CN101538186B - Method for preparing compounds containing difluoromethylene - Google Patents

Method for preparing compounds containing difluoromethylene Download PDF

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CN101538186B
CN101538186B CN2009100499273A CN200910049927A CN101538186B CN 101538186 B CN101538186 B CN 101538186B CN 2009100499273 A CN2009100499273 A CN 2009100499273A CN 200910049927 A CN200910049927 A CN 200910049927A CN 101538186 B CN101538186 B CN 101538186B
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alkyl
sicf
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tube sealing
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CN101538186A (en
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胡金波
王飞
张伟
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention relates to a method for synthesizing compounds containing difluoromethylene group, more specifically a method for synthesizing difluoromethylene (in fact difluorocyclopropyl) compounds. Monohalogendifluoromethyl trialkylsilane(RaRbRcSiCF2X) used as difluorocarbene reagent is reacted with olefin compounds containing double bond of carbon in the presence of the initiator with catalytic amounts for 2-20 hours to obtain compounds containing difluorocyclopropyl. The monohalogendifluoromethyl trialkylsilane used in the invention can be prepared easily, which is a highly effective new difluorocarbene reagent with a good universal adaptation.

Description

A kind of preparation contains the method for difluoro methylene compound
Technical field
The present invention relates to the compound method of fluorine-containing medicines, pesticide intermediate, is to utilize a halogen difluoromethyl trialkyl silane (R first aR bR cSiCF 2X) come the synthetic method that contains the difluoro methylene compound.
Background technology
Introducing difluoromethyl or difluoro methylene often can effectively improve the physiologically active of organic molecule in the molecule, so at medicine, more and more come into one's own in the fields such as agricultural chemicals and material.((a) Kirsch, P.ModernFluoroorganic Chemistry:Synthesis, Reactivity, Applications; Wiley-VCH:Weinheim, 2004. (b) Organofluorine Compounds:chemistry and Applications; Hiyama, T., Ed.; Springer:New York, 2000.) be a kind of approach preferably that achieves the above object with the difluorocarbene as a kind of difluoromethyl or difluoro methylene building block.
The most cost-effective so far difluorocarbene's precursor is Freon22 gas (HCF 2Cl) ((a) Miller, T.G.; Thanassi, J.W.J.Org.Chem.1960,25,2009. (b) Shen, T.Y.; Lucas, S.; Sarett, L.H.Tetrahedron Lett.1961,2,43. (c) Langlois, B.J.Fluorine Chem.1988,41,247. (d) Morimota, K.; Makino, K.; Sakata, G.J.Fluorine Chem.1992,59,417.), but Freon gas has destruction to atmospheric ozone layer.And its reactive behavior is general, and needed amount is bigger.In addition ClF 2CCOONa and ClF 2CCOOMe relatively effectively uses wider method ((a) Christensen, S.B., IV; Dabbs, H.E.; Karpinski, J.M.PCT International Application, WO 96/23754,1996. (b) Ho, J.Z.; Elmore, C.S.; Wallace, M.A.; Yao, D.; Braun, M.P.; Dean, D.C.; Melillo, D.G.; Chen, C.-Y.Helvetica Chim.Acta 2005,88,1040. (c) O ' shea, P.D.; Chen, C.-Y.; Chen, W.; Dagneau, P.; Frey, L.E.; Grabowski, E.J.J.; Marcantonio, K.M.; Reamer, R.A.; Tan, L.; Tillyer, R.D.; Roy, A.; Wang, X.; Zhao, D.J.Org.Chem.2005,70,3021.).The metallic compound of trifluoromethyl such as Me 3SnCF 3, PhHgCF 3, BrZnCF 3, BrCdCF 3Also can be as Cabbeen reagent, but its synthetic relative complex, toxicity is high, thus big limitations its application ((a) Seyferth, D.; Hoppe, S.P., J.Organomet.Chem., 1971,26,64. (b) Seyferth, D.; Hoppe, S.P; Darragh.K.V., J.Am.Chem.Soc.1969,91,6536.).Other is like CF 2Br 2((a) Dolbier, W.R.; Burkholder, Jr.C R, J.Org.Chem., 1990,55; 589; (b) Dolbier, W.R.; Wojtowicz, J.H.; Burkholder, C.R., J.Org.Chem., 1990; 55,5420; (c) Crabbe, P.; Cervantes, A.; Cruz A.; Galeazzi, E.; Iriarte, J.; Velarde, E., J.Am.Chem.Soc, 1973,95,6655), FSO 2CF 2COOH (Chen, Q.-Y.; Wu, S.-W.J.Fluorine Chem.1989,44,433.), FSO 2CF 2COOSiMe 3(Tian, F.; Virginie, B.; Duan, J.X., Dolbier, W.R.Jr.; Chen, Q.Y., Org Lett., 2000,2,563.) etc. certain application is also arranged, but generally do not possess higher universality and selectivity.
People such as Prakash had reported a halogen difluoromethyl trimethyl silane ((Me) in 1997 3SiCF 2X) compound method, and reported nucleophilic reaction (Yudin, the A.K. of this reagent; Prakash, G.K.S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G.A., J.Am.Chem.Soc, 1997,119,1572.).
Utilize a halogen difluoromethyl trialkyl silane ((R in this patent aR bR cSiCF 2X) as a kind of highly effective difluorocarbene's reagent, can be with the difluoro methylene reaction of its utilization to carbon-carbon double bond.
Summary of the invention
