Fully-substituted pyrrole compound and preparation method thereof

Abstract

The invention discloses a fully-substituted pyrrole compound, which is characterized in that raw materials including an alkyne compound and an isonitrile compound have structural diversity and can be used for synthesizing fully-substituted pyrrole compounds of different types and structures; compared with reaction raw materials reported in the prior art, the reaction raw material diphenylacetylene and the same type of substrate thereof have the advantages of simplicity, easiness in obtaining and stable character; the fully-substituted pyrrole compound has relatively good diversity and functional group tolerance, so that the fully-substituted pyrrole compound has wide applicability; different substitution sites on the heterocyclic skeleton of the fully-substituted pyrrole compound are further modified, so that intermediates of chemical products and drug structures can be obtained; according to the target product disclosed by the invention, pyrrole is taken as a key parent nucleus, amide and other unsaturated groups are introduced to a ring, and the structure has potential pharmacological activity; cheap transition metal nickel is used as a catalyst; the method is good in yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically 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 palladium-catalyzed scheme for the generation of fully substituted pyrroles from alkynes and tert-butyl isonitriles in 2008 (J. Organometallic Chem. 2009, 694, 1333). In 2016, Zhu Jieping's group reported a palladium-catalyzed three-component reaction of propyne carbonate, isonitrile and alcohol, and obtained fully substituted pyrroles with good yields (Org. Lett. 2017, 19, 270). However, the reactions reported above can only trigger the cyclization reaction to obtain fully substituted pyrroles using high-cost precious metal palladium catalysts. In 2024, our research group reported a nickel-catalyzed cyclization reaction of acetylenic nitrile and tert-butyl isonitrile under simple conditions (Tetrahedron Lett. 2024, 146, 155194). This scheme provides an inexpensive catalytic system to achieve the preparation of fully substituted pyrroles. However, the substrate range of this synthesis method is limited, and only the substituted group at the 3rd position of the obtained pyrrole five-membered ring can be transformed by replacing the substrate, and complex or functional pyrroles cannot be obtained. Therefore, it is particularly important to develop a synthesis scheme for fully substituted pyrroles with easily available raw materials, cheap catalysts, and diverse product structures. 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. To achieve the above object, the following technical scheme is proposed:

[0005] A fully substituted pyrrole compound represented by formula (I);

[0006]

[0007] In formula (I), R1 is selected from a hydrogen atom, a methyl group, a halogen atom or a 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.

[0008] Furthermore, the R 1 is selected from hydrogen, methyl, F, CL, trifluoromethyl, R 2 Selected from a hydrogen atom and a methyl group.

[0009] Furthermore, the fully substituted pyrrole compound is one of the following:

[0010]

[0011]

[0012] Furthermore, the method is carried out according to the following steps: under a nitrogen atmosphere, diphenylacetylene as shown in formula (II) and isonitrile as shown in formula (III) are used as reaction raw materials, and react completely at 100-150°C (preferably 6-18 hours) (preferably 120°C, 12 hours) in an organic solvent under the action of a catalyst and a salt. After the reaction is completed, 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, and the salt is one or more of sodium thiosulfate, zinc oxide 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;

[0013]

[0014] Furthermore, the organic solvent is toluene.

[0015] Furthermore, the amount of the organic solvent used is 34.48 to 38.47 mL / g based on the mass of the isonitrile represented by formula (III).

[0016] 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.

[0017] Furthermore, the salt is sodium thiosulfate, zinc oxide, zinc selenide, preferably sodium thiosulfate.

[0018] 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 as shown in formula (I), wherein the volume ratio of petroleum ether to ethyl acetate in the mixture is 20 to 40:1.

[0019] The present invention also relates to the application of the fully substituted pyrrole compound as a luminescent material.

