A method for preparing phosphine oxides by clean and efficient electrochemical oxidation

Abstract

The present application belongs to the field of organic electrochemical oxidation technology, and relates to a method for preparing oxidized phosphine compounds by clean and efficient electrochemical oxidation. Organic phosphine compounds I are mixed with electrolyte, water and solvent to obtain a mixed solution; the mixed solution is subjected to electrochemical reaction by passing electricity to prepare oxidized phosphine compounds II. The present application realizes green and efficient preparation of phosphine oxide compounds with various structures and electrical properties under room temperature conditions by using cheap and readily available electrolyte sodium chloride and water as an oxygen source. Compared with the current widely used oxidation method, the present application has the advantages of not needing to add oxidizing agents and catalysts, not needing to be carried out under inert gas protection, safe and clean reaction process, high efficiency, simple post-treatment and separation process and the like. The present application uses green electrons as an oxidizing agent, avoiding the widely used complex oxidation systems at present, such as hydrogen peroxide system, metal oxide catalytic oxidation system and organic catalyst oxidation system.

Description

Technical Field

[0001] This invention belongs to the field of organic electrochemical oxidation technology, and relates to a clean and efficient method for preparing phosphine oxide compounds by electrochemical oxidation. Background Technology

[0002] Organophosphine compounds and organophosphine oxides play important roles and have wide applications in human production and daily life. Phosphine oxides possess characteristics such as good stability, strong polarity and lipophilicity, and good in vivo solubility, and are found in small molecule drugs, fine chemicals, special functional materials, and bioactive macromolecular structural frameworks (e.g., the anticancer drug brigatinib, thermally activated delayed fluorescence materials, organophosphine reagents, and organophosphine ligands for catalysts). Furthermore, phosphine oxide (P=O) bonds exhibit excellent coordination dissociation capabilities, making them widely used as efficient separation and extraction agents for rare earth metals, homogeneous catalysts, and for regulating the activity of phosphine ligands in metal catalysis. Organophosphine oxides can be prepared by oxidizing low-valent organophosphine compounds with an equivalent or excess oxidant, such as by adding excess hydrogen peroxide solution to oxidize low-valent phosphine to high-valent phosphine (Eur. J. Org. Chem. 2023, 26, e202300397). Recently, Kenneth M. Nicholas's group at the University of Oklahoma reported a successful green oxidation process of triphenylphosphine to triphenylphosphine oxide using oxygen as an oxidant via a molybdenum dioxide complex catalyst and an oxygen atom transfer strategy (Eur. J. Inorg. Chem. 2024, 27, e202300397). Besides oxidant oxidation, Professor Chen Qian's group at Guangdong University of Technology reported an oxidation system composed of an electrophilic fluorinating agent (Selectfluor) and water, achieving the oxidation of trivalent phosphine within 5 minutes. This reaction has a wide range of applications and yields a series of phosphine oxides in high yield (Tetrahedron Lett., 2016, 57, 3379–3381.). In recent years, organic electrochemical reactions have attracted increasing interest from researchers. Compared to the oxidation reactions involving stoichiometric oxidants reported in the above literature, organic electrochemical oxidation uses green electrons as the oxidant, requiring no additional oxidant. Furthermore, the redox potential of the system can be controlled by simply adjusting the current or voltage, enabling efficient and green oxidation of substrates with different redox potentials. Organic electrochemical oxidation strategies reduce the use of external oxidants, decrease the generation of byproducts and waste liquids, improve the atom economy of the reaction, and produce no inorganic salts after the reaction. Furthermore, organic electrochemical reactions do not require expensive reaction equipment, the reaction process is simple and easy to control, and it is highly operable. Summary of the Invention

[0003] The technical problem to be solved by this invention addresses the issues existing in the preparation process of phosphine oxide compounds in the prior art, such as: ① the use of equivalent or excess oxidant; ② the need for metal catalysts for catalytic oxidation; ③ the high cost of various additives; and ④ the large volume of waste salt and waste liquid in post-treatment. This invention discloses a method that uses electrons as a green oxidant, water as a green oxygen source, and inexpensive and abundant sodium chloride as an electrolyte. Furthermore, it provides a mild electrochemical oxidation process for the efficient preparation of phosphine oxide products, with good reaction versatility, high yield and atom economy, simple operation of the oxidation process, low energy consumption, and reduced production costs and purification difficulties for these products.

[0004] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0005] This invention discloses a clean and efficient electrochemical oxidation method for preparing phosphine oxide compounds. The method involves mixing organophosphine compound I with an electrolyte, water, and a solvent to obtain a mixture; then subjecting the mixture to an electrochemical reaction to obtain phosphine oxide compound II.

[0006] The organophosphorus compound I is

[0007] The phosphine oxide compound II is

[0008] When the organophosphine compound I is When the phosphine oxide compound II is

[0009]

[0010] When the aforementioned organophosphorus compound I is When the phosphine oxide compound II is

[0011] Wherein, R1, R2, and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted aromatic, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocyclic; the substitution is made by any number of the same or different substituents; the substituents are halogens, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylacyl, ester, amide, cyano, or diphenylphosphine.

