阅读说明：本技术 一种碱催化的脱羧胺化制备胺类化合物的方法 (Method for preparing amine compound by base-catalyzed decarboxylation amination ) 是由 戴啟谱 李培贺 王峥 付辉 于 2019-08-29 设计创作，主要内容包括：本发明公开了一种碱催化的由羧酸或或羧酸衍生物(酯)制备胺类化合物的方法,所述方法为烷基、芳基或杂环芳香羧酸或酯与羟胺类化合物反应得到酰氧基氨基甲酸酯中间体,在碱的作用下发生脱羧胺化反应从而得到胺类化合物。与传统的同类反应如Curtis重排、Lossen重排反应相比,本方法操作简便,反应条件温和,底物更加稳定,原子利用率高,副产物仅为二氧化碳无污染,并且产率可达到90％,适合产业化生产。(The invention discloses a method for preparing amine compounds from carboxylic acids or carboxylic acid derivatives (esters) under the catalysis of alkali. Compared with the traditional similar reactions such as Curtis rearrangement reaction and Lossen rearrangement reaction, the method has the advantages of simple and convenient operation, mild reaction conditions, more stable substrate, high atom utilization rate, no pollution of the byproduct carbon dioxide, high yield up to 90 percent and suitability for industrial production.)

1. A method for synthesizing amine compounds by decarboxylated amine under base catalysis is characterized in that carboxylic acid or carboxylic acid derivatives (esters) are used as raw materials, hydroxylamine is used as a nitrogen source to generate acyloxy carbamate intermediates, and decarboxylation reaction is carried out under base catalysis to generate alkyl or aryl amine compounds, so that conversion from the carboxylic acid or carboxylic acid derivatives (esters) to the amine is realized.

2. A base-catalysed amine decarboxylation process according to claim 1, wherein the starting carboxylic acid is an alkyl or aryl or heterocyclic aromatic acid, the ester is an aryl, benzyl or alkyl ester of an alkyl, aryl or heterocyclic aryl carboxylic acid, and the hydroxylamine is an N-formate protected hydroxylamine.

3. A base-catalysed chemical synthesis of amines by decarboxylation of amines according to claim 1, wherein the base used in the decarboxylation amination reaction is K₂CO₃、Cs₂CO₃、^tBuONa, KOH and DBU.

4. A base-catalysed decarboxylated amine synthesis process to amines according to claim 1, wherein the solvent used in the decarboxylated amination reaction is one of toluene, chlorobenzene, acetonitrile, chloroform.

5. A base-catalyzed method of synthesizing amines by decarboxylation of amines according to claim 1, wherein the decarboxylation amination reaction temperature is from ambient temperature to 100 ℃.

6. A base-catalyzed amine decarboxylation process for the synthesis of amines according to claim 1, wherein the synthesized amines include N-formate protected alkylamines, arylamines, heterocyclic arylamines, and the like.

Technical Field

The invention relates to a simple and convenient method for preparing amine compounds from carboxylic acid under the catalysis of alkali, in particular to a method for converting carboxylic acid or carboxylic acid derivative (ester) serving as a starting material into the amine compounds by undergoing a decarboxylation reaction under the catalysis of alkali by using hydroxylamine as a nitrogen source through an acyloxy carbamate intermediate.

Background

The synthesis of amine compounds is a long-standing topic in the field of organic synthesis. Since amines are important structural units in the fields of organic chemistry, biology, medicine, materials and the like, a method for synthesizing amines conveniently and efficiently is concerned by numerous chemists. The conventional approaches for synthesizing amine compounds, such as the coupling reaction of halogenated hydrocarbon catalyzed by transition metal and amine or the nitration reduction process, all face the problems of high price of the starting material halogenated hydrocarbon, generation of halogen acid waste which pollutes the environment, and difficult concentrated acid treatment. Therefore, it is important to find a synthetic method with cheap and easily available starting materials, simple and convenient operation and environmental protection.

