Method for catalyzing coupling reaction of quinoxalinone and derivative thereof with electrophilic reagent by using lithium silicon amide

Abstract

The invention discloses a method for catalyzing coupling reaction of quinoxalinone and derivatives thereof with an electrophilic reagent by using silicon lithium amide, which comprises the following steps: under the protection of inert gas, carrying out coupling reaction on quinoxalinone and derivatives thereof with the electrophilic reagent in the presence of bis (trimethylsilyl) lithium amide, diethyl phosphite and a solvent; the functionalized quinoxalinone and the derivative thereof are obtained. According to the method, the bis (trimethylsilyl) lithium amide catalyst which is simple in structure and low in usage amount is adopted, efficient catalysis of the coupling reaction of quinoxalinone and the derivative thereof with the electrophilic reagent under the mild reaction condition is achieved, dependence on excessive alkali or oxidizing agents is remarkably reduced, the reaction time is greatly shortened, and the yield of the quinoxalinone and the derivative thereof is increased. The reaction efficiency is improved, a series of 3-site functionalized quinoxalinone and derivatives thereof are prepared, and the reaction has good universality.

Description

Technical Field

[0001] The invention relates to the technical field of quinoxalinone functionalization, and in particular to a method for using lithium silanamide to catalyze the coupling reaction of quinoxalinone and its derivatives with an electrophilic reagent. Background Art

[0002] Quinoxalinones and their derivatives are a key class of nitrogen heterocyclic compounds that are widely found in natural products and drug molecules. Due to their unique chemical structure and diverse biological activities, these compounds have received extensive attention and research, especially C(3)-substituted quinoxalinones, which 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, anticonvulsant, anti-allergic and anti-thrombotic, but are also important precursors for the synthesis of aminoquinoxalinones, thioquinoxalinones and other substances.

[0003] In the study of C(3) functionalization of quinoxalinone, a variety of methods have been developed, mainly including transition metal-promoted and light-promoted. These methods involve various reaction types such as alkylation, amination, arylation, etc., involving free radical mechanisms or transition metal coordination activation mechanisms, providing multiple ways to achieve C(3) functionalization of quinoxalinone.

[0004] However, although these methods have made some progress in the functionalization of quinoxalinone C(3), there are still some problems and challenges. First, most reactions require the use of excess base or a large excess of oxidant, which leads to relatively harsh reaction conditions, which not only increases production costs but also may have a negative impact on the environment. Secondly, although photocatalytic and photopromoted quinoxalinone C(3) functionalization reactions have received increasing attention in recent years, transition metal-catalyzed reactions of this type still dominate. This limits the selectivity and efficiency of the reaction to a certain extent, and also increases the cost and complexity of the catalyst. Therefore, it is urgent to develop a quinoxalinone C(3) functionalization method with mild conditions, cheap and readily available catalysts, and higher efficiency to overcome the shortcomings of the existing technology. Summary of the invention

[0005] In order to solve the above technical problems, the purpose of the present invention is to provide a method for catalyzing the coupling reaction of quinoxalinone and its derivatives with electrophilic reagents using lithium silanamide, which adopts a lithium silanamide catalyst with a simple structure and a low usage amount to achieve efficient catalysis under mild reaction conditions, which not only significantly reduces the dependence on excess base or oxidant, but also greatly shortens the reaction time and improves the reaction efficiency.

[0006] The above-mentioned purpose of the present invention is achieved through the following technical solutions: A method for the coupling reaction of quinoxalinone and its derivatives with an electrophilic reagent catalyzed by lithium silanamide comprises the following steps: under the protection of an inert gas, quinoxalinone and its derivatives and an electrophilic reagent are reacted in the presence of lithium bis(trimethylsilyl)amide (LiN(SiMe 3 ) 2 ), diethyl phosphite and a solvent to carry out a coupling reaction to obtain a functionalized quinoxalinone and its derivatives; The structural formula of the quinoxalinone and its derivatives is , where R 1 is selected from one of saturated or unsaturated alkyl, benzyl and ethoxycarbonylmethyl, R 2 , R 3 , R 4 , R 5 Each is independently selected from one of hydrogen, halogen and saturated or unsaturated alkyl; The electrophilic reagent is selected from one or more of methyl acrylate, methyl methacrylate and phenyl vinyl sulfone; The amount of the bis(trimethylsilyl) lithium amide used is 1-5 mol% of the amount of quinoxalinone and its derivatives used.

