N-alkylation of indole derivatives

Abstract

The present invention provides methods for the efficient preparation of indole derivatives of the formulawherein X is methyl or benzyl; and R, R, Rand Rare independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or Rand Rcombined together with the carbon atoms to which they are attached form a fused 6-membered aromatic ring; by reacting indoles of the formulawherein R, R, Rand Rhave meanings as defined for formula I, with dimethyl carbonate when X is methyl, or with dibenzyl carbonate when X is benzyl, in the presence of a catalytic amount of a base at an ambient temperature to afford compounds of formula I wherein X, R, R, Rand Rhave meanings as defined herein above. In particular, the present invention provides methylation and benzylation of the indole nitrogen in nearly quantitative yields using 1,4-diazabicyclo[2.2.2]octane as the base in a catalytic amount under mild conditions, wherein the alkylations may be conducted in the absence or the presence of an ionic liquid, under microwave irradiation or utilizing conventional heat, or combinations thereof.