CN114349704A - Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof - Google Patents
Trifluoromethyl conjugated pyrazole spiro cyclopropane compound and synthesis method thereof Download PDFInfo
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 28
- -1 pyrazole spiro cyclopropane compound Chemical class 0.000 title claims abstract description 22
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 19
- ZQLAVYZSSPTFPN-UHFFFAOYSA-N C1CC11N=NC=C1 Chemical class C1CC11N=NC=C1 ZQLAVYZSSPTFPN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 230000000996 additive effect Effects 0.000 claims abstract description 10
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- XSGHLZBESSREDT-UHFFFAOYSA-N methylenecyclopropane Chemical class C=C1CC1 XSGHLZBESSREDT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001879 copper Chemical class 0.000 claims abstract description 5
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 172
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 74
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 238000004293 19F NMR spectroscopy Methods 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000010791 quenching Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 229910014263 BrF3 Inorganic materials 0.000 description 4
- 229910020323 ClF3 Inorganic materials 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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Abstract
The invention discloses trifluoromethyl conjugated pyrazole spiro propane compounds and a synthesis method thereof, belonging to the technical field of organic synthesis. Mixing substituted methylene cyclopropane 1, 1-substituted pyrazolidone compounds 2, inorganic base, copper salt or silver salt additive and trifluoroethanol 3, and heating to react to prepare trifluoromethyl conjugated pyrazole spiro cyclopropane compounds 4; the synthesis method is efficiently completed through one-pot series reaction among substituted methylene cyclopropane, 1-substituted pyrazolidone and trifluoroethanol, the whole process has high atom economy, mild reaction conditions and simple and efficient process; meanwhile, the method has the advantages of wide substrate range, good functional group tolerance and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing trifluoromethyl conjugated pyrazole spiro cyclopropane compounds.
Background
As is well known, the spiro skeleton is widely present in natural products, drugs, organic ligands and perfume molecules, and has important research value. Among them, the pyrazole spiropropane derivative has attracted people's attention because of having a large tonicity and a remarkable biological activity, and is one of the advantageous structures for the development of new drugs. In addition, the pyrispirocyclopropane derivative also has active and various reaction properties and becomes a general intermediate for synthesizing medicaments, agricultural chemicals and organic photoelectric materials.
On the other hand, the trifluoromethyl structural fragment is an indispensable component of various drug molecules due to the unique electronic property and spatial size of fluorine atoms, and at present, 30% of the drug molecules on the market contain fluorine atoms.
According to the pharmacophore split principle, the trifluoromethyl conjugated pyrazole spiro cyclopropane compound containing the two dominant structural units is expected to have more remarkable biological activity and physical and chemical properties and potential application and development values.
At present, no report is available on the synthesis of trifluoromethyl conjugated pyrazole spiro cyclopropane compounds. Therefore, the research and development of the efficient sustainable method for synthesizing the trifluoromethyl conjugated pyrazole spiro cyclopropane compound by the simple and convenient way and process from the simple and easily obtained raw materials have very important theoretical significance and application prospect.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a trifluoromethyl conjugated pyrazole spiro propane compound and a synthesis method thereof, the synthesis method is efficiently completed through one-pot tandem reaction among substituted methylene cyclopropane, 1-substituted pyrazolidone and trifluoroethanol, and the invention has the advantages of wide substrate range, mild reaction conditions, good functional group tolerance and the like.
The trifluoromethyl conjugated pyrazole spiro cyclopropane compound provided by the invention has a structural general formula as follows:
wherein R is1Is naphthyl, thienyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is mono-or poly-substituted C1-4Alkyl radical, C1-4Alkoxy, halogen, phenyl, trifluoromethyl, C1-4Alkoxycarbonyl or nitro radicals, R2Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is mono-or poly-substituted C1-4Alkyl radical, C1-4Alkoxy, benzyloxy, nitro or halogen.
The invention also provides a synthesis method of the trifluoromethyl conjugated pyrazole spiro cyclopropane compound, which adopts the technical scheme that:
a method for synthesizing trifluoromethyl conjugated pyrazole spiro cyclopropane compounds comprises the following operations: mixing substituted methylene cyclopropane 1, 1-substituted pyrazolidone compounds 2, inorganic alkali, copper salt or silver salt additive and trifluoroethanol 3, heating and reacting to prepare trifluoromethyl conjugated pyrazole spiro cyclopropane compounds 4, wherein the reaction equation is as follows:
wherein R is1Is naphthyl, thienyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is mono-or poly-substituted C1-4Alkyl radical, C1-4Alkoxy, halogen, phenyl, trifluoromethyl, C1-4Alkoxycarbonyl or nitro radicals, R2Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is mono-or poly-substituted C1-4Alkyl radical, C1-4Alkoxy, benzyloxy, nitro or halogen.
Further, in the above technical solution, the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, or sodium hydroxide.
Further, in the above technical solution, the copper salt additive is copper acetate, copper chloride, cuprous chloride or cuprous iodide; the silver salt additive is silver hexafluoroantimonate or silver acetate.
Further, in the technical scheme, the molar ratio of the substituted methylene cyclopropane 1 to the 1-substituted pyrazolidone 2 to the inorganic base to the additive is 1-2:1-1.2:1-2: 0.5-1.
Further, in the above technical scheme, the reaction temperature is 40-60 ℃.
Further, in the above technical solution, the reaction is performed in an air or oxygen atmosphere.
The invention has the beneficial effects that:
compared with the prior art, the invention has the following advantages: (1) the synthesis of the trifluoromethyl conjugated pyrazole spiro cyclopropane compound is completed through one-pot tandem reaction among 1-substituted pyrazolidone, substituted methylene cyclopropane and trifluoroethanol, and the whole process has high atom economy, mild reaction conditions and simple and efficient process; (2) the raw materials are cheap and easy to obtain, the substrate has wide application range and the functional group tolerance is good; (3) air is used as an oxidant, so that the method has the characteristics of green and economy.
Drawings
FIG. 1 is an X-ray single crystal diffractogram of Compound 4aj in example 3.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Adding the compound 2a, the inorganic base, the additive and the trifluoroethanol (3) into a 15mL reaction tube in sequence, then adding the compound 1a, sealing the reaction tube under the air condition, and placing the reaction tube in a heating module to be heated and stirred for reaction. After the reaction is finished, cooling to room temperature, adding saturated ammonium chloride solution to quench the reaction, filtering with diatomite, extracting the filtrate with ethyl acetate, drying the organic phase, performing suction filtration, spin-drying, and separating by silica gel column (petroleum ether/ethyl acetate: 30/1) to obtain a light yellow oily product 4 aa.
A series of results are obtained by changing reaction conditions such as inorganic base, additives, reaction temperature, material ratio and the like of the reaction, and are shown in Table 1.
TABLE 1 Synthesis of 4aa under different conditionsa
Example 2
To a 15mL pressure resistant tube were added 2a (38mg,0.2mmol), cuprous iodide (19.1mg,0.1mmol), sodium hydroxide (8.0mg,0.2mmol), 1a (52.1mg,0.4mmol), and trifluoroethanol (3, 2mL) in that order, the reaction tube was sealed, and placed in a 50 ℃ oil bath for reaction for 12 h. After the reaction was completed, the reaction system was cooled to room temperature, and a saturated ammonium chloride solution was added to quench the reaction, and the reaction was filtered through celite, and the filtrate was extracted with ethyl acetate, and after the organic phase was dried, the filtrate was suction-filtered and spin-dried, and separated by silica gel column (petroleum ether/ethyl acetate ═ 30/1) to obtain 4aa (56.6mg, 68%) as a pale yellow oily product.1H NMR(600MHz,DMSO-d6):δ7.43(s,5H),7.27(t,J＝7.2Hz,2H),7.20(d,J＝8.4Hz,2H),6.82(t,J＝7.8Hz,1H),4.85(q,J＝9.0Hz,2H),4.63(s,1H),1.34-1.30(m,1H),1.25(s,3H),1.24(s,3H),1.18-1.11(m,2H),0.93-0.89(m,1H).13C NMR(100MHz,DMSO-d6):δ175.0,156.8,147.8,130.8,129.7,129.4,129.2,127.6,123.9(q,1JC-F＝276.1Hz),119.6,114.3,69.5,60.7(q,2JC-F＝35.1Hz),48.9,32.6,25.6,19.4,15.9,7.4.19F NMR(376MHz,DMSO-d6):δ-72.34(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H24F3N2O2 417.1784；Found 417.1779.
Example 3
Method and procedure according to example 2a,bBy changing the reactant 1 and the reactant 2, various trifluoromethyl conjugated pyrazole spiro propane compounds 4 can be synthesized, and the specific results are as follows:
areaction conditions are as follows: 1(0.4mmol),2(0.2mmol), CuI (0.1mmol), NaOH (0.2mmol), trifluoroethanol (3, 2mL), 50 ℃, 12h, air atmosphere;bthe isolation yield.
Representative product characterization data are as follows:
2,2,2-Trifluoroethyl 2-methyl-2-(7-phenyl-5-(p-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ab)
1H NMR(400MHz,DMSO-d6):δ7.43-7.40(m,5H),7.10-7.05(m,4H),4.84(qd,J1＝8.8Hz,J2＝1.6Hz,2H),4.56(s,1H),2.23(s,3H),1.31-1.28(m,1H),1.23(s,3H),1.22(s,3H),1.15-1.10(m,2H),0.89-0.86(m,1H).13C NMR(100MHz,DMSO-d6):δ175.1,156.3,145.7,130.9,129.8,129.6,129.2,128.4,127.5,124.0(q,1JC-F＝273.0Hz),114.6,69.8,60.7(q,2JC-F＝34.4Hz),48.8,32.6,25.6,20.5,19.4,15.9,7.3.19F NMR(376MHz,DMSO-d6):δ-72.31(t,J＝9.4Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found 431.1945.
2,2,2-Trifluoroethyl 2-(5-(4-ethylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methylpropanoate(4ac)
1H NMR(400MHz,DMSO-d6):δ7.43-7.40(m,5H),7.10(s,4H),4.84(q,J＝9.2Hz,2H),4.56(s,1H),2.55-2.51(m,2H),1.32-1.29(m,1H),1.23(s,6H),1.17-1.09(m,5H),0.90-0.85(m,1H).13CNMR(100MHz,DMSO-d6):δ175.1,156.5,145.9,135.0,130.9,129.6,129.2,128.6,127.5,124.0(q,1JC-F＝275.6Hz),114.5,69.9,60.7(q,2JC-F＝32.4Hz),48.8,32.6,27.8,25.6,19.4,16.4,15.9,7.3.19F NMR(376MHz,DMSO-d6):δ-72.32(t,J＝9.4Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O2 445.2097；Found 445.2086.
2,2,2-Trifluoroethyl 2-(5-(4-isopropylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ad)
1H NMR(400MHz,DMSO-d6):δ7.44-7.40(m,5H),7.15-7.09(m,4H),4.84(q,J＝8.8Hz,2H),4.55(s,1H),2.84-2.77(m,1H),1.32-1.28(m,1H),1.23(s,6H),1.18(s,3H),1.17(s,3H),1.14-1.10(m,2H),0.90-0.84(m,1H).13C NMR(100MHz,DMSO-d6):δ175.1,156.6,146.0,139.7,130.8,129.6,129.2,127.5,127.1,124.0(q,1JC-F＝275.8Hz),114.4,69.9,60.7(q,2JC-F＝35.0Hz),48.8,33.0,32.6,25.6,24.6,24.5,19.4,15.9,7.3.19F NMR(376MHz,DMSO-d6):δ-72.32(t,J＝10.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C26H30F3N2O2459.2254；Found 459.2250.
2,2,2-Trifluoroethyl 2-(5-(4-methoxyphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ae)
1H NMR(600MHz,DMSO-d6):δ7.42-7.40(m,5H),7.14-7.12(m,2H),6.89-6.87(m,2H),4.83(qd,J1＝9.0H,J2＝4.2Hz,2H),4.50(s,1H),3.71(s,3H),1.29-1.27(m,1H),1.228(s,3H),1.225(s,3H),1.14-1.11(m,2H),0.87-0.84(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,156.3,153.6,142.1,130.9,129.5,129.2,127.5,124.0(q,1JC-F＝275.7Hz),116.3,114.8,70.5,60.6(q,2JC-F＝35.1Hz),55.7,48.7,32.5,25.6,19.3,15.9,7.3.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝7.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O3447.1890；Found 447.1884.
2,2,2-Trifluoroethyl 2-(5-(4-(benzyloxy)phenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4af)
1H NMR(400MHz,CDCl3):δ7.44-7.42(m,2H),7.40-7.34(m,7H),7.33-7.29(m,1H),7.21-7.17(m,2H),6.94-6.92(m,2H),5.03(s,2H),4.53(s,1H),4.52-4.46(m,2H),1.35(s,3H),1.33(s,3H),1.31-1.28(m,1H),1.12-1.05(m,2H),0.85-0.81(m,1H).13C NMR(100MHz,CDCl3):δ175.7,156.4,152.8,142.4,137.5,130.9,129.1,128.6,127.9,127.5,127.3,123.0(q,1JC-F＝276.0Hz),116.1,115.6,70.6,70.3,60.5(q,2JC-F＝36.9Hz),48.9,32.6,25.7,18.8,16.2,7.3.19F NMR(376MHz,CDCl3):δ-73.54(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C30H30F3N2O3 523.2203；Found 523.2196.
