阅读说明：本技术 具有螺三环骨架的双二氢呋喃并吡咯酮衍生物的合成方法 (Synthesis method of dihydrofuropyrrolone derivative with spirotricyclic framework ) 是由 刘慧敏 王坤 缪春宝 杨海涛 吕新宇 陈新 于 2021-06-30 设计创作，主要内容包括：本发明属于有机合成技术领域,具体涉及一种具有螺三环骨架的双二氢呋喃并吡咯酮衍生物的合成方法。以丙二酸酯取代的O-酰基肟与双分子环状1,3-二羰基化合物为原料,铜盐做催化剂,在有机溶剂和外加氧化剂条件下进行反应,首次制备出具有螺三环骨架的双二氢呋喃并吡咯酮衍生物。具有选用的原料简单易得、催化剂廉价易得、操作简单、底物适用性好、官能团容忍性好等优点。除此之外,该方法普适性广、反应条件温和、合成路线短、应用前景广阔。在合成具有螺三环骨架的双二氢呋喃并吡咯酮衍生物的方法上有极高的应用价值。合成的化合物对Hep具有良好的选择性和生物活性。(The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a dihydrofuropyrrolopyrrole derivative with a spirotricyclic framework. The method comprises the steps of taking malonate substituted O-acyl oxime and bimolecular cyclic 1, 3-dicarbonyl compounds as raw materials, taking copper salt as a catalyst, and reacting under the conditions of an organic solvent and an external oxidant to prepare the dihydrofuropyrrolone derivative with a spirotricyclic framework for the first time. The method has the advantages of simple and easily-obtained raw materials, cheap and easily-obtained catalyst, simple operation, good substrate applicability, good functional group tolerance and the like. In addition, the method has the advantages of wide universality, mild reaction conditions, short synthetic route and wide application prospect. Has extremely high application value in the method for synthesizing the dihydrofuropyrrolone derivative with the spirotricyclic framework. The synthesized compound has good selectivity and bioactivity on Hep.)

1. A synthetic method of a dihydrofuropyrrolone derivative with a spirotricyclic framework is characterized in that: the synthesis method comprises the following steps: copper salt is used as a catalyst, O-acyl oxime substituted by malonate and a cyclic 1, 3-dicarbonyl compound are used as raw materials to react in a solvent, and the dihydrofuropyrrolone derivative with a spirotricyclic framework is obtained after separation and purification.

2. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the copper salt catalyst is selected from one of copper acetate, cuprous chloride, cuprous bromide, cuprous iodide, copper trifluoroacetate and copper trifluoromethanesulfonate.

3. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the organic solvent is one of acetonitrile, dioxane, 1, 2-dichloroethane, ethylene glycol dimethyl ether, N-dimethylformamide and dimethyl sulfoxide.

4. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: if a catalytic amount of copper salt is used, an additional oxidizing agent is required for the reaction, and the oxidizing agent is tert-butyl peroxide.

5. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the molar ratio of the malonate substituted O-acyl oxime to the cyclic 1, 3-dicarbonyl compound to the copper salt catalyst to the oxidant is 1.0:1.0-2.0:0.2-2.5:0-3.0, and the reaction temperature is 60-80 ℃.

6. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the malonate substituted O-acyl oxime has a general formula shown in 1:

wherein R is¹Selected from alkyl, phenyl, and various substituted phenyl; unsubstituted or substituted heterocycle; wherein, the substituent on the phenyl is selected from methyl, methoxy, bromine atom, chlorine atom, fluorine atom, nitro and trifluoromethyl; the substituents of the heterocyclic ring are selected from bromine atoms.

7. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the cyclic 1, 3-dicarbonyl compound is selected from daminone, 1, 3-cyclohexanedione, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione, 5-methyl-1, 3-cyclohexanedione, 1, 3-cyclopentanedione, 1, 3-cycloheptanedione, 1, 3-indanedione, 4-hydroxyacetoacetate lactone, acetylacetone and dibenzoyl methane.

8. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the structural general formula of the dihydrofuropyrrolopyrrole derivative with the spirotricyclic framework is shown as the following formula:

wherein R is selected from alkyl, phenyl and various substituted phenyl; unsubstituted or substituted heterocycle; wherein, the substituent on the phenyl is selected from methyl, methoxy, bromine atom, chlorine atom, fluorine atom, nitro and trifluoromethyl; the substituents of the heterocyclic ring are selected from bromine atoms.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a dihydrofuropyrrolopyrrole derivative with a spirotricyclic framework based on O-acyl oxime and a cyclic 1, 3-dicarbonyl compound under the catalysis of copper salt.

Background

O-acyloximes are readily obtained from the corresponding carbonyl compounds, and the N-O bond is very easily broken, so O-acyloximes have very high reactivity. In the last decade, O-acyloximes have proven to be a very efficient organic synthon, which can be used to prepare a variety of nitrogen-containing heterocyclic compounds, such as pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole and pyridine, under the catalysis of transition metals such as ruthenium, rhodium, palladium, copper and the like.

Natural products extracted from plants are an important source of drug discovery, and thus chemists have invested a great deal of time and effort in the synthesis of natural products. The dihydrofuropyrrolopyrrole ketone skeleton derivative is a novel spirotricyclic skeleton structure, and no compound with the structure is reported so far, and the spirotricyclic skeleton structure has crowded quaternary carbon centers, so that great challenges are generated in the synthesis of the spirotricyclic skeleton derivative. Similar spirotricyclic framework structures are found in many natural products, for example (—) syringolactone 1[ j. org. chem.1993,58, 2940-; j.org.chem.1997,62, 4780-4784), ascorbyl terpenoid A-D compounds [ J.am.chem.Soc.2018,140,2485-2492] and Incarviditone [ chem.Biodiversity.2009,6, 779-783; org.Lett.2012,14,4878-4881 ]. Syringolactone is a very specific molecule both chemically and biologically, as evidenced by their structure and their role as non-protein selective factors of plant allergy. The ascorbyl terpenoid A-D compounds have unique chemical structures and biological activities. The dihydrofuropyrrolone derivative with spirotricyclic framework has unprecedented structure and potential biological activity, and is expected to make contribution to the aspects of treatment medicines of metabolic disorder and cardiovascular diseases.

