A cyclopentenone derivative, a method for synthesizing the same and use thereof

Abstract

The application discloses a cyclopentenone derivative, a synthesis method and application thereof, uses 2-((Z)-3-iodoallyl)-malononitrile as raw material, and provides a synthesis method of the cyclopentenone derivative. 2+ The method uses formic acid as an additive, which can be used as a proton source for protonolysis of an intermediate on one hand, and can also be used as a reducing agent for Pd 2+ species on the other hand, so that efficient catalytic conversion effect is realized. The method is simple to operate, has good functional group compatibility, and provides a new idea for synthesizing polysubstituted cyclopentenone derivatives.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a cyclopentenone derivative and a synthesis method and application thereof. BACKGROUND

[0002] Cyclopentenone is a very important organic compound, and its electron-poor olefin and carbonyl functional groups have high reactivity, which is an important intermediate for organic synthesis and drug synthesis. At the same time, the cyclopentenone structural unit also widely exists in natural products and drug molecules. Therefore, in recent years, the synthesis method of cyclopentenone has attracted more and more attention.

[0003] The traditional synthesis method of cyclopentenone compounds mainly includes Pauson-Khand reaction and Nazarov cyclization reaction. However, the conditions of these reactions are harsh, and the preparation steps of the raw materials are also complicated. In view of the above reasons, it is very necessary and valuable to develop a more simple and efficient method to synthesize cyclopentenone derivatives.

[0004] Cyanide is a less common electrophilic group in palladium-catalyzed coupling reactions, which generally involves migration insertion of nitrile group into C-Pd 2+ intermediate, but due to the high stability of the C-N triple bond of the nitrile group, the migration insertion is very difficult, in addition, the C=N-Pd 2+ intermediate formed by migration insertion, in which N-Pd is a weak bond, which is easily protonated, and finally releases imine product and Pd 2+ species, which is very suitable for developing Pd(II) - catalyzed nitrile group conversion reaction, which is one of the current popular strategies for catalytic conversion of nitrile group. On this basis, the present application takes a different approach, and imagines adding a suitable reducing agent to reduce the finally generated Pd 2+ species into Pd(0), so as to realize a new method of Pd(0) - catalyzed nitrile group conversion. SUMMARY

[0005] This section aims to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, abstract and title, and such simplifications or omissions cannot be used to limit the scope of the present application.

[0006] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0007] Therefore, the purpose of the present application is to overcome the deficiencies in the prior art, and to provide a cyclopentenone derivative.

[0008] The structure of the cyclopentenone derivative compound is shown in formula (II):

[0009]

[0010] wherein, R 1 , R 2 , R 3 are independent groups, R 1 is selected from one of aryl, alkyl, R 2 is selected from one of aryl, alkyl, R 3 is selected from one of phenyl, alkyl.

[0011] As a preferred scheme of the cyclopentenone derivative of the present application, wherein: the cyclopentenone derivative is one of the compounds shown in formula (II-1) to formula (II-12);

[0012]

[0013] Another object of the present application is to provide a synthesis method of a cyclopentenone derivative.

[0014] To solve the above technical problems, the present application provides the following technical scheme: comprising,

[0015] 2-((Z)-3-iodoallyl)-malononitrile, formic acid, a palladium catalyst and an alkaline additive are added to an organic solvent, and heated under nitrogen to react, and after the reaction is completed, post-treatment is performed to obtain a cyclopentenone derivative;

[0016] wherein, the structure of the 2-((Z)-3-iodoallyl)-malononitrile is shown in formula (I):

[0017]

[0018] wherein, R 1 , R 2 , R 3 are independent groups, R 1 is selected from one of aryl, alkyl, R 2 is selected from one of aryl, alkyl, R 3 is selected from one of phenyl, alkyl.

[0019] As a preferred scheme of the synthesis method of the cyclopentenone derivative of the present application, wherein: the catalyst comprises one or more of palladium acetate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium chloride, palladium bromide, palladium iodide, and bis(triphenylphosphine)palladium chloride

[0020] As a preferred scheme of the synthesis method of the cyclopentenone derivative according to the present application, wherein: the base additive comprises one or more of diisopropylethylamine, triethylamine, sodium carbonate.

