CN115448816A - Synthesis method of beta fluoro-alkenyl alcohol - Google Patents
Synthesis method of beta fluoro-alkenyl alcohol Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- -1 fluoro-alkenyl alcohol Chemical compound 0.000 title abstract description 25
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims abstract description 24
- 238000013032 photocatalytic reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002841 Lewis acid Substances 0.000 claims abstract description 15
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 15
- 229910000160 potassium phosphate Inorganic materials 0.000 claims abstract description 12
- 235000011009 potassium phosphates Nutrition 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 12
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- DFWBBWHFNTZGBV-UHFFFAOYSA-N (2,2-difluoro-1-phenylethenyl)benzene Chemical group C=1C=CC=CC=1C(=C(F)F)C1=CC=CC=C1 DFWBBWHFNTZGBV-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 claims description 3
- VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 claims description 3
- 229950009195 phenylpropanol Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000002253 acid Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000001699 photocatalysis Effects 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical compound C12=CC=CC=C2C2=CC=CC=C2N1C1=C(C#N)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C(N2C3=CC=CC=C3C3=CC=CC=C32)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C1C#N PRWATGACIORDEL-UHFFFAOYSA-N 0.000 description 6
- 239000011941 photocatalyst Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001723 carbon free-radicals Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005274 electronic transitions Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
- C07C29/34—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups by condensation involving hydroxy groups or the mineral ester groups derived therefrom, e.g. Guerbet reaction
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The application discloses a method for synthesizing beta-fluoro-alkenyl alcohol. The synthesis method comprises the following steps: in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, blue light is adopted to irradiate the gem-difluoroolefin and the alcohol to carry out photocatalytic reaction to obtain the beta fluoro-alkenyl alcohol. According to the synthesis method, a strategy of photocatalytic hydrogen atom transfer is adopted, so that the alpha hydroxyl carbon free radical and the alkenyl free radical are subjected to coupling reaction, and the beta fluoro-alkenyl alcohol is finally obtained. The synthesis method has mild conditions, does not need dangerous reagents such as strong acid, strong alkali and the like, and has higher yield.
Description
The technical field is as follows:
the application belongs to the field of organic synthesis, and particularly relates to a synthetic method of beta fluoro alkenyl alcohol.
The background art comprises the following steps:
fluorine-containing organic compounds play an important role in the fields of pharmaceuticals, medicine, agricultural chemistry, and the like. Introduction of fluorine atoms into organic molecules may increase the solubility, lipophilicity, metabolic stability, and the like of the organic molecules. It is estimated that about 20% to 25% of drugs and 30% to 40% of agrochemicals contain fluorine atoms. Among these, the structure of monofluoroolefins is particularly important. In organic synthesis, it is considered one of the most useful fluoride synthetic molecules, widely present in pharmaceutical molecules as peptide bond equivalent groups in pharmaceutical chemistry. Among these, β -fluoro alkenyl alcohol is attracting attention as an important monofluoro olefin. However, current methods for the synthesis of β -fluoroalkenyl alcohols are very limited.
Patent application WO 2009017190A1 discloses the following route for the synthesis of β -fluoro-alkenyl alcohols:
diaryl ketone reacts with triethyl 2-fluoro-2-phosphoryl acetate in the presence of sodium hydride to generate intermediate fluoro alkenyl ester, then reacts with Grignard reagent in the presence of boron tribromide, is quenched by adding saturated ammonium chloride solution after cooling, and the product is obtained after extraction, drying and concentration, and the yield is 85%. However, the method has the disadvantages of multiple steps, long route, need of high-activity Grignard reagent and strong alkali, harsh reaction conditions, narrow application range and high cost.
Patent application WO2008037604 A1 discloses the following synthetic route for β fluoro alkenyl alcohols:
beta-bromo-alkenyl alcohol reacts with tert-butyl lithium and N-fluoro-bis-benzenesulfonamide (NFSI) at-78 ℃, saturated ammonium chloride solution is added for quenching, and beta-fluoro-alkenyl alcohol is obtained after extraction, drying and column chromatography, wherein the yield is 36%. However, the method has the disadvantages of difficult obtainment of starting materials, low yield, use of high-activity strong base, poor safety, harsh reaction conditions, narrow application range and high cost.