[0007] The present invention provides a method for the coupling reaction of quinoxalinone and its derivatives with electrophilic reagents catalyzed by lithium silanamide. Different from the free radical process experienced by most reported photocatalytic or transition metal-catalyzed functionalization reactions of quinoxalinone and its derivatives, the reaction mechanism of the present invention may undergo a 1,2-hydrogen migration process to achieve polarity reversal of the carbon-nitrogen double bond, followed by a reaction between the carbon anion and the electrophilic reagent, and finally obtaining the target product.

[0008] Furthermore, the inert gas is argon.

[0009] Furthermore, R 1 One selected from the group consisting of C1-C8 saturated or unsaturated alkyl, benzyl and ethoxycarbonylmethyl.

[0010] Furthermore, R 1 One selected from the group consisting of methyl, ethyl, n-octyl, allyl and benzyl.

[0011] Furthermore, R 2 , R 3 , R 4 , R 5 Each is independently selected from one of hydrogen, halogen and C1-C8 saturated alkyl.

[0012] Furthermore, R 2 , R 3 , R 4 , R 5 Each is independently selected from one of hydrogen, chlorine, bromine and methyl.

[0013] Furthermore, the quinoxalinone and its derivatives are selected from the compounds shown in the following structures: .

[0014] Preferably, the amount of the bis(trimethylsilyl) lithium amide used is 1-5 mol % of the amount of quinoxalinone and its derivatives used.

[0015] Furthermore, the molar ratio of the quinoxalinone and its derivatives to the electrophilic reagent is 1:(1-5), preferably 1:(1.1-3.3).

[0016] Furthermore, the molar ratio of the quinoxalinone and its derivatives to diethyl phosphite is 1:(1-3).

[0017] Furthermore, the coupling reaction is carried out at 20-70°C, preferably at 20-40°C, and more preferably at 20-25°C.

[0018] Furthermore, the coupling reaction time is 3 min-3 h, preferably 3-10 min.

[0019] Furthermore, the solvent is selected from mesitylene, n-hexane, toluene, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile and N,N - one or more of dimethylformamide, preferably a solvent with less polarity, such as one or more of n-hexane, toluene and mesitylene.

[0020] The beneficial effects of the present invention are: The present invention adopts a bis(trimethylsilyl)amide lithium catalyst with a simple structure and low usage amount, and realizes efficient catalysis of the coupling reaction of quinoxalinone and its derivatives with electrophilic reagents under mild reaction conditions, which not only significantly reduces the dependence on excess base or oxidant, but also greatly shortens the reaction time and improves the reaction efficiency, thereby preparing a series of quinoxalinone and its derivatives functionalized at the 3rd position, and the reaction has good universality. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The 3-methoxycarbonylethyl functionalized N -The crystal structure of ethylquinoxalinone.

[0022] Figure 2 This is the crystal structure diagram of 4,4'-diethyl-[2,2'-diquinoxaline]-3,3'-dione prepared in Comparative Example 1. DETAILED DESCRIPTION

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used herein 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.

[0024] The present invention is 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 implement it, but the embodiments are not intended to limit the present invention.

[0025] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used are all available from commercial sources unless otherwise specified.

[0026] The room temperature in the following examples and comparative examples is 25°C.

