A process for the catalytic synthesis of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrol-2(5H)-one and derivatives thereof

Abstract

This invention discloses a catalytic synthesis method for 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2-( 5H A method for reacting 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compounds and diethyl phosphonate in an organic solvent under the presence of a base catalyst undergoes a Michael addition and a 1,4-P-Brook rearrangement tandem reaction. Sodium ethoxide is then added for hydrolysis to yield 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2,3-dione compounds and their derivatives. 5H )-ketone. This invention achieves 3-hydroxypyrrole-2-( )-ketone in one step through a series of reactions in a one-pot reaction mode. 5H Alkylation of ketones at the C(4) position: The catalyst used is mild and readily available, enabling highly efficient catalytic reactions with good yields of the target product. It is both economical and environmentally friendly, making it suitable for large-scale applications.

Description

A method for the catalytic synthesis of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one and its derivatives Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for the catalytic synthesis of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one and its derivatives. Background Technology

[0002] The 3-hydroxypyrrole-2(5H)-one structural unit is a class of nitrogen heterocyclic skeletons with important applications, widely found in natural products and drug molecules. Compounds built based on this core structure possess rich and unique biological activities, making them a research focus in the field of medicinal chemistry. Among them, 3-hydroxypyrrole-2(5H)-one derivatives functionalized at the C(4) position exhibit key pharmacological activities such as activating glucoskinase, blocking HIV replication, and inhibiting trypanosomiasis, showing outstanding application potential in the development of drugs for metabolic diseases, antiviral drugs, and antiparasitic drugs.

[0003] Among the publicly disclosed 3-hydroxypyrrole-2(5H)-one derivatives, the functionalization of the C(4) position is mainly acyl substitution, aryl substitution, and spirocyclization. Existing methods for achieving monoalkylation of the C(4) position of 3-hydroxypyrrole-2(5H)-one mainly rely on two technical routes: one is a multi-component, multi-step synthetic route using amines, substituted acrylates, and oxalate diesters as raw materials, which completes the C(4) alkylation through multiple steps. This method requires the use of stoichiometric acids and bases as promoters or relies on noble metal catalysts to participate in the reaction, resulting in cumbersome reaction steps and complex operation. The other is a hydrogenation reduction route using 4-methylene-3-hydroxypyrrole-2(5H)-one as a substrate, which achieves C(4) alkylation through hydrogenation catalyzed by noble metals such as Pt or reduction by metal hydrides. However, this route usually has a low reaction yield, and the use of noble metal catalysts increases costs. The above methods still have significant drawbacks. For example, the use of precious metal catalysts and the addition of metered acids and bases not only increase production costs but also lead to harsh reaction conditions, high requirements for equipment corrosion resistance, and easy environmental pollution. Furthermore, the multi-step reaction process is time-consuming and the yield of some pathways is not ideal, making it difficult to meet the needs of large-scale preparation.

[0004] Therefore, there is an urgent need to develop a method for the monoalkylation of 3-hydroxypyrrole-2(5H)-one at the C(4) position that is mild in reaction conditions, has inexpensive and readily available catalysts, and is highly efficient and simple, so as to promote the synthesis and application research of this type of active compound. Summary of the Invention

[0005] The purpose of this invention is to solve the technical problems of existing methods for the monoalkylation of 3-hydroxypyrrole-2(5H)-one at the C(4) position, such as cumbersome reaction steps, complex operation, the need for precious metal catalysts or metered acid / base, harsh reaction conditions, high production costs, high environmental pollution risks, and unsatisfactory yields. This invention provides a method for the catalytic synthesis of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one and its derivatives.

[0006] The above-mentioned objective of the present invention is achieved through the following technical solution:

[0007] The first aspect of this invention provides a method for the catalytic synthesis of diethyl 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate, comprising the following steps:

[0008] 1-Arylmethyl-4-arylmethylenepyrrole-2,3-dione compounds and diethyl phosphonate undergo a Michael addition and 1,4-P-Brook rearrangement tandem reaction in an organic solvent in the presence of a base catalyst to obtain the 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl ester.

[0009] The structural formula of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound is as follows: Among them, Ar 1 Selected from one of phenyl (Ph), halophenyl, methoxyphenyl, methylphenyl, naphthyl, 1,4-benzodioxane, thienyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, and hydroxyphenyl, Ar 2 Selected from one of phenyl (Ph), halophenyl, and methoxyphenyl;

[0010] The alkaline catalyst is selected from one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and cesium carbonate (Cs2CO3);

[0011] The structural formula of the diethyl 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate is as follows: .

