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Synlett 2013; 24(20): 2751-2757
DOI: 10.1055/s-0033-1339927
DOI: 10.1055/s-0033-1339927
letter
Ligand-Free, Copper-Catalyzed Ullmann-Type C–N Coupling: Regioselective Synthesis of Azole-Substituted Imidazo[1,2-a]pyridines
Further Information
Publication History
Received: 30 July 2013
Accepted after revision: 15 September 2013
Publication Date:
06 November 2013 (online)
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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 reactionSupporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
- Supporting Information
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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]+.