CN114262290B - 4-methylene pyrrolidine-2-thioketone compound, and synthetic method and application thereof - Google Patents
4-methylene pyrrolidine-2-thioketone compound, and synthetic method and application thereof Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052709 silver Inorganic materials 0.000 claims abstract description 10
- 239000004332 silver Substances 0.000 claims abstract description 10
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007259 addition reaction Methods 0.000 claims abstract description 5
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract 2
- 238000003786 synthesis reaction Methods 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 101710134784 Agnoprotein Proteins 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 150000004982 aromatic amines Chemical class 0.000 claims 4
- 125000003441 thioacyl group Chemical group 0.000 claims 4
- -1 thioacyl fluoride Chemical compound 0.000 abstract description 42
- 239000002994 raw material Substances 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 86
- 239000000047 product Substances 0.000 description 56
- 239000011734 sodium Substances 0.000 description 32
- 238000002474 experimental method Methods 0.000 description 28
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 27
- 230000035484 reaction time Effects 0.000 description 27
- 239000007858 starting material Substances 0.000 description 14
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000000922 anti-bactericidal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- IMWUREPEYPRYOR-UHFFFAOYSA-N pyrrolidine-2-thione Chemical compound S=C1CCCN1 IMWUREPEYPRYOR-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a 4-methylene pyrrolidine-2-thioketone compound and a synthesis method thereof, wherein N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in a formula (1) and a malonate compound shown in a formula (2) are used as raw materials, and the 4-methylene pyrrolidine-2-thioketone compound is obtained through an addition reaction of carbon ends with adjustable position and chemical selectivity to alkyne in an organic solvent at 40-82 ℃ in the presence of a silver catalyst and inorganic base. The invention also discloses a potential application value of the 4-methylene pyrrolidine-2-thioketone compound in the aspect of drug synthesis.
Description
Technical Field
The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to a 4-methylene pyrrolidine-2-thioketone compound and a synthetic method and application thereof.
Background
Thopyrrolidone is a very important class of nitrogen-containing five-membered heterocyclic compounds, which is the basic unit structure in numerous drug molecules. In recent years, the biological activity of derivative structures of thiopyrrolidone such as 4-methylene pyrrolidine-2-thioketone compounds is widely studied, and the compounds can be used for anti-inflammatory, bactericidal and anticancer drugs and can also be used as constituent fragments and basic units of various complex drug molecules. Therefore, the development of a simple and efficient method for synthesizing the 4-methylene pyrrolidine-2-thioketone compound has great research value.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, and provides a 4-methylene pyrrolidine-2-thioketone compound and a synthesis method thereof, wherein the synthesis method adopts a silver catalyst which is easy to prepare and a readily available raw material and inorganic base, and synthesizes the 4-methylene pyrrolidine-2-thioketone compound with medium to good yield through the efficient generation position and the addition reaction of a chemically selective controllable carbon end to alkyne. The method has the advantages of simple operation, atom economy, step economy, green and high efficiency, wide substrate application range and the like.
The specific technical scheme for realizing the aim of the invention is as follows:
a class of 4-methylene pyrrolidine-2-thioketone compounds has the structure of the following formula (3):
wherein,
R 1 is alkyl or aryl;
R 2 is aryl;
R 3 is hydrogen or alkyl;
R 4 is alkyl.
A method for synthesizing 4-methylene pyrrolidine-2-thioketone compounds comprises the following steps: N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in a formula (1), a malonate compound shown in a formula (2), a silver catalyst and inorganic alkali are subjected to an efficient addition reaction of carbon ends with adjustable generation positions and chemical selectivity to alkyne in an organic solvent at the temperature of 40-82 ℃ to obtain the 4-methylene pyrrolidine-2-thioketone compound; the process is shown in a reaction formula (I):
wherein,
R 1 is alkyl or aryl;
R 2 is aryl;
R 3 is hydrogen or methyl;
R 4 methyl or ethyl;
wherein the molar ratio of the N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in the formula (1) to the dicarbonyl compound shown in the formula (2) is 1:1.0-4.0; the molar ratio of the N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in the formula (1) to the silver catalyst is 1:0.05-1.0; the molar ratio of the N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in the formula (1) to the inorganic base is 1:1.0-4.0.
Wherein the palladium catalyst is AgSbF 6 、Ag 2 O、AgOTf、AgOAc、Ag 2 CO 3 、AgCO 2 CF 3 、AgBF 4 、AgF、AgNO 3 Or AgNTf 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably AgOTf.
Wherein the inorganic base is NaO t Bu、LiO t Bu、KOH、K 3 PO 4 、K 2 CO 3 、NaOH、K 2 HPO 4 、KH 2 PO 4 Or Cs 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably Cs 2 CO 3 。
Wherein the organic solvent is anhydrous acetonitrile, anhydrous toluene, anhydrous 1, 4-dioxane, anhydrous dimethyl sulfoxide, anhydrous N, N-dimethylformamide, anhydrous 1, 2-dichloroethane, anhydrous tetrahydrofuran, dichloromethane or chloroform; preferably anhydrous 1, 2-dichloroethane.
