PART 1: COMBINATORIAL SYNTHESIS OF N-HETEROCYCLES PART 2: DEVELOPMENT OF A POLYMER-SUPPORTED HANTZSCH ESTER HE RONGJUN (B.Sc., HUBEI UNIVERSITY) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2007 Acknowledgements I would like to express my heartfelt gratitude to my supervisor, Dr. Lam Yulin, for her invaluable guidance, continuous flow of ideas, source of inspiration and warm-hearted care during my studies. Although extremely busy with her schedule, she is always available for helpful discussion and encouragement. I am thankful to Dr. Patrick H Toy, Department of Chemistry at University of Hong Kong, for his stimulating suggestions on part of my thesis. I am also grateful to Assoc. Prof. Go Mei Lin for allowing me to use her microwave reactor. Special thanks go to the following people for their gracious help and warm friendship: - all my lab partners: Che Jun, Ching Shi Min, Fang Zhanxiong, Fu Han, Gao Yongnian, Kong Kah Hoe, and Makam Shantha Kumar Raghavendra. Without them, the research life could not be so enjoyable and fulfilling. - Many teachers and my friends in Department of Chemistry at NUS who provided help and support during this time. - Staff from the NMR, MS, Chromatography laboratories and lab supplies who with cheerfulness and patience helped me greatly in the analyses and purchasing of chemicals. Acknowledgement is also recorded for the Research Scholarship provided by the National University of Singapore for the period of August 2003 to April 2007. Lastly, I could not have done this project without the sustaining love and encouragement from my girlfriend Nguyen Thi Thuy Linh and my family members. i Table of Contents Acknowledgements i Table of Contents ii Summary xiii List of Tables xv List of Figures and Schemes xvi List of Abbreviations xix List of Publications xxiii Part 1: Combinatorial Synthesis of N-Heterocycles Chapter Introduction 1.1 Combinatorial solid-phase synthesis 1.1.1 Solid supports in combinatorial solid-phase synthesis 1.1.1.1 Polystyrene 1.1.1.2 Tentagel 1.1.1.3 Polyamide 1.1.1.4 Poly(acrylic amide-ethylene glycol) copolymers 1.1.1.5 Inorganic materials 1.1.2 Linkers in combinatorial solid-phase synthesis 1.1.2.1 Acid-labile linkers 1.1.2.2 Nucleophile-labile linkers 1.1.2.3 Photo-labile linkers 1.1.2.4 Safety-catch linkers ii 1.1.2.5 Traceless linkers 10 1.1.2.6 Other linkers 11 1.1.3 Analytical methods in solid-phase synthesis 12 1.1.3.1 FTIR method 12 1.1.3.2 Gel-phase NMR 13 1.1.3.3 High-resolution magic angle spinning (HR-MAS) NMR 13 1.1.3.4 Spectrophotometric methods 13 1.2 Combinatorial solution-phase synthesis 14 1.2.1 Combinatorial solution-phase pool synthesis 14 1.2.2 Combinatorial solution-phase parallel synthesis 15 1.3 Objectives of