A benzoxadiazine derivative and an electrochemical synthesis method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical and chemical intermediate synthesis, and specifically discloses a benzoxadiazine derivative and an electrochemical synthesis method thereof. A hydrazone compound, a p-aminophenol compound, an electrolyte, and a solvent are mixed and an electrochemical reaction is carried out under energized conditions to obtain the benzoxadiazine derivative. The method of the present invention does not require the use of metal catalysts, oxidants, or acid-base additives, but only utilizes electrooxidation to induce the addition of hydroxyl radicals to hydrazone molecules, with hydrogen as a byproduct. The method has the advantages of readily available raw materials, simple operation, and adaptable electrolytes and solvents, and has great implementation value and socioeconomic benefits.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical and chemical intermediate synthesis, and in particular to a benzoxadiazine derivative and an electrochemical synthesis method thereof. Background Art

[0002] Heterocyclic structures are widely present in many pharmaceutical compounds and natural products. 1,3,4-oxadiazine is an important six-membered heterocyclic ring and one of the most important backbones for a wide range of bioactive molecules. 1,3,4-oxadiazine structures are frequently found in pharmaceuticals and agrochemicals with remarkable biological properties. They possess diverse biological properties, such as antibacterial, antimicrobial, acaricidal, insecticidal, and anticonvulsant activities. Examples include the fungicide marbofloxacin, used primarily for respiratory, digestive, urinary, and skin infections caused by susceptible bacteria in cattle, pigs, dogs, and cats; the chemotherapy drug oxadiazine, which has antiviral activity against herpes simplex virus; and indolecarb, developed by DuPont and active against lepidopteran larvae. Therefore, a general strategy for constructing 1,3,4-oxadiazine cores is crucial for fragment-based drug discovery.

[0003] The reported synthetic methods for this class of compounds primarily include metal-catalyzed CH activation, nanocatalyzed cyclization, high-temperature intermolecular cyclization in alkaline solutions, acid-catalyzed reductive coupling synthesis, and oxidant-mediated intermolecular cyclization. A representative synthetic method includes the following: In 2015, Professor Wang Lei's team developed a 4-(dimethylamino)pyridine (DMAP)-catalyzed [2+4] cycloaddition reaction of allenoates with N-acyldiazenes, providing an atom-efficient route to 1,3,4-oxadiazines. However, the practicality of this method is limited by the instability of the N-acyldiazenes used as starting materials. (Zhang, Q.; Meng, LG; Zhang, J.; Wang, L. DMAP-Catalyzed [2+4] Cycloadditions of Allenoates with N-Acyldiazenes: Direct Method to 1,3,4-Oxadiazine Derivatives. Org Lett. 2015, 17, 3272-5.) In 2018, Fayez M. Eissa reported that o-bromophenol and acylhydrazide derivatives were refluxed in ethylene glycol in NaHCO3 aqueous solution to obtain oxadiazine derivatives. (Eissa, FM, Green Synthesis. Antibacterial, and Antifungal Activities of 1,3,4-Oxadiazines. J. Heterocycl. Chem. 2018, 55, 1479-1483.) In 2017, Vaezeh Fathi Vavsari et al. synthesized 1,3,4-oxadiazines from three components: cyclohexyl isocyanate, hydrazide derivatives, and cyclic ketones, using SBA·Pr-SO3H as a catalyst, and spatially oriented the pore intermediate of the catalyst on it. (FathiVavsari, V.; MohammadiZiarani, G.; Balalaie, S.; Badiei, A.; Golmohammadi, F.; Ramezanpour, S.; Rominger, F. Unexpected Synthesis of 1,3,4-Oxadiazines using extraordinary effect of SBA-Pr-SO3H as the Nano-catalyst. Chemistry Select. 2017, 2, 3496-3499.) In 2018, T. Prabhakar Reddy's team used 4-quinol and azoimine as substrates and a catalytic amount of base (KOtBu) to catalyze the [3+3] cycloaddition to synthesize 1,3,4-oxadiazines.(Reddy, TP; Krishna, AV; Ramachary, DB Catalytic [3+3]-Cycloaddition for Regioselective Preparation of Tricyclic Oxadiazines. Org Lett. 2018, 20, 6979-6983.) In 2020, Zhong Fangrui's research group proposed a heme-catalyzed oxidation of phenol and hydrazone to form imine [3+3] cycloaddition to synthesize 1,3,4-oxadiazines. (Zuo, H.; Qin, J.; Zhang, W.; Bashir, MA; Yu, Q.; Zhao, W.; Wu, G.; Zhong, F. Hemin-Catalyzed Oxidative Phenol-Hydrazone[3+3]Cycloaddition Enables Rapid Construction of 1,3,4-Oxadiazines. Org Lett. 2020, 22, 6911-6916.) In 2021, the Jose Cortes Vazquez group developed a Sc(OTf)3-catalyzed, synergistically activated [3+3] cyclization reaction of 1,3-dipolar diaziridine and dipolar quinone to synthesize 1,3,4-oxadiazines. (Cortes Vazquez, J.; Davis, J.; Nesterov, VN; Wang, H.; Luo, W. Sc(OTf)3-Catalyzed Formal[3+3]Cycloaddition Reaction of Diaziridines and Quinones for the Synthesis of Benzo[e][1,3,4]oxadiazines. Org Lett. 2021, 23, 3136-3140.).

