A synthetic method for converting pyridine into aromatic dialdehydes

Abstract

This invention belongs to the field of organic synthesis, specifically relating to a synthetic method for converting pyridine into aromatic dialdehydes. The synthetic method for converting pyridine into aromatic dialdehydes includes the following steps: activating pyridine with an activating reagent, reacting the activated pyridine with an amine via nucleophilic ring-opening to generate alenin, then introducing a Vilsmeier reagent, followed by ring closure and hydrolysis to obtain the aromatic dialdehyde. The substrate used in this method, pyridine, is inexpensive and readily available. Furthermore, the modification techniques for pyridine are mature, the operation is simple, the functional groups are abundant, the reaction yield is good, the atom economy is excellent, and the reaction has good tolerance to functional groups, applicable to common alkyl, halogen, alkoxy, aryl, and ester groups, whether monosubstituted or polysubstituted; it has good application potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing pyridine into aromatic dialdehydes. Background Technology

[0002] Naphthalene-1,3-dicarboxaldehyde is an important organic compound whose molecular structure contains two aldehyde groups (-CHO) attached to the 1 and 3 positions of the naphthalene ring. Currently, there are four main methods for the synthesis of naphthalene-1,3-dicarboxaldehyde. The first method uses 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde as a starting material, reacting it with 2,3-dichloro-5,6-dicyano-p-benzoquinone. The specific method is as follows:

[0003]

[0004] The drawback of this method is that the raw materials are not readily available, and no commercially available products containing the raw materials have been found.

[0005] The second method uses 1,3-dimethylnaphthalene as a raw material, and obtains the product through bromination, hydrolysis, and oxidation. The specific procedure is as follows:

[0006]

[0007] The problem with this method is that the raw materials are expensive, with commercially available 1,3-dimethylnaphthalene costing 500 RMB / g; and it requires multiple reaction steps, some of which are difficult to control, resulting in a low yield.

[0008] The third method uses 1,4-dihydro-1-naphthoic acid as a raw material, and obtains the product by formylation with Vilsmeier reagent. The specific scheme is as follows:

[0009]

[0010] The disadvantages of this method are that the raw materials are not readily available. There are no commercially available products of 1,4-dihydro-1-naphthoic acid, and related raw materials, such as 1,4-dihydrobenzoic acid, are expensive, costing RMB 2400 / g. Furthermore, the substrate is limited, and it is only applicable to 1,4-dihydrobenzoic acid and 1,4-dihydrobenzoic acid containing methyl substituents, as well as 1,4-dihydro-1-naphthoic acid.

[0011] The fourth method uses 1,1'-(naphthalene-1,3-diyl(methylene))bis(pyridin-1-onium) as a raw material, and processes it with pyridine, sodium hydroxide, p-dimethylaminonitrobenzene, sulfuric acid, etc. The specific scheme is as follows:

[0012]

[0013] The drawback of this approach is the scarcity of raw materials. Besides the aforementioned disadvantages, these synthetic methods only synthesize naphthalene-1,3-dicarboxaldehyde, without examples of other functionalized naphthalene dialdehydes or polycyclic aromatic dialdehydes. Therefore, there is an urgent need for a method for synthesizing aromatic dialdehydes that uses readily available, cost-effective, and efficient raw materials. The synthetic method for converting pyridine into aromatic dialdehydes invented in this patent has better atom economy, better tolerance to functional groups, and a wider range and variety of products. Summary of the Invention

[0014] To address the problems and shortcomings of existing technologies, this invention provides a synthetic method for converting pyridine into aromatic dialdehydes, comprising the following steps:

[0015] Pyridine was activated with an activating reagent, and the activated pyridine was nucleophilically ring-opened with an amine to generate alenin. Vilsmeier reagent was then introduced, and aromatic dialdehyde was obtained through ring closure and hydrolysis.

[0016] Furthermore, the activating agent is any one of 1-chloro-2,4-dinitrobenzene, trifluoromethanesulfonic anhydride, benzyl bromide, haloalkanes, and acyl halides.

