A method for preparing a multi-substituted 3-dihydropyrrole compound

Abstract

The present invention discloses a method for preparing polysubstituted 3-dihydropyrrole compounds. The method includes: using propargylamine and α-diazoester as starting materials, a copper salt as a catalyst, and under room temperature conditions, through metal carbene insertion and intramolecular cyclization reactions to generate polysubstituted 3-dihydropyrrole compounds. This method has easily accessible raw materials, simple operation, mild synthesis reaction conditions, and the functional groups have diversity.

Description

Technical Field

[0001] The present invention relates to a method for preparing a compound, and particularly to a method for preparing a polysubstituted 3-dihydropyrrole compound. Background Art

[0002] As an important structural branch of heterocyclic compounds, five-membered nitrogen-containing heterocycles are widely used in medicinal chemistry, molecular chemistry, and functional materials. Among them, 3-dihydropyrrole compounds are an important class of nitrogen heterocyclic compounds, which are commonly found in many bioactive compounds and natural products, such as bilirubin, aureomycin, and lactam. Their structure is as follows:

[0003]

[0004] In the field of biomedicine, 3-dihydropyrrole compounds also have good biological activities. For example, peptide deformylase inhibitors with good antiviral activities (Bioorg. Med. Chem. Lett., 2010, 20, 3592 - 3595), antioxidants for treating oxidative damage (J. Med. Chem., 1998, 41, 3477 - 3492), and analgesic and anti-inflammatory drugs (Eur. J. Med. Chem., 1979, 14, 189 - 189). In addition, the 3-dihydropyrrole compound skeleton also exists in spindle protein inhibitors (J. Med. Chem., 2008, 51, 4239 - 4252), and spiroindole derivatives with antibacterial activities (Eur. J. Med. Chem., 2012, 51, 79 - 91). Given the wide range of pharmacological and physiological activities of 3-dihydropyrrole compounds, it is of certain research significance to develop new reactions, new methods, and new strategies for their diverse synthesis.

[0005]

[0006] Currently known methods for synthesizing 3-dihydropyrrole include: (1) The self-cyclization reaction of N-carbamoyl allene catalyzed by silver salt. (2) The self-cyclization reaction of N-p-toluenesulfonyl allene at high temperature catalyzed by an equivalent amount of base. (3) The [3 + 2] cyclization reaction of azomethine lactone and allenoate catalyzed by triethylamine. Although the above methods have been used for 3-dihydropyrrole compounds, these methods all require the use of expensive raw material reagents, and there are problems such as high cost, harsh reaction conditions, and poor economy. Currently, there has been no report on the synthesis of polysubstituted 3-dihydropyrrole compounds starting from easily prepared propargylamine and α-diazoester. Summary of the Invention

[0007] Objective of the Invention: The present invention aims to provide a method for preparing polysubstituted 3-dihydropyrrole compounds. Starting from easily preparable propargylamines and α-diazo esters with structural diversity and multiple reaction centers, polysubstituted 3-dihydropyrrole compounds with potential pharmaceutical activities are synthesized under room temperature conditions.

[0008] Technical Solution: The method for preparing polysubstituted 3-dihydropyrrole compounds according to the present invention includes the following steps:

[0009] Using propargylamine compounds 2 and α-diazo ester compounds 3 as starting materials, and a copper salt as a catalyst, 3-dihydropyrrole compounds of general formula 1 are formed through the formation of a copper carbene intermediate and intramolecular cyclization reaction under room temperature conditions;

[0010] The synthetic route is as follows:

[0011]

[0012] R 1 is selected from phenyl, aryl substituted with halogen, alkyl or alkoxy;

[0013] R 2 is selected from phenyl, naphthalene ring;

[0014] R 3 is selected from naphthyl, phenyl, aryl substituted with halogen, alkyl or alkoxy;

[0015] R 4 is alkyl, allyl or benzyl.

[0016] Furthermore, the R 1 is selected from phenyl, aryl substituted with halogen, methyl or methoxy; R 2 is selected from phenyl, naphthalene ring; R 3 is selected from naphthyl, phenyl, aryl substituted with halogen, methyl or methoxy; R 4 is alkyl, allyl or benzyl with 1-4 carbon atoms.

[0017] Furthermore, the molar ratio of the propargylamine compound 2 to the α-diazo ester compound 3 in the step is 1:1 to 1:3.

