A fully substituted pyrrole compound and a preparation method thereof

Abstract

The application discloses a kind of all-substituted pyrrole compounds, the raw material alkyne compound of the application has structural diversity with isonitrile compound, can be used to synthesize different types and structures of all-substituted pyrrole compounds;Reaction raw material diphenylacetylene and its same type substrate compared with the raw material of the reaction reported by predecessors, have the advantages of simple and easy to obtain, stable nature;All-substituted pyrrole compounds have good diversity and functional group tolerance, so it has wide application;Further modification is carried out to different substitution sites on the heterocyclic skeleton of all-substituted pyrrole compounds, and intermediates of chemical products and drug structures can be obtained;The target product of the application takes pyrrole as the key mother nucleus, while amide and other unsaturated groups are introduced on the ring, and the structure has potential pharmacological activity;Cheap transition metal nickel is used as catalyst;The yield of the application is good.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a fully substituted pyrrole compound and a preparation method thereof. Background Art

[0002] Fully substituted pyrrole has a five-membered aromatic heterocyclic ring and is widely used as a raw material for organic synthesis, medicine, pesticides, fragrances, rubber vulcanization accelerators, epoxy resin curing agents, etc.

[0003] In recent years, the synthesis of fully substituted pyrroles has attracted great attention, and various synthetic methods have been developed. These include condensation, organic small molecule catalysis or metal catalysis. The synthesis of pyrroles by condensation methods usually faces problems such as poor chemical selectivity and relatively severe reaction conditions. Metal-catalyzed cascade reactions have unique advantages in constructing cyclic compounds. Isonitriles are often used in transition metal-catalyzed cascade reactions because of their electrophilic and nucleophilic properties. At present, many methods for the preparation of fully substituted pyrroles by metal-catalyzed cyclization involving isonitriles have been reported. Among them, the Inoue group reported a scheme in 2008 for the palladium-catalyzed reaction of alkynes and tert-butyl isonitrile to generate fully substituted pyrroles ( J. Organometallic Chemistry . 2009, 694 , 1333). In 2016, Zhu Jieping's research group reported a palladium-catalyzed three-component reaction of propyne carbonate, isonitrile, and alcohol, obtaining fully substituted pyrroles in good yields ( Org. Lett . 2017, 19 ,270). However, the reactions reported above can only be triggered by the use of expensive precious metal palladium catalysts to produce fully substituted pyrroles. In 2024, our group reported a nickel-catalyzed cyclization reaction of alkynyl nitriles with tert-butyl isonitrile under simple conditions ( Tetrahedron Lett. 2024, 146 , 155194). This scheme provides an inexpensive catalytic system for the preparation of fully substituted pyrroles. However, this synthesis method has a limited substrate range, and only the 3-position substituent of the resulting pyrrole five-membered ring can be modified by substrate substitution, preventing the production of complex or functional pyrroles. Therefore, the development of a synthetic scheme for fully substituted pyrroles with readily available starting materials, inexpensive catalysts, and a diverse product structure is crucial. Summary of the Invention

[0004] In view of the above problems, the object of the present invention is to provide a novel fully substituted pyrrole and a method for synthesizing the same.

[0005] In order to achieve the above objectives, the following technical solutions are proposed:

[0006] A fully substituted pyrrole compound represented by formula (I);

[0007]

[0008] In formula (I), R 1 is selected from hydrogen atom, methyl group, halogen atom or trifluoromethyl group, R 2 is selected from hydrogen atom, methyl group, halogen atom, wherein the halogen atom is F, CL, Br or I, and all R1 in formula (I) are the same, and all R 2 same.

[0009] Furthermore, the R 1 Selected from hydrogen atom, methyl, F, Cl, trifluoromethyl, R 2 Selected from hydrogen atom and methyl group.

[0010] Furthermore, the fully substituted pyrrole compound is one of the following:

[0011]

[0012]

[0013] .

[0014] Furthermore, the method is carried out according to the following steps: under a nitrogen atmosphere, using diphenylacetylene as shown in formula (II) and isocyanide as shown in formula (III) as reaction raw materials, reacting completely at 100~150°C (preferably 6~18 hours) (preferably 120°C, 12 hours) in an organic solvent with a catalyst and a salt. After the reaction, the reaction solution is separated and purified by silica gel column chromatography to obtain a pyrrole compound as shown in formula (I), wherein the catalyst is NiBr2, the salt is one or more of sodium thiosulfate or zinc selenide, and the molar ratio of isocyanide shown in formula (III), diphenylacetylene shown in formula (II), catalyst, and salt is 1:1~3: 0.05~0.2:1~4.