2,2,2-Trifluoroethyl 2-(5-(4-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ag)
1H NMR(600MHz,CDCl3):δ7.39-7.35(m,5H),7.20-7.18(m,2H),6.99-6.96(m,2H),4.56(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.8Hz,2H),1.35(s,3H),1.33-1.30(m,4H),1.13-1.08(m,2H),0.88-0.85(m,1H).13C NMR(150MHz,CDCl3):δ175.6,157.01,157.00(d,1JC-F＝235.5Hz),144.3(d,4JC-F＝2.0Hz),130.7,129.2,128.6,127.4,123.0(q,1JC-F＝275.6Hz),115.5(d,3JC-F＝6.8Hz),115.4(d,2JC-F＝21.8Hz),70.1,60.6(q,2JC-F＝35.4Hz),49.0,32.7,25.7,18.8,16.2,7.4.19F NMR(565MHz,CDCl3):δ-73.56(t,J＝7.9Hz),-125.47–-125.52(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1685.
2,2,2-Trifluoroethyl 2-(5-(4-chlorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ah)
1H NMR(600MHz,DMSO-d6):δ7.45-7.41(m,5H),7.30-7.28(m,2H),7.19-7.17(m,2H),4.84(qd,J＝9.0Hz,J＝4.8Hz,2H),4.61(s,1H),1.34-1.30(m,1H),1.23(s,3H),1.22(s,3H),1.17-1.12(m,2H),0.96-0.93(m,1H).13C NMR(150MHz,DMSO-d6):δ174.9,157.5,146.5,130.5,129.9,129.23,129.16,127.6,125.8(q,1JC-F＝276.3Hz),123.0,115.8,69.6,60.7(q,2JC-F＝34.5Hz),48.9,32.8,25.5,19.5,15.8,7.5.19F NMR(565MHz,DMSO-d6):δ-72.24(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2 451.1395；Found 451.1390.
2,2,2-Trifluoroethyl 2-(5-(4-bromophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ai)
1H NMR(400MHz,DMSO-d6):δ7.45-7.39(m,7H),7.16-7.12(m,2H),4.85(qd,J1＝8.8Hz,J2＝1.6Hz,2H),4.61(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.17-1.12(m,2H),0.98-0.92(s,1H).13C NMR(100MHz,DMSO-d6):δ174.9,157.5,146.9,132.0,130.5,129.9,129.2,127.6,123.9(q,1JC-F＝276.0Hz),116.3,110.7,69.5,60.7(q,2JC-F＝34.7Hz),48.9,32.8,25.5,19.5,15.8,7.5.19F NMR(376MHz,DMSO-d6):δ-72.26(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found 495.0875.
2,2,2-Trifluoroethyl 2-methyl-2-(5-(4-nitrophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4aj)
1H NMR(600MHz,DMSO-d6):δ8.16(d,J＝9.6Hz,2H),7.50-7.45(m,5H),7.31(d,J＝9.6Hz,2H),4.90(s,1H),4.85(q,J＝9.0Hz,2H),1.42-1.39(m,1H),1.24-1.22(m,7H),1.15-1.12(m,2H).13C NMR(150MHz,DMSO-d6):δ174.5,160.9,151.8,138.7,130.5,129.8,129.4,127.8,126.1,123.9(q,1JC-F＝276.0Hz),113.4,69.1,60.9(q,2JC-F＝35.0Hz),49.0,33.1,25.4,20.0,15.6,7.9.19F NMR(565MHz,DMSO-d6):δ-72.18(t,J＝8.5 Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F3N3O4 462.1635；Found 462.1624.
2,2,2-Trifluoroethyl 2-(5-(2-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ak)
1H NMR(400MHz,DMSO-d6):δ7.59(td,J1＝8.4Hz,J2＝1.6Hz,1H),7.43-7.39(m,5H),7.23-7.13(m,2H),7.03-6.98(m,1H),4.78(s,1H),4.74(qd,J1＝8.8Hz,J2＝1.2Hz,2H),1.39-1.33(m,1H),1.22(s,3H),1.17-1.13(m,1H),1.09-1.04(m,4H),1.01-0.96(m,1H).13C NMR(100MHz,DMSO-d6):δ174.4,155.1,153.1(d,1JC-F＝241.8Hz),134.9(d,2JC-F＝8.7Hz),130.7,129.5,129.2,127.6,125.5(d,4JC-F＝2.7Hz),123.9(q,1JC-F＝275.4Hz),123.4(d,3JC-F＝7.8Hz),122.4(d,3JC-F＝3.2Hz),116.8(d,2JC-F＝20.4Hz),71.6(d,4JC-F＝6.5Hz),60.6(q,2JC-F＝34.3Hz),48.9,32.8,24.2,19.6,15.1,7.4.19F NMR(376MHz,DMSO-d6):δ-72.36(t,J＝9.4Hz),-122.68–-122.76(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1687.
2,2,2-Trifluoroethyl 2-methyl-2-(7-phenyl-5-(m-tolyl)-5,6-diazaspiro[2.4]hept-6--4-yl)propanoate(4al)
1H NMR(600MHz,DMSO-d6):δ7.43-7.41(m,5H),7.14(t,J＝7.8Hz,1H),7.05(s,1H),6.93(dd,J1＝7.8Hz,J2＝1.8Hz,1H),6.64(d,J＝7.2Hz,1H),4.84(q,J＝8.4Hz,2H),4.60(s,1H),2.28(s,3H),1.32-1.29(m,1H),1.23(s,3H),1.22(s,3H),1.16-1.11(m,2H),0.92-0.89(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,156.6,147.7,138.6,130.8,129.7,129.24,129.20,127.5,124.0(q,1JC-F＝275.6Hz),120.4,115.0,111.5,69.5,60.7(q,2JC-F＝34.1Hz),48.8,32.6,25.6,21.9,19.5,15.9,7.4.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝8.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found 431.1945.
2,2,2-Trifluoroethyl 2-(5-(3-methoxyphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4am)
1H NMR(400MHz,DMSO-d6):δ7.45-7.41(m,5H),7.16(t,J＝8.0Hz,1H),6.75-6.70(m,2H),6.42(dd,J1＝8.0Hz,J2＝2.0Hz,1H),4.84(q,J＝8.8Hz,2H),4.58(s,1H),3.73(s,3H),1.32-1.30(m,1H),1.23(s,6H),1.15-1.10(m,2H),0.93-0.90(m,1H).13C NMR(100MHz,DMSO-d6):δ175.0,160.5,157.0,149.0,130.7,130.2,129.8,129.2,127.6,124.0(q,1JC-F＝275.4Hz),106.9,105.1,100.4,69.6,60.7(q,2JC-F＝34.6Hz),55.4,48.8,32.6,25.7,19.5,15.8,7.4.19F NMR(376MHz,DMSO-d6):δ-72.30(t,J＝7.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O3447.1890；Found 447.1883.
