A preparation method of hydroxyketone compounds based on electrosynthesis and hydroxyketone compounds prepared therefrom

Abstract

The present invention discloses a method for preparing a hydroxyketone compound based on electrosynthesis and the hydroxyketone compound prepared therefrom, and belongs to the technical field of preparation of hydroxyketone compounds. The method for preparing a hydroxyketone compound based on electrosynthesis comprises the following steps: in a protective atmosphere, in an organic solvent, using an epoxy compound shown in Formula 1, an aryl iodide shown in Formula 2, and a carbon monoxide source as reaction raw materials, and under electrochemical conditions, in the presence of a promoter and a metal catalyst, an electroreduction carbonylation reaction occurs to obtain a hydroxyketone compound as shown in Formula 3; and the reaction process is shown in Reaction Formula (1). According to the method of the present invention, the use of metal powder as a reducing agent is avoided, the operation method is simple, and the safety is good.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of hydroxyketone compounds, and more particularly to a method for preparing hydroxyketone compounds based on electrosynthesis and the prepared hydroxyketone compounds. Background Art

[0002] β- / γ-hydroxyketones are widely found in pharmaceuticals, natural products, and bioactive molecules. They are also important organic synthesis intermediates used in pharmaceuticals and pesticides, serving as key components in the preparation of pharmaceutical molecules and fine chemicals, as shown below. Therefore, the preparation of β- / γ-hydroxyketones has become a research hotspot.

[0003]

[0004] To date, many methods for preparing β / γ-hydroxyketone compounds have been reported. Among them, the preparation method using aldehydes and ketones as raw materials through aldol condensation (adol) reaction is relatively common. This method uses an acid or base as a promoter to generate hydroxyketone compounds through aldehyde-ketone condensation reaction. This method generally has poor reaction selectivity and is prone to dimerization. The substrate applicability of this method is poor and it is not suitable for the preparation of γ-hydroxyketones. The synthesis method has significant limitations. Another effective method for synthesizing β / γ-hydroxyketone compounds is oxidation or reduction reaction, that is, selective reduction reaction of 1,n-diketones or selective oxidation reaction of 1,n-diols. However, the need for pre-preparation of raw materials and the difficulty of selectivity control seriously limit the application of this solution.

[0005] With the recent development of carbonylation reactions, a variety of transition metal-catalyzed carbonylation reactions have been developed for the preparation of ketone-containing compounds. This transition metal-catalyzed reaction, which utilizes carbon monoxide insertion, is an important chemical transformation for the construction of ketone-containing compounds and their derivatives and has been applied in industrial synthesis technology. Transition metal-catalyzed reductive carbonylation is an attractive option, using a halide, a carbon monoxide source, and other electrophilic reagents for three-component coupling. However, most electrophilic coupling reactions require metal powder reducing agents, such as zinc powder and manganese powder, which are difficult to post-process and have safety issues. Summary of the Invention

[0006] In response to the above problems, the present invention provides a method for preparing hydroxyketone compounds based on electrosynthesis and the hydroxyketone compounds prepared therefrom. According to the method of the present invention, the use of metal powder as a reducing agent is avoided, the operation method is simple, and the safety is good.

[0007] The first object of the present invention is to provide a method for preparing hydroxyketone compounds based on electrosynthesis, comprising the following steps:

[0008] Under protective atmosphere, in an organic solvent, an epoxy compound represented by Formula 1, an aryl iodide represented by Formula 2, and a carbon monoxide source are used as reaction raw materials. Under electrochemical conditions, in the presence of a promoter and a metal catalyst, an electroreduction carbonylation reaction occurs to obtain a β / γ-hydroxyketone compound represented by Formula 3. The reaction process is shown in Reaction Formula (1):

[0009]

[0010] Among them, R 1 is any one of a linear alkyl group, a cycloalkyl group and hydrogen.

[0011] R 2 is any one of a linear alkyl group, a cycloalkyl group and hydrogen.

[0012] R 3 is any one of a linear alkyl group, a cycloalkyl group and hydrogen.

[0013] or R 1 With R 2 Together with their carbon atoms, they form a cycloalkyl group, or R 1 With R 3 Together with their carbon atoms, they form a cycloalkyl group, or R 2 With R 3 They are bonded to the carbon atoms they carry to form substituted heteroatom cycloalkyl groups.

[0014] R 4 It is any one of a straight-chain alkoxy group, a straight-chain alkyl group, a halogen group, an amino-protecting group, and a hydroxyl-protecting group.

