A method for the synthesis of 3-indolinones

Abstract

This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing 3-indolone. Using N-methylbenzylamine compounds of Formula 1 and methyl 2-fluorobenzoate compounds of Formula 2, in the presence of a strong base (lithium di(trimethylsilyl)amino) and a cesium salt additive (cesium fluoride), and mixed with an organic solvent (methyl tert-butyl ether), 3-indolone of Formula 3 is synthesized. The raw materials used in this invention are simple and readily available, and a one-pot method for synthesizing 3-indolone is constructed, which has advantages such as simple synthesis method, economic and environmental friendliness, and wide applicability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing 3-indolone. Background Technology

[0002] 3-Indolones are unique aromatic heterocyclic skeletons and distinctive substructures for constructing alkaloids and bioactive molecules. As an important intermediate, 3-indolones have been widely used in the synthesis of bioactive natural products and clinical drug candidates, such as isatis root extract A (chemical formula A), vincristine (2) (chemical formula B), and alkaloid (1) (chemical formula C). Furthermore, 3-indolones are valuable precursors used in the synthesis of fused indole-containing systems, the synthesis of substituted heteroaromatic hydrocarbons, and the heterocyclization of indolinones. Therefore, the development of simple methods for 3-indolones has attracted considerable attention. The most common synthetic methods focus on the direct oxidation of their indole derivatives with oxides; however, these starting materials typically require multiple steps. Therefore, we need to find a more convenient and rapid route to generate 3-indolones using simple and efficient starting materials.

[0003] Summary of the Invention

[0004] This invention provides a one-pot synthesis of 3-indolones from N-methylbenzylamine and methyl 2-fluorobenzoate, yielding a variety of 3-indolones with biological activity and medicinal value. This synthetic method is convenient and efficient. The specific scheme is as follows:

[0005]

[0006] A method for synthesizing a 3-indolone compound involves reacting an N-methylbenzylamine compound (Formula 1) and a methyl 2-fluorobenzoate compound (Formula 2) with an organic solvent in the presence of a strong base and a cesium salt additive to synthesize the 3-indolone compound (Formula 3).

[0007] Where R 1 Selected from methoxy, halogen, 2-naphthyl, thiophene, etc., R 2 Selected from methoxy, methyl, phenyl, 1-naphthyl, etc.

[0008] The method of this invention enables one-pot synthesis of 3-indolone compounds, reducing reaction steps and thus increasing product yield; the raw materials used in the synthesis method are convenient and economical; R in this invention... 1 R 2 It offers a variety of options and has wider applicability.

[0009] Preferred, R 1R2 is selected from methoxy, halogen, 2-naphthyl, thiophene, etc., and R2 is selected from methoxy, methyl, phenyl, 1-naphthyl, etc.

[0010] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen.

[0011] Preferably, the synthesis takes place in the presence of a strong base, a cesium salt additive, and an organic solvent.

[0012] Preferably, the strong base is lithium di(trimethylsilyl)amino; and the cesium salt additive is cesium fluoride.

[0013] Preferably, the organic solvent is methyl tert-butyl ether.

[0014] Preferably, the molar ratio of N-methylbenzylamine (Formula 1), methyl 2-fluorobenzoate (Formula 2), strong base, and cesium salt additive in the reaction is 1-1:1-1:1-1; and the reaction temperature is 110°C.

[0015] Preferably, using the method of the present invention, 3-indolone with the following structure can be synthesized:

[0016]

[0017]

[0018] 3-Indolone was synthesized by reacting N-methylbenzylamine and methyl 2-fluorobenzoate in a mixture of a strong base (lithium di(trimethylsilyl)amino) and an organic solvent (methyl tert-butyl ether) in the presence of a cesium salt additive (cesium fluoride).

[0019] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0020] The raw materials used in the synthesis method of this invention are all inexpensive and readily available;

[0021] The synthesis method of this invention does not use transition metal catalysts, making it green and environmentally friendly;

[0022] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and increases the yield of the product due to fewer reaction steps.

[0023] The operation steps required by this invention are relatively simple, requiring no extreme heating or cooling, and the reaction can be carried out under normal pressure, making it safe and convenient.