Disclosure of Invention

The invention discloses a method for preparing a dihydrofuropyrrolone derivative with a spirotricyclic framework by reacting in an organic solvent under the conditions of taking malonate substituted O-acyl oxime and a bimolecular cyclic 1, 3-dicarbonyl compound as raw materials, taking copper salt as a catalyst and adding an oxidant, and provides a novel method for synthesizing the dihydrofuropyrrolone derivative with the spirotricyclic framework.

The invention aims to provide a dihydrofuropyrrolopyrrole ketone derivative with a spirotricyclic framework. They have stable molecular structure, excellent chemical property and potential bioactivity.

In order to achieve the above purpose, the structural general formula of the dihydrofuropyrrolopyrrole derivative with spirotricyclic framework provided by the invention is shown as 3:

wherein R is selected from alkyl, phenyl and various substituted phenyl; unsubstituted or substituted heterocycle; wherein, the substituent on the phenyl is selected from methyl, methoxy, bromine atom, chlorine atom, fluorine atom, nitro and trifluoromethyl; the substituents of the heterocyclic ring are selected from bromine atoms.

Wherein the cyclic 1, 3-dicarbonyl compound is selected from the group consisting of daminone, 1, 3-cyclohexanedione, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione, 5-methyl-1, 3-cyclohexanedione, 1, 3-cyclopentanedione, 1, 3-cycloheptanedione, 1, 3-indanedione, 4-hydroxyacetoacetate lactone, acetylacetone, and dibenzoylmethane.

It is still another object of the present invention to provide a compact method for synthesizing dihydrofuropyrrolopyrrole derivatives having spirotricyclic skeleton. The method has the advantages of simple and easily obtained raw materials, low catalyst price, good functional group tolerance, good substrate adaptability and simple operation steps. In addition, the method also has the advantages of mild reaction conditions, short synthetic route, convenient post-treatment, wide application prospect and the like, and has important application value in the method for synthesizing the dihydrofuropyrrolone derivative with the spirotricyclic framework.

The synthesis method of the dihydrofuropyrrolopyrrole ketone skeleton derivative provided by the invention specifically comprises the following steps: copper salt is used as a catalyst, O-acyl oxime substituted by malonate and a cyclic 1, 3-dicarbonyl compound are used as raw materials, the raw materials react in a solvent, and a product is obtained after purification. The reaction process is as follows:

the copper salt catalyst is selected from one of cupric acetate, cuprous chloride, cuprous bromide, cuprous iodide, cupric trifluoroacetate and copper trifluoromethanesulfonate.

If a catalytic amount of copper salt is used, an additional oxidizing agent is required for the reaction, and the oxidizing agent is tert-butyl peroxide.

The organic solvent is one of acetonitrile, dioxane, 1, 2-dichloroethane, ethylene glycol dimethyl ether, N-dimethylformamide and dimethyl sulfoxide.

The molar ratio of the malonate substituted O-acyl oxime to the cyclic 1, 3-dicarbonyl compound to the copper salt catalyst to the external oxidant is 1.0:1.0-2.0:0.2-2.5:3.0, and the reaction temperature is 60-80 ℃.

Malonate substituted O-acyloximes have the general formula 1:

wherein R is¹Selected from alkyl, phenyl, and various substituted phenyl; unsubstituted or substituted heterocycle; wherein, the substituent on the phenyl is selected from methyl, methoxy, bromine atom, chlorine atom, fluorine atom, nitro and trifluoromethyl; the substituents of the heterocyclic ring are selected from bromine atoms.

The cyclic 1, 3-dicarbonyl compound is selected from the group consisting of daminone, 1, 3-cyclohexanedione, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione, 5-methyl-1, 3-cyclohexanedione, 1, 3-cyclopentadione, 1, 3-cycloheptanedione, 1, 3-indanedione, 4-hydroxyacetoacetate lactone, acetylacetone, and dibenzoylmethane.

The invention has the beneficial effects that: the malonate-substituted O-acyl oxime and bimolecular cyclic 1, 3-dicarbonyl compound are used as raw materials, copper salt is used as a catalyst, a proper oxidant is added, the reaction is carried out in an organic solvent, five new chemical bonds are constructed through one-step reaction, and the simple synthesis of the dihydrofuropyrrolone derivative with the spirotricyclic framework is realized for the first time. The O-acyl oxime substituted by malonate which is simple and easy to obtain is used as a pyrrolidon precursor with an ortho-position amphiphilic center, and a cyclic 1, 3-dicarbonyl compound is used as a nucleophilic reagent with a double nucleophilic site, so that the reaction can be smoothly carried out. The invention has the characteristics of simple and easily obtained raw materials, cheap and easily obtained catalyst, good functional group tolerance, mild reaction conditions, short synthetic route and the like.

The invention adopts an MTT method to carry out anti-cancer activity test on three typical compounds, and the result shows that the compounds 3ba and 3ca have better inhibition effect and selectivity on HepG2 when the compounds are at 50 mu M.

Drawings

FIGS. 1 and 2 show Compound 3aa¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 3 and 4 show Compound 3ba¹H-NMR(400MHz,CDCl₃) Spectrogram and¹³C-NMR(100MHz,CDCl₃) A spectrogram;

FIGS. 5 and 6 show Compound 3ca¹H-NMR(400MHz,CDCl₃) Spectrogram and¹³C-NMR(100MHz,CDCl₃) A spectrogram;

FIGS. 7 and 8 show Compound 3da¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 9 and 10 show Compound 3ea¹H-NMR(400MHz,CDCl₃) Spectrogram and¹³C-NMR(100MHz,CDCl₃) A spectrogram;

FIGS. 11 and 12 show the compound 3fa¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 13 and 14 are schematic illustrationsCompound 3ga¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 15 and 16 are views of Compound 3ha¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile;

FIGS. 17 and 18 are of Compound 3ia¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile;

FIGS. 19 and 20 are of Compound 3ja¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 21 and 22 shows Compound 3ka¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 23 and 24 are of Compound 3la¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 25 and 26 are of compound 3ma¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 27 and 28 are views of Compound 3na¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile;

FIGS. 29 and 30 are of Compound 3oa¹H-NMR(300MHz,CDCl₃) Spectrogram and¹³C-NMR(75MHz,CDCl₃) A spectrogram;

FIGS. 31 and 32 are views of Compound 3pa¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile;

FIGS. 33 and 34 are of Compound 3ab¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile.