[0015] It should be noted that the present invention, while ensuring that the epoxy compound shown in Formula 1, the aryl iodide shown in Formula 2, and the carbon monoxide source are used as the reaction raw materials to synthesize β / γ-hydroxyketone compounds, avoids the use of zinc powder or manganese powder as a metal reducing agent to carry out the electroreduction carbonylation reaction. Among them, the use of electrochemical reduction instead of the traditional chemical reduction process has obvious advantages: 1. controllable electron transport; 2. adjustable voltage; 3. direct electroactivation of the substrate; 4. milder reaction conditions; 5. easier to scale up the reaction.

[0016] The present invention can select the corresponding substrate raw material according to actual needs. In the epoxy compound shown in Formula 1 used in the present invention, R1 is any one of a straight-chain alkyl group, a cycloalkyl group and hydrogen; R2 is any one of a straight-chain alkyl group, a cycloalkyl group and hydrogen; and R3 is any one of a straight-chain alkyl group, a cycloalkyl group and hydrogen. 4 It is any one of a straight-chain alkoxy group, a straight-chain alkyl group, a halogen, an amino protecting group, and a hydroxy protecting group. As shown in Formula 2, it is an aryl iodide containing different substituents on the benzene ring.

[0017] In a preferred embodiment of the present invention, R 1 It is one of hydrogen, butyl, ethyl, methyl and trifluoromethyl.

[0018] R 2 It is one of butyl, ethyl, methyl, trifluoromethyl and hydrogen.

[0019] R 3 It is one of butyl, ethyl, methyl, trifluoromethyl and hydrogen.

[0020] or R 1 With R 2 Together with the carbon atoms they carry, they form a 6-membered cycloalkyl group; or R 1 With R 2 Together with the carbon atoms they carry, they form a 5-membered cycloalkyl group; or R 2 With R 3 Bonded to their carbon atoms

[0021]

[0022] R 4 is a single or multiple substituent, and the substituent is meta-substituted methoxy, ortho-substituted methoxy, para-substituted methoxy, fluorine, tert-butyloxycarbonylamino, tert-butyldimethylsilyloxy, Any one of, or R 4 The two substituents are N-phenyl-benzindole.

[0023] In order to better describe the substituents used in the epoxy compound shown in Formula 1, the present invention takes the right side as R based on the orientation or position relationship shown in the structural formula. 1 , the group on the left is R 2 and R 3 When the epoxy compound shown in formula 1 has only one group on the left side, R 2 The description is only for the convenience of describing the present invention and simplifying the description, and therefore should not be understood as limiting the present invention.

[0024] More preferably, R 1 For hydrogen.

[0025] R 2 It is one of butyl, ethyl, methyl, trifluoromethyl and hydrogen.

[0026] R 3 is hydrogen or methyl.

[0027] or R 1 With R 2 Together with the carbon atoms they carry, they form a 6-membered cycloalkyl group; or R 1 With R2 Together with the carbon atoms they carry, they form a 5-membered cycloalkyl group; or R 2 With R 3 Bonded to their carbon atoms

[0028]

[0029] R 4 is a single or multiple substituent, and the substituent is meta-substituted methoxy, ortho-substituted methoxy, para-substituted methoxy, fluorine, tert-butyloxycarbonylamino (-NHBoc), tert-butyldimethylsilyloxy (TBSO-), Any one of, or R 4 The two substituents are N-phenyl-benzindole.

[0030] The carbon monoxide source used in the present invention can provide carbon monoxide by reacting with the catalyst at room temperature. For example, in a preferred embodiment of the present invention, the carbon monoxide source used is any one of n-propyl chloroformate, ethyl oxalyl chloride, oxalyl chloride, etc. The n-propyl chloroformate considered in the present invention has good stability, is not easily oxidized by air, and is more suitable for industrial production. Therefore, in a preferred embodiment of the present invention, n-propyl chloroformate is used as the carbon monoxide source.

[0031] In order to ensure that the added promoter can achieve the ring-opening effect of the epoxide in reaction formula (1), in a preferred embodiment of the present invention, the promoter is any one of sodium iodide, potassium iodide, tetrabutylammonium iodide, and iodotrimethylsilane.

[0032] And in order to ensure that the three-component reaction raw materials are fully reacted under the action of the metal catalyst and the promoter, the present invention explores the effect of the dosage ratio of the three-component reaction raw materials, the metal catalyst and the promoter on the target product obtained during the experiment, and in the present invention, when the molar ratio of the epoxy compound as shown in Formula 1, the aryl iodide as shown in Formula 2, the carbon monoxide source, the metal catalyst and the promoter is less than (1 to 1.5): (1.5 to 3): 1: (0.05 to 0.15): (1 to 1.5), the yield of the target product obtained will be significantly reduced. Therefore, in a preferred embodiment of the present invention, when the molar ratio of the epoxy compound as shown in Formula 1, the aryl iodide as shown in Formula 2, the carbon monoxide source, the metal catalyst and the promoter is 1.5: 2: 1: 0.1: 1.2.

