CN108358868B - Preparation method of 2-substituted benzothiazole compound - Google Patents
Preparation method of 2-substituted benzothiazole compound Download PDFInfo
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
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- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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Abstract
The invention provides a novel preparation method of a 2-substituted benzothiazole compound, and relates to the field of organic synthetic chemistry. The novel preparation method provided by the invention adopts toluene or derivatives thereof to react with o-aminothiophenol in one step in the presence of a catalyst, an oxidant and an additive through a free radical reaction process to generate the 2-substituted benzothiazole compound. By way of example and not limitation, the scheme provided by the invention has the following beneficial effects: the method adopts a free radical method for the first time to enable toluene or derivatives thereof and o-aminothiophenol to generate the 2-substituted benzothiazole through one-step coupling of C-S bond and C-N bond construction, has the advantages of high efficiency, simplicity, environmental friendliness, easily available raw materials, high product purity and the like, and has good application value and research prospect.
Description
Technical Field
The invention belongs to the field of organic synthetic chemistry, and particularly relates to a preparation method of a 2-substituted benzothiazole compound.
Background
Benzothiazole compounds are very important nitrogen-containing heterocyclic compounds, are common structural units of secondary metabolites in organisms, and are bicyclic compounds with pharmaceutical activity. Because sulfur atoms have the characteristics of killing bacteria, fluorescence, luminescence and the like, benzothiazole and derivatives thereof have extremely important effects in the aspects of biomedicine and agriculture, for example, in the field of agriculture, benzothiazole compounds have plant virus resisting activity, insecticidal activity, herbicidal activity and plant cell division inhibiting property and are widely applied to agriculture; in the field of medicine, clinical medicine proves that benzothiazole drugs have the functions of resisting cancer, bacteria, viruses, inflammation, tumors and the like. In addition, benzothiazole compounds are widely used in the fields of fluorescence analysis and organometallic chemistry. Meanwhile, the structure of the benzothiazole compound is easy to modify, and the benzothiazole compound can be used as a chemical intermediate to participate in the synthesis of complex organic matters.
The 2-substituted benzothiazole is synthesized by a plurality of methods, and is mainly formed by taking aromatic aldehyde and acid anhydride as raw materials to perform intermolecular coupling or taking o-halothioamide as a raw material to perform intramolecular coupling and cyclization. Although the methods have characteristics and certain potential application value, many of the methods have the defects of difficult acquisition of raw materials, harsh reaction conditions, complicated post-treatment conditions and the like, so the application of the methods is limited.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of a 2-substituted benzothiazole compound.
The invention makes use of the direct free radical addition reaction of toluene or its derivatives and o-amino thiophenol for the first time to make sp3C-H activation is carried out to construct a C-S bond and a C-N bond, and a 2-substituted benzothiazole compound is synthesized in one step, so that the defect that unstable aldehydes and acid anhydrides are used as raw materials in the traditional method is overcome. According to the invention, the 2-substituted benzothiazole compound is synthesized by directly utilizing toluene or derivatives thereof, and the catalytic activity is high, the conditions are mild, the atom utilization rate is high in the reaction process, so that the green chemical concept is met; meanwhile, the used raw materials are very cheap and easily available in the market, and the reaction process is simple and convenient to operate.
In order to achieve the above object, the present invention provides the following technical solutions:
toluene or a derivative (II) thereof and o-aminothiophenol react with di-tert-butyl peroxide (DTBP) at 120 ℃ for 18-24h in the presence of methanesulfonic acid in the presence of copper salt as a catalyst to generate a 2-substituted benzothiazole compound (I) in one step, wherein the reaction formula (1) is as follows:
wherein:
r is one or more of hydrogen, fluorine, chlorine, bromine, methyl or phenyl.
Further, the preparation method of the 2-substituted benzothiazole compound provided by the invention comprises the following specific steps:
0.06mmol of copper salt catalyst, 0.3mmol of o-aminothiophenol, 1.2mmol of di-tert-butyl peroxide and 0.3mmol of methanesulfonic acid are added into 2mL of toluene or its derivative, and refluxed at 120 ℃ for 20 hours; after completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, vacuum filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain product, wherein the eluent is petroleum ether and ethyl acetateAn ester mixed solvent.
In a preferred embodiment, the copper salt catalyst is cuprous oxide, or cuprous iodide, or cupric acetate, or cuprous chloride; further preferably, the copper salt catalyst is cuprous oxide.
