A green synthetic method of electrochemical catalysis of sulfonylation of isoxazole derivatives

Abstract

The application discloses a novel and efficient electrochemical catalytic synthesis of sulfone isoxazole derivatives. The method uses beta, gamma-unsaturated ketone oxime and p-toluenesulfonyl hydrazine as starting materials, under the condition of C(+) / C(-) as an electrode, a current of 10 mA, and reaction at room temperature for 4 h, the oxidation sulfonation reaction of the alkenyl oxime substrate can be smoothly realized, and sulfone isoxazole derivatives are obtained. The sulfone radical is generated by anodic single electron oxidation of p-toluenesulfonyl hydrazine, then the radical addition is carried out on the alkenyl oxime, the benzyl radical is generated, then the radical oxidation reaction of the benzyl position and the intramolecular nucleophilic cyclization reaction are further carried out at the anode to generate the sulfone isoxazole product. Compared with the traditional synthesis scheme, the application only needs to add inorganic electrolyte as a conductive medium under mild conditions, without the addition of metal and additional oxidants, and the sulfone group can be introduced into the skeleton of the isoxazole ring under the electrochemical condition, and the aryl alkyl sulfone compound constructed is widely used in medicines, biologically active products and materials, and has important biological and synthetic research value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis intermediates, and relates to a green synthesis method of a sulfonylated isoxazole derivative, in particular, an efficient and economical electrochemical catalytic reaction, and a green preparation method without metal and external oxidant. BACKGROUND

[0002] The isoxazole ring is a skeleton with an advantageous structure in heterocyclic compounds, and is widely present in antipsychotic, antidepressant, and antibacterial drugs, attracting a large number of biological and organic chemists to study it. In the isoxazole structure synthesized by the present application, an arylalkyl sulfone structure is constructed in one step, which is also an important organic synthesis intermediate, such as an important coupling fragment in Ramberg-Baecklund reaction and Julia olefination reaction, so the synthesis of isoxazole compounds containing a sulfone group has always been a research hotspot, and new synthesis strategies are continuously developed. The traditional method for synthesizing the sulfone group isoxazole compound in the past is to realize the construction of the compound by using an equivalent or catalytic amount of copper salt and an equivalent of additive, and the atomic economy is not high, while the present method adopts a free radical tandem cyclization reaction of intramolecular olefin oxime and p-toluenesulfonyl hydrazine, and realizes the intramolecular olefin oxidation sulfonylation reaction in one step, which is green and clean, and does not need the participation of transition metals and equivalent additives, and conforms to the concept of green chemistry development.

[0003] The difunctionalization of alkenes has become a powerful tool for the construction of diverse chemical structures. Compared with the previously reported reactions for constructing arylalkyl sulfone between olefins and sulfone reagents, the synthesis of sulfone-substituted heterocyclic compounds through cyclization mode has not been well explored. The previously reported methods generally construct heterocyclic compounds through copper salt or iodine catalysis, however, the disadvantage of these methods is that they need to go through a two-step thiolation / oxidation process to obtain arylalkyl sulfone. Therefore, a method for directly synthesizing sulfone-substituted heterocyclic compounds from olefins and sulfone reagents is very urgent. The present application adopts electrochemical catalysis to convert electrical energy into chemical energy, and successfully synthesizes the sulfone group isoxazole compound through one-step tandem cyclization reaction, enriches the synthesis strategy of the compound, and has certain innovation significance. SUMMARY

[0004] The present application is dedicated to developing a green, inexpensive, efficient and clean electrochemical catalytic radical tandem cyclization reaction of beta, gamma-unsaturated oxime and p-toluenesulfonyl hydrazine to construct a sulfonylated isoxazole ring skeleton. Compared with the traditional method, the present method efficiently synthesizes the sulfone group isoxazole derivative under mild conditions without the participation of any metal and additive, and obtains a medium to good yield.