Wherein the temperature of the reaction is 40-82 ℃.
Wherein the reaction time is 4-24 hours.
Wherein, the method of the invention also comprises the steps of post-treatment and column chromatography separation and purification; wherein, the separation and purification are carried out by column chromatography with the mixed solvent of ethyl acetate and petroleum ether as eluent, and the volume ratio of the mixed solvent of ethyl acetate and petroleum ether is 1:3-1:5.
In one embodiment, the method of the present invention comprises: N-propargyl-N-alkyl/aryl amine thioacyl fluoride shown in a formula (1), a malonate compound shown in a formula (2) and an inorganic base of a silver catalyst are placed in an organic solvent, and TLC monitoring is carried out at 60 ℃ until the reaction of the raw material (1) is completed; filtering to remove precipitate in the reaction system, concentrating the filtrate under reduced pressure, and separating the residue by column chromatography with petroleum ether/ethyl acetate mixed solvent to obtain 4-methylene pyrrolidine-2-thioketone shown in formula (3).
The method for synthesizing the 4-methylene pyrrolidine-2-thioketone compound is characterized in that N-propargyl-N-alkyl/aryl amine thioacyl fluoride, malonate compounds, silver catalysts and inorganic alkali are placed in an organic solvent, and the 4-methylene pyrrolidine-2-thioketone compound is obtained through efficient intermolecular series experiments at 60 ℃; and (3) performing post-treatment and column chromatography separation and purification to obtain the purified 4-methylene pyrrolidine-2-thioketone compound.
The invention also provides application of the 4-methylene pyrrolidine-2-thioketone compound in the aspects of biological pharmacy and materials.
The invention adopts the silver catalyst which is easy to prepare and easy to obtain and the inorganic alkali to obtain the 4-methylene pyrrolidine-2-thioketone compound through the addition reaction of the carbon end to alkyne with high-efficiency generation position and controllable chemical selectivity. The method has the advantages of simple operation, green and high efficiency, economical atomic steps, wide substrate application range and the like. The 4-methylene pyrrolidine-2-thioketone synthesized by the invention is a novel compound, is synthesized for the first time, and can be applied to biological pharmacy and special preparations.
Drawings
FIGS. 1 to 10 show nuclear magnetic resonance of 4-methylenepyrrolidine-2-thione compounds synthesized according to examples 1 to 10 of the present invention 1 H NMR、 13 C NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, but the scope of the present invention is not limited to the following examples. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.
Example 1
Adding AgNTf into the dried reaction tube 2 (7.8 mg,0.02 mmol) and Cs 2 CO 3 (162.9 mg,0.5 mmol) and 4mL of anhydrous 1, 2-dichloroethane-dissolved phenyl (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride (53.8 mg,0.2 mmol) were added and dimethyl malonate (66.0 mg,0.5 mmol) was added using a microinjection syringe. The reaction was allowed to react at 60 ℃ for 4 hours, TLC monitored the complete consumption of the starting N-propargyl-N-alkyl/aryl amine thioacyl fluoride, then the solvent was spun dry under vacuum and the residue purified by silica gel column chromatography to give 62.5mg of pure product. The structure is shown as a formula (3-1). The yield thereof was found to be 82%. (1. Under the same conditions, the yield was 40% when sodium hydroxide was used instead of cesium carbonate, 2. Under the same conditions, the yield was 29% when sodium tert-butoxide was used instead of cesium carbonate, 3. Under the same conditions, the yield was 18% when lithium tert-butoxide was used instead of cesium carbonate, 4. Under the same conditions, the yield was 9% when sodium phosphate was used instead of cesium carbonate, 5. Under the same conditions, the yield was 30% when potassium hydroxide was used instead of cesium carbonate, 6. Under the same conditions, the yield was 30% when dipotassium phosphate was used instead of cesium carbonate, 7. Under the same conditions, the yield was 21% when potassium dihydrogen phosphate was used instead of cesium carbonate, 8. Under the same conditions, agSbF) 6 Instead of AgNTf 2 When the yield was 54%;9. under the same conditions, ag 