A method for synthesizing 2-thiobenzothiazole compounds

Abstract

The present invention proposes a kind of synthetic method of 2 thiobenzothiazole compounds, with 2 iodinated aryl isothiocyanates and thiol as substrates, add alkali (potassium carbonate) and catalyst / ligand (cuprous iodide / 1,10 phenanthroline) reaction, 2 thiobenzothiazole compounds can be efficiently synthesized. Compared with prior art, this method has fast reaction rate and conversion rate close to quantitative; Reaction conditions are mild, green and friendly and post-processing is simple; Substrate has a wide range of applications, and rich structural target objects can be obtained; Method is simple and easy, does not require inert gas protection, and is insensitive to air moisture. 2 thiobenzothiazole compounds are important skeletons of many drugs and bioactive molecules, and this method can provide a widely applicable preparation method for the synthesis of such compounds.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemistry and chemical engineering, and particularly relates to a method for synthesizing 2-thiobenzothiazole compounds which are widely used in the synthesis of natural products and active drugs. Background Art

[0002] Benzothiazoles are an important and abundant class of fused heterocyclic compounds with a wide range of biological activities, including antitumor, antiviral, antibacterial, antiulcer, and anticonvulsant properties. Furthermore, compounds containing the benzothiazole skeleton are widely found in various pharmaceuticals, natural products, and synthetic intermediates. Studies have shown that the 2-substituent has a greater impact on the activity of benzothiazoles. In particular, 2-thiobenzothiazoles exhibit a wider range of biological activities, including as nonsteroidal anti-inflammatory drugs (COX-2 inhibitors), protein inhibitors (Pma1 inhibitors), heat shock protein HSP-90 inhibitors, and cathepsin D inhibitors. Therefore, the development of efficient methods for the preparation of 2-substituted benzothiazoles is highly desirable.

[0003] To date, there are many synthetic methods for constructing benzothiazole skeletons, mainly including the following: reactions based on o-aminothiophenol; dehydrogenation aromatization reactions; sulfur-mediated or catalyzed redox neutral reactions; and coupled cyclization reactions.

[0004] (1) Reaction based on o-aminothiophenol

[0005] o-Aminothiophenol is one of the most commonly used raw materials for the synthesis of 2-substituted benzothiazole derivatives. It can be synthesized through condensation and cyclization with aldehydes, ketones, and carboxylic acid derivatives. In 2009, the Ma Dawei group (Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009, 48, 4222) reported a practical method for the synthesis of 2-substituted benzothiazoles using 2-haloanilides and sulfides as raw materials under copper catalysis.

[0006]

[0007] In 2012, Wu Anxin's group (Zhu, Y.; Jia, F.; Liu, M.; Wu, XA Org. Lett. 2012, 14, 4414.) reported a method for constructing a 2-aroylbenzothiazole skeleton using 2-aminothiophenol and aromatic methyl ketone, aromatic vinyl, 2-hydroxyaryl ketone or 1-arylethanol via phenylglyoxal intermediate mediated by iodine or iodine / o-iodobenzoic acid (IBX).

[0008]

[0009] In the same year, Deng Guojun's group (Liao, Y.; Qi, H.; Chen, S.; Jiang, P.; Zhou, W.; Deng, GJ Org. Lett. 2012, 14, 6004.) reported a new method for the oxygen-promoted synthesis of 2-arylbenzothiazoles.

[0010]

[0011] In 2019, Zhang Jinli, Wu Yangjie, et al. (Zhang, J.; Qiao, M..; Chen, L.; Dong, Y.; Jiao, C.; Liao, S.; Wu, Y. Org. Chem. Front. 2019, 6, 2844.) reported a dehydrogenative cyclization reaction of a thiol substrate ArCH2SH with o-aminobenzenethiol in air, and directly synthesized 2-substituted benzothiazoles in a one-pot method under metal-free and special oxidant-free conditions.

[0012]

[0013] (2) Dehydrogenation aromatization reaction

[0014] 2-Arylbenzothiazoles can be produced by dehydrogenation of 2,3-dihydrobenzothiazole. Traditional reactions typically require harsh conditions and a corresponding hydrogen acceptor, and require transition metal catalysis. In recent years, the reaction conditions and techniques used in this dehydrogenation process have evolved significantly, such as the absence of metal catalysis, oxygen-free conditions, and the absence of a hydrogen acceptor.

[0015] In 2017, the Li Yang group (He, K.; Tan, F.; Zhou, C.; Zhou, G.; Yang, X.; Li, Y. Angew. Chem., Int. Ed. 2017, 56, 3080.) reported a method combining visible-light-mediated redox catalysis with cobalt catalysis for acceptor-free dehydrogenation of tetrahydroquinolines, indoles, and other N-heterocycles at room temperature. This catalytic system can be used to dehydrogenate 2,3-dihydrobenzothiazole to the corresponding 2-arylbenzothiazole.

