阅读说明：本技术 一种基于取代碘苯制备异硫脲化合物的方法 (Method for preparing isothiourea compound based on substituted iodobenzene ) 是由 张士磊 陈晓冬 刘学军 于 2021-08-18 设计创作，主要内容包括：本发明公开了一种基于取代碘苯制备异硫脲化合物的方法,以硫脲与取代碘苯为底物,在金属氢化物存在下、溶剂中反应,制备异硫脲化合物。异硫脲结构广泛存在于一些活性的天然产物、化学药物及反应催化剂、材料改性剂中,是重要的化学合成砌块。本发明使用取代碘苯作为底物,在NaH作用下与硫脲化合物进行亲核加成反应,实现了首次利用碘苯直接与硫脲进行C-S偶联生成异硫脲化合物,方案操作十分简便,无需金属催化,原料廉价易得,官能团耐受性好。为S-芳基异硫脲砌块的化合物合成提供了一种优秀方案。(The invention discloses a method for preparing an isothiourea compound based on substituted iodobenzene, which takes thiourea and substituted iodobenzene as substrates to react in a solvent in the presence of metal hydride to prepare the isothiourea compound. The isothiourea structure widely exists in active natural products, chemical drugs, reaction catalysts and material modifiers, and is an important chemical synthesis building block. The invention uses the substituted iodobenzene as a substrate to perform nucleophilic addition reaction with the thiourea compound under the action of NaH, realizes the purpose of directly performing C-S coupling on the iodobenzene and the thiourea for the first time to generate the isothiourea compound, has very simple and convenient scheme operation, does not need metal catalysis, has cheap and easily obtained raw materials and good functional group tolerance. Provides an excellent scheme for the compound synthesis of S-aryl isothiourea building blocks.)

1. A method for preparing an isothiourea compound based on substituted iodobenzene is characterized in that thiourea and substituted iodobenzene are used as substrates and react in a solvent in the presence of metal hydride to prepare the isothiourea compound;

the chemical structural formula of the substituted iodobenzene is as follows:

、

the chemical structural formula of the thiourea is as follows:

the chemical structural formula of the isothiourea compound is as follows:

、

r is selected from one or more of halogen, substituted or unsubstituted alkyl, alkoxy, substituted or unsubstituted phenyl and substituted or unsubstituted heterocyclic radical; r¹Selected from hydrogen, halogen or alkyl.

2. The method for preparing isothiourea compounds based on substituted iodobenzene as claimed in claim 1, wherein R is selected from one or more of halogen, alkyl, alkoxy, phenyl; r¹Selected from chlorine.

3. The method for preparing an isothiourea compound based on substituted iodobenzene as claimed in claim 1, wherein the substituted iodobenzene has one or more substituents.

4. The process for preparing an isothiourea compound based on substituted iodobenzene as claimed in claim 1, wherein the metal hydride is sodium hydride.

5. The method for preparing an isothiourea compound based on substituted iodobenzene according to claim 1, wherein the reaction is carried out in a solvent in the presence of a metal hydride, and the reaction is carried out at room temperature for 8 to 50 hours without using any other substance.

6. The method for preparing isothiourea compounds based on substituted iodobenzene as claimed in claim 1, wherein the metal hydride is used in an amount of 3 to 5 times the molar amount of thiourea; the dosage of the substituted iodobenzene is 1-2 times of the molar weight of the thiourea.

7. The process for preparing an isothiourea compound based on substituted iodobenzene as claimed in claim 6, wherein the metal hydride is used in an amount of 4 times the molar amount of thiourea; the dosage of the substituted iodobenzene is 1.5 times of the molar quantity of the thiourea.

8. The method for preparing the isothiourea compound based on the substituted iodobenzene as claimed in claim 1, wherein the solvent is one or more of dimethylacetamide, tetrahydrofuran, acetonitrile, ethylene glycol dimethyl ether and toluene.

9. The application of metal hydride in the reaction of thiourea and substituted iodobenzene to prepare an isothiourea compound is characterized in that the chemical structural formula of the substituted iodobenzene is as follows:

、

the chemical structural formula of the thiourea is as follows:

the chemical structural formula of the isothiourea compound is as follows:

、

r is selected from one or more of halogen, substituted or unsubstituted alkyl, alkoxy, substituted or unsubstituted phenyl and substituted or unsubstituted heterocyclic radical; r¹Selected from hydrogen, halogen or alkyl.