FIGS. 35 and 36 for Compound 3bb¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile.

FIGS. 37 and 38 show the compounds 3eb¹H-NMR(400MHz,d₆-DMSO) profile and¹³C-NMR(100MHz, d₆-DMSO) profile.

Detailed Description

The invention is further illustrated and described below by means of specific embodiments, without being limited thereto.

Example 1

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3aa in 65% yield.

The resulting product was tested using the following equipment: AVANCE 300MHz NMR spectrometer (Bruker, TMS as internal standard); SGW X-4 micro melting point apparatus (thermometer uncorrected). The following examples were tested in the same manner as the present examples.

3aa(white solid,73.9mg,65％,mp 224-226℃):¹H NMR(300MHz,D6-DMSO)δ7.59(br, 1H),7.36-7.46(m,3H),7.25-7.32(m,2H),4.00-4.18(m,2H),2.58(s,2H),2.29(s,2H),2.25(d,J ＝16.0Hz,1H),2.15(d,J＝16.0Hz,1H),2.01(d,J＝18.0Hz,1H),1.33(d,J＝18.0Hz,1H), 1.18-1.24(m,9H),1.06(s,1H),0.91(s,1H)；¹³C NMR(75MHz,D6-DMSO)δ193.0,191.9,179.1, 175.9,170.4,166.9,133.2,130.2,128.6,126.6,111.7,107.8,105.6,102.5,64.3,62.7,51.7,51.5, 38.2,37.2,34.0,33.7,29.3,28.7,28.6,27.5,13.8；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₂NO₇ 506.2179,found 506.2177.

Example 2

Mixing oxime ester 1b (0.3mmol) of diethyl malonate substituted 4-methoxyacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ba in 54% yield.

3ba(white solid,65.1mg,54％,mp 209-211℃):¹H NMR(400MHz,D6-DMSO)δ7.19(d,J ＝8.9Hz,2H),7.03(br,1H),6.90(d,J＝8.9Hz,2H)，4.14(dq,J＝10.7,7.2Hz,1H),4.06(dq,J＝ 10.7,7.2Hz,1H),3.83(s,3H),2.58(d,J＝18.3Hz,1H),2.53(d,J＝18.3Hz,1H),2.28(s,2H), 2.27(d,J＝16.0Hz,1H),2.17(d,J＝16.0Hz,1H),2.07(d,J＝17.8Hz,1H),1.45(d,J＝17.8Hz, 1H),1.22(t,J＝7.3Hz,3H),1.22(s,3H),1.20(s,3H),1.07(s,3H),0.94(s,3H)；¹³C NMR(100 MHz,d₆-DMSO)δ192.3,190.6,179.2,174.9,169.1,166.5,160.3,128.0,125.2,113.6,111.2, 106.8,106.0,101.6,63.8,61.4,55.4,51.2,50.8,37.0,36.3,33.4,33.2,28.7,28.5,27.2,26.7,13.6； HRMS(ESI)m/z[M+H]⁺Calcd for C₃₀H₃₄NO₈ 536.2284,found 536.2280.

Example 3

Mixing oxime ester 1c (0.3mmol) of diethyl malonate substituted 4-methylacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO (Φ 18X 150mm, dry tube with calcium chloride attached to the top of the tube) were placed in a 60 deg.C oil bath and stirred 0And 5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ca in 61% yield.

3ca(white solid,70.9mg,61％,mp 211-213℃):¹H NMR(400MHz,D6-DMSO)δ7.20(d,J ＝8.3Hz,2H)，7.14(d,J＝8.3Hz,2H),6.91(br,1H),4.15(dq,J＝10.7,7.2Hz,1H),4.06(dq,J ＝10.7,7.2Hz,1H),2.59(d,J＝18.1Hz,1H),2.54(d,J＝18.1Hz,1H),2.39(s,3H),2.29(s,2H), 2.27(d,J＝16.0Hz,1H),2.16(d,J＝16.0Hz,1H),2.05(d,J＝17.8Hz,1H),1.41(d,J＝17.9Hz, 1H),1.23(t,J＝7.2Hz,3H),1.22(s,3H),1.21(s,3H),1.07(s,3H),0.94(s,3H)；¹³C NMR(75 MHz,D6-DMSO)δ193.0,191.9,179.0,176.0,170.3,166.9,140.2,130.2,129.2,126.5,111.6, 107.8,105.7,102.4,64.3,62.7,51.7,51.4,38.2,37.3,33.9,33.7,29.4,28.7,28.6,27.4,21.4,13.8； HRMS(ESI)m/z[M+H]⁺Calcd for C₃₀H₃₄NO₇ 520.2335,found 520.2328.

Example 4

Mixing oxime ester 1d (0.3mmol) of diethyl malonate substituted 4-fluoro acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3da in 45% yield.

3da(white solid,53.3mg,45％,mp 222-223℃):¹H NMR(300MHz,D6-DMSO)δ7.58(br, 1H),7.32(dd,J＝8.8,5.1Hz,2H),7.09(t,J＝8.5Hz,2H),4.00-4.19(m,2H),2.57(s,2H),2.29(s, 2H),2.26(d,J＝15.9Hz,1H),2.18(d,J＝15.9Hz,1H),2.06(d,J＝17.9Hz,1H),1.42(d,J＝ 18.2,1H),1.18-1.25(m,9H),1.07(s,3H),0.94(s,3H)；¹³C NMR(75MHz,D6-DMSO)δ193.0, 192.4,179.0,175.9,170.4,166.9,165.3,163.7(d,J¹ _C-F＝250.3Hz),129.1(d,J⁴ _C-F＝3.2Hz), 129.0(d,J³ _C-F＝8.6Hz),115.5(d,J² _C-F＝21.9Hz),111.8,107.7,105.6,102.2,64.3,62.6,51.7, 51.4,38.2,37.2,33.9,33.7,29.3,28.7,28.5,27.3,13.8；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₁FNO₇ 524.2085,found 524.2080.

