CN117263801A - Method for preparing difluoromethyl compounds by photocatalysis LMCT - Google Patents
Method for preparing difluoromethyl compounds by photocatalysis LMCT Download PDFInfo
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- CN117263801A CN117263801A CN202311210078.1A CN202311210078A CN117263801A CN 117263801 A CN117263801 A CN 117263801A CN 202311210078 A CN202311210078 A CN 202311210078A CN 117263801 A CN117263801 A CN 117263801A
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 230000001699 photocatalysis Effects 0.000 title claims abstract description 29
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 title claims description 34
- 238000007146 photocatalysis Methods 0.000 title claims description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 239000002904 solvent Substances 0.000 claims abstract description 40
- -1 difluoromethyl compound Chemical class 0.000 claims abstract description 36
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 35
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 claims abstract description 21
- QLPCAAJSEQIZOP-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenethiol Chemical compound CC(C)C1=CC(C(C)C)=C(S)C(C(C)C)=C1 QLPCAAJSEQIZOP-UHFFFAOYSA-N 0.000 claims abstract description 19
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 claims abstract description 10
- 239000011259 mixed solution Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 33
- 238000004809 thin layer chromatography Methods 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 abstract description 29
- 239000003054 catalyst Substances 0.000 abstract description 10
- 239000002184 metal Substances 0.000 abstract description 9
- 229910052751 metal Inorganic materials 0.000 abstract description 9
- 230000003197 catalytic effect Effects 0.000 abstract description 7
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 230000004913 activation Effects 0.000 abstract description 2
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract description 2
- 238000010493 gram-scale synthesis Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000011261 inert gas Substances 0.000 abstract 1
- 230000001678 irradiating effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 238000001228 spectrum Methods 0.000 description 30
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 13
- 239000011737 fluorine Substances 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000011941 photocatalyst Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 238000007405 data analysis Methods 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 3
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- DBXLLKFZSNRRLF-UHFFFAOYSA-N 2-hydroxy-3-methoxy-5-prop-2-enylbenzoic acid Chemical compound COC1=CC(CC=C)=CC(C(O)=O)=C1O DBXLLKFZSNRRLF-UHFFFAOYSA-N 0.000 description 1
- LQLOHAJUXSDIGF-UHFFFAOYSA-N 2-methylprop-2-enyl benzoate Chemical compound CC(=C)COC(=O)C1=CC=CC=C1 LQLOHAJUXSDIGF-UHFFFAOYSA-N 0.000 description 1
- JHXJAWXZLWDDED-UHFFFAOYSA-N 4-(4-ethenylcyclohexyl)benzonitrile Chemical group C1CC(C=C)CCC1C1=CC=C(C#N)C=C1 JHXJAWXZLWDDED-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LYJHVEDILOKZCG-UHFFFAOYSA-N Allyl benzoate Chemical compound C=CCOC(=O)C1=CC=CC=C1 LYJHVEDILOKZCG-UHFFFAOYSA-N 0.000 description 1
- DYFGYJGZUKRYKY-UHFFFAOYSA-N FC(F)[Zn] Chemical compound FC(F)[Zn] DYFGYJGZUKRYKY-UHFFFAOYSA-N 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PBGVMIDTGGTBFS-UHFFFAOYSA-N but-3-enylbenzene Chemical group C=CCCC1=CC=CC=C1 PBGVMIDTGGTBFS-UHFFFAOYSA-N 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- OOKFLLNDYNWCHK-UHFFFAOYSA-N difluoromethyl(trimethyl)silane Chemical compound C[Si](C)(C)C(F)F OOKFLLNDYNWCHK-UHFFFAOYSA-N 0.000 description 1
- YCDHVKWTZBVDKD-UHFFFAOYSA-L disodium 6-hydroxy-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].C1=CC=C2C(N=NC3=C4C=CC(=CC4=CC=C3O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 YCDHVKWTZBVDKD-UHFFFAOYSA-L 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005799 fluoromethylation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/02—Addition
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/272—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/803—Processes of preparation
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/50—Organo-phosphines
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- C07C2601/14—The ring being saturated
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- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
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Abstract
The invention belongs to the technical field of catalytic synthesis, and particularly relates to a method for preparing a difluoromethyl compound by a photocatalytic LMCT strategy. The invention solves the problems that the existing synthesis method is too complicated and needs pre-activation and stoichiometric oxidant. The method comprises the following steps: olefin compound, difluoroacetic acid, 2,4, 6-triisopropylthiophenol and Fe (acac) 3 Adding the mixture into a solvent to obtain a reaction mixed solution, and irradiating the reaction mixed solution with LEDs light sources at room temperature in an inert gas atmosphere to obtain the difluoromethyl compound. The invention shows the green reaction; the reaction is mild; the method has the advantages of very simple operation, commercially available various raw materials, easy preparation of olefin, high-efficiency gram-scale synthesis of the reaction by using a catalytic amount of low-cost metal catalyst through a one-pot method, and potential industrial application value. The invention is applied to the field of organic synthesis.
