r on} “an n F . u .._n-I-v-~.uu u. . LIBRARIES MICHIGAN STATE UNIVERSITY EAST LANSING, MICH 48824-1048 This is to certify that the dissertation entitled Synthesis of Carbazoquinocin-C, Naphthopyrans and Conocurvone Analogs With Carbene Complexes presented by Manish Rawat has been accepted towards fulfillment of the requirements for the Doctoral degree in Chemistry M\m\§\~o- .D Lx- XNNV/ Major Professor's Signature - September 27, 2004 Date MSU is an Affirmative Action/Equal Opportunity Institution PLACE IN RETURN Box to remove this checkout from your record. T O AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 6I01 c:/ClRC/DatoDue.p65-p.15 SYNTHESIS OF CARBAZOQUINOClN-C, NAPHTHOPYRANS AND CONOCURVONE ANALOGS WITH CARBENE COMPLEXES By Manish Rawat A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 2004 ABSTRACT SYNTHESIS OF CARBAZOQUINOCIN-C, NAPHTHOPYRANS AND CONOCURVONE ANALOGS WITH CARBENE COMPLEXES By Manish Rawat A successful syntheses of Fischer indole carbene complexes has been achieved and their utility in the synthesis of carbazoquinocin-C via the photochemical ortho-benzannulation with carbon monoxide and also via the thermal ortho-benzannulation with isonitriles has been demonstrated. An improved method for the oxidation of the hydroquinone of the natural product carbazoquinocin-C has also been developed. Benzannulation reactions of chromene carbene complexes with simple alkynes have been investigated. High yields of naphthopyran phenols have been realized from these reactions and require in-situ protection of the phenolic functionality using protecting groups such as TMSCI, TBSCI, MOMCI, A020 to be most effective. The corresponding quinones of these naphthopyran phenols are stable which is in contrast to the corresponding unprotected naphthopyran phenols. Conocurvone, a remarkable anti-HIV active natural product, possesses a tris-naphthoquinone pyran core structure. In an effort towards the total synthesis of conocurvone the reaction of various aryl carbene complexes with bis-TIPS- 1,3,5-hexatriyne and ortho-aryl diynes have been investigated. The reaction of the phenyl carbene complex with bis-TIPS 1,3,5-hexatriyne, intriguingly, forms a furan instead of a phenol by reacting at the central triple bond of the triyne. Furan products have been observed before in the reaction of chromium Fischer carbene complex with alkynes but only as a minor product. Surprisingly, the reaction of the chromene carbene complex and the bis-TIPS 1,3,5-hexatriyne gave neither a furan nor a phenol. Instead, the reaction gave an unexpected product that results from an addition to the central alkyne of the triyne and then an addition to the double bond present in chromene carbene complex. The intriguing outcome of the phenyl carbene complex and chromenyl carbene complex with bis-TIPS 1,3,5-hexatriyne has been explained by PM3(TM) and DFT calculations. ACKNOWLEDGMENTS I would like to express my deep gratitude to Professor William D. Wulff for his patience, encouragement, suggestions and stimulating ideas over the last five years. It has been an enriching experience and a great honor to learn from Professor Wulff. Professor Wulff’s sense of humor and genuine interest in all aspects of chemistry has been inspirational and educational. I am indebted to Professor Robert E. Maleczka, Milton Ft. Smith and Professor David P. Weliky for being in my Ph.D. committee, their support, suggestions and writing letters of recommendation. Thanks to Victor for helping me with the Computational studies, Dr. Jiang for conocurvone studies, Remy for the TIPS triyne synthesis and Dr. Rui Huang for elemental analysis/X-ray. l, specially, thank Dr. Reddy, Vijay, Dr. Billy Mitchell, Glenn, Kostas and Victor for their valuable friendship and useful discussions on a wide range of topics including chemistry. It was a great pleasure for me to work with a number of past and present labmates who have made the five years here far more enjoyable including Yonghong, Yu, Yiqian, Ding, Gang, Cory, Kostas, Jie, Zhenjie, Chunrui and Alex. I would like to thank Abhi/Manasi, Rg, MaheshNasudha, Vivek, Shilu, Bhushan, Nag, Bala, Bani and Somnath for their friendship and moral support during these five years. iv I dedicate this thesis to my parents whose unending love, support, and encouragement have helped me in achieving this milestone. I can never thank them enough for what they have given to me and many sacrifices they have made for me. I thank my brothers Mikku and Rinku for their cheerful nature and support. TABLE OF CONTENTS LIST OF SCHEMES ....................................................................... iv LIST OF TABLES .......................................................................... x LIST OF FIGURES ........................................................................ xi LIST OF ABBREVIATIONS .............................................................. xiii CHAPTER ONE: DOTZ-WULFF BENZANNULATION REACTION AND ORTHO-BENZANNULATION REACTION OF FISCHER CARBENE COMPLEXES ................................................................................. 1 1.1 Introduction to Fischer carbene complexes ............................... 1 1.2 Benzannulation reaction of Fischer carbene complexes ............... 3 1.3 Ortho-benzannulation of Fischer carbene complexes .................. 12 CHAPTER TWO: SYNTHESIS AND PROPERTIES OF 3H-NAPHTHO[2,1- b]PYRANS:A HISTORICAL PERSPECTIVE ...................................... 22 2.1 Introduction ....................................................................... 22 2.2 Introduction to photochromic properties of 3H-naphtho[2,1-b] pyrans 2.3 Natural products with the 3-H-naphtho[2,1-b]pyran skeleton ......... 28 2.4 Conventional methods of synthesizing 3H-naptho[2,1-b]pyrans ....................................................................................... 30 2.5 Total Synthesis of natural products 81 to 89 ............................. 37 CHAPTER THREE: SYNTHESIS AND BENZANNULATION EXPLORATIONS OF CHROMEN-s-YL CARBENE COMPLEX ....................................... 41 3.1 Introduction ....................................................................... 41 3.2 Synthesis of chromium chromen-S-yl carbene complex .............. 42 3.2.1 Hepworth’s Method ......................................................... 42 3.2.2 Nicolaou’s Method ......................................................... 43 3.2.3 Allylic alcohol cyclization approach .................................... 44 3.2.4 Chromenone Approach .................................................... 47 3.3 Chromium chromen-S-yl carbene complex 175: Study of Dotz-Wulff Benzannulation reaction ....................................................... 54 vi CHAPTER FOUR: SYNTHETIC STUDIES TOWARD CONOCURVONE .................................................................................... 67 4.1 Introduction to conocurvone 36 .............................................. 67 4.2 Oxidative oligomerization of monomeric quinone to synthesize cyclic tris-quinones similar to conocurvone 36 ........................... 71 4.3 Previous semisynthesis and synthetic approaches toward conocurvone 36 .................................................................. 72 4.3.1 Boyd and co-workers ....................................................... 73 4.3.2 Liebeskind approach ....................................................... 74 4.3.3 Stagliano’s approach ....................................................... 75 4.3.4 Previous synthetic efforts in the Wulff laboratory .................... 78 4.4 New studies toward the synthesis of conocurvone from the reaction of carbene complexes with triynes ............................... 81 4.4.1 Reaction of aryl carbene complexes with bis-TIPS triyne 39.... 83 4.4.1.1 Reaction of phenyl carbene complex 22 with the bis-TIPS triyne 39 ................................................................... 83 4.4.1.2 Reaction of chromene carbene complex 175 and chromane complex 235 with bis-TIPS triyne 39 .............................. 93 4.4.1.3 Tungsten carbene complex 274: synthesis and reactivity....97 4.4.1.4 Reaction of bis-phenyl triyne 224 with aryl carbene complex 22 and 175 ............................................................... 100 4.4.2 Reaction of alkenyl and aryl carbene complexes with diyne 102 4.4.2.1 Synthesis of mono-silylated ortho-aryl diynes 288, 289, 290 ............................................................................... 104 4.4.2.2 Reaction of aryl carbene complex 22 with ortho-aryl diynes 221, 287, 288, 289, 290 .............................................. 107 4.4.2.3 Reaction of ortho-aryl diyne 289 with alkenyl complexes ....110 4.5 Mechanistic considerations ................................................... 112 4.5.1 The mechanism of reaction of complex 22 with triyne 39 ........ 112 4.5.2 Olefin-addition product 269 formation from chromene carbene complex 175 with bis-TIPS triyne 39 ................................. 123 4.6 Summary .......................................................................... 135 4.7 Future work ....................................................................... 136 CHAPTER FIVE : ASYMMETRIC ALLYLATION OF IMINES ............... 140 5.1 Introduction ....................................................................... 140 5.2 Asymmetric allylation: Background information ......................... 141 5.2.1 Yamamoto and co-workers ............................................... 141 5.2.2 Jorgensen and co-workers ............................................... 143 5.2.3 Lectka and co-workers .................................................... 143 5.2.4 Kobayashi and Co-workers ............................................... 144 5.3 Attempted allylation of benzhydrylimines of the type 367 ............ 145 5.4 Attempted allylation of benzaldimines 378 ............................... 149 CHAPTER SIX: TOTAL SYNTHESIS OF CARBAZOOUINOClN-C: APPLICATION OF THE ORTHO-BENZANNULATION OF FISCHER vii CARBENE COMPLEXES TO CARBAZOLE-3,4-QUINONE ALKALOIDS ................................................................................................... 154 6.1 Introduction ....................................................................... 154 6.2 Conventional routes to synthesize carbazoquinocin-C ................. 157 6.3 Synthesis of carbazoquinocin-C ............................................. 159 6.3.1 Synthesis of carbene complexes of the type 403 ................... 160 6.3.2 Photoinduced route to carbazoquinocin-C ........................... 164 6.3.3 Thermal ortho-benzannulation route to carbazoquinocin-C ......167 CHAPTER SEVEN: EXPERIMENTAL SECTION .................................. 171 APPENDIX .................................................................................... 249 REFERENCE ................................................................................. 264 viii Scheme 1 .1 Scheme 1.2 Scheme 1.3 Scheme 1.4 Scheme 1.5 Scheme 1.6 Scheme 1.7 Scheme 1.8 Scheme 1.9 Scheme 1 .10 Scheme 1.1 1 Scheme 1 .12 Scheme 2.1 Scheme 2.2 Scheme 2.3 Scheme 2.4 Scheme 2.5 LIST OF SCHEMES Schemetic diagram showing the synthesis of carbene complex ................................................................... 3 Benzannulation using Fischer carbene complex and alkyne .............................................................................. 4 Mechanism of the benzannulation reaction ...................... 5 Mechanism of cyclopentadiene and furan product formation .............................................................................. 6 Different reaction products in a benzannulation reaction ..... 7 Regioselectivity of benzannulation reaction ...................... 8 Reterosynthetic analysis of conocurvone ........................ 11 Photoexcitation of Fischer carbene complexes ................. 12 Photoinduced ortho-benzannulation reaction .................... 15 Thermally controlled ortho-benzannulation reaction ........... 17 Photo-induced orfho-benzannulation of amino carbene complexes ............................................................... 18 Thermally controlled ortho-benzannulation of alkoxy carbene complexes using f-BuNC ............................................. 19 Applications of chromene carbene complex in conocurvone and napthopyrans synthesis ......................................... 23 3H-naphto[2,1-b]pyrans shows photochromic properties.....24 Behaviour of naphthopyrans on exposure to irradiation ...... 25 Substituent effect on photochromic properties of naphthopyran 72 ........................................................ 26 Steric effects from the substituents at C-1 and C-2 position Scheme 2.6 Scheme 2.7 Scheme 2.8 Scheme 2.9 Scheme 2.10 Scheme 2.11 Scheme 2.12 Scheme 2.13 Scheme 2.14 Scheme 2.15 Scheme 2.16 Scheme 2.17 Scheme 2.18 Scheme 2.19 Scheme 2.20 Scheme 2.21 Scheme 3.1 Scheme 3.2 Scheme 3.3 .............................................................................. 27 Photochemical response of 6- and 8- position substituted naphthopyran ............................................................ 27 Thiophene substituted naphthopyrans ............................ 28 Natural products with 3-H-naphtho[2,1-b]pyran skeleton.... 29 Acid catalyzed cyclization of aryl-propargyl ethers ............ 31 Rupe rearrangement ................................................... 32 Carriera’s protocol for synthesizing 3H-naphtho[2,1-b]pyran .............................................................................. 33 Benzochromanone to 3,3-dialkyl naphthopyran ................ 34 Benzocoumarins to 3,3-dialkyl naphthopyran ................... 34 Condensation of 2—naphthol and a,B-unsaturated aldehydes .............................................................................. 35 Transformation of 116 to 3,3-dialkyl naphthopyran 117 ...... 35 Transformation of 118 to 3,3-dialkyl naphthopyran 114..... 36 Oxidative cyclization of orfho-(3,3-dimethylallyl)naphthols...36 Synthesis of naphthoquinone pyran 81 synthesis from 123 .............................................................................. 37 Synthesis of naphthoquinone pyrans 83, 84 and 85 from 123 .................................................................. 38 Synthesis of naphthoquinone pyran 81 and naphthoquinones 86 and 87 ................................................................ 39 Transformation of naphthopyran 129 to naphthoquinone 88 .............................................................................. 40 Benzannulation of chromene carbene complex 135 .......... 41 Four approaches for synthesizing halochromene 141 ......... 42 Hepworth protocol for synthesis of lodo-chromene 142 ....... 43 Scheme 3.4 Scheme 3.5 Scheme 3.6 Scheme 3.7 Scheme 3.8 Scheme 3.9 Scheme 3.10 Scheme 3.11 Scheme 3.12 Scheme 3.13 Scheme 3.14 Scheme 3.15 Scheme 3.16 Scheme 3.17 Scheme 3.18 Scheme 3.19 Scheme 3.20 Scheme 3.21 Scheme 3.22 Scheme 3.23 Scheme 3.24 Nicoloaou’s protocol for synthesis of 5-bromochromene 7.. 44 Snieckus and Talley ortho-Iithiation strategy .................... 44 Ortho-Iithiation approach towards 141 ............................. 45 Allylic-alcohol cyclization approach ................................. 45 Synthesis of bromoanisaldehyde 162 .............................. 46 Allylic alcohol cyclization approach continued ................... 47 Chromenone approach ................................................ 48 Synthesis of chromene triflate 168 ................................. 48 Reaction of resorcinol 169 with 3-methyl-but-2-enal 109.49 Palladium catalyzed triflate-Sn exchange ........................ 50 Palladium catalyzed triflate-Sn exchange ........................ 51 Stannyl cuprate addition to chromene triflate 168 .............. 51 Bromination of chromene stannane 170 .......................... 52 Chromene carbene complex 175 synthesis ..................... 54 Benzannulation of complex 175 with phenyl acetylene ....... 55 Benzannulation of complex 175 with phenyl acetylene ...... 56 Benzannulation of complex 175 with phenyl acetylene using different protecting group ............................................. 58 Benzannulation of complex 175 with phenyl acetylene using TMSCI protecting group in different solvents .................... 59 Benzannulation of complex 175 with 1-pentyne, 3-hexyne and trimethylsilyl acetylene .......................................... 61 Synthesis of quinone 181 ............................................. 62 Synthesis of quinone 181 ............................................. 63 xi Scheme 3.25 Scheme 3.26 Scheme 3.27 Scheme 3.28 Scheme 4.1 Scheme 4.2 Scheme 4.3 Scheme 4.4 Scheme 4.5 Scheme 4.6 Scheme 4.7 Scheme 4.8 Scheme 4.9 Scheme 4.10 Scheme 4.11 Scheme 4.12 Scheme 4.13 Scheme 4.14 Scheme 4.15 Scheme 4.16 Scheme 4.17 Synthesis of quinone 181 ............................................. 64 Synthesis of quinone 181 ............................................. 64 Synthesis of quinone 178 ............................................. 65 Synthesis of quinone 178 ............................................. 66 Autocatalytic oligomerization of quinones ........................ 72 Boyd’s semisynthesis of conocurvone 36 ........................ 73 Liebeskind’s approach to conocurvone 36 ....................... 75 Stagliano’s use of doubly activated zwitterionic quinones... 77 Stagliano’s synthesis of trimeric quinones using 2,3- dihaloquinones .......................................................... 78 Retrosynthetic analysis of conocurvone 36 ...................... 79 Benzannulation approach to tris-quinone 223 ................... 80 Benzannulation reactions of cyclohexenyl carbene complex 219 with conjugated triynes 224 and 225 ............ 81 Reaction of aryl carbene complex 219 with triynes 39 and 224 ................................................................... 82 Reaction of complex 22 with silyl substituted triyne 39 ........ 84 Desilylation of phenyl furan 236 ..................................... 85 Aryl furan formation .................................................... 86 Proposed pathway for the formation of 236 and 237 ......... 87 Solvent study of reaction of complex 22 with triyne 39 ....... 88 Waters and Wulff study on reaction of complex 252 with 3-hexyn-2-one 253 .................................................... 89 Waters and Wulff study on reaction of complex 256 with alkyne 253 ............................................................... 90 Proposed intermediates for phenol and lactone formation. . . 91 xii Scheme 4.18 Scheme 4.19 Scheme 4.20 Scheme 4.21 Scheme 4.22 Scheme 4.23 Scheme 4.24 Scheme 4.25 Scheme 4.26 Scheme 4.27 Scheme 4.28 Scheme 4.29 Scheme 4.30 Scheme 4.31 Scheme 4.32 Scheme 4.33 Scheme 4.34 Scheme 4.35 Scheme 4.36 Scheme 4.37 Reaction of electron deficient complex 234 with triyne 39... 92 Possible products on reaction of complex 175 with triyne 39 ........................................................................... 93 Benzannulation of complex 175 with triyne 39 .................. 95 Chromane complex 235 synthesis ................................. 96 Benzannulation of complex 235 with 1-pentyne and triyne 39 ........................................................................... 96 Tungsten carbene complex synthesis and reactivity .......... 98 Reaction of complex 274 with triyne 39 ........................... 99 Mechanism for the formation of cyclopentenone 275 ......... 99 Reaction of complex 22 with triyne 224 ........................... 101 Possible polymerization pathway of complex 285 .............. 101 Reaction of complex 175 with 224 ................................. 102 Retrosynthesis for conocurvone analogue 286 ................ 103 Two possible routes for forming 288-290 ......................... 104 Chemoselective desilylation of phenol 220 ....................... 105 Protection of phenol 294 .............................................. 106 Reaction of complex 22 with ortho-aryl diynes 221 and 287 .......................................................................... 108 Reaction of complex 22 with ortho-aryl diynes 288, 289, 290 .......................................................................... 109 Regiocontrolled synthesis trimer 301 .............................. 111 Attempted transformation of 301 to 302 ........................... 112 Possible intermediates from the reaction of phenyl carbene complex 22 at the terminal position of triyne 39 ................. 113 xiii Scheme 4.38 Scheme 4.39 Scheme 4.40 Scheme 4.41 Scheme 4.42 Scheme 4.43 Scheme 4.44 Scheme 4.45 Scheme 4.46 Scheme 4.47 Scheme 4.48 Scheme 4.49 Scheme 5.1 Scheme 5.2 Scheme 5.3 Scheme 5.4 Scheme 5.5 Scheme 5.6 Scheme 5.7 Scheme 5.8 Scheme 5.9 Possible intermediates and products from the reaction of complex 22 at the terminal position of triyne 39 ................. 114 Mechanism for the formation of furan 236 ........................ 116 Furan 236 formation from (Z)-ketene complex 310b .......... 118 Energy of furan 236 .................................................... 120 Proposed mechanism for the formation of 269 .................. 124 Chromacyclobutane intermediate in cyclopropanation reaction .................................................................... 125 Tandem alkyne insertion and cyclopropanation reaction..... 126 Proposed mechanism for the formation of 265, 266 and 269 ......................................................................... 127 Energy of furan 265 and olefin-addition product 269 .......... 131 Reaction of complex 334: Surrogate for an aryl complex... 137 Retrosynthesis of formation of conocurvone analogue 340 .......................................................................... 138 Retrosynthesis of formation of complex 341 ..................... 139 52 isomerization of C-N bond and selectivity of the reaction .................................................................... 141 Palladium catalyst for asymmetric allylation ..................... 142 Allyl-Palladium catalyst for asymmetric allylation ............... 142 Copper catalyst for asymmetric allylation ......................... 143 Palladium chlorate catalyst for asymmetric allylation .......... 143 Zirconium catalyst for asymmetric allylation ..................... 144 B(OPh)3/(S)-VAPOL catalyst for aziridination reaction ........ 145 Boron catalyst for asymmetric allylation ........................... 146 Catalyst investigated for asymmetric allylation .................. 148 xiv Scheme 5.10 Scheme 5.11 Scheme 5.12 Scheme 6.1 Scheme 6.2 Scheme 6.3 Scheme 6.4 Scheme 6.5 Scheme 6.6 Scheme 6.7 Scheme 6.8 Scheme 6.9 Scheme 6.10 Scheme 6.11 Scheme 6.12 Scheme 6.13 Scheme 6.14 Scheme 6.15 Scheme 6.16 Scheme 6.17 Scheme 6.18 Ytterbium triflate catalyst for asymmetric allylation ............. 151 Proposed structure of Yb-VANOL catalyst ....................... 152 Proposed transition state of the catalyst 380 - imine complex ................................................................... 153 Photoinduced ortho-benzannulation reaction of 382 via 383 .......................................................................... 156 Thermal ortho-benzannulation of 44 via 58 ...................... 156 Hibino’s approach to cabazoquinocin-C .......................... 157 Knolker’s approach to cabazoquinocin-C ........................ 158 Knolker’s approach to cabazoquinocin C ......................... 158 Pindur’s approach to cabazoquinocin C ........................... 159 Retrosynthetic analysis of cabazaquinocin C .................... 160 lndolyl heptyl ketone 405 from indole-2-carboxylic acid 406 .......................................................................... 161 Vinyl indole 409 from indole heptyl ketone 405 ................. 161 Synthesis of carbene complex precursor 410 ................... 162 Synthesis of carbene complex precursors 413 and 414 ...... 163 Synthesis of carbene complexes 415, 416 and 417 ........... 163 Photoinduced orfho-benzannulation of 41 and 42 .............. 165 Debenzylation of 418 and 419 ....................................... 166 Demethylation and oxidation of 421 to carbazoquinocin-C...167 Thermal ortho-benzannulation of 415 and 417 .................. 168 Oxidation of 426 to carbazoquinocin-C ............................ 169 Conversion of 52 to carbazoquinocin-C ........................... 170 XV Table 4.1 Table 4.2 Table A.1.1. Table A.1.2. Table A.1.3. Table A.1.4. Table A.1.5. Table A.2.1 Table A.2.2 Table A.2.3. Table A.2.4. Table A.2.5. LIST OF TABLES Energetic of the products and the intermediates involved in formation of furan 236 ................................................. 121 Energetics of the products and the intermediates involved in formation of 265, 266, 269 ........................................... 129 Crystal data and structure refinement for 184 .................. 251 Atomic coordinates [x 104), equivalent isotropic displacement parameters (A2 x 10 ), and occupancies for 184 .............. 252 Bond lengths [A] and angles [deg] for 184 ...................... 253 Anisotropic displacement parameters (A2 x 103) for 184 ..... 255 Hydrogen coordinates ( x 104), isotropic displacement parameters (A2 x 103), and occupancies for 184 ............... 256 Crystal data and structure refinement for 299 ................. 258 Atomic coordinates gx 104), equivalent isotropic displacement parameters (A2 x 10 ), and occupancies for 299 ............... 259 Bond lengths [A] and angles [deg] for 299 ....................... 260 Anisotropic displacement parameters (A2 x 103) for 299. . . 262 Hydrogen coordinates ( x 104), isotropic displacement parameters (A2 x 103), and occupancies for 299 ............... 263 xvi Figure 1.1 Figure 1.2 Figure 1.3 Figure 1.4 Figure 1.5 Figure 1.6 Figure 4.1 Figure 4.2 Figure 4.3 Figure 4.4 Figure 4.5 Figure 4.6 Figure 4.7 Figure 4.8 Figure 4.9 Figure 4.10 Figure 4.11 LIST OF FIGURES (Images in this thesis are presented in color) Electronic description of carbene complexes ...................... 2 Natural products and asymmetric ligands .......................... 10 One-electron energy level diagram for tungsten complex [W(CO)5{C(OMe)Ph}] .................................................... 14 Structure of calphostins ................................................. 19 Structure of tanshinones ............................................... 20 Structure of Carbazole-3,4-quinone alkaloids ..................... 21 Australia map and conospermum incurvum ........................ 67 Conocurvone 36, its analogue 194 and teretifolione B 195.... 69 Proton NMR of conocurvone 36 ....................................... 70 Diynes 231, 232 and tris-aryl derivative 233 ....................... 83 Aryl carbene complexes 22, 175, 234 and 235 .................... 83 Diynes 288, 289, 290 and Iris-aryl derivative 291 ................ 103 Transition state for Chemoselective desilylation of 220 ......... 106 Diynes 221, 287, 288, 289 and 290 .................................. 107 Energy of the intermediates and the products where TIPS group is replaced by TMS group .................................................. 122 PM3(TM) optimized structure of the intermediates and the products where TIPS group is replaced by TMS group ...................... 123 Energy of the intermediates and the products where TIPS group is replaced by TMS group .................................................. 132 xvii Figure 4.12 Figure 4.13 Figure 6.1 Figure A.1 Figure A.2 PM3(TM) optimized structure of the intermediates and the products where TIPS group is replaced by TMS group ..................... 134 Alkenyl carbene complexes 332, 333 and 334 .................... 136 Carbazole-3,4-quinone alkaloids ...................................... 155 ORTEP Diagram of Compound 184 ................................. 250 ORTEP Diagram of Compound 299 ................................ 257 xviii Ac Bh BINOL Bn Bu tBuNC CAN DBN DBU DCC DDQ DFI' DIPEA DMAP DMF DMSO DMP DTBMP Et20 LIST OF ABBREVIATIONS Acetyl Benzhydryl 1 ,1 '-Bi-2-naphthol Benzyl Butyl tert-Butyl isocyanide Cerium Ammonium Nitrate 1,5-Diazabicyclo [4.3.0]non-5-ene 1 ,8-diazabicyclo[4.3.0]undec-7-ene Dicyclohexylcarbodiimide 2,3-Dichloro-5,6—dicyano-1 ,4- Benzoquinone Density Functional Theory N,N-Diisopropylethylamine 4-(Dimethylamino)pyridine Dimethyl formamide Dimethylsulfoxide 2,6-Dimethylpyridine 2,6-di-tert-butyI-4-methyl pyridine Diethyl ether xix LF Me MLCT MOM NBS NMI Ph PMB PMP PPTS i-Pr TBAF TMEDA Ts Tf20 TFA THF TIPS TMS UV VANOL VAPOL Ligand Field Methyl Metal-to-Iigand charge-transfer Methoxymethyl Ether N-Bromosuccinimide N-methylimidazole Phenyl para-methoxy benzyl 1 ,2,2,6,6-pentamethylpiperidine Pyridinium p-toluene sulfonate isopropyl Tetrabutylammonium Fluoride N,N,N',N'-Tetramethylethylenediamine p—Toluenesulfonyl Trifloromethanesulfonic anhydride Trifloroacetic Acid Tetrahydrofuran Triisopropylsilyl Trimethylsilyl Ultra-violet Vaulted Binaphthol Vaulted Biphenanthrol XX CHAPTER ONE Dotz -Wulff Benzannulation Reaction And Ortho-Benzannulation of Dienyl Fischer Carbene Complexes 1.1 Introduction to Fischer carbene complexes Compounds containing formal metal-to-carbon double bonds are known as carbene complexes. In 1964, Fischer and Maasbol reported the first example of a carbene complex which was prepared from the reaction of hexacarbonyltungsten with methyl or phenyl lithium followed by protonation and then reaction with diazomethane.1 Fischer carbene complexes, represented by 1a are characterized by having the metal in a low oxidation state, by n-accepting auxiliary ligands and by heteroatorn substituents on the carbene carbon atom capable of donating n—electron density. They possess singlet carbene ligands as shown in Figure 1.1 since the carbon donates the pair of electrons present in the sp2 orbital to the empty orbitals of the metal to form the o-bond. This is accompanied by concurrent back-donation of the d-electrons from the metal to the empty p orbital of the carbene carbon. The heteroatorn competes with the attached metal fragment for n—back donation into the empty p orbital of the carbene carbon thereby stabilizing the carbene complex by reducing the carbon atom’s electronic deficiency. This significantly increases the contribution from resonance structure 1b, which is evident by the increased hindered rotation about the heteroatom-carbene complex bonds in going from the alkoxy to amino stabilized complexes (C-N: 25 kcalmol", C-0: 14 kcalmol"). Figure 1.1 Electronic description of carbene complexes. OMe _ OMe H + _ H (CO)5Cr=< (CO)5Cr—< CICpZTa=(CO)50r=( -- 9 HXR R agent 3 4 R1 w 4 2 XR3 = SR3, NR32 R14N+Br O- RZCOX OCOR * (cc)50r=( ———> (CO)50r=< 6 R a n 1.2 Benzannulation reaction of Fischer carbene complexes In 1975, Dotz reported the first examples of the reaction of a,B-unsaturated Fischer carbene complexes 9 with alkynes 10 (Scheme 1.2).3 This reaction furnishes chromium tricarbonyl complexed para-alkoxy phenols 11 which upon oxidation provide phenols 12 or para-quinones 13. This is an [3+2+1] annulation reaction in which the resulting benzene ring is comprised of three carbons from the mB-unsaturated carbene complex, two carbons from the alkyne and one carbon from the carbon monoxide ligand. This reaction is quite general with yields as high has 99 % in certain cases. Scheme 1.2 Benzannulation using Fischer carbene complex and alkyne OH R1 RL OxidaflyRsfiRs OH OMe (co)50r=§::R2 +91. : Rs RZ=H :1J¢ERL 12 R3 R1 R8 Oxidation (CO)3Cr/ OMe 9 10 :;:?::L RS The metal-free phenol 12 can be derived from complex 11 by ligand displacement (CO, PPh3)4a'4b or by oxidative workup (air, FeCIa-DMF complex, 4° pyridine N-oxide‘d) (Scheme 1.2). Strong oxidizing agents like CAN,40 lead oxide, 4° nitric acid,"‘El silver oxide" and iodine49 generally forms quinone 13. The mechanism5 of the benzannulation reaction of a,B-unsaturated Fischer carbene complex 9 with alkyne 10 is shown in Scheme 1.3. The reaction initiates with a CO loss giving 16-electron unsaturated species 14. Kinetic studies designate this step as rate limiting.5b This is followed by alkyne coordination and insertion to form 111-n3 vinyl complex 15. Extended Huckel calculations by Hoffmann in 1991, rule out a metallacyclobutene 14a that would be expected from a [2+2] addition of the carbene complex and the alkyne as an intermediate or a transition state in this step.5"'5d Carbon monoxide insertion in (E)-15 then leads to n4-vinyl ketene complex 16, which upon six-electron cyclization and tautomerization furnishes the phenol-metal tricarbonyl complex 11 (Scheme 1.3). For alkenyl carbene complexes, carbon monoxide insertion and electrocyclic ring closure takes place in the same step, as there is no local minimum for the 11‘- vinyl ketene complex 16.59 This is, however, a two-step process for the aryl carbene complexes as revealed by the OFT calculations.5°'5"59 Scheme 1.3 Mechanism of the benzannulation reaction 0M9 0M9 R3 \OR (OC)sM=S___R2 R 5 (Dow; / nS—-* R 0 L RS 21 Scheme 1.5 shows some of the other products that can be obtained in \\3M(CO) (2H 8 addition to the phenol 25 from the reaction of an aryl Fischer carbene complex with an alkyne. Exhaustive studies have been done on a wide range of tungsten, chromium and molybdenum carbene complexes with several sterically and electronically perturbed alkynes.seal Based on these empirical results, the following generalizations can be made for factors that favor the formation of phenol products. Scheme 1.5 Different reaction products in a benzannulation reaction R S OMe + MeO |+Rs Rs M6 R OMe 0 ::the/$_2\ + PHM 0M9 +M:Ofi:lh 0R3 27 (OC)5Cr OMe 22 1. Metal Effect: The order of selectivity for the CO-inserted phenol product is chromium > tungsten > molybdenum. Tungsten and molybdenum carbene complexes, unlike chromium carbene complexes predominantly give non-CO inserted products like indenes and cyclopentadienes. 