Palladium-Catalyzed Arylation of Azole Compounds with Aryl Halides in the Presence of Alkali Metal Carbonates and the Use of Copper Iodide in the Reaction

Abstract

The reactions of iodobenzene with azole compounds, 1,2-disubstituted imidazoles and 2-substituted oxazoles and thiazoles, were examined in the presence of catalytic amounts of Pd(OAc)2 and PPh3 in DMF using alkali metal carbonates as bases. It was found that the coupling products, 5-arylazoles, could be selectively produced in good yields by using Cs2CO3. In the case that their 2-position is unsubstituted, the site could also be arylated. In reactions using bromobenzene in place of iodobenzene, K2CO3 was also as effective as Cs2CO3. The addition of a stoichiometric amount of CuI appeared to specifically promote the reactions of thiazoles as well as those of thiophene derivatives. The reactions of 2-unsubstituted azole compounds with aryl iodides could be mediated by CuI to some extent without using the palladium species to give 2-arylazoles.

Direct transition metal-catalyzed functionalization of heteroaromatic compounds

“…3 It was found that in the presence of catalytic amounts of Pd(OAc) 2 and PPh 3 in DMF, the coupling products, 5-arylated azoles 17, can be synthesized selectively in good yields. 3 Interestingly, it was shown that the addition of stoichiometric Cu(I) salt significantly increases reactivity of the C-2 position of azoles leading to 2-arylated products 18. Although the trend of reactivity in the electrophilic reactions of the azole ring is known to be C-5>C-4>C-2, in the presence of CuI alone (no Pd catalysis), a substantial amount of C-2 substituted product formed, which was attributed to an alternative operating mechanism.…”

“…It was proposed that exchange of the most acidic proton at C-2 with Cu results in an organocopper intermediate, which is enabled to undergo cross-coupling with aryl halide to form C-2 arylated product 18 (Scheme 9). 3 Furthermore, Miura reported a method for palladium-catalyzed multiple arylation of thiophenes 19 and 22 (Scheme 10). 25 Thiophene carboxamides were shown to undergo triarylation, accompanied by formal decarbamoylation in the presence of Pd(OAc) 2 , Buchwald's ligand (P(o-biphenyl)( t Bu) 2 ) or P( t Bu) 3 , and Cs 2 CO 3 in refluxing xylene.…”

“…3 Furthermore, Miura reported a method for palladium-catalyzed multiple arylation of thiophenes 19 and 22 (Scheme 10). 25 Thiophene carboxamides were shown to undergo triarylation, accompanied by formal decarbamoylation in the presence of Pd(OAc) 2 , Buchwald's ligand (P(o-biphenyl)( t Bu) 2 ) or P( t Bu) 3 , and Cs 2 CO 3 in refluxing xylene. 25 3-Substituted thiophenes 19, bearing EWGs, can also be converted to triarylated products 21 in high yields.…”

“…This mechanism has often been considered as the most probable mechanism for arylation of heterocycles. 3,5,13,14 Naturally, the absence of an isotope effect in the arylation of 11 (Scheme 6) does not contradict pathway A, as the deprotonation event in the electrophilic mechanisms is not a rate-limiting step. 15 Additionally, it is well known that the pyrrole ring of an indolizine is electron-rich and easily undergoes electrophilic substitution reactions.…”

“…four distinct mechanisms have been proposed to date: electrophilic aromatic substitution (A), 3 C-H activation (B), 4 cross-coupling (C), 3 and Heck-type arylation (D) 5 (Scheme 2).…”