Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from alpha-Oxoketene Dithioacetals and beta-(Methylthio)-beta-(het)aryl-2-propenones

An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding a-oxoketene dithioacetals or beta-(het)aryl/(methylthio)enone precursors has been reported. In the first protocol, the alpha-oxoketene dithioacetals or beta-(methylthio)enones were converted to the corresponding alpha-bromo-beta-(methylthio)enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/(het)aryloxazoles via concomitant formation of the C4-N and C5-O bond via enamide intermediates. In the second approach, the starting alpha-oxoketene dithioacetals or beta-(methylthio)-beta-(het)arylenones were subjected to base induced conjugate addition-elimination with various primary amides to furnish beta-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C-H functionalization/C-O bond formation, afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4-(methylthio)/(het)aryl-5-(het)aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-(n-butyl)oxazoles from the corresponding 4- or 5-(methylthio)oxazoles.