[0017] Furthermore, the pyridine activated by 1-chloro-2,4-dinitrobenzene in the activating agent is either N-2,4-dinitrobenzene-3-(hetero)arylpyridine quaternary ammonium salt or N-2,4-dinitrobenzene-3-enylpyridine quaternary ammonium salt.

[0018] Furthermore, the pyridine has any of the following structural formulas:

[0019]

[0020] In the formula, R1 is selected from any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, heteroaryl, halogen, and alkoxy, and the number of R1 is 1 to 2, and the binding site of R1 is at least one of the remaining 5 unbound 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 element C, N, O, and S.

[0021] Furthermore, the aromatic dialdehyde has the structural formula of any of the following:

[0022]

[0023] In the formula, R1 is selected from any one of hydrogen, C1-C12 alkyl, functionalized alkyl, aryl, heteroaryl, halogen, and alkoxy, and the binding site of R1 is the 6th or 7th 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 element of C, N, O, and S.

[0024] Furthermore, in the step of the ring-opening reaction between the activated pyridine and the amine, chloroform is used as the solvent, the reaction temperature is 0-30℃, and the reaction time is 1-2 hours.

[0025] Furthermore, the amine includes any one of primary amines and secondary amines.

[0026] Furthermore, in the reaction of the ring-opening product with Vilsmeier reagent, the reaction temperature is 40-80℃ and the reaction time is 6-20 hours.

[0027] Furthermore, the molar ratio of the activated pyridine to Vilsmeier reagent is 1:6 to 10.

[0028] Technical effect

[0029] (1) The present invention provides a synthetic method for converting pyridine into aromatic dialdehydes. The substrate used in this method, pyridine, is inexpensive and readily available. Furthermore, the modification technology for pyridine is mature, the operation is simple, the functional groups are abundant, the reaction yield is good, the atom economy is excellent, and the method has good tolerance for functional groups. It is applicable to common alkyl, halogen, alkoxy, aryl, ester groups, etc., whether monosubstituted or polysubstituted. Moreover, the product is a diverse range of aromatic dialdehydes.

[0030] (2) The synthetic method for converting pyridine into aromatic dialdehydes provided by this invention yields a wider range and more diverse products, most of which are first-time synthesized and currently have no other synthetic methods. Furthermore, the dialdehyde products can be further modified through oxidation, reduction, nucleophilic addition, aldol condensation, etc., to construct more complex molecular structures.

[0031] (3) The present invention provides a synthetic method for converting pyridine into aromatic dialdehyde. This method has broad prospects. For drug molecules, drug molecule fragments or precursors containing meta-substituents in pyridine fragments, the present invention can be used to modify and alter the pyridine structural fragments to construct products with special drug effects. Through further modification, complex compound molecules and drug molecules with greater application potential can be obtained. Attached Figure Description

[0032] To more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of the present invention and should not be considered as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort. In the drawings:

[0033] Figure 1The naphthalene-1,3-dicarboxaldehyde 2-a of Example 1 of this invention 1 H NMR spectrum;

[0034] Figure 2 The naphthalene-1,3-dicarboxaldehyde 2-a of Example 1 of this invention 13 C NMR spectrum;

[0035] Figure 3 The benzofuran-5,7-dicarboxaldehyde 2-b of Example 2 of this invention 1 H NMR spectrum;

[0036] Figure 4 The benzofuran-5,7-dicarboxaldehyde 2-b of Example 2 of this invention 13 C NMR spectrum;

[0037] Figure 5 The 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c of Example 3 of this invention 1 H NMR spectrum;

[0038] Figure 6 The 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c of Example 3 of this invention 13 C10 NMR spectrum. Detailed Implementation