[0016]

[0017] In 2016, Maier et al. (Maier, AFG; Tussing, S.; Schneider, T.; U.; Qu, Z.; Grimme, S.; Paradies, J. Angew. Chem., Int. Ed. 2016, 55, 12219.) reported a novel acceptor-free dehydrogenation reaction of heterocycles catalyzed by a hindered Lewis acid-base pair (Flps), which they successfully applied to the oxidative dehydrogenation of various N-heterocyclic compounds. This catalytic system was used for the dehydrogenation of benzothiazoline to 2-phenylbenzothiazole in moderate yields. A hindered Lewis acid-base pair (Flps) is a molecule or mixture containing both Lewis acid and Lewis base sites. Due to the significant steric hindrance, the two sites cannot bind, resulting in unique reaction properties.

[0018]

[0019] (3) Sulfur-mediated or catalyzed redox neutral reactions

[0020] Sulfur-mediated or catalyzed substrate redox reactions are an emerging approach for the synthesis of 2-substituted benzothiazole derivatives and other heterocyclic compounds. Elemental sulfur can serve as a sulfur source and an effective oxidant in organic synthesis reactions, promoting redox reactions.

[0021] In 2014, Nguyen et al. (Nguyen, TB; Ermolenko, L.; Retailleau, P.; Al-Mourabit, A. Angew. Chem., Int. Ed. 2014, 53, 13808.) reported a three-component redox reaction of o-halonitrobenzene and benzylamine in the presence of elemental sulfur to synthesize 2-substituted benzothiazole derivatives.

[0022]

[0023] In 2017, Zhang Feng, Deng Guojun, et al. (Li, G.; Jiang, J.; Zhang, F.; Xiao, F.; Deng, G. Org. Biomol. Chem. 2017, 15, 10024.) reported a metal-free oxidative cyclization of o-aminothiophenol with aryl acetylene or styrene for the synthesis of 2-alkylbenzothiazoles and 2-acylbenzothiazoles. Elemental sulfur served as an effective oxidant, affording 2-substituted benzothiazoles in high yields under mild conditions.

[0024]

[0025] In 2019, Zhang Feng, Deng Guojun, et al. (Xing, Q.; Ma, Y.; Xie, H.; Xiao, F.; Zhang, F.; Deng, G. J. Org. Chem. 2019, 84, 1238.) reported an iron-salt-catalyzed synthesis of 2-arylbenzothiazoles from nitroaromatic compounds, alcohols, and elemental sulfur. The reaction achieved a sequential assembly of nitro group reduction, C—N condensation, and C—S bond coupling, exhibiting good functional group tolerance. However, compared to similar reactions, the reaction time was longer and the temperature was higher.

[0026]

[0027] In 2019, Sun Peipei's group (Zhang, J.; Zhao, X.; Liu, P.; Sun, P.P. J. Org. Chem. 2019, 84, 12596.) reported a method for preparing 2-substituted benzothiazoles by reacting aniline, ether and elemental sulfur under transition metal-free and special oxidant-free conditions.

[0028]

[0029] In 2014, Han Shiqing's group (Tong, Y.; Pan, Q.; Jiang, Z.; Miao, D.; Shi, X.; Han S.Q. Tetrahedron Lett. 2014, 55, 54993) reported a green and facile method for the synthesis of 2-substituted benzothiazoles from inexpensive 2-chloronitrobenzene, elemental sulfur, and aromatic benzylamines. The reaction proceeded in the absence of solvent and catalyst, yielding moderate to good yields. In 2016, Han Shiqing's group (Gan, H.; Miao, D.; Pan, Q.; Hu, R.; Li, X.; Han, S. Chem. - Asian J. 2016, 11, 1770) used elemental sulfur as the oxidant to prepare 2-substituted benzothiazoles using arylmethyl chlorides and 2-aminothiophenol under metal-free conditions. In the reaction, elemental sulfur does not serve as a sulfur source in the product but participates in the reaction as an oxidant, and moderate to excellent yields are obtained.

[0030]

[0031] (4) Coupling cyclization reaction

[0032] Thioamides undergo intramolecular cyclization through direct or dehydrogenative coupling at the ortho position, or aromatic isothiocyanates are coupled with amines to form thioureas. The latter intramolecular ortho coupling reaction is also a common method for preparing 2-substituted benzothiazoles.

[0033] In 2014, Li Pixu's group (Cheng, Y.; Peng, Q.; Fan, W.; Li, PJ Org. Chem. 2014, 79, 5812.) reported a Pd / C-catalyzed C—S bond formation method for the intramolecular cyclization of o-iodophenylthioamide derivatives to prepare 2-aryl, 2-alkyl and 2-aminobenzothiazoles.

