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Efficient Solution-Phase Parallel Synthesis of 4-Substituted N-Protected Piperidines

Wang, Xiaoyang ; Kauppi, Anna M. ; Olsson, Roger LU orcid and Almqvist, Fredrik (2003) In European Journal of Organic Chemistry 2003(23). p.4586-4592
Abstract

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 NaHCO3 (sat.). The N-acyl group can conveniently be exchanged from... (More)

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 NaHCO3 (sat.). The N-acyl group can conveniently be exchanged from N-phenoxycarbonyl to N-tBoc, thus allowing orthogonal deprotection strategies.

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author
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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Copper, Hydrogenations, Nitrogen heterocycles, Parallel synthesis, Zinc
in
European Journal of Organic Chemistry
volume
2003
issue
23
pages
4586 - 4592
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:0345168768
ISSN
1434-193X
DOI
10.1002/ejoc.200300387
language
English
LU publication?
no
id
bc2d1350-5485-4068-bd7a-7bd7212b5302
date added to LUP
2019-10-02 09:49:49
date last changed
2022-02-01 01:07:40
@article{bc2d1350-5485-4068-bd7a-7bd7212b5302,
  abstract     = {{<p>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<sub>3</sub> (sat.). The N-acyl group can conveniently be exchanged from N-phenoxycarbonyl to N-tBoc, thus allowing orthogonal deprotection strategies.</p>}},
  author       = {{Wang, Xiaoyang and Kauppi, Anna M. and Olsson, Roger and Almqvist, Fredrik}},
  issn         = {{1434-193X}},
  keywords     = {{Copper; Hydrogenations; Nitrogen heterocycles; Parallel synthesis; Zinc}},
  language     = {{eng}},
  number       = {{23}},
  pages        = {{4586--4592}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{European Journal of Organic Chemistry}},
  title        = {{Efficient Solution-Phase Parallel Synthesis of 4-Substituted N-Protected Piperidines}},
  url          = {{http://dx.doi.org/10.1002/ejoc.200300387}},
  doi          = {{10.1002/ejoc.200300387}},
  volume       = {{2003}},
  year         = {{2003}},
}