[0015] .

[0016] Furthermore, the organic solvent is toluene.

[0017] Furthermore, the amount of the organic solvent used is 34.48-38.47 mL / g based on the mass of the isonitrile represented by formula (III).

[0018] Furthermore, the molar ratio of the isonitrile represented by formula (III), the diphenylacetylene represented by formula (II), the catalyst, and the salt is 1:2:0.1:3.

[0019] Furthermore, the salt is sodium thiosulfate.

[0020] Furthermore, after the reaction is completed, the specific operation process of silica gel column chromatography separation and purification is as follows: after the reaction is completed, the reaction solution is concentrated and subjected to column chromatography, a mixture of petroleum ether and ethyl acetate is used as an eluent, the eluate containing the target compound is collected, concentrated, distilled and dried to obtain a pyrrole compound represented by formula (I), wherein the volume ratio of petroleum ether to ethyl acetate in the mixture is 20~40:1.

[0021] The present invention also relates to the use of the fully substituted pyrrole compound as a luminescent material.

[0022] The beneficial effects of the present invention are as follows: the raw material acetylene compounds and isonitrile compounds of the present invention have structural diversity and can be used to synthesize fully substituted pyrrole compounds of different types and structures; the present invention has a good yield; the reaction raw material diphenylacetylene and substrates of the same type have the advantages of being simple to obtain and having stable properties compared with the raw materials of reactions reported by previous researchers (benzyne nitrile and propynyl carbonate); the fully substituted pyrrole compounds have good diversity and functional group tolerance, and therefore have wide applicability; further modification of different substitution sites on the heterocyclic skeleton of the fully substituted pyrrole compounds can obtain intermediates of chemical products and drug structures; the target product of the present invention uses pyrrole as the key mother nucleus, and at the same time introduces amides and other unsaturated groups on the ring, and this type of structure has potential pharmacological activity; cheap transition metal nickel is used as a catalyst; and a new type of fully substituted pyrrole structure is proposed. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : Fluorescence test experimental image of compound 3aa (Example 1)

[0024] Figure 2 : Fluorescence test experimental image of compound 3ba (Example 13)

[0025] Figure 3 : Fluorescence test experimental image of compound 3ca (Example 14)

[0026] Figure 4 : Fluorescence test experimental image of compound 3da (Example 15)

[0027] Figure 5 : Fluorescence test experimental image of compound 3ab (Example 16)

[0028] Figure 6 : Fluorescence test experimental image of compound 3ea (Example 17) DETAILED DESCRIPTION

[0029] The present invention will be further described in detail with reference to the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that those skilled in the art can think of are included in the present invention, and are protected by the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products, and the product purity is identified by nuclear magnetic resonance.

[0030] Example 1

[0031] Synthesis of fully substituted pyrrole compound 3aa:

[0032]

[0033] Under a nitrogen atmosphere, a reaction tube was charged with 1a (0.4 mmol, 71.2 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr2 (0.02 mmol, 4.36 mg, 10 mol%), and Na2S2O3 (0.6 mmol, 95 mg, 3.0 equiv.). Toluene (1 mL) was added as the solvent. The reaction system was incubated at 120°C for 12 hours and monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and one teaspoon of silica gel was added to the reaction mixture. The solvent was then removed by rotary evaporation. The product was separated by column chromatography (100 mesh) using a mixed solvent of petroleum ether and ethyl acetate (400 mL of petroleum ether and 20 mL of ethyl acetate) in a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected and the eluent was removed to obtain the product 3aa (26.5 mg) as an off-white solid in a yield of 63%.

[0034] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.35 (m, 2H), 7.28 (t, J=7.3 Hz, 2H), 7.25 – 7.19 (m, 1H), 7.00 (s, 2H), 6.84 – 6.68 (m, 5H), 6.68 –6.59 (m, 2H), 6.47 (s, 1H), 6.44 (s, 2H), 4.83 (s, 1H), 2.33 (s, 3H), 2.30(s, 6H), 2.21 – 2.14 (m, 3H), 2.06 (s, 3H), 2.03 (s, 6H), 1.96 (s, 6H).

[0035] Example 2

[0036] The temperature was lowered to 100°C, and other operations were carried out as in Example 1 to obtain 23.1 mg of the compound with a yield of 55%.

