A method for coupling reaction of quinoxalinone and its derivatives with electrophilic reagents catalyzed by lithium silylamine

Abstract

The present invention discloses a method for the coupling reaction of quinoxalinones and their derivatives with electrophiles catalyzed by lithium bis(trimethylsilyl)amide, comprising the following steps: under the protection of an inert gas, quinoxalinones and their derivatives react with electrophiles in the presence of lithium bis(trimethylsilyl)amide, diethyl phosphite and a solvent to carry out a coupling reaction, obtaining functionalized quinoxalinones and their derivatives. The present invention uses a lithium bis(trimethylsilyl)amide catalyst with a simple structure and a low usage amount, achieving efficient catalysis for the coupling reaction of quinoxalinones and their derivatives with electrophiles under mild reaction conditions. It not only significantly reduces the dependence on excessive bases or oxidants, but also greatly shortens the reaction time, improves the reaction efficiency, and prepares a series of 3-position functionalized quinoxalinones and their derivatives, and the reaction has good generality.

Description

Technical Field

[0001] The present invention relates to the technical field of quinoxalinone functionalization, and particularly to a method for catalyzing the coupling reaction of quinoxalinone and its derivatives with electrophiles by lithium silylamine. Background Art

[0002] Quinoxalinone and its derivatives, as a class of key heterocyclic nitrogen compounds, are widely present in natural products and drug molecules. Due to their unique chemical structures and diverse biological activities, these compounds have received extensive attention and research. Especially, C(3)-substituted quinoxalinones not only exhibit important biological activities and a wide range of pharmacological effects, such as anti-tumor, anti-diabetic, anti-depressant, antibacterial, antiviral, anti-inflammatory, antioxidant, anti-convulsant, anti-allergic, and anti-thrombotic effects, but also are important precursors for synthesizing aminoquinoxalinones, thioquinoxalinones, and other substances.

[0003] In the research on the functionalization of the C(3) position of quinoxalinone, a variety of methods have been developed, mainly including two categories: transition metal promotion and photo-promotion. These methods involve various reaction types such as alkylation, amination, and arylation, and involve free radical mechanisms or transition metal coordination activation mechanisms, providing multiple ways to achieve the functionalization of the C(3) position of quinoxalinone.

[0004] However, although these methods have made certain progress in the functionalization of the C(3) position of quinoxalinone, there are still some problems and challenges. First, in most reactions, an excessive amount of base or a greatly excessive amount of oxidant is required, which leads to relatively harsh reaction conditions, not only increasing the production cost but also potentially having a negative impact on the environment. Second, although photocatalytic and photo-promoted C(3) position functionalization reactions of quinoxalinone have received increasing attention in recent years, transition metal-catalyzed reactions of this type still occupy the mainstream position. This to a certain extent limits the selectivity and efficiency of the reaction, and also increases the cost and complexity of the catalyst. Therefore, there is an urgent need to develop a method for the functionalization of the C(3) position of quinoxalinone with mild conditions, inexpensive and easily available catalysts, and higher efficiency to overcome the deficiencies of the existing technology. Summary of the Invention

[0005] To solve the above technical problems, the object of the present invention is to provide a method for catalyzing the coupling reaction of quinoxalinone and its derivatives with electrophiles by lithium silylamine. By using a lithium silylamine catalyst with a simple structure and a low dosage, high-efficiency catalysis is achieved under mild reaction conditions, not only significantly reducing the dependence on excessive base or oxidant, but also greatly shortening the reaction time and improving the reaction efficiency.

[0006] The above object of the present invention is achieved by the following technical solutions:

[0007] A method for the coupling reaction of quinoxalinone and its derivatives with electrophiles catalyzed by lithium silylamine, comprising the following steps: Under the protection of an inert gas, quinoxalinone and its derivatives react with electrophiles in the presence of lithium bis(trimethylsilyl)amide (LiN(SiMe3)2), diethyl phosphite, and a solvent to carry out a coupling reaction to obtain functionalized quinoxalinone and its derivatives;

[0008] The structural formula of the quinoxalinone and its derivatives is , where R1 is selected from one of saturated or unsaturated alkyl, benzyl, and ethoxycarbonylmethyl, and R2, R3, R4, and R5 are each independently selected from one of hydrogen, halogen, and saturated or unsaturated alkyl;

[0009] The electrophile is selected from one or more of methyl acrylate, methyl methacrylate, and phenyl vinyl sulfone;

[0010] The amount of lithium bis(trimethylsilyl)amide used accounts for 1-5 mol% of the amount of quinoxalinone and its derivatives used.

