Heterocyclic substituted gamma, delta-unsaturated butenolides and their use

Abstract

The application discloses a heterocycle-substituted gamma, delta-unsaturated butenolide in the field of organic synthesis technology, and a structural formula is as follows: wherein the heterocycle skeleton can independently represent a benzopentazacyclic nitrogen heterocycle skeleton, a benzohexazacyclic nitrogen heterocycle skeleton, a benzopentazacyclic oxygen heterocycle skeleton, a benzohexazacyclic oxygen heterocycle skeleton or a fused heterocycle skeleton. Research finds that the compound has the activities of resisting leukemia, lung cancer, liver cancer, breast cancer and colon cancer.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to heterocyclic substituted γ,δ-unsaturated butenolactones and their applications. Background Technology

[0002] γ,δ-unsaturated butenolactones, as a characteristic class of heterocyclic skeletons, are important structural units in many natural products and pharmaceutical active molecules. Furthermore, the γ,δ-unsaturated exocyclic double bonds and butenolactones in their structures are easily transformed into epoxides, butenolamides, and other structural units through functional groups, further contributing to the diversity of their molecular structures. Given the broad pharmaceutical activity and potential applications of γ,δ-unsaturated butenolactone compounds, developing efficient and universal synthetic techniques for constructing novel and diverse compounds of this class is undoubtedly of great significance.

[0003] Currently, the synthesis of γ-alkenylbutenolactones is mainly achieved through the following pathways: (1) base-catalyzed self-condensation reaction of 1,3-dicarbonyl compounds; (2) transition metal-catalyzed addition / cyclization tandem reaction of α-keto acids and alkyne compounds; (3) transition metal-catalyzed cross-coupling / cyclization tandem reaction of β-haloacrylic acid derivatives and alkyne compounds; (4) multi-step synthetic transformation based on ribose; (5) intramolecular olefin metathesis / desulfonation tandem reaction of allyl acrylate; (6) transition metal-catalyzed intramolecular cyclization / migration rearrangement tandem reaction of α-diazocarbonyl acid propargyl esters. However, existing synthetic techniques suffer from several problems: (1) In addition to the core structural unit of γ,δ-unsaturated butenolactone, the auxiliary structures of these compounds are mainly alkyl branches, and there is a lack of effective methods for synthesizing compounds with heterocyclic auxiliary structures that have better applicability; (2) Existing synthetic routes have strong substrate specificity, and the synthesized γ,δ-unsaturated butenolactone structures are not diverse enough, and the synthetic methods lack universality; (3) The substrate preparation of some synthetic methods is difficult or the reaction conditions are very harsh. In summary, developing new synthetic techniques with abundant and more universal substrate sources to achieve the diverse construction of novel γ,δ-unsaturated butenolactone compounds remains a challenging task. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention designs several novel heterocyclic-substituted γ,δ-unsaturated butenolactone structures.

[0005] One objective of this invention is to provide several novel and diverse γ,δ-unsaturated butenolactone compounds, whose general structural formulas are as follows:

[0006]

[0007] In the formula: the heterocyclic skeleton can be independently represented as a benzo5-membered nitrogen heterocyclic skeleton, a benzo6-membered nitrogen heterocyclic skeleton, a benzo5-membered oxygen heterocyclic skeleton, a benzo6-membered oxygen heterocyclic skeleton, or a fused heterocyclic skeleton.

[0008] Furthermore, (1) when the heterocyclic skeleton is a benzo[5] nitrogen heterocyclic skeleton, it has the following two general formulas:

[0009] General Formula 1:

[0010]

[0011] R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl;

[0012] R 3 It is independently selected from methyl, ethyl, n-propyl, benzyl, p-methoxybenzyl, cyclopropylmethyl or 3-thiophenemethyl;

[0013] 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;

[0014] R is independently selected from methyl, trifluoromethyl, or phenyl;

[0015] General Formula 2:

[0016]

[0017] R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl;

[0018] R 3 It is independently selected from hydrogen, methyl, ethyl, benzyl, n-propyl, or cyclopropyl;

[0019] 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;

[0020] R is independently selected from methyl, trifluoromethyl, or phenyl;

[0021] (2) When the heterocyclic skeleton is a benzo-hexa-nitrogen heterocyclic skeleton, it has the following two general formulas:

[0022]

[0023] R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl;

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

[0025] 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;

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

[0027] (3) When the heterocyclic skeleton is a benzo5-membered oxygen heterocyclic skeleton, it has the following general formula:

[0028]

[0029] R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl;

[0030] 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;

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

[0032] (4) When the heterocyclic skeleton is a benzo-6-membered oxygen heterocyclic skeleton, it has the following general formula:

[0033]

[0034] R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl;

[0035] 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;

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

[0037] (5) When the heterocyclic skeleton is a fused heterocyclic skeleton, it has the following two general formulas:

[0038]

[0039] R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl;

[0040] 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;

[0041] Accordingly, R is independently selected from methyl, trifluoromethyl, or phenyl.

