Preparation method of heterocycle-substituted gamma, delta-unsaturated butene lactone

Abstract

The invention discloses a preparation method of heterocycle-substituted gamma, delta-unsaturated butene lactone in the technical field of organic synthesis, and the synthesis route is as follows: # imgabs0 #: step 1, sequentially adding a metal palladium catalyst, a phosphine ligand, alkali, cyclopropenone and different iodobenzene-substituted olefins, then adding an organic solvent to obtain a mixture, and reacting for 2-4 hours; stirring the mixture at a certain reaction temperature under the protection of inert gas; and 2, after the reaction is finished, carrying out post-treatment separation to obtain the corresponding heterocycle substituted gamma, delta-unsaturated butene lactone. Researches find that the compound has the activity of resisting leukemia, lung cancer, liver cancer, breast cancer and colon cancer.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a method for preparing heterocyclic substituted gamma, delta-unsaturated butenolide. Background Art

[0002] As a characteristic heterocyclic skeleton, γ,δ-unsaturated butenolide is an important structural unit of many natural products and active pharmaceutical molecules. Moreover, the γ,δ-unsaturated exocyclic double bonds and butenolide in its structure can be easily converted into structural units such as epoxy and butenolide through functional groups, thereby further realizing the diversity of its molecular structure. In view of the wide range of pharmaceutical activities and potential application prospects of γ,δ-unsaturated butenolide compounds, it is undoubtedly of great significance to develop efficient and general synthetic technologies for the construction of such compounds with novel and diverse structures.

[0003] At present, the synthesis of γ-alkenyl butenolide compounds is mainly achieved through the following routes: (1) base-catalyzed self-condensation reaction of 1,3-dicarbonyl compounds; (2) transition metal-catalyzed addition / cyclization tandem reaction of α-keto acids and alkynyl compounds; (3) transition metal-catalyzed cross-coupling / cyclization tandem reaction of β-haloacrylic acid derivatives and alkynyl compounds; (4) ribose-based multi-step synthetic transformation; (5) intramolecular olefin metathesis / desulfonylation tandem reaction of allyl acrylate; (6) transition metal-catalyzed intramolecular cyclization / migration rearrangement tandem reaction of α-diazocarbonyl acid propargyl esters. However, the existing synthesis technology has the following main problems: (1) In addition to the core structural unit of γ,δ-unsaturated butenolide, the auxiliary structures of such compounds obtained by synthesis are mainly some alkyl side chains. There is still a lack of effective methods for the synthesis of such compounds with heterocyclic auxiliary structures with better applicability; (2) The substrate specificity of the existing synthesis pathway is relatively strong, the structure of the synthesized γ,δ-unsaturated butenolide is not diverse enough, and the synthesis method lacks versatility; (3) The substrate preparation of some synthesis methods is relatively difficult or the reaction conditions are very harsh. In summary, it is still a challenging task to develop new synthesis technologies with rich substrate sources and more versatility to achieve the diverse construction of novel γ,δ-unsaturated butenolide compounds. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention designs several new structures of heterocyclic substituted γ,δ-unsaturated butenolide.

[0005] The purpose of the present invention is to provide a method for preparing several novel and diverse γ,δ-unsaturated butene lactone compounds, the general structural formula of which is as follows:

[0006]

[0007] The synthetic route is as follows:

[0008]

[0009] Wherein: the heterocyclic skeleton can be independently represented by a benzo five-membered nitrogen heterocyclic skeleton, a benzo six-membered nitrogen heterocyclic skeleton, a benzo five-membered oxygen heterocyclic skeleton, a benzo six-membered oxygen heterocyclic skeleton or a condensed heterocyclic skeleton;

[0010] Preparation: including the following steps:

[0011] Step 1: sequentially adding a metal palladium catalyst, a phosphine ligand, a base, a cyclopropenone and olefins substituted with different iodophenyl groups, and then adding an organic solvent to obtain a mixture, and stirring the mixture at a certain reaction temperature under the protection of an inert gas;

[0012] Step 2: After the reaction is completed, the corresponding heterocyclic substituted γ,δ-unsaturated butene lactone is separated by post-treatment.

[0013] Further, the structural formula of the cyclopropenone is as follows:

[0014]

[0015] In the structural formula of cyclopropenone: R 1 , R 2 Each is independently selected from hydrogen, methyl, ethyl or phenyl.

[0016] Furthermore, olefins substituted with different iodophenyl groups have the following corresponding structures:

[0017] Structure 1:

[0018]

[0019] R 3 independently selected from methyl, ethyl, n-propyl, benzyl, p-methoxybenzyl, cyclopropylmethyl or 3-thienylmethyl;

[0020] Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 4-methylphenyl, 4,5-dimethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxycarbonylphenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methoxycarbonylphenyl, 6-methylphenyl, 6-fluorophenyl or 6-chlorophenyl;

[0021] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0022] Structure 2:

[0023]

[0024] R 3 independently selected from hydrogen, methyl, ethyl, benzyl, n-propyl or cyclopropyl;

[0025] Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4,5-dimethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl, 6-fluorophenyl or 6-chlorophenyl;

[0026] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0027] Structure 3:

[0028]

[0029] R 3 independently selected from hydrogen, methyl, ethyl, n-propyl, benzyl, cyclopropyl or alkyl;

[0030] Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl or 6-fluorophenyl;

[0031] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0032] Structure 4:

[0033]

[0034] R 3 independently selected from hydrogen, methyl, ethyl, n-propyl, benzyl or cyclopropyl;

[0035] Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl or 6-fluorophenyl;

[0036] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0037] Structure 5:

[0038]

[0039] Ar is independently selected from phenyl, 3-methylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4,5-dimethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl or 3,6-dimethylphenyl;

[0040] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0041] Structure 6:

[0042]

[0043] Ar is independently selected from phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl or 6-methylphenyl;

[0044] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0045] Structure 7:

[0046]

[0047] Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl or 7-bromophenyl;

[0048] Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl;

[0049] Structure 8:

[0050]

[0051] Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl or 7-bromophenyl;

[0052] Accordingly, R is independently selected from methyl, trifluoromethyl, and phenyl.

[0053] Further, (1) when the heterocyclic skeleton is a benzo five-membered nitrogen heterocyclic skeleton, it has the following two general formulas:

[0054] General formula 1:

[0055]

[0056] R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl;

[0057] R 3 independently selected from methyl, ethyl, n-propyl, benzyl, p-methoxybenzyl, cyclopropylmethyl or 3-thienylmethyl;

[0058] Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5,6-dimethylphenyl, 5-methoxyphenyl, 5-tert-butylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methoxycarbonylphenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxycarbonylphenyl, 7-methylphenyl, 7-fluorophenyl or 7-chlorophenyl;

[0059] R is independently selected from methyl, trifluoromethyl or phenyl;

[0060] General formula 2:

[0061]

[0062] R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl;

[0063] R 3 independently selected from hydrogen, methyl, ethyl, benzyl, n-propyl or cyclopropyl;

[0064] Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5,6-dimethylphenyl, 5-methoxyphenyl, 5-tert-butylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl or 7-chlorophenyl;

[0065] R is independently selected from methyl, trifluoromethyl or phenyl;

[0066] (2) When the heterocyclic skeleton is a benzo six-membered nitrogen heterocyclic skeleton, it has the following two general formulas:

[0067]

[0068] R1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl;

[0069] Accordingly, R 3 independently selected from hydrogen, methyl, ethyl, n-propyl, benzyl or cyclopropyl;

[0070] Accordingly, Ar is independently selected from phenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-methoxyphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl, 8-methylphenyl or 8-fluorophenyl;

[0071] Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl;

[0072] (3) When the heterocyclic skeleton is a benzo five-membered oxygen heterocyclic skeleton, it has the following general formula:

[0073]

[0074] R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl;

[0075] Accordingly, Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5,6-dimethylphenyl, 5-methoxyphenyl, 5-tert-butylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl or 4,7-dimethylphenyl;

[0076] Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl;

[0077] (4) When the heterocyclic skeleton is a benzo six-membered oxygen heterocyclic skeleton, it has the following general formula:

[0078]

[0079] R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl;

[0080] Accordingly, Ar is independently selected from various substituted phenyl groups such as phenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-methoxyphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl or 8-methylphenyl;

[0081] Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl;

[0082] (5) When the heterocyclic skeleton is a condensed heterocyclic skeleton, it has the following two general formulas:

[0083]

[0084] R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl;

[0085] Accordingly, Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl or 7-bromophenyl;

[0086] Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl.

