A method for preparing dihydroquinolinopyrrole derivatives by catalysis of trifluoromethanesulfonic acid compounds

Abstract

The present invention belongs to the technical field of catalytic methods and catalysts, and specifically relates to a method for preparing dihydroquinolinopyrrole derivatives by catalyzing trifluoromethanesulfonic acid compounds. The method adopts a synergistic catalytic system, uses trifluoromethanesulfonic acid compounds as catalysts, and achieves efficient preparation of dihydroquinolinopyrrole derivatives through an intermolecular tandem cyclization reaction between 1,4-pyridinethioyl and aminomalononitrile. The method has significant advantages such as mild conditions and high selectivity. The method adopts simple and readily available raw materials, avoids the use of traditional complex substrates, and exhibits excellent functional group compatibility. The method can tolerate various substituents such as nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole and thiophene, providing a new strategy for constructing the skeleton of dihydroquinolinopyrrole derivatives. The method is characterized by simple operation, high yield and good chemical selectivity, and provides an important reference for the industrial production of such compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of catalytic methods and catalysts, and particularly relates to a method for preparing dihydroquinolinopyrrole derivatives by catalyzing trifluoromethanesulfonic acid compounds. Background Art

[0002] Dihydroquinolinopyrrolidine derivatives are formed by the fusion of dihydroquinoline (1,2- or 1,4-dihydroquinoline) with a pyrrole ring and may contain various substituents. They typically exhibit diverse biological activities and pharmaceutical potential. For example, PARP inhibitors containing dihydroquinolinopyrrolidine structures can inhibit topoisomerases or kinases and have anti-tumor activity. They also have inhibitory effects on Staphylococcus aureus (MRSA) and HIV protease. They also act as 5-HT receptor modulators or MAO inhibitors, exhibiting neuroprotective effects and potential for the treatment of depression or Parkinson's disease. Some derivatives can inhibit COX-2 or NF-κB pathways and have anti-inflammatory potential. Therefore, dihydroquinolinopyrrolidine derivatives have attracted considerable attention in medicinal chemistry and organic synthesis, particularly as alkaloid analogs or drug backbones.

[0003] Currently, the synthesis methods of dihydroquinolinone pyrrole derivatives include: (1) Multicomponent reactions (MCRs): Ugi reaction, Pictet-Spengler reaction, etc. can be used to construct quinolinone pyrrole skeleton. (2) Cycloaddition reaction: 1,3-dipolar cycloaddition can be used to construct pyrrole ring. (3) Transition metal catalysis: Palladium-catalyzed CH activation or copper-catalyzed click chemistry can be used to construct complex structures; (4) Reductive amination / cyclization: quinolinone and pyrrolamine are condensed under the action of a reducing agent. However, the existing methods still have significant limitations: (1) Dependence on precious metal catalytic systems leads to increased costs; (2) Specific substrates require multiple steps of pre-activation treatment; (3) The reaction often requires harsh and drastic conditions such as high temperature; (4) Regioselectivity control and product yield need to be improved. Therefore, the development of new synthetic methods based on readily available raw materials and the construction of dihydroquinolinone pyrrole derivatives in one step under mild conditions is of great scientific significance for the advancement of related drug molecules.

[0004] In response to the above technical problems, the present invention breaks through the traditional synthesis paradigm and develops a synergistic catalytic system of oxidants and trifluoromethanesulfonic acid compounds. Using commercial raw materials 1,4-pyridinium sulfide and aminomalononitrile as starting materials, the target product is efficiently constructed through intermolecular tandem cyclization reactions. This invention embodies the practicality of sulfur atoms in assisting the formation of ring systems and enriches the synthetic methods of molecular modification and diversified construction of the skeleton of dihydroquinolinopyrrole derivatives. Summary of the Invention

[0005] The primary purpose of the present invention is to provide a method for preparing dihydroquinolinopyrrole derivatives catalyzed by trifluoromethanesulfonic acid compounds. The reaction formula of the method is as follows:

[0006] ;

[0007] Among them, R 1 is an alkyl group; R 2 is any one of nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole and thiophene;

[0008] The specific steps include:

[0009] (1) Under argon atmosphere, dissolve the aminomalononitrile compound in a solvent, add an oxidant, and stir the reaction at room temperature;

[0010] (2) adding 1,4-pyridylthioyl salt and a catalyst trifluoromethanesulfonic acid compound to the reaction described in step (1), and heating the reaction system in an oil bath;

[0011] (3) After the reaction is completed, cool, filter, wash, concentrate under reduced pressure, and purify and elute to obtain the target product.

[0012] Preferably, the solvent in step (1) is one or more of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane and methanol.

[0013] Preferably, the solvent in step (1) is acetonitrile or tetrahydrofuran.

[0014] Preferably, the oxidant in step (1) is 2,3-dichloro-5,6-dicyanobenzoquinone.

[0015] Preferably, the trifluoromethanesulfonic acid compound as the catalyst in step (2) is one or more of Zn(OTf)2, Cu(OTf)2, Al(OTf)3, Mg(OTf)2, Sc(OTf)3, and In(OTf)3.

[0016] Preferably, the oil bath temperature in step (2) is 60-100°C.

[0017] Preferably, the reaction time in step (2) is 24-36 hours.

[0018] Preferably, diatomaceous earth is used for filtration in step (3), dichloromethane is used for washing, and silica gel column chromatography is used for purification and elution. The eluent in the silica gel column chromatography is petroleum ether and ethyl acetate, and the ratio of petroleum ether to ethyl acetate is 10:1.

[0019] The beneficial effects of the present invention are as follows: the present invention provides a method for preparing dihydroquinolinopyrrole derivatives by catalyzing trifluoromethanesulfonic acid compounds, wherein the method uses a synergistic catalytic system of an oxidant and a trifluoromethanesulfonic acid compound, takes commercial raw materials 1,4-pyridinium sulfide and aminomalononitrile as starting materials, and achieves efficient construction of the target product through an intermolecular tandem cyclization reaction; compared with existing methods for synthesizing dihydroquinolinopyrrole derivatives, the method has significant advantages such as mild conditions and high selectivity, and the method adopts simple and readily available raw materials, avoids the use of traditional complex substrates, and exhibits excellent functional group compatibility, and can tolerate a variety of substituents such as nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole and thiophene, providing a new strategy for the construction of the skeleton of dihydroquinolinopyrrole derivatives. The method is characterized by simple operation, high yield and good chemical selectivity, and provides an important reference for the industrial production of such compounds. The invention embodies the practicality of sulfur atoms in the formation of auxiliary ring systems, enriches the molecular modification and diversified synthesis methods of such skeletons. DETAILED DESCRIPTION

[0020] The scope of protection of the present invention is further illustrated below through specific embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0021] It should be noted that, in the following examples, unless otherwise specified, the methods described are conventional methods and the reagents described can be purchased from commercial sources.

[0022] In the following examples, Zn(OTf)2 is a trifluoromethanesulfonic acid compound, which is widely used in catalytic reactions.

[0023] In the following examples, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is a commonly used organic oxidant.

[0024] In the following examples, the Schlenk tube is a laboratory glass instrument designed for anhydrous and oxygen-free operations and is widely used in chemical reactions that are sensitive to air / moisture (such as organometallic synthesis, transition metal catalysis, free radical reactions, etc.).

[0025] Example 1

[0026] Under argon, substrate 2a (0.3 mmol) was dissolved in dry acetonitrile (2 mL), followed by the addition of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol). The mixture was reacted at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in a 60°C oil bath for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through celite, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The product 3a was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the desired product 3a.

[0027]

[0028] Product testing data are as follows:

[0029] White solid, yield 80%.

