阅读说明：本技术 一种以芳香醛为底物合成喹唑啉类化合物的方法 (Method for synthesizing quinazoline compound by taking aromatic aldehyde as substrate ) 是由 张方林 刘娜 于 2020-06-24 设计创作，主要内容包括：本发明提供了一种以芳香醛为底物合成喹唑啉类化合物的方法,具体包括以下步骤：1)以式Ⅰ所示的芳香醛为起始物料,在钌催化剂的催化作用下与N-芳磺酰氧基邻苯二甲酰亚胺进行交叉偶联反应,得到式Ⅱ所示中间体；2)式Ⅱ所示的中间体与氨化试剂进行氨化反应得到式Ⅲ所示的喹唑啉衍生物。合成路线如下：<Image he="130" wi="700" file="DDA0002556082240000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a method for synthesizing a quinazoline compound by taking aromatic aldehyde as a substrate, which specifically comprises the following steps: 1) taking aromatic aldehyde shown as a formula I as an initial material, and carrying out cross coupling reaction with N-aryl sulfonyl phthalimide under the catalytic action of a ruthenium catalyst to obtain an intermediate shown as a formula II; 2) and carrying out an amination reaction on the intermediate shown in the formula II and an amination reagent to obtain the quinazoline derivative shown in the formula III. The synthetic route is as follows:)

1. A method for synthesizing quinazoline compounds by taking aromatic aldehyde as a substrate is characterized in that the synthetic route is as follows:

wherein ring A is phenyl, thienyl, furyl or pyridyl;

r is hydrogen, halogen, alkane with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, and is positioned at the ortho-position or meta-position of the aldehyde group, or is positioned in the disubstituted position of any two positions of the ring A;

the method specifically comprises the following steps:

1) taking aromatic aldehyde shown as a formula I as an initial material, and carrying out cross coupling reaction with N-aryl sulfonyl phthalimide under the catalytic action of a ruthenium catalyst to obtain an intermediate shown as a formula II;

2) and carrying out an amination reaction on the intermediate shown in the formula II and an amination reagent to obtain the quinazoline derivative shown in the formula III.

2. The method for synthesizing quinazoline compounds using aromatic aldehyde as a substrate according to claim 1, wherein the molar ratio of the aromatic aldehyde to the N-arylsulfonylphthalimide in the step 1) is 1: 1 to 3.

3. The method for synthesizing quinazoline compounds using aromatic aldehyde as a substrate according to claim 1, wherein the cross-coupling reaction conditions in step 1) are as follows: dissolving aromatic aldehyde and N-arylsulphonoyloxyphthalimide in a solvent, adding a ruthenium catalyst, a silver salt oxidant, an alkali additive and an aniline compound, and reacting at 80-120 ℃ for 12-48 h.

4. The method for synthesizing quinazoline compounds according to claim 3, wherein the solvent is one of toluene, dichloromethane, chloroform, 1, 4-dioxane, ethylene glycol dimethyl ether, and 1, 2-dichloroethane, and the mass ratio of the solvent volume to the aromatic aldehyde is 8-100 mL/g.

5. The method for synthesizing quinazoline compounds according to claim 3, wherein the ruthenium catalyst is selected from one of ruthenium trichloride, ruthenium acetate, ruthenium (II) trinitronitrosyl, and bis (4-methylisoprophenyl) dichloride ruthenium, and the amount of the catalyst is 0.5-5% by mole of the aromatic aldehyde.

6. The method for synthesizing quinazoline compounds according to claim 3, wherein the silver salt oxidant is selected from one of silver carbonate, silver hexafluoroantimonate and silver nitrate, and the amount of the silver salt oxidant is 0.1-1 times of the molar amount of the aromatic aldehyde.

7. The method for synthesizing quinazoline compounds according to claim 3, wherein the alkali additive is selected from one of lithium acetate, lithium carbonate, sodium acetate and potassium acetate, and the amount of the alkali additive is 0.1-1 times of the molar amount of the aromatic aldehyde.

8. The method for synthesizing quinazoline compounds according to claim 3, wherein the aniline compounds are aniline derivatives whose benzene ring is mono-or poly-substituted with halogen, nitro or trifluoromethyl.

9. The method for synthesizing quinazoline compounds according to claim 1, wherein the ammoniation reagent in step 2) is ammonium acetate or NH₃Methanol solution (from NH)₃Dissolved in methanol) to obtain the NH₃The methanol solution of (2) had a concentration of 33 wt%; step 2), the molar ratio of the intermediate shown in the formula II to ammonium acetate is 1: 3-5, wherein the mass ratio of the intermediate shown in the formula II to the anhydrous methanol solution containing 33% of ammonia is 1: 1 to 3.

