阅读说明：本技术 一种非金属催化的硫叶立德与芳香胺的***反应构建c-n键的方法及应用 (Method for constructing C-N bond through insertion reaction of nonmetal-catalyzed sulfur ylide and aromatic amine and application ) 是由 海俐 吴勇 管玫 何花 严开川 李江联 于 2020-06-24 设计创作，主要内容包括：本发明涉及一种非金属催化的硫叶立德与芳香胺的插入反应构建C-N键的方法及应用。该方法采用水作为反应溶剂,在温和的条件下硫叶立德发生N-H插入反应,用于构建C-N键。作为一种构建C-N键的途径,该方法克服了传统的使用金属催化剂或氧化剂的缺点。在这个方法基础上,通过使用不同的芳香胺作为底物可以获得各种α-氨基酸酯衍生物。本方法原料易得,避免了金属催化剂、氧化剂和有机溶剂的使用,是一种温和、有效、环境友好的制备α-氨基酸酯的方法,具有广阔的应用前景。(The invention relates to a method for constructing a C-N bond by nonmetallic catalysis of insertion reaction of sulfur ylide and aromatic amine and application thereof. The method adopts water as a reaction solvent, and the thioylide undergoes an N-H insertion reaction under mild conditions to construct a C-N bond. As a way of constructing C-N bonds, the method overcomes the disadvantages of the conventional use of metal catalysts or oxidizing agents. On the basis of this method, various α -amino acid ester derivatives can be obtained by using different aromatic amines as substrates. The method has the advantages of easily obtained raw materials, avoidance of the use of metal catalysts, oxidants and organic solvents, mild, effective and environment-friendly preparation of the alpha-amino acid ester, and wide application prospect.)

1. A method for constructing C-N bond by insertion reaction of sulfur ylide and aromatic amine catalyzed by nonmetal and application thereof are characterized in that a sulfur ylide compound and aromatic amine are used as initial raw materials, pure water is used as a solvent, and an alpha-amino acid ester derivative is synthesized under the action of an additive, wherein the chemical reaction formula is as follows:

wherein:

R₁is one of methyl, ethyl, isopropyl and cyclohexyl;

R₂is one of hydrogen and methyl;

ar is one of substituted or unsubstituted phenyl, naphthyl, indolyl, pyridyl and furyl.

2. The method for preparing alpha-amino acid ester by constructing C-N bond according to claim 1, characterized by using the following preparation steps:

sequentially adding a sulfur ylide compound, aromatic amine, an additive and water into a clean reactor, and putting the reactor into an oil bath at 35 ℃ for reaction for 24 hours; after the reaction is finished, the solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the product.

3. The method according to claim 1 and 2, wherein the additive is one or more of nitric acid, sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, trifluoroacetic acid, benzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, 2,4, 6-trimethylbenzoic acid, and acetic acid.

4. The process according to claims 1 and 2, characterized in that the solvent is water.

5. The method according to claim 1 or 2, wherein the molar ratio of the sulfur ylide compound, the aromatic amine and the additive is 1 (2.0-5.0) to (0.5-3.0).

Technical Field

Relates to a novel green synthesis method for constructing a C-N bond and synthesizing alpha-amino acid ester by nonmetallic catalysis of insertion reaction of sulfur ylide and aromatic amine, belonging to the technical field of organic synthetic chemistry.

