A preparation method of indol-3-ylalkyl malonate compounds

Abstract

The present invention discloses a method for preparing an indole-3-ylalkyl malonate compound. The method uses economical, cheap and readily available reaction raw materials, and is carried out under mild electrochemical conditions by reacting C (sp) with three components. 3 )–H / C(sp 2 )–H functionalization reaction, one-step construction to obtain indole-3-alkyl malonate compounds. This method is through C(sp 3 )‑H / C(sp 2 )-H functionalization regioselective pathway, with H2 as the only theoretical byproduct. Mechanistic studies suggest that the reaction proceeds via C(sp 3 )-H bond oxidation to generate alkyl radicals, radical addition to C=C bond, single electron oxidation and C(sp 2 Compared with existing methods, the preparation method of the present invention has the advantages of cheap and readily available raw materials, a wide range of reaction substrates, high yield of target products and good atom economy of the reaction.

Description

Technical Field

[0001] The present application belongs to the technical field of organic electrochemical synthesis, and specifically relates to a method for preparing an indole-3-ylalkyl malonate compound. Background Art

[0002] Indole and its derivatives are widely found in nature and are mainly used to make spices, dyes, materials, pesticides, medicines, etc. They are important organic synthesis intermediates and have broad application prospects. In the field of medicine, indole structure is one of the important precursors for the design and development of new drugs because of its significant physiological activity. For example, EP1006112A1 discloses indol-3-ylethyl malonate compounds.

[0003]

[0004] The invention discloses a synthetic intermediate of 3-hydroxy-2(1H)-pyridone or 3-hydroxy-4(1H)-pyridone derivatives used as reactive oxygen species (ROS) scavengers. For example, CN1569834A discloses indol-3-ylmethylmalonic acid ester compounds used as PPARγ agonists and as drugs for the treatment of type 2 diabetes.

[0005] Given the wide range of uses for indol-3-ylalkyl malonates, their synthesis methods have attracted widespread interest among organic synthetic chemists. CN104119262A discloses an asymmetric Friedel-Crafts alkylation reaction of indole and benzylidene malonate in the presence of a copper / chiral catalyst to prepare indol-3-ylalkyl malonate compounds. CN105949110A discloses a ball-milling method for preparing indol-3-ylalkyl malonate compounds by reacting 2-phenyl-3-arylmethylindole and malonate in the presence of a metallic iron salt catalyst, DDQ as an oxidant, and silica gel as a grinding aid. In addition, the preparation of indol-3-ylalkyl malonate compounds by reacting 1,1-cyclopropanedicarboxylate with indole compounds under various conditions is a common preparation method in the art (Tetrahedron Letters, Vol., 38, No. 34, pp. 5949-5952; Tetrahedron Letters., 55, (2014), 5280–5282; Tetrahedron., 72, (2016), 613-624; Org. Lett., Vol. 13, No. 16, 4180-4183; Org. Lett., Vol. 15, No. 10, 2558-2561; J. Am. Chem. Soc., 2013, 135, 7851-7854, etc.). The inventors' research group reported the preparation of indol-3-ylalkyl malonates through an intermolecular 1,2-alkylarylation reaction of styrene with indole and α-carbonylalkyl bromides under fac-[Ir(ppy)]3 photocatalytic conditions (J.Org.Chem., 2016, 81, 7148-7154). However, the above-mentioned methods disclosed in the prior art still suffer from the drawback of using expensive and difficult-to-obtain raw materials and / or reagents, such as brominated raw materials, cyclopropanedicarboxylates, photocatalysts, and / or chiral catalysts. This results in high process costs and makes these methods unsuitable for industrial production.

[0006] Organic electrosynthesis is an interdisciplinary subject involving electrochemistry, organic synthesis, and chemical engineering. It is known as "ancient methods, new technologies." It is a new technology that uses electrons as reagents to achieve organic chemical synthesis through the gain and loss of electrons. Therefore, the method of organic electrosynthesis fully meets the requirements of atom economy and is a "green synthesis" technology. In the present invention, the inventors disclose a method for preparing a novel organic electrosynthesis reaction system using economical and readily available raw materials (arylene, malonate, and indole) and a three-component C(sp) reaction under electrochemical conditions. 3 )–H / C(sp 2 )–H functionalization reaction, a one-step construction of indol-3-ylalkyl malonate compounds. This method provides a novel method for the preparation of indol-3-yl alkyl malonate compounds by C(sp 3)-H / C(sp 2 )-H functionalization, in which H2 is the only theoretical byproduct. Mechanistic studies suggest that the reaction proceeds via C(sp 3 )-H bond oxidation to generate alkyl radicals, radical addition to C=C bond, single electron oxidation and C(sp 2 )-H functionalization cascade reaction proceeds. Summary of the Invention