our studies 15 1.4 References 17 Chapter Combinatorial Solid-Phase Synthesis of Xanthines 2.1 Introduction 20 2.1.1 Importance of xanthines 20 2.1.2 General methods for solution-phase synthesis of xanthines 21 2.1.3 Objectives and scope of this study 22 2.2 Results and discussion 2.2.1 Solid-phase synthesis of 1,3-substituted xanthines 2.2.1.1 Solution-phase synthesis of 1,3-substituted xanthines 2.2.1.1.1 Synthesis of ethyl N-(2,4-dimethoxybenzyl) glycinate 23 23 23 23 (2-1-8) iii 2.2.1.1.2 Synthesis of ethyl 5-amino-3-(2,4-dimethoxybenzyl)-3H- 24 imidazole-4-carboxylate (2-1-10) 2.2.1.1.3 Synthesis of ethyl 3-(2,4-dimethoxybenzyl)-5- 25 (3-phenylureido)-3H-imidazole-4-carboxylate (2-1-11) 2.2.1.1.4 Synthesis of 7-(2,4-dimethoxybenzyl)-1-phenylxanthine 25 (2-1-12) 2.2.1.1.5 Synthesis of 7-(2,4-dimethoxybenzyl)-1-phenyl-3- 26 substitutedxanthine (2-1-13) 2.2.1.1.6 Synthesis of 3-methyl-1-phenylxanthine (2-1-7b) 26 2.2.1.2 Solid-phase synthesis of 1,3-substituted xanthines 27 2.2.2 Traceless solid-phase synthesis of substituted xanthines 31 2.2.2.1 Solution-phase synthesis of substituted xanthines 31 2.2.2.1.1 Synthesis of benzyl N-butyl glycinate (2-2-10) 31 2.2.2.1.2 Synthesis of benzyl 2-(N-butyl-N'-cyanoformamidino) 32 acetate (2-2-11) 2.2.2.1.3 Synthesis of benzyl 2-(N-butyl-N'-cyanoacetamidino) 33 acetate (2-2-11a) and benzyl 2-(N-butyl-N'cyanobenzamidino)acetate (2-2-11b) 2.2.2.1.4 Synthesis of benzyl 5-amino-3-butyl-3H-imidazole- 34 4-carboxylate (2-2-12) iv 2.2.2.1.5 Synthesis of benzyl 3-butyl-5-(3-hexylureido)-3H- 34 imidazole-4-carboxylate (2-2-13) and 7-butyl-1-hexylxanthine (2-2-7a) 2.2.2.2 Traceless solid-phase synthesis of substituted xanthines 35 2.3 Conclusion 37 2.4 Experimental 37 2.4.1 Solid-phase synthesis of 1,3-substituted xanthines 37 2.4.1.1 Synthesis of ethyl N-(2,4-dimethoxybenzyl) glycinate (2-1-8) 37 2.4.1.2 Synthesis of ethyl 5-amino-3-(2,4-dimethoxybenzyl)-3H- 38 imidazole-4-carboxylate (2-1-10) 2.4.1.3 Synthesis of ethyl 3-(2,4-dimethoxybenzyl)-5-(3-phenylureido) 39 -3H-imidazole-4-carboxylate (2-1-11) 2.4.1.4 Synthesis of 7-(2,4-dimethoxybenzyl)-1-phenylxanthine 39 (2-1-12) 2.4.1.5 Synthesis of 7-(2,4-dimethoxybenzyl)-3-methyl- 40 1-phenylxanthine (2-1-13) 2.4.1.6 Synthesis of 3-methyl-1-phenylxanthine (2-1-7b) 40 2.4.1.7 Preparation of ethyl N-(2-methoxy-4-phenoxybenzyl) glycinate 41 resin (2-1-2) 2.4.1.8 Preparation of ethyl 4-amino-1-(2-methoxy-4-phenoxybenzyl)- 41 imidazole-5-carboxylate resin (2-1-3) v 2.4.1.9 Preparation of ethyl 4-(3-substitutedureido)-1-(2-methoxy-4- 42 phenoxybenzyl)-imidazole-5-carboxylate resin (2-1-4) 2.4.1.10 Preparation of 1-substituted-7-(2-methoxy-4-phenoxybenzyl) 42 xanthine resin (2-1-5) 2.4.1.11 Preparation of 