Clean and efficient method for preparing phosphine oxide compound through electrochemical oxidation

Abstract

The invention belongs to the technical field of organic electrochemical oxidation, and relates to a clean and efficient method for preparing phosphine oxide compounds through electrochemical oxidation. Mixing an organic phosphine compound I with an electrolyte, water and a solvent to obtain a mixed solution; and electrifying the mixed solution for electrochemical reaction to prepare the phosphine oxide compound II. According to the invention, electrolyte sodium chloride and water which are cheap and easy to obtain are used as oxygen sources, and green and efficient preparation of phosphine oxide compounds with various structures and various electrical properties is realized at room temperature. Compared with an oxidation method which is widely used at present, the method has the advantages that an oxidizing agent and a catalyst do not need to be added, inert gas protection is not needed, the reaction process is safe and high in cleaning efficiency, and the post-treatment and separation process is simple. According to the invention, green electrons are used as an oxidizing agent, so that complex oxidation systems, such as a hydrogen peroxide system, a metal oxide catalytic oxidation system and an organic catalyst oxidation system, which are widely used nowadays are avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of organic electrochemical oxidation and relates to a method for preparing phosphine oxide compounds by clean and efficient electrochemical oxidation. Background Art

[0002] Organophosphine compounds and organophosphine oxide compounds play an important role and are widely used in human production and life. Phosphine oxide compounds have the characteristics of good stability, strong polarity and lipophilicity, and good solubility in the body. They are present in small molecule drugs, fine chemicals, special functional materials, and bioactive macromolecular structure skeletons (such as: anticancer drug brigatinib, thermally activated delayed fluorescence materials, organophosphine reagents, organophosphine ligands for catalysts, etc.). In addition, phosphine oxygen (P=O) bond molecules also have very good coordination dissociation ability and are widely used in rare earth metal efficient separation extractants, homogeneous catalysts, and regulation of metal catalytic active phosphine ligands. Organophosphine oxide compounds can be prepared by oxidation of low-valent organophosphine compounds by adding an equivalent or excess oxidant, such as adding an excess of hydrogen peroxide solution to achieve oxidation of 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 that they used molybdenum dioxide complex catalysts and oxygen atom transfer strategies to successfully achieve a green oxidation process of triphenylphosphine to triphenylphosphine oxide using oxygen as an oxidant (Eur. J. Inorg. Chem. 2024, 27, e202300397). In addition to oxidant oxidation, Professor Chen Qian's group at Guangdong University of Technology reported that they used an electrophilic fluorination agent (Selectfluor) and water to form an oxidation system to achieve the oxidation reaction of trivalent phosphine within 5 minutes. The reaction has a wide range of applications and a series of phosphine oxide compounds can be obtained in high yields (Tetrahedron Lett., 2016, 57, 3379–3381.). In recent years, organic electrochemical reactions have attracted the interest of more and more scientific researchers. Compared with the above-mentioned literature reports that equivalent oxidants participate in oxidation reactions, organic electrochemical oxidation uses green electrons as oxidants, and the process does not require the participation of additional oxidants. The redox potential of the system can be regulated by simply adjusting the current or voltage, and the oxidation process of substrates with different redox potentials can be achieved efficiently and greenly. Organic electrochemical oxidation strategies reduce the use of external oxidants, reduce the generation of by-products and waste liquids, improve the atomic economy of the reaction, and no inorganic salts are produced in the post-reaction treatment. At the same time, organic electrochemical reactions do not require expensive reaction equipment, the reaction process is simple and easy to control, and the operability is strong. Summary of the invention

[0003] The technical problem to be solved by the present invention is to solve the problems existing in the preparation process of existing phosphine oxide compounds in the prior art, such as: 1. use of equivalent or excess oxidant; 2. need for metal catalyst catalytic oxidation; 3. high cost of using various additives; 4. large amount of waste salt and waste liquid in post-treatment, etc. The present invention discloses a method using electrons as green oxidants, water as green oxygen source, and cheap and abundant sodium chloride as electrolyte; further, the mild electrochemical oxidation process is used to efficiently prepare phosphine oxide products, the reaction has good universality, high yield and atomic economy, the oxidation process is simple to operate, and the energy consumption is low, thereby reducing the production cost of such products and the difficulty of separation and purification.