[0024] R in this invention 1 R 2 Since there are many options, the method of the present invention has a wider range of applications and can synthesize a variety of 3-indolones. Attached Figure Description

[0025] The attached figures are the proton and carbon NMR spectra of the products from each embodiment. The figures are numbered according to the embodiment numbers. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The carbon NMR spectrum of the product obtained in Example 1; Figure 2A The above is the proton NMR spectrum of the product obtained in Example 2. Figure 2B The carbon NMR spectrum of the product obtained in Example 2; Figure 3A The image shows the proton NMR spectrum of the product obtained in Example 3. Figure 3B The carbon NMR spectrum of the product obtained in Example 3; Figure 4A The above is the proton NMR spectrum of the product obtained in Example 4. Figure 4B The carbon NMR spectrum of the product obtained in Example 4; Figure 5A The above is the proton NMR spectrum of the product obtained in Example 5. Figure 5B The carbon NMR spectrum of the product obtained in Example 5; Figure 6A The above is the proton NMR spectrum of the product obtained in Example 6. Figure 6B The carbon NMR spectrum of the product obtained in Example 6; Figure 7A The above is the proton NMR spectrum of the product obtained in Example 7. Figure 7B The carbon NMR spectrum of the product obtained in Example 7; Figure 8A The above is the proton NMR spectrum of the product obtained in Example 8. Figure 8B The carbon NMR spectrum of the product obtained in Example 8; Figure 9A The image shows the proton NMR spectrum of the product obtained in Example 9. Figure 9B The carbon NMR spectrum of the product obtained in Example 9; Figure 10A The above is the proton NMR spectrum of the product obtained in Example 10. Figure 10B The image shows the carbon NMR spectrum of the product obtained in Example 10. Specific Implementation

[0026] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M.

[0027] Example 1

[0028] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methylbenzylamine (12.9 μL, 0.1 mmol), methyl 2-fluorobenzoate (12.8 μL, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The tube was then sealed and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (19.0 mg, 85% yield) as a white solid. 1 H NMR (401MHz, CHCl3) δ7.91-7.87 (m, 1H), 7.48-7.43 (m, 2H), 7.40-7.32 (m, 3H), 7.21-7.13 (m, 3H), 5.34 (s, 1H), 2.98 (s, 3H)ppm. 13 C NMR (101MHz, CDCl3) δ168.7, 146.0, 136.9, 131.6, 131.5, 129.1, 128.6, 128.3, 127.4, 123.4, 122.9, 66.5, 27.5ppm.

[0029] By changing the raw materials in Example 1, the following 10 sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding NMR spectrum of the product is shown in Figure 1. The NMR spectra of the products in the remaining sets 2-10 correspond to the sequence numbers of the respective examples.

[0030] The table lists the structural formulas of the products in each of the 1-10 embodiments. The last column lists the yield of the products in each embodiment and indicates the specific implementation conditions of each embodiment. The specific meaning of the implementation conditions of each embodiment is shown below the table.

[0031]

[0032]

[0033] Example 2

[0034] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mmol), N-(4-methoxybenzyl)-N-methylamine (15.0 μL, 0.1 mmol), methyl 2-fluorobenzoate (12.8 μL, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The microwave-safe tube was then sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by the slow addition of three drops of water. The reaction mixture was passed through a silica short pad and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (20.2 mg, 80% yield) as a white solid. 1 H NMR (400MHz, CHCl3) δ7.90-7.84 (m, 1H), 7.50-7.42 (m, 2H), 7.21-7.15 (m, 1H), 7 .08-7.02(m, 2H), 6.91-6.86(m, 2H), 5.30(s, 1H), 3.81(s, 3H), 2.95(s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ168.6, 159.8, 146.3, 131.6, 128.7, 128.2, 127.3, 123.3, 122.9, 114.4, 114.1, 66.0, 55.3, 27.3ppm.

