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Efficient Solution‐Phase Parallel Synthesis of 4‐Substituted N ‐Protected Piperidines
Author(s) -
Wang Xiaoyang,
Kauppi Anna M.,
Olsson Roger,
Almqvist Fredrik
Publication year - 2003
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200300387
Subject(s) - chemistry , maleic anhydride , sequence (biology) , combinatorial chemistry , organic chemistry , protecting group , catalysis , reaction conditions , medicinal chemistry , copolymer , biochemistry , alkyl , polymer
Practical conditions for the synthesis of 4‐substituted N ‐protected piperidines through CuCN·2LiBr‐catalyzed organozinc additions to 1‐acylpyridinium salts and subsequent hydrogen‐transfer hydrogenation have been established. The reaction sequence is performed at room temperature and provides 4‐substituted N ‐protected piperidines in excellent overall yields without the isolation of intermediate dihydropyridines. In those cases in which the organozinc addition results in mixtures of 2‐ and 4‐substituted dihydropyridines, the 2‐substituted isomers are efficiently scavenged with maleic anhydride and subsequently removed by a mild extractive workup with NaHCO 3 (sat.). The N ‐acyl group can conveniently be exchanged from N ‐phenoxycarbonyl to N ‐ t Boc, thus allowing orthogonal deprotection strategies. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)