Palladium-catalyzed aerobic oxidative C–H amination: synthesis of 2-unsubstituted and 2-substituted N-aryl benzimidazoles

Abstract

Palladium-catalyzed aerobic synthesis of 2-unsubstituted and 2-substituted N-aryl benzimidazoles has been described from N,N′-bis(aryl)amidines via oxidative C–H amination.

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The recent advances in transition metal catalysis have led to the development of effective methods for the construction of carbon–heteroatom bonds.¹ Among them, C–H activation protocols are attractive because they are atom economical and obviate the need for preactivated substrate precursors. Significant progress has been made using predominantly Ru,² Rh,³ Pd,⁴ Ag⁵ and Cu⁶ based catalytic systems. Herein, we wish to report the first Pd-catalyzed direct synthesis of 2-unsubstituted and 2-substituted N-aryl benzimidazoles from N,N′-bis(aryl)amidines via oxidative C–H amination. The protocols are straightforward and the target molecules can be obtained using molecular oxygen as the terminal oxidant.

N-Aryl benzimidazoles are a class of prominent heterocyclic motifs that exhibit a wide range of biological properties such as Nek2^7a and lymphocyte specific kinase (Lck) inhibition (Fig. 1).^7b In addition, they are substrate precursors for the preparation of an important class of N-heterocyclic carbenes (NHCs)⁸ that have been successfully utilized as ligands in organocatalysis as well as in transition metal catalysis.

Fig. 1 Some examples of pharmaceutically active N-aryl benzimidazoles.

The classical approaches employed for the synthesis of the N-aryl benzimidazoles involve condensation followed by the oxidative cyclization of o-phenylenediamine with carboxylic acids or carboxylic acid derivatives (Scheme 1, route a).⁹ However, these processes often suffer due to the unavailability of suitably substituted substrate precursors. Furthermore, the oxidative cyclization requires the combination of strong acids and elevated temperature.

Scheme 1 Methods available for the synthesis of N-aryl benzimidazoles: (a) classical method, (b–e) cross-coupling and (f) C–H amination.

Some of these limitations have been circumvented by the recent development of cross-coupling reactions using transition metal catalysis.^10–12 For example, Pd^11a–b or Co^11c or Cu^11d–g based catalytic systems have been explored for domino reactions of amines with 2-bromophenyl isocyanides (Scheme 1, route b), the intermolecular C–N cross-coupling of benzimidazole with aryl boronic acids (Scheme 1, route c), the cyclization of 2-haloaryl amidines (Scheme 1, route d) or the cross-coupling reaction followed by condensation of 2-haloacetanilides with anilines to afford N-aryl benzimidazoles (Scheme 1, route e). Recently, the synthesis of benzimidazole has been shown via C–H activation, however, these methods are limited to the construction of N-methyl or N-unsubstituted benzimidazoles^6d,f and not effective for the synthesis of N-arylbenzimidazoles. Development of new methods for the direct synthesis of N-aryl benzimidazole structural framework via C–H activation/C–N bond formation would thus valuable in organic synthesis (Scheme 1, route f).

First, the optimization of the reaction conditions was carried out with N,N′-diphenyl formamidine 1a as a model substrate that can be readily prepared from aniline and triethylorthoformate (see the ESI†). The substrate 1a underwent C–H activation followed by intramolecular C–N bond formation to afford the desired N-phenyl benzimidazole 2a in 46% yield when the reaction was carried out in the presence of 10 mol % Pd(PPh₃)₂Cl₂ and 2 equiv. Cs₂CO₃ in DMSO under molecular oxygen (Table 1, entry 1). Yield of the heterocycle 2a could be further increased to 63% when activated 4 Å molecular sieves were added as an additive (entry 2). Palladium sources such as Pd(PPh₃)₂(OAc)₂, Pd(CH₃CN)₂Cl₂ and Pd(PhCN)₂Cl₂ were less effective compared to Pd(PPh₃)₂Cl₂ affording 2a in 10–30% yield (entries 3–5). In contrast, Pd(OAc)₂ led to decomposition of the starting material 1a and no desired 2a was obtained. When 1a was subjected to 5 mol % Pd(PPh₃)₂Cl₂, the yield of 2a dropped significantly (entry 6). Control experiments confirmed that 2a was not formed in the absence of the palladium catalyst (entry 7).

