A method for the synthesis of a thioester-functionalized 2-oxoindole

Abstract

The application discloses a synthesis method of a thioester functionalized 2-oxoindole, and belongs to the technical field of organic synthesis. The method is to use an iodine acetyl aniline derivative and a thioester as raw materials, to add a base and a solvent under the action of a palladium catalyst and a ligand, to perform one-pot reaction, and to synthesize a series of thioester functionalized 2-oxoindole compounds at a temperature of 70-100 DEG C. The reaction avoids directly using toxic CO gas or a strong stimulating gas smell aryl thio phenol or thiol and other substances, and has the advantages of mild reaction condition, simple operation, strong substrate universality, easy availability of raw materials, high yield, easy separation of target products and the like.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 2-oxoindole functionalized with a thioester. BACKGROUND

[0002] Thioester units are widely present in many biologically active compounds and agrochemicals, and are important and effective synthons in organic chemistry and life processes. Therefore, this structural unit has attracted synthetic chemists, and various synthetic methods have been developed. Among the various strategies for synthesizing thioesters, two widely used synthetic pathways are: (1) direct condensation of carboxylic acid derivatives (acid chlorides, acid anhydrides and carboxylic acids) and thiols; (2) CO insertion carbonylation reaction of thiols with aryl halides, alkenes or alkynes. The above two methods have obvious limitations, requiring toxic CO gas or thiols or sulfides with strong irritating odor. By reviewing the literature, although there are many reported methods for synthesizing aromatic, olefinic or acetylenic compounds containing thioester skeletons (Org. Lett. 2022, 24, 7555-7559; Angew. Chem., Int. Ed. 2021, 60, 17178-17184; J. Org. Chem. 1997, 62, 3422-3423, etc.), there is only one reported method for synthesizing 2-oxoindole compounds containing thioesters (Chin. J. Chem. 2023, 41, 188-192). However, this method still uses sulfuryl chloride with strong irritation as a reaction substrate, and has the disadvantages of harsh reaction conditions, complex operation and long reaction time.

[0003] In summary, in view of the various deficiencies of the existing preparation methods, it is of great research significance and practical application value to develop an effective method for preparing 2-oxoindole functionalized with a thioester, which has strong substrate universality and uses safe and easily available raw materials. SUMMARY

[0004] Technical problems solved:

[0005] The present application solves the technical problems that the existing technology requires toxic CO gas or thiols or sulfides with strong irritating odor, uses sulfuryl chloride with strong irritation as a reaction substrate, and has the disadvantages of harsh reaction conditions, complex operation and long reaction time, and provides a synthesis method of 2-oxoindole functionalized with a thioester, which has safe and easily available raw materials, low cost, convenient operation and high reaction efficiency.

[0006] Technical scheme:

[0007] To achieve the above-mentioned purpose, the technical scheme is as follows:

[0008] The application relates to a synthesis method of a 2-oxoindole derivative with a thioester function, which comprises the following steps: taking an iodine acetyl aniline derivative and a thioester into a reaction tube, adding a palladium catalyst, a ligand, a base and an organic solvent into the reaction tube in sequence, removing air in the reaction container, filling N2, stirring, heating to 70-100 DEG C, and reacting for 10-16 hours.

[0009] Further, the synthesis method comprises the following specific steps:

[0010] First step: the iodine acetyl aniline derivative and the thioester are added into the reaction tube, the palladium catalyst, the ligand, the base and the organic solvent are added in sequence; air in the reaction container is removed, N2 is filled, and the reaction is carried out under stirring and heating to 70-100 DEG C; the reaction time is 10-16 hours.

[0011] Second step: the reaction progress is detected by using thin layer chromatography; when the reaction system is free of raw materials, the reaction is ended; the reaction system is cooled, the organic solvent is removed by rotary evaporation under reduced pressure, and the residue is mixed with silica gel and separated by column chromatography to obtain the 2-oxoindole derivative with a thioester function.

