阅读说明：本技术 一种醇取代的(e,e)-构型的枝型共轭二烯衍生物及其制备方法 (Alcohol-substituted (E, E) -configuration branched conjugated diene derivative and preparation method thereof ) 是由 张坚 钟国富 孟轲轲 丁丽媛 于 2019-09-30 设计创作，主要内容包括：本发明提供了一种醇取代的(E,E)-构型的枝型共轭二烯衍生物及其合成方法,属于有机合成领域,该合成方法中将烯基醇化合物、缺电子烯烃、过渡金属盐催化剂、配体、氧化剂以及碱与醇作为添加剂置于有机溶剂中,于惰气氛围下加热反应,实现羟基导向下的烯基醇与缺电子烯烃的氧化偶联反应；反应经历了羟基导向下的烯基同碳位碳氢键的活化,形成双键在环外的exo-环金属过渡态,表现出较宽的底物范围和较好的官能团兼容性。本发明的合成方法利用廉价的氨基酸作为配体,操作简单,条件温和,底物适用性广,产率可达15～82％,适用于结构较为复杂的具有特殊生物活性化合物的化学修饰,具有广泛的应用前景,在制备方法上是一种有效补充。(The invention provides an alcohol-substituted (E, E) -configuration branched conjugated diene derivative and a synthesis method thereof, belonging to the field of organic synthesis, wherein in the synthesis method, an alkenyl alcohol compound, electron-deficient olefin, a transition metal salt catalyst, a ligand, an oxidant, alkali and alcohol are used as additives to be placed in an organic solvent and heated to react in an inert gas atmosphere, so that the oxidative coupling reaction of the hydroxyl-oriented alkenyl alcohol and the electron-deficient olefin is realized; the reaction is activated by the carbon-hydrogen bond between the alkenyl guided by the hydroxyl and the carbon, and an exo-ring metal transition state with double bonds outside the ring is formed, so that the wide substrate range and the good functional group compatibility are shown. The synthetic method disclosed by the invention uses cheap amino acid as a ligand, is simple to operate, mild in condition, wide in substrate applicability and suitable for chemical modification of a compound with a complex structure and special biological activity, has a wide application prospect, and is an effective supplement in a preparation method, and the yield can reach 15-82%.)

1. An alcohol-substituted (E, E) -configured branched conjugated diene derivative, wherein the alcohol-substituted (E, E) -configured branched conjugated diene derivative has a structure represented by formula I, formula II or formula III:

in the formula I, R¹Is C_1～8Alkyl, ester substituted C_1～8Hydrocarbyl radical, C_1～8Hydroxyalkyl or C_6～10An aryl group; r²Is H, methyl or with R¹Connecting to form five-membered ring and six-membered ring; r³Is H, cycloalkyl, an oxygen-containing heterocycle, C_1～6Alkyl, alkenyl, biphenyl, or substituted aryl; the substituent of the substituted aryl is C_1～6Alkyl of (C)_1～6Alkoxy of (a), or halogen; r⁴Is ester group, ketone carbonyl group, aryl group, amide group and phosphonate group; in the formula II R⁵Is C_1～6An alkyl group; r⁶Is H or C_1～3An alkyl group; r⁷Is C_1～6An ester group; in the formula III, R⁸Is C_1～8An alkyl group;R⁹is C_1～6An ester group.

2. The method for synthesizing the alcohol-substituted (E, E) -configured branched conjugated diene derivative according to claim 1, wherein the alkenyl alcohol compound, the electron-deficient olefin, the transition metal salt catalyst, the ligand, the oxidant, the alkali and the additive are placed in an organic solvent and heated to react in an inert gas atmosphere to obtain the compound having the structure shown in formula I, formula II or formula III.

3. The synthesis method according to claim 2, wherein the alkenyl alcohol compound is a substituted 2-allyl alcohol represented by formula V, a substituted 3-alkene butanol represented by formula IV or a substituted 4-alkene pentanol represented by formula VI;

in the formula IV, R¹，R²，R³Is in accordance with formula I; in the formula V, R⁵，R⁶Is as defined for formula II; in the formula VI R⁸Is in accordance with formula III;

the electron-deficient olefin is acrylate, substituted styrene, substituted acrylamide or alkenyl phosphonate shown as formula VII, formula VIII or formula IX:

r in the formula VII⁴Is in accordance with formula I; r in the formula VIII⁷Is as defined for formula II; in the formula IX R⁹In accordance with formula III.

4. The synthesis method of claim 2, wherein the transition metal salt catalyst is a palladium salt; the palladium salt is palladium acetate or palladium chloride.

5. The method of synthesis of claim 2, wherein the ligand is an amino acid; the amino acid is N-acetyl phenylalanine or N-acetyl glycine.

6. The method of synthesis of claim 2, wherein the silver salt of an oxidizing agent; the silver salt is silver carbonate or silver oxide.

7. The synthesis method of claim 2, wherein the base is cesium carbonate, potassium carbonate or lithium hydroxide; the additive is trifluoroethanol or trifluoroisopropanol.

