Synthesis method of beta-carbonyl ester compound

Abstract

The invention discloses a beta-carbonyl ester compound synthesis method, which comprises the following steps: mixing carboxylic acid, alkenyl ester, a catalyst, a ligand, silane, a reducing agent and an organic solvent, stirring and reacting at 20-120 DEG C for 4-24 hours to obtain a reaction solution, and separating and purifying the reaction solution through a silica gel column to obtain the beta-carbonyl ester compound. The method has the advantages of high yield, high regioselectivity, mild reaction conditions, simple and easily available reaction raw materials, low price, stable character, no pungent smell and environmental protection.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing beta-carbonyl ester compounds. Background Art

[0002] β-Carboxyl ester compounds are an important structural unit widely found in natural products and active drug molecules, and are an important chemical raw material intermediate. Alkenyl esters and carboxylic acids are a class of widely available basic chemical raw materials, among which the hydroacylation reaction of olefins has developed into an important method for the industrial production of fine chemicals such as aldehydes and alcohols. The palladium, silver, and copper-catalyzed decarboxylation coupling strategy has made aromatic carboxylic acids a cheap source of aromatic groups, while carboxylic acids as acyl sources are still rarely reported in the literature. Previously, most of the aromatic carboxylic acids were pre-activated and converted into the corresponding acyl chlorides, esters, anhydrides, amides and other intermediates, which were then used in various metal-catalyzed coupling reactions to synthesize acyl compounds. In 2006, Chul-Ho Jun's group reported the rhodium-catalyzed hydroacylation of alkenyl esters, in which more active aromatic aldehydes were used as carbonyl sources (Eur. J. Org. Chem. 2006, 11, 2504-2507); in 2018, Yang Hua's group reported the photocatalytic hydroacylation of alkenyl esters to synthesize 1,4-dicarbonyl compounds, in which more active aromatic chlorides were used as carbonyl sources (Chem Asian J. 2018, 13, 271-274); in 2021, Zhu Shaolin's group reported the nickel-catalyzed three-component asymmetric reductive hydroacylation of simple olefins, which used ethyl chloroformate as a special carbonyl source (J. Am. Chem. Soc. 2021, 143, 14089); the hydroacylation reactions reported by previous researchers are currently limited to special more active carbonyl sources. Currently, the dehydroxylation of unactivated carboxylic acids to provide carbonyl sources is only reported as a free radical process. The present invention provides a nickel-catalyzed hydrogenation acylation reaction of α, β-unsaturated olefins, wherein unactivated carboxylic acid is used as an acyl source, and an efficient and inexpensive catalytic system is developed to achieve the preparation of acyl ester derivatives, which has important research significance and potential application value. Summary of the invention

[0003] In view of the above problems, the object of the present invention is to provide a method for synthesizing β-carbonyl ester compounds.

[0004] In order to achieve the above objectives, the following technical solutions are proposed:

[0005] The present invention provides a method for synthesizing a β-carbonyl ester compound. The specific method is as follows: in a nitrogen atmosphere, a carboxylic acid as shown in formula (I), an alkenyl ester as shown in formula (II), a catalyst, a ligand, a silane, a reducing agent, and an organic solvent are mixed, and the mixture is stirred and reacted at 20° C. to 120° C. for 4 to 24 hours (preferably at 60° C. for 12 hours) to obtain a reaction solution, and the reaction solution is separated and purified by silica gel column chromatography to obtain a β-carbonyl ester compound as shown in formula (III).

[0006]

[0007] Wherein, R in formula (I) or formula (III) 1 is selected from phenyl, p-methoxybenzene, p-phenylbenzene, p-cyanobenzene, hexyl, deoxynyl, chloropropyl, cyclohexanemethyl, benzyl, cyclopentyl, naphthyl or furan, and R in formula (II) or formula (III) is 2 is selected from hydrogen, methyl or phenyl, R 3 is selected from ethyl or benzyl, and the catalyst is NiBr 2 、NiCl 2 , or NiBr 2 (DME), the ligand is triphenylphosphine, 2,2'-bipyridine, 1,10-phenanthroline or α,α,α-terpyridine, and the molar ratio of the carboxylic acid compound represented by formula (I) to the alkenyl ester represented by formula (II), the catalyst, the ligand, the silane, and the reducing agent is 1:1-2:0.02-0.1:0.05-0.2:1-5:1-5.

