阅读说明：本技术 一种邻烯基芳香腈化合物及其制备方法 (O-alkenyl aromatic nitrile compound and preparation method thereof ) 是由 饶建行 李先纬 欧阳文森 于 2019-11-27 设计创作，主要内容包括：本发明属于有机合成的技术领域,尤其涉及一种邻烯基芳香腈化合物及其制备方法。本申请提供了一种邻烯基芳香腈化合物,所述邻烯基芳香腈化合物的结构式如式(Ⅰ)所示。本申请还提供了邻烯基芳香腈化合物的制备方法,包括：将式(Ⅱ)所示化合物和式(III)所示化合物溶于惰性溶剂中,在碱性条件,氧化剂和金属催化剂的作用下进行反应,得到邻烯基芳香腈化合物。本申请的方法具有官能团兼容性好、底物范围广,可以应用于包括萘、吲哚等区域选择性引入氰基和烯烃两种官能团,且能应用于包括丙磺舒等药物分子的后期修饰中,具有重要的应用潜能,并有效解决现有常规合成邻烯基芳香腈化合物的方法复杂的技术问题。(The invention belongs to the technical field of organic synthesis, and particularly relates to an o-alkenyl aromatic nitrile compound and a preparation method thereof. The application provides an o-alkenyl aromatic nitrile compound, and the structural formula of the o-alkenyl aromatic nitrile compound is shown as a formula (I). The present application also provides a method for preparing an o-alkenyl aromatic nitrile compound, comprising: dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent, and reacting under the alkaline condition and the action of an oxidant and a metal catalyst to obtain the o-alkenyl aromatic nitrile compound. The method has good functional group compatibility and wide substrate range, can be applied to regioselectively introducing two functional groups of cyano and alkene, such as naphthalene and indole, can be applied to the later modification of drug molecules, such as probenecid, and the like, has important application potential, and effectively solves the technical problem that the conventional method for synthesizing the o-alkenyl aromatic nitrile compound is complex.)

1. An o-alkenyl aromatic nitrile compound, characterized in that the structural formula of the o-alkenyl aromatic nitrile compound is shown as formula (I);

wherein R is¹Selected from C1-C20 hydrocarbyl, halogen, ester group, carbonyl, nitro, substituted amino; ar is selected from aryl of C5-C30 or aryl heterocyclic of C5-C30; r⁰Is selected from H orThe R is²Is selected from C1-C20 alkyl, halogen, ester group, carbonyl, nitro, aryl of C5-C30 of substituted amino or aromatic heterocyclic group of C5-C30, or is terminal olefin substituted by polyfluoro.

2. The o-alkenyl aromatic nitrile compound according to claim 1, wherein the aromatic heterocyclic ring of the aromatic heterocyclic group having C5 to C30 is a substituted benzene ring, naphthalene, furan, thiophene, indole or pyrrole.

3. A method for producing an o-alkenyl aromatic nitrile compound according to claim 1 or 2, comprising the steps of:

dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent, and reacting under the alkaline condition and the action of an oxidant and a metal catalyst to obtain an o-alkenyl aromatic nitrile compound shown in a formula (I);

wherein the content of the first and second substances,

4. the production method according to claim 3, wherein the metal catalyst is selected from one or more of a divalent palladium metal catalyst, a divalent ruthenium metal catalyst, or a trivalent rhodium metal catalyst, and a trivalent iridium metal catalyst.

5. The method according to claim 3, wherein the base for adjusting the basic condition is selected from one or more of sodium acetate, cesium acetate, potassium acetate, sodium carbonate, and potassium phosphate.

6. The method of claim 3, wherein the oxidizing agent is selected from one or more of silver acetate, silver carbonate, silver triflate, silver nitrate, copper acetate, cuprous halide, copper halide, ferric trihalide, and ferric nitrate.

7. The method according to claim 3, wherein the inert solvent is one or more selected from the group consisting of toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol, and acetone.

8. The method according to claim 3, wherein the reaction temperature is 80 ℃ to 120 ℃; the reaction time is 8-36 h.

9. The method according to claim 3, further comprising a halide ion scavenger selected from the group consisting of bis (trifluoromethanesulfonyl) imide silver salt, silver hexafluoroantimonate and/or trifluoromethanesulfonyl imide silver salt.

