CN114149353B - N-alkyl/N-aryl thioamide derivatives, and synthetic method and application thereof - Google Patents
N-alkyl/N-aryl thioamide derivatives, and synthetic method and application thereof Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 3
- 150000001412 amines Chemical class 0.000 claims abstract description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- -1 methoxy, methyl Chemical group 0.000 claims description 39
- 230000035484 reaction time Effects 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000007529 inorganic bases Chemical class 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 148
- 238000005160 1H NMR spectroscopy Methods 0.000 description 75
- 239000000047 product Substances 0.000 description 74
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 38
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 37
- 238000002474 experimental method Methods 0.000 description 36
- 239000007858 starting material Substances 0.000 description 36
- 125000000217 alkyl group Chemical group 0.000 description 6
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 150000003556 thioamides Chemical class 0.000 description 3
- MGDDHBBPSNIXFW-UHFFFAOYSA-N (3-fluorophenyl)-methylcarbamic acid Chemical compound OC(=O)N(C)C1=CC=CC(F)=C1 MGDDHBBPSNIXFW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- FIYXUOWXHWJDAM-UHFFFAOYSA-N methyl sulfamate Chemical compound COS(N)(=O)=O FIYXUOWXHWJDAM-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PJDFCXVCTACHPX-UHFFFAOYSA-N N-methyl-N-(3-methylphenyl)carbamoyl fluoride Chemical compound CC1=CC(=CC=C1)N(C)C(=O)F PJDFCXVCTACHPX-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- RYFCSKVXWRJEOB-UHFFFAOYSA-N dibenzyl propanedioate Chemical compound C=1C=CC=CC=1COC(=O)CC(=O)OCC1=CC=CC=C1 RYFCSKVXWRJEOB-UHFFFAOYSA-N 0.000 description 1
- ZMYJSOIMFGAQRQ-UHFFFAOYSA-N dimethyl 2-benzylpropanedioate Chemical compound COC(=O)C(C(=O)OC)CC1=CC=CC=C1 ZMYJSOIMFGAQRQ-UHFFFAOYSA-N 0.000 description 1
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000004763 sulfides Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of N-alkyl/N-aryl thioamide derivatives, which takes amine thiocarboxyfluoride and malonate shown in a formula (1) as raw materials, and carries out nucleophilic substitution reaction in an organic solvent at the temperature of 80 ℃ in the presence of inorganic alkali to obtain the N-alkyl/N-aryl thioamide derivatives. The synthesis method of the N-alkyl/N-aryl thioamide derivative has the advantages of simple operation, atom economy, economy in steps, green and high efficiency, wide substrate application range and the like through condition control. The invention also discloses application of the N-alkyl/N-aryl thioamide derivative in the aspects of biological pharmacy and special preparations.
Description
Technical Field
The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to N-alkyl/N-aryl thioamide derivatives, a synthetic method and application thereof.
Background
Thioamides are a very important class of organic sulfides which have high stability and are more reactive in chemical nature than amides, and can undergo a series of conversion reactions. The research results in recent years show that the thioamide compounds have wide biological activity, can be used for resisting inflammation, sterilization and tuberculosis, and can be used as special reagents or intermediates. Therefore, the development of a simple and efficient method for synthesizing thioamides and derivatives thereof is of great research value.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and providing N-alkyl/N-aryl thioamide derivatives and a synthesis method thereof, wherein the synthesis method adopts easily prepared raw materials and green inorganic base, and synthesizes the N-alkyl/N-aryl thioamide derivatives with good to excellent yield through simple and efficient nucleophilic substitution reaction in an atomic and step economical way. The method has the advantages of simple operation, atom economy, step economy, green and high efficiency, wide substrate application range and the like.
The invention provides a synthesis method of an N-alkyl/N-aryl thioamide derivative.
The invention provides an N-alkyl/N-aryl thioamide derivative, which has the structure shown in the following formula (2):
wherein R 1 is hydrogen, alkyl, phenyl, acyl, ester, halogen, alkoxy, sulfonamide, etc.;
R 2 is alkyl, benzyl, substituted alkyl, etc.;
r 3、R4 is independently alkyl, benzyl or the like.
Preferably, R 1 is hydrogen, methyl, methoxy, sulfonamide, halogen, ethyl formate, acetyl, phenyl, etc.;
R 2 is methyl, ethyl, isopropyl, n-hexyl, benzyl, phenethyl, 3-methoxypropyl, etc.;
R 3、R4 is independently methyl, ethyl, isopropyl, benzyl, etc.
The invention provides a synthesis method of an N-alkyl/N-aryl thioamide derivative, which comprises the following steps: nucleophilic substitution reaction is carried out on amine thiocarboxyfluoride, malonate and inorganic base shown in the formula (1) in an organic solvent at the temperature of 80 ℃ to obtain the N-alkyl/N-aryl thioamide derivative. The process is shown in a reaction formula (I):
wherein R 1 is hydrogen, alkyl, phenyl, acyl, ester, halogen, alkoxy, sulfonamide, etc.;
R 2 is alkyl, benzyl, substituted alkyl, etc.;
r 3、R4 is independently alkyl, benzyl or the like.
