N-Heterocyclic Carbene Catalysis for Facile Access to Pentasubstituted 4H-Pyran Derivatives

Abstract

The synthesis of polysubstituted 4H-pyran derivatives has attracted considerable attention due to its wide application in agrochemicals, pharmaceuticals, and other functional molecules. We report an N-heterocyclic carbene-catalyzed [3+3] annulation reaction of β-ketone esters with enynals for rapid access to pentasubstituted 4H-pyran derivatives through a regioselective activation of the ynal. A series of 4H-pyran derivatives bearing various substituents were obtained in moderate to excellent yields. This method could find further applications in the synthesis of structurally diverse 4H-pyran-derived functional molecules from readily available starting materials.

Key words

N-heterocyclic carbene catalysis - organocatalysis - pyrans - regioselectivity - ketone esters - enynals

Publication History

Received: 15 September 2023

Accepted after revision: 24 January 2024

Accepted Manuscript online:
24 January 2024

Article published online:
15 February 2024

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• 8 4H-Pyrans 3a–i and 4a–n; General Procedure Under a N₂, the appropriate 1 (0.12 mmol) and 2 (0.10 mmol) together with NHC (0.02 mmol), K₂CO₃ (0.15 mmol), and DQ (0.15 mmol) were dissolved in anhyd THF (1.0 mL), and then EtOH (100 μL) was added. The mixture was stirred for 48 h at r.t. and then purified by column chromatography (silica gel). 5-Ethyl 3-Methyl 2-(2-ethoxy-2-oxoethyl)-4,6-diphenyl-4H-pyran-3,5-dicarboxylate (3a) Yellow oil; yield: 36.8 mg, 84%. ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.34 (m, 7 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.24–7.19 (m, 1 H), 4.93 (s, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.00–3.82 (m, 4 H), 3.66 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.89 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl3): δ = 168.8, 166.4, 166.3, 156.9, 155.2, 144.5, 133.8, 129.8, 128.9 (2 C), 128.4 (2 C), 128.4 (2 C), 127.9 (2 C), 127.0, 110.4, 109.6, 61.3, 60.5, 51.8, 39.2, 38.3, 14.2, 13.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₆NaO₇: 473.1570; found: 473.1562. 3-Ethyl 5-Methyl 6-(2-ethoxy-2-oxoethyl)-2,4-diphenyl-3,4-dihydro-2H-pyran-3,5-dicarboxylate (5) 10% Pd/C (50 mg) was added to a solution of 3a (443.96 μmol, 200 mg) in EtOH (20.0 mL) under a N₂ atmosphere. The suspension was degassed in vacuum and purged with H₂ (balloon) several times. The mixture was stirred at r.t. for 24 h and then filtered through Celite, which was washed with EtOH (3 × 10 mL). The combined organic solution was concentrated under reduced pressure to afford a crude product that was purified by flash chromatography (silica gel) to give a colorless solid; yield: 159.1 mg (79%); mp 117–118 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.26 (m, 5 H), 7.24–7.11 (m, 5 H), 5.30 (d, J = 2.6 Hz, 1 H), 4.49 (d, J = 7.9 Hz, 1 H), 4.39 (d, J = 16.6 Hz, 1 H), 4.23–4.12 (m, 2 H), 3.60 (dd, J = 16.6, 0.8 Hz, 1 H), 3.48 (q, J = 7.1 Hz, 2 H), 3.42 (dd, J = 8.0, 2.7 Hz, 1 H), 3.37 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 0.65 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.4, 168.3, 167.7, 160.7, 140.6, 137.4, 128.4 (2 C), 128.1 (2 C), 128.1 (2 C), 127.3, 126.6, 125.6 (2 C), 106.7, 78.0, 60.9, 59.8, 52.2, 51.0, 42.2, 39.1, 14.2, 13.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₈NaO₇: 475.1727; found: 475.1732.