Regioselective α- and β-metallations of thiophene derivatives bearing the 4,4-dimethyloxazolin-2-yl group. Application of the method to syntheses of 2,3- and 2,5-disubstituted thiophene derivatives

Abstract

The effects of change of solvent, metallating agent, reaction time and temperature, and of the presence or absence of agents capable of complex formation with either the lithium cation or the oxazoline moiety, on the lithiation of 4,4-dimethyl-2-(2-thienyl)oxazoline are explored. Conditions are thereby estab-lished for high-yielding syntheses of the 3- and 5-lithio-intermediates and for control of regioselectivity of metallation. The nucleophilicity of the 3-lithio-intermediate is profoundly solvent dependent, and appropriate conditions for reaction of both 3- and 5-lithiated species with a wide variety of electrophiles are presented. Syntheses of a range of 2,3- and 2,5-disubstituted thiophene derivatives have thereby been achieved, utilising, in addition, a new method for the transformation of oxazolino into carboxy functionality.

The balance between basicity and nucleophilicity of the 3-lithio-intermediate in its reaction with [¹H₆]- and [²H₆]-acetone is shown to be sensitive to isotope effects.