Preferably, R 1 is hydrogen, methyl, methoxy, sulfonamide, halogen, ethyl formate, acetyl, phenyl, etc.;
R 2 is methyl, ethyl, isopropyl, n-hexyl, benzyl, phenethyl, 3-methoxypropyl, etc.;
R 3、R4 is independently methyl, ethyl, isopropyl, benzyl, etc.
Wherein the molar ratio of the amine thiocarboxyfluoride shown in the formula (1) to the malonate is 1:1.5; the molar ratio of the amine thiocarboxyfluoride shown in the formula (1) to the inorganic base is 1: (1.5-3); preferably, it is 1:1.5, 1:2. 1:2.5, 1:3, a step of; further preferably, it is 1:2.5.
Wherein the inorganic base is potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, sodium hydride; preferably cesium carbonate.
Wherein the organic solvent is tetrahydrofuran or acetonitrile; preferably acetonitrile.
Wherein the temperature of the reaction is preferably 80 ℃.
Wherein the reaction time is 8-12 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 1:3-1:10.
In one embodiment, the method of the present invention comprises: reacting amine thiocarboxyfluoride shown in formula (1), malonate and inorganic base in an organic solvent at 80 ℃, and monitoring the reaction of the raw materials by TLC. 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 N-alkyl/N-arylthioamide derivative shown in formula (2).
The method for synthesizing the N-alkyl/N-aryl thioamide derivative is characterized in that amine thiocarboxyfluoride, malonate and inorganic base are subjected to simple and efficient nucleophilic substitution reaction in an organic solvent at the temperature of 80 ℃ to obtain the N-alkyl/N-aryl thioamide derivative; and (3) performing post-treatment and column chromatography separation and purification to obtain the purified N-alkyl/N-arylthioamide derivative.
The invention also provides application of the N-alkyl/N-aryl thioamide derivative in the aspects of biological pharmacy and special preparations.
The invention adopts the starting materials easy to prepare and green and environment-friendly inorganic alkali, and efficiently constructs the N-alkyl/N-aryl thioamide derivatives through nucleophilic substitution reaction. The method has the advantages of simple operation, green and high efficiency, economical atomic steps, wide substrate application range and the like. The N-alkyl/N-aryl thioamide derivatives synthesized by the invention are novel compounds, are synthesized for the first time, and can be applied to biological pharmacy and special preparations.
Drawings
FIGS. 1-37 are nuclear magnetic resonance 1H NMR、13 C NMR spectra of N-alkyl/N-arylthioamide derivatives synthesized in examples 1-37 of the present invention.
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
Methyl (phenyl) aminothiofluoride (169.04 mg,1 mmol), dimethyl malonate (0.17 mL,1.5 mmol), cesium carbonate (814.5 mg,2.5 mmol) were added to a 100mL reaction flask, 15mL of acetonitrile was added, the reaction system temperature was 80℃and the reaction was carried out for 12 hours, TLC monitored complete consumption of methyl (phenyl) aminothiofluoride, then insoluble solids were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give pure product 280.6mg. The structure is shown as a formula (2-1). The yield was 87%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 1, and the product ：1H NMR(500MHz,CDCl3)δ7.51–7.41(m,3H),7.20(dd,J＝5.3,3.3Hz,2H),4.67(s,1H),3.75(s,3H),3.71(s,6H).13C NMR(126MHz,CDCl3)δ192.42,165.52,144.76,130.32,129.31,125.70,63.85,53.07,45.71.
HRMS(EI)m/z calculated forC13H15NO4S[M]+281.0722,found 281.0723.
Example 2
The experimental procedure of this example was essentially the same as that of example 1, except that (4-methoxyphenyl) (methyl) aminothiofluoro was used as the starting material in this example, and the reaction time was 18 hours at 80℃to give a product represented by the following formula (2-2). The yield was 86%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 2, and the product ：1H NMR(500MHz,CDCl3)δ7.26(d,J＝8.1Hz,2H),7.06(d,J＝8.3Hz,2H),4.69(s,1H),3.73(s,3H),3.71(s,6H),2.40(s,3H).13C NMR(126MHz,CDCl3)δ192.48,165.58,142.25,139.44,130.85,125.32,63.80,53.06,45.76,21.16.
HRMS(EI)m/z calculated forC14H17NO5S[M]+311.0827,found 311.0823.
Example 3
The experimental procedure of this example was substantially the same as that of example 1, except that methyl (p-tolyl) aminomethylthio-fluoro was used as the starting material in this example, and the reaction time was 12 hours at 80℃to give a product represented by the following structural formula (2-3). The yield was 78%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 3, and the product ：1H NMR(500MHz,CDCl3)δ7.26(d,J＝8.1Hz,2H),7.06(d,J＝8.3Hz,2H),4.69(s,1H),3.73(s,3H),3.72(s,6H),2.40(s,3H).13C NMR(126MHz,CDCl3)δ192.50,165.59,142.26,139.45,130.86,125.33,63.81,53.06,45.76,21.17.
HRMS(EI)m/z calculated forC14H17NO4S[M]+295.0878,found 295.0881.
