Bromine-Radical-Mediated Synthesis of β-Functionalized β,γ- and δ,ε-Unsaturated Ketones via C–H Functionalization of Aldehydes

Published as part of the ISHC Conference Special Section

Abstract

The bromine-radical-mediated allylation reaction of aldehydes was studied. In the presence of V-65 as radical initiator, the reaction of aldehydes with allyl bromides gave β,γ-unsaturated ketones in good yields (13 examples, 45–84%). The reaction is triggered by hydrogen abstraction from the aldehyde by bromine radical to form an acyl radical, which undergoes an S_H2′-type addition–elimination reaction with allyl bromides to give coupling products with liberation of bromine radical. Three-component coupling reactions comprising aldehydes, electron-deficient alkenes, and methallyl bromide also proceeded to give δ,ε-unsaturated ketones.

Key words

bromine radical - S_H2′ reaction - β,γ-unsaturated ketones - δ,ε-unsaturated ketones - three-component reaction

• References and Notes

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• 14 General Procedure for the Synthesis of 3 To a 20 mL two-necked round-bottom flask attached with a reflux condenser were added V-65 (25 mg, 0.1 mmol) and K₂CO₃ (138 mg, 1.0 mmol), and this flask was purged with argon. Then, 1-nonanal (1a, 71 mg, 0.5 mmol), methyl 2-(bromomethyl)acrylate (2a, 269 mg, 1.5 mmol), and degassed benzene (5 mL) were added. The mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered through a short plug of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO₂ (hexane/EtOAc = 1:0 to 30:1) and preparative HPLC (chloroform) to give methyl 2-methylene-4-oxododecanoate (3b, 101 mg, 84%). Colorless oil; R_f = 0.55 (hexane/EtOAc = 5:1). ¹H NMR (500 MHz, CDCl₃): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.20–1.33 (m, 10 H), 1.55–1.65 (m, 2 H), 2.47 (t, J = 7.4 Hz, 2 H), 3.40 (s, 2 H), 3.74 (s, 3 H), 5.63 (s, 1 H), 6.33 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.02, 22.58, 23.67, 29.10, 29.30, 31.76, 42.63, 45.63, 52.00, 128.53, 134.25, 166.78, 207.42. IR (neat): 2953, 2926, 2855, 1720, 1638 cm^–1. MS (EI): m/z (relative intensity): 240 (12) [M]⁺, 209 (5) [M – OMe]⁺, 141 (100), 82 (14), 71 (25), 57 (26), 55 (11). HRMS (EI): m/z calcd for C₁₄H₂₃O₃ [M]⁺: 240.1725; found: 240.1725.
• 15 General Procedure for the Synthesis of 5 To a 20 mL two-necked round-bottom flask attached with a reflux condenser were added AIBN (16 mg, 0.1 mmol) and K₂CO₃ (138 mg, 1.0 mmol), and this flask was purged with argon. Then, 1-nonanal (1a, 71 mg, 0.5 mmol), acrylonitrile (4a, 53 mg, 1.0 mmol), methallyl bromide (2e, 203 mg, 1.5 mmol), and degassed benzene (5 mL) were added. The mixture was stirred at 80 °C for 4 h. The reaction mixture was filtered through a short plug of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO₂ (hexane/EtOAc = 1:0 to 30:1) and preparative HPLC (CHCl₃) to give 2-(2-methylallyl)-4-oxododecanenitrile (5a, 71.1 mg, 57%). Compound 5a is known in literature, and all spectral data matched that reported.^6b