[0087] Wherein, the metal palladium catalyst is zero-valent palladium or divalent palladium, and the zero-valent palladium is Pd 2 (dba) 3 ·CHCl 3、 Pd 2 (dba) 3 、Pd(dba) 2 、Pd( t Bu 3 P) 2 、Pd(PPh 3 ) 4 、(Cy 3 P) 2 Pd、Bis[1,2-bis(Ph 2 P)ethane]Pd; divalent palladium is PdCl 2 , PdCl 2 ·(CH 3 CN) 2 、(Ph 3 P) 2 PdCl 2 , PdBr 2 , PdI 2 、Pd(OAc) 2 、Pd(TFA) 2 、Pd(OTf) 2 、[Pd(allyl)Cl] 2 、Pd(Phos)Cl 2 、Pd(OTf)2 (dippp), {[ t Bu 3 P]PdI} 2 、(NHC)Pd(ally)Cl、Di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium、(η 3 -ally)(η 3 -Cp)Pd, [1,1'-Bis(Ph 2 P)ferrocene]PdCl 2 Preferably Pd 2 (dba) 3 .

[0088] The phosphine ligand is one of the following structures, and preferably ligands L8 and L9.

[0089]

[0090] The base is an organic base or an inorganic base, the organic base is one of triethylamine, diisopropylethylamine, DABCO, 4-N,N-dimethylaminopyridine, and pyridine; the inorganic base is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, and potassium tert-butoxide. Preferably, the inorganic base is, and more preferably, potassium carbonate.

[0091] Furthermore, the organic solvent is a hydrocarbon, an alcohol, an ether, an amide or a nitrile, preferably a hydrocarbon, and more preferably toluene.

[0092] Furthermore, step 1 needs to be carried out in a closed container under the protection of an inert gas.

[0093] Furthermore, the post-treatment method includes recrystallization or column chromatography, preferably column chromatography separation method.

[0094] Furthermore, in step 1, the reaction temperature is 50° C. to 100° C., and the corresponding reaction time is 24 to 72 hours, preferably 80° C. At 80° C., the conversion of the raw materials is more complete, and the yield of the corresponding product is higher.

[0095] Pd 2 (dba) 3 The reaction between N-2-iodophenyl acrylamide 1a and cyclopropenone 2a catalyzed by the combination of Pd and ligand L9 is used as an example to illustrate the process of the Heck coupling cascade reaction. 2 (dba) 3Ligand exchange occurs with ligand L9 to generate a new Pd(0) species I. Then, Pd(0) species I generates palladium species II through oxidative addition to the CI bond in substrate 1a, which generates a new palladium species III through further intramolecular olefin transfer insertion. Subsequently, palladium species III forms palladium species IV through oxidative addition to the CC bond of cyclopropenone 2a, and palladium species IV generates palladium species V through reductive elimination. Next, palladium species V forms a new palladium species VI through transfer insertion of carbon monoxide generated by in-situ activation of cyclopropenone 2a, and species VI generates palladium species VII through the enol tautomerization process of the carbonyl group under the action of a base. Finally, palladium species VII undergoes reductive elimination to generate the final γ,δ-unsaturated butenolide product 3a and Pd(0) species I to complete the entire catalytic cycle. The reaction mechanism is shown in the following formula:

[0096]

[0097] The present invention uses metal palladium to catalyze the Heck coupling tandem reaction of cyclopropenone and olefins substituted with different iodophenyls to synthesize several new structures of heterocyclic-substituted γ,δ-unsaturated butenolides, which is an innovative expansion and powerful supplement to the types and synthetic technical methods of γ,δ-unsaturated butenolide compounds. The technical method has the advantages of simple substrate preparation, abundant sources, wide application range, simple post-treatment and high yield.

[0098] The obtained novel γ,δ-unsaturated butenolide compounds have certain anti-tumor (including leukemia HL-60, lung cancer A549, liver cancer cell HepG2, breast cancer cell MDA-MB-231 and colon cancer SW480) drug activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] Figure 1 Compound 3a prepared in Example 7 1 H NMR spectrum;

[0100] Figure 2 Compound 3a prepared in Example 7 13 C NMR spectrum;

[0101] Figure 3 For Example 31, compound 5a was prepared 1 H NMR spectrum;

[0102] Figure 4 For Example 31, compound 5a was prepared 13 C NMR spectrum;

[0103] Figure 5 For Example 46, compound 7a was prepared 1 H NMR spectrum;

[0104] Figure 6 For Example 46, compound 7a was prepared 13 C NMR spectrum;

[0105] Figure 7 The single crystal diffraction pattern of compound 3a prepared in Example 7;

[0106] Figure 8 is the single crystal diffraction pattern of compound 5k prepared in Example 41;

[0107] Fig. 9 This is the single crystal diffraction pattern of compound 7d prepared in Example 49. DETAILED DESCRIPTION

[0108] The following is further described in detail through specific implementation methods:

[0109] The method for preparing several novel structures of heterocyclic substituted γ,δ-unsaturated butenolide of the present invention comprises the following steps:

[0110] Step 1: Add a metal palladium catalyst, a phosphine ligand, a base, a cyclopropenone and olefins substituted with different iodophenyl groups into a reaction tube in sequence, and then add an organic solvent, and stir the mixture at a reaction temperature of 50° C. to 100° C. under the protection of an inert gas;

[0111] Step 2: After the reaction is completed, the corresponding heterocyclic substituted γ,δ-unsaturated butene lactone is separated by post-treatment.

[0112] For example: 0.01mmol Pd 2 (dba) 3 , 0.02mmol ligand L8 or L9, 0.3mmol K 2 CO 3 , 1.0 mmol cyclopropenone, and 0.2 mmol olefins substituted with different iodophenyl groups are dissolved in 2 mL toluene, and the mixture is stirred at 80°C for a corresponding period of time under argon protection; after the reaction is completed, the residue is directly separated by column chromatography to obtain the corresponding heterocyclic substituted γ,δ-unsaturated butene lactone.

[0113] The preparation method of several heterocyclic substituted γ,δ-unsaturated butene lactones of the present invention adopts cyclopropenones of different structures and olefins substituted with iodophenyls of different structures to synthesize different types of heterocyclic substituted γ,δ-unsaturated butene lactones 3a-y, 5a-o, 7a-e, and the specific structural formulas are as follows:

[0114]

[0115]

[0116] In the present invention, the yield of the product is the isolated yield, and the structure of the product is confirmed by nuclear magnetic resonance and X-ray single crystal diffractometer testing.

[0117] Embodiments 1 to 7:

[0118]

[0119] In a 4 mL dry reaction bottle, 0.01 mmol of palladium catalyst, 0.02 mmol of ligand, 0.3 mmol of base, 0.6 or 1.0 mmol of diphenylcyclopropenone 2a, and 0.2 mmol of N-(2-iodophenyl)-N-methyl-2-(trifluoromethyl)-2-acrylamide were dissolved in 2 mL of organic solvent, and the mixture was stirred under heating and argon protection, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain product 3a (see Table 1 below for the example results).

[0120]

[0121] Embodiments 8 to 30:

[0122]

[0123] In a 4 mL dry reaction bottle, 0.01 mmol Pd 2 (dba) 3 , 0.02mmol ligand L9, 0.3mmol K 2 CO 3 , 1.0mmol cyclopropenone 2, 0.2mmol substituted acrylamide 1 were dissolved in 2mL toluene, the mixture was stirred at 80°C under argon protection for 24 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain product 3 (see Table 2 below for the example results).

