CN114057578A - Derivative of 2-trifluoromethyl cyclopentanone and preparation method thereof - Google Patents
Derivative of 2-trifluoromethyl cyclopentanone and preparation method thereof Download PDFInfo
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- CN114057578A CN114057578A CN202111392974.5A CN202111392974A CN114057578A CN 114057578 A CN114057578 A CN 114057578A CN 202111392974 A CN202111392974 A CN 202111392974A CN 114057578 A CN114057578 A CN 114057578A
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- LQVDWRMXWKNZNG-UHFFFAOYSA-N 2-(trifluoromethyl)cyclopentan-1-one Chemical class FC(F)(F)C1CCCC1=O LQVDWRMXWKNZNG-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000011941 photocatalyst Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 230000035484 reaction time Effects 0.000 claims description 9
- -1 p-formylphenyl Chemical group 0.000 claims description 8
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical group C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 150000003862 amino acid derivatives Chemical group 0.000 claims description 5
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical group CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 claims description 5
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical group 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 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- KAVUKAXLXGRUCD-UHFFFAOYSA-M sodium trifluoromethanesulfinate Chemical group [Na+].[O-]S(=O)C(F)(F)F KAVUKAXLXGRUCD-UHFFFAOYSA-M 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 150000001345 alkine derivatives Chemical class 0.000 abstract description 8
- BGTOWKSIORTVQH-HOSYLAQJSA-N cyclopentanone Chemical class O=[13C]1CCCC1 BGTOWKSIORTVQH-HOSYLAQJSA-N 0.000 abstract description 8
- 238000012546 transfer Methods 0.000 abstract description 8
- 238000007363 ring formation reaction Methods 0.000 abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 4
- 238000013461 design Methods 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 230000027756 respiratory electron transport chain Effects 0.000 abstract description 3
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- NFCYUWQBLNAIDA-UHFFFAOYSA-N FC(F)(F)C1=CCCC1=O Chemical class FC(F)(F)C1=CCCC1=O NFCYUWQBLNAIDA-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing 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 48
- 239000003814 drug Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 11
- 229910052731 fluorine Inorganic materials 0.000 description 11
- 239000011737 fluorine Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000004293 19F NMR spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000010183 spectrum analysis Methods 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 2
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 2
- 229910014263 BrF3 Inorganic materials 0.000 description 1
- BAPPFRYEDRVJBX-UHFFFAOYSA-N C1(CCCC1)=O.C(CCCCC(=O)O)(=O)O Chemical compound C1(CCCC1)=O.C(CCCCC(=O)O)(=O)O BAPPFRYEDRVJBX-UHFFFAOYSA-N 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 1
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002302 Nylon 6,6 Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- REHHBTUVMSHZNT-UHFFFAOYSA-N bromocyclohexatriene Chemical group BrC1=CC=C=C[CH]1 REHHBTUVMSHZNT-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- JYRIJBPELVXSTC-UHFFFAOYSA-N cycloprop-2-yn-1-one Chemical compound O=C1C#C1 JYRIJBPELVXSTC-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000006323 endo cyclization reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000006328 exo cyclization reaction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
- C07C49/567—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings containing halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
- C07C49/583—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings containing —CHO groups
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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
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/04—Five-membered rings
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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Abstract
The invention discloses a 2-trifluoromethyl cyclopentenone derivative and a preparation method thereof, wherein a photocatalyst and a trifluoro reagent are added into N, N-dimethylformamide, then added into an alkynone compound with a structure shown in a formula II, a reaction system is formed under a certain reaction environment, and after the reaction is finished, the 2-trifluoromethyl with the structure shown in the formula I in claim 1 is obtained through post treatmentDerivatives of cyclopentanone. The invention skillfully designs that the carbonyl is taken as a guide group, so that the trifluoromethyl radical is selectively added to the internal alkyne in a regioselective manner, and then the hydrogen transfer, 5-internal cyclization, electron transfer and proton transfer are carried out to start the reaction. The method has the advantages of mild reaction conditions, wide substrate application range and simple operation, and provides a new way for synthesizing the complex 2-trifluoromethyl cyclopentanone derivative.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a 2-trifluoromethyl cyclopentanone derivative and a preparation method thereof.
