Synthesis of pyrrolo[1,2-a]quinoxaline compounds from nitro-pyrroloarene and carbon dioxide and a method thereof

Abstract

The application discloses a kind of nitryl pyrrole arene and carbon dioxide synthesis pyrrolo [1, 2-a] quinoxaline compound and synthesis method thereof, using simple and easy nitryl pyrrole arene and carbon dioxide as raw material, under the mediation of cheap and easy polymethyl hydrogen siloxane, using efficient catalytic system, it is first reduced to amino that nitryl, subsequently again with polymethyl hydrogen siloxane capture carbon dioxide after the reaction of silicon ester generated, and then intramolecular electrophilic cyclization is obtained target product.The method is simple, one pot realizes reduction and cyclization multi-step reaction, step economy is efficient and target compound is rich in variety.In addition, the substrate of the method of the application is better in universality, under the optimized reaction condition, target product is easy to separate, has potential application value in material and pharmaceutical field.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitryl pyrrole arene and carbon dioxide. BACKGROUND

[0002] Pyrrolo[1,2-a]quinoxaline, as an important class of nitrogen heterocyclic arene, has been widely used in the fields of medicinal chemistry, biochemistry and material science.[a)Guillon, J.; Boulouard, M.; Rault, S. J. Pharm. Pharmacol. 2000, 52, 1369. [b)Alleca, S.; Corona, P.; La Colla, P. Farmaco. 2003, 58, 639. In 1965, Cheeseman et al. first reported the synthesis of pyrrolo[1,2-a]quinoxaline, but the reaction process was complicated and time-consuming, and the target product was finally synthesized in two steps.[c)Cheeseman, G.; Tuck, B. Chem. Ind. 1965, 1382. In recent years, with the rapid development of metal-catalyzed reactions, a large number of methods for synthesizing the skeleton of this class of molecules have been discovered. For example, the classic Ullmann reaction for constructing C-N bond has attracted much attention from chemists due to its cheap and readily available copper catalyst and low toxicity and high catalytic activity. In 2008, Ma Dazhao's group synthesized pyrrolo[1,2-a]quinoxaline compounds by using the hydrolysis of trifluoroacetyl and the formation of intermolecular amino compounds in CuI-catalyzed coupling reaction.[d)Yuan, Q.; Ma, D. J. Org. Chem. 2008, 73, 5159. In 2010, Reeves' group synthesized this class of molecules from simple substrates, but the reaction temperature was high and expensive ligands were needed.[e)Reeves, J. T.; Fandrick, D. R.; Senanayake, C. H. J. Org. Chem. 2010, 75, 992. In 2013, Ma Chen's group synthesized pyrrolo[1,2-a]quinoxaline compounds by using copper acetate to catalyze N-sulfonyl-2-halogen aniline compounds and 2-(chloromethyl)-1H-benzo[d]imidazole, but the single nature of the substrate range limited the application range of this class of reactions.[f)Huang, A. P.; Chen, Y. M.; Ma, C. Org. Lett. 2013, 21, 5480. Therefore, developing an efficient and economical method for synthesizing this class of molecules is an important direction for the current exploration in this field. SUMMARY

[0003] In view of the problems in the prior art, the present application aims to provide a method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitryl pyrrole arene and carbon dioxide, which comprises the following steps: taking nitryl pyrrole arene and carbon dioxide as raw materials, heating the reaction in an organic solvent, and then separating and purifying to obtain pyrrolo[1,2-a]quinoxaline compounds, wherein the raw materials are simple and easy to obtain, the reaction operation is simple, the reaction conditions are mild, the production cost is low, and the atomic utilization rate is high.

[0004] The present application is realized by the following technical solutions:

[0005] A method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitryl pyrrole arene and carbon dioxide, which comprises the following steps:

[0006] Poly methyl hydrogen siloxane and 1,2-bis(diphenyl phosphor) benzene are sequentially added to an organic solvent, then copper acetate is added as a catalyst, carbon dioxide is filled, and a formic acid siloxane solution is obtained after reaction; then 1-(2-nitrophenyl)-1H-pyrrole compounds and 1,8-diazabicycloundec-7-ene are added, and heating and stirring are carried out under the action of carbon dioxide gas and the catalysis of iridium chloride and copper trifluoromethane sulfonate, and then pyrrolo[1,2-a]quinoxaline compounds are obtained after separation and purification.