Therefore, there is a need to develop a novel method for synthesizing β -fluoroalkenyl alcohols.
The invention content is as follows:
in view of the above-mentioned shortcomings of the prior art, an object of the present application is to provide a method for synthesizing β fluoro-alkenyl alcohol, wherein a strategy of photocatalytic hydrogen atom transfer is adopted to perform a coupling reaction between an α hydroxyl carbon radical and an alkenyl radical, so as to obtain β fluoro-alkenyl alcohol. The synthesis method has mild conditions, does not need dangerous reagents such as strong acid, strong alkali and the like, and has higher yield.
In order to achieve the above objects, in a first aspect, the present application provides a method for synthesizing a β -fluoro alkenyl alcohol, the method comprising:
in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, blue light is adopted to irradiate the geminal difluoroolefin and the alcohol to perform photocatalytic reaction to obtain the beta fluoroolefine alcohol.
In one possible embodiment in combination with the first aspect, the molar ratio of alcohol, 4-CzIPN, quinuclidine, lewis acid, potassium phosphate, and geminal difluoroolefin is (2.5-3.5): 0.025-0.035): 0.25-0.35): 1.2-1.8): 0.8-1.2): 1.
In combination with the first aspect, in one possible embodiment, the lewis acid may be zinc chloride or lithium chloride.
In a possible embodiment, in combination with the first aspect, the time of the photocatalytic reaction is 18 to 30 hours, preferably 24 hours.
In a possible embodiment in combination with the first aspect, the temperature of the photocatalytic reaction is between 15 ℃ and 35 ℃, preferably 25 ℃.
In one possible embodiment in combination with the first aspect, the photocatalytic reaction is performed in the absence of oxygen and moisture.
With reference to the first aspect, in a possible embodiment, the blue light has a wavelength of 420nm to 480nm.
With reference to the first aspect, in one possible embodiment, the light intensity of the blue light is 0.8cd to 1.0cd.
In a possible embodiment in combination with the first aspect, the geminal difluoroolefin may be 1, 1-difluoro-2, 2-diphenylethylene, 1-difluoro-2, 2-di-4 '-chlorophenylethylene, 1-difluoro-2, 2-di-4' -fluorophenylethylene or 1, 1-difluoro-2-biphenylethylene.
In one possible embodiment in combination with the first aspect, the alcohol may be hexanol, cyclohexylmethanol, or phenylpropanol.
In one possible embodiment in combination with the first aspect, the photocatalytic reaction may be carried out in the presence of a solvent including dimethylsulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
According to the technical scheme provided by the application, compared with the prior art, the method at least comprises the following beneficial effects:
according to the synthesis method of beta fluoro alkenyl alcohol, a visible light catalysis strategy is adopted, alcohol and gem-difluoroolefin are directly used as raw materials, the operation is safe and simple, the cost is low, the reaction condition is mild, the substrate range is wide, and a green, efficient and safe path is provided for synthesis of beta fluoro alkenyl alcohol compounds.
Drawings
Fig. 1 is a reaction mechanism of a method of synthesizing a β -fluoroalkenyl alcohol according to one embodiment of the present application.
Detailed Description
In order that those skilled in the art will be able to more clearly understand the present application, the present application will be described in detail below with reference to examples. Before the description is given, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present application on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the application, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the application, and the scope of the application claims should be determined only by the claims.
In the prior art, the synthesis of beta fluoro-alkenyl alcohol usually uses high-activity reagents, high-risk reagents, transition metals, harsh reaction conditions and the like, and has poor safety, narrow application range and higher cost. In view of these problems, an object of the present application is to provide a method for synthesizing a β -fluoro-alkenyl alcohol, which employs a photocatalytic hydrogen atom transfer strategy to perform a coupling reaction between an α -hydroxy carbon radical and an alkenyl radical, thereby obtaining the β -fluoro-alkenyl alcohol. The synthesis method has mild conditions, does not need dangerous reagents such as strong acid, strong alkali and the like, and has high yield.
In order to achieve the above objects, in a first aspect, the present application provides a method for synthesizing a β -fluoro alkenyl alcohol, the method comprising:
in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, blue light is adopted to irradiate the gem-difluoroolefin and the alcohol to carry out photocatalytic reaction to obtain the beta fluoro-alkenyl alcohol.