10. The method for synthesizing quinazoline compounds using aromatic aldehyde as a substrate according to claim 1, wherein the reaction conditions in step 2) are as follows: dissolving an intermediate shown as a formula II and an ammoniation reagent in a solvent, and reacting for 12-24h at 40-70 ℃; the solvent is selected from one of methanol, ethanol, isopropanol and n-butanol, and the mass ratio of the volume of the solvent to the intermediate shown in the formula II is 15-50 mL/g.

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a simple method for obtaining a quinazoline compound by activating C-H bonds at ortho positions of aromatic aldehyde by using the aromatic aldehyde as a substrate.

Background

Quinazoline structures are important nitrogen-containing heterocyclic compounds, which are commonly found in natural products and medicines with antimalarial, antitumor, antibacterial, antihypertensive, anticonvulsant and antitubercular effects, and the following medicines all contain quinazoline structures:

in the past decades, various methods have been developed for the synthesis of quinazoline compounds. The traditional methods generally use aniline as a substrate, and obtain quinazoline derivatives by condensation or coupling:

such reactions suffer from a number of limitations, such as higher reaction temperature, poor substrate adaptability, difficult availability of part of the substrate, and low yield. Thus, the development of new efficient and environmentally friendly methods for obtaining quinazolines from stable and readily available substrates remains a major challenge in the field of synthesis.

Disclosure of Invention

The invention aims to solve the technical problem of providing a synthetic method of quinazoline derivatives with strong substrate universality, cheap materials and easy obtainment aiming at the defects in the prior art, and the method has simple steps and high conversion efficiency.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

provides a method for synthesizing quinazoline compounds by using aromatic aldehyde as a substrate, and the synthetic route is as follows:

wherein ring A is phenyl, thienyl, furyl or pyridyl;

r is hydrogen, halogen, alkane with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, and is positioned at the ortho-position or meta-position of the aldehyde group, or is positioned in the disubstituted position of any two positions of the ring A;

the method specifically comprises the following steps:

1) taking aromatic aldehyde shown as a formula I as an initial material, and carrying out cross coupling reaction with N-aryl sulfonyl phthalimide under the catalytic action of a ruthenium catalyst to obtain an intermediate shown as a formula II;

2) and carrying out an amination reaction on the intermediate shown in the formula II and an amination reagent to obtain the quinazoline derivative shown in the formula III.

According to the scheme, the molar ratio of the aromatic aldehyde to the N-aromatic sulfonyl acyloxy phthalimide in the step 1) is 1: 1 to 3. The structural formula of the N-arylsulfonylphthalimide is as follows:

is abbreviated as

According to the scheme, the cross-coupling reaction conditions in the step 1) are as follows: dissolving aromatic aldehyde and N-arylsulphonoyloxyphthalimide in a solvent, adding a ruthenium catalyst, a silver salt oxidant, an alkali additive and an aniline compound, and reacting at 80-120 ℃ for 12-48 h.

According to the scheme, the solvent is one of toluene, dichloromethane, trichloromethane, 1, 4-dioxane, ethylene glycol dimethyl ether and 1, 2-dichloroethane, and the mass ratio of the volume of the solvent to the aromatic aldehyde is 8-100 mL/g.

According to the scheme, the ruthenium catalyst is selected from one of ruthenium trichloride, ruthenium acetate, ruthenium (II) trinitronitrosyl and dichlorobis (4-methyl isopropylphenyl) ruthenium, and the dosage of the catalyst is 0.5-5% of the molar weight of aromatic aldehyde.

According to the scheme, the silver salt oxidant is one selected from silver carbonate, silver hexafluoroantimonate and silver nitrate, and the dosage of the silver salt oxidant is 0.1-1 time of the molar quantity of the aromatic aldehyde.

According to the scheme, the alkali additive is selected from one of lithium acetate, lithium carbonate, sodium acetate and potassium acetate, and the using amount of the alkali additive is 0.1-1 time of the molar amount of the aromatic aldehyde. The alkali additive is complexed with a metal catalyst to activate the C-H bond at the ortho position of the benzaldehyde.

