Applied Chemical Engineering

Imidazole and phenyl rings are fused at positions 4 and 5 to form the benzimidazole structure. The benzimidazole mono- and disubstituted derivatives are extremely intriguing heterocyclic chemical compounds. They can be synthesized using a straightforward condensation method between o-phenylenediamine and a carbonyl compound under various conditions as well as a nucleophilic substitution reaction. The catalytical effects of benzimidazole derivatives, which include oxidation of olefins, oxidation of alcohol, etc, play a significant role in the catalysis. This review describes various synthetic routes for synthesizing functionalized benzimidazole derivatives and catalytic application of benzimidazole Schiff base metal complexes and benzimidazole amide.

1. Lee YT, Tan YJ, Oon CE. Benzimidazole and its derivatives as cancer therapeutics: The potential role from traditional to precision medicine. Acta Pharmaceutica Sinica B 2023; 13(2): 478–497. doi: 10.1016/j.apsb.2022.09.010

2. Gaba M, Mohan C. Development of drugs based on imidazole and benzimidazole bioactive heterocycles: Recent advances and future directions. Medicinal Chemistry Research 2016; 25: 173–210. doi: 10.1007/s00044-015-1495-5

3. Yerragunta V, Patil P, Srujana S, et al. Benzimidazole derivatives and its biological importance: A review. PharmaTutor 2014; 2(3): 109–113.

4. Patil A, Ganguly S, Surana S. A systematic review of benzimidazole derivatives as an antiulcer agent. Rasayan Journal of Chemistry 2008; 1(3): 447–460.

5. Kubo K, Oda K, Kaneko T, et al. Synthesis of 2-[[(4-fluoroalkoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazoles as antiulcer agents. Chemical & Pharmaceutical Bulletin 1990; 38(10): 2853–2858. doi: 10.1248/cpb.38.2853

6. Walia R, Hedaitullah Md, Farha Naaz S, et al. Benzimidazole derivatives—An overview. International Journal of Research in Pharmacy and Chemistry 2011; 1(3): 565–574.

7. Grassi A, Ippen J, Bruno M, Thomas G. BAY P 1455, a thiazolylaminobenzimidazole derivative with gastroprotective properties in the rat. European Journal of Pharmacology 1991; 195(2): 251–259. doi: 10.1016/0014-2999(91)90543-y

8. Ozkay Y, Tunali Y, Karaca H, Isikdag I. Antimicrobial activity and a SAR study of some novel Benzimidazole derivatives bearing hydrazone moiety. European Journal of Medicinal Chemistry 2010; 45(8): 3293–3298. doi: 10.1016/j.ejmech.2010.04.012

9. Ladenburg A. Derivate von diaminen. Berichte der Deutschen Chemischen Gesellschaft 1875; 8(1): 677–678.

10. Ladenburg A. Condensationsvorgänge in der Orthoreihe. Berichte der Deutschen Chemischen Gesellschaft 1877; 10(1): 1123–1131.

11. Phillips MA. CCCXVII.—The formation of 2-substituted benzimidazoles. Journal of the Chemical Society (Resumed) 1928; 13: 2393–2399. doi: 10.1039/JR9280002393

12. Phillips MA. XXV.—The formation of 2-methylbenzimidazoles. Journal of the Chemical Society (Resumed) 1928; 13: 172–177. doi: 10.1039/JR9280000172

13. Phillips MA. CCCLXXXII.—The formation of 1-substituted benziminazoles. Journal of the Chemical Society (Resumed) 1929; 8: 2820–2828. doi: 10.1039/JR9290002820

14. Weidenhagen R. Eine neue synthese von benzimidazol-derivaten. Berichte der Deutschen Chemischen Gesellschaft (A and B Series) 1936; 69(10): 2263–2272.

