CN111732567A

CN111732567A - Chromone framework-containing polycyclic compound, and preparation method and application thereof

Info

Publication number: CN111732567A
Application number: CN202010553398.7A
Authority: CN
Inventors: 韩文勇; 贺晨; 李菲; 陈永正; 崔宝东; 万南微
Original assignee: Zunyi Medical University
Current assignee: Zunyi Medical University
Priority date: 2020-06-17
Filing date: 2020-06-17
Publication date: 2020-10-02
Anticipated expiration: 2040-06-17
Also published as: CN111732567B

Abstract

The invention discloses a polycyclic compound containing a chromone skeleton, a preparation method and application thereof, wherein a 3-iodo chromone compound and norbornene are used as building blocks, palladium acetate is used as a catalyst, and the building blocks and the norbornene are subjected to a domino cycloaddition reaction of [2+2+1] with a bromobenzyl compound in an organic solvent to obtain a series of polycyclic compounds containing the chromone skeleton. By adjusting the solvent, diastereoselective changes of the product are achieved. The chromone skeleton-containing polycyclic compound contains a chromone skeleton with potential biological activity, can provide a compound source for biological activity screening, and has important application value for screening of medicines and pharmaceutical industry. Meanwhile, the invention screens the tumor growth inhibition activity of two tumor cell strains, namely a human non-small cell lung cancer cell (A549) and a human liver cancer cell (HepG2), and finds that the compounds have certain tumor cell growth inhibition activity and can be applied to preparation of antitumor drugs.

Description

Chromone framework-containing polycyclic compound, and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a chromone skeleton-containing polycyclic compound, a preparation method and application thereof.

Background

The heterocyclic structure is an important component in the molecular structure of modern drugs, and the existence of the heterocyclic skeleton often determines the important biological activity and pharmaceutical activity of the drug molecule. The new synthesis strategy for constructing heterocyclic compounds by efficiently synthesizing multiple bonds has profound application in the synthesis of natural products, bioactive molecules and functional materials, and is an important target of modern organic chemistry. Among the oxygen-containing heterocyclic compounds, chromones are an important class of structural units that are widely found in many natural products and pharmaceutical molecules with important biological activities. Therefore, the development of an efficient synthesis method for constructing the chromone compound has important significance for modern medicine molecule organic synthesis methodology.

In 1997, the italian scientist Catellani found for the first time that, with aryl halide as a raw material and palladium as a catalyst, norbornene can be used as a transient guiding group to realize the bifunctional of ortho-position and home-position of iodo-aromatic hydrocarbon. The palladium/norbornene concerted catalyzed domino coupling reaction, namely the Catellari reaction, has the advantages that: the activation of carbon-hydrogen bonds at the ortho positions of the carbon-iodine bonds is realized, the normal positions of the carbon-iodine bonds are terminated through a Heck reaction, three carbon-carbon bonds are constructed by a one-pot method, and 1,2, 3-trisubstituted aromatic hydrocarbon is generated.

Since the palladium/norbornene coupling reaction reported by the Catellari group, this methodology has become a powerful tool for the construction of di/tri-functional poly-substituted aromatic hydrocarbons and plays a very important role in the synthesis of pharmaceuticals and natural products. Subsequently, more and more researchers have studied and expanded the Catellani response, developing a range of different types of responses. Depending on the type of reaction, we can classify the reaction into the following categories:

1. terminating the reaction by ortho-and para-bifunctional

Since 1997, significant scientific contributions from Catellari, Lautens and other researchers have shown that, similar to Catellari cross-coupling reactions, the ortho and home positions of iodoaromatics can be selectively coupled to electrophiles and nucleophiles, respectively, via aryl-norbornene-palladium ring intermediates (ANP). In 2018, the group of Dow fir topic was extensively summarized. In the past decades, nucleophile couplings using the Catellani reaction include Heck coupling, Suzuki coupling, alkyne insertion, Sonogashira coupling, cyanation, direct arylation, amidation/amination to form aryl ethers, hydrogenolysis, enolization coupling, 1, 2-carbonyl addition, vinylation, boration, thiolation, and selenization, among others. The electrophiles which can be introduced in the ortho position range mainly from ortho alkylation, ortho arylation, ortho amination and ortho acylation.

2. Terminating the reaction by intramolecular functionalization

Norbornene is used as a transient guiding group, besides the double functionalization of the ortho-position and the home-position of aryl iodide, in 2000, the Lautens group also develops the Catellani reaction into an intramolecular functionalization reaction, and Lautens and the like firstly use bromoolefin as a substrate and synthesize a polycyclic compound through intermolecular alkylation and intramolecular Heck coupling by utilizing the double functionalization characteristic of the Catellani reaction. The reaction has good compatibility, can be compatible with carbon chains with different numbers of carbon atoms, and can introduce heteroatoms into the carbon chains so as to synthesize heterocyclic compounds. Five-, six-or seven-membered ring compounds can be synthesized by controlling the number of carbon atoms.

3. Terminating the reaction by meta-functionalization

By using norbornene as a transient medium, the group of the problem of the left-right gold rights uses simple and common ortho-oriented substituents, and the meta-selective activation of carbon-hydrogen bonds is realized. In 2015, the group of Yujingan subjects performed meta-selective C-H activation using amide as an inducing group and norbornene as a transient director. The reaction is initiated with divalent palladium to give a meta-activated product. Almost simultaneously, the subject group of Dongbianb takes N, N-dimethylbenzylamine as a substrate, and realizes the meta-selective C-H activation.

Based on the background, in 2013, a kuronghe topic group develops a novel method for realizing regioselectivity control of a palladium/norbornene system in C-H activation through a [2+2+2] tandem cyclization reaction of 3-iodochromone and iodobenzene with norbornene participation by using palladium as a catalyst.

Therefore, in summary, norbornene is used as a transient director, so that the primary, the ortho, the meta and various functionalization in molecules of the halogenated aromatic hydrocarbon can be realized, thereby realizing the synthesis of the polysubstituted aromatic hydrocarbon. In addition, the group of Catellari, Lautens, etc. proposed that norbornane-containing polycyclic compounds can be constructed by utilizing 2, 3-bifunctional of norbornene, which allows norbornene to serve as a C2 unit in a palladium-catalyzed domino reaction.

However, the current methods for preparing chromone compounds by using norbornene have the following disadvantages: although a series of reports have been made that norbornene participates in palladium-catalyzed [2+2+2] reaction as a C2 unit for constructing a polycyclic compound containing a chromone framework, the reaction raw material is iodobenzene with higher price. Meanwhile, a method for synthesizing a polycyclic compound having a chromone skeleton by using a [2+2+1] reaction in which norbornene participates as a C2 unit has not been reported.

Disclosure of Invention

The invention aims to provide a chromone skeleton-containing polycyclic compound, a preparation method and application thereof, wherein a 3-iodo-chromone compound and norbornene are used as building blocks and react with a benzyl bromide derivative to generate a series of chromone skeleton-containing polycyclic compounds, the series of chromone skeleton-containing polycyclic compounds can establish a good material basis for application in drug discovery and drug availability evaluation, and the synthesis method of the molecules is a domino coupling reaction synthesized by a one-pot method, and has the advantages of simple operation and good substrate universality.

In order to achieve the purpose, the invention provides the following scheme:

the invention provides a chromone skeleton-containing polycyclic compound which has a structure shown in a formula I:

wherein R is¹、R²Independently H, halogen, nitryl, cyano, C1-C10 alkyl, C1-C10 alkoxy, aldehyde group, ester group, amino, heteroaryl, phenyl or alkyl substituted phenyl.

The invention provides a chromone skeleton-containing polycyclic compound which has a structure shown in a formula II:

The invention also provides a preparation method of the chromone framework-containing polycyclic compound with the structure shown in the formula I, which comprises the following steps: mixing a 3-iodo chromone compound, a benzyl bromide compound, norbornene, alkali, a palladium catalyst, a phosphine ligand and an organic solvent, and performing a serial cyclization reaction to obtain a polycyclic compound containing a chromone framework;

the 3-iodo-chromone compound has a structure shown in a formula III, the benzyl bromide compound has a structure shown in a formula IV,

As a further improvement of the invention, in the preparation method of the polycyclic compound containing the chromone framework and having the structure shown in the formula I, the base comprises at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, potassium acetate and sodium pivalate.