[0027] Example 1 A LiN(SiMe 3 ) 2 catalytic N A method for the coupling reaction of 1-ethylquinoxaline-2(1H)-one with methyl acrylate, comprising the following steps: Under argon protection, LiN(SiMe 3 ) 2 (1.5 mol%, relative to 1a) and 0.22 mmol diethyl phosphite (HOP(OEt) 2 ) were added to the reaction bottle and stirred at room temperature, and then 0.20 mmol N -ethylquinoxalinone 1a, 0.22 mmol methyl acrylate 5a ( ) and 0.5 mL of mesitylene were reacted at room temperature for 2 hours. The reaction system was quenched with water and separated by rapid column chromatography to obtain a white solid. The results of H NMR, C NMR, high-resolution mass spectrometry and X-ray single crystal diffraction analysis showed that the white solid was 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone 6aa, LiN(SiMe 3 ) 2 catalytic N The reaction equation for the coupling reaction of -ethylquinoxalinone and methyl acrylate is: .

[0028] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 10.0 Hz, 1H), 7.52 (t, J = 7.8 Hz,1H), 7.33 – 7.28 (m, 2H), 4.32 (q, 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.

[0029] 3-methoxycarbonylethyl functionalized N The crystal structure of -ethylquinoxalinone 6aa is shown in Figure 1 30% ellipsoidal ratio; CCDC 2428753. Example 1 demonstrates the coupling of the electropositive carbon of the carbon-nitrogen double bond in quinoxalinone with the electropositive carbon of the carbon-carbon double bond in the Michael acceptor methyl acrylate.

[0030] Example 2 A LiN(SiMe 3 ) 2 catalytic N -The method for the coupling reaction of ethylquinoxalinone and methyl acrylate comprises the following steps: Under argon protection, LiN(SiMe 3 ) 2 (1.5 mol%, relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and stirred, followed by the addition of 0.20 mmol N -ethylquinoxalinone, 0.44 mmol methyl acrylate and 0.5 mL mesitylene were reacted at room temperature for 2 hours. The reaction system was quenched with water and separated by rapid column chromatography to obtain 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone.

[0031] Example 3 A LiN(SiMe 3 ) 2 catalytic N -The method for the coupling reaction of ethylquinoxalinone and methyl acrylate comprises the following steps: Under argon protection, LiN(SiMe 3 )2 (1.5 mol%, relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and mixed, and then 0.20 mmol N -ethylquinoxalinone, 0.66 mmol methyl acrylate and 0.5 mL mesitylene were reacted at room temperature for 2 hours. The reaction system was quenched with water and separated by rapid column chromatography to obtain 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone.

[0032] Example 4 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 3, except that the reaction is carried out at 50°C.

[0033] Example 5 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 3, except that the reaction is carried out at 70°C.

[0034] Example 6 A LiN(SiMe 3 ) 2 catalytic N -The method for the coupling reaction of ethylquinoxalinone and methyl acrylate comprises the following steps: Under argon protection, LiN(SiMe 3 ) 2 (1.5 mol%, relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and mixed, and then 0.20 mmol N -ethylquinoxalinone, 0.66 mmol methyl acrylate and 0.5 mL mesitylene were reacted at room temperature for 30 min. The reaction system was quenched with water and separated by rapid column chromatography to obtain 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone.

[0035] Example 7 A LiN(SiMe 3 ) 2 catalytic N -The method for the coupling reaction of ethylquinoxalinone and methyl acrylate comprises the following steps: Under argon protection, LiN(SiMe 3 ) 2 (1.5 mol%, relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and stirred, followed by the addition of 0.20 mmol N -ethylquinoxalinone, 0.66 mmol methyl acrylate and 0.5 mL mesitylene were reacted at room temperature for 5 min. The reaction system was quenched with water and separated by rapid column chromatography to obtain 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone.

[0036] Example 8 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that mesitylene is replaced by n-hexane.

[0037] Example 9 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that mesitylene is replaced by toluene.

[0038] Example 10 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that mesitylene is replaced by 1,2-dichloroethane.

[0039] Embodiment 11 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that mesitylene is replaced by dichloromethane.

[0040] Example 12 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that mesitylene is replaced by tetrahydrofuran.