Example 4
The experimental procedure of this example was essentially the same as that of example 1, except that (4- (N, 4-dimethylphenylsulfonamido) phenyl) (methyl) sulfamoyl fluoride was used as the starting material, and the reaction time was 8 hours at 80℃to obtain the product represented by the following structural formula (2-4). The yield was 78%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 4, and the product ：1H NMR(500MHz,CDCl3)δ7.42(d,J＝8.2Hz,2H),7.30–7.26(m,2H),7.23(d,J＝8.7Hz,2H),7.14(d,J＝8.7Hz,2H),4.63(s,1H),3.73(s,9H),3.17(s,3H),2.43(s,3H).13C NMR(126MHz,CDCl3)δ192.56,165.38,144.12,143.02,142.42,132.91,129.59,127.79,127.78,126.30,64.13,53.19,45.67,37.67,21.59.
HRMS(EI)m/z calculated forC21H24N2O6S2[M]+464.1076,found 464.1072.
Example 5
The experimental procedure of this example was essentially the same as that of example 1, except that (4-fluorophenyl) (methyl) aminothiofluoro was used as the starting material in this example, and the reaction time was 8 hours at 80℃to obtain a product represented by the following structural formula (2-5). The yield was 80%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 5, and the product ：1H NMR(500MHz,CDCl3)δ7.24–7.13(m,4H),4.64(s,1H),3.73(s,3H),3.72(s,6H).13C NMR(126MHz,CDCl3)δ192.82,165.41,163.38,161.38,140.73,140.70,127.82,127.75,117.42,117.24,63.87,53.14,45.84.
HRMS(EI)m/z calculated forC13H14NO4SF[M]+299.0628,found 299.0625.
Example 6
The experimental procedure of this example was essentially the same as that of example 1, except that (4-chlorophenyl) (methyl) aminothiofluoro was used as the starting material in this example, and the reaction time was 8 hours at 80℃to give the product represented by the structural formula (2-6). The yield was 85%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 6, and the product ：1H NMR(500MHz,CDCl3)δ7.45(d,J＝8.6Hz,2H),7.16(d,J＝8.6Hz,2H),4.64(s,1H),3.72(s,9H).13C NMR(126MHz,CDCl3)δ192.62,165.37,143.17,135.33,130.55,127.26,63.80,53.17,45.74.
HRMS(EI)m/z calculated forC13H14NO4SCl[M]+315.0322,found 315.0329.
Example 7
The experimental procedure of this example was essentially the same as that of example 1, except that (4-bromophenyl) (methyl) aminothiofluoro was used as the starting material in this example, and the reaction time was 10 hours at 80℃to give the product represented by the structural formula (2-7). The yield was 88%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 7, and the product ：1H NMR(500MHz,CDCl3)δ7.61(d,J＝8.6Hz,2H),7.10(d,J＝8.6Hz,2H),4.64(s,1H),3.72(s,9H).13C NMR(126MHz,CDCl3)δ192.52,165.36,143.68,133.56,127.55,123.33,63.77,53.18,45.70.
HRMS(EI)m/z calculated forC13H14NO4SBr[M]+358.9827,found 358.9832.
Example 8
The experimental procedure of this example was essentially the same as that of example 1, except that the starting material used in this example was (4-iodophenyl) (methyl) carbamic acid thiofluoride, and the reaction time was 8 hours at 80℃to give the product represented by the structural formula (2-8). The yield thereof was found to be 97%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 8, and the product ：1H NMR(600MHz,CDCl3)δ7.76–7.72(m,2H),6.91–6.87(m,2H),4.58(s,1H),3.65(s,6H),3.64(s,3H).13C NMR(151MHz,CDCl3)δ192.43,165.36,144.39,139.55,127.69,94.87,63.75,53.20,45.68.
HRMS(EI)m/z calculated forC13H14INO4S[M]+ 406.9688,found406.9690.
Example 9
The experimental procedure of this example was essentially the same as that of example 1, except that ethyl 4- ((fluorothioformyl) (methyl) amino) benzoate was used as the starting material, and the reaction time was 8 hours at 80℃to give the product represented by the structural formula (2-9). The yield thereof was found to be 83%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 9, and the product ：1H NMR(500MHz,CDCl3)δ8.15(d,J＝8.5Hz,2H),7.30(d,J＝8.5Hz,2H),4.63(s,1H),4.42(q,J＝7.1Hz,2H),3.75(s,3H),3.72(s,6H),1.42(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ192.33,165.31,165.14,148.36,131.64,131.33,125.96,63.79,61.59,53.18,45.60,14.28.
HRMS(EI)m/z calculated forC16H19NO6S[M]+353.0933,found 353.0930.
Example 10
The experimental procedure of this example was essentially the same as that of example 1, except that (4-acetylphenyl) (methyl) aminothiofluoro was used as the starting material, and the reaction time was 8 hours at 80℃to give the product represented by the structural formula (2-10). The yield was 78%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 10, and the product ：1H NMR(500MHz,CDCl3)δ8.07(d,J＝8.5Hz,2H),7.34(d,J＝8.4Hz,2H),4.64(s,1H),3.75(s,3H),3.72(s,6H),2.65(s,3H).13C NMR(126MHz,CDCl3)δ196.44,192.29,165.27,148.48,137.39,130.34,126.24,63.76,53.19,45.59,26.73.