Table 1 Effect of palladium catalysts

Entry	Pd-source	Yield (%) ^a,^b
a A mixture of N,N′-diphenyl formamidine 1a (0.5 mmol), Pd-source (10 mol %), Cs2CO3 (1 mmol) and 4 Å MS (50 mg) were stirred at 120 °C in DMSO (1 mL) under an oxygen balloon. b Isolated yield. c Without 4 Å MS. d Pd(PPh3)2Cl2 (5 mol %) used. n.d. = Not detected.
1^c	Pd(PPh3)2Cl2	46
2	Pd(PPh3)2Cl2	63
3	Pd(PPh3)2(OAc)2	30
4	Pd(CH3CN)2Cl2	11
5	Pd(PhCN)2Cl2	10
6^d	Pd(PPh3)2Cl2	35
7	—	n.d.

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Among the bases screened, Cs₂CO₃, K₂CO₃, Ag₂CO₃, K₃PO₄ and Na₂CO₃, the former yielded the best results (Table 2, entries 1–5). The reactions with K₂CO₃, K₃PO₄, Na₂CO₃, Ag₂CO₃ and KOH gave 2a in 10–50% yield. In contrast, Ag₂CO₃ and KOH led to the decomposition of 1a and no product 2a was obtained. When the amount of Cs₂CO₃ was lowered to 1.5 equiv, the yield of 2a was dropped to 45% (entry 6).

Table 2 Effect of bases

Entry	Base	Yield (%) ^a,^b
a Substrate 1a (0.5 mmol), Pd(PPh3)2Cl2 (10 mol %), base (1 mmol) and 4 Å MS (50 mg) were stirred at 120 °C in DMSO (1 mL) under an oxygen balloon. b Isolated yield. c Cs2CO3 (0.75 mmol) used. n.d. = Not detected.
1	K2CO3	50
2	Na2CO3	10
3	K3PO4	40
4	KOH	n.d.
5	Ag2CO3	n.d.
6^c	Cs2CO3	45

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The reaction using DMF provided 2a in moderate yield (Table 3, entries 1–4). In contrast, N-methyl-2-pyrrolidone (NMP), toluene and acetonitrile yielded inferior results. A similar result was obtained when the reaction was subjected to 70 °C or under N₂ atmosphere (entries 5–6). However, a reaction with air led to the formation of 2a in moderate yield (entry 7). In summary, the optimized conditions in DMSO include Pd(PPh₃)₂Cl₂ (10 mol %) and Cs₂CO₃ (2 equiv) at 120 °C for 30 h under an oxygen balloon.

Table 3 Effect of solvent, temperature and atmosphere

Entry	Solvent	Yield (%) ^a,^b
a Substrate 1a (0.5 mmol), Pd(PPh3)2Cl2 (10 mol %), Cs2CO3 (1 mmol) and 4 Å MS (50 mg) were stirred at 120 °C in solvent (1 mL) under an oxygen balloon. b Isolated yield. c Reaction T = 70 °C. d Under N2 . e Under air. n.d. = Not detected.
1	DMF	45
2	NMP	n.d.
3	toluene	n.d.
4	CH3CN	n.d.
5^c	DMSO	n.d.
6^d	DMSO	n.d.
7^e	DMSO	35

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Next, the scope of the procedure was studied for the reactions of the substituted N,N′-bis(aryl)formamidines (Table 4, entries 1–7). N,N′-Bis(phenyl)formamidine 1b with methyl substituents at the o-position of both the phenyl rings did not cyclize, which may be due to the steric hindrance of the methyl groups (entry 2). However, the symmetrical substrates 1c–g with methyl, ethyl, fluoro and 2-propyl substituents at m- as well as the p- positions of both the phenyl rings cyclized at the hindered aryl C–H bonds to give the respective N-aryl benzimidazoles 2c–g as a single regioisomer in 63–75% yield (entries 3–7). Similarly, unsymmetrical N,N′-bis(aryl)formamidine having methyl substituents at the m- and p-positions 1h could be converted into benzimidazole 2h in 75% yield (entry 8).