2,2,2-Trifluoroethyl 2-(5-(3-fluorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4an)
1H NMR(600MHz,DMSO-d6):δ7.46-7.43(m,5H),7.28(q,J＝7.8Hz,1H),6.99-6.94(m,2H),6.61(td,J1＝8.4Hz,J2＝1.8Hz,1H),4.84-4.82(q,J1＝9.0Hz,J2＝2.4Hz,2H),4.64(s,1H),1.35-1.31(m,1H),1.24(s,6H),1.19-1.15(m,1H),1.13-1.11(m,1H),1.00-0.96(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,163.4(d,1JC-F＝239.9Hz),157.9,149.4(d,3JC-F＝11.4Hz),131.0(d,3JC-F＝10.1Hz),130.4,129.9,129.2,127.7,123.9(q,1JC-F＝276.0Hz),110.0,105.7(d,2JC-F＝21.8Hz),101.2(d,2JC-F＝25.8Hz),69.6,60.7(q,2JC-F＝34.7Hz),48.9,32.8,25.5,19.6,15.8,7.5.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝8.5Hz),-112.40–-112.45(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1692.
2,2,2-Trifluoroethyl 2-(5-(3-chlorophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ao)
1H NMR(600MHz,DMSO-d6):δ7.47-7.42(m,5H),7.28(t,J＝7.8Hz,1H),7.22-7.21(m,1H),7.07(dd,J1＝7.8Hz,J2＝1.8Hz,1H),6.84(dd,J1＝8.4Hz,J2＝1.8Hz,1H),4.86-4.81(m,2H),4.65(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.19-1.15(m,1H),1.13-1.10(m,1H),1.02-0.98(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,158.0,148.8,134.1,131.0,130.4,130.0,129.3,127.7,123.9(q,1JC-F＝275.0Hz),118.9,113.8,112.6,69.4,60.7(q,2JC-F＝34.5Hz),48.9,32.8,25.5,19.6,15.8,7.6.19F NMR(565MHz,DMSO-d6):δ-72.25(t,J＝9.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2 451.1395；Found 451.1386.
2,2,2-Trifluoroethyl 2-(5-(3-bromophenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ap)
1H NMR(600MHz,DMSO-d6):δ7.47-7.42(m,5H),7.373-7.366(m,1H),7.21(t,J＝8.4Hz,1H),7.11(dd,J1＝8.4Hz,J2＝1.8Hz,1H),6.97(d,J＝7.8Hz,1H),4.84(q,J＝9.0Hz,2H),4.65(s,1H),1.35-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.18-1.15(m,1H),1.14-1.10(m,1H),1.02-0.98(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,158.0,148.9,131.3,130.4,130.0,129.3,127.7,123.9(q,1JC-F＝275.4Hz),122.8,121.8,116.6,112.9,69.4,60.7(q,2JC-F＝34.8Hz),48.9,32.8,25.5,19.6,15.8,7.6.19F NMR(565MHz,DMSO-d6):δ-72.27(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found 495.0881.
2,2,2-Trifluoroethyl 2-(5-(3,5-dimethylphenyl)-7-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4aq)
1H NMR(400MHz,CDCl3):δ7.40-7.35(m,5H),6.89(s,2H),6.52(s,1H),4.62(s,1H),4.52(q,J＝8.4Hz,2H),2.30(s,6H),1.35(s,3H),1.33(s,3H),1.30-1.26(m,1H),1.12-1.04(m,2H),0.89-0.83(m,1H).13C NMR(100MHz,CDCl3):δ175.8,156.5,147.8,138.6,130.9,129.1,128.6,127.4,123.0(q,1JC-F＝275.4Hz),121.3,112.1,69.4,60.5(q,2JC-F＝36.2Hz),49.0,32.6,25.9,21.7,18.9,16.1,7.3.19F NMR(376MHz,CDCl3):δ-73.58(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O2 445.2097；Found 445.2090..
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(p-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ba)
1H NMR(600MHz,CDCl3):δ7.30-7.23(m,6H),7.17(d,J＝7.8Hz,2H),6.86-6.83(m,1H),4.61(s,1H),4.50(qd,J1＝8.4Hz,J2＝0.6Hz,2H),2.35(s,3H),1.35(s,3H),1.34(s,3H),1.32-1.30(m,1H),1.10-1.05(m,2H),0.86-0.82(m,1H).13C NMR(150MHz,CDCl3):δ175.7,156.9,147.9,139.3,129.3,129.0,127.9,127.3,123.0(q,1JC-F＝275.7Hz),119.3,114.2,69.6,60.6(q,2JC-F＝36.5Hz),49.0,32.7,25.8,21.3.18.9,16.1,7.3.19F NMR(575MHz,CDCl3):δ-73.54(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2431.1941；Found 431.1936.
2,2,2-Trifluoroethyl 2-(7-(4-(tert-butyl)phenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ca)
1H NMR(600MHz,CDCl3):δ7.39-7.37(m,2H),7.35-7.33(m,2H),7.28-7.24(m,4H),6.86-6.83(m,1H),4.61(s,1H),4.51(q,J＝8.4Hz,2H),1.38-1.36(m,1H),1.35(s,3H),1.34(s,3H),1.32(s,9H),1.13-1.07(m,2H),0.87-0.84(m,1H).13C NMR(150MHz,CDCl3):δ175.7,156.8,152.4,147.9,128.9,127.9,127.0,125.6,123.0(d,1JC-F＝275.4Hz),119.2,114.2,69.6,60.6(q,2JC-F＝36.9Hz),49.0,34.7,32.7,31.2,25.8,18.9,16.2,7.3.19F NMR(575MHz,CDCl3):δ-73.56(t,J＝9.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C27H32F3N2O2473.2410；Found 473.2398.
2,2,2-Trifluoroethyl 2-(7-(4-methoxyphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4da)
1H NMR(600MHz,DMSO-d6):δ7.37(d,J＝9.0Hz,2H),7.25(t,J＝7.8Hz,2H),7.16(d,J＝8.4Hz,2H),6.97(d,J＝8.4Hz,2H),6.8(t,J＝7.2Hz,1H),4.84(qd,J1＝9.0Hz,J2＝3.0Hz,2H),4.56(s,1H),3.78(s,3H),1.33-1.31(m,1H),1.23(s,3H),1.22(s,3H),1.13-1.09(m,2H),0.89-0.86(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,160.5,156.7,148.0,129.4,129.0,124.0(q,1JC-F＝276.9Hz),123.0,119.4,114.7,114.2,69.7,60.7(q,JC-F＝35.3Hz),55.7,48.8,32.6,25.6,19.4,15.8,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝7.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O3 447.1890；Found 447.1897.