[0004] Although there are many methods for synthesizing 1,3,4-oxadiazine, there are still some drawbacks, such as the numerous steps, expensive raw materials, the use of metal catalysts and oxidants, harsh reaction conditions, and large amounts of waste. Therefore, the development of efficient, clean, and inexpensive methods for synthesizing 1,3,4-oxadiazine derivatives remains of great significance. Summary of the Invention

[0005] In view of this, the present invention provides an electrochemical synthesis method for benzoxadiazine derivatives to solve the problems of the existing synthesis method, such as complex process, the need to use a large amount of reagents, harsh reaction conditions, and a large amount of three wastes.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for electrochemically synthesizing benzoxadiazine derivatives comprises the following steps:

[0008] The hydrazone compound and the p-aminophenol compound are subjected to an electrochemical reaction under an electric condition to obtain a benzoxadiazine derivative;

[0009] The structure of the benzoxadiazine derivative is

[0010] The structure of the hydrazone compound is

[0011] The structure of the p-aminophenol compound is

[0012] Among them, R 1 including one of an alkyl ring, a phenyl ring, a phenethyl ring, a thiophene ring and a pyridine ring;

[0013] R 2 including one of an alkyl group, an alkoxy group, and a halogen group;

[0014] R 3 including one of alkyl, alkoxy, halogen and trifluoromethyl;

[0015] R 4 including one of tert-butyloxycarbonyl, ethoxycarbonyl and p-toluenesulfonyl;

[0016] R 5 Includes one of an alkyl group, an alkoxy group, and a halogen group.

[0017] Preferably, the molar ratio of the hydrazone compound to the p-aminophenol compound is 0.5-1:1-1.5.

[0018] Preferably, the current of the electrochemical reaction is 1-5 mA, and the time is 10-22 h.

[0019] Preferably, the electrochemical reaction is carried out in an organic solvent.

[0020] Preferably, the organic solvent comprises one or more of acetonitrile, acetone and tetrahydrofuran;

[0021] The molar volume ratio of the hydrazone compound to the organic solvent is 0.1-1 mmol:6 mL.

[0022] Preferably, the reaction system of the electrochemical reaction further includes an electrolyte.

[0023] Preferably, the electrolyte comprises one or more of tetrabutylammonium tetrafluoroborate, potassium hexafluorophosphate, tetrabutylammonium hexafluorophosphate and lithium perchlorate;

[0024] The molar ratio of the hydrazone compound to the electrolyte is 0.5-1:0.5-1.

[0025] Another object of the present invention is to provide a benzoxadiazine derivative prepared by the electrochemical synthesis method.

[0026] It can be seen from the above technical solutions that compared with the prior art, the present invention has the following beneficial effects:

[0027] The preparation method disclosed in the present invention avoids the use of toxic or dangerous redox agents, expensive metal catalysts, and does not require acid or base additives. The reaction can occur at room temperature, using only electrooxidation to induce the intermolecular addition of hydroxyl radicals with hydrazones to synthesize benzoxadiazine derivatives, and the reaction conditions are mild. The byproduct is hydrogen, which is environmentally friendly. The benzoxadiazine derivatives obtained by the present invention are an important class of pharmaceutically active structural matrix with a wide range of pharmacological effects. The target structure synthesized by the present invention can effectively kill Pseudomonas aeruginosa and Staphylococcus aureus and can be further developed into a new antibacterial drug. In addition, the method for synthesizing benzoxadiazine derivatives of the present invention has the characteristics of readily available raw materials, simple operation, and adaptable electrolytes and solvents, and has great implementation value and social and economic benefits. DETAILED DESCRIPTION

[0028] The present invention provides an electrochemical synthesis method of benzoxadiazine derivatives, comprising the following steps:

[0029] The hydrazone compound and the p-aminophenol compound are subjected to an electrochemical reaction under an electric condition to obtain a benzoxadiazine derivative;

[0030] The structure of the benzoxadiazine derivative is

[0031] The structure of the hydrazone compound is

[0032] The structure of the p-aminophenol compound is

[0033] Among them, R 1 including one of an alkyl ring, a phenyl ring, a phenethyl ring, a thiophene ring and a pyridine ring;

[0034] R 2 including one of an alkyl group, an alkoxy group, and a halogen group;

[0035] R 3 including one of alkyl, alkoxy, halogen and trifluoromethyl;

[0036] R 4 including one of tert-butyloxycarbonyl, ethoxycarbonyl and p-toluenesulfonyl;

[0037] R5 Includes one of an alkyl group, an alkoxy group, and a halogen group.

[0038] In the present invention, the alkyl group may specifically be methyl or ethyl, and the halogen group may specifically be fluorine, chlorine, bromine or iodine.

