201.7 (20,000), 238.3 (9,160), 320.2 (152) nm; LRMS (EI) m/z 260 (M + ) , 137, 136, 95, 81(100), 79, 69, 67, 55, 41; HRMS (EI) m/z 260.1580 (Calcd for C i 7 H 2 1 F O , 260.1577); Anal. Calcd for C 1 7 H 2 i F O : C, 78.41; H , 8.14. Found: C, 78.24; H , 8.18. X-ray crystallographic data: space group, P2\/a; a = 13.952(2) A, b = 6.4153(9) A, c = 16.271(1) A; a= 90 °, p= 109.170(9) °, y= 90 °; V= 1375.6(3) A 3; Z = 4; radiation, Cu-Koc; R = 0.054. 9.2.3 Synthesis of/7-Cyanophenyl cw-9-Decalyl Ketone (45) C N H 45 170 Chapter 9. Synthesis of Starting Materials To a solution of 2.86 g (11 mmol) of ketone 44 in 70 mL of dry DMSO (distilled over calcium hydride) was added 0.90 g (13.4 mmol) of potassium cyanide. The solution was heated to near reflux. During the whole heating process, the reaction mixture turned from clear to cloudy and the color changed from pale yellow to orange to dark red-orange. The progress of the reaction was monitored by gas chromatography and the heating was stopped after 24 h. After cooling to room temperature, the solution was poured into water. Diethyl ether was used to extract the mixture and the ethereal layer was washed successively with 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. After the removal of the solvent, the remaining off-white solid was flash chromatographed on silica gel with 1/10 (v/v) diethyl ether/petroleum ether as the eluent. Ketone 45 was obtained as a white solid (2.45 g, 87 %). Recrystallization from methanol gave colorless needles. mp 110.5-111.5 °C; *H NMR (CDC1 3, 400 MHz) 8 7.68-7.62 (m, 4H, ArH), 2.31 (m, IH, R 3 CH), 1.87-1.81 (m, 2H), 1.76-1.70 (m, 2H), 1.68-1.25 (m, 12H) ppm; 1 3 C NMR (CDCI3, 75 MHz, 55 °C, APT: C, C H 2 : +; C H , C H 3 : -) 8 209.68 (+, C=0), 144.58 (+), 131.77 (-), 127.80 (-), 118.01 (+), 113.85 (+, CN), 53.28 (+), 35.61 (-), 31.43 (+), 28.12 (+), 23.08 (+), 22.77 (+) ppm; IR (KBr) 3072, 2924, 2862, 2223 (CN), 1682 ( C O ) , 1552, 1472, 1447, 1399, 1349, 1290, 1234, 1161, 1119, 1096, 1007, 978, 954, 929, 906, 887, 864, 850, 834, 757, 716, 647, 604,590, 537,508 cm"1; UV (hexane) 200.3 (17,340), 241.7 (12,700), 279.3 (948), 326.2 (176) nm; LRMS (EI) m/z 267 (M + ) , 138, 137(100), 136, 131, 130, 95, 81; 171 Chapter 9. Synthesis of Starting Materials HRMS (EI) m/z 267.1623 (Calcd for C , 8 H 2 i N O , 267.1623); Anal. Calcd for C 1 8 H 2 1 N O : C, 80.85; H , 7.92; N , 5.24. Found: C, 81.12; H , 7.96; N , 5.04. X-ray crystallographic data: space group, P i ; a = 10.861(6) A, b = 11.296(7) A, c = 6.507(3) A; a = 104.26(5) °, /? = 101.71(5) °, y = 102.13(5) °; V = 728.6(8) A 3; Z = 2; radiation, M o - K a ; R = 0.046. 9.2.4 Synthesis of /j-Carbohydroxyphenyl c/s-9-Decalyl Ketone (46) Ketone 45 (2.447 g, 9.165 mmol) was added to a solution containing 64.3 g of potassium hydroxide, 20 mL of ethanol and 98 mL of water. The mixture was refluxed for 22 h and then cooled to room temperature. Diethyl ether (50 mL) was used to extract the mixture and the aqueous layer was treated with concentrated hydrochloric acid until strongly acidic. A large amount of white precipitate was formed. Another 100 mL of water was added to dissolve the potassium chloride and the mixture was extracted with ethyl acetate until both phases were clear. The organic layer was dried over magnesium sulfate and the solvent was removed to afford white solid 46 (2.40 g, 92 %). Recrystallization of 46 from a mixture of ethanol and water gave colorless needles. ^ \ X O O H H 46 172 Chapter 9. Synthesis of Starting Materials mp 215-217 °C; 'H NMR (CDCI3, 400 MHz) 5 8.10 (d, J= 8.3 Hz, 2H, ArH), 7.64 (d, J = 8.3 Hz, 2H, ArH), 2.35 (m, IH, R 3 CH), 1.92-1.70 (m, 5H), 1.70-1.28 (m, 11H) ppm, no COOH signal was observed due to proton exchange with a trace amount of water in the solvent; , 3 C NMR (CDCI3, 75 MHz, 55 °C, APT: C, C H 2 : +; C H , C H 3 : -) 5 211.14 (+, ketone C=0), 170.58 (+, acid C=0), 145.52 (+), 130.24 (+), 129.82 (-), 127.21 (-), 53.25 (+), 35.63 (-), 31.44 (+), 28.19 (+), 23.15 (+), 22.83 (+) ppm; IR (KBr) 3217, 2926, 2858, 1729 (acid C=0), 1670 (ketone C=0), 1570, 1504, 1448, 1406, 1387, 1290, 1230, 1164, 1127, 1116, 1025, 1006, 955, 931, 903, 860, 793, 755, 727, 697,668,629 cm"1; UV (methanol) 203.6 (14,200), 243.9 (15,600) nm; LRMS (EI) m/z 286 (M + ) , 269, 150, 149, 137, 136, 95, 81 (100), 79, 69, 67, 65, 55, 41, 39; HRMS (EI) m/z 286.1571 (Calcd for C18H22O3, 286.1569); Anal . Calcd for C , 8 H 2 20 3 : C, 75.48; H, 7.75. Found: C, 75.53; H , 7.77. 173 Chapter 9. Synthesis of Starting Materials 9.2.5 Synthesis of p-Carbomethoxyphenyl cw-9-Decalyl Ketone (47) i 2 M e H 47 Keto acid 46 (0.700 g, 2.447 mmol) was added to 35 mL of dry methanol containing 0.52 g of /7-toluenesulfonic acid (monohydrate) and refluxed for 21 h. After cooling to room temperature, the reaction mixture was poured into 40 mL of ice-water. A large amount of white precipitate was formed. Hexane was then used to extract the mixture and the extract was washed with water, 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. The solvent was removed and 0.710 g (97 %) of white solid 47 was obtained. Recrystallization of 47 from methanol gave colorless needles. mp 85-86 °C; 'H NMR (CDC1 3, 400 MHz) 8 8.02 (d, J= 8.4 Hz, 2H, ArH), 7.60 (d, J= 8.4 Hz, 2H, ArH), 3.90 (s, 3H, CH 3 ) , 2.35 (m, IH, R 3 CH), 1.88-1.70 (m, 4H), 1.70-1.26 (m, 11H) ppm; , 3 C NMR ( C D C I 3 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 210.53 (+, ketone C=0), 166.19 (+, ester C=0), 144.63 (+), 131.29 (+), 129.05 (-), 127.04 (-), 53.02 (+), 52.06 (-, CH 3 ) , 35.51 (-), 31.27 (+, br), 28.05 (+), 23.04 (+), 22.69 (+) ppm; 174 Chapter 9. Synthesis of Starting Materials IR (KBr) 2926, 2856, 1729 (ester C=0), 1669 (ketone C O ) , 1569, 1501, 1447, 1434, 1401, 1277, 1229, 1193, 1158, 1108, 1018, 1007, 955, 931, 903, 862, 828, 799, 784, 763, 727, 709, 570 cm"1; UV (methanol) 204.3 (13,100), 243.9 (16,700), 280.6 (1,250) nm; LRMS (EI) m/z 300 (M + ) , 285, 269, 164 (100), 164, 137, 136, 95, 81; HRMS (EI) m/z 300.1720 (Calcd for C 1 9 H 2 4 O 3 , 300.1726); Anal. Calcd for C 1 9 H 2 4 O 3 : C, 75.96; H , 8.06. Found: C, 76.14; H , 8.03. X-ray crystallographic data: space group, P2\/a; a = 13.881(5) k,b = 6.362(2) A, c = 18.197(8) A; a = 90 °, J3= 97.77(4) °, y= 90 °; V= 1591(1) A 3; Z = 4; radiation, Mo-Kot; R = 0.062. 9.3 Synthesis of the frans-Ketones 50-54 9.3.1 Synthesis of fran.s-9-Decalyl Phenyl Ketone (50) zraws-9-Decalyl carbonyl chloride 49 was prepared from jra/ts-9-decalyl carboxylic acid 48 in near quantitative yield by the same procedure described in section 9.2.1. H 50 175 Chapter 9. Synthesis of Starting Materials A solution of 6.63 g (33.1 mmol) of the above acid chloride 49 in 53 mL of dry THF was cooled to 0-5 °C in an ice-water bath. Then 29.2 mL of 1.7 M phenyllithium (49.6 mmol) in cyclohexane-diethyl ether was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to quench the reaction. The aqueous layer was extracted with ether and the combined organic layer was washed successively with 10% sodium bicarbonate solution, water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and subjected to flash chromatography on silica gel with 1/20 (v/v) diethyl ether/petroleum ether as the eluent to afford 0.83 g (10 %) of white solid. Recrystallization from methanol gave ketone 50 as colorless cubes. mp 49.5-50 °C; ' H N M R (CDC1 3, 400 MHz): 5 7.60-7.55 (m, 2H, ArH), 7.42-7.30 (m, 3H, ArH), 2.36-2.30 (m, ,2H), 2.06-1.94 (m, 2H), 1.80-1.72 (m, 2H), 1.58-1.50 (m, 2H), 1.42-1.16 (m, 9H) ppm; , 3 C N M R (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 209.07 (+, C=0), 141.03 (+), 130.06 (-), 127.91 (-), 127.10 (-), 53.70 (+), 48.18 (-), 38.09 (+), 29.37 (+), 26.98 (+), 23.39 (+) ppm; IR(CHC1 3 ) 2930, 2859, 1676 (C=0), 1597, 1453, 1312, 1251, 1209, 1154, 971 cm"1; UV (hexane) 201.1 (18,000), 236.3 (7,830), 271.9 (500), 329.3 (123) nm; L R M S (EI) m/z 242 (M + ) , 137, 136(100), 105, 95, 81, 55, 41; H R M S (EI) m/z 242.1666 (Calcd for C i 7 H 2 2 0 , 242.1671). Anal . Calcd for C i 7 H 2 2 0 : C, 84.24; H , 9.16. Found: C, 84.22; H , 9.29. 176 Chapter 9. Synthesis of Starting Materials 9.3.2 Synthesis of *ra«s-9-Decalyl /?-Fluorophenyl Ketone (51) F 51 zra/w-9-Decalyl carbonyl chloride 49 was prepared in the same way as described for the preparation of ketone 50. A solution of 4.63 g (23.1 mmol) of acid chloride 49 in 50 mL of dry THF was cooled to 0-5 °C in an ice-water bath and 23.0 mL of 2.0 M 4-fluorophenyl magnesium bromide (46.2 mmol) in diethyl ether was added slowly. The solution was allowed to warm to room temperature and stirred overnight. After quenching with water, the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. After removal of the solvent, the resulting yellow solid was subjected to flash chromatography on silica gel with a mixture of 1/20 (v/v) diethyl ether/petroleum ether as the eluent. White solid (4.50 g, 75 %) was obtained and recrystallization from methanol gave ketone 51 as colorless plates. nip 73.5-75 °C; N M R (CDC1 3, 200 MHz): 5 7.68 (m, 2H, ArH), 7.02 (m, 2H, ArH), 2.32 (m, 2H), 1.97 (m, 2H), 1.74 (m, 2H), 1.60-1.00 (m, 11H) ppm; 177 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 207.23 (+, C=0), 165.42, 162.09 (+, VC-F = 250 Hz), 136.71 (+), 129.94, 129.83 (-, VC-F = 8 Hz), 115.04, 114.75 (-, VC-F= 22 Hz), 53.65 (+), 48.29 (-), 38.25 (+), 29.33 (+), 26.93 (+), 23.31 (+) ppm; IR (CHCI3) 2930, 2859, 1674 (C=0), 1599, 1505, 1454, 1312, 1234, 1208, 1157, 972, 843 cm"1; UV (hexane) 199.6 (19,600), 240.4 (8,100), 326.9 (125) nm; LRMS (EI) m/z 260 (M + ) , 242, 137, 136, 123, 95, 81(100), 67, 55, 41; HRMS (EI) m/z 260.1571 (Calcd for C i 7 H 2 i F O , 260.1577); Anal. Calcd for C 1 7 H 2 i F O : C, 78.41; H , 8.14. Found: C, 78.49; H , 8.19. X-ray crystallographic data: space group, Pbca; a = 13.164(2) A, b = 29.298(3) A, c = 7.2919(6) A; a = 90 °, /? = 90 °, y= 90 °; V= 2812.3(6) A3; Z = 8; radiation, Cu-Ka; R = 0.057. 9.3.3 Synthesis of/>-Cyanophenyl fra/Js-9-Decalyl Ketone (52) To a solution of 3.68 g (14.2 mmol) of ketone 51 in 70 mL of dry DMSO (distilled over calcium hydride) was added 1.39 g (28.3 mmol) of sodium cyanide. The solution was heated H 52 178 Chapter 9. Synthesis of Starting Materials to near reflux for 20 h. After cooling to room temperature, the solution was poured into water. Diethyl ether was used to extract the mixture and the ethereal layer was washed successively with 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. After removing the solvent, the off-white solid was flash chromatographed on silica gel with 1/20 (v/v) diethyl ether/petroleum ether as the eluent. Ketone 52 was obtained as a white solid (3.16 g, 84 %). Recrystallization from methanol gave colorless needles. mp 123-124 °C; *H NMR (CD 2C1 3 , 400 MHz) 5 7.68 (d, J = 8.3 Hz, 2H, ArH), 7.60 (d, J = 8.3 Hz, 2H, ArH), 2.17 (m, 2H), 1.93 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H), 1.43-1.12 (m, 9H) ppm; 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 207.98 (+, C=0), 144.93 (+), 131.87 (-), 127.38 (-), 118.11 (+), 113.51 (+, CN), 53.95 (+), 47.77 (-), 37.67 (+), 29.13 (+), 26.78 (+), 23.41 (+) ppm; IR (CHCI3) 2931, 2859, 2233 (CN), 1682 (C=0), 1456, 1312, 1152, 986, 972, 925, 878, 840 cm"1; UV (hexane) 199.2 (22,400), 242.1 (14,300), 279.3 (974), 330.5 (177) nm; LRMS (EI) m/z 267 (M + ) , 249, 137, 131, 95, 81 (100), 67, 55, 41; HRMS (EI) m/z 267.1624 (Calcd for C i 8 H 2 i N O , 267.1623); Anal . Calcd for C , 8 H 2 , N O : C, 80.85; H, 7.92; N , 5.24. Found: C, 80.69; H , 8.01; N , 5.15. X-ray crystallographic data: space group, P2\/c; a = 7.957(1) A, b = 21.067(2) A, c = 9.016(1) A; a= 90 °, fi= 93.77(1) °, y= 90°;V= 1508.1(3) A3; Z = 4; radiation, Cu-Ka; R = 0.055. 179 Chapter 9. Synthesis of Starting Materials 9.3.4 Synthesis of /?-Carbohydroxyphenyl fra«s-9-Decalyl Ketone (53) ^ \ . C O O H H 53 Ketone 45 (1.50 g, 5.62 mmol) was added to a solution containing 39 g of potassium hydroxide, 12 mL of ethanol and 59 mL of water. The mixture was refluxed for 22 h and then cooled to room temperature. Diethyl ether (50 mL) was used to extract the mixture and the aqueous layer was treated with concentrated hydrochloric acid until strongly acidic. A large amount of white precipitate was formed. Another 100 mL of water was added to dissolve the potassium chloride and the mixture was extracted with ethyl acetate until both phases were clear. The organic layer was dried over magnesium sulfate and the solvent was removed to afford white solid 53 (1.43 g, 89 %). Recrystallization of 53 from a mixture of ethanol and water gave colorless needles. mp 243.5-244.5 °C; ' H N M R (DMSO, 400 MHz) 5 13.15 (s, IH, OH), 8.00 (d, J= 8.4 Hz, 2H, ArH), 7.64 (d, J= 8.4 Hz, 2H, ArH), 2.20 (m, 2H), 1.96 (m, 2H), 1.72 (m, 2H), 1.52 (m, 2H), 1.40-1.22 (m, 7H), 1.18-1.04 (m, 2H) ppm; 180 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 8 209.15 (+, ketone C=0), 170.99 (+, acid C=0), 146.11 (+), 130.13 (+), 129.92 (-), 126.81 (-), 53.94 (+), 47.88 (-); 37.77 (+), 29.25 (+), 26.89 (+), 23.46 (+) ppm; IR (KBr) 3400-2400 (br, acid OH), 2927, 2859, 2666, 1690 (C=0), 1607, 1566, 1501, 1448, 1424, 1288, 1209, 1127, 1017, 987, 971, 927, 880, 860, 813, 786, 736, 707, 552 cm"1; UV (methanol) 203.7 (13,200), 242.8 (13,800) nm; LRMS (EI) m/z 286 (M + ) , 269, 241, 150, 137, 136, 95, 81 (100), 69, 67, 55, 41; HRMS (EI) m/z 286.1560 (Calcd for C18H22O3, 286.1569); Anal. Calcd for C18H22O3: C, 75.48; H , 7.75. Found: C, 75.46; H , 7.81. X-ray crystallographic data: space group, PI; a = 10.969(1) A , b = 11.022(2) A , c = 6.8221(7) A ; a = 96.59(1) °, j5 = 93.033(9) °, y = 69.244(9) °; V = 766.1(2) A 3 ; Z = 2; radiation, Cu-Koc; R = 0.055. 9.3.5 Synthesis of />-Carbomethoxyphenyl fnms-9-Decalyl Ketone (54) H 54 181 Chapter 9. Synthesis of Starting Materials Keto acid 53 was converted quantitatively into keto-ester 54 by treatment with excess ethereal diazomethane solution. After the solvent was evaporated, a white solid was obtained. Recrystallization from methanol gave ketone 54 as colorless needles. mp 111-112 °C; 'H NMR (CDC1 3, 400 MHz) 5 8.02 (d, J= 8.4 Hz, 2H, ArH), 7.56 (d, J= 8.4 Hz, 2H, ArH), 3.91 (s, 3H, CH 3 ) , 2.22 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.56 (m, 2H), 1.40-1.14 (m, 9H) ppm; 1 3 C NMR (CDCI3, 100 MHz, APT: C, C H 2 : -; C H , C H 3 : +) 5 208.88 (-, ketone C=0), 166.32 (-, ester C=0), 145.21 (-), 131.15 (-), 129.21 (+), 126.75 (+), 53.87 (-), 52.17 (+, CH 3 ) , 47.97 (+), 37.81 (-), 29.25 (-), 26.88 (-), 23.40 (-) ppm; IR (CDCI3) 2932, 2859, 1722 (ester C=0), 1680 (ketone C=0), 1444, 1401, 1311, 1284, 1204, 1115, 1021, 987, 971, 858, 827 cm"1; LRMS (EI) m/z 300 (M + ) , 285, 269, 241, 164, 137, 136, 95, 81 (100), 69, 55, 41; HRMS (EI) m/z 300.1719 (Calcd for C19H24O3, 300.1726); Anal. Calcd for C i 9 H 2 4 0 3 : C, 75.96; H , 8.06. Found: C, 75.99; H , 8.14. 