CN109776546B - Method for preparing indolopyrrolidone compound - Google Patents
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Abstract
The invention relates to the technical field of organic chemical synthesis, in particular to a method for preparing an indolopyrrolidone compound, which comprises the following steps: under the condition of the existence of a catalyst, Lewis acid and a zinc reagent, the indole compound shown in the formula II and alkyne shown in the formula III are subjected to C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I. The synthesis of the indolopyrrolidone compound is realized by reacting indole and alkyne in a solvent in the presence of a catalyst, Lewis acid and a zinc reagent.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a method for preparing an indolopyrrolidone compound.
Background
Indolopyrrolidone compounds are important nitrogen-containing heterocyclic compounds and widely exist in nature. It has various biological activities and special chemical properties, can be used as active structural units of a plurality of natural products and medicines, and has important research value and application prospect in the fields of organic synthesis, medicines and chemical industry.
The preparation method of indolopyrrolidone compounds in the prior art mainly comprises the following steps: the following methods are disclosed in j.org.chem.2017,82, 5263-5273: (as shown in FIG. 1); the method uses a ruthenium catalyst to catalyze the reaction of indole and alkyne to produce the indolopyrrole compound, but uses a substrate, namely, the R 'substituent in alkyne is mainly methyl, although R' is an example of aryl, the corresponding yield is not high (< 79%); the following methods are disclosed in j.am.chem.soc.2014,136, 5424-5431: (as shown in FIG. 2) which uses a cobalt catalyst to catalyze the reaction of indole with alkyne to produce indolopyrrole compounds, but uses as substrate alkyne groups methyl for the R 'substituent, although there are also examples where R' is aryl, the corresponding yields are not high (< 72%); the following methods are disclosed in chem.lett.2015,44, 1104-1106: it is mainly focused on the reaction of sulfamide with alkyne (as shown in fig. 3), only one involving indole (as shown in fig. 4), and the yield is low (39%).
Therefore, the development of new methods for preparing indolopyrrolones is of great significance.
Disclosure of Invention
The invention aims to provide a method for preparing an indolopyrrolidone compound.
The structural formula of the indolopyrrolidone compound is shown in a formula I:
R1independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from: hydrogen, deuterium, halogen, alkyl (specifically, alkyl having 1 to 20 carbon atoms), cycloalkyl (specifically, cycloalkyl having 3 to 20 ring carbon atoms), heteroalkyl (heteroatom-containing alkyl substituent, such as-CH)2CH2N(CH3)2) (in particular heteroalkyl having from 1 to 20 carbon atoms), aralkyl (alkyl substituents bearing an aryl group, such as, in the simplest case, benzyl, PhCH2-, that is, an aralkyl group having 7 carbon atoms) (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof;
Raand RbEach independently selected from: an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms, a halogen-substituted aryl group, an alkoxy-substituted aryl group, an alkyl-substituted aryl group), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof.
The method for preparing the indolopyrrolidone compound provided by the invention comprises the following steps:
in the presence of a catalyst, Lewis acid and a zinc reagent, leading the indole compound shown in the formula II and alkyne shown in the formula III to undergo C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I:
in the formula II, R1Independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from: hydrogen, deuterium, halogen, an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof; specifically, R1Selected from: hydrogen, deuterium, halogen, methyl, methoxy, benzyl, benzyloxy;
R2and R3Each independently selected from: an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof;
specifically, R2，R3Is a phenyl group, and the phenyl group,
formula IIIIn, RaAnd RbEach independently selected from: an alkyl group (specifically, an alkyl group having 1 to 20 carbon atoms), a cycloalkyl group (specifically, a cycloalkyl group having 3 to 20 ring carbon atoms), a heteroalkyl group (specifically, a heteroalkyl group having 1 to 20 carbon atoms), an aralkyl group (specifically, an aralkyl group having 7 to 30 carbon atoms), an alkoxy group (specifically, an alkoxy group having 1 to 20 carbon atoms), an aryloxy group (specifically, an aryloxy group having 6 to 30 carbon atoms), an aryl group (specifically, an aryl group having 6 to 30 carbon atoms, a halogen-substituted aryl group, an alkoxy-substituted aryl group, an alkyl-substituted aryl group), an alkylsilyl group (specifically, an alkylsilyl group having 3 to 20 carbon atoms), an arylsilyl group (specifically, an arylsilyl group having 6 to 20 carbon atoms), and combinations thereof; raAnd RbEach independently selected from the group consisting of halogen, propyl, isopropyl, cyclopropyl, n-butyl, phenyl, halophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, and naphthyl;
in the above process, the catalyst may be a rhenium complex,
the rhenium complex contains at least one CO ligand;
specifically, the rhenium complex may specifically be rhenium decacarbonyl.
