A method for preparing arylhydrazine compounds

Abstract

The application discloses a preparation method of arylhydrazine compounds. The preparation method of the arylhydrazine compounds comprises the following steps: mixing a mixed metal catalyst, a thiourea compound, a compound of formula I and a compound of formula II under alkaline conditions to obtain a mixture, and performing reaction to obtain the arylhydrazine compounds. The general formula of the compound of formula I is as follows: the general formula of the compound of formula II is as follows: R 2 NHNH2. The preparation method can synthesize the arylhydrazine compounds in one step, the preparation method can select inexpensive and easily obtained catalysts and raw materials, the preparation method has good selectivity, is non-toxic, has high yield, is low in cost and is convenient for large-scale preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of arylhydrazine compounds. BACKGROUND

[0002] Arylhydrazine is an important fine chemical raw material, and is a synthetic building block for synthesizing indole, carbazole, indazole, arylpyrazole and aryltriazole structural fragments. These heterocyclic fragments are widely present in drugs, pesticides and polymer materials. In addition, arylhydrazine is also used to prepare molecular glasses for various purposes.

[0003] Due to the important application value, the efficient preparation of arylhydrazine compounds has attracted much attention of synthetic chemists. At present, the main strategies for preparing arylhydrazine compounds include: (1) taking arylamine as a starting material, arylhydrazine compounds are prepared through the steps of diazotization, reduction of diazonium salt, hydrolysis, neutralization and distillation. For example, the prior art uses SnCl2 to reduce diazonium salt, but the method has high cost and generates toxic by-products. At present, sulfite is more commonly used as a reducing agent in industry, but the diazonium intermediate generated in the production process is explosive, and a large amount of solid waste and liquid waste are generated, which has great environmental pressure and is difficult to handle; (2) aryl chloride and hydrazine are coupled under the action of [Pd(Cinnamyl)Cl]2 catalyst and Mor-Dal-Phos (N-[2-di(1-adamantane) phosphylphenyl] morpholine) ligand, and arylhydrazine compounds can be synthesized in a yield of 27-95% in one step. It should be pointed out that the method needs a high catalyst dosage and has high cost; (3) a research group reports that the coupling reaction of heterocyclic aryl bromide or chloride and Boc-NHNH2 is realized by using Ni / photocatalyst, and a series of Boc-substituted heterocyclic arylhydrazine compounds can be synthesized. The limitation of the method is that the pre-prepared BocNHNH2 must be used as a hydrazine source, and the method is only suitable for electron-deficient heterocyclic aryl halides; (4) recently, a research group uses aryl iodide or aryl bromide and hydrazine as raw materials, and Cu II

[0004] Therefore, there is an urgent need for a new arylhydrazine preparation method to solve the above problems. SUMMARY

[0005] The technical problem solved by the present application is:

[0006] The present application provides a preparation method of arylhydrazine compounds.

[0007] ​To solve the technical problem, the technical solution adopted by the present application is:

[0008] A preparation method of arylhydrazine compound, comprising the following steps:

[0009] Mixing a mixed metal catalyst, a thiourea compound, a compound of formula I and a compound of formula II under alkaline conditions to obtain a mixture, and reacting to obtain the arylhydrazine compound;

[0010] The compound of formula I has the general formula:

[0011] The compound of formula II has the general formula: R 2 NHNH2;

[0012] The arylhydrazine compound includes the following general formula:

[0013] Wherein, R 1 and R 2 are independently selected from at least one of hydrogen, alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, ester oxygen, ester, nitro, fluorine, hydroxyl, thiol, amide, amine, aryl, substituted aryl, heteroaryl;

[0014] Wherein, X is a halogen group.

[0015] According to the embodiments of the present application, one of the technical solutions in the technical solution has at least one of the following advantages or beneficial effects:

[0016] 1. After mixing the mixed metal catalyst, the thiourea compound, the compound of formula I and the compound of formula II under alkaline conditions, the Ullmann coupling reaction is carried out to obtain the arylhydrazine compound.

