阅读说明：本技术 一种以醋酸铵介导的苯并噻唑类化合物的合成方法 (Method for synthesizing ammonium acetate mediated benzothiazole compound ) 是由 朱小明 王志强 王成勇 张复兴 邝代治 于 2020-08-05 设计创作，主要内容包括：本发明公开了一种以醋酸铵介导的苯并噻唑类化合物的合成方法。该合成方法为：在反应管中,加入邻卤苯胺衍生物、硫化钾、二甲基亚砜、催化剂、添加剂1和添加剂2,在130~150℃下搅拌反应,反应结束后冷却至室温,产物经分离纯化,得到所述苯并噻唑类化合物。本发明发展了以K<Sub>2</Sub>S为硫源,DMSO为碳源和氧化剂,邻卤苯胺衍生物为底物,醋酸铵介导三组分一锅法合成苯并噻唑类化合物的方法。该方法反应步骤少、反应条件温和,且具有较好的官能团容忍性等优点。(The invention discloses a method for synthesizing an ammonium acetate mediated benzothiazole compound. The synthesis method comprises the following steps: adding an o-halophenylamine derivative, potassium sulfide, dimethyl sulfoxide, a catalyst, an additive 1 and an additive 2 into a reaction tube, stirring and reacting at 130-150 ℃, cooling to room temperature after the reaction is finished, and separating and purifying a product to obtain the benzothiazole compound. The invention develops the general formula of K 2 S is a sulfur source, DMSO is a carbon source and an oxidant, an o-halophenylamine derivative is a substrate, and an ammonium acetate mediated three-component one-pot method is used for synthesizing the benzothiazole compound. The method has the advantages of few reaction steps, mild reaction conditions, better functional group tolerance and the like.)

1. a method for synthesizing benzothiazole compounds mediated by ammonium acetate is characterized by comprising the following steps:

adding an o-iodoaniline derivative, potassium sulfide, dimethyl sulfoxide, a catalyst, an additive 1 and an additive 2 into a reaction tube, stirring and reacting at 130-150 ℃, cooling to room temperature after the reaction is finished, and separating and purifying a product to obtain the benzothiazole compound.

2. The method of claim 1, wherein the chemical reaction equation of the synthesis process is as follows:

wherein R is selected from one or more of unsubstituted C6-C10 aryl, methyl, cyano, nitro, methoxy, halogen and ester.

3. The process according to claim 1 or 2, wherein the o-iodoaniline derivative is 2-iodo-4-methylaniline, 2-iodo-4-cyanoaniline, methyl 4-amino-3-iodobenzoate, 2-iodo-4-nitroaniline, 2-iodo-4-methoxyaniline, 2-iodo-4-fluoroaniline, 2-iodo-4-chloroaniline, 2-iodo-4-bromoaniline, 2-iodo-5-methylaniline, 2-iodo-5-methoxyaniline, 2-iodo-5-fluoroaniline, 2-iodo-5-chloroaniline, 2, 4-dichloroaniline, 4-chloro-2-fluoro-6-iodoaniline, 2-amino-3-iodopyridine, 1-iodo-2-naphthylamine.

4. The synthesis method according to claims 1-3, wherein the molar ratio of the added potassium sulfide to the o-iodoaniline derivative is 2-4: 1.

5. A synthesis method according to claims 1-3, characterized in that the dimethyl sulfoxide addition is 2 ml.

6. The synthesis method of claims 1-3, wherein the catalyst is one of cupric chloride, cupric bromide, cuprous iodide, cupric acetate; the molar ratio of the addition amount of the catalyst to the o-iodoaniline derivative is 0.1-0.4: 1.

7. The synthesis method according to claims 1-3, wherein the additive 1 is one of ammonium carbonate and ammonium acetate; the molar ratio of the addition amount of the additive to the o-iodoaniline derivative is 5-7: 1.

8. A synthesis method according to claims 1-3, characterized in that the additive 2 is water; the addition amount of the solvent is 40-120 ul.

9. The synthesis method according to claim 1 to 3, wherein the stirring temperature is 130-150 ℃; the reaction time is 8-12 hours.