2. Carbene Ligand Effect: Fischer carbene complexes with alkenyl carbene ligands are less susceptible to reaction conditions (solvent, temperature and concentration) than are aryl carbene ligands. Furan products of the type 24 are more common for aryl carbene complex than for alkenyl complexes 3. Regioselectivity: The largest substituent on the alkyne is generally incorporated orfho to the phenol functionality in the product 25. In the case of terminal alkynes, a single isomer is usually formed and regioisomeric ratios greater than 250:1 have been measured in certain cases.8 The regioselectivity of internal alkynes depends on the difference in the steric bulk between the two substituents. The preferred regioselectivity in terminal alkynes has been explained on the basis of interactions of substitutents RL and Rs from the alkyne with the CO ligands in the vinyl carbene complexed intermediate 15b. Hoffman’s extended Huckel calculations shows that the substituent at 2-position of the vinyl carbene complexed intermediate is at least one angstrom closer to its nearest CO ligand than the substituent in the 1-position (Scheme 1.6).5°'5d However, it is not known for sure whether the alkyne insertion intermediates 15a and 15b are in equilibrium in favor of 15a, or whether the regiodifferentiation takes place kinetically at the alkyne insertion step. For alkynes with a tributyl stannane substituents9a or for alkynes with electron withdrawing groups,9b opposite regioselectivity is observed. However, the predominance of electronic factors over steric factors is rare. Scheme 1.6 Regioselectivity of Benzannulation Reaction 3 OR \ 2 1\\ Rs OC-M-CO CC CC OMe - (CO)50r R2 (E) 156 R3 OR — ”‘9 R1 / \\‘ Rs R39R1 yl' R20:C Race) :10: 16 RL ( 4 R 1\‘ RL 2R5 \ >04 M ___ M W OC-M-CO C" °' 00 CO (E)- 15b 4. Chemoselectivity: Sterically hindered alkynes are less reactive than alkynes with smaller substituents. Terminal alkynes are more reactive than internal alkynes. 5. Solvents effects: Non-polar and non-coordinating polar solvents give higher yield of phenol products in most instances. The amount of side products increases in DMF and CH3CN. 6. Concentration Effects: Higher alkyne concentrations favor phenol formation. This is known as the allochemical effect.10 In the vinyl carbene complexed intermediate 15 (Scheme 1.3) either solvent or alkyne can displace the weakly coordinated double bond. Alkynes can act both as 2- and 4-electron donors so that the metal center would remain electronically saturated after the CO insertion if it occurs with a switch of the alkyne from 2 to 4 electron donor. This pathway is expected to be faster than the uninduced CO insertion (El-15 since maintaining an 18—electron metal species should lower the energy barrier 7. Temperature Effects: High temperature adversely affects the regioselectivity of the benzannulation reaction and favors the formation of non- CO inserted products. 8. Stereoselectivity: Chirality on the alkyne and on the carbene ligand has been used for introducing planar, axial and central chirality in the product. Central chirality can be induced using B,B-disubstituted (1.6-unsaturated carbene complexes. The reaction of carbene complexes with alkynes has been utilized for the synthesis of a plethora of biologically active natural products and drugs possessing para-oxygenated benzene products or para-quinone moieties. Some of the compounds that belong to this category, are vitamins K1 29,11 anthracyclones (daunomycinone 30),12 furanochromone (khellin 31 and sphondin 32),‘:”"“'13b and fredericamycin A 33, (Figure 1.2).14 The benzannulation reaction has also been used in the synthesis of the chiral vaulted biaryl ligands VAPOL 34 and VANOL 35.15a These ligands have been used to generate superior catalysts 150 for Diels-Alder reaction, 15" aziridination reaction and iminoaldol reaction.15d Figure 1.2 Natural products and asymmetric ligands 29 Vitamin K1 0 O | OMeO o O 0 OMe OMe 31 Sphondin 32 Khellin 34 (S)-VAPOL 35 (S)-VANOL One of the goals of this thesis is to develop an approach to conocurvone 36 based on the reaction of three equivalents of complex 38 with triyne 39. Conocurvone 36 shows remarkable anti-HIV activity.16 It possess three quinone units which prompted us to explore the reaction of the carbene complexes with conjugated triynes to acquire the three quinone rings in one step. The three repeating units are derived from the natural product teretifolion-B, which constitutes of 3H-naphtho-7,10—dione[2,1-b]pyran unit. The reaction of chromene carbene complex 38 with triyne 39 could provide a direct route for the synthesis of the 3H-naphtho[2,1-b] pyran framework (Scheme 1.7). The synthetic efforts toward the total synthesis of conocurvone 36 and the utilization of Fischer carbene complexes in the synthesis of a library of 3H-naphtho-7,10-dione[2,1- b]pyrans will be discussed in Chapters four and three respectively. Scheme 1.7 Reterosynthetic analysis of conocurvone Dotz-Wulff Benzannulation reaction 1. Dotz-Wulff Benzannulation / reaction 2. Desilylation 3. Ox'dat'on H300 Cr(CO)5 ' ' / + TIPS—E—Z—Z—TIPS ~ 0 g‘ 38 39 1.3 Ortho-benzannulation of Fischer carbene complexes Heteroatom stabilized carbene complexes of the Group 6 metals are normally thermally stable to CO insertion to give ketene complexes. However, Hegedus and McGuire (1982) reported that metal coordinated vinyl ketenes 40a or 40b could be generated by photolysis of Fischer carbene complexes (Scheme 1.8).17 They showed that CO insertion could be induced in chromium and molybdenum Fischer carbene complexes by irradiation into the Metal Ligand Charge Transfer (MLCT) band. This results in the generation of a transient species, either the short-lived metallacyclopropanone 40a or metal bound ketene 40b, which was found to have ketene like reactivity. Hegedus has exploited these metal ketene intermediates for various cycloadditions reactions to generate a variety of compounds such as cyclobutanones 41, B-lactams 42 and B-lactones 43.18 Scheme 1.8 Photoexcitation of Fischer carbene complexes OC (I300?) M h 1' MeO Fi MeO Ft I,“ _. V OC/cHK e (0040' or (COMO-if CO R O O 39 \ 40a 40b J R, Y o If RSHJL R3 a? l MeO R1R4| MeO R5 R MeO R3 O 41 J 2 O O R N R 43 / 0/4 2‘R4 A number of photochemical studies of the Fischer carbene complexes have been carried out.18 The electronic absorption spectrum of metal carbene complexes shows three low-lying bands at 500nm, 350-450nm and 300-350nm. These are respectively assigned to a spin-forbidden metal-to-ligand charge- transfer (MLCT) transition, a spin allowed MLCT transition, and ligand field (LF) transition. A simplified one-electron energy level diagram for the tungsten methoxy phenyl carbene complex is shown in Figure 1.3. The filled sp2 orbital overlaps with the empty metal dz2 orbital to give bonding {a1 (0)} and antibonding {2a1(c‘)} combinations. A similar overlap of the empty carbene px orbital with a filled dn orbital gives rise to bonding {b1(1t)} and antibonding {2b1(n*)} molecular orbitals. The molecular orbital calculation on [Cr(CO)5{C(OMe)Me} places 2b1(1r‘) below 2a1(o"') in the energy level diagram. The LF bands are observed due to the promotions of the electron to the metal centered dx2-y2 orbital (or c”) orbital. The MLCT band results from the excitation of electron from a non-bonding metal- centered orbital to a carbene-carbon p orbital centered n‘ orbital. l3 Figure 1.3 One-electron energy level diagram for tungsten complex [W(C0)5{C(OMe)Ph}l a1(dx2-y.2-) --------- 3a1 ,,,,,,,,,, 2a1(8') a1‘~~‘:~. I I \ I I I I \ I “ I ...... \.---....- , \ Q‘ \ ’/ blidxz).b2(dyz>““3‘~.;-.\ ”If ans-03p?) + ......... \ 53-- “)1 ” a2 (dxy) all? a1(s) W(C0)5 (QC)5w= O 1 + 2 rearrangement O. R R 958 96 97 R3 \ F12 1 Tautomerization: I OH electrocyclisation: 1.5-H shift 0’ 98 This approach is marred by low yields due to competitive Meyer-Schuster and Rupe rearrangements (Scheme 2.10).37 The Rupe rearrangement deals with the acid-catalyzed isomerization of tertiary ol-acetylenic alcohol 99 to predominantly form a,B-unsaturated ketone 104 rather than the a,B-unsaturated aldehydes formed in Schuster—Meyer rearrangement. This rearrangement is believed to proceed via a dehydration-hydration sequence with enynes as intermediates. The first step involves the acid catalyzed dehydration of alcohol to form the tertiary propargyl carbocation 100 followed by proton elimination to form enyne 101. Further electrophillic attack of proton on enyne 101 gives secondary carbonium ion 102, which upon quenching with water furnishes wit-unsaturated ketone 104. The Meyer-Schuster rearrangement is the isomerization of 31 Si secondary and tertiary a-acetylenic alcohols 92 to a,B-unsaturated carbonyl compounds 106. The requirement for this rearrangement is the absence of hydrogen atom in the homopropargylic position. Thus the secondary or tertiary carbocation 95a obtained upon acid catalyzed dehydration of the propargylic alcohol can not undergo proton elimination to form enynes. Instead, the propargylic carbocation 958 reacts via the allenyl cation resonance structure 95b which is trapped by water to furnish the a,B-unsaturated carbonyl product 106. Effectively, the rearrangement involves a 1,3 shift of the hydroxyl group. Scheme 2.10 Rupe rearrangement 100 101 ,. OH 0 H+ . 102 103 104 Schuster-Meyer Rearrangement R3 R3 1 R2 OH R2 R2 92 95a R1 95b R1 R3 Rex?” R1,R2=tert-Bu orAr ‘—’ > ' I R =H,al lora l 92 OH 0 3 ky 'y 105 105 Carriera has dramatically improved the yields of these reactions by using (MeO)3CH as dehydrating agent in the presence of the PPTS (Scheme 2.11)?3 The reaction of diphenylpropargyl alcohols 107 and 2-naphthol 91 using the PPTS (pyridinium p-toluene sulfonate) and (CH30)3CH combination gives a 92% 32 yield of the napthopyran 108, which is significantly higher than with p-TsOH (toluene solvent, 62% yield), p-TsOH with silica support (56%) or with PPTS alone (2% yield).33 Scheme 2.11 Carriera’s protocol for synthesizing 3H-naphtho[2,1-b]pyran ArOH + LP“ R9399” Product ”0 Ph 107 AFOH Reagent Yield Product OH PPTS, (MeO)30H 92% p-TsOH/Silica 56% 91 p-TsOH 62% PPTS 2% PPTS, (MeO)3CH 80% Silica/p-TsOH 17% p-TsOH 12% Tanaka has reported a solvent-free solid—state version of this reaction. In this protocol a mixture of diaryl propargyl alcohol, p-TsOH, 2-naphthol and a small amount of silica gel was thoroughly ground and left at room temperature for 1 hour to give the napthopyran (12-57% yield).35 Sartori has utilized HSM-360 zeolite for the reaction of alkyl-aryl propargyl alcohol with 2-naphthol for synthesizing naphthopyrans. Zeolite HSM-360 and p- TsOH give comparable yields.36 In brief, Bronsted acids like p-TsOH provide a general approach for the synthesis of C-3 alkyl-alkyl, aryl-aryl and alkyl-aryl substituted naphthopyrans. ln Carriera and Tanaka’s reports, there are no examples of alkyl-alkyl substituted 33 naphthopyrans. Satori’s method is general for obtaining C-3 alkyl-aryl or alkyl- alkyl substituted naphthopyrans. b) Kabbe’s synthesis: This synthesis commences with naphthopyran 111 and requires the reduction of ketone followed by dehydration (Scheme 2.12). Alternatively, naphthopyran 111 can be treated with PBr3 to obtain bromo- derivatives of naphthopyrans 112. This approach requires a multistep sequences and it is not as widely used.38 Scheme 2.12 Benzochromanone to 3,3—dialkyl naphthopyran O Br / CD 0 13 CO 0 111 112 28% yield 0) Benzocoumarin approach: The reaction of benzocoumarin 113 with Grignard reagents and subsequent dehydration gives substituted naphthopyrans (Scheme 2.13). This method is low yielding for 3,3-diaryl naphthopyrans 108.39 Scheme 2.13 Benzocoumarins to 3,3-dialkyl naphthopyran R 0 a) RMgBr _ 0 R Yield 0‘ b) glacial AcOH 00 CH3 (114) 75% O 113 Ph (108) 20/o d) Acid/Base catalyzed condensation of aldehydes and phenols: Condensation of 2-naphthol with 0t,B-unsaturated aldehydes can be effected by heating in 4-picoline,‘°a glacial acetic acid / PhB(OH)24°° and the Lewis acid titaniumtetroethoxide40c to furnish naphthopyran 114 (Scheme 2.14). 34 Scheme 2.14 Condensation of 2-naphthol and mil-unsaturated aldehydes O W / OH — 93 ° Rea ent V 91 g 114 Reagents (% Yield): 4-methylpyridine/heat (80%), glacial acetic acid/PhB(OH)2 (95%) titanium tetraethoxide (39%) e) Zammattio’s Approach: Zammattio has utilized the acid catalyzed ring opening of epoxide 116 followed by dehydration as a method for synthesizing functionalized naphthopyran 117. Epoxide 116 can be obtained in two steps by reaction of the commercially available 2-hydroxy-1-naphthaldehyde 115 with allyl Grignard reagents (Scheme 2.15).41 Scheme 2.15 Transformation of 116 to 3,3-dialkyl naphthopyran 117 O H ::<' HO O / OH “OH 3. MgBr ‘ OH p-TsOH O 00 b. epoxidatiorr 0O DO 115 115 117 17% yield over 3 steps f) Talley’s Approach: Lithium-halogen exchange of 1-bromo-2-naphthol 118 with n-butyllithium followed by reaction with 109 produces allylic alcohol 119, which upon acid catalyzed cyclization yields 3,3—dimethyl naphthopyran 114 (Scheme 2.16).42 35 Scheme 2.16 Transformation of 118 to 3,3-dialkyl naphthopyran 114 Br HO I / OH a) 2 GQUIV n-C4H9Li OH p-TsOH DC 0 118 b) M I I H / 119 114 90% 109 g) Oxidation of orfho-allylic phenols: Cyclodehydrogenation of orfho-(3,3- dimethylallyl)naphthols (120 and 121) using 2,3-dichloro-5,6- dicyanobenzoquinone438 or trityltetrafluoroborate43b is another way of synthesizing naphthopyrans (114 and 122, Scheme 2.17). Scheme 2.17 Oxidative cyclization of orfho-(3,3-dimethylallyl)naphthols R l I I OH Reagent ‘ R Reagent % Yield (product) CH3 120 Trityltetrofluoroborate 85 (114) — 121 DDQ 46 (122) In summary, acid catalyzed condensation of the phenols and the propargyl alcohol is the best and the most widely used method to synthesize a diverse range of 3H-naphtho[2,1-b]pyrans. Other methods are also efficient but they only work well for specific substrates. 36 Be Sc HG 2.5 Total Synthesis of natural products 81 to 89 Cannon and coworkers have achieved the unambiguous characterization of naphthopyrans 81 to 89 by their total synthesis (Scheme 2.8).2’3‘3“44 To confirm the structures of the nine quinones, compounds 81, 83 and 89 were synthesized and subsequently derivatized to the quinones (84, 85, 86, 87, 88). The structure of compound 85 has been confirmed both by synthesis and X-ray analysiszaa'b The synthesis of 81 is shown in Scheme 2.18. Reaction of naphthalene- 2,7—diol 123 with 1,1-dimethoxy—3-methylbutan-S-ol 124 in pyridine solvent gave 125, which upon reaction with phenyl diazonium chloride formed azo dye 126 (Scheme 2.18). Reduction of 126 with Na28204 and then oxidation of the product with FeCI3 yielded orfho-quinone 127. Compound 127 upon oxidation, using '280 Baillie and Thomson’s protoco and C-methylation furnished compound 81. Scheme 2.18 Synthesis of naphthoquinone pyran 81 synthesis from 123 HO“EEOH K: HO E l/O Pyridine 123 125 a) Na2S2O4 a) t-,BuOK 02 o b) FeCla 0‘? b)( (CHsCOO)2 37 A similar sequence of reactions was used to prepare compound 83 from naphthalene-2,7-diol 123 (Scheme 2.19). Condensation of 123 with citral 128 in pyridine solvent gave compound 129, subsequent diazotization with phenyl diazonium chloride, reduction with Na28204 and oxidation with FeCI3 yielded orfho-quinone 131. Compound 83 was obtained by oxidation of orfho-quinone 131. C-methylation of 83 gave 84 and then O-methylation afforded compound 85. Scheme 2.19 Synthesis of naphthoquinone pyrans 83, 84 and 85 from 123 a) N828204 b) FeCi3 38 The synthesis of the naphthoquinone 86 with an open pyran ring was then achieved from 125. The free alcohol in 125 was protected using MOMCl to afford 132 (Scheme 2.20). The protected naphthopyran 132 was reduced using Li in liquid NH3 followed by immediate O-methylation and acid hydrolysis to give compound 133 (Scheme 2.20). Compound 133 was then oxidized to the para- quinone 89 with Fremy’s salt. C-methylation of 89 yielded para-quinone 87. Demethylation of compound 87 with sodium ethoxide afforded para-quinone 86. Treatment of 87 with HBr resulted in demethylation followed by acid-catalyzed cyclization to furnish compound 81. Scheme 2.20 Synthesis of naphthoquinone pyran 81 and naphthoquinones 86 and 87 OH OMOM I gill IWOMCI Ii.” \ '—"‘ 0 \ a) Li, liquid NHzL “0 0C OCHs 0 O O b) O-methylation H+ 125 132 c) 133 a) Fremy's I Salt [HFBMN( OCH3 O HO OH GO \OE o O HO HO OCH3 as (CH3000)2 0O 0 / 0 V ”° 00 ° / .. o .. 0 81 39 A reaction sequence similar to that used for the conversion of 125 to 86 (Scheme 2.20), was used to transform compound 129 to 88 (Scheme 2.21). Scheme 2.21 Transformation of naphthopyran 129 to naphthoquinone 88 In summary, 3H-naphtho[2,1-b]pyrans are important structures in natural product chemistry and important photochromic compounds. However, there are limited numbers of method for synthesizing these naphthopyrans and naphthoquinone pyrans. One of the most widely used methods is the acid catalyzed cyclization of propargyl alcohols and naphthol derivatives. This method is, however, marred by low yields. Carriera has drastically improved the yield of this reaction by using trimethyl ortho formate with PPTS. This method is good for making napthopyrans with aryl substituents (alkyl substituents are not reported) at C-3 carbon atom. All other methods generally require multi-steps for the synthesis of naphthopyrans. Thus there is an essential need to develop new methodologies to access these compounds. Chapter 3 explores the benzannulation reaction of Fischer carbene complexes with alkynes as an unique new approach. 40 CHAPTER THREE SYNTHESIS AND BENZANNULATION EXPLORATIONS OF CHROMEN-5-YL CARBENE COMPLEX 3.1 Introduction Chapter two documents the importance of 3H-naphtho[2,1-b]pyrans. In this Chapter the synthesis of chromene carbene complex 135 and its reactions with various alkynes to access naphthoquinonepyrans of the type 138 and naphthopyrans of the type 139, will be discussed. The study begins with targeted synthesis and reactions of carbene complex 135 where R1, R2 = CH3 (Scheme 3.1). Scheme 3.1 Benzannulation of chromene carbene complex 135 R R3 o \ O \ R2 Oxidation O R1 (OC)3Cr R 138 R : R3 R3\ OCH3 \ R2 136 \ HO O R1 R2 Oxidation R 135 04 R1 a 137 R O OCH3 HO \ R2 0 1 139 R 41 3.2 Synthesis of chromium chromen-S-yl carbene complex 135 Fischer carbene complexes with aryl substituents are typically made from the corresponding aryl halides. In the case of carbene complex 135, this would require the aryl halide of the type 140. Four different strategies were considered for the synthesis of 5-halochromene (141 or 142) viz. Hepworth,45 Nicolaou,"’6 42,47,48 49.50 allylic alcohol cyclization and Chromenone approaches (Scheme 3.2). The three out of four approaches i.e., Nicolaou’s, allylic alcohol cyclization and Chromenone approaches have been examined in the present work. Hepworth’s approach has not yet been tried. Scheme 3.2 Four approaches for synthesizing halochromene 141 egg /v m/ 12; g: Fr< W a) Nicolaou's Approach; b) Hepworth's Approach; c) Allylic Alcohol cyclization d) Chromenone approach 3.2.1 Hepworth’s Method Hepworth has synthesized 5-iodochromene 142 starting from 146, which was obtained from phenol in two steps (Scheme 3.3).45 This utilizes the ability of benzylic alcohol to direct ortho-lithiation. The reaction of 2,2-dimethylchroman-4- 42 ol 146 with n-BuLi/TMEDA gave a dilithiated compound, which upon reaction with l2 afforded iodide 148 in 46 % yield. This sequence gave a lower yield of 5- bromochromanol (12 %) 147. The acid catalyzed dehydration of 148 furnished 5- iodo chromene 142 in 79 % yield. Scheme 3.3 Hepworth protocol for synthesis of 5-Iodo-2H-chromene 142 OH X OH X a. n-BuLi/TMEDA_ p-TsOH/Heat \ o b. x2 0 o 145 147, X=Br, 12% 142,X=|,7g % 148, X = I, 46 °/o 3.2.2 Nicolaou’s Method Nicolaou’s protocol uses the reaction of polystyrene based selenium- bromide resin and orfho-allylic phenols for synthesizing libraries of 2H- benzopyran units.46 He has demonstrated that orfho-allylic phenol obtained by the reaction of phenol derivatives with allyl bromide, upon sequential treatment with phenyl selenyl bromide resin and hydrogen peroxide yields 2H-chromenes. The desired bromochromene 141 was isolated in 90 % purity using this method starting from commercially available 3-bromo-phenol 149 (Scheme 3.4). However, the selective C-alkylation of 3-bromophenol 149 could not be achieved using the reported protocol. The reaction of sodium phenolate, generated from NaH and 3-bromophenol 149, gave an inseparable mixture of products when reacted with 4-bromo-2-methyl-2-butene which was comprised of mono— and di-allylated products as indicated by GC-MS. 43 801 3.2 Oli' the Sc The 95 Scheme 3.4 Nicoloaou’s protocol for synthesis of 5-bromochromene 141 Br Br Br OH b) 4-bromo-2-methyl OH b. H202 O -2-butene 149 143 141, 90 % purity 3.2.3 Allylic alcohol cyclization approach 478 Talley“, Cruz-Almanza and Snieckus,47b have employed the reaction of on‘ho—lithiated aromatic alcohol with aldehyde to produce allyl-benzyl alcohols of the type 151 which upon cyclization yields the 2H-chromenes (Scheme 3.5). Scheme 3.5 Snieckus and Talley ortho-Iithiation strategy Talley, 1983 CEOH a.n-BuLi 0” 1+“ 0 R1 Br I" W0 F11 \ R1 150 H ‘51 OH 152 109 Snieckus, 2001 Et2NOCO R, a. t-BuLi/THF,-78 °c \ 1 = 0 R a b.109 153 R2 c.AcOH 154 R2 R1 = 000N192, OMe, F, OMOM; R2 = CH3, OMe This approach can not be utilized for the synthesis of 8-bromochromene. The generation of 145 would require selective metal-halogen exchange of 2,3- dibromophenol 155 (Scheme 3.6). The metal-halogen exchange could potentially lead expl Sci 5-l 2-l S I \‘I So lead to the formation of two anions 156 and 158. Further, these anions would be expected to be susceptible to bromide elimination to form benzyne 157. Scheme 3.6 Ortho-lithiation approach towards 141 00 OH OH 4. ..... —'X'-—" _ Br Br \ l a i “5 ' E . r OLi 0“ \ 0r . 157 Br 153 141 An alternative approach to obtain benzylic-allylic alcohol 145, for preparing 5-bromo-2H-chromene 141, is by the reaction of 5-bromosalicaldehyde 159 with 2-methylpropenyllithium (Scheme 3.7). The requisite aldehyde 159 for this synthesis has been previously prepared by Couture for other purposes.48 Scheme 3.7 Allylic-alcohol cyclization approach Br OH OH OH 0 ' \ \ / Ll/Y H 2) :) 0 Br Br 145 141 159 Couture’s synthesis of 159 started with installation of an orfho-directing imidazolidine group by reacting aldehyde 160 with bis-1,2-(methylamino)ethane to give 161. Imidazolidine 161 was then ortho-lithiated (3 equiv of t-BuLi) and brominated using dibromotetrachloroethane (3 equiv) which, upon acidic workup provided 2-bromoanisaldehyde 162. The orfho-lithiation and bromination step were reported at room temperature by Couture to give 162 in 78 % yield. When 45 this reaction was repeated under the same conditions, a 2:1 mixture of bromoanisaldehyde 162 and chloroanisaldehyde 163 was obtained in 35 % yield (entry 1, Scheme 3.8). It was found that the ratio of 162 : 163 showed a noticeable dependence on the temperature of the reaction (Scheme 3.8). Optimal conditions required orfho-lithiation at -40 °C and the addition of the brominating agent at -78 °C which gave a 69 % yield of 162 (entry 8) and only a trace amount of163(162:163=50:1). Scheme 3.8 Synthesis of bromoanisaldehyde 162 \ \O O m \o \N’> a) f-BuLi , Et2O, \o .0 O O (2%” —NH HN— T @N 64333) Et 0 = @5511. d” MgSO4, EtOH \ terftp (T: 2 Br Cl 160 161.77% c)2NHCI,rt,1 h 162 153 Entry t-BuLi Temp T1 Temp T2 Ratio Yield (Equivalent) (°C) (°C) 162 : 163 162 + 163 (%) 1 3.0 25 25 1 :0.5 35 2 2.0 25 25 1 :0.3 48 3 1.2 25 25 1 :0.3 41 4 1.2 25 25 - No product3 5 2.0 14 14 to 25 1 : 0.3 43 6 3.0 0 0 to 25 1 : 0.18 52 7 3.0 -20 -20 to 25 1 : 0.18 72 8 3.0 -40 -78 to 25 50 : 1 69 All reaction were carried out in EtZO (0.1 M) solvent with 3 equiv of (BrgClC)2 as the brominating agent. a) NBS (3 equiv) and Br2 (3 equiv) were used as the brominating agent. Demethylation of 162 using BBr3 afforded 2-bromosalicaldehyde 159 in excellent yield (94 % yield). Aldehyde 159 was then reacted with 2-methyl propenyl lithium to obtain crude benzylic-allylic alcohol 145 (Scheme 3.9). The 46 crude reaction mixture was subjected to acid catalyzed cyclization which afforded a mixture of 141 and 165 after column chromatography (141 : 165 = 10 : 1). Further purification using Kugelhrohr distillation afforded 141 : 165 in a 40:1 ratio and in 60 % yield from 159. The structure for the compound 165 was assigned on the basis of its molecular weight. This route provided 5-bromo chromene 141 in 30 % overall yield from commercially available anisaldehyde 160. Scheme 3.9 Allylic alcohol cyclization approach continued OH 0 Li \ ,EtZO OH OH OH / GM. (2294) / / = + Br -40 °C, 30 min Br Br 145 164 159 then0°C4h Br TsOH, toluene _ m+ O 141 , 60% 3.2.4 Chromenone approach In order to improve the overall yield of 141 another route for its synthesis was explored. This pathway used 5-hydroxychromene 166, which can be obtained in two steps from commercially available cyclohexadienone 167 and 3- methyl-2-butenal 109 (Scheme 3.10).49 The proposed conversion of phenol 166 to bromochromene 141 is based on the methodology that has been developed for related compounds utilizing triflation, Pd catalyzed triflate-Sn exchange and NBS mediated Sn-Br transfer.5°‘i"b 47 Scheme 3.10 Chromenone approach Br OH O 0 (if): m: C103“ 0 O O 141 166 167 109 According to the literature procedure, 1,2-ethanediammonium acetate catalyzed condensation of 1,3-cyclohexanedione 167 and 3-methyl-but-2-enal 109 in methanol afforded Chromenone 144 in 78 % yield (Scheme 3.11).49a Groot and Jansen have reported a yield of 82 % for the same reaction when instead of using 1,2-ethanediammonium acetate the reaction was refluxed in pyridine.49b Sequential DDQ oxidation50 and triflation of compound 144 gave chromene 168 in two steps and in 51 % yield. Scheme 3.11 Synthesis of chromene triflate 168 O / O o W 109 : I \ 1 ,2-ethanediammonium- O O acetate, EtOH 157 144, 78 % l DDQ, Dioxane OTf OH \ 0 o 168, 97 % 166, 53 % The DDQ oxidation of 144 to 166 was less than optimal (53 % yield). Thus, a high yielding method for chromenol 166 synthesis was desired. Jacobsen has reported that refluxing of naphthalen-2,7-diol 123 with citral 128 in 4-picoline gives 82 % yield of naphthopyran 129.“4 This prompted us to examine the base assisted condensation of resorcinol 169 with 109 to synthesize 166 48 CI al I? even though Crombie and Whiting have reported low yields in a related reaction with resorcinol.51 Refluxing a mixture of resorcinol 169 and 109 in pyridine or picoline solvent yielded a complex mixture of compounds, with the desired chromenol 166 being formed in less than 10 % yield in each case (Scheme 3.12). Scheme 3.12 Reaction of resorcinol 169 with 3-methyl-but-2-enal 109 O H N CH 128 OH Ho 0 4-picoline 123 129, 82% O / OH YT OH CL 109 ; (I) + Mixture of compounds Pyridine, reflux o 169 OH 166 Less than 10 % The next step was to carry out palladium catalyzed triflate-tin exchange on triflate 168. Heating 168 with hexamethylditin and Pd(PPh3)4 in THF solvent led to the recovery of most of the starting material after 48 h (Scheme 3.13, entry 1).523 Further optimization of the reaction conditions revealed that high reaction temperatures and long reaction times are requisite for the reaction to go to completion. GC analysis of the reaction mixture, after heating of reaction mixture at 110 °C for 96 h, showed the presence of the desired (2,2-dimethyl-2H- chromen-5-yl)-trimethyl-stannane 170 (84 %) along with chromene 171 (7 %) and another unidentified compound (9 %) (entry 4). The attempt at purification of 170 using silica gel column chromatography was of no avail, as it yielded a 49 mixture of 170, 171 and triphenylphosphine. Attempts to reduce the reaction time by switching to high boiling solvents like DMF and dibutyl ether proved futile. Dibutyl ether resulted in the precipitation of the Pd black at 120 °C and the starting material remained intact after an (entry 5). A significant amount of the side product 171 was observed in DMF solvent, although the reaction was very fast with 100 % conversion in 20 minutes at 160 °C (entry 6). Reduction of the temperature from 160 to 120 °C didn’t show any improvement in the ratio of 170 : 171 (entry 7). Scheme 3.13 Palladium catalyzed triflate-Sn exchange OTf SnM93 5 { Pd(PPh3)4,(M93$n)2 m m LiCl, Tern 0 16(8)1 Time p 17113 171 Entry Solvent Temp Time (h) Conversion GC Ratio (0.1M) (°C) (%) 170 (%) 171 (%) 1. THF 60 48 3 3a — 2. Dioxane 105 8 10 10 - 3. Dioxane 1 05 48 77 25 28 4. Dioxane 1 1 0 96 1 00 84 7 5. Dibutyl ether 120 8 2 - - 6. DMF 160 0.2 100 19 54 7. DMF 110 100 100 29 69 Unless othenlvise stated all reactions were carried using 0.1 M solution of solvent using 168:(Me3Sn)2:Pd(PPh3)4:dppf:LiCl in the ratio of 1:0.9:0.02:0.45:6.0. a) no dppf used. Steric hindrance from the hydrogen at C-4 in chromene trilflate 168 may be source of the low reactivity. It is known from previous studies that palladium catalyzed triflate-Sn exchange of phenyl triflate 172 using hexamethylditin 50 requires 22 h to go to completion at 98 °C in dioxane solvent (Scheme 3.14),52b whereas only 77 % conversion of chromenyl triflate 168 to stannane 170 was obtained in dioxane solvent at 105 °C after 48 h (entry 3, Scheme 3.13). Scheme 3.14 Palladium catalyzed triflate-Sn exchange OTf SI'IM63 Pd(PPh3)4. LiCl : O (Megsnlz. dioxane O 04 98 °C, 22 h 04 172 173 An alternative method to convert triflate 168 to stannane 170 is to use stannyl cuprates which can be synthesized in-situ using tributyltinhydride, n-BuLi and CuCN.53 This method is attractive because all of the reagents are cheap. The coupling approach shown in Scheme 3.13, requires Pd(PPh3)4, dppf and hexamethylditin, all of which are expensive. The reaction of 168 with the tributylstannyl higher order cuprate was examined at different temperatures ranging from -78 °C to -25 °C, but in all cases a mixture of starting material 168 and phenol 166 was obtained in ratios ranging from 0.6 : 1 to 1 : 1 depending on the reaction temperature (Scheme 3.15). Thus the only way to access stannane 170 is via the coupling route. Scheme 3.15 Stannyl cuprate addition to chromene triflate 168 OTf 0T1 OH \ (BU3Sn)2CuCNLi2, THF \ \ : + O -78 °C to -25 °C 0 Q 168 168 166 Triflatezphenol 0.6:1 to 1:1 51 The impure chromene stannane 170 obtained after silica gel purification was then converted to the corresponding bromochromene 141. The reaction of stannane 170 with bromine resulted in decomposition of starting material (Scheme 3.16). Tin-lithium exchange of chromene stannane 170 with n-BuLi and then Li-Br exchange using NBS resulted in a mixture of bromochromene 141 and chromene 166 in the ratio of 14 : 61 by GC. A mixture of bromochromene 141, chromene 171 and chlorochromene 174 was observed in the ratio of 44 : 28 : 29 by GC when NBS was replaced by dibromotetrachloroethane. The structure of compound 174 was assigned based on the molecular weight obtained using GC- MS. Eventually, treatment of 170 with the mild brominating agent NBS provided the desired Sn-Br exchange to give chromene 141 in 65 % yield from chromene triflate 168. Furthermore, the overall yield of 141 from 168 can be increased to 75 % in two steps by quenching the crude reaction mixture containing chromene stannane 170 with NBS. Scheme 3.16 Bromination of chromene stannane 170 Br Decomposition Brz, CHZCIZ a) n-BuLi, Et20 \ \ of t 5 1 starting material I» NBS' Et20 o O SnM63 141, 14% 171, 61 % \ __ Br Br 0 \ \ 170 + \ - O O a n-BuLl, Et 0 3‘35- THF ) 2 >141. 