[0017] 2. In the method, the addition of the thiourea compound forms a complex with the metal catalyst, which serves as a substantial catalyst to catalyze the reaction and enables the product prepared by the present application to have a yield of 91%. Due to the presence of the complex catalyst in the preparation method of arylhydrazine compound, the synthesis steps of the preparation method can be further reduced, and the yield of the preparation method can be greatly improved.

[0018] 3. In the method, the addition of the base has two effects, the first being to neutralize the hydrochloric acid generated in the reaction process, and the second being to enhance the nucleophilicity of R 2 NHNH2.

[0019] 4. The preparation method has fewer synthesis steps and is simple, which is beneficial to industrial production. In the preparation method of the present application, there is no need to perform diazotization, reduction of diazonium salt and other steps, which overcomes the defect that the prior art must use electron-deficient heterocyclic aryl halide as raw material.

[0020] 5. The preparation method can synthesize arylhydrazine compounds in one step, and the preparation method has the advantages of good selectivity, no toxicity, high yield, low cost and convenience for large-scale preparation.

[0021] According to an embodiment of the present application, the metal catalyst comprises a copper salt catalyst, and the copper salt catalyst comprises at least one of acetylacetone copper, tea polyphenol-Cu II complex, tetraphenylporphyrin copper, copper oxalate, cuprous iodide, copper nitrate, copper perchlorate, copper hydroxide, copper sulfate, copper acetate, copper oxide, copper bromide, cuprous bromide and copper triflate.

[0022] The copper salt catalyst is relatively low in price, and the use of the above catalyst greatly reduces the production cost; meanwhile, the copper catalyst has good catalytic effect on the reaction, thereby greatly improving the yield of the reaction.

[0023] The copper salt has high catalytic efficiency (only 5% of an equivalent is needed to catalyze the smooth progress of the reaction) and is low in price, low in production cost,

[0024] According to an embodiment of the present application, the thiourea compound comprises at least one of the following structural formulas:

[0025]

[0026]

[0027]

[0028] wherein, R 3 -R 11 is independently selected from at least one of hydrogen, alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, ester-oxy, ester, nitro, fluorine, hydroxyl, thiol, amide, amine, aryl, substituted aryl, heteroaryl.

[0029] The present application modifies the catalyst by using the thiourea compound ligand, changes the electrical properties and stability of the catalyst after forming the complex, and then shows significant differences in catalytic activity (reaction speed and conversion rate). The addition of different thiourea compound ligands can increase the yield of the product prepared by the method of the present application from 12% to 91%. It can also be seen that the selection of the specific thiourea compound ligand and the catalyst has a great influence on the yield of the product, and this selection scheme is also the contribution of the present application to the field.

[0030] According to some embodiments of the present application, the basic condition comprises mixing a basic compound with the mixture. The basic compound comprises at least one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate.

[0031] The above-mentioned base can significantly activate the carbon-chlorine bond, and the price of the above-mentioned base is low, which can reduce the production cost.

[0032] According to some embodiments of the present application, the amount ratio of the basic compound to the substance of formula I is 1.2-5:1-2.

[0033] According to some embodiments of the present application, the amount ratio of the basic compound to the substance of formula I is 2-5:1-2.

[0034] According to some embodiments of the present application, the amount ratio of the basic compound to the substance of formula I is 3-4:1-1.5.

[0035] According to some embodiments of the present application, the amount ratio of the basic compound to the substance of formula I is 4-5:1.5-2.

[0036] According to some embodiments of the present application, the alkyl group is a C 1～5 alkyl group.

[0037] According to some embodiments of the present application, the alkyl group comprises at least one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0038] According to some embodiments of the present application, the alkoxy group is a C 1～5 alkoxy group.

[0039] According to some embodiments of the present application, the alkoxy group comprises at least one of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0040] According to some embodiments of the present application, the haloalkyl group is a C 1～5 haloalkyl group.

[0041] According to some embodiments of the present application, the haloalkyl group comprises at least one of fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl.

[0042] According to some embodiments of the present application, the fluoroalkyl group is a C 1～5 fluoroalkyl group.

[0043] According to some embodiments of the present application, the fluoroalkyl group comprises trifluoromethyl.

[0044] According to some embodiments of the present application, the chloroalkyl group is a C 1～5 chloroalkyl group.

