Cascade alkenyl amination/Heck reaction promoted by a bifunctional palladium catalyst: a novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides.Chemistry. 2005 Apr 08; 11(8):2276-83.C
A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.