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Synthesis 2010(4): 605-612  
DOI: 10.1055/s-0029-1218599
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Two-Step Synthesis of 3,4-Disubstituted Piperidines from Acyclic Precursors through Tetrahydropyridine Intermediates

José M. Aurrecoechea*, José M. Gorgojo, Carlos Saornil
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Apartado 644, 48080 Bilbao, Spain
Fax: +34(94)6013500; e-Mail: jm.aurrecoechea@ehu.es;
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Publication History

Received 10 July 2009
Publication Date:
11 December 2009 (online)

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Abstract

Cyclocondensation between acyclic 5-aminopent-2-enoate esters and aliphatic aldehydes containing an unsubstituted α-methylene unit affords 1,2,3,4-tetrahydropyridine derivatives in good yields. The reaction has been applied to a range of aldehydes, showing good functional group tolerance. Chemoselective hydride reduction of the enamine double bond provides 3,4-disubstituted tertiary piperidine derivatives with acceptable to good diastereoselectivities, whereas catalytic hydrogenation of N-benzyl derivatives leads directly to the corresponding secondary piperidines.

Key words

condensation - cyclizations - reductions - piperidines - stereoselective synthesis

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8

This was indicated by the presence in the crude ¹H NMR spectrum of new doublets at ca. δ = 5.3 and 6.8 ppm replacing the characteristic phenylacetaldehyde signals.

12

Stereochemical elucidation based on NOE measurements was impractical in this case due to signal overlap. In previous work, we have confirmed the validity of assignments based on the observation of γ-gauche effects using NOE studies on related piperidine derivatives (see ref. 3).

13

Also characteristic of the cis-isomers was the room temperature broadening of some of the ¹³C NMR resonances, because of conformational interconversion between two equatorial/axial conformers, whereas the corresponding signals in the diequatorial trans-isomers were sharp.