44 % + 171, 28 % O o b) BI‘CIZCCCIng‘, CI 141, 65 /o Et20 \ The percentage represents the GC ratio of the crude reaction mixture 0 174, 29 % 52 The Chromenone approach provides 5-bromochromene 141 in 30 % overall yield starting from cyclohexane-1,3-dione 167 and 3-methyl-but-2-enal 109. The bromochromene 141 produced from this method can be obtained in pure form and does not require tedious workup or purification procedures. However this approach is marred by the use of expensive reagents as stated earlier. The initial approach involving the allylic alcohol cyclization provides overall comparable yield (30 %) but does not require use of expensive reagent. However in this approach, the bromochromene 141 was isolated in the ratio of 40 : 1 (141 : 165) after column chromatography and lengthy Kugelhrohr distillation. In addition, a disadvantage is that both bromides 141 and 165 are converted to carbene complexes and they can only be separated by careful chromatography. These shortcomings give the Chromenone approach an edge over the allylic alcohol cyclization method. Finally, the synthesis of chromene carbene complex 175 was achieved by the standard Fischer procedure as indicated in Scheme 3.17. Treatment of 141 with 2equiv of t-BuLi, subsequent reaction with Cr(CO)6 and final alkylation with Me30BF4 gave 175 in 81 % yield as red crystalline solid. This carbene complex is much more stable than other aryl carbene complex. It can be stored at room temperature for 6 - 7 days under Ar atmosphere without significant decomposition. Furthermore, it shows essentially no decomposition after 2 days in the presence of air and light. 53 Scheme 3.17 Chromene carbene complex 175 synthesis Br MeO Cr(CO)5 a) f-BuLi, EtZO, -78 °C \ s \ m b) Cr(CO)6, EtZO, 0 °C to rt 0 rt for 8 h 0 141 c) MegOBF4, CH20l2, rt, 175' 81% 1 h 30 min 3.3 Chromium chromen-5-yl carbene complex 175: Study of Ddtz-Wulff Benzannulation Reaction With the synthesis of carbene complex 175, the stage is set for exploring the benzannulation reaction of chromene carbene complex 175 and a new method for the synthesis of 3H-naphtho[2,1-b]pyrans. Four alkynes were selected for this study: phenyl acetylene, 3-hexyne, 1-pentyne and trimethylsilyl acetylene. The study was initiated with phenyl acetylene and as a consequence most of the optimization of temperature and solvent effect was performed on this alkyne. The first reaction of phenyl acetylene with carbene complex 175 gave disappointing results. Heating carbene complex 175 with phenyl acetylene for 24 h at 60 °C followed by air oxidation, to remove any chromium tricarbonyl group, yielded a mixture of compounds containing trace amounts of the desired naphtholpyran 177 and the corresponding quinone 178 (Scheme 3.18). On subjecting 1-pentyne to similar reaction conditions, naphtholpyran 180 was not obtained. Instead quinone 181 was isolated in 16 % yield. Similarly, 3-hexyne did not give a clean reaction with complex 175. 54 Scheme 3.18 Benzannulation of complex 175 with phenyl acetylene .. (3% 176 benzene, 50 °C, 24 6 HO D. Air oxidation, rt, 10 h MeO Cr(CO)5 \ O 175 a. E_/— OMe 179 I‘ _ \ + r \ benzene, 50 °C, 24 h HO O b. Air oxidation, rt, 10 h 0 13° 1 1 1 °/ Not observed 8 ’ 6 0 One possible explanation for these observations is that the phenols 177 and 180 (or their chromiumtricarbonyl complexes) are not stable to these reaction conditions. Specifically, these two phenols could be either decomposing during the course of the benzannulation reaction or could be sensitive to conditions of the air oxidation. To render phenols 177 and 180 more robust and thus increase the yields of these reactions, it was decided to trap the phenol products during the benzannulation reaction by adding protecting reagents at the beginning of the reaction.54 This type of process has been previously reported for a number of different electrophiles.“ Upon heating complex 175 and phenyl acetylene in the presence of TBSCI and Hunig’s base in benzene for 24 h at 50 °C, the product naphtholpyran 182 was isolated in 27 % yield (entry 2, Scheme 3.19). When the reaction was run at room temperature for 6 days, compound 182 was obtained in 45 % yield 55 (entry 3). The more reactive TBSOTf gave a slightly higher yield 57 % at 60 °C temperature (entry 4). Scheme 3.19 Benzannulation of complex 175 with phenyl acetylene MeO Cr(CO)5 I I a. Benzene, Hunig's base \ + protecting reagent 0 b. Air oxidation, 175 176 rt, 10 h 177,182 0 Entry Protecting reagent P Compound (% Yield) 1 - H Complex mixture observed8| 2 TBSCI TBS 182 (27) 3 TBSCI TBS 182 (45)b 4 TBSOTf TBS 182 (57)0 Unless otherwise specified, the benzannulation reactions were carried out in benzene (0.05 M) with protecting reagent (3 equiv), Hunig’s base (5 equiv) and 1:2 mixture of complex 175 to phenyl acetylene for 24 h under Ar at 50 °C. a) No Hunig’s base is used. b) Reaction was carried out at 25 °C for 6 days. c) Reaction was carried out at 60 °C, compound 182 (P=TBS) was isolated after column chromatography as mixture of compounds, the yield of compound 182 was determined using toluene as internal standard. The size of the protecting group plays a role in this reaction. When the bulkier TBS group was replaced by smaller TMS protecting group, the yield of the reaction increased notably from 27 % to 65 % (entry 1, Scheme 3.20). Surprisingly, when the more reactive TMSOTf was employed the yield decreased markedly (entry 4). Encouraged by the success with the smaller trimethylsilyl protecting group, other protecting groups were examined. Reaction of complex 175 with phenyl acetylene in the presence of Ac20 yielded compound 184 in a 57 % yield (entry 5). The structure of compound 184 has been confirmed by X-ray 56 crystallography. DMAP is known to greatly accelerate the acetylation of alcohols.55 However, DMAP did not have any effect on the yield of the compound 184 (entry 6). Another smaller but less reactive protecting group, MOMCI, provided a yield of 185 (60 % yield) comparable to that of compound 183 from TMSCI (entry 7). Triflic anhydride as a protecting group was also investigated since it would provide a facile route for the introduction of carbon substitutents via metal-catalyzed coupling reactions. This reaction was tried via two different procedures: concurrent protection and stepwise protection (entry 8).10 In the first approach, complex 175, phenyl acetylene, Tf20 and Hunig’s base were dissolved in benzene and heated to 50 °C for 24 h. In the second approach, complex 175 and phenyl acetylene were first heated in benzene for 24 h at 50 °C. Then the reaction mixture was cooled and Tf20 and Hunig’s base were added and the reaction mixture was stirred for another 24 h at 25 °C under Ar atmosphere. Both pathways proved unsuccessful in yielding the desired compound. The stepwise approach was tested for phenylacetylene with a TMSCI additive which proved to be detrimental to the yield of the reaction. The yield decreased from 65 % (concurrent approach, entry 1) to 25 % (stepwise approach, entry 2). Compound 183 was isolated in a yield of 62 % when the reaction mixture was degassed, using freeze-pump-thaw, after addition of the additives TMSCI and Hunig’s base (entry 3). This indicates that the low yield in stepwise approach was due to the trace amount of air which possibly entered the reaction flask during the addition of the additives. 57 Scheme 3.20 Benzannulation of complex 175 with phenyl acetylene using different protecting group. MeO Cr(CO)5 I I OMe \ \ + a. Benzene, Hunig's base 0 protecting reagent : PO \ 0 b. Air oxidation, 0 175 176 "-10“ 183-185 0 Entry Protecting reagent P Compound (% yield) 1 TMSCI TMS 183 (65) 2 TMSCI TMS 183 (25) a 3 TMSCI TMS 183 (62) b 4 TMSOTf TMS 183 (25) 5 A620 Ac 184 (57) 6 AC20 Ac 184 (57) ° 7 MOMCI MOM 185 (60) 8 ngO Tf Complex mixture observedd Unless otherwise specified the benzannulation reactions were carried out in benzene (0.05 M) solvent with protecting reagent (3 equiv), Hunig’s base (5 equiv) and 1 : 2 mixture of complex 175 to phenyl acetylene for 24 h under Ar at 50 °C. a) Stepwise method: After 24 h, TMSCI and Hunig’s base was added and the reaction mixture was stirred for another 24 h at room temperature (No free-pumpcthaw degassing done). b) Stepwise method: After 24 h, TMSCI and Hunig’s base was added and reaction mixture was degassed using freeze- pump-thaw which was followed with stirring continued for another 24 h at room temperature under Ar. c) DMAP (5 mol %) used. d) Attempted with two procedures (see text). The benzannulation of complex 175 with phenyl acetylene did not show any dependence on the temperature. Upon increasing the temperature from 50 to 125 °C there was only a small change in the yield of compound 183 (entry 1-4, Scheme 3.21). However, this reaction is dependent on the solvent used. There was a slight decrease in the yield of the reaction with an increase in the coordination ability of the solvent (entry 5 and 6). 58 Scheme 3.21 Benzannulation of complex 175 with phenyl acetylene using TMSCI protecting group In different solvents MeO Cr(CO)5 II OMe / a. Benzene, Hunig's base + TMSCI : TMSO O b. Air oxidation, 175 180 rt, 10 h 133 Entry Temperature (°C) Solvent % yield 1 50 Benzene 65 2 75 Benzene 67 3 100 Benzene 68 4 125 Benzene 68 5 50 THF 60 6 50 CH30N 55 Unless otherwise specified the benzannulation reactions were carried out in benzene (0.05 M) solvent with TMSCI (3 equiv), Hunig’s base (5 equiv) and 1:2 mixture of complex 175 to phenyl acetylene for 24 h under Ar. After documenting that TMS is the best protective group for the benzannulation product from the reaction of carbene complex 175 with phenyl acetylene, the investigation was then turned to examine the generality of this protecting group for other alkynes. The reaction of carbene complex 175 with 1- pentyne in the presence of TMSCI and Hunig’s base furnished excellent yields (97 % of 187) for the benzannulation product (entry 1, Scheme 3.22). The yield of 187 dropped from 97 % in concurrent approach (entry 1) to 50 % in stepwise approach (entry 2). Compound 187 could be isolated in a yield of 87 % when the stepwise approach involved the degassing of the reaction mixture using the freeze-pump-thaw method after addition of the additives (TMSCI, Hunig’s base) 59 (entry 3). This incremental increase in yield upon degassing the solvent is consistent with the results of stepwise reaction of complex 175 with phenyl acetylene (Scheme 3.20 entry 1 and 2). This indicates that for a stepwise approach it is essential to freeze-thaw the reaction mixture after the addition of additives to obtain higher yields of benzannulated products. The relatively bulkier reagent TBSCI afforded a 78 % yield of the TBS protected napthopyranol 188 and 10 % of the corresponding quinone 181 (entry 4). The TMSCI protecting group was further examined for 3-hexyne. The benzannulation reaction of complex 175 with 3-hexyne in the presence of TMSCI and Hunig’s base gave a nearly quantitative yield of the product 189 (entry 5). Whereas the TMS group in 187 is stable to silica gel, the TMS group in 189 is not, but luckily essentially pure compound was obtained after filtration of the reaction mixture through Celite with pentane. As with 1-pentyne, the protection of the product from 3-hexyne with TBSCI gave a high yield (entry 6). Benzannulation of trimethylsilyl acetylene with complex 175 did not give a clean reaction when the sterically bulky TBSCI was used as the protecting reagent for the phenol functionality (entry 8). The relatively smaller TMS protecting group again proved fruitful here and yielded the benzannulated product 191 in 89 % yield (entry 7). The less reactive but relatively small protecting group MOMCI also afforded excellent yield of 193 with trimethylsilylacetylene (entry 9). This benzannulation reaction was also done at room temperature in the presence of MOMCI, and after 5 days a 70 % yield of compound 193 was obtained (entry 10). 6O Scheme 3.22 Benzannulation of complex 175 with 1-pentyne, 3-hexyne and trimethylsilyl acetylene MeO Cr(CO)5 R' - . R R OMe a. Benzene, Hunig's base 0 1, *2 52:55:23?” o \ 175 186 n' 10 h 187-1930 Entry Protecting P R R' Compound Compound Reagent (% yield)‘1 1 TMSCI TMS Propyl H 187 97 2 TMSCI TMS Propyl H 187 50” 3 TMSCI TMS Propyl H 187 89° 4 TBSCI TBS Propyl H 188 78(1 5 TMSCI TMS Ethyl Ethyl 189 95° 6 TBSCI TBS Ethyl Ethyl 190 85 7 TMSCI TMS TMS H 191 89 8 TBSCI TBS TMS H 192° - 9 MOMCI MOM TMS H 193 85 10 MOMCI MOM TMS H 193 70' Unless otherwise specified the benzannulation reactions were carried out in benzene (0.1 M) solvent with 1:2:3:5 ratio of complex 175:alkyne:protecting reagentzHunig’s base for 24 h at 50 °C under Ar. a) Isolated by chromatography using silica gel. b) Stepwise method: After 24 h, TMSCI and Hunig’s base was added and the reaction mixture was stirred for another 24 h at room temperature (No free-pump-thaw degassing done). 0) Stepwise method: After 24 h, TMSCI and Hunig’s base was added and reaction mixture was degassed using freeze- pump-thaw which was followed with stirring continued for another 24 h at room temperature under Ar. d) Slightly impure quinone 181 was isolated in 10 % yield. 9) The product was isolated by filtration of crude reaction mixture through Celite using pentane. f) A complex mixture was observed which was not analyzed. f) The reaction was carried out at room temperature for 5 days. 61 Scheme 3.22 continued M90 Cr(CO)5 I l a) Benzene, 50 °C, 24 h OMe \ \ + b) Tf20, Hunig's base, rt, 24h‘ O o 0) Air oxidation, rt, 12h “‘0 O \ 175 0 188869% Pd(PPh3)4 (20 mol %), K3PO4 (2.0 SQUIV) 1,4-dioxane, 80 °C, 3 day 000 69 % 188b Naphthol pyran triflate 118a could be obtained by the reaction of carbene complex 175 with 1-pentyne via stepwise method in which reaction mixture was degassed using freeze-pump-thaw after addition of TMSCI and Hunig’s base, which was followed with continued stirring for another 24 h at room temperature under Ar. The Suzuki coupling of naphthol pyran triflate 118a with phenyl boronic acid in the presence of Pd catalyst provided 188b in 69 % yield. After establishing the optimal conditions for the synthesis of protected naphtholpyrans of the type 139 (Scheme 3.1), attention was focused on their deprotection to form unprotected naphtholpyrans 139 and on their oxidation to naphthoquinonepyrans 138. Compound 187, which was isolated in quantitive yield from the benzannulation reaction of complex 175 with 1-pentyne, was chosen for these studies. The desilylation of compound 187 using TBAF afforded naphtholpyran 180 in 75 % yield (Scheme 3.23). This alcohol is not particularly stable and was 62 contaminated with a small amount of unidentified impurity after purification. Ceric ammonium nitrate (CAN) oxidation of alcohol 180 furnished quinone 181 in 56 % yield. Quinone 181 is robust in air/light and does not decompose readily. Thus it was decided to optimize the conditions for the relatively stable quinone 181. Scheme 3.23 Synthesis of quinone 181 OMe OMe 0 o \ > TMSO O THF ”0 O \ THF/H20 o o o 187 180. 75 % 181, 56% (42 % from 187) Considering the instability of the alcohol 180 it was decided not to isolate it after desilylation. The naphthopyran 187 was treated with TBAF in THF solvent for 10 min at 0 °C (Scheme 3.24). The reaction was then quenched with water and extracted with ethylacetate. Removal of organic solvent gave crude alcohol 180, which, without any purification, was oxidized using CAN to afford quinone 181 in 66 % yield in two steps. Scheme 3.24 Synthesis of quinone 181 a. TBAF, THF 6. CAN, THF/H207 O 181, 66 % Next, the efficiency of the conversion of carbene complex 175 to quinone 181 was examined when the protected phenol 187 was not purified. The crude 63 reaction mixture after benzannulation was first treated with TBAF and then, after workup, it was oxidized using CAN (Scheme 3.25). This resulted a 65 % yield of quinone 181. Notice that this is essentially the same overall yield of 181 that is obtained when 187 is purified by silica gel chromatography ( 97 X 66 = 64 %). Scheme 3.25 Synthesis of quinone 181 M60 Cr(CO)5 a) Benzene, 50 °C TMSCI, Base / + T b) TBAF. THF 0 II c) CAN. THF/H20 175 The direct conversion of carbene complex 175 to quinone 181 was 181 65 % yield from 175 investigated without in-situ protection of the phenol. After heating complex 175 and 1-pentyne in benzene solvent at 50 °C for 24 h, the crude reaction mixture was subjected to oxidation conditions using CAN. This reaction afforded naphthoquinone 181 in 58 % yield (Scheme 3.26). The proctection of the phenol during the course of the reaction thus has only a minimal effect on the outcome. Scheme 3.26 Synthesis of quinone 181 M90 Cr(CO)5 i a) Benzene, 50 °C / + t b) CAN, THF/HzO 0 || 175 181 58 °/e Now that the efficiency of the reaction of carbene complex 175 and 1- pentyne in the synthesis of naphthoquinone pyran 181 is well understood, the same reaction with phenyl acetylene was examined for the synthesis of quinone 64 178. First compound 183 was desilylated to obtain phenol 177 in 65 % yield which like phenol 180 was relatively unstable. CAN oxidation of 177 provided 178 in 50 % yield (Scheme 3.27). The overall yield of naphthoquinone 178 was 32 % starting from 183. Naphthoquionone pyran 178 is stable to air and light as is quinone 181. Scheme 3.27 Synthesis of quinone 178 O OMe O OMe 0 0 TMSO Q \ THF Ho 0 \ o o 183 177’ 65 % 178, 50 % (32 % from 183) Next, the direct conversion of 175 to quinone 178 is investigated without the in-situ protection of the phenol. Reaction of 175 with phenyl acetylene in the absence of any additive followed by CAN oxidation provided a 25 % yield of the corresponding quinone 178 (Scheme 3.28). Notice that this is the essentially same overall yield that is obtained when protected phenol 183 is isolated (65 X 32 = 21 %). This suggests that the phenol and/or quinone from phenyl acetylene are more sensitive to the oxidation conditions (CAN) than they are from 1- pentyne. This suggests that in future work, the yields of these quinones might be optimized by screening other oxidizing agents. 65 Scheme 3.28 Synthesis of quinone 178 MeO Cr(CO)5 a) Benzene, 50 °C / + e O 175 176 178, 25 % In summary, the naphthoquinone pyrans 178 and 181 were obtained in moderate yields from the benzannulation reaction of carbene complex 175 with 1-pentyne and phenyl acetylene. These quinones are highly stable and are not very sensitive to air and light. On the contrary, the unprotected naphtholpyrans 177 and 180 are unstable compounds and are relatively difficult to isolate in pure form. High yields for the benzannulation reaction of complex 175 with different alkynes can be obtained by the concurrent protection using protecting groups such as TMSCI, TBSCI, MOMCI, A020 etc, which form naptholpyran derivatives of the type 139 with protected phenolic functionality. The success of these benzannulation reactions of chromene carbene complex 175 shows a dependence on the bulkiness of the protecting group and on the nature of the alkyne. 66 CHAPTER FOUR Synthetic Studies toward Conocurvone 4.1 Introduction to conocurvone 36 Conospermum (Proteaceae) is a genus of about 50 species, all of which occur only in Australia. Most of these species inhabit the south of Western Australia with the exception of few which can be found in eastern states (Figure 4.1). They are generally called "smokebushes" because, with some species, the appearance of the flowering plant from a distance resembles puffs of smoke. Conspermum incurvum is one of the western species, which forms a spreading shrub up to 1.5 metres high. The leaves are linear and rounded in cross-section to about 25 mm long. The small, greyish-white flowers occur in late spring in clusters about 250 mm long at the ends of the branches. Figure 4.1 Australia map and conospermum incurvum I Conospermum species is found Conospermum incurvum in the region colored in red. 67 Conospermum has traditionally been used by indigenous peoples for a variety of therapeutic purposes and especially for “old age” diseases such as rheumatism and lumbago. In the 1960s, smokebush was collected and screened for scientific purposes by the US National Cancer Institute (NCI), under license from the West Australian Government. This shrub was unsuccessfully tested for cancer resistant properties by NCI in early 1980s and was stored for several years. In the late 1980s testing was resumed, but this time for anti-HIV activity. In 1993, Boyd and co-workers at NCI discovered that remarkable in-vitro anti-HIV activity is exhibited by the organic extract obtained from the shrub conospermum-incurvum.‘6'56 Bioassay-guided fractionation and purification led to the isolation of conocurvone 36 as the active agent (Figure 4.2). Biological tests showed that conocurvone 36 completely averted the death of HIV 1 - infected human lymphoblastoid cells (CEM — 83) at a concentration of EC s 0.02 uM. Conocurvone has an unusually high therapeutic index of 2500. 68 Figure 4.2 Conocurvone 36, its analogue 194 and teretifolione B 195 36 Conocurvone Conocurvone 36 is a novel trimeric naphthoquinone and a deoxy-trimer of teretifolion B 195, a previously known compound that was first isolated from conospermum teretifolium. Conocurvone consists of two teretifolion B subunits joined at their C - 3 positions to the C - 2 and the C - 3 position of a 2- deoxyteretifolione B subunit. Conocurvone 36 was obtained in a yield of 22 mg per kg plant material. The proton NMR of conocurvone 36 is very complex as it possesses some satellite peaks which show integrations of less than one proton (Figure 4.3). It was first speculated to be the impurities eluted along with conocurvone during the isolation from the organic extract of conospermum incurvum. However, the variation of the ratio of satellite peaks in proton NMR under different temperatures and solvents indicated that rotamers and tautomers of 69 conocurvone 36 were in equilibrium with each other on the NMR time scale and were responsible for these satellite peaks. The unambiguous characterization of conocurvone 36 was achieved by its synthesis from teretifolion B (Section 4.2), which showed a proton NMR spectrum identical to the natural product isolated from conospermum incurvum. Figure 4.3 Proton NMR of conocurvone 36 M _ TT1 71 I I I I I l I I TT—rrr' I YT 1 Y 7 Y I I 1 I 1“ 5 l‘ 7 6 5 4 3 2 1 ppm Structure-activity relationship studies have revealed that conocurvone 36 and its derivative 194 show identical anti-HIV activity. However, the monomer teretifolione B 195 and its dimer does not show any HIV resistance. The mechanism of its action is not known, and it is surmised that its inhibitory action occurs in the late phase of the viral replication cycle, since a time course study showed that conocurvone 36, it added 48 h post infection, could still protect T- cells from the cytopathogenic effect of HIV-1. The possibility has been 70 recognized that conocurvone 36 can assume a helical conformation that winds into the groove of the DNA strand. Additional interactions may be expected between the quinonoid hydroxyl groups and peptides, like those that play a role in coloring hair and skin with henna. It will be interesting to see if any of these hypotheses is confirmed. Furthermore, it will not only be interesting but very important to answer the following questions: will conocurvone 36 be the prototype of new class of anti-HIV active compounds and what role does the trimeric quinone carbon framework plays in the biological activity? 4.2 Oxidative oligomerization of monomeric quinone to synthesize cyclic tris-quinones similar to conocurvone 36 Oxidative oligomerization of quinones is a well-known phenomenon.56 Direct oxidative dimerization of monomeric quinones like 196 requires harsh reaction conditions and needs a hydroxyl or amino group on the quinonoid double bond. However, it is also known that monomeric 1,4-quinones can be oligomerized much more easily under acidic or basic conditions.57 Naphthoquinone, 1,4-anthraquinone, and numerous derivatives can be smoothly converted into dimers and cyclo-trimers (which are an important structural class of natural products) by heating in pyridine/ethanol, or by warming in acetic acid.58 It has been speculated that this process is autocatalytic in which traces of hydroquinone 197, which are always present, does a Michael addition to the excess of quinone 196 to form a biaryltetrol 199 (Scheme 41).“ Dehydrogenation of this intermediate by the monomeric quinone 196 yields the 71 biaryldiquinone 200 and further reaction with hydroquinone 197 occurs until all the monomeric quinone was transformed. The dimer 200 could then react further to yield trimer 201. It was not possible to isolate the trimer 201 since it was easily converted into the trimeric cyclic quionone 202. So the stability of conocurvone 36 is apparently due to the presence of hydroxyl groups at position 2 of the two terminal quinones which prevent cyclization. Scheme 4.1 Autocatalytic oligomerization of quinones 4.3 Previous semisynthesis and synthetic approaches toward Conocurvone 36 Boyd and co-workers at NCI unambiguously assigned the stmcture of conocurvone 36 by its semisynthesis.16 In addition to this work two other groups, Liebeskind’s group60 from Emory University and Stagliano’s group61 from the University of Illinois at Chicago have developed two different approaches for 72 synthesizing the trimeric core of conocurvone 36. However, no successful total synthesis of conocurvone 36 has been reported yet. All the three of these synthetic efforts are mentioned briefly in this section. 4.3.1 Boyd and co-workers Boyd and co-workers have used the autocatalytic oxidation of quinones approach to synthesize conocurvone 36 from teretifolione B 195.16 The naturally occurring teretifolione B 195 was first deoxygenated to give 203 (Scheme 4.2). Compound 203 was then warmed with two equivalents of 195 in pyridine to afford conocurvone 36 in 4 % yield. Similarly, the analogue 194 was obtained in 9 % yield upon warming teretifoline B 195 with naphthoquinone 196 in glacial acetic acid. Scheme 4.2 Boyd’s semisynthesis of conocurvone 36 a) p-BI'C5H4COCI, EtaN O b) PhSH, Et3N c) Raney Ni NoYmm Reponed 73 Scheme 4.2 Boyd’s semisynthesis of conocurvone 36 continued 195 I o i ' H HOAc,100°C H 196 o pyridine, 80 °C 194, 9% / Liebeskind’s group has utilized thermal and photochemical induced 4.3.2 Liebeskind approach reactions of cobalt complexes 205 and 2058 with biaryl acetylenes of the type 204 to obtain the quinone complex 206, which could be converted to the corresponding tris—benzoquinones 207 upon CAN oxidation (Scheme 4.3).60 The isolated tris-benzoquinones are yellow solids and are soluble in organic solvents such as CH20I2, THF and EtOAc. The tris-benzoquinones 207 are not as unstable as the corresponding tris-naphthoquinone described by Brockmann.59 Upon exposure to air and light the solids quickly darken but without substantial decomposition. Two of the limitations of this approach are: a) the sterically hindered biaryl acetylenes of the type 204 are difficult to obtain using the Stille coupling reaction of bis(tri-n-butylstannyl)acetylene and the sterically hindered 74 iodoarenes the Stille cross-coupling reaction is known to be sensitive to sterics.62 b) The reaction of the cobalt complexes with diarylacetylenes fail to give any product with the alkynes of the type 204 where R3 at H. Scheme 4.3 Liebeskind’s approach to conocurvone 36 R‘ OCH3 R4 Q / RZQCEE + RDQCCRL hv or A o H 00 R3 3 204 205: R4 = CH3, L = E128 2058: R4-R4 = benzo, L = CO R1 R2 206. 61 - 92 °/o Ce(IV) R4 R3 0 a, 207,75-86 % 4.3.3 Stagliano’s approach The Stagliano group has used two different approaches to synthesize the trimeric framework of the conocurvone 36.61 The first approach involves the use of the doubly activated zwitterionic quinones 20863 for the regiocontrolled synthesis of the conocurvone core.6‘a'° The double activation of the quinone results from the presence of the reactive hypervalent iodide and unreactive masked triflate in the form of an alkoxide. 75 The palladium catalyzed coupling of quinone 208a and 208b with naphthopyranyl stannane 211a and activation of the resulting phenol as a triflate provided the biaryl compounds 209a and 209b in moderate yields (Scheme 4.4).‘31‘3'b Triflate 209a underwent palladium catalyzed coupling with 211b to afford only a 35 % yield of the tris-aromatic compound 210a along with other side products. Extensive studies, performed to increase the yield of 21 08, concluded that the sterically hindered ortho- substituted stannane 211 plays a role in the formation of the side products. An unhindered p-anisylstannane undenlvent coupling with 2098 to give a higher yield of the tris-arene 212 (53 %). On the other hand, the dimer 209b gave excellent yields of 210b (86 %) upon coupling with 21 1 b. 76 Scheme 4.4 Stagliano’s use of doubly activated zwitterionic quinones C e a) Cul,Pd(PPh3)4 0 *0 211a, DMF, n4 6) c ' Tf ,b R '\: b) 20 ase R 0 GO \ \ 2088R=H 2098R=H, 37% 208b R: OMe 209!) R = OMe, 21 % \é / “63:;C 211aR= MOM 211bR= EtzNCO\§ 210aR=H ,35 % ‘ 210bR=OMe, 86% \é / In Stagliano’s second approach, 2,3-dihaloquinones of the type 214 were subjected to stepwise halogen exchange by hydroxyquinone 213 and 217 to furnish tris-benzoquinones having the conocurvone framework (Scheme 4.5).610 One of the examples of tris-benzoquinone synthesis using this approach is described here. The reaction of lawsone 213 with the commercially available 2,3- dichloronaphthoquionone 214 and CSzCOa in acetonitrile yielded 215 in 93 % yield. The free hydroxyl group in 215 was methylated to form dimer 216. Dimer 216 was then reacted with potassium salt 217 to provide the brilliant red colored trimeric quinone monomethyl ether 218 in 39 % yield. 77 Scheme 4.5 Stagliano’s synthesis of trimeric quinones using 2,3- dihaloquinones 0 0 WHO OH CI 0‘ + 0‘ Cs2003, CH30N CI Cl 213 O 214 0 0 215 93% . o [(CH3)3OBF4 H300 0 _ + lCHzCIz '0 0‘ OK 0 H 0 CC 217 0 218, 39% HO O 216, 32% 4.3.4 Previous synthetic efforts in the Wulff laboratory The retrosynthetic analysis developed by the Wulff group for the synthesis of conocurvone 36 is outlined in Scheme 4.6. The key step of this strategy involves the reaction of a chromium carbene complex 38 with conjugated triyne 39. The reaction of one equivalent of chromene carbene complex 38 with hexatriyne 39 followed by oxidation and desilylation is anticipated to give diyne 37. Further reaction of 37 with two equivalent of chromene carbene complex 38 is expected to furnish the conocurvone core. This project was initiated by graduate student Xiao-Wu Jiang and the results of her studies can be found in her thesis and is summarized below.64 78 Scheme 4.6 Retrosynthetic analysis of conocurvone 36 Détz-Wulff Benzannulation reaction 1. D6tz-Wulff Benzannulation / reaction 2. Desilylation 3. Oxidation H300 CF(CO)5 / + TIPSfiTIPS : 0 7f 38 39 Jiang was able to successfully implement this strategy in the synthesis of tris-quinone 223 which utilizes cyclohexenyl chromium complex 219 and the silyl substituted hexatriyne 39 (Scheme 4.7). The reaction of complex 219 and TIPS triyne 39 gave the mono-benzannulated product 220 in 81 % yield. After acetylation of 220 and desilylation, the orfho-aryl diyne 221 so obtained was reacted with two more equivalent of carbene complex 219 to give 222. Finally, compound 222 was converted to tris-quinone 223 (57 % from 222) by reductive cleavage of acetyl groups using LiAlH4 and exhaustive oxidation using CAN.‘54 79 Scheme 4.7 Benzannulation approach to tris-quinone 223 'll'IPS TIPS (00)50r W" H H¢ Toluene a) A020, Base 219 + H3 b)TBAF, THF OMe\ TIPS OMe\ “3 220 31 % 55 % from 220 TIPS 219, Solvent 1 b) CAN 223, 57 % in two steps Jiang also explored the benzannulation reaction of the aryl- and alkyl- substituted triynes 224 and 225 with complex 219 (Scheme 4.8). The reaction of the cyclohexenyl complex 219 with 1,6-diphenylhexatriyne 224 gave a mixture of the products 226 and 228 (entry 1), both of which resulted from the reaction of the carbene complex at the end alkyne of the triyne. The reaction could be driven to give only the double-benzannulation product 228 with 5 equiv of carbene complex (entry 2). The selective formation of 226 could be accomplished if 5 equiv of triyne was used (entry 3). The use of the larger adamantyl groups on the triyne 225 did not result in the formation of any detectable amount at the product resulting from reaction of the central alkyne unit (entry 4).64 8O Scheme 4.8 Benzannulation reactions of cyclohexenyl carbene complex 219 with conjugated triynes 224 and 225 R OCH3 H OH ICOI5CI Solvent, A R ‘27 .. 