CN115448816B - 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 abstract description 13
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims abstract description 24
- -1 difluoro alkene Chemical group 0.000 claims abstract description 16
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002841 Lewis acid Substances 0.000 claims abstract description 14
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 14
- 229910000160 potassium phosphate Inorganic materials 0.000 claims abstract description 12
- 235000011009 potassium phosphates Nutrition 0.000 claims abstract description 12
- 238000013032 photocatalytic reaction Methods 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 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
- 230000002194 synthesizing effect 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
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 239000005977 Ethylene Substances 0.000 claims description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 4
- 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
- 230000015572 biosynthetic process Effects 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
- 238000010189 synthetic method Methods 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 230000001699 photocatalysis Effects 0.000 abstract description 8
- 239000003513 alkali Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 238000007146 photocatalysis Methods 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 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
- 150000001875 compounds Chemical class 0.000 description 5
- 239000011941 photocatalyst Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 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
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- 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
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-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
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000006293 aldehyde allylation reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission 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
- 239000003054 catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 230000007613 environmental effect Effects 0.000 description 1
- 230000005281 excited state Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000002500 ions Chemical class 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
- 230000001404 mediated effect 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
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- 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 & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The application discloses a synthesis method of 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 geminal difluoro alkene and alcohol to generate photocatalysis reaction, so as to obtain beta-fluoro alkenyl alcohol. According to the synthesis method, a strategy of photocatalytic hydrogen atom transfer is adopted, so that the alpha-hydroxy carbon free radical and the alkenyl free radical are subjected to coupling reaction, and finally the beta-fluoro alkenyl alcohol is 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
Technical field:
the application belongs to the field of organic synthesis, and particularly relates to a synthesis method of beta-fluoro alkenyl alcohol.
The background technology is as follows:
the fluorine-containing organic compound plays an important role in the fields of pharmacy, medicine, agricultural chemistry and the like. The introduction of fluorine atoms into organic molecules can increase the solubility, lipophilicity, metabolic stability, etc. of the organic molecules. It is estimated that approximately 20% to 25% of the drugs and 30% to 40% of the agrochemicals contain fluorine atoms. Of these, the structure of the monofluoroolefin is particularly important. In organic synthesis, it is considered one of the most useful fluoride synthesis molecules, being a peptide bond equivalent group in pharmaceutical chemistry, widely present in medical molecules. Among these, β -fluoroalkenyl alcohol is attracting attention as an important monofluoroolefin. However, the methods for synthesizing β -fluoroalkenyl alcohols are currently very limited.
Patent application WO 2009017190A1 discloses the following synthetic route to β -fluoroalkenyl alcohols:
diaryl ketone and 2-fluoro-2-phosphoryl acetic acid triethyl are adopted to react in the presence of sodium hydride to generate intermediate fluoro alkenyl ester, then the intermediate fluoro alkenyl ester reacts with Grignard reagent in the presence of boron tribromide, saturated ammonium chloride solution is added for quenching after cooling, and the product is obtained after extraction, drying and concentration, wherein the yield is 85%. However, the method has the advantages of multiple steps, long route, demanding reaction conditions, narrow application range and high cost, and needs high-activity Grignard reagent and strong alkali.
Patent application WO2008037604 A1 discloses the following synthetic route to β -fluoroalkenyl alcohols:
beta-bromoalkenyl alcohol is adopted to react with tert-butyl lithium and N-fluoro bis-benzene sulfonamide (NFSI) at the temperature of minus 78 ℃, then saturated ammonium chloride solution is added for quenching, and the beta-fluoroalkenyl alcohol is obtained after extraction, drying and column chromatography, wherein the yield is 36 percent. However, the method has the advantages of difficult acquisition of the initial raw materials, low yield, use of strong alkali with high activity, poor safety, harsh reaction conditions, narrow application range and higher cost.
Therefore, there is a need to develop novel methods for synthesizing β -fluoroalkenyl alcohols.
