Halothiazole synthesis

Two of the most frequently used approaches for halothiazole synthesis are direct halogenation of thiazoles and the Sandmeyer reaction of aminothiazoles. The third method, an exchange between a stannylthiazole and a halogen, is not practical in the context of palladium chemistry simply because the stannylthiazole can be used directly in a Stille coupling. 

Some variants of the classic Sandmeyer conditions have been used for halothiazole synthesis. For example, sodium nitrite can be replaced with isoamyl nitrite or rm-buty] nitrite as illustrated by the transformation of 2-aminobenzothiazole 6 to 2-bromobenzothiazole 7 [10,11]. 

Salicylaldehyde, Schiff base with, 99 Salmonella typhi, 152 Salts, of acetamido thiazoles, 91 Sandmeyer reaction, in halothiazoles synthesis, 12... 

Thiazolyl sulfamic acids, rearrangement of sulfonic acid, 70 rearrangement to sulfonic acid, 75 by sulfonation, 75 2-Thiazolyl sulfenyl chloride, transformation to, thiazolyl disulfides. 412 2-Thiazolyl sulfide, in hydrocarbon synthesis, 406 oxidation of, with m-chloroperbenzoic acid, 415 with CrOj, 415 with Hj02,405,415 with KMn04,415 physical properties, infrared, 405 NMR, 404 pKa, 404 ultraviolet, 404 preparation of, from 2-halothiazoles and 5-Thiazolyl sulfides, bis-5-thiazolyl sulfide, oxidation of, 415 general, 418 5-(2-hydroxythiazolyl)phenyl sulfide case, 418 physical properties, 418 preparation of, 417-418 table of compounds, 493-496 uses of. 442 2-Thiazolyl sulfinic acid, decomposition of, 413 preparation of, from 2-acetamidothiazole sulfonyl chloride, 413 from A-4-thiazoline-2-thione and H, 0, 393,413 table of compounds, 472-473 5-Thiazolyl sulfinic add, preparation of,... 

The synthesis of thiazole boronic acids is quite complicated. In fact, attempts to prepare 2-thiazoleboronic acid were unsuccessful [27]. As a consequence, the Suzuki reaction involving thiazoles is only possible when the thiazole component serves as the electrophilic coupling partner. Halothiazoles have shown the greatest utility in this regard. For instance, 2,5-di-(2-thienyl)thiazole (45) was prepared by the union of 2,5-dibromothiazole and easily accessible 2-thiopheneboronic acid [27]. Unfortunately, the yield was poor and analogous reactions of 2,5-dibromothiazole with 3-thiopheneboronic acid and 2-selenopheneboronic acid both failed. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

Aminothiazole is easily diazotized in a concentrated solution of nitric and phosphoric acid. A large-scale procedure for the diazotization of 2-aminothiazole and its conversion to 2-bromothiazole has been reported . The synthesis of 2-halothiazoles can be easily achieved from 2-aminothiazole by (i) diazotization and (ii) treatment with CuCl, CuBr, or Nal <85JHC1621>. When the diazonium salt derived from 2-aminothiazole is treated with sodium azide the 2-azido derivative in equilibrium with its tetrazole cyclization product are obtained <92BMC1603>. 

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