Description
Technical Field
The invention belongs to the technical field of catalytic synthesis, and particularly relates to a method for preparing difluoromethyl compounds by a photocatalytic LMCT strategy.
Background
Fluorine has the unique ability to modulate the polarity, metabolic stability, lipophilicity, and solubility of potential drug candidates, and therefore the development of new fluorine-containing compounds is of great research interest. Difluoromethyl (CF) 2 H) Has the same polarity and polarity with hydroxyl (-OH) and thiol (-SH) units, and is a lipophilic hydrogen bond donor. Thus, CF is selectively added to the molecular structure 2 H groups, especially by CF 2 Before HIt would be of great importance to realize a hydrodifluoromethylation reaction with olefins.
CF for difluoromethylation reaction reported previously 2 H precursors include (difluoromethyl) zinc reagents, difluoromethyltrimethylsilane, and difluoroalkylsulfonyl compounds, etc., but most processes rely on preactivated precursors that require multi-step preparation, resulting in a significant increase in reaction costs. Difluoroacetic acid is an excellent source of fluorine and is also a plentiful industrial feedstock for the production of various pharmaceutical intermediates. It would therefore be of great interest to develop a synthetic scheme that uses such inexpensive industrial chemicals as difluoroalkylating agents. However, the use of difluoroacetic acid is greatly affected by the high oxidation potential of the difluoroalkyl carboxylic acid anion, and the use of stoichiometric iodine reagents makes the reaction less atom economical, although the formation of difluoromethyl radicals can be achieved using high valent iodine salts. Therefore, the key problem to be solved is to find a method for synthesizing difluoromethyl compounds through a cheap metal catalyzed reaction, which is green and mild in condition, convenient, efficient, economical and environment-friendly.
Disclosure of Invention
The invention solves the problems that the existing synthesis method is complicated and needs pre-activation and stoichiometric oxidant, and provides a method for preparing difluoromethyl compounds by photocatalysis LMCT.
The present invention utilizes a photocatalytic LMCT strategy by using a catalytic amount of Fe (acac) 3 As a photocatalyst, the catalyst undergoes ligand-to-metal charge transfer (LMCT) under the action of photocatalysis to generate a difluoromethyl radical intermediate, further attacks olefin, realizes the difluoromethylation reaction of the olefin under the action of a hydrogen atom transfer catalyst 2,4, 6-triisopropylthiophenol, and provides a milder, green and efficient method.
A method for preparing difluoromethyl compounds by photocatalysis LMCT comprises the following steps:
1. olefin compound, difluoroacetic acid, 2,4, 6-triisopropylthiophenol and Fe (acac) 3 Adding the mixture into a solvent to obtain a reaction mixed solution;
2. and under the condition of nitrogen atmosphere and room temperature, adopting LED light sources to irradiate the reaction mixed solution for 24-36h, then extracting, removing the solvent by rotary evaporation, and separating and purifying by a thin layer chromatography to obtain the product, namely the difluoromethyl compound, thus completing the preparation.
Further, the chemical structural formula of the olefinic compound in the first step is:R 1 is phenyl or alkyl compound, R 2 Is phenyl or alkyl compound.
Further, in the step one, the solvent is dimethyl sulfoxide.