[0008] Furthermore, the silane is diphenylsilane, diethoxysilane or triethoxysilane (preferably triethoxysilane).

[0009] Furthermore, the reducing agent is zinc, magnesium or manganese (preferably zinc).

[0010] Further, the organic solvent is dioxane, anisole or tetrahydrofuran (preferably tetrahydrofuran).

[0011] Furthermore, the volume of the organic solvent is 20.5 to 123.0 ml / g (preferably 41 ml / g) based on the mass of the carboxylic acid represented by formula (I).

[0012] Furthermore, the molar ratio of the carboxylic acid compound represented by formula (I) to the alkenyl ester represented by formula (II), the catalyst, the ligand, the silane, and the reducing agent is 1:1.2:0.05:0.1:3:3.

[0013] Further, the catalyst is NiBr 2 (DME).

[0014] Furthermore, the ligand is α,α,α-terpyridine.

[0015] Furthermore, the specific operation process of the silica gel column chromatography separation and purification is: concentrating the reaction solution, performing column chromatography, eluting with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 30 to 15:1 as an eluent, collecting the eluate containing the target compound, concentrating, distilling and drying.

[0016] Furthermore, the β-carbonyl ester compound is one of the following:

[0017]

[0018] The beneficial effects of the present invention are: the present invention has high yield, high regional selectivity, mild reaction conditions, simple and easy to obtain reaction raw materials, low price, stable properties, no irritating odor, and environmental protection. DETAILED DESCRIPTION

[0019] In conjunction with the following specific examples, the present invention is further described in detail, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products, and the product purity is identified by nuclear magnetic resonance.

[0020] Example 1

[0021] Synthesis of compound 3a:

[0022]

[0023] Under nitrogen atmosphere, benzoic acid 1a (0.2 mmol, 24.4 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH(0.6mmol,98.4mg,3.0equiv),Zinc(0.6mmol,39.0mg,3.0equiv),NiBr 2(DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.70mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3a (yield 84%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ7.82(d,J=7.7Hz,2H),7.50(t,J=7.2Hz,1H),7.39(t,J=7.8Hz,2H),4.09(q,J=7.1Hz,2H),1.53(s,6H),1.02(t,J=7.1Hz,3H).

[0024] Embodiment 2:

[0025] NiBr 2 (DME) to NiBr 2 The other operations were the same as in Example 1 to obtain product 3a (26.8 mg) with a yield of 61%.

[0026] Embodiment 3:

[0027] NiBr 2 (DME) to NiCl 2 The other operations were the same as in Example 1 to obtain product 3a (26.4 mg) with a yield of 60%.

[0028] Embodiment 4:

[0029] NiBr 2 The amount of (DME) was changed to (6.2 mg, 0.02 mmol), and the other operations were the same as in Example 1 to obtain product 3a (36.5 mg) with a yield of 83%.

[0030] Embodiment 5:

[0031] NiBr 2 The amount of (DME) was changed to (1.8 mg, 0.005 mmol), and the other operations were the same as in Example 1 to obtain product 3a (36.5 mg) with a yield of 26%.

[0032] Embodiment 6:

[0033] The amount of triethoxysilane was changed to (32.8 mg, 0.2 mmol), and the other operations were the same as in Example 1 to obtain product 3a (2.2 mg) with a yield of 5%.

[0034] Embodiment 7:

[0035] The amount of triethoxysilane was changed to (164 mg, 1.0 mmol), and the other operations were the same as in Example 1 to obtain product 3a (32.6 mg) with a yield of 74%.

[0036] Embodiment 8:

[0037] Triethoxysilane was replaced with diphenylsilane, and other operations were carried out in the same manner as in Example 1 to obtain product 3a (22.9 mg) with a yield of 52%.

[0038] Embodiment 9:

[0039] Triethoxysilane was replaced with diethoxysilane, and other operations were carried out in the same manner as in Example 1 to obtain product 3a (22.4 mg) with a yield of 51%.

[0040] Embodiment 10:

[0041] The amount of zinc was changed to (13 mg, 0.2 mmol), and the other operations were the same as in Example 1 to obtain product 3a (6.6 mg) with a yield of 15%.