[0011] The present invention provides a method for the coupling reaction of quinoxalinone and its derivatives with electrophiles catalyzed by lithium silylamine. Different from most of the reported photocatalytic or transition-metal-catalyzed functionalization reactions of quinoxalinone and its derivatives that undergo a radical process, the reaction mechanism of the present invention may undergo a 1,2-hydrogen migration process, achieving the polarity inversion of the carbon-nitrogen double bond, and then the reaction of the carbanion with the electrophile, finally obtaining the target product.

[0012] Further, the inert gas is argon.

[0013] Further, R1 is selected from one of C1-C8 saturated or unsaturated alkyl, benzyl, and ethoxycarbonylmethyl.

[0014] Further, R1 is selected from one of methyl, ethyl, n-octyl, allyl, and benzyl.

[0015] Further, R2, R3, R4, and R5 are each independently selected from one of hydrogen, halogen, and C1-C8 saturated alkyl.

[0016] Further, R2, R3, R4, and R5 are each independently selected from one of hydrogen, chlorine, bromine, and methyl.

[0017] Further, the quinoxalinone and its derivatives are selected from the compounds shown in the following structures:

[0018] .

[0019] Preferably, the amount of lithium bis(trimethylsilyl)amide used accounts for 1-5 mol% of the amount of quinoxalinone and its derivatives used.

[0020] Furthermore, the molar ratio of the quinoxalinone and its derivatives to the electrophilic reagent is 1:(1 - 5), preferably 1:(1.1 - 3.3).

[0021] Furthermore, the molar ratio of the quinoxalinone and its derivatives to diethyl phosphite is 1:(1 - 3).

[0022] Furthermore, the coupling reaction is carried out at 20 - 70 °C, preferably at 20 - 40 °C, more preferably at 20 - 25 °C.

[0023] Furthermore, the time of the coupling reaction is 3 min - 3 h, preferably 3 - 10 min.

[0024] Furthermore, the solvent is selected from one or more of mesitylene, n - hexane, toluene, 1,2 - dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile and N,N - dimethylformamide, and preferably solvents with relatively low polarity, such as one or more of n - hexane, toluene and mesitylene.

[0025] The beneficial effects of the present invention are as follows:

[0026] The present invention uses the lithium bis(trimethylsilyl)amide catalyst with a simple structure and low usage amount, realizing the efficient catalysis of the coupling reaction of quinoxalinone and its derivatives with electrophilic reagents under mild reaction conditions. It not only significantly reduces the dependence on excessive bases or oxidants, but also greatly shortens the reaction time, improves the reaction efficiency, and prepares a series of 3 - position functionalized quinoxalinone and its derivatives, and the reaction has good generality. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The crystal structure diagram of 3 - methoxycarbonylethyl - functionalized N - ethylquinoxalinone prepared in Example 1.

[0028] Figure 2 The crystal structure diagram of 4,4'-diethyl - [2,2'-biquinoxaline]-3,3'-dione prepared in Comparative Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0030] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the embodiments cited are not intended to limit the present invention.

[0031] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified.

[0032] The room temperature in the following examples and comparative examples is 25 °C.

[0033] Example 1

[0034] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone (1-ethylquinoxalin-2(1H)-one) with methyl acrylate, comprising the following steps:

[0035] Under the condition of argon protection, LiN(SiMe3)2 (1.5 mol%, dosage relative to 1a) and 0.22 mmol diethyl phosphite (HOP(OEt)2) were added to the reaction flask and stirred at room temperature, and then 0.20 mmol N -ethylquinoxalinone 1a, 0.22 mmol methyl acrylate 5a ( ) and 0.5 mL mesitylene were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction system was quenched with water, it was separated by flash column chromatography to obtain a white solid. From the results of 1H NMR, 13C NMR, high-resolution mass spectrometry and X-ray single crystal diffraction analysis, it can be known that the white solid is 3-methoxycarbonylethyl-functionalized N -ethylquinoxalinone 6aa, and the reaction equation for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with methyl acrylate is:

[0036] .

[0037] The product has the following 1H NMR data:

[0038] 1 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J J = 10.0 Hz, 1H), 7.52 (t, J J = 7.8 Hz,1H), 7.33 – 7.28 (m, 2H), 4.32 (q, J J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.28 (t, J= 7.0 Hz, 2H), 2.88 (t, J = 7.0 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) ppm。

[0039] 3-Methoxycarbonylethyl-functionalized N -ethylquinoxalinone 6aa is shown in the crystal structure diagram as Figure 1 follows, 30% ellipsoid; CCDC 2428753. Example 1 confirmed that the electropositive carbon of the carbon-nitrogen double bond in quinoxalinone was coupled with the electropositive carbon of the carbon-carbon double bond in the Michael acceptor methyl acrylate.