[0012] Further, the reaction formula of the method is as follows:

[0013]

[0014] In the formula, R is selected from one of alkyl and benzyl; R 1 is selected from one of alkyl, alkoxy, halogen, ester group, cyano, nitro and trifluoromethyl; R 2 is one of alkyl and phenyl; R 3 is one of alkyl, halogen, alkoxy and trifluoromethyl.

[0015] Further, the palladium catalyst is one of palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium chloride, palladium trifluoroacetate, allyl palladium chloride or bis(acetonitrile)palladium dichloride.

[0016] Further, the ligand is one of triarylphosphine ligand, trialkylphosphine ligand or bidentate phosphine ligand derivative.

[0017] Further, the base is one of potassium acetate, cesium acetate, potassium carbonate and sodium acetate.

[0018] Further, the organic solvent is one of ethylene glycol dimethyl ether, dioxane, toluene, tetrahydrofuran and 1,2-dichloroethane.

[0019] Further, the iodoacetanilide derivative is one of N-(2-iodo-5-methylphenyl)-N-methylmethacrylamide, N-(2-iodo-4-methoxyphenyl)-N-methylmethacrylamide, N-(4-chloro-2-iodophenyl)-N-methylmethacrylamide, N-(4-nitro-2-iodophenyl)-N-methylmethacrylamide, 3-iodo-4-(N-methylmethacrylamido)benzoic acid methyl ester, N-benzyl-N-(2-iodophenyl)methacrylamide, and N-(2-iodophenyl)-N-methyl-2-phenylacrylamide; and the thioester is one of S-p-tolyl methyl sulfide, S-p-methoxyphenyl methyl sulfide, S-p-bromophenyl methyl sulfide, S-p-chlorophenyl methyl sulfide, and S-benzyl methyl sulfide.

[0020] Further, the molar ratio of the iodoacetanilide derivative, the thioester, the palladium catalyst, the ligand, and the base is 0.1:0.2:0.005:0.01:0.3; and the concentration of the iodoacetanilide derivative in the mixed solution is 0.1 mol / L.

[0021] Further, the post-treatment step is as follows: after the reaction is completed, the organic solvent is removed by rotary evaporation, and the target product is obtained by column chromatography; and the eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1 to 2:1.

[0022] The principle of the above-mentioned synthesis method of the thioester-functionalized 2-oxoindole lies in that, under the catalysis of the metal palladium, the thioester can be decomposed to generate CO gas, which directly participates in the reaction to construct the thioester functional group in the system without the need of additional CO gas or its precursor.

[0023] Advantages:

[0024] The present application provides a synthesis method of a thioester-functionalized 2-oxoindole, which has the following advantages compared with the prior art:

[0025] 1. The present application efficiently synthesizes a thioester-functionalized 2-oxoindole derivative by using an iodoacetanilide derivative and a thioester as raw materials, under the joint action of a palladium catalyst, a ligand, and a basic compound, through intramolecular Heck cyclization, in-situ CO insertion, and nucleophilic capture processes. The reaction has low cost, and the raw materials are safe and easy to obtain, and has the advantages of good functional group tolerance, wide substrate universality, etc.

[0026] 2. Direct use of CO gas is avoided;

[0027] 3. Direct use of an aryl thiol with strong odor irritation or mercaptan is avoided;

[0028] 4. Compared with the prior art, the method of the present application improves the overall yield by 15% to 30%, and in addition, the operation is simple and convenient; the method can be effectively applied to the synthesis of 3-alkenyloxy indole compounds containing a benzene sulfoxide structure, which can be used as an active inhibitor of tyrosine kinase and also shows effective cytotoxicity (IC 50 = 1.34 ± 0.03 μM, Eur. J. Med. Chem. 2021, 216, 113334). DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0030] A synthesis method of a 2-oxoindole functionalized with a thioester is as shown in the following formula:

[0031]

[0032] In the formula, R is selected from one of alkyl and benzyl; R 1 is selected from one of alkyl, alkoxy, halogen, ester, cyano, nitro and trifluoromethyl; R 2 is one of alkyl and phenyl; R 3 is one of alkyl, halogen, alkoxy and trifluoromethyl.

