A method for synthesizing 2-substituted quinoxaline compounds

Abstract

The present invention discloses a method for synthesizing 2-substituted quinoxaline compounds, belonging to the technical field of the synthesis of quinoxaline compounds. The key points of the technical solution of the present invention are as follows: A saturated cyclic amine compound and an o-phenylenediamine compound are dissolved in a solvent, and then an oxammonium salt T + X ‑ or an oxammonium salt T + X ‑ and an additive are added, and the target product 2-substituted quinoxaline compound is prepared by reacting at 0-50°C under an air atmosphere. The present invention directly synthesizes 2-substituted quinoxaline compounds by promoting the tandem reaction between saturated cyclic amine compounds and o-phenylenediamine compounds through an oxammonium salt. This reaction directly constructs 2-substituted quinoxaline compounds containing highly reactive functional groups of amino groups. The whole process is simple to operate and does not require any metal catalyst; the raw materials are simple and easily available, and the reaction conditions are mild; the scope of application of the substrate is wide, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of quinoxaline compounds, and particularly relates to a method for synthesizing 2-substituted quinoxaline compounds. Background Art

[0002] 2-Substituted quinoxaline compounds, due to their large conjugated structure and diverse transformations of the 2-position substituents, are important structural units of many luminescent materials and antibacterial drugs, and have important research value in the fields of polymer materials and drug synthesis. At present, there are mainly the following two methods for the synthesis of 2-substituted quinoxaline compounds: First, using halogenated quinoxaline as a raw material and further completing the reaction through nucleophilic substitution with Grignard reagents. Although this method is relatively reliable, there are still problems such as expensive reaction raw materials, harsh reaction conditions, and cumbersome reaction steps where sensitive functional groups need to be protected first and then deprotected later; Second, the corresponding 2-substituted quinoxaline compounds can also be synthesized through the condensation reaction of o-phenylenediamine with 1,2-diketone / 1,2-diol / α-bromo ketone compounds. However, this method often has problems such as unstable / difficult-to-prepare raw materials or the need for noble metal catalysis. In view of this, it is of great significance to further study and develop a simple, efficient new method for synthesizing 2-substituted quinoxaline compounds based on mild reaction conditions starting from easily available simple raw materials. Summary of the Invention

[0003] The technical problem solved by the present invention is to provide a method for synthesizing 2-substituted quinoxaline compounds. This method synthesizes 2-substituted quinoxaline compounds containing highly reactive functional groups through a one-pot multi-step tandem reaction of easily available saturated cyclic amine compounds and o-phenylenediamine compounds, and has the advantages of simple operation, mild conditions, wide substrate scope, etc., and is suitable for industrial production.

[0004] The present invention adopts the following technical solution to solve the above technical problem. A method for synthesizing 2-substituted quinoxaline compounds is characterized in that the specific synthesis process is as follows: Dissolve saturated cyclic amine compound 1 and o-phenylenediamine compound 2 in a solvent, and then add oxammonium salt T + X - or oxammonium salt T + X - and an additive, and react at 0 - 50 °C under an air atmosphere to obtain the target product 2-substituted quinoxaline compound 3. The reaction equation in this synthesis method is:

[0005]

[0006] where R is phenyl, substituted phenyl or naphthyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine, C 1-4 alkyl or phenyl; R 1 is C1-4 An alkyl group or a phenyl group; R 2 is hydrogen, fluorine, chlorine, bromine or C 1-4 alkyl; X - is BF4 - , ClO4 - , PF6 - or OTf - ; The additive is potassium thiocyanate.

[0007] Further defined, the solvent is N,N-dimethylformamide, ethanol, dimethyl sulfoxide or dichloromethane.

[0008] Further defined, the molar ratio of the saturated cyclic amine compound 1, the o-phenylenediamine compound 2, the oxoammonium salt T + X - to the additive is 1:1 - 2:2 - 3:0 - 2.