[0039] In the present invention, the hydrazone compound can be specifically 1-(diphenylmethylene)-2-phenylhydrazine, (E)-1-((4-methoxyphenyl)(phenyl)methylene)-2-phenylhydrazine, (E)-1-phenyl-2-(phenyl(m-tolyl)methylene)hydrazine, (E)-1-((2-fluorophenyl)(phenyl)methylene)-2-phenylhydrazine, (E)-1-((3-chlorophenyl)(phenyl)methylene)-2-phenylhydrazine, (E)-1-((4-chlorophenyl)(phenyl)methylene)-2-phenylhydrazine, (E)-2-(phenyl(2-phenylhydrazineylidene)methyl)pyridine, (E)-1-phenyl-2-(phenyl(thiophene)methylene)pyridine, 1-(diphenylmethylene)-2-(o-tolyl)hydrazine, 1-(diphenylmethylene)-2-(m-tolyl)hydrazine, 1-(diphenylmethylene)-2-(p-tolyl)hydrazine, 1-(diphenylmethylene)-2-(4-(trifluoromethyl)phenyl)hydrazine, 1-(3-chlorophenyl)-2-(diphenylmethylene)hydrazine or 1-(3-chlorophenyl)-2-(diphenylmethylene)hydrazine.

[0040] In the present invention, the molar ratio of the hydrazone compound to the p-aminophenol compound is 0.5-1:1-1.5, preferably 0.6-0.9:1.1-1.4, more preferably 0.7-0.8:1.2-1.3, and further preferably 0.75:1.25.

[0041] In the present invention, the current of the electrochemical reaction is 1-5 mA, specifically 2 mA, 3 mA, or 4 mA; the time is 10-22 h, specifically 12 h, 14 h, 15 h, 16 h, 18 h, or 20 h.

[0042] In the present invention, the electrode for the electrochemical reaction is preferably a platinum electrode or a nickel foam electrode.

[0043] In the present invention, the electrochemical reaction is carried out in an organic solvent.

[0044] In the present invention, the organic solvent includes one or more of acetonitrile, acetone and tetrahydrofuran.

[0045] In the present invention, the mass volume ratio of the hydrazone compound to the organic solvent is 0.1-1 mmol:6 mL, preferably 0.2-0.8 mmol:6 mL, more preferably 0.4-0.6 mmol:6 mL, and further preferably 0.5 mmol:6 mL.

[0046] In the present invention, the reaction system of the electrochemical reaction further includes an electrolyte.

[0047] In the present invention, the electrolyte includes one or more of tetrabutylammonium tetrafluoroborate, potassium hexafluorophosphate, tetrabutylammonium hexafluorophosphate and lithium perchlorate.

[0048] In the present invention, the molar ratio of the hydrazone compound to the electrolyte is 0.5-1:0.5-1, preferably 0.6-0.9:0.6-0.9, more preferably 0.7-0.8:0.7-0.8, and further preferably 0.75:0.75.

[0049] In the present invention, the reaction equation is as follows:

[0050]

[0051] The present invention also provides a benzoxadiazine derivative prepared by the electrochemical synthesis method.

[0052] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0053] Example 1: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[E][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0054] 1-(Diphenylmethylene)-2-phenylhydrazine (IIa, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h. The reaction was monitored for completion by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 30 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent. 122 mg of a yellow solid was obtained by silica gel column chromatography. Yield: 85%. The structural formula of Ia is:

[0055]

[0056] 1 H NMR(600MHz,Chloroform-d)δ8.48(d,J=7.8Hz,1H),8.30(d,J=7.8Hz,1H),7.79–7.68(m,2 H),7.48-7.41(m,3H),7.27(d,J=7.2Hz,1H),4.41(t,J=6.6Hz,2H),3.09(t,J=6.6Hz,2H).

[0057] 13 C NMR (100MHz, Chloroform-d) δ161.7,149.4,147.8,137.1,134.2,131.7,129.6,128.1,127.6,127.6,127.5,126.9,126.5,120.8,39.6,27.5.

[0058] HRMS(ESI)calcd for C 16 H 13 N2O[M+H] + :249.1022,found:249.1031.

[0059] Example 2: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0060] The only difference between this example and Example 1 is that tetrabutylammonium tetrafluoroborate is replaced by potassium hexafluorophosphate in equal moles, and 112 mg of a yellow solid is finally obtained. Yield: 78%.

[0061] Example 3: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0062] The only difference between this example and Example 1 is that tetrabutylammonium tetrafluoroborate is replaced by tetrabutylammonium hexafluorophosphate in equal moles, and 96 mg of a yellow solid is finally obtained. Yield: 67%.

[0063] Example 4: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0064] The only difference between this example and Example 1 is that tetrabutylammonium tetrafluoroborate is replaced by lithium perchlorate in equal moles, and 92 mg of a yellow solid is finally obtained. Yield: 64%.

[0065] Example 5: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0066] The only difference between this example and Example 1 is that the platinum electrode is replaced by a nickel foam electrode, and 105 mg of yellow solid is finally obtained. Yield: 73%.

[0067] Example 6: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0068] The only difference between this example and Example 1 is that the current was adjusted to 2 mA, and 112 mg of yellow solid was finally obtained. Yield: 78%.

[0069] Example 7: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0070] The only difference between this example and Example 1 is that the current was adjusted to 3 mA, and 99 mg of yellow solid was finally obtained. Yield: 69%.

[0071] Example 8: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0072] The only difference between this example and Example 1 is that the organic solvent acetone is replaced by acetonitrile in equal volume, and 80 mg of yellow solid is finally obtained. Yield: 56%.

