CN117946134A - Method for preparing sulfur-containing 1,2, 4-triazole derivative - Google Patents
Method for preparing sulfur-containing 1,2, 4-triazole derivative Download PDFInfo
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- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 title claims abstract description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 21
- 239000011593 sulfur Substances 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 15
- -1 aldehyde hydrazone compound Chemical class 0.000 claims abstract description 42
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 36
- 239000012363 selectfluor Substances 0.000 claims abstract description 36
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims abstract description 10
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 72
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 3
- 229940116357 potassium thiocyanate Drugs 0.000 claims description 3
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 51
- 230000035484 reaction time Effects 0.000 abstract description 30
- 239000000758 substrate Substances 0.000 abstract description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 238000004440 column chromatography Methods 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 21
- 239000007858 starting material Substances 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 8
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 238000003756 stirring Methods 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- DEFUMLHLEJNWIO-UHFFFAOYSA-N 2-methylbenzenecarbothioamide Chemical compound CC1=CC=CC=C1C(N)=S DEFUMLHLEJNWIO-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical class C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002573 chemokine receptor CXCR2 antagonist Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000013384 organic framework Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for preparing a sulfur-containing 1,2, 4-triazole derivative, belonging to the technical field of heterocyclic compounds; the method comprises the steps of mixing an aldehyde hydrazone compound, thiocyanate, a Selectfluor reagent and an organic solvent, and reacting for 1-5 hours at the temperature of 25-40 ℃ to obtain a sulfur-containing 1,2, 4-triazole derivative; the method has the advantages of mild reaction conditions, short reaction time, wide substrate application range and high yield.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a sulfur-containing 1,2, 4-triazole derivative.
Background
1,2, 4-Triazole building blocks are an important organic framework, which are widely present in drug molecules with good biological activity. The sulfur-containing 1,2, 4-triazole derivative is a special triazole compound, has antibacterial activity, CXCR2 receptor antagonist and HIV-1 inhibitor, and can be used as a fluorescent multifunctional detection and marking platform.
The SelectFluor reagent is a commercial oxidizing reagent with excellent performance, has the advantages of high reaction activity, safety, low toxicity and the like, and in recent years, the application of the SelectFluor reagent is more and more focused and researched by scientific researchers. In 2015, the Zhu Chen subject group achieved oxime C (sp 3) -H functionalization in aqueous medium under a Selectfluor/tetrabutylammonium iodide (Bu 4 NI) catalytic system to give 4, 5-dihydroisoxazole derivatives (eur. J. Org. Chem.2015, 2015 (23), 5084-5088). In 2018, the poplar group reported the formation of biologically active benzisothiazol-3-one derivatives from the oxidation of 2-methylthiobenzamide by Selectfluor (eur. J. Org. Chem.2018, 2018 (40), 5520-5523).
In the prior art, NBS and ammonium persulfate are adopted as oxidizing agents to synthesize the sulfur-containing 1,2, 4-triazole derivatives, but the reaction time is long and the reaction yield is low.
At present, the method for preparing the sulfur-containing 1,2, 4-triazole compound by oxidizing thiocyanate with a Selectfluor reagent has not been reported in domestic and foreign documents.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a method for preparing a sulfur-containing 1,2, 4-triazole derivative, which realizes the following aims: the reaction time is reduced, and the yield of the product is improved.
In order to solve the technical problems, the invention adopts the following technical scheme:
A method for preparing a sulfur-containing 1,2, 4-triazole derivative comprises the steps of mixing an aldehyde hydrazone compound, thiocyanate, a Selectfluor reagent and an organic solvent, and reacting for 1-5 hours at the temperature of 25-40 ℃ to obtain the sulfur-containing 1,2, 4-triazole derivative.
The aldehyde hydrazone compound has a structural formula:
；
The structural formula of the sulfur-containing 1,2, 4-triazole derivative is as follows:
Wherein X is any one of carbon and oxygen; ar is a benzene ring or naphthalene ring;
When Ar is a benzene ring, R represents a substituent at any position on the benzene ring and is independently any one of hydrogen, methyl, methoxy, halogen, cyano, trifluoromethyl and nitro;
when Ar is a naphthalene ring, R is hydrogen.
The thiocyanate is one of ammonium thiocyanate, sodium thiocyanate and potassium thiocyanate.
The organic solvent is one of acetonitrile, ethanol, 1, 2-dichloroethane and ethyl acetate.
The molar ratio of the aldehyde hydrazone compound to thiocyanate is 1 (1-2); the molar ratio of the aldehyde hydrazone compound to the Selectfluor reagent is 1: (1-1.5).
