Preparation method of polysubstituted butene lactone compound

Abstract

The invention discloses a preparation method of a polysubstituted butene lactone compound, which comprises the following step: by taking cyclopropenone and amide as initial raw materials and trimethylphosphine as a catalyst, carrying out [3 + 2] cycloaddition reaction under the conditions of no water, no oxygen and room temperature to generate the polysubstituted butene lactone compound. The generated polysubstituted butene lactone compounds are new compounds, have certain potential pharmaceutical activity, and can be further converted into functionalized products. The reaction raw materials are easy to obtain, the reaction conditions are mild, the method has the characteristics of no metal and environmental protection, and the functional groups are diversified.

Description

TECHNICAL FIELD

[0001] The present application relates to a new class of phosphine-catalyzed annulation reaction, in particular to a synthetic method of a polysubstituted butenolide compound. BACKGROUND

[0002] γ-Butenolides are the basic framework of many naturally occurring bioactive compounds. For example, protoanemonin with antibacterial properties, Bovelide as a flavoring agent, Xerulin and Xerulinic acid that inhibit cholesterol biosynthesis, Aruncin B with antitumor effects, and thienyl butenolides with cytotoxicity (structures as follows). In addition, their potential as useful synthetic intermediates in the total synthesis of natural compounds has also been demonstrated. Therefore, in recent years, synthetic chemists have paid great attention to the development of synthetic strategies for this challenging scaffold.

[0003]

[0004] Five-membered ring esters are the basic skeleton of γ-butenolides and γ-butyrolactones, which are structural cores shared by numerous natural products. γ-Butenolides, γ-butyrolactones and their derivatives, especially in enantiomerically pure form, show an impressive range of biological activities that are important for the development of physiological and therapeutic drugs. For example, Strigol, which contains γ-butyrolactone in addition to chiral γ-butenolide, is believed to trigger the germination of parasitic plant seeds and inhibit the branching of plant shoots. Avenolide, a Streptomyces hormone containing a γ-butenolide core, has been shown to control the antibiotic production of Avenomycin (Chem. Rev. 2017, 117, 15, 10502-10566).

[0005]

[0006] Organophosphine-catalyzed reactions are a new type of organic catalytic reaction that can use simple raw materials (such as: allenes, unsaturated alkynes and unsaturated alkenes, etc.) to construct many structurally complex compounds. It uses the lone pair of electrons on the organic phosphine to attack the unsaturated alkenes, alkynes or allenes to generate active intermediates, which can further react with electrophilic reagents to generate the corresponding products and remove the catalyst organic phosphine. The reaction process does not require the use of metal catalysts, and the reaction conditions are simple and mild, and has been used for the synthesis of many drugs or active compounds.

[0007] SUMMARY

[0008] The present application aims to provide a synthesis method of the multi-substituted butenolide compound, which uses cyclopropenone and amide as starting materials, and synthesizes the multi-substituted butenolide compound with potential drug activity under the conditions of no water, no oxygen and room temperature.

[0009] The present application provides a preparation method of a multi-substituted butenolide compound, which comprises: using cyclopropenone 1 and amide 2 as starting materials, and using organic phosphorus as a catalyst to generate the multi-substituted butenolide compound of general formula 3 through [3+2] cycloaddition reaction under the protection of inert gas; The molecular structural formulae of cyclopropenone 1 and amide 2 are as follows:

[0010] The structural formula of the multi-substituted butenolide compound is as follows:

[0011] Among them, R 1 is a substituted or unsubstituted C6~C 10 aryl group or C5~C 10 heteroaryl group containing one or more of N, O or S, and the substituent on the C6~C 10 aryl group or C5~C 10 heteroaryl group is selected from one of C1~C4 alkyl, C1~C4 alkoxy, bromine, trifluoromethyl; R 2 , R 3 are independently selected from C1~C4 alkyl, or R 2 , R 3 and the N connected with R 2 and R 3 form a five-membered or six-membered heterocyclic group; X is an O or S atom.

[0012] As a preferred, R 1 is a phenyl group, a phenyl group with a substituent on the benzene ring or a 2-methylthiophene, and the substituent on the benzene ring is one of methyl, methoxy, tert-butyl, fluorine, chlorine, bromine and trifluoromethyl; R 2 , R 3 are independently selected from one of methyl, ethyl and n-butyl, or R 2 , R 3 and the C connected with R 2 and R 3 form a morpholinyl group.

