阅读说明：本技术 一种利用混合苯乙烯衍生物与n,n-二甲基甲酰胺构建3,5-二取代吡啶的方法 (Method for constructing 3,5-disubstituted pyridine by using mixed styrene derivative and N, N-dimethylformamide ) 是由 郭灿城 刘海平 郭欣 于 2020-06-08 设计创作，主要内容包括：本发明公开了一种利用混合苯乙烯衍生物与N,N-二甲基甲酰胺构建3,5-二取代吡啶的方法,该方法是混合苯乙烯衍生物与N,N-二甲基甲酰胺及过二硫酸盐在碘盐催化作用下进行环化反应,同时得到对称性和不对称混合3,5-二取代吡啶产物,该方法利用碘盐催化混合苯乙烯衍生物和DMF一步氧化环化合成3,5-二取代吡啶,具有原料及催化剂成本低,反应条件温和,可以同时高收率获得对称性和不对称性的3,5-二取代吡啶等优点。(The invention discloses a method for constructing 3,5-disubstituted pyridine by using mixed styrene derivatives and N, N-dimethylformamide, which comprises the step of carrying out cyclization reaction on the mixed styrene derivatives, the N, N-dimethylformamide and peroxydisulfate under the catalysis of iodonium salt to obtain a symmetrical and asymmetrical mixed 3,5-disubstituted pyridine product.)

1. A method for constructing 3,5-disubstituted pyridine by using a mixed styrene derivative and N, N-dimethylformamide is characterized in that: carrying out cyclization reaction on the mixed styrene derivative, N-dimethylformamide and peroxydisulfate under the catalysis of iodonium salt to obtain 3,5-disubstituted pyridine;

the mixed styrene derivative is composed of aryl ethylene with a structure shown in a formula 1 and aryl ethylene with a structure shown in a formula 2:

the 3,5-disubstituted pyridine consists of3, 5-disubstituted pyridines with structures of formulas 3 to 5:

wherein the content of the first and second substances,

R₁and R₂Independently selected from hydrogen, alkyl or halogen substituents, and R₁And R₂The same groups are not selected at the same time.

2. The method of claim 1, wherein the 3,5-disubstituted pyridine is prepared by mixing a styrene derivative with N, N-dimethylformamide, and comprises the following steps:

the alkyl group is C₁～C₅Alkyl groups of (a);

the halogen substituent is fluorine or chlorine.

3. The method of claim 1, wherein the 3,5-disubstituted pyridine is prepared by mixing a styrene derivative with N, N-dimethylformamide, and comprises the following steps: the molar ratio of the styrene derivative with the structure shown in the formula 1 to the styrene derivative with the structure shown in the formula 2 is 1-3: 1-3.

4. The method of claim 1, wherein the 3,5-disubstituted pyridine is prepared by mixing a styrene derivative with N, N-dimethylformamide, and comprises the following steps: the total molar ratio of the peroxydisulfate to the mixed styrene derivative is 1-5: 1.

5. The method of claim 4, wherein the step of preparing 3,5-disubstituted pyridine comprises mixing styrene derivative with N, N-dimethylformamide, wherein: the peroxydisulfate is at least one of potassium peroxydisulfate, ammonium peroxydisulfate and sodium peroxydisulfate.

6. The method of claim 1, wherein the 3,5-disubstituted pyridine is prepared by mixing a styrene derivative with N, N-dimethylformamide, and comprises the following steps: the total molar ratio of the iodized salt to the mixed styrene derivative is 0.5-4: 1.

7. The method of claim 6, wherein the step of preparing 3,5-disubstituted pyridine comprises mixing styrene derivative with N, N-dimethylformamide: the iodine salt is potassium iodide and/or ammonium iodide.

8. The method of claim 1, wherein the 3,5-disubstituted pyridine is prepared by mixing a styrene derivative with N, N-dimethylformamide, and comprises the following steps: the amount of N, N-dimethylformamide used is in excess relative to the mixed styrene derivatives.