[0012] In this invention, Ar 2 The choice of CH2 is based on the protecting group characteristics of the benzyl structure, which facilitates the removal of the aryl methyl group from the target compound to restore the NH structure on the pyrrole ring, and also facilitates further substitution reactions of NH with other functional groups. Furthermore, the electronic effects of the substituents on the aryl group have a relatively small impact on the reactivity. 1The selection of aryl groups is based on reactivity, substrate compatibility, and product derivatization: by changing the substituents on the aryl group, the reaction rate and selectivity can be controlled by electronic effects and steric hindrance; the introduction of active groups such as cyano, nitro, hydroxyl, and trifluoromethyl groups on the aryl group not only verifies the good tolerance of the reaction system to these groups under mild conditions, but also provides a feasible path for subsequent derivatization reactions of active groups; while the introduction of heteroaryl groups such as thiophene and 1,4-benzodioxane can enrich the structural diversity of the products and lay the structural foundation for the subsequent screening of the bioactivity of derivatives.

[0013] The reaction equation for the preparation of diethyl 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate in this invention is as follows:

[0014] .

[0015] Furthermore, the molar ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to diethyl phosphonate is 1.0:(1.1-1.5).

[0016] Furthermore, the base catalyst is preferably DBU and / or Cs₂CO₃, more preferably DBU. The organic base catalyst provided by this invention has good compatibility with the reaction system. DBU is a strong organic base with large steric hindrance, which can efficiently activate the α-hydrogen of diethyl phosphonate, while avoiding side reactions such as nucleophilic addition with the substrate.

[0017] Furthermore, the amount of the alkaline catalyst is 5-15 mol% of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound, preferably 5-10 mol%, more preferably 7-10 mol%.

[0018] Furthermore, the organic solvent is selected from one or more of n-hexane, toluene, mesitylene, tetrahydrofuran, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide.

[0019] Furthermore, the ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to the organic solvent is 0.2-0.4 mmol : 0.5-1.5 mL.

[0020] Furthermore, the temperature of the series reaction is 0-60 ℃, preferably 15-25 ℃.

[0021] Furthermore, the duration of the tandem reaction is 10-30 min, preferably 15-30 min.

[0022] Furthermore, after the tandem reaction is completed, a separation and purification step is included, wherein the separation and purification method includes column chromatography.

[0023] A second aspect of the present invention provides a method for the catalytic synthesis of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one, comprising the following steps:

[0024] 1-Arylmethyl-4-arylmethylenepyrrole-2,3-dione compounds and diethyl phosphonate undergo a Michael addition and 1,4-P-Brook rearrangement tandem reaction in an organic solvent in the presence of a base catalyst. Subsequently, sodium ethoxide (EtONa) is added for hydrolysis to obtain the 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one.

[0025] The structural formula of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound is as follows: Among them, Ar 1 Selected from one of phenyl (Ph), halophenyl, methoxyphenyl, methylphenyl, naphthyl, 1,4-benzodioxane, thienyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, and hydroxyphenyl, Ar 2 Selected from one of phenyl (Ph), halophenyl, and methoxyphenyl;

[0026] The alkaline catalyst is selected from one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and cesium carbonate (Cs2CO3);

[0027] The structural formula of the 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one is as follows: .

[0028] The reaction equation for the preparation of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one in this invention is as follows:

[0029] .

[0030] Furthermore, the molar ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to diethyl phosphonate is 1.0:(1.1-1.5).

[0031] Furthermore, the alkaline catalyst is preferably DBU and / or Cs2CO3, more preferably DBU.

[0032] Furthermore, the amount of the alkaline catalyst is 5-15 mol% of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound, preferably 5-10 mol%, more preferably 7-10 mol%.

[0033] Furthermore, the organic solvent is selected from one or more of n-hexane, toluene, mesitylene, tetrahydrofuran, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide.

[0034] Furthermore, the ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to the organic solvent is 0.2-0.4 mmol : 0.5-1.5 mL.

[0035] Furthermore, the temperature of the series reaction is 0-60 ℃, preferably 15-25 ℃.

[0036] Furthermore, the duration of the tandem reaction is 10-30 min, preferably 15-30 min.

[0037] Furthermore, after the tandem reaction is completed, a separation and purification step is included, wherein the separation and purification method includes column chromatography.

[0038] Furthermore, the molar ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to sodium ethoxide is 1:(8-12).

[0039] Furthermore, the hydrolysis reaction is carried out at a temperature of 15-25 °C.

[0040] Furthermore, the hydrolysis reaction takes 0.5-2 hours.

