Method for preparing dihydroquinolinopyrrole derivative through catalysis of trifluoromethane sulfonic acid compound

Abstract

The invention belongs to the technical field of catalytic methods and catalysts, and particularly relates to a method for preparing dihydroquinolopyrrole derivatives by catalyzing trifluoromethanesulfonic acid compounds, which is characterized in that 1, 2-dihydroquinolopyrrole derivatives are prepared from 1, 2-dihydroquinolopyrrole through a synergistic catalytic system by taking the trifluoromethanesulfonic acid compounds as a catalyst. According to the present invention, 2, 4-pyrithione onium salt and aminomalononitrile are subjected to an intermolecular tandem cyclization reaction to achieve the efficient preparation of the dihydroquinolopyrrole derivative, the method has significant advantages of mild conditions, high selectivity and the like, the simple and easily available raw materials are adopted, the use of the traditional complex substrate is avoided, the excellent functional group compatibility is represented, and the preparation method is suitable for industrial production. The dihydroquinolinopyrrole derivative disclosed by the invention can tolerate various substituent groups such as nitryl, halogen, piperonyl, alkyl, aryl, alkoxy, indole and thiophene, provides a new strategy for construction of a dihydroquinolinopyrrole derivative skeleton, has the characteristics of simplicity and convenience in operation, high yield and good chemical selectivity, and provides important reference for industrial production of the compound.

Description

Technical Field

[0001] The present invention belongs to the technical field of catalytic methods and catalysts, and particularly relates to a method for catalytically preparing dihydroquinolinopyrrolidine derivatives by using a trifluoromethanesulfonic acid compound. Background Art

[0002] Dihydroquinolinopyrrolidine derivatives are formed by the annulation of dihydroquinoline (1,2- or 1,4-dihydroquinoline) with a pyrrole ring and may contain different substituents; they usually exhibit diverse biological activities and pharmaceutical potentials. For example, PARP inhibitors containing a dihydroquinolinopyrrolidine structure can inhibit topoisomerase or kinase and have antitumor activity; they also have inhibitory effects on Staphylococcus aureus (MRSA), HIV protease, etc.; as 5-HT receptor regulators or MAO inhibitors, they have neuroprotective effects and may be used in the treatment of depression or Parkinson's disease; some derivatives can inhibit the COX-2 or NF-κB pathways and have anti-inflammatory potential. Therefore, dihydroquinolinopyrrolidine derivatives have attracted much attention in medicinal chemistry and organic synthesis, especially as alkaloid analogs or pharmaceutical skeletons.

[0003] Currently, the synthetic methods of dihydroquinolinopyrrolidine derivatives include: (1) Multicomponent reactions (MCRs): Ugi reaction, Pictet-Spengler reaction, etc. can be used to construct the quinolinopyrrolidine skeleton. (2) Cycloaddition reactions: 1,3-dipolar cycloaddition can be used to construct the pyrrole ring. (3) Transition metal catalysis: Palladium-catalyzed C-H activation or copper-catalyzed click chemistry can be used to construct complex structures; (4) Reductive amination / cyclization: Condensation of quinolinone with pyrrolamine under the action of a reducing agent. However, the existing methods still have significant limitations: (1) Dependence on noble metal catalytic systems leads to increased costs; (2) Specific substrates need to be pre-activated through multiple steps; (3) Reactions often require harsh conditions such as high temperature; (4) The control of regioselectivity and the product yield need to be improved. Therefore, developing a new synthetic method for constructing dihydroquinolinopyrrolidine derivatives in one step based on readily available raw materials under mild conditions has important scientific significance for promoting the research and development of related drug molecules.

[0004] Aiming at the above technical problems, the present invention breaks through the traditional synthesis paradigm and develops a synergistic catalytic system of an oxidant and a trifluoromethanesulfonic acid compound. Starting from the commercial raw materials 1,4-pyridinium thioinner salt and aminomalononitrile, the efficient construction of the target product is realized through an intermolecular tandem cyclization reaction. This invention demonstrates the practicality of sulfur atoms in assisting the formation of the ring system and enriches the synthetic methods for molecular modification and diverse construction of the dihydroquinolinopyrrolidine derivative skeleton. Summary of the Invention

[0005] The primary objective of the present invention is to provide a method for catalytically preparing dihydroquinolinopyrrole derivatives using a trifluoromethanesulfonic acid compound. The reaction formula of the method is as follows: ;

[0006] Wherein, R 1 is an alkyl group; R 2 is any one of nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole, and thiophene; Specifically, it includes the following steps: (1) Under an argon atmosphere, dissolve the aminomalononitrile compound in a solvent, and then add an oxidant, and stir the reaction at room temperature; (2) Add 1,4-pyridinium thiolate and a catalyst trifluoromethanesulfonic acid compound to the reaction in step (1), and heat the reaction system in an oil bath; (3) After the reaction is completed, cool, filter, wash, concentrate under reduced pressure, and purify and elute to obtain the target product.