1,3-substituted-7-(2-methoxy-4-phenoxy 42 benzyl)xanthine resin (2-1-6) 2.4.1.12 Preparation of 1,3-substituted xanthine (2-1-7a - 2-1-7l) 42 2.4.1.13 Preparation of 1-substituted thioxanthine (2-1-7m - 2-1-7p) 43 2.4.2 Traceless solid-phase synthesis of substituted xanthines 46 2.4.2.1 Synthesis of benzyl bromoacetate (2-2-9) 46 2.4.2.2 Synthesis of benzyl N-butyl glycinate (2-2-10) 47 2.4.2.3 Synthesis of benzyl 2-(N-butyl-N'-cyanoformamidino)acetate 47 (2-2-11) 2.4.2.4 Synthesis of benzyl 5-amino-3-butyl-3H-imidazole-4- 48 carboxylate (2-2-12) 2.4.2.5 Synthesis of benzyl 3-butyl-5-(3-hexylureido)-3H-imidazole-4- 48 carboxylate (2-2-13) 2.4.2.6 Synthesis of 7-butyl-1-hexylxanthine (2-2-7a) 49 2.4.2.7 Preparation of benzyl bromoacetate resin (2-2-2) 50 2.4.2.8 Preparation of benzyl N-substituted glycinate resin (2-2-3) 50 2.4.2.9 Preparation of benzyl 2-(N-substituted-N'-cyanoformamidino) 50 acetate resin (2-2-4) vi 2.4.2.10 Preparation of benzyl 2-(N-substituted-N'-cyanoacetamidino) 50 acetate resin (2-2-4) (R2=CH3) 2.4.2.11 Preparation of benzyl 2-(N-substituted-N'-cyanobenzamidino) 51 acetate resin (2-2-4) (R2=Ph) 2.4.2.12 Preparation of benzyl 5-amino-(3-substituted)imidazole-4- 51 carboxylate resin (2-2-5) 2.4.2.13 Preparation of benzyl 5-(3-substitutedureido)-imidazole-4- 52 carboxylate (2-2-6) 2.4.2.14 Preparation of 1,7- or 1,7,8-substituted xanthines (2-2-7) 52 2.4.2.15 Preparation of 1,3,7- or 1,3,7,8-substituted xanthines (2-2-7) 52 2.5 References 59 Chapter Combinatorial Solution-Phase Synthesis of Polycyclic Guanines 3.1 Introduction 62 3.1.1 Importance of polycyclic guanines 62 3.1.2 General methods for solution-phase synthesis of polycyclic guanines 62 3.1.3 Objectives and scope of this study 63 3.2 Results and discussion 64 3.2.1 Synthesis of 2-thioxanthines (3-5) 64 3.2.2 Synthesis of 7-benzyl-2-(methylthio)-1-substituted-1H- 65 purin-6(7H)-one (3-6) 3.2.3 Synthesis of 7-benzyl-2-(methylsulfonyl)-1-substituted-1H- 65 purin-6(7H)-one (3-7) vii 3.2.4 Synthesis of 7-benzyl-2-(hydroxyalkylamino)-1-substituted-1H- 65 purin-6(7H)-one (3-8) 3.2.5 Synthesis of polycyclic guanines (3-9) 67 3.3 Conclusion 68 3.4 Experimental 68 3.4.1 Synthesis of ethyl N-benzyl glycinate (3-2) 69 3.4.2 Synthesis of ethyl 5-amino-3-benzyl-3H-imidazole-4-carboxylate 69 (3-3) 3.4.3 Synthesis of ethyl 3-benzyl-5-(3-alkylthioureido)-3H-imidazole-4- 70 carboxylate (3-4) 3.4.4 Synthesis of 2-thioxanthines (3-5) 71 3.4.5 Synthesis of 7-benzyl-2-methylthio-1-substituted-1H- 73 purin-6(7H)-one (3-6) 3.4.6 Synthesis of 7-benzyl-2-methylsulfonyl-1-substituted-1H- 74 purin-6(7H)-one (3-7) 3.4.7 Synthesis of 7-benzyl-2-hydroxyalkylamino-1-substituted-1H- 75 purin-6(7H)-one (3-8) 3.4.8 Synthesis of polycyclic guanines (3-9) 