9. The method for producing 3,5-disubstituted pyridine using a mixture of a styrene derivative and N, N-dimethylformamide according to any one of claims 1 to 8, wherein: the cyclization reaction conditions are as follows: reacting for 18-30 hours at the temperature of 120-150 ℃.

10. The method of claim 9, wherein the step of preparing 3,5-disubstituted pyridine comprises mixing styrene derivative with N, N-dimethylformamide, wherein: the cyclization reaction conditions are as follows: reacting for 20-28 hours at 130-140 ℃.

Technical Field

The invention relates to a method for synthesizing 3,5-disubstituted pyridine, in particular to a method for obtaining mixed 3,5-disubstituted pyridine with a symmetrical structure and an asymmetrical structure by one-step cyclization reaction of mixed styrene derivatives and N, N-dimethylformamide under the oxidation action of peroxydisulfate and the catalytic action of iodide, belonging to the technical field of organic synthesis.

Background

Pyridine compounds are heterocyclic compounds which are widely researched so far. The derivatives thereof are ubiquitous in various natural products and have important significance in medicine and agricultural chemical research. Among the substituted pyridines, some 3,5-disubstituted pyridines exhibit significant antibacterial activity, such as Sch-21418, i.e., 3, 5-bis (4-hydroxyphenyl) pyridines, which have comparatively good inhibitory activity against inflammatory factors. In the immunized rat model, bis-imidazopyridine inhibited DNA topoisomerase II and was cytotoxic to Pneumocystis carinii, while having moderate anti-HIV-1 activity. The wide pharmacological properties of substituted pyridines have stimulated research interest in organic synthetic chemists.

Currently, the synthesis of3,5-diarylpyridines still relies to a large extent on transition metal catalyzed cross-coupling reactions at higher temperatures (Jacquesrid U, Router S, Dias N, et al. Synthesis of 2,5-and 3,5-diarylpyridine derivatives for DNA recognition and cytoxicity. European Journal of Medicinal Chemistry 2005,40(11): 1087. multidentate cyclization 1095.) only a few reports suggest that 3,5-disubstituted pyridines can be constructed by small molecule multicomponent cyclization reactions (Sathish M, Chemna J, Hari Krishana N, et al. Iron-mediated-site synthesis of3,5-diarylpyridines from. beta. -nitrostyrenes. Journal of Organic Chemistry 2016. 2159.).

In 1953, Eliel and his colleagues studied the synthesis of papaverine and isolated a new compound characterized as 3, 5-bis (3, 4-dimethoxyphenyl) pyridine, instead of papaverine (Chen W-T, Bao W-H, Ying W-W, et. compressor-catalyzed chromatography reaction of 2-oxides with intermediates: simple synthesis of irregular urea derivatives, emission Journal of organic chemistry,2018,7(6): 1057-.

In 2003, Bennasar and colleagues reported reactions for the synthesis of3, 5-disubstituted pyridines from 3-substituted pyridines (Bennasar M L s, Zulaca E, Roca T, et al. A synthetic entry to 3,5-disubstituted pyridine. tetrahedrons Letters,2003,44(25): 4711-. The reaction is that after acylation reaction of N-alkyl-1, 4-dihydropyridine derivative, the target product is obtained through N-dealkylation and oxidation in turn, and the reaction is as the following equation. The synthesis route of the reaction is long, and the product yield is low.

In 2010, Chuang group reported the synthesis of a series of disubstituted pyridine derivatives from acetic acid promoted acryloyl azide compounds via cycloaddition (Chuang T H, Chen Y C, Pola S.Use of the current utilization arrangement of acrylic based azides in the synthesis of3, 5-disubstucted pyridine, the mechanical reactants, the Journal of Organic Chemistry,2010,75(19):6625-6630.) as a more convenient synthetic method for the production of3, 5-disubstituted pyridine, the reaction equation below, which gives 3,5-disubstituted pyridine with poor selectivity to obtain two different pyridine products.