[0007] Preferably, the solvent in step (1) is one or more of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, and methanol.

[0008] Preferably, the solvent in step (1) is acetonitrile or tetrahydrofuran.

[0009] Preferably, the oxidant in step (1) is 2,3-dichloro-5,6-dicyanobenzoquinone.

[0010] Preferably, 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.

[0011] Preferably, the oil bath temperature in step (2) is 60 - 100 °C.

[0012] Preferably, the reaction time in step (2) is 24 - 36 h.

[0013] Preferably, for the filtration in step (3), diatomaceous earth is used, for the washing, dichloromethane is used, and for the purification and elution, silica gel column chromatography is used. The eluent in the silica gel column chromatography is petroleum ether and ethyl acetate, and petroleum ether:ethyl acetate = 10:1.

[0014] The beneficial effects of the present invention are as follows: The present invention provides a method for catalytically preparing dihydroquinolinopyrrole derivatives with a trifluoromethanesulfonic acid compound. The method uses a synergistic catalytic system, that is, a synergistic catalytic system of an oxidant and a trifluoromethanesulfonic acid compound. Starting from commercially available raw materials 1,4-pyridinium sulfide inner salt and aminomalononitrile, the efficient construction of the target product is achieved through an intermolecular tandem cyclization reaction. Compared with the existing methods for synthesizing dihydroquinolinopyrrole derivatives, it has significant advantages such as mild reaction conditions and high selectivity. The method uses simple and easily available raw materials, avoids the use of traditional complex substrates, and exhibits excellent functional group compatibility, tolerating various substituents such as nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole, and thiophene. It provides a new strategy for the construction of the dihydroquinolinopyrrole derivative skeleton. Its characteristics of simple operation, high yield, and good chemoselectivity provide an important reference for the industrial production of such compounds. The present invention demonstrates the practicality of sulfur atoms in assisting the formation of the ring system and enriches the molecular modification and diverse synthesis methods of such skeletons. Detailed implementation manners

[0015] The protection scope of the present invention will be further described below through specific examples. However, it should not be understood that the scope of the above-mentioned 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.

[0016] It should be noted that in the following examples, unless otherwise specified, the methods are all conventional methods, and the reagents can all be obtained through commercial channels.

[0017] In the following examples, Zn(OTf)2 is a trifluoromethanesulfonic acid compound, which is widely used in catalytic reactions.

[0018] In the following examples, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is a commonly used organic oxidant.

[0019] In the following examples, the Schlenk reaction tube is a laboratory glass instrument designed specifically for anhydrous and anaerobic operations and is widely used in chemical reactions sensitive to air / moisture (such as organometallic synthesis, transition metal catalysis, free radical reactions, etc.).

[0020] Example 1

[0021] Under an argon atmosphere, the substrate 2a (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, 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) elution to obtain the target product 3a.

[0022]

[0023] The product detection data are as follows: White solid, yield 80%.

[0024] 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).

[0025] 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. Example 2 Under an argon atmosphere, the substrate 2b (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, 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) elution to obtain the target product 3b.

[0026]

[0027] Pale yellow solid, yield 71%.

[0028] 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).

[0029] 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. Example 3

[0030] Under an argon atmosphere, substrate 2c (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thioinner salt 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, 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) elution to obtain the target product 3c.

[0031]

[0032] Pale yellow solid, yield 69%.

[0033] 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J J = 6.0 Hz, 1H), 7.30 – 7.22 (m, 2H), 4.25 (t, J J = 6.8 Hz, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.12 (t, J J = 6.8 Hz, 2H).

[0034] 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. Example 4

[0035] Under an argon atmosphere, substrate 2d (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. It was purified and eluted by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3d.

[0036]

[0037] Pale yellow solid, yield 68%.

[0038] 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).

[0039] 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. Example 5

[0040] Under an argon atmosphere, substrate 2e (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. It was purified by elution through silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3e.