[0040] Example 2

[0041] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with methyl acrylate, comprising the following steps:

[0042] Under the protection of argon, LiN(SiMe3)2 (1.5 mol%, the dosage relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and mixed and stirred, and then 0.20 mmol N -ethylquinoxalinone, 0.44 mmol methyl acrylate and 0.5 mL mesitylene were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction system was quenched with water, it was separated by flash column chromatography to obtain 3-methoxycarbonylethyl-functionalized N -ethylquinoxalinone.

[0043] Example 3

[0044] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with methyl acrylate, comprising the following steps:

[0045] Under the protection of argon, LiN(SiMe3)2 (1.5 mol%, the dosage relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and mixed and stirred, and then 0.20 mmol N -ethylquinoxalinone, 0.66 mmol methyl acrylate and 0.5 mL mesitylene were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction system was quenched with water, it was separated by flash column chromatography to obtain 3-methoxycarbonylethyl-functionalized N -ethylquinoxalinone.

[0046] Example 4

[0047] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with methyl acrylate is basically the same as Example 3, except that the reaction is carried out at 50 °C.

[0048] Example 5

[0049] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with methyl acrylate is basically the same as Example 3, except that the reaction is carried out at 70 °C.

[0050] Example 6

[0051] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with methyl acrylate comprises the following steps:

[0052] Under the protection of argon, LiN(SiMe3)2 (1.5 mol%, dosage relative to N -ethylquinoxalinone) and 0.22 mmol of diethyl phosphite are added to the reaction flask and mixed and stirred. Then, 0.20 mmol of N -ethylquinoxalinone, 0.66 mmol of methyl acrylate and 0.5 mL of mesitylene are added in sequence, and the reaction is carried out at room temperature for 30 min. After the reaction system is quenched with water, it is separated by flash column chromatography to obtain 3-methoxycarbonylethyl-functionalized N -ethylquinoxalinone.

[0053] Example 7

[0054] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with methyl acrylate comprises the following steps:

[0055] Under the protection of argon, LiN(SiMe3)2 (1.5 mol%, dosage relative to N -ethylquinoxalinone) and 0.22 mmol of diethyl phosphite are added to the reaction flask and mixed and stirred. Then, 0.20 mmol of N -ethylquinoxalinone, 0.66 mmol of methyl acrylate and 0.5 mL of mesitylene are added in sequence, and the reaction is carried out at room temperature for 5 min. After the reaction system is quenched with water, it is separated by flash column chromatography to obtain 3-methoxycarbonylethyl-functionalized N -ethylquinoxalinone.

[0056] Example 8

[0057] A method for the coupling reaction of LiN(SiMe3)2-catalyzed NMethod for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by n-hexane.

[0058] Example 9

[0059] A method catalyzed by LiN(SiMe3)2 N Method for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by toluene.

[0060] Example 10

[0061] A method catalyzed by LiN(SiMe3)2 N Method for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by 1,2-dichloroethane.

[0062] Example 11

[0063] A method catalyzed by LiN(SiMe3)2 N Method for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by dichloromethane.

[0064] Example 12

[0065] A method catalyzed by LiN(SiMe3)2 N Method for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by tetrahydrofuran.

[0066] Example 13

[0067] A method catalyzed by LiN(SiMe3)2 N Method for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by acetonitrile.

[0068] Example 14

[0069] A method catalyzed by LiN(SiMe3)2 N Method for the coupling reaction of -ethylquinoxalinone with methyl acrylate, which is basically the same as Example 7, except that: mesitylene is replaced by N,N -dimethylformamide.

[0070] Example 15

[0071] A method catalyzed by LiN(SiMe3)2 NThe method for the coupling reaction of -ethylquinoxalinone with methyl acrylate is basically the same as that in Example 7, except that: 0.5 mL of mesitylene is replaced by 0.3 mL of mesitylene.

[0072] Example 16

[0073] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with methyl acrylate is basically the same as that in Example 7, except that: 0.5 mL of mesitylene is replaced by 1.0 mL of mesitylene.

