Organocatalyst-Induced Multicomponent Reaction: An Efficient Procedure for the Activation of Amides

Abstract

An efficient organocatalytic route for the activation of amide derivatives is reported. In this transformation, amide derivatives were employed as a potential bidentate nucleophile in a reaction involving isoquinoline and propiolates using tetrabutylphosphonium acetate to form 1,2-dihydroisoquinoline skeletons.

Keywords

multicomponent reaction - propiolate - amide - 1,2-dihydroisoquinoline - tetrabutylphosphonium acetate

• References and Notes

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• 17 Typical Procedure for the Preparation of 4 and 6 To a stirred solution of amide (1.5 mmol), propiolate (1.0 mmol), and TBPA (20 mol%) in THF (3 mL), the N-heterocycle (1.0 mmol) was added slowly at 25 °C (for 10 min), and the resulting mixture was stirred at ambient temperature for 12 h. After completion of the reaction (monitored by TLC), the mixture was evaporated in vacuo followed by addition of H₂O (10 mL), and the pH was adjusted to 2 using concentrated HCl. Afterwards, CH₂Cl₂ (5 mL) was added, the mixture was stirred for an additional 30 min, and two layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL), the combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo to yield the crude product (purity 75–82%). The crude product was further purified by recrystallization from CH₂Cl₂–Et₂O. Representative Analytical Data Methyl 3-(1-Benzamidoisoquinolin-2(1H)-yl)acrylate (4a) The crude product was purified by recrystallization from CH₂Cl₂–Et₂O affording 0.30 g (89%) of 4a as an orange powder; mp 142–144 °C. IR (KBr): ν_max = 1723, 1640, 1546, 1320, 1126 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.67 (3 H, s, MeO), 5.71 (1 H, d, ³ J = 7.1 Hz, CH), 5.97 (1 H, d, ³ J = 7.6 Hz, CH), 6.69 (1 H, d, ³ J = 7.1 Hz, CH), 6.82 (1 H, d, ³ J = 5.9 Hz, CH), 7.29 (1 H, t, ³ J = 7.0 Hz, CH), 7.29–7.48 (5 H, m, 5 CH), 7.64 (1 H, d, ³ J = 11.4, CH), 7.68–8.80 (3 H, m, 3 CH), 7.89 (1 H, d, ³ J = 5.9, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 52.6 (MeO), 66.5 (CH), 93.6 (CH), 104.1 (CH), 125.1 (CH), 125.4 (CH), 125.7 (CH), 125.8 (CH), 126.4 (2 CH), 126.9 (CH), 129.0 (2 CH), 133.1 (CH), 133.6 (C), 134.1 (C), 138.9 (C), 144.1 (C), 165.1 (C), 166.4 (C). MS: m/z (%) = 334 (2) [M⁺], 320 (12), 276 (25), 172 (37), 105 (56), 77 (100). Anal. Calcd for C₂₀H₁₈N₂O₃ (334.38): C, 71.84; H, 5.43; N, 8.38. Found: C, 72.08; H, 5.64; N, 8.41. Ethyl 3-(1-Benzamidoisoquinolin-2(1H)-yl)acrylate (4b) The crude product was purified by recrystallization from CH₂Cl₂–Et₂O affording 0.31 g (88%) of 4b as an orange powder; mp 130–133 °C. IR (KBr): ν_max = 1726, 1648, 1540, 1337, 1134 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (3 H, t, ³ J = 6.4 Hz, Me), 4.36 (2 H, q, ³ J = 6.4 Hz, CH₂), 5.64 (1 H, d, ³ J = 7.6 Hz, CH), 5.93 (1 H, d, ³ J = 7.0 Hz, CH), 6.67 (1 H, d, ³ J = 7.3 Hz, CH), 6.71 (1 H, d, ³ J = 6.5 Hz, CH), 7.24 (1 H, t, ³ J = 7.1 Hz, CH), 7.27–7.40 (5 H, m, 5 CH), 7.70 (1 H, d, ³ J = 11.6 Hz, CH), 7.68-5.80 (3 H, m, 3 CH), 7.84 (1 H, d, ³ J = 6.5 Hz, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 14.9 (Me), 65.7 (CH), 68.7 (CH₂), 91.4 (CH), 105.4 (CH), 125.3 (CH), 125.5 (CH), 126.1 (CH), 126.6 (CH), 127.0 (2 CH), 127.4 (CH), 128.7 (2 CH), 132.8 (CH), 132.9 (C), 133.7 (C), 140.1 (C), 143.7 (C), 165.6 (C), 166.9 (C). MS: m/z (%) = 348 (5) [M⁺], 320 (11), 276 (19), 172 (43), 105 (69), 77 (100). Anal. Calcd for C₂₁H₂₀N₂O₃ (348.40): C, 72.40; H, 5.79; N, 8.04. Found: C, 72.56; H, 5.93; N, 8.13.