10. Use according to claim 9, wherein the metal hydride is sodium hydride.

Technical Field

The invention belongs to organic synthesis, and particularly relates to a method for preparing an isothiourea compound based on substituted iodobenzene.

Background

The structure of the S-isothiourea compound exists in a plurality of chemical molecules, is widely applied to the fields of functional materials and medicines, and attracts the great interest of scientists. Also, in recent years, thiourea derivatives have begun to be powerful tools for asymmetric organocatalysis. For the synthesis of S-isothiourea compounds, halobenzene or phenylboronic acid is generally used for C-S coupling of thiourea under a metal catalyst, but the experimental method has harsh reaction conditions (air sensitivity, strong base/high temperature), large catalyst loading capacity and serious pollution of metal reagents. In addition, sulfur-containing species can rapidly and irreversibly deactivate various types of metal catalysts, making metal-catalyzed C-S bond formation a solution that is not preferred by a large number of organic synthesizers.

Since the 21 st century, the metal-catalyzed coupling reaction has been a hot tide, and the Chan-Lam reaction has become an effective and practical alternative method for constructing C-S bonds. Dong group has a long-term research interest in the synthesis and application of isothioureas, and a series of simple methods for converting thioureas to S-isothiourea compounds by means of metal catalysts have been reported in recent years. 2018, in Cu (OAc)₂·H₂O is used as a catalyst, bipyridine is used as a ligand, An ideal S-isothiourea compound is synthesized, and the yield is basically 90% [ Liu X, Zhuang S B, Zhu H, et al, An effective Chan-Lam S-Aryl of Aryl thio Acids.Eur. J. Org. Chem. 2018, 4483-4489]. Then, they continue to use cheap metallic Copper as a catalyst and couple iodobenzene with thiourea to produce S-isothiourea compounds [ Zhu H, Liu X, Chang C Z, et al, coater-catalyzed C-S cross contamination reaction: S-alkylation of aryl thioureas without ligand participation.Synthesis. 2017, 49, 5211-5216]The source of the starting material iodobenzene is more extensive than phenylboronic acid.

Metal catalyzed processes, while generally applicable to the synthesis of a variety of isothiourea compounds, also suffer from several disadvantages. If high temperature is needed, the reaction time is long, the catalyst loading capacity is large, the reagent price is expensive, and metal waste pollution is easily caused. Therefore, it is highly desirable to develop a metal-free, inexpensive-raw material, non-air sensitive reaction system for the preparation of S-isothiourea compounds.

Disclosure of Invention

The invention discloses a method for preparing an isothiourea compound based on substituted iodobenzene, which can carry out nucleophilic reaction on the substituted iodobenzene and thiourea under mild, economic and simple conditions to generate an S-isothiourea compound without transition metal catalysis, and the substituted iodobenzene is used as a precursor, so that the raw material source is simple.

The invention adopts the following technical scheme:

a method for preparing an isothiourea compound based on substituted iodobenzene comprises the step of reacting thiourea and substituted iodobenzene serving as substrates in a solvent in the presence of a metal hydride to obtain the isothiourea compound.

In the invention, the chemical structural formula of the substituted iodobenzene is as follows:

、

the chemical structural formula of the thiourea is as follows:

the chemical structural formula of the isothiourea compound is as follows:

、

r is selected from one or more of halogen, substituted or unsubstituted alkyl, alkoxy, substituted or unsubstituted phenyl and substituted or unsubstituted heterocyclic radical; r¹Selected from hydrogen, halogen or alkyl, preferably chlorine. The substituent has obvious influence on organic synthesis, particularly reaction time and substrate dosage are obviously related to the substituent, so that the product yield is influenced by the substituent. The reaction of the thiourea disclosed by the invention and the substituted iodobenzene is carried out in a solvent in the presence of a metal hydride, and other substances are not needed, and the reaction is carried out at room temperature for 8-50 hours to obtain the isothiourea compound as a single product.

In the present invention, the metal hydride is sodium hydride, potassium hydride, calcium hydride, lithium hydride, or the like; the dosage of the metal hydride is 3-5 times of the molar weight of the thiourea. Furthermore, the using amount of the substituted iodobenzene is 1-2 times of the molar amount of the thiourea. Preferably, the metal hydride is used in an amount of 4 times the molar amount of thiourea; the dosage of the substituted iodobenzene is 1.5 times of the molar quantity of the thiourea.