[0021] As a preferred scheme of the synthesis method of the cyclopentenone derivative according to the present application, wherein: the organic solvent comprises one or more of 1,2-dichloroethane, N-methylpyrrolidone, dichloromethane, dimethyl sulfoxide, methyl tert-butyl ether, 1,4-dioxane.

[0022] As a preferred scheme of the synthesis method of the cyclopentenone derivative according to the present application, wherein: the concentration of the 2-((Z)-3-iodoallyl)-malononitrile compound in the organic solvent is 0.1-0.5 mmol / ml.

[0023] As a preferred scheme of the synthesis method of the cyclopentenone derivative according to the present application, wherein: the mass of the formic acid is 120-500% of the 2-((Z)-3-iodoallyl)-malononitrile compound, the mass of the palladium catalyst is 1-5% of the 2-((Z)-3-iodoallyl)-malononitrile compound, and the mass of the base additive is 100-500% of the 2-((Z)-3-iodoallyl)-malononitrile compound.

[0024] Still another object of the present application is to provide an application of the cyclopentenone derivative compound in preparing an anticancer drug or as an intermediate in drug synthesis.

[0025] The present application has the following beneficial effects:

[0026] The present application uses 2-((Z)-3-iodoallyl)-malononitrile as a raw material to provide a synthesis method of a cyclopentenone derivative, using formic acid as an additive, which can act as a proton source for the protonolysis of the intermediate C=N-Pd 2+ and as a reducing agent for Pd 2+ species, achieving efficient catalytic conversion effect. The method is simple to operate, has good functional group compatibility, and provides a new idea for synthesizing polysubstituted cyclopentenone derivatives. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor. Among them:

[0028] Figure 1 The hydrogen spectrum (A) and carbon spectrum (B) spectra of the compound obtained in Example 1 of the present application.

[0029] Figure 2 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 2 of the present application are shown in the following;

[0030] Figure 3 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 3 of the present application are shown in the following;

[0031] Figure 4 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 4 of the present application are shown in the following;

[0032] Figure 5 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 5 of the present application are shown in the following;

[0033] Figure 6 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 6 of the present application are shown in the following;

[0034] Figure 7 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 7 of the present application are shown in the following;

[0035] Figure 8 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 8 of the present application are shown in the following;

[0036] Figure 9 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 9 of the present application are shown in the following;

[0037] Figure 10 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 10 of the present application are shown in the following;

[0038] Figure 11 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 11 of the present application are shown in the following;

[0039] Figure 12 The hydrogen spectrum (A) and carbon spectrum (B) of the compound obtained in Example 12 of the present application are shown in the following; DETAILED DESCRIPTION

[0040] In order to make the above objectives, features and advantages of the present application more obvious and comprehensible, the specific embodiments of the present application will be described in detail below with reference to the description examples.

[0041] In the following description, a lot of specific details are set forth in order to provide a thorough understanding of the present application, however, the present application can be implemented in other different ways from those described herein, and those skilled in the art can make similar generalization without departing from the connotation of the present application, therefore, the present application is not limited by the specific examples disclosed below.

[0042] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0043] Unless otherwise specified, all raw materials used in this invention are commercially available analytical grade materials commonly used in the field.

[0044] The proton and carbon spectral analysis conditions for the compounds of this invention are as follows:

[0045] The proton NMR spectrum was tested on a 400MHz NMR instrument, and the carbon NMR spectrum was tested on a 101MHz NMR instrument. The test conditions were both at room temperature, with tetramethylsilane as an internal standard, and the samples were dissolved in deuterated chloroform.

[0046] Example 1

[0047] This embodiment provides a method for synthesizing 1-benzyl-2-oxo-4-phenylcyclopent-3-en-1-onitrile from (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malonadionitrile, the synthesis process of which is based on formula (III-1):

[0048]

[0049] Under a nitrogen atmosphere, Pd(OAc)2 (0.020 mmol), (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile (I-1) (0.20 mmol), diisopropylethylamine (DIPEA) (1.0 mmol), formic acid (0.24 mmol), and solvent 1,2-dichloroethane (2.0 mL) were added to a 25 mL flask, and the mixture was then reacted at 90 °C for 16 hours.