[0034]

[0035] In 2014, Liang Yun's group (Zhang, X.; Zeng, W.; Yang, Y.; Huang, H.; Liang, Y. Org. Lett. 2014, 16, 876.) reported an efficient copper-catalyzed method for preparing 2-substituted benzothiazoles. This method catalyzes two C-S bond couplings between N-benzyl-2-iodoaniline and potassium sulfide to prepare 2-substituted benzothiazoles.

[0036]

[0037] In 2018, Natarajan et al. (Natarajan, P.; Muskan, M.; Brar, N.K.; Kaur, J. J. Org. Chem. Front. 2018, 5, 1527.) reported a visible-light-mediated redox reaction that couples thiophenols with nitriles via C—S and C—N bonds to form imine radical intermediates, which then undergo intramolecular cyclization to prepare 2-substituted benzothiazoles. The reaction is driven by visible light, uses O₂ in air as the oxidant, and requires only 2.0 mol% of an organic dye as a catalyst, achieving high atom economy.

[0038]

[0039] In summary, the important applications of benzothiazole derivatives in many fields such as biomedicine and materials science are constantly being discovered and studied, and their synthesis methods are also expected to be widely developed. Currently, the synthesis methods of 2-substituted benzothiazoles are constantly being updated, but many problems still exist. For example, most reactions mediated or catalyzed by elemental sulfur require high temperatures and long reaction times, and the substrate applicability of dehydrogenation reactions is poor. At the same time, many new methods and technologies are being used to synthesize 2-substituted benzothiazoles, such as the synthesis of special heterogeneous catalysts, ultrasound methods, microwave-assisted methods, and the widespread use of electrochemistry and photochemistry, which greatly shorten reaction times. Therefore, the development of new technologies and methods for the synthesis of 2-substituted benzothiazoles, as well as the ability to apply many synthetic schemes beyond the laboratory to large-scale production, are future development trends. Summary of the Invention

[0040] (1) Technical issues to be solved

[0041] The present invention provides a method for synthesizing 2-thiobenzothiazole compounds to solve the technical problem of how to synthesize 2-substituted benzothiazoles.

[0042] (2) Technical solution

[0043] In order to solve the above technical problems, the present invention provides a method for synthesizing 2-thiobenzothiazole compounds. The synthesis method comprises the following steps: using 2-iodoaryl isothiocyanate and thiol as raw materials, potassium carbonate as an acid binding agent, cuprous iodide as a catalyst, 1,10-phenanthroline as a ligand, and ethanol and water as solvents, and synthesizing the compounds according to the following reaction formula:

[0044]

[0045] In the formula, R is at least one of hydrogen, methyl, fluorine, and bromine; and R' is at least one of benzyl, 4-methylbenzyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, and 4-nitrophenyl.

[0046] Furthermore, the volume ratio of ethanol to water is 1:1.

[0047] Further, the reaction was carried out at 50° C. for 10 to 15 minutes.

[0048] Furthermore, the specific steps of the synthesis method are: adding 2-iodoaryl isothiocyanate and thiol to a reaction flask, adding an ethanol solution of cuprous iodide and 1,10-phenanthroline, adding an aqueous potassium carbonate solution, and reacting at 50°C for 10 to 15 minutes until the raw materials disappear; adding saturated brine to quench the reaction, extracting with dichloromethane three times, and separating and purifying by column chromatography to obtain a 2-thiobenzothiazole compound.

[0049] Furthermore, the molar ratio of 2-iodinated aryl isothiocyanate, thiol, potassium carbonate, cuprous iodide, and 1,10-phenanthroline is 1:1.2:0.6:0.001:0.002.

[0050] (3) Beneficial effects

[0051] The present invention proposes a method for synthesizing 2-thiobenzothiazole compounds. 2-iodoaryl isothiocyanate and thiol are used as substrates, and a base (potassium carbonate) and a catalyst / ligand (copper iodide / 1,10-phenanthroline) are added for reaction, thereby efficiently synthesizing 2-thiobenzothiazole compounds. Compared with the existing technology, the present method has a fast reaction rate and a nearly quantitative conversion rate; the reaction conditions are mild, the product is environmentally friendly, and the post-processing is simple; the substrate has a wide range of applications, and a rich range of target structures can be obtained; the method is simple and easy to use, does not require inert gas protection, and is insensitive to air moisture. 2-Thiobenzothiazole compounds are important skeletons of many drugs and bioactive molecules. The present method can provide a widely applicable preparation method for the synthesis of such compounds. DETAILED DESCRIPTION

[0052] In order to make the purpose, content and advantages of the present invention more clear, the specific implementation methods of the present invention are further described in detail below with reference to the embodiments.