Table 4 Substrate scope of the palladium-catalyzed synthesis of 2-substituted/unsubstituted N-aryl benzimidazoles.

Entry	Substrate	Time (h)	Product (yield, %)^a^b	Entry	Substrate	Time (h)	Product (yield, %)^a^b
a Reaction conditions: ^a substrate 1a–p (0.5 mmol), Pd(PPh3)2Cl2 (10 mol %), Cs2CO3 (1 mmol) and 4 Å MS (50 mg) were stirred at 120 °C under an O2 balloon. b Isolated yield.
1		30		9		48
2		30		10		60
3		36
				11	R^1, R^2 = Et 1k	48	2k (68)
				12	R^1, R^2 = F 1l	30	2l (75)
				13	R^1, R^2 = Me 1m	48	2m (75)
				14	R^1, R^2 = i-Pr 1n	50	2n (78)
4	R^1, R^2 = Et 1d	36	2d(66)	15		60
5	R^1, R^2 = F 1e	38	2e (74)
6	R^1, R^2 = Me 1f	30	2f (63)
7	R^1, R^2 = i-Pr 1g	48	2g (75)
8		30		16		60

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The protocol was also compatible for the cyclization of N,N′-bis(aryl)acetamidines and N,N′-bis(aryl)benzamidines to afford 2- substituted N-aryl benzimidazoles (Table 2, entries 9–16). For example, bis(aryl)acetamidine 1i proceeded via cyclization to give 2-methyl N-aryl benzimidazole 2i in 65% yield (entry 9). Likewise, the symmetrical bis(aryl)acetamidines 1j–n with methyl, ethyl, fluoro and 2-methyl substituents at m- as well as the p-positions of both the phenyl rings underwent reactions to give the corresponding 2-methyl N-aryl benzimidazoles 2j–n in 68–78% yield (entries 10–14). Furthermore, the unsymmetrical N,N′- bis(aryl)benzamidines 1o–p having methyl and nitro groups at the p-position of one of the phenyl rings could be cyclized to give the respective 1,2-diaryl benzimidazoles 2o–p in 80–82% yield. Recrystallization of 2n and 2p in CH₂Cl₂ gave crystals whose structures were confirmed unambiguously by single crystal X-ray analysis (see the ESI†).

In summary, palladium-catalyzed C–H aerobic oxidative amination of bis(aryl)amidines have been developed to afford N-aryl benzimidazoles. The reaction provided a general route for the synthesis of 2-unsubstituted as well as 2-alkyl/-aryl substituted N-aryl benzimidazoles.

Acknowledgements

We thank Department of Science and Technology, New Delhi, and Council of Scientific and Industrial Research, New Delhi, for generous financial support. One of us (K.K.) thanks Indian Institute of Technology Guwahati for Senior Research Fellowship.

