阅读说明：本技术 一种2,2-双磺酰基-2h-氮丙啶的合成方法 (Synthetic method of 2, 2-bis-sulfonyl-2H-aziridine ) 是由 胡明 岳欣 李金恒 于 2019-10-08 设计创作，主要内容包括：本发明提供一种新颖的制备2,2-双磺酰基-2H-氮丙啶类化合物的方法。该方法经芳基丙炔酸类化合物和亚磺酸钠类化合物的氧化脱羧串联环化反应,使用亚硝酸叔丁酯作为氮源,在无金属催化条件下,经过一步反应构建两个C-S键、一个C-N键、一个C＝N键,合成了2,2-双磺酰基-2H-氮丙啶类化合物。(The invention provides a novel method for preparing 2, 2-bis-sulfonyl-2H-aziridine compounds. According to the method, an aryl propiolic acid compound and a sodium sulfinate compound are subjected to oxidative decarboxylation tandem cyclization reaction, tert-butyl nitrite is used as a nitrogen source, and under the condition of no metal catalysis, two C-S bonds, one C-N bond and one C-N bond are constructed through one-step reaction, so that the 2, 2-bis-sulfonyl-2H-aziridine compound is synthesized.)

1. A synthetic method of a 2, 2-bis-sulfonyl-2H-aziridine compound shown as a formula I comprises the following steps:

adding a propiolic acid compound shown as a formula II, sodium sulfinate shown as a formula III, t-BuONO (tert-butyl nitrite), tetrabutylammonium halide, an oxidant and an organic solvent into a Schlenk tube-sealed reactor, then placing the reactor in an oil bath kettle at 60-100 ℃ under an inert atmosphere for stirring reaction, monitoring the reaction to be complete through TLC or GC-MS, and carrying out post-treatment to obtain a 2, 2-bis-sulfonyl-2H-aziridine compound shown as a formula I;

the reaction formula is as follows:

in the above reaction formula, R₁Represents substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_3-20A heteroaryl group; wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more, each substituent being independently selected from halogen, C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Acyl, -CN,And wherein in said heteroaryl, the heteroatoms may be selected from one or more of N, S, and/or O;

R₂selected from substituted or unsubstituted C_1-20Alkyl radical, C_3-20Cycloalkyl, substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_3-20A heteroaryl group; and wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more, each substituent being independently selected from halogen, C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Acyl, -CN, C_1-6alkyl-O-C (O) -; and wherein in said heteroaryl, the heteroatoms may be selected from one or more of N, S, and/or O;

wherein the tetrabutylammonium halide is selected from any one of tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium iodide;

the oxidant is selected from TBHP, DTBP, TBPB, BPO or PhI (OAc)₂Any one of them.

2. The method of synthesis of claim 1, wherein formula R₁Represents a substituted or unsubstituted phenyl, naphthyl, thienyl group; wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more, each substituent being independently selected from halogen, methyl, methoxy, tert-butyl, -CF₃、-CN、-Ac、

R₂Selected from substituted or unsubstituted C_1-6Alkyl, cyclopropyl, substituted or unsubstituted phenyl, thienyl; and wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more, each substituent being independently selected from halogen, methyl, methoxy, tert-butyl, -CF₃、-CN、-Ac、MeO-C(O)-。

3. The method of any one of claims 1-2, wherein the compound of formula II is selected from the group consisting of compounds represented by the following structural formulae II-1 to II-19:

the compound of formula III is selected from the group consisting of compounds represented by the following structural formulae III-1 to III-10:

4. the process of any one of claims 1 to 3, wherein the tetrabutylammonium halide is selected from tetrabutylammonium fluoride (TBAF); the oxidant is selected from TBHP.

5. The method according to any one of claims 1 to 4, wherein the organic solvent is selected from any one of acetonitrile, toluene or DMF; preferably, the organic solvent is selected from acetonitrile.

6. The method according to any one of claims 1 to 5, wherein the molar ratio of the propiolic acid compound of the formula II, the sodium sulfinate of the formula III, t-BuONO (tert-butyl nitrite), the tetrabutylammonium halide and the oxidant is 1: 3 to 5: 0.01 to 0.1: 1 to 3; preferably, the molar ratio of the propiolic acid compound shown in the formula II, the sodium sulfinate shown in the formula III, t-BuONO (tert-butyl nitrite), tetrabutylammonium halide and the oxidant is 1: 4: 0.05: 2.

7. The method according to any one of claims 1 to 6, wherein the inert atmosphere is an argon atmosphere or a nitrogen atmosphere, preferably an argon atmosphere.