[0053] Example 1

[0054] Synthesis of (3a) using 2-iodinated aryl isothiocyanate (1a) and benzyl mercaptan (2a) as raw materials:

[0055]

[0056] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of benzyl mercaptan (2a) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 95%.

[0057] White solid,yield 95%,49mg; 1 H NMR (300MHz, Chloroform-d) δ7.90(d,J=8.1Hz,1H),7.73(d,J=7.9Hz,1H),7.44(t,J=6.6Hz,3H),7.36–7.25(m,4H),4.60(s,2H). 13 C NMR(75MHz,Chloroform-d)δ166.36,153.05,136.06,135.22,129.09,128.65,127.71,126.01,124.22,121.46,120.96,37.61.HRMS(ESI-TOF,m / z):calcd for C 14 H11 NS2[M+H] + 258.0411,found 258.0412.

[0058] Example 2

[0059] Synthesis of (3b) using 2-iodoaryl isothiocyanate (1a) and 4-methylbenzyl mercaptan (2b) as raw materials:

[0060]

[0061] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 4-methylbenzyl mercaptan (2b) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 95%.

[0062] White solid,yield 95%,51mg; 1 H NMR (300MHz, Chloroform-d) δ7.89(d,J=8.1Hz,1H),7.71(d,J=7.9Hz,1H),7.44–7.20(m,4H),7.11(d,J=7.9Hz,2H),4.55(s,2H),2.31(s,3H). 13 C NMR(75MHz,Chloroform-d)δ166.52,153.05,137.44,135.16,132.83,129.31,128 .96,125.94,124.13,121.40,120.90,37.40,21.10.HRMS(ESI-TOF,m / z):calcdfor C 15 H 13 NS2[M+H] + 272.0568,found 272.0569.

[0063] Example 3

[0064] Synthesis of (3c) using 2-iodoaryl isothiocyanate (1a) and 2-methoxybenzenethiol (2c) as raw materials:

[0065]

[0066] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 2-methoxybenzenethiol (2c) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0067] White solid,yield 90%,49mg; 1 H NMR(300MHz,Chloroform-d)δ7.88(d,J=8.1Hz,1H),7.70(dd,J=7.5,1.5Hz,1H),7.64(d,J=7.8Hz,1H),7 .53(td,J=8.1,1.7Hz,1H),7.41(d,J=8.2Hz,1H),7.30–7.21(m,1H),7.04(d,J=8.6Hz,2H),3.86(s,3H). 13 C NMR(75MHz,Chloroform-d)δ169.96,159.87,154.00,137.48,135.52,132.78,125.94 ,124.00,121.77,121.49,120.66,117.59,111.88,56.02.HRMS(ESI-TOF,m / z):calcd for C 14 H 11 NOS2[M+H] + 274.0360,found 274.0362.

[0068] Example 4

[0069] Synthesis (3d) using 2-iodoaryl isothiocyanate (1a) and 3-methoxybenzenethiol (2d) as raw materials:

[0070]

[0071] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 3-methoxybenzenethiol (2d) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 91%.

[0072] White solid,yield 91%,49mg; 1 H NMR(300MHz,Chloroform-d)δ7.86(d,J=8.1Hz,1H),7.68(dd,J=7.6,1.5Hz,1H),7.61(d,J=7.9Hz,1 H),7.54–7.46(m,1H),7.37(t,J=7.3Hz,1H),7.22(t,J=7.6Hz,1H),7.07–6.97(m,2H),3.82(s,3H). 13 C NMR(75MHz,Chloroform-d)δ169.86,159.75,153.89,137.35,135.40,132.71,125.84 ,123.91,121.63,121.39,120.58,117.40,111.79,55.91.HRMS(ESI-TOF,m / z):calcd for C 14 H 11 NOS2[M+H] + 274.0360,found 274.0353.

[0073] Example 5

[0074] Synthesis of (3e) using 2-iodoaryl isothiocyanate (1a) and 4-fluorobenzenethiol (2e) as raw materials:

[0075]

[0076] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 4-fluorobenzenethiol (2e) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0077] White solid,yield 90%,47mg; 1 H NMR(300MHz,Chloroform-d)δ7.88(d,J=8.2Hz,1H),7.74(dd,J=8.6,5.3Hz,2H),7 .67(d,J=7.9Hz,1H),7.46–7.37(m,1H),7.32–7.24(m,1H),7.19(t,J=8.5Hz,2H).13 C NMR (75MHz, Chloroform-d) δ168.15,153.70,136.55,135.46,133.08,128.91,126.26,125.16,124.52,122.02,120.83. 19 F NMR(282MHz,Chloroform-d)δ-109.08(tt,J=8.4,5.2Hz).HRMS C 13 H8FNS2(m / z)calcd for[M+H] + 262.0160,found 262.0159.