Further, the chemical structural formula of the difluoroacetic acid in the first step is as follows:
further, the chemical structural formula of the 2,4, 6-triisopropylthiophenol in the first step is:
the reaction formula of the invention:
the invention provides a reaction mechanism based on difluoromethylation reaction of olefin, which is as follows:
initially, fe (acac) 3 Can be complexed with difluoroacetic acid to obtain an intermediate I, the intermediate I is subjected to LMCT process under the induction of light to release a free radical intermediate II, the intermediate I can be further decarboxylated to generate a difluoromethyl free radical intermediate III, at the moment, the difluoromethyl free radical can attack olefin to generate an intermediate IV, and then hydrogen protons are obtained under the action of a hydrogen atom transfer catalyst to realize the di-olefin of the olefinAnd the fluoromethylation process, and simultaneously, the thiol free radical intermediate can carry out electron transfer with ferrous iron to realize a double-catalytic cycle process.
The invention has the beneficial effects that:
compared with the prior art, the invention constructs the difluoromethyl compound by a method with low-cost metal catalysis LMCT strategy, which is more green and mild, has atom economy, is simple and convenient and has the following advantages:
(1) The reaction system is a difluoromethylation reaction of olefin, and can realize the construction of complex difluoromethyl compounds by using a low-cost metal catalyst through a photoinduction LMCT strategy one-step reaction, and the operation is convenient.
(2) The reaction can realize the synthesis of the difluoromethyl compound which is challenging by illumination at room temperature, and the reaction condition is very green and mild.
(3) The reaction system uses difluoroacetic acid, 2,4, 6-triisopropylthiophenol and Fe (acac) 3 The method is a cheap and easily available chemical, the difluoromethyl compound is a main product of the reaction, the atomic economy of the reaction is reflected, and the reaction system is economical and has high efficiency.
(4) The reaction system has better substrate universality, can carry out a large number of experiments by a one-pot method, can realize the synthesis of gram-scale reaction by light irradiation for 36-48 hours at room temperature, has better yield, and shows high efficiency of the reaction.
(5) The conversion of the reaction can be realized by using a catalytic amount of cheap metal catalyst and a catalytic amount of hydrogen atom transfer catalyst, and the participation of stoichiometric oxidant is not needed, so that the method has the advantages of saving and protecting the environment of the reaction and has potential application value.
The method is used for preparing the difluoromethyl compounds.
Drawings
FIG. 1 shows difluoromethyl-based compound-1 obtained in example 1 1 H NMR spectrum;
FIG. 2 shows difluoromethyl-based compound-1 obtained in example 1 13 C NMR spectrum;
FIG. 3 is the result of example 1Difluoromethyl compounds-1 19 F NMR spectrum.
Detailed Description
The first embodiment is as follows: the method for preparing the difluoromethyl compound by photocatalysis LMCT in the embodiment comprises the following steps:
1. olefin compound, difluoroacetic acid, 2,4, 6-triisopropylthiophenol and Fe (acac) 3 Adding the mixture into a solvent to obtain a reaction mixed solution;
2. and under the condition of nitrogen atmosphere and room temperature, adopting LED light sources to irradiate the reaction mixed solution for 24-36h, then extracting, removing the solvent by rotary evaporation, and separating and purifying by a thin layer chromatography to obtain the product, namely the difluoromethyl compound, thus completing the preparation.
According to the invention, the difluoromethylation of olefin can be realized through the synergistic catalysis of the catalytic amount of cheap metal and the catalytic amount of the hydrogen atom transfer catalyst, so that the reaction is green; the difluoromethyl compound can be prepared at room temperature, so that the reaction mildness is reflected; and using inexpensive, commercially available Fe (acac) 3 As a metal catalyst, the method is economical and environment-friendly. The method has the advantages of simple operation, commercially available various raw materials, easy preparation of olefin, high-efficiency gram-scale synthesis of the reaction by using a catalytic amount of the cheap metal catalyst through a one-pot method, and potential industrial application value. The invention is applied to the field of organic synthesis.
The second embodiment is; the first difference between this embodiment and the specific embodiment is that: the chemical structural formula of the olefin compound in the first step is as follows:R 1 is phenyl or alkyl compound, R 2 Is phenyl or alkyl compound. The other is the same as in the first embodiment.
