Synthesis method of thiohydrazone compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a thiohydrazone compound. The synthesis method of the thiohydrazone compound comprises the following steps: taking (isocyano-imino) triphenylphosphine and one of thiophenol substances, thiol substances and disulfide substances as reactants, taking methanol or a mixed solution of methanol and water as a solvent, carrying out a reaction, and carrying out separation and purification to obtain the thiohydrazone compound. The synthesis method provided by the invention has the advantages of mild conditions, no need of additional metals and additives, easy separation of products, high yield and green and efficient reaction.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing thiohydrazone compounds. Background Art

[0002] Thiohydrazone compounds have a wide range of biological and pharmaceutical activities and are widely used in pharmaceutical chemistry. They are important intermediates for the synthesis of amines, ketones and diazo compounds and play an important role in the synthesis, application and research of pesticides, chiral additives and optoelectronic materials.

[0003] The structures of common thiohydrazone compounds are as follows: , , , .

[0004] The isonitrile functional group shows extremely rich reaction properties due to its unique structure. When the isonitrile group exists in the form of zwitterionic resonance, the terminal carbon atom has weak nucleophilicity and can combine with electrophilic reagents (such as protons, Lewis acids, aldehydes, imines, etc.) and undergo subsequent reactions to synthesize various amides and their analogs. When the isonitrile group exists in the form of carbene, the terminal carbon atom can undergo carbene insertion reaction under metal-free or metal-catalyzed conditions. In addition, the isonitrile part can also break the R-NC bond under special circumstances to react as a cyanide donor. The isonitrile functional group in N-isonitrile is directly connected to the nitrogen atom, and the reaction type is similar to that of C-isonitrile. At the same time, due to its unique CNN skeleton, it has special reactivity and is widely used in the construction of nitrogen-containing compounds. As a stable functionalized isonitrile, (isocyanoimino)triphenylphosphine has become an efficient synthetic strategy for the synthesis of heterocyclic compounds by virtue of its highly active isonitrile functional group.

[0005] (Isocyanoimido)triphenylphosphine is an N-isonitrile that is easy to prepare and synthesize. There are many reported reactions, which mainly include the following two categories.

[0006] The first type is the reaction of (isocyanoimino)triphenylphosphine with carbonyl compounds. In existing reports, the carbon-carbonyl bond of ketones is broken and reacted with (isocyanoimino)triphenylphosphine. Under the action of silver catalyst, various ketones can be converted into iminophosphine and nitrile compounds with high yields; (isocyanoimino)triphenylphosphine reacts with acyl chlorides and further reacts with p-toluenesulfonyl chloride in the presence of triethylamine as solvent at room temperature to obtain diazoketone compounds safely and efficiently; (isocyanoimino)triphenylphosphine reacts with acids in the presence of dichloromethane as solvent at room temperature to efficiently synthesize 134 oxadiazole compounds.

[0007] The second type is the reaction of (isocyanoimino)triphenylphosphine with alkynes. In existing reports, (isocyanoimino)triphenylphosphine is used as a cyanide source, and silver catalyzes the direct cyanation of alkyne carbon-hydrogen bonds, which is safe, green and efficient; (isocyanoimino)triphenylphosphine and alkynes undergo a 3+2 cycloaddition reaction under the action of an equivalent amount of silver and a catalytic amount of molybdenum hexacarbonyl to obtain monosubstituted pyrazoles; (isocyanoimino)triphenylphosphine and alkynes undergo an aminocyanation reaction under the action of a silver catalyst to synthesize β-aminoacrylonitrile with regio- and stereoselectivity.

[0008] Therefore, using (isocyanimido)triphenylphosphine as a reaction raw material to synthesize thiohydrazone compounds is a new research direction. Summary of the invention

[0009] In view of the deficiencies in the prior art, the present invention aims to provide a method for synthesizing thiohydrazone compounds, wherein (isocyanimido)triphenylphosphine and thiophenol or thiol or disulfide substances are used as reaction raw materials to synthesize thiohydrazone compounds, the reaction conditions are mild, no additional metals and additives are required, the product is easy to separate and the yield is high, and the reaction is green and efficient.

[0010] The technical purpose of the present invention is achieved through the following technical solutions: A method for synthesizing thiohydrazone compounds comprises taking (isocyanimido)triphenylphosphine and one of thiophenols, thiols and disulfides as reactants, taking methanol or a mixture of methanol and water as solvent for reaction, and separating and purifying to obtain thiohydrazone compounds.

[0011] In the present invention, the structural formula of the (isocyanimido)triphenylphosphine is: .

[0012] In the present invention, the structural formula of the thiophenols is: ; Among them, R1 is one of 4-methyl, 4-methoxy, 4-butyl, 4-trifluoromethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, 3-methoxy, 3-methyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-methoxy, 2-methyl, 2-fluoro, 2-chloro, 2-bromo, 2,4-difluoro, and 3,5-dimethyl.