The carboxylic acid is used as a synthon for constructing carbon-nitrogen bonds to synthesize amine compounds, so that the problem of environmental pollution caused by halogen is avoided, and the price is lower. The conventional amination reaction using carboxylic acid as a substrate mostly adopts a rearrangement reaction, decarboxylation amination or decarbonylation amination reaction as a reaction process. Among the most representative works are the Lossen rearrangement, the Hoffmann rearrangement and the Curtis rearrangement. The three rearrangement reactions generate various forms of isocyanate intermediates, and then generate different amine products such as carbamate, primary amine, urea and the like with various nucleophiles such as alcohol, water, amine and the like. The Lossen rearrangement requires the use of an acylation reagent in advance and then the removal of the acylation reagent, so that the atom utilization rate is too low; the Hoffmann rearrangement requires strong alkali and bromine, so that the problem of environmental pollution is serious; curtis rearrangement requires the use of explosive azides and is prone to danger. Therefore, it is necessary to find a simpler, more green, economical and practical method for synthesizing amine compounds.

Disclosure of Invention

The invention aims to provide a method for synthesizing an amine compound by constructing a carbon-nitrogen bond through decarboxylation under the catalysis of alkali, so that the conversion from carboxylic acid to amine is realized, and the problems of low atom utilization rate, harsh reaction conditions and unstable substrate of the traditional decarboxylation amination reaction are solved.

The purpose of the invention is realized by the following technology, and the scheme is as follows:

(1) if the substrate is a carboxylic acid: adding carboxylic acid into anhydrous dichloromethane, adding N, N-Carbonyl Diimidazole (CDI) at 0 ℃, adding hydroxylamine after half an hour, stirring at normal temperature until the raw materials react completely to obtain acyloxy carbamate, and separating and purifying by column chromatography. Placing acyloxy carbamate in a reaction bottle, adding alkali and a solvent into the reaction bottle, placing the reaction bottle on a heating table, stirring, monitoring the reaction process by a TLC plate until the raw materials are reacted completely, and purifying by silica gel column chromatography to obtain the corresponding alkyl or aryl amine compound.

(2) If the substrate is an ester: adding ester, hydroxylamine, alkali and solvent into a reaction bottle, heating and stirring until the reaction is complete, and performing column chromatography separation to obtain pure alkylamine or aromatic amine compounds.

The reaction formula is as follows:

wherein R is¹Is a substituent such as alkylaryl, R²Is a formate protecting group such as Boc or Cbz, R³Aryl, benzyl, alkyl, and the like.

In the case of synthesizing acyloxycarbonylaminates according to the above-mentioned scheme (1), the molar ratio of carboxylic acid, CDI and hydroxylamine was 1:1:1, the reaction time was 1.5 hours, and the amount of dichloromethane was 0.5 mol/mL.

In the scheme (1), the dosage of the acyloxy carbamate and the alkali is 1:1.5, and the alkali of the alkali is inorganic alkali K₂CO₃、Cs₂CO₃、^tBuONa, KOH or organic base such as DBU, wherein the solvent is one of toluene, chlorobenzene, acetonitrile and chloroform, and the reaction temperature is 80-120 ℃.

In the scheme (2), the mass ratio of the ester, the hydroxylamine and the alkali is 1: 1-1.2: 2-3. The first step of acyloxycarbamate formation is a reversible transesterification process and the second step is an irreversible decarboxylation amination process. The invention controls the reaction to proceed in positive direction by introducing irreversible decarboxylation process. The reaction time is 10-12 hours.

Has the advantages that:

(1) the method starts from carboxylic acid or ester, reacts with hydroxylamine to obtain acyloxy carbamate, removes carbon dioxide under the action of alkali to obtain a corresponding amine compound, improves the traditional Curtis rearrangement and Lossen rearrangement conditions, avoids the use of explosive azide, saves the atom utilization rate, and is a great breakthrough in the synthesis method.