HRMS(EI)m/z calculated forC15H17NO5S[M]+323.0827,found 323.0833.
Example 11
The experimental procedure of this example was essentially the same as that of example 1, except that (2-methoxyphenyl) (methyl) aminomethylthio-fluoro (199.1 mg,1 mmol), dimethyl malonate (396.3 mg,3 mmol), cesium carbonate (1629.0 mg,5 mmol) and acetonitrile (15 mL) were used as the starting materials, and the reaction time at 80℃was 18 hours, and the obtained product was represented by the following structural formula (2-11). The yield was 64%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 11, and the product ：1H NMR(500MHz,CDCl3)δ7.40(t,J＝7.9Hz,1H),7.11(d,J＝7.7Hz,1H),7.01(dd,J＝16.4,8.2Hz,2H),4.55(s,1H),3.88(s,3H),3.74(s,3H),3.66(s,6H).13C NMR(126MHz,CDCl3)δ193.20,165.70,165.45,153.22,132.85,130.87,127.26,121.24,112.45,63.85,55.77,53.00,52.95,44.58.
HRMS(EI)m/z calculated forC14H17NO5S[M]+311.0827,found 311.0823.
Example 12
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (o-tolyl) aminothiofluoro (183.1 mg,1 mmol), dimethyl malonate (396.3 mg,3 mmol), cesium carbonate (1629.0 mg,5 mmol) and acetonitrile (15 mL) were used as the starting materials, and the reaction time at 80℃was 18 hours, and the obtained product was represented by the following structural formula (2-12). The yield was 76%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 12, and the product ：1H NMR(500MHz,CDCl3)δ7.34(d,J＝4.4Hz,2H),7.27(ddd,J＝8.6,6.3,2.7Hz,1H),7.07(d,J＝7.7Hz,1H),4.47(s,1H),3.73(s,3H),3.69(s,3H),3.67(s,3H),2.27(s,3H).13C NMR(126MHz,CDCl3)δ192.56,165.42,165.38,143.57,133.87,132.04,129.66,127.70,125.98,77.36,77.11,76.85,63.61,53.09,53.02,44.14,17.28.
HRMS(EI)m/z calculated forC14H17NO4S[M]+295.0878,found 295.0882.
Example 13
The experimental procedure of this example was essentially the same as that of example 1, except that (3-methoxyphenyl) (methyl) aminothiofluoro was used as the starting material in this example, and the reaction time was 12 hours at 80℃to give a product represented by the following structural formulae (2-13). The yield was 86%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 13, and the product ：1H NMR(500MHz,CDCl3)δ7.36(t,J＝8.1Hz,1H),6.95(dd,J＝8.4,2.2Hz,1H),6.77(d,J＝7.8Hz,1H),6.71(s,1H),4.72(s,1H),3.82(s,3H),3.74(s,3H),3.72(s,6H).13C NMR(126MHz,CDCl3)δ192.36,165.61,160.88,145.76,131.07,117.57,114.92,111.37,63.74,55.57,53.08,45.55.
HRMS(EI)m/z calculated forC14H17NO5S[M]+ 311.0827,found 311.0828.
Example 14
The experimental procedure of this example was essentially the same as that of example 1, wherein methyl (m-tolyl) carbamoyl fluoride was used as the starting material, and the reaction time was 12 hours at 80℃to give the product represented by the structural formulae (2-14). The yield was 84%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 14, and the product ：1H NMR(500MHz,CDCl3)δ7.34(t,J＝7.7Hz,1H),7.23(d,J＝7.7Hz,1H),6.98(d,J＝9.6Hz,2H),4.67(s,1H),3.73(s,3H),3.72(s,6H),2.39(s,3H).13C NMR(126MHz,CDCl3)δ192.32,165.60,144.72,140.65,130.05,130.00,126.09,122.52,63.90,53.04,45.64,21.26.
HRMS(EI)m/z calculated forC14H17NO4S[M]+ 295.0878,found 295.0875.
Example 15
The experimental procedure of this example was essentially the same as that of example 1, wherein the starting material used in this example was [1,1' -biphenyl ] -3-yl (methyl) aminothiofluoro, and the reaction time was 10 hours at 80℃to give the product represented by the structural formula (2-15). The yield was 85%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 15, and the product ：1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.8Hz,1H),7.59–7.51(m,3H),7.47(t,J＝7.6Hz,2H),7.43–7.38(m,2H),7.18(d,J＝7.9Hz,1H),4.74(s,1H),3.80(s,3H),3.68(d,J＝29.6Hz,6H).13C NMR(126MHz,CDCl3)δ192.47,165.59,145.26,143.58,139.07,130.72,129.11,128.33,127.78,126.98,124.39,124.18,63.96,53.10,45.73.
HRMS(EI)m/z calculated forC19H19NO4S[M]+357.1035,found 357.1031.