2,2,2-Trifluoroethyl 2-(7-(4-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ea)
1H NMR(600MHz,DMSO-d6):δ7.50-7.46(m,2H),7.28-7.23(m,4H),7.18(d,J＝7.8Hz,2H),6.82(t,J＝7.2Hz,1H),4.87-4.82(m,2H),4.62(s,1H),1.33-1.29(m,1H),1.23(s,6H),1.17-1.11(m,2H),0.93-0.90(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,163.1(d,1JC-F＝245.3Hz),155.9,147.7,129.9(d,3JC-F＝7.35Hz),129.4,127.2(d,4JC-F＝3.6Hz),124.0(q,1JC-F＝277.2Hz),119.6,116.2(d,2JC-F＝22.8Hz),114.3,69.5,60.7(q,2JC-F＝35.0Hz),48.8,32.6,25.6,19.5,15.8,7.4.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝9.0Hz),-111.92–-111.95(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1679.
2,2,2-Trifluoroethyl 2-(7-(4-chlorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4fa)
1H NMR(600MHz,DMSO-d6):δ7.48-7.45(m,4H),7.27(t,J＝9.0Hz,2H),7.19(d,J＝7.8Hz,2H),6.83(t,J＝7.2Hz,1H),4.84(qd,J1＝9.0Hz,J2＝1.2Hz,2H),4.64(s,1H),1.37-1.35(m,1H),1.22(s,6H),1.18-1.14(m,2H),0.94-0.92(m,1H).13C NMR(150MHz,DMSO-d6):δ174.9,155.4,147.5,134.5,129.6,129.4,129.3,129.2,124.0(q,1JC-F＝276.3Hz),119.8,114.4,69.6,60.7(q,2JC-F＝34.7Hz),48.9,32.5,25.6,19.5,15.9,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝7.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2451.1395；Found 451.1393.
2,2,2-Trifluoroethyl 2-(7-(4-bromophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ga)
1H NMR(600MHz,CDCl3):δ7.50-7.48(m,2H),7.29-7.26(m,4H),7.25-7.23(m,2H),6.88-6.85(m,1H),4.65(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.8Hz,2H),1.34-1.30(m,7H),1.14-1.10(m,1H),1.09-1.05(m,1H),0.89-0.86(m,1H).13C NMR(150MHz,CDCl3):δ175.6,155.1,147.4,131.9,129.8,129.0,128.8,123.5,122.9(q,1JC-F＝275.6Hz),119.6,114.3,69.5,60.6(q,2JC-F＝36.8Hz),49.0,32.5,25.8,18.9,16.2,7.3.19F NMR(565MHz,CDCl3):δ-73.54(t,J＝7.9Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found 495.0874.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(4-(trifluoromethyl)phenyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ha)
1H NMR(400MHz,DMSO-d6):δ7.76(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),7.31-7.22(m,4H),6.86(t,J＝6.8Hz,1H),4.84(q,J＝9.2Hz,2H),4.72(s,1H),1.45-1.42(m,1H),1.24-1.18(m,8H),1.01-0.97(m,1H).13C NMR(100MHz,DMSO-d6):δ174.9,154.6,147.1,134.8,129.6(q,2JC-F＝35.4Hz),129.4,128.1,126.1(q,3JC-F＝3.5Hz),124.5(q,1JC-F＝269.8Hz),123.9(q,1JC-F＝275.4Hz),120.0,114.6,69.6,60.7(q,2JC-F＝35.3Hz),48.9,32.4,25.6,19.5,16.0,7.4.19F NMR(376MHz,DMSO-d6):δ-61.39(s),-72.35(t,J＝10.2Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H23F6N2O2 485.1658；Found 485.1651.
2,2,2-Trifluoroethyl 2-methyl-2-(7-(4-nitrophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ia)
1H NMR(400MHz,CDCl3):δ8.22-8.19(m,2H),7.61-7.58(m,2H),7.33-7.26(m,4H),6.93-6.89(m,1H),4.76(s,1H),4.52(q,J＝8.4Hz,2H),1.48-1.44(m,1H),1.32(s,3H),1.30(s,3H),1.23-1.18(m,2H),0.99-0.95(m,1H).13C NMR(100MHz,CDCl3):δ175.3,152.5,147.7,146.5,137.5,129.1,127.3,123.9,122.9(q,1JC-F＝275.7Hz),120.3,114.7,69.7,60.6(q,2JC-F＝36.5Hz),49.2,32.3,25.9,18.9,16.6,7.4.19F NMR(376MHz,CDCl3):δ-73.55(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F3N3O4 462.1635；Found 462.1630.
Methyl 4-(7-(2-methyl-1-oxo-1-(2,2,2-trifluoroethoxy)propan-2-yl)-6-phenyl-5,6-diazaspiro[2.4]hept-4-en-4-yl)benzoate(4ja)
1H NMR(400MHz,CDCl3):δ8.02(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,2H),7.31-7.25(m,4H),6.90-6.86(m,1H),4.69(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.2Hz,2H),3.92(s,3H),1.42-1.38(m,1H),1.34(s,3H),1.32(s,3H),1.78-1.14(m,2H),0.93-0.89(m,1H).13C NMR(100MHz,CDCl3):δ175.5,166.6,154.7,147.2,135.3,130.4,129.8,129.0,126.9,122.9(q,1JC-F＝275.4Hz),119.8,114.4,69.6,60.6(q,2JC-F＝36.4Hz),52.3,49.1,32.5,25.8,18.9,16.4,7.4.19F NMR(376MHz,CDCl3):δ-73.46(t,J＝9.8Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H26F3N2O4 475.1839；Found 475.1821.
2,2,2-Trifluoroethyl 2-(7-([1,1'-biphenyl]-4-yl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ka)
1H NMR(400MHz,CDCl3):δ7.60-7.58(m,4H),7.50-7.43(m,4H),7.38-7.34(m,1H),7.31-7.24(m,4H),6.88-6.84(m,1H),4.65(s,1H),4.52(q,J＝8.4Hz,2H),1.44-1.41(m,1H),1.37(s,3H),1.35(s,3H),1.19-1.10(m,2H),0.92-0.88(m,1H).13C NMR(100MHz,CDCl3):δ175.7,156.1,147.7,142.0,140.4,129.7,129.0,128.9,127.70,127.66,127.3,127.1,123.0(q,1JC-F＝275.4Hz),119.4,114.2,69.6,60.6(q,2JC-F＝37.3Hz),49.1,32.7,25.8,18.9,16.3,7.4.19F NMR(376MHz,CDCl3):δ-73.53(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C29H28F3N2O2 493.2097；Found 493.2088.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(o-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4la)
1H NMR(600MHz,DMSO-d6):δ7.34-7.30(m,2H),7.28-7.24(m,3H),7.18(d,J＝7.8Hz,2H),7.14(d,J＝7.8Hz,1H),6.83(t,J＝7.2Hz,1H),4.86(qd,J1＝9.0Hz,J2＝5.4Hz,2H),4.62(s,1H),2.30(s,3H),1.37(s,3H),1.27(s,3H),1.12-1.09(m,1H),0.89-0.85(m,1H),0.83-0.79(m,1H),0.70-0.67(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,157.7,148.7,137.6,131.0,129.5,129.4,129.2,126.0,124.0(q,1JC-F＝276.6Hz),119.6,114.4,68.1,60.7(q,2JC-F＝35.0Hz),48.8,33.9,26.0,20.1,19.4,14.5,7.4.19F NMR(565MHz,DMSO-d6):δ-72.30(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found 431.1937.
