Polysubstituted pyrrole derivative and preparation method thereof
阅读说明：本技术 一种多取代吡咯衍生物及其制备方法 (Polysubstituted pyrrole derivative and preparation method thereof ) 是由 金毅 罗开秀 林军 于翔林 程鹏 于 2019-11-27 设计创作，主要内容包括：一种多取代吡咯衍生物及其制备方法,涉及有机合成领域,该制备方法利用重氮类化合物或苯腙类化合物与氨基取代的不饱和羰基化合物反应,经过碳碳插入、环化反应及[1,5]迁移串级反应,成功构建吡咯环,高效高产率地得到了一系列的多取代吡咯衍生物。该制备方法的原料均可以通过简单反应得到,具有原料廉价易得的优势。同时,该制备方法条件温和、环境友好,适合进行规模化的生产,具有较好的应用价值。(A polysubstituted pyrrole derivative and its preparation method, relate to the organic synthetic field, said preparation method utilizes diazo compound or phenylhydrazone compound to react with unsaturated carbonyl compound substituted by amino, through carbon insertion, cyclization reaction and [1,5] migration cascade reaction, construct pyrrole ring successfully, have got a series of polysubstituted pyrrole derivatives with high efficiency and high yield. The raw materials of the preparation method can be obtained through simple reaction, and have the advantages of low price and easy obtainment of the raw materials. Meanwhile, the preparation method is mild in condition, environment-friendly, suitable for large-scale production and high in application value.)
1. The polysubstituted pyrrole derivative is characterized by having a structural formula
In the formula, R1、R3、R6The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R3、R6The number of (b) may be 1 to 3, and binding sites thereofAt least one of five unsubstituted positions on the benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r4、R5The alkyl groups are the same or different and are independently selected from C1-C6 alkyl groups or C1-C6 substituted alkyl groups.
2. The polysubstituted pyrrole derivative according to claim 1, wherein R is1、R3、R6The same or different from each other, each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, fluorine, chlorine, bromine or nitro; r2Selected from C1-C4 alkyl, C1-C4 substituted alkyl, phenyl or substituted phenyl; r4、R5The alkyl groups are the same or different and are independently selected from C1-C4 alkyl groups or C1-C4 substituted alkyl groups.
3. The polysubstituted pyrrole derivative according to claim 2, wherein R is1Selected from hydrogen, methyl, methoxy, fluoro, bromo or nitro; r2Selected from methyl, n-butyl, cyclopropyl or phenyl; r3Selected from hydrogen, methyl, methoxy, fluoro or chloro; r4Selected from methyl or ethyl; r5Selected from methyl or ethyl; r6Selected from hydrogen, methyl, fluorine or chlorine.
4. A method for preparing polysubstituted pyrrole derivatives, which comprises the following steps:
carrying out cyclization reaction on a compound I and a compound II, and rearranging to obtain the polysubstituted pyrrole derivative;
wherein the structural formula of the compound I is
In the formula, R1、R3The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R3The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r4Selected from C1-C6 alkyl or C1-C6 substituted alkyl.
5. The preparation method according to claim 4, wherein the reaction of the compound I and the compound II is carried out under the action of a metal catalyst, and the metal catalyst comprises any one of palladium acetate, rhodium acetate dimer, silver acetate, trifluoromethyl silver acetate, silver carbonate, silver nitrate, silver trifluoromethanesulfonate and silver fluoride; preferably, the amount of the metal catalyst is 3mol% to 10 mol%.
6. The polysubstituted pyrrole derivative according to claim 6, wherein said compound II solution is slowly added dropwise to said compound I, said metal catalyst mixed solution for reaction; preferably, the reaction temperature of the compound I and the compound II is 0-60 ℃.
7. A method for preparing polysubstituted pyrrole derivatives, which comprises the following steps:
carrying out cyclization reaction on a compound I and a compound III, and rearranging to obtain the polysubstituted pyrrole derivative;
wherein the structural formula of the compound I is
In the formula, R1、R6The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R6The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r5Selected from C1-C6 alkyl or C1-C6 substituted alkyl.
