Green and High Efficient Synthesis of 2-Aryl Benzimidazoles: Reaction of Arylidene Malononitrile and 1,2-Phenylenediamine Derivatives in Water or Solvent-Free Conditions


A fast, high efficiency and environmentally friendly procedure for the synthesis of 2-aryl benzim-idazole derivatives has been reported. Reaction between 1,2-phenylenediamine derivatives and arylidene malononitrile under aqueous media and also solvent-free conditions generates 2-aryl benzimidazole derivatives with a high yield.

Share and Cite:

Habibi, A. , Valizadeh, Y. , Mollazadeh, M. and Alizadeh, A. (2015) Green and High Efficient Synthesis of 2-Aryl Benzimidazoles: Reaction of Arylidene Malononitrile and 1,2-Phenylenediamine Derivatives in Water or Solvent-Free Conditions. International Journal of Organic Chemistry, 5, 256-263. doi: 10.4236/ijoc.2015.54025.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Lindstrom, U.M. (2007) Organic Reactions in Water: Principles Strategies and Applications. Blackwell, Oxford.
[2] Lindstrom, U.M. (2002) Stereoselective Organic Reactions in Water. Chemical Reviews, 102, 2751-2772.
[3] Shapiro. N. and Vigalok. A. (2008) Highly Efficient Organic Reactions “on Water”, “in Water”, and Both. Angewandte Chemie, 120, 2891-2894.
[4] Li, C.-J. (2005) Organic Reactions in Aqueous Media with a Focus on Carbon-Carbon Bond Formations:? A Decade Update. Chemical Reviews, 105, 3095-3166.
[5] Grieco, P.A. (1998) Organic Synthesis in Water. Blackie Academic & Professional, London.
[6] Li, C.-J. and Chan, T.-H. (2007) Comprehensive Organic Reactions in Aqueous Media. Wiley & Sons, New York.
[7] Rida, S.M.S., EI-Hawash, A.M., Fahmy, H.T.Y., Hazzaa, A.A. and EI-Meligy, M.M.M. (2006) Synthesis of Novel Benzofuran and Related Benzimidazole Derivatives for Evaluation of in Vitro Anti-HIV-1, Anticancer and Antimicrobial Activities. Archives of Pharmacal Research, 29, 826-833.
[8] Roth, T., Morningstar, M.L., Boyer, P.L., Hughes, S.H., Buckheitjr, R.W. and Michejda, C.J. (1997) Synthesis and Biological Activity of Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2-Aryl-Substituted Benzimidazoles. Journal of Medicinal Chemistry, 40, 4199-4207.
[9] Hisano, T., Ichikawa, M., Tsumoto, K. and Tasaki, M. (1982) Synthesis of Benzoxazoles, Benzothiazoles and Benzimidazoles and Evaluation of Their Antifungal, Insecticidal and Herbicidal Activities. Chemical and Pharmaceutical Bulletin, 30, 2996-3004.
[10] Migawa, M.T., Girardet, J.-L., Walker, J.A., Koszalka, G.W., Chamberlain, S.D., Drach, J.C. and Townsend, L.B. (1998) Design, Synthesis, and Antiviral Activity of α-Nucleosides:? d- and l-Isomers of Lyxofuranosyl- and (5-Deoxylyxofuranosyl)benzimidazoles. Journal of Medicinal Chemistry, 41, 1242-1251.
[11] Dreyer, C. and Hausen, P. (1978) Inhibition of Mammalian RNA Polymerase by 5,6-Dichlororibofuranosylbenzimi- dazole (DRB) and DRB Triphosphate. Nucleic Acids Research, 5, 3325-3335.
[12] Porcari, A.R., Devivar, R.V., Kucera, L.S., Drach, J.C. and Townsend, L.B. (1998) Design, Synthesis, and Antiviral Evaluations of 1-(Substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as Nonnucleoside Analogues of 2,5,6- Trichloro-1-(β-d-ribofuranosyl)benzimidazole. Journal of Medicinal Chemistry, 41, 1252-1262.
[13] Erhardt, P.W. (1987) In Search of the Digitalis Replacement. Journal of Medicinal Chemistry, 30, 231-237.
[14] Tomczuk, B.E., Taylor Jr., C.R., Moses, L.M., Sutherland, D.B., Lo, Y.S., Johnson, D.N., Kinnier, W.B. and Kilpatrick, B.F. (1991) 2-Phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides as Non-Benzodiazepine Anticonvulsants and Anxiolytics. Journal of Medicinal Chemistry, 34, 2993-3006.