2,2,2-Trifluoroethyl 2-(7-(2-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ma)
1H NMR(600MHz,DMSO-d6):δ7.54-7.50(m,1H),7.36(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.32(t,J＝9.0Hz,1H),7.29-7.25(m,3H),7.18(d,J＝8.4Hz,2H),6.84(t,J＝7.8Hz,1H),4.85(q,J＝9.0Hz,2H),4.69(s,1H),1.33(s,3H),1.24(s,3H),1.16-1.12(m,1H),0.90-0.81(m,3H).13C NMR(150MHz,DMSO-d6):δ175.0,160.3(d,1JC-F＝245.1Hz),154.3,147.9,132.2(d,3JC-F＝8.1Hz),132.0(d,4JC-F＝2.0Hz),129.4,125.2(d,3JC-F＝2.7Hz),124.0(q,1JC-F＝276.0Hz),119.9,118.0(d,2JC-F＝16.2Hz),116.5(d,2JC-F＝21.5Hz),114.6,68.4,60.7(q,2JC-F＝34.8Hz),48.9,33.6,25.8,19.1,15.2,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29(t,J＝9.6Hz),-113.04–-113.08(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1689.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(m-tolyl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4na)
1H NMR(400MHz,DMSO-d6):δ7.32-7.24(m,5H),7.19-7.17(m,3H),6.81(t,J＝7.2Hz,1H),4.88-4.81(m,2H),4.60(s,1H),2.34(s,3H),1.34-1.27(m,1H),1.243(s,3H),1.235(s,3H),1.17-1.07(m,2H),0.91-0.87(m,1H).13C NMR(100MHz,DMSO-d6):δ175.0,157.0,147.8,138.5,130.7,130.4,129.4,129.0,128.1,124.6,124.0(q,1JC-F＝276.2Hz),119.5,114.3,69.5,60.7(q,2JC-F＝34.6Hz),48.8,32.6,25.6,21.4,19.5,15.9,7.4.19F NMR(376MHz,DMSO-d6):δ-72.32(t,J＝9.4Hz).HRMS(ESI)m/z:[M+H]+Calcd for C24H26F3N2O2 431.1941；Found 431.1943.
2,2,2-Trifluoroethyl 2-(7-(3-fluorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4oa)
1H NMR(400MHz,DMSO-d6):δ7.50-7.44(m,1H),7.30-7.20(m,7H),6.84(t,J＝7.2Hz,1H),4.84(qd,J1＝8.8Hz,J2＝1.2Hz,2H),4.67(s,1H),1.40-1.36(m,1H),1.23(s,3H),1.22(s,3H),1.19-1.14(m,2H),0.96-0.92(m,1H).13C NMR(100MHz,DMSO-d6):δ174.9,162.6(d,1JC-F＝242.9Hz),155.1(d,4JC-F＝2.5Hz),147.4,133.0(d,3JC-F＝7.8Hz),131.3(d,3JC-F＝8.3Hz),129.4,124.0(q,1JC-F＝276.0Hz),123.5(d,4JC-F＝3.4Hz),119.8,116.5(d,2JC-F＝21.0Hz),114.5,114.2(d,2JC-F＝22.2Hz),69.6,60.7(q,2JC-F＝34.9Hz),48.9,32.5,25.6,19.5,16.0,7.5.19FNMR(376MHz,DMSO-d6):δ-72.31(t,J＝9.0Hz),-112.21–-112.28(m).HRMS(ESI)m/z:[M+H]+Calcd for C23H23F4N2O2 435.1690；Found 435.1677.
2,2,2-Trifluoroethyl 2-(7-(3-chlorophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4pa)
1H NMR(400MHz,DMSO-d6):δ7.51-7.43(m,3H),7.36-7.33(m,1H),7.29-7.25(m,2H),7.22-7.20(m,2H),6.84(t,J＝7.2Hz,1H),4.87-4.80(m,2H),4.67(s,1H),1.37-1.34(m,1H),1.23(s,3H),1.22(s,3H),1.19-1.17(m,2H),0.96-0.93(m,1H).13C NMR(100MHz,DMSO-d6):δ174.9,154.9,147.3,134.0,132.8,131.1,129.5,129.4,127.1,125.8,124.1(q,1JC-F＝276.1Hz),119.9,114.5,69.6,60.7(q,2JC-F＝34.8Hz),48.9,32.5,25.6,19.5,16.0,7.5.19F NMR(376MHz,DMSO-d6):δ-72.31(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23ClF3N2O2 451.1395；Found 451.1394.
2,2,2-Trifluoroethyl 2-(7-(3-bromophenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4qa)
1H NMR(600MHz,DMSO-d6):δ7.64-7.62(m,2H),7.384-7.375(m,2H),7.27(t,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),6.84(t,J＝7.8Hz,1H),4.86-4.81(m,2H),4.67(s,1H),1.37-1.34(m,1H),1.23(s,3H),1.21(s,3H),1.19-1.16(m,2H),0.95-0.92(m,1H).13C NMR(150MHz,DMSO-d6):δ174.9,154.8,147.3,133.1,132.4,131.4,129.9,129.4,126.2,123.9(q,1JC-F＝275.6Hz),122.5,119.9,114.5,69.6,60.7(q,2JC-F＝35.1Hz),48.9,32.4,25.6,19.5,16.0,7.5.19F NMR(565MHz,DMSO-d6):δ-72.28(t,J＝9.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C23H23BrF3N2O2 495.0890；Found 495.0878.
2,2,2-Trifluoroethyl 2-(7-(3,4-dimethylphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4ra)
1H NMR(600MHz,DMSO-d6):δ7.25(t,J＝7.8Hz,2H),7.22(s,1H),7.18-7.16(m,3H),7.10(d,J＝7.8Hz,1H)6.81(t,J＝7.2Hz,1H),4.87-4.82(m,2H),4.58(s,1H),2.25(s,3H),2.23(s,3H),1.33-1.29(m,1H),1.23(s,6H),1.13-1.08(m,2H),0.88-0.86(m,1H).13C NMR(150MHz,DMSO-d6):δ175.1,157.1,147.9,138.1,137.2,130.2,129.4,128.6,128.2,124.9,124.0(q,1JC-F＝279.2Hz),119.4,114.2,69.6,60.7(q,2JC-F＝34.8Hz),48.8,32.7,25.6,19.8,19.7,19.5,15.8,7.4.19F NMR(565MHz,DMSO-d6):δ-72.29–-72.33(m).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O2 445.2097；Found 445.2094.