Background

The importance of nitrogen-containing compounds is self-evident due to their ubiquitous presence in natural products, medicinal molecules and multifunctional materials. Over the past decades, the construction of C-N bonds has led to commercializationThe wide concern of the scientists. Metal-catalyzed C-N cross-coupling reactions have been widely used as one of the methods for constructing C-N bonds since the first discovery by Ullmann and Goldberg that copper compounds can be used for constructing C-N bonds (Ber. Dtsch. Chem. Ges.1903,36, 2382;Ber. Dtsch. Chem. Ges.1906,39, 1691;Chem Soc Rev2013,42, 9283;Org. Process Res. Dev.2015,19, 1327;Chem. Rev.2016,116, 12564). However, this method requires the use of previously activated starting materials such as halides and the like, while producing equivalent halide salts as by-products. In recent years, N-H insertion reaction of carbene(s) ((Angew. Chem. Int. Ed.2017,56, 4156;Chem. Eur. J.2008,14, 3995;Chem. Soc. Rev.2013,42, 4918;Angew. Chem. Int. Ed.2016,55,9134;Angew. Chem. Int. Ed.2015,54, 14503;Chem. Commun.2015,51, 1532-4;Angew. Chem. Int. Ed.2014,531636.) and direct amination of the C-H bondChem. Soc. Rev.2014,43, 901;ACS Catal.2016,6, 610;Chem. Soc. Rev.2011,40, 5068;ACS Catal.2016, 6, 2341;Acc. Chem. Res.2015,481040-52) have received attention as a new way of constructing C — N bonds due to their atom and step economics, but the problems of use of transition metals and instability of the starting materials remain to be solved. The metal-free strategy based on the free radical chemistry is a new efficient and green approach. While these strategies avoid the use of transition metals, the general excess oxidant and substrate specificity issues limit the widespread use of C — N bond structures to some extent. Thiephilide compounds have been regarded as important synthetic precursors since their discovery, except in epoxidation, cyclopropanation, azidation and [2,3 ]]In addition to their primary applications in rearrangement or stevens rearrangement, sulfur ylide compounds have gained considerable attention in recent years as potential safe substitutes for diazo compounds in metal carbene reactions, including intercalation reactions and C-H activation. In 2016, Burtoloso reported the insertion of a thioylide compound into an aryl thiol in the absence of a catalyst, but this strategy did notSuitable for amines compounds (A), (B), (COrg. Lett.2016,18, 3034)。

Disclosure of Invention

Aiming at various problems of the existing method for constructing the C-N bond, the invention aims to provide a method for constructing the C-N bond by the N-H insertion reaction of the sulfur ylide in water and at a mild temperature without a metal catalyst or an oxidant.

In order to achieve the purpose, the invention adopts the following technical scheme:

the alpha-amino acid ester derivative is synthesized by taking a sulfur ylide compound and aromatic amine as initial raw materials and pure water as a solvent under the action of an additive, and the chemical reaction formula is shown as follows:

wherein:

R₁is one of methyl, ethyl, isopropyl and cyclohexyl;

R₂is one of hydrogen and methyl;

ar is one of substituted or unsubstituted phenyl, naphthyl, indolyl, pyridyl and furyl.

The preparation method comprises the following steps:

(1) sequentially adding a sulfur ylide compound, aromatic amine, an additive and water into a clean reactor, and putting the reactor into an oil bath at 35 ℃ for reaction for 24 hours.

(2) After the reaction is finished, the solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the product.

The additive in the step (1) is one or more of nitric acid, sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, trifluoroacetic acid, benzoic acid, adamantane formic acid, p-toluenesulfonic acid, 2,4, 6-trimethyl benzoic acid and acetic acid.

A sulfoylide compound in the step (1): aromatic amine: the molar ratio of the additive is 1: (2.0-5.0): (0.5 to 3.0).

By adopting the technical scheme, the invention has the following advantages: compared with the traditional synthesis method which needs to activate a substrate in advance, use transition metal, oxidant, organic solvent and the like, the method has the advantages of easily obtained raw materials, no need of metal catalyst or oxidant, mild and cheap substitution for the traditional method for constructing the C-N bond, and wide application prospect.

Nuclear magnetic resonance hydrogen spectrum (¹H NMR), carbon spectrum (¹³C NMR) and high resolution mass spectrometry (Agilent 1946B mass spectrometer) were performed to confirm the structure of the synthesized α -amino acid ester derivative, wherein the NMR spectra were measured using a Varian INOVA-400 nuclear magnetic resonance spectrometer with Tetramethylsilane (TMS) as an internal standard (0 ppm) and deuterated chloroform as a solvent.

Detailed description of the invention

The present invention will be further described with reference to specific embodiments to assist in understanding the invention. It is not intended that the scope of the invention be limited thereby, but rather that the invention be defined by the claims appended hereto.