Background
Cyclopentanone as five-membered heterocyclic compound containing carbonyl group has been widely used as intermediate in fields of perfume, medicine, pesticide, etc., and can be used in synthesis of novel perfume, anti-inflammatory and anticancer medicine, pesticide, and herbicide. In addition, various natural and non-natural drugs also contain the fragment. Prostaglandin D2(PGD2) is a more biologically active prostaglandin and is involved in a number of important physiological processes.
Common synthesis method of cyclopentanone adipic acid or ester derivatives of adipic acid is subjected to intramolecular condensation at high temperature in the presence of a catalyst to generate cyclopentanone. However, this reaction requires high temperatures (>250 ℃) and the instability of reactive groups at high temperatures limits the application to the synthesis of cyclopentanone derivatives.
Cyclopentanol and its derivative are prepared through dehydrogenation and alcohol oxidation in the presence of catalyst.
Further, oxidation with cyclopentane or cyclopentene, intramolecular condensation with 1, 6-hexanediol and nylon 66, and the like are also commonly used in the synthesis of cyclopentanone. However, the above method has problems of many side reactions, high requirements for equipment, and low conditions, and thus has limitations in the application of cyclopentanone derivatives. At present, the free radical reaction is developed rapidly due to the advantages of mild reaction conditions, high tolerance with functional groups and the like.
In recent years, the synthesis of five-membered cyclics by radical addition-migration-cyclization (RATC) of alkynes has received attention, however, the strategy is limited to the conversion of terminal alkynes, which often generate cyclopentylmethyl derivatives by anti-Markovnikov addition, radical migration and 5-exo cyclization. In contrast, formation of the internal ring compound by 5-endo cyclization initiated by addition of intermolecular radicals to internal alkynes remains a significant challenge due to the non-ideal regioselectivity of the radical for internal alkyne addition.
Fluorine-containing organic chemistry has been one of the hot areas of interest to chemists. The fluorine-containing compound is widely applied to the fields of medicines, pesticides, materials and the like, and how to introduce fluorine-containing groups (-F, -CF) into the compound3、-CF2-etc.), has been of widespread interest to chemists. Introduction of fluorine-containing groups into drug molecules is one of the important strategies for drug modification. On one hand, due to the strong electron withdrawing property of fluorine, the introduction of fluorine into a drug molecule can change the acid-base property of fluorine, thereby improving the lipid solubility of the drug molecule. On the other hand, fluorine has strong electron-withdrawing ability and maximum electronegativity, so that the introduction of fluorine into drug molecules can enhance the oxidation resistance of the drug molecules and improve the stability of the drug molecules.
In addition, in consideration of the multifunctionality of cyclopentanone and the superiority of fluorine-containing compounds, various fluorine-containing cyclopentanone compounds are synthesized, so that the application value of the cyclopentanone compounds can be better developed, and the cyclopentanone compounds have important significance in theoretical research and practical application.
Disclosure of Invention
The invention provides a 2-trifluoromethyl cyclopentanone derivative and a preparation method thereof, which take carbonyl as a guide group, and realize 5-internal selective trifluoromethyl carbocyclization reaction of an alkynone compound through free radical addition-migration-cyclization-electron transfer-proton transfer, thereby constructing stereoselective synthesis of the 2-trifluoromethyl cyclopentanone derivative. Under the condition of photocatalysis, trifluoromethyl free radical is regioselectively added to internal alkyne, and then 1, 5-hydrogen atom transfer, 5-internal cyclization and electron are carried outTransfer and proton transfer to achieve this reaction. The method is based on a free radical serial cyclization reaction strategy to synthesize the 2-trifluoromethyl cyclopentanone with a cyclopentanone ring skeleton structure, and the construction of the 2-trifluoromethyl cyclopentanone is efficiently realized.And isThe reactionHas the advantages ofMild condition and wide substrate application rangeEtc. ofThe structural diversity synthesis of the preparation method of the 2-trifluoromethyl cyclopentanone derivative can be realized by changing the substituent, the reaction yield is moderate to good, the operation is simple, and a new way is provided for the synthesis of cyclopentanone compounds.