2,2,2-Trifluoroethyl 2-(7-(3,4-dimethoxyphenyl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)-2-methyl propanoate(4sa)
1H NMR(400MHz,CDCl3):δ7.30-7.24(m,4H),7.07(d,J＝1.2Hz,1H),6.87-6.81(m,3H),4.61(s,1H),4.52(qd,J1＝8.4Hz,J2＝1.2Hz,2H),3.91(s,3H),3.89(s,3H),1.42-1.39(m,1H),1.36(s,3H),1.34(s,3H),1.12-1.07(m,2H),0.87-0.84(m,1H).13C NMR(100MHz,CDCl3):δ175.7,156.5,150.1,149.1,147.9,129.0,123.4,123.0(q,1JC-F＝276.4Hz),119.5,119.3,114.2,110.9,69.7,60.6(q,2JC-F＝36.6Hz),56.02,56.00,49.0,32.6,25.8,19.0,16.3,7.5.19F NMR(376MHz,CDCl3):δ-73.55(t,J＝8.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H28F3N2O4 477.1996；Found 477.1979.
2,2,2-Trifluoroethyl 2-methyl-2-(7-(naphthalen-2-yl)-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ta)
1H NMR(600MHz,DMSO-d6):δ8.04-8.03(m,1H),7.96-7.93(m,3H),7.68(d,J＝8.4Hz,1H),7.57-7.54(m,2H),7.29(t,J＝8.4Hz,2H),7.24(d,J＝7.8Hz,2H),6.84(t,J＝7.2Hz,1H),4.89-4.84(m,2H),4.68(s,1H),1.59-1.55(m,1H),1.29(s,3H),1.27-1.25(m,4H),1.22-1.19(m,1H),0.99-0.96(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,156.2,147.6,133.4,133.2,129.5,129.0,128.7,128.3,128.0,127.3,127.1,126.2,125.5,124.0(q,1JC-F＝275.6Hz),119.7,114.4,69.7,60.7(q,2JC-F＝35.0Hz),49.0,32.8,25.7,19.6,16.1,7.7.19F NMR(565MHz,DMSO-d6):δ-72.24(t,J＝9.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C27H26F3N2O2 467.1941；Found 467.1921.
2,2,2-Trifluoroethyl 2-methyl-2-(5-phenyl-7-(thiophen-2-yl)-5,6-diazaspiro[2.4]hept-6-en-4-yl)propanoate(4ua)
1H NMR(600MHz,DMSO-d6):δ7.60(d,J＝4.8Hz,1H),7.27(t,J＝9.0Hz,2H),7.16(d,J＝8.4Hz,2H),7.13(d,J＝3.0Hz,1H),7.09-7.08(m,1H),6.83(t,J＝7.8Hz,1H),4.88-4.82(m,2H),4.65(s,1H),1.69-1.65(m,1H),1.29-1.25(m,1H),1.20(s,3H),1.19(s,3H),1.17-1.14(m,1H),0.98-0.94(m,1H).13C NMR(150MHz,DMSO-d6):δ175.0,151.5,147.5,132.7,129.5,128.7,128.1,125.7,124.0(q,1JC-F＝275.4Hz),119.8,114.4,69.6,60.7(q,2JC-F＝37.3Hz),48.9,32.6,25.7,19.3,16.3,8.0.19F NMR(565MHz,DMSO-d6):δ-72.25(t,J＝11.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C21H22F3N2O2S 423.1349；Found 423.1330.
example 4
The product trifluoromethyl conjugated pyrazole spiro cyclopropane compound 4 synthesized by the method is subjected to a series of reactions, so that a further derivative is synthesized. For example:
in a 25mL round bottom flask, 4aa (200mg,0.48mmol) is dissolved in ultra-dry dichloromethane (10mL), then the system is vacuumized and filled with argon, then the system is placed in an ice-water bath, diisobutylaluminum hydride (1.5M in tolumen, 1.6mL,2.4mmol) is slowly added dropwise to the system, then the reaction system is reacted at 0 ℃ for 3h, and after the reaction is finished, saturated ammonium chloride solution is slowly added to quench the reaction. The organic phase was extracted with ether, washed with water, dried, filtered and the organic phase was concentrated through a silica gel column (petroleum ether/ethyl acetate: 10/1) to give product 5(135.9mg, 88%) as a pale yellow solid.1H NMR(400MHz,CDCl3):δ7.47-7.44(m,2H),7.38-7.35(m,3H),7.27-7.23(m,4H),6.83-6.79(m,1H),3.98(s,1H),3.50(s,2H),1.92(br s,1H),1.74-1.68(m,1H),1.56-1.50(m,1H),1.04(s,3H),1.03(s,3H),0.84-0.78(m,1H),0.72-0.67(m,1H).13C NMR(100MHz,CDCl3):δ158.0,147.9,131.0,129.1,128.9,128.6,127.6,118.8,113.9,71.4,70.1,42.7,31.0,22.9,22.7,15.0,8.0.HRMS(ESI)m/z:[M+H]+Calcd for C21H25N2O 321.1961；Found 321.1954.
In a 50mL round bottom flask 4aa (700mg,1.68mmol) was dissolved in 1, 4-dioxane (5mL) followed by the addition of sodium hydroxide solution (0.6mL,6M) and the system was placed in a 60 ℃ oil bath for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted hydrochloric acid (2M) was slowly added to adjust the pH of the system to 1, the organic phase was extracted with ethyl acetate, washed with water, dried, filtered, the organic phase was concentrated, and separated on a silica gel column (petroleum ether/ethyl acetate 3/1) to obtain product 6(527.5mg, 94%) as a pale yellow solid.1H NMR(400MHz,DMSO-d6):δ12.76(br s,1H),7.42(s,5H),7.24(t,J＝8.8Hz,2H),7.19(d,J＝7.6Hz,2H),6.79(t,J＝6.8Hz,1H),4.60(s,1H),1.36-1.27(m,2H),1.18(s,3H),1.16(s,3H),1.11-1.06(m,1H),0.92-0.87(m,1H).13C NMR(100MHz,DMSO-d6):δ178.5,156.8,148.1,131.0,129.6,129.3,129.2,127.5,119.2,114.2,69.8,48.4,32.7,26.1,19.5,15.9,7.4.HRMS(ESI)m/z:[M+H]+Calcd for C21H23N2O2 335.1754；Found 335.1742.