[0037] Example 3

[0038] The temperature was raised to 150°C, and other operations were carried out as in Example 1 to obtain 16.8 mg of the compound with a yield of 40%.

[0039] Example 4

[0040] The amount of diphenylacetylene was changed to (35.6 mg, 0.2 mmol), and the other operations were the same as in Example 1 to obtain 24.2 mg, with a yield of 57.6%.

[0041] Example 5

[0042] The amount of diphenylacetylene was changed to (106.8 mg, 0.6 mmol), and the other operations were the same as in Example 1 to obtain 12.2 mg, with a yield of 28.6%.

[0043] Example 6

[0044] The amount of nickel bromide was changed to (2.18 mg, 5 mol%), and the other operations were the same as in Example 1 to obtain 14.1 mg, with a yield of 33.3%.

[0045] Example 7

[0046] The amount of nickel bromide was changed to (6.54 mg, 15 mol%), and the other operations were the same as in Example 1 to obtain 25 mg, with a yield of 59.5%.

[0047] Comparative Example 1

[0048] Without adding nickel bromide, other operations were the same as in Example 1, but no target product was obtained.

[0049] Example 8

[0050] The amount of sodium thiosulfate was changed to (63 mg, 0.4 mol), and the other operations were the same as in Example 1 to obtain 22.6 mg, with a yield of 53.7%.

[0051] Example 19

[0052] The amount of sodium thiosulfate was changed to (126 mg, 0.8 mol), and the other operations were the same as in Example 1 to obtain 13 mg, with a yield of 31.2%.

[0053] Comparative Example 2

[0054] No sodium thiosulfate was added, and other operations were the same as in Example 1, but no target product was obtained.

[0055] Example 10

[0056] The amount of sodium thiosulfate was replaced with zinc selenide (86.4 mg, 0.6 mol), and the other operations were the same as in Example 1 to obtain 20.4 mg, with a yield of 48.6%.

[0057] Example 11

[0058] The reaction time was reduced to 6 hours, and the other operations were the same as in Example 1 to obtain 12.4 mg of the compound with a yield of 29.5%.

[0059] Example 12

[0060] The reaction time was increased to 18 hours, and other operations were carried out as in Example 1 to obtain 26.0 mg of the compound with a yield of 60.1%.

[0061] Example 13

[0062] Synthesis of fully substituted pyrrole compound 3ba:

[0063]

[0064] Under a nitrogen atmosphere, a reaction tube was charged with 1b (0.4 mmol, 98.8 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr2 (0.02 mmol, 4.36 mg, 10.0 mol%), and Na2S2O3 (0.6 mmol, 95 mg, 3.0 equiv.). Toluene (1 mL) was added as solvent. The reaction system was incubated at 120°C for 12 hours and monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and one teaspoon of silica gel was added to the reaction mixture. The solvent was then removed by rotary evaporation. The product was separated by column chromatography (100 mesh) using a mixed solvent of petroleum ether and ethyl acetate (400 mL of petroleum ether and 20 mL of ethyl acetate) in a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected and the eluent was removed to obtain the product 3ba (29.8 mg) as a light yellow oily liquid (yield 64%).

[0065] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.30 (m, 2H), 7.30 – 7.22(m, 2H), 7.02 (s, 2H), 6.77 (s, 2H), 6.74 – 6.67 (m, 2H), 6.54 – 6.44 (m,4H), 6.35 (s, 1H), 4.81 (s, 1H), 2.32 (s, 3H), 2.30 (s, 6H), 2.19 (s, 3H), 2.13 (d, J = 5.8 Hz, 3H), 2.08 (d, J = 3.7 Hz, 1H), 2.01 (s, 6H), 1.98 (s, 6H).

[0066] Example 14

[0067] Synthesis of fully substituted pyrrole compound 3ca:

[0068]

[0069] Under a nitrogen atmosphere, a reaction tube was charged with 1c (0.4 mmol, 85.6 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr2 (0.02 mmol, 4.36 mg, 10.0 mol%), and Na2S2O3 (0.6 mmol, 95 mg, 3.0 equiv.). Toluene (1 mL) was added as solvent. The reaction system was incubated at 120°C for 12 hours and monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. One teaspoon of silica gel was added to the reaction solution, and the solvent was removed by rotary evaporation. The product was separated by column chromatography (100 mesh) using a mixed solvent of petroleum ether and ethyl acetate (400 mL, 20 mL, by volume) at a ratio of 20:1. The eluate containing the target product was collected and the eluent was removed to obtain the product 3ca (30.2 mg, a light yellow oily liquid, in a yield of 68%).