In this application, a photocatalyst (PC, 4-CzIPN as used herein) is excited under blue light illumination, and the excited photocatalyst oxidizes quinuclidine to produce a quinuclidine radical cation intermediate. Under the action of Lewis Acid (LA), the alcohol is coordinated with the Lewis acid. The generated complex and quinuclidine radical cation intermediate generate Hydrogen Atom Transfer (HAT) process to generate alpha carbon radical intermediate of alcohol. The reduced photocatalyst negative ions can be used as a reducing agent to reduce geminal difluoroolefin to generate free radicals and fluorine negative ions. The two radicals formed can undergo a coupling reaction to form the β -fluoroalkenyl alcohol.
The chemical name of the 4-CzIPN is 2,4,5,6-tetra (9-carbazolyl) -isophthalonitrile, CAS number: 1416881-52-1, is an excellent photocatalyst. The chemical name of said quinuclidine is 1-azabicyclo [2.2.2] octane, CAS number: 100-76-5 is a cyclic aliphatic amine which can be used as a ligand in the reaction. The lewis acid can accept and transfer electrons in a photocatalytic reaction. The potassium phosphate is a strong base and weak acid salt, and can neutralize hydrogen fluoride which is a byproduct of the reaction. By combining these compounds, the photocatalytic reaction can be sufficiently promoted, and β -fluoroalkenyl alcohol can be obtained.
In addition, the geminal difluoroolefin refers to a molecule in which two fluorine atoms are simultaneously bonded to one carbon atom in a carbon-carbon double bond of an olefin. The beta-fluoroalkenyl alcohol refers to a molecule in which a fluorine atom and an alkenyl group are simultaneously bonded to the beta position of an alcohol.
In one possible embodiment in combination with the first aspect, the molar ratio of alcohol, 4-CzIPN, quinuclidine, lewis acid, potassium phosphate, and geminal difluoroolefin is (2.5-3.5): 0.025-0.035): 0.25-0.35): 1.2-1.8): 0.8-1.2): 1.
In one possible embodiment, in combination with the first aspect, the time of the photocatalytic reaction is 18 to 30 hours (e.g., 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, or 30 hours, or any other specific value within the range), and preferably 24 hours. In the present application, a side reaction may occur if the reaction time of the photocatalytic reaction is too long, and the yield may be reduced if the reaction time is too short.
In a possible embodiment in combination with the first aspect, the temperature of the photocatalytic reaction is between 15 ℃ and 35 ℃, i.e. in the room temperature range (e.g. it may be 15 ℃, 17 ℃,19 ℃, 21 ℃, 23 ℃, 25 ℃, 27 ℃, 29 ℃, 31 ℃, 33 ℃ or 35 ℃, or any other specific value of said range), preferably 25 ℃. In this application, too high a temperature of the photocatalytic reaction may cause side reactions to occur, and too low a temperature may decrease the rate of the reaction, resulting in a decrease in yield. Moreover, the temperature condition of the photocatalytic reaction is very mild, is about in the room temperature range, does not need to be strongly regulated and controlled, and is green and energy-saving.
In a possible embodiment in combination with the first aspect, the photocatalytic reaction is performed under exclusion of oxygen and moisture. In this application, active species such as oxygen or moisture deactivate the catalytic components, affecting the reaction and should therefore be sequestered. Therefore, the photocatalytic reaction of the present application can be performed under the protection of an inert gas (e.g., nitrogen). In addition, the container for the photocatalytic reaction is not particularly limited as long as it can satisfy the reaction requirements and insulate oxygen and moisture. For example, a laboratory may use a Schlenk (Schlenk) bottle to perform the reaction, but the present application is not limited thereto.
In a possible embodiment, with reference to the first aspect, the blue light has a wavelength of 420nm to 480nm. In the wave range, the electronic transition and transfer of the 4-CzIPN can be promoted, and the photocatalysis is realized.
In a possible embodiment, in combination with the first aspect, the light intensity of the blue light is 0.8cd to 1.0cd. In the light intensity range, sufficient light energy can be continuously supplied to the reaction system to promote the reaction to fully proceed.
Further, the light source of the blue light is not particularly limited as long as it can provide light radiation of a desired wavelength and intensity. However, from the viewpoint of energy saving, environmental protection, and the like, the light source is preferably an LED light source.
