Synthesis method for converting pyridine into aromatic dialdehyde

Abstract

The present invention belongs to the field of organic synthesis, and specifically relates to a synthesis method for converting pyridine into an aromatic dialdehyde. A method for converting pyridine into an aromatic dialdehyde comprises the following steps: activating pyridine using an activating reagent, performing nucleophilic ring-opening of the activated pyridine with an amine to generate streptomycin, then introducing a Vilsmeier reagent, and obtaining an aromatic dialdehyde through ring formation and hydrolysis. The substrate used in this method, namely pyridine, is inexpensive and readily available, and pyridine modification techniques are mature. The operation is simple, functional groups are abundant, reaction yield is relatively good, the atom economy is favorable, and the reaction shows good functional group tolerance. It is applicable to common substituents such as alkyl, halogen, alkoxy, aryl and ester groups, whether mono-substituted or multi-substituted, and has good application potential.

Description

A synthetic method for converting pyridine into aromatic dialdehyde TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthetic method for converting pyridine into aromatic dialdehyde. BACKGROUND

[0002] Naphthalene-1,3-dicarboxaldehyde is an important organic compound, and its molecular structure comprises two aldehyde groups (-CHO) connected to the 1 and 3 positions of a naphthalene ring. Currently, there are four schemes for synthesizing naphthalene-1,3-dicarboxaldehyde in the prior art. The first method uses 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde as a raw material, which is reacted with 2,3-dichloro-5,6-dicyano-p-benzoquinone, and the specific scheme is as follows:

[0003] The disadvantage of this method is that the raw material is not easy to obtain, and no commercial product of the raw material has been found.

[0004] The second method uses 1,3-dimethylnaphthalene as a raw material, which is subjected to bromination, hydrolysis and oxidation to obtain the product, and the specific scheme is as follows:

[0005] The problem of this method is that the raw material is expensive, and the price of commercially available 1,3-dimethylnaphthalene is 500 RMB / g; and multiple steps are required, some steps are not easy to control, and the yield is low.

[0006] The third method uses 1,4-dihydro-1-naphthalene carboxylic acid as a raw material, which is subjected to formylation by Vilsmeier reagent to obtain the product, and the specific scheme is as follows:

[0007] The disadvantage of this method is that the raw material is not easy to obtain, and no commercial product of 1,4-dihydro-1-naphthalene carboxylic acid has been found. Related raw materials, such as 1,4-dihydrobenzoic acid, are expensive, with a price of 2400 RMB / g; and the substrate is limited, and is only suitable for 1,4-dihydrobenzoic acid, 1,4-dihydrobenzoic acid containing a methyl substituent, and 1,4-dihydro-1-naphthalene carboxylic acid.

[0008] The fourth method uses 1,1'-(naphthalene-1,3-diyl(methylene))bis(pyridin-1-ium) as a raw material, which is treated with pyridine, sodium hydroxide, p-dimethylaminonitrobenzene, sulfuric acid, and the like, and the specific scheme is as follows:

[0009] The disadvantage of this scheme is that the raw material is not easy to obtain; in addition to the above-mentioned disadvantages, these synthetic methods only synthesize naphthalene-1,3-dicarboxaldehyde, and there is no other functional group naphthalene dicarboxaldehyde or polycyclic aromatic dicarboxaldehyde, so an economic and efficient method for synthesizing aromatic dicarboxaldehyde is urgently needed. The synthetic method for converting pyridine into aromatic dicarboxaldehyde invented by the patent has better atomic economy, good functional group tolerance, and more abundant and diverse product range. SUMMARY

[0010] In view of the problems and shortcomings of the prior art, the present application provides a synthetic method for converting pyridine into aromatic dicarboxaldehyde, comprising the following steps:

[0011] The activated pyridine is used to activate the pyridine, and the activated pyridine is subjected to nucleophilic ring opening with amine to generate chain cyanin, and then Vilsmeier reagent is introduced to obtain aromatic dicarboxaldehyde through ring closure and hydrolysis.

[0012] Further, the activated reagent is any one of 1-chloro-2,4-dinitrobenzene, triflic anhydride, benzyl bromide, halogenated alkane, and acyl halide.

[0013] Further, the activated pyridine in the activated reagent is any one of N-2,4-dinitrobenzene-3-(hetero)aryl pyridine quaternary ammonium salt and N-2,4-dinitrobenzene-3-alkenyl pyridine quaternary ammonium salt.