[0004] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0005] The invention discloses a method for preparing phosphine oxide compounds by clean and efficient electrochemical oxidation. An organic phosphine compound I is mixed with an electrolyte, water and a solvent to obtain a mixed solution; the mixed solution is energized to perform an electrochemical reaction to obtain a phosphine oxide compound II.

[0006] The organic phosphine compound I is

[0007] The phosphine oxide compound II is

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

[0009]

[0010] When the organic phosphine 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 substituted by any number of identical or different substituents; the substituent is halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, ester, amide, cyano, or diphenylphosphino;

[0012] Wherein, the electrochemical reaction is carried out in a conventional electrolytic cell or the electrochemical reaction is carried out in an electrochemical microchannel reaction device;

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

[0014] Wherein, the electrochemical reaction does not require inert gas protection.

[0015] Wherein, in the electrochemical reaction, there is no catalyst, no acidic additive, no alkaline additive, and no oxidant.

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

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

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

[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 organic phosphine compound I to the electrolyte is (1-10): (1-3); the volume ratio of the water to the solvent is 2: (6-42); the ratio of the molar amount of the organic phosphine compound I to the total volume amount of the water and the solvent is (0.5-8.0) mmol: (8-44) mL.

[0024] In some embodiments, preferably, the molar ratio of the organic phosphine 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 organic phosphine compound I to the total volume amount of the water and the solvent is (0.5-8.0) mmol: (10-42) mL, further 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 performed at room temperature.

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

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

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

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

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

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

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

[0035] The organic phosphine compound I is mixed with an electrolyte, water and a solvent to obtain a mixed solution; the mixed solution is pumped into an electrochemical microchannel continuous flow reactor of an electrochemical microchannel reaction device to perform an electrochemical reaction to obtain a phosphine oxide compound II.

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

[0037] In some embodiments, preferably, the flow rate of the mixed liquid pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reaction device is 0.10 mL / min to 0.35 mL / min, and further preferably is 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, in the electrochemical microchannel continuous flow reactor, the residence time of the electrochemical reaction is 10.0 min to 100.0 min.

[0039] In some embodiments, preferably, in the electrochemical microchannel continuous flow reactor, the residence time of the electrochemical reaction is 14.0 min to 100.0 min, and 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 electrical box and a receiver; wherein the feed pump, the electrochemical microchannel continuous flow reactor and the receiver are connected in series in sequence through a connecting pipe; the positive electrode of the electrical box is connected to the anode electrode of the electrochemical microchannel continuous flow reactor; the negative electrode of the electrical box is connected to the cathode electrode of the electrochemical microchannel continuous flow reactor.

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

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

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

[0044] Beneficial effects:

[0045] (1) The present invention uses cheap and readily available electrolytes (NaCl) and water (H2O) as oxygen sources at room temperature to achieve green and efficient preparation of phosphine oxide compounds with various structures and electrical properties. Compared with the currently widely used oxidation methods, the present invention has the advantages of no need for external oxidants and catalysts, no need to be carried out under the protection of inert gas, safe and clean reaction process with high efficiency, simple post-treatment and separation process, etc. The present invention uses green electrons as oxidants to avoid 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 conversion of organic phosphine compounds to phosphine oxides in an environmentally friendly and efficient manner, with rapid reaction, high yield, easy product separation, low environmental pollution, and less wastewater discharge.