[0041] Furthermore, after the hydrolysis reaction is completed, the process also includes steps of quenching with saturated ammonium chloride solution, extraction with ethyl acetate, drying with anhydrous sodium sulfate, and separation by column chromatography.

[0042] The above-described technical solution of the present invention has the following beneficial effects:

[0043] 1. This invention employs a one-pot reaction mode, achieving the preparation of diethyl 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate and the C(4)-alkylation of 1-arylmethyl-3-hydroxypyrrole-2(5H)-one in one step through continuous Michael addition and 1,4-P-Brook rearrangement reactions. This reduces reaction steps and intermediate product separation and purification, thereby reducing energy, solvent consumption, and manual labor input, and improving reaction efficiency. Furthermore, this method exhibits good functional group tolerance and a wide range of substrate applicability, compatible with various aryl and heteroaryl substrates. It can efficiently prepare a series of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-ones and their derivatives, providing an efficient and feasible route for the diversified synthesis of such compounds, with broad application prospects.

[0044] 2. The catalytic synthesis method provided by this invention has excellent technical effects and industrial application value. The whole adopts a catalytic reaction system, and DBU is selected as the core organic base catalyst. This catalyst is mild and readily available. It can achieve efficient catalysis without relying on precious metal catalysts, which greatly reduces the cost of raw materials. At the same time, it avoids the product purity problem and environmental pollution risk caused by precious metal residues, and has both economic and environmental friendliness.

[0045] 3. This invention features mild reaction conditions, requiring no harsh reaction environments such as high temperature or high pressure. It can proceed smoothly at room temperature, with short reaction time and simple operation, eliminating the need for complex equipment and procedures. This provides a solid foundation for industrial-scale production, effectively improving production efficiency and reducing energy consumption. Furthermore, this method exhibits high catalytic efficiency and good yield of the target product. The 1,4-P-Brook rearrangement during the reaction process demonstrates high regioselectivity, effectively preventing side reactions and further ensuring product yield and purity. Detailed Implementation

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0047] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0048] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used are commercially available.

[0049] Example 1

[0050] A method for the DBU-catalyzed synthesis of diethyl 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate includes the following steps:

[0051]

[0052] DBU (0.03 mmol, 10 mol% of 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione (1a)), 0.33 mmol diethyl phosphonate (2), 0.30 mmol 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione (1a), and 1.0 mL n-hexane were mixed thoroughly and stirred at room temperature (20 °C) for 30 min. After the reaction, the reaction system was separated by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain a colorless oil. The structure was characterized by 1H NMR, 1C NMR, and high-resolution mass spectrometry, confirming that the colorless oil was 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl ester (3a). The NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.25 (m,5H), 7.24 – 7.22 (m, 1H), 7.19 – 7.17 (m, 4H), 4.54 (s, 2H), 4.41 – 4.31 (m,4H), 3.79 (d,J= 2.0 Hz, 2H), 3.53 (d,J= 3.6 Hz, 2H), 1.41 – 1.37 (m, 6H)ppm.

[0053] Example 2

[0054] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that hexane is replaced with toluene.

[0055] Example 3

[0056] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that n-hexane is replaced with mesitylene.

[0057] Example 4

[0058] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that n-hexane is replaced with tetrahydrofuran.

[0059] Example 5

[0060] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that n-hexane is replaced with 1,4-dioxane.

[0061] Example 6

[0062] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that n-hexane is replaced with acetonitrile.

[0063] Example 7

[0064] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that n-hexane is replaced with N,N-dimethylformamide.

[0065] Example 8

[0066] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that 1.0 mL of n-hexane is replaced with 0.5 mL of n-hexane.

[0067] Example 9

[0068] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that 1.0 mL of n-hexane is replaced with 1.5 mL of n-hexane.

[0069] Example 10

[0070] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that the reaction is carried out by stirring at 60 °C for 30 min.

[0071] Example 11

[0072] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that the reaction is stirred at 0 °C for 30 min.

[0073] Example 12

[0074] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that the reaction is stirred at room temperature (20 °C) for 20 min.

[0075] Example 13

[0076] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that the reaction is stirred at room temperature (20 °C) for 15 min.

[0077] Example 14

[0078] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by DBU catalysis is basically the same as that in Example 1, except that the reaction is stirred at room temperature (20 °C) for 10 min.

[0079] Example 15

[0080] A method for the DBU-catalyzed synthesis of diethyl 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate includes the following steps:

[0081] DBU (0.03 mmol, representing 10 mol% of 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a)), 0.45 mmol diethyl phosphonate (2), 0.30 mmol 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a), and 1.0 mL n-hexane were mixed thoroughly and stirred at room temperature (20 °C) for 15 min. After the reaction was complete, the reaction system was separated by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain a colorless oil. The structure was characterized by 1H NMR, 1C NMR, and high-resolution mass spectrometry, confirming that the colorless oil was 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl ester (3a).

