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Paper | Special issue | Vol 79, No. 1, 2009, pp.1061-1072
Published online, 19th February, 2009
DOI: 10.3987/COM-09-S(D)84
Probes for Narcotic Receptor Mediated Phenomena. 38. An Expeditious Synthesis of rac-cis-4a-Ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol and rac-cis-2-Methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol

Malliga R. Iyer, Jeffrey R. Deschamps, Arthur E. Jacobson, and Kenner C. Rice*

*Laboratory of Medicinal Chemistry,
National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bldg 8, Rm B122, Bethesda, Maryland 20892-0815, U.S.A.

Abstract

A high-yielding five-step synthesis of cis-benzofuropyridin-6-ols provided an improved route to compounds with low to subnanomolar affinity at opioid receptors and high antinociceptive potency. This synthesis provided the known rac-cis-4a-ethyl-2-methyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1a) in high yield, and the novel rac-cis-2-methyl-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol (1b). It was achieved using NBS to prepare the key intermediate 7. Di-demethylation followed by subsequent displacement of the bromine by the phenolic ion in hot Et3N gave the desired 1a. The structure of 1a was confirmed by X-ray crystallography.