CN110746335B - Polysubstituted pyrrole compound and synthesis method thereof - Google Patents
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Abstract
The invention discloses a polysubstituted pyrrole compound and a synthesis method thereof. Enamine ketone and alpha-diazo ester are used as initial raw materials, copper salt is used as a catalyst, and under the heating condition, the polysubstituted pyrrole compound is generated through carbene insertion reaction and aryl migration reaction. The method has the advantages of novel and easily-obtained raw materials, simple and convenient operation, simple and mild synthesis reaction conditions and wide substrate universality.
Description
Technical Field
The invention relates to a pyrrole derivative and a synthetic method thereof, in particular to a polysubstituted pyrrole compound and a synthetic method thereof.
Background
Pyrrole is an important class of compounds in pharmaceutical research and is an important backbone structure possessed by many natural products. As a structural unit, pyrrole is one of the basic biochemical entities, and is easily attacked by electrophilicity due to its structural specificity and electron-rich property, and it contains nitrogen atom, so it can interact with many biomolecules through hydrogen bond. These properties make it important in both natural and artificial drugs, and have antiviral, antibacterial, antitumor, antihypercholesterolemic effects (top. heterocyclic. chem., 2006, 2, 53). The currently marketed polysubstituted pyrrole drugs include atorvastatin, nonsteroidal analgesic and anti-inflammatory drugs, tolmetin, chlorfenapyr, and pinworm. The current synthesis methods are as follows: (1) the 1, 4-dicarbonyl compound and the amine compound are subjected to cyclization reaction; (2) adding alkyne, ketone and ammonium salt; (3) reacting the 1, 3-dicarbonyl compound with azide to form a ring; (4) alkyne and isoxazole cyclizations and the like.
The synthesis of polysubstituted pyrazine by taking enaminone and alpha-diazo ester as starting materials has not been reported.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a polysubstituted pyrrole compound with simple and convenient operation, high yield and various product structures and a synthesis method thereof.
The technical scheme is as follows: the invention provides a polysubstituted pyrrole compound with a general formula 1:
wherein R is1Is phenyl or aryl;
R2is phenyl, benzyl, aryl, allyl or alkyl;
R3is hydrogen, a benzene ring or an aryl group;
R4is methyl, ethyl, benzyl or allyl.
Further, the polysubstituted pyrrole compound with the general formula 1 is any one of the following compounds:
the synthesis method of the polysubstituted pyrrole compound with the general formula 1 is characterized in that: the method comprises the following steps: the synthetic route is shown as the following reaction formula:
1-keto-1-aryl-3- (N, N-dimethyl) amino-2-propene and amine are refluxed in an ethanol solvent to generate enaminone 2 (reaction formula 1). 1, 8-diazabicycloundecen-7-ene (DBU) is used as a catalyst, phenylacetate and p-toluenesulfonyl azide are dissolved in acetonitrile and are placed in a microwave reactor for reaction, and alpha-diazo ester 3 (reaction formula 2) is obtained. Taking enaminone 2 and alpha-diazo ester 3 as initial raw materials, taking copper salt as a catalyst, and generating the polysubstituted pyrrole compound (reaction formula 3) with the general formula 1 through copper carbene intermediate formation, cyclization and aryl migration reaction under the heating condition.
Further, the mol ratio of the enaminone 2 to the alpha-diazo ester 3 is 1:0.1-1: 5. The copper salt is CuCl or CuBr2、Cu(NTf2)2、CuSO4、Cu(NO2)2、Cu(OTf)2、CuOTf、Cu(OAc)2Or [ Cu (MeCN)4]PF6The molar ratio of the enaminone 2 to the copper salt is 1:0.01-1: 1. One or a mixture of two of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), 1, 2-Dichloroethane (DCE), 1, 4-dioxane, acetonitrile or toluene is added as a reaction solvent in the synthesis process.
Further, the reaction atmosphere is air, nitrogen or argon; the reaction time is 0.1-48 h; the reaction temperature is 10-120 ℃.