8. The method of synthesis according to claim 2, wherein the alkenyl alcohol compound: electron deficient olefins: transition metal salt catalyst: amino acid ligand: oxidizing agent: alkali: the mass ratio of the additives is 1: 1-2: 0.05-0.15: 0.2-0.8: 1.0-2.0: 0.2-0.5: 5 to 15.

9. The synthesis method according to claim 2, wherein the volume usage amount of the organic solvent is 3-5L/mol based on the amount of the alkenyl alcohol compound; the heating reaction temperature is 50-100 ℃, and the reaction time is 16-24 hours.

10. The synthesis method according to claim 2, wherein the organic solvent is one or more of toluene, tetrahydrofuran, 1, 4-dioxane, 1, 2-dichloroethane, ethanol, and dimethoxyethane.

Technical Field

The invention relates to the field of organic synthesis, in particular to an alcohol-substituted (E, E) -branched conjugated diene derivative and a synthesis method thereof.

Background

In recent years, there has been much interest in the selective functionalization of C-H bonds under the catalysis of transition metals and under the action of a directing group, in which methods a transition metal can interact with a directing group and insert a specific C-H bond, achieving selective cleavage and functionalization of the specific C-H bond by forming a ring metal transition state; the guide group strategy is researched more in aryl and alkyl carbon-hydrogen bond functionalization, but the research on the strategy in olefin carbon-hydrogen bond selective conversion is not sufficient, probably due to the high activity and instability of olefin, at present, the selective functionalization of olefin carbon-hydrogen bond under the action of the guide group is only limited to the cutting and functionalization of alkenyl ortho/cis carbon-hydrogen bond, and the reaction of carbon-hydrogen bond at other positions is rarely reported.

The Engle topic group reported the C-H bond olefines guided by 8-aminoquinoline amides to the carbon position for olefines to olefines through N, N-bidentate Six-Membered ring metal transition states (C (alkenyl) -H Activation via Six-member Palladacycles: Catalytic 1,3-Diene Synthesis.J.Am.Chem.Soc.2018,140, 5805). More recently, the Carreira group reported that the amide-directed carbon-hydrogen bond Iodination of olefins at the carbon position of 2-picolinic acid was mainly via the N, N-bidentate six-membered metal transition (Palladium-catalyst regioselective C-H Iodination of inactive olefins. J.am.chem.Soc.2019,141, 8758). However, these methods have some limitations, such as: 1) the activation of specific carbon-hydrogen bonds can only be realized through the transition state of the six-membered ring metal; 2) the installation and removal of the N, N-bidentate directing group makes the reaction cumbersome, limiting its application.

Alkenyl alcohol is a common organic compound, and particularly, the alkenyl alcohol is widely available in natural products and medicines, the realization of selective chemical conversion of the alkenyl alcohol by using the alkenyl alcohol as a raw material has important significance, the reports on carbon-hydrogen bond functionalization of alkenyl alcohol compounds are limited, and particularly, the alkenyl carbon-hydrogen bond selective activation and functionalization are realized by using a weakly coordinated hydroxyl group as a guide group, so that the alkenyl alcohol compounds are more efficient and practical.

Loh topic group has reported that oxidative coupling of alkenyl alcohols with electron-deficient olefins can yield linear conjugated diene derivatives (chemical conversion Control in the Stereoselective alkenyl sp2C-H Bond catalysis reaction, Angew. chem., int. Ed.2017,56,5091) that undergo hydroxyl-directed activation of the alkenyl ortho carbon-hydrogen Bond to form an endo-ring metal transition state with a double Bond in the ring, which is only suitable for the reaction of terminal olefins and is ineffective for internal olefins.

Disclosure of Invention

The invention provides an alcohol-substituted (E, E) -configuration branched conjugated diene derivative and a synthesis method thereof, wherein the synthesis method is an oxidative coupling reaction of hydroxyl-guided alkenyl alcohol and electron-deficient olefin for preparing branched conjugated diene; the reaction is activated by the carbon-hydrogen bond between the alkenyl guided by the hydroxyl and the carbon, and an exo-ring metal transition state with double bonds outside the ring is formed, so that the wide substrate range and the good functional group compatibility are shown.

An alcohol-substituted (E, E) -configuration branched conjugated diene derivative, having a structural formula shown in formula I, formula II and formula III:

in the formula I, R¹Is C_1～8Alkyl and ester substituted C_1～8Hydrocarbyl radical, C_1～8Hydroxyalkyl or C_6～10An aryl group; r²Is H, methyl or with R¹Connecting to form five-membered ring and six-membered ring; r³Is H, cycloalkyl, an oxygen-containing heterocycle, C_1～6Alkyl, alkenyl, biphenyl, or substituted aryl; the substituent of the substituted aryl is C_1～6Alkyl of (C)_1～6Alkoxy of (a), or halogen; r⁴Is ester group, ketone carbonyl group, aryl group, amide group and phosphonate group; in the formula II R⁵Is C_1～6An alkyl group; r⁶Is H or C_1～3An alkyl group; r⁷Is C_1～6An ester group; in the formula III, R⁸Is C_1～8An alkyl group; r⁹Is C_1～6An ester group.