8. The method according to any one of claims 1 to 7, wherein the reaction time of the stirring reaction is 3 to 12 hours, preferably 6 hours; the reaction temperature is preferably 80 ℃.

9. The operation of the post-processing is as follows: after completion of the reaction, the reaction solution was extracted with ethyl acetate (3 × 10mL), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was separated by silica gel column chromatography (n-hexane/ethyl acetate 8: 1, V/V) to give the target product of formula I.

Technical Field

The application belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of 2, 2-bis-sulfonyl-2H-aziridine.

Background

Organic compounds containing sulfonyl groups, including sulfonyl heterocycles and derivatives thereof, are an important class of basic building blocks in organic synthesis, pharmaceutical chemistry, and material science. In particular, heterocycles having one or more sulfonyl groups exhibit unique chemical and biological properties. Therefore, the development of efficient synthetic methods for introducing sulfonyl groups into heterocyclic backbones has attracted considerable attention from synthetic chemists. 2H-aziridines are important N-heterocyclic compounds, ubiquitous in natural products, pharmaceuticals, agrochemicals, and organic materials. In addition, 2H-aziridine has proven to be a versatile precursor for nitriles, electrophiles, and is widely used in the synthesis of complex nitrogen-containing acyclic molecules and various nitrogen heterocyclic compounds, such as pyrrole, indole, pyrazolo [1, 5-a ] pyridine, oxazole, isoxazole, piperidine, and the like. In view of the wide variety of uses of such compounds, various efficient synthetic routes to synthesize such compounds have been reported in the prior art.

The inventor reports a simple synthesis method of 2, 2-bis-sulfonyl-2H-aziridine, which uses a terminal alkyne compound and a sodium sulfinate compound as raw materials, and uses tert-butyl nitrite as a nitrogen source to prepare the 2, 2-bis-sulfonyl-2H-aziridine through a one-step reaction of multi-component cyclization. The method has the advantages that common and easily-commercially-available reagents are used as starting raw materials, and the terminal alkyne is multifunctional under mild and metal-free catalytic reaction conditions, so that the method has good chemical and regional selectivity, and avoids the use of strong base and expensive metal catalysts in the classical method for synthesizing 2H-aziridine compounds (chem. There remains an urgent need for sustainable chemical and pharmaceutical industries to develop new metal-free and step-economical strategies to obtain 2H-aziridine compounds.

Decarboxylative conversion of organic acids has become one of the general synthetic methods for the construction of C-C or C-heteroatoms, aryl propiolic acids are more stable and easier to handle than terminal alkynes. Inspired by the advantages, the inventor proposes a novel decarboxylation tandem cyclization reaction of an aryl propiolic acid compound and sodium sulfinate, uses tert-butyl nitrite as a nitrogen source, and synthesizes the 2, 2-bis-sulfonyl-2H-aziridine compound under the condition of no metal catalysis.

Disclosure of Invention

The invention aims to overcome the defects existing in the prior art for preparing 2, 2-bis-sulfonyl-2H-aziridine compounds by using aryl acetylene compounds, and provides a novel method for preparing 2, 2-bis-sulfonyl-2H-aziridine compounds. According to the method, an aryl propiolic acid compound and sodium sulfinate are subjected to oxidative decarboxylation tandem cyclization reaction, tert-butyl nitrite is used as a nitrogen source, and under the condition of no metal catalysis, two C-S bonds, one C-N bond and one C-N bond are constructed through one-step reaction, so that the 2, 2-bis-sulfonyl-2H-aziridine compound is synthesized.

In order to solve the technical problem, the invention provides a method for synthesizing a 2, 2-bis-sulfonyl-2H-aziridine compound shown in formula I, which comprises the following steps:

adding a propiolic acid compound shown as a formula II, sodium sulfinate shown as a formula III, t-BuONO (tert-butyl nitrite), tetrabutylammonium halide, an oxidant and an organic solvent into a Schlenk tube-sealed reactor, then placing the reactor in an oil bath kettle at 60-100 ℃ under an inert atmosphere for stirring reaction, monitoring the reaction completion by TLC or GC-MS, and carrying out post-treatment to obtain the 2, 2-bis-sulfonyl-2H-aziridine compound shown as a formula I.

According to the synthesis method of the invention, the reaction formula is as follows:

in the above reaction formula, R₁Represents substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_3-20A heteroaryl group; wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more depending on R₁The number of sites of the group that can be substituted. Each substituent is independently selected from halogen, C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Acyl, -CN, And wherein in said heteroaryl, the heteroatoms may be selected from one or more of N, S, and/or O.