(2) Compared with the prior report, the invention uses the cheap carboxylic acid or ester, avoids the use of halogen which is expensive and difficult to treat, does not use transition metal, has simple and easy operation and meets the requirement of industrial production.

Drawings

FIG. 1 is a schematic representation of N-Boc ethylamine prepared in example 1¹H nuclear magnetic resonance spectrum;

FIG. 2 is a diagram of N-Boc ethylamine prepared in example 1¹³C nuclear magnetic resonance spectrum;

FIG. 3 is a graph of N-Cbz phenylethylamine prepared in example 2¹H nuclear magnetic resonance spectrum;

FIG. 4 is a graph of N-Cbz phenylethylamine prepared in example 2¹³C nuclear magnetic resonance spectrum;

FIG. 5 is a graph showing the results of N-Boc phenethylamines obtained in examples 3 and 6¹H nuclear magnetic resonance spectrum;

FIG. 6 is a graph showing the results of N-Boc phenethylamines obtained in examples 3 and 6¹³C nuclear magnetic resonance spectrum;

FIG. 7 shows the preparation of N-Boc aniline in examples 4 and 7¹H nuclear magnetic resonance spectrum;

FIG. 8 is a schematic representation of N-Boc aniline from examples 4 and 7¹³C nuclear magnetic resonance spectrum;

FIG. 9 is a schematic representation of N-Boc-2-iodoaniline prepared in example 5¹H nuclear magnetic resonance spectrum;

FIG. 10 is a schematic representation of N-Boc-2-iodoaniline prepared in example 5¹³C nuclear magnetic resonance spectrum;

Detailed Description

The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments, but is not limited thereto.

Scheme 1, synthesis of amines from carboxylic acids:

(1) the synthesis steps of the N-Boc ethylamine are as follows: adding 0.74g (10mmol) of propionic acid into 20ml of dried dichloromethane, adding 1.78g (CDI) of N, N-carbonyl diimidazole at 0 ℃, adding 1.47g of N-Boc-hydroxylamine after half an hour, stirring at normal temperature, monitoring by using a TLC plate until the raw material reaction is complete, and purifying by passing through a column to obtain tert-butyl propionyl oxycarbamate; weighing 57mg (0.3mmol) of tert-butyl propoxy carbamate and 1.5 times of equivalent of base, placing the mixture into 3mL of solvent, placing the mixture on a heating table at 100 ℃, stirring the mixture for 2 hours, monitoring the mixture by using a TLC plate until the raw materials are completely reacted, separating and purifying the mixture by using column chromatography to obtain a target product, wherein the yield is 62%, and a nuclear magnetic spectrum is shown in a figure 1 and a figure 2.

(2) The synthesis steps of the N-Cbz phenylethylamine are as follows: adding 1.5g (10mmol) of phenylpropionic acid into 20ml of dried dichloromethane, adding 1.78g (CDI) of N, N-carbonyl diimidazole at 0 ℃, adding 1.84g of N- (benzylcarbonyloxy) hydroxylamine after half an hour, stirring at normal temperature, monitoring by using a TLC plate until the raw materials are completely reacted, and purifying by passing through a column to obtain benzyl ((3-phenylpropionyl) oxy) carbamate; 89.8mg (0.3mmol) of benzyl ((3-phenylpropionyl) oxy) carbamate and 1.5 times equivalent of a base are weighed out and placed in a 3mL solvent, and stirred on a heating table at 100 ℃ for 1 hour, monitored by a TLC plate until the reaction of the raw materials is completed, and purified by column chromatography to obtain the target product. The yield was 79%, and the nuclear magnetic spectrum was as shown in FIGS. 3 and 4.