Example 5

Mixing oxime ester 1e (0.3mmol) of diethyl malonate substituted 4-chloroacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ea in 40% yield.

3ea(white solid,48.6mg,40％,mp 224-225℃):¹H NMR(400MHz,D6-DMSO)δ7.54(br, 1H),7.38(d,J＝8.6Hz,2H),7.27(d,J＝8.6Hz,2H),4.01-4.17(m,2H),2.57(s,2H),2.29(s, 2H),2.26(d,J＝15.8Hz,1H),2.19(d,J＝15.8Hz,1H),2.06(d,J＝18.0Hz,1H),1.44(d,J＝ 18.0,1H),1.18-1.25(m,9H),1.07(s,3H),0.95(s,3H)；¹³C NMR(100MHz,D6-DMSO)δ193.0, 192.4,179.0,175.9,170.3,166.9,136.3,131.9,128.7,128.4,111.8,107.8,105.4,102.4,64.4,62.7, 51.7,51.4,38.2,37.3,33.9,33.8,29.4,28.8,28.5,27.3,13.8；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₁ClNO₇ 540.1789,found 540.1788.

Example 6

The oxime ester 1f (0.3mmol) of diethyl malonate substituted 4-bromoacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 4 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum.

The residue was purified by column chromatography to give 3fa in 43% yield.

3fa(white solid,56.8mg,43％,mp 211-213℃):¹H NMR(300MHz,D6-DMSO)δ7.56(br, 1H),7.54(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),4.00-4.19(m,2H),2.57(s,2H),2.29(s, 2H),2.26(d,J＝15.8Hz,1H),2.19(d,J＝15.8Hz,1H),2.06(d,J＝18.1Hz,1H),1.44(d,J＝ 18.1,1H),1.19-1.24(m,9H),1.07(s,3H),0.95(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ192.3, 190.6,179.2,174.7,169.1,166.4,132.9,131.4,128.8,123.3,111.2,106.8,105.3,101.7,63.9,61.5, 51.1,50.8,36.9,36.3,33.4,33.3,28.7,28.6,27.1,26.6,13.6；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₁BrNO₇ 584.1284,found 584.1283.

Example 7

1g (0.3mmol) of oxime ester of diethyl malonate substituted 4-nitroacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 2 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum.

The residue was purified by column chromatography to give 3ga in 35% yield.

3ga(white solid,43.6mg,35％,mp 251-253℃):¹H NMR(300MHz,D6-DMSO)δ7.26(d,J ＝8.9Hz,2H),7.91(br,1H),7.67(d,J＝8.9Hz,2H),4.00-4.19(m,2H),2.63(d,J＝18.3Hz, 1H),2.57(d,J＝18.3Hz,1H),2.31(s,2H),2.26(d,J＝16.3Hz,1H),2.21(d,J＝16.3Hz,1H), 2.03(d,J＝17.8Hz,1H),1.37(d,J＝17.9Hz,1H),1.18-1.26(m,9H),1.05(s,3H),0.94(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ192.3,190.7,179.2,174.8,169.1,166.3,148.5,140.4,128.2, 123.6,111.2,106.8,104.9,102.1,64.1,61.6,51.1,50.8,36.9,36.2,33.4,33.4,28.6,28.6,27.0, 26.6,13.6；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₁N₂O₉551.2030,found 551.2024.

Example 8

Mixing oxime ester of diethyl malonate substituted 4-trifluoromethyl acetophenone for 1h (0.3mmol), daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and mixing the above with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ha in 47% yield.

3ha(white solid,60.4mg,47％,mp 251-253℃):¹H NMR(400MHz,d₆-DMSO)δ10.31(s, 1H),7.86(d,J＝8.3Hz,2H),7.50(d,J＝8.3Hz,2H),3.86-3.99(m,2H),2.86(d,J＝18.1Hz, 1H),2.58(d,J＝18.1Hz,1H),2.31(d,J＝16.0Hz,1H),2.17(d,J＝15.0Hz,1H),2.13(d,J＝ 16.0Hz,1H),2.07(t,J＝15.0,1H),2.03(t,J＝18.0,1H),1.18(d,J＝18.0Hz,1H),1.13(s,3H), 1.12(s,3H),1.11(t,J＝7.1Hz,3H),0.96(s,3H),0.83(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ 192.3,190.6,179.3,174.6,169.1,166.3,138.0,130.2(d,J² _C-F＝32.0Hz),127.7,125.3,125.3(d, J³ _C-F＝3.5Hz),123.9(d,J¹ _C-F＝272.6Hz),111.3,106.8,105.0,102.0,63.9,61.6,51.1,50.8,36.9, 36.2,33.4,33.2,28.7,28.5,27.1,26.6,13.6；HRMS(ESI)m/z[M+H]⁺Calcd for C₃₀H₃₁F₃NO₇ 574.2053,found 574.2049.

Example 9

Mixing oxime ester 1i (0.3mmol) of diethyl malonate substituted 4-oxyacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 1.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ia in 45% yield.

