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.
A general synthetic method for producing 4-substituted indoles was developed. Fischer indolization of phenylhydrazones with a chlorine atom on the ortho position selectively gave 7-chloro-4-substituted indoles, which were then converted to 4-substituted indoles through catalytic hydrogenation. Cyclization of one derivative with polyphosphoric acid occurred at the 5-position of the indole ring, forming a tricyclic ketone. This approach addresses the difficulty of introducing substituents at the 4-position via intermolecular reactions and offers a useful route to 4-substituted indole derivatives, which are of interest due to the psychotomimetic activity of compounds like lysergic acid diethylamide and psilocybin.