[0045] According to some embodiments of the present application, the bromoalkyl group is a C 1～5 bromoalkyl group.

[0046] According to some embodiments of the present application, the iodoalkyl group is a C 1～5 iodoalkyl group.

[0047] According to some embodiments of the present application, the aryl group is a C 5～20 aryl group.

[0048] According to some embodiments of the present application, the aryl group comprises at least one of a phenyl group, a naphthyl group.

[0049] According to some embodiments of the present application, the heteroaryl group is a C 1～20 heteroaryl group.

[0050] According to some embodiments of the present application, the heteroaryl group comprises at least one of a thienyl group, a furanyl group, a pyridyl group, an imidazolyl group, a thiazolyl group, a piperazinyl group.

[0051] According to some embodiments of the present application, at least one H in the substituted aryl group is substituted with a corresponding group as defined herein.

[0052] According to some embodiments of the present application, the substituted aryl group comprises a substituted phenyl group.

[0053] According to some embodiments of the present application, the substitution position in the substituted phenyl group can be an ortho position, a meta position, and a para position.

[0054] According to some embodiments of the present application, the substituted phenyl group comprises at least one of an ortho-methoxyphenyl group, a phenol group, a nitrophenyl group, a benzyl group, a cyanophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a tolyl group.

[0055] Without being specifically defined, any substituent of the present application can be connected to the parent structure at any position that can be substituted.

[0056] According to some embodiments of the present application, the halogen atom comprises at least one of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0057] According to some embodiments of the present application, the hydroxyalkyl group is a C1-C5 hydroxyalkyl group.

[0058] According to some embodiments of the present application, the hydroxyalkyl group comprises at least one of a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group.

[0059] According to some embodiments of the present application, the acyloxy group is a C1-C6 acyloxy group. 10 According to some embodiments of the present application, the acyloxy group is a C1-C6 acyloxy group.

[0060] According to some embodiments of the present application, the acyloxy group is -CH2COOEt.

[0061] According to some embodiments of the present application, the amido group is one of a sulfonamide group, a carbonamide group, an acetamide group, and a benzamide group.

[0062] According to some embodiments of the present application, the sulfonamide group is a sulfonamide ethyl group.

[0063] According to some embodiments of the present application, the sulfonamide ethyl group is -CH2CH2NHTs.

[0064] By selecting the above substituents, the yield of the preparation method of the present application is improved.

[0065] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.1-2:1:1.2-10.0.

[0066] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.1-0.2:1:1.2-3.0.

[0067] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.1-0.5:1:1.2-3.0.

[0068] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.5-1:1:1.2-3.0.

[0069] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.5-2:1:1.2-3.0.

[0070] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.1-0.2:1:2-3.0.

[0071] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I, and the compound of formula II is 0.1-0.2:1:1.2-5.0.

[0072] According to an embodiment of the present application, the mass ratio of the thiourea compound, the compound of formula I and the compound of formula II is 0.1-0.2:1:3.0-5.0.

[0073] According to an embodiment of the present application, the mass ratio of the compound of formula I and the metal catalyst is 1-2:0.05-0.1.

[0074] According to an embodiment of the present application, the mass ratio of the compound of formula I and the metal catalyst is 1-2:0.05-0.06.

[0075] According to an embodiment of the present application, the mass ratio of the compound of formula I and the metal catalyst is 1.5-2:0.05-0.08.

[0076] According to an embodiment of the present application, the mass ratio of the compound of formula I and the metal catalyst is 1-2:0.05-0.1.

[0077] According to an embodiment of the present application, the mixture further comprises a solvent, and the solvent comprises at least one of dimethyl sulfoxide, water, chlorobenzene, toluene, nitromethane, nitrobenzene, chloroform, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, pyridine and methyl tert-butyl ether.

[0078] According to an embodiment of the present application, the molar concentration of the compound of formula I in the mixture is 0.1-2.0 mol / L.

[0079] According to an embodiment of the present application, the reaction temperature is 60-150°C.

[0080] According to an embodiment of the present application, the reaction temperature is 60-150°C.