As a further improvement of the invention, in the preparation method of the polycyclic compound containing the chromone framework and having the structure shown in the formula I, the palladium catalyst comprises at least one of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium trifluoroacetate, palladium pivalate and cinnamyl palladium chloride dimer.

In a further improvement of the present invention, in the preparation method of the chromone skeleton-containing polycyclic compound having the structure shown in formula i, the phosphine ligand includes at least one of triphenylphosphine, tris (4-methylphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (4-fluorophenyl) phosphine, tris (3-methylphenyl) phosphine, tris (3-methoxyphenyl) phosphine, tris (3-fluorophenyl) phosphine, tris (2-methylphenyl) phosphine, tris (2-methoxyphenyl) phosphine, tris (2-fluorophenyl) phosphine, tricyclohexylphosphine, 1, 2-bis (dimethylphosphine) ethane, and tris (2-furyl) phosphine.

As a further improvement of the invention, in the preparation method of the chromone skeleton-containing polycyclic compound with the structure shown in the formula I, the molar ratio of the 3-iodo chromone compound, the benzyl bromide compound, the norbornene, the alkali, the palladium catalyst and the phosphine ligand is 1: 1-5: 1-3: 0.02-0.2: 0.05-0.25.

As a further improvement of the invention, in the preparation method of the chromone skeleton polycyclic compound with the structure shown in the formula I, the organic solvent comprises ethylene glycol dimethyl ether, acetonitrile, tertiary amyl alcohol, N-dimethylformamide, N-methylpyrrolidone, mesitylene/acetonitrile, mesitylene/N, N-dimethylformamide and mesitylene/N-methylpyrrolidone.

As a further improvement of the invention, in the preparation method of the chromone framework-containing polycyclic compound with the structure shown in the formula I, the temperature of the tandem cyclization reaction is 60-120 ℃, and the reaction time is 10-48 hours.

The invention also provides a preparation method of the chromone framework-containing polycyclic compound with the structure shown in the formula II, which comprises the following steps: mixing a 3-iodo chromone compound, a benzyl bromide compound, norbornene, alkali, a palladium catalyst, a phosphine ligand and an organic solvent, and performing a serial cyclization reaction to obtain a polycyclic compound containing a chromone framework;

As a further improvement of the invention, in the preparation method of the chromone skeleton polycyclic compound with the structure shown in the formula II, the molar ratio of the 3-iodo chromone compound, the benzyl bromide compound, the norbornene, the alkali, the palladium catalyst and the phosphine ligand is 1: 1-5: 1-3: 0.02-0.2: 0.05-0.25.

In a further improvement of the invention, in the preparation method of the chromone skeleton-containing polycyclic compound having the structure shown in formula II, the organic solvent comprises toluene, trifluorotoluene, o-xylene, mesitylene/ethylene glycol dimethyl ether, and 1, 2-dichloromethane.

As a further improvement of the invention, in the preparation method of the chromone framework-containing polycyclic compound with the structure shown in the formula II, the temperature of the tandem cyclization reaction is 60-120 ℃, and the reaction time is 10-48 hours.

As a further improvement of the invention, in the preparation method of the polycyclic compound containing a chromone framework and having the structure shown in formula II, the base comprises at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium acetate, potassium acetate and sodium pivalate.

In a further improvement of the invention, in the preparation method of the chromone framework-containing polycyclic compound having the structure shown in formula II, the palladium catalyst comprises at least one of tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium trifluoroacetate, palladium pivalate and cinnamyl palladium chloride dimer.

In a further improvement of the present invention, in the method for preparing a chromone skeleton-containing polycyclic compound having a structure represented by formula ii, the phosphine ligand includes at least one of triphenylphosphine, tris (4-methylphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (4-fluorophenyl) phosphine, tris (3-methylphenyl) phosphine, tris (3-methoxyphenyl) phosphine, tris (3-fluorophenyl) phosphine, tris (2-methylphenyl) phosphine, tris (2-methoxyphenyl) phosphine, tris (2-fluorophenyl) phosphine, tricyclohexylphosphine, 1, 2-bis (dimethylphosphine) ethane, and tris (2-furyl) phosphine.

The invention also provides an application of the chromone skeleton-containing polycyclic compound with the structure shown in the formula I or the chromone skeleton-containing polycyclic compound with the structure shown in the formula II in preparing antitumor drugs.

The invention discloses the following technical effects:

the invention provides a chromone-containing polycyclic compound which has structures shown in a formula I and a formula II. The chromone skeleton-containing polycyclic compound provided by the invention contains a chromone skeleton with potential biological activity, is an important drug active molecule, provides a compound source for drug screening, and is beneficial to promoting the development of the pharmaceutical industry. The invention provides a new way for realizing the diversity synthesis of the chromone framework-containing polycyclic compound by regulating the diastereoselectivity of the product through the solvent. Experimental results show that the chromone skeleton-containing polycyclic compound provided by the invention has antitumor activity.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without inventive exercise.

FIG. 1 shows a single crystal X-ray diffraction structure of Compound 4a obtained in example 1;

FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of Compound 4a obtained in example 1;

FIG. 3 is a nuclear magnetic resonance carbon spectrum of Compound 4a obtained in example 1;

FIG. 4 shows a single-crystal X-ray diffraction structure of Compound 4a' obtained in example 27;

FIG. 5 is a NMR spectrum of compound 4a' obtained in example 27;

FIG. 6 shows a nuclear magnetic resonance carbon spectrum of Compound 4a' obtained in example 27.

Detailed Description

Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the 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. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.

Example 1

Adding 3-iodochromone (0.2mmol), benzyl bromide (0.22mmol), norbornene (0.8mmol,75.3mg), palladium acetate (0.02mmol,4.5mg), tris (2-methylphenyl) phosphorus (0.04mmol,12.2mg), potassium phosphate (0.4mmol,84.9mg), mesitylene (1.2mL) and acetonitrile (0.8mL) into a 4mL reaction flask at 100 ℃ under nitrogen, reacting at 100 ℃ for 24h, cooling to room temperature after the reaction is finished, subjecting the obtained reaction solution to column chromatography (eluent is obtained by mixing ethyl acetate and petroleum ether according to a volume ratio of 50: 1-20: 1), removing the solvent from the solution obtained by column chromatography to obtain 23mg of a yellow solid (4a) and 20mg of a pale yellow solid obtained by mixing 4a and 4a', wherein the total yield is 65%, and the diastereoselectivity is 86:14, the melting point: 158.0-159.3 ℃.

The yellow solid was characterized by single crystal X-ray diffraction and the results are shown in figure 1. From FIG. 1, it can be seen that the target compound 4a contains a single chromone skeleton structural unit.

Performing nuclear magnetic characterization on the yellow solid, wherein the result is shown in fig. 2-3, fig. 2 is a nuclear magnetic resonance hydrogen spectrogram of 4a, fig. 3 is a nuclear magnetic resonance carbon spectrogram of 4a, and specific data are as follows:

¹H NMR(400MHz,CDCl₃)8.25(d,J＝8.0Hz,1H),7.54(t,J＝7.8Hz,1H),7.36–7.26(m,5H),7.15(d,J＝7.4Hz,2H),3.89(s,1H),3.28(d,J＝7.5Hz,1H),2.66(d,J＝4.1Hz,1H),2.29–2.20(m,2H),1.68–1.59(m,1H),1.56-1.49(m,1H),1.44–1.33(m,2H),1.22–1.12(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.8,169.7,157.2,142.4,133.0,129.0,127.7,127.2,125.9,124.9,124.4,123.4,118.3,57.4,53.0,49.1,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.for C₂₃H₂₁O₂[M+H]⁺329.1536；found 329.1535.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 a:

example 2

The 3-iodo chromone in example 1 was replaced with 3-iodo-5-methoxy chromone under the same conditions as in example 1, to give a light green solid with a yield of 43.0mg and a yield of 60%, and the diastereoselectivity was measured to be 99:1 and the melting point was 175.9-177.1 ℃.