[0050] After the reaction was complete, the reaction system was cooled to 30°C, 2 mL of hydrochloric acid (1 M) was added and stirred for 2 h. The reaction mixture was then extracted with DCM (2 × 20 mL), the organic phase was dried with Na2SO4, stirred and filtered, and the solvent was removed under reduced pressure. The residue was then purified by silica gel column chromatography (eluent: EtOAc / PE (5:1)) to give 1-benzyl-2-oxo-4-phenylcyclopent-3-ene-1-nitrile (II-1), with a final product yield of 72%.

[0051] The characterization results of the product in this embodiment are as follows: Figure 1 As shown, the characterization data is: White solid, Mp: 140.3-142.5℃. 1H NMR (400 MHz, Chloroform-d) δ: 7.55-7.33 (m, 5H), 7.31-7.20 (m, 5H), 6.48 (t, J = 1.7 Hz, 1H), 3.34-3.25 (m, 2H), 3.19 (dd, J = 18.3, 1.6 Hz, 1H), 2.93 (d, J = 13.8 Hz, 1H). 13 CNMR (101 MHz, CDC13) δ: 199.3, 171.8, 134.2, 132.5, 132.4, 130.1, 129.2, 128.8, 127.9, 127.1, 123.8, 119.6, 47.6, 41.5, 38.7. HRMS-ESI Calcd for [C 19 H 16 NO] + (M+H + ): 274.1226, found: 274.1225.

[0052] Comparative Example 1

[0053] The difference between this comparative example and Example 1 is that no reducing agent is added, and the rest of the process is the same as Example 1. The result is that the target product cannot be synthesized.

[0054] Comparative Example 2

[0055] The difference between this comparative example and Example 1 is that the reducing agent formic acid is replaced by zinc powder, and the rest of the process is the same as Example 1. The result is that the target product cannot be synthesized.

[0056] Comparative Example 3

[0057] The difference between this comparative example and Example 1 is that the reducing agent formic acid is replaced by trimethylsilane, and the rest of the process is the same as Example 1. The result is that the target product cannot be synthesized.

[0058] Comparative Example 4

[0059] The difference between this comparative example and Example 1 is that the reducing agent formic acid is replaced by ammonium formate, and the rest of the process is the same as Example 1. The result is that the target product cannot be synthesized.

[0060] Comparative Example 5

[0061] The difference between this comparative example and Example 1 is that the amount of reducing agent formic acid is 0.12 mmol, and the rest of the process is the same as Example 1. The result is that the yield of the target product is only 30%.

[0062] Comparative Example 6

[0063] The difference between this comparative example and Example 1 is that the amount of reducing agent formic acid is adjusted to 0.36 mmol, and the remaining steps are the same as Example 1. The result is that the yield of the target product is 75%.

[0064] Comparative Example 7

[0065] The difference between this comparative example and Example 1 is that the amount of reducing agent formic acid is adjusted to 1.00 mmol, and the remaining steps are the same as Example 1. The result is that the yield of the target product is 75%.

[0066] It can be seen that further increasing the amount of formic acid cannot continue to improve the yield of the target product, so the amount of formic acid is selected as 0.24 mmol.

[0067] Example 2

[0068] The difference between this example and Example 1 is only that the raw material (E)-2-benzyl-2-(3-iodo-2-phenylallyl) malononitrile is adjusted to (E)-2-benzyl-2-(3-iodo-2-(p-tolyl) allyl) malononitrile (I-2), and the synthesis process is referred to formula (III-2):

[0069]

[0070] The remaining process parameters are the same as Example 1, and the yield of the final product is 63%.

[0071] The characterization results of the product of this example are shown in Figure 2 , and the characterization data are: White solid, Mp: 145.6-149.4 °C. 1 H NMR (400 MHz, Chloroform-d) δ: 7.39 (d, J = 8.0 Hz, 2H), 7.26-7.17 (m, 7H), 6.43 (d, J = 1.6 Hz, 1H), 3.31-3.25 (m, 2H), 3.17 (dd, J = 18.4, 1.6 Hz, 1H), 2.92 (d, J = 13.6 Hz, 1H), 2.34 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ: 199.3, 171.8, 143.5, 134.3, 130.1, 129.9, 129.7, 128.8, 127.9, 127.1, 122.8, 119.7, 47.6, 41.5, 38.7, 21.7. HRMS-ESI Calcd for [C 20 H 18 NO] + (M+H + ): 288.1383, found: 288.1382.