[0078] Example 6

[0079] Synthesis of (3f) using 2-iodoaryl isothiocyanate (1a) and 4-chlorobenzenethiol (2f) as raw materials:

[0080]

[0081] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 4-chlorobenzenethiol (2f) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 92%.

[0082] White solid,yield 92%,51mg; 1 H NMR (300MHz, Chloroform-d) δ7.88 (d, J = 8.1Hz, 1H), 7.71–7.63 (m, 3H), 7.48–7.38 (m, 3H), 7.32–7.25 (m, 1H). 13 C NMR(75MHz,Chloroform-d)δ168.45,153.73,136.91,136.44,135.44,130.13,128.25,126.25,124.49,122.00,120.82.HRMS(ESI-TOF,m / z):calcd for C 13 H8ClNS2[M+H] + 277.9865,found277.9864.

[0083] Example 7

[0084] Synthesized from 2-iodinated aryl isothiocyanate (1a) and 4-bromobenzenethiol (2g) (3g):

[0085]

[0086] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 4-bromobenzenethiol (2 g) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0087] White solid,yield 90%,57mg; 1 H NMR (300MHz, Chloroform-d) δ7.87(d,J=8.2Hz,1H),7.66(d,J=8.0Hz,1H),7.58(s,4H),7.40(t,J=7.3Hz,1H),7.31–7.23(m,1H). 13 C NMR(75MHz,Chloroform-d)δ168.16,153.69,136.55,135.45,133.08,128.90,126.25,125.16,124.51,122.01,120.82.HRMS(ESI-TOF,m / z):calcd for C 13 H8BrNS2[M+H] + 321.9360,found 321.9364.

[0088] Example 8

[0089] Synthesis (3h) using 2-iodoaryl isothiocyanate (1a) and 4-nitrobenzenethiol (2h) as raw materials:

[0090]

[0091] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 4-nitrobenzene mercaptan (2h) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 92%.

[0092] White solid,yield 92%,53mg; 1 H NMR (300MHz, Chloroform-d) δ8.25(d,J=8.9Hz,2H),7.98(d,J=8.1Hz,1H),7.84–7.74(m,3H),7.49(t,J=7.7Hz,1H),7.39(t,J=7.6Hz,1H). 13 C NMR(75MHz,Chloroform-d)δ162.77,153.32,147.79,140.02,132.63,126.64,125.52,124.47,122.77,121.15.HRMS(ESI-TOF,m / z):calcd for C 13 H8N2O2S2[M+H] + 289.0105,found 289.0105.

[0093] Example 9

[0094] Synthesis of (3i) using 2-iodinated aryl isothiocyanate (1a) and n-butyl mercaptan (2i) as raw materials:

[0095]

[0096] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of n-butyl mercaptan (3i) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 92%.

[0097] White solid,yield 92%,41mg; 1 H NMR(300MHz,Chloroform-d)δ7.86(d,J=8.1Hz,1H),7.73(dd,J=8.0,1.3Hz,1H),7.44–7.36(m,1H),7 .30–7.22(m,1H),3.34(t,J=7.3Hz,2H),1.87–1.73(m,2H),1.58–1.42(m,2H),0.96(t,J=7.3Hz,3H). 13C NMR(75MHz,Chloroform-d)δ167.34,153.87,135.07,125.91,124.01,121.36,120.83,33.25,31.17,21.86,13.55.HRMS(ESI-TOF,m / z):calcd for C 13 H8N2O2S2[M+H] + 224.0562,found224.0563.

[0098] Example 10

[0099] Synthesis (3j) from 2-iodinated aryl isothiocyanate (1a) and n-tetradecyl mercaptan (2j):

[0100]

[0101] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of n-tetradecyl mercaptan (2j) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 94%.

[0102] White solid,yield 94%,68mg; 1 H NMR(300MHz,Chloroform-d)δ7.86(d,J=8.2Hz,1H),7.74(d,J=8.0Hz,1H),7.45–7.35(m,1H), 7.33–7.24(m,1H),3.33(t,J=7.4Hz,2H),1.87–1.75(m,2H),1.25(s,22H),0.92–0.84(m,3H). 13 C NMR(75MHz,Chloroform-d)δ166.96,153.82,135.08,127.62,124.01,122.64,120.84,34.36,31.89,29 .66,29.64,29.62,29.54,29.43,29.34,29.13,29.05,28.74,22.67,14.93.HRMS(ESI-TOF,m / z):calcd for C 13 H8N2O2S2[M+H] + 364.2133,found364.2133.

[0103] Example 11

[0104] Synthesis of (3k) using 2-iodinated aryl isothiocyanate (1a) and adamantanethiol (2k) as raw materials:

[0105]

[0106] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of adamantanethiol (2k) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 90%.

