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Transition metal-catalyzed alkyl group transfer between alkylamines has been known as amine exchange reaction (amine scrambling reaction) and used for the synthesis of unsymmetrical amines and N-heterocycles and the study of the metabolism of amines. During the course of our studies directed towards transition metal-catalyzed C-N bond activation of alkylamines, we developed an alkyl (or alkanol) group transfer from alkylamines (or alkanolamines) to Natom of anilines as well as α-carbon of ketones, which leads to a regioselective α-alkylation of ketones. The former transfer eventually leads to indoles and quinolines under the employed reaction conditions. However, except for our findings, there have been known only a few examples for the synthesis of N-heterocycles using such an amine exchange reaction. It is known that hydropyrimidines, imidazolidines and imidazoles could be formed by palladium-catalyzed intermolecular amine exchange reaction between diamines and alkylamines. Diamines were found to be cyclized to pyrrolidine, piperidine, and azepane via ruthenium-catalyzed intramolecular amine exchange reaction. On the other hand, in connection with this report, Murahashi et al. reported that N-methylbenzylamine reacts with o-phenylenediamine in the presence of Pd/C to give 2-phenylbenzimidazole and 1benzyl-2-phenylbenzimidazole in 37% and 25% yields, respectively. Under these circumstances, the present reaction was disclosed during the course of seeking for a more efficient catalytic system on an intrinsic amine exchange reaction. Herein this report describes an efficient synthesis of benzimidazoles via palladium-catalyzed amine exchange reaction from trialkylamines to o-phenylenediamine in an aqueous medium. To investigate the effect of reaction variants such as solvent, reaction temperature and time, o-phenylenediamine (1) and tributylamine (2a) were chosen as a model reaction. Treatment of equimolar amounts of 1 and 2a in toluene at 110 C for 20 h in the presence of a catalytic amount of 5% Pd/C afforded 2-propylbenzimidazole (3a) in 47% isolated yield with 67% conversion of 1 (run 1). Performing the reaction for a longer reaction time under two-fold molar ratio of 2a to 1 gave no improvement in the yield of 3a (run 2). Higher reaction temperature in toluene was needed for the effective formation of 3a (run 3). However, the reaction carried out under the further addition of H2O resulted in an increased yield of 3a (72%) along with concomitant formation of further N-alkylated benzimidazole 4 (2%) (run 4). In spite of further elaboration for the optimization of reaction conditions (runs 5-7), the best result in terms of the yield of 3a and the selectivity of 3a to 4 is best accomplished under the standard set of condition shown in run 4 of Table 1. Based on reaction conditions of Table 1, various trialkylamines 2 were subjected to the reaction with 1 in order to investigate the reaction scope, and several representative results are summarized in Table 2. An array of trialkylamines (2a-e) having straight alkyl chains reacted with 1 and the corresponding benzimidazoles (3a-e) were obtained in a range of 57-72% yields. Generally, the product yield gradually decreased as the alkyl chain length on 2a-e increases. Thus, in the reaction with 2d and 2e, a longer reaction time was needed for the allowable yield of products. Furthermore, in the case of 2e, three-fold molar ratio of 2e to 1 was necessary for the effective formation of 3e. When the reaction was carried out with two-fold molar ratio of 2e to 1 for 40 h under the employed conditions, 3e was obtained in 31% yield. In the reaction with trialkylamines (2f and 2g) having branched alkyl chains, similar reaction rate and yield were observed with triisoamylamine (2g), whereas higher reaction

bulletin of the korean chemical society

An Efficient Synthesis of Benzimidazoles via Palladium-Catalyzed Amine Exchange Reaction from Trialkylamines to o-Phenylenediamine in an Aqueous Medium