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Difluoromethylation reaction of paracarbonyl copound participated with [(phenylsulfonyl) difluoromethyl] trimethyl silane

A technology of trimethylsilane and carbonyl compounds, applied in the field of high-efficiency difluoromethylation reagent-[difluoromethyl]trimethylsilane, which can solve the problem of excessive carbonyl substrates, lower utilization rate, substrate enolization, etc. problem, to achieve the effect of high yield and easy condition control

Inactive Publication Date: 2006-01-25
SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method can carry out nucleophilic addition reaction to many carbonyl compounds, and then reduce the sulfone group to obtain difluoromethyl alcohol, there are the following disadvantages: (a) the reaction conditions are harsh (need to strictly control the low temperature -78 ° C); ( b) excess carbonyl substrate is required; (c) excess base is required, which makes substrates (especially aliphatic aldehydes) susceptible to enolization and thus reduces utilization; (d) the removal of sulfone groups involves environmental unfriendliness The reagent (sodium amalgam) does not meet the requirements of environmental protection

Method used

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  • Difluoromethylation reaction of paracarbonyl copound participated with [(phenylsulfonyl) difluoromethyl] trimethyl silane
  • Difluoromethylation reaction of paracarbonyl copound participated with [(phenylsulfonyl) difluoromethyl] trimethyl silane
  • Difluoromethylation reaction of paracarbonyl copound participated with [(phenylsulfonyl) difluoromethyl] trimethyl silane

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Experimental program
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Effect test

Embodiment 1

[0018] [(Benzenesulfonyl)difluoromethyl]trimethylsilane (TMS-CF 2 SO 2 A typical preparation method of Ph): Cool a solution of tetrahydrofuran (50mL) containing difluorobromomethylphenyl sulfone (5.0g, 18.4mmol) and trimethylchlorosilane (3.8mL, 27.7mmol) to -78°C, then A solution of n-butyllithium in hexane (1.6M, 20.7 mL, 33.2 mmol) was added slowly. The reaction mixture was stirred at -78°C for 1 hour, then quenched by the addition of cold saturated aqueous ammonium chloride. The mixed solution was extracted three times with diethyl ether (50 mL each time), and then the combined organic phases were washed with cold saturated aqueous sodium chloride solution and water respectively, and dried over anhydrous sodium sulfate. After removing the solvent on a rotary evaporator, the crude product was distilled under reduced pressure to obtain 3.8 g of [(benzenesulfonyl)difluoromethyl]trimethylsilane, yield: 78%. Boiling point 102-104 ℃ 1 mm Hg. NMR Characterization: 1 H NMR (C...

Embodiment 2

[0020] Carbonyl compound (2) and TMSCF 2 SO 2 Typical method of Ph reaction: under nitrogen protection, 2-naphthaldehyde (2a, 78mg, 0.5mmol) and TMSCF 2 SO 2 Ph (1, 0.6 mmol) was dissolved in dry THF (2.5 mL) and cooled to -78°C. Then, 13 mg of tetrabutyl(triphenyldifluoro)ammonium silicate (TBAF) was added to the above mixed solution. The reaction system was slowly warmed to room temperature with stirring, and stirred overnight. Then tetrabutylammonium fluoride (TBAF, 1.0 mol / L, 0.65 mL) was added into the reaction mixture, stirred for 30 minutes, and then 5 mL of saline solution was added. Extract with diethyl ether 3 times, 15 ml each time. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography to obtain product 3a, 141 mg of white solid, with a yield of 81%. NMR data: 1 H NMR (CDCl 3 ): δ3.67(s, 1H); 5.77(d, J=12Hz, 1H); 7.35-8.15(m, 1...

Embodiment 3

[0022] Typical method of desulfone reaction involving magnesium metal: in a solution containing compound 3a (250mg, 0.7mmol) and 7.5 milliliters of dimethylformamide (DMF), add 4 milliliters of 1:1 acetic acid-sodium acetate buffered aqueous solution (8mol / L). 252 mg of magnesium bars were added in portions to the reaction solution, and then the mixture was stirred at room temperature for 3 hours. Then 30 ml of water was added, and extracted three times with 20 ml of ether. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent in a rotary evaporator, the crude product was separated by silica gel column chromatography to obtain product 4a as a white solid, 133 mg, yield 91%. NMR data: 1 H NMR (CDCl 3): δ2.93(s, 1H); 5.86(td, J=56.2Hz, 4.7Hz, 1H); 4.95(td, J=10.1Hz, 4.7Hz, 1H); 7.45-7.60(m, 3H); 7.80-7.92(m, 4H). 13 CNMR (CDCl 3 ): δ73.74(t, J=2...

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Abstract

The invention relates to a process for synthesizing difluoro methanol product yield including difluoro methanol from difluoro-methylation reaction of ((phenylsulfonyl) difluoromethyl) trimethyl silicane adding carbonyl compound (aldehyde or ketone), the process consists of fluorinion-initiated (phenylsulfonyl) difluoromethyl methylation reaction and magnesium-participated reduction de-sulfonation reaction, The advantages of the disclosed process include simple process, high yield, economy and reaction environment friendliness.

Description

technical field [0001] The invention relates to a high-efficiency difluoromethylation reagent-[(benzenesulfonyl)difluoromethyl]trimethylsilane (TMSCF 2 SO 2 Ph), used this reagent for the first time to achieve the difluoromethylation reaction of catalytic carbonyl compounds under the trigger of fluoride ion. TMSCF 2 SO 2 Ph reagent is an important difluoromethylation reagent for the synthesis of fluorine-containing drugs and fluorine-containing materials. The method of the invention is a difluoromethylation reaction initiated by fluoride ions and a selective desulfone reaction participated in by metal magnesium, and is an environment-friendly reaction. Background technique [0002] Fluorochemicals are widely used in drug design and new material development. The selective introduction of fluorine atoms or fluorine-containing building blocks into organic molecules can greatly enhance the biological activity of these molecules. Therefore, the research on selective fluorin...

Claims

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Application Information

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IPC IPC(8): C07C29/38C07C29/62
Inventor 胡金波倪传法
Owner SHANGHAI INST OF ORGANIC CHEMISTRY - CHINESE ACAD OF SCI
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