[0033] The present invention does not limit the specific type of organic solvent used in the reaction, as long as the epoxy compound shown in Formula 1, the aryl iodide shown in Formula 2, the carbon monoxide source, the metal catalyst and the promoter all have good solubility, so that the components can fully react to form a hydroxyketone compound as shown in Formula 3. For example, in a preferred embodiment of the present invention, the organic solvent used is acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, acetone, dichloromethane and dichloroethane. In a preferred embodiment of the present invention, it was found that N,N-dimethylacetamide and 1,4-dioxane were mixed in a volume ratio of 2:1 for the best effect.

[0034] In order to further ensure that the epoxy compound shown in Formula 1, the aryl iodide shown in Formula 2, the carbon monoxide source, the metal catalyst and the promoter can fully prepare the hydroxy ketone compound of Formula 3 under the conditions of the electroreduction reaction, the present invention explores the effect of different currents on the target product during the experiment, and in the present invention, when the current is 5mA, more uninserted carbonyl products will be generated by the reaction, resulting in a decrease in the yield of the target product. When the current of the reaction is 15mA, the reaction generates carbon monoxide at an increased rate, and the reaction carbonylation efficiency is improved. Therefore, in a preferred embodiment of the present invention, the current of the reaction is 15mA.

[0035] In a preferred embodiment of the present invention, the protective gas atmosphere is any one of nitrogen atmosphere and argon atmosphere, and the pressure of the protective gas atmosphere is 1atm to 6atm to ensure the safety of the reaction. This is because according to the method of the present invention, the raw materials are sensitive to oxygen during the reaction, so the present invention needs to be carried out under the protection of inert gas.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] While ensuring that the three components of the reaction are used as raw materials to synthesize β- / γ-hydroxyketone compounds—an epoxy compound (Formula 1), an aryl iodide (Formula 2), and a carbon monoxide source—the present invention avoids the use of zinc or manganese powder as a metal reducing agent to conduct an electrochemical reduction carbonylation reaction. Using electrochemical reduction instead of traditional chemical reduction processes offers significant advantages: 1. Controllable electron transfer; 2. Adjustable voltage; 3. Direct electroactivation of the substrate; 4. Milder reaction conditions; and 5. Easier scalability of the reaction.

[0038] The preparation method of the present invention has mild conditions, simple operation, short reaction time, good functional group tolerance, good substrate applicability, low cost and easy availability, high preparation efficiency and high yield of the obtained hydroxyketone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the reaction mechanism of the present invention. DETAILED DESCRIPTION

[0040] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0041] It should be noted that in this invention, trimethylsilane iodide is denoted as TMSI, dimethyl ether is denoted as DMA, tetrabutylammonium hexafluorophosphate is denoted as TBAP6, and 4,4'-di-tert-butyl-2,2'-pyridine is denoted as dtbpy. Nickel(II) chloride dimethyl ether, CAS No. 29046-78-4, is denoted as NiCl2·dme. Propyl chloroformate is denoted as ClCO2Pr.

[0042] Reaction mechanism Figure 1 As shown, aryl iodide and Ni 0 Species A undergoes oxidative addition to generate the intermediate Ni II Species B, ClCOOPr, reacts with nickel catalyst under electroreduction conditions to generate CO gas. CO migrates with species B to generate species D. Epoxide generates free radical F under the action of TMSI and nickel, which is then captured by species D to generate Ni III Species G then undergoes reductive elimination and acidification to give the target product.

[0043] Example 1

[0044] Preparation of compound 3a:

[0045]

[0046] As shown in reaction formula (2), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction was performed with ethyl acetate (10 ml x 3), followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as the eluent to obtain the purified target compound represented by Formula 3a in a yield of 74%. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0047] 1 H NMR (400MHz, CDCl3) δ7.94–7.90(m,2H),6.94–6.90(m,2H),4.21–4.15(m,1H),3.86(s,3H),3.12(dd,J=17 .5,2.6Hz,1H),2.95(dd,J=17.5,9.1Hz,1H),1.65–1.44(m,3H),1.39–1.31(m,3H),0.90(t,J=7.1Hz,3H).

