A new protocol for the direct C-2 arylation of azoles, including free (NH)-imidazole, -benzimidazole and -indole

Recently, in the course of our investigations on the synthesis of vicinal diaryl-substituted 1H-imidazoles by transition metal-catalyzed direct arylation procedures via C–H bond activation,1,2 we reported a new, reliable and convenient method for the regioselective Pd- and Cu-mediated direct C-2 arylation of azoles, including free (NH)–imidazole, –benzimidazole and –indole, under base-free and ligandless conditions.3 The preliminary results obtained in this context encouraged us to perform a more in-depth study in order to determine the most suitable reaction conditions for performing efficiently the Pd- and Cu-mediated direct C-2 arylation of various kinds of azoles. Thus, we found that 1-aryl-1H-imidazoles, 1-methyl-1H-imidazole, 1H-imidazole, thiazole, 1H-benzimidazole, 1-benzyl-1H-imidazole and benzothiazole can undergo regioselective C-2 arylation by reaction with 2 equiv of an aryl iodide in DMF at 140°C for 48 h in the presence of 5 mol % Pd(OAc)2 and 2 equiv of CuI, under base-free and ligandless conditions, to provide the required 2-arylazoles in satisfactory to excellent yields. DMA and DMPU could also be used as solvents, but the arylation in toluene or dioxane didn’t proceed at all. The arylation reaction could also be performed using 5 mol % Pd/C and 2 equiv of CuI in DMF at 140 °C, and under these conditions the required azoles were prepared in yields similar to those obtained via reactions performed under homogeneous conditions, although the reaction times were longer (ca. 72 h). We also found that the best results for the C-2 arylation of indole could be obtained when the reaction was performed by treatment of the azole with 2 equiv of an aryl iodide in the presence of 5 mol % Pd(OAc)2 and 2 equiv of CuI in DMA at 160 °C instead of in DMF at 140 °C. However, also using these modified experimental conditions the required 2-aryl-1H-indoles were obtained in modest yields. Modified reaction conditions were also used to prepare in a good yield 2-(4-methoxyphenyl)oxazole which we previously obtained in a low yield.3 In fact, when 3 equiv of oxazole were reacted with 1 equiv of iodoanisole in DMF at 140°C for 74 h in the presence of 5 mol % Pd(OAc)2 and 2 equiv of CuI, the required 2-arylazole was obtained in 74 % yield. Interestingly, aryl bromides could also be used as electrophiles in the Pd- and Cu-mediated C-2 arylation of the above mentioned heterocycles, provided that 4 equiv of NaI were added to the reagents. 1,2-Diphenyl-1H-imidazole was so prepared in 47 % yield from 1-phenyl-1H-imidazole and 2 equiv of bromobenzene. Our new C-2 arylation method was then applied for preparing some bioactive heterocycle derivatives such as 4-methyl-2-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)-1H-imidazole, which is a selective COX-2 inhibitor,4 and 2-(4-nitrophenyl)-1H-benzimidazole, which is a key intermediate for the synthesis of heparanase inhibitors,5 in 78 and 89 % yield, respectively. At present, we are performing studies on the synthesis of 2,4(5)-diaryl-1H-imidazoles via reaction sequences involving the Pd- and Cu-mediated C-2 arylation of 4(5)-aryl-1H-imidazoles or 5-aryl-1-benzyl-1H-imidazoles under base-free and ligandless conditions.