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

[0048] (4) Microchannel continuous flow reaction has the following typical advantages over kettle reaction: ① Efficient mass and heat transfer accelerates the reaction process; ② Large specific surface area and efficient heat transfer area are conducive to the evacuation of reaction heat during the reaction; ③ The online volume of the reactor is small and the reaction process is safe. Furthermore, in order to verify the practical application potential of the method of the present invention, increase the efficiency of the reaction and better control the reaction process, an attempt was made to transfer the reaction from the undivided electrolytic cell to the electrochemical microchannel reaction device to examine the reaction amplification performance, the maximum load of the equipment and make corresponding optimizations. The experimental results show that the use of microflow field technology can achieve the amplification and continuous production of the reaction. The catalytic process has no obvious heat release, does not require high temperature and high pressure, and the process is more green, efficient, gentle and safe. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0050] Figure 1 Schematic diagram of the electrochemical microchannel reaction device used in the embodiments of the present invention. DETAILED DESCRIPTION

[0051] The present invention is further described in detail below in conjunction with specific examples. The protection scope of the present invention is not limited thereto, but also includes the electrochemical oxidation of other low-valent organic phosphines derived from this invention and the conversion of related phosphine oxide products.

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

[0053] The electrochemical microchannel reaction device used in the embodiment of the present invention is shown in FIG. Figure 1 As shown, it includes a connecting pipe, a feed pump, an electrochemical microchannel continuous flow reactor, an electrical box and a receiver; wherein the feed pump, the electrochemical microchannel continuous flow reactor and the receiver are connected in series in sequence through the connecting pipe; the positive electrode of the electrical box is connected to the anode electrode of the electrochemical microchannel continuous flow reactor; the negative electrode of the electrical box is connected to the cathode electrode of the electrochemical microchannel continuous flow reactor.

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

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

[0056] Wherein, the model of the feed pump is Leifu TYD01.

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

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

[0059] Among them, the electric box is model MS-305DS.

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

[0061]

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

[0063] The H NMR spectrum data of the product triphenylphosphine oxide are: 1 H NMR (400MHz,CDCl3)δ7.70–7.57(m,6H),7.55–7.53(m,3H),7.49–7.44(m,6H). The data were consistent with those reported in the literature (Masaru Kondo,Tomohiro Agou.Catalytic Aerobic Photooxidation of Triarylphosphines usingDibenzo-fused 1,4-Azaborines.Chem.Commun.,2022,58,5001-5004.)

[0064] Example 2 to Example 8: Changing the electrolyte

[0065] The experimental method is the same as that of Example 1, except that the electrolyte is replaced by tetrabutylammonium hexafluorophosphate (TBAPF6), tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBACl), tetrabutylammonium tetrafluoroborate (TBABF4), sodium chloride (NaCl), potassium bromide (none), or no electrolyte. The 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: Table 1 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0069] Example 9 to Example 11: Changing the constant current

[0070] The experimental method is the same as that of Example 6, except that the constant current is set to 5 mA, 20 mA, or no constant current is 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 Embodiment 11 NaCl 0 0

[0073] Note: Table 2 aThe yield of product triphenylphosphine oxide is obtained by actual separation.

[0074] Example 12 to Example 14: Changing the Electrode

[0075] The experimental method is the same as that of Example 6, except that the electrodes are changed: (1) the cathode and the anode are both platinum electrodes; (2) the platinum electrode is the anode and the carbon rod is the cathode; (3) the cathode and the anode are both 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 rod Platinum sheet 96 Example 12 NaCl 10 Platinum sheet Platinum sheet 86 Example 13 NaCl 10 Platinum sheet Carbon rod 83 Embodiment 14 NaCl 10 Carbon rod Carbon rod 79

[0078] Note: Table 3 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0079] Example 15 to Example 20: Changing the solvent

[0080] The experimental method is the same as that of Example 6, except that the solvents are changed to: (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), and activated molecular sieves are added to the reaction solution during the reaction to remove water. Specific data are shown in Table 4.

[0081] Table 4

[0082]

[0083]

[0084] Note: Table 4 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0085] The main reason why the product triphenylphosphine oxide can be obtained in Examples 15 to 17 is that the solvent contains a trace of water; acetonitrile is used in Examples 19 and 20, and the acetonitrile solvent itself contains water. After dehydration by molecular sieve, 28% of the product can still be obtained. The main reason is that the reaction system is not protected by inert gas, and the air contains a trace of water, which leads to the formation of the product. In Example 18, water is used alone as the solvent, and the main reason why the reaction cannot proceed smoothly is that the raw materials are not well soluble in pure water, and the reaction intermediates are unstable under the condition of a large amount of water, which leads to the failure of the product to be smoothly generated.

