CN113735752B - Method for preparing isothiourea compound based on substituted iodobenzene - Google Patents
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Abstract
The invention discloses a method for preparing isothiourea compound based on substituted iodobenzene, which takes thiourea and substituted iodobenzene as substrates, and prepares isothiourea compound by reaction in the presence of metal hydride and in a solvent. Isothiourea structures are widely existing in some active natural products, chemical drugs, reaction catalysts and material modifiers, and are important chemical synthesis building blocks. The invention uses the substituted iodobenzene as a substrate, and carries out nucleophilic addition reaction with thiourea compound under the action of NaH, thus realizing the first time of directly carrying out C-S coupling with thiourea by using the iodobenzene to generate the isothiourea compound. Provides an excellent scheme for the compound synthesis of the S-aryl isothiourea building block.
Description
Technical Field
The invention belongs to organic synthesis, and particularly relates to a method for preparing isothiourea compound based on substituted iodobenzene.
Background
S-isothiourea compound 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. In recent years, thiourea derivatives have also begun to become powerful tools for asymmetric organocatalysis. For the synthesis of S-isothiourea compounds, halobenzene or phenylboronic acid is usually used for C-S coupling of thiourea under a metal catalyst, but the experimental method has harsh reaction conditions (air sensitivity, strong alkali/high temperature), large catalyst loading and serious pollution of metal reagents. In addition, sulfur-containing species can rapidly and irreversibly deactivate various metal catalysts, making metal-catalyzed C-S bond formation schemes less preferred by a wide range of organic synthesizers.
Since the 21 st century, metal-catalyzed coupling reactions have been a popular hot-dip, and the Chan-Lam reaction has become an effective and practical alternative to the construction of C-S bonds. The Dong group has long been interested in the synthesis of isothiouronium and its use, and in recent years a series of simple processes for the conversion of thiourea to S-isothiouronium compounds by means of metal catalysts have been reported. In 2018, in Cu (OAc) 2 ·H 2 O is used as a catalyst, bipyridine is used as a ligand, and an ideal S-isothiourea compound is synthesized, and the yield is basically 90% [ Liu X, zhang S B, zhu H, et al An Efficient Chan-Lam S-Arylation of Arylthioureas with Aryl Boronic Acids.Eur. J. Org. Chem. 2018, 4483-4489]. They then continue to use inexpensive metallic copper as a catalyst to couple iodobenzene with thiourea without ligand participation to form S-isothiourea compounds [ Zhu H, liu X ], Chang C Z, et al. Copper-catalyzed C-S crosscoupling reaction: S-arylation of arylthioureas. Synthesis. 2017, 49, 5211-5216]The source of the raw material iodized benzene is wider than that of phenylboronic acid.
Although the metal catalyzed process is generally applicable to the synthesis of various isothiourea compounds, it also has some drawbacks. If high temperature is needed, the reaction time is long, the catalyst loading is large, the reagent price is high, and the pollution of metal waste is easy to cause. Therefore, it is highly desirable to develop a reaction system that is free of metal catalysis, inexpensive in raw materials, and non-air sensitive to produce 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 to generate an S-isothiourea compound under mild, economical and simple conditions, does not need transition metal catalysis, takes the substituted iodobenzene as a precursor, and has simple raw material sources.
The invention adopts the following technical scheme:
a method for preparing isothiourea compound based on substituted iodobenzene uses thiourea and substituted iodobenzene as substrates, and the isothiourea compound is obtained by reacting in the presence of metal hydride and in a solvent.
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 isothiourea compound has the chemical structural formula 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 group; r is R 1 Selected from hydrogen, halogen or alkyl, preferably chlorine. The substituent has obvious influence on organic synthesis, especially the reaction time, the substrate dosage and the substituent are obviously related, so that the product yield is influenced by the substituent. The reaction of thiourea and substituted iodobenzene disclosed by the invention is carried out in the presence of metal hydride and in a solvent without other substances, and the obtained isothiourea compound is a single product after the reaction is carried out for 8-50 hours at room temperature.