[0072] Example 3

[0073] The difference between this example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (E)-2-benzyl-2-(3-iodo-2-(3,5-dimethylphenyl)allyl)malononitrile (I-3), and the synthesis process is referred to formula (III-3):

[0074]

[0075] The rest of the process parameters are the same as in Example 1, and the yield of the final product is 75%.

[0076] The characterization results of the product of this example are shown in Figure 3 The characterization data: white amorphous solid. 1 HNMR (400 MHz, Chloroform-d) δ: 7.30-7.20 (m, 5H), 7.11-7.08 (m, 3H), 6.44 (t, J = 1.7 Hz, 1H), 3.32-3.24 (m, 2H), 3.16 (dd, J = 18.4, 1.7 Hz, 1H), 2.90 (d, J = 13.8 Hz, 1H), 2.28 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ: 199.3, 172.3, 138.9, 134.3, 132.3, 130.1, 128.8, 127.9, 124.9, 123.5, 119.7, 47.6, 41.5, 38.8, 21.3. HRMS-ESI Calcd for [C 21 H 20 NO] + (M+H + ): 302.1539, found: 302.1538.

[0077] Example 4

[0078] The difference between this example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (Z)-2-benzyl-2-(2-(iodomethylidene)butyl)allyl)malononitrile (I-4), and the synthesis process is referred to formula (III-4):

[0079]

[0080] The rest of the process parameters are the same as in Example 1, and the yield of the final product is 75%.

[0081] The characterization results of the product of the present example are shown in Table 1 below. Figure 4 White solid, Mp: 55.4-59.8 °C. 1 H NMR (400 MHz, Chloroform-d) δ: 7.28-7.21 (m, 3H), 7.18-7.16 (m, 2H), 5.86 (t, J = 1.6 Hz, 1H), 3.17 (d, J = 13.6 Hz, 1H), 2.93-2.81 (m, 2H), 2.74 (dd, J = 18.8, 1.6 Hz, 1H), 2.36-2.18 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ: 200.0, 182.8, 182.7, 134.1, 130.0, 128.7, 127.9, 125.7, 119.7, 47.3, 41.3, 41.3, 26.5, 11.2. HRMS-ESI Calcd for [C 15 H 16 NO] + (M+H + ): 226.1226, found: 226.1225.4

[0082] Example 5

[0083] The difference between the present example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (Z)-2-benzyl-2-(2-(iodomethyl)hexyl)allyl)malononitrile (I-5), and the synthesis process is referred to formula (III-5):

[0084]

[0085] The remaining process parameters are the same as those in Example 1, and the yield of the final product is 80%.

[0086] The characterization results of the product of the present example are shown in Table 1 below. Figure 5 Oily liquid. 1H NMR(400MHz,Chloroform-d)δ:7.27-7.21(m,3H),7.17-7.14(m,2H),5.85(t,J=1.6Hz,1H),3.16(d,J=13.6Hz,1H),2.95(d,J=13.6Hz,1H), 2.85(dd,J=18.8,2.0Hz,1H),2.73(dd,J=18.8,1.6Hz,1H),2.33-2.18(m,2H),1.41-1.31(m,2H),1.22-1.13(m,3H),0.81(t,J=7.2Hz,3H). 13 C NMR(101MHz, CDCl3)δ:200.0,181.5,134.0,130.1,128.7,127.9,126.6,119.7,47.2,41.3,32.9,28.9,22.2,13.7.HRMS-ESI Calcd for[C 17 H 20 NO] + (M+H + ):254.1539,found:288.1382.

[0087] Example 6

[0088] The only difference between this embodiment and Example 1 is that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is changed to (Z)-2-benzyl-2-(5-(benzyloxy)-2-(iodomethylene)pentyl)malononitrile (I-6), and the synthesis process is as described in formula (III-6):

[0089]

[0090] All other process parameters were the same as in Example 1, and the final product yield was 72%.