[0042] Embodiment 11:

[0043] The amount of zinc was changed to (65 mg, 1.0 mmol), and the other operations were the same as in Example 1 to obtain product 3a (26.4 mg) with a yield of 60%.

[0044] Embodiment 12:

[0045] Zinc was replaced with magnesium, and other operations were carried out in the same manner as in Example 1 to obtain product 3a (13.2 mg) with a yield of 30%.

[0046] Embodiment 13:

[0047] Zinc was replaced with manganese, and other operations were carried out in the same manner as in Example 1 to obtain product 3a (14.1 mg) with a yield of 32%.

[0048] Embodiment 14:

[0049] The solvent tetrahydrofuran was changed to anisole, and the other operations were the same as in Example 1 to obtain the product 3a (17.6 mg) with a yield of 40%.

[0050] Embodiment 15:

[0051] The solvent tetrahydrofuran was replaced with dioxane, and other operations were carried out as in Example 1 to obtain the product 3a (13.2 mg) with a yield of 30%.

[0052] Embodiment 16:

[0053] The solvent tetrahydrofuran was changed from 41 ml / g to 20.5 ml / g based on the mass of benzoic acid. Other operations were carried out in the same manner as in Example 1 to obtain product 3a (26.4 mg) with a yield of 60%.

[0054] Embodiment 17:

[0055] The solvent tetrahydrofuran was changed from 41 ml / g to 123.0 ml / g based on the mass of benzoic acid. Other operations were carried out in the same manner as in Example 1 to obtain product 3a (24.6 mg) with a yield of 56%.

[0056] Embodiment 18:

[0057] The temperature was lowered to 20°C, and other operations were carried out as in Example 1 to obtain product 3a (24.6 mg) with a yield of 56%.

[0058] Embodiment 19:

[0059] The temperature was raised to 120°C and other operations were carried out as in Example 1 to obtain product 3a (32.1 mg) with a yield of 73%.

[0060] Embodiment 20:

[0061] The reaction time was shortened to 4 hours, and other operations were carried out the same as in Example 1 to obtain product 3a (22.0 mg) with a yield of 50%.

[0062] Embodiment 21:

[0063] The reaction time was extended to 24 hours, and other operations were carried out the same as in Example 1 to obtain product 3a (37.4 mg) with a yield of 85%.

[0064] Embodiment 22:

[0065] The amount of α,α,α-terpyridine was changed to (2.9 mg, 0.01 mmol), and the other operations were the same as in Example 1 to obtain product 3a (26.8 mg) with a yield of 61%.

[0066] Embodiment 23:

[0067] The amount of α,α,α-terpyridine was changed to (9.4 mg, 0.04 mmol), and the other operations were the same as Example 1 to obtain product 3a (36.1 mg) with a yield of 82%.

[0068] Embodiment 24:

[0069] The α,α,α-terpyridine was replaced with triphenylphosphine, and the other operations were the same as in Example 1 to obtain the product 3a (6.6 mg) with a yield of 15%.

[0070] Embodiment 25:

[0071] The α,α,α-terpyridine was replaced with 2,2'-bipyridine, and the other operations were the same as in Example 1 to obtain the product 3a (28.6 g) with a yield of 65%.

[0072] Embodiment 26:

[0073] The α,α,α-terpyridine was replaced with 1,10-phenanthroline, and the other operations were the same as in Example 1 to obtain the product 3a (17.6 g) with a yield of 40%.

[0074] Embodiment 27:

[0075] The amount of ethyl methacrylate in Example 1 was changed to (0.2 mmol, 22.8 mg, 1 equiv), and the other operations were the same as in Example 1 to obtain product 3a (26.8 g) with a yield of 61%.

[0076] Embodiment 28:

[0077] The amount of ethyl methacrylate in Example 1 was changed to (0.4 mmol, 45.6 mg, 2 equiv), and the other operations were the same as in Example 1 to obtain product 3a (33.0 g) with a yield of 75%.

[0078] Embodiment 29:

[0079] Synthesis of compound 3b:

[0080]

[0081] Under nitrogen atmosphere, p-methoxybenzoic acid 1b (0.2 mmol, 30.4 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2(DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). The mixture of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3b (yield 68%). (Eluent polarity: petroleum ether / ethyl acetate 30:1). 1 HNMR (400MHz, CDCl 3 )δ7.83(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),4.10(q,J=7.0Hz,2H),3.84(s,3H),1.51(s,6H),1.06(t,J=7.1Hz,3H).