00 + % 219 I I OMe § R R 226 R = Phenyl 229 R = Phenyl 0“ 224 = Pheny' 227 R = 1- Admantyl 229 R = 1- Admantyl 225 = 1- Admantyl 219 : T ri y n e Compound Compound Entry Triyne (°/o Yield) (% Yield) 1. 1 :1 224 226 (32) 228 (6) 2. a 5:1 224 - 228 (69) 3. a 1 :5 224 226 (43) - 4. 1 :1 225 227 (41) 229 (23) All reactions were carried out in THF (0.05 M) at 55 °C under Ar. a) The concentration of the solution was 0.2 M. 4.4 New studies toward the synthesis of conocurvone from the reaction of carbene complexes with triynes Attempts to extend these reactions of conjugated triynes to aryl carbene complexes were also carried out by Jiang and the key results from her thesis are shown below. The reaction of complex 22 with the triyne 224 in THF at 90 °C for 24 h gave a complicated mixture of small amounts of products which was difficult to separate and characterize. One of the components was tentatively assigned as the naphthol 230 based on the 1H NMR spectrum of partially purified material (Scheme 4.9). The reaction of the phenyl carbene complex 22 with bis-silyl triyne 39 was also investigated by Jiang. She reported that the reaction gave a 59 °/o 81 yield of a compound that was tentatively assigned as the naphthalene 230a (Scheme 4.9). The rest of this chapter describes the extension of the methodology developed by Jiang for the synthesis of tris-quinones that is summarized above. Scheme 4.9 Reaction of aryl carbene complex 219 with triynes 39 and 224 OCH3 OH ICOISC' ,_ _ _ _ n THF, 90°C P“ C + Pu _ _ _ rh : $0 224 24h Q 22 233M997. § Ph OTIPS (CO)5CI' Toluene, 90 °C H : :- : :33 24h - % OMe \ \ 230a, 59 % TIPS BO/ILS I w w 10 The aims of the present work are threefold: 1) to more completely define the outcome of the reaction of aryl carbene complexes with triynes 39 and 224, 2) to examine the reaction of aryl carbene complexes with diynes of the type 231, and 3) to investigate the reactions of both alkenyl and aryl carbene complexes with the mono-silylated diynes of the type 232 in an attempt to accomplish the regiocontrolled synthesis of tris-quinone framework of conocurvone with three different A, B and C rings 233 (Figure 4.4). 82 Figure 4.4 Diynes 231 , 232 and trls-quinone derivative 233 o R3 OCH3 OR OR 4 (CO)50r RI é R‘ é R R R2 \ R2 \ R2 \ \ 5 OCH3 OCH3 TIPS R 22 231 232 4.4.1 Reaction of aryl carbene complexes with bls-TIPS triyne 39 This section will describe the reaction of the four aryl carbene complex shown in Figure 4.5 with triynes 39 and 224. Figure 4.5 Aryl carbene complexes 22, 175, 234 and 235 OCHa OCHB MeO Cr(CO)5 H300 Cr(CO)s (CO)5Cr (CO)5Cr ‘23 / o O 22 234 CF3 175 235 4.4.1.1 Reaction of the phenyl carbene complex 22 with the bis-TIPS triyne 39 The reaction of the phenyl carbene complex 22 and triyne 39 that was originally carried out by Jiang was repeated since the 1H NMR spectrum did not give a splitting pattern for the aromatic region that would be expected for the proposed naphthalene product 230a (Scheme 4.9). When the reaction was repeated and all the spectral data collected and carefully analyzed it was concluded that the product from this reaction was the furan 236 (Scheme 4.10). 83 Scheme 4.10 Reaction of complex 22 with silyl substituted triyne 39 TIPS OCH3 II TIPS (“”5013 + II Toluene,90°C_ 24h 22 || 39 TIPS 236, 69 °/o P f OCH3/ 00 % OH 237 Not Observed TIPS TIPS The chemoselectivity of the furan product 236 was unambiguously determined by the desilylation of furan 236 which yielded compound 238 showing two acetylenic protons in 1H NMR (Scheme 4.11). This demonstrates that the reaction occurred on the central alkyne of 39. Cleavage of the silyl groups in the other two possible isomers 239 and 241 resulting from the reaction of an end alkyne in 39, would give products 240 and 242 with only one acetylene hydrogen. 84 Scheme 4.11 Desilylation of phenyl furan 236 TIPS I \ 001-13 0 242 Not Observed Furan products of this type have been observed before in the reaction of chromium Fischer carbene complex with alkynes, but usually only as a minor products.6"55 An example where this is not the case is the reaction of the ferrocenyl Fischer carbene complex 243 with di-phenyl acetylene 244, which exclusively gives the ferrocenyl furan complex 245 (Scheme 4.12).?“ In another example, the reaction of furanyl complex 246 with methyl-4—pentynoate 247 gives a mixture of furanyl furan 248 and benzofuran 249 (Scheme 4.12).65b 85 Scheme 4.12 Aryl furan formation. Ph Ph OCH3 / \ . Cr(CO)5 PhCECPh O OCHS F6 244 F9 249 .0 245, 45 / COZCHa 001-13 ll OCH HO \ 3 Q/gCNCOE + Solvent 8 IP 002013 A OCH3 246 247 248, 22 % 249, 52 % In effort to shift the outcome of the reaction of the phenyl carbene complex 22 and triyne 39 from the furan product 236 to the phenol product 237, this reaction was examined in various solvents. It can be anticipated that solvents could influence the outcome of the reaction. The reaction of carbene complex 22 with triyne 39 could produce either the Z-vinyl carbene complexed intermediate 250b or the E-vinyl carbene complexed intermediate 250a or a mixture of both (Scheme 4.13). The phenol product 237 can only come from the E-isomer 250a and previous studies indicate that the furan product 236 is formed from the Z- isomer 248b.65 86 Scheme 4.13 Proposed pathway for the formation of 236 and 237 OC-Cr-CO 1 ., CC '00 00 CO 250a E-isomer 3g 250b Z-isomer OCH3 l 1 OH / TIPS Ukcmcok TIPS // 00 / =2 \\ \ OCH3 TIPS 237 236 It can be anticipated that E and Z-vinyl carbene complexes 250a and 250b could be isomerized via the zwitterion 251. Thus if the formation of 250b is kinetically favored in toluene as solvent, then the switch to a more polar solvent may lead to the isomerization of 250b to 250a and an increase in the amount of 237 formed from the reaction. However, the data in Scheme 4.14 reveals that the yields of 236 are similar in a non-coordinating, non-polar solvent like toluene (69 %) and in a non-coordinating polar solvent such as dichloromethane (65 %) (Scheme 4.14). For the coordinating polar solvent THF, the yield decreased to 51 % and a complex mixture was observed for the highly coordinating acetonitrile solvent. 87 Scheme 4.14 Solvent study of reaction of complex 22 with triyne 39 TIPS TIPS OCH3 II TIPS // (CO)5Cr + I I solvent, 90 °C ‘ \ ’2 > 24 h ' I 0 00H3 22 I I 39 235 TIPS Entry Solvent 236, Yield ( °/o) 1 Toluene 69 2 Benzene 67 3 CH2CI2 65 4 THF 51 5 CH3CN Mixture of compounds Unless otherwise specified the reactions were carried out in 0.05 M solvent using 1 : 1 equivalent of complex 22 and triyne 39 These results are consistent with the studies done by Waters and Wulff on the reaction of phenoxydihydropyranyl chromium carbene complex 252 with 3- hexyn-2-one 253 (Scheme 4.15).66 Two different products 254 and 255 are obtained in this reaction via the intermediates (E)-259a and (Z)-259b, respectively (Scheme 4.17). The ratio of these two products did not show any significant dependence on the solvent used for the reaction. 88 5“ 345‘ L~’?&.m;—h¢» . Scheme 4.15 Waters and Wulff study on reactlon of complex 252 with 3- hexyn-2-one 253 0 H30 0 0 O‘Q'CFa a) THF, 0.05 M, (00’5”? + I I 70 °C, 24 h b) Oxidation 0:540 F3C Fa/COQE 255 252 253 Entry Solvent 254 / 255 Yield (%) 1 CGHG 74/26 67 2 CHzClz 72/28 51 3 THF 71/29 56 4 CHgCN 68/32 37 However, the ratio of phenol 254 to lactone 255 could be controlled by changing the electron-deficient aryl group in complex 252 with an electron-rich substituent. Complex 256, containing an electron-rich aryl group, upon reaction with 3-hexyn-2-one 253 in THF solvent gave 51 % yield of products 257 and 258 in a ratio of 39 : 61 (Scheme 4.16). 89 Scheme 4.16 Waters and Wulff study on reaction of complex 256 with 3- hexyn-2-one 253 / O OQN . (0050 \ a) THF, 0. 05 M, / _ 70 °C, 24 h Et 4. 0 0b) Oxidation 00 O + Cg / 256 0257 259 ( 257 : 258 (39 : 61, 51 %) The differences in the product distribution between the electron-poor complex 252 and the electron-rich complex 256 have been explained by Waters and Wulff according to the reaction intermediates shown in Scheme 4.17. First it is clear that in these reactions the phenol product 254 (or 257) must come from the E-vinyl carbene complexed intermediate 259a (or 261a) and that the lactone product 255 (or 258) must come from the Z-vinyl carbene complexed intermediate 259b (or 261 b). The working hypothesis is that an increase in the electron-donating ability of the oxygen substituent leads to an increased preference for the Z-vinyl carbene complex intermediate which has the oxygen substituent trans to the ketone. Hence, in accord with observation, the amino substituted complex 256 would be expected to give a greater proportion of the lactone product than the CF3 substituted 252. 90 Scheme 4.17 Proposed intermediates for phenol and lactone formation OOPS CF3 O O o ”\R) °c\/—< ——+ 254 \ I O .\ l \I o OC-lCrl-CO )\Cr(CO)3 00 CO 260a (E)-259a CO CO I —’ 2 \ ’1, O O:C'\ / O 55 OC'érfCO 260b goes 00 CO S=Solvent (2)2595 / 0 UN OS CR9 \NQ’O ~“‘\ . x W I I/ o 257 t I,’ O 258 OC-Cr-CO OC'lCrl—CO 0d ’00 00 CO (E)-261a (Z)-261b Waters and Wulff also concluded from their studies that in the absence of ketone group on the vinyl carbene compelxed intermediate (259 or 261, Scheme 4.17), there is then a tendency for an increased electron-donating ability of a substituent to have an increased preference for that substituent to be anti to the carbene carbon (C-1) of the vinyl carbene complexed intermediate. Given unexpected and undesired formation of the furan 236 from the reaction of the phenyl carbene complex 22 with triyne 39, it was thus considered 91 possible that this reaction could be shifted in favor of the desired phenol product 237 by proper control of the electronics (Scheme 4.10). For example, since the reaction of the phenyl carbene complex 22 with triyne 39 preferentially proceeds only through the Z-vinyl carbene complex 250b (Scheme 4.13), it might be expected that the reaction of the para-CFa substituted phenyl carbene complex 234 (Scheme 4.18) might be shifted towards the E-vinyl carbene complex 264a and lead to at least the formation of some phenol product 263. However, as the experiment in Scheme 4.18 shows, this reaction only gave the furan product 262 in 65 % yield. Scheme 4.18 Reaction of electron deficient complex 234 with triyne 39 TIPS TIPS T OCH3/ TIPS OCH3 II TIPS / (CO)5Cr + II Toluene,90°C F C 00 \ II 24 I‘ OCH3 OH TIPS 39 263 23‘ CFS F30 Not Observed TIPS GOP», H300\“‘ ' : TIPS TIPS : \ "I —-> 263 oc-lcy—co 00 CO (Z)-264b More Stable Thus the reaction with triynes must be subject to subtle differences not present in the reactions of simple alkynes. 92 4.4.1.2 Reaction of chromene carbene complex 175 and chromane complex 235 with bis-TIPS triyne 39 As a continuation of the effort to develop methodology for the synthesis of conocurvone and its analogs, the reaction of chromene carbene complex 175 with triyne 39 was investigated. Based on the reactivity of phenyl carbene complex 22 with this triyne (Scheme 4.10), it was anticipated the reaction of chromene carbene complex 175 with triyne 39 would preferably give furan 265 rather than 3H-naphtho[f]pyran 266 (Scheme 4.19). Nonetheless, the possibility that this complex could provide a direct access to an intermediate 267, the key to a synthesis of conocurvone, was enough to stimulate the examination of the reaction. Scheme 4.19 Possible products on reaction of complex 175 with triyne 39 TIPS TIPS MeO // And / Or 0 / 3 \ / 9 \ TIPS Toluene, 90 °C / MeO Cr(CO)5 TIPS O 175 O 93 Surprisingly, the reaction of chromene carbene complex 175 and triyne 39 gave neither the furan 265 nor the phenol 266. Instead, the reaction gave the unexpected product 269 that results from alkyne addition and thus an addition to the double bond present in carbene complex 175. Given the instability of naphthopyran phenols 266 (Chapter 3) the benzannulation reaction of chromene carbene complex 175 with triyne 39 was initially done in the presence of additives TMSCI and DIPEA.54 Upon heating a mixture of chromene carbene complex 175 and triyne 39 for 24 h at 50 °C in benzene, the TLC showed only starting material with a very faint spot corresponding to a product. The same reaction upon heating at 90 °C for 24 h yielded a non-TMS containing product (entry 1, Scheme 4.20). Similarly, when the TMSCI additive was replaced by MOMCI, the same product was isolated with no evidence of MOM incorporation (entry 2). Since these protecting groups were not incorporated the reaction was performed between chromene carbene complex 175 and triyne 39 in the absence of any additive which as expected afforded the same product in 80 °/o yield. The structure of this product has been assigned as 269 on the basis of its spectral data (Scheme 4.20). The chemoselectivity of the olefin-addition product 269 was unambiguously determined by the desilylation of 269 which yielded compound 269a showing two acetylenic protons in 1H NMR (Scheme 4.20). There is no precedent for this type of benzannulation reaction in the literature. The mechanistic details proposed for the formation of this product are given in section 4.8.2 along with calculations to support this mechanism. 94 Solvent studies reveal that the polar non-coordinating solvent dichloromethane gives the best yield for the reaction and that polar solvents with strong coordination abilities such as DMF and CH3CN generally lead to only trace amount of 269 (Scheme 4.20). Scheme 4.20 Benzannulation of complex 175 with triyne 39 TIPS TIPS I I ’ I I MeO Cr(CO)5 TIPS \ \ a) Solvent (0.05 M), + l | = o 90 °C, 24 h 0 O 175 I I b) Air oxidation, rt, 10 h O O TIPS . Entry Solvent 269 Yield (%) 1 Benzenea 74 2 Benzeneb 71 3 Benzene 80 4 CH20I2 88 5 THF 75 6 CHach - 7 DMFc - Unless otherwise specified the reactions were carried out in 0.05 M solvent using 1 : 1 equivalent of complex 175 and triyne 39 a) additive TMSCI and Hunig’s base used, b) additive MOMCI and Hunig’s base used. c) a complex mixture was observed which showed traces of 269 by TLC. The intriguing involvement of the double bond in C1-C2 position of chromene carbene complex 175 in the reaction with the triyne 39 raises the question: what would be the product from the reaction of triyne 39 and chromane complex 235 where this double-bond has been removed? Bromochromane 270 was obtained by the hydrogenation of chromene 141 using 5 °/o Rh on alumina.67 95 This Rh catalyst is known to selectively perform hydrogenation of double bonds in the presence of aryl halides.67 Using the standard Fischer protocol, 270 was converted to chromane complex 235 in 65 % yield (Scheme 4.21). Scheme 4.21 Chromane complex 235 synthesis Br 3, H300 Cr(CO)5 (I: 5 °/o Rh on alumina a) t'BULI IZGQI' I32? 0 H2 (1 atm) O b) Cr(CO)6, Etzo C) M93OBF4, CH2CI2 O 141 270. 92 % 235, 65 % As expected, chromane complex 235, reacted with 1-pentyne in the presence of TBSCI and Hunig’s base to give the benzannulation product 271 (Scheme 4.22).54 The reaction of the chromane complex 235 with the TIPS triyne 39 gave the furan product 272 in 75 % isolated yield.6'65 Thus, chromane complex 235 displayed the same reactivity towards triyne 39 as the phenyl carbene complex 22 (Scheme 4.10). Scheme 4.22 Benzannulation of complex 235 with 1-pentyne and triyne 39 ' = D OTBS Benzene O H3CO Cr(CO)5 Hunig's base 271 77 % H300 —\—= TBSCI O fl OCH3 TIPS CO CH TIPS 273 Not Observed \ // \ 235 272, 75 °/o 96 4.4.1.3 Tungsten carbene complex 274: synthesis and reactivity Intrigued by the high yields of the non-CO inserted olefin-addition product 269 obtained from the reaction of chromene carbene complex 175 with triyne 39, it was decided to explore the possibility of making this reaction general for simple aliphatic- and aromatic alkynes (Scheme 4.23). In contrast to the reaction of carbene complex 175 with triyne 39 (Scheme 4.20), the reaction of 175 with Simple alkynes occur with CO-insertion and cyclization to give the normal benzannulated product (Chapter 3) and no observable amount of the product corresponding to 269 (Scheme 4.20) where the double-bond is involved. However, it may be possible that tungsten complexes would form products of the type 269 with simple alkynes. Tungsten carbene complexes are known to form non-CO inserted 5 membered ring products upon reaction with alkynes.7 The CO insertion process is slower for tungsten than for chromium, and thus for the tungsten complex 274 reaction with the double-bond does not have to compete with CO insertion. The only question is can the reaction with the double-bond compete with the 5-membered ring formation. The tungsten carbene complex 274 was made using the standard Fischer protocol from bromochromene 141 as shown in Scheme 4.23. The reaction of the complex 274 with 3-hexyne at 90 °C in toluene solvent gave cyclopentenone 275 in 90 % yield with no trace of the benzannulated product 277 or of product 278 resulting from cyclization to the double bond. A similar result was observed upon heating 274 with phenyl acetylene except that the reaction was slower. After 48 h at 90 °C the reaction mixture showed a mixture of compounds which consisted of 97 a significant amount of carbene complex 274 and very small amount of cyclized product 276. Scheme 4.23 Tungsten carbene complex 274: synthesis and reactivity Bf M60 W(CO)5 / a) t-BuLI (2 eq), Et2=O / C) M63OBF4, CH2CI2 O 141 274, 66 % MeO W(CO)5 OMe \ _ 1) Toluene, 90 °C, 24 h a + /—-—:_—\ ; \ O 2) Air oxidation, 24 h O 274 275, 90 % MeO W(CO)5 OMe _ 1)Toluene, 9000.241: 0 a) \ C _ 2) Au ox1datIon 24h ' + 274 274 276 OOMG MeO H0 2780 Not observed Not observed The reaction was further performed at 130 °C in which complex 274 (89 mg, 0.169 mmol) was heated with 1 equiv of triyne 39. The reaction mixture was stirred for 24 h at 130 °C and for 12 h in air at room temperature. The reaction mixture was then filtered through celite, concentrated in vacuuo and the residue was chromatographed using 2 % ethyl acetate in hexane which afforded 85 mg of a mixture of compounds. The column was then flushed using a gradient of 5 % ethyl acetate in hexane to neat ethyl acetate to give 9 mg of a complex mixture which did not showed any aromatic protons in the 1H NMR spectrum nor any 98 distinct spot in the TLC plate. The 85 mg of complex mixture was again purified using 2.5 % benzene in hexane which afforded three fractions: first fraction and the third fraction which weighed 30 mg and 18 mg, respectively showed very faint peaks at the aromatic region in 1H NMR spectrum. The second fraction (30 mg) consisted of two compounds complex 274 and olefin-addition product 269 in the ratio of 10 : 1. The triyne 39 was consumed during the course of the reaction as revealed by the TLC. The recovery of approximately 30 % of the complex 274 and the total consumption of the triyne 269 indicates the possibility of oligomerization of triyne 269 initiated by the complex 269. As tungsten complexes are known to induce polymerization of alkynes.68 Surprisingly, no reaction was observed between triyne 39 and tungsten complex 274 at 90 °C. Upon heating to 160 °C both triyne and complex were consumed but no predominant product was observed on TLC and 1H NMR analysis of the crude reaction mixture (Scheme 4.24). Scheme 4.24 Reaction of complex 274 with triyne 39 TIPS TIPS II M90 W(C0)5 II Meo W(CO)5 TIPS \ OMe \ 1) Toluene, 130 °C, 24 h \ 0 o + 2) Air oxidation, 24h ' o + O 274 || 274 o 269 TIPS 39 The mechanism for the formation of cyclopentenone 275 is shown in Scheme 4.25 and is based on a mechanism that has been proposed for related tungsten complexes.7 The reaction is initiated by a CO loss from complex 274 to 99 form tetracarbonyl tungsten complex 279 which is followed by hexyne coordination and insertion to form the vinyl carbene complexed intermediate 281. This complex 281 then forms cyclopentanone 275 via metallacyclohexadiene 282. Scheme 4.25 Mechanism for the formation of cyclopentenone 275. O | M60 W(CO)5 M60 W(CO)4 I ifsgtri‘gn ~‘OM6 / - CO / + H —— O O \ "I 274 279 290 OC'WTCO 05 ’00 281, E-isomer MeO Reductive -— / \ Elimination o M(CO)4 282 4.4.1.4 Reaction of bis-phenyl triyne 224 with aryl carbene complex 22 and 175 Reaction of cyclohexenyl complex 219 with bis-phenyl-1,3,5-hexatriyne 224 takes place at a terminal alkyne unit to give the product 226 (Scheme 4.8).64 Thus it was expected that the reaction of phenyl carbene complex 22 with triyne 224 would give mono-benzannulated product. This product was tentatively identified from this reaction by Jiang as 230, but its structure was not confirmed. This reaction was repeated and found to give several products but none were formed in more than a few percent yield. One of the major products was isolated 100 in 3 % yield and identified by its 1H NMR spectrum as the naphthol 230 (Scheme 4.26). The regioselectivity of the reaction was probed by methylation of the hydroquinone 230 which gave an unsymmetrical diyne 283 (Scheme 4.26). A lack of symmetry in the proton NMR spectrum ruled out the regioisomer 284. Due to the low yields, none of the products from this reaction were completely characterized. Scheme 4.26 Reaction of complex 22 with triyne 224 Ph H300 Cr(CO)5 OCH é 3/ / Benzene 90 °C + Ph : : 1: Ph ’ P CO 24 h Ph 224 22 OH 230, 3 °/o T CH NaH then 0 3% Ph (CH3)2304 Ph 00 we 2 § / OCH3 Ph CO 284 Ph Not observed OCH3 283. 96 % The low yield in this case could be due to multiple alkyne insertion in the vinyl carbene complex 285 by reaction with triyne 224 (Scheme 4.27). Scheme 4.27 Possible polymerization pathway of complex 285. @,.OM9 ' : Ph Ph : , ,1 224 ' —’ Polymerization I OC-CE—CO 06 ’CO 285, E-isomer 101 A similar outcome was observed for the reaction of chromene carbene complex 175 with triyne 224. This resulted in a complex mixture of compounds all of which were formed in small amounts. No benzannulation product could be detected in this reaction (Scheme 4.28). Scheme 4.28 Reaction of complex 175 with 224 Ph H300 Cr(CO)5 I I / Benzene, 90 °Q 100 % conversion O + 24 h ' Complex mixture 175 I I224 Ph 4.4.2 Reaction of alkenyl and aryl carbene complexes with diyne The results of the studies of aryl complexes with triyne 39 reveal that it will not be possible to introduce the A-ring of conocurvone 36 directly as a naphthoquinone. Attention was next focused on whether the B and C fused-rings of the conocurvone analogue 286 could be introduced directly as naphthoquinones by reaction of ortho-aryl diyne 221 with aryl complexes. As shown by Jiang, these complexes can be prepared directly by the reaction of the cyclohexenyl complex 219 with triyne 39 (Scheme 4.7). The reaction of chromene carbene complex 175 with orfho-aryl diyne 221 or 287, after some chemical transformations, should give conocurvone analogue 286 (Scheme 4.29). This would be an important accomplishment based on the fact that anti- HIV activity of conocurvone 36 and its analogue 194 (Figure 4.2) is found to be identical by Boyd and co-workers at NCI.16 102 Scheme 4.29 Retrosynthesis for conocurvone analogue 286 R// 3 ( )5 OCH3\\ I/0 221 R: OAc 287 R: CH3 This study will include the reactions of orfho-aryl diynes 221 and 287 with the chromene carbene complex 175 and the phenyl carbene complex 22. In addition, orfho-aryl diynes 288, 289, 290 will also be studied (Figure 4.6). These diynes would provide a facile tool for the synthesis of conocurvone derivatives of the type 291 with three different ring systems A, B and C. Figure 4.6 Diynes 288, 289, 290 and tris-aryl derivative 291 O 3 R 0" a o Cr(CO)5 1 0 R4 (>4... s “o . OCH3 TIPS R2 0 R5 22 288 R = Me ® 289 R = Ac 0291 Rs 290 R = TBS The preparation of orfho-aryl diynes 288, 289, 290 is discussed in section 4.4.2.1. The reactivity of all five diynes with the phenyl carbene complex 22 and the chromene carbene complex 175 is described in section 4.4.2.2. Finally, section 4.4.2.3 will explore the reaction of orfho-aryl diyne 289 with alkenyl complexes. 103 4.4.2.1 Synthesis of mono-sllylated orfho-aryl diynes 288, 289, 290 Theoretically, two routes are possible for synthesizing the monosilylated orfho-aryl diynes 288, 289 and 290 (Scheme 4.30). Route A involves phenol 220 protection followed by controlled desilylation of diyne 293. In the second route, selective desilylation and then the protection of phenol 294 is required. The route that was examined in detail was Route B. After considerable experimentation, it was found that the desilylation of 220 could be made chemoselective. Scheme 4.30 Two possible routes for forming 288-290 OH TIPS // \\ OR TIPS CW? 292 .. o \ . e . Q‘Oeoo'\°° ‘ ‘ 32/176 1} , o ‘o TIPS / 23:49 TIPS 4" on Route A // \\ O x c} H / 6 (If \ % OCH3\ TIPS 09.9,; OH é O\ 0M6 TIPS 1’49). “a“ 80“ R = Me, 288 220 00 8090 R = Ac, 289 Q 9 R = TBS, 290 Route 3 OMe TIPS 294 Jiang has observed the chemoselective desilylation of 220 but the conditions were not optimized. Further, the structure of the desilylated product was wrongly assigned as 292 (Scheme 4.30), which has now been assigned as 294 based on an X-ray analysis of a derivative (vide infra). The selective desilylation of 220 under different reaction conditions is shown in Scheme 4.31. Reaction of phenol 220 with TBAF in THF solvent at room temperature for 1 h 104 affords a 21 % yield of monosilylated 294 and 41 °/o of nonsilylated 295. Lowering the temperature to 0-10 °C yielded 294 : 295 in the ratio of 53 : 32. Exclusive formation of 294 was observed when the reaction was done either for 10 min at 0 °C or for 1 h at -20 °C in 86 % and 76 % yields, respectively. The chemoselectivity of mono-desilylation of 220 was confirmed by an X-ray structure of 299 (Scheme 4.35) which was derived from 289. Scheme 4.31 Chemoselective desilylation of phenol 220 CH TIPS OH OH / / / / TBAF, THF= / / Temp., Time + % % % OCH3 TIPS OMe TIPS OMe 220 294 295 Yield (%) Entry Temp. (°C) Conc. (M) Time (h) 294 295 1 25 0.03 1 21 41 2 0-10 0.03 1 53 32 3 0-10 0.06 1 55 32 4 0 0.03 1 0 min 863 - 5 -20 0.03 1 77 - Unless otherwise specified the reactions were carried out in THF solvent using 220 (1 equiv) and TBAF (3 equiv) at the stated temperature and time. a) Product was contaminated with small amount of impurities. One possible explanation for the selective desilylation of the TIPS group in the position ortho to the free hydroxyl group in 220 could be the hydrogen bonding between hydrogen atom of the OH functional group and the fluoride ion as shown in Figure 4.7. The most favorable angle for the formation of hydrogen bonding (i.e., O'H'“F angle for transition state 296) is 180 degrees. Thus, the hydrogen bonding would place fluoride ion in proximity to the TIPS group in ortho 105 position to the hydroxyl group and hence favor its removal over the TIPS group ortho to the OMe functional group in 289. Figure 4.7 Transition state for chemoselective desilylation of 220 H'TF“ T’ O/éfi % OCH3 TI PS 296 0) After selective desilylation, orfho-aryl diynes 288, 289 and 290 could be prepared from 294 by using appropriate silylating, methylating and acetylating agents, respectively, as outlined in Scheme 4.32. Scheme 4.32 Protection of phenol 294 00113 ¢ NaH then (CH3)2$O4~ % OMe TIPS 288, 95% OH OAc ¢ . ¢ % % TIPS OMe TIPS OMe 294 289, 98% OTBS é TBSCI, lmidazole .7 % OMe TIPS 290, 56% 106 4.4.2.2 Reaction of aryl carbene complex 22 with orfho-aryl diynes 221, 287, 288, 289, 290 The reactions of the phenyl carbene complex 22 with the five orfho-aryl diynes 221, 287, 288, 289, 290 were studied (Figure 4.8). The reactions were examined in toluene, CH2CI2 and acetonitrile to study the effect of non-polar, polar non-coordinating and polar-coordinating solvents. Figure 4.8 Diynes 221, 287, 288, 289 and 290 OR OR ¢ ¢ : : :% I \; 0M9 OCH3 TIPS 221 R=Ac 288H=M6 287R=Me 289R=AC 290 R = TBS The reaction of the phenyl carbene complex 22 with ortho-aryl diynes 221 and 287 resulted in a mixture of compounds which were not easy to purify and identify. Attempts at purification by silica gel chromatography generally lead to the isolation of a mixture of products, which did not show any major products by TLC, GC-MS and 1H NMR. The phenyl carbene complex 22 was either consumed during the reaction or remained in trace amounts as indicated by a faint spot by TLC. The orfho-aryl diynes 221 and 287 could be recovered in 10 % to 15 °/o yield after chromatography on silica gel (Scheme 4.33). 107 Scheme 4.33 Reaction of complex 22 with orfho-aryl diynes 221 and 287 OMe OR é Solvent Cr(CO)s+ .0 = Result § 70 °C, 24 h 22 OMe 221 R = Ac 287 R = Me Entry R Diyne Solvent Diyne recovered (%) 1 . Ac 221 Toluene 15 2. Ac 221 CH3CN 10 3. Me 287 Toluene 12 4. Me 287 CHacN 14 Unless otherwise specified reaction was done using diyne (1.0 equiv) and complex 22 (1.0 equiv) in indicated solvent (0.05 M). a) Generally, the TLC plate shows a mixture of very close compounds which were not possible to separate using column chromatography. A summary of the results obtained from the reactions of the mono-silylated orfho-aryl diynes 288, 289, 290 and phenyl carbene complex 22 are shown in Scheme 4.34. These reactions resulted in the recovery of significant amount of diynes after silica gel chromatography, up to 64 % yield (entry 4). The corresponding carbene complex was either totally consumed or was only present in trace amounts as indicated by a very faint spot on the TLC plate. The reactions of orfho-aryl diynes 288, 289, 290 were also carried out with complex 22 in the presence of TMSCI and Hunig’s base (entry 2, 7, 12). This should result in the formation of a bis-phenol with both phenol groups protected with TMS which 108 Scheme 4.34 Reaction of complex 22 with orfho-aryl diynes 288, 289, 290 OMe é Solvent @mcow 7o 00 24 h = Result . OMe \\ TIPS , 22 1.1 equw 1.0 equiv Entry R Diyne Additive Solvent Diyne recovery (% Yield) 1 OMe 288 - Toluene 36 2 OMe 288 Hunig’s base, Toluene 36 TMSCI 3 OMe 288 - CHZClz 36 4 OMe 288 - CHaCN 64 5 OMe 288 - Silica 24 6 OAc 289 - Toluene 36 7 OAc 289 Hunig’s base, Toluene 32 TMSCI 8 OAc 289 - CH2C|2 32 9 OAc 289 - CH3CN 40 10 OAc 289 - Silica 48 1 1 OTBS 290 - Toluene 30 12 OTBS 290 Hunig’s base, Toluene 26 TMSCI 1 3 OTBS 290 - CHchg 26 1 4 OTBS 290 - CH30N 20 1 5 OTBS 290 - Silica 42 Unless otherwise specified reaction was done using diyne (1.0 equiv) and complex 22 (1.0 equiv) in indicated solvent (0.05 M). might be more stable to the reaction conditions. However, the proton NMR of crude reaction mixture only showed 3-4 peaks near 0 ppm which were relatively 109 very small. This further documents that the reactions of phenyl carbene complex 22 with orfho-aryl diynes 288, 289, 290 are undergoing side reactions faster than the formation of phenol product (Scheme 4.34). Silica supported benzannulation of phenyl carbene complex 22 with the three diynes did not produce different results (entry 5, 10 and 15).69 Finally, the reaction of the chromene carbene complex 175 with orfho-aryl diyne 221 was investigated. At 50 °C, no reaction took place and at 90 °C consumption of both of the starting materials was observed with the clear formation of no predominant silica gel mobile product. 4.4.2.3 Reaction of orfho-aryl diyne 289 with alkenyl complexes The orfho-aryl diyne 289 possesses two potential alkyne units where benzannulation can take place. However, sterically encumbered alkynes are known to undergo benzannulation reaction much slower than the sterically unhindered alkynes.7o Thus, it was anticipated that the non-silylated alkyne in 289 would undergo benzannulation faster than the silylated alkyne in orfho-aryl diynes 288 - 290. The acetyl protected orfho-aryl diyne 289 was chosen to illustrate the ability of this route to provide a synthesis of conocurvone derivatives of the type 291 (Figure 4.6). Heating a mixture of on‘ho—aryl diyne 289, carbene complex 297, Ac20 and Hunig’s base in toluene gave compound 298 in 52 °/o yield after purification by column chromatography (Scheme 4.35). This biaryl compound 298 upon desilylation afforded compound 299 in a 94 % yield. The structure of compound 299 was confirmed by X-ray analysis, which also confirms the chemoselectivity of the mono-desilylation of phenol 220 (Scheme 4.31). 