阅读说明：本技术 一种2,3-二氢喹啉-4-酮生物活性骨架及其合成方法和应用 (2, 3-dihydroquinoline-4-ketone bioactive skeleton and synthesis method and application thereof ) 是由 李爱国 王亮 解容浩 尹相莹 陈宁 梁国磊 于 2021-08-30 设计创作，主要内容包括：本发明公开了一种2,3-二氢喹啉-4-酮生物活性骨架及其合成方法和应用,属于化学合成技术领域。其技术方案为：2,3-二氢喹啉-4-酮生物活性骨架的结构式如下：式中,R～(1)为氮杂环、乙基中任意一种；R～(2)为氮杂环、甲基中任意一种；R～(3)为氢原子、甲氧基中任意一种；R～(4)为芳香基、杂芳香基、脂肪族取代基、α,β-不饱和芳香基或α,β-不饱和脂肪族取代基、α,β-苯炔基中任意一种。本发明具有反应条件温和、底物普适性好、步骤经济性、原子经济性、化学选择性高、副产物少、产率高、原料低廉等优点,便于将来工业化应用。(The invention discloses a 2, 3-dihydroquinoline-4-ketone bioactive skeleton and a synthesis method and application thereof, belonging to the technical field of chemical synthesis. The technical scheme is as follows: the structural formula of the 2, 3-dihydroquinoline-4-ketone bioactive framework is as follows: in the formula, R 1 Is any one of nitrogen heterocycle and ethyl; r 2 Is any one of nitrogen heterocycle and methyl; r 3 Is any one of hydrogen atom and methoxyl; r 4 Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl. The method has the advantages of mild reaction conditions, good substrate universality, step economy, atom economy, high chemical selectivity, few byproducts, high yield, low raw material cost and the like, and is convenient for future industrial application.)

1. A 2, 3-dihydroquinolin-4-one bioactive scaffold, having a structural formula:

in the formula, R¹Is any one of nitrogen heterocycle and ethyl; r²Is any one of nitrogen heterocycle and methyl; r³Is any one of hydrogen atom and methoxyl; r⁴Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.

2. A method of synthesizing a 2, 3-dihydroquinolin-4-one bioactive scaffold as recited in claim 1, comprising the step of:

uniformly mixing 2-aminobenzoyl methyl acetate compounds and formaldehyde compounds in a molar ratio of 1:1.2-1:1.5 in a solvent, and reacting at 80-120 ℃ to obtain 2, 3-dihydroquinolin-4-one compounds;

wherein, the structural formula of the 2-aminobenzoyl methyl acetate compound is as follows:

wherein R is¹Is any one of nitrogen heterocycle and ethyl; r²Is any one of nitrogen heterocycle and methyl; r³Is any one of hydrogen atom and methoxyl;

wherein, the structural formula of the formaldehyde compound is as follows:

wherein R is⁴Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.

3. The method of synthesis according to claim 2, wherein the solvent is ethanol or 1, 2-dichloroethane; preferably, the solvent is 1, 2-dichloroethane.

4. The synthesis method according to claim 2, characterized in that the solvent is used in an amount of: adding 8-12L of solvent into each mole of formaldehyde compound; preferably, 10L of solvent is added per mole of formaldehyde-based compound.

5. The synthesis method according to claim 2, wherein a catalyst is added before the reaction, and the catalyst is a Bronsted acid and a Lewis acid; preferably, the catalyst is Sc (OTf)₃。

6. The synthesis method according to claim 5, wherein the catalyst is used in an amount of 10 to 20 mol%.

7. The synthesis process of claim 5, wherein a catalyst support is added prior to the reaction, the catalyst support beingAnd (3) a molecular sieve.

8. The synthesis method according to claim 7, wherein the catalyst carrier is used in an amount of 6 to 7 times the mass of the formaldehyde-based compound.

9. The synthesis process according to claim 2, characterized in that before the reaction, a base is added, which is piperidine, in an amount of 4-6 mol%.

