阅读说明：本技术 含吡喃和中环骨架的三环稠合芳香体系化合物及其合成和应用 (Tricyclic condensed aromatic system compound containing pyran and medium ring skeleton and synthesis and application thereof ) 是由 李艳忠 杨亚婕 尹利强 宋博 王孟丹 徐穆榕 于 2020-04-29 设计创作，主要内容包括：本发明公开了一种包含吡喃和中环骨架的三环稠合芳香体系化合物及其合成方法。所述合成方法采用“一锅两步法”,具体为,首先通过碱促进环状酮类化合物的C-C键切断得到七、八元环类扩环产物,接下来与第三组分丁炔二酯类化合物进行分子内的环加成反应以及羟基迁移。本发明制备方法具有高效经济、操作简单、原料简单易得、普适性好、收率良好、对环境友好等优点。本发明还提供了式(I)含吡喃和中环骨架的三环稠合芳香体系化合物在药物研发和材料发展中的潜在应用价值。(The invention discloses a tricyclic fused aromatic system compound containing pyran and a medium-ring skeleton and a synthesis method thereof. The synthesis method adopts a one-pot two-step method, and specifically comprises the steps of firstly promoting the C-C bond of a cyclic ketone compound to be cut off through alkali to obtain seven-membered and eight-membered ring expanded products, and then carrying out intramolecular cycloaddition reaction and hydroxyl migration with a third component butynediol compound. The preparation method has the advantages of high efficiency, economy, simple operation, simple and easily obtained raw materials, good universality, good yield, environmental friendliness and the like. The invention also provides the potential application value of the tricyclic condensed aromatic system compound containing pyran and medium ring skeleton in the formula (I) in the research and development of medicines and materials.)

1. The tricyclic fused aromatic system compound containing pyran and a medium ring skeleton is characterized in that the structure is shown as the formula (I):

wherein the content of the first and second substances,

R¹is phenyl, alkyl substituted phenyl, alkoxy substitutedPhenyl, halogen-substituted phenyl, naphthyl;

R²is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl;

R³hydrogen, phenyl, alkyl substituted phenyl, halogen substituted phenyl;

R⁴is an alkyl group;

R⁵is ester group, carbonyl group or cyano group.

2. The tricyclic fused aromatic system compound having a pyran and a monocyclic skeleton according to claim 1, wherein R is¹Is phenyl, methyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, naphthyl; r²Is phenyl, methyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl; r³Hydrogen, phenyl, methyl-substituted phenyl, halogen-substituted phenyl; r⁴Is methyl or ethyl; r⁵Is ester group, carbonyl group or cyano group.

3. The tricyclic fused aromatic system compound having a pyran and a monocyclic skeleton according to claim 1, wherein R is¹Is phenyl, p-methylphenyl, p-chlorophenyl, 3, 4-dimethoxyphenyl, naphthyl; r²Is phenyl, p-methylphenyl, p-methoxyphenyl; r³Is phenyl, meta-methylphenyl, hydrogen; r⁴Is methyl, ethyl; r⁵Ethyl acetate and cyano.

4. A synthetic method of a tricyclic condensed aromatic system compound containing pyran and a middle ring skeleton is characterized in that in the first step, in a solvent, an alkynone compound and a cyclic ketone compound are used as raw materials, and a C-C bond cutting reaction is carried out under the promotion action of alkali to obtain a ring expanding reaction intermediate; secondly, adding a butynediol diester compound for reaction to obtain a tricyclic condensed aromatic system compound containing pyran and a medium ring skeleton shown in the formula (I), wherein the reaction process is shown in the formula (II):

wherein the content of the first and second substances,

R¹is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, naphthyl;

R²is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl;

R³hydrogen, phenyl, alkyl substituted phenyl, halogen substituted phenyl;

R⁴is an alkyl group;

R⁵is ester group, carbonyl group or cyano group.

5. The synthetic method of claim 4 wherein R is¹Is phenyl, methyl substituted phenyl, methoxy substituted phenyl, chlorine substituted phenyl, naphthyl; r²Is phenyl, methyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl; r³Hydrogen, phenyl, methyl-substituted phenyl, halogen-substituted phenyl; r⁴Is methyl or ethyl; r⁵Is ester group, carbonyl group or cyano group.

6. The method of synthesis of claim 4, wherein the base is a promoter and the base comprises K₂CO₃、Na₂CO₃、Cs₂CO₃、NaOH、^tBuOK。

7. The method of claim 4, wherein the solvent is N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, 1, 2-dichloroethane, or toluene.

8. The synthesis process according to claim 4, characterized in that the reaction temperature in the first step is between 30 and 70 ℃; and/or, in the second step, the temperature of the reaction is 30-70 ℃.

9. The synthesis method according to claim 4, wherein the reaction time in the first step is 1h to 3 h; and/or, in the second step, the reaction time is 1h-3 h.