A2-trifluoromethyl cyclopentanone derivative has a structure of formula I:
wherein R is1Is one of p-formylphenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, fenofibrate derivative, amino acid derivative and clofibrate derivative.
The fenofibrate derivative is of a structure shown as a formula I-1, the amino acid derivative is of a structure shown as a formula I-2, and the clofibrate derivative is of a structure shown as a formula I-3.
A preparation method of a 2-trifluoromethyl cyclopentanone derivative is characterized by comprising the following steps:
adding a photocatalyst and a trifluoro reagent into N, N-dimethylformamide, then adding into an alkynone compound with a structure shown in a formula II, forming a reaction system under a certain reaction environment, and carrying out post-treatment after the reaction is finished to obtain a 2-trifluoromethyl cyclopentanone derivative with a structure shown in a formula I;
wherein R is1Is p-formylphenyl, p-bromoPhenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, fenofibrate derivative, amino acid derivative, clofibrate derivative.
The alkynone compound with the structure of the formula II is shown in the formula II1-II 3.
The specific synthetic route involved in the reaction is shown below:
according to the preparation method, under the catalysis of a photocatalyst, trifluoromethyl free radicals are released by a trifluoromethyl reagent, alkynyl in alkynone is subjected to addition, and the generated alkenyl free radicals form the final 2-trifluoromethyl cyclopentanone derivative through hydrogen migration, 5-internal cyclization, electron transfer and proton transfer.
According to the preparation method of the 2-trifluoromethyl cyclopentanone derivative, the reaction environment is a nitrogen atmosphere, the distance is about 5 cm, and blue light irradiation is carried out at 5-35 ℃ by 10-30W.
The catalyst is photocatalyst 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4CzIPN), and the trifluoromethylating reagent is sodium trifluoromethylsulfinate CF3SO2Na。
The preparation method of the 2-trifluoromethyl cyclopentanone derivative comprises the following steps of (1) mol ratio of the alkynone with the structure of the formula II, a trifluoromethyl reagent and a catalyst: 1-5: 0.01 to 2.
The preparation method of the 2-trifluoromethyl cyclopentanone derivative is characterized in that the molar ratio of the alkynone, the trifluoromethyl reagent and the catalyst is 1: 1-3: 0.05 to 1.
According to the preparation method of the 2-trifluoromethyl cyclopentanone derivative, the reaction time of the reaction system is 15-30 h.
The preparation method of the 2-trifluoromethyl cyclopentanone derivative comprises the following steps: quenching, suction filtering, extracting, washing organic phase, drying and column chromatography separation.
The preparation method of the 2-trifluoromethyl cyclopentanone derivative comprises the steps of quenching by adding water and ethyl acetate, extracting by using ethyl acetate, and washing an organic phase by adopting saturationSaltWashing with water, drying with anhydrous sodium sulfate, and separating with silica gel column chromatography.
Compared with the prior art, the invention has the following advantages:
1. the ingenious design takes carbonyl as a guide group, so that trifluoromethyl radical is regioselectively added to internal alkyne, and then hydrogen transfer, 5-internal cyclization, electron transfer and proton transfer are carried out to start reaction.
2. Based on the ingenious reaction design, the trifluoromethylation and cyclization reactions are realized at the same time, and the construction of the 2-trifluoromethyl cyclopentanone compound is realized.
3. The problem of non-ideal regioselectivity of free radicals due to internal alkyne addition is solved.
4. The reaction condition is mild, the operation is simple, the functional group compatibility is good, and the 2-trifluoromethyl cyclopentanone compound formed by evolution of a series of medicines has good application prospect.