(3) The synthesis steps of the N-Boc amphetamine are as follows: adding 1.5g (10mmol) of phenylpropionic acid into 20ml of dried dichloromethane, adding 1.78g (CDI) of N, N-carbonyl diimidazole at 0 ℃, adding 1.47g of N-Boc hydroxylamine after half an hour, stirring at normal temperature, monitoring by using a TLC plate until the raw material reaction is complete, and purifying by passing through a column to obtain tert-butyl (3-phenylpropanolamixy) carbamate; 79.6mg (0.3mmol) of tert-butyl (3-phenylpropanolamino) carbamate and 1.5 times equivalent of base are weighed out and placed in a solvent, the solvent is placed on a heating table at 100 ℃ and stirred for 1 hour, the TLC plate is used for monitoring until the raw materials are completely reacted, and the target product is obtained after column chromatography separation and purification. The yield was 81%, and the nuclear magnetic spectrum was as shown in FIGS. 5 and 6.

(4) The synthesis steps of the N-Boc aniline are as follows: adding 1.2g (10mmol) of benzoic acid into 20ml of dry dichloromethane, adding 1.78g (CDI) of N, N-carbonyl diimidazole at 0 ℃, adding 1.47g of N-Boc hydroxylamine after half an hour, stirring at normal temperature, monitoring by using a TLC plate until the raw material reaction is complete, and purifying by passing through a column to obtain tert-butyl (benzoyloxy) carbamate; tert-butyl (benzoyloxy) carbamate 71.3mg (0.3mmol), 1.5 fold equivalent of base were weighed into 3mL of solvent, placed on a 80 ℃ heating table and stirred for 2 hours, monitored by TLC plate until the reaction of the raw materials was completed, and purified by column chromatography to obtain the target product. The yield was 71%, and the nuclear magnetic spectrum was as shown in FIGS. 7 and 8.

(5) The synthesis steps of the N-Boc-2-iodoaniline are as follows: adding 2.5g (10mmol) of 2-iodobenzoic acid into 20ml of dried dichloromethane, adding 1.78g (CDI) of N, N-carbonyldiimidazole at 0 ℃, adding 1.47g of N-Boc hydroxylamine after half an hour, stirring at normal temperature, monitoring by using a TLC plate until the raw material is completely reacted, and purifying by passing through a column to obtain tert-butyl ((2-iodobenzoyl) oxy) carbamate; 109mg (0.3mmol) of tert-butyl ((2-iodobenzoyl) oxy) carbamate and 1.5 times equivalent of base are weighed out and placed in a solvent, stirred on a heating table at 80 ℃, monitored by TLC until the raw materials are completely reacted, and purified by column chromatography to obtain the target product. The yield was 90%, and the nuclear magnetic spectrum was as shown in FIGS. 9 and 10.

Scheme 2, synthesis of amines from esters:

(6) the synthesis of N-Boc phenethylamine comprises the following steps: adding 68mg (0.3mmol) of phenyl 3-phenylpropionate, 48mg (0.36mmol) of N-Boc hydroxylamine, 0.6mmol of a base and 3mL of a solvent into a Schlenk tube dried in advance, vacuumizing, introducing argon, replacing three times, placing at 100 ℃ for reacting for 12 hours, monitoring by TLC until the reaction is complete, and separating by column chromatography to obtain a target product with the yield of 77%, wherein a nuclear magnetic spectrum diagram is shown in a figure 5 and a figure 6.

(7) The synthesis of N-Boc aniline comprises the following steps: 60mg (0.3mmol) of phenyl benzoate, 48mg (0.36mmol) of N-Boc hydroxylamine and base (0.6mmol) were weighed out in 3mL of solvent, reacted at 100 ℃ for 12 hours, TLC monitored until the reaction was complete, and column chromatography gave the desired product in 66% yield, as shown in FIGS. 7 and 8.

The present invention includes, but is not limited to, the above embodiments, it should be understood that the embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention, and any equivalent replacement or partial modification made under the principle of the spirit of the present invention should be considered as being within the scope of the present invention.