PALLADIUM(II)-CATALYZED OXIDATIVE FUNCTIONALIZATION OF C-H BONDS USING ALKYNE AS BUILDING BLOCK PENG SHI-YONG （B. Sc. Nankai University） A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2014 Declaration I hereby declare that this thesis is my original work and it has been written by me in its entirety, under the supervision of Dr. Wang Jian, Chemistry Department, National University of Singapore, between Aug. 2010 and Aug. 2014. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. The content of the thesis has been published in: 1) S. Y. Peng, T. Gao, S. F. Sun, Y. H. Peng, M. H. Wu, H. B. Guo, J. Wang*, Adv. Synth. Catal. 2014, 356, 319. 2) S. Y. Peng, L. Wang, J. Wang*, Chem. Eur. J. 2013, 19, 13322. 3) S. Y. Peng, L. Wang, J. Y. Huang, S. F. Sun, H. B. Guo, J. Wang*, Adv. Synth. Catal. 2013, 355, 2550. 4) S. Y. Peng, L. Wang, H. B. Guo, S, F. Sun, J. Wang*, Org. Biomol. Chem. 2012, 10, 2537. 5) S. Y. Peng, L. Wang, J. Wang*, Org. Biomol. Chem. 2012, 10, 225. Name Signature I Date Acknowledgements It is my great pleasure to take this opportunity to express my gratitude and thanks to all the people who have helped and encouraged me during my Ph.D. studies. Nothing in this thesis would have been possible without each and every one of you. Thank you! First and foremost, I want to express my deepest respect and most sincere gratitude to my supervisor, Prof. Dr. Wang Jian, for offering me the great opportunity to be his Ph.D. student and guiding me to the intriguing and challenging field of palladium chemistry. Dr. Wang is a great supervisor to me. He has great passion and enthusiasm for chemistry, even when it did not want to cooperate. I would like to thank him for supporting me, teaching me and guiding me within the chemistry community, and thanks for encouraging me in my ambitions. His broad knowledge, enthusiasm, inspiration and dedication to science will with no doubt benefit me through all my life. His believing in me as a chemist gives me the confidence to go forward to further pursue my research career. Next, I wish to express my warm and sincere thanks to my senior, Dr. Wang Lei, who has helped me enormously with my research projects in National University of Singapore. Our extensive discussion has been very helpful for me to understand what the problem was and how to solve it. This thesis would be impossible without his generous help. Besides, I also want to give my great appreciation to another senior, Miss Ren Qiao, for her valuable advice and friendly help, although we have focused II on different research fields. I would like to thank all my lab mates in Dr. Wang’s lab, past and present, our postdoctors: Dr. Gao Yao-Jun, Dr. Xue Fei and Dr. Li Wen-Jun, our Masters: Huang Yuan, Wang Peng-Cheng, Lu Xian, Xiao Dan and Xue Cheng-Wen, our lovely and active Honours: Ng Hui-Fen, Siaw Woon-Yew etc., whose effective collaboration, helpful discussion and friendship have greatly helped me during my four years’ life and studies. I also want to thank the research scholarship provided by National University of Singapore. In addition, I want to extend my gratitude to all the laboratory staff of our chemistry department, particularly Madam Tan Geok-Kheng and Madam Hong Yi-Mian for X-ray crystallography analysis, Madam Han Yan-Hui and Dr. Wu Ji- En for NMR training and