Quinoxaline direct CH bond amination method

Abstract

The invention discloses a method for directly aminating a C-H bond of quinoxaline, which comprises the following steps: by taking a quinoxaline compound, an azole and a derivative thereof as raw materials, directly carrying out cross dehydrogenation coupling under the action of an oxidizing agent and an additive to synthesize a quinoxaline C-H bond aminated product. The preparation method provided by the invention overcomes the limitation of the existing metal-free catalysis technology, has the advantages of simple synthesis steps, simplicity and convenience in operation, cheap and easily available raw materials, good compatibility of the synthesis method to functional groups, high chemical selectivity, high atom economy and the like, and strictly follows the green and sustainable development concept. The method not only effectively solves the problems that a substrate and a special catalyst need to be prepared in advance, electrochemical conditions are harsh and the like in the existing method, but also better conforms to the concepts of green and sustainable chemistry, and provides more effective technical support for further modification and chemical conversion of quinoxaline drugs. The obtained aminated quinoxaline compound is expected to play an important role in the fields of luminescent materials, pharmaceutical active molecules and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for direct amination of a quinoxaline CH bond. Background Art

[0002] Electron-deficient nitrogen-containing heterocyclic quinoxaline is a nitrogen-containing heterocyclic compound with wide application value. Since its two imine nitrogen atoms are on the same ring of quinoxaline, it has a more electron-deficient property than compounds such as quinoline. Due to its various biological activities related to medicinal chemistry and a large number of luminescent properties, in the past few decades, scientists have used quinoxaline skeletons to design and develop many dyes, fluorescent materials, electroluminescent materials, and organic sensitizers for solar cell applications and polymer optoelectronic materials, as well as biologically active drugs with antibacterial, antiviral, and anticancer activities.

[0003] To this end, great efforts have been made to develop new synthetic strategies and methods to seek more efficient functionalization of the quinoxaline skeleton. However, due to its inherent electron-deficient properties, quinoxaline has extremely low reaction efficiency and poor selectivity when used as a free radical addition receptor. The direct CH functionalization of electron-deficient heterocycles remains a difficult problem in synthetic chemistry. In addition, it is also a major challenge in synthetic chemistry to directly construct the CN bond on the quinoxaline skeleton without relying on pre-installed functional groups.

[0004] With the continuous development of synthetic chemistry and the increasingly severe environmental and resource problems, the development of atom-economical synthesis methods has become one of the important criteria for synthetic chemists to design new reactions. Metal-free catalytic technology, with its remarkable environmental friendliness, cost-effectiveness, high reaction selectivity and efficiency, wide substrate adaptability, and excellent safety and stability, has shown great application potential and important research value in many fields such as chemical synthesis, drug development, and materials science. Therefore, it has attracted widespread attention from academia and industry. However, the development of metal-free catalytic reactions faces many challenges, especially the problems of insufficient catalytic activity and difficulty in precisely controlling product selectivity, which limits its widespread promotion in practical applications. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a simple, practical, green and efficient method for realizing direct amination of the CH bond of quinoxaline, which has the significant advantages of easy availability of raw materials, simple operation, excellent selectivity and high atom economy.

[0006] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0007] A method for direct CH bond amination of quinoxaline is disclosed. Quinoxaline compounds and azoles and derivatives thereof are used as raw materials, and the CH bond amination product of quinoxaline is directly synthesized through cross-dehydrogenation coupling under the action of an oxidant and an additive.

[0008] The above-mentioned method for direct amination of the CH bond of quinoxaline is carried out as follows: Compound 1, Compound 2, an oxidant, an additive and a solvent are added to a reactor, and the reaction is stirred. After the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product, and the crude product is purified by thin layer chromatography to obtain a product of quinoxaline CH bond amination.

[0009] The above method for direct amination of the CH bond of quinoxaline complies with the following reaction formula:

[0010]

[0011] In the formula, compound 1 is a quinoxaline compound, and compound 2 is an azole and its derivatives.