The rhenium complex is used in an amount of 1 to 30 mol%, specifically 5 mol%, based on the molar amount of the indole compound represented by formula II.
The lewis acid may be: at least one of zinc chloride, zinc bromide, zinc fluoride, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc cyanide, aluminum chloride, ferric chloride, cupric chloride, silver trifluoromethanesulfonate, cupric bromide, ferric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, ferrous chloride, and ferrous bromide,
the dosage of the Lewis acid is 1 to 100 percent of the molar weight of the indole compound shown in the formula II;
preferably, the lewis acid is zinc chloride, and the amount of the lewis acid is 10 to 100 percent of the molar amount of the indole compound shown in formula II; more preferably, the lewis acid is used in an amount of 20% to 40% or 30% of the molar amount of the indole compound of formula II.
The zinc reagent may be: the organic zinc reagent can be dimethyl zinc or diethyl zinc.
The dosage of the zinc reagent is 1 to 100 percent of the indole compound shown in the formula II; preferably, the zinc reagent is used in an amount of 10% to 50% of the indole compound of formula II; more preferably, the zinc reagent is used in an amount of 30% of the indole compound of formula II.
The molar ratio of the indole compound shown in the formula II to the alkyne shown in the formula III can be 1:1 to 1: 10; specifically, the mol ratio of the indole compound shown in the formula II to the alkyne shown in the formula III is 1: 2.5.
The C-H bond activation/C-N bond cleavage reaction is carried out in a solvent which can be: at least one of benzene, toluene and xylene, and specifically toluene.
In the system of C-H bond activation/C-N bond cleavage reaction, the molar concentration of the indole compound shown in the formula II can be 0.01-2 mol/L, and specifically, the molar concentration of the indole compound shown in the formula II is 0.2 mol/L.
The temperature range of the C-H bond activation/C-N bond cleavage reaction is 50-150 ℃, and the time range is 10-100H.
The synthesis method has higher reaction yield, and substrates containing different substituents can better participate in the reaction, such as alkyl, aryl, alkoxy, halogen and the like, and have wider substituent compatibility.
Drawings
FIG. 1 is a reaction equation for the production of an indolopyrrole compound by the reaction of indole with alkyne using a ruthenium catalyst in the prior art.
FIG. 2 is a reaction equation for producing an indolopyrrole compound by the reaction of indole and alkyne catalyzed by a cobalt catalyst in the prior art.
FIG. 3 is a prior art reaction equation for a thioamide with an alkyne.
FIG. 4 is a reaction equation of indole and alkyne disclosed in the prior art.
FIG. 5 is a reaction equation for preparing 1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 1 of the invention.
FIG. 6 is a reaction equation for preparing 7-methyl-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 2 of the present invention.
FIG. 7 is a reaction equation for preparing 7-methoxy-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 3 of the invention.
FIG. 8 is a reaction equation for preparing 7-chloro-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 4 of the invention.
FIG. 9 is a reaction equation for preparing 1, 2-di-p-methylphenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 5 of the invention.
