Ligand-Free, Copper-Catalyzed Ullmann-Type C–N Coupling: Regioselective Synthesis of Azole-Substituted Imidazo[1,2-a]pyridines

Abstract

A simple and highly efficient protocol for the regioselective synthesis of azole-substituted imidazo[1,2-a]pyridines has been developed using a ligand-free, copper-catalyzed Ullmann-type C–N coupling of 2-(2-bromophenyl)imidazo[1,2-a]pyridines with different azoles and in situ generated 1,2,3-triazoles. The reactions proceeded smoothly to furnish azolo-imidazo[1,2-a]pyridines in good to excellent yields (65–96%).

Key words

copper - ligand-free C–N coupling - imidazo[1,2-a]pyridines - 1,2,3-triazole - CuAAC - tandem reaction

• References and Notes

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• 20 General Procedure for the Synthesis of Compound 3 A round-bottom flask (10 mL) was charged with 2-(2-bromophenyl)imidazo[1,2-a]pyridine (1, 0.36 mmol), azole 2 (0.439 mmol), CuI (0.07 mmol), K₂CO₃ (0.732 mmol), and DMF (2.0 mL). The resulting solution was stirred at 150 °C in an oil bath for 2 h under nitrogen atmosphere. On completion, the reaction mass was filtered through Celite and washed with EtOAc. The filtrate was washed with H₂O, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography (EtOAc–hexane, 2:3) to obtain the product 3.
• 21 General Procedure for the Synthesis of Compound 6 A round-bottom flask (10 mL) was charged with 2-(2-bromophenyl)imidazo[1,2-a]pyridine (1, 0.36 mmol), sodium azide (4, 0.439 mmol), phenylacetylene (5a, 0.439 mmol), CuCl₂·2H₂O (0.073 mmol), K₂CO₃ (0.732 mmol), and DMF (2.0 mL). The resulting solution was stirred at 100 °C in an oil bath for 3 h. On completion, the reaction mass was filtered through Celite and washed with EtOAc. The filtrate was washed with H₂O, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography (EtOAc–hexane, 2:3) to obtain product 6.
• 22 Spectroscopic Data of Selected Compounds 2-[2-(1H-Imidazol-1-yl)phenyl]H-imidazo[1,2-a]pyridine (3a) Yield 92%; colorless solid; mp 149–151 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (dd, J = 7.9, 1.4 Hz, 1 H), 7.89 (dt, J = 6.8, 1.1 Hz, 1 H), 7.65–7.55 (m, 3 H), 7.44 (td, J = 7.6, 1.5 Hz, 1 H), 7.34 (dd, J = 7.8, 1.2 Hz, 1 H), 7.29 (s, 1 H), 7.18–7.14 (m, 1 H), 7.06 (s, 1 H), 6.73 (td, J = 6.8, 1.1 Hz, 1 H), 6.29 (s, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 144.86, 140.10, 137.36, 134.31, 131.38, 129.95, 129.78, 129.67, 128.37, 127.71, 125.82, 125.06, 120.48, 117.43, 112.53, 109.70. HRMS: m/z calcd for C₁₆H₁₃N₄ ⁺: 261.1135; found: 261.1119 [M + H]⁺. 2-[2-(4-Methyl-1H-imidazol-1-yl)phenyl]H-imidazo [1,2-a]pyridine (3b) Yield 90%; colorless; mp 174–177 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.41 (dd, J = 7.9, 1.4 Hz, 1 H), 7.90 (dt, J = 6.8, 1.0 Hz, 1 H), 7.62–7.52 (m, 2 H), 7.47 (s, 1 H), 7.40 (td, J = 7.6, 1.5 Hz, 1 H), 7.32–7.26 (m, 1 H), 7.18–7.11 (m, 1 H), 6.76 (s, 1 H), 6.72 (td, J = 6.8, 1.1 Hz, 1 H), 6.40 (s, 1 H), 2.34 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.82, 140.26, 138.83, 136.50, 134.55, 131.26, 129.88, 129.43, 128.30, 127.79, 125.84, 124.96, 117.43, 116.77, 112.46, 109.88, 13.76. HRMS: m/z calcd for C₁₇H₁₅N₄ ⁺: 275.1291; found: 275.1278 [M + H]⁺. 2-[2-(4-Phenyl-1H-1,2,3-triazol-1-yl)phenyl]H-imidazo[1,2-a]pyridine (6a) Yield 76%; off-white solid; mp 189–192 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.89 (s, 1 H), 8.43 (d, J = 6.8 Hz, 1 H), 8.29 (d, J = 7.8 Hz, 1 H), 7.93 (d, J = 7.3 Hz, 2 H), 7.79–7.69 (m, 1 H), 7.59 (d, J = 3.1 Hz, 2 H), 7.51 (d, J = 4.8 Hz, 1 H), 7.46 (d, J = 7.7 Hz, 2 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.27–7.15 (m, 1 H), 6.93 (s, 1 H), 6.80 (t, J = 6.7 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 147.98, 145.06, 140.34, 134.62, 131.26, 130.65, 130.56, 130.40, 128.86, 128.44, 128.29, 127.47, 126.15, 125.84, 125.00, 122.05, 117.55, 112.53, 110.39. HRMS: m/z calcd for C₂₁H₁₆N₅ ⁺: 338.1400; found: 338.1405 [M + H]⁺.