Has the advantages that: the synthesized enamine ketone 2 and alpha-diazo ester 3 have structural diversity, and can synthesize substituted pyrrole derivatives with different types and structures. Synthons 2 and 3 are easy to prepare, the preparation raw materials are cheap and easy to obtain, the cost is low, and the industrial production is easy to realize. The synthesis of the polysubstituted pyrrole compound has good functional group tolerance and diversity, so the polysubstituted pyrrole compound has wide applicability. Different substitution sites of a skeleton of the polysubstituted pyrrole compound are modified to obtain an intermediate of a structure of a medicament and a chemical product, and a 2-site ester group and a 4-site hydrogen atom in the structure are groups capable of being further functionalized. The compound of the invention has significant pharmacological activities of inhibiting cell division and cytotoxin, inhibiting HIV-1 virus integrase, regulating immunity and the like. The synthesis method has the advantages of cheap and easily-obtained raw materials, simple and convenient operation, good yield of target products and capability of further functionalization.
Detailed Description
1-keto-1-aryl-3- (N, N-dimethyl) amino-2-propylene A and amine B are refluxed in an ethanol solvent to generate enaminone 2 (reaction formula 1).
The specific process is as follows: dissolving 1-ketone-1-aryl-3- (N, N-dimethyl) amino-2-propylene A (10.0mmol) and organic amine B (20.0mmol) in 30mL ethanol, and stirring in an oil bath at 80 ℃ for reaction for 6 hours. After cooling to room temperature, the volatile components were removed under reduced pressure and then separated by column chromatography on silica gel (eluent petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v 20: 1) to give the desired product 2. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Phenylacetate C is reacted with p-toluenesulfonyl azide D in acetonitrile solvent with 1, 8-diazabicycloundec-7-ene as the base by microwave to produce alpha-diazo ester 3 (equation 2).
The specific process is as follows: phenylacetate C (10.0mmol) and p-toluenesulfonyl azide D (11.0mmol) are dissolved in 8ml of acetonitrile, 1, 8-diazabicycloundec-7-ene (15.0mmol) is added dropwise in an ice bath, stirred for 5min and then placed in a microwave reactor for reaction at 40 ℃ for 1h under 40W. Cooled to room temperature, added with 20ml of saturated ammonium chloride, extracted with dichloromethane and water, collected organic phase, dried over anhydrous sodium sulfate, filtered, and subjected to removal of volatile components under reduced pressure, followed by separation by silica gel column chromatography (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 100: 1) to obtain the objective product 3. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.
Example 1
1-keto-1-phenyl-3-benzylamino-2-propene 2a (0.5mmol) and copper tetraacetonitrile hexafluorophosphate (0.005mmol) were sequentially weighed into a 25mL Schlenk reaction flask, 3mL of acetonitrile was added, the mixture was stirred in an oil bath at 40 ℃ for 2 minutes, and methyl α -diazophenylacetate 3a (0.6mmol) was added and reacted for 20 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by separation by silica gel column chromatography (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 50: 1) to obtain the objective product 1aa (110mg, yield 60%) as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 2
1-keto-1-phenyl-3-benzylamino-2-propene 2a (0.5mmol) and cuprous trifluoromethanesulfonate (0.1mmol) are sequentially weighed and placed in a 25mL Schlenk reaction flask, 2mL of DMF is added, stirring is carried out in an oil bath at 60 ℃ for 2 minutes, ethyl alpha-diazophenylacetate 3b (0.7mmol) is added, and reaction is carried out for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as the eluent) to give the desired product 1ab (105mg, yield 55%) as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 3
