CN112225685B - 3-cyanoindole compound, preparation method and application thereof - Google Patents
3-cyanoindole compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a method for constructing 3-cyanoindole by a series reaction. The method comprises the following steps: the compound with the structure shown in the formula (1) and 4-isoxazole boronic acid pinacol ester are subjected to a suzuki reaction, isoxazole fragmentation is induced by alkali, and aldimine condensation is carried out, so that the 3-cyanoindole compound with the structure shown in the formula (2) is prepared. The invention selects a proper compound with the structure shown in the formula (1) as a substrate to realize the high-efficiency coupling of the compound with the structure shown in the formula (1), thereby preparing the 3-cyanoindole compound with the structure shown in the formula (2) at low cost. The 3-cyanoindole compound obtained by the invention can be used as a bioactive compound and a pharmaceutical intermediate.
Description
Technical Field
The invention relates to an arylamine compound, in particular to a 3-cyanoindole compound, and a preparation method and application thereof.
Background
Aryl and heteroaryl nitriles are of interest for a wide range of applications in medical and functional materials. The efficient synthesis of various aryl and heteroaryl nitriles having various structures has been extensively studied in recent years. Among these structures, 3-cyanoindole and its derivatives are important structural motifs of many biologically active compounds and general precursors of drugs. The importance of this framework has led to the development of a number of synthetic methods.
Direct C (sp) at position 3 of indole2The (-) H cyanation reaction is one of the most straightforward methods, however, the general method often uses toxic cyano sources (e.g., KCN or CuCN) or requires harsh reaction conditions (e.g., using POCl)3And high temperature). Functional transformations of 3-substituted indoles (e.g., 3-carbonyl, oximino, hydroxymethyl or halide substituted indoles) remain powerful tools for the synthesis of 3-cyanoindoles. In these cases, multiple synthetic steps are always required from commercial reagents to substrates with specific functional groups. Although the above methods have proven reliable and efficient in the synthesis of 3-cyanoindoles, in most cases only N-protected indoles or 3-cyanoindoles with free-NH units are obtained for the specific process. Therefore, the development of a new process for the economical, safe and feasible preparation of N-protected indoles and 3-cyanoindoles bearing a free-NH unit remains a great challenge.
Disclosure of Invention
The technical problem to be solved by the embodiment of the invention is to provide a 3-cyanoindole compound and a preparation method thereof.
In order to realize the purpose, the technical scheme is as follows: a process for preparing a 3-cyanoindole compound, the process comprising: in the presence of a catalyst, carrying out a Suzuki catalytic reaction on a compound with a structure shown in a formula (1) and 4-isoxazoleboronic acid pinacol ester, and after the reaction is finished, carrying out post-treatment to obtain a 3-cyanoindole compound with a structure shown in a formula (2);
wherein R is1、R2、R3、R4And R5Each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstitutedOr unsubstituted arylbenzyl, wherein the substituents for substituted alkyl, substituted cycloalkyl, substituted aryl and substituted arylbenzyl are each independently selected from one or more of fluoro, chloro, bromo, nitro, methyl, methoxy, trifluoromethyl, hydroxy and acetamido; x is Cl, Br, I, OTf.
The process for preparing a 3-cyanoindole compound according to claim 1, wherein: the aryl is phenyl, naphthyl, thienyl, furyl or pyridyl, the arylbenzyl is benzyl or naphthylbenzyl, and the substituent group in the substituted aryl or arylbenzyl is one or more of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl, hydroxyl and acetamido.
The aryl is phenyl, naphthyl, thienyl, furyl or pyridyl, the arylbenzyl is benzyl or naphthylbenzyl, and the substituent in the alkyl, the cycloalkyl, the aryl or the arylbenzyl is one or more of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl, hydroxyl and acetamido.