10. The process according to claim 3, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is 1: (1-5); the dosage of the metal catalyst is 1-5 mol% of the dosage of the compound shown in the formula (II).

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to an o-alkenyl aromatic nitrile compound and a preparation method thereof.

Background

Nitrile compounds have versatile utility and are widely used in organic synthesis, pharmaceutical and chemical industries. Nitriles also serve as precursors or intermediates for imines, ketones, amides, esters, alcohols, amines in the traditional field of organic synthesis. Nitriles also occupy an important seat in clinical drugs, pesticides and dyes, based on the special properties of the cyano functionality. The linear structure of the carbon-nitrogen triple bond of the cyano function of the nitrile and its occupation of only one eighth of the methyl group also allows easy penetration of the cyano group into the targeting molecule.

In view of the diversity of reactivity of the cyano functions, the reaction of arylnitrile derivatives is mainly focused on the transformation of the cyano functions. Generally, the nucleophilic activity of lone pair pairs on the nitrogen atom of the aryl nitrile, as well as the electrophilic activity of the carbon atom, promote the abundant reactivity of the nitrile compound.

Because o-alkenyl substituted aromatic nitrile compounds can be used as synthesis intermediates for rapidly synthesizing bioactive molecular frameworks including coumarin, o-alkenyl aromatic nitrile compounds are receiving more and more attention. However, since the cyano group is used as a strong electron-withdrawing group and a group with strong coordination, the o-alkenyl aromatic nitrile is difficult to obtain by direct oxidation Heck reaction starting from aromatic ring carbon-hydrogen bond, and if the o-alkenyl aromatic nitrile compound is synthesized by using an o-halogen substituted aromatic nitrile which is not easily available, the cost of the whole process is increased, and the multi-substituted o-alkenyl aromatic nitrile is difficult to obtain, so that the existing method for synthesizing the multi-substituted o-alkenyl aromatic nitrile compound is few.

Disclosure of Invention

In view of this, the present application provides an o-alkenyl aromatic nitrile compound and a preparation method thereof, which effectively solve the technical problems of complex synthesis method and high cost of the conventional method for synthesizing an o-alkenyl aromatic nitrile compound.

In a first aspect, the present application provides an o-alkenyl aromatic nitrile compound having a structural formula shown in formula (i);

wherein R is¹Selected from C1-C20 alkyl, halogen, ester group, carbonyl, nitryl and substituted amino; ar is selected from aryl of C5-C30 or aryl heterocyclic of C5-C30; r⁰Is selected from H orThe R is²Is selected from C1-C20 alkyl, halogen, ester group, carbonyl, nitro, aryl of C5-C30 of substituted amino or aromatic heterocyclic group of C5-C30, or is terminal olefin substituted by polyfluoro.

Wherein when R is⁰Is selected from

When it is in the structural formula

Wherein when R is⁰When selected from H, the structural formula is

Preferably, said formula (I) R¹At any position of Ar.

Preferably, the aromatic heterocyclic ring of the aromatic heterocyclic group having C5-C30 is a substituted benzene ring, naphthalene, furan, thiophene, indole or pyrrole.

In a second aspect, the present application provides a method for preparing an o-alkenyl aromatic nitrile compound, comprising the steps of:

dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent, and reacting under the alkaline condition and the action of an oxidant and a metal catalyst to obtain an o-alkenyl aromatic nitrile compound;

wherein the content of the first and second substances,

wherein when the ratio of olefin to imidate substrate is adjusted, the reaction can yield R⁰Is composed of

2, 6-diolefin substituted benzonitrile of (a).

In the preparation method, aryl imine ester compounds shown in a formula (II) and olefin compounds shown in a formula (III) are adopted, and imine esters with benzene rings and aryl ethylene substrates are taken as examples: by sp of imidates²Under the assistance of lone pair electrons on a nitrogen atom in hybridized imine functional group, the distance between trivalent rhodium or divalent ruthenium and an aromatic ring is shortened to form a pi complex, ortho hydrogen atoms of imidate on the aromatic ring are separated in a coordinated metallization-deprotonation (CMD) mode under the promotion of alkali in a system such as sodium acetate and the like, and a metal organic cyclic intermediate at the center of a rhodium or ruthenium catalyst is formed in situ.