8. The production method according to claim 7, wherein the reaction of the compound I and the compound III is carried out under the action of a metal catalyst comprising any one of palladium acetate, rhodium acetate dimer, silver acetate, silver trifluoromethyl acetate, silver carbonate, silver nitrate, silver trifluoromethanesulfonate and silver fluoride, and a base comprising any one of lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; preferably, the amount of the metal catalyst is 3mol% to 10 mol%.
9. The production method according to claim 8, wherein the compound III is added dropwise to a mixed solution of the compound I, the metal catalyst, and the base to react; preferably, the reaction temperature of the compound I and the compound III is 60-130 ℃.
10. The preparation method according to claim 9, wherein the compound I is obtained by reacting compound IV with N, N-dimethylformamide formal to obtain the compound V; then reacting the compound V with a compound VI to obtain the compound;
wherein the structural formula of the compound IV is
In the formula, R1Selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl.
Technical Field
The invention relates to the field of organic synthesis, in particular to a polysubstituted pyrrole derivative and a preparation method thereof.
Background
Pyrrole is an important five-membered nitrogen-containing heterocyclic compound, widely exists in natural products and drug molecules, and is gradually applied deeply in material science. In 1857, pyrrole was first isolated from bone pyrolysis products, and heme, chlorophyll, bile pigment, pyrrolidide alkaloid and vitamin B12 containing pyrrole ring play irreplaceable important roles in the life process of animal and plant. In addition, compounds containing an azole ring are widely present in natural compounds such as alkaloids and proteins, and many compounds also contain an azole ring in natural dyes and drugs. The pyrrole structural unit is a common structural group of natural products, is a very important compound in a large number of natural products, and the compound containing the pyrrole ring shows various physiological activities and has extremely wide application value in the aspects of medicine and material science.
The pyrrole compounds have unique biological activity and wide application, so that the synthesis research of the compounds is greatly advanced in recent years, and common traditional synthesis methods comprise a Knorr synthesis method, a Paal-Knorr synthesis method, a Hantzseh synthesis method and the like. In recent decades, various methods for synthesizing azoles have been reported, however, as the application fields of azoles become wider and wider, simple and effective synthetic methods have been the targets of scientists. Modern methods for the synthesis of polysubstituted pyrroles are mainly based on transition metal catalyzed cyclization and multicomponent coupling reactions ([ 4+1], [3+2], [2+2+1] addition reactions). However, the raw materials in the reactions are complex to prepare, and an ideal synthesis strategy is to obtain the raw materials easily, to obtain the catalyst cheaply, to obtain the catalyst under mild reaction conditions and to reduce environmental pollution.
Therefore, it would be very valuable to develop a strategy for the efficient synthesis of polysubstituted pyrrole derivatives from simple and readily available starting materials.
Disclosure of Invention
The invention aims to provide a polysubstituted pyrrole derivative which has a novel structure, is simple and easy to prepare and has better application potential in the fields of medicine, material science and the like.
The invention also aims to provide a preparation method of the polysubstituted pyrrole derivative, which has the advantages of simple and easily obtained raw materials, friendly reaction environment, convenience, high efficiency and better industrial application prospect.
The embodiment of the invention is realized by the following steps:
a polysubstituted pyrrole derivative has a structural formula
In the formula, R1、R3、R6The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R3、R6The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r4、R5The alkyl groups are the same or different and are independently selected from C1-C6 alkyl groups or C1-C6 substituted alkyl groups.
A process for the preparation of a polysubstituted pyrrole derivative comprising:
carrying out cyclization reaction on the compound I and the compound II, and rearranging to obtain a polysubstituted pyrrole derivative;
wherein the structural formula of the compound I is
In the formula, R1、R3The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R3The number of the (b) can be 1-3, and the binding sites are five unsubstituted sites on a benzene ringAt least one of; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r4Selected from C1-C6 alkyl or C1-C6 substituted alkyl.
