Reaction of Imidazoles, Oxazoles and Thiazoles

The order of reactivity for the reaction sites of azole compounds in electrophilic reactions is known to be 5 4 2 (77). Thus, arylation at the relatively electron-rich 5-position may be considered to be similar to that of pyrroles, furans and thiophenes. In contrast, reaction at the 2-position may be considered to proceed in a 

The reaction of 1-methyl-IH-imidazole with 2equiv. of iodo benzene leads to the production of its 5-phenyl derivative as the major product, along with the 2,5-diphenyl derivative. Interestingly, the addition of 2equiv. of Cul as promoter produces the 2-phenyl derivative, together with the 2,5-diphenyl derivative, but no 5-phenyl derivative is formed (Equation 10.54) [78]. It has been proposed that the 2-selectivity arises from the participation of a 2-imidazolylcopper species as intermediate [79-81]. 

Although, examples of the arylation of oxazole itself are Umited, the reaction with 2-chloro-3,6-dialkylpyridazines at the 5-position is known [58]. 2-Phenyloxa-zole [78] and benzoxazole [58, 78,91,92] are good substrates for the direct arylation (Equations 10.58 and 10.59) [78]. The arylation of oxazolo[4,5-fe]pyridine can be carried out under mild conditions (Equation 10.60) [93]. Treatment of ethyl 4-oxazolecarboxylate with iodobenzene in the presence of a catalyst system consisting of Pd(OAc)2 and IMes affords its 2-phenylated product predominantly (Equation 10.61) [94]. The regjoselectivity may be attributable to steric reasons. 

5-diarylation of thiazole can be carried out effectively with a bulky phosphine ligand. In this case, no monoarylated product is observed, even in the early stage of the reaction, which suggests that the second arylation proceeds relatively rapidly (Equation 10.62) [95]. The selective 2-arylation of thiazole is accomplished by using Cul and BU4NF as cocatalyst and base, respectively (Equation 10.63) [96]. By using Pd(OH)2/C as catalyst, the 5-position can be arylated selectively (Equation 10.64) [97]. The palladium-catalyzed arylation of thiazole as well as 1-methylpyrrole with a polymer-Unked aryl iodide has been reported [98]. 

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