3.5 References 76 79 Chapter Microwave-Assisted Combinatorial Solid-Phase Synthesis of Pyrazolidine-3,5-diones 4.1 Introduction 81 viii 4.1.1 Importance of pyrazolidine-3,5-diones 81 4.1.2 General methods for solution-phase synthesis of 82 pyrazolidine-3,5-diones 4.1.3 General methods for solid-phase synthesis of pyrazolidine-3,5-diones 83 4.1.4 Objectives and scope of this study 84 4.2 Results and discussion 4.2.1 Solution-Phase synthesis of pyrazolidine-3,5-diones 85 85 4.2.1.1 Synthesis of benzyl 3-benzylidenecarbazate (4-9) 85 4.2.1.2 Synthesis of benzyl 3-benzylidene-2-methylcarbazate (4-10) 87 4.2.1.3 Synthesis of benzyl 3-benzyl-2-methylcarbazate (4-11) 88 4.2.1.4 Synthesis of benzyl 3-benzyl-3-ethoxycarbonylacetyl-2- 89 methylcarbazate (4-12) 4.2.1.5 Synthesis of 1-benzyl-4-ethoxycarbonyl-2-methyl 90 pyrazolidine-3,5-dione (4-7-2a) 4.2.1.6 Synthesis of 1-benzyl-2-methylpyrazolidine-3,5-dione (4-7-1a) 91 4.2.1.7 Synthesis of 1-benzyl-2,4-dimethyl-4-ethoxycarbonyl 91 pyrazolidine-3,5-dione (4-7-3a) 4.2.2 Solid-phase synthesis of pyrazolidine-3,5-diones 92 4.3 Conclusion 94 4.4 Experimental 95 4.4.1 Synthesis of benzyl 3-benzylidenecarbazate (4-9) 95 4.4.2 Synthesis of benzyl 3-benzylidene-2-methylcarbazate (4-10) 96 ix 220 210 200 190 11.0 180 10.0 170 160 9.0 150 140 8.0 13 130 120 110 51.7546 50.9093 49.5101 49.3425 49.1676 49.0000 48.8324 48.6575 48.4899 47.2073 46.2381 12.0 105.9436 13.0 149.8209 143.4153 137.9935 137.6729 129.8826 129.3652 128.9426 128.8187 128.4179 128.3159 156.3286 155.7310 7.0 100 90 6.0 80 5.0 70 1.9996 2.1640 5.0750 4.1143 4.0967 4.0778 3.9227 3.9038 3.8862 3.3138 3.3100 3.3075 3.3037 4.8657 5.4583 2.1813 7.9306 7.3582 7.3544 7.3393 7.3330 7.3279 7.3191 7.3153 7.3002 7.2977 7.2838 7.2763 7.2712 7.2611 7.2460 7.2233 7.2132 7.2094 7.2031 7.1943 2.0000 10.213 1.0071 Integral H NMR of 3-9f (ppm) 4.0 60 3.0 50 2.0 40 30 1.0 20 10 0.0 C NMR of 3-9f (ppm) -10 188 190 180 170 8.0 160 7.6 150 7.2 6.8 140 6.4 130 6.0 120 5.6 13 5.2 110 4.8 100 4.4 90 4.0 3.6 80 67.3775 8.4 77.4280 77.0000 76.5794 8.8 135.8342 133.6574 129.9383 128.5141 128.2706 128.2263 127.4958 127.2375 126.9128 9.2 145.0287 153.6697 9.6 1.9885 8.0007 2.0736 0.9781 1.0000 Integral 5.2461 7.3819 7.3703 7.3505 7.3424 7.3320 7.2600 7.8439 7.6663 7.6593 7.6477 7.6349 8.6738 H NMR of 4-9 (ppm) 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 0.8 20 0.4 10 0.0 C NMR of 4-9 (ppm) 189 190 180 170 8.0 160 7.6 150 7.2 6.8 140 6.4 130 6.0 120 5.6 13 5.2 110 4.8 100 4.4 90 4.0 3.6 80 3.2 70 2.8 60 36.8868 8.4 53.8146 8.8 67.1709 9.2 77.4280 77.0000 76.5794 9.6 137.0813 136.1663 128.8978 128.2189 128.0935 127.8352 127.6728 127.2153 156.4812 3.0195 2.0386 2.0000 10.016 Integral 3.0407 4.0215 5.2182 7.4689 7.4225 