[0014] Further, the structure of the pyridine is any one of the following:

[0015] In the formula, R1 is selected from any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, heteroaryl, halogen, and alkoxy, the number of R1 is 1-2, and the combination site of R1 is at least one of the remaining 5 combination sites on the benzene ring; R2 is selected from any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, and heteroaryl; Y is selected from any one of C, N, O, and S.

[0016] Further, the structure of the aromatic dicarboxaldehyde is any one of the following:

[0017] In the formula, R1 is selected from any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, heteroaryl, halogen, and alkoxy, the combination site of R1 is the 6,7 site of the naphthalene ring, R2 is selected from any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, and heteroaryl; Y is selected from any one of C, N, O, and S.

[0018] Further, the step of ring-opening reaction of the activated pyridine and amine uses chloroform as solvent, the reaction temperature is 0-30℃, and the reaction time is 1-2 hours.

[0019] Further, the amine includes any one of primary amine and secondary amine.

[0020] Further, in the reaction of the ring-opened product and Vilsmeier reagent, the reaction temperature is 40-80℃, and the reaction time is 6-20 hours.

[0021] Further, the molar ratio of the activated pyridine and Vilsmeier reagent is 1:6-10.

[0022] Technical effects

[0023] (1) The synthesis method for converting pyridine into aromatic dialdehyde provided by the present application uses pyridine as substrate, which is cheap and easy to obtain, and the modification technology for pyridine is mature, simple to operate, rich in functional groups, has good reaction yield, good atom economy, good tolerance to functional groups, and is applicable to single substitution or multi-substitution of common alkyl, halogen, alkoxy, aryl, ester group, etc. The product is a kind of aromatic dialdehyde with rich types.

[0024] (2) The synthesis method for converting pyridine into aromatic dialdehyde provided by the present application has more rich types and ranges of products, and most of the products are synthesized for the first time, and there is no other synthesis method. In addition, the dialdehyde structure of the product can be further modified through oxidation, reduction, nucleophilic addition, aldol condensation, etc. to construct more complex structure molecules.

[0025] (3) The synthesis method for converting pyridine into aromatic dialdehyde provided by the present application has wide prospects. For drug molecules, drug molecule fragments or precursors containing a pyridine fragment with a meta-substituted group, the pyridine structure fragment can be modified and modified by the present application to construct products containing special drug effects, and through further modification, complex compound molecules and drug molecules with greater application potential can be obtained. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the example embodiments of the present application, the following will briefly introduce the drawings needed in the examples. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can also be obtained without creative labor. In the drawings:

[0027] Figure 1 is a synthesis scheme of naphthalene-1,3-dialdehyde 2-a in Example 1 of the present application.1 HNMR spectrum;

[0028] Figure 2 is a HNMR spectrum of naphthalene-1,3-dicarboxaldehyde 2-a of Example 1 of the present application; 13 CNMR spectrum;

[0029] Figure 3 is a HNMR spectrum of benzofuran-5,7-dicarboxaldehyde 2-b of Example 2 of the present application; 1 HNMR spectrum;

[0030] Figure 4 is a CNMR spectrum of benzofuran-5,7-dicarboxaldehyde 2-b of Example 2 of the present application; 13 CNMR spectrum;

[0031] Figure 5 is a HNMR spectrum of 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c of Example 3 of the present application; 1 HNMR spectrum;

[0032] Figure 6 is a CNMR spectrum of 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c of Example 3 of the present application; 13 CNMR spectrum. DETAILED DESCRIPTION

[0033] The technical solutions of the present application will be described clearly and completely below in combination with Examples 1-3 of the present application and Figures 1-6. Obviously, the described examples are only some of the examples of the present application, but not all the examples. Based on the examples in the present application, all the other examples obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0034] The present application provides a synthetic method for converting pyridine into aromatic dialdehyde, which specifically comprises the following steps: activating pyridine by using an activating agent (1-chloro-2,4-dinitrobenzene (DNP-Cl), trifluoromethanesulfonic anhydride, benzyl bromide, halogenated alkane, acyl halide, etc. can be used), preferably, 1-chloro-2,4-dinitrobenzene has the best activation effect. The activated pyridine is subjected to nucleophilic ring-opening with amine to generate chain cyanin, then Vilsmeier reagent is introduced, and aromatic dialdehyde is obtained through ring closure and hydrolysis; the organic solvent used in the activation process includes at least one of acetone, ethanol, methanol and toluene, the reaction temperature is 40-80°C, and the reaction time is 12-24 hours which is the best; the quaternary ammonium activation product is directly precipitated or obtained through fast silica gel column chromatography (petroleum ether / ethyl acetate is first selected as the mobile phase, and then ethanol is selected as the mobile phase).