Jiano topic group reported utilization (NH)₄)₂Ce(NO₃)₆As a nitrogen source, copper catalyzes the reaction for cyclizing and synthesizing 3,5-disubstituted pyridine from Chihibabin-type phenylacetaldehyde (Li Z, Huang X, Chen F, et al. Cu-catalyzed condensation synthesis of pyridines and 2- (1H) -pyridines from acetic anhydrides and ligands, 2015,17(3):584-587.) the following reaction scheme is given. In 2014, yellow and colleagues have reported a reaction for synthesizing 3,5-disubstituted pyridine from phenylacetaldehyde, which can synthesize substituted pyridine from phenylacetaldehyde without metal catalysis by using ammonium acetate as a nitrogen source (Yan R, Zhou X, Li M, ethyl. metal-free synthesis of substistied pyridines from aldehydes and NH4 OAcurder air. RSC Advances,2014,4(92): 50369-50372.).

In 2016, Kamal and colleagues reported the iron-catalyzed synthesis of3, 5-disubstituted pyridines from β -nitrostyrene (Sathish M, Chemna J, Hari Krishna N, et al, iron-catalyzed one-pot synthesis of3,5-diarylpyridines from β -nitrostyrenes. the Journal of Organic Chemistry,2016,81(5): 2159-. The reaction has the advantages of simple operation, mild condition, short reaction time and the like, but the cost of the substrate raw material is high. The reaction is as follows.

Disclosure of Invention

Aiming at the defects of high raw material cost, metal catalysis, low yield and the like of a synthetic method of3, 5-disubstituted pyridine in the prior art, the invention aims to provide a method for synthesizing the 3,5-disubstituted pyridine by catalyzing mixed styrene derivatives and DMF (dimethyl formamide) through one-step oxidative cyclization by using iodonium salt, the method has the advantages of low cost of raw materials and catalysts, mild reaction conditions and capability of obtaining the symmetrical and asymmetrical 3,5-disubstituted pyridine at high yield.

In order to achieve the technical purpose, the invention provides a method for constructing 3,5-disubstituted pyridine by using a mixed styrene derivative and N, N-dimethylformamide, which comprises the step of carrying out cyclization reaction on the mixed styrene derivative, the N, N-dimethylformamide and peroxydisulfate under the catalysis of iodonium salt to obtain the 3,5-disubstituted pyridine;

the mixed styrene derivative is composed of aryl ethylene with a structure shown in a formula 1 and aryl ethylene with a structure shown in a formula 2:

the 3,5-disubstituted pyridine consists of3, 5-disubstituted pyridines with structures of formulas 3 to 5:

wherein the content of the first and second substances,

R₁and R₂Independently selected from hydrogen, alkyl or halogen substituents, and R₁And R₂The same groups are not selected at the same time.

As a preferred embodiment, R₁And R₂Different 3,5-disubstituted pyridines can be obtained by using different substituent groups, which are common substituent groups on a benzene ring. R₁And R₂The position of the substituent on the benzene ring is not limited and can be ortho, meta or para of the vinyl, R₁And R₂The same substituents are not present and asymmetric 3,5-disubstituted pyridine products are not obtained when the same substituents are selected. R₁And R₂When different substituents are selected, the product contains both symmetrical and asymmetrical 3,5-disubstituted pyridine products. R₁And R₂Are common small molecule organic radicals, e.g. C₁～C₅Alkyl or halogen substituents of (a). In general, the alkyl group may be a straight chain alkyl group or a branched chain alkyl group, preferably a straight chain alkyl group such as methyl, ethyl, propyl, butyl, and the like. Halogen substituents are often fluorine substituents or chlorine substituents. In general, the cyclization reaction product of the mixed styrene derivative and DMF has a higher ratio of the asymmetric 3,5-disubstituted pyridine product relative to the symmetric 3,5-disubstituted pyridine product. The influence of the electron effect on the cyclization reaction of DMF and styrene derivatives is slightly different, the yield of the product with the substituent of tert-butyl on the benzene ring is higher than that of the product with the substituent of methyl on the benzene ring, and the yield of the product with the substituent of methyl on the benzene ring is higher than that of the product with the substituent of halogen on the benzene ring, which indicates that the reaction effect gradually becomes better along with the increase of the electron donating capability of the substituent on the benzene ring.