[0042] Furthermore, its structural formula is as follows:

[0043]

[0044]

[0045] A second objective of this invention is to provide the application of heterocyclic substituted γ,δ-unsaturated butenolactones in the preparation of antitumor drugs, particularly in the preparation of drugs for leukemia, lung cancer, liver cancer, breast cancer, or colon cancer.

[0046] The present invention is prepared by the following steps: Step 1: Palladium catalyst, phosphine ligand, base, cyclopropenone and olefins with different iodophenyl substitutions are added sequentially to the reaction tube, followed by the addition of organic solvent. The mixture is stirred under reaction temperature of 50℃~100℃ and inert gas protection.

[0047] Step 2: After the reaction is complete, the corresponding heterocyclic substituted γ,δ-unsaturated butenolactone is obtained through post-processing and separation. The synthetic route is shown below:

[0048]

[0049] Among them, the palladium catalyst is either zero-valent palladium or divalent palladium, with zero-valent palladium being Pd2(dba)3·CHCl. 3、 Pd2(dba)3, Pd(dba)2, Pd( t One of the following: Bu3P)2, Pd(PPh3)4, (Cy3P)2Pd, Bis[1,2-bis(Ph2P)ethane]Pd; divalent palladium is one of 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-chlorodi[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium、(η 3 -ally)(η 3 One of -Cp)Pd and [1,1'-Bis(Ph2P)ferrocene]PdCl2.

[0050] Phosphine ligands are one of the following structures.

[0051]

[0052] The base can be an organic or inorganic base. The organic base is one of triethylamine, diisopropylethylamine, DABCO, 4-N,N-dimethylaminopyridine, pyridine, etc.; 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, potassium tert-butoxide.

[0053] Furthermore, the organic solvent is a hydrocarbon, alcohol, ether, amide, or nitrile.

[0054] Further post-processing methods include recrystallization or column chromatography.

[0055] Furthermore, the reaction time is 24–72 hours.

[0056] The Heck coupling tandem reaction process is illustrated using the combination of Pd2(dba)3 and ligand L9 as an example to catalyze the reaction between N-2-iodophenylacrylamide 1a and cyclopropenone 2a. First, Pd2(dba)3 and ligand L9 undergo ligand exchange to generate a new Pd(0) species I. Then, Pd(0) species I generates palladium species II via oxidative addition to the CI bond in substrate 1a, which further undergoes intramolecular olefin transfer insertion to generate a new palladium species III. Subsequently, palladium species III forms palladium species IV via oxidative addition to the CC bond in cyclopropenone 2a, and palladium species IV undergoes reductive elimination to generate palladium species V. Next, palladium species V forms a new palladium species VI via the transfer insertion of carbon monoxide generated from the in-situ activation of cyclopropenone 2a, and species VI undergoes a carbonyl-enol tautomerization process under the action of a base to generate palladium species VII. Finally, palladium species VII undergoes reductive elimination to generate the final γ,δ-unsaturated butenolide product 3a and Pd(0) species I, completing the entire catalytic cycle. The reaction mechanism is shown in the following equation:

[0057]

[0058] This invention utilizes palladium-catalyzed Heck coupling tandem reactions of cyclopropenone and alkenes with different iodophenyl substitutions to synthesize several novel heterocyclic substituted γ,δ-unsaturated butenolactone structures. This invention represents an innovative expansion and powerful supplement to the types of γ,δ-unsaturated butenolactone compounds and synthetic techniques. This technique has advantages such as simple substrate preparation, abundant substrate sources, wide applicability, simple post-processing, and high yield. Attached Figure Description

[0059] Figure 1 Compound 3a prepared in Example 7 1 H NMR spectrum;

[0060] Figure 2 Compound 3a prepared in Example 7 13 C NMR spectrum;

[0061] Figure 3 Compound 5a was prepared for Example 31. 1 H NMR spectrum;

[0062] Figure 4 Compound 5a was prepared for Example 31. 13 C NMR spectrum;

[0063] Figure 5 Compound 7a was prepared for Example 46. 1 H NMR spectrum;

[0064] Figure 6Compound 7a was prepared for Example 46. 13 C NMR spectrum;

[0065] Figure 7 The single-crystal diffraction pattern of compound 3a prepared in Example 7;

[0066] Figure 8 The single-crystal diffraction pattern of compound 5k prepared in Example 41;

[0067] Figure 9 The single-crystal diffraction pattern of compound 7d prepared in Example 49 is shown. Detailed Implementation

[0068] The following detailed description illustrates the specific implementation method:

[0069] The present invention discloses a method for preparing several novel heterocyclic substituted γ,δ-unsaturated butenolactone structures, comprising the following steps:

[0070] Step 1: Add palladium catalyst, phosphine ligand, base, cyclopropenone and olefins with different iodophenyl substitutions to the reaction tube in sequence, then add organic solvent. Stir the mixture at a reaction temperature of 50℃~100℃ under inert gas protection.