[0073] Example 9: Preparation of tert-butyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ia)

[0074] The only difference between this example and Example 1 is that the organic solvent acetone is replaced by tetrahydrofuran in equal volume, and 70 mg of yellow solid is finally obtained. Yield: 49%.

[0075] The conductivity of different solvents varies greatly, and the electron transfer rate affects the experimental process and has an impact on the experimental yield.

[0076] Example 10: Preparation of tert-butyl (3-(4-methoxyphenyl)-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ib)

[0077] (E)-1-((4-methoxyphenyl)(phenyl)methylene)-2-phenylhydrazine (IIb, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) and separated by silica gel column chromatography to obtain 133 mg of a yellow solid. Yield: 87%. The structural formula of Ib is:

[0078]

[0079] 1 H NMR(400MHz,Chloroform-d)δ7.79–7.76(m,2H),7.72–7.67(m,2H),7.60–7.57(m,2H),7.47(dd,J=4.8,1.6Hz,3H),7 .38–7.34(m,2H),7.04(d,J=8.8Hz,2H),6.91–6.85(m,2H),6.67–6.61(m,2H),6.29(s,1H),3.80(s,3H),1.49(s,9H).

[0080] 13C NMR(100MHz,Chloroform-d)δ159.0,151.6,150.7,141.6,133.5,132.4,131.5,131.0,129. 6,129.0,128.8,128.0,127.7,127.6,122.6,120.1,115.5,113.4,102.0,55.0,28.2,28.1.

[0081] HRMS(ESI)calcd for C 31 H 32 N3O4[M+H] + :510.2388,found:510.2386.

[0082] Example 11: Preparation of tert-butyl (1,3-diphenyl-3-(m-tolyl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ic)

[0083] (E)-1-phenyl-2-(phenyl(m-tolyl)methylene)hydrazine (IIc, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washings were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) and separated by silica gel column chromatography to obtain 120 mg of a yellow solid. Yield: 81%. The structural formula of Ic is:

[0084]

[0085] 1H NMR(400MHz,Chloroform-d)δ7.78(dd,J=7.6,4.0Hz,2H),7.71(d,J=7.6Hz,2H),7.55(s,1H),7.52–7.44(m,4H),7.35(t,J=7.2Hz,2H),7.29(d, J=7.2Hz,1H),7.24(t,J=7.6Hz,1H),7.10(d,J=7.6Hz,1H),7.03(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),6.26(s,1H),2.35(s,3H),1.49(s,9H).

[0086] 13 C NMR(100MHz,Chloroform-d)δ153.4,152.3,151.3,142.2,142.1,138.4,132.1,131.6,129.4,1 29.2,128.7,128.6,128.5,128.3,128.2,125.3,123.3,122.1,120.6,119.6,102.5,28.8,22.1.

[0087] HRMS(ESI)calcd for C 31 H 32 N3O3[M+H] + :494.2139,found:494.2141.

[0088] Example 12: Preparation of tert-butyl (3-(2-fluorophenyl)-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Id)

[0089] (E)-1-((2-fluorophenyl)(phenyl)methylene)-2-phenylhydrazine (IId, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 116 mg of a yellow solid. Yield: 78%. The structural formula of Id is:

[0090]

[0091] 1 H NMR(400MHz,Chloroform-d)δ7.95(td,J=7.6,1.6Hz,1H),7.82–7.77(m,2H),7.71–7.68(m,2H),7.47(dd,J=4.4,2.4Hz,3H),7.36–7.33(m,2 H),7.28(d,J=2.0Hz,2H),7.19(dd,J=7.6,1.2Hz,1H),7.04(d,J=8.8Hz,2H),6.93–6.88(m,1H),6.79–6.75(m,2H),6.28(s,1H),1.47(s,9H).

[0092] 13 C NMR (100MHz, Chloroform-d) δ160.9,158.4,153.0,152.0,150.6,140.4,132.7,131.5,130.6,130.5(d,J=8.4Hz),129.6(d,J=3.2Hz ),129.5,129.2,128.2,127.6,123.7(d,J=3.5Hz),123.7,123.1,121.2,116.6(d,J=22.1Hz),100.9(d,J=4.2Hz),116.5,82.0,28.4.

[0093] 19 FNMR(376MHz,Chloroform-d)δ-107.53.

[0094] HRMS(ESI)calcd for C 30 H 29 FN3O3[M+H] + :498.2188,found:498.2187.

[0095] Example 13: Preparation of tert-butyl (3-(3-chlorophenyl)-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ie)

[0096] (E)-1-((3-chlorophenyl)(phenyl)methylene)-2-phenylhydrazine (IIe, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washings were combined, and the solvent was evaporated under reduced pressure. The concentrate was distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 117 mg of a yellow solid. Yield: 76%. The structural formula of Ie is:

[0097]

[0098] 1 H NMR(400MHz,Chloroform-d)δ7.81–7.74(m,3H),7.69–7.65(m,2H),7.56–7.53(m,1H),7.51–7.45(m,3H), 7.37–7.33(m,2H),7.32–7.26(m,3H),7.04(d,J=8.8Hz,2H),6.68–6.57(m,2H),6.27(s,1H),1.48(s,9H).