A third embodiment; this embodiment differs from the first or second embodiment in that: in the first step, the solvent is dimethyl sulfoxide. The other is the same as the first or second embodiment.
A fourth embodiment; this embodiment differs from one of the first to third embodiments in that: the dosage ratio of the olefin compound to the solvent is 0.07-0.1 mmol:1mL. The other is the same as in one of the first to third embodiments.
A fifth embodiment; this embodiment differs from one to four embodiments in that: the dosage ratio of the difluoroacetic acid to the solvent in the first step is 0.8-1.2 mmol:1mL. The others are the same as in one to one fourth embodiments.
A sixth specific embodiment; this embodiment differs from one of the first to fifth embodiments in that: the dosage ratio of the 2,4, 6-triisopropylthiophenol to the solvent in the first step is 2-3 mg:1mL. The others are the same as in one of the first to fifth embodiments.
A seventh embodiment; this embodiment differs from one of the first to sixth embodiments in that: step one the Fe (acac) 3 The dosage ratio of the solvent is 3.5-4.5 mg:1mL. The others are the same as in one of the first to sixth embodiments.
The eighth embodiment; this embodiment differs from one of the first to seventh embodiments in that: and step two, controlling the wavelength of the light source of the LEDs to be 380-400 nm and the power to be 10W. The other is the same as in one of the first to seventh embodiments.
A ninth embodiment; this embodiment differs from one to eight of the embodiments in that: and step two, the solvent used for separating and purifying by the thin layer chromatography is a mixture of petroleum ether and ethyl acetate. The others are the same as in one to eight embodiments.
The specific embodiment is ten; this embodiment differs from one of the embodiments one to nine in that: the volume ratio of petroleum ether to ethyl acetate is (2-10): 1. the others are the same as in one of the embodiments one to nine.
The present invention is not limited to the above embodiments, and the object of the invention can be achieved by one or a combination of several embodiments.
Example 1:
the method for preparing the difluoromethyl compound by photocatalysis LMCT comprises the following steps:
in this example, the olefin a1 is 2-methylallyl benzoate having the structural formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 To 2mL of solvent DMSO, then 0.2mmol of olefin a1, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid were sequentially added to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-1 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 86%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝8.04(d,J＝7.6Hz,2H),7.58(t,J＝7.4Hz,1H),7.46(t,J＝7.7Hz,2H),5.97(tt,J＝56.6,4.8Hz,1H),4.29-4.13(m,2H),2.27(dq,J＝13.2,6.5Hz,1H),2.15-1.98(m,1H),1.93-1.72(m,1H),1.13(d,J＝6.8Hz,3H). 19 F NMR(376MHz,Chloroform-d)δppm＝-113.75--115.92(m). 13 C NMR(101MHz,Chloroform-d)δppm＝166.47,133.17,130.06,129.60,128.52,116.59(t,J＝238.9Hz),68.96,37.98(t,J＝20.8Hz),28.02(t,J＝5.3Hz),17.14.HRMS(ESI)(m/z):[M+H] + called.for C 12 H 15 F 2 O 2 :229.1040,found:229.1032.
example 2:
the method for preparing the difluoromethyl compound by photocatalysis LMCT comprises the following steps:
the olefin a2 of this example is 4-phenyl-1-butene having the formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a2, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-2 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 72%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝7.28(t,J＝7.4Hz,2H),7.22-7.13(m,3H),5.78(tt,J＝56.9,4.5Hz,1H),2.67-2.59(m,2H),1.92-1.76(m,2H),1.68(p,J＝7.6Hz,2H),1.50(q,J＝8.4Hz,2H). 19 F NMR(376MHz,Chloroform-d)δppm＝7.28-115.81(dt,J＝57.0,17.5Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝142.02,128.42,125.90,121.89-110.77(m),35.71,34.01(t,J＝20.7Hz),30.93,21.82(t,J＝5.5Hz).HRMS(ESI)(m/z):[M+H] + called.for C 11 H 15 F 2 :185.1142,found:185.1140.