9.4 Synthesis of cis- and frans-Chiral salts 55-74 9.4.1 General Procedure Chiral salts were prepared by dissolving 1 equivalent of keto acid 46 or 53 and 1.00-1.16 equivalents of the corresponding optically pure amine in the warm solvents indicated. The 182 Chapter 9. Synthesis of Starting Materials crystals were collected and used for spectroscopic and elemental analyses as well as photochemical studies. 9.4.2 Synthesis of c/s-Chiral salts 55-66 (i?)-(+)-l-Phenyl-Ethylamine Salt of Keto Acid 46 (55) Keto acid 46 (72.3 mg, 0.25 mmol) and 32.5 ul (30.55 mg, 025 mmol) of (R)-(+)-l-phenyl-ethylamine were dissolved in hot ethanol. Upon cooling, crystals of salt 55 were obtained (86 mg, 83.5%) as colorless needles. mp 216.5-218 °C; 'H NMR (CD 3 OD, 200 MHz) 5 7.95 (d, J= 8.5 Hz, 2H, ArH), 7.60 (d, J= 8.5 Hz, 2H, ArH), 7.40 (m, 5H, ArH), 4.40 (q, J= 6.8 Hz, IH), 2.40 (m, IH, R 3 CH) , 2.00-1.20 (m, 19H) ppm, no N H 3 + signal was observed due to proton exchange with the solvent; , 3 C NMR (CDC1 3 and CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 212.25 (+, ketone C=0), 172.33 (+, acid C=0), 142.19 (+), 139.40 (+), 137.60 (+), 128.80 (-), 128.53 (-), H 55 183 Chapter 9. Synthesis of Starting Materials 128.39 (-), 126.60 (-), 126.02 (-), 52.85 (+), 50.67 (-), 35.39 (-), 27.82 (+, br), 22.48 (+, br), 20.72 (-) ppm; IR (KBr) 2928, 2861, 2760, 2640, 2540, 2219, 1670, 1635, 1578, 1524, 1458, 1382, 1290, 1233, 1166, 1136, 1091, 1006, 956, 932, 905, 865, 837, 794, 767, 732, 969, 572, 534, 494, 465 cm"1; UV (methanol) 206.5 (14,875), 245.2 (10,080) nm; LRMS (FAB, +LSEV1S, matrix: thioglycerol) m/z 408 (M + +l), 378, 336, 287, 122 (100), 105; H R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 408.2533 (M + +l) (Calcd for C26H34NO3, 408.2539); Anal. Calcd for C z e ^ N O y ' A f L O : C, 75.82; H, 8.14; N , 3.40. Found: C, 76.05; H , 8.20; N , 3.38. GSH-)-l-Phenyl-Ethylamine Salt of Keto Acid 46 (56) Salt 56 was prepared as colorless needles in 73.5 % yield using the same procedure as for salt 55. Its melting point.and spectroscopic data were identical to those of salt 55. H 56 184 Chapter 9. Synthesis of Starting Materials Anal . Calcd for CzeH^NOy'AHzO: C, 75.82; H , 8.14; N , 3.40. Found: C, 75.95; H, 8.19; N , 3.39. (li?, 25)-(-)-Ephedrine Salt of Keto Acid 46 (57) Keto acid 46 (181 mg, 0.63 mmol) and 113 mg (0.68 mmol) of (li?, 2<S)-(-)-ephedrine were dissolved in warm methanol and allowed to cool to room temperature to yield salt 57 as thin needles (255 mg, 89.3%). mp 170-172 °C; ' H N M R (CD 3 OD, 200 MHz) 5 7.92 (d, J= 8.3 Hz, 2H, ArH), 7.56 (d, J= 8.3 Hz, 2H, ArH), 7.40-7.20 (m, 5H, ArH), 5.10 (d, J= 2.9 Hz, IH), 3.39 (dq, J= 2.9 Hz and J = 6.7 Hz, IH), 2.74 (s, 3H, CH 3 ) , 2.40(m, IH, R 3 CH), 2.00-1.20 (m, 16H), 1.02 (d, J= 6.7 Hz, 3H, CH 3 ) ppm, no OH and N H 2 + signal were observed due to proton exchange with the solvent; 1 3 C N M R (CD 3 OD, 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 5 213.33 (+, ketone C=0), 173.60 (+, acid C O ) , 143.52 (+), 141.46 (+), 129.85 (-), 129.52 (-), 128.90 (-), 127.97 (-), 126.96 (-), 71.76 (-), 61.43 (-), 54.22 (+), 37.07 (-), 31.46 (-), 29.22 (+, br), 23.90 (+, br), 9.96 (-) ppm; . 0 H 57 185 Chapter 9. Synthesis of Starting Materials IR (KBr) 3236, 2926, 2858, 2489, 1672, 1636, 1593, 1548, 1494, 1447, 1385, 1290, 1233, 1205, 1158, 1118, 1052, 1026, 1005, 993, 955, 931, 903, 867, 836, 794, 749, 733, 699, 571,521,466 cm"1; UV (methanol) 207.5 (18,550), 245.4 (12,110) nm; L R M S (FAB, +LSIMS, matrix: glycerol) m/z 452 (M ++l), 417, 287, 166 (100), 148; H R M S (FAB, +LSIMS, matrix: glycerol) m/z 452.2816 (M + +l) (Calcd for C28H38NO4, 452.2801); Anal . Calcd for CagHsvMVAHzO: C, 73.04; H , 8.26; N , 3.04. Found: C, 72.79; H, 8.16; N , 3.09. (15, 2JR)-(+)-Ephedrine Salt of Keto Acid 46 (58) Salt 58 was prepared in the same way as described for the preparation of 57 except the solvent was changed to acetonitrile containing a few drops of methanol. The salt was collected as colorless thin needles (86.9% yield). Its melting point and spectroscopic data are identical to those of 57. Anal. Calcd for C ^ H S T N C V A E L O : C, 73.04; H , 8.26; N , 3.04. Found: C, 73.31; H , 8.15; N , 3.05. . 0 H 58 186 Chapter 9. Synthesis of Starting Materials (IR, 25)-(-)-Norephedrine Salt of Keto Acid 46 (59) 59 Salt 59 was prepared by dissolving 153.6 mg (0.54 mmol) of keto acid 46 and 87.7 mg (0.58 mmol) of (\R, 25)-(-)-norephedrine in a hot mixture of acetonitrile and methanol. After cooling to room temperature, 222.2 mg (94.7%) of colorless plates 59 were obtained. mp 173.5-174.5 °C; ' H N M R (CD 3 OD, 200 MHz) 5 7.91 (d, J= 7.9 Hz, 2H, ArH), 7.55 (d, J = 7.9 Hz, 2H, ArH), 7.40-7.20 (m, 5H, ArH), 3.45 (dq, / = 3.6 Hz and J = 6.8 Hz, IH), 2.40(m, IH, R 3 CH), 2.00-1.20 (m, 16H), 1.02 (d, J = 6.8 Hz, 3H, CH 3 ) ppm, another C H peak was hidden underneath the water peak, no OH or N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C N M R (CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 6 213.32 (+, ketone C=0), 174.20 (+, acid C O ) , 143.26 (+), 141.61 (+), 140.65 (+), 129.77 (-), 129.50 (-), 128.94 (-), 127.94 (-), 127.15 (-), 73.58 (-), 54.21 (+), 53.64 (-), 37.08 (-), 29.17 (+, br), 23.82 (+, br), 12.42 (-) ppm; 187 Chapter 9. Synthesis of Starting Materials IR (KBr) 3191, 2931, 2858, 1657, 1582, 1538, 1450, 1386, 1291, 1234, 1165, 1132, 1100, 1060, 1027, 1006, 956, 932, 906, 864, 837, 791, 735, 702, 576, 521, 467 cm - 1; UV (methanol) 207.9 (21,670), 245.4 (14,350) nm; LRMS (FAB, +LSIMS, matrix: thioglycerol) m/z 438 (M + +l), 408, 287, 152 (100); HRMS (FAB, +LSEMS, matrix: thioglycerol) m/z 438.2638 (M + +l) (Calcd for C27H36NO4, 438.2644); Anal. Calcd for C27H35NO4: C, 74.10; H , 8.07; N , 3.20. Found: C, 73.99; H , 8.26; N , 3.21. (IS, 2i?)-(+)-Norephedrine Salt of Keto Acid 46 (60) 60 Salt 60 was prepared in the same way as salt 59. The product was collected as colorless plates (92.3%). The melting point and spectroscopic data of 60 are identical to those of 59. Anal. Calcd for C 2 7 H 3 5 N 0 4 : C, 74.10; H , 8.07; N , 3.20. Found: C, 74.29; H , 8.09; N , 3.18. 188 Chapter 9. Synthesis of Starting Materials (-)-Pseudoephedrine Salt of Keto Acid 46 (61) 61 Keto acid 46 (147.1 mg, 0.51 mmol) and 92.4 mg (0.55 mmol) of (-)-pseudoephedrine were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, colorless thin needles 61 were formed (202.2 mg, 87.2%). mp 163-165 °C; ' H N M R (CD 3 OD, 200 MHz) 8 7.92 (d, J= 8.3 Hz, 2H, ArH), 7.56 (d, J= 8.3 Hz, 2H, ArH), 7.40-7.20 (m, 5H, ArH), 4.50 (d, J = 9.3 Hz, IH), 3.30 (m, IH, partly hidden under solvent peak), 2.67 (s, 3H, CH 3 ) , 2.35(m, IH, R 3 CH), 2.00-1.20 (m, 16H), 1.02 (d, J= 6.6 Hz, 3H, CH 3 ) ppm, no OH or N H 2 + signal was observed due to proton exchange with the solvent; 1 3 C N M R (CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 213.31 (+, ketone C=0), 174.22 (+, acid C=0), 143.25 (+), 142.00 (+), 140.71 (+), 129.78 (-), 129.67 (-), 128.18 (-), 127.94 (-), 75.65 (-), 61.70 (-), 54.20 (+), 37.06 (-), 30.50 (-), 29.23 (+, br), 23.82 (+, br), 12.69 (-) ppm; IR (KBr) 3284, 3030, 2923, 2860, 2495, 1661, 1593, 1551, 1447, 1386, 1291, 1237, 1195, 1167, 1131, 1110, 1079, 1043, 1005, 956, 934, 901, 872, 835, 796, 755, 738, 699, 633, 579, 546, 520, 463 cm"1; 189 Chapter 9. Synthesis of Starting Materials UV (methanol) 207.8 (18,700), 245.6 (12,240) nm; L R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 452 (M + +l), 331, 287, 166 (100), 148; H R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 452.2800 (M + +l) (Calcd for C28Fi38N04, 452.2801); Anal . Calcd for C z g ^ y M V A H z O : C, 73.04; H , 8.26; N , 3.04. Found: C, 73.14; H , 8.40; N , 3.09. (5)-(+)-Prolinol Salt of Keto Acid 46 (62) Salt 62 was prepared by dissolving 132.0 mg (0.46 mmol) of keto acid 46 and 50 ul (51.2 mg, 0.51 mmol) of (S)-(+)-prolinol in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, 62 was obtained as colorless plates (118.7 mg, 66.5 %). mp 178-181 °C; ' H N M R (CD 3 OD, 200 MHz) 5 7.92 (d, J= 8.3 Hz, 2H, ArH), 7.57 (d, J= 8.3 Hz, 2H, ArH), 3.85-3.50 (m, 3H), 3.30-3.10 (m, 2H, partly hidden under the solvent peak), 2.35(m, IH, R 3 CH) , 2.10-1.20 (m, 20H) ppm, no OH or N H 2 + signal was observed due to proton exchange with the solvent; H 62 190 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 213.32 (+, ketone C=0), 174.34 (+, acid C=0), 143.28 (+), 140.69 (+), 129.77 (-), 127.94 (-), 62.78 (-), 61.67 (-), 54.22 (+), 46.51 (+), 37.10 (-), 29.23 (+, br), 27.13 (+), 24.91 (+), 23.82 (+, br) ppm; IR (KBr) 3176, 2926, 2857, 1665, 1630, 1582, 1537, 1445, 1386, 1290, 1230, 1164, 1133, 1093, 1026, 1006, 955, 932, 906, 865, 839, 793, 764, 732, 572, 534, 469 cm"1; UV (methanol) 203.9 (15,820), 245.7 (11,460) nm; LRMS (FAB, continuous flow +LSIMS, mobile phase: water/methanol/glycerol (50/50/1)) m/z 388 (M + +l), 287, 269, 203, 171, 102 (100); HRMS (FAB, +LSIMS, matrix: thioglycerol) m/z 388.2498 (M + +l) (Calcd for C23H34NO4, 388.2488); Anal. Calcd for C 2 3 H33N0 4 : C, 71.27; H, 8.59; N , 3.62. Found: C, 71.11; H , 8.68; N , 3.73. L-Prolinamide Salt of Keto Acid 46 (63) Salt 63 was prepared by dissolving 143.3 mg (0.50 mmol) of keto acid 46 and 62 mg (0.53 mmol) of L-prolinamide in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 63 was obtained as small colorless plates (168.6 mg, 84.1 %). . 0 H 63 191 Chapter 9. Synthesis of Starting Materials mp 176-179 °C; ' H N M R (CD3OD, 200 MHz) 8 7.93 (d, J= 8.3 Hz, 2H, ArH), 7.57 (d, J= 8.3 Hz, 2H, ArH), 4.19 (dd, J= 7.9 Hz and J= 6.2 Hz, IH), 3.30 (m, IH, partly hidden under the solvent peak), 2.40 (m, 2H), 2.10-1.20 (m, 20H) ppm, no N H 2 or N H 2 + signal was observed due to proton exchange with the solvent; , 3 C N M R (CD3OD, 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 5 213.30 (+, ketone C=0), 173.86 (+, acid C=0), 172.84 (+, amide C=0), 143.49 (+), 140.05 (+), 129.82 (-), 127.98 (-), 60.94 (-), 54.22 (+), 47.30 (+), 37.08 (-), 31.26 (+), 29.22 (+, br), 25.35 (+), 23.86 (+, br) ppm; IR (KBr) 3333, 2926, 2859, 2448, 1713, 1674, 1626, 1587, 1548, 1449, 1375, 1282, 1237, 1133, 1027, 1007, 960, 904, 876, 833, 804, 789, 743, 713, 639 cm"1; UV (methanol) 204.8 (17,850), 244.8 (14,500) nm; L R M S (FAB, +LSIMS, matrix: glycerol + methanol) m/z 401 (M + +l), 379, 287, 115; H R M S (FAB, +LSIMS, matrix: glycerol + methanol) m/z 401.2436 (M + +l) (Calcd for C 2 3 H 3 3N 2 04, 401.2440); Anal. Calcd for C 2 3 H 3 2 N 2 0 4 : C, 68.96; H, 8.06; N , 7.00. Found: C, 69.18; H, 7.98; N , 6.98. 192 Chapter 9. Synthesis of Starting Materials (IR, 25)-(+)-c/s-l-Amino-2-Indanol Salt of Keto Acid 46 (64) Keto acid 46 (111.6 mg, 0.39 mmol) and 68.4 mg (0.45 mmol) of (IR, 2S)-(+)-cis-\-amino-2-indanol were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, colorless needles of 64 were formed (130.7 mg, 77.0 %). mp 204 °C (decomp); ' H N M R (CD 3 OD, 200 MHz) 5 7.92 (d, J= 8.3 Hz, 2H, ArH), 7.56 (d, J= 8.3 Hz, 2H, ArH), 7.43 (d, J= 6.6 Hz, IH, ArH), 7.40-7.20 (m, 3H, ArH), 4.67 (q, J= 5.7 Hz, IH), 4.52 (d, J= 5.7 Hz, IH), 3.30-2.90 (m, 2H, partly hidden under the solvent peak), 2.40(m, IH, R 3 CH), 2.10-1.20 (m, 16H) ppm, no OH or N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C N M R (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 213.34 (+, ketone C=0), 174.12 (+, acid C=0), 143.29 (+), 142.78 (+), 140.55 (+), 138.33 (+), 130.80 (-), 129.80 (-), 128.39 (-), 127.93 (-), 126.63 (-), 126.17 (-), 72.01 (-), 58.64 (-), 54.21 (+), 40.08 (+), 37.09 (-), 29.21 (+, br), 23.83 (+, br) ppm; IR (KBr) 3240, 2931, 2857, 1667, 1580, 1537, 1453, 1397, 1291, 1233, 1160, 1135, 1104, 1047, 1007, 955, 932, 902, 868, 837, 793, 732, 574, 524, 472 cm"1; 193 Chapter 9. Synthesis of Starting Materials UV (methanol) 208.9 (21,000), 245.5 (14,675) nm; LRMS (FAB, +LSIMS, matrix: thioglycerol) m/z 436 (M + +l), 406, 287, 150 (100); HRMS (FAB, +LSIMS, matrix: thioglycerol) m/z 436.2492 (M + +l) (Calcd for C27H34NO4, 436.2488); Anal. Calcd for C27H33NO4: C, 74.44; H , 7.64; N , 3.22. Found: C, 74.59; H , 7.64; N , 3.17. (i?)_(+)-2-Phenyl-l-Propylamine Salt of Keto Acid 46 (65) H Keto acid 46 (111.5 mg, 0.39 mmol) and 60 uL (56.7 mg, 0.42 mmol) of (R)-(+)-2-phenyl-1-propylamine were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, crystals of 65 were obtained as colorless needles (133.1 mg, 81.1 %). mp 176-177 °C; 'H NMR (CD3OD, 200 MHz) 5 7.90 (d,J= 8.3 Hz, 2H, ArH), 7.54 (d, J= 8.3 Hz, 2H, ArH), 7.40-7.20 (m, 5H, ArH), 3.15-3.00 (m, 3H), 2.40 (m, IH, R 3 CH) , 2.00-1.20 (m, 19H) ppm, no N H 3 + signal was observed due to proton exchange with the solvent; 194 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 213.40 (+, ketone C=0), 174.19 (+, acid C=0), 143.39 (+), 143.26 (+), 140.64 (+), 130.13 (-), 129.78 (-), 128.50 (-), 128.22 (-), 127.95 (-), 54.21 (+), 46.86 (+), 39.75 (-), 37.08 (-), 29.22 (+, br), 23.84 (+, br), 19.90 (-) ppm; IR (KBr) 2927, 2861, 2178, 1662, 1636, 1576, 1505, 1449, 1386, 1290, 1232, 1167, 1135, 1112, 1027, 1006, 955, 934, 900, 870, 836, 795, 763, 734, 702, 571, 537, 498, 467 cm' 1; UV (methanol) 206.6 (18,640), 245.5 (11,500) nm; LRMS (FAB, +LSIMS, matrix: glycerol) m/z All (M + +l), 287, 228, 136 (100), 119; HRMS (FAB, +LSIMS, matrix: glycerol) m/z 41126S9 (M + +l) (Calcd for C27H36NO3, 422.2695); Anal. Calcd for C27H35NO3: C, 76.92; H , 8.37; N, 3.32. Found: C, 76.70; H , 8.43; N, 3.29. (7?)-(+)-Bornylamine Salt of Keto Acid 46 (66) Salt 66 was prepared by dissolving 104.3 mg (0.36 mmol) of keto acid 46 and 61.7 mg (0.39 mmol) of (i?)-(+)-bornylamine in a hot mixture of acetonitrile and methanol. Upon H 66 195 Chapter 9. Synthesis of Starting Materials cooling to room temperature, salt 66 was obtained as small colorless plates (101.8 mg, 63.6 %). mp 216.5-217.5 °C; *H N M R (CD 3 OD, 200 MHz) 8 7.92 (d, J= 8.3 Hz, 2H, ArH), 7.57 (d, J= 8.3 Hz, 2H, ArH), 3.35 (m, IH, partly hidden under the solvent peak), 2.40-2.20 (m, 2H), 1.90-1.15 (m, 21H), 1.06 (dd, J= 4.2 Hz and J = 13.7 Hz, IH), 0.92-0.89 (m, 9H, 3CH 3) ppm, no N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C N M R (CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 213.32 (+, ketone C=0), 174.23 (+, acid C=0), 143.23 (+), 140.82 (+), 129.79 (-), 127.96 (-), 57.93 (-), 54.23 (+), 45.84 (-), 37.12 (-), 35.56 (+), 29.25 (+, br), 28.57 (+), 27.97 (+), 23.87 (+, br), 19.87 (-), 18.75 (-), 13.36 (-) ppm, the other two carbon signals were hidden under the solvent peak; IR (KBr) 2927, 2190, 1672, 1636, 1581, 1538, 1456, 1382, 1334, 1292, 1235, 1167, 1133, 1109, 1049, 1025, 1005, 978, 956, 933, 904, 867, 836, 793, 765, 733, 574, 532, 499, 470 cm"1; UV (methanol) 204.4 (14,800), 245.3 (11,300) nm; L R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 440 (M + +l), 410, 343, 287, 214, 154 (100), 137, 81; H R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 440.3163 (M + +l) (Calcd for C 2 8 H 4 2 N 0 3 , 440.3165); Anal . Calcd for C 2 8 H 4 i N 0 3 : C, 76.48; H , 9.41; N , 3.19. Found: C, 76.19; H , 9.57; N , 3.21. 196 Chapter 9. Synthesis of Starting Materials 9.4.3 Synthesis of trans-Chiral Salts 67-74 (5)-(-)-l-Phenyl-Ethylamine Salt of Keto Acid 53 (67) H 67 Keto acid 53 (114 mg, 0.40 mmol) and 51.3 ul (48 mg, 0.40 mmol) of (/?)