Tetrahedron. Author manuscript; available in PMC Feb 4, 2013.

Published in final edited form as:

Tetrahedron. Feb 4, 2012; 68(5): 1359–1366.

Published online Dec 13, 2011. doi:  10.1016/j.tet.2011.12.013

PMCID: PMC3358821

NIHMSID: NIHMS344972

Acid-Facilitated Debenzylation of N-Boc, N-Benzyl Double Protected 2-Aminopyridinomethylpyrrolidine Derivatives

Haitao Ji,^1,2 Qing Jing,¹ Jinwen Huang,^1,3 and Richard B. Silverman^1,*

¹Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113

^*Correspondence to the Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, Phone: 847-491-5653, Email: ude.nretsewhtron.mehc@namgA

²Current address: Department of Chemistry, University of Utah, Salt Lake City, UT 84112-0850

³Current address: Shanghai HotMed Sciences Co., Ltd., Shanghai Zhangjiang Hi-Tech, Park,211-214 NO.518, Bibo Road, Shanghai, China

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Abstract

2-Aminopyridinomethyl pyrrolidines represent a class of highly potent and selective neuronal nitric oxide synthase inhibitors. Conditions for a Mitsunobu reaction of a naphthol and a hindered secondary alcohol were optimized to give good to excellent yields. A key step in the synthesis of these inhibitors is the deprotection of the benzyl group from the N-Boc and N-Bn double protected 2-aminopyridine ring at a late stage of the synthesis, which has been proven difficult in our previous syntheses. Acetic acid was found to facilitate the N-Bn deprotection.

Keywords: 2-Aminopyridinomethyl pyrrolidines, Mitsunobu reaction, N-Benzyl deprotection, Palladium-catalyzed hydrogenation