[0012] The electrochemical reaction is carried out in a conventional electrolytic cell or in an electrochemical microchannel reaction device.

[0013] When the electrochemical reaction is carried out in a conventional electrolytic cell, the electrolyte is sodium chloride.

[0014] The electrochemical reaction described herein does not require inert gas protection.

[0015] The electrochemical reaction described herein is conducted without catalysts, acidic additives, alkaline additives, or oxidants.

[0016] In some embodiments, R1, R2, and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted aromatic groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; the substitution is performed by any number of identical or different substituents; the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, or diphenylphosphine groups.

[0017] In some embodiments, preferably, R1, R2, and R3 are independently selected from substituted or unsubstituted ethyl, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted cyclohexyl; the substitution is substituted by any number of the same or different substituents; the substituent is methyl, methoxy, or diphenylphosphine.

[0018] In some embodiments, the electrolyte is any one or a combination of several of tetraethylammonium perchlorate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium tetrafluoroborate, sodium chloride, and potassium bromide; the solvent is any one or a combination of several of acetonitrile, ethanol, dichloroethane, N,N-dimethylformamide, and methyl tert-butyl ether.

[0019] In some embodiments, preferably, the solvent is a mixture of acetonitrile and ethanol, more preferably a mixture of acetonitrile and ethanol in a volume ratio of (8-28) mL:(2-12) mL, and even more preferably 8 mL:2 mL or 28 mL:12 mL.

[0020] In some embodiments, preferably, the solvent is a mixture of acetonitrile and dichloroethane, more preferably a mixture of acetonitrile and dichloroethane in a volume ratio of (8-28) mL:(2-12) mL, and even more preferably 8 mL:2 mL or 28 mL:12 mL.

[0021] In some embodiments, preferably, the solvent is a mixture of acetonitrile and N,N-dimethylformamide, more preferably a mixture of acetonitrile and N,N-dimethylformamide in a volume ratio of (8-28) mL:(2-12) mL, and even more preferably 8 mL:2 mL or 28 mL:12 mL.

[0022] In some embodiments, preferably, the solvent is a mixture of acetonitrile and methyl tert-butyl ether, more preferably a mixture of acetonitrile and methyl tert-butyl ether in a volume ratio of (8-28) mL:(2-12) mL, and even more preferably 8 mL:2 mL or 28 mL:12 mL.

[0023] In some embodiments, the molar ratio of the organophosphorus compound I to the electrolyte is (1-10):(1-3); the volume ratio of the water to the solvent is 2:(6-42); and the ratio of the molar amount of the organophosphorus compound I to the total volume of the water and solvent is (0.5-8.0) mmol:(8-44) mL.

[0024] In some embodiments, preferably, the molar ratio of the organophosphorus compound I to the electrolyte is 1:1, 1:2, 2:1, 5:1, or 10:3.

[0025] In some embodiments, preferably, the volume ratio of water to solvent is 2:(8-40), more preferably 2:8 or 2:40.

[0026] In some embodiments, preferably, the ratio of the molar amount of the organophosphorus compound I to the total volume of the water and solvent is (0.5-8.0) mmol:(10-42) mL, more preferably 0.5 mmol:10 mL, 0.5 mmol:42 mL, 1 mmol:42 mL, 2 mmol:42 mL, 4 mmol:42 mL, or 8 mmol:42 mL.

[0027] In some embodiments, the electrochemical reaction is carried out at room temperature.

[0028] When the electrochemical reaction is carried out in a conventional electrolytic cell, the reaction time is 1 to 4 hours, preferably 3 hours.

[0029] When the electrochemical reaction is carried out in a conventional electrolytic cell, a constant current is applied in an open system, without the need for inert gas protection.

[0030] In some embodiments, the electrochemical reaction is carried out with a constant current of 10mA to 330mA; the anode electrode of the electrochemical reaction is a carbon rod or a platinum sheet; the cathode electrode of the electrochemical reaction is a carbon rod or a platinum sheet.

[0031] In some embodiments, preferably, the electrochemical reaction is carried out at a constant current of 10mA, 20mA, 25mA, 150mA, 160mA, 250mA, 280mA, or 330mA.

[0032] In some embodiments, preferably, the anode electrode of the electrochemical reaction is a carbon rod.

[0033] In some embodiments, preferably, the cathode electrode of the electrochemical reaction is a carbon rod.

[0034] In some embodiments, when the electrochemical reaction is carried out in an electrochemical microchannel reaction device, the following steps are included:

[0035] Organophosphorus compound I was mixed with electrolyte, water, and solvent to obtain a mixture; the mixture was then pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reaction device to carry out an electrochemical reaction, thereby obtaining phosphorus oxide compound II.

[0036] In some embodiments, the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reaction device is 0.10 mL / min to 0.40 mL / min.

[0037] In some embodiments, preferably, the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reaction device is 0.10 mL / min to 0.35 mL / min, more preferably 0.10 mL / min, 0.20 mL / min, 0.25 mL / min, 0.30 mL / min, or 0.35 mL / min.

