A simple and efficient approach to the synthesis of 2-substituted benzimidazole via sp³ C–H functionalization

1 Introduction

Transition metal catalyzed sp³ C–H bond activation and subsequent C–N bond formation have attracted great interest in recent years (Lyons and Sanford, 2010; Godula and Sames, 2006; Dick and Sanford, 2006; Collet et al., 2009; Li, 2008). Synthetic methodology using metal free coupling reaction (Tu et al., 2008; Fan et al., 2009; Batracharya and Daugulis, 2008; Zhang and Li, 2006; Zhang et al., 2010) provides advantages, such as higher atom economy, shorter synthetic route and more economical feedstock, which lead to “benign by design” green chemistry (Winterton, 2001; Anastas and Warner, 1998). Applications of such metal free C–H functionalization tandem reaction can be of great importance in synthesizing heterocyclic rings. 2-Substituted benzimidazoles have drawn much attention for their various biological and pharmacological activities (Tebbe et al., 1997; Porcari et al., 1998; Migawa et al., 1998; Fonseca et al., 2001; Elokdah et al., 1998).

A number of methods for the synthesis of 2-substituted benzimidazole have been reported. Among these, most classical approaches start with o-phenylenediamine. One such approach involves the condensation of o-phenylenediamine with acid chloride (Grimmet, 1984; Wright, 1951; Middleton and Wibberley, 1980; Hisane et al., 1982). The second approach involves the reaction of o-phenylenediamine with aldehyde in the presence of an stoichiometric or catalytic amount of oxidant (Vanden et al., 1995; Lee and Janda, 2001; Chikashita et al., 1987; Patzold et al., 1992; Bhatagar and George, 1968; Stephens et al., 1949; Beaulieu et al., 2003; Bahrami et al., 2007; Varala et al., 2007; Du and Wang, 2007; Mukhopadhyay and Tapaswi, 2008; Chen et al., 2008). Another approach involves the reaction of o-phenylenediamine with alcohol at high temperatures (Kondo et al., 1991; Wilfred and Taylor, 2004). Recently, 2-substituted benzimidazoles have been synthesized via CuI/amino acid catalyzed coupling reaction of 2-haloacetanilides with primary amines (Zhou et al., 2007) or ammonia (Diao et al., 2009). Buchwald has reported the use of a novel Cu(OAc)₂ catalytic system for C–H functionalization/C–N bond formation for the synthesis of benzimidazoles (Brasche and Buchwald, 2008). Although a wide range of methods are available for synthesis of benzimidazoles, a real need exists for new procedures that support many kinds of structural diversity and various substitution patterns in the target library.

Recent report on cross dehydrogenative coupling (CDC) using non-metal catalytic oxidation system (Tu et al., 2008; Fan et al., 2009; Batracharya and Daugulis, 2008; Zhang and Li, 2006; Zhang et al., 2010) has prompted us to develop a simple and efficient approach to the synthesis of benzimidazoles derivatives. Here we report a simple, efficient, tandem oxidative dehydrative coupling reaction of N-benzylbezene-1,2-diamine in the presence of oxidant tert-butyl hydroperoxide (TBHP) in solvent acetonitrile to give substituted benzimidazole derivatives (Scheme 1).

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Scheme 1

Tandem oxidative cyclization of different N-substituted benzene-1,2-diamines.

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2 Materials and methods

3 Results and discussion

To begin with the study of intramolecular CDC, we chose N-benzylbezene-1,2-diamine as standard substrate to search for potential oxidant and suitable reaction conditions (Table 1).

Initially when N-benzylbezene-1,2-diamine was treated with 5 mol.% of iodine with 2 eq. TBHP at room temperature for 12 h, 42% of the product was obtained (Table 1, entry 1) but without iodine no product was formed (Table 1, entry 2). After the ratios of iodine, N-benzylbezene-1,2-diamine and TBHP (2 eq.) were optimized, the reaction yield was improved to 92% (Table 1, entry 3). The other environmentally benign oxidants, such as ter-BuOCl, aqueous H₂O₂ and oxygen were also examined but only H₂O₂ gave the product in low yield. In addition, we tried other organic oxidants, such as DDQ, PhI(OAc)₂. With DDQ, only a trace amount of product was obtained (Table 1, entry 7) whereas 1 eq. PhI(OAc)₂ gave the product in low yield (Table 1, entry 9). When 2 eq. PhI(OAc)₂ was employed in acetonitrile without additives, the product was formed in good yield. With TBHP solution in hexane as an oxidant the yield was good. To optimize the choice of solvents, various solvents like DMSO, dioxane, hexane, and toluene were tried. It was observed that acetonitrile was the best among all. However, in toluene and dioxane no product was observed, with dimethyl sulphoxide, the desired product was obtained in lower yield 45%. Using the optimized conditions, we next explored the scope and generality of the process. Various derivatives of N-substituted bezene1,2-diamine were prepared by the coupling of alkyl amines and 2-iodonitrobenzene (Prokopcova and Kappe, 2007), and followed by a nitro reduction reaction.

To establish generality of reaction different N-substituted benzene-1,2-diamine derivatives were investigated as reaction substrates and found that various substrates were converted into corresponding product with moderate to good yield under these conditions. The results are summarized in Table 2.

Table 2 Synthesis of benzimidazole derivatives by dehydrative C–N bond formation method.

Entry no.	Substrate 1	Product 2	Time (h)	Yield (%)
2a			2	90
2b			2	86
2c			4	69
2d			2.5	75
2e			3	90
2f			3	80
2g			3.5	70
2h			2.5	72
2i			2.	88
2j			2.5	75
2k			2.5	73
2l			2	94
2m			2	90
2n			2	87
2o			3	76
2p			4	71
2q			4	67
2r			3.5	74
2s			4	80
2t			4	65
2u		No product was formed	4	0
2v		No product was formed	4	0

When methoxy group was moved from the para to the ortho position of the benzylic amine ring the yield was reduced from 86% to 69% (Table 2, entry 2c), which indicated that steric hindrance dis favored this reaction. The electron withdrawing substituents favored the reaction as compared to the electron donating substituents. Functional group like OH was not affected during oxidation process (Table 2, entry 2d). The reaction condition was suitable for unsaturated functional group that can also survive the reaction condition. (Table 2, entry 2p–t). Several heterocyclic amines afforded the product with moderate to good yield. However, N-substituted cyclohexyl, butyl, derivatives of 1,2-benzenediamine failed to yield the desired product (Table 2, entry 2u–v). This indicated that weak C–H bond should be present adjacent to amino group for this reaction.

On the basis of the experimental results and previous reports [2h–j], we propose a tentative mechanism as shown in Scheme 2. First 1aaa is formed in the presence of I₂ and TBHP, which on further oxidation afford the product 2a.

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Scheme 2

Tentative reaction mechanism.

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4 Conclusion

In summary, we have developed a facile and efficient tandem reaction followed by a sp³ C–H functionalization oxidative synthesis of 2-substituted benzimidazole from readily available starting materials. In contrast to traditional methods for the synthesis of benzimidazoles, the reaction conditions are much milder and reaction substrates were extended. Therefore, this method is an alternative to the synthesis of benzimidazole.