[0099] 13 C NMR(100MHz,Chloroform-d)δ153.0,151.8,150.5,144.0,141.3,134.4,132.1,131.6,129.7,129. 2,128.6,128.4,128.3,127.9,127.8,127.4,127.3,126.1,123.0,120.3,119.4,101.4,80.4,28.5.

[0100] HRMS(ESI)calcd for C 30 H 29 ClN3O3[M+H] + :514.1892,found:514.1895.

[0101] Example 14: Preparation of tert-butyl (3-(4-chlorophenyl)-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (If)

[0102] (E)-1-((4-chlorophenyl)(phenyl)methylene)-2-phenylhydrazine (IIf, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washings were combined, and the solvent was evaporated under reduced pressure. The concentrate was distilled under reduced pressure at 45°C for 30 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 114 mg of a yellow solid. Yield: 74%. The structural formula of If is:

[0103]

[0104] 1 H NMR(400MHz,Chloroform-d)δ7.77–7.72(m,2H),7.66–7.61(m,4H),7.48–7.44(m,3H), 7.37–7.25(m,6H),7.03(d,J=8.6Hz,2H),6.65–6.59(m,2H),6.26(s,1H),1.47(s,9H).

[0105] 13 C NMR(100MHz,Chloroform-d)δ153.4,152.2,150.9,141.7,140.8,134.4,132.5,131.9,129. 7,129.5,128.9,128.8,128.6,128.2,128.1,123.3,122.1,120.7,119.7,102.1,80.7,28.8.

[0106] HRMS(ESI)calcd for C 30 H 29 ClN3O3[M+H] + :514.1892,found:514.1889.

[0107] Example 15: Preparation of tert-butyl (1,3-diphenyl-3-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (1 g)

[0108] (E)-2-(Phenyl(2-phenylhydrazinylidene)methyl)pyridine (IIg, 0.3mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45mmol), tetrabutylammonium tetrafluoroborate (0.3mmol), and acetone (6mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1mA. The reaction was stirred at room temperature for 12h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and microwaved for 5min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 89mg of a yellow solid. Yield: 62%. The structural formula of Ig is:

[0109]

[0110] 1 H NMR (400MHz, Chloroform-d) δ8.59 (ddd, J=4.8, 1.6, 0.8Hz, 1H), 7.90 (dt, J=8. 4,1.2Hz,1H),7.78(m,3H),7.75(t,J=1.2Hz,1H),7.71(td,J=7.8,2.0Hz,1H),7 .49–7.42(m,3H),7.38–7.33(m,2H),7.30–7.27(m,1H),7.16(ddd,J=7.6,4.8, 1.2Hz,1H),7.03(d,J=8.4Hz,2H),6.70–6.66(m,2H),6.34(s,1H),1.46(s,9H).

[0111] 13 C NMR(100MHz,Chloroform-d)δ160.2,152.7,151.6,150.4,149.0,140.3,136.5,131.8,1 31.2,128.8,128.1,127.9,127.7,122.7,122.5,120.0,119.0,115.6,101.6,79.9,28.1.

[0112] HRMS(ESI)calcd for C 29 H 29 N4O3[M+H] + :481.2235,found:481.2233.

[0113] Example 16: Preparation of tert-butyl (1,3-diphenyl-3-(thiophen-2-yl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ih)

[0114] (E)-1-phenyl-2-(phenyl(thiophen-2-yl)methylene)hydrazine (IIh, 0.45 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 hours, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 minutes. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (15:1) as the eluent and separated by silica gel column chromatography to obtain 122 mg of a yellow solid. Yield: 86%. The structural formula of Ih is:

[0115]

[0116] 1 H NMR(400MHz,Chloroform-d)δ7.81(dd,J=7.2,3.6Hz,2H),7.77–7.72(m,2H),7.51–7.48(m,3H),7.41 –7.35(m,4H),7.09–7.05(m,3H),6.79(d,J=8.4Hz,1H),6.72–6.68(m,2H),6.30(s,1H),1.50(s,9H).

[0117] 13 C NMR(100MHz,Chloroform-d)δ153.6,152.5,151.6,144.8,144.4,141.3,140.8,131.6,130.9,1 29.7,129.3,129.2,129.0,128.3,127.6,126.3,126.1,123.1,115.9,113.1,101.3,80.4,28.5.

[0118] HRMS(ESI)calcd for C 28 H 28 N3O3S[M+H] + :486.1846,found:486.1843.

[0119] Example 17: Preparation of tert-butyl (3-methyl-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ii)

[0120] (Z)-1-phenyl-2-(1-phenylethylidene)hydrazine (IIi, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 hours, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 minutes. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (15:1) as the eluent and separated by silica gel column chromatography to obtain 84 mg of a yellow solid. Yield: 67%. The structural formula of Ii is:

[0121]

[0122] 1 H NMR(400MHz,Chloroform-d)δ7.83–7.73(m,2H),7.69–7.63(m,2H),7.51–7.45(m,3H),7.39–7.34(m,2H) ,7.33–7.28(m,1H),7.12(d,J=8.8Hz,2H),6.81(d,J=8.8Hz,2H),6.32(s,1H),1.85(s,3H),1.48(s,9H).

