Chiral oxazoline ligands with two different six-membered azaheteroaromatic rings – synthesis and application in the Cu-catalyzed nitroaldol reaction

Abstract

Abstract Synthesis and catalytic activity of chiral ligands 5,6-diphenyl-3-{3-[(4S/R)-4-R/Ar-4,5-dihydro-1,3-oxazol-2-yl]pyridin-2-yl}amino-1,2,4-triazines 2 and their analogs 3 possessing an N-oxide function in the pyridine ring are described. The pivotal step in the synthesis of ligands 2 is the Buchwald-Hartwig Pd-catalyzed cross-coupling reaction between 3-bromo-5,6-diphenyl-1,2,4-triazine (7a) and enantiopure 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-amines 6a–d. Aromatic nucleophilic substitution of chlorine in 3-chloro-5,6-diphenyl-1,2,4-triazine (7b) with 3-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-amine 1-oxides 12 was investigated as the key reaction in the synthesis of ligands 3. Two undesired derivatives 13 or 14, resulting from unexpected reactions of 3, were isolated depending on reaction conditions. Compounds 2 and 3 as well as the side products 13 and 14 were screened as chiral ligands in the copper catalyzed enatioselective nitroaldol reaction.