Copper-Catalyzed Multi-Component Reactions (eBook)

Copper-CatalyzedMulti-Component Reactions 3
Supervisor’s Foreword 6
Acknowledgments 7
Contents 8
1 Introduction 13
References 17
Part ISynthesis of Indole Derivatives 19
2 Construction of 2-(Aminomethyl)indoles Through Copper-Catalyzed Domino Three-Component Coupling and Cyclization 20
2.1…Introduction 20
2.1.1 Synthesis of 2-(Aminomethyl)indoles Using Several Amines and Aldehydes 21
2.1.2 Synthesis of Substituted 2-(Aminomethyl)indoles Using Various Ethynylanilines and Secondary Amines 24
2.1.3 Construction of Polycyclic Indoles by Palladium-Catalyzed C--H Functionalization 25
2.1.4 Synthetic Application to Calindol, Benzo[e][1,2]thiazines, and Indene 25
2.2…Experimental Section 30
2.2.1 General Methods 30
2.2.1.1 N-(tert-Butoxycarbonyl)-2-iodo-N-tosylaniline (S2) 30
2.2.1.2 N-(tert-Butoxycarbonyl)-N-tosyl-2-[(trimethylsilyl)ethynyl]aniline (S3) 31
2.2.1.3 N-(tert-Butoxycarbonyl)-2-ethynyl-N-tosylaniline (S4) 31
2.2.1.4 N-(tert-Butoxycarbonyl)-2-[3-(piperidin-1-yl)propy-1-nyl]- N-tosylaniline (S5) 31
2.2.1.5 2-[3-(Piperidin-1-yl)prop-1-ynyl]-N-tosylaniline (8) 32
2.2.1.6 Synthesis of 2-[(Piperidin-1-yl)methyl]-1-tosylindole 7b from 8 32
2.2.1.7 2-Ethynyl-N-(p-toluenesulfonyl)-4-(trifluoromethyl)aniline (1b) 33
2.2.1.8 2-Ethynyl-4-(methoxycarbonyl)-N-(p-toluenesulfonyl)aniline (1c) 34
2.2.1.9 2-Ethynyl-4-methyl-N-(p-toluenesulfonyl)aniline (1d) 34
2.2.1.10 2-Ethynyl-N-(p-toluenesulfonyl)-5-(trifluoromethyl)aniline (1e) 34
2.2.1.11 2-Ethynyl-5-(methoxycarbonyl)-N-(p-toluenesulfonyl)aniline (1f) 35
2.2.2 General Procedure for Synthesis of 2-(Aminomethyl)indole 35
2.2.2.1 Synthesis of 2-[(N,N-Diisopropylamino)methyl]-1-tosylindole (7a) 35
2.2.2.2 2-[(Piperidin-1-yl)methyl]-1-tosylindole (7b) from 1a 36
2.2.2.3 2-[(Pyrrolidin-1-yl)methyl]-1-tosylindole (7c) 36
2.2.2.4 2-[(N,N-Diethylamino)methyl]-1-tosylindole (7d) 36
2.2.2.5 2-[(N,N-Diallylamino)methyl]-1-tosylindole (7e) 36
2.2.2.6 2-[(N,N-Dibenzylamino)methyl]-1-tosylindole (7f) 37
2.2.2.7 2-[1-(Piperidin-1-yl)butyl]-1-tosylindole (7g) 37
2.2.2.8 2-[2-Methyl-1-(piperidin-1-yl)propyl]-1-tosylindole (7h) 37
2.2.2.9 2-[Phenyl(piperidin-1-yl)methyl)-1-tosylindole (7i) 38
2.2.2.10 2-{[4-(Methoxycarbonyl)phenyl](piperidin-1-yl)methyl}-1-tosylindole (7j) 38
2.2.2.11 2-[(Piperidin-1-yl)(p-tolyl)methyl]-1-tosylindole (7k) 38
2.2.2.12 2-[(2-Bromophenyl)(piperidin-1-yl)methyl]-1-tosylindole (7l) 39
2.2.2.13 Enantioselective Synthesis of 2-[1-(Piperidin-1-yl)butyl]-1-tosylindole (7g) 39
2.2.2.14 2-[(N,N-Dibenzylamino)methyl]-1-tosyl-5-(trifluoromethyl)indole (7m) 39
2.2.2.15 2-[(N,N-Dibenzylamino)methyl]-5-(methoxycarbonyl)-1-tosylindole (7n) 40
2.2.2.16 2-[(N,N-Dibenzylamino)methyl]-5-methyl-1-tosylindole (7o) 40
2.2.2.17 2-[(N,N-Dibenzylamino)methyl]-1-tosyl-6-(trifluoromethyl)indole (7p) 40
2.2.2.18 2-[(N,N-Dibenzylamino)methyl]-6-(methoxycarbonyl)-1-tosylindole (7q) 41
2.2.2.19 2-{[N-(2-Bromoprop-2-en-1-yl)-N-butylamino]methyl}-1-tosylindole (7r) 41
2.2.2.20 2-{[N-(2-Bromoprop-2-en-1-yl)-N-butylamino]methyl}-1-tosyl-5-trifluoromethylindole (7s) 42