3ia(white solid,57.5mg,45％,mp 226-228℃):¹H NMR(400MHz,d₆-DMSO)δ10.20(s, 1H),7.28(d,J＝8.7Hz,2H),7.13(d,J＝8.7Hz,2H),3.84-3.99(m,2H),2.83(d,J＝18.0Hz, 1H),2.56(d,J＝18.1Hz,1H),2.29(d,J＝15.9Hz,1H),2.28(s,3H),2.12(d,J＝15.9Hz,1H), 2.10(d,J＝15.3Hz,1H),2.05(d,J＝15.3Hz,1H),2.00(d,J＝18.0Hz,1H),1.28(d,J＝17.8Hz, 1H),1.12(s,3H),1.11(s,3H),1.11(t,J＝7.2Hz,3H),0.96(s,3H),0.85(s,3H)；¹³C NMR(100 MHz,d₆-DMSO)δ192.3,190.6,179.4,174.8,169.2,169.0,166.4,151.6,130.8,128.1,121.9, 111.3,106.8,105.4,101.7,63.7,61.5,51.1,50.8,36.1,33.4,33.1,28.6,28.5,27.1,26.7,20.8,13.6； HRMS(ESI)m/z[M+H]⁺Calcd for C₃₁H₃₄NO₉564.2234,found 564.2232.

Example 10

Mixing oxime ester 1j (0.3mmol) of diethyl malonate substituted 4-phenylacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ja in 52% yield.

3ja(white solid,68.1mg,52％,mp 211-213℃):¹H NMR(300MHz,D6-DMSO)δ7.63(d,J ＝8.4Hz,2H),7.59(d,J＝7.3Hz,2H),7.48(t,J＝7.3Hz,2H),7.40(t,J＝7.2Hz,1H),7.35(d,J ＝8.3Hz,2H),7.12(br,1H),4.01-4.20(m,2H),2.62(d,J＝18.2Hz,1H),2.56(d,J＝18.2Hz, 1H),2.30(s,2H),2.28(d,J＝16.1Hz,1H),2.17(d,J＝16.1Hz,1H),2.06(d,J＝17.9Hz,1H), 1.41(d,J＝17.9Hz,1H),1.19-1.27(m,9H),1.06(s,3H),0.92(s,3H)；¹³C NMR(75MHz, d₆-DMSO)δ192.2,190.5,179.3,174.8,169.1,166.5,141.4,139.1,132.5,129.1,128.0,127.2, 126.8,126.5,111.3,106.9,105.7,101.8,63.9,61.4,51.1,50.8,37.0,36.3,33.4,33.2,28.6,28.5, 27.2,26.7,13.6；HRMS(ESI)m/z[M+H]⁺Calcd for C₃₅H₃₆NO₇ 582.2492,found 582.2483.

Example 11

Mixing oxime ester 1k (0.3mmol) of diethyl malonate substituted 3-nitroacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 4 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum.

The residue was purified by column chromatography to give 3ka in 37% yield.

3ka(white solid,45.5mg,37％,mp 193-195℃):¹H NMR(300MHz,D6-DMSO)δ8.31 (ddd,J＝8.2,2.2,1.0Hz,1H),8.18(t,J＝1.9Hz,2H),7.87(br,1H),7.84(ddd,J＝7.8,1.7,1.1 Hz),7.64(t,J＝8.0Hz,1H),4.00-4.19(m,2H),2.67(d,J＝18.2Hz,1H),2.58(d,J＝18.2Hz, 1H),2.34(d,J＝16.5Hz,1H),2.29(d,J＝16.5Hz,1H),2.28(d,J＝16.3Hz,1H),2.22(d,J＝ 16.3Hz,1H),2.04(d,J＝18.0Hz,1H),1.37(d,J＝18.0Hz,1H),1.24(s,6H),1.21(t,J＝7.2Hz, 3H),1.06(s,3H),0.93(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ192.4,190.6,179.3,174.6,169.1, 166.2,147.7,135.6,133.6,130.5,125.1,120.8,111.2,106.8,104.7,101.9,63.9,61.7,51.0,50.7, 36.9,36.1,33.5,33.2,28.6,28.1,27.0,26.8,13.6；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₁N₂O₉ 551.2030,found 551.2028.

Example 12

1l (0.3mmol) of oxime ester of diethyl malonate substituted 2-fluoroacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3la in 54% yield.

3la(white solid,63.9mg,54％,mp 240-242℃):¹H NMR(300MHz,D6-DMSO)δ7.70(br, 1H),7.35-7.49(m,2H),7.17(t,J＝7.7Hz,1H),7.10(dd,J＝11.2,8.1Hz,1H),4.01-4.19(m,2H), 2.53(d,J＝18.1Hz,1H),18.2(d,J＝18.1Hz,1H),2.32(d,J＝16.3Hz,1H),2.26(d,J＝16.3Hz, 1H),2.22(d,J＝16.0Hz,1H),2.11(d,J＝17.9Hz,1H),2.09(d,J＝16.0Hz,1H),1.28(d,J＝ 18.1Hz,1H),1.21(t,J＝7.2Hz,3H),1.20(s,3H),1.19(s,3H),1.03(s,3H),0.80(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ192.2,190.5,178.8,174.9,168.6,166.2,160.5(d,J¹ _C-F＝251.6Hz), 132.8(d,J³ _C-F＝8.6Hz),128.3,124.3(d,J³ _C-F＝2.4Hz),120.6(d,J² _C-F＝11.4Hz),116.3(d,J² _C-F＝22.1Hz),110.8,107.1,104.6,101.5,63.7,61.5,51.0,50.8,37.1,36.1,33.7,33.0,28.2,27.9,27.4, 27.1,13.7；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₁FNO₇ 524.2085,found 524.2083.

Example 13

1m (0.3mmol) of oxime ester of diethyl malonate substituted 2, 4-dichloroacetophenone, 2a (0.45mmol) of daminone, Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 4 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ma in 45% yield.