The invention comprises the following steps:
in view of the shortcomings of the prior art, an object of the present application is to provide a method for synthesizing β -fluoroalkenyl alcohol, wherein a policy of photocatalytic hydrogen atom transfer is adopted to enable α -hydroxy carbon radicals and alkenyl radicals to undergo a coupling reaction, and finally β -fluoroalkenyl alcohol is 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.
In order to achieve the above object, in a first aspect, the present application provides a synthesis method of β -fluoroalkenyl alcohol, the synthesis method comprising:
in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, blue light is adopted to irradiate geminal difluoro alkene and alcohol to generate photocatalysis reaction, so as to obtain beta-fluoro alkenyl alcohol.
In combination with the first aspect, in one possible embodiment, the molar ratio of alcohol, 4-CzIPN, quinuclidine, lewis acid, potassium phosphate, and gem-difluoroolefin is (2.5-3.5): (0.025-0.035): (0.25-0.35): (1.2-1.8): (0.8-1.2): 1.
With reference to the first aspect, in a possible embodiment, the lewis acid may be zinc chloride or lithium chloride.
With reference to the first aspect, in a possible embodiment, the time of the photocatalytic reaction is 18 to 30 hours, preferably 24 hours.
With reference to the first aspect, in a possible embodiment, the temperature of the photocatalytic reaction is between 15 ℃ and 35 ℃, preferably 25 ℃.
With reference to the first aspect, in a possible embodiment, the photocatalytic reaction is performed under conditions of oxygen and moisture exclusion.
With reference to the first aspect, in a possible implementation manner, the wavelength of the blue light is 420nm to 480nm.
With reference to the first aspect, in a possible implementation manner, the light intensity of the blue light is 0.8cd to 1.0cd.
With reference to the first aspect, in one possible embodiment, the geminal difluoroolefin may be 1, 1-difluoro-2, 2-diphenylethylene, 1-difluoro-2, 2-di-4 '-chlorophenyl ethylene, 1-difluoro-2, 2-di-4' -fluorophenylethylene or 1, 1-difluoro-2-diphenylethylene.
With reference to the first aspect, in one possible embodiment, the alcohol may be hexanol, cyclohexylmethanol, or phenylpropanol.
With reference to the first aspect, in one possible embodiment, the photocatalytic reaction may be performed in the presence of a solvent including dimethyl sulfoxide, 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 method for synthesizing the beta-fluoroalkenyl alcohol, a visible light catalytic strategy is adopted, the alcohol and the gem-difluoro olefin are directly used as raw materials, the operation is safe and simple, the cost is low, the reaction condition is mild, meanwhile, a wider substrate range is provided, and a green, efficient and safe way is provided for synthesizing the beta-fluoroalkenyl alcohol compound.
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 the present application may be more clearly understood by those skilled in the art, the present application will be described in detail with reference to examples. Before the description, it is to be understood that the terms used in this 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 set forth herein is for the purpose of illustration only and is not intended to limit the scope of the application, so that it should be understood that other equivalents and modifications may be made thereto without departing from the spirit and scope of the application, which is set forth in the claims below.
In the prior art, the synthesis of beta-fluoro alkenyl alcohol generally uses high-activity reagents, high-risk reagents, transition metals, harsh reaction conditions and the like, and has the advantages of poor safety, narrow application range and higher cost. In view of these problems, it is an object of the present application to provide a method for synthesizing β -fluoroalkenyl alcohol, which employs a strategy of photocatalytic hydrogen atom transfer to allow coupling reaction of α -hydroxycarbon radicals with alkenyl radicals, and finally obtains β -fluoroalkenyl 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 object, in a first aspect, the present application provides a synthesis method of β -fluoroalkenyl alcohol, the synthesis method comprising:
in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, blue light is adopted to irradiate geminal difluoro alkene and alcohol to generate photocatalysis reaction, so as to obtain beta-fluoro alkenyl alcohol.