The invention also provides a synthetic method of the alcohol-substituted (E, E) -configuration branched conjugated diene derivative, which comprises the following steps:

placing alkenyl alcohol compound, electron-deficient olefin, transition metal salt catalyst, ligand, oxidant, alkali and additive in an organic solvent, heating and reacting in an inert gas atmosphere, and after the reaction is finished, carrying out post-treatment on the reaction solution to obtain the compound shown in formula I, formula II or formula III corresponding to the reactant.

The reaction mechanism is as follows: after the hydroxyl in the alkenyl alcohol is coordinated with the metallic palladium, the metallic palladium is inserted into an alkenyl carbon-hydrogen bond at the same carbon position (oxidation addition process) to form a cyclometaltransition state with a quaternary, quinary or senary double bond outside the ring, and then the coordination and insertion of electron-deficient olefin are carried out, and then the beta-hydrogen is eliminated, thus obtaining the alkenylation product. The amino acid acts as a ligand and promotes the cleavage of the alkenyl carbon-hydrogen bond.

Preferably, the alkenyl alcohol compound is substituted 2-allyl alcohol shown in a formula V, substituted 3-alkene butanol shown in a formula IV or substituted 4-alkene pentanol shown in a formula VI;

in the formula IV, R¹，R²，R³Is in accordance with formula I; in the formula V, R⁵，R⁶Is as defined for formula II; in the formula VI R⁸Is in accordance with formula III;

the electron-deficient olefin is acrylate, substituted styrene, substituted acrylamide or alkenyl phosphonate shown as formula VII, formula VIII or formula IX:

r in the formula VII⁴Is in accordance with formula I; r in the formula VIII⁷Is as defined for formula II; in the formula IX R⁹In accordance with formula III.

Preferably, the transition metal salt catalyst is a palladium salt; more preferably, the palladium salt is palladium acetate or palladium chloride.

Preferably, the ligand is an amino acid; more preferably, the amino acid is N-acetylphenylalanine or N-acetylglycine.

Preferably, the silver salt of an oxidizing agent; the silver salt is silver carbonate or silver oxide; further preferred is silver carbonate.

Preferably, the alkali is cesium carbonate, potassium carbonate or lithium hydroxide; the additive is trifluoroethanol or trifluoroisopropanol.

Preferably, in the synthesis method, the ratio of the alkenyl alcohol compound: electron deficient olefins: transition metal salt catalyst: amino acid ligand: oxidizing agent: alkali: the mass ratio of the additives is 1: 1-2: 0.05-0.15: 0.2-0.8: 1.0-2.0: 0.2-0.5: 5 to 15.

Preferably, the volume usage amount of the organic solvent is 3-5L/mol based on the amount of the alkenyl alcohol compound.

Preferably, the organic solvent is one or more of toluene, tetrahydrofuran, 1, 4-dioxane, 1, 2-dichloroethane, ethanol and dimethoxyethane.

Preferably, the heating reaction temperature is 50-100 ℃, and the reaction time is 16-24 hours.

The post-treatment of the invention comprises the following steps: loading the reaction liquid into a column, dissolving and transferring the residual reaction liquid by using dichloromethane, and performing column chromatography separation by using silica gel, wherein an eluent is a mixture of the following components in a volume ratio of 1: 2-5, collecting the eluent containing the target compound, concentrating and drying to obtain the corresponding target product.

Further preferably, the present invention prepares the branched conjugated diene from simple raw materials of alkenyl alcohol and electron-deficient olefin under relatively mild conditions using a simple transition metal salt as a catalyst, an amino acid as a ligand, a silver salt as an oxidant, a base and an alcohol as additives, according to the following reaction formula:

the invention has the following beneficial effects:

(1) the invention provides a method for efficiently synthesizing a branched conjugated diene compound by using alkenyl alcohol and electron-deficient olefin, and the obtained products are all brand-new and have not been reported.

(2) The synthetic method disclosed by the invention is simple to operate, mild in reaction conditions, wide in substrate application range, wide in application range and wide in application range, and the yield can reach 15-82%.

(3) The synthesis method of the invention realizes the selective cutting and functionalization of the carbon-hydrogen bond of the internal olefin, greatly widens the selective conversion range of the olefin, and simultaneously utilizes cheap amino acid as a ligand, so that the raw material source is wide, the economic benefit is higher, and the production pressure is lower.

(4) The synthetic raw materials are economical and easy to obtain, are suitable for chemical modification of compounds with complex structures and special biological activity, have wide application prospects, and are an effective supplement in the preparation method.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of a product obtained in example 1 of the present invention;

FIG. 2 is a nuclear magnetic hydrogen spectrum of a product obtained in example 27 of the present invention;

FIG. 3 shows the nuclear magnetic hydrogen spectrum of the product obtained in example 29 of the present invention.

Detailed Description

The present invention will be further described with reference to the following examples, in which the experimental methods used are, unless otherwise specified, conventional ones, and materials, reagents and the like used in the examples are, unless otherwise specified, commercially available.