阅读说明：本技术 γ-烯基酮及其制备方法 (Gamma-alkenyl ketone and preparation method thereof ) 是由 邢栋 陈甜甜 杨海见 杨扬 阎子龙 于 2019-09-29 设计创作，主要内容包括：本发明公开了一种γ-烯基酮的制备方法,以苯乙酮、1,3-丁二烯为原料,在有机溶剂、催化剂、添加剂和配体存在的条件下,可以以高收率、高区域选择性得到目标产物。本发明具有高原子经济性、高区域选择性、高收率等优势,可实现廉价基础的有机化学品1,3-丁二烯到高附加值γ-烯基酮的高效转化,采用廉价的催化剂,不仅使反应条件更中性温和,也使实验操作更为安全简单。本发明合成的γ-烯基酮是一种很有用的合成中间体,通过一系列的转化可以得到一系列药物分子前体或关键中间体,具有广阔的应用前景。(The invention discloses a preparation method of gamma-alkenyl ketone, which takes acetophenone and 1, 3-butadiene as raw materials and can obtain a target product with high yield and high regioselectivity under the condition of the existence of an organic solvent, a catalyst, an additive and a ligand. The method has the advantages of high atom economy, high regioselectivity, high yield and the like, can realize the high-efficiency conversion of the cheap basic organic chemical 1, 3-butadiene to the gamma-alkenyl ketone with high added value, adopts the cheap catalyst, and not only ensures that the reaction condition is more neutral and mild, but also ensures that the experimental operation is safer and simpler. The gamma-alkenyl ketone synthesized by the invention is a very useful synthesis intermediate, can obtain a series of drug molecular precursors or key intermediates through a series of conversions, and has wide application prospect.)

1. A method for synthesizing gamma-alkenyl ketone comprises the steps of taking ketone and 1, 3-butadiene as reaction raw materials to react in the presence of an organic solvent, a catalyst, an additive and a ligand to obtain the gamma-alkenyl ketone; the reaction is as follows:

wherein:

R ₁is hydrogen atom, chain alkane substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, cycloalkyl, phenyl substituted by alkyl, phenyl substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, phenyl substituted by aromatic ring or aromatic heterocyclic ring, aromatic heterocyclic ring;

r2 is hydrogen atom, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen atom substituted phenyl, aromatic heterocycle, acyl, nitrile group, amide group and carboxyl.

2. The method of synthesis of claim 1, wherein R is ₁Hydrogen atom, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N-dimethyl substituted phenyl, fluorine substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl; r ₂Hydrogen atom, C1-C6 alkyl and phenyl.

3. The method of claim 1, wherein the additive is one of water, methanol, ethanol, isopropanol, and phenol.

4. The synthesis method according to claim 1, wherein the solvent is one or more of CPME, toluene, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, 1, 2-dichloroethane, ethyl acetate, methanol, and ethanol.

5. The method of synthesis according to claim 1, wherein the catalyst is a metal catalyst selected from the group consisting of ni (cod) ₂。

6. The synthesis process according to claim 1, wherein the ligand is a bidentate or monodentate ligand having a good coordination effect with nickel.

7. The method of synthesis according to claim 1, wherein the ketone: 1, 3-butadiene: additive: catalyst: the molar ratio of the ligands is 1: (2-5): (1.0-10): (0.01-0.1): (0.01-0.1); and/or the addition amount of the organic solvent is 0.5mL/mmol based on the using amount of the ketone.

8. The synthesis method according to claim 1, wherein the reaction temperature is 90-130 ℃; and/or the reaction time is 2-24 hours.

9. Gamma-alkenyl ketones characterized by the structural formula (3 a):

wherein:

R ₁is hydrogen atom, chain alkane substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, cycloalkyl, phenyl substituted by alkyl, benzene substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atomAryl, aryl or heteroaryl substituted phenyl, heteroaryl;

R ₂is hydrogen atom, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen atom substituted phenyl, aromatic heterocycle, acyl, nitrile group, amide group and carboxyl.

10. The gamma-alkenyl ketone of claim 9, wherein R is ₁Hydrogen atom, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N-dimethyl substituted phenyl, fluorine substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl; r ₂Hydrogen atom, C1-C6 alkyl and phenyl.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to gamma-alkenyl ketone and a preparation method thereof.

