Synthesis of 2‐Substituted Tryptamines via Cyanide‐Catalyzed Imino‐Stetter Reaction

Abstract

Herein, we describe the development of a twostep protocol for the synthesis of 2-substituted tryptamine derivatives from 2-aminocinnamyl nitriles and aldehydes. The cyanide-catalyzed imino-Stetter reaction of 2-aminocinnamyl nitriles and aldehydes provided 2-substituted indole-3-acetonitrile derivatives. Subsequent reduction of the nitrile group afforded the desired 2-substituted tryptamine derivatives. The utility of this protocol was demonstrated in the synthesis of a potential inhibitor of 15lipoxygenase. Furthermore, the resulting 2-substituted indole-3-acetonitriles were converted to several 2,3-disubstituted indole derivatives upon transformation of the nitrile group into other functional groups.

A cyanide-catalyzed imino-Stetter reaction enables the concise total syntheses of rucaparib

“…(4) Very recently, our group has developed a protocol for the synthesis of 2-substituted indole-3-acetonitriles using the cyanide-catalyzed imino-Stetter reaction of aldimines derived from 2-aminocinnamonitriles and aldehydes. 30 …”

“…(5) Since 2-aminocinnamonitriles, one of the key building blocks for the cyanide-catalyzed imino-Stetter reaction, are prepared by the Heck reaction of an aryl halide and acrylonitrile, 30 4,6-disubstituted 2-aminocinnamonitrile can be synthesized in a much more efficient manner via the Heck reaction of a suitable aryl halide (or pseudohalide) and acrylonitrile.…”

“…Indole-3-acetonitrile 6c could be prepared from 2-aminocinnamonitrile 4c and aldehyde 5 via the key cyanide-catalyzed imino-Stetter reaction. 30 2-Aminocinnamonitrile 4c could be prepared using the Heck reaction of an appropriate aryl halide (or pseudohalide) 21 with acrylonitrile.…”

“…Aldimine formation from 4c and 5 using TiCl 4 as a dehydrating reagent followed by the cyanide-catalyzed imino-Stetter reaction afforded the desired indole-3-acetonitrile 6c in 80% yield on a 10 mmol scale. 12–14,30…”

Cyanide Anions as Nucleophilic Catalysts in Organic Synthesis

“…The submission of -(aminoaryl)-,-unsaturated nitriles instead of amino-cinnamates to the imino-Stetter reaction opens an elegant pathway to tryptamine derivatives (Scheme 21). 86 The conversion of ortho-amino-cinnamates with 2-formylindoles as aromatic aldehydes yields imines 78, which allows the cyanide-catalyzed preparation of frameworks with the 2,2′-biindole substructure (products 79 and 80). These intermediates could be further processed to related alkaloids arcyriaflavin A (81, four steps from 79), 87 calothrixin B (82, five steps from 79), 87 and iheyamine A (83, five steps from 80).…”