[0012] Compound 1 is quinoxaline, compound 2 is an azole compound; the oxidant is peroxide, metal oxide, iodine-containing oxide; the additive is acid, base, inorganic salt; the solvent is dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, trifluorotoluene, dimethyl sulfoxide, toluene and methanol or a combination thereof.

[0013] The iodine-containing oxide is bis(trifluoroacetyloxy)iodobenzene, iodobenzene diacetic acid or a combination thereof; the peroxide is ammonium persulfate, potassium persulfate, tert-butyl hydroperoxide or a combination thereof; the base is trimethylsilyl azide, diphenylphosphoryl azide, tetrabutylammonium azide, sodium azide or a combination thereof.

[0014] The oxidant is bis(trifluoroacetyloxy)iodobenzene; the additive is trimethylsilane azide; and the solvent is dichloromethane.

[0015] The molar ratio of compound 1 to compound 2 is 1:1-10; the reaction temperature is 0-150° C., and the reaction time is 0-48 h.

[0016] The molar ratio of compound 1 to compound 2 is 1:2; the reaction temperature is room temperature, and the reaction time is 4 hours.

[0017] The reactor is a Schlenk tube.

[0018] In view of the problems existing in the synthesis of direct CH bond amination derivatives of quinoxaline at present, the inventor has established a method for direct amination of quinoxaline CH bond, using quinoxaline compounds and azoles and derivatives thereof as raw materials, and synthesizing the product of quinoxaline CH bond amination directly by cross-dehydrogenation coupling under the action of oxidants and additives (metal-free catalysis). Compared with the traditional method, the present invention has developed an innovative synthesis strategy, which has obvious advantages in terms of synthesis conditions and practicality, overcomes the limitations of existing metal-free catalytic technology, has the advantages of simple synthesis steps, easy operation, cheap and easy to obtain raw materials, good compatibility of the synthesis method with functional groups, chemical selectivity and high atom economy, and strictly follows the concept of green and sustainable development. This method not only effectively solves the problems of needing to pre-prepare substrates, special catalysts, harsh electrochemical conditions, etc. in the existing methods, but also conforms to the concept of green and sustainable chemistry, and also provides more effective technical support for the further modification and chemical transformation of quinoxaline drugs, and the obtained aminated quinoxaline compounds are expected to play an important role in the fields of luminescent materials, pharmaceutically active molecules, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The hydrogen spectrum of the product obtained in Example 1 is shown in FIG.

[0020] Figure 2 This is the carbon spectrum of the product obtained in Example 1.

[0021] Figure 3 This is the hydrogen spectrum of the product obtained in Example 2.

[0022] Figure 4 This is the carbon spectrum of the product obtained in Example 2.

[0023] Figure 5 This is the hydrogen spectrum of the product obtained in Example 3.

[0024] Figure 6 This is the carbon spectrum of the product obtained in Example 3.

[0025] Figure 7 This is the hydrogen spectrum of the product obtained in Example 4.

[0026] Figure 8 This is the carbon spectrum of the product obtained in Example 4.

[0027] Fig. 9 This is the hydrogen spectrum of the product obtained in Example 5.

[0028] Fig.10 This is the carbon spectrum of the product obtained in Example 5. DETAILED DESCRIPTION

[0029] Example 1

[0030] 0.25mmol quinoxaline, 1.0mL dichloromethane, 0.5mmol pyrazole, 0.5mmol trimethylsilyl azide, and 0.5mmol bistrifluoroacetoxy iodobenzene were added to a Schlenk tube in sequence. Then, after stirring and reacting at room temperature for 4 hours, stirring was stopped, and the solvent was removed by rotary evaporation under reduced pressure. Then, the product was separated and purified by thin layer chromatography (the eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain the target product.

[0031] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 1 and Figure 2 The structural characterization data are as follows:

[0032] 1 H NMR (600MHz, Chloroform-d) δ9.66 (s, 1H), 8.69 (d, J = 2.7Hz, 1H), 8.10 (d, J = 8.3Hz, 1H), 7.96 (d, J = 9 .6Hz, 1H), 7.83 (d, J=1.5Hz, 1H), 7.74 (t, J=8.4Hz, 1H), 7.68 (t, J=8.3Hz, 1H), 6.55 (t, J=6.0Hz, 1H).