FIG. 10 is a reaction equation for the preparation of 1, 2-bis (4-methoxyphenyl) -3H-pyrrolo [1,2-a ] indol-3-one in example 6 of the invention.
FIG. 11 is a reaction equation for the preparation of 1, 2-bis (4-chlorophenyl) -3H-pyrrolo [1,2-a ] indol-3-one in example 7 of the present invention.
FIG. 12 is a reaction scheme for the preparation of 1, 2-bis (3-bromophenyl) -3H-pyrrolo [1,2-a ] indol-3-one in example 8 of the present invention.
FIG. 13 is a reaction equation for the preparation of 1-tert-butyl-2-phenyl-3H-pyrrolo [1,2-a ] indol-3-one in example 9 of the present invention.
FIG. 14 is a reaction equation for the preparation of 1, 2-dipropyl-3H-pyrrolo [1,2-a ] indol-3-one in example 10 of the invention.
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
According to one embodiment of the present invention, there is disclosed a method for preparing an indolopyrrolidone compound, the method comprising the steps of:
under the condition of the existence of a catalyst, Lewis acid and a zinc reagent, the indole compound shown in the formula II and alkyne shown in the formula III are subjected to C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I;
wherein the content of the first and second substances,
R1independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from the group consisting of: hydrogen, deuterium, halogen, alkyl groups having 1 to 20 carbon atoms, cycloalkyl groups having 3 to 20 ring carbon atoms, heteroalkyl groups having 1 to 20 carbon atoms, aralkyl groups having 7 to 30 carbon atoms, alkoxy groups having 1 to 20 carbon atoms, aryloxy groups having 6 to 30 carbon atoms, aryl groups having 6 to 30 carbon atoms, alkylsilyl groups having 3 to 20 carbon atoms, arylsilyl groups having 6 to 20 carbon atoms, and combinations thereof;
R2，R3，Raand RbEach independently selected from the group consisting of: an alkyl group having 1 to 20 carbon atoms, a cycloalkyl group having 3 to 20 ring carbon atoms, a heteroalkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an aryloxy group having 6 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkylsilyl group having 3 to 20 carbon atoms, an arylsilyl group having 6 to 20 carbon atoms, and combinations thereof.
According to one embodiment of the invention, wherein R is1Selected from the group consisting of hydrogen, deuterium, halogen, alkyl groups having 1 to 20 carbon atoms, cycloalkyl groups having 3 to 20 ring carbon atoms, aralkyl groups having 7 to 30 carbon atoms, alkoxy groups having 1 to 20 carbon atoms, aryloxy groups having 6 to 30 carbon atoms and aryl groups having 6 to 30 carbon atoms; preferably, R1Selected from hydrogen, deuterium, halogen, methyl, methoxy, benzyl and benzyloxy.
According to one embodiment of the invention, wherein R is2，R3，RaAnd RbEach independently selected from the group consisting of halogen, alkyl groups having 1 to 20 carbon atoms,cycloalkyl having 3 to 20 ring carbon atoms, aralkyl having 7 to 30 carbon atoms, alkoxy having 1 to 20 carbon atoms, aryloxy having 6 to 30 carbon atoms, aryl having 6 to 30 carbon atoms; preferably, R2，R3Is phenyl, RaAnd RbEach independently selected from the group consisting of halogen, propyl, isopropyl, cyclopropyl, n-butyl, phenyl, halophenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, and naphthyl.
According to one embodiment of the invention, wherein the catalyst is a rhenium complex, the rhenium complex contains at least one CO ligand; preferably, the rhenium complex is rhenium decacarbonyl.
According to an embodiment of the present invention, wherein the lewis acid is at least one selected from the group consisting of zinc chloride, zinc bromide, zinc fluoride, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc cyanide, aluminum chloride, ferric chloride, cupric chloride, silver trifluoromethanesulfonate, cupric bromide, ferric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, ferrous chloride and ferrous bromide, and the amount of the lewis acid is 1 to 100% of the molar amount of the indole compound represented by formula II; preferably, the lewis acid is zinc chloride, and the amount of the lewis acid is 10 to 100 percent of the molar amount of the indole compound shown in formula II; more preferably, the amount of the lewis acid is 30% of the molar amount of the indole compound of formula II.