In this application, a photocatalyst (PC, as used herein, 4-CzIPN) is excited under blue light irradiation, and the photocatalyst in the excited state oxidizes quinuclidine to produce a quinuclidine radical cation intermediate. Under the action of a Lewis Acid (LA), the alcohol coordinates to the Lewis acid. The generated complex and quinuclidine free radical positive ion intermediate generate a Hydrogen Atom Transfer (HAT) process to generate an alpha carbon free radical intermediate of alcohol. The reduced photocatalyst anions can be used as a reducing agent to reduce gem-difluoro olefins to generate free radicals and fluoride anions. The two generated free radicals can undergo a coupling reaction to generate beta-fluoro alkenyl 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 the 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 may accept and transfer electrons in a photocatalytic reaction. The potassium phosphate is a strong alkali weak acid salt, and can neutralize hydrogen fluoride which is a byproduct of the reaction. By combining these compounds, the progress of the photocatalytic reaction can be sufficiently promoted, and thus the β -fluoroalkenyl alcohol can be obtained.
Further, the geminal difluoroolefin refers to a molecule in which one carbon atom in the carbon-carbon double bond of the olefin is simultaneously linked with two fluorine atoms. The beta-fluoroalkenyl alcohol refers to a molecule in which a fluorine atom and an alkenyl group are simultaneously connected to the beta position of the alcohol.
In combination with the first aspect, in one possible embodiment, the molar ratio of alcohol, 4-CzIPN, quinuclidine, lewis acid, potassium phosphate, and gem-difluoroolefin is (2.5-3.5): (0.025-0.035): (0.25-0.35): (1.2-1.8): (0.8-1.2): 1.
With reference to the first aspect, in a possible embodiment, the time of the photocatalytic reaction is 18 to 30 hours (for example, may be 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours or 30 hours, or any other specific value within the range), preferably 24 hours. In the present application, side reactions may occur when the reaction time of the photocatalytic reaction is too long, and the yield may be reduced when the reaction time is too short.
With reference to the first aspect, in a possible embodiment, the temperature of the photocatalytic reaction is in the range of 15 ℃ to 35 ℃, i.e. room temperature (e.g. may be 15 ℃, 17 ℃,19 ℃, 21 ℃, 23 ℃, 25 ℃, 27 ℃, 29 ℃, 31 ℃, 33 ℃ or 35 ℃, or any other specific value of the range), preferably 25 ℃. In the present application, too high a temperature of the photocatalytic reaction may cause side reactions to occur, and too low a temperature may reduce the reaction rate, resulting in a decrease in yield. In addition, the temperature condition of the photocatalytic reaction is very mild, and the photocatalytic reaction is in a room temperature range, does not need strong regulation and control, and is green and energy-saving.
With reference to the first aspect, in a possible embodiment, the photocatalytic reaction is performed under conditions of oxygen and moisture exclusion. In this application, the active substances such as oxygen or moisture deactivate the catalytic components and affect the progress of the reaction, and should therefore be excluded. Thus, the photocatalytic reaction of the present application may be carried out 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 isolate oxygen and moisture. For example, a laboratory may employ a Schlenk (Schlenk) bottle to perform the reaction, but the present application is not limited thereto.
With reference to the first aspect, in a possible implementation manner, the wavelength of the blue light is 420nm to 480nm. In the wave range, the electronic transition and transmission of the 4-CzIPN can be promoted, and the photocatalysis is realized.
With reference to the first aspect, in a possible implementation manner, the light intensity of the blue light is 0.8cd to 1.0cd. Within the light intensity range, sufficient light energy can be continuously supplied to the reaction system to promote the reaction to proceed sufficiently.
In addition, 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, the light source is preferably an LED light source from the viewpoint of energy saving, environmental protection, and the like.
With reference to the first aspect, in one possible embodiment, the geminal difluoroolefin may be 1, 1-difluoro-2, 2-diphenylethylene, 1-difluoro-2, 2-di-4 '-chlorophenyl ethylene, 1-difluoro-2, 2-di-4' -fluorophenylethylene or 1, 1-difluoro-2-diphenylethylene.
