A Bioinspired Catalytic Aerobic Oxidative CH Functionalization of Primary Aliphatic Amines: Synthesis of 1,2‐Disubstituted Benzimidazoles

Abstract

Aerobic oxidative C–H functionalization of primary aliphatic amines has been accomplished with a biomimetic cooperative catalytic system to furnish 1,2-disubstituted benzimidazoles that play an important role as drug discovery targets. This one-pot atom-economical multistep process, which proceeds under mild conditions, with ambient air and equimolar amounts of each coupling partner, constitutes a convenient environmentally friendly strategy to functionalize non-activated aliphatic amines that remain challenging substrates for non-enzymatic catalytic aerobic systems.

Catalytic Oxidative Coupling of Primary Amines under Air: A Flexible Route to Benzimidazole Derivatives

“…This result indicates that N-methyl-o-aminoaniline (3a) is much more reactive than its N-phenyl congener as with the latter only 30 % (45 % conversion) of the related 1,2-disubstituted benzimidazole was isolated under the same experimental conditions. [14] The full conversion of 3a could be achieved after 48 h at 45°C, giving benzimidazole 4aa in 86 % yield (Scheme 3). We attempted to reduce the reaction time by increasing the temperature to 60°C but, after 24 h, the yield of benzimidazole 4aa decreased to 37 % yield (45 % conversion) due to the slow decomposition of the o-iminoquinone organocatalyst 1 ox to melanin-like polymers.…”

“…[14] Therefore, the only possibility for avoiding the formation of byproduct 5a, which is formed in the presence of MeOH, was to change the nature of the solvent. Thus, we performed optimization studies on the CuBr 2 /1 ox -mediated aerobic oxidative condensation of o-aminoaniline 3a with nonactivated aminomethylcyclohexane (2k) as the amine substrate (Table 2).…”

“…[14] The catalytic process, inspired by copper amine oxidase activity, combines two redox couples in a way reminiscent of other biomimetic catalytic systems: [9b,15] low loadings of biocompatible CuBr 2 as electron-transfer mediator and the topaquinone-like substrate-selective catalyst 1 ox generated in situ from the oxidation of 1 red by CuBr 2 /air (Scheme 2) are sufficient to activate the α-C-H bond of aliphatic primary amines, which are then converted, in the presence of o-aminoanilines, into cross-coupled imines B through a transamination process that leads to the homocoupled imine intermediate A, followed by dynamic transimination.…”

“…This promised to be a trivial exercise due to the related chemistry of its N-phenyl congener that we had recently reported. [14] However, applying the conditions that had previously proven most effective (6 mol-% 1 red precursor of 1 ox , 0.4 mol-% CuBr 2 , MeOH, 45°C, air), the oxidative condensation of N-methyl-o-aminoaniline (3a) with a range of primary amines 2 was not selective, affording, in addition to the desired 1,2-disubstituted benzimidazole product 4, N-methylbenzimidazole (5a) as a minor product. Its formation, in an isolated yield of up to 28 %, was favored when the rate of the main reaction was affected either by steric effects in the case of benzylic amines (Table 1, entry 7) or by the decreased reactivity of the -branched alkylamines (Table 1, entries 17 and 18).…”

“…To date, mainly N-phenyl-o-aminoaniline had been engaged in the oxidative condensation reaction with a range of primary amine substrates to produce 2-substituted N-phenylbenzimidazoles. [14] For a more comprehensive investigation of the potential of the bioinspired cooperative catalytic system, variation of the o-aminoaniline substrate is essential. From this perspective, there are several challenges inherent to this cascade reaction sequence that need to be addressed.…”