1-keto-1-phenyl-3-benzylamino-2-propene 2a (0.5mmol) and copper acetate (0.1mmol) are weighed in sequence into a 25mL Schlenk reaction flask, 2mL of DCE is added, the mixture is stirred in an oil bath at 80 ℃ for 2 minutes, ethyl α -diazoacetate 3c (2.5mmol) is added, after reaction for 48 hours, the mixture is cooled to room temperature, dichloromethane and water are extracted, the organic phase is collected, dried over anhydrous sodium sulfate, filtered, the volatile components are removed under reduced pressure, and then silica gel column chromatography is performed (eluent is petroleum ether (60-90 ℃)/ethyl acetate, v/v is 50: 1) to obtain the target product 1ac (61mg, yield 40%) as colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 4
1-keto-1-phenyl-3-benzylamino-2-propene 2a (4mmol) and copper bromide (0.05mmol) are sequentially weighed into a 25mL Schlenk reaction flask, 3mL of DMSO is added, the mixture is stirred in an oil bath at 80 ℃ for 2 minutes, and then benzyl α -diazoacetate 3d (0.4mmol) is added to react for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v 50: 1) to obtain the target product 1ad (122mg, yield 55%) as a white oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 5
1-keto-1-phenyl-3-benzylamino-2-propene 2a (0.7mmol) and copper sulfate (0.08mmol) are sequentially weighed into a 25mL Schlenk reaction flask, 2mL of toluene is added, stirring is carried out in an oil bath at 120 ℃ for 2 minutes, and alpha-diazophenylacetic acid allyl ester 3e (1.2mmol) is added for reaction for 0.1 hour. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as the eluent) to give the objective product 1ae (118mg, yield 60%) as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 6
1-keto-1-phenyl-3-benzylamino-2-propene 2a (0.5mmol) and copper tetraacetonitrile hexafluorophosphate (0.1mmol) are sequentially weighed into a 25mL Schlenk reaction flask, 2mL of toluene is added, stirring is carried out in an oil bath at 80 ℃ for 2 minutes, 4-bromo-alpha-diazophenylacetic acid methyl ester 3f (1mmol) is added, and the reaction is carried out for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as eluent) to obtain the desired product 1af (134mg, yield 60%) as a brown oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 7
1-keto-1-phenyl-3-allylamino-2-propene 2b (0.4mmol) and cuprous chloride (0.15mmol) were sequentially weighed into a 25mL Schlenk reaction flask, 2mL of DCE was added, the mixture was stirred in an oil bath at 80 ℃ for 2 minutes, and methyl α -diazophenylacetate 3a (1.2mmol) was added and reacted for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as eluent) to obtain 1ba (87mg, yield 55%) as the objective product as a colorless oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 8
1-keto-1-phenyl-3- (4-methyl) anilino-2-propene 2c (0.6mmol) and copper trifluoromethanesulfonate (0.05mmol) are weighed in sequence into a 25mL Schlenk reaction flask, 2mL of DCM is added, the mixture is stirred for 2 minutes in an oil bath at 40 ℃, methyl alpha-diazophenylacetate 3a (0.6mmol 1) is added, and the reaction is carried out for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as an eluent) to give the desired product 1ca as a yellow oil (119mg, yield 65%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 9
1-keto-1-phenyl-3- (3-methoxy) anilino-2-propene 2d (0.5mmol) and copper sulfate (0.5mmol) are weighed in sequence into a 25mL Schlenk reaction flask, 4mL of DCM is added, stirring is carried out in an oil bath at 40 ℃ for 2 minutes, methyl alpha-diazophenylacetate 3a (0.5mmol) is added, and reaction is carried out for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v. 50: 1 as eluent) to give the desired product 1da as a yellow oil (119mg, yield 60%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 10
