HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 5, 2014, pp. 1229-1236
Received, 18th February, 2014, Accepted, 17th March, 2014, Published online, 18th March, 2014.
DOI: 10.3987/COM-14-12966

■ Synthesis of 2-Arylbenzimidazole Analogues

Meng-Yang Chang,* Chieh-Kai Chan, and Yi-Chia Chen

Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, TaiwanNo. 100, Shih-Chuan 1st Rd., San Ming District, Kaohsiung 80708, Taiwan, R.O.C.

Abstract

Substituted 2-arylbenzimidazoles (4) were easily synthesized in good yields starting from the condensation reaction of 1,2-diaminobenzenes (1) with β-ketosulfones (5) in the presence of boiling HOAc.

Benzimidazole ring system is a key pharmacophore for an increasing important series of nitrogen heterocycles which display a wide range of biological and therapeutic activities.1,2 A considerable number of attempts have been made to develop the bicyclic benzannulated framework. Transition metal-catalyzed intermolecular or intramolecular cyclization of 2-haloanilides/analogues3 and condensation of substituted 1,2-diaminobenzenes with benzaldehydes,4 carboxylic acids,5 or one-carbon synthons6 are two main synthetic routes. In most cases, the prepared routes toward 2-arylbenzimidazoles analogues require various oxidative reagents, the participation of strong acids, the involvement of different transition metals, or microwave irradiation.

Recently, Kidwai reported that Zn(OAc)2 promoted the synthesis of diazepines (3) through the reaction of 1,2-diaminobenzenes (1) and 1,3-diketones (2).7a The phenomena of double condensation reaction had been demonstrated by Varma and Leazer under the solvent-free and microwave irradiation conditions (see Scheme 1).7b To change the catalytic reaction conditions, Yu and Bao had developed that the synthesis of 2-arylbenzimidazole (4) by p-TsOH mediated the condensation reaction of 1,2-diaminobenzenes (1) and 1,3-diketones (2) in MeCN.8a The major difference for constructing two frameworks of diazepines (3) and 2-arylbenzimidazoles (4) was the reaction conditions. To avoid the uncontrollable condensation conditions, β-ketosulfones (5) was chosen as a new one-carbon synthon for generating substituted 2-arylbenzimidazoles (4). Herein, we would like to describe a facile methodology for synthesizing substituted 2-arylbenzimidazoles (4) via the condensation reaction of 1,2-diaminobenzenes (1) with β-ketosulfones (5) in the presence of boiling HOAc.
β-Ketosulfones (5) were easily prepared from the nucleophilic substitution of commercially available 2-bromoacetophenone analogues (6, Ar = a, Ph; b, 4-ClPh; c, 4-MeOPh; d, 2,5-(MeO)2Ph; e, 4-NO2Ph; f, 4-PhPh) with sodium sulfinates (7, NaSO2X, X = a, Tol; b, Ph; c, Me) in nearly quantitative yields for 6 h under a boiling co-solvent of 1,4-dioxane and water (v/v = 1/1) condition. Without further purification, condensation of 1,2-diaminobenzenes (1) with the resulting β-ketosulfones (5) provided substituted 2-arylbenzimidazoles (4) in the presence of HOAc at reflux temperature. Adjusting the reaction time, better results were detected in 5 h for the reaction of 1a with 5a. To elongate reaction time (20 h), product 4a provided with only 68% yield. Entries 1~13 showed that ten substituted 2-arylbenzimidazoles (4a-j) were isolated in 77~90% yields via once purification, as shown in Table 1. The structure of 2-(4-chlorophenyl)-1H-benzoimidazole (4b) was determined using single-crystal X-ray analysis.9

For the possible mechanism of 1a with 5a, the formation of intermediate A was first proposed via the intermolecular condensation process, as shown in Scheme 2. After the intramolecular ring-closure was occurred, intermediate B should be generated. Furthermore, by removal of MeSO2Tol, 4a was formed via carbon-carbon bond cleavage under thermal conditions.8a

Following this protocol, bis-benzimidazoles (9a-b) were formed in 65% and 54% yields, respectively via the double condensation of bis-diaminobenzene (8) with two equivalents of β-ketosulfones (5a) or (5e), as shown in Scheme 3.10 Interestingly, the symmetric bis-benzimidazole skeleton with antitumor activities had been reported as a new class of DNA minor groove binding agents.10b

In summary, we have successfully presented a facile route for the synthesis of 2-arylbenzimidazoles (4) via the condensation reaction of 1,2-diaminobenzenes (1) with β-ketosulfones (5) in the presence of boiling HOAc. Bis-benzimidazoles (9a-b) were also prepared by the method. This synthesis begins with simple starting materials and reagents, and provides a new synthetic route toward 2-arylbenzimidazoles.