[0082] Embodiment 30:

[0083] Synthesis of compound 3c:

[0084]

[0085] Under nitrogen atmosphere, p-methoxybenzoic acid 1c (0.2 mmol, 30.4 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3c (yield 65%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 HNMR (400MHz, CDCl 3)δ7.93(d,J=8.5Hz,2H),7.67–7.60(m,4H),7.47(t,J=7.1Hz,2H),7.39(t ,J=7.3Hz,1H),4.15(q,J=7.1Hz,2H),1.58(s,6H),1.08(t,J=7.1Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ197.32(s),175.12(s),145.32(s),139.72(s),133.85(s),129.31(s),128.98( s),128.28(s),127.23(s),127.06(s),61.44(s),53.32(s),23.97(s),13.83(s).

[0086] Embodiment 31:

[0087] Synthesis of compound 3d:

[0088]

[0089] Under nitrogen atmosphere, p-cyanobenzoic acid 1d (0.2 mmol, 29.4 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3d (yield 41%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ7.90(d,J=8.5Hz,2H),7.72(d,J=8.6Hz,2H),4.11(q,J=7.1Hz,2H),1.53(s,6H),1.05(t,J=7.1Hz,3H). 13 C NMR (101 MHz, CDCl3 )δ196.66(s),174.30(s),138.53(s),132.33(s),128.99(s),117.82(s),1 15.99(s),61.70(s),53.54(s),23.66(s),13.78(s).HRMS(ESI)m / z:[M+Na + ]Calcd for C 14 H 15 NNaO 3 + :268.0950;Found:268.0951.

[0090] Embodiment 32:

[0091] Synthesis of compound 3e:

[0092]

[0093] Under nitrogen atmosphere, 2-naphthoic acid 1e (0.2 mmol, 34.4 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv.), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3e (yield 64%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ8.37(s,1H),7.92(d,J=8.5Hz,2H),7.85(d,J=9.2Hz,2H),7.56(m,2H),4.12(q,J=7.1Hz,2H),1.62(s,6H),1.02(t,J=7.1Hz,3H).

[0094] Embodiment 33:

[0095] Synthesis of compound 3f:

[0096]

[0097] Under nitrogen atmosphere, furanic acid 1f (0.2 mmol, 22.4 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3f (yield 69%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ7.51(d,J=0.8Hz,1H),7.20(d,J=3.6Hz,1H),6.50(dd,J=3.6,1.6Hz,1H),4.11(q,J=7.1Hz,2H),1.48(s,6H),1.07(t,J=7.1Hz,3H).

[0098] Embodiment 34:

[0099] Synthesis of compound 3g:

[0100]

[0101] Under nitrogen atmosphere, benzoic acid 1a (0.2 mmol, 24.4 mg, 1.0 equiv), ethyl phenylacrylate 2 g (0.24 mmol, 42.2 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2(DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). The mixture of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain 3g of the product (yield 47%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ7.70(d,J=7.3Hz,2H),7.54–7.43(m,3H),7.38–7.28(m,6H),4.20–4.12(m,2H),1.93(s,3H),1.07(t,J=7.1Hz,3H).

[0102] Embodiment 35:

[0103] Synthesis of compound 3h:

[0104]

[0105] Under nitrogen atmosphere, benzoic acid 1a (0.2 mmol, 24.4 mg, 1.0 equiv), benzyl methacrylate 2h (0.24 mmol, 42.2 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3h (yield 71%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3)δ7.79(d,J=7.5Hz,2H),7.50(t,J=7.4Hz,1H),7.38–7.32(m,2H),7.28–7.23(m,3H),7.09(d,J=6.3Hz,2H),5.10(s,2H),1.59(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ197.55(s),174.80(s),135.09(s),135.05(s),132.65(s),128.61(s),12 8.48(s),128.43(s),128.26(s),128.25(s),67.14(s),53.34(s),23.99(s).