[0071] Step 2: After the reaction is complete, the corresponding heterocyclic substituted γ,δ-unsaturated butenolactone is obtained by post-processing and separation.

[0072] For example, 0.01 mmol Pd2(dba)3, 0.02 mmol ligand L8 or L9, 0.3 mmol K2CO3, 1.0 mmol cyclopropenone, and 0.2 mmol of olefins with different iodophenyl substitutions are dissolved in 2 mL of toluene. The mixture is stirred at 80 °C under argon protection for the appropriate time. After the reaction is complete, the residue can be directly separated by column chromatography to obtain the corresponding heterocyclic substituted γ,δ-unsaturated butenolactone.

[0073] The present invention discloses a method for preparing several novel heterocyclic substituted γ,δ-unsaturated butenolactone structures. Different types of heterocyclic substituted γ,δ-unsaturated butenolactones 3a-y, 5a-o, and 7a-e are synthesized using cyclopropenones with different structures and iodophenyl-substituted alkenes with different structures. The specific structural formulas are as follows:

[0074]

[0075]

[0076] In this invention, the yield of the product is the separation yield, and the structure of the product is confirmed by nuclear magnetic resonance and X-ray single crystal diffraction.

[0077] Examples 1-7:

[0078]

[0079] In a 4 mL dry reaction flask, 0.01 mmol palladium catalyst, 0.02 mmol ligand, 0.3 mmol base, 0.6 or 1.0 mmol diphenylcyclopropenone 2a, and 0.2 mmol N-(2-iodophenyl)-N-methyl-2-(trifluoromethyl)-2-acrylamide 1a were dissolved in 2 mL organic solvent. 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 purified by column chromatography to obtain product 3a (the results of the examples are shown in Table 1 below).

[0080]

[0081] Examples 8-30:

[0082]

[0083] In a 4 mL dry reaction flask, 0.01 mmol Pd2(dba)3, 0.02 mmol ligand L9, 0.3 mmol K2CO3, 1.0 mmol cyclopropenone 2, and 0.2 mmol substituted acrylamide 1 were dissolved in 2 mL 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 purified by column chromatography to obtain product 3 (the results of the examples are shown in Table 2 below).

[0084]

[0085]

[0086] The characterization data of products 3a to x in the examples are as follows:

[0087] Characterization data of product 3a: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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(376MHz,CDCl3)δ-73.05(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 19 F3NO3[M+H] + 462.1312; found: 462.1313.

[0088] Product 3b characterization data: 1 H NMR (400MHz, CDCl3) 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, CDCl3)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 F3NO3[M+H] + 476.1468; found: 476.1467.

[0089] Product 3C characterization data: 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) δ170.1,166.8,151.5,148.6,142.4,139.2,131.5,130.1,129.5,129.3,129.1,128.6,12 8.5,127.4,126.4,124.4(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(376MHz,CDCl3)δ-73.16(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 23 F3NO3[M+H] + 490.1625; found: 490.1626.

[0090] 3D characterization data of the product: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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 ,128.5,127.4,126.1,124.9,124.3(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(376MHz, CDCl3)δ-73.07(s, 3F).HRMS(ESI-TOF)calcd.for C 28 H 21 F3NO3[M+H] + 476.1468; found: 476.1464.

[0091] Product 3e characterization data: 11H NMR (400 MHz, CDCl3) δ 7.50 - 7.43 (m, 3H), 7.30 - 7.21 (m, 7H), 7.0 (s, 1H), 6.95 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.65 (s, 1H), 3.80 (s, 3H), 3.34 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 169.6, 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 = 283.8 Hz, 1C), 114.6, 113.1, 109.5, 104.5, 56.9 (q, J = 28.3 Hz, 1C), 55.9, 27.4. 19 19F NMR (376 MHz, CDCl3) δ -73.01 (s, 3F). HRMS (ESI-TOF) calcd. for C 28 H 21 F3NO4 [M + H] + 492.1417; found: 492.1410.

[0092] Characterization data of product 3f: 1 1H NMR (400 MHz, CDCl3) δ 7.45 - 7.44 (m 5H), 7.29 (d, J = 8.0 Hz, 4H), 7.25 - 7.20 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 5.66 (s, 1H), 3.34 (s, 3H), 1.34 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 170.0, 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, J = 283.8 Hz, 1C), 123.1, 108.6, 104.7, 56.9 (q, J = 28.3 Hz, 1C), 34.8, 31.6, 27.2. 19 19F NMR (376 MHz, CDCl3) δ -72.70 (s, 3F). HRMS (ESI-TOF) calcd. for C 31 H 27 F3NO3 [M + H] +518.1938; found: 518.1939.