Example 16
The experimental procedure of this example was substantially the same as that of example 1, except that the starting material used in this example was (3-fluorophenyl) (methyl) carbamic acid thiofluoro (3-fluorophenyl) (methyl) carbamic acid at 80℃for 8 hours, and the obtained product was represented by the following structural formulae (2-16). The yield thereof was found to be 82%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 16, and the product ：1H NMR(500MHz,CDCl3)δ7.47(dd,J＝14.4,8.1Hz,1H),7.17(td,J＝8.3,2.2Hz,1H),7.03(d,J＝8.0Hz,1H),6.98–6.93(m,1H),4.65(s,1H),3.73(d,J＝3.6Hz,9H).13C NMR(126MHz,CDCl3)δ192.57,165.37,164.09,162.09,145.89(d,J＝9.2Hz),131.69(d,J＝9.1Hz),121.75(d,J＝3.4Hz),116.61(d,J＝20.9Hz),113.61(d,J＝22.8Hz),63.83,53.16,45.56.
HRMS(EI)m/z calculated forC13H14FNO4S[M]+ 299.0628,found 299.0631.
Example 17
The experimental procedure of this example was essentially the same as that of example 1, except that (3-chlorophenyl) (methyl) aminothiofluoro was used as the starting material in this example, and the reaction time was 10 hours at 80℃to give the product represented by the structural formula (2-17). The yield was 68%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 17, and the product ：1H NMR(500MHz,CDCl3)δ7.43(d,J＝5.0Hz,2H),7.22(s,1H),7.15–7.10(m,1H),4.62(s,1H),3.73(d,J＝2.9Hz,9H).13C NMR(126MHz,CDCl3)δ192.60,165.37,145.64,135.86,131.32,129.64,126.37,124.13,63.99,53.19,45.60.
HRMS(EI)m/z calculated forC13H14NO4S[M]+315.0332,found 315.0336.
Example 18
The experimental procedure of this example was essentially the same as that of example 1, except that the starting material used in this example was (3, 5-dimethoxyphenyl) (methyl) carbamic acid thiofluoride, and the reaction time was 10 hours at 80℃to give the product represented by the structural formula (2-18). The yield was 85%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 18, and the product ：1H NMR(500MHz,CDCl3)δ6.40(t,J＝2.2Hz,1H),6.24(d,J＝2.2Hz,2H),4.70(s,1H),3.72(s,6H),3.66(s,6H),3.65(s,3H).13C NMR(126MHz,CDCl3)δ192.27,165.72,161.86,146.25,103.79,100.98,63.62,55.66,53.08,45.37.
HRMS(EI)m/z calculated forC15H19NO6S[M]+ 341.0933,found341.0938.
Example 19
The experimental procedure of this example was essentially the same as that of example 1, except that (3, 5-difluorophenyl) (methyl) aminothiocarbonyl fluoride was used as the starting material, and the reaction time was 8 hours at 80℃to give the product represented by the structural formula (2-19). The yield was 85%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 19, and the product ：1H NMR(500MHz,CDCl3)δ6.86(tt,J＝8.6,2.2Hz,1H),6.78–6.68(m,2H),4.57(s,1H),3.67(s,6H),3.64(s,3H).13C NMR(126MHz,CDCl3)δ192.64(s),165.25(s),164.49(d,J＝14.0Hz),162.47(d,J＝14.0Hz),146.47(t,J＝11.7Hz),110.12(d,J＝7.1Hz),109.96(d,J＝7.1Hz),105.36(t,J＝25.1Hz),63.80(s),53.25(s),45.41(s).
HRMS(EI)m/z calculated for C13H13F2NO4S[M]+ 317.0533,found317.0527.
Example 20
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (naphthalen-1-yl) aminothiofluoro was used as the starting material, and the reaction time was 16 hours at 80℃to give a product represented by the following structural formula (2-20). The yield was 96%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 20, and the product ：1H NMR(500MHz,CDCl3)δ7.95(t,J＝8.5Hz,2H),7.72(d,J＝8.1Hz,1H),7.63(dt,J＝13.9,6.7Hz,2H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.2Hz,1H),4.48(s,1H),3.84(s,3H),3.68(s,3H),3.56(s,3H).13C NMR(126MHz,CDCl3)δ193.67,165.63,165.33,140.89,134.72,130.01,128.79,128.21,128.18,127.43,125.55,124.04,122.09,63.78,53.04,52.92,45.30.
HRMS(EI)m/z calculated forC17H17NO4S[M]+331.0878,found 331.0875.
Example 21
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (naphthalen-2-yl) aminothiofluoro was used as the starting material, and the reaction time was 12 hours at 80℃to give a product represented by the structural formula (2-21). The yield thereof was found to be 63%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 21, and the product ：1H NMR(500MHz,CDCl3)δ7.95(d,J＝8.7Hz,1H),7.93–7.88(m,1H),7.86–7.81(m,1H),7.67(d,J＝1.4Hz,1H),7.59(p,J＝6.1Hz,2H),7.31–7.26(m,1H),4.72(s,1H),3.83(s,3H),3.68(s,6H).13C NMR(126MHz,CDCl3)δ192.62,165.58,141.99,133.39,132.81,130.73,128.03,127.99,127.61,127.59,124.69,122.93,64.00,53.05,45.80.
HRMS(EI)m/z calculated forC17H17NO4S[M]+331.0878,found 331.0875.