[0081] According to an embodiment of the present application, the reaction time is 10-24 hours.

[0082] According to an embodiment of the present application, after the reaction, the solution is cooled, the product is filtered through a short plug of neutral alumina, washed with dichloromethane / methanol (25:1), and the eluted solution is concentrated. The product is diluted with dichloromethane, acidified with 37% HCl to pH=3-4. The precipitate is filtered, washed with dichloromethane, and dried at room temperature to obtain the corresponding arylhydrazine hydrochloride.

[0083] Other features and advantages of the present application will be set forth in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following or can be learned by practice of the present application. DETAILED DESCRIPTION

[0084] The technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application.

[0085] The reagents, methods and devices used in the present application are conventional reagents, methods and devices in the technical field unless otherwise specified.

[0086] The arylhydrazine compounds in the following examples are prepared by the following method, and the specific steps are as follows:

[0087] Under the protection of nitrogen atmosphere at room temperature, copper salt (0.1 mmol, 5 mol% in the mixture), thiourea compound (ligand, 0.2 mmol, 10 mol% in the mixture), base (10 mmol, 5 eq.) and solvent (5.0 mL, 0.4 M) are sequentially added to a sealed tube containing a magnet. After adding, continue to stir at the same temperature for 0.5 h. Under the condition of passing nitrogen, arylhydrazine compound (2 mmol, 1 eq.) and formula II compound (6 mmol, 3 eq.) are sequentially added and stirred until uniform, and the mixture is heated to 100 degrees. The solution is cooled and filtered through neutral alumina, washed with dichloromethane / methanol (25:1), and the eluted solution is concentrated. Dilute with dichloromethane, acidify to pH = 3-4 with 37% HCl. The precipitate is filtered, washed with dichloromethane, and dried at room temperature to obtain the arylhydrazine compound and by-product.

[0088] The above method for preparing arylhydrazine compounds includes the following reaction formula:

[0089]

[0090] Wherein, 2a is an arylhydrazine compound, 2b is a by-product aniline, and 2c is a by-product benzene.

[0091] Examples 1-44 arylhydrazine compounds are prepared according to the above method, wherein the catalyst Cu(acac)2: thiourea compound: t BuOK (base is potassium tert-butoxide) = 5 mol%: 10 mol%: 5 eq., solvent: DMSO (dimethyl sulfoxide) (0.4 M); reaction temperature: 100°C; reaction time: 24 h.

[0092] The difference between examples 1-44 is only that the specific structure of the thiourea compound is different. The specific structure of the thiourea compound is shown in Table 1.

[0093] Table 1

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] Example 4 and Examples 45-54 were prepared according to the above method for preparing arylhydrazines, wherein the catalyst: thiourea compound used in Example 4: t BuOK (base is potassium tert-butoxide) = 5 mol%: 10 mol%: 5 eq.; reaction temperature: 100 °C; reaction time: 24 h.

[0103] The only difference between Example 4 and Examples 45-54 is the solvent. The specific solvents are shown in Table 2.

[0104] Table 2

[0105]

[0106]

[0107] Example 4 and Examples 55-60 were prepared according to the above method for preparing arylhydrazines, wherein the catalyst: thiourea compound used in Example 4: t BuOK (base is potassium tert-butoxide) = 5 mol%: 10 mol%: 5 eq.; solvent: DMSO (0.4 M), reaction temperature: 100 °C; reaction time: 24 h.

[0108] The only difference between Example 4 and Examples 55-60 is the catalyst. The specific catalysts are shown in Table 3.

[0109] Table 3

[0110]

[0111] Example 4 and Examples 61-64 were prepared according to the above method for preparing arylhydrazines, wherein the catalyst: thiourea compound used in Example 4: tBuOK (base is potassium tert-butoxide) = 5 mol%: 10 mol%: 5 eq.; solvent: DMSO (dimethylsulfoxide) (0.4 M), reaction temperature: 100 °C; reaction time: 24 h.

[0112] The difference between Example 4 and Examples 61-64 is only the additive. The details are shown in Table 4.