[0013] Preferably, the thiophenol substance is one of the following substances: p-toluene thiophenol, p-methoxythiophenol, p-butylthiophenol, p-trifluoromethoxythiophenol, p-fluorothiophenol, p-chlorothiophenol, p-bromothiophenol, p-trifluoromethylthiophenol, m-methoxythiophenol, m-methylthiophenol, m-trifluoromethylthiophenol, m-fluorothiophenol, m-chlorothiophenol, m-bromothiophenol, o-methoxythiophenol, o-methylthiophenol, o-fluorothiophenol, o-chlorothiophenol, o-bromothiophenol, 2,4-dichlorothiophenol, and 3,5-dimethylthiophenol.

[0014] When (isocyanimido)triphenylphosphine and thiophenols are used as reaction raw materials to synthesize thiohydrazone compounds, the molar ratio of (isocyanimido)triphenylphosphine to thiophenols is 1:(1-2), preferably 1:1.5; the solvent is methanol, and the molar volume ratio of (isocyanimido)triphenylphosphine to the solvent is 1 mol:(10-20)L, preferably 1 mol:15L; the reaction temperature is 40-60°C, preferably 60°C.

[0015] The reaction process of the (isocyanoimido)triphenylphosphine and thiophenol substances is as follows: .

[0016] Taking p-toluenethiophenol as an example, based on free radical capture experiments and nitrogen protection control experiments, the reaction mechanism is speculated and discussed. The reaction mechanism of (isocyanoimino)triphenylphosphine and thiophenols is as follows: under heating conditions, p-toluenethiophenol will produce thiol radicals, which will then attack the isonitrile carbon atom of (isocyanoimino)triphenylphosphine to generate a thioimine radical intermediate. This intermediate will undergo a HAT reaction with another molecule of p-toluenethiophenol to capture a hydrogen atom and generate a new molecule of thiol radical to participate in the cycle, thereby achieving efficient preparation of thiohydrazone compounds. The reaction mechanism is as follows Figure 1 shown.

[0017] In the present invention, the thiol substance is one of the following substances: n-butyl mercaptan, n-hexyl mercaptan, 2-naphthalenethiol, p-tolylmethyl mercaptan, 4-(trifluoromethyl)benzyl mercaptan, 2-thiophenethiol, (3S, 5S, 7S)-adamantane-1-thiol, furan-2-methyl mercaptan; and their structural formulas are as follows: .

[0018] When (isocyanimido)triphenylphosphine and thiol substances are used as reaction raw materials to synthesize thiohydrazone compounds, the molar ratio of (isocyanimido)triphenylphosphine to thiol substances is 1: (1-2), preferably 1: 1.5; the solvent is methanol, and the molar volume ratio of (isocyanimido)triphenylphosphine to the solvent is 1 mol: (10-20) L, preferably 1 mol: 15 L; the reaction temperature is 40-60° C., preferably 60° C.

[0019] In the present invention, the structural formula of the disulfide substance is: or ; Among them, R2 is one of hydrogen, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-methoxy, 4-trifluoromethyl, 3-methoxy, and 3-fluoro.

[0020] Preferably, the disulfide substance is one of the following substances: p-toluene disulfide, diphenyl disulfide, 1,2-bis(4-fluorophenyl) disulfide, 1,2-bis(4-chlorophenyl) disulfide, 1,2-bis(4-bromophenyl) disulfide, 1,2-bis(4-methoxyphenyl) disulfide, 1,2-bis(4-(trifluoromethyl)phenyl) disulfide, 1,2-bis(3-methoxyphenyl) disulfide, 1,2-bis(3-fluorophenyl) disulfide, and dithiophene disulfide.

[0021] When (isocyanimido)triphenylphosphine and disulfide substances are used as reaction raw materials to synthesize thiohydrazone compounds, the molar ratio of (isocyanimido)triphenylphosphine to disulfide substances is 1:(2-4), preferably 1:3; the solvent is a mixture of methanol and water in a volume ratio of (15-25):1, preferably a mixture of methanol and water in a volume ratio of 20:1; the molar volume ratio of (isocyanimido)triphenylphosphine to the solvent is 1 mol:(3-8)L, preferably 1 mol:5L; the reaction temperature is 100-120°C, preferably 120°C.

[0022] The reaction process of the (isocyanoimido)triphenylphosphine and disulfide substances is as follows: .

[0023] Taking p-toluene disulfide as an example, based on free radical capture verification experiments, light protection treatment, and control experiments such as the construction of a nitrogen protection system, the reaction mechanism is speculated and discussed. The reaction mechanism of (isocyanatoimido)triphenylphosphine and disulfide substances is: under the action of air oxidation, disulfide will produce sulfide radicals. After the sulfide radicals are generated from disulfide, they will selectively attack the carbon atom at the isonitrile end of N-isonitrile, thereby promoting the formation of sulfoimine free radical intermediates. The intermediate reacts with another molecule of sulfide free radicals to achieve efficient and rapid synthesis of disulfide hydrazone compounds. The reaction mechanism is as follows: Figure 2 shown.

[0024] In the present invention, after the reaction is completed, the reaction system is first quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, and then dried with anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain a product thiohydrazone compound.

