A preparation method of 3-(o-cyanobenzyl)indole-2-one compounds

Abstract

The invention discloses a novel method for synthesizing 3-(o-cyanobenzyl)indole-2-one compounds. The method discloses for the first time a novel method for synthesizing a 3-(o-cyanobenzyl)indole-2-one compound by using acrylamide compounds and 3-aminoindazole as raw materials and performing a diarylation reaction through copper-catalyzed oxidation to conveniently construct and obtain a desired target product.

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthesis, and relates to a method for preparing an indole ketone compound, and specifically to a method for preparing a 3-(o-cyanobenzyl)indole-2-one compound. Background Art

[0002] Oxindole is an important building block in natural products, drugs and bioactive molecules, with a wide range of pharmaceutical and biological properties. 2 Kinase inhibitors have been shown to inhibit NeK in living cells. 2 It showed strong inhibitory effects on other mitotic kinases, but did not show inhibitory effects on other mitotic kinases ( J. Med. Chem. 2011, 54 , 4133–4146). Because oxindoles have important biological potential, efficient and mild methods for preparing oxindoles are desirable in the art.

[0003] Acrylamide compounds are important building blocks in organic synthesis due to their active double bonds. The typical method for the transformation of acrylamide compounds is free radical-promoted cyclization, which obtains functional oxindole compounds through free radical addition and then intermolecular cyclization with the N-aryl moiety. Therefore, free radical-promoted difunctionalization reaction pathways using propionamide compounds as raw materials have been widely developed by organic synthetic chemists. For example, the inventor's research group reported that acrylamide compounds were reacted with cyclic ketone oxime and K in the presence of iron catalyst. 2 S 2 O 5 Cyanoalkylsulfonylation / arylation reactions were used to synthesize cyanoalkylsulfonylated indolones (Adv. Synth. Catal. 2020, 362, 3004–3010).

[0004] In the past few years, 3-aminoindazole has become a key intermediate in organic chemistry and pharmaceutical industry. 3-aminoindazole can undergo two different types of reactions, including denitrogenation coupling reaction and condensation reaction with carbonyl compounds. Recently, Song's group reported the copper-catalyzed oxidative denitrogenation coupling reaction of 3-aminoindazole with enamines to prepare 1-aminoisoquinoline (Org. Lett. 2019, 21, 8869–8873). In 2018, the group reported the denitrogenation cross-coupling reaction of 3-aminoindazole with aromatic heterocycles (Org. Lett. 2018, 20, 6161–6165). In 2019, the group reported the use of 3-aminoindazole as an arylation agent to synthesize aromatic enamines via Cu-catalyzed CH arylation (Org. Chem. Front. 2020, 7, 25–29). In 2019, the Bai group reported the regioselective synthesis of 4-arylpyrimidine[1,2-b]indazoles from 3-aminoindole, ethylamine and aldehyde compounds by aerobic oxidation promoted by NH4I (Org. Lett. 2019, 21, 6074–6078). In 2018, the Song group provided a one-pot method to generate pyrimidine[1,2- b ]-indazole (Adv. Synth. Catal. 2018, 360,1943–1948).

[0005] Although 3-aminoindazole is widely used in organic synthesis, there is still a lack of effective methods for selectively oxidizing the carbon-carbon double bonds in acrylamide and 3-aminoindazole to diarylate. Inspired by these results and after intensive research, the inventor believes that 3-aminoindazole may provide a cyano-substituted aryl group with the assistance of a Cu catalyst and an oxidant through two CN bond cleavages. Then, the aryl group can react with acrylamide to obtain very useful oxindole derivatives in a reactor. After in-depth research and a large number of innovative experiments, the inventor proposed a copper-catalyzed oxidation diaryl reaction in the present invention, using acrylamide compounds and 3-aminoindazole as raw materials, for the synthesis of 3-(o-cyanobenzyl)indole-2-one compounds. Summary of the invention

[0006] The purpose of the present invention is to enrich the synthesis strategies of the prior art and provide a new method for synthesizing 3-(o-cyanobenzyl)indol-2-one compounds. The method discloses for the first time a diarylation reaction using acrylamide compounds and 3-aminoindazole as raw materials through copper-catalyzed oxidation to conveniently construct and obtain the desired target product.