2 O replaces AgNTf 2 When the yield was 54%;10. under the same conditions, agOAc replaces AgNTf 2 When the yield was 58%;11. under the same conditions, ag 2 CO 3 Instead of AgNTf 2 When the yield was 50%;12. AgCO under the same conditions as above 2 CF 3 Instead of AgNTf 2 When the yield was 49%;13. AgBF under the same conditions as above 4 Instead of AgNTf 2 Yield at the time of53%;14. under the same conditions, agF replaces AgNTf 2 When the yield is 45%;15. AgNO under the same conditions as above 3 Instead of AgNTf 2 When the reaction was carried out, the yield was 43%;16. under the same conditions, agOTf replaces AgNTf 2 When the reaction was carried out, the yield was 66%;17. under the same conditions, when anhydrous acetonitrile is used for replacing anhydrous dichloroethane, the yield is 70%;18. under the same conditions, when anhydrous tetrahydrofuran is used for replacing anhydrous dichloroethane, the yield is 54%;19. under the same conditions, when anhydrous thionyl chloride is used for replacing anhydrous dichloroethane, the yield is 15%;20. under the same conditions, when anhydrous N, N-dimethylformamide replaces anhydrous dichloroethane, the yield is 20%;21. under the same conditions, when anhydrous dichloromethane is used for replacing the anhydrous dichloroethane, the yield is 75%;22. the yield was 60% when anhydrous chloroform was used instead of anhydrous dichloroethane. 23. Under the same conditions, the temperature is 80 ℃ instead of 60 ℃, and the yield is 73%;24. under the same conditions, the temperature is 50 ℃ instead of 60 ℃, and the yield is 65%;25. under the same conditions, the temperature is 40 ℃ instead of 60 ℃, and the yield is 40%;26. under the same conditions, the temperature is 70 ℃ instead of 60 ℃, and the yield is 70%;27. under the same conditions, the temperature was 82℃instead of 60℃and the yield was 69%.28. Under the same conditions, no AgNTf 2 At the time, the yield was 50
Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 1, the product: 1 H NMR(500MHz,CDCl 3 )δ7.61–7.54(m,2H),7.50(t,J＝7.9Hz,2H),7.44(d,J＝7.4Hz,2H),7.38(dd,J＝16.1,7.7Hz,3H),7.31(d,J＝7.3Hz,1H),6.78(s,1H),4.87(d,J＝1.8Hz,2H),3.61(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.6,165.1,139.6,134.3,129.5,129.2,129.1,128.6,128.4,128.4,128.4,125.1,75.5,63.6,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 19 NNaO 4 S 404.0933,found 404.0926。
example 2
The experimental procedure of this example is essentially the same as that of example 1, using (3-phenylprop-2-yn-1-yl) (p-tolyl) amino as starting materialThe thioacyl fluoride and dimethyl malonate react for 6 hours at 60 ℃, and the obtained product is shown as a structural formula (3-2). The yield was 90%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 2, the product: 1 H NMR(500MHz,CDCl 3 )δ7.43(dd,J＝7.8,3.3Hz,4H),7.37(t,J＝7.6Hz,2H),7.30(t,J＝7.0Hz,3H),6.77(s,1H),4.85(d,J＝1.7Hz,2H),3.61(s,6H),2.39(s,3H). 13 C NMR(125MHz,CDCl 3 )δ194.4,165.1,138.5,136.9,134.2,130.0,129.1,128.5,128.4,128.3,124.9,75.4,63.7,53.3,21.2.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 4 S 418.1089,found 418.1079。
example 3
The experimental procedure of this example was essentially the same as that of example 1, except that (4-fluorophenyl) (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride and dimethyl malonate were used as the starting materials, and the reaction time was 10 hours at 60℃to obtain a product represented by the following formula (3-3). The yield was 71%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 3, the product: 1 H NMR(500MHz,CDCl 3 )δ7.58–7.51(m,2H),7.43(d,J＝7.5Hz,2H),7.37(dd,J＝10.2,4.8Hz,2H),7.30(t,J＝7.3Hz,1H),7.21–7.15(m,2H),6.78(s,1H),4.84(d,J＝1.8Hz,2H),3.61(s,6H). 13 C NMR(126MHz,CDCl 3 )δ195.0,165.0,161.8(d,J＝249.6Hz),135.4(d,J＝3.3Hz),134.1,129.4,128.8,128.5,128.5,128.4,127.2(d,J＝8.7Hz),116.4(d,J＝23.0Hz),75.3,63.6,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 FNNaO 4 S 422.0839,found 422.0844。
example 4
The experimental method of the embodiment is basically and practicallyExample 1 the starting materials used in this example were (2-methylphenyl) (3-phenylprop-2-yn-1-yl) aminothioformylfluoride and dimethyl malonate, and the reaction time was 6 hours at 60℃to give the product represented by the structural formula (3-4). The yield was 87%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 5, the product: 1 H NMR(600MHz,CDCl 3 )δ7.41(d,J＝7.3Hz,2H),7.39–7.28(m,6H),7.23(d,J＝7.1Hz,1H),6.76(s,1H),4.77(d,J＝1.8Hz,2H),3.63(s,6H),2.28(s,3H). 13 C NMR(150MHz,CDCl 3 )δ194.6,165.0,138.1,135.4,134.1,131.6,129.9,129.4,129.0,128.6,128.4,128.4,127.5,126.1,74.5,63.3,53.2,17.2.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 4 S 418.1089,found 418.1095。