The ratio of the aldehyde hydrazone compound to the organic solvent is 0.2mmol (1-2 mL).
The Chinese name of the SelectFluor reagent is: 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt having a structural formula shown in formula III:
the preferable technical scheme is as follows:
The aldehyde hydrazone compound is N-morpholine-1-phenyl methane imine, 1- (4-trifluoromethyl phenyl) -N-morpholine methyl imine, 1- (4-cyano phenyl) -N-morpholine methyl imine, N-morpholine-1- (naphthalene-1-yl) methyl imine, N-morpholine-1- (naphthalene-2-yl) methyl imine, 1- (naphthalene-1-yl) -N- (piperidine-1-yl) methyl imine;
the specific structural formula is as follows:
；
The thiocyanate is ammonium thiocyanate;
The organic solvent is acetonitrile;
the molar ratio of the aldehyde hydrazone compound to thiocyanate is 1 (1.5-2); the molar ratio of the aldehyde hydrazone compound to the Selectfluor reagent is 1: (1.4-1.5);
the ratio of the aldehyde hydrazone compound to the organic solvent is 0.2 mmol/1 mL;
The reaction temperature is 25-40 ℃ and the reaction time is 1-3h.
Compared with the prior art, the invention has the following beneficial effects:
The method for preparing the sulfur-containing 1,2, 4-triazole derivative has the advantages that the application range of the substrate is wide, the reaction time is 1-5h, and the reaction yield is 60-99%; the preferable technical scheme is that the reaction time is 1-3h, and the reaction yield is 90-99%.
Detailed Description
The invention is further illustrated below in conjunction with specific examples, which are not to be construed as limiting the invention. Reagents, materials, instruments, and the like used in the following examples are commercially available unless otherwise indicated.
Example 1: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.4 mmol,30.4 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, then acetonitrile 1mL was added as a solvent, and the reaction was stirred and completed with complete consumption of starting material as detected by TLC and reaction time of 3 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 46.2mg, yield 94%.
Product nuclear magnetic data:
1H NMR (400 MHz, CDCl3)：δ8.24-8.22 (m, 2H), 7.57 (t,J= 7.6 Hz, 1H), 7.48 (t,J= 8.0 Hz, 2H), 4.27 (s,4H), 3.44 (br s, 4H).
13C NMR (100 MHz, CDCl3)：δ198.6, 178.1,133.1, 129.3, 128.8, 127.9, 63.1, 60.2。
Example 2: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), sodium thiocyanate (0.4 mmol,32.4 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, then acetonitrile 1mL was added as a solvent, and the reaction was stirred and completed with complete consumption of starting material as detected by TLC and reaction time of 3 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 37.2mg, yield 76%.
Example 3: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), potassium thiocyanate (0.4 mmol,38.9 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, then acetonitrile 1mL was added as a solvent, and the reaction was stirred and completed with complete consumption of starting material as detected by TLC and reaction time of 3 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 29.4mg in 60% yield.
Example 4: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.4 mmol,30.4 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, then 1mL of solvent ethanol was added, and the reaction was stirred and detected by TLC, the raw material consumption was complete, and the reaction time was 3 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 32.3mg, yield 66%.
Example 5: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.4 mmol,30.4 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, then 1mL of solvent 1, 2-dichloroethane was added and the reaction was stirred. The consumption of starting material was complete as measured by TLC, and the reaction time was 4 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 39.2mg, yield 80%.
Example 6: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.4 mmol,30.4 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, followed by addition of 1mL of ethyl acetate as a solvent, and the reaction was stirred and completed with complete consumption of raw materials as detected by TLC and a reaction time of 5 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 36.8mg, yield 75%.
Example 7: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.4 mmol,30.4 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, and then solvent acetonitrile 1mL was added thereto and reacted under stirring at 40℃with complete consumption of raw materials as detected by TLC, the reaction time was 2 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 44.6mg, yield 91%.
Example 8: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, and then solvent acetonitrile 1mL was added thereto and reacted under stirring at 30℃with complete consumption of raw materials as detected by TLC, the reaction time was 2 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 44.1mg, 90% yield.
Example 9: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.2 mmol,15.2 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added, and the reaction was stirred and detected by TLC, the raw material consumption was complete, and the reaction time was 2 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 34.6mg, 70% yield.
Example 10: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.2 mmol,22.8 mg) and SelectFluor reagent (0.2 mmol,70.9 mg) were added to a 10mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added, and the reaction was stirred and detected by TLC, the raw material consumption was complete, and the reaction time was 2 hours. The reaction mixture was concentrated in vacuo and the crude product was separated by column chromatography to give 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 30.1mg, 61% yield.
