Indole synthesis by radical cyclization of o‐alkenylphenyl isocyanides and its application to the total synthesis of natural products

Abstract

Development of indole synthesis by tin‐mediated radical cyclization of o‐alkenylphenyl isocyanide is described. Upon heating o‐alkenylphenyl isocyanide in the presence of tri‐n‐butyltin hydride and AIBN, 2‐stannyl‐3‐substituted indole was formed via 5‐exo‐trig cyclization of the imidoyl radical intermediate. After acidic workup, 3‐substituted indoles were isolated. For substrates bearing simple alkyl groups, a substantial amount of tetrahydroquinoline derivatives were generated through 6‐endo‐trig cyclization. This undesired cyclization was suppressed by using an excess amount (five equivalents based on o‐alkenylphenyl isocyanide) of ethanethiol instead of tri‐n‐butyltin hydride. The 2‐stannylindole intermediates proved to be a suitable substrate for Stille coupling, giving 2,3‐disubstituted indoles in a one‐pot procedure. In addition, the 2‐stannylindole intermediates could be converted to 2‐iodoindoles by treatment with iodine or N‐iodosuccinimide. The 2‐iodoindoles thus obtained served as good substrates for Heck reactions, Stille couplings, Suzuki couplings, and palladium‐mediated carbonylations, to afford a variety of 2,3‐disubstituted indoles. The utility of this protocol was demonstrated by application to synthetic studies on gelsemine and discorhabdin A, and the total synthesis of an aspidosperma alkaloid, (–)‐vindoline. © 2002 The Japan Chemical Journal Forum and John Wiley & Sons, Inc. Chem Rec 2: 37–45, 2002