[0009] Compared with the prior art, the present invention has the following advantages: (1) The present invention directly synthesizes 2-substituted quinoxaline compounds through the tandem reaction between saturated cyclic amine compounds and o-phenylenediamine compounds promoted by oxoammonium salts. This reaction directly constructs 2-substituted quinoxaline compounds containing highly reactive functional groups of amino groups. The whole process is simple to operate and does not require any metal catalysts; (2) The raw materials are simple and easily available, and the reaction conditions are mild; (3) The scope of substrate applicability is wide. Therefore, the present invention provides an economical and practical new method for the synthesis of 2-substituted quinoxaline compounds. Specific Embodiments

[0010] The following further elaborates on the above content of the present invention through examples, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0011] Example 1

[0012]

[0013] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 6 h under an air atmosphere, and then 10 mL of saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation to dryness, separation by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) gave the brown solid product 3a (36 mg, 68%). The characterization data of this compound are as follows:1 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.10 - 8.04 (m, 2H), 7.76 - 7.71 (m, 2H), 7.18 - 7.14 (m, 2H), 6.69 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 2H), 3.88 (brs, 1H), 3.28 (t, J = 6.8 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.24 - 2.20 (m, 2H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3): δ 156.7, 148.2, 145.8, 142.2, 141.3, 130.1, 129.3, 129.2, 129.1, 128.9, 117.4, 112.8, 43.4, 33.8, 28.6. HRMS (ESI) m / z: [M + H] + Calcd for C 17 18 18 15N3 264.1495; Found 264.1486.

[0014] Example 2

[0015] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + PF6 - (120 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 6 h under an air atmosphere, then quenched by adding 10 mL of saturated sodium chloride solution, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate. Filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (28 mg, 54%).

[0016] Example 3

[0017] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + ClO4 -(102 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (26 mg, 50%).

[0018] Example 4

[0019] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + OTf - (122 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (21 mg, 40%).

[0020] Example 5

[0021] 1a (32 mg, 0.2 mmol), EtOH (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (30 mg, 58%).

[0022] Example 6

[0023] 1a (32 mg, 0.2 mmol), DMSO (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 -(97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (25 mg, 48%).

[0024] Example 7

[0025] 1a (32 mg, 0.2 mmol), DCM (1 mL), 2a (43 mg, 0.4 mmol), and T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (28 mg, 54%).

[0026] Example 8

[0027] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (22 mg, 0.2 mmol), and T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 0 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (21 mg, 40%).

[0028] Example 9

[0029] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), and T + BF4 -(146 mg, 0.6 mmol) and KSCN (19 mg, 0.2 mmol) were added successively to a reaction tube. The mixture was stirred at 50 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (35 mg, 67%).

[0030] Example 10

[0031] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol) and T + BF4 - (97 mg, 0.4 mmol) were added successively to a reaction tube. The mixture was stirred at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (21 mg, 40%).

[0032] Example 11

[0033] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (38 mg, 0.4 mmol) were added successively to a reaction tube. The mixture was stirred at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3a (27 mg, 53%).

[0034] Example 12

[0035]

[0036] 1b (36 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 -(97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to afford the brown liquid product 3b (42 mg, 74%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 5.2 Hz, 1H), 8.10 - 8.03 (m, 2H), 7.78 - 7.70 (m, 2H), 6.90 - 6.84 (m, 2H), 6.56 - 6.51 (m, 2H), 3.78 (brs, 1H), 3.23 (t, J = 6.8 Hz, 2H), 3.15 (t, J = 7.2 Hz, 2H), 2.24 - 2.17 (m, 2H). 13 13C{ 1 1H} NMR (100 MHz, CDCl3): δ 156.6, 155.8 (d, 1 J C-F = 233.3 Hz), 145.9, 144.5 (d, 4 J C-F = 2.1 Hz), 142.2, 141.4, 130.1, 129.2 (d, 3 J C-F = 9.4 Hz), 128.9, 115.7 (d, 2 J C-F = 22.3 Hz), 113.6, 113.5, 44.1, 33.7, 28.5. 19 19F{ 1 1H} NMR (CDCl3, 376 MHz): δ -128.2. HRMS (ESI) m / z: [M + H] + Calcd for C 17 18 17 H

[0037] Example 13

[0038]

[0039] 1c (35 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), and T + BF4 -(97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3c (33 mg, 60%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.09 - 8.03 (m, 2H), 7.77 - 7.69 (m, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 8.4 Hz, 2H), 3.70 (brs, 1H), 3.25 (t, J = 7.2 Hz, 2H), 3.14 (t, J = 7.6 Hz, 2H), 2.23 - 2.16 (m, 5H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3): δ 156.8, 145.9, 145.8, 142.2, 141.3, 130.1, 129.8, 129.3, 129.1, 128.9, 126.7, 113.1, 43.8, 33.8, 28.7, 20.4. HRMS (ESI) m / z: [M + H] + Calcd for C 18 19 20 15N3 278.1652; Found 278.1641.