Example 11: synthesis of 2-phenyl-4-thioxy-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1-phenylmethanimine (0.2 mmol,38 mg), ammonium thiocyanate (0.4 mmol,30.4 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, and then acetonitrile 2mL, a solvent, was added thereto and stirred at 40℃for reaction, and the consumption of the raw materials was complete as detected by TLC, and the reaction time was 2 hours. Subsequently, the reaction mixture was concentrated in vacuo, and the crude product was separated by column chromatography to give 2-phenyl-4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 42.6mg, yield 86%.
Example 12: 4-thioxy-2- (p-tolyl) -8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1- (p-tolyl) azomethine (0.2 mmol,40.8 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then acetonitrile as a solvent 1mL was added thereto, and the reaction was stirred at 40℃and completed with complete consumption of the starting materials as detected by TLC, with a reaction time of 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 4-thioxy-2- (p-tolyl) -8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 40.6mg in 78% yield.
Product nuclear magnetic data:
1H NMR (CDCl3, 400 MHz):8.04 (d,J= 8.0 Hz, 2H), 7.21 (d,J= 8.0 Hz, 2H), 4.19 (s, 4H), 3.31 (br s, 4H), 2.35 (s, 3H).
13CNMR (CDCl3, 100 MHz)：δ198.4, 177.9, 143.9, 129.5, 129.2, 125.1, 63.1, 60.2, 21.8。
Example 13:2- (4-methoxyphenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
1- (4-Methoxyphenyl) -N-morpholinomethionine (0.2 mmol,44 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.3 mmol,106.3 mg) were added to a 10mL dry reaction tube at room temperature, and then acetonitrile as a solvent 1mL was added thereto under stirring at 40℃to complete the consumption of the raw materials as detected by TLC, and the reaction time was 5 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (4-methoxyphenyl) -4-thioxy-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 39.6mg in 72% yield.
Product nuclear magnetic data:
1H NMR (400 MHz, CDCl3)：δ8.19-8.16 (m, 2H), 6.97-6.94 (m, 2H), 4.26 (s, 4H), 3.87 (s, 3H), 2.83 (br s, 4H).
13C NMR(100 MHz, CDCl3)：δ198.1, 177.4, 163.6, 131.2, 120.2, 114.2, 63.1, 60.2, 55.6。
Example 14:2- (4-fluorophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
1- (4-Fluorophenyl) -N-morpholinomethionine (0.2 mmol,41.6 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then acetonitrile as solvent 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC, the reaction time was 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (4-fluorophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 42.5mg, 80% yield.
Product nuclear magnetic data:
1H NMR (400 MHz, CDCl3)：δδ8.26-8.21 (m, 2H), 7.18-7.12 (m, 2H), 4.26 (s, 4H), 3.41
(brs, 4H)。
13C NMR (100MHz, CDCl3)：δ198.6, 177.1, 165.9 (JC-F= 252.0 Hz), 131.7 (JC-F= 8.0 Hz), 124.2 (JC-F= 3.0 Hz), 116.0 (JC-F= 22.0 Hz), 63.1, 60.3.
Example 15:2- (4-chlorophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
1- (4-Chlorophenyl) -N-morpholinomethionine (0.2 mmol,44.8 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (4-chlorophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 47.5mg, 85% yield.
Product nuclear magnetic data:
1H NMR (400 MHz, CDCl3)：δ8.18-8.15 (m, 2H), 7.47-7.44 (m, 2H), 4.27 (s, 4H), 3.42 (br s, 4H).
13CNMR (100 MHz, CDCl3)：δ198.7, 177.3, 139.5, 130.6, 129.2, 126.5, 63.1, 60.3。
Example 16:2- (4-bromophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
1- (4-Bromophenyl) -N-morpholinomethionine (0.2 mmol,53.6 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (4-bromophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 45.2mg, 70% yield.
Product nuclear magnetic data:
1H NMR (400 MHz, CDCl3)：δ 8.11-8.07 (m, 2H),7.63-7.60 (m, 2H), 4.26 (t,J= 5.6 Hz, 4H), 3.45 (br s, 4H).
13C NMR(100 MHz, CDCl3)：δ198.7, 177.5, 132.2, 130.7, 128.1, 126.9, 63.1, 60.3。
example 17: 4-thioxy-2- (4- (trifluoromethyl) phenyl) -8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
1- (4-Trifluoromethylphenyl) -N-morpholinomethionine (0.2 mmol,51.6 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and was complete as detected by TLC with 2 hours of reaction time. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (4-trifluoromethylphenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 58.2mg, 92% yield.
