CN113429416B - Synthesis method of dihydrofuropyrrolone derivative with spirotricyclic framework - Google Patents

Synthesis method of dihydrofuropyrrolone derivative with spirotricyclic framework Download PDF

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CN113429416B
CN113429416B CN202110738249.2A CN202110738249A CN113429416B CN 113429416 B CN113429416 B CN 113429416B CN 202110738249 A CN202110738249 A CN 202110738249A CN 113429416 B CN113429416 B CN 113429416B
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刘慧敏
王坤
缪春宝
杨海涛
吕新宇
陈新
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Abstract

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.

Description

Synthesis method of dihydrofuropyrrolone derivative with spirotricyclic framework
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.
Figure RE-GDA0003215025950000011
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:
Figure RE-GDA0003215025950000021
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:
Figure RE-GDA0003215025950000022
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:
Figure RE-GDA0003215025950000031
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 show Compound 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) SpectrumA drawing;
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 chromatographyThe reaction yielded 3aa in 65% yield.
Figure RE-GDA0003215025950000051
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.
Figure RE-GDA0003215025950000052
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 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 3ca in 61% yield.
Figure RE-GDA0003215025950000061
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.
Figure RE-GDA0003215025950000071
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.
Figure RE-GDA0003215025950000072
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). All the extracted organic phases are combined together,with anhydrous Na2SO4Drying, then filtering and finally concentrating under vacuum.
The residue was purified by column chromatography to give 3fa in 43% yield.
Figure RE-GDA0003215025950000081
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.
Figure RE-GDA0003215025950000091
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 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 3ha in 47% yield.
Figure RE-GDA0003215025950000092
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.
Figure RE-GDA0003215025950000101
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.
Figure RE-GDA0003215025950000111
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. TLC monitoring reaction completionThen, 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.
Figure RE-GDA0003215025950000112
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.
Figure RE-GDA0003215025950000121
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.
Figure RE-GDA0003215025950000131
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 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 3na in 64% yield.
Figure RE-GDA0003215025950000132
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.
Figure RE-GDA0003215025950000141
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.
Figure RE-GDA0003215025950000151
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 the completion of the reaction was monitored by TLC, the reaction mixture was addedTo which was added 20mL of 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 5ab in 59% yield.
Figure RE-GDA0003215025950000152
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.
Figure RE-GDA0003215025950000161
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 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 3eb in 53% yield.
Figure RE-GDA0003215025950000171
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.
Figure RE-GDA0003215025950000172
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-butylPeroxide (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.
Figure RE-GDA0003215025950000181
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 passed through the columnPurification by chromatography gave 3ec with a yield of 41%.
Figure RE-GDA0003215025950000191
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.
Figure RE-GDA0003215025950000192
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 ofThe aqueous DMSO is placed in a test tube (. PHI.18X 150mm, a dry test tube containing calcium chloride is attached to the top of the test tube) and stirred in an oil bath at 60 ℃ 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
Mixing oxime ester 1a (0.3mmol) of diethyl malonate substituted acetophenone, daminone 2a (0.45mmol), 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 analytical gradeDMF was placed in a test tube and stirred in an oil bath at 60 ℃ for 0.5h under nitrogen (Φ 18X 150mm, 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 well4Calculating the required cell amount, re-suspending the cell liquid, and taking outDiluting the required amount with 1640 medium containing 10% FBS, inoculating into 96-well plate, placing at 37 deg.C and 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.
TABLE 1
Figure RE-GDA0003215025950000221

Claims (3)

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, an oxidant is added, 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 dihydrofuropyrrolone derivative with a spirotricyclic framework is obtained after separation and purification;
the copper salt catalyst is selected from one of copper acetate, cuprous chloride, cuprous bromide, cuprous iodide, copper trifluoroacetate and copper trifluoromethanesulfonate; the oxidant is tert-butyl peroxide;
the malonate substituted O-acyl oxime has a general formula shown in 1:
Figure FDA0003537904080000011
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 heterocycle are selected from bromine atoms;
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;
the structural general formula of the dihydrofuropyrrolopyrrole derivative with the spirotricyclic framework is shown as the following formula:
Figure FDA0003537904080000012
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.
2. The method for synthesizing a dihydrofuropyrrolone derivative having a spirotricyclic skeleton according to claim 1, characterized in that: the solvent is one of acetonitrile, dioxane, 1, 2-dichloroethane, ethylene glycol dimethyl ether, N-dimethylformamide and dimethyl sulfoxide.
3. 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 ℃.
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