One-Pot Synthesis of 3-(1,2,3,4-Tetrahydroisoquinolin-1-yl)-isoquinolin-1(2H)-ones by DEAD-Promoted Oxidative Ugi–Wittig ­Reaction Starting from Phosphonium Salt Precursors

Abstract

A new one-pot synthesis of 3-(1,2,3,4-tetrahydroisoquinolin-1-yl)-isoquinolin-1(2H)-ones by DEAD-promoted oxidative Ugi–­Wittig reaction was developed. The sequential reactions of (2-carboxybenzyl)triphenylphosphonium salts, isocyanides, and N-aryl-1,2,3,4-tetrahydroisoquinolines produced 3-(1,2,3,4-tetrahydroisoquinolin-1-yl)-isoquinolin-1(2H)-ones in moderate to good overall yields in the presence of DEAD and Et₃N.

Key words

isoquinolin-1(2H)-one - oxidative Ugi reaction - Wittig reaction - (2-carboxybenzyl)triphenylphosphonium salt - 1,2,3,4-tetrahydroisoquinoline

• References and Notes

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• 31 Preparation of 3-(1,2,3,4-Tetrahydroisoquinolin-1-yl)-isoquinolin-1(2H)-ones 5: General ProcedureTo a mixture of N-aryl-1,2,3,4-tetrahydroisoquinoline 3 (1 mmol), isocyanide 2 (1 mmol), phosphonium salt 1 (1 mmol) in anhydrous CH₂Cl₂ (3 mL) was added dropwise of a solution of DEAD (0.191 g, 1.1 mmol) in anhydrous CH₂Cl₂ (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 24 h, and then the solvent was removed under reduced pressure. Et₃N (0.202 g, 2 mmol) with toluene (5 mL) was added to the reaction system, and the reaction mixture was stirred at 110 °C for 2 h. The solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 30:1 to 20:1, v/v) to give 5. Compound 5a: light yellow solid (yield 0.426 g, 82%), mp 272–273 (C. ¹H NMR (600 MHz, CDCl₃): δ = 8.12 (d, J = 7.2 Hz, 1 H, ArH), 7.62–7.10 (m, 15 H, ArH), 6.93 (t, J = 6.6 Hz, 1 H, ArH), 6.64 (s, 1 H, =CH), 6.23 (d, J = 14.4 Hz, 1 H, NCH₂ ^a), 5.82 (s, 1 H, NCH), 5.22 (d, J = 13.8 Hz, 1 H, NCH₂ ^b), 3.72–3.49 (m, 2 H, NCH₂), 2.91–2.50 (m, 2 H, CH₂), 2.36 (s, 3 H, CH₃) ppm. ¹³C NMR (150 MHz, CDCl₃) δ = 162.6, 148.1, 145.2, 142.9, 135.8, 135.2, 134.5, 132.9, 132.3, 129.7, 129.6, 129.3, 128.7, 128.1, 127.7, 127.2, 126.4, 126.3, 124.2, 120.9, 118.0, 111.2, 62.0, 57.3, 42.5, 24.1, 21.6 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₂H₂₈N₂O₃SNa: 543.1713; found: 543.1734.