[0007] A method for preparing a 3-(o-cyanobenzyl)indole-2-one compound provided by the present invention comprises the following steps:

[0008] The N-aryl acrylamide compound shown in Formula 1, the 3-aminoindazole compound shown in Formula 2, a copper catalyst, an oxidant and an organic solvent are sequentially added to a Schlenk seal reaction reactor, and the atmosphere in the reactor is replaced with an inert atmosphere, followed by heating and stirring for reaction. After the reaction is complete, the 3-(o-cyanobenzyl)indole-2-one compound shown in Formula 3 is obtained by post-treatment; the reaction formula is as follows:

[0009] ;

[0010] In the above reaction formula, R 1 Selected from substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 2-20 Heteroaryl, substituted or unsubstituted C 6-20 Aryl-C 1-20 Alkyl, C 2-20 Acyl, C 1-20 Alkoxycarbonyl.

[0011] R 2 , R 5 independently represent one or more (e.g., 2, 3, 4 and / or 5) substituents on the attached benzene ring, each R 2 , R 5 are independently selected from hydrogen, halogen, -NO 2 , -CN, substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted C 1-20 Alkoxy, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 6-20 Aryloxy, C 2-20 Acyl, C 1-20 Alkoxycarbonyl; or two adjacent R 2 or two adjacent R 5 The substituents are connected to each other and to the two R 2 or two R 5 The benzene ring carbon atoms of the substituents are taken together to form a five- to seven-membered ring structure which may or may not contain heteroatoms.

[0012] R 3 Selected from substituted or unsubstituted C 1-20 Alkyl, substituted or unsubstituted C 6-20 Aryl-C 1-20 Alkyl, substituted or unsubstituted C 1-20 Alkyl-C(O)-OC 1-6alkyl.

[0013] R 4 Selected from hydrogen or C 1-20 alkyl.

[0014] Preferably, in the above reaction formula, R 1 Selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted C 6-12 Aryl-C 1-3 alkyl.

[0015] R 2 , R 5 independently represent one or more (e.g., 2, 3, 4 and / or 5) substituents on the attached benzene ring, each R 2 , R 5 are independently selected from hydrogen, halogen, -NO 2 , -CN, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-12 Aryl, substituted or unsubstituted C 6-12 Aryloxy, C 1-6 Alkoxycarbonyl; or two adjacent R 2 or two adjacent R 5 The substituents are connected to each other and to the two R 2 or two R 5 The benzene ring carbon atoms of the substituents are taken together to form a five- to seven-membered ring structure which may or may not contain heteroatoms.

[0016] R 3 Selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-12 Aryl-C 1-3 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C(O)-OC 1-3 alkyl.

[0017] R 4 Selected from hydrogen.

[0018] In any part of the present invention, the term "substituted or unsubstituted" means substituted by one or more substituents, each of which is independently selected from halogen (fluorine, chlorine, bromine, iodine), methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, phenoxy, -NO 2 、-CN.

[0019] In any part of the present invention, examples of the "alkyl" part having a limited number of carbon atoms (including the "alkyl" part in all groups such as alkoxy and acyl) can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hexyl, etc.

[0020] In any part of the present invention, examples of "aryl" moieties (including aryloxy) having a limited number of carbon atoms may be selected from phenyl, naphthyl, anthracenyl, and phenanthryl.

[0021] In any part of the present invention, the "substituted or unsubstituted C 2-20 The heteroatoms in the "heteroaryl" and "five to seven membered cyclic structure containing or not containing heteroatoms" are independently selected from O, N, and S.

[0022] Therefore, most preferably, in the above reaction formula of the present invention, R 1 Selected from methyl, phenyl, benzyl, 4-methylbenzyl, 4-fluorobenzyl.

[0023] R 2 Selected from hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, iodine, -CF 3 、-NO 2 , -CO 2 Et, phenoxy; or two adjacent R 2 The substituents are connected to each other and to the two R 2 The benzene ring carbon atoms of the substituents together form a benzene ring structure.

[0024] R 3 Selected from methyl, benzyl, CH 2 OAc.

[0025] R 4 Selected from hydrogen.

[0026] R 5 Selected from hydrogen, methyl, fluorine, chlorine, bromine, iodine, methoxy, -CF 3 、-NO 2 .

[0027] According to the aforementioned preparation method of the present invention, wherein the copper catalyst is selected from Cu(OAc) 2 , CuBr, CuCl, preferably Cu(OAc) 2 .

[0028] According to the aforementioned preparation method of the present invention, wherein the oxidant is selected from TBHP (tert-butyl peroxide), TBPB (tert-butyl perbenzoate), DTBP (di-tert-butyl peroxide), CHP (isopropylbenzene hydroperoxide), PhI (OAc) 2Preferably, it is TBHP (tert-butyl peroxide).

