Method for isopentenylation of pyridine
By combining photocatalysis and palladium catalysis, isopreneated and isopreneated compounds of pyridine were synthesized under mild conditions. This solved the problem of constructing active carbon-carbon double bond sites in pyridine compounds in existing technologies, and achieved efficient conversion of pyridine compounds. The products have broad potential for synthetic applications.
Patent Information
- Application Number
- CN202410530624.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-29
- Publication Date
- 2025-10-31
AI Technical Summary
Existing technologies struggle to efficiently synthesize isopreneated and isopreneated compounds of pyridine under mild conditions, and there is a lack of effective methods to construct the carbon-carbon double bond active reaction sites of pyridine compounds.
A combination of photocatalysis and palladium catalysis was employed, using specific photocatalysts, palladium catalysts, ligands, base additives, and reducing agents to carry out the reaction in a solvent, and pyridine was isopreneated and isopentenylated by irradiation with a blue-violet LED light source.
Isoprendinated and isopentenylated compounds of pyridine were successfully synthesized under mild conditions. The starting materials were readily available, the reaction route was universal, and the products have broad application prospects in the field of synthesis.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for isopentenylating pyridine. Background Technology
[0002] Pyridine is one of the most common aromatic heterocyclic compounds, and natural products and drugs with pyridine as their backbone are widely available. Conjugated enynes are extremely useful synthons that can introduce unsaturated carbon-carbon double bonds into compounds. Through the reaction of bromopyridine with enynes, isoprene- and isopentenylated compounds of pyridine can be obtained, achieving further transformation of pyridine compounds.
[0003] This invention employs a combination of photocatalysis and palladium catalysis. The raw materials are simple and readily available, and the reaction conditions are mild. Under the action of a reducing agent, isopreneated and isopreneated compounds of pyridine can be constructed, providing active reaction sites such as carbon-carbon double bonds for further conversion of pyridine compounds.
[0004] In summary, this paper describes a simple and mild method for the isopentenylation of pyridine. Summary of the Invention
[0005] The purpose of this invention is to provide a method for isopentenylating pyridine.
[0006]
[0007] Reaction 1: Isoprendylation of pyridine; Reaction 2: Isoprendylation of pyridine
[0008] The specific operating steps are as follows (reaction formulas 1 and 2):
[0009] The reaction was carried out in a reactor by sequentially adding bromopyridine 1, enyne 2, a photocatalyst, a palladium catalyst, a ligand, a base additive, a reducing agent, and a solvent. The reaction was carried out at room temperature under light of a certain wavelength for 10-48 hours. After the reaction was completed, compounds 3, which were pyridine isopreneated and isopreneated, were separated.
[0010] The molar ratio of bromopyridine 1 to enyne 2 is 1-10:1, with a preferred ratio of 2-4:1.
[0011] The photocatalysts used are tri(2-phenyl)pyridine iridium Ir(ppy)3, (4,4'-di-tert-butyl-2,2'-bipyridine)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6, bis((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, bis((2-phenyl)pyridine)(1,1'-dimethyl-2,2'-biimazole)iridium hexafluorophosphate [Ir(ppy)2(bim)]PF6, and bis(( One or more of the following: (2-phenyl)pyridine)(1,10-o-phenanthroline)iridium hexafluorophosphate [Ir(ppy)2(phen)]PF6, ruthenium tripyridine chloride hexahydrate Ru(bpy)3Cl2·6H2O, tris(1,10-o-phenanthroline)ruthenium hexafluorophosphate Ru(phen)3(PF6)2, 9-trimethylmethyl-10-methylacridinium perchlorate Acr-MesClO4, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile 4CzIPN, preferably tris(2-phenyl)pyridine iridium Ir(ppy)3; the amount of photocatalyst is 1-5% molar equivalent of enyne 2, preferably 3-5% molar equivalent.
[0012] The palladium catalyst used is one of palladium chloride, palladium bromide, palladium trifluoroacetate, palladium acetate, and palladium hydroxide, with palladium chloride being preferred; the amount of palladium catalyst used is 1-10% molar equivalent of enyne 2, preferably 5-10% molar equivalent.
[0013] The ligand used is 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene Xantphos; the amount of ligand used is 1-10% molar equivalent of enyne 2, preferably 5-10% molar equivalent.