[0048] 13 C NMR (101MHz, CDCl3) δ199.75,163.93,130.50,129.98,113.90,68.00,55.59,44.58,36.32,27.84,22.77,14.14.

[0049] Example 2

[0050] Preparation of compound 3b:

[0051]

[0052] As shown in reaction formula (3), under nitrogen protection in a glove box, the epoxide of formula 1b (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target product represented by formula 3b in a yield of 56%.

[0053] 1 H NMR (400MHz, CDCl3) δ8.13–7.77(m,2H),7.05–6.82(m,2H),4.13–4.06(m,1H),3.85(s,3H),3.43(s,1H ), 3.11(dd,J=17.4,2.5Hz,1H),2.94(dd,J=17.4,9.1Hz,1H),1.66–1.48(m,2H),0.99(t,J=7.4Hz,3H).

[0054] 13 C NMR (101MHz, CDCl3) δ199.71,163.92,130.50,129.98,113.89,69.34,55.59,44.15,29.47,10.07.

[0055] HRMS(ESI)m / z:[M+Na] + Calcd for C 12 H 16 NaO3 + 231.0992; Found 231.1000.

[0056] Example 3

[0057] Preparation of compound 3c:

[0058]

[0059] As shown in reaction formula (4), under nitrogen protection in a glove box, the epoxide of formula 1c (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target product represented by formula 3c in a yield of 57%.

[0060] 1 HNMR (400MHz, CDCl3) δ7.94–7.90(m,2H),6.94–6.91(m,2H),3.85(s,3H),3.07(s,2H),1.31(s,6H).

[0061] 13 C NMR (101MHz, CDCl3) δ200.45,164.03,130.57,130.41,113.93,70.04,55.62,48.05,29.66.

[0062] HRMS(ESI)m / z:[M+Na] + Calcd for C 12 H 16 NaO3 + 231.0992;Found 231.1002.

[0063] Example 4

[0064] Preparation of compound 3d:

[0065]

[0066] As shown in reaction formula (5), under nitrogen protection in a glove box, the epoxide of formula 1d (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol%) (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 3:1 as eluent to obtain the purified target product represented by formula 3d in a yield of 74%.

[0067] 1 H NMR (400MHz, CDCl3) δ7.91–7.87(m,2H),6.92(dd,J=8.6,1.2Hz,2H),4.29(s,1H),3.89–3.80(m,5H) ,3.21(t,J=12.6Hz,2H),3.03(s,2H),1.79–1.71(m,2H),1.50(dd,J=12.7,4.6Hz,2H),1.43(s,9H).

[0068] 13 C NMR (101MHz, CDCl3) δ200.03,164.23,154.95,130.59,130.22,114.01,79.41,69.16,55.64,47.45,39.48,37.07,28.54.

[0069] HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 27 NNaO5 + 372.1781; Found 372.1789.

[0070] Example 5

[0071] Preparation of compound 3e:

[0072]

[0073] As shown in reaction formula (6), under nitrogen protection in a glove box, the epoxide 1e (0.75 mmol, 1.5 equiv.) of formula 1e, the aryl iodide (0.5 mmol, 1.0 equiv.) of formula 2a, ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target product represented by formula 3e in a yield of 44%.

[0074] 1 H NMR (400MHz, CDCl3) δ7.95–7.91(m,2H),6.97–6.93(m,2H),4.71–4.63(m,1H),3.87(s,3H),3.32(dd,J=17.5,9.0Hz,1H),3.24(dd,J=17.6,2.9Hz,1H).

[0075] 13 C NMR (101MHz, CDCl3) δ196.23, 164.44, 130.73, 129.14, 124.94 (d, J = 280.8Hz), 114.12, 67.20 (q, J = 32.0Hz), 55.67, 37.79.

[0076] 19 F NMR (376 MHz, CDCl3) δ-79.10.

[0077] Example 7

[0078] Preparation of compound 3f:

[0079]

[0080] As shown in reaction formula (7), under nitrogen protection in a glove box, the epoxide of formula 1f (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target product represented by formula 3f in a yield of 53%.

[0081] 1 H NMR (400MHz, CDCl3) δ7.96–7.91(m,2H),6.96–6.89(m,2H),4.04(ddd,J=10.7,9.2,4.3Hz,1H),3.84(s,3H) ,3.20(ddt,J=11.5,5.8,3.4Hz,1H),2.56(s,1H),2.08–2.03(m,2H),1.82–1.70(m,2H),1.43–1.27(m,4H).