[0038] In some embodiments, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 10.0 min to 100.0 min.

[0039] In some embodiments, preferably, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 14.0 min to 100.0 min, more preferably 14.3 min, 16.7 min, 20 min, 25 min, 50.0 min, or 100 min.

[0040] In some embodiments, the electrochemical microchannel reaction device includes a connecting pipe, a feed pump, an electrochemical microchannel continuous flow reactor, an electrostatic precipitator, and a receiver; wherein the feed pump, the electrochemical microchannel continuous flow reactor, and the receiver are connected in series via the connecting pipe; the positive electrode of the electrostatic precipitator is connected to the anode electrode of the electrochemical microchannel continuous flow reactor; and the negative electrode of the electrostatic precipitator is connected to the cathode electrode of the electrochemical microchannel continuous flow reactor.

[0041] The electrochemical microchannel continuous flow reactor (electrochemical synthesizer) has a reactor volume of 3-14 mL, preferably 5 mL or 10 mL.

[0042] The electrochemical microchannel continuous flow reactor (electrochemical synthesizer) is a tubular reactor with a diameter of 0.5–3.0 mm, preferably 1.0 mm.

[0043] The anode material of the electrochemical microchannel continuous flow reactor is graphite or platinum sheet, preferably graphite; the cathode material of the electrochemical microchannel continuous flow reactor is graphite or platinum sheet, preferably platinum sheet.

[0044] Beneficial effects:

[0045] (1) This invention utilizes readily available and inexpensive electrolytes (NaCl) and water (H2O) as oxygen sources, and achieves the green and efficient preparation of various phosphine oxides with diverse structures and electrical properties at room temperature. Compared with currently widely used oxidation methods, this invention has advantages such as no need for external oxidants and catalysts, no need for inert gas protection, a safe, clean, and efficient reaction process, and simple post-processing and separation. This invention uses green electrons as oxidants, avoiding the complex oxidation systems widely used today, such as hydrogen peroxide systems, metal oxide catalytic oxidation systems, and organic catalyst oxidation systems.

[0046] (2) The method provided by the present invention does not require inert gas protection and can realize the electrochemical oxidation of organophosphorus compounds to phosphine oxides in a green and efficient manner. The reaction is fast, the yield is high, the product is easy to separate, the environmental pollution is small, and the wastewater discharge is small.

[0047] (3) This invention achieves efficient oxidation of low-valent phosphine compounds through an organic electrochemical green oxidation process. Compared with the past equivalent or excess H2O2 oxidation, metal-catalyzed oxidation, and other oxidation reactions, this invention has good substrate universality, high yield and atom economy, simple operation of the oxidation process, low energy consumption, and reduces the production cost and separation and purification difficulty of such products.

[0048] (4) Microchannel continuous flow reactions have the following typical advantages over batch reactions: ① Highly efficient mass and heat transfer accelerates the reaction process; ② Large specific surface area and efficient heat transfer area facilitate heat removal during the reaction; ③ Small online reactor volume ensures safe reaction process. Furthermore, to verify the practical application potential of the method of this invention, increase reaction efficiency, and better control the reaction process, the reaction was transferred from a non-separated electrolytic cell to an electrochemical microchannel reaction device to investigate the scale-up performance, maximum equipment load, and make corresponding optimizations. Experimental results show that microfluidic technology can achieve scale-up and continuous production of the reaction, with no significant exothermic reaction during catalysis, no need for high temperature and high pressure, and a greener, more efficient, milder, and safer process. Attached Figure Description

[0049] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0050] Figure 1 This is a diagram of the electrochemical microchannel reaction device used in the embodiments of the present invention. Detailed Implementation

[0051] The present invention will be further described in detail below with reference to specific embodiments. The scope of protection of the present invention is not limited to this, but also includes other low-valent organophosphorus electrochemical oxidation and conversion of related phosphine oxide products derived from this invention.

[0052] The experimental methods mentioned in the following examples are all conventional methods, i.e., common and universal methods. All experimental reagents and materials can be purchased from commercial channels.

[0053] The electrochemical microchannel reaction device used in the embodiments of the present invention is shown in the figure below. Figure 1 As shown, it includes connecting pipes, a feed pump, an electrochemical microchannel continuous flow reactor, an electrostatic precipitator, and a receiver; wherein, the feed pump, the electrochemical microchannel continuous flow reactor, and the receiver are connected in series via connecting pipes; the positive electrode of the electrostatic precipitator is connected to the anode electrode of the electrochemical microchannel continuous flow reactor; the negative electrode of the electrostatic precipitator is connected to the cathode electrode of the electrochemical microchannel continuous flow reactor.

[0054] The anode material of the electrochemical microchannel continuous flow reactor is graphite; the cathode material of the electrochemical microchannel continuous flow reactor is platinum sheet.

[0055] The diameter of the connecting pipe is 1 mm.

[0056] The feed pump mentioned is model number Ref TYD01.

[0057] The electrochemical microchannel continuous flow reactor (electrochemical synthesizer) has a reactor volume of 5 mL or 10 mL.