[0005] To achieve the purpose of the present application, the following scheme is adopted: a green synthesis method of a sulfone group isoxazole derivative,

[0006] The reaction equation is:

[0007]

[0008] Wherein: R 1 = F, Cl, Br, CH3, OCH 3, CF 3; R 2 = aryl, alkyl

[0009] Specifically comprising the following steps:

[0010] 1) β, γ-unsaturated ketone oxime and p-toluenesulfonyl hydrazine are added to the reactor for reaction, the temperature is controlled at 25~30℃, C(+) / C(-) is selected as the electrode, acetonitrile / water 3:1 (8 mL), and the reaction is carried out at room temperature for 4.0~5.0 h;

[0011] 2) After the reaction is completed, acetonitrile is removed by rotary evaporation, diluted with water, extracted with ethyl acetate, the organic phases are combined, dried, most of the solvent is removed by reduced pressure distillation, and the crude product is separated and purified by column chromatography with ethyl acetate and petroleum ether as eluents to obtain the target product;

[0012] As preferred: the molar ratio of β, γ-unsaturated ketone oxime to p-toluenesulfonyl hydrazine is 1:5.

[0013] As preferred: the volume ratio of petroleum ether to ethyl acetate is 10:1~5:1.

[0014] Compared with the existing synthesis method, the beneficial effects of the present application are:

[0015] 1) The present application uses inexpensive p-toluenesulfonyl hydrazine as a sulfonyl source, and denitrogenation under electrochemical conditions produces sulfonyl radicals without adding peroxide, which not only expands the cost economic benefits, but also successfully realizes the intramolecular oxidative sulfonylation of allyl oxime molecules, and the benefits are considerable.

[0016] 2) The sulfonyl isoxazole skeleton synthesized by the present application can be used as an organic synthesis intermediate and can be widely used to provide effective fragments for new synthesis of drugs and materials.

[0017] 3) The present application uses electrochemical catalysis to convert clean and inexpensive electrical energy into chemical energy, efficiently constructs the sulfonylated isoxazole structure, improves the conversion efficiency, and greatly shortens the chemical reaction time. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The preparation of 3,5-diphenyl-5-(p-toluenesulfonylmethylene)-4,5-dihydroisoxazole for Example 1 1H-NMR nuclear magnetic resonance spectrum;

[0019] Figure 2 Preparation of 5-phenyl-3-(m-tolyl)-5-(p-tolylsulfonylmethylidene)-4,5- dihydroisoxazole for Example 2 1 H-NMR nuclear magnetic resonance spectrum;

[0020] Figure 3 Preparation of 3-(4-bromophenyl)-5-phenyl-5-(p-tolylsulfonylmethylidene)-4,5- dihydroisoxazole for Example 3 1 H-NMR nuclear magnetic resonance spectrum;

[0021] Figure 4 Preparation of 3-(4-chlorophenyl)-5-phenyl-5-(p-tolylsulfonylmethylidene)-4,5- dihydroisoxazole for Example 4 1 H-NMR nuclear magnetic resonance spectrum;

[0022] Figure 5 Preparation of 3-(4-tert-butylphenyl)-5-phenyl-5-(p-tolylsulfonylmethylidene)-4,5- dihydroisoxazole for Example 5 1 H-NMR nuclear magnetic resonance spectrum;

[0023] Figure 6 Preparation of 5-phenyl-5-(2,2,2-trifluoroethyl)-3-(p-tolylsulfonylmethylidene)-4,5- dihydroisoxazole for Example 6 1 H-NMR nuclear magnetic resonance spectrum; DETAILED DESCRIPTION

[0024] The present application uses β, γ-unsaturated ketoxime, p-tolylsulfonyl hydrazine as the starting material, under the condition of C(+) / C(-) as the electrode, a current of I = 10 mA, and a reaction time of 4 h at room temperature, wherein the molar ratio of β, γ-unsaturated ketoxime to p-tolylsulfonyl hydrazine is 1:5, the intramolecular olefin double functionalization reaction of unsaturated ketoxime is realized, and p-tolylsulfonylated isoxazole derivatives are efficiently synthesized. In the reaction equation, CH3CN is acetonitrile, and Ts is p-tolylsulfonyl.