References

1. For some recent examples, see: (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400; (b) S. Wurtz and F. Glorius, Acc. Chem. Res., 2008, 41, 1523; (c) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954; (d) J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651; (e) G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008, 108, 3054; (f) M. Meldal and C. W. Tornoe, Chem. Rev., 2008, 108, 2952; (g) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108, 3395; (h) T. R. M. Rauws, B. U. W. Maes, Chem. Soc. Rev. DOI: 10.1039/c1cs15236j; (i) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem., Int. Ed., 2011, 50, 11062; (j) D. S. Surry and S. L. Buchwald, Chem. Sci., 2011, 2, 27; (k) J. P. Wolfe, S. Wagaw, J-F. Marcoux and S. L. Buchwald, Acc. Chem. Res., 1998, 31, 805; (l) J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046; (m) J. F. Hratwig, Acc. Chem. Res., 1998, 31, 852; (n) N. Guimond, S. I. Gorelsky and K. Fagnou, J. Am. Chem. Soc., 2011, 133, 6449; (o) D. R. Stuart, P. Alsabeh, M. Kuhn and K. Fagnou, J. Am. Chem. Soc., 2010, 132, 18326; (p) R. J. Lundgren, B. D. Peters, P. G. Alsabeh and M. Stradiotto, Angew. Chem., Int. Ed., 2010, 49, 4071; (q) P. G. Alsabeh, R. J. Lundgren, L. E. Longobardi and M. Stradiotto, Chem. Commun., 2011, 47, 6936.
2. For examples, see: (a) A. K. M. Long, R. P. Yu, G. H. Timmer and J. F. Berry, J. Am. Chem. Soc., 2010, 132, 12228; (b) S. K.-Y. Leung, W.-M. Tsui, J.-S. Huang, C.-M. Che, J.-L. Liang and N. Zhu, J. Am. Chem. Soc., 2005, 127, 16629; (c) W. G. Shou, J. Li, T. Guo, Z. Lin and G. Jia, Organometallics, 2009, 28, 6847.
3. For some examples, see: (a) J. Du Bois, Org. Process Res. Dev., 2011, 15, 758; (b) D. N. Zalatan and J. Du Bois, J. Am. Chem. Soc., 2009, 131, 7558; (c) P. M. Wehn and J. Du Bois, Org. Lett., 2005, 7, 4685; (d) A. Norder, P. Herrmann, E. Herdtweck and T. Bach, Org. Lett., 2010, 12, 3690; (e) D. E. Olson and J. Du Bois, J. Am. Chem. Soc., 2008, 130, 11248; (f) D. N. Zalatan and J. Du Bois, J. Am. Chem. Soc., 2008, 130, 9220; (g) C. G. Espino, K. W. Fiori, M. Kim and J. Du Bois, J. Am. Chem. Soc., 2004, 126, 15378.
4. For some studies, see: (a) K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto and K. Hiroya, Org. Lett., 2007, 9, 2931; (b) J. A. Jordan-Hore, C. C. C. Johansson, M. Gulias, E. M. Beck and M. J. Gaunt, J. Am. Chem. Soc., 2008, 130, 16184; (c) T.-S. Mei, X. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 10806; (d) G. T. Rice and M. C. White, J. Am. Chem. Soc., 2009, 131, 11707; (e) L. Wu, S. Qiu and G. Liu, Org. Lett., 2009, 11, 2707; (f) W. C. P. Tsang, N. Zheng and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 14560; (g) Q. Xiao, W.-H. Wang, G. Liu, F.-K. Meng, J.-H. Chen, Z. Yang and Z.-J. Shi, Chem.–Eur. J., 2009, 15, 7292; (h) J. J. Neumann, S. Rakshit, T. Droge and F. Glorius, Angew. Chem., Int. Ed., 2009, 48, 6892; (i) E. J. Yoo, S. Ma, T.-S. Mei, K. S. L. Chan and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 7652; (j) R. I. McDonald, P. B. White, A. B. Weinstein, C. P. Tam and S. S. Stahl, Org. Lett., 2011, 13, 2830; (k) G. Yang and W. Zhang, Org. Lett., 2012, 14, 268; (l) S. W. Youn, J. H. Bihn and B. S. Kim, Org. Lett., 2011, 13, 3738; (m) R. K. Kumar, M. A. Ali and T. Punniyamurthy, Org. Lett., 2011, 13, 2102; (n) X. Ye, G. Liu, B. V. Popp and S. S. Stahl, J. Org. Chem., 2011, 76, 1031; (o) B. Haffemayer, M. Gulias and M. J. Gaunt, Chem. Sci., 2011, 2, 312; (p) K. J. Fraunhoffer and M. C. White, J. Am. Chem. Soc., 2007, 129, 7274; (q) A. M. Wagner and M. S. Sanford, Org. Lett., 2011, 13, 288; (r) A. D. Satterfield, A. Kubota and M. S. Sanford, Org. Lett., 2011, 13, 1076; (s) S. A. Reed and M. C. White, J. Am. Chem. Soc., 2008, 130, 3316.