[0058] The electrochemical microchannel continuous flow reactor (electrochemical synthesizer) is a tubular reactor with a tube diameter of 1.0 mm.

[0059] The electrical box mentioned above is model MS-305DS.

[0060] Example 1: Electrochemical oxidation preparation process of triphenylphosphine oxide

[0061]

[0062] Electrochemical autoclave anodic oxidation reaction: 0.5 mmol triphenylphosphine, 1.0 mmol tetraethylammonium perchlorate electrolyte, acetonitrile solvent, and water (8:2, 10 mL) were added sequentially to a clean, dry, unseparated electrolytic cell. A carbon rod was used as the anode and a platinum sheet as the cathode. A constant current of 10 mA was applied at room temperature, and the reaction was stirred for 3 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was separated by silica gel column chromatography with eluent to obtain the target product triphenylphosphine oxide, a white powder with a yield of 65%.

[0063] The 1H NMR spectrum data of the product triphenylphosphine oxide are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.70–7.57 (m, 6H), 7.55–7.53 (m, 3H), 7.49–7.44 (m, 6H). This data is consistent with reported data in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0064] Examples 2-8: Changing the electrolyte

[0065] The experimental method was the same as in Example 1, except that the electrolytes were replaced with tetrabutylammonium hexafluorophosphate (TBAPF6), tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBACl), tetrabutylammonium tetrafluoroborate (TBABF4), sodium chloride (NaCl), potassium bromide (none), and no electrolyte was added. Specific experimental results are shown in Table 1.

[0066] Table 1

[0067] electrolytes <![CDATA[Yield a (%)]]> Example 1 <![CDATA[Et4NClO4]]> 65 Example 2 <![CDATA[TBAPF6]]> 90 Example 3 TBAF 89 Example 4 TBACl 92 Example 5 <![CDATA[TBABF4]]> 90 Example 6 NaCl 96 Example 7 KBr 91 Example 8 none 65

[0068] Note: In Table 1 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0069] Examples 9-11: Changing the constant current

[0070] The experimental method was the same as in Example 6, except that the constant current was set to 5mA, 20mA, and no constant current was applied. Specific experimental results are shown in Table 2.

[0071] Table 2

[0072] electrolytes Current(I / mA) <![CDATA[Yield a (%)]]> Example 6 NaCl 10 96 Example 9 NaCl 5 68 Example 10 NaCl 20 90 Example 11 NaCl 0 0

[0073] Note: In Table 2 aThe oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0074] Examples 12-14: Changing the electrodes

[0075] The experimental method was the same as in Example 6, except that the electrodes were changed: (1) both the cathode and anode were platinum sheet electrodes; (2) the platinum sheet was used as the anode and the carbon rod as the cathode; (3) both the cathode and anode were used as carbon rods. Specific experimental data are shown in Table 3.

[0076] Table 3

[0077] electrolytes Current(I / mA) Anode material cathode material <![CDATA[Yield a (%)]]> Example 6 NaCl 10 carbon rods Platinum 96 Example 12 NaCl 10 Platinum Platinum 86 Example 13 NaCl 10 Platinum carbon rods 83 Example 14 NaCl 10 carbon rods carbon rods 79

[0078] Note: In Table 3 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0079] Examples 15-20: Changing the solvent

[0080] The experimental method was the same as in Example 6, except that the solvents were changed. The solvents were: (1) acetonitrile and ethanol (volume ratio 8:2, 10 mL); (2) acetonitrile and dichloroethane (volume ratio 8:2, 10 mL); (3) acetonitrile and N,N-dimethylformamide (volume ratio 8:2, 10 mL); (4) water (10 mL); (5) acetonitrile (10 mL); (6) acetonitrile (10 mL). Activated molecular sieves were added to the reaction solution to remove water during the reaction. Specific data are shown in Table 4.

[0081] Table 4

[0082]

[0083]

[0084] Note: In Table 4 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0085] The main reason why the product triphenylphosphine oxide could be obtained in Examples 15-17 was that the solvent contained trace amounts of water. In Examples 19-20, acetonitrile was used, and although acetonitrile solvent itself contains water, 28% product could still be obtained after removing the water using a molecular sieve. This was mainly because the reaction system was not protected by an inert gas, and trace amounts of water in the air led to product formation. In Example 18, water was used alone as the solvent, and the reaction could not proceed smoothly mainly because the raw material has poor solubility in pure water, and the reaction intermediate is unstable under conditions of large amounts of water, thus preventing the product from forming successfully.

[0086] Example 21:

[0087]

[0088] The experimental method in this embodiment is the same as in Example 6, except that the substrate is tris(p-methoxyphenyl)phosphine. The final target product, tris(p-methoxyphenyl)phosphine oxide, is a white to pale yellow powder with a yield of 92%.

[0089] The 1H NMR spectrum data of the product tris(p-methoxyphenyl)phosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.54–7.49 (dd, J = 8.8, 2.7 Hz, 6H), 6.91–6.88 (m, 6H), 3.77 (s, 9H). This data is consistent with reported data in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0090] Example 22:

[0091]

[0092] The experimental method in this embodiment is the same as in Example 6, except that the substrate is tris(p-methylphenyl)phosphine. The final target product, tris(p-methylphenyl)phosphine oxide, is a white powder with a yield of 85%.