[0124]

[0125]

[0126] The characterization data of products 3a-x in the examples are as follows:

[0127] Characterization data of product 3a: 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.38(m,5H),7.30-7.23(m,7H),7.13(t,J=7.6Hz,1H),6.98(d,J=8.0Hz,1H),5.67(s,1H),3.37(s,3H). 13C NMR (101 MHz, CDCl 3 )δ169.9,166.7,151.7,148.5,144.5,130.6,130.5,130.1,129.4,129.3 129.1,128.6,128.5,127.4,125.5,125.4,124.9,124.2(q,J=283.8Hz,1C),123.4,109.3,104.6,56.6(q,J=28.3Hz,1C),27.3. 19 F NMR (376 MHz, CDCl 3 )δ-73.05(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 19 F 3 NO 3 [M+H] + 462.1312; found:462.1313.

[0128] Product 3b characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.48(d,J=6.8Hz,3H),7.36-7.121(m,8H),6.91(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),5.73(s,1H),3.36(s,3H),2.32(s,3H). 13 CNMR (101MHz, CDCl 3 )δ170.2,166.7,151.4,148.2,145.1,135.9,130.3,130.2,129.6,129.5,129.4,129.3,129.0,128.6,128.5,127.6, 126.2,124.9(q,J=284.8Hz,1C),123.2,107.0,103.9,57.3(q,J=27.3Hz,1C),27.4,19.7.HRMS(ESI-TOF)calcd.for C 28 H 21 F 3 NO 3 [M+H] + 476.1468; found:476.1467.

[0129] Product 3c characterization data: 1 H NMR (400 MHz, CDCl 3)δ7.50-7.43(m,3H),7.31-7.21(m,7H),7.12(s,1H),6.78(s,1H),5.66(s,1H)3.35(s,3H),2.33(s,3H),2.25(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ170.1,166.8,151.5,148.6,142.4,139.2,131.5,130.1,129.5,129.3,129.1,128.6,128.5,127. 4,126.4,124.4(q,J=283.8Hz,1C),122.2,110.7,105.13,56.6(q,J=28.3Hz,1C),27.3,20.5,19.7. 19 F NMR (376 MHz, CDCl 3 )δ-73.16(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 23 F 3 NO 3 [M+H] + 490.1625; found:490.1626.

[0130] Product 3D characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.51-7.44(m,3H),7.36-7.20(m,8H),7.18(s,1H),6.87(d,J=8.0Hz,1H),5.68(s,1H),3.36(s,3H),2.36(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ169.9,166.7,151.6,148.5,142.1,133.0,130.9,130.1,129.4,129.3,129.2,129.1,128.6,128.5,1 27.4,126.1,124.9,124.3(q,J=283.8Hz,1C),120.1,109.0,104.8,56.7(q,J=28.3Hz,1C),27.3,21.3. 19 F NMR (376 MHz, CDCl 3 )δ-73.07(s,3F).HRMS(ESI-TOF)calcd.for C 28 H 21 F3 NO 3 [M+H] + 476.1468; found:476.1464.

[0131] Characterization data of product 3e: 1 H NMR (400 MHz, CDCl 3 )δ7.50-7.43(m,3H),7.30-7.21(m,7H),7.0(s,1H),6.95(dd,J=8.8Hz,2.4Hz,1H),6.88(d,J=8.4Hz,1H),5.65(s,1H),3.80(s,3H),3.34(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ169.6,166.7,156.3,151.8,148.5,137.9,130.1,129.4,129.3,129.2,129.1,128.6,128.5,127. 5,126.0,124.2(q,J=283.8Hz,1C),114.6,113.1,109.5,104.5,56.9(q,J=28.3Hz,1C),55.9,27.4. 19 F NMR (376 MHz, CDCl 3 )δ-73.01(s,3F).HRMS(ESI-TOF)calcd.for C 28 H 21 F 3 NO 4 [M+H] + 492.1417; found:492.1410.

[0132] Product 3f characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.44(m 5H),7.29(d,J=8.0Hz,4H),7.25-7.20(m,3H),6.89(d,J=8.4Hz,1H),5.66(s,1H),3.34(s,3H),1.34(s,9H). 13 CNMR (101MHz, CDCl 3)δ170.0,166.81,151.7,148.7,146.7,141.9,131.1,130.1,129.7,129.5,129.3,129.1,128.6,128.5,127 .3,127.2,124.2,124.3(q,JC283.8Hz,1C),123.1,108.6,104.7,56.9(q,JC28.3Hz,1C),34.8,31.6,27.2. 19 F NMR (376MHz, CDCl 3 )δ-72.70(s,3F).HRMS(ESI-TOF)calcd 31 H 27 F 3 WHEN 3 [M+H] + 518.1938;found:5

[0133] Unlimited 3g installation: 1 H NMR (400MHz, CDCl 3 )δ7.51-7.44(m,3H),7.33(dd,J)8.0Hz,2.4Hz 1H), 7.29-7.22(m,7H),6.80(t,JS8.8Hz,1H),6.72(dd,J8.4Hz,2.0Hz,1H),5.63(s,1H),3.35(s,3H). 13 C NMR (101MHz, CDCl 3 )δ170.2,166.6,164.4(d,JS249.5Hz,1C),151.9,148.4,146.2(d,JS12.1Hz ,1C),130.2,129.5,129.4,129.3,129.2,129.1,128.5,128.4,127.5,126.9( d,JC10.1Hz,1C),124.1,(q,JC284.8Hz,1C),120.2(d,JC3.0Hz,1C),109.8(d ,JC22.2Hz,1C),104.2,98.2(d,JS28.3Hz,1C),56.3(q,JC28.3Hz,1C),2 19 F NMR (376MHz, CDCl 3 )δ-73.17(s,3F),-108.23(d,J)5.2Hz,1F).HRMS(ESI-TOF)calcd 27 H 18 F4 NO 3 [M+H] + 480.1217; found:480.1223.

[0134] Product 3h characterization data:. 1 H NMR (400 MHz, CDCl 3 )δ7.56(dd,J=8.4Hz,2.0Hz,1H),7.52-7.45(m,4H),7.31-7.22(m 7H),6.87(d,J=8.0Hz,1H),5.62(s,1H),3.36(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ169.5,166.5,152.1,148.3,143.7,133.5,130.3,129.5,129.4,129.3,129.2,129.1,128.6,128. 5,128.4,127.7,126.8,124.0(q,J=283.8Hz,1C),115.9,110.7,103.7,56.6(q,J=28.3Hz,1C),27.4. 19 F NMR (376 MHz, CDCl 3 )δ-73.05(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 17 CIF 3 NNaO 3 [M+Na] + 518.0741; found:518.0738.

[0135] Product 3i characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.52-7.46(m,3H),7.42(dd,J=8.4Hz,2.0Hz,1H),7.33-7.22(m,8H),6.92(d,J=8.4Hz,1H),5.63(s,1H),3.37(s,3H). 13 C NMR (101 MHz, CDCl 3)δ169.6,166.5,152.1,148.3,143.2,130.6,130.3,129.5,129.4,129.3,129.2,129.1,128.7,128. 5,128.4,127.7,126.5,125.8,124.0(q,J=284.8Hz,1C),110.2,103.7,56.6(q,J=28.3Hz,1C),27.5. 19 F NMR (376 MHz, CDCl 3 )δ-73.08(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 18 F 3 NO 3 [M+H] + 540.0417; found:540.0420.

[0136] Product 3j characterization data: 1 H NMR (400 MHz, CDCl 3 )δ8.19(d,J=8.0Hz,1H),8.02(s,1H),7.48(d,J=6.8Hz,3H),7.35-7.19(m,7H),7.04(d,J=8.0Hz,1H),5.70(s,1H),3.91(s,3H),3.42(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ170.2,166.4,152.0,148.5,148.3,133.1,130.3,129.5,129.4,129.3,129.2,129.1,128.5,128.4,127. 6,126.7,125.5,125.2,124.0(q,J=283.8Hz,1C),119.8,108.9,103.9,56.4(q,J=28.3Hz,1C),52.3,27.5. 19 F NMR (376 MHz, CDCl 3 )δ-73.09(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 21 F 3 NO 5 [M+H] + 520.1366; found:520.1373.