10. The method of synthesis according to claim 4, wherein the acetylenic ketone compound: cyclic ketone compounds: butyne diester compounds: the molar ratio of the alkali is 1: (1.0-1.7): (2.5-3.5): (0.5-3.0).

Technical Field

The invention belongs to the technical field of organic compounds and synthesis, and relates to synthesis and application of a tricyclic condensed aromatic system compound containing pyran and a medium ring skeleton, which is synthesized by three groups of hierarchical combined reactions promoted by alkali.

Background

Fused cyclic compounds hold an important position in modern organic chemistry, are widely present in natural products, and are the main structural units of many material molecules and drug molecules. Therefore, the development of new methods for constructing various cyclic compounds easily and efficiently has been the focus of research in the field of organic synthesis and pharmaceutical chemistry. On one hand, the seven-membered ring compound and the eight-membered ring compound are main structural units of a plurality of natural products and medicines, mostly have stronger biological activity, have important functions in the field of medicine, and can be used for researches on transmembrane tyrosine kinase, anti-inflammatory, antiviral and antitumor medicines and the like. On the other hand, as is well known, pyran compounds are an important class of oxygen-containing heterocyclic compounds, are important structural units of a plurality of natural products, synthetic drugs, candidate drugs and functional materials, and molecules containing pyran skeletons are general intermediates in organic synthesis and can be used for producing bioactive molecules aiming at different targets. Therefore, developing a simple and efficient method by which a fused ring compound fused with a seven-eight membered ring and a pyran skeleton can be prepared is an important means for enriching active drug molecules and functional material molecules.

Cyclic compounds have broad prospects in medicinal chemistry, but unstable trans-cyclic interactions and entropy reduction during cyclization make preparation by traditional cyclization methods difficult. Thus, ring expansion reactions are increasingly being used to synthesize seven-eight membered ring compounds. For example: documents (1) c.kitsio, j.j.hindes, p.i' Anson, p.jackson, t.c.wilson, e.k.daly, h.r.felstead, p.hearnshaw, w.p.unscorth, angelw.chem.int.ed.2015, 54,15794; (2) y.zhou, y. -l.wei, j.rodriguez, y.coquerel, angelw.chem.int.ed.2019, 58,456. There are also many reports on the synthesis of pyran rings, such as: document (1) Gu, h; sun, x.; wang, y.; wu, h.; wu, p.rscadv.2018,8,1737; (2) xie, j.; xing, w.l.; sha, f.; wu, x.y.eur.j.org.chem.2016, 3983-399. the prior art also has disadvantages such as complicated and difficult-to-prepare reaction raw materials, severe reaction conditions, limited substrate range, expensive reaction reagents, etc. Therefore, it is necessary to develop a more economical, simple and mild reaction condition method for preparing tricyclic fused aromatic system compounds containing pyran and medium ring skeleton.

Disclosure of Invention

The invention aims to provide synthesis and application of a tricyclic fused aromatic system compound containing pyran and a medium-ring framework, which are realized by taking an alkynone, a cyclic ketone compound and a butyndiester compound as raw materials and realizing three-component reaction through a 'one-pot two-step method' only under the promotion of alkali, wherein C-C bond cutting, intermolecular cycloaddition reaction and hydroxyl migration, and the tricyclic fused aromatic system compound containing the pyran and the medium-ring framework is efficiently and conveniently obtained.

The invention provides an unreported tricyclic condensed aromatic system compound containing pyran and a medium ring framework, which has a structure shown in a formula (I):

wherein the content of the first and second substances,

R¹is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, naphthyl;

R²is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl;

R³hydrogen, phenyl, alkyl substituted phenyl, halogen substituted phenyl;

R⁴is an alkyl group;

R⁵is ester group, carbonyl group or cyano group.

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

R¹is phenyl, methyl substituted phenyl, methoxy substituted phenyl, chlorine substituted phenyl, naphthyl;

R²is phenyl, methyl substituted phenyl, methoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl;

R³hydrogen, phenyl, methyl-substituted phenyl, halogen-substituted phenyl;

R⁴is methyl or ethyl;

R⁵is ester group, carbonyl group or cyano group.

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

R¹is phenyl, p-methylphenyl, p-chlorophenyl, 3, 4-dimethoxyphenyl, naphthyl;

R²is phenyl, p-methylphenyl, p-methoxyphenyl;

R³is phenyl, meta-methylphenyl, hydrogen;

R⁴is methyl, ethyl;

R⁵ethyl acetate and cyano.