[0082] Example 16

[0083] A method for the DBU-catalyzed synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate is essentially the same as in Example 15, except that DBU (0.03 mmol, amounting to 10 mol% of 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a)) is replaced with DBU (0.021 mmol, amounting to 7 mol% of 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a)).

[0084] Example 17

[0085] A method for the DBU-catalyzed synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate is essentially the same as in Example 15, except that DBU (0.03 mmol, amounting to 10 mol% of 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a)) is replaced with DBU (0.015 mmol, amounting to 5 mol% of 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a)).

[0086] Example 18

[0087] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl catalyzed by DABCO is basically the same as that in Example 15, except that DBU is replaced with 1,4-diazabicyclo[2.2.2]octane (DABCO, structural formula: ).

[0088] Example 19

[0089] A method for the DBN-catalyzed synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl ester is essentially the same as in Example 15, except that DBU is replaced with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN, structural formula: ).

[0090] Example 20

[0091] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate by Cs2CO3 catalysis is basically the same as that in Example 15, except that DBU is replaced with cesium carbonate (Cs2CO3).

[0092] Example 21

[0093] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 96%, and the NMR characterization data were as follows: 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.26 (m, 3H), 7.20 – 7.14 (m, 4H), 6.99 – 6.93 (m, 2H), 4.54 (s, 2H), 4.40 – 4.31 (m, 4H), 3.76(d,J= 2.4 Hz, 2H), 3.52 (d,J= 4.0 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0094] Example 22

[0095] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 91%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m, 2H), 7.27– 7.23 (m, 3H), 7.19 – 7.13 (m, 4H), 4.54 (s, 2H), 4.40 – 4.30 (m, 4H), 3.76(d,J= 2.4 Hz, 2H), 3.53 (d,J= 4.0 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0096] Example 23

[0097] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 92%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.38 (m, 2H),7.32 – 7.25 (m, 3H), 7.19 – 7.17 (m, 2H), 7.10 – 7.06 (m, 2H), 4.54 (s, 2H),4.42 – 4.28 (m, 4H), 3.74 (d,J= 2.4 Hz, 2H), 3.52 (d,J= 3.6 Hz, 2H), 1.41– 1.37 (m, 6H) ppm.

[0098] Example 24

[0099] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 89%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.34 – 7.25 (m, 5H), 7.23– 7.15 (m, 4H), 4.54 (s, 2H), 4.41 – 4.31 (m, 4H), 3.94 (d,J= 2.4 Hz, 2H), 3.57 (d,J= 4.0 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0100] Example 25

[0101] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 90%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.25 (m, 3H), 7.23– 7.18 (m, 5H), 7.10 – 7.08 (m, 1H), 4.55 (s, 2H), 4.40 – 4.31 (m, 4H), 3.77(d,J= 2.4 Hz, 2H), 3.55 (d,J= 3.6 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0102] Example 26

[0103] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 89%, and the NMR characterization data were as follows: 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.24 (m,3H), 7.19 – 7.16 (m, 2H), 7.12 – 7.08 (m, 2H), 6.83 – 6.79 (m, 2H), 4.53 (s,2H), 4.41 – 4.31 (m, 4H), 3.75 (s, 3H), 3.72 (d,J= 2.4 Hz, 2H), 3.53 (d,J= 3.6 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0104] Example 27

[0105] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 99%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.31 – 7.24 (m, 3H),7.18 – 7.16 (m, 2H), 7.09 – 7.05 (m, 4H), 4.52 (s, 2H), 4.40 – 4.31 (m, 4H),3.74 (d,J= 2.4 Hz, 2H), 3.53 (d,J= 4.0 Hz, 2H), 2.29 (s, 3H), 1.41 – 1.37(m, 6H) ppm.

[0106] Example 28

[0107] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 99%, and the NMR characterization data were as follows: 1H NMR (400 MHz, CDCl3) δ 7.96 (d,J= 8.4Hz, 1H), 7.84 – 7.82 (m, 1H), 7.74 (d,J= 8.0 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.37 – 7.34 (m, 1H), 7.29 – 7.19 (m, 4H), 7.09 – 7.07 (m, 2H), 4.45 – 4.36(m, 6H), 4.24 (d,J= 2.4 Hz, 2H), 3.38 (d,J= 4.0 Hz, 2H), 1.43 – 1.39 (m,6H) ppm.