In a 25mL two-necked flask, 6(150mg,0.45mmol) was dissolvedIn ultra dry dichloromethane (3mL), a drop of N, N-dimethylformamide was added, followed by vacuum and argon. The flask was placed in an ice-water bath, oxalyl chloride (86.3mg,0.68mmol) was slowly added dropwise, and after the addition was complete, the reaction was carried out at 0 ℃ for 1.5 hours. Unreacted oxalyl chloride was removed by rotation, the resulting crude product was dissolved in ultra dry dichloromethane (3mL), aluminum trichloride (90.7mg,0.68mmol) was added, and the reaction was continued at 0 ℃ for 1.5 hours under an argon atmosphere. After the reaction was completed, water was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was washed with water, dried, filtered, concentrated and separated on a silica gel column (petroleum ether/ethyl acetate 20/1) to give product 7(50.5mg, 35%) as a yellow solid.1H NMR(400MHz,CDCl3):δ7.90(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.57(d,J＝8.0Hz,1H),7.49-7.47(m,2H),7.45-7.41(m,1H),7.39-7.37(m,3H),6.85-6.81(m,1H),4.17(s,1H),1.68-1.64(m,1H),1.52-1.46(m,1H),1.27-1.23(m,1H),1.19(s,6H),0.88-0.83(m,1H).13C NMR(100MHz,CDCl3):δ197.2,156.4,146.3,135.1,130.7,129.3,128.7,128.6,127.4,118.9,115.3,113.6,69.1,45.0,31.8,17.9,17.6,11.9,11.2.HRMS(ESI)m/z:[M+H]+Calcd for C21H21N2O 317.1648；Found 317.1629.
4ai (69.3mg,0.14mmol), phenylacetylene (23. mu.L, 0.21mmol), triphenylphosphine (7.3mg,0.028mmol), potassium phosphate (36.1mg,0.17mmol), palladium acetate (1.6mg,0.007mmol) and dimethyl sulfoxide (2mL) were added successively to a 15mL reaction tube, and reacted in an 80 ℃ oil bath under argon atmosphere for 24 hours. After the reaction is finished, the reaction solution is cooled to room temperature, and sodium bicarbonate solution is slowly added to quench the reaction. Extraction with ethyl acetate, washing of the organic phase with water, drying, filtration, concentration and separation on silica gel column (petroleum ether/ethyl acetate. RTM. 30/1) gave 8(25.5mg, 35%) as a yellow solid.1H NMR(600MHz,DMSO-d6):δ7.51(d,J＝8.4Hz,2H),7.46-7.36(m,10H),7.21(d,J＝7.8Hz,2H),4.85(qd,J1＝8.4Hz,J2＝2.4Hz,2H),4.71(s,1H),1.38-1.34(m,1H),1.24(s,6H),1.19-1.13(m,2H),1.02-0.98(m,1H).13C NMR(150MHz,DMSO-d6):δ174.8,157.8,147.4,132.9,131.5,130.4,129.9,129.3,129.2,128.7,127.6,124.0(q,1JC-F＝276.2Hz),123.5,114.2,112.4,90.7,88.3,69.2,60.8(q,2JC-F＝34.8Hz),49.0,32.8,25.6,19.6,15.8,7.6.19F NMR(565MHz,DMSO-d6):δ-72.20(t,J＝8.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C31H28F3N2O2 517.2097；Found 517.2087.
4ga (48.5mg,0.098mmol), phenylacetylene (16. mu.L, 0.15mmol), triphenylphosphine (5.1mg,0.02mmol), potassium phosphate (25.5mg,0.12mmol), palladium acetate (1.1mg,0.005mmol) and dimethyl sulfoxide (2mL) were added in this order to a 15mL reaction tube, and the mixture was put in an 80 ℃ oil bath and reacted under argon atmosphere for 24 hours. After the reaction is finished, the reaction solution is cooled to room temperature, and sodium bicarbonate solution is slowly added to quench the reaction. Extraction with ethyl acetate, washing of the organic phase with water, drying, filtration, concentration and separation on silica gel column (petroleum ether/ethyl acetate 30/1) gave 9(30.9mg, 61%) as a pale yellow solid.1H NMR(400MHz,CDCl3):δ7.55-7.50(m,4H),7.41-7.39(m,2H),7.37-7.34(m,3H),7.29-7.25(m,4H),6.89-6.85(m,1H),4.66(s,1H),4.51(qd,J1＝8.4Hz,J2＝1.2Hz,2H),1.41-1.38(m,1H),1.35(s,3H),1.33(s,3H),1.62-1.12(m,2H),0.91-0.87(m,1H).13C NMR(100MHz,CDCl3):δ175.6,155.3,147.4,131.8,131.7,130.6,129.0,128.5,128.4,127.0,124.1,123.1,122.9(q,1JC-F＝276.0Hz),119.6,114.3,91.0,89.0,69.6,60.6(q,2JC-F＝36.9Hz),49.1,32.5,25.8,18.9,16.4,7.4.19F NMR(376MHz,CDCl3):δ-73.55(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H]+Calcd for C31H28F3N2O2 517.2097；Found 517.2088.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (7)
1. A trifluoromethyl conjugated pyrazole spiro cyclopropane compound has a structural general formula as follows:
wherein R is1Is naphthyl, thienyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is mono-or poly-substituted C1-4Alkyl radical, C1-4Alkoxy, halogen, phenyl, trifluoromethyl, C1-4Alkoxycarbonyl or nitro radicals, R2Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is mono-or poly-substituted C1-4Alkyl radical, C1-4Alkoxy, benzyloxy, nitro or halogen.
2. A process for the synthesis of trifluoromethyl conjugated pyrazole spirocyclopropane compounds according to claim 1, comprising the following operations: mixing substituted methylene cyclopropane 1, 1-substituted pyrazolidone compounds 2, inorganic base, copper salt or silver salt additive and trifluoroethanol 3, and heating to react to prepare trifluoromethyl conjugated pyrazole spiro cyclopropane compounds 4; the reaction equation is:
wherein R is1And R2The substituents are the same as in claim 1.
3. The process for the synthesis of trifluoromethyl conjugated pyrazole spirocyclopropane compounds according to claim 2, characterized in that: the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide.
4. The process for the synthesis of trifluoromethyl conjugated pyrazole spirocyclopropane compounds according to claim 2, characterized in that: the copper salt additive is copper acetate, copper chloride, cuprous chloride or cuprous iodide; the silver salt additive is silver hexafluoroantimonate or silver acetate.
5. The process for the synthesis of trifluoromethyl conjugated pyrazole spirocyclopropane compounds according to claim 2, characterized in that: the molar ratio of the substituted methylene cyclopropane 1 to the 1-substituted pyrazolidone 2 to the inorganic base to the additive is 1-2:1-1.2:1-2: 0.5-1.
6. The process for the synthesis of trifluoromethyl conjugated pyrazole spirocyclopropane compounds according to claim 2, characterized in that: the reaction temperature is 40-60 ℃.
7. A process for the synthesis of trifluoromethyl conjugated pyrazole spiro cyclopropane compounds according to claims 2 to 6, characterized in that: the reaction is carried out under air or oxygen atmosphere.
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