As a preferable scheme, the molar ratio of the styrene derivative with the structure shown in the formula 1 to the styrene derivative with the structure shown in the formula 2 is 1-3: 1-3. Within the selected range, too high or too low of either styrene derivative will favor a symmetrical 3,5-disubstituted pyridine product, preferably in a ratio of 1: 1.

As a preferred technical scheme, the total molar ratio of the peroxydisulfate to the mixed styrene derivative is 1-5: 1; the total molar ratio of peroxydisulfate to mixed styrene derivatives is most preferably 3-4: 1. Too high or too low a proportion of peroxodisulfate will reduce the overall yield of3, 5-disubstituted pyridine product.

As a preferred technical scheme, the peroxydisulfate is at least one of potassium peroxydisulfate, ammonium peroxydisulfate and sodium peroxydisulfate. Most preferred is potassium peroxodisulfate.

As a preferable technical scheme, the total molar ratio of the iodized salt to the mixed styrene derivative is 0.5-4: 1. The total molar ratio of the iodonium salt to the mixed styrene derivative is most preferably 1.5-2: 1.

As a preferred technical scheme, the iodine salt is potassium iodide and/or ammonium iodide; most preferred is potassium iodide.

As a preferred embodiment, the amount of N, N-dimethylformamide used is in excess relative to the mixed styrene derivatives, N-dimethylformamide acting as a benign solvent for the reaction on the one hand and as a substrate for the reaction on the other hand, so that a sufficient excess of N, N-dimethylformamide relative to styrene may be used.

As a preferred technical scheme, the cyclization reaction conditions are as follows: reacting for 18-30 hours at the temperature of 120-150 ℃. Most preferred conditions for the cyclization reaction are: reacting for 20-28 hours at 130-140 ℃.

The reaction mechanism of the invention for constructing the 3,5-disubstituted pyridine by using the mixed styrene derivative and the N, N-dimethylformamide through cyclization reaction is as follows: DMF is easily decomposed under the action of potassium iodide and potassium peroxodisulfate to form formaldehyde and dimethylamine, and at the same time, styrene derivative A (containing R)₁Substituents) at KI/K₂S₂O₈Oxidizing under the action of the catalyst to generate phenylacetaldehyde compounds 2, condensing the phenylacetaldehyde compounds 2 with formaldehyde to obtain an intermediate 3, carrying out ammonia-aldehyde condensation on the intermediate 3 and dimethylamine to obtain an intermediate 4 positive ion, and carrying out reaction on the intermediate 4 and a styrene derivative B (containing R)₂Substituent) or styrenated compound A (containingR₁Substituent) to obtain the target product. Likewise, it is possible to use the styrene derivative B (containing R)₂Substituent group) is oxidized into phenylacetaldehyde compounds 2, the reaction mechanism is similar to that described above, and three types of3, 5-disubstituted pyridines of AA, AB and BB are finally obtained, and the AB type 3,5-disubstituted pyridine can be obtained in both reaction modes, and the proportion of the AB type 3,5-disubstituted pyridine is higher than that of the AA type 3,5-disubstituted pyridine or the BB type 3,5-disubstituted pyridine.

Alternatively, the first and second electrodes may be,

compared with the prior art, the technical scheme of the invention has the following beneficial technical effects:

the technical scheme of the invention adopts cheap and easily available styrene derivatives as a carbon source and DMF as a carbon-nitrogen source, and has the advantages of wide raw material source and low cost;

according to the technical scheme, transition metal is not required to be used as a catalyst, and iodine salt which is pollution-free and low in cost is used as the catalyst;

the technical scheme of the invention has mild reaction conditions, can obtain the target product by one-pot reaction in one step, has simple steps and operation, and is beneficial to expanding production;

the technical scheme of the invention has high yield of the target product of the cyclization reaction, and can simultaneously obtain two 3,5-disubstituted pyridine products of symmetry and asymmetry;

the technical scheme of the invention has wide adaptability to substrates, and corresponding 3,5-disubstituted pyridine can be obtained by some styrene derivatives containing common substituent groups.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of 3- (3-methyl) phenyl-5- (2-chloro) phenyl-pyridine prepared in example 1;