15. Hassner A, Namboothiri I. Organic Syntheses Based on Name Reactions, 3rd ed. Elsevier; 2012.

16. Mamedov VA. Recent advances in the synthesis of benzimidazol(on)es via rearrangements of quinoxalin(on)es. Royal Society of Chemistry Advances 2016; 6: 42132–42172. doi: 10.1039/c6ra03907c

17. Mamedov VA. Quinoxalines: Synthesis, Reactions, Mechanisms and Structure. Springer International Publishing; 2016.

18. Mamedov VA, Zhukova NA. Recent developments towards synthesis of (het)arylbenzimidzoles. Synthesis 2021; 53: 1849–1878. doi: 10.1055/s-0037-1610767

19. Hashem HE, Bakri YE. An overview on novel synthetic approaches and medicinal applications of benzimidazole compounds. Arabian Journal of Chemistry 2021; 14(11): 103418. doi: 10.1016/j.arabjc.2021.103418

20. Rithe SR, Jagtap RS, Ubarhande SS. One pot synthesis of substituted benzimidazole derivatives and their charcterization. Rasayan Journal of Chemistry 2015; 8(2): 213–217.

21. Alam SAMF, Ahmad T, Nazmuzzaman M, et al. Synthesis of benzimidazole derivatives containing Schiff base exhibiting antimicrobial activities. International Journal of Research Studies in Biosciences 2017; 5(7): 18–24. doi: 10.20431/2349-0365.0507003

22. Nguyen TB, Ermolenko L, Corbin M, Al-Mourabit A. Fe/S-catalyzed decarboxylative redox condensation of arylacetic acids with nitroarenes. Organic Chemistry Frontiers 2014; 1: 1157–1160. doi: 10.1039/C4QO00221K

23. Chikkula KV, Sundararajan R. Analgesic, anti-inflammatory, and antimicrobial activities of novel isoxazole/pyrimidine/pyrazole substituted benzimidazole analogs. Medicinal chemistry research 2017; 26: 3026–3037. doi: 10.1007/s00044-017-2000-0

24. Alinezhad H, Salehian F, Biparva P. Synthesis of benzimidazole derivatives using heterogeneous ZnO nanoparticles. Synthetic Communications 2012; 42: 102–108. doi: 10.1080/00397911.2010.522294

25. Thakuria H, Das G. An expeditious one-pot solvent-free synthesis of benzimidazole derivatives. Archive for Organic Chemistry 2008; 2008(15): 321–328. doi: 10.3998/ark.5550190.0009.f28

26. Deba B, Chakrabortya A, Hossainb J, Majumdar S. A task-specific ionic-liquid-mediated solvent-free protocol for direct access to dimethyl acetal protected benzimidazole 2-carboxaldehydes. SynOpen 2020; 4: 89–95. doi: 10.1055/s-0040-1706391

27. Alizadeh A, Noaparast Z, Sabahnoo H, Zohreh N. An unprecedented and concise method for the synthesis of 1,3-thiazino-[3,4a][1,3]bnzimidazole via a three-component reaction. Synlett 2010; 10: 1469–1472. doi: 10.1055/s-0029-1219934

28. Chari MA, Zaied-A-Mosaa, Shobha D, Malayalama S. Synthesis of multifunctionalised 2-substituted benzimidazoles using copper (II) hydroxide as efficient solid catalyst. International Journal of Organic Chemistry 2013; 3(4): 243–250. doi: 10.4236/ijoc.2013.34035

29. Venkateswarlu Y, Kumar SR, Leelavathi P. Facile and efficient one-pot synthesis of benzimidazole using lanthanum chloride. Organic and Medicinal Chemistry Letters 2013; 3: 7(2013). doi: 10.1186/2191-2858-3-7

30. Kadu VR, Chavan HV, Gholap SS. Additive free greener synthesis of 1,2- disubstituted benzimidazole using aqueous extract of Acacia concinna pods as an efficient surfactant type catalyst. Polycyclic Aromatic Compounds 2019; 41(6): 1263–1273. doi: 10.1080/10406638.2019.1670219

31. Azeez S, Sureshbabu P, Chaudhary P, et al. Tert-Butyl nitrite catalyzed synthesis of benzimidazoles from o-phenylenediamine and aldehydes at room temperature. Tetrahedron Letters 2020; 61(14): 151735. doi: 10.1016/j.tetlet.2020.151735

32. Alaqeel SI. Synthetic approaches to benzimidazoles from o-phenylenediamine: A literature review. Journal of Saudi Chemical Society 2016; 21(2): 229–237. doi: 10.1016/j.jscs.2016.08.001

33. Dhanalakshmi P, Thimmarayaperumal S, Shanmugam S. Metal catalyst free one-pot synthesis of 2-arylbenzimidazoles from a-aroylketene dithioacetals. Royal Society of Chemistry Advances 2014; 4: 12028–12036. doi: 10.1039/C3RA47761D

