Regioselective Palladium-Catalyzed Arylation and Heteroarylation of ­Imidazo[1,2-a]pyridines

Abstract

Palladium-catalyzed direct arylation and heteroarylation of imidazo[1,2-a]pyridines at the 3-position are described. The optimization of the reaction in conventional heating and the adaptation under microwaves irradiation is reported. The compatibility of the synthesis with the presence of bromo or chloro substituents in the 6-position was investigated.

palladium-catalyzed coupling - arylation - heteroarylation - imidazo[1,2-a]pyridines - microwave irradiation

References and Notes

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Procedure for Synthesis of 6-Chloro-3- m -tolyl-imidazo[1,2- a ]pyridine 2 under Coventional Heating:
A mixture of 3-bromotoluene (0.12 mL, 0.98 mmol), 6-chloroimidazo[1,2-a]pyridine (0.1 g, 0.66 mmol), K₂CO₃ (0.18 g, 1.3 mmol), PPh₃ (0.0073 g, 0.033 mmol) and Pd(OAc)₂ (0.017 g, 0.063 mmol) in 1,4-dioxane (2 mL) was heated to 100 °C. The reaction was stirred for 48 h, and then the mixture was cooled to r.t. and extracted with CH₂Cl₂ (3 ×). The combined organic layer was dried over MgSO₄ and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc-PE) to give 6-chloro-3-m-tolylimidazo[1,2-a]pyridine(2) as an oil (146 mg, 92% yield). ¹H NMR (250 MHz, CDCl₃): δ = 2.45 (s, 3 H, CH₃), 7.16 (dd, J = 1.9, 9.4 Hz, 1 H), 7.26 (d, J = 7.5 Hz, 1 H), 7.33 (m, 2 H), 7.43 (t, J = 7.5, 8.2 Hz, 1 H), 7.62 (d, J = 9.4 Hz, 1 H), 7.63 (s, 1 H), 8.34 (d, J = 1.9 Hz, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 22.1, 119.2, 121.6, 122.0, 125.7, 126.2, 129.2, 129.44 (2 × CH), 129.9 (2 × CH), 130.1, 133.9, 139.9.

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<A NAME="RG20806ST-26">26</A>

Procedure for Synthesis of 6-Chloro-3- m -tolyl-imidazo[1,2- a ]pyridine 2 under Microwave Irradiation: The 6-chloroimidazo[1,2-a]pyridine (0.1 g, 0.66 mmol) was dissolved in 1,4-dioxane-EtOH (1.5 mL; 2:1) in a microwave vial equipped with a stir bar. 3-Bromotoluene (0.12 mL, 0.98 mmol), K₂CO₃ (0.18 g, 1.3 mmol), PPh₃ (0.0073 g, 0.033 mmol) and Pd(OAc)₂ (0.017 g, 0.063 mmol) were added under argon and subjected to microwave irradiation for 1 h at 130 °C with stirring. The reaction vessel was allowed to cool to r.t. and was diluted with CH₂Cl₂ (15 mL). The mixture was extracted with CH₂Cl₂ (3 ×). The combined organic layer was dried over MgSO₄ and concentrated under vacuum. The crude material thus obtained was purified by column chromatography on silica gel (EtOAc-PE) to give 6-chloro-3-m-tolylimidazo[1,2-a]pyridine(2) as an oil (148 mg, 93% yield).