Further provided is a compound having a structure represented by formula (1) wherein the compound is one or more of the structures represented by the following formulae:
formula (1-1): r1Is H, R2Is H, R3Is H, R4Is CH3、R5H, X is Cl, Br, I, OTf;
formula (1-2): r1Is H, R2Is H, R3Is H, R4Is OCH3、R5H, X is Cl, Br, I, OTf;
formula (1-3): r1Is H, R2Is H, R3Is H, R4Is F, R5H, X is Cl, Br, I, OTf;
formula (1-4): r1Is H, R2Is H, R3Is H, R4Is Br, R5H, X is Cl, Br, I, OTf;
formula (1-5): r1Is H, R2Is H, R3Is H, R4Is NO2、R5H, X is Cl, Br, I, OTf；
Formula (1-6): r1Is H, R2Is H, R3Is CF3、R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-7): r1Is H, R2Is H, R3Is Br, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-8): r1Is H, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-9): r1Is CH3，R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-10): r1is-n-Bu, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-11): r1is-i-Pr, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-12): r1is-t-Bu, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-13): r1is-Ph, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-14): r1Is 2-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-15): r1Is 3-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formulae (1-16): r1Is 3-n-butylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-17): r1Is 4-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-18): r1Is 2-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formulae (1-19): r1Is 2-chlorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-20): r1Is 3-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-21): r1Is 4-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-22): r1Is 4-methoxyphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-23): r1Is 3-biphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-24): r1Is 3-naphthyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf.
The invention also provides a 3-cyanoindole compound prepared by the method. The yield of the product is above 70%.
The 3-cyanoindole compound with the structure shown in the formula (2) is prepared by selecting a proper compound with the structure shown in the formula (1) as a substrate, carrying out Suzuki reaction on the compound with the structure shown in the formula (1) and 4-isoxazoleboronic acid pinacol ester in the presence of a catalyst, carrying out alkali-induced isoxazole fragmentation, and then carrying out aldimine condensation. The 3-cyanoindole compound obtained by the invention can be used as a structural building block of a bioactive compound, a medicament and a ligand. The process allows the economical, safe and feasible preparation of N-protected indoles and 3-cyanoindoles with free-NH units
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples.
The invention provides a preparation method of a novel 3-cyanoindole compound, wherein the method comprises the following steps: in the presence of a catalyst, a compound with a structure shown in a formula (1) and 4-isoxazole boronic acid pinacol ester are subjected to a suzuki reaction, isoxazole fragmentation is induced by alkali, and aldimine condensation is carried out, so that a 3-cyanoindole compound with a structure shown in a formula (2) is prepared.
Wherein R is1、R2、R3、R4And R5Each independently is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylbenzyl, wherein the substituents for substituted alkyl, substituted cycloalkyl, substituted aryl, and substituted arylbenzyl are each independently selected from one or more of fluoro, chloro, bromo, nitro, methyl, methoxy, trifluoromethyl, hydroxy, and acetamido;
x is Cl, Br, I, OTf.
The inventors of the present invention have found that a compound having a structure represented by formula (2) can be produced in higher yield when the following preferences are made for the group of the compound having a structure represented by formula (1), and that preferred ranges for the group of the compound having a structure represented by formula (1) are: r1Is C1-C6 alkyl, C4-C8 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylbenzyl, the aryl is phenyl, naphthyl, thienyl, furyl or pyridyl, the arylbenzyl is benzyl or naphthylbenzyl, and the substituent in the substituted aryl or arylbenzyl is fluorine, chlorine, nitro, methyl, methoxy, trifluoroOne or more of methyl, hydroxy and acetamido; r2、 R3、R4、R5Each independently hydrogen, C1-C6 alkyl, C4-C8 cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylbenzyl, the aryl being phenyl, naphthyl, thienyl, furyl, or pyridyl, the arylbenzyl being benzyl or naphthylbenzyl, the substituents in the substituted aryl or arylbenzyl being one or more of fluoro, chloro, bromo, nitro, methyl, methoxy, trifluoromethyl, hydroxy, and acetamido;
in a preferred embodiment of the present invention, the compound of formula (1) is one or more of the structures of the following formulae:
formula (1-1): r1Is H, R2Is H, R3Is H, R4Is CH3、R5H, X is Cl, Br, I, OTf;
formula (1-2): r1Is H, R2Is H, R3Is H, R4Is OCH3、R5H, X is Cl, Br, I, OTf;
formula (1-3): r1Is H, R2Is H, R3Is H, R4Is F, R5H, X is Cl, Br, I, OTf;
formula (1-4): r1Is H, R2Is H, R3Is H, R4Is Br, R5H, X is Cl, Br, I, OTf;
formula (1-5): r1Is H, R2Is H, R3Is H, R4Is NO2、R5H, X is Cl, Br, I, OTf;
formula (1-6): r1Is H, R2Is H, R3Is CF3、R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-7): r1Is H, R2Is H, R3Is Br, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-8): r1Is H, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-9): r1Is CH3，R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-10): r1is-n-Bu, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-11): r1is-i-Pr, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-12): r1is-t-Bu, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-13): r1is-Ph, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-14): r1Is 2-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-15): r1Is 3-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formulae (1-16): r1Is 3-n-butylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-17): r1Is 4-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-18): r1Is 2-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formulae (1-19): r1Is 2-chlorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I,OTf；
Formula (1-20): r1Is 3-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-21): r1Is 4-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-22): r1Is 4-methoxyphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-23): r1Is 3-biphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-24): r1Is 3-naphthyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf.