testing, Madam Wong Lai-Kwai and Madam Liu Qi-Ping for mass analysis. Thanks also go to the administrative and technical staff, especially Madam Suriawati Binte Sa’Ad in our department administrative office, Mr. Lee Yoon-Kuang, Mr. Phua Wei-De Victor and Mr. Soffiyan Bin Hamzah in our lab supply store. I would also like to express my sincere thanks to all my friends in Singapore for their help during the past four years. I will definitely miss and treasure their friendships. Finally, my deepest gratitude goes to my family for their unflagging love and support throughout my life. THANK YOU! III Table of Contents Declaration I Acknowledge ments . II Table of Contents .IV Summary .IX List of Tables XI List of Figures XIII List of Schemes XIV List of Abbreviations XIX List of Publications XXIII Chapter Introduction 1.1 Transition-Metal-Catalyzed C-H Bond Functionalization 1.2 Traditional Pd(0)-Catalyzed Cross-Coupling Reactions 1.3 Modern Pd-Catalyzed C-H Functionalization Reactions 12 1.3.1 C-H Bond Functionalization via Pd(0)/Pd(II) Catalysis . 13 1.3.2 C-H Bond Functionalization via Pd(II)/Pd(IV) Catalysis . 15 1.3.3 C-H Bond Functionalization via Pd(0)/Pd(II)/Pd(IV) Catalysis . 18 1.3.4 C-H Bond Functionalization via Pd(II)/Pd(0) Catalysis . 20 1.4 Pd-Catalyzed Alkyne Transformation via C-H Functionalization 27 1.4.1 Pd-Catalyzed Alkynylation Reactions 28 1.4.2 Pd-Catalyzed Alkyne Cycloaromatization Reactions . 39 1.5 Project Objectives . 49 IV Chapter Palladium-Catalyzed [2+2+1] Oxidative Annulation of 4-Hydroxycoumarins with Unactivated Internal Alkynes: Access to Spiro Cyclopentadiene-chroman-2,4-dione Complexes 52 2.1 Introduction . 53 2.2 Results and Discussion . 54 2.3 Conclusion 60 2.4 Experimental Section 61 2.4.1 General Information 61 2.4.2 Preparation and Characterization of Compounds 2-3 . 62 2.4.3 Preparation and Characterization of Compounds 2-4 . 74 2.4.4 Preparation and Characterization of Compound 2-5 79 2.4.5 Preparation and Characterization of Compound 2-6 80 2.4.6 X-ray Crystallographic Analysis . 80 Chapter Palladium-Catalyzed Oxidative Annulation via C–H/N–H Functionalization: Access to Substituted Pyrroles 84 3.1 Introduction . 85 3.2 Results and Discussion . 87 3.3 Conclusion 93 3.4 Experimental Section 94 3.4.1 General Information 94 3.4.2 Preparation and Characterization of Compounds 3-3 . 95 3.4.3 Preparation and Characterization of Compound 3-4 110 V 3.4.4 Preparation and Characterization of Compound 3-5 110 3.4.5 X-ray Crystallographic Analysis . 111 Chapter Direct Access to Highly Substituted 1-Naphthols through Palladium-Catalyzed Oxidative Annulation of Benzoylacetates and Inte rnal Alkynes 115 4.1 Introduction . 116 4.2 Results and Discussion . 118 4.2.1 Reaction Optimization 118 4.2.2 Substrate Scope . 119 4.2.3 Competition Experiments . 122 4.2.4 Synthetic Transformations 123 4.2.5 Mechanistic Investigation . 126 4.3 Conclusion 127 4.4 Experimental Section 128 4.4.1 General information 128 4.4.2 Preparation and Characterization of Compounds 4-3 . 129 4.4.3 Intermolecular Competition Experiments . 148 4.4.4. Kinetic Study . 