[0093] Characterization data of 3g of product: 1 H NMR (400MHz, CDCl3) δ7.51-7.44 (m, 3H), 7.33 (dd, J = 8.0Hz, 2.4Hz 1H),7.29-7.22(m,7H),6.80(t,J=8.8Hz,1H),6.72(dd,J=8.4Hz,2.0Hz,1H),5.63(s,1H),3.35(s,3H). 13 C NMR (101MHz, CDCl3) δ170.2, 166.6, 164.4 (d, J = 249.5Hz, 1C), 151.9, 148.4, 146. 2(d,J=12.1Hz,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=284.8Hz,1C),120.2(d,J=3.0Hz,1C),109 .8(d,J=22.2Hz,1C),104.2,98.2(d,J=28.3Hz,1C),56.3(q,J=28.3Hz,1C),27.5. 19 F NMR(376MHz, CDCl3)δ-73.17(s,3F),-108.23(d,J=5.2Hz,1F).HRMS(ESI-TOF)calcd.for C 27 H 18 F4NO3[M+H] + 480.1217; found: 480.1223.

[0094] Product characterization data after 3 hours: 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) δ169.5,166.5,152.1,148.3,143.7,133.5,130.3,129.5,129.4,129.3,129.2,129.1,12 8.6,128.5,128.4,127.7,126.8,124.0(q,J=283.8Hz,1C),115.9,110.7,103.7,56.6(q,J=28.3Hz,1C),27.4. 19 F NMR(376MHz,CDCl3)δ-73.05(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 17 ClF3NNaO3[M+Na] + 518.0741; found: 518.0738.

[0095] Product 3i characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ169.6,166.5,152.1,148.3,143.2,130.6,130.3,129.5,129.4,129.3,129.2,129.1,12 8.7,128.5,128.4,127.7,126.5,125.8,124.0(q,J=284.8Hz,1C),110.2,103.7,56.6(q,J=28.3Hz,1C),27.5. 19 F NMR(376MHz,CDCl3)δ-73.08(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 18 BrF3NO3[M+H] + 540.0417; found: 540.0420.

[0096] Product 3j characterization data: 11H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.48 (d, J = 6.8 Hz, 3H), 7.35 - 7.19 (m, 7H), 7.04 (d, J = 8.0 Hz, 1H), 5.70 (s, 1H), 3.91 (s, 3H), 3.42 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 170.2, 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 = 283.8 Hz, 1C), 119.8, 108.9, 103.9, 56.4 (q, J = 28.3 Hz, 1C), 52.3, 27.5. 19 19F NMR (376 MHz, CDCl3) δ -73.09 (s, 3F). HRMS (ESI-TOF) calcd. for C 29 H 21 F3NO5 [M + H] + 520.1366; found: 520.1373.

[0097] Characterization data of product 3k: 1 1H NMR (400 MHz, CDCl3) δ 7.50 - 7.42 (m, 3H), 7.29 - 7.20 (m, 8H), 6.61 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 5.64 (s, 1H), 3.85 (s, 3H), 3.34 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 170.5, 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 = 283.8 Hz, 1C), 116.6, 110.1, 107.5, 105.0, 97.0, 56.3 (q, J = 31.3 Hz, 1C), 55.7, 27.3. 19 19F NMR (376 MHz, CDCl3) δ -73.22 (s, 3F). HRMS (ESI-TOF) calcd. for C 28 H 21 F3NO4 [M + H] +492.1417; found: 492.1423.

[0098] Product 3L characterization data: 1 H NMR (400MHz, CDCl3) 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(101MHz,CDCl3)δ170.2,166.6,164.4(d,J=249.5Hz,1C),151.8,148.4,1 46.2(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=23.2Hz,1C),104.1,98.2(d,J=28.3Hz,1C),56.2(q,J=28.3Hz,1C),27.4. 19 FNMR(376MHz, CDCl3)δ-73.16(s,3F),-108.22(dd,J=13.5Hz,5.3Hz,1F).HRMS(ESI-TOF)calcd.for C 27 H 18 F4NO3[M+H] + 480.1217; found: 480.1223.

[0099] Product 3m characterization data: 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) δ169.9,166.5,152.0,148.4,145.7,136.6,131.2,130.2,129.5,129.4,129.3,129.1,12 8.5,128.4,127.6,126.5,124.0(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(376MHz,CDCl3)δ-73.03(s,3F).HRMS(ESI-TOF)calcd.for C 27 H 18 ClF3NO3[M+H] + 496.0922; found: 496.0923.

[0100] Product 3n characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ169.7,166.5,166.3,152.1,148.4,144.9,132.6,130.3,129.6,129.5,129.4,129.3,129.2,12 9.1,128.5,128.4,127.7,125.5,125.2,124.0(q,J=283.8Hz,1C),109.9,103.6,56.7(q,J=28.3Hz,1C),52.7,27.5. 19 F NMR(376MHz,CDCl3)δ-72.81(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 21 F3NO5[M+H] + 520.1366; found: 520.1372.

