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CC BY 4.0 · SynOpen 2018; 02(03): 0234-0239
DOI: 10.1055/s-0037-1610361
DOI: 10.1055/s-0037-1610361
letter
(Sila)Difluoromethylation of Fluorenyllithium with CF3H and CF3TMS
Financial support was provided by JST ACT-C Grant Number JPMJCR12Z7 and JSPS KAKENHI Grant Number 26620078. We thank TOSOH F-TECH, INC. for the gift of CF3H and CF3TMS. We are grateful to Dr. Kohsuke Aikawa for his useful discussions and suggestions.Weitere Informationen
Publikationsverlauf
Received: 11. April 2018
Accepted: 25. Mai 2018
Publikationsdatum:
19. Juli 2018 (online)
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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 - difluorocarbeneSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610361.
- Supporting Information
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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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For reviews, see:
For reviews, see:
Selected reports for metal-mediated or -catalyzed difluoromethylations of aryl halides, see:
For reviews, see:
Difluoromethylations with fluoroform reported by other groups: