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Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines

Karen Mollet (UGent) , Saron Catak (UGent) , Michel Waroquier (UGent) , Veronique Van Speybroeck (UGent) , Matthias D'hooghe (UGent) and Norbert De Kimpe (UGent)
(2011) JOURNAL OF ORGANIC CHEMISTRY. 76(20). p.8364-8375
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HPC-UGent: the central High Performance Computing infrastructure of Ghent University
Abstract
The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding beta-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S(N)2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.
Keywords
SUBSTITUTED PIPERIDINES, THERMOCHEMICAL KINETICS, DENSITY FUNCTIONALS, THEORETICAL RATIONALIZATION, MOLECULAR-ORBITAL METHODS, CONTINUUM SOLVENT CALCULATIONS, AZETIDINES, PYRROLIDINES, BETA-LACTAMS, BUILDING-BLOCKS

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Citation

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Chicago
Mollet, Karen, Saron Catak, Michel Waroquier, Veronique Van Speybroeck, Matthias D’hooghe, and Norbert De Kimpe. 2011. “Stereoselective Synthesis of Cis-3,4-disubstituted Piperidines Through Ring Transformation of 2-(2-mesyloxyethyl)azetidines.” Journal of Organic Chemistry 76 (20): 8364–8375.
APA
Mollet, K., Catak, S., Waroquier, M., Van Speybroeck, V., D’hooghe, M., & De Kimpe, N. (2011). Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines. JOURNAL OF ORGANIC CHEMISTRY, 76(20), 8364–8375.
Vancouver
1.
Mollet K, Catak S, Waroquier M, Van Speybroeck V, D’hooghe M, De Kimpe N. Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines. JOURNAL OF ORGANIC CHEMISTRY. 2011;76(20):8364–75.
MLA
Mollet, Karen, Saron Catak, Michel Waroquier, et al. “Stereoselective Synthesis of Cis-3,4-disubstituted Piperidines Through Ring Transformation of 2-(2-mesyloxyethyl)azetidines.” JOURNAL OF ORGANIC CHEMISTRY 76.20 (2011): 8364–8375. Print.
@article{1943641,
  abstract     = {The reactivity of 2-(2-mesyloxyethyl)azetidines, obtained through monochloroalane reduction and mesylation of the corresponding beta-lactams, with regard to different nucleophiles was evaluated for the first time, resulting in the stereoselective preparation of a variety of new 4-acetoxy-, 4-hydroxy-, 4-bromo-, and 4-formyloxypiperidines. During these reactions, transient 1-azoniabicyclo[2.2.0]hexanes were prone to undergo an S(N)2-type ring opening to afford the final azaheterocycles, which was rationalized by means of a detailed computational analysis. This approach constitutes a convenient alternative for the known preparation of 3,4-disubstituted 5,5-dimethylpiperidines, providing an easy access to the 5,5-nor-dimethyl analogues as valuable templates in medicinal chemistry. Furthermore, cis-4-bromo-3-(phenoxy or benzyloxy)piperidines were elaborated into the piperidin-3-one framework via dehydrobromination followed by acid hydrolysis.},
  author       = {Mollet, Karen and Catak, Saron and Waroquier, Michel and Van Speybroeck, Veronique and D'hooghe, Matthias and De Kimpe, Norbert},
  issn         = {0022-3263},
  journal      = {JOURNAL OF ORGANIC CHEMISTRY},
  keyword      = {SUBSTITUTED PIPERIDINES,THERMOCHEMICAL KINETICS,DENSITY FUNCTIONALS,THEORETICAL RATIONALIZATION,MOLECULAR-ORBITAL METHODS,CONTINUUM SOLVENT CALCULATIONS,AZETIDINES,PYRROLIDINES,BETA-LACTAMS,BUILDING-BLOCKS},
  language     = {eng},
  number       = {20},
  pages        = {8364--8375},
  title        = {Stereoselective synthesis of cis-3,4-disubstituted piperidines through ring transformation of 2-(2-mesyloxyethyl)azetidines},
  url          = {http://dx.doi.org/10.1021/jo201556t},
  volume       = {76},
  year         = {2011},
}

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