[0025] Example 1: Synthesis of 3,5-diphenyl-5-(p-tolylsulfonylmethylidene)-4,5- dihydroisoxazole

[0026]

[0027] Into a 25 mL electrochemical reaction cell, 1,3-diphenyl-but-3-en-1-one oxime (0.2 mmol, 47.4 mg), p-tolylsulfonyl hydrazine (1.0 mmol, 186.2 mg), CH3CN (5 mL), and 0.1 M Na2SO4 (5 mL) were added. nEt4NPF6(110 mg, 0.05 M), CH3CN:H2O = 3:1 (8 mL), under the condition of C(+) / C(-) as electrode, constant current I = 10 mA, magnetic stirring reaction at room temperature for 4~5 hours; after the reaction was completed, remove acetonitrile by distillation under reduced pressure, dilute with water, extract with ethyl acetate three times, combine the organic phase, concentrate under reduced pressure to obtain the crude product, the crude product is eluted with petroleum ether: ethyl acetate (10:1-5:1) as eluent, after column chromatography separation and purification, the target product is obtained as a white solid with a yield of 70%.

[0028] The nuclear magnetic data thereof are as follows:

[0029] 1 H NMR (300 MHz, CDCl3) δ 7.69-7.63 (m, 4H), 7.43 – 7.39 (m, 5H), 7.34– 7.23 (m, 5H), 4.55 (d, J = 16.8 Hz, 1H), 3.87 (s, 2H), 3.65 (d, J = 17.1Hz,1H), 2.42 (s, 3H).

[0030] Example 2: Synthesis of 5-phenyl-3-(m-tolyl)-5-(p-tolylsulfonylmethylene)-4,5- dihydroisoxazole

[0031]

[0032] Into a 25 mL electrochemical cell, 3-phenyl-1-(m-tolyl)-but-3-en-1-one oxime (0.2 mmol, 50.3 mg), p-tolylsulfonylhydrazine (1.0 mmol, 186.2 mg), n Et4NPF6(110 mg, 0.05 M), CH3CN:H2O = 3:1 (8 mL), under the condition of C(+) / C(-) as electrode, constant current I = 10 mA, magnetic stirring reaction at room temperature for 4~5 hours; after the reaction was completed, remove acetonitrile by distillation under reduced pressure, dilute with water, extract with ethyl acetate three times, combine the organic phase, concentrate under reduced pressure to obtain the crude product, the crude product is eluted with petroleum ether: ethyl acetate (10:1-5:1) as eluent, after column chromatography separation and purification, the target product is obtained as a white solid with a yield of 54%.

[0033] The nuclear magnetic data thereof are as follows:

[0034] 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J= 8.2 Hz, 2H), 7.50 – 7.45 (m, 2H), 7.42-7.38 (m, 2H), 7.34 – 7.29(m, 4H), 7.26-7.23 (m, 3H), 4.54 (d, J = 17.1 Hz,1H), 3.87 (s, 2H), 3.64 (d, J = 16.8 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H).

[0035] Example 3: Synthesis of 3-(4-bromophenyl)-5-phenyl-5-(p-toluenesulfonylmethylene)-4,5-dihydroisoxazole

[0036] 1-(4-bromophenyl)-3-phenylbut-3-en-1-one oxime (0.2 mmol, 63.2 mg) and p-toluenesulfonyl hydrazine (1.0 mmol, 186.2 mg) were added to a 25 mL electrochemical reaction cell. n Et4NPF6 (110 mg, 0.05 M), CH3CN:H2O = 3:1 (8 mL), under the condition of C(+) / C(-) as electrode, under a constant current of I = 10 mA, the reaction was carried out at room temperature with magnetic stirring for 4-5 hours. After the reaction was completed, acetonitrile was removed by vacuum distillation, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, and concentrated under vacuum to obtain crude product. The crude product was eluted with petroleum ether:ethyl acetate (10:1-5:1) as eluent, and purified by column chromatography to obtain the target product as a pale yellow solid with a yield of 62%.

