4.8 Article

Modular Synthesis of Indoles from Imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-Catalyzed Cascade Process

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 131, Issue 11, Pages 4031-4041

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/ja808652a

Keywords

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Funding

  1. Fundacion Ramon Areces [CTQ2004-08077, CTQ2007-61048, IB 05-136]
  2. Ministerio de Educacion y Ciencia of Spain

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A detailed study of the scope of a new Pd-catalyzed synthesis of indoles from 1,2-dihaloarenes and o-halobenzene sulfonates and imines is described. The cascade reaction comprises an imine alpha-arylation followed by an intramolecular C-N bond-forming reaction promoted by the same Pd catalyst. The reaction. with 1,2-dibromobenzene shows wide scope and allows the introduction of aryl, alkyl, and vinyl substituents at different positions of the five-membered ring of the indole. The regioselective synthesis of indoles substituted in the six-membered ring can be carried out by employing o-dihalobenzene derivatives with two different halogens, taking advantage of the different reactivities of I, Br, and Cl in oxidative addition reactions. This paper also introduces a method for the efficient cleavage of the N-t-butyl group, thus allowing for the preparation of N-H indoles through the same methodology. Finally, the reaction with o-halosulfonates has been studied. The best substrates are o-chlorononaflates, which lead to indoles in very high yield. The reaction is particularly appropriate for the synthesis of the challenging 6-substituted indoles. In view of the availability of o-chlorophenols, which are direct precursors of the chlorononaflates, this reaction represents an efficient entry into indoles substituted in the six-membered ring. The concept is illustrated by the preparation of a 4,6-disubstituted indole from naturally occurring anethole.

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