[0041] Embodiment 13 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that mesitylene is replaced by acetonitrile.

[0042] Embodiment 14 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that mesitylene is replaced by N,N -Dimethylformamide.

[0043] Embodiment 15 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that 0.5 mL of mesitylene is replaced by 0.3 mL of mesitylene.

[0044] Example 16 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 7, except that 0.5 mL of mesitylene is replaced with 1.0 mL of mesitylene.

[0045] Embodiment 17 A LiN(SiMe 3 ) 2 catalytic N -The method for the coupling reaction of ethylquinoxalinone and methyl acrylate comprises the following steps: Under argon protection, LiN(SiMe 3 ) 2 (1.0 mol%, relative to N -ethylquinoxalinone) and 0.22 mmol diethyl phosphite were added to the reaction flask and stirred, followed by the addition of 0.20 mmol N -ethylquinoxalinone, 0.66 mmol methyl acrylate and 0.5 mL mesitylene were reacted at room temperature for 5 min. The reaction system was quenched with water and separated by rapid column chromatography to obtain 3-methoxycarbonylethyl functionalized N -Ethylquinoxalinone.

[0046] Embodiment 18 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -methylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Methylquinoxalinone 1b ( ).

[0047] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) 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.

[0048] Embodiment 19 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of n-octylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Octylquinoxalinone 1c ( ).

[0049] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) 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.

[0050] Embodiment 20 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of allylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Allylquinoxalinone 1d ( ).

[0051] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) 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.

[0052] Embodiment 21 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of benzylquinoxalinone with methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Benzylquinoxalinone 1e ( ).

[0053] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3) 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.

[0054] Embodiment 22 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethoxycarbonylmethylquinoxalinone with methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethoxycarbonylmethylquinoxalinone 1f ( ).

[0055] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 – 7.82 (m, 1H), 7.51 – 7.48 (m, 1H), 7.36 – 7.32 (m, 1H), 7.06 (d, J = 9.6 Hz, 0H), 5.04 (s, 1H), 3.78 (s, 1H), 3.71(s, 1H), 3.29 (t, J = 7.0 Hz, 1H), 2.89 (t, J = 7.0 Hz, 1H), 1.67 (s, 2H) ppm.

[0056] Embodiment 23 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-5-chloroquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-5-chloroquinoxalinone 1g ( ).

[0057] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 – 7.38 (m, 2H), 7.24 – 7.22 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 3.32 (t, J = 6.7 Hz, 2H), 2.91 (t, J = 6.7Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H) ppm.

[0058] Embodiment 24 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-6-chloroquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-6-chloroquinoxalinone 1h ( ).

[0059] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 8.9, 2.5Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.27(t, J = 6.9 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H) ppm.

[0060] Embodiment 25 A LiN(SiMe 3 ) 2 catalytic NThe method for the coupling reaction of ethyl-7-chloroquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-7-chloroquinoxalinone 1i ( ).

[0061] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d, J = 8.5 Hz, 1H), 7.30 – 7.26 (m, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.26 (t, J = 6.9 Hz, 2H), 2.86 (t, J = 6.9Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) ppm.

[0062] Embodiment 26 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-8-chloroquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-8-chloroquinoxalinone 1j ( ).

[0063] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 – 7.68 (m, 1H), 7.60 – 7.57 (m, 1H), 7.50 – 7.46 (m, 1H), 4.56 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.32 (t, J = 7.0 Hz,2H), 2.98 (t, J = 7.0 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H) ppm.

[0064] Embodiment 27 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-5-methylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-5-methylquinoxalinone 1k ( ).

[0065] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 9.4 Hz,2H), 4.31 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.31 (t, J = 6.7 Hz, 2H), 2.87 (t, J =6.7 Hz, 2H), 2.62 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H) ppm.

[0066] Embodiment 28 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-6-methylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-6-methylquinoxalinone 1l ( ).

[0067] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) 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.