[0040] Example 14

[0041]

[0042] 1d (47 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were stirred and reacted at 25 °C for 6 h under an air atmosphere. Then, 10 mL of saturated sodium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown solid product 3d (38 mg, 56%). The characterization data of this compound are as follows: 1HNMR(400MHz,CDCl3):δ8.75(s,1H),8.10 - 8.04(m,2H),7.78 - 7.69(m,2H),7.54 - 7.51(m,2H),7.42(d,J=8.4Hz,2H),7.38(t,J=8.0Hz,2H),7.24 - 7.22(m,1H),6.68(d,J=8.4Hz,2H),3.92(brs,1H),3.32(t,J=7.2Hz,2H),3.16(t,J=7.6Hz,2H),2.27 - 2.20(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ156.7,147.6,145.9,142.2,141.4,141.3,130.3,130.2,129.3,129.2,128.9,128.7,128.0,126.3,126.1,113.1,43.5,33.8,28.6.HRMS(ESI)m / z:[M + H] + CalcdforC 23 H 22 N3340.1808;Found340.1796。

[0043] Example 15

[0044]

[0045] Add 1e(48mg,0.2mmol), DMF(1mL), 2a(43mg,0.4mmol), T + BF4 - (97mg,0.4mmol) and KSCN(19mg,0.2mmol) into the reaction tube in sequence. Stir and react at 25℃ for 6h under air atmosphere, then add 10mL saturated sodium chloride solution to quench the reaction. Extract with ethyl acetate(10mL×3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, evaporate to dryness, and separate by silica gel column chromatography(petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the brown liquid product 3e(42mg, 61%). The characterization data of this compound are as follows: 1HNMR(400MHz,CDCl3):δ8.68(s,1H),8.03 - 7.98(m,2H),7.72 - 7.64(m,2H),6.93(t,J=8.0Hz,1H),6.75(t,J=0.8Hz,1H),6.73 - 6.69(m,1H),6.47(dd,J1=8.0Hz,J2=1.6Hz,1H),3.19(t,J=6.8Hz,2H),3.08(t,J=7.6Hz,2H),2.19 - 2.11(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ156.4,149.2,145.8,142.1,141.4,130.5,130.2,129.3,129.2,128.8,123.4,120.3,115.4,111.8,43.4,33.6,28.1.HRMS(ESI)m / z:[M + H] + CalcdforC 17 H 17 BrN3342.0600;Found342.0580。

[0046] Example 16

[0047]

[0048] 1f(40mg,0.2mmol), DMF(1mL), 2a(43mg,0.4mmol), T + BF4 - (97mg,0.4mmol) and KSCN(19mg,0.2mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 6 h under an air atmosphere, then quenched by adding 10 mL of saturated sodium chloride solution, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation, the product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the yellow liquid product 3f(36mg, 60%). The characterization data of this compound are as follows: 1HNMR(400MHz,CDCl3):δ8.72(s,1H),8.09 - 8.03(m,2H),7.75 - 7.67(m,2H),7.23 - 7.20(m,1H),7.11(d,J=7.2Hz,1H),6.66(dd,J1=8.4Hz,J2=1.2Hz,1H),6.61 - 6.57(m,1H),4.45(brs,1H),3.31(t,J=6.8Hz,2H),3.13(t,J=7.6Hz,2H),2.28 - 2.21(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ156.4,145.8,143.9,142.2,141.4,130.1,129.3,129.2,129.1,128.9,127.8,110.1,117.2,111.2,43.1,33.6,28.1.HRMS(ESI)m / z:[M + H] + CalcdforC 17 H 17 ClN3298.1106;Found298.1086。

[0049] Example 16

[0050]

[0051] Add 1g (35mg, 0.2mmol), DMF (1mL), 2a (43mg, 0.4mmol), T + BF4 - (97mg, 0.4mmol) and KSCN (19mg, 0.2mmol) into a reaction tube in sequence. Stir and react at 25 °C for 6 h under an air atmosphere. Then add 10 mL of saturated sodium chloride solution to quench the reaction. Extract with ethyl acetate (10 mL × 3). Combine the organic phases and dry over anhydrous sodium sulfate. Filter, rotary evaporate, and separate by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain 3g (35mg, 63%) of a brown solid product. The characterization data of this compound are as follows: 1HNMR(400MHz,CDCl3):δ8.75(s,1H),8.07(t,J=8.0Hz,2H),7.77 - 7.70(m,2H),7.13(t,J=8.0Hz,2H),6.66(t,J=7.2Hz,1H),6.54(d,J=7.6Hz,2H),3.66(brs,1H),3.35 - 3.30(m,1H),3.16 - 3.13(m,2H),2.32 - 2.27(m,1H),2.09 - 2.04(m,1H),1.46(d,J=6.8Hz,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ160.6,148.2,145.3,142.3,141.6,130.2,129.4,129.34,129.3,129.2,117.5,113.0,42.2,38.3,36.0,21.0.HRMS(ESI)m / z:[M + H] + CalcdforC 18 H 20 N3278.1652;Found278.1643。