[0074] Example 17

[0075] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with methyl acrylate comprises the following steps:

[0076] Under the protection of argon, LiN(SiMe3)2 (1.0 mol%, dosage relative to N -ethylquinoxalinone) and 0.22 mmol of diethyl phosphite are added to the reaction flask and mixed and stirred, and then 0.20 mmol of N -ethylquinoxalinone, 0.66 mmol of methyl acrylate and 0.5 mL of mesitylene are successively added, and the reaction is carried out at room temperature for 5 min. After the reaction system is quenched with water, it is separated by flash column chromatography to obtain 3-methoxycarbonylethyl-functionalized N -ethylquinoxalinone.

[0077] Example 18

[0078] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -methylquinoxalinone with methyl acrylate is basically the same as that in Example 17, except that: N -ethylquinoxalinone is replaced by N -methylquinoxalinone 1b ( ).

[0079] The product has the following 1H NMR data:

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.34 – 7.28 (m, 2H), 3.70 (s, 3H), 3.69 (s, 3H), 3.28 (t, J= 7.1 Hz, 2H), 2.88 (t, J = 7.0 Hz, 2H) ppm。

[0081] Example 19

[0082] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -n-octylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -ethylquinoxalinone is replaced with N -n-octylquinoxalinone 1c ( ).

[0083] The product has the following 1H NMR data:

[0084] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 9.7 Hz, 1H), 7.53 – 7.49 (m, 1H),7.32 – 7.28 (m, 2H), 4.25 – 4.21 (m, 2H), 3.70 (s, 3H), 3.28 (t, J = 7.0 Hz,2H), 2.88 (t, J = 7.0 Hz, 2H), 1.78 – 1.71 (m, 2H), 1.46 – 1.28 (m, 10H), 0.90– 0.86 (m, 3H) ppm。

[0085] Example 20

[0086] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -allylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -ethylquinoxalinone is replaced with N -allylquinoxalinone 1d ( ).

[0087] The product has the following 1H NMR data:

[0088] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J= 9.6 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.33 – 7.26 (m, 2H), 5.98 – 5.88 (m, 1H), 5.26 (d, J = 10.5 Hz, 1H), 5.17 (d, J = 14.5 Hz, 1H), 4.90 (d, J = 7.0 Hz, 2H), 3.70 (s, 3H), 3.29 (t, J = 6.9 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H) ppm。

[0089] Example 21

[0090] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -benzylquinoxalinone with methyl acrylate is basically the same as Example 17, except that: N -ethylquinoxalinone is replaced with N -benzylquinoxalinone 1e ( ).

[0091] Product The 1H NMR data are as follows:

[0092] 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.9 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.32 – 7.27 (m, 3H), 7.26 – 7.22 (m, 4H), 5.49 (s, 2H), 3.71 (s, 3H), 3.34 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H) ppm。

[0093] Example 22

[0094] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethoxycarbonylmethylquinoxalinone with methyl acrylate is basically the same as Example 17, except that: N -ethylquinoxalinone is replaced with N -ethoxycarbonylmethylquinoxalinone 1f ( ).

[0095] Product The 1H NMR data are as follows:

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.84 – 7.82 (m, 1H), 7.51 – 7.48 (m, 1H),7.36 – 7.32 (m, 1H), 7.06 (d, J J = 9.6 Hz, 0H), 5.04 (s, 1H), 3.78 (s, 1H), 3.71(s, 1H), 3.29 (t, J J = 7.0 Hz, 1H), 2.89 (t, J J = 7.0 Hz, 1H), 1.67 (s, 2H) ppm。

[0097] Example 23

[0098] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-5-chloroquinoxalinone with methyl acrylate is basically the same as Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-5-chloroquinoxalinone 1 g ( ).

[0099] The product The 1H NMR data are as follows:

[0100] 1 H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, 2H), 7.24 – 7.22 (m, 1H),4.31 (q, J J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.32 (t, J J = 6.7 Hz, 2H), 2.91 (t, J J = 6.7Hz, 2H), 1.36 (t, J J = 7.2 Hz, 3H) ppm。

[0101] Example 24

[0102] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-6-chloroquinoxalinone with methyl acrylate is basically the same as Example 17, except that: N -ethylquinoxalinone is replaced with N-Ethyl-6-chloroquinoxalin-1(2H)-one )

[0103] The 1H NMR data of the product are as follows:

[0104] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J J = 2.5 Hz, 1H), 7.47 (dd, J J = 8.9, 2.5Hz, 1H), 7.26 (d, J J = 7.1 Hz, 1H), 4.29 (q, J J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.27(t, J J = 6.9 Hz, 2H), 2.86 (t, J J = 6.9 Hz, 2H), 1.36 (t, J J = 7.2 Hz, 3H) ppm.