[0091] The characterization results of the product in this embodiment are as follows: Figure 6 As shown, the characterization data is: oilyliquid. 1 H NMR(400MHz,Chloroform-d)δ:7.30-7.21(m,8H),7.15-7.12(m,2H),5.84(t,J=1.6Hz,1H),4.38(s,2H),3.37-7.27( m,2H),3.13(d,J=13.6Hz,1H),2.88-2.79(m,2H),2.73(dd,J=18.8,1.6Hz,1H),2.45-2.30(m,2H),1.77-1.62(m,2H). 13C NMR(101MHz, CDCl3)δ:200.0,181.1,138.0,134.1,130.1,128.7,128.5,127 .9,127.8,126.6,119.6,73.2,68.8,47.3,41.3,41.2,30.2,27.0.HRMS-ESI Calcd for[C 23 H 24 NO2] + (M+H + ):346.1802,found:346.1801.

[0092] Example 7

[0093] The only difference between this embodiment and Example 1 is that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is changed to (E)-2-(3-iodo-2-phenylallyl)-2-(4-methylbenzyl)malononitrile (I-7). The synthesis process is as described in formula (III-7):

[0094]

[0095] All other process parameters were the same as in Example 1, and the final product yield was 70%.

[0096] The characterization results of the product in this embodiment are as follows: Figure 7 As shown, the characterization data is: white amorphous solid. 1 HNMR(400MHz,Chloroform-d)δ:7.51-7.35(m,5H),7.11(d,J=8.0Hz,2H),7.05(d,J=8. 0Hz,2H),6.46(t,J=1.6Hz,1H),3.30-3.15(m,3H),2.88(d,J=13.6Hz,1H),2.23(s,3H). 13 C NMR(101MHz, CDCl3)δ:199.4,171.8,137.7,132.6,132.4,131.1,130.0,129.5,129.3,127.2,123.8,119.7,47.7,41.2,38.7,21.1.HRMS-ESI Calcd for[C 20 H 17 NO] + (M+H + ):288.1383,found:288.1384.

[0097] Example 8

[0098] The difference between this example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (E)-2-(3-iodo-2-phenylallyl)-2-phenethylmalononitrile (I-9), and the synthesis process is referred to formula (III-9):

[0099]

[0100] The rest of the process parameters are the same as in Example 1, and the yield of the final product is 71%.

[0101] The characterization results of the product of this example are as shown in Figure 8 The characterization data: oil liquid. 1 H NMR (400 MHz, Chloroform-d) δ: 7.54-7.51 (m, 2H), 7.49-7.38 (m, 3H), 7.32-7.29 (m, 2H), 6.48 (t, J = 1.6 Hz, 1H), 6.34 (dd, J = 2.0, 0.8 Hz, 1H), 3.38 (dd, J = 18.4, 2.0 Hz, 1H), 3.14-3.08 (m, 2H), 2.85 (d, J = 14.4 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ: 199.2, 172.0, 143.6, 141.3, 132.6, 132.3, 129.3, 127.1, 123.8, 119.7, 117.8, 111.4, 46.7, 39.2, 31.6. HRMS-ESI Calcd for [C 17 H 14 NO2] + (M+H + ): 264.1019, found: 264.1020.

[0102] Example 9

[0103] The difference between this example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (E)-2-(3-iodo-2-phenylallyl)-2-phenethylmalononitrile (I-9), and the synthesis process is referred to formula (III-9):

[0104]

[0105] The rest of the process parameters are the same as in Example 1, and the yield of the final product is 71%.

[0106] The characterization results of the product of this example are as shown in Figure 9White solid, Mp: 117.1-121.0 °C.1H NMR (400 MHz, Chloroform-d) δ: 7.55-7.52 (m, 2H), 7.47-7.39 (m, 3H), 7.24-7.19 (m, 2H), 7.17-7.10 (m, 3H), 6.51 (t, J = 1.6 Hz, 1H), 3.46 (dd, J = 18.4, 1.6 Hz, 1H), 3.04 (dd, J = 18.4, 1.6 Hz, 1H), 2.97-2.89 (m, 1H), 2.80-2.71 (m, 1H), 2.30-2.22 (m, 1H), 1.97-1.88 (m, 1H).13C NMR (101 MHz, CDCl3) δ: 199.5, 171.5, 139.8, 132.6, 132.3, 129.3, 128.7, 128.5, 127.2, 126.6, 123.8, 119.4, 46.6, 40.4, 38.5, 31.6. HRMS-ESI Calcd for [C 20 H 17 NO] + (M+H + ): 288.1383, found: 288.1387.