-(+)- 1-phenyl-ethylamine were dissolved in hot methanol. Upon cooling, crystals of salt 67 were obtained (115 mg, 71 %) as colorless needles. mp 248-250 °C; ' H N M R (CD 3 OD, 200 MHz) 5 7.92 (d, J= 8.5 Hz, 2H, ArH), 7.56 (d, J = 8.5 Hz, 2H, ArH), 7.40 (m, 5H, ArH), 4.40 (q, J= 6.8 Hz, IH), 2.42-2.30 (m, 2H), 2.10-1.10 (m, 18H) ppm, no NH3 + signal was observed due to proton exchange with the solvent; , 3 C N M R (CDCI3 and CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 211.30 (+, ketone C=0), 174.10 (+), 143.98 (+), 140.47 (+), 140.15 (+), 130.27 (-), 130.06 (-), 129.88 (-), 127.62 (-), 127.59 (-), 55.00 (+), 52.30 (-), 49.40 (-), 39.02 (+), 30.62 (+), 28.07 (+), 24.51 (+), 20.99 (-) ppm; 197 Chapter 9. Synthesis of Starting Materials IR (KBr) 2921, 2851, 1673, 1613, 1528, 1455, 1397, 1316, 1205, 1157, 1136, 1094, 1069, 1014, 990, 972, 926, 882, 869, 839, 796, 768, 753, 737, 698, 591, 538, 486 cm"1; UV (methanol) 207.3 (17,560), 244.1 (11,250) nm; LRMS (FAB, +LSIMS, matrix: thioglycerol) m/z 408 (M + +l), 287, 122 (100), 105; HRMS (FAB, +LSIMS, matrix: thioglycerol) m/z 408.2532 (M + +l) (Calcd for C26H34NO3, 408.2539); Anal. Calcd for C 2 6H3 3 N0 3 : C, 76.62; H , 8.16; N , 3.44. Found: C, 76.56; H , 8.12; N , 3.43. (l?)-(+)-l-Phenyl-Ethylamine Salt of Keto Acid 53 (68) Salt 68 was prepared using the same procedure as for salt 67 except that a mixture of methanol and acetonitrile was used as the solvent. The crystals were obtained in a yield of 64.3 % as colorless needles. Its melting point and spectroscopic data were identical to those of salt 67. Anal. Calcd for C26H33NO3: C, 76.62; H , 8.16; N , 3.44. Found: C, 76.54; H , 8.09; N , 3.60. 198 Chapter 9. Synthesis of Starting Materials (IR, 25)-(-)-Ephedrine Salt of Keto Acid 53 (69) Keto acid 53 (78.4 mg, 0.27 mmol) and 51.6 mg (0.31 mmol) of (\R, 2<S)-(-)-ephedrine were dissolved in a warm methanol/acetonitrile mixture and allowed to cool to room temperature to yield salt 69 as thin needles (101.9 mg, 82.4 %). mp 191-193 °C; ' H N M R (CD 3 OD, 200 MHz) 8 7.95 (d, / = 8.3 Hz, 2H, ArH), 7.50 (d, J= 8.3 Hz, 2H, ArH), 7.45-7.20 (m, 5H, ArH), 4.50 (d, J= 2.9 Hz, IH), 3.40-3.25 (m, IH), 2.70 (s, 3H, CH 3 ) , 2.40-2.20 (m, 2H), 2.10-1.10 (m, 15H), 1.05 (d, J= 6.7 Hz, 3H, CH 3 ) ppm, no OH and N H 2 + signal were observed due to proton exchange with the solvent; 1 3 C N M R (CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 211.30 (+, ketone C=0), 174.23 (+, acid C=0), 143.93 (+), 142.01 (+), 140.62 (+), 129.88 (-), 129.80 (-), 129.70 (-), 128.18 (-), 127.62 (-), 75.69 (-), 61.71 (-), 54.99 (+), 49.38 (-), 39.01 (+), 30.61 (+), 30.51 (-), 28.06 (+), 24.50 (+), 12.70 (-) ppm; 199 Chapter 9. Synthesis of Starting Materials IR (KBr) 3191, 3068, 2933, 2849, 2517, 1664, 1637, 1596, 1553, 1493, 1445, 1363, 1311, 1249, 1204, 1153, 1130, 1100, 1075, 1058, 1045, 1029, 999, 971, 928, 880, 869, 834, 798, 768, 739, 701, 629, 536, 485, 462 cm"1; L R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 452 (M + +l), 331, 287, 269, 166 (100), 148; H R M S (FAB, +LSLMS, matrix: thioglycerol) m/z 452.2800 (M + +l) (Calcd for C28H 3 8 N0 4 , 452.2801); Anal . Calcd for C28H37NO4: C, 74.47; H , 8.26; N , 3.10. Found: C, 74.39; H, 8.23; N , 3.17. (IR, 2S)-(-)-Norephedrine Salt of Keto Acid 53 (70) Salt 70 was prepared by dissolving 75.6 mg (0.26 mmol) of keto acid 53 and 42.5 mg (0.28 mmol) of (li?, 21S)-(-)-norephedrine in a hot mixture of acetonitrile and methanol. After cooling to room temperature, 62.5 mg (54 %) of colorless plates of salt 70 were obtained. mp 186-188 °C; , 0 H 70 200 Chapter 9. Synthesis of Starting Materials *H N M R ( C D 3 O D , 200 MHz) 5 7.95 (d, J= 7.9 Hz, 2H, ArH), 7.55 (d, J = 7.9 Hz, 2H, ArH), 7.45-7.20 (m, 5H, ArH), 3.50 (m, IH), 2.45-2.25 (m, 2H), 2.20-0.90 (m, 19H) ppm, another C H peak was hidden underneath the water peak, no OH or N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C N M R (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 211.29 (+, ketone C O ) , 174.24 (+, acid C O ) , 143.94 (+), 141.62 (+), 140.54 (+), 129.87 (-), 129.51 (-), 128.95 (-), 127.63 (-), 127.15 (-), 73.61 (-), 54.99 (+), 53.64 (-), 49.38 (-), 39.02 (+), 30.61 (+), 28.06 (+), 24.51 (+), 12.46 (-)ppm; IR (KBr) 3272, 2927, 2857, 1672, 1581, 1526, 1451, 1397, 1314, 1213, 1154, 1137, 1097, 1049, 988, 972, 927, 880, 866, 841, 796, 747, 707, 552 cm"1; L R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 438 (M + +l), 285, 269, 152 (100), 134; H R M S (FAB, +LSIMS, matrix: thioglycerol) m/z 438.2635 (M + +l) (Calcd for C27H36NO4, 438.2644); Anal . Calcd for C27H 3 5 N0 4 : C, 74.10; H , 8.07; N , 3.20. Found: C, 73.81; H , 7.98; N , 3.29. (-)-Pseudoephedrine Salt of Keto Acid 53 (71) 201 Chapter 9. Synthesis of Starting Materials Keto acid 53 (65.7 mg, 0.23 mmol) and 42.7 mg (0.26 mmol) of (-)-pseudoephedrine were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, colorless thin needles of salt 71 were formed (77.3 mg, 74.6 %). mp 193-195 °C; ] H N M R (CD 3 OD, 200 MHz) 5 8.00 (d,J= 8.3 Hz, 2H, ArH), 7.55 (d, J= 8.3 Hz, 2H, ArH), 7.50-7.30 (m, 5H, ArH), 4.55 (d, J= 9.3 Hz, IH), 3.30 (m, IH, partly hidden under the solvent peak), 2.70 (s, 3H, CH 3 ) , 2.45-2.25 (m, 2H), 2.20-1.15 (m, 15H), 1.05 (d, J= 6.6 Hz, 3H, CH3) ppm, no OH or N H 2 + signal was observed due to proton exchange with the solvent; , 3 C N M R (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 211.34 (+, ketone C=0), 174.20 (+, acid C=0), 143.97 (+), 142.01 (+), 140.58 (+), 129.89 (-), 129.80 (-), 129.71 (-), 128.19 (-), 127.62 (-), 75.71 (-), 61.75 (-), 55.02 (+), 49.41 (-), 39.03 (+), 30.62 (+), 30.55 (-), 28.06 (+), 24.51 (+), 12.73 (-) ppm; IR (KBr) 3192, 3068, 2932, 2857, 2516, 1665, 1597, 1553, 1494, 1446, 1364, 1311, 1204, 1154, 1131, 1100, 1059, 1046, 1029, 999, 972, 928, 880, 869, 834, 799, 767, 739, 702, 630,537, 486 cm - 1; L R M S (FAB, +LSIMS, matrix: glycerol) m/z 452 (M ++l), 331, 287, 258, 225, 166 (100), 148; H R M S (FAB, +LSIMS, matrix: glycerol) m/z 452.2811 (M + +l) (Calcd for C 2 8 H 3 8 N 0 4 , 452.2801); Anal . Calcd for C 2 8 H 3 7 N 0 4 : C, 74.47; H, 8.26; N , 3.10. Found: C, 74.76; H , 8.20; N , 3.24. 202 Chapter 9. Synthesis of Starting Materials (IR, 25)-(+)-c/s-l-Amino-2-Indanol Salt of Keto Acid 53 (72) Keto acid 53 (67.9 mg, 0.24 mmol) and 37.5 mg (0.25 mmol) of (IR, 25)-(+)-cw-l-amino-2-indanol were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, colorless needles of salt 72 were formed (84.7 mg, 82.0 %). mp 198 °C (decomp); ' H N M R (CD 3 OD, 200 MHz) 8 7.95 (d, J= 8.3 Hz, 2H, ArH), 7.60-7.20 (m, 6H, ArH), 4.70 (q, J= 5.7 Hz, IH), 4.60 (d, J= 5.7 Hz, IH), 3.30-3.00 (m, 2H, partly hidden under the solvent peak), 2.35(m, 2H), 2.10-1.10 (m, 15H) ppm, no OH or N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C N M R (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 211.30 (+, ketone C O ) , 174.02 (+, acid C O ) , 144.03 (+), 142.81 (+), 140.30 (+), 138.25 (+), 130.85 (-), 129.90 (-), 128.42 (-), 127.63 (-), 126.67 (-), 126.17 (-), 71.97 (-), 58.63 (-), 55.00 (+), 49.39 (-), 40.10 (+), 39.02 (+), 30.61 (+), 28.07 (+), 24.51 (+) ppm; IR (KBr) 2921, 2856, 1673, 1578, 1534, 1456, 1398, 1315, 1205, 1156, 1136, 1096, 1050, 990, 972, 926, 881, 839, 795, 738, 542, 488 cm"1; L R M S (FAB, +LSDVIS, matrix: glycerol) m/z 436 (M ++l), 379, 287, 150 (100); 203 Chapter 9. Synthesis of Starting Materials HRMS (FAB, +LSIMS, matrix: glycerol) m/z 436.2482 (M + +l) (Calcd for C27H34NO4, 436.2488); Anal. Calcd for C27H33NO4: C, 74.44; H , 7.64; N , 3.22. Found: C, 74.42; H, 7.62; N , 3.25. (i?).(+)-2-Phenyl-l-Propylamine Salt of Keto Acid 53 (73) H Keto acid 53 (69.8 mg, 0.24 mmol) and 36.7 mg (0.27 mmol) of (K)-(+)-2-phenyl-l-propylamine were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, crystals of salt 73 were obtained as colorless needles (94.9 mg, 92.3 %). nip 160-162 °C; *H NMR ( C D 3 O D , 200 MHz) 5 7.95 (d, J= 8.3 Hz, 2H, ArH), 7.55 (d, J= 8.3 Hz, 2H, ArH), 7.40-7.15 (m, 5H, ArH), 3.20-2.90 (m, 3H), 2.55-2.25 (m, 2H), 2.15-1.15 (m, 18H) ppm, no N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C NMR (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 211.33 (+, ketone C=0), 174.14 (+, acid C=0), 143.98 (+), 143.42 (+), 140.63 (+), 130.15 (-), 129.88 (-), 128.53 (-), 204 Chapter 9. Synthesis of Starting Materials 128.23 (-), 127.62 (-), 55.02 (+), 49.41 (-), 46.93 (+), 39.68 (-), 30.62 (+), 29.03 (+), 28.06 (+), 24.51 (+), 13.90 (-)ppm; IR (KBr) 2922, 2858, 1671, 1586, 1510, 1456, 1397, 1314, 1300, 1250, 1207, 1153, 1060, 1030, 989, 972, 925, 881, 869, 839, 795, 764, 737, 701, 564, 542, 489 cm"1; LRMS (FAB, +LSIMS, matrix: glycerol) m/z All (M ++l), 287, 269, 228, 189, 149, 136 (100), 119; HRMS (FAB, +LSIMS, matrix: glycerol) m/z 422.2701 (M + +l) (Calcd for C 2 7 H 3 6 N O 3 , 422.2695); Anal. Calcd for C27H35NO3: C, 76.92; H , 8.37; N , 3.32. Found: C, 77.02; H , 8.37; N , 3.34. (#)_(+)-Bornylamine Salt of Keto Acid 53 (74) 74 Salt 74 was prepared by dissolving 83.4 mg (0.29 mmol) of keto acid 53 and 47.1 mg (0.31 mmol) of (i?)-(+)-bornylamine in a hot mixture of acetonitrile and methanol. Upon cooling to room temperature, salt 74 was obtained as small colorless plates (118.8 mg, 92.8 %). 205 Chapter 9. Synthesis of Starting Materials mp 192-195 °C; ! H NMR ( C D 3 O D , 200 MHz) 5 7.95 (d, J= 8.3 Hz, 2H, ArH), 7.55 (d, J = 8.3 Hz, 2H, ArH), 3.60-3.30 (m, IH, partly hidden under the solvent peak), 2.50-2.30 (m, 3H), 2.20-0.90 (m, 3 OH) ppm, no N H 3 + signal was observed due to proton exchange with the solvent; 1 3 C NMR (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) S 211.30 (+, ketone C=0), 174.25 (+, acid C=0), 143.88 (+), 140.77 (+), 129.85 (-), 127.60 (-), 57.93 (-), 55.01 (-), 50.04 (+), 49.42 (-), 45.85 (-), 39.03 (+), 35.64 (+), 30.61 (+), 28.56 (+), 28.06 (+), 27.94 (+), 24.50 (+), 19.86 (-), 16.73 (-), 13.33 (-) ppm, one carbon signal was hidden under the solvent peak; IR (KBr) 2982, 1667, 1631, 1582, 1538, 1451, 1392, 1313, 1250, 1209, 1154, 1134, 1113, 1050, 1012, 990, 972, 928, 880, 867, 835, 796, 756, 737, 713, 542, 490, 460 cm"1; LRMS (FAB, +LSEVIS, matrix: glycerol) m/z 440 (M + +l), 287, 269, 246, 226, 154 (100), 137,81; HRMS (FAB, +LSFMS, matrix: glycerol) m/z 440.3170 (M + +l) (Calcd for C28H42NO3, 440.3165); Anal. Calcd for C28H41NO3: C, 76.50; H , 9.40; N, 3.19. Found: C, 76.60; H, 9.48; N, 3.32. 9.5 Synthesis of Cyclopentyl Ketones 126-130 and Cyclohexyl Ketone 145 9.5.1 Synthesis of Phenyl 1-Phenylcyclopentyl Ketone 126 0. Ph 126 206 Chapter 9. Synthesis of Starting Materials To 2.46 g (12.9 mmol) of 1-phenylcyclopentyl carboxylic acid 124 was added 20 mL (274 mmol) of thionyl chloride. The solution was stirred at room temperature for 30 min and then refluxed for another 3 h. After cooling to room temperature, the excess thionyl chloride was removed by applying vacuum to the reaction mixture with a water aspirator. At the final stage of the evaporation, gentle heating was applied. The residue was placed under vacuum to remove the last traces of thionyl chloride. The resulting crude acid chloride 125 was vacuum distilled with a Kugelrohr oven at 168-180 °C/4 mmHg to yield a colorless oil (2.50 g, 93 %). A solution of 382 mg (1.83 mmol) of the above acid chloride 125 in 10 mL of dry THF was cooled to 0-5 °C in an ice-water bath. Then 2.4 mL of 1.0 M phenylmagnesium bromide THF solution (2.40 mmol) was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. After quenching with water, the aqueous layer was extracted with diethyl ether and the combined organic layer was washed successively with 10% sodium bicarbonate solution, water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and subjected to flash chromatography on silica gel with 1/50 (v/v) diethyl ether/petroleum ether as the eluent to afford 408 mg (89 %) of colorless oil. Crystallization in methanol in the refrigerator gave ketone 126 as colorless prisms. mp 48-49 °C; *H N M R (CDC1 3, 200 MHz): 5 7.60-7.50 (m, 2H, ArH), 7.35-7.10 (m, 8H, ArH), 2.55-2.35 (m, 2H), 2.15-1.95 (m, 2H), 1.80-1.50 (m, 4H) ppm; 207 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 202.06 (+, C O ) , 144.52 (+), 136.12(+), 131.71 (-), 129.83 (-), 128.87 (-), 127.90 (-), 126.50 (-), 125.98 (-), 63.37 (+), 37.40 (+), 24.66 (+) ppm; IR (CDCI3) 3064, 2962, 2875, 1673 ( C O ) , 1599, 1580, 1448, 1382, 1238, 1180, 1096, 911, 731, 651, 548, 477, 466, 456 cm"1; LRMS (DCI, NH 3 ) m/z 251 (M + +l , 100), 145, 144, 105, 91; HRMS (DCI, NH 3 ) m/z 251.1437 (Calcd for C ] 8 H i 9 0 , 251.1436). • Anal. Calcd for C ] 8 H 1 9 0 : C, 86.36; H , 7.25. Found: C, 86.09; H , 7.27. 9.5.2 Synthesis of/>-Fluorophenyl 1-Phenylcyclopentyl Ketone 127 1-Phenylcyclopentyl carbonyl chloride 125 was prepared in the same way as described for the synthesis of ketone 126. A solution of 2.14 g (10.3 mmol) of acid chloride 125 in 20 mL of dry THF was cooled to 0-5 °C in an ice-water bath. Then 12.0 mL of 1.0 M phenylmagnesium bromide THF solution (12.0 mmol) was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. After quenching with water, the aqueous layer was extracted with diethyl ether and the combined organic layer was washed successively with 5 % sodium bicarbonate solution, water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and subjected to flash chromatography on 127 208 Chapter 9. Synthesis of Starting Materials silica gel with a 1/20 (v/v) mixture of diethyl ether/petroleum ether as the eluent to afford 2.04 g (74 %) of ketone 127 as a pale yellow oil. 'H NMR (CDC1 3, 400 MHz): 8 7.70-7.60 (m, 2H, ArH), 7.40-7.10 (m, 5H, ArH), 6.90-6.80 (m, 2H, ArH), 2.55-2.40 (m, 2H), 2.20-2.00 (m, 2H), 1.80-1.60 (m, 4H) ppm; 1 3 C NMR (CDCI3, 50 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 200.22 (+, C=0), 167.09 and 162.05 (+, 'JC-F = 254 Hz), 144.45 (+), 132.55 and 132.37 (-, 3JC-F = 9 Hz), 132.20 and 132.15 (-, VC-F = 3 Hz), 128.92 (-), 126.56 (-), 125.82 (-), 115.13 and 114.69 (-, V C - F = 22 Hz), 63.18 (+), 37.41 (+), 24.68 (+) ppm; IR (neat) 3061, 2959, 2873, 1680 (C=0), 1599, 1505, 1448, 1408, 1299, 1235, 1157, 1098, 1013, 932, 896, 846, 750, 702, 604, 570 cm"1; LRMS (EI) m/z 268 (M + ), 146, 145 (100), 144, 123, 115, 95, 91, 67; HRMS (EI) m/z 268.1267 (Calcd for C , 8 H , 7 F O , 28.1263). Anal. Calcd for C i 8 H i 7 F O : C, 80.57; H , 6.39. Found: C, 80.66; H , 6.43. 