example 5
The experimental procedure of this example was essentially the same as that of example 1, except that (3-chlorophenyl) (3-phenylprop-2-yn-1-yl) aminothioformylfluoride and dimethyl malonate were used as the starting materials, and the reaction time was 8 hours at 60℃to obtain the product represented by the following formula (3-5). The yield was 75%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 5, the product: 1 H NMR(500MHz,CDCl 3 )δ7.61(s,1H),7.51(d,J＝8.0Hz,1H),7.42(t,J＝7.9Hz,3H),7.37(t,J＝7.6Hz,3H),7.30(t,J＝7.3Hz,1H),6.79(s,1H),4.85(d,J＝1.3Hz,2H),3.60(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.9,164.9,140.5,134.9,134.1,130.4,129.5,128.6,128.5,128.5,128.4,128.4,125.3,123.4,75.4,63.3,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 ClNNaO 4 S 438.0543,found 438.0538。
example 6
The experimental procedure of this example was essentially the same as that of example 1, except that benzyl (3-phenylprop-2-yn-1-yl) aminothioformyl fluoride and dimethyl malonate were used as raw materials, and the reaction time at 60℃was 15 hours, and the obtained product was represented by the following structural formula (3-6). The yield was 69%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 6, the product: 1 H NMR(600MHz,CDCl 3 )δ7.41–7.26(m,10H),6.62(s,1H),5.10(s,2H),4.37(s,2H),3.56(s,6H). 13 C NMR(150MHz,CDCl 3 )δ194.3,164.9,134.2,129.0,129.0,128.5,128.3,128.2,128.2,128.2,74.6,59.5,53.1,51.6.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 4 S 418.1089,found 418.1077。
example 7
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-methoxyphenyl) prop-2-yn-1-yl) (phenyl) aminothioformylfluoride and dimethyl malonate were used as the starting materials, and the reaction time was 10 hours at 60℃to obtain the product represented by the following structural formula (3-7). The yield thereof was found to be 57%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 7, the product: 1 H NMR(500MHz,CDCl 3 )δ7.56(d,J＝7.7Hz,2H),7.49(t,J＝7.8Hz,2H),7.41(dd,J＝11.5,8.2Hz,3H),6.90(d,J＝8.7Hz,2H),6.69(s,1H),4.86(d,J＝1.5Hz,2H),3.82(s,3H),3.65(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.7,165.1,159.6,139.5,130.1,129.4,128.7,128.3,126.8,126.6,125.1,113.7,75.3,63.7,55.2,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 5 S 434.1038,found 434.1042。
example 8
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (2-fluorophenyl) prop-2-yn-1-yl) (phenyl) aminothioformyl fluoride and dimethyl malonate were used as the starting materials, and the reaction time was 10 hours at 60℃to obtain the product represented by the following structural formula (3-8). The yield was 77%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 8, the product: 1 H NMR(500MHz,CDCl 3 )δ7.61–7.54(m,3H),7.49(dd,J＝10.6,5.1Hz,2H),7.38(t,J＝7.4Hz,1H),7.34–7.28(m,1H),7.15(t,J＝7.3Hz,1H),7.10–7.03(m,1H),6.85(s,1H),4.90(d,J＝1.8Hz,2H),3.62(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.1,164.8,160.0(d,J＝247.5Hz),139.3,131.7,130.3(d,J＝8.3Hz),129.8(d,J＝2.2Hz),129.3,128.3,125.0,123.9(d,J＝3.7Hz),122.1(d,J＝13.5Hz),121.6(d,J＝4.7Hz),115.0(d,J＝22.5Hz),75.4,63.3,53.2.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 FNNaO 4 S 422.0839,found 422.0842。
example 9
The experimental procedure of this example was essentially the same as that of example 1, except that phenyl (4-phenylbut-3-yn-2-yl) aminothioformyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 24 hours at 60℃to obtain a product represented by the following structural formula (3-9). The yield was 60%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 9, the product: 1 H NMR(600MHz,CDCl 3 )δ7.60–7.16(m,10H),6.76(s,1H),5.06(q,J＝6.4Hz,1H),3.62(d,J＝71.9Hz,6H),1.50(d,J＝6.4Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ194.3,165.7,165.2,140.5,135.5,135.1,129.6,128.8,128.6,128.2,127.5,126.8,120.3,92.7,70.9,53.3,51.4,22.9.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 4 S 418.1089,found 418.1082. 1 H NMR(600MHz,CDCl 3 )δ7.60–7.16(m,10H),6.51(s,1H),4.93(q,J＝6.3Hz,1H),3.62(d,J＝71.9Hz,6H),1.45(d,J＝6.5Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ194.3,165.2,164.1,138.5,135.4,134.2,129.3,128.6,128.5,128.2,127.2,126.7,120.3,74.8,69.1,53.1,51.4,19.6.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 4 S 418.1089,found 418.1082。