[0035] Example 1

[0036] A synthetic method for converting pyridine into aromatic dialdehyde, which comprises the following steps: the reaction formula is as follows:

[0037] wherein DNP is a 2,4-dinitrophenyl group;

[0038] Into a 25 mL reaction tube was added a magnetic stir bar, N-2,4-dinitrophenyl-3- phenylpyridinium salt 1-a (0.1 mmol, 35.7 mg), chloroform (1.0 mL), and pyrrolidine (0.3 mmol, 24.6 uL) under air. The reaction mixture was stirred at room temperature for 5 min, then capped with a rubber septum, and stirred at room temperature for 1 h. The solution was added to Vilsmeier reagent (freshly prepared), capped with a rubber septum, and stirred at 60 °C for 10 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate as the mobile phase to give naphthalene-1,3-dicarboxaldehyde 1-b (pale yellow solid, 92% yield).

[0039] Naphthalene-1,3-dicarboxaldehyde 2-a was characterized as follows:

[0040] as a pale yellow solid,

[0041] 1 HNMR (400 MHz, Chloroform-d) δ 10.41 (s, 1H), 10.21 (s, 1H), 9.37 - 9.19 (d, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.08 (dd, J = 8.2, 1.4 Hz, 1H), 7.83 (ddd, J = 8.6, 7.0, 1.4 Hz, 1H), 7.70 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H);

[0042] 13 CNMR (101 MHz, CDC13) δ 192.0, 189.8, 138.9, 132.5, 132.2, 132.0, 131.9, 131.2, 131.1, 129.1, 127.1, 124.5.

[0043] Example 2

[0044] A synthetic method for converting pyridine to aromatic dialdehyde, comprising the following steps:

[0045] wherein DNP is a 2,4-dinitrophenyl group;

[0046] In air, a 25 mL reaction tube was charged with a magnetic stir bar, N-2,4-dinitrobenzene-3-(furan-3-yl)pyridinium salt 1-b (0.1 mmol, 34.7 mg), chloroform (1.0 mL). After stirring at room temperature for 5 min, pyrrolidine (0.3 mmol, 24.6 ul) was added dropwise, and the reaction tube was capped with a rubber septum. After stirring at room temperature for 1 h, the solution was added to Vilsmeier reagent (freshly prepared), and the reaction tube was capped with a rubber septum. The reaction mixture was stirred at 60 °C for 10 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using petroleum ether / ethyl acetate as the eluent to give benzofuran-5,7-dicarboxaldehyde 2-b (pale yellow solid, 70% yield).

[0047] Benzofuran-5,7-dicarboxaldehyde 2-b was characterized as follows:

[0048] as a pale yellow solid,

[0049] 1 HNMR (400 MHz, Chloroform-d) δ 10.28 (s, 1H), 10.16 (s, 1H), 8.29 (d, J = 1.3 Hz, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 2.2, 0.9 Hz, 1H);

[0050] 13 CNMR (101 MHz, CDC13) δ 191.0, 190.4, 155.4, 151.9, 133.0, 131.5, 129.6, 117.7, 107.5.

[0051] Example 3

[0052] A synthetic method for converting pyridine to aromatic dialdehyde, comprising the following steps:

[0053] wherein DNP is a 2,4-dinitrophenyl group;

[0054] In air, a 25 mL reaction test tube was added with a magnetic stirrer, N-2,4-dinitrobenzene-3-(cyclohex-1-en-1-yl) pyridine quaternary ammonium salt 1-c (0.1 mmol, 36.1 mg), chloroform (1.0 ml); after stirring at room temperature for 5 minutes, pyrrolidine (0.3 mmol, 24.6 ul) was added dropwise, and then a rubber plug was inserted, and after stirring at room temperature for 1 hour, the above solution was added into Vilsmeier reagent (freshly prepared), a rubber plug was inserted, and reaction was carried out at 60°C for 10 hours; after the reaction was completed, the reaction system was cooled to room temperature, and the solvent was removed under reduced pressure; petroleum ether / ethyl acetate was selected as the mobile phase, and fast silica gel column chromatography was used for purification to obtain 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c (light yellow liquid, yield 76%).

[0055] 5,6,7,8-Tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c was characterized as follows:

[0056] It is a light yellow liquid.