9.5.3 Synthesis ofp-Cyanophenyl 1-Phenylcyclopentyl Ketone (128) To a solution of 2.04 g (7.62 mmol) of ketone 127 in 70 mL of dry DMSO (distilled over calcium hydride) was added 1.18 g (18 mmol) of potassium cyanide. The solution was heated to near reflux in the dark. During the whole heating process, the reaction mixture turned from Ph 128 209 Chapter 9. Synthesis of Starting Materials clear to cloudy and the color changed from pale yellow to orange to dark red-orange. The progress of the reaction was monitored by gas chromatography and the heating was stopped after 52 h. After cooling to room temperature, the solution was poured into water. Diethyl ether was used to extract the mixture and the ethereal layer was washed successively with 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. After removing the solvent, the off-white solid was flash chromatographed on silica gel with a 1/15 (v/v) mixture of diethyl ether/petroleum ether as the eluent. Ketone 128 was obtained as a white solid (1.16 g, 55 %). Recrystallization from methanol gave colorless needles. mp 63.5-65 °C; *H NMR (CDC1 3, 200 MHz): 5 7.70 (d, J= 8.5 Hz, 2H, ArH), 7.50 (d, J= 8.5 Hz, 2H, ArH), 7.40-7.20 (m, 5H, ArH), 2.60-2.40 (m, 2H), 2.20-2.00 (m, 2H), 1.90-1.60 (m, 4H) ppm; 1 3 C NMR ( C D C I 3 , 50 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 200.46 (+, C=0), 143.21 (+), 139.53 (+), 131.61 (-), 129.84 (-), 128.98 (-), 126.81 (-), 125.79 (-), 117.80 (+), 114.75 (+), 63.30 (+), 36.85 (+), 24.40 (+) ppm; IR (neat) 3061, 2957, 2873, 2230 (CN), 1681 (C=0), 1601, 1494, 1448, 1404, 1291, 1238, 1174, 1117, 1032, 1013,933,895,854, 751,703,594, 544 cm"1; LRMS (EI) m/z 275 (M + ) , 146, 145 (100), 102, 91, 77, 67; HRMS (EI) m/z 275.1304 (Calcd for C i 9 H 1 7 N O , 275.1310); Anal . Calcd for C i 9 H i 7 N O : C, 82.88; H , 6.22; N , 5.09. Found: C, 82.68; H , 6.22; N , 5.12. 210 Chapter 9. Synthesis of Starting Materials 9.5.4 Synthesis of/>-Carohydoxyphenyl 1-Phenylcyclopentyl Ketone (129) O o C 0 2 H 129 Ketone 128 (1.16 g, 4.2 mmol) was added to a solution containing 32 g of potassium hydroxide, 10 mL of ethanol and 49 mL of water. The mixture was refluxed in the dark for 20 h and then cooled to room temperature. Diethyl ether (50 mL) was used to extract the mixture and the aqueous layer was treated with concentrated hydrochloric acid until it was strongly acidic. A large amount of white precipitate was formed. Another 100 mL of water was added to dissolve the potassium chloride and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed to afford white solid 129 (680 mg, 55 %). Recrystallization of acid 129 from methanol gave colorless needles. mp 203-205 °C; *H NMR (CD 3 OD, 200 MHz): 5 7.85 (d, J= 8.5 Hz, 2H, ArH), 7.55 (d,J= 8.5 Hz, 2H, ArH), 7.30-7.05 (m, 5H, ArH), 2.50-2.30 (m, 2H), 2.15-1.95 (m, 2H), 1.80-1.50 (m, 4H) ppm; 1 3 C NMR (CD3OD, 50 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 203.23 (+, ketone C=0), 168.74 (acid C=0), 145.08 (+), 141.18 (+), 134.59 (+), 130.59 (-), 130.24 (-), 130.12 (-), 127.92 (-), 127.22 (-), 64.84 (+), 38.14 (+), 25.46 (+) ppm; IR (KBr) 3300-2000 (br, acid OH), 2963, 1685 (C=0), 1572, 1504, 1422, 1283, 1239, 1128, 1016, 938, 870, 798, 758, 723, 699, 527 cm"1; LRMS (EI) m/z 294 (M + ) , 146, 145 (100), 144, 115, 91; 211 Chapter 9. Synthesis of Starting Materials HRMS (EI) m/z 294.1258 (Calcd for C , 9 H i 8 0 3 , 294.1256). Anal. Calcd for CwHigtV/tffcO: C, 76.28; H, 6.20. Found: C, 76.67; H , 6.15. 9.5.5 Synthesis of />-Carbomethoxyphenyl 1-Phenylcyclopentyl Ketone (130) Keto acid 129 was quantitatively converted into methyl ester 130 by treatment with excess ethereal diazomethane solution. After solvent evaporation, white solid was obtained. Recrystallization from methanol gave ketone 130 as colorless needles. mp 88-90 °C; *H NMR (CDC1 3, 200 MHz): 5 7.84 (d,J= 8.7 Hz, 2H, ArH), 7.55 (d, J= 8.5 Hz, 2H, ArH), 7.30-7.10 (m, 5H, ArH), 3.82 (s, 3H, CH 3 ) , 2.52-2.38 (m, 2H), 2.15-1.95 (m, 2H), 1.80-1.57 (m, 4H) ppm; 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 201.73 (+, ketone C O ) , 166.26 (ester C=0), 143.80 (+), 139.92 (+), 132.45 (+), 129.52 (-), 129.11 (-), 128.98 (-), 126.75 (-), 126.03 (-), 63.53 (+), 52.29 (-, CH 3 ) , 37.11 (+), 24.58 (+) ppm; IR (KBr) 3022, 2947, 2865, 1722 (ester C=0), 1672 (ketone C O ) , 1503, 1438, 1407, 1350, 1291, 1238, 1195, 1118, 1016, 958, 888, 866,819, 760, 722, 701,584 cm"1; LRMS (DCI+, NH 3 ) m/z 309 (M ++l), 163, 146, 145 (100), 144, 91; HRMS (DCI+, NH 3 ) m/z 309.1490 (Calcd for C 2 0 H 2 i O 3 , 309.1491); 130 212 Chapter 9. Synthesis of Starting Materials Anal. Calcd for C20H20O3: C, 77.90; H , 6.54. Found: C, 77.53; H , 6.59. 9.5.6 Synthesis of Phenyl 1-Phenylcyclohexyl Ketone (145) O 145 To 783 mg (3.84 mmol) of 1-phenylcyclohexyl carboxylic acid was added 10 mL (137 mmol) of thionyl chloride. The solution was stirred at room temperature for 30 min and then refluxed for another 2 h. After cooling to room temperature, the excess thionyl chloride was removed by applying vacuum to the reaction mixture with a water aspirator. At the final stage of the evaporation, gentle heating was applied. The residue was placed under vacuum to remove the last traces of thionyl chloride. The resulting crude acid chloride was used without further purification. The solution of the above acid chloride in 10 mL of dry THF was cooled to 0-5 °C in an ice-water bath. Then 4.5 mL of 1.0 M phenylmagnesium bromide THF solution (4.5 mmol) was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight. After quenching with water, the aqueous layer was extracted with diethyl ether and the combined organic layer was washed successively with 10% sodium bicarbonate solution, water, brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated and subjected to flash chromatography on silica gel with a 1/20 (v/v) mixture of diethyl ether/petroleum ether as the eluent to afford 828 mg (82 %) of white solid. Recrystallization in methanol gave ketone 145 as colorless plates. 213 Chapter 9. Synthesis of Starting Materials mp 70.5-72 °C; ! H NMR (CDCI3, 200 MHz): 5 7.50-7.10 (m, 10H, ArH), 2.60-2.40 (m, 2H), 1.90-1.15 (m, 8H) ppm; 1 3 C NMR (CDCI3, 50 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 205.02 (+, C=0), 144.11 (+), 138.43 (+), 131.02 (-), 128.99 (-), 128.61 (-), 127.79 (-), 126.89 (-), 126.21 (-), 55.46 (+), 35.95 (+), 25.80 (+), 23.26 (+) ppm; IR(KBr) 2941, 2860, 1665 (C=0), 1597, 1494, 1451, 1299, 1259, 1229, 1181, 1132, 987, 879, 783, 753, 695, 636, 560 cm"1; LRMS (EI) m/z 264 (M + ) , 160, 159 (100), 158, 117, 105, 91; HRMS (EI) m/z 264.1513 (Calcd for C 1 9 H 2 0 O , 264.1514). Anal. Calcd for C i 9 H 2 0 O : C, 86.32; H, 7.63. Found: C, 86.52; H , 7.75. 9.6 Synthesis of the Chiral Salts of Acid 129 (131-134) Chiral salts were prepared by dissolving 1 equivalent of keto acid 129 and 1.07-1.44 equivalents of the corresponding optically pure amine in the warm solvents indicated. The crystals were collected and used for spectroscopic and elemental analyses as well as photochemical studies. 214 Chapter 9. Synthesis of Starting Materials (J?)-(+)-Bornylamme Salt of Keto Acid 129 (131) CO2 0 © N H 3 131 Salt 131 was prepared by dissolving 66.2 mg (0.23 mmol) of keto acid 129 and 36.9 mg (0.24 mmol) of (i?)-(+)-bomylamine in hot methanol. Upon cooling to room temperature, salt 131 was obtained as very thin white needles (83.1 mg, 83 %). mp 191-193 °C; • , ' H N M R (CD 3 OD, 200 MHz) 5 7.72 (d, J= 8.5 Hz, 2H, ArH), 7.54 (d, J = 8.5 Hz, 2H, ArH), 7.30-7.10 (m, 5H, ArH), 3.35 (m, IH, partly hidden under the solvent peak), 2.50-1.95 (m, 5H), 1.90-1.40 (m, 8H), 1.35-1.00 (m, 2H), 0.90 (s, 3H, CH 3 ) , 0.89 (s, 3H, CH 3 ) , 0.87 (s, 3H, CH 3 ) ppm, no N H 3 + signal was observed due to proton exchange with the solvent; , 3 C N M R (CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 203.60 (+, ketone C=0), 174.03 (+, acid C=0), 145.56 (+), 142.44 (+), 138.78 (+), 130.35 (-), 130.04 (-), 129.61 (-), 127.77 (-), 127.16 (-), 64.79 (+), 57.90 (-), 45.81 (-), 38.32 (+), 35.50 (+), 28.54 (+), 27.95 (+), 25.51 (+), 19.84 (-), 18.73 (-), 13.33 (-) ppm, the other two carbon signals were hidden under solvent peak; IR (KBr) 2957, 2182, 1667, 1631, 1582, 1533, 1459, 1377, 1303, 1241, 1135, 1110, 1050, 1031, 1012, 893, 877, 821, 802, 761, 732, 702, 585, 525 cm"1; 215 Chapter 9. Synthesis of Starting Materials L R M S (FAB, +LSIMS, matrix: glycerol) m/z 448 (M + +l), 295, 154 (100), 137; H R M S (FAB, +LSIMS, matrix: glycerol) m/z 448.2851 (M + +l) (Calcd for C 2 9 H 3 8 N O 3 , 448.2852); Anal . Calcd for C z ^ N C ^ / O i z O : C, 77.08; H , 8.31; N , 3.10. Found: C, 76.63; H , 8.33; N , 3.52. (-)-Pseudoephedrine Salt of Keto Acid 129 (132) O, • C O ? H &<. Ph H 2 N © 132 Keto acid 129 ( 4 9 . 5 mg, 0.17 mmol) and 34 .6 mg (0.21 mmol) of (-)-pseudoephedrine were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, thin white needles of salt 132 were formed (30.8 mg, 40 %). mp 144-146 °C; ' H N M R (CD3OD, 200 MHz) 6 7.80-7.70 (m, 2H, ArH), 7.60-7.50 (m, 2H, ArH), 7.40-7.10 (m, 10H, ArH), 4.50 (d, J= 9.2 Hz, IH), 3.30 (m, IH, partly hidden under the solvent peak), 2.68 (s, 3 H , CH 3 ) , 2.55-2.35(m, 2H), 2.20-2.00 (m, 2H), 1.85-1.55 (m, 4 H ) , 1.05 (d, J = 6.6 Hz, 3 H , C H 3 ) ppm, no OH or N H 2 + signal was observed due to proton exchange with the solvent; 216 Chapter 9. Synthesis of Starting Materials 1 3 C NMR (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 203.62 (+, ketone C=0), 174.00 (+, acid C=0), 145.55 (+), 142.02 (+), 141.98 (+), 138.80 (+), 130.35 (-), 130.04 (-), 129.80 (-), 129.72 (-), 129.64 (-), 128.18 (-), 127.77 (-), 127.17 (-), 75.66 (-), 64.80 (+), 61.71 (-), 38.32 (+), 30.49 (-), 25.51 (+), 12.67 (-) ppm; IR (KBr) 3226, 2959, 2873, 2454, 1681, 1592, 1548, 1495, 1471, 1451, 1388, 1236, 1209, 1084, 1051, 1013, 936, 876, 837, 802, 759, 737, 701, 529 cm"1; LRMS (FAB, +LSFMS, matrix: glycerol) m/z 460 (M + +l), 331, 295, 166 (100), 148; HRMS (FAB, +LSIMS, matrix: glycerol) m/z 460.2485 (M + +l) (Calcd for C 2 9 H 3 4 N O 4 , 460.2488); Anal. Calcd for C 2 9 H 3 3 N O 4 : C, 75.79; H , 7.24; N, 3.05. Found: C, 76.23; H , 7.19; N, 3.37. (li?, 2S)-(-)-Norephedrine Salt of Keto Acid 129 (133) Salt 133 was prepared by dissolving 45.9 mg (0.16 mmol) of keto acid 129 and 33.5 mg (0.22 mmol) of (li?, 25)-(-)-norephedrine in a hot mixture of acetonitrile and methanol. After cooling to room temperature, 65.9 mg (95 %) of salt 133 was obtained as a white powder. 133 mp 168-170 °C; 217 Chapter 9. Synthesis of Starting Materials 'H NMR (CD3OD, 200 MHz) 5 7.74 (d, J = 8.8 Hz, 2H, ArH), 7.53 (d, J= 8.8 Hz, 2H, ArH), 7.35-7.10 (m, 10H, ArH), 3.45 (dq, / = 3.6 Hz and J= 6.8 Hz, IH), 2.50-2.30 (m, 2H), 2.15-1.98 (m, 2H), 1.70-1.55 (m, 2H), 1.03 (d, J= 6.8 Hz, 3H, CH 3 ) ppm, another C H peak was hidden underneath the water peak, no OH or NH3 + signal was observed due to proton exchange with the solvent; 1 3 C NMR (CD3OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 203.63 (+, ketone C=0), 174.09 (+, acid C=0), 145.55 (+), 142.07 (+), 141.61 (+), 138.78 (+), 130.34 (-), 130.03 (-), 129.74 (-), 129.61 (-), 129.51 (-), 128.96 (-), 127.76 (-), 127.15 (-), 73.84 (-), 64.79 (+), 53.63 (-), 38.31 (+), 25.50 (+), 12.47 (-) ppm; IR (KBr) 2961, 1673, 1585, 1538, 1449, 1378, 1246, 1099, 1059, 1015, 987, 876, 821, 760, 739, 701,583 cm"1; LRMS (FAB, +LSIMS, matrix: glycerol) m/z 446 (M ++l), 295, 244, 152 (100), 134; HRMS (FAB, +LSIMS, matrix: glycerol) m/z 446.2332 (M + +l) (Calcd for C28H32NO4, 446.2331); Anal. Calcd for C28H31NO4: C, 75.48; H, 7.01; N, 3.14. Found: C, 73.90; H , 7.02; N, 3.81. (S)-(-)-l-Phenyl-Ethylamine Salt of Keto Acid 129 (134) © 134 218 Chapter 9. Synthesis of Starting Materials Keto acid 129 (54.5 mg, 0.19 mmol) and 32.3 mg (0.27 mmol) of (S)-(-)-l-phenyl-ethylamine were dissolved in a hot mixture of acetonitrile and methanol. Upon cooling, crystals of salt 134 were obtained (40.2 mg, 52 %) as colorless thin needles. mp 165-167 °C; *H NMR (CD 3 OD, 200 MHz) 5 7.75-7.65 (m, 2H, ArH), 7.55-7.45 (m, 2H, ArH), 7.45-7.20 (m, 10H, ArH), 4.40 (q, J= 6.8 Hz, IH), 2.55-2.30 (m, 2H), 2.15-1.95 (m, 2H), 1.80-1.50 (m, 7H) ppm, no NH3 + signal was observed due to proton exchange with the solvent; 1 3 C NMR (CDCI3 and CD 3 OD, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 203.60 (+, ketone C=0), 174.03 (+, acid C=0), 145.55(+), 142.05 (+), 140.09 (+), 138.78 (+), 130.35 (-), 130.24 (-), 129.75 (-), 129.61 (-), 127.76 (-), 127.60 (-), 127.16 (-), 64.79 (+), 52.26 (-), 38.31 (+), 25.51 (+), 20.95 (-)ppm; IR (KBr) 2952, 1668, 1581, 1532, 1456, 1387, 1242, 1092, 1032, 1013, 875, 819, 801, 760, 735,700, 591, 510 cm - 1; LRMS (FAB, +LSIMS, matrix: glycerol) m/z 416 (M + +l), 295, 145, 121 (100), 105, 91; HRMS (FAB, +LSIMS, matrix: glycerol) m/z 416.2223 (M + +l) (Calcd for C27H29NO3, 416.2226); Anal. Calcd for C27H 2 9 N0 3 : C, 78.04; H , 7.03; N, 3.37. Found: C, 75.82; H, 6.93; N, 3.91. 9.7 Synthesis of Ketones 162 and 164 219 Chapter 9. Synthesis of Starting Materials O Ph N a H , C H 3 I T H F *" Ph Ph O 165 162 Deoxybenzoin 165 (2.0 g, 10.2 mmol) was dissolved in 10 mL of dry THF and the solution was slowly added to a mixture containing 0.937 g (23.4 mmol) of sodium hydride (60% w/w dispersion in mineral oil) and 2.5 mL (5.7 g, 40 mmol) of iodomethane in 50 mL of dry THF at 0 °C. The reaction system was allowed to warm to room temperature and stirred overnight. After quenching with saturated ammonium chloride solution, the resulting mixture was extracted with diethyl ether, and the organic layer was washed successively with water, brine and dried over magnesium sulfate. Removal of solvent and subsequent flash chromatography with 1/40 (v/v) diethyl ether/petroleum ether as the eluent yielded a colorless oil. Recrystallization from methanol afforded ketone 162 as colorless plates (1.51 g, 66 %). mp 44-45 °C (l i t . 1 3 7 b 45-46 °C); *H NMR (CDCI3, 300 MHz) 5 7.48-7.20 (m, 10H), 1.59 (s, 6H, CH 3 ) ; IR (KBr) 2971, 1673 (C=0), 1596, 1496, 1462, 1445, 1391, 1363, 1251, 1146, 1078, 1028, 975, 800, 764, 708, 634, 570 cm"1 O O M e 166 164 220 Chapter 9. Synthesis of Starting Materials Triphenylmethane 166 (748 mg, 3.07 mmol) was dissolved in 4 mL of diethyl ether and 10 mL of THF. To this solution was slowly added 1.95 mL (3.12 mmol) of n-butyl lithium (1.6 M solution in hexane) at room temperature whereupon a dark red solution was produced. After stirring for 30 min, this solution was added to 422 mg (2.47 mmol) of freshly distilled anisoyl chloride in 10 mL of THF. The reaction mixture was quenched with water following 6.5 h of stirring at room temperature, and the organic layer was washed successively with water and brine and dried over magnesium sulfate. Crude ketone 164 was obtained after radial chormatography on silica gel with 20/1 (v/v) petroleum ether/diethyl ether as the eluent. Recrystallization from a mixture of benzene and methanol afforded colorless plates (210 mg, 22 %). mp 183-185 °C (lit . 1 3 6 1 84-185°C) 'H NMR (CDC1 3, 300 MHz) 5 7.70 (d, J= 9.1 Hz, 2H), 7.27-7.22 (m, 15H), 6.66 (d, J = 9.1 Hz, 2H), 3.77 (s, 3H, CH 3 ) ; IR (KBr) 3032, 1672 ( C O ) , 1597, 1494, 1313, 1268, 1223, 1163, 1031, 838, 812, 742, 703,642, 605 cm"1. 