EXPERIMENTAL
General. THF was distilled prior to use. All other reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400/200 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a mass spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal structures were obtained with an Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were carried out with Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid Analyzer or Elementar Vario EL III.
A representative synthetic procedure of 2-arylbenzimidazoles (4) is as follows: Sodium sulfinates (7, NaSO2X, 6.0 mmol) was added to a solution of 2-bromoacetophenones (6, 5.0 mmol) in co-solvent of 1,4-dioxane and water (20 mL, v/v = 1:1) at rt. The reaction mixture was stirred at reflux for 6 h. The reaction mixture was cooled to rt, concentrated, and partitioned with CH2Cl2 (3 x 30 mL) and water (30 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude β-ketosulfones (5) under reduced pressure in nearly quantitative yields. Without further purification, β-ketosulfones (5) (1.05 mmol) was added to a solution of 1,2-diaminobenzenes (1, 1.0 mmol) in HOAc (1 mL) at rt. The reaction mixture was stirred at reflux for 5 h. The reaction mixture was cooled to rt, concentrated, and partitioned with EtOAc (3 x 30 mL) and saturated NaHCO3(aq) (30 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 1/1) afforded 2-arylbenzimidazoles (4).
2-Phenyl-1H-benzimidazole (4a).3c Yield = 86% (167 mg); mp 289-292 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C13H11N2 195.0922, found 195.0933; 1H NMR (400 MHz, DMSO-d6): δ 12.93 (br s, 1H), 8.20-8.17 (m, 2H), 7.67 (br s, 1H), 7.58-7.47 (m, 4H), 7.22-7.20 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 151.22, 143.81, 135.00, 130.17, 129.83, 128.95 (2x), 126.43 (2x), 122.52, 121.68, 118.87, 111.32.
2-(4-Chlorophenyl)-1H-benzimidazole (4b).3c Yield = 78% (178 mg); mp 288-290 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C13H10ClN2 229.0533, found 229.0540; 1H NMR (400 MHz, DMSO-d6): δ 12.99 (br s, 1H), 8.23-8.17 (m, 2H), 7.69-7.56 (m, 4H), 7.22-7.21 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 150.13 (2x), 134.47 (2x), 129.05 (2x), 128.30, 128.11 (2x), 122.71, 121.88, 118.96, 111.43. Single-crystal X-Ray diagram: crystal of compound (4b) was grown by slow diffusion of EtOH into a solution of compound (4b) in EtOAc to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c a, a = 9.1642(7) Å, b = 9.7348(7) Å, c = 23.5043(18) Å, V = 2096.9(3) Å3, Z = 8, dcalcd = 1.449 g/cm3, F(000) = 944, 2θ range 1.733~26.710o, R indices (all data) R1 = 0.0347, wR2 = 0.0743.
2-(4-Methoxyphenyl)-1H-benzimidazole (4c).3c Yield = 89% (199 mg); mp 229-233 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C14H13N2O 225.1028, found 225.1032; 1H NMR (400 MHz, DMSO-d6 + CDCl3): δ 12.73 (br s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.61 (br d, J = 6.0 Hz, 1H), 7.48 (br d, J = 6.4 Hz, 1H), 7.17-7.13 (m, 2H), 7.09 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6 + CDCl3): δ 160.57, 151.36, 143.86, 134.94, 127.98 (2x), 122.67, 121.98, 121.37, 118.40, 114.24 (2x), 110.96, 55.24.
2-(2,5-Dimethoxyphenyl)-1H-benzimidazole (4d).10a Yield = 86% (218 mg); mp 230-234 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C15H15N2O2 255.1134, found 255.1139; 1H NMR (400 MHz, CDCl3): δ 8.15 (t, J = 2.0 Hz, 1H), 7.69-7.67 (m, 2H), 7.66 (br s, 1H), 7.29-7.24 (m, 2H), 6.98 (d, J = 2.0 Hz, 1H), 6.98 (s, 1H), 4.03 (s, 3H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.28, 151.36, 149.25, 123.15 (2x), 119.07 (2x), 114.85, 113.15 (2x), 113.04 (3x), 56.51, 56.19.
2-(4-Nitrophenyl)-1H-benzimidazole (4e).10b Yield = 77% (184 mg); mp > 300 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C13H10N3O2 240.0773, found 240.0768; 1H NMR (400 MHz, DMSO-d6): δ 13.28 (br s, 1H), 8.43-8.36 (m, 4H), 7.70 (br s, 1H), 7.61 (br s, 1H), 7.27-7.26 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 149.00 (2x), 147.79, 136.02 (2x), 127.38 (2x), 124.28 (2x), 123.57, 122.42, 119.50, 111.85.