Performing nuclear magnetic characterization on the light green solid, wherein the specific result data are as follows:

¹H NMR(400MHz,CDCl₃)7.40(t,J＝8.4Hz,1H),7.34–7.28(m,2H),7.26–7.21(m,1H),7.15–7.11(m,2H),6.86–6.82(m,1H),6.77–6.73(m,1H),3.95(s,3H),3.84–3.81(m,1H),3.25–3.15(m,1H),2.68(d,J＝4.2Hz,1H),2.24(d,J＝4.2Hz,1H),2.20–2.15(m,1H),1.66–1.56(m,1H),1.54–1.46(m,1H),1.42–1.31(m,2H),1.18–1.10(m,2H)；

¹³CNMR(100MHz,CDCl₃)176.9,167.1,160.4,159.6,142.5,133.0,129.0,127.7,127.2,124.7,115.2,110.6,106.4,57.1,56.6,53.2,49.3,42.9,39.0,32.8,28.9,28.7.HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₃[M+H]⁺359.1642；found 359.1645.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 b:

example 3

The 3-iodo chromone in example 1 was replaced with 3-iodo-6-methyl chromone under the same conditions as in example 1, to give a yellow solid with a yield of 52.0mg and a yield of 76%, and the diastereoselectivity of 81:19 and melting point of 169.5-171.3 ℃.

Performing nuclear magnetic characterization on the green solid, wherein the specific result data are as follows:

¹H NMR(400MHz,CDCl₃)8.03–8.00(m,1H),7.36–7.29(m,3H),7.27–7.24(m,1H),7.18(d,J＝8.5Hz,1H),7.15–7.13(m,2H),3.89–3.85(m,1H),3.29–3.25(m,1H),2.65(d,J＝4.2Hz,1H),2.42(s,3H),2.26(d,J＝4.3Hz,1H),2.24–2.19(m,1H),1.66–1.58(m,1H),1.57–1.47(m,1H),1.44–1.31(m,2H),1.22–1.11(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.9,169.6,155.6,142.6,134.9,134.2,129.0,127.7,127.2,125.3,124.1,123.3,118.1,57.5,53.0,49.1,42.9,39.2,32.9,29.0,28.7,21.0；HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₂[M+H]⁺343.1693；found 343.1697.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 c:

example 4

The 3-iodo chromone in example 1 was replaced with 3-iodo-6-methoxy chromone under the same conditions as in example 1, to give a yellow solid with a yield of 66.0mg and a yield of 92%, and the diastereoselectivity was determined to be 84:16, and the melting point was 170.0-171.5 ℃.

Performing nuclear magnetism characterization on the yellow solid, wherein the specific result data are as follows:

¹H NMR(400MHz,CDCl₃)7.61(d,J＝3.0Hz,1H),7.32(t,J＝7.7Hz,2H),7.26–7.18(m,2H),7.14(d,J＝6.6Hz,3H),3.86(s,4H),3.28(d,J＝7.5Hz,1H),2.66(d,J＝4.0Hz,1H),2.28–2.20(m,2H),1.68–1.58(m,1H),1.53(t,J＝8.1Hz,1H),1.45–1.37(m,1H),1.33(d,J＝10.1Hz,1H),1.21–1.10(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.6,169.6,156.7,151.9,142.4,129.0,127.6,127.2,125.0,122.8,122.7,119.6,105.1,57.3,55.9,53.0,49.0,42.8,39.0,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₃[M+H]⁺359.1642；found 359.1648.

analysis shows that the structure of the product obtained in this example is shown in formula 4 d:

example 5

The 3-iodo-chromone in example 1 was replaced with 3-iodo-6-fluoro-chromone under the same conditions as in example 1, to give a yellow solid with a yield of 45.0mg and a yield of 65%, and the diastereoselectivity was 87:13 and the melting point was 183.6-185.3 ℃.

¹H NMR(400MHz,CDCl₃)7.87(dd,J＝8.4,2.8Hz,1H),7.33(t,J＝7.4Hz,2H),7.29–7.23(m,3H),7.14(d,J＝7.4Hz,2H),3.88(t,J＝2.9Hz,1H),3.27(d,J＝7.6Hz,1H),2.64(d,J＝4.1Hz,1H),2.29–2.22(m,2H),1.67–1.59(m,1H),1.58–1.48(m,1H),1.45–1.37(m,1H),1.33(d,J＝10.5Hz,1H),1.22–1.13(m,2H)；

¹³C NMR(100MHz,CDCl₃)175.9(d,J＝2.3Hz,1C),170.2,159.5(d,J＝246.1Hz,1C),153.3(d,J＝1.7Hz,1C),142.2,129.1,127.7,127.3,125.7(d,J＝6.9Hz,1C),122.9,121.1(d,J＝25.4Hz,1C),120.3(d,J＝8.1Hz,1C),110.7(d,J＝23.6Hz,1C),57.4,53.0,49.0,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.for C₂₃H₂₀FO₂[M+H]⁺347.1442；found 347.1443.

analysis shows that the structure of the product obtained in this example is shown in formula 4 e:

example 6

The 3-iodo-chromone in example 1 was replaced with 3-iodo-6-bromo-chromone under the same conditions as in example 1, to give a yellow solid with a yield of 51.0mg and a yield of 63%, and the diastereoselectivity was 93:7 and the melting point was 222.6-223.9 ℃.

¹H NMR(400MHz,CDCl₃)8.35(d,J＝2.5Hz,1H),7.65–7.59(m,1H),7.33(t,J＝7.4Hz,2H),7.28–7.24(m,1H),7.18(d,J＝8.9Hz,1H),7.13(d,J＝7.4Hz,2H),3.87(t,J＝2.8Hz,1H),3.27(d,J＝7.6Hz,1H),2.63(d,J＝4.2Hz,1H),2.30–2.21(m,2H),1.69–1.61(m,1H),1.58–1.48(m,1H),1.43–1.36(m,1H),1.32(d,J＝10.5Hz,1H),1.22–1.12(m,2H)；

¹³C NMR(100MHz,CDCl₃)175.5,170.1,156.0,142.1,135.9,129.1,128.6,127.7,127.4,125.9,123.6,120.3,118.4,57.4,53.0,49.0,42.8,39.1,32.9,28.9,28.6；HRMS(ESI-TOF):calcd.for C₂₃H₂₀BrO₂[M+H]⁺407.0641；found 407.0645.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 g:

example 7

The 3-iodo chromone in example 1 is replaced by 3-iodo-7-methyl chromone under the same conditions as in example 1, and a yellow solid is finally obtained with a yield of 44.0mg and a yield of 64%, and the diastereoselectivity is detected to be 84:16, and the melting point is 167.5-169.5 ℃.

¹H NMR(400MHz,CDCl₃)8.12(t,J＝7.4Hz,1H),7.34–7.24(m,3H),7.21–7.03(m,4H),3.92–3.81(m,1H),3.29–3.20(m,1H),2.65(d,J＝5.7Hz,1H),2.39(d,J＝6.4Hz,3H),2.29–2.18(m,2H),1.66–1.58(m,1H),1.57–1.48(m,1H),1.45–1.30(m,2H),1.13–1.10(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.9,169.4,157.4,144.3,142.5,129.0,127.7,127.2,126.4,125.6,123.3,122.2,118.2,57.4,53.0,49.1,42.8,39.2,32.8,29.0,28.7,21.8；HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₂[M+H]⁺343.1693；found 343.1691.

as can be seen from analysis, the structure of the product obtained in this example is shown in formula 4 i:

example 8

The 3-iodo chromone in example 1 was replaced with 3-iodo-7-methoxy chromone under the same conditions as in example 1, to give a yellow solid with a yield of 61.0mg and a yield of 85%, and the diastereoselectivity was found to be 88:12, and the melting point was 125.2-127.2 ℃.

