Palladium(0)-Catalyzed Alkylarylation of N-Alkyl-N-methacryloylbenzamides with Alkyl Iodides

Abstract

An efficient Pd(0)-catalyzed alkylarylation of N-alkyl-N-methacryloylbenzamides with alkyl iodides for the synthesis of isoquinoline-1,3-diones is described. A highlight of the method is its excellent functional-group tolerance. Mechanistic investigations suggest that a radical addition/cyclization process is probably involved in the sequences.

Key words

palladium catalysis - alkyl iodides - radical addition - alkylmethacryloylbenzamides - isoquinolinediones - alkylarylation

• References and Notes

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• 10 Isoquinoline-1,3-diones 3; General ProcedureAn oven-dried Schlenk tube (10 mL) equipped with a magnetic stirrer bar was charged with N-methacryloyl-N-methylbenzamide (1, 0.2 mmol), CyI (2, 0.4 mmol), 10% PdCl₂(PPh₃)₂ (0.02 mmol), 20% DPE-phos (0.04 mmol), and K₂CO₃ (2 equiv). The tube was evacuated and backfilled with N₂ three times. Toluene (2.0 mL) was then added from a syringe under N₂, and the mixture was stirred for 18 h at 100 °C. The reaction was quenched with H₂O (5 mL), and the resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated. The crude product was purified by flash column chromatography [silica gel, PE–EtOAc (30:1)].4-(Cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione (3a)Colorless solid; yield: 45.0 mg (78%); mp 49–51 °C. IR KBr: 3070, 2918, 2848, 1708, 1663, 1615, 1590, 1356, 1306, 1092, 1055, 747, 693 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.25–8.27 (m, 1 H), 7.62–7.65 (m, 1 H), 7.40–7.45 (m, 2 H), 3.39 (s, 3 H), 2.31–2.36 (m, 1 H), 1.88–1.92 (m, 1 H), 1.56 (s, 3 H), 1.44–1.51 (m, 3 H), 1.23–1.26 (m, 1 H), 1.14–1.17 (m, 1 H), 0.73–1.00 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.8, 164.4, 143.9, 133.7, 128.8, 127.1, 125.7, 124.5, 49.5, 46.6, 34.2, 32.9, 31.6, 27.1, 25.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₂₃NNaO₂: 308.16210; found: 308.16260.