[0007] Preferably, the reaction formula of the pyrrolo[1,2-a]quinoxaline compounds is as follows:

[0008]

[0009] wherein R is selected from hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, disubstituted alkyl, disubstituted halogen, carboxyl or hydroxyl.

[0010] Preferably, the mass ratio of poly methyl hydrogen siloxane, copper acetate, 1,2-bis(diphenyl phosphor) benzene, 1-(2-nitrophenyl)-1H-pyrrole compounds, iridium chloride, copper trifluoromethane sulfonate and 1,8-diazabicycloundec-7-ene is 10:0.02:0.04:1:0.05:1.3:2.5.

[0011] Preferably, the concentration of 1-(2-nitrophenyl)-1H-pyrrole compounds in the organic solvent is 0.1-0.5 mol / L.

[0012] Preferably, the nitryl pyrrole arene compound comprises one of 1-(2-nitrophenyl)-1H-pyrrole, 1-(2-fluoro-6-nitrophenyl)-1H-pyrrole, 1-(5-methyl-2-nitrophenyl)-1H-pyrrole, 1-(5-methoxy-2-nitrophenyl)-1H-pyrrole, 1-(5-cyclopropyl-2-nitrophenyl)-1H-pyrrole, 1-(5-fluoro-2-nitrophenyl)-1H-pyrrole, 1-(5-chloro-2-nitrophenyl)-1H-pyrrole, 1-(5-bromo-2-nitrophenyl)-1H-pyrrole, 1-(4-bromo-2-nitrophenyl)-1H-pyrrole, 1-(4-iodo-2-nitrophenyl)-1H-pyrrole, 1-[2-nitro-4-(trifluoromethyl)phenyl]-1H-pyrrole, 1-(4,5-dimethyl-2-nitrophenyl)-1H-pyrrole, 1-(4,5-dichloro-2-nitrophenyl)-1H-pyrrole, 1-(5-chloro-4-fluoro-2-nitrophenyl)-1H-pyrrole, 1-(4,5-difluoro-2-nitrophenyl)-1H-pyrrole, 1-(2,3-difluoro-6-nitrophenyl)-1H-pyrrole, 3-nitro-4-(1H-pyrrol-1-yl)benzoic acid, 3-nitro-4-(1H-pyrrol-1-yl)phenol.

[0013] Preferably, the organic solvent is 1,4-dioxane.

[0014] Preferably, the specific process of separation and purification comprises diluting the reaction solution with ethyl acetate, washing the mixture with saturated sodium bicarbonate aqueous solution, concentrating the mixture in vacuum, and purifying the mixture on a silica gel chromatographic column to obtain the pyrrolo[1,2-a]quinoxaline compound.

[0015] Preferably, the heating temperature is 65-120°C, and the stirring time is 0.5-24h.

[0016] A pyrrolo[1,2-a]quinoxaline compound is prepared by the above synthesis method.

[0017] Preferably, the pyrrolo[1,2-a]quinoxaline compound has the following structural formula:

[0018]

[0019] wherein R is selected from hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, disubstituted alkyl, disubstituted halogen, carboxyl, or hydroxyl.

[0020] Compared with the prior art, the present application has the following beneficial technical effects:

[0021] The application uses simple and easy nitro pyrrole arene and carbon dioxide as reaction raw materials, carbon dioxide as carbon one synthesizer, 1,2-bis(diphenyl phosphine) benzene as ligand, under the mediation of cheap and easy polymethyl hydrogen siloxane, using efficient catalytic system of iridium chloride, copper acetate and copper trifluoromethane sulfonate, wherein, copper acetate is used as catalyst for capturing carbon dioxide, iridium chloride and copper trifluoromethane sulfonate are used as catalyst for catalyzing formylation and cyclization reaction, so that the nitro group is reduced to amino group first, then reacts with the silicon ester generated after the capture of carbon dioxide by polymethyl hydrogen siloxane, and then intramolecular electrophilic cyclization is carried out to obtain the target product. The synthesis method is simple to operate, realizes reduction and cyclization multi-step reaction in one pot, is economical and efficient in steps, and the target compound is rich in variety.

