A process for the preparation of 2-substituted benzothiazole compounds

Abstract

This invention discloses a method for preparing a 2-substituted benzothiazole compound, comprising the following steps: first, a mercaptophenylglycine derivative, a Lewis acid, and a photocatalyst are added sequentially to an organic solvent in a molar ratio of 1:0.2:0.02; the mixture is then irradiated with visible light in air and stirred at room temperature until the reaction is complete; the organic solvent is then removed by vacuum distillation; and finally, the 2-substituted benzothiazole compound is obtained by column chromatography. This invention has the advantages of mild reaction conditions, being green, low-cost, and highly efficient.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation technology, specifically a method for preparing 2-substituted benzothiazole compounds. Background Technology

[0002] The benzothiazole skeleton is widely found in various active compounds and existing drugs. Generally, the biological activity of benzothiazole derivatives can be significantly affected by introducing different substituents on the benzene ring or different active groups at the 2-position. Among them, the substituent at the 2-position has the greatest impact on the activity of benzothiazole, and 2-substituted benzothiazole has a variety of pharmacological activities such as antibacterial, antiviral and anticancer, and has a wide range of applications.

[0003] Currently, 2-substituted benzothiazole compounds are mainly synthesized through the condensation reaction of mercaptoaniline with aldehydes or the functionalization reaction of benzothiazole compounds. However, these methods generally suffer from drawbacks such as high reaction temperatures, the need for anhydrous solutions, the requirement of strong acids, and the need for pre-functionalization of the substrate. These demanding conditions and high costs limit the application of 2-substituted benzothiazole compounds. Therefore, there is an urgent need to develop a simple, inexpensive, and efficient method for synthesizing 2-substituted benzothiazole compounds. Summary of the Invention

[0004] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing 2-substituted benzothiazole compounds, which has the advantages of mild reaction conditions, greenness, low cost and high efficiency.

[0005] To achieve the above objectives, the present invention employs the following technical solution:

[0006] A method for preparing a 2-substituted benzothiazole compound, comprising the following steps:

[0007] First, mercaptophenylglycine derivative, Lewis acid, and photocatalyst were added sequentially to an organic solvent in a molar ratio of 1:0.2:0.02. The mixture was then irradiated with visible light and stirred at room temperature until fully reacted. The organic solvent was then removed by vacuum distillation. Finally, column chromatography was used to obtain the 2-substituted benzothiazole compound. The chemical reaction formula is as follows:

[0008]

[0009] In the formula: R 1 The substituent is an electron-donating or electron-withdrawing group, R 2 The substituents are alkyl, alkoxy, aryl, or substituted amino groups.

[0010] Furthermore, the electron-donating group is alkyl, ether, aryl, or amino; the electron-withdrawing group is halogen, trifluoromethyl, or nitro.

[0011] Furthermore, the mercaptophenylglycine derivative is any one of (2-mercaptophenyl)glycine ethyl ester, (2-mercapto-5-chlorophenyl)glycine ethyl ester, or (2-mercapto-5-trifluoromethyl)glycine tert-ethyl ester.

[0012] Furthermore, the Lewis acid is Cu(OTf)2, Cu(OAc)2, Fe(OTf)2, Ce(OTf)3, CuSO4, or FeSO4.

[0013] Furthermore, the photocatalyst is ruthenium tri(2,2-bipyridine)chloride hexahydrate, rhodamine 6G, or rose red.

[0014] Furthermore, the organic solvent is any one of dichloromethane, toluene, 1,2-dichloroethane, acetonitrile, ethyl acetate, or tetrahydrofuran.

[0015] Furthermore, the visible light irradiation uses an energy-saving lamp, sunlight, or a blue LED lamp as the light source.

[0016] Furthermore, the stirring time is 10–24 hours.

[0017] Furthermore, the eluent used in the column chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 8:1.