9.8 Independent Synthesis of Ketones 173,174 and 179 f rans-chalcone 173 221 Chapter 9. Synthesis of Starting Materials trans-Chalcone (165 mg, 0.79 mmol) was dissolved in 10 mL of dry THF and the solution was cooled to 0 °C in an ice bath. Then 0.82 mL (0.82 mmol) of phenylmagnesium bromide (1.0 M solution in THF) was slowly added and the mixture was stirred for 1 h. After quenching with 5% ammonium chloride solution, the two layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed successively with 10% sodium carbonate solution, water, brine and dried over magnesium sulfate. Recrystallization of the crude product from methanol afforded ketone 173 as colorless plates (133 mg, 58.7%). mp 92-93°C (lit. 1 4 3 92-94°C); ' H N M R (CDCI3, 200 MHz) 6 7.92 (d, J= 6.9 Hz, 2H, ArH), 7.60-7.35 (m, 3H, ArH), 7.30-7.10 (m, 10H, ArH), 4.82 (t, J= 7.3 Hz, IH, CH), 3.73 (d, J= 7.3 Hz, 2H, CH 2 ) ; , 3 C N M R (CDCI3, 75 MHz) 5 197.97 (C=0), 144.12, 137.01, 133.08, 128.58, 128.55, 128.04, 127.62, 126.36, 45.89, 44.70 ppm; IR (KBr) 3026, 1678 ( C O ) , 1595, 1495, 1448, 1376, 1264, 1214, 1087, 1034, 987, 922, 782, 750, 704, 609, 568, 551 cm"1; Deoxybenzoin 165 (506 mg, 2.58 mmol) was dissolved in 7.5 mL of dry THF and the solution was slowly added to a solution containing 115 mg (2.88 mmol) of sodium hydride O 165 174 222 Chapter 9. Synthesis of Starting Materials (60% w/w dispersion in mineral oil) and 0.3 mL (684 mg, 4.82 mmol) of iodomethane in 7.5 mL of dry THF at 0 °C. The reaction system was allowed to warm to room temperature and then stirred for 4.5 h. After quenching with 5 % ammonium chloride solution, the resulting mixture was extracted with diethyl ether, and the organic layer was washed successively with water, brine and dried over magnesium sulfate. Removal of solvent and subsequent radial chromatography with 15/1 (v/v) petroleum ether/diethyl ether as the eluent yielded a colorless oil. Upon freezing, ketone 174 was obtained as a white solid (358 mg, 66 %). mp 49-49.5 °C (lit . 1 4 4 52-54 °C); IR (neat) 3062, 3027, 2976, 2931, 1684 (C=0), 1598, 1582, 1493, 1449, 1373, 1341, 1252, 1222, 1177, 1072, 1030, 1002, 953, 759, 699, 565, 512 cm"1; ' H N M R (CDC1 3, 400 MHz) 6 7.92-7.90 (m, 2H, ArH), 7.44-7.14 (m, 8H, ArH), 4.64 (q, J= 6.8 Hz, IH, CH), 1.49 (d, J= 6.8 Hz, 3H, CH 3 ) ppm. Diphenylacetic acid (271 mg, 1.28 mmol) was dissolved in 3 mL of thionyl chloride and the solution was stirred at room temperature overnight. After the removal of excess thionyl chloride under reduced pressure, the acid chloride was dissolved in 10 mL of THF and cooled to 0 °C in an ice bath. To this solution was slowly added 1.40 mL (1.40 mmol) of phenylmagnesium bromide (1.0 M solution in THF) and the mixture was stirred overnight. Ph O 179 223 Chapter 9. Synthesis of Starting Materials The reaction was quenched with water and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water, brine and dried over magnesium sulfate. Ketone 179 was obtained as a white solid (244 mg, 70 %) after radial chromatography with 20/1 (v/v) petroleum ether/diethyl ether as the eluent. Recrystallization in methanol gave colorless needles. mp 133-135 °C (lit . 1 4 5 131-132 °C); IR (KBr) 3026, 1680 (C=0), 1595, 1494, 1448, 1357, 1273, 1206, 1077, 1032, 998, 877, 828, 765, 740, 694, 613, 564 cm"1; ! H N M R (CDC1 3, 400 MHz) 5 8.03-8.01 (m, 2H, ArH), 7.53-7.26 (m, 13H, ArH), 6.06 (s, IH, CH) ppm. 224 Chapter 10. Photochemical Studies and Quantum Yields Chapter 10. Photochemical Studies and Quantum Yields 10.1 General Considerations Light Source and Filter A l l irradiations were performed using a 450W Hanovia medium pressure mercury lamp in a water-cooled immersion well. Light from the lamp was filtered through a Pyrex glass sleeve (transmits X > 290 ran). Solution-State Photolyses HPLC-grade or spectral-grade solvents were used for all solution-state photochemical reactions. Solutions were purged with nitrogen or argon for at least 30 minutes before irradiation, and the reactions were performed either in sealed vessels or under a positive pressure of nitrogen or argon. Solid-State Photolyses The ground crystals of the solid material were sandwiched between two Pyrex plates which were Scotch-taped to keep the sample in position. The whole assembly was thermal-sealed in a poly(ethylene) bag under a positive pressure of nitrogen or argon. The samples were placed ca. 10 cm from the lamp and irradiated for the required length of time at the temperature indicated. For some compounds that required low temperature during photolysis, a Cryocool CC-100 II Immersion Cooling System (Neslab Instrument Inc.) was used with 225 Chapter 10. Photochemical Studies and Quantum Yields ethanol as the coolant. Following irradiation, the sample was quantitatively washed from the plates with an appropriate solvent, and concentrated in vacuo. For neutral molecules, the sample was directly analyzed by gas chromatography. The reaction mixtures containing chiral organic salts were first derivatized to their corresponding methyl esters by treatment with excess ethereal diazomethane solution and then subjected to gas chromatography. Microanalysis Microanalysis results were reported only for those photoproducts that were isolated with enough quantities. 10.2 Photochemical Studies of cw-Ketones 43-47 10.2.1 Photolysis of Ketone 43 43 75 79 83 An acetonitrile solution (15 mL) of 160 mg of ketone 43 was purged with nitrogen for 30 minutes and photolyzed for 20 h. After removing the solvent, the residue was subjected to repetitive flash chromatography on silica gel with 50/1 (v/v) petroleum ether/ditheyl ether as the eluent to collect enough material for analysis. 226 Chapter 10. Photochemical Studies and Quantum Yields white solid; mp 53.5-54.5 °C; J H N M R (C 6 D 6 , 400 MHz) 5 7.27-7.10 (m, 5H, H13-17), 2.74-2.65 (m, 2H, H7 and H6), 2.12-2.03 (m, 2H, H2 and H10'), 1.83-1.77 (m, IH, H8), 1.73-1.63 (m, 3H, H4, 4' and 8'), 1.58-1.30 (m, 6H, H3, 3', 5, 5', 10 and 2'), 1.21-1.14 (m, IH, 9'), 1.08 (s, IH, OH), 0.92-0.78 (m, IH, 9) ppm; 1 3 C N M R (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 5 144.89 (+, Ar-C), 128.75 (-, Ar-CH), 127.20 (-, Ar-CH), 126.21 (-, Ar-C), 84.52 (+, C l l ) , 47.81 (-, C7), 47.33 (+, C l ) , 40.63 (-, C6), 31.02 (+, C2), 26.52 (+, C4), 25.51 (+, C10), 22.60 (+, C8), 21.50 (+, C5), 21.23 (+, C3), 14.52 (+, C9) ppm; IR(KBr) 3518 (OH), 3058, 3030, 2932, 2862, 1493, 1477, 1449, 1374, 1338, 1314, 1272, 1216, 1191, 1132, 1071, 1027, 995, 965, 938, 914, 879, 844, 804, 777, 758, 709, 676, 580 cm"1; L R M S (EI) m/z 242 (M + ) , 241, 225, 224, 147, 146, 145, 137, 136, 133, 131, 122, 121, 120, 107, 106, 105, 95, 81 (100), 77, 69, 67, 55, 41; H R M S (EI) m/z 242.1671 (Calcd for C i 7 H 2 2 0 , 242.1671); 227 Chapter 10. Photochemical Studies and Quantum Yields Anal. Calcd for C i 7 H 2 2 0 : C, 84.24; H , 9.16. Found: C, 84.09; H , 9.28. (IS*, 6S*, 9S*, 10R*)-10-Phenyltricyclo[7.1.1.01,6]undecan-10-ol (79) white solid; mp 29.5-31.5 °C; J H NMR (C 6 D 6 , 400 MHz) 5 7.25-7.05 (m, 5H, H13-17), 2.52 (m, IH, H9), 2.24-2.19 (m, 2H, H l l and 2'), 1.96 (m, IH, H6), 1.79 (m, IH, H8), 1.66 (m, IH, H8'), 1.60-1.55 (m, 2H, H4 and 3'), 1.51 (d, J= 8.8 Hz, IH, H l l ' ) , 1.41-1.36 (m, 2H, H5 and 2), 1.25-1.05 (m, 5H, OH, H7' , 5', 4' and 3), 0.82 (m, IH, H7) ppm; , 3 C NMR (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 6 143.33 (+, Ar-C), 128.55 (-, Ar-CH), 127.25 (-, Ar-CH), 82.26 (+, C10), 50.93 (+, C l ) , 41.16 (-, C9), 39.39 (-, C6), 32.73 (+, C5), 31.73 (+, C2), 30.59 (+, C l l ) , 27.03 (+, C8), 26.83 (+, C3), 23.02 (+, C7), 23.01 (+, C4) ppm; IR(CHC1 3) 3594 (OH), 2931,2854, 1448, 1334, 1019, 970,914 cm"1; LRMS (EI) m/z 242 (M + ) , 225, 224, 187, 146, 145, 137, 136, 133, 132, 122, 105 (100), 91,77,55,43; HRMS (EI) m/z 242.1666 (Calcd for C ] 7 H 2 2 0 , 242.1671); Anal. Calcd for C 1 7 H 2 2 0 : C, 84.24; H, 9.16. Found: C, 84.06; H , 8.99. 228 Chapter 10. Photochemical Studies and Quantum Yields Tetracyclo[7.4.4.01,9.02,7]heptadeca-2(3),4,6-trien-8-one (83) 5 83 colorless oil; ' H N M R (CDC1 3, 400 MHz) 5 7.75 (d, J= 7.4 Hz, IH), 7.53 (t, J= 7.6 Hz, IH), 7.40 (d, J= 7.6 Hz, IH), 7.33 (t, J= 7.4 Hz, IH), 1.82-1.74 (m, 2H), 1.69-1.63 (m, 2H), 1.55-1.45 (m, 8H), 1.33-1.23 (m, 4H) ppm; , 3 C N M R (CDCI3, 75 MHz) 5 209.90 (C=0), 161.05, 134.00, 133.74, 126.92, 125.12, 122.02, 54.38, 45.36, 36.01, 30.58, 22.89, 22.27 ppm; IR (CDCI3) 2935, 2861, 1704 (C=0), 1605, 1453, 1288 cm"1; L R M S (EI) m/z 240(M+), 222, 212, 211, 199, 198, 198, 186 (100), 185, 184, 183, 179, 165, 157, 141, 129, 128, 115, 91, 77, 55; H R M S (EI) m/z 240.1515 (Calcd for C i 7 H 2 0 O , 240.1514). Photolysis of ketone 43 (ca. 20 mg) in the solid state at -20°C gave cyclobutanol 79 as the major product. Details can be found in Table 3.1. 229 Chapter 10. Photochemical Studies and Quantum Yields 10.1.2 Photolysis of Ketone 44 A n acetonitrile solution (15 mL) of ketone 44 (200 mg) was degassed with nitrogen for 30 minutes and photolyzed for 22 h. After removing the solvent, the residue was subjected to radial chromatography on silica gel with 40/1 (v/v) hexanes/ethyl acetate as the eluent to collect enough material for analysis. white solid; mp 53.5-55 °C; 230 Chapter 10. Photochemical Studies and Quantum Yields *H N M R (CDCI3, 400 MHz) 5 7.18 (dd, J= 5.5 Hz and J= 8.7 Hz, 2H, ArH), 7.00 (t, J = 8.7 Hz, 2H, ArH), 2.72 (m, IH, H7), 2.49 (m, IH, H6), 2.22 (m, IH, H2), 1.97 (dt, J = 6.1 Hz a n d / = 11.8 Hz, IH, H10'), 1.85-1.35 (m, 11H, H8, 8', 3, 3', 4, 4', 5, 5', 10 and OH), 1.30 (m, IH, H9'), 0.72 (m, IH, 9) ppm; 1 3 C N M R (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 163.85 and 160.60 (+, VC-F = 244 Hz, C15), 140.72 and 140.67 (+, V C . F = 4 Hz, C12), 128.00 and 127.85 (-, 3 Jc- F = 11 Hz, C13 and 17), 115.68 and 115.40 (-, V C - F = 21 Hz, C14 and 16), 83.82 (+, C l l ) , 47.80 (-, C7), 47.23 (+, C l ) , 40.61 (-, C6), 30.82 (+, C2), 26.46 (+, C4), 25.38 (+, CIO), 22.46 (+, C8), 21.47 (+, C5), 21.17 (+, C3), 14.33 (+, C9) ppm; IR(KBr) 3447 (OH), 2937, 2867, 1604, 1509, 1478, 1446, 1409, 1326, 1298, 1219, 1157, 1135, 1096, 1075, 1019, 996, 978, 951, 920, 880, 841, 813, 734, 651, 598, 577, 531, 494, 466 cm"1; L R M S (EI) m/z 260 (M + ), 259, 242, 164, 163, 151, 149, 147, 137, 136, 133, 123, 122, 120, 109, 107, 81(100), 67, 55, 53, 41, 39; H R M S (EI) m/z 260.1576 (Calcd for C17H21OF, 260.1577); Anal. Calcd for C i 7 H 2 , O F : C, 78.41; H , 8.14. Found: C, 78.23; H, 8.25. 231 Chapter 10. Photochemical Studies and Quantum Yields (IS*, 6S*, 9S*, lO^VlO^-FluorophenyOtricycloIT.l.l .O^^undecan-lO-ol (80) white solid; mp 59-61 °C; J H N M R (C 6 D 6 , 400 MHz) 5 6.97 (dd, J= 5.6 Hz and J - 8.7 Hz, 2H, ArH), 6.82 (t, J = 8.7 Hz, 2H, ArH), 2.45 (m, IH, H9), 2.22 (m, IH, H l l ) , 2.15 (dd, J= 1.7 Hz and J= 12.8 Hz, IH, H2'), 1.85 (m, IH, H6), 1.74-1.62 (m, 2H, H8 and 8'), 1.62-1.53 (m, 2H, H4 and 3'), 1.51 (d, J= 8.8 Hz, IH, H l l ' ) , 1.40 (m, IH, H5), 1.30 (dt, J= 3.1 Hz and J= 12.8 Hz, IH, H2), 1.25-1.05 (m, 5H, H5' , 7', 4', 3 and OH), 0.84 (m, IH, 7) ppm; 1 3 C N M R (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 163.75 and 160.51 (+, VC-F = 244 Hz, C15), 139.18 and 139.13 (+, V C - F = 3 Hz, C12), 129.00 and 128.89 (-, 3 J C - F = 8 Hz, C13 and 17), 115.47 and 115.19 (-, 2 J C - F = 21 Hz, C14 and 16), 81.59 (+, C10), 50.80 (+, C l ) , 41.13 (-, C9), 39.37 (-, C6), 32.67 (+, C5), 31.56 (+, C2), 30.61 (+, C l l ) , 26.94 (+, C8), 26.76 (+, C3), 22.90 (+, CT), 22.85 (+, CA) ppm; IR(CHC1 3 ) 3620 (OH), 2975, 2930, 1604, 1449, 1391, 1253, 1047, 878, 839 cm"1; L R M S (EI) m/z 260 (M + ) , 243, 242, 205, 165, 164, 163, 151, 138, 137, 136, 135, 133, 132, 125, 123 (100), 122, 110, 109, 95; H R M S (EI) m/z 260.1577 (Calcd for C i 7 H 2 1 O F , 260.1577); Anal . Calcd for C 1 7 H 2 1 O F : C, 78.41; H , 8.14. Found: C, 78.11; H , 8.39. 232 Chapter 10. Photochemical Studies and Quantum Yields 4-Fluorotetracyclo[7.4.4.01,9.02'7]heptadeca-2(3),4,6-trien-8-one (84) white solid; mp 72-75 °C; ' H N M R (CDCI3, 400 MHz) 5 7.74 (dd,J= 8.1 Hz and 5.3 Hz, IH, ArH), 7.04-6.98 (m, 2H, ArH), 1.82-1.77 (m, 2H), 1.67-1.62 (m, 2H), 1.55-1.42 (m, 8H), 1.33-1.23 (m, 4H) ppm; 1 3 C N M R (CDCI3, 75 MHz) 5 208.09 (C=0), 168.48 and 165.10 ('JC-F = 255 Hz), 164.36 and 164.25 ( 3 / C -F = 9 Hz), 127.44 and 127.32 ( 3 J C - F = 9 Hz), 114.86 and 114.55 ( V C - F = 23 Hz), 114.59 and 114.55 ( 4 J C . F = 3 Hz), 109.65 and 109.35 ( 2 J C -F = 23 Hz), 54.71, 45.50, 35.97, 30.66, 22.81,22.27 ppm; IR(CDC1 3 ) 2936, 2862, 1704 ( C O ) , 1613, 1453, 1245, 1191 cm"1; L R M S (EI) m/z 258 (M + ) , 229, 217, 216, 215, 204 (100), 203, 183, 176, 175, 159, 147, 146, 133, 109; H R M S (EI) m/z 258.1419 (Calcd for C y H ^ F O , 258.1420). Photolysis of ketone 44 (ca. 30 mg) in the solid state at -20°C gave cyclobutanol 76 as the major product. Details can be found in Table 3.1. a The pure form was not obtained. The analysis was based on an 80% pure sample. 233 Chapter 10. Photochemical Studies and Quantum Yields 10.1.3 Photolysis of Ketone 45 45 77 81 85 A n acetonitrile solution (20 mL) of ketone 45 (162 mg) was degassed with nitrogen for 30 minutes and photolyzed for 28 h. After removing the solvent, the residue was subjected to flash chromatography on silica gel with 50/1 (v/v) hexanes/ethyl acetate as the eluent to afford pure ketone 85 and a mixture of cyclobutanols 77 and 81. Attempts to separate compounds 77 and 81 by chromatography were not successful. The pure compounds were finally obtained by fractional crystallization from diethyl ether. (IS*, 6S*, 7R*, HS*)-ll-(4-Cyanophenyl)tricyclo[5.3.1.01'6]undec-ll-ol (77) white solid; 234 Chapter 10. Photochemical Studies and Quantum Yields mpl23-125 °C; *H N M R (C 6 D 6 , 400 MHz) 8 7.06 (d,J= 8.4 Hz, 2H, H14 and 16), 6.76 (d, J= 8.4 Hz, 2H, H13 and 17), 2.55-2.50 (m, 2H, H7 and 6), 2.02-1.85 (m, 2H, H10' and 2), 1.68 (m, IH, H4'), 1.62-1.27 (m, 7H, H8, 8', 3, 3', 4, 5 and 5'), 1.19 (s, IH, OH), 1.18-1.05 (m, 3H, H2' , 9' and 10), 0.55-0.45 (m, IH, 9) ppm; 1 3 C N M R (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 148.91 (+, C15), 132.40 (-, C14 and 16), 126.63 (-, C13 and 17), 118.94 (+, C12), 111.32 (+, CN), 83.77 (+, C l l ) , 47.58 (-, C7), 47.20 (+, C l ) , 40.47 (-, C6), 30.73 (+, C2), 26.30 (+, C4), 25.09 (+, CIO), 22.13 (+, C8), 21.22 (+, C5), 21.04 (+, C3), 14.34 (+, C9) ppm; IR (KBr) 3522 (O-H), 3066, 2911, 2869, 2232 (CN), 1607, 1503, 1477, 1448, 1404, 1367, 1346, 1278, 1218, 1197, 1136, 1111, 1079, 1023, 997, 959, 939, 921, 882, 856, 840, 806, 755 cm"1; L R M S (EI) m/z 267 (M + ) , 249, 171, 170, 158, 137, 135, 131, 130, 122, 107, 103, 102, 95, 93, 91, 81 (100), 79, 77, 69, 67, 55, 43, 41, 39; H R M S (EI) m/z 267.1622 (Calcd for C i 8 H 2 i N O , 267.1623); Anal . Calcd for C i 8 H 2 1 N O : C, 80.85; H, 7.92; N , 5.24. Found: C, 81.00; H , 7.95; N , 5.08. 