150 4.4.5 Large Scale Application 151 4.4.6 Preparation and Characterization of Compound 4-4 152 4.4.7 Preparation and Characterization of Compound 4-5 153 4.4.8 Preparation and Characterization of Compound 4-6 154 VI 4.4.9 Preparation and Characterization of Compound 4-7 155 4.4.10 Preparation and Characterization of Compound 4-8 156 4.4.11 Preparation and Characterization of Compound 4-9 157 4.4.12 Preparation and Characterization of Compound 4-10 158 4.4.13 Preparation and Characterization of Compound 4-11 159 4.4.14 Preparation and Characterization of Compound 4-12 160 4.4.15 Preparation and Characterization of Compound 4-13 161 4.4.16 X-ray Crystallographic Analysis . 162 Chapter Iron-catalyze d Ene-type Propargylation of Diarylethylenes with Propargyl Alcohols . 164 5.1 Introduction . 165 5.2 Results and Discussion . 166 5.3 Conclusion 172 5.4 Experimental Section 172 5.4.1 General Information 172 5.4.2 Preparation and Characterization of Compounds 5-3 . 173 5.4.3 X-ray Crystallographic Analysis . 187 Chapter Facile Synthesis of 4-Substituted 3,4-Dihydrocoumarins via an Organocatalytic Double Decarboxylation Process 189 6.1 Introduction . 190 6.2 Results and Discussion . 192 6.3 Conclusion 198 VII 6.4 Experimental Section 198 6.4.1 General Information 198 6.4.2 Preparation and Characterization of Compounds 6-3 . 199 References . 208 H NMR and 13 C NMR Spectra of Major Compounds………………………….228 VIII Summary One of the over-arching goals of the research in Dr. Wang’s lab is to develop methodologies for the regioselective and diverse functionalization of C–H bonds. The Pd(II)-catalyzed C-H activation/functionalization organic transformations have become a practical and powerful tool in organic chemistry. This thesis describes my efforts during my Ph.D. research for Pd(II)-catalyzed C–H functionalization reactions that result in the formation of many biologically and pharmaceutically important molecules utilizing alkyne as a universal building block. Chapter gave a brief introduction of transition metal catalysis, followed by a general evaluation of the research progress of Pd-chemistry, particularly Pd- mediated alkyne transformations, which were elucidated with selected examples. Chapter described an efficient synthesis of an interesting spiro cyclopentadiene-chroman-2,4-dione heterocycles. The method employed a direct Pd(II)-catalyzed oxidative [2+2+1] cycloaddition of readily available starting materials: 4-hydroxycoumarins and unactivated internal alkynes. Various substituents were well tolerated in the reaction, which led to a number of unique molecular structures. Chapter developed an efficient synthesis of highly substituted pyrroles. The method utilized simple and readily available enamines and alkynes, and employed direct Pd(II)-catalyzed oxidative annulation procedure. A mechanistic investigation of pyrrole- forming reaction established a viable catalytic cycle. The mild nature of the reaction and the significance of the pyrrole scaffold as structural element should renIX 210 200 190 10.0 180 9.5 OH 170 9.0 8.5 160 150 8.0 140 7.5 130 7.0 6.5 120 242 6.0 110 5.5 (ppm) 100 5.0 90 4.5 80 4.0 70 3.5 60 29.4300 29.2769 29.1166 28.9636 28.8105 28.6575 28.5045 10.5 62.7187 11.0 115.9311 11.5 152.2440 139.7316 139.5130 137.9025 132.8086 131.5115 130.0321 127.4451 127.4087 126.3739 126.2063 126.1334 124.6905 124.6322 121.7172 205.2742 1.9998 4.0028 5.9982 1.9868 0.9985 1.0000 Integral OH OH Ph Ph 4-6 (d-Acetone) (ppm) 3.0 50 2.5 40 2.0 30 1.5 20 1.0 10 0.5 OH Ph Ph 4-6 (d-Acetone) 2.0853 