[0101] Product 3O characterization data: 11H NMR (400 MHz, CDCl3) δ 7.52 - 7.45 (m, 5H), 7.42 - 7.36 (m, 3H), 7.34 - 7.22 (m, 9H), 7.08 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.73 (s, 1H), 5.10 (dd, J = 24.8 Hz, 16.0 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 170.0, 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, J = 284.8 Hz, 1C), 123.4, 110.4, 104.3, 56.8 (q, J = 28.3 Hz, 1C), 44.8. 19 19F NMR (376 MHz, CDCl3) δ -73.26 (s, 3F). HRMS (ESI-TOF) calcd. for C 33 H 23 F3NO3 [M + H] + 538.1625; found: 538.1630.

[0102] Characterization data of product 3p: 1 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.40 (m, 4H), 7.35 (d, J = 7.2 Hz, 1H), 7.31 - 7.23 (m, 7H), 7.11 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 5.67 (s, 1H), 4.03 (td, J = 14.0 Hz, 7.2 Hz, 1H), 3.80 (td, J = 14.0 Hz, 6.8 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 169.5, 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, J = 283.8 Hz, 1C) 123.2, 109.4, 104.7, 56.7 (q, J = 27.3 Hz, 1C), 35.8, 11.9. 19F NMR(376MHz,CDCl3)δ-73.24(s,3F).HRMS(ESI-TOF)calcd.for C 28 H 21 F3NO3[M+H] + 476.1468; found: 476.1472.

[0103] Product 3q characterization data: 1 H NMR (400MHz, CDCl3) 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),6.99(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, CDCl3) δ169.8,166.7,151.7,148.4,144.1,130.5,130.1,129.5,129.4,129.3,129.1,128.6,128.5,1 27.4,125.6,125.2,124.3(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(376MHz,CDCl3)δ-73.27(s,3F).HRMS(ESI-TOF)calcd.for C 29 H 23 F3NO3[M+H] + 490.1625; found: 490.1624.

[0104] Product 3r characterization data: 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) δ167.0,166.7,159.3,151.7,148.5,143.7,130.4,130.2,129.4,129.3,129.1,128.6,128.5,128.4,12 7.5,126.9,125.4,125.0,124.3(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(376MHz,CDCl3)δ-73.27(s,3F).HRMS(ESI-TOF)calcd.for C 34 H 25 F3NO4[M+H] + 568.1730; found: 568.1727.

[0105] Product 3s characterization data: 1 H NMR (400MHz, CDCl3) 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),3.8 1(dd,J=14.4Hz,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 (101MHz, CDCl3) δ169.9,166.7,151.7,148.4,144.2,130.5,130.1,129.5,129.4,129.3,129.2,128.6,128.5,12 8.2,127.4,125.6,125.2,124.3(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(376MHz,CDCl3)δ-73.31(s,3F).HRMS(ESI-TOF)calcd.for C 30 H 23 F3NO3[M+H] + 502.1625; found: 502.1625.

[0106] Product 3t characterization data:1 1H NMR (400 MHz, CDCl3) δ 7.53 - 7.45 (m, 3H), 7.37 - 7.22 (m, 11H), 7.17 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 5.09 (dd, J = 35.6 Hz, 16.0 Hz, 2H). 13 13C NMR (101 MHz, CDCl3) δ 169.7, 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, 125.4, 125.0, 124.3 (q, J = 284.8 Hz, 1C), 123.4, 122.7, 110.3, 104.3, 77.36, 56.7 (q, J = 28.3 Hz, 1C), 40.6. 19 19F NMR (376 MHz, CDCl3) δ -73.30 (s, 3F). HRMS (ESI-TOF) calcd. for C 31 H 21 F3NO3S [M + H] + 544.1189; found: 544.1193.

[0107] Characterization data of product 3u: 1 1H NMR (400 MHz, CDCl3): δ 7.26 - 7.21 (m, 4H), 7.13 (t, J = 7.6 Hz, 2H), 6.68 - 6.66 (m, 3H), 4.20 (t, J = 7.2 Hz, 1H), 3.88 (d, J = 5.2 Hz, 1H), 3.69 (s, 1H), 3.37 (d, J = 5.2 Hz, 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 13C NMR (101 MHz, CDCl3) δ 170.2, 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 NO3 [M + H] + 408.1594; found: 408.1597.

[0108] Product 3V characterization data: 1 H NMR (400MHz, CDCl3) δ7.43-7.38(m,5H),7.30-7.29(m,9H),7.25-7.21(m,3 H),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, CDCl3) δ176.8,167.5,150.4,149.12,144.1,140.2,131.8,130.0,129.8,129.3,129.2,129.1, 129.0,128.9,128.4,128.0,127.3,126.5,126.0,123.2,115.1,108.9,57.1,27.1.HRMS(ESI-TOF)calcd.for C 32 H 24 NO3[M+H] + 470.1751; found: 470.1754.

[0109] Product 3W characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ170.1,167.0,152.0,147.9,144.5,140.3,139.5,130.5,130.0,129.3,129.2,129.1,127.0,1 26.6,125.9,125.6,125.1,124.3(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,CDCl3)δ-73.06(s,3F).HRMS(ESI-TOF)calcd.forC 29 H 23 F3NO3[M+H] + 490.1625; found: 490.1623.