¹H NMR(400MHz,CDCl₃)8.13(d,J＝8.9Hz,1H),7.33(t,J＝7.3Hz,2H),7.28–7.22(m,1H),7.18–7.11(m,2H),6.91(dd,J＝8.9,2.4Hz,1H),6.69(d,J＝2.4Hz,1H),3.90–3.83(m,1H),3.79(s,3H),3.25(d,J＝7.5Hz,1H),2.64(d,J＝4.2Hz,1H),2.26(d,J＝4.2Hz,1H),2.21(dd,J＝7.8,3.5Hz,1H),1.67–1.57(m,1H),1.57–1.47(m,1H),1.45–1.38(m,1H),1.38–1.31(m,1H),1.21–1.10(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.4,169.1,163.6,159.0,142.6,129.0,127.7,127.2,127.1,123.3,118.3,114.2,100.6,57.4,55.8,53.1,49.0,42.8,39.1,32.8,29.0,28.6；HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₃[M+H]⁺359.1642；found 359.1647.

analysis shows that the structure of the product obtained in this example is shown in formula 4 j:

example 9

The 3-iodo chromone in example 1 was replaced with 3-iodo-7-fluoro chromone under the same conditions as in example 1 to give a white solid with a yield of 49.0mg and a yield of 71%, and the diastereoselectivity was 86:14 and the melting point was 121.2-123.3 ℃.

Performing nuclear magnetism characterization on the white solid, wherein the specific result data are as follows:

¹H NMR(400MHz,CDCl₃)8.27–8.21(m,1H),7.36–7.30(m,2H),7.29–7.23(m,1H),7.16–7.12(m,2H),7.10–7.04(m,1H),6.97(dd,J＝9.2,2.4Hz,1H),3.87(t,J＝2.9Hz,1H),3.26(dd,J＝7.6,2.0Hz,1H),2.64(d,J＝4.2Hz,1H),2.29–2.21(m,2H),1.69–1.58(m,1H),1.58–1.48(m,1H),1.45–1.31(m,2H),1.21–1.13(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.0,169.9(d,J＝1.4Hz,1C),165.3(d,J＝254.1Hz,1C),158.2(d,J＝13.2Hz,1C),142.2,129.1,128.3(d,J＝10.4Hz,1C),127.7,127.4,123.6,121.3(d,J＝2.5Hz,1C),113.6(d,J＝22.6Hz,1C),105.1(d,J＝25.5Hz,1C),57.4,53.0,49.0,42.8,39.1,32.9,29.0,28.6；HRMS(ESI-TOF):calcd.for C₂₃H₂₀FO₂[M+H]⁺347.1442；found 347.1448.

analysis shows that the structure of the product obtained in this example is shown in formula 4 k:

example 10

The 3-iodo chromone in example 1 was replaced with 3-iodo-7-bromo chromone under the same conditions as in example 1 to give a white solid with a yield of 60.0mg and a yield of 74%, and the diastereoselectivity was determined to be 81:19 and the melting point was 172.9-174.8 ℃.

¹H NMR(400MHz,CDCl₃)8.09(d,J＝8.5Hz,1H),7.53–7.41(m,2H),7.32(dd,J＝8.1,6.5Hz,2H),7.28–7.24(m,1H),7.13(dd,J＝7.2,1.8Hz,2H),3.86(dd,J＝3.6,2.2Hz,1H),3.25(d,J＝7.6Hz,1H),2.63(d,J＝4.1Hz,1H),3.28–3.22(m,1H),2.63(d,J＝4.2Hz,1H),2.30–2.21(m,2H),1.64–1.49(m,2H),1.43–1.31(m,2H),1.21–1.14(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.12,169.9,157.3,142.1,129.1,128.6,127.7,127.4,127.3,127.2,123.7,123.4,121.5,57.4,52.9,49.1,42.8,39.1,32.9,29.0,28.6；HRMS(ESI-TOF):calcd.for C₂₃H₂₀BrO₂[M+H]⁺407.0641；found 407.0642.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 m:

example 11

The 3-iodo-chromone in example 1 was replaced with 3-iodo-8-nitro-chromone under the same conditions as in example 1, to give a yellow solid with a yield of 35.0mg and a yield of 47%, which was determined to have a diastereoselectivity of 99:1 and a melting point of 149.5-151.2 ℃.

¹H NMR(400MHz,CDCl₃)8.51(dd,J＝8.0,1.7Hz,1H),8.19(dd,J＝7.9,1.7Hz,1H),7.45(t,J＝7.9Hz,1H),7.36–7.29(m,2H),7.28–7.22(m,1H),7.22–7.15(m,2H),3.97(t,J＝2.9Hz,1H),3.30(d,J＝7.6Hz,1H),2.64(d,J＝4.2Hz,1H),2.37(dd,J＝7.9,3.4Hz,1H),2.30(d,J＝4.2Hz,1H),1.70–1.61(m,1H),1.60–1.51(m,1H),1.47–1.33(m,2H),1.27–1.17(m,2H)；

¹³C NMR(100MHz,CDCl₃)174.7,170.3,149.4,141.2,139.2,131.8,129.2,129.1,127.7,127.6,126.4,124.2,123.8,57.1,52.1,49.1,42.9,39.1,33.0,28.9,28.7；HRMS(ESI-TOF):calcd.for C₂₃H₂₀NO₄[M+H]⁺374.1387；found 374.1382.

analysis shows that the structure of the product obtained in this example is shown in formula 4 o:

example 12

The 3-iodo chromone in example 1 was replaced with 3-iodo-6, 7-dimethyl chromone under the same conditions as in example 1 to give a yellow solid with a yield of 52.0mg, 73% yield, 82:18 diastereoselectivity, and 220.2-221.7 ℃ melting point.

¹H NMR(400MHz,CDCl₃)7.95(s,1H),7.34–7.28(m,2H),7.26–7.22(m,1H),7.13(d,J＝7.3Hz,2H),7.07(s,1H),3.86(d,J＝3.8Hz,1H),3.26(d,J＝7.5Hz,1H),2.64(s,1H),2.31(s,3H),2.28(s,3H),2.25(s,1H),2.23–2.18(m,1H),1.65–1.57(m,1H),1.56–1.46(m,1H),1.45–1.37(m,1H),1.33(d,J＝10.5Hz,1H),1.21–1.11(m,2H)；

¹³C NMR(100MHz,CDCl₃)177.0,169.3,155.8,143.3,142.6,134.1,129.0,127.7,127.2,125.5,123.1,122.2,118.5,57.4,53.0,49.1,42.8,39.2,32.8,28.0,28.7,20.4,19.4.HRMS(ESI-TOF):calcd.for C₂₅H₂₅O₂[M+H]⁺357.1849；found 357.1855.

analysis shows that the structure of the product obtained in this example is shown in formula 4 p:

example 13

The 3-iodo chromone in example 1 was replaced with 3-iodo-7, 8-naphthochromone under the same conditions as in example 1, to give a yellow solid with a yield of 50.0mg and a yield of 66%, and the diastereoselectivity was determined to be 93:7 and the melting point was 192.0-193.4 ℃.

¹H NMR(400MHz,CDCl₃)8.24–8.16(m,2H),7.85(d,J＝8.2Hz,1H),7.72(d,J＝8.7Hz,1H),7.59(t,J＝7.6Hz,1H),7.50(t,J＝7.8Hz,1H),7.38–7.31(m,2H),7.30–7.25(m,1H),7.23(d,J＝7.9Hz,2H),4.05(d,J＝3.1Hz,1H),3.35(d,J＝7.5Hz,1H),2.75–2.70(m,1H),2.36–2.29(m,2H),1.71–1.61(m,1H),1.61–1.51(m,1H),1.50–1.36(m,2H),1.30–1.16(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.8,168.8,154.5,142.5,135.6,129.1,129.0,128.0,127.6,127.3,126.9,125.0,124.6,124.2,122.3,121.1,120.6,57.2,53.0,49.1,42.9,39.1,32.9,29.0,28.7；HRMS(ESI-TOF):calcd.for C₂₇H₂₃O₂[M+H]⁺379.1693；found379.1690.

analysis shows that the structure of the product obtained in this example is shown in formula 4 r:

example 14

The benzyl bromide in example 1 was replaced with 1-bromomethyl-2-fluorobenzene under the same conditions as in example 1 to give a yellow solid with a yield of 44.0mg and a yield of 64%, which was determined to have a 99:1 diastereoselectivity and a melting point of 144.4-145.6 ℃.