[0123] 13 C NMR(100MHz,Chloroform-d)δ153.4,152.1,151.2,141.7,133.3,131.7,129.5,1 28.9,128.4,126.9,123.2,122.2,119.9,116.1,115.8,102.3,80.8,28.8,26.4.

[0124] HRMS(ESI)calcd for C 25 H 28 N3O3[M+H] + :418.2126,found:418.2133.

[0125] Example 18: Preparation of tert-butyl (3-ethyl-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ij)

[0126] (Z)-1-phenyl-2-(1-phenylpropylene)hydrazine (IIj, 0.45 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 hours. The reaction was monitored for completion by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 minutes. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (25:1) as the eluent and separated by silica gel column chromatography to obtain 89 mg of a yellow solid. Yield: 85%. The structural formula of Ij is:

[0127]

[0128] 1 H NMR(400MHz,Chloroform-d)δ7.79–7.73(m,2H),7.73–7.68(m,2H),7.49–7.44(m,3H),7.39–7.34(m,2H),7.33–7.28 (m,1H),7.04(d,J=8.8Hz,2H),6.69–6.52(m,2H),6.27(s,1H),2.37–2.20(m,2H),1.47(s,9H),0.89(t,J=7.2Hz,3H).

[0129] 13 C NMR(100MHz,Chloroform-d)δ152.8,151.7,150.6,139.6,131.5,130.9,128.8,128 .1,127.6,127.0,122.5,119.7,119.3,115.5,115.1,102.6,80.0,34.2,28.1,7.6.

[0130] HRMS(ESI)calcd for C 26 H 30 N3O3[M+H] + :432.2282,found:432.2289.

[0131] Example 19: Preparation of tert-butyl (3-benzyl-1,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ik)

[0132] (Z)-1-(1,2-diphenylethylidene)-2-phenylhydrazine (IIk, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h, and the completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washings were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (25:1) and separated by silica gel column chromatography to obtain 95 mg of a yellow solid. Yield: 64%. The structural formula of Ik is:

[0133]

[0134] 1 H NMR(400MHz,Chloroform-d)δ7.81–7.73(m,2H),7.53–7.46(m,5H),7.28–7.24(m,3H),7.18–7.11(m,3H),7.00( d,J=8.8Hz,2H),6.93(dd,J=7.6,1.6Hz,2H),6.56–6.49(m,2H),6.24(s,1H),3.49(d,J=2.0Hz,2H),1.47(s,9H).

[0135] 13 C NMR(100MHz,Chloroform-d)δ153.1,151.9,150.8,139.2,135.1,131.5,131.4,131.4,129.7,1 29.2,128.2,127.9,127.7,127.6,126.6,122.9,119.5,119.4,115.5,101.6,80.3,49.2,28.4.

[0136] HRMS(ESI)calcd for C 31 H 32 N3O3[M+H] + :494.2439,found:494.2445.

[0137] Example 20: Preparation of tert-butyl (3,3-diphenyl-1-(o-tolyl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (I1)

[0138] 1-(Diphenylmethylene)-2-(o-tolyl)hydrazine (IIIa, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 hours, and the reaction was monitored for completion by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 minutes. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 109 mg of a yellow solid. Yield: 74%. The structural formula of III is:

[0139]

[0140] 1 H NMR(400MHz,Chloroform-d)δ7.75(ddd,J=8.4,3.2,1.6Hz,4H),7.51–7.46(m,1H),7.43–7.35(m,5H),7.35–7.32(m,2H),7.27(d, J=7.2Hz,2H),7.07(d,J=8.4Hz,2H),6.67(dd,J=9.2,2.8Hz,2H),6.34–6.26(m,1H),2.28(d,J=2.0Hz,3H),1.52(d,J=2.0Hz,9H).

[0141] 13 C NMR(100MHz,Chloroform-d)δ153.1,151.3,150.1,141.9,138.2,131.6,131.3,131. 1,128.4,128.2,127.9,126.4,119.9,119.4,115.8,115.7,102.4,80.3,28.5,17.2.

[0142] HRMS(ESI)calcd for C 31 H 32 N3O3[M+H] + :494.2439,found:494.2443.

[0143] Example 21: Preparation of tert-butyl (3,3-diphenyl-1-(m-tolyl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Im)

[0144] 1-(Diphenylmethylene)-2-(m-tolyl)hydrazine (IIm, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent. 112 mg of a yellow solid was obtained by silica gel column chromatography. Yield: 76%. The structural formula of Im is:

[0145]

[0146] 1 H NMR(400MHz,Chloroform-d)δ7.70(s,4H),7.61–7.58(m,2H),7.36(ddd,J=7.7,6.0,1.2Hz,5H),7 .32–7.27(m,3H),7.04(d,J=8.4Hz,2H),6.67–6.62(m,2H),6.28(s,1H),2.44(s,3H),1.49(s,9H).

[0147] 13 C NMR(100MHz,Chloroform-d)δ153.1,152.0,150.9,141.9,139.1,132.1,131.8,130. 2,128.9,128.4,128.1,127.9,123.5,121.8,120.3,120.1,102.2,80.3,28.5,21.4.