[0105] Example 25

[0106] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -Ethyl-7-chloroquinoxalin-1(2H)-one with methyl acrylate is basically the same as Example 17, except that: N -Ethylquinoxalin-1(2H)-one is replaced with N -Ethyl-7-chloroquinoxalin-1(2H)-one 1i ( )

[0107] The 1H NMR data of the product are as follows:

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J J = 8.5 Hz, 1H), 7.30 – 7.26 (m, 2H),4.26 (q, J J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.26 (t, J J = 6.9 Hz, 2H), 2.86 (t, J J = 6.9Hz, 2H), 1.37 (t, J J = 7.2 Hz, 3H) ppm.

[0109] Example 26

[0110] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-8-chloroquinoxalinone with methyl acrylate is basically the same as that of Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-8-chloroquinoxalinone 1j ( ).

[0111] The 1H NMR data of the product are as follows:

[0112] 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.68 (m, 1H), 7.60 – 7.57 (m, 1H), 7.50 – 7.46 (m, 1H), 4.56 (q, J J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.32 (t, J J = 7.0 Hz, 2H), 2.98 (t, J J = 7.0 Hz, 2H), 1.49 (t, J J = 7.1 Hz, 3H) ppm.

[0113] Example 27

[0114] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-5-methylquinoxalinone with methyl acrylate is basically the same as that of Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-5-methylquinoxalinone 1k ( ).

[0115] The 1H NMR data of the product are as follows:

[0116] 1 H NMR (400 MHz, CDCl3) δ 7.39 (t, J J = 7.9 Hz, 1H), 7.16 (d, J J = 9.4 Hz, 2H), 4.31 (q, J J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.31 (t, J J = 6.7 Hz, 2H), 2.87 (t, J J = 6.7 Hz, 2H), 2.62 (s, 3H), 1.36 (t,J = 7.2 Hz, 3H) ppm.

[0117] Example 28

[0118] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-6-methylquinoxalinone with methyl acrylate is basically the same as Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-6-methylquinoxalinone 1l ( ).

[0119] The product has the following 1H NMR data:

[0120] 1 H NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (m, 1H), 7.35 – 7.28 (m, 1H),7.22 – 7.14 (m, 1H), 4.29 (q, J = 6.6 Hz, 2H), 3.70 (d, J = 2.6 Hz, 3H), 3.29 –3.24 (m, 2H), 2.89 – 2.85 (m, 2H), 2.47 (d, J = 28.4 Hz, 3H), 1.39 – 1.34 (m,3H) ppm.

[0121] Example 29

[0122] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-7-bromoquinoxalinone with methyl acrylate is basically the same as Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-7-bromoquinoxalinone 1n ( ).

[0123] The product has the following 1H NMR data:

[0124] 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.9, 2.3Hz, 1H), 7.19 (d, J= 8.9 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.28(t, J = 6.9 Hz, 2H), 2.86 (t, J = 6.8 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H) ppm。

[0125] Example 30

[0126] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-6,7-dimethylquinoxalinone with methyl acrylate is basically the same as that in Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-6,7-dimethylquinoxalinone 1o ( ).

[0127] The product has the following 1H NMR data:

[0128] 1 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.07 (s, 1H), 4.29 (q, J = 7.3Hz, 2H), 3.70 (s, 3H), 3.25 (t, J = 7.1 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H), 2.41(s, 3H), 2.33 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H) ppm.

[0129] Example 31

[0130] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethyl-6,7-dichloroquinoxalinone with methyl acrylate is basically the same as that in Example 17, except that: N -ethylquinoxalinone is replaced with N -ethyl-6,7-dichloroquinoxalinone 1p ( ).

[0131] The product has the following 1H NMR data:

[0132] 11H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.39 (s, 1H), 4.25 (q, J J = 7.2Hz, 2H), 3.71 (s, 3H), 3.26 (t, J J = 6.8 Hz, 2H), 2.85 (t, J J = 6.8 Hz, 2H), 1.37(t, J J = 7.2 Hz, 3H) ppm。

[0133] Example 32

[0134] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with methyl methacrylate is basically the same as Example 17, except that: methyl acrylate is replaced by methyl methacrylate 5b ( ).