[0018] Compared with the prior art, the present invention has the following technical effects:

[0019] This invention synthesizes 2-substituted benzothiazole compounds by oxidative cyclization of mercaptophenylglycine derivatives under visible light catalysis. Visible light, which is inexpensive, abundant, and green, is used for catalysis, eliminating the need for external photosensitizers. Oxygen from the air serves as a green oxidant, requiring no additional strong oxidants. Therefore, this invention offers advantages such as inexpensive and readily available raw materials, mild and green reaction conditions, simple operation, and a wide variety of products. Furthermore, the yield of 2-substituted benzothiazole compounds is as high as 85%–92%. Attached Figure Description

[0020] Figure 1 : Ethyl 1,3-benzothiazole-2-carboxylate prepared in Example 1 1 H NMR spectrum;

[0021] Figure 2 : Ethyl 1,3-benzothiazole-2-carboxylate prepared in Example 1 13 C NMR spectrum. Detailed Implementation

[0022] The specific content of the present invention will be further explained in detail below with reference to the embodiments.

[0023] In Examples 1 to 3, the eluent used in column chromatography was a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1.

[0024] The rose red used in Example 3 has the CAS number 63183-44-8 and a molecular number of C. 28 H 31 ClN2O3.

[0025] Example 1

[0026] First, 10 mmol of (2-mercaptophenyl)glycine ethyl ester, 2 mmol of Cu(OTf)2, and 0.2 mmol of rhodamine 6G were weighed and added sequentially to 30 mL of dichloromethane. The mixture was then irradiated with a 26W energy-saving lamp and stirred in air at room temperature for 10 h. The dichloromethane was then removed by vacuum distillation, followed by purification by column chromatography to obtain a pale yellow solid, 1,3-benzothiazol-2-carboxylic acid ethyl ester, with the following structural formula:

[0027]

[0028] The yield of ethyl 1,3-benzothiazole-2-carboxylate prepared in Example 1 was 92%, with a melting point of 68.1–72.7 °C. (See [reference needed]). Figure 1 and Figure 2 The ethyl 1,3-benzothiazole-2-carboxylate prepared in Example 1 was determined using nuclear magnetic resonance spectroscopy. The results were as follows: IR (KBr, cm⁻¹) -1 1750; 1 H NMR (400MHz, CDCl3) δ = 1.4 (t, J = 6.4, 3H), 4.4 (q, J = 6.4, 2H), 7.3-7.5 (m, 2H), 7.9-8.0 (m, 2H); 13 C NMR(100MHz, CDCl3)δ=14.0,62.5,122.5,124.5,126.7,126.9,135.4,152.2,156.5,160.8.HRMS(ESI)calcd for C 11 H 12 NO2S(M+H + )208.0427,found 208.0425.

[0029] Example 2

[0030] First, 10 mmol of (2-mercapto-5-chlorophenyl)glycine ethyl ester, 2 mmol of Cu(OTf)₂, and 0.2 mmol of tris(2,2-bipyridine)chloride hexahydrate were weighed and added sequentially to 30 mL of 1,2-dichloroethane. The mixture was then exposed to sunlight and stirred at room temperature for 24 h. The 1,2-dichloroethane was removed by vacuum distillation, followed by purification by column chromatography to obtain a brown solid compound, 1,3-benzothiazol-5-chloro-2-carboxylic acid ethyl ester, with the following structural formula:

[0031]

[0032] The yield of compound 1,3-benzothiazole-5-chloro-2-carboxylic acid ethyl ester prepared in Example 2 was 85%, with a melting point of 91-93.1℃. The IR (KBr, cm⁻¹) of compound 1,3-benzothiazole-5-chloro-2-carboxylic acid ethyl ester prepared in Example 2 was determined using nuclear magnetic resonance spectroscopy. The results were as follows: -1 )3334,1743,1583,1330,1164; 1 H NMR (400MHz, CDCl3) δ8.24(d,J=1.9Hz,1H),7.91(d,J=8.7Hz,1H),7.53(dd,J=8.6,1.96Hz),4.57(q,J=7.2Hz,2H),1.50(t,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl3) δ160.3,160.3,154.0,135.0,133.3,128.3,125.1,123.0,63.4,14.3.