[0086] Embodiment 21:

[0087]

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

[0089] The product tri(p-methoxyphenyl)phosphine oxide in this example has the following H NMR spectrum data: 1 H NMR (400 MHz, CDCl3) δ7.54–7.49 (dd, J=8.8, 2.7 Hz, 6H), 6.91–6.88 (m, 6H), 3.77 (s, 9H). Comparison is 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.).

[0090] Embodiment 22:

[0091]

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

[0093] The H-NMR spectrum data of the product tri(p-methylphenyl)phosphine oxide in this example are: 1 H NMR (400 MHz, CDCl3) δ7.56–7.51 (dd, J=8.0, 2.0 Hz, 6H), 7.26–7.23 (dd, J=8.0, 2.0 Hz, 6H), 2.39 (s, 9H). Comparison is 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.).

[0094] Embodiment 23:

[0095]

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

[0097] The H NMR spectrum data of the product tri(m-methylphenyl)phosphine oxide in this example are: 1 H NMR (400 MHz, CDCl3) δ7.59–7.56 (d, J=11.6 Hz, 3H), 7.38–7.31 (m, 9H), 2.36 (s, 9H). Comparison is 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.).

[0098] Embodiment 24:

[0099]

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

[0101] The product tri(o-methylphenyl)phosphine oxide in this example has the following H NMR spectrum data: 1 H NMR (400 MHz, CDCl3) δ7.45–7.42 (m, 3H), 7.33–7.30 (m, 3H), 7.17–7.07 (m, 6H), 2.50 (s, 9H). Comparison is 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.).

[0102] Embodiment 25:

[0103]

[0104] The experimental method of this example is the same as that of Example 6, except that the substrate is tri(2-furyl)phosphine. The target product tri(2-furyl)phosphine oxide is obtained as a light yellow solid with a yield of 78%.

[0105] The H-NMR spectrum data of tri(2-furyl)phosphine oxide, the product in this example, are: 1 H NMR (400 MHz, CDCl3) δ7.75–7.73 (m, 3H), 7.19–7.17 (m, 3H), 6.57–6.55 (m, 3H). 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.).

[0106] Embodiment 26:

[0107]

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

[0109] The product pyridine diphenylphosphine oxide in this example has the following H NMR spectrum data: 1 H NMR (400 MHz, CDCl3) δ8.79–8.77 (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). The data were consistent with those 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.).

[0110] Embodiment 27:

[0111]

[0112] The experimental method of this example is the same as that of Example 6, except that the substrate is ethyl diphenyl phosphine. The target product ethyl diphenyl phosphine oxide is obtained in the form of white powder with a yield of 93%.

[0113] The product ethyl diphenyl phosphine oxide in this example has the following H NMR spectrum data: 1 H NMR (400 MHz, CDCl3) δ7.76–7.71 (m, 4H), 7.53–7.47 (m, 6H), 2.33–2.26 (m, 2H), 1.26–1.16 (m, 3H). The data were consistent with those reported in the literature (Chen-Kun Li, Ze-Kun Tao, Adedamola Shoberu, Wei Zhang, Jian-Ping Zou. Org. Lett., 2022, 24, 6083-6087.).

[0114] Embodiment 28:

[0115]

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

[0117] The H NMR spectrum data of the product phenyl dicyclohexyl phosphine oxide in this example are: 1 H NMR (400 MHz, CDCl3) δ7.68–7.63 (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). The data were consistent with those reported 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] Embodiment 29:

[0119]

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

[0121] The product tricyclohexylphosphine oxide in this example has the following hydrogen nuclear magnetic spectrum data: 1H NMR (400 MHz, CDCl3) δ1.88–1.60 (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] Embodiment 30:

[0123]

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

[0125] The nuclear magnetic hydrogen spectrum data and nuclear magnetic phosphorus spectrum data of the product (2-(diphenylphosphino)phenyl)diphenylphosphine oxide in this example are: 1 H NMR(400MHz,DMSO)δ7.75–7.69(m,2H),7.51(m,4H),7.38(m,18H), 31 P NMR (162 MHz, DMSO) δ 29.44, -13.59. Comparison is consistent with the data reported in the literature (Vladimir V. Grushin. Organometallics 2001, 20, 3950–3961.).