[0135] The product has the following 1H NMR data:

[0136] 1 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J J = 8.3 Hz, 1H), 7.54 – 7.50 (m, 1H),7.33 – 7.29 (m, 2H), 4.31 (q, J J = 7.3 Hz, 2H), 3.68 (s, 3H), 3.39 – 3.33 (m,1H), 3.26 – 3.17 (m, 1H), 3.06 (dd, J J = 16.8, 5.5 Hz, 1H), 1.37 (t, J J = 7.2 Hz,3H), 1.32 (d, J J = 7.0 Hz, 3H) ppm。

[0137] Example 33

[0138] A method for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with phenyl vinyl sulfone is basically the same as Example 17, except that: methyl acrylate is replaced by phenyl vinyl sulfone 7 ( ).

[0139] The product has the following 1H NMR data:

[0140] 1 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.95 (m, 2H), 7.77 (d, J J = 8.0 Hz, 1H),7.61 – 7.50 (m, 4H), 7.34 – 7.28 (m, 2H), 4.27 (q, J J = 7.2 Hz, 2H), 3.78 – 3.75(m, 2H), 3.36 – 3.32 (m, 2H), 1.34 (t, J J = 7.2 Hz, 3H) ppm。

[0141] Comparative Example 1

[0142] A method for the reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with diethyl phosphite, comprising the following steps:

[0143] Under the protection of argon, LiN(SiMe3)2 (1.5 mol%, dosage relative to 1a), 0.22 mmol of diethyl phosphite 2, 0.20 mmol of N -ethylquinoxalinone 1a and 0.5 mL of mesitylene were stirred and mixed, and after reacting at room temperature for 30 min, the reaction was quenched with water. After the reaction system was separated by flash column chromatography, a colorless oil and a less polar red solid were obtained. Through analysis by 1H NMR, 13C NMR, high-resolution mass spectrometry, deuterium oxide experiment, X-ray single crystal diffraction, etc., it was confirmed that the colorless oil was the product 3a of the hydrophosphination reaction of the C=N double bond of the substrate 1a with diethyl phosphite, and the red solid was the coupling product 4a of the dimerization of 1a. The reaction equation for the reaction of LiN(SiMe3)2 catalyzed N -ethyl-substituted quinoxalinone with diethyl phosphite is as follows:

[0144] .

[0145] The 1H NMR data of the product are as follows:

[0146] 1 1H NMR (400 MHz, CDCl3) δ 6.93 – 6.77 (m, 4H), 4.61 (s, 1H), 4.40 (d, J J = 12.1 Hz, 1H), 4.22 – 4.06 (m, 3H), 3.99 – 3.87 (m, 2H), 3.81 – 3.70 (m,1H), 1.35 (t, J= 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H) ppm.

[0147] The crystal structure diagram of the coupling product 4a (4,4'-diethyl-[2,2'-biquinoxaline]-3,3'-dione) is as shown in Figure 2 Figure; 30% ellipsoid ratio; CCDC 2431864.

[0148] Comparative Example 2

[0149] A method for the coupling reaction of N -ethylquinoxalinone with methyl acrylate is basically the same as that in Example 1, except that: diethyl phosphite is not added.

[0150] Comparative Example 3

[0151] A method for catalyzing N the coupling reaction of N -ethylquinoxalinone with methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe3)2 (1.5 mol%, dosage relative to N -ethylquinoxalinone) is replaced by LiN(SiMe3)2 (0.5 mol%, dosage relative to

[0152] -ethylquinoxalinone).

[0153] A N method for the coupling reaction of

[0154] -ethylquinoxalinone with methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe3)2 is not added.

[0155] A method for catalyzing N the coupling reaction of

[0156] -ethylquinoxalinone with methyl acrylate by NaN(SiMe3)2 is basically the same as that in Example 7, except that: LiN(SiMe3)2 is replaced by NaN(SiMe3)2.

[0157] A method for catalyzing N the coupling reaction of

[0158] Comparative Example 7

[0159] A method for the coupling reaction of NaOH-catalyzed N -ethylquinoxalinone with methyl acrylate is basically the same as Example 7, except that LiN(SiMe3)2 is replaced by NaOH.

[0160] Comparative Example 8

[0161] A method for the coupling reaction of DBU-catalyzed N -ethylquinoxalinone with methyl acrylate is basically the same as Example 7, except that LiN(SiMe3)2 is replaced by DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

[0162] Comparative Example 9

[0163] A n BuLi-catalyzed N method for the coupling reaction of -ethylquinoxalinone with methyl acrylate is basically the same as Example 7, except that LiN(SiMe3)2 is replaced by n BuLi (n-butyllithium).

[0164] Comparative Example 10

[0165] A method for the coupling reaction of LDA-catalyzed N -ethylquinoxalinone with methyl acrylate is basically the same as Example 7, except that LiN(SiMe3)2 is replaced by LDA (lithium diisopropylamide).