10. Use of the 2, 3-dihydroquinolin-4-one bioactive scaffold synthesized by the method of synthesis according to any one of claims 2 to 9 in antimalarial, anticancer, analgesic drugs.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a 2, 3-dihydroquinoline-4-ketone bioactive skeleton and a synthesis method and application thereof.

Background

The 2, 3-dihydroquinoline-4-ketone bioactive skeleton compound is an important heterocyclic compound and has wide application in the fields of malaria resistance, cancer resistance, pain relief and the like. For example, 2-ferrocene-2, 3-dihydroquinolin-4-one was found to have good antimalarial activity by Angela Patti topic group of CNR Biochemical research institute, Italy, 2012. 2011, Chul Min Park topic group of Korean institute of chemical and technology, discovered 1- (arylsulfonyl) -2, 3-dihydroquinolin-4-one derivatives against 5-HT₆Exhibit high binding affinity (IC)₅₀8nM) has good selectivity for serotonin and dopamine, showing excellent anticancer activity. In 1965, 1,2,2,3, 3-pentamethylquinolin-4-one was found to have a significant analgesic effect on mice by Atwal subject group of university of Illinois, USA. The compounds are all 2, 3-dihydroquinoline-4-ketone derivatives. In view of the importance of 2, 3-dihydroquinolin-4-one skeletons in the medical field, efficient synthesis of such skeletons has become a focus of research in the field of organic synthesis.

The task group Tamio Hayashi of Kyoto university, Japan, 2005 synthesized a 2-aryl-2, 3-dihydroquinolin-4-one skeleton by rhodium-catalyzed 1,4 addition reaction of aryl zinc (org. Lett.2005,7, 5317-one 5319). The reaction requires a noble metal rhodium catalyst, which increases the reaction cost.

In 2015, the TakahikoAkiyama project group at Japan institute of learning university reported a method for asymmetric synthesis of 2, 3-dihydroquinolin-4-one skeleton catalyzed by chiral phosphoric acid (org. Lett.2015,17, 3202-substituted 3205), which is expensive in chiral phosphoric acid and long in reaction time.

In 2010, the project group of SergeyA.Kozmin, American university of Chicago, utilizes quinolone and ketene to generate 2, 3-dihydroquinolin-4-one skeleton through cycloaddition under the catalysis of trifluoroacetic acid, the reaction uses strong acid trifluoroacetic acid as a catalyst, and an N-H bond on the quinolone needs to be protected and deprotected, thereby increasing the reaction steps.

Although the reaction can synthesize the 2, 3-dihydroquinolin-4-one skeleton with high efficiency, the application of the reactions is greatly limited, especially the application of the reactions in the pharmaceutical production industry is limited, because the expensive metal catalyst or the reaction has long reaction time, long route and poor substrate universality.

Therefore, how to efficiently construct the 2, 3-dihydroquinolin-4-one skeleton by using cheap and easily-obtained raw materials and green and mild reaction conditions is a problem which needs to be solved at present.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: the invention overcomes the defects of the prior art, provides the 2, 3-dihydroquinolin-4-one bioactive framework, and the synthesis method and the application thereof, has the advantages of mild reaction conditions, good substrate universality, step economy, atom economy, high chemical selectivity, few byproducts, high yield, low raw material cost and the like, and is convenient for future industrial application.

The technical scheme of the invention is as follows:

in a first aspect, the present invention provides a 2, 3-dihydroquinolin-4-one bioactive scaffold having the formula:

in the formula, R¹Is any one of nitrogen heterocycle and ethyl; r²Is any one of nitrogen heterocycle and methyl; r³Is any one of hydrogen atom and methoxyl; r⁴Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.