1-keto-1-phenyl-3- (4-fluoro) anilino-2-propene 2e (0.5mmol) and copper trifluoromethanesulfonate (0.02mmol) are weighed in sequence into a 25mL Schlenk reaction flask, 2mL of DCE is added, the mixture is stirred in an oil bath at 80 ℃ for 2 minutes, and methyl α -diazophenylacetate 3a (0.7mmol) is added and reacted for 32 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as the eluent) to obtain the objective product 1ea as a brown oil (115mg, yield 60%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 11
1-keto-1- (4-fluoro) phenyl-3-benzylamino-2-propene 2f (1.5mmol) and copper nitrate (0.13mmol) are weighed in sequence into a 25mL Schlenk reaction flask, 5mL of DMF is added, the mixture is stirred in an oil bath at 80 ℃ for 2 minutes, and alpha-diazophenylacetic acid methyl ester 3a (0.6mmol) is added for reaction for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as eluent) to obtain the objective product 1fa as a brown oil (125mg, yield 65%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 12
2g (0.7mmol) of 1-keto-1- (4-chloro) phenyl-3-benzylamino-2-propene and 0.04mmol of cuprous trifluoromethanesulfonate were sequentially weighed and placed in a 25mL Schlenk reaction flask, 5mL of toluene was added, and the mixture was stirred in an oil bath at 80 ℃ for 2 minutes, followed by addition of methyl α -diazophenylacetate 3a (0.8mmol) and reaction for 18 hours. After completion of the reaction, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate, v/v ═ 50: 1 as eluent) to give the desired product 1ga (130mg, yield 65%) as a brown oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 13
1-keto-1- (4-bromo) phenyl-3-benzylamino-2-propene was weighed in this order for 2 hours (0.5mmol) and copper nitrate (0.12mmol) in a 25mL Schlenk reaction flask, 5mL of acetonitrile was added, and the mixture was stirred in an oil bath at 80 ℃ for 2 minutes, and then methyl α -diazophenylacetate 3a (0.8mmol) was added and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, dichloromethane and water were extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the volatile components were removed under reduced pressure, followed by silica gel column chromatography (eluent petroleum ether (60-90 ℃)/ethyl acetate, v/v ═ 50: 1) to obtain the objective product 1ha (145mg, yield 65%) as a brown oil. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
The characterization data of the target product are as follows:
1-keto-1-phenyl-3-benzylamino-2-propene (2a), yellow solid, m.p.80-83 ℃.1H NMR(400MHz，CDCl3)δ 10.57(s，1H)，7.86(dd，J＝8.2，1.9Hz，2H)，7.16-7.43(m，8H)，6.98(dd，J＝12.7，7.5Hz，1H)，5.74(d，J＝7.5Hz，1H)，4.41(d，J＝6.2Hz，2H).13C{1H}NMR(100MHz，CDCl3)δ 190.1，154.2，139.0，137.6，130.9，128.7，128.3，127.7，127.4，127.0，90.8，52.6.C16H15HRMS theoretical value of NO ([ M + H)]+): 238.1154, respectively; measurement value: 238.1147.
methyl α -diazophenylacetate (3a), an orange oily liquid.1H NMR(400MHz，CDCl3)δ7.49(dd，J＝8.5，1.1Hz，2H)，7.39(t，J＝7.9Hz，2H)，7.19(t，J＝7.4Hz，1H)，3.87(s，3H).13C{1H}NMR(100MHz，CDCl3) HRMS theoretical values ([ M + H ] of delta 165.55, 128.94, 125.82, 125.48, 123.92, 51.97.C9H9O2]+): 177.0586 measurement: 177.0588.
1-benzyl-2-carbomethoxy-3-phenyl-5-phenylpyrrole derivative (1aa), colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.38(dd，J＝8.3，1.3Hz，2H)，7.32-7.26(m，7H)，7.22(d，J＝7.3Hz，1H)，7.16(d，J＝8.1Hz，2H)，7.11(t，J＝7.3Hz，1H)，6.84(d，J＝7.1Hz，2H)，6.27(s，1H)，5.53(s，2H)，3.44(s，3H).13C{1H}NMR(100MHz，CDCl3)δ162.10，140.80，139.29，136.48，134.13，131.91，129.44，129.29，128.50，128.45，128.30，127.59，126.82，126.65，125.65，119.30，112.16，50.75，49.65.C26H23NO2HRMS theoretical value of ([ M + H ]]+): 368.1572, respectively; measurement value: 368.1566.
1-benzyl-2-carbethoxy-3-phenyl-5-phenylpyrrole derivative (1ab), colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.50(d，J＝7.0Hz，2H)，7.41(d，J＝1.9Hz，1H)，7.39(d，J＝1.4Hz，4H)，7.38-7.36(m，2H)，7.33(d，J＝7.3Hz，1H)，7.28(t，J＝7.3Hz，2H)，7.22(t，J＝7.3Hz，1H)，6.96(d，J＝7.2Hz，2H)，6.38(s，1H)，5.65(s，2H)，4.05(q，J＝7.1Hz，2H)，0.98(t，J＝7.1Hz，3H).13C{1H}NMR(100MHz，CDCl3)δ161.83，140.70，139.53，136.77，134.19，132.14，129.62，129.60，128.64，128.60，128.40，127.63，126.93，126.75，125.84，119.85，112.20，59.99，49.76，13.76.C27H25NO2HRMS theoretical value of ([ M + H ]]+): 382.1729, respectively; measurement value: 382.1735.