The compound of formula (1) of the present invention is prepared by methods conventional in the art, and preferably, the compound of formula (1) is prepared as shown in scheme one below:
as shown in the first scheme, the preparation method of the formula (1) specifically comprises the following steps: under the protection of nitrogen, 2-iodobromobenzene, amine, palladium acetate, 1' -bis (diphenylphosphino) ferrocene and sodium tert-butoxide are dissolved in the toluene solution. Stirring the reaction at 110 deg.C for 5h, adjusting pH to 5 with 1M hydrochloric acid, separating organic layer, extracting water layer with extractant (such as chloroform, dichloromethane or ethyl acetate) for 2-3 times, combining organic layers, and adding anhydrous Na2SO4Drying, decompressing and distilling out the solution, and obtaining the product by flash column chromatography, wherein the yield is generally 70-90%.
According to the invention, the catalyst is a ruthenium (Ru), rhodium (Rh), iridium (Ir) or palladium (Pd) complex.
To is coming toThe compound shown in the formula (1) is more favorable for catalyzing Suzuki reaction, and preferably, the catalyst is selected from one of the following formulas: PdCl2(PPh3)2,Pd(PPh3)4，PdCl2dppf。
According to the invention, the 3-cyanoindole compound can be obtained with high yield by using the catalyst. Then, according to the structural characteristics of the compound with the structure shown in the formula (1), in order to optimize the catalytic activity of the catalyst on the compound with the structure shown in the formula (1), the molar ratio of the compound with the structure shown in the formula (1) to the used amount of the chiral catalyst is preferably 10-2000: 1, for example, may be 10 to 30: 1. 20-40: 1. 30-50: 1. 45-100 parts of: 1. 50-150: 1. 50-200: 1. 100-250: 1. 100-300: 1. 350-400: 1. 450-500: 1. 500-1000: 1 or 500-1500: 1, more preferably 10 to 1000: 1, more preferably 10 to 100: 1.
the suzuki coupling reaction can adopt the conditions of the coupling reaction which are conventional in the field, but in order to better match the catalytic action of the catalyst of the invention on the substrate, the conditions of the coupling reaction preferably comprise: the temperature is 30-130 ℃ and the time is 1-72 hours. The temperature as the conditions for the above addition reaction may be, for example, 30 to 130 ℃, 30 to 90 ℃, 30 to 60 ℃, 50 to 130 ℃, 50 to 90 ℃ or 60 to 130 ℃, more preferably 90 to 130 ℃, still more preferably 100 ℃ to 130 ℃. The time period as the condition of the above reaction may be, for example, 1 to 5 hours, 6 to 10 hours, 11 to 15 hours, 16 to 20 hours or 16 to 20 hours, more preferably 2 to 24 hours, still more preferably 6 to 16 hours. The addition reaction described above can be carried out in a variety of reaction vessels.