[0020] 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 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 propargyl 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 amides and other unsaturated groups are introduced into the ring, and this type of structure has potential pharmacological activity; cheap transition metal nickel is used as a catalyst; and a novel fully substituted pyrrole structure is proposed. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : Fluorescence test experimental image of compound 3aa (Example 1)

[0022] Figure 2 : Fluorescence test experimental image of compound 3ba (Example 13)

[0023] Figure 3 : Fluorescence test experimental image of compound 3ca (Example 14)

[0024] Figure 4 : Fluorescence test experimental image of compound 3da (Example 15)

[0025] Figure 5 : Fluorescence test experimental image of compound 3ab (Example 16)

[0026] Figure 6 : Fluorescence test experimental image of compound 3ea (Example 17) DETAILED DESCRIPTION

[0027] In conjunction with the following specific examples, the present invention is further described in detail, 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 can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all 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.

[0028] Example 1

[0029] Synthesis of fully substituted pyrrole compound 3aa:

[0030]

[0031] Under nitrogen atmosphere, 1a (0.4 mmol, 71.2 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr 2 (0.02mmol, 4.36mg, 10mol%), Na 2 S 2 O 3 (0.6mmol, 95mg, 3.0equiv.), toluene (1mL) was added as solvent. The reaction system was reacted at 120℃ for 12 hours, and the reaction was followed by thin layer chromatography. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. A spoonful of silica gel was added to the reaction solution and the solvent was removed by rotary evaporator. Column chromatography (100 mesh) was used for separation, and a mixed solvent of petroleum ether:ethyl acetate (petroleum ether 400mL, ethyl acetate 20mL) with a volume ratio of 20:1 was used as the eluent for elution. The eluent containing the target product was collected, and the product 3aa was obtained after removing the eluent, 26.5mg (the product was an off-white solid, with a yield of 63%).

[0032] Characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.47–7.35(m,2H),7.28(t,J=7.3Hz,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).

[0033] Example 2

[0034] The temperature was lowered to 100°C, and other operations were carried out in the same manner as in Example 1 to obtain 23.1 mg of the compound with a yield of 55%.

[0035] Example 3

[0036] The temperature was raised to 150°C, and other operations were performed as in Example 1 to obtain 16.8 mg, with a yield of 40%.

[0037] Example 4

[0038] The amount of diphenylacetylene was changed to (35.6 mg, 0.2 mmol), and the other operations were the same as in Example 1, yielding 24.2 mg, with a yield of 57.6%.

[0039] Example 5

[0040] The amount of diphenylacetylene was changed to (106.8 mg, 0.6 mmol), and the other operations were the same as in Example 1, yielding 12.2 mg with a yield of 28.6%.

[0041] Example 6

[0042] The amount of nickel bromide was changed to (2.18 mg, 5 mol%), and the other operations were the same as in Example 1, yielding 14.1 mg with a yield of 33.3%.

[0043] Example 7

[0044] 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%.

[0045] Comparative Example 1

[0046] Without adding nickel bromide, other operations were the same as in Example 1, but the target product was not obtained.

[0047] Example 8

[0048] The amount of sodium thiosulfate was changed to (63 mg, 0.4 mol), and the other operations were the same as in Example 1, yielding 22.6 mg, with a yield of 53.7%.

[0049] Embodiment 19

[0050] The amount of sodium thiosulfate was changed to (126 mg, 0.8 mol), and the other operations were the same as in Example 1, yielding 13 mg, with a yield of 31.2%.

[0051] Comparative Example 2

[0052] No sodium thiosulfate was added, and other operations were the same as in Example 1, but no target product was obtained.

[0053] Example 10

[0054] The amount of sodium thiosulfate was changed to 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%.

[0055] Embodiment 11

[0056] The reaction time was reduced to 6 hours, and the other operations were the same as in Example 1, to obtain 12.4 mg, with a yield of 29.5%.

[0057] Example 12

[0058] The reaction time was increased to 18 hours, and other operations were performed the same as in Example 1 to obtain 26.0 mg of the compound with a yield of 60.1%.