[0052] Example17

[0053]

[0054] 1h(38mg,0.2mmol),DMF(1mL),2a(43mg,0.4mmol),T + BF4 - (97mg,0.4mmol)andKSCN(19mg,0.2mmol)were successively added into a reaction tube,and the mixture was stirred at 25℃ for 6h under an air atmosphere.Then the reaction was quenched by adding 10mL of saturated sodium chloride solution,and the mixture was extracted with ethyl acetate(10mL×3).The organic phases were combined,dried over anhydrous sodium sulfate.Filtered,rotary evaporated,and separated by silica gel column chromatography(petroleum ether / ethyl acetate = 2 / 1,v / v)to obtain the yellow liquid product 3h(32mg,54%).The characterization data of this compound are as follows: 1 HNMR(600MHz,CDCl3):δ8.72(s,1H),8.09 - 8.03(m,2H),7.76 - 7.70(m,2H),6.96(d,J = 8.4Hz,2H),6.51(d,J = 8.4Hz,2H),3.62 - 3.58(m,1H),3.16 - 3.12(m,2H),2.22(s,3H),2.11 - 2.05(m,2H),1.26(d,J = 6.6Hz,3H). 13 C{1 1H NMR (150 MHz, CDCl3): δ 157.2, 145.9, 145.1, 142.2, 141.2, 130.0, 129.8, 129.2, 129.1, 128.8, 126.4, 113.5, 48.7, 36.3, 33.1, 21.1, 20.4. HRMS (ESI) m / z: [M+Na] + Calcd for C 19 H 21 N3Na 314.1628; Found 314.1628.

[0055] Example 18

[0056]

[0057] 1i (42 mg, 0.2 mmol), DMF (1 mL), 2a (43 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were successively added into a reaction tube. The mixture was stirred at 25 °C for 6 h under an air atmosphere, then quenched with 10 mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate. Filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to obtain the yellow liquid product 3i (30 mg, 48%). The characterization data of this compound are as follows: 1 1H NMR (600 MHz, CDCl3): δ 8.78 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.79 - 7.72 (m, 4H), 7.42 (t, J = 7.8 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.64 (brs, 1H), 3.45 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H), 2.40 - 2.38 (m, 2H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3): δ 156.8, 145.9, 143.3, 142.2, 141.4, 134.3, 130.1, 129.3, 129.2, 128.9, 128.6, 126.6, 125.7, 124.6, 123.4, 119.9, 117.3, 104.2, 43.8, 34.0, 28.0. HRMS (ESI) m / z: [M+H] + Calcd for C21 H 20 N3314.1652, Found 314.1647。

[0058] Example 19

[0059]

[0060] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2b (49 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 6 h under an air atmosphere, then quenched by adding 10 mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation, separation by silica gel column (petroleum ether / ethyl acetate = 2 / 1, v / v) gave a mixture of yellow liquid products 3j and 3j' (34 mg, 61%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 0.2H), 8.71 (s, 0.8H), 7.92 - 7.90 (m, 1H), 7.64 - 7.56 (m, 2H), 7.18 - 7.14 (m, 2H), 6.71 - 6.67 (m, 1H), 6.61 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 2H), 3.92 (brs, 1H), 3.30 - 3.25 (m, 2H), 3.17 - 3.12 (m, 2H), 2.79 (s, 3H), 2.27 - 2.18 (m, 2H). 13 C{ 1 1H} NMR (150 MHz, CDCl3): δ 155.3, 148.3, 145.3, 144.4, 141.3, 141.2, 137.2, 130.0, 129.9, 129.3, 129.2, 128.8, 127.0, 126.7, 117.4, 117.3, 112.8, 43.4, 43.3, 33.7, 33.5, 28.7, 28.2, 17.3, 17.2. HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 20 N3 278.1652; Found 278.1637。

[0061] Example 20

[0062]