[0137] Product 3k characterization data: 1H NMR (400 MHz, CDCl 3 )δ7.50-7.42(m,3H),7.29-7.20(m,8H),6.61(dd,J=8.4Hz,2.4Hz,1H),6.54(d,J=2.0Hz,1H),5.64(s,1H),3.85(s,3H),3.34(s,3H). 13 CNMR (101MHz, CDCl 3 )δ170.5,166.8,161.8,151.5,148.6,145.8,130.1,129.4,129.3,129.2,129.1,128.6,128.5,127.3, 126.4,124.2(q,J=283.8Hz,1C),116.6,110.1,107.5,105.0,97.0,56.3(q,J=31.3Hz,1C),55.7,27.3. 19 F NMR (376 MHz, CDCl 3 )δ-73.22(s,3F).HRMS(ESI-TOF)calcd.for C 28 H 21 F 3 NO 4 [M+H] + 492.1417; found:492.1423.

[0138] Characterization data of product 31: 1 H NMR (400 MHz, CDCl 3 )δ7.50-7.43(m,3H),7.33(dd,J=8.0Hz,5.6Hz,1H),7.29-7.21(m,7H),6.80(td ,J=9.2Hz,2.4Hz,1H),6.72(dd,J=8.8Hz,2.4Hz,1H),5.64(s,1H),3.35(s,3H). 13 C NMR (101 MHz, CDCl 3)δ170.2,166.6,164.4(d,J=249.5Hz,1C),151.8,148.4,146.2(d,J=11. 1Hz,1C),130.2,129.5,129.4,129.3,129.2,129.1,128.5,128.4,127.5 ,126.9(d,J=10.1Hz,1C),124.1(q,J=283.8Hz,1C),120.2,109.8(d,J=2 3.2Hz, 1C), 104.1, 98.2 (d, J=28.3Hz, 1C), 56.2 (q, J=28.3Hz, 1C), 27.4. 19 FNMR (376MHz, CDCl 3 )δ-73.16(s,3F),-108.22(dd,J=13.5Hz,5.3Hz,1F).HRMS(ESI-TOF)calcd.for C 27 H 18 F 4 NO 3 [M+H] + 480.1217; found:480.1223.

[0139] Product 3m characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.48(d,J=6.8Hz,3H),7.32-7.25(m,8H),7.12(d,J=7.2Hz,1H),7.00(s,1H),5.64(s,1H),3.36(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ169.9,166.5,152.0,148.4,145.7,136.6,131.2,130.2,129.5,129.4,129.3,129.1,128.5,128. 4,127.6,126.5,124.0(q,J=283.8Hz,1C),123.4,123.2,110.0,103.9,56.3(q,J=28.3Hz,1C),27.4. 19 F NMR (376 MHz, CDCl 3 )δ-73.03(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 18 CIF 3 NO 3 [M+H] +496.0922; found:496.0923.

[0140] Product 3n characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.86(dd,J=8.0Hz,1.2Hz,1H),7.64(s,1H),7.52-7.45(m,4H),7.30-7.21(m,7H),5.65(s,1H),3.96(s,3H),3.42(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ169.7,166.5,166.3,152.1,148.4,144.9,132.6,130.3,129.6,129.5,129.4,129.3,129.2,129.1,128. 5,128.4,127.7,125.5,125.2,124.0(q,J=283.8Hz,1C),109.9,103.6,56.7(q,J=28.3Hz,1C),52.7,27.5. 19 F NMR (376 MHz, CDCl 3 )δ-72.81(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 21 F 3 NO 5 [M+H] + 520.1366; found:520.1372.

[0141] Product 3o characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.52-7.45(m,5H),7.42-7.36(m,3H),7.34-7.22(m,9H),7.08(t,J=7.6H z,1H),6.78(d,J=7.6Hz,1H),5.73(s,1H),5.10(dd,J=24.8Hz,16.0Hz,2H). 13 C NMR (101 MHz, CDCl 3)δ170.0,166.7,151.8,148.5,143.7,134.9,130.5,130.2,130.1,129.4,129.3,129.2,129.1,129.0,128.6,128. 5,127.8,127.5,127.2,125.4,125.0,124.3(q,J284.8Hz,1C),123.4,110.4,104.3,56.8(q,J28.3Hz,1C),44.8. 19 F NMR (376MHz, CDCl 3 )δ-73.26(s,3F).HRMS(ESI-TOF)calcd 33 H 23 F 3 WHEN 3 [M+H] + 538.1625;found:5

[0142] Download 3p version: 1 H NMR (400MHz, CDCl 3 )δ7.48-7.40(m,4H),7.35(d,J7.2Hz,1H),7.31-7.23(m,7H),7.11(t,J7.2Hz,1H),7.00(d,J7.6Hz, 1H),5.67(s,1H),4.03(td,J14.0Hz,7.2Hz,1H),3.80(td,J14.0Hz,6.8Hz,1H),1.43(t,J7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ169.5,166.7,151.7,148.4,143.6,130.5,130.1,129.5,129.4,129.3,129.2,129.1,128.6,128.5, 127.5,125.6,125.4,124.3(q,J283.8Hz,1C)123.2,109.4,104.7,56.7(q,J27.3Hz,1C),35.8,11.9. 19 F NMR (376MHz, CDCl 3 )δ-73.24(s,3F).HRMS(ESI-TOF)calcd 28 H 21 F 3 WHEN 3 [M+H] +476.1468; found:476.1472.

[0143] Product 3q characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.51-7.43(m,3H),7.40(d,J=8.0Hz,1H),7.35(d,J=7.2Hz,1H),7.31-7.21(m,7H),7.10(t,J=7.6Hz,1H),6.9 9(d,J=8.0Hz,1H),5.67(s,1H),3.89-3.82(m,1H),3.79-3.72(m,1H),1.90-1.84(m,2H),1.05(t,J=7.6Hz,3H). 13 CNMR (101MHz, CDCl 3 )δ169.8,166.7,151.7,148.4,144.1,130.5,130.1,129.5,129.4,129.3,129.1,128.6,128.5,127.4,125 .6,125.2,124.3(q,J=283.8Hz,1C),123.1,109.5,104.7,104.6,56.6(q,J=28.3Hz,1C),42.7,20.4,11.6. 19 F NMR (376 MHz, CDCl 3 )δ-73.27(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 23 F 3 NO 3 [M+H] + 490.1625; found:490.1624.

[0144] Product 3r characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.53-7.46(m,3H),7.41-7.37(m,2H),7.35-7.23(m,9H),7.08(t,J=7.6Hz,1H),6.94(d,J= 8.4Hz, 2H), 6.80 (d, J=8.0Hz, 1H), 5.73 (s, 1H), 5.04 (dd, J=37.2Hz, 15.6Hz, 2H), 3.79 (s, 3H). 13 C NMR (101 MHz, CDCl 3)δ167.0,166.7,159.3,151.7,148.5,143.7,130.4,130.2,129.4,129.3,129.1,128.6,128.5,128.4,127.5,126. 9,125.4,125.0,124.3(q,J=284.8Hz,1C),123.3,114.4,110.5,104.4,104.3,56.7(q,J=27.3Hz,1C),55.4,44.3. 19 F NMR (376 MHz, CDCl 3 )δ-73.27(s,3F).HRMS(ESI-TOF)calcd.for C 34 H 25 F 3 NO 4 [M+H] + 568.1730; found:568.1727.

[0145] Product 3s characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.51-7.40(m,4H),7.36(d,J=7.2Hz,1H),7.31-7.20(m,7H),7.13-7.06(m,2H),5.68(s,1H),3.81(dd,J=1 4.4Hz, 10.8Hz, 1H), 3.69 (dd, J=14.4Hz, 6.8Hz, 1H), 1.36-1.32 (m, 1H), 0.71-0.58 (m, 2H), 0.51-0.39 (m, 2H). 13 C NMR (101 MHz, CDCl 3 )δ169.9,166.7,151.7,148.4,144.2,130.5,130.1,129.5,129.4,129.3,129.2,128.6,128.5,128.2,127. 4,125.6,125.2,124.3(q,J=283.8Hz,1C),123.1,109.7,104.7,56.7(q,J=14.1Hz,1C),45.4,9.3,4.2,3.9. 19 F NMR (376 MHz, CDCl 3 )δ-73.31(s,3F).HRMS(ESI-TOF)calcd.for C 30 H 23 F 3 NO 3 [M+H]+ 502.1625; found:502.1625.