2-Biphenyl-4-yl-1H-benzimidazole (4f).10c Yield = 82% (221 mg); mp 296-300 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C19H15N2 271.1235, found 271.1242; 1H NMR (400 MHz, DMSO-d6): δ 12.98 (br s, 1H), 8.30-8.28 (m, 2H), 7.89-7.86 (m, 2H), 7.78-7.75 (m, 2H), 7.68 (br s, 1H), 7.56 (br s, 1H), 7.51-7.47 (m, 2H), 7.42-7.38 (m, 1H), 7.23-7.21 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 150.93, 148.83, 141.27, 139.25, 135.06, 129.14, 129.01 (2x), 127.86, 127.12 (2x), 127.00 (2x), 126.67 (2x), 122.52, 121.73, 118.85, 111.29.
2-Phenyl-1H-naphtho[2,3-d]imidazole (4g).5e Yield = 80% (195 mg); mp 212-216 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C17H13N2 245.1079, found 245.1083; 1H NMR (400 MHz, DMSO-d6): δ 12.98 (br s, 1H), 8.31-8.28 (m, 2H), 8.03-8.01 (m, 3H), 7.63-7.55 (m, 3H), 7.41-7.32 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 156.24, 155.36, 144.33, 135.79, 130.67, 130.30, 129.77, 129.03 (2x), 128.07, 127.39, 127.08 (2x), 123.78, 123.04, 115.22, 106.53.
5,6-Dichloro-2-phenyl-1H-benzimidazole (4h).5e Yield = 82% (215 mg); mp 210-213 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C13H9Cl2N2 263.0143, found 263.0148; 1H NMR (200 MHz, DMSO-d6): δ 12.57 (br s, 1H), 8.05-8.00 (m, 2H), 7.52-7.45 (m, 3H), 7.36 (s, 2H).
5,6-Dimethyl-2-phenyl-1H-benzimidazole (4i).5e Yield = 86% (191 mg); mp 190-192 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C15H15N2 223.1235, found 223.1241; 1H NMR (200 MHz, DMSO-d6): δ 12.90 (br s, 1H), 8.04-8.01 (m, 2H), 7.53-7.43 (m, 3H), 7.34 (s, 2H), 2.34 (s, 6H).
2-Phenyl-1H-benzimidazole-5-carboxylic acid methyl ester (4j).3g Yield = 76% (192 mg); mp 196-198 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C15H13N2O2 253.0977, found 253.0983; 1H NMR (400 MHz, CDCl3): δ 8.32-8.31 (m, 1H), 8.13-8.10 (m, 2H), 7.93 (dd, J = 1.6, 8.4 Hz, 1H), 7.60 (br s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42-7.34 (m, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.77, 154.34, 142.75, 138.16, 130.80, 129.10 (2x), 128.91, 127.00 (2x), 124.73, 124.48, 117.02, 115.08, 52.18.
A representative synthetic procedure of bis-2-arylbenzimidazoles (9a-b) is as follows: β-Ketosulfones (5a or 5e, 1.0 mmol) was added to a solution of bis-diaminobenzene (8, 96 mg, 0.45 mmol) in HOAc (1 mL) at rt. The reaction mixture was stirred at reflux for 5 h. The reaction mixture was cooled to rt, concentrated, and partitioned with EtOAc (3 x 30 mL) and saturated NaHCO3(aq) (30 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 1/1) afforded products (9a-b).
2,2'-Bis-phenyl-1H,1'H-[5,5']bibenzimidazolyl (9a).11a Yield = 65% (113 mg); mp > 300 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C26H19N4 387.1610, found 387.1620; 1H NMR (400 MHz, DMSO-d6 + CDCl3): δ12.83 (br s, 2H), 8.17-8.15 (m, 4H), 7.81 (br s, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.51-7.39 (m, 8H); 13C NMR (100 MHz, DMSO-d6 + CDCl3): δ 151.68 (2x), 136.10 (2x), 129.58 (2x), 129.39 (2x), 128.41 (6x), 126.32 (6x), 122.00 (2x), 114.98 (2x), 112.73 (2x).
2,2'-Bis-(4-methoxyphenyl)-1H,1'H-[5,5']bibenzimidazolyl (9b).11b Yield = 54% (108 mg); mp 269-272 oC (recrystallized from EtOAc); HRMS (ESI, M++1) calcd for C28H23N4O2 447.1821, found 447.1826; 1H NMR (400 MHz, DMSO-d6 + CDCl3): δ 8.10 (d, J = 8.4 Hz, 4H), 7.76 (br d, J = 1.2 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.46 (dd, J = 1.2, 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 4H), 3.82 (s, 6H); 13C NMR (100 MHz, DMSO-d6 + CDCl3): δ 160.57 (2x), 151.80 (2x), 139.29 (2x), 138.30 (2x), 135.77 (2x), 127.90 (4x), 122.07 (2x), 121.58 (2x), 114.75 (2x), 113.87 (4x), 112.35 (2x), 54.95 (2x).

ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council of the Republic of China for its financial support (NSC 102-2113-M-037-005-MY2).

References

1. (a) D. A. Horton, G. T. Bourne, and M. L. Smythe, Chem. Rev., 2003, 103, 893; CrossRef (b) M. Alamgir, D. StC. Black, and N. Kumar, ‘Synthesis Reactivity and Biological Activitity of Benzimidazoles. Topics in Heterocyclic Chemistry’, Spirnger: Berlin, Germany, 2007; Vol. 9, pp. 87-118; (c) L. C. R. Carvalho, E. Fernandes, and M. M. B. Marques, Chem. Eur. J., 2011, 17, 12544; CrossRef (d) M. Boiani and M. Gonzalez, Mini-Rev. Med. Chem., 2005, 5, 409; CrossRef (e) S. S. Panda, R. Malik, and S. C. Jain, Curr. Org. Chem., 2012, 16, 1905. CrossRef
2. (a) G. L. Gravatt, B. C. Baguley, and W. A. Denny, J. Med. Chem., 1994, 37, 4338; CrossRef (b) L. Hu, M. L. Kully, D. W. Boykin, and N. Abood, Bioorg. Med. Chem. Lett., 2009, 19, 3374; CrossRef . CrossRef
3. For transition metal promoted synthesis, for Ru or Ir, see: (a) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, O. Saidi, and J. M. J. Williams, Org. Lett., 2009, 11, 2039; CrossRef For Co, see: (b) M. A. Chari, D. Shobha, and T. Sasaki, Tetrahedron Lett., 2011, 52, 5575; CrossRef For Co or Fe, see: (c) T. B. Nguyen, J. Le Bescont, L. Ermolenko, and A. Al-Mourabit, Org. Lett., 2013, 15, 6218; CrossRef For Pd, see: (d) A. J. Rosenberg, J. Zhao, and D. A. Clark, Org. Lett., 2012, 14, 1761; For Ce, see: (e) R. Shelkar, S. Sarode, and J. Nagarkar, Tetrahedron Lett., 2013, 54, 6986; CrossRef For Cu, see: (f) S. M. Inamdar, V. K. More, and S. K. Mandal, Tetrahedron Lett., 2013, 54, 579; CrossRef (g) Y. Kim, M. R. Kumar, N. Park, Y. Heo, and S. Lee, J. Org. Chem., 2011, 76, 9577; CrossRef (h) M. M. Guru, M. A. Ali, and T. Punniyamurthy, J. Org. Chem., 2011, 76, 5295; CrossRef (i) J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang, and C. Chen, J. Org. Chem., 2011, 76, 716; CrossRef (j) X. Diao, Y. Wang, Y. Jiang, and D. Ma, J. Org. Chem., 2009, 74, 7974; CrossRef (k) P. Saha, T. Ramana, N. Purkait, A. M. Ashif, R. Paul, and T. Punniyamurthy, J. Org. Chem., 2009, 74, 8719; CrossRef (l) D. Yang, H. Fu, L. Hu, Y. Jiang, and Y. Zhao, J. Org. Chem., 2008, 73, 7841; CrossRef (m) G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71, 1802; CrossRef (n) J, Li, S. Benard, L. Neuville, and J. Zhu, Org. Lett., 2012, 14, 5980.