[0014] The alkaline additive used is one or two of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium phosphate, and potassium carbonate, with potassium carbonate being preferred; the amount of alkaline additive used is 2-10 times the molar equivalent of alkenyne 2, preferably 2-5 times the molar equivalent.
[0015] The reducing agent used is one of 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl ester, triethylamine, and diisopropylethylamine, preferably 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl ester; the amount of reducing agent used is 1-10 molar equivalents of enyne 2, preferably 1.5-5 molar equivalents.
[0016] The solvent used is a mixed solvent, one of which is water, and the other is one of ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, preferably tetrahydrofuran; the volume ratio of the mixed solvent water to the solvent is 1:4, and the amount of solvent used is 1-5 ml of the mixed solvent per 0.2 mmol of enyne-2, preferably 1-2 ml.
[0017] The illumination uses blue-violet LED light sources with wavelengths between 380nm and 460nm, with a preferred wavelength of around 450nm.
[0018] The present invention has the following advantages:
[0019] First, the reactant, bromopyridine, is simple, readily available, and inexpensive, and the reaction system is mild. Second, this method can synthesize isopreneated and isopentenylated compounds of pyridine, and the reaction route is versatile. Finally, the obtained product has great potential for application in the field of synthesis and is a useful synthetic intermediate for the transformation of pyridine molecules. Detailed Implementation
[0020] To better understand the present invention, the following examples are provided. The reaction materials and results of Examples 1-21 are shown in Table 2.
[0021] In the table, all bromopyridine starting materials are commercially available compounds. Among the enyne substrates, 2a is a commercially available compound, while 2b, 2c, and 2d are known compounds. Their synthetic routes are as follows:
[0022]
[0023] Table 1
[0024]
[0025] The reaction was carried out in a reactor by sequentially adding bromopyridine 1 (0.50 mmol), enyne 2a (1.0 mmol), palladium acetate catalyst (5 mol% of the amount of bromopyridine 1), ligand 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene Xantphos (5 mol% of the amount of bromopyridine 1), base additive potassium carbonate (twice the molar equivalent of bromopyridine 1), and tetrahydrofuran (2 mL). The reaction was carried out at 30 °C for 24 hours. After the reaction was completed, 2b, 2c, and 2d were obtained by column chromatography.
[0026]
[0027] Table 2. Reaction results for different substituents
[0028]
[0029]
[0030]
[0031]
[0032] Example 1
[0033] The reaction was carried out in a photoreactor, with the following components added sequentially: bromopyridine 1a (0.3 mmol), enyne 2a (0.2 mmol), photocatalyst tris(2-phenyl)pyridine-iridium Ir(ppy)3 (3 mol% of enyne 2a), palladium catalyst palladium chloride (5 mol% of enyne 2a), ligand 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) Xantphos (5 mol% of enyne 2a), and base additive potassium carbonate (twice the molar amount of enyne 2a). The reaction mixture, consisting of diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (1.5 molar equivalents of the amount of enyne 2a) and a mixed solvent of tetrahydrofuran and water (1.25 mL, volume ratio 4:1), was reacted at room temperature under LED illumination at a wavelength of 450 nm for 24 hours. After the reaction, the pyridine-substituted conjugated diene 3a was obtained by column chromatography in 83% yield. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry. The detection data are as follows:
[0034] (3a): Colorless oil, 26.4mg, 83% yield, R f =0.60(petroleum ether / ethylacetate10 / 1). 1 H NMR (400MHz, Chloroform-d) δ7.52(t,J=7.7Hz,1H),7.08(d,J=7.7Hz,1H),7.05(d,J=7. 6Hz,1H),5.43(s,1H),5.40(s,1H),5.12(s,1H),4.87(s,1H),2.56(s,3H),2.00(s,3H); 13 C NMR(100MHz,Chloroform-d)δ158.8,157.8,150.4,142.7,136.2,121.6,120.3,117.0,115.9,24.7,21.2; HRMS calculated for C 11 H 14 N[M+H] + 160.1121, found 160.1122.
[0035] Example 2:
[0036] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the raw material differences described in Table 2, the photocatalyst was bis((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6 (3 mol% of the amount of enyne 2). The yield of product 3b was 44%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0037]
[0038] The known compound 4b can be obtained through a one-step conversion. The specific steps are as follows: 3b (0.10 mmol), potassium sulfide (0.20 mmol) and dimethyl sulfoxide (1 mL) are added to the reactor and reacted at 140 °C for 24 hours. After the reaction, the known compound 4b is obtained by column chromatography and can be used as a ligand for metal catalysis. Reference: [1] Oae, Shigeru; Inubushi, Yoichi; Yoshihara, Masakuni, Heteroatom Chemistry 1994, 5, 223-228.