In the invention, the solvent is one or more of dimethylacetamide DMA, tetrahydrofuran THF, acetonitrile CH3CN, ethylene glycol dimethyl ether DME and Toluene Toluene, THF and DMA are preferred, and the volume ratio of the two is preferably (4-8) to 1.

Metal catalysis can be used for synthesizing isothiourea compounds, but has some disadvantages, such as high temperature, long reaction time, large catalyst loading capacity, expensive reagent and easy pollution of metal wastes. Therefore, it is highly desirable to develop a metal-free, inexpensive-raw material, non-air sensitive reaction system for the preparation of S-isothiourea compounds. In recent years, chemists have tried to directly use N-substituted imidazoles to undergo nucleophilic substitution reactions with disulfides to conveniently produce S-arylimidazoles without the need for metal catalysts, but have required deprotonation using N-BuLi, and the reactions have poor safety without the need for water and oxygen-free atmospheres. The invention uses the substituted iodobenzene and the thiourea compound to carry out nucleophilic addition reaction under the action of NaH, thereby realizing that the substituted iodobenzene is directly used for carrying out C-S coupling with the thiourea for the first time to generate S- (substituted iodoaryl) isothiourea, and the reaction of the ortho-substituted diiodobenzene and the thiourea has good regioselectivity. The scheme has the advantages of simple and convenient operation, no need of metal catalysis, cheap and easily obtained raw materials and good functional group tolerance. Provides an excellent scheme for the drug synthesis of S-isothiourea compound building blocks, and has great significance for the future drug synthesis development.

Drawings

FIG. 1 shows the NMR spectrum of Compound 10 al.

Detailed Description

The invention takes thiourea and substituted iodobenzene as substrates, can complete the reaction in the presence of metal hydride and solvent, obtains the product isothiourea compound with high yield, does not need other substances, and solves the problems of the prior art that a metal catalyst, a format reagent and the like are needed.

The raw materials related to the invention are all existing products, can be purchased in the market, and can also be prepared according to the existing method. The nuclear magnetism H spectrum of the compound is detected by Agilent 400 MHz and Bruker 400 MHz instruments, the C spectrum is detected by Bruker 400 MHz instruments, and the sample solvent is a deuterated reagent (CDCl)₃Ord ₆-DMSO), both containing TMS internal standards, nuclear magnetic data reports including: chemical shift, peak area integral, coupling constant, peak type, etc. Single crystal detection was performed using an X-ray single crystal diffractometer (D8 Quest). TLC thin layer chromatography plate is produced in yellow sea chemical plant of tobacco stage, and is visually monitored at 254nm or 365nm wavelength, and KMnO is used as color developing agent₄Iodine, phosphomolybdic acid and dinitrophenylhydrazine, and the mesh number of silica gel used for the rapid column chromatography is 200-300 meshes. All the reagents are commercially available analytically pure or chemically pure, and are used directly without special indication. The anhydrous solvent is either a redistilled solvent or a commercially available dry solvent (carbofuran).

The present invention employs, unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy. Unless a specific definition is set forth, the terminology used herein in the description of analytical chemistry, organic synthetic chemistry, is art-known. Standard techniques can be used in chemical synthesis, chemical analysis. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds. When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH₂O-is equivalent to-OCH₂-. Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.

In the present invention, halogen means fluorine, chlorine, bromine or iodine; hydroxy means an-OH group; hydroxyalkyl refers to alkyl substituted with hydroxy (-OH); carbonyl means a-C (= O) -group; nitro means-NO₂(ii) a Cyano means-CN; amino means-NH₂(ii) a Carboxyl means-COOH.

Synthesis example the starting material for the substituted iodobenzene 11 was as follows:

、、、、

the reaction raw materials of the invention are conventional products on the market or compounds disclosed in the prior literature, and the applicant gives part of the preparation method for detailed description, but the invention is not limited to the method.

In N₂Under protection, periodic acid (4.0 mmol, 0.4 equiv), I, was added to a two-necked flask₂(8.0 mmol, 0.8 equiv) was dissolved in 15 mL MeOH and magnetically stirred, then o-dimethoxybenzene (10 mmol, 1.0 equiv) was added and the reaction was brought to 70 deg.C and stirred overnight, TLC monitoring the progress of the reaction. After the reaction is finished, cooling the reaction liquid to room temperature, and adding a proper amount of NaHSO₃Treating the reaction liquid with water solution to white, filtering, collecting filter cake, drying to obtain white solid product with yield of 80%,¹H NMR (400 MHz, CDCl₃) δ 7.23 (s, 2H), 3.83 (s, 6H)。