[0022] Further, the substrate of the method of the application has good universality, under the optimized reaction conditions, the target product is easy to separate, the raw materials are simple and easy to obtain, the reaction operation is simple, the reaction conditions are mild, the production cost is low, the atomic utilization rate is high, and the method has potential application value in the fields of materials and medicine, BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 HNMR spectrum of the product prepared in Example 1 1 ;

[0024] Figure 2 CNMR spectrum of the product prepared in Example 1 13 ;

[0025] Figure 3 HNMR spectrum of the product prepared in Example 2 1 ;

[0026] Figure 4 CNMR spectrum of the product prepared in Example 2 13 ;

[0027] Figure 5 HNMR spectrum of the product prepared in Example 3 1 ;

[0028] Figure 6 CNMR spectrum of the product prepared in Example 3 13 ;

[0029] Figure 7 HNMR spectrum of the product prepared in Example 4 1 ;

[0030] Figure 8 CNMR spectrum of the product prepared in Example 4 13 ;

[0031] Figure 9H NMR spectrum of the product prepared for Example 5 1 H NMR spectrum of the product prepared for Example 5

[0032] Figure 10 H NMR spectrum of the product prepared for Example 5 13 H NMR spectrum of the product prepared for Example 5

[0033] Figure 11 H NMR spectrum of the product prepared for Example 6 1 H NMR spectrum of the product prepared for Example 6

[0034] Figure 12 H NMR spectrum of the product prepared for Example 6 13 H NMR spectrum of the product prepared for Example 6

[0035] Figure 13 H NMR spectrum of the product prepared for Example 7 1 H NMR spectrum of the product prepared for Example 7

[0036] Figure 14 H NMR spectrum of the product prepared for Example 7 13 H NMR spectrum of the product prepared for Example 7

[0037] Figure 15 H NMR spectrum of the product prepared for Example 8 1 H NMR spectrum of the product prepared for Example 8

[0038] Figure 16 H NMR spectrum of the product prepared for Example 8 13 H NMR spectrum of the product prepared for Example 8

[0039] Figure 17 H NMR spectrum of the product prepared for Example 9 1 H NMR spectrum of the product prepared for Example 9

[0040] Figure 18 H NMR spectrum of the product prepared for Example 9 13 H NMR spectrum of the product prepared for Example 9

[0041] Figure 19 H NMR spectrum of the product prepared for Example 10 1 H NMR spectrum of the product prepared for Example 10

[0042] Figure 20 H NMR spectrum of the product prepared for Example 10 13 H NMR spectrum of the product prepared for Example 10

[0043] Figure 21 H NMR spectrum of the product prepared for Example 11 1 H NMR spectrum of the product prepared for Example 11

[0044] Figure 22 H NMR spectrum of the product prepared for Example 11 13 H NMR spectrum of the product prepared for Example 11

[0045] Figure 23 H NMR spectrum of the product prepared for Example 12; 1 H NMR spectrum;

[0046] Figure 24 H NMR spectrum of the product prepared for Example 12; 13 C NMR spectrum;

[0047] Figure 25 H NMR spectrum of the product prepared for Example 13; 1 H NMR spectrum;

[0048] Figure 26 H NMR spectrum of the product prepared for Example 13; 13 C NMR spectrum;

[0049] Figure 27 H NMR spectrum of the product prepared for Example 14; 1 H NMR spectrum;

[0050] Figure 28 H NMR spectrum of the product prepared for Example 14; 13 C NMR spectrum;

[0051] Figure 29 H NMR spectrum of the product prepared for Example 15; 1 H NMR spectrum;

[0052] Figure 30 H NMR spectrum of the product prepared for Example 15; 13 C NMR spectrum.

[0053] Figure 31 H NMR spectrum of the product prepared for Example 16; 1 H NMR spectrum;

[0054] Figure 32 H NMR spectrum of the product prepared for Example 16; 13 C NMR spectrum;

[0055] Figure 33 H NMR spectrum of the product prepared for Example 17; 1 H NMR spectrum;

[0056] Figure 34 H NMR spectrum of the product prepared for Example 17; 13 C NMR spectrum;

[0057] Figure 35 H NMR spectrum of the product prepared for Example 18; 1 H NMR spectrum;

[0058] Figure 36 H NMR spectrum of the product prepared for Example 18; 13 C NMR spectrum. Detailed Implementation

[0059] The present invention will be further described in detail below with reference to specific embodiments. These descriptions are for explanation purposes only and are not intended to limit the scope of the invention.