[0063] 1a (32 mg, 0.2 mmol), DMF (1 mL), 2c (50 mg, 0.4 mmol), T + BF4 - (97 mg, 0.4 mmol) and KSCN (19 mg, 0.2 mmol) were successively added into a reaction tube. The reaction was stirred at 25 °C for 6 h under an air atmosphere, then quenched by adding 10 mL of saturated sodium chloride solution, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and evaporation, separation by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) gave a mixture of yellow liquid products 3k and 3k' (29 mg, 52%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.09 - 8.05 (m, 1H), 7.68 - 7.65 (m, 1H), 7.51 - 7.46 (m, 1H), 7.18 - 7.14 (m, 2H), 6.69 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 8.0 Hz, 2H), 3.86 (brs, 1H), 3.27 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 7.6 Hz, 2H), 2.24 - 2.17 (m, 2H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3): δ 162.9 (d, 1 J C-F = 250.5 Hz), 157.6, 148.1, 146.6, 145.1 (d, 4 J C-F = 3.3 Hz), 143.1, 143.0, 138.5, 131.3 (d, 3 J C-F = 11.0 Hz), 130.9 (d, 3 J C-F = 9.9 Hz), 120.4 (d, 2 J C-F = 26.3 Hz), 119.5 (d, 2 J C-F = 27.9 Hz), 117.5, 112.9, 112.8, 112.7, 112.6, 112.4, 43.4, 33.7, 33.6, 28.6, 28.5. 19 19F{ 1 1H} NMR (CDCl3, 376 MHz): δ -108.0, -109.4. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H17 FN3282.1401; Found282.1390.

[0064] Example 21

[0065]

[0066] 3a (53 mg, 0.2 mmol), THF (1 mL) and t BuONO (80 μL, 0.6 mmol, 90%) were successively added into a reaction tube. The mixture was stirred at room temperature for 12 h under an air atmosphere, then concentrated in vacuo and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give the yellow liquid product 4 (36 mg, 58%). The characterization data of this compound are as follows: 1 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.18 - 8.13 (m, 2H), 7.92 - 7.83 (m, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.50 - 7.47 (m, 2H), 7.40 - 7.36 (m, 1H), 4.52 (t, J = 7.2 Hz, 2H), 3.64 (t, J = 7.2 Hz, 2H). 13 13C{ 1 1H} NMR (150 MHz, CDCl3): δ 198.7, 145.7, 144.1, 142.9, 141.4, 140.9, 132.5, 131.0, 130.4, 129.6, 129.5, 127.6, 119.8, 39.9, 34.6. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 15 N4O2 307.1190; Found 307.1188.

[0067]

[0068] Using compound 4 as the reaction substrate, 2 - ester - substituted quinoxaline compounds 6 with antibacterial activity can be simply synthesized by the oxidation and esterification methods reported in the following literature [1-2] References:

[0069] References:

[0070] [1] N. Yue, B. Ji, L. Liu, G. Tao, S. A. Eremin, L. Wu, Food Agr. Immunol., 2009, 20, 173 - 183.

[0071] [2]L.E.Seitz, W.J.Suling, R.C.Reynolds, J.Med.Chem., 2002, 45, 5604-5606。

[0072] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-substituted quinoxaline compounds, characterized in that The specific synthesis process is as follows: Dissolve the saturated cyclic amine compound 1 and the o-phenylenediamine compound 2 in a solvent, and then add the oxammonium salt T to the reaction system. + X - or the oxammonium salt T + X - and an additive, and react at 0 - 50 °C under an air atmosphere to obtain the target product, the 2-substituted quinoxaline compound 3. The reaction equation in this synthesis method is: wherein R is phenyl, substituted phenyl or naphthyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine, C 1-4 alkyl or phenyl; R 1 is C 1-4 alkyl or phenyl; R 2 is hydrogen, fluorine, chlorine, bromine or C 1-4 alkyl; X - is BF4 - 、ClO4 - 、PF6 - or OTf - ; the additive is potassium thiocyanate.

2. The synthesis method of the 2-substituted quinoxaline compounds according to claim 1, wherein: The solvent is N,N-dimethylformamide, ethanol, dimethyl sulfoxide or dichloromethane.

3. The synthesis method of the 2-substituted quinoxaline compound according to claim 1, characterized in that: The saturated cyclic amine compound 1, o-phenylenediamine compound 2, and oxammonium salt T + X - The molar ratio of the feed of the additive to them is 1:1 - 2:2 - 3:0 - 2.

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