In a preferred embodiment, the toluene or derivative thereof is 4-fluorotoluene, or 4-chlorotoluene, or 4-bromotoluene, or 2-methylnaphthalene, or 2-methyltoluene, or 4-methyltoluene, or 3, 5-dimethyltoluene, or 3, 4-dichlorotoluene, or 3-fluorotoluene, or 2-fluorotoluene, or 3-chlorotoluene, or 3-bromotoluene.
The method has the characteristics of simple reaction process, simple post-treatment, environmental protection, easily obtained raw materials, high comprehensive yield and the like.
To further clarify the mechanism of this reaction: first, when 0.06mmol cuprous oxide is used as a catalyst, 0.3mmol methanesulfonic acid is reacted with 1.2mmol di-tert-butyl peroxide (DTBP) at 120 ℃ for 20 hours in the presence of toluene and o-aminothiophenol to obtain 2-phenylbenzothiazole with the highest yield, the experimental process is easy to operate, and fewer by-products are produced, so we can select the conditions as the "optimal experimental conditions".
The invention has carried out the following experiments: initially, the present invention speculates that toluene is first oxidized to benzaldehyde, which then reacts with ortho-aminothiophenol to form benzothiazole. To confirm the presumption of the present invention, 2mL of benzaldehyde was reacted with 0.3mmol of o-aminothiophenol under "optimal experimental conditions", which is represented by the following formula (2):
the yield of 2-phenylbenzothiazole was 0%. It can therefore be denied that the reaction according to the invention is via benzaldehyde, an intermediate step.
Further, the present invention speculates that the reaction of toluene and o-aminothiophenol to form benzothiazole is a free radical process. To confirm this presumption, the present invention has performed some experiments as follows:
under the "best experimental conditions", when we added 0.3mmol of 2,2,6, 6-tetramethylpiperidine oxide (TEMPO) and 0.6mmol of TEMPO, the reaction yields were 61% and 37%, respectively, and when the amount of TEMPO was increased to 0.9mmol, no product was formed, and the reaction formula (3) is shown below:
since 2,2,6, 6-tetramethylpiperidine oxide (TEMPO) is a radical quencher, the reaction yield gradually decreased when 0.3mmol and 0.6mmol of TEMPO were added, respectively, and the reaction did not occur until 0.9mmol was added, confirming that the reaction of the present invention did undergo a radical process when it occurred.
To demonstrate that cleavage of methyl C-H on toluene is the rate determining step in the reaction, we reacted 1mL of toluene and 1mL of deuterated toluene, mixed with ortho-aminothiophenol under "optimal experimental conditions", equation (4) shown below:
by passing1HNMR (FIG. 1) analysis showed that the reaction of the product of formula (4) with standard 2-phenylbenzothiazole1After comparison of the HNMR spectra (FIG. 2), it was found that the standard 2-phenylbenzothiazole should have 3.00 hydrogens in the 7.58-7.46ppm range, but the product of equation (4) should have 2.62 hydrogens, so that the ratio of the rates of the product 2-phenylbenzothiazole and 2-deuterated methylbenzothiazole was 6.8:1, indicating the rate-determining step of the reaction upon cleavage of the C-H bond of the benzyl group.
To clarify one intermediate of the reaction history, we tried to react the 2- (benzylthio) aniline compound (a possible reaction intermediate) under "best experimental conditions" to obtain 65% of 2-phenylbenzothiazole, which is shown in the following reaction formula (5):
equation (5) illustrates that the reaction provided by the present invention passes through the intermediate of 2- (benzylthio) aniline.
Through a series of analogy experiments, the reaction mechanism of the preparation method provided by the invention is as follows (as shown in fig. 2):
(a) DTBP as radical initiator first and Cu+Cleavage into tert-butoxy radical I and Cu+Is oxidized into Cu2+With tert-butoxy conjugate II;
(b) the tert-butoxy radical gets a hydrogen from toluene to become tert-butyl hydroperoxide and toluene to become benzyl radical III; the benzyl radical III can either be coupled to the product 6 itself or can participate in the subsequent reaction.
(c) The compound II is combined with o-aminothiophenol to generate a metal complex IV;
(d) the benzyl radical III generated previously combined with the metal complex IV to form 2- (benzylthio) aniline 5 (from equation (5) we can determine that the reaction did go through intermediate compound 5); in the presence of copper salt and DTBP, the 2- (benzylthio) aniline 5 loses one hydrogen atom on a carbon atom adjacent to sulfur to obtain an intermediate V, then is further oxidized to form a compound VI through a single electron transfer process, then a nitrogen atom is attacked to generate intramolecular cyclization to form VII, and finally, the final product benzothiazole is generated through DTBP oxidation.