[0060] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0061] Example 1

[0062] Preparation of pyrrolo[1,2-a]quinoxaline

[0063] Add 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphine)benzene, and 0.124 g of polymethylhydrosiloxane sequentially to a 20 mL Shrek tube, followed by 1.0 mL of dried 1,4-dioxane. Then, purge with carbon dioxide three times using a double-row tube and an oil pump. Stir at 65 °C for 30 minutes to obtain a pale yellow solution. After the reaction is complete, remove the reaction tube containing the formate solution from the oil bath. Subsequently, under a carbon dioxide atmosphere, add 1.0 mL of dried 1,4-dioxane, 0.2 mmol of 1-(2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)₂, and 0.5 mmol of DBU sequentially. Seal the Shrek tube and stir in an oil bath at 120 °C for 24 hours. After the reaction is complete, cool to room temperature, dilute with ethyl acetate, and wash once with a saturated sodium bicarbonate aqueous solution. Finally, the mixture was concentrated under vacuum and purified by silica gel column chromatography to give 23.5 mg of a pale yellow solid in 70% yield. The structural formula of the product is as follows:

[0064]

[0065] like Figure 1 and Figure 2 As shown, the product's NMR characterization is as follows: 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 7.95 (d, J = 8.0Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=8.2Hz,1H),7.51(t,J=7.7Hz,1H),7.43(t,J=7.6Hz,1H),6.92–6.83(m,2H). 13C NMR (100 MHz, CDC13) δ 145.7, 135.7, 130.0, 127.9, 127.7, 126.3, 125.1, 114.1, 113.9, 113.7, 107.2.

[0066] Example 2

[0067] Preparation of 9-fluoropyrrolo[l,2-a]quinoxaline

[0068] Into a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was completed, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(2-fluoro-6-nitrophenyl)-lH-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2 and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution once. Finally, the mixture was concentrated in vacuo and purified using a silica gel chromatography column to give 25.7 mg of a yellow solid in 69% yield. The structure of the product is as follows:

[0069]

[0070] As shown in Figure 3 and Figure 4 , the product was characterized by NMR: 1 H NMR (400 MHz, CDC13) δ 8.82 (s, 1H), 8.28 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.41 - 7.27 (m, 3H), 6.98 - 6.89 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 152.3 (d, J = 248.8 Hz), 146.6, 138.4, 126.5, 125.3, 124.2 (d, J = 9.0 Hz), 120.6 (d, J = 17.1 Hz), 118.1, 114.2 (d, J = 5.1 Hz), 114.0, 107.6. 19 F NMR (376 MHz, CDC13) δ -123.96.

[0071] Example 3

[0072] 8-methylpyrrolo[l,2-a]quinoxaline

[0073] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was completed, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(5-methyl-2-nitrophenyl)-lH-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography to give 19.7 mg of a yellow solid in 54% yield. The structure of the product was confirmed by NMR as follows:

[0074]

[0075] As shown in Figure 5 and Figure 6 NMR characterization of the product: 1 H NMR (400 MHz, CDC13) δ 8.78 (s, 1H), 7.95 - 7.82 (m, 2H), 7.65 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 6.88 (s, 2H), 2.56 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 144.8, 138.2, 133.7, 129.7, 127.7, 126.5, 126.4, 113.8, 113.7, 106.8, 21.7.

[0076] Example 4

[0077] Preparation of 8-methoxypyrrrolo[l,2-a]quinoxaline

[0078] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was completed, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(5-methoxy-2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography to give 21.0 mg of a white solid in 53% yield. The structure of the product was confirmed by NMR:

[0079]

[0080] The product was characterized by NMR as shown in Figure 7 and Figure 8 1 H NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.81 (t, J = 1.8 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.86 (dt, J = 5.5, 3.7 Hz, 2H), 3.95 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 159.2, 143.2, 131.2, 130.1, 128.7, 126.3, 114.0, 113.6, 112.7, 106.6, 97.5, 55.8.

[0081] Example 5

[0082] Preparation of 8-cyclopropylpyrrolo[1,2-a]quinoxaline

[0083] ​To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was complete, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(5-cyclopropyl-2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography to give 22.5 mg of a brown solid in 54% yield. The structure of the product was confirmed by NMR:

[0084]

[0085] As shown in Figure 9 and Figure 10 NMR characterization of the product: 1 H NMR (400 MHz, CDC13) δ 8.74 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 2.0 Hz, 2H), 2.15 - 2.05 (m, 1H), 1.14 - 1.07 (m, 2H), 0.89 - 0.81 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 144.7, 133.8, 129.8, 127.8, 126.5, 122.6, 113.9, 113.8, 110.7, 107.0, 99.9, 15.9, 10.1.

