CN100335486C - Preparation method of [(phenyl sulfonyl) difluoro methyl] trimethyl silane - Google Patents
Preparation method of [(phenyl sulfonyl) difluoro methyl] trimethyl silane Download PDFInfo
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- CN100335486C CN100335486C CNB2005100277602A CN200510027760A CN100335486C CN 100335486 C CN100335486 C CN 100335486C CN B2005100277602 A CNB2005100277602 A CN B2005100277602A CN 200510027760 A CN200510027760 A CN 200510027760A CN 100335486 C CN100335486 C CN 100335486C
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- difluoromethyl
- phenylsulfonyl
- phenyl sulfone
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- methyl phenyl
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Abstract
The present invention relates to a preparation method for [(phenylsulfonyl) difluoromethyl] trimethyl silane (TMS-CF2SO2Ph). More specifically, difluoromethyl phenyl group sulfone or a halogenating difluoromethyl phenyl group sulfone is used as a raw material which reacts with chlorotrimethylsilane to generate [(phenylsulfonyl) difluoromethyl] trimethyl silane in an organic solvent at the temperature of-78 DEG C to the room temperature under the condition that C1 to C4 lithium alkyl or 4-dimethylamino ethene exists. The method of the present invention is simple, and the obtained [(phenylsulfonyl) difluoromethyl] trimethyl silane can be used for catalyzing carbonyl compounds for a difluoro methylation reaction.
Description
Technical Field
The invention relates to a high-efficiency difluoromethylation reagent- [ (phenylsulfonyl) difluoromethyl]Trimethylsilane (TMSCF)2SO2Ph) is used. The reagent is an important difluoromethylation reagent for synthesizing fluorine-containing medicaments and fluorine-containing materials.
Background
The fluorine-containing compound has wide application in drug design and new material development. The selective introduction of fluorine atoms or fluorine-containing building blocks into organic molecules can greatly improve the biological activity of the molecules. Therefore, the research of selective fluorination and fluorination reactions is increasingly gaining attention in the fields of medicine, pesticide, materials and the like. Although the fluorination, trifluormethylation reaction has been extensively studied, the difluoromethylation reaction has been relatively much less studied. Due to difluoromethyl (CF)2H) With hydroxymethyl (CH)2OH) has isotacticity (isosteric) and isopolar (iosporlar), and can also be used as a lipophilic hydrogen bond donor, so that the difluoromethyl compound has potential wide application in life science research, drug design and new material development.
The present inventors have recently reported the use of difluoromethyl phenyl sulfone (PhSO)2CF2H) Nucleophilic difluoromethylation of carbonyl compounds (including aldehydes, ketones) (Prakash, g.k.s.; hu, j.; wang, y.; olah, g.a.eur.j.org.chem.2005, 2218). Although this method can perform a nucleophilic addition reaction on many carbonyl compounds and then reduce the desulfonyl group to obtain difluoromethyl alcohol, it has the following disadvantages: (a) the reaction conditions are harsh (the low temperature needs to be strictly controlled to be-78 ℃); (b) an excess of carbonyl substrate is required; (c) excess base is required to make the substrate (especially the aliphatic aldehyde)susceptible to enolization, thereby reducing the utilization rate; (d) the removal of the sulfone group involves a reagent (sodium amalgam) which is not friendly to the environment, and is not environment-friendly. The invention aims at the defects to carry out improvement research and utilizes the TMSCF for the first time2SO2Ph is used as a novel nucleophilic difluromethylation reagent to realize the high-efficiency and environment-friendly difluromethylation reaction.
[ (phenylsulfonyl) difluoromethyl]Trimethylsilane (TMSCF)2SO2Ph) preparation although reported, due to the use of mCPBA oxidized PhSCF2SiMe3The process of (a), in which an operation of alkali neutralization is used in the post-treatment, which results in a large amount of hydrolysis of the product, has great limitations (Prakash, g.k.s.; Hu,
J.；Olah，G. A.J.Org.Chem.2003, 68, 4457). The invention develops a new pair of TMSCF2SO2A method for preparing a Ph reagent.
Disclosure of Invention
The invention aims to provide [ (phenylsulfonyl) difluoromethyl)]Trimethylsilane (TMS-CF)2SO2Ph) is used.
The [ (phenylsulfonyl) difluoromethyl group) of the present invention]Trimethylsilane (TMS-CF)2SO2Ph) is a compound having the following structural formula:
(TMSCF2SO2Ph)
the preparation method of the present invention can be represented by the following typical reaction formula:
(X＝Cl，Br，I，H，etc.)
the method is concretely, when the mixture is neutralized to-78-room temperature in an organic solvent, the reaction is carried out at C1-4In the presence of alkyl lithium or tetradimethylamino ethylene (TDAE), difluoromethyl phenyl sulfone or difluorohalogenated methyl phenyl sulfone is used as a raw material to react with trimethylchlorosilane for 0.1-2 hours to generate [ (phenylsulfonyl) difluoromethyl group]Trimethylsilane.