[0039] The following will describe in conjunction with embodiments 1-3 of the present invention and appendices. Figures 1-6 The technical solutions of the present invention have been clearly and completely described. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0040] This invention provides a synthetic method for converting pyridine into aromatic dialdehydes, specifically comprising the following steps: activating pyridine with an activating reagent (such as 1-chloro-2,4-dinitrobenzene (DNP-Cl), trifluoromethanesulfonic anhydride, benzyl bromide, haloalkanes, acyl halides, etc.), preferably with 1-chloro-2,4-dinitrobenzene showing the best activation effect. The activated pyridine undergoes nucleophilic ring-opening with an amine to generate alenin, followed by Vilsmeier reagent, and then ring-closure and hydrolysis to obtain the aromatic dialdehyde. The organic solvent used in the activation process includes at least one of acetone, ethanol, methanol, and toluene; the optimal reaction temperature is 40-80℃, and the optimal reaction time is 12-24 hours. The quaternary ammonium activation product is either directly precipitated or purified by rapid silica gel column chromatography (first using petroleum ether / ethyl acetate as the mobile phase, then using ethanol as the mobile phase).

[0041] Example 1

[0042] A synthetic method for converting pyridine into aromatic dialdehyde includes the following steps: The reaction formula is as follows:

[0043]

[0044] In the formula, DNP is a 2,4-dinitrophenyl group;

[0045] In air, a magnetic osmosis device, N-2,4-dinitrophenyl-3-phenylpyridine quaternary ammonium salt 1-a (0.1 mmol, 35.7 mg), and chloroform (1.0 mL) were added to a 25 mL reaction tube. After stirring for 5 minutes at room temperature, pyrrolidine (0.3 mmol, 24.6 μL) was added dropwise, and the tube was sealed with a rubber stopper. After stirring at room temperature for 1 hour, the solution was added to Vilsmeier reagent (freshly prepared), sealed with a rubber stopper, and reacted 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. Using petroleum ether / ethyl acetate as the mobile phase, rapid silica gel column chromatography was used to purify naphthalene-1,3-dicarboxaldehyde 1-b (pale yellow solid, yield 92%).

[0046] The characterization of naphthalene-1,3-dicarboxaldehyde 2-a is as follows:

[0047] It is a pale yellow solid.

[0048] 1 H NMR(400MHz,Chloroform-d)δ10.41(s,1H),10.21(s,1H),9.37–9.19(d,1H),8.55(d,J=1.7Hz,1H),8.43(d,J =1.7Hz,1H), 8.08(dd,J=8.2,1.4Hz,1H), 7.83(ddd,J=8.6,7.0,1.4Hz,1H), 7.70(ddd,J=8.1,6.9,1.2Hz,1H);

[0049] 13 C NMR (101MHz, CDCl3) δ192.0,189.8,138.9,132.5,132.2,132.0,131.9,131.2,131.1,129.1,127.1,124.5.

[0050] Example 2

[0051] A synthetic method for converting pyridine into aromatic dialdehyde includes the following steps: The reaction formula is as follows:

[0052]

[0053] In the formula, DNP is a 2,4-dinitrophenyl group;

[0054] In air, a magnetic flux, N-2,4-dinitrophenyl-3-(furan-3-yl)pyridine quaternary ammonium salt 1-b (0.1 mmol, 34.7 mg), and chloroform (1.0 mL) were added to a 25 mL reaction tube. After stirring for 5 minutes at room temperature, pyrrolidine (0.3 mmol, 24.6 μL) was added dropwise, and the tube was stoppered with a rubber stopper. After stirring at room temperature for 1 hour, the solution was added to Vilsmeier reagent (freshly prepared), the tube was stoppered again, and the 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. Using petroleum ether / ethyl acetate as the mobile phase, rapid silica gel column chromatography was used to purify benzofuran-5,7-dicarboxaldehyde 2-b (pale yellow solid, 70% yield).

[0055] The characterization of benzofuran-5,7-dicarboxaldehyde 2-b is as follows:

[0056] It is a pale yellow solid.

[0057] 1 H NMR (400MHz, Chloroform-d) δ10.28(s,1H), 10.16(s,1H), 8.29(d,J=1.3Hz,1H), 8.25(d,J=1.2Hz,1H), 8.01(d,J=2.2Hz,1H), 7.62(dd,J=2.2,0.9Hz,1H);

[0058] 13 C NMR (101MHz, CDCl3) δ191.0,190.4,155.4,151.9,133.0,131.5,129.6,117.7,107.5.