[0113] Table 4

[0114] No. Additive Example 4 -- Example 61 NaBF4 Example 62 Na2SO3 Example 63 KBr Example 64 18-crown-6

[0115] Example 4 and Examples 65-67 are prepared according to the above method for preparing arylhydrazines, wherein the catalyst is the thiourea compound used in Example 4: t BuOK (base is potassium tert-butoxide) = 5 mol%: 10 mol%: 5 eq.; solvent: DMSO (dimethylsulfoxide) (0.4 M), reaction temperature: 100 °C.

[0116] The difference between Example 4 and Examples 65-67 is only the reaction time. The details are shown in Table 5.

[0117] Table 5

[0118]

[0119] Performance test:

[0120] The reaction yield of each step is calculated by GC (gas chromatography) or HPLC (high performance liquid chromatography), and each step is analyzed by Qingdao silica gel thin layer analysis plate, detected by UV (ultraviolet spectrophotometry), iodine coloration, and anisaldehyde acetic acid solution after immersion and heating coloration.

[0121] The conversion rate and yield of compound 2a and its by-products aniline 2b and benzene 2c prepared in different thiourea compound ligands in Examples 1-44 are shown in Table 6.

[0122] Table 6

[0123]

[0124]

[0125] As can be seen from Table 6, although the difference between Examples 1-44 is only in the structure of the thiourea compound, the conversion rate and yield of the product prepared by preparing the arylhydrazine compound according to the above method are quite different. For the conversion rate, Example 39 only reaches 12%, while Example 25 can reach 91%. Similarly, for the yield of 2a, 2b and 2c, some of the yields are only trace amounts, and some of the yields exceed the detection limit of the instrument. The present application modifies the catalyst by the thiourea compound ligand to form a complex, which changes the electrical characteristics and stability of the catalyst, and then exhibits significant differences in catalytic activity (reaction speed and conversion rate). It can also be seen that the selection of a specific thiourea compound ligand and catalyst has a great influence on the yield of the product, and this selection scheme is also a contribution of the present application to the art.

[0126] In addition, among the by-products, aniline (2b) is generated by the reduction of phenylhydrazine, and benzene (2c) is generated by the direct elimination of the copper salt after the oxidative insertion of chlorobenzene, so the yield of the by-products is also related to the electrical characteristics and stability of the catalyst.

[0127] The conversion rate and yield of compound 2a and its by-products aniline 2b and benzene 2c prepared in Examples 4 and 45-54 in different solvents are shown in Table 7.

[0128] Table 7

[0129]

[0130] The conversion rate and yield of compound 2a and its by-products aniline 2b and benzene 2c prepared in Examples 4 and Examples 55-60 in different catalysts are shown in Table 8.

[0131] Table 8

[0132]

[0133] The conversion rate and yield of compound 2a and its by-products aniline 2b and benzene 2c prepared in Examples 4 and Examples 61-64 in different catalysts are shown in Table 9.

[0134] Table 9

[0135]

[0136] The conversion rate and yield of compound 2a and its by-products aniline 2b and benzene 2c prepared in Examples 4 and Examples 65-67 in different catalysts are shown in Table 10.

[0137] Table 10

[0138]

[0139] The above merely illustrates the embodiments of the present application, and is not intended to limit the patent scope of the present application. Any equivalent variation or direct or indirect application in the related technical field based on the content of the present application should be included in the patent protection scope of the present application.

Claims

1. A method for preparing an arylhydrazine compound, characterized by: The method comprises the following steps: mixing a metal catalyst, a ligand, a compound of formula I, a compound of formula II, and a solvent to obtain a mixture, and reacting the mixture to obtain the aryl hydrazine compound; The arylhydrazine compound has a structural formula of: ; the metal catalyst is selected from Cu(acac)2; the structure of said ligand is selected from one of , , , , , , , , , , , , , , , . the solvent is dimethyl sulfoxide.

2. The method of claim 1, wherein: The mass ratio of the ligand, the compound of formula I, and the compound of formula II is 0.1-2:1:1.2-10.

0.

3. The method of claim 1, wherein: The mass ratio of the compound of formula I and the metal catalyst is 1-2:0.05-0.

1.

4. The method of claim 1, wherein: The reaction temperature is 60-150°C.

Images