Copper-Catalyzed Multi-Component Reactions (eBook)

Synthesis of Nitrogen-Containing Polycyclic Compounds

Yusuke Ohta (Autor)

eBook Download: PDF

2011 | 2011
XVI, 104 Seiten
Springer Berlin (Verlag)
978-3-642-15473-7 (ISBN)

Infos

A copper-catalyzed direct synthesis of 2-(aminomethyl)indoles by catalytic domino reaction including multi-component coupling was developed, and is the first example of a three-component indole formation without producing salts as a byproduct. Based on this reaction, a copper-catalyzed synthesis of 3-(aminomethyl)isoquinoline was accomplished which represents an unprecedented isoquinoline synthesis through a four-component coupling reaction. Following these results, extensive application studies using one-pot palladium-, acid-, or base-promoted cyclization revealed that indole- or isoquinoline-fused polycyclic compounds can be readily synthesized through multi-component reactions. As the concept of Green Chemistry becomes ever more important, these findings may provide efficient and atom-economical approaches to the diversity-oriented synthesis of bioactive compounds containing a complex structure. This could lead to development of promising drug leads with structural complexity. The work of this thesis will go on to inspire the synthetic research of many readers.

Inhalt

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

Produkt-Details

• Erscheint lt. Verlag: 20.1.2011
• Reihe/Serie: Springer Theses
• Reihe/Serie: Springer Theses
• Zusatzinfo: XVI, 104 p.
• Verlagsort: Berlin
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie ► Organische Chemie
• Themenwelt: Technik
• Schlagworte: atom economy • Bioactive Compounds • complex heterocyclic structures • copper salt • Green chemistry • indole derivatives • isoquinoline derivatives • multicomponent coupling • multi-component reaction • one-pot reaction
• ISBN-10: 3-642-15473-5 / 3642154735
• ISBN-13: 978-3-642-15473-7 / 9783642154737