A method for selectively synthesizing 2-amidoquinoline-n-oxide compounds from quinoline-n-oxide compounds

Abstract

The application discloses a method for selectively synthesizing 2-amido quinoline-N-oxide compounds from quinoline-N-oxide compounds, which uses copper hexafluorophosphate tetraacetonitrile and silver acetate as catalysts and isoxazolidinone as nitrogen source, does not need to add expensive ligands, and can obtain the product under mild conditions. The application has the advantages of low cost, mild reaction condition, high selectivity and the like, and avoids the use of noble metals such as rhodium, iridium and palladium. The method is suitable for different substituted quinoline-N-oxide compounds and other polysubstituted isoxazolidinone substrates.

Description

Technical Field

[0001] This invention belongs to the field of CH bond activation technology, specifically relating to a method for the selective synthesis of 2-acylaminoquinoline-N-oxide compounds based on tetraacetonitrile copper hexafluorophosphate and silver acetate catalysis of quinoline-N-oxide compounds. Background Technology

[0002] Quinoline derivatives are important starting materials and intermediates in the chemical industry, widely used to synthesize a variety of chemical products, including dyes, pharmaceuticals, and agrochemicals. The synthesis of quinolines, in particular, plays a crucial role in medicinal chemistry and organic synthetic chemistry, as seen in the production of cinchonidine and cinchona alkaloids. Furthermore, the microbial and anticancer activities of 2-acylquinoline-N-oxides have been reported (Antibiotics & Chemotherapy (Northfield, Ill.), 1956, 6, 261-267; J. Org. Chem., 1961, 26, 2831-2833). Therefore, it is essential to develop efficient methods for the synthesis of 2-acylquinolines and their derivatives through simple and direct CH bond activation.

[0003] In 2013, Li Gang's research group reported a system using copper acetate as a catalyst, silver carbonate as an oxidant, and lactam as a nitrogen source to activate the CH bond of quinoline-N-oxides, thereby synthesizing various derivatives of 2-aminoquinoline-N-oxides. This method has a low catalyst loading and good functional group compatibility. Furthermore, this catalytic system can also achieve the reaction of cyclohexylamine and cyclopentylamine (Org. Lett., 2013, 15, 5198-5201).

[0004] In 2014, Cui Xiuling's research group reported the synthesis of 2-aminoquinoline-N-oxide and its derivatives by activating the CH bond of quinoline-N-oxide under mild conditions using 10 mol% CuI as a catalyst, air as an oxidant, and cyclic amines and common secondary amines as nitrogen sources (Org. Lett., 2014, 16, 1840-1843).

[0005] In 2017, Samanta's research group used CuI as a catalyst to achieve the desired effect. 2 Using nitrogen as a nitrogen source, the CH bond of quinoline-N-oxide was activated, marking the first successful synthesis of 2-arylaminoquinoline-N-oxide. This reaction exhibits excellent versatility and atom economy. Furthermore, this project has led to the synthesis of a series of compounds with highly conjugated systems using this method (J. Org. Chem., 2017, 82, 8933-8942).

[0006] The above methods are subject to substrate limitations, only allowing the synthesis of tertiary and aromatic amines, and not secondary or primary amines. Furthermore, they suffer from drawbacks such as long reaction times, high reaction temperatures, stringent conditions, and complex operations, leading to environmental pollution and economic costs, particularly severe in large-scale industrial production. Therefore, developing a mild and efficient strategy for the preparation of 2-acylaminoquinoline-N-oxides is of significant scientific research importance. Summary of the Invention

[0007] The purpose of this invention is to provide a method for the selective synthesis of 2-amide-quinoline-N-oxide compounds using tetraacetonitrile copper hexafluorophosphate and silver acetate as catalysts.

[0008] To achieve the above objectives, the technical solution adopted in this invention is as follows: using copper hexafluorophosphate and silver acetate as catalysts, the quinoline-N-oxide compound shown in Formula I and the isoxazolidinone shown in Formula II are reacted in dichloroethane at 75-85°C for 12-24 hours. After the reaction is complete, the mixture is separated and purified to obtain the 2-acylaminoquinoline-N-oxide compound shown in Formula I′.