[0025] The thiohydrazone compounds synthesized by the present invention are the following substances: [(E)-[(4-methylphenyl)thio]methylidene]hydrazine, [(E)-[(4-methoxyphenyl)thio]methylidene]hydrazine, [(E)-{[4-(2-methylprop-2-yl)phenyl]thio}methylidene]hydrazine, [(E)-[(4-fluorophenyl)thio]methylidene]hydrazine, [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine, [(E)-[(3-methoxyphenyl)thio]methylidene]hydrazine, [(E)-[(3-methylphenyl)thio]methylidene]hydrazine, [(E)-[(3-fluorophenyl)thio]methylidene]hydrazine, [(E)-[(3-chlorophenyl)thio]methylidene]hydrazine, [(E)-[ [(E)-{[3-(trifluoromethyl)phenyl]thio}methylidene]hydrazine, [(E)-[(2-methoxyphenyl)thio]methylidene]hydrazine, [(E)-[(2-methylphenyl)thio]methylidene]hydrazine, [(E)-[(2-fluorophenyl)thio]methylidene]hydrazine, [(E)-[(2-chlorophenyl)thio]methylidene]hydrazine, [(E)-[(2-bromophenyl)thio]methylidene]hydrazine, [(E)-{[2-(trifluoromethyl)phenyl]thio}methylidene]hydrazine, [(E)-(butylthio)methylidene]hydrazine, [(E)-(hexylthio)methylidene]hydrazine, 1-[(E)-[(3,5-dimethylphenyl)thio]methylidene]hydrazine 1-[(E)-(tricyclo[3.3.1.13,7]dec-1-ylthio)methylidene]hydrazine, [(E)-[(4-methylphenyl)methyl]thio}methylidene]hydrazine, 1-[(E)-[(2,4-difluorophenyl)thio]methylidene]hydrazine, [(E)-({[4-(trifluoromethyl)phenyl]methyl}thio)methylidene]hydrazine, [(E)-[(furan-2-ylmethyl)thio]methylidene]hydrazine, 1-[(E)-(tricyclo[3.3.1.13,7]dec-1-ylthio)methylidene]hydrazine, [(E)-[(4-methylphenyl)thio]methylidene][(E)-phenylmethylidene]hydrazine, [(E)-({4-[(trifluoromethyl)phenyl]methyl}thio] [(bis((4-( ...

[0026] The present invention utilizes (isocyanoimido)triphenylphosphine to react with thiophenol or thiol or disulfide to synthesize thiohydrazone compounds. This synthesis method can cleverly introduce sulfur atoms when constructing the hydrazone functional group, and is applicable to the efficient preparation of thiohydrazone and disulfide hydrazone compounds, and has the advantages of simple operation, mild reaction conditions, and green economy. Among them, the first system uses (isocyanoimido)triphenylphosphine and thiophenol substances as starting materials, methanol as a reaction solvent, and synthesizes a series of thiohydrazone compounds efficiently and environmentally friendly through free radical reactions. This reaction process has significant advantages, mild reaction conditions, easy to obtain reaction raw materials, and can be achieved without additional catalysts or oxidants. It provides a green and efficient synthesis strategy for the preparation of thiohydrazone compounds, which is of great significance in pharmaceutical chemistry and pesticide chemistry; the second system uses (isocyanoimido)triphenylphosphine and thiol substances as starting materials, and methanol as a reaction solvent. , when the substituent is an electron-donating group or an electron-withdrawing group, good to excellent yields can be obtained. When the substituent is a halogen, the target product is given in good yield. The reaction is also applicable to alkyl mercaptans and heterocyclic mercaptans. The third system uses (isocyanimido)triphenylphosphine and disulfide substances as starting materials and a mixture of methanol and water as the reaction solvent to efficiently prepare a series of dithiohydrazone compounds. This reaction has multiple advantages. The raw materials are cheap and easy to obtain. No metals or additives are required. The operation process is simple and the post-reaction treatment is convenient. It also has the characteristics of green and clean.

[0027] The thiohydrazone compounds synthesized by the present invention can be used to prepare the following derivatives through derivatization reactions: [(E)-[(4-Methylphenyl)thio]methylidene][(E)-phenylmethylidene]hydrazine; 2-[(4-Methylphenyl)thio]-5-phenyl-1,3,4-oxadiazole; 3-[(4-Methylphenyl)thio]-4,5-diphenyl-1,2,4-diazaphosphacyclopentane; (diazomethyl)(p-tolyl)sulfane; N-{2-[(4-methylphenyl)thio]-1-phenylethyl}aniline; (2,3-Diphenylcyclopropyl)(4-methylphenyl)sulfane; [(E)-[(4-Methylphenyl)thio]methylenehydrazine; [(E)-[(4-Methylphenyl)sulfonyl]methylenehydrazine; N-{[(E)-[(4-methylphenyl)thio]methylidene]amino}-4-methylbenzenesulfonamide; (4-methylphenyl){[(4-methylphenyl)thio]methyl}sulfane; Methoxy{bis[(4-methylphenyl)thio]}methane.