[0093] The 1H NMR spectrum data of the product tris(p-methylphenyl)phosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.56–7.51 (dd, J = 8.0, 2.0Hz, 6H), 7.26–7.23 (dd, J = 8.0, 2.0Hz, 6H), 2.39 (s, 9H). This data is consistent with reported data in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0094] Example 23:

[0095]

[0096] The experimental method in this embodiment is the same as in Example 6, except that the substrate is tris(m-methylphenyl)phosphine. The final target product, tris(m-tolyl)phosphine oxide, is a white solid with a yield of 91%.

[0097] The 1H NMR spectrum data of the product tris(m-methylphenyl)phosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.59–7.56 (d, J = 11.6 Hz, 3H), 7.38–7.31 (m, 9H), 2.36 (s, 9H). This data is consistent with reported data in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0098] Example 24:

[0099]

[0100] The experimental method in this embodiment is the same as in Example 6, except that the substrate is tris(o-methylphenyl)phosphine. The final target product, tris(o-methylphenyl)phosphine oxide, is a white solid with a yield of 96%.

[0101] The 1H NMR spectrum data of the product tris(o-methylphenyl)phosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.45–7.42 (m, 3H), 7.33–7.30 (m, 3H), 7.17–7.07 (m, 6H), 2.50 (s, 9H). This data is consistent with reported data in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0102] Example 25:

[0103]

[0104] The experimental method in this embodiment is the same as in Example 6, except that the substrate is tris(2-furanyl)phosphine. The final target product, tris(2-furanyl)phosphine oxide, is a pale yellow solid with a yield of 78%.

[0105] The 1H NMR spectrum data of the product tris(2-furanyl)phosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.75–7.73 (m, 3H), 7.19–7.17 (m, 3H), 6.57–6.55 (m, 3H). This data was consistent with reported data in the literature (Qian Chen, Jiekun Zeng, Xinxing Yan, Yulin Huang, Zhiyun Du, Kun Zhang, Chunxiao Wen. Mild and Efficient Oxidation of Phosphorus (III) Compounds with Selectfluor. Tetrahedron Lett., 2016, 57, 3379–3381.).

[0106] Example 26:

[0107]

[0108] The experimental method in this embodiment is the same as in Example 6, except that the substrate is pyridine diphenylphosphine. The final target product obtained is pyridine diphenylphosphine oxide, a pale yellow powder, with a yield of 85%.

[0109] The 1H NMR spectrum data of the product pyridine diphenylphosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 8.79–8.77 (d, J = 4.4 Hz, 1H), 8.33–8.29 (m, 1H), 7.91–7.86 (m, 5H), 7.54–7.51 (m, 2H), 7.45 (m, 4H), 7.41–7.37 (m, 1H). This data is consistent with reported data in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0110] Example 27:

[0111]

[0112] The experimental method in this embodiment is the same as in Example 6, except that the substrate is ethyldiphenylphosphine. The final target product, ethyldiphenylphosphine oxide, is a white powder with a yield of 93%.

[0113] The 1H NMR spectrum data of the product ethyl diphenylphosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.76–7.71 (m, 4H), 7.53–7.47 (m, 6H), 2.33–2.26 (m, 2H), 1.26–1.16 (m, 3H). The results were consistent with reported data in the literature (Chen-Kun Li, Ze-Kun Tao, Adedamola Shoberu, Wei Zhang, Jian-Ping Zou. Org. Lett., 2022, 24, 6083-6087.).

[0114] Example 28:

[0115]

[0116] The experimental method in this embodiment is the same as in Example 6, except that the substrate is phenyldicyclohexylphosphine. The final target product, phenyldicyclohexylphosphine oxide, is a white powder with a yield of 94%.

[0117] The 1H NMR spectrum data of the product phenyldicyclohexylphosphine oxide in this embodiment are as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.68–7.63 (m, 2H), 7.52–7.44 (m, 3H), 2.07–2.01 (m, 4H), 1.81–1.51 (m, 8H), 1.32–1.08 (m, 10H). This data is consistent with reported data in the literature (Chunya Li, and Li-Biao Han. Palladium-Catalyzed Solvent-Free Preparation of Arylphosphonates ArP(O)(OAr)₂from(ArO)₃P via the Michaelis–Arbuzov Rearrangement. Organometallics 2020, 39, 3613–3617.).

[0118] Example 29:

[0119]

[0120] The experimental method in this embodiment is the same as in Example 6, except that the substrate is tricyclohexylphosphine. The final target product, tricyclohexylphosphine oxide, is a white solid with a yield of 84%.

[0121] The 1H NMR spectrum data of the product tricyclohexylphosphine oxide in this embodiment are as follows: 1¹H NMR (400MHz, CDCl₃) δ 1.88–1.60 (m, 18H), 1.43–1.08 (m, 15H). The results were consistent with those reported in the literature (Qian Chen, Jiekun Zeng, Xinxing Yan, Yulin Huang, Zhiyun Du, Kun Zhang, Chunxiao Wen. Mild and Efficient Oxidation of Phosphorus (III) Compounds with Selectfluor. Tetrahedron Lett., 2016, 57, 3379–3381.).