[0009]

[0010] In the formula, R1 represents any one of H, C1-C6 alkyl, C1-C4 alkoxy, and halogen; R2 represents any one of H, C1-C6 alkyl, phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halophenyl, C1-C6 alkyl, and C3-C6 cycloalkyl. Preferably, R1 represents any one of fluorine, chlorine, bromine, methyl, isopropyl, and methoxy, and R2 represents any one of H, methyl, phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, fluorophenyl, methyl, ethyl, and cyclopropyl.

[0011] In the above synthesis method, the amount of copper hexafluorophosphate tetraacetonitrile added is preferably 15% to 25% of the molar amount of the quinoline-N-oxide compound, and the amount of silver acetate added is preferably 15% to 25% of the molar amount of the quinoline-N-oxide compound.

[0012] In the above synthesis method, it is preferred that the amount of isoxazolidinone added is 2 to 3 times the molar amount of the quinoline-N-oxide compound.

[0013] In the above synthesis method, it is preferred to react in air at 80°C for 12 to 24 hours.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0015] 1. This invention provides the first report on the synthesis of 2-acylaminoquinoline-N-oxide compounds using a tetraacetonitrile copper hexafluorophosphate and silver acetate catalytic system, offering new insights for subsequent research on the CH activation at position 2 of quinoline-N-oxide compounds.

[0016] 2. The synthesis method of this invention is simple and green, and the use of isoxazolidinone as a nitrogen source improves the safety of the reaction.

[0017] 3. The reaction conditions of this invention are mild, the operation is simple, and the target product has high selectivity.

[0018] 4. The catalyst used in this invention is commercially available, environmentally friendly, has low preparation cost, and is simple to operate.

[0019] 5. This invention has excellent substrate universality, applicable to various quinoline-N-oxides, and is also well compatible with some halogen and other reducing functional groups. Detailed Implementation

[0020] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0021] Example 1

[0022] Synthesize compound 1 with the following structural formula.

[0023]

[0024] Quinoline-N-oxide (40.0 mg, 0.28 mmol), phenylisoxazolone (91.4 mg, 0.56 mmol), copper hexafluorophosphate tetraacetonitrile (20.9 mg, 0.056 mmol), and silver acetate (9.3 mg, 0.056 mmol) were dissolved in 4 mL of dichloroethane and heated to 80 °C for 12 h. After the reaction was complete, it was quenched with 0.5 mL of hydrochloric acid and 10 mL of saturated ammonium chloride, extracted with dichloromethane (5 mL x 3), dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by column chromatography (dichloromethane: ethyl acetate = 1:2) to give 154.0 mg of a grayish-white solid compound, with a yield of 73%.

[0025] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3): δ = 11.31 (bs, 1H), 8.78 (d, J = 8.0Hz, 1H), 8.65 (d, J = 8.0Hz, 1H), 8.06 (d, J = 8.0Hz, 2H), 7.87-7.81 (m, 3H), 7.53-7.64 (m, 4H); 13C NMR (100MHz, CDCl3): δ=165.8,139.3,138.2,133.3,133.2,131.4,129.1,128.4,127.9,127.0,125.8,118.8,113.0.

[0026] Example 2

[0027] Synthesize compound 2 with the following structural formula.

[0028]

[0029] In this embodiment, equimolar 8-methylquinoline-N-oxide was used to replace the quinoline-N-oxide in Example 1, and the other steps were the same as in Example 1, to obtain compound 2 with a yield of 54%.

[0030] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ=11.47(bs,1H),8.72(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,2H),7.77(d,J=8.0Hz ,1H),7.64-7.58(m,2H),7.53-7.49(m,2H),7.45(d,J=8.0Hz,1H),7.36(t,8.0Hz,1H),3.22(s,3H); 13 CNMR (100MHz, CDCl3) δ = 165.9, 143.3, 139.0, 134.4, 133.5, 133.0, 132.1, 129.0, 128.7, 127.9, 127.6, 127.2, 126.6, 112.9, 24.8.

[0031] Example 3

[0032] Synthesize compound 3 with the following structural formula.

[0033]

[0034] In this embodiment, equimolar 6-bromoquinoline-N-oxide was used to replace the quinoline-N-oxide in Example 1, and the other steps were the same as in Example 1, to obtain compound 3 with a yield of 57%.

[0035] The spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ = 11.22 (bs, 1H), 8.84 (d, J = 8.0Hz, 1H), 8.63 (d, J = 8.0Hz, 1H), 8 .19(d,J=8.0Hz,1H),8.06(d,J=8.0Hz,2H),7.82(d,J=8.0Hz,1H),7.56-7.51(m,4H); 13 C NMR (100MHz, CDCl3) δ = 165.7, 142.6, 140.1, 133.3, 133.0, 131.4, 130.9, 129.1, 127.9, 127.6, 125.1, 122.7, 118.7, 113.9.

[0036] Example 4

[0037] Synthesize compound 4 with the following structural formula.

[0038]

[0039] In this embodiment, equimolar amounts of 7-methylquinoline-N-oxide were used to replace the quinoline-N-oxide in Example 1, and the other steps were the same as in Example 1, to obtain compound 4 with a yield of 71%.

[0040] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ = 11.31 (bs, 1H), 8.68 (d, J = 8.0Hz, 1H), 8.44 (s, 1H), 8.07 (d, J = 8.0Hz, 2H), 7 .82(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.63-7.53(m,3H),7.40(d,J=8.0Hz,1H),2.60(s,3H); 13 C NMR (100MHz, CDCl3) δ = 165.8, 142.5, 139.2, 133.4, 133.1, 132.6, 131.0, 130.7, 129.1, 128.1, 127.9, 127.4, 124.0, 117.9, 112.1, 22.4.

[0041] Example 5

[0042] Synthesize compound 5 with the following structural formula.

[0043]

[0044] In this embodiment, equimolar amounts of 4-chloroquinoline-N-oxide were used to replace the quinoline-N-oxide in Example 1, and the other steps were the same as in Example 1, to obtain compound 5 with a yield of 73%.

[0045] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ = 11.22 (bs, 1H), 8.95 (s, 1H), 8.68 (d, J = 8.0Hz, 1H), 8.21 ( d,J=8.0Hz,1H),8.06(d,J=8.0Hz,2H),7.86(t,J=8.0Hz,1H),7.53-7.69(m,4H); 13 C NMR (100MHz, CDCl3) δ = 165.7, 141.9, 139.6, 133.4, 133.0, 132.1, 129.2, 127.9, 127.8, 125.4, 123.8, 119.3, 113.2.

[0046] Example 6

[0047] Synthesize compound 6 with the following structural formula.

[0048]

[0049] In this embodiment, equimolar 6-fluoroquinoline-N-oxide was used to replace the quinoline-N-oxide in Example 1, and the other steps were the same as in Example 1, to obtain compound 6 with a yield of 75%.

[0050] The spectral data of the obtained product are as follows 1 H NMR (400MHz, CDCl3) δ=11.17(bs,1H),8.80(d,J=8.0Hz,1H),8.67(bs,1H),8,05(d,J=8.0Hz,2H),7.78(d,J=8.0Hz,1H),7.64-7.48(m,5H); 13 C NMR (100MHz, CDCl3) δ = 165.7, 160.1 (d, J = 250Hz), 142.0, 136.3, 133.2, 133.2, 127.9, 12 7.2, 126.6 (d, J = 10Hz), 121.6 (d, J = 10Hz), 121.0 (d, J = 26Hz), 114.4, 112.0 (d, J = 23Hz).

[0051] Example 7

[0052] Synthesize compound 7 with the following structural formula.

[0053]

[0054] In this embodiment, equimolar 6-isopropylquinoline-N-oxide was used to replace the quinoline-N-oxide in Example 1, and the other steps were the same as in Example 1, to obtain compound 7 with a yield of 72%.

[0055] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ=11.25(bs,1H),8.71(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.02(d,J=8.0Hz,1H),7.79(d,J=7.9 Hz,1H),6.67(d,J=8.0Hz,1H),6.61(d,J=8.0Hz,1H),7.48-7.58(m,4H),3.05(septet,J=4Hz,1H),1.31(d,J=4.0Hz,6H); 13 C NMR (100MHz, CDCl3) δ = 165.7, 147.8, 137.8, 133.3, 133.0, 131.2, 129.0, 128.0, 127.8, 126.0, 124.6, 118.6, 113.0, 33.9, 23.8.

[0056] Example 8

[0057] Synthesize compound 8 with the following structural formula.

[0058]

[0059] In this embodiment, equimolar 4-fluorophenyloxazolone was used to replace phenylisoxazolone in Example 1, and the other steps were the same as in Example 1, to obtain compound 8 with a yield of 78%.

[0060] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ = 11.27 (bs, 1H), 8.74 (d, J = 8.0Hz, 1H), 8.65 (d, J = 8.0Hz, 1H), 8.08 (dd,J=4.0,4.0Hz,2H),7.86-7.78(m,3H),7.59(t,J=8.0Hz,3H),7.23(t,J=8.0Hz,2H); 13 C NMR (100MHz, CDCl3) δ = 166.6 (d, J = 253Hz), 164.6, 139.2, 131.4, 130.5, 130.4, 29.5, 128.4, 127.1, 125.8, 118.7, 116.4, 116.2, 113.0.

[0061] Example 9

[0062] Synthesize compound 9 with the following structural formula.

[0063]

[0064] In this embodiment, equimolar (4-methyl)phenyloxazolone was used to replace phenylisoxazolone in Example 1, and the other steps were the same as in Example 1, to obtain compound 9 with a yield of 79%.

[0065] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ = 11.24 (bs, 1H), 8.76 (d, J = 8.0Hz, 1H), 8.64 (d, J = 8.0Hz, 1H), 7.96 (d, J=8.0Hz,2H),7.85-7.77(m,3H),7.56(t,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),2.43(s,3H); 13 C NMR (100MHz, CDCl3) δ = 165.6, 144.0, 142.4, 139.2, 131.3, 130.4, 129.8, 128.3, 127.9, 126.9, 118.7, 113.1, 21.7.

[0066] Example 10

[0067] Synthesize compound 10 with the following structural formula.

[0068]

[0069] In this embodiment, equimolar (4-ethyl)phenyloxazolone was used to replace phenylisoxazolone in Example 1, and the other steps were the same as in Example 1, to obtain compound 10 with a yield of 68%.

[0070] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ = 11.29 (bs, 1H), 8.77 (d, J = 8.0Hz, 1H), 8.66 (d, J = 8.0Hz, 1H), 7.86 (d, J = 8.0Hz, 2H), 7 .88-7.79(m,3H),7.58(t,J=8.0Hz,1H),7.37(d,J=8.0Hz,1H),2.65(q,J=8.2Hz,2H),1.18(t,J=8.1Hz,3H); 13C NMR (100MHz, CDCl3) δ = 165.8, 150.2, 142.5, 139.2, 131.4, 130.7, 128.6, 118.8, 113.21, 29.0, 15.3.

[0071] Example 11

[0072] Synthesize compound 11 with the following structural formula.

[0073]

[0074] In this embodiment, methylisoxazolone (72.72 mg, 0.72 mmol) was used to replace phenylisoxazolone (91.4 mg, 0.56 mmol) in Example 1, the reaction time was extended to 24 h, and the other steps were the same as in Example 1, to obtain a grayish-white solid compound 11 with a yield of 89%.

[0075] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d) 6 )δ=10.8(bs,1H),8.43(t,J=8.0Hz,2H),7.98-7.91(m,2H),7.77(t,J=8.1Hz,1H),7.58(d,J=8.1Hz,1H),2.28(s,3H); 13 C NMR (100MHz, DMSO-d) 6 )δ=170.4,141.6,139.1,131.0,128.6,127.0,126.6,125.6,118.3,113.6,24.7.

