C-H functionalization/C-N bond formation: copper-catalyzed synthesis of benzimidazoles from amidines.

An immense effort has been made to develop efficient strategies for the direct functionalization of C H bonds using transition-metal catalysis. For the most part, ruthenium-, rhodium-, and palladium-based catalysts have been applied to effect either C C or C Het (Het= heteroatom) bond formation by replacement of a C H bond. Few examples have been described that employ copper as catalysts, which is particular attractive due to its low cost and low toxicity. Herein, we disclose a new Cu(OAc)2catalyzed synthesis of benzimidazoles from amidines through a C H functionalization/C N bond-forming process that uses oxygen as the oxidant and generates water as the only direct waste product. Recently, we reported that carbazoles could be formed by intramolecular C H bond functionalization. We were eager to extend our approach to the synthesis of other classes of heterocycles, such as benzimidazoles, which are of considerable importance in medicinal chemistry. Brain0s palladiumcatalyzed N-arylation of (ortho-bromophenyl)amidines to give benzimidazoles inspired us to use amidines as our starting materials. The cyclization of amidines by oxidative means had been reported earlier. However, the use of stoichiometric amounts of reagents, such as Pb(OAc)4 [9] and iodine(III) compounds, and a rather narrow functionalgroup scope—only examples with Me, Cl, and Br substituents were reported—are major disadvantages. NaOCl is known to promote the cyclization as well via N-chlorinated amidines. Although the low cost of NaOCl is an appealing feature, low to moderate yields were obtained for amidines bearing functional groups, and as mentioned in one report, chlorinated side products might be anticipated when this method is applied. Altogether, these drawbacks prompted us to reinvestigate this transformation. We started our study by examining the conversion of Nphenylbenzamidine (1) into 2-phenylbenzimidazole (2). After an initial screen of palladium and copper catalysts, solvents, and reaction temperatures, we found that the use of 15 mol% Cu(OAc)2 in DMSO at 100 8C under an oxygen atmosphere produced 2 after 18 h in 19% yield with a low conversion of 1 (Table 1, entry 1). Using 5 equivalents of pyridine or triethylamine as a basic additive, the conversion was enhanced, but