[0070] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.39 – 7.31 (m, 2H), 7.04 – 6.95(m, 4H), 6.76 (s, 2H), 6.58 – 6.51 (m, 2H), 6.49 – 6.40 (m, 4H), 6.35 (s,1H), 4.78 (s, 1H), 2.33 (s, 3H), 2.30 (m, 6H), 2.18 (d, J = 4 Hz, 3H), 2.09(d, J = 4Hz, 3H), 2.03 (d, J = 4 Hz, 7H), 1.97 (s, 5H).

[0071] Example 15

[0072] Synthesis of fully substituted pyrrole compound 3da:

[0073]

[0074] Under a nitrogen atmosphere, a reaction tube was charged with 1d (0.4 mmol, 82.4 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr2 (0.02 mmol, 4.36 mg, 10.0 mol%), and Na2S2O3 (0.6 mmol, 95 mg, 3.0 equiv.). Toluene (1 mL) was added as solvent. The reaction system was incubated at 120°C for 12 hours and monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and one teaspoon of silica gel was added to the reaction mixture. The solvent was then removed by rotary evaporation. The product was separated by column chromatography (100 mesh) using a mixed solvent of petroleum ether and ethyl acetate (400 mL of petroleum ether and 20 mL of ethyl acetate) in a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected and the eluent was removed to obtain the product 3da (23.7 mg) as a colorless, transparent, oily liquid in a yield of 54%.

[0075] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.29 (m, 3H), 7.07 (d, J = 7.8 Hz,2H), 6.96 (s, 2H), 6.73 (s, 2H), 6.51 (m, 4H), 6.42 (s, 2H), 4.78 (s, 1H),2.32 – 2.23 (m, 12H), 2.15 (s, 3H), 2.11 (s, 3H), 2.08 – 2.05 (m, 3H), 1.99 (s, 6H), 1.97 – 1.89 (s, 6H).

[0076] Example 16

[0077] Synthesis of fully substituted pyrrole compound 3ab:

[0078]

[0079] Under a nitrogen atmosphere, a reaction tube was charged with 1a (0.4 mmol, 71.2 mg, 2.0 equiv.), 2b (0.2 mmol, 29 mg, 1.0 equiv.), NiBr2 (0.02 mmol, 4.36 mg, 10.0 mol%), and Na2S2O3 (0.6 mmol, 95 mg, 3.0 equiv.). Toluene (1 mL) was added as solvent. The reaction system was incubated at 120°C for 12 hours and monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, and one teaspoon of silica gel was added to the reaction mixture. The solvent was then removed by rotary evaporation. The product was separated by column chromatography (100 mesh) using a mixed solvent of petroleum ether and ethyl acetate (400 mL, 20 mL, by volume) at a 20:1 ratio. The eluate containing the target product was collected and the eluent was removed to obtain the product 3ab (21.6 mg, light yellow solid, yield 55%).

[0080] Characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.39 (m, 2H), 7.37 – 7.13(m, 6H), 6.99 – 6.88 (m, 3H), 6.86 – 6.71 (m, 3H), 6.71 – 6.61 (m, 5H), 6.58 (s, 1H), 4.89 (s, 1H), 2.34 (s, 6H), 2.08 (s, 6H), 1.98 (s, 6H).

[0081] Example 17

[0082] Synthesis of fully substituted pyrrole compound 3ea:

[0083]

[0084] Under a nitrogen atmosphere, a reaction tube was charged with 1e (0.4 mmol, 71.2 mg, 6.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr2 (0.02 mmol, 4.36 mg, 10.0 mol%), and Na2S2O3 (0.6 mmol, 95 mg, 9.0 equiv.). Toluene (1 mL) was added as the solvent. The reaction system was incubated at 120°C for 12 hours and monitored by thin-layer chromatography. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. One teaspoon of silica gel was added to the reaction solution, and the solvent was removed by rotary evaporation. The product was separated by column chromatography (100 mesh) using a mixed solvent of petroleum ether and ethyl acetate (400 mL of petroleum ether and 20 mL of ethyl acetate) in a volume ratio of 20:1 as the eluent. The eluate containing the target product was collected and the eluent was removed to obtain the product 3ea (24 mg) as a colorless, transparent, oily liquid (yield 47%).