[0028] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention uses (isocyanoimido)triphenylphosphine and thiophenols, thiols or disulfides as raw materials. When thiophenols are used as raw materials, thiophenols will generate thiol radicals, which will then attack the isonitrile terminal carbon atom of (isocyanoimido)triphenylphosphine to generate a thioimine radical intermediate. The intermediate undergoes a HAT reaction with another thiophenol molecule to capture a hydrogen atom, and at the same time, a new thiol radical molecule is generated to participate in the cycle, thereby achieving efficient preparation of thiohydrazone compounds. When thiol substances are used as raw materials, when the substituents are electron-donating groups and electron-withdrawing groups, good to excellent yields can be obtained. When the substituents are halogens, the target product is given in good yields. The reaction is also applicable to alkylthiols and heterocyclic thiols, and the target product can be obtained in medium to high yields. When disulfide substances are used as raw materials, most disulfides with electron-donating groups (methoxy, methyl, trifluoromethyl, etc.) at the para position can obtain disulfide hydrazone compound products with medium to high yields. Disulfides with halogen groups (fluorine, chlorine, bromine, etc.) at the para position have good tolerance to the reaction and can obtain disulfide hydrazone compound products with medium to high yields. The steric hindrance of the meta-substituent has no obvious effect on the yield of the target product. Dithiophene disulfide can also obtain the target product with medium yields. (2) The reaction conditions of the present invention are simple and mild, applicable to a wide range of substrates, and the product is easy to separate and has a high yield, which is conducive to industrial production; (3) The thiohydrazone compounds synthesized by the present invention can be further derivatized to obtain sulfoxide or sulfone compounds, diazo compound precursors, important drug intermediate acylhydrazone compounds, 134-oxadiazole compounds with biological and pharmaceutical activities, and asymmetric azine with important application value in optoelectronic liquid crystal materials, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The diagram is a reaction mechanism diagram of (isocyanimido)triphenylphosphine and thiophenol substances of the present invention; Figure 2 The diagram is a reaction mechanism diagram of (isocyanimido)triphenylphosphine and disulfide substances of the present invention; Figure 3 This is the H NMR spectrum of the product of Example 1 of the present invention; Figure 4 This is the NMR carbon spectrum of the product of Example 1 of the present invention; Figure 5 This is the H NMR spectrum of the product of Example 2 of the present invention; Figure 6 This is the NMR carbon spectrum of the product of Example 2 of the present invention; Figure 7 This is the H NMR spectrum of the product of Example 3 of the present invention; Figure 8 This is the NMR carbon spectrum of the product of Example 3 of the present invention; Fig. 9 This is the H NMR spectrum of the product of Example 4 of the present invention; Fig.10 This is the NMR carbon spectrum of the product of Example 4 of the present invention; Fig.11 This is the nuclear magnetic fluorine spectrum of the product of Example 4 of the present invention; Fig.12 This is the H NMR spectrum of the product of Example 5 of the present invention; Fig.13 This is the NMR carbon spectrum of the product of Example 5 of the present invention; Fig.14 This is the H NMR spectrum of the product of Example 6 of the present invention; Fig.15 This is the NMR carbon spectrum of the product of Example 6 of the present invention; Fig.16 This is the H NMR spectrum of the product of Example 7 of the present invention; Fig.17 This is the NMR carbon spectrum of the product of Example 7 of the present invention; Fig.18 This is the H NMR spectrum of the product of Example 8 of the present invention; Fig.19 This is the NMR carbon spectrum of the product of Example 8 of the present invention; Fig. 20 This is the NMR fluorine spectrum of the product of Example 8 of the present invention; Fig.21 This is the H NMR spectrum of the product of Example 9 of the present invention; Fig. 22 This is the NMR carbon spectrum of the product of Example 9 of the present invention; Fig.23This is the H NMR spectrum of the product of Example 10 of the present invention; Fig.24 This is the NMR carbon spectrum of the product of Example 10 of the present invention; Fig.25 This is the H NMR spectrum of the product of Example 11 of the present invention; Fig.26 This is the NMR carbon spectrum of the product of Example 11 of the present invention; Fig. 27 This is the H NMR spectrum of the product of Synthesis Example 1 of the present invention; Fig.28 This is the NMR carbon spectrum of the product of Synthesis Example 1 of the present invention. DETAILED DESCRIPTION

[0030] The present invention is further described below with reference to the examples. The raw materials used in the examples, unless otherwise specified, are all commercially available conventional raw materials; the process methods used in the examples, unless otherwise specified, are all conventional methods in the art.

[0031] Example 1 This example synthesizes [(E)-[(4-methylphenyl)thio]methylidene]hydrazine, and the structural formula is as follows: .