[0166] Comparative Example 11

[0167] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethyl-6-methoxyquinoxalinone with methyl acrylate is basically the same as Example 17, except that N -ethylquinoxalinone is replaced by N -ethyl-6-methoxyquinoxalinone 1m ( ).

[0168] Comparative Example 12

[0169] A method for the coupling reaction of LiN(SiMe3)2-catalyzed N -ethylquinoxalinone with chalcone is basically the same as Example 17, except that methyl acrylate is replaced by chalcone 9 ( ).

[0170] The 1H NMR data of the product are as follows:

[0171] 1H NMR (400 MHz, CDCl3) δ 8.02 – 8.00 (m, 2H), 7.73 (dd, J = 8.0, 1.5Hz, 1H), 7.57 – 7.43 (m, 6H), 7.31 – 7.27 (m, 3H), 7.25 – 7.19 (m, 2H), 5.41(dd, J = 10.6, 4.1 Hz, 1H), 4.48 – 4.41 (m, 1H), 4.31 – 4.19 (m, 2H), 3.42 (dd, J = 17.7, 4.1 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H) ppm.

[0172] Test Example 1

[0173] Examples 1-7 and Comparative Example 2 explored the feed ratio of the reaction ( N -Ethylquinoxalinone, diethyl phosphite and methyl acrylate), temperature and time have an important influence on the catalytic activity of LiN(SiMe3)2 N -Effect of the coupling reaction of ethylquinoxalinone and methyl acrylate, the test results are shown in Table 1:

[0174] Table 1 Reaction parameters and product separation yields of Examples 1-7 and Comparative Example 2

[0175]

[0176] As can be seen from Table 1, although the 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone has no phosphate group in its structure, but in Comparative Example 2, no diethyl phosphite was added, and no 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone is generated, which illustrates the necessity of diethyl phosphite in the reaction system. Compared with Example 1, Example 2 and Example 3 illustrate that increasing the amount of methyl acrylate can improve the separation yield of the product, reaching 74% and 81% respectively. Compared with Example 3, Example 4 and Example 5 show that the increase in temperature has little effect on the separation yield of the product. Compared with Example 3, Example 6 and Example 7 found that if the reaction time is shortened from 2 h to 30 min or 5 min, the reaction can still proceed smoothly and achieve almost the same separation yield.

[0177] Test Example 2

[0178] Examples 7 - 16 explored the effects of the type and amount of solvent on the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with methyl acrylate, and the test results are shown in Table 2:

[0179] Table 2 Reaction parameters and separation yields of products in Examples 7 - 16

[0180]

[0181] As can be seen from Table 2, the increase in solvent polarity is accompanied by a gradual decrease in the separation yield of the product. When the solvents are n - hexane, toluene, and mesitylene with relatively low polarity, the reaction yields are all relatively high. Although the reaction can reach a 70% yield when n - hexane is used as the solvent, n - hexane has poor solubility for the reaction substrate N -ethylquinoxalinone; compared with toluene as the reaction solvent with a yield of 63%, mesitylene can reach a higher yield of 81%. The reaction yields of solvents such as 1,2 - dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile, and N,N N,N - dimethylformamide are all relatively low. Therefore, mesitylene is the best solvent for the coupling reaction of LiN(SiMe3)2 catalyzed N -ethylquinoxalinone with methyl acrylate. In addition, compared with Example 7, Examples 15 and 16 show that 0.3 mL and 0.5 mL of mesitylene have little difference in the reaction yield, but the yield will decrease when 1.0 mL of mesitylene is used as the solvent for this reaction. Considering that 0.5 mL of mesitylene can dissolve the raw materials more fully and enable the reaction to proceed smoothly, 0.5 mL is selected as the optimal amount of the solvent.

[0182] Test Example 3

[0183] Examples 7, 17 and Comparative Examples 3 - 10 explored the effects of the type and amount of catalyst on the coupling reaction of N -ethylquinoxalinone with methyl acrylate, and the test results are shown in Table 3:

[0184] Table 3 Reaction parameters and separation yields of products in Examples 7, 17 and Comparative Examples 3 - 10

[0185]

[0186] As can be seen from Table 3, when the amount of the catalyst is reduced to 1.0 mol%, the reaction yield does not decrease significantly; when the amount of the catalyst is reduced to 0.5 mol%, the reaction hardly occurs. In addition, Comparative Example 4 shows that the reaction cannot proceed without a catalyst. Among several silylamino alkali metal salts, LiN(SiMe3)2 has the best catalytic effect. The reaction yield drops significantly when NaN(SiMe3)2 is used as the catalyst, and KN(SiMe3)2 cannot catalyze the reaction. Representative bases such as the inorganic base NaOH and the organic base DBU cannot catalyze the reaction. Among the two organolithium salts, n BuLi has no effect on the reaction, and LDA only gives a product with a yield of 54% under the same conditions. Therefore, 1.0 mol% of LiN(SiMe3)2 is selected as the N optimal catalyst for the coupling reaction of 2-ethylquinoxalin-2(1H)-one with methyl acrylate.