[0059] Embodiment 13

[0060] Synthesis of fully substituted pyrrole compound 3ba:

[0061]

[0062] Under nitrogen atmosphere, 1b (0.4 mmol, 98.8 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr 2 (0.02mmol, 4.36mg, 10.0mol%), Na 2 S 2 O 3 (0.6mmol, 95mg, 3.0equiv.), toluene (1mL) was added as solvent. The reaction system was reacted at 120℃ for 12 hours, and the reaction was followed by thin layer chromatography. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. A spoonful of silica gel was added to the reaction solution and the solvent was removed by rotary evaporator. Column chromatography (100 mesh) was used for separation, and a mixed solvent of petroleum ether:ethyl acetate (petroleum ether 400mL, ethyl acetate 20mL) with a volume ratio of 20:1 was used as the eluent for elution. The eluent containing the target product was collected, and the product 3ba was obtained after removing the eluent, 29.8mg (the product was a light yellow oily liquid, with a yield of 64%).

[0063] Characterization data: 1 H NMR (400 MHz, CDCl 3)δ7.36–7.30(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=5.8Hz,3H),2.08(d,J=3.7Hz,1H),2.01(s,6H),1.98(s,6H).

[0064] Embodiment 14

[0065] Synthesis of fully substituted pyrrole compound 3ca:

[0066]

[0067] Under nitrogen atmosphere, 1c (0.4 mmol, 85.6 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr 2 (0.02mmol, 4.36mg, 10.0mol%), Na 2 S 2 O 3 (0.6mmol, 95mg, 3.0equiv.), toluene (1mL) was added as solvent. The reaction system was reacted at 120℃ for 12 hours, and the reaction was followed by thin layer chromatography. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. A spoonful of silica gel was added to the reaction solution and the solvent was removed by rotary evaporator. Column chromatography (100 mesh) was used for separation, and a mixed solvent of petroleum ether:ethyl acetate (petroleum ether 400mL, ethyl acetate 20mL) with a volume ratio of 20:1 was used as the eluent for elution. The eluent containing the target product was collected, and the product 3ca was obtained after removing the eluent, 30.2mg (the product was a light yellow oily liquid, and the yield was 68%).

[0068] Characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.39–7.31(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),4.7 8(s,1H),2.33(s,3H),2.30(m,6H),2.18(d,J=4Hz,3H),2.09(d,J=4Hz,3H),2.03(d,J=4Hz,7H),1.97(s,5H).

[0069] Embodiment 15

[0070] Synthesis of fully substituted pyrrole compound 3da:

[0071]

[0072] Under nitrogen atmosphere, 1d (0.4 mmol, 82.4 mg, 2.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr 2 (0.02mmol, 4.36mg, 10.0mol%), Na 2 S 2 O 3 (0.6mmol, 95mg, 3.0equiv.), toluene (1mL) was added as solvent. The reaction system was reacted at 120℃ for 12 hours, and the reaction was followed by thin layer chromatography. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. A spoonful of silica gel was added to the reaction solution and the solvent was removed by rotary evaporator. Column chromatography (100 mesh) was used for separation, and a mixed solvent of petroleum ether:ethyl acetate (petroleum ether 400mL, ethyl acetate 20mL) with a volume ratio of 20:1 was used as the eluent for elution. The eluent containing the target product was collected, and the product 3da was obtained after removing the eluent, 23.7mg (the product was a colorless transparent oily liquid, with a yield of 54%).

[0073] Characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.29(m,3H),7.07(d,J=7.8Hz,2H),6.96(s,2H),6.73(s,2H),6.51(m,4H),6.42(s,2H),4.78(s,1 H),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).

[0074] Example 16

[0075] Synthesis of fully substituted pyrrole compound 3ab:

[0076]

[0077] Under nitrogen atmosphere, 1a (0.4 mmol, 71.2 mg, 2.0 equiv.), 2b (0.2 mmol, 29 mg, 1.0 equiv.), NiBr 2(0.02mmol, 4.36mg, 10.0mol%), Na 2 S 2 O 3 (0.6mmol, 95mg, 3.0equiv.), toluene (1mL) was added as solvent. The reaction system was reacted at 120℃ for 12 hours, and the reaction was followed by thin layer chromatography. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. A spoonful of silica gel was added to the reaction solution and the solvent was removed by rotary evaporator. Column chromatography (100 mesh) was used for separation, and a mixed solvent of petroleum ether:ethyl acetate (petroleum ether 400mL, ethyl acetate 20mL) with a volume ratio of 20:1 was used as the eluent for elution. The eluent containing the target product was collected, and the product 3ab was obtained after removing the eluent, 21.6mg (the product was a light yellow solid, yield 55%).