[0068] Embodiment 29 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-7-bromoquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-7-bromoquinoxalinone 1n( ).

[0069] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) 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.

[0070] Embodiment 30 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-6,7-dimethylquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-6,7-dimethylquinoxalinone 1o( ).

[0071] product The H NMR spectrum data are as follows: 1H NMR (400 MHz, CDCl 3 ) 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.

[0072] Embodiment 31 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-6,7-dichloroquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-6,7-dichloroquinoxalinone 1p ( ).

[0073] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (s, 1H), 7.39 (s, 1H), 4.25 (q, J = 7.2Hz, 2H), 3.71 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2H), 1.37(t, J = 7.2 Hz, 3H) ppm.

[0074] Embodiment 32 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone with methyl methacrylate is basically the same as that in Example 17, except that methyl acrylate is replaced by methyl methacrylate 5b ( ).

[0075] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 8.3 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.33 – 7.29 (m, 2H), 4.31 (q, 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 = 16.8, 5.5 Hz, 1H), 1.37 (t, J = 7.2 Hz,3H), 1.32 (d, J = 7.0 Hz, 3H) ppm.

[0076] Embodiment 33 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone with phenyl vinyl sulfone is basically the same as that in Example 17, except that methyl acrylate is replaced by phenyl vinyl sulfone 7 ( ).

[0077] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 – 7.95 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H),7.61 – 7.50 (m, 4H), 7.34 – 7.28 (m, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3.78 – 3.75(m, 2H), 3.36 – 3.32 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H) ppm.

[0078] Comparative Example 1 A LiN(SiMe 3 ) 2 catalytic N -The method for reacting ethylquinoxalinone with diethyl phosphite comprises the following steps: Under argon protection, LiN(SiMe 3 )2 (1.5 mol%, relative to 1a), 0.22 mmol diethyl phosphite 2, 0.20 mmol N -Ethylquinoxalinone 1a and 0.5 mL mesitylene were stirred and mixed, and reacted at room temperature for 30 minutes before quenching with water. After rapid column chromatography, the reaction system was separated to obtain a colorless oil and a red solid with low polarity. The analysis of H NMR, C spectroscopy, high-resolution mass spectrometry, heavy water experiment, and X-ray single crystal diffraction confirmed that the colorless oil was the product 3a of the phosphine hydrogenation reaction of the C=N double bond of substrate 1a with diethyl phosphite, and the red solid was the coupling product 4a of dimerization of 1a, LiN(SiMe 3 ) 2 catalytic N The reaction equation of the reaction of -ethyl substituted quinoxalinone with diethyl phosphite is: .

[0079] The H NMR spectrum data of the product are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 6.93 – 6.77 (m, 4H), 4.61 (s, 1H), 4.40 (d, 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.

[0080] The crystal structure of the coupling product 4a (4,4'-diethyl-[2,2'-diquinoxaline]-3,3'-dione) is shown in Figure 2 Shown, 30% ellipsoidality; CCDC 2431864.

[0081] Comparative Example 2 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is substantially the same as that in Example 1, except that diethyl phosphite is not added.

[0082] Comparative Example 3 A catalyst NThe method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 (1.5 mol%, relative to N -ethylquinoxalinone) was replaced by LiN(SiMe 3 ) 2 (0.5mol%, relative to N -ethylquinoxalinone).

[0083] Comparative Example 4 A sort of N The method for the coupling reaction of -ethylquinoxalinone with methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 .

[0084] Comparative Example 5 A NaN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 Replaced by NaN(SiMe 3 ) 2 .

[0085] Comparative Example 6 A KN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 Replaced by KN(SiMe 3 ) 2 .

[0086] Comparative Example 7 A NaOH catalyzed N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 Replace with NaOH.

[0087] Comparative Example 8 A DBU catalytic N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 )2 Replaced with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

[0088] Comparative Example 9 A sort of n BuLi Catalysis N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 Replace with n BuLi (n-butyllithium).