According to a preferred embodiment of the present invention, wherein the zinc reagent is a methyl zinc reagent, said zinc reagent is used in an amount of 1% to 100% of the indole compound represented by formula II; preferably, the zinc reagent is used in an amount of 10% to 50% of the indole compound of formula II; more preferably, the zinc reagent is used in an amount of 30% of the indole compound of formula II.
According to a preferred embodiment of the present invention, wherein the molar ratio of the indole compound of formula II to the alkyne of formula III is from 1:1 to 1: 10; preferably, the mol ratio of the indole compound shown in the formula II to the alkyne shown in the formula III is 1: 2.5.
According to a preferred embodiment of the present invention, the solvent in the system in which the C-H bond activation/C-N bond cleavage reaction is carried out may be selected from benzene, toluene, xylene, preferably toluene.
According to a preferred embodiment of the present invention, in the system of C-H bond activation/C-N bond cleavage reaction, the molar concentration of the indole compound represented by formula II is 0.01 to 2mol/L, and preferably, the molar concentration of the indole compound represented by formula II is 0.2 mol/L.
According to a preferred embodiment of the present invention, wherein said C-H bond activation/C-N bond cleavage formation reaction is carried out at a temperature in the range of 50 to 150 ℃ for a time in the range of 10-100H.
The preparation method of the compounds of formula-II and formula-III referred to in the following examples is:
a preparation method of the formula-II: under a nitrogen atmosphere, 1.2 equivalents of the sodium hydride solid were suspended in dry tetrahydrofuran at zero degrees centigrade, 1 equivalent of the corresponding indole compound was added, and stirring was continued for one hour at zero degrees centigrade. Then, 1.1 equivalents of N, N-dibenzoylcarbamoyl chloride was added to the system. After the addition was complete, the reaction was allowed to gradually warm to room temperature and the reaction was continued overnight. Quenching the reaction with saturated ammonium chloride aqueous solution, extracting with anhydrous ether, drying the organic phase with anhydrous magnesium sulfate, filtering, and removing the organic solvent to obtain a crude product. The pure product, namely the compound of the formula-II is obtained by column chromatography separation.
A preparation method of the formula-III: to a dry Schlenk flask, 6 mol% of bis (triphenylphosphine) palladium dichloride, 10 mol% of cuprous iodide, 1 equivalent of the corresponding aryl iodide reagent (or aryl bromide reagent) was added under nitrogen atmosphere at room temperature. With stirring, dry toluene, 1, 8-diazabicycloundecen-7-ene, 0.5 equivalents of triethylethynylsilane, and 40 mol% water were injected. The reaction system was placed in a dark environment and allowed to continue the reaction for 18 hours. After the reaction is finished, adding water into the system for quenching reaction, extracting with anhydrous ether, washing the organic phase with 10% hydrochloric acid for three times, drying the organic phase with anhydrous magnesium sulfate, filtering, and removing the organic solvent to obtain a crude product. And (4) obtaining a pure product, namely the compound of the formula-III by column chromatography separation.
Example 1
Preparation of 1, 2-Diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-a) according to the reaction equation shown in FIG. 5
Into a 25mL Schlenk flask, at N2N, N-Diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give 141.2mg of the objective product (formula I-a) in 88% yield.
The target product was characterized as follows:1H NMR(400MHz，CDCl3)：δ7.76(d,J＝8.0Hz,1H),7.46-7.42(m,4H),7.40-7.35(m,4H),7.33–7.26(m,4H),7.09(t,J＝7.6Hz,1H),6.49(s,1H)；13C NMR(100MHz，CDCl3):164.45,141.64,141.32,134.54,133.73,131.94,131.42,130.47,129.68,129.53,128.80,128.47,128.39,128.29,127.29,123.33,122.57,112.54,108.16；HRMS(ESI):Calculated for C23H16NO([M+H]+) 322.12264, found 322.12231, with correct structure.