Background

From an economic and environmental point of view it is desirable to build the C-C bond from simple chemical starting materials in an atom-economic way without producing stoichiometric by-products 1, 3-butadiene, as a structurally simple organic synthesis substrate, with an annual yield of more than 1000 ten thousand tons, mainly for the manufacture of rubber, polymers and chemicals, with the advancement of research, it has been gradually recognized that it has great potential in building more efficient C-C bond formation processes, hi this context, Krische rate first uses 1, 3-butadiene as a nucleophile for reductive carbonyl addition of aldehydes (science.2012,336,324-327), more recently Buchwald has developed a CuH catalyzed reduction strategy, under the catalytic action of Cu and ferrocene ligands, 1, 3-butadiene reacts with simple ketones to give high-selectivity allylic alcohols (j.am. chem.soc.2019,141, 62-70), as a transition metal intermediate, while on the other hand the economic and easy to develop a simple allylic ketone precursor for dimerization of allylic alcohols and simple butadiene- α, which are relatively easy to challenge to obtain a nucleophilic reaction of polybutenyl-ketone and a bulky allylic ketone, which is a relatively easy to control and easy to obtain a nucleophilic intermediate of butadiene, which is a bulky allylic ketone.

Disclosure of Invention

The invention aims to overcome the defects in the prior art, discloses an α -alkylation reaction of simple ketone and 1, 3-butadiene, which is economic, green, efficient, good in selectivity and wide in substrate range, obtains the required α -allylation target product 3a with 82% separation yield by using an additive under the conditions of a catalyst and a ligand, and has excellent regioselectivity.

The chemical reaction mechanism involved in the invention is shown as the following formula (I): first, a Ni (0)/IMes catalyst coordinates with butadiene to form complex A, A protonates to form Ni-pi-allyl intermediate B, the hydroxidizing species of intermediate B deprotonates ketone 1a to form the corresponding enolate intermediate C, or H ₂The direct oxidative addition of O to Ni (0) produces HO-Ni-H species D. The Ni-H species can undergo olefin insertion to form a Ni-pi-allyl intermediate B, or deprotonation of 1a to an enolized intermediate E, followed by olefin insertion to yield intermediate C enolate and subsequent C-C coupling between the allyl fragments of intermediate CTo the desired product 3a and regenerating the nickel (0) catalyst.

The invention provides a synthesis method of gamma-alkenyl ketone, which comprises the steps of taking ketone and 1, 3-butadiene as reaction raw materials to react in the presence of an organic solvent, a catalyst, a ligand and an additive to obtain a product gamma-alkenyl ketone; the reaction equation of the synthesis method is as follows:

wherein:

R ₁hydrogen atom, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, cycloalkyl, phenyl substituted by alkyl, phenyl substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, phenyl substituted by aromatic ring or aromatic heterocyclic ring, aromatic heterocyclic group and the like;

R ₂is hydrogen atom, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen atom substituted phenyl, aromatic heterocyclic radical, acyl, nitrile group, amide group, carboxyl group, etc.

Preferably, the first and second electrodes are formed of a metal,

R ₁hydrogen atom, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N-dimethyl substituted phenyl, fluorine substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl;

R ₂hydrogen atom, C1-C6 alkyl and phenyl.

It is further preferred that the first and second liquid crystal compositions,

R ₁is hydrogen atom, methyl, ethyl, isopropyl, cyclohexyl, phenyl, p-methylphenyl, p-ethoxyphenyl, p-N, N-dimethylphenyl, p-fluorophenylP-trifluoromethylphenyl, m-methylphenyl, m-methoxyphenyl, 1-naphthyl, 2-naphthyl, 3, 5-dimethylphenyl, 3, 5-difluorophenyl, furyl, thienyl, ferrocenyl;

R ₂hydrogen atom, methyl, n-propyl and phenyl.

In the invention, the ketone compound comprises acetone, cyclopentanone, cyclohexanone, cyclododecanone, 3-pentanone, cyclohexyl methyl ketone, furyl methyl ketone, various indanones, thiazolyl methyl ketone, acetophenone, various substituted phenyl methyl ketones and various aryl methyl ketones.

The invention adopts water or fatty alcohol as the only additive, avoids the use of alkali metal and strong alkali which are easy to cause waste and pollutants, not only ensures that the reaction system is green and has low pollution, but also ensures that the reaction can occur under the condition of neutral pH, and can realize wider compatibility of substrate functional groups.

In the reaction of the invention, enol ketone generated by double activation of metal to ketone and 1, 3-butadiene attacks pi-allyl nickel nucleophilically, and α -allyl alkylation product with high yield and high regioselectivity is formed by further reduction elimination.

In the invention, the solvent is one or more of CPME, toluene, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, 1, 2-dichloroethane, ethyl acetate, methanol, ethanol and the like; preferably, it is CPME.

In the present invention, the catalyst is a metal catalyst selected from the group consisting of Ni (COD) ₂。

In the invention, the ligand is a bidentate or monodentate ligand with better coordination effect with nickel; preferably, are azacarbene ligands IMes.