[0033] The specific steps are as follows:

[0034] First step: iodinated acetyl aniline derivatives and thioester are added into a reaction tube, and a palladium catalyst, a ligand, a base and a solvent are sequentially added; the air in the reaction container is discharged and N2 is filled, and the reaction is carried out under stirring and heating to 70-100℃, and the reaction time is 10-16 hours.

[0035] Second step: the reaction progress is detected by thin layer chromatography, and the reaction is ended when there is no raw material in the reaction system; the reaction system is cooled, concentrated under reduced pressure, and the residue is mixed with silica gel and separated by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 10:1-2:1) to obtain 2-oxoindole derivatives functionalized with thioester.

[0036] The palladium catalyst is one of palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium chloride, palladium trifluoroacetate, allyl palladium chloride or bis(acetonitrile)palladium dichloride, and the palladium catalyst is preferably palladium acetate.

[0037] The ligand is one of triarylphosphine ligand, trialkylphosphine ligand or bidentate phosphine ligand derivative, preferably the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0038] The base is one of potassium acetate, cesium acetate, potassium carbonate, sodium acetate.

[0039] The solvent is one of ethylene glycol dimethyl ether, dioxane, toluene, tetrahydrofuran or 1,2-dichloroethane.

[0040] The temperature of the reaction is 70-100℃, preferably the temperature is 90℃;

[0041] The time of the reaction is 10-16 hours, preferably the reaction time is 12 hours;

[0042] The molar ratio of the iodoacetylaniline derivative, the thioester, the palladium catalyst, the ligand, the base is 0.1:0.2:0.005:0.01:0.3;

[0043] The concentration of the iodoacetylaniline derivative in the mixture of the solvent is 0.1 mol / L;

[0044] The post-processing step is: after the reaction is completed, the organic solvent is removed by rotary evaporation, and the target product is obtained by column chromatography separation; the volume ratio of the eluent petroleum ether and ethyl acetate in the column chromatography is 10:1-2:1 mixture.

[0045] Example 1:

[0046] A synthesis method of a thioester functionalized 2-oxoindole, synthesis of S-(p-tolyl)-2-(1,3,6-trimethyl-2-oxoindol-3-yl) ethyl thioester

[0047]

[0048] Into a 25 mL reaction bottle, N-(2-iodo-5-methylphenyl)-N-methylmethacrylamide (63.0 mg, 0.2 mmol), S-p-tolyl methyl thioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) were added in turn, vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, placed in an oil bath with a temperature of 90℃ and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and then column chromatography separation (petroleum ether / ethyl acetate = 5:1) was performed to obtain a light yellow liquid (56 mg, yield 83%).

[0049] 1H NMR (400 MHz, Chloroform-d) δ 7.16 - 7.05 (m, 5H), 6.85 (d, J = 7.5 Hz, 1H), 6.65 (s, 1H), 3.22 (d, J = 6.0 Hz, 2H), 3.19 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H), 1.38 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.14, 179.81, 143.55, 139.84, 138.36, 134.48, 130.09, 129.38, 123.83, 122.91, 122.68, 109.38, 49.88, 46.08, 26.53, 24.30, 21.93, 21.43. HRMS (ESI) m / z: [M+H] + calcd for C 20 H 22 NO2S340.1366; found: 340.1368.

[0050] Example 2:

[0051] A method for synthesizing a 2-oxoindole functionalized with a thioester, synthesis of S-(p-tolyl)-2-(5-methoxy-l,3-dimethyl-2-oxoindol-3-yl) ethyl thioester

[0052]

[0053] Into a 25 mL reaction vial was added N-(2-iodo-4-methoxyphenyl)-N- methylmethacrylamide (66.2 mg, 0.2 mmol), S-p-tolyl methyl thioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) sequentially, vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 3: 1) to give a light yellow liquid (50 mg, yield 71%).