Example 2
Preparation of 7-methyl-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-b) according to the reaction equation shown in FIG. 6
Into a 25mL Schlenk flask, at N2Under the protection of (1), 5-methyl-N, N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 163.2mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. Concentrating the filtrate, and separating by column chromatography (eluent is petroleum ether: dichloromethane is 5/1, v/v) to obtain target product (formula I-a)164.2mg, yield 98%.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.64(d,J＝8.1Hz,1H),7.47–7.41(m,4H),7.41–7.34(m,3H),7.33–7.26(m,3H),7.19(s,1H),7.10(d,J＝8.1Hz,1H),6.43(s,1H),2.37(s,3H)。13C NMR(126MHz,CDCl3):δ164.44(s),141.55(d,J＝2.2Hz),134.04(s),132.85(d,J＝16.3Hz),131.89(s),131.56(s),130.62(s),129.63(d,J＝9.8Hz),128.85(s),128.41(dd,J＝14.0,12.5Hz),122.82(s),112.20(s),108.16(s),77.31(s),77.06(s),76.80(s),21.38(s)。HRMS(APCI):calcd for C24H18NO([M+H]336.13829 as (+) and 336.13781 as found in the specification, and has correct structure.
Example 3
Preparation of 7-methoxy-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-c) according to the reaction equation shown in FIG. 7
Into a 25mL Schlenk flask, at N2Under the protection of (3), 5-methoxy-N, N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 171.2mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give 156.2mg of the objective product (formula I-a) in 89% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.64(d,J＝8.6Hz,1H),7.43(ddd,J＝8.9,6.7,5.0Hz,4H),7.37(td,J＝8.6,4.5Hz,3H),7.33–7.28(m,3H),6.93–6.85(m,2H),6.42(s,1H),3.81(s,3H).13C NMR(126MHz,CDCl3):δ164.36(s),156.45(s),142.36(s),141.56(s),134.80(s),132.02(s),131.59(s),130.67(s),129.81(s),129.63(t,J＝22.2Hz),128.98(s),128.63(dd,J＝38.2,26.6Hz),114.59(s),113.08(s),108.15(s),106.87(s),77.41(s),77.03(d,J＝32.0Hz),55.89(s).HRMS(APCI):Calcd for C24H18NO2([M+H]352.13321 as (+) and 352.13293 as Found, with correct structure.
Example 4
Preparation of 7-chloro-1, 2-diphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-d) according to the reaction equation shown in FIG. 8
Into a 25mL Schlenk flask, at N2Under the protection of (3), 5-chloro-N, N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 173.4mg), 1, 2-diphenylacetylene (1.25mmol, 222.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give 150.9mg of the objective product (formula I-a) in 85% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.65(d,J＝8.5Hz,1H),7.45–7.34(m,8H),7.33–7.28(m,3H),7.23(dd,J＝8.5,2.0Hz,1H),6.42(s,1H).13C NMR(126MHz,CDCl3):δ164.25(s),142.54(s),141.64(s),134.97(s),132.80(s),132.27(s),131.18(s),130.25(s),129.94(s),129.58(s),128.95(s),128.72(d,J＝12.7Hz),128.46(d,J＝10.8Hz),127.16(s),122.29(s),113.28(s),107.06(s),77.33(s),77.08(s),76.82(s).HRMS(APCI):Calcd for C23H15ClNO([M+H]356.08367 as (+) and 356.08304 as Found, with correct structure.
Example 5
Preparation of 1, 2-di-p-methylphenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-e) according to the reaction equation shown in FIG. 9
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-di-p-methylphenyl acetylene (1.25mmol, 257.9mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. Concentrating the filtrate, passing through column layerChromatography (eluent petroleum ether: dichloromethane 5/1, v/v) gave 132.6mg, 76% yield of the title product (formula I-a).