In a second aspect, as shown in fig. 1, the present invention also provides a method for synthesizing the above 2, 3-dihydroquinolin-4-one bioactive skeleton, comprising the steps of:

uniformly mixing 2-aminobenzoyl methyl acetate compounds and formaldehyde compounds in a molar ratio of 1:1.2-1:1.5 in a solvent, and reacting at 80-120 ℃ to obtain 2, 3-dihydroquinolin-4-one compounds;

wherein, the structural formula of the 2-aminobenzoyl methyl acetate compound is as follows:

wherein R is¹Is any one of nitrogen heterocycle and ethyl; r²Is any one of nitrogen heterocycle and methyl; r³Is any one of hydrogen atom and methoxyl;

wherein, the structural formula of the formaldehyde compound is as follows:

wherein R is⁴Is an aromatic group, a heteroaromatic group, an aliphatic substituentAnd any one of alpha, beta-unsaturated aromatic group, alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.

The reaction conditions can be detected by thin layer chromatography, and purification is carried out after the reaction is finished to obtain a purified product of the 2, 3-dihydroquinolin-4-one compound.

The reaction process is as follows:

2-aminobenzoyl methyl acetate compounds and formaldehyde compounds are subjected to Knoevenagel condensation reaction to form intermediate product electron-deficient olefin, and the electron-deficient olefin is used as a driving force to initiate intramolecular [1,7]]-hydroshifting/cyclizing to form the final 2, 3-dihydroquinolin-4-one compound. The synthetic route is concretely as follows (2-aminobenzoyl methyl acetate compound)For example):

preferably, the solvent is ethanol or 1, 2-dichloroethane; preferably, the solvent is 1, 2-dichloroethane.

Preferably, the solvent is used in an amount of: adding 8-12L of solvent into each mole of formaldehyde compound; preferably, 10L of solvent is added per mole of formaldehyde-based compound.

Preferably, adding a catalyst before the reaction, wherein the catalyst is Bronsted acid and Lewis acid; preferably, the catalyst is Sc (OTf)₃。

Preferably, the catalyst is used in an amount of 10 to 20 mol%.

Preferably, a catalyst carrier is added before the reaction, and the catalyst carrier isAnd (3) a molecular sieve.

Preferably, the dosage of the catalyst carrier is 6 to 7 times of the mass of the formaldehyde compound.

Preferably, a base is added before the reaction, wherein the base is piperidine and is used in an amount of 4-6 mol%.

The compounds to which the present invention relates may exist in the form of one or more stereoisomers. The various isomers include enantiomers, diastereomers, geometric isomers. It is within the scope of the present invention for these isomers to include mixtures of these isomers.

In a third aspect, the invention also provides application of the 2, 3-dihydroquinolin-4-one bioactive skeleton synthesized by the synthesis method in antimalarial, anticancer and analgesic drugs.

Compared with the prior art, the invention has the following beneficial effects:

1. the synthesis reaction realizes the neutral redox tandem Knoevenagel condensation/[ 1,7] -hydrogen migration/cyclization reaction to construct the 2, 3-dihydroquinoline-4-ketone bioactive framework compound under mild conditions, and provides a convenient and simple synthesis method for the 2, 3-dihydroquinoline-4-ketone bioactive framework.

2. The synthetic method has good substrate universality, the substrate substituent can be an electron-withdrawing group or an electron-donating group, and the position of the substituent has no obvious influence on the reaction yield. The invention provides experimental basis for the efficient construction of the 2, 3-dihydroquinoline-4-ketone bioactive skeleton, and has good practical significance and application value.

3. The synthetic method introduces allyl/propargyl into the 3-position of the 2, 3-dihydroquinoline-4-ketone bioactive skeleton, is beneficial to constructing other functional compounds, and lays a foundation for more applications of the 2, 3-dihydroquinoline-4-ketone bioactive skeleton.

4. The synthetic method disclosed by the invention is short in reaction route, only water is contained as a byproduct, the principles of atom economy and environmental protection are met, and the green and efficient synthesis of the 2, 3-dihydroquinolin-4-one bioactive framework is realized.

Drawings

FIG. 1 is a scheme of the synthesis process of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments and the like used in the following examples are commercially available unless otherwise specified.