A process for the preparation of a polysubstituted pyrrole derivative comprising:
carrying out cyclization reaction on the compound I and the compound III, and rearranging to obtain a polysubstituted pyrrole derivative;
wherein the structural formula of the compound I is
In the formula, R1、R6The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R6The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r5Selected from C1-C6 alkyl or C1-C6 substituted alkyl.
The embodiment of the invention has the beneficial effects that:
the embodiment of the invention provides a polysubstituted pyrrole derivative and a preparation method thereof, the preparation method utilizes a diazo compound or a phenylhydrazone compound to react with an amino-substituted unsaturated carbonyl compound, and a pyrrole ring is successfully constructed through carbon-carbon insertion, cyclization reaction and [1,5] migration cascade reaction, so that a series of polysubstituted pyrrole derivatives are obtained efficiently and at high yield. The raw materials of the preparation method can be obtained through simple reaction, and have the advantages of low price and easy obtainment of the raw materials. Meanwhile, the preparation method is mild in condition, environment-friendly, suitable for large-scale production and high in application value.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The polysubstituted pyrrole derivative and the preparation method thereof according to the embodiment of the present invention will be described in detail below.
The embodiment of the invention provides a polysubstituted pyrrole derivative with a structural formula
In the formula, R1、R3、R6The alkyl groups are the same or different and are independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro. R2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r4、R5The alkyl groups are the same or different and are independently selected from C1-C6 alkyl groups or C1-C6 substituted alkyl groups. The C1-C6 alkyl group can be a straight-chain alkyl group or a branched-chain alkyl group, and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, tert-butyl and the like. The C1-C6 substituted alkyl refers to a C1-C6 alkyl group in which at least one hydrogen atom is substituted by halogen, hydroxyl, alkoxy or aryl. C1-C6 alkoxy includes but is not limited to methoxy, ethoxy, propoxy, butoxy, and the like. The C1-C6 substituted alkoxy refers to a group formed by substituting at least one hydrogen atom in C1-C6 alkyl by halogen, hydroxyl, alkoxy or aryl, and includes but is not limited to 2-methoxyethoxy and 3-methoxypropoxy.
Further, R1、R3、R6All can be1 to 3, and the binding site is at least one of five unsubstituted sites on the benzene ring. With R1By way of example, that is, there may be a single R on the same phenyl ring1Substituted by radicals, also 2 or 3R1And (4) substituting the group. In the presence of 2 or 3R1Is substituted by radicals, each R1The groups may be the same or different groups.
Preferably, R1、R3、R6The same or different from each other, each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, fluorine, chlorine, bromine or nitro; r2Selected from C1-C4 alkyl, C1-C4 substituted alkyl, phenyl or substituted phenyl; r4、R5The alkyl groups are the same or different and are independently selected from C1-C4 alkyl groups or C1-C4 substituted alkyl groups.
More preferably, R1Selected from hydrogen, methyl, methoxy, fluoro, bromo or nitro; r2Selected from methyl, n-butyl, cyclopropyl or phenyl; r3Selected from hydrogen, methyl, methoxy, fluoro or chloro; r4Selected from methyl or ethyl; r5Selected from methyl or ethyl; r6Selected from hydrogen, methyl, fluorine or chlorine.
The embodiment of the invention also provides a preparation method of the polysubstituted pyrrole derivative, which comprises the following steps:
carrying out cyclization reaction on the compound I and the compound II, and rearranging to obtain a polysubstituted pyrrole derivative;
wherein the structural formula of the compound I isThe structural formula of the compound II is
In the formula, R1、R3The same or different, each independently selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkylC1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R3The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r4Selected from C1-C6 alkyl or C1-C6 substituted alkyl.