[0007] The purpose of the present invention is to overcome the defects of the prior art and to provide a novel method for preparing a novel catalytic converter comprising economical, cheap and readily available reaction raw materials (arylethylene, malonate and indole) and a C(sp 3 )–H / C(sp 2 )–H functionalization reaction, a new method for obtaining indol-3-ylalkyl malonate compounds in one step. This method provides a new method for obtaining indol-3-yl alkyl malonate compounds by C(sp 3 )-H / C(sp 2 )-H functionalization, in which H2 is the only theoretical byproduct. Mechanistic studies suggest that the reaction proceeds via C(sp 3 )-H bond oxidation to generate alkyl radicals, radical addition to C=C bond, single electron oxidation and C(sp 2 Compared with existing methods, the preparation method of the present invention has the advantages of cheap and readily available raw materials, a wide range of reaction substrates, high yield of target products and good atom economy of the reaction.

[0008] According to the present invention, a method for preparing an indol-3-ylalkyl malonate compound comprises the following steps:

[0009] To an electrolytic reactor equipped with a platinum cathode and a graphite felt anode, an aromatic olefin compound represented by Formula 1, a malonate compound represented by Formula 2, and an indole compound represented by Formula 3 are added in sequence, followed by the addition of a catalyst Cp2Fe, a base, an electrolyte, and an organic solvent. The reactor is placed in an inert atmosphere and at a certain temperature, and a constant current is passed through the reactor for stirring and electrolysis until the reaction is complete. After the reaction is complete, the indole-3-ylalkyl malonate compound represented by Formula 4 is obtained through post-treatment. The reaction formula is as follows:

[0010]

[0011] wherein R1 is selected from substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 2-20 Heteroaryl; wherein the substituent in the substituted is selected from halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Alkylthio, C 6-14 Aryl, C 6-14 Aryloxy, C 6-14 Aryl-C 1-3 alkoxy;

[0012] R2, R3 are independently selected from hydrogen, C 1-6 alkyl;

[0013] R4 is selected from hydrogen, halogen, C 1-6 Alkyl, -CO2R', wherein R' is selected from C 1-6 alkyl;

[0014] R5 is selected from C 1-6 Alkyl, C 6-14 Aryl-C 1-3 alkyl;

[0015] R6 is selected from halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, phenyl;

[0016] R7 is selected from C 1-6 Alkyl, C 6-14 Aryl-C 1-3 alkyl.

[0017] In the present invention, the alkyl group or alkyl moiety having the stated number of carbon atoms is linear or branched, and the alkyl group is preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.

[0018] In the present invention, the aryl group having the aforementioned number of carbon atoms is selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, etc., preferably phenyl or naphthyl.

[0019] In the present invention, the heteroatom in the heteroaryl group having the stated number of carbon atoms is one or more of N, O, and S. Preferred heteroaryl groups include, but are not limited to, thienyl, pyrimidinyl, pyridyl, furyl, indolyl, benzofuranyl, benzothienyl, and the like.

[0020] In the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0021] According to the aforementioned preparation method of the present invention, preferably, R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, benzofuranyl, benzodioxolanyl; wherein the substituent in the substituted is selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, methylthio, phenyl, phenoxy, benzyloxy;

[0022] R2, R3 are independently selected from hydrogen, methyl;

[0023] R4 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, -CO2R', wherein R' is selected from methyl or ethyl;

[0024] R5 is selected from methyl, ethyl, tert-butyl, benzyl;

[0025] R6 is selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, methoxy, trifluoromethyl, phenyl;

[0026] R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-hexyl, benzyl, biphenylmethyl.

[0027] Most preferably, the compound of formula 1 is selected from one of the following compounds:

[0028]

[0029] The compound of formula 2 is selected from one of the following compounds:

[0030]

[0031] The compound of formula 3 is selected from one of the following compounds:

[0032]

[0033] According to the aforementioned preparation method of the present invention, wherein the base is one or more of sodium acetate, sodium carbonate, sodium bicarbonate, sodium hydroxide, and ethylamine, and most preferably sodium acetate.

[0034] According to the aforementioned preparation method of the present invention, wherein the electrolyte is n Bu4NBF4, n Bu4NPF6, n One or more of Bu4NHSO4, most preferably n Bu4NBF4.

[0035] According to the aforementioned preparation method of the present invention, the organic solvent is one or a mixture of tetrahydrofuran, acetonitrile, dioxane, DMF, and DMSO, preferably a mixture of tetrahydrofuran and acetonitrile. Further preferably, the volume ratio of tetrahydrofuran to acetonitrile in the mixture is 1:(0.5-2), most preferably 1:1.

[0036] According to the aforementioned preparation method of the present invention, the molar ratio of the aromatic olefin compound represented by Formula 1, the malonate compound represented by Formula 2, the indole compound represented by Formula 3, the catalyst Cp2Fe, the electrolyte and the base is 1:(1~3):(1~3):(0.05~0.2):(1~3):(0.8~1.2), preferably 1:2:2:0.1:2:1.