[0054] 1H NMR (400 MHz, Chloroform-d) δ 7.11 (q, J = 8.2 Hz, 4H), 6.88 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.5, 2.5 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 3.30 - 3.21 (m, 2H), 3.19 (s, 3H), 2.31 (s, 3H), 1.39 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.04, 179.16, 155.96, 139.88, 137.06, 134.51, 133.74, 130.12, 123.76, 112.21, 110.67, 108.63, 55.98, 49.77, 46.68, 26.65, 24.34, 21.44. HRMS (ESI) m / z: [M + H] + calcd for C 20 H 22 NO3S 356.1315; found: 356.1315.

[0055] Example 3:

[0056] A method for synthesizing a 2-oxoindole functionalized with a thioester, synthesis of S-(p-tolyl)-2-(5-chloro-l,3-dimethyl-2-oxoindol-3-yl) ethyl thioester

[0057]

[0058] Into a 25 mL reaction vial was added N-(4-chloro-2-iodophenyl)-N- methylmethacrylamide (67.0 mg, 0.2 mmol), S-p-tolyl methyl thioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) sequentially, vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and then separated by column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain a light yellow liquid (53 mg, yield 74%).

[0059] 1H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.19 (m, 2H), 7.18 - 7.07 (m, 4H), 6.73 (d, J = 8.8 Hz, 1H), 3.27 (t, J = 16.5 Hz, 2H), 3.19 (s, 3H), 2.32 (s, 3H), 1.38 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.10, 179.03, 142.13, 140.05, 134.55, 134.11, 130.19, 128.17, 127.77, 123.46, 123.36, 109.33, 49.57, 46.37, 26.68, 24.18, 21.44. HRMS (ESI) m / z: [M + H] + calcd for C 19 H 19 NClO2S 360.0820; found: 360.0822.

[0060] Example 4

[0061] A method of synthesizing a 2-oxoindole functionalized with a thioester, synthesis of S-(p-tolyl)-2-(5-nitro-l,3-dimethyl-2-oxoindol-3-yl) ethyl thioester

[0062]

[0063] Into a 25 mL reaction vial was added N-(4-nitro-2-iodophenyl)-N- methylmethacrylamide (69.0 mg, 0.2 mmol), S-p-tolyl methyl thioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) sequentially, vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 3: 1) to give a light yellow liquid (38 mg, 51% yield).

[0064] 1H NMR (400 MHz, Chloroform-d) δ 8.17 (dt, J = 8.7, 1.7 Hz, 1H), 8.09 - 7.98 (m, 1H), 7.05 (q, J = 8.0 Hz, 4H), 6.81 (d, J = 8.6 Hz, 1H), 3.42 - 3.22 (m, 2H), 3.20 (d, J = 1.3 Hz, 3H), 2.24 (s, 3H), 1.34 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.13, 179.57, 149.37, 143.20, 140.15, 134.44, 133.32, 130.16, 125.62, 122.96, 118.21, 107.89, 49.52, 45.83, 26.92, 24.22, 21.35. HRMS (ESI) m / z: [M+H] + calcd for C 19 H 19 N2O4S 371.1060; found: 371.1060.

[0065] Example 5

[0066] A method of synthesizing a 2-oxoindole functionalized with a thioester, synthesis of methyl 1,3-dimethyl-2-oxo-3-(2-oxo-2-(p-tolylthio)ethyl)indolin-5-carboxylate

[0067]

[0068] Into a 25 mL reaction vial was added 3-iodo-4-(N-methylmethacrylamido)benzoic acid methyl ester (72.0 mg, 0.2 mmol), S-p-tolyl methyl sulfide (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol), and potassium acetate (58.8 mg, 0.6 mmol), vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 3:1) to give a light yellow liquid (47 mg, yield 62%).