2.2.2.21 2-{[N-(2-Bromoprop-2-en-1-yl)-N-butylamino]methyl}-5-(methoxycarbonyl)-1-tosylindole (7t) 42
2.2.2.22 2-{[N-(2-Bromoprop-2-en-1-yl)-N-butylamino]methyl}-5-methyl-1-tosylindole (7u) 42
2.2.2.23 2-{[N-(2-Bromoprop-2-en-1-yl)-N-butylamino]methyl}-1-tosyl-6-(trifluoromethyl)indole (7v) 43
2.2.2.24 2-{[N-(2-Bromoprop-2-en-1-yl)-N-butylamino]methyl}-6-(methoxycarbonyl)-1-tosylindole (7w) 43
2.2.2.25 2-{[N-(2-Bromobenzyl)-N-butylamino]methyl}-1-tosylindole (7x) 44
2.2.3 General Procedure for Synthesis of Tetrahydropyridine-Fused Indole 44
2.2.3.1 Synthesis of 2-Butyl-4-methylene-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9a) 44
2.2.3.2 2-Butyl-4-methylene-9-tosyl-6-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9b) 44
2.2.3.3 2-Butyl-4-methylene-6-(methoxycarbonyl)-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9c) 45
2.2.3.4 2-Butyl-6-methyl-4-methylene-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9d) 45
2.2.3.5 2-Butyl-4-methylene-9-tosyl-7-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9e) 45
2.2.3.6 2-Butyl-7-(methoxycarbonyl)-4-methylene-9-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9f) 46
2.2.3.7 6-Butyl-8-tosyl-5,6,7,8-tetrahydrobenzo[e]indolo[2,3-c]azepine (10) 46
2.2.3.8 N-[1-(Naphthalen-1-yl)ethyl]prop-2-en-1-amine (11) 47
2.2.3.9 2-{N-(Prop-2-en-1-yl)-N-[1-(naphthalen-1-yl)ethyl]aminomethyl}-1-tosylindole (12) 47
2.2.3.10 Calindol (13) 47
2.2.3.11 2-Ethynyl-N-methylbenzenesulfonamide (14a) 48
2.2.3.12 N-Ethyl-2-ethynylbenzenesulfonamide (14b) 49
2.2.3.13 2-Ethynyl-N-p-tolylbenzenesulfonamide (14c) 49
2.2.3.14 2-Ethynyl-N-phenylbenzenesulfonamide (14d) 50
2.2.3.15 2-Ethynyl-N-(4-methoxyphenyl)benzenesulfonamide (14e) 51
2.2.3.16 N-(4-Chlorophenyl)-2-ethynylbenzenesulfonamide (14f) 51
2.2.4 General Procedure for Synthesis of Benzo[e][1,2]thiazine-1,1-dioxide 52
2.2.4.1 3-[(N,N-Diisopropylamino)methyl]-2-methyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (15a) 52
2.2.4.2 3-[(N,N-Diisopropylamino)methyl]-2-ethyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (15b) 52
2.2.4.3 3-[(N,N-Diisopropylamino)methyl]-2-(p-tolyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (15c) 52
2.2.4.4 3-[(N,N-Diisopropylamino)methyl]-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (15d) 53
2.2.4.5 3-[(N,N-Diisopropylamino)methyl]-2-(4-methoxyphenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (15e) 53
2.2.4.6 2-(4-Chlorophenyl)-3-[(N,N-diisopropylamino)methyl]-2H-benzo[e][1,2]thiazine-1,1-dioxide (15f) 53
2.2.4.7 Dimethyl 2-(2-Iodophenyl)malonate (S12) 54
2.2.4.8 Dimethyl 2-(2-Ethynylphenyl)malonate (16) 54
2.2.4.9 Dimethyl 2-[(N,N-Diisopropylamino)methyl]indene-1,1-dicarboxylate (17) 55
References 55
3 Facile Synthesis of 1,2,3,4-Tetrahydro- beta -Carbolines by One-Pot Domino Three-Component Indole Formation and Nucleophilic Cyclization 57
3.1…Experimental Section 62
3.1.1 General Methods 62
3.1.2 General Procedure for Synthesis of N-Arylsulfonyl-2-ethynylaniline: Synthesis of 2-Ethynyl-N-mesitylenesulfonylaniline (1c) 63
3.1.3 N-(p-Bromobenzenesulfonyl)-2-ethynylaniline (1e) 63
3.1.4 N-(p-Chlorobenzenesulfonyl)-2-ethynylaniline (1f) 64
