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J Org Chem. 2011 Oct 21;76(20):8477-82. doi: 10.1021/jo201237h. Epub 2011 Sep 13.

Synthesis of fused imidazoles, pyrroles, and indoles with a defined stereocenter α to nitrogen utilizing Mitsunobu alkylation followed by palladium-catalyzed cyclization.

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Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States.


Nitrogen-containing fused heterocycles comprise many compounds that demonstrate interesting biological activities. A new synthetic approach involving Mitsunobu alkylation of imidazoles, pyrroles, and indoles followed by palladium-catalyzed cyclization has been developed providing access to fused heterocycles with a defined stereochemistry α to nitrogen. While ethyl imidazole or indole carboxylates are good substrates for Mitsunobu alkylation with optically pure secondary benzylic alcohols, the corresponding pyrroles are poor substrates presumably due to the increased pK(a) of the NH. The presence of a synthetically versatile trichloroacetyl functional group on the pyrroles significantly reduces the pK(a) and thereby facilitates Mitsunobu alkylation. Subsequent cyclization of the alkylated products mediated by palladium in the presence or absence of a ligand gave fused heterocycles in good to excellent yields.

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