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. 2013 Oct 30;135(43):16074-7.
doi: 10.1021/ja4096472. Epub 2013 Oct 16.

Simple catalytic mechanism for the direct coupling of α-carbonyls with functionalized amines: a one-step synthesis of Plavix

Ryan W Evans  1 , Jason R Zbieg, Shaolin Zhu, Wei Li, David W C MacMillan
Affiliations

Simple catalytic mechanism for the direct coupling of α-carbonyls with functionalized amines: a one-step synthesis of Plavix

Ryan W Evans et al. J Am Chem Soc. .

Abstract

The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino-substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high-profile pharmaceutical agents, Plavix and amfepramone.

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Figures

Figure 1
Figure 1
Medicinal use, strategies towards α-amino carbonyls.
Scheme 1
Scheme 1
Design of Cu(II)-catalyzed carbonyl–amine coupling.
See this image and copyright information in PMC

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