Method for synthesizing 2-cyanomethylindoline-3-ketone compound through Cu (0) catalytic system

Abstract

The invention discloses a method for synthesizing 2-cyanomethyl indoline-3-ketone through a Cu (O) catalytic system, and the synthesis method comprises the following steps: reacting a 2-(ethynyl) nitrobenzene compound and an organic phosphorus compound in an acetonitrile solvent under the action of copper powder to obtain a 2-cyanomethyl indoline-3-ketone compound. The method has the advantages of easily available raw materials, mild reaction conditions, simple operation, high yield, wide substrate range, no need of a noble metal catalyst in the reaction and the like. The structure of the prepared 2-cyanomethylindoline-3-ketone compound has certain uniqueness, and the 2-cyanomethylindoline-3-ketone compound can be used for carrying out structural modification and transformation work on subsequent molecules, and shows important application value in the research direction of cytotoxicity in the field of medicinal chemistry.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compounds, and particularly relates to a method for synthesizing 2-cyanomethylindolin-3-one compounds through a Cu(O) catalytic system. Background Art

[0002] Cyano groups are common in drug structures. Since 2012, more than a dozen small molecule drugs approved by the US FDA have incorporated cyano groups into their structures, including bosutinib for the treatment of leukemia and neratinib for the treatment of breast cancer. Furthermore, the cyano group is a versatile group that can be transformed into carboxylic acids, amides, and amines. One of the main strategies for introducing cyano groups into organic compounds is the reaction of α-cyano carbanions. This method is simple and easy to implement, but is generally limited to activated nitriles (J. Org. Chem. 2017, 82, 4489-4496).

[0003] Substituted indole compounds are an important class of organic heterocyclic molecules, whose structural frameworks are ubiquitous in a variety of bioactive molecules, natural products, and multifunctional materials. Indolin-3-one is a key structural motif in natural alkaloids, bioactive compounds, dyes, and fluorescent probes (Org. Lett. 2010, 12, 2370-2373). Indolin-3-one derivatives constitute a class of organic small molecules with enormous potential for biomedical applications.

[0004] Drugs containing cyano functional groups have good biocompatibility, and derivatives of aromatic nitrile compounds are widely used in drugs, dyes, and pesticides. We list several typical cyano-containing drug molecules below, such as carutamide, citalopram, and cyanomemazine. Aryl nitrile compounds are also an important class of intermediates in organic chemistry (Org. Chem. Front, 2014, 1, 186-189). Currently, there are relatively few methods for synthesizing cyano-functionalized indolinone compounds. For example, DTBP is used as an oxidant for synthesis (ChemComm, 2014, 50, 15049-15051); a series of cyano-functionalized 2-indolinone derivatives are obtained using DIAD, DTBP, and copper-catalyzed cyano cycloaddition reactions of activated alkenes (Eur. J. Org. Chem, 2015, 7, 1606-1612).

[0005] Among the reported methods, only one method synthesizes the 2-cyanomethylindolin-3-one structure. This method uses indolinone as a substrate, and a catalytic system consisting of di(dibenzylideneacetone)palladium and tri-tert-amylphosphine is reacted with bromoacetonitrile in a multi-step reaction to obtain the product 2-cyanomethylindolin-3-one. At the same time, preliminary biological activity assays have shown that the selected indole-substituted indolin-3-one exhibits good cytotoxic activity against the human colon cancer cell line HCT-116 (Chem. Commun., 2020, 56, 4660-4663).

[0006] However, the known methods still have many problems, such as complex reaction conditions, many additives, complicated post-processing, unsatisfactory reaction, etc. Therefore, it is of great application value to develop a simple and efficient synthetic method for introducing cyano functional groups into aromatic groups.

[0007] Summary of the Invention

[0008] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0009] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0010] One of the objectives of the present invention is to provide a method for synthesizing 2-cyanomethylindolin-3-one compounds, which has the advantages of readily available raw materials, mild reaction conditions, simple operation, high yield and a wide range of substrates.