[0013] The synthesis route is shown in the following reaction formula,

[0014] wherein: Further, the catalyst is trimethylphosphine.

[0015] Further, the molar ratio of cyclopropenone 1 to trimethylphosphine is 1:0.3.

[0016] Further, the molar ratio of cyclopropenone 1 to amide is 1:50.

[0017] Further, the reaction is carried out in a reaction solvent, which is a mixture of n-hexane and amide 2. The molar concentration of cyclopropenone 1 in the reaction solvent is 0.15 M.

[0018] Further, the reaction atmosphere is nitrogen; the reaction time is 0.5 h; and the reaction temperature is room temperature.

[0019] Further, after the reaction is completed, the following post-process is carried out: The reaction is quenched by adding saturated brine, the aqueous phase is extracted with ethyl acetate, the organic phase is collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components are removed under reduced pressure, and then the target product is separated by silica gel column chromatography.

[0020] The product obtained according to the above method is mostly a known compound.

[0021] Advantages: Compared with the prior art, the present application has the following advantages: 1) The synthesis of sub-cyclopropenone 1 and amide 2 has structural diversity, which can be used to synthesize different types and structures of polysubstituted butenolide compounds 3.

[0022] 2) The synthesis of sub-cyclopropenone 1 and amide 2 is easy to prepare, the raw materials are cheap and easy to obtain, the cost is low, and it is easy to industrialize.

[0023] 3) The synthesis of polysubstituted butenolide compounds 3 uses a relatively non-toxic phosphine reagent as a catalyst, and is environmentally friendly.

[0024] 4) The synthesis of polysubstituted butenolide compounds has good functional group tolerance and diversity, and therefore has wide application.

[0025] 5) The 5-amino group in the backbone structure of polysubstituted butenolide compounds 3 is a functional group, and this structure can be used as an intermediate for drug and chemical product structures.

[0026] 6) This synthesis method can reach a gram-scale, and has great implementation value and social and economic benefits.

[0027] 7) The 2-furanone ring structure obtained contains potential drug activity, the operation is simple, and the yield of the target product is good. DETAILED DESCRIPTION

[0028] The application will be described in detail below with reference to specific embodiments.

[0029] The starting material cyclopropenone 1 in the following examples can be prepared according to the prior art, for example: Synthesis of cyclopropenone 1: Phenylacetic acid A was reacted with a condensing agent in THF at room temperature to form diaryl ketone B. Diaryl ketone B was reacted with bromine in acetic acid to form bromo diaryl ketone C. Finally, bromo diaryl ketone C was reacted with triethylamine in dichloromethane to form cyclopropenone 1 (Reaction Scheme 1).

[0030]

[0031] The specific process is as follows: substituted phenylacetic acid (10 mmol), DCC (10.5 mmol) and DMAP (3.0 mmol) were weighed into a reaction bottle, THF (15 mL) was added under an oxygen-free environment, and the reaction was carried out at room temperature for 1 h. After the reaction was filtered under reduced pressure, the diaryl ketone was purified by silica gel column chromatography. The diaryl ketone (2 mmol) was dissolved in acetic acid (4 mL), and a bromine solution (4.1 mmol) was added dropwise under an oxygen-free and room temperature condition. After the reaction was carried out at room temperature for 3 h, the reaction was poured into water, and the product was collected by filtration. The crude product (dibromo ketone) was air-dried for several hours, then dissolved in dichloromethane (4 mL), and the solution was added to a stirring solution of triethylamine (5 mmol). Dichloromethane (2 mL) was added, and stirring was carried out at room temperature for 1 h. The reaction mixture was extracted with DCM (3 x 50 mL), then washed with 1M hydrochloric acid (50 mL) and brine, dried over anhydrous magnesium sulfate, and the volatile components were removed under reduced pressure. The target product 1 was obtained by silica gel column chromatography. The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0032] R 1 is an aryl group; R 2 , R 3 is one of methyl, ethyl, n-butyl, and morpholine; X is an O or S atom; wherein the aryl group is a phenyl group, a phenyl group having a substituent on the benzene ring, or 2-methylthiophene, and the substituent on the benzene ring is one of methyl, methoxy, tert-butyl, fluorine, chlorine, bromine, and trifluoromethyl.

