Palladium-Catalyzed Regioselective Heck–Suzuki–Miyaura Cascade Cyclization for the Synthesis of Trisubstituted Arylideneisoquinolinones

Abstract

An Ugi four-component reaction was used to construct propargylamide starting materials for a subsequent domino Heck–Suzuki–Miyaura cross-coupling reaction to give derivatives of 4-benzylidene-1-oxo-3,4-dihydro-1H-isoquinoline.

Key words

Ugi reaction - multicomponent reactions - propargylamides - domino reaction - Heck–Suzuki–Miyaura reaction - isoquinolinones

• References and Notes

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• 24 2-[(4E)-4-Benzylidene-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]-2-(4-chlorophenyl)-N-cyclohexylacetamide (7a): Typical Procedure Ugi adduct 5a (0.5 mmol) was mixed with PhB(OH)₂ (0.6 mmol), Na₂CO₃ (1.5 mmol), and Pd(OAc)₂ (0.1 mmol) in 3:1 1,4-dioxane–H₂O (6 mL), and the resulting solution was stirred at 80 °C under argon for 12 h. When the reaction was complete (TLC), the mixture was filtered through Celite, and the filtrate was diluted with H₂O (10 mL) and EtOAc (10 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated under reduced pressure. The resultant crude product was purified by preparative TLC [silica gel, hexane–EtOAc (8:2)] to give a white solid; 79% yield; mp 200–202 °C. IR (KBr): 3274, 3074, 2929, 2853, 1639, 1293 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.34 (d, J = 7.3 Hz, 1 H), 7.98 (d, J = 7.4 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 2 H), 7.44–7.37 (m, 1 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.31–7.24 (m, 4 H), 7.22–7.15 (m, 2 H), 7.08 (d, J = 7.4 Hz, 1 H), 6.58 (s, 1 H), 6.43 (s, 1 H), 4.40 (d, J = 13.0 Hz, 1 H), 3.69 (d, J = 13.0 Hz, 1 H), 3.63 (s, 1 H), 1.83–1.79 (m, 1 H), 1.78–1.73 (m, 1 H), 1.69–1.62 (m, 2 H), 1.54 (d, J = 11.4 Hz, 1 H), 1.30–1.06 (m, 5 H). ¹³C NMR (500 MHz, CDCl3): δ = 167.52, 163.50, 135.76, 135.26, 135.18, 132.59, 131.11, 131.04, 130.42, 130.31, 129.13, 129.09, 128.64, 128.57, 127.66, 126.33, 58.29, 51.53, 47.86, 32.22, 32.12, 25.13, 24.53, 24.45. Anal. Calcd for C₃₀H₂₉ClN₂O₂: C, 74.29; H, 6.03; N, 5.78. Found: C, 74.30; H, 6.05; N, 5.75.