110 Compound 299 was reacted with 2-propenyl carbene complex 300 in the presence of TMSCI and Hunig’s base and afforded two rotamers of compound 301 in a ratio of 2 : 1 in 60 % total yield. Scheme 4.35 Regiocontrolled synthesis trimer 301 OMe OAc ¢ MeO OAc O +/_€:CI'(CO)5 Benzene,A020 \ _ Hunig's base .0 OAc \ \ \ OMe TIPS 297 OMe TIPS 289 298, 52% OMe TBAF, THF OMe MeO OTMS :gmtcou on 0 .0 OAc Tl TM l, ouene, SC § 301, 60% H . b _ unIg's ase Rotamers 2.1 OMe OMe 299, 94 % The conversion of tris-phenol 301 to tris-quinone 302 is shown in Scheme 4.36. Desilylation of 301 using TBAF could be achieved by stirring at 0 °C for 20 min. The TLC of the desilylated reaction mixture showed the presence of two compounds corresponding to the two rotamers at R = 0.25 and R, = 0.32 (Hexane : ethylacetate 9 : 2). The crude product so obtained after the workup of the reaction mixture was then reduced using LiAlH4 by stirring at 0 °C for 1 h 30 min. After 1 h 30 min the reaction mixture was quenched with H20 and extracted with ethyl acetate. The ethyl acetate was evaporated to obtain an oily residue. This residue was then dissolved in THF and was treated with 8 equivalents of CAN which at 0 °C for 10 min. The workup of the reaction mixture and the 111 purification of the residue obtained after the workup yielded the unsymmetrical tris-quinone in 51 % yield. Scheme 4.36 Transformation of 301 to 302 OMe a. TBAF, THF OAc b. LiAIH4, THF > OTMS c. CAN, THF/H20 301 OMe 51% 302 4.5 Mechanistic Considerations This section considers possible mechanisms for the reaction of phenyl carbene complex 22 and the chromene carbene complex 175 with triyne 39. These considerations are taken from what is known about the mechanism of the reaction of Fischer carbene complexes with simple alkynes5 and also from calculations done here at MSU with help from Victor Prutyanov. 4.5.1 The Mechanism of reaction of complex 22 with triyne 39 Six different products are possible from the reaction of phenyl carbene complex 22 with the triyne 39. Two of the possible products 236 and 237 arise from the reaction at the internal position of the triyne and these are shown in Scheme 4.39. Two other possibilities (phenol 305 and furan 241) arise from the vinyl carbene complexed intermediates from (E)- 303a and (Z)-303b and these, in turn, arise from the reaction of phenyl carbene complex 22 at the terminal position of triyne 39 (Scheme 4.37). 112 Scheme 4.37 Possible lntermedlates from the reaction of phenyl carbene complex 22 at the terminal position of triyne 39 [150... I Z TIPS 'V O .,\OCH3 9 H300 OC-Cr-CO \\ TIPS '\ — TIPS 06 ’00 TIPS Z : TIPS ‘1" 304 ‘1” oc-lcr—co ——‘-———- OC-Cr-CO oc '00 05 ’co 303a. E-isomer 303b, Z-isomer I @CIICOIS TIPS OH 22 The remaining two possible products 308 and 239 arises from vinyl carbene complexed intermediates 306a and 306b and are regioisomers of 305 and 241, Irespectively (Scheme 4.38). In 306a and 306b the bulky TIPS substituent on carbon C—2 is 1A closer to a CO ligand than it would be if it were on carbon C-1 such as they are in intermediates 303a and 303b.“5d The steric interaction between the TIPS substituent on carbon C-2 and the CO ligand on chromium render the formation of intermediates 306a and 306b energetically unfavorable in comparison to the intermediates 303a and 303b. This same steric argument has been used to explain the regioselectivity of simple internal 113 alkynes.7 Thus the probability of formation of products 308 and 239 is considered to be unlikely. Scheme 4.38 Possible intermediates and products from the reaction of complex 22 at the terminal position of triyne 39 OCH3 ®TIPS TIPS I I \ 3,.OCH3 \ 9 —)_,°‘ OC-lCr-CO 1 TIPS ’co ._ _ 2 0C _ TIPS —— 30;; TIPS — OC- \lCr-CO CC CC 3068, E-isomer / OCH3 TIPS ”@C'ICOIS OHI ¢ ¢ 22 00 OCH3 308 The mechanism shown in Scheme 4.39 can be used to account for the exclusive formation of furan 236 out of all of the four remaining possible products. Complex 22 would be expected to undergo a rate determining loss of a CO ligand5b followed by either insertion of the central alkyne in 39 to give the nIma-vinyl carbene complexed intermediates (E)-250a and (Z)-250b or insertion at the end-alkyne in 39 to give the n‘,n3-vinyl carbene complexed intermediates (E)-303a and (Z)-303b. Here it is assumed that these intermediates are in rapid equilibrium with each other with respect to CO insertion which gives the vinyl ketene intermediates 309a, 309b, 310a and 310b. DFT calculations by Hess59 114 and experimental results for reactions with simple alkynes from our lab6b have established that, for reactions with simple alkynes, cyclization and aromatization of the vinyl ketene intermediate is faster than deinsertion of the carbon monoxide which regenerates the, n‘,n3-vinyl carbene complexed intermediate. However, these studies did not include any examples of triynes or even diynes nor any examples of mono-ynes that have a silicon substituent. It is thus assumed here that the cylizations of vinyl ketene intermediate 309a is slow relative to CO deinsertion. Support for the slow electrocyclization of 309a comes from the known ability of silicon to greatly increase the stability of metal-free ketenesm and from observations that stable metal-free silyl-substituted vinyl ketenes can be isolated from the reaction of Fischer carbene complexes and silyl-substituted 71"“ In addition, electrocyclization in 309a and 310a would be alkynes. accompanied with the disruption of aromaticity of the phenyl ring. This will help to slow down electrocyclization of both 309a and 310a. 115 Scheme 4.39 Mechanism for the formation of furan 236 \ / l ‘OCH3/ // \ SIPQ \ / ‘ . \ TIPS ____:\; (OCgCC; _ : TIPS (OC)3%T_{:(“ : : TIPS TIPS “PS”, 3098 \ /3 @6043 H300\\\ Om TIPS — "_‘*—— TIPS OC-lCr-CO 303a. E-isomer OC- lCr- CO CC CC 39 39 QC CO 303b, Z-isomer \ OCH3 / 39 39 / 22 \ Q (2“OCH3 H3CON‘T ' : TIPS — .' : TIPS TIPS _ _—“—— TIPS — 00- cr— co OC‘,CI,"C° 250a E- -isomer 250b Z-isomer / \ .~OCH3 CH3 Q (00) Cr/ : TIPS /0\(‘ 6=c\ (0080'?— : TIPS \\ 3108 310b TIPS \ /“ TIPS OH TIPS H CO 0 CC T 3 H a // \\ OCH3 TIPS TIPS 236 TIPS 237 116 The Z-isomers 250b and 303b are proposed to be in equilibrium with each other and with the E-isomers of 250a and 303a (Scheme 4.39). The Z-isomers, 250b and 303b can be in equilibrium with the corresponding CO insertion products i.e., 310b and 309b. It would be expected that of the two ketenes 310b and 309b, the silicon stabilized ketene 309b should be less reactive towards nucleophillic attack by the methoxy oxygen. Based on this expectation, the observation that the silyl-substituted triyne produces furan 236 as a result of reaction at the central alkyne can then be accounted for by reversible CO insertion in (E)-303a, (Z)-303b and (E)-250a and a non-reversible CO insertion in 250b which can then lead to a depletion of an equilibrium between (E)-303a, (2)- 303b and (E)-250a via intramolecular nucleophilic attack of the methoxy group at the ketene carbon and the formation of 236. The reason for these reversible CO insertions in ketenes 309a and 309b is the stabilization of the ketene by the silicon substituent,71 and in 310a it is the disruption of aromaticity of the phenyl ring which would accompany the electrocyclization step. It is not possible to rule out another scenario that involves a non-reversible CO insertion for all of the vinyl ketene intermediates and a product determination that is the result of equilibrium between (E)-303a, (Z)-303b, (E)-250a, (Z)-250b, where the formation of (Z)-250b is favored, and thus the furan 236. The most likely mechanism for the conversion of the ketene complex 310b to furan 236 is shown in Scheme 4.40. Nucleophilic attack of methoxy oxygen on the ketene carbon would give zwitterion 311, which upon rearrangement furnishes furan 236 via the intermediacy of the carbene complex 313 which 117 provides the furan ring upon nucleophilic addition of the carbonyl oxygen to the carbene carbon (Scheme 4.40). This proposal is based on the mechanism for the formation of furans from carbene complexes with mono-alkynes that has been worked out by the research groups of Wulff65b and Rudler.659 Scheme 4.40 Furan 236 formation from (Z)-ketene complex 310b 8H3~Ph H39 :93? Ph n(OC)CrQ—‘ __ o (*9 o e ph O 0 e _ TIPS Y _ Cr(CO) \ ——. n 0: ———§ _\ / \ Cr(CO)n // \\ \\ 31°” / 311\ TIPS 3’12 TIPS TIPS TIPS TIPS H300 0 H3659 0 lg) “300 (in 0.100),, \ / U 1 «00),, // \\ // \\ // \\ 313 TIPS 236 TIPS TIPS 314 “pg TIPS TIPS Preliminary calculation studies were performed with Victor Prutyanov to rationalize the formation of furan 236 and are discussed below. In these calculations the central issue will be the relative energies of intermediates on the paths to furan 236 vs phenol 237. Thus, the energies of the products 305 and 241 and the intermediates involved 303a, 303b, 309a and 309b, arising from the reaction of phenyl carbene complex 22 to the terminal alkyne of triyne 39 are not considered. To help render the calculations simpler, the TIPS substituent in all the intermediates and products has been replaced by the TMS group. The PM3(TM) method was used to optimize the silylated intermediates (250a, 250b, 310a, 310b) and the products (236, 237). The single point energy of these PM3(T M) optimized structures (Figure 4.10) were then calculated using the DFT 118 (BP86/DN*) method. The energy of intermediates 250a, 250b, 310a, 310b and the products 236 and 237 from the reaction are shown in Table 4.1. In evaluating the relative energies of the intermediates and products for this reaction an immediate problem was encountered. While, the intermediates 250a, 250b, 310a and 310b are metal complexes, the products that are actually isolated from these reactions, furan 236 and phenol 237 are not metal complexes. This will lead to large energy differences between the intermediates and products. As a solution to this problem the energy of furan 236 and of phenol 237 was determined by adding the energy of a tricarbonyl chromium fragment using the equations shown in Scheme 4.41. The energy of furan 236 was determined to be E(DFT)236 = -1545.68194 which is extremely low in comparison to the intermediates 250a, 250b, 310a, 310b. This is because of the absence of chromium and the CO ligands in 236. Thus the energy of 236 was calculated using the equation shown in Scheme 4.41. It is assumed that the reaction of complex 22 with 39 in benzene would form complex 315 along with the furan product 236. The chromium tricarbonyl complex of furan 236 is identified as 236* but it is not clear how the chromium tricarbonyl group would be complexed to 236. The energy of 236* was calculated by subtracting the energy of benzene (E(DFT) = -232.31431 h/p) from the summation of the energy of furan 236 (E(DFT) = -1545.68194 h/p) and the energy of 315 (E(DFT) = -1617.24843 h/p). The problem of naphthol 237 not having a metal was handled in two different ways. In the first case the calculation were performed on chromium 119 tricarbonyl complex of 237 (i.e., of complex 237a) and E(DFT)237a = - 2930.60909 h/p (Table 4.1, entry 2) was obtained. Complex 237a was chosen because its formation would be consistent with the experimental observation that the product of the reaction of carbene complex with alkynes is a chromium tricarbonyl complex where the chromium is 116-coordinated to the newly formed benzene ring.3 In the second method, the energy of the metal complex of naphthol 237 was determined in the same way as was the metal complex of furan 236. Thus, 237* was calculated by adding the energy of naphthol 237 (E(DFT)237 = -1545.6842 h/p) and energy of complex 315 (E(DFT)315 = - 1617.24843 h/p) and deducting the energy of benzene (E(DFDbenzene = - 232.31431 h/p). This energy was found to be E(DFT) 237* = -2930.61832 h/p. Although the energies for the two methods of accounting for the metal complex of 237 vary by 5.8kcal / mole, this is not large enough difference to affect the overall conclusion from the calculations. Scheme 4.41 Energy of furan 236 E(DFT)236" _ _ (Table1,entry 5) E(DFT) 236 T E(DFTI315 E(DFT) Benzene E(DFT) 237* = _ (Table 1, entry 7) E(DFD 237 + E(DFT) 315 E(DFT) Benzene OH TIPS \ é H300 0 I \ 70(00):, \ / X \ Cr(CO) \ 3 OCH3 TIPS // 236 \\ 315 237a TIPS TIPS 120 Table 4.1 Energetic of the products 236 and 237 and intermediates involved in their formation Entry Intermediates PM3(TM) Single point Energy differencee and Heat of energyc (Em —2930.61606) Productsa Formation” (h/p) d X 627.5 (kcal/mol) (kcanol) 1 . 236* 87.106 -2930.61 606 0 2. 237a -75.935 -2930.60909 4.37367 3. 237* -75.935 -2930.61832 -1.41815 4. 250a -88.535 -2930.55835 36.21 303 5. 250b -90.054 ~2930.47528 87.93785 6. 310a -60.91 293044371 108.14960 7. 310b -1 04.64 -2930.55683 37.1 6682 a) The energy calculated is that of the intermediates and the products when TIPS group in the acetylenic position is replaced by TMS. b) lnterrnediates shown in column 1 were optimized and their heat of formation were calculated using PM3(TM) method. 0) Single point energy of PM3(TM) optimized structure was calculated using DFT(BP86)/DN* method. d) h/p = hartree/particle. e) Em: energy of the intermediate in column 1. The following assumption has been made to interpret the results of the calculations: the energy of the intermediates correlate with the energy of their transition states. The profile of the reaction of phenyl carbene complex 22 with triyne 39 is shown in Figure 4.9. The calculations Show that (E)-310b is more stable than (Z)-310a by 71 kcal/mol. One of the possible explanations for such a big difference in energy is that, in (E)-310a, the 18 electron chromium complex formation requires the coordination of the double bond of the benzene ring which would lead to the disruption of aromaticity. This is, however, not the case in 310b, in which a lone pair of electrons from the oxygen can coordinate with chromium to make it an 18 electron chromium complex. Another important point 121 to note from reaction profile in Figure 4.9 is that, (E)-250a is more stable than (Z)-250b. The stability of (E)-250a can be explained in terms of the trans-effect. The “trans-effect” favors an electron—donating substituent (i.e., OMe in (E)-250a) at the C-3 position of vinyl carbene complex intermediate (E)-250a to be trans to the carbene carbon (C-1) of the vinyl carbene complexed intermediate (E)-250a (For details see section 4.4.1.1).66 The calculations further reveal that the furan precursors vinyl carbene complex (Z)-250b and (ZI-vinyl ketene 310b are both lower in energy than the (E)-ketene 310a that is responsible for phenol product formation. Thus an equilibrium between (E)-250a, (Z)-250b, (E)-310a and (2)- 310b would favor the relatively low energy intermediate _(Z)-ketene 310b which would then undergo irreversible nucleOphilic addition and rearrangement to form furan 236. Figure 4.9 Energy of the intermediates and the products where TIPS group is replaced by TMS group 108 kcal 2930-41. (151-awe l’—\ E II ,”’ ,’ ‘3‘\ § (4213-2501: a ’ 4' 88 kcal \.\ 2 4’ ‘~ g ll”, \‘ .2 \\ , 37kcal .; ””1, \\ \‘\ (5-31% 9 ’ ‘\ — m \ \ Lfi (E)-2503 ‘.\ 36 kcal \ 4kcal -2930.61 ‘~ 2371! 236* Reaction Coordinate T 122 Figure 4.10 PM3(TM) optimized structure of the intermediates and the products where TIPS group is replaced by TMS group (Z)—310b (Z)-250b 236 4.5.2 The formation of the olefin-addition product 269 from the reaction of chromene carbene complex 175 with triyne 39 A possible mechanism for the formation of unprecedented product 269 formed in the reaction of chromene carbene complex 175 and triyne 39 is as shown in Scheme 4.42. As in the reaction of the phenyl carbene complex 22 with 39 the first step most likely involves the rate limiting loss of CO from chromene carbene complex 175 to give a 16-electron complex which undergoes alkyne 123 coordination and insertion to form vinyl carbene complex (E)-316 (Scheme 4.42). It is then proposed that vinyl carbene complex (E)-316 undergoes a rearrangement to form another vinyl carbene complexed intermediate 317. The [2 + 2] cycloaddition of olefins and Fischer carbene complexes are well (172'73 and in this case intermediate 317 would undergo [2+2] establishe cycloaddition to form Chromacyclobutane 318. Finally, Chromacyclobutane 318 could undergo B-hydride elimination and reductive elimination to give compound 269. Scheme 4.42 Proposed mechanism for the formation of 269 TIPS O I MeO Cr(CO)5|l alk yne / insertion AOMG .OMe + ' : TIPS ~. : TIPS O TIPS : I,’ TIPS _ \ 175 I I OC'lér—CO OC—‘ng—co TIPS CC ’00 31700 co 39 316. E-isomer [2+2]cycloaddition TIPS II ”x TIPS Cr(CO)4 MeO / - TIPS O Reductive- / B—hydride O Elimination elimination O OMe TIPS 269 319 Chromacyclobutanes are known to be intermediates involved in the cyclopropanation reaction of a,B-unsaturated ester such as 320 with complexes such as 22 (Scheme 4.43).72 The cyclopropanation reaction in a few case has 124 been observed to give a side product of the type 322 which results from B- hydride elimination in the Chromacyclobutane 323.720 Scheme 4.43 Chromacyclobutane intermediate in cyclopropanation reaction OCHs CO CH (00150 0 c H 2 3 OCH3 + 00113 _6;2. + W OCH3 COch3 22 32° 321, 71% 322, 2% H COQCH3 °o Reductive elimination OCH B—hydride elimination ,, 321, 71/ i (OC)5Cr 3 2 322, M Reductive elimination 323 Harvey has reported the tandem alkyne insertion and cyclopropanation reaction of the reaction of Fischer carbene complex 325 with enyne 324 (Scheme 4.44).73 This reaction is very similar to the reaction of chromene carbene complex 175 with triyne 39 since it also involves the insertion of an alkyne into the carbene ligand and then an intermolecular [2 + 2] cycloaddition of the in-situ generated carbene complex 326 with an alkene. The difference here is two told: one, that the metallocyclobutane intermediate 327 undergoes reductive elimination rather than B-hydride elimination and, two, the olefin is part of the acetylene and not part of the carbene complex. 125 _.___ .- M‘fl .. ‘1‘.“s‘. ‘ ' Scheme 4.44 Tandem alkyne insertion and cyclopropanation reaction CO Me C02M6 MO(CO)5 \ 2 \ )L BU OCH3 325 MO(CO)5 324% B“ / 326 M60 BU COzMe / 002MB Bu / M0 M90 (CO)5 328 M60 327 In addition to the olefin-addition product 269, two other possible products from this reaction are the furan 265 and the naphthol 266 (Scheme 4.45). Carbon monoxide insertion in (E)-316 would form vinyl ketene complex (E)-329 which upon electrocyclic ring closure should give 266. Alternatively, (E)-316 may undergo isomerization to form Z-vinyl carbene complex 330 which upon CO insertion and cyclization will afford chromenyl furan 265 (Scheme 4.45).6'65 126 Scheme 4.45 Proposed mechanism for the formation of 265, 266 and 269 TIPS ll / TIPS / .OMe (OC)3Cr : Ozcx 329 TIPS TIPS O l _.OMe : : TIPS ‘ : TIPS TIPS : T'PS [2+2] OC-Cr-CO OC‘CF—CO Cycloaddition 4 , l 4 OC co oc CO 316, E-isomer 317 QC 330, Z-isomer 127 It is proposed that intermediate (E)-316 is in equilibrium with the intermediates 317, (Z)-330, (Zl-331 and 329. The electrocyclization of intermediate 329 is expected to be a slow process as it would be accompanied by the disruption of aromaticity of chromene ring. It is further proposed that irreversible [2+2] cycloaddition of intermediate 317 is faster than the nucleophilic attack of methoxy oxygen on the ketene carbon in 331. The exclusive formation of olefin-addition product 269 can then be explained by the irreversible [2 + 2] cycloaddition in 317 which would deplete the equilibrium between (E)-316, 317, (El-329 and (Z)-33O in favor of 317 and hence to preferential formation of 269. Another possibility could be that CO insertion is not reversible and that a product determination results from an equilibrium between (E)-316, 317 and (Z)- 330 and which is more favorable for 317. Preliminary calculations performed with Victor Prutyanov to rationalize the formation of olefin-addition product 269 are discussed below. To simplify the calculations, the TIPS substituent in all the intermediates and products has been replaced by a TMS group. The PM3(T M) method was used to optimize the silylated intermediates ((E)-316, 317, 318, 319, (E)-329, (Z)-330, (Z)-331) and products (265, 266, 269). The single point energy of these PM3(TM) optimized structures (Figure 4.12) were then calculated using the DFT (BP86/DN*) method. The energy of all the intermediates and possible products from the reaction are shown in Table 4.2. 128 ‘w«~..;' “.‘_‘ . . Table 4.2 Energetics of the products 265, 266, 269 and the intermediates involved in their formation Intermediates PM3(tm) Single point Energy difference" Entry and Heat of energy6 (Em —2930.61606) X Productsa Formation” (h/p) d 627.5 (kcal/mol) (kcanol) 1 . 265* -68.316 -3200.05654 0 2. 266a -103.1 65 -3200.00234 33.9854 3. 266* -1 30.032 -3200.0636 -4.45525 4. 269* -85.999 -3200.00852 30.1 0243 5. 316 -114.897 -3200.00162 34.43720 6. 317 -128.571 -3199.93228 77.54645 7. 318 -1 14.352 -3199.98966 41.94210 8. 319 -124.397 -3199.28895 79.64858 9. 329 -87.148 -31 99.89670 1 00.2745 10. 330 -114.939 -3199.28811 84.9133 1 1 . 331 -82.106 -3199.90603 94.41993 a) The energy calculated is that of the intermediates and the products when TIPS group in the acetylenic position is replaced by TMS. b) Intermediates and products shown in column 1 were optimized and their heat of formation were calculated using PM3(TM) method. c) The single point energy of the PM3(TM) optimized structure was calculated using DFl'(BP86)/DN* method. d) h/p = hartree/particle. e) Em = energy of the intermediate in column 1. The problem of the lack of a chromium and its CO ligands in the products 269, 265 and 266 was handled in a manner similar to that for the reaction of complex 22 with triyne 39 (Scheme 4.39). The chromium tricarbonyl complexes of 269 and 265 are indicated by 269* and 265*, respectively. The energies of 265* and 269* was calculated according to the equation shown in Scheme 4.46. The energy of the metal complex 265* (Table 4.2, entry 1) was calculated by 129 subtracting the energy of benzene (E(DFT)benzene = -232.31431 h/p) from the summation of the energy of furan 265 (E(DFT)265 = -1815.12242 h/p) and energy of complex 315 (E(DFT)315 = -1617.24843 h/p). The energy of olefin-addition product 269* (Table 4.2, entry 4) was calculated by subtracting the energy of benzene (E(DFT)benzene = -232.31431 h/p) from the summation of the energy of 269 (E(DFT)269 = -1701.78933 h/p), energy of CO (E(DFT)CO = -113.36183 h/p) and the energy of 315 (E(DFT)315 = -1617.24843 h/p) as shown in Scheme 4.46 . Notice that for calculating the energy of olefin-addition product 269, the energy of CO has also been included since 269 is a non-CO inserted olefin-addition product. The energy of metal complex of naphtholpyran 266 was calculated in two different ways. In the first case, the calculation was performed on the tricarbonyl complex of 266a and an energy of E(DFT)266a = -3199.95101 h/p was obtained (Table 4.2, entry 2). As was the case for 237, the kinetic product of the reaction is expected to be the arene complex 266a with the Cr(CO)3 group coordinated to the newly formed benzene as has been clearly established in the reaction of Fischer carbene complexes with mono-ynes.3 In the second case and without prejudice for where the Cr(CO)3 group is, the energy of the naphtholpyran 266*, (Table 4.2, entry 3) was calculated by adding the energy of naphtholpyran 266 (E(DFT)266 = -1815.12952) and energy of complex 315 (E(DFT)315 = - 1617.24843 h/p) and deducting the energy of benzene (E(DFT)benzene = - 232.31431 h/p) from their summation, as shown in Scheme 4.46. The energy difference between E(DFT)266a and E(DFT)266* is approximately 38 kcanol. 130 This difference is much larger than it was for 237 but does not effect the conclusions from the calculations. Scheme 4.46 Energy of furan 265 and olefin-addition product 269 E(DFT) 265* (Table 2, entry 1) E(DFT) 265 + E(DFD 315 - E(DFT) Benzene E(DFI') 266a _ _ (Table 2, am“, 2) — E(DFT) 266 + E(DFT) 315 15(an Benzene E(DFT) 269* _ 5(5)”? 269 + E(DFT) 315 + 12(an co} (Tablez, entry 4) _ E (DFT) Benzene TIPS TIPS H \\ OMe / TIPS _ MeO / / o O OMe O TIPS / \ Xc co -—Cr(CO)3 O / " ’3 “° S o 0 266a || 269 255 TIPS Figure 4.11 shows the energy profile of the formation of olefin-addition product 269. To interpret the results of the calculation the following assumption is made: the energy of the intermediates correlates with the energy of their transition states. It is further assumed that [2+2] cycloaddition is an irreversible step. 131 Figure 4.11 Energy of the intermediates and the products where TIPS group is replaced by TMS group 100 kcal -31 99.896 (E)-329 — r 1 p, || (&'331 " '9' 214 k 1 ~ (2133031)." °a \ I. ' '1‘1 \‘1 I I. I' 85 kcal'. ‘1 ‘1 il ,' '1' ‘1 ‘1‘ 1' ,’ 1 ‘1 \ 79 kcal 1' x 31., ‘~, ‘~ 1 319 l I \ -3199.9§2_- '1 I, _ I. 1‘ \\ ’F‘ '1 ', ’I’ 1“ 1‘ 1‘ ‘1 ’I 1“ "I ’1 ,’ 77kca \‘ E ‘\ [I x \‘ I ,l " I, ‘01 '1 ” ‘1 ‘1 I I m r "I; I” I“ 1“ ’1’ 1“ 1“ E 'l’: ,’ 1‘ 1‘ 1| ’I I“ 1“ i x t 41 kcal/ ~. ~. ""1 ‘ ‘ ‘ ’1 1‘ 1‘ g é}! .' ‘\ 318 I 1“ 1“ 'I I | \ \ U l | \ \ E . |‘1 ‘ \‘\ “1 (E)-316 1 266a ~__ 34 kcal '1' 34 kcal ‘. 269* '1 ‘. 30 kcal II \\ 1 1 '. 1 ‘. ‘1 '1 ‘1 ‘ \ 1 “ -3200 056 '1 265* ° _ 1 266* ~. _ — 0 kcal -4.4 kcal Reaction coordinate The calculations show that (Z)-331 is more stable than (E)-329 by 6 kcal/mol and (E)-316 is more stable than (Z)-330 by 51 kcal/mol. The explanation for increased stability of intermediates (Z)-331 and (E)-316 is same as that of the 132 stability of (E)-250a and (Z)-310b over (Z)-250b and (E)-310a as discussed in section 4.5.1. However, the energy difference between (E)-329 and (Z)-331 is only 6 kcal/mol which is much smaller than the energy difference between (E)- 310a and (Z)-310b (71kcal/mol) in which the chromenyl ring is replaced by phenyl ring (Scheme 4.39). The reason for such a big discrepancy in energy is not well understood. It is evident from the reaction profile that the formation of the olefin- addition product 269 involves two high-energy steps: rearrangement of the (E)- vinyl carbene complex (E)-316 to form the carbene olefin complex 317 and then B-hydride elimination in complex 318 to give 319 which leads to product upon reductive elimination. However the energies of the intermediates 317 and 319 on this pathway are significantly lower than the energy of (E)-329 and (Z)-330 which are on the pathway for the formation of products 266 and 265, respectively. Thus, an equilibrium between (E)-316, 317, (E)-329, (Z)-330 and (Z)-331 would be in favor of (E)-316 which upon [2+2] cycloaddition, B-hydn‘de elimination, and reductive elimination would furnish olefin-addition product 269. 133 Figure 4.12 PM3(T M) optimized structure of the intermediates and the products where TIPS group is replaced by TMS group .34‘ Q 134 4.6 Summary In summary, it has been established that aromatic carbene complexes 22, 234, 235 (Figure 4.5) will react with bis-TlPS-triyne 39 give aryl furans 236, 262, 272. The formation of aryl furans is neither perturbed by reaction temperature nor by the electronics of the carbene complex. The reactions of aryl carbene complexes 22 and 175 with bisphenyl-1,3,5-triyne 224 give either very low yields of the benzannulation product or decomposition of the starting materials. Furthermore, reactions of the phenyl carbene complex 22 with orfho-aryl diynes 221, 287, 288, 289, 290 result in the consumption of the starting carbene complex but in no discreet product formation. The reaction of chromene carbene complex 175 with bis-TIPS triyne gives an undesired but unprecedented olefin- addition product 269. The formation of this new product, if generalized for simple internal and terminal alkynes, would provide an excellent pathway to access a new class of naphthopyrans. 135 4.7 Future Work The reactions of the cyclohexenyl carbene complex 219 and bis-TIPS- triyne 39 or ortho-aryl diynes 221 and 289 work extremely well for synthesizing tris-quinones the type 223 (Scheme 4.7). This is, however, not the case for aromatic carbene complexes. An alternative approach to access aromatic tris- quinone of the type 286 (Scheme 4.29) is to use a,B-unsaturated carbene complexes of the type 332, 333 and 334 (Figure 4.13). Complexes 332 and 333 are not known in the literature. However, the synthesis of their corresponding vinyl bromides is known.7“'75 Figure 4.13 Alkenyl carbene complexes 332, 333 and 334 H3CO Cr(CO)5 H300 CrICO)s H300 CrICols 332 333 334 Yang and Wulff have reported the synthesis of complex 334.76 It has been shown that the reaction of complex 334 with phenyl acetylene affords dihydronaphthalene 335 which was converted to naphthalene 336 upon DDQ oxidation (Scheme 4.47). Thus, the reaction of carbene complex 334 with triyne 39 could give rest of the tris-aromatic phenols 338 or tris-aromatic quinones 339 (Scheme 4.47). 136 Scheme 4.47 Reaction of complex 334: Surrogate for an aryl complex H300 Cr(CO)5 finds Solvent 4. ————> \ / H (00130 ecu3 OCH3 334 H3CO Cr(CO)5 \ TMS 334 With this same strategy, tris-quinones of the type 268 would require the reaction of bis-TIPS triyne 39 and chromane complex 341 (Scheme 4.48). 137 Scheme 4.48 Retrosynthesis of formation of conocurvone analogue 340 Oxidation Benzannulation reaction H300 Cr(CO)5 + TIPS—Z—E—E—TIPS O 341 39 The chromane complex 341 can be obtained via two different routes (Scheme 4.49). Route A involves the transformation of Chromenone 342 to hydrazone 343,77 which is expected to give complex 341, upon its sequential treatment with f-BuLi, Cr(CO)6 and a methylating agent (Scheme 4.49). Shapiro reaction has been previously used for the formation of carbene complexes.12b In Route B, the chromanone 342 can be converted to vinyltriflate 344 which on palladium catalyzed triflate-tin exchange followed by quenching with a brominating agent would afford bromochromane 345 (Scheme 4.49). Standard Fischer protocol would transform 345 to 341. Chromanone 342 can be isolated in 92 % from the reductive hydrogenation of 144 using 5 % Rh on alumina. However this reaction does not go to completion when Wilkinson’s catalyst is used instead of 5 % Rh on alumina. 138 Scheme 4.49 Retrosynthesis of formation of complex 341 144 H CO C C 5%Rh 3 r( m5 on alummina, or} = @g F. 1 900, 3 Br 342.92% 99 003’ 2 O 345 In summary, synthesis of tris aromatic quinones of the type 339 and 268 would require the a,B-unsaturated Fischer carbene complexes of the type 334, 341, respectively. 139 CHAPTER FIVE Asymmetric Allylation of Imines 5.1 Introduction Nature possesses a plethora of chiral nitrogen containing molecules which are of significant biological importance. There is an utmost need of creating facile synthetic pathways for the synthesis of enatiomerically pure nitrogen-containing compounds using readily available and environmentally benign starting materials. Nucleophilic addition to imines for the construction of C-H bonds by reductive amination and C-C bonds by allylation, aza Diels—Alder reactions, imino-aldol additions, imino-cyanation and imino-ene reactions are but a few of the methods used to access chiral amines.78 Although catalytic enantioselective additions to aldehydes and ketones have been well investigated, there are only a limited numbers of reports on additions to the asymmetric additions to imines. The two main reasons which make the reaction of imines less favorable are: a) the turnover of the catalyst is limited by normally greater basicity of the product amine versus the imine starting material, and b) the ability of the imines to exist in E and Z-ismers and therefore can give rise to diastereomers upon binding with the catalyst which decreases the selectivity of the nucleophile and result in lower asymmetric induction (Scheme 5.1). 140 Scheme 5.1 E-Z isomerization of C-N bond and selectivity of the reaction 3 3 NI.R |.R 123:9? T A natal back-side front-side attack attack back-side front-side attack attack 3 3 HER HN'R 1 L 2 1 2 R RUB R NUR 348 349 Catalytic asymmetric allylation is one of the reactions of imines which has not been studied in detail. This chapter discusses an attempt to access chiral homoallylic amines by reaction of aldimines with allyltributyl stannane. 5.2 Asymmetric allylation: Background information There are only four reports on the catalytic version of the enantioselective allylation reaction of imines and these are discussed below. 