2.0538 2.0500 2.0450 4.7732 8.3675 8.3511 7.4963 7.4938 7.4837 7.4800 7.4661 7.4636 7.3942 7.3778 7.3753 7.3652 7.3488 7.3325 7.2076 7.1938 7.1786 7.1761 7.1597 7.1509 7.1358 7.1320 7.1169 7.0828 7.0803 7.0765 7.0740 7.0664 7.0639 7.0601 210 200 9.5 190 180 2.0042 8.5 8.0 170 160 7.5 150 7.0 140 130 6.5 6.0 120 243 5.5 110 (ppm) 100 5.0 4.5 90 4.0 80 3.5 70 60 3.0 50 2.5 40 1.0076 1.0081 1.0016 0.9964 1.0046 0.9996 1.0008 4.9898 3.4177 2.0032 3.9976 1.0000 9.0 30 25.1719 10.0 30.5208 10.5 77.5608 77.4151 77.1600 76.9049 149.5163 142.1925 140.2103 139.6419 139.5763 132.3181 131.7789 131.6477 131.0793 130.3432 130.2704 128.6744 127.8801 127.7125 127.6688 127.6542 127.4210 126.6631 126.3716 126.2769 126.1239 126.0364 125.2421 124.6591 121.6786 114.6390 Integral Ph O Ph Ph 4-7 (CDCl3) (ppm) 2.0 1.5 Ph O Ph Ph 4-7 (CDCl3) 20 1.0 0.5 10 2.8147 2.8021 2.7932 2.7806 2.7680 2.7579 2.7466 2.5247 2.5184 2.5146 2.5083 2.4907 2.4844 2.4806 2.4743 2.3053 2.2990 2.2940 2.2877 2.2839 2.2776 2.2726 2.2663 2.2612 2.1566 2.1465 2.1351 2.1250 2.1187 2.1137 2.1087 2.1036 2.0986 2.0872 2.0759 2.0683 5.3008 5.2832 5.2781 7.5235 7.5058 7.4970 7.4781 7.4642 7.4478 7.4012 7.3924 7.3861 7.3810 7.3785 7.3747 7.3634 7.2600 7.2537 7.2499 7.2449 7.2348 7.2209 7.1818 7.1768 7.1680 7.1629 7.1503 7.1440 7.1402 7.0595 7.0558 7.0520 7.0469 7.0432 7.0003 6.9889 6.9864 210 200 190 180 8.5 170 8.0 160 7.5 150 7.0 140 6.5 130 6.0 120 244 5.5 110 5.0 (ppm) 100 4.5 90 4.0 80 3.5 70 52.3101 9.0 77.4151 77.1600 76.9050 9.5 85.0960 10.0 98.4537 10.5 140.0063 138.7529 138.1335 136.6177 135.6266 132.7627 132.1651 131.9028 131.1449 130.3068 128.9004 128.6016 127.8291 127.7198 127.4939 127.3481 127.1149 126.9838 126.8818 123.1798 118.3410 169.2287 2.9972 6.9858 3.5372 3.0024 0.9951 3.9990 1.0000 Integral Ph CO2Me Ph Ph 4-8 (CDCl3) (ppm) 3.0 60 2.5 50 2.0 40 1.5 30 1.0 20 0.5 Ph CO2Me Ph Ph 4-8 (CDCl3) 10 3.6241 8.5838 8.5674 7.6496 7.6407 7.6357 7.6256 7.6218 7.6054 7.5891 7.4932 7.4907 7.4794 7.4768 7.4617 7.3987 7.3873 7.3848 7.3785 7.2487 7.2323 7.2285 7.2146 7.1327 7.1276 7.1201 7.1075 210 200 190 180 8.5 170 8.0 160 7.5 150 7.0 140 6.5 130 6.0 120 245 5.5 110 5.0 (ppm) 100 4.5 90 4.0 80 3.5 70 60 3.0 50 14.4230 9.0 52.1206 9.5 60.9164 10.0 77.4151 77.1600 76.9049 10.5 141.3472 140.3998 138.7674 138.1845 135.6703 132.8720 132.4857 131.0720 130.3214 130.2995 129.9935 127.8218 127.6906 127.4939 127.4064 127.1222 127.0785 126.9546 126.2988 125.3077 169.3380 166.1971 3.0076 2.9919 2.0059 0.9964 7.0075 3.3349 1.0030 1.9967 0.9952 1.0000 Integral CO2Et CO2Me Ph Ph 4-9 (CDCl3) (ppm) 2.5 40 2.0 30 1.5 20 1.0 10 0.5 CO2Et CO2Me Ph Ph 4-9 (CDCl3) 1.3875 1.3724 1.3585 3.4740 4.3414 4.3275 4.3124 4.2985 8.3467 8.3140 8.1501 8.1337 7.6168 7.6004 7.5941 7.5777 7.5638 7.4831 7.4680 7.4529 7.2600 7.2474 7.2323 7.2272 7.2134 7.1453 7.1314 7.1251 7.1163 7.1049 7.0999 7.0885 6.3951 6.3636 210 200 9.5 190 9.0 180 8.5 170 8.0 160 7.5 150 7.0 140 6.5 130 6.0 120 246 5.5 110 5.0 (ppm) 100 4.5 90 4.0 80 70 52.1424 10.0 77.4078 77.1600 76.9049 10.5 140.2395 139.9990 138.5197 137.1642 134.0161 131.8809 131.1740 130.3724 130.0299 129.9133 128.8712 128.1643 127.7417 127.2242 127.1004 126.8526 126.6048 126.3643 169.1704 3.0073 2.0007 4.9969 3.2985 0.9972 2.0038 1.0002 1.0000 Integral CO2Me Ph Ph 4-10 (CDCl3) (ppm) 3.5 60 3.0 50 2.5 40 2.0 30 1.5 CO2Me