[15] Spasov, A.A., Yozhitsa, I.N. and Bugaeva, L.I. (1999) Benzimidazole Derivatives: Spectrum of Pharmacological Activity and Toxicological Properties (A Review). Pharmaceutical Chemistry Journal, 33, 232-243.
[16] Gravatt, G.L., Baguley, B.C., Wilson, W.R. and Denny, W.A. (1994) DNA-Directed Alkylating Agents. 6. Synthesis and Antitumor Activity of DNA Minor Groove-Targeted Aniline Mustard Analogs of Pibenzimol (Hoechst 33258). Journal of Medicinal Chemistry, 37, 4338-4345.
[17] Horton, D.A., Bourne, G.T. and Smythe, M.L. (2003) The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures. Chemical Reviews, 103, 893-930.
[18] Kim, J.S., Gatto, B., Yu, C., Liu, A., Liu, L.F. and La Voie, E.J. (1996) Substituted 2,5’-Bi-1H-benzimidazoles:? Topoisomerase I Inhibition and Cytotoxicity. Journal of Medicinal Chemistry, 39, 992-998.
[19] Lu, J., Yang, B. and Bai, Y. (2002) Microwave Irradiation Synthesis of 2-Substituted Benzimidazoles Using PPA as a Catalyst under Solvent-Free Conditions. Synthetic Communications, 32, 3703-3709.
[20] Geratz, J.D., Stevens, F.M., Polakoski, K.L. and Parrish, R.F. (1979) Amidino-Substituted Aromatic Heterocycles as Probes of the Specificity Pocket of Trypsin-Like Proteases. Archives of Biochemistry and Biophysics, 197, 551-559.
[21] Tidwell, R.R., Geratz., J.D., Dann, O., Volz, G., Zeh, D. and Loewe, H. (1978) Diarylamidine Derivatives with One or Both of the Aryl Moieties Consisting of an Indole or Indole-Like Ring. Inhibitors of Arginine-Specific Esteroproteases. Journal of Medicinal Chemistry, 21, 613-623.
[22] Fairley, T.A., Tidwell, R.R., Donkor, I., Naiman, N.A., Ohemeng, K.A., Lombardy, R.J., Bentley, J.A. and Cory, M. (1993) Structure, DNA Minor Groove Binding, and Base Pair Specificity of Alkyl- and Aryl-Linked Bis(amidinobenzi- midazoles) and Bis(amidinoindoles). Journal of Medicinal Chemistry, 36, 1746-1753.
[23] Riadi, Y., Mamouni, R., Azzalou, R., EI Haddad, M., Routier, S., Guillaumet, G. and Lazar, S. (2011) An Efficient and Reusable Heterogeneous Catalyst Animal Bone Meal for Facile Synthesis of Benzimidazoles, Benzoxazoles, and Benzothiazoles. Tetrahedron Letters, 52, 3492-3495.
[24] Bachhav, H.M., Bhagat, S.B. and Telvekar, V.N. (2011) Efficient Protocol for the Synthesis of Quinoxaline, Benzoxazole and Benzimidazole Derivatives Using Glycerol as Green Solvent. Tetrahedron Letters, 52, 5697-5701.
[25] Blacker, A.J., Farah, M.M., Hall, M.I. Marsden, S.P, Saidi, O. and Williams, J.M. (2009) Synthesis of Benzazoles by Hydrogen-Transfer Catalysis. Organic Letters, 11, 2039-2042.
[26] Patil, V.D., Patil, J., Rege, P. and Dere, G. (2011) Mild and Efficient Synthesis of Benzimidazole Using Lead Peroxide Under Solvent-Free Conditions. Synthetic Communications, 41, 58-62.
[27] Saha, P., Ramana, T., Purkait, N., Ashif, A.M., Paul, R. and Punniyamurthy, T. (2009) Ligand-Free Copper-Catalyzed Synthesis of Substituted Benzimidazoles, 2-Aminobenzimidazoles, 2-Aminobenzothiazoles, and Benzoxazoles. Journal of Organic Chemistry, 74, 8719-8725.
[28] Evindar, G. and Batey, R.A. (2006) Parallel Synthesis of a Library of Ben-zoxazoles and Benzothiazoles Using Ligand- Accelerated Copper-Catalyzed Cyclizations of Ortho-Halobenzanilides. Journal of Organic Chemistry, 71, 1802-1808.