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.75(dd,J＝8.0,0.5Hz,1H),7.40–7.31(m,5H),7.29–7.25(m,1H),7.17(d,J＝7.9Hz,2H),7.12(d,J＝7.9Hz,2H),7.08(td,J＝7.7,0.9Hz,1H),6.47(s,1H),2.38(s,3H),2.35(s,3H).13C NMR(126MHz,CDCl3):δ164.85(s),141.64(s),141.12(s),139.91(s),138.35(s),134.55(s),133.85(s),131.48(s),129.50(d,J＝11.5Hz),129.09(s),128.73(s),128.45(s),127.81(s),127.15(s),123.26(s),122.52(s),112.54(s),107.80(s),77.32(s),77.07(s),76.81(s),21.49(d,J＝9.2Hz).HRMS(APCI):Calcd for C25H20NO([M+H]350.15394 as (+) and 350.15375 as Found, with correct structure.
Example 6
Preparation of 1, 2-bis (4-methoxyphenyl) -3H-pyrrolo [1,2-a ] indol-3-one (formula I-f) according to the reaction equation shown in FIG. 10
Into a 25mL Schlenk flask, at N2N, N-Diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-bis (4-methoxyphenyl) acetylene (1.25mmol, 297.9mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give 181.0mg of the objective product (formula I-a) in 95% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.75(d,J＝7.9Hz,1H),7.48–7.35(m,5H),7.30–7.22(m,1H),7.08(t,J＝7.4Hz,1H),6.88(dd,J＝16.6,8.8Hz,4H),3.84(s,3H),3.81(s,3H).13C NMR(126MHz,CDCl3):δ165.11(s),160.65(s),159.62(s),141.71(s),140.07(s),134.47(s),133.84(s),130.93(s),130.35(s),130.04(s),127.05(s),124.02(s),123.24(d,J＝9.5Hz),122.44(s),114.27(s),113.89(s),112.48(s),107.49(s),77.31(s),77.06(s),76.80(s),55.31(d,J＝11.2Hz).HRMS(APCI):Calcd for C25H20NO3([M+H]382.14377 as (+) and 382.14342 as Found, with correct structure.
Example 7
Preparation of 1, 2-bis (4-chlorophenyl) -3H-pyrrolo [1,2-a ] indol-3-one (formula I-g) according to the reaction equation shown in FIG. 11
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-bis (4-chlorophenyl) acetylene (1.25mmol, 308.9mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 24h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the desired product (formula I-a)175.1mg, 90% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.73(d,J＝8.0Hz,1H),7.41–7.33(m,7H),7.32–7.26(m,3H),7.10(t,J＝7.6Hz,1H),6.46(s,1H).13C NMR(126MHz,CDCl3):δ163.98(s),140.81(d,J＝7.9Hz),136.12(s),134.74(d,J＝15.9Hz),133.75(s),131.10(s),130.90(s),129.87(s),129.70(s),129.48(s),128.83(d,J＝18.0Hz),127.78(s),123.74(s),122.91(s),112.76(s),108.70(s),77.41(s),77.16(s),76.91(s).HRMS(APCI):Calcd for C23H14Cl2NO([M+H]390.04470, Found 390.04438, with correct structure.