The invention also provides a preparation method of the tricyclic condensed aromatic system compound containing pyran and mid-ring skeleton shown in formula (I), which comprises the following steps of firstly, taking an alkynone compound and a cyclic ketone compound as raw materials in a solvent, and reacting under the promotion action of alkali to obtain a ring expanding reaction intermediate; secondly, adding a butynediol diester compound for reaction to obtain a tricyclic condensed aromatic system compound containing pyran and a medium ring skeleton shown in the formula (I), wherein the reaction process is shown in the reaction formula (II):

wherein the content of the first and second substances,

R¹is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, naphthyl;

R²is phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, cyano substituted phenyl, trifluoromethyl substituted phenyl;

R³hydrogen, phenyl, alkyl substituted phenyl, halogen substituted phenyl;

R⁴is an alkyl group;

R⁵is ester group, carbonyl group or cyano group.

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

R¹is phenyl, methyl substituted phenyl, methoxy substituted phenyl, chlorine substituted phenyl, naphthyl;

R²is phenyl, methyl-substituted phenyl, methoxy-substituted benzeneA group selected from the group consisting of halogen-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl;

R³hydrogen, phenyl, methyl-substituted phenyl, halogen-substituted phenyl;

R⁴is methyl or ethyl;

R⁵is ester group, carbonyl group or cyano group.

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

R¹is phenyl, p-methylphenyl, p-chlorophenyl, 3, 4-dimethoxyphenyl, naphthyl;

R²is phenyl, p-methylphenyl, p-methoxyphenyl;

R³is phenyl, meta-methylphenyl, hydrogen;

R⁴is methyl, ethyl;

R⁵ethyl acetate and cyano.

Wherein the alkynone compound is an alkynone compound with an electron-withdrawing substituent connected to a benzene ring, and an alkynone compound with an electron-donating substituent connected to a benzene ring; the cyclic ketone compound is cyclohexanone or cyclopentanone with electron-withdrawing substituent groups connected to the ortho-position of carbonyl group.

Wherein the base is an accelerator, and the base comprises K₂CO₃、Na₂CO₃、Cs₂CO₃、NaOH、^tBuOK, etc.; preferably, is K₂CO₃。

Wherein the solvent is N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, 1, 2-dichloroethane, toluene and the like; preferably, the solvent is N, N-dimethylformamide.

Wherein the reaction temperature in the first step is 30-70 ℃; preferably 50 deg.c.

Wherein the reaction time in the first step is 1-3 h; preferably, it is 3 h.

Wherein the reaction temperature in the second step is 30-70 ℃; preferably 50 deg.c.

Wherein the reaction time in the second step is 1-3 h; preferably, it is 3 h.

Wherein the alkynone compound: cyclic ketone compounds: butyne diester compounds: the molar ratio of the alkali is 1: (1.0-1.7): (2.5-3.5): (0.5-3.0). Preferably, the acetylenic ketone compound: cyclic ketone compounds: butyne diester compounds: the molar ratio of the alkali is 1: 1.5: 3: 1.

among them, the reaction is preferably carried out under air.

In a preferred embodiment, the synthesis method of the present invention is: firstly, in a solvent, taking an alkynone compound and a cyclic ketone compound as raw materials, and carrying out C-C sigma-bond activation under the promotion action of alkali to obtain an intermediate of ring expansion reaction; secondly, adding a butynediol diester compound, performing intermolecular cycloaddition reaction and hydroxyl migration, and synthesizing to obtain a tricyclic condensed aromatic system compound containing pyran and a monocyclic skeleton as shown in the formula (I); the reaction is shown in the following reaction formula (II-1):

wherein R is¹、R²、R³、R⁴、R⁵Is as defined in formula (II).

The construction of seven-and eight-membered ring framework compounds by traditional cyclization methods is a very challenging research topic due to unfavorable ring-to-ring interactions and entropy reduction during cyclization. The prior synthesis method of the seven-membered ring compound and the eight-membered ring compound generally has the defects of complex raw materials, poor reaction selectivity, lower yield, harsh reaction conditions, expensive reaction reagents and the like. In addition, the pyran skeleton has important bioactivity and is an important oxygen-containing heterocyclic compound. Therefore, many studies on the synthesis of tricyclic fused aromatic system compounds containing a pyran and a medium-ring skeleton have been focused. The invention reports that the seven-and eight-membered ring compounds are obtained by alkali-promoted ring expansion reaction of the cyclic ketone compounds, and then the seven-and eight-membered ring compounds and the third component butynediol compound carry out intramolecular cycloaddition reaction and hydroxyl migration, and the construction of the pyran ring and the seven-and eight-membered ring compounds is simultaneously realized by a one-pot two-step method. The product has novel skeleton and potential application value in natural product synthesis, drug molecule modification, new drug research and development and functional material synthesis.

The invention has the following advantages: the synthesis method has the advantages of high efficiency, economy, simple operation, simple and easily obtained raw materials, good universality, good yield (72-87%), environmental friendliness and the like. The tricyclic condensed aromatic system compound containing pyran and a medium ring skeleton provided by the invention is a main structural unit in a plurality of natural products and medicines, and most of the tricyclic condensed aromatic system compound has stronger biological activity. Can be used for organic synthesis intermediates and has great research value in the aspect of drug synthesis.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.