3.1.5 2-Ethynyl-N-(p-fluorosulfonyl)aniline (1g) 64
3.1.6 General Procedure for Synthesis of 1,2,3,4-Tetrahydro- beta -carboline by Domino Copper-Catalyzed Three-Component Indole Formation and Cyclization with t-BuOK: Synthesis of 2-Methyl-1-propyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6a) and 2-Methyl-1-propyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (8a) (Table 1, Entry 11) 64
3.1.7 2-Methyl-1-[2-(trimethylsilyl)ethenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6b) and 2-Methyl-1-[2(trimethylsilyl)ethenyl]-1,2,3,4-tetrahydropyrazino[1,2-a]indole (8b) 65
3.1.8 1-(Benzyloxymethyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6c) and 1-(Benzyloxymethyl)2-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (8c) 66
3.1.9 2-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6d) 66
3.1.10 General Procedure for Synthesis of 1,2,3,4-Tetrahydro- beta -carboline by Domino Copper-Catalyzed Three-Component Indole Formation and Cyclization with MsOH: Synthesis of 2-Methyl-2,3-dihydropyrido[3,4-b]indol-4(9H)-one (7a) (Conditions A) 67
3.1.11 2-Allyl-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-one (7b) 67
3.1.12 2-Butyl-2,3-dihydro-1H-pyrido[3,4-b] indol-4(9H)-one (7c) 68
3.1.13 General Procedure for Synthesis of 1,2,3,4-Tetrahydro- beta -carboline by Domino Copper-Catalyzed Three-Component Indole Formation and Cyclization by MsOH: Synthesis of 2-Benzyl-2,3-dihydro1H-pyrido[3,4-b]indol-4(9H)-one (7d) (Conditions B) 68
3.1.14 (R)-2,3-Dimethyl-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-one (7e) (Conditions C) 69
3.1.15 (R)-3-Isobutyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b] indol-4(9H)-one (7f) 69
3.1.16 (R)-3-Benzyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b] indol-4(9H)-one (7g) 69
3.1.17 5,6,8,9,10,11,11a,12-Octahydroindolo[3,2-b]quinolizine (7h) 70
References 70
4 Concise Synthesis of Indole-Fused 1,4-Diazepines through Copper(I)-Catalyzed Domino Three-Component Coupling-Cyclization-N-Arylation under Microwave Irradiation 72
4.1…Experimental Section 76
4.1.1 General Methods 76
4.1.2 General Procedure for Synthesi of 2-Ethynyl-N-methanesufonylaniline: Synthesis of 2-Ethynyl-N-methane sulfonyl-4-methoxycarbonylaniline (1b) 77
4.1.3 2-Ethynyl-N-methanesulfonyl-4-trifluoromethyl carbonylaniline (1c) 77
4.1.4 2-Ethynyl-N-methanesulfonyl-4-methylaniline (1d) 78
4.1.5 2-Ethynyl-N-methanesulfonyl-5-trifluoromethyl carbonylaniline (1e) 78
4.1.6 General Procedure for Synthesis of Indole-Fused 1,4-Diazepine through Three-Component Indole Formation-N-Arylation: Synthesis of 7-n-Butyl-7,8-dihydro-6H-benzo[f]indolo[1,2-a][1,4]diazepine (3a) 78
4.1.7 7-Methyl-7,8-dihydro-6H-benzo[f]indolo[1,2-a][1,4] diazepine (3b) 79
4.1.8 7-Benzyl-7,8-dihydro-6H-benzo[f]indolo[1,2-a][1,4]diazepine (3c) 79
4.1.9 7-Allyl-7,8-dihydro-6H-benzo[f]indolo[1,2-a][1,4]diazepine (3d) 80
4.1.10 7-Allyl-3-methoxycarbonyl-7,8-dihydro-6H-benzo[f]indolo[1,2-a][1,4]diazepine (3e) 80
4.1.11 7-Allyl-3-trifluoromethyl-7,8-dihydro-6H-benzo[f] indolo[1,2-a][1,4]di-azepine (3f) 80
4.1.12 7-Allyl-3-methyl-7,8-dihydro-6H-benzo[f]indolo[1,2-a][1,4]diazepine (3g) 81