[0037] According to the aforementioned preparation method of the present invention, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably an argon atmosphere.

[0038] According to the aforementioned preparation method of the present invention, the certain temperature is room temperature to 60°C, preferably 40 to 60°C, and more preferably 50°C.

[0039] According to the aforementioned preparation method of the present invention, the magnitude of the constant current is 5-20 mA, preferably 10 mA. The time required for the complete reaction is generally 2-6 hours, preferably 4 hours.

[0040] According to the aforementioned preparation method of the present invention, the post-treatment operation is as follows: the reaction solution is quenched by adding water, extracted with ethyl acetate, the organic phases are combined, dried and concentrated to obtain a residue, and then separated by silica gel column chromatography to obtain the indol-3-ylalkyl malonate compound shown in Formula 4.

[0041] Compared with the prior art, the preparation method disclosed in the present invention has the following significant advantages:

[0042] The present invention is a novel method for preparing a novel catalyst comprising the following steps: using economical, cheap and readily available reaction raw materials (arylethylene, malonate and indole) and reacting the catalyst under electrochemical conditions to form a three-component C (sp 3 )–H / C(sp 2 )–H functionalization reaction, a new method for obtaining indol-3-ylalkyl malonate compounds in one step. This method provides a new method for obtaining indol-3-yl alkyl malonate compounds by C(sp 3 )-H / C(sp 2 )-H functionalization, in which H2 is the only theoretical byproduct. Mechanistic studies suggest that the reaction proceeds via C(sp 3 )-H bond oxidation to generate alkyl radicals, radical addition to C=C bond, single electron oxidation and C(sp 2 Compared with existing methods, the preparation method of the present invention has the advantages of cheap and readily available raw materials, a wide range of reaction substrates, high yield of target products and good atom economy of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Schematic diagram of the reaction mechanism of the present invention.

[0044] Figure 2 This is a diagram of the reaction device of the present invention. DETAILED DESCRIPTION

[0045] The present invention will be further described in detail below with reference to specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the reagents used are all purchased through conventional commercial channels in the art without further purification, drying, etc.

[0046] Examples 1-15

[0047] Using p-methoxystyrene shown in Formula 1a, diethyl malonate shown in Formula 2a, and N-methylindole shown in Formula 3a as template substrates, the effects of different synthesis conditions on the yield of the target product 4aaa were investigated. The results are shown in Table 1. The reaction formula is as follows:

[0048]

[0049] Table 1:

[0050]

[0051]

[0052] Taking Example 1 as an example, the typical test operation is as follows:

[0053] To an unpartitioned three-necked flask (10 mL), p-methoxystyrene (0.2 mmol) of formula 1a, diethyl malonate (0.4 mmol, 2.0 eq) of formula 2a, N-methylindole (0.4 mmol, 2.0 eq) of formula 3a, NaOAc (0.2 mmol, 1.0 eq), n Bu4NBF4 (0.4 mmol, 2.0 eq), Cp2Fe (10 mol%), THF (2 mL) and MeCN (2 mL). A three-necked flask was then equipped with a platinum cathode (1.0 × 1.0 cm 2 ) and a graphite felt anode (10×10×3 mm). The atmosphere in the reactor was replaced with argon. The reaction mixture was subjected to a stirring electrolysis reaction at a constant current of 10 mA and 50°C for 4 hours. The reaction was complete as determined by TLC. The reaction solution was quenched with water and then extracted with ethyl acetate (3×10 mL). The organic phases were combined, anhydrous sodium sulfate was added, and the mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was separated by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) to obtain the target product 4aaa in a yield of 66.0 mg and a yield of 78%; it was a yellow oily liquid. 1H NMR(500MHz, CDCl3)δ7.46(d,J=8.0Hz,1H),7.25-7.21(m,3H),7.17(t,J=7.5 Hz,1H),7.01(t,J=7.5Hz,1H),6.85(s,1H),6.82(d,J=8.5Hz,2H),4.22-4.17 (m,3H),4.16-4.10(m,2H),3.75(s,3H),3.71(s,3H),3.36-3.33(m,1H),2.82 -2.76(m,1H),2.58-2.52(m,1H),1.26(t,J=7.0Hz,3H),1.21(t,J=7.0Hz,3H); 13 C NMR (125MHz, CDCl3) δ169.5,169.5,158.0,137.2,135.6,128.8,127.1,125.9,121.6,119 .5,118.7,117.6,113.8,109.1,61.3,55.1,55.1,50.3,39.7,35.0,32.6,14.0,14.0; HRMS m / z(ESI)calcd for C 25 H 29 NO5[M+Na] + 446.1938,found446.1931.

[0054] Except for the reaction conditions listed in Table 1, the other reaction conditions and operations of Examples 2-15 are the same as those of Example 1.