[0082] 13 C NMR (101MHz, CDCl3) δ202.25,163.66,130.86,129.60,113.86,70.88,55.56,53.57,33.64,29.93,25.62,24.69.

[0083] Example 8

[0084] Preparation of compound 3g:

[0085]

[0086] As shown in reaction formula (8), under nitrogen protection in a glove box, the epoxide of formula 1g (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2M dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target product shown in formula 3g in a yield of 57%.

[0087] 1 H NMR (400MHz, CDCl3) δ7.99–7.95(m,2H),6.94–6.90(m,2H),4.56(q,J=5.7Hz,1H),3.85(s,3H),3.60(d dd,J=9.4,7.6,5.1Hz,1H),2.17–2.08(m,1H),2.02–1.95(m,1H),1.87–1.79(m,2H),1.76–1.66(m,2H).

[0088] 13 C NMR (101MHz, CDCl3) δ200.55,163.60,130.98,129.89,113.84,76.08,55.57,55.05,35.05,28.91,22.94.

[0089] HRMS(ESI)m / z:[M+H] + Calcd for C 13 H 17 O3 + 221.1172; Found 221.1152.

[0090] Example 9

[0091] Preparation of compound 3h:

[0092]

[0093] As shown in reaction formula (9), under nitrogen protection in a glove box, the epoxide of formula 1h (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography (petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent) to obtain the purified target product represented by formula 3h in a yield of 47%.

[0094] 1 HNMR(400MHz, CDCl3)δ7.96–7.92(m,2H),6.94–6.89(m,2H),3.85(s,3H),3. 71(t,J=6.0Hz,2H),3.07(t,J=7.0Hz,2H),2.20(br,1H),2.02–1.94(m,2H).

[0095] 13 C NMR (101MHz, CDCl3) δ199.24,163.54,130.41,129.92,113.74,62.40,55.48,35.02,27.10.

[0096] Example 10

[0097] Preparation of compound 3i:

[0098]

[0099] As shown in reaction formula (10), under nitrogen protection in a glove box, the epoxide represented by formula 1i (0.75 mmol, 1.5 equiv.), the aryl iodide represented by formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine accounting for 15 mol% of the aryl iodide represented by formula 2a, and NiCl2·dme accounting for 10 mol% of the aryl iodide represented by formula 2a were added to a reaction tube containing a magnetic particle, 4 mL of DMA and 2.0 mL of 1,4-dioxane were added, a zinc sheet was used as an anode, and carbon felt was used as a cathode. The reaction was carried out at a current of 15 mA for four hours. After dilution with water, ethyl acetate (10 ml × 3) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 8:1 as eluent to obtain the purified target product represented by formula 3i in a yield of 48%.

[0100] 1 HNMR (400MHz, CDCl3) δ7.96–7.92(m,2H),6.95–6.91(m,2H),3.86(s,3H),3.71–3.58(m,2H),3.24–3.17(m ,2H),3.02–2.98(m,2H),1.95(dd,J=9.3,6.2Hz,2H),1.63–1.59(m,2H),1.53–1.44(m,11H),0.12(s,9H).

[0101] 13 C NMR (101MHz, CDCl3) δ198.45,163.46,154.86,130.24,130.06,113.76,79.36,73.34,55.48,37.30,35.47,32.17,28.47,2.62.

[0102] HRMS(ESI)m / z:[M+Na] + Calcd for C 23 H 37 NNaO5Si + 458.2333; Found 458.2336.

[0103] Example 11

[0104] Preparation of compound 3j:

[0105]

[0106] As shown in reaction formula (11), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2b (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2b), and NiCl2·dme (10 mol% of the aryl iodide of formula 2b) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction with ethyl acetate (10 ml x 3) was added, followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as the eluent to obtain the purified target compound represented by Formula 3j in a 65% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0107] 1 H NMR (400MHz, CDCl3) δ7.51(dt,J=7.7,1.2Hz,1H),7.45(dd,J=2.7,1.6Hz,1H),7.35(t,J=8.0Hz,1H),7.10(ddd,J=8.2,2.6,1.0Hz,1H),4.22–4.16(m, 1H),3.83(s,3H),3.27(s,1H),3.13(dd,J=17.6,2.7Hz,1H),3.00(dd,J=17 .6,9.0Hz,1H),1.64–1.42(m,3H),1.40–1.30(m,3H),0.90(t,J=7.1Hz,3H).

[0108] 13 C NMR (101MHz, CDCl3) δ200.95,159.94,138.24,129.76,120.87,120.02,112.35,67.88,55.53,45.26,36.31,27.83,22.76,14.14.

