Palladium-Catalyzed Regioselective Coupling of Secondary Propargyl Carbonates and Ethyl 2-(pyridin-2-yl)acetate Derivatives: Facile Access to C-3 Benzylated Indolizines

Abstract

A palladium-catalyzed ligand controlled regioselective ­coupling reaction of secondary propargyl carbonates and ethyl 2-(pyridin-2-yl)acetate derivatives has been described, leading to C-3 benzyl­ated indolizines for the first time in moderate to good yields. DBFphos as the ligand is crucial to this high regioselective annulation reaction, and a plausible reaction mechanism has been proposed.

Key words

regioselective coupling - propargyl carbonate - C-3 ­benzylated indolizine - DBFphos - synthetic method

• References and Notes

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• 15 General Procedure for the Synthesis of Indolizines from Propargyl Carbonates and Ethyl 2-(pyridin-2-yl)acetate Derivatives: Ethyl 2-(pyridin-2-yl)acetate (1a, 0.4 mmol), 1,3-diphenylprop-2-yn-1-yl methyl carbonate (2a, 0.2 mmol), Pd₂(dba)₃ (0.01 mmol), DBFphos (0.02 mmol), K₂CO₃ (0.4 mmol) were mixed under N₂ atmosphere in DMF (2 mL). The reaction tube was heated in an oil bath at 120 °C for 16 h. After completion of the reaction, the reaction mixture was extracted with EtOAc (3 × 15 mL), and the solvent was removed under reduced pressure. The remaining crude product was then purified through column chromatography using silica gel (EtOAc–petroleum ether = 1:5) to afford 3a as a white solid in 65% yield. ¹H NMR (500 MHz, CDCl₃): δ = 8.24 (dd, J = 9.2, 1.3 Hz, 1 H), 7.53 (d, J = 7.0 Hz, 1 H), 7.23–7.32 (m, 5 H), 7.15 (t, J = 7.3 Hz, 2 H), 7.10 (t, J = 7.2 Hz, 1 H), 6.93– 6.99 (m, 3 H), 6.54 (td, J = 6.8, 1.3 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 4.08 (s, 2 H), 1.06 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2, 137.5, 136.2, 135.4, 131.5, 130.5, 128.9, 127.8, 127.7, 127.1, 126.7, 123.4, 122.2, 121.4, 120.2, 112.6, 102.0, 59.3, 30.2, 14.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₂NO₂ : 356.1645; found 356.1642.