235 Chapter 10. Photochemical Studies and Quantum Yields (IS*, 6S*, 9S*, lOR^-lO^^CyanophenyOtricyclop.l.l.O^^undec-lO-ol (81) white solid; mp 154-155 °C; *H NMR (C 6 D 6 , 400 MHz) 5 7.08 (d, J= 8.4 Hz, 2H, H14 and 16), 6.84 (d,J= 8.4 Hz, 2H, H13 and 17), 2.36-2.32 (m, IH, H9), 2.16-2.10 (m, IH, H l l ) , 2.08-2.02 (m, IH, H2'), 1.72-1.64 (m, IH, H6), 1.60-1.50 (m, 4H, H8, 8', 4 and 3'), 1.44 (d, J= 8.9 Hz, IH, H l l ' ) , 1.37 (m, IH, H5), 1.23-1.12 (m, 2H, H2 and 5'), 1.12-1.02 (m, 3H, OH, H4' and 3), 1.00-0.90 (m, IH, H7'), 0.78 (m, IH, H7) ppm; 1 3 C NMR (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 147.46 (+, C15), 132.17 (-, C14 and 16), 127.65 (-, C13 and 17), 118.92 (+, C12), 111.44 (+, CN), 81.50 (+, C10), 50.81 (+, C l ) , 40.90 (-, C9), 39.22 (-, C6), 32.49 (+, C5), 31.47 (+, C2), 30.57 (+, C l l ) , 26.71 (+, C8), 26.68 (+, C3), 22.77 (+, C7), 22.69 (+, C4) ppm; IR (KBr) 3486 (OH), 2926, 2849, 2234 (CN), 1608, 1504, 1447, 1406, 1374, 1331, 1288, 1230, 1181, 1137, 1106, 1028, 980, 962, 930, 856, 841, 745, 581, 542 cm"1; LRMS (EI) m/z 267 (M + ) , 250, 249 (100), 212, 172, 171, 170, 158, 137, 135, 133, 131, 130, 122, 117, 109, 102, 93, 81, 67, 55; HRMS (EI) m/z 267.1621 (Calcd for C , 8 H 2 i N O , 267.1623); 236 Chapter 10. Photochemical Studies and Quantum Yields Anal. Calcd for C i 8 H 2 i N O : C, 80.85; H , 7.92; N , 5.24. Found: C, 81.04; H , 7.94; N , 5.20. 4-Cyanotetracyclo[7.4.4.01,9.02,7]heptadeca-2(3),4,6-triene-8-one (85) 5 white solid; mp 125-127 °C; *H N M R (CDC1 3, 400 MHz) 5 7.82 (d, J= 7.6 Hz, IH, ArH), 7.65 (br s, IH, ArH), 7.63 (dd, J = 7.6 Hz and 1.3 Hz, IH, ArH), 1.87-1.80 (m, 2H), 1.67-1.60 (m, 2H), 1.58-1.40 (m, 8H), 1.35-1.20 (m, 4H) ppm; 1 3 C N M R (CDCI3, 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 5 208.01 (+, C=0), 161.07 (+), 137.61 (+), 131.07 (-), 126.18 (-), 125.79 (-), 118.48 (+), 116.76 (+, CN), 54.83 (+), 45.72 (+), 35.89 (+), 30.21 (+), 22.70 (+), 22.16 (+) ppm; IR(CHC1 3 ) 2935,2861,2232 (CN), 1720 (C=0), 1608, 1454, 1316, 1104, 995, 894 cm"1; L R M S (EI) m/z 265(M+), 247, 236, 224, 223, 222, 212, 211 (100), 210, 209, 208, 194, 191, 190, 183, 182, 180, 170, 169, 166, 154, 153, 140, 127, 77, 41, 39; H R M S (EI) m/z 265.1471 (Calcd for C i 8 H ] 9 N O , 265.1467); Anal. Calcd for C , 8 H 1 9 N O : C, 81.46; H, 7.22; N , 5.28. Found: C, 81.51; H , 7.27; N , 5.20. Photolysis of ketone 45 (ca. 30 mg) in the solid state at room temperature gave cyclobutanol 77 as the major product. Details can be found in Table 3.1. 237 Chapter 10. Photochemical Studies and Quantum Yields 10.1.4 Photolysis of Ketone 47 An acetonitrile solution (20 mL) of ketone 47 (145 mg) was degassed with nitrogen for 30 minutes and photolyzed for 23 h. After removing the solvent, the residue was subjected to repetitive flash chromatography on silica gel with 40/1 (v/v) hexanes/ethyl acetate as the eluent to afford pure ketone 86 and enough cyclobutanols 78 and 82 for analysis. (IS*, 6S*, 7R*, HS*)-ll-(4-Carbomethoxyphenyl)tricyclo[5.3.1.01'6]undec-ll-ol (78) white solid; mpl37-138 °C; 238 Chapter 10. Photochemical Studies and Quantum Yields *H NMR (C 6 D 6 , 500 MHz) 5 8.10 (d, J= 8.4 Hz, 2H, H14 and 16), 7.05 (d, J= 8.4 Hz, 2H, H13 and 15), 3.53 (s, 3H, CH 3 ) , 2.66-2.58 (m, 2H, H7 and 6), 2.08-1.96 (m, 2H, H10' and 2), 1.74-1.58 (m, 3H, H4' , 8 and 8'), 1.54-1.30 (m, 5H, H3, 3', 4, 5 and 5'), 1.30-1.10 (m, 4H, H10, 2', OH and 9'), 0.76-0.64 (m, IH, H9) ppm; 1 3 C NMR (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 166.64 (+, ester C=0, C18), 149.46 (+, C15), 130.33 (-, C14 and 16), 129.43 (+, C12), 126.21 (-, C13 and 17), 84.06 (+, C l l ) , 51.62 (-, CH 3 ) , 47.77 (-, C7), 47.33 (+, C l ) , 40.57 (-, C6), 30.87 (+, C2), 26.41 (+, C4), 25.27 (+, C10), 22.35 (+, C8), 21.35 (+, C5), 21.14 (+, C3), 14.49 (+, C9) ppm; IR(KBr) 3483 (OH), 2932, 2866, 1696 (ester C=0), 1608, 1567, 1440, 1404, 1309, 1288, 1195, 1173, 1117, 1081, 1024, 949, 862, 784,718 cm"1; LRMS (EI) m/z 300 (M + ) , 285, 282, 269, 241, 204, 164, 163, 145, 137, 136, 122, 95, 94, 93,81 (100), 79, 67, 59,41; HRMS (EI) m/z 300.1724 (Calcd for C 1 9 H 2 4 0 3 , 300.1726); Anal. Calcd for C i 9 H 2 4 0 3 : C, 75.96; H , 8.06. Found: C, 75.65; H , 8.04. (lS*,6S*,9S*,10R*)-10-(4-Carbomethoxyphenyl)tricyclo[7.1.1.01'6]undec-10-ol (82) 4 5 , 0 o - , 19 8 82 white solid; mp 73.5-75 °C; 239 Chapter 10. Photochemical Studies and Quantum Yields ' H N M R (C 6 D 6 , 500 MHz) 5 8.11 (d, J= 8.4 Hz, 2H, H14 and 16), 7.16 (d, J= 8.4 Hz, 2H, H13 and 17), 3.53 (s, 3H, CH 3 ) , 2.50-2.45 (m, IH, H9), 2.25-2.20 (m, IH, H l l ) , 2.18-2.13 (m, IH, H2'), 1.91-1.84 (m, IH, H6), 1.75-1.60 (m, 2H, H8 and 8'), 1.60-1.52 (m, 2H, H4' and 3'), 1.50 (d, J= 8.8 Hz, IH, H l l ' ) , 1.42-1.30 (m, 3H, H5, OH and 2), 1.25-1.05 (m, 4H, H5' , 4', 7' and 3), 0.87-0.77 (m, IH, H7) ppm; I 3 C N M R (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 5 166.64 (+, ester C=0, C18), 148.00 (+, C15), 130.04 (-, C14 and 16), 129.38 (+, C12), 127.23 (-, C13 and 17), 81.79 (+, CIO), 51.64 (-, CH 3 ) , 50.94 (+, C l ) , 41.08 (-, C9), 39.29 (-, C6), 32.58 (+, C5), 31.59 (+, C2), 30.65 (+, C l l ) , 26.89 (+, C8), 26.72 (+, C3), 22.86 (+, C4 and 6) ppm; IR (CHC13) 3591 (OH), 3013, 2929, 2853, 1718 (ester C=0), 1611, 1438, 1284, 1230, 1214, 1117, 1018, 860, 795, 785, 780, 775, 769, 764, 754, 736, 666, 490, 474, 462 cm"1; L R M S (EI) m/z 300 (M + ) , 285, 282, 269, 245, 241, 191, 164, 163, 159, 145, 137, 133, 122 (100), 107, 95, 93, 91, 81, 80, 79, 77, 76, 69, 67, 59, 55, 53, 43, 41, 39; H R M S (EI) m/z 300.1729 (Calcd for C i 9 H 2 4 0 3 , 300.1726); Anal . Calcd for C i 9 H 2 4 0 3 : C, 75.96; H, 8.06. Found: C, 75.65; H , 8.11. X-ray crystallographic data: space group, P\; a = 8.8083(3) A, b = 17.365(7) A, c = 6.182(2) A; a= 90.99(3) °, /?= 109.53(3) °, y= 79.04(3) °; V= 801.9(5) A 3; Z = 2; radiation, Cu-Ka; R = 0.060. 240 Chapter 10. Photochemical Studies and Quantum Yields 4-Carbomethoxytetracyclo[7.4.4.01,9.02'7]heptadeca-2(3),4,6-triene-8-one (86) 5 86 white solid; mp 89.5-91.5 °C; *H NMR (C 6 D 6 , 400 MHz) 5 8.16 (d, J = 0.5 Hz, IH, ArH), 7.97 (dd, J= 7.8 Hz and 1.3 Hz, IH, ArH), 7.78 (dd, J= 7.8 Hz and 0.5 Hz, IH, ArH), 3.50 (s, 3H, CH 3 ) , 1.70-1.60 (m, 2H), 1.48-1.38 (m, 2H), 1.32-1.10 (m, 10H), 1.08-0.98 (m, 2H) ppm; 1 3 C NMR (C 6 D 6 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 207.47 (+, ketone C O ) , 166.33 (+, ester C O ) , 160.81 (+), 138.34 (+), 135.06 (+), 128.95 (-), 125.27 (-), 123.53 (-), 54.82 (+), 51.85 (-, CH 3 ) , 45.44 (+), 35.85 (+), 30.50 (+), 22.99 (+), 22.35 (+) ppm; IR (KBr) 2932, 2853, 1725 (ester C O ) , 1718 (ketone C O ) , 1613, 1433, 1325, 1281, 1263, 1222, 1185, 1136, 1097, 1076, 1037, 997, 986, 974, 951, 911, 891, 859, 841, 788, 757, 691 cm"1; LRMS (EI) m/z 298(M +, 100), 269, 267, 257, 256, 255, 244, 243, 242, 216, 215, 203, 185, 183, 165, 155, 153, 141, 128, 115; HRMS (EI) m/z 298.1569 (Calcd for C i 9 H 2 2 0 3 , 298.1569); Anal. Calcd for C 1 9 H 2 2 0 3 : C, 76.47; H , 7.44. Found: C, 76.38; H , 7.46; 241 Chapter 10. Photochemical Studies and Quantum Yields X-ray crystallographic data: space group, P2\\ a = 11.209(1) A , b = 10.149(1) A , c = 7.5641(8) A ; a= 90 °, /?= 70.368(9) °, y = 90 °; V= 810.5(2) A 3 ; Z = 2; radiation, Cu-Koc; R = 0.041. Photolysis of ketone 47 (ca. 80 mg) in the solid state at -20 °C gave cyclobutanol 78 and cyclopropanol 87. Details can be found in Table 3.1. ll-(4-Carbomethoxyphenyl)tricyclo[4.4.1.01,6]undec-ll-ol (87) mp 116.5-118 °C; ! H NMR (C 6 D 6 , 400 MHz) 5 8.15 (d, J = 8.4 Hz, 2H, ArH), 7.15 (d, J = 8.4 Hz, 2H, ArH), 3.55 (s, 3H, CH 3 ) , 2.12-1.95 (m, 2H), 1.70-1.48 (m, 4H), 1.48-1.28 (m, 4H), 1.25-1.10 (m, 4H), 1.10-0.80 (m, 3H) ppm; 1 3 C NMR (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 166.63 (+, ester C=0), 145.77 (+), 130.99 (-), 130.24 (-), 129.59 (+), 65.34 (+), 51.60 (-, CH 3 ) , 30.08 (+), 27.25 (+), 23.50 (+), 20.05 (+), 19.71 (+) ppm; IR (KBr) 3489 (OH), 2926, 2866, 1708 (ester C=0), 1611, 1461, 1438, 1401, 1284, 1189, 1134, 1119, 1102, 1071, 1018, 962, 863, 831, 780, 753, 715, 563, 531 cm"1; 87 white solid; 242 Chapter 10. Photochemical Studies and Quantum Yields LRMS (EI) m/z 300(M+), 298, 285, 269, 257, 244, 243, 242, 241 (100), 225, 223, 199, 164, 163, 137, 136, 135; HRMS (EI) m/z 300.1725 (Calcd for C 1 9 H 2 4 O 3 , 300.1722); Anal. Calcd for C 1 9 H 2 4 O 3 : C, 75.96; H, 8.06. Found: C, 76.16; H , 7.94. 10.3 Photochemical Studies of fra«s-Ketones 50-54 10.3.1 Photolysis of Ketone 50 H 50 94 98 Ketone 50 (107 mg) was dissolved in 10 mL of a 4/1 (v/v) mixture of tert-butanol and benzene, and the solution was purged with nitrogen for 30 minutes prior to photolysis for 57 h. After removing the solvent, the residue was filtered through a short silica gel column and subjected to a radial chromatography on silica gel with 20/1 (v/v) petroleum ether/diethyl ether as the eluent to isolate cyclobutanol 94 and ketone 98. 243 Chapter 10. Photochemical Studies and Quantum Yields colorless oil; *H N M R (CD 2C1 2 , 500 MHz) 5 7.36-7.32 (m, 2H, H14 and 16), 7.30-7.24 (m, 3H, H13, 15 and 17), 2.42 (m, IH, H7), 2.26 (m, IH, H2), 2.12-2.02 (m, IH, H5), 2.00-1.80 (m, 5H, H8', 10, 5', 8 and 3), 1.74-1.62 (m, 2H, H4 and 10'), 1.57 (m, 2H, H3' and OH), 1.50 (dd, J = 11.0 and 8.2 Hz, IH, H6), 1.33-1.20 (m, 2H, H9' and 2'), 1.13 (tq, J= 13.2 and 3.5 Hz, IH, H4'), 0.68 (m, IH, H9) ppm; 1 3 C N M R (CD2CI2, 100 MHz, DEPT: C: nil; C H 2 : -; C H , C H 3 : +) 5 145.76 (nil, C12), 128.65 (+, C14 and 16), 127.00 (+, C15), 124.82 (+, C13 and 17), 83.76 (nil, C l l ) , 46.20 (+, C6 and 7), 43.94 (nil, C l ) , 40.12 (-, C10), 31.46 (-, C2), 29.81 (-, C8), 28.12 (-, C5), 23.87 (-, C4), 23.62 (-, C3), 14.89 (-, C9) ppm; IR (CHCI3) 3590 (OH), 2929, 2866, 1602, 1494, 1450, 1328, 1286, 1233, 1197, 1101, 1081,1016,996,827 cm"1; L R M S (EI) m/z 242 (M + ) , 224, 146, 136, 122, 105 (100), 95, 81, 77, 67, 55, 51, 41; H R M S (EI) m/z 242.1665 (Calcd for C i 7 H 2 2 0 , 242.1671); Anal . Calcd for C7H22O: C, 84.24; H , 9.16. Found: C, 84.46; H , 8.99. 244 Chapter 10. Photochemical Studies and Quantum Yields (IS*, 9R*)-Tetracyclo[7.5.3.0110.03'8]heptadeca-3(4),5,7-trien-2-one (98) 4 5 13 11 9 17 6 12 10 98 colorless oil; J H N M R (CD 2C1 2 , 500 MHz) 8 7.96 (dd, J= 7.6 and 1.4 Hz, IH, H7), 7.46 (dt, J= 1.4 and 7.6 Hz, IH, H6), 7.31 (dt, J= 7.6 and 1.2 Hz, IH, H5), 7.23 (d,J= 7.6 Hz, H4), 2.90 (m, IH, H9), 2.10-2.05 (m, 2H, H15' and 10), 2.05-1.85 (m, 3H, H17', 14 and 11'), 1.78 (m, IH, H12), 1.63 (m, IH, H13'), 1.58-1.35 (m, 4H, H13, 11, 16' and 17), 1.35-1.05 (m, 4H, H14', 12', 15 and 16) ppm; 1 3 C N M R (CD2CI2, 100 MHz, DEPT: C: nil; C H 2 : -; C H , C H 3 : +) 8 204.88 (nil, C2), 149.06 (nil, C3), 134.27 (nil, C8), 133.62 (+, C6), 128.18 (+, C4), 126.76 (+, C5), 126.61 (+, C7), 45.90 (nil, C l ) , 43.34 (+, C10), 41.36 (+, C9), 33.08 (-, C14), 27.72 (-, C15), 26.62 (-, C l l ) , 26.44 (-, C12), 24.72 (-, C17), 22.15 (-, C13), 18.56 (-, C16) ppm; IR (CHCI3) 2934, 2863, 1674 (C=0), 1599, 1453, 1264, 1265, 1155, 1016, 954 cm"1; L R M S (EI) m/z 240 ( M + , 100), 222, 211, 198, 194, 179, 165, 115, 91, 77, 39; H R M S (EI) m/z 240.1519 (Calcd for C i 7 H 2 0 O , 240.1514); Crystals of ketone 50 (ca. 30mg) were photolyzed at room temperature for 50 h., and cyclobutanol 94 was obtained as the sole product. Details can be found in Table 5.1. 245 Chapter 10. Photochemical Studies and Quantum Yields 10.1.2 Photolysis of Ketone 51 Ketone 51 (102 mg) was dissolved in 10 mL of a 4/1 (v/v) mixture of tert-butanol and benzene, and the solution was purged with nitrogen for 30 minutes prior to photolysis for 57.5 h. After removing the solvent, the residue was filtered through a short silica gel column and subjected to a radial chromatography on silica gel with 50/1 (v/v) petroleum ether/diethyl ether as the eluent to isolate cyclobutanol 95 and ketone 99. 246 Chapter 10. Photochemical Studies and Quantum Yields colorless oil; J H NMR (CD 2C1 2 , 500 MHz) 8 7.29-7.25 (m, 2H, HI3 and 17), 7.06-7.01 (m, 2H, H14 and 16), 2.40 (m, IH, H7), 2.22 (m, IH, H2), 2.10-2.00 (m, IH, H5), 1.98-1.76 (m, 5H, H5' , 10, 8', 8 and 3), 1.74-1.64 (m, 2H, H4 and 10'), 1.60-1.48 (m, 3H, H3 ' , OH and H6), 1.36-1.08 (m, 3H, H9' , 4' and 2'), 0.69 (m, IH, H9) ppm; 1 3 C NMR (CD2CI2, 100 MHz, DEPT: C: nil; C H 2 : -; C H , C H 3 : +) 8 163.30 and 160.86 (nil, 'JC-F = 243 Hz, C15), 142.41 and 142.38 (nil, V C - F = 3 Hz, C12), 127.15 and 127.07 (+, VC-F = 8 Hz, C13 and 17), 115.76 and 115.55 (+, 2 J C -F = 20 Hz, C14 and 16), 83.42 (nil, C l l ) , 46.68 (+, C7), 46.57 (+, C6), 44.24 (nil, C l ) , 40.39 (-, C10), 31.68 (-, C2), 30.11 (-, C8), 28.51 (-, C5), 24.24 (-, C4), 23.98 (-, C3), 15.14 (-, C9) ppm; IR (CDCI3) 3590 (OH), 2930, 2867, 1603, 1511, 1450, 1330, 1228, 1157, 1083, 1016, 996, 840, 827 cm"1; LRMS (EI) m/z 260 (M + ) , 242, 164, 151, 137, 136, 123 (100), 122, 109, 95, 81, 67, 55, 51,41; HRMS (EI) m/z 260.1568 (Calcd for C i 7 H 2 , F O , 260.1577); Anal. Calcd for C 1 7 H 2 1 F O : C, 78.41; H , 8.14. Found: C, 78.32; H , 8.14. (IS*, 9R*)-6-Fluorotetracyclo[7.5.3.01,10.03'8]heptadeca-3(4),5,7-trien-2-one (99) 4 5 247 Chapter 10. Photochemical Studies and Quantum Yields white solid; mp 84-85.5 °C; *H N M R ( C D C I 3 , 500 MHz) 5 8.02 (dd, J= 8.6 and 6.0 Hz, IH, H4), 6.96 (dt, J = 2.6 and 8.6 Hz, IH, H5), 6.85 (dd, J= 2.6 and 9.0 Hz, IH, H7), 2.84 (m, IH, H9), 2.10-2.03 (m, 2H, H15' and 10), 2.02-1.92 (m, 2H, H17' and 14), 1.85 (dq, J= 13.0 and 3.8 Hz, IH, H l l ' ) , 1.77 (m, 1H,H12), 1.62 (m, 1H,H13'), 1.53-1.38 (m, 4H, H13, 11, 16' and 17), 1.36-1.08 (m, 4H, H14', 12', 15 and 16) ppm; 1 3 C N M R ( C D C I 3 , 125 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 203.44 (+, C2), 166.77 and 164.74 (+, VC-F = 255 Hz, C6), 151.56 and 151.49 (+, 3 J C - F = 9 Hz, C8), 130.52 and 130.50 (+, VC-F = 3 Hz, C3), 129.71 and 129.63 (-, 3 J C -F = 10 Hz, C4), 114.09 and 113.92 (-, 2 J C - F = 21 Hz, C5), 114.06 and 113.89 (-, 2 J C -F = 21 Hz, C7), 45.41 (+, C l ) , 42.80 (-, CIO), 41.17 (-, C9), 32.51 (+, C14), 27.11 (+, C15), 26.17 (+, C l l ) , 25.92 (+, C12), 24.20 (+, C17), 21.67 (+, C13), 18.09 (+, C16) ppm; IR (CHCI3 ) 2936, 2864, 1675 ( C O ) , 1606, 1587, 1485, 1446, 1320, 1282, 1248, 1186, 1131, 1022, 964, 856 cm"1; L R M S (EI) m/z 258 ( M + , 100), 240, 229, 212, 197, 183, 175, 159, 146, 133, 123, 109, 91, 79, 67,55,41; H R M S (EI) m/z 258.1411 (Calcd for C17H19FO, 258.1420); Anal. Calcd for C i 7 H 1 9 F O : C, 79.03; H , 7.42. Found: C, 79.00; H , 7.50. Crystals of ketone 51 (ca. 30 mg) were photolyzed at room temperature for 44.5 h., and cyclobutanol 95 was obtained as the major product. Details can be found in Table 5.1. 