[0032] The synthesis method is: (Isocyanoimido)triphenylphosphine (0.2 mmol), p-toluene thiophenol (0.3 mmol) and 3 mL of methanol were added to a pressure tube and heated at 60°C for 7 h. After the reaction, the reaction system was quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain [(E)-[(4-methylphenyl)thio]methylidene]hydrazine, weighing 30.6 mg, with a yield of 92%. The hydrogen and carbon spectra were as follows: Figure 3-4 As shown, where: 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.0 Hz, 2H), 7.23 - 7.15 (m,3H), 5.40 (s, 2H), 2.36 (s, 3H).

[0033] 13 C NMR (100 MHz, CDCl3) δ138.8, 138.2, 132.6, 130.3, 127.4, 21.2.

[0034] HRMS (ESI) m / z: [M+H] +Calculation for C8H 11 N2S + 167.0638; found 167.0633.

[0035] Example 2 This example synthesizes [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine, and the structural formula is as follows: .

[0036] The synthesis method is: (Isocyanoimido)triphenylphosphine (0.2 mmol), p-chlorobenzenethiol (0.4 mmol) and 4 mL of methanol were added to a pressure tube and heated at 40°C for 10 h. After the reaction, the reaction system was quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine with a yield of 96%. The hydrogen and carbon spectra were as follows: Figure 5-6 As shown, where: 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 7.15 (s, 1H), 5.47 (s, 2H).

[0037] 13 C NMR (101 MHz, CDCl3) δ 135.9, 134.9, 133.5, 129.7, 129.6.

[0038] HRMS (ESI) m / z: [M+H] + Calcd for C7H8ClN2S + 187.0092; found 187.0092.

[0039] Example 3 This example synthesizes [(E)-[(3-methylphenyl)thio]methylidene]hydrazine, and the structural formula is as follows: .

[0040] The synthesis method is: (Isocyanoimido)triphenylphosphine (0.2 mmol), m-methylthiophenol (0.2 mmol) and 2 mL of methanol were added to a pressure tube and heated at 50°C for 8 h. After the reaction, the reaction system was quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine with a yield of 92%. The hydrogen and carbon spectra were as follows: Figure 7-8 As shown, where: 1 H NMR(400 MHz, CDCl3)δ 7.30 - 7.25 (m, 3H), 7.23 (s, 1H), 7.20 - 7.13(m, 1H), 5.43 (s, 2H), 2.36 (s, 3H).

[0041] 13 C NMR (101 MHz, CDCl3)δ 139.5, 137.5, 132.9, 130.8, 130.7, 129.35,129.32, 21.2.

[0042] HRMS (ESI) m / z: [M+H] + Calculation for C8H 11 N2S + 167.0638; found 167.0654.

[0043] Example 4 In this example, on the basis of Example 1, p-toluene thiophenol was replaced with an equal molar amount of m-trifluoromethylbenzenethiol to synthesize [(E)-{[3-(trifluoromethyl)phenyl]thio}methylidene]hydrazine, the structural formula of which is as follows: .

[0044] The product yield is 80%, and the hydrogen spectrum, carbon spectrum, and fluorine spectrum are as follows Figure 9-11 As shown, where: 1 H NMR(400 MHz, CDCl3)δ 7.39 - 7.31 (m, 1H), 7.26 - 7.16 (m, 3H), 7.09- 7.02 (m, 1H), 5.50 (s, 2H).

[0045] 13C NMR (101 MHz, CDCl3)) δ 135.1, 134.3, 132.7, 132.0 (q, J = 32.8Hz), 130.0, 128.6 (q, J = 3.8 Hz), 125.1 (q, J = 3.7 Hz), 123.5 (q, J = 273.7Hz).

[0046] 19 F NMR (376 MHz, CDCl3)δ -63.8.

[0047] HRMS (ESI) m / z: [M+H] + Calculation for C8H8F3N2S + 221.0355; found 221.0352.

[0048] Example 5 In this example, on the basis of Example 1, p-toluene thiophenol was replaced with an equal molar amount of o-methoxybenzenethiol to synthesize [(E)-[(2-methoxyphenyl)thio]methylidene]hydrazine, and the structural formula is as follows: .

[0049] The product yield was 88%, and the hydrogen and carbon spectra were as follows: Figure 12-13 As shown, where: 1 H NMR(400 MHz, CDCl3) δ 7.43 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H), 7.38- 7.32 (m, 1H), 7.16 (s, 1H), 7.00 - 6.92 (m, 2H), 5.46 (s, 2H), 3.89 (s,3H). 13 C NMR (101 MHz, CDCl3)δ 158.4, 137.1, 134.0, 130.3, 121.4, 118.6,111.4. HRMS (ESI) m / z: [M+H] + Calculation for C8H 11 N2OS + 183.0587; found 183.0574. Example 6 In this example, based on Example 1, p-toluene thiophenol was replaced with an equal molar amount of 2-naphthalenethiol to synthesize [(E)-(naphthalene-2-ylthio)methylidene]hydrazine, and the structural formula is as follows: .

[0050] The product yield was 87%, and the hydrogen and carbon spectra were as follows: Figure 14-15 As shown, where: 1 H NMR(400 MHz, CDCl3)δ 7.95 (brs, 1H), 7.85 - 7.74 (m, 3H), 7.53 -7.46 (m, 3H), 7.31 (s, 1H), 5.50 (s, 2H).