[0109] HRMS(ESI)m / z:[M+Na] + Calcd for C 14 H 20 NaO3 +259.1305; Found 259.1318.

[0110] Example 12

[0111] Preparation of compound 3k:

[0112]

[0113] As shown in reaction formula (12), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2c (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2c), and NiCl2·dme (10 mol% of the aryl iodide of formula 2c) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction was performed with ethyl acetate (10 ml x 3), followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as the eluent to obtain the purified target compound represented by Formula 3k in a 37% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0114] 1 HNMR (400MHz, CDCl3) δ7.71(dd,J=7.7,1.9Hz,1H),7.47(ddd,J=8.9,7.3,1.9Hz,1H),7.02–6.95(m,2H),4.17–4.11(m,1H),3.90(s,3H ),3.29(s,1H),3.23(dd,J=18.0,2.4Hz,1H),3.00(dd,J=18.0,9.2Hz,1H),1.59–1.41(m,3H),1.40–1.29(m,3H),0.90(t,J=7.1Hz,3H).

[0115] 13 C NMR (101MHz, CDCl3) δ203.36,158.95,134.11,130.41,127.93,120.81,111.73,68.23,55.60,50.49,36.38,27.87,22.79,14.16.

[0116] HRMS(ESI)m / z:[M+Na] + Calcd for C 14 H 20 NaO3 + 259.1305; Found 259.1312.

[0117] Example 13

[0118] Preparation of compound 3l:

[0119]

[0120] As shown in reaction formula (13), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2d (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2d), and NiCl2·dme (10 mol% of the aryl iodide of formula 2d) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction with ethyl acetate (10 ml x 3) was added, followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 31 in a 64% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0121] 1 H NMR (400MHz, CDCl3) δ7.63–7.55(m,2H),7.28–7.25(m,1H),4.22–4.16(m,1H),3.18(s,1H),3.10(dd,J=17.7,2. 7Hz,1H),2.98(dd,J=17.6,9.0Hz,1H),2.32(s,3H),1.61–1.45(m,3H),1.39–1.30(m,3H),0.90(t,J=7.1Hz,3H).

[0122] 13C NMR (101MHz, CDCl3) δ199.65, 161.36 (d, J = 246.9Hz), 136.67, 136.61, 131.75 (d, J = 4.9Hz), 131.45 (d, J = 17.5Hz),123.81,123.78,114.50(d,J=23.2Hz),67.81,45.13,36.30,27.81,22.74,14.98,14.94,14.11.

[0123] 19 F NMR (376MHz,CDCl3)δ-115.90.

[0124] HRMS(ESI)m / z:[M+K] + Calcd for C 14 H 19 FKO2 + 277.1001; Found 277.1002.

[0125] Example 14

[0126] Preparation of compound 3m:

[0127]

[0128] As shown in reaction formula (14), under nitrogen protection in a glove box, the epoxide 1a (0.75 mmol, 1.5 equiv.) of formula 1a, the aryl iodide 2e (0.5 mmol, 1.0 equiv.) of formula 2e, ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2e), and NiCl2·dme (10 mol% of the aryl iodide of formula 2e) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction with ethyl acetate (10 ml x 3) was added, followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound 3m in a 53% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0129] 1HNMR (400MHz, CDCl3) δ7.89–7.85(m,2H),7.46–7.43(m,2H),6.99(s,1H),4.21–4.15(m,1H),3.41(s,1H),3.11(d d,J=17.5,2.7Hz,1H),2.95(dd,J=17.5,9.1Hz,1H),1.61–1.38(m,12H),1.36–1.29(m,3H),0.89(t,J=7.1Hz,3H).

[0130] 13 C NMR (101MHz, CDCl3) δ199.82,152.30,143.54,131.38,129.71,117.55,81.43,67.99,44.65,36.31,28.34,27.83,22.75,14.13.

[0131] HRMS(ESI)m / z:[M+Na] + Calcd for C 18 H 27 NNaO4 + 344.1832; Found 344.1833.

[0132] Example 15

[0133] Preparation of compound 3n:

[0134]

[0135] As shown in reaction formula (15), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2f (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2f), and NiCl2·dme (10 mol% of the aryl iodide of formula 2f) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction was performed with ethyl acetate (10 ml x 3), drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 3n in a 64% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0136] 1 H NMR (400MHz, CDCl3) δ7.88–7.85(m,2H),6.87–6.85(m,2H),4.17(td,J=8.1,3.9Hz,1H),3.41(s,1H),3.11(d,J=17.4Hz,1H),2.9 5(dd,J=18.1,8.6Hz,1H),1.63–1.45(m,3H),1.38–1.30(m,3H),0.97(d,J=1.3Hz,9H),0.92–0.89(m,3H),0.22(d,J=1.2Hz,6H).