[0108] Example 29

[0109] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 80%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.25 (m,3H), 7.20 – 7.18 (m, 2H), 6.76 (d,J= 8.4 Hz, 1H), 6.68 (d,J= 2.4 Hz, 1H), 6.64 (dd,J= 8.4, 2.4 Hz, 1H), 4.54 (s, 2H), 4.41 – 4.31 (m, 4H), 4.23 –4.18 (m, 4H), 3.66 (d,J= 2.0 Hz, 2H), 3.54 (d,J= 4.0 Hz, 2H), 1.41 – 1.37(m, 6H)ppm.

[0110] Example 30

[0111] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 88%, and the NMR characterization data were as follows: 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.24 (m, 4H), 7.20 –7.18 (m, 2H), 7.03 (d,J= 2.0 Hz, 1H), 6.94 – 6.93 (m, 1H), 4.55 (s, 2H),4.39 – 4.30 (m, 4H), 3.79 (d,J= 2.4 Hz, 2H), 3.57 (d,J= 4.0 Hz, 2H), 1.40– 1.36 (m, 6H) ppm.

[0112] Example 31

[0113] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 77%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.45 (d,J= 8.4Hz, 1H), 7.34 – 7.27 (m, 4H), 7.21 – 7.19 (m, 2H), 7.09 (dd,J= 8.4, 2.8 Hz,1H), 4.57 (s, 2H), 4.43 – 4.30 (m, 4H), 3.92 (d,J= 2.4 Hz, 2H), 3.59 (d,J= 3.6 Hz, 2H), 1.42 – 1.38 (m, 6H) ppm.

[0114] Example 32

[0115] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 62%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.60 – 7.58 (m, 1H),7.38 – 7.28 (m, 7H), 6.93 – 6.91 (m, 1H), 4.84 – 4.67 (m, 2H), 4.42 – 4.34(m, 2H), 4.30 – 4.17 (m, 4H), 3.98 – 3.87 (m, 2H), 1.37 – 1.30 (m, 6H) ppm.

[0116] Example 33

[0117] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with Replacing n-hexane with N,N-dimethylformamide yielded a separation yield of 52%, and the NMR characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ 7.60 – 7.57 (m, 2H), 7.35 – 7.28 (m, 5H), 7.20 – 7.17 (m, 2H), 4.55 (s, 2H), 4.40 – 4.30 (m, 4H), 3.85 (d,J= 2.0 Hz, 2H), 3.52 (d,J= 3.6Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0118] Example 34

[0119] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with Replacing hexane with tetrahydrofuran and stirring the reaction at room temperature (20 °C) for 1 h, the yield of the separated product was 35%. NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.13 (m, 2H), 7.41 – 7.39 (m, 2H), 7.31 – 7.27 (m, 3H), 7.20 – 7.18 (m, 2H), 4.56 (s, 2H), 4.41 – 4.31 (m, 4H), 3.90 (d,J= 2.4 Hz, 2H), 3.54 (d,J= 3.6 Hz, 2H), 1.41 – 1.38 (m, 6H) ppm.

[0120] Example 35

[0121] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with Replacing n-hexane with 1,4-dioxane resulted in a product separation yield of 42%, and the NMR characterization data are as follows:1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.36 – 7.31 (m, 3H), 7.08 (d,J= 8.4 Hz, 2H), 6.77(d,J= 8.8 Hz, 2H), 6.64 – 6.63 (m, 1H), 6.55 – 6.51 (m, 1H), 4.65 (d,J=15.2 Hz, 1H), 4.44 (d,J= 15.2Hz, 1H), 4.24 – 4.19 (m, 1H), 4.15 – 4.04 (m,6H), 4.02 – 3.98 (m, 1H), 1.22 – 1.18 (m, 6H) ppm.

[0122] Example 36

[0123] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 77%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.31 – 7.27 (m,3H), 7.26 – 7.22 (m, 2H), 7.20 – 7.17 (m, 2H), 7.14 – 7.11 (m, 2H), 4.50 (s,2H), 4.40 – 4.31 (m, 4H), 3.79 (d,J= 2.0 Hz, 2H), 3.52 (d,J= 3.6 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0124] Example 37

[0125] A DBU-catalyzed synthesis The method is basically the same as in Example 15, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 86%, and the NMR characterization data were as follows: 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.26(m, 2H), 7.23 – 7.17 (m, 3H), 7.12 – 7.10 (m, 2H), 6.84 – 6.80 (m, 2H), 4.47(s, 2H), 4.40 – 4.31 (m, 4H), 3.78 (d,J= 2.4 Hz, 2H), 3.76 (s, 3H), 3.51 (d,J= 4.0 Hz, 2H), 1.41 – 1.37 (m, 6H) ppm.