[0033] The application will be described in detail below with reference to specific embodiments, but the scope of the application is not limited to the following. Example 1

[0034]

[0035] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone 1a (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3a (27.3 mg, yield 65%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0036] Example 2

[0037] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone 1a (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3a (27.3 mg, yield 65%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectroscopy.

[0038] Example 3

[0039] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, 4-tert-butyl-diaromatic cyclopropenone 1d (0.15 mmol) was weighed in the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3d (29.2 mg, yield 50%) was obtained in the form of a white solid by silica gel column chromatography separation (eluent: petroleum ether / ethyl acetate, v / v = 20:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0040] Example 4

[0041] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, 4-tert-butyl-diaromatic cyclopropenone 1d (0.15 mmol) was weighed in the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3d (29.2 mg, yield 50%) was obtained in the form of a white solid by silica gel column chromatography separation (eluent: petroleum ether / ethyl acetate, v / v = 20:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0042] Example 5

[0043] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, 4-chloro-diaryl cyclopropenone 1f (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3f (29.3 mg, yield 56%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0044] Example 6

[0045] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, 4-chloro-diaryl cyclopropenone 1f (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3f (29.3 mg, yield 56%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0046] Example 7

[0047] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, 4-methoxy-diaromatic cyclopropenone 1h (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3h (21.5 mg, yield 31%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 2:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0048] Example 8

[0049] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, 4-methoxy-diaromatic cyclopropenone 1h (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3h (21.5 mg, yield 31%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 2:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0050] Example 9

[0051] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, 4-trifluoromethyl-diaromatic cyclopropenone 1i (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, the reaction was quenched by adding saturated brine, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3i (48.1 mg, yield 77%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0052] Example 10

[0053] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, 2-methyl-thiophene cyclopropenone 1j (0.15 mmol) was weighed into the reaction tube, 0.42 ml of n-hexane and DMF 2a (0.58 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, the reaction was quenched by adding saturated brine, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3j (36.7 mg, yield 77%) was obtained in the form of a yellow solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0054] Example 11

[0055] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, diaromatic cyclopropenone la (0.15 mmol) was weighed into the reaction tube, 0.16 ml of n-hexane and N,N-diethylformamide 2c (0.84 ml, 7.5 mmol) were sequentially added, and finally trimethylphosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, the reaction was quenched by adding saturated brine, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3l (37.6 mg, yield 82%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 20:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0056] Example 12

[0057] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, diaromatic cyclopropenone la (0.15 mmol) was weighed into the reaction tube, 0.16 ml of n-hexane and N,N-diethylformamide 2c (0.84 ml, 7.5 mmol) were sequentially added, and finally trimethylphosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, the reaction was quenched by adding saturated brine, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3l (37.6 mg, yield 82%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 20:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0058] Example 13

[0059] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone la (0.15 mmol) was weighed into the reaction tube, N,N-di-n-butylformamide 2d (1 ml, 7.5 mmol) was added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3m (45.7 mg, yield 42%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 20:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0060] Example 14

[0061] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the tube was filled with nitrogen, vacuumed, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone la (0.15 mmol) was weighed into the reaction tube, N,N-di-n-butylformamide 2d (1 ml, 7.5 mmol) was added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3m (45.7 mg, yield 42%) was obtained in the form of a white solid by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, v / v = 20:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0062] Example 15

[0063] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone 1a (0.15 mmol) was weighed into the reaction tube, 0.36 ml of n-hexane and N,N-dimethylthiocarbamide 2f (0.64 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3o (26.0 mg, yield 59%) was obtained in the form of a yellow solid by silica gel column chromatography separation (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0064] Comparative Example 1:

[0065] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone 1a (0.15 mmol) was weighed into the reaction tube, 0.36 ml of n-hexane and N,N-dimethylthiocarbamide 2f (0.64 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3o (26.0 mg, yield 59%) was obtained in the form of a yellow solid by silica gel column chromatography separation (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0066] Comparative Example 2:

[0067] In a reaction tube, 3A MS was weighed, a rotor was added, and after blowing with a hot air gun for 3 min, the reaction tube was filled with nitrogen, vacuumed three times, and the above operation was repeated three times. After the reaction tube was cooled, diaryl cyclopropenone 1a (0.15 mmol) was weighed into the reaction tube, 0.36 ml of n-hexane and N,N-dimethylthiocarbamide 2f (0.64 ml, 7.5 mmol) were sequentially added, and finally trimethyl phosphine (0.045 mmol) was added. The reaction was carried out under anhydrous and anaerobic conditions at room temperature for 30 min. After the reaction was completed, saturated brine was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure. Then, the target product 3o (26.0 mg, yield 59%) was obtained in the form of a yellow solid by silica gel column chromatography separation (eluent: petroleum ether / ethyl acetate, v / v = 15:1). The target product was confirmed by nuclear magnetic resonance spectrum.