[0106] Embodiment 36:

[0107] Synthesis of compound 3i:

[0108]

[0109] Under nitrogen atmosphere, benzoic acid 1a (0.2 mmol, 24.4 mg, 1.0 equiv), ethyl acrylate 2i (0.24 mmol, 24.0 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3i (yield 61%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ7.97(d,J=7.6Hz,2H),7.57(t,J=7.3Hz,1H),7.47(t,J=7.8Hz,2H),4.37(q,J =7.1Hz, 1H), 4.14 (q, J = 7.1Hz, 2H), 1.49 (d, J = 7.1Hz, 3H), 1.16 (t, J = 7.1Hz, 3H). 13C NMR (101 MHz, CDCl 3 )δ195.94(s),170.92(s),135.88(s),133.46(s),128.73(s),128.59(s),61.38(s),48.37(s),13.96(s),13.75(s).

[0110] Embodiment 37:

[0111] Synthesis of compound 3j:

[0112]

[0113] Under nitrogen atmosphere, heptanoic acid 1j (0.2 mmol, 26.0 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3j (yield 67%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ4.15(q,J=7.1Hz,2H),2.41(t,J=7.3Hz,2H),1.58–1.51(m,2H),1.33(s,6H),1.28–1.21(m,9H),0.85(t,J=6.7Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ208.20(s),173.80(s),61.23(s),55.57(s),37.95(s),31.59(s),28.80(s),23.84(s),22.47(s),21.86(s),13.99(s).HRMS(ESI)m / z:[M+Na + ]Calcd for C 13H 24 NaO 3 + :251.1623;Found:251.1629.

[0114] Embodiment 38:

[0115] Synthesis of compound 3k:

[0116]

[0117] Under nitrogen atmosphere, undecanoic acid 1c (0.2 mmol, 37.3 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH(0.6mmol,98.4mg,3.0equiv),Zinc(0.6mmol,39.0mg,3.0equiv),NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3k (yield 41%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ4.15(q,J=7.1Hz,2H),2.40(t,J=7.2Hz,2H),1.59–1.47(m,2H),1.32(s,6H),1.29–1.15(m,17H),0.84(t,J=6.6Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ208.14(s),173.78(s),61.20(s),55.55(s),37.94(s),31.86(s),29.53(s),29.45(s) ),29.40(s),29.28(s),29.14(s),23.88(s),22.64(s),21.85(s),14.06(s),13.99(s).

[0118] Embodiment 39:

[0119] Synthesis of compound 3l:

[0120]

[0121] Under nitrogen atmosphere, 4-chloropropionic acid 1l (0.2 mmol, 24.5 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3l (yield 75%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ4.16(q,J=7.1Hz,2H),3.53(t,J=6.2Hz,2H),2.64(t,J=6.8Hz,2H),2.04(p,J=6.5Hz,2H),1.35(s,6H),1.24(t,J=7.1Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ207.16(s),173.49(s),61.44(s),55.50(s),44.24(s),34.68(s),26.58(s),21.89(s),13.99(s).HRMS(ESI)m / z:[M+Na + ]Calcd for C 10 H 17 ClNaO 3 + :243.0764;Found:243.0769.

[0122] Embodiment 40:

[0123] Synthesis of compound 3m:

[0124]

[0125] Under nitrogen atmosphere, cyclohexyl acetic acid 1m (0.2mmol, 28.4mg, 1.0equiv), ethyl methacrylate 2a (0.24mmol, 27.4mg, 1.2equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3m (yield 57%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ4.14(q,J=7.1Hz,2H),2.27(d,J=6.7Hz,2H),1.87–1.83(m,1H),1.62(d,J=8. 9Hz,5H),1.30(s,6H),1.25–1.19(m,5H),1.13–1.03(m,1H),0.90–0.77(m,2H). 13 CNMR (101MHz, CDCl 3 )δ207.37(s),173.72(s),61.23(s),55.71(s),45.51(s),33.19(s),33.06(s),26.20(s),26.08(s),21.76(s),13.99(s).

[0126] Embodiment 41:

[0127] Synthesis of compound 3n:

[0128]

[0129] Under nitrogen atmosphere, phenylacetic acid 1n (0.2 mmol, 27.2 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2 (DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3n (yield 51%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (400 MHz, CDCl 3 )δ7.35–7.25(m,3H),7.20(d,J=7.0Hz,2H),4.19(q,J=7.1Hz,2H),3.80(s,2H),1.44(s,6H),1.26(t,J=7.1Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ205.24(s),173.58(s),134.10(s),129.52(s),128.44(s),126.92(s),61.48(s),55.86(s),44.68(s),21.96(s),14.02(s).