[0039] Example 3:
[0040] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the raw material differences described in Table 2, the photocatalyst was 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile 4CzIPN (5 mol% of the amount of enyne 2). The yield of product 3C was 75%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.
[0041] Example 4:
[0042] The operation process and conditions were the same as in Example 1. The difference from Example 1 was the difference in raw materials described in Table 2. The 3-day yield of the product was 65%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.
[0043] Example 5:
[0044] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the photocatalyst was 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile 4CzIPN (5 mol% of the amount of enyne 2), the yield of product 3e was 71%, and the structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.
[0045] Example 6:
[0046] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the palladium catalyst was palladium acetate (5 mol% of the amount of enyne 2), the yield of product 3f was 66%, and the structure of the compound was identified by NMR (1H NMR and 1C NMR) and high-resolution mass spectrometry.
[0047] Example 7:
[0048] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the solvent was a mixture of 2-methyltetrahydrofuran and water (1.25 mL, 4:1). The yield of the product was 63% (3 g). The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0049] Example 8:
[0050] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the photocatalyst was (4,4'-di-tert-butyl-2,2'-bipyridine)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6 (5 mol% of the amount of enyne 2). The product yield was 85% after 3 hours. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0051] Example 9:
[0052] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the photocatalyst was (4,4'-di-tert-butyl-2,2'-bipyridine)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6, (5 mol% of the amount of enyne 2). The reaction was carried out under light at a wavelength of 400 nm, and the yield of product 3i was 68%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0053] Example 10:
[0054] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the base additive was potassium phosphate (the amount used was 2 equivalents of the amount of enyne 2), the yield of product 3j was 73%, and the structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.
[0055] Example 11:
[0056] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent was triethylamine (the amount used was 2 equivalents of the amount of enyne 2), the yield of product 3k was 55%, and the structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.
[0057] Example 12:
[0058] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the palladium catalyst was palladium acetate (5 mol% of the amount of enyne 2), the yield of product 3l was 73%, and the structure of the compound was identified by NMR (1H NMR and 1C NMR) and high-resolution mass spectrometry.
[0059] Example 13:
[0060] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the photocatalyst was 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile 4CzIPN (5 mol% of the amount of enyne 2), the product yield was 55%, and the structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0061] Example 14:
[0062] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent was 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (3.0 equivalents of the amount of enyne 2a), the yield of product 3n was 60%, and the structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0063] Example 15:
[0064] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the photocatalyst was 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile 4CzIPN (5 mol% of the amount of enyne 2), the yield of product 3o was 54%, and the structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.
[0065] Example 16:
[0066] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent was 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (4.0 equivalents of the amount of enyne 2), the product 3p yield was 67%, and the structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0067] Example 17:
[0068] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent was 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (4.0 equivalents of the amount of enyne 2), the product 3q yield was 88%, and the structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0069] Example 18:
[0070] The operating procedures and conditions were the same as in Example 1, except that, apart from the differences described in Table 2, the reducing agent was diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (4.0 equivalents of the amount of enyne 2), the yield of product 3r was 70%, and the structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0071] Example 19:
[0072] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (the amount used was 4.0 equivalents of the amount of enyne 2) was reacted under light at a wavelength of 400 nm. The product yield was 62% in 3 s. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.
[0073] Example 20:
[0074] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent was 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (the amount used was 5.0 equivalents of the amount of enyne 2), the product yield was 71%, and the structure of the compound was identified by NMR (1H NMR and 1C NMR) and high-resolution mass spectrometry.
[0075] Example 21:
[0076] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, the reducing agent was 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (the amount used was 5.0 equivalents of the amount of enyne 2), the product 3u yield was 69%, and the structure of the compound was identified by NMR (1H NMR and 1C NMR) and high-resolution mass spectrometry.
[0077] Comparative Example 1:
[0078] The raw materials, operating procedures and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, no photocatalyst was added and product 3a was not obtained.
