Abstract
A new approach to 1,2,5-trisubstituted 1H-indole-3-carboxylic esters has been developed and studied. The method begins with the preparation of imines from aldehyde and primary amine derivatives. Treatment of these imines with the K(2)CO(3)-derived anion from methyl 2-(2-fluoro-5-nitrophenyl)acetate or methyl 2-(5-cyano-2-fluorophenyl)acetate in DMF initiates a [3+2] cyclization by addition of the anion to the imine followed by ring closure of the adduct nitrogen to the activated aromatic moiety via an S(N)Ar process. Twenty-one examples are reported. Temperatures required for the conversion range from 90 to 95 °C for the nitro-activated substrates to 125 to 130 °C for the cyano-activated precursors. Though efficient and atom economical, limitations arise from steric hindrance in the reacting partners. The initial indoline formed is not observed but instead undergoes spontaneous air oxidation to the give the aromatic heterocycle. Imines from nonaromatic aldehydes and amines are also possible, but these give slightly lower yields of 1H-indoles and only react with the nitro-activated substrates. The results are presented with a discussion of the mechanism and the factors important to the success of the reaction.