Copper-Catalyzed Enantioselective N-H Insertion Reactions

Key words

copper - N-H insertion reaction - chiral spiro bisoxazolines - α-diazoesters - α-amino acid derivatives

Significance

A highly enantioselective catalytic insertion of α-diazoesters into N-H bonds is reported. The catalyst is prepared from a Cu(I) source, a spiro-bisoxazoline ligand, and a BARF counterion. A wide range of substituted anilines and naphthalenamines could be used for the insertion reaction with complete conversions observed within two hours and high yields and enantio­selectivities were obtained. However, an electron-donating group in the para position of a phenyl-substituted aniline or a halogen at the ortho position resulted in slightly lower enantioselectivities for unknown reasons. The ester group on the diazoester could be changed with negligible effect; however, the diazo substituent is more sensitive and can lead to lower yields or ee values. No enantioselectivity was induced with N-meth­ylaniline and benzamide, and cyclohexylamine was inert under the reported conditions.

Comment

Although significant effort has been focused on diazoesters over the years, a highly enantioselective catalytic N-H insertion has remained elusive until the present communication. The authors note that the spiro-bisoxazoline ligand, which was developed in their labs, provided optimal enantioselectivities compared to other spiro bisoxazolines, with one diastereomer of the ligand exhibiting a matched combination of chiralities. Also, the nature of the counterion significantly affects the reaction; the catalyst with the BARF counterion has high enough activity that only 1 mol% of the catalyst is needed. Copper(II) could also be used as the catalyst precursor; however, it provides lower ee values. Chloroform and benzene could also be used as solvents, though using acetonitrile resulted in significantly longer reaction times.