In the invention, the metal hydride is sodium hydride, potassium hydride, calcium hydride, lithium hydride and the like; the dosage of the metal hydride is 3 to 5 times of the molar quantity of the thiourea. Further, the usage 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 usage amount of the substituted iodobenzene is 1.5 times of the molar amount 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 tolene, preferably THF and DMA, and the volume ratio of the two is preferably (4-8) to 1.
Metal catalysis can be used for synthesizing isothiourea compounds, but has the defects of high temperature, long reaction time, large catalyst loading, high reagent price and easy pollution of metal waste. Therefore, it is highly desirable to develop a reaction system that is free of metal catalysis, inexpensive in raw materials, and non-air sensitive to produce S-isothiourea compounds. In recent years, chemists have been trying to directly use N-substituted imidazole to react with disulfide for nucleophilic substitution, and a metal catalyst is not required to conveniently generate S-arylated imidazole, but N-BuLi is required to carry out deprotonation, so that the reaction needs no water or oxygen atmosphere, and the safety is poor. The invention uses the substituted iodobenzene and the thiourea compound to carry out nucleophilic addition reaction under the action of NaH, realizes that the substituted iodobenzene is directly coupled with thiourea to form S- (substituted iodoaryl) isothiourea by C-S for the first time, and has good regioselectivity in the reaction of ortho-substituted diiodobenzene and thiourea. The scheme is very simple and convenient to operate, metal catalysis is not needed, raw materials are cheap and easy to obtain, and the tolerance of functional groups is good. Provides an excellent scheme for the drug synthesis of S-isothiourea compound blocks, and has great significance for the future drug synthesis development.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of compound 10al.
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 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 involved in the invention are all existing products, are commercially available and can be prepared according to the existing method. The nuclear magnetic H spectrum of the compound is detected by an Agilent 400 MHz instrument and a Bruker 400 MHz instrument, the C spectrum is detected by the Bruker 400 MHz instrument, and the sample solvent is deuterated reagent (CDCl) 3 Or (b)d 6 DMSO), all containing TMS internal standard, nuclear magnetic data report including: chemical shift, integration of peak area, coupling constant, peak pattern, etc. The single crystal was detected by using an X-ray single crystal diffractometer (D8 Quest). TLC thin layer chromatography plate is produced by yellow sea chemical plant of tobacco table, and is visually monitored at 254nm or 365nm wavelength, and the color-developing agent is KMnO 4 Iodine, phosphomolybdic acid and dinitrophenylhydrazine, and the silica gel mesh number used for the flash column chromatography is 200-300 meshes. All reagents are commercially available analytically pure or chemically pure, and are directly used without special description. The anhydrous solvents are either the distilled solvents or commercially available dry solvents (carbofuran).
Unless otherwise indicated, the present invention employs conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy. Unless specifically defined otherwise, terms used herein in the description of analytical chemistry, organic synthetic chemistry, and the like are known in the art. Can be used forStandard techniques are used in chemical synthesis, chemical analysis. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -. Certain chemical groups defined herein are preceded by a simplified symbol 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 reduced notation does not include carbon that may be present in a substituent of the group.
In the present invention, halogen means fluorine, chlorine, bromine or iodine; hydroxy refers to an-OH group; hydroxyalkyl refers to alkyl substituted with hydroxy (-OH); carbonyl refers to a-C (=o) -group; nitro refers to-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the Cyano refers to-CN; amino means-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the Carboxyl refers to-COOH.
Synthesis example the starting material substituted iodobenzene 11 is as follows:
the reaction materials of the present invention are commercially available conventional products or compounds disclosed in the prior art, and the applicant gives a detailed description of some of the preparation methods, but the present invention is not limited thereto.