example 10
The experimental procedure of this example was essentially the same as that of example 1, and the starting materials used in this example were phenyl (3-phenylprop-2-yn-1-yl) aminothioformylfluoride and diethyl malonate, and the reaction time was 24 hours at 60℃to give the product represented by the structural formula (3-10). The yield was 68%. Nuclear magnetic resonance 1 H NMR、 13 The C NMR spectrum is shown in FIG. 10, the product: 1 H NMR(500MHz,CDCl 3 )δ7.55(d,J＝8.2Hz,2H),7.50(t,J＝7.9Hz,4H),7.41–7.33(m,3H),7.28(dd,J＝15.0,7.8Hz,1H),6.75(s,1H),4.87(s,2H),4.16–3.99(m,4H),1.11(t,J＝7.1Hz,6H). 13 C NMR(125MHz,CDCl 3 )δ195.0,164.4,139.6,134.3,129.4,128.9,128.8,128.7,128.3,125.1,75.2,63.7,62.3,13.6.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 23 H 23 NNaO 4 S 432.1246,found 432.1237。
example 11
The experimental procedure of this example was essentially the same as that of example 1, except that (2-fluorophenyl) (3-phenylprop-2-yn-1-yl) aminothioformylfluoride and dimethyl malonate were used as the starting materials, and the reaction time was 8 hours at 60℃to obtain the product represented by the following structural formula (3-11). The yield was 72%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.47–7.39(m,2H),7.30–7.20(m,2H),5.57(s,1H),5.45(s,1H),4.71(s,2H),3.86(s,6H). 13 C NMR(125MHz,CDCl 3 )δ195.6,166.0,157.1(d,J＝253.3Hz),137.6,130.7(d,J＝7.9Hz),128.8,127.0(d,J＝12.2Hz),124.9(d,J＝3.8Hz),117.1(d,J＝19.1Hz),113.6,75.6,60.2(d,J＝2.7Hz),53.6.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 15 H 14 FNNaO 4 S 346.0526,found 346.0513。
example 12
The experimental procedure of this example was essentially the same as that of example 1, except that (4-chlorophenyl) (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride and dimethyl malonate were used as the starting materials, and the reaction time was 10 hours at 60℃to obtain the product represented by the structural formula (3-12). The yield was 79%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.54(d,J＝8.6Hz,2H),7.44(dd,J＝14.2,8.1Hz,4H),7.37(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),6.79(s,1H),4.85(d,J＝1.0Hz,2H),3.60(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.8,164.9,137.9,134.1,134.0,129.6,129.5,128.6,128.5,128.4,128.4,126.4,75.4,63.3,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 ClNNaO 4 S 438.0543,found 438.0538。
example 13
The experimental procedure of this example was essentially the same as that of example 1, except that (3-methoxyphenyl) (3-phenylprop-2-yn-1-yl) aminothioformylfluoride and dimethyl malonate were used as the starting materials, and the reaction time was 9 hours at 60℃to obtain the product represented by the following structural formula (3-13). The yield was 76%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.44–7.35(m,5H),7.30(t,J＝7.3Hz,1H),7.18(t,J＝2.1Hz,1H),7.10(dd,J＝7.8,1.4Hz,1H),6.92(dd,J＝8.3,2.3Hz,1H),6.78(s,1H),4.86(d,J＝1.6Hz,2H),3.83(s,3H),3.60(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.4,165.0,160.2,140.5,134.2,130.2,129.1,129.0,128.5,128.4,116.9,114.0,111.0,75.5,63.6,55.5,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 5 S 434.1038,found 434.1036。
example 14
The experimental method of this example is basically the same as that of example 1, and the raw materials adopted in this example are naphthyl (3-phenylprop-2-yn-1-yl) aminothioformyl fluoride and dimethyl malonate, and the reaction time is 18 hours at 60 ℃, and the obtained product is shown as structural formula (3-14). The yield was 73%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.95(d,J＝8.5Hz,2H),7.83(dd,J＝7.5,5.4Hz,1H),7.62–7.53(m,3H),7.51(d,J＝7.2Hz,1H),7.46(d,J＝7.5Hz,2H),7.40(t,J＝7.6Hz,2H),7.32(t,J＝7.3Hz,1H),6.79(s,1H),5.00–4.87(m,2H),3.70(d,J＝5.2Hz,6H). 13 C NMR(125MHz,CDCl 3 )δ196.0,165.2,165.1,136.3,134.6,134.2,129.9,129.7,129.2,128.9,128.7,128.4,128.3,127.5,126.8,125.7,124.6,122.2,74.8,64.3,53.4,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 25 H 21 NNaO 4 S 454.1089,found 454.1089。
example 15