example 3:
the method for preparing the difluoromethyl compound by photocatalysis LMCT comprises the following steps:
in this example, olefin a3 is 5-allyl-2-hydroxy-3-methoxybenzoic acid methyl ester of the formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a3, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-3 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 68%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝10.86(s,1H),7.23(s,1H),6.86(d,J＝1.7Hz,1H),5.82(tt,J＝56.5,4.1Hz,1H),3.95(s,3H),3.90(s,3H),2.61(t,J＝7.4Hz,2H),1.96-1.72(m,4H). 19 F NMR(376MHz,Chloroform-d)δppm＝-115.79(dt,J＝56.8,17.1Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝170.79,150.44,148.50,131.54,120.02,117.17(t,J＝239.0Hz),116.94,112.20,56.21,52.40,34.73,33.42(t,J＝20.9Hz),23.74(t,J＝5.2Hz).HRMS(ESI)(m/z):[M+H] + called.for C 13 H 17 F 2 O 4 :275.1095,found:275.1089.
example 4
The method for preparing the difluoromethyl compound by photocatalysis LMCT comprises the following steps:
the olefin a4 of this example is 4- (4-vinylcyclohexyl) benzonitrile of the formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a4, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; argon is introduced to deoxidize for 5min, howeverThen under the stirring condition of a magnetic stirrer, LEDs with the power of 10W and the wavelength of 390nm plus or minus 10nm are adopted to illuminate for 24 hours at room temperature, and TLC is used for monitoring the reaction progress; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-4 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 67%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝7.57(d,J＝8.3Hz,2H),7.30(d,J＝8.2Hz,2H),5.81(tt,J＝57.0,4.5Hz,1H),2.54(t,J＝12.3Hz,1H),1.99-1.80(m,6H),1.52-1.31(m,5H),1.10(q,J＝12.1,11.5Hz,2H). 19 FNMR(376MHz,Chloroform-d)δppm＝-115.68(dt,J＝56.8,17.6Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝152.94,132.26,127.70,119.21,117.62(t,J＝238.9Hz),109.72,44.58,36.62,33.62,32.96,31.67(t,J＝20.7Hz),29.22(t,J＝5.0Hz).HRMS(ESI)(m/z):[M+H] + called.for C 16 H 20 F 2 N:286.1383,found:286.1385.
example 5:
the invention relates to a method for preparing difluoromethyl compounds by photocatalysis LMCT, which comprises the following steps:
in this example, the olefin a5 is allyl benzoate having the structural formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a5, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction, the solvent was removed by extraction and distillation under reduced pressure, followed by passing through a thin layerSeparating by chromatography to obtain a product, and identifying the product as a difluoromethyl compound-5 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high-resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 56%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝8.04(d,J＝7.1Hz,2H),7.57(t,J＝6.8Hz,1H),7.45(t,J＝7.7Hz,2H),6.10-5.73(m,1H),4.38(t,J＝6.0Hz,2H),2.08-1.93(m,4H). 19 F NMR(376MHz,Chloroform-d)δppm＝-116.25(dt,J＝56.7,17.2Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝166.52,133.15,130.08,129.61,128.49,116.82(t,J＝239.1Hz),63.94,31.04(t,J＝21.5Hz),21.65(t,J＝5.6Hz).HRMS(ESI)(m/z):[M+H] + called.for C 11 H 13 F 2 O 2 :215.0884,found:215.0882.
example 6:
the invention relates to a method for preparing difluoromethyl compounds by photocatalysis LMCT, which comprises the following steps:
in this example, the olefin a6 is allyloxyphenol having the formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a6, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-6 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 71%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝7.31-7.24(m,2H),6.95(t,J＝7.3Hz,1H),6.88(d,J＝7.9Hz,2H),5.90(tt,J＝56.6,4.2Hz,1H),3.99(t,J＝5.9Hz,2H),2.13-1.86(m,4H). 19 F NMR(376MHz,Chloroform-d)δppm＝-116.07(dt,J＝56.7,17.4Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝158.74,129.56,120.93,117.15(t,J＝238.8Hz),114.48,66.70,31.10(t,J＝21.3Hz),22.17(t,J＝5.6Hz).HRMS(ESI)(m/z):[M+H] + called.for C 10 H 13 F 2 O:187.0934,found:187.0944.
