Organocatalytic Synthesis of Benzimidazole Derivatives

Abstract

A synthetic route for the production of chiral derivatives of benzimidazole is presented. Different commercially available amines are evaluated as organocatalysts for the stereoselective aldol addition of N1-benzimidazolyl acetaldehyde, previously prepared by N-alkylation of benzimidazole, with cyclic ketones. When cyclohexanone was used, l-prolinamide proved to be the most efficient catalyst, giving (S)-2-((R)-2-(1H-benzo[d]imidazol-1-yl)-1-hydroxyethyl)cyclohexanone in 92% yield, 90% ee and 92:8 dr (anti/syn).

Key words

benzimidazole - chiral - organocatalysis - l-prolinamide - imidazolidinone

• References

• 1 Shah K, Chhabra S, Shrivastava SK, Mishra P. Med. Chem. Res. 2013; 22: 5077
• 2 Singh PK, Silakari OM. Benzimidazole: Journey from Single Targeting to Multitargeting Molecule (Chap. 2). In Key Heterocycle Cores for Designing Multitargeting Molecules. Silakari OM. Elsevier; Amsterdam: 2018

For reviews on structure–activity relationship studies of benzimidazole-based molecules, see:
• 3a Yadav G, Ganguly S. Eur. J. Med. Chem. 2015; 97: 419
• 3b Shrivastava N, Naim MJ, Alam MJ, Nawaz F, Ahmed S, Alam O. Arch. Pharm. 2017; 350: e201700040
• 3c Veerasamy R, Roy A, Karunakaran R, Rajak H. Pharmaceuticals 2021; 14: 663
• 3d Choudhary S, Arora M, Verma H, Kumar M, Silakari O. Eur. J. Pharm. 2021; 899: 174027
• 4a Bansal Y, Silakari O. Bioorg. Med. Chem. 2012; 20: 6208
• 4b Law CS, Yeong KY. ChemMedChem 2021; 16: 1861
• 5a Beaulieu PL, Bös M, Bousquet Y, Fazal G, Gauthier J, Gillard J, Kukolj G. Bioorg. Med. Chem. Lett. 2004; 14: 967
• 5b Hue BT. B, Nguyen PH, De T Q, Van Hieu M, Jo E, Van Tuan N, Windisch MP. ChemMedChem 2020; 15: 1453
• 5c Mermer A, Keles T, Sirin Y. Bioorg. Chem. 2021; 114: 105076
• 6a Faheem M, Rathaur A, Pandey A, Kumar Singh V, Tiwari AK. ChemistrySelect 2020; 5: 3981
• 6b Francesconi V, Cichero E, Schenone S, Naesens L, Tonelli M. Molecules 2020; 25: 1487
• 7 Nag A. Asymmetric Synthesis of Drugs and Natural Products. CRC Press; Boca Raton: 2018
• 8 Khose VN, John ME, Pandey AD, Karnik AV. Tetrahedron: Asymmetry 2017; 28: 1233
• 9a Trost BM, Brindle CS. Chem. Soc. Rev. 2010; 39: 1600
• 9b Heravi MM, Zadsirjan V, Dehghani M, Hosseintash N. Tetrahedron: Asymmetry 2017; 28: 587
• 10 List B, Lerner RA, Barbas CF. J. Am. Chem. Soc. 2000; 122: 2395
• 11 Geary LM, Hultin PG. Tetrahedron: Asymmetry 2009; 20: 131
• 12a Vicario JL, Badia D, Carrillo L, Reyes E. Organocatalytic Enantioselective Conjugate Addition Reactions: A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules. The Royal Society of Chemistry; Cambridge: 2010
• 12b Han B, He XH, Liu YQ, Peng C, Li JL. Chem. Soc. Rev. 2021; 50: 1522
• 13a Palazzolo MA, Nigro MJ, Iribarren AM, Lewkowicz ES. Eur. J. Org. Chem. 2016; 6: 921
• 13b Nigro MJ, Palazzolo MA, Colasurdo D, Iribarren AM, Lewkowicz ES. Catal. Commun. 2019; 121: 73

For N-alkylation strategies, see:
• 14a Cuadro AM, Matia MP, Garcia JL, Vaquero JJ, Alvarez-Builla J. Synth. Commun. 1991; 21: 535
• 14b Chen S, Graceffa RF, Boezio AA. Org. Lett. 2016; 18: 16
• 14c Clanton NA, Spiller TE, Ortiz E, Gao Z, Rodriguez-Poirier JM, del Monte AJ, Frantz DE. Org. Lett. 2021; 23: 3233
• 15 Palazzolo MA, Pérez-Sánchez M, Iribarren AM, Lewkowicz ES, de María PD. Tetrahedron Lett. 2012; 53: 6797
• 16 Gruttadauria M, Giacolone F, Noto R. Adv. Synth. Catal. 2009; 351: 33
• 17a Liu J, Wang L. Synthesis 2017; 49: 960
• 17b Vachan BS, Karuppasamy M, Vinoth P, Vivek Kumar S, Perumal S, Sridharan V, Menéndez JC. Adv. Synth. Catal. 2020; 362: 87
• 18 Gruttadauria M, Giacolone F, Noto R. Adv. Synth. Catal. 2009; 351: 33
• 19 Zhang F, Peng Y, Liao S, Gong Y. Tetrahedron 2007; 63: 4636
• 20 Peng F, Shao Z. J. Mol. Catal. A: Chem. 2008; 285: 1
• 21 Martinez-Castaneda A, Rodriguez-Solla H, Concellon C, del Amo V. J. Org. Chem. 2012; 77: 10375
• 22a Notz W, List B. J. Am. Chem. Soc. 2000; 122: 7386
• 22b Popik O, Pasternak-Suder M, Lesniak K, Jawiczuk M, Gorecki M, Frelek J, Mlynarski J. J. Org. Chem. 2014; 79: 5728
• 23 Chen M, Sun J. Angew. Chem. Int. Ed. 2017; 129: 12128
• 24 Xiao JA, Wang CM, Wang J, Ou GC, Zhang XY, Yang H. Tetrahedron 2015; 71: 805
• 25a Kanzian T, Lakhdar S, Mayr H. Angew. Chem. Int. Ed. 2010; 49: 9526
• 25b Sanchez D, Castro-Alvarez A, Vilarrasa J. Tetrahedron Lett. 2013; 54: 6381
• 26 Hiesinger K, Dar’in D, Proschak E, Krasavin M. J. Med. Chem. 2020; 64: 150
• 27 Khalaj A, Bazaz RD, Shekarchi M. Monatsh. Chem. 1997; 128: 395