[0055] Based on the optimized reaction conditions, we further explored the universality of these optimal reaction conditions for substituents. We first tested the reactions of various aromatic olefin compounds, malonate compounds, and N-methylindole under the optimized reaction conditions (Example 1). The yields and product structure characterization results are shown below:

[0056]

[0057] Structural characterization of the product:

[0058] Compound 4baa: 1H NMR(400MHz, CDCl3) δ7.47(d,J=8.0Hz,1H),7.25(d,J=7.6Hz,1H),7.21-7.15 (M,3H),7.08(d,J=7.6Hz,2H),7.01(t,J=7.6Hz,1H),6.85(s,1H),4.22-4.16 (m,3H),4.15-4.08(m,2H),3.72(s,3H),3.36-3.32(m,1H),2.82-3.75(m,1H) ,2.61-2.53(m,1H),2.29(s,3H),1.26(t,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H).

[0059] Compound 4caa: 1 H NMR (500MHz, CDCl3) δ7.46(d,J=7.5Hz,1H),7.41(d,J=7.0Hz,2H),7.37(t,J=8.0Hz,2H),7. 31(t,J=7.5Hz,1H),7.24-7.21(m,3H),7.16(s,1H),7.01(t,J=7.5Hz,1H),6.89(d,J=8.5Hz, 2H),6.85(s,1H),5.01(s,2H),4.21-4.17(m,3H),4.16-4.09(m,2H),3.73(s,3H),3.62-3.3 3(m,1H),2.81-2.75(m,1H),2.58-2.52(m,1H),1.26(t,J=7.0Hz,3H),1.21(t,J=7.0Hz,3H).

[0060] Compound 4daa: 1 H NMR (500MHz, CDCl3) δ7.44(d,J=8.0Hz,1H),7.24(d,J=2.5Hz,2H),7.22(s, 1H),7.20-7.16(m,3H),7.01(t,J=7.5Hz,1H),6.86(s,1H),4.21-4.17(m,3 H),4.16-4.09(m,2H),3.73(s,3H),3.35-3.32(m,1H),2.81-2.75(m,1H),2 .59-2.53(m,1H),2.44(s,3H),1.26(t,J=7.5Hz,3H),1.22(t,J=7.5Hz,3H).

[0061] Compound 4eaa: 1H NMR (500MHz, CDCl3) δ7.52-7.50(m,1H),7.23-7.19(m,2H),7.17-7.12(m,2H),7.02-6.99(m,1H),6.88(s,1H),6. 86-6.82(m,2H),4.83-4.75(m,1H),4.23-4.17(m,1H),4.16-4.08(m,3H),3.82(s,3H),3.69(s,3H),3.36-3.33(m 1H),2.83-2.77(m,1H),2.59-2,52(m,1H),1.23(t,J=6.5Hz,3H),1.20(t,J=6.5Hz,3H).

[0062] Compound 4gaa: 1 H NMR (500MHz, CDCl3) δ7.42-7.40 (m, 1H), 7.29 (d, J = 2.0Hz, 1H), 7.28-7.26 ( m,1H),7.22-7.14(m,2H),7.03-7.00(m,1H),6.89(s,1H),6.84(d,J=8.5Hz, 1H),4.22-4.10(m,5H),3.85(s,3H),3.76(s,3H),3.35-3.32(m,1H),2.78-2 .72(m,1H),2.56-2.51(m,1H),1.27(t,J=7.0Hz,3H),1.23(t,J=7.0Hz,3H).

[0063] Compound 4haa: 1 H NMR (500MHz, CDCl3) δ7.45(d,J=8.0Hz,1H),7.18(t,J=7.5Hz,1H),7.02(t,J=7.0Hz ,1H),6.80(s,1H),6.80-6.76(m,2H),6.72(d,J=7.5Hz,1H),5.90-5.88(m,2H),4.22 -4.17(m,2H),4.14-4.12(m,2H),4.13-4.10(m,1H),3.75(s,3H),3.37-3.34(m,1H) ,2.79-2.73(m,1H),2.54-2.48(m,1H),1.27(t,J=7.0Hz,3H),1.23(t,J=7.0Hz,3H).

[0064] Compound 4iaa: 1H NMR (500MHz, CDCl3) δ7.63(d,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),7.13(t,J=7.5Hz,1H ),7.01(t,J=7.5Hz,1H),6.94(s,1H),6.10(s,2H),4.95-4.90(m,1H),4.25-4.20(m,1H ),4.17-4.12(m,1H),4.11-4.03(m,2H),3.77(s,9H),3.70(s,3H),3.28-3.25(m,1H),2 .95-2.89(m,1H),2.82-2.76(m,1H),1.27-1.24(t,J=7.0Hz,3H),1.19(t,J=7.0Hz,3H).