[0126] Example 38

[0127] A method for the DBU-catalyzed synthesis of 1,4-dibenzyl-3-hydroxypyrrole-2(5H)-one includes the following steps:

[0128]

[0129] DBU (0.03 mmol, 10 mol% of 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione (1a)), 0.45 mmol diethyl phosphonate (2), 0.30 mmol 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione (1a), and 1.0 mL n-hexane were mixed thoroughly and stirred at room temperature (20 °C) for 15 min. Then, 3.00 mmol sodium ethoxide was added to the reaction system, and the reaction was continued at room temperature (20 °C) for 1 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to obtain a white solid. The structure was characterized by 1H NMR, 1C NMR, and high-resolution mass spectrometry, confirming that the white solid was 1,4-dibenzyl-3-hydroxypyrrole-2(5H)-one (4a), with a separation yield of 80%. The NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ8.50 (br s, 1H), 7.32 – 7.29 (m, 1H), 7.28 – 7.23 (m, 4H), 7.20 – 7.16 (m,5H), 4.58 (s, 2H), 3.66 (s, 2H), 3.50 (s, 2H) ppm.

[0130] Example 39

[0131] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 80%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.89 (br s, 1H), 7.31 –7.24 (m, 3H), 7.20 – 7.18 (m, 2H), 7.14 – 7.11 (m, 2H), 6.96 – 6.90 (m, 2H), 4.59 (s, 2H), 3.62 (s, 2H), 3.49 (s, 2H) ppm.

[0132] Example 40

[0133] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 72%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.89 (br s, 1H), 7.32 –7.24 (m, 3H), 7.22 – 7.17 (m, 4H), 7.11 – 7.09 (m, 2H), 4.58 (s, 2H), 3.62(s, 2H), 3.49 (s, 2H) ppm.

[0134] Example 41

[0135] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 77%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.29 (br s, 1H), 7.40– 7.36 (m, 2H), 7.34 – 7.27 (m, 3H), 7.20 – 7.18 (m, 2H), 7.06 – 7.03 (m,2H), 4.59 (s, 2H), 3.61 (s, 2H), 3.49 (s, 2H) ppm.

[0136] Example 42

[0137] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 75%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.80 (br s, 1H), 7.32 –7.26 (m, 4H), 7.25 – 7.24 (m, 1H), 7.20 – 7.10 (m, 4H), 4.59 (s, 2H), 3.80(s, 2H), 3.55 (s, 2H) ppm.

[0138] Example 43

[0139] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 79%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 9.01 (br s, 1H), 7.32 –7.24 (m, 3H), 7.20 – 7.14 (m, 5H), 7.07 – 7.04 (m, 1H), 4.59 (s, 2H), 3.62(s, 2H), 3.50 (s, 2H) ppm.

[0140] Example 44

[0141] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 74%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.62 (br s, 1H),7.33 – 7.28 (m, 3H), 7.20 – 7.18 (m, 2H), 7.09 – 7.07 (m, 2H), 6.81 – 6.79(m, 2H), 4.58 (s, 2H), 3.77 (s, 3H), 3.60 (s, 2H), 3.50 (s, 2H) ppm.

[0142] Example 45

[0143] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 91%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.81 (br s, 1H), 7.30– 7.21 (m, 3H), 7.19 – 7.16 (m, 2H), 7.05 – 7.03 (m, 4H), 4.57 (s, 2H), 3.62(s, 2H), 3.49 (s, 2H), 2.28 (s, 3H) ppm.

[0144] Example 46

[0145] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 91%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.82 (br s, 1H),8.10 (d,J= 9.6 Hz, 1H), 7.83 – 7.80 (m, 1H), 7.72 (d,J= 8.0 Hz, 1H), 7.52– 7.43 (m, 2H), 7.36 – 7.32 (m, 1H), 7.28 – 7.21 (m, 4H), 7.13 – 7.11 (m,2H), 4.50 (s, 2H), 4.10 (s, 2H), 3.37 (s, 2H) ppm.

[0146] Example 47

[0147] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 76%, and the NMR characterization data were as follows: 1H NMR (400 MHz, CDCl3) δ 8.77 (br s, 1H), 7.32 –7.28 (m, 2H), 7.27 – 7.24 (m, 1H), 7.23 – 7.18 (m, 3H), 6.95 – 6.94 (m, 1H), 6.90 (dd,J= 4.8, 1.2 Hz, 1H), 4.59 (s, 2H), 3.67 (s, 2H), 3.53 (s, 2H) ppm.