¹H NMR(400MHz,CDCl₃)8.24(d,J＝8.0Hz,1H),7.55(t,J＝7.9Hz,1H),7.40–7.28(m,2H),7.27–7.18(m,1H),7.07(t,J＝8.8Hz,2H),7.00(t,J＝7.6Hz,1H),4.23(d,J＝3.9Hz,1H),3.27(d,J＝7.6Hz,1H),2.66(d,J＝4.3Hz,1H),2.33(d,J＝4.2Hz,1H),2.23–2.16(m,1H),1.68–1.48(m,2H),1.44–1.33(m,2H),1.22–1.20(m,2H)；

¹³C NMR(100MHz,CDCl₃)176.7,168.7,160.53(d,J＝246.5Hz,1C),157.2,133.1,129.2,129.1,129.0(d,J＝4.1Hz,1C),128.8(d,J＝8.1Hz,1C),125.9,125.0,124.6(d,J＝3.5Hz,1C),124.2(d,J＝60.1Hz,1C),118.3,115.8(d,J＝21.9Hz,1C),52.2,50.2(d,J＝2.6Hz,1C),49.2,42.7,39.2,32.9,28.9,28.6；HRMS(ESI-TOF):calcd.for C₂₃H₂₀FO₂[M+H]⁺347.1442；found 347.1445.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 s:

example 15

The benzyl bromide in example 1 was replaced with 1-bromomethyl-3-methylbenzene under otherwise the same conditions as in example 1 to give a yellow solid in 45.0mg yield of 66% with a diastereoselectivity of 81:19 and a melting point of 149.5-151.9 ℃.

1H NMR(400MHz,CDCl3)8.25(dd,J＝8.0,1.7Hz,1H),7.57–7.51(m,1H),7.38–7.28(m,2H),7.25–7.18(m,1H),7.07(d,J＝7.6Hz,1H),6.98–6.92(m,2H),3.87–3.83(m,1H),3.28(d,J＝7.5Hz,1H),2.66(d,J＝4.2Hz,1H),2.32(s,3H),2.26(d,J＝4.2Hz,1H),2.22(dd,J＝7.4,3.4Hz,1H),1.68–1.58(m,1H),1.58–1.47(m,1H),1.45–1.37(m,1H),1.37–1.31(m,1H),1.22–1.13(m,2H)；

13C NMR(100MHz,CDCl3)176.9,169.9,157.2,142.4,138.8,133.0,128.9,128.4,128.0,125.9,124.9,124.7,124.5,123.4,118.4,57.4,53.0,49.1,42.8,39.1,32.8,28.9,28.6,21.6；HRMS(ESI-TOF):calcd.forC₂₄H₂₃O₂[M+H]⁺343.1693；found343.1692.

analysis shows that the structure of the product obtained in this example is shown in formula 4 t:

example 16

The benzyl bromide in example 1 was replaced with 1-bromomethyl-3-chlorobenzene under the same conditions as in example 1 to give a white solid with a yield of 45.0mg and a yield of 62%, which was determined to have a diastereoselectivity of 83:17 and a melting point of 119.6-120.9 ℃.

1H NMR(400MHz,CDCl3)8.24(dd,J＝8.0,1.7Hz,1H),7.60–7.52(m,1H),7.35(t,J＝7.5Hz,1H),7.29(d,J＝8.4Hz,1H),7.26–7.21(m,2H),7.14(d,J＝2.0Hz,1H),7.05–6.98(m,1H),3.88–3.83(m,1H),3.27(d,J＝7.5Hz,1H),2.65(d,J＝4.1Hz,1H),2.25(d,J＝4.2Hz,1H),2.19(dd,J＝7.9,3.5Hz,1H),1.68–1.58(m,1H),1.58–1.48(m,1H),1.45–1.36m,1H),1.35–1.29(m,1H),1.21–1.13(m,2H)；

13C NMR(100MHz,CDCl3)176.7,168.8,157.2,144.3,134.8,133.2,130.3,127.9,127.5,125.9,125.9,125.1,124.4,123.6,118.3,57.0,52.8,49.1,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.forC₂₃H₂0ClO₂[M+H]⁺363.1146；found 363.1153.

analysis shows that the structure of the product obtained in this example is shown in formula 4 v:

example 17

The benzyl bromide from example 1 was replaced with 1-bromomethyl-3-cyanobenzene under otherwise the same conditions as in example 1 to give a yellow oil in 54.0mg yield of 76% with an diastereomeric selectivity of 84: 16.

The yellow oil is subjected to nuclear magnetic characterization, and specific result data are as follows:

1H NMR(400MHz,CDCl3)8.24(dd,J＝8.0,1.7Hz,1H),7.61–7.52(m,2H),7.48–7.40(m,2H),7.40–7.33(m,2H),7.31–7.22(m,1H),3.95–3.89(m,1H),3.28(d,J＝7.5Hz,1H),2.66(d,J＝4.1Hz,1H),2.27(d,J＝4.2Hz,1H),2.18(dd,J＝7.8,3.5Hz,1H),1.69–1.60(m,1H),1.60–1.50(m,1H),1.46–1.37(m,1H),1.36–1.30(m,1H),1.24–1.14(m,2H)；

13C NMR(100MHz,CDCl3)176.6,168.0,157.1,143.7,133.3,132.1,131.4,131.1,130.0,126.0,125.2,124.4,123.9,118.7,118.2,113.1,56.9,52.8,49.2,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.forC₂₄H₂0NO₂[M+H]⁺354.1489；found354.1492.

as can be seen from analysis, the structure of the product obtained in this example is shown in formula 4 w:

example 18

The benzyl bromide in example 1 was replaced with 3-bromomethylbenzaldehyde and the other conditions were the same as in example 1 to give a yellow solid with a yield of 57.0mg and 80% yield, which was determined to have a 99:1 diastereoselectivity and a melting point of 140.0-142.2 ℃.

1H NMR(400MHz,CDCl3)9.98(s,1H),8.22(dd,J＝7.9,1.7Hz,1H),7.79–7.74(m,1H),7.68(d,J＝1.7Hz,1H),7.57–7.46(m,2H),7.43–7.38(m,1H),7.37–7.31(m,1H),7.28–7.23(m,1H),3.99–3.96(m,1H),3.33–3.27(m,1H),2.66(d,J＝4.1Hz,1H),2.28(d,J＝4.1Hz,1H),2.21(dd,J＝7.8,3.6Hz,1H),1.68–1.58(m,1H),1.58–1.48(m,1H),1.44–1.30(m,2H),1.20–1.12(m,2H)；

13C NMR(100MHz,CDCl3)192.2,176.7,168.6,157.1,143.4,137.0,133.7,133.2,129.8,129.0,128.5,125.9,125.1,124.4,123.7,118.2,57.0,52.8,49.2,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.forC₂₄H₂₁O₃[M+H]⁺357.1485；found357.1488.

analysis shows that the structure of the product obtained in this example is shown in formula 4 x:

example 19

The benzyl bromide in example 1 was replaced with 1-bromomethyl-3-nitrobenzene under the same conditions as in example 1 to give a yellow solid with a yield of 54.0mg and a yield of 72% and a diastereoselectivity of 99:1, determined by melting point 152.5-153.9 ℃.

1H NMR(400MHz,CDCl3)8.24(dd,J＝8.0,1.7Hz,1H),8.15–8.10(m,1H),8.04(t,J＝1.9Hz,1H),7.60–7.44(m,3H),7.37(t,J＝7.5Hz,1H),7.30–7.23(m,1H),4.01(t,J＝3.0Hz,1H),3.32(d,J＝7.5Hz,1H),2.68(d,J＝4.1Hz,1H),2.30(d,J＝4.2Hz,1H),2.22(dd,J＝7.7,3.6Hz,1H),1.69–1.61(m,1H),1.61–1.51(m,1H),1.47–1.38(m,1H),1.38–1.32(m,1H),1.23–1.16(m,2H)；

13C NMR(100MHz,CDCl3)176.7,167.9,157.2,148.7,144.2,133.8,133.3,130.1,126.1,125.3,124.4,123.9,122.8,122.5,118.2,57.0,52.9,49.3,42.8,39.1,32.9,28.9,28.6；HRMS(ESI-TOF):calcd.forC₂₃H₂0NO₄[M+H]⁺374.1387；found 374.1387.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 y:

example 20

The benzyl bromide in example 1 was replaced with 1-bromomethyl-4-biphenyl under the same conditions as in example 1 to give a yellow oil in 41.0mg yield of 51% with a diastereoselectivity of 99: 1.