1-benzyl-2-carbethoxy-3-hydro-5-phenylpyrrole derivative (1ac) as a colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.36(d，J＝1.8Hz，1H)，7.33(d，J＝2.9Hz，1H)，7.32(s，2H)，7.30(s，2H)，7.26(s，2H)，7.24(s，1H)，6.99(d，J＝6.7Hz，2H)，6.66(d，J＝1.8Hz，1H)，5.10(s，2H)，4.27(q，J＝7.1Hz，2H)，1.32(t，J＝7.1Hz，3H).13C{1H}NMR(100MHz，CDCl3)δ164.99，137.55，135.94，132.23，129.26，128.94，128.62，127.89，127.86，127.71，126.80，116.31，110.08，59.87，51.29，14.61.C20H19NO2HRMS theoretical value of ([ M + H ]]+): 306.1416, respectively; measurement value: 306.1419.
1-benzyl-2-carbobenzoxy-3-phenyl-5-phenylpyrrole derivative (1ad), colorless oily liquid.1H NMR(400MHz，CDCl3)67.40(dd，J＝7.6，1.9Hz，2H)，7.36-7.31(m，5H)，7.29-7.24(m，3H)，7.24-7.18(m，3H)，7.15(m，3H)，6.88(t，J＝6.7Hz，4H)，6.32(s，1H)，5.60(s，2H)，5.00(s，2H).13C{1H}NMR(100MHz，CDCl3)δ161.56，141.00，139.42，136.75，135.80，134.67，132.05，129.63，129.58，128.63，128.60，128.44，128.23，127.99，127.76，127.74，126.95，126.74，125.84，119.46，112.44，65.70，49.77.C31H25NO2HRMS theoretical value of ([ M + H ]]+): 444.185, respectively; measurement value: 444.1881.
1-benzyl-2-allylester-3-phenyl-5-phenylpyrrole derivative (1ae) as colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.44(d，J＝7.1Hz，2H)，7.37-7.29(m，7H)，7.28-7.19(m，3H)，7.15(t，J＝7.2Hz，1H)，6.90(d，J＝7.3Hz，2H)，6.32(s，1H)，5.59(s，2H)，5.58-5.51(m，1H)，4.95(dd，J＝10.5，1.2Hz，1H)，4.86(d，J＝17.2，1.2Hz，1H)，4.44(d，J＝5.5Hz，2H).13C{1H}NMR(100MHz，CDCl3)δ161.44，140.96，139.41，136.68，134.52，132.05，131.94，129.59，129.57，128.62，128.57，128.42，127.70，126.94，126.78，125.82，119.47，117.62，112.33，64.71，49.76.C27H23NO2HRMS theoretical value of ([ M + H ]]+): 394.1729, respectively; measurement value: 294.1727.
1-benzyl-2-carbomethoxy-3- (4-bromo) phenyl-5-phenylpyrrole derivative (1af), yellow oily liquid.1H NMR(400MHz，CDCl3)δ7.48(d，J＝8.4Hz，2H)，7.35(s，5H)，7.32(d，J＝8.4Hz，2H)，7.24(t，J＝7.3Hz，2H)，7.18(t，J＝7.2Hz，1H)，6.90(d，J＝7.3Hz，2H)，6.30(s，1H)，5.59(s，2H)，3.53(s，3H).13C{1H}NMR(100MHz，CDCl3)δ161.94，141.11，139.25，135.61，132.98，131.84，131.13，130.81，129.56，128.66，128.60，12854，127.02，125.77，120.88，119.39，112.10，50.93，49.85.C25H20BrNO2HRMS theoretical value of ([ M + H ]]+): 446.0677, respectively; measurement value: 446.0679.
1-allyl-2-carbomethoxy-3-phenyl-5-phenylpyrrole derivative (1ba), colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.50-7.44(m，5H)，7.43-7.29(m，5H)，6.30(s，1H)，6.00(dd，J＝17.2，10.4Hz，1H)，5.14(dd，J＝10.4，1.2Hz，1H)，5.03-4.94(m，2H)，4.88(dd，J＝17.2，1.2Hz，1H)，3.66(s，3H).13C{1H}NMR(100MHz，CDCl3)δ162.37，140.42，136.76，135.76，133.87，132.14，129.58，129.42，128.53，128.42，127.70，126.71，119.08，115.55，112.05，50.88，48.58.C21H19NO2HRMS theoretical value of ([ M + H ]]+): 318.1416, respectively; measurement value: 318.1415.
1- (4-methyl)) Phenyl-2-carbomethoxy-3-phenyl-5-phenylpyrrole derivative (1ca), colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.53(d，J＝7.1Hz，2H)，7.41(t，J＝7.4Hz，2H)，7.33(t，J＝7.3Hz，1H)，7.22-7.18(m，3H)，7.17-7.10(m，6H)，6.48(s，1H)，3.51(s，3H)，2.38(s，3H).13C{1H}NMR(100MHz，CDCl3)δ161.94，139.79，137.86，136.84，136.25，133.39，132.02，129.41，129.23，129.03，128.35，128.12，127.86，127.46，126.93，121.45，112.19，51.00，21.37.C25H21NO2HRMS theoretical value of ([ M + H ]]+): 368.1572, respectively; measurement value: 368.1577.
1- (3-methoxy) benzyl-2-carbomethoxy-3-phenyl-5-phenylpyrrole derivative (1da) as a colorless oily liquid.1H NMR(400MHz，CDCl3)δ7.45(d，J＝7.1Hz，2H)，7.39-7.35(m，7H)，7.30(t，J＝7.3Hz，1H)，7.17(t，J＝7.9Hz，1H)，6.73(d，J＝10.4Hz，1H)，6.52(d，J＝7.6Hz，1H)，6.45(s，1H)，6.34(s，1H)，5.58(s，2H)，3.72(s，3H)，3.54(s，3H).13C{1H}NMR(100MHz，CDCl3)δ161.12，158.73，140.00，139.81，135.53，133.18，130.93，128.50，128.46，128.33，127.53，127.31，126.59，125.66，118.34，117.04，111.24，111.21，110.35，54.06，49.78，48.55.C26H23NO3HRMS theoretical value of ([ M + H ]]+): 398.4740, respectively; measurement value: 398.4718.
1- (4-fluoro) benzyl-2-carbomethoxy-3-phenyl-5-phenylpyrrole derivative (1ea) as a yellow oily liquid.1H NMR(400MHz，CDCl3)δ7.49(d，J＝7.0Hz，2H)，7.44-7.37(m，7H)，7.33(t，J＝7.3Hz，1H)，6.97(t，J＝8.7Hz，2H)，6.92(t，J＝7.1Hz，2H)，6.38(s，1H)，5.60(s，2H)，3.58(s，3H).13C{1H}NMR(100MHz，CDCl3)δ，162.27，161.86(d，J＝243.4Hz)，160.64，140.90，136.51，135.06(d，J＝3.1Hz)，134.42，131.95，129.56，129.41，128.68，128.52，127.74，127.54(d，J＝8Hz)，126.85，119.31，115.43(d，J＝21.5Hz).，112.45，50.90，49.08.C25H20FNO2HRMS theoretical value of ([ M + H ]]+): 386.1478, respectively; measurement value: 386.1477.
1-benzyl-2-carbomethoxy-3-phenyl-5- (4-fluoro) phenylpyrrole derivative (1fa), yellow oily liquid.1H NMR(400MHz，CDCl3)δ7.35(d，J＝7.0Hz，2H)，7.26(t，J＝7.4Hz，2H)，7.20(m，3H)，7.15(t，J＝7.3Hz，2H)，7.09(d，J＝7.2Hz，1H)，6.93(t，J＝8.7Hz，2H)，6.80(d，J＝7.2Hz，2H)，6.21(s，1H)，5.47(s，2H)，3.42(s，3H).13C{1H}NMR(100MHz，CDCl3)δ162.85(d，J＝248.6Hz)，162.20，139.73，139.24，136.49，134.14，131.38(d，J＝8.2Hz)，129.40，128.64，128.10(d，J＝3.4Hz)，127.74，127.04，126.84，125.71，119.52，115.66(d，J＝21.6Hz)，112.36，50.89，49.70.C25H20FNO2HRMS theoretical value of ([ M + H ]]+): 386.1478, respectively; measurement value: 386.1476.