3ma(white solid,58.5mg,45％,mp 223-225℃):¹H NMR(300MHz,D6-DMSO)δ7.69(br, 1H),7.67(d,J＝8.7Hz,1H),7.46(d,J＝2.1Hz,1H),7.31(dd,J＝8.6,2.1Hz,1H),4.06-4.16(m, 2H),2.54(d,J＝18.5Hz,1H),2.47(d,J＝18.5Hz,1H),2.34(d,J＝16.0Hz,1H),2.26(d,J＝ 16.2Hz,1H),2.08-2.24(m,3H),1.33(d,J＝17.9Hz,1H),1.22(t,J＝7.2Hz,3H),1.21(s,3H), 1.18(s,3H),1.05(s,3H),0.85(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ192.4,190.6,179.1, 174.9,168.2,166.2,135.7,134.8,131.0,130.9,129.6,127.3,110.7,108.1,104.7,101.9,63.7,61.6, 51.0,50.7,37.2,36.2,33.7,33.1,28.4,28.1,27.7,26.9,13.7；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₉H₃₀Cl₂NO₇ 574.1399,found 574.1398.

Example 14

Mixing oxime ester 1n (0.3mmol) of diethyl malonate substituted 2, 4-dimethylacetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in tubes (. phi.18X 150mm, dry tubes containing calcium chloride were connectedTo the top of the tube), stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3na in 64% yield.

3na(white solid,77.1mg,64％,mp 230-231℃):¹H NMR(400MHz,d₆-DMSO)δ10.14(s, 1H),7.09(s,1H),7.06(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,1H),3.96(dq,J＝10.7,7.2Hz,1H), 3.85(dq,J＝10.7,7.2Hz,1H),2.64(d,J＝18.5Hz,1H),2.59(d,J＝18.5Hz,1H),2.18-2.30(m, 8H),2.04(d,J＝18.0,1H),2.03(d,J＝15.7,1H),1.89(d,J＝15.7Hz,1H),1.08-1.14(m,9H), 0.93(s,3H),0.92(d,J＝18.0Hz,1H),0.70(s,3H)；¹³C NMR(100MHz,d₆-DMSO)δ192.3, 190.5,178.7,175.0,168.0,166.4,139.5,137.8,132.8,128.2,127.7,126.0,110.8,108.3,106.6, 101.4,63.4,61.4,51.1,50.7,37.2,36.1,33.6,32.9,28.6,27.9,27.8,26.7,20.7,20.4,13.7；HRMS (ESI)m/z[M+H]⁺Calcd for C₃₁H₃₆NO₇ 534.2492,found 534.2482.

Example 15

Replacement of Oxime ester of diethyl malonate substituted 5-bromo-2-acetylthiophene 1o (0.3mmol), daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. PHI.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 3 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum.

The residue was purified by column chromatography to give 3oa in 47% yield.

3oa(white solid,62.7mg,47％,mp 214-217℃):¹H NMR(300MHz,D6-DMSO)δ7.39(br, 1H),7.00(d,J＝3.9Hz,1H),6.92(d,J＝3.9Hz,1H),4.14(dq,J＝10.7,7.2Hz,1H),4.04(dq,J＝ 10.7,7.2Hz,1H),2.52(s,2H),2.22-2.33(m,4H),2.22(d,J＝18.0Hz,1H),1.78(d,J＝18.0Hz, 1H),1.22(t,J＝7.2Hz,3H),1.20(s,3H),1.18(s,3H),1.12(s,3H),1.03(s,3H)；¹³C NMR(100 MHz,d₆-DMSO)δ192.2,190.5,178.4,175.2,169.0,166.2,138.1,131.1,128.7,114.0,111.3, 106.7,103.5,101.4,64.0,61.6,51.1,50.7,36.8,36.5,33.5,33.4,28.6,28.2,27.2,26.7,13.6； HRMS(ESI)m/z[M+H]⁺Calcd for C₂₇H₂₉BrNO₇S 590.0848,found 590.0848.

Example 16

Mixing oxime ester 1p (0.3mmol) of diethyl malonate substituted 2-acetylfuran, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 4 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum.

The residue was purified by column chromatography to give 3pa in 33% yield.

3pa(white solid,36.6mg,33％,mp 191-193℃):¹H NMR(400MHz,d₆-DMSO)δ10.23(s, 1H),7.82(dd,J＝1.8,0.8Hz,1H),6.58(dd,J＝3.4,0.8Hz,1H),6.55(dd,J＝3.4,1.8Hz,1H), 3.84-3.96(m,2H),2.71(d,J＝18.0Hz,1H),2.53(d,J＝18.0Hz,1H),2.28(d,J＝16.0Hz,1H), 2.23(d,J＝17.7Hz,1H),2.15(s,2H),2.09(d,J＝16.0Hz,1H),1.72(d,J＝17.7Hz,1H),1.10(t, J＝7.2Hz,3H),1.09(s,3H),1.08(s,3H),1.03(s,3H),0.95(s,3H)；¹³C NMR(100MHz, d₆-DMSO)δ192.1,190.5,178.8,175.3,169.2,166.3,145.7,145.6,111.4,111.0,111.0,107.0, 101.8,101.4,64.1,61.5,51.1,50.7,37.0,36.3,33.5,28.4,28.1,27.1,27.1,13.6；HRMS(ESI)m/z [M+H]⁺Calcd for C₂₇H₃₀NO₈ 496.1971,found 496.1967.

Example 17

The oxime ester 1a (0.3mmol) of the acetophenone substituted by diethyl malonate, 1, 3-cyclohexanedione 2b (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 5ab in 59% yield.

3ab(white solid,59.7mg,59％,mp 238-241℃):¹H NMR(400MHz,d₆-DMSO)δ10.17(s, 1H),7.42-7.51(m,3H),7.24-7.31(m,2H),3.86-3.97(m,2H),2.89(ddd,J＝18.2,7.6,5.5Hz,1H), 2.70(dt,J＝18.1,5.6Hz,1H),2.06-2.40(m,6H),1.93-2.05(m,1H),1.72-1.84(m,1H),1.59-1.71 (m,1H),1.07-1.18(m,4H)；¹³C NMR(100MHz,d₆-DMSO)δ193.1,190.8,180.4,175.9,169.0, 166.0,133.4,129.8,128.2,126.6,112.4,108.0,105.6,101.3,63.9,61.4,37.0,36.7,23.7,22.8,20.8, 20.5,13.7；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₅H₂₄NO₇ 450.1553,found 450.1549.