[0078] Characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.50–7.39(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).

[0079] Embodiment 17

[0080] Synthesis of fully substituted pyrrole compound 3ea:

[0081]

[0082] Under nitrogen atmosphere, 1e (0.4 mmol, 71.2 mg, 6.0 equiv.), 2a (0.2 mmol, 29 mg, 1.0 equiv.), NiBr 2 (0.02mmol, 4.36mg, 10.0mol%), Na 2 S 2 O 3(0.6mmol, 95mg, 9.0equiv.), toluene (1mL) was added as solvent. The reaction system was reacted at 120℃ for 12 hours, and the reaction was followed by thin layer chromatography. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate. A spoonful of silica gel was added to the reaction solution and the solvent was removed by rotary evaporator. Column chromatography (100 mesh) was used for separation, and a mixed solvent of petroleum ether:ethyl acetate (petroleum ether 400mL, ethyl acetate 20mL) with a volume ratio of 20:1 was used as the eluent for elution. The eluent containing the target product was collected, and the product 3ea, 24mg (the product was a colorless transparent oily liquid, with a yield of 47%) was obtained after removing the eluent.

[0083] Characterization data: 1 H NMR (400 MHz, CDCl 3) δ7.59–7.48 (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). Example 28

[0084] Fluorescence property test of fully substituted pyrrole compounds

[0085] In the present invention, aromatic groups are attached to the substitution positions of the four carbon atoms of the fully substituted pyrrole compounds, 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. From the perspective of the luminescent material, this constitutes a conjugated system with good optical properties. We found in the reaction that when the target product is dissolved in dichloromethane and smeared on a TLC plate, the strong fluorescence emission of the target product can be clearly observed under ultraviolet light. 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 TLC plates, and the intensity of its fluorescence emission was observed. The experimental results are as follows Figure 1-Figure 6 As shown, the several products tested can emit strong fluorescence, but compared with the standard compound product 3aa, when an electron-withdrawing group such as chlorine atom (3ba), fluorine atom (3ca), and trifluoromethyl (3ea) is introduced into the para position of the benzene ring, the fluorescence performance of the target product is enhanced. Therefore, the fully substituted pyrrole compounds obtained by this preparation method have practical application value in constructing new luminescent materials containing pyrrole skeletons.

Claims

1. A fully substituted pyrrole compound represented by formula (I); In formula (I), R 1 is selected from a hydrogen atom, a methyl group, a halogen atom or a 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 in formula (I) 1 Same, all R 2 same.

2. A fully substituted pyrrole compound as claimed in claim 1, characterized in that The R 1 is selected from hydrogen, methyl, F, CL, trifluoromethyl, R 2 Selected from a hydrogen atom and a methyl group.

3. A fully substituted pyrrole compound as claimed in claim 1, characterized in that The compound is one of the following:

4. A method for preparing the fully substituted pyrrole compound as claimed in claim 1, characterized in that The method is carried out according to the following steps: under a nitrogen atmosphere, diphenylacetylene as shown in formula (II) and isonitrile as shown in formula (III) are used as reaction raw materials, and react completely at 100-150°C in an organic solvent under the action of a catalyst and a salt. After the reaction is completed, 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, and the salt is one or more of sodium thiosulfate, zinc oxide 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 for preparing the fully substituted pyrrole compound according to claim 1, characterized in that The organic solvent is toluene.

6. The method of claim 1, 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, characterized in that The salts are sodium thiosulfate, zinc oxide and zinc selenide.

9. The method for synthesizing a fully substituted pyrrole compound according to claim 4, characterized in that 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 as shown in formula (I), wherein the volume ratio of petroleum ether to ethyl acetate in the mixture is 20 to 40:

1.

10. Use of the fully substituted pyrrole compound as claimed in claim 1 as a luminescent material.

Images