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A Flexible, Palladium-Catalyzed Indole and Azaindole Synthesis by Direct Annulation of Chloroanilines and Chloroaminopyridines with Ketones

Marc Nazaré*, Claudia Schneider, Andreas Lindenschmidt, David William Will

*Aventis Pharma Deutschland GmbH, Medicinal Chemistry, DI&A Chemistry, Building G878, 65926 Frankfurt am Main, Germany, Email: marc.nazareaventis.com

M. Nazare, C. Schneider, A. Lindenschmidt, D. W. Will, Angew. Chem. Int. Ed., 2004, 43, 4526-4528.

DOI: 10.1002/anie.200460122


Abstract

A new, mild, and efficient method for the synthesis of polyfunctionalized indoles by direct reaction of substituted 2-chloroanilines with cyclic or acyclic ketones was developed. This procedure is simple to carry out and broadly applicable.

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Details

​The document discusses a new, flexible, and efficient palladium-catalyzed method for synthesizing indoles and azaindoles through the direct annulation of 2-chloroanilines and ortho-chloroaminopyridines with ketones. This method addresses the limitations of previous techniques that used 2-iodoanilines, which are less commercially available and more expensive. The optimized reaction conditions involve using [Pd(tBu3P)2] as the catalyst, K3PO4 as the base, and acetic acid as an additive in dimethylacetamide (DMA) at 140°C. This combination yields high selectivity and almost quantitative conversion to the desired indole products. The method is broadly applicable, tolerating various substitution patterns and functional groups, and works with both cyclic and acyclic ketones. The procedure is simple, mild, and extends the range of products that can be synthesized regiospecifically from easily available starting materials. This new method is a valuable addition to existing synthetic routes for indoles, offering a more accessible and cost-effective approach.


Key Words

annulation, cyclization, indoles, azaindoles, nitrogen heterocycles, palladium


ID: J06-Y2004-530