[0011] In order to solve the above technical problems, the present invention provides the following technical solution: a method for synthesizing 2-cyanomethylindolin-3-one compounds, comprising:

[0012] 2-(Ethylene)nitrobenzene compounds and triphenylphosphine are added to an organic solvent, heated and stirred, and separated and purified by rotary evaporation chromatography to obtain the target product 2-cyanomethylindolin-3-one;

[0013] The organic solvent is acetonitrile;

[0014] The target product 2-cyanomethylindolin-3-one compound is shown in formula (I):

[0015]

[0016] The 2-(ethynyl)nitrobenzene compound is represented by formula (II):

[0017]

[0018] Among them, R 1 、R 2 are independent groups;

[0019] R 1 One selected from hydrogen, alkyl, alkoxy, halogen, carbonyl, ester, carboxyl, nitro, and cyano;

[0020] R 2 One selected from hydrogen, alkyl, carbonyl, ester, carboxyl, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, thienyl, furyl, indolyl, and trimethylsilyl;

[0021] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the heating and stirring is performed by heating to 20-90° C. and stirring at 400-500 rpm for 3-10 hours.

[0022] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the separation and purification by rotary evaporation chromatography is performed using 100-200 mesh column chromatography silica gel separation, the developing solvent is petroleum ether and ethyl acetate, and the volume ratio of ethyl acetate:petroleum ether is 1:20 to 1:4.

[0023] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the volume molar ratio of the organic solvent to the 2-(ethynyl)nitrobenzene compound is 1:0.1 in mL:mol.

[0024] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the molar ratio of the 2-(ethynyl)nitrobenzene compound to triphenylphosphine is 1 to 3:5.

[0025] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the molar ratio of the 2-(ethynyl)nitrobenzene compound to triphenylphosphine is 1 to 5.

[0026] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the copper catalyst is one or more of copper powder, cuprous oxide, cupric chloride, and cuprous chloride; preferably, the copper catalyst is copper powder.

[0027] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the molar ratio of the copper catalyst to the 2-(ethynyl)nitrobenzene compound is 0.2 to 1:1.

[0028] As a preferred embodiment of the method for synthesizing 2-cyanomethylindolin-3-one compounds of the present invention, the molar ratio of the copper catalyst to the 2-(ethynyl)nitrobenzene compound is 0.2:1.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The present invention provides a simple and efficient synthesis method for 2-cyanomethylindolin-3-one compounds. The required catalyst is inexpensive and readily available, the reaction conditions are mild, the operation is simple, the substrate range is wide, and the yield is high. The present invention provides a copper-catalyzed reaction method for introducing a cyano group into a compound using acetonitrile and 2-(ethynyl)nitrobenzene compounds as raw materials, and efficiently constructs 2-indolone derivatives with cyano functionalization. The discovery of the present invention solves the problem of introducing a cyano functional group into a compound and is of great significance for the transformation of compounds containing a cyano functional group.

[0031] (2) The structure of the 2-cyanomethylindolin-3-one compounds provided by the present invention has certain uniqueness, which can be used for structural modification and transformation of subsequent molecules, and shows important application value in the research direction of cytotoxicity in the field of medicinal chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0033] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target product 1 prepared in Example 1 of the present invention;

[0034] Figure 2 This is the carbon NMR spectrum of the target product 1 prepared in Example 1 of the present invention;

[0035] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the target product 2 prepared in Example 2 of the present invention;

[0036] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the target product 3 prepared in Example 3 of the present invention;

[0037] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the target product 4 prepared in Example 4 of the present invention;

[0038] Figure 6This is the hydrogen nuclear magnetic resonance spectrum of the target product 5 prepared in Example 5 of the present invention;

[0039] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the target product 6 prepared in Example 6 of the present invention;

[0040] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of the target product 7 prepared in Example 7 of the present invention;

[0041] Figure 9 This is the hydrogen nuclear magnetic resonance spectrum of the target product 8 prepared in Example 8 of the present invention;

[0042] Figure 10 This is the hydrogen nuclear magnetic resonance spectrum of the target product 9 prepared in Example 9 of the present invention;

[0043] Figure 11 is the hydrogen nuclear magnetic resonance spectrum of the target product 10 prepared in Example 10 of the present invention; DETAILED DESCRIPTION

[0044] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0045] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0046] Secondly, the term "one embodiment" or "embodiment" 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 various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0047] Example 1

[0048] To a 10 mL test tube, 2-(ethynylphenyl)nitrobenzene 2a (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL) were added sequentially and stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 1 as a yellow solid. The yield was calculated to be 92%.