[0146] Characterization data of product 3t: 1 H NMR (400 MHz, CDCl 3 )δ7.53-7.45(m,3H),7.37-7.22(m,11H),7.17(dd,J=4.8Hz,1.2Hz,1H),7.10(t,J =7.6Hz, 1H), 6.85 (d, J = 7.6Hz, 1H), 5.72 (s, 1H), 5.09 (dd, J = 35.6Hz, 16.0Hz, 2H). 13 C NMR (101 MHz, CDCl 3 )δ169.7,166.7,151.8,148.5,143.6,135.6,130.5,130.2,129.4,129.3,129.1,128.5,127.5,126.9,1 25.4,125.0,124.3(q,J=284.8Hz,1C),123.4,122.7,110.3,104.3,77.36,56.7(q,J=28.3Hz,1C),40.6. 19 F NMR (376 MHz, CDCl 3 )δ-73.30(s,3F).HRMS(ESI-TOF)calcd.for C 31 H 21 F 3 NO 3 S[M+H] + 544.1189; found:544.1193.

[0147] Product 3u characterization data: 1 H NMR (400 MHz, CDCl 3 ): δ7.26-7.21(m,4H),7.13(t,J=7.6Hz,2H),6.68-6.66(m,3H),4.20(t,J=7.2Hz,1H),3.88(d,J=5.2Hz,1H),3 .69(s,1H),3.37(d,J=5.2Hz,1H),2.39-2.29(m,2H),2.15-2.08(m,1H),1.87-1.84(m,2H),1.64-1.55(m,1H). 13 C NMR (101 MHz, CDCl 3)δ170.2,147.1,136.8,129.4,129.1,128.6,118.0,117.5,113.1,63.0,57.7,48.0,33.8,31.9,21.8.HRMS(ESI-TOF)calcd.for C 27 H 22 NO 3 [M+H] + 408.1594; found:408.1597.

[0148] Product 3v characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.43-7.38(m,5H),7.30-7.29(m,9H),7.25-7.21(m,3H),7.16(t,J=7.6Hz,1H),6.99(d,J=8.0Hz,1H),5.84(s,1H),3.30(s,3H). 13 CNMR (101MHz, CDCl 3 )δ176.8,167.5,150.4,149.12,144.1,140.2,131.8,130.0,129.8,129.3,129.2,129.1,129.0,12 8.9,128.4,128.0,127.3,126.5,126.0,123.2,115.1,108.9,57.1,27.1.HRMS(ESI-TOF)calcd.for C 32 H 24 NO 3 [M+H] + 470.1751; found:470.1754.

[0149] Product 3w characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.44-7.37(m,2H),7.27-7.25(m,2H),7.20-7.17(m,4H),7.12(t,J=7.6Hz,1H),7.04(d ,J=8.0Hz,2H),6.97(d,J=7.6Hz,1H),5.65(s,1H),3.37(s,3H),2.42(s,3H),2.29(s,3H). 13 C NMR (101 MHz, CDCl 3)δ170.1,167.0,152.0,147.9,144.5,140.3,139.5,130.5,130.0,129.3,129.2,129.1,127.0,126.6,125 .9,125.6,125.1,124.3(q,J=283.8Hz,1C),123.4,109.2,104.0,56.7(q,J=28.3Hz,1C),27.3,21.6,21.5. 19 FNMR (376MHz, CDCl 3 )δ-73.06(s,3F).HRMS(ESI-TOF)calcd.forC 29 H 23 F 3 NO 3 [M+H] + 490.1625; found:490.1623.

[0150] Product 3x characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.48(d,J=8.0Hz,2H),7.44-7.40(m,2H),7.26-7.24(m,6H),7.14(t,J=7.6Hz ,1H),6.99(d,J=7.6Hz,1H),5.67(s,1H),3.39(s,3H),1.40(s,9H),1.28(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ170.1,167.1,153.4,152.4,152.0,147.8,144.6,130.5,129.0,128.9,126.9,126.6,126.2,125.9,125.6,125.4 ,125.1,124.4(q,J=283.8Hz,1C),123.4,109.2,104.0,56.7(q,J=28.3Hz,1C),53.6,35.1,34.9,31.4,31.3,27.3. 19 F NMR (376 MHz, CDCl 3 )δ-72.99(s,3F).HRMS(ESI-TOF)calcd.for C 35 H 35 F 3 NO 3 [M+H] + 574.2564; found:574.2566.

[0151] Embodiments 31 to 41:

[0152]

[0153] In a 4 mL dry reaction bottle, 0.01 mmol Pd 2 (dba) 3 , 0.02mmol ligand L8, 0.3mmol K 2 CO 3 , 1.0 mmol of diphenylcyclopropenone 2a, 0.2 mmol of N-2-iodophenylallylamine 4 were dissolved in 2 mL of toluene, and the mixture was stirred at 80°C under argon protection for 48 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain product 5. (See Table 3 below for the example results).

[0154]

[0155] Embodiments 42 to 45:

[0156]

[0157] In a 4 mL dry reaction bottle, 0.01 mmol Pd 2 (dba) 3 、0.02mmol ligand L8 / L9、0.3mmolK 2 CO 3 , 1.0mmol of diphenylcyclopropenone 2a, and 0.2mmol of 2-iodophenyl substituted olefin 4 were dissolved in 2mL of toluene, and the mixture was stirred at 80°C under argon protection for 48 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain product 5. (See Table 4 below for the example results).

[0158]

[0159] The characterization data of products 5a-o in the examples are as follows:

[0160] Product 5a characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.36(m,5H),7.28-7.24(m,5H),7.15-7.11(m,2H),6.73(t,J=7.6Hz,1H),6.51( d,J=8.0Hz,1H),5.61(s,1H),3.54(dd,J=11.6Hz,9.2Hz,2H),2.78(s,3H),1.66(s,3H). 13C NMR (101 MHz, CDCl 3 )δ168.6,151.8,150.2,148.7,136.7,130.4,129.7,129.4,129.3,129.2,129.1,128.9 128.4,128.3,125.4,122.5,121.4,118.3,107.8,69.5,45.2,35.9,26.3.HRMS(ESI-TOF)calcd.forC 27 H 24 NO 2 [M+H] + 394.1802; found:394.1804.

[0161] Product 5b characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.39(m,5H),7.28-26(m,5H),7.12(t,J=8.0Hz,2H),6.70(t,J=7.6Hz,1H) ,6.52(d,J=7.6Hz,1H),5.64(s,1H),3.58(dd,J=22.4Hz,8.8Hz,2H),3.31-3.22(m 1H),3.17-3.08(m,1H),1.66(s,3H),1.20(t,J=7.6Hz,3H) 13 CNMR (101MHz, CDCl 3 )δ168.6,150.6,150.2,148.7,136.7,130.4,129.7,129.4,129.3,129.2,129.1,12 8.8,128.4,128.3,125.4,122.6,121.6,117.9,107.6,65.8,45.0,42.6,26.6,11.8.

[0162] Product 5c characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.39(m,3H),7.38-7.32(m,5H),7.31-7.24(m,6H),7.18-7.07(m,3H),6.72(t,J=7.2Hz,1H),6.53(d,J=7. 6Hz,1H),5.63(s,1H),4.39(d,J=15.2Hz,1H),4.23(d,J=15.2Hz,1H),3.55(dd,J=13.6Hz,9.2Hz,2H),1.68(s,3H).13 C NMR (101 MHz, CDCl 3 )δ168.6,150.8,150.1,148.7,138.2,136.5,130.4,129.7,129.4,129.3,129.1,128.9,128.7,128.4,128. 3,127.8,127.3,125.4,122.8,121.2,118.2,107.4,67.2,52.8,45.2,29.8,26.5.HRMS(ESI-TOF)calcd.for C 33 H 27 KNO 2 [M+K] + 508.1673; found:508.1659.