[0079] Comparative Example 2:
[0080] The raw materials, operating procedures and conditions were the same as in Example 1. The difference from Example 1 was that, except for the differences described in Table 2, no palladium catalyst was added, and product 3a was not obtained.
Claims
1. A method for isopentenylating pyridine, characterized in that: Using substituted bromopyridine 1 and enyne 2 as starting materials, compound 3, which is pyridine isopreneated and / or isopreneated, is generated by the following reaction: In reaction formulas (1) and / or (2), bromopyridine compound 1 may or may not contain other substituents R. 1 Other substituents may be one or more of H, methyl, hydroxymethyl, methoxy, acetamido, trifluoromethyl, ethyl formate, cyano, bromine or chlorine atoms; In reaction (2), the pyridine-substituted enyne 2 may or may not contain other substituents R. 2 Other substituents may be one or more of H, methyl, hydroxymethyl, methoxy, acetamido, trifluoromethyl, ethyl formate, cyano, bromine, or chlorine atoms.
2. The method for preparing pyridine isopreneated and isopreneated compound 3 according to claim 1, characterized in that: The specific operating steps are as follows: The reaction is carried out in a reactor by sequentially adding bromopyridine 1, enyne 2, a photocatalyst, a palladium catalyst, a ligand, an alkaline additive, a reducing agent, and a solvent. The reaction is carried out at room temperature under light for 10-48 hours (preferably 18-36 hours). After the reaction is completed, compound 3, which is pyridine isopreneated and / or isopreneated, is separated.
3. The method according to claim 2, characterized in that: The molar ratio of bromopyridine 1 to enyne 2 is 1-10:1, with a preferred ratio of 2-4:
1.
4. The method according to claim 2, characterized in that: The photocatalysts used are tri(2-phenyl)pyridine iridium Ir(ppy)3, (4,4'-di-tert-butyl-2,2'-bipyridine)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6, bis((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, bis((2-phenyl)pyridine)(1,1'-dimethyl-2,2'-biimazole)iridium hexafluorophosphate [Ir(ppy)2(bim)]PF6, and bis(( One or more of the following: (2-phenyl)pyridine)(1,10-o-phenanthroline)iridium hexafluorophosphate [Ir(ppy)2(phen)]PF6, ruthenium tripyridine chloride hexahydrate Ru(bpy)3Cl2·6H2O, tris(1,10-o-phenanthroline)ruthenium hexafluorophosphate Ru(phen)3(PF6)2, 9-trimethylmethyl-10-methylacridinium perchlorate Acr-MesClO4, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile 4CzIPN, preferably tris(2-phenyl)pyridine iridium Ir(ppy)3; the amount of photocatalyst is 1-5% molar equivalent of enyne 2, preferably 3-5% molar equivalent.
5. The method according to claim 2, characterized in that: The palladium catalyst used is one of palladium chloride, palladium bromide, palladium trifluoroacetate, palladium acetate, and palladium hydroxide, with palladium chloride being preferred; the amount of palladium catalyst used is 1-10% molar equivalent of enyne 2, preferably 5-10% molar equivalent.
6. The method according to claim 2, characterized in that: The ligand used is 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene Xantphos; the amount of ligand used is 1-10% molar equivalent of enyne 2, preferably 5-10% molar equivalent.
7. The method according to claim 2, characterized in that: The alkaline additive used is one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium phosphate, and potassium carbonate, with potassium carbonate being preferred; the amount of alkaline additive used is 2-10 times the molar equivalent of alkenyne 2, preferably 2-5 times the molar equivalent.
8. The method according to claim 2, characterized in that: The reducing agent used is one or more of 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl ester, triethylamine, and diisopropylethylamine, preferably 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl ester; the amount of reducing agent used is 1-10 molar equivalents of enyne 2, preferably 1.5-5 molar equivalents.
9. The method according to claim 2, characterized in that: The solvent used is a mixed solvent, consisting of water and one or more organic solvents selected from ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, with tetrahydrofuran being preferred. The volume ratio of the mixed solvent (water to organic solvent) is between 1:3 and 1:10, preferably between 1:4 and 1:
5. The amount of solvent used is 1-5 mL of the mixed solvent per 0.2 mmol of enyne-2, preferably 1-2 mL.
10. The method according to claim 2, characterized in that: The illumination should be blue-violet light with a wavelength between 360nm and 460nm (e.g., LED light source), preferably with a wavelength of around 440-460nm.