[0051] 13 C NMR (101 MHz, CDCl3)δ 136.9, 133.7, 132.8, 131.6, 129.3, 129.1,128.3, 127.8, 127.6,127.0, 126.9.

[0052] HRMS (ESI) m / z: [M+H] + Calculate for C 11 H 11 N2S + 203.0638; found 203.0636.

[0053] Example 7 In this example, based on Example 3, m-methylthiophenol was replaced with an equal molar amount of 2-thiophenethiol to synthesize [(E)-(thiophen-2-ylthio)methylidene]hydrazine, and the structural formula is as follows: .

[0054] The product yield was 73%, and the hydrogen and carbon spectra were as follows: Figure 16-17 As shown, where: 1 H NMR (400 MHz, CDCl3)δ 7.47 (dd, J1 = 1.2 Hz, J2 = 5.6 Hz, 1H), 7.25 (dd, J1 = 1.2 Hz, J2 = 3.6 Hz, 1H), 7.10 (s, 1H), 7.06 (dd, J1 = 3.6 Hz, J2 =5.6 Hz, 1H), 5.39 (s, 2H).

[0055] 13C NMR (101 MHz, CDCl3)δ 138.4, 135.3, 131.1, 128.1, 127.2.

[0056] HRMS (ESI) m / z: [M+H] + Calcd for C5H7N2S2 + 159.0046; found 159.0041.

[0057] Example 8 In this example, based on Example 2, p-chlorobenzenethiol was replaced with an equal molar amount of 4-(trifluoromethyl)benzyl mercaptan to synthesize [(E)-({[4-(trifluoromethyl)phenyl]methyl}thio)methylidene]hydrazine, the structural formula of which is as follows: .

[0058] The product yield was 77%, and the hydrogen spectrum, carbon spectrum, and fluorine spectrum were as follows: Figure 18-20 As shown, where: 1 H NMR (400 MHz, CDCl3)δ 7.53 (dd, J1 = 8.0 Hz, J2 = 58.4 Hz, 4H), 7.09 (s, 1H), 5.33 (s, 2H), 4.10 (s, 2H).

[0059] 13 C NMR (101 MHz, CDCl3)δ 141.3, 136.0, 130.0 (q, J = 32.7 Hz), 129.1,124.0 (q, J = 273.1 Hz), 125.9 (q, J = 3.7 Hz).

[0060] 19 F NMR (376 MHz, CDCl3) δ -57.9.

[0061] HRMS (ESI) m / z: [M+H] + calculation for C9H 10 F3N2S + 235.0512; found 235.0331.

[0062] Example 9 This example synthesizes diphenylmethylcarbohydrazide disulfate, the structural formula of which is as follows: .

[0063] The synthesis method is: (Isocyanoimido)triphenylphosphine (0.2 mmol) and p-toluene disulfide (0.6 mmol) were dissolved in a pressure tube containing 1 mL of solvent (methanol: water = 20:1), and heated at 120 ° C for 10 h. After the reaction, the reaction system was quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain the target product diphenylmethylcarbohydrazide disulfate, weighing 40.4 mg, with a yield of 70%. The hydrogen and carbon spectra were as follows: Figure 21-22 As shown, where: 1 H NMR (400 MHz, CDCl3) δ 7.23 - 7.15 (m, 4H), 7.13 - 7.05 (m, 4H), 5.92 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H).

[0064] 13 C NMR (100 MHz, CDCl3) δ 138.5, 138.3, 137.9, 133.0, 132.6, 129.9,129.7, 128.6, 126.6, 21.3, 21.2.

[0065] HRMS (ESI) m / z:calcd for C 15 H 17 N2S2 + 289.0828; found 289.0824.

[0066] Example 10 This example synthesizes {bis[(4-chlorophenyl)thio]methylidene}hydrazine, and the structural formula is as follows: .

[0067] The synthesis method is: (Isocyanoamino)triphenylphosphine (0.2 mmol) and 1,2-bis(4-chlorophenyl) disulfide (0.4 mmol) were dissolved in a pressure tube containing 1 mL of solvent (methanol: water = 15:1), and the reaction was heated at 110°C for 12 h. After the reaction, the reaction system was quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain the target product {bis[(4-chlorophenyl)thio]methylidene}hydrazine with a yield of 61%. The hydrogen and carbon spectra were as follows: Figure 23-24 As shown, where: 1H NMR (400 MHz, CDCl3)δ 7.37 - 7.07 (m, 8H), 6.10 (s, 2H).

[0068] 13 C NMR (100 MHz, CDCl3)δ 135.1, 134.6, 134.4, 133.6, 133.5, 130.7,129.3, 129.1, 128.6.

[0069] HRMS (ESI) m / z: [M+H] + Calculate for C 13 H 11 Cl2N2S2 + 328.9736; found328.9724.

[0070] Embodiment 11 This example synthesizes [bis(thiophene-2-ylthio)methylidene]hydrazine, and the structural formula is as follows: .