[0089] Comparative Example 10 A LDA catalyst N The method for the coupling reaction of -ethylquinoxalinone and methyl acrylate is basically the same as that in Example 7, except that: LiN(SiMe 3 ) 2 Replaced with LDA (lithium diisopropylamide).

[0090] Comparative Example 11 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of ethyl-6-methoxyquinoxalinone and methyl acrylate is basically the same as that in Example 17, except that: N -Ethylquinoxalinone is replaced by N -Ethyl-6-methoxyquinoxalinone 1m( ).

[0091] Comparative Example 12 A LiN(SiMe 3 ) 2 catalytic N The method for the coupling reaction of -ethylquinoxalinone with chalcone is basically the same as that in Example 17, except that methyl acrylate is replaced by chalcone 9 ( ).

[0092] product The H NMR spectrum data are as follows: 1 H NMR (400 MHz, CDCl 3 ) 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.

[0093] Test Example 1 Examples 1-7 and Comparative Example 2 explored the feed ratio of the reaction ( N -Ethylquinoxalinone, diethyl phosphite and methyl acrylate), temperature, time and LiN (SiMe 3 ) 2 catalytic N -Effect of the coupling reaction of ethylquinoxalinone and methyl acrylate, the test results are shown in Table 1: Table 1 Reaction parameters and product separation yields of Examples 1-7 and Comparative Example 2

[0094] 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.

[0095] Test Example 2 Examples 7-16 investigated the effects of solvent type and amount on LiN(SiMe 3 ) 2 catalytic N -Effect of the coupling reaction of ethylquinoxalinone and methyl acrylate, the test results are shown in Table 2: Table 2 Reaction parameters and product separation yields of Examples 7-16

[0096] 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 solvent is selected from n-hexane, toluene, and mesitylene with lower polarity, the reaction yield is higher. Although the reaction can reach a yield of 70% when n-hexane is used as the solvent, n-hexane has a low affinity for the reaction substrate. N -Ethylquinoxalinone has poor solubility; compared with toluene as the reaction solvent, which can achieve a yield of 63%, mesitylene can achieve a higher yield of 81%. 1,2-Dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile and N,N -Dimethylformamide and other solvents have low reaction yields, so mesitylene is LiN (SiMe 3 ) 2 catalytic N -The best solvent for the coupling reaction of ethylquinoxalinone and methyl acrylate. In addition, compared with Example 7, 0.3 mL and 0.5 mL of mesitylene did not make much difference in the reaction yield in Example 15 and Example 16, but the yield decreased when 1.0 mL of mesitylene was used as the solvent for the reaction. Considering that 0.5 mL of mesitylene can more fully dissolve the raw materials and enable the reaction to proceed smoothly, 0.5 mL is selected as the optimal amount of the solvent.

[0097] Test Example 3 Example 7, Example 17 and Comparative Examples 3-10 explored the effects of the type and amount of catalyst on the catalytic performance. N -Effect of the coupling reaction of ethylquinoxalinone and methyl acrylate, the test results are shown in Table 3: Table 3 Reaction parameters and product separation yields of Example 7, Example 17 and Comparative Examples 3-10

[0098] It can be seen from Table 3 that when the amount of catalyst is reduced to 1.0 mol%, the reaction yield does not decrease significantly; when the amount of catalyst is reduced to 0.5 mol%, the reaction can hardly occur. In addition, Comparative Example 4 shows that the reaction cannot proceed without a catalyst. Among several silicon amine alkali metal salts, LiN(SiMe 3 ) 2 The catalytic effect is the best, NaN(SiMe 3 ) 2 When used as a catalyst, the reaction yield dropped significantly. 3 ) 2 Cannot catalyze the reaction. Representative bases such as inorganic base NaOH and organic base DBU cannot catalyze the reaction. Among the two organic lithium salts, nBuLi has no effect on the reaction, and LDA only produces 54% yield of product under the same conditions. Therefore, 1.0 mol% LiN(SiMe 3 ) 2 As a catalyst N -The best catalyst for the coupling reaction of ethylquinoxalinone with methyl acrylate.