Example 22
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (thiophen-2-yl) aminothiofluoro was used as the starting material in this example, and the reaction time was 12 hours at 80℃to give a product represented by the following structural formula (2-22). The yield was 72%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 22, and the product ：1H NMR(500MHz,CDCl3)δ7.43(dd,J＝5.1,3.2Hz,1H),7.21(dd,J＝3.1,1.3Hz,1H),6.94(dd,J＝5.1,1.3Hz,1H),4.76(s,1H),3.73(s,6H),3.71(s,3H).13C NMR(126MHz,CDCl3)δ193.33,165.58,142.47,127.59,124.13,121.01,64.02,53.11,45.42.
HRMS(EI)m/z calculated for C11H13NO4S2[M]+287.0286,found 287.0289.
Example 23
The experimental procedure of this example was substantially the same as that of example 1, except that methyl (phenyl) aminothiofluoride and diethyl malonate were used as the raw materials, and the reaction time was 12 hours at 80℃to obtain the product represented by the structural formula (2-23). The yield was 69%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 23, and the product ：1H NMR(500MHz,CDCl3)δ7.45(dq,J＝14.4,7.1Hz,3H),7.21(d,J＝7.4Hz,2H),4.62(s,1H),4.17(q,J＝7.1Hz,4H),3.75(s,3H),1.22(t,J＝7.1Hz,6H).13C NMR(126MHz,CDCl3)δ192.76,165.14,144.87,130.24,129.14,125.84,64.05,62.09,45.65,13.90.
HRMS(EI)m/z calculated forC15H19NO4S[M]+309.1035,found 309.1037.
Example 24
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (phenyl) aminothiofluoride (169.0 mg,1 mmol) was used as the starting material, diisopropyl malonate (582.1 mg,3 mmol), cesium carbonate (1629.0 mg,5 mmol) and acetonitrile (15 mL), and the reaction time was 12 hours at 80℃to give the product represented by the following structural formula (2-24). The yield was 76%. Nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 24, and the product ：1H NMR(500MHz,CDCl3)δ7.43(dq,J＝14.1,7.0Hz,3H),7.21(d,J＝7.4Hz,2H),5.02(dt,J＝12.5,6.2Hz,2H),4.54(s,1H),3.74(s,3H),1.23(d,J＝6.2Hz,6H),1.16(d,J＝6.2Hz,6H).13C NMR(126MHz,CDCl3)δ193.12,164.72,144.95,130.18,128.99,125.93,69.73,64.27,45.54,21.51,21.37.
HRMS(EI)m/z calculated forC17H23NO4S[M]+337.1348,found 337.1352.
Example 25
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (phenyl) aminothiofluoride and dibenzyl malonate were used as the starting materials, and the reaction time was 18 hours at 80℃to give the product represented by the structural formula (2-25). The yield was 88%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 25, and the product ：1H NMR(500MHz,CDCl3)δ7.35–7.24(m,14H),7.04(d,J＝7.6Hz,2H),5.12(q,J＝12.2Hz,4H),4.71(s,1H),3.70(s,3H).13C NMR(126MHz,CDCl3)δ192.26,164.90,144.71,135.07,130.25,129.09,128.53,128.49,128.39,125.72,67.83,64.08,45.65.
HRMS(EI)m/z calculated forC25H23NO4S[M]+433.1348,found 433.1345.
Example 26
The experimental procedure of this example was essentially the same as that of example 1, except that methyl (phenyl) aminothiofluoride and dimethyl benzyl malonate were used as the starting materials, and the reaction time was 12 hours at 80℃to give the product represented by the structural formulae (2-26). The yield was 95%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 26, and the product ：1H NMR(500MHz,CDCl3)δ7.47–7.27(m,8H),7.12(ddd,J＝34.6,26.9,14.4Hz,2H),5.18–5.09(m,2H),4.69(s,1H),3.72(s,3H),3.69(s,3H).13C NMR(126MHz,CDCl3)δ192.36,165.52,164.89,144.75,135.08,130.29,129.19,128.55,128.51,128.44,125.71,67.78,63.98,53.06,45.68.
HRMS(EI)m/z calculated for C19H19NO4S[M]+357.1035,found 357.1039.
Example 27
The experimental procedure of this example was essentially the same as that of example 1, except that ethyl (phenyl) aminothiofluoride was used as the starting material, and the reaction time was 18 hours at 80℃to give the product represented by the structural formula (2-27). The yield thereof was found to be 83%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 27, and the product ：1H NMR(500MHz,CDCl3)δ7.51–7.42(m,3H),7.18–7.14(m,2H),4.58(s,1H),4.32(q,J＝7.1Hz,2H),3.70(s,6H),1.28(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)δ191.75,165.56,142.94,130.22,129.35,126.67,64.24,53.03,51.82,11.03.
HRMS(EI)m/z calculated for C14H17NO4S[M]+295.0878,found 295.0879.
Example 28
The experimental procedure of this example was essentially the same as that of example 1, and the starting material used in this example was isopropyl (phenyl) aminothiofluoride, which was reacted at 80℃for 18 hours to give the product represented by the structural formula (2-28). The yield was 58%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 28, and the product ：1H NMR(500MHz,CDCl3)δ7.51–7.43(m,3H),7.08(dd,J＝6.4,2.8Hz,2H),5.91(hept,J＝6.7Hz,1H),4.46(s,1H),3.69(s,6H),1.15(d,J＝6.7Hz,6H).13C NMR(126MHz,CDCl3)δ192.02,165.67,138.92,129.69,129.53,128.41,64.73,53.41,52.99,19.99.