It is noted that the present application stereoselectively yields cyano-containing polysubstituted diarylethene compounds of the E-configuration. Through the design and synthesis of a substrate, the imidate is used as a precursor of the aromatic nitrile to promote the simple and efficient synthesis of the o-alkenyl aromatic nitrile, and an important alternative scheme is provided for the simple and fast synthesis of the related aromatic nitrile.

Preferably, the metal catalyst is selected from one or more of a divalent palladium metal catalyst, a divalent ruthenium metal catalyst, or a trivalent rhodium metal catalyst and a trivalent iridium metal catalyst.

Specifically, the metal catalyst is selected from palladium acetate and palladium chloride; one or more of ruthenium trichloride, dichloro (p-methylisopropylphenyl) ruthenium (II) dimer, dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, trisacetonitrile (pentamethylcyclopentadienyl) bis (hexafluoroantimonate) rhodium, dichloro (pentamethylcyclopentadienyl) iridium dimer, and dichloro (pentamethylcyclopentadienyl) bis (hexafluoroantimonate) rhodium (III). More preferably (pentamethylcyclopentadienyl) rhodium chloride dimer.

More preferably dichloro (pentamethylcyclopentadienyl) rhodium dimer.

More preferably, the preparation method of the application also comprises a halide ion capturing agent, wherein the halide ion capturing agent is selected from monovalent silver salts; the monovalent silver salt is selected from bis (trifluoromethane sulfonyl) imide silver salt, silver hexafluoroantimonate (AgSbF)₆) Or/and trifluoromethanesulfonimide silver salt (AgNTf)₂). The monovalent silver salt not only acts as a halide ion capture agent, but the anion in the silver salt is now more electronegative and plays an important role in generating more electrophilic active catalyst species of trivalent rhodium or divalent ruthenium. The control experiment shows that when the monovalent silver salt is not added in the reaction condition, the reaction efficiency is greatly reduced: in the case of product 1a, the yield under standard conditions was 75%, whereas in the control run without the addition of the monovalent silver salt, the reaction yield of product 1a was only 36%. Because the anion of the silver salt is more electronegative than the chloride ion, the reaction efficiency is improved by the action of the monovalent silver salt and the metal catalyst to promote the in situ formation of a more electrophilic metal catalyst species.

Preferably, the base for adjusting the basic condition is selected from one or more of sodium acetate, cesium acetate, potassium acetate, sodium carbonate and potassium phosphate. More preferably sodium acetate.

Preferably, the oxidant is selected from one or more of silver acetate, silver carbonate, silver triflate, silver nitrate, copper acetate, cuprous halide, cupric halide, ferric trihalide and ferric nitrate. More preferably copper acetate.

Preferably, the inert solvent is selected from one or more of toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol and acetone. More preferably 1, 2-dichloroethane.

Preferably, the reaction temperature is 80-120 ℃; the reaction time is 8-36 h.

More preferably, the temperature of the reaction is 100 ℃; the reaction time is 8-36 h.

Preferably, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is 1: (1-5); more preferably, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is 1: (1-4).

More preferably, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is 1: 2.

Preferably, the amount of the metal catalyst is 1 mol% to 5 mol%, more preferably 2 mol%, of the amount of the compound represented by the formula (II).

Preferably, the amount of the base is 5-50 mol%, more preferably 15 mol% of the amount of the compound shown in the formula (II);

the amount of the oxidizing agent is 10 to 300 mol%, more preferably 30 mol%, of the amount of the compound represented by the formula (II).

The concentration of the compound represented by the formula (II) in the inert solvent is 0.1mol/L to 3.0mol/L, preferably 0.2 mol/L.

Because cyano is a strong electron-withdrawing group, and an electron-rich aromatic ring is often used in the direct oxidation Heck reaction of a common aromatic ring to promote the action of the normal aromatic ring and an electrophilic high-valence metal catalyst, the property of the substrate is difficult to carry out the oxidation Heck reaction, so that the o-alkenyl aromatic nitrile is difficult to obtain by the direct oxidation Heck reaction starting from the carbon-hydrogen bond of the aromatic ring; meanwhile, the cyano-group is a functional group which has strong coordination capacity and shows linear coordination, and the property also makes the cyano-group difficult to be compatible in many common metal-catalyzed coupling reactions; the linear coordination feature makes it difficult to achieve the desired ortho-selectivity for cyano-promoted aryl oxidation Heck reactions via metal-catalyzed orientation. Due to the particularity of the cyano group, the existing method for synthesizing the o-alkenyl aromatic nitrile compound has the defects that the existing synthetic method has complex synthetic method and high cost because the synthetic method needs raw materials which are not easy to obtain and multiple steps of reactions are carried out. In conclusion, the prior conventional method is difficult to obtain the regio-stereoselective o-alkenyl aromatic nitrile compound by a direct and efficient oxidative coupling mode.