[0065] Compound 4jaa: 1 H NMR (400MHz, CDCl3) δ7.72-7.67(m,2H),7.64(d,J=8.5Hz,1H),7.49-7.46(m,1H),7.39-7.37( m,1H),7.26-7.24(m,1H),7.18-7.14(m,1H),7.13-7.07(m,2H),7.02-6.96(m,1H),6.91(s,1H ),4.38-4.34(m,1H),4.23-4.17(m,2H),4.15-4.03(m,2H),3.88(s,3H),3.73(s,3H),3.40-3. 36(m,1H),2.91-2.84(m,1H),2.71-2.65(m,1H),1.26(t,J=7.2Hz,3H),1.18(t,J=7.2Hz,3H).

[0066] Compound 4kaa: 1 H NMR (500MHz, CDCl3) δ7.58(d,J=8.0Hz,1H),7.26(d,J=8.5Hz,1H),7.20(t,J=8.0Hz,1H),7.08-7.05(m,2H),6.89(s,1H),6.77(d,J=5.0Hz,1H), 4.59(t,J=8.0Hz,1H),4.21-4.13(m,4H),3.73(s,3H),3.43-3.40(m,1H ),2.85-2.70(m,1H),2.57-2.51(m,1H),2.21(s,3H),1.28-1.21(m,6H).

[0067] Compound 41a: 11H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.47 - 7.46 (m, 1H), 7.42 - 7.40 (m, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.23 - 7.15 (m, 3H), 7.09 - 7.06 (m, 1H), 7.00 (s, 1H), 6.51 (s, 1H), 4.50 - 4.45 (m, 1H), 4.24 - 4.20 (m, 1H), 4.18 - 4.11 (m, 3H), 3.75 (s, 3H), 3.43 (t, J = 7.5 Hz, 1H), 2.86 - 2.73 (m, 2H), 1.24 - 1.21 (m, 6H).

[0068] Compound 4maa: 1 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 4.5 Hz, 1H), 7.19 - 7.14 (m, 3H), 6.99 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 6.05 - 6.00 (m, 1H), 5.47 - 5.41 (m, 1H), 4.83 (d, J = 7.5 Hz, 1H), 4.18 - 4.07 (m, 4H), 3.77 (s, 3H), 3.71 (s, 3H), 3.40 (t, J = 7.5 Hz, 1H), 2.66 (t, J = 7.0 Hz, 2H), 1.22 - 1.18 (m, 6H).

[0069] Compound 4naa: 1 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.21 - 7.18 (m, 1H), 7.16 - 7.11 (m, 2H), 7.08 - 7.05 (m, 1H), 7.02 - 6.99 (m, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.49 (s, 1H), 4.35 (d, J = 6.5 Hz, 1H), 4.21 - 4.14 (m, 4H), 3.68 (s, 3H), 3.53 (d, J = 8.0 Hz, 1H), 3.01 - 2.96 (m, 1H), 2.94 (t, J = 6.5 Hz, 2H), 2.16 - 2.13 (m, 1H), 1.67 - 1.63 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H).

[0070] Compound 4oaa: 1H NMR(500MHz, CDCl3)δ7.64(d,J=8.0Hz,1H),7.27(d,J=8.5Hz,1H),7.21-7.18(m,1H),7.16-7.1 1(m,2H),7.08-7.05(m,1H),7.02-6.99(m,1H),6.97(d,J=7.5Hz,1H),6.49(s,1H),4.35(d,J=6 .5Hz,1H),4.21-4.14(m,4H),3.68(s,3H),3.53(d,J=8.0Hz,1H),3.01-2.96(m,1H),2.94(t,J= 6.5Hz,2H),2.16-2.13(m,1H),1.67-1.63(m,1H),1.26(t,J=7.0Hz,3H),1.22(t,J=7.0Hz,3H).

[0071] Compound 4paa: 1 H NMR (500MHz, CDCl3) δ7.2-7.24(m,2H),7.22(t,J=1.0Hz,1H),7.13-7.10(m,1H), 7.02(s,1H),6.96(d,J=8.0Hz,1H),6.86-6.83(m,1H),6.78-6.75(m,2H),4.09-4 .00(m,2H),3.81-3.76(m,5H),3.75(s,3H),3.32(t,J=5.5Hz,1H),2.98-2.94(m, 1H), 2.90-2.86 (m, 1H), 1.65 (s, 3H), 1.19 (t, J = 7.5Hz, 3H), 1.06 (t, J = 7.0Hz, 3H).

[0072] Compound 4aba: 1 H NMR (500MHz, CDCl3) δ7.46-7.42(m,1H),7.24-7.20(m,3H),7.18-7.15(m,1H),7.02-6.99(m,1H),6.86-6.79(m,3H),4.17- 4.13(m,1H),3.74(s,3H),3.72(s,3H),3.70(s,3H),3.65(s,3H),3.41-3.38(m,1H),2.83-2.77(m,1H),2.59-2.53(m,1H).