5.2.1 Yamamoto and co-workers The first asymmetric catalytic allylation of imines was reported by Yamamoto and co-workers (1998) using chiral rt-allyl palladium catalyst 352 and allyltributyl stannane as nucleophile (Scheme 5.2).79a'b'c It has been proposed that allyltributyl stannane 351 reacts with the Pd(ll) catalyst to form a chiral nucleophillic bis-n—palladium species which selectively reacts with imines to form the enatiomerically enriched homoallylic amines 353. The reaction tolerated 141 aromatic, aliphatic and mil-unsaturated imines and gave good yields (30 % - 80 %) and enantioselectivities (40 °/o - 91 %). Scheme 5.2 Palladium catalyst for asymmetric allylation .01, |>® 2 N32 352 HEB R1JLH + WSHBU3 = R1W 350 351 THF, DMF 353 R1 = Phenyl, p-MeOCeH4, 2-naphthyl, Ph-CH=CH, cyclohexyl Yield 30 - 83 % R2 = Bn, p-MeOCeH4CH2, phenyl, propyl ee 40 - 82 % Yamamoto has further extended the scope of the reaction, by replacing the toxic allyltributyl stannane 351 with the environmentally benign allyltrimethylsilanes 354 and obtained the homoallylic amines 353 in yields as high as 95 % with moderate to high enantioselectivities (52 °/e - 90 %) (Scheme 5.3).79"'e The reactions of imines with allylsilanes are generally very slow and sluggish. This problem was overcome by using a palladium-TBAF cocatalyst system. Scheme 5.3 Allyl-palladium catalyst for asymmetric allylation .CL E129 ®€Pdchd - ~ 2 NR2 ' 352 HN'R 1Jl\ + WS'M93 > R1“ “350“ 354 TBAF, hexane/THF 353 R1 = Phenyl, p-MeOC6H4, 2-naphthyl, Ph-CH=CH, cyclohexyl Yield 34 - 96 % R2 = 8n, p-MeOCeH4CH2, propyl ee 64 - 80 % 142 5.2.2 Jargensen and co-workers In 1999, Jergensen and co-workers reported the catalytic asymmetric allylation of N-tosyl oc-imino ester 355 using allyl stannane 351 and silane 354 (Scheme 5.4).80 The allyl silane gave low yields (58 °/e - 64 %) and moderate enantioselectivities (34 % - 47 %). However, allyltributyl stannane afforded high yields (up to 90 °/e) and moderate to high enantioselectivities (23 % - 83 %). Scheme 5.4 Copper catalyst for asymmetric allylation Ts HN Tol- BINAP CuPF6 O ? 351=SnBu3CH2C|2 EDI/\A 355 354 R2: SiMe3 356 R1 Yield ee SnBu3 87 % 80 % SiMe3 34 % 58 % 5.2.3 Lectka and co-workers Lectka (2002) has demonstrated the successful asymmetric reaction of N- tosyl a—imino esters and allylsilanes using a palladium BINAP catalyst.81 Excellent yields of homoallylic amines 358 have been observed in all the reported cases. However, the enantioselectivity varied from 64 % - 92 % (Scheme 5.5). Scheme 5.5 Palladium chlorate catalyst for asymmetric allylation N/TS HN/ ,TS R1 VOE/EH + éfMS BINAP, Pd(ClO4)2 VON o R2 CH2C|2 358 R = 5H, Ph, Me Yield 85 - 91% R2 = H, M6 66 64 - 92 °/o 143 5.2.4 Kobayashi and co-workers Kobayashi has used the bidendate imines of the type 359, allyl tributyl stannanes (360, 361, 362, 363) and the zirconium-based catalyst 365 and 366 for asymmetric allylation reactions.82 The acceleration in rate and incremental increase in enantioselectivity was observed when the free alcohol functionality was present in the allylating agent such as in 362 and 363. He proposed that the free alcohol functionality in 362 and 363 binds to the Zr catalyst along with the bidendate imine which is followed by intramolecular attack of allyl stannne to the imine 359. This reaction provided 71 °/e - 85 °/e yield and 87 % - 99 % ee. However, this approach has two limitations. First, it is applicable to only aryl imines with the exception of imine derived from cyclohexanecarboxaldehyde. Second, the allylating agent (allyltributyl stannane) must have a CH20H substitutent (362 and 363) at the C-3 position for faster reaction rate and high asymmetric induction. Scheme 5.6 Zirconium catalyst for asymmetric allylation “° 06’“ 3 ND RMSVBW 10 mol% 365 or 366> NH R2 + _ R1JLH H R2 Toluene 0 °C R1 3 359 2 3 364 R 360 R = CH3, R = H . R1 = Phenyl, 1-naphthyl, 2 3 Yield 71 - 84 % 361 R = CHQOTBS, R = H 99 137-95% “my" p'C'C6H3 362 R2 = CHZOH. R3 = H 363 R2 = CHzOH, R3 = CH3 CO X 0. l{OtBu Z 365 X = Cl ((R)-3,3'-CIZBINOL) CO 0' ‘OlBu 366x: Br ((R)-3,3'-Br2BINOL) x 144 In summary, Yamamoto’s palladium catalyst 352 is general for the asymmetric allylation of a wide variety of aliphatic and aromatic imines. Jorgensen’s and Lectka’s catalysts are limited to only N-tosyl-or-imino esters for the allylation reaction. The Zr catalyst used by Kobayashi is useful for allylation reaction of aromatic imines with allyl stannanes possessing a methylene alcohol functionality in the C-3 position. Therefore, thus far there is no general Lewis acid catalyzed asymmetric allylation reaction of imines derived from both alkyl and aryl aldehydes. 5.3 Attempted allylation of benzhydrylimines of the type 367 Antilla and Wulff have reported an asymmetric aziridination of imines (obtained from benzhydryl amine and aldehydes) using ethyldiazoacetate and a triphenylborate-(S)-VANOL catalyst.83 The high asymmetric induction in the aziridination reaction of imines using this B(OPh)3 - (S)-VANOL catalyst inspired the present investigation of this catalyst for asymmetric allylation reaction (Scheme 5.7). Scheme 5.7 B(OPh)3/(S)-VAPOL catalyst for aziridination reactlon Ph Ph ,8h 0 S-VAPOL/B(OPh)3 Y .Bh N 10 IO/ N HN COgEt JL , ee < m° °> 2 2.: + _ R H N2 Solvent, 25°C R 359 C02Et IR1H RIH) 367 368 Yield 50-90 % 370 as 90-98 % .Bh Bu Sn. ,Bh O N S-VAPOL/B(OPh) 3 N I + NSnBu3 ................ .3 Bh = - 357 351 371 O 145 The first and foremost problem that was anticipated for VAPOL - Boron catalyst in asymmetric allylation reaction, was the issue of turnover. However, it could be imagined that the complex between the homoallylic amine 371 and the catalyst 372 would be weak because of steric reasons (Scheme 5.8). If the steric interactions in the catalyst — homoallylic amine complex 373 were great enough they could shift the equilibrium towards the free catalyst 372 which would result in its high turnover. Scheme 5.8 Boron catalyst for asymmetric allylation Allylation studies were initiated with the imines 374 and 375 derived from the reaction of benzhydryl amines and benzaldehyde and the more reactive para- nitrobenzaldehyde respectively (Scheme 5.9). The allylating agent employed for allylation was allyltributyl stannane. A variety of catalysts were screened which were obtained from the reaction of VAPOL with Lewis acids such as triphenylborate, titanium tetra-isopropoxide, zirconium tetraisopropoxde, bromoborane, diethylaluminum chloride and dichloro-diisopropoxy titanium (IV). Scheme 5.9 summarizes the catalyst preparation and shows the results of the allylation reactions performed using these catalysts. Both the imines 374 (entry 1, 3, 4, 5, 9, 10, 11, 12, 13) and 375 (entry 2, 6, 7, 8, 9) 146 ————————_—’— .___...--_*‘.-.z- . ,. - showed low conversions and poor enantioselectivities. In order to address the low conversion problem different additives like i-PrSMR'n (MR'n) = SiMea, BEtz, AlEt2 were considered. Yu and Coworkers have used additives of the type i- PrSMR'n as synergetic reagents to construct an effective catalytic cycle in the allylation reaction of aldehydes with allyl stannanes catalyzed by BINOL-Ti catalyst.84 They proposed that the synergetic effect arises from the Sn-S and M- O bond-forming steps which reinforces regeneration of the BINOL-Ti catalyst by producing strong Sn-S and MO bonds rather than weaker M-S bond. However, the addition of i-PrSBEtz did not have any effect on the yield or on the enantioselectivity of the allylation reaction with imines (entries 3 and 7). 147 Scheme 5.9 Catalyst investigated for asymmetric allylation “(Eh H.N.Bh H + WSHBU3 Catalyst : OM CHZCIZ (0.1 M) R1 R‘ 374 R = H 376 R = H 375 R = N02 377 R = N02 Entry Catalyst Preparation Reaction lmine Conversion ee Temperature/ (%) (%) Reaction Time 1. 0.2 equiv B(OPh)3 + 0.2 No equiv (R)-VANOL 25 °C, 24 h 374 reaction - 2. 0.2 equiv B(OPh)3 + 0.2 equiv (S)-VANOL -78 °C, 2 h; 375 16 22.0 0 °C, 18 h 3. 0.2 equiv B(OPh)3 + 0.2 equiv (S)-VANOL + 1.1 equiv 25 °C, 24 h 374 14 2.3 i-PrSBEtg 4. 0.2 equiv HzBBrSMez + 0.2 equiv (S)-VANOL 25 °C, 24 h 374 5 - 5. 0.2 equiv EtzAlCl + 0.2 equiv (S)-VANOL -78 °C, 2 h; 374 5 - 0 °C, 18 h 6. 0.2 equiv EtzAlCl + 0.2 equiv (S)-VANOL + 0.2 equiv 25 °C, 24 h 375 13 18.7 PhOH 7. 0.2 equiv EtzAlCl + 0.2 equiv (S)-VANOL + 0.2 equiv -78 °C to rt 3 h, 375 4 - PhOH + 1.1 equiv i-PrSBEt2 rt for 24 h 8. 0.2 equiv EtzAICl + 0.2 equiv (S)-VANOL + 0.2 equiv -78 °C, 2 h; 375 14 10.9 AgOTf 0 °C, 18 h 9. 0.2 equiv Ti(Oi-Pr)4 + 0.2 No equiv (S)-VANOL -78 °C, 2 h; 374/375 reaction - 25 °C, 18 h 10. 0.2 equiv Ti(Oi—Pr)2Cl2 + 0.2 No equiv (S)-VANOL + 4 A M. S. 25 °C, 24 h 374 reaction - 11. 0.2 equiv Ti(Oi-Pr)20|2 + 0.2 equiv (S)-VANOL + 4 A MS. 25 °C, 24 h 374 50 0 +0.4 equiv AgOTf 12. 0.2 equiv Zr(Oi-Pr)4.i-PrOH + No 0.2 equiv (S)-VANOL 25 °C, 24 h 374 reaction - 13. 0.2 equiv Zr(Oi—Pr)4.i-PrOH + No 0.2 equiv (S)-VANOL + NMI 25 °C, 24 h 374 reaction - Unless otherwise specified the reaction was carried out in CHZCIZ (0.1M). Chiralcel OD column was used to determine the enantiomeric excess of amines 376 and 377. 148 5.4 Attempted allylation of benzaldimines 378 Attention was then focused on benzaldimines of the type 378 for the allylation reaction (Scheme 5.10). Kobayashi has used this type of imine for allylation reactions but with only specific types of allyl stannanes as mentioned in Section 5.2. The bidendate imine 378 coordinates with the catalyst through the N and O atoms. This restricts the conformation of the imine in the catalyst-imine complex and increases the probability of selectivity control in the reaction. The preliminary investigations of the allylation of imine 378 with allyltributyl stannane employed chiral Lewis acids derived from Yb(OTf)3, a chiral ligand ((S)- VAPOL, (S)-VANOL, (R)-BINOL), and various amine additives. This class of chiral Lewis acid catalyst system has been developed and implemented by Kobayashi in Diels-Alder reactions,85 aza DieIs-Alder reactions86 and 1,3-dipolar cycloaddition87 reactions but not for the allylation reactions. The chiral catalyst for the allylation reaction was prepared using 0.21 equiv of Yb(OTf)3, 0.21 equiv of the bis-phenol ((R)-BINOL, (S)-VANOL and (S)- VAPOL) and 0.42 equiv of DBU (1 ,8-diazabicyclo[4.3.0]undec-7-ene). In addition to aldimine 378, allyltributyl stannane 351, and the chiral catalyst derived from Yb(OTf)3 and DBU, another amine additive DTBMP (2, 6-di-tert—butyI-4-methyl pyridine) was used. The yields for the allylation reaction varied from 16 % - 92 °/e and enantioselectivity of up to 67 °/e could be obtained as shown in Scheme 5.10. A comparison of entry 1, entry 14 and entry 15 shows a dependence of the yield and enantioselectivity on the steric bulk of the catalyst. For the catalyst derived from bulky VAPOL ligand, both the yield and enantioselectivity were low 149 (entry 14). For relatively less sterically hindered BINOL ligand the yield (92 %) was excellent which contrasts with an extremely poor enantioselectivity. The VANOL ligand which falls between VANOL and BINOL in terms of steric bulkiness, afforded both moderate yield and moderate enantioselectivity (entries 1 - 8). Two factors were varied in an effort to improve the yield and asymmetric induction in the reaction: temperature of the reaction and the different amine additive. Temperature studies revealed that -20 °C is the optimum temperature for the reaction with the VANOL catalyst (entries 5 and 6). At very low temperature (-40 °C) no reaction was observed (entries 7 and 8) and the reaction at room temperature compromised the enantioselectivity of the product (entry 1). Several different amine additives were tested to improve the enantioselectivity of the homoallylic amine and they are DTBMP (2,6-di-tert-butyl-4-methyl pyridine, DBU (1,8-diazabicyclo[4.3.0]undec-7-ene), DBN (1,5-diazabicyclo [4.3.0]non-5- ene), DMP (2,6-dimethylpyridine), NMI (N-methylimidazole) and 2,4,6—collidine. Surprisingly, all these additives failed to give any reaction (entries 9 - 13) with the exception of 2,4,6 collidine (entry 8) which afforded very low yield but moderate enantioselectivity for the reaction. 150 Scheme 5.10 Ytterbium triflate catalyst for asymmetric allylation N H‘N I H + WSnBu3 Catalyst t \ CHZCIZ (0.1 M) 378 379 Entry Catalyst Amine Temp (°C)/ Yield (%) ee (%) Additive Time(h) Yb(OTf)3 + (S)' 1. VANOL + DBU“ + DTBMP” 25°C, 8h 56 49.3 4A MS, 0 °C, 45 2. min DTBMP 0°C, 3 11 77 52.0 10 °C, 15 n 3. DTBMP 0 °C, 19 h 46 61.3 4. DTBMP 0 °C, 40 h 62 62.0 5. DTBMP -20 °C, 20 11 46 67.0 6. DTBMP -20 °C, 42 n 23 66.0 7. DTBMP -40 °C, 21 h No reaction - 8. 2,4,6- -40 °c to 10 °C, 16 53.0 Collidine 3n;10°c,15n 9. DBU " No reaction - 10. PMPc " " - 11. DBN“ " " - 12. NMI° " " - 13. DMP' " " - 14. Yb(OTf)3 + (S)- VAPOL + DBU + DTBMP 25 °C,8h 28 5.2 4A MS, 0 °C, 45 min 15. Yb(OTf)3 + (n)- BINOL + DBU + 4A DTBMP 25 °C, 8 h 92 3.0 MS, 0 °C, 45 min In all reactions allyltributyltin 351 : Imine 375 : amine additive were used in the ratio of 2 : 1 : 1. All reactions were performed in dichloromethane (0.1 M). Chiralcel OD column was used to determine the enantiomeric excess of amine 379. a) DBU = 1,8-diazabicyclo[4.3.0]undec-7- ene, b) DTBMP = 2, 6-di-fert-butyl-4-methyl pyridine c) PMP = 1,2,2,6,6- pentamethylpiperidine, d) DBN =1,5-diazabicyclo[4.3.0]non-5-ene, e) NMI =N-methyl imidazole , f) DMP = 2, 6-dimethylpyridine. 151 The proposed structure 380 of the chiral Yb catalyst shown in Scheme 5.11 is based on a similar structure proposed by Kobayashi for the Diets-Alder reaction with BINOL.85'87 In the chiral catalyst, (S)-VANOL coordinates with Yb(OTf)3 and two molecule of DBU forms hydrogen bonds with the two phenolic hydrogens of the ligand (S)—VANOL. Thus in this catalyst the axial chirality of (S)- VANOL is transferred via the hydrogen bonds to the amine (DBU). Scheme 5.11 Proposed structure of Yb-VANOL catalyst The proposed structure for the transition state of the catalyst-imine complex 381 is based on a similar structure proposed by Kobayashi for the aza Diets-Alder reaction is shown in Scheme 5.12.86 The imine 378 acts as a bindendate ligand and its N and O atoms coordinate with the Yb of the catalyst 380. The amine (DTBMP) additive is believed to form hydrogen bonds with the phenolic hydrogen of the coordinated imine 378. This restricts the conformation of the imine 378 and results in moderate selectivity. According to the proposed structure, the top face of the imine is shielded by the DBU and the allyltributyl stannane then approach from the bottom face to afford enantiomerically enriched homoallylic amine. 152 Scheme 5.12 Proposed transition state of the catalyst 380-imine complex In summary, it has been shown that moderate yields and enantioselectivities can be obtained for the allylation reaction of aldimine 378 . with allyltributyl stannane using catalyst systems derived from (S)-VANOL, Yb(OTf)3, DBU and DTBMP. 153 CHAPTER SIX Total Synthesis of Carbazoquinocin-C: Application of the orfho-Benzannulation of Fischer Carbene Complexes to Carbazole 3,4-quinone Alkaloids 6.1 Introduction The carbazole-3,4-quinone unit has been found in a number of molecules which have been discovered largely upon screening several microorganims for compounds possessing activity against lipid peroxidation and for those possessing neuronal cell protecting activity.26 These molecules include carbazoquinocins A-F 65, carquinostatins A and B 66 and lavanduquinocin 67 (Figure 6.1). The potency of these molecules together with the unique carbazole- 3,4-quinone substructure in these molecules have prompted the development of a number of synthetic strategies to this family of natural products.88 The syntheses reported to date include carbazoquinocins A38" 8,889 Osaa'g D,"""’h E- F,889 88k,l carquinostatin A,8‘3b"'j and lavanduquinocin. 154 Figure 6.1 Carbazole-3,4-qulnone alkaloids R=(CH2)2CHM9CH2M9 R=(CH2)4CHM62 R=(CH2)6M6 R=(CH2)4CHMGCH2M6 R=(CH2)5CH M92 65 Carbaz uinocin A-F °q R=(CH2)6CHM62 1199.99??? 66 Carquinostatin A A: R = H 67 Lavandoquinocin B: R =OH This chapter discusses a unique approach to the synthesis of the carbazole-3,4-quinone alkaloids in which the orfho-quinone unit is constructed via an orfho-benzannulation reaction of a doubly unsaturated Fischer carbene complex. Inspired by the pioneering work of Hegedus,17 Wulff and Yang envisioned the possibility of such a reaction that involves the photoinduced coupling of a carbon monoxide ligand and a carbene ligand to give a doubly unsaturated ketene of the type 383 which undergoes electrocyclic ring closure to give an ortho-methoxyphenol of type 384 (Scheme 6.1). In 1989, Yang and Wulff reported the first example of ortho-benzannulation of carbene complex 44, which yielded the ortho-alkoxyphenol 46 in 18% yield (Scheme 6.1 12° 155 Scheme 6.1 Photoinduced orfho-benzannulation reaction of 382 via 383 OMe OMe (CO)5CI’ R1 hv 0:0 R1 HO 0M6 / _. / R4 R1 R4 \ 2 R4 \ 2 Re R n3 R R3 R2 382 ' 383 7 384 / Cr(CO)5 hv / OH THF 0 44 46, 18% Merlic and coworkers later improved the yield (from 18% to 93%) of this reaction by performing it under a CO atmosphere.21 Merlic further extended the scope of the reaction by using isoelectronic isocyanides as a surrogate for CO. Thus reaction of complex 44 with tert-BuNC yielded orfho-alkoxy aniline 59 via dienylketimine complex 58 (Scheme-6.2).24 Scheme 6.2 Thermal ortho-benzannulation of 44 via 58 F — / Cr(CO)5 - 1 i t BuNC / CeN-f-Bu . NH-t—Bu THF \ & CI’(CO)3 44 53 59, 83°/o Carbazoquinocin-C 650 has been targeted to document the application of orfho-benzannulation methodology towards carbazoIe-3,4-quinone alkaloids 156 (Figure 6.1). The generality of this reaction makes this approach amenable for the synthesis of other members of this family. 6.2 Conventional routes to synthesize carbazoquinocin-C: Hibino reported the first total synthesis of carbazoquinocin-C in 1997.”3 Hibino utilized the electrocyclic ring closure of an in-situ generated diene-allene 387 to synthesize the carbazole framework 386 of carbazoquinocin-C (Scheme 6.3). The 3-alkenyl-2-propargyl indole 388 obtained from 3-iodoindole carboxaldehyde 389 was heated in tert-BuOH in the presence of potassium tert- butoxide to generate allene 387, which immediately undenlvent electrocyclization to form carbazole 386. Carbazole 386 was then converted to carbazoquinocin-C 650 in seven steps. Scheme 6.3 Hibino’s approach to cabazoquinocin C O O OEt OEt 2) ::= N n-hept n OMOM u OMOM H 385 386 Carbazoquinocin C 65 C OEt _ OEt ' I ___.. / "" Isz H / C \ \ \ 4:: (2:: N o N OMOM N OMOM H R H 389 388 ' 387 _ Knblker has reported three syntheses of carbazoquinocin-C using the Fe mediated and Pd mediated/catalyzed coupling reactions.88 In his first approach, carbazole framework 390 was derived from coupling of the 115-iron complex 391 with the highly functionalized aniline 392 (Scheme 64).”: 157 Scheme 6.4 Kndlker’s approach to cabazoquinocin-C O O o (OC)3Fe\——— 0(OC)=:F9 o 0 =2 \ N C7H15 N H C7H15 C792,415 I Carbazaquinocin C 390 65 C The key step in his second route (Route B) is the palladium-catalyzed oxidative cyclization of N, N-diarylamines 394 derived from aniline 396 and para- quinone 395 (Scheme 6.5).88d His third route utilizes the palladium-mediated oxidative cyclization of N, N diaryl amine 398 obtained from aniline 396 and orfho-quinone 397 (Scheme 6.5). 88" Scheme 6.5 Kn6lker’s approach to cabazoquinocin C OCH3 d7: Pd(ll) Q Nfifiimiis \iCHa H 393 O 395 H Route 8 0 0 Route C O 396NH2 Q Pd(|l) ©N¢E “o 0 = N C7H15 H C7H15 C H Carbazaquinocin C 398 7 15 65 C 397 Pindur has synthesized carbazoquinocin-C via AICI3 mediated cyclization of 2-vinyl indole 399 and oxalyl chloride 400 (Scheme 6.6).”‘9 Vinyl indole 399 was prepared from the commercially available starting material 1- 158 (phenylsulfonyl)indole in two steps. This is the most efficient approach for the synthesis of carbazoquinocin-C in comparison to all the approaches described above. The orfho-benzannulation approach for the synthesis of carbazoquinocin- C, described in this chapter requires at least five more steps from the vinyl indole of the type 25. Thus, the orfho-benzannulation approach is less effective than Pindur’s synthesis of carbazoquinocin-C. Nonetheless, the synthesis described in this chapter documents a useful application of onho-benzannulation approach in the synthesis of carbazole-3,4-quinone alkaloids. Scheme 6.6 Pindur’s approach to cabazoquinocin C o O O O Q 2:) W + (3|)ka C H u C7H15 u 7 15 CI 400 Carbazaquinocin C 399 65C 6.3 Synthesis of carbazoquinocin-C The retrosynthetic synthetic analysis of carbazoquinocin-C that is employed in the present work is outlined in Scheme 6.7. This strategy for the synthesis of carbazoquinocin-C involves the intermediacy of the 3-hydroxy-4- methoxycarbazole 401, or as an alternative, the 3-amino-4-methoxycarbazole 402 from either of which the natural product can be generated by oxidation of the phenol ring. The key steps in the synthesis are thus to be the photoinduced CO insertion/cyclization and/or the thermally induced tert-BuNC insertion/cyclization of the or,fl,;4,§ -unsaturated carbene complex 403. It was envisioned that this 159 3-bromo(2-vinyl)indolylcarbene complex 403 could be prepared from the commercially available indole-2-caboxylic acid 406. The different N-protecting groups evaluated are TBS, benzyl and the relatively labile PMB group. Scheme 6.7 Retrosynthetic analysis of cabazaquinocln C R10 OH O O ’7» [‘32 O O 401 (OC)5Cr OR‘ o 0 H N n-hept N n-hept b H R10 NHIBU 19°$0 hz Carbazoquinocin C 403 “5 ° 0 N n-hept #12 O 402 0 Br (>34 <——— Cm <= \ 1 N OH N n-hept N n-hept H H hz 406 405 404 6.3.1 Synthesis of carbene complexes of the type 403 The commercially available indole-2-carboxylic acid 406 was converted to the Weinreb’s amide 407 using a reported procedure (Scheme-6.8).89 Amide 407 upon treatment with heptyl magnesium bromide afforded 1-(1H—indol-2-yI)-octan- 1-one 405 in 80 °/e yield. 160 Scheme 6.8 lndolyl heptyl ketone 405 from Indole-2-carboxylic acid 406 H \ / m0 DCC, Eth ‘ wN-O n-heptMgBr_ Wit-hem m 0 HC|.HN(OM9)M6 u C THF, 80 % n O 406 407 405 The conversion of 405 to protected indole of the type 404 (Scheme 6.7) requires N-protection, olefination, and bromination and considerable time was spent investigating the optimal order of these steps. Bromination of indole 405 was successful to give 3-bromoindole 408 but all attempts to carryout a Wittig reaction on this substrate failed (Scheme 6.9). Scheme 6.9 Vinyl indole 409 from indole heptyl ketone 405 mnhept NBS, KOH ©:§_«n-hept Rxgiigon \B I’ n-hept N O DMF = N O ——X—* N 405 H 408 5" 409 it Entry Equiv Reagent Time Temperature Result (h) (°C) 1 2.4 Et3PPh3Br, 4 25 Starting material n-BuLi, THF observed 2. ” ” 4 80 Low conversion 1.2 EtgPPh3Br, 24 25 Starting material KHMDS, THF observed 4. 2.4 ” 24 25 Starting material observed 5. 5 ” 24 25 Low conversion Unless otherwise specified all reactions were carried out in THF solvent (0.1M) at 25 O C. 161 In contrast, the olefination of ketone 405 proceeded smoothly to give the 2-vinyl indole 399 in 93% yield as a 1.0 : 0.84 mixture of E/Z isomers (Scheme 6.10). The bromination of 399 was successful; however, the resulting 3- bromoindole 409 is not particularly stable. Immediate treatment with NaH and TBSCI gave the stable N-silylated indole 410 in 45 % yield for two steps. Scheme 6.10 Synthesis of carbene complex precursor 410 n-het N O P11315113+ 8? u 405 399 93% E: 2: 1.0 : 0.84 NBS KOH, DMF Br Br #3 S TBSCI ” 410 409 Given the instability of bromoindole 409, the reverse of the bromination/protection sequence was investigated and found to be far more practical. The 2-vinylindole 399 was first protected either as the N-benzyl- or N- para-methoxybenzyl derivatives 411 and 412 in 70 % and 72 % yield, respectively (Scheme 6.11). Bromination gave the carbene precursors 413 and 414 in excellent yields. ' 162 ." ,.-~- 1 Emma-4%— —-i_-‘~.._-._-__.\..«_—_-. _ Scheme 6.11 Synthesis of carbene complex precursors 413 and 414 Br NaH BnBr n-he t ' n-he t \ p or \ n-hept \ D 1911 NaH, PMBCIAV N NBS N P DMF P 399 411 P = Bn 70% 413 P = Bn 90% 412 P = PMB 70% 414 P = PMB 89% Carbene complexes 415 - 417 were prepared by the standard Fischer procedure in moderate yields. These complexes were usually obtained with a small amount (5 - 10 %) of a side product resulting from the reduction of the bromide in the precursors 413 and 414 (Scheme 6.12). These reduced products were not easily separated from the carbene complexes and thus were carried to the next step in those cases where they could be removed. The yields for the carbene complexes 415 - 416 have the amount of the reduced products factored out. The TBS-protected indole 410 could not be converted to the corresponding carbene complex. The only observable product was the 3-unsubstituted indole resulting from reduction of the bromide in 410. Scheme 6.12 Synthesis of carbene complexes 415, 416 and 417 Br 11 t . M90 Cr(CO)5 \ ”hept H —NH HN— 4, N M9304. EtOH \ 160 161 77% yield To a stirred solution of orfho-anisaldehyde 160 (6.67 gm, 49.3 mmol) in EtOH (200 mL) was added N,N-dimethylethylenediamine (5.27 gm, 60 mmol) dropwise. The reaction mixture was stirred at room temperature for 24 h followed by filtration through a pad of M9804 and washing by ether. The ether/ethanol 171 solution was concentrated in vacuo and the product was purified by crystallization from hexane to afford the 7.65 gm of imidazolidinone 161 as white crystalline solid. Spectral data for 161: Mp 40 - 42 °c (lit48 41 - 42 °C); 1H NMR (300 MHz, c0c13) 5 2.20 (s, 6 H), 2.54-2.60 (m, 4 H), 3.80 (s, 3 H), 4.01 (s, 1 H), 6.87 (dd, 1 H, J = 1.0, 8.4 Hz), 6.95 (dt, J=7.4, 0.9 Hz), 7.21 (m, 1 H), 7.65 (dd, 1 H, J = 1.9, 7.4 Hz). Synthesis of anisaldehyde (162) \o \N’> a) t-BuLI EtZO, H H I“ b) (Bf:§lC)2, Etzo; + 162 163 -78 °C to rt 161 c) 2N HCI, rt, 1h To a stirred solution of 161 (9.05 gm, 43.8 mmol) in 350 mL ether at -40 °C was added tert-BuLi (52 mL, 87.6 mmol, 1.7 M solution in pentane) over 1 h. The reaction mixture was warmed to -20 °C and stirred at this temperature for 7 h then the reaction mixture was cooled to -78 °C and transferred by Cannula to a solution of (BrCl2C)2 (29 mg, 87.6 mmol) in 150 mL Et20 at 0 °C over 1h. The reaction mixture was warmed to room temperature over 2 h and then the mixture was stirred at this temperature for 12 h. The reaction was then quenched carefully with 2 N HCI (750 mL) and stirred at room temperature for 1 h. This was followed by extraction of the water layer with 4 x 200 mL CH2CI2. The CHzclz layer was washed with 200 mL of a saturated solution of ammonium chloride solution. The water layer was then back extracted with 3 x 100 mL dichloromethane. The combined organic layer was dried and concentrated in 172 vacuo. The product was purified by silica gel column chromatography using (20 % to 40 %) EtOAc : hexane to give 6.5 gm of a mixture of 162 and 163 in the ratio of 50 : 1 (162 : 163) as off-white solid. When the reaction was run at 25 °C a 2 : 1 mixture of 162 and 163 obtained. The structure of 162 was assigned by comparison of the reported 1H NMR spectrum and MP. The structure of 163 was tentatively assigned by the presence of peaks at 8 = 10.36 in the crude 1H NMR spectrum and by two a peak at m/z = 170 and 172 in a 3 : 1 ratio in the mass spectrum. Spectral data for 162: Mp = 56 - 58 °c (111“8 57 - 58 °C); 1H NMR (300 MHz, CDCI3)I 6 3.89 (s, 3H), 6.92 (d, 1 H, J = 8.2 Hz), 7.21 (d, 1 H, J = 8.5 Hz), 7.30 (t, 1 H, J = 8.3 Hz), 10.39 (s, 1 H). Synthesis of salicaldehyde (159) \ 0 0 OH 0 did BBT3, CHZCIZ‘ dH Br Br 162 159, 94% To a stirred solution of 162 (6.5 gm, 30 mmol) in 50 mL CH2CI2 was added 40 mL of BBr3 (1.0 M solution in CH2CI2) dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred for 30 min before quenching with 20 mL of water. The organic layer was separated and the aqueous layer was extracted with 2x50 mL of CHzclz. The organic layer was dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography using ether/ hexane (1 / 10) eluent to give bromosalicaldehyde 159 (94 % yield) as light green solid. 173 Spectral data for 159: Mp = 50 - 52 °c (lit95 51 - 52 °C); 1H NMR (500 MHz, cock): 8 6.91 (d, 1 H, .J = 8.3 Hz), 7.13 (dd, 1 H, J = 1.0, 7.8 Hz), 7.30 (t, 1 H, J = 8.3 Hz) 10.30 (s, 1 H), 11.95 (s, 1 H). Synthesis of bromochromene (141) OH 0 U/Yfitzo Br Br d H (2299) _ TsOH, Toluene \ + \ Br -40 °C, 30 min 0 159:94°/° then0°C,4h 141 1650 141:165=40:1,60%yield To a stirred solution of 1-bromo-2-methyl-penten-1-ene (3.87 gm, 28.67 mmol) in 100 mL ether at -78 °C was added tert-BuLi (34 mL, 57.34 mmol) over 15 min. After stirring for 30 min, the reaction mixture was transferred by cannula to a solution of 159 (2.62 gm, 13.03 mmol) in 100 mL ether at -78 °C. The solution was stirred at -78 °C for 2 h and slowly warmed to room temperature. The stirring was continued at room temperature for another 16 h. After 16 h, the reaction was quenched by careful addition of 20 mL water and 20 mL saturated ammonium chloride solution. The water layer was extracted with 3 x 30 mL ether. The organic layer was then washed with 20 x 2 mL of brine, dried over M9804 and concentrated in vacuo to give a light green oil. The crude compound so obtained was dissolved in toluene and TsOH (50 mg) was added. The reaction mixture was heated to 50 °C for 1 h. After 1 h, the reaction mixture was filtered through Celite, concentrated in vacuo and purified by silica gel column chromatography using (1 °/c) EtOAc : hexane solvent system. This gave a mixture of compounds 141 and 165 in the ratio of 5 : 1 (141 : 165) along with a 174 small amount of an unidentified impurity. Further purification was done using Kugelrohr distillation which afforded a 60 °/c yield of bromochromene 141 and 165 in the ratio (141 : 165) of 40 : 1 as colorless liquid (GC). The structure of 165 was tentatively assigned by two peaks at m/z = 294 and 296 in a 100 : 98 ratio in the mass spectrum. Spectral data for 141: 1H NMR (500 MHz, cock.) 8 1.40 (s, 6 H), 5.68 (d, 1 H, J = 10.0 Hz), 6.62 (d, 1H, J = 6.62 Hz), 6.70 (d, 1 H, J = 9.0), 6.92 (t, 1 H, J = 8.1 Hz), 7.06 (dd, 1 H, J = 1.1, 8.0 Hz); 13c NMR (75MHz, cock.) 8 127.72, 76.29, 115.80, 121.12, 121.14, 121.42, 124.711, 129.44, 132.18, 154.10; Mass spectrum (El) m/z (% rel. int.) 240 (8, 818r), 238 (9, 79Br), 226 (12, 81Sr), 224 (18, 798r), 225 (100, B‘Br), 223 (83, 798r), 144 (17, 818r), 115 (12, 79Sr). ); IR (neat) 3056, 2976, 2926, 1558, 1444 cm"; Anal. calcd. for CanBrO: C, 55.25; H, 4.64. Found: C, 55.52; H, 4.72. Synthesis of Chromenone (144) O / O O \(T 109 t I \ 1 ,2-ethanediammonium- O acetate, EtOH 161 144 78% yield To a stirred solution of cyclohexane-1,3-dione 161 (24.1 gm, 215 mmol) and 1,2- ethanediammoniumacetate in methanol (300 mL) was added 3-methyl-but-2-enal (18.11 gm, 215 mmol) over a duration of 5 h. The reaction mixture was then stirred for 24 h at room temperature. After 24 h, the reaction mixture was diluted with 500 mL ether and washed with 50 mL water and 50 mL brine. The water layer was extracted with 2 X 50 mL ether. The combined organic layer was dried 175 over M9304 and concentrated in vacuo. The product was purified by silica gel column chromatography using ether : hexanes (1 : 7) as eluent to give 30.5 gm of chromenone 144 (78 °/c) yield. Spectral data for 144: Mp = 40 - 42 °c (lit49b 40 - 41 °C); 1H NMR (500 MHz, CDCI3) 6 1.66 (s, 6 H), 1.85-1.95 (m, 2 H), 2.26-2.36 (m, 4 H), 5.17 (d, 1 H, J = 9.3 Hz), 6.34 (d, 1 H, J = 9.8 H). Synthesis of chromenol (166) 0 OH 0 o ‘44 166, 53 % To a stirred solution of chromenone 144 (3.36 gm, 18.8 mmol) in 230 mL dioxane was added a solution of DDQ (8.96 gm, 39.5 mmol) in 60 mL dioxane. The reaction mixture was stirred at room temperature for 3h and then heated to 110 °C for 42 h. After 42 h, the reaction mixture was cooled to room temperature and filtered through Celite, concentrated in vacuo and the residue was purified by silica gel column chromatography using a gradient of 1 % to 5 % of EtOAc in hexane eluent. The yellow solid so obtained was then recrystallized with ether to afford chromenol 166 as yellow crystalline solid in 53 % yield. Spectral data for 166: Mp = 113 - 115 °C; (lit“QC 114 - 116 °C); 1H NMR (500 MHz, CDCI3) 8 1.41 (s, 6 H), 4.83 (s, 1 H), 5.58 (d, 1 H, J = 9.7 Hz), 6.28 (d, 1 H, J = 8.3 Hz), 6.40 (d, 1 H, J = 8.8 Hz), 6.61 (d, 1 H, J = 10.2 Hz), 6.92 (t, 1 H, J = 7.8 Hz). 