[0187] Test Example 4

[0188] Examples 17 - 33 and Comparative Examples 11 - 12 explored the reaction generality of quinoxalinone derivatives and electrophiles, and the test results are shown in Table 4:

[0189] Table 4 Reaction parameters, products and their isolated yields of Examples 17 - 33 and Comparative Examples 11 - 12

[0190]

[0191]

[0192]

[0193]

[0194] As can be seen from Table 4, the reaction effects of quinoxalinone derivatives with different protecting groups at the N(1) position are different. When the N(1) position is substituted with methyl, ethyl, n-octyl, allyl, or benzyl, which have relatively strong electron-donating abilities, the reaction can proceed smoothly, and the yields of the corresponding products can reach 62% - 82%. However, when the N(1) position is substituted with an ester-functionalized alkyl group (ethoxycarbonylmethyl), the yield of the corresponding product decreases. The reaction conditions vary when different positions of the aromatic ring of quinoxalinone derivatives are substituted with chlorine. The results show that the substrate with chlorine substitution at the 6th position in Example 24 has the highest reaction activity, and the reaction is almost complete. While the substrate with chlorine substitution at the 7th position in Example 25 has the worst reaction activity under the same conditions. The influence of the electronic effect of substituents on the aromatic ring was investigated, and the results show that the reaction yield decreases with the increase in the electron-withdrawing ability of the substituents at the 5th position: at the 5th position, the yield of the product obtained from the reaction of quinoxalinone derivative 1k substituted with methyl is higher than that of the substrate 1g substituted with chlorine. Contrary to this result, when the 6th position of quinoxalinone derivative is substituted with chlorine, the reaction yield can reach 98%. When substituted with methyl having a certain electron-donating ability in Example 28, the reaction yield drops to 75%. When substituted with methoxy having a strong electron-donating ability in Comparative Example 11, the reaction cannot proceed. The reaction activities of quinoxalinone derivatives with double substitutions at the 6th and 7th positions in Examples 30 and 31 also show a certain decrease.

[0195] In addition, the investigation results of other electrophilic reagents show that the reactions involving methyl methacrylate and phenyl vinyl sulfone can obtain the corresponding products with isolated yields of 71% and 79% respectively, while chalcone can only generate the target product with a yield of 18%. This may be due to the electron delocalization and steric hindrance effects of chalcone. In summary, the electronic effect of substituents on the aromatic ring of quinoxalinone derivatives may be the main factor affecting the reaction activity.

[0196] Obviously, the above-mentioned embodiments of the present invention are only examples for clearly explaining the present invention, and are not intended to limit the implementation manners of the present invention. Those skilled in the art should understand that other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. Any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for coupling quinoxalinone and its derivatives with electrophilic reagents catalyzed by lithium silylamide, characterized in that, Comprising the following steps: Under the protection of inert gas, quinoxalinone and its derivatives are subjected to a coupling reaction with an electrophilic reagent in the presence of lithium bis(trimethylsilyl)amide, diethyl phosphite and a solvent to obtain functionalized quinoxalinone and its derivatives; The quinoxalinone and its derivatives are selected from the compounds shown by the following structures: ； The electrophilic reagent is selected from one or more of methyl acrylate, methyl methacrylate and phenyl vinyl sulfone; The dosage of lithium bis(trimethylsilyl)amide accounts for 1-5 mol% of the dosage of quinoxalinone and its derivatives; The coupling reaction is carried out at 20-70 °C; the time of the coupling reaction is 3 min-3 h; The functionalized quinoxalinone and its derivatives are selected from the compounds shown by the following structures: 。 2. The method according to claim 1, wherein The molar ratio of the quinoxalinone and its derivatives to the electrophilic reagent is 1:(1-5).

3. The method according to claim 1, wherein The molar ratio of the quinoxalinone and its derivatives to diethyl phosphite is 1:(1-3).

4. The method according to claim 1, wherein The solvent is selected from one or more of mesitylene, n-hexane, toluene, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile and N,N- dimethylformamide.

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