Ph Ph 4-10 (CDCl3) 20 1.0 0.5 10 3.6064 8.4123 8.0000 7.9849 7.9824 7.5613 7.5487 7.5437 7.5336 7.4895 7.4768 7.4731 7.4592 7.2650 7.2600 7.2512 7.2373 7.2310 7.2234 7.2184 7.1617 7.1478 7.1339 7.1276 7.1238 7.1188 7.1125 7.1087 7.0961 7.0608 7.0570 7.0444 210 10.0 200 9.5 190 9.0 180 8.5 170 8.0 160 7.5 150 7.0 140 6.5 130 6.0 120 247 5.5 (ppm) 110 (ppm) 5.0 100 4.5 90 4.0 80 3.5 70 51.3139 10.5 77.3080 77.0529 76.7979 169.2090 139.2652 139.0612 138.5292 135.5341 135.4685 135.4321 133.9163 133.3479 133.0782 132.7066 132.0289 131.3730 131.1908 130.5204 130.2143 128.4580 128.4216 128.0645 127.8240 127.6783 127.3139 127.2629 127.1026 127.0006 126.8913 126.8694 126.6508 126.4030 126.1844 125.8783 125.1787 3.0007 14.361 2.0048 2.0048 1.0000 1.9976 Integral CO2Me Ph Ph 4-11 (CDCl3) 3.0 60 2.5 50 2.0 40 1.5 30 1.0 20 0.5 CO2Me Ph Ph 4-11 (CDCl3) 10 2.9559 7.9698 7.9660 7.9547 7.9484 7.9307 7.7025 7.6849 7.6017 7.5878 7.5727 7.5613 7.5197 7.5033 7.4920 7.4781 7.4315 7.4289 7.4189 7.4151 7.4012 7.3987 7.3836 7.3684 7.3533 7.3382 7.3293 7.3230 7.3142 7.3041 7.3016 7.2903 7.2764 7.2739 7.2600 7.2222 7.2083 7.1755 7.1364 7.1238 7.1175 7.1150 7.1024 210 200 9.5 190 9.0 180 8.5 170 8.0 160 7.5 150 7.0 140 6.5 130 6.0 120 5.5 110 248 5.0 (ppm) 100 4.5 90 4.0 80 70 51.6105 10.0 77.4151 77.1600 76.9122 10.5 139.2921 138.8549 138.6290 137.9804 137.0549 135.3424 133.1125 132.9667 131.5530 131.3125 130.4817 130.4234 128.1716 127.9020 127.8145 127.3554 127.1878 127.0785 127.0421 126.9255 126.7797 126.4226 169.5493 2.9966 7.0063 2.9987 7.0121 1.0043 1.0000 Integral Ph CO2Me Ph Ph 4-12 (CDCl3) (ppm) 3.5 60 3.0 50 2.5 40 2.0 30 1.5 Ph CO2Me Ph Ph 4-12 (CDCl3) 20 1.0 0.5 10 3.1992 7.7164 7.7113 7.7076 7.7038 7.6975 7.6685 7.6622 7.6571 7.6533 7.6496 7.5147 7.5058 7.4882 7.4806 7.4743 7.4630 7.4542 7.4478 7.4415 7.4340 7.3029 7.2890 7.2751 7.2600 7.2461 7.2146 7.2108 7.1982 7.1818 7.1680 7.1528 7.1364 7.1314 7.1188 210 200 190 180 170 8.0 160 7.5 150 7.0 140 6.5 130 6.0 120 249 5.5 110 5.0 (ppm) 100 4.5 90 4.0 80 3.5 70 3.0 60 2.5 50 40 30.3386 8.5 2.0 30 23.1023 9.0 39.2365 9.5 51.6396 10.0 77.4151 77.1600 76.9049 10.5 139.7658 138.8185 137.7254 135.5464 134.6719 133.3748 133.2072 131.4145 131.3708 130.4234 127.8145 127.7125 127.2461 126.7579 126.6923 126.5830 126.1093 125.1692 170.6497 8.1765 8.1602 7.6004 7.5827 7.5651 7.5487 7.5336 7.4340 7.4176 7.4025 7.2600 7.2449 7.2310 7.2171 7.2070 7.1932 7.1402 7.1251 7.1125 7.0936 7.0873 7.0797 5.9894 1.0046 1.0257 1.0131 2.2637 2.2499 2.2373 2.2234 2.2095 2.1969 2.1830 1.5918 3.4223 4-13 (CDCl3) 3.0857 3.0706 Ph 2.9933 Ph 2.0018 7.0038 3.0030 0.9978 1.0010 0.9981 1.0000 Integral CO2Me (ppm) 1.5 1.0 20 0.5 CO2Me Ph Ph 4-13 (CDCl3) 10 190 8.8 180 8.4 170 8.0 160 7.6 150 7.2 6.8 140 6.4 130 6.0 120 5.6 5.2 110 250 4.8 100 (ppm) 4.4 90 4.0 80 3.6 70 37.0494 9.2 77.4291 77.0000 76.5782 71.7707 9.6 84.3530 142.0861 141.5770 139.9697 139.0460 129.8311 128.6092 128.5074 128.1365 128.0492 127.5983 127.5256 127.2783 126.9437 1.0004 1.0030 1.0000 15.703 Integral 2.4066 2.4055 2.3984 4.5448 4.5366 4.5109 4.5027 6.1764 6.1429 7.4594 7.4370 7.4315 7.4118 7.3964 7.3909 7.3679 7.3504 7.3411 7.3345 7.3274 7.3203 7.3137 7.3088 7.3016 7.2655 7.2600 7.2463 7.2293 7.2200 Chapter Ph Ph 5-3aa (CDCl3) (ppm) 3.2 2.8 60 2.4 50 2.0 40 1.6 30 1.2 0.8 20 0.4 10 0.0 Ph Ph 5-3aa (CDCl3) 190 180 8.4 170 8.0 160 7.6 150 7.2 6.8 140 6.4 130 6.0 120 5.6 5.2 110 251 4.8 100 (ppm) 4.4 90 4.0 80 37.8567 8.8 77.4218 77.0000 76.5782 9.2 83.9530 9.6 89.7496 141.7152 140.6315 139.1551 131.7003 129.9329 128.5874 128.4929 128.4565 128.1947 128.1365 127.8965 127.5401 127.4601 127.3946 126.8564 123.5763 1.0013 1.0000 20.683 Integral Ph Ph 5-3au (CDCl3) (ppm) 3.6 70 3.2 2.8 60 2.4 50 2.0 40 1.6 30 1.2 0.8 20 0.4 10 0.0 Ph Ph 5-3au (CDCl3) 4.6270 4.5931 6.1254 6.0914 7.3729 7.3586 7.3471 7.3405 7.3219 7.3131 7.3077 7.2973 7.2901 7.2600 7.2540 7.2364 7.2326 7.2091 7.2041 7.1833 7.1778 7.1729 7.1625 7.1548 7.1439 7.1362 7.1258 210 200 190 O 180 170 7.2 160 6.8 150 6.4 140 6.0 130 5.6 5.2 120 4.8 110 252 4.4 (ppm) 100 4.0 90 3.6 80 3.2 70 2.8 60 2.4 50 34.2844 31.8698 7.6 47.3176 8.0 77.4351 77.0060 76.5842 8.4 117.2912 8.8 134.3609 129.7062 129.2844 129.0226 127.6116 126.8625 124.6878 124.4551 9.2 6.9986 4.0112 1.0000 1.9985 O 151.2998 9.6 167.1913 194.9742 Integral 3.7492 3.7322 3.7246 3.7081 3.6906 3.6846 3.6670 3.0047 2.9817 2.9718 2.9461 2.9231 2.9088 2.9050 2.8940 7.4730 7.4636 7.4505 7.4423 7.4209 7.4154 7.4122 7.4001 7.3464 7.3420 7.3218 7.3157 7.2993 7.2872 7.2818 7.2615 7.2560 7.1985 7.1941 7.1738 7.1695 7.1486 7.1404 7.1371 7.1136 7.1103 Chapter O O S 6-3bb (CDCl3) (ppm) 2.0 1.6 40 1.2 30 0.8 O S 6-3bb (CDCl3) O 20 0.4 0.0 10 210 200 190 8.0 O 180 7.6 170 7.2 160 6.8 150 6.4 140 6.0 130 5.6 5.2 120 4.8 110 253 4.4 (ppm) 100 4.0 90 3.6 80 3.2 70 2.8 60 2.4 2.0 50 40 34.5244 31.5716 8.4 38.9755 8.8 77.4060 76.9842 76.5624 9.2 129.4444 129.0880 127.5680 126.0624 124.7315 124.6006 121.3059 117.3494 9.6 151.3434 150.2015 169.3441 167.2786 4.0497 1.0000 9.0391 Integral O O O O 6-3ib (CDCl3) (ppm) 1.6 1.2 30 0.8 O O 6-3ib (CDCl3) O 20 0.4 0.0 10 3.7700 3.7525 3.7454 3.7284 3.7114 3.7043 3.6868 2.9970 2.9839 2.9784 2.9685 2.9356 2.9126 2.8880 7.4330 7.4149 7.4105 7.4056 7.3935 7.3875 7.3787 7.3721 7.3634 7.3535 7.3519 7.3480 7.3398 7.3343 7.3031 7.2987 7.2954 7.2746 7.2681 7.2538 7.2500 7.2461 7.2220 7.2182 7.1974 7.1935 7.1722 7.1678 7.1629 7.1601 7.1355 7.1311 7.0911 7.0862 7.0818 7.0747 7.0610 7.0571 7.0538 190 180 O 170 9.6 160 9.2 150 8.8 8.4 140 8.0 130 7.6 7.2 120 41.3174 40.7137 40.4301 40.1537 39.8773 39.6010 39.3173 39.0409 34.2480 33.2225 31.5425 24.3058 10.0 119.6549 116.8912 10.4 128.7971 128.2225 126.7679 126.3679 124.6878 10.8 136.9719 11.2 143.7358 11.6 151.4380 168.6313 168.0640 6.8 110 6.4 254 6.0 100 (ppm) 5.6 90 5.2 80 4.8 4.4 70 4.0 60 3.6 50 3.2 2.8 40 5.9954 4.0148 1.0372 0.9960 4.0445 2.0031 1.9919 1.0000 Integral O O H N 6-3jb (CDCl3) O (ppm) 2.4 30 2.0 1.6 20 1.2 10 0.8 0.4 O H N 6-3jb (CDCl3) O 3.0803 3.0595 3.0266 3.0058 2.8666 2.8436 2.8206 2.7938 2.7784 2.7395 2.7247 2.6902 2.6650 2.6409 2.6135 2.5872 2.5626 2.5379 2.5144 2.5083 2.5023 2.4963 2.4903 1.1765 1.1535 3.6479 3.6243 3.6040 3.5882 3.5646 7.4560 7.4280 7.3333 7.3272 7.3218 7.3081 7.3015 7.2955 7.2757 7.2703 7.1645 7.1508 7.1470 7.1360 7.1262 7.1223 7.1021 7.0769 9.8627 210 200 O 190 180 170 160 6.8 150 6.4 140 6.0 130 5.6 120 5.2 110 255 4.8 (ppm) 100 4.4 90 4.0 80 70 2.0332 1.0461 1.9965 2.0799 2.0030 1.0000 1.9951 2.0110 3.6 3.2 2.8 60 2.4 50 40 30.3900 7.2 34.6458 7.6 42.8222 8.0 77.2551 77.0000 76.7449 8.4 117.1316 8.8 136.3046 133.5354 128.6748 127.9606 127.8513 125.7962 