example 7:
the method for preparing the difluoromethyl compound by photocatalysis LMCT comprises the following steps:
in this example, the olefin a7 is 2-methylallyl nicotinate of the formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a7, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-7 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 78%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝9.23(s,1H),8.80(d,J＝4.4Hz,1H),8.31(d,J＝7.9Hz,1H),7.43(dd,J＝7.9,4.9Hz,1H),5.97(tt,J＝56.5,4.7Hz,1H),4.37-4.16(m,2H),2.30(dt,J＝13.4,6.6Hz,1H),2.13-1.98(m,1H),1.92-1.75(m,1H),1.15(d,J＝6.8Hz,3H). 19 F NMR(376MHz,Chloroform-d)δppm＝-114.88(dtd,J＝56.6,17.5,10.0Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝165.09,153.55,150.79,137.12,125.97,123.45,116.41(t,J＝239.0Hz),69.32,37.79(t,J＝20.9Hz),27.90(t,J＝5.2Hz),17.09.HRMS(ESI)(m/z):[M+H] + called.for C 11 H 14 F 2 NO 2 :230.0993,found:230.0997.
example 8:
the method for preparing the difluoromethyl compound by photocatalysis LMCT comprises the following steps:
the olefin a8 of this example is 2-methylallylthiophene-2-carboxylic acid ester of the formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a8, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-8 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 66%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝7.81(d,J＝3.7Hz,1H),7.57(d,J＝5.0Hz,1H),7.20-7.04(m,1H),5.96(tt,J＝56.6,4.8Hz,1H),4.34-4.05(m,2H),2.34-2.17(m,1H),2.13-1.95(m,1H),1.91-1.73(m,1H),1.11(d,J＝6.8Hz,3H). 19 F NMR(376MHz,Chloroform-d)δppm＝-108.38--125.13(m). 13 C NMR(101MHz,Chloroform-d)δppm＝162.09,133.60,132.61,127.91,116.56(t,J＝238.9Hz),69.05,37.97(t,J＝20.9Hz),28.02(t,J＝5.3Hz),17.08.HRMS(ESI)(m/z):[M+H] + called.for C 10 H 13 F 2 O 2 S:235.0604,found:235.0600.
example 9:
the invention relates to a method for preparing difluoromethyl compounds by photocatalysis LMCT, which comprises the following steps:
in this example, olefin a9 is allyl diphenyl phosphine oxide having the structural formula
5mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 2mL of solvent DMSO was added, followed by 0.2mmol of olefin a9, 8mmol (8. Mu.L) of 2,4, 6-triisopropylthiophenol and 1.0mmol (66. Mu.L) of difluoroacetic acid in this order to obtain a reaction mixture; introducing argon to deoxidize for 5min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 24h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-9 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 64%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝7.77-7.71(m,4H),7.50(ddd,J＝13.9,6.8,4.7Hz,6H),5.79(tt,J＝56.4,4.3Hz,1H),2.40-2.27(m,2H),2.09-1.74(m,4H). 19 F NMR(376MHz,Chloroform-d)δppm＝-115.96(dt,J＝56.5,17.3Hz). 13 C NMR(101MHz,Chloroform-d)δppm＝132.00,131.97,130.80,130.71,128.88,128.76,116.76(t,J＝239.4Hz),34.76(td,J＝21.0,13.6Hz),29.52,28.81,14.79(q,J＝5.8Hz).HRMS(ESI)(m/z):[M+H] + called.for C 16 H 18 F 2 OP:295.1063,found:295.1070.