[0018] Furthermore, the catalyst copper salt in the step is one or more of CuCl2, CuBr2, Cu(OAc)2, Cu(OTf)2, Cu(MeCN)4PF6, CuCl, CuBr, CuOAc or CuOTf.

[0019] Furthermore, the molar ratio of the propargylamine compound 2 to the copper salt in the step is 1:0.01 - 1:1.

[0020] Further, the reaction solvent described in the step is one or a mixture of two of acetonitrile, dichloromethane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene, chloroform, 1,4-dioxane, ethanol or dichloroethane.

[0021] Further, the reaction atmosphere is air, oxygen, nitrogen or argon; the reaction time is 0.5 - 12 hours, and the optimal reaction time is 1 - 8 hours; the reaction temperature is 25 - 120 °C.

[0022] Advantages: Compared with the prior art, the present invention has the following remarkable advantages:

[0023] (1) The synthons propargylamine 2 and α-diazoester 3 have structural diversity and can be used to synthesize polysubstituted 3-dihydropyridine compounds 1 with different types and structures;

[0024] (2) The synthons propargylamine 2 and α-diazoester 3 are both easy to prepare, the raw materials for preparation are cheap and easily available, the cost is low, and it is easy to industrialize production;

[0025] (3) The synthesis reaction of polysubstituted 3-dihydropyridine compounds 1 uses relatively non-toxic copper-based reagents with lower prices as catalysts, has a cost advantage, and is environmentally friendly;

[0026] (4) The synthesis of polysubstituted 3-dihydropyridine compounds has good functional group tolerance and diversity, so it has wide applications;

[0027] (5) The reaction conditions of this method are mild, the yield is high, and it can reach the gram scale, and the highest yield can reach 81%. It has great implementation value and social and economic benefits. Specific Embodiments

[0028] The following makes a detailed description of the present application in combination with specific embodiments.

[0029] The synthesis of the starting materials propargylamine 2 and α-diazoester 3 in the following examples can be prepared according to the prior art, for example:

[0030] Synthesis of propargylamine 2:

[0031] At 110 °C, using toluene as the solvent and copper iodide as the catalyst, aniline derivative A, benzaldehyde derivative B and phenylacetylene C react to form propargylamine 2 (Reaction Scheme 1).

[0032]

[0033] The specific process is as follows: Aniline derivative A (6.5 mmol), benzaldehyde derivative B (5 mmol), and phenylacetylene C (6.5 mmol) are dissolved in 20 mL of toluene. Then, copper(I) iodide (1 mmol) as a catalyst is added, and the mixture is stirred and reacted in an oil bath at 110 °C. TLC detection is carried out, and the reaction is stopped when the raw material benzaldehyde derivative has completely reacted. After cooling to room temperature, it is washed with saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the volatile components are removed under reduced pressure. Then, it is separated by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 10:1) to obtain the target product 2. The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0034] Synthesis of α-diazo ester 3:

[0035] Aryl acetate D and p-toluenesulfonyl azide E, in acetonitrile solvent, with 1,8-diazabicycloundec-7-ene (DBU) as the base, react through microwave irradiation to form α-diazo ester 3 (Reaction Scheme 2).

[0036]

[0037] The specific process is as follows: Aryl acetate D (10 mmol) and p-toluenesulfonyl azide E (11 mmol) are dissolved in 20 mL of acetonitrile. 1,8-Diazabicycloundec-7-ene (15 mmol) is added dropwise in an ice bath. After stirring for 5 minutes, it is placed in a microwave reactor and reacted at 40 °C and 40 W for 1 hour. After cooling to room temperature, 20 mL of saturated ammonium chloride is added, and it is extracted with dichloromethane and water. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and the volatile components are removed under reduced pressure. Then, it is separated by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 100:1) to obtain the target product 3. The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0038] Among them,

[0039] R 1 is selected from phenyl, aryl substituted with halogen, alkyl, or alkoxy;

[0040] R 2 is selected from phenyl, naphthalene ring;

[0041] R 3 is selected from naphthyl, phenyl, aryl substituted with halogen, alkyl, or alkoxy;

[0042] R 4 is alkyl, allyl, or benzyl.