In combination with the first aspect, in one possible embodiment, the geminal difluoroolefin may be 1, 1-difluoro-2, 2-diphenylethylene, 1-difluoro-2, 2-di-4 '-chlorophenylethylene, 1-difluoro-2, 2-di-4' -fluorophenylethylene or 1, 1-difluoro-2-biphenylethylene.
In combination with the first aspect, in one possible embodiment, the alcohol may be hexanol, cyclohexylmethanol, or phenylpropanol.
In one possible embodiment in combination with the first aspect, the photocatalytic reaction may be carried out in the presence of a solvent including dimethylsulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
According to the synthesis method of beta fluoro alkenyl alcohol, a visible light catalysis strategy is adopted, alcohol and gem-difluoroolefin are directly used as raw materials, the operation is safe and simple, the cost is low, the reaction condition is mild, the substrate range is wide, and a green, efficient and safe path is provided for synthesis of beta fluoro alkenyl alcohol compounds.
Examples
Sources of materials
4CzIPN, according to the document F.Calogero et al, "Nickel-media Enantioselective phosphor alloy of Aldehydes with Visible Light", angew.chem.Int.Ed.2022,61, e202114981; the compound was synthesized by Angew. Chem.2022,134, e202114981 (DOI: 10.1002/anie.202114981);
1, 1-difluoro-2, 2-diphenylethylene, synthesized according to the article Wang et al, "organic Selective Construction of1H-Iso and resins continuous Tri-and Difluoromethylated Quantum Stereogenic center via Palladium-catalyst C-H Bond immunization", ACS Catal.2021,11,19,12367-12374 (DOI: 10.1021/acid.1c03682);
1, 1-difluoro-2, 2-bis-4' -chlorophenylethylene, synthesized according to the article Wang et al, "organic Synthesis of 1H-Isoidols contacting Tri-and Difluoromethylated Quantum catalytic Synthesis C-H Bond immunization", ACS Catal.2021,11,19,12367-12374 (DOI: 10.1021/acid.1c03682);
1, 1-difluoro-2-biphenylethylene, synthesized according to the reference Pan et al, "Electrochemical-produced Nickel-Catalyzed reduced catalysis of Aryl Halides", org.Lett.2022,24,20,3647-3651 (DOI: 10.1021/acs.orglett.2c01247);
quinuclidine, 99% pure, available from Shanghai Tantake Tech, inc.;
zinc chloride, 99% pure, available from Anhuizheng science and technology, inc.;
lithium chloride, 99% pure, was purchased from scientific and technical company, inc., of Anhui Zehnder.
Example 1:
4CzIPN (2.4mg, 0.003mmol), quinuclidine (3.3mg, 0.03mmol), zinc chloride (20.5mg, 0.15mmol), and potassium phosphate (21.2mg, 0.1mmol) were added to a Schlenk bottle. 1, 1-difluoro-2, 2-diphenylethylene (18. Mu.L, 0.1 mmol), hexanol (38. Mu.L, 0.3 mmol) and DMSO (2 mL) were added under nitrogen blanket. Degassing the solution to remove oxygen from the solvent. After completion, the solution was yellow. The Schlang bottle was stirred at room temperature (25 ℃) for 24 hours under a blue LED light source of 420 to 480nm (18W, 0.8 to 1.0 cd). The solution became light in color after the reaction was completed. Quenched by the addition of 2mL of water, extracted three times with 5mL of diethyl ether, and the organic layer was washed with 2mL of saturated brine. The product was isolated by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 5).
Example 2:
4CzIPN (2.4mg, 0.003mmol), quinuclidine (3.3mg, 0.03mmol), zinc chloride (20.5mg, 0.15mmol), and potassium phosphate (21.2mg, 0.1mmol) were added to a Schlenk bottle. 1, 1-difluoro-2, 2-di-4' -fluorophenylethylene (20. Mu.L, 0.1 mmol), hexanol (38. Mu.L, 0.3 mmol), and DMSO (2 mL) were added under nitrogen. Degassing the solution to remove oxygen from the solvent. After completion, the solution was yellow. The Schlenk bottle was stirred at room temperature (25 ℃) for 24 hours under a blue LED light source of 420 to 480nm (18W, 0.8 to 1.0 cd). The solution became light in color after the reaction was completed. Quenched by addition of 2mL of water, extracted three times with 5mL of diethyl ether, and the organic layer washed with 2mL of saturated brine. The product was isolated by column chromatography on silica gel (mobile phase: petroleum ether: ethyl acetate = 5) to give the product as a colorless oil in 87% yield.