Product nuclear magnetic data:
1H NMR (300 MHz, CDCl3)：δ8.36 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 1H), 4.29 (t, J = 4.8 Hz, 2H), 3.46 (br s, 4H)..
13C NMR (100 MHz, CDCl3)：δ199.0, 177.3, 134.5 (q, J = 32.7 Hz), 131.4, 129.6, 125.8, 125.7, 123.7 (q, J = 272.4 Hz), 63.1, 60.4.
Example 18:2- (4-cyanophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
1- (4-Cyanophenyl) -N-morpholinomethionine (0.2 mmol,43.0 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a10 mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (4-cyanophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 44.1mg, 90% yield.
Product nuclear magnetic data:
1H NMR (400 MHz, CDCl3)：δ8.33-8.30 (m, 2H), 7.76-7.74 (m, 2H), 4.26 (t,J= 4.8 Hz, 4H), 3.42 (br s, 4H).
13C NMR (100 MHz, CDCl3)：δ199.0, 176.9, 132.4, 132.2, 129.6, 118.0, 116.2, 63.0, 60.3.
Example 19:2- (naphthalen-1-yl) -4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1- (naphthalen-1-yl) azomethine (0.2 mmol,48.0 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a10 mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 1 hour. The reaction mixture was concentrated in vacuo and the crude was isolated by column chromatography to give 2- (naphthalen-1-yl) -4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 58.9mg in 99% yield.
1H NMR (400 MHz, CDCl3)：δ9.18 (d,J= 8.6 Hz, 1H), 8.64 (d,J= 7.3 Hz, 1H), 8.05 (d,J= 8.1 Hz, 1H), 7.93 (d,J= 8.1 Hz, 1H), 7.68 –7.64(m, 1H), 7.59 –7.55 (m, 2H), 4.40 (br s, 4H), 3.49 (brs, 4H).
13C NMR (100 MHz, CDCl3)：δ196.59, 178.89, 134.06, 134.01, 133.15, 131.10, 129.17, 128.11, 126.42, 126.38, 125.14, 124.17, 63.32, 60.36.
Example 20:2- (naphthalen-2-yl) -4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1- (naphthalen-2-yl) azomethine (0.2 mmol,48.0 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a10 mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 1 hour. The reaction mixture was concentrated in vacuo and the crude was isolated by column chromatography to give 2- (naphthalen-2-yl) -4-thioxo-8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid 58.3mg in 98% yield.
1H NMR (400 MHz, CDCl3)：δ8.85 (s, 1H), 8.20 (d,J= 10.5 Hz, 1H), 7.96 (d,J= 7.9 Hz, 1H), 7.92 –7.85 (m, 2H), 7.62 –7.51 (m, 2H), 4.30 (br s, 4H), 3.47 (br s, 4H).
13C NMR (100 MHz, CDCl3)：δ198.4, 178.0, 135.7, 132.9, 131.7, 129.5, 128.6, 128.4, 127.9, 126.9, 125.1, 124.3, 63.2, 60.3.
Example 21: 4-thioxy-2- (o-tolyl) -8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1- (o-tolyl) azomethine (0.2 mmol,40.8 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a 10mL dry reaction tube at room temperature, then acetonitrile as a solvent 1mL was added thereto, and the reaction was stirred at 40℃and completed with complete consumption of the starting materials as detected by TLC, with a reaction time of 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 4-thioxy-2- (o-tolyl) -8-oxa-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 44.9mg, 86% yield.
1H NMR (400 MHz, CDCl3)：δ8.27-8.25 (m, 1H), 7.45-7.40 (m, 1H), 7.31 (t,J= 7.6 Hz, 2H), 4.26 (s, 4H), 3.41 (br s, 4H), 2.68 (s, 3H).
13C NMR (100 MHz, CDCl3)：δ197.1, 179.0, 139.8, 132.4, 132.1, 131.8, 126.8, 126.1, 63.2, 60.2, 23.1.
Example 22: 4-thioxy-2- (p-tolyl) -1,3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N- (piperidin-1-yl) -1- (p-tolyl) azomethine (0.2 mmol,40.4 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a10 mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 3 hours. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 4-thioxy-2- (p-tolyl) -1,3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 42mg, 81% yield.
1H NMR (400 MHz, CDCl3)：δ8.11-8.09 (m, 2H), 7.25 (d,J= 8.0 Hz, 2H), 3.84 (t,J= 14.6 Hz, 2H), 2.84 (d,J= 10.0 Hz, 2H), 2.40 (s, 3H), 2.35 (s, 2H), 2.03-1.92 (m, 3H), 1.70-1.63 (m, 1H).