Compared with the prior art, the invention has the beneficial effects that: according to the invention, the 2-substituted benzothiazole compound is directly synthesized in one step through toluene or derivatives thereof, and the catalytic activity is high, the conditions are mild, the atom utilization rate is high in the reaction process, and the green chemical concept is met; meanwhile, the used raw materials are very cheap and easily available in the market, and the reaction process is simple and convenient to operate.
Drawings
FIG. 1 is a nuclear magnetic diagram of the product of toluene and deuterated toluene mixed and o-aminothiophenol under the "best experimental conditions" provided by the invention;
FIG. 2 is a standard 2-phenylbenzothiazole nuclear magnetic map provided by the present invention;
FIG. 3 is a reaction mechanism diagram of the preparation method provided by the present invention.
Detailed Description
The present invention will be further described with reference to the following examples.
The reaction materials used in the following examples, such as toluene or its derivative (II), o-aminothiophenol and the like, are readily available.
The following examples are intended to enable those skilled in the art to better understand the present invention, but the present invention is not limited to the examples.
Example 1
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of toluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of 45.6mg mixed solvent of petroleum ether and ethyl acetate with yield of 72%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.09(dd,J＝8.7,4.5Hz,3H),7.90(d,J＝7.9Hz,1H),7.52–7.46(m,4H),7.38(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.07,154.15,135.07,133.64,130.97,129.02,127.57,126.32,125.19,123.24,121.62.HRMS(ESI):calculated for C13H10NS(M+H)+:212.0528,found:212.0540.
Example 2
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous iodide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-tert-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to2mL of toluene, and refluxing at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of 31.7mg mixed solvent of petroleum ether and ethyl acetate with 50% yield.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.09(dd,J＝8.7,4.5Hz,3H),7.90(d,J＝7.9Hz,1H),7.52–7.46(m,4H),7.38(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.07,154.15,135.07,133.64,130.97,129.02,127.57,126.32,125.19,123.24,121.62.HRMS(ESI):calculated for C13H10NS(M+H)+:212.0528,found:212.0540.
Example 3
A method for synthesizing 2-substituted benzothiazole compound (2-phenylbenzothiazole) by toluene and derivatives in one step comprises the following steps:
0.06mmol of copper acetate, 0.3mmol of o-aminothiophenol, 1.2mmol of di-tert-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of toluene and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, which is 38.6mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 61%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.09(dd,J＝8.7,4.5Hz,3H),7.90(d,J＝7.9Hz,1H),7.52–7.46(m,4H),7.38(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.07,154.15,135.07,133.64,130.97,129.02,127.57,126.32,125.19,123.24,121.62.HRMS(ESI):calculated for C13H10NS(M+H)+:212.0528,found:212.0540.
Example 4
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous chloride, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of toluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of product (34.8 mg, 55% yield) mixed solvent of petroleum ether and ethyl acetate.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.09(dd,J＝8.7,4.5Hz,3H),7.90(d,J＝7.9Hz,1H),7.52–7.46(m,4H),7.38(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.07,154.15,135.07,133.64,130.97,129.02,127.57,126.32,125.19,123.24,121.62.HRMS(ESI):calculated for C13H10NS(M+H)+:212.0528,found:212.0540.
Example 5
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 4-fluorotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of 50.7mg mixed solvent of petroleum ether and ethyl acetate with yield of 80%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.12–8.00(m,3H),7.88(d,J＝7.9Hz,1H),7.48(t,J＝7.7Hz,1H),7.37(t,J＝8.0Hz,1H),7.17(t,J＝8.6Hz,2H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝166.72,165.68,163.18,154.08,135.04,129.55,126.40,125.23,123.18,121.60,116.03.HRMS(ESI):calculated for C13H9FNS(M+H)+:230.0434,found:230.0431.
Example 6
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 4-chlorotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain product eluent 56.6mg of mixed solvent of petroleum ether and ethyl acetate with 77% yield.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.04(dd,J＝16.8,8.3Hz,3H),7.90(d,J＝8.0Hz,1H),7.48(dd,J＝10.8,8.5Hz,3H),7.40(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝166.62,154.05,137.03,135.04,132.10,129.27,128.71,126.48,125.41,123.29,121.65.HRMS(ESI):calculated for C13H9ClNS(M+H)+:246.0139,found:246.0168.