FIG. 2 is a nuclear magnetic carbon spectrum of 3- (3-methyl) phenyl-5- (2-chloro) phenyl-pyridine prepared in example 1;

FIG. 3 is a nuclear magnetic hydrogen spectrum of 3-phenyl-5- (4-tert-butyl) phenylpyridine prepared in example 3;

FIG. 4 is a nuclear magnetic carbon spectrum of 3-phenyl-5- (4-tert-butyl) phenylpyridine prepared in example 3.

Detailed Description

The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.

The chemicals used in the following examples are commercially available, conventional, analytically pure chemicals.

N, N-Dimethylformamide (DMF), styrene and 4-tert-butylstyrene are taken as template substrates, and factors influencing the cyclization reaction are systematically examined, wherein the factors comprise the type and the amount of an oxidant, the type and the amount of an additive, the reaction temperature, the reaction time and the like.

1. Optimization of oxidant species:

under the condition of ensuring that other factors of the reaction are not changed, different kinds of oxidants are respectively added into the system to investigate the influence of the oxidants on the cyclization reaction. The results of the experiment are shown in table 1. When potassium peroxodisulfate (K) is used₂S₂O₈) When the N, N-dimethylformamide is used as an oxidant for cyclization reaction of a synthon, the total yield of the 3,5-disubstituted pyridine reaches 56 percent. Better yields can be achieved with ammonium peroxodisulfate and sodium peroxodisulfate.

TABLE 1 Effect of oxidizing Agents on the reaction

Reaction conditions are as follows: styrene (0.25mmol), 4-tert-butylstyrene (0.25mmol), DMF (2mL), KI (0.75mmol), oxidizing agent (1.5mmol) were reacted at 140 ℃ for 24 h.

2. Optimizing the using amount of the oxidant:

when determiningPotassium peroxodisulfate (K)₂S₂O₈) Is the optimum oxidant for promoting the reaction, by adding an equal gradient of K₂S₂O₈The amount of oxidant used was examined. The results of the experiment are shown in table 2. Through control experiments, when the dosage of the added oxidant is between 0 mmol and 1.5mmol, the total yield of the 3,5-disubstituted pyridine is increased along with the gradual increase of the dosage of the oxidant; when the amount of the oxidizing agent added is 0, the reaction does not proceed, indicating that the oxidizing agent is one of the indispensable conditions for the reaction; when the amount of the added oxidizing agent is 1.5mmol, the total yield of the 3,5-disubstituted pyridine is 56% at the highest, and when the amount of the added oxidizing agent is increased, the total yield of the 3,5-disubstituted pyridine is reduced, which is probably because the amount of the added oxidizing agent increases reaction byproducts to hinder the generation of the target product. Therefore, it can be finally determined that the optimum amount of the oxidizing agent is 1.5 mmol.

TABLE 2 Effect of oxidant usage on the reaction

Reaction conditions are as follows: styrene (0.25mmol), 4-tert-butylstyrene (0.25mmol), DMF (2mL), KI (0.75mmol), K₂S₂O₈(X mmol) and reacted at 140 ℃ for 24 h.

3. Optimization of additive types: after the type and the dosage of the oxidant are determined through the experiments, the additive is optimized on the basis. First, the type of additive is optimized to find out the appropriate additive. The results of the experiment are shown in table 3. When potassium iodide is added into the reaction system, the reaction effect is that the total yield of the 3,5-disubstituted pyridine is 56 percent, and the ammonium iodide is inferior. When the iodine simple substance is added, the reaction yield is low, and when no additive or additives of tetrabutylammonium iodide (TBAI) and cuprous iodide (CuI) are added, the reaction basically does not proceed. Thus, it was finally determined that potassium iodide was the optimum additive.