[0148] Example 48

[0149] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 72%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 9.08 (br s, 1H), 7.41 (d,J= 8.4 Hz, 1H), 7.33 – 7.24 (m, 4H), 7.21 – 7.19 (m, 2H), 7.03 (dd,J= 8.4, 2.4 Hz, 1H), 4.61 (s, 2H), 3.77 (s, 2H), 3.57 (s, 2H) ppm.

[0150] Example 49

[0151] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 56%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.87 (br s, 1H), 7.51(d,J= 8.0 Hz, 2H), 7.33 – 7.27 (m, 5H), 7.21 – 7.19 (m, 2H), 4.60 (s, 2H), 3.71 (s, 2H), 3.52 (s, 2H) ppm.

[0152] Example 50

[0153] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 72%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 8.35 (br s, 1H),7.29 – 7.25 (m, 4H), 7.22 – 7.16 (m, 3H), 7.14 – 7.12 (m, 2H), 4.55 (s, 2H),3.67 (s, 2H), 3.50 (s, 2H) ppm.

[0154] Example 51

[0155] A DBU-catalyzed synthesis The method is basically the same as in Example 38, except that 1-benzyl-4-benzylmethylenepyrrolidine-2,3-dione (1a) is replaced with The separation yield of the obtained product was 78%, and the NMR characterization data were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.97 (br s,1H), 7.29 – 7.25 (m, 2H), 7.22 – 7.16 (m, 3H), 7.15 – 7.11 (m, 2H), 6.85 –6.82 (m, 2H), 4.52 (s, 2H), 3.78 (s, 3H), 3.66 (s, 2H), 3.48 (s, 2H) ppm.

[0156] Comparative Example 1

[0157] 0.45 mmol diethyl phosphonate (2), 0.30 mmol 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione (1a) and 1.0 mL n-hexane were mixed thoroughly and stirred at room temperature (20 °C) for 15 min.

[0158] Comparative Example 2

[0159] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate catalyzed by Et3N is basically the same as that in Example 15, except that DBU is replaced with triethylamine (Et3N).

[0160] Comparative Example 3

[0161] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate catalyzed by DIPEA is essentially the same as in Example 15, except that DBU is replaced with N,N-diisopropylethylamine (DIPEA, structural formula [insert structural formula here]). ).

[0162] Comparative Example 4

[0163] A method for the DMAP-catalyzed synthesis of diethyl 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate is essentially the same as in Example 15, except that DBU is replaced with 4-dimethylaminopyridine (DMAP, structural formula [insert structural formula here]). ).

[0164] Comparative Example 5

[0165] A method for synthesizing 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate catalyzed by Ph3P is basically the same as that in Example 15, except that DBU is replaced with triphenylphosphine (Ph3P).

[0166] Test Example 1

[0167] Examples 1-9 investigated the effects of solvent type and amount on the DBU-catalyzed synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate. The test results are shown in Table 1.

[0168] Table 1. Reaction parameters and product separation yields of Examples 1-9

[0169]

[0170] Table 1 shows that the type and amount of solvent have a significant impact on the yield of DBU-catalyzed synthesis of diethyl 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate. The nonpolar alkane solvent n-hexane is the optimal solvent for this reaction, achieving a high yield of 88% with 1.0 mL. Adjusting the amount to 0.5 mL increases the yield to 90%, and further increasing to 1.5 mL slightly decreases the yield but still maintains 87%, demonstrating good overall adaptability. Among other solvent types, the weakly polar toluene, tetrahydrofuran, and 1,4-dioxane yielded the next highest yields, while the strongly polar acetonitrile and N,N-dimethylformamide significantly reduced the yields. This indicates that the catalytic reaction proceeds more efficiently in nonpolar solvent systems, while strongly polar solvents significantly inhibit reaction efficiency.

[0171] Test Example 2

[0172] Examples 1 and 10-15 investigated the effects of feed ratio (molar ratio of 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione to diethyl phosphonate), temperature, and time on the DBU-catalyzed synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate. The test results are shown in Table 2.

[0173] Table 2. Reaction parameters and product separation yields for Examples 1 and 10-15.