Example 1

1. This example provides a method for synthesizing a bioactive framework of 2, 3-dihydroquinolin-4-one, comprising the steps of:

taking 0.1mmol of 2-aminobenzoyl methyl acetate compound in a reaction bottle, and sequentially adding 1mL of solvent, 0.15mmol of formaldehyde compound and catalyst. Controlling the reaction temperature of the system, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the reaction of the raw materials is complete. After the reaction is finished, separating and purifying by using a silica gel column, and performing rotary evaporation on the purified product to obtain the target product. The reaction formula is as follows:

2. according to the method, 9 groups of parallel test groups are set up, and different catalysts and solvents are respectively adopted. The catalyst is acetic acid/ammonium acetate Ac (OH)/NH respectively₄OAc, Piperidine Piperidine, scandium triflate Sc (OTf)₃Copper trifluoromethanesulfonate Cu (OTf)₂Ytterbium triflate Yb (OTf)₃Indium tribromide InBr₃FeCl, ferric chloride₃Boron trifluoride diethyl etherate BF₃.Et₂O, tfOH trifluoromethanesulfonate; the solvents are respectively toluene, ethanol and 12-dichloroethane. The specific catalysts, solvent types and corresponding yields used in the experimental groups are shown in table 1:

TABLE 1 reaction yield of methyl 2-aminobenzoylacetate compound and benzaldehyde under different catalyst conditions

Note: the above yields are isolated yields. Different objects are prepared, and the catalytic effect of the catalyst is shown as follows: scandium triflate>Boron trifluoride diethyl etherate>Ferric chloride>Indium tribromide>Trifluoromethanesulfonic acid>Ytterbium trifluoromethanesulfonate>Piperidine; the effect of the above base is shown by piperidine>Triethylamine>Cesium carbonate>Potassium carbonate>Sodium hydroxide; the effect of the catalyst carrier is shown by addingMolecular sieves>Without addition ofAnd (3) a molecular sieve.

According to the analysis of the parallel test results, the following results are obtained: the synthesis reaction of the invention can be carried out by adding piperidine when ethanol is used as a solvent, but the yield of the product is slightly low; when Bronsted acid and Lewis acid are used as catalysts, the reaction can be carried out, and the catalytic effect of scandium trifluoromethanesulfonate is best; when toluene is used as a solvent, the reaction cannot be carried out; the yield of ethanol as a reaction solvent is slightly low; when 1, 2-dichloroethane is used as a solvent, the highest yield can reach 78% by screening the catalyst. The alkali was screened to find that organic bases were more favorable for the reaction than inorganic bases, and piperidine was most effective as the alkali. Without addition ofMolecular sieves react poorly and are addedMolecular sieves are used to facilitate the reaction.

3. According to the method, the following 6 parallel test groups are set, and different reaction conditions are adopted, such as: different raw material ratios and different reaction temperatures. The catalyst was unified with scandium triflate (20 mol%). The solvent is 1, 2-dichloroethane. The specific settings for the different test groups are shown in table 2:

TABLE 2 reaction yield of methyl 2-aminobenzoylacetate compound and benzaldehyde under different reaction conditions

According to the analysis of the parallel test results, the following results are obtained: the synthesis reaction can be carried out by adding 8-12L of solvent into each mole of 2-aminobenzoyl methyl acetate compound when 1, 2-dichloroethane is used as the solvent, and the yield is highest when 10L of solvent is added into each mole of 2-aminobenzoyl methyl acetate compound; the reaction can be carried out at 80-120 deg.C, with the best conversion effect at 100 deg.C.

In the following examples 2 to 9, the reactions were carried out in accordance with the procedure of example 1; in the reaction system, the raw materials of the 2-aminobenzoyl methyl acetate compound and the formaldehyde compound are respectively 0.1mmol and 0.15mmol, and the reaction system is added with 20mol percent of Sc (OTf)₃Under the catalysis of scandium trifluoromethanesulfonate, 1mL of 1, 2-dichloroethane is used as a solvent, and the reaction is continuously stirred at the temperature of 100 ℃ until the raw materials are completely reacted, so that corresponding target products are respectively obtained.

Example 2

Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, benzaldehyde

The product is as follows: chemical formula C₂₁H₂₁NO₃

Molecular weight: 335.4030

Structural formula (xvi):

yield: 79 percent

¹H NMR(500MHz,CDCl₃)δ7.69(d,J＝7.9Hz,1H),7.38(t,J＝7.7Hz,1H),7.09–7.02(m,3H),6.94(d,J＝4.3Hz,2H),6.67(dd,J＝18.1,10.7Hz,1H),6.57(d,J＝8.4Hz,1H),4.17(dd,J＝9.5,5.6Hz,1H),3.81(s,3H),3.48(ddd,J＝17.8,15.6,8.9Hz,2H),3.32(d,J＝13.7Hz,1H),2.90(d,J＝13.7Hz,1H),2.20–2.12(m,1H),2.09–1.91(m,3H).¹³C NMR(126MHz,CDCl₃)δ190.86(s),171.96(s),148.38(s),136.30(s),135.54(s),130.71(s),129.17(s),127.47(s),126.46(s),118.29(s),116.59(s),112.73(s),77.34(d,J＝6.5Hz),77.11(s),76.86(s),63.44(s),61.74(s),52.60(s),46.83(s),31.74(s),26.23(s),22.95(s).HRMS(ESI):calcd for C₂₁H₂₁NO₃Na[M+Na]⁺:358.3922,found:358.3924.

Example 3

Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, p-nitrobenzaldehyde

The product is as follows: chemical formula C₂₁H₂₀N₂O₅

Molecular weight: 380.1372

Structural formula (xvi):

yield: 72 percent

¹H NMR(500MHz,CDCl₃)δ7.91(d,J＝8.6Hz,1H),7.67(d,J＝7.9Hz,1H),7.43(t,J＝7.7Hz,1H),7.10(d,J＝8.6Hz,1H),6.72(t,J＝7.5Hz,1H),6.63(d,J＝8.4Hz,1H),4.20(t,J＝7.4Hz,1H),3.83(d,J＝9.0Hz,2H),3.53(ddd,J＝17.4,11.8,7.5Hz,1H),3.43(d,J＝13.5Hz,1H),2.99–2.88(m,1H),2.22(dd,J＝11.5,7.6Hz,1H),2.09–1.95(m,2H).¹³C NMR(126MHz,CDCl₃)δ190.10(s),171.62(s),148.39(s),146.63(s),144.50(s),136.08(s),131.64(s),129.07(s),122.58(s),118.01(s),117.10(s),112.97(s),77.33(s),77.08(s),76.83(s),63.42(s),61.98(s),52.84(s),46.88(s),31.13(s),26.21(s),22.89(s).HRMS(ESI):calcd for C₂₁H₂₀N₂O₅Na[M+Na]⁺:403.3892,found:403.3896.

Example 4

Raw materials: n, N-diethylbenzoylacetic acid methyl ester, o-bromobenzaldehyde

The product is as follows: chemical formula C₂₁H₂₂BrNO₃

Molecular weight: 416.3150

Structural formula (xvi):

yield: 68 percent of

¹H NMR(500MHz,CDCl₃)δ7.93(dd,J＝7.9,1.5Hz,1H),7.51(dd,J＝13.4,5.2Hz,2H),7.38–7.31(m,1H),7.24(t,J＝7.5Hz,1H),7.06(td,J＝7.9,1.5Hz,1H),6.68(t,J＝7.4Hz,1H),6.59(d,J＝8.5Hz,1H),5.29(s,1H),4.12(q,J＝6.8Hz,1H),3.81(d,J＝14.5Hz,1H),3.49(dq,J＝14.2,7.0Hz,1H),3.30(s,3H),3.16(dq,J＝14.6,7.3Hz,1H),3.03(d,J＝14.5Hz,1H),1.26(d,J＝6.8Hz,3H),1.20(t,J＝7.1Hz,3H).¹³C NMR(126MHz,CDCl₃)δ191.09(s),170.39(s),147.58(s),136.85(s),135.65(s),132.80(s),131.89(s),128.61(s),128.27(s),127.24(s),126.11(s),118.65(s),116.09(s),112.34(s),77.31(s),77.06(s),76.80(s),62.16(s),61.45(s),52.09(s),44.83(s),34.47(s),12.90(s),10.78(s).HRMS(ESI):calcd for C₂₁H₂₂BrNO₃Na[M+Na]⁺:439.3042,found:439.3046.

Example 5

Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, 5-bromo-2-furaldehyde

The product is as follows: chemical formula C₁₉H₁₈BrNO₄

Molecular weight: 404.2600

Structural formula (xvi):

yield: 68 percent of

¹H NMR(500MHz,CDCl₃)δ7.80(dd,J＝8.0,1.6Hz,1H),7.36(ddd,J＝8.5,7.1,1.6Hz,1H),6.69(dd,J＝11.1,3.8Hz,1H),6.55(d,J＝8.4Hz,1H),6.00(d,J＝3.2Hz,1H),5.91–5.85(m,1H),4.20(dt,J＝9.9,6.1Hz,1H),3.82(s,3H),3.51–3.35(m,2H),3.18(dd,J＝15.3,7.1Hz,1H),3.10(d,J＝15.4Hz,1H),2.18(dtd,J＝11.4,7.8,3.5Hz,1H),2.01–1.87(m,3H).¹³C NMR(126MHz,CDCl₃)δ190.90(s),171.03(s),152.67(s),148.58(s),135.67(s),129.03(s),119.27(s),117.44(s),116.57(s),112.79(s),111.99(s),111.42(s),77.28(d,J＝6.5Hz),77.05(s),76.79(s),62.51(s),60.22(s),52.67(s),46.62(s),26.03(d,J＝16.7Hz),22.88(s).HRMS(ESI):calcd for C₁₉H₁₈BrNO₄Na[M+Na]⁺:427.2492,found:427.2494.

Example 6

Raw materials: 2-Tetrahydropyrrole-benzoyl-acetic acid methyl ester, 2-quinolinecarboxaldehyde

The product is as follows: chemical formula C₂₄H₂₂N₂O₃

Molecular weight: 386.4510

Structural formula (xvi):

yield: 65 percent of

¹H NMR(500MHz,CDCl₃)δ7.79(t,J＝7.5Hz,1H),7.77–7.71(m,2H),7.64(t,J＝8.7Hz,1H),7.60–7.53(m,1H),7.40(dt,J＝16.5,4.8Hz,1H),7.25–7.21(m,2H),6.67–6.60(m,1H),6.29(d,J＝8.4Hz,1H),4.34–4.22(m,1H),3.82(s,3H),3.64–3.55(m,1H),3.46(d,J＝13.8Hz,1H),3.37–3.26(m,2H),2.37–2.25(m,1H),2.23–2.13(m,1H),2.10–1.89(m,2H).¹³C NMR(126MHz,CDCl₃)δ191.43(s),171.88(s),157.77(s),148.36(s),147.19(s),135.37(s),134.80(s),128.98(d,J＝15.9Hz),128.72(s),127.36(s),126.73(s),125.78(s),122.89(s),118.47(s),116.30(s),112.62(s),77.29(d,J＝6.3Hz),77.06(s),76.81(s),63.12(s),61.05(s),52.70(s),46.52(s),36.40(s),26.58(s),23.04(s).HRMS(ESI):calcd for C₂₄H₂₂N₂O₃Na[M+Na]⁺:409.4402,found:409.4407.