[0030] 1 H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m, 2H), 7.33 – 7.28 (m, 3H), 4.24(t, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.14 (t, J = 6.8 Hz, 2H).

[0031] 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.5, 132.6, 132.3, 129.4, 128.4,127.9, 125.6, 125.1, 122.6, 114.8, 111.3, 105.9, 53.0, 52.3, 43.4, 28.5.

[0032] Example 2

[0033] Under argon, substrate 2b (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv) were then added directly to the system. The reaction system was then placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the desired product 3b.

[0034]

[0035] Pale yellow solid, yield 71%.

[0036] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.25-8.22 (m, 1H), 7.72 (d, J = 7.2 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.32 (t, J = 6.8 Hz, 2H).

[0037] 13 C NMR (100 MHz, DMSO -d6) δ 164.9, 161.2, 146.9, 141.2, 130.4,126.4, 124.0, 122.0, 119.2, 114.7, 111.0, 106.8, 53.1, 52.6, 40.0, 27.8.

[0038] Example 3

[0039] Under argon, substrate 2c (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3c.

[0040]

[0041] Pale yellow solid, yield 69%.

[0042] 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 6.0 Hz, 1H), 7.30 – 7.22 (m, 2H), 4.25 (t, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.12 (t, J = 6.8 Hz, 2H).

[0043] 13 C NMR (100 MHz, CDCl3) δ 165.2, 161.3, 133.6, 131.3, 130.6, 129.6,129.3, 127.1, 125.1, 122.7, 115.3, 110.9, 106.4, 53.0, 52.3, 43.3, 28.0.

[0044] Example 4

[0045] Under argon, substrate 2d (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3d.

[0046]

[0047] Pale yellow solid, yield 68%.

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 2.0 Hz, 1H), 7.46 – 7.43 (m, 1H),7.16 (d, J = 8.0 Hz, 1H), 4.25 (t, J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H).

[0049] 13 C NMR (100 MHz, CDCl3) δ 165.2, 161.3, 132.2, 131.2, 131.0, 129.8,128.2, 127.5, 122.9, 121.6, 115.5, 111.0, 106.5, 53.1, 52.4, 43.3, 28.2.

[0050] Example 5

[0051] Under argon, substrate 2e (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The product 3e was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the desired product.

[0052]

[0053] White solid, yield 76%.

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.17 – 7.11 (m, 2H), 4.21 (t, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 2.34 (s,1H).

[0055] 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.5, 137.6, 132.7, 130.2, 129.3,128.2, 125.6, 125.5, 122.5, 114.7, 111.3, 105.9, 52.9, 52.2, 43.6, 28.1,21.3.

[0056] Example 6

[0057] Under argon, substrate 2f (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was then placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the desired product 3f.

[0058]

[0059] White solid, yield 65%.

[0060] 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.58 – 7.54 (m, 3H), 7.48 –7.46 (m, 2H), 7.40 – 7.34 (m, 2H), 4.28 (t, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.92(s, 3H), 3.18 (t, J = 6.8 Hz, 2H).

[0061] 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.5, 140.9, 140.0, 132.6, 131.1,129.0, 128.8, 128.0, 127.8, 126.8, 126.1, 123.9, 122.8, 115.0, 111.3, 106.1,53.0, 52.3, 43.5, 28.2.

[0062] Example 7

[0063] Under argon, 2 g (0.3 mmol) of the substrate was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. Then, 1,4-pyridiniumthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through celite, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) afforded 3 g of the desired product.

[0064]

[0065] White solid, yield 63%.

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.17 (s, J = 8.4 Hz, 1H), 6.87 –6.85 (m, 1H), 4.22 (t, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.80 (s,3H), 3.06 (t, J = 6.8 Hz, 2H).

[0067] 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.5, 159.0, 132.6, 129.3, 126.4,122.6, 115.5, 115.0, 111.3, 110.2, 105.9, 55.3, 52.9, 52.3, 43.8, 27.7.