With reference to the first aspect, in one possible embodiment, the alcohol may be hexanol, cyclohexylmethanol, or phenylpropanol.
With reference to the first aspect, in one possible embodiment, the photocatalytic reaction may be performed in the presence of a solvent including dimethyl sulfoxide, N-dimethylformamide, and N, N-dimethylacetamide.
According to the method for synthesizing the beta-fluoroalkenyl alcohol, a visible light catalytic strategy is adopted, the alcohol and the gem-difluoro olefin are directly used as raw materials, the operation is safe and simple, the cost is low, the reaction condition is mild, meanwhile, a wider substrate range is provided, and a green, efficient and safe way is provided for synthesizing the beta-fluoroalkenyl alcohol compound.
Examples
Material source
4CzIPN, according to F.Calogero et al, "Nickel-Mediated Enantioselective Photoredox Allylation of Aldehydes with Visible Light", angew.chem.int.ed.2022,61, e202114981; angew.chem.2022,134, e202114981 (DOI: 10.1002/anie.202114981) synthesized the compound;
1, 1-difluoro-2, 2-diphenylethylene according to Wang et al, "Enantioselective Construction of H-Isoindoles Containing Tri-and Difluoromethylated Quaternary Stereogenic Centers via Palladium-Catalyzed C-H Bond Imidoylation", ACS Catal.2021,11,19,12367-12374 (DOI: 10.1021/acscat al.1c03682) this compound was synthesized;
1, 1-difluoro-2, 2-di-4' -chlorophenyl ethylene according to Wang et al, "Enantioselective Construction of H-Isoindoles Containing Tri-and Difluoromethylated Quaternary Stereogenic Centers via Palladium-Catalyzed C-H Bond Imidoylation", ACS Catal.2021,11,19,12367-12374 (DOI: 10.1021/acscat al.1c03682) this compound was synthesized;
1, 1-difluoro-2-biphenylethylene according to the literature Pan et al, "Electrochemical-processed Nickel-Catalyzed Reductive Allylation of Aryl Halides", org. Lett.2022,24,20,3647-3651 (DOI: 10.1021/acs. Orglett. 2c0147) this compound was synthesized;
quinuclidine, 99% pure, purchased from Shanghai Taitan technologies Co., ltd;
zinc chloride, 99% pure, purchased from Anhuizhen technologies, inc.;
lithium chloride, 99% pure, was purchased from Anhui Zesheng technologies, inc.
Example 1:
4CzIPN (2.4 mg,0.03 mmol), quinuclidine (3.3 mg,0.03 mmol), zinc chloride (20.5 mg,0.15 mmol) and potassium phosphate (21.2 mg,0.1 mmol) were added to a Schlemk 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. The solution is degassed to remove oxygen from the solvent. After completion, the solution was yellow. The schlemk bottle was placed under a blue LED light source (18W, 0.8-1.0 cd) at 420-480 nm and stirred at room temperature (25 ℃) for 24 hours. The color of the solution becomes light after the reaction is finished. 2mL of water was added, the mixture was quenched, extracted three times with 5mL of diethyl ether, and the organic layer was washed with 2mL of saturated brine. The product was isolated by column chromatography on silica gel (mobile phase: petroleum ether: ethyl acetate=5:1) to give the product as a colourless oil in 93% yield.
Example 2:
4CzIPN (2.4 mg,0.03 mmol), quinuclidine (3.3 mg,0.03 mmol), zinc chloride (20.5 mg,0.15 mmol) and potassium phosphate (21.2 mg,0.1 mmol) were added to a Schlemk 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. The solution is degassed to remove oxygen from the solvent. After completion, the solution was yellow. The schlemk bottle was placed under a blue LED light source (18W, 0.8-1.0 cd) at 420-480 nm and stirred at room temperature (25 ℃) for 24 hours. The color of the solution becomes light after the reaction is finished. 2mL of water was added, the mixture was quenched, extracted three times with 5mL of diethyl ether, and the organic layer was washed with 2mL of saturated brine. The product was isolated by column chromatography on silica gel (mobile phase: petroleum ether: ethyl acetate=5:1) to give the product as a colourless oil in 87% yield.