34. Mamedov VA, Zhukova NA, Gubaidullin AT, et al. One-pot synthesis of 7-(benzimidazol-2-yl)thioxolumazine and -lumazine derivatives via h2so4-catalyzed rearrangement of quinoxalinones when exposed to 5,6-diamino-2-mercapto- and 2,5,6-triaminopyrimidin-4-ols. The Journal of Organic Chemistry 2018; 83(24): 14942−14953. doi: 10.1021/acs.joc.8b02161

35. Mamedov VA, Saifina DF, Rizvanov IK, Gubaidullin AT. A versatile one-step method for the synthesis of benzimidazoles from quinoxalinones and arylenediamines via a novel rearrangement. Tetrahedron Letters 2008; 49(31): 4644–4647. doi: 10.1016/j.tetlet.2008.05.060

36. Mamedov VA, Kadyrova SF, Zhukova NA, et al. Friedlander reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties (German). Tetrahedron 2014; 70(35): 5934–5946. doi: 10.1016/j.tet.2014.06.007

37. Mamedov VA, Zhukova NA, Kadyrova MS, et al. Acid-catalyzed rearrangement of 3-cyanoquinoxalin-2(1H)-ones when exposed to 1,2-diaminobenzenes: Synthesis of 2,2’- bibenzimidazoles. The Journal of Organic Chemistry 2019; 84: 13572–13581. doi: 10.1021/acs.joc.9b01840

38. Mamedov VA, Khafizova EA, Algaeva NE, et al. Acid-catalyzed multicomponent rearrangements via 2-((quinoxalin-3(4H)-on-2-yl)(aryl)methylene)malononitriles, generated in situ, for divergent synthesis of pyrroles with different substitution patterns. The Journal of Organic Chemistry 2020; 85(15): 9887–9904. doi: 10.1021/acs.joc.0c01180

39. Tyagi N, Kumar R, Mahiya K, Mathur P. Copper(II) complexes of a new tetradentate bis-benzimidazolyl diamide ligand with disulfanediyl linker: Synthesis, characterization and oxidation of some pyridyl, napthyl and benzyl alcohols. Journal of Coordination Chemistry 2013; 66: 3335–3348. doi: 10.1080/00958972.2013.835403

40. Kumar R, Mathur P. Oxidation of phenyl propyne catalyzed by copper(II) complexes of a benzimidazolyl Schiff base ligand: Effect of acid/base, oxidant, surfactant and morphology. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2015; 136: 818–823. doi: 10.1016/j.saa.2014.09.099

41. Kumar R, Mathur P. Aerobic oxidation of 1,10-phenanthroline to phendione catalyzed by copper(II) complexes of a benzimidazolyl Schiff base. Royal Society of Chemistry Advances 2014; 4: 33190–33193. doi: 10.1039/C4RA03651D

42. Ahuja G, Kumar R, Mathur P. Oxidation of olefins catalyzed by Iron (III) complexes of bis-benzimidazolyl diamide ligands. Journal of Molecular Structure 2012; 1011: 166–171. doi: 10.1016/j.molstruc.2011.12.047

43. Mudi PK, Mahato RK, Joshi M. Copper(II) complexes with a benzimidazole functionalized Schiff base: Synthesis, crystal structures, and role of ancillary ions in phenoxazinone synthase activity. Applied Organometalic Chemistry 2021; 35(6): e6211. doi: 10.1002/aoc.6211

44. Abdolmalekiab A, Molaviana MR. Synthesis and characterization of Co nanocomposite based on Poly(benzimidazole-amide) matrix and their behavior as catalyst in oxidation reaction. Polymer-Plastics Technology and Engineering 2015; 54(12): 1241–1250. doi: 10.1080/03602559.2015.1010214

45. Kumar R, Mahiya K, Mathur P. Synthesis, spectral and structural characterization of Cu(II) complexes of a tridentate NNO donor Schiff base carrying a pendant benzimidazolyl arm. Indian journal of Chemistry 2011; 50A: 775–780.

46. Shilpa ML, Gayathri V. Reduction of olefins, nitroarenes and Schiff base compounds by a polymer-supported [2-(2’-pyridyl)benzimidazole]palladium complex. Transition Metal Chemistry 2016; 41: 393–401. doi: 10.1007/s11243-016-0035-6.