Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α‑Oxoketene Dithioacetals and β‑(Methylthio)-β-(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 α-oxoketene dithioacetals
or β-(het)­aryl/(methylthio)­enone precursors has been reported.
In the first protocol, the α-oxoketene dithioacetals or β-(methylthio)­enones
were converted to the corresponding α-bromo-β-(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 α-oxoketene
dithioacetals or β-(methylthio)-β-(het)­arylenones were
subjected to base induced conjugate addition–elimination with
various primary amides to furnish β-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.