The purpose of this invention is to provide the synthetic method that contains the difluoro methylene group compound, is exactly the synthetic compound that contains difluoro methylene (actual is the difluoro cyclopropyl) type specifically.It is a kind of method of the efficient and compound that universality is good inserts carbon-carbon double bond the alkenes compounds difluoro methylene.
Method of the present invention adopts a halogen difluoromethyl trialkyl silane (R aR bR cSiCF 2X, wherein R a, R b, R cBe the alkyl of C1-C6, perhaps phenyl, X is a halogen) as difluorocarbene's reagent, it can be introduced difluoro methylene in the organic molecule, is a kind of mild condition, productive rate is high, universality is high reagent.
The compound method of reaction of the present invention is following:
In organic solvent, under 60～150 ℃, the alkenes compounds that contains carbon-carbon double bond is a raw material, under the condition of the initiator that adds catalytic amount, reacts 2～20 hours with a halogen difluoromethyl trialkyl silane, makes to contain difluoro cyclopropyl compounds;
Said olefin(e) compound is R 1, R 2, R 3Or R 4Substituted alkene; Wherein, R 1Be the alkyl of H, C1-C12, trimethyl silicon based, aryl, R 5Or/and R 6The alkyl of substituted aryl, the substituted C1-C4 of aryl or R 5Or/and R 6The alkyl of the substituted C1-C4 of substituted aryl; Described R 5Or R 6Be the alkyl of H, C1-C4, alkoxyl group or the difluoro-methoxy of C1-C4; Make and contain difluoro cyclopropyl compounds.Wherein a part of product can further change into β-fluorine α, beta unsaturated ketone again.
Aryl described in the compound method is a phenyl or naphthyl;
Described solvent can be ether, THF, glycol dimethyl ether, toluene, DMAC N,N etc.
Catalytic amount of initiator described in the compound method generally is tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Methanaminium, N,N,N-trimethyl-, fluoride, tetrabutyl ammonium acetate etc.
The mol ratio of the alkenes compounds described in the compound method, a halogen difluoromethyl trialkyl silane and initiator is 1: 1～4: 0.01～0.1, and recommending mol ratio is 1: 2～3: 0.02～0.04.
Type reaction is following:
Figure G2009100499273D00031
Traditional method is generally used has destructive Freon gas to ozone, and the general yield of additive method is lower, and universality is poor.Advantages such as and above method adopts same type of difluorocarbene's reagent, and such reagent can not make through Freon gas, and reaction conditions is gentle, and productive rate is high, and it is good to have universality, and selectivity is strong.
Embodiment
Utilize following embodiment will help to understand the present invention, but do not limit content of the present invention.
Embodiment 1
With vinylbenzene
Figure G2009100499273D00041
(104mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure G2009100499273D00042
126mg, productive rate 82%.
Embodiment 2
With vinylbenzene (132mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure G2009100499273D00044
104mg, productive rate 57%.
Embodiment 3
With vinylbenzene
Figure G2009100499273D00045
(84mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure G2009100499273D00046
fluorine spectrum productive rate 80%.
Embodiment 4
With vinylbenzene
Figure DEST_PATH_GSB00000729716900011
(84mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product fluorine spectrum productive rate 66%.
Embodiment 5
With vinylbenzene
Figure DEST_PATH_GSB00000729716900013
(112mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure DEST_PATH_GSB00000729716900014
fluorine spectrum productive rate 71%.
Embodiment 6
With tetrahydrobenzene
Figure DEST_PATH_GSB00000729716900015
(82mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4mlTHF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure DEST_PATH_GSB00000729716900016
fluorine spectrum productive rate 82%.
Embodiment 7
With vinylbenzene
Figure DEST_PATH_GSB00000729716900017
(118mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure G2009100499273D00057
1126mg, productive rate 75%.
Embodiment 8
With vinylbenzene (118mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure G2009100499273D00062
126mg, productive rate 75%.
Embodiment 9
With vinylbenzene (164mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product 120mg, productive rate 56%.
Embodiment 10
With vinylbenzene (178mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product
Figure G2009100499273D00066
160mg, productive rate 70%.
Embodiment 11
With vinylbenzene
Figure G2009100499273D00067
(214mg, 1.0mmol), (Me) 3SiCF 2Cl (474mg, 3.0mmol) and 4ml THF (heavily steaming) join in the tube sealing with syringe, add rapidly tetrabutylammonium chloride (6mg, 0.02mmol) in reaction solution, the tube sealing of screwing, again with tube sealing as in 110 ℃ the oil bath, stirring reaction 4 hours.Make product 140mg, productive rate 53%.

