Synthesis of 2,4-Disubstituted Imidazoles via Nucleophilic Catalysis

Abstract

A convergent, microwave-assisted protocol for the synthesis of disubstituted NH-imidazoles via nucleophilic catalysis is described. The substituted imidazoles are accessed via the intramolecular addition of a variety of amidoxime substrates to activated alkynes followed by a thermally induced rearrangement of the in situ generated O-vinylamid­oxime species. The unprotected imidazoles contain an aryl group at the 2-position as well as an ester moiety at the 4-position.

Key words

nucleophilic catalysis - imidazole - heterocycles - microwave - ¹⁹F NMR - rearrangement

• References and Notes


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• 16 2,4-Disubstituted Imidazoles 4; General Procedure An oven-dried microwave vial was loaded with the desired amidoxime 2 (0.66 mmol) and DABCO (7.4 mg, 0.066 mmol), then methyl propiolate (55 mg, 0.66 mmol) in dry DMF (3 mL) was added under a nitrogen atmosphere. The reaction mixture was subjected to a two-stage microwave irradiation sequence (Stage 1: 80 °C, 15 min; Stage 2: 240 °C, 2 min). The mixture was concentrated under reduced pressure and the obtained residue dissolved in EtOAc (20 mL), washed with H₂O (2 × 10 mL) and dried over anhydrous Na₂SO₄. The residue after solvent evaporation was purified by flash column chromatography on silica gel (PE/EtOAc) to afford the desired imidazole 4.
• 17 Methyl 2-(m-Tolyl)-1H-imidazole-4-carboxylate (4g) Yield: 35 mg (25%); yellow solid; mp 168–170 °C. ¹H NMR (DMSO-d ₆): δ = 13.22 (br s, 1 H, NH), 7.92 (s, 1 H, CH), 7.87 (s, 1 H, Ar), 7.81 (d, J = 7.6 Hz, 1 H, Ar), 7.35 (t, J = 7.7 Hz, 1 H, Ar), 7.21 (d, J = 7.6 Hz, 1 H, Ar), 3.78 (s, 3 H, Me), 2.36 (s, 3 H, Me). ¹³C{¹H} NMR (DMSO-d ₆): δ = 162.8, 147.2, 138.0, 129.68, 129.66, 128.7, 126.1, 122.7, 51.1, 21.0 (2 С missed). HRMS (ESI/Q-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₃N₂O₂: 217.0977; found: 217.0970.