The experimental procedure of this example was essentially the same as that of example 1, except that (4-bromophenyl) (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 11 hours at 60℃to obtain a product represented by the following structural formula (3-15). The yield was 75%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.61(dd,J＝9.1,2.2Hz,2H),7.48(d,J＝8.7Hz,2H),7.43(d,J＝7.4Hz,2H),7.37(t,J＝7.5Hz,2H),7.30(t,J＝7.3Hz,1H),6.79(s,1H),4.85(d,J＝1.6Hz,2H),3.59(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.7,164.9,138.4,134.1,132.5,129.5,128.5,128.5,128.4,128.4,126.7,121.9,75.4,63.2,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 BrNNaO 4 S 482.0038,found 482.0036。
example 16
The experimental procedure of this example was essentially the same as that of example 1, except that the starting materials used in this example were cyclohexyl (3-phenylprop-2-yn-1-yl) aminothioformyl fluoride and dimethyl malonate, and the reaction time was 18 hours at 60℃to give the product represented by the following structural formula (3-16). The yield was 78%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.35(dt,J＝15.1,7.5Hz,4H),7.30–7.24(m,1H),6.71(s,1H),4.87–4.64(m,1H),4.45(d,J＝1.6Hz,2H),3.55(s,6H),2.00(d,J＝7.0Hz,2H),1.87(t,J＝10.1Hz,2H),1.75(d,J＝12.9Hz,1H),1.52–1.39(m,4H),1.49–1.27(m,1H). 13 C NMR(125MHz,CDCl 3 )δ192.4,165.1,134.3,129.4,128.8,128.5,128.3,128.2,74.9,56.7,56.0,53.0,29.0,25.4,25.2.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 25 NNaO 4 S 410.1402,found 410.1390。
example 17
The experimental procedure of this example was essentially the same as that of example 1, except that hexyl (3-phenylprop-2-yn-1-yl) aminothioformyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 20 hours at 60℃to obtain a product represented by the following structural formula (3-17). The yield was 59%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.34(q,J＝7.8Hz,4H),7.30–7.25(m,1H),6.70(s,1H),4.51(d,J＝1.4Hz,2H),3.88–3.83(m,2H),3.55(s,6H),1.77–1.68(m,2H),1.40–1.29(m,6H),0.90(t,J＝6.9Hz,3H). 13 C NMR(125MHz,CDCl 3 )δ193.2,167.4,165.0,134.3,129.4,128.7,128.5,128.3,128.2,74.7,60.2,53.1,53.1,51.1,48.1,31.4,26.3,25.9,22.5,14.0.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 27 NNaO 4 S 412.1559,found 412.1553。
example 18
The experimental procedure of this example was essentially the same as that of example 1, except that (2- (2-thiophene)) ethyl (3-phenylprop-2-yn-1-yl) aminothioformylfluoride and dimethyl malonate were used as raw materials, and the reaction time at 60℃was 5 hours, and the obtained product was represented by the structural formula (3-18). The yield thereof was found to be 61%. The product is: 1 H NMR(600MHz,CDCl 3 )δ7.37–7.30(m,4H),7.29–7.24(m,1H),7.20(dd,J＝5.1,1.2Hz,1H),6.96(dd,J＝5.1,3.4Hz,1H),6.89(dd,J＝3.4,1.2Hz,1H),6.60(t,J＝1.8Hz,1H),4.27(d,J＝1.9Hz,2H),4.09(t,J＝6.9Hz,2H),3.55(s,6H),3.36–3.25(m,2H). 13 C NMR(151MHz,CDCl 3 )δ193.48,164.94,140.12,134.18,129.38,128.75,128.39,128.25,128.18,127.15,125.93,124.29,74.66,61.37,53.10,49.92,25.97.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 21 NNaO 4 S 2 438.0810,found 438.0811。
example 19
The experimental procedure of this example was essentially the same as that of example 1, except that (4-trifluoromethylphenyl) (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 22 hours at 60℃to obtain the product represented by the following structural formula (3-19). The yield was 71%. The product is: 1 H NMR(500MHz,CDCl3)δ7.82–7.69(m,4H),7.44(d,J＝7.4Hz,2H),7.38(dd,J＝10.3,4.8Hz,2H),7.31(dd,J＝8.3,6.3Hz,1H),6.82(s,1H),4.90(d,J＝1.8Hz,2H),3.61(s,6H). 13 C NMR(125MHz,CDCl 3 )δ195.1,164.9,142.4,134.1,130.0(q,J＝33.0Hz),129.7,128.5,128.5,128.4,128.3,126.5(q,J＝3.7Hz),125.3,124.7,75.6,63.0,53.4.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 18 F 3 NNaO 4 S 472.0807,found 472.0809。
example 20
The experimental procedure of this example was essentially the same as that of example 1, except that (4-iodophenyl) (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 6 hours at 60℃to obtain a product represented by the following structural formula (3-20). The yield was 70%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.81(d,J＝8.4Hz,2H),7.43(d,J＝7.5Hz,2H),7.37(t,J＝8.3Hz,4H),7.30(t,J＝7.3Hz,1H),6.79(s,1H),4.84(d,J＝1.6Hz,2H),3.60(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.7,164.9,139.1,138.5,134.1,129.5,128.6,128.5,128.4,128.4,126.8,93.4,75.5,63.2,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 INNaO 4 S 529.9899,found 529.9894。
example 21
