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. 2019 Mar 14;10(16):4509-4514.
doi: 10.1039/c9sc00323a. eCollection 2019 Apr 28.

Secondary amines as coupling partners in direct catalytic asymmetric reductive amination

Zitong Wu  1 , Shaozhi Du  1 , Guorui Gao  2 , Wenkun Yang  1 , Xiongyu Yang  1 , Haizhou Huang  1 , Mingxin Chang  1
Affiliations

Secondary amines as coupling partners in direct catalytic asymmetric reductive amination

Zitong Wu et al. Chem Sci. .

Abstract

The secondary amine participating asymmetric reductive amination remains an unsolved problem in organic synthesis. Here we show for the first time that secondary amines are capable of effectively serving as N-sources in direct asymmetric reductive amination to afford corresponding tertiary chiral amines with the help of a selected additive set under mild conditions (0-25 °C). The applied chiral phosphoramidite ligands are readily prepared from BINOL and easily modified. Compared with common tertiary chiral amine synthetic methods, this procedure is much more concise and scalable, as exemplified by the facile synthesis of rivastigmine and N-methyl-1-phenylethanamine.

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Figures

Fig. 1
Fig. 1. Selected chiral tertiary amine drugs.
Scheme 1
Scheme 1. Routes for the synthesis of chiral tertiary amines.
Scheme 2
Scheme 2. Practical application of DARA of secondary amines to prepare tertiary amines.
Scheme 3
Scheme 3. Deuterium incorporation studies.
Scheme 4
Scheme 4. Proposed reaction pathways.
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