阅读说明：本技术 一种制备芳基异硫脲的方法 (Method for preparing aryl isothiourea ) 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：本发明公开了一种制备芳基异硫脲的方法,将氢化物悬于溶剂中,然后依次加入硫脲、邻二碘苯,接着反应,制备芳基异硫脲。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中,是重要的化学合成砌块。现有合成需要过渡金属介导,存在条件苛刻、金属催化剂污染等问题。本发明以氢化钠作用于邻二碘苯,与硫脲进行S-芳基化合成S-(2-碘芳基)异硫脲,该方法操作简单,底物范围广泛,且邻位取代的二碘苯具有高度的区域选择性,尤其是,本发明公开的方法在5小时内的反应时间下,能够取得优异的收率。(The invention discloses a method for preparing aryl isothiourea, which comprises the steps of suspending hydride in a solvent, then sequentially adding thiourea and o-diiodobenzene, and then reacting to prepare aryl isothiourea. The isothiourea structure widely exists in active natural products, chemical drugs and reaction catalysts, and is an important chemical synthesis building block. The prior synthesis needs transition metal mediation and has the problems of harsh conditions, metal catalyst pollution and the like. The method has the advantages that sodium hydride acts on the o-diiodobenzene, and S-arylation is carried out on the o-diiodobenzene and thiourea to synthesize the S- (2-iodoaryl) isothiourea, the method is simple to operate, the substrate range is wide, the o-substituted diiodobenzene has high regioselectivity, and particularly, the method disclosed by the invention can obtain excellent yield within 5 hours.)

1. A method for preparing aryl isothiourea is characterized in that hydride is suspended in a solvent, then thiourea and o-diiodobenzene are sequentially added, and then reaction is carried out to prepare aryl isothiourea;

the chemical structural formula of the thiourea is as follows:

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

wherein R is¹、R²、R³Independently selected from hydrogen, electron withdrawing groups, electron donating groups or protecting groups.

2. The process for preparing arylisothioureas according to claim 1 wherein R¹、R²、R³Independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl; or R¹、R²Constituting a cyclic group.

3. The process for preparing arylisothioureas according to claim 1 wherein the addition of thiourea is followed by conventional stirring and the addition of ortho-diiodobenzene.

4. The method for preparing the aryl isothiourea as claimed in claim 1, wherein the solvent is one or more of dimethylacetamide, tetrahydrofuran, acetonitrile, ethylene glycol dimethyl ether and toluene.

5. The process for preparing arylisothioureas according to claim 1 wherein the reaction is carried out in a solvent in the presence of a metal hydride, without further substances, using thiourea and o-diiodobenzene as substrates.

6. The process for preparing arylisothioureas according to claim 1 wherein the metal hydride is sodium hydride.

7. The method for preparing arylisothiourea according to claim 1, wherein the metal hydride is used in an amount of 3 to 6 times the molar amount of thiourea; the dosage of the o-diiodobenzene is 1-3 times of the molar weight of the thiourea.

8. The method for preparing arylisothiourea according to claim 1, wherein the reaction is carried out at room temperature for 1 to 4 hours.

9. The application of metal hydride in the reaction of thiourea and o-diiodobenzene to prepare aryl isothiourea is characterized in that the chemical structural formula of the thiourea is as follows:

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

wherein R is¹、R²、R³Independently selected from hydrogen, electron withdrawing groups, electron donating groups or protecting groups.

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 aryl isothiourea.

Background

The S-aryl isothiourea compound has wide application in the fields of agriculture, chemistry and medicine [ "Phenoxyphenylthioureas": Drabek J, B ç ger M,FR2465720A1, 1980, and 4.939.257, 1988。Nicholson A, Perry J D, James A L, Stanforth S P, et al. Int. J. Antimicrob. Agents2012, 39, 27-32]attracting great interest to numerous chemists and mediogists. Agriculturally, isothiourea derivatives can be used as herbicides [ Kogan M, Dinizo S E, Fancher L W,BR8602373A. 1987]pesticides [ Drabek J, Boeger M, Ehrenfree J, et al.Rec. Adv. Chem. Insect Control II. 1990, 170-183]An acaricide [ Pascual A, Rindlisbacher A.Pest Manage. Sci. 1994, 42, 253-263]And the like. Chemically, compounds of the isothiourea structure can be used as Catalysts [ Taylor J E, Bull S D, Williams J. ChemInform Abstract: Amidines, Isothioureas, and Guanidines as nucleic acids Catalysts.Chem. Soc. Rev. 2012, 41, 2109-2121]And a transition metal catalyzed ligand. Has wider application in the aspect of medicine and has good antiviral and antihistamine activity. Therefore, more and more isothiourea drug molecules are synthesized and designed, show very meaningful biological effects, effectively promote the development of the field of medicine, and have been researched in the aspects of HIV-1 inhibitors, anti-infective agents, central nervous agents, valine protein inhibitors and the like.