7.4086 7.3854 7.3738 7.3505 7.3285 7.3006 7.2600 H NMR of 4-11 (ppm) 2.4 50 2.0 1.6 40 1.2 30 0.8 20 0.4 10 0.0 C NMR of 4-11 (ppm) 190 190 180 170 160 7.6 150 7.2 6.8 140 6.4 130 6.0 5.6 13 120 5.2 110 4.8 100 4.4 90 4.0 3.6 80 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 0.8 20 10.9784 8.0 20.4238 8.4 36.5030 8.8 47.1291 44.7825 9.2 77.4280 77.0000 76.5794 9.6 134.6905 128.9716 128.3886 127.6212 167.8747 167.0334 3.0133 2.0000 1.9753 2.0186 2.0000 4.9971 Integral 1.4972 1.4728 1.4484 1.4240 1.3972 1.3728 0.7779 0.7535 0.7291 3.1724 3.4357 3.4113 3.3869 4.7402 7.3079 7.2884 7.2664 7.2494 7.1957 7.1884 7.1811 7.1713 H NMR of 4-7-1c (ppm) 0.4 10 0.0 C NMR of 4-7-1c (ppm) 191 190 180 170 160 7.6 7.2 150 6.8 140 6.4 130 6.0 5.6 13 120 5.2 110 4.8 100 4.4 90 4.0 3.6 80 3.2 70 2.8 2.4 2.0 1.6 60 50 40 1.2 30 15.0044 8.0 49.5101 49.3425 49.1749 49.0000 48.8324 48.6575 48.4899 47.8559 47.1854 8.4 60.5505 8.8 83.1633 9.2 118.2957 9.6 138.1903 133.8907 129.3580 128.9426 128.4325 171.5519 169.3001 3.0602 2.0056 2.0997 2.0306 2.0223 1.0000 5.0241 Integral 1.2790 1.2651 1.2500 3.3163 3.3125 3.3100 3.3062 3.3024 4.2467 4.2329 4.2190 4.2039 4.0841 4.0727 4.8481 4.7409 5.1242 5.0889 5.0574 5.0372 5.6814 5.6688 5.6600 5.6575 5.6487 5.6348 5.6260 5.6234 5.6146 5.6020 7.2057 7.1817 H NMR of 4-7-2b (ppm) 0.8 20 0.4 0.0 C NMR of 4-7-2b (ppm) 10 192 190 180 170 160 150 140 6.5 130 6.0 13 120 5.5 110 5.0 4.5 100 90 4.0 80 3.5 70 3.0 60 2.5 50 38.9751 7.0 46.6420 7.5 55.2831 8.0 77.4280 77.2066 77.0000 76.5794 8.5 114.4272 113.2097 9.0 125.4296 9.5 131.7019 130.6909 129.0380 128.4846 128.1451 161.7647 159.5804 3.7905 3.6187 2.0000 4.5485 4.4939 4.3407 4.2873 6.7597 6.7307 6.6599 6.6320 7.4341 7.4109 7.4005 7.3877 7.3819 7.3645 7.3401 7.3169 7.3088 7.3041 7.2821 7.2763 7.2600 5.9863 4.0407 7.9920 5.0408 Integral H NMR of 4-7-3e (ppm) 2.0 1.5 40 1.0 30 0.5 20 0.0 C NMR of 4-7-3e (ppm) 10 193 190 180 8.4 170 8.0 160 7.6 150 7.2 6.8 140 6.4 130 6.0 120 5.6 13 5.2 110 4.8 100 4.4 90 4.0 3.6 80 64.6989 8.8 77.4206 77.0000 76.5720 9.2 113.7041 9.6 127.0825 126.2413 140.3577 136.8083 136.4098 1.2053 2.0684 1.0315 1.0494 1.0000 4.1507 Integral 2.4735 4.4863 5.1572 5.1212 5.6668 5.6087 6.6522 6.6162 6.5942 6.5570 7.2848 7.2581 7.1746 7.1479 H NMR of 5-16 (ppm) 3.2 70 2.8 60 2.4 50 2.0 1.6 40 1.2 30 0.8 20 0.4 10 0.0 C NMR of 5-16 (ppm) 194 220 210 200 190 180 170 160 150 140 130 120 6.0 110 100 5.0 90 80 4.0 70 60 50 30.0463 13 7.0 49.9701 8.0 66.8020 9.0 77.4206 77.0000 76.5720 10.0 114.4272 11.0 128.5731 126.3667 12.0 137.7971 136.2180 134.6905 13.0 166.8490 200.1807 2.6459 1.7734 1.9798 1.1495 1.0245 1.0000 4.0557 Integral 2.2386 3.4899 5.2844 5.2484 5.1556 5.7859 5.7278 6.7539 6.7179 6.6947 6.6587 7.4167 