124.6594 9.2 151.4114 9.6 167.8954 196.7752 Integral O O O 6-3kb (CDCl3) (ppm) 2.0 1.6 30 1.2 20 0.8 10 0.4 O O 6-3kb (CDCl3) 3.8049 3.7973 3.7935 3.7847 3.7822 3.7784 3.7708 3.7582 3.2426 3.2300 3.2060 3.1947 3.1783 3.1632 3.1430 3.1279 2.8669 2.8543 2.8341 2.8228 2.8064 2.7988 2.7749 2.7660 7.8216 7.8190 7.8052 7.8027 7.4950 7.4925 7.4900 7.4774 7.4660 7.4635 7.3715 7.3551 7.3437 7.3400 7.2240 7.2202 7.2088 7.2051 7.2000 7.1962 7.1836 7.1811 7.1685 7.1660 7.0336 7.0185 7.0059 7.0034 6.9945 6.9781 210 200 190 O 180 8.0 7.6 170 7.2 160 6.8 150 6.4 140 6.0 130 5.6 120 5.2 110 256 4.8 (ppm) 100 4.4 90 4.0 80 3.6 70 3.2 2.8 60 2.4 50 2.0 40 30 22.9369 8.4 34.1667 32.2575 8.8 77.3080 77.0529 76.7979 9.2 130.0030 127.3577 125.1933 122.3367 117.6800 116.7035 9.6 151.1946 166.0463 1.9833 2.0223 1.0000 1.0012 0.9986 0.9954 1.0000 Integral O O CN 6-3lb (CDCl3) (ppm) 1.6 1.2 20 0.8 10 0.4 O CN 6-3lb (CDCl3) 3.4803 3.4665 3.4551 3.4438 3.4299 3.0265 3.0139 2.9937 2.9823 2.9256 2.9155 2.8928 2.8827 2.8764 2.6861 2.6709 7.3823 7.3798 7.3646 7.3508 7.3483 7.3142 7.3117 7.2991 7.2600 7.2197 7.2171 7.2045 7.1894 7.1238 7.1075 210 200 190 180 O 170 7.2 160 6.8 150 6.4 140 6.0 130 5.6 5.2 120 4.8 110 257 4.4 (ppm) 100 4.0 90 3.6 80 3.2 70 2.8 60 2.4 2.0 50 40 37.1254 34.1813 7.6 41.1189 8.0 77.3371 77.0821 76.8270 8.4 117.3594 8.8 130.2070 129.0265 127.8896 124.7779 124.5374 123.8160 9.2 147.0263 145.5032 9.6 151.2821 167.4601 1.9914 1.0606 1.0327 1.0000 1.0078 1.9965 2.0121 0.9962 1.9984 Integral O O O 2N 6-3mb (CDCl3) (ppm) 1.6 1.2 30 0.8 O O 2N 6-3mb (CDCl3) 20 0.4 0.0 10 3.2539 3.2476 3.2388 3.2325 3.2275 3.2212 3.2123 3.2060 2.9678 2.9526 2.9413 2.9262 2.8719 2.8556 2.8455 2.8291 2.7799 2.7686 2.7484 2.7370 2.7093 2.7030 2.6778 2.6702 8.0762 8.0598 7.2378 7.2353 7.2215 7.2076 7.2038 7.1950 7.1496 7.1332 7.0210 7.0046 6.9945 6.9794 6.9643 6.8407 6.8281 [...]... reactions Scheme 1.9 C- H bond cleavage of electron-rich heterocycles via Pd(0)/Pd(II) catalysis Scheme 1.10 C- H bond activation of non-heterocycles via Pd(0)/Pd(II) catalysis Scheme 1.11 Pd(0)/Pd(II) catalytic cycle Scheme 1.12 ortho-Methylation of anilide via Pd(II)/Pd(IV) catalytic cycle Scheme 1.13 X-ray structures of Pd(IV) complexes Scheme 1.14 Pd(II)/Pd(IV) catalytic cycle Scheme 1.15 C- H bond arylation... 1.3 C- H bond functionalization by catalytic transition metal complexes Scheme 1.4 ‘Inner-sphere’ mechanism of C- H activation Scheme 1.5 ‘Outer-sphere’ mechanism of C- H activation Scheme 1.6 Gaunt’s iterative Cu -catalyzed arylation methodology of anilines Scheme 1.7 Yu’s end-on-template-directed meta-selective C- H functionalizaiton Scheme 1.8 Mechanisms for Pd(0) -catalyzed cross-coupling reactions Scheme... use of stoichiometric amount of transition metal complex.[5] The reaction mechanism of such C- H bond cleavage reactions has been elucidated by a large number of review articles.[5,6] Scheme 1.2 C- H bond functionalization of azobenzene by stoichiometric transition metal complex Cp2 Ni N N Cp2Ni N N NiCp H Transition- metal -catalyzed functionalization of C- H bonds appeared in the early 1990s (Scheme... olefins in the presence of a Ru-catalyst (Scheme 1. 3c) .