example 10:
the invention relates to a method for preparing difluoromethyl compounds by photocatalysis LMCT, which comprises the following steps:
the olefin a10 of this example is 4,4a,5,6,7, 8-hexahydro- (4R, 4aS, 6R) -4,4 a-dimethyl-6- (1-methylethenyl) -2 (3H) -naphthalenone of the formula
Gram-scale reaction, 70mg (8 mmol%) of photocatalyst Fe (acac) was taken 3 40mL of solvent DMSO was added, followed by the sequential addition of 4mmol of olefin a10, 8mmol (100. Mu.L) of 2,4, 6-triisopropylthiophenol, and 16mmol (1.2 mL) of difluoroacetic acid to give a reaction mixture; introducing argon to deoxidize for 15min, then adopting LEDs with power of 10W and wavelength of 390nm plus or minus 10nm to illuminate for 48h at room temperature under the stirring condition of a magnetic stirrer, and monitoring the reaction progress by TLC; after the reaction is finished, the solvent is removed by extraction and reduced pressure distillation, then the product is obtained by separating by a thin layer chromatography, and the product is identified as the difluoromethyl compound-10 by nuclear magnetic hydrogen spectrum, carbon spectrum, fluorine spectrum and high resolution mass spectrum, wherein the structural formula is as follows:
purity 99%, yield 82% (dr=1:1); the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,Chloroform-d)δppm＝6.06-5.70(m,2H),2.52-2.19(m,4H),2.04-1.79(m,4H),1.66(dd,J＝17.8,6.9Hz,3H),1.25-1.13(m,1H),1.11-1.07(m,3H),0.96(t,J＝7.4Hz,7H). 19 F NMR(376MHz,Chloroform-d)δppm＝-111.45--121.97(m). 13 C NMR(101MHz,Chloroform-d)δppm＝199.63,170.61,124.67,117.27(t,J＝238.8Hz,diastereomer 1),117.22(t,J＝238.8Hz,diastereomer 2),42.43,42.08,40.85,40.57,39.30,39.20,38.58(t,J＝20.0Hz diastereomer 1),38.10(t,J＝20.1Hz diastereomer 2),37.63,33.03,32.92,32.20,29.79,28.33,16.97,16.39,16.02,14.99.HRMS(ESI)(m/z):[M+H] + called.for C 16 H 25 F 2 O:271.1873,found:271.1879。
Claims (10)
1. a method for preparing difluoromethyl compounds by photocatalysis LMCT is characterized by comprising the following steps:
1. olefin compound, difluoroacetic acid, 2,4, 6-triisopropylthiophenol and Fe (acac) 3 Adding the mixture into a solvent to obtain a reaction mixed solution;
2. and under the condition of nitrogen atmosphere and room temperature, adopting LED light sources to irradiate the reaction mixed solution for 24-36h, then extracting, removing the solvent by rotary evaporation, and separating and purifying by a thin layer chromatography to obtain the product, namely the difluoromethyl compound, thus completing the preparation.
2. The method for preparing difluoromethyl compounds by means of photocatalytic LMCT according to claim 1, wherein the chemical structural formula of the olefinic compound in the step one is:R 1 is phenyl or alkyl compound, R 2 Is phenyl or alkyl compound.
3. The method for preparing difluoromethyl compounds by means of photocatalytic LMCT according to claim 1, wherein in step one the solvent is dimethyl sulfoxide.
4. The method for preparing difluoromethyl compounds by photocatalysis LMCT according to claim 1, wherein the dosage ratio of the olefin compound to the solvent in the step one is 0.07-0.1 mmol:1mL.
5. The method for preparing difluoromethyl compounds by photocatalysis LMCT according to claim 1, wherein the dosage ratio of the difluoroacetic acid to the solvent in the step one is 0.8-1.2 mmol:1mL.
6. The method for preparing difluoromethyl compounds by photocatalysis LMCT according to claim 1, wherein the dosage ratio of 2,4, 6-triisopropylthiophenol to solvent in the step one is 2-3 mg:1mL.
7. The method for preparing difluoromethyl compounds by photocatalytic LMCT according to claim 1, characterized by step one the Fe (acac) 3 The dosage ratio of the solvent is 3.5-4.5 mg:1mL.
8. The method for preparing difluoromethyl compounds by means of photocatalytic LMCT according to claim 1, wherein the wavelength of the light source of the LEDs is 380-400 nm and the power is 10W.
9. The method for preparing difluoromethyl compounds by photocatalysis LMCT according to claim 1, wherein the solvent used for separation and purification by thin layer chromatography in the second step is a mixture of petroleum ether and ethyl acetate.
10. The method for preparing difluoromethyl compounds by photocatalysis LMCT according to claim 9, wherein the volume ratio of petroleum ether to ethyl acetate is (2-10): 1.
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