[0057] 1 HNMR (400MHz, Chloroform-d) δ 10.31 (s, 1H), 10.01 (s, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 3.26 (t, J=6.1 Hz, 2H), 2.91 (t, J=6.2 Hz, 2H), 1.92-1.78 (m, 4H);

[0058] 13 CNMR (101MHz, CDCl3) δ 192.1, 191.3, 146.6, 140.1, 134.7, 134.5, 133.9, 131.8, 29.9, 27.0, 22.3, 21.9.

[0059] The synthesis method for converting pyridine into aromatic dialdehyde provided by the application activates pyridine by using 1-chloro-2,4-dinitrobenzene quaternary ammonium, generates chain cyanin by nucleophilic ring opening of the activated pyridine and amine, introduces Vilsmeier reagent, and obtains aromatic dialdehyde through ring closure and hydrolysis.

[0060] The synthesis method for converting pyridine into aromatic dialdehyde provided by the application has the following main advantages: firstly, the raw material is cheap and easy to obtain; the raw material is pyridine, and the modification technology of pyridine is mature, simple to operate, rich in functional groups, good in reaction yield, good in atomic economy, good in functional group tolerance, applicable to common alkyl, halogen, alkoxy, aryl, ester group, and single substitution or multiple substitution.

[0061] The application provides a synthesis method for converting pyridine into aromatic dialdehyde, and the obtained product is more rich in range and type. In addition, the product with a dialdehyde structure can be further modified through oxidation, reduction, nucleophilic addition, hydroxy aldehyde condensation and the like, so as to construct a more complex structure molecule.

[0062] The application provides a synthesis method for converting pyridine into aromatic dialdehyde, and the obtained product is more rich in range and type. In addition, the product with a dialdehyde structure can be further modified through oxidation, reduction, nucleophilic addition, hydroxy aldehyde condensation and the like, so as to construct a more complex structure molecule.

Claims

1. A synthetic method for converting pyridine to aromatic dialdehydes, characterized by, The method comprises the following steps: The pyridine is activated by an activating agent, the activated pyridine is subjected to nucleophilic ring-opening reaction with an amine to obtain a chainocin, and then a Vilsmeier reagent is introduced to obtain an aromatic dialdehyde through ring closure and hydrolysis.

2. The method of claim 1, wherein the method comprises: reacting the pyridine with the compound of formula (II) to form the compound of formula (III); and reacting the compound of formula (III) with the compound of formula (IV) to form the compound of formula (V). The activating agent is any one of 1-chloro-2,4-dinitrobenzene, triflic anhydride, benzyl bromide, halogenated alkane, and acyl halide.

3. The method of claim 2, wherein the method comprises: reacting the pyridine with the compound of formula (II) to form the compound of formula (III); and reacting the compound of formula (III) with the compound of formula (IV) to form the compound of formula (V). The activated pyridine in the activating agent is any one of N-2,4-dinitrobenzene-3-(hetero)aryl pyridine quaternary ammonium salt and N-2,4-dinitrobenzene-3-alkenyl pyridine quaternary ammonium salt.

4. The method of claim 1, wherein the method is characterized by, The pyridine has a structural formula that is any one of the following: In the formula, R1 is any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, heteroaryl, halogen, and alkoxy, the number of R1 is 1-2, and the combination site of R1 is at least one of the remaining 5 combination sites on the benzene ring; R2 is any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, and heteroaryl; and Y is any one of C, N, O, and S.

5. The method of claim 1, wherein the method is characterized by, The structural formula of the aromatic dialdehyde is any one of the following: In the formula, R1 is any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, heteroaryl, halogen, and alkoxy, the combination site of R1 is the 6,7 site of the naphthalene ring, R2 is any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, and heteroaryl; and Y is any one of C, N, O, and S.

6. The method of claim 1, wherein the method is characterized by, The nucleophilic ring-opening reaction of the activated pyridine with the amine is carried out using chloroform as a solvent, the reaction temperature is 0-30°C, and the reaction time is 1-2 hours.

7. The method of claim 1, wherein the method is characterized by, The amine includes any one of primary amine and secondary amine.

8. The method of claim 1, wherein the method is characterized by, In the reaction of the ring-opening product with the Vilsmeier reagent, the reaction temperature is 40-80°C, and the reaction time is 6-20 hours.

9. The method of claim 1, wherein the method is characterized by, The molar ratio of the activated pyridine to the Vilsmeier reagent is 1:6-10.

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