Cascade Alkenyl Amination/Heck Reaction Promoted by a Bifunctional Palladium Catalyst: A Novel One‐Pot Synthesis of Indoles from o‐Haloanilines and Alkenyl Halides

Abstract

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.

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…Barluenga [150] has exploited the large difference in reactivity of 2-aminoaryl halides and vinyl halides towards palladium-catalyzed amination in order to bring about a one-pot synthesis of indoles from o-haloanilines and vinyl bromides. It was suggested that ring closure occurs via a Heck process.…”

Transition metals in organic synthesis: Highlights for the year 2005

“…An intermolecular amidation-intramolecular Heck reaction of 2-halobenzenamines and alkenylhalides to give indoles was described (Eq. (61)) [549]. Palladium catalyzed a sequential N-arylation-carboamination of 1-amino-4-enes (Eq.…”

A General Method for the Direct α‐Arylation of Aldehydes with Aryl Bromides and Chlorides

“…[15,16] In a process closely related to the Merck indole synthesis, [17] we believe that this reaction proceeds through the intermediacy of an aldimine, which tautomerizes to the enamine and undergoes an intramolecular arylation and subsequent isomerization to afford the 3-substituted indole. [18,19] Although not yet investigated in detail, a-arylations also occurred with lower catalyst loadings ( Table 2, entries 1 and 12).…”