[0107] White solid,yield 90%,54mg; 1 H NMR (300MHz, Chloroform-d) δ8.01(d,J=6.9Hz,1H),7.80(d,J=8.0Hz,1H),7.49–7.41(m,1H),7.39–7.32(m,1H),2.12(d,J=17.8Hz,9H),1.70(s,6H). 13 C NMR(75MHz,Chloroform-d)δ164.22,155.30,135.91,127.48,124.39,123.26,121.30,51.41,44.24,37.15,27.45.HRMS(ESI-TOF,m / z):calcd for[M+H] + 302.1037,found 302.1030.

[0108] Example 12

[0109] Synthesis of (3l) using 2-iodoarylphenyl isothiocyanate (1a) and 2-propanethiol (2l) as raw materials:

[0110]

[0111] 0.2 mmol of 2-iodophenyl isothiocyanate (1a) and 0.24 mmol of 2-propanethiol (2k) were added to a reaction flask, followed by an ethanol solution of 0.002 mmol of cuprous iodide and 0.004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0112] White solid,yield 90%,38mg; 1 H NMR (300MHz, Chloroform-d) δ7.88(d,J=8.1Hz,1H),7.75(d,J=9.2Hz,1H),7.45–7.36(m,1H),7.32–7.23(m,1H),4.19–3.98(m,1H),1.50(d,J=6.8Hz,6H). 13 C NMR(75MHz,Chloroform-d)δ166.42,152.06,135.21,125.36,122.91,121.92,120.86,41.99,23.86.HRMS(ESI-TOF,m / z):calcd for C 10 H 11 NS2[M+H] + 210.0411,found 210.0411.

[0113] Example 13

[0114] Synthesized from 2-iodo-4-methylphenyl isothiocyanate (1b) and 4-fluorobenzenethiol (2e) (3m):

[0115]

[0116] 0.2 mmol of 2-iodo-4-methylphenyl isothiocyanate (1b) and 0.24 mmol of 4-fluorobenzenethiol (2e) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0117] White solid,yield 90%,49mg; 1H NMR (300MHz, Chloroform-d) δ7.78–7.64 (m, 3H), 7.53 (d, J = 8.2Hz, 1H), 7.24–7.05 (m, 3H), 2.46 (s, 3H). 13 C NMR (75MHz, Chloroform-d) δ 154.27, 137.77, 137.68 (d, J = 8.8Hz), 132.41, 125.94, 122.06, 120.30, 117.15 (d, J = 22.2Hz), 23.01. 19 F NMR(282MHz,Chloroform-d)δ-109.06(tt,J=8.5,5.2Hz).HRMS(ESI-TOF,m / z):calcd for C 14 H 10 FNS2[M+H] + 276.0317,found276.0317.

[0118] Example 14

[0119] Synthesis (3n) using 2-iodo-4-methylphenyl isothiocyanate (1b) and 4-chlorobenzenethiol (2e) as raw materials:

[0120]

[0121] 0.2 mmol of 2-iodo-4-methylphenyl isothiocyanate (1b) and 0.24 mmol of 4-chlorobenzenethiol (2f) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 92%.

[0122] White solid,yield 92%,53mg; 1 H NMR (300MHz, Chloroform-d) δ7.73–7.61 (m, 3H), 7.54 (d, J = 8.2Hz, 1H), 7.49–7.39 (m, 2H), 7.18–7.08 (m, 1H), 2.46 (s, 3H). 13C NMR(75MHz,Chloroform-d)δ168.14,154.10,136.77,136.38,136.29,132.48,130.06,1 28.50,126.07,122.12,120.31,77.42,77.00,76.58,21.44.HRMS(ESI-TOF,m / z):calcd forC 14 H 10 ClNS2[M+H] + 292.0021,found 292.0023.

[0123] Example 15

[0124] Synthesis (3o) from 2-iodo-4-methylphenyl isothiocyanate (1b) and benzyl mercaptan (2a):

[0125]

[0126] 0.2 mmol of 2-iodo-4-methylphenyl isothiocyanate (1b) and 0.24 mmol of benzyl mercaptan (2a) were added to a reaction flask, and an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline was added, followed by 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 91%.

[0127] White solid,yield 91%,49mg; 1 H NMR(300MHz,Chloroform-d)δ7.70(s,1H),7.59(d,J=8.1Hz,1H),7.44(d,J=6 .8Hz,2H),7.36–7.22(m,3H),7.11(d,J=7.8Hz,1H),4.57(s,2H),2.46(s,3H). 13 C NMR(75MHz,Chloroform-d)δ166.27,153.42,137.27,132.13,129.08,127.67,125.72,121.66,120.43,43.15,37.64,21.43.HRMS(ESI-TOF,m / z):calcdfor C 15 H 13 NS2[M+H] + 272.0568,found272.0564.

