Electrochemical Synthesis of 2-Bromoethyl and 2-Iodoethyl Ketones from Cyclopropanols

Abstract

A simple electrochemical protocol for the preparation of 2-bromoethyl- and 2-iodoethyl ketones from cyclopropanols and magnesium halides has been developed. The reaction proceeded with exclusive regioselectivity and without epimerization of the α-stereocenter in the products. We also showed that the synthesized diastereomerically pure 2-bromoethyl ketones undergo smooth copper and nickel-catalyzed alkylation, alkenylation, and arylations reactions.

Key words

electrochemistry - cyclopropanols - haloethyl ketones - ring opening - cross-coupling

• References and Notes


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• 7 2-Haloethyl Ketones: General Procedure A 50 mL vial equipped with a stirring bar was charged with a 0.03–0.05 M solution of the appropriate cyclopropanol (1 equiv) in 2:1 MeCN–H₂O followed by MgBr₂ (1 equiv) or MgI₂·Et₂O (1 equiv). The vial was then closed with an electrode holder containing a graphite anode and cathode. Electrolysis of the reaction mixture was carried out at rt and a constant current of 3.6 mA/cm². When the reaction was complete (40–80 min), it was quenched with 5% aq Na₂SO₃ (2 mL) and the mixture was diluted with H₂O and extracted with DCM (3 × 5 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude product was then purified by flash column chromatography. 3-(Bromomethyl)-1-{[tert-butyl(diphenyl)silyl]oxy}-9-hydroxynonan-4-one (10k) Colorless oil; yield: 39.4 mg (76%). ¹H NMR (500 MHz, CDCl₃): δ = 7.67–7.60 (m, 4 H), 7.47–7.36 (m, 6 H), 3.69–3.60 (m, 4 H), 3.58–3.52 (m, 1 H), 3.39 (dd, J = 9.9, 4.7 Hz, 1 H), 3.26–3.17 (m, 1 H), 2.54 (t, J = 7.2 Hz, 2 H), 1.93–1.83 (m, 1 H), 1.72–1.53 (m, 5 H), 1.39–1.30 (m, 2 H), 1.06 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 211.2, 135.7, 133.4, 130.0, 127.9, 62.8, 61.3, 50.5, 43.3, 34.0, 32.6, 32.2, 27.0, 25.3, 23.0, 19.3. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₆H₃₇BrNaO₃Si: 527.1588; found: 527.1582. (±)-4-(Bromomethyl)-6-{[tert-butyl(diphenyl)silyl]oxy}-1-phenyloctan-3-one [(±)-10p] Colorless oil; yield: 38 mg (82%). ¹H NMR (500 MHz, CDCl₃): δ = 7.70–7.61 (m, 4 H), 7.45–7.33 (m, 6 H), 7.30–7.24 (m, 2 H), 7.23–7.17 (m, 1 H), 7.13–7.07 (m, 2 H), 3.61 (tt, J = 6.7, 4.7 Hz, 1 H), 3.34 (dd, J = 10.0, 8.5 Hz, 1 H), 3.17 (dd, J = 10.0, 4.8 Hz, 1 H), 2.98 (tt, J = 8.2, 4.9 Hz, 1 H), 2.86–2.65 (m, 3 H), 2.52 (ddd, J = 17.9, 9.5, 5.7 Hz, 1 H), 1.89 (ddd, J = 14.1, 7.9, 4.7 Hz, 1 H), 1.52–1.41 (m, 3 H), 1.06 (s, 9 H), 0.75 (t, J = 7.4 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 209.9, 141.1, 136.0, 134.3, 134.0, 129.9, 129.9, 128.6, 128.5, 127.8, 127.7, 126.2, 73.0, 50.2, 45.0, 37.4, 32.9, 29.8, 29.2, 27.2, 19.5, 9.1. HRMS (ESI+): m/z [M + H]⁺ calcd for C₃₁H₄₀BrO₂Si: 551.1975; found: 551.1976.
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