[0110] Product 3x characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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(376MHz,CDCl3)δ-72.99(s,3F).HRMS(ESI-TOF)calcd.for C 35 H 35 F3NO3[M+H] + 574.2564; found: 574.2566.

[0111] Examples 31-41:

[0112]

[0113] In a 4 mL dry reaction flask, 0.01 mmol Pd2(dba)3, 0.02 mmol ligand L8, 0.3 mmol K2CO3, 1.0 mmol diphenylcyclopropenone 2a, and 0.2 mmol N-2-iodophenylallylamine 4 were dissolved in 2 mL 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 purified by column chromatography to obtain product 5 (the results of the examples are shown in Table 3 below).

[0114]

[0115] Examples 42-45:

[0116]

[0117] In a 4 mL dry reaction flask, 0.01 mmol Pd2(dba)3, 0.02 mmol ligands L8 / L9, 0.3 mmol K2CO3, 1.0 mmol diphenylcyclopropenone 2a, and 0.2 mmol 2-iodophenyl-substituted olefin 4 were dissolved in 2 mL 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 purified by column chromatography to obtain product 5 (the results of the examples are shown in Table 4 below).

[0118]

[0119] The characterization data of products 5a-o in the examples are as follows:

[0120] Product 5a characterization data: 1 H NMR (400MHz, CDCl3) δ7.45-7.36(m,5H),7.28-7.24(m,5H),7.15-7.11(m,2H),6.73(t,J=7.6Hz,1 H), 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). 13 C NMR (101MHz, CDCl3) 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 NO2[M+H] + 394.1802; found: 394.1804.

[0121] Characterization data of product 5b: 1 H NMR (400MHz, CDCl3) 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) 13CNMR (101MHz, CDCl3) δ168.6,150.6,150.2,148.7,136.7,130.4,129.7,129.4,129.3,129.2, 129.1,128.8,128.4,128.3,125.4,122.6,121.6,117.9,107.6,65.8,45.0,42.6,26.6,11.8.

[0122] Product 5C characterization data: 1 H NMR (400MHz, CDCl3) 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),6.5 3(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 (101MHz, CDCl3) δ168.6,150.8,150.1,148.7,138.2,136.5,130.4,129.7,129.4,129.3,129.1,128.9,128.7,12 8.4,128.3,127.8,127.3,125.4,122.8,121.2,118.2,107.4,67.2,52.8,45.2,29.8,26.5.HRMS(ESI-TOF)calcd.for C 33 H 27 KNO2 [M+K] + 508.1673; found: 508.1659.

[0123] 5-day characterization data of the product: 1 H NMR (400MHz, CDCl3) 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=8.4Hz,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). 13C NMR (101MHz, CDCl3) δ172.3,158.2,147.6,142.1,131.3,130.5,130.4,130.3,129.5,129.3,129.0, 128.9,128.8,128.5,128.2,119.8,117.6,112.5,111.5,80.3,49.9,20.8.HRMS(ESI-TOF)calcd.for C 26 H 22 NO2[M+H] + 380.1645; found: 380.1644.

[0124] Product 5e characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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 NO2[M+H] + 408.1958; found: 408.1953.

[0125] 5f characterization data of the product: 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) δ168.6,150.3,150.2,148.5,136.4,134.3,130.4,129.6,129.4,129.3,129.2,129.1,12 8.8,128.4,126.3,125.3,123.9,121.7,109.9,70.1,45.1,36.6,26.1,20.4,19.4.HRMS(ESI-TOF)calcd.forC 29 H 27 NNaO2[M+Na] + 444.1934; found: 444.1924.

[0126] Characterization data of 5g of product: 1 H NMR (400MHz, CDCl3) δ7.43-7.37(m,5H),7.28-7.26(m,5H),7.17(dd,J=4.8Hz,2.8Hz,2 H),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 (101MHz, CDCl3) δ168.6,150.2,149.8,148.6,141.6,136.5,130.5,129.7,129.4,129.3,129.2,129.0,128.9,1 28.4,125.3,124.9,121.7,119.8,107.4,70.0,45.5,36.3,34.4,31.9,29.9,26.1,1.2.HRMS(ESI-TOF)calcd.forC 31 H 31 NNaO2[M+Na] + 472.2247; found: 472.2247.

[0127] Product characterization data after 5 hours: 1 H NMR (400MHz, CDCl3) 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,1H),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). 13C NMR (101MHz, CDCl3) 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),1 10.2(d,J=24.2Hz,1C),108.1(d,J=9.1Hz,1C),70.0,45.2,36.6,26.0. 19 F NMR(376MHz,CDCl3)δ-126.41(m,1F).HRMS(ESI-TOF)calcd.forC 27 H 23 FNO2[M+H] + 412.1707; found: 412.1710.

[0128] Product 5i characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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, CDCl3)δ-60.40(s,3F).

