A method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis

Abstract

The present invention discloses a method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis. 2-isocyanato-1,1'-biphenyl and diphenylphosphine oxide are mixed, a catalyst, a ligand, an electrolyte, and a solvent are added to form a mixed solution, and the mixed solution is electrolyzed by a flow electrolysis apparatus to obtain 6-phosphonylated phenanthridine. The catalyst is Mn(OAc)2. Using flow electrolysis, the efficient synthesis of 6-phosphonylated phenanthridine under electrocatalytic conditions is achieved for the first time. Only a catalytic amount of manganese acetate is required as a catalyst, and electrons are used as a clean oxidizing agent, avoiding the use of toxic and harmful chemical oxidizing agents. This reduces costs while significantly reducing energy consumption and the emission of "three wastes." Therefore, the process is environmentally friendly and the safety of the reaction is greatly improved.

Description

Technical Field

[0001] The invention belongs to the technical field of electrocatalytic organic synthesis, and particularly relates to a method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis. Background Art

[0002] Phenanthridine compounds are an important class of nitrogen-containing heterocycles and are one of the important structural units of natural products and drug molecules. For example, both trisphaeridine and lycobetaine alkaloids contain phenanthridine structures. In addition, phosphonyl groups, as an important class of phosphine-containing groups, can significantly change the physical and chemical properties of compounds. Therefore, introducing a phosphonyl group to the 6-position of phenanthridine is one of the important ways to improve the physicochemical properties of phenanthridine. Given the important uses of 6-phosphonylated phenanthridines, developing efficient synthetic methods and then rapidly constructing 6-phosphonylated phenanthridines is one of the research hotspots in organic synthetic chemistry, but it is also one of the difficulties.

[0003] Currently, the synthesis of 6-phosphonylated phenanthridines relies entirely on the radical tandem cyclization of 2-isocyanato-1,1'-biphenyl and diphenylphosphine oxide. Based on the reaction conditions, these strategies can be divided into two main categories: 1) Relying on the oxidation of chemically equivalent metal salts to promote the cyclization of 2-isocyanato-1,1'-biphenyl and diphenylphosphine oxide, thereby synthesizing the 6-phosphonylated phenanthridine. The equivalent metal salts used include AgOAc (3 equivalents, reference: Org. Lett. 2014, 16 ,250-233), Mn(OAc)3(3 equivalents, references: Tetrahedron 2014, 70 , 4652-4656). 2) The above cyclization reaction is promoted by combining a catalyst and a chemically equivalent strong oxidant to synthesize the 6-phosphonylated phenanthridine; the strong oxidant used is tert-butyl peroxide (TBHP, 2 equivalents, J. Am. Chem. Soc. 2021, 143 , 964-972), potassium persulfate (K2S2O8, 3 equivalents, references: Org. Lett. 2016, 18 , 4928-4931), and iodobenzene diacetate (PhI(OAc)2, 3 equivalents, reference: Tetrahedron 2014, 70 , 6985-6990). For the first reaction type, the use of chemically equivalent metal salts can result in severe heavy metal pollution, making this process incompatible with the era of green synthesis. Furthermore, the use of expensive AgOAc significantly increases production costs. For the second reaction type, the use of chemically equivalent, flammable and explosive strong oxidants not only poses serious process safety issues but also results in significant waste discharge after the reaction.

[0004] In summary, the synthesis of 6-phosphonylated phenanthridines is limited by the use of stoichiometric amounts of metal salts or stoichiometric amounts of flammable and explosive strong oxidants. Developing a novel catalytic synthesis method for the green synthesis of 6-phosphonylated phenanthridines has important research significance and practical application value. However, such a method has not yet been reported in the literature. Summary of the Invention

[0005] In response to the problems of high cost, low safety and high pollution in the synthesis process of 6-phosphonylated phenanthridine in the prior art, the present invention provides a method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis. The catalytic reaction uses electrons as a clean oxidant, which can avoid the use of chemically equivalent metal salts and chemical oxidants.

[0006] The present invention is achieved through the following technical solutions:

[0007] A method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis, comprising mixing 2-isocyano-1,1'-biphenyl I and diphenylphosphine oxide II, adding a catalyst, a ligand, an electrolyte, and a solvent to form a mixed solution, and electrolyzing the mixed solution through a flow electrolysis device to obtain 6-phosphonylated phenanthridine III;

[0008]

[0009] where R 1 is Me, OMe, F, Cl or CF3;

[0010] The catalyst is Mn(OAc)2, and the molar ratio of the catalyst to I is 0.5-2:10.

[0011] Preferably, the molar ratio of the amount of catalyst to I is 1:10.