[0033] 13 C NMR (151MHz, Chloroform-d) δ145.02, 143.36, 141.29, 140.16, 138.00, 130.98, 129.39, 128.94, 128.42, 127.67, 109.04.

[0034] According to the above data, the structure of the obtained product is as follows:

[0035]

[0036] Example 2

[0037] 0.25 mmol quinoxaline, 1.0 mL 1,2-dichloroethane, 0.5 mmol 4-chloropyrazole, 0.5 mmol trimethylsilyl azide, and 0.5 mmol bis(trifluoroacetoxy)iodobenzene were added to a Schlenk tube in sequence. After stirring at room temperature for 12 hours, stirring was stopped, and the solvent was removed by rotary evaporation under reduced pressure. The product was separated and purified by thin layer chromatography (the eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain the target product.

[0038] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 3 and Figure 4 The structural characterization data are as follows:

[0039] 1 H NMR (600MHz, Chloroform-d) δ9.61 (s, 1H), 8.68 (s, 1H), 8.12 (d, J=9.8Hz, 1H), 7 .97 (d, J=7.5Hz, 1H), 7.78 (t, J=6.0Hz, 1H), 7.75 (s, 1H), 7.72 (t, J=8.3Hz, 1H).

[0040] 13 C NMR (151MHz, Chloroform-d) δ144.38, 141.86, 141.52, 140.00, 137.25, 131.25, 129.49, 129.34, 128.48, 125.44, 114.57.

[0041] According to the above data, the structure of the obtained product is as follows:

[0042]

[0043] Example 3

[0044] 0.25 mmol quinoxaline, 1.0 mL dichloromethane, 0.5 mmol 4-bromopyrazole, 0.5 mmol trimethylsilyl azide and 0.5 mmol bis(trifluoroacetoxy)iodobenzene were added to a Schlenk tube in sequence. After stirring at 60°C for 16 hours, stirring was stopped and the solvent was removed by rotary evaporation under reduced pressure. The product was separated and purified by thin layer chromatography (the eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain the target product.

[0045] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 5 and Figure 6 The structural characterization data are as follows:

[0046] 1 H NMR (600MHz, Chloroform-d) δ9.63 (s, 1H), 8.74 (s, 1H), 8.13 (d, J=9.7Hz, 1H), 7.98 (d, J=9.8Hz, 1H), 7.82-7.77 (m, 2H), 7.74 (t, J=7.7Hz, 1H).

[0047] 13 C NMR (151MHz, Chloroform-d) δ144.29, 143.84, 141.58, 140.02, 137.30, 131.29, 129.51, 129.39, 128.51, 127.77, 98.13.

[0048] According to the above data, the structure of the obtained product is as follows:

[0049]

[0050] Example 4

[0051] 0.25 mmol quinoxaline, 1.0 mL dichloromethane, 0.5 mmol 4-phenylpyrazole, 0.5 mmol diphenylphosphoryl azide, and 0.5 mmol bis(trifluoroacetoxy)iodobenzene were added to a Schlenk tube in sequence. After stirring at room temperature for 2 hours, stirring was stopped, and the solvent was removed by rotary evaporation under reduced pressure. The product was separated and purified by thin layer chromatography (the eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain the target product.

[0052] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Figure 7 and Figure 8 The structural characterization data are as follows:

[0053] 1 H NMR (600MHz, Chloroform-d) δ9.70 (s, 1H), 8.94 (s, 1H), 8.22-8.10 (m, 2H), 8.01 (d, J=9.1Hz, 1H), 7.79 (t , J=6.0Hz, 1H), 7.72 (t, J=8.3Hz, 1H), 7.64 (d, J=6.8Hz, 2H), 7.43 (t, J=7.7Hz, 2H), 7.32 (t, J=7.4Hz, 1H).