[0129] Characterization data of product 5j: 11H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.48 - 7.41 (m, 3H), 7.37 - 7.35 (m, 2H), 7.28 - 7.25 (m, 5H), 6.34 (d, J = 8.8 Hz, 1H), 5.51 (s, 1H), 3.95 (d, J = 10.0 Hz, 1H), 3.80 (d, J = 10.0 Hz, 1H), 2.96 (s, 3H), 1.62 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 168.1, 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 = 12.1 Hz, 1C), 28.1 (d, J = 8.1 Hz, 1C). HRMS (ESI - TOF) calcd. for C 27 H 23 N2O4 [M + H] + 439.1652; found: 439.1652.

[0130] Characterization data of product 5k: 1 1H NMR (400 MHz, CDCl3) δ 7.46 - 7.36 (m, 5H), 7.28 - 7.24 (m, 5H), 6.99 (d, J = 7.6 Hz, 1H), 6.66 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 6.44 (d, J = 1.6 Hz, 1H), 5.53 (s, 1H), 3.56 (dd, J = 18.8 Hz, 9.2 Hz, 2H), 2.76 (s, 3H), 1.63 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 168.4, 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 ClNO2 [M + H] + 428.1412; found: 428.1414.

[0131] Characterization data of product 5L: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ175.1,167.2,164.3,149.8,149.0,143.7,134.1,129.9,129.4,129.3,129.2, 129.1,128.8,128.4,127.9,126.6,126.5,123.7,116.7,47.6,31.3,27.6.HRMS(ESI-TOF)calcd.for C 28 H 22 NO4[M+H] + 436.1543; found: 436.1546.

[0132] Product 5m characterization data: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ168.8,150.7,147.9,141.3,134.1,130.5,129.6,129.5,129.4,129.3,129.0,128.7 ,128.4,127.6,127.1,126.5,126.3,125.1,123.6,65.3,58.8,46.3,41.7,27.8.HRMS(ESI-TOF)calcd.for C 28 H 26 NO2[M+H] + 408.1958; found: 408.1959.

[0133] Product 5n characterization data: 1H NMR (400MHz, 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 (101MHz, CDCl3) δ168.5,150.4,150.0,140.7,133.3,130.4,129.6,129.4,129.3,129.1,128.8, 128.4,127.5,127.3,126.7,125.4,124.4,120.5,74.9,68.8,39.9,25.6.HRMS(ESI-TOF)calcd.for C 27 H 23 O3[M+H] + 395.1642; found: 395.1645.

[0134] Product 5O characterization data: 1 H NMR (400MHz, CDCl3) 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),6.83(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 (101MHz, CDCl3) δ168.2,159.0,149.7,149.2,134.4,130.2,129.8,129.4,129.2,129.1,129.0, 128.9,128.5,125.8,123.2,121.2,119.7,110.2,83.7,46.8,29.8,27.2.HRMS(ESI-TOF)calcd.ForC 26 H 21 O3[M+H] + 381.1485; found: 381.1486.

[0135] Examples 46-50:

[0136]

[0137] In a 4 mL dry reaction flask, 0.01 mmol Pd2(dba)3, 0.02 mmol ligand L8, 0.3 mmol K2CO3, 1.0 mmol diphenylcyclopropenone 2a, and 0.2 mmol N-substituted-2-(2-iodophenyl)indole derivative 6 were dissolved in 2 mL 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 purified by column chromatography to obtain product 7 (the results of the examples are shown in Table 5 below).

[0138]

[0139]

[0140] Characterization data of product 7a: 1 H NMR (400MHz, CDCl3) 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=5.6Hz,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 (101MHz, CDCl3) δ171.4,167.6,150.2,149.4,139.1,135.6,135.5,130.9,130.1,129.8,129.4,129.3,129.2,12 9.1,129.0,128.9,128.4,127.8,127.5,126.4,125.5,124.8,124.1,123.8,120.8,117.0,116.8,103.9,49.5,31.1.

[0141] Characterization data of product 7b: 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) 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.

[0142] Product 7c characterization data: 1 H NMR (400MHz, CDCl3) 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).

[0143] 7-day characterization data of the product: 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ171.4,167.4,150.2,149.2,139.3,136.8,133.9,132.2,130.4,130.1,129.9,129.5,129.4,12 9.3,129.2,129.1,128.9,128.4,127.9,127.5,126.5,125.5,124.3,123.3,120.3,117.7,116.8,102.9,49.2,31.1.

[0144] Product 7e characterization data: 1H NMR(400MHz, CDCl3)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), 7.15-7.12(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 (101MHz, CDCl3) δ168.2,150.0,149.8,139.3,137.3,137.2,135.0,129.7,129.4,129.3,129.2,129.1,129.0,1 28.9,128.4,128.1,127.9,127.8,125.9,125.7,125.0,122.1,120.8,120.1,118.7,109.2,97.2,50.6,41.6,25.0.