[0130] Embodiment 42:

[0131] Synthesis of compound 3o:

[0132]

[0133] Under nitrogen atmosphere, cyclopentanoic acid 1o (0.2 mmol, 22.8 mg, 1.0 equiv), ethyl methacrylate 2a (0.24 mmol, 27.4 mg, 1.2 equiv), (EtO) were added to the reaction tube. 3 SiH (0.6mmol, 98.4mg, 3.0equiv), Zinc (0.6mmol, 39.0mg, 3.0equiv), NiBr 2(DME) (0.01mmol, 3.1mg, 5mol%), α,α,α-terpyridine (0.02mmol, 4.7mg, 10mol%), tetrahydrofuran 1ml. The reaction system was reacted at 60℃ for 12 hours. After the reaction, the reaction solution was concentrated and subjected to column chromatography (100 mesh silica gel). A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1 (including 300ml of petroleum ether and 10ml of ethyl acetate) was used as the eluent for elution. The eluent containing the target compound was collected, concentrated, distilled and dried to obtain the product 3o (yield 46%). (Eluent polarity: petroleum ether / ethyl acetate = 30:1). 1 H NMR (500 MHz, CDCl 3 )δ4.15(q,J=7.5Hz,2H),2.95(p,J=7.5Hz,1H),1.80–1.70(m,4H),1.69–1.61(m,2H),1.58–1.48(m,2H),1.33(s,6H),1.23(t,J=7.0Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ212.61(s),173.85(s),61.21(s),55.93(s),47.46(s),32.31(s),26.46(s),21.61(s),14.06(s).HRMS(ESI)m / z:[M+Na + ]Calcd for C 12 H 20 NaO 3 + :235.1310;Found:235.1315.

Claims

1. A method for synthesizing a β-carbonyl ester compound, the specific method is as follows: under a nitrogen atmosphere, a carboxylic acid as represented by formula (I), an alkenyl ester as represented by formula (II), a catalyst, a ligand, a silane, a reducing agent, and an organic solvent are mixed and stirred at 20° C. to 120° C. for 4 to 24 hours to obtain a reaction solution, and the reaction solution is separated and purified by silica gel column chromatography to obtain a β-carbonyl ester compound as represented by formula (III), in, In formula (I) or formula (III), R 1 is selected from phenyl, p-methoxybenzene, p-phenylbenzene, p-cyanobenzene, hexyl, deoxynyl, chloropropyl, cyclohexanemethyl, benzyl, cyclopentyl, naphthyl or furan, and R in formula (II) or formula (III) is 2 is selected from hydrogen, methyl or phenyl, R 3 Selected from ethyl or benzyl, the catalyst is NiBr2, NiCl2, or NiBr2(DME), the ligand is triphenylphosphine, 2,2'-bipyridine, 1,10-phenanthroline or α,α,α-terpyridine, and the molar ratio of the carboxylic acid compound represented by formula (I) to the alkenyl ester represented by formula (II), the catalyst, the ligand, the silane, and the reducing agent is 1:1~2:0.02~0.1:0.05~0.2:1~5:1~5.

2. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The silane is diphenylsilane, diethoxysilane or triethoxysilane.

3. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The reducing agent is zinc, magnesium or manganese.

4. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The organic solvent is dioxane, anisole or tetrahydrofuran.

5. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The volume of the organic solvent is 20.5-123.0 ml / g based on the mass of the carboxylic acid represented by formula (I).

6. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The molar ratio of the carboxylic acid compound represented by formula (I) to the alkenyl ester represented by formula (II), the catalyst, the ligand, the silane and the reducing agent is 1:1.2:0.05:0.1:3:

3.

7. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The catalyst is NiBr2(DME).

8. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The ligand is α,α,α-terpyridine.

9. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The specific operation process of the silica gel column separation and purification is: concentrating the reaction solution, performing column chromatography, eluting with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 30 to 15:1 as an eluent, collecting the eluate containing the target compound, concentrating, distilling and drying.

10. The method for synthesizing β-carbonyl ester compounds according to claim 1, characterized in that: The β-carbonyl ester compound is one of the following:

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