Palladium-Catalyzed Direct 1,4-Addition of Heteroarenes to α,β-Unsaturated Ketones via C–H Activation

Abstract

Palladium-catalyzed direct conjugate additions of heteroarenes to α,β-unsaturated ketones via C–H activation are described. The reactions of heteroarenes with α,β-unsaturated ketones proceeded smoothly in the presence of PdCl₂ as a catalyst under mild conditions to give the corresponding Michael adducts in moderate to excellent yields.

Key words

palladium catalyst - direct conjugate addition - heteroarene - unsaturated ketone - C–H activation

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• 12 General Procedure To a mixture of PdCl₂ (0.025 mol, 4.4 mg), α,β-unsaturated ketone 2 (0.5 mmol), and MeOH (2.0 mL), heteroarene 1 (1.0 mmol, 2.0 equiv) was added. After the resultant mixture was stirred at r.t. for 24 h, the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel (eluent: PE–EtOAc = 10:1 to 20:1, v/v) to afford the desired product 3. 4-(5-Methoxythiophen-2-yl)-4-phenylbutan-2-one (3b) Colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.19–7.31 (m, 5 H), 6.37 (d, J = 3.8 Hz, 1 H), 5.94 (d, J = 3.8 Hz, 1 H), 4.62 (t, J = 7.4 Hz, 1 H), 3.80 (s, 3 H), 3.18 (dd, J = 16.6, 7.5 Hz, 1 H), 3.07 (dd, J = 16.6, 7.3 Hz, 1 H), 2.10 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 206.4, 165.1, 143.4, 134.0, 128.7, 127.6, 126.9, 121.2, 102.8, 60.2, 50.6, 42.0, 30.7. IR (neat): 3413, 3026, 2925, 1715, 1559, 1505, 1451, 1430, 1355, 1203, 1153, 990, 762, 698 cm^–1. HRMS (EI): m/z calcd for C₁₅H₁₆O₂S [M]⁺: 260.0871; found: 260.0876. 4-(Furan-2-yl)nonan-2-one (3e) Colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.28 (dd, J = 1.8, 0.8 Hz, 1 H), 6.25 (dd, J = 3.1, 1.9 Hz, 1 H), 5.98 (dd, J = 3.2, 0.8 Hz, 1 H), 3.22–3.30 (m, 1 H), 2.78 (dd, J = 16.3, 7.6 Hz, 1 H), 2.63 (dd, J = 16.3, 6.6 Hz, 1 H), 2.07 (s, 3 H), 1.49–1.66 (m, 2 H), 1.21–1.26 (m, 6 H), 0.85 (t, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 207.6, 157.5, 140.9, 110.0, 105.1, 48.0, 34.5, 34.0, 31.6, 30.3, 26.8, 22.5, 14.0. IR (neat): 2956, 2929, 2858, 1719, 1360, 1159, 1148, 1010, 729 cm^–1. ESI-HRMS: m/z calcd for C₁₃H₂₀O₂ [M + Na]⁺: 231.1361; found: 231.1364. 4-(1-Methyl-1H-pyrrol-2-yl)nonan-2-one (3g) Colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 6.45 (t, J = 1.8, 1.9 Hz, 1 H), 6.04 (t, J = 3.1, 3.0 Hz, 1 H), 5.84 (dd, J = 3.2, 1.8 Hz, 1 H), 3.57 (s, 3 H), 3.19–3.26 (m, 1 H), 2.74 (dd, J = 16.7, 7.5 Hz, 1 H), 2.65 (dd, J = 16.6, 6.5 Hz, 1 H), 2.04 (s, 3 H), 1.50–1.56 (m, 2 H), 1.19–1.26 (m, 6 H), 0.84 (t, J = 6.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 208.3, 136.7, 120.9, 106.8, 104.1, 50.2, 36.6, 33.9, 32.0, 31.8, 31.0, 27.1, 22.7, 14.2. IR (neat): 2954, 2927, 2856, 1716, 1489, 1359, 1299, 1162, 702 cm^–1. ESI-HRMS: m/z calcd for C₁₄H₂₃NO [M + Na]⁺: 244.1677; found: 244.1684
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