1-benzyl-2-carbomethoxy-3-phenyl-5- (4-chloro) phenylpyrrole derivative (1ga), brown oily liquid.1H NMR(400MHz，CDCl3)δ7.34(d，J＝7.1Hz，2H)，7.26(t，J＝7.4Hz，2H)，7.21(d，J＝6.5Hz，1H)，7.20-7.17(m，3H)，7.15(t，J＝7.4Hz，3H)，7.08(t，J＝7.3Hz，1H)，6.80(d，J＝7.2Hz，2H)，6.23(s，1H)，5.47(s，2H)，3.42(s，3H).13C{1H}NMR(100MHz，CDCl3)δ162.13，139.50，139.15，136.39，134.55，134.18，130.76，130.44，129.37，128.86，128.65，127.74，127.07，126.86，125.66，119.82，112.46，50.91，49.75.C25H20ClNO2HRMS theoretical value of ([ M + H ]]+): 402.4483, respectively; measurement value: 402.4487.
1-benzyl-2-carbomethoxy-3-phenyl-5- (4-bromo) phenylpyrrole derivative (1ha), brown oily liquid.1H NMR(400MHz，CDCl3)δ7.46-7.39(m，4H)，7.33(t，J＝7.4Hz，2H)，7.26(d，J＝7.3Hz，1H)，7.22(t，J＝7.4Hz，2H)，7.18-7.12(m，3H)，6.87(d，J＝7.2Hz，2H)，6.30(s，1H)，5.54(s，2H)，3.49(s，3H).13C{1H}NMR(100MHz，CDCl3)δ162.10，139.48，139.12，136.35，134.19，131.80，131.00，130.88，129.36，128.65，127.73，127.07，126.85，125.64，122.76，119.86，112.43，50.90，49.74.C25H20BrNO2HRMS theoretical value of ([ M + H ]]+): 445.0677, respectively; measurement value: 445.0679.
Claims (4)
1. a synthetic method of polysubstituted pyrrole compounds with a general formula 1 is characterized in that: the method comprises the following steps: the synthetic route is shown as the following reaction formula:
taking enaminone 2 and alpha-diazo ester 3 as initial raw materials, taking copper salt as a catalyst, and generating a polysubstituted pyrrole compound with a general formula 1 through copper carbene intermediate formation, cyclization and ester group transfer reaction under the heating condition,
wherein R is1Is aryl;
R2is aryl, benzyl or allyl;
R3is hydrogen or aryl;
R4is methyl, ethyl, benzyl or allyl;
the mol ratio of the enaminone 2 to the alpha-diazo ester 3 is 1:0.1-1: 5;
the copper salt is CuCl or CuBr2、Cu(NTf2)2、CuSO4、Cu(NO2)2、Cu(OTf)2、CuOTf、Cu(OAc)2Or [ Cu (MeCN) 4]PF6The molar ratio of the enaminone 2 to the copper salt is 1:0.01-1: 1.
2. The method for synthesizing polysubstituted pyrrole compounds having general formula 1 according to claim 1, wherein: the polysubstituted pyrrole compound with the general formula 1 is any one of the following compounds:
3. the method for synthesizing polysubstituted pyrrole compounds having general formula 1 according to claim 1, wherein: one or a mixture of two of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), 1, 2-Dichloroethane (DCE), 1, 4-dioxane, acetonitrile or toluene is added as a reaction solvent in the synthesis process.
4. The method for synthesizing polysubstituted pyrrole compounds having general formula 1 according to claim 1, wherein: the reaction atmosphere is air, nitrogen or argon; the reaction time is 0.1-48 h; the reaction temperature is 10-120 ℃.
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