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Synlett 2011(9): 1195-1211  
DOI: 10.1055/s-0030-1260558
ACCOUNT
© Georg Thieme Verlag Stuttgart ˙ New York

Development of New N,N-Ligands for the Enantioselective Copper(II)-Catalyzed Henry Reaction

Gonzalo Blay*, Víctor Hernández-Olmos, José R. Pedro*
Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot (València), Spain
Fax: +34(96)3544328; e-Mail: jose.r.pedro@uv.es; e-Mail: gonzalo.blay@uv.es;
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Publication History

Received 13 December 2010
Publication Date:
13 May 2011 (online)

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Abstract

This account shows our efforts towards the development of new N,N-ligands and their application in the asymmetric Henry reaction. Iminopyridine ligands were prepared by the condensation of chiral monoterpene ketones and pyridinylalkylamines. The complexes of these ligands with copper(II) ions catalyzed the enantio­selective addition of nitromethane to aldehydes with generally high yields and moderate enantioselectivities. The same reaction with other nitroalkanes gave racemic products. Stereoselective reduction of the imino group allowed us to obtain new aminopyridine ligands. The new ligands were shown to be more efficient, and they catalyzed the addition of nitromethane and also larger nitroalkanes to aldehydes to give the corresponding products in generally very high yields and excellent enantiomeric excesses. We have used this aminopyridine catalytic system in the first catalytic enantioselective Henry reactions with bromo(nitro)methane and methyl 4-nitrobutanoate. The reaction involving the latter substrate gave multifunctional chiral building blocks that were transformed into γ-lactams and δ-lactones. The application of the reaction to the synthesis of known amino(aryl)ethanol pharmaceuticals is also reported. Im­inopyridine ligands, however, were more efficient in the addition of nitromethane to α-keto esters.

1 Introduction

1.1 Enantioselective Copper(II)-Catalyzed Henry Reaction

2 Enantioselective Henry Reaction with Aldehydes Catalyzed by Copper(II)-Iminopyridine Complexes

2.1 Design and Synthesis of Iminopyridine Ligands

2.2 Enantioselective Addition of Nitromethane to Aldehydes

2.3 Stereochemical Models

3 Enantioselective Henry Reaction with Aldehydes Catalyzed by Copper(II)-Aminopyridine Complexes

3.1 Design and Synthesis of Aminopyridine Ligands

3.2 Enantioselective Addition of Nitroalkanes to Aldehydes

3.3 Enantioselective Addition of Bromo(nitro)methane to ­Aldehydes

3.4 Enantioselective Addition of Methyl 4-nitrobutanoate to Aldehydes

3.5 Synthesis of Chiral Amino(aryl)ethanol Derivatives

4 Enantioselective Henry Reaction with α-Keto Esters

5 Conclusion

Key words

asymmetric catalysis - nucleophilic additions - nitro ­alcohols - C 1-symmetry - N,N-ligands