Claims (3)

1. a synthetic method that contains the difluoro methylene compound is characterized in that in organic solvent under 60～150 ℃, the alkenes compounds that contains carbon-carbon double bond is a raw material, under the condition of the initiator that adds catalytic amount, with difluorocarbene's reagent R aR bR cSiCF 2X reacted 2～20 hours, made to contain difluoro cyclopropyl compounds;
Said olefin(e) compound is R 1Substituted alkene; Wherein, R 1Be the alkyl of H, C1-C12, trimethyl silicon based, aryl, R 5Or/and R 6The alkyl of substituted aryl, the substituted C1-C4 of aryl or R 5Or/and R 6The alkyl of the substituted C1-C4 of substituted aryl; Described R 5Or R 6Be the alkyl of C1-C4, alkoxyl group or the difluoro-methoxy of C1-C4;
Described aryl is a phenyl or naphthyl;
Described initiator is tetrabutyl ammonium fluoride, tetrabutylammonium chloride, Methanaminium, N,N,N-trimethyl-, fluoride or tetrabutyl ammonium acetate;
Described alkenes compounds, difluorocarbene's reagent R aR bR cSiCF 2The mol ratio of X and initiator is 1: 1～4: 0.01～0.1;
R wherein a, R b, R cBe the alkyl of C1-C6, perhaps phenyl, X is a halogen.
2. the method for claim 1 is characterized in that described alkenes compounds, difluorocarbene's reagent R aR bR cSiCF 2The mol ratio of X and initiator is 1: 2～3: 0.02～0.04.
3. the method for claim 1 is characterized in that described solvent is ether, THF, glycol dimethyl ether, toluene or DMAC N,N.
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Citations (1)

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US3989845A (en) * 1974-12-26 1976-11-02 W. R. Grace & Co. Anesthetic chlorocyclopropanes

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Publication number Priority date Publication date Assignee Title
US3989845A (en) * 1974-12-26 1976-11-02 W. R. Grace & Co. Anesthetic chlorocyclopropanes

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