7.3900 7.3273 7.3006 H NMR of 5-17 (ppm) 3.0 2.0 40 30 1.0 20 0.0 C NMR of 5-17 (ppm) 10 195 220 210 200 190 180 170 160 150 6.0 140 5.6 13 5.2 130 120 4.8 110 4.4 4.0 100 3.6 90 3.2 80 2.8 70 2.4 60 2.0 50 1.6 40 1.2 30 19.1029 18.8815 6.4 24.7923 6.8 50.9072 7.2 65.1195 7.6 77.4206 77.0000 76.5794 8.0 99.2482 98.9309 8.4 113.9328 8.8 127.9828 126.2118 9.2 140.9775 137.1403 136.3655 9.6 145.7076 145.1615 168.3543 167.6385 6.3420 1.9982 3.1962 2.0281 1.0584 1.1064 0.9912 4.1320 Integral 2.1655 3.3042 3.6768 5.2496 5.2136 5.1428 5.7626 5.7034 6.7423 6.7063 6.6843 6.6483 7.3958 7.3691 7.3238 7.2971 H NMR of 5-4 (ppm) 0.8 C NMR of 5-4 20 0.4 0.0 (ppm) 10 196 9.6 9.2 8.8 8.4 8.0 7.6 7.2 6.8 6.8 6.4 6.4 6.0 6.0 5.6 5.6 5.2 5.2 4.8 4.8 4.4 4.4 4.0 4.0 3.6 3.6 (ppm) H NMR of 5-19 2.8 2.4 3.2 2.8 2.4 18.019 3.2 2.0 1.6 1.2 1.2 0.9421 0.8945 1.6 1.1417 1.4180 2.0 1.5782 1.8173 1.9647 2.2108 7.2 2.7766 7.6 3.4725 8.0 1.6139 8.4 5.0871 8.8 6.5740 6.4788 9.2 7.0511 7.2600 9.6 2.0000 26.422 Integral 36.376 8.5830 4.1836 0.1063 0.9653 1.1591 1.4644 1.8718 2.2026 2.8828 3.3820 1.8953 3.0000 3.8799 3.7685 3.6745 5.1382 5.3134 6.6100 7.1091 7.2600 8.7504 0.8999 1.9330 2.2346 2.1907 54.141 0.5505 Integral H NMR of 5-18 0.8 0.8 0.4 0.0 (ppm) 0.4 0.0 197 9.6 9.2 8.8 8.4 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 33.088 7.2003 2.0 1.6 1.2 0.0750 0.9409 1.1347 1.4203 1.6269 1.8207 2.1899 2.9409 3.3541 0.7313 3.6489 1.5970 3.8683 4.5810 5.0999 5.2670 6.5740 6.4881 7.0662 7.2600 8.7957 3.0000 0.3747 0.2838 2.5936 0.9420 43.658 0.1039 Integral H NMR of 5-20 (ppm) 0.8 0.4 0.0 198 220 210 200 190 180 170 8.4 160 7.8 150 7.2 140 6.6 13 130 6.0 120 5.4 110 100 4.8 90 4.2 80 3.6 70 3.0 60 2.4 50 27.4272 9.0 44.0097 9.6 77.4291 77.0000 76.5782 10.2 123.3218 10.8 128.9656 11.4 148.2754 146.1226 200.2047 2.1846 2.2220 2.1757 2.1185 1.0000 Integral 3.0313 3.0066 2.9831 2.8549 2.8308 2.8094 2.8067 7.3401 7.3111 8.0447 8.0156 9.7693 H NMR of 5-21a (ppm) 1.8 40 1.2 30 0.6 20 0.0 C NMR of 5-21a (ppm) 10 199 190 180 170 160 7.0 150 140 6.5 130 6.0 5.5 13 120 110 5.0 4.5 100 90 4.0 80 3.5 70 48.2433 7.5 77.4206 77.0000 76.5794 8.0 112.8776 8.5 117.5781 9.0 129.1856 128.5584 127.4589 127.1637 9.5 139.3615 147.9804 1.0004 1.9921 10.000 Integral 3.6622 4.2065 6.6371 6.6128 6.5884 6.5315 6.5048 7.2709 7.2500 7.2291 7.2036 7.1873 7.1804 7.1711 7.1595 7.1455 7.0945 7.0689 7.0422 H NMR of 5-22a (ppm) 3.0 60 2.5 2.0 50 1.5 40 1.0 30 0.5 20 0.0 C NMR of 5-22a (ppm) 10 200 190 180 170 160 150 140 130 6.0 5.5 13 120 5.0 110 4.5 100 90 4.0 80 41.4618 6.5 77.4206 77.0000 76.5794 7.0 106.9890 7.5 113.2244 110.2949 8.0 118.0947 8.5 129.1930 9.0 141.8852 9.5 147.4712 152.6440 1.0496 2.0487 1.9329 3.0000 1.9569 0.9839 Integral 3.7313 