[9] Since these discoveries, the chemistry of transition- metal -catalyzed functionalization of C- H bonds in organic synthesis has rapidly expanded Scheme 1.3 C- H bond functionalization by catalytic transition metal complexes 2 Cp2Zr a) Me Me N N H Me Me N Me H2 , DCM b) O O N H R N Ru3(CO)12 CO(150 psi ) 150 oC c) H R N R O O R1 R [RuH2(CO)(PPh3)3] Toluene,... show high selectivity for weaker C- H bonds, such as benzylic, allylic and adjacent to a heteroatom, because of the radical and/or cationic intermediate Scheme 1.5 ‘Outer-sphere’ mechanism of C- H activation a) Direct Insertion H X R = [M] X [M] H R = [M] X H R b) H Atom Extraction Radical Rebound H H X R [M] X [M] R It should be noted that there are other different classifications of transition- metal -catalyzed. .. C H Bond Functionalization R H H In 1963, Kleiman and Dubeck reported C- H bond cleavage of azobenzene by 1 stoichiometric transition metal complex Cp2 Ni (Scheme 1.2).[4] Although the reaction mechanism for this metalation reaction has not been elucidated, the ortho -C- H bond was apparently cleaved After this pioneering study, many research groups have reported about the cleavage of C- H bonds via the... (hetero)aromatic compounds formation via Pd(II) -catalyzed oxidative annulation of alkynes Scheme 1.53 Initial try for Fe -catalyzed and metal-free reactions Scheme 2.1 Pd -catalyzed cascade reactions of 4-hydroxycoumarins with internal alkynes Scheme 2.2 Cyclic ketone as substrate Scheme 2.3 Plausible mechanism Scheme 2.4 Plausible mechanism Scheme 2.5 Transformations of compound 2-4aa Scheme 3.1 Transition-... metal -catalyzed pyrrole synthesis Scheme 3.2 Initial try Scheme 3.3 Substrate scope of N-protected 4-aminocoumarin and β-enaminones Scheme 3.4 Synthetic transformations of compound 3-3aa Scheme 3.5 Plausible mechanism Scheme 4.1 Challenges in the synthesis of 1-naphthols Scheme 4.2 Competition experiments Scheme 4.3 Synthetic transformations of compound 4-3aa Scheme 4.4 Synthetic transformations of compound... cycloaromatization of alkynes Scheme 1.44 Benzene formation via Pd(II) -catalyzed oxidative cycloaromatization of alkynes and alkenes Scheme 1.45 Naphthalene formation via Pd(II) -catalyzed oxidative cycloaromatization of alkynes Scheme 1.46 PAHs via Pd(II) -catalyzed oxidative cycloaromatization of alkynes Scheme 1.47 Traditional Pd(0) -catalyzed heterocarbocycle formation Scheme 1.48 Indole synthesis via Pd(II) -catalyzed. .. unactivated internal alkynes as building blocks to synthesize biologically and pharmaceutically important molecules via Pd -catalyzed C- H functionalization strategies So, the next section will give a brief summary of Pd-chemistry, including traditional Pd -catalyzed crossing-coupling reactions and modern Pd -catalyzed C- H functionalization/ C- C coupling reactions, and then put an emphasis on recent Pd-catalyzed . end-on-template-directed meta-selective C- H functionalizaiton Scheme 1.8 Mechanisms for Pd(0) -catalyzed cross-coupling reactions Scheme 1.9 C- H bond cleavage of electron-rich heterocycles via Pd(0)/Pd(II) catalysis. reactions Scheme 2.1 Pd -catalyzed cascade reactions of 4-hydroxycoumarins with internal alkynes Scheme 2.2 Cyclic ketone as substrate Scheme 2.3 Plausible mechanism Scheme 2.4 Plausible mechanism. cycle Scheme 1.13 X-ray structures of Pd(IV) complexes Scheme 1.14 Pd(II)/Pd(IV) catalytic cycle Scheme 1.15 C- H bond arylation via Pd(II)/Pd(IV) catalytic cycle Scheme 1.16 C- H bond activation