[0033] Example 3

[0034] First, 10 mmol of (2-mercapto-5-trifluoromethyl)glycine tert-ethyl ester, 2 mmol of Fe(OTf)2, and 0.2 mmol of rose red were weighed and added sequentially to 30 mL of toluene. The mixture was irradiated with an 18W blue LED lamp and stirred in air at room temperature for 18 h. Toluene was then removed by vacuum distillation, followed by purification by column chromatography to obtain a yellow solid, 1,3-benzothiazol-5-trifluoromethyl-2-carboxylic acid ethyl ester, with the following structural formula:

[0035]

[0036] The yield of compound 1,3-benzothiazole-5-trifluoromethyl-2-carboxylic acid ethyl ester prepared in Example 3 was 90%, with a melting point of 73-75 °C. Nuclear magnetic resonance spectroscopy (NMR) was used to determine the ethyl ester of compound 1,3-benzothiazole-5-trifluoromethyl-2-carboxylic acid prepared in Example 3, and the results were: mp 73-75 °C; IR (KBr, cm⁻¹) -1)3078,2989,1736,1493,1344,1114; 1 HNMR (400MHz, CDCl3) δ8.53(s,1H),8.13(d,J=8.5Hz,1H),7.79(dd,J=8.5,1.3Hz,1H),4.60(q,J=7.1Hz,2H),1.52(t,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl3) δ160.8,160.0,152.9,139.9,130.2,129.9,123.6,122.8,122.5,63.2,14.1.

[0037] The Lewis acids selected in this invention, in addition to Cu(OTf)2 and Fe(OTf)2 used in Examples 1 to 3, also include Cu(OAc)2, Ce(OTf)3, CuSO4 or FeSO4 and other metal salts with the same catalytic function.

[0038] The photocatalysts used in this invention, in addition to ruthenium hexahydrate tris(2,2-bipyridine)chloride, rhodamine 6G and rose red used in Examples 1 to 3, also include other Ru complexes, Ir complexes or other organic dyes with photocatalytic activity.

[0039] In addition to dichloromethane, toluene, and 1,2-dichloroethane used in Examples 1 to 3, the organic solvents selected in this invention can also be acetonitrile, ethyl acetate, or tetrahydrofuran.

Claims

1. A method for preparing a 2-substituted benzothiazole compound, characterized in that, Includes the following steps: First, mercaptophenylglycine derivative, Lewis acid, and photocatalyst were added sequentially to an organic solvent in a molar ratio of 1:0.2:0.

02. The mixture was then irradiated with visible light and stirred at room temperature until fully reacted. The organic solvent was then removed by vacuum distillation. Finally, column chromatography was used to obtain the 2-substituted benzothiazole compound. The chemical reaction formula is as follows: In the formula: R 1 The substituents are H, 5-Cl, or 5-trifluoromethyl, R 2 The substituent is -OEt; The photocatalyst is ruthenium tri(2,2-bipyridine) chloride hexahydrate, rhodamine 6G, or rose red.

2. The method for preparing the 2-substituted benzothiazole compound according to claim 1, characterized in that, The mercaptophenylglycine derivative is any one of (2-mercaptophenyl)glycine ethyl ester, (2-mercapto-5-chlorophenyl)glycine ethyl ester, or (2-mercapto-5-trifluoromethyl)glycine tert-ethyl ester.

3. The method for preparing the 2-substituted benzothiazole compound according to claim 1, characterized in that, The Lewis acid is Cu(OTf)2, Cu(OAc)2, Fe(OTf)2, Ce(OTf)3, CuSO4, or FeSO4.

4. The method for preparing the 2-substituted benzothiazole compound according to claim 1, characterized in that, The organic solvent is any one of dichloromethane, toluene, 1,2-dichloroethane, acetonitrile, ethyl acetate, or tetrahydrofuran.

5. The method for preparing the 2-substituted benzothiazole compound according to claim 1, characterized in that, The visible light irradiation uses energy-saving lamps, sunlight, or blue LED lights as the light source.

6. The method for preparing the 2-substituted benzothiazole compound according to claim 1, characterized in that, The stirring time is 10 to 24 hours.

7. The method for preparing the 2-substituted benzothiazole compound according to claim 1, characterized in that, The column chromatography uses a mixture of petroleum ether and ethyl acetate as the eluent, with a volume ratio of 8:1.

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