[0122] Example 30:

[0123]

[0124] The experimental method in this embodiment is the same as in Example 6, except that the substrate is 1,2-bis(diphenylphosphine)benzene. The final target product obtained is (2-(diphenylphosphine)phenyl)diphenylphosphine oxide, a light red powder, with a yield of 87%.

[0125] In this embodiment, the 1H NMR and 1P NMR spectra of the product (2-(diphenylphosphino)phenyl)diphenylphosphine oxide are as follows: 1 H NMR(400MHz,DMSO)δ7.75–7.69(m,2H),7.51(m,4H),7.38(m,18H), 31 PNMR (162MHz, DMSO) δ 29.44, -13.59. The results were consistent with the data reported in the literature (Vladimir V. Grushin. Organometallics 2001, 20, 3950–3961.).

[0126] Example 31:

[0127]

[0128] The experimental method in this embodiment is the same as in Example 6, except that the substrate is (S)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine. The final target product (S)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine oxide is a white solid with a yield of 50%.

[0129] In this embodiment, the 1H NMR and 1P NMR spectra of the product (S)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine)oxy are as follows: 1H NMR (400MHz, CDCl3) δ7.79–7.73(m,4H),7.65–7.60(m,4H),7.39–7.28(m,12H),7.20–7.13(m,8H),6.73–6.72(d,J=3.7Hz,4H), 31 P NMR (162MHz, CDCl3) δ 28.51. The results were consistent with the data reported in the literature (Masaru Kondo, Tomohiro Agou. Catalytic Aerobic Photooxidation of Triarylphosphines using Dibenzo-fused 1,4-Azaborines. Chem. Commun., 2022, 58, 5001-5004.).

[0130] To verify the practical application potential of the above method, increase the efficiency of the reaction, and better control the reaction process, we attempted to transfer the reaction from a non-separated electrolytic cell to an electrochemical microchannel reactor to examine the scale-up performance of the reaction, the maximum load of the equipment, and to make corresponding optimizations.

[0131] Examples 32-34: Synthesis of Triphenylphosphine Oxide using Electrochemical Microchannel Reaction Technology

[0132] Electrochemical microchannel continuous flow oxidation reaction process: Add 0.5 mmol triphenylphosphine and 1.0 mmol electrolyte Et4NClO4 to a clean and dry beaker. Use 40 mL acetonitrile and 2 mL H2O as a solvent and mix to obtain a mixture. Use a 50 mL plastic syringe to draw up the mixture for later use.

[0133] A syringe containing the mixture was fixed to an automatic injection pump and adjusted to a specific flow rate. The syringe outlet was connected to the inlet of a self-made electrochemical microchannel continuous flow reactor with a retention volume of 5 mL. This reactor used graphite as the anode and a platinum sheet as the cathode. A constant current of 25 mA was applied to the reactor, and the electrochemical reaction was carried out at room temperature. The reaction solution was collected from the reactor outlet. The organic solvent was removed by rotary evaporation, and the product was separated by silica gel column chromatography using an eluent to obtain the target product, triphenylphosphine oxide, as a white solid.

[0134] In a self-made electrochemical microchannel continuous flow reactor, based on the above reaction conditions and feed ratio, the relationship between the flow rate and the yield of the target oxidation product was investigated and optimized. Specific experimental data are shown in Table 5. The residence time was 20.0 min at a flow rate of 0.25 mL / min; 16.7 min at a flow rate of 0.30 mL / min; and 14.3 min at a flow rate of 0.35 mL / min.

[0135] Table 5

[0136] molar ratio of triphenylphosphine to electrolyte Flow rate (mL / min) <![CDATA[Yield a (%)]]> Example 32 1：2 0.25 93 Example 33 1：2 0.30 80 Example 34 1：2 0.35 70

[0137] Note: In Table 5 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0138] Examples 35 to 37:

[0139] The experimental method in this embodiment is the same as in Example 32, except that the amount of triphenylphosphine used is 1 mmol, while the amounts of other materials and reaction conditions are the same. The difference lies in adjusting the reaction flow rate. In a self-made electrochemical microchannel continuous flow reactor, based on the above reaction conditions and feed ratio, the relationship between the flow rate and the yield of the target oxidation product in the microchannel continuous flow reaction was investigated and optimized. The specific experimental data results are shown in Table 6. The reaction residence time was 50.0 min at a flow rate of 0.10 mL / min; 25.0 min at a flow rate of 0.20 mL / min; and 16.7 min at a flow rate of 0.30 mL / min.

[0140] Table 6

[0141] molar ratio of triphenylphosphine to electrolyte Flow rate (mL / min) <![CDATA[Yield a (%)]]> Example 35 1：1 0.10 95 Example 36 1：1 0.20 45 Example 37 1：1 0.30 35

[0142] Note: The oxygen yield of the product triphenylphosphine in Table 6 was obtained from actual separation.