248 Chapter 10. Photochemical Studies and Quantum Yields 10.1.3 Photolysis of Ketone 52 CN Ketone 52 (136 mg) was dissolved in 10 mL of a 4/1 (v/v) mixture of tert-butanol and benzene, and the solution was purged with nitrogen for 30 minutes prior to photolysis for 71 h. After removing the solvent, the residue was filtered through a short silica gel column and subjected to radial chromatography on silica gel with 20/1 (v/v) petroleum ether/diethyl ether as the eluent to isolate cyclobutanol 96 and nitrile 100. (IS*, 6S*, 7R*, HS*)-ll-(4-Cyanophenyl)tricyclo[5.3.1.01'6]undec-ll-ol (96) white solid; 249 Chapter 10. Photochemical Studies and Quantum Yields mp 174-176 °C; *H N M R (CDCh, 500 MHz) 8 7.61 (d, J= 8.2 Hz, 2H, H14 and 16), 7.36 (d, J= 8.2 Hz, 2H, H13 and 17), 2.43 (m, IH, H7), 2.18 (m, IH, H2), 2.05-1.92 (m, 2H, H5 and 5'), 1.92-- 1.80 (m, 3H, H10, 8' and 8), 1.80-1.65 (m, 3H, H3, 4 and 10'), 1.65-1.55 (m, 3H, H3' , OH andH6), 1.35-1.20 (m, 2H, H9' and 2'), 1.10 (m, IH, H4'), 0.60 (m, IH, H9) ppm; 1 3 C N M R ( C D C I 3 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 150.21 (+, C15), 132.62 (-, C14 and 16), 125.65 (-, C13 and 17), 118.80 (+, C12), 110.73 (+, CN), 83.16 (+, C l l ) , 46.04 (-, C7), 45.97 (-, C6), 43.81 (+, C l ) , 39.70 (+, CIO), 31.12 (+, C2), 29.43 (+, C8), 28.09 (+, C5), 23.60 (+, C4), 23.50 (+, C3), 14.77 (+, C9) ppm; IR ( C H C I 3 ) 3586 (OH), 2933, 2868, 2231 (CN), 1607, 1504, 1451, 1403, 1325, 1268, 1197,1018,999,844 cm"1; L R M S (EI) m/z 267 (M + ) , 249, 171 (100), 158, 137, 130, 122, 102, 95, 81, 67, 55, 41, 28; H R M S (EI) m/z 267.1620 (Calcd for C i 8 H 2 i N O , 267.1623); Anal . Calcd for C i 8 H 2 i N O : C, 80.85; H, 7.92; N , 5.24. Found: C, 81.06; H , 7.87; N , 5.10. (IS*, 2R*, 8R*)-2-(4-Cyanophenyl)-rra/is-decalin (100) 100 pale yellow oil; 250 Chapter 10. Photochemical Studies and Quantum Yields ' H N M R (CDCI3, 500 MHz) 5 7.54 (d, J= 8.3 Hz, 2H, H13 and 15), 7.22 (d,J= 8.3 Hz, 2H, H12 and 16), 2.24-2.19 (m, IH, H2), 1.81-1.73 (m, 2H, H4 and 3'), 1.68-1.55 (m, 4H, H 5 \ 7, 8 and 9'), 1.46-1.38 (m, 2H, H3 and 4'), 1.27-0.95 (m, 7H, H7, 10, 1, 6, 5, 9 and 8), 0.76-0.67 (m, IH, H10') ppm; 1 3 C N M R (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 150.27 (+, C14), 132.18 (-, C13 and 15), 128.43 (-, C12 and 16), 119.23 (+, C l l ) , 109.50 (+, CN), 51.35 (-, C2), 47.69 (-, C l ) , 43.06 (-, C6), 35.45 (+, C3), 34.22 (+, C5), 33.99 (+, C8), 31.13 (+, CIO), 26.51 (+, C7 and 9), 26.28 (+, C4) ppm; IR(CDC1 3 ) 2926, 2854, 2228 (CN), 1606, 1504, 1447, 1417, 1178, 835, 821 cm"1; L R M S (DCI+) m/z 240 (M ++l), 239 (100), 129, 116, 95, 81; H R M S (DCI+) m/z 239.1677 (Calcd for C , 7 H 2 i N , 239.1674); Anal. Calcd for C 1 7 H 2 i N : C, 85.31; H, 8.84; N , 5.85. Found: C, 84.76; H , 8.87; N , 5.74. Crystals of ketone 52 (ca. 30 mg) were photolyzed at room temperature for 44.5 h., and cyclobutanol 96 was obtained as the only product. Details can be found in Table 5.1. 251 Chapter 10. Photochemical Studies and Quantum Yields 10.1.4 Photolysis of Ketone 54 C 0 2 M e Ketone 54 (103 mg) was dissolved in 10 mL of a 4/1 (v/v) mixture of tert-butanol and benzene, and the solution was purged with nitrogen for 30 minutes prior to photolysis for 76 h. After removing the solvent, the residue was filtered through a short silica gel column and subjected to radial chromatography on silica gel with 20/1 (v/v) petroleum ether/diethyl ether as the eluent to isolate cyclobutanol 97 and methyl ester 101. (IS*, 6S*, 7R*, llS^-ll^-CarbomethoxyphenyOtricycloISJ.l.O'^undec-ll-ol (97) O white solid; 252 Chapter 10. Photochemical Studies and Quantum Yields mp 118-119.5 °C; ' H N M R (CD 2C1 2 , 500 MHz) 8 7.98 (d, J= 8.4 Hz, 2H, HI4 and 16), 7.36 (d, J= 8.4 Hz, 2H, H13 and 17), 3.88 (s, 3H, CH 3 ) , 2.44 (m, IH, H7), 2.26 (m, IH, H2), 2.12-1.76 (m, 6H, H5, 5', 8, 8', 10 and 3), 1.76-1.64 (m, 2H, H4 and 10'), 1.64-1.48 (m, 3H, H 3 \ OH and H6), 1.36-1.08 (m, 3H, H9' , 2' and 4'), 0.65 (m, IH, H9) ppm; , 3 C N M R (CD 2C1 2 , 75 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 8 167.10 (+, C=0), 150.78 (+, C15), 130.25 (-, C14 and 16), 129.12 (+, C12), 125.29 (-, C13 and 17), 83.56 (+, C l l ) , 52.28 (-, CH 3 ) , 46.61 (-, C7), 46.57 (-, C6), 44.23 (+, C l ) , 40.21 (+, CIO), 31.62 (+, C2), 29.96 (+, C8), 28.55 (+, C5), 24.17 (+, C4), 23.97 (+, C3), 15.23 (+, C3) ppm; IR (KBr) 3435 (OH), 2922, 1707 (C=0), 1612, 1442, 1408, 1365, 1283, 1196, 1110, 1022, 999, 949, 929, 863, 825, 780, 714, 574 cm"1; L R M S (EI) m/z 300 (M + ) , 285, 282, 241, 204, 191, 164, 163, 145, 137, 136, 122 (100), 107, 95,81,67, 55,41,28; H R M S (EI) m/z 300.1731 (Calcd for C i 9 H 2 4 0 3 , 300.1726); Anal. Calcd for C i 9 H 2 4 0 3 : C, 75.96; H , 8.06. Found: C, 75.94; H , 8.14. 253 Chapter 10. Photochemical Studies and Quantum Yields (IS*, 2R*, 8R*)-(4-Carbomethoxyphenyl)-^a«s-decalin (101) 101 white solid; mp 86-88 °C; ' H N M R (CDCI3, 400 MHz) 5 7.92 (d, J= 8.4 Hz, 2H, H13 and 15), 7.23 (d, J= 8.4 Hz, 2H, H12 and 16), 3.89 (s, 3H, CH 3 ) , 2.32-2.23 (m, IH, H2), 1.85-1.75 (m, 2H, H4 and 3'), 1.72-1.42 (m, 6H, H5' , 7, 8, 9', H3 and 4'), 1.32-1.00 (m, 7H, H7, 10, 1, 6, 5, 9 and 8), 0.82-0.70 (m, lH,H10' )ppm; 1 3 C N M R (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 167.20 (+, C=0), 152.16 (+, C14), 129.60 (-, C13 and 15), 127.72 (-, C12 and 16), 51.92 (-, C2), 51.21 (-, CH 3 ) , 47.81 (-, C l ) , 43.15 (-, C6), 35.51 (+, C3), 34.30 (+, C5), 34.11 (+, C8), 31.15 (+, CIO), 26.59 (+, C7 and 9), 26.39 (+, C4) ppm; IR(CHC1 3 ) 2926, 2853, 1715 (C=0), 1608, 1442, 1286, 1180, 1115, 983 cm"1; L R M S (EI) m/z 272 ( M + , 100), 240, 191, 177, 162, 150, 131, 115, 103,95,81; H R M S (DCI+) m/z 272.1778 (Calcd for C i 8 H 2 4 0 2 , 272.1776); Anal. Calcd for C , 8 H 2 4 0 2 : C, 79.37; H , 8.88. Found: C, 79.42; H , 8.72. 254 Chapter 10. Photochemical Studies and Quantum Yields 10.4 Photochemical Studies of Ketones 126,128,130 and 145 10.4.1 Photolysis of Ketone 126 e x o - P h endo-Ph 136 139 An acetonitrile solution (6 mL) of ketone 126 (115 mg) was purged with argon for 30 minutes and irradiated for 15 h. The reaction mixture was subjected to radial chromatography on silica gel with 100/1 (v/v) petroleum ether/diethyl ether as the eluent. Compound 135 was separated as a white powder. 1,1 '-Diphenyl-1,1 '-bicyclopentyl (135) 135 white solid; 255 Chapter 10. Photochemical Studies and Quantum Yields mp 140.5-141.5 °C (lit . 1 4 6 140.5-141.5 °C, l i t . 1 4 7 137 °C); ' H N M R (C 6 D 6 , 200 MHz) 5 7.10-7.00 (m, 6H, ArH), 6.95-6.80 (m, 4H, ArH), 2.22-2.05 (m, 4H), 1.80-1.60 (m, 4H), 1.60-1.15 (m, 8H) ppm; 1 3 C N M R (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 144.21 (+), 128.77 (-), 127.25 (-), 125.80 (-), 58.07 (+), 33.96 (+), 22.60 (+) ppm; IR (KBr) 3022, 2960, 2869, 1597, 1496, 1456, 1441, 1323, 1300, 1232, 1188, 1127, 1034, 965, 929, 735, 705, 673, 526, 500 cm"1; L R M S (DCI+) m/z 290 (M + ) , 213, 145 (100), 144; H R M S (DCI+) m/z 290.2029 (Calcd for C 2 2H 2 6 , 290.2035); Anal . Calcd for C 2 2 H 2 6 : C, 90.98; H, 9.02. Found: C, 90.93; H , 8.98. Crystals of ketone 126 (ca. 50 mg) were photolyzed at low temperature (-20 °C or -30 °C) to various conversions. The results are listed in Table 7.2. The reaction mixture was subjected to radial choramtography on silica gel with 15/1 (v/v) petroleum ether/diethyl ether as the eluent, and oxetanes 136 and 139 were obtained. (lS*,5S*,7S*)-6-Oxa-l,7-diphenylbicydo[3.2.0]heptane (136) 17 3 136 256 Chapter 10. Photochemical Studies and Quantum Yields colorless oil; ] H N M R (C 6 D 6 , 400 MHz) 5 7.14 (m, 2H, H15&19), 6.99 (m, 2H, H16&18), 6.92-6.64 (m, 3H, H10, 12&17), 6.64-6.58 (m, 3H, H9, 13&11), 5.43 (d, J= 3.0 Hz, IH, H5), 5.40 (s, IH, H7), 2.37 (m, IH, H3'), 2.20-2.08 (m, 2H, H2'&4') , 1.83 (dt, 7 = 6.6 and 12.5 Hz, IH, H3), 1.51 (dt, J= 6.6 and 12.5 Hz, IH, H2), 1.29 (m, IH, H4) ppm; 1 3 C N M R (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 141.90 (+, C8 or C14), 141.51 (+, C8 orC14), 127.95 (-, C10&12), 127.87 (-, C16&18), 127.26 (-, C9&13), 127.19 (-, C17), 126.65 (-, C15&19), 125.98 (-, C l l ) , 90.05 (-, C7), 88.12 (-, C5), 59.12 (+, C l ) , 39.42 (+, C2), 35.09 (+, C4), 25.03 (+, C3) ppm; IR (neat) 3030, 2944, 1602, 1496, 1449, 1302, 1213, 1155, 1086, 1034, 995, 956, 928, 880, 851, 753, 698, 583, 548 cm"1; L R M S (EI) m/z 250 (M + ) , 145, 144(100), 143, 129, 115, 105,91,77, 66; H R M S (EI) m/z 250.1361 (Calcd for CigHigO, 250.1358); Anal . Calcd for C 1 8 H 1 8 0 : C, 86.36; H , 7.25. Found: C, 86.10; H , 7.20. (lS*,5S*,7R*)-6-Oxa-l,7-diphenylbicyclo[3.2.0]heptane (139) 17 3 139 colorless oil; 257 Chapter 10. Photochemical Studies and Quantum Yields *H N M R (C 6 D 6 , 400 MHz) 8 7.40-7.05 (m, 10H, ArH), 5.99 (s, IH, H7), 5.38 (d,J= 3.5 Hz, IH, H5), 2.10-1.94 (m, 2H, H4'&3'), 1.88 (dd, J= 7.7 and 13.2 Hz, IH, H2'), 1.52-1.34 (m, 2H, H3&2), 1.22 (m, IH, H4) ppm; 1 3 C N M R (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 8 145.94 (+), 139.97 (+), 128.91 (-), 128.35 (-), 127.19 (-), 126.50 (-), 126.37 (-), 125.16 (-), 89.64 (-, C5), 87.78 (-, C7), 58.48 (+, C l ) , 34.45 (+, C4), 34.38 (+, C2), 25.84 (+, C3) ppm; IR (neat) 3027, 2948, 1602, 1495, 1447, 1305, 1212, 1158, 1070, 1031, 1001, 929, 893, 847, 760, 700, 644, 617, 558, 525 cm"1; L R M S (CI+, NH 3 ) m/z 250 (M + ) , 145, 144(100), 143, 129, 128, 115, 105,91,72; H R M S (CI+, NH 3 ) m/z 250.1356 (Calcd for C 1 8 H 1 8 0 , 250.1358); Anal . Calcd for C , 8 H , 8 0 : C, 86.36; H , 7.25. Found: C, 86.81; H , 7.10. 10.1.2 Photolysis of Ketone 128 CHoCN A r hv 135 128 r - P h + exo-Ar endo-Ar 137 140 258 Chapter 10. Photochemical Studies and Quantum Yields An acetonitrile solution (5 mL) of ketone 128 (50 mg) was purged with argon for 30 minutes and irradiated for 5.5 h. The reaction mixture was subjected to radial chromatography on silica gel with 100/1 (v/v) petroleum ether/diethyl ether as the eluent. Compound 135 was separated as a white powder. The analytical data are listed in the previous section. Crystals of ketone 128 (ca. 50 mg) were photolyzed at room temperature for 46 h. The results are listed in Table 7.2. The reaction mixture was subjected to radial choramtography on silica gel with 15/1 (v/v) petroleum ether/diethyl ether as the eluent and oxetanes 137 and 140 were obtained. (lS*,5S*,6S*)-6-(4-Cyanophenyl)-7-oxa-5-phenylbicyclo[3.2.0]heptane (137) C N 137 white solid; mp: 67-68.5 °C *H N M R (C 6 D 6 , 400 MHz) 5 7.30-6.60 (m, 9H, ArH), 5.23 (d, J= 3.4 Hz, IH, HI), 5.11 (s, IH, H6), 2.26 (m, IH, H3'), 2.02 (m, 2H, H2'&4') , 1.79 (dt, J= 6.8 and 12.4 Hz, IH, H3), 1.45 (dt, 7= 6.8 and 12.8 Hz, IH, H4), 1.21 (m, IH, H2) ppm; 259 Chapter 10. Photochemical Studies and Quantum Yields 1 3 C NMR (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 145.55 (+, C14), 140.20 (+, C8), 131.32 (-, C16&18), 128.09 (-, C10&12), 127.10 (-, C9&13), 126.69 (-, C15&19), 126.54 (-, C l l ) , 119.09 (+, C17), 111.78 (+, CN), 90.05 (-, C6), 89.61 (-, C l ) , 61.40 (+, C5), 41.54 (+, C4), 37.89 (+, C2), 28.25 (+, C3) ppm; IR (KBr) 2953, 2224 (CN), 1607, 1499, 1448, 1412, 1274, 1088, 1004, 927, 845, 807, 765,701,564 cm - 1; LRMS (EI) m/z 275 (M + ) , 145, 144(100), 143, 129, 128, 115, 102, 91, 77, 66; HRMS (EI) m/z 275.1303 (Calcd for C i 9 H 1 7 N O , 275.1310); Anal. Calcd for C 1 9 H i 7 N O : C, 82.88; H, 6.22; N , 5.09. Found: C, 83.02; H, 6.10; N , 5.00. (lS*,5S*,6R*)-6-(4-Cyanophenyl)-7-oxa-5-phenylbicyclo[3.2.0]heptane (140) C N 140 colorless oil; lH NMR (C 6 D 6 , 400 MHz) 8 7.30-6.95 (m, 9H, ArH), 5.68 (s, IH, H6), 5.27 (d, J= 3.4 Hz, IH, HI), 1.88 (dd, J= 6.3 and 13.9 Hz, IH, H2'), 1.67 (m, IH, H3'), 1.53 (dd, ./ = 6.9 and 13.4 Hz, IH, H4'), 1.45-1.25 (m, 2H, H3&4), 1.12 (m, IH, H2) ppm; 260 Chapter 10. Photochemical Studies and Quantum Yields 1 3 C N M R (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 144.44 (+), 143.97 (+), 131.76 (-), 128.98 (-), 126.89 (-), 126.28 (-), 125.56 (-), 119.17 (+), 112.03 (+, CN), 91.22 (-, C l ) , 88.37 (-, C6), 60.78 (+, C5), 37.30 (+, C2), 37.14 (+, C4), 28.98 (+, C3) ppm; IR(neat) 2953, 2228 (CN), 1609, 1497, 1446, 1008, 928, 795, 760, 701, 567 cm"1; L R M S (CI+,NH 3) m/z 275 (M + ) , 145, 144(100), 143, 129, 128, 115, 91, 77, 66, 51; H R M S (CI+, NH 3 ) m/z 275.1306 (Calcd for C , 9 H 1 7 N O , 275.1310); Anal . Calcd for C i 9 H , 7 N O : C, 82.88; H , 6.22; N , 5.09. Found: C, 83.17; H , 6.05; N , 5.21. 10.1.3 Photolysis of Ketone 130 138 141 An acetonitrile solution (5 mL) of ketone 130 (30 mg) was purged with argon for 30 minutes and irradiated for 3 h. The reaction mixture was subjected to radial chromatography on silica gel with 100/1 (v/v) petroleum ether/diethyl ether as the eluent. Compound 135 was separated as a white powder. The analytical data are listed in section 10.4.1. 261 Chapter 10. Photochemical Studies and Quantum Yields Crystals of ketone 130 were photolyzed at room temperature to various conversions. The results are listed in Table 7.2. The reaction mixture was subjected to radial chroamtography on silica gel with 15/1 (v/v) petroleum ether/diethyl ether as the eluent and oxetanes 138 and 141 were obtained. (lS*,5S*,6S*)-6-(4-Carbomethoxyphenyl)-7-oxa-5-phenylbicyclo[3.2.0]heptane (138) 3 138 white solid; mp: 89-91 °C ' H N M R (C 6 D 6 , 400 MHz) 5 7.97 (d, J = 8.3 Hz, 2H, ArH), 7.09 (d, J = 8.3 Hz, 2H, ArH), 6.88-6.84 (m, 2H, ArH), 6.77-6.73 (m, 3H, ArH), 5.35 (d, J= 3.4 Hz, IH, HI), 5.31 (s, IH, H6), 3.38 (s, 3H, CH 3 ) , 2.32 (m, IH, H3'), 2.10 (m, 2H, H2'&4') , 1.82 (dt, J= 6.8 and 12.4 Hz, IH, H3), 1.50 (dt, J= 6.8 and 12.8 Hz, IH, H4), 1.35-1.18 (m, IH, H2) ppm; 1 3 C N M R (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 166.40 (+, ester C=0), 146.56 (+), 141.12 (+), 129.33 (-), 127.19 (-), 126.39 (-), 126.32 (-), 89.29 (-, C6), 88.16 (-, C l ) , 59.16 (+, C5), 51.31 (-, CH 3 ) , 38.81 (+, C4), 34.90 (+, C2), 24.88 (+, C3) ppm; 262 Chapter 10. Photochemical Studies and Quantum Yields IR (KBr) 2928, 1718 (ester C O ) , 1611, 1497, 1431, 1414, 1283, 1173, 1103, 999, 930, 861,825,756, 700, 549 cm"1; LRMS (DCI+, NH 3 ) m/z 309 (M ++l), 145, 144(100), 143, 129; HRMS (DCI+, NH 3 ) m/z 309.1504 (Calcd for C 2 0 H 2 i O 3 , 309.1491). (lS*,5S*,6R*)-6-(4-Carbomethoxyphenyl)-7-oxa-5-phenylbicyclo[3.2.0]heptane (141) 3 141 colorless oil; *H NMR (C 6 D 6 , 400 MHz) 5 8.14 (d, J= 8.0 Hz, ArH), 7.32 (d, J = 8.0 Hz, 2H, ArH), 7.20-7.05 (m, 5H, ArH), 5.88 (s, IH, H6), 5.34 (d, J= 3.4 Hz, IH, HI), 2.00-1.82 (m, 2H, H2'&3'), 1.74 (dd, IH, H4'), 1.50-1.14 (m, 3H, H2,3&4) ppm; 1 3 C NMR (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 166.56 (+, ester C O ) , 145.44 (+), 144.99 (+), 129.81 (-), 128.96 (-), 126.67 (-), 126.32 (-), 125.11 (-), 89.86 (-, C l ) , 87.44 (-, C6), 58.56 (+, C5), 51.50 (-, CH 3 ) , 34.30 (+, C2), 34.21 (+, C4), 25.68 (+, C3) ppm; IR (CHC13) 3025, 2955, 1718 ( C O ) , 1612, 1438, 1284, 1211, 1175, 1116, 1004, 928 cm"1; LRMS (DCI+, NH 3 ) m/z 309 (M ++l), 225, 145, 144(100), 143, 129; 263 Chapter 10. Photochemical Studies and Quantum Yields H R M S (DCI+, NH 3 ) m/z 309.1483 (Calcd for C 2 0 H 2 1 O 3 , 309.1491). 10.1.4 Photolysis of Ketone 145 An acetonitrile solution (20 mL) of ketone 145 (147 mg) was purged with nitrogen for 30 minutes and irradiated for 15 h. The reaction mixture was subjected to radial chromatography on silica gel with 15/1 (v/v) petroleum ether/diethyl ether as the eluent. Compound 147 was separated as a white powder and product 148 was obtained as a colorless oil. l,l'-Diphenyl-l,l'-bicyclohexyl (147) 147 white solid; mp 186.5-188 °C (lit.1 4 6l81.5-183.5 °C, l i t . 