10. The synthesis method according to claims 1 to 3, characterized in that the separation and purification operations are: and (3) enabling the reaction liquid to pass through a short column, extracting with ethyl acetate, combining organic phases, drying with anhydrous magnesium sulfate, filtering, evaporating under reduced pressure to remove the organic solvent to obtain a crude product, and purifying by column chromatography to obtain the benzothiazole compound.

Technical Field

The invention belongs to the field of benzothiazole compounds, and particularly relates to a synthesis method of an ammonium acetate mediated benzothiazole compound.

Background

Benzothiazole is an important organic compound, and is a core skeleton of benzothiazole derivatives, so that the benzothiazole has important application value in the fields of medicines, chemical engineering and the like; secondly, because the benzothiazole at the 2-position is relatively active, a plurality of methods for synthesizing 2-substituted benzothiazole compounds have been developed by utilizing the functionalization of the 2-position C-H bond(A. Arora, J. D.Weaver,Org. Lett. 2016,18, 3996; X. Dai, Y. Zhu, Z. Wang, J. Weng,Chin. J. Org. Chem.2017,37,1924.), is an important raw material for synthesizing the 2-substituted benzothiazole compound. However, compared with the research reports on the synthesis method of 2-substituted benzothiazole compounds, the research reports on the synthesis method of benzothiazole compounds by chemical researchers are less, and the synthesis of benzothiazole compounds still remains to use organic sulfur reagents as sulfur sources. The more traditional method is to remove amino group by using 2-aminobenzothiazole as a substrate under the action of amyl nitrite to obtain a benzothiazole compound (G.M. Fischer, M.K. Klein, E. Daltrozzo, A. Zumbusch,Eur. J. Org. Chem. 2011,2011, 3421.). The reaction precursor 2-aminobenzothiazole of the method is not easy to obtain and can be obtained by utilizing aromatic amine to react under certain reaction conditions, which undoubtedly increases the cost of the reaction and limits the development of the reaction. Another reaction method is to use o-mercaptoaniline as a substrate and CO₂(S, Chun, S, Yang, Y, K, Chung, Tetrahedron 2017, 73, 3438; X, Gao, B, Yu, Z, Yang, Y, ZHao, H, ZHang, L, Hao, B, Han, Z, Liu, ACS Catal 2015, 5, 6648.) or DMF (X, Gao, B, Yu, Q, Mei, Z, Yang, Y, ZHao, H, ZHang, L, Hao, Z, Liu,New J. Chem.2016,40,8282.) carbon source is provided, and the benzothiazole compounds are synthesized. The reaction substrate is unstable and the reaction conditions are harsh.

Therefore, it is very meaningful to develop a raw material which is easy to obtain and has better stability by using an inorganic sulfur reagent as a sulfur source, and synthesize the benzothiazole compound by a green and efficient method. The invention develops a method for synthesizing benzothiazole compounds by using o-iodoaniline as a substrate, potassium sulfide as a sulfur source, DMSO as a carbon source and performing a series reaction of three components in a one-pot method. The method has the advantages of few reaction steps, mild reaction conditions, better functional group compatibility and the like.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide an ammonium acetate mediated benzothiazole compoundThe method is provided. The invention develops a new medicine with K₂S is a sulfur source, DMSO is a carbon source and an oxidant, an o-halophenylamine derivative is a substrate, and an ammonium acetate mediated three-component one-pot method is used for synthesizing the benzothiazole compound. The method has the advantages of few reaction steps, mild reaction conditions, higher functional group tolerance and the like, and develops a valuable path which is simple to operate, direct and atom-economical for the synthesis of the benzothiazole compounds.

The purpose of the invention is realized by the following technical scheme.

A method for synthesizing benzothiazole compounds mediated by ammonium acetate comprises the following steps:

adding an o-iodoaniline derivative, potassium sulfide, dimethyl sulfoxide, a catalyst, an additive and a solvent into a reaction tube, stirring and reacting at 130-150 ℃, cooling to room temperature after the reaction is finished, and separating and purifying a product to obtain the benzothiazole compound.

Further, the chemical reaction equation of the synthesis process is as follows:

wherein R is selected from one or more of unsubstituted C6-C10 aryl, methyl, cyano, nitro, methoxy, halogen and ester.