[0049] The reaction formula of Example 1 is:

[0050]

[0051] The H NMR spectrum of compound 1 prepared in Example 1 is as follows: Figure 1 As shown; the C NMR spectrum of compound 1 prepared in Example 1 is as shown Figure 2 shown.

[0052] 1 H NMR (600MHz, CDCl3) 67.60 (d, J=6.8Hz, 1H), 7.41-7.34 (m, 1H), 7.49 (d, J=7.5Hz, 2H), 7.41-7.33 (m, 3H) , 7.01 (d, J=8.2Hz, 1H), 6.92-6.89 (m, 1H), 5.50 (s, 1H), 3.30 (d, J=16.7Hz, 1H), 2.93 (d, J=16.8Hz, 1H); 13 C NMR (151MHz, CDCl3) δ198.0, 160.2, 138.5, 135.8, 129.3, 128.9, 125.9, 125.3, 120.4, 118.4, 116.6, 112.4, 68.1, 27.2.

[0053] Example 2

[0054] To a 10 mL test tube, 4-fluoro-1-nitro-2-(phenylethynyl)benzene 2b (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL) were added sequentially and stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 2 as a yellow solid. The yield was calculated to be 67%.

[0055] The reaction formula of Example 2 is:

[0056]

[0057] The H NMR spectrum of compound 2 prepared in Example 2 is as follows: Figure 3 shown.

[0058] 1H NMR (400MHz, CDCl3) δ7.49 (d, J=7.3Hz, 2H), 7.43-7.37 (m, 3H), 7.38-7.28 (m, 1H), 7.27 (d, J =7.5Hz, 1H), 7.03-6.97 (m, 1H), 5.47 (s, 1H), 3.29 (d, J = 16.7Hz, 1H), 2.97 (d, J = 16.7Hz, 1H); 13 C NMR (101MHz, CDCl3) δ197.8, 158.4, 156.9, 135.6, 129.4, 129.1, 126.5 (d, J=25. 5Hz), 125.2, 118.9, 116.5, 113.6 (d, J=7.4Hz), 110.6 (d, J=22.7Hz), 69.1, 27.3.

[0059] Example 3

[0060] To a 10 mL test tube were added 4-chloro-2-nitro-1-(phenylethynyl)benzene 2c (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL). The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 3 as a yellow solid. The yield was calculated to be 70%.

[0061] The reaction formula of Example 3 is:

[0062]

[0063] The H NMR spectrum of compound 3 prepared in Example 3 is as follows: Figure 4 shown.

[0064] 1 H NMR (400MHz, CDCl3) δ7.50 (d, J=8.3Hz, 1H), 7.46 (d, J=7.4Hz, 2H), 7.41-7.34 (m, 3H), 7.00 (s, 1H), 6.85 (d, J = 8.3Hz, 1H), 5.75 (s, 1H), 3.28 (d, J = 16.8Hz, 1H), 2.95 (d, J = 16.8Hz, 1H); 13C NMR (101MHz, CDCl3) δ196.7, 160.5, 145.0, 135.4, 129.4, 129.1, 126.8, 125.2, 121.1, 116.7, 116.4, 112.3, 68.5, 27.2.

[0065] Example 4

[0066] To a 10 mL test tube were added 1-((4-fluorophenyl)ethynyl)-2-nitrobenzene 2d (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL) in sequence. The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 4 as a yellow solid. The yield was calculated to be 80%.

[0067] The reaction formula of Example 4 is:

[0068]

[0069] The H NMR spectrum of compound 4 prepared in Example 4 is as follows: Figure 5 shown.

[0070] 1 H NMR (400MHz, CDCl3) δ7.62-7.53(m, 2H), 7.52-7.47(m, 2H), 7.11-7.02(m, 2H), 7.00(d, J=8 .3Hz, 1H), 6.95-6.86 (m, 1H), 5.55 (s, 1H), 3.27 (d, J=16.8Hz, 1H), 2.88 (d, J=16.7Hz, 1H); 13 C NMR (101MHz, CDCl3) δ197.8, 163.0 (J=249.1Hz), 160.0, 138.6, 131.6 (J=3.3Hz), 1 27.3 (J=8.4Hz), 125.9, 120.4, 118.1, 116.4, 116.2 (J=21.8Hz), 112.4, 67.5, 27.5.

