Oxa-Michael Addition to ?,?-Unsaturated Nitriles: An Expedient Route to ?-Amino Alcohols and Derivatives.

ABSTRACT: Water addition to ?,?-unsaturated nitriles would give facile access to the ?-hydroxy-nitriles, which in turn can be hydrogenated to the ?-amino alcohols. We have previously shown that alcohols readily add in 1,4-fashion to these substrates using Milstein's Ru(PNN) pincer complex as catalyst. However, attempted water addition to ?,?-unsaturated nitriles gave the 3-hydroxynitriles in mediocre yields. On the other hand, addition of benzyl alcohol proceeded in excellent yields for a variety of ?-substituted unsaturated nitriles. Subsequent treatment of the benzyl alcohol addition products with TMSCl/FeCl₃ resulted in the formation of 3-hydroxy-alkylnitriles. The 3-benzyloxy-alkylnitriles obtained from oxa-Michael addition also could be hydrogenated directly in the presence of acid to give the amino alcohols as their HCl salts in excellent yields. Hydrogenation under neutral conditions gave a mixture of the secondary and tertiary amines. Hydrogenation in the presence of base and Boc-anhydride gave the orthogonally bis-protected amino alcohols, in which the benzyl ether can subsequently be cleaved to yield Boc-protected amino alcohols. Thus, a variety of molecular scaffolds with a 1,3-relationship between O- and N-functional group is accessible starting from oxa-Michael addition of benzyl alcohol to ?,?-unsaturated nitriles.

SUBMITTER: Guo B 

PROVIDER: S-EPMC6147005 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature