A method for synthesizing thiosemicarbazone compounds

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing thiosemicarbazone compounds. The method for synthesizing thiosemicarbazone compounds uses (isocyanimino) triphenylphosphine and one of thiophenol substances, thiol substances, and disulfide substances as reactants, and uses methanol or a mixed solution of methanol and water as a solvent for reaction. After separation and purification, thiosemicarbazone compounds are obtained. The synthesis method of the present invention has mild conditions, does not require additional metals and additives, the product is easy to separate and has a high yield, and the reaction is green and efficient.

Description

Technical Field

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

[0002] Thiosemicarbazone compounds have a wide range of biological and pharmaceutical activities, are widely used in medicinal chemistry, and are important intermediates for synthesizing amines, ketones, and diazo compounds, playing an important role in the synthesis and research of pesticides, chiral auxiliaries, optoelectronic materials, etc.

[0003] The common structures of thiosemicarbazone compounds are as follows:

[0004] , , , .

[0005] Isocyanide functional groups exhibit extremely rich reaction properties due to their unique structures. When the isocyanide group exists in the zwitterionic resonance form, 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 isocyanide group exists in the carbene form, the terminal carbon atom can undergo carbene insertion reactions under metal-free or metal-catalyzed conditions. In addition, the isocyanide moiety can also break the R-NC bond as a cyano donor for reactions under special circumstances. In N-isocyanides, the isocyanide functional group is directly connected to the nitrogen atom, and the reaction types are similar to those of C-isocyanides. At the same time, due to its unique C-N-N skeleton, it has special reactivity and is widely used in the construction of nitrogen-containing compounds. As a stable functionalized isocyanide, (isocyanimino)triphenylphosphine, with its highly active isocyanide functional group, the reactions it participates in have become an efficient synthetic strategy for synthesizing heterocyclic compounds.

[0006] (Isocyanimino)triphenylphosphine, as an easily preparable N-isocyanide, has many reported reactions, mainly including the following two categories.

[0007] The first category is the reaction of (isocyanimino)triphenylphosphine with carbonyl compounds. In existing reports, the carbon-carbonyl bond of the ketone breaks and reacts with (isocyanimino)triphenylphosphine. Under the action of a silver catalyst, various ketones can be converted into iminophosphines and nitrile compounds in high yields; (isocyanimino)triphenylphosphine reacts with acyl chlorides, and then further reacts with p-toluenesulfonyl chloride under the condition of triethylamine as a solvent at room temperature to safely and efficiently obtain diazoketone compounds; (isocyanimino)triphenylphosphine reacts with acids to efficiently synthesize 1,3,4-oxadiazole compounds under the condition of dichloromethane as a solvent at room temperature.

[0008] The second category is the reaction of (isocyanimino)triphenylphosphine with alkynes. In existing reports, (isocyanimino)triphenylphosphine is used as a cyanide source, and silver-catalyzed direct cyanation of the carbon-hydrogen bond of alkynes is safe, green and efficient; (isocyanimino)triphenylphosphine and alkynes undergo a 3+2 cycloaddition reaction under the action of equivalent silver and catalytic amount of molybdenum hexacarbonyl to obtain monosubstituted pyrazoles; (isocyanimino)triphenylphosphine and alkynes undergo aminocyanation reaction under the action of a silver catalyst to synthesize β-aminoacrylonitrile regioselectively and stereoselectively.

[0009] Therefore, using (isocyanimino)triphenylphosphine as a reaction raw material to synthesize thiosemicarbazone compounds is a new research direction. Summary of the Invention

[0010] Aiming at the deficiencies of the existing technology, the present invention aims to provide a method for synthesizing thiosemicarbazone compounds, using (isocyanimino)triphenylphosphine and thiophenol or thiol or disulfide compounds as reaction raw materials to synthesize thiosemicarbazone compounds. The reaction conditions are mild, no additional metal and additives are required, the product is easy to separate and the yield is high, and the reaction is green and efficient.

[0011] The technical object of the present invention is realized by the following technical solutions:

[0012] A method for synthesizing thiosemicarbazone compounds, using (isocyanimino)triphenylphosphine and one of thiophenol substances, thiol substances, and disulfide substances as reactants, and using methanol or a mixed solution of methanol and water as a solvent for reaction, and obtaining thiosemicarbazone compounds through separation and purification.

[0013] In the present invention, the structural formula of the (isocyanimino)triphenylphosphine is: .

[0014] In the present invention, the structural formula of the thiophenol substance is:

[0015] ;

[0016] 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, 3,5-dimethyl.

[0017] 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.

[0018] 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.

[0019] The reaction process of the (isocyanoimido)triphenylphosphine and thiophenol substances is as follows:

[0020] .

[0021] 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.

[0022] 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:

[0023] .

[0024] When synthesizing thiosemicarbazone compounds using (isocyanatoimino)triphenylphosphine and thiol substances as reaction raw materials, the molar ratio of (isocyanatoimino)triphenylphosphine to thiol substances is 1:(1 - 2), preferably 1:1.5; the solvent is methanol, and the molar volume ratio of (isocyanatoimino)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.

[0025] In the present invention, the structural formula of the disulfide substance is:

[0026] or ;

[0027] Among them, R2 is one of hydrogen, 4 - methyl, 4 - fluoro, 4 - chloro, 4 - bromo, 4 - methoxy, 4 - trifluoromethyl, 3 - methoxy, 3 - fluoro.

[0028] Preferably, the disulfide substance is one of the following substances: p - tolyl 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) disulfane, 1,2 - bis(4 - (trifluoromethyl)phenyl) disulfane, 1,2 - bis(3 - methoxyphenyl) disulfane, 1,2 - bis(3 - fluorophenyl) disulfide, dithiophene disulfide.

[0029] When synthesizing thiosemicarbazone compounds using (isocyanatoimino)triphenylphosphine and disulfide substances as reaction raw materials, the molar ratio of (isocyanatoimino)triphenylphosphine to disulfide substances is 1:(2 - 4), preferably 1:3; the solvent is a mixed solution of methanol and water with a volume ratio of (15 - 25):1, preferably a mixed solution of methanol and water with a volume ratio of 20:1; the molar volume ratio of (isocyanatoimino)triphenylphosphine to the solvent is 1 mol:(3 - 8) L, preferably 1 mol:5 L; the reaction temperature is 100 - 120 °C, preferably 120 °C.

[0030] The reaction process of the (isocyanatoimino)triphenylphosphine and the disulfide substance is as follows:

[0031] .

[0032] Taking p - tolyl disulfide as an example, based on control experiments such as radical trapping verification experiments, light - avoidance treatment, and construction of a nitrogen - protection system, the reaction mechanism was speculated and discussed. The reaction mechanism of (isocyanatoimino) triphenylphosphine and disulfide substances is as follows: Under the action of air oxidation, disulfide will generate sulfur radicals. After the sulfur radicals are generated from disulfide, they will selectively attack the isocyanide - terminal carbon atom of N - isocyanide, thereby promoting the formation of a thioimine radical intermediate. The intermediate reacts with another molecule of sulfur radical to achieve the efficient and rapid synthesis of dithiohydrazone compounds. The reaction mechanism is as Figure 2 shown.

[0033] In the present invention, after the reaction is completed, the reaction system is quenched with saturated Na2CO3 solution first, then extracted with dichloromethane, and then dried over anhydrous Na2SO4, distilled under reduced pressure, and purified by column chromatography to obtain the product dithiohydrazone compounds.

[0034] The thiosemicarbazone compounds synthesized in the present invention are the following substances: [(E)-[(4-methylphenyl)thio]methylidene]hydrazine, [(E)-[(4-methoxyphenyl)thio]methylidene]hydrazine, [(E)-{[4-(2-methylpropan-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-bromophenyl)thio]methylidene]hydrazine, [(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, [(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)oxy]phenyl}thio)methylidene]hydrazine, {bis[(4-methylphenyl)thio]methylidene}hydrazine, [bis(phenylthio)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.

[0035] The present invention synthesizes thiosemicarbazone compounds by reacting (isocyanatoimino)triphenylphosphine with thiophenol or thiol or disulfide. This synthesis method can skillfully introduce sulfur atoms when constructing the hydrazone functional group, and is applicable to the efficient preparation of thiosemicarbazone and dithiosemicarbazone compounds. It has the advantages of simple operation, mild reaction conditions, and being green and economical. Among them, the first system uses (isocyanatoimino)triphenylphosphine and thiophenol substances as starting materials, methanol as the reaction solvent, and synthesizes a series of thiosemicarbazone compounds through a radical reaction, which has significant advantages. The reaction conditions are mild, the reaction raw materials are easily available, and it can be achieved without additional catalysts or oxidants, providing a green and efficient synthetic strategy for the preparation of thiosemicarbazone compounds, which is of great significance in medicinal chemistry and pesticide chemistry; the second system uses (isocyanatoimino)triphenylphosphine and thiol substances as starting materials, methanol as the reaction solvent. When the substituents are electron-donating groups and electron-withdrawing groups, good to excellent yields can be obtained. When the substituent is a halogen, the target product is given in good yield, and this reaction is also applicable to alkyl thiols and heterocyclic thiols; the third system uses (isocyanatoimino)triphenylphosphine and disulfide substances as starting materials, a mixed solution of methanol and water as the reaction solvent, and efficiently prepares a series of bisthiosemicarbazone compounds. This reaction has multiple advantages, such as low-cost and easily accessible raw materials, no need to use any metals and additives, simple operation process, convenient post-reaction treatment, and also has the characteristics of being green and clean.

[0036] The thiosemicarbazone compounds synthesized by the present invention can be used to prepare the following derivatives through derivatization reactions:

[0037]

[0038] [(E)-[(4-methylphenyl)thio]methylidene][(E)-phenylmethylidene]hydrazine;

[0039]

[0040] 2-[(4-methylphenyl)thio]-5-phenyl-1,3,4-oxadiazole;

[0041]

[0042] 3-[(4-methylphenyl)thio]-4,5-diphenyl-1,2,4-diazaphospholane;

[0043]

[0044] (diazo-methyl)(p-tolyl)sulfane;

[0045]

[0046] N-{2-[(4-methylphenyl)thio]-1-phenylethyl}aniline;

[0047]

[0048] (2,3-Diphenylcyclopropyl)(4-methylphenyl)sulfane;

[0049]

[0050] [(E)-[(4-Methylphenyl)thio]methylenehydrazine;

[0051]

[0052] [(E)-[(4-Methylphenyl)sulfonyl]methylenehydrazine;

[0053]

[0054] N-{[(E)-[(4-methylphenyl)thio]methylidene]amino}-4-methylbenzenesulfonamide;

[0055]

[0056] (4-methylphenyl){[(4-methylphenyl)thio]methyl}sulfane;

[0057]

[0058] Methoxy{bis[(4-methylphenyl)thio]}methane.

[0059] Compared with the prior art, the present invention has the following beneficial effects:

[0060] (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.

[0061] 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.

[0062] When using disulfide substances as raw materials, most disulfides with electron-donating groups (such as methoxy, methyl, trifluoromethyl, etc.) at the para-position can obtain dithiosemicarbazone compounds with medium to high yields. Disulfides with halogen groups (such as fluorine, chlorine, bromine, etc.) at the para-position have good tolerance to this reaction and can obtain dithiosemicarbazone compounds with medium to high yields. The steric hindrance of meta-substituents has no obvious effect on the yield of the target product, and dithienyl disulfide can also obtain the target product with a medium yield;

[0063] (2) The reaction conditions of the present invention are simple and mild, applicable to a wide range of substrates, the products are easy to separate and the yields are relatively high, which is conducive to industrial production;

[0064] (3) The thiosemicarbazone compounds synthesized by the present invention can be further derivatized to obtain sulfoxide or sulfone compounds, diazo compound precursors, important pharmaceutical intermediate acylhydrazone compounds, 1,3,4-oxadiazole compounds with biological and pharmaceutical activities, and asymmetric azines with important application values in optoelectronic liquid crystal materials, etc. Brief Description of the Drawings

[0065] Figure 1 It is the reaction mechanism diagram of (isocyanatoimino) triphenylphosphine and thiophenol substances of the present invention;

[0066] Figure 2 It is the reaction mechanism diagram of (isocyanatoimino) triphenylphosphine and disulfide substances of the present invention;

[0067] Figure 3 It is the 1H NMR spectrum of the product of Example 1 of the present invention;

[0068] Figure 4 It is the 13C NMR spectrum of the product of Example 1 of the present invention;

[0069] Figure 5 It is the 1H NMR spectrum of the product of Example 2 of the present invention;

[0070] Figure 6 It is the 13C NMR spectrum of the product of Example 2 of the present invention;

[0071] Figure 7 It is the 1H NMR spectrum of the product of Example 3 of the present invention;

[0072] Figure 8 It is the 13C NMR spectrum of the product of Example 3 of the present invention;

[0073] Figure 9 It is the 1H NMR spectrum of the product of Example 4 of the present invention;

[0074] Figure 10 It is the 13C NMR spectrum of the product of Example 4 of the present invention;

[0075] Figure 1119F NMR spectrum of the product of Example 4 of the present invention;

[0076] Figure 12 1H NMR spectrum of the product of Example 5 of the present invention;

[0077] Figure 13 13C NMR spectrum of the product of Example 5 of the present invention;

[0078] Figure 14 1H NMR spectrum of the product of Example 6 of the present invention;

[0079] Figure 15 13C NMR spectrum of the product of Example 6 of the present invention;

[0080] Figure 16 1H NMR spectrum of the product of Example 7 of the present invention;

[0081] Figure 17 13C NMR spectrum of the product of Example 7 of the present invention;

[0082] Figure 18 1H NMR spectrum of the product of Example 8 of the present invention;

[0083] Figure 19 13C NMR spectrum of the product of Example 8 of the present invention;

[0084] Figure 20 19F NMR spectrum of the product of Example 8 of the present invention;

[0085] Figure 21 1H NMR spectrum of the product of Example 9 of the present invention;

[0086] Figure 22 13C NMR spectrum of the product of Example 9 of the present invention;

[0087] Figure 23 1H NMR spectrum of the product of Example 10 of the present invention;

[0088] Figure 24 13C NMR spectrum of the product of Example 10 of the present invention;

[0089] Figure 25 1H NMR spectrum of the product of Example 11 of the present invention;

[0090] Figure 26 13C NMR spectrum of the product of Example 11 of the present invention;

[0091] Figure 27 1H NMR spectrum of the product of Application Synthesis Example 1 of the present invention;

[0092] Figure 28 13C NMR spectrum of the product of Application Synthesis Example 1 of the present invention. Detailed implementation mode

[0093] The present invention will be further described below in conjunction with embodiments. The raw materials used in the embodiments are all commercially available conventional raw materials unless otherwise specified; the process methods used in the embodiments are all conventional methods in the art unless otherwise specified.

[0094] Example 1

[0095] In this example, [(E)-[(4-methylphenyl)thio]methylidene]hydrazine is synthesized, and its structural formula is as follows:

[0096] 。

[0097] The synthesis method is as follows:

[0098] (Isocyanimino)triphenylphosphine (0.2 mmol), p-toluenethiol (0.3 mmol) and 3 mL of methanol are added to a pressure-resistant tube, and the mixture is heated and reacted at 60 °C for 7 h. After the reaction is completed, the reaction system is quenched with 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 1H NMR and 13C NMR spectra are as Figure 3-4 shown below, where:

[0099] 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J J = 8.0 Hz, 2H), 7.23 - 7.15 (m, 3H), 5.40 (s, 2H), 2.36 (s, 3H).

[0100] 13 C NMR (100 MHz, CDCl3) δ 138.8, 138.2, 132.6, 130.3, 127.4, 21.2.

[0101] HRMS (ESI) m / z: [M+H] + calcd for C8H 11 N2S + 167.0638; found 167.0633.

[0102] Example 2

[0103] In this example, [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine is synthesized, and its structural formula is as follows:

[0104] 。

[0105] The synthesis method is as follows:

[0106] (Isocyanimino)triphenylphosphine (0.2 mmol), 4-chlorothiophenol (0.4 mmol) and 4 mL of methanol were added to a pressure-resistant tube, and the mixture was heated at 40 °C for 10 h. After the reaction was completed, the reaction system was quenched with saturated Na2CO3 solution, followed by extraction with dichloromethane, drying over anhydrous Na2SO4, distillation under reduced pressure, and purification by column chromatography to obtain [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine with a yield of 96%. The 1H NMR and 13C NMR spectra are as follows Figure 5-6 shown below, where:

[0107] 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).

[0108] 13 C NMR (101 MHz, CDCl3) δ 135.9, 134.9, 133.5, 129.7, 129.6.

[0109] HRMS (ESI) m / z: [M+H] + calcd for C7H8ClN2S + 187.0092; found 187.0092.

[0110] Example 3

[0111] In this example, [(E)-[(3-methylphenyl)thio]methylidene]hydrazine was synthesized, and its structural formula is as follows:

[0112] .

[0113] The synthesis method is as follows:

[0114] (Isocyanimino)triphenylphosphine (0.2 mmol), m-methylthiophenol (0.2 mmol) and 2 mL of methanol were added to a pressure-resistant tube, and the mixture was heated at 50 °C for 8 h. After the reaction was completed, the reaction system was quenched with saturated Na2CO3 solution, followed by extraction with dichloromethane, drying over anhydrous Na2SO4, distillation under reduced pressure, and purification by column chromatography to obtain [(E)-[(4-chlorophenyl)thio]methylidene]hydrazine with a yield of 92%. The 1H NMR and 13C NMR spectra are as follows Figure 7-8 shown below, where:

[0115] 1 1H 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).

[0116] 13 13C NMR (101 MHz, CDCl3) δ 139.5, 137.5, 132.9, 130.8, 130.7, 129.35, 129.32, 21.2.

[0117] HRMS (ESI) m / z: [M+H] + calcd for C8H 11 N2S + 167.0638; found 167.0654.

[0118] Example 4

[0119] On the basis of Example 1, p-methylthiophenol was replaced with an equimolar amount of m-trifluoromethylthiophenol to synthesize [(E)-{[3-(trifluoromethyl)phenyl]sulfanyl}methylidene]hydrazine, and the structural formula is as follows:

[0120] .

[0121] The product yield was 80%, and the hydrogen spectrum, carbon spectrum, and fluorine spectrum are as Figure 9-11 shown, where:

[0122] 1 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.31 (m, 1H), 7.26 - 7.16 (m, 3H), 7.09 - 7.02 (m, 1H),

[0123] 5.50 (s, 2H).

[0124] 13 13C NMR (101 MHz, CDCl3)) δ 135.1, 134.3, 132.7, 132.0 (q, J = 32.8 Hz), 130.0, 128.6 (q, J = 3.8 Hz), 125.1 (q, J = 3.7 Hz), 123.5 (q, J = 273.7 Hz).

[0125] 1919F NMR (376 MHz, CDCl3) δ -63.8。

[0126] HRMS (ESI) m / z: [M+H] + calcd for C8H8F3N2S + 221.0355; found 221.0352。

[0127] Example 5

[0128] On the basis of Example 1, p-methylthiophenol was replaced with an equimolar amount of o-methoxythiophenol to synthesize [(E)-[(2-methoxyphenyl)thio]methylidene]hydrazine, and the structural formula is as follows:

[0129] 。

[0130] The product yield was 88%, and the 1H NMR and 13C NMR spectra are as Figure 12-13 shown, where:

[0131] 1 1H 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).

[0132] 13 13C NMR (101 MHz, CDCl3)δ 158.4, 137.1, 134.0, 130.3, 121.4, 118.6,111.4.

[0133] HRMS (ESI) m / z: [M+H] + calcd for C8H 11 N2OS + 183.0587; found 183.0574.

[0134] Example 6

[0135] On the basis of Example 1, p-methylthiophenol was replaced with an equimolar amount of 2-naphthalenethiol to synthesize [(E)-(naphthalen-2-ylthio)methylidene]hydrazine, and the structural formula is as follows:

[0136] 。

[0137] The product yield was 87%, and the 1H NMR and 13C NMR spectra are asFigure 14-15 as shown below, where:

[0138] 1 1H 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).