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. The Dong group has long-term research interest in the synthesis and application of isothiourea, and reports in recent yearsA series of simple processes for converting thiourea to S-arylisothioureas over metal catalysts are described. 2018, in Cu (OAc)₂·H₂O is used as a catalyst, bipyridine is used as a ligand, the ideal S-Aryl isothiourea 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]Various functional group-substituted arylthioureas and arylboronic acids are well tolerated. Then, they continue to use inexpensive metallic Copper as a catalyst and couple iodobenzene with thiourea to produce S-arylisothiourea [ Zhu H, Liu X, Chang C Z, et al, Copper-catalyzed C-S crosslinking reaction: S-alkylation of arylthioureas without ligand participation.Synthesis. 2017, 49, 5211-5216]The source of the starting material iodobenzene is more extensive than phenylboronic acid. In order to improve the applicability of the metal-catalyzed isothiourea synthesis scheme on industrial production, the metal-catalyzed isothiourea synthesis scheme is optimized and improved. The Maes project group reports a new process for the three-component synthesis of S-arylated and S-alkylated isothioureas [ Mampuys P, Zhu Y, Vlaar T, et al using CuI for the catalysis of anilines, sulfonates and isocyanides.Angew. Chem. Int. Ed. 2014, 53,12849-12854]. The authors first achieved the insertion of an isocyanide into a sulfonate ester to form an isothiocyanatothioum intermediate, followed by reaction with aniline to form isothiourea, under copper metal catalysis.

The S-aryl isothiourea structure exists in a plurality of chemical molecules, is widely applied to the fields of functional materials and medicines, and attracts great interest of scientists. Besides the requirement of simple and easily available reaction raw materials, the reaction temperature and the reaction time are as mild as possible, which is also the pursuit direction of organic synthesis.

Disclosure of Invention

The invention discloses a method for preparing aryl isothiourea, which can generate S-aryl isothiourea by nucleophilic reaction with thiourea under mild, economic and simple conditions, particularly, the time for preparing a product by the reaction is less than 5 hours, so that energy is saved, and the problem of unstable reaction possibly caused by long-time reaction is avoided, thereby being a very desirable aryl C-S bond forming scheme.

The invention adopts the following technical scheme:

a process for preparing arylisothiourea includes such steps as suspending hydride in solvent, sequentially adding thiourea and o-diiodobenzene, and reaction.

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

the chemical structural formula of the o-diiodobenzene is as follows:

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

in the above structural formula, R¹、R²、R³Independently selected from hydrogen, electron withdrawing groups, electron donating groups or protecting groups such as halogen, cyano, alkenyl, substituted or unsubstituted alkyl, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl; further, substituted means that one or more hydrogen atoms on the group are substituted with a substituent; the substituent of the substituted alkyl and the substituted amino is independently selected from halogen, OH and NH₂CN, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted or halogenated C2-C6 acyl, and unsubstituted or halogenated 4-to 8-membered saturated heterocyclic or carbocyclic ring; wherein, the heterocyclic ring contains N, O, S. Or R¹、R²Constituting a cyclic group, in particular, R¹、R²To the connection R¹、R²N of (a) constitutes a cyclic group, the ringThe cyclic group may be a monocyclic structure or a polycyclic structure.

The reaction of the thiourea disclosed by the invention and the o-diiodobenzene 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 1-4 hours to obtain the aryl isothiourea 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 3-6 times of the molar weight of the thiourea. Furthermore, the dosage of the o-diiodobenzene is 1-3 times of the molar weight 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 (4-7) to 1.

Although the metal catalysis method is suitable for synthesizing the isothiourea compound, the method also has the defects of 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-arylisothioureas. 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 o-diiodobenzene and the thiourea compound to carry out nucleophilic addition reaction under the action of NaH, thereby realizing that the o-diiodobenzene is directly coupled with the thiourea through C-S for the first time to generate the S- (2-iodoaryl) isothiourea, and the reaction of the o-substituted di-iodobenzene 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-aryl isothiourea building blocks, and has great significance for the future drug synthesis development.