Preferably, in the synthesis method of the present invention, the iodoaniline derivative is 2-iodo-4-methylaniline, 2-iodo-4-cyanoaniline, 4-amino-3-iodobenzoic acid methyl ester, 2-iodo-4-nitroaniline, 2-iodo-4-methoxyaniline, 2-iodo-4-fluoroaniline, 2-iodo-4-chloroaniline, 2-iodo-4-bromoaniline, 2-iodo-5-methylaniline, 2-iodo-5-methoxyaniline, 2-iodo-5-fluoroaniline, 2-iodo-5-chloroaniline, 2, 4-dichloroaniline, 4-chloro-2-fluoro-6-iodoaniline, 2-amino-3-iodopyridine, 1-iodo-2-naphthylamine.

Furthermore, the molar ratio of the added potassium sulfide to the o-iodoaniline derivative is 2-4: 1, and preferably 3: 1.

Further, the amount of dimethyl sulfoxide added was 2 mL.

Further, the catalyst is one of cupric chloride, cupric bromide, cuprous iodide and cupric acetate, and is preferably cuprous iodide.

Furthermore, the molar ratio of the added amount of the catalyst to the o-iodoaniline derivative is 0.1-0.4: 1, and preferably 0.2: 1.

Further, the additive 1 is one of ammonium carbonate and ammonium acetate, and preferably ammonium acetate.

Furthermore, the molar ratio of the addition amount of the additive 1 to the o-iodoaniline derivative is 5-7: 1, and preferably 6: 1.

Further, the addition amount of the additive 2 is 40-120 ul, and preferably 80 ul.

Further, the stirring temperature is 130-150 ℃, and preferably 140 ℃.

Further, the stirring reaction time is 9-15 hours, preferably 10 hours.

Further, the separation and purification operations are as follows: and (2) enabling the reaction liquid to pass through a short column, extracting with ethyl acetate, combining organic phases, drying with anhydrous magnesium sulfate, filtering, evaporating under reduced pressure to remove the organic solvent to obtain a crude product, and purifying by column chromatography to obtain the 2-substituted benzothiazole compound.

The invention develops a novel method for synthesizing benzothiazole compounds (6-m) by three-component 'one-pot' series reaction through the construction of C-S and C-N bonds under the mediation of ammonium acetate by using o-iodoaniline as a substrate, potassium sulfide as a sulfur source and DMSO (dimethyl sulfoxide) as a sulfur source and an oxidant.

Compared with the prior art, the invention has the following advantages and beneficial effects:

(1) the invention provides a method for synthesizing an ammonium acetate mediated benzothiazole compound. The invention provides a new medicine composition with K₂S is a sulfur source, DMSO is a carbon source and an oxidant, an o-halophenylamine derivative is a substrate, and an ammonium acetate mediated three-component one-pot method is used for synthesizing the benzothiazole compound. The method has the advantages of few reaction steps, mild reaction conditions, higher functional group tolerance and the like.

(2) Benzothiazole is an important intermediate for synthesizing 2-substituted benzothiazole compounds, but the research on the synthesis method of benzothiazole compounds is less at the present stage, and the invention develops an efficient, simple and green method for synthesizing benzothiazole compounds.

Drawings

Fig. 1 and 2 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 1, respectively.

Fig. 3 and 4 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 2, respectively.

Fig. 5 and 6 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 3, respectively.

Fig. 7 and 8 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 4, respectively.

Fig. 9 and 10 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 5, respectively.

Fig. 11 and 12 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 6, respectively.

Fig. 13 and 14 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 7, respectively.

Fig. 15 and 16 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 8, respectively.

Fig. 17 and 18 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 9, respectively.

Fig. 19 and 20 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 10, respectively.

Fig. 21 and 22 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 11, respectively.

Fig. 23 and 24 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 12, respectively.

Fig. 25 and 26 are a hydrogen spectrum and a carbon spectrum of the objective product obtained in example 13, respectively.

Detailed description of the invention

The technical solutions of the present invention are further described in detail below with reference to specific examples and drawings, but the scope and implementation of the present invention are not limited thereto.