[0054] 13 C NMR (151MHz, Chloroform-d) δ144.92, 141.37, 141.30, 140.24, 137.90, 131.11, 129.49, 129.16, 129.02, 128.41, 127.55, 126.12, 126.08, 123.72.

[0055] According to the above data, the structure of the obtained product is as follows:

[0056]

[0057] Example 5

[0058] 0.25 mmol quinoxaline, 1.0 mL dichloromethane, 0.5 mmol 4-pyrazolecarboxylic acid ethyl ester, 0.5 mmol trimethylsilyl azide, and 0.5 mmol iodophenyl diacetic acid were added to a Schlenk tube in sequence. After stirring at 80°C for 24 hours, stirring was stopped, and the solvent was removed by rotary evaporation under reduced pressure. The product was separated and purified by thin layer chromatography (the eluent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain the target product.

[0059] The hydrogen spectrum and carbon spectrum of the obtained product are as follows: Fig. 9 and Fig.10 The structural characterization data are as follows:

[0060] 1 H NMR (600MHz, Chloroform-d) δ9.65 (s, 1H), 9.15 (s, 1H), 8.19 (s, 1H), 8.13 (d, J=9.7Hz, 1H), 8.00 (d, J= 7.4Hz, 1H), 7.80 (t, J=8.4Hz, 1H), 7.75 (t, J=8.3Hz, 1H), 4.37 (q, J=7.1Hz, 2H), 1.40 (t, J=7.1Hz, 3H).

[0061] 13 C NMR (151MHz, Chloroform-d) δ162.55, 144.39, 143.85, 141.82, 140.02, 137.67, 131.37, 130.75, 129.69, 129.51, 128.61, 118.09, 60.86, 14.51.

[0062] According to the above data, the structure of the obtained product is as follows:

[0063]

Claims

1. A method for direct amination of a quinoxaline CH bond, characterized in that: The invention uses quinoxaline compounds, azoles and their derivatives as raw materials, and directly synthesizes the CH bond amination product of quinoxaline through cross-dehydrogenation coupling under the action of oxidants and additives.

2. The method for direct amination of quinoxaline CH bonds according to claim 1, characterized in that The operation is carried out as follows: Compound 1, Compound 2, an oxidant, an additive and a solvent are added into a reactor, and the reaction is stirred. After the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product is purified by thin layer chromatography to obtain a product of CH bond amination of quinoxaline.

3. The method for direct amination of quinoxaline CH bonds according to claim 2, characterized in that The following reaction formula is met: In the formula, compound 1 is a quinoxaline compound, and compound 2 is an azole and its derivatives.

4. The method for direct amination of quinoxaline CH bonds according to claim 3, characterized in that: The compound 1 is quinoxaline, and the compound 2 is an azole compound; the oxidant is a peroxide, a metal oxide, or an iodine-containing oxide; the additive is an acid, a base, or an inorganic salt; and the solvent is dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, trifluorotoluene, dimethyl sulfoxide, toluene, methanol, or a combination thereof.

5. The method for direct amination of quinoxaline CH bonds according to claim 4, characterized in that: The iodine-containing oxide is bis(trifluoroacetyloxy)iodobenzene, iodobenzene diacetic acid or a combination thereof; the peroxide is ammonium persulfate, potassium persulfate, tert-butyl hydroperoxide or a combination thereof; the base is trimethylsilane azide, diphenylphosphoryl azide, tetrabutylammonium azide, sodium azide or a combination thereof.

6. The method for direct amination of quinoxaline CH bonds according to claim 5, characterized in that: The oxidant is bis(trifluoroacetyloxy)iodobenzene; the additive is trimethylsilane; and the solvent is dichloromethane.

7. The method for direct amination of quinoxaline CH bonds according to claim 2, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:1-10; the reaction temperature is 0-150° C., and the reaction time is 0-48 hours.

8. The method for direct amination of quinoxaline CH bonds according to claim 7, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:2; the reaction temperature is room temperature, and the reaction time is 4 hours.

9. The method for direct amination of quinoxaline CH bonds according to claim 1, characterized in that: The reactor is a Schlenk tube.

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