[0068] Typical compound characterization data are as follows: CAS: 2247306-66-5 5-(dimethylamino)-3,4-diphenylfuran-2(5H)-one (3a), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.28 – 7.43 (m, 10H), 6.06 (s, 1H), 2.46 (s, 6H). CAS: 2247306-67-6 5-(dimethylamino)-3,4-diphenylfuran-2(5H)-one (3a), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 4H), 7.14 (dd, J = 16.4, 7.6 Hz, 4H), 6.01 (s, 1H), 2.44 (s, 6H), 2.36 (s, 3H), 2.34 (s, 3H). CAS: 2652031-78-0 5-(dimethylamino)-3,4-diphenylfuran-2(5H)-one (3a), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.22 – 7.12 (m, 7H), 6.04 (s, 1H), 2.45 (s, 6H), 2.32 (s, 3H), 2.28 (s, 3H). 3,4-Di(4-(tert-butyl)phenyl)-5-(dimethylamino)furan-2(5H)-one (3d), white solid. 1 HNMR (400 MHz, CDCl3) δ 7.43 – 7.30 (m, 8H), 6.01 (s, 1H), 2.46 (s, 6H), 1.33 (s, 9H), 1.31 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 172.13, 153.58, 153.41, 151.93, 129.18, 128.78, 128.60, 128.21, 127.52, 125.67, 125.63, 98.01, 38.95, 35.00, 34.86, 31.39, 31.25. CAS: 2247306-68-7 5-(dimethylamino)-3,4-diphenylfuran-2(5H)-one (3a), white solid. 1H NMR (400 MHz, CDC13) δ 7.32 - 7.47 (m, 4H), 6.94 - 7.10 (m, 4H), 5.98 (d, J = 12.8 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H). CAS: 2247306-69-8 5-(dimethylamino)-3,4-di(4-chlorophenyl)-2(5H)-furanone (3f), white solid. 1 H NMR (400 MHz, CDC13) δ 7.39 - 7.28 (m, 8H), 6.00 (s, 1H), 2.44 (s, 6H). CAS: 2247306-70-1 5-(dimethylamino)-3,4-di(4-bromophenyl)-2(5H)-furanone (3g), white solid. 1 H NMR (400 MHz, CDC13) δ 7.42 -7.45 (m, 4H), 7.28 (t, J = 7.4 Hz, 4H), 6.00 (s, 1H), 2.44 (s, 6H). CAS: 2251859-36-4 5-(dimethylamino)-3,4-di(4-methoxyphenyl)furan-2(5H)-one (3h), white solid. 1 H NMR (400 MHz, CDC13) δ 7.39 (dd, J = 16.4, 8.8 Hz, 4H), 6.89 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.97 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.44 (s, 6H). 5-(dimethylamino)-3,4-di(4-(trifluoromethyl)phenyl)furan-2(5H)-one (3i), white solid. 1 HNMR (400 MHz, CDC13) δ 7.39 (dd, J = 16.4, 8.8 Hz, 4H), 6.89 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.97 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.44 (s, 6H). CAS: 2247306-73-4 5-(dimethylamino)-3,4-di(5-methylthiophen-2-yl)-2(5H)-furanone (3j), yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 4.0 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.74 (dd, J = 14.0, 3.6 Hz, 2H), 5.80 (s, 1H), 2.52 (s, 3H),2.48 (s, 9H). CAS: 2247306-75-6 5-(ethyl(methyl)amino)-3,4-diphenyl-2(5H)-furanone (3k), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.43 – 7.28 (m, 10H), 6.15 (s, 1H), 2.94 – 2.78(m, 2H), 2.35 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H). CAS: 193359-63-6 5-(diethylamino)-3,4-diphenyl-2(5H)-furanone (3l), white solid. 1 HNMR (400 MHz, CDCl3) δ 7.45 – 7.27 (m, 10H), 6.25 (s, 1H), 2.72 – 2.90 (m,4H), 1.02 (t, J = 7.2 Hz, 6H). CAS: 2247306-74-5 5-(dibutylamino)-3,4-diphenyl-2(5H)-furanone (3m), white solid. 1 HNMR (400 MHz, CDCl3) δ 7.45 – 7.27 (m, 10H), 6.26 (s, 1H), 2.69 (s, 4H), 1.39(s, 4H), 1.14 (s, 4H), 0.82 (t, J = 7.2 Hz, 6H). CAS: 2247306-78-9 5-morpholino-3,4-diphenylfuran-2(5H)-one (3n), white solid. 1 HNMR (400 MHz, CDCl3) δ 7.46– 7.30 (m, 10H), 5.99 (s, 1H), 3.70 – 3.55 (m,4H), 2.84 (t, J = 4.8 Hz, 4H). CAS: 2251859-39-7 6-(dimethylamino)-3,4-diphenylthiophene-2(5H)-one (3o), yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.24– 7.29 (m, 6H), 7.16– 7.20 (m, 2H), 7.15 –7.10 (m, 2H), 6.22 (s, 1H), 2.29 (s, 6H).

