N-[2-(1-Methoxyindol-3-yl)ethyl]-1-methoxyindole-3-acetamide (43a), its N-methyl analog (43b), and N-[2-(1-methoxyindol-3-yl)ethyl]indole-3-acet-amide (51) are prepared by the following route (Scheme 8) [23].

Condensation of tryptamines (14,44) with indole-3-acetic acid (45) provides N-[2-(indol-3-yl)ethyl]indole-3-acetamides (46a, 81%; 46b, 98%). Reduction of 46a with Et3SiH/TFA produces bis-2,3-dihydroindole derivative (47a, 90%), while the reduction with NaBH3CN gives rise to 47a (42%) and 48 (45%), a product reduced selectively at the tryptamine pyrrole part.

Scheme 8 Synthesis of N-[2-(1-alkoxyindol-3-yl)ethyl]-1-alkoxyindole-3-acetamides

Reduction of 46b with Et3SiH/TFA produces similarly N-methyl-bis-2,3-dihydroindole (47b, 85%). Employing the tungstate method, 47a,b and 48 are converted to N-[2-(1-hydroxyindol-3-yl)ethyl]-1-hydroxyindole-3-acet-amides (49a, 51%; 49b, 39%) and N-[2-(1-hydroxyindol-3-yl)ethyl]indole-3-acetamide (50, 55%), respectively. Subsequent methylation of 49a,b and 50 affords 43a (91%), 43b (72%), and 51 (100%).

Chemical Reactions of 1-Hydroxyindoles, -Tryptamines, and -Tryptophans

Alkylation with sec-Alkyl Halides and ferf-Butyldimethylsilyl Chloride

Alkylation of 1-hydroxyindoles, -tryptamines, and -tryptophans is readily achieved with various prim-alkyl halides in the presence of bases due to the acidic nature [14] of these 1-hydroxyindole compounds. Diazoalkanes are also useful alkylating reagents [5-7].

As for the introduction of a secondary alkyl moiety to the 1-hydroxy oxygen, the usual alkyl halide method has given poor results. However, employing preformed cesium salt of 1-hydroxyindoles in DMF, this difficulty has been overcome (Scheme 9) [24]. Thus, the reaction of Nb-methoxycarbonyl-1-hydroxytryptamine (52) with methyl 2-bromopropionate, 2-bromopropane, cyclohexyl bromide, and 1-phenethylbromide gives birth to the corresponding 1-(1-methoxycarbonyl)ethoxy (53a, 88%), 1-(2-propyl)oxy (53b, 87%), 1-cyclohexyloxy (53c, 19%), and 1-(1-methyl)benzyloxy derivatives (53d, 80%), respectively. 1-i-Butyldimethylsilyloxy-Nb-methoxycarbonyl-tryptamine (54) can be obtained by the conventional i-butyldimethylsilyl chloride and imidazole method [24].

Scheme 9 Alkylation with sec-alkyl halides and ieri-butyldimethylsilyl chloride

Electrophilic Substitution Reactions

Upon electrophilic substitution reactions, the introduction of either a meth-oxy or a hydroxy group onto the 1-position of the indole nucleus causes alteration of its positional reactivity [5-7]. Halogenation and Friedel-Crafts acylation are presented as additional examples.

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