A method for preparing multifunctionalized indolizine derivatives by copper catalysis

Abstract

The present invention provides a method for preparing a copper-catalyzed synthesis of multifunctionalized indolizine derivatives, and relates to the field of organic synthesis. The method provided by the present invention uses 1,4-amphoteric thiopyridinium salt and a diazo compound as raw materials, and reacts to prepare a trifunctionalized indolizine compound under the action of a copper catalyst. The method for preparing trifunctionalized indolizine disclosed in the present invention is simple and easy to operate, has a wide range of application of reaction substrates, a high yield, and a novel method. In addition, the compound has a strong fluorescence emission intensity and has broad application prospects in the pharmaceutical industry, synthetic chemistry, and materials science.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for preparing a multifunctionalized indolizine derivative by copper catalysis. Background Art

[0002] Indolizine compounds are widely found in natural products, synthetic drugs and agrochemicals. These compounds have good biological and pharmaceutical activities, and they are widely used in antibacterial, antiviral, anti-inflammatory, and cardiovascular drugs, such as testosterone 3R reductase inhibitors, as 5-HT4 receptor antagonists, and as central nervous system depressants. Therefore, the synthesis of indolizine compounds has always attracted the attention of pharmacologists, biologists and chemists.

[0003] Indolizine derivatives are a class of heterocyclic compounds containing 10 π electrons and trans-ring nitrogen atoms, and are isoelectronic versions of indole. Indolizine natural products and many of their analogs have very important biological activities, such as cytotoxicity, mutagenicity, anticancer, antibacterial, and anti-oxidative properties.

[0004] In the past few decades, indolizine has a wide range of application prospects in the fields of drug molecules, electroluminescent materials and fluorescent dyes, and has received increasing attention. Among them, multi-substituted indolizine derivatives are an important synthetic compound among indolizine derivatives, which have many special properties and are used in many fields. In particular, when there are three substituents on the indolizine ring, it has drug activity such as inhibiting histamine H3 receptors, anti-spasmodic and anti-inflammatory. This type of indolizine compound can be generated through 1,3-dipolar cycloaddition.

[0005] Patent CN 102276601 B discloses a method for preparing an indolizine derivative, which uses an alkyl glyoxylate, an α-bromoacetophenone derivative and pyridine as raw materials, refluxes in an organic solvent in the presence of sodium carbonate for 12 to 24 hours, and then washes with water, extracts, concentrates, and is purified by column chromatography or recrystallization to obtain the indolizine derivative.

[0006] Patent CN 105801576 A provides a method for synthesizing an indolizine compound, which uses pyridine ylide and phenylpropiophenal as raw materials to synthesize an indolizine derivative under mild conditions in an alkaline environment.

[0007] Patent CN 114014858 A discloses a method for preparing polysubstituted indolizine derivatives. In this method, N-substituted pyridinium salts directly prepared from halogenated compounds and pyridine derivatives, quinoline derivatives or isoquinoline are reacted with electron-deficient olefins in the presence of nitrite to prepare polysubstituted indolizine derivatives, which greatly reduces the production cost of preparing polysubstituted indolizine derivatives in the prior art.

[0008] In the past decade of research, people have been working hard to develop efficient methods for synthesizing indolizine derivatives and to achieve the CH regioselective functionalization of indolizine. In this field, researchers have made great progress in the regioselective CH diselenylation, dicarbonylation, formiation, dithiocarbamateization, disulfide and deconstructive cycloaromatization of indolizine, but the construction of indolizine compounds containing ester, amide, trifluoromethyl, cyano, diethyl phosphate and other functional groups has not been reported.

[0009] Based on this, the present invention selects a 1,4-amphoteric thiopyridinium salt with multiple reactivity, air stability, no odor, and easy operation as a raw material, which undergoes a nucleophilic reaction with a carbene precursor produced by a diazo compound through an intramolecular cycloaddition reaction to obtain a [4+1] cyclization product multifunctionalized indolizine derivative. Functionalized indolizine has good advantages such as low biological toxicity and high biological activity, and is widely used in the pharmaceutical, luminescent material and other industries. The present invention discloses a new method for the efficient copper-catalyzed synthesis of multifunctionalized indolizine, and tests the ultraviolet absorption and fluorescence emission spectra of the synthesized compounds, indicating that the compounds have a strong fluorescence emission intensity. Summary of the invention

[0010] The present invention aims at the problems existing in the prior art and provides a method for preparing multifunctionalized indolizine derivatives by copper catalysis. The method has wide application range of reaction substrates, high efficiency, no additives, high yield, and the obtained products have strong fluorescence emission intensity.

[0011] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0012] The present invention provides a method for preparing a multifunctional indolizine derivative by copper catalysis, wherein 1,4-amphoteric thiopyridinium salt and a diazo compound are used as raw materials and react under the action of a copper catalyst, and the reaction formula is:

[0013]

[0014] in,

[0015] R, R1, R2 are each independently selected from a hydrogen atom; a substituted or unsubstituted alkyl group, a dimethyl phosphonate group, a ketocarbonyl group, an aldehyde group, a halogen group, an amine group, a cyano group, an amide group or an ester group;

[0016] A is selected from the group consisting of N + Substituted cycloalkyl, heterocyclic group.

[0017] Preferably,

[0018] R is selected from a hydrogen atom; a substituted or unsubstituted C1-C 20 Alkyl, the substituted substituent is selected from C1-6 Alkyl, C 1-6 Alkoxy, halogen, aryl;

[0019] R1 is selected from a hydrogen atom; a substituted or unsubstituted C1-C 20 Alkyl, the substituted substituent is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, aryl;

[0020] R2 is selected from hydrogen atom; substituted or unsubstituted C1-C 20 Alkyl, dimethyl phosphonate, C1-C 20 Ketone carbonyl, C1-C 20 Aldehyde, halogen, amine, cyano, amide or C1-C 20 An ester group, wherein the substituted substituent is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, aryl;

[0021] A is selected from the group consisting of N + Substituted C3-C 20 Cycloalkyl, C3-C 20 Heterocyclic group.

[0022] Preferably,

[0023] R is selected from hydrogen atom; substituted or unsubstituted C1-C 10 Alkyl, the substituted substituent is selected from C 1-3 Alkyl, C 1-3 Alkoxy, halogen, aryl;

[0024] R1 is selected from hydrogen atom; substituted or unsubstituted C1-C 10 Alkyl, the substituted substituent is selected from C 1-3 Alkyl, C 1-3 Alkoxy, halogen, aryl;

[0025] R2 is selected from hydrogen atom; substituted or unsubstituted C1-C 10 Alkyl, dimethyl phosphonate, C1-C 10 Ketone carbonyl, C1-C 10 Aldehyde, halogen, amine, cyano, amide or C1-C 10 An ester group, wherein the substituted substituent is selected from C 1-3 Alkyl, C 1-3 Alkoxy, halogen, aryl;

[0026] A is selected from the group consisting of N + Substituted C3-C 10 Cycloalkyl, C3-C 10 The heterocyclic group has a heteroatom selected from sulfur, nitrogen and oxygen.

[0027] Preferably,

[0028] R is selected from hydrogen atom; substituted or unsubstituted C1-C6 alkyl, wherein the substituted substituent is selected from C 1-3 Alkyl, C 1-3 Alkoxy, halogen, aryl;

[0029] R1 is selected from hydrogen atom; substituted or unsubstituted C1-C6 alkyl, wherein the substituted substituent is selected from C 1-3 Alkyl, C 1-3 Alkoxy, halogen, aryl;

[0030] R2 is selected from hydrogen atom; substituted or unsubstituted C1-C6 alkyl, dimethyl phosphonate, halogen, amine, cyano, amide or C1-C6 ester, wherein the substituted substituent is selected from C 1-3 Alkyl, C 1-3 Alkoxy, halogen, aryl;

[0031] A is selected from the group consisting of N + Substituted pyrrole ring, benzene ring, naphthalene ring.

[0032] Further preferably, R is selected from a hydrogen atom or a methyl group;

[0033] R1 is a methyl group;

[0034] R2 is selected from ethyl formate, trifluoromethyl, dimethyl phosphonate, amide or cyano;

[0035] A is selected from the following structural formula:

[0036]

[0037] Preferably, the copper catalyst is selected from at least one of CuBr and CuI.

[0038] Preferably, the concentration of the copper catalyst is 2-8 mol %; further preferably, the concentration of the copper catalyst is 5 mol %.

[0039] Preferably, the solvent used in the reaction is selected from at least one of DCE, MeCN, MeOH and Toluene; further preferably, the solvent used in the reaction is selected from at least one of DCE and Toluene.

[0040] Preferably, the reaction conditions are: reaction temperature is 70-110° C., and reaction time is 10-20 h; further preferably, the reaction conditions are: reaction temperature is 80° C., and reaction time is 12 h.

[0041] Preferably, the molar ratio of the raw material 1,4-amphoteric thiopyridinium salt to the diazo compound is 1:1.2-1.5.

[0042] Preferably, the molar ratio of the copper catalyst to the raw material 1,4-amphoteric thiopyridinium salt is 20:1.

[0043] Preferably, the molar ratio of the solvent to the raw material 1,4-amphoteric thiopyridinium salt is 0.5-2:1.

[0044] Preferably, the copper-catalyzed synthesis method for preparing multifunctionalized indolizine derivatives has the reaction formula:

[0045]

[0046] Among them, the groups R, R1, and R2 are alkyl groups.

[0047] Preferably, the copper-catalyzed synthesis method for preparing multifunctionalized indolizine derivatives has the reaction formula:

[0048]

[0049] Wherein, the group R is an alkyl group.

[0050] Preferably, the copper-catalyzed synthesis method for preparing multifunctionalized indolizine derivatives has the reaction formula:

[0051]

[0052] Wherein, the group R is an alkyl group.

[0053] Preferably, the copper-catalyzed synthesis method for preparing multifunctionalized indolizine derivatives has the reaction formula:

[0054]

[0055] Preferably, the copper-catalyzed synthesis method for preparing multifunctionalized indolizine derivatives has the reaction formula:

[0056]

[0057] Preferably, the copper-catalyzed synthesis method for preparing multifunctionalized indolizine derivatives has the reaction formula:

[0058]

[0059] Unless otherwise specified, the term "alkyl" as used herein includes branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, including all isomers. Common abbreviations for alkyl groups, such as methyl, can be represented by "Me" or CH3, ethyl, can be represented by "Et" or CH2CH3, propyl, can be represented by "Pr" or CH2CH2CH3, butyl, can be represented by "Bu" or CH2CH2CH2CH3, etc. For example, "C 1-4 "C1-C4 alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms, including all isomers. 1-4 Alkyl includes n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl and methyl. 1-10 "Alkyl" and the like have similar meanings.

[0060] The term "alkoxy" refers to straight and branched chain alkyl groups having the indicated number of carbon atoms attached through an oxygen bridge.

[0061] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

[0062] The term "aryl" refers to aromatic mono- and polycyclic carbon ring systems wherein the individual carbon rings in the polycyclic system are fused or linked to each other by single bonds. Typical aryl groups include phenyl, naphthyl and biphenylene.

[0063] The term "heterocycle" refers to a ring structure composed of carbon atoms and non-carbon atoms, such as nitrogen, oxygen and sulfur. Typical heterocyclic groups include pyridine, quinoline, tropane, phenothiazine, benzodiazepine, furan, pyrazolone and pyrimidine.

[0064] The copper-catalyzed synthesis of trisubstituted functionalized indolizine of the present invention has a mechanism in which: its expression is as follows: Figure 1 As shown. The mechanism may be: first, the diazo compound interacts with the copper (I) catalyst to generate the copper carbene intermediate A and release nitrogen. Then the carbene part is inserted into the 1,4-amphoteric thiopyridinium salt 1a to obtain the cyclized complex B. The copper (I) catalyst in the intermediate B is removed to generate the corresponding pyrido [2,1-c] [1,4] thiazine intermediate C, which is then subjected to molecular Michale addition to generate the fused intermediate D. Intermediate D generates the indolizine 3a through desulfurization and tautomerization reactions.

[0065] Compared with the prior art, the present invention has the following beneficial effects:

[0066] The method for preparing trifunctionalized indolizine by the technical solution of the present invention is simple and easy to operate, has a wide range of application of reaction substrates, high yield, and a novel method. In addition, the compound has a strong fluorescence emission intensity and has broad application prospects in the pharmaceutical industry, synthetic chemistry and material science. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 is a mechanistic expression of the copper-catalyzed synthesis of trisubstituted functionalized indolizines of the present invention;

[0068] Figure 2 is the ultraviolet absorption spectrum of the trisubstituted functionalized indolizine 3a synthesized in the present invention;

[0069] Figure 3 It is the fluorescence emission spectrum of the trisubstituted functionalized indolizine 3a synthesized in the present invention. DETAILED DESCRIPTION

[0070] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0071] The professional terms and abbreviations involved in this patent are explained as follows:

[0072] DCE: dichloroethane; MeCN: acetonitrile; MeOH: methanol; Toluene: toluene; CuBr: copper bromide; CuI: copper iodide

[0073] Embodiment 1:

[0074] 75.9 mg (0.3 mmol) of 1,4-amphothiopyridinium salt shown below and 51.3 mg (0.45 mmol) of ethyl diazoacetate substrate were added to a reaction tube with a stirring bar, followed by the addition of 5 mol% of catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and the target product 3a was separated by silica gel chromatography after being spin-dried with a yield of 82%.

[0075]

[0076] 1H NMR(400MHz, CDCl3)δ9.49(d,J=7.1Hz,1H),8.33(d,J=9.0Hz,1H),7.42–7.34(m,1H),7.03(d d,J=10.6,3.7Hz,1H),4.36(q,J=7.1Hz,2H),4.00(s,3H),3.91(s,3H),1.39(t,J=7.1Hz,3H).

[0077] 13 C NMR (100MHz, CDCl3) δ166.3,162.9,160.4,137.9,130.5,127.9,126.7,119.9,115.4,111.7,103.2,60.4,52.8,51.9,14.3.

[0078] HRMS(GC / QTOF)m / z:Calcd for C 15 H 15 NO6[M] + 305.0899; Found 305.0900.

[0079] Embodiment 2:

[0080] 75.9 mg (0.3 mmol) of 1,4-amphothiopyridinium salt shown below and 79.2 mg (0.45 mmol) of benzyl diazoacetate substrate were added to a reaction tube with a stirring bar, followed by the addition of 5 mol% of the catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product in a yield of 72%.

[0081]

[0082] 1 H NMR (400MHz, CCDCl3) δ9.49 (d, J = 7.1 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 7.38 (ddd, J = 2 5.7,11.8,4.9Hz,6H),7.03(t,J=7.0Hz,1H),5.33(s,2H),3.88(s,4H),3.71(s,3H).

[0083] 13C NMR (100MHz, CDCl3) δ166.2,162.7,160.5,138.2,135.9,130.5,128.6,128. 5,128.3,127.9,127.1,126.9,119.9,115.6,111.9,102.7,66.5,52.7,52.1.

[0084] HRMS(GC / QTOF)m / z:Calcd for C 20 H 17 NO6[M] + 367.1056; Found 367.1054.

[0085] Embodiment 3:

[0086] 90.9 mg (0.3 mmol) of 1,4-amphoterric isoquinoline thiolate as shown below and 51.3 mg (0.45 mmol) of ethyl diazoacetate substrate were added to a reaction tube with a stirring bar, followed by the addition of 5 mol% of the catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and the target product was separated by silica gel chromatography after being spin-dried to obtain a 63% yield.

[0087]

[0088] 1 H NMR (400MHz, CDCl3) δ9.50–9.42(m,1H),9.30(d,J=7.5Hz,1H),7.72–7.68(m,1H),7.65–7.57(m,2 H),7.19(d,J=7.5Hz,1H),4.41(q,J=7.1Hz,2H),3.98(s,3H),3.93(s,3H),1.41(t,J=7.1Hz,3H).

[0089] 13 C NMR (100MHz, CDCl3) δ166.56,163.90,160.44,134.71,130.34,129.84,129.31,128.02 ,127.39,126.98,124.51,123.93,116.04,113.39,108.08,61.26,52.67,52.25,14.16.

[0090] HRMS(GC / QTOF)m / z:Calcd for C 19 H 17 NO6[M] +Found 355.1056.

[0091] Embodiment 4:

[0092] 75.9 mg (0.3 mmol) of 1,4-amphothiopyridine salt shown below and 49.5 mg (0.45 mmol) of diazotrifluoroethane substrate were added to a reaction tube with a stirrer, followed by the addition of 5 mol% of the catalyst CuBr and then the addition of Toluene (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and then spin-dried and separated by silica gel chromatography to obtain the target product in a yield of 79%.

[0093]

[0094] 1 H NMR (400MHz, CDCl3) δ9.48(d,J=7.2Hz,1H),7.73(d,J=9.1Hz,1H),7.34–7.25(m,1H),7.09–6.95(m,1H),3.98(s,3H),3.91(s,3H).

[0095] 13 C NMR (100MHz, CDCl3) δ165.2, 160.4, 134.3 (q, J = 2.7Hz), 127.8, 126.7 (q, J = 2.6Hz), 125.6, 123.2 (q, J = 267.5Hz), 117.9, 115.2, 111.4, 102.2 (q, J = 37.7Hz), 53.2, 52.2.

[0096] 19 F NMR (376MHz,CDCl3)δ-54.98.

[0097] HRMS(GC / QTOF)m / z:Calcd for C 13 H 10 F3NO4[M] + 301.0562; Found 301.0556.

[0098] Embodiment 5:

[0099] 75.9 mg (0.3 mmol) of 1,4-amphothiopyridinium salt shown below and 30.2 mg (0.45 mmol) of diazoacetonitrile substrate were added to a reaction tube with a stirring bar, followed by the addition of 5 mol% of the catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and the target product was separated by silica gel chromatography after being spin-dried to obtain a 75% yield.

[0100]

[0101] 1 H NMR (400MHz, CDCl3) δ9.44(d,J=7.2Hz,1H),7.78(d,J=8.9Hz,1H),7.47–7.38(m,1H),7.11(t,J=7.1Hz,1H),4.02(s,3H),3.94(s,3H).

[0102] 13 C NMR (100MHz, CDCl3) δ163.4,160.2,139.3,129.6,128.3,126.9,125.7,118.1,116.3,113.7,113.5,84.6,53.3,52.4.

[0103] HRMS(GC / QTOF)m / z:Calcd for C 13 H 10 N2O4[M] + 258.0641; Found 258.0643.

[0104] Embodiment 6:

[0105] 75.9 mg (0.3 mmol) of 1,4-amphothiopyridine salt shown below and 78.8 mg (0.45 mmol) of N-phenyldiazoacetamide substrate were added to a reaction tube with a stirrer, followed by the addition of 5 mol% of the catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and the target product was separated by silica gel chromatography after being spin-dried to obtain a yield of 82%.

[0106]

[0107] 1 H NMR (400MHz, CDCl3) δ9.40(d,J=7.1Hz,1H),8.44(dd,J=9.1,1.3Hz,1H),7.35(d,J=3.6Hz,4H),7. 30(d,J=7.3Hz,1H),7.03(dt,J=13.9,6.4Hz,2H),4.62(d,J=5.6Hz,2H),3.90(s,3H),3.82(s,3H).

[0108] 13C NMR (100MHz, CDCl3) δ168.3,163.4,160.6,138.5,137.7,128.8,127.7,127.5,127.3,125.9,125.7,120.7,115.7,111.7,107.5,53.2,52.1,43.6.

[0109] HRMS(GC / QTOF)m / z:Calcd for C 20 H 18 N2O5[M] + 366.1216; Found 366.1209.

[0110] Embodiment 7:

[0111] 75.9 mg (0.3 mmol) of 1,4-amphothiopyridinium salt shown below and 80.1 mg (0.45 mmol) of diethyl diazomethylphosphonate substrate were added to a reaction tube with a stirring bar, followed by the addition of 5 mol% of the catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and the target product was separated by silica gel chromatography after being spin-dried to obtain a 53% yield.

[0112]

[0113] 1 H NMR(400MHz, CDCl3)δ9.49(d,J=6.8Hz,1H),8.16(d,J=9.0Hz,1H),7.35–7.30(m,1H),7.05(td ,J=7.0,1.0Hz,2H),4.22–4.11(m,2H),4.04(qd,J=7.5,2.9Hz,3H),3.98(s,3H),3.91(s,6H).

[0114] 13 C NMR (100MHz, CDCl3) δ166.1,166.1,160.4,160.4,140.0,139.8,132.7,132.6,129.5,127.9 ,126.4,125.9,119.8,115.3,112.6,112.5,98.8,96.7,62.2,62.2,52.9,52.01,16.3,16.2.

[0115] HRMS(GC / QTOF)m / z:Calcd for C 16 H 20 NO7P[M] +369.0977; Found 369.0986.

[0116] Embodiment 8:

[0117] 76.8 mg (0.3 mmol) of 1,4-amphoteriosulfoimidazole salt shown below and 51.3 mg (0.45 mmol) of ethyl diazoacetate substrate were added to a reaction tube with a stirring bar, followed by the addition of 5 mol% of the catalyst CuBr and DCE (2 ml) solvent to dissolve it. The mixture was stirred in a stirrer at 80°C for 12 hours, and the target product was separated by silica gel chromatography after being spin-dried to obtain a 41% yield.

[0118]

[0119] 1 H NMR (400MHz, CDCl3) δ7.59(d,J=2.2Hz,1H),6.73(d,J=2.2Hz,1H),4.19(q,J=7.1Hz,2H),4.01(s,3H),3.88(s,3H),3.79(s,3H),1.26(t,J=7.1Hz,3H).

[0120] 13 C NMR (100MHz, CDCl3) δ163.1,162.7,160.5,136.2,123.5,111.1,109.5,105.8,97.2,60.2,52.8,51.8,36.1,29.9.

[0121] HRMS(GC / QTOF)m / z:Calcd for C 14 H 16 N2O6[M] + 308.1008; Found 308.1007.

[0122] Comparative Example 1:

[0123] The only difference from Example 1 is that the catalyst is replaced by CuO from CuBr, and the yield is 0%.

[0124] Comparative Example 2:

[0125] The only difference from Example 1 is that the catalyst is replaced by CuI instead of CuBr, and the yield is 63%. 1 H NMR, 13 C NMR and HRMS were consistent with the product of Example 1.

[0126] Comparative Example 3:

[0127] The only difference from Example 1 is that the reaction temperature is changed to 50° C. and the reaction time is changed to 5 h, and the yield is 54%. 1 HNMR, 13 C NMR and HRMS were consistent with the product of Example 1.

[0128] Comparative Example 4:

[0129] The only difference from Example 1 is that 5 mol % CuBr is changed to 10 mol %, and the yield is 80%. 1 H NMR, 13 CNMR and HRMS were consistent with the product in Example 1.

[0130] The ultraviolet absorption and fluorescence emission spectra of the compounds synthesized by the method were tested, indicating that the compounds had strong fluorescence emission intensity.

[0131] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a multifunctional indolizine derivative by copper catalysis, characterized in that: 1,4-amphoteric thiopyridinium salt and diazo compound are used as raw materials, and react in the presence of a copper catalyst and a solvent. The reaction formula is: in, R is selected from a hydrogen atom or a methyl group; R1 is a methyl group; R2 is selected from ethyl formate, trifluoromethyl, dimethyl phosphonate, amide or cyano; A is selected from the following structural formula: 、 ； The copper catalyst is selected from CuBr; The concentration of the copper catalyst is 5 mol; The molar ratio of the raw material 1,4-amphoteric thiopyridinium salt to the diazo compound is 1:1.2-1.5; The molar ratio of the copper catalyst to the raw material 1,4-amphoteric thiopyridinium salt is 20:1; The solvent is selected from at least one of dichloroethane, acetonitrile, methanol and toluene; The reaction temperature is 70-110°C.

2. The preparation method according to claim 1, characterized in that: The solvent used in the reaction is selected from at least one of ethylene dichloride and toluene.

3. The preparation method according to claim 1, characterized in that: The reaction conditions are: reaction time is 10-20h.

4. The preparation method according to claim 3, characterized in that: The reaction conditions are: reaction temperature is 80° C., and reaction time is 12 h.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the solvent to the raw material 1,4-amphoteric thiopyridinium salt is 0.5-2:1.

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