Synlett 2022; 33(11): 1092-1096
DOI: 10.1055/s-0041-1737489
letter

(2-Aminoaryl)iminophosphoranes as Versatile Starting Materials for the Synthesis of 1-Aryl-2-trifluoromethylbenzimidazoles

Magdalena Walewska-Królikiewicz
a   Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224, Poland
,
Bogdan Wilk
b   Monmouth University, 400 Cedar Ave, West Long Branch, NJ 07764, USA
,
Andrzej Kwast
a   Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224, Poland
,
Zbigniew Wróbel
a   Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224, Poland
› Author Affiliations
This work was financed by a subvention from the Institute of Organic Chemistry, Polska Akademia Nauk (Polish Academy of Sciences).


Abstract

A new route to 2-(trifluoromethyl)benzimidazoles is described which involves the condensation of (2-arylamino)iminophosphoranes with trifluoroacetyl esters or trifluoroacetic anhydride. The method allows the synthesis of the title compounds from simple nitroarenes without the use of separate reduction steps and metallic reagents or expensive catalysts.

Supporting Information



Publication History

Received: 23 March 2022

Accepted after revision: 06 May 2022

Article published online:
09 June 2022

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  • 13 General Procedures for the Synthesis of 2(Trifluoromethyl)benzimidazoles 2 Procedure A: Iminophosphorane 1 (3 mmol) was dissolved in dry DCM (15 mL) under nitrogen, and Et3N (480 μL, 3.6 mmol) was added. The mixture was cooled in a dry ice bath, and trifluoroacetic anhydride (600 μL, 3.3 mmol) was added. The cooling bath was removed, and the mixture was stirred at r.t. overnight. The mixture was poured into cold water (100 mL), extracted with DCM (3 × 50 mL), dried with MgSO4, and the solvent was evaporated under reduced pressure. The residue was then separated by column chromatography (silica gel, hexane/EtOAc) to obtain pure product 2. Procedure B: Iminophosphorane 1 (3 mmol) was dissolved in dry DMF (10 mL). NaH (150 mg, 3.6 mmol, 60% suspension in mineral oil) was added, and the mixture was stirred at r.t. for 20 min. The reaction was then carried out at the temperature and time indicated in Scheme 3 as B1: 60 °C/3 h; B2: 60 °C/5 h; B3: 70 °C/3 h; B4: 75 °C/2 h; B5: r.t./1 h. After the evolution of H2 ceased, the mixture was cooled to r.t., and an excess of CF3CO2Et (1.5 mL) was added. The mixture was stirred at r.t. overnight. The reaction mixture was poured into sat. NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed with water and dried with Na2SO4. The solvent was then evaporated, and the residue was purified by column chromatography (silica gel, hexane/EtOAc) to obtain pure product 2. Procedure C: Iminophosphorane 1 (3 mmol) was dissolved under N2 in freshly distilled dry THF (20 mL), and the mixture was cooled to –78 °C. n-BuLi (2.2 mL, 3.6 mmol, 1.6 M in hexane) was added followed by addition of HMPA (3 mL). The mixture was stirred at –78 °C for 20 min, and an excess of CF3CO2Et (1.5 mL) was added. The cooling bath was removed, and the mixture was stirred at r.t. overnight. The reaction mixture was poured into sat. NH4Cl (100 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed with water and dried with Na2SO4. The solvent was then evaporated, and the residue was separated by column chromatography (silica gel, hexane/EtOAc) to obtain pure product. 6-Fluoro-1-(4-methylphenyl)-2-(trifluoromethyl)-1H-benzimidazole (2a) Procedure B1; yield 443 mg (83%); yellow oil. 1H NMR (600 MHz, CDCl3): δ = 2.49 (s, 3 H), 6.82 (dd, J = 8.4, 2.4 Hz, 1 H), 7.14 (ddd, J = 9.1, 9.1, 2.4 Hz, 1 H), 7.27–7.30 (m, 2 H), 7.37–7.39 (m, 2 H), 7.86 (dd, J = 9.1, 4.6 Hz, 1 H). 13C NMR (150 MHz, CDCl3): δ = 21.3, 97.7 (d, J FC = 27.7 Hz), 113.0 (d, J FC = 26.0 Hz), 118.6 (q, J FC = 271.7 Hz), 122.5 (d, J FC = 9.8 Hz), 127.0, 130.5, 131.4, 137.0, 137.6 (d, J FC = 13.2 Hz), 144.4, 141.5 (q, J FC = 37.6 Hz), 161.3 (d, J FC = 243.9 Hz). MS (EI): m/z = 294 (100) [M]+, 225 (16), 91 (20). HRMS (EI): m/z calcd for C15H10F4N2 [M]+: 294.0780; found: 294.0775.
  • 14 N-{2,4-Dichloro-6-[(2,6-dimethylphenyl)(trifluoroacetyl)amino]phenyl}-2,2,2-trifluoroacetamide (3) Procedure A; yield 1.26 g (89%); colorless crystals, mp 149–151 °C. 1H NMR (500 MHz, CDCl3): δ = 2.15 (s, 6 H), 6.71 (d, J = 2.1 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 2.1 Hz, 1 H), 7.66 (br s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 17.9, 115.6 (q, J FC = 287.8 Hz), 115.7 (q, J FC = 288.4, Hz), 123.4, 125.7, 129.5, 129.6, 130.6, 135.3, 135.5, 135.7, 137.0, 137.8, 154.5 (q, J FC = 38.1 Hz), 158.4 (q, J FC = 37.6 Hz). MS (EI): m/z = 474 (68), 472 (100) [M]+, 405 (98), 403 (66), 339 (48), 264 (32), 261 (46), 105 (62). HRMS (EI): m/z calcd for C18H12 35Cl2F6N2O2 [M]+: 472.0180; found: 472.0175.
  • 15 CCDC 2160756 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures