Preparation method of spiroquinolinone containing ester group and perfluoroalkyl unit

Abstract

The invention provides a preparation method of spiroquinolinone containing ester groups and perfluoroalkyl units, and belongs to the technical field of heterocyclic compounds. The preparation method comprises the following steps: adding a palladium catalyst, a ligand, alkali, bicyclo [1.1. 0] butyramide, perfluoroiodobutane, formic acid and phenol into an organic solvent, reacting at 90-110 DEG C for 18-22 hours, and performing post-treatment to obtain the spiroquinolinone containing ester groups and perfluoroalkyl units. The preparation method is simple and convenient to operate, the initial raw materials are cheap and easy to obtain, the reaction efficiency is high, the substrate compatibility is good, and spiroquinolinone containing ester groups and perfluoroalkyl units can be efficiently and rapidly synthesized in one step.

Description

Technical Field

[0001] This application relates to a method for preparing spirocyclic quinolinones containing ester groups and perfluoroalkyl units, belonging to the field of heterocyclic compound technology. Background Technology

[0002] Polycyclic quinolinones are an important class of structural units, widely found in natural products and drug molecules, and possess a variety of biological activities. J. Med. Chem. 2014, 57 , 1252-1275; Eur. J. Med. Chem. 2015, 97 , 97-08; Org. Lett. 2005, 7 (5701-5704). Among the following three structures: 1. Acetylcholinesterase inhibitor; 2. Yaequinolone J1 (insecticide); 3. Euodenine A (TLR4 antagonist).

[0003] .

[0004] Tandem cyclization reactions provide an important method for the direct and efficient synthesis of complex polycyclic systems. Chem. Soc. Rev. 2009, 38 (2993-3009). However, there are few reports on the synthesis of functionalized polycyclic quinolinones based on tandem cyclization reactions, and their application is not widespread at present, but they have great application potential and need to be studied in depth. Summary of the Invention

[0005] In view of this, this application provides a method for preparing spirocyclic quinolinones containing ester groups and perfluoroalkyl units. The preparation steps are simple, and the obtained spirocyclic quinolinones containing ester groups and perfluoroalkyl units can simultaneously accommodate multiple functional groups, have good substrate compatibility, and have excellent applicability.

[0006] Specifically, this application is implemented through the following scheme: A method for preparing a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit, comprising a palladium catalyst, a ligand, a base, a bicyclic [1.1.0]butyramide, and a perfluoroiodobutane ( n C4H9I), formic acid ([CO]), and phenol are added to an organic solvent and reacted at 90-110°C for 18-22 hours. The product is then post-treated to obtain a spirocyclic quinolinone containing ester groups and perfluoroalkyl units.

[0007] .

[0008] In the structures of the above compounds, R 1 R 4Selected from hydrogen, C1-C6 alkyl groups, and halogens; R 2 The phenyl group is either substituted or unsubstituted, wherein the substituent on the substituted phenyl group is selected from any one of C1-C6 alkyl, C1-C6 alkoxy, or halogen; R 3 It is selected from any one of C1 to C6 alkyl or benzyl groups.

[0009] The reaction equation for the above process is expressed as follows: .

[0010] The above scheme uses bicyclic [1.1.0]butyramide as the starting material. Palladium (II) is reduced by a phosphine ligand to generate active palladium (0). Palladium (0) reacts with perfluoroiodobutane via single-electron transfer (SET) to generate a perfluoroalkyl radical and palladium (I). Subsequently, the perfluoroalkyl radical undergoes a cycloaddition reaction with bicyclic [1.1.0]butyramide to generate a tertiary radical, which undergoes intramolecular cyclization to generate an alkenyl radical. Next, palladium (I) combines with the alkenyl radical to generate an alkenyl palladium (II) intermediate. Then, CO released from formic acid inserts into the alkenyl palladium (II) intermediate to obtain an acyl palladium (II) complex. Finally, phenol nucleophilically attacks the acyl palladium (II) complex, and reductive elimination yields a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit.

[0011] Furthermore, as a preferred option: The molar ratio of bicyclic [1.1.0]butyramide, perfluoroiodobutane, formic acid, phenol, palladium catalyst, ligand, and base is 1.0:2.0:5.0:2.0:0.1:0.2:3.0.

[0012] During the preparation of materials, the amount of organic solvent used should be sufficient to dissolve the raw materials well. Therefore, it is best to control the amount of organic solvent used for each 0.2 mmol of bicyclo[1.1.0]butyramide to around 2.0 mL.

[0013] The organic solvent is trifluorotoluene (PhCF3), at which point all raw materials can be converted into products with a high conversion rate.

[0014] The palladium catalyst is palladium acetate (Pd(OAc)2), which has a relatively high reaction efficiency among many palladium catalysts in the preparation system of this application.

[0015] The ligand is bis(2-diphenylphosphine)phenyl ether (DPEphos).

[0016] When palladium acetate is chosen as the palladium catalyst and bis(2-diphenylphosphine)phenyl ether is chosen as the ligand, the molar ratio of palladium acetate to bis(2-diphenylphosphine)phenyl ether is 0.1:0.2.

[0017] The alkali is cesium carbonate (Cs2CO3).

[0018] The post-processing procedure is as follows: the reaction product is filtered, mixed with silica gel, and finally purified by column chromatography to obtain the corresponding spirocyclic quinolinone containing ester group and perfluoroalkyl unit. The column chromatography purification parameters can be set using conventional methods.

[0019] The spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit is any one of the following structural formulas: .

[0020] In the above preparation methods, perfluoroiodobutane, phenol, palladium acetate, bis(2-diphenylphosphine)phenyl ether, and cesium carbonate are generally commercially available products, all of which are readily available from the market. Bicyclo[1.1.0]butyramide can be synthesized from the corresponding o-iodoaniline.

[0021] Compared with the prior art, the beneficial effects of the present invention are reflected in: No synthetic methods have been reported for polycyclic quinolinones, especially spirocyclic quinolinones containing ester groups and perfluoroalkyl units as provided in this application. The preparation method provided in this application is easy to operate, with simple post-processing; the starting materials are inexpensive and readily available, the substrate functional group tolerance is wide, and the reaction efficiency is high. It is a one-step, efficient, and rapid synthesis of spirocyclic quinolinones containing ester groups and perfluoroalkyl units, and has strong practicality.

[0022] The spirocyclic quinolinones containing ester groups and perfluoroalkyl units provided in this case belong to the category of polycyclic quinolinones and possess a variety of biological activities, such as insecticidal antibiotics and inhibitors, as described in the background art. Detailed Implementation

[0023] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below with reference to specific examples in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0024] In a 10 mL Schlenk tube, add 0.2 mmol of bicyclo[1.1.0]butyramide (II), 0.4 mmol of perfluoroiodobutane, 1.0 mmol of formic acid, 0.4 mmol of phenol (III), 0.02 mmol of palladium acetate, 0.04 mmol of bis(2-diphenylphosphine)phenyl ether, 0.6 mmol of cesium carbonate, and 2.0 mL of trifluorotoluene (organic solvent). Mix well and react at 100 °C for 20 hours. The substituents R at each position are then analyzed. 1 R 2R 3 R 4 The results are shown in Table 1. After the reaction was complete, the sample was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding spirocyclic quinolinone (I) containing ester and perfluoroalkyl units.

[0025] The reaction equation for the above process is expressed as follows: .

[0026] Table 1: Substituents of bicyclic [1.1.0]butyramide and phenol and corresponding product yields .

[0027] The above synthesis results show that this method is applicable to the reaction of bicyclic [1.1.0]butyramide and phenol under various substituent conditions, and thus prepares spirocyclic quinolinones with different substituents containing ester groups and perfluoroalkyl units. The yields of each spirocyclic quinolinone containing ester groups and perfluoroalkyl units are maintained above 60%, which confirms that the preparation method of this application has good substrate applicability.

[0028] Meanwhile, the applicant also confirmed the structure of the products obtained from the above reactions, using Examples 1 to 5 as examples, and the detection results are as follows: The spirocyclic quinolinone structure containing ester and perfluoroalkyl units prepared in Example 1 is shown in formula (I-1), and its nuclear magnetic resonance (NMR) 1 H NMR, 13 C NMR, 19 The F NMR and high-resolution (HRMS) detection data are as follows: .

[0029] 1 H NMR (400 MHz, CDCl3) δ 7.63 – 7.53 (m, 1H), 7.38 – 7.31 (m, 5H), 7.26 – 7.13 (m, 3H), 7.12 – 7.06 (m, 2H), 7.04 – 7.00 (m, 1H), 6.70 – 6.61 (m, 2H), 3.41 (s, 1.78H), 3.38 (s, 1.16H), 2.91 – 2.60 (m, 1H), 2.37 – 2.09 (m,2H), 1.97 – 1.58 (m, 2H); 13 C{ 1 H NMR (100 MHz, CDCl3) δ171.1, 170.5, 166.9, 166.7, 150.1, 138.3, 138.2, 136.5, 135.6, 133.7, 133.6, 133.3, 132.2, 129.69, 129.66, 129.4, 129.1, 129.0, 128.9, 128.6, 128.4, 127.0, 126.9, 126.0, 125.9, 124.7, 123.3, 123.1, 121.01, 120.97, 115.1, 114.8, 46.5, 46.3, 30.53, 30.47, 29.5, 29.4, 29.2, 28.9, 28.6, 28.4; 19 F NMR (377 MHz, CDCl3) δ -81.13 (s, 3F), -119.95 – -122.60 (m, 2F), -124.09 (d, J = 68.7 Hz, 2F), -126.22 – -126.65 (m, 2F); HRMS (ESI-TOF) m / z: [M+Na] + Calculated for C 31 H 22 F9NNaO3 + : 650.1348; found: 650.1344.

[0030] The spirocyclic quinolinone structure containing ester and perfluoroalkyl units prepared in Example 2 is shown in formula (I-2), and its nuclear magnetic resonance (NMR) is... 1 H NMR, 13 C NMR, 19 The F NMR and high-resolution (HRMS) detection data are as follows: .

[0031] 1 H NMR (400 MHz, CDCl3) δ7.62 – 7.58 (m, 1H), 7.54 – 7.27 (m, 6H), 7.23 – 7.09 (m, 4H), 6.75 – 6.69 (m, 1H), 6.67 – 6.59 (m, 1H), 3.50 (s, 1.67H), 3.46 (s, 1.32H), 2.92 – 2.71 (m, 1H), 2.47 – 2.18 (m, 2H), 2.09 – 1.63 (m,2H); 13 C{ 1 H NMR (100 MHz, CDCl3) δ 171.3, 170.7, 166.8, 166.6, 150.79, 150.77, 138.61, 138.56, 137.5, 136.6, 134.7, 133.7, 133.4, 133.3, 132.0, 130.19, 130.17, 130.15, 129.6, 129.5, 129.4, 129.0, 128.8, 127.3, 127.1, 126.56, 126.53, 126.2, 124.9, 123.6, 123.4, 122.1, 122.0, 119.81, 119.77, 115.5, 115.2, 46.8, 46.6, 30.9, 30.8, 29.8, 29.7, 29.5, 29.2, 29.0, 28.7; 19 F NMR (377 MHz, CDCl3) δ -79.10 – -84.92 (m, 3F), -120.62 – -121.80(m, 2F), -123.82 – -124.22 (m, 2F), -126.29 – -126.52 (m, 2F); HRMS (ESI-TOF)m / z: [M+Na] + Calculated for C 31 H 21 ClF9NNaO3 + : 684.0958; found: 684.0954.

[0032] Example 3 prepared a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit, as shown in formula (I-3), whose nuclear magnetic resonance (NMR) was... 1 H NMR, 13 C NMR,19 The F NMR and high-resolution (HRMS) detection data are as follows: .

[0033] 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.37 – 7.25 (m, 3H), 7.25 – 7.01 (m, 4H), 7.00 – 6.81 (m, 2H), 6.81 – 6.71(m, 2H), 3.89 – 3.83 (m, 3H), 3.49 (s, 1.80H), 3.46 (s, 1.20H), 3.01 – 2.67(m, 1H), 2.59 – 1.73 (m, 3H), 1.71 – 1.29 (m, 1H); 13 C{ 1 H NMR (100 MHz, CDCl3) δ 171.2, 170.6, 166.9, 166.8, 159.7, 159.5, 150.2, 138.5, 138.4, 136.7, 135.8, 135.0, 134.6, 133.5, 132.2, 129.84, 129.79, 129.5, 129.3, 127.1, 127.0, 126.11, 126.07, 124.8, 123.4, 123.2, 121.16, 121.13, 121.06, 115.31, 115.29, 115.0, 55.3, 46.6, 46.4, 30.7, 30.6, 29.7, 29.6, 29.3, 29.1, 28.8, 28.6; 19 F NMR (377 MHz, CDCl3) δ -81.76 (s, 3F), -120.42 – -123.36 (m, 2F), -124.40 – -124.90 (m, 2F), -127.10 (d, J = 10.7 Hz, 2F); HRMS (ESI-TOF) m / z: [M+Na] + Calculated for C 32 H24 F9NNaO4 + : 680.1454; found: 680.1447.

[0034] The spirocyclic quinolinone structure containing ester and perfluoroalkyl units prepared in Example 4 is shown in formula (I-4), and its nuclear magnetic resonance (NMR) 1 H NMR, 13 C NMR, 19 The F NMR and high-resolution (HRMS) detection data are as follows: .

[0035] 1 H NMR (400 MHz, CDCl3) δ 7.56 – 7.52 (m, 1H), 7.51 – 7.31 (m, 5H), 7.30 – 7.25 (m, 2H), 7.22 – 7.12 (m, 1H), 7.01 – 6.94 (m, 1H), 6.90 (s, 1H), 6.81 – 6.72 (m, 2H), 3.48 (s, 1.94H), 3.44 (s, 1.03H), 2.96 – 2.70 (m, 1H), 2.42 (s, 3H), 2.29 – 1.95 (m, 2H), 1.89 – 1.53 (m, 2H); 13 C{ 1 H NMR (100 MHz, CDCl3) δ 171.5, 170.9, 167.3, 167.2, 150.4, 140.3, 138.54, 138.47, 137.0, 136.1, 134.2, 133.8, 133.3, 131.9, 129.67, 129.66, 129.5, 129.2, 129.1, 128.9, 128.6, 127.3, 127.1, 126.2, 124.2, 124.0, 123.5, 122.2, 121.4, 121.3, 116.3, 116.0, 47.0, 46.8, 29.9, 29.84, 29.76, 29.5, 29.3, 29.0, 21.9; 19 F NMR (377 MHz, CDCl3) δ-81.72 (s, 3F), -120.23 – -123.14 (m, 2F), -124.70 (d, J = 64.1 Hz, 2F), -127.07 (d, J = 13.0 Hz, 2F); HRMS (ESI-TOF) m / z:[M+Na] + Calculated for C 32 H 24 F9NNaO3 + : 664.1505; found: 664.1499.

[0036] The spirocyclic quinolinone structure containing ester and perfluoroalkyl units prepared in Example 5 is shown in formula (I-5), and its nuclear magnetic resonance (NMR) 1 H NMR, 13 C NMR, 19 The F NMR and high-resolution (HRMS) detection data are as follows: .

