Practical Synthesis of Functionalized Chromeno[3,4-c]pyridine Derivatives via a CuCl₂-Catalyzed Tandem Reaction of the Blaise Reaction Intermediates and 3-Cyanocoumarins

Abstract

This work discloses a novel and efficient protocol for the construction of functionalized chromeno[3,4-c]pyridine derivatives from the Blaise reaction intermediates and 3-cyanocoumarins through a CuCl₂-catalyzed sequential Michael addition/intramolecular cyclization/oxidative aromatization reaction. This new method shows the advantages of mild reaction conditions, easy workup, nonchromatographic purification technique, good functional group tolerance, and moderate to good yields.

Key words

tandem reaction - CuCl₂-catalyzed - Blaise reaction intermediates - 3-cyanocoumarins - chromeno[3,4-c]pyridines

• References and Notes

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• 22 General Procedure for the One-Pot Synthesis of 3aTo a stirred suspension of commercial zinc dust (520 mg, 8.0 mmol) was added methanesulfonic acid (2.5 mg) in anhydrous THF (10 mL). After 10 min of reflux, 4-chlorobenzonitrile (548 mg, 4.0 mmol) was added all at once. While maintaining reflux temperature, tert-butyl bromoacetate (1.17 g, 6.0 mmol) was added over 1 h with a syringe pump, and the reaction mixture was further heated at reflux for 1 h (all nitrile was converted into intermediate Aa, monitored by TLC). To the reaction mixture was added CuCl₂ (53.6 mg, 0.4 mmol) and a solution of 3-cyanocoumarin (342 mg, 2.0 mmol) in THF (3.0 mL), the reaction mixture was stirred at reflux temperature under dry air. After the reaction was completed (monitored by TLC), the solution was quenched with saturated aqueous NH₄Cl (10 mL), then neutralized with saturated aqueous Na₂CO₃ solution (15 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was washed with methanol or ethanol to give the pure product 3a (658 mg, 78%); pale yellow powder, mp 269–270 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.30 (s, 1 H), 8.16 (s, 1 H), 7.96 (dd, J = 8.4, 1.2 Hz, 1 H), 7.72–7.67 (m, 1 H), 7.60–7.55 (m, 2 H), 7.50–7.44 (m, 3 H), 7.39–7.35 (m, 1 H), 1.25 (s, 9 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 168.10, 161.63, 161.11, 159.89, 152.27, 141.19, 138.33, 134.15, 133.49, 130.71, 128.43, 126.28, 124.59, 118.23, 115.87, 114.58, 96.82, 83.48, 27.41. MS (ESI): m/z = 423 [M – H]⁺. HRMS-ESI: m/z calcd for C₂₃H₂₀ClN₂O₄ [M – H]⁺: 423.1106; found: 423.1083.