[0086] Example 6

[0087] Preparation of 8-fluoropyrrolo[1,2-a]quinoxaline

[0088] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double manifold and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was complete, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(5-fluoro-2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was complete, it was cooled to room temperature, diluted with ethyl acetate, and washed once with saturated aqueous sodium bicarbonate. Finally, the mixture was concentrated in vacuo and purified using a silica gel chromatography column to give 25.0 mg of a light yellow solid in 67% yield. The structure of the product is shown below:

[0089]

[0090] As shown in Figure 11 and Figure 12 , the product was characterized by NMR: 1 H NMR (400 MHz, CDC13) δ 8.76 (s, 1H), 7.93 (t, J = 8.9, 5.8 Hz, 1H), 7.80 (s, 1H), 7.51 (d, J = 9.2, 2.7 Hz, 1H), 7.15 (t, J = 8.6, 4.3 Hz, 1H), 6.89 (d, J = 2.0 Hz, 2H). 13 C NMR (100 MHz, CDC13) δ 161.5 (d, J = 248.5 Hz), 144.9 (d, J = 2.7 Hz), 132.4, 131.9 (d, J = 9.8 Hz), 128.7 (d, J = 11.2 Hz), 126.1, 114.5, 114.3, 113.1 (d, J = 23.2 Hz), 107.5, 100.6 (d, J = 26.9 Hz). 19 F NMR (376 MHz, CDC13) δ -110.42.

[0091] Example 7

[0092] Preparation of 8-chloropyrrolo[l,2-a]quinoxaline

[0093] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was complete, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(5-chloro-2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography to give 25.1 mg of a light yellow solid in 62% yield. The structure of the product was confirmed by NMR:

[0094]

[0095] As shown in Figure 13 and Figure 14 , the product was characterized by NMR: 1 H NMR (400 MHz, CDC13) δ 8.77 (s, 1H), 7.92 - 7.78 (m, 3H), 7.38 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 4.9 Hz, 2H). 13 C NMR (100 MHz, CDC13) δ 145.8, 134.3, 133.1, 131.2, 128.5, 126.2, 125.5, 114.5, 114.4, 113.9, 107.8.

[0096] Example 8

[0097] Preparation of 8-bromopyrrolo[1,2-a]quinoxaline

[0098] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was complete, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(5-bromo-2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. Finally, the mixture was concentrated in vacuo and purified using a silica gel chromatography column to give 22.2 mg of a yellow solid in 45% yield. The structure of the product was confirmed by NMR:

[0099]

[0100] As shown in Figure 15 and Figure 16 , the product was characterized by NMR: 1 H NMR (400 MHz, CDC13) δ 8.79 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.86 (t, J = 1.8 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.7, 1H), 6.96 - 6.85 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 146.0, 134.7, 131.4, 128.8, 128.4, 126.3, 121.0, 116.9, 114.6, 114.4, 107.9.

[0101] Example 9

[0102] Preparation of 7-(trifluoromethyl)pyrrolo[1,2-a]quinoxaline

[0103] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double-tube and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was completed, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-[2-nitro-4-(trifluoromethyl)phenyl]-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution once. Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography to give 31.2 mg of white solid in 66% yield. The structure of the product was confirmed by NMR as shown below:

[0104]

[0105] As shown in Figure 17 and Figure 18 , the product was characterized by NMR as follows: 1 H NMR (400 MHz, CDC13) δ 8.84 (s, 1H), 8.22 (s, 1H), 8.00 - 7.89 (m, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.01 - 6.90 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 147.0, 135.5, 130.0, 127.6, 127.2 (q, J = 33.2 Hz), 126.4, 124.1 (d, J = 3.9 Hz), 123.8 (q, J = 271.8 Hz), 114.9, 114.8, 114.5, 108.4. 19 F NMR (376 MHz, CDC13) δ -61.94.

[0106] Example 10

[0107] Preparation of 7,8-dimethylpyrrolo[1,2-a]quinoxaline

[0108] To a 20 mL Schlenk tube was added 0.004 mmol of copper acetate, 0.008 mmol of 1,2-bis(diphenylphosphino)benzene and 0.124 g of polymethylhydrosiloxane, followed by 1.0 mL of dry 1,4-dioxane. The tube was then charged with carbon dioxide three times using a double manifold and oil pump. The mixture was stirred at 65 °C for 30 min to give a light yellow solution. After the reaction was complete, the reaction tube containing the silicon formate solution was removed from the oil bath. Subsequently, 1.0 mL of dry 1,4-dioxane, 0.2 mmol of 1-(4,5-dimethyl-2-nitrophenyl)-1H-pyrrole, 0.05 mmol of iridium trichloride, 0.26 mmol of Cu(OTf)2, and 0.5 mmol of DBU were added sequentially under a carbon dioxide atmosphere. The Schlenk tube was sealed and stirred in a 120 °C oil bath for 24 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and washed once with saturated aqueous sodium bicarbonate. Finally, the mixture was concentrated in vacuo and purified by silica gel chromatography to give 19.6 mg of a yellow solid in 50% yield. The structure of the product is shown below:

[0109]

[0110] As shown in Figure 19 and Figure 20 , the product was characterized by NMR: 1 H NMR (400 MHz, CDC13) δ 8.73 (s, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 6.84 (s, 2H), 2.43 (s, 3H), 2.38 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 144.8, 137.2, 133.9, 130.0, 126.4, 125.8, 114.2, 113.5, 106.6, 20.3, 19.5.

[0111] Example 11

[0112] Preparation of 7-bromopyrrolo[1,2-a]quinoxaline

[0113] Example 11 differs from Example 1 in that 1-(2-nitrophenyl)-1H-pyrrole was replaced by 1-(4-iodo-2-nitrophenyl)-1H-pyrrole, and the rest of the preparation was the same. This resulted in 29.2 mg of a light yellow solid in 59% yield. The structure of the product is shown below:

[0114]

[0115] As shown in Figure 21 and Figure 22As shown, the product's NMR characterization is as follows: H NMR (400MHz, CDCl3) δ 8.75 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.65 (d, J = 8.2Hz, 1H), 7.54 (d, J = 9.0Hz, 1H), 6.94–6.84 (m, 2H). 13 C NMR (100MHz, CDCl3) δ146.6,136.9,132.4,130.4,126.9,126.2,117.6,115.1,114.5,114.4,107.9.

[0116] Example 12

[0117] Preparation of 7-iodopyrrolo[1,2-a]quinoxaline

[0118] Example 12 differs from Example 1 in that the 1-(2-nitrophenyl)-1H-pyrrole compound used is 1-(4-iodo-2-nitrophenyl)-1H-pyrrole. The rest of the preparation process is the same, yielding 32.9 mg of brown solid with a yield of 56%. The structural formula of the obtained product is as follows:

[0119]

[0120] like Figure 23 and Figure 24 As shown, the product's NMR characterization is as follows: 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.30(s,1H),7.89(s,1H),7.83–7.73(m,1H),7.65–7.55(m,1H),6.96–6.86(m,2H). 13 C NMR (100MHz, CDCl3) δ146.5,138.7,137.2,136.2,127.6,126.3,115.4,114.4,108.0,88.2.

[0121] Example 13

[0122] Preparation of pyrrolo[1,2-a]quinoxaline-7-carboxylic acid

[0123] Example 13 differs from Example 1 in that the 1-(2-nitrophenyl)-1H-pyrrole compound used is 3-nitro-4-(1H-pyrrole-1-yl)benzoic acid. The rest of the preparation process is the same, yielding 21.6 mg of a yellow solid with a yield of 51%. The structural formula of the obtained product is as follows:

[0124]

[0125] likeFigure 25 and Figure 26 As shown, the product's NMR characterization is as follows: 1 H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.97(s,1H),8.55(d,J=2.6Hz,1H),8.43– 8.38(m,2H),8.11(d,J=8.7Hz,1H),7.09(d,J=3.9Hz,1H),7.01(t,J=3.3Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ167.2,147.2,135.3,131.2,131.1,129.0,128.0,126.5,117.4,115.8,115.5,109.1.

[0126] Example 14

[0127] Preparation of pyrrolo[1,2-a]quinoxaline-7-ol

[0128] Example 14 differs from Example 1 in that the 1-(2-nitrophenyl)-1H-pyrrole compound used is 3-nitro-4-(1H-pyrrole-1-yl)phenol. The rest of the preparation process is the same, yielding 16.6 mg of a yellow solid with a yield of 45%. The structural formula of the obtained product is as follows:

[0129]

[0130] like Figure 27 and Figure 28 As shown, the product's NMR characterization is as follows: 1 H NMR (400MHz, DMSO-d) 6 )δ9.78(s,1H),8.81(s,1H),8.34(s,1H),8.13(d,J=8.9Hz,1H),7.22(d,J=2.7Hz,1H),7.1–7.02(m,1H),6.97–6.80(m,2H). 13 C NMR (100MHz, DMSO-d6) δ155.4,146.3,137.1,126.0,121.3,117.1,116.1,115.6,113.9,113.9,107.4.