Example 18

Mixing oxime ester 1b (0.3mmol) of diethyl malonate substituted 4-methoxyacetophenone, 1,3 cyclohexanedione 2b (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 1 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3bb in 41% yield.

3bb(white solid,44.5mg,41％,mp 241-249℃):¹H NMR(400MHz,d₆-DMSO)δ10.14(s, 1H),7.16(d,J＝9.0Hz,2H),7.00(d,J＝8.8Hz,2H),3.83-3.95(m,2H),3.76(s,3H),2.85(ddd, J＝18.2,7.6,5.6Hz,1H),2.65(dt,J＝18.3,5.6Hz,1H),2.33(ddd,J＝16.7,9.0,4.8Hz,1H), 2.04-2.28(m,5H),1.91-2.03(m,1H),1.73-1.85(m,1H),1.59-1.72(m,1H),1.25(dt,J＝18.0,5.7 Hz,1H),1.10(t,J＝7.2Hz,3H)；¹³C NMR(100MHz,d₆-DMSO)δ193.7,191.5,180.8,176.5, 169.3,166.3,160.6,128.3,125.3,113.8,112.6,108.2,106.0,101.3,64.0,61.7,55.6,37.2,36.9, 24.0,23.1,21.1,20.8,13.9；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₆H₂₆NO₈ 480.1658,found 480.1654.

Example 19

The oxime ester 1e (0.3mmol) of diethyl malonate substituted 4-chloroacetophenone, 1, 3-cyclohexanedione 2b (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 2 h. After the completion of the TLC monitoring reaction, 20m was added to the reaction mixtureL H₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3eb in 53% yield.

3eb(white solid,57.7mg,53％,mp 282-289℃):¹H NMR(400MHz,d₆-DMSO)δ10.21(s, 1H),7.54(d,J＝8.6Hz,2H),7.31(d,J＝8.6Hz,2H),3.85-3.97(m,2H),2.88(ddd,J＝18.2,7.6, 5.6Hz,1H),2.69(dt,J＝18.1,5.8Hz,1H),2.34(ddd,J＝16.7,9.0,5.0Hz,1H),2.17-2.30(m, 4H),2.05-2.17(m,1H),1.92-2.05(m,1H),1.76-1.88(m,1H),1.64-1.76(m,1H),1.25(dt,J＝17.9, 5.5Hz,1H),1.10(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,d₆-DMSO)δ193.1,190.9,180.3,175.8, 169.0,165.9,134.7,132.5,128.7,128.3,112.4,108.0,105.1,101.3,63.9,61.4,37.0,36.6,23.7, 22.9,20.8,20.5,13.7；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₅H₂₃ClNO₇ 484.1163,found 484.1161.

Example 20

The oxime ester 1a (0.3mmol) of acetophenone substituted by diethyl malonate, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione 2c (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 1 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ac in 53% yield.

3ac(white solid,60.9mg,53％,mp 227-230℃):¹H NMR(400MHz,d₆-DMSO)δ10.45(s, 1H),7.46-7.52(m,3H),7.25-7.33(m,2H),3.93-4.06(m,2H),3.26(d,J＝18.1Hz,1H),2.93(d,J ＝18.1Hz,1H),2.41(d,J＝18.1Hz,1H),1.62(d,J＝18.1Hz,1H),1.50(s,3H),1.48(s,3H), 1.34(s,3H),1.23(s,3H),1.13(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,d₆-DMSO)δ175.7,170.8, 168.7,166.3,161.1,160.1,132.8,130.2,128.5,126.5,106.9,102.1,101.7,97.2,80.4,79.6,63.3, 62.0,34.1,33.3,28.1,27.9,26.8,26.4,13.6；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₇H₂₈NO₉ 510.1764,found 510.1759.

Example 21

The oxime ester 1b (0.3mmol) of diethyl malonate substituted 4-methoxyacetophenone, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione 2c (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3bc in 48% yield.

3bc(white solid,58.0mg,48％,mp 232-234℃):¹H NMR(400MHz,d₆-DMSO)δ10.39(s, 1H),7.20(d,J＝8.9Hz,2H),7.02(d,J＝8.9Hz,2H),3.93-4.05(m,2H),3.79(s,3H),3.23(d,J＝ 18.6Hz,1H),2.90(d,J＝18.6Hz,1H),2.44(d,J＝17.7Hz,1H),1.72(d,J＝17.7Hz,1H),1.49 (s,3H),1.47(s,3H),1.35(s,3H),1.24(s,3H),1.12(t,J＝7.2Hz,3H)；¹³C NMR(100MHz, d₆-DMSO)δ175.6,170.8,168.6,166.3,161.1,160.5,160.1,128.0,124.5,113.8,107.1,101.9, 101.7,97.1,80.3,79.6,63.3,62.0,55.4,34.1,33.3,28.0,27.9,26.8,26.4,13.6；HRMS(ESI)m/z [M+H]⁺Calcd for C₂₈H₃₀NO₁₀ 540.1870,found 540.1862.

Example 22

The oxime ester 1e (0.3mmol) of diethyl malonate substituted 4-methoxyacetophenone, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione 2c (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 1 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ec with a yield of 41%.

3ec(white solid,50.6mg,41％,mp 234-237℃):¹H NMR(400MHz,d₆-DMSO)δ10.50(s, 1H),7.57(d,J＝8.7Hz,2H),7.32(d,J＝8.6Hz,2H),3.99(q,J＝7.1Hz,2H),3.26(d,J＝18.2 Hz,1H),2.91(d,J＝18.2Hz,1H),2.45(d,J＝17.9Hz,1H),1.80(d,J＝17.7Hz,1H),1.49(s,3H), 1.47(s,3H),1.35(s,3H),1.25(s,3H),1.12(t,J＝7.2Hz,3H)；¹³C NMR(100MHz,d₆-DMSO)δ 176.0,171.2,169.1,166.7,161.5,160.5,135.5,132.4,129.1,129.0,106.8,102.5,102.2,97.7,80.9, 80.2,63.9,62.5,34.5,33.8,28.6,28.4,27.2,26.8,14.1；HRMS(ESI)m/z[M+H]⁺Calcd for C₂₇H₂₇ClNO₉ 544.1374,found 544.1370.