[0041]

[0042] White solid, yield 76%.

[0043] 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).

[0044] 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. Example 6

[0045] Under an argon atmosphere, substrate 2f (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thioinner salt 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. It was purified and eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product 3f.

[0046]

[0047] White solid, yield 65%.

[0048] 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).

[0049] 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. Example VII

[0050] Under an argon atmosphere, 2 g (0.3 mmol) of the substrate was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 3 g of the target product.

[0051]

[0052] White solid, yield 63%.

[0053] 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.17 (s, J J = 8.4 Hz, 1H), 6.87 –6.85 (m, 1H), 4.22 (t, J J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.80 (s,3H), 3.06 (t, J J = 6.8 Hz, 2H).

[0054] 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. Example VIII

[0055] Under an argon atmosphere, the substrate 2h (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, 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 target product 3h.

[0056]

[0057] Pale yellow solid, yield 70%.

[0058] 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).

[0059] 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. Example IX

[0060] Under an argon atmosphere, substrate 2i (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, 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) elution to obtain the target product 3i.

[0061]

[0062] Pale yellow solid, yield 65%.

[0063] 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).

[0064] 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. Example X

[0065] Under an argon atmosphere, substrate 2j (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. It was purified by elution through silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3j.

[0066]

[0067] White solid, yield 76%.

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J J = 8.8 Hz, 1H), 6.84 – 6.78 (m, 2H), 4.20 (t, J J = 6.8 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.10 (t, J J = 6.8 Hz, 2H).

[0069] 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. Example XI

[0070] Under an argon atmosphere, substrate 2k (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3k.

[0071]

[0072] Brown solid, yield 60%.

[0073] 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.38 (s, 1H), 4.25 (t, J J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.11 (t, J J = 6.8 Hz, 2H).

[0074] 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. Example XII

[0075] Under an argon atmosphere, dissolve substrate 2l (0.3 mmol) in dry acetonitrile (2 mL). Subsequently, add 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol). After reacting the mixture at room temperature for 1 h, directly add 1,4-pyridinium thioinner salt 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) to the system. Place the reaction system in an oil bath at 60 ºC and react for 36 h. After the reaction is completed, cool the system to room temperature, filter using diatomaceous earth, wash with dichloromethane (5 mL), concentrate the filtrate under reduced pressure, and purify and elute by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3l.

[0076]

[0077] Brown solid, yield 56%.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 6.73 (s, 1H), 4.29 (t, J = 6.8 Hz, 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).

[0079] 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. Example Thirteen

[0080] Under an argon atmosphere, substrate 2m (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, 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) elution to obtain the target product 3m.

[0081]

[0082] White solid, yield 56%.

[0083] 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).

[0084] 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. Example XIV

[0085] Under an argon atmosphere, the substrate 2n (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3n.

[0086]

[0087] White solid, yield 72%.

[0088] 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J J = 5.2 Hz, 1H), 7.20 (d, J J = 5.6 Hz,1H), 4.30 (t, J J = 6.8 Hz, 2H), 3.90 (s, 6H), 3.26 (t, J J = 6.8 Hz, 2H).

[0089] 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. Example XV

[0090] Under an argon atmosphere, substrate 2o (0.3 mmol) was dissolved in dry acetonitrile (2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1a (50.6 mg, 0.2 mmol) and zinc trifluoromethanesulfonate (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. It was purified and eluted by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3o.

[0091]

[0092] The yield was 23%.

[0093] 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).

[0094] 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. Example XVI

[0095] Under an argon atmosphere, the substrate 2a (0.3 mmol) was dissolved in dry acetonitrile (2 mL). Subsequently, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 68.1 mg, 0.36 mmol) was added. After the mixture was reacted at room temperature for 1 h, 1,4-pyridinium thiolate 1b (50.6 mg, 0.2 mmol) and zinc bis(trifluoromethanesulfonate) (14.5 mg, 0.2 equiv.) were directly added to the system. The reaction system was placed in an oil bath at 60 ºC and reacted for 36 h. After the reaction was completed, the system was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane (5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target product 3ba.

[0096]

[0097] White solid, yield 78%.

[0098] 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), 4.17 (t, J J = 6.8 Hz, 2H), 3.07(t, J J = 6.8 Hz, 2H), 1.34 – 1.29 (m, 6H).

[0099] 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. Example XVII

[0100] According to the method described in Example 1, the photocatalyst, base or solvent was changed simultaneously or individually, and the effect on the yield was observed.