Example 8
Preparation of 1, 2-bis (3-bromophenyl) -3H-pyrrolo [1,2-a ] indol-3-one (formula I-H) according to the reaction equation shown in FIG. 12
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 1, 2-bis (3-bromophenyl) acetylene (1.25mmol, 420.0mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heatedReaction was carried out at 150 ℃ for 24h, after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give the desired product (formula I-a)199.9mg, 84% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.75(d,J＝7.9Hz,1H),7.63(dd,J＝3.6,1.8Hz,2H),7.59–7.54(m,1H),7.45(ddd,J＝8.0,1.8,1.0Hz,1H),7.42(d,J＝7.8Hz,1H),7.35–7.28(m,3H),7.25(dd,J＝8.4,7.3Hz,1H),7.18(t,J＝7.9Hz,1H),7.12(td,J＝7.7,0.8Hz,1H),6.52(s,1H).13C NMR(126MHz,CDCl3):δ163.57(s),140.86(s),140.48(s),134.65(s),133.64(s),133.03(d,J＝5.9Hz),132.32(s),132.03(s),131.78(s),131.12(d,J＝3.7Hz),130.56(s),129.94(s),128.06(s),127.87(s),127.16(s),123.76(s),123.01(d,J＝14.9Hz),122.52(s),112.73(s),109.07(s).HRMS(APCI):Calcdfor C23H14Br2NO([M+H]477.94367 (+) and Found 477.94332 (479.94124).
Example 9
According to the reaction equation shown in FIG. 13, 1-tert-butyl-2-phenyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-I)
Into a 25mL Schlenk flask, at N2Under the protection of (1), N-diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), 3, 3-dimethylbutynylbenzene (1.25mmol, 197.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 ℃ for reaction for 48h, after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to give 127.9mg of the objective product (formula I-a) in 85% yield.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.69(d,J＝7.9Hz,1H),7.41(dd,J＝5.2,1.9Hz,3H),7.37–7.30(m,2H),7.27(d,J＝7.7Hz,1H),7.25–7.19(m,1H),7.03(t,J＝7.5Hz,1H),5.95(s,1H),1.24(s,9H).13C NMR(126MHz,CDCl3):δ165.13,143.69,142.88,141.17,134.62,133.90,133.76,128.69,128.47,128.10,126.72,123.13,122.39,112.39,105.95,34.53,30.39.HRMS(APCI):Calcd for C21H20ON([M+H]+) 302.15394, Found 302.15369, with correct structure.
Example 10
Preparation of 1, 2-dipropyl-3H-pyrrolo [1,2-a ] indol-3-one (formula I-j) according to the reaction equation shown in FIG. 14
Into a 25mL Schlenk flask, at N2N, N-Diphenyl-1H-indole-1-carboxamide (0.5mmol, 156.2mg), oct-4-yne (1.25mmol, 137.8mg), Re2(CO)10A mixture of (0.025mmol, 16.3mg), zinc chloride (0.15mmol, 20.4mg), dimethylzinc (0.15mmol, 1.2M, 0.125mL) and dry toluene (2.5mL) was heated to 150 deg.C for 72h and after completion of the reaction, the reaction was diluted with DCM and filtered through a thin layer of silica gel, which was washed with EA. The filtrate was concentrated and then separated by column chromatography (eluent petroleum ether: dichloromethane 5/1, v/v) to obtain the objective product (formula I-a)29.1mg, yield 23%.
The target product was characterized as follows:1H NMR(500MHz,CDCl3):δ7.64(dd,J＝7.9,0.9Hz,1H),7.34(dt,J＝7.8,0.9Hz,1H),7.21(td,J＝7.7,1.2Hz,1H),7.03(td,J＝7.6,1.1Hz,1H),6.28(s,1H),2.44(dd,J＝8.4,6.9Hz,2H),2.32–2.24(m,2H),1.72–1.62(m,2H),1.62–1.51(m,2H),1.01(t,J＝7.4Hz,3H),0.97(t,J＝7.4Hz,3H).13C NMR(126MHz,CDCl3):δ166.01,144.40,142.52,135.55,134.27,133.97,126.50,122.71,122.19,112.03,104.73,28.04,25.73,22.33,22.30,14.09,14.00.HRMS(APCI):Calcd for C17H20ON([M+H]254.15394 as (+) and 254.15411 as Found, with correct structure.