[0071] The synthesis method is: (Isocyanoimido)triphenylphosphine (0.2 mmol) and dithiophene disulfide (0.8 mmol) were dissolved in a pressure tube containing 1.6 mL of solvent (methanol: water = 25:1), and heated at 100 ° C for 12 h. After the reaction, the reaction system was quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain the target product [bis(thiophene-2-ylthio)methylidene]hydrazine with a yield of 48%. The hydrogen and carbon spectra were as follows: Figure 25-26 As shown, where: 1 H NMR (400 MHz, CDCl3)δ 7.52 (dd, J1 = 1.2 Hz, J2 = 5.6 Hz, 1H), 7.48 (dd, J1 = 1.2 Hz, J2 = 5.2 Hz, 1H), 7.25 (dd, J1 = 1.2 Hz, J2 = 3.6 Hz, 1H), 7.16 (dd, J1 = 1.6 Hz, J2 = 3.6 Hz, 1H), 7.08- 7.01 (m, 2H), 5.96 (s, 2H).

[0072] 13C NMR (100 MHz, CDCl3)δ 137.9, 136.7, 135.5, 131.7, 131.4, 129.4,127.8, 127.5, 126.4.

[0073] HRMS (ESI) m / z: [M+H] + Calcd for C9H9N2S4 + 272.9644; found 272.9658.

[0074] Application Synthesis Example 1 This example synthesizes [(E)-[(4-methylphenyl)thio]methylene][(E)-phenylmethylene]hydrazine, the structural formula is as follows: .

[0075] The synthesis method is: The p-tolyl group ( E )-Methanehydrazinethioate (0.2 mmol, 33.2 mg) and benzaldehyde (0.3 mmol, 1.5 equiv, 31.8 mg) were dissolved in methanol (3 mL). Stirred at 60 °C in an air atmosphere for 7 hours. After the reaction, the mixture was quenched with saturated Na2CO3 solution and then extracted with dichloromethane (DCM). Drying over anhydrous Na2SO4 and distillation under reduced pressure. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain the target thioazine product (38.7 mg, 76%). The hydrogen and carbon spectra are as follows Figure 27-28 As shown, where: 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.01 (s, 1H), 7.88 - 7.83 (m,2H), 7.47 - 7.40 (m, 5H), 7.21 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.6,160.3, 139.1,133.8, 132.9, 131.4,130.3,129.0, 128.8,128.7, 21.2. HRMS (ESI) m / z: [M+H] + Calculate for C 15 H 15N2S + 255.0951; found 255.0950。

Claims

1. A method for synthesizing a thiohydrazone compound, characterized in that: Using (isocyanimido)triphenylphosphine and one of thiophenols, thiols and disulfides as reactants, using methanol or a mixture of methanol and water as a solvent for reaction, and separating and purifying to obtain a thiohydrazone compound; The structural formula of the thiophenols is: ， Wherein, R1 is one of 4-methyl, 4-methoxy, 4-butyl, 4-trifluoromethoxy, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, 3-methoxy, 3-methyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-methoxy, 2-methyl, 2-fluoro, 2-chloro, 2-bromo, 2,4-difluoro, and 3,5-dimethyl; The thiol substance is one of the following substances: n-butyl mercaptan, n-hexyl mercaptan, 2-naphthalenethiol, p-tolylmethyl mercaptan, 4-(trifluoromethyl)benzyl mercaptan, 2-thiophenethiol, (3S, 5S, 7S)-adamantane-1-thiol, furan-2-methyl mercaptan; and their structural formulas are as follows: The structural formula of the disulfide substance is: or ; Among them, R2 is one of hydrogen, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-methoxy, 4-trifluoromethyl, 3-methoxy, and 3-fluoro.

2. The method for synthesizing thiohydrazone compounds according to claim 1, characterized in that: When (isocyanimido)triphenylphosphine and thiophenols are used as reaction raw materials to synthesize thiohydrazone compounds, the molar ratio of (isocyanimido)triphenylphosphine to thiophenols is 1:(1-2); the solvent is methanol, and the molar volume ratio of (isocyanimido)triphenylphosphine to the solvent is 1 mol:(10-20)L; the reaction temperature is 40-60°C.

3. The method for synthesizing thiohydrazone compounds according to claim 1, characterized in that: When (isocyanimido)triphenylphosphine and thiol substances are used as reaction raw materials to synthesize thiohydrazone compounds, the molar ratio of (isocyanimido)triphenylphosphine to thiol substances is 1: (1-2); the solvent is methanol, and the molar volume ratio of (isocyanimido)triphenylphosphine to the solvent is 1 mol: (10-20) L; the reaction temperature is 40-60°C.

4. The method for synthesizing thiohydrazone compounds according to claim 1, characterized in that: When (isocyanimido)triphenylphosphine and disulfide substances are used as reaction raw materials to synthesize thiohydrazone compounds, the molar ratio of (isocyanimido)triphenylphosphine to disulfide substances is 1: (2-4); the solvent is a mixed solution of methanol and water in a volume ratio of (15-25) : 1, and the molar volume ratio of (isocyanimido)triphenylphosphine to the solvent is 1 mol: (3-8) L; the reaction temperature is 100-120°C.