[0137] 13 C NMR (101MHz, CDCl3) δ199.84,160.78,130.52,130.41,120.09,67.98,44.61,36.33,27.84,25.65,22.77,18.32,14.14,-4.29.

[0138] HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 32 NaO3Si + 359.2013;Found359.2014.

[0139] Example 16

[0140] Preparation of compound 3o:

[0141]

[0142] As shown in reaction formula (16), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2g (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2g), and NiCl2·dme (10 mol% of the aryl iodide of formula 2g) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction with ethyl acetate (10 ml x 3) was added, followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 3o in a 61% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0143] 1 HNMR(400MHz, CDCl3)δ8.78(d,J=1.7Hz,1H),8.20(d,J=7.7Hz,1H),8.04(dd,J=8.7, 1.8Hz,1H),7.62(t,J=7.7Hz,2H),7.52(dd,J=8.0,2.8Hz,3H),7.44(d,J=7.4Hz,1H), 7.40–7.33(m,3H),4.31–4.25(m,1H),3.59(s,1H),3.33(dd,J=17.4,2.5Hz,1H),3.16 (dd,J=17.4,9.2Hz,1H),1.72–1.51(m,3H),1.47–1.34(m,3H),0.95(t,J=7.0Hz,3H).

[0144] 13C NMR (101MHz, CDCl3) δ200.59,143.92,141.89,136.89,130.20,129.37,128.31,127.20,126.96,126.4 7,123.48,123.31,121.72,121.14,120.69,110.44,109.68,68.21,44.86,36.43,27.93,22.85,14.21.

[0145] HRMS(ESI)m / z:[M+Na] + Calcd for C 22 H 26 NO2 + 394.1778; Found 394.1779.

[0146] Example 17

[0147] Preparation of compound 3p:

[0148]

[0149] As shown in reaction formula (17), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2h (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4-tert-butylbipyridine (15 mol% of the aryl iodide of formula 2h), and NiCl2·dme (10 mol% of the aryl iodide of formula 2h) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction with ethyl acetate (10 ml x 3) was added, followed by drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 3p in a 62% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0150] 1H NMR (400MHz, CDCl3) δ7.86–7.82(m,2H),6.81–6.78(m,2H),4.21–4.11(m,3H),3.07(dd,J=17.4,2.6Hz,1H),2.93(dd ,J=17.4,9.0Hz,1H),1.61(s,6H),1.58–1.41(m,3H),1.36–1.27(m,3H),1.17(t,J=7.1Hz,3H),0.87(t,J=7.1Hz,3H).

[0151] 13 C NMR (101MHz, CDCl3) δ199.66,173.70,160.20,130.45,130.07,117.41,79.44,67.92,61.78,44.66,36.32,27.81,25.41,22.74,14.12,14.08.

[0152] HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 28 NaO5 + 359.1829; Found 359.1828.

[0153] Example 18

[0154] Preparation of compound 3a:

[0155]

[0156] As shown in reaction formula (2), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. An iron sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 15 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction was performed with ethyl acetate (10 ml x 3), drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 3a in a 15% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0157] Example 19

[0158] Preparation of compound 3a:

[0159]

[0160] As shown in reaction formula (2), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 5 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction was performed with ethyl acetate (10 ml x 3), drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 3a in a 32% yield. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0161] Example 20

[0162] Preparation of compound 3a:

[0163]

[0164] As shown in reaction formula (2), under nitrogen protection in a glove box, the epoxide of formula 1a (0.75 mmol, 1.5 equiv.), the aryl iodide of formula 2a (0.5 mmol, 1.0 equiv.), ClCO2Pr (1.5 mmol, 3.0 equiv.), TMSI (0.6 mmol, 1.2 equiv.), tetrabutylammonium hexafluorophosphate (0.72 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (15 mol% of the aryl iodide of formula 2a), and NiCl2·dme (10 mol% of the aryl iodide of formula 2a) were added to a reaction tube containing a magnetic particle. 4 mL of DMA and 2.0 mL of 1,4-dioxane were added. A zinc sheet was used as the anode and carbon felt was used as the cathode. The reaction was carried out at a current of 10 mA for four hours. After the reaction was completed, 3 mL of 2 mol / L dilute hydrochloric acid was added and stirred for 1 hour. After dilution with water, extraction was performed with ethyl acetate (10 ml x 3), drying over anhydrous sodium sulfate, filtration, concentration, and separation by thin-layer chromatography using petroleum ether / ethyl acetate in a volume ratio of 5:1 as eluent to obtain the purified target compound represented by Formula 3a in a yield of 54%. It should be noted that in this example, the butyl group in the epoxide represented by Formula 1a is n-butyl.