The difluoromethyl phenyl sulfone or difluorohalogenated methyl phenyl sulfone, trimethyl chlorosilane and C1-4The molar ratio of the alkyl lithium or the tetradimethylamino ethylene is 1: 1-2 in sequence; the difluorohalomethylphenylsulfone is difluoro-chloro, bromo or iodo-methylphenylsulfone.
The solvent can be diethyl ether, tetrahydrofuran, dimethyl sulfoxide and the like.
The [ (phenylsulfonyl) difluoromethyl]trimethyl silane can catalyze carbonyl compounds to perform difluoromethylation reaction, and can be represented by the following typical chemical reaction equation:
the method is the most ideal synthesis method for realizing difluoromethylation on carbonyl compounds, and has the advantages of: (1) atomic economy of reaction. The invention can initiate the direct addition reaction of two reactants with nearly equal equivalence ratio only by using catalytic amount of fluoride, and has high yield. (2) The reaction conditions are easy to control. (3) Particularly, the method has great advantages over other methods for easily enolizing aldehyde substrates. (4) The method for removing the sulfone utilizes metal magnesium, and is relatively environment-friendly.
Detailed Description
The following examples will help to understand the present invention, but do not limit the contents of the present invention.
Example 1
[ (phenylsulfonyl) difluoromethyl]Trimethylsilane (TMS-CF)2SO2Ph) typical preparation method: a solution of difluorobromomethylphenylsulfone (5.0g, 18.4mmol) and chlorotrimethylsilane (3.8mL, 27.7mmol) in tetrahydrofuran (50mL) was cooled to-78 deg.C and then n-butyllithium in hexane (1.6M, 20.7mL, 33.2mmol) was added slowly. The reaction mixture was stirred at-78 ℃ for 1 hour and then quenched by addition of cold saturated aqueous ammonium chloride solution. The mixed solution was extracted three times with ether (50mL each), and then the combined organic phases were washed with cold saturated aqueous sodium chloride solution, water, respectively, and dried over anhydrous sodium sulfate. After removal of the solvent on a rotary evaporator, the crude product was distilled under reduced pressure to give 3.8 g of [ (phenylsulfonyl) difluoromethyl group []]Trimethylsilane, yield: 78 percent. Boiling point 102 and 104 ℃ 1 mmHg. Nuclear magnetic resonance characterization:1H NMR(CDCl3)：δ0.42(s，9H)；7.60(t，2H)；7.73(t，1H)；7.94(d，2H).19F NMR(CDCl3)：δ-112.9(s)。
example 2
Using difluoromethyl phenyl sulfone (PhSO)2CF2H) Preparation of [ (phenylsulfonyl) Compound as starting MaterialDifluoromethyl group]Trimethylsilane: a solution of difluoromethylphenylsulfone (5.0g, 26mmol) and chlorotrimethylsilane (4.2 g, 39mmol) in tetrahydrofuran (50mL) was cooled to-78 deg.C and then n-butyllithium in hexane (1.6M, 29.2mL, 46.8mmol) was added slowly. The reaction mixture was stirred at-78 ℃ for 3 hours and then quenched by addition of cold saturated aqueous ammonium chloride. The mixed solution was extracted three times with ether (50mL each), and then the combined organic phases were washed with cold saturated aqueous sodium chloride solution, water, respectively, and dried over anhydrous sodium sulfate. After removal of the solvent on a rotary evaporator, the crude product was distilled under reduced pressure to give 3.9 g of [ (phenylsulfonyl) difluoromethyl group []]Trimethylsilane, yield: 57 percent. The nmr characterization data were the same as in example 1.
Example 3
Preparing [ (phenylsulfonyl) difluoromethyl]trimethylsilane using difluorobromomethylphenyl sulfone, trimethylchlorosilane, tetradimethylaminoethylene: prepared from difluorobromomethylphenylsulfone (30mmol), trimethylchlorosilane (45mmol) and tetradimethylaminoethylene [ (phenylsulfonyl) difluoromethyl](60mmol) was dissolved in dry dimethylformamide (60 ml) and stirred at-30 ℃ to room temperature for 8 hours. The post-treatment method was the same as in example 1-2. The product, [ (phenylsulfonyl) difluoromethyl]trimethylsilane, was observed to have a conversion yield of greater than 60% using nuclear magnetic resonance spectroscopy. Characterization data is as above.