13C NMR (100 MHz, CDCl3)：δ200.0, 177.1, 143.4, 129.4, 129.1, 125.4, 62.1, 22.2, 21.8, 21.5.
Example 23:2- (naphthalen-1-yl) -4-thio-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
/>
1- (Naphthalen-1-yl) -N- (piperidin-1-yl) azomethine (0.2 mmol,47.4 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a10 mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 1 hour. The reaction mixture was concentrated in vacuo and the crude was isolated by column chromatography to give 2- (naphthalen-1-yl) -4-thio-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 54.5mg, 93% yield.
1H NMR (400 MHz, CDCl3)：δ9.19 (d,J= 8.8 Hz, 1H), 8.63-8.61 (m, 1H), 8.03 (d,J= 8.0 Hz, 1H), 7.92 (d,J= 8.4 Hz, 1H), 7.66-7.62 (m, 1H), 7.58-7.54 (m, 2H), 3.95 (t,J= 11.6 Hz, 2H), 2.99 (d,J= 10.8 Hz, 2H), 2.46 (d,J= 12.4 Hz, 2H), 2.12-2.02 (m, 3H), 1.70 (s, 1H).
13C NMR (100 MHz, CDCl3)：δ198.2, 178.2, 134.0, 133.6, 132.8, 131.1, 129.0, 127.9, 126.5, 126.3, 125.1, 124.5, 62.3, 22.4, 21.6.
Example 24:2- (3-nitrophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-onium-3-yl
N-morpholin-1- (3-nitrophenyl) azomethine (0.2 mmol,47 mg), ammonium thiocyanate (0.3 mmol,22.8 mg) and SelectFluor reagent (0.28 mmol,99.3 mg) were added to a10 mL dry reaction tube at room temperature, then solvent acetonitrile 1mL was added and the reaction was stirred at 40℃and complete consumption of starting material was detected by TLC with a reaction time of 1 hour. The reaction mixture was concentrated in vacuo and the crude product was isolated by column chromatography to give 2- (3-nitrophenyl) -4-thioxo-8-oxo-1, 3, 5-triazaspiro [4.5] dec-1-en-5-ium-3-yl compound as a pale yellow solid, 42mg, 72% yield.
1H NMR (400 MHz, CDCl3)：δ9.03 (t,J= 2.0 Hz, 1H), 8.56-8.54 (m, 1H), 8.41-8.38 (m, 1H), 7.68 (t,J= 8.0 Hz, 1H), 4.29 (t,J= 4.4 Hz, 4H), 3.46 (br s, 4H).
13C NMR (100 MHz, CDCl3)：δ199.2, 176.7, 148.5, 135.1, 130.0, 129.9, 127.3, 123.8, 63.0, 60.5.
Claims (6)
1. A process for preparing a sulfur-containing 1,2, 4-triazole derivative characterized by: the method comprises the steps of mixing an aldehyde hydrazone compound, thiocyanate, a Selectfluor reagent and an organic solvent, and reacting for 1-5 hours at the temperature of 25-40 ℃ to obtain the sulfur-containing 1,2, 4-triazole derivative.
2. A process for producing a sulfur-containing 1,2, 4-triazole derivative according to claim 1, characterized in that: the aldehyde hydrazone compound has a structural formula:
；
The structural formula of the sulfur-containing 1,2, 4-triazole derivative is as follows:
；
Wherein X is any one of carbon and oxygen; ar is a benzene ring or naphthalene ring;
When Ar is a benzene ring, R represents a substituent at any position on the benzene ring and is independently any one of hydrogen, methyl, methoxy, halogen, cyano, trifluoromethyl and nitro;
when Ar is a naphthalene ring, R is hydrogen.
3. A process for producing a sulfur-containing 1,2, 4-triazole derivative according to claim 1, characterized in that: the thiocyanate is one of ammonium thiocyanate, sodium thiocyanate and potassium thiocyanate.
4. A process for producing a sulfur-containing 1,2, 4-triazole derivative according to claim 1, characterized in that: the organic solvent is one of acetonitrile, ethanol, 1, 2-dichloroethane and ethyl acetate.
5. A process for producing a sulfur-containing 1,2, 4-triazole derivative according to claim 1, characterized in that: the molar ratio of the aldehyde hydrazone compound to thiocyanate is 1 (1-2); the molar ratio of the aldehyde hydrazone compound to the Selectfluor reagent is 1: (1-1.5).
6. A process for producing a sulfur-containing 1,2, 4-triazole derivative according to claim 1, characterized in that: the proportion of the aldehyde hydrazone compound to the organic solvent is 0.2mmol (1-2 mL).
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