Synthesis of optically active 2-substituted azetidine-2-carbonitriles from chiral 1-arylethylamine via α-alkylation of N-borane complexes?

RSC Advances Pub Date: 2021-07-06 DOI: 10.1039/D1RA04585G

Abstract

The base-promoted α-alkylation of N-((S)-1-arylethyl)azetidine-2-carbonitriles 3 via formation of their N-borane complexes 4 was investigated. For example, treatment of diastereomerically pure borane N-((S)-1′-(4′′-methoxyphenyl)ethyl)azetidine-2-carbonitrile complex (1S,2S,1′S)-4b with 1.2 equivalents of LDA at ?78 °C followed by 1.3 equivalents of benzyl bromide at ?78 °C and warming to room temperature produced α-benzylated (2S,1′S)-5ba in 72% yield and (2R,1′S)-5ba in 2% yield. A mechanism for this diastereoselective α-alkylation was proposed. Our method enables the production of optically active 2-substituted azetidine-2-carbonitriles, such as α-benzylated (S)-10a and (R)-10a, starting from commercially available (S)-(1-(4-methoxyphenyl)ethyl)amine.

Graphical abstract: Synthesis of optically active 2-substituted azetidine-2-carbonitriles from chiral 1-arylethylamine via α-alkylation of N-borane complexes
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