[0174]

[0175] Table 2 shows that the feed ratio, reaction temperature, and reaction time all significantly affect the yield of DBU-catalyzed synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl diethyl phosphate. The yield at room temperature (20 °C) was significantly higher than at high temperatures (60 °C) and low temperatures (0 °C), with both high and low temperatures leading to a significant decrease in yield. Regarding reaction time, a relatively high yield of 87% was obtained at 20 °C after 15 min. Shortening the reaction time to 10 min resulted in a decrease in yield, while extending it to 20 min and 30 min did not significantly improve the yield, indicating that the reaction is fast at room temperature and can be completed quickly. Adjusting the molar ratio of 1-benzyl-4-benzylmethylpyrrolidine-2,3-dione to diethyl phosphonate from 1.0:1.1 to 1.0:1.5 and reacting at 20 °C for 15 min... Under the condition of min, the yield increased from 87% to 91%. An appropriate excess of diethyl phosphonate can improve the substrate conversion and achieve further optimization of the yield.

[0176] Test Example 3

[0177] Examples 15-20 and Comparative Examples 1-5 investigated the effects of catalyst type and dosage on the catalytic synthesis of 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate. The test results are shown in Table 3.

[0178] Table 3. Reaction parameters and product separation yields of Examples 15-20 and Comparative Examples 1-5

[0179]

[0180] Table 3 shows that the type and amount of catalyst have a crucial impact on the synthesis yield of diethyl 1,4-dibenzyl-2-oxo-2,5-dihydro-1H-pyrrole-3-yl phosphate. This reaction can only occur in the presence of a catalyst, and no target product is formed without a catalyst. In terms of catalyst type, DBU is the optimal catalyst for this reaction, achieving a yield of 91% at a dosage of 10 mol%, which is far superior to catalysts such as DABCO, DBN, Cs2CO3, Et3N, DIPEA, DMAP, and Ph3P at the same dosage. The amount of DBU also has a significant impact on the reaction. When the dosage is reduced from 10 mol% to 7 mol%, the yield drops to 82%, and when it is further reduced to 5 mol%, the yield drops sharply to 18%, indicating that insufficient catalyst dosage will lead to a significant decrease in catalytic activity and a significant reduction in substrate conversion.

[0181] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art should understand that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for the catalytic synthesis of diethyl 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate, characterized in that, The process includes the following steps: reacting a 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound and diethyl phosphonate in an organic solvent in the presence of a base catalyst via a Michael addition and a 1,4-P-Brook rearrangement tandem reaction to obtain the 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl ester; the structural formula of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound is as follows: Among them, Ar 1 Selected from one of phenyl, halophenyl, methoxyphenyl, methylphenyl, naphthyl, 1,4-benzodioxane, thienyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, and hydroxyphenyl, Ar 2 The base catalyst is selected from one of phenyl, halophenyl, and methoxyphenyl; the base catalyst is selected from one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, and cesium carbonate; the structural formula of the 1-arylmethyl-2-oxo-4-arylmethyl-2,5-dihydro-1H-pyrrole-3-yl phosphate diethyl ester is as follows: 。 2. The method according to claim 1, characterized in that, The molar ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to diethyl phosphonate is 1.0:(1.1-1.5).

3. The method according to claim 1, characterized in that, The amount of the base catalyst used is 5-15 mol of 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound.

4. The method according to claim 1, characterized in that, The organic solvent is selected from one or more of n-hexane, toluene, mesitylene, tetrahydrofuran, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide.

5. The method according to claim 1, characterized in that, The ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to the organic solvent is 0.2-0.4 mmol : 0.5-1.5 mL.

6. The method according to claim 1, characterized in that, The temperature of the series reaction is 0-60 ℃.

7. The method according to claim 1, characterized in that, The time for the series reaction is 10-30 min.

8. A method for the catalytic synthesis of 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one, characterized in that, The process includes the following steps: reacting a 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound and diethyl phosphonate in an organic solvent in the presence of a base catalyst via a Michael addition and a 1,4-P-Brook rearrangement tandem reaction, followed by hydrolysis with sodium ethoxide to obtain the 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one; the structural formula of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound is as follows: Among them, Ar 1 Selected from one of phenyl, halophenyl, methoxyphenyl, methylphenyl, naphthyl, 1,4-benzodioxane, thienyl, trifluoromethylphenyl, cyanophenyl, nitrophenyl, and hydroxyphenyl, Ar 2 The base catalyst is selected from one of phenyl, halophenyl, and methoxyphenyl; the base catalyst is selected from one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, and cesium carbonate; the structural formula of the 1-arylmethyl-4-arylmethyl-3-hydroxypyrrole-2(5H)-one is [insert structural formula here]. 。 9. The method according to claim 8, characterized in that, The molar ratio of the 1-arylmethyl-4-arylmethylenepyrrole-2,3-dione compound to sodium ethoxide is 1:(8-12).

10. The method according to claim 8, characterized in that, The hydrolysis reaction is carried out at a temperature of 15-25 ℃.

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