In the invention, the additive is H ₂O, methanol, ethanol, isopropanol, phenol, or other types of aliphatic alcohols, or molecules containing alcoholic hydroxyl groups; preferably, is H ₂O。

In the present invention, the ketone: 1, 3-butadiene: additive: catalyst: the molar ratio of the ligands is 1: (2-5): (1.0-10): (0.01-0.1): (0.01-0.1); preferably 1.0:3.0:1.0:0.1: 0.1.

In the invention, the addition amount of the organic solvent is 0.5mL/mmol based on the use amount of the ketone.

In the invention, the reaction temperature is 90-130 ℃; preferably 130 deg.c.

In the invention, the reaction time is 2-24 h; preferably, it is 2 h.

The invention also comprises a post-processing step: and (3) carrying out column chromatography on the crude reaction liquid obtained by the reaction by using a solution with the volume ratio of diethyl ether to petroleum ether being 1: 100-1: 200, and obtaining the gamma-alkenyl ketone with high yield and high regioselectivity.

The method for separating and purifying the crude product in the method comprises the step of carrying out column chromatography on the crude reaction liquid by using a mobile phase with the volume ratio of diethyl ether to petroleum ether being 1: 100-1: 200.

In a specific embodiment, the synthesis of the gamma-alkenyl ketones of the present invention comprises: in a glove box, a metal catalyst Ni (COD) ₂(0.02mmol,0.1eq) and the cocatalyst (ligand) are IMes (0.02mmol,0.1eq) dissolved in solvent CPME (0.2mL), stirred at room temperature for 5 minutes and then added with ketone (0.2mmol,1.0eq), 1, 3-butadiene (0.6mmol,3eq) and water (0.2mmol,1eq) in sequence; reacting the reaction solution at 130 ℃ for 2h, cooling to room temperature, and performing column chromatography on the crude reaction solution by using a solution with a volume ratio of diethyl ether to petroleum ether being 1: 100-1: 200 to obtain a pure target product, wherein the reaction process is shown as the following formula (B):

wherein R is ₁、R ₂Is as defined in formula (A).

The invention also provides gamma-alkenyl ketone, the structure of which is shown as the formula (3 a):

wherein:

r1 is a hydrogen atom, a linear alkane substituent substituted with an oxygen atom, a nitrogen atom, a boron atom, a silicon atom or a halogen atom, a cycloalkyl group, a phenyl group, an alkyl-substituted phenyl group, a phenyl group substituted with an oxygen atom, a nitrogen atom, a boron atom, a silicon atom or a halogen atom, an aromatic ring-or aromatic heterocyclic-substituted phenyl group, an aromatic heterocyclic group or the like;

R ₂is hydrogen atom, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen atom substituted phenyl, aromatic heterocyclic radical, acyl, nitrile group, amide group, carboxyl group, etc.

Preferably, the first and second electrodes are formed of a metal,

R ₁hydrogen atom, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N-dimethyl substituted phenyl, fluorine substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl;

R ₂hydrogen atom, C1-C6 alkyl and phenyl.

It is further preferred that the first and second liquid crystal compositions,

r1 is hydrogen atom, methyl, ethyl, isopropyl, cyclohexyl, phenyl, p-methylphenyl, p-ethoxyphenyl, p-N, N-dimethylphenyl, p-fluorophenyl, p-trifluoromethylphenyl, m-methylphenyl, m-methoxyphenyl, 1-naphthyl, 2-naphthyl, 3, 5-dimethylphenyl, 3, 5-difluorophenyl, furyl, thienyl, ferrocenyl;

r2 is hydrogen atom, methyl, n-propyl, phenyl.

The invention also provides application of the gamma-alkenyl ketone in synthesizing a drug intermediate and the like.

The synthesis method of the invention can be used for the structure optimization and synthesis of a plurality of bioactive substances.

The reaction mechanism involved in the invention is as follows: the nucleophilic attack of enol ketone generated by double activation of metal to ketone and 1, 3-butadiene to pi-allyl nickel further eliminates by reduction to form gamma-alkenyl ketone with high yield and high regioselectivity.

The beneficial effects of the invention include: the reaction being carried out in the presence of a metal catalyst, a ligand and an additiveConditional one-step construction of gamma-alkenyl ketones, this conversion being carried out under neutral conditions without base and redox, using only H ₂The synthesized α -allyl alkylation product can be used as a chemical and chemical synthesis intermediate to obtain products which are difficult to obtain by other methods through further reaction, and has strong economic applicability.

Detailed Description

The following examples are given to illustrate specific applications of the present invention and are not intended to be limiting. Without prejudice to the spirit of the invention, the most powerful products of the invention, both potential and valuable, are embraced by the following description, which is set forth in the appended claims.