5. The method for synthesizing thiohydrazone compounds according to claim 1, characterized in that: After the reaction is completed, the reaction system is first quenched with a saturated Na2CO3 solution, then extracted with dichloromethane, and then dried with anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain the product thiohydrazone compound.

6. The method for synthesizing thiohydrazone compounds according to claim 1, characterized in that: The synthesized thiohydrazone compounds are the following substances: [(E)-[(4-methylphenyl)thio]methylidene]hydrazine, [(E)-[(4-methoxyphenyl)thio]methylidene]hydrazine, [(E)-{[4-(2-methylprop-2-yl)phenyl]thio}methylidene]hydrazine, [(E)-[(4-fluorophenyl)thio]methylidene]hydrazine, [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine, [(E)-[(3-methoxyphenyl)thio]methylidene]hydrazine, [(E)-[(3-methylphenyl)thio]methylidene]hydrazine, [(E)-[(3-fluorophenyl)thio]methylidene]hydrazine, [(E)-[(3-chlorophenyl)thio]methylidene]hydrazine, [(E)-[(3 1-[(E)-[(3-(trifluoromethyl)phenyl]thio}methylidene]hydrazine, [(E)-[(2-methoxyphenyl)thio]methylidene]hydrazine, [(E)-[(2-methylphenyl)thio]methylidene]hydrazine, [(E)-[(2-fluorophenyl)thio]methylidene]hydrazine, [(E)-[(2-chlorophenyl)thio]methylidene]hydrazine, [(E)-[(2-bromophenyl)thio]methylidene]hydrazine, [(E)-{[2-(trifluoromethyl)phenyl]thio}methylidene]hydrazine, [(E)-(butylthio)methylidene]hydrazine, [(E)-(hexylthio)methylidene]hydrazine, 1-[(E)-[(3,5-dimethylphenyl)thio]methylidene]hydrazine ]hydrazine, [(E)-(naphthalen-2-ylthio)methylidene]hydrazine, [(E)-(thiophen-2-ylthio)methylidene]hydrazine, [(E)-{[(4-methylphenyl)methyl]thio}methylidene]hydrazine, 1-[(E)-[(2,4-difluorophenyl)thio]methylidene]hydrazine, [(E)-({[4-(trifluoromethyl)phenyl]methyl}thio)methylidene]hydrazine, [(E)-[(furan-2-ylmethyl)thio]methylidene]hydrazine, 1-[(E)-(tricyclo[3.3.1.13,7]dec-1-ylthio)methylidene]hydrazine, [(E)-[(4-methylphenyl)thio]methylidene][(E)-phenylmethylidene]hydrazine, [(E)-({4-[(trifluoromethyl) [(bis[(4-(trifluoromethyl)phenyl]thio]methylidene)hydrazine, {bis[(3-methoxyphenyl)thio]methylidene}hydrazine, {bis[(3-chlorophenyl)thio]methylidene}hydrazine, [bis(thiophen-2-ylthio)methylidene]hydrazine, {bis[(4-fluorophenyl)thio]methylidene}hydrazine, {bis[(4-chlorophenyl)thio]methylidene}hydrazine, {bis[(4-bromophenyl)thio]methylidene}hydrazine, {bis[(4-methoxyphenyl)thio]methylidene}hydrazine, (bis{[4-(trifluoromethyl)phenyl]thio}methylidene)hydrazine, {bis[(3-methoxyphenyl)thio]methylidene}hydrazine, {bis[(3-chlorophenyl)thio]methylidene}hydrazine, [bis(thiophen-2-ylthio)methylidene]hydrazine, {bis[(4-methylphenyl)thio]methylidene}[(Z)-phenylmethylidene]hydrazine.

7. The method for synthesizing thiohydrazone compounds according to claim 1, characterized in that: The synthesized thiohydrazone compounds are used to prepare the following derivatives through derivatization reactions: [(E)-[(4-Methylphenyl)thio]methylidene][(E)-phenylmethylidene]hydrazine; 2-[(4-Methylphenyl)thio]-5-phenyl-1,3,4-oxadiazole; 3-[(4-Methylphenyl)thio]-4,5-diphenyl-1,2,4-diazaphosphacyclopentane; (diazomethyl)(p-tolyl)sulfane; N-{2-[(4-methylphenyl)thio]-1-phenylethyl}aniline; (2,3-Diphenylcyclopropyl)(4-methylphenyl)sulfane; [(E)-[(4-Methylphenyl)thio]methylenehydrazine; [(E)-[(4-Methylphenyl)sulfonyl]methylenehydrazine; N-{[(E)-[(4-methylphenyl)thio]methylidene]amino}-4-methylbenzenesulfonamide; (4-methylphenyl){[(4-methylphenyl)thio]methyl}sulfane; Methoxy{bis[(4-methylphenyl)thio]}methane.

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