Detailed Description
Example 1
Sequential addition of CF to a dry reaction tube3SO2Na (62.4mg,0.4mmol), 4CzIPN (3.2mg,0.02mmol), nitrogen was purged three times under vacuum, and then the alkynone derivative II-a (37.2mg,0.2mmol) dissolved in 2mL of N, N-dimethylformamide was added. After the system was reacted at room temperature for 18 hours, the reaction was quenched by adding water to the reaction system, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was dried by spinning, and column chromatography was performed to separate petroleum ethers/EtOAc 40:1 to give a white solid I-a, yield: 81% dr>20:1，1H NMR(600MHz,CDCl3)δ10.04(s,1H),7.91(d,J＝8.2Hz,2H),7.40(d,J＝8.2Hz,2H),3.54-3.44(m,2H),2.49(s,2H),1.20(s,3H),0.81(s,3H).13C NMR(151MHz,CDCl3)δ206.02,191.60,142.83,135.80,129.70,129.02,124.43(q,J＝279.6Hz),54.88,54.48,54.22(q,J＝26.6Hz),38.40,27.01,22.85.19F NMR(565MHz,CDCl3)δ-66.23.HRMS(ESI)m/z:[M+H]+Calcd for C15H15F3O2+H+285.1097；Found 285.1095.
The reaction formula is as follows:
example 2
The same procedure as in example 1 was followed except that the alkynone of the formula II-b of example 1 was replaced with the alkynone of the formula II-b and the reaction time was 28 hours, to isolate a white solid I-b in yield: 72% yield, dr>20:1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),7.14(d,J＝8.4Hz,2H),3.38(dq,J＝12.2,8.6Hz,1H),3.33(d,J＝12.4Hz,1H),2.45(s,2H),1.16(s,3H),0.78(s,3H).13C NMR(151MHz,CDCl3)δ206.51,134.27,133.44,129.58,128.57,124.51(q,J＝279.4Hz),54.88,54.18(q,J＝26.3Hz),53.21,38.13,26.90,22.73.19F NMR(565MHz,CDCl3)δ-66.23.HRMS(ESI)m/z:[M+H]+Calcd for C14H14BrF3O+H+:335.0253；Found335.0255。
the reaction formula is as follows:
example 3
The same procedure as in example 1 was followed except that the alkynone of the formula II-c of example 1 was replaced with the alkynone of the formula II-c and the reaction time was 28 hours, to isolate a white solid I-c in yield: 72% yield, dr>20:1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.52-7.49(m,2H),7.12-7.06(m,2H),3.41-3.31(m,2H),2.45(s,2H),1.16(s,3H),0.78(s,3H).13C NMR(151MHz,CDCl3)δ206.49,134.27,133.45,129.58,128.57,124.51(q,J＝279.5Hz),54.88(q,J＝1.0Hz),54.24(q,J＝26.4Hz),53.21(q,J＝0.9Hz),38.13,26.91,22.73.19F NMR(565MHz,CDCl3)δ-66.22.HRMS(ESI)m/z:[M+H]+Calcd for C14H14ClF3O+H+:291.0758。
the reaction formula is as follows:
example 4
The same procedure as in example 1 was followed except that the alkynone of the formula II-d of example 1 was replaced with the alkynone of the formula II-d and the reaction time was 28 hours, to obtain white solids I-d in yield: 75% yield, dr>20:1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.17(dd,J＝8.6,5.3Hz,2H),7.07(dd,J＝11.9,5.3Hz,2H),3.42-3.33(m,2H),2.45(s,2H),1.16(s,3H),0.78(s,3H).13C NMR(151MHz,CDCl3)δ206.72,162.17(d,J＝246.2Hz),131.46(d,J＝3.3Hz),129.76(d,J＝7.9Hz),124.58(q,J＝279.4Hz),115.32(d,J＝21.4Hz),54.89,54.39(q,J＝26.3Hz),53.09,38.10(q,J＝1.0Hz),26.90,22.72.19F NMR(565MHz,CDCl3)δ-66.24,-115.01.HRMS(ESI)m/z:[M+H]+Calcd for C14H14F4O+H+:275.1054；Found 275.1055。
the reaction formula is as follows:
example 5
The same procedure as in example 1 was followed except that the alkynone of the formula II-e in example 1 was replaced with the alkynone of the formula II-e and the reaction time was 20 hours, to obtain white solids I-e with yields: 78% yield, dr>20:1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.17(d,J＝7.9Hz,2H),7.08(d,J＝8.0Hz,2H),3.42(dq,J＝12.2,9.0Hz,1H),3.33(d,J＝12.4Hz,1H),2.44(s,2H),2.36(s,3H),1.15(s,3H),0.78(s,3H).13C NMR(151MHz,CDCl3)δ207.37,137.16,132.65,129.01,128.17,124.68(q,J＝279.6Hz),55.06,54.24(q,J＝26.2Hz),53.41,38.11,27.00,22.84,21.06.19F NMR(565MHz,CDCl3)δ-66.22.HRMS(ESI)m/z:[M+Na]+Calcd for C15H17F3O+Na+:293.1124；Found 293.1123。
the reaction formula is as follows:
example 6
The same procedure as in example 1 was repeated except that the alkynone derivative of the fenofibrate class represented by the formula II-1 was used instead of the alkynone represented by the formula II-a in example 1 and the reaction time was 26 hours, to separate yellow liquid I-1, yield: 78% yield, dr>20:1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.81-7.75(m,4H),7.32(d,J＝8.2Hz,2H),6.89-6.86(m,2H),5.13-5.06(m,1H),3.52(dq,J＝12.5,8.5Hz,1H),3.47(d,J＝12.4Hz,1H),2.49(s,2H),1.67(s,6H),1.22(d,J＝6.2Hz,6H),1.22(s,3H),0.82(s,3H).13C NMR(151MHz,CDCl3)δ206.40,194.91,173.13,159.69,140.13,137.43,132.02,130.40,129.83,128.22,125.43(q,J＝271.7Hz),117.24,79.42,69.33,58.45,54.96,54.24(q,J＝26.5Hz),53.74,53.43,38.34,27.01,25.38,25.37,22.86,21.52,18.42.19F NMR(565MHz,CDCl3)δ-66.15.HRMS(ESI)m/z:[M+H]+Calcd for C28H31F3O5+H+:505.2196；Found 505.2198。
the reaction formula is as follows:
example 7
The same procedure as in example 1 was repeated except that the alkynone derivative of the amino acids represented by the formula II-2 was used in place of the alkynone represented by the formula II-a in example 1 and the reaction time was 22 hours, to separate a yellow liquid I-2, yield: 61% yield, dr ═ 1.3: 1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ8.04(d,J＝7.9Hz,2H),7.32(d,J＝7.8Hz,2H),5.59-5.53(m,1H),4.55(t,J＝7.8Hz,0.45H,minor rotamer),4.45(t,J＝7.9Hz,0.55H,major rotamer),3.88-3.85(m,1H),3.79(s,1.30H,minor rotamer),3.78(s,1.70H,major rotamer),3.73-3.71(m,1H),3.54-3.44(m,2H),2.59-2.50(m,3H),2.39-2.31(m,1H),1.48(s,3.90H,minor rotamer),1.45(s,5.10H,major rotamer),1.20(s,3H),0.81(s,3H).13C NMR(151MHz,CDCl3)δ199.95,183.70,172.80,165.19,154.31,130.16,129.47,127.67(q,J＝279.4Hz),80.75,73.69,58.00,57.62,52.37(q,J＝29.6Hz),52.27,50.87,43.04,36.72,33.93,29.71,28.25,26.62.19F NMR(565MHz,CDCl3)δ-66.23.HRMS(ESI)m/z:[M+Na]+Calcd for C26H32F3NO7+Na+:550.2023；Found 550.2031。
the reaction formula is as follows:
example 8
The same procedure as in example 1 was repeated except that clofibrate acetylene ketone derivative represented by the formula II-3 was used in place of the acetylene ketone represented by the formula II-a in example 1 and the reaction time was 22 hours, to separate yellow liquid I-3, yield: 56% yield, dr>20:1. Product spectrum analysis:1H NMR(600MHz,CDCl3)δ7.05(d,J＝8.6Hz,2H),6.83(d,J＝8.7Hz,2H),4.23(q,J＝7.1Hz,2H),3.36(dq,J＝12.4,8.8Hz,1H),3.29(d,J＝12.4Hz,1H),2.42(s,2H),1.61(s,6H),1.21(t,J＝7.1Hz,3H),1.13(s,3H),0.76(s,3H).13C NMR(151MHz,CDCl3)δ207.15,174.16,154.89,129.11,128.94,124.63(q,J＝279.2Hz),118.63,79.19,61.41,54.95,54.32(q,J＝26.3Hz),53.06,38.10,26.97,25.45,25.43,22.78,14.00.19F NMR(565MHz,CDCl3)δ-66.24.HRMS(ESI)m/z:[M+Na]+Calcd for C20H25F3O4+Na+ :409.1597；Found 409.1599.。