4.3419 7.3935 7.3900 7.2600 7.2461 7.2217 7.2182 7.1938 6.8038 6.7795 6.7539 6.7249 6.7214 6.6959 6.3558 6.3500 6.3453 6.3395 6.2664 6.2583 H NMR of 5-22e (ppm) 3.5 70 3.0 60 2.5 2.0 50 1.5 40 1.0 30 0.5 20 0.0 C NMR of 5-22e (ppm) 10 201 220 210 200 190 180 170 160 150 140 130 120 110 100 40.3338 40.0608 39.7804 39.5000 39.2270 38.9466 38.6661 101.6548 113.7050 C NMR of 5-23 129.1570 150.8370 13 90 80 70 60 50 40 30 20 10 (ppm) 202 IR Spectrum of 5-18 IR Spectrum of 5-19 IR Spectrum of 5-20 203 [...]... and react A1B1C1 A1B2C1 A1B1C2 A1B2C2 A1B1C3 A1B2C3 A1B1C4 A1B2C4 A2B1C1 A2B2C1 A2B1C2 A2B2C2 A2B1C3 A2B2C3 A2B1C4 A2B2C4 A3B1C1 A3B2C1 A3B1C2 A3B2C2 A3B1C3 A3B2C3 A3B1C4 A3B2C4 A1B3C1 A1B4C1 A1B3C2 A1B4C2 A1B3C3 A1B4C3 A1B3C4 A1B4C4 A2B3C1 A2B4C1 A2B3C2 A2B4C2 A2B3C3 A2B4C3 A2B3C4 A2B4C4 A3B3C1 A3B4C1 A3B3C2 A3B4C2 A3B3C3 A3B4C3 A3B3C4 A3B4C4 A3B5C1 A1B5C2 A3B5C2 A1B5C3 A3B5C3 A1B5C4 A3B5C4 A1B5C1... Hantzsch ester 11 9 5 .2. 2 .1 Synthesis of 4-vinylbenzyl alcohol (5 -16 ) 11 9 5 .2. 2 .2 Synthesis of 4-vinylbenzyl acetoacetate (5 -17 ) 12 0 5 .2. 2.3 Synthesis of 3-(4-vinylbenzyl)-5-methyl -2, 6-dimethyl- 12 0 1, 4-dihydropyridine-3,5-dicarboxylate (5-4) 5 .2. 2.4 Synthesis of polymer 5 -18 12 0 5 .2. 2.5 Synthesis of polymer 5 -19 12 1 5 .2. 2.6 Synthesis of polymer 5 -20 12 2 5 .2. 3 Reductions of α,β-unsaturated aldehydes by polymer- supported. .. Polymer- Supported Hantzsch Ester 5 .1 Introduction 5 .1. 1 Soluble polymer- supported reagents and catalysts 11 2 11 2 5 .1. 1 .1 Soluble polymer supports 11 3 5 .1. 1 .2 Characterizations of soluble polymer- supported reagents 11 4 and catalysts 5 .1. 2 Hantzsch ester 11 4 5 .1. 3 Objectives and scope of this study 11 6 5 .2 Results and discussion 11 7 5 .2 .1 Design and synthesis of monomers 11 7 5 .2. 2 Synthesis of a polymer- supported Hantzsch. .. polymer- supported 12 3 Hantzsch ester 5 .2. 4 Reductive amination by polymer- supported Hantzsch ester 12 6 xi 5 .2. 5 Aromatization of benzoquinone by polymer- supported 12 8 Hantzsch ester 5.3 Conclusion 12 8 5.4 Experimental 12 8 5.4 .1 Synthesis of 4-vinylbenzyl alcohol (5 -16 ) 12 9 5.4 .2 Synthesis of 4-vinylbenzyl acetoacetate (5 -17 ) 12 9 5.4.3 Synthesis of monomer 5-4 13 0 5.4.4 Synthesis of polymer 5 -18 13 0 5.4.5 Synthesis. .. Xanthines 31 Scheme 2- 7 Synthesis of 2- 2 -10 31 Scheme 2- 8 Synthesis of 2- 2 - 12 32 Scheme 2- 9 Synthesis of 2- 2 -11 a 33 Scheme 2 -10 Synthesis of 2- 2 -11 b 34 Scheme 2 -11 Traceless Solution-Phase Synthesis of Substituted Xanthines 35 Scheme 3 -1 Synthesis of Polycyclic Guanines via 2- Chloropurine 63 Scheme 3 -2 Synthesis of Polycyclic Guanines via Thiomethyl Pyrimidine 63 Scheme 3-3 Combinatorial Solution-Phase Synthesis. .. deconvolution of bioactive