1 4 7 181.5 °C); 264 Chapter 10. Photochemical Studies and Quantum Yields ] H N M R ( C D C I 3 , 200 MHz) 5 7.25-7.10 (m, 6H, ArH), 7.00-6.85 (m, 4H, ArH), 2.40-2.20 (m, 4H), 1.55-1.25 (m, 10H), 1.25-0.90 (m, 6H) ppm; 1 3 C N M R ( C D C I 3 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 141.23 (+), 130.73 (-), 126.62 (-), 125.07 (-), 49.32 (+), 30.20 (+), 26.62 (+), 22.60 (+) ppm; IR (KBr) 3058, 2924, 2860, 1473, 1444, 1349, 1017, 785, 728, 704, 656, 529 cm - 1; L R M S (DCI+, NH 3 ) m/z 336 (M ++NH 4), 159 (100), 158, 91, 81; H R M S (DCI+, NH 3 ) m/z 336.2692 (Calcd for C 2 4 H 3 4 N , 336.2691); Anal . Calcd for C 2 4 H 3 o : C, 90.51; H , 9.49. Found: C, 90.60; H , 9.57. (lR*,5S*,6S*)-l,6-Diphenylbicyclo[3.3.1]heptan-6-ol (148) colorless oil; ' H N M R (C 6 D 6 , 500 MHz) 5 7.51-7.49 (m, 2H, H9&13), 7.32-7.30 (m, 2H, H15&19), 7.24-7.21 (m, 2H, H10&12), 7.15-7.04 (m, 4H, H16,18,l 1&17), 3.07-3.03 (m, IH, H7), 2.70-2.67 (m, IH, H5), 2.50-2.44 (m, IH, H2), 2.02-1.96 (m, IH, H2'), 1.88-1.82 (m, IH, H4), 1.74-1.68 (m, IH, H4'), 1.58-1.53 (m, 2H, OH&H7') , 1.45-1.37 (m, IH, H3'), 1.19-1.10 (m, IH, H3) ppm; 265 Chapter 10. Photochemical Studies and Quantum Yields 1 3 C NMR (C 6 D 6 , 100 MHz, APT: C, C H 2 : +; CH, C H 3 : -) 5 144.47 (+, C8), 143.97 (+, C14), 128.61 (-, C16&18), 128.49 (-, C10&12), 127.88 (-, c9&13), 127.23 (-, C17), 127.00 (-, C15&19), 126.39 (-, C l l ) , 83.37 (+, C6), 53.05 (+, C l ) , 41.01 (-, C5), 35.30 (+, C2), 34.84 (+, CT), 27.15 (+m C4), 15.44 (+, C3) ppm; IR(neat) 3431 (OH), 3056, 3025, 2942, 2865, 1602, 1495, 1446, 1321, 1096, 1078, 1014, 954, 915, 770, 701, 624, 561 cm"1; LRMS (EI) m/z 264 (M + ) , 246, 146, 145, 144(100), 133, 132, 129, 118, 105,91,77; HRMS (EI) m/z 264.1515 (Calcd for C i 9 H 2 0 O , 264.1514); Anal. Calcd for C , 9 H 2 0 O : C, 86.32; H, 7.63. Found: C, 86.09; H , 7.82. The solid-state photolysis of ketone 145 (ca. 30 mg) was performed at -20 °C for 22.5 h and cyclobutanol 148 was obtained as the major product (75 % yield, 12 % conversion). 10.5 Photochemical Studies of Ketones 162,146,163 and 164 10.5.1 Photolysis of Ketone 162 + PhCHO 167 90 + O 162 168 169 solid state. W trace amount of 90 and 169 -20°C, 9h 266 Chapter 10. Photochemical Studies and Quantum Yields A benzene solution (5 mL) of ketone 162 (104 mg) was purged with nitrogen for 30 min prior to photolysis. After 24 h of irradiation, the reaction mixture was subjected to GC-MS for analysis and compound 167 was identified as the major product along with compounds 90, 168 and 169. The solid state photolysis was performed at -20 °C for 9 h and trace amounts of compounds 90 and 169 were detected by GC-MS analysis. 10.5.2 Photolysis of Ketone 146 Ph Ph Ph O 146 CH 3CN hv 97% conv. solid state Ph Ph. -10°C 35% conv. + ^ + PhCHO OPh Ph H 170 (Z/E) Ph + Ph 172 171 90 P h ^ - y P h Ph O 173 170 (Z/E) + 172 + 90 Ketone 146 (68 mg) was dissolved in 5 mL of acetonitrile and the solution was purged with nitrogen for 30 min before photolysis. After 5 h of irradiation, the reaction mixture turned yellow and GC analysis showed a 97 % conversion. Radial chromatography on silica gel was used to separate the products with 40/1 (v/v) petroleum ether/diethyl ether as the eluent. The 267 Chapter 10. Photochemical Studies and Quantum Yields structures of compounds 90 and 171-173 were determined by comparison with authentic samples; and the Z/E configuration of enol ether 170 could not be assigned. (Z or £)-l-Phenoxy-l,2-diphenyl-l-propene (170a) white solid; mp 100-101.5 °C; UV 270.7(12,600) nm; *H NMR (CDC1 3, 400 MHz) 5 7.53-7.48 (m, 2H, ArH), 7.45-7.40 (m, 2H, ArH), 7.34-7.18 (m, 6H, ArH), 7.14-7.08 (m, 2H, ArH), 6.90-6.78 (m, 3H, ArH), 2.23 (s, 3H, CH 3 ) ppm; 1 3 C NMR ( C D C I 3 , 100 MHz, APT: C, C H 2 : -; C H , C H 3 : +) 5 157.33 (-), 145.29 (-), 140.45 (-), 135.62 (-), 129.68 (+), 129.10 (+), 128.03 (+), 128.02 (+), 127.93 (+), 127.76 (+), 126.83 (+), 124.11 (-), 121.30 (+), 116.99 (+), 19.96 (+) ppm; IR (KBr) 3020, 1595, 1491, 1439, 1225, 1168, 1094, 1067, 1029, 1005, 920, 880, 798, 750, 697, 593,523 cm"1; LRMS (EI) m/z 286 (M + ) , 193 (100), 181, 178, 115, 91, 65; HRMS (EI) m/z 286.1348 (Calcd for C 2 i H i 8 0 , 286.1358); Anal. Calcd for C 2 i H 1 8 0 : C, 88.08; H, 6.34. Found: C, 88.28; H , 6.29. Ph' OPh 170a 268 Chapter 10. Photochemical Studies and Quantum Yields (Z or £)-l-Phenoxy-l,2-diphenyl-l-propene (170b) Ph OPh 170b white solid; mp 65-68 °C; UV 271.6(13,900) nm; 'H NMR (CDC1 3, 400 MHz) 8 7.25-7.18 (m, 7H, ArH), 7.16-7.12 (m, 2H, ArH), 7.06-7.02 (m, 3H, ArH), 7.02-6.97 (m, 2H, ArH), 6.94-6.89 (m, IH, ArH), 2.18 (s, 3H, CH 3 ) ppm; 1 3 C NMR ( C D C I 3 , 100 MHz, APT: C, C H 2 : -; C H , C H 3 : +) 8 156.95 (-), 145.78 (-), 141.40 (-), 135.19 (-), 129.61 (+), 129.44 (+), 129.12 (+), 128.28 (+), 127.65 (+), 127.37 (+), 126.74 (+), 126.70 (-), 121.44 (+), 115.98 (+), 19.23 (+)ppm; IR (KBr) 2914, 1643, 1597, 1489, 1443, 1239, 1216, 1163, 1114, 1060, 1024, 984, 920, 883, 859, 779, 766, 749, 698, 584 cm"1; LRMS (EI) m/z 286 (M + ) , 193 (100), 181, 178, 115, 91; HRMS (EI) m/z 286.1358 (Calcd for C 2 i H 1 8 0 , 286.1358); Anal. Calcd for C 2 i H I 8 0 : C, 88.08; H , 6.34. Found: C, 88.35; H , 6.27. Solid-state photolysis of ketone 146 (22 mg) was performed at -10 °C for 6 h. GC analysis indicated that 35 % of the starting material was converted and that a Z/E mixture of 269 Chapter 10. Photochemical Studies and Quantum Yields enol ether 170 was the major product. Small amounts of compounds 90 and 172 were also detected. 10.1.3 Photolysis of Ketone 163 O P h 3 C - C - P h " 163 hv b e n z e n e , 53% conv. P h O P h X\ + Ph P h 175a Ph O P h f r OHO) + P h C H O + 90 177 solid state.. 176a + P h 3 C H 166 178a r.t. 67% conv. 175a 176a Ketone 163 (117 mg) was dissolved in 6 mL of benzene and the solution was purged with nitrogen for 30 min prior to photolysis. After 24 h of irradiation, the solution had turned yellow and G C analysis indicated a 53 % conversion. The reaction mixture was subjected to radial chromatography on silica gel with gradient elution from 200/1 to 5/1 (v/v) petroleum ether/diethyl ether as the eluent. 270 Chapter 10. Photochemical Studies and Quantum Yields 1-Phenoxy-l,2,2-triphenylethylene (175a) P h x _ / 0 P h P h 7 V h 175a white solid; mp 178-180 °C (lit . 1 2 7 178-180°C); ! H NMR (CD 2C1 2 , 400 MHz) 8 7.25-7.18 (m, 12H, ArH), 7.12-7.08 (m, 5H, ArH), 7.00-6.98 (m, 2H, ArH), 6.91 (m, IH, ArH) ppm; 1 3 C NMR (CD2CI2, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 157.66 (+), 147.40 (+), 141.08 (+), 140.74 (+), 135.68 (+), 131.63 (-), 130.81 (+), 130.60 (-), 129.72 (-), 129.49 (-), 128.41 (-), 128.26 (-), 128.19 (-), 128.15 (-), 127.49 (-), 127.21 (-), 122.15 (-), 117.63 (-) ppm; IR (KBr) 3051, 1597, 1489, 1290, 1221, 1182, 1164, 1075, 1063, 1027, 945, 782, 752, 696, 639, 609, 590, 517 cm - 1; LRMS (EI) m/z 348 (M + ) , 256, 255 (100), 254, 253, 252, 243, 240, 239, 178, 177, 176, 165, 77; HRMS (EI) m/z 348.1517 (Calcd for C 2 6 H 2 oO, 348.1514); Anal. Calcd for C 26H 2 0O: C, 89.62; H , 5.79. Found: C, 89.33; H , 5.81. 271 Chapter 10. Photochemical Studies and Quantum Yields 9-Phenoxy-10-phenylphenanthrene (176a) Ph OPh 176a white solid; mp 145-146 °C (lit . 1 2 7 150-152 °C); 'H NMR (CDC1 3, 400 MHz) 8 8.77 (d, J= 8.4 Hz, 2H), 8.03 (dd, J= 8.2 and 0.8 Hz, IH), 7.69-7.48 (m, 5H), 7.33-7.26 (m, 3H), 7.07 (m, 2H), 6.85 (t, J = 7.4 Hz, IH), 6.66 (m, 2H) ppm; 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 159.27 (+), 145.57 (+), 135.52 (+), 132.60 (+), 131.50 (+), 130.39 (-), 129.71 (+), 129.19 (-), 128.87 (+), 127.95 (-), 127.49 (+), 127.31 (-), 127.11 (-, br), 126.83 (-), 126.07 (-), 122.69 (-), 121.26 (-), 115.55 (-) ppm; IR (CDCI3) 3079, 3033, 1593, 1490, 1448, 1424, 1371, 1324, 1291, 1218, 1165, 1109, 1075, 1064, 1042 cm"1; LRMS (EI) m/z 346 ( M + , 100), 268, 252, 250, 241, 239, 226, 165, 119, 77, 55; HRMS (EI) m/z 346.1359 (Calcd for C2 6 H, 8 0, 346.1358). 272 Chapter 10. Photochemical Studies and Quantum Yields 9-Phenyl-9-benzoylfluorene (178a) O P h ^ ^ - P h 178a *H NMR (C 6 D 6 , 400 MHz) 5 7.72-7.70 (m, IH), 7.54-7.42 (m, 5H), 7.34-7.31 (m, 2H), 7.13-6.92 (m, 7H), 6.83-6.71 (m, 3H) ppm; 1 3 C NMR (CDC1 3, 75 MHz) 5 146014, 142.35, 141.01, 137.72, 131.75, 129.02, 128.57, 128.32, 128.27, 127.89, 127.79, 127.35, 126.81, 120.27 ppm, some carbon signals are missing due to the dilution of the sample; IR (CDCI3 ) 3065, 1672 (C=0), 1599, 1494, 1450, 1280, 1227 cm"1; LRMS (DCI+, NH3+CH4) m/z 347 (M ++l), 241, 239, 105 (100); HRMS (DCI+, NH 3 ) m/z 347.1438 (Calcd for C 2 6 H i 9 0 , 347.1426). Solid-state photolysis of ketone 163 (ca. 100 mg) was performed at room temperature, and enol ether 175a was formed as the major product with a small amount of phenanthrene derivative 176a detected by GC-MS. 273 Chapter 10. Photochemical Studies and Quantum Yields 10.1.4 Photolysis of Ketone 164 Ph OPh Ketone 164 (44 mg) was dissolved in 5 mL of benzene and the solution was purged with nitrogen for 30 min prior to photolysis. After 26 h of irradiation, the solution had turned yellow and GC analysis indicated a 95 % conversion. The reaction mixture was subjected to radial chromatography on silica gel with gradient elution from 200/1 to 20/1 (v/v) petroleum ether/diethyl ether as the eluent. 274 Chapter 10. Photochemical Studies and Quantum Yields l-(4-Methoxyphenyl)-l-phenoxy-2,2-diphenylethylene (175b)b Ph O P h Ph > O M e 175b white solid; 'H NMR ( C D C I 3 , 400 MHz) 8 7.23-7.09 (m, 14H, ArH), 6.95 (d, J= 7.8 Hz, 2H), 6.88 (t, J= 7.8 Hz, IH), 6.57 (d,J= 8.9 Hz, 2H), 3.68 (s, 3H, CH 3 ) ppm; 1 3 C NMR (CD 2C1 2 , 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 8 158.99 (+), 157.51 (+), 146.96 (+), 141.03 (+), 140.37 (+), 131.45 (-), 131.38 (-), 129.25 (-), 129.07 (-), 128.08 (-), 127.87 (-), 127.53 (+), 126.91 (-), 126.63 (-), 121.54 (-), 117.24 (-), 113.29 (-), 56.10 (-) ppm; IR(KBr)2961, 1596, 1511, 1490, 1462, 1443, 1695, 1249, 1219, 1175, 1063, 1033 cm"1; LRMS (EI) m/z 378 (M + ) , 362, 286 285 (100), 270, 269, 254, 253, 252, 241, 240, 239, 226, 215, 202, 178, 165, 150, 135, 120, 96, 77, 65; HRMS (EI) m/z 378.1622 (Calcd for C 2 7 H 2 2 0 2 , 378.1620). b The pure form of this compound was not obtained. Analysis was based on a 85 % pure sample. 275 Chapter 10. Photochemical Studies and Quantum Yields 6-Methoxy-9-phenoxy-10-phenylphenanthrene (176b) Ph OPh € ^ 176b ° M e ! H NMR (CDCI3, 400 MHz) 5 8.67 (d, J= 8.3 Hz, IH), 8.12 (d, J= 2.4 Hz, IH), 7.94 (d, J= 9.0 Hz, IH), 7.63-7.56 (m, 2H), 7.49-7.45 (m, IH), 7.34-7.25 (m, 5H), 7.18 (dd, J= 2.4 and 9.0 Hz, IH), 7.07 (m, 2H), 6.84 (t, J = 7.3 Hz, IH), 6.65 (d,J= 7.9 Hz, 2H), 4.02 (s, 3H, CH 3 ) ppm; 1 3 C NMR (CDCI3, 75 MHz, APT: C, C H 2 : +; C H , C H 3 : -) 5 159.31 (+), 158.95 (+), 145.64 (+), 135.63 (+), 133.16 (+), 133.10 (+), 130.57 (-), 129.18 (-), 128.29 (+), 127.93 (-), 127.31 (+), 127.18 (-), 127.09 (-), 126.91 (-), 125.63 (-), 121.97 (+), 121.22 (-), 117.04 (-), 116.98 (-), 115.54 (-), 104.50 (-), 104.34 (-), 55.53 (-) ppm; IR (CDCI3) 2961, 1620, 1596, 1527, 1503, 1490, 1456, 1440, 1381, 1317, 1244, 1216, 1166, 1110, 1074, 1036 cm"1; LRMS (EI) m/z 376 ( M + , 100), 271, 255, 239, 228, 226, 149, 77, 51; HRMS (EI) m/z 376.1467 (Calcd for C27H20O2, 376.1463). 276 Chapter 10. Photochemical Studies and Quantum Yields 9-(4-Methoxybenzoyl)-9-phenylfluorene (178b) 178b 'H NMR ( C D C I 3 , 400 MHz) 5 7.79 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.41-7.35 (m, 4H), 7.27-7.17 (m, 7H), 6.62 (d,J= 9.0 Hz, 2H), 3.73 (s, 3H, CH 3 ) ppm; IR(CDC1 3) 2932, 1667 ( C O ) , 1600, 1510, 1451, 1243, 1174, 1033 cm"1; LRMS (DCI+, NH 3 ) m/z 377 (M ++l), 135 (100); HRMS (DCI+, NH 3 ) m/z 377.1544 (Calcd for C 2 7 H 2 1 O 2 , 377.1541). Solid-state photolysis of ketone 164 (ca. 50 mg) was performed at room temperature, and enol ether 175b was formed as the major product with phenanthrene derivative 176b as the minor product as detected by GC-MS. 10.6 Quantum Yields and Quenching Studies of Ketone 43 A l l the solvents and most chemicals used for kinetic measurements were treated as indicated below prior to use. Other chemicals were used without further purification. Thiophene-free dry benzene was obtained by washing commercial benzene with concentrated 277 Chapter 10. Photochemical Studies and Quantum Yields sulfuric acid, water, 10% sodium hydroxide solution and water, drying over calcium chloride and distilling over sodium metal. tert-Butanol was dried over magnesium sulfate and refluxed and distilled over aluminum tri(7-butoxide). Acetophenone and valerophenone were freshly vacuum distilled. Quencher 2,5-dimethyl-2,4-hexadiene was refluxed and distilled over lithium aluminum hydride. Internal standards rc-nonadecane and n-tetradecane were used without further purification. A l l the glassware including sample tubes (Corning rimless 100 x 13 mm Pyrex Culture Tubes, 9820-13), volumetric pipettes and flasks (Class A) were cleaned by boiling in soapy distilled water overnight followed by four rinse cycles in boiling distilled water. The clean sample tubes were heated with an oxygen-gas torch below the label and stretched to about 7 cm. Irradiations were conducted in a merry-go-round apparatus83 with a 450W Hanovia medium-pressure mercury lamp. The wavelength of 313nm was isolated by a filter combination of 7-54 Corning glass plates and an aqueous solution of 0.002 M potassium chromate containing 5% potassium carbonate. A temperature of 20 ± 2 °C was maintained by passing cold water through a large copper coil inside the water bath which contains the entire apparatus. Photochemical generation of acetophenone from valerophenone was used as the actinometer. The quantum yield of this reaction is known to be 0.33 at 313 nm for an opaque solution of valerophenone (ca. 0.1 M) in benzene.148 w-Nonadecane and «-tetradecane were used as the internal standards for the solutions of ketone 43 and actinometer, respectively. The concentration for C M was approximately 5 x 10"3 M and that of Qg was about 3.5 x 10"3 M . For quenching studies, the concentration of the quencher 2,5-dimethyl-2,4-hexadiene varied 278 Chapter 10. Photochemical Studies and Quantum Yields from 0 M to near 1 M . A l l substrate and actinometer solutions were subjected to four freeze-pump-thaw cycles and flame-sealed under vacuum. A l l quantitative photoproduct measurements were performed using standard gas chromatographic techniques. The G C response factor for each product was calculated relative to the proper internal standards ( CM or C19). For this purpose, a standard solution of each product with known concentration of internal standard was prepared and injected. G C data were based on the average of three chromatographic runs. Quantum yield data were calculated from parallel irradiations of two actinometer solutions and a substrate solution, and the average result from these two actinometers was used. Quantum yields reported are based on a plot of quantum yield versus photoproduct concentration and are extrapolated back to 0 % conversion. 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