According to the present invention, the solvent used in the reaction is not particularly limited, and may be water and a conventional organic solvent, for example, imidazole ionic liquid [ BMIM ]]PF6One or more of water, Dichloromethane (DCM), 1, 2-dichloroethane, chloroform, Ethyl Acetate (EA), Tetrahydrofuran (THF), benzene, toluene, xylene, chlorobenzene, diethyl ether, dioxane, acetone, dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), dimethylacetamide (DMAc), and C1-C10 monoalcohols,among them, the monohydric alcohol of C1-C10 is preferably one or more of methanol (MeOH), ethanol (EtOH), propanol, n-butanol (n-BuOH) and Isopropanol (IPA). More preferably, the solvent is one or more of methanol (MeOH), ethanol (EtOH), Isopropanol (IPA), n-butanol (n-BuOH), Dichloromethane (DCM), Tetrahydrofuran (THF), toluene, Ethyl Acetate (EA), and acetone. Wherein, when methanol (MeOH), ethanol (EtOH), Isopropanol (IPA), n-butanol (n-BuOH), Dichloromethane (DCM), Tetrahydrofuran (THF), toluene, Ethyl Acetate (EA) or acetone is used as solvent, the 3-cyano indole product with the yield of more than 60% can be obtained. When ethanol (EtOH), Isopropanol (IPA), n-butanol (n-BuOH), Dichloromethane (DCM), 1, 2-Dichloroethane (DCE), Tetrahydrofuran (THF), 1, 4-dioxane (dioxane), dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), and dimethylacetamide (DMAc) are used as solvents, a 3-cyanoindole product with a yield of 80% or more can be obtained. In order to further obtain the 3-cyanoindole compound in high yield, the solvent is preferably dimethyl sulfoxide (DMSO), Dimethylformamide (DMF) or dimethylacetamide (DMAc). Most preferably dimethyl sulfoxide (DMSO) is used as solvent.
According to the present invention, the amount of the compound having the structure represented by formula (1) to be used is not particularly limited as long as the 3-cyanoindole compound of the present invention can be obtained, and preferably, the amount of the compound having the structure represented by formula (1) to be used is 0.2 to 1mmol, more preferably 0.2 to 0.6mmol, in terms of mole per 1mL of the solvent.
The present invention will be described in detail below by way of examples.
In the following examples of the present invention,
conversion rate of reaction: which represents what proportion of the starting materials of the reaction is converted to the product, usually in percentage, and is calculated by the formula: conversion ═ reactant of conversion]/([ reactant of conversion)]+ [ unconverted reactants)]) x 100%. The conversion rate of the catalytic suzuki coupling reaction is that the reaction mixture before purification is directly subjected to nuclear magnetic resonance hydrogen spectrum (1H-NMR), wherein the peak area of the characteristic peak of the unreacted raw material and the peak area of the characteristic peak converted into the product are regarded as the peak area of the characteristic peak, respectivelyThe concentration of unconverted reactants and converted reactants was calculated according to the above formula to obtain the conversion.
Preparation of amine compound with structure shown as formula (1)
Preparation of 2-bromoaniline example 1
Preparation of amine compounds of the structure represented by the formula (1-15): 2-bromoiodobenzene (3.96 mmol, 1.12g), 3-methylaniline (517mg, 4.83mmol), palladium (II) acetate (44.9mg, 200. mu. mol), 1' -bis (diphenylphosphino) ferrocene (222mg, 400. mu. mol) and sodium tert-butoxide (538mg, 5.60mmol) were dissolved in toluene (5mL) under nitrogen. The reaction was stirred at 110 ℃ for 5h, then cooled to room temperature and adjusted to pH 5 by the addition of 1M aqueous HCl. The organics were extracted from the aqueous layer with ethyl acetate and the combined organic extracts were concentrated under reduced pressure to give the crude product which was further purified by column chromatography (eluent petroleum ether) to give 2-bromoaniline in 90% yield.1H NMR(400MHz,CDCl3):δ(ppm) 7.51(d,J＝8.0Hz,1H),7.25-7.13(m,3H),6.97-6.95(m,2H),6.86(d,J＝4.0Hz, 1H),6.72(t,J＝8.0Hz,1H),6.04(s,1H),2.33(s,3H)；13C NMR(125MHz,CDCl3): δ(ppm)141.9,139.5,133.1,129.4,128.2,123.7,121.2,120.9,117.5,116.1,112.3, 21.6.HRMS(ESI)m/z calcd.for C13H13BrN+(M+H)+262.0226,found 262.0219.
Preparation of 2-bromoaniline
And (3) preparing the amine compound with the structure shown in the formula (1-16).
According to the procedure of preparation example 1, except for using 3-n-butylaniline (720.8mg, 4.83mmol) in place of 3-methylaniline in the step, the compound (novel compound) having the structure represented by formula (1-16) was obtained in a yield of 95%.1H NMR(400MHz,CDCl3):δ(ppm)7.52(d,J＝8.0Hz,1H), 7.20-7.09(m,6H),6.71(t,J＝8.0Hz,1H),6.05(s,1H),2.61(t,J＝8.0Hz,2H), 1.66-1.57(m,2H),1.44-1.34(m,2H),0.96(t,J＝8.0Hz,3H)；13C NMR(125MHz, CDCl3):δ(ppm)142.,139.2,138.0,133.0,129.5,128.2,121.4,120.4,115.3,111.7, 35.2,33.9,22.5,14.1.HRMS(ESI)m/z calcd.for C16H19BrN+(M+H)+304.0695, found 304.0683.