[29] Yang, D., Fu, H., Hu, L., Jiang, Y. and Zhao, Y. (2008) Copper-Catalyzed Synthesis of Benzimidazoles via Cascade Reactions of O-Haloacetanilide Derivatives with Amidine Hydrochlorides. Journal of Organic Chemistry, 73, 7841- 7844.
[30] Kamila, S., Koh, B. and Biehl, E.R. (2006) Microwave-Assisted “Green” Synthesis of 2-Alkyl/Arylbenzothiazoles in One Pot: A Facile Approach to Anti-Tumor Drugs. Journal of Heterocyclic Chemistry, 43, 1609-1612.
[31] Kamila, S., Zhang, H. and Biehl, E.R. (2005) One-Pot Synthesis of 2-Aryl- and 2-Alkylbenzothiazoles under Microwave Irradiation. Heterocycles, 65, 2119-2126.
[32] Cai, L., Ji, X., Yao, Z., Xu, F. and Shen, Q. (2011) Efficient Synthesis of Functionalized Benzimidazoles and Perimidines: Ytterbium Chloride Catalyzed C-C Bond Cleavage. Chinese Journal of Chemistry, 29, 1880-1886.
[33] Wang, Z.-X. and Qin, H.-L. (2005) Reaction of 1,3-Dicarbonyl Compounds with o-Phenylenediamine or 3,3’-Diami nobenzidine in Water or under Solvent-Free Conditions via Microwave Irradiation. Journal of Heterocyclic Chemistry, 42, 1001-1005.
[34] Yu, C., Guo, P., Jin, C. and Su, W. (2009) The Synthesis of Benzimidazole Derivatives in the Absence of Solvent and Catalys. Journal of Chemical Research, 5, 333-336.
[35] Itoh, K., Ishida, H. and Chikashita, H. (1982) The Reactions of Benzylidenmalononitriles β-Nitrostyrenes with o-Phenylenediamine including the New Organic Redox Reactions between the Olefins and 2-Phenylbenzimidazolines. Chemistry Letters, 1117-1118.
[36] Li, J., Benard, S., Neuville, L. and Zhu, J. (2012) Copper Catalyzed N-Arylation of Amidines with Aryl Boronic Acids and One-Pot Synthesis of Benzimidazoles by a Chan-Lam-Evans N-Arylation and C-H Activation/C-N Bond Forming Process. Organic Letters, 14, 5980-5983.
[37] Chari, M.A., Shobha, D., Kenawy, E.R., Al-Deyab, S.S., Subba Reddy, B.V. and Vinu, A. (2010) Nanoporous Aluminosilicate Catalyst with 3D Cage-Type Porous Structure as an Efficient Catalyst for the Synthesis of Benzimidazole Derivatives. Tetrahedron Letters, 51, 5195-5199.
[38] Lei, M., Ma, L. and Hu, L. (2012) One-Pot Synthesis of 1H-Benzimidazole Derivatives Using Thiamine Hydrochloride as a Reusable Organocatalyst. Synthetic Communications, 42, 2981-2993.
[39] Rostamizadeh, S., Aryan, R. and Ghaieni, H.R. (2011) Aqueous 1 M Glucose Solution as a Novel and Fully Green Reaction Medium and Catalyst for the Oxidant-Free Synthesis of 2-Arylbenzimidazoles. Synthetic Communications, 41, 1794-1804.
[40] Saha, D., Saha, A. and Ranu, B.C. (2009) Remarkable Influence of Substituent in Ionic Liquid in Control of Reaction: Simple, Efficient and Hazardous Organic Solvent Free Procedure for the Synthesis of 2-Aryl Benzimidazoles Promoted by Ionic Liquid, [pmim]BF4. Green Chemistry, 11, 733-737.
[41] Heravi, M.M., Tajbakhsh, M., Ahmadi, A.N. and Mohajerani, B. (2006) Zeolites. Efficient and Eco-Friendly Catalysts for the Synthesis of Benzimidazoles. Monatshefte fur Chemie, 137, 175-179.
[42] Cohen, V.I. (1979) A New Method of Synthesis of Some 2-Aryl and 2-Heterocyclic Benzimidazole, Benzox-azole and Benzothiazole Derivatives. Journal of Heterocyclic Chemistry, 16, 13-16.
[43] Lam, T., Hilgers, M.T., Cunningham, M.L., Kwan, B.P., Nelson, K.J., Brown-Driver, V., Ong, V., Trzoos, M., Hough, G., Joy Shaw, K. and Finn, J. (2014) Structure-Based Design of New Dihy-drofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines. Journal of Medicinal Chemistry, 57, 651-668.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.