[0071] Example 5

[0072] To a 10 mL test tube were added 1-((4-chlorophenyl)ethynyl)-2-nitrobenzene 2e (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL) in sequence. The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 5 as a yellow solid. The yield was calculated to be 87%.

[0073] The reaction formula of Example 5 is:

[0074]

[0075] The H NMR spectrum of compound 5 prepared in Example 5 is as follows: Figure 6 shown.

[0076] 1 H NMR (400MHz, CDCl3) δ7.61-7.51 (m, 2H), 7.45 (d, J=6.9Hz, 2H), 7.34 (d, J=6.8Hz, 2H), 6.99 (d, J=8.3Hz, 1H), 6.93-6.87 (m, 1H), 5.64 (s, 1H), 3.26 (d, J=16.8Hz, 1H), 2.88 (d, J=16.7Hz, 1H); 13 C NMR (101MHz, CDCl3) δ197.6, 160.1, 138.7, 135.1, 134.4, 129.4, 126.9, 125.9, 120.5, 118.0, 116.4, 112.4, 67.5, 27.4.

[0077] Example 6

[0078] To a 10 mL test tube were added 4-methyl-2-nitro-1-(phenylethynyl)benzene 2f (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL). The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 6 as a yellow solid. The yield was calculated to be 65%.

[0079] The reaction formula of Example 6 is:

[0080]

[0081] The H NMR spectrum of compound 6 prepared in Example 6 is as follows: Figure 7 shown.

[0082] 1 H NMR (400MHz, CDCl3) δ7.47 (d, J=8.3Hz, 3H), 7.40-7.30 (m, 3H), 6.81 (s, 1H), 6.72 (d, J =8.0Hz, 1H), 5.44 (s, 1H), 3.28 (d, J = 16.7Hz, 1H), 2.91 (d, J = 16.7Hz, 1H), 2.40 (s, 3H); 13 C NMR (101MHz, CDCl3) δ197.3, 160.8, 150.4, 136.1, 129.3, 128.8, 125.6, 125.2, 122.2, 116.7, 116.1, 112.4, 68.3, 27.2, 22.6.

[0083] Example 7

[0084] To a 10 mL test tube were added 2 g (0.1 mmol) of 1-nitro-2-(p-toluethynyl)benzene, triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL) in sequence. The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 7 as a yellow solid. The yield was calculated to be 92%.

[0085] The reaction formula of Example 7 is:

[0086]

[0087] The H NMR spectrum of compound 7 prepared in Example 7 is as follows: Figure 8 shown.

[0088] 1 H NMR (400MHz, CDCl3) δ7.61-7.49 (m, 2H), 7.38-7.32 (m, 2H), 7.17 (d, J=7.8Hz, 2H), 6.99 (d, J=8.2Hz , 1H), 6.92-6.86 (m, 1H), 5.55 (s, 1H), 3.27 (d, J=16.6Hz, 1H), 2.89 (d, J=16.8Hz, 1H), 2.32 (s, 3H); 13C NMR (101MHz, CDCl3) δ198.3, 160.3, 138.8, 138.3, 132.8, 130.0, 125.8, 125.1, 120.2, 118.3, 116.8, 112.4, 67.9, 27.1, 21.0.

[0089] Example 8

[0090] To a 10 mL test tube were added 1-((4-ethylphenyl)ethynyl)-2-nitrobenzene 2h (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL) in sequence. The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 8 as a yellow solid. The yield was calculated to be 92%.

[0091] The reaction formula of Example 8 is:

[0092]

[0093] The H NMR spectrum of compound 8 prepared in Example 8 is as follows: Figure 9 shown.

[0094] 1 H NMR (400MHz, CDCl3) δ7.58 (d, J=7.8Hz, 1H), 7.56-7.50 (m, 1H), 7.38 (d, J=7.9Hz, 2H), 7.20 (d, J=7.9Hz, 2H), 6.99 (d, J=8.2Hz, 1 H), 6.92-6.84 (m, 1H), 5.57 (s, 1H), 3.27 (d, J=16.7Hz, 1H), 2.90 (d, J=16.7Hz, 1H), 2.62 (q, J=7.6Hz, 2H), 1.20 (t, J=7.6Hz, 3H); 13 C NMR (101MHz, CDCl3) δ198.3, 160.3, 145.1, 138.3, 133.0, 128.8, 125.8, 125.2, 120.2, 118.4, 116.8, 112.4, 68.0, 28.4, 27.1, 15.4.

