A method for preparing pyridine ferrocene compound

Abstract

The present invention relates to a method for synthesizing a pyridine ferrocene compound. Specifically, ferrocene and a halogenated pyridine compound are prepared by irradiation with blue-violet LED light under the action of a photocatalyst, an acid and an additive. The present invention obtains a series of pyridine ferrocene compounds through simple and safe steps.

Description

Technical Field

[0001] The invention relates to a method for preparing a pyridine ferrocene compound. Background Art

[0002] Ferrocene is the most special organometallic compound with a sandwich structure. Due to its unique structure, ferrocene and its derivatives have important application value in the fields of material science, medicinal chemistry, and catalytic chemistry. The use of ferrocene-derived ligands in the field of homogeneous catalysis has developed many simple and efficient organic compound synthesis routes and promoted the development of pharmaceutical synthetic chemistry. In the traditional ferrocene pyridylation process, it is often necessary to go through more cumbersome experimental steps and strictly anhydrous and oxygen-free experimental conditions, and use flammable organic lithium reagents, which greatly limits the efficiency of the synthesis process and creates safety hazards.

[0003] Compared with the traditional synthesis method of pyridine ferrocene compounds, the route used in the present invention is simple, the target product can be obtained in one step, and particularly strict anhydrous and oxygen-free conditions are not required. The reaction is carried out under light at room temperature, and the conditions are mild. At the same time, the flammable and explosive organic lithium reagents required in the traditional route are also avoided.

[0004] In summary, this paper describes a novel photocatalytic synthesis method for pyridine-ferrocene compounds with simple steps, mild conditions and safety. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing pyridine ferrocene.

[0006]

[0007] Reaction equation 1: Synthesis of pyridine ferrocene compounds

[0008] The specific operation steps are as follows (reaction equation 1):

[0009] The reaction is carried out in a reactor, and a ferrocene compound 1, a halogenated pyridine 2, a photocatalyst, an acid, an additive, and a solvent are added in sequence under a nitrogen atmosphere, and the reaction is carried out at room temperature under the irradiation of a blue-violet LED lamp for 8-24 hours; after the reaction is completed, the pyridine ferrocene compound 3 is separated and obtained.

[0010] The ferrocene compound 1 includes ferrocene, 1,1'-dimethylferrocene, 1,1'-diethylferrocene, 1,2,3,4,5-pentamethylferrocene, and 1-phenyl-2,3,4,5-tetramethylferrocene.

[0011] In the halogenated pyridine compound, X can be a chlorine, bromine, or iodine atom, and the substitution position can be at the ortho or para position of the pyridine nitrogen atom. When X is an iodine atom, the substitution position can be extended to the meta position of the pyridine nitrogen atom. Other substituents on the halogenated pyridine compound can be alkyl, hydroxymethyl, hydroxyl, amine, and hydroxyl and amine with derived protective groups.

[0012] The molar ratio of the ferrocene compound 1 to the halogenated pyridine 2 is 1:1-3, preferably 1:2.

[0013] The photocatalysts are tris(2-phenyl)pyridine iridium complex 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'-di One or more of the following: iridium hexafluorophosphate (methyl-2,2'-biimidazole) [Ir(ppy)2(bim)]PF6, bis((2-phenyl)pyridine)(1,10-phenanthroline) iridium hexafluorophosphate [Ir(ppy)2(phen)]PF6, terpyridine ruthenium chloride hexahydrate Ru(bpy)3Cl2·6H2O, tris(1,10-phenanthroline) ruthenium hexafluorophosphate Ru(phen)3(PF6)2, 9-mesityl-10-methylacridine perchlorate Acr-MesClO4, Rose Bengal, Acid Red 94, preferably tris(2-phenyl)pyridine iridium Ir(ppy)3; the amount of the photocatalyst is 1-5% molar equivalent, preferably 1% molar equivalent.

[0014] The acid is one or more of acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid, preferably methanesulfonic acid; the amount of the acid is 0.2-5.0 molar equivalents, preferably 0.5-1.0 molar equivalents.

[0015] The additive is one or more of lithium chloride, sodium chloride, potassium chloride, zinc chloride, lithium fluoride, sodium fluoride, potassium fluoride and cesium fluoride, preferably potassium chloride; the dosage of the additive is 0.5-5.0 molar equivalents, preferably 1.0-2.0 molar equivalents.

[0016] The solvent is one or more of trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, preferably hexafluoroisopropanol; the amount of the solvent is 10-50 ml, preferably 10 ml, per mmol of ferrocene compound.

[0017] The light is a blue-violet LED light source between 360nm-460nm, preferably a light source with a wavelength of about 430nm.