[0131] Example 15

[0132] Preparation of 7,8-dichloropyrrolo[1,2-a]quinoxaline

[0133] Example 15 differs from Example 1 in that the 1-(2-nitrophenyl)-1H-pyrrole compound used is 1-(4,5-dichloro-2-nitrophenyl)-1H-pyrrole. The rest of the preparation process is the same, yielding 30.3 mg of a white solid with a yield of 64%. The structural formula of the obtained product is as follows:

[0134]

[0135] like Figure 29 and Figure 30 As shown, the product's NMR characterization is as follows: 1 H NMR (400MHz, CDCl) 3 )δ8.79(s,1H),8.04(s,1H),7.95(s,1H),7.88–7.83(m,1H),6.97–6.90(m,2H). 13 C NMR (100MHz, CDCl3) δ146.9,135.3,131.4,131.1,128.9,127.2,126.2,115.5,115.0,114.9,108.6.

[0136] Example 16

[0137] Preparation of 8-chloro-7-fluoropyrrolo[1,2-a]quinoxaline

[0138] Example 16 differs from Example 1 in that the 1-(2-nitrophenyl)-1H-pyrrole compound used is 1-(5-chloro-4-fluoro-2-nitrophenyl)-1H-pyrrole. The rest of the preparation process is the same, yielding 30.4 mg of a white solid with a yield of 69%. The structural formula of the obtained product is as follows:

[0139]

[0140] like Figure 31 and Figure 32 As shown, the product's NMR characterization is as follows: 1 H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 7.88 (d, J = 6.6Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 9.5Hz, 1H), 6.91 (d, J = 11.3Hz, 2H). 13 C NMR (100MHz, CDCl3) δ155.1 (d, J = 246.9Hz), 146.8, 135.6 (d, J = 10.1Hz), 126.1, 124.9, 120.7 (d, J = 20.2Hz), 116.5 (d, J = 22.1Hz), 115.4, 114.6, 108.3. 19F NMR (376 MHz, CDCb) δ -118.87.

[0141] Example 17

[0142] Preparation of 7,8-difluoropyrrolo[l,2-a]quinoxaline

[0143] Example 17 differs from Example 1 in that the 1-(2-nitrophenyl)-lH-pyrrole compound is replaced by 1-(4,5-difluoro-2-nitrophenyl)-lH-pyrrole, and the rest of the preparation is the same. 32.3 mg of yellow solid is obtained with a yield of 79%, and the structure of the product is as follows:

[0144]

[0145] As shown in Figure 33 and Figure 34 , the product nuclear magnetic resonance is characterized: 1 H NMR (400 MHz, CDCb) δ 8.78 (s, 1H), 7.86-7.71 (m, 2H), 7.64 (t, J = 10.5, 7.3 Hz, 1H), 6.99-6.86 (m, 2H). 13 C NMR (100 MHz, CDCb) δ 150.0 (dd, J = 176.6, 14.5 Hz), 147.5 (dd, J = 172.2, 14.4 Hz), 146.0 (d, J = 2.9 Hz), 132.5 (d, J = 9.2 Hz), 125.9, 124.4 (d, J = 7.9 Hz), 117.6 (d, J = 18.0 Hz), 114.6, 114.5, 108.0, 102.4 (d, J = 22.1 Hz). 19 F NMR (376 MHz, CDCb) δ -134.00, -140.03.

[0146] Example 18

[0147] Preparation of 8,9-difluoropyrrolo[l,2-a]quinoxaline

[0148] Example 18 differs from Example 1 in that the 1-(2-nitrophenyl)-lH-pyrrole compound is replaced by (2,3-difluoro-6-nitro-m-phenyl)-lH-pyrrole, and the rest of the preparation is the same. 25.7 mg of yellow solid is obtained with a yield of 63%, and the structure of the product is as follows:

[0149]

[0150] As shown in Figure 35 and Figure 36 , the product nuclear magnetic resonance is characterized: 1H NMR (400 MHz, CDC13) δ 8.77 (s, 1H), 7.80 - 7.71 (m, 2H), 7.67 - 7.58 (m, 1H), 6.96 - 6.87 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 150.0 (q, J = 176.4, 14.3 Hz), 147.5 (q, J = 172.2, 14.2 Hz), 146.0 (d, J = 2.9 Hz), 132.5 (d, J = 10.1 Hz), 125.9, 124.4 (d, J = 8.8 Hz), 117.6 (d, J = 18.1 Hz), 114.6, 114.5, 107.9, 102.4 (d, J = 22.2 Hz). 19 F NMR (376 MHz, CDC13) δ -133.91, -139.95.

