Thiazole 2-halides, coupling reactions

Cross-coupling Reactions. Several metalated and halo-genated thiazole species have been used for cross-coupling reactions, especially under Stille and Suzuki conditions However, there are not many examples of the direct use of 2-(trimethylsilyl)thiazole (1) in cross-coupling reactions with aryl or heteroaryl halides or triflates. 

Hosomi and coworkers described the cross-coupling reaction between arylsilanes or heteroarylsilanes and aryl halides mediated by a copper(I) salt. In particular, the cross-coupling reaction of 2-TST (1) with iodobenzene under fluoride- and palladium-free conditions (eq 31) was examined employing different solvents and copper(I) salts (Table 1). The yield of the product was increased in polar solvents such as 1,3-dimethyl-2-imidazolidinone (DMI). In addition, it was found that the reaction was best promoted by CuOCgFs because of the strong affinity of pentafluorophenoxide ion to the silicon atom, resulting in an accelerated transfer of the thiazole group to copper. 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

The extensive work carried out by Beller in recent years has contributed to the field with a series of interesting examples, most of them based on the system palladium/di-1 -adamantyl- -butylphosphine (BuPAdj). Thus, they reported the use of ammonia as the nitrogen source for the palladium-catalyzed aminocarbonylation of aryl halides, providing a straightforward method to prepare primary amides with excellent applicability and functional group tolerance [4]. In the same group, the first carbonylative C—H activation reactions of heteroarenes to form diaryl ketones 4 were developed [5], A series of nonpreactivated heteroarenes 3 (oxazoles, thiazoles, and imidazoles) were successfully carbonylative coupled to a wide range of aryl iodides (Scheme 3.2). To avoid the formation of the noncarbonylative... 

At the same time, Itami and coworkers described a very similar series of couplings of azoles (benzthiazoles, benzoxazoles, benzimidazoles, thiazoles, and imidazoles) with aryl and heteroaryl halides and triflates using nickel(ll) acetate-bipyridyl and nickel(II) acetate-dppf catalysts, with lithium t-butoxide in dioxan. The Ni(OAc)2. bipy catalyst system was optimal for aryl/heteroaryl bromides and iodides (Scheme 5.4, Table 5.3), and the Ni(OAc)2.dppf system was effective for aryl/heteroaryl chlorides and triflates (Scheme 5.5, Table 5.4). Reaction temperatures were 85°C for the former and 140°C for the latter, and in both cases 1.5 equivalents of lithium /-butox-ide was required, a considerably lower loading than required under Miura s conditions. Fortuitously, there are a number of final products common to both authors,... 

Readily available Ifl-perfluoroalkanes can also be used for radical alkylation. This method employs, for example, thiazolyl iodide and 1/f-perfluoroalkane reagents, DMPU solvent, TMPjZn base, and a copper chloride/phenanthroline catalyst [8]. The reaction mechanism includes deprotonation of IH-perfluoroalkanes with TMPjZn to afford bis(perflnoroalkyl)zinc species. Subsequent transmetalla-tion with copper halide produces a mixture of anionic Cu species that reacts with aryl iodides (including thiazoles), either directly or via a neutral perfluoroalkyl compound, to give the coupling product. 

Low yields were obtained in the absence of pivalic acid however, employing greater than 30% pivalic acid did not further improve yields or reactivity. Substrates that performed well included C3-substituted benzothiophenes, C2-substituted thiophenes, pyrroles, imidazole, triazole, imidazopyridine, thiazole, and oxazoles, which could be efficiently arylated with aryl bromides. Unfortunately, benzofuran produced low yields (29% with 2-bromotoluene), and furans encountered issues with diarylation, which could be minimized by using more sterically hindered aryl bromides. Arylation of indolizines could be achieved, albeit electron-deficient aryl bromides required longer reaction times (16-24 h). Heterocyclic aryl bromides, such as 3-bromopyridine, could also be employed with thiazole. Problematic aryl halides included cyano, nitro, acetyl, pyridyl functionalities, and N-heterocyclic V-oxides. Other coupling partners, such as aryl tri-flates and aryl chlorides, performed poorly under the reaction conditions. Unsuitable heterocycles included unprotected imidazoles, 2-aminothiazole, isoxazole, benzothiazole, and benzoxa-zole, which failed to produce arylated products. 

Knochel showed that 2-thiazolylzinc species 42 cross-coupled with aromatic or aliphatic electrophiles to give the corresponding products 43 and 44, respectively, in the presence of copper and palladium catalysts. 2,4-Dibromothiazole has been used as halide in Negishi reactions the crosscoupling took place selectively in the 2-position in 50-62% yield. The formation of zinc species in the 5-position of thiazole can also be prepared if the 2-position was protected with a trimethylsilyl group as in 45 before the organozinc derivative 46 was formed in the 5-position. The subsequent... 

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