[0018] The present invention has the following advantages:

[0019] First, the raw materials of the reaction, ferrocene and halogenated pyridine, are simple and easily available. Second, the reaction conditions are mild and safe, and the reaction steps are simple and efficient. Finally, the obtained pyridine ferrocene has high added value and can be used to synthesize various high value-added ligands, organic functional materials, etc. DETAILED DESCRIPTION

[0020] In order to better understand the present invention, the following examples are provided for illustration. The reaction materials and results of Examples 1-23 are shown in Table 1.

[0021] Table 1 Reaction results of different substituted allyl alcohols

[0022]

[0023]

[0024]

[0025]

[0026] It can be seen from the results in Table 1 that the halogenated pyridine compounds with different substituents can react with ferrocene under the action of photocatalysts, acids and additives and are well converted into pyridine ferrocene compounds under light.

[0027] Example 1

[0028] The reaction was carried out in a reactor, and ferrocene 1a (0.2 mmol), halogenated pyridine 2a (0.4 mmol), tri(2-phenyl)pyridine iridium Ir(ppy)3 (1 mol% of the ferrocene compound), methanesulfonic acid (0.1 mmol), potassium fluoride (0.2 mmol), and hexafluoroisopropanol (2.0 mL) were added in sequence and reacted under a 430 nm LED light source and room temperature for 30 hours. After the reaction was completed, a saturated sodium hydroxide solution was added to neutralize to a pH>7, and the pyridine ferrocene compound 3a was separated by column chromatography with a yield of 83%. The compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0029] The test data are as follows:

[0030] 3a:Orange solid,46.0mg,83%yield,R f=0.35(petroleum ether / ethylacetate 10 / 1). 1 H NMR(400MHz,Chloroform-d)δ7.46(t,J=7.7Hz,1H),7.24(d,J=7.5Hz,1H),6.92( d,J=7.5Hz,1H),4.93–4.87(m,2H),4.39–4.33(m,2H),4.04(s,5H),2.54(s,3H); 13 C NMR (100MHz, Chloroform-d) δ158.4,157.8,136.0,120.0,117.3,84.5,69.63,69.57,67.4,24.7.

[0031] Embodiment 2:

[0032] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the additive is potassium chloride, and the addition amount is 1.0 molar equivalent (the amount used is 1.0 molar equivalent of ferrocene 1a). The yield of product 3b is 75%. The compound (product) is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry. Product 3b is a known compound, Karlheinz Sünkel, Ramona Branzan, Stefan Weigand, Inorganica Chimica Acta 2013, 399, 193–199.

[0033] Embodiment 3:

[0034] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the acid was benzoic acid, the amount used was 3.0 molar equivalents, the yield of the product 3c was 44%, and the structure of the compound was identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0035] Embodiment 4:

[0036] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the solvent was trifluoroethanol, the yield of the product 3d was 48%, and the structure of the compound was identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0037] Embodiment 5:

[0038] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the amount of halogenated pyridine 2e is 3.0 molar equivalents (the amount is 3.0 molar equivalents of ferrocene 1a), the yield of product 3e is 49%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0039] Embodiment 6:

[0040] The operation process and conditions were the same as those in Example 5. The yield of product 3f was 96%. The structure of the compound was identified by IR, NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0041] Embodiment 7:

[0042] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the wavelength of the LED light source is 365 nm, the yield of the product 3 g is 79%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0043] Embodiment 8:

[0044] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the wavelength of the LED light source is 390 nm, the product 3h yield is 67%, and the compound is subjected to infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0045] Embodiment 9:

[0046] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is terpyridine ruthenium chloride hexahydrate Ru(bpy)3Cl2·6H2O, the amount used is 3% molar equivalent, the yield of product 3i is 80%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0047] Embodiment 10:

[0048] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is (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, and the amount used is 2% molar equivalent of the amount of ferrocene compound. The yield of product 3j is 78%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0049] Embodiment 11:

[0050] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the wavelength of the LED light source is 456 nm, the yield of the product 3k is 40%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0051] Embodiment 12:

[0052] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is (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, and the amount used is 2% molar equivalent of the amount of ferrocene compound. The yield of product 31 is 53%. The structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0053] Embodiment 13:

[0054] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the solvent was trifluoroethanol, the yield of the product 3m was 51%, and the structure of the compound was identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0055] Embodiment 14:

[0056] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the additive is cesium fluoride, and the added amount is 1.0 molar equivalent (the amount used is 1.0 molar equivalent of ferrocene 1a). The yield of the product 3n is 56%. The structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0057] Embodiment 15:

[0058] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the solvent was trifluoroethanol, the yield of the product 3o was 52%, and the structure of the compound was identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0059] Embodiment 16:

[0060] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the acid is acetic acid, the amount used is 3.0 molar equivalents of the ferrocene compound, the yield of the product 3p is 59%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0061] Embodiment 17:

[0062] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the wavelength of the LED light source is 390 nm, the yield of the product 3q is 49%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0063] Embodiment 18:

[0064] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the acid is trifluoroacetic acid, the amount used is 2.0 molar equivalents of the ferrocene compound, the yield of the product 3r is 45%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0065] Embodiment 19:

[0066] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the acid is benzoic acid, the amount used is 2.0 molar equivalents of the ferrocene compound, the yield of the product 3s is 49%, and the structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0067] Embodiment 20:

[0068] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is (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, and the amount used is 3% molar equivalent of the amount of ferrocene compound. The yield of product 3t is 48%. The structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0069] Embodiment 21:

[0070] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is di((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, and the amount used is 1% molar equivalent of the amount of ferrocene compound. The yield of the product 3u is 46%. The structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0071] Embodiment 22:

[0072] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is di((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, and the amount used is 1% molar equivalent of the amount of ferrocene compound. The yield of product 3v is 93%, and the ratio of meta-product to ortho-product is 1.2:1. The structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0073] Embodiment 23:

[0074] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is di((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, and the amount used is 2% molar equivalent of the amount of ferrocene compound. The yield of product 3w is 71%, and the ratio of meta-product to ortho-product is 1.6:1. The structure of the compound is identified by infrared, nuclear magnetic resonance (hydrogen spectrum and carbon spectrum), and high-resolution mass spectrometry.

[0075] Comparative Example 1:

[0076] The raw materials, operating procedures and conditions were the same as those in Example 1, except that, in addition to the differences described in Table 1, no photocatalyst was added and no product 3a was obtained.

[0077] Comparative Example 2:

[0078] The raw materials, operation process and conditions were the same as those in Example 1, except that, in addition to the differences described in Table 1, no acid was added and no product 3a was obtained.

Claims

1. A method for synthesizing a pyridine ferrocene compound, characterized in that: Using ferrocene compounds and halogenated pyridine compounds as raw materials to generate pyridine ferrocene compounds. The ferrocene compound is selected from one of ferrocene, 1,1'-dimethylferrocene, 1,1'-diethylferrocene, 1,2,3,4,5-pentamethylferrocene, and 1-phenyl-2,3,4,5-tetramethylferrocene; In the halogenated pyridine compound, the halogen X is one of chlorine, bromine and iodine atoms, and the substitution position is one of the ortho and para positions of the pyridine nitrogen atom; When the halogen X is an iodine atom, the substitution position is extended to the meta position of the pyridine nitrogen atom; the halogenated pyridine compound does not contain or contains other substituents, and the other substituents are alkyl, hydroxymethyl, hydroxyl, amino, tert-butyloxycarbonyl-protected hydroxyl and amine with acetyl or tert-butyloxycarbonyl protection; The specific steps are as follows: The reaction is carried out in a reactor, a ferrocene compound, a halogenated pyridine compound, a photocatalyst, an acid, an additive, and a solvent are added under a nitrogen atmosphere, and the reaction is carried out at room temperature under the irradiation of a blue-violet LED lamp with a wavelength of 360-460nm for 8-48 hours; after the reaction is completed, the pyridine ferrocene compound is separated; The photocatalyst used is one or more of tris(2-phenyl)pyridine iridium complex Ir(ppy)3, (4,4'-di-tert-butyl-2,2'-bipyridyl)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'-bipyridyl)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, terpyridyl ruthenium chloride hexahydrate Ru(bpy)3Cl2·6H2O; The acid is one or more of acetic acid, benzoic acid, methanesulfonic acid and trifluoroacetic acid; The additive is one or more of potassium chloride, potassium fluoride and cesium fluoride; The solvent is one or more of trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether; The reaction formula is as follows: 。 2. The method according to claim 1, characterized in that: The molar ratio of the ferrocene compound to the halogenated pyridine compound is 1:1-3.

3. The method according to claim 2, characterized in that: The molar ratio of the ferrocene compound to the halogenated pyridine compound is 1:1-2.

4. The method according to claim 1, characterized in that: The amount of the photocatalyst used is 1-5% molar equivalent relative to the ferrocene compound.

5. The method according to claim 4, characterized in that: The amount of the photocatalyst used relative to the ferrocene compound is 1-3% molar equivalent.

6. The method according to claim 1, characterized in that: The amount of the acid used is 0.2-5.0 molar equivalents relative to the ferrocene compound.

7. The method according to claim 6, characterized in that: The amount of the acid used is 0.5-1.0 molar equivalent relative to the ferrocene compound.

8. The method according to claim 1, characterized in that: The amount of the additive used relative to the ferrocene compound is 0.5-5.0 molar equivalents.

9. The method according to claim 8, characterized in that: The amount of the additive used relative to the ferrocene compound is 1.0-2.0 molar equivalents.

10. The method according to claim 1, characterized in that: The amount of the solvent used is 10-50 ml per mmol of the ferrocene compound 1.

11. The method according to claim 10, characterized in that: The amount of the solvent used is 10-20 ml per mmol of the ferrocene compound 1.

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