[0073] Compound 4aca: 1H NMR (500MHz, CDCl3) δ7.36 (d, J = 8.0Hz, 1H), 7.32-7.26 (m, 8H), 7.24-7.21 (m, 3H), 7.18-7.12 (m, 3H), 6.99-6.96 (m, 1H), 6.78-6.7 6(m,3H),5.17-5.07(m,4H),4.14-4.11(m,1H),3.73(s,3H),3.68(s,3H),3.48-3.45(m,1H),2.85-2.79(m,1H),2.62-2.56(m,1H).

[0074] Compound 4ada: 1 H NMR (500MHz, CDCl3) δ7.47-7.45(m,1H),7.26-7.21(m,3H),7.19-7.16(m,1H),7.02 -6.99(m,1H),6.85(d,J=4.5Hz,1H),6.82(d,J=8.5Hz,2H),4.21-4.15(m,2H),4.15- 4.07(m,1H),3.76(s,3H),3.73(s,3H),3.26-3.22(m,1H),2.77-2.71(m,1H),2.54-2 .47(m,1H),1.47(s,5H),1.42(s,5H),1.26(t,J=7.0Hz,2H),1.22(t,J=7.01Hz,2H).

[0075] Compound 4aea: 1 H NMR (400MHz, CDCl3) δ7.56-7.53(m,1H),7.25-7.21(m,3H),7.17-7.13(m,1H), 7.04-7.00(m,1H),6.82-6.75(m,3H),4.31-4.27(m,1H),4.02-3.92(m,1H),3. 91-3.81(m,2H),3.74(s,3H),3.69(s,3H),3.68-3.61(m,1H),2.86-2.81(m,1H ), 2.74-2.69 (m, 1H), 1.42 (s, 3H), 1.12 (t, J = 7.2Hz, 3H), 1.08 (t, J = 7.2Hz, 3H).

[0076] Compound 4afa: 1H NMR (500MHz, CDCl3) δ7.50 (d, J = 7.5Hz, 1H), 7.27-7.23 (m, 3H), 7.17 (t, J = 7.5Hz, 1H), 7.03 (t, J = 7.0Hz, 1H), 6. 81-6.79(m,3H),4.51(t,J=6.0Hz,1H),3.75(s,3H),3.70(s,3H),3.47(s,3H),3.43(s,3H),3.10-2.99(m,2H).

[0077] Compound 4aga: 1 H NMR (500MHz, CDCl3) δ7.45(d,J=7.5Hz,1H),7.21(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,1H),7.07(d,J=7.0Hz,1H),6.93(d,J=7.5Hz,1H),6.76(s,1H),6 .70(d,J=8.0Hz,2H),4.62(t,J=6.0Hz,1H),3.85-3.81(m,6H),3.65(s,3H) ,3.61(s,3H),3.06-3.02(m,1H),2.91-2.87(m,1H),1.03(t,J=7.0Hz,9H).

[0078] Furthermore, the universality of the optimal reaction conditions of the present invention for different indole compounds was investigated, and the results are as follows:

[0079]

[0080] Structural characterization of the product:

[0081] Compound 4aab: 1 H NMR (500MHz, CDCl3) δ7.24-7.17(m,4H),7.02(s,1H),6.98(t,J=8.0Hz,1H),6.80(d,J=8.5Hz,2H),5.04(t,J=8.0Hz,1H),4.25-4.10(m, 3H), 4.11-4.04(m,1H),3.75(s,3H),3.74(s,3H),3.44(t,J=7.5Hz,1H),2.68-2.56(m,2H),1.25(d,J=7.0Hz,3H),1.21(t,J=7.0Hz,3H).

[0082] Compound 4aac: 1H NMR (500MHz, CDCl3) δ7.39(d,J=1.5Hz,1H),7.19(d,J=6.5Hz,2H),7.16-7.09(m,2H),6.88(s,1H),6.83(d,J=9.0Hz,2H),4.22-4.18(m,2H),4.1 7-4.09(m,3H),3.77(s,3H),3.70(s,3H),3.32-3.29(m,1H),2.75-2.69 (m,1H),2.57-2.51(m,1H),1.27(t,J=7.0Hz,3H),1.22(t,J=7.0Hz,3H).

[0083] Compound 4aad: 1 H NMR(500MHz, CDCl3)δ7.75(d,J=0.5Hz,1H),7.40-7.38(m,1H),7.29(d,J=8.5 Hz,1H),7.17(d,J=8.5Hz,2H),7.01(s,1H),6.84(d,J=9.0Hz,2H),4.24-4.20( m,2H),4.18-4.10(m,3H),3.79-3.78(d,J=4.5Hz,6H),3.31-3.28(m,1H),2.76 -2.71(m,1H),2.56-2.51(m,1H),1.29(t,J=7.0Hz,3H),1.23(t,J=7.0Hz,3H).