[0148] HRMS(ESI)calcd for C 31 H 32 N3O3[M+H] + :494.2439,found:494.2421.

[0149] Example 22: Preparation of tert-butyl (3,3-diphenyl-1-(p-tolyl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (In)

[0150] 1-(Diphenylmethylene)-2-(p-tolyl)hydrazine (IIn, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 hours. The reaction was monitored for completion by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 minutes. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent. 118 mg of a yellow solid was obtained by silica gel column chromatography. Yield: 80%. The structural formula of In is:

[0151]

[0152] 1 H NMR(400MHz,Chloroform-d)δ7.78–7.61(m,6H),7.38–7.33(m,4H),7.31–7.26(m,4H) ,7.03(d,J=8.4Hz,2H),6.65(d,J=9.0Hz,2H),6.26(s,1H),2.43(s,3H),1.49(s,9H).

[0153] 13 C NMR(100MHz,Chloroform-d)δ152.9,150.9,149.9,141.9,141.85,132.5,131.7,130.1,1 29.6,128.3,127.9,127.8,122.9,121.7,120.3,119.2,115.7,101.9,80.19,3.35,21.4.

[0154] HRMS(ESI)calcd for C 31 H 32 N3O3[M+H] + :494.2439,found:494.2444.

[0155] Example 23: Preparation of tert-butyl (3,3-diphenyl-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Io)

[0156] 1-(Diphenylmethylene)-2-(4-(trifluoromethyl)phenyl)hydrazine (IIo, 0.3 mmol), tert-butyl (4-hydroxyphenyl)carbamate (IIIa, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 105 mg of a yellow solid. Yield: 64%. The structural formula of Io is:

[0157]

[0158] 1 H NMR(400MHz,Chloroform-d)δ7.82(d,J=8.4Hz,2H),7.72(d,J=8.4Hz,2H),7.69–7.66(m,4H),7.34(d ,J=7.6Hz,4H),7.32–7.28(m,2H),7.03(d,J=8.4Hz,2H),6.61–6.57(m,2H),6.25(s,1H),1.47(s,9H).

[0159] 13 C NMR(100MHz,Chloroform-d)δ153.8,153.0,150.7,141.3,132.77(d,J=32.7Hz),132.0,130.1(d,J=27 .8Hz),128.5,128.4,128.3,127.8,126.4(q,J=3.8Hz),123.1,120.2,119.4,112.6,102.7,80.4,28.4.

[0160] 19 FNMR(375MHz,Chloroform-d)δ-62.65.

[0161] HRMS(ESI)calcd for C 31 H 29F3N3O3[M+H] + :548.2156,found:548.2164.

[0162] Example 24: Preparation of tert-butyl (1-(3-chlorophenyl)-5-methyl-3,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Iq)

[0163] 1-(3-chlorophenyl)-2-(diphenylmethylene)hydrazine (IIp, 0.3 mmol), tert-butyl (4-hydroxy-3-methylphenyl)carbamate (IIIc, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) and separated by silica gel column chromatography to obtain 122 mg of a yellow solid. Yield: 85%. The structural formula of Iq is:

[0164]

[0165] 1 H NMR(400MHz,Chloroform-d)δ7.72–7.67(m,6H),7.45–7.42(m,2H),7.35(d,J=7.6Hz,4H),7.30(dd,J=7.6,1.6Hz, 2H),7.21–7.17(m,1H),6.60(dd,J=9.2,2.8Hz,1H),6.21(s,1H),6.00(d,J=8.8Hz,1H),2.49(s,3H),1.48(s,9H).

[0166] 13 C NMR(100MHz,Chloroform-d)δ153.0,150.2,148.8,141.9,137.3,131.3,130.1,129.8.129.4,129.2,1 29.1,129.00,128.4,128.3,128.2,128.0,127.5,126.6,124.1,119.1,114.1,102.2,77.4,28.3,17.7.

[0167] HRMS(ESI)calcd for C31 H 31 ClN3O3[M+H] + :528.2049,found:528.2054.

[0168] Example 25: Preparation of benzyl (1-(3-chlorophenyl)-3,3-diphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ip)

[0169] 1-(3-chlorophenyl)-2-(diphenylmethylene)hydrazine (IIp, 0.3 mmol), benzyl (4-hydroxyphenyl)carbamate (IIIb, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 1 mA. The reaction was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent. 112 mg of a yellow solid was obtained by silica gel column chromatography. Yield: 68%. The structural formula of Ip is:

[0170]

[0171] 1 H NMR(400MHz,Chloroform-d)δ7.72–7.65(m,6H),7.43–7.40(m,2H),7.37–7.31(m,9H) ),7.30–7.27(m,2H),7.07–7.00(m,2H),6.62–6.58(m,2H),6.47(s,1H),5.13(s,2H).

[0172] 13 C NMR(100MHz,Chloroform-d)δ153.6,151.2,150.2,141.5,137.5,136.2,132.6,131.3,130.2 ,129.4,128.7,128.5,128.4,128.2,127.8,124.3,120.3,119.4,116.8,115.8,102.3,67.0.

[0173] HRMS(ESI)calcd for C 31 H 29 F3N3O3[M+H] +:548.1736,found:548.1742.