[0069] 1H NMR (400 MHz, Chloroform-d) δ 7.70 (dt, J = 7.7, 1.2 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.09 - 6.92 (m, 4H), 3.85 (s, 3H), 3.35 - 3.13 (m, 5H), 2.23 (s, 3H), 1.32 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 193.89, 179.08, 166.78, 143.81, 139.93, 137.57, 134.37, 130.29, 130.07, 124.32, 123.34, 122.45, 108.98, 52.33, 49.53, 46.26, 26.66, 24.05, 21.33. HRMS (ESI) m / z: [M + H] + calcd for C 21 H 22 NO4S 384.1264; found: 384.1268.

[0070] Example 6:

[0071] A method for synthesizing a 2-oxoindole functionalized with a thioester, synthesis of S-(p-tolyl) 2-(l-benzyl-3-methyl-2-oxoindolin-3-yl) ethyl thioester

[0072]

[0073] Into a 25 mL reaction vial was added N-benzyl-N-(2-iodophenyl)methyl acrylamide (75.4 mg, 0.2 mmol), S-p-tolyl methyl thioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol), vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give a light yellow liquid (70 mg, 87% yield).

[0074] 1H NMR (400 MHz, Chloroform-d) δ 7.31 - 7.22 (m, 6 H), 7.16 - 7.05 (m, 5 H), 7.00 (t, J = 7.5 Hz, 1 H), 6.67 (d, J = 7.8 Hz, 1 H), 5.03 (d, J = 15.8 Hz, 1 H), 4.82 (d, J = 15.8 Hz, 1 H), 3.38 - 3.21 (m, 2 H), 2.32 (s, 3 H), 1.46 (s, 3 H). 13 C NMR (101 MHz, Chloroform-d) δ 194.06, 179.55, 142.53, 139.82, 136.05, 134.43, 132.31, 130.06, 128.81, 128.17, 127.55, 127.30, 123.80, 122.98, 122.50, 109.46, 49.68, 46.42, 44.00, 24.71, 21.44. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 24 NO2S 402.1522; found: 402.1526.

[0075] Example 7:

[0076] A method for the synthesis of a 2-oxoindole functionalized with a thioester, synthesis of S-(p-tolyl)-2-(l-methyl-2-oxo-3-phenylindol-3-yl) ethyl thioester

[0077]

[0078] Into a 25 mL reaction vial was added N-(2-iodophenyl)-N-methyl-2-phenylacrylamide (72.6 mg, 0.2 mmol), S-p-tolyl methyl thioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) sequentially, vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless liquid (60 mg, yield 78%).

[0079] 1H NMR (400 MHz, Chloroform-d) δ 7.34 - 7.14 (m, 7H), 7.04 (dd, J = 12.6, 7.7 Hz, 3H), 6.94 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 3.73 (d, J = 16.0 Hz, 1H), 3.57 (d, J = 16.0 Hz, 1H), 3.10 (s, 3H), 2.22 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 193.70, 177.60, 144.55, 139.87, 138.94, 134.45, 130.17, 130.09, 128.80, 127.81, 126.75, 125.16, 123.64, 122.43, 108.69, 53.80, 50.31, 26.83, 21.41. HRMS (ESI) m / z: [M + H] + calcd for C 24 H 22 NO2S388.1366; found: 388.1360.

[0080] Example 8

[0081] A method for synthesizing a 2-oxoindole functionalized with a thioester, synthesis of S-(4-methoxyphenyl)-2-(l,3,6-trimethyl-2-oxoindol-3-yl) ethyl thioester

[0082]

[0083] Into a 25 mL reaction vial was added N-(2-iodo-5-methylphenyl)-N- methylmethacrylamide (63.0 mg, 0.2 mmol), S-p-methoxyphenyl methyl thioester (67.2 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) sequentially, vacuumed and filled with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and then separated by column chromatography (petroleum ether / ethyl acetate = 3: 1) to obtain a light yellow liquid (51 mg, yield 72%).