[0012] Preferably, the anode of the flow electrolysis device is a graphite sheet, the cathode is a platinum sheet, the flow rate is 0.2-0.3 mL / min, and the current is 8-12 mA.

[0013] Preferably, the molar ratio of II to I is 1:2.

[0014] Preferably, the ligand is 4,4'-di-tert-butylbipyridine, and the molar ratio of the ligand to I is 0.5-1.5:10.

[0015] Preferably, the electrolyte is one or more of lithium perchlorate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium acetate, and tetrabutylammonium hexafluorophosphate, and the molar ratio of the electrolyte to I is 0.5 to 2:2.

[0016] Preferably, the electrolyte is tetrabutylammonium tetrafluoroborate, and the molar ratio of tetrabutylammonium tetrafluoroborate to I is 1:2.

[0017] Preferably, the solvent is a mixed solution of acetonitrile and acetic acid, and the amount of the solvent is such that the molar concentration of I in the solvent is 0.05 mol / L.

[0018] Preferably, the volume ratio of acetonitrile to acetic acid in the solvent is 1:1.5.

[0019] Preferably, the reaction temperature of the electrolysis is 20-30°C.

[0020] The process of the flow electrolysis synthesis of 6-phosphonylphenanthridine of the present invention is as follows:

[0021]

[0022] Beneficial effects

[0023] The present invention utilizes flow electrolysis to achieve, for the first time, the efficient synthesis of 6-phosphonylated phenanthridine under electrocatalytic conditions. Only a catalytic amount of manganese acetate is required as a catalyst, overcoming the drawbacks of conventional methods requiring the use of chemically equivalent metal salts or expensive silver salts. Electrons are used as a clean oxidizing agent, avoiding the use of toxic and harmful chemical oxidizing agents. This reduces costs while significantly reducing energy consumption and the emission of "three wastes." Therefore, the process is environmentally friendly, in line with the "dual carbon" era, and greatly improves the safety of the reaction. DETAILED DESCRIPTION

[0024] The present invention will be further described below with reference to specific embodiments. It should be understood that the following embodiments are only intended to illustrate the implementation of the present invention and are not intended to limit the operations and operating scope of the present invention. Variations derived therefrom are still within the scope of protection of the claims of the present invention.

[0025] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0026] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0027] Example 1

[0028] Synthesis of III-1:

[0029] 2-Isocyano-1,1'-biphenyl (0.5 mmol), diphenylphosphine oxide (1 mmol), Mn(OAc)2 (0.05 mmol, 10 mol%), 4,4'-di-tert-butylbipyridyl (0.05 mmol, 10 mol%), tetrabutylammonium tetrafluoroborate (0.25 mmol), acetonitrile (4 mL) and acetic acid (6 mL) were added to the reaction vessel and mixed. The solution was then pumped into the electrolysis device (anode: graphite sheet, cathode: platinum sheet) by a peristaltic pump at a flow rate of 0.25 mL / min, a current of 10 mA, and a reaction temperature of 25 ℃. o C. After 40 minutes of reaction, the mixed solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried, and the solvent was removed under reduced pressure. Finally, the crude product obtained under reduced pressure was separated and purified by column chromatography to obtain III-1. Yield: 69%

[0030] .

[0031] Example 2

[0032] Synthesis of III-2:

[0033] 2-Isocyano-1,1'-4-methoxybiphenyl (0.5 mmol), diphenylphosphine oxide (1 mmol), Mn(OAc)2 (0.05 mmol, 10 mol%), 4,4'-di-tert-butylbipyridyl (0.05 mmol, 10 mol%), tetrabutylammonium tetrafluoroborate (0.25 mmol), acetonitrile (4 mL) and acetic acid (6 mL) were added to the reaction vessel and mixed. The solution was then pumped into the electrolysis device (anode: graphite sheet, cathode: platinum sheet) by a peristaltic pump at a flow rate of 0.25 mL / min, a current of 10 mA, and a reaction temperature of 25 ℃. o C. After 40 min, the reaction was completed, and the mixed solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried, and the solvent was removed under reduced pressure. Finally, the crude product obtained under reduced pressure was separated and purified by column chromatography to obtain III-2, with a yield of 59%; .

[0034] Example 3

[0035] Synthesis of III-3

[0036] 2-Isocyano-1,1'-4-fluorobiphenyl (0.5 mmol), diphenylphosphine oxide (1 mmol), Mn(OAc)2 (0.05 mmol, 10 mol%), 4,4'-di-tert-butylbipyridyl (0.05 mmol, 10 mol%), tetrabutylammonium tetrafluoroborate (0.25 mmol), acetonitrile (4 mL) and acetic acid (6 mL) were added to the reaction vessel and mixed. The solution was then pumped into the electrolysis device (anode: graphite sheet, cathode: platinum sheet) by a peristaltic pump at a flow rate of 0.25 mL / min, a current of 10 mA, and a reaction temperature of 25 ℃. o C. After 40 min, the reaction was completed, and the mixed solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried, and the solvent was removed under reduced pressure. Finally, the crude product obtained under reduced pressure was separated and purified by column chromatography to obtain III-3, with a yield of 70%;

[0037] .