Example 3:
4CzIPN (2.4 mg,0.03 mmol), quinuclidine (3.3 mg,0.03 mmol), lithium chloride (7.0 mg,0.15 mmol) and potassium phosphate (21.2 mg,0.1 mmol) were added to a Schlemk 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. The solution is degassed to remove oxygen from the solvent. After completion, the solution was yellow. The schlemk bottle was placed under a blue LED light source (18W, 0.8-1.0 cd) at 420-480 nm and stirred at room temperature (25 ℃) for 24h. The color of the solution becomes light after the reaction is finished. 2mL of water was added, the mixture was quenched, extracted three times with 5mL of diethyl ether, and the organic layer was washed with 2mL of saturated brine. The product was isolated by column chromatography on silica gel (mobile phase: petroleum ether: ethyl acetate=5:1) to give the product as a colourless oil (mixture of E/Z configuration; E/Z=1:1), in 60% yield.
Comparative examples 1-5:
a photocatalytic experiment was performed in the same manner as in example 1 except for the conditions of table 1 below, and the yields thereof are also shown in table 1.
TABLE 1
| Comparative examples | Conditions (conditions) | Yield% |
| 1 | No illumination | 0 |
| 2 | Matt catalyst (4 CzIPN) | 0 |
| 3 | Quinuclidine-free ring | 0 |
| 4 | Lewis acid-free (Zinc chloride) | 0 |
| 5 | Potassium phosphate free | 26 |
In Table 1, the yields were obtained by using benzotrifluoride as an internal standard by 19 F-NMR measured yield.
From the results of table 1 above, it was found that the desired product was not obtained in the absence of light, photocatalyst, quinuclidine or lewis acid, while the yield was reduced to 26% in the absence of base.
The foregoing is merely 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 about changes or substitutions within the technical scope of the present application, and the changes and substitutions are intended to 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 (8)
1. A method for synthesizing beta-fluoroalkenyl alcohol, the method comprising:
in the presence of 4-CzIPN, quinuclidine, lewis acid and potassium phosphate, adopting blue light to irradiate geminal difluoro olefin and alcohol to make photocatalytic reaction to obtain beta-fluoro alkenyl alcohol,
wherein the Lewis acid is zinc chloride or lithium chloride,
wherein, the wavelength of the blue light is 420 nm-480 nm, and the light intensity is 0.8 cd-1.0 cd,
wherein the geminal difluoroolefin is 1, 1-difluoro-2, 2-diphenylethylene, 1-difluoro-2, 2-di-4 '-chlorophenyl ethylene, 1-difluoro-2, 2-di-4' -fluorophenylethylene or 1, 1-difluoro-2-diphenylethylene, and
wherein the alcohol is hexanol, cyclohexylmethanol or phenylpropanol.
2. The synthetic method according to claim 1, wherein the molar ratio of alcohol, 4-CzIPN, quinuclidine, lewis acid, potassium phosphate and gem-difluoroolefin is (2.5-3.5): 0.025-0.035): 0.25-0.35: 1.2-1.8:
(0.8～1.2):1。
3. the method of claim 1, wherein the photocatalytic reaction takes 18 to 30 hours.
4. A method of synthesis according to claim 3, wherein the photocatalytic reaction takes 24 hours.
5. The method of claim 1, wherein the temperature of the photocatalytic reaction is 15 ℃ to 35 ℃.
6. The method of claim 5, wherein the temperature of the photocatalytic reaction is 25 ℃.
7. The method of claim 1, wherein the photocatalytic reaction is performed under conditions that exclude oxygen and moisture.
8. The synthetic method of 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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