Iron-Catalyzed Direct Cross-Coupling of Ethers and Thioether with Alcohols for the Synthesis of Mixed Acetals

§ These authors contributed equally to this work.

Abstract

An iron-catalyzed direct O-alkylation of alcohols via α-C(sp³)–H activation of ethers and a thioether has been established that tolerates cyclic and acyclic ethers and alcohols containing aromatic N-heterocyclic moieties, providing an efficient and green method for the synthesis of mixed acetals with good to excellent yields. The robustness of this protocol is demonstrated by the late-stage oxidation of a structurally complex natural product.

Key words

iron catalysis - oxidation - alcohols - ethers - mixed acetals - synthetic methods

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• 22 Typical procedure for the synthesis of 3ba: A 25 mL flask equipped with a magnetic stir bar was charged with FeBr₂ (5.5 mg, 0.025 mmol), 2-(4-methoxyphenyl)ethanol 1b (39.2 mg, 0.25 mmol), PMHS (170 μL, 0.75 mmol), DTBP (94 μL, 0.5 mmol) and THF (2 mL) before standard cycles evacuation and backfilling with dry N₂. The mixture was then stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with diethyl ether (3 × 15 mL). The organic phases were combined, and the volatile components were evaporated in a rotary evaporator. The residue was purified by column chromatography on silica gel (petroleum ether/diethyl ether = 50:1) to afford 3ba (49.0 mg, 90%) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 7.18 (dt, J ₁ = 8.73 Hz, J ₂ = 2.54 Hz, 2 H), 6.87 (dt, J ₁ = 8.73 Hz, J ₂ = 2.54 Hz, 2 H), 5.15 (q, J = 2.07 Hz, 1 H), 3.90–3.82 (m, 3 H), 3.80 (s, 3 H), 3.62 (dt, J ₁ = 9.72 Hz, J ₂ = 4.84 Hz, 1 H), 2.86 (t, J = 7.23 Hz, 2 H), 2.03–1.79 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.9, 131.0, 129.7, 113.6, 103.7, 68.1, 66.7, 55.1, 35.3, 32.2, 23.4.