[0084] 1H NMR (400 MHz, Chloroform-d) δ 7.12 (t, J = 8.1 Hz, 3H), 6.90 - 6.80 (m, 3H), 6.65 (s, 1H), 3.76 (s, 3H), 3.28 - 3.12 (m, 5H), 2.36 (s, 3H), 1.38 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.63, 179.80, 160.72, 143.56, 138.34, 136.12, 129.41, 122.90, 122.67, 118.09, 114.90, 109.36, 55.40, 49.73, 46.07, 26.50, 24.29, 21.91. HRMS (ESI) m / z: [M + H] + calcd for C 20 H 22 NO3S 356.1315; found: 356.1317.

[0085] Example 9

[0086] A method of synthesizing a 2-oxoindole functionalized with a thioester, synthesis of S-(4-bromophenyl)-2-(l,3,6-trimethyl-2-oxoindol-3-yl) ethyl thioester

[0087]

[0088] Into a 25 mL reaction vial was added N-(2-iodo-5-methylphenyl)-N- methylmethacrylamide (63.0 mg, 0.2 mmol), S-p-bromophenyl methyl thioester (86.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol) and sodium acetate (49.2 mg, 0.6 mmol), vacuumed and filled with nitrogen. Then 2.0 mL of toluene was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 5: 1) to give a light yellow liquid (62 mg, yield 77%).

[0089] 1 H NMR (400 MHz, Chloroform-d) δ 7.46 (d, J = 8.4 Hz, 2H), 7.26 - 7.20 (m, 2H), 7.13 - 7.03 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 3.36 - 3.18 (m, 5H), 1.38 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 192.97, 178.88, 142.13, 136.01, 133.95, 132.55, 128.31, 127.83, 126.01, 124.46, 123.27, 109.41, 49.78, 46.35, 26.70, 24.22. HRMS (ESI) m / z: [M+H] + calcd for C 19 H 19 NBrO2S 404.0314; found: 404.0314.

[0090] Example 10

[0091] A method for the synthesis of a 2-oxoindole functionalized with a thioester, synthesis of S-(4-chlorophenyl)-2-(l,3,6-trimethyl-2-oxoindol-3-yl) ethyl thioester

[0092]

[0093] Into a 25 mL reaction vial was added N-(2-iodo-5-methylphenyl)-N- methylmethacrylamide (63.0 mg, 0.2 mmol), S-p-chlorophenyl methyl thioester (68.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.6 mg, 0.02 mmol) and sodium acetate (49.2 mg, 0.6 mmol) sequentially, vacuumed and filled with nitrogen. Then 2.0 mL of toluene was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 5: 1) to give a light yellow liquid (57 mg, 79% yield).

[0094] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 - 7.29 (m, 2H), 7.25 - 7.19 (m, 2H), 7.16 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 3.35 - 3.19 (m, 5H), 1.39 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 193.13, 178.91, 142.18, 136.21, 135.82, 134.01, 129.64, 128.34, 127.89, 125.45, 123.33, 109.42, 49.81, 46.40, 26.72, 24.24. HRMS (ESI) m / z: [M+H] + calcd for C 19 H 19 NClO2S 360.0820; found: 360.0828.

[0095] Example 11

[0096] A method of synthesis of a 2-oxoindole functionalized thioester, synthesis of S-benzyl-2-(1,3,6-trimethyl-2-oxoindolin-3-yl) ethyl thioester

[0097]

[0098] Into a 25 mL reaction vial was added N-(2-iodo-5-methylphenyl)-N- methylmethacrylamide (63.0 mg, 0.2 mmol), S-benzyl methylthioester (60.8 mg, 0.4 mmol), palladium acetate (2.24 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (11.6 mg, 0.02 mmol) and potassium acetate (58.8 mg, 0.6 mmol) sequentially, vacuumed and flushed with nitrogen. Then 2.0 mL of 1,4-dioxane was added, sealed, and stirred in an oil bath at 90 °C for 12 h. After the reaction was complete, the solvent was removed by rotary evaporation, and then isolated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give a light yellow liquid (47 mg, yield 69%).