Example 3:
4CzIPN (2.4mg, 0.003mmol), quinuclidine (3.3mg, 0.03mmol), lithium chloride (7.0mg, 0.15mmol), and potassium phosphate (21.2mg, 0.1mmol) were added to a Schlenk bottle. 1, 1-difluoro-2-biphenylethylene (21.6 mg,0.1 mmol), hexanol (38. Mu.L, 0.3 mmol) and DMSO (2 mL) were added under nitrogen. Degassing the solution to remove oxygen from the solvent. After completion, the solution was yellow. The Schlang bottle is placed under a 420-480 nm blue LED light source (18W, 0.8-1.0 cd) and stirred for 24 hours at room temperature (25 ℃). The solution became light in color after the reaction was completed. Quenched by addition of 2mL of water, extracted three times with 5mL of diethyl ether, and the organic layer washed with 2mL of saturated brine. The product was isolated by column chromatography on silica gel (mobile phase: petroleum ether: ethyl acetate = 5) to give a colorless oily product (mixed product of E/Z configuration; E/Z = 1) in a yield of 60%.
Comparative examples 1 to 5:
except for the conditions of the following table 1, a photocatalytic experiment was performed in the same manner as in example 1, and the yields thereof are also shown in table 1.
[ Table 1]
| Comparative examples | Condition | Yield% |
| 1 | Without illumination | 0 |
| 2 | Matt catalyst (4 CZIPN) | 0 |
| 3 | Without quinuclidine | 0 |
| 4 | No Lewis acid (Zinc chloride) | 0 |
| 5 | Potassium phosphate free | 26 |
In Table 1, the yields are determined using trifluorotoluene as internal standard by 19 Yield by F-NMR.
As can be seen from the results of table 1 above, the target product was not obtained in the absence of light, photocatalyst, quinuclidine or lewis acid, while the yield decreased to 26% in the absence of base.
The above description is only for the specific embodiments of the present application, but the scope of the present application is not limited thereto, and any person skilled in the art can easily think of the changes or substitutions within the technical scope of the present application, and shall be covered by the scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.
Claims (10)
1. A method for synthesizing beta-fluoro-alkenyl alcohol, comprising:
in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, blue light is adopted to irradiate the geminal difluoroolefin and the alcohol to perform photocatalytic reaction to obtain the beta fluoroolefine alcohol.
2. The synthesis method according to claim 1, wherein the molar ratio of the alcohol, the 4-CzIPN, the quinuclidine, the Lewis acid, the potassium phosphate and the geminal difluoroolefin is (2.5-3.5) to (0.025-0.035) to (0.25-0.35) to (1.2-1.8) to (0.8-1.2) to 1.
3. The method of synthesis of claim 1, wherein the lewis acid is zinc chloride or lithium chloride.
4. The synthesis process according to claim 1, characterized in that the photocatalytic reaction is carried out for a period of 18 to 30 hours, preferably 24 hours.
5. The synthesis process according to claim 1, characterized in that the temperature of the photocatalytic reaction is between 15 ℃ and 35 ℃, preferably 25 ℃.
6. The method of synthesis according to claim 1, wherein the photocatalytic reaction is carried out in the absence of oxygen and moisture.
7. The synthesis method according to claim 1, characterized in that the blue light has a wavelength of 420nm to 480nm and a light intensity of 0.8cd to 1.0cd.
8. The synthesis method according to claim 1, wherein the gem-difluoroolefin is 1, 1-difluoro-2, 2-diphenylethylene, 1-difluoro-2, 2-di-4 '-chlorophenylethylene, 1-difluoro-2, 2-di-4' -fluorophenylethylene or 1, 1-difluoro-2-biphenylethylene.
9. The method of synthesis according to claim 1, wherein the alcohol is hexanol, cyclohexylmethanol or phenylpropanol.
10. The synthesis method according to claim 1, wherein the photocatalytic reaction is carried out in the presence of a solvent comprising dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
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