[0037] Its NMR data are as follows:

[0038] 1 H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 2H), 7.54 (s, 2H), 7.42 –7.38 (m, 3H), 7.35-7.24 (m, 6H), 4.54 (d, J = 16.8 Hz, 1H), 3.86 (s, 2H), 3.62(d, J = 17.1Hz, 1H), 2.42 (s, 3H).

[0039] Example 4: Synthesis of 3-(4-chlorophenyl)-5-phenyl-5-(p-toluenesulfonylmethylene)-4,5-dihydroisoxazole

[0040] To a 25 mL electrochemical cell was added 1-(4-tert-butylphenyl)-3-phenylbut-3-en-1- one oxime (0.2 mmol, 58.7 mg), p-tolylsulfonylhydrazide (1.0 mmol, 186.2 mg), n Et4NPF6(110 mg, 0.05 M), CH3CN:H2O =3:1 (8 mL), under the condition of C(+) / C(-) as electrodes, constant current I =10 mA, the reaction was stirred magnetically at room temperature for 4~5 hours; after the reaction was completed, the acetonitrile was removed by reduced pressure distillation, diluted with water, extracted with ethyl acetate three times, combined the organic phase, concentrated under reduced pressure to obtain the crude product, the crude product was eluted with petroleum ether: ethyl acetate (10:1-5:1) as eluent, after column chromatography separation and purification, the target product was obtained as white foam, the yield was 73%.

[0041] The nuclear magnetic data are as follows:

[0042] 1 H NMR (300 MHz, CDCl3) δ 7.62 (dd, J = 10.2Hz, J = 8.4 Hz, 4H), 7.41 –7.34 (m, 4H), 7.33 – 7.24 (m, 5H), 4.54 (d, J = 16.8 Hz, 1H), 3.86 (s, 2H),3.62 (d, J = 16.8 Hz, 1H), 2.42 (s, 3H).

[0043] Example 5: Synthesis of 3-(4-tert-butylphenyl)-5-phenyl-5-(p-tolylsulfonylmethyl)-4,5- dihydroisoxazole

[0044] To a 25 mL electrochemical cell was added 1-(4-tert-butylphenyl)-3-phenylbut-3-en-1- one oxime (0.2 mmol, 58.7 mg), p-tolylsulfonylhydrazide (1.0 mmol, 186.2 mg), nEt4NPF6(110 mg, 0.05 M), CH3CN:H2O =3:1 (8 mL), under the condition of C(+) / C(-) as electrode, constant current I =10 mA, magnetic stirring reaction at room temperature for 4~5 hours; after the reaction was completed, remove acetonitrile by distillation under reduced pressure, dilute with water, extract with ethyl acetate three times, combine the organic phase, concentrate under reduced pressure to obtain the crude product, the crude product is eluted with petroleum ether: ethyl acetate (10:1-5:1) as eluent, after column chromatography separation and purification, the target product is obtained as a white solid with a yield of 50%.

[0045] The nuclear magnetic data thereof are as follows:

[0046] 1 H NMR (300 MHz, CDCl3) δ 7.63 (t, J = 8.7 Hz, 4H), 7.44 – 7.38 (m, 4H),7.31-7.23 (m, 5H), 4.54 (d, J = 16.8 Hz, 1H), 3.86 (s, 2H), 3.63 (d, J = 16.8 Hz,1H), 2.41 (s, 3H), 1.33 (s, 9H).

