Synlett
DOI: 10.1055/s-0039-1690797
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© Georg Thieme Verlag Stuttgart · New York

A Green, Scalable, One-Minute Synthesis of Benzimidazoles

Vijayaragavan Elumalai
UiT The Arctic University of Norway, Department of Chemistry, Chemical Synthesis and Analysis Division, Hansine Hansens veg 54, 9037 Tromsø, Norway   Email: jorn.h.hansen@uit.no   Email: vijayaragavan.elumalai@uit.no
,
Jørn H. Hansen
› Author Affiliations
The authors gratefully acknowledge funding for this work by the Research Council of Norway (Grant no. 275043 CasCat).
Further Information

Publication History

Received: 08 October 2019

Accepted after revision: 20 December 2019

Publication Date:
24 January 2020 (online)

Published as part of the ISySyCat2019 Special Issue

Abstract

Herein is reported a substantially improved synthesis of 2-substituted benzimidazoles by condensation of 1,2-diaminoarenes and aldehydes using methanol as the reaction medium. The developed method afforded moderate to excellent yields (33–96%) at ambient temperature, displays high functional group tolerance, is conducted open to air, and requires only one minute reaction time under catalyst- and additive-free conditions. Moreover, the efficient protocol permits scale-up to multi-gram scale synthesis of benzimidazoles and will become a method of choice when constructing such heterocyclic systems.

Supporting Information

 
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  • 16 2-([1,1'-Biphenyl]-4-yl)-1H-benzo[d]imidazole (3g); Typical Procedure In a 25 mL round-bottomed flask, diamine 1g (100 mg, 0.93 mmol) was dissolved in MeOH (5 mL). To the stirred solution was added aldehyde 2g (169 mg, 0.925 mmol) and it was stirred for 1 min at rt. Then, the reaction was quenched with water (10 mL), diluted with EtOAc (50 mL), and washed with water (30 mL). The water layer was extracted with EtOAc (2 × 30 mL). The organic layers were combined and dried with anhydrous Na2SO4. The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The crude product was further isolated by using flash chromatography (EtOAc/n-pentane, 20:80) to obtain compound 3g as a yellow solid. Yield: 200 mg (80%); Rf = 0.48 (EtOAc/n-pentane, 30:70). 1H NMR (400 MHz, acetone-d 6): δ = 8.58 (s, 1 H), 7.99–7.92 (m, 2 H), 7.70–7.64 (m, 2 H), 7.64–7.57 (m, 2 H), 7.36 (dd, J = 8.4, 6.9 Hz, 2 H), 7.31–7.22 (m, 1 H), 7.02 (dd, J = 7.8, 1.4 Hz, 1 H), 6.87 (td, J = 7.6, 1.4 Hz, 1 H), 6.66 (dd, J = 8.0, 1.4 Hz, 1 H), 6.50 (td, J = 7.5, 1.4 Hz, 1 H). 13C NMR (101 MHz, acetone-d 6): δ = 156.6, 144.7, 129.8, 129.7, 128.5, 128.3, 127.8, 127.6, 117.6, 117.5, 115.6. HRMS: m/z [M + H]+ calcd for C19H15N2 +: 271.1230; found: 271.1232.
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  • 19 Gram-Scale Synthesis of 2-(4-Nitrophenyl)-1H-benzo[d]imidazole (3b) In a 250 mL round-bottomed flask, benzene-1,2-diamine 1b (2.00 g, 18.5 mmol) was dissolved in MeOH (50 mL). To the stirred solution was added 4-nitrobenzaldehyde 2b (2.80 g, 18.5 mmol) and it was stirred for 1 min at rt. Then, the reaction was quenched with water (40 mL) and diluted with EtOAc (50 mL). After a while, crystals were formed in the reaction mixture at rt. The crystals were filtered off and dried to obtain compound 3b as dark-brown crystals. Yield: 2.85 g (65%). 1H NMR (400 MHz, DMSO-d 6): δ = 8.83 (s, 1 H), 8.40–8.30 (m, 2 H), 8.34–8.22 (m, 2 H), 7.24 (dd, J = 8.0, 1.5 Hz, 1 H), 7.03 (ddd, J = 8.3, 7.2, 1.4 Hz, 1 H), 6.76 (dd, J = 8.1, 1.4 Hz, 1 H), 6.63–6.53 (m, 1 H). 13C NMR (101 MHz, DMSO-d 6): δ = 153.5, 148.3, 144.9, 142.4, 133.9, 129.4, 128.8, 123.9, 117.0, 116.0, 115.1. HRMS: m/z [M – H] calcd for C13H8N3O2 : 238.0622; found: 238.0623.