[0038] Example 4

[0039] Synthesis of III-4

[0040] 2-Isocyano-1,1'-4-chlorobiphenyl (0.5 mmol), diphenylphosphine oxide (1 mmol), Mn(OAc)2 (0.05 mmol, 10 mol%), 4,4'-di-tert-butylbipyridyl (0.05 mmol, 10 mol%), tetrabutylammonium tetrafluoroborate (0.25 mmol), acetonitrile (4 mL) and acetic acid (6 mL) were added to the reaction vessel, and then the above solution was pumped into the electrolysis device (the anode was a graphite sheet and the cathode was a platinum sheet) by a peristaltic pump at a flow rate of 0.25 mL / min, a current of 10 mA, and a reaction temperature of 25 ℃. o C. After 40 min, the reaction was completed, and the mixed solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried, and the solvent was removed under reduced pressure. Finally, the crude product obtained under reduced pressure was separated and purified by column chromatography to obtain III-4 in a yield of 74%;

[0041] .

[0042] Example 5

[0043] Synthesis of III-5:

[0044] 2-Isocyano-1,1'-4-trifluoromethylbiphenyl (0.5 mmol), diphenylphosphine oxide (1 mmol), Mn(OAc)2 (0.05 mmol, 10 mol%), 4,4'-di-tert-butylbipyridyl (0.05 mmol, 10 mol%), tetrabutylammonium tetrafluoroborate (0.25 mmol), acetonitrile (4 mL) and acetic acid (6 mL) were added to the reaction vessel, and then the above solution was pumped into the electrolysis device (the anode was a graphite sheet and the cathode was a platinum sheet) by a peristaltic pump at a flow rate of 0.25 mL / min, a current of 10 mA, and a reaction temperature of 25 ℃. o C. After 40 min, the reaction was completed, and the mixed solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried, and the solvent was removed under reduced pressure. Finally, the crude product obtained under reduced pressure was separated and purified by column chromatography to obtain III-5 in a yield of 65%;

[0045] .

Claims

1. A method for synthesizing 6-phosphonylphenanthridine by flow electrolysis, characterized in that: 2-isocyanato-1,1'-biphenyl I and diphenylphosphine oxide II are mixed, a catalyst, a ligand, an electrolyte and a solvent are added to form a mixed solution, and the mixed solution is electrolyzed through a flow electrolysis device to obtain 6-phosphonylated phenanthridine III; where R 1 is Me, OMe, F, Cl or CF3; The catalyst is Mn(OAc)2, and the molar ratio of the catalyst to I is 0.5-2:10; The ligand is 4,4'-di-tert-butylbipyridine; The electrolyte is one or more of lithium perchlorate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium acetate, and tetrabutylammonium hexafluorophosphate; The solvent is a mixed solution of acetonitrile and acetic acid.

2. The method for synthesizing 6-phosphonylphenanthridine by flow electrolysis according to claim 1, characterized in that: The molar ratio of the amount of catalyst to I is 1:

10.

3. The method for synthesizing 6-phosphonylphenanthridine by flow electrolysis according to claim 1, characterized in that: The anode of the flow electrolysis device is a graphite sheet, the cathode is a platinum sheet, the flow rate is 0.2-0.3 mL / min, and the current is 8-12 mA.

4. The method for synthesizing 6-phosphonylphenanthridine by flow electrolysis according to claim 1, characterized in that: The molar ratio of II to I is 1:

2.

5. The method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis according to claim 1, characterized in that: The molar ratio of the ligand to I is 0.5-1.5:

10.

6. The method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis according to claim 1, characterized in that: The molar ratio of the amount of electrolyte to I is 0.5~2:

2.

7. The method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis according to claim 6, characterized in that: The electrolyte is tetrabutylammonium tetrafluoroborate, and the molar ratio of tetrabutylammonium tetrafluoroborate to I is 1:

2.

8. The method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis according to claim 1, wherein: The amount of solvent used is such that the molar concentration of I in the solvent is 0.05 mol / L.

9. The method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis according to claim 8, characterized in that: The volume ratio of acetonitrile to acetic acid in the solvent is 1:1.

5.

10. The method for synthesizing 6-phosphonylated phenanthridine by flow electrolysis according to claim 1, characterized in that: The reaction temperature of the electrolysis is 20-30°C.

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