[0174] Example 26: Preparation of ethyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Ir)

[0175] 1-(Diphenylmethylene)-2-phenylhydrazine (IIa, 0.3 mmol), ethyl (4-hydroxyphenyl)urethane (IIIr, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 3 mA. The reaction was stirred at room temperature for 12 hours, and the reaction was monitored for completion by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 minutes. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent and separated by silica gel column chromatography to obtain 103 mg of a yellow solid. Yield: 76%. The structural formula of Ir is:

[0176]

[0177] 1 H NMR(400MHz,Chloroform-d)δ7.82–7.78(m,2H),7.74(d,J=7.8Hz,4H),7.53–7.46(m,3H),7.38(t,J=7.4Hz,4H),7.34 –7.27(m,2H),7.07(d,J=8.6Hz,2H),6.67(d,J=7.0Hz,2H),6.48(s,1H),4.18(q,J=7.2Hz,2H),1.28(t,J=7.1Hz,3H).

[0178] 13 C NMR(100MHz,Chloroform-d)δ151.8,141.6,137.5,132.5,131.3,130.1,129. 0,128.3,128.3,128.2,128.0,127.7,122.8,120.2,115.7,102.1,61.1,14.5.

[0179] HRMS(ESI)calcd for C 28 H 26 N3O3[M+H] + :452.1969,found:452.1972.

[0180] Example 27: Preparation of ethyl (1,3,3-triphenyl-2,3-dihydro-1H-benzo[e][1,3,4]oxadiazin-7-yl)carbamate (Is)

[0181] 1-(Diphenylmethylene)-2-phenylhydrazine (IIa, 0.3 mmol), N-(4-hydroxyphenyl)-4-methylbenzenesulfonamide (IIIs, 0.45 mmol), tetrabutylammonium tetrafluoroborate (0.3 mmol), and acetone (6 mL) were added to a reaction tube. A graphite felt electrode and a platinum electrode were inserted. The current was adjusted to a constant current of 3 mA. The reaction was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction was stopped, and the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined and distilled under reduced pressure at 45°C for 45 min. The concentrate was eluted with a mixture of petroleum ether and ethyl acetate (20:1) as the eluent. 123 mg of a yellow solid was obtained by silica gel column chromatography. Yield: 74%. The structural formula of Is is:

[0182]

[0183] 1 H NMR(400MHz,Chloroform-d)δ7.76–7.72(m,2H),7.69–7.65(m,4H),7.51–7.47

[0184] (m,3H),7.45–7.41(m,2H),7.37–7.33(m,4H),7.33–7.27(m,2H),7.11(d,J= 8.0Hz,2H),6.72–6.67(m,2H),6.58–6.53(m,2H),6.20(s,1H),2.37(s,3H).

[0185] 13 C NMR(100MHz,Chloroform-d)δ153.3,151.6,143.4,141.3,135.7,132.4,131.3,130.0 ,129.3,129.3,129.0,128.3,128.0,127.6,127.2,124.2,122.7,120.3,102.3,21.5.

[0186] HRMS(ESI)calcd for C 32 H 28 N3O3S[M+H] + :534.1846,found:534.1850.

[0187] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0188] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for electrochemical synthesis of benzoxadiazine derivatives, characterized in that: The following steps are involved: The hydrazone compound and the p-aminophenol compound are subjected to an electrochemical reaction under an electric condition to obtain a benzoxadiazine derivative; The structure of the benzoxadiazine derivative is The structure of the hydrazone compound is The structure of the p-aminophenol compound is Among them, R 1 including one of an alkyl ring, a phenyl ring, a phenethyl ring, a thiophene ring and a pyridine ring; R 2 including one of an alkyl group, an alkoxy group, and a halogen group; R 3 including one of alkyl, alkoxy, halogen and trifluoromethyl; R 4 including one of tert-butyloxycarbonyl, ethoxycarbonyl and p-toluenesulfonyl; R 5 including one of an alkyl group, an alkoxy group, and a halogen group; The current of the electrochemical reaction is 1 to 5 mA; The electrochemical reaction is carried out in an organic solvent, and the reaction system of the electrochemical reaction also includes an electrolyte.

2. The electrochemical synthesis method of a benzoxadiazine derivative according to claim 1, characterized in that: The molar ratio of the hydrazone compound to the p-aminophenol compound is 0.5-1:1-1.

5.

3. The electrochemical synthesis method of a benzoxadiazine derivative according to claim 1 or 2, characterized in that: The electrochemical reaction time is 10 to 22 hours.

4. The electrochemical synthesis method of a benzoxadiazine derivative according to claim 1, characterized in that: The organic solvent includes one or more of acetonitrile, acetone and tetrahydrofuran; The molar volume ratio of the hydrazone compound to the organic solvent is 0.1-1 mmol:6 mL.

5. The electrochemical synthesis method of a benzoxadiazine derivative according to claim 1, characterized in that: The electrolyte includes one or more of tetrabutylammonium tetrafluoroborate, potassium hexafluorophosphate, tetrabutylammonium hexafluorophosphate and lithium perchlorate; The molar ratio of the hydrazone compound to the electrolyte is 0.5-1:0.5-1.

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