At N 2 Under protected conditions, periodic acid (4.0 mmol, 0.4 equiv) was added to a two-necked flask, I 2 (8.0 mmol, 0.8 equiv) in 15 mL MeOH solution was magnetically stirred, then o-dimethoxybenzene (10 mmol, 1.0 equiv) was added and the reaction was moved to 70℃and stirred overnight, TLC monitored for reaction progress. After the reaction was completed, the reaction mixture was cooled to room temperature, and then cooled to room temperature with an appropriate amount of NaHSO 3 The aqueous solution treatment reaction solution is white, the filtration is carried out, the filter cake is collected, the drying is carried out, the white solid product is obtained, the yield is 80 percent, 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (s, 2H), 3.83 (s, 6H)。
under ice bath condition, naNO is added 2 (4.6 mmol, 2.3 equiv) was dissolved in concentrated sulfuric acid (3 mL) and stirred magnetically, then diaminonaphthalene (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 completed, stirring was continued at 0deg.C for 10 min, and then the reaction solution was slowly added dropwise to KI (20 mmol, 10 equiv) +H 2 In O (6 mL) solution, the mixture was heated to 60℃to react 1 h. After completion of the reaction, saturated NaHCO was used 3 Washing, 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, separating by flash column chromatography (pure PE) to obtain white solid product with 36% yield, 1 H NMR (400 MHz, CDCl 3 ) 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)。
n under room temperature conditions 2 Protection, adding into two-mouth bottleK 2 CO 3 (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 magnetically. 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 completed, insoluble substances are removed by filtration, a proper amount of water is added, ethyl acetate is used for extraction for 4 times, a small amount of water is used for washing for 2 times, the organic layers are combined, the mixture is washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and dried by spin, a proper amount of silica gel powder is added for sample mixing, and the mixture is subjected to rapid column chromatography separation (PE: EA=10:1), so that an oily propenyl alkynol product is finally obtained, and the yield is 70%. The propenyl alkynol product (6.9 mmol, 1.0 equiv) of the last step was dissolved in CH at room temperature 3 NO 3 (70 mL) and then adding I 2 (12.4 mmol, 1.8 equiv) was magnetically stirred and the reaction monitored by TLC after 1h was complete. With a proper amount of NaHSO 3 The aqueous solution is treated, extracted 3 times with ethyl acetate, the organic layers are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and rotary evaporated to dryness to obtain crude product. To the crude was dissolved in dichloromethane (140 mL), DDQ (13.8 mmol, 2.0 equiv) was added and magnetically stirred at room temperature, TLC monitored the reaction and after 2 h the reaction was complete. Adding a proper amount of diluted Na into the reaction solution 2 SO 3 Extracting the solution with ethyl acetate for 3 times, mixing 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 35% yield, 1 H NMR (400 MHz, CDCl 3 ) 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 1
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 the addition was completed, stirred 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 completion of the reaction for 8 hours, ice water and tetrahydrofuran were added to quench the reaction, extraction was performed 3 times with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, spin-dried, and then a proper amount of silica gel powder was added to mix the sample, followed by flash column chromatography to obtain thiourea compound product 10ak.
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 the addition was completed, stirred 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, TLC monitored for reaction completion. After the reaction was completed, ice water and tetrahydrofuran were added to quench the reaction, extraction was performed 3 times with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, spin-dried, and then a proper amount of silica gel powder was added to mix the sample, followed by flash column chromatography to obtain thiourea compound product 10al.
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 the addition was completed, stirred 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, TLC monitored for reaction completion. After the reaction, ice water and tetrahydrofuran are added to quench the reaction, ethyl acetate is added for extraction for 3 times, the organic layers are combined, washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, spin-dried, and then a proper amount of silica gel powder is added for sample mixing, and the thiourea compound product 10am is obtained after rapid column chromatography separation.
Example IV
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 the addition was completed, stirred 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, TLC monitored the reaction was complete. After the reaction was completed, ice water and tetrahydrofuran were added to quench the reaction, extraction was performed 3 times with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, spin-dried, and then a proper amount of silica gel powder was added to mix the sample, followed by flash column chromatography to obtain thiourea compound product 10as.
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 the addition was completed, stirred 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, TLC monitored for reaction completion. After the reaction, ice water and tetrahydrofuran are added to quench the reaction, ethyl acetate is added for extraction for 3 times, the organic layers are combined, washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, spin-dried, and then a proper amount of silica gel powder is added for sample mixing, and the thiourea compound product 10at is obtained after rapid column chromatography separation.
