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Cascade Alkenyl Amination/Heck Reaction Promoted by a Bifunctional Palladium Catalyst: A Novel One‐Pot Synthesis of Indoles from o ‐Haloanilines and Alkenyl Halides
Author(s) -
Barluenga José,
Fernández M. Alejandro,
Aznar Fernando,
Valdés Carlos
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200401274
Subject(s) - amination , chemistry , bifunctional , heck reaction , catalysis , aryl , indole test , chemoselectivity , cascade reaction , reactivity (psychology) , intramolecular force , medicinal chemistry , organic chemistry , palladium , combinatorial chemistry , alkyl , medicine , alternative medicine , pathology
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 α‐bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd 2 (dba) 3 ]/DavePhos, NaO t Bu, toluene combination at 100 °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 [Pd 2 (dba) 3 ]/X‐Phos promoted the formation of the indole ring also from the less reactive chloroanilines.