An isonitrile-alkyne cascade to di-substituted indoles

Intramolecular tin and sulfur mediated free-radical cyclizations between an aryl isonitfile and a pendant TMSsubstituted alkyne give 2,3-disubstituted indoles from 5-exo-dig cyclization and nucleophilic trapping of the resulting indolenine intermediate. © 1999 Elsevier Science Ltd. All fights reserved. In spite of the fact that Fischer first described their synthesis some 115 years ago, 1 the generation of indoles continues to be an area of active research. Undoubtedly, their presence in a number of bioactive molecules plays a role in the current level of activity. Of the various methods to substituted indole ring systems, Fukayama's isonitrile-alkene free-radical coupling reactions are among the most efficient (Eq. 1). 2 ~ R BusSnH ~ ~ N S~B I t AIBN, CHsCN u~ 2 H (1) Our interest in the synthesis of indole containing natural products directed our attention to the analogous alkyne-isonitfile free-radical reactions. 3 As depicted in Scheme 1, if isonitfile 3 proceeded through a mechanism similar to Fukayama's, 2 the radical cyclization would result in 4. Indolenine 4 is reminiscent of the intermediate from the fragmentation of gramine and should therefore be susceptible to attack by nucleophiles. 4,5 From our perspective, the development of a cascade of this nature would allow us to access a number of highly functionafized indoles from very simple precursors. Described herein are our preliminary experiments which demonstrate the successful execution of this strategy.