[0076] Example 12

[0077] Synthesize compound 12 with the following structural formula.

[0078]

[0079] In this embodiment, ethylisoxazolone (82.8 mg, 0.72 mmol) was used to replace phenylisoxazolone (91.4 mg, 0.56 mmol) in Example 1, the reaction time was extended to 24 h, and the other steps were the same as in Example 1, to obtain a grayish-white solid compound 12 with a yield of 73%.

[0080] The spectral data of the obtained product are as follows: 1H NMR (400MHz, CDCl3) δ = 10.4 (bs, 1H), 8.72 (d, J = 8.0Hz, 2H), 7.88-7.71 (m, 3H), 7.51 ( t,J=8.1Hz,1H),2.62(q,J=8.3Hz,2H),2.62(q,J=8.3Hz,2H),1,25(t,J=8.3Hz,3H); 13 C NMR (100MHz, CDCl3) δ = 173.5, 142.1, 139.0, 131.0, 128.7, 127.3, 126.7, 125.8, 118.6, 113.2, 31.7, 9.8.

[0081] Example 13

[0082] Synthesize compound 13 with the following structural formula.

[0083]

[0084] In this embodiment, cyclopropylisoxazolone (91.4 mg, 0.72 mmol) was used to replace phenylisoxazolone (91.4 mg, 0.56 mmol) in Example 1, the reaction time was extended to 24 h, and the other steps were the same as in Example 1, to obtain a grayish-white solid compound 13 with a yield of 91%.

[0085] The spectral data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d) 6 )δ=10.8(bs,1H),8.43(d,J=8.0Hz,1H),8.39(d,J=8.1Hz,1H),7.93(d,J=7.8Hz,1H),7.88(d,J=7.9 Hz,1H),7.74(t,J=8.1Hz,1H),7.54(t,J=8.0Hz,1H),2.42(t,J=7.3Hz,1H),0.82(d,,J=7.2Hz,4H); 13 C NMR (100MHz, DMSO-d) 6 )δ=174.1,141.9,139.5,131.4,129.0,127.4,127.0,126.0,118.7,114.2,15.3,9.4.

Claims

1. A method for selectively synthesizing 2-acylaminoquinoline-N-oxide compounds from quinoline-N-oxide compounds, characterized in that: Using tetraacetonitrile copper hexafluorophosphate and silver acetate as catalysts, the quinoline-N-oxide compound shown in Formula I and the isoxazolidinone shown in Formula II were reacted in dichloroethane at 75-85°C for 12-24 hours. After the reaction was completed, the mixture was separated and purified to obtain the 2-acylaminoquinoline-N-oxide compound shown in Formula I′. In the formula, R1 represents any one of H, C1-C6 alkyl, C1-C4 alkoxy, and halogen; R2 represents any one of phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halophenyl, C1-C6 alkyl, and C3-C6 cycloalkyl.

2. The method for selectively synthesizing 2-acylaminoquinoline-N-oxide compounds from quinoline-N-oxide compounds according to claim 1, characterized in that: R1 represents any one of fluorine, chlorine, bromine, methyl, isopropyl, and methoxy, and R2 represents any one of phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, fluorophenyl, methyl, ethyl, and cyclopropyl.

3. The method for selectively synthesizing 2-acylaminoquinoline-N-oxide compounds from quinoline-N-oxide compounds according to claim 1 or 2, characterized in that: The amount of copper hexafluorophosphate tetraacetonitrile added is 15% to 25% of the molar amount of quinoline-N-oxide compounds, and the amount of silver acetate added is 15% to 25% of the molar amount of quinoline-N-oxide compounds.

4. The method for selectively synthesizing 2-acylaminoquinoline-N-oxide compounds from quinoline-N-oxide compounds according to claim 1 or 2, characterized in that: The amount of isoxazolidinone added is 2 to 3 times the molar amount of the quinoline-N-oxide compound.

5. The method for selectively synthesizing 2-acylaminoquinoline-N-oxide compounds from quinoline-N-oxide compounds according to claim 1 or 2, characterized in that: React at 80°C in air for 12–24 hours.

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