Example 7
A method for synthesizing 2-substituted benzothiazole compounds (2- (4-bromophenyl) benzothiazole) by toluene and derivatives in one step comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 4-bromotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, it was cooled to room temperature and the reaction mixture was taken up with 30mL of acetic acidDiluting with ethyl ester, sequentially adding 8mL of saturated saline solution and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, which is 54.8mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 63%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.06(d,J＝8.1Hz,1H),7.95(d,J＝8.5Hz,2H),7.89(d,J＝7.9Hz,1H),7.62(d,J＝8.5Hz,2H),7.50(t,J＝7.7Hz,1H),7.39(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝166.67,154.05,135.02,132.52,132.21,128.88,126.49,125.43,125.40,123.30,121.65.HRMS(ESI):calculated for C13H9BrNS(M+H)+:289.9634,found:289.9627.
Example 8
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 2-methylnaphthalene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of 27.4mg mixed solvent of petroleum ether and ethyl acetate with yield of 35%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.57(s,1H),8.21(dd,J＝8.6,1.6Hz,1H),8.12(d,J＝8.1Hz,1H),7.95(q,J＝8.0,7.2Hz,3H),7.90–7.86(m,1H),7.58–7.48(m,3H),7.40(t,J＝7.6Hz,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.12,154.24,135.13,134.61,133.19,130.99,128.82,127.87,127.59,127.46,126.88,126.39,125.25,124.44,123.24,121.64.HRMS(ESI):calculated for C17H12NS(M+H)+:262.0685,found:262.0666.
Example 9
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 2-methyltoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, which is 29.7mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 44%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.10(d,J＝8.1Hz,1H),7.93(d,J＝7.9Hz,1H),7.75(d,J＝7.5Hz,1H),7.51(t,J＝7.7Hz,1H),7.43–7.29(m,4H),2.66(s,3H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝167.98,153.77,137.23,135.58,133.07,131.51,130.52,129.98,126.11,125.07,123.36,121.34,21.33.HRMS(ESI):calculated for C14H12NS(M+H)+:226.0685,found:226.0693.
Example 10
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 4-methyltoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, which is 35.8mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 53%.
Product data: white solidd.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.06(d,J＝8.1Hz,1H),7.98(d,J＝8.1Hz,2H),7.89(d,J＝8.0Hz,1H),7.52–7.45(m,1H),7.40–7.34(m,1H),7.30(d,J＝7.9Hz,2H),2.42(s,3H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.24,154.16,141.42,134.94,130.95,129.71,127.48,126.23,124.99,123.04,121.55,21.52.HRMS(ESI):calculated for C14H12NS(M+H)+:226.0685,found:226.0674.
Example 11
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 3, 5-dimethyltoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of 29.3mg mixed solvent of petroleum ether and ethyl acetate with yield of 41%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.07(d,J＝8.1Hz,1H),7.89(d,J＝8.0Hz,1H),7.71(s,2H),7.48(t,J＝7.7Hz,1H),7.37(t,J＝7.6Hz,1H),7.12(s,1H),2.40(s,6H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝168.57,154.10,138.72,134.99,133.44,132.75,126.24,125.34,125.04,123.10,121.57,21.22.HRMS(ESI):calculated for C15H14NS(M+H)+:240.0841,found:240.0844.
Example 12
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 3, 4-dichlorotoluene, and refluxed at 120 ℃ for 20 hours. After the reaction is completed, coolingThe reaction mixture was diluted with 30mL of ethyl acetate and then successively with 8mL of saturated brine and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent which is 50.4mg of mixed solvent of petroleum ether and ethyl acetate, wherein the yield is 60%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.19(s,1H),8.06(d,J＝8.1Hz,1H),7.92–7.84(m,2H),7.56–7.48(m,2H),7.44–7.38(m,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝165.03,153.91,135.07,133.42,130.95,129.01,126.65,125.71,123.54,121.70.HRMS(ESI):calculated for C13H8NSCl2(M+H)+:279.9749,found:279.9739.
Example 13
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 3-fluorotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain eluent of 48.4mg mixed solvent of petroleum ether and ethyl acetate with yield of 70%.
Product data: white solid.1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.08(d,J＝8.1Hz,1H),7.89(d,J＝8.0Hz,1H),7.86–7.79(m,2H),7.53–7.37(m,3H),7.21–7.14(m,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝166.48,164.28,161.82,153.97,135.72,135.64,135.09,130.66,130.58,126.52,125.55,123.45,123.30,121.68,117.93,117.71,114.43,114.20,58.45,53.43,18.43.HRMS(ESI):calculated for C13H8NSNaF(M+Na)+:252.0254,found:252.0269.