[0128] Example 16

[0129] Synthesize (3p) using 2-iodo-4-methylphenyl isothiocyanate (1b) and 2-propanethiol (2l) as raw materials:

[0130]

[0131] 0.2 mmol of 2-iodo-4-methylphenyl isothiocyanate (1b) and 0.24 mmol of 2-propanethiol (2l) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0132] White solid,yield 90%,40mg; 1 H NMR (300MHz, Chloroform-d) δ7.70 (s, 1H), 7.62 (d, J = 8.1Hz, 1H), 7.12 (d, J = 7.3Hz, 1H), 4.14–3.99 (m, 1H), 2.47 (s, 3H), 1.50 (d, J = 6.7Hz, 6H). 13 C NMR(75MHz,Chloroform-d)δ166.32,153.33,135.37,132.81,126.27,122.23,120.36,39.42,23.25,21.92.HRMS(ESI-TOF,m / z):calcd for C 11 H 13 NS2[M+H] + 224.0568,found 224.0567.

[0133] Example 17

[0134] Synthesized from 2-iodo-4,5-dimethylphenylisothiocyanate (1c) and 4-methylbenzyl mercaptan (2b) (3q):

[0135]

[0136] 0.2 mmol of 2-iodo-4,5-dimethylphenylisothiocyanate (1c) and 0.24 mmol of 4-methylbenzyl mercaptan (2b) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 90%.

[0137] White solid,yield 90%,54mg; 1 H NMR (300MHz, Chloroform-d) δ7.67(s,1H),7.47(s,1H),7.32(d,J=8.0Hz,2H),7.12(d,J=7.7Hz,2H),4.53(s,2H),2.39–2.29(m,9H). 13 C NMR(75MHz,Chloroform-d)δ165.35,151.09,137.83,134.66,133.56,133.09,132.61 ,129.33,128.99,122.83,120.97,37.01,22.26,19.17.HRMS(ESI-TOF,m / z):calcdfor C 17 H 17 NS2[M+H] + 300.0881,found 300.0880.

[0138] Example 18

[0139] Synthesis of (3r) using 2-iodo-4,5-dimethylphenylisothiocyanate (1c) and 2-propanethiol (2l) as raw materials:

[0140]

[0141] 0.2 mmol of 2-iodo-4,5-dimethylphenyl isothiocyanate (1c) and 0.24 mmol of 2-propanethiol (2l) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 93%.

[0142] White solid,yield 93%,44mg; 1H NMR (300MHz, Chloroform-d) δ7.67(s,1H),7.49(s,1H),4.03(p,J=6.8Hz,1H),2.35(d,J=5.9Hz,6H),1.49(d,J=6.8Hz,6H). 13 C NMR(75MHz,Chloroform-d)δ165.41,152.95,135.02,133.57,132.69,121.96,120.88,40.38,23.26,20.09,19.99.HRMS(ESI-TOF,m / z):calcd for C 12 H 15 NS2[M+H] + 238.0724,found238.0724.

[0143] Example 19

[0144] Synthesized from 2-iodo-4-fluorophenyl isothiocyanate (1d) and 4-methylbenzyl mercaptan (2b) (3s):

[0145]

[0146] 0.2 mmol of 2-iodo-4-fluorophenyl isothiocyanate (1d) and 0.24 mmol of 4-methylbenzyl mercaptan (2b) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 92%.

[0147] White solid,yield 92%,53mg; 1 H NMR (300MHz, Chloroform-d) δ7.70–7.55(m,2H),7.35(d,J=6.2Hz,2H),7.15(d,J=6.9Hz,2H),7.06(td,J=8.8,2.5Hz,1H),4.57(s,2H),2.35(s,3H). 13C NMR (75MHz, Chloroform-d) δ 169.30, 162.37, 159.76, 154.02 (d, J = 12.1Hz), 136.91, 132. 73,129.39,129.00,121.45(d,J=9.9Hz),113.67,112.37,108.09,107.03,37.47,20.74. 19 F NMR(282MHz,Chloroform-d)δ-116.15(td,J=9.2,5.1Hz).HRMS(ESI-TOF,m / z):calcd for C 15 H 12 FNS2[M+H] + 290.0473,found 290.0473.

[0148] Example 20

[0149] Synthesize (3t) using 2-iodo-4-fluorophenyl isothiocyanate (1d) and 2-propanethiol (2l) as raw materials:

[0150]

[0151] 0.2 mmol of 2-iodo-4-fluorophenyl isothiocyanate (1d) and 0.24 mmol of 2-propanethiol (2l) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 95%.