1H NMR(400MHz,CDCl3)8.30–8.23(m,1H),7.64–7.52(m,5H),7.46–7.29(m,5H),7.26–7.20(m,2H),3.94(t,J＝2.8Hz,1H),3.31(d,J＝7.5Hz,1H),2.68(d,J＝4.3Hz,1H),2.33–2.23(m,2H),1.70–1.50(m,2H),1.48–1.33(m,2H),1.26–1.16(m,2H)；

13C NMR(100MHz,CDCl3)176.9,169.7,157.3,141.5,140.8,140.3,133.1,128.9,128.1,127.8,127.5,127.2,126.0,125.0,124.5,123.5,118.3,57.1,53.0,49.2,42.9,39.2,32.9,29.0,28.7；HRMS(ESI-TOF):calcd.forC₂₉H₂₅O₂[M+H]⁺405.1849；found405.1854.

analysis shows that the structure of the product obtained in this example is shown in formula 4 aa:

example 21

The benzyl bromide in example 1 was replaced with 1-bromomethyl-4-fluorobenzene under the same conditions as in example 1 to give a white solid with a yield of 44.0mg and a yield of 64% and a diastereoselectivity of 88:12 and a melting point of 167.0-168.5 ℃.

1H NMR(400MHz,CDCl3)8.23(d,J＝7.9Hz,1H),7.54(t,J＝8.0Hz,1H),7.34(t,J＝7.5Hz,1H),7.31–7.23(m,1H),7.11–7.07(m,2H),7.00(t,J＝8.0Hz,2H),3.89–3.85(m,1H),3.26(d,J＝7.5Hz,1H),2.65(d,J＝4.4Hz,1H),2.25(d,J＝4.4Hz,1H),2.17(dd,J＝7.5,3.7Hz,1H),1.69–1.58(m,1H),1.58–1.47(m,1H),1.45–1.35(m,1H),1.32(d,J＝10.5Hz,1H),1.22–1.12(m,2H)；

13C NMR(100MHz,CDCl3)176.7,169.4,162.0(d,J＝245.7Hz,1C),157.2,138.1(d,J＝3.2Hz,1C),133.1,129.2(d,J＝8.0Hz,1C),125.9,125.0,124.4,123.3,118.2,115.9(d,J＝21.4Hz,1C),56.6,53.0,49.0,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.forC₂₃H₂₀FO₂[M+H]⁺347.1442；found 347.1442.

analysis shows that the structure of the product obtained in this example is shown in formula 4 ab:

example 22

The benzyl bromide in example 1 was replaced with 4-bromomethylbenzaldehyde and the other conditions were the same as in example 1 to give a yellow solid with a yield of 51.0mg in 72% and a diastereoselectivity of 90:10 and a melting point of 148.2-150.0 ℃.

1H NMR(400MHz,CDCl3)9.96(s,1H),8.22(dd,J＝8.0,1.6Hz,1H),7.83(d,J＝7.9Hz,2H),7.54(ddd,J＝8.6,7.1,1.7Hz,1H),7.37–7.28(m,3H),7.26–7.23(m,1H),3.97(t,J＝2.9Hz,1H),3.28(d,J＝7.6Hz,1H),2.65(d,J＝4.1Hz,1H),2.28(d,J＝4.1Hz,1H),2.20(dd,J＝7.8,3.5Hz,1H),1.67–1.58(m,1H),1.58–1.48(m,1H),1.44–1.29(m,2H),1.21–1.12(m,2H)；

13C NMR(100MHz,CDCl3)191.8,176.6,168.5,157.1,149.1,135.5,133.2,130.5,128.4,125.9,125.1,124.4,123.8,118.2,57.4,52.8,49.2,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.forC₂₄H₂₁O₃[M+H]⁺357.1485；found 357.1486.

analysis shows that the structure of the product obtained in this example is shown in formula 4 cd:

example 23

The benzyl bromide in example 1 was replaced with 4-bromomethylbenzophenone and the other conditions were the same as in example 1 to give a yellow solid with a yield of 70.0mg in 81% and a diastereoselectivity of 99:1 and a melting point of 187.3-188.8 ℃.

1H NMR(400MHz,CDCl3)8.26(dd,J＝8.0,1.7Hz,1H),7.82–7.76(m,4H),7.60–7.54(m,2H),7.46(t,J＝7.6Hz,2H),7.37(t,J＝7.5Hz,1H),7.31–7.24(m,3H),4.00(t,J＝2.8Hz,1H),3.32(d,J＝7.5Hz,1H),2.69(d,J＝4.0Hz,1H),2.31(d,J＝4.1Hz,1H),2.27(dd,J＝7.7,3.5Hz,1H),1.71–1.61(m,1H),1.61–1.51(m,1H),1.47–1.34(m,2H),1.25–1.15(m,2H)；

13C NMR(100MHz,CDCl3)196.2,176.7,168.8,157.2,146.9,137.6,136.6,133.2,132.6,130.9,130.1,128.4,127.6,125.9,125.1,124.4,123.7,118.3,57.3,52.9,49.2,42.8,39.1,32.8,28.9,28.6；HRMS(ESI-TOF):calcd.forC₃₀H₂₅O₃[M+H]⁺433.1798；found 433.1792.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 ae:

example 24

The benzyl bromide in example 1 was replaced with 2, 6-dimethylbenzyl bromide under otherwise the same conditions as in example 1 to give a yellow solid in 59.0mg yield of 83% with a diastereoselectivity of 89:11 and a melting point of 208.0-209.8 deg.C.

1H NMR(400MHz,CDCl3)8.27–8.23(m,1H),7.57–7.51(m,1H),7.38–7.30(m,2H),7.11–7.05(m,2H),6.98–6.94(m,1H),4.48(dd,J＝4.9,2.2Hz,1H),3.31–3.27(m,1H),2.76(d,J＝4.1Hz,1H),2.52(s,3H),2.34–2.28(m,2H),2.04(s,3H),1.71–1.60(m,1H),1.60–1.50(m,1H),1.49–1.40(m,2H),1.26–1.14(m,2H)；

13C NMR(100MHz,CDCl3)176.5,171.1,156.9,137.6,137.2,136.8,132.9,130.3,128.5,127.2,125.8,125.0,124.4,123.0,118.3,52.0,50.9,50.0,43.0,39.5,33.3,29.0 28.4,21.8,20.1；HRMS(ESI-TOF):calcd.forC₂₅H₂₄NaO₂[M+Na]⁺379.1669；found379.1674.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 af:

example 25

The benzyl bromide in example 1 was replaced with 1-bromomethylnaphthalene under otherwise the same conditions as in example 1 to give a yellow solid with a yield of 50.0mg and a yield of 66% and a diastereoselectivity of 94:6 and a melting point of 159.5-161.3 ℃.

1H NMR(400MHz,CDCl3)8.40–8.15(m,2H),7.90(d,J＝7.9Hz,1H),7.78(d,J＝8.2Hz,1H),7.69–7.45(m,3H),7.45–7.30(m,2H),7.23(d,J＝7.6Hz,1H),7.02(s,1H),4.83(d,J＝19.4Hz,1H),3.38(s,1H),2.77(s,1H),2.52(s,1H),2.31–2.10(m,1H),1.72–1.67(m,1H),1.60–1.48(m,2H),1.47–1.34(m,1H),1.26(d,J＝10.4Hz,1H),1.19–1.08(m,1H)；

13C NMR(100MHz,CDCl3)176.7,169.9,157.2,134.3,133.0,131.4,129.2,127.6,126.6,125.9,125.8,125.0,124.5,124.2,123.3,118.3,53.1,51.8,49.3,43.1,39.2,33.3,33.2,33.0,28.8；HRMS(ESI-TOF):calcd.forC₂₇H₂₂NaO₂[M+Na]⁺401.1512；found401.1506.

analysis shows that the structure of the product obtained in this example is shown as formula 4 ah:

example 26

The benzyl bromide in example 1 was replaced with ethyl bromoacetate and the other conditions were the same as in example 1 to give a white solid with a yield of 19.5mg and a yield of 30% and a diastereoselectivity of 99:1 and a melting point of 105.8-107.6 ℃.