[0068] Example 8

[0069] Under argon, the substrate 2h (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. Then, 1,4-pyridiniumthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3h.

[0070]

[0071] Pale yellow solid, yield 70%.

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 2H), 7.20 – 7.16 (m, 1H), 4.26 (t, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H).

[0073] 13 C NMR (100 MHz, CDCl3) δ 165.6, 161.3, 133.4, 132.1, 131.4, 129.0,127.6, 124.3, 124.2, 122.9, 115.5, 111.0, 106.0, 53.0, 52.3, 43.0, 28.4.

[0074] Embodiment 9

[0075] Under argon, substrate 2i (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3i.

[0076]

[0077] Pale yellow solid, yield 65%.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 9.2 Hz, 1H), 7.44 – 7.42 (m, 2H), 4.23 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.12 (t, J = 6.8 Hz, 2H).

[0079] 13 C NMR (100 MHz, CDCl3) δ 165.5, 161.3, 134.2, 131.8, 131.3, 131.1,126.7, 123.4, 122.9, 115.0, 111.1, 106.3, 53.0, 52.3, 43.2, 28.3.

[0080] Example 10

[0081] Under argon, substrate 2j (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The product 3j was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the desired product.

[0082]

[0083] White solid, yield 76%.

[0084] 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.8 Hz, 1H), 6.84 – 6.78 (m, 2H), 4.20 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.10 (t, J =6.8 Hz, 2H).

[0085] 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.6, 160.4, 134.3, 133.2, 126.9,122.8, 118.5, 113.9, 113.4, 113.1, 111.5, 105.3, 55.4, 52.8, 52.2, 43.2,28.9.

[0086] Example 11

[0087] Under argon, substrate 2k (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was then placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3k.

[0088]

[0089] Brown solid, yield 60%.

[0090] 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.38 (s, 1H), 4.25 (t, J = 6.8Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.11 (t, J = 6.8 Hz, 2H).

[0091] 13 C NMR (100 MHz, CDCl3) δ 165.0, 161.2, 133.2, 132.1, 132.0, 130.7,130.0, 127.0, 125.5, 123.1, 115.4, 110.8, 106.7, 53.0, 52.4, 43.1, 27.9.

[0092] Example 12

[0093] Under argon, substrate 2l (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3l.

[0094]

[0095] Brown solid, yield 56%.

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 6.73 (s, 1H), 4.29 (t, J = 6.8Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.05 (t, J =6.8 Hz, 2H).

[0097] 13 C NMR (100 MHz, CDCl3) δ 165.9, 161.6, 149.8, 148.2, 133.2, 125.5,122.8, 118.2, 113.3, 111.4, 110.9, 108.4, 105.4, 55.9, 55.8, 52.7, 52.2,43.4, 28.0.

[0098] Example 13

[0099] Under argon, substrate 2m (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3m.

[0100]

[0101] White solid, yield 56%.

[0102] 1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 6.72 (s, 1H), 5.99 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.03 (t, J = 6.8 Hz, 2H).

[0103] 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.5, 148.5, 147.4, 132.9, 127.3,122.7, 119.3, 113.8, 111.4, 108.6, 105.6, 105.4, 101.6, 52.9, 52.2, 43.4,28.7.

[0104] Example 14

[0105] Under argon, substrate 2n (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was then placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3n.

[0106]

[0107] White solid, yield 72%.

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.6 Hz,1H), 4.30 (t, J = 6.8 Hz, 2H), 3.90 (s, 6H), 3.26 (t, J = 6.8 Hz, 2H).

[0109] 13 C NMR (100 MHz, CDCl3) δ 165.9, 161.6, 149.8, 148.2, 133.2, 125.5,122.8, 118.1, 113.3, 111.4, 110.9, 108.4, 105.4, 55.9, 55.8, 52.7, 52.2,43.4, 28.0.

[0110] Example 15

[0111] Under argon, substrate 2o (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3o.

[0112]

[0113] Yield 23%.