Example 4
Carbonyl compounds with TMSCF2SO2Typical methods for the Ph reaction: under nitrogen, 2-naphthaldehyde (78mg, 0.5mmol) and TMSCF2SO2Ph (1, 0.6mmol) was dissolved in dry tetrahydrofuran (2.5mL) and cooled to-78 ℃. Then, 13 mg of tetrabutylammonium (triphenyldifluoro) silicate (TBAF) was added to the above mixed solution. The reaction was slowly warmed to room temperature with stirring and stirred overnight. Tetrabutylammonium fluoride (TBAF, 1.0mol/L, 0.65mL) was then added to the reaction mixture, which was stirred for 30 minutes, followed by addition of 5mL of a saline solution. Extracting with diethyl ether for 3 times15 ml. Drying the combined organic phase with anhydrous magnesium sulfate, removing solvent under vacuum, and separating the crude product by silica gel column chromatography to obtain the compound with molecular formula of
141 mg of white solid, 81% yield of product 3a (b). Nuclear magnetic data:1H NMR(CDCl3)：δ 3.67(s，1H)；5.77(d，J＝12Hz，1H)；7.35-8.15(m，12H).13C NMR(CDCl3)：δ 71.39(dd，J＝26Hz，19.6Hz)；120.41(dd，J＝297Hz，287Hz)；124.92；126.35；126.70；127.64；128.0；128.18；128.22；129.24；130.57；131.14；132.82；132.84；133.71；135.43.19F NMR(CDCl3): delta-103.8 (d, 237Hz, 1F); -121.5(dd, J237 Hz, 21Hz, 1F), mass spectrum (EI, m/z): 348 (M)+) 157, 129, 128, 127, 77 elemental analysis: theoretical value C18H14F2O3S: c, 62.06; h, 4.05; experimental value C, 61.85; h, 4.10.
Example 5
A typical method for the desulfonation reaction involving magnesium metal: to a solution containing compound 3a (250mg, 0.7mmol) and 7.5 ml of Dimethylformamide (DMF) was added 4 ml of 1: 1 aqueous acetic acid-sodium acetate buffer (8 mol/L). 252 mg of magnesium rods were added in portions to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Then 30 ml of water are added and extracted 3 times with 20 ml of ether each time. For the combined organic phaseThe mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, respectively, and dried over anhydrous magnesium sulfate. After removal of the solvent on a rotary evaporator, the crude product was chromatographed on a silica gel column to give product 4a as a white solid, 133 mg, 91% yield. Nuclear magnetic data:1H NMR(CDCl3)：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).13CNMR(CDCl3)：δ73.74(t，J＝24.5Hz)；115.84(t，J＝245Hz)；124.30；126.44；126.55；126.61；127.72；128.11；128.47；133.06；133.24；133.52.19F NMR(CDCl3): -127.3(ddd, J-284 Hz, 56Hz, 9Hz, 1F); -127.9(ddd, J-284 Hz, 56Hz, 10Hz, 1F), mass spectrum (EI, m/z): 208 (M)+) 157, 129, 128, 127, 102, 77 high resolution mass spectrometry (EI): theoretical value of m/z C12H10F2O(M+)208.0697, Experimental value 208.0699.
Claims (2)
1, a [ (phenylsulfonyl) difluoromethyl group]A process for preparing trimethylsilane, characterized in that it is neutralized at-78 deg.C to room temperature in an organic solvent at C1-4In the presence of alkyl lithium or tetradimethylamino ethylene, difluoromethyl phenyl sulfone or difluorohalogenated methyl phenyl sulfone is used as a raw material to react with trimethylchlorosilane for 0.1-2 hours to generate [ (phenylsulfonyl) difluoromethyl group]Trimethylsilane; the difluoromethyl phenyl sulfone or difluorohalogenated methyl phenyl sulfone, trimethyl chlorosilane and C1-4The molar ratio of the alkyl lithium or the tetradimethylamino ethylene is 1: 1-2 in sequence; the difluoro halogenated methyl phenyl sulfone is difluoro chloro methyl phenyl sulfone, difluoro bromo methyl phenyl sulfone or difluoro iodo methyl phenyl sulfone.
The method of claim 1, wherein the organic solvent is diethyl ether, tetrahydrofuran or dimethylsulfoxide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05230075A (en) * | 1992-02-19 | 1993-09-07 | Sagami Chem Res Center | Production of alcohol derivative having difluoromethyl group at alpha-position |
| US6803477B2 (en) * | 2001-11-29 | 2004-10-12 | University Of Southern California | Magnesium mediated preparation of fluorinated alkyl silanes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05230075A (en) * | 1992-02-19 | 1993-09-07 | Sagami Chem Res Center | Production of alcohol derivative having difluoromethyl group at alpha-position |
| US6803477B2 (en) * | 2001-11-29 | 2004-10-12 | University Of Southern California | Magnesium mediated preparation of fluorinated alkyl silanes |
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