1H NMR(400MHz,CDCl3)8.20(d,J＝8.0Hz,1H),7.59(t,J＝7.6Hz,1H),7.44–7.32(m,2H),4.25–4.12(m,2H),3.60(d,J＝3.0Hz,1H),3.18(d,J＝7.5Hz,1H),2.58(s,1H),2.48–2.41(m,1H),2.20(s,1H),1.71–1.45(m,3H),1.39(t,J＝9.8Hz,1H),1.25(d,J＝7.1Hz,3H),1.14(dd,J＝26.2,10.7Hz,2H)；

13C NMR(100MHz,CDCl3)176.6,171.2,164.5,157.1,133.3,126.0,125.2,124.6,124.4,118.3,61.7,56.5,49.4,47.2,42.7,39.0,32.8,28.8,28.5,14.3；HRMS(ESI-TOF):calcd.forC₂₀H₂₁O₄[M+H]⁺325.1434；found325.1439.

analysis shows that the structure of the product obtained in this example is shown in formula 4 aj:

example 27

3-iodochromone (0.2mmol), benzyl bromide (0.22mmol), norbornene (0.8mmol,75.3mg), palladium acetate (0.02mmol,4.5mg), tris (2-methylphenyl) phosphorus (0.04mmol,12.2mg), potassium phosphate (0.4mmol,84.9mg) and mesitylene (2mL) are added to a 4mL reaction flask under nitrogen at 100 ℃ for reaction at 100 ℃ for 24h, after the reaction is finished, the reaction solution is cooled to room temperature, column chromatography is performed on the obtained reaction solution (eluent is obtained by mixing ethyl acetate and petroleum ether according to a volume ratio of 50: 1-20: 1), the solution obtained by column chromatography is subjected to solvent removal to obtain a white solid (4a')39.4mg with a yield of 60%, and the diastereoselectivity is detected to be 86:14, and the melting point: 196.5 to 198.2 ℃.

The white solid was characterized by single crystal X-ray diffraction and the results are shown in fig. 4. As can be seen from FIG. 4, the target compound 4a' contains a chromone backbone structural unit.

Performing nuclear magnetic characterization on the white solid, wherein the result is shown in fig. 5-6, wherein fig. 5 is a nuclear magnetic resonance hydrogen spectrogram, fig. 6 is a nuclear magnetic resonance carbon spectrogram, and specific data are as follows:

1H NMR(400MHz,CDCl3)8.26(dd,J＝7.9,1.7Hz,1H),7.62–7.55(m,1H),7.41–7.23(m,5H),7.18–7.12(m,2H),4.77(d,J＝10.5Hz,1H),3.28(d,J＝7.5Hz,1H),2.67(d,J＝4.4Hz,1H),2.61–2.53(m,1H),1.62–1.51(m,1H),1.45(d,J＝4.2Hz,1H),1.42–1.31(m,2H),1.28(dt,J＝10.3,1.9Hz,1H),1.13–1.04(m,1H),0.87(dt,J＝10.3,1.5Hz,1H)；

13C NMR(100MHz,CDCl3)176.7,169.3,157.2,137.5,133.1,129.2,128.6,127.0,126.0,125.1,124.6,123.9,118.3,53.5,49.8,46.9,38.3,37.6,33.5,29.4,28.8；HRMS(ESI-TOF):calcd.for C₂₃H₂₁O₂[M+H]⁺329.1536；found 329.1538.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 a':

example 28

The 3-iodo chromone in example 27 was replaced with 3-iodo-6-methyl chromone under the same conditions as in example 27 to give a yellow solid with a yield of 34.0mg and 50% yield, and the diastereoselectivity was determined to be 84:16 and the melting point to be 206.4-207.3 ℃.

1H NMR(400MHz,CDCl3)8.06–8.02(m,1H),7.41–7.32(m,3H),7.31–7.23(m,2H),7.16–7.11(m,2H),4.75(d,J＝10.5Hz,1H),3.30–3.24(m,1H),2.66(d,J＝4.5Hz,1H),2.60–2.52(m,1H),2.44(s,3H),1.61–1.51(m,1H),1.44(d,J＝4.4Hz,1H),1.42–1.30(m,2H),1.30–1.23(m,1H),1.12–1.03(m,1H),0.88–0.83(m,1H)；

13C NMR(100MHz,CDCl3)176.8,169.2,155.5,137.6,135.0,134.2,129.2,128.5,126.9,125.3,124.3,123.7,118.0,53.5,49.8,46.9,38.3,37.6,33.5,29.4,28.8,21.0；HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₂[M+H]⁺343.1693；found 343.1688.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 c':

example 29

The 3-iodo chromone in example 27 was replaced with 3-iodo-6-fluoro chromone under the same conditions as in example 27 to give a yellow solid with a yield of 49.0mg and a yield of 70%, and the diastereoselectivity was 82:18 and the melting point was 179.4-181.1 ℃.

1H NMR(400MHz,CDCl3)7.89(dd,J＝8.4,3.1Hz,1H),7.39–7.33(m,3H),7.32–7.26(m,2H),7.16–7.11(m,2H),4.76(d,J＝10.5Hz,1H),3.29–3.25(m,1H),2.65(d,J＝4.5Hz,1H),2.62–2.55(m,1H),1.62–1.51(m,1H),1.46(d,J＝4.2Hz,1H),1.42–1.30(m,2H),1.29–1.23(m,1H),1.13–1.03(m,1H),0.91–0.85(m,1H)；

13C NMR(100MHz,CDCl3)175.8,169.8,159.6(d,J＝246.2Hz,1C),153.3(d,J＝1.9Hz,1C),137.3,129.2,128.6,127.1,125.9(d,J＝7.0Hz,1C),123.3,121.1(d,J＝25.4Hz,1C),120.2(d,J＝8.0Hz,1C),110.4(d,J＝23.6Hz,1C),53.1,49.6,46.2,38.2,37.6,33.5,29.4,28.7；HRMS(ESI-TOF):calcd.for C₂₃H₂0FO₂[M+H]⁺347.1442；found347.1440.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 e':

example 30

The 3-iodo chromone in example 27 was replaced with 3-iodo-7-chloro chromone under the same conditions as in example 27 to give a yellow solid with a yield of 53.0mg and a yield of 73%, which was determined to have a diastereoselectivity of 81:19 and a melting point of 148.8-150.5 ℃.

1H NMR(400MHz,CDCl3)8.20(d,J＝8.5Hz,1H),7.42–7.27(m,5H),7.14(dd,J＝7.1,1.8Hz,2H),4.77(d,J＝10.5Hz,1H),3.28(d,J＝7.5Hz,1H),2.66(d,J＝4.4Hz,1H),2.63–2.55(m,1H),1.63–1.53(m,1H),1.47(d,J＝4.1Hz,1H),1.43–1.31(m,2H),1.31–1.24(m,1H),1.14–1.05(m,1H),0.92–0.86(m,1H)；

13C NMR(100MHz,CDCl3)175.8,169.5,157.3,139.0,137.1,129.1,128.6,127.3,127.1,125.9,124.2,123.2,118.4,53.5,49.7,46.9,38.3,37.6,33.5,29.4,28.7；HRMS(ESI-TOF):calcd.for C₂₃H₂₀ClO₂[M+H]⁺363.1146；found 363.1144.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 l':

example 31

The benzyl bromide from example 27 was replaced with 1-bromomethyl-4-methylbenzene under otherwise the same conditions as in example 27 to give a yellow solid in 51.4mg yield of 75% with a diastereoselectivity of 82:18 as measured at 163.2-164.6 ℃.