[0114] 1 H NMR (400 MHz, CDCl3) δ 10.6 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.45(d, J = 8.4 Hz, 1H), 7.30-7.27 (m, 1H), 7.19-7.15 (m, 1H), 4.33 (t, J = 6.8 Hz,2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.28 (t, J = 6.8 Hz, 2H).

[0115] 13 C NMR (100 MHz, CDCl3) δ 164.9, 162.3, 136.5, 133.8, 125.7, 125.1,124.3, 124.2, 120.5, 119.0, 112.2, 111.1, 110.7, 109.1, 107.1, 52.6, 52.5,44.9, 20.1.

[0116] Example 16

[0117] Under argon, substrate 2a (0.3 mmol) was dissolved in dry acetonitrile (2 mL). 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was then added. The mixture was allowed to react at room temperature for 1 h. 1,4-Pyridinylthioyl 1b (50.6 mg, 0.2 mmol) and zinc bistrifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were then added directly to the system. The reaction system was placed in an oil bath at 60°C for 36 h. After completion of the reaction, the system was cooled to room temperature, filtered through Celite, and washed with dichloromethane (5 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the desired product 3ba.

[0118]

[0119] White solid, yield 78%.

[0120] 1 H NMR (400 MHz, CDCl3) δ 7.61-7.59 (m, 1H), 7.25 – 7.20 (m, 3H), 4.38–4.27 (m, 4H),

[0121] 4.17 (t, J = 6.8 Hz, 2H), 3.07(t, J = 6.8 Hz, 2H), 1.34 – 1.29 (m, 6H).

[0122] 13 C NMR (100 MHz, CDCl3) δ 164.6, 161.7, 135.2, 132.6, 126.9, 124.8,124.2, 123.5, 112.1, 111.1, 106.0, 52.5, 52.3, 44.0, 23.8.

[0123] Example 17

[0124] According to the method described in Example 1, the photocatalyst, base or solvent were changed simultaneously or individually to observe their effects on the yield.

[0125]

[0126] The comparison of the conditions and product yields is shown in Table 1.

[0127] Table 1 Effect of different conditions on yield

[0128] entry <![CDATA[Ratio b > Catalyst (equiv.) solvent Temperature (°C) Yield% 1 1:1 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 53 1:1.2 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 68 3 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 80 4 1:2 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 76 5 1.5:1 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 65 6 1:1.5 <![CDATA[Cu(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 51 7 1:1.5 <![CDATA[Al(OTf)3(0.2)]]> <![CDATA[CH3CN]]> 60 49 8 1:1.5 <![CDATA[Mg(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 60 63 9 1:1.5 <![CDATA[Sc(OTf)3(0.2)]]> <![CDATA[CH3CN]]> 60 71 10 1:1.5 <![CDATA[In(OTf)3(0.2)]]> <![CDATA[CH3CN]]> 60 64 11 1:1.5 <![CDATA[Al(OTf)3(0.2)]]> <![CDATA[CH3CN]]> 60 55 12 1:1.5 <![CDATA[FeCl3(0.2)]]> <![CDATA[CH3CN]]> 60 <![CDATA[n.d. d ]]> 13 1:1.5 <![CDATA[Zn(OTf)2(0.1)]]> <![CDATA[CH3CN]]> 60 69 14 1:1.5 <![CDATA[Zn(OTf)2(0.05)]]> <![CDATA[CH3CN]]> 60 51 15 1:1.5 <![CDATA[Zn(OTf)2(0.3)]]> <![CDATA[CH3CN]]> 60 72 <![CDATA[16 e ]]> 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> DCE 60 43 <![CDATA[17 e ]]> 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> THF 60 56 <![CDATA[18 e ]]> 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> 1,4-dioxane 60 37 <![CDATA[19 e ]]> 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> MeOH 60 45 20 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> rt <![CDATA[n.d. d ]]> 21 1:1.5 <![CDATA[Zn(OTf)2(0.2)]]> <![CDATA[CH3CN]]> 100 59 22 1:1.5 - <![CDATA[CH3CN]]> 60 23