5. (a) S. H. Cho, J. Y. Kim, S. Y. Lee and S. Chang, Angew. Chem., Int. Ed., 2009, 48, 9127; (b) C-G. Yang, N. W. Reich, Z. Shi and C. He;, Org. Lett., 2005, 7, 4553.
6. For some examples, see: (a) K.-S. Masters, T. R. M. Rauws, A. K. Yadav, W. A. Herrebout, B. Van der Veken and B. U. W. Maes, Chem.–Eur. J., 2011, 17, 6315; (b) L. Zhang, G. Y. Ang and S. Chiba, Org. Lett., 2010, 12, 3682; (c) D. Monguchi, T. Fujiwara, H. Furukawa and A. Mori, Org. Lett., 2009, 11, 1607; (d) G. Brasche and S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 1932; (e) X. Wang, Y. Jin, Y. Zhao, L. Zhu and H. Fu, Org. Lett., 2012, 14, 452; (f) M. M. Guru, M. A. Ali and T. Punniyamurthy, J. Org. Chem., 2011, 76, 5295.
7. For some examples, see: (a) S. Solanki, P. Innocenti, C. Mas-Droux, K. Boxall, C. Barillari, R. L. M. Van Montfort, G. W. Aherne, R. Bayliss and S. Hoelder, J. Med. Chem., 2011, 54, 1626; (b) M. Sabat, J. C. VanRens, M. J. Laufersweiler, T. A. Brugel, J. Maier, A. Golebiowski, B. De, V. Easwaran, L. C. Hsieh, R. L. Walter, M. J. Mekel, A. Evdokimov and M. J. Janusz, Bioorg. Med. Chem. Lett., 2006, 16, 5973.
8. For some examples, see: (a) A. Chan and K. A. Scheidt, J. Am. Chem. Soc., 2007, 129, 5334; (b) K. Iwamoto, M. Hamaya, N. Hashimoto, H. Kimura, Y. Suzuki and M. Sato, Tetrahedron Lett., 2006, 47, 7175; (c) A. Miyashita, Y. Suzuki, K. Iwamoto and T. Higashino, Chem. Pharm. Bull., 1994, 42, 2633.
9. Y. Wang, K. Sarris, D. R. Sauer and S. W. Djuric, Tetrahedron Lett., 2006, 47, 4823.
10. For recent reviews on benzimidazole synthesis, see: L. C. R. Carvalho, E. Fernandes and M. M. B. Marques, Chem.–Eur. J., 2011, 17, 12544 and references cited therein..
11. For examples on the synthesis of N-aryl benzimidazoles, see: (a) C. T. Brain and S. A. Brunton, Tetrahedron Lett., 2002, 43, 1893; (b) N. Zheng, K. W. Anderson, X. Huang, H. N. Nguyen and S. L. Buchwald, Angew. Chem., Int. Ed., 2007, 46, 7509; (c) P. Saha, M. A. Ali, P. Ghosh and T. Punniyamurthy, Org. Biomol. Chem., 2010, 8, 5692; (d) A. V. Lygin and A. de Meijere, Eur. J. Org. Chem., 2009, 5138; (e) M. T. Wentzel, J. B. Hewgley, R. M. Kamble, P. D. Wall and M. C. Kozlowski, Adv. Synth. Catal., 2009, 351, 931; (f) P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul and T. Punniyamurthy, J. Org. Chem., 2009, 74, 8719; (g) J. Zhu, H. Xie, Z. Chen, S. Li and Y. Wu, Chem. Commun., 2009, 2338; (h) K. Hirano, A. T. Biju and F. Glorius, J. Org. Chem., 2009, 74, 9570.
12. For an example on the synthesis of N-alkyl benzimidazoles, see: (a) C. T. Brain and J. T. Seer, J. Org. Chem., 2003, 68, 6814; (b) N. Zheng and S. L. Buchwald, Org. Lett., 2007, 9, 4749.

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Footnote

† Electronic Supplementary Information (ESI) available: experimental procedure, CCDC 863007 (2n) and 863008 (2p) and NMR spectra (¹H and ¹³C) See DOI: 10.1039/c2ra20328f/

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