[0043] Example 1

[0044]

[0045] Weigh N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), methyl 2-diazo-2-phenylacetate 3a (0.5 mmol) and copper(II) chloride (0.005 mmol) successively into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1a (144 mg, yield 65%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0046] Example 2

[0047]

[0048] Weigh N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), isobutyl 2-diazo-2-phenylacetate 3b (0.5 mmol) and copper(II) chloride (0.005 mmol) successively into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1b (127 mg, yield 54%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0049] Example 3

[0050]

[0051] Weigh N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), benzyl 2-diazo-2-phenylacetate 3c (0.5 mmol) and copper(II) chloride (0.005 mmol) successively into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1c (200 mg, yield 79%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0052] Example 4

[0053]

[0054] Weigh successively N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), ethyl 2-diazo-2-naphthaleneacetate 3d (0.5 mmol) and copper chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and place it at room temperature for reaction for 1 hour. After the reaction is completed, add saturated brine to quench the reaction, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1d (109 mg, yield 44%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0055] Example 5

[0056]

[0057] Weigh successively N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), methyl 2-(4-bromophenyl)-2-diazoacetate 3e (0.5 mmol) and copper chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and place it at room temperature for reaction for 1 hour. After the reaction is completed, add saturated brine to quench the reaction, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the yellow solid target product 1e (198 mg, yield 78%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0058] Example 6

[0059]

[0060] Weigh successively N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), methyl 2-(4-methylphenyl)-2-diazoacetate 3f (0.5 mmol) and copper(II) chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1f (137 mg, yield 62%). The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0061] Example 7

[0062]

[0063] Weigh successively N-(1,3-diphenylprop-2-en-1-yl)aniline 2a (0.5 mmol), methyl 2-(4-methoxyphenyl)-2-diazoacetate 3g (0.5 mmol) and copper(II) chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1g (186 mg, yield 81%). The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0064] Example 8

[0065]

[0066] Weigh successively N-(1-(naphthalen-2-yl)-3-phenylprop-2-en-1-yl)aniline 2b (0.5 mmol), methyl 2-diazobenzoate 3a (0.5 mmol) and copper(II) chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1h (132 mg, yield 55%). The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0067] Example 9

[0068]

[0069] Weigh 4-bromo-N-(1,3-diphenylprop-2-en-1-yl)aniline 2c (0.5 mmol), methyl 2-diazo-2-phenylacetate 3a (0.5 mmol) and copper chloride (0.005 mmol) into a 25 mL reaction tube in sequence. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1i (186 mg, yield 73%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0070] Example 10

[0071]

[0072] Weigh 4-chloro-N-(1,3-diphenylprop-2-en-1-yl)aniline 2d (0.5 mmol), methyl 2-diazo-2-phenylacetate 3a (0.5 mmol) and copper chloride (0.005 mmol) into a 25 mL reaction tube in sequence. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1j (125 mg, yield 54%). The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0073] Example 11

[0074]

[0075] Weigh successively 4-methyl-N-(1,3-diphenylprop-2-en-1-yl)aniline 2e (0.5 mmol), methyl 2-diazo-2-phenylacetate 3a (0.5 mmol) and copper(II) chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1i (149 mg, yield 67%). The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0076] Example 12

[0077]

[0078] Weigh successively 4-methoxy-N-(1,3-diphenylprop-2-en-1-yl)aniline 2f (0.5 mmol), methyl 2-diazo-2-phenylacetate 3a (0.5 mmol) and copper(II) chloride (0.005 mmol) into a 25 mL reaction tube. Under air, add 5 mL of EtOH solvent, and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with saturated brine, extract the aqueous phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, filter, remove the volatile components under reduced pressure, and then separate by silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate, v / v = 20:1) to obtain the white solid target product 1l (186 mg, yield 81%). The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0079] Characterization data of typical compounds

[0080] Methyl 1,2,3,5-tetraphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1a), white solid. 1 H NMR(400MHz,CDCl3)δ7.64(d,J=7.0Hz,2H),7.53(d,J=7.0Hz,2H),7.40(t,J=7.6Hz,2H),7.30(t,J=7.3Hz,1H),7.25(t,J=7.3Hz,2H),7.23–7.15(m,4H),7.01–6.95(m,4H),6.60(d,J=7.2Hz,1H),6.56(d,J=7.9Hz,3H),6.17(d,J=2.2Hz,1H),6.04(d,J=2.2Hz,1H),3.87(s,3H). 1313C NMR (100 MHz, CDCl3) δ 171.5, 143.3, 143.2, 141.1, 138.4, 133.4, 129.7, 129.0, 128.6, 128.4, 128.2, 128.14, 128.08, 128.0, 127.6, 127.5, 126.9, 117.3, 115.5, 81.3, 71.3, 52.6. C 30 H 25 HRMS calculated value for NO2 ([M+Na] + ): 454.1778; found: 454.1788

[0081] Isobutyl 1,2,3,5-tetraphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1b), white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.9 Hz, 2H), 7.61 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.35–7.27 (m, 3H), 7.27–7.21 (m, 2H), 7.19 (t, J = 7.2 Hz, 2H), 7.03–6.95 (m, 4H), 6.64–6.56 (m, 3H), 6.23 (d, J = 2.2 Hz, 1H), 6.05 (d, J = 2.2 Hz, 1H), 4.17–4.02 (m, 2H), 1.93 (dp, J = 13.5, 6.7 Hz, 1H), 0.84 (d, J = 6.7 Hz, 6H) 13 13C NMR (100 MHz, CDCl3) δ 171.0, 143.2, 143.1, 141.3, 138.7, 133.7, 129.9, 128.9, 128.6, 128.22, 128.17, 128.09, 128.05, 128.0, 127.6, 127.4, 126.9, 117.2, 115.6, 81.5, 72.3, 71.1, 27.7, 19.3, 19.2. C 33 H 31 HRMS calculated value for NO2 ([M+Na] + ): 496.2247; found: 496.2264

[0082] Benzyl 1,2,3,5-tetraphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1c), white solid. 11H NMR (400 MHz, CDCl3)) δ 7.60 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.4 Hz, 3H), 7.31 (d, J = 7.6 Hz, 3H), 7.29–7.27 (m, 1H), 7.26–7.19 (m, 8H), 7.13 (t, J = 7.5 Hz, 2H), 6.98 (t, J = 7.8 Hz, 2H), 6.91 (d, J = 7.7 Hz, 2H), 6.61 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 6.15 (d, J = 2.2 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 5.37 (d, J = 12.0 Hz, 1H), 5.27 (d, J = 12.1 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 170.8, 143.2, 141.1, 138.6, 135.1, 133.5, 130.0, 129.0, 128.8, 128.60, 128.59, 128.5, 128.33, 128.32, 128.1, 128.0, 127.6, 127.4, 127.0, 117.3, 115.6, 81.4, 71.27, 67.85.C 36 H 29 HRMS calculated for + NO2 ([M+Na]+): 530.2091; found: 530.2104

[0083] Ethyl 2-(naphthalen-1-yl)-1,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1d), white solid. 1HNMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.42–7.37 (m, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.03 (t, J = 7.6 Hz, 2H), 6.84 (t, J = 7.8 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 7.7 Hz, 2H), 6.48 (t, J = 6.9 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.24 (d, J = 2.6 Hz, 1H), 4.45–4.31 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.8, 143.4, 142.4, 140.5, 135.5, 134.2, 132.6, 131.6, 130.3, 130.1, 129.4, 129.2, 129.0, 128.2, 127.7, 127.5, 127.4, 127.3, 126.8, 126.5, 125.8, 124.6, 123.5, 117.3, 115.2, 84.6, 70.3, 61.5, 13.9.C 35 H 29 HRMS of NO2 ([M+Na] + ): 518.2091; found: 518.2102

[0084] Methyl 2-(4-bromophenyl)-1,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1e), yellow solid. 1 HNMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 2H), 7.44–7.37 (m, 4H), 7.35 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.25–7.22 (m, 1H), 7.20 (t, J = 7.1 Hz, 2H), 7.04–6.96 (m, 4H), 6.62 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 8.2 Hz, 2H), 6.17 (d, J = 2.1 Hz, 1H), 6.01 (d, J = 1.8 Hz, 1H), 3.87 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 171.4, 142.91, 142.86, 140.8, 137.6, 132.9, 131.2, 130.4, 129.8, 129.0, 128.6, 128.4, 128.2, 128.1, 127.5, 126.9, 121.7, 117.5, 115.3, 80.6, 71.2, 52.8. C 30 H 24 HRMS calculated for BrNO2 ([M+Na] + ): 532.0883; found: 532.0886

[0085] Methyl 2-(4-tolyl)-1,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1f), white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.27 (q, J = 8.5 Hz, 3H), 7.14 (d, J = 8.1 Hz, 2H), 7.11 (dd, J = 8.0, 2.0 Hz, 3H), 7.07 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 9.0 Hz, 3H), 6.26 (d, J = 2.2 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 3.92 (s, 3H), 2.35 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 171.5, 143.3, 143.2, 141.2, 137.1, 135.3, 133.4, 129.4, 128.9, 128.8, 128.4, 128.3, 128.1, 128.0, 127.9, 127.4, 126.8, 117.1, 115.4, 81.0, 77.5, 52.4, 21.1. C 31 H 27 HRMS calculated for NO2 ([M+Na] + ): 468.1934; found: 468.1950

[0086] Methyl 2-(4-methoxyphenyl)-1,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1g), white solid. 11H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.1 Hz, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.17 (t, J = 7.0 Hz, 2H), 7.02–6.94 (m, 4H), 6.76 (d, J = 9.0 Hz, 2H), 6.58 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 6.15 (d, J = 2.2 Hz, 1H), 5.99 (d, J = 2.2 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 171.7, 158.7, 143.4, 143.2, 141.2, 133.5, 130.4, 129.8, 129.3, 129.0, 128.4, 128.2, 128.1, 128.0, 127.4, 126.9, 117.1, 115.4, 113.4, 80.8, 71.1, 55.2, 52.6.C 31 H 27 HRMS calculated for NO3 ([M+Na] + ): 484.1883; found: 484.1879

[0087] Methyl 5-(naphthalen-2-yl)-1,2,3-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1h), white solid. 1 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.87 (t, J = 8.3 Hz, 2H), 7.85–7.78 (m, 2H), 7.54 (d, J = 7.1 Hz, 2H), 7.52–7.44 (m, 2H), 7.26 (t, J = 7.3 Hz, 2H), 7.23–7.13 (m, 4H), 6.99–6.91 (m, 4H), 6.60 (d, J = 9.0 Hz, 2H), 6.56 (d, J = 7.2 Hz, 1H), 6.19 (d, J = 5.6 Hz, 2H), 3.92 (s, 3H). 13CNMR (100 MHz, CDCl3) δ 171.5, 143.5, 143.2, 138.9, 138.4, 133.8, 133.4, 133.1, 129.5, 128.9, 128.6, 128.4, 128.3, 128.2, 128.13, 128.06, 128.0, 127.9, 127.6, 126.2, 125.9, 125.7, 125.0, 117.3, 115.5, 81.4, 71.5, 52.6. C 34 H 27 HRMS theoretical value of NO3 ([M + Na] + ): 504.1934; Measured value: 504.1947

[0088] Methyl 1-(4-bromophenyl)-2,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1i), white solid. 1 HNMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 6.9 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.28–7.23 (m, 2H), 7.20 (t, J = 7.2 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.49 (d, J = 8.7 Hz, 2H), 6.20 (d, J = 2.2 Hz, 1H), 6.02 (d, J = 2.3 Hz, 1H), 3.89 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.0, 143.3, 142.2, 140.5, 137.9, 133.3, 131.1, 129.4, 129.1, 128.5, 128.24, 128.19, 128.18, 128.0, 127.8, 127.6, 126.7, 117.0, 109.7, 81.4, 71.4, 52.6. C 30 H 24 HRMS theoretical value of BrNO2 ([M + Na] + ): 532.0883; Measured value: 532.0870

[0089] Methyl 1-(4-chlorophenyl)-2,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1j), white solid. 1HNMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.25–7.19 (m, 3H), 7.17 (d, J = 7.4 Hz, 2H), 6.95–6.87 (m, 4H), 6.46 (d, J = 9.0 Hz, 2H), 6.15 (d, J = 2.2 Hz, 1H), 5.97 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H) 13 C NMR (100 MHz, CDCl3) δ 171.1, 143.3, 141.8, 140.6, 138.0, 133.3, 129.5, 129.1, 128.5, 128.29, 128.26, 128.23, 128.20, 128.0, 127.8, 127.7, 126.8, 122.3, 116.5, 81.5, 71.5, 52.7. C 30 H 24 HRMS theoretical value of ClNO2 ([M+Na] + ): 488.1388; measured value: 488.1402

[0090] Methyl 1-(4-methylphenyl)-2,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1k), white solid. 1 HNMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 7.3 Hz, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.7 Hz, 4H), 7.09 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 6.60 (d, J = 8.2 Hz, 2H), 6.27 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 3.94 (s, 3H), 2.21 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.5, 143.3, 141.3, 140.9, 138.5, 133.4, 129.7, 129.0, 128.9, 128.5, 128.2, 128.1, 128.0, 127.9, 127.5, 127.4, 126.8, 126.2, 115.4, 81.2, 71.3, 52.4, 20.3. C 31 H 27Theoretical HRMS value of NO2 ([M+Na] + ): 468.1934; Measured value: 468.1950

[0091] Methyl 1-(4-methoxyphenyl)-2,3,5-triphenyl-2,5-dihydro-1H-pyrrole-2-carboxylate (1l), white solid. 1 HNMR(400MHz,CDCl3)δ7.63(d,J=8.1Hz,2H),7.49(d,J=8.6Hz,2H),7.39(t,J=7.6Hz,2H),7.29(t,J=7.3Hz,1H),7.25–7.20(m,3H),7.20–7.14(m,3H),6.99(d,J=8.0Hz,2H),6.59–6.54(m,2H),6.54–6.49(m,2H),6.19(d,J=2.2Hz,1H),5.97(d,J=2.2Hz,1H),3.86(s,3H),3.62(s,3H). 13 C NMR(100MHz,CDCl3)δ171.8,151.7,143.3,141.5,138.5,137.4,133.5,130.0,128.9,128.6,128.2,128.1,128.04,127.99,127.5,127.4,127.0,116.8,114.0,81.6,71.4,55.4,52.5.C 31 H 27 Theoretical HRMS value of NO3 ([M+Na] + ): 484.1883; Measured value: 484.1884.

Claims

1. A method for preparing a multi-substituted 3-dihydropyrrole compound, characterized in that: The method comprises the following steps: Using propargylamine compounds 2 and α-diazo ester compounds 3 as starting materials, and a copper salt as a catalyst, 3-dihydropyrrole compounds of general formula 1 are generated through the formation of a copper carbene intermediate and an intramolecular cyclization reaction at room temperature; The synthetic route is as follows: R 1 selected from phenyl, aryl substituted with halogen, alkyl or alkoxy; R 2 Selected from phenyl and naphthalene ring; R 3 selected from naphthyl, phenyl, aryl substituted with halogen, alkyl or alkoxy; R 4 is alkyl, allyl or benzyl; the catalyst copper salt is CuCl2, CuBr2, Cu(OTf)2 or CuOTf; the reaction solvent is one or a mixture of two of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, 1,4-dioxane, ethanol or dichloroethane.

2. The preparation method of the multi-substituted 3-dihydropyrrole compounds according to claim 1, wherein: The said R 1 is selected from phenyl, aryl substituted with halogen, methyl or methoxy; R 2 is selected from phenyl, naphthalene ring; R 3 is selected from naphthyl, phenyl, aryl substituted with halogen, methyl or methoxy; R 4 is an alkyl group, allyl group or benzyl group having 1 to 4 carbon atoms.

3. The preparation method of the multi-substituted 3-dihydropyrrole compound according to claim 1, characterized in that: The molar ratio of the propargylamine compounds 2 to the α-diazo ester compounds 3 is 1:1 to 1:

3.

4. The preparation method of the multi-substituted 3-dihydropyrrole compound according to claim 1, wherein: The molar ratio of the propargylamine compounds 2 to the copper salt is 1:0.01 - 1:

1.

5. The preparation method of the multi-substituted 3-dihydropyrrole compound according to claim 1, characterized in that: The reaction atmosphere is air, oxygen, nitrogen or argon.

6. The preparation method of the multi-substituted 3-dihydropyrrole compound according to claim 1, wherein: The reaction time is 0.5 - 12 hours.

7. The preparation method of the multi-substituted 3-dihydropyrrole compound according to claim 1, wherein: The reaction time is 1 - 8 hours.

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