[0139] 13 13C 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.

[0140] HRMS (ESI) m / z: [M+H] + calcd for C 11 H 11 N2S + 203.0638; found 203.0636.

[0141] Example 7

[0142] On the basis of Example 3, this example replaces m-methylthiophenol with an equimolar amount of 2-thiophenethiol to synthesize [(E)-(thiophen-2-ylthio)methylene]hydrazine, and the structural formula is as follows:

[0143] .

[0144] The product yield is 73%, and the hydrogen spectrum and carbon spectrum are as Figure 16-17 shown below, where:

[0145] 1 1H 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).

[0146] 13 13C NMR (101 MHz, CDCl3) δ 138.4, 135.3, 131.1, 128.1, 127.2.

[0147] HRMS (ESI) m / z: [M+H] + calcd for C5H7N2S2 + 159.0046; found 159.0041。

[0148] Example 8

[0149] On the basis of Example 2, this example replaces p-chlorothiophenol with an equimolar amount of 4-(trifluoromethyl)benzyl mercaptan to synthesize [(E)-({[4-(trifluoromethyl)phenyl]methyl}sulfanyl)methylidene]hydrazine, and the structural formula is as follows:

[0150] 。

[0151] The product yield is 77%, and the 1H NMR, 13C NMR, and 19F NMR spectra are as Figure 18-20 shown, where:

[0152] 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)。

[0153] 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

[0154] Hz), 125.9 (q, J = 3.7 Hz)。

[0155] 19 F NMR(376 MHz, CDCl3)δ -57.9。

[0156] HRMS (ESI) m / z: [M+H] + calcd for C9H 10 F3N2S + 235.0512; found 235.0331。

[0157] Example 9

[0158] This example synthesizes diphenylmethyl carbonylhydrazine disulfate, and the structural formula is as follows:

[0159] 。

[0160] The synthesis method is as follows:

[0161] (Isocyanatoimino)triphenylphosphine (0.2 mmol) and p - tolyl disulfide (0.6 mmol) were dissolved in a pressure - resistant tube containing 1 mL of solvent (methanol: water = 20:1), and heated at 120 °C for 10 h. After the reaction was completed, the reaction system was quenched with 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 dibenzylcarbonylhydrazine disulfate, weighing 40.4 mg, with a yield of 70%. The 1H NMR and 13C NMR spectra are as follows Figure 21-22 shown below, where:

[0162] 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).

[0163] 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.

[0164] HRMS (ESI) m / z: calcd for C 15 H 17 N2S2 + 289.0828; found 289.0824.

[0165] Example 10

[0166] In this example, {bis[(4 - chlorophenyl)thio]methylidene}hydrazine was synthesized, and its structural formula is as follows:

[0167] .

[0168] The synthesis method is as follows:

[0169] (Isocyanimino)triphenylphosphine (0.2 mmol) and 1,2-bis(4-chlorophenyl) disulfide (0.4 mmol) were dissolved in a pressure-resistant tube containing 1 mL of solvent (methanol:water = 15:1), and heated at 110 °C for 12 h. After the reaction was completed, the reaction system was quenched with saturated Na2CO3 solution, followed by extraction with dichloromethane, drying over anhydrous Na2SO4, distillation under reduced pressure, and purification by column chromatography to obtain the target product {bis[(4-chlorophenyl)thio]methylidene}hydrazine with a yield of 61%. The 1H NMR and 13C NMR spectra are as Figure 23-24 shown below, where:

[0170] 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.07 (m, 8H), 6.10 (s, 2H).

[0171] 13 13C NMR (100 MHz, CDCl3) δ 135.1, 134.6, 134.4, 133.6, 133.5, 130.7, 129.3, 129.1, 128.6.

[0172] HRMS (ESI) m / z: [M+H] + calcd for C 13 H 11 Cl2N2S2 + 328.9736; found 328.9724.

[0173] Example 11

[0174] In this example, [bis(thiophen-2-ylthio)methylidene]hydrazine was synthesized, and its structural formula is as follows:

[0175] .