Preparation of 2-bromoaniline
And (3) preparing the amine compound with the structure shown in the formula (1-18).
According to the procedure of preparation example 1, except for replacing 3-methylaniline in the step with 2-fluoroaniline (536.7mg, 4.83mmol), the compound (novel compound) having the structure shown by the formula (1-3) was obtained in a yield of 90%.1H NMR(400MHz,CDCl3):δ(ppm)7.60(d,J＝8.0Hz,1H),7.34(d, J＝8.0Hz,1H),7.28-7.24(m,2H),7.18(s,1H),7.05-7.02(m,2H),6.86(t,J＝8.0 Hz,1H),6.12(s,1H)；13C NMR(125MHz,CDCl3):δ(ppm)143.4,140.5,135.2, 133.3,130.5,128.3,122.3,122.2,119.2,117.4,117.3,113.4.HRMS(ESI)m/z calcd. for C12H10BrNF+(M+H)+265.9975,found 265.9980.
Preparation of 2-bromoaniline example 4
And (3) preparing the amine compound with the structure shown in the formula (1-23).
According to the method of preparation example 1, except for using 3-aminobiphenyl (817.3mg,4.83mmol) in place of 3-methylaniline in the step, the compound having the structure represented by formula (1-24) was obtained in a yield of 92%.1H NMR(400MHz,CDCl3):δ(ppm)7.49-7.47(m,2H),7.45-7.43(m,1H),7.35-7.20 (m,6H),7.18-7.14(m,1H),7.10-7.02(m,2H),6.65(t,J＝8.0Hz,1H),6.06(s,1H)； 13C NMR(125MHz,CDCl3):δ(ppm)142.9,142.3,141.6,141.0,133.2,130.0,128.9, 128.3,127.6,127.3,121.7,121.3,119.1,116.3,112.6.HRMS(ESI)m/z calcd.for C18H15BrN+(M+H)+324.0382,found 324.0392.
Examples 1 to 15
This example illustrates the preparation of 3-cyanoindole compounds of the present invention and the products thereof.
In a Schlenk tube, 0.015mmol of a catalyst, 0.6mmol of a base, and an amine compound (0.2mmol) having a structure represented by formula (1-1) were dissolved in 2mL of a solvent, and the reaction was stirred for 16 hours after replacing the air with nitrogen. Subjecting the obtained reaction solution to silica gelColumn chromatography to obtain pure product. The reaction conversion rate is determined by directly passing the reaction solution before purification through nuclear magnetic resonance1The H-NMR was characterized, and the results are shown in Table 1. The results of identifying the obtained compound having the structure represented by the formula (2-1) are shown in Table 3.
TABLE 1 Synthesis Condition settings and conversion ratios for examples 1-15
Examples 16 to 39
This example illustrates the preparation of 3-cyanoindole compounds of the present invention and the products thereof.
In a Schlenk tube, 0.015mmol of the catalyst PdCl2(dppf), 0.6mmol of KF, and an amine compound of the specified structure (0.2mmol) were dissolved in 2mL of DMSO, and after the air was replaced with nitrogen, the reaction was stirred at 130 ℃ for 16 hours. The resulting reaction solution was subjected to silica gel column chromatography to remove the catalyst. The reaction conversion rate is determined by directly subjecting the reaction solution before purification to nuclear magnetic resonance1The H-NMR was characterized, and the results are shown in Table 2. The results of the identification of the obtained products are shown in Table 3, respectively.