[0145] Antitumor activity verification:

[0146] Several heterocyclic substituted γ,δ-unsaturated butenolactone compounds prepared in the examples were selected, and their in vitro antitumor activity 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 (MTT colorimetric method).

[0147] The following description uses compound 3a from Example 7 as an example. The specific experimental procedures are as follows:

[0148] Experimental methods:

[0149] 1. Cell seeding: Prepare a single-cell suspension using culture medium (DMEM or RMPI1640) containing 10% fetal bovine serum. Seed 3,000 to 15,000 cells per well into a 96-well plate, with a volume of 100 μl per well. The cells should be seeded and cultured 12 to 24 hours in advance.

[0150] 2. Add the solution of the compound to be tested: Dissolve the compound in DMSO, and screen the compound at concentrations of 40 μM, 8 μM, 1.6 μM, 0.32 μM and 0.064 μM, with a final volume of 200 μL per well. Each treatment has 3 replicates.

[0151] 3. Color development: After culturing at 37°C for 48 hours, discard the culture medium in the wells of adherent cells, and add 20 μL of MTS solution and 100 μL of culture medium to each well; discard 100 μL of culture supernatant in the wells of suspended cells, and add 20 μL of MTS solution to each well; set up 3 blank replicates (a mixture of 20 μL of MTS solution and 100 μL of culture medium), and continue incubation for 2-4 hours to allow the reaction to proceed fully before measuring the absorbance.

[0152] 4. Colorimetric analysis: Select a wavelength of 492 nm, use a multi-functional microplate reader (MULTISKAN FC) to read the absorbance values ​​of each well, record the results, and after data processing, plot the cell growth curve with concentration as the x-axis and cell viability as the y-axis. Calculate the IC50 value of the compound using the Reed and Muench method.

[0153] 5. Positive control compounds: Two positive control compounds, doxorubicin (Dox) and paclitaxel (Taxol), were used in each experiment. Cell growth curves were plotted with concentration on the x-axis and cell viability on the y-axis. The IC50 of the compounds was calculated using the Reed-Muench method. 50 value.

[0154] Table 6 shows the inhibitory effects of some of the compounds in 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).

[0155]

[0156]

[0157] The results showed that the several heterocyclic-substituted γ,δ-unsaturated butenolactone compounds prepared in this invention exhibited varying degrees of inhibitory activity against human leukemia cells (HL-60), lung cancer cells (A549), liver cancer cells (HepG2), breast cancer cells (MDA-MB-231), and colon cancer cells (SW480). Compound 3a selectively showed good inhibitory activity against leukemia cells (HL-60), breast cancer cells (MDA-MB-231), and colon cancer cells (SW480). Compound 5n selectively showed good inhibitory activity against leukemia cells (HL-60) and colon cancer cells (SW480). Compounds 5m, 7a, and 7e all showed superior inhibitory activity against all five tumor cell types. In particular, compound 7e demonstrated superior inhibitory activity against leukemia cells (HL-60) and colon cancer cells (SW480) compared to the positive control, showing potential for further in-depth activity studies.

[0158] 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 1-9 As shown.

[0159] The above descriptions are merely embodiments of the present invention. Commonly known structures and characteristics of the solutions are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the structure of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A heterocyclic-substituted γ,δ-unsaturated butenolactone, characterized in that, Its general structural formula is as follows: In the formula, the heterocyclic skeleton can be independently represented as a benzo5-membered nitrogen heterocyclic skeleton, a benzo6-membered nitrogen heterocyclic skeleton, a benzo5-membered oxygen heterocyclic skeleton, a benzo6-membered oxygen heterocyclic skeleton, or a fused heterocyclic skeleton, and the dashed line indicates its presence or absence; (1) When the heterocyclic skeleton is a benzo[5] nitrogen heterocyclic skeleton, it has the following two general formulas: General Formula 1: ， R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl; R 3 It is independently selected from methyl, ethyl, n-propyl, benzyl, p-methoxybenzyl, cyclopropylmethyl or 3-thiophenemethyl; 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 Each is independently selected from hydrogen, methyl, ethyl, or phenyl; R 3 It is 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 benzohexa-nitrogen heterocyclic skeleton, it has the following two general formulas: ， ， R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, or phenyl; Accordingly, R 3 It is 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 benzo5-membered oxygen heterocyclic skeleton, it has the following general formula: ， R 1 R 2 Each is 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-6-membered oxygen heterocyclic skeleton, it has the following general formula: ， R 1 R 2 Each is 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 fused heterocyclic skeleton, it has the following two general formulas: ， ， R 1 R 2 Each is 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.

2. The heterocyclic substituted γ,δ-unsaturated butenolactone according to claim 1, characterized in that, Its structural formula is as follows: 。 3. The use of the heterocyclic substituted γ,δ-unsaturated butenolactone according to claim 1 or 2 in the preparation of antitumor drugs, characterized in that, The tumors mentioned include leukemia, lung cancer, liver cancer, breast cancer, or colon cancer.

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