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-fluorophenyl) prop-2-yn-1-yl) (phenyl) aminothioformyl fluoride and dimethyl malonate were used as the starting materials, and the reaction time was 12 hours at 60℃to obtain the product represented by the following structural formula (3-21). The yield was 62%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.55(d,J＝7.7Hz,2H),7.52–7.43(m,4H),7.38(dd,J＝10.8,3.9Hz,1H),7.06(t,J＝8.6Hz,2H),6.73(s,1H),4.86(d,J＝0.8Hz,2H),3.64(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.3,165.0,162.5(d,J＝250.0Hz),139.4,130.5(d,J＝8.7Hz),130.3(d,J＝3.7Hz),129.4,128.9(d,J＝1.0Hz),128.4,128.0,125.0,115.4,115.2,75.3,63.4,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 FNNaO 4 S 422.0839,found 422.0829。
example 22
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-chlorophenyl) prop-2-yn-1-yl) (phenyl) aminothioformyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 12 hours at 60℃to obtain the product represented by the following structural formula (3-22). The yield was 75%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.55(d,J＝7.7Hz,2H),7.49(t,J＝7.7Hz,2H),7.43–7.32(m,5H),6.72(s,1H),4.86(d,J＝1.2Hz,2H),3.64(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.2,164.9,139.3,134.3,132.6,129.9,129.6,129.4,128.6,128.4,128.0,125.0,75.4,63.4,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 ClNNaO 4 S 438.0543,found 438.0537。
example 23
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-bromophenyl) prop-2-yn-1-yl) (phenyl) aminothioformylfluoride and dimethyl malonate were used as raw materials, and the reaction time was 10 hours at 60℃to obtain the product represented by the structural formula (3-23). The yield was 85%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.55(d,J＝8.4Hz,2H),7.49(t,J＝7.2Hz,5H),7.34(d,J＝8.1Hz,2H),6.70(s,1H),4.85(s,2H),3.64(d,J＝0.9Hz,6H). 13 C NMR(125MHz,CDCl 3 )δ194.2,164.9,139.3,133.0,131.9,131.5,130.1,129.4,128.4,128.0,125.0,122.5,75.4,63.4,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 BrNNaO 4 S 482.0038,found 482.0032. 1 H NMR(500MHz,CDCl 3 )δ7.55(d,J＝8.4Hz,2H),7.42–7.37(m,5H),7.09(d,J＝8.1Hz,2H),6.74(s,1H),4.99(d,J＝1.6Hz,2H),3.88(d,J＝0.9Hz,6H). 13 C NMR(125MHz,CDCl 3 )δ193.3,166.3,139.5,133.8,131.9,130.0,130.0,129.5,128.6,127.3,125.5,122.5,77.6,60.6,53.7.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 BrNNaO 4 S 482.0038,found 482.0032。
example 24
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-trifluoromethylphenyl) prop-2-yn-1-yl) (phenyl) aminothioformyl fluoride and dimethyl malonate were used as raw materials, and the reaction time was 24 hours at 60℃to obtain the product represented by the following structural formula (3-24). The yield thereof was found to be 63%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.63(d,J＝8.3Hz,2H),7.61–7.47(m,4H),7.42–7.34(m,1H),7.35(d,J＝8.2Hz,2H),6.85(t,J＝2.2Hz,1H),5.04(d,J＝2.5Hz,2H),3.89(s,6H). 13 C NMR(125MHz,CDCl 3 )δ193.2,166.2,139.5,138.3,131.9,129.5,128.8,128.7,127.1,125.7(q,J＝3.7Hz),125.5,125.0,122.6,77.6,60.5,53.7.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C22H18F3NNaO4S 472.0807,found 472.0809. 1 H NMR(500MHz,CDCl 3 )δ7.63(d,J＝8.3Hz,2H),7.61–7.47(m,4H),7.40–7.34(m,1H),7.35(d,J＝8.2Hz,2H),6.81(s,1H),4.89(d,J＝1.7Hz,2H),3.61(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.0,164.8,139.3,137.7,131.4,129.4,128.8,128.4,127.9,125.2(q,J＝3.7Hz),125.0,124.9,122.8,75.5,63.3,53.4.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 18 F 3 NNaO 4 S 472.0807,found 472.0794。
example 25
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (3-fluorophenyl) prop-2-yn-1-yl) (phenyl) aminothioformyl fluoride and dimethyl malonate were used as the starting materials, and the reaction time at 60℃was 15 hours, and the obtained product was represented by the following structural formula (3-25). The yield was 71%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.56(d,J＝8.0Hz,2H),7.50(t,J＝7.8Hz,2H),7.40–7.31(m,2H),7.25(d,J＝7.9Hz,1H),7.17(d,J＝10.0Hz,1H),7.01(td,J＝8.3,2.3Hz,1H),6.74(s,1H),4.86(d,J＝1.7Hz,2H),3.65(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.2,164.9,162.6(d,J＝243.7Hz),139.4,136.3(d,J＝8.0Hz),130.4,129.9(d,J＝8.3Hz),129.4,128.4,127.9(d,J＝2.2Hz),125.0,124.2(d,J＝2.9Hz),115.4(d,J＝46.2Hz),115.3(d,J＝2.6Hz),115.1,75.5,63.3,53.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 21 H 18 FNNaO 4 S 422.0839,found 422.0834。
example 26