under the condition of ice bath, NaNO is added₂(4.6 mmol, 2.3 equiv) was dissolved in concentrated sulfuric acid (3 mL) and magnetically stirred, thenDiaminonaphthalene (2.0 mmol, 1.0 equiv) was dissolved in glacial acetic acid (4.5 mL) and slowly added with magnetic stirring, after the addition was complete, stirring was continued at 0 ℃ for 10 min, and then the reaction solution was slowly added dropwise to KI (20 mmol, 10 equiv) + H₂O (6 mL) solution, heated to 60 ℃ and reacted for 1 h. After the reaction was complete, saturated NaHCO was used₃Washing, extracting with ethyl acetate for 3 times, mixing organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, spin drying solvent, mixing with appropriate amount of silica gel powder, performing flash column chromatography and column separation (pure PE) to obtain white solid product with yield of 36%,¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 2H), 7.67 (dd, J = 6.1, 3.2 Hz, 2H), 7.49 (dd, J = 6.2, 3.2 Hz, 2H)。

at room temperature, N₂Protection, adding K into a two-mouth bottle₂CO₃(14 mmol, 1.4 equiv), BuNBr (1.5 mmol, 0.15 equiv), CuI (0.5 mmol, 0.05 equiv), then 1-phenyl-2-propyn-1-ol (10 mmol, 1.0 equiv) was dissolved in anhydrous DMF (15 mL) and added with magnetic stirring. After stirring for 15 min, 3-chloro-2-methylpropene (15 mmol, 1.5 equiv) was added and stirring was continued at room temperature for 24 h. After the reaction is finished, filtering to remove insoluble substances, adding a proper amount of water, extracting for 4 times by ethyl acetate, washing for 2 times by a small amount of water, combining organic layers, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, spin-drying, adding a proper amount of silica gel powder, mixing, and performing flash column chromatography (PE: EA =10: 1) to finally obtain an oily propenyl alkynol product with the yield of 70%. The propenylalkynol product (6.9 mmol, 1.0 equiv) from the previous step was dissolved in CH at room temperature₃NO₃(70 mL) and then I was added₂(12.4 mmol, 1.8 equiv) was magnetically stirred and the reaction was monitored by TLC and after 1h was complete. With a proper amount of NaHSO₃Treating with water solution, extracting with ethyl acetate for 3 times, mixing organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and rotary evaporating to obtain crude product.The crude product was dissolved in dichloromethane (140 mL), DDQ (13.8 mmol, 2.0 equiv) was added and the reaction was monitored by TLC with magnetic stirring at room temperature and after 2 h the reaction was complete. Adding a proper amount of diluted Na into the reaction solution₂SO₃Extracting the solution with ethyl acetate for 3 times, combining organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, rotary evaporating to dryness to obtain white solid product 11at with yield of 35%,¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.44 – 7.35 (m, 3H), 7.26 – 7.21 (m, 2H), 7.03 (s, 1H), 2.26 (s, 3H)。

example one

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after addition was completed stirring at room temperature for 2min, then substituted diiodobenzene 11ak (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, and TLC monitored for reaction completion. After 8 hours of reaction, adding ice water and tetrahydrofuran for quenching reaction, extracting for 3 times by using ethyl acetate, combining organic layers, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, spin-drying a solvent, adding a proper amount of silica gel powder for sample mixing, and performing flash column chromatography separation to obtain the thiourea compound product 10 ak.

Example two

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after addition was completed stirring at room temperature for 2min, then substituted diiodobenzene 11al (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, and TLC monitored for reaction completion. After the reaction is finished, adding ice water and tetrahydrofuran to quench the reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding a proper amount of silica gel powder to mix samples, and performing rapid column chromatography separation to obtain the thiourea compound product 10 al.

EXAMPLE III

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after addition was completed stirring at room temperature for 2min, then substituted diiodobenzene 11am (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, and TLC monitored for reaction completion. After the reaction is finished, adding ice water and tetrahydrofuran to quench the reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding a proper amount of silica gel powder to mix samples, and performing rapid column chromatography separation to obtain the thiourea compound product 10 am.

Example four

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after addition was completed stirring at room temperature for 2min, then substituted diiodobenzene 11as (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, and TLC monitored for reaction completion. After the reaction is finished, adding ice water and tetrahydrofuran to quench the reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding a proper amount of silica gel powder to mix samples, and performing rapid column chromatography separation to obtain the thiourea compound product 10 as.

