A One-Pot Sonogashira Coupling and Annulation Reaction: An Efficient Route toward 4H-Quinolizin-4-ones

Abstract

An efficient one-pot Sonogashira coupling and annulation reaction affording 4H-quinolizin-4-ones in moderate to excellent yields is described. A variety of substituted iodoarenes and 2-alkylazaarenes were well tolerated, and especially the unsaturated double and triple bonds were compatible under the standard conditions.

Key words

one-pot - Sonogashira coupling - quinolizinone - 2-alkylazaarene - annulation reaction

• References and Notes

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• 11 Ethyl 4-oxo-2-phenyl-4H-quinolizine-1-carboxylate (4a) – Typical Procedure An oven-dried screw cap test tube was charged with a magnetic stir bar, Pd(PPh₃)₂Cl₂ (2 mol%), CuI (4 mol%), and K₂CO₃ (0.4 mmol). The tube was then evacuated and backfilled with argon. The evacuated/backfill sequence was repeated two additional times. Under a counter-flow of argon, DMF (1 mL), iodoarene (1a, 0.2 mmol), and methyl propiolate (2a, 0.3 mmol) were added. The tube was placed in a preheated oil bath at 80 °C, and the mixture was stirred vigorously for 10 min. Then the screw cap was opened and 2-pyridyl ethyl ester (3a, 0.2 mmol) was added in air at 80 °C. The mixture was allowed to react for another 8 h at 80 °C in air atmosphere. After the reaction was finished, water (5 mL) was added, and the solution was extracted with ethyl acetate (3 × 5 mL), the combined extract was dried with anhydrous MgSO₄. Solvent was removed, and the residue was separated by column chromatography (petroleum ether/ethyl acetate, 2:1) to give 4a (50 mg, 86%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 9.20 (d, J = 7.3 Hz, 1 H), 8.20–8.14 (m, 1 H), 7.50 (ddd, J = 9.2, 6.6, 1.4 Hz, 1 H), 7.35 (dtt, J = 9.7, 7.0, 2.5 Hz, 5 H), 7.10–7.05 (m, 1 H), 6.55 (s, 1 H), 3.91 (q, J = 7.2 Hz, 2 H), 0.74 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.3, 157.4, 152.0, 142.1, 140.1, 132.2, 128.3, 128.3, 127.9, 127.4, 123.2, 115.5, 109.0, 106.9, 61.2, 13.2. MS (EI): m/z = 293, 265, 248, 237, 220, 193, 165, 95, 78, 51.