Example 23

The oxime ester 1a (0.3mmol) of acetophenone substituted by diethyl malonate, 5-methylcyclohexane-1, 3-dione 2d (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 0.5 h. After completion of the TLC monitoring reaction, 20mL of H was added to the reaction mixture₂O, and the above mixture was extracted with EtOAc (30 mL. times.3). Combining all the extracted organic phases together with anhydrous Na₂SO₄Drying, then filtering and finally concentrating under vacuum. The residue was purified by column chromatography to give 3ad in 51% yield.

3ad(mixture of four stereoisomers,white solid,54.9mg,51％)HRMS(ESI)m/z[M+H]⁺ Calcd for C₂₇H₂₈O₇ 478.1866,found 478.1859.

Example 24

The oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), CuCl (0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a test tube (phi 18X 150mm, a dry test tube with calcium chloride attached to the top of the test tube) and stirred in a 60 ℃ oil bath for 3 h. TLC monitored the reaction to give 3aa in 43% yield.

Example 25

Oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), CuBr (0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a test tube (phi 18X 150mm, a dry test tube containing calcium chloride was attached to the top of the test tube) and stirred in an oil bath at 60 ℃ for 3 h. TLC monitored the reaction to give 3aa in 26% yield.

Example 26

Oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), CuI (0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a test tube (phi 18X 150mm, a dry test tube with calcium chloride was attached to the top of the test tube) and stirred in an oil bath at 60 ℃ for 3 h. TLC monitored the reaction to give 3aa in 34% yield.

Example 27

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.6mmol), Cu (OAc)₂(0.75mmol) and 3mL of analytically pure DMSO were placed in a test tube and stirred in a 60 ℃ oil bath for 1h under nitrogen. TLC monitored the reaction to give 3aa in 54% yield.

Example 28

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.45mmol) and 3mL of anhydrous DMSO were placed in a test tube and stirred in an oil bath at 60 ℃ for 1h under air. TLC monitored the reaction to give 3aa in 63% yield.

Example 29

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.45mmol) and 3mL of anhydrous DMSO were placed in a tube (. PHI.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 1 h. TLC monitored the reaction to give 3aa in 66% yield.

Example 30

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol) and 3mL of anhydrous DMSO were placed in a tube (. PHI.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 3 h. The reaction was monitored by TLC to 3aa, 39% yield.

Example 31

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.06mmol) and 3mL of anhydrous DMSO were placed in a tube (. PHI.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 3 h. The reaction was monitored by TLC to 3aa, 21% yield.

Example 32

The oxime ester 1a (0.3mmol) of acetophenone substituted by diethyl malonate and the daminone 2a (0.45 m)mol)、Cu(OAc)₂(0.09mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 2 h. The reaction was monitored by TLC to 3aa, 55% yield.

Example 33

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in an 80 ℃ oil bath under nitrogen for 0.5 h. TLC monitored the reaction to give 3aa in 42% yield.

Example 34

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of analytically pure DMF were placed in a test tube and stirred in a 60 ℃ oil bath for 0.5h under nitrogen (18X 150 mm. phi., dry tube with calcium chloride attached to the top of the tube). TLC monitored the reaction to give 3aa in 45% yield.

Comparative example 1

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. PHI.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 40 ℃ oil bath for 4h under nitrogen. The reaction was monitored by TLC, yielding only a trace of 3 aa.

Comparative example 2

Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), Cu (OAc)₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of analytically pure toluene were placed in a test tube (. PHI.18X 150mm, a dry test tube containing calcium chloride was attached to the top of the test tube) and stirred in a 60 ℃ oil bath for 3h under nitrogen. TLC monitored the reaction to give 3aa in 10% yield.

Comparative example 3

The oxime ester 1a (0.3mmol) of acetophenone substituted by diethyl malonate, daminone 2a (0.45mmol), CuCl₂(0.12mmol), di-tert-butyl peroxide (0.9mmol) and 3mL of anhydrous DMSO were placed in a tube (. phi.18X 150mm, a dry tube containing calcium chloride was attached to the top of the tube) and stirred in a 60 ℃ oil bath for 4 h. The reaction was monitored by TLC, yielding only a trace of 3 aa.

In vitro anti-cancer Activity assay

Research on anticancer activity: 3 cancer cells of H460 (lung cancer cell), HepG2 (liver cancer cell) and A549 (lung cancer cell) are selected as test cell strains to perform in-vitro anticancer activity tests on three typical compounds 3ba, 3ab and 3bc, and 5-fluorouracil is used as a positive control. The cancer cells in the logarithmic growth phase are centrifuged and then evenly blown by 1640 complete culture medium of 1 mL. According to the addition of 100. mu.L of medium per well, 1.2X 10 per well⁴To request, calculate the required cell mass, then resuspend the cell fluid, take out the required amount and use 10% FBS 1640 medium dilution, seed in 96-well plate, put at 37 degrees C, 5% CO₂And incubating the culture box for 16-18 h. And when the cell density reaches 70-80%, performing drug intervention. 60 mu L of the test compound at 50 mu M is added, the incubation is continued for 72h, 3 multiple wells are set for each intervention, and a blank control and a positive control are set in each plate. Incubate for 72h, add 50 μ L10% MTT and continue incubation for 4 h. MTT is absorbed from a 96-well plate, DMSO is added into the plate at a concentration of 100 mu L/well, the plate is shaken for 10min and placed into an enzyme-labeling instrument, and the OD value at 570nm is measured. From the OD value, the inhibition rate of the compound at 50. mu.M on cancer cells was calculated. The results are shown in Table 1. The test result shows that the three compounds have no obvious difference on the A549 inhibition effect at 50 mu M, but 3ba and 3bc have obvious selectivity on HepG 2. When reacting with 6, 6-dimethyldihydro-2H-pyran-2, 4(3H) -dione 2c, the inhibitory effect on HepG2 is significantly improved.