[0095] Example 9

[0096] To a 10 mL test tube were added 4-fluoro-1-nitro-2-(p-toluethynyl)benzene 2i (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL). The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 9 as a yellow solid. The yield was calculated to be 86%.

[0097] The reaction formula of Example 9 is:

[0098]

[0099] The H NMR spectrum of compound 9 prepared in Example 9 is as follows: Figure 10 shown.

[0100] 1 H NMR (400MHz, CDCl3) δ7.33 (d, J=6.3Hz, 2H), 7.29 (d, J=8.5Hz, 1H), 7.24 (d, J=7.4Hz, 1H), 7.18 (d, J=7.9 Hz, 2H), 6.97 (d, J=9.0Hz, 1H), 5.40 (s, 1H), 3.25 (d, J=16.6Hz, 1H), 2.92 (d, J=16.6Hz, 1H), 2.33 (s, 3H); 13 C NMR (101MHz, CDCl3) δ198.1, 157.1 (d, J = 239.9Hz), 157.0, 139.0, 132.5, 130.1, 126.4 (d, J =25.5Hz), 125.0, 118.9, 116.6, 113.6 (d, J = 7.5Hz), 110.5 (d, J = 22.8Hz), 69.1, 27.2, 21.0.

[0101] Example 10:

[0102] To a 10 mL test tube were added 4-methyl-2-nitro-1-(p-toluethynyl)benzene 2j (0.1 mmol), triphenylphosphine (0.5 mmol), copper powder (20% mmol), and acetonitrile (1 mL). The mixture was stirred at 90°C under nitrogen for 10 hours. The reaction was monitored by TLC. After completion, the solvent was removed by rotary evaporation. The crude product was chromatographed on a 100-200 mesh silica gel column using a gradient elution method consisting of a mixture of petroleum ether and ethyl acetate (volume ratio of 20:1 to 4:1). The eluate was collected and the solvent was removed by rotary evaporation to obtain the desired product 10 as a yellow solid. The yield was calculated to be 72%.

[0103] The reaction formula of Example 10 is:

[0104]

[0105] The H NMR spectrum of compound 10 prepared in Example 10 is as follows: Figure 11 shown.

[0106] 1 H NMR (400MHz, CDCl3) δ7.47 (d, J=8.0Hz, 1H), 7.34 (d, J=8.3Hz, 2H), 7.17 (d, J=7.9Hz, 2H), 6.80 (s, 1H), 6.7 1 (d, J=8.0Hz, 1H), 5.40 (s, 1H), 3.26 (d, J=16.8Hz, 1H), 2.89 (d, J=16.7Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H); 13 C NMR (101MHz, CDCl3) δ197.5, 160.7, 150.3, 138.7, 133.1, 130.0, 125.6, 125.1, 122.1, 116.8, 116.2, 112.4, 68.7, 27.1, 22.6, 21.1.

[0107] Example 11

[0108] Example 11 is basically the same as Example 1, except for the addition amount of the organophosphorus compound, the temperature, and the copper catalyst, as shown in Table 1 below.

[0109] Table 1

[0110]

[0111] As can be seen from Table 1, under the same reactions conditions, the consumption of triphenylphosphine is larger on reaction influence, and when the consumption of triphenylphosphine is reduced to 0.3mmol, 0.2mmol and 0.12mmol, reaction yield is reduced to 75%, 70% and 60%, and productive rate decreases successively.When the temperature of reaction is reduced to 60 ℃, the product of trace amount can only be detected by TLC, and when the temperature of reaction is reduced to 60 ℃, reaction yield is reduced to 55%.Under the same reactions conditions, use CuCl Observe faint product point, can not obtain product with CuCl, CuBr, use Cu O is 91% as catalyst yield.The consumption of the preferred triphenylphosphine of the present invention is 0.5mmol, and temperature of reaction is 90 ℃, and copper powder realizes optimum yield as catalyzer.