In summary, the embodiments of the present invention provide a preparation method of polysubstituted isoindoline, which utilizes indole and alkyne to react in a solvent in the presence of a catalyst, lewis acid and a zinc reagent, so as to realize synthesis of polysubstituted isoindoline.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (9)
1. A process for preparing an indolopyrrolidone compound having the formula I:
in the formula I, R1Independently represent mono-, di-, tri-, tetra-or unsubstituted;
R1each independently selected from: hydrogen, deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, aralkyl, alkoxy, aryloxy, aryl, alkylsilyl, arylsilyl, and combinations thereof;
Raand RbEach independently selected from: alkyl, cycloalkyl, heteroalkyl, aralkyl, alkoxy, aryloxy, aryl, alkylsilyl, arylsilyl, and combinations thereof;
the method comprises the following steps:
in the presence of a catalyst, Lewis acid and a zinc reagent, leading the indole compound shown in the formula II and alkyne shown in the formula III to undergo C-H bond activation/C-N bond cleavage reaction to obtain the indolopyrrolidone compound shown in the formula I:
in the formula II R1In the same formula I as R1；
R2And R3Each independently selected from: alkyl, cycloalkyl, heteroalkyl, aralkyl, alkoxy, aryloxy, aryl, alkylsilyl, arylsilyl, and combinations thereof;
in the formula III, RaAnd RbIn the same formula I as RaAnd Rb；
The catalyst is a rhenium complex containing at least one CO ligand;
the Lewis acid is: at least one of zinc chloride, zinc bromide, zinc fluoride, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc cyanide, aluminum chloride, ferric chloride, cupric chloride, silver trifluoromethanesulfonate, cupric bromide, ferric bromide, cupric iodide, cuprous chloride, cuprous bromide, cuprous iodide, ferrous chloride, and ferrous bromide;
the zinc reagent is an organic zinc reagent.
2. The method of claim 1, wherein: the rhenium complex is used in an amount of 1 to 30 mol% based on the molar amount of the indole compound of formula II.
3. The method of claim 1, wherein: the dosage of the Lewis acid is 1 to 100 percent of the molar weight of the indole compound shown in the formula II.
4. The method of claim 1, wherein: the dosage of the zinc reagent is 1% -100% of the indole compound shown in the formula II.
5. The method of claim 1, wherein: the zinc reagent is dimethyl zinc and/or diethyl zinc.
6. The method of claim 1, wherein: the mol ratio of the indole compound shown in the formula II to the alkyne shown in the formula III is 1:1-1: 10.
7. The method of claim 1, wherein: the C-H bond activation/C-N bond cleavage reaction is carried out in a solvent,
the solvent is as follows: at least one of benzene, toluene and xylene.
8. The method of claim 1, wherein: in the system of C-H bond activation/C-N bond cleavage reaction, the molar concentration of the indole compound shown in the formula II is 0.01-2 mol/L.
9. The method of claim 1, wherein: the temperature of the C-H bond activation/C-N bond cleavage reaction is 50-150 ℃, and the time is 10-100H.
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| CN107151226A (en) * | 2016-03-04 | 2017-09-12 | 中国科学院化学研究所 | A kind of preparation method of polysubstituted isoindolinone |
| CN108148065A (en) * | 2017-12-21 | 2018-06-12 | 河南省科学院化学研究所有限公司 | A kind of synthetic method of 11,12- dihydros -11- Phenylindoles simultaneously [2,3-a] carbazole |
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| CN106967055A (en) * | 2017-04-07 | 2017-07-21 | 中国科学院化学研究所 | A kind of preparation method of polysubstituted isoindoline |
| CN108148065A (en) * | 2017-12-21 | 2018-06-12 | 河南省科学院化学研究所有限公司 | A kind of synthetic method of 11,12- dihydros -11- Phenylindoles simultaneously [2,3-a] carbazole |
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| Ruthenium(II)-Catalyzed Redox-Neutral[3+2] Annulation of Indoles with Internal Alkynes via C-H Bond Activation: Accessing a Pyrroloindolone Scaffold;Yanan Xie et al.;《J. Org. Chem.》;20170409;第82卷;第5263-5273页 * |
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