The reaction schemes and the product structural formulas and yields of examples one to five are as follows:
the yield is separation yield, and the marked time is the time for TLC monitoring reaction completion; the product nuclear magnetic data are as follows:
1 H NMR (400 MHz, CDCl 3 ) 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). 13 C NMR (101 MHz, CDCl 3 ) 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。
1 H NMR (400 MHz, CDCl 3 ) 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). 13 C NMR (101 MHz, CDCl 3 ) 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。
1 H NMR (400 MHz, CDCl 3 ) 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).13 C NMR (101 MHz, CDCl 3 ) 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。
1 H NMR (400 MHz, CDCl 3 ) 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). 13 C NMR (101 MHz, CDCl 3 ) 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。
1 H NMR (400 MHz, CDCl 3 ) 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). 13 C NMR (101 MHz, CDCl 3 ) 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) was weighed into a reaction flask, suspended in anhydrous THF (0.8 mL THF) and stirred, thiourea 9c (0.3 mmol, 1.0 equiv, dissolved in 0.2 mL DMA) was added dropwise during stirring, after the addition was completed, stirring was performed 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 for 8 h, after quenching with ice water and tetrahydrofuran, ethyl acetate extraction was performed 3 times, the organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, spin-dried solvent was added, and a proper amount of silica gel powder was added for stirring, followed by flash column chromatography to separate, thereby obtaining the thiourea compound product.
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 used for C-S coupling with thiourea to generate S- (substituted iodoaryl) isothiourea compound for the first time, and further, the product of the invention has iodobenzene and can react with alkynyl, sulfhydryl, piperazine and other groups by adopting a conventional method to obtain more drug molecules; 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 of engineering materials. The method is very simple and convenient to operate, does not need metal catalysis, has low-cost and easily-obtained raw materials and good functional group tolerance, provides an excellent scheme for the substance synthesis of the S-isothiourea compound block, and has great significance for the future development of drug synthesis or the structural design of small molecular functional compounds.
Claims (8)
1. A method for preparing isothiourea compound based on substituted iodobenzene is characterized in that isothiourea compound is prepared by taking thiourea and substituted iodobenzene as substrates and reacting in the presence of metal hydride and in a solvent;
the chemical structural formula of the substituted iodobenzene is as follows:
the chemical structural formula of the thiourea is as follows:
the isothiourea compound has the chemical structural formula 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 group; r is R 1 Selected from hydrogen, halogen or alkyl.
2. The method for producing isothiourea compound based on substituted iodobenzene as claimed in claim 1, characterized in that R is selected from one or several of halogen, alkyl, alkoxy, phenyl; r is R 1 Selected from chlorine.
3. The method for producing isothiourea compounds based on substituted iodobenzene as claimed in claim 1, characterized in that in the substituted iodobenzene, one or more substituents are present.
4. The method for producing isothiourea compound based on substituted iodobenzene as claimed in claim 1, characterized in that the metal hydride is sodium hydride.
5. The process for preparing isothiourea compounds based on substituted iodobenzene as claimed in claim 1, characterized in that the reaction is carried out in the presence of metal hydride in a solvent without other substances, and the reaction is carried out at room temperature for 8 to 50 hours.
6. The method for producing isothiourea compound based on substituted iodobenzene as claimed in claim 1, characterized in that the amount of metal hydride is 3 to 5 times the molar amount of thiourea; the usage amount of the substituted iodobenzene is 1-2 times of the molar amount of the thiourea.
7. The method for producing isothiourea compound based on substituted iodobenzene as claimed in claim 6, characterized in that the amount of metal hydride is 4 times the molar amount of thiourea; the usage amount of the substituted iodobenzene is 1.5 times of the molar amount of the thiourea.
8. The method for preparing isothiourea compound based on substituted iodobenzene according to claim 1, characterized in that the solvent is one or more of dimethylacetamide, tetrahydrofuran, acetonitrile, ethylene glycol dimethyl ether and toluene.
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