EXAMPLE five

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after addition was completed stirring at room temperature for 2min, then substituted diiodobenzene 11at (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, and TLC monitored for reaction completion. After the reaction is finished, adding ice water and tetrahydrofuran to quench the reaction, extracting for 3 times by ethyl acetate, combining organic layers, washing by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering, spin-drying a solvent, adding a proper amount of silica gel powder to mix a sample, and performing rapid column chromatography separation to obtain the thiourea compound product 10 at.

The reaction schemes of the first to fifth examples, the structural formula of the product and the yield are as follows:

the yield is the separation yield, and the marked time is the time for monitoring the completion of the reaction by TLC; the product nuclear magnetic data are as follows:

¹H NMR (400 MHz, CDCl₃) δ 7.09 (s, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.56 – 6.50 (m, 3H), 3.82 (s, 3H), 3.72 (s, 3H), 3.19 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 153.35, 149.42, 149.34, 148.93, 128.16, 127.84, 126.88, 123.17, 121.85, 116.48, 92.94, 56.44, 55.81, 40.13。

¹H NMR (400 MHz, CDCl₃) δ 6.79 (d, J = 8.5 Hz, 2H), 6.34 (d, J = 8.5 Hz, 2H), 3.18 (s, 6H), 2.44 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.04, 148.04, 138.58, 138.45, 136.27, 135.83, 132.93, 127.35, 125.97, 121.97, 113.69, 39.98, 28.76, 21.85, 18.70, 17.19。

¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.67 – 7.56 (m, 3H), 7.47 (pd, J = 6.9, 3.4 Hz, 2H), 6.87 – 6.79 (m, 2H), 6.62 – 6.51 (m, 2H), 3.20 (s, 6H).¹³C NMR (101 MHz, CDCl₃) δ 152.75, 148.74, 139.04, 133.61, 133.37, 133.02, 131.84, 128.16, 127.39, 127.34, 127.18, 126.47, 123.18, 98.60, 40.09。

¹H NMR (400 MHz, CDCl₃) δ 7.13 (t, J = 8.0 Hz, 1H), 7.08 – 7.01 (m, 2H), 6.80 (dd, J = 7.9, 1.2 Hz, 1H), 6.67 – 6.59 (m, 2H), 6.56 (dd, J = 8.2, 1.1 Hz, 1H), 3.83 (s, 3H), 3.11 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 158.88, 152.43, 148.96, 140.08, 129.41, 128.33, 127.35, 123.42, 123.28, 108.63, 92.71, 56.80, 39.85。

¹H NMR (400 MHz, CDCl₃) δ 7.42 – 7.36 (m, 3H), 7.19 (dd, J = 7.6, 1.7 Hz, 2H), 7.03 – 6.97 (m, 2H), 6.94 (d, J = 1.9 Hz, 1H), 6.80 (d, J = 1.9 Hz, 1H), 6.64 – 6.57 (m, 2H), 3.24 (s, 6H), 2.21 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.39, 148.81, 148.51, 145.27, 138.12, 137.99, 132.41, 129.16, 128.18, 128.00, 127.72, 126.84, 123.31, 103.04, 40.08, 20.72。

EXAMPLE six

KH (1.2 mmol, 4.0 equiv) is weighed in a reaction bottle, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) is added dropwise during stirring, after the addition is finished, stirring is carried out at room temperature for 2min, then substituted diiodobenzene 11al (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) is added, stirring is carried out continuously at room temperature, after 8 h, ice water and tetrahydrofuran are added for quenching reaction, ethyl acetate is extracted for 3 times, organic layers are combined, saturated sodium chloride solution is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, a proper amount of solvent is added, silica gel powder is added for stirring, and rapid column chromatography separation is carried out, so that the thiourea compound product is not obtained.

The invention uses substituted iodobenzene to carry out nucleophilic addition reaction with thiourea compound under the action of NaH, thus realizing that the substituted iodobenzene is directly coupled with thiourea by C-S for the first time to generate S- (substituted iodoaryl) isothiourea compound; on the other hand, the product provided by the invention contains halogen and benzene ring, so that the product can be used as a flame retardant modifier for engineering materials. The scheme of the invention has the advantages of simple operation, no need of metal catalysis, cheap and easily available raw materials and good functional group tolerance, provides an excellent scheme for the substance synthesis of S-isothiourea compound building blocks, and has great significance for the future drug synthesis development or the structural design of small molecule functional compounds.