R₂Selected from substituted or unsubstituted C_1-20Alkyl radical, C_3-20Cycloalkyl, substituted or unsubstituted C_6-20Aryl, substituted or unsubstituted C_3-20A heteroaryl group. And as previously mentioned, wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more depending on R₂The number of sites of the group that can be substituted. Each substituent is independently selected from halogen, C_1-6Alkyl, halogen substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Acyl, -CN, C_1-6alkyl-O-C (O) -; and wherein in said heteroaryl, the heteroatoms may be selected from one or more of N, S, and/or O.

Preferably, of the formula R₁Represents a substituted or unsubstituted phenyl, naphthyl, thienyl group; wherein in said "substituted or unsubstituted", the number of substituents may be selected from 1 or more, for example, 1, 2, 3, 4, 5 substituents. Each substituent is independently selected from halogen, methyl, methoxy, tert-butyl, -CF₃、-CN、-Ac、

R₂Selected from substituted or unsubstituted C_1-6Alkyl, cyclopropyl, substituted or unsubstituted phenyl, thienyl. And as mentioned above, in the "substituted or unsubstituted" mentioned above, the number of the substituents may be selected from 1 or more, for example, when it is a substituted or unsubstituted phenyl group, the number of the substituents may be 1, 2, 3, 4, 5. Each substituent is independently selected from halogen, methyl, methoxy, tert-butyl, -CF₃、-CN、-Ac、MeO-C(O)-。

Most preferably, the compound of formula II is selected from the group consisting of the compounds represented by the following structural formulae II-1 to II-19:

the compound of formula III is selected from the group consisting of compounds represented by the following structural formulae III-1 to III-10:

according to the foregoing synthesis method of the present invention, the tetrabutylammonium halide may be any one selected from tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium iodide; preferably, the tetrabutylammonium halide is selected from tetrabutylammonium fluoride (TBAF).

The aforementioned synthesis method according to the present invention, wherein the oxidizing agent is selected from TBHP, DTBP, TBPB, BPO or PhI (OAc)₂Any one of the above; preferably, the oxidant is selected from TBHP.

The aforementioned synthesis method according to the present invention, wherein the organic solvent is selected from any one of acetonitrile, toluene or DMF; preferably, the organic solvent is selected from acetonitrile. The amount of the organic solvent to be added can be routinely determined by those skilled in the art.

According to the synthesis method, the molar ratio of the propiolic acid compound shown in the formula II, the sodium sulfinate shown in the formula III, the t-BuONO (tert-butyl nitrite), the tetrabutylammonium halide and the oxidant is 1 to (3-5) to (0.01-0.1) to (1-3); preferably, the molar ratio of the propiolic acid compound shown in the formula II, the sodium sulfinate shown in the formula III, t-BuONO (tert-butyl nitrite), tetrabutylammonium halide and the oxidant is 1: 4: 0.05: 2.

According to the aforementioned synthesis method of the present invention, the inert atmosphere is an argon atmosphere or a nitrogen atmosphere, preferably an argon atmosphere.

According to the synthesis method, the reaction time of the stirring reaction is 3-12 hours, preferably 6 hours; the reaction temperature is preferably 80 ℃.

The synthesis method according to the invention, wherein the post-treatment is performed as follows: after completion of the reaction, the reaction solution was extracted with ethyl acetate (3 × 10mL), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was separated by silica gel column chromatography (n-hexane/ethyl acetate 8: 1, V/V) to give the target product of formula I.

The method of the invention achieves the following beneficial technical effects:

1) the invention firstly provides an oxidative decarboxylation tandem cyclization reaction of a (hetero) aryl propiolic acid compound and sodium sulfinate, uses tert-butyl nitrite as a nitrogen source, and synthesizes a 2, 2-disulfonyl-2H-aziridine compound by constructing two C-S bonds, a C-N bond and a C ═ N bond through one-step reaction under the condition of no metal catalysis.

2) The method of the invention uses (hetero) aryl propiolic acid compound as raw material, and overcomes the defects that the corresponding (hetero) aryl acetylene compound in the prior art is too active in chemical property and difficult in actual operation of reaction. In addition, a novel catalytic reaction system is constructed by the method, and the results of examples 1-16 show that the use of TBHP and TBAF has a remarkable promoting effect on the reaction; and a substrate development test shows that the catalytic system has good reaction substrate adaptability and can obtain good to excellent target product yield. A novel and efficient way is developed for the synthesis of the 2, 2-bis-sulfonyl-2H-aziridine compound, and the method has the advantages of mild reaction conditions, stable property of the selected reagent, easy obtainment, low price and environmental friendliness.

Detailed Description

The present invention will be described in further detail with reference to specific examples. Hereinafter, unless otherwise specified, the methods are all conventional in the art, and the reagents used are all commercially available.