[0151] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0152] The above description is only the preferred embodiment of the present application, not any form of limitation to the present application; anyone skilled in the art can easily implement the present application according to the drawings and the above description; however, anyone skilled in the art can make some changes, modifications and equivalent changes to the above-mentioned technical contents without departing from the scope of the present application; meanwhile, any equivalent changes, modifications and evolution of the above-mentioned embodiments according to the essential technology of the present application are still within the protection scope of the present application.

Claims

1. A method for synthesizing a pyrrolo[1,2-a]quinoxaline compound by synthesizing a nitryl pyrrole arene and carbon dioxide, characterized in that, comprising the steps of: A mixture of 1,2-bis(diphenylphosphino)benzene and copper acetate is added to an organic solvent, and carbon dioxide is introduced into the mixture. Then, a 1-(2-nitrophenyl)-1H-pyrrole compound and 1,8-diazabicycloundec-7-ene are added to the mixture, and heating and stirring are performed in the presence of carbon dioxide. After the reaction, a pyrrolo[1,2- a ]quinoxaline compound is obtained by separation and purification. the 1-(2-nitrophenyl)-1H-pyrrole compound is selected from one of 1-(2-nitrophenyl)-1H-pyrrole, 1-(2-fluoro-6-nitrophenyl)-1H-pyrrole, 1-(5-methyl-2-nitrophenyl)-1H-pyrrole, 1-(5-methoxy-2-nitrophenyl)-1H-pyrrole, 1-(5-cyclopropyl-2-nitrophenyl)-1H-pyrrole, 1-(5-fluoro-2-nitrophenyl)-1H-pyrrole, 1-(5-chloro-2-nitrophenyl)-1H-pyrrole, 1-(5-bromo-2-nitrophenyl)-1H-pyrrole, 1-(4-bromo-2-nitrophenyl)-1H-pyrrole, 1-(4-iodo-2-nitrophenyl)-1H-pyrrole, 1-[2-nitro-4-(trifluoromethyl)phenyl]-1H-pyrrole, 1-(4,5-dimethyl-2-nitrophenyl)-1H-pyrrole, 1-(4,5-dichloro-2-nitrophenyl)-1H-pyrrole, 1-(5-chloro-4-fluoro-2-nitrophenyl)-1H-pyrrole, 1-(4,5-difluoro-2-nitrophenyl)-1H-pyrrole, 1-(2,3-difluoro-6-nitro-m-phenyl)-1H-pyrrole, 3-nitro-4-(1H-pyrrol-1-yl)benzoic acid, 3-nitro-4-(1H-pyrrol-1-yl)phenol; said pyrrolo[1,2- a ]quinoxaline compounds have a structural formula selected from the group consisting of: , , , , , , , , , , , , , , , , , one of. 2.The method for synthesizing pyrrolo [1, 2-a] quinoxaline compounds by synthesizing nitryl pyrrole arene and carbon dioxide according to claim 1, characterized in that, the poly(methylhydro)siloxane, copper acetate, 1,2-bis(diphenylphosphoryl)benzene, 1-(2-nitrophenyl)-1H-pyrrole compound, iridium chloride, copper trifluoromethanesulfonate, and 1,8-diazabicycloundec-7-ene are in a molar ratio of 10:0.02:0.04:1:0.05:1.3:2.

5.

3. The method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitryl pyrrolo arene and carbon dioxide according to claim 1, characterized in that, the 1-(2-nitrophenyl)-1H-pyrrole compound is in a concentration of 0.1-0.5 moles / liter in the organic solvent.

4. The method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitropyrrole aromatics and carbon dioxide according to claim 1, characterized in that, the organic solvent is 1,4-dioxane.

5. The method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitropyrrole aromatics and carbon dioxide according to claim 1, characterized in that, The specific process of the separation and purification is that the reaction solution is diluted with ethyl acetate, then washed with saturated sodium bicarbonate aqueous solution, then the mixture is concentrated in vacuum and purified by a silica gel chromatographic column to obtain a pyrrolo[1,2- a ]quinoxaline compound.

6. The method for synthesizing pyrrolo[1,2-a]quinoxaline compounds from nitryl pyrrolo arene and carbon dioxide according to claim 1, characterized in that, the heating temperature is 65-120 °C and the stirring time is 0.5-24 h.

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