[0176] The synthesis method is as follows:

[0177] (Isocyanimino)triphenylphosphine (0.2 mmol) and 2,2'-dithienyl disulfide (0.8 mmol) were dissolved in a pressure-resistant tube containing 1.6 mL of solvent (methanol:water = 25:1), and heated at 100 °C for 12 h. After the reaction was completed, the reaction system was quenched with saturated Na2CO3 solution, followed by extraction with dichloromethane, drying over anhydrous Na2SO4, distillation under reduced pressure, and purification by column chromatography to obtain the target product [bis(thiophen-2-ylthio)methylidene]hydrazine with a yield of 48%. The 1H NMR and 13C NMR spectra are as Figure 25-26 shown below, where:

[0178] 11H 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).

[0179] 13 13C NMR (100 MHz, CDCl3) δ 137.9, 136.7, 135.5, 131.7, 131.4, 129.4, 127.8, 127.5, 126.4.

[0180] HRMS (ESI) m / z: [M+H] + calcd for C9H9N2S4 + 272.9644; found 272.9658.

[0181] Synthetic Example 1

[0182] This example synthesizes

[0183] [(E)-[(4-methylphenyl)thio]methylene][(E)-phenylmethylene]hydrazine, and the structural formula is as follows:

[0184] .

[0185] The synthesis method is as follows:

[0186] Dissolve p-tolyl ( E )-methanethiosemicarbazide (0.2 mmol, 33.2 mg) and benzaldehyde (0.3 mmol, 1.5 equiv, 31.8 mg) in methanol (3 mL). Stir at 60 °C in an air atmosphere for 7 hours. After the reaction is completed, quench the mixture with saturated Na2CO3 solution, and then extract with dichloromethane (DCM). Dry over anhydrous Na2SO4 and distill under reduced pressure. Finally, purify the crude product by column chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain the target thioazine product (38.7 mg, 76%). The hydrogen spectrum and carbon spectrum are as Figure 27-28 shown, where:

[0187] 11H 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 J = 8.0 Hz, 2H), 2.38 (s, 3H).

[0188] 13 13C 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.

[0189] HRMS (ESI) m / z: [M+H] + calcd for C 15 H 15 N2S + 255.0951; found 255.0950。

Claims

1. A method for synthesizing a thiosemicarbazone compound, characterized in that: Using (isocyanimino)triphenylphosphine and one of thiophenol substances, thiol substances, and disulfide substances as reactants, and using methanol or a mixed solution of methanol and water as a solvent for reaction, after separation and purification, a thiosemicarbazone compound is obtained; The structural formula of the thiophenol substance 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, 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, furan-2-methyl mercaptan; their structural formulas are in turn: 、 、 、 、 、 ； 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, 3-fluoro.

2. The synthesis method of the thiosemicarbazone compound according to claim 1, characterized in that: When using (isocyanimino)triphenylphosphine and thiophenol substances as reaction raw materials to synthesize thiosemicarbazone compounds, the molar ratio of (isocyanimino)triphenylphosphine to thiophenol substances is 1:(1 - 2); the solvent is methanol, and the molar volume ratio of (isocyanimino)triphenylphosphine to the solvent is 1mol:(10 - 20)L; the reaction temperature is 40 - 60°C.

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

4. The synthesis method of the thiosemicarbazone compound according to claim 1, wherein: When using (isocyanimino)triphenylphosphine and disulfide substances as reaction raw materials to synthesize thiosemicarbazone compounds, the molar ratio of (isocyanimino)triphenylphosphine to disulfide substances is 1:(2 - 4); the solvent is a mixed solution of methanol and water with a volume ratio of (15 - 25):1, and the molar volume ratio of (isocyanimino)triphenylphosphine to the solvent is 1mol:(3 - 8)L; the reaction temperature is 100 - 120°C.

5. The synthesis method of the thiosemicarbazone compound according to claim 1, wherein: After the reaction is completed, first quench the reaction system with saturated Na2CO3 solution, then extract with dichloromethane, and then dry over anhydrous Na2SO4, distill under reduced pressure, and separate and purify by column chromatography to obtain the product thiosemicarbazone compound.

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