4.1.13 7-Allyl-2-trifluoromethyl-7,8-dihydro-6H-benzo[f] indolo[1,2-a][1,4]diazepine (3h) 81
4.1.14 Synthesis of N-[(2-bromothiophen-3-yl)methyl]butan-1-amine (4) 82
4.1.15 7-Allyl-7,8-dihydro-6H-pyrydo[3,2-f]indolo[1,2-a][1,4] diazepine (5) 82
4.1.16 Synthesis of N-((2-bromopyridin-3-yl)methyl)prop-2-en-1-amine (6) 82
4.1.17 7-Allyl-7,8-dihydro-6H-indolo[1,2-a]thieno[2,3-f][1,4]diazepine (7) 83
References 83
Part IISynthesis of Isoquinoline Derivatives 85
5 Facile Synthesis of 3-(Aminomethyl)isoquinoline by Copper-Catalyzed Domino Four-Component Coupling and Cyclization 86
5.1…Introduction 86
5.2…Experimental Section 90
5.2.1 General Methods 90
5.2.1.1 2-Ethynylbenzaldehyde (1a) 90
5.2.1.2 2-Ethynyl-4-fluorobenzaldehyde (1b) 90
5.2.1.3 2-Ethynyl-5-fluorobenzaldehyde (1c) 91
5.2.1.4 2-Ethynyl-4-methylbenzaldehyde (1d) 91
5.2.1.5 2-Ethynyl-5-methoxybenzaldehyde (1e) 91
5.2.2 General Procedure for Four-Component Isoquioline Formation 92
5.2.2.1 Synthesis of 3-[(Diisopropylaminino)methyl]isoquinoline (6a) 92
5.2.2.2 3-{Bis[(R)-1-phenylethyl]aminomethyl}isoquinoline (6c) 92
5.2.2.3 3-[(Diallylamino)methyl]isoquinoline (6d) 92
5.2.2.4 3-(Piperidin-1-ylmethyl)isoquinoline (6e) 93
5.2.2.5 3-[(Pyrrolidin-1-yl)methyl]isoquinoline (6f) 93
5.2.2.6 3-[(Diisopropylamino)methyl]-6-fluoroisoquinoline (7) 93
5.2.2.7 3-[(Diisopropylamino)methyl]-7-fluoroisoquinoline (8) 94
5.2.2.8 3-[(Diisopropylamino)methyl]-6-methylquinoline (9) 94
5.2.2.9 3-[(Diisopropylamino)methyl]-7-methoxyquinoline (10) 94
References 95
6 Rapid Access to 3-(Aminomethyl)isoquinoline-Fused Polycyclic Compounds by Copper-Catalyzed Four Component Coupling, Cascade Cyclization, and Oxidation 96
6.1…Experimental Section 101
6.1.1 General Procedure for Synthesis of (Aminomethyl)isoquinoline-Fused Polycyclic Compounds by Domino Mannich-Type Reaction and Cascade Cyclization: Synthesis of 6-[(N,N-Diisopropylamino)methyl]-3,4-dihydro-2H-pyrimido[2,1-a]isoquinoline (12a) (Table 1, Entry 10) 101
6.1.2 6-[(N,N-Diisopropylamino)methyl]-9-Fluoro-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12b) 102
6.1.3 6-[(N,N-Diisopropylamino)methyl]-10-Fluoro-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12c). 102
6.1.4 6-[(N,N-Diisopropylamino)methyl]-9-Methyl-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12d) 103
6.1.5 6-[(N,N-Diisopropylamino)methyl]-10-Methoxy-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12e) 103
6.1.6 6-(Piperidin-1-ylmethyl)-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12f) 103
6.1.7 6-[(N,N-Diallylamino)methyl]-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12g) 104
6.1.8 6-{[N,N-Bis((R)-1-phenylethyl)amino]methyl}-3,4-Dihydro-2H-Pyrimido[2,1-a]isoquinoline (12h) 104
6.1.9 5-[(N,N-Diisopropylamino)methyl]-2,3-Dihydroimidazo[2,1-a]isoquinoline (13) 105
6.1.10 7-[(N,N-Diisopropylamino)methyl]-2,3,4,5-Tetrahydro[1,3]diazepino[2,1-a]isoquinoline (14) 105
6.1.11 8-[(N,N-Diisopropylamino)methyl]-3,4,5,6-Tetrahydro-2H-[1,3]diazocino[2,1-a]isoquinoline (15) 105
6.1.12 6-[(N,N-Diisopropylamino)methyl]benzimidazo[2,1-a]isoquinoline (16) 106
References 106
7 Conclusions 108