[0035] Example 3

[0036] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), (4-chloro-benzyl)-methylamine (14.3 mg, 0.1 mmol), methyl 2-fluorobenzoate (12.8 μL, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave tube with a magnetic inlet. The microwave tube was sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with another 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (16.7 mg, 65% yield) as a pale yellow solid.1 H NMR (400MHz, CDCl3) δ7.91-7.85 (m, 1H), 7.50-7.43 (m, 2H), 7.37-7.32 (m, 2H), 7.18-7.14 (m, 1H), 7.11-7.06 (m, 2H), 5.32 (s, 1H), 2.96 (s, 3H)ppm. 13 C{ 1 H) NMR (101MHz, CDCl3) δ168.7, 145.7, 135.7, 134.6, 131.9, 131.6, 129.5, 128.9, 128.6, 123.7, 123.0, 66.0, 27.6ppm.

[0037] Example 4

[0038] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methyl-2-naphthylamine (16.5 mg, 0.1 mmol), methyl 2-fluorobenzoate (12.8 μL, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The microwave-safe tube was then sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (18.6 mg, 68% yield) as a white solid. 1 H NMR (400MHz, CHCl3) δ7.94-7.77 (m, 5H), 7.55-7.42 (m, 4H), 7.20-7.16 (m, 1H), 6.99 (dd, J=8.5, 1.8Hz, 1H), 5.49 (s, 1H), 3.00 (s, 3H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ168.7, 145.9, 134.3, 133.3, 133.2, 131.7, 131.6, 129.3 , 128.4, 127.8, 127.7, 127.4, 126.6, 126.5, 123.9, 123.4, 123.0, 66.7, 27.5ppm.

[0039] Example 5

[0040] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methyl-2-thiophene methylamine (12.1 μL, 0.1 mmol), methyl 2-fluorobenzoate (12.8 μL, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The microwave-safe tube was then sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (29.8 mg, 77% yield) as a white solid. 1 H NMR (400MHz, CHCl3) δ7.90-7.85 (m, 1H), 7.53-7.45 (m, 2H), 7.32-7.28 (m, 2H) , 7.15-7.12 (m, 1H), 7.04-6.99 (m, 1H), 5.65 (s, 1H), 3.02 (d, J=2.0Hz, 3H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ168.0, 145.2, 140.1, 131.7, 131.3, 128.6, 127.3, 126.9, 126.5, 123.4, 123.0, 61.7, 27.4ppm.

[0041] Example 6

[0042] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methylbenzylamine (12.9 μL, 0.1 mmol), methyl 2-fluoro-6-methoxybenzoate (15.6 μL, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave tube with a magnetic inlet. The microwave tube was sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with another 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (13.9 mg, 55% yield) as a white solid. 1H NMR (400MHz, CHCl3) δ7.39-7.31 (m, 4H), 7.18-7.13 (m, 2H), 6.87 (d, J=8.3Hz, 1H), 6.73 (d, J=7.5Hz, 1H), 5.27 (s, 1H), 3.98 (s, 3H), 2.92 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ167.5, 156.9, 148.6, 137.2, 133.2, 129.0, 128.5, 127.3, 118.7, 115.0, 110.2, 65.9, 55.8, 27.3ppm.

[0043] Example 7

[0044] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methylbenzylamine (12.9 μL, 0.1 mmol), methyl 2-fluoro-5-methylbenzoate (16.8 mg, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The microwave-safe tube was sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with another 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (14.9 mg, 63% yield) as a white solid. 1 H NMR (400MHz, CHCl3) δ7.69 (s, 1H), 7.36-7.31 (m, 3H), 7.27-7.24 (m, 1H), 7.15- 7.11 (m, 2H), 7.05 (d, J=7.7Hz, 1H), 5.29 (s, 1H), 2.96 (s, 3H), 2.42 (s, 3H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ168.8, 143.3, 138.3, 137.2, 132.6, 131.7, 129.0, 128.5, 127.3, 123.6, 122.6, 66.3, 27.4, 21.2ppm.

[0045] Example 8

[0046] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methylbenzylamine (12.9 μL, 0.1 mmol), methyl 3-chloro-2-fluorobenzoate (18.9 mg, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The microwave-safe tube was then sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with another 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (16.7 mg, 65% yield) as a white solid. 1 H NMR (400MHz, CHCl3) δ7.50 (dd, J=7.3, 1.1Hz, 1H), 7.40 (dd, J=8.0, 1.1Hz, 1H), 7.37-7.30 (m, 6H), 4.64 (s, 1H), 2.59 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ166.3, 144.4, 135.8, 133.6, 133.0, 131.0, 129.7, 128.6, 128.3, 126.5, 121.5, 90.9, 23.8ppm.