[0152] White solid,yield 95%,43mg; 1 H NMR (300MHz, Chloroform-d) δ7.65(dd,J=8.8,5.1Hz,1H),7.55(dd,J=9.6,2.5Hz,1H),7.05(td,J=8.8,2.5Hz,1H),4.14–4.01(m,1H),1.50(d,J=6.8Hz,6H). 13 C NMR (75MHz, Chloroform-d) δ168.54, 163.33, 160.11, 154.27 (d, J = 12.1Hz), 130.45, 121.36 (d, J = 9.9Hz), 112.66, 108.12, 39.49, 23.20. 19FNMR(282MHz,Chloroform-d)δ-116.33(dt,J=9.2,4.6Hz).HRMS(ESI-TOF,m / z):calcd forC 10 H 10 FNS2[M+H] + 228.0317,found228.0318.

[0153] Example 21

[0154] Synthesis (3u) from 2-iodo-4-bromophenyl isothiocyanate (1e) and 4-methylbenzyl mercaptan (2b):

[0155]

[0156] 0.2 mmol of 2-iodo-4-bromophenyl isothiocyanate (1e) and 0.24 mmol of 4-methylbenzyl mercaptan (2b) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid with a yield of 80%.

[0157] White solid,yield 90%,63mg; 1 H NMR (300MHz, Chloroform-d) δ8.04(d,J=1.9Hz,1H),7.59(d,J=8.5Hz,1H),7.43–7.31(m,3H),7.14(d,J=7.8Hz,2H),4.56(s,2H),2.34(s,3H). 13 C NMR(75MHz,Chloroform-d)δ168.62,154.24,137.64,134.06,132.76,129.40,129 .02,127.17,124.36,121.91,119.64,37.44,21.14.HRMS(ESI-TOF,m / z):calcdfor C 15 H 12 BrNS2[M+H] + 349.9673,found 349.9672.

[0158] Example 22

[0159] Synthesize (3v) using 2-iodo-4-bromophenyl isothiocyanate (1e) and 2-propanethiol (2l) as raw materials:

[0160]

[0161] 0.2 mmol of 2-iodo-4-bromophenyl isothiocyanate (1e) and 0.24 mmol of 2-propanethiol (2l) were added to a reaction flask, followed by an ethanol solution of 0.0002 mmol of cuprous iodide and 0.0004 mmol of 1,10-phenanthroline, and 0.12 mmol of potassium carbonate. The mixture was reacted at 50°C for 15 min, and extracted three times with saturated brine and dichloromethane. The organic phases were combined, dried, and separated by column chromatography to obtain the pure product as a colorless oily liquid in a yield of 94%.

[0162] White solid,yield 94%,54mg; 1 H NMR (300MHz, Chloroform-d) δ8.02(d,J=1.9Hz,1H),7.60(d,J=8.5Hz,1H),7.39(dd,J=8.5,1.9Hz,1H),4.09(p,J=6.8Hz,1H),1.51(d,J=6.8Hz,6H). 13 C NMR(75MHz,Chloroform-d)δ168.62,154.51,133.98,127.12,124.39,121.84,119.57,39.53,23.19.HRMS(ESI-TOF,m / z):calcd for C 10 H 10 BrNS2[M+H] + 287.9516,found 287.9514.

[0163] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-thiobenzothiazole compounds, characterized in that: The synthesis method is to use 2-iodinated aryl isothiocyanate and thiol as raw materials, potassium carbonate as an acid binding agent, cuprous iodide as a catalyst, 1,10-phenanthroline as a ligand, ethanol and water as solvents, and perform the synthesis according to the following reaction formula: In the formula, R is at least one of hydrogen, methyl, fluorine, and bromine; R' is at least one of benzyl, 4-methylbenzyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, and 4-nitrophenyl; wherein, The volume ratio of ethanol to water is 1:1; the reaction is carried out at 50°C for 10 to 15 minutes.

2. The method for synthesizing 2-thiobenzothiazole compounds according to claim 1, wherein: The specific steps of the synthesis method are: adding 2-iodinated aryl isothiocyanate and thiol into a reaction bottle, adding cuprous iodide and an ethanol solution of 1,10-phenanthroline, adding a potassium carbonate aqueous solution, reacting at 50°C for 10 to 15 minutes until the raw materials disappear; adding saturated salt water to quench the reaction, extracting with dichloromethane three times, and separating and purifying by column chromatography to obtain a 2-thiobenzothiazole compound.

3. The method for synthesizing 2-thiobenzothiazole compounds according to claim 2, wherein: The molar ratio of the 2-iodinated aryl isothiocyanate, thiol, potassium carbonate, cuprous iodide and 1,10-phenanthroline is 1:1.2:0.6:0.001:0.002.

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