[0069] The above compounds (3a), (3b), (3c), (3e), (3f), (3g), (3h), (3j), (3k), (3l), (3m), (3n), (3o) are known compounds.

Claims

1. A method for preparing polysubstituted butenolactone compounds, characterized in that, include: Starting with cyclopropenone 1 and amide 2, and using organophosphorus as a catalyst, a polysubstituted butene lactone compound of general formula 3 was generated through a [3+2] cycloaddition reaction under inert gas protection. The molecular structural formulas of cyclopropenone 1 and amide 2 are as follows: ； The structural formulas of polysubstituted butene lactones are as follows: ； Among them, R 1 C6~C, whether substituted or not 10 Aryl or C5~C 10 Heteroaryl groups, wherein the heteroaryl group contains one or more of N, O, or S, and the C6~C 10 Aryl or C5~C 10 The substituent on the heteroaryl group is selected from one of C1-C4 alkyl, C1-C4 alkoxy, bromine, and trifluoromethyl. R 2 R 3 Independently selected from C1-C4 alkyl groups, or R 2 R 3 With connection R 2 and R 3 Together with N, they form five- or six-membered heterocyclic groups; X is an O or S atom.

2. The method for preparing polysubstituted butenolactone compounds according to claim 1, characterized in that: R 1 It is a phenyl group, a phenyl group with a substituent on the benzene ring, or a 2-methylthiophene group. The substituent on the phenyl group is one of methyl, methoxy, tert-butyl, fluorine, chlorine, bromine, or trifluoromethyl. R 2 R 3 Independently selected from one of methyl, ethyl, n-butyl, or R 2 R 3 With connection R 2 and R 3 The N atoms together form a morpholino group; X is an O or S atom.

3. The method for preparing polysubstituted butenolactone compounds according to claim 1, characterized in that: The organophosphine mentioned is trimethylphosphine, triphenylphosphine, or tributylphosphine.

4. The method for preparing polysubstituted butenolactone compounds according to claim 1, characterized in that: The molar ratio of cyclopropenone 1 to organophosphorus is 1:0.2~0.4; The molar ratio of cyclopropenone 1 to amide is 1:45~55.

5. The method for preparing polysubstituted butenolactone compounds according to claim 4, characterized in that: The molar ratio of cyclopropenone 1 to organophosphorus is 1:0.

3.

6. The method for preparing polysubstituted butenolactone compounds according to claim 4, characterized in that: The molar ratio of cyclopropenone 1 to amide 2 is 1:

50.

7. The method for preparing polysubstituted butene lactone compounds according to claim 1, characterized in that: The reaction solvent is a mixture of n-hexane and amide 2; the molar concentration of cyclopropenone 1 in the reaction solvent is 0.1~0.2 M.

8. The method for preparing polysubstituted butene lactone compounds according to claim 7, characterized in that: The molar concentration of cyclopropenone 1 in the reaction solvent is 0.15 M.

9. The method for preparing polysubstituted butenolactone compounds according to claim 1, characterized in that: The reaction time is 0.5~5h; the reaction temperature is 20~30℃.

10. The method for preparing polysubstituted butene lactone compounds according to claim 9, characterized in that: The reaction atmosphere is nitrogen; molecular sieves are also added to the reaction system.

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