1H NMR(400MHz,CDCl3)8.28(dd,J＝8.0,1.7Hz,1H),7.59(ddd,J＝8.6,7.2,1.8Hz,1H),7.42–7.35(m,2H),7.18(d,J＝7.8Hz,2H),7.08–7.03(m,2H),4.74(d,J＝10.5Hz,1H),3.29(d,J＝7.5Hz,1H),2.68(d,J＝4.3Hz,1H),2.56(ddd,J＝10.6,7.5,1.5Hz,1H),2.37(s,3H),1.64–1.52(m,1H),1.49(d,J＝4.2Hz,1H),1.44–1.26(m,3H),1.14–1.05(m,1H),0.92–0.85(m,1H)；

13C NMR(100MHz,CDCl3)176.7,169.6,157.2,136.6,134.3,133.0,129.2,129.1,125.9,125.0,124.6,123.7,118.3,53.2,49.7,46.8,38.3,37.6,33.5,29.4,28.8,21.2；HRMS(ESI-TOF):calcd.for C₂₄H₂₃O₂[M+H]⁺343.1693；found 343.1690.

as can be seen from the analysis, the structure of the product obtained in this example is shown in formula 4 z':

example 32

The benzyl bromide in example 27 was replaced with 1-bromomethyl-4-fluorobenzene under the same conditions as in example 27 to give a yellow solid with a yield of 47.0mg and 68% yield, and the diastereoselectivity was found to be 84:16 with a melting point of 141.6-142.6 ℃.

1H NMR(400MHz,CDCl3)8.27(dd,J＝8.0,1.7Hz,1H),7.64–7.57(m,1H),7.43–7.34(m,2H),7.16–7.09(m,2H),7.09–7.02(m,2H),4.75(d,J＝10.5Hz,1H),3.28(d,J＝7.5Hz,1H),2.67(d,J＝4.4Hz,1H),2.59–2.52(m,1H),1.63–1.52(m,1H),1.46(d,J＝4.0Hz,1H),1.43–1.32(m,2H),1.29–1.21(m,1H),1.15–1.05(m,1H),0.92–0.82(m,1H)；

13C NMR(100MHz,CDCl3)176.6,168.9,161.8(d,J＝245.6Hz,1C),157.1,133.1,130.6(d,J＝7.8Hz,1C),126.0,125.1,124.5,123.8,118.2,115.5(d,J＝21.3Hz,1C),52.8,49.7,46.8,38.3,37.5,33.4,29.4,28.7；HRMS(ESI-TOF):calcd.for C₂₃H₂₀FO₂[M+H]⁺347.1442；found 347.1445.

analysis shows that the structure of the product obtained in this example is shown as formula 4 ab':

application example 1

The polycyclic compound containing chromone skeleton obtained in the example is used for treating human non-small cell lung cancer cells: cytotoxicity assay of a549 cells:

a549 cells (4X 103) were plated on a 96-well plate and cultured in 100. mu.L, 10. mu.L, 1. mu.L, 0.1. mu.L and 0.01. mu.L of LDMEM medium, respectively, for 24 hours. Then, compound 4c (i.e., the compound obtained in example 3) was added to the medium at concentrations of 0.01. mu. mol/mL, 0.1. mu. mol/mL, 1. mu. mol/mL, 10. mu. mol/mL, and 100. mu. mol/mL. After 48 hours of incubation, MTT (10. mu.L, 0.5mg/mL) was added to the medium and the cells were cultured at 37 ℃ for an additional 4 hours. The medium was removed and 100 μ L of dimethyl sulfoxide was added to dissolve the crystalline formazan (formazan). OD570 was measured with an ELx800 microplate reader (Bio-Tek, Winooski, VT, USA) and the background absorbance was subtracted. The half-inhibitory concentration IC50 of compound 4c on A549 cells was 10.586. mu. mol/L.

The compounds 4e, 4k, 4m, 4s, 4y, 4ab, 4c ', 4e ' and 4ab ' were tested for the A549 cell half-inhibitory concentration IC50 using the method described above, the results being in order>100μmol/L、26.697μmol/L、41.651μmol/L、>100μmol/L、57.708μmol/L、40.907μmol/L、>100. mu. mol/L, 13.784. mu. mol/L and 4.885. mu. mol/L. While the IC of positive control cisplatin on A549 tumor cells₅₀It was 1.105. mu. mol/L.

Therefore, the chromone-containing polycyclic compound provided by the invention has excellent antitumor activity.

Application example 2

The polycyclic compound containing chromone skeleton obtained in the example is used for treating human hepatoma cells: cytotoxicity testing of HepG2 cells:

HepG2 cells (4 × 103) were plated in 96-well plates and cultured in 100. mu.L, 10. mu.L, 1. mu.L, 0.1. mu.L and 0.01. mu.L LDMEM medium for 24 hours, then Compound 4c (i.e., the compound obtained in example 3) was added to the medium at concentrations of 0.01. mu. mol/mL, 0.1. mu. mol/mL, 1. mu. mol/mL, 10. mu. mol/mL and 100. mu. mol/mL, after 48 hours of incubation, MTT (10. mu.L, 0.5mg/mL) was added to the medium and the cells were cultured at 37 ℃ for an additional 4 hours, the medium was removed and 100. mu.L of dimethyl sulfoxide was added to dissolve crystalline formazan (formazan). OD570 was measured with ELx800 microplate reader (Bio-Tek, Winooski, VT, USA), background absorbance 570 was subtracted from the half inhibitory concentration of Compound 4c on HepGIC 2 cells₅₀It was 31.642. mu. mol/L.

Compounds 4e, 4k, 4m, 4s, 4y, 4ab, 4c ', 4e ' and 4ab ' were tested for half inhibitory concentration IC on HepG2 cells using the method described above₅₀The result is sequentially>100μmol/L、3.193μmol/L、>100μmol/L、32.613μmol/L、75.602μmol/L、>100μmol/L、>100. mu. mol/L, 11.807. mu. mol/L and 11.071. mu. mol/L. Positive control cisplatinIC on HepG2 tumor cells₅₀It was 0.729. mu. mol/L.

The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.

Claims

1. A chromone-containing framework polycyclic compound is characterized by having a structure shown in a formula I:

2. A chromone-containing framework polycyclic compound is characterized by having a structure shown in a formula II:

3. A method for preparing a polycyclic compound having a chromone skeleton according to claim 1, comprising the steps of: mixing a 3-iodo chromone compound, a benzyl bromide compound, norbornene, alkali, a palladium catalyst, a phosphine ligand and an organic solvent, and performing a serial cyclization reaction to obtain a polycyclic compound containing a chromone framework;

4. The method for preparing the polycyclic compound containing the chromone skeleton according to claim 3, wherein the molar ratio of the 3-iodochromone compound to the benzyl bromide compound to the norbornene, the base to the palladium catalyst to the phosphine ligand is 1: 1-5: 1-3: 0.02-0.2: 0.05-0.25.

5. The method according to claim 3, wherein the organic solvent comprises ethylene glycol dimethyl ether, acetonitrile, t-amyl alcohol, N-dimethylformamide, N-methylpyrrolidone, mesitylene/acetonitrile, mesitylene/N, N-dimethylformamide, mesitylene/N-methylpyrrolidone.

6. The method for preparing the polycyclic compound having a chromone skeleton according to claim 3, wherein the temperature of the tandem cyclization reaction is 60 to 120 ℃ and the reaction time is 10 to 48 hours.

7. A method for preparing a polycyclic compound having a chromone skeleton according to claim 2, comprising the steps of: mixing a 3-iodo chromone compound, a benzyl bromide compound, norbornene, alkali, a palladium catalyst, a phosphine ligand and an organic solvent, and performing a serial cyclization reaction to obtain a polycyclic compound containing a chromone framework;

8. The method for preparing the polycyclic compound containing the chromone skeleton according to claim 7, wherein the molar ratio of the 3-iodochromone compound to the benzyl bromide compound to the norbornene, the base to the palladium catalyst to the phosphine ligand is 1: 1-5: 1-3: 0.02-0.2: 0.05-0.25.

9. The method according to claim 7, wherein the organic solvent comprises toluene, trifluorotoluene, o-xylene, mesitylene/ethylene glycol dimethyl ether, and 1, 2-dichloromethane.

10. Use of the chromone skeleton-containing polycyclic compound of claim 1 or 2 in preparing an antitumor drug.