[0112] In the preparation of the target product of the present invention, a series of 2-cyanomethylindolin-3-one compounds can be efficiently synthesized by regulating a series of conditions, including the type of copper catalyst selected, the amount of organophosphorus added, and the reaction temperature. Among them, copper powder has the best effect and the highest yield when used with different copper catalysts, such as cupric chloride, cuprous chloride, cuprous bromide, and cuprous oxide. The target product can be obtained at different temperatures within the range of 60 to 90°C, with 90°C being the most effective and having the highest yield. The corresponding product can be obtained with different amounts of organophosphorus added, ranging from 1.2 to 5 equivalents, with 5 equivalents being the most effective and having the highest yield.

[0113] The present invention provides a simple and efficient synthesis method of 2-cyanomethylindolin-3-one compounds. The method comprises the following steps: an organic phosphorus compound is reacted with a 2-(ethynyl)nitrobenzene compound to obtain a reaction intermediate, an imine ketone, and the target product, 2-cyanomethylindolin-3-one compounds, is obtained under the catalytic action of copper.

[0114] The raw material used in the present invention, 2-(ethynyl)nitrobenzene, is readily available, and the reaction does not require a metal catalyst. The reaction conditions are mild, the operation is simple, the substrate range is wide, and the yield is high. Nitriles are very common among active drug molecules and are widely used in the pharmaceutical industry. The present invention provides a reaction method for introducing a cyano group into a compound, offering a new method for efficiently constructing cyano-functionalized 2-indoleone derivatives.

[0115] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing 2-cyanomethylindolin-3-one compounds using a Cu(0) catalytic system, characterized in that: include, 2-(Ethylene)nitrobenzene compounds, triphenylphosphine, and copper powder are added to an organic solvent, heated and stirred, and separated and purified by rotary evaporation chromatography to obtain the target product 2-cyanomethylindolin-3-one; The organic solvent is acetonitrile; The target product 2-cyanomethylindolin-3-one compound is shown in formula (I): The 2-(ethynyl)nitrobenzene compound is represented by formula (II): In formulas (I) to (II), R 1 、R 2 are independent groups; R 1 One selected from hydrogen, alkoxy, halogen, carbonyl, ester, carboxyl, nitro, and cyano; R 2 One selected from hydrogen, alkyl, carbonyl, ester, carboxyl, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, thienyl, furyl, indolyl, and trimethylsilyl.

2. The method for synthesizing 2-cyanomethylindolin-3-one compounds as claimed in claim 1, wherein: The heating and stirring is heating to 20-90° C. and stirring at 400-500 rpm for 3-10 hours.

3. The method for synthesizing 2-cyanomethylindolin-3-one compounds as claimed in claim 1 or 2, wherein The rotary evaporation chromatography is used for separation and purification, which adopts 100-200 mesh column chromatography silica gel separation, and the developing solvent is petroleum ether and ethyl acetate, and the volume ratio of ethyl acetate: petroleum ether is 1:20-1:

4.

4. The method for synthesizing 2-cyanomethylindolin-3-one compounds according to claim 1 or 2, wherein: The volume molar ratio of the organic solvent to the 2-(ethynyl)nitrobenzene compound is 1:0.1 in mL:mol.

5. The method for synthesizing 2-cyanomethylindolin-3-one compounds as claimed in claim 1, wherein: The molar ratio of the 2-(ethynyl)nitrobenzene compound to triphenylphosphine is 1 to 3:

5.

6. The method for synthesizing 2-cyanomethylindolin-3-one compounds according to claim 1 or 5, wherein: The molar ratio of the 2-(ethynyl)nitrobenzene compound to triphenylphosphine is 1-5.

7. The method for synthesizing 2-cyanomethylindolin-3-one compounds according to any one of claims 1, 2 and 4, wherein: The copper catalyst is one or more of copper powder, cuprous oxide, cupric chloride, and cuprous chloride.

8. The method for synthesizing 2-cyanomethylindolin-3-one compounds according to claim 1, wherein: The molar ratio of the copper catalyst to the 2-(ethynyl)nitrobenzene compound is 0.2-1:

1.

9. The method for synthesizing 2-cyanomethylindolin-3-one compounds according to claim 1, wherein: The molar ratio of the copper catalyst to the 2-(ethynyl)nitrobenzene compound is 0.2:1.

Images