[0143] Examples 38 to 40:

[0144] The experimental method in this embodiment is the same as in Example 32, except that the amount of triphenylphosphine used is 2 mmol, the flow rate is limited to 0.2 mL / min (reaction residence time is 25.0 min), and the amounts of other materials and reaction conditions are the same. The difference is the adjustment of the current. In the self-made electrochemical microchannel continuous flow reactor, based on the above reaction conditions and feed ratio, the relationship between the current magnitude and the yield of the target oxidation product in the microchannel continuous flow reaction was investigated and optimized. The specific experimental data results are shown in Table 7.

[0145] Table 7

[0146]

[0147] Note: In Table 7 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0148] Examples 41 to 45:

[0149] The experimental method in this embodiment is the same as in Example 32, except that the amount of triphenylphosphine used is 4 mmol, the amount of Et4NClO4 is 1.2 mmol, the flow rate is limited to 0.2 mL / min (reaction residence time is 25.0 min), and the amounts of other materials and reaction conditions are the same. The difference lies in the adjustment of the current. In the self-made electrochemical microchannel continuous flow reactor, based on the above reaction conditions and feed ratio, the relationship between the current magnitude and the yield of the target oxidation product in the microchannel continuous flow reaction was investigated and optimized. The specific experimental data results are shown in Table 8.

[0150] Table 8

[0151]

[0152]

[0153] Note: In Table 8 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0154] Example 46:

[0155] The experimental method in this embodiment is the same as in Example 41, except that the flow rate is adjusted to 0.1 mL / min (reaction residence time is 50.0 min), while other material amounts and reaction conditions are the same. Specific experimental data results are shown in Table 9.

[0156] Table 9

[0157]

[0158] Note: In Table 9 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0159] Examples 47 to 49:

[0160] To further scale up the reaction and increase its efficiency and yield, the reaction was moved from a 5 mL electrochemical microchannel continuous flow apparatus to a 10 mL apparatus. The reagents were prepared as follows: 8 mmol triphenylphosphine, 1.6 mmol Et4NClO4, and 2 mL H2O were dissolved in acetonitrile / methyl tert-butyl ether (28 mL / 12 mL) to enhance solubility, and the mixture was shaken well. The reactants were then introduced into the 10 mL electrochemical microchannel reactor via an autosampler to participate in the electrochemical oxidation reaction.

[0161] Add 8 mmol of triphenylphosphine, 1.6 mmol of Et4NClO4, and 2 mL of H2O to a clean, dry beaker. Dissolve the H2O in acetonitrile / methyl tert-butyl ether (28 mL / 12 mL), mix and shake well to obtain a mixture. Use a 50 mL plastic syringe to draw up the mixture for later use.

[0162] A syringe containing the mixture was fixed to an automatic injection pump, and the flow rate was adjusted to 0.1 mL / min (reaction residence time 100.0 min). The syringe outlet was connected to the inlet of a self-made electrochemical microchannel continuous flow reactor with a retention volume of 10 mL. This electrochemical microchannel continuous flow reactor used graphite as the anode and a platinum sheet as the cathode. Different constant currents were connected to the reactor, and the electrochemical reaction was carried out at room temperature. The reaction solution was collected from the reactor outlet. The organic solvent was removed by rotary evaporation, and the product was separated by silica gel column chromatography with eluent to obtain the target product triphenylphosphine oxide, which was a white solid.

[0163] In a self-made electrochemical microchannel continuous flow reactor, based on the above reaction scale and feed ratio, the relationship between the magnitude of the oxidation current and the yield of the target product in the microchannel continuous flow reaction was investigated and optimized. The specific experimental data results are shown in Table 10.

[0164] Table 10

[0165] molar ratio of triphenylphosphine to electrolyte Current(I / mA) <![CDATA[Yield a (%)]]> Example 47 5：1 300 40 Example 48 5：1 330 60 Example 49 5：1 370 /

[0166] Note: In Table 10 a The oxygen yield of the product triphenylphosphine was obtained through actual separation.

