An Improved Method for Difluorocyclopropanation of Alkenes

Abstract

Difluorocyclopropanation of alkenes using fluorinated acetate salts using convential heating is often a slow, inefficient, and energy-intensive process. We report here a modified protocol which enables the rapid (<5 min) preparation of 1,1-difluorocyclopropanes, using microwave irradiation. The new procedure is not only considerably faster than previously reported methods, but it also employs easily removed, low boiling-point solvents and avoids the use of highly toxic or ozone-depleting substances.

Key words

difluorocyclopropane - cyclopropanation - microwave - pharmacophore - greener

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• 10 Data for 2a Clear colorless oil (269.5 mg, 75%); R_f = 0.30 (100% hexanes). ¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.25 (5 H, m), 1.71–1.66 (1 H, m), 1.52 (3 H, dd, J = 3.0, 2.0 Hz), 1.43–1.40 (1 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 139.1, 128.5, 128.3, 127.2, 114.5, 31.2, 22.5, 21.4. ¹⁹F NMR (400 MHz, CDCl₃): δ = –132.3 to –132.7 (1 F, m), –137.3 to –137.7 (1 F, m). IR: ν_max = 2981, 1500, 1469, 1445, 1369, 1300, 1208.9, 1172, 1097, 1065, 1006, 932, 902, 869, 765, 716, 610, 545, 480 cm^–1. MS: m/z calcd for C₁₀H₁₀F₂: 168.0751; found: 168.9; m/z calcd for C₉H₇F₂ = 153.0506; found: 153.1.
• 11 Typical Experimental Procedure Sodium chlorodifluoroacetate (914 mg 6.0 mmol) was completely dissolved in a THF solution (4.0 mL) of alkene (2.0 mmol) and exposed to MW irradiation (using a Milestone MicroSYNTH reactor and Q20 vessel with Weflon^® button and magnetic stirring bead). Twist control, rotor control, start parameters, and continuous power were all selected. T2 control was used with 89% stirring. Method parameters were set at 300 W, 170 °C, 00:05:00). After sampling for quantitative NMR studies, the reaction mixture was diluted with H₂O (20.0 mL) and the crude reaction product extracted into Et₂O (3 × 20.0 mL). The combined organic extracts were dried over anhydrous MgSO₄ and the solvent removed in vacuo to yield the crude product as a brown oil. The crude reaction products were purified by column chromatography using 100% hexanes as eluent.