[0037] 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 1H), 7.56 – 7.46 (m, 4H), 7.42 – 7.28 (m, 7H), 7.26 – 7.12 (m, 4H), 7.11 – 7.02 (m, 1H), 6.77 – 6.66(m, 2H), 5.46 – 5.35 (m, 0.75H), 5.36 – 5.20 (m, 1.33H), 3.13 – 2.75 (m, 1H), 2.67 – 2.22 (m, 2H), 2.19 – 1.61 (m, 2H); 13 C{ 1 H NMR (100 MHz, CDCl3) δ171.7, 171.1, 167.1, 167.0, 150.4, 137.8, 136.9, 136.8, 136.0, 134.1, 133.8, 133.5, 132.9, 129.93, 129.87, 129.5, 129.42, 129.38, 129.3, 129.03, 128.96, 128.7, 127.4, 127.3, 127.19, 127.15, 126.4, 126.3, 126.22, 126.19, 125.9, 123.9, 123.7, 121.3, 116.6, 116.3, 47.0, 46.9, 46.8, 33.4, 29.8, 29.6, 29.5, 29.3, 29.2, 29.0, 27.4; 19 F NMR (377 MHz, CDCl3) δ -81.08 (s, 3F), -119.91 – -122.48 (m, 2F), -123.82 – -124.22 (m, 2F), -126.42 (d, J = 13.1 Hz, 2F); HRMS (ESI-TOF) m / z: [M+Na] + Calculated for C 37 H 26 F9NNaO3 + : 726.1661; found: 726.1661.

[0038] The above test results confirm that the method in this case can indeed synthesize a variety of polycyclic quinolinones with the activities described in the background art, filling the gap that such quinolinones exist only in natural products and drug molecules but lack industrial synthesis methods.

[0039] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit, characterized in that: Palladium catalyst, ligand, base, bicyclic [1.1.0]butyramide, perfluorobutane, formic acid, and phenol were added to an organic solvent and reacted at 90-110°C for 18-22 hours to obtain a spirocyclic quinolinone containing ester and perfluoroalkyl units. ， R 1 R 4 Selected from hydrogen, C1-C6 alkyl groups, and halogens; R 2 The phenyl group is either substituted or unsubstituted, wherein the substituent on the substituted phenyl group is selected from any one of C1-C6 alkyl, C1-C6 alkoxy, or halogen; R 3 It is selected from any one of C1 to C6 alkyl or benzyl groups.

2. The method for preparing a spirocyclic quinoline ketone containing an ester group and a perfluoroalkyl unit according to claim 1, characterized in that: The molar ratio of bicyclic [1.1.0]butyramide, perfluoroiodobutane, formic acid, phenol, palladium catalyst, ligand, and base is 1.0:2.0:5.0:2.0:0.1:0.2:3.

0.

3. The method for preparing a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit according to claim 1, characterized in that: The organic solvent is trifluorotoluene.

4. The method for preparing a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

5. The method for preparing a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit according to claim 1, characterized in that: The ligand is bis(2-diphenylphosphine)phenyl ether.

6. The method for preparing a spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit according to claim 1, characterized in that: The alkali is cesium carbonate.

7. The method for preparing a spirocyclic quinoline ketone containing an ester group and a perfluoroalkyl unit according to claim 1, characterized in that, The reaction product was post-processed to obtain spirocyclic quinolinone. The post-processing process was as follows: the reaction product was filtered, mixed with silica gel, and finally purified by column chromatography to obtain the corresponding spirocyclic quinolinone containing ester group and perfluoroalkyl unit.

8. A method for preparing a spirocyclic quinoline ketone containing an ester group and a perfluoroalkyl unit according to any one of claims 1 to 7, characterized in that, The spirocyclic quinolinone containing an ester group and a perfluoroalkyl unit is any one of the following structural formulas: 。

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