Simple syntheses of lespedamine and 5-bromo-n,n-dimethyltryptamine based on 1-hydroxyindole chemistry

Chemists synthesized various 1-hydroxyindoles for the first time. Using methylation or acid-catalyzed nucleophilic bromination of N,N-dimethyl-1-hydroxytryptamine, they achieved simple syntheses of lespedamine and 5-bromo-N,N-dimethyltryptamine. Lespedamine was originally isolated from Lespedeza bicolor var. japonica, and 5-bromo-N,N-dimethyltryptamine from the marine sponge Smenospongia aurea. The work supports a biosynthetic hypothesis that these compounds, along with bufotenine, may originate from N,N-dimethyl-1-hydroxytryptamine as a common intermediate. The syntheses proceeded via reduction of N,N-dimethyltryptamine to a dihydro compound, oxidation to the 1-hydroxyindole, then methylation or bromination.

Study at a glance

Abstract

Various types of 1-hydroxyindoles were prepared for the first time.Through methylation or acid catalyzed nucleophilic bromination of N,N-dimethyl-1 -hydroxytryptamine, simple syntheses of lespedamine and 5-bromo-N,N-dimethyltryptamine were achieved, respectively.~espedaminez (1 a, Scheme 1) was isolated from Lespedeza bicolorvar.japonica Nakai and -b r o m o -~, ~-d i m e t h ~l t r y ~t a m i n e ~(2 a) from marine sponge Smenospongia aure.Bufotenine (3a),4 1 a, and 2 a seem to have no relation to each other.However, if we assume the existence of N,N-dirnethyl-I-hydroxytryptamine (4 a). 1 a, 2 a, and 3 a might be expected to originate from 4 a as a common intermediate.Along this biosynthetic working hypothesis,5 we have now achieved the simple syntheses of 1 a and 2 a through 4a.We have succeeded for the first time in the syntheses6 of various 1-hydroxyindoles, Initially, N,N-dimethyltryptamine ( 6) was prepared from indole (5) according to either the known two step sequence7 (87% yield) of N,N-dimethylindole-3-glyoxylamide formation and treatment with LiAIH4 or direct dimethylation of tryptamine8 (70% yield).Reduction of 6 with triethylsilane9 i n CF3COOH afforded 2,3-dihydro-N,N-dimethyltryptamine (7 a) in 92% yield.Oxidation of 7 a with Na2W04.2H20 and 30% ~~0 ~5 3 6 in MeOH-Hz0 produced 55% y i e l d of N,N-dimethyl-1hydroxytryptamine (4a, mp 179.5-1 80.0°C) as stable crystals.Subsequent methylation of 4 a with diazomethane afforded lespedamine (1 a) in 53% yield.One pot preparation of 1 a from 7 a i n