Regioselectivity in the lithiation of methyl-substituted thiazole- and oxazole-carboxylic acids and carboxamides: general methods for the elaboration of trisubstituted thiazoles and oxazoles

Abstract

A number of anionic intermediates have been developed which are suitable for the elaboration of trisubstituted thiazoles and oxazoles. Thus, deprotonation of 2, 4-dimethylthiazole-5-carboxylic acid 9 using either BuLi or LDA occurs regiospecifically at the 2-methyl site to give dianion 10 which has been condensed with a range of electrophiles leading to high yields of the homologues 11. The chemistry of the corresponding oxazole 17 is essentially the same, leading to homologues 19via dianion 18. When the 2-position is substituted by a phenyl group, as in 4-methyl-2-phenylthiazole-5-carboxylic acid 23, deprotonation of the 4-methyl group, although relatively more difficult, is possible to give dianion 24 and thence homologues 25. Similar reactions of the corresponding oxazole 26a appeared to be less useful. Deprotonations of the 2,5-dimethyl isomers 28a and 31a were not regiospecific but occurred in varying proportions at both sites under a variety of conditions. Again, substitution of the 2-position by a phenyl group allowed regiospecific deprotonation of the 5-methyl group in acids 33 and 36a. The thiazole dianion 34 gave good yields of the expected derivatives 35 upon reactions with electrophiles. The regioselectivity problems associated with deprotonations of the 2,5-dimethylazole acids 28a and 31a were solved by conversion into the corresponding amides 37 and 40, both of which underwent regiospecific deprotonation using BuLi leading to the monoanions 38 and 41 and thence to the homologues 39 and 42.