Drawings

FIG. 1 is a nuclear magnetic spectrum of Compound 10 a;

figure 2 is an x-ray crystallographic analysis of compound 10 n.

Detailed Description

The invention takes thiourea and o-diiodobenzene as substrates, can complete reaction at room temperature in the presence of metal hydride and solvent, obtains the product aryl isothiourea with high yield without other substances, and solves the problems of the prior art that a metal catalyst, a format reagent and the like are required.

The raw materials involved in 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 a group havingAn alkyl group as defined below having a total of from 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.

EXAMPLE one preparation of aryl isothioureas

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in 0.8 mL of anhydrous THF and stirred conventionally, thiourea 9 (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL of DMA) was added dropwise during stirring, after completion of addition, stirring was carried out at room temperature for 1min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL of THF) was then added, stirring was continued at room temperature, and the completion of the reaction was monitored by TLC. 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 aryl isothiourea 10 product.

The different reaction substrates thiourea 9 and the corresponding product arylisothiourea 10 obtained are as follows:

the above yields are isolated yields, and the times indicated are the time for which the reaction was completed by TLC monitoring, the superscript b indicating the amount of sodium hydride used as 5 equivalents, and the superscript c indicating the amount of sodium hydride used as 4.5 equivalents.

The above partial product data are characterized as follows:

¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 15.2, 7.2 Hz, 2H), 7.13 (t, J = 7.5 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.80 (t, J = 7.0 Hz, 1H), 6.73 (d, J = 7.6 Hz, 2H), 3.11 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 152.11, 150.32, 139.61, 138.56, 131.52, 128.66, 128.47, 128.00, 122.33, 122.11, 100.85, 39.88。

¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 3.8 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.82 (dd, J = 7.7, 4.1 Hz, 1H), 6.60 (d, J= 8.3 Hz, 2H), 3.14 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 152.56, 148.87, 139.69, 137.92, 131.90, 128.65, 128.36, 128.27, 127.33, 123.33, 101.29, 39.97。

¹H NMR (400 MHz, CDCl₃) δ 7.63 (dd, J = 7.9, 1.2 Hz, 1H), 7.16 – 7.10 (m, 2H), 7.06 (m, 2H), 6.87 – 6.80 (m, 2H), 6.79 – 6.71 (m, 1H), 3.21 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 153.04, 150.45, 139.66, 137.13, 132.83, 130.52 (d, J = 31.3 Hz), 128.75, 128.54 (d, J = 8.1 Hz), 125.66, 125.10, 122.95, 119.03 (q, J = 11.1 Hz), 118.39 (q, J = 12.1 Hz), 102.03, 40.07. ¹⁹F NMR (377 MHz, CDCl₃) δ -62.49。

¹H NMR (400 MHz, CDCl₃) δ 7.64 (dd, J = 7.9, 1.3 Hz, 1H), 7.10 (dtd, J= 9.1, 7.9, 1.5 Hz, 2H), 6.87 (dd, J = 8.8, 0.7 Hz, 2H), 6.78 (m, 1H), 6.65 – 6.57 (m, 2H), 3.19 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 152.82, 148.86, 144.10, 144.08, 139.69, 137.45, 132.62, 128.57, 128.38, 122.76, 121.98, 121.24, 119.44, 101.98, 40.04。

¹H NMR (400 MHz, CDCl₃) δ 8.07 – 8.03 (m, 1H), 7.98 (t, J = 1.6 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.11 (dt, J = 5.5, 3.4 Hz, 2H), 6.92 (dd, J = 3.4, 1.3 Hz, 2H), 6.78 (m, 1H), 3.19 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 153.51, 146.50, 143.38, 142.58, 139.74, 137.21, 132.33, 129.08, 128.72, 128.56, 123.09, 101.57, 40.04。

¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 7.6 Hz, 1H), 7.69 – 7.63 (m, 1H), 7.50 – 7.44 (m, 1H), 7.35 (m, 3H), 7.25 (d, J = 7.0 Hz, 1H), 7.04 (dd, J= 7.8, 1.2 Hz, 1H), 6.87 (dd, J = 11.0, 4.2 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.58 – 6.48 (m, 1H), 3.25 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 152.51, 146.83, 139.38, 137.41, 134.08, 132.43, 128.23, 128.17, 127.84, 127.61, 125.89, 125.67, 124.64, 124.07, 122.29, 116.42, 102.20, 40.14。

¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J = 7.9, 1.0 Hz, 1H), 7.22 (dd, J = 7.9, 1.4 Hz, 1H), 7.12 (m, 3H), 6.87 (t, J = 7.4 Hz, 1H), 6.79 (td, J = 7.8, 1.5 Hz, 1H), 6.73 (d, J = 7.4 Hz, 2H), 3.57 (t, J = 6.6 Hz, 4H), 1.93 – 1.87 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 150.32, 148.21, 139.56, 138.38, 131.28, 128.67, 128.40, 127.92, 122.40, 122.16, 101.05, 49.23, 25.50。

¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.19 (m, 3H), 6.96 (t, J = 7.1 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.6 Hz, 2H), 3.53 (m, 4H), 3.25 (m, 4H), 1.45 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 154.66, 153.39, 149.58, 139.85, 138.03, 132.95, 128.70, 128.64, 128.58, 122.98, 121.69, 102.31, 80.13, 47.93, 28.47。

¹H NMR (400 MHz, CDCl₃) δ 7.63 – 7.57 (m, 1H), 7.32 – 7.26 (m, 2H), 7.18 – 7.12 (m, 2H), 7.11 – 7.00 (m, 4H), 6.99 – 6.92 (m, 4H), 6.73 (m, 1H), 3.45 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.40, 149.74, 145.62, 139.39, 137.43, 134.15, 128.78, 128.67, 128.49, 128.10, 126.02, 125.55, 123.18, 121.91, 104.22, 42.26。

¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 7.9, 1.2 Hz, 1H), 7.26 – 7.21 (m, 2H), 7.19 – 7.13 (m, 2H), 7.13 – 7.07 (m, 1H), 7.06 – 6.97 (m, 3H), 6.94 (m, 4H), 6.73 (m, 1H), 6.11 (m, 1H), 5.15 – 5.02 (m, 2H), 4.54 – 4.41 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 152.07, 149.61, 143.99, 139.34, 137.55, 134.00, 133.84, 128.71, 128.62, 128.44, 128.11, 127.07, 125.88, 122.99, 121.83, 117.92, 103.89, 56.63。

¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.16 – 7.11 (m, 1H), 7.10 – 7.05 (m, 2H), 6.87 (t, J = 7.1 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 7.4 Hz, 2H), 5.81 (m, 2H), 5.24 (s, 1H), 5.20 (d, J = 7.9 Hz, 3H), 4.17 (d, J = 5.0 Hz, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 151.31, 149.93, 139.48, 137.92, 133.85, 133.73, 132.62, 131.20, 128.87, 128.42, 128.35, 128.30, 128.20, 122.13, 121.85, 117.51, 117.41, 101.84, 51.68。

¹H NMR (400 MHz, CDCl₃) δ 8.38 (dd, J = 4.8, 1.5 Hz, 1H), 7.71 (dd, J = 7.9, 1.2 Hz, 1H), 7.42 (dd, J = 7.7, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 1.5 Hz, 1H), 7.23 – 7.14 (m, 4H), 7.12 (m, 1H), 7.08 (m, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.84 (td, J = 7.7, 1.5 Hz, 1H), 6.79 (dd, J = 8.3, 1.0 Hz, 2H), 4.05 – 3.90 (m, 2H), 3.36 (m, 2H), 3.14 (m, 2H), 2.88 – 2.75 (m, 2H), 2.36 – 2.23 (m, 3H), 2.19 – 2.11 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 157.10, 153.12, 149.94, 146.71, 139.75, 139.61, 138.47, 137.93, 137.71, 137.64, 133.94, 133.46, 132.99, 132.68, 130.63, 129.07, 128.64, 128.55, 128.47, 126.24, 122.77, 122.38, 121.86, 101.96, 49.06, 31.78, 31.55, 30.61, 30.49。

¹H NMR (400 MHz, CDCl₃) δ 7.78 (dd, J = 7.9, 1.1 Hz, 1H), 7.45 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.23 (t, J = 7.8 Hz, 2H), 7.08 – 7.00 (m, 3H), 6.97 (m, 2H), 6.93 – 6.84 (m, 3H), 6.63 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 6.14 (dd, J = 8.5, 2.5 Hz, 1H), 5.88 (s, 2H), 4.51 (m, 2H), 3.47 (m, 2H), 3.08 – 2.93 (m, 2H), 2.67 (td, J = 12.0, 3.8 Hz, 1H), 1.77 (dd, J = 13.3, 3.4 Hz, 1H), 1.73 – 1.63 (m, 1H), 1.50 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 161.65 (d, J = 246.4 Hz), 154.33, 153.78, 150.00, 148.22, 141.75, 139.78, 139.12, 139.09, 138.75, 133.23, 128.76 (d, J = 8.1 Hz), 128.63, 128.55 (d, J = 1.0 Hz), 122.92, 121.92, 115.58 (d, J = 21.2 Hz), 107.91, 105.71, 102.63, 101.18, 98.16, 68.80, 51.77, 48.68, 44.28, 41.74, 33.63. ¹⁹F NMR (377 MHz, CDCl₃) δ -116.05。

¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.16 – 7.07 (m, 4H), 6.99 – 6.94 (m, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 7.8 Hz, 2H), 5.73 (dd, J = 8.0, 4.8 Hz, 1H), 3.93 – 3.73 (m, 2H), 3.13 (s, 3H), 2.63 – 2.38 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 153.30, 151.35, 150.08, 144.82, 139.57, 138.32, 134.71, 131.72, 128.62, 128.42, 128.10, 127.60, 126.78, 126.47, 126.19, 125.78, 125.44, 124.99, 124.85, 122.26, 122.00, 120.89, 107.09, 101.17, 74.48, 49.05, 38.41, 37.14。

¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J = 7.9, 1.2 Hz, 1H), 7.29 (dd, J= 7.9, 1.5 Hz, 1H), 7.20 – 7.15 (m, 2H), 7.13 (s, 1H), 6.95 (t, J = 7.3 Hz, 2H), 6.82 (m, 1H), 6.78 – 6.73 (m, 2H), 6.63 (d, J = 8.5 Hz, 1H), 3.87 (d, J= 1.3 Hz, 6H), 3.85 (s, 3H), 3.64 – 3.58 (m, 4H), 3.44 (s, 2H), 2.37 – 2.31 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 153.03, 152.74, 152.62, 149.89, 142.33, 139.57, 138.40, 132.49, 128.46, 128.43, 128.20, 125.08, 122.58, 121.79, 106.99, 101.54, 61.22, 60.82, 56.40, 56.01, 52.51, 47.94。

¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J = 7.9, 0.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.40 – 7.33 (m, 4H), 7.30 (m, 1H), 7.21 – 7.12 (m, 2H), 7.09 (t, J = 7.8 Hz, 2H), 6.97 – 6.86 (m, 3H), 6.83 – 6.77 (m, 1H), 6.60 (d, J = 7.3 Hz, 2H), 5.24 (dd, J = 9.0, 4.0 Hz, 1H), 3.73 (m, 2H), 3.12 (s, 3H), 2.35 – 2.15 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 160.60, 151.64, 150.15, 140.98, 139.72, 138.50, 131.84, 129.13, 128.73, 128.55, 128.22, 127.01 (q, J = 11.1 Hz), 125.94, 125.89, 123.28 (d, J = 6.1 Hz), 122.99, 122.46, 122.04, 116.04, 101.23, 78.41, 49.15, 38.26, 37.07. ¹⁹F NMR (377 MHz, CDCl₃) δ -61.52。

the structural formula of the substrate thiourea 9 can be seen from the structural formula of the product, and is as follows:

r is phenyl, substituted phenyl, heterocycle, naphthyl, etc.; r¹、R²As before.

The method specifically comprises the following steps:

the reaction substrates of the present invention are either conventionally available commercially or can be prepared according to conventional methods, for example

At room temperature, using N₂For protection, isothiocyanate (2.0 mmol) was weighed into a two-necked flask and 5 mL of THF was added and magnetically stirred. Then, 2M dimethylamine-THF solution (1.1 equiv) was added by syringe, the reaction was further stirred at room temperature, and the progress of the reaction was monitored by TLC. After the reaction is finished, transferring the reaction solution to a single-mouth round-bottom bottle, directly spin-drying the solvent, and then using petroleum ether and ethyl acetatePulping the ethyl acetate mixed solvent, performing suction filtration, and collecting a filter cake to obtain a pure white solid product.

At room temperature, using N₂For protection, phenyl isothiocyanate (2.0 mmol) was weighed into a two-necked flask and added 5 mL of EtOH for magnetic stirring. The EtOH-dissolved secondary amine compound (1.1 equiv) was then added via syringe, the reaction was continued to stir at room temperature and the progress of the reaction was monitored by TLC. And (3) after the reaction is finished, separating out white insoluble solids in the reaction solution, transferring the reaction solution to a single-mouth round-bottom bottle, directly spin-drying the solvent, pulping by using a mixed solvent of petroleum ether and ethyl acetate, performing suction filtration, collecting a filter cake, and drying to obtain a pure white solid product.

