(Sila)Difluoromethylation of Fluorenyllithium with CF₃H and CF₃TMS

Dedicated to Professor V. Snieckus on the occasion of his 80th birthday.

Abstract

Difluoromethylation of the C9-H site of the fluorene ring using lithium base and fluoroform (CF₃H), which is one of the most cost-effective difluoromethylating reagents, is attained to give difluoromethylated fluorenes with an all-carbon quaternary center. The Ruppert–Prakash reagent (CF₃TMS) can also be applied to the present reaction system, providing siladifluoromethylated fluorenes that can be utilized for sequential carbon–carbon bond-forming reactions through activation of the silyl group.

Key words

fluoroform - Ruppert–Prakash reagent - bioisostere - fluorene - difluoromethylation - difluoromethyl - difluoromethylene - difluorocarbene

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• 13 Typical Procedure for Difluoromethylation with CF₃HTo a solution of 9-phenyl-9H-fluorene 1a (0.10 mmol, 24.2 mg) in THF (1.0 mL) was added n-butyllithium solution (1.6 M in hexane, 0.11 mmol, 69 μL) at –78 °C. After stirring for 5 minutes at the same temperature, fluoroform (0.20 mmol, 4.5 mL) was bubbled slowly into the mixture via a gas-tight syringe. After stirring for 1 h at –78 °C, the reaction was quenched with water. The organic layer was extracted with diethyl ether, washed with brine, and dried over anhydrous MgSO₄. After filtration, the solvent was removed under reduced pressure. The NMR yield was determined by using benzotrifluoride (BTF) as an internal standard. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate, 50:1 as eluent) to afford 2a (44% NMR yield, 37% isolated yield) as a colorless liquid.Compound 2a: ¹H NMR (300 MHz, CDCl₃): δ = 7.81(d, J = 7.6 Hz, 2 H), 7.50–7.44 (m, 4 H), 7.35–7.26 (m, 7 H), 6.12 (t, J _H–F = 55.5 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃): δ = 145.2 (t, J _C–F = 3.2 Hz), 141.3 (s), 138.5 (s), 128.8 (s), 128.6 (s), 127.9 (s), 127.6 (s), 127.4 (s), 126.6 (s), 120.2 (s), 117.7 (t, J _C–F = 248.7 Hz), 62.5 (t, J _C–F = 19.6 Hz); ¹⁹F NMR (282 MHz, CDCl₃): δ = –119.3 (d, J _H–F = 55.2 Hz, 2 F); FTIR (neat): 3062, 3037, 2961, 2928, 1497, 1450, 1376, 1128, 1064, 734 cm^–1; HRMS (APCI-TOF): m/z [M+H]⁺ calcd for C₂₀H₁₅F₂: 293.1142; found: 293.1143.
• 14 Typical Procedure for Siladifluoromethylation with CF₃TMSTo a solution of 9-phenyl-9H-fluorene 1a (0.10 mmol, 24.2 mg) in THF (1.0 mL) was added n-butyllithium solution (1.6 M in hexane, 0.11 mmol, 69 μL) at –78 °C. After stirring for 5 minutes at the same temperature, CF₃TMS (0.20 mmol, 30 μL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water, the organic layer was extracted with diethyl ether, washed with brine, and dried over anhydrous MgSO₄. After filtration, the solvent was removed under reduced pressure. The NMR yield was determined by using benzotrifluoride (BTF) as an internal standard. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate, 50:1 as eluent) to afford 4a as a colorless liquid.Compound 4a: ¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 7.6 Hz, 2 H), 7.60 (d, J = 7.6 Hz, 2 H), 7.52–7.44 (m, 4 H), 7.34–7.20 (m, 5 H), –0.50 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃): δ = 146.8 (t, J _C–F = 4.4 Hz), 141.5 (s), 140.1 (s), 131.5 (t, J _C–F = 272.0 Hz), 128.8 (t, J _C–F = 2.7 Hz), 128.7 (s), 128.3 (s), 128.1 (s), 127.9 (s), 126.7 (s), 120.0 (s), 65.2 (t, J _C–F = 19.5 Hz), –3.8 (t, J _C–F = 2.3 Hz); ¹⁹F NMR (282 MHz, CDCl₃): δ = –107.7 (s, 2 F); FTIR (neat): 3060, 2958, 2899, 1495, 1449, 1253, 1075, 985, 847, 745 cm^–1; HRMS (APCI-TOF): m/z [M+H+CH₃CN]⁺ calcd for C₂₅H₂₆F₂NSi: 406.1803; found: 406.1818.
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