[0047] Example 9

[0048] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methylbenzylamine (12.9 μL, 0.1 mmol), methyl 3-fluoro-3-nitro-[1,1-biphenyl]-4-carboxylic acid (23.0 mg, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave tube with a magnetic inlet. The microwave tube was sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluting with petroleum ether: ethyl acetate = 5:1) to obtain a pale yellow solid (13.5 mg, 45% yield). 1H NMR (400MHz, CHCl3) δ: 7.98-7.90 (m, 1H), 7.73-7.64 (m, 1H), 7.55-7.48 (m, 2H), 7.43-7.33 (m, 7H), 7.22-7.14 (m, 2H), 5.39 (s, 1H), 3.00 (s, 3H) ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ: 168.5, 146.7, 144.9, 140.3, 136.8, 130.5, 129.2, 128.8, 128.7, 127.9, 127.6, 127.44, 127.36, 123.7, 121.6, 66.6, 27.6ppm.

[0049] Example 10

[0050] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.3 mmol), CsF (45.6 mg, 0.3 mol), N-methylbenzylamine (12.9 μL, 0.1 mmol), methyl 4-(naphthyl-1-yl)benzoate (28.0 mg, 0.1 mmol), and TBME (0.3 mL) were added sequentially to a dry microwave-safe tube with a magnetic inlet. The microwave-safe tube was then sealed with a cap and removed from the glove box. The reaction mixture was heated in an oil bath at 110 °C for 12 hours. The flask was removed from the oil bath, cooled to room temperature, exposed to air, and then the reaction was quenched by slowly adding three drops of water. The reaction mixture was passed through a silica short pad and washed with an additional 3 mL of ethyl acetate (3 x 1 mL), and the combined solutions were concentrated under reduced pressure. The crude product was purified by rapid silica column chromatography (eluting with petroleum ether:ethyl acetate = 5:1) to give the product (22.7 mg, 65% yield) as a yellow solid. 1 H NMR (400MHz, CHCl3) δ7.99 (d, J=7.8Hz, 1H), 7.88-7.80 (m, 2H), 7.72 (d, J=8.4Hz, 1H), 7.57 (dd, J=7.8, 1. 4Hz, 1H), 7.45 (tt, J=6.9, 1.8Hz, 2H), 7.40-7.28 (m, 6H), 7.21-7.13 (m, 2H), 5.40 (s, 1H), 3.01 (s, 3H)ppm. 13 C{ 1H}NMR(101MHz,CDCl3)δ168.5,146.2,144.4,139.1,136.7,133.6,131.1,130.5,130.3,129.1,128.6,128.3,128.1,127.3,127.0,126.2,125.8,125.4,125.2,124.5,123.2,66.5,27.6ppm.

Claims

1. A method for synthesizing 3-indolones, characterized in that: a compound of N-methylbenzylamine shown in formula 1 and a compound of methyl 2-fluorobenzoate shown in formula 2 are mixed with an organic solvent to react in the presence of a strong base and cesium fluoride to synthesize a compound of 3-indolones shown in formula 3; the strong base is lithium bis(trimethylsilyl)amide. a compound of N-methylbenzylamine and a compound of methyl 2-fluorobenzoate are mixed with an organic solvent to react in the presence of a strong base and cesium fluoride to synthesize a product of 3-indolones; the compound of N-methylbenzylamine and the compound of methyl 2-fluorobenzoate, and the product of 3-indolones are shown in the following table: wherein R 1 is selected from methoxy, halogen, R 2 is selected from methoxy, methyl, phenyl, 1-naphthyl.

2. A method of synthesizing 3-indolinones, characterized by: the reaction is carried out under nitrogen protection.

3. The method of synthesis according to claim 1 or 2, wherein, the organic solvent is methyl tert-butyl ether.

4. The method of synthesis according to claim 1 or 2, wherein, the compound of N-methylbenzylamine, the compound of methyl 2-fluorobenzoate, and the product of 3-indolones are one of the following tables:

5. The method of synthesis of claim 1, wherein, ​

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