Example 7

Raw materials: 2-tetrahydropyrrole benzoylacetic acid methyl ester, phenylpropargylaldehyde

The product is as follows: chemical formula C₂₃H₂₁NO₃

Molecular weight: 359.4250

Structural formula (xvi):

yield: 70 percent of

¹H NMR(500MHz,CDCl₃)δ7.93(t,J＝8.9Hz,1H),7.43–7.36(m,1H),7.22(d,J＝6.1Hz,5H),6.73(t,J＝7.5Hz,1H),6.62(d,J＝8.4Hz,1H),4.28(dt,J＝13.0,6.9Hz,1H),3.89(d,J＝9.9Hz,3H),3.54(dd,J＝16.7,7.6Hz,1H),3.50–3.42(m,1H),2.97(d,J＝17.1Hz,1H),2.91–2.84(m,1H),2.30–2.18(m,2H),2.13–1.93(m,2H).¹³C NMR(126MHz,CDCl₃)δ190.47(s),170.67(s),149.00(s),135.88(s),131.53(s),129.22(s),128.05(s),127.71(s),123.48(s),117.18(s),116.60(s),113.06(s),85.71(s),82.43(s),77.40(s),77.15(s),76.89(s),62.38(s),59.49(s),52.76(s),46.75(s),26.55(s),23.25(s),18.31(s).HRMS(ESI):calcd for C₂₃H₂₁NO₃Na[M+Na]⁺:382.4142,found:382.4145.

Example 8

Raw materials: 4-methoxy-2-tetrahydropyrrole benzoylacetic acid methyl ester, phenylpropargylaldehyde

The product is as follows: chemical formula C₂₄H₂₃NO₄

Molecular weight: 389.4510

Structural formula (xvi):

yield: 76 percent of

¹H NMR(500MHz,CDCl₃)δ7.75(d,J＝8.9Hz,1H),7.14–7.07(m,5H),6.20(dd,J＝8.9,2.3Hz,1H),5.83(d,J＝2.2Hz,1H),4.20(dd,J＝9.0,6.3Hz,1H),3.74(s,3H),3.67(s,3H),3.41–3.28(m,2H),2.89–2.80(m,1H),2.77(d,J＝17.2Hz,1H),2.18–2.06(m,2H),1.89(qdd,J＝11.5,9.4,3.2Hz,3H).¹³C NMR(126MHz,CDCl₃)δ189.01(s),170.87(s),166.07(s),150.88(s),131.84–131.02(m),131.28–131.02(m),128.02(s),127.66(s),123.59(s),111.55(s),105.44(s),95.61(s),85.96(s),82.22(s),77.43(d,J＝6.7Hz),77.20(s),76.94(s),62.38(s),59.23(s),55.35(s),52.71(s),46.77(s),26.67(s),23.26(s),18.80(s).HRMS(ESI):calcd for C₂₄H₂₃NO₄Na[M+Na]⁺:412.4402,found:412.4405.

Example 9

Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, 3-methylcrotonal

The product is as follows: chemical formula C₁₉H₂₃NO₃

Molecular weight: 313.3970

Structural formula (xvi):

yield: 66 percent

¹H NMR(500MHz,CDCl₃)δ7.82–7.76(m,1H),7.41–7.33(m,1H),6.69(dt,J＝15.0,7.5Hz,1H),6.60(d,J＝8.4Hz,1H),5.17(t,J＝7.5Hz,1H),4.23–4.10(m,1H),3.82(s,3H),3.59–3.44(m,2H),2.58–2.48(m,1H),2.42–2.31(m,1H),2.05–1.90(m,3H),1.55(s,4H),1.16(d,J＝18.8Hz,3H).¹³C NMR(126MHz,CDCl₃)δ191.65(s),171.92(s),148.39(s),135.42(s),134.19(s),129.07(s),118.90(s),117.48(s),116.28(s),112.46(s),77.27(d,J＝6.3Hz),77.04(s),76.79(s),62.82(s),60.12(s),52.43(s),46.70(s),26.26(s),25.88(s),24.52(s),23.05(s),17.13(s).HRMS(ESI):calcd for C₁₉H₂₃NO₃Na[M+Na]⁺:336.3862,found:336.3865.

Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.