4. For H2O2, see: (a) K. Bahrami, M. M. Khodaei, and F. Naali, J. Org. Chem., 2008, 73, 6835; CrossRef For PhI(OAc)2, see: (b) L.-H. Du and Y.-G. Wang, Synthesis, 2007, 675; CrossRef For Oxone, see: (c) P. L. Beaulieu, B. Hache, and E. von Moos, Synthesis, 2003, 1683; CrossRef For t-BuOCl, see: (d) S. S. Patil and V. D. Bobade, Synth. Commun., 2009, 40, 206. CrossRef
5. (a) W. Cui, R. B. Kargbo, Z. Sajjadi-Hashemi, F. Ahmed, and J. F. Gauuan, Synlett, 2012, 247; CrossRef (b) H. Sharghi and O. Asemani, Synth. Commun., 2009, 39, 860; CrossRef (c) X. Wen, J. El Bakali, R. Deprez-Poulain, and B. Deprez, Tetrahedron Lett., 2012, 53, 2440; CrossRef (d) V. K. Tandon and M. Kumar, Tetrahedron Lett., 2004, 45, 4185; CrossRef (e) Y. Wang, K. Sarris, D. R. Sauer, and S. W. Djuric, Tetrahedron Lett., 2006, 47, 4823. CrossRef
6. For amines, see: (a) T. B. Nguyen, L. Ermolenko, W. A. Dean, and A. Al-Mourabit, Org. Lett., 2012, 14, 5948; CrossRef For nitriles, see: (b) J. Sluiter and J. Christoffers, Synlett, 2009, 63; CrossRef For orthoesters, see: (c) G. Bastug, C. Eviolitte, and I. E. Marko, Org. Lett., 2012, 14, 3502; CrossRef For imidates, see: (d) S. Caron, B. P. Jones, and L. Wei, Synthesis, 2012, 3049. CrossRef
7. (a) M. Kidwai, A. Jain, and R. Poddar, J. Organomet. Chem., 2011, 696, 1939; CrossRef (b) B. R. Vaddula, R. S. Varma, and J. Leazer, Tetrahedron Lett., 2013, 54, 1538. CrossRef
8. For β-diketones, see: (a) M. S. Mayo, X. Yu, X. Zhou, X. Feng, Y. Yamamoto, and M. Bao, Org. Lett., 2014, 16, 764; CrossRef For β-ketoesters, see: (b) K. Bougrin and M. Soufiaoui, Tetrahedron Lett., 1995, 36, 3683; CrossRef (c) N. Zhao, Y. L. Wang, and J. Y. Wang, J. Chin. Chem. Soc., 2005, 52, 535.
9. CCDC 986626 (4b) contains the supplementary crystallographic data for this paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
10. (a) D. Secci, A. Bolasco, M. D'Ascenzio, F. Della Sala, S. Carradori, and M. Yanez, J. Heterocycl. Chem., 2012, 49, 1187; CrossRef (b) L. Pan, Y. Qu, Z. Wu, and X. Zhou, Tetrahedron, 2013, 69, 1717; CrossRef (c) R. G. Bergman, J. A. Ellman, J. C. Lewis, and J. Y. Wu, Angew. Chem. Int. Ed., 2006, 45, 1589. CrossRef
11. (a) D. N. Gary, J. Heterocycl. Chem., 1970, 7, 947; CrossRef (b) J. Baron, A. Mann, Y. Opoku-Boahen, E. Johansson, G. Parkinson, L. R. Kelland, and S. Neidle, J. Med. Chem., 2001, 44, 138. CrossRef