[0047] Example 6: Synthesis of 5-phenyl-5-(2,2,2-trifluoroethyl)-3-(4-p-toluenesulfonyl methylene)-4,5-dihydroisoxazole

[0048] Into a 25 mL electrochemical cell, 3-phenyl-1-(4-trifluoromethylphenyl)but-3-en-1-one oxime (0.2 mmol, 61.0 mg), p-toluenesulfonyl hydrazide (1.0 mmol, 186.2 mg), n Et4NPF6(110 mg, 0.05 M), CH3CN:H2O =3:1 (8 mL), under the condition of C(+) / C(-) as electrode, constant current I =10 mA, magnetic stirring reaction at room temperature for 4~5 hours; after the reaction was completed, remove acetonitrile by distillation under reduced pressure, dilute with water, extract with ethyl acetate three times, combine the organic phase, concentrate under reduced pressure to obtain the crude product, the crude product is eluted with petroleum ether: ethyl acetate (10:1-5:1) as eluent, after column chromatography separation and purification, the target product is obtained as a white solid with a yield of 68%.

[0049] The nuclear magnetic data thereof are as follows:

[0050] 1 H NMR (300 MHz, CDCl3) δ 7.79 (d,J = 8.1 Hz, 2H), 7.68-7.63 (m, 4H),7.42-7.38 (m, 2H), 7.36 – 7.25 (m, 5H), 4.59 (d, J = 16.8 Hz, 1H), 3.88 (s,2H), 3.66 (d, J = 17.1Hz, 1H), 2.42 (s, 3H).

[0051] Compared with the prior synthesis method, the present application has the beneficial effects that:

[0052] 1) The present application uses cheap p-toluenesulfonyl hydrazide as a sulfonyl source, and denitrogenation under electrochemical conditions produces sulfonyl radicals without adding peroxide, which not only expands the cost economic benefits, but also successfully realizes the intramolecular oxidative sulfonylation of allyl oxime molecules, and the benefits are considerable.

[0053] 2) The synthesized sulfonyl isoxazole skeleton in the present application can be used as an organic synthesis intermediate, and can be widely used to provide effective fragments for new synthesis of drugs and materials.

[0054] 3) The present application uses electrochemical catalysis to convert clean and cheap electrical energy into chemical energy, efficiently constructs the sulfonylated isoxazole structure, improves the conversion efficiency, and greatly shortens the chemical reaction time.

[0055] The present application has a wide application in the fields of medicine, materials, organic synthesis and the like, in addition, the present application is simple to operate, green and clean, has mild reaction conditions, low cost, short reaction time, and has a broad application prospect.

[0056] The above examples are only preferred embodiments, and any method using the present application or any equivalent replacement, modification or the like belongs to the protection scope of the present application.

Claims

1. A green synthesis method of sulfone-based isoxazole derivatives, the main synthesis steps are as follows: 1) Green synthesis of p-toluenesulfonyl-substituted isoxazole derivatives β, γ-unsaturated ketoxime and p-toluenesulfonyl hydrazine are added to the reactor for reaction, the temperature is controlled at 25~30℃, C(+) / C(-) is selected as the electrode, I=10mA, 0.05M tetraethylammonium hexafluorophosphate is selected as the electrolyte, acetonitrile / water is selected as the solvent, the total volume of the solvent is 8mL, the reaction is carried out at room temperature for 4~5h, and the reaction equation is as follows: wherein R 1 = F,Cl, Br, CH3, OCH3, CF3; R 2 = aryl, alkyl; 2) After the reaction is completed, acetonitrile is removed by rotary evaporation, diluted with water, extracted with ethyl acetate, combined organic phase, dried, most of the solvent is removed by reduced pressure distillation, and the crude product is separated and purified by column chromatography with ethyl acetate and petroleum ether as eluent to obtain the target product.

2. A green process for the synthesis of sulfonylated isoxazole derivatives according to claim 1, characterized by: The molar ratio of β, γ-unsaturated ketoxime to p-toluenesulfonyl hydrazine is 1:5, and the volume ratio of acetonitrile to water is 3:

1.

3. A green process for the synthesis of sulfonylated isoxazole derivatives according to claim 1 or 2, characterized by: The volume ratio of petroleum ether to ethyl acetate is 10:1~5:1.

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