[0099] Test Example 4 Examples 17-33 and Comparative Examples 11-12 explored the universality of the reactions of quinoxalinone derivatives and electrophilic reagents. The test results are shown in Table 4: Table 4 Reaction parameters, products and their separation yields of Examples 17-33 and Comparative Examples 11-12

[0100]

[0101]

[0102]

[0103] As can be seen from Table 4, the reaction effects of quinoxalinone derivatives with different protecting groups at N(1) are different. When N(1) carries a methyl, ethyl, n-octyl, allyl, or benzyl group with strong electron-donating ability, the reaction can proceed smoothly, and the yield of the corresponding product can reach 62%-82%; but when N(1) carries an alkyl group (ethoxycarbonylmethyl) with ester functionalization, the yield of the corresponding product decreases. The reaction conditions when different positions of the aromatic ring of the quinoxalinone derivative are substituted by chlorine are different. The results show that the substrate substituted by chlorine at position 6 in Example 24 has the highest reaction activity and the reaction is almost complete; while the substrate chlorinated at position 7 in Example 25 has the worst reaction activity under the same conditions. The influence of the electronic effect of the substituent on the aromatic ring was investigated, and the results showed that the reaction yield decreases with the enhancement of the electron-withdrawing ability of the substituent at position 5: at position 5, the product yield of the reaction of the methyl-substituted quinoxalinone derivative 1k is higher than that of the chlorine-substituted substrate 1g. In contrast to this result, when the 6-position of the quinoxalinone derivative is substituted with chlorine, the reaction yield can reach 98%, when it is substituted with a methyl group having a certain electron donating ability in Example 28, the reaction yield drops to 75%, and when it is substituted with a methoxy group having a strong electron donating ability in Comparative Example 11, the reaction cannot proceed. The reactivity of the disubstituted quinoxalinone derivatives at the 6- and 7-positions in Examples 30 and 31 also shows a certain decrease.

[0104] In addition, the results of the investigation of other electrophilic reagents showed that the reaction of methyl methacrylate and phenyl vinyl sulfone could obtain the corresponding products with 71% and 79% isolation yields, respectively, while chalcone could only generate the target product with a yield of 18%, which may be due to the electron delocalization and steric hindrance of chalcone. In summary, the electronic effect of the substituents on the aromatic ring of quinoxalinone derivatives may be the main factor affecting the reaction activity.

[0105] Obviously, the above embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments 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 list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for the coupling reaction of quinoxalinone and its derivatives with electrophilic reagents catalyzed by lithium silanamide, characterized in that: The following steps are involved: Under the protection of inert gas, quinoxalinone and its derivatives are coupled 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 structural formula of the quinoxalinone and its derivatives is , wherein 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; The electrophilic reagent is selected from one or more of methyl acrylate, methyl methacrylate and phenyl vinyl sulfone; The amount of the bis(trimethylsilyl) lithium amide used is 1-5 mol% of the amount of quinoxalinone and its derivatives used.

2. The method according to claim 1, characterized in that R1 is selected from one of C1-C8 saturated or unsaturated alkyl, benzyl and ethoxycarbonylmethyl.

3. The method according to claim 2, characterized in that R1 is selected from one of methyl, ethyl, n-octyl, allyl and benzyl.

4. The method according to claim 1, characterized in that: R2, R3, R4, and R5 are each independently selected from one of hydrogen, halogen, and C1-C8 saturated alkyl.

5. The method according to claim 1, characterized in that The quinoxalinone and its derivatives are selected from the compounds shown in the following structures: 。 6. The method according to claim 1, characterized in that The molar ratio of the quinoxalinone and its derivatives to the electrophilic reagent is 1:(1-5).

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

8. The method according to claim 1, characterized in that The coupling reaction is carried out at 20-70°C.

9. The method according to claim 1, characterized in that The coupling reaction time is 3 min-3 h.

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

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