[0165] The present invention utilizes a metal-catalyzed electroreduction carbonylation method to synthesize a series of hydroxyketone compounds 3a-3q. These compounds contain tert-butyloxycarbonyl (NHBoc) and dimethyl tert-butylsilyl ether (OTBS), which can be used for subsequent deprotection and further functionalization for the derivatization of drug molecules. A derivative of the drug molecule clofibrate, represented by formula 3p, was prepared using the method of the present invention and may exhibit certain biological activity. Furthermore, a series of chirally preserved hydroxyketones, such as 3b, were prepared using the method of the present invention.

[0166] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0167] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. A method for preparing hydroxyketone compounds based on electrosynthesis, characterized in that: The following steps are involved: Under protective atmosphere, in an organic solvent, with the epoxy compound shown in Formula 1, the aryl iodide shown in Formula 2 and a carbon monoxide source as reaction raw materials, under electrochemical conditions, in the presence of a promoter and a metal catalyst, an electroreduction carbonylation reaction occurs to obtain a hydroxyketone compound as shown in Formula 3; and the reaction process is shown in Reaction Formula (1): ； Among them, R 1 is any one of a straight-chain alkyl group, a cycloalkyl group, a trifluoromethyl group, and hydrogen; R 2 is any one of a straight-chain alkyl group, a cycloalkyl group, a trifluoromethyl group, and hydrogen; R 3 is any one of a straight-chain alkyl group, a cycloalkyl group, a trifluoromethyl group, and hydrogen; or R 1 With R 2 Together with their carbon atoms, they form a cycloalkyl group, or R 1 With R 3 Together with their carbon atoms, they form a cycloalkyl group, or R 2 With R 3 Bonded to their carbon atoms to form substituted heteroatom cycloalkyl groups; R 4 is a single or multiple substituent, and the substituent is any one of a straight-chain alkoxy group, a straight-chain alkyl group, a halogen, an amino protecting group, and a hydroxyl protecting group; The accelerator is any one of sodium iodide, tetrabutylammonium iodide, potassium iodide, and iodotrimethylsilane; The carbon monoxide source is any one of n-propyl chloroformate, ethyl oxalyl chloride, and oxalyl chloride; The metal catalyst is nickel(II) chloride ethylene glycol dimethyl ether; The current under electrochemical conditions is 5mA~15mA.

2. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: R 1 is one of hydrogen, butyl, ethyl, methyl, and trifluoromethyl; R 2 is one of butyl, ethyl, methyl, trifluoromethyl, and hydrogen; R 3 is one of butyl, ethyl, methyl, trifluoromethyl, and hydrogen; or R 1 With R 2 Together with the carbon atoms they carry, they form a 6-membered cycloalkyl group; or R 1 With R 2 Together with the carbon atoms they carry, they form a 5-membered cycloalkyl group; or R 2 With R 3 Bonded to their carbon atoms ; R 4 is a single or multiple substituent, and the substituent is meta-substituted methoxy, ortho-substituted methoxy, para-substituted methoxy, fluorine, tert-butyloxycarbonylamino, tert-butyldimethylsilyloxy, Any one of, or R 4 The two substituents are N-phenyl-benzindole.

3. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The molar ratio of the epoxide represented by Formula 1 to the carbon monoxide source is 1 to 1.5:1; The molar ratio of the aryl iodide shown in Formula 2 to the carbon monoxide source is 1.5-3:

1.

4. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The electroreduction carbonylation reaction takes 4 to 6 hours at room temperature and 3 to 6 hours under electrochemical conditions. The anode used is a zinc sheet or an iron sheet, and the cathode is a carbon felt.

5. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The ratio of the organic solvent to the alkyl halide represented by Formula 1 is 5 mL to 10 mL: 0.5 mmol.

6. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The carbon monoxide source is propyl chloroformate, and the molar ratio of the carbon monoxide source to the metal catalyst is 1:0.05-0.

15.

7. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The molar ratio of the carbon monoxide source to the promoter is 1:1~1.

5.

8. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The organic solvent is any one of acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran and acetone.

9. The method for preparing hydroxyketone compounds based on electrosynthesis according to claim 1, characterized in that: The pressure of the protective gas is 1~6atm.

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