[0126] Embodiment 31:

[0127]

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

[0129] The nuclear magnetic hydrogen spectrum data and nuclear magnetic phosphorus spectrum data of the product (S)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine oxide in this example are: 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 (162 MHz, CDCl3) δ 28.51. Comparison is 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] In order to verify the practical application potential of the above method, increase the efficiency of the reaction and better control the reaction process, attempts were made to transfer the reaction from the undivided electrolytic cell to the electrochemical microchannel reaction device to examine the reaction scale-up performance, the maximum load of the equipment and make corresponding optimizations.

[0131] Example 32-Example 34: Synthesis of triphenylphosphine oxide by electrochemical microchannel reaction technology

[0132] Electrochemical microchannel continuous flow oxidation reaction process: add 0.5mmol triphenylphosphine and 1.0mmol electrolyte Et4NClO4 into a clean and dry beaker, mix 40mL acetonitrile and 2mL H2O as solvent, mix to obtain a mixed solution; select a 50mL plastic syringe to absorb the above mixed solution for use.

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

[0134] In a self-made electrochemical microchannel continuous flow reactor, according to 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, and the specific experimental data results are shown in Table 5. The flow rate was 0.25 mL / min, and the reaction residence time was 20.0 min; the flow rate was 0.30 mL / min, and the reaction residence time was 16.7 min; the flow rate was 0.35 mL / min, and the reaction residence time was 14.3 min.

[0135] Table 5

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

[0137] Note: Table 5 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0138] Embodiment 35~embodiment 37:

[0139] The experimental method of this embodiment is the same as that of Example 32, except that the amount of triphenylphosphine is 1 mmol, the amount of other materials and the reaction conditions are the same, and the difference is that the reaction flow rate is adjusted. In a self-made electrochemical microchannel continuous flow reactor, according to 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 is investigated and optimized, and the specific experimental data results are shown in Table 6. The flow rate is 0.10 mL / min, and the reaction residence time is 50.0 min; the flow rate is 0.20 mL / min, and the reaction residence time is 25.0 min; the flow rate is 0.30 mL / min, and the reaction residence time is 16.7 min.

[0140] Table 6

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

[0142] Note: The product triphenylphosphine oxide yields in Table 6 were obtained from actual separation.

[0143] Embodiment 38~embodiment 40:

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

[0145] Table 7

[0146]

[0147] Note: Table 7 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0148] Embodiment 41~embodiment 45:

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

[0150] Table 8

[0151]

[0152]

[0153] Note: Table 8 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0154] Embodiment 46:

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

[0156] Table 9

[0157]

[0158] Note: Table 9 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0159] Embodiment 47~embodiment 49:

[0160] In order to continue to expand the reaction and increase the efficiency and yield of the reaction, the reaction was transferred from the 5mL electrochemical microchannel continuous flow experimental device to the 10mL electrochemical microchannel continuous flow experimental device. The reaction reagents were formulated as follows: 8mmol triphenylphosphine, 1.6mmol Et4NClO4, H2O (2mL) to increase solubility, dissolved in acetonitrile / methyl tert-butyl ether (28mL / 12mL), and mixed and shaken. The raw materials were pushed into the 10mL electrochemical microchannel reactor through an automatic sample injector to participate in the electrochemical oxidation reaction.

[0161] Add 8 mmol triphenylphosphine, 1.6 mmol Et4NClO4, H2O (2 mL) dissolved in acetonitrile / methyl tert-butyl ether (28 mL / 12 mL) into a clean and dry beaker, mix and shake to obtain a mixed solution; select a 50 mL plastic syringe to absorb the above mixed solution for use.