[0163] Characterization data of product 5d: 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.45(m,2H),7.40-7.39(m,3H),7.24-7.17(m,5H),6.86(d,J=7.6Hz,1H),6.69(d,J=8.4 Hz,1H),6.58(t,J=7.6Hz,1H),6.53(s,1H),4.98(s,1H),4.92(s,1H),3.74(s,2H),1.82(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ172.3,158.2,147.6,142.1,131.3,130.5,130.4,130.3,129.5,129.3,129.0,128.9,12 8.8,128.5,128.2,119.8,117.6,112.5,111.5,80.3,49.9,20.8.HRMS(ESI-TOF)calcd.for C 26 H 22 NO 2 [M+H] + 380.1645; found:380.1644.

[0164] Characterization data of product 5e: 1 H NMR (400 MHz, CDCl 3)δ7.45-7.36(m,5H),7.28-7.25(m,5H),6.94(d,J=7.6Hz,2H),6.44(d,J=7.6Hz,1H) ,5.60(s,1H),3.49(dd,J=14.4Hz,8.8Hz,2H),2.74(s,3H),2.26(s,3H),1.65(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.6,150.2,149.8,148.7,136.9,130.43(s),129.6,129.4,129.3,129.2,129.1,128.9,128.7, 128.4,127.9,125.4,123.4,121.4,108.0,70.0,45.3,36.5,26.1,21.0.HRMS(ESI-TOF)calcd.forC 28 H 26 NO 2 [M+H] + 408.1958; found:408.1953.

[0165] Product 5f characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.36(m,5H),7.28-7.24(m,5H),6.90(s,1H),6.37(s,1H),5.61(s,1H),3 .47(dd,J=12.4Hz,8.8Hz,2H)2.74(s,3H),2.22(s,3H),2.18(s,3H),1.65(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.6,150.3,150.2,148.5,136.4,134.3,130.4,129.6,129.4,129.3,129.2,129.1,128.8,128. 4,126.3,125.3,123.9,121.7,109.9,70.1,45.1,36.6,26.1,20.4,19.4.HRMS(ESI-TOF)calcd.forC 29 H 27 NNaO 2 [M+Na] + 444.1934; found:444.1924.

[0166] Product 5g characterization data: 1H NMR (400 MHz, CDCl 3 )δ7.43-7.37(m,5H),7.28-7.26(m,5H),7.17(dd,J=4.8Hz,2.8Hz,2H),6.48- 6.46(m,1H),5.63(s,1H),3.50(s,2H),2.76(s,3H),1.67(s,3H),1.29(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ168.6,150.2,149.8,148.6,141.6,136.5,130.5,129.7,129.4,129.3,129.2,129.0,128.9,128.4,125 .3,124.9,121.7,119.8,107.4,70.0,45.5,36.3,34.4,31.9,29.9,26.1,1.2.HRMS(ESI-TOF)calcd.forC 31 H 31 NNaO 2 [M+Na] + 472.2247; found:472.2247.

[0167] Product 5h characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.41(m,3H),7.39-7.34(m,3H),7.28(d,J=1.6Hz,2H),7.24(d,J=1.6Hz,1H),7.13(d,J=7.2Hz,1 H),6.85-6.78(m,2H),6.40(dd,J=8.4Hz,4.0Hz,1H),5.52(s,1H),3.52(s,2H),2.74(s,3H),1.64(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.4,157.0(d,J=236.3Hz,1C),150.0,148.9,148.1,138.2(d,J=8.1Hz,1C),130.3,129.8,129.4,129.2(d,J=6.1Hz,1C),128.9, 128.7,128.5,128.2,125.6,120.2,114.2(d,J=23.2Hz,1C),110.2(d,J=24.2Hz,1C),108.1(d,J=9.1Hz,1C),70.0,45.2,36.6,26.0.19 F NMR (376 MHz, CDCl 3 )δ-126.41(m,1F).HRMS(ESI-TOF)calcd.forC 27 H 23 FNO 2 [M+H] + 412.1707; found:412.1710.

[0168] Product 5i characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.40(m,3H),7.39-7.36(m,3H),7.28-7.25(m,6H),6.46(d,J=8.0Hz ,1H),5.54(s,1H),3.67(dd,J=19.6Hz,9.2Hz,2H),2.84(s,3H),1.65(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.4,154.0,149.9,149.0,136.8,130.2,129.8,129.4,129.2,129.1,129.0,128.5,126.4(q,J=4.0Hz,1C),125 .8,125.2(q,J=271.7Hz,1C),120.1,119.6(q,J=33.3Hz,1C),119.5(q,J=4.0Hz,1C),106.3,69.0,44.9,34.9,26.8. 19 FNMR (376MHz, CDCl 3 )δ-60.40(s,3F).

[0169] Product 5j characterization data: 1 H NMR (400 MHz, CDCl 3 )δ8.10(dd,J=8.8Hz,2.4Hz,1H),7.87(d,J=2.4Hz,1H),7.48-7.41(m,3H),7.37-7.35(m,2H),7.28-7.25(m,5H ),6.34(d,J=8.8Hz,1H),5.51(s,1H),3.95(d,J=10.0Hz,1H),3.80(d,J=10.0Hz,1H),2.96(s,3H),1.62(s,3H). 13 CNMR (101MHz, CDCl 3)δ168.1,155.9,149.8,149.3,138.4,136.8,130.0,129.3,129.1,129.0,128.9,128.5,127.4,127,3 126.0,119.3,119.2 104.4,104.3,68.5,44.3,33.8(d,J=12.1Hz,1C),28.1(d,J=8.1Hz,1C).HRMS(ESI-TOF)calcd.for C 27 H 23 N 2 O 4 [M+H] + 439.1652; found:439.1652.

[0170] Product 5k characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.36(m,5H),7.28-7.24(m,5H),6.99(d,J=7.6Hz,1H),6.66(dd,J=7.6Hz,1.6Hz,1H), 6.44(d,J=1.6Hz,1H),5.53(s,1H),3.56(dd,J=18.8Hz,9.2Hz,2H),2.76(s,3H),1.63(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.4,152.9,150.0,148.8,135.2,134.1,130.3,129.7,129.3,129.2,129.1,128.9,128. 5128.4,125.5,123.3,120.6,117.8,107.8,69.5,44.8,35.4,26.3.HRMS(ESI-TOF)calcd.for C 27 H 23 ClNO 2 [M+H] + 428.1412; found:428.1414.

[0171] Characterization data of product 51: 1 H NMR (400 MHz, CDCl 3)δ8.27(d,J=8.0Hz,1H),7.61(t,J=6.8Hz,1H),7.49-7.44(m,4H),7.35(d ,J=8.0Hz,1H),7.30-7.20(m,7H),5.57(s,1H),3.46(s,3H),1.88(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ175.1,167.2,164.3,149.8,149.0,143.7,134.1,129.9,129.4,129.3,129.2,129.1,12 8.8,128.4,127.9,126.6,126.5,123.7,116.7,47.6,31.3,27.6.HRMS(ESI-TOF)calcd.for C 28 H 22 NO 4 [M+H] + 436.1543; found:436.1546.

[0172] Product 5m characterization data: 1 H NMR (400 MHz, CDCl 3 )δ7.38-7.35(m,6H),7.26-7.18(m,6H),7.13(t,J=6.8Hz,1H),7.01(d,J=7.2Hz,1H),5.60(s ,1H),3.57(s,2H),2.83(d,J=11.2Hz,1H),2.68(d,J=11.6Hz,1H),2.43(s,3H),1.78(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.8,150.7,147.9,141.3,134.1,130.5,129.6,129.5,129.4,129.3,129.0,128.7,128.4,1 27.6,127.1,126.5,126.3,125.1,123.6,65.3,58.8,46.3,41.7,27.8.HRMS(ESI-TOF)calcd.for C 28 H 26 NO 2 [M+H] + 408.1958; found:408.1959.

