Preparation method of indole-3-yl alkyl malonate compound

Abstract

The invention discloses a preparation method of an indole-3-yl alkyl malonate compound and a preparation method of the indole-3-yl alkyl malonate compound. According to the method, reaction raw materials which are economical, cheap and easy to obtain are subjected to a three-component C (sp3)-H / C (sp2)-H functionalization reaction under a mild electrochemical condition, and the indole-3-alkyl malonate compound is obtained through one-step construction. According to the method, a C (sp3)-H / C (sp2)-H functionalization regioselective pathway is adopted, and H2 is a unique theoretical byproduct. Mechanism studies show that the reaction generates alkyl free radicals through C (sp3)-H bond oxidation, the free radicals are added to C = C bonds, and single electron oxidation and C (sp2)-H functionalization cascade reaction are carried out. Compared with an existing method, the preparation method has the outstanding advantages that the raw materials are cheap and easy to obtain, the reaction substrate is wide in application range, the target product yield is high, and the atom economy of the reaction is good.

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 indol-3-yl alkyl malonate compound. Background Art

[0002] Indole and its derivatives are widely present 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. Especially 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 synthetic intermediates 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] In view of the wide range of uses of indol-3-yl alkyl malonate compounds, their synthesis methods have aroused widespread interest among organic synthetic chemists. CN104119262A discloses the preparation of indol-3-yl alkyl malonate compounds by asymmetric Friedel-Crafts alkylation reaction of indole and benzylidene malonate in the presence of copper / chiral catalyst; CN105949110A discloses the preparation of indol-3-yl alkyl malonate compounds by ball milling reaction of 2-phenyl-3-arylmethyl indole and malonate in the presence of metal iron salt catalysis, DDQ as an oxidant, silica gel as a grinding aid, and ball milling reaction. 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 inventor's research group reported that in the photocatalytic conditions of fac-[Ir(ppy)]3, styrene and indole, α-carbonyl alkyl bromide intermolecular 1,2-alkyl arylation reaction prepared indol-3-yl alkyl malonate compounds (J.Org.Chem., 2016, 81, 7148-7154). However, the above method disclosed in the prior art still has the defect of using expensive and difficult to obtain raw materials and / or reagents, such as brominated raw materials, cyclopropane dicarboxylate, photocatalyst and / or chiral catalyst, etc., resulting in high process costs of the above method, which is not suitable for industrial production.

[0006] Organic electrosynthesis is an interdisciplinary subject involving electrochemistry, organic synthesis and chemical engineering, and is known as "ancient method, new technology". 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 of using economical and readily available reaction raw materials (arylene, malonate and indole) and three components of C (sp 3 )–H / C(sp 2 )–H functionalization reaction, a one-step construction of indol-3-ylalkylmalonate compounds. This method provides a novel method for obtaining indol-3-ylalkylmalonate compounds by C(sp 3)-H / C(sp 2 )-H functionalization, 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, free 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: an economical, cheap and readily available reaction raw material (arylene, malonate and indole), a C (sp 3 )–H / C(sp 2 )–H functionalization reaction, a new method for one-step construction of indol-3-ylalkylmalonate compounds. This method provides a new method for obtaining indol-3-ylalkylmalonate compounds by C(sp 3 )-H / C(sp 2 )-H functionalization, 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, free radical addition to C=C bond, single electron oxidation and C(sp 2 Compared with the existing methods, the preparation method of the present invention has the advantages of cheap and easy-to-obtain raw materials, wide adaptability of reaction substrates, high yield of target products and good atom economy of the reaction.

[0008] A method for preparing an indol-3-yl alkyl malonate compound provided by the present invention comprises the following steps:

[0009] Into 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, and then a catalyst Cp2Fe, an alkali, an electrolyte, and an organic solvent are added, the reactor is placed in an inert atmosphere and at a certain temperature, a constant current is passed for stirring and electrolysis reaction until the reaction is complete, and after the reaction is complete, an indole-3-yl alkyl malonate compound represented by Formula 4 is obtained by 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 Haloalkyl, 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 stated 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, furanyl, 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 and 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 sodium acetate is most preferred.

[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, wherein the organic solvent is one or more of tetrahydrofuran, acetonitrile, dioxane, DMF, DMSO, preferably a mixed solvent of tetrahydrofuran and acetonitrile. Further preferably, the volume ratio of tetrahydrofuran and acetonitrile in the mixed solvent 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 shown in Formula 1, the malonic ester 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), 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 current 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-yl alkyl 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 invention discloses a novel method for preparing a novel catalyst for preparing a catalyst by using economical, cheap and readily available reaction raw materials (arylene, malonate and indole) and reacting the three components of C (sp 3 )–H / C(sp 2 )–H functionalization reaction, a new method for one-step construction of indol-3-ylalkylmalonate compounds. This method provides a new method for obtaining indol-3-ylalkylmalonate compounds by C(sp 3 )-H / C(sp 2 )-H functionalization, 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, free radical addition to C=C bond, single electron oxidation and C(sp 2 Compared with the existing methods, the preparation method of the present invention has the advantages of cheap and easy-to-obtain raw materials, wide adaptability 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 is further described in detail below in conjunction with 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, and 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] Into 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 placed in a 10 mA constant current, 50° C. and stirred for electrolysis for 4 hours, the reaction was complete as detected by TLC, water was added to the reaction solution for quenching, and then extracted with ethyl acetate (3×10 mL), the organic phases were combined, anhydrous sodium sulfate was added, filtered, and concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography (eluting solvent was n-hexane / ethyl acetate) to obtain the target product 4aaa, with a yield of 66.0 mg and a yield of 78%; 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, found 446.1931.

[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] On the basis of obtaining the optimized reaction conditions, the universality of the optimal reaction conditions for substituents was further explored. First, the reaction of different aromatic olefin compounds, malonate compounds and N-methyl indole under the optimized reaction conditions (Example 1) was tested, and 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 to 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-described 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 changes 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-yl alkyl malonate compound, characterized in that: The method comprises the following steps: sequentially adding an aromatic olefin compound shown in Formula 1, a malonate compound shown in Formula 2 and an indole compound shown in Formula 3 to an electrolytic reactor equipped with a platinum cathode and a graphite felt anode, then adding a catalyst Cp2Fe, an alkali, an electrolyte and an organic solvent, placing the reactor in an inert atmosphere and at a certain temperature, stirring and electrolyzing the reactor with a constant current until the reaction is complete, and after the reaction is complete, obtaining an indol-3-yl alkyl malonate compound shown in 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 Haloalkyl, 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.

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 and 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, and sodium acetate is most preferred.

5. The preparation method according to claim 1 or 2, characterized in that: The electrolyte is n Bu4NBF4, n Bu4NPF6, n One or more of Bu4NHSO4, most preferably n Bu4NBF4.

6. The preparation method according to claim 1 or 2, characterized in that: The organic solvent is one or more of tetrahydrofuran, acetonitrile, dioxane, DMF, and DMSO, preferably a mixed solvent of tetrahydrofuran and acetonitrile; further preferably, the volume ratio of tetrahydrofuran and acetonitrile in the mixed solvent is 1:(0.5-2), and most preferably 1:

1.

7. 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 malonic ester 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), preferably 1:2:2:0.1:2:

1.

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

9. The preparation method according to claim 1 or 2, characterized in that: The certain temperature is room temperature to 60°C, preferably 40 to 60°C, and more preferably 50°C; the current of the constant current is 5-20mA, preferably 10mA; the time required for the complete reaction is generally 2 to 6h, preferably 4h.

10. 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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