However, aryl nitriles are a very important class of organic synthetic building blocks, and important compounds such as nitrogen-containing heterocycles, carboxylic acids, benzylamines, ketones, amides and the like can be obtained through one-step conversion. Therefore, development of a simple and efficient method for synthesizing an arylnitrile from a simple and readily available raw material is still desired.

The preparation method of the o-alkenyl aromatic nitrile compound disclosed by the application comprises the following steps: by using common easily-obtained aryl imine ester derivatives as substrates, the selective activation reaction based on the carbon-hydrogen bond of the aromatic ring is realized under the catalytic action of a divalent palladium metal catalyst, a divalent ruthenium metal catalyst or a trivalent rhodium metal catalyst and a trivalent iridium metal catalyst, so that the high-efficiency method for quickly constructing various different substituted o-alkenyl substituted aromatic cyanation products is obtained. The application discovers that the novel synthesis strategy that the cyano-functional group is obtained by using the easily-converted imine ester as a cyano-precursor, promoting the direct ortho-position selective carbon-hydrogen bond activation of the aromatic ring and oxidizing Heck reaction, and then carrying out in-situ hydrolysis can be used for efficiently and selectively synthesizing the o-alkenyl aromatic nitrile compound. The preparation method of the o-alkenyl aromatic nitrile compound can directly perform oxidation Heck reaction of the aromatic ring with regioselectivity and the terminal olefin, and has good atom economy and step economy. The application realizes the synthesis of the o-vinyl substituted aryl nitrile derivative with simplicity, high efficiency and high selectivity, and the o-alkenyl aromatic nitrile compound can be used as a precursor of a ligand such as o-vinylphenyl oxazoline derivatives, coumarin derivatives, o-vinylbenzylamine, o-vinylbenzoic acid, o-acetylbenzoic acid and the like. More importantly, the conversion of the application has good step economy, namely the oxidation coupling reaction of the aromatic ring carbon-hydrogen bond and the terminal olefin carbon-hydrogen bond is directly utilized, and the reaction can be applied to the later derivatization of drug molecules (such as probenecid), so that a new strategy is provided for the subsequent rapid construction of a corresponding molecular library with potential bioactivity. Therefore, the method realizes the later-stage modification of the reaction in the drug molecules such as probenecid, and considers that the imidate can be synthesized by taking the aromatic ring and the aryl halide as precursors, so the method has wide application potential and is expected to obtain good application prospect in the development of later-stage modification, new drugs and new materials.

In conclusion, the method for simply, conveniently and efficiently synthesizing the o-alkenyl substituted aromatic nitrile compound with wide practicability can be used as an important synthetic intermediate and quickly synthesizing molecules with important biological activity; in view of the wide application of aromatic nitriles in the field of functional materials, the reaction is expected to be applied to the development of novel materials.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.

FIG. 1 shows the NMR of (E) -2- (3-bromostyryl) -benzonitrile (1a) in example 1 of the present invention¹H, spectrogram;

FIG. 2 shows the NMR of (E) -2- (3-bromostyryl) -benzonitrile (1a) in example 1 of the present invention¹³C, spectrum;

FIG. 3 shows the NMR of (E) -2- (4-tert-butylstyryl) -4-fluorobenzonitrile (1b) provided in example 2 of the present invention¹H, spectrogram;

FIG. 4 shows the NMR of (E) -2- (4-tert-butylstyryl) -4-fluorobenzonitrile (1b) provided in example 2 of the present invention¹³C, spectrum;

FIG. 5 shows the NMR of (E) -2- (4-tert-butylstyryl) -4-fluorobenzonitrile (1b) provided in example 3 of the present invention¹⁹F, spectrum;

FIG. 6 shows the NMR of (E) -3- (4-tert-butylstyryl) -2-naphthonitrile (1c) provided in example 4 of the present invention¹H, spectrogram;

FIG. 7 shows the NMR of (E) -3- (4-tert-butylstyryl) -2-naphthonitrile (1c) provided in example 4 of the present invention¹³C, spectrum;

