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

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.

Key words

cyclization - condensation - heterocycles - annulation - benzimidazoles

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