TABLE 2 substrates, products and yields for the reactions of examples 16-39
TABLE 3 NMR spectra analysis of the coupling products
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
It should be noted that the technical features described in the above embodiments can be combined in any suitable manner without contradiction, and various possible combinations of the features are not described in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (5)
1. A process for preparing a 3-cyanoindole compound, comprising: in the presence of a catalyst, carrying out a Suzuki catalytic reaction on a compound with a structure shown in a formula (1) and 4-isoxazoleboronic acid pinacol ester, and after the reaction is finished, carrying out post-treatment to obtain a 3-cyanoindole compound with a structure shown in a formula (2);
wherein R is1、R2、R3、R4And R5Each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylbenzyl, wherein the substituents for substituted alkyl, substituted cycloalkyl, substituted aryl, and substituted arylbenzyl are each independently selected from the group consisting of fluoro, chloro, nitro, methyl, methoxy, and tri-arylOne or more of fluoromethyl, hydroxy and acetamido;
x is Cl, Br, I, OTf;
the catalyst is selected from one of the following formulas: PdCl2(PPh3)2, Pd(PPh3)4，PdCl2dppf；
Alkali is added in the reaction, and the alkali is KF and Cs2CO3、K2CO3、Na2CO3、LiOH、Na3PO4、NaHCO3One kind of (1).
2. The process for preparing a 3-cyanoindole compound according to claim 1, wherein: the aryl is phenyl, naphthyl, thienyl, furyl or pyridyl, the arylbenzyl is benzyl or naphthylbenzyl, and the substituent group in the substituted aryl or arylbenzyl is one or more of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl, hydroxyl and acetamido.
3. The method for preparing a 3-cyanoindole compound according to claim 1, wherein the compound having the structure represented by formula (1) is one or more of the following structures:
formula (1-1): r1Is H, R2Is H, R3Is H, R4Is CH3、R5H, X is Cl, Br, I, OTf;
formula (1-2): r1Is H, R2Is H, R3Is H, R4Is OCH3、R5H, X is Cl, Br, I, OTf;
formula (1-3): r1Is H, R2Is H, R3Is H, R4Is F, R5H, X is Cl, Br, I, OTf;
formula (1-4): r1Is H, R2Is H, R3Is H, R4Is Br, R5H, X is Cl, Br, I, OTf;
formula (1-5): r1Is H, R2Is a compound of formula (I) in the formula (H),R3is H, R4Is NO2、R5H, X is Cl, Br, I, OTf;
formula (1-6): r1Is H, R2Is H, R3Is CF3、R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-7): r1Is H, R2Is H, R3Is Br, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-8): r1Is H, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-9): r1Is CH3，R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-10): r1For the purpose ofn-Bu，R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-11): r1For the purpose ofi-Pr，R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-12): r1For the purpose oft-Bu，R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-13): r1is-Ph, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-14): r1Is 2-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-15): r1Is 3-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formulae (1-16): r1Is 3-n-butylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-17): r1Is 4-methylphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-18): r1Is 2-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formulae (1-19): r1Is 2-chlorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-20): r1Is 3-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-21): r1Is 4-fluorophenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-22): r1Is 4-methoxyphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-23): r1Is 3-biphenyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf;
formula (1-24): r1Is 3-naphthyl, R2Is H, R3Is H, R4Is H, R5H, X is Cl, Br, I, OTf.
4. The process for preparing a 3-cyanoindole compound according to claim 1, wherein: the substituents in the substituted alkyl, substituted cycloalkyl, substituted aryl and substituted arylbenzyl groups are each independently selected from one or more of fluorine, chlorine, nitro, methyl, methoxy, trifluoromethyl, hydroxyl and acetamido.
5. The process for preparing a 3-cyanoindole compound according to claim 1, wherein: the molar ratio of the compound with the structure shown in the formula (1) to the used amount of the catalyst is 10-2000: 1.
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| CN102816104A (en) * | 2012-08-30 | 2012-12-12 | 浙江大学 | 3-cyanoindole compound synthesis method |
| CN104788359A (en) * | 2015-04-07 | 2015-07-22 | 湖南大学 | Synthesis method of copper-promoted 3-cyano-substituted-indole compound |
| CN106278989A (en) * | 2016-08-08 | 2017-01-04 | 河南师范大学 | The synthetic method of 3 cyanogen radical indole compounds |
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| CN102816104A (en) * | 2012-08-30 | 2012-12-12 | 浙江大学 | 3-cyanoindole compound synthesis method |
| CN104788359A (en) * | 2015-04-07 | 2015-07-22 | 湖南大学 | Synthesis method of copper-promoted 3-cyano-substituted-indole compound |
| CN106278989A (en) * | 2016-08-08 | 2017-01-04 | 河南师范大学 | The synthetic method of 3 cyanogen radical indole compounds |
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