Further, the reaction of the compound I and the compound II is carried out under the action of a metal catalyst, wherein the metal catalyst comprises any one of palladium acetate, rhodium acetate dimer, silver acetate, trifluoromethyl silver acetate, silver carbonate, silver nitrate, silver trifluoromethanesulfonate and silver fluoride; the dosage of the metal catalyst is 3-10 mol%.
Alternatively, the reaction is carried out by slowly dropping a solution of the compound II into a mixed solution of the compound I and the metal catalyst. The solvent for the reaction may be at least one of tetrahydrofuran, 1, 4-dioxane, chloroform, dichloromethane, and toluene. The molar ratio of compound I to compound II is 1: 1.5 to 2.5. The reaction temperature of the compound I and the compound II is 0-60 ℃. Under the reaction conditions, the reaction effect of the compound I and the compound II is better, and the polysubstituted pyrrole derivative can be obtained efficiently and with high yield.
The embodiment of the invention also provides another preparation method of the polysubstituted pyrrole derivative, which comprises the following steps:
carrying out cyclization reaction on the compound I and the compound III, and rearranging to obtain a polysubstituted pyrrole derivative;
wherein the structural formula of the compound I is
In the formula, R1、R6Are identical to each other orIndependently, each is selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1、R6The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl; r5Selected from C1-C6 alkyl or C1-C6 substituted alkyl.
Further, the reaction of compound I and compound III is carried out under the action of a metal catalyst and a base, the metal catalyst includes any one of palladium acetate, rhodium acetate dimer, silver acetate, silver trifluoromethyl acetate, silver carbonate, silver nitrate, silver trifluoromethanesulfonate and silver fluoride, and the base includes any one of lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate. Preferably, the metal catalyst is used in an amount of 3mol% to 10 mol%. The molar weight of the alkali is 1-1.5 times of that of the compound I.
Alternatively, the compound III is added dropwise into a mixed solution of the compound I, the metal catalyst and the base for reaction. The solvent for the reaction comprises at least one of xylene, N-dimethylformamide, toluene and 1, 4-dioxane. The molar ratio of compound I to compound III is 1: 1-2, and the reaction temperature is 60-130 ℃. Under the reaction conditions, the reaction effect of the compound I and the compound III is better, and the polysubstituted pyrrole derivative can be obtained efficiently and with high yield.
Further, the compound I is prepared by reacting a compound IV with N, N-dimethylformamide methylal to obtain a compound V; then reacting the compound V with the compound VI to obtain the compound VI;
wherein the structural formula of the compound IV is
In the formula, R1Selected from hydrogen, C1-C6 alkyl, C1-C6 substituted alkyl, C1-C6 alkoxy, C1-C6 substituted alkoxy, halogen or nitro; r1The number of the (b) can be 1-3, and the binding site is at least one of five unsubstituted sites on a benzene ring; r2Selected from C1-C6 alkyl, C1-C8 substituted alkyl, phenyl or substituted phenyl.
Wherein the structural formula of the N, N-dimethylformamide methylal is shown as
The reaction of the compound V and the compound VI is carried out for 12-24 h at the temperature of 80-150 ℃. Alternatively, after the reaction is finished, a crude product of the compound I is obtained by reduced pressure distillation and then purified by recrystallization.
Further, the compound II is obtained by diazotizing the compound VII, for example, by reacting the compound VII with 4-acetamidobenzenesulfonyl azide. The reaction is carried out at the temperature of-10-5 ℃, alkali is needed for catalysis, and the reaction time is 4-10 hours. And after the reaction is finished, extracting, rotary steaming and column chromatography separation are carried out to obtain a compound II. The structural formula of the compound VII is
Further, the compound III is obtained by reacting the compound VIII with p-toluenesulfonyl hydrazide. The reaction temperature is 50-100 ℃, and the reaction time is 2-8 h. After the reaction is finished, carrying out suction filtration to obtain a compound III.
The features and properties of the present invention are described in further detail below with reference to examples.
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