[0085] Characterization data: 1 H NMR (400 MHz, CDCl 3) δ 7.59 – 7.48 (m, 4H), 7.06 (s, 2H), 6.97 (d, J = 8.1 Hz, 2H), 6.80 – 6.75 (m, 2H), 6.65 (d, J = 8.0 Hz, 2H), 6.42(s, 2H), 6.26 (s, 1H), 4.86 (s, 1H), 2.35 (s, 9H), 2.19 (s, 3H), 2.03 (m,9H), 1.95 (s, 6H).

[0086] Example 28

[0087] Fluorescence properties test of fully substituted pyrrole compounds

[0088] In the present application, the aromatic group is connected to all four carbon atoms of the tetra-substituted pyrrole compound, and the protecting group on the nitrogen is a phenyl group. When the para-position of the phenyl group is a strong electron-withdrawing group, the whole is electron-withdrawing, which forms a conjugated system and has good optical properties from the perspective of light-emitting materials. We found in the reaction that the target product can emit strong fluorescence under UV light when it is dissolved in dichloromethane and smeared on a TLC plate. In order to explore the fluorescence properties of different reaction products, we selected the products of Examples 1, 13, 14, 15, 16 and 17 (products 3aa, 3ba, 3ca, 3da, 3ab and 3ea, respectively) for testing experiments. 0.2 mmol of the target product was dissolved in 2 mL of dichloromethane and smeared on a TLC plate, respectively, to observe the intensity of fluorescence emission. The experimental results are shown in Figures 1-6 The several tested products can all emit strong fluorescence, but compared with the standard compound product 3aa, the fluorescence properties of the target product are enhanced when the para-position of the benzene ring is introduced with an electron-withdrawing group, such as a chlorine atom (3ba), a fluorine atom (3ca) or a trifluoromethyl group (3ea). Therefore, the tetra-substituted pyrrole compound obtained by the preparation method has practical application value in the construction of new light-emitting materials containing a pyrrole skeleton.

Claims

1. A fully substituted pyrrole compound represented by formula (I); In formula (I), R 1 is selected from hydrogen atom, methyl group, halogen atom or trifluoromethyl group, R 2 is selected from hydrogen atom, methyl group, halogen atom, wherein the halogen atom is F, Cl, Br or I, and all R 1 Same, all R 2 same.

2. A fully substituted pyrrole compound according to claim 1, characterized in that The R 1 Selected from hydrogen atom, methyl, F, Cl, trifluoromethyl, R 2 Selected from hydrogen atom and methyl group.

3. A fully substituted pyrrole compound according to claim 1, characterized in that The compound is one of the following: 。 4. A method for preparing the fully substituted pyrrole compound according to claim 1, characterized in that The method is carried out according to the following steps: under a nitrogen atmosphere, using diphenylacetylene as shown in formula (II) and isonitrile as shown in formula (III) as reaction raw materials, reacting them completely in an organic solvent with a catalyst and a salt at 100-150°C. After the reaction, the reaction solution is separated and purified by silica gel column chromatography to obtain a pyrrole compound as shown in formula (I), wherein the catalyst is NiBr2, the salt is one or more of sodium thiosulfate or zinc selenide, and the molar ratio of isonitrile as shown in formula (III), diphenylacetylene as shown in formula (II), catalyst, and salt is 1:1-3: 0.05-0.2:1-4; 。 5. The method of claim 4, wherein the method comprises: The organic solvent is toluene.

6. The method of claim 4, wherein the method comprises: The amount of the organic solvent used is 34.48-38.47 mL / g based on the mass of the isonitrile represented by formula (III).

7. The method for synthesizing a fully substituted pyrrole compound according to claim 4, wherein: The molar ratio of the isonitrile represented by formula (III), the diphenylacetylene represented by formula (II), the catalyst, and the salt is 1:2:0.1:

3.

8. The method for synthesizing the fully substituted pyrrole compound according to claim 4, wherein The salt is sodium thiosulfate.

9. The method for synthesizing a fully substituted pyrrole compound according to claim 4, wherein After the reaction is completed, the specific operation process of silica gel column chromatography separation and purification is as follows: after the reaction is completed, the reaction solution is concentrated and subjected to column chromatography, a mixture of petroleum ether and ethyl acetate is used as an eluent, the eluate containing the target compound is collected, concentrated, distilled and dried to obtain a pyrrole compound represented by formula (I), wherein the volume ratio of petroleum ether to ethyl acetate in the mixture is 20~40:

1.

10. Use of the fully substituted pyrrole compound according to claim 1 as a luminescent material.

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