Example 14
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 2-fluorotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, which is 44.1mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 64 percent.
Product data:1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.42(td,J＝7.7,1.5Hz,1H),8.13(d,J＝8.2Hz,1H),7.95(d,J＝8.0Hz,1H),7.56–7.38(m,3H),7.31(t,J＝7.6Hz,1H),7.28–7.23(m,1H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝161.80,161.12,161.06,159.28,152.53,135.76,135.68,132.18,132.09,129.73,126.31,125.30,124.67,123.27,121.47,121.37,116.50,116.28.HRMS(ESI):calculated for C13H10NSNa(M+Na)+:252.0254,found:252.0263.
example 15
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 3-chlorotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, which is 44.8mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 61%.
Product data:1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.12(s,1H),8.08(d,J＝8.2Hz,1H),7.93(dd,J＝12.2,7.7Hz,2H),7.51(t,J＝7.7Hz,1H),7.48–7.39(m,3H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝166.30,153.97,135.26,135.16,135.08,130.86,130.26,127.41,126.55,125.69,125.57,123.45,121.69.HRMS(ESI):calculated for C13H9NSCl(M+H)+:246.0139,found:246.0123.
example 16
A preparation method of 2-substituted benzothiazole compounds comprises the following steps:
0.06mmol of cuprous oxide, 0.3mmol of o-aminothiophenol, 1.2mmol of di-t-butyl peroxide, and 0.3mmol of methanesulfonic acid were added to 2mL of 3-bromotoluene, and refluxed at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and finally separating by using thin layer chromatography or column chromatography to obtain the product eluent, 51.3mg of mixed solvent of petroleum ether and ethyl acetate, with the yield of 59%.
Product data:1H NMR(400MHz,CDCl3,25℃,TMS):δ＝8.27(s,1H),8.08(d,J＝8.1Hz,1H),7.98(d,J＝7.8Hz,1H),7.91(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.51(t,J＝7.7Hz,1H),7.38(dt,J＝20.5,7.6Hz,2H).13C NMR(101MHz,CDCl3,25℃,TMS):δ＝166.15,153.96,135.48,135.08,133.78,130.49,130.26,126.55,126.15,125.57,123.44,123.18,121.69.HRMS(ESI):calculated for C13H9NSBr(M+H)+:289.9634,found:289.9627.
the above description is only illustrative of the preferred embodiments of the present invention and should not be taken as limiting the scope of the invention in any way. Any changes or modifications made by those skilled in the art based on the above disclosure should be considered as equivalent effective embodiments, and all the changes or modifications should fall within the protection scope of the technical solution of the present invention.
Claims (3)
1. A preparation method of 2-substituted benzothiazole compounds is characterized in that: toluene or a derivative (II) thereof reacts with o-aminothiophenol and di-tert-butyl peroxide (DTBP) at 120 ℃ for 18-24h in the presence of a catalyst and methanesulfonic acid to generate a 2-substituted benzothiazole compound (I) in one step, wherein the reaction formula (1) is as follows:
wherein:
r is one or more of hydrogen, fluorine, chlorine, bromine, methyl or phenyl;
the method comprises the following specific steps:
adding 0.06mmol of catalyst, 0.3mmol of o-aminothiophenol, 1.2mmol of di-tert-butyl peroxide and 0.3mmol of methanesulfonic acid into 2mL of toluene or its derivative, and refluxing at 120 ℃ for 20 hours; after completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 30mL of ethyl acetate, and then successively diluted with 8mL of saturated saline and 8mL of NaHSO3The solution was washed with 8mL of a saturated aqueous salt solution and then with anhydrous Na2SO4Drying, suction filtering, spin drying, and separating by thin layer chromatography or column chromatography to obtain product, wherein the eluent is mixed solvent of petroleum ether and ethyl acetate;
the catalyst is cuprous oxide, cuprous iodide, cupric acetate, or cuprous chloride.
2. The method for preparing 2-substituted benzothiazole compounds according to claim 1, wherein: the catalyst is cuprous oxide.
3. The method for preparing 2-substituted benzothiazole compounds according to claim 1, wherein: the toluene derivative is 4-fluorotoluene, or 4-chlorotoluene, or 4-bromotoluene, or 2-methyltoluene, or 4-methyltoluene, or 3, 5-dimethyltoluene, or 3, 4-dichlorotoluene, or 3-fluorotoluene, or 2-fluorotoluene, or 3-chlorotoluene, or 3-bromotoluene.
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