Conversion of anilines to chiral benzylic amines via formal one-carbon insertion into aromatic C\u2013N bonds

Lei Li,Qiuqin He,Min Yang,Renhua Fan

doi:10.1038/s41467-020-18593-4

Lei Li, Qiuqin He + Show 2 more

Open Access

https://doi.org/10.1038/s41467-020-18593-4

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Journal: Nature Communications	Publication Date: Sep 23, 2020
Citations: 14	License type: open-access

Affiliation: Fudan University, Gannan Medical University

Abstract

Insertion of atoms into aromatic carbon-nitrogen bonds is an appealing method for the synthesis of nitrogen-containing molecules and it has the advantage of the availability and abundance of anilines. However, the direct cleavage of aromatic carbon-nitrogen bonds is challenging due to the particularly inert and stable nature of these bonds. Here we report a formal, enantioselective one-carbon insertion into an aromatic carbon-nitrogen bond via an aromaticity dissembly-reconstruction process to directly convert anilines to chiral α-branched benzylic amines. The process involves oxidative dearomatization of para-substituted anilines, chiral sulfur ylide-mediated asymmetric aziridination, and subsequent rearrangement. Chiral sulfur ylides serve as one-carbon insertion units.

Highlights

Insertion of atoms into aromatic carbon-nitrogen bonds is an appealing method for the synthesis of nitrogen-containing molecules and it has the advantage of the availability and abundance of anilines
Chiral sulfur ylides serve as the one-carbon insertion unit
Subsequent rearrangement might be promoted by a Brønsted or Lewis acid to redevelop the aromaticity and complete the formal enantioselective one-carbon insertion

Summary

Results

Subsequent rearrangement might be promoted by a Brønsted or Lewis acid to redevelop the aromaticity and complete the formal enantioselective one-carbon insertion. This builds the nitrogen-substituted benzylic stereocenter and is accompanied by migration of the para-substituent to the meta position and concomitant para-substitution by a nucleophilic reagent. To implement this strategy, the rapid oxidative dearomatization of p-toluidine 1 was tested by examining various oxidants including mCPBA, AcOOH, t-BuOOH, H2O2, PhI (OAc)[2], and PhIO. When 20 mol% Cu(OTf)[2] was used instead of 2 equivalents CF3COOH, the yield of 2 was improved to 79% yield and 96% ee (for details, see Supplementary Table 1 in the Supplementary Information)

H H N Ts

H NHTs I

H NHTs X

H NHTs R2

Discussion

Methods