[0099] 1 H NMR (400 MHz, Chloroform-d) δ 7.20 (dd, J = 4.9, 1.9 Hz, 3H), 7.11 - 6.97 (m, 3H), 6.83 (d, J = 7.5 Hz, 1H), 6.66 (s, 1H), 3.93 (s, 2H), 3.24 - 3.05 (m, 5H), 2.39 (s, 3H), 1.36 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 194.75, 179.87, 143.57, 138.39, 137.33, 129.23, 128.77, 128.59, 127.23, 122.99, 122.66, 109.33, 50.34, 46.24, 33.19, 26.51, 24.34, 22.00. HRMS (ESI) m / z: [M + H] + calcd for C 20 H 22 NO2S 340.1366; found: 340.1368.

[0100] The above merely describes several specific embodiments of the present application, which are described in more detail and in more detail, but the protection scope of the present application is not limited thereto. Any modification, equivalent replacement and improvement of the above embodiments according to the technical essence of the present application without departing from the technical solution range of the present application, all still belong to the protection scope of the technical solution of the present application.

Claims

1. A method of synthesis of a 2-oxoindole functionalized with a thioester, characterized in that: The 2-oxoindole derivative functionalized by thioester can be obtained by using iodinated acetoanilide derivative and thioester as raw materials, under the joint action of palladium catalyst, ligand and base in organic solvent and through post-treatment; The iodinated acetoanilide derivative is one of N-(2-iodo-5-methylphenyl)-N-methyl methacrylamide, N-(2-iodo-4-methoxyphenyl)-N-methyl methacrylamide, N-(4-chloro-2-iodophenyl)-N-methyl methacrylamide, N-(4-nitro-2-iodophenyl)-N-methyl methacrylamide, 3-iodo-4-(N-methyl methacrylamido)benzoic acid methyl ester, N-benzyl-N-(2-iodophenyl) methacrylamide and N-(2-iodophenyl)-N-methyl-2-phenyl acrylamide; The thioester is one of S-p-tolyl methyl thioester, S-p-methoxyphenyl methyl thioester, S-p-bromophenyl methyl thioester, S-p-chlorophenyl methyl thioester and S-benzyl methyl thioester; The palladium catalyst is palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium trifluoroacetate or bis(acetonitrile)palladium dichloride; The ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; The base is one of potassium acetate, cesium acetate, potassium carbonate and sodium acetate; The organic solvent is ethylene glycol dimethyl ether, dioxane, toluene, tetrahydrofuran or 1,2-dichloroethane; The reaction equation of the synthesis method is as follows: .

2. The method of claim 1, wherein the sulfur ester functionalized 2-oxoindole is synthesized by the reaction of a 2-oxoindole with a sulfur ester of formula (II) ###0001### (II) in the presence of a base. The synthesis method comprises the following specific steps: In the first step, the iodinated acetoanilide derivative and the thioester are added into a reaction tube, and the palladium catalyst, the ligand, the base and the organic solvent are sequentially added; the air in the reaction container is discharged and N2 is filled; the reaction is carried out under stirring and temperature rising to 70-100 DEG C, and the reaction time is 10-16 hours; In the second step, the reaction progress is detected by using thin layer chromatography; when the reaction system is free of raw materials, the reaction is ended; the reaction system is cooled; the organic solvent is removed by rotary evaporation under reduced pressure; the residue is mixed with silica gel and separated by column chromatography to obtain the 2-oxoindole derivative functionalized by thioester.

3. The method of synthesis of a sulphide functionalized 2-oxoindole according to claim 1, characterized in that: The molar ratio of the iodinated acetoanilide derivative, the thioester, the palladium catalyst, the ligand and the base is 0.1:0.2:0.005:0.01:0.3; the concentration of the iodinated acetoanilide derivative in the mixed solution of the organic solvent is 0.1 mol / L.

4. The method of claim 1, wherein the sulfur ester functionalized 2-oxoindole is synthesized by the reaction of a 2-oxoindole with a sulfur ester of formula (II) ###0002### (II) in the presence of a base. The post-treatment step is as follows: after the reaction is ended, the organic solvent is removed by rotary evaporation; and the target product is obtained by column chromatography; the eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1-2:1.

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