[0173] Product 5n characterization data: 1 H NMR (400 MHz, CDCl3 )δ7.44-7.34(m,6H),7.26-7.23(m,6H),7.18(t,J=7.6Hz,1H),6.98(d,J=7.2Hz,1H), 5.51(s,1H),4.82(s,2H),4.00(d,J=11.2Hz,1H),3.83(d,J=11.2Hz,1H),1.76(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.5,150.4,150.0,140.7,133.3,130.4,129.6,129.4,129.3,129.1,128.8,128.4,12 7.5,127.3,126.7,125.4,124.4,120.5,74.9,68.8,39.9,25.6.HRMS(ESI-TOF)calcd.for C 27 H 23 O 3 [M+H] + 395.1642; found:395.1645.

[0174] Characterization data of product 5o: 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.36(m,5H),7.28-7.21(m,6H),7.17(t,J=7.6Hz,1H),6.91(t,J=7.2Hz,1H),6.8 3(d,J=8.0Hz,1H),5.57(s,1H),4.70(d,J=8.8Hz,1H),4.61(d,J=9.2Hz,1H),1.69(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.2,159.0,149.7,149.2,134.4,130.2,129.8,129.4,129.2,129.1,129.0,128.9,12 8.5,125.8,123.2,121.2,119.7,110.2,83.7,46.8,29.8,27.2.HRMS(ESI-TOF)calcd.ForC 26 H 21 O 3 [M+H] + 381.1485; found:381.1486.

[0175] Embodiments 46 to 50:

[0176]

[0177] In a 4 mL dry reaction bottle, 0.01 mmol Pd 2 (dba) 3 , 0.02mmol ligand L8, 0.3mmol K 2 CO 3 , 1.0mmol diphenylcyclopropenone 2a, 0.2mmol N-substituted-2-(2-iodophenyl)indole derivative 6 were dissolved in 2mL toluene, the mixture was stirred at 80°C under argon protection for 48 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the mixture was separated and purified by column chromatography to obtain product 7. (See Table 5 below for the example results).

[0178]

[0179]

[0180] Product 7a characterization data: 1 H NMR (400 MHz, CDCl 3 )δ8.51(d,J=8.0Hz,1H),7.87(d,J=7.6Hz,1H),7.61(d,J=7.5Hz,1H),7.44(d,J=5.6 Hz,3H),7.38-7.28(m,9H),7.23-7.21(m,3H),7.09(s,1H),5.63(s,1H),1.96(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ171.4,167.6,150.2,149.4,139.1,135.6,135.5,130.9,130.1,129.8,129.4,129.3,129.2,129.1,129. 0,128.9,128.4,127.8,127.5,126.4,125.5,124.8,124.1,123.8,120.8,117.0,116.8,103.9,49.5,31.1.

[0181] Product 7b characterization data: 1 H NMR (400 MHz, CDCl 3)δ8.39(d,J=8.8Hz,1H),7.86(d,J=7.6Hz,1H),7.45-7.41(m,4H),7.38-7.30( m,8H),7.25-7.19(m,3H),7.02(s,1H),5.65(s,1H),2.48(s,3H),1.97(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ171.2,167.6,150.2,149.4,139.0,135.5,134.5,133.8 131.1,130.1,129.8,129.4,129.3,129.2,129.0,128.9,128.7,128.4,127.8,1 27.5,126.8,126.4,124.0,123.9,120.7,117.1,116.4,103.7,49.4,31.0,21.6.

[0182] Product 7c characterization data: 1 H NMR (400 MHz, CDCl 3 )δ8.37(d,J=12.8Hz,1H),7.91-7.81(m,1H),7.53-7.44(m,4H),7.39-7.28(m,8H),7.25-7. 23(m,1H),7.18-7.14(m,2H),7.05(s,1H),5.66(s,1H),2.55(d,J=40.4Hz,3H),1.97(s,3H).

[0183] Product 7d characterization data: 1 H NMR (400 MHz, CDCl 3 )δ8.44(d,J=8.4Hz,1H),7.86(d,J=5.2Hz,1H),7.58(s,1H),7.46-7.45(m,3H) ,7.39-7.28(m,8H),7.24-7.20(m,3H),7.02(s,1H),5.64(s,1H),1.95(s,3H). 13 C NMR (101 MHz, CDCl 3)δ171.4,167.4,150.2,149.2,139.3,136.8,133.9,132.2,130.4,130.1,129.9,129.5,129.4,129.3,129. 2,129.1,128.9,128.4,127.9,127.5,126.5,125.5,124.3,123.3,120.3,117.7,116.8,102.9,49.2,31.1.

[0184] Characterization data of product 7e: 1 H NMR (400 MHz, CDCl 3 )δ7.81(d,J=7.6Hz,1H),7.67(d,J=8.0Hz,1H),7.46-7.32(m,8H),7.30-7.22(m,5H),7.15-7.1 2(m,3H),6.90(s,1H),5.40(s,1H),4.53(d,J=12.0Hz,1H),4.20(d,J=12.0Hz,1H),1.77(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ168.2,150.0,149.8,139.3,137.3,137.2,135.0,129.7,129.4,129.3,129.2,129.1,129.0,128.9,128 .4,128.1,127.9,127.8,125.9,125.7,125.0,122.1,120.8,120.1,118.7,109.2,97.2,50.6,41.6,25.0.

[0185] Anti-tumor activity verification:

[0186] Several heterocyclic substituted γ,δ-unsaturated butenolide compounds prepared in the examples were selected, and their in vitro antitumor activity (MTT colorimetric method) was tested using human leukemia cells (HL-60), lung cancer cells (A549), liver cancer cells (HepG2), breast cancer cells (MDA-MB-231), and colon cancer cells (SW480) as receptors.

[0187] Taking compound 3a of Example 7 as an example, the specific experimental operation is as follows:

[0188] Experimental methods:

[0189] 1. Inoculation of cells: Prepare a single cell suspension with culture medium (DMEM or RMPI1640) containing 10% fetal bovine serum, inoculate 3000 to 15000 cells per well into a 96-well plate, with a volume of 100 μl per well. The cells should be inoculated and cultured 12 to 24 hours in advance.

[0190] 2. Add the solution of the compound to be tested: dissolve the compound in DMSO, and screen the compound at concentrations of 40uM, 8uM, 1.6uM, 0.32uM, and 0.064uM. The final volume of each well is 200μL, and 3 replicate wells are set for each treatment.

[0191] 3. Color development: After culturing at 37 degrees Celsius for 48 hours, discard the culture medium in the wells of adherent cells, add 20 μL of MTS solution and 100 μL of culture medium to each well; discard 100 μL of culture supernatant of suspended cells, add 20 μL of MTS solution to each well; set up 3 blank replicate wells (a mixture of 20 μL MTS solution and 100 μL culture medium), continue incubation for 2 to 4 hours, allow the reaction to proceed fully, and then measure the light absorbance value.

[0192] 4. Colorimetry: Select 492nm wavelength, use a multifunctional microplate reader (MULTISKAN FC) to read the light absorption value of each well, record the results, and after data processing, draw a cell growth curve with concentration as the horizontal axis and cell survival rate as the vertical axis. Apply the two-point method (Reed and Muench method) to calculate the IC50 value of the compound.

[0193] 5. Positive control compounds: Two positive compounds, doxorubicin (Dox) and paclitaxel (Taxol), were set in each experiment. The cell growth curve was drawn with the concentration as the horizontal axis and the cell survival rate as the vertical axis. The IC of the compound was calculated using the two-point method (Reed and Muench method) 50 value.

[0194] Table 6 shows the inhibitory effects of some compounds of the examples on the proliferation of human leukemia cells (HL-60), lung cancer cells (A549), liver cancer cells (HepG2), breast cancer cells (MDA-MB-231), and colon cancer cells (SW480).

[0195]

[0196]

[0197] The results show that the several heterocyclic substituted γ,δ-unsaturated butenolide compounds prepared by the present invention have different degrees of inhibitory effects on human leukemia cells (HL-60), lung cancer cells (A549), liver cancer cells (HepG2), breast cancer cells (MDA-MB-231), and colon cancer cells (SW480). Among them, compound 3a selectively has good inhibitory activity on leukemia cells (HL-60), breast cancer cells (MDA-MB-231) and colon cancer cells (SW480), compound 5n selectively has good inhibitory activity on leukemia cells (HL-60) and colon cancer cells (SW480), and compounds 5m, 7a, and 7e have excellent inhibitory activity on five tumor cells at the same time. In particular, compound 7e shows better inhibitory activity than the positive control drug in inhibiting leukemia cells (HL-60) and colon cancer cells (SW480), showing the potential for further in-depth research on activity.