[0162] The syringe containing the mixed solution is fixed on an automatic injection pump, the flow rate is adjusted to 0.1mL / min (reaction residence time is 100.0min), and the syringe outlet is connected to the inlet of a self-made electrochemical microchannel continuous flow reactor with a retention volume of 10mL; the electrochemical microchannel continuous flow reactor uses graphite as an anode and a platinum sheet as a cathode, and different constant currents are connected to the electrochemical microchannel continuous flow reactor, and an electrochemical reaction is carried out at room temperature, and the reaction solution is collected from the reactor outlet. The organic solvent is removed by rotary evaporation, and a silica gel column is separated with an eluent to obtain the target product triphenylphosphine oxide as 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 size 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] The molar ratio of triphenylphosphine to electrolyte Current(I / mA) <![CDATA[Yield a (%)]]> Embodiment 47 5：1 300 40 Embodiment 48 5：1 330 60 Embodiment 49 5：1 370 /

[0166] Note: Table 10 a The yield of product triphenylphosphine oxide is obtained by actual separation.

[0167] The present invention provides a method and idea for preparing phosphine oxide compounds by clean and efficient electrochemical oxidation. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for preparing phosphine oxide compounds by clean and efficient electrochemical oxidation, characterized in that: The organic phosphine compound I is mixed with an electrolyte, water and a solvent to obtain a mixed solution; the mixed solution is energized to perform an electrochemical reaction to obtain a phosphine oxide compound II; The organic phosphine compound I is The phosphine oxide compound II is When the organic phosphine compound I is When the phosphine oxide compound II is When the organic phosphine 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 substituted by any number of identical or different substituents; the substituent is halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, ester, amide, cyano, or diphenylphosphino; Wherein, the electrochemical reaction is carried out in a conventional electrolytic cell or the electrochemical reaction is carried out in an electrochemical microchannel reaction device; Wherein, when the electrochemical reaction is carried out in a conventional electrolytic cell, the electrolyte is sodium chloride.

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

3. The method according to claim 1, characterized in that The electrolyte is any one of tetraethylammonium perchlorate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium tetrafluoroborate, sodium chloride and potassium bromide, or a combination thereof; the solvent is any one of acetonitrile, ethanol, dichloroethane, N,N-dimethylformamide and methyl tert-butyl ether, or a combination thereof.

4. The method according to claim 1, characterized in that: The molar ratio of the organic phosphine compound I to the electrolyte is (1-10):(1-3); the volume ratio of the water to the solvent is 2:(6-42); the ratio of the molar amount of the organic phosphine compound I to the total volume amount of the water and the solvent is (0.5-8.0) mmol:(8-44) mL.

5. The method according to claim 1, characterized in that The electrochemical reaction is carried out at room temperature.

6. The method according to claim 1, characterized in that In the electrochemical reaction, the constant current is 10mA to 330mA; in the electrochemical reaction, the anode electrode is a carbon rod or a platinum sheet; in the electrochemical reaction, the cathode electrode is a carbon rod or a platinum sheet.

7. The method according to claim 1, characterized in that When the electrochemical reaction is carried out in an electrochemical microchannel reaction device, the steps include: The organic phosphine compound I is mixed with an electrolyte, water and a solvent to obtain a mixed solution; the mixed solution is pumped into an electrochemical microchannel continuous flow reactor of an electrochemical microchannel reaction device to perform an electrochemical reaction to obtain a phosphine oxide compound II.

8. The method according to claim 7, characterized in that The flow rate of the mixed solution pumped into the electrochemical microchannel continuous flow reactor of the electrochemical microchannel reaction device is 0.10 mL / min to 0.40 mL / min.

9. The method according to claim 7, characterized in that: In the electrochemical microchannel continuous flow reactor, the residence time of the electrochemical reaction is 10.0 min to 100.0 min.

10. 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 electrical box and a receiver; wherein the feed pump, the electrochemical microchannel continuous flow reactor and the receiver are connected in series in sequence through the connecting pipe; the positive electrode of the electrical box is connected to the anode electrode of the electrochemical microchannel continuous flow reactor; the negative electrode of the electrical box is connected to the cathode electrode of the electrochemical microchannel continuous flow reactor.

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