[0059] Example 3

[0060] A synthetic method for converting pyridine into aromatic dialdehyde includes the following steps: The reaction formula is as follows:

[0061]

[0062] In the formula, DNP is a 2,4-dinitrophenyl group;

[0063] In air, a magnetic osmosis device, N-2,4-dinitrophenyl-3-(cyclohex-1-en-1-yl)pyridine quaternary ammonium salt 1-c (0.1 mmol, 36.1 mg), and chloroform (1.0 mL) were added to a 25 mL reaction tube. After stirring at room temperature for 5 minutes, pyrrolidine (0.3 mmol, 24.6 μL) was added dropwise, and the tube was sealed with a rubber stopper. After stirring at room temperature for 1 hour, the solution was added to Vilsmeier reagent (freshly prepared), sealed with a rubber stopper, and reacted 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. Using petroleum ether / ethyl acetate as the mobile phase, 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c (pale yellow liquid, yield 76%) was purified by rapid silica gel column chromatography.

[0064] The characterization of 5,6,7,8-tetrahydronaphthalene-1,3-dicarboxaldehyde 2-c is as follows:

[0065] It is a pale yellow liquid;

[0066] 1 H NMR (400MHz, Chloroform-d) δ10.31 (s, 1H), 10.01 (s, 1H), 8.10 (d, J=1.8Hz, 1H), 7. 80 (d, J=1.7Hz, 1H), 3.26 (t, J=6.1Hz, 2H), 2.91 (t, J=6.2Hz, 2H), 1.92–1.78 (m, 4H);

[0067] 13 C NMR (101MHz, CDCl3) δ192.1,191.3,146.6,140.1,134.7,134.5,133.9,131.8,29.9,27.0,22.3,21.9.

[0068] The present invention provides a synthetic method for converting pyridine into aromatic dialdehyde, which involves activating pyridine with 1-chloro-2,4-dinitrophenyl quaternary ammonium, nucleophilically ring-opening the activated pyridine with an amine to generate acrylonitrile, introducing Vilsmeier reagent, and obtaining aromatic dialdehyde through ring closure and hydrolysis.

[0069] The present invention provides a synthetic method for converting pyridine into aromatic dialdehyde. Its main advantages are that the raw materials are inexpensive and readily available, pyridine is used as the raw material, the modification technology of pyridine is mature, the operation is simple, the functional groups are abundant, the reaction yield is good, the atom economy is good, and the tolerance to functional groups is good. It is applicable to common alkyl, halogen, alkoxy, aryl, and ester groups, as well as mono- or poly-substituted groups.

[0070] This invention provides a synthetic method for converting pyridine into aromatic dialdehydes, resulting in a wider range and variety of products. Furthermore, the dialdehyde products can be further modified through oxidation, reduction, nucleophilic addition, aldol condensation, etc., to construct more complex molecular structures.

[0071] This invention provides a synthetic method for converting pyridine into aromatic dialdehydes. By modifying and altering drug molecules, drug fragments, or precursors containing meta-substituents using this invention, products with specific drug effects can be constructed. Further modification can yield complex compound molecules and drug molecules with greater application potential.

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 generate a chain cyanine, and then a Vilsmeier reagent is introduced to perform ring closure and hydrolysis to obtain an aromatic dialdehyde; the activating agent is 1-chloro-2, 4-dinitrobenzene, and the activated pyridine 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.

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 structural formula of the pyridine is any one of the following: 、 、 、 ； In the formula, R1 is any one of hydrogen, C1-C12 alkyl, aryl, 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 and aryl; Y is any one of C, N, O and S.

3. 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, aryl, 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 and aryl; Y is any one of C, N, O and S.

4. The method of claim 1, wherein the method is characterized by, The step of subjecting the activated pyridine to nucleophilic ring-opening reaction with an amine is performed by using chloroform as a solvent, the reaction temperature is 0-30℃, and the reaction time is 1-2 hours.

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

6. 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℃, and the reaction time is 6-20 hours.

7. 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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