[0084] Compound 4aae: 1 H NMR (400MHz, CDCl3) δ7.31-7.29(m,1H),7.22-7.19(m,2H),6.84-6.80(m,2 H),6.74(d,J=0.8Hz,1H),6.71-6.66(m,2H),4.23-4.17(m,2H),4.16-4.08 (m,3H),3.83(s,3H),3.75(s,3H),3.66(s,3H),3.37-3.32(m,1H),2.80-2. 73(m,1H),2.56-2.49(m,1H),1.26(t,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H).

[0085] Compound 4aaf: 1H NMR (500MHz, CDCl3) δ7.35-7.32(m,1H),7.20(d,J=9.0Hz,2H),6.92-6.89(m,1H),6.83-6.82(m,3H),6.78-6.74(m,1H),4.22-4.18(m,2H),4.1 -4.09(m,3H),3.76(s,3H),3.67(s,3H),3.34-3.31(m,1H),2.79-2.73( m, 1H), 2.55-2.49 (m, 1H), 1.26 (t, J = 7.0Hz, 3H), 1.21 (t, J = 7.0Hz, 3H).

[0086] Compound 4aag: 1 H NMR (500MHz, CDCl3) δ7.55-7.46(m,5H),7.41(t,J=7.5Hz,2H),7.32(t,J=7.0Hz,1H ),7.24-7.22(m,3H),7.16-7.11(m,3H),7.03-7.00(m,2H),6.82(d,J=8.5Hz,2H),5. 30(s,2H),4.23-4.17(m,3H),4.15-4.08(m,2H),3.75(s,3H),3.41(t,J=7.5Hz,,1H) ,2.84-2.78(m,1H),2.60-2.53(m,1H),1.26(t,J=7.0Hz,3H),1.20(t,J=7.1Hz,3H).

[0087] Compound 4aah: 1 H NMR (500MHz, CDCl3) δ7.43(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,2H),7.14(t, J=7.5Hz,1H),6.98(t,J=7.5Hz,1H),6.91(s,1H),6.81(d,J=8.5Hz,2H),4.22-4.14(m,4H),4.13- 4.09(m,1H),4.04(t,J=7.0Hz,2H),3.75(s,3H),3.34(t,J=7.0Hz,1H),2.81-2.75(m,1H),2.58-2 .52(m,1H),1.80(t,J=7.0Hz,2H),1.29-1.25(m,9H),1.21(t,J=7.0Hz,3H),0.88(t,J=6.5Hz,3H).

[0088] Compound 4aaj: 1H NMR (500MHz, CDCl3) δ7.25-7.22(m,3H),6.91(t,J=7.0Hz,1H),6.85(d,J=6.5 Hz,2H),6.82(d,J=8.5Hz,2H),4.21-4.12(m,5H),4.07(t,J=5.0Hz,2H),3.75 (s,3H),3.35(t,J=7.5Hz,1H),2.94(t,J=6.0Hz,2H),2.83-2.78(m,1H),2.59 -2.53(m,1H),2.21-2.17(m,2H),1.26(t,J=7.0Hz,3H),1.22(t,J=7.0Hz,3H).

[0089] Compound 4aak: 1 H NMR (500MHz, CDCl3) δ7.69-7.67(m,1H),7.43-7.40(m,3H),7.35-7.33(m,1 H),7.28-7.24(m,2H),7.24-7.21(m,3H),7.11-7.08(m,1H),6.80-6.75(m,2 H),4.08-3.98(m,2H),3.97-3.84(m,3H),3.75(s,3H),3.54(s,3H),3.21-3 .18(m,1H),2.86-2.70(m,2H),1.11(t,J=6.4Hz,3H),1.09(t,J=6.4Hz,3H).

[0090] Compound 4aal: 1 H NMR (400MHz, CDCl3) δ7.56-7.54(m,1H),7.22-7.16(m,2H),7.15-7.08(m,3H) ,6.84-6.78(m,2H),4.52-4.48(m,1H),4.34-4.06(m,3H),4.02-3.95(m,1H), 3.90-3.83(m,1H),3.77(s,3H),3.41(s,3H),3.32-3.24(m,1H),2.98-2.88(m ,1H),2.74(m,1H),2.32(s,3H),1.26(t,J=7.2Hz,3H),1.12(t,J=7.2Hz,3H).

[0091] Compound 4aam: 1H NMR(500MHz, CDCl3)δ7.05-7.03(m,2H),6.81-6.80(m,2H),6.52(t,J=2.0Hz, 1H),6.14-6.13(m,1H),6.10-6.09(m,1H),4.24-4.18(m,2H),4.18-4.10(m,2H ),3.90(t,J=8.0Hz,1H),3.76(s,3H),3.38(t,J=7.5Hz,1H),3.28(s,3H),2.62 -2.56(m,1H),2.46-2.40(m,1H),1.27(t,J=7.5Hz,3H),1.23(t,J=7.5Hz,3H).