176 Synthesis of chromene triflate (168) OH on m T120, CH20I2 \ o 7 o 166 168, 97 % yield To a stirred solution of 166 (200 mg, 1.13 mmol) in 10 mL CH20I2 at 0 °C was added diisopropylethyl amine (235 pL, 1.35 mmol) and ngO (208 pL, 1.13 mmol). The reaction mixture was stirred at 0 °C for 2 h. After 2 h, the reaction mixture was concentrated in vacuo, purified by silica gel column chromatography using 5 % EtOAc : hexane solvent system to give compound 168 (324 mg, 93 °/c yield) as colorless oil. Spectral data for 168: 1H NMR (500 MHz, com.) 8 1.43 (s, 6 H), 5.76 (d, 1 H, J = 8.2 Hz), 6.51 (d, 1 H, J = 9.7 Hz), 6.78 (d, 2 H, J = 7.8 Hz), 7.11 (t, 1 H, J = 8.3 Hz); ”C NMR (75MHz, CDCI3) 8 27.71, 76.72, 113.28, 115.01, 115.17, 116.48, 118.62 (q, J = 319 Hz), 129.04, 132.99, 145.17, 154.31. IR (neat) 2980, 2937, 1637, 1616, 1568 cm"; Mass spectrum (FAB) m/z (°/c rel. int.) 308 (M*) (5), 293 (24), 256 (5), 161 (13), 160 (100), 159 (17), 132 (13); Anal. calcd. for C12H11F304S: C, 46.75; H, 3.60. Found: C, 46.52; H, 3.35. Synthesis of chromene stannane (1 70) OTf P d(PPh3)4 SnM83 m (M63Snl2. LiCI _ m+ \ dioxane V (:E :lv 0 o O 0 168 11° c, 96“ 170 171 To a mixture of hexamethylditin (675 mg, 2.17 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol) dppf ( 54 mg, 0.10 mmol) and LiCI (552 mg, 13.02 mmol) was added a 177 solution of compound 168 (670 mg, 2.17 mmol) in 15 mL dioxane. The solution was deoxygenated using the freeze-thaw method (-196 to 25 °C, 3 cycles). The reaction mixture was then stirred at 110 °C for 3 days. After 3 days, the reaction mixture was filtered through Celite and washed using hexane. The solvent was then concentrated in vacuo to give a mixture of compounds which consisted of 170 and 171 (84 : 7) along with triphenyl phosphine and small amounts of other impurities. This mixture was loaded onto silica gel column and eluted with and hexane and EtOAc (20 : 1) to give a mixture of compounds but with the amounts of 170 and 171 enhanced and in the same ratio. The following 1H NMR data for 170 was extracted from the 1H NMR spectrum of the mixture Spectral data for 170: 1H NMR (500 MHz, cock.) 8 0.30 (s, 9 H), 1.41 (s, 6 H), 5.61 (d, 1 H, J = 9.6 Hz), 6.28 (s, 1 H, J = 9.0 Hz), 6.74 (dd, 1 H, J = 0.5, 8.0 Hz), 6.94 (dd, 1 H, J = 0.6, 7.2 Hz), 7.06 (t, 1 H, J = 7.4 Hz). Synthesis of bromochromene (141) OTf a) Pd(PPh3)4, (Me3Sn)2, LiCl Br \ Dioxane, 110 °C, 96 h ‘ \ o b) NBS, THF 0 168 141 To a mixture of hexamethylditin (675 mg, 2.17 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), dppf ( 54 mg, 0.10 mmol) and LiCl (552 mg, 13.02 mmol) was added solution of compound 168 (670 mg, 2.17 mmol) in 15 mL dioxane. The solution was deoxygenated using freeze-thaw method (-196 to 25 °C, 3 cycles). The reaction mixture was then stirred at 110 °C for 3 days. After 3 days, the reaction mixture was filtered through Celite and washed using hexane. The solvent was 178 then 1 dissc for l puril S-brl 198C Synl T0: bron Wai‘ 'llw Stirl rem M83 was and then evaporated using rotary evaporater to give an oily residue, which was again dissolved in THF and solid NBS (579 mg, 3.25 mmol) was added. After stirring for 1 h at room temperature, the reaction mixture was concentrated in vacuo and purified by flash silica gel column chromatography (5 %) ether : pentane to give 5-bromo chromene 141 as colorless oil in 75 % yield. The compound from this reaction had spectral data identical with that reported above. Synthesis of chromene carbene complex (1 75) Br M60 Cr(CO)5 a) t-BuLi, 5120, -78 °c \ : \ m b) CI’(CO)6, Eth, 0 CC to it 0 rt for 8h 0 141 C) M6303F4, CH2C|2, rt, 175, 81% yield 1 h 30 min To a flame-dried 100 mL round-bottomed flask containing a solution of bromochromene 141 (1.310 gm, 5.5 mmol) in ether (25 mL) at -78 °C was added ter BuLi (6.5 mL, 11 mmol, 1.7 M solution in pentane). The reaction mixture was warmed to 0 °C, stirred at this temperature for 5 min and cooled to -78 °C before it was transferred by cannula to a suspension of Cr(CO)6 (1.32 gm, 6.0 mmol) in 15 mL ether maintained at 0 °C. The reaction mixture turned dark red in 5 min. Stirring was continued for 6 h at room temperature which was followed by removal of ether under vacuum and addition of 10 mL dichloromethane. MeaoBF4 (1.63 gm, 11 mmol) was then added at room temperature and reaction was further stirred for 2 h. The reaction mixture was then filtered through Celite and concentrated in vacuo. The product was purified by silica gel column 179 chromatography using EtOAc : hexane (5 %) to give 1.75 gm (81 % yield) of carbene complex 175 as red crystalline solid. Spectral data for 175: Mp = 95 - 97 °C; 1H NMR (500 MHz, CDCI3) 5 1.41 (s, 6 H), 4.18 (s, 3 H), 5.56 (d, 1 H, J = 10.2 Hz), 5.96 (d, 1 H, J = 10.0 Hz), 6.37 (d, 1 H, J = 7.70 Hz), 6.70 (dd, 1 H, 0.9, 8.3 Hz), 7.14 (t, 1 H, J = 7.9 Hz); 13c NMR (75 MHz, CDCI3) 8 27.63, 65.66, 76.16, 110.98, 112.93, 116.38, 118.17, 129.06, 132.68, 152.88, 215.85, 224.60, 357.52, one sp2 C not located; IR (neat) 2980, 2064, 1934, 1566, 1442 cm"; Mass spectrum (FAB) m/z (% rel. int.) 394 M“, 366 (82), 310 (78), 282 (100), 254 (70), 203 (25); Anal. calcd. for C(8H140r07: C, 54.83; H, 3.58. Found: C, 54.53; H, 3.41. Synthesis of naphthol pyran (182) M90 Cf(CO)5 l I O \ a) Benzene OMe \ + TBSCI, Hunig's base 0 D) Air oxidation, ' T330 0 \ rt. 10h O 175 176 182 To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (100 mg, 0.254 mmol), 5 mL benzene, phenyl acetylene 176 (56 pL, 0.508 mmol), TBSCI (115 mg, 0.762 mmol) and N,N-diisopropylethylamine (55 pL, 1.270 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 180 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (5 %) EtOAc and hexanes to give naphthopyran 182 (31 mg) in 27 °/c yield as a colorless liquid. Spectral data for 182: 1H NMR (500 MHz, CDCI3) 8 -0.41 (s, 6 H), 0.97 (s, 9 H), 1.47 (s, 6 H), 3. 92 (s, 3 H), 5.58, (d, 1 H, J = 10.2 Hz), 6.83 (s, 1 H), 7.04 (d, 1 H, J = 9.1 Hz), 7.27-7.34 (m, 1 H), 7.40 (t, 2 H, J = 7.8Hz), 7.63 (dd, 2 H, J = 1.4, 7.2 Hz), 7.76 (d, 1 H, J = 10.2 Hz), 7.98 (d, 1 H, J = 9.1 Hz); 13c NMR (75 MHz, CDCI3) 5 -4.36, 18.45, 26.08, 27.86, 55.85, 74.72, 109.75, 114.40, 118.14, 122.47, 123.32, 124.61, 125.19, 125.89, 126.66, 127.11, 128.11, 130.25, 140.16, 142.01, 151.57, 151.92; IR (neat) 2955, 2930, 2856, 1452, 1381 cm"; Mass spectrum (El) m/z (% rel. int.) 447 M+ + 1 (16), 446 M“ (9), 422 (27), 432 (100), 417 (6), 390 (3); Anal. calcd. for C28H340381: C, 75.29; H, 7.67. Found: C, 74.99; H, 7.40. Synthesis of naphtholpyran (163) a) Benzene O OMe \ + TMSCI, Hunig's base 0 D) Air oxidation, ' TMSO O \ rt. 10h O 175 176 183 To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (25 mg, 0.063 mmol), 1.2 mL benzene, phenyl acetylene (14 pL, 0.126 mmol), TMSCI (24 pL, 0.189 mmol) and N,N-diisopropylethylamine (55 ,uL, 0.315 mmol). The 181 system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (5 %) EtOAc : hexanes to give naphthopyran 183 (16.5 mg) in 65 % yield as colorless liquid. Spectral data for 183: 1H NMR (500 MHz, CDCI3) 8 - 0.16 (s, 9 H), 1.47 (s, 6 H), 3.91 (s, 3 H), 5.58 (d, 1 H, J = 10.1 Hz), 6.79 (s, 1 H), 7.04 (d, 1 H, J = 9.6 Hz), 7.26-7.34 (m, 1 H), 7.41 (t, 2 H, J = 7.5 Hz), 7.58 (dd, 2 H, J = 1.6, 6.9 Hz), 7.75 (d, 1 H, J = 10.2 Hz), 7.85 (d, 1 H, J = 9.34 Hz); 13c NMR (75 MHz, CDCl3) 8 0.32, 27.35, 55.87, 74.76, 109.53, 114.51, 118.50, 112.48, 123.29, 124.64, 124.87, 125.89, 126.75, 127.18, 128.20, 130.17, 140.09, 142.43, 151.59, 151.99; lFl (neat) 2965, 2939, 2848, 1452, 1366 cm"; Mass spectrum (El) m/z (°/c rel. int.) 405 M*+ 1 (11), 404 M+ (36), 391 (23), 390 (100), 376 (6), 375 (15), 374 (5), 302 (5); Anal. calcd. for 025H23038i: C,74.22; H, 6.98. Found: C, 73.99; H, 7.39. Synthesis of naphtholpyran (184) MeO Cr(c0)5 H O a) Benzene 0M9 \ + Ac20, Hunig'ibase‘ 0 O b) Air oxidation, 7 A00 0 \ rt, 10h o 175 176 184 To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (100 mg, 182 0.254 mmol), benzene (5.0 mL), phenyl acetylene (56 pL, 0.508 mmol), acetic anhydride (72 pL, 0.762 mmol) and N,N-diisopropylethylamine (221 ,uL, 1.270 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (15 %) EtOAc : hexane to give naphthopyran 184 (58 mg) in 58 % yield as white solid. Spectral data for 184: Mp = 164 - 166 0c 1H NMR (500 MHz, c0c13) 1.45 (s, 6 H), 2.15 (s, 3 H), 3.95 (s, 3 H), 5.60 (d, 1 H, J = 10.2 Hz), 6.83 (s, 1 H), 7.09 (d, 1 H, J = 8.8 Hz), 7.31-7.37 (m, 1 H), 7.42 (t, 2 H, J = 7.60 Hz), 7.50 (dd, 2 H, J = 1.4, 7.6 Hz), 7.59 (d, 1 H, J = 8.8 Hz), 7.72 (d, 1 H, J = 10.2 Hz); 130 NMR (75 MHz, CDCla) 6 20.71, 27.19, 55.71, 74.86, 108.10, 115.15, 120.01, 122.30, 122.71, 123.06, 124.45, 127.37, 127.74, 128.14, 128.38, 128.96, 137.22, 138.18, 152.16, 154.89, 169.65; IR (neat) 3059, 3014, 2970, 2926, 1759, 1622 cm"; Mass spectrum (El) m/z (% rel. int.) 375 M+ + 1 (23), 374 M+ (77), 360 (11), 318 (100), 302 (26); Anal. calcd. for 022H3003Si: C,76.99; H, 5.92. Found: C, 77.09; H, 6.16. 183 Synthesis of naphthol pyran (185) MeO or(00)5 I l O a) Benzene OMe \ + MOMCI, Hunig's base 0 D) Air oxidation, ' MOMO O \ l't. 10h O 175 176 185 To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (100 mg, 0.254 mmol) in benzene (5.0 mL), phenyl acetylene 176 (56 ,uL, 0.508 mmol), acetic anhydride (58 pL, 0.762 mmol) and N,N-diisopropylethylamine (221 pL, 1.270 mmol) in benzene (5.0 mL). The system was deoxygenated by the freeze- pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (5 %) EtOAc : hexane to give naphthopyran 185 (57 mg) in 60 % yield as colorless liquid. Spectral data for 185: 1H NMR (500 MHz, c0013) 8 1.46 (s, 6 H), 3.17 (s, 3 H), 3.93 (s, 3 H), 4.7 (s, 2 H), 5.58 (d, 1 H, J = 10.2Hz), 6.80 (s, 1 H), 7.10 (d, 1 H, J = 9.3 Hz), 7.28-7.37 (m, 1 H), 7.43 (t, 2 H, J = 7.5 Hz), 7.62 (dd, 2 H, J = 1.4, 7.5 Hz), 7.73 (d, 1 H, 10.1 Hz), 8.06 (d, 1H, J = 9.0 Hz); “*0 NMR (75 MHz, coma) 8 27.25, 55.74, 57.55, 74.78, 99.71, 108.92, 114.79, 119.33, 122.47, 123.17, 184 124.15, 126.11, 126.96, 127.38, 127.60, 128.34, 129.63, 139.25, 143.87, 152.12, 153.43; IR (neat) 2974, 2934, 1613, 1591, 1371 cm"; Mass spectrum (El) m/z(°/c rel. int.) 377 M+ + 1 (29), 376 M+ (100), 363 (12), 332 (40), 330 (17), 301 (11), 300 (14); Anal. calcd. for C24H2404Z C,76.57; H, 6.43. Found: C, 76.75; H, 6.29. Synthesis of naphthol pyran (187) M60 Cr(CO)5 I I a) Benzene OMe \ + TMSCI, Hunig's base 0 O b) Air oxidation, 7 TMSO O \ 175 O rt, 10h 187, 97 % To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (25 mg, 0.063 mmol), benzene (1.2 mL), 1-pentyne (13 ,uL, 0.126 mmol), TMSCI (24 ,uL, 0.189 mmol) and N,N-diisopropylethylamine (55 pL, 0.315 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (5 %) EtOAc : hexanes to give naphthopyran 187 (22.4 mg) in 98 % yield as colorless liquid. Spectral data for 187: 1H NMR (500 MHz, c0013) 8 0.25 (s, 9 H), 0.97 (t, 8 H, J = 7.17 Hz), 1.44 (s, 6 H), 1.59-1.74 (m, 2 H), 2.68-2.78 (m, 2 H), 3.88 (s, 3 H), 5.55 (d, 1 H, J =10.1 Hz), 6.63 (s, 1 H), 6.98 (dd, 1 H, J = 0.6, 9.1 Hz), 7.71 (dd, 1 H, 185 J = 0.6, 10.3 Hz), 7.80 (d, 1 H, J = 9.07 Hz); 13c NMR (75 MHz, cock.) 8 0.91, 14.20, 23.48, 27.33, 32.91, 55.85, 74.59, 109.45, 114.45, 118.09, 121.55, 123.39, 124.25, 124.38, 125.57, 127.04, 142.81, 151.22, 141.32; IR (neat) 2961, 2930,2870, 1591, 1454, 1307 cm"; Mass spectrum (El) m/z (% rel. int.) 371 MM. 1 (24), 370 M+ (82), 358 (11), 356 (100), 355 (19); Anal. calcd. for C22H30038i: c, 71.31; H, 8.16. Found: C, 71.75; H, 8.43. Synthesis of naphthol pyran (188) M90 C’(CO)5 a) Benzene \ I I TBSCI, Hunig's base + D) Air oxidation, $330 0 ft, 10h 175 To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum 188 131 188:181 =7:1, 89%yield threaded Teflon stopcock was added chromene carbene complex 175 (100 mg, 0.254 mmol), benzene (5.0 mL), 1-pentyne (56 pL, 0.508 mmol), TBSCI (115 mg, 0.762 mmol) and N,N-diisopropylethylamine (55 ,uL, 1.270 mmol) were then added to the reaction mixture. The system was deoxygenated by the freeze- pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (25 °/c) benzene : hexane to give 188 in 78 % yield along with 10 % yield of slightly impure quinone 181. 186 Spectral data for 188: 1H NMR (500 MHz, c0013) 8 0.11 (s, 6 H), 0.93 (t, 3 H, J = 7.2 Hz), 1.07 (s, 9 H), 1.43 (s, 6 H), 1.52-1.70 (m, 2 H), 2.63 (t, 2 H, J = 7.7 Hz), 3.87 (s, 3 H), 5.53 (d, 1 H, J = 10.2 Hz), 6. 63 (s, 1 H), 6.95 (d, 1 H, J = 9,1 Hz), 7.70 (d, 1 H, J = 10.2 Hz), 7.83 (d, 1 H, J = 9.1 Hz); ”C NMR (75 MHz, CDCI3) 5 -3.29, 14.02, 18.64, 23.61, 26.12, 27.26, 32.61, 55.84, 74.53, 109.55, 114.27, 117.61, 121.56, 123.39, 124.49, 124.72, 125.39, 126.91, 142.32, 151.16, 151.24; IR (neat) 2959, 2930, 2858, 1591, 1454, 1337 cm"; Mass spectrum (El) m/z (°/c rel. int.) 413 M“ + 1 (95), 412 M” (15), 400 (22), 399 (79), 398 (100), 383 (6); Anal. calcd. for 025H36038i: C, 72.77; H, 8.79; Found: C, 72.60; H, 8.40. Spectral data for 181: Refer to page 192. Synthesis of naphthol pyran (1888) M90 Cr(CO)5 H a) Benzene, 50 °C, 24 h 0M6 b Ti 0, Huni 's base, rt, 24h O \ \ + ) 2 g = TfO \ c) Air oxidation, rt, 12h 0 o 175 188869% To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (75 mg, 0.189 mmol) in benzene (3.8 mL) and 1-pentyne (47 pL, 0.473 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature, sealed and the mixture was then stirred at 55 °C for 24 h. The reaction mixture was cooled to 0 °C and was added trifloromethane sulfonic anhydride (48 pL, 0.283 mmol) and N,N-diisopropylethylamine (66 pL, 0.378 mmol). The system was deoxygenated 187 by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles) and back-filled with Ar at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was then filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (5 %) EtOAc : hexane to give naphthopyran 1888 (56 mg) in 69 % yield as off-white solid. Spectral data of 188a: Mp = 90-92 °C; 1H NMR (500 MHz, CDCI3) 6 0.98 (t, 3 H, J = 7.3 Hz), 1.62-1.76 (m, 2 H), 2.74-2.82(m, 2 H), 3.94 (s, 3 H), 5.59 (d, 1 H, J = 10.3 Hz), 6.64 (s, 1 H), 7.14 (d, 1 H, J = 9.3 Hz), 7.64 (d, 1 H, J = 9.8 Hz), 7.80 (d, 1 H, J = 9.3 Hz); 13c NMR (75 MHz, cock) 8 13.89, 23.32, 27.24, 32.52, 55.64, 74.90, 107.37, 115.02, 118.87 (q, J = 318 Hz), 120.46, 121.91, 122.33, 122.66, 124.36, 128.14, 130.12, 136.37, 152.07, 156.27. IR (neat) 2970, 2936, 2876m 1628m 1456 cm“; Mass spectrum (FAB) m/z (% rel. int.) 430 M+ (98), 415 (20), 297 (100), 281 (15), 267 (15); HRMS (FAB) calcd for m/z Con21F305S 430.1062, measd 430.1064. Synthesis of Suzuki Coupling Product (188b) OMe Pd(PPh3)4 (20 MOI °/o), 0M6 K3PO4 (2.0 equiv) O \ A: \ )§_ 1,4-dioxane, 80 °C, 3 days 0 0 0 o 1888 69 % 188b To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added Pd(PPh3)4 (20 mg, 0.017 mmol), phenyl boronic acid (17 mg, 0.14 mmol), K3PO4 (30 mg, 0.14 mmol) and naphthol pyran 188 triflate 188a (31 mg, 0.07 mmol) in 1,4 dioxane (4 mL). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature, sealed and the reaction mixture was stirred at 80 °C for 3 days. The reaction mixture was then filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (5 %) EtOAc : hexane to give coupling product 188b (17.4 mg) in 69 °/o yield as off-white solid. Spectral data of 188b: Mp = 107-108 °C; 1H NMR (500 MHz, CDCI3) 6 0.80 (t, 3 H, J = 7.3 Hz), 1.44 (s, 6 H), 1.46-1.58 (m, 2 H), 2.34-2.42 (m, 2 H), 3.98 (s, 3 H), 5.57 (d, 1 H, J = 10.2 Hz), 6.78 (s, 1 H), 6.86 (d, 1 H, J = 9.3 Hz), 7.10 (d, 1 H, J = 9.3 Hz), 7.10 (d, 1 H, J = 9.3 Hz), 7.18-7.22 (m, 2 H), 7.36-7.40(m, 1 H), 7.40- 7.46 (m, 2 H), 7.76 (d, 1 H, J = 10.3 Hz); 13c NMR (75 MHz, CDCla) 8 14.13, 24.64, 27.15, 35.87, 55.46, 74.46, 108.25, 114.41, 118.51, 120.52, 123.68, 126.73, 127.06, 128.10, 128.18, 130.83, 130.88, 131.46, 135.42, 140.08, 150.88, 156.05; IR (neat) 2959, 2928, 2870, 1630; Mass spectrum (FAB) m/z (°/c rel. int.) 359 M+ +1 (60), 358 M+ (100), 343 (60); HRMS (FAB) calcd for m/z C25H2602 358.1933, measd 358.1935. Synthesis of naphthol pyran (189) M90 CT(CO)5 a) Benzene OMe \ ., H TMSCI,Hunig's base 0 b) Air oxidation, TMSO O \ 0 rt, 10h 175 0 189, 95 % 189 To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (18 mg, 0.045 mmol), benzene (1.9 mL), 3-hexyne (11 uL, 0.090 mmol), TMSCI (12 uL, 0.135 mmol) and N,N-diisopropylethylamine (39 uL, 0.742 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and allowed to stir for 12 h, filtered through Celite and concentrated in vacuo. The reaction mixture was diluted in 10 mL of pentane and kept at 0 °C for 5 h. After 5 h, the pentane solution was filtered through Celite and concentrated in vacuo to give 16.5 mg (95 %) of pure naphthopyran 189 as a light yellow oil. Spectral data for 189: 1H NMR (500 MHz, CDCI3) 6 0.26 (s, 9 H), 1.14 (t, 3 H, J = 7.8 Hz), 1.22 (t, 3 H, J = 7.3 Hz), 1.46 (s, 6 H), 2.71 (q, 2 H, J = 7.6 Hz), 2.79 (q, 2 H, J = 7.5 Hz), 3.63 (s, 3 H), 5.59 (d, 1 H, J = 9.8 Hz), 6.93 (d, 1 H, J = 8.8 Hz), 7.59 (d, 1 H, J = 9.8 Hz), 7.80 (d, 1 H, J = 9.3 Hz); 13c NMR (125 MHz, CDCI3) 8 0.94, 14.64, 16.00, 20.23, 20.61, 27.09, 61.38, 74.64, 113.03, 117.01, 123.00, 123.43, 123.99, 124.68, 126.80, 126.96, 134.83, 145.80, 148.70, 151.40; IR (neat) 2970, 2936, 2882, 1639 cm“; Mass spectrum (FAB) m/z (°/c rel. int.); 385 M+ + 1 (40), 384 M+ (100), 369 (40), 283 (5); HRMS (FAB) calcd for m/z C23H3203$i 384.2120, measd 384.2124. 190 Synthesis of naphthol pyran (190) MeO Cr(CO)5 a) Benzene OMe \ \ , I TBSCI, Hunig's base 0 D) Air oxidation, TBSO \ 0 rt, 10h 175 0 190, 85 % To a flame-dried 25 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (100 mg, 0.254 mmol), benzene (5.0 mL), 3-hexyne (58 ,uL, 0.508 mmol), TBSCI (115 mg, 0.762 mmol) and N,N-diisopropylethylamine (55 pL, 1.270 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and stirred for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (25 %) benzene : hexane to give naphthopyran 190 (92 mg) in 85 °/c yield as a white solid. Spectral data for 190: Mp = 104 - 106 °c; 1H NMR (500 MHz, cock.) 8 0.14 (s, 6 H), 1.07 (s, 9 H), 1.09 (t, 3 H, J = 7.5 Hz), 1.22 (t, 3 H, 7.4 Hz), 1.46 (s, 6 H), 2.60-2.90 (m, 4 H), 3.63 (s, 3 H), 5.59 (d, 1 H, J = 10.0 Hz), 6.90 (d, 1 H, J = 9.1 Hz), 7.59 (d, 1 H, J = 10.0 Hz), 7.83 (d, 1 H, J = 9.1 Hz); 13c NMR (75 MHz, CDC'g) 6 -3.09, 14.91, 16.04, 18.70, 20.17, 20.33, 26.10, 27.06, 61.37, 74.63, 112.89, 116.58, 123.06, 123.50, 123.84, 125.24, 126.86, 127.04, 134.94, 145.27, 148.70, 151.41; IR (neat) 2969, 2982, 2869, 1449, 1377, 1257 cm"; Mass 191 spectrum (El) m/z (°/c rel. int.) 427 M“ + 1 (75), 426 M“ (8), 413 (54), 412 (100), 411 (10); Anal. Calcd. for C26H3303Si: C,73.19; H, 8.98. Found: C, 73.45; H, 9.21. Synthesis of naphthol pyran (191) M60 Cr(CO)5 a) Benzene TMS OMe \ . Ill TMSCI, Hunig's bale 0 D) Air oxidation, TMSO \ O TMS n, 10h 0 175 0 191, 89 % To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (25 mg, 0.063 mmol), benzene (1.2 mL), trimethylsilylacetylene (25 ,uL, 0.126 mmol), TMSCI (24 pL, 0.189 mmol) and N,N-diisopropylethylamine (55 pL, 0.315 mmol) were then added to the reaction mixture. The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air and stirred for 12 h, filtered through Celite and concentrated in vacuo. The product was purified by silica gel column chromatography using (2 %) EtOAc : hexanes to give naphthopyran 191 (22.5 mg) in 89 °/c yield as white solid. Spectral data for 191: Mp = 79 - 81 °c; 1H NMR (300 MHz, CDCI3) 8 0.25 (s, 9 H), 0.34 (s, 9 H), 1.44 (s, 6 H), 3.88 (s, 3 H), 5.54 (d, 1 H, J = 10.1 Hz), 6.77 (s, 1 H), 6.96 (dd, 1 H, J = 0.9, 9.2 Hz), 7.71 (dd, 1 H, J = 0.7, 10.1 Hz), 7.85 (d, 1 H, J = 9.2 Hz); 130 NMR (75 MHz, CDCI3) 8 0.26, 1.62, 27.32, 55.92, 74.77, 112.41, 114.41, 117.63, 120.26, 123.30, 123.98, 124.96, 125.07, 126.89, 150.96, 151.58, 192 152.11; IR (neat) 2955, 2926, 2855, 1448, 1389 cm"; Mass spectrum (El) m/z (% rel. int.) 400 M” (24), 387(12), 386 (100), 371 (6), 297 (5); Anal. calcd. for 0227132038123 C, 65.95, H, 8..05 FOUHdI C, 66.06, H, 8..40 Synthesis of naphthol pyran (193) M60 Cf(CO)5 a) Benzene TMS OMe \ ., l MOMCl,Hunig's tESLe O 0) Air oxidation, 'MOMo \ 0 TMS rt, 10h O 175 0 193, 85 % To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (100 mg, 0.254 mmol) and benzene (5 mL). The trimethylsilyl acetylene (72 pL, 0.508 mmol), MOMCI (58 pL, 0.762 mmol) and N,N-diisopropylethylamine (221 pL, 1.270 mmol) were then added to the reaction mixture. The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was stirred at 50 °C for 24 h and then at room temperature for another 24 h. The reaction mixture was opened to air stirred for 12 h, filtered through Celite and concentrated in vacuo. The product was purified by silica gel column chromatography using (5 %) benzene : hexane to give naphthopyran 193 (81 mg) in 85 °/c yield as a white solid. Spectral data for 193: Mp = 86 - 88 °C; 1H NMR (500 MHz, cock.) 8 0.35 (s, 9 H), 1.44 (s, 6 H), 3.63 (s, 3 H), 3.90 (s, 3 H), 5.02 (s, 2 H), 5.55 (d, 1 H, J = 9.8 Hz), 6.78 (s, 1 H), 7.05 (dd, 1 H, J = 1.0, 8.8 Hz), 7.70 (d, 1 H, J = 10.2 Hz), 8.0 (d, 1 H, J = 9.3 Hz); 13c NMR (75 MHz, cock.) 8 0.01, 27.25, 55.74, 57.71, 193 .*.R 74.79, 101.00, 111.28, 114.28, 118.91, 123.20, 124.12, 124.31, 125.54, 125.40, 127.09, 152.32, 153.04, 153.31; IR (neat) 2953, 2895, 2840, 1603, 1450 cm"; Mass spectrum (El) m/z (% rel. int.) 373 M+ + 1 (100), 372 M+ (80), 358 (66), 357 (18), 328 (16), 298 (23), 297 (22), 296 (23); Anal. calcd. for C21H2304Si: C, 67.71; H, 7.58. Found: C, 68.08; H, 7.96. Synthesis of naphthol pyran (180) OMe OMe TMSO 0. \ %‘L—F’ HO 0O \ 0 o 186 180, 75 % To a stirred solution of 186 (31 mg, 0.083 mmol) in 5 mL THF at 0°C was added TBAF (166 pL, 0.166 mmol, 1.0 M solution in THF) dropwise. The reaction mixture was stirred for 30 min and, quenched with 5 mL water and extracted with EtOAc (2 x 10 mL). The organic layer was concentrated in vacuo and the product was purified by silica gel column chromatography using 5 % EtOAc : hexane to give slightly impure compound 180 in 75 % yield (18.5 mg) as a colorless oil. This compound contained slight amounts of impurities and its purity could not be enhanced by additional chromatography. This compound was fully characterized upon conversion to quinone 181. Spectral data for 180: 1H NMR (500 MHz, CDCI3) 6 0.99 (t, 3 H, J = 7.3 Hz), 1.44 (s, 6 H), 1.60-1.78 (m, 2 H), 2.63 (t, 2 H, J = 7.7 Hz), 3.87 (s, 3 H), 4.63 (s, 1 H), 5.56 (d, 1 H, J = 10.1 Hz), 6.60 (s, 1 H), 7.03 (dd, 1 H, J = 0.6, 9.1 Hz), 7.71 (dd, 1 H, J = 0.6, 10.5 Hz), 7.95 (d, 1H, J = 9.1 Hz); 13c NMR (75 MHz, CDCI3) 8 194 14.03, 23.34, 27.20, 32.09, 56.15, 74.62, 109.75, 114.52, 118.39, 118.45, 121.58, 122.16, 122.83, 123.26, 127.28, 142.52, 150.84, 1 sp2 C not located; IR (neat) 3455, 2961, 2930, 2870, 1626, 1454 cm"; Mass spectrum (El) m/z(°/c rel. int.) 298 M’r (29), 284 (21), 283 (100), 268 (21), 239 (10). Synthesis of naphthoquinone pyran (181) 0 OMe AN HO C \ t O O 180 To a stirred solution of 180 (9.0 mg, 0.030 mmol) in 2 mL THF at 0 °C was added 0 181,56% CAN (41 mg, 0.075 mmol) in 0.2 mL water. The reaction mixture was stirred for 30 min at 0 °C and then quenched with water. The water layer was then extracted with 2 x 10 mL EtOAc. The combined organic layer was washed with 5 mL of water, dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 5 °/c EtOAc : hexane to give a 65 % yield of quinone 181 as a yellow oil. Spectral data for 181: 1H NMR (500 MHz, CDCIa) 6 0.97 (t, 3 H, J = 7.3 Hz), 1.45 (s, 6 H), 1.50-62 (m, 2 H), 2.42-2.52 (m, 2 H), 5.89 (d, 1 H, J = 10.2 Hz), 6.63 (t, 1 H, J = 1.3 Hz), 7.03 (dd, 1 H, J = 0.8, 8.5 Hz), 7.74 (dd, 1 H, J = 0.7, 10.4 Hz), 7.94 (d, 1 H, J = 8.5 Hz); 13c NMR (75 MHz, CDCI3) 8 13.85, 21.17, 27.99, 31.05, 76.88, 119.88, 120.47, 121.08, 126.57, 126.81, 128.90, 134.69, 136.12, 150.11, 158.58, 184.50, 188.06; Mass spectrum (El) m/z (% rel. int.) 282 M“, 268 (21), 195 — 7 “—'"— h ~m_fifi-.w--a . _ «Xx. .. 267 (100), 239 (4), 238(4), 210 (4); IR (neat) 2964, 2930,2874, 1657, 1298 cm'1 ; Anal. calcd. for C18H1803: C,76.57; H, 6.43. Found: C, 76.42; H, 6.01. Synthesis of naphthol pyran (177) O OMe TBAF O THF “0 C \ o 177, 65 % To a stirred solution of 183 (20 mg, 0.049 mmol) in 5 mL THF at 0 °C was added TBAF (73 pL, 0.073 mmol, 1.0 M solution in THF) dropwise. The reaction mixture was stirred for 30 min and then quenched with 2 mL water. The reaction mixture was extracted with EtOAc (2 x 10 mL), dried over M9804 and then the organic layer was concentrated in vacuo and purified by silica gel column chromatography using 5 % EtOAc : hexane to give compound 177 in 65 °/c yield as a colorless oil. The 1H NMR spectrum revealed that the phenol 177 was not completely pure. The compound was not stable long enough to provide a good 13C NMR spectrum. This compound was characterized by conversion to the quinone 178. Spectral data for 177: 1H NMR (500 MHz, cock.) 8 1.46 (s, 6 H), 3.89 (s, 3 H), 5.40 (s, 1 H), 5.59 (cl, 1 H, J = 10.1 Hz), 6.73 (s, 1 H), 7.08 (cl, 1 H, J = 8.8 Hz), 7.36-7.44 (m, 1 H) 7.48-7.54 (m, 4 H), 7.75 (d, 1 H, J = 10.0 Hz), 8.10 (d, 1 H, J = 9.1 Hz); Mass spectrum (El) m/z (% rel. int.) 332 M“ (39), 318 (26), 317 (15), 303 (27); IR (neat) 3555, 2970, 2926, 2851.1626, 1591, 1454 cm". 196 ’"M ‘f" ‘ ...~. ~“ .— -“,- “a... ‘ .~_>-. 4»- .~_~«-~ Synthesis of naphthoquinone pyran (178) O O 0M9 AN HO O \ = O THF / H20 0 o 177 To a stirred solution of 177 (10.5 mg, 0.031 mmol) in 2 mL THF at 0 °C was O \ O 178, 50 °/c added CAN (43 mg, 0.077 mmol) in 0.5 mL water. The reaction mixture was stirred for 30 min at 0 °C and then quenched with water. The water layer was then extracted with 2 x 10 mL EtOAc. The combined organic layer was washed with 5 mL of water, dried over M9304 and concentrated in vacuo. The product was purified by silica gel column chromatography using 5 % EtOAc : hexane to give a 65 % yield of quinone 178 as orange solid. 1 Spectral data for 178: Mp = 156 - 158 °c; 1H NMR (500 MHz, CDCI3) 8 1.47 (s, 6 H), 5.93 (d, 1 H, J = 10.2 Hz), 6.94 (s, 1 H), 7.09 (dd, 1 H, J = 1.0, 8.8 Hz), 7.68- 7.90 (m, 3 H), 7.50-7.52 (m, 2 H), 7.78 (d, 1 H, 10.1 Hz), 8.03 (d, 1 H, 8.8 Hz); 13c NMR (75 MHz, cock.) 8 28.02, 77.03, 119.84, 120.43, 121.39, 126.93, 128.29, 129.38, 129.39, 129.82, 133.30, 134.95, 136.48, 146.64, 158.74, 183.60, 187.95, one sp2 C not located; IR (neat) 3061, 2978, 2930,1655 cm“; Mass spectrum (El) m/z (% rel. int.) 316 M+ (2), 302 (26), 301 (100), 273 (2); HRMS (FAB) calcd for m/z C21H1603 316.3499, measd 317.1177 (M* + 1). 197 Synthesis of ortho-aryl diyne (220) OMe OH / TlPs (CO)5Cr Toluene / + TIPS : : :: TIPS —-—T 219 § 39 OMe TIPS 220, 81% To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added cyclohexenyl carbene complex 219 (0.885 mg, 2.8 mmol), bis-TIPS triyne 39 (1.1 gm, 2.8 mmol) and toluene (44 mL). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The mixture was then stirred at 90 °C for 24 h. After 24h, the reaction mixture was opened to air and stirred for 12h, filtered through Celite and concentrated in vacuo. The product was purified by silica gel chromatography using hexane and ethyl acetate (10 : 1) as eluent to give an 81 % yield of 220 as an orange oil. Spectral data for 220: 1H (300 MHz, cock.) 8 1.08-1.13 (m, 42 H), 1.71-1.73 (m, 4 H), 2.65-2.69 (m, 4 H), 3.80 (s, 3 H), 6.01 (s, 1 H); 13c (75 MHz, cock.) 8 11.16, 11.34, 18.73, 21.95, 22.07, 23.54, 23.82, 60.38, 98.26, 100.23, 108.56, 101.42, 101.17, 114.66, 125.50, 133.77, 151.70, 153.38, one Sp3 C not located; IR (neat): 3502, 2941, 2868, 2132, 1468, 1452, 1408, 1311, 1043, 884 cm-1; Mass spectrum (El) m/z (% rel. int.) 538 M+ (25), 454 (18), 453 (55), 168 (18), 154 (19), 141 (16), 87 (33), 73 (59), 59 (100), HRMS (FAB) calcd for m/z 033H54028i2 538.3662, measd 538.3664. Anal, Calcd. for C33H54023i2: C, 73.54; H, 10.10. Found: C, 72.84, H, 10.66. 198 Synthesis of furan (236) TIPS TIPS OCH3 || ”’3 (CO)5C' + H Toluene, 90 °e 24 n ' OCHa 22 H 39 236, 69% yield TIPS To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added phenyl carbene complex 22 (80 mg, 0.254 mmol), bis-TIPS triyne 39 (100 mg, 0.254) and toluene (6.0 mL). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 90 °C for 24 h. After 24 h, the mixture was opened to air and allowed to stir for 4 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using benzene and hexane (3 : 10) to give phenyl furan 236 in 69 % yield as a yellow oil. Spectral data for 236: 1H (300 MHz, cock.) 8 1.14 (m, 21 H), 1.18 (m, 21 H), 4.24 (s, 3 H), 7.26-7.39 (m, 4 H), 8.04-8.07 (m, 1 H); 1H (500 MHz, c606): 0.80- 1.40 (m, 42 H), 3.59 (s, 3 H), 7.03 (t, 1H, J = 7.5 Hz), 7.20 (t, 2H, J = 7.8 Hz), 8.16 (dd, 2H, J = 1.0, 8.6 Hz); 13c (75 MHz, CDCI3) 8 11.31, 11.34, 18.71, 18.72, 59.32, 85.92, 94.86, 95.98, 98.27, 98.81, 106.06, 124.29, 127.57, 128.33, 129.65, 145.63, 161.09; IR (neat): 2946, 2888, 2149, 1605, 1464, 1387, 1161, 199 1119, 1065, 995, 884, 793, 762, 677 cm-1; Mass spectrum (El) m/z (% rel. int.) 534 M“ (82), 434 (100), 391 (15), 168 (27), 154 (19), 105 (22), 73 (27), 59 (65), HRMS (FAB) calcd for m/z 033H50028i2 534.3349, measd 534.3348. Synthesis of furan (238) TIPS TIPS / \\ / \\ // l \ OCH fl'i. \ o 3 THF ’0 OCH3 236 238, 57% To a stirred solution of 236 (86 mg, 0.159 mmol) in 3 mL THF at 0 °C was added TBAF (500 pL, 0.447 mmol, 1.0 M solution in THF). The reaction mixture was warmed to room temperature and stirring continued at this temperature for 3 h. The reaction mixture was quenched with sat aq ammonium chloride (1 x 5 ml.) and extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over MgSO. and concentrated in vacuo. The product was purified by silica gel column chromatography (1 °/c EtOAc / Hexane) to give 20 mg (57 % yield) of a light brown oil that was identified as 238. The presence of two alkynyl hydrogens is only consistent with structure 238. Spectral data for 238: 1H NMR (300 MHz, CDCla) 6 3.22 (s, 1 H), 3.49 (s, 1 H), 4.19 (s, 3 H), 7.27 (tt, 1 H, J = 7.5, 1.1 Hz), 7.35-7.40 (m, 2 H), 7.90-7.95 (m, 2 H); 13c NMR (75 MHz, cock.) 8 59.0, 73.2, 75.3, 81.4, 84.3, 84.6, 104.6, 124.1, 127.9, 128.5, 129.2, 145.9, 160.8; IR (neat): 3300, 2924, 2856, 2584, 2114, 1728, 1610 cm-1; Mass spectrum (FAB) m/z (% rel. int.) 222 M” (100), 207 (16); HRMS (FAB) calcd for m/z C15H1002 222.0681, measd 222.0678. 200 why—‘qfi-L «so..- .. —7 .‘42. .- Synthesis of ortho-aryl diyne (221) CH TIPS 0A6 / é / a) Ac20, Base: b TBAF, THF 4 ’ % OMe TIPS OMe 220 221, 55% from 220 The following procedure is slightly modified from that originally reported by Jiang.64 To a solution of compound 220 (0.62 gm, 1.16 mmol) in CH2Cl2 (20 mL) was added 0.14 mL Ac20, 0.14 mL pyridine and 14 mg DMAP in that order. The mixture was stirred at room temperature for 18 h. The reaction was quenched with H20 and extracted with CH2C|2. The extract was washed with H20 and brine and then dried over MgSO... After concentration, the residue was dissolved in 20 mL THF and TBAF (5 mmol, 5 mL of a 1.0 M solution in THF) was added at 0 °C. The mixture was stirred at 0 °C temperature for 15 min. The reaction was quenched by water and extracted with ether. The organic layer was washed with H20 (1 X 10) and brine (1 X 10) and then dried with MgSO... The organic layer was concentrated in vacuo and the product was purified by silica gel column chromatography using hexanes and EtOAc (10 : 1) to give 0.180 g of compound 221 as a white solid. The yield was 58 %. The spectral data for 221 matched that previously reported by Jiang.64 Synthesis of naphthol (226) Ph H3CO Cr(CO)5 OCH é 3/ B 0C / + Ph : : : Ph enzene, 90 : CO 22,, 24h Ph 22 OH 226, 3% 201 To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added phenyl carbene complex 22 (80 mg, 0.254 mmol), bis-phenyl triyne 224 (57 mg, 0.254 mmol) and benzene (6.0 mL). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The mixture was then stirred at 90 °C for 24 h. The reaction mixture was diluted with 10 mL CHzclz, allowed to stir opened to air for 12 h. The solution was filtered through a fritted funnel dry packed with Celite 545 and concentrated using a rotary evaporator. The crude reaction mixture appeared by TLC and 1H NMR to be a complicated mixture of many compounds none of which was estimated (after column chromatography) to have been formed in more than 8 - 10 °/c yield. The crude mixture was loaded onto a silica gel column and elueted with a solvent gradient that ranged from pure hexanes to 5 % EtOAc in hexanes. Several fractions were collected but only one compound was obtained in pure form. This compound was tentatively identified as the phenol 226 which was judged to have been formed in 3 % yield based the amount isolated material (5 mg) and the weight of additional fractions that contained 226 along with other compounds. Spectral data for 226: 1H NMR (500 MHz, c0c13) 8 4.15 (s, 3 H), 5.41 (s, 1 H), 7.12- 7.18 (m, 2 H), 7.20-7.26 (m, 2 H), 7.46-7.60 (m, 8 H), 8.14-8.16 (m, 1 H), 8.20-8.25 (m, 1 H). 202 Synthesis of naphthol derivative (283) Ph / Ph OCH3 ¢ OCH3 / / ¢ / CO Nachen A CD ph (CH3)2SO4 ph OH OCH3 226 283.96% A flame-dried round-bottomed flask (5 mL) filled with Argon was charged with a solution of 226 (5 mg, 0.013 mmol) in 1 mL THF. Solid NaH (10 mg, 60 °/c disperson in mineral oil) was then added to the reaction mixture at room temperature. After 5 minutes, dimethylsulfate (50 pL) was added and stirring was continued at room temperature for 6 h. The reaction mixture was loaded onto a silica gel column and eluted using (5 °/c) EtOAc in hexane to give a 96 % yield of a yellow solid. Spectral data for 283: 1H NMR (500 MHz, cock.) 8 3.51 (s, 3 H), 4.18 (s, 3 H), 7.17-7.21 (m, 2 H), 7.22-7.26 (m, 3 H), 7.39-7.44 (m, 1 H), 7.45-7.51 (m, 2 H), 7.53-7.59 (m, 4 H), 8.12-8 .17 (m, 1 H), 8.17-8.21 (m, 1 H). Synthesis of olefin-addition product (269) TIPS | I was MeO Cr(CO)5 ‘ MeO é \ + TIPS : : : TIPS a) 0142012 (0.05 M), > O o 90 °c, 24 h 0 175 39 b) Alr OXIdatlon, rt, 10 h 0 269, 88 % To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 175 (50 mg, 203 0.127 mmol), bis-TIPS triyne 39 (49 mg, 0.127) and dichloromethane (2.5 mL). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The mixture was then stirred at 90 °C for 24 h. The reaction was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The product was purified by silica gel column chromatography using (2 : 98) EtOAc : hexane to give an olefin-addition product 269 (66 mg) in 88 °/c yield as a brown oil. Spectral data for 269: 1H NMR (500 MHz, c0c13) 8 1.17 (s, 21 H), 1.15 (s, 21 H), 1.36 (s, 6 H), 3.22 (s, 2 H), 4.03 (s, 3 H), 6.91 (dd, 1 H, J = 0.8, 7.7 Hz), 7.39 (t, 1 H, J = 8.2 Hz), 7.60 (dd, 1 H, J = 1.1, 8.5 Hz); 13c NMR (125 MHz, CDCI3) 8 11.40, 11.48, 18.81, 18.82, 26.29, 39.65, 61.63, 75.39, 99.64, 100.03, 101.47, 103.21, 112.56, 114.20, 119.04, 121.08, 128.00, 128.33, 130.62, 151.82, 158.26, one sp2 C not located; Mass spectrum (FAB) m/z (°/o rel. int.) 588 M” (100), 488 (60), 445 (20), 157 (19); IR (neat) 2943, 2888, 2145, 1464 cm"; Anal. calcd. for C37H5602$i2I C,75.45; H, 9.58. Found: C, 75.59; H, 9.56. Synthesis of olefin-addition product (269a) 2698, 68 % 204 To a stirred solution of 269 (54 mg, 0.09 mmol) in 5 mL THF at room temperature was added TBAF (0.27 mmol, 270 0L, 1 M solution in THF). After 5 min at room temperature, the reaction mixture was quenched with 5 mL water and diluted with EtOAc (20 mL). The organic layer was washed with 5 mL water, dried over MgSO4, concentrated in vacuo. The product was purified by silica gel column chromatography using hexane / EtOAc (20 / 1) as eluent to give 17 mg of compound 2698 (68 % yield) as a colorless oil. Spectral data for 269a: 1H NMR (500 MHz, coc13) 8 1.38 (s, 6 H), 3.20 (s, 2 H), 3.55 (s, 1 H), 3.61 (s, 1 H), 4.09 (s, 3 H), 6.95 (dd, 1 H, J = 1.0, 6.9 Hz), 7.43 (t, 1 H, J = 7.8 Hz), 7.64 (dd, 1 H, J = 1.0, 8.6 Hz); “’0 NMR (125 MHz, CDCI3) 8 26.88, 39.10, 61.89, 75.52, 78.75, 79.96, 85.20, 85.69, 112.81, 113.09, 114.29, 117.80, 121.16, 128.10, 128.75, 130.36, 151.95, 158.11; IR (neat) 3289, 2974, 2928, 2851, 1578, 1489 cm“; Mass spectrum (El) m/z (% rel. int.); 276 (W), 275 (47), 261 (42), 260 (48), 246 (30), 245 (23), 203 (65), 202 (67); Anal. calcd. for C19H1502; C, 82.58; H, 5.84; FOURd; C, 82.39; H, 5.62. Synthesis of bromochromane (270) Bi Br {1: 5% Rh on alumine 0 H2 (1atm) O 141 270, 92% yield To a stirred solution of 141 (100 mg, 0.418 mmol) in 15 mL EtOH was added 50 mg of Rh on alumina (5 % Rh on alumina). The reaction mixture was stirred for 2 h at room temperature under H2 atmosphere (1 atm). After 2 h, the reaction mixture was filtered through Celite and concentrated in vacuo. The product was 205 purified by silica gel column chromatography using hexane / EtOAc (20 / 1) as eluent to give bromochromane 270 in 92 % yield as a colorless oil. Spectral data for 270: 1H NMR (500 MHz, cock.) 8 1.32 (s, 6 H), 1.81 (t, 2 H, J = 6.8 Hz), 2.74 (t, 2 H, J = 6.9 Hz), 6.74 (d, 1 H, J = 8.2 Hz), 6.95 (t, 1 H, J = 8.1 Hz), 7.09 (d, 1 H, J = 8.3 Hz); 130 NMR (75 MHz, CDCI3) 6 23.85, 26.47, 32.75, 74.30, 116.50, 121.27, 123.44, 125.19, 127.93, 144.07; IR (neat) 2976.54, 2930, 1593, 1566 cm"; Mass spectrum (FAB) m/z (% rel. int.) 242 (96, 81Br), 240 (100, 79Br), 227 (12, 81Br), 225 (13, 79Br), 187 (14, B‘Br), 185 (17, 79Br), 161 (91), 146 (28), 145 (29); Anal. calcd. for C11H13Br0: C, 54.79; H, 5.43. Found: C, 54.66; H, 5.20. Synthesis of chromane carbene complex (235) Br H3CO CT(CO)5 a) t-BuLi (260). E120 o b) Cr(CO)5, EtZO - C) M93OBF4, CH2C12 O 270 235, 65% yield To a flame-dried 100 mL round-bottomed flask containing a solution of bromochromane 270 (310 mg, 1.45 mmol) in ether (10 mL) at -78 °C was added felt-BuLi (1.7 mL, 2.90 mmol, 1.7 M solution in pentane). The mixture was warmed to 0 °C, stirred at 0 °C temperature for 5 min and cooled to -78 °C before it was transferred by cannula to a suspension of Cr(CO)6 (350 gm, 1.59 mmol) in 10 mL ether maintained at 0 °C. The reaction mixture turned dark red in 5 min. Stirring was continued for 6 h at room temperature which was followed by removal of ether under vacuum and addition of 10 mL dichloromethane. M6303F4 (1.63 gm, 11 mmol) was then added at room temperature and reaction 206 was further stirred for 2 h. The reaction mixture was then filtered through Celite and concentrated in vacuo. The product was purified by silica gel column chromatography (5 %) EtOAc : hexane to give 344 mg (65 % yield) of carbene complex 235 as an orange solid. Spectral data for 235: Decomposes above 108 °C; 1H NMR (500 MHz, CDCI3) 6 1.32 (s, 6 H), 1.78 (br, s, 2 H), 2.43 (br, s, 2 H), 4.25 (br, s, 3 H), 6.35 (d, 1 H, J = 6.84), 6.70 (d, 1 H, J = 7.81 Hz), 7.14 (d, 1 H, J = 7.8 Hz); 13c NMR (75 MHz, CDCI3) 6 19.94, 26.82, 32.25, 65.47, 74.23, 110.11, 111.44, 117.12, 127.56, 154.05, 216.00, 224.22, 359.39, one sp2 C not located; Mass spectrum (FAB) m/z (% rel. int.) 396 M+ (38), 368 (80), 312 (82), 284 (100), 256 (90), 205 (38), 189 (40); IR (neat) 2978, 2064, 1930, 1576 cm"; Anal. calcd. for C18H160r07: c, 54.55; H, 4.07. Found: C, 54.66; H, 3.96. Synthesis of naphthol pyran (271) H300 Cf(CO)5 H3CO a) LBSCI, %enzene O unl 's ase + 13 . g. . > OTBS O D) Air OXIdatlon O 235 271, 77% To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromane carbene complex 235 (35 mg, 0.088 mmol), benzene (1.7 mL), 1-pentyne (18 ,uL, 0.090 mmol), TBSCI (40 mg, 0.264 mmol) and N,N-diisopropylethylamine (77 ,uL, 0.440 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The mixture 207 h—- ‘fi-N‘ L‘v..~.e-.2.. ' was then stirred at 50 °C for 24 h and at 25 °C for another 24 h. The reaction was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using hexane and EtOAc (20 : 1) to give a 77 % yield of naphthopyran 271 (28 mg) as a colorless oil. Spectral data for 271: 1H NMR (500 MHz, cool.) 8 0.11(s, 6 H), 0.93 (t, 3 H, J = 7.3 Hz), 1.08 (s, 9 H), 1.34 (s, 6 H), 1.55-1.65 (m, 2 H), 1.79 (t, 2 H, J = 6.6 Hz), 2.58-2.68 (m, 2 H), 3.41 (t, 2 H, J = 6.8 Hz), 3.84 (s, 3 H), 6.59 (s, 1 H), 6.90 (d, 1 H, J = 9.9 Hz), 7.77 (d, 1 H, J = 9.3 Hz); 13c NMR (125 MHz, CDCI3) 8 -3.30, 14.02, 18.64, 23.04, 23.67, 26.13, 26.52, 32.60, 33.57, 55.74, 72.98, 108.92, 113.69, 118.82, 122.68, 124.21, 125.00, 125.02, 142.20, 151.04, 151.83; IR (neat) 2957, 2930, 2858, 1603, 1460 cm"; Mass spectrum (FAB) m/z (% rel. int.) 415 M+ + 1 (40), 414 (100), 413 (20), 400 (10), 399 (10), 357 (5); HRMS (FAB) calcd for m/z C25H38038i 414.2590, measd 414.2587. Synthesis of furan (272) H300 Cr(CO)5 H300 O + TIPS : : : TIPS a)B°"Z°"°’9° Ce 0 39 D) Air Oxidation 235 272, 75% To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromane carbene complex 235 (50 mg, 0.126 mmol), bis-TIPS triyne 39 (49 mg, 0.127) and benzene (2.6 mL). The 208 system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The mixture was then stirred at 90 °C for 24 h. The reaction was opened to air and allowed to stir for 2 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using (1 : 2) benzene : hexane to give chromanylfuran 272 (49 mg) in 63 % yield as brown oil. This compound decomposes quickly and as a result it was not possible to obtain a 130 NMR spectrum. Spectral data for 272: 1H NMR (300 MHz, cool.) 8 1.11 (s, 21 H), 1.153 (s, 21 H), 1.37 (s, 6 H), 1.80 (t, 2 H, J = 6.6 Hz), 2.88 (t, 2 H, J = 6.6 Hz), 4.24 (s, 3 H), 6.82 (dd, 1 H, J = 1.3, 8.2 Hz), 7.09 (t, 1 H, J = 8.0 Hz), 7.40 (dd, 1 H, J = 1.3, 7.6 Hz); Mass spectrum (FAB) m/z (% rel. int.) 619 M“ + 1 (38), 618 M+ (40), 591 (45), 578 (32); IR (neat) 2943, 2868, 2148, 1606, 1579 cm“; Anal. calcd. for C38H5303Si2: C, 73.73; H, 9.44; Found: C, 73.55; H, 9.62. Synthesis of tungsten carbene complex (274) / a) t-BuLi (260). Etzo / o b) W(c0)6. Et20 ' C) M6303F4, CH2C12 O 141 274, 66% yield To a flame-dried 100 mL round-bottomed flask containing a solution of bromochromene 141 (536 mg, 2.24 mmol) in ether (20 mL) at -78 °C was added tert-BuLi (2.6 mL, 4.48 mmol, 1.7 M solution in pentane). The reaction mixture was warmed to 0 °C, stirred at this temperature for 5 min and cooled to -78 °C before it was transferred by cannula to a suspension of W(CO)6 (867 mg, 2.46 209 mmol) in 10 mL ether maintained at 0 °C. Stirring was continued for 6 h at room temperature which was followed by removal of ether under vacuum and addition of 10 mL dichloromethane. M6303F4 (497 gm, 3.36 mmol) was then added at room temperature and reaction was further stirred for 2h. This was followed by filtration through Celite, concentration in vacuo and purification by silica gel column chromatography (5 %) EtOAc and hexane to give 773 mg (66 % yield) of carbene complex 274 as an orange solid. Spectral data for 274: Mp = 76 - 78 °C; 1H NMR (500 MHz, CDCI3) 6 1.41 (s, 6 H), 4.54 (br, s, 3 H), 5.65 (d, 1 H, J = 9.8 Hz), 6.04 (d, 1 H, J = 9.9 Hz), 6.49 (d, 1 H, J = 6.9 Hz), 6.68 (dd, 1 H, J = 0.8, 8.1 Hz), 7.11 (t, 1 H, J = 8.6 Hz); 13c NMR (75 MHz, CDCI3) 6 27.64, 76.00, 77.20, 114.44, 111.86, 116.58, 118.48, 128.29, 132.00, 152.58, 196.77, three Cs not located; Mass spectrum (FAB) m/z (% rel. int.) 526 M* (40), 498 (40), 469 (38),; 442 (50), 386 (25), 341 (20), 203(100); IR (neat) 2980, 2071, 1925, 1442 cm"; Anal. calcd. for C13H1407W: C, 41.09; H, 2.68;. Found: C, 41.49; H, 2.70. Synthesis of cyclopentene (275) M90 W(CO)5 0MB 0 \ + : 1)Toluene,90°C, 241:1 \ \ O 2) Air oxidation, 24 h 0 274 275. 90% To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added chromene carbene complex 274 (107 mg, 0.203 mmol), toluene (4 mL) and 3-hexyne (46 ,uL, 0.406 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The 210 flask was back-filled with Ar at room temperature and sealed. The mixture was then stirred at 90 °C for 24 h. After 24 h, the reaction was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using hexane and benzene (5 : 2) to give 275 (52 mg) in 91 % yield as a colorless oil. Spectral data for 275: 1H NMR (500 MHz, CDCI3) 8 0.54 (t, 3 H, J = 7.3 Hz), 1.11 (t, 3 H, J = 7.6 Hz), 1.40 (s, 3 H), 1.43 (s, 3 H), 1.66-1.76 (m, 1 H), 1.88-1.99 (m, 1 H), 2.06-2.16 (m, 1 H), 2.60-2.72 (m, 1 H), 3.26 (t, 1 H, J = 4.8 Hz), 3.75 (s, 3 H), 5.61 (d, 1 H, J = 9.8 Hz), 6.57 (d, 1 H, J :78 Hz), 7.01 (d, 1 H, J = 10.3 Hz), 7.02 (d, 1 H, J = 8.3 Hz); 13c NMR (75 MHz, CDCI3) 8 8.34, 14.19, 18.10, 22.40, 27.51, 27.97, 45.17, 60.37, 75.25, 112.35, 113.65, 119.26, 122.61, 130.14, 135.08, 135.89, 137.48, 151.70, 153.98; IR (neat) 2968, 2932, 2870, 1631, 1593 cm"; Mass spectrum (FAB) m/z (% rel. int.) 285 M” +11 (90), 284 M+ (100), 283 (70), 269 (80), 255 (30), 225 (30); HRMS (FAB) calcd for m/z C19H2402 284.1776, found 284.1777 (M+). Synthesis of ortho-aryl diyne (294) CH TIPS OH // TBAF,THF Cm? -20 °c, 1 11 § § OCH3 TIPS OMe TIPS 220 294, 77% To a stirred solution of 220 (1.1 gm, 2.04 mmol) in 20 ml. THF at -20 °C was added TBAF (4 mL, 4.04 mmol, 1.0 M solution in THF). The reaction mixture was stirred at -20 °C for 1 h, quenched with 10 mL water and extracted with 2 X 20 211 — —. _ .- 4's" __\.S‘ .3 mL EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo and the product was purified by silica gel column chromatography using a gradient of hexane and benzne (3 : 1 to 1 : 1) as eluent to give a 77 % yield of 294 (600 mg) as a light brown oil. Spectral data for 294: 1H NMR (500 MHz, CDCI3) 8 1.13 (s, 21 H), 1.65-1.80 (m, 4 H), 2.55-2.75 (m, 4 H), 3.56 (s, 1 H), 3.83 (s, 3 H), 5.73 (s, 1 H); 13c NMR (125 MHz, CDCla) 6 11.35, 18.67, 21.88, 22.01, 23.50, 23.81, 60.44, 77.65, 86.75, 98.72, 101.11, 107.60, 115.60, 125.95, 134.10, 151.48, 153.07; IR (neat) 3518, 3308, 2939, 2864, 2155, 1450 cm"; Mass spectrum (El) m/z (% rel. int.) 382 M+ (80), 339 (100), 340 (29), 339 (100), 325 (66), 283 (24), 282 (23); Anal. Calcd. for C24H3402Si: C, 75.34; H, 8.96; Found: C, 75.04; H, 8.88. Synthesis of ortho-aryl diyne (295) CH TIPS OH / / / TBAF, THF / \ 25 °c, 24 n \ \ \ OCH3 TIPS OMe 220 295 To a stirred solution of 220 (21 mg, 0.039 mmol) in 5 mL THF was added TBAF (120 III, 0.117 mmol, 1.0 M solution in THF). The mixture was stirred at room temperature for 12 h and then quenched with 5 mL water. The reaction mixture was then extracted with 2 X 10 mL of EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo and the product was purified by silica gel column chromatography using hexane and EtOAc (10 : 1) to give diyne 295 in 70 % yield as a colorless oil. 212 Spectral data for 295: 1H NMR (500 MHz, CDCI3) 6 1.60-1.70 (m, 4 H), 2.50-2.59 (m, 4 H), 3.46 (s, 1 H), 3.64 (s, 1 H), 3.83 (s, 3 H), 5.75 (s, 1 H); 13c NMR (125 MHz, CDCI3) 6 21.76, 21.87, 23.49, 23.77, 60.56, 77.20, 79.35, 84.15, 86.85, 107.39, 113.97, 126.65, 134.33, 151.58, 153.48; IR (neat) 3507, 3287, 2936, 2862, 2839, 2106, 1452; Mass spectrum (El) m/z (% rel. int.) 227 M+ + 1 (80), 227 (90), 225 (35), 165 (35), 152 (30); Anal. Calcd. for C(5H1402: C, 79.62; H, 6.24; Found: C, 79.99; H, 6.35. Synthesis of ortho-aryldiyne (288) / .0 NaH then (CH3)2$O4 .0 \ THF 7 \ \ 0M9 “'33 OMe \ TIPS 294 288, 95% To a stirred solution of 294 (556 mg, 1.45 mmol) in 10 mL THF was added solid sodium hydride (76 mg, 1.90 mmol, 60 % dispersion in mineral oil). The reaction mixture was stirred for 15 min at room temperature and then (CH3)2S04 (275 uL, 2.90 mmol) was added. After stirring for 24 h at room temperature, the reaction mixture was quenched with 5 mL water and diluted with 20 mL EtOAc. The aqueous layer was washed with another 10 mL of EtOAc. The combined organic layer was dried over M9804 and concentrated in vacuo. The product was purified by silica gel column chromatography using hexane and benzene (1 : 1) to give the diyne 288 as an off-white solid in 95 % (432 mg) yield. 213 Spectral data for 288: Mp = 48 - 50 °C; 1H NMR (500 MHz, cock.) ) 8 1.05 (s, 21 H), 1.56-1.68 (m, 4 H), 2.52-2.64 (m, 4 H), 3.31 (s, 1 H), 3.74 (s, 3 H), 3.77 (s, 3 H); ‘30 NMR (125 MHz, cock.) 8 11.36, 18.66, 22.00, 22.01, 23.74, 60.19, 60.28, 78.75, 84.50, 99.06, 101.05, 116.36, 117.91, 133.10, 133.55, 155.70, 155.96, one sp3 C not located; IR (neat) 3314, 2939, 2864, 2152, 2112, 1454 cm' 1; Mass spectrum (El) m/z (% rel. int.) 396 W (100), 354 (27), 339 (17), 324 (15), 311 (28), 281 (22); Anal. Calcd. for CZ5H36028i: C, 75.70; H, 9.15; Found: C, 75.60; H, 8.85. Synthesis of ortho-aryldiyne (289) CH OAc é é A020, Hunig's Basee S % 0M9 TIPS OMe TIPS 294 289, 98% To a solution of 294 (26 mg, 0.068 mmol) in CH20I2 (5 mL) was added DMAP (1.7 mg, 0.014 mmol), Ac20 (10 ,uL, 0.081 mmol) and Hunig’s base (24 ,uL, 0.136 mmol). The reaction mixture was stirred at room temperature for 24 h, quenched with 5 mL water and extracted with EtOAc (2 X 20 mL). The organic layer was washed with 10 mL water, dried over M9804 and concentrated in vacuo. The product was purified by silica gel column chromatography using hexane : EtOAc (20 : 1) to give 28 mg of 289 (98 % yield) as an off-white solid. Spectral data for 289: Mp = 96 - 98 °C; 1H NMR (500 MHz, CDCla) 6 1.12 (s, 21 H), 1.65-1.75 (m, 4 H), 2.30 (s, 3 H), 2.42-2.58 (m, 2 H), 2.62-2.78 (m, 2 H), 3.31 (s, 1 H), 3.88 (s, 3 H); 13c NMR (125 MHz, coc13) 8 11.35, 18.67, 20.58, 21.68, 21.79, 23.71, 23.78, 60.29, 77.17, 84.54, 99.84, 100.65, 117.11, 117.97, 132.14, 214 133.60, 146.55, 157.21, 168.63; IR (neat) 3314, 2939, 2884, 2154, 1768, 1452 cm"; Mass spectrum (El) m/z (% rel. int.) 424 M* (10), 383 (91), 382 (100), 340 (20), 267 (7); Anal. Calcd. for 026H36038i: C, 73.54; H, 8.54; Found: C, 73.77; H, 9.03. Synthesis of ortho-aryl diyne (290) OH é OTBS? TBSCI, lmidazole : § CH2C|2, 25 °C, 24 h § OMe TIPS OMe TIPS 294 290, 56% To a stirred solution of 294 (200 mg, 0.523 mmol) in 10 mL CHzclz was added TBSCI (157 mg, 1.046 mmol) and imidazole (107 mg, 1.569). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then concentrated in vacuo and the product was purified by silica gel column chromatography using hexane and benzene (3 : 1) to give a 56 % yield of 290 (145.5 mg) as an off white solid. Spectral data for 290: 62 - 64 °C; 1H NMR (500 MHz, CDCla) 6 0.25 (s, 6 H), 1.02 (s, 9 H), 1.14 (s, 21 H), 1.63-1.74 (m, 4 H), 2.58 (1,2 H, J = 5.9 Hz), 2.69 (t, 2 H, J = 6.2 Hz), 3.27 (s, 1 H), 3.85 (s, 3 H); 13c NMR (125 MHz, CDCI3) 8 -2.39, 11.42, 18.71, 22.04, 22.21, 23.82, 25.29, 26.20, 60.25, 80.76, 84.79, 98.59, 101.62, 114.35, 117.85, 131.38, 133.24, 151.09, 154.06, one sp3 C not located; IR (neat) 3314, 2937, 2862, 2152, 1462 cm"; Mass spectrum (El) m/z (% rel. int.) 496 M+ (16), 440 (42), 425 (100), 383 (15), 341 (19); Anal. Calcd. for anH43028i2: C, 72.52; H, 9.74; Found: C, 72.53; H, 9.64. 215 Synthesis of bis-aryl phenol derivative (298) OMe OA H C é MeO OAC O +/_€:CFICO)5 Toluene,Ac20 \ — Hunig's base .0 OAc \ \ \ OMe “'33 297 OMe TIPS 289 298, 52% To a flame-dried 10 mL flask with the 14/20 joint replaced by a high-vacuum threaded Teflon stopcock was added 2-butenyl carbene complex 297 (108.24 mg, 0.373 mmol), toluene (7.0 mL), bis-alkyne 289 (144 mg, 0.339 mmol), Ac20 (106 ,uL, 1.119 mmol) and N,N—diisopropylethylamine (325 ,uL, 1.865 mmol). The system was deoxygenated by the freeze-pump-thaw method (-196 to 25 °C, 3 cycles). The flask was back-filled with Ar at room temperature and sealed. The reaction mixture was then stirred at 80 °C for 48 h. After 48 h, the reaction mixture was opened to air and allowed to stir for 12 h. The reaction mixture was filtered through Celite, concentrated in vacuo and the product was purified by silica gel column chromatography using hexane and EtOAc (10 :1) to give a 57 % yield (125 mg) of biaryl 298 as a brownish oil. Spectral data for 298: 1H NMR (500 MHz, CDCI3) 8 0.89 (s, 21 H), 1.60-1.85 (m, 4 H), 1.95 (s, 3 H), 1.97 (s, 3 H), 2.01 (s, 3 H), 2.12 (s, 3 H), 2.28-2.68 (m, 2 H), 2.68-2.82 (m, 2 H), 3.70 (s, 3 H), 3.90 (s, 3 H), 6.54 (s, 1 H); ‘30 NMR (125 MHz, CDCI3) 6 11.14, 12.00, 13.47, 18.32, 20.42, 20.45, 21.91, 21.98, 23.60, 23.95, 55.63, 60.20, 98.11, 101.12, 110.04, 115.82, 125.84, 126.33, 130.00, 131.48, 131.96, 132.16, 140.77, 142.76, 154.60, 157.21, 168.78, 169.62; IR (neat) 2941, 2864, 2154, 1765 cm“; Mass spectrum (FAB) m/z (% rel. int.) 593 M+ + 1 (40), 216 551 (45), 550 (100), 549 (90), 508 (40), 507 (70), 465 (35); Anal. calcd. for 035H48063i: C, 70.91; H, 8.16; Found: C, 71.27; H, 8.19. Synthesis of bis-aryl phenol derivative (299) OMe OMe OAc 0 OAc O .0 TBAF, THF .0 GAO OAC \\ % OMe TIPS OMe 298 299, 94 "/c To a stirred solution of 298 (35 mg, 0.059 mmol) in 1 mL THF at 0 °C was added TBAF (118 ,uL, 0.118 mmol, 1.0 M solution in THF). After stirring for 1 h at 0 °C, the reaction mixture was diluted with 10 mL EtOAc and queched with 5 mL water. The organic layer was separated and the aqueous layer was washed with 2 X 10 mL EtOAc. The organic layer was washed with 5 mL of water, dried over MgSO4, conc. in vacuo and purified by silica gel column chromatography using hexane : EtOAc (3 : 1) as eluent to give 299 (24 mg, 94 % yield) as a white crystalline solid. The compound was characterized by X-ray diffraction. The data is in the appendix. Spectral data for 299: Mp = 149 - 151 °C; 1H NMR (500 MHz, CDCI3) 6 1.64-1.84 (m, 4 H), 1.95 (s, 3 H), 1.98 (s, 3 H), 2.07 (s, 3 H), 2.17 (s, 3 H), 2.30-2.60 (m, 2 H), 2.70-2.82 (m, 2 H), 3.10 (s, 1 H), 3.73 (s, 3 H), 3.88 (s, 3 H), 6.59 (s, 1 H); 13c NMR (125 MHz, CDCI3) 6 12.23, 13.59, 20.38, 20.47, 21.86, 21.90, 23.61, 24.04, 55.76, 60.34, 78.14, 84.33, 110.49, 114.28, 125.87, 126.12, 130.01, 131.73, 132.07, 132.61, 140.57, 142.80, 154.56, 157.86, 168.74, 169.25; IR (neat) 3283, 2937, 2862, 1761 cm"; Mass spectrum (El) m/z(% rel. int.) 437 M*+ 1, 395 (31), 217 394 (100), 380 (22), 353 (55), 338 (50); Anal. calcd. for C25H2306; C, 71.54; H, 6.47. Found: C, 71.47; H, 6.41. Synthesis of tris-aryl phenol derivative (301) OMe OMe MeO Cr CO OAc =25igma(I)] R1 = 0.0402, wR2 = 0.1127 R indices (all data) R1 = 0.0670, wR2 = 0.1282 Largest diff. peak and hole 0.217 and —0.202 e.A“—3 251 orthogonalized Uij tensor. 252 Table A.1.2. Atomic coordinates ( x 104); equivalent isotropic displacement parameters (A x 103), and occupancies for 184 x y z U(eq) Occ. 0(1) —1144(2) 9312(1) 3941(1) 28(1) 1 0(2) —2028(2) 9618(2) 4905(1) 30(1) 1 0(3) —2641(2) 8579(1) 5657(1) 28(1) 1 0(4) -2366(2) 7256(1) 5357(1) 28(1) 1 015) -149312) 6903(1) 4353(1) 27(1) 1 C(6) -783(2) 7927(1) 364311) 26(1) 1 017) 156(2) 7552(1) 2651(1) 28(1) 1 0(8) 1243(2) 8371(2) 1967(1) 33(1) 1 0(9) 1822(2) 8026(2) 976(1) 38(1) 1 0110) 1268(2) 6894(2) 503(1) 37(1) 1 0111) —324(2) 7457(2) -6712) 49(1) 1 0(12) 2579(2) 6137(2) -265(2) 50(1) 1 0(13) 1009(1) 5799(1) 1417(1) 36(1) 1 0114) 175(2) 6243(1) 2358(1) 29(1) 1 0115) —560(2) 5246(1) 3045(1) 33(1) 1 0116) —134312) 5552(1) 4033(1) 31(1) 1 0117) -601(1) 1031011) 318311) 3511) 1 0118) -1288(2) 1173512) 3293(2) 43(1) 1 0119) —3583(2) 899112) 668911) 3011) 1 0120) -463812) 1030012) 665511) 3411) 1 0121) -552912) 1072512) 7601(1) 38(1) 1 0122) -5379(2) 9845(2) 859711) 4211) 1 0123) -432012) 854912) 865311) 4211) 1 0124) ~3426(2) 8122(2) 771111) 3611) 1 0125) -2876(l) 615311) 6080(1) 3211) 1 C(26) —442412) 5963(1) 6046(1) 3011) 1 0127) -5368(1) 665411) 539611) 4111) 1 C(28) ~472512) 4803(2) 6918(1) 4311) 1 U(eq) is defined as one third of the trace of the Table A.1.3. Bond lengths [A] and angles [deg] for 184 C(li-O(l7) C(1)-C(2) C(1)-C(6) C(2l-C(3) C(3)-C(4) C(3)-C(l9l C(4)-O(25) C(4)-C(5) C(5)-C(l6) C(5)-C(6) C(6)-C(7) C(7)-C(l4) C(7)-C(8) C(8)-C(9I C(9l-C110) C(10)-O(l3) C(10)-C(ll) C(10)-C(12) 0(13)-C(14) C(14)-C(15) C(15)-C116) O(l7)-C(18) C(19)-C(20) C(l9l-C(24) C(20)-C(21) C(21)-C(22) C(22)-C(23) C(23i-C(24) O(25)-C(26) C(26)-O(27) C(26)-C(28) O(l7)-C(1)-C(2) O(l7)—C(l)-C(6) C(2)-C(1)-C(6) C(ll-C(2)-C(3) C(4I-CI3l-CIZI C(4)-C(3)-C(l9) C(2l-CI3)-C(l9) C(3l-CI4)-O(25) C(3)-C(4)-C(5) O(25)-C(4)-C(5) C(l6)-C(5)-C(4) C(16)—C(5)-C(6) C(4)-C(5)-C(6) C(5)-C(6)-C(l) C(5)-C(6)-C(7) CIl)-C(6)-C(7) C(14)-C(7)-C(6) C(l4I-CI7l-C(8) 253 F’F‘P’F‘FtP‘P‘F‘F‘F‘F’F’P‘F‘F’F‘P’k‘h‘h‘k’k’F’P‘F’H’P‘P’H‘P‘H 122 115 121 121 124 118 123 117. 115. .3699(15) .3723(l9) .4282I18) .4211(l9) .3737(19) .4900119) .4107(15) .4223(l8) .4203(18) .4244(18) .4382(18) .3861(18) .47l4(l9) .328(2) .504(2) .4669(17) .522I2) .525(2) .3706Il6) .4048(19) .365(2) .4217I18) .397(2) .4034Il9) .389(2) .383I2) .388(2) .387(2) .3599(l6) .2011(l7) .48912) .78(12) .46(ll) .72(12) .90(13) 116. .23(12) .75(12) 120. 122. 116. 121. 119. 119. 116. 119. .73(12) 98(12) 37(11) 88(12) 66(11) 06(12) 32(12) 61(12) 61(12) 54(12) 89(12) 86(12) C(6)-C(7)-C(8) C(9)-C(8)-C(7) C(8)-C(9)-C(10) O(l3)-C(lO)-C(9) O(l3)-C(lO)-C(ll) C(9)-C(10)-C(ll) O(l3)—C(lO)-C(12) C(9)-C(lO)-C(12) C(ll)-C(10)-C(12) C(14)-O(l3)-C(10) 0(13)-C(14)-C(7) 0(13)-C(14)-C(15) C(7)~C(14)-C(15) C(l6)-C(lS)-C(l4) C(15)-C(l6)-C(5) C(1)-O(l7)-C(18) C(20)-C(l9)-C(24) C(20)-C(19)-C(3) C(24)-C(19)-C(3) C(21)-C(20)-C(19) C(22)-C(21)-C(20) C(21)-C(22)-C(23) C(24)-C(23)-C(22) C(23)-C(24)-C(l9) C(26)-O(25)-C(4) O(27)-C(26)-O(25) O(27)-C(26)-C(28) O(25)-C(26)-C(28) 125 119 108 111 112 111 122 115 120 120 117. .23(13) .43(12) .33(13) 121. 119. 119. .33(15) .49(15) 118 119 122 120 120 118. 123. 127. 109 .94(l2) .44113) 120. 90(13) .31112) 108. .47(13) 104. 68(13) 16(13) .45I14) .41(l4) 116. 58(10) .24(12) .48(12) 122. 12(12) .29(12) .43(12) 11(11) 09(14) 88115) 97(15) 92110) 18(12) 10(13) .73(12) 254 Symmetry transformations used to generate equivalent atoms: Table A.1.4. Anisotropic displacement parameters (A2 x 103) for 184 U11 U22 U33 U23 U13 U12 C(l) 33(1) 26(1) 28(1) -2(1) -1(1) -12(1) C(2) 36(1) 28(1) 29(1) -5(1) -2(1) -11(1) C(3) 28(1) 32(1) 25(1) -1(1) —4(1) -8(1) C(4) 27(1) 28(1) 27(1) 4(1) -4(1) -10(1) C(5) 26(1) 25(1) 29(1) 1(1) —6(1) -7(1) C(6) 28(1) 26(1) 27(1) -1(1) -5(1) -8(1) C(7) 28(1) 26(1) 29(1) -2(1) -3(1) -5(1) C(8) 33(1) 31(1) 37(1) -4(1) 2(1) -10(1) C(9) 39(1) 37(1) 38(1) -4(1) 9(1) -12(1) C(10) 40(1) 35(1) 33(1) -5(1) 5(1) -7(1) C(11) 51(1) 55(1) 38(1) -5(1) -6(1) —7(1) C(12) 53(1) 53(1) 44(1) -l7(l) 14(1) -10(1) 0(13) 42(1) 30(1) 34(1) -9(1) 4(1) -6(1) C(14) 28(1) 28(1) 31(1) -4(1) -2(1) -4(1) C(15) 37(1) 23(1) 40(1) -5(1) -3(1) -7(1) C(16) 33(1) 24(1) 36(1) 1(1) -3(1) -9(1) 0(17) 49(1) 24(1) 34(1) -4(1) 10(1) —l4(1) C(18) 64(1) 24(1) 39(1) -2(1) 6(1) -11(1) C(19) 30(1) 36(1) 27(1) —3(1) —2(1) -11(1) C(20) 35(1) 39(1) 28(1) -2(1) -5(1) -9(1) C(21) 33(1) 45(1) 37(1) -9(1) -2(1) -4(1) C(22) 38(1) 58(1) 32(1) —10(1) 2(1) -11(1) C(23) 46(1) 52(1) 27(1) 0(1) —2(1) -14(1) C(24) 36(1) 40(1) 30(1) -l(1) -4(1) -9(1) C(25) 31(1) 32(1) 31(1) 6(1) -3(1) -11(1) C(26) 29(1) 30(1) 31(1) -4(1) 2(1) -7(1) C(27) 32(1) 41(1) 46(1) 5(1) -8(1) -8(1) C(28) 43(1) 46(1) 41(1) 7(1) -2(1) -20(1) The anisotropic displacement factor exponent takes the form: -2pi2[h2a*2U11+...+2hka*b*U12] 255 Table A.1.5. Hydrogen coordinates ( x 10‘), isotropic displacement parameters (A2 x 103), and occupancies for 184 x y z U(eq) Occ. H(2) -2241(18) 10577(17) 5101(12) 36 l H(8) 1629(19) 9134(16) 2281(13) 40 1 H(9) 2620(20) 8450(17) 507(14) 46 l H(llA) -680(30) 6710(20) -385(17) 73 l H(llB) -l80(30) 8230(20) -674(l7) 73 1 H(llC) -1230(30) 7880(20) 469(17) 73 l H(12A) 2180(30) 5360(20) —530(17) 75 1 H(lZB) 3610(30) 5710(20) 160(18) 75 1 H(12C) 2910(30) 6740(20) —902(18) 75 1 H(lS) -443(l9) 4279(17) 2810(12) 40 1 H(16) -l831(19) 4884(17) 4502(13) 37 l H(18A) -910(20) 12250(20) 2630(16) 64 l H(lBB) —890(20) 12020(20) 3967(17) 64 1 H(18C) —2490(30) 11930(20) 3284(16) 64 1 H(20) —4775(l9) 10926(17) 5971(13) 41 l H(21) -6260(20) 11652(l8) 7532(13) 46 1 H(22) —6000(20) 10135(18) 9285(14) 51 1 H(23) -4220(20) 7910(18) 9382(15) 50 l H(24) -2670(20) 7216(18) 7756(13) 43 1 H(28A) -4050(30) 4650(20) 7462(17) 65 1 H(28B) —4420(20) 3950(20) 6632(16) 65 1 H(28C) -5810(30) 4730(20) 7012(15) 65 l 256 Figure A.2 ORTEP Diagram of Compound 299 c one 23. u C .3 . . . 0N. .- one As. 5‘ . o .. 5.” .2.... o: .- «Us. 28. 98:6 0:». .4521 e as. me. .49» 94./3:2 8.... .5P___.o§ .8. c . .2 I". Z S. I o .1111. one .4. pt 8. 2: 29 .———.u“ . ‘W 28.4 c ’1 29 1.. away 98. vomvcoae .II. I c 221 >8» 1 28. ‘ 257 Table A.2.1 Crystal data and structure refinement for 299 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected / unique Completeness to theta = 28.29 Refinement method Data / restraints / parameters Goodness—of—fit on F2 Final R indices [I>2sigma(I)] (all data) R indices Largest diff. peak and hole 258 —13<=h<=13, 299 C26 H28 06 436.48 173(2) K 0.71073 A Monoclinic P2(1)/c a = 10.132(2) A b = 8.0145(16) A c = 28.714(6) A alpha = 90 deg. beta = 97.58(3) deg. gamma = 90 deg. 2311.4(8) A3 4 1.254 Mg/m3 0.089 mm-l 928 0.4 x 0.4 X 0.3 mm 1.43 to 28.29 deg. —10<=k<=10, -37<=l<=38 26866 / 5615 [R(int) = 0.0275] 97.9% Full—matrix least-squares on F2 5615 / 0 / 389 1.004 R1 = 0.0446, wR2 = 0.1315 R1 = 0.0640, wR2 = 0.1419 0.284 and —O.232 e.A-3 Table A.2.2 Atomic coordinates ( x 10‘), equivalent isotropic displacement parameters (A2 x 103), and occupancies for 299 x y z U(eq) Occ. C(1) 6995(1) 7033(2) —11(1) 35(1) 1 C(2) 5837(1) 7216(2) 200(1) 30(1) 1 C(3) 5956(1) 7376(2) 690(1) 27(1) 1 C(4) 7174(1) 7429(2) 973(1) 28(1) 1 C(5) 8324(1) 7276(2) 759(1) 33(1) 1 C(6) 8227(1) 7069(2) 275(1) 36(1) 1 C(7) 6939(2) 6776(3) —534(1) 47(1) 1 C(8) 4486(2) 7264(2) -89(1) 40(1) 1 0(9) 9331(1) 6892(2) 45(1) 54(1) 1 C(10) 10595l2) 6986(4) 323(1) 65(1) 1 0(11) 4772(1) 7379(1) 899(1) 31(1) 1 C(12) 4385(1) 8837(2) 1075(1) 33(1) 1 0(13) 4983(1) 10113(1) 1052(1) 47(1) 1 C(14) 3147(2) 8609(3) 1297(1) 64(1) 1 C(15) 7309(1) 7713(2) 1492(1) 26(1) 1 C(16) 6951(1) 6496(2) 1806(1) 28(1) 1 C(17) 7135(1) 6840(2) 2288(1) 29(1) 1 C(18) 7742(1) 8315(2) 2470(1) 30(1) 1 C(19) 8107(1) 9521(2) 2160(1) 29(1) 1 C(20) 7849(1) 9194(2) 1679(1) 27(1) 1 C(21) 7982(2) 8575(2) 2998(1) 39(1) 1 C(22) 8965(2) 10006(2) 3137(1) 54(1) 1 C(23) 8631(2) 11526(2) 2837(1) 52(1) 1 C(24) 8759(2) 11157(2) 2329(1) 40(1) 1 C(25) 6435(1) 4909(2) 1636(1) 32(1) 1 C(26) 6034(2) 3589(2) 1491(1) 40(1) 1 0(27) 6742(1) 5670(1) 2596(1) 38(1) 1 C(28) 5341(2) 5715(3) 2620(1) 48(1) 1 0(29) 8013(1) 10496(1) 1363(1) 31(1) 1 C(30) 9240(1) 10822(2) 1249(1) 37(1) 1 0(31) 10217(1) 10041(2) 1396(1) 49(1) 1 C(32) 9159(2) 12269(3) 919(1) 64(1) 1 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 259 Table A.2.3. Bond lengths [A] and angles [deg] for 299 C(1)-C(2) C(1)-C(6) C(1)-C(7) C(2)-C(3) C(2)-C(8) C(3)-C(4) C(3)-C(11) C(4)-C(5) C(4)-C(15) C(5)-C(6) C(6)-0(9) 0(9)-C(10) O(ll)-C(12) C(12)-0(13) C(12)-C(14) C(15)-C(20) C(15)-C(16) C(16)-C(17) C(16)-C(25) C(17)-C(27) C(17)-C(18) C(18)-C(19) C(18)-C(21) C(19)-C(20) C(19)-C(24) C(20)-C(29) C(21)-C(22) C(22)-C(23) C(23)-C(24) C(25)-C(26) C(27)-C(28) O(29)-C(30) C(30)-C(31) C(30)-C(32) C(2)-C(1)-C(6) C(2)—C(1)-C(7) C(6)-C(1)-C(7) C(1)-C(2)-C(3) C(1)-C(2)-C(8) C(3)—C(2)—C(8) C(4)-C(3)-C(2) C(4)-C(3)-O(1l) C(2)-C(3l-OIll) C(3)-C(4)-C(5) C(3)-C(4i-C(15) C(5)-C(4)-C(15) C(6)—C(5)-C(4) 0(9)-C(6)-C(5) O(9)-C(6)-C(l) C(5)-C(6)-C(l) 260 FtF’F’H‘F‘F‘F‘F‘P’F’PtktktkthtktktkthtkthtPththtF'h‘k'k’k'h‘k‘h‘k‘k‘ 118. 121. 119. 118. 121. 120. .97(12) .43(11) .49(1l) .99(12) 123. .77(11) 119. .39(13) .72(12) .89(12) 122 119 117 117 118 122 115 121 .398(2) .401(2) .509(2) .4002(18) .5047(19) .3863(18) .4097(15) .3940(l9) .4944(17) .3899(19) .3791(l7) .419(2) .3522(16) .1952(18) .491(2) .3855(18) .4077(18) .4005(18) .4358(18) .3831(16) .4013(19) .3967(19) .5190(18) .3963(18) .5192(19) .4059(16) .537(2) .505(3) .512(2) .189(2) .431(2) .3526(17) .1999(l9) .493(2) 51(12) 54(13) 95(13) 65(12) 17(13) 18(12) 19(11) 94(12) C(6)-O(9)—C(10) C(12)-O(ll)-C(3) 0(13)-C(12)-O(11) 0(13)-C(12)-C(14) C(11)—C(12)-C(l4) C(20)-C(15)-C(16) C(20)-C(15)-C(4) C(16)-C(15)-C(4) C(17)-C(16)-C(15) C(17)-C(16)-C(25) C(15)-C(16)-C(25) O(27)-C(17)-C(l6) O(27)-C(17)-C(18) C(16)-C(17)-C(18) C(19)-C(18)-C(17) C(19)-C(18)-C(21) C(17)-C(18)-C(21) C(18)-C(19)-C(20) C(18)-C(19)-C(24) C(20)-C(19)-C(24) C(15)-C(20)-C(19) C(15)-C(20)-O(29) C(19)-C(20)-O(29) C(18)-C(21)-C(22) C(23)-C(22)—C(21) C(22)-C(23)-C(24) C(23)-C(24)-C(19) C(26)—C(25)-C(16) C(17)-O(27)-C(28) C(30)-O(29)-C(20) O(31)-C(30)-O(29) O(31)-C(30)-C(32) O(29)—C(30)-C(32) 116. 117. 122. 126. 110. 117. 119. 122. 119. 120. 120. 119. 118. 121. 119. 121. 119. 118. 122. 119. 123. 117. 118. 111. 111. 110. 112. 178. 112. 119. 123. 127. 109. 98(12) 80(10) 96(12) 17(14) 87(14) 86(11) 76(11) 34(11) 03(11) 30(12) 65(11) 16(12) 87(12) 93(12) 10(12) 41(12) 49(12) 06(12) 31(12) 64(12) 84(12) 41(11) 41(11) 99(13) 51(14) 69(15) 84(14) 43(16) 58(11) 35(10) 80(14) 01(15) 19(14) 261 Symmetry transformations used to generate equivalent atoms: Table A.2.4. Anisotropic displacement parameters (A2 x 103) for 299 Ull U22 U33 U23 U13 U12 C(l) 35(1) 41(1) 29(1) -3(1) 2(1) 6(1) C(2) 29(1) 29(1) 31(1) -l(l) 1(1) 1(1) C(3) 26(1) 24(1) 32(1) -2(1) 6(1) 0(1) C(4) 30(1) 26(1) 27(1) -3(1) 4(1) 1(1) C(S) 27(1) 42(1) 30(1) -4(1) 2(1) 4(1) C(6) 29(1) 51(1) 31(1) -4(1) 7(1) 8(1) C(7) 41(1) 72(1) 28(1) -3(1) 2(1) 14(1) C(8) 32(1) 52(1) 35(1) 0(1) -2(1) -1(1) C(9) 31(1) 102(1) 31(1) -6(1) 8(1) 14(1) C(10) 30(1) 123(2) 43(1) -3(1) 9(1) 12(1) C(11) 27(1) 31(1) 35(1) -1(1) 7(1) -4(1) C(12) 26(1) 41(1) 32(1) -6(1) 1(1) 3(1) C(13) 37(1) 32(1) 72(1) -9(1) 9(1) 3(1) C(14) 36(1) 98(2) 61(1) -29(1) 21(1) -12(1) C(15) 23(1) 30(1) 27(1) -3(1) 4(1) 3(1) C(16) 26(1) 27(1) 30(1) -2(1) 2(1) 3(1) C(17) 26(1) 31(1) 30(1) 2(1) 4(1) 4(1) C(18) 24(1) 35(1) 29(1) -6(1) 2(1) 5(1) C(19) 24(1) 31(1) 33(1) -6(1) 2(1) 2(1) C(20) 22(1) 28(1) 31(1) -1(1) 4(1) 2(1) C(21) 41(1) 49(1) 28(1) -7(1) 2(1) 4(1) C(22) 58(1) 63(1) 37(1) -17(1) —4(1) -5(1) C(23) 64(1) 50(1) 43(1) -l9(l) 8(1) -l3(1) C(24) 41(1) 39(1) 40(1) —11(1) 2(1) —7(1) C(25) 36(1) 30(1) 30(1) 1(1) 4(1) 2(1) C(26) 50(1) 28(1) 39(1) -2(1) 2(1) -2(1) 0(27) 40(1) 41(1) 32(1) 8(1) 4(1) -1(1) C(28) 43(1) 60(1) 44(1) 6(1) 13(1) —6(1) C(29) 28(1) 29(1) 36(1) 1(1) 5(1) —2(1) C(30) 32(1) 46(1) 35(1) -4(1) 8(1) -7(1) C(31) 29(1) 65(1) 54(1) 1(1) 10(1) —l(1) C(32) 54(1) 78(2) 59(1) 25(1) 12(1) -14(1) The anisotropic displacement factor exponent takes the form: —2 pi2 [if a*2'U11 + ... + 2 h k a* b* U12 ] 262 Table A.2.5. Hydrogen coordinates ( x 10‘), isotropic displacement parameters (A2 x 103), and occupancies for 299 x y z U(eq) Occ. H(S) 9182(17) 7298(19) 955(6) 37(4) 1 H(7A) 6520(30) 7580(40) -681(10) 99(9) 1 H(7B) 7790(20) 6410(30) -613(8) 73(6) 1 H(7C) 6250(30) 5950(40) -664(10) 112(9) 1 H(8A) 4340(20) 8210(30) -311(10) 93(8) 1 H(8B) 4400(20) 6370(30) -317(9) 79(7) 1 H(8C) 3700(30) 7260(30) 86(10) 102(9) 1 H(lOA) 11190(20) 6760(30) 112(8) 73(6) 1 H(lOB) 10700(20) 8170(30) 412(8) 61(6) 1 H(lOC) 10760(20) 6030(30) 588(9) 79(7) 1 H(14A) 2871 7464 1268 95 1 H(14B) 2456 9310 1141 95 l H(14C) 3317 8907 1623 95 1 H(21A) 8330(17) 7500(20) 3148(6) 42(4) 1 H(21B) 7110(20) 8850(20) 3113(7) 58(5) 1 H(22A) 8920(20) 10240(30) 3495(7) 64(6) 1 H(22B) 9950(20) 9700(30) 3075(8) 76(7) 1 H(23A) 7620(20) 11810(30) 2882(8) 70(6) 1 H(23B) 9170(20) 12540(30) 2946(7) 63(6) 1 H(24A) 9712(19) 11130(20) 2287(6) 47(5) 1 H(24B) 8340(20) 12120(30) 2130(7) 58(5) 1 H(26) 5775(18) 2550(20) 1375(7) 48(5) 1 H(28A) 4820(20) 5640(30) 2290(9) 81(7) 1 H(28B) 5120(20) 4840(30) 2828(7) 61(6) 1 H(28C) 5100(30) 6740(40) 2738(11) 105(9) 1 H(32A) 9990(30) 12510(30) 833(9) 88(8) 1 H(BZB) 8470(30) 12220(40) 686(12) 119(11) 1 H(32C) 8750(40) 13270(50) 1066(13) 142(13) 1 263 Reference: 1. 2. 10. 11. 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