Example two

NaH (0.9 mmol, 3.0 equiv) was weighed into the reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9a (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 1min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, 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 an o-iodophenyl sulfide product 10 with the separation yield of 29%.

NaH (1.5 mmol, 5.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9a (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 1min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, 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 an o-iodophenyl sulfide product 10 with the separation yield of 73%.

NaH (1.2 mmol, 4.0 equiv) was weighed into the reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9a (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 1min, diiodobenzene 2a (0.45 mmol, 1.5 equiv, dissolved in 0.2 mL THF) was added, stirring was continued at room temperature, 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 an o-iodophenyl thioether product 10 with the separation yield of 72%.

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL) and stirred, thiourea 9a (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 1min, diiodobenzene 2a (0.6 mmol, 2.0 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 an o-iodophenyl thioether product 10, wherein the yield is as above. Performing single factor conversion, and replacing all solvents with DMA to obtain an o-iodophenyl sulfide product 10 with a separation yield of 54%; all solvents are replaced by THF to obtain an o-iodophenyl sulfide product 10 with a separation yield of 69%; all solvents are replaced by 1, 4-dioxane to obtain a product 10; replacing all solvents with DME to obtain an o-iodophenyl sulfide product 10 with a separation yield of 51%; THF (0.8 mL) was changed to THF (0.4 mL), i.e. THF: DMA = 3:1, to give product 10, iodophenylsulfide, isolated in 72% yield; the THF was changed to DME, i.e. DME: DMA = 5:1, yielding the product o-iodophenylsulfide 10 with an isolated yield of 57%.

The NaH (1.2 mmol, 4.0 equiv) was replaced with the same equivalent of KH, LiH or CaH₂Weighing in a reaction bottle, suspending in anhydrous THF (0.8 mL THF) and stirring, adding thiourea 9a (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) dropwise during stirring, stirring at room temperature for 1min after the addition is finished, then adding diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF), continuing stirring at room temperature for 24 h, then adding ice water and tetrahydrofuran to quench the reaction, extracting with ethyl acetate for 3 times, combining organic layers, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, spinning to dry a solvent, adding a proper amount of silica gel powder to mix a sample, and performing flash column chromatography to separate, wherein no o-iodobenzene product 10 can be obtained. The NaH (4.0 equiv) was replaced by BuLi (2.5 equiv) at-78 ℃ and room temperature to give the product, o-iodophenylsulfide, 10, in an isolated yield of 36%.

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9a (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after addition was completed, stirring was carried out at room temperature for 1min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, and stirring was carried out at 0 ℃ for 12 hours, whereby no product 10 of o-iodobenzene sulfide was obtained.

NaH (1.2 mmol, 4.0 equiv) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9a (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 1min, diiodobenzene 2a (0.6 mmol, 2.0 equiv, dissolved in 0.2 mL THF) was added, stirring was carried out at 40 ℃ and the reaction was monitored by TLC for completion (1 h). 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 an o-iodophenyl thioether product 10 with the separation yield of 58%.

The invention utilizes the reaction of a large amount of thiourea with different structures and o-diiodobenzene to successfully synthesize abundant and diverse S- (2-iodoaryl) isothiourea in a short time, further discloses the S-arylation reaction of some complex drug molecules, tests the functional group tolerance of the method in various drug molecules, and results are very satisfactory, and a plurality of modified complex drug molecules can generate S-o-iodoarylation products through o-diiodobenzene. All products were structurally characterized by a series of nuclear magnetic resonance techniques, given as schematic in fig. 1, and the single crystal structure of 10n was confirmed by x-ray crystallography analysis (fig. 2). The reaction between the thiourea substrate and the diiodobenzene can be confirmed to carry out C-S coupling, and the ortho position of the C-S bond benzene ring is provided with iodine.

The invention uses the o-diiodobenzene to carry out nucleophilic addition reaction with a thiourea compound under the action of NaH, thereby realizing that the first time the benzyne is directly coupled with the thiourea through C-S to generate S- (2-iodoaryl) isothiourea, and the reaction of the o-substituted diiodobenzene and the thiourea has good regioselectivity. In addition, the product of the invention contains halogen, and part of the product has reactive groups, such as olefinic bonds, and can be used as a flame retardant modifier for engineering materials. 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-aryl isothiourea building blocks, and has great significance for future drug synthesis and functional small molecule development.