[0167] This invention provides a method for the clean and efficient electrochemical oxidation preparation of phosphine oxide compounds. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A clean and efficient electrochemical oxidation method for preparing phosphine oxide compounds, characterized in that, Organophosphorus compound I was mixed with electrolyte, water, and solvent to obtain a mixture; the mixture was then subjected to an electrochemical reaction to obtain phosphorus oxide compound II. The organophosphorus compound I is or ; The phosphine oxide compound II is or ; When the organophosphine compound I is When the phosphine oxide compound II is ; When the organophosphine compound I is When the phosphine oxide compound II is ; Wherein, R1, R2, and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted aromatic, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocyclic; the substitution is by any number of the same or different substituents; the substituents are halogens, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylacyl, ester, amide, cyano, or diphenylphosphine. The electrochemical reaction is carried out in a conventional electrolytic cell or in an electrochemical microchannel reaction device. When the electrochemical reaction is carried out in a conventional electrolytic cell, the electrolyte is sodium chloride; When the electrochemical reaction is carried out in a conventional electrolytic cell, the solvent is acetonitrile; the molar ratio of the organophosphorus compound I to the electrolyte is 1:2; the volume ratio of water to solvent is 2:8; the ratio of the molar amount of the organophosphorus compound I to the total volume of water and solvent is 0.5 mmol:10 mL; the constant current for the electrochemical reaction is 10 mA; the anode electrode for the electrochemical reaction is a carbon rod; and the cathode electrode for the electrochemical reaction is a platinum sheet. When the electrochemical reaction is carried out in an electrochemical microchannel reaction device, the following steps are included: Organophosphorus compound I was mixed with electrolyte, water, and solvent to obtain a mixture; the mixture was then pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reaction device to carry out an electrochemical reaction, thereby obtaining phosphorus oxide compound II; When the electrochemical reaction is carried out in an electrochemical microchannel reactor: the electrolyte is tetraethylammonium perchlorate; When the electrochemical reaction is carried out in an electrochemical microchannel reactor: the solvent is acetonitrile, the molar ratio of organophosphorus compound I to electrolyte is 1:2, the volume ratio of water to solvent is 2:40, the ratio of the molar amount of organophosphorus compound I to the total volume of water and solvent is 0.5 mmol:42 mL, and the constant current of the electrochemical reaction is 25 mA; wherein, when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.25 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 20.0 min; when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.30 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 16.7 min; when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.35 mL / min... At a flow rate of mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 14.3 min; Alternatively, when the electrochemical reaction is carried out in an electrochemical microchannel reactor: the solvent is acetonitrile, the molar ratio of the organophosphorus compound I to the electrolyte is 1:1, the volume ratio of water to solvent is 2:40, the molar amount of the organophosphorus compound I to the total volume of water and solvent is 1 mmol:42 mL, and the constant current of the electrochemical reaction is 25 mA; wherein, when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.10 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 50.0 min; Alternatively, when the electrochemical reaction is carried out in an electrochemical microchannel reactor: the solvent is acetonitrile, the molar ratio of the organophosphorus compound I to the electrolyte is 2:1, the volume ratio of water to solvent is 2:40, the molar amount of the organophosphorus compound I to the total volume of water and solvent is 2 mmol:42 mL, and the constant current of the electrochemical reaction is 150 mA or 160 mA; wherein, when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.20 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 25.0 min; Alternatively, when the electrochemical reaction is carried out in an electrochemical microchannel reactor: the solvent is acetonitrile, the molar ratio of the organophosphorus compound I to the electrolyte is 10:3, the volume ratio of water to solvent is 2:40, the molar amount of the organophosphorus compound I to the total volume of water and solvent is 4 mmol:42 mL, and the constant current of the electrochemical reaction is 250 mA or 280 mA; wherein, when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.20 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 25.0 min; Alternatively, when the electrochemical reaction is carried out in an electrochemical microchannel reactor: the solvent is acetonitrile, the molar ratio of the organophosphorus compound I to the electrolyte is 10:3, the volume ratio of water to solvent is 2:40, the molar amount of the organophosphorus compound I to the total volume of water and solvent is 4 mmol:42 mL, and the constant current of the electrochemical reaction is 160 mA; wherein, when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.10 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 50.0 min; Alternatively, when the electrochemical reaction is carried out in an electrochemical microchannel reactor: the solvent is a mixture of acetonitrile and methyl tert-butyl ether in a volume ratio of 28 mL:12 mL, the molar ratio of organophosphorus compound I to electrolyte is 5:1, the volume ratio of water to solvent is 2:40, the molar amount of organophosphorus compound I to the total volume of water and solvent is 8 mmol:42 mL, and the constant current of the electrochemical reaction is 330 mA; wherein, when the flow rate of the mixture pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reactor is 0.10 mL / min, the residence time of the electrochemical reaction in the electrochemical microchannel continuous flow reactor is 100.0 min; When the electrochemical reaction is carried out in an electrochemical microchannel reactor: the anode electrode of the electrochemical reaction is a carbon rod; the cathode electrode of the electrochemical reaction is a platinum sheet.

2. The method according to claim 1, characterized in that, R1, R2, and R3 are independently selected from substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted aromatic groups, or substituted or unsubstituted C3-C8 cycloalkyl groups; the substitution is performed by any number of identical or different substituents; the substituents are C1-C4 alkyl groups, C1-C4 alkoxy groups, or diphenylphosphine groups.

3. The method according to claim 1, characterized in that, The electrochemical reaction described herein takes place at room temperature.

4. The method according to claim 1, characterized in that, The electrochemical microchannel reaction device includes a connecting pipe, a feed pump, an electrochemical microchannel continuous flow reactor, an electrostatic precipitator, and a receiver; wherein the feed pump, the electrochemical microchannel continuous flow reactor, and the receiver are connected in series via the connecting pipe; the positive electrode of the electrostatic precipitator is connected to the anode electrode of the electrochemical microchannel continuous flow reactor; and the negative electrode of the electrostatic precipitator is connected to the cathode electrode of the electrochemical microchannel continuous flow reactor.

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