[0107] Example 10

[0108] The difference between this example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is replaced by (E)-2-(3-iodo-2-phenylallyl)-2-isopropylmalononitrile (I-10), and the synthesis process is according to formula ((III-10):

[0109]

[0110] The rest of the process parameters are the same as in Example 1, and the yield of the final product is 80%.

[0111] The characterization results of the product of this example are as follows: Figure 10Characterization data: oily liquid.1H NMR (400 MHz, Chloroform-d) δ: 7.62-7.58 (m, 2H), 7.51-7.41 (m, 3H), 6.54 (t, J = 1.6 Hz, 1H), 3.35 (dd, J = 18.3, 2.0 Hz, 1H), 3.11 (dd, J = 18.3, 1.6 Hz, 1H), 2.39-2.28 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).13C NMR (101 MHz, CDCl3) δ: 199.9, 171.9, 132.5, 132.4, 129.3, 127.1, 125.0, 119.8, 51.2, 36.7, 34.1, 18.4, 16.8. HRMS-ESI Calcd for [C 15 H 16 NO2] + (M+H + ): 226.1226, found: 226.1226.

[0112] Example 11

[0113] The difference between this example and Example 1 is only that the starting material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (E)-2-benzyl-2-(3-iodo-2-phenyl-2- enebutyl)malononitrile (I-11), and the synthesis process is referred to formula (III-11):

[0114]

[0115] The rest of the process parameters are the same as in Example 1, and the yield of the final product is 65%.

[0116] The characterization results of the product of this example are shown in Figure 11 Characterization data: white amorphous solid. 1 HNMR (400 MHz, Chloroform-d) δ: 7.39-7.36 (m, 3H), 7.28-7.16 (m, 7H), 3.28-3.18 (m, 2H), 3.07-2.96 (m, 2H), 1.87 (t, J = 2.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ: 200.5, 164.9, 134.5, 134.1, 130.5, 130.0, 128.9, 128.7, 127.9, 127.6, 119.8, 46.2, 41.8, 39.6, 10.3. HRMS-ESI Calcd for [C20 H 18 NO] + (M+H + ):288.1383,found:288.1380.

[0117] Example 12

[0118] The difference between this example and Example 1 is only that the raw material (E)-2-benzyl-2-(3-iodo-2-phenylallyl)malononitrile is adjusted to (E)-2-benzyl-2-(3-iodo-2-phenyl-2- enebutyl)malononitrile (I-12), and the synthesis process is referred to formula (III-12):

[0119]

[0120] The remaining process parameters are the same as in Example 1, and the yield of the final product is 78%.

[0121] The characterization results of the product of this example are shown in Table 1, and the characterization data are: white amorphous solid. Figure 12 1 HNMR (400 MHz, Chloroform-d) δ: 7.29-7.16 (m, 11H), 7.07-7.00 (m, 4H), 3.37-3.30 (m, 2H), 3.22-3.17 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ: 198.6, 166.1, 137.3, 133.9, 133.7, 130.8, 130.7, 130.1, 129.3, 128.8, 128.7, 128.6, 128.1, 128.0, 46.6, 42.0, 39.7. HRMS-ESI Calcd for [C 25 H 20 NO] + (M+H+):350.1539,found:350.1539.

[0122] Example 13

[0123] This example verifies the in vitro inhibition of cancer cells by cyclopentenone derivatives, specifically:

[0124] ​Human breast cancer MDA-MB-231 and MDA-MB-468 were purchased from the cell bank of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and the two cells were placed in a mixture of Dulbecco's modified Eagle's medium, nutrient mixture F-12 (DMEM / F-12), 10% (v / v) fetal bovine serum (FBS), 50 mg / mL penicillin and 50 mg / mL streptomycin, and cultured in a humidified incubator at 37°C with 5% carbon dioxide.

[0125] Cancer cells (MDA-MB-231, MDA-MB-468) were seeded in a 96-well culture plate at a density of 5000-7000 cells per well (100 per well), and the cells were cultured overnight (16 hours) in a humidified incubator at 37°C with 5% carbon dioxide. Different concentrations of test samples of synthetic compounds II-6 and compound II-8 of the present application were tested in triplicate, and then incubated at 37°C for 48 hours. The ratio of DMSO in the culture medium was not more than 0.1%.