[0198] Compounds 3a, 5a, and 7a were extracted for NMR spectroscopy analysis, and compounds 3a, 5k, and 7d were extracted for single crystal structure analysis. Figures 1 to 9 shown.

[0199] The above is only an embodiment of the present invention, and the common sense of the known specific structure and characteristics in the scheme is not described too much here. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the scope of protection of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims. The above is only an embodiment of the present invention, and the common sense of the known specific structure and characteristics in the scheme is not described too much here. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the scope of protection of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing heterocyclic substituted γ,δ-unsaturated butenolide, characterized in that: Its general structure is as follows: The synthetic route is as follows: Wherein: the heterocyclic skeleton can be independently represented by a benzo five-membered nitrogen heterocyclic skeleton, a benzo six-membered nitrogen heterocyclic skeleton, a benzo five-membered oxygen heterocyclic skeleton, a benzo six-membered oxygen heterocyclic skeleton or a condensed heterocyclic skeleton; Preparation: including the following steps: Step 1: sequentially adding a metal palladium catalyst, a phosphine ligand, a base, a cyclopropenone and olefins substituted with different iodophenyl groups, and then adding an organic solvent to obtain a mixture, and stirring the mixture at a certain reaction temperature under the protection of an inert gas; Step 2: After the reaction is completed, the corresponding heterocyclic substituted γ,δ-unsaturated butene lactone is separated by post-treatment.

2. The method for preparing the heterocyclic substituted γ,δ-unsaturated butenolide according to claim 1, characterized in that: The structural formula of the cyclopropenone is shown below: In the structural formula of cyclopropenone: R 1 , R 2 Each is independently selected from hydrogen, methyl, ethyl or phenyl.

3. The method for preparing the heterocyclic substituted γ,δ-unsaturated butenolide according to claim 1, characterized in that: Different iodophenyl-substituted alkenes have the following corresponding structures: Structure 1: R 3 independently selected from methyl, ethyl, n-propyl, benzyl, p-methoxybenzyl, cyclopropylmethyl or 3-thienylmethyl; Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 4-methylphenyl, 4,5-dimethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxycarbonylphenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methoxycarbonylphenyl, 6-methylphenyl, 6-fluorophenyl or 6-chlorophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 2: R 3 independently selected from hydrogen, methyl, ethyl, benzyl, n-propyl or cyclopropyl; Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4,5-dimethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl, 6-fluorophenyl or 6-chlorophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 3: R 3 independently selected from hydrogen, methyl, ethyl, n-propyl, benzyl, cyclopropyl or alkyl; Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl or 6-fluorophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 4: R 3 independently selected from hydrogen, methyl, ethyl, n-propyl, benzyl or cyclopropyl; Accordingly, Ar is independently selected from phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl or 6-fluorophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 5: Ar is independently selected from phenyl, 3-methylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4,5-dimethylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 6-methylphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl or 3,6-dimethylphenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 6: Ar is independently selected from phenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl or 6-methylphenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 7: Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl or 7-bromophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, phenyl; Structure 8: Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl or 7-bromophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl, and phenyl.

4. The method for preparing the heterocyclic substituted γ,δ-unsaturated butenolide according to claim 1, characterized in that: (1) When the heterocyclic skeleton is a benzo five-membered nitrogen heterocyclic skeleton, it has the following two general formulas: General formula 1: R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl; R 3 independently selected from methyl, ethyl, n-propyl, benzyl, p-methoxybenzyl, cyclopropylmethyl or 3-thienylmethyl; Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5,6-dimethylphenyl, 5-methoxyphenyl, 5-tert-butylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-methoxycarbonylphenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 6-methoxycarbonylphenyl, 7-methylphenyl, 7-fluorophenyl or 7-chlorophenyl; R is independently selected from methyl, trifluoromethyl or phenyl; General formula 2: R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl; R 3 independently selected from hydrogen, methyl, ethyl, benzyl, n-propyl or cyclopropyl; Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5,6-dimethylphenyl, 5-methoxyphenyl, 5-tert-butylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl or 7-chlorophenyl; R is independently selected from methyl, trifluoromethyl or phenyl; (2) When the heterocyclic skeleton is a benzo six-membered nitrogen heterocyclic skeleton, it has the following two general formulas: R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl; Accordingly, R 3 independently selected from hydrogen, methyl, ethyl, n-propyl, benzyl or cyclopropyl; Accordingly, Ar is independently selected from phenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-methoxyphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl, 8-methylphenyl or 8-fluorophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl; (3) When the heterocyclic skeleton is a benzo five-membered oxygen heterocyclic skeleton, it has the following general formula: R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl; Accordingly, Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5,6-dimethylphenyl, 5-methoxyphenyl, 5-tert-butylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl or 4,7-dimethylphenyl; Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl; (4) When the heterocyclic skeleton is a benzo six-membered oxygen heterocyclic skeleton, it has the following general formula: R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl; Accordingly, Ar is independently selected from phenyl, 5-methylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-methoxyphenyl, 7-fluorophenyl, 7-chlorophenyl, 7-bromophenyl or 8-methylphenyl; Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl; (5) When the heterocyclic skeleton is a condensed heterocyclic skeleton, it has the following two general formulas: R 1 , R 2 are independently selected from hydrogen, methyl, ethyl or phenyl; Accordingly, Ar is independently selected from phenyl, 4-methylphenyl, 5-methylphenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-nitrophenyl, 6-methylphenyl, 6-methoxyphenyl, 6-fluorophenyl, 6-chlorophenyl, 6-bromophenyl, 7-methylphenyl, 7-fluorophenyl, 7-chlorophenyl or 7-bromophenyl; Accordingly, R is independently selected from methyl, trifluoromethyl or phenyl.

5. The method for preparing the heterocyclic substituted γ,δ-unsaturated butenolide according to any one of claims 1 to 4, characterized in that: The metal palladium catalyst in step 1 is zero-valent palladium or divalent palladium, and the zero-valent palladium is Pd2(dba)3·CHCl 3、 Pd2(dba)3, Pd(dba)2, Pd( t Bu3P)2, Pd(PPh3)4, (Cy3P)2Pd, Bis[1,2-bis(Ph2P)ethane]Pd; divalent palladium is PdCl2, PdCl2·(CH3CN)2, (Ph3P)2PdCl2, PdBr2, PdI2, Pd(OAc)2, Pd(TFA)2, Pd(OTf)2, [Pd(allyl)Cl]2, Pd(Phos)Cl2, Pd(OTf)2(dippp), {[ t Bu3P]PdI}2, (NHC)Pd(ally)Cl, Di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium, (η 3 -ally)(η 3 -Cp)Pd, [1,1'-Bis(Ph2P)ferrocene]PdCl2.

6. The method for preparing the heterocyclic substituted γ,δ-unsaturated butenolide according to claim 5, characterized in that: The phosphine ligand in step 1 is one of the following structures, 7. The method for preparing heterocyclic substituted γ,δ-unsaturated butenolide according to claim 5, characterized in that: The base in step 1 is an organic base or an inorganic base, the organic base is one of triethylamine, diisopropylethylamine, DABCO, 4-N,N-dimethylaminopyridine or pyridine; the inorganic base is one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide or potassium tert-butoxide.

8. The method for preparing heterocyclic substituted γ,δ-unsaturated butenolide according to claim 5, characterized in that: The organic solvent in step 1 is hydrocarbon, alcohol, ether, amide or nitrile; the reaction temperature in step 1 is 50° C. to 100° C., and the corresponding reaction time is 24 to 72 hours.

9. The method for preparing heterocyclic substituted γ,δ-unsaturated butenolide according to claim 5, characterized in that: The post-treatment method in step 2 includes recrystallization or column chromatography.

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