HRMS(EI)m/z calculated for C15H19NO4S[M]+ 309.1035,found 309.1031.
Example 29
The experimental procedure of this example was essentially the same as that of example 1, wherein hexyl (phenyl) aminomethylthio-fluoro was used as the starting material, and the reaction time was 16 hours at 80℃to give the product represented by the structural formulae (2-29). The yield thereof was found to be 83%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 29, and the product ：1H NMR(500MHz,CDCl3)δ7.50–7.40(m,3H),7.18–7.12(m,2H),4.57(s,1H),4.27–4.20(m,2H),3.70(s,6H),1.71(dt,J＝15.6,7.6Hz,2H),1.33–1.25(m,6H),0.86(t,J＝6.8Hz,3H).13C NMR(126MHz,CDCl3)δ191.99,165.58,143.32,130.18,129.27,126.62,64.27,56.92,53.03,31.43,26.34,25.78,22.52,13.97.
HRMS(EI)m/z calculated forC18H25NO4S[M]+351.1504,found 351.1507.
Example 30
The experimental procedure of this example was essentially the same as that of example 1, except that phenethyl (phenyl) aminomethylthio-fluoro (259.1 mg,1 mmol), dimethyl malonate (396.3 mg,3 mmol), cesium carbonate (1629.0 mg,5 mmol) and acetonitrile (15 mL) were used as the starting materials, and the resultant product was represented by the following structural formula (2-30) at 80 ℃. The yield was 54%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 30, and the product ：1H NMR(500MHz,CDCl3)δ7.47–7.41(m,3H),7.29–7.24(m,2H),7.24–7.18(m,3H),7.08(dd,J＝7.7,1.8Hz,2H),4.59(s,1H),4.47–4.41(m,2H),3.71(s,6H),3.15–3.09(m,2H).13C NMR(126MHz,CDCl3)δ192.30,165.55,143.62,137.94,130.27,129.36,128.85,128.54,126.60,126.52,64.31,58.35,53.08,31.68.
HRMS(EI)m/z calculated for C20H21NO4S[M]+371.1191,found 371.1196.
Example 31
The experimental procedure of this example was essentially the same as that of example 1, except that (3-methoxypropyl) (phenyl) aminomethylthio-fluoro (226.1 mg,1 mmol), dimethyl malonate (396.3 mg,3 mmol), cesium carbonate (1629.0 mg,5 mmol) and acetonitrile (15 mL) were used as the starting materials, and the resultant product was represented by the following structural formula (2-31). The yield was 86%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 31, and the product ：1H NMR(500MHz,CDCl3)δ7.49–7.40(m,3H),7.18–7.14(m,2H),4.58(s,1H),4.37–4.32(m,2H),3.70(s,6H),3.46(t,J＝6.1Hz,2H),3.28(s,3H),2.07–2.00(m,2H).13C NMR(126MHz,CDCl3)δ192.38,165.55,143.31,130.25,129.35,126.60,70.05,64.27,58.65,54.53,53.03,26.21.
HRMS(EI)m/z calculated forC16H21NO5S[M]+ 339.1140,found 339.1137.
Example 32
The experimental procedure of this example was essentially the same as that of example 1, wherein fluorine benzyl (phenyl) thiocarbamate was used as the starting material, and the reaction time was 18 hours at 80℃to give the product represented by the structural formula (2-32). The yield was 77%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 32, and the product ：1H NMR(600MHz,CDCl3)δ7.35(ddd,J＝9.5,6.5,1.4Hz,5H),7.31–7.27(m,3H),6.97(dd,J＝7.8,1.7Hz,2H),5.60(s,2H),4.65(s,1H),3.74(s,6H).13C NMR(151MHz,CDCl3)δ193.50,165.59,142.70,134.93,130.00,129.38,128.73,128.53,127.92,126.83,64.30,59.80,53.14.
HRMS(EI)m/z calculated forC19H19NO4S[M]+ 357.1035,found 357.1038.
Example 33
The experimental procedure of this example was essentially the same as that of example 1, wherein fluorine benzyl (4-methoxyphenyl) thiocarbamate was used as the starting material, and the reaction time was 12 hours at 80℃to give a product represented by the following structural formula (2-33). The yield was 94%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 33, and the product ：1H NMR(600MHz,CDCl3)δ7.21(d,J＝23.8Hz,5H),6.75(dd,J＝24.7,8.0Hz,4H),5.47(s,2H),4.59(s,1H),3.70(s,3H),3.64(s,6H).13C NMR(151MHz,CDCl3)δ193.97,165.68,159.78,135.24,135.08,128.77,128.51,127.89,114.96,64.27,59.90,55.52,53.12.
HRMS(EI)m/z calculated forC20H21NO5S[M]+ 387.1140,found 387.1143.
Example 34
The experimental procedure of this example was essentially the same as that of example 1, wherein fluorine benzyl (4-chlorophenyl) thiocarbamate was used as the starting material, and the reaction time was 8 hours at 80℃to give a product represented by the following structural formula (2-34). The yield was 87%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 34, and the product ：1H NMR(600MHz,CDCl3)δ7.22(d,J＝8.7Hz,7H),6.82(d,J＝7.7Hz,2H),5.47(s,2H),4.52(s,1H),3.65(s,6H).13C NMR(151MHz,CDCl3)δ193.60,165.43,141.01,135.45,134.68,130.22,128.73,128.66,128.33,128.12,64.22,59.75,53.23.
HRMS(EI)m/z calculated forC19H18ClNO4S[M]+391.0645,found 391.0652.
Example 35
The experimental procedure of this example was essentially the same as that of example 1, wherein the starting material used in this example was fluorine benzyl (4-bromophenyl) thiocarbamate, and the reaction time was 10 hours at 80℃to give a product represented by the following structural formula (2-35). The yield was 96%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 35, and the product ：1H NMR(600MHz,CDCl3)δ7.39(d,J＝7.8Hz,2H),7.21(d,J＝13.7Hz,5H),6.76(d,J＝7.8Hz,2H),5.47(s,2H),4.52(s,1H),3.65(s,6H).13C NMR(151MHz,CDCl3)δ193.52,165.42,141.55,134.67,133.22,128.72,128.67,128.60,128.13,123.55,64.20,59.72,53.24.
HRMS(EI)m/z calculated forC19H18BrNO4S[M]+ 435.0140,found435.0138.
Example 36
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The experimental procedure of this example was essentially the same as that of example 1, except that ethyl 4- (benzyl (fluorocarbon thiocarbonyl) amino) benzoate was used as the starting material, and the reaction time was 8 hours at 80℃to give the product represented by the structural formula (2-36). The yield was 72%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 36, and the product ：1H NMR(600MHz,CDCl3)δ7.94(d,J＝8.5Hz,2H),7.21(q,J＝6.0Hz,5H),6.96(d,J＝8.5Hz,2H),5.51(s,2H),4.50(s,1H),4.30(q,J＝7.1Hz,2H),3.65(s,6H),1.31(t,J＝7.1Hz,3H).13C NMR(151MHz,CDCl3)δ193.24,165.38,165.20,146.32,134.60,131.35,131.26,128.73,128.65,128.13,127.08,64.22,61.58,59.69,53.25,14.28.
HRMS(EI)m/z calculated forC22H23NO6S[M]+ 429.1246,found 429.1243.
Example 37
The experimental procedure of this example was essentially the same as that of example 1, except that (carbonylbis (4, 1-phenylene)) bis (methylaminomethylthiofluoro) (364.4 mg,1 mmol), dimethyl malonate (396.3 mg,3 mmol), cesium carbonate (1629.0 mg,5 mmol) and acetonitrile (15 mL) were used as the starting materials, and the reaction time was 4 hours at 80℃to give the product represented by the following structural formulae (2-37). The yield was 79%. The nuclear magnetic resonance 1H NMR、13 C NMR spectrum is shown in FIG. 37, and the product ：1H NMR(600MHz,CDCl3)δ7.84(d,J＝8.4Hz,4H),7.32(d,J＝8.3Hz,4H),4.62(s,2H),3.72(s,6H),3.66(s,12H).13C NMR(151MHz,CDCl3)δ193.43,192.36,165.28,148.42,137.30,131.90,126.32,63.89,53.28,45.67.
HRMS(EI)m/z calculated forC27H28N2O9S2[M]+ 588.1236,found588.1232.
Claims (4)
1. The preparation method of the N-alkyl/N-aryl thioamide derivative is characterized in that the N-alkyl/N-aryl thioamide derivative is synthesized according to the following method:
Amine thiocarboxyfluoride, malonate and inorganic base shown in a formula (1) are subjected to nucleophilic substitution reaction in an organic solvent at the temperature of 80 ℃ to obtain the N-alkyl/N-aryl thioamide derivative; the inorganic base is cesium carbonate; the organic solvent is acetonitrile; the molar ratio of the amine thiocarboxyfluoride shown in the formula (1) to the malonate is 1:1.5; the molar ratio of the amine thiocarboxyfluoride shown in the formula (1) to the inorganic base is 1:2.5;
The process is shown in a reaction formula (I):
In the reaction scheme (I),
R 1 is hydrogen, methoxy, methyl, halogen, ethyl formate, acetyl, phenyl;
R 2 is methyl, ethyl, isopropyl, n-hexyl, benzyl, 3-methoxypropyl, phenethyl;
R 3、R4 is methyl, ethyl, isopropyl and benzyl independently.
2. The process of claim 1, wherein the reaction time is 8 to 12 hours.
3. The method of claim 1, further comprising a post-treatment and column chromatography separation purification step; 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 1:3-1:10.
4. The method of manufacturing according to claim 1, characterized in that the method comprises: reacting amine thiocarboxyfluoride shown in formula (1), malonate and inorganic base in an organic solvent at 80 ℃, and monitoring by TLC until the raw materials are reacted; 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 N-alkyl/N-arylthioamide derivative shown in formula (2).
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