compounds from assay data: iterative deconvolution,4 position scanning deconvolution7a and tagging.7b 2 Figure 1- 1 Mix-Split Synthesis A3 A1 Split and react A2 A1 A3 A2 Mix A1 A2 A3 B2 B1 B3 B5 B4 Split and react A1B1 A1B2 A1B3 A1B4 A1B5 A2B1 A2B2 A2B3 A2B4 A2B5 A3B1 A3B2 A3B3 A3B4 A3B5 Mix A1B1 A1B3 A2B1 A2B2 A2B3 A3B1 A3B2 A3B3 A1B4 A3B4 A2B5 A2B4 C1 A1B2 A1B5 A3B5 C2 C4... The polymer- supported Hantzsch ester was successfully applied for the reduction of α,β-unsaturated aldehydes, reductive amination between aldehydes and aniline and reduction of benzoquinones xiv List of Tables Table 2 -1 Synthesis of 2 -1- 8 24 Table 2- 2 Synthesis of 2 -1- 13 26 Table 2- 3 Synthesis of 2 -1- 7b 26 Table 2- 4 Synthesis of 2- 2 -11 a 33 Table 3 -1 Synthesis of 3-8a 67 Table 4 -1 Synthesis of 4 -10 88... Scheme 1- 6 Enzyme Promoted Cleavage in SPS 12 Scheme 2 -1 Synthesis of Xanthines via 5,6-Diamino Uracil 21 Scheme 2- 2 Synthesis of Xanthines via Imidazole 22 Scheme 2- 3 Derivatization of Xanthine Using a Solid-Support 22 Scheme 2- 4 Solution-Phase Synthesis of 1, 3-Substituted Xanthines 23 Scheme 2- 5 Solid-Phase Synthesis of 1, 3-Substituted Xanthines 27 Scheme 2- 6 Solution-Phase Synthesis of Substituted Xanthines... 4-ethoxycarbonyl -1, 2- substituted 10 1 pyrazolidine-3,5-dione (4-7 -2) 4.4 .14 Preparation of 4-cyano/(4-nitro)phenyl -1, 2- substituted 10 1 pyrazolidine-3,5-dione (4-7 -2) 4.4 .15 Preparation of 1, 2- substitutedpyrazolidine-3,5-dione (4-7 -1) 10 2 4.4 .16 Preparation of 1, 2, 4,4-substitutedpyrazolidine-3,5-dione (4-7-3) 10 2 4.5 References 11 0 x Part 2: Development of a Polymer- Supported Hantzsch Ester Chapter 5 Development of a Polymer- Supported. .. Solution-Phase Synthesis of 85 Pyrazolidine-3,5-diones Scheme 4-6 Synthesis of Benzyl Carbazate 87 Scheme 4-7 Microwave-Assisted SPS of Pyrazolidine-3,5-diones 92 Scheme 5 -1 Synthesis of Dihydropyridines and Hantzsch Ester 11 6 Scheme 5 -2 Synthesis of Monomer 5 -1 118 Scheme 5-3 Synthesis of a Polymer- Supported Hantzsch Ester 5 -18 via 11 9 Monomer 5-4 Scheme 5-4 Synthesis of a Polymer- Supported Hantzsch Ester . (2 -1- 11) 25 2. 2 .1. 1.4 Synthesis of 7- (2, 4-dimethoxybenzyl) -1- phenylxanthine (2 -1- 12) 25 2. 2 .1. 1.5 Synthesis of 7- (2, 4-dimethoxybenzyl) -1- phenyl-3- substitutedxanthine (2 -1- 13) 26 2. 2 .1. 1.6. reduction of benzoquinones. xv List of Tables Table 2 -1 Synthesis of 2 -1- 8 24 Table 2- 2 Synthesis of 2 -1- 13 26 Table 2- 3 Synthesis of 2 -1- 7b 26 Table 2- 4 Synthesis of 2- 2 -11 a 33 Table. 11 7 5 .2 .1 Design and synthesis of monomers 11 7 5 .2. 2 Synthesis of a polymer-supported Hantzsch ester 11 9 5 .2. 2 .1 Synthesis of 4-vinylbenzyl alcohol (5 -16 ) 11 9 5 .2. 2 .2 Synthesis of 4-vinylbenzyl