One-Pot Synthesis of Isoquinolin-1(2H)-ones by a Sequential Ugi 4CC/Wittig Process

Abstract

A one-pot synthetic approach to isoquinolin-1(2H)-ones through a Ugi/Wittig sequence has been developed. The reaction of phosphonium salt, aldehyde, secondary amine, and isocyanide produced isoquinolin-1(2H)-ones in good yields through sequential Ugi condensation and intramolecular Wittig reaction in the presence of K₂CO₃.

Key words

one-pot synthesis - Ugi reaction - Wittig reaction - phosphonium salts - secondary amines

• References and Notes

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• 23 General procedure for the one-pot preparation of isoquinolin-1(2H)-ones 6: Aldehyde 2 (1 mmol), (2-carboxyphenyl)triphenylphosphonium bromide (1; 0.48 g, 1 mmol), and isocyanide 4 (1 mmol) were added sequentially to a solution of secondary amine 3 (1 mmol) in anhydrous CH₂Cl₂ (5 mL) at room temperature. Molecular sieves (4 Å, 1 g) were added and the reaction was stirred at ambient temperature for 12–24 h. The molecular sieves were filtered off and the solvent was removed under reduced pressure, then anhydrous toluene (5 mL) and potassium carbonate (0.27 g, 2 mmol) were added. The reaction mixture was stirred for 1–2 h at 70–80 °C, the solid was filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography (Et₂O–petroleum ether, 1:2) to give isoquinolin-1(2H)-ones 6. Data for 6a: Yield: 0.318 g (79%); white solid; mp 165–166 °C; ¹H NMR (CDCl₃, 600 MHz): δ = 8.31 (d, J = 7.8 Hz, 1 H, Ar-H), 7.62–7.26 (m, 8 H, Ar-H), 6.66 (s, 0.5 H, =CH), 4.82 (s, 0.5 H, =CH), 4.42–3.77 (m, 6 H, 2CH and 2OCH₂), 2.82–2.62 (m, 4 H, 2NCH₂), 2.28–0.53 (m, 10 H, 5CH₂); ¹³C NMR (CDCl₃, 100 MHz): δ = 163.8, 142.4, 137.1, 135.8, 131.9, 129.6, 129.4, 128.5, 127.4, 126.4, 126.3, 125.6, 105.1, 71.6, 67.0, 58.9, 53.2, 28.6, 27.7, 26.4, 25.1; MS (EI, 70 eV): m/z (%) = 402 (19) [M]⁺, 319 (60), 317 (33), 315 (39), 272 (25), 259 (22), 235 (52), 176 (100), 91 (18); Anal. Calcd for C₂₆H₃₀N₂O₂: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.69; H, 7.70; N, 7.25.
• 24 Crystallographic data for 6k have been deposited in the Cambridge Crystallographic Data Center as supplementary publication numbers CCDC-1412470. Copies of the data may be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:[phone] or e-mail: [e-mail]).