Ether Synthesis through Reductive Cross-Coupling of Ketones with Alcohols Using Me₂SiHCl as both Reductant and Lewis Acid

Published as part of the Cluster Silicon in Synthesis and Catalysis

Abstract

We report that a Lewis acidic silane, Me₂SiHCl, can mediate the direct cross-coupling of a wide range of carbonyl compounds with alcohols to form dialkyl ethers. The reaction is operationally simple, tolerates a range of polar functional groups, can be utilized to make sterically hindered ethers, and is extendable to sulfur and nitrogen nucleo­philes.

Key words

silanes - Lewis acid - ketones - alcohols - ethers - reductive coupling

• References and Notes

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• 13 General procedure for the reductive etherification reaction: To a mixture of carbonyl (0.25 mmol) and alcohol (0.275 mmol, 1.1 equiv) in acetonitrile (0.5 mL) was added chlorodimethyl-silane (0.275 mmol, 1.1 equiv) under argon. The reaction mixture was stirred at room temperature (ca. 25 °C) for 12 h. The reaction was then quenched by adding a drop of aqueous NaHCO₃ solution under air. The resulting mixture was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (pentane/DCM or pentane/MTBE).
• 14 (8R,9S,13S,14S,17S)-17-(Cyclohexyloxy)-13-methyl-7,8,9,11, 12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-ol (Table 3, Entry 7): White solid. ¹H NMR (500 MHz, CDCl₃): δ = 7.15 (d, J = 8.5 Hz, 1 H), 6.62 (dd, J = 8.5, 2.7 Hz, 1 H), 6.55 (d, J = 2.7 Hz, 1 H), 4.55 (s, 1 H), 3.49 (dd, J = 8.5, 8.5 Hz, 1 H), 3.32–3.23 (m, 1 H), 2.89–2.74 (m, 2 H), 2.31–2.21 (m, 1 H), 2.20–2.11 (m, 1 H), 2.06–1.93 (m, 2 H), 1.94–1.80 (m, 3 H), 1.79–1.69 (m, 2 H), 1.71–1.60 (m, 1 H), 1.58–1.42 (m, 3 H), 1.45–1.36 (m, 1 H), 1.39–1.10 (m, 9 H), 0.79 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.4, 138.5, 133.1, 126.7, 115.4, 112.7, 86.5, 77.1, 50.3, 44.2, 43.4, 38.8, 37.9, 33.3, 33.2, 29.8, 29.1, 27.3, 26.6, 26.0, 24.6, 24.5, 23.3, 11.9. HRMS (ESI+): m/z [M+H]⁺ calcd for C₂₄H₃₅O₂: 355.26316; found: 355.26335