The experimental procedure of this example was essentially the same as that of example 1, except that (3- (4-cyanophenyl) prop-2-yn-1-yl) (phenyl) aminothioformylfluoride and dimethyl malonate were used as raw materials, and the reaction time was 15 hours at 60℃to obtain the product represented by the structural formula (3-26). The yield was 66%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.78(d,J＝7.9Hz,1H),7.71(s,1H),7.60(d,J＝7.6Hz,1H),7.57–7.45(m,5H),7.45–7.37(m,1H),6.76(s,1H),4.88(d,J＝1.5Hz,2H),3.66(s,6H). 13 C NMR(125MHz,CDCl 3 )δ193.9,164.8,139.2,135.5,132.5,132.3,132.1,131.6,129.6,129.4,128.5,126.8,125.0,118.3,112.5,75.5,63.1,53.5.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C22H18N2NaO4S 429.0885,found 429.0872. 1 H NMR(500MHz,CDCl 3 )δ7.60(d,J＝7.6Hz,1H),7.57–7.45(m,7H),7.45–7.37(m,1H),6.80(t,J＝2.2Hz,1H),5.02(d,J＝2.4Hz,2H),3.90(s,6H). 13 C NMR(125MHz,CDCl 3 )δ193.0,166.1,139.4,136.1,132.8,132.4,131.6,131.6,129.7,129.3,128.8,126.3,125.5,118.1,113.2,77.6,60.3,53.8.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 18 N 2 NaO 4 S 429.0885,found 429.0872。
example 27
The experimental procedure of this example was essentially the same as that of example 1, except that (4-methoxyphenyl) (3-phenylprop-2-yn-1-yl) aminothioacyl fluoride and dimethyl malonate were used as the starting materials, and the reaction time was 6 hours at 60℃to obtain the product represented by the following structural formula (3-27). The yield was 74%. The product is: 1 H NMR(500MHz,CDCl 3 )δ7.52–7.28(m,7H),7.04–6.96(m,2H),6.77(s,1H),4.83(d,J＝1.7Hz,2H),3.84(s,3H),3.60(s,6H). 13 C NMR(125MHz,CDCl 3 )δ194.4,165.1,159.1,134.2,132.2,129.1,129.0,128.5,128.3,128.3,126.4,114.6,75.3,63.8,55.5,53.2.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 22 H 21 NNaO 5 S 434.1038,found 434.1033。
example 28
The experimental procedure of this example was essentially the same as that of example 1, except that ethyl 4- ((thiocarboxyfluoro) (3-phenylprop-2-yn-1-yl) amino) benzoate and dimethyl malonate were used as the starting materials, and the reaction time was 19 hours at 60℃to give the product represented by the structural formula (3-28). The yield was 71%. The product is: 1 H NMR(600MHz,CDCl 3 )δ8.16(d,J＝8.5Hz,2H),7.73(d,J＝8.5Hz,2H),7.44(d,J＝7.5Hz,2H),7.37(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),6.81(s,1H),4.91(s,2H),4.40(q,J＝7.1Hz,2H),3.60(s,6H),1.41(t,J＝7.1Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ194.8,165.5,164.9,143.2,134.1,130.7,129.9,129.5,128.5,128.4,128.4,124.6,75.7,63.0,61.3,53.3,14.3.HRMS(ESI-TOF)m/z:[M+Na] + calculated for C 24 H 23 NNaO 6 S476.1144,found 476.1140。
Claims (1)
1. a method for synthesizing a 4-methylene pyrrolidine-2-thioketone compound, which is characterized in that the compound has the structure of the following formula (3):
wherein,
R 1 is alkyl or aryl;
R 2 is aryl;
R 3 is hydrogen or alkyl;
R 4 is alkyl;
the synthesis process comprises the following steps: N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in a formula (1), a compound shown in a formula (2), a silver catalyst and inorganic alkali are subjected to addition reaction of carbon ends with adjustable position and chemical selectivity to alkyne in an organic solvent at the temperature of 40-82 ℃ for 4-24 hours, and the 4-methylene pyrrolidine-2-thioketone compound is obtained through post-treatment and column chromatography separation and purification; the process is shown in a reaction formula (I):
the molar ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the compound shown in the formula (2) is 1:1.0-4.0; the mol ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the silver catalyst is 1:0.05-1.0; the mol ratio of the N-propargyl-N-alkyl or aryl amine thioacyl fluoride shown in the formula (1) to the inorganic base is 1:1.0-4.0;
the silver catalyst is AgSbF 6 、Ag 2 O、AgOTf、AgOAc、Ag 2 CO 3 、AgCO 2 CF 3 、AgBF 4 、AgF、AgNO 3 Or AgNTf 2 ；
The inorganic base is NaO t Bu、LiO t Bu、KOH、NaOH、K 2 HPO 4 、KH 2 PO 4 Or Cs 2 CO 3 ；
The organic solvent is anhydrous acetonitrile, anhydrous N, N-dimethylformamide, anhydrous 1, 2-dichloroethane, anhydrous tetrahydrofuran, anhydrous dichloromethane or anhydrous chloroform;
the post-treatment and column chromatography separation and purification comprises the following steps: filtering to remove precipitate in the reaction system, concentrating the filtrate under reduced pressure, and separating the residue by column chromatography with petroleum ether/ethyl acetate mixed solvent, wherein the volume ratio of ethyl acetate to petroleum ether mixed solvent is 1:3-5.
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