Efficient and scalable synthesis of α,α-disubstituted β-amino amides?

Organic & Biomolecular Chemistry Pub Date: 2016-07-12 DOI: 10.1039/C6OB01219A

Abstract

A practical and efficient methodology for the preparation of 2-aminoethyl α,α-disubstituted β-amino amides in three steps from methyl cyanoacetate has been developed. The key step in the synthesis was the chemoselective reduction of the nitrile group in presence of an amide and aryl halide functionalities. Reduction with RANEY? Nickel catalyst, either with molecular hydrogen (8–10 bar) or under transfer hydrogenation conditions, necessitated in situ protection of the resulting amines with Boc2O, whereas aryl bromide containing nitriles could be chemoselectively reduced with ZnCl2/NaBH4 without debromination. The developed protocol involved only one chromatographic purification step and can be performed at gram scale.

Graphical abstract: Efficient and scalable synthesis of α,α-disubstituted β-amino amides
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