[0129] Unless otherwise noted, the reaction steps were as follows: 2a (0.3 mmol, 59.1 mg), DDQ (0.3 mmol, 68.1 mg), and acetonitrile (2 mL) were added to a dry, sealed tube under argon and stirred at room temperature for 1 h. 1a (0.2 mmol, 50.6 mg), the catalyst, and 2 mL of solvent were then added, and the reaction was continued at 60°C for 36 h. b 1a:2a (molar ratio), d nd = Not detected. e 2a (0.3 mmol, 59.1 mg), DDQ (0.3 mmol, 68.1 mg), and acetonitrile (2 mL) were added and reacted at room temperature for 1 h. After the reaction was complete, the magnetic particle was removed and the mixture was concentrated under reduced pressure. Then, 1a (0.2 mmol, 50.6 mg), catalyst (0.2 equiv.), and 2 mL of solvent were added and the system was reacted at 60 ºC for 36 h.

[0130] As shown in Table 1, under the reaction conditions of this invention, the isolated yield reached 71%. The trifluoromethanesulfonic acid compound Zn(OTf)2 provided the highest yield compared to other Lewis acids, and the solvent acetonitrile outperformed tetrahydrofuran, methanol, and 1,4-dioxane. A variety of functional groups, such as methyl, methoxy, phenyl, and halogen, were compatible with this reaction and converted into the target product.

[0131] In summary, the present invention provides a method for preparing dihydroquinolinopyrrole derivatives by catalysis of trifluoromethanesulfonic acid compounds. The method uses a synergistic catalytic system of an oxidant and a trifluoromethanesulfonic acid compound, takes commercial raw materials 1,4-pyridylsulfonium salt and aminomalononitrile as starting materials, and achieves efficient construction of the target product through an intermolecular tandem cyclization reaction. Compared with the existing methods for synthesizing dihydroquinolinopyrrole derivatives, the method has significant advantages such as mild conditions and high selectivity. The method uses simple and readily available raw materials, avoids the use of traditional complex substrates, and exhibits excellent functional group compatibility, and can tolerate various substituents such as nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole and thiophene, providing a new strategy for the construction of the skeleton of dihydroquinolinopyrrole derivatives. Its simple operation, high yield and good chemical selectivity provide an important reference for the industrial production of such compounds. The invention embodies the practicality of sulfur atoms in the formation of auxiliary ring systems, enriches the molecular modification and diversified synthesis methods of such skeletons.

Claims

1. A method for preparing dihydroquinolinopyrrole derivatives by catalysis of trifluoromethanesulfonic acid compounds, characterized in that: The reaction formula of the method is as follows: ； Among them, R 1 is an alkyl group; R 2 is any one of nitro, halogen, alkyl, aryl, and alkoxy; The specific steps include: (1) Under argon atmosphere, dissolve the aminomalononitrile compound in a solvent, add an oxidant, and stir the reaction at room temperature; (2) adding 1,4-pyridylthioyl salt and a catalyst trifluoromethanesulfonic acid compound to the reaction described in step (1), and heating the reaction system in an oil bath; (3) After the reaction is completed, cooling, filtering, washing, concentrating under reduced pressure, and purifying and eluting to obtain the target product; The catalyst trifluoromethanesulfonic acid compound in step (2) is one or more of Zn(OTf)2, Cu(OTf)2, Al(OTf)3, Mg(OTf)2, Sc(OTf)3, and In(OTf)3.

2. The method according to claim 1, wherein The filtration in step (3) was performed using diatomaceous earth, the washing was performed using dichloromethane, and the purification and elution were performed using silica gel column chromatography. The eluents in the silica gel column chromatography were petroleum ether and ethyl acetate, and the ratio of petroleum ether to ethyl acetate was 10:1.

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