TABLE 3 Effect of additive type on the reaction

Reaction conditions are as follows: styrene (0.25mmol), 4-tert-butylstyrene (0.25mmol), DMF (2mL), K₂S₂O₈(1.5mmol), additive (0.75mmol), reacted at 140 ℃ for 24 h.

4. Optimizing the dosage of the additive:

the most suitable type of additive for this reaction was determined by the above experiment, and the amount of additive used was examined next. The results of the experiment are shown in table 4. It is found through control experiments that when the amount of potassium iodide (KI) added to the system is 0, the reaction does not proceed, which indicates that the additive is one of the indispensable conditions for the olefin cyclization reaction, the total yield of3, 5-disubstituted pyridine gradually increases with the increase of the amount of potassium iodide, and when the amount of potassium iodide is 0.75mmol, the total yield of3, 5-disubstituted pyridine is 56% at most. When the amount of potassium iodide is further increased thereafter, the yield of the objective product is rather decreased and the by-products are increased. Thus, the most suitable amount of additive was finally determined to be 0.75 mmol.

TABLE 4 Effect of additive amounts on the reaction

Reaction conditions are as follows: styrene (0.25mmol), 4-tert-butylstyrene (0).25mmol)，DMF(2mL)，K₂S₂O₈(1.5mmol), KI (Xmmol) and reacted at 140 ℃ for 24 h.

5. Optimization of reaction temperature:

temperature is a very important influencing factor for chemical reactions. Therefore, the temperature factor is systematically studied. The results of the experiment are shown in Table 5. From the results, it can be seen that: when the reaction temperature is gradually increased from 80 ℃ to 140 ℃, the total yield of the 3,5-disubstituted pyridine is gradually increased, and when the temperature is continuously increased to 150 ℃ and 155 ℃, the total yield of the 3,5-disubstituted pyridine is reduced. The yield of the target product reached a maximum of 56% at a temperature of 140 ℃. Therefore, 140 ℃ was chosen as the optimum temperature for the reaction.

TABLE 5 influence of reaction temperature on the reaction

Reaction conditions are as follows: styrene (0.25mmol), 4-tert-butylstyrene (0.25mmol), DMF (2mL), K₂S₂O₈(1.5mmol), KI (0.75mmol), reacted for 24 h.

6. Optimization of reaction time

For a chemical reaction, the length of the reaction is critical to the effect of the magnitude of the reaction yield. After the types and the amounts of the oxidizing agents and the additives are determined, control experiments of the reaction from 6h to 48h are explored. The results of the experiment are shown in Table 6. The total yield of the 3,5-disubstituted pyridine is gradually increased along with the increase of the reaction time, the reaction effect is best when the reaction time is 24 hours, and the total yield of the 3,5-disubstituted pyridine reaches 56 percent. The reaction time was continued to increase, and the reaction yield did not increase significantly but decreased, so 24h was selected as the optimum reaction time.

TABLE 6 Effect of reaction time on the reaction

Reaction conditions are as follows: styrene (0.25mmol), 4-tert-butylstyrene (0.25mmol), DMF (2mL), K₂S₂O₈(1.5mmol) and KI (0.75mmol) were reacted at 140 ℃.

In summary, by examining the factors such as the type and amount of the oxidant, the type and amount of the additive, the reaction temperature and the reaction time, the optimal reaction conditions for the cyclization reaction of DMF and olefin are finally determined as follows: styrene (0.25mmol), 4-tert-butylstyrene (0.25mmol), DMF (2mL), K₂S₂O₈(1.5mmol), KI (0.75mmol), at 140 ℃ for 24 h.

After the optimal reaction conditions are determined through the optimized reaction experiment, the application range and functional group compatibility of the reaction of synthesizing the 3,5-disubstituted pyridine compound by cyclizing the N, N-dimethylformamide and the olefin to the olefin compound are considered, and the following examples are all carried out under the optimal reaction conditions.