the reaction formula is as follows:
Claims (10)
1. a2-trifluoromethyl cyclopentanone derivative is characterized by having a structure of formula I:
wherein R is1Is one of p-formylphenyl, p-bromophenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, fenofibrate derivative substituent, amino acid derivative substituent and clofibrate derivative substituent.
2. The 2-trifluoromethylcyclopentanone derivative according to claim 1, wherein the derivative is a fenofibrate derivative with a structure of formula I-1, an amino acid derivative with a structure of formula I-2, or a clofibrate derivative with a structure of formula I-3;
3. 2-trifluoromethylcyclopentanone derivative according to claim 1 or 2, characterized in that it comprises the following steps:
adding a photocatalyst and a trifluoromethyl reagent into N, N-dimethylformamide, then adding into an alkynone compound with a structure shown in a formula II, forming a reaction system under a reaction environment, and carrying out post-treatment after the reaction is finished to obtain a derivative of the 2-trifluoromethyl cyclopentanone with the structure shown in the formula I;
wherein-R in the structure of formula II1and-R in the structure of formula I1Have the same meaning.
4. The 2-trifluoromethylcyclopentanone derivative of claim 3, wherein the alkynone compound of formula II is of formula II-1, II-2 or II-3;
5. the method for preparing 2-trifluoromethylcyclopentanone derivative according to claim 3, wherein the reaction environment is a nitrogen atmosphere, and the blue light is irradiated at 5-35 ℃ with 10-30W.
6. The method for preparing 2-trifluoromethylcyclopentanone derivatives as claimed in claim 3, wherein the photocatalyst is 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile, and the trifluoromethylating agent is sodium trifluoromethylsulfinate.
7. The method for preparing 2-trifluoromethyl cyclopentanone derivative according to claim 3, wherein the molar ratio of the alkynone having the structure of formula II, the trifluoromethylating agent, and the photocatalyst is 1: 1-5: 0.01 to 2.
8. The method for preparing 2-trifluoromethyl cyclopentanone derivative according to claim 7, wherein the molar ratio of the alkynone having the structure of formula II, the trifluoromethylating agent, and the photocatalyst is 1: 1-3: 0.05 to 1.
9. The method for preparing a 2-trifluoromethylcyclopentanone derivative according to claim 3, wherein the reaction time of the reaction system is 15 to 30 hours.
10. The process for the preparation of 2-trifluoromethylcyclopentanone derivatives as claimed in claim 3, wherein the post-treatment comprises: quenching, suction filtering, extracting, washing organic phase, drying and column chromatography separation.
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