[0101]

[0102] The comparison of the condition changes and product yields is shown in Table 1.

[0103] Table 1 Effects of different conditions on the yield Entry <![CDATA[Ratio b > Catalyst (equiv.) Solvent Temperature (ºC) 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 Unless otherwise specified, the specific reaction steps are as follows: Under argon atmosphere, 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, and the mixture was stirred at room temperature for 1 h. Then 1a (0.2 mmol, 50.6 mg), the catalyst and 2 mL of the solvent were added, and the reaction system was reacted at 60 ºC for 36 h. b 1a:2a (molar ratio), d n.d. = not detected. e 2a (0.3 mmol, 59.1 mg), DDQ (0.3 mmol, 68.1 mg) and acetonitrile (2 mL) were added, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the magnetic stir bar was taken out, and the mixture was concentrated under reduced pressure. Then 1a (0.2 mmol, 50.6 mg), the catalyst (0.2 equiv.) and 2 mL of the solvent were added, and the reaction system was reacted at 60 ºC for 36 h.

[0104] As can be seen from the data results in Table 1, under the reaction conditions of the present invention, the isolated yield is as high as 71%. The trifluoromethanesulfonic acid compound Zn(OTf)2 gives the optimal yield compared with other Lewis acids. The solvent acetonitrile is superior to tetrahydrofuran, methanol and 1,4-dioxane. Multiple functional groups such as methyl, methoxy, phenyl and halogen can be compatible with this reaction to be converted into the target product.

[0105] In summary, the present invention provides a method for catalytic preparation of dihydroquinolinopyrrole derivatives with trifluoromethanesulfonic acid compounds. The method uses a synergistic catalytic system, that is, a synergistic catalytic system of an oxidant and a trifluoromethanesulfonic acid compound. Starting from commercially available raw materials 1,4-pyridinium sulfide inner salt and aminomalononitrile, the efficient construction of the target product is realized through an intermolecular tandem cyclization reaction. Compared with the existing methods for synthesizing dihydroquinolinopyrrole derivatives, it has significant advantages such as mild conditions and high selectivity. The method uses simple and easily 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 dihydroquinolinopyrrole derivative skeleton. Its characteristics of simple operation, high yield and good chemoselectivity provide an important reference for the industrial production of such compounds. The invention reflects the practicality of sulfur atoms in assisting the formation of the ring system, and enriches the molecular modification and diverse synthesis methods of such skeletons.

Claims

1. A method for catalytically preparing dihydroquinolinopyrrole derivatives with a trifluoromethanesulfonic acid-based compound, characterized in that, The reaction formula of the said method is as follows: ； Among them, R 1 is an alkyl group; R 2 is any one of nitro, halogen, piperonyl, alkyl, aryl, alkoxy, indole and thiophene; Specifically, it includes the following steps: (1) Under an argon atmosphere, dissolve the aminomalononitrile compound in a solvent, and then add an oxidant, and stir the reaction at room temperature; (2) Add 1,4-pyridinium thiolate and a catalyst trifluoromethanesulfonic acid compound to the reaction in step (1), and heat the reaction system in an oil bath; (3) After the reaction is completed, cool, filter, wash, concentrate under reduced pressure, and purify and elute to obtain the target product.

2. The method according to claim 1, characterized in that, The solvent described in step (1) is one or more of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, and methanol.

3. The method according to claim 2, characterized in that, The solvent described in step (1) is acetonitrile or tetrahydrofuran.

4. The method according to claim 1, characterized in that, The oxidant described in step (1) is 2,3-dichloro-5,6-dicyanobenzoquinone.

5. The method according to claim 1, characterized in that, The catalyst trifluoromethanesulfonic acid compound described in step (2) is one or more of Zn(OTf)2, Cu(OTf)2, Al(OTf)3, Mg(OTf)2, Sc(OTf)3, In(OTf)3.

6. The method according to claim 1, characterized in that, The oil bath temperature described in step (2) is 60 - 100 °C.

7. The method according to claim 1, characterized in that, The reaction time described in step (2) is 24 - 36 h.

8. The method according to claim 1, characterized in that, For the filtration in step (3), diatomaceous earth is used, for the washing, dichloromethane is used, and for the purification and elution, silica gel column chromatography is used. The eluent in the silica gel column chromatography is petroleum ether and ethyl acetate, and petroleum ether:ethyl acetate = 10:1.

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