According to the scheme, the aniline compound is an aniline derivative with a benzene ring being mono-substituted or multi-substituted by halogen, nitryl or trifluoromethyl. The aniline and the aromatic aldehyde form an imine structure and play a role of a guide group. The aldehyde group is a weak guiding group, and the aniline compound can be condensed with the aldehyde group to form an imine structure with strong guiding effect, namely a transient guiding group, so that the C-H bond at the ortho position of the aromatic aldehyde is activated.

Preferably, the aniline compound is selected from one of 2-fluoro-5-trifluoromethylaniline, 2-fluoro-aniline, 2-trifluoromethylaniline, and 2-chloroaniline, and the amount of the aniline compound is 0.3 to 1 time of the molar amount of the aromatic aldehyde.

According to the scheme, the ammoniation reagent in the step 2) is ammonium acetate or NH₃Methanol solution (from NH)₃Dissolved in methanol) to obtain the NH₃The concentration of the methanol solution of (2) was 33 wt%.

According to the scheme, the molar ratio of the intermediate shown in the formula II in the step 2) to ammonium acetate is 1: 3-5, wherein the mass ratio of the intermediate shown in the formula II to the anhydrous methanol solution containing 33% of ammonia is 1: 1 to 3.

According to the scheme, the reaction conditions in the step 2) are as follows: dissolving the intermediate shown in the formula II and an ammoniation reagent in a solvent, and reacting for 12-24h at 40-70 ℃.

According to the scheme, the solvent is selected from one of methanol, ethanol, isopropanol and n-butanol, and the mass ratio of the volume of the solvent to the intermediate shown in the formula II is 15-50 mL/g.

The method comprises the steps of taking aromatic aldehyde shown as a formula I as an initial material, activating an ortho-position C-H bond under the catalysis of a ruthenium metal catalyst, carrying out cross coupling reaction with N-arylsulfonyloxy phthalimide to obtain an intermediate shown as a formula II, and carrying out an ammoniation reaction on the intermediate shown as the formula II and an ammoniation reagent to obtain a quinazoline derivative shown as a formula III.

Specifically, the mechanism of the cross-coupling reaction is as follows:

firstly, aromatic aldehyde and aniline compound are condensed to form reversible imine A, silver salt oxidant is oxidized, ruthenium catalyst and alkali additive are complexed to form active substance B, and then, imine A is ortho-position C (sp)²) H activation to form critical metalsA five-membered ring C. Then, N-arylsulfonyloxyphthalimide 2a migrates to insert coordination to form a six-membered intermediate E. And (3) carrying out protonolysis on the intermediate E under the action of alkali, and leaving metal to obtain an imine substance F with the ortho-position of a benzene ring substituted by phthalimide. Then the imine is automatically dissociated, and the aldehyde group is recovered to obtain the aromatic aldehyde derivative with ortho-position substituted by phthalimide.

The invention has the beneficial effects that: the method takes cheap and easily-obtained aromatic aldehyde and N-arylsulfonyloxy phthalimide as starting materials, adopts an instant guide group strategy, carries out C-H bond activation and functional group construction under the catalysis of a ruthenium catalyst, has mild reaction conditions and high conversion efficiency (the cross-coupling reaction yield reaches 71-89% under short reaction time and the ammonification reaction yield reaches about 80%), overcomes the defect that the requirement for constructing a quinazoline reaction substrate by using a metal catalyst in the prior art is relatively strict, and provides a method for synthesizing the quinazoline compound, which has simple steps, strong substrate universality and cheap and easily-obtained materials.

Drawings

FIG. 1 is a diagram of Compound 1-a prepared in example 1 of the present invention¹An H-NMR spectrum;

FIG. 2 is a diagram of Compound 1-a prepared in example 1¹³A C-NMR spectrum;

FIG. 3 is a photograph of Compound 1 prepared in example 1¹An H-NMR spectrum;

FIG. 4 is a photograph of Compound 1 prepared in example 1¹³A C-NMR spectrum;

FIG. 5 is a photograph of Compound 2-a prepared in example 2¹An H-NMR spectrum;

FIG. 6 is a photograph of Compound 2-a prepared in example 2¹³A C-NMR spectrum;

FIG. 7 is a photograph of Compound 3-a prepared in example 3¹An H-NMR spectrum;

FIG. 8 is a photograph of Compound 3-a prepared in example 3¹³A C-NMR spectrum;

FIG. 9 is a photograph of Compound 4-a prepared in example 4¹An H-NMR spectrum;

FIG. 10 is the preparation of example 4Of Compound 4-a¹³C-NMR spectrum.

Detailed Description

In order to make the technical solutions of the present invention better understood, the present invention is further described in detail below with reference to the accompanying drawings.