[0126] After the culture was completed, 10 μL of the sample was placed in a CCK-8 cell counting kit, and the plate was incubated in a carbon dioxide incubator for 4 hours. The absorbance was measured at a wavelength of 450 nm, and the cytotoxic activity was expressed as IC 50 value.

[0127] The test results showed that the IC 50 values of compound II-6 for MDA-MB-231 and MDA-MB-468 were 0.542 μM and 0.369 μM, respectively; the IC 50 values of compound II-8 for MDA-MB-231 and MDA-MB-468 were 0.412 μM and 0.285 μM, respectively, indicating that the compounds of the present application have inhibitory effects on the two types of cancer cells and can be used to prepare anticancer drugs.

[0128] Example 14

[0129] This example provides an application of the synthetic cyclopentenone derivative of the present application in the synthesis of β-amino acids. The specific application method is shown in formula (IV):

[0130]

[0131] After the catalytic reaction of the 2-((Z)-3-iodoallyl)-malononitrile compound is completed, the amine is obtained by directly adding methanol and sodium borohydride to the reaction system without hydrolysis, and the cyano group in the hydrolysis product is obtained. β-amino acid with two chiral centers.

[0132] In conclusion, the application uses 2-((Z)-3-iodoallyl)-malononitrile as a raw material to provide a synthesis method of a cyclopentenone derivative, formic acid is used as an additive, which can be used as a C=N-Pd 2+ proton source for intermediate protonolysis, and also as a Pd 2+ reducing agent for the species, achieving efficient catalytic conversion effect, and the synthesized cyclopentenone derivative can be used as an intermediate for organic synthesis and drug synthesis, the method is simple to operate, has good functional group compatibility, and provides a new idea for synthesizing polysubstituted cyclopentenone derivatives.

[0133] It should be noted that the above examples are only used to illustrate the technical solutions of the application and are not limiting, although the application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the application can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the application, which should be covered in the scope of the claims of the application.

Claims

1. A method for synthesizing a cyclopentenone derivative, characterized by: The application relates to a preparation method of a cyclopentenone derivative. 2-((Z)-3-iodoallyl)-malononitrile, formic acid, palladium acetate and diisopropylethylamine are added into an organic solvent, and the reaction is heated under the condition of nitrogen; after the reaction is completed, post-treatment is carried out, so that the cyclopentenone derivative is obtained; The structure of the 2-((Z)-3-iodoallyl)-malononitrile is shown in the formula (I). Formula (I); In formula (I), R 1 , R 2 , R 3 are each independently a group, R 1 is selected from one of aryl, alkyl, R 2 is selected from one of aryl, alkyl, R 3 is selected from one of phenyl, alkyl; The structure of the cyclopentenone derivative compound is shown in the formula (II). Formula (II); In formula (II), R 1 , R 2 , R 3 are each independently a group, R 1 is selected from one of aryl, alkyl, R 2 is selected from one of aryl, alkyl, R 3 is selected from one of phenyl, alkyl.

2. The method for synthesizing cyclopentenone derivatives as described in claim 1, characterized in that: The organic solvent includes one or more of 1,2-dichloroethane, N-methylpyrrolidone, dichloromethane, dimethyl sulfoxide, methyl tert-butyl ether and 1,4-dioxane.

3. The synthesis method of the cyclopentenone derivative according to claim 1, characterized by: The concentration of the 2-((Z)-3-iodoallyl)-malononitrile in the organic solvent is 0.1-0.5 mmol / ml.

4. The method for synthesizing cyclopentenone derivatives as described in claim 1, characterized in that: The mass of the formic acid is 120-500% of that of the 2-((Z)-3-iodoallyl)-malononitrile, the mass of the palladium acetate is 1-5% of that of the 2-((Z)-3-iodoallyl)-malononitrile, and the mass of the diisopropylethylamine is 100-500% of that of the 2-((Z)-3-iodoallyl)-malononitrile.

5. The method for synthesizing cyclopentenone derivatives as described in claim 1, characterized in that: The reaction temperature of the heating reaction is 60-100 DEG C, and the reaction time is 12-24 h.

6. A cyclopentenone derivative, characterized by: The cyclopentenone derivative has the structure shown in the formula. 。 7. The application of the cyclopentenone derivative in claim 6 in the preparation of an anticancer drug.

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