[0092] The above embodiments are only preferred embodiments of the present invention and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious modifications made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing an indol-3-ylalkyl malonate compound, characterized in that: The method comprises the following steps: sequentially adding an aryl olefin compound represented by Formula 1, a malonate compound represented by Formula 2, and an indole compound represented by Formula 3 to an electrolytic reactor equipped with a platinum cathode and a graphite felt anode, then adding a catalyst Cp2Fe, a base, an electrolyte, and an organic solvent, placing the reactor in an inert atmosphere and at a certain temperature, stirring and electrolyzing the reaction until the reaction is complete through a constant current, and after the reaction is complete, obtaining an indol-3-ylalkyl malonate compound represented by Formula 4 through post-treatment; the reaction formula is as follows: wherein R1 is selected from substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 2-20 Heteroaryl; wherein the substituent in the substituted is selected from halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 6-14 Aryl, C 6-14 Aryloxy, C 6-14 Aryl-C 1-3 alkoxy; R2, R3 are independently selected from hydrogen, C 1-6 alkyl; R4 is selected from hydrogen, halogen, C 1-6 Alkyl, -CO2R', wherein R' is selected from C 1-6 alkyl; R5 is selected from C 1-6 Alkyl, C 6-14 Aryl-C 1-3 alkyl; R6 is selected from halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, phenyl; R7 is selected from C 1-6 Alkyl, C 6-14 Aryl-C 1-3 alkyl; Wherein, the electrolyte is n Bu4NBF4, n Bu4NPF6, n One or more of Bu4NHSO4; the constant current is 5-20mA.

2. The preparation method according to claim 1, characterized in that R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, benzofuranyl, benzodioxolanyl; wherein the substituent in the substituted is selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, methylthio, phenyl, phenoxy, benzyloxy; R2, R3 are independently selected from hydrogen, methyl; R4 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, -CO2R', wherein R' is selected from methyl or ethyl; R5 is selected from methyl, ethyl, tert-butyl, benzyl; R6 is selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, methoxy, trifluoromethyl, phenyl; R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-hexyl, benzyl, biphenylmethyl.

3. The preparation method according to claim 1 or 2, characterized in that The compound of formula 1 is selected from one of the following compounds: The compound of formula 2 is selected from one of the following compounds: The compound of formula 3 is selected from one of the following compounds:

4. The preparation method according to claim 1 or 2, characterized in that The base is one or more of sodium acetate, sodium carbonate, sodium bicarbonate, sodium hydroxide and ethylamine.

5. The preparation method according to claim 4, wherein The base is sodium acetate.

6. The preparation method according to claim 1 or 2, characterized in that The electrolyte is n Bu4NBF4.

7. The preparation method according to claim 1 or 2, characterized in that The organic solvent is one or a mixed solvent of tetrahydrofuran, acetonitrile, dioxane, DMF and DMSO.

8. The preparation method according to claim 7, characterized in that The organic solvent is a mixed solvent of tetrahydrofuran and acetonitrile.

9. The preparation method according to claim 8, characterized in that The volume ratio of tetrahydrofuran and acetonitrile in the mixed solvent is 1:(0.5-2).

10. The preparation method according to claim 9, characterized in that The volume ratio of tetrahydrofuran and acetonitrile in the mixed solvent is 1:

1.

11. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the aromatic olefin compound shown in formula 1, the malonate compound shown in formula 2, the indole compound shown in formula 3, the catalyst Cp2Fe, the electrolyte and the base is 1:(1~3):(1~3):(0.05~0.2):(1~3):(0.8~1.2).

12. The preparation method according to claim 11, characterized in that The molar ratio of the aromatic olefin compound shown in Formula 1, the malonate compound shown in Formula 2, the indole compound shown in Formula 3, the catalyst Cp2Fe, the electrolyte and the base is 1:2:2:0.1:2:

1.

13. The preparation method according to claim 1 or 2, characterized in that: The inert atmosphere is a nitrogen atmosphere or an argon atmosphere.

14. The preparation method according to claim 13, characterized in that The inert atmosphere is an argon atmosphere.

15. The preparation method according to claim 1 or 2, characterized in that: The certain temperature is room temperature to 60° C., the magnitude of the constant current is 10 mA, and the time required for the complete reaction is 2 to 6 hours.

16. The preparation method according to claim 15, characterized in that The certain temperature is 50° C., and the time required for the complete reaction is 4 hours.

17. The preparation method according to claim 1 or 2, characterized in that: The post-treatment operation is as follows: the reaction solution is quenched with water, extracted with ethyl acetate, the organic phases are combined, dried and concentrated to obtain a residue, and then separated by silica gel column chromatography to obtain the indol-3-ylalkyl malonate compound shown in formula 4.

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