FIG. 8 shows the NMR of (E) -2- (4-tert-butylstyryl) -4-trifluoromethylbenzonitrile (1d) in example 5 of the present invention¹H, spectrogram;

FIG. 9 shows the NMR of (E) -2- (4-tert-butylstyryl) -4-trifluoromethylbenzonitrile (1d) in example 5 of the present invention¹³C, spectrum;

FIG. 10 shows the NMR of (E) -2- (4-tert-butylstyryl) -4-trifluoromethylbenzonitrile (1d) in example 5 of the present invention¹⁹F, spectrum;

FIG. 11 is a NMR chart of (E) -3- (3- (4-tert-butylstyryl) -4-cyanophenoxy) propyl 4- (N, N-dipropylsulfonamido) benzoate (1E) according to example 8 of the present invention¹H, spectrogram;

FIG. 12 shows NMR spectra of (E) -3- (3- (4-tert-butylstyryl) -4-cyanophenoxy) propyl 4- (N, N-dipropylsulfonamido) benzoate (1E) in example 8 according to the present invention¹³C, spectrum;

FIG. 13 is an NMR spectrum of (E) -2- (3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10, 10-heptadecafluorodec-1-en-1-yl) benzonitrile (1f) according to example 9 of the present invention¹H, spectrogram;

FIG. 14 shows NMR spectra of (E) -2- (3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10, 10-heptadecafluorodec-1-en-1-yl) benzonitrile (1f) in example 9 of the present invention¹³C, spectrum;

FIG. 15 shows NMR spectra of (E) -2- (3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10, 10-heptadecafluorodec-1-en-1-yl) benzonitrile (1f) in example 9 of the present invention¹⁹F, spectrum;

FIG. 16 shows the NMR of 4, 6-bis ((E) -4-tert-butylstyrene-1-p-toluenesulfonyl-1H-indole-5-carbonitrile (1g) according to example 10 of the present invention¹H, spectrogram;

FIG. 17 shows NMR spectra of 4, 6-bis ((E) -4-t-butylstyrene-1-p-toluenesulfonyl-1H-indole-5-carbonitrile (1g) according to example 10 of the present invention¹³C, spectrum;

FIG. 18 shows the NMR of (E) -3- (4-tert-butylstyrene) thiophene-2-carbonitrile (1h) according to example 10 of the present invention¹H, spectrogram;

FIG. 19 shows the NMR of (E) -3- (4-tert-butylstyrene) thiophene-2-carbonitrile (1h) according to example 10 of the present invention¹³And C, spectrum.

Detailed Description

The application provides an o-alkenyl aromatic nitrile compound and a preparation method thereof, and effectively solves the technical problems of complex synthesis method and high cost of the conventional o-alkenyl aromatic nitrile compound synthesis method.

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The present application discloses a method for preparing an o-alkenyl aromatic nitrile compound preferably comprising the steps of: charging successively an imidate derivative represented by the formula (II) (0.1mmol) in a reactor under an atmospheric oxygen atmosphere,

then 2.5mg of dichloro (pentamethylcyclopentadienyl) rhodium dimer, 7.8mg of bistrifluoromethanesulfonylimide silver salt, 4.9mg of sodium acetate and 12.0mg of copper acetate were added in this order, a solution of the olefinic compound represented by the formula (III) (0.2mmol) in 1, 2-dichloroethane (1.0mL) was injected into the reactor with a syringe and allowed to react at 100 ℃ for 12 hours,and (3) determining the reaction is finished by thin-layer chromatography analysis, carrying out suction filtration on the reaction solution through diatomite, carrying out rotary evaporation and concentration on 400-mesh silica gel to prepare dry powder, and separating a reaction product by adopting column chromatography, wherein the volume ratio of the 400-mesh silica gel to the developing agent is 200: 1-50: 1 and ethyl acetate to obtain the o-alkenyl aromatic nitrile compound.

In summary, the present invention provides an o-alkenyl aromatic nitrile compound, wherein the structural formula of the o-alkenyl aromatic nitrile compound is shown as formula (i); wherein R is¹And R²Independently selected from C1-C20 alkyl, halogen, ester group, carbonyl, nitro and substituted amino; ar is selected from aryl of C5-C30 or aryl heterocyclic of C5-C30.

The raw materials used in the following examples are all commercially available or self-made.