3 - (aminomethyl) Indole Derivatives

Indole-3-methylamine is an important pharmaceutical intermediate and a starting material for the syntheses of phytoalexins. Although its structure is simple, indole-3-methylamine is very unstable under basic conditions and easily becomes deep red by forming polymerized compounds through a 3-methyleneindolenine intermediate when exposed to air. Indole-3-methyl-amine and its l-protected derivatives were usually prepared by reduction of indole-3-carboxaldehyde oxime. These methods often encountered difficulties of low yield, nonreproductability, and polymerization. Therefore, development of a simple and practical method for the preparation of stable indole-3-methylamine derivatives is highly desirable in light of the instability and usefulness of indole-3-methylamine. Classic Hofmann rearrangement usually requires a harsh basic aqueous condition, which sometimes negates the possible usefulness of Hofmann rearrangement in the preparation of base-sensitive amines. In recent years, polyvalent iodine, especially diacetoxy iodobenzene has been reported as a mild reagent for Hofmann rearrangement. A series of alkyl carbamates of l-protected indole-3-methylamines, alkyl carbamates of thiophenylmethylamines, and pyrrolylmethylamines were prepared from the corresponding acetamides in good to excellent yields via diacetoxyiodobenzene-promoted Hofmann rearrangement. For a successful Hofmann rearrangement, an electron-withdrawing group on position-1 of indolylacetamide and pyrrolylacetamide was required. The stable 1-Ts protected indole-3-methylamine was obtained via deprotection of tert-butyl carbamate of indole-3-methylamine. The synthesized indole-3-methylamine was demonstrated to serve well as a stable precursor of indole-3-methylamine.