[0029] According to the aforementioned preparation method of the present invention, the molar ratio of the N-aryl acrylamide compound shown in Formula 1, the 3-aminoindazole compound shown in Formula 2, the copper catalyst, and the oxidant is 1: (1~3): (0.01~0.04): (1~5); preferably, the molar ratio of the N-aryl acrylamide compound shown in Formula 1, the 3-aminoindazole compound shown in Formula 2, the copper catalyst, and the oxidant is 1: 2: 0.02: 2.5.

[0030] According to the aforementioned preparation method of the present invention, the organic solvent is selected from any one of acetonitrile and DMSO, preferably acetonitrile.

[0031] According to the aforementioned preparation method of the present invention, wherein the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably an argon atmosphere.

[0032] According to the aforementioned preparation method of the present invention, wherein the reaction temperature of the heating and stirring reaction is 110-130°C, preferably 120°C; the reaction time of the heating and stirring reaction is 12-48h, preferably 24h.

[0033] According to the aforementioned preparation method of the present invention, wherein the post-processing operation is as follows:

[0034] The reaction mixture was washed with brine, the aqueous phase was extracted three times with EtOAc, the organic phases were combined and washed with anhydrous Na 2 SO 4 The residue was dried and concentrated in vacuo to obtain a residue, which was separated by silica gel column chromatography to obtain a pure 3-(o-cyanobenzyl)indol-2-one compound of formula 3. DETAILED DESCRIPTION

[0035] The present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are conventional methods in the art, and the reagents and raw materials used can be purchased through conventional commercial channels and / or prepared by reference to typical synthesis methods in the field of organic synthesis.

[0036] Example 1-26 Reaction Condition Optimization Test

[0037] Using the acrylamide compound shown in Formula 1a and the 3-aminoindazole shown in Formula 2a as templates, a reaction condition optimization test was conducted, and representative test results were screened out and shown in Table 1. The reaction formula is as follows:

[0038] .

[0039] Table 1:

[0040]

[0041] In Table 1, except for the reaction condition variables shown in Examples 2-26 which are different from those in Example 1, the other reaction conditions and operations are the same.

[0042] The specific operations of Example 1 are as follows:

[0043] The acrylamide compound represented by formula 1a (0.2 mmol), 3-aminoindazole represented by formula 2a (0.4 mmol, 2 eqiuv), Cu(OAc) were added to the Schlenk seal reaction reactor in sequence. 2 (20 mol%), aq. TBHP (0.5 mmol, 2.5 eqiuv) and CH 3 CN (2 mL). The atmosphere in the reactor was then replaced with argon three times (1 atm), and the reaction was carried out at 120 °C (oil bath temperature) for 24 h until the starting materials were completely consumed (TLC and GC-MS monitoring). After the reaction was completed, the reaction mixture was washed with brine, the aqueous phase was extracted with EtOAc (3 × 10 mL), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying and vacuum concentration gave a residue, which was separated by silica gel column chromatography (n-hexane / ethyl acetate, volume ratio = 10: 1 to 5: 1) to give the target product shown in Formula 3. 73%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.39-7.30(m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 7.20-7.15 (m, 2H), 7.07-7.03 (m, 1H), 6.63(d, J = 8.0 Hz, 1H), 3.41-3.34 (m, 2H), 3.10 (s, 3H), 1.53 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.6, 142.6, 140.4, 132.4, 131.9, 131.5, 130.0, 128.1,127.1, 124.1, 122.5, 118.3, 113.7, 107.7, 50.0, 41.8, 26.0, 23.2; HRMS (ESI-TOF) m / z : C 18 H 17N 2 O (M + H) + calcd for 277.1335, found 277.1341.

[0044] As can be seen from Table 1, the best reaction conditions for the copper-catalyzed oxidation diarylation reaction of the present invention are the reaction conditions of Example 1. On the basis of obtaining the best reaction conditions, the inventors further investigated the universality of the best reaction conditions for the reaction substrate substituents by changing the types of reaction substrates and performing the reaction according to the reaction conditions of Example 1. The reaction formula is as follows:

[0045] .

[0046] The result is as follows:

[0047]

[0048] The characterization spectrum of the target compound is as follows.

[0049] Yield: 37.7 mg, 65%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.45 (d, J = 7.6 Hz, 1H), 7.35-7.32 (m, 1H), 7.26-7.20 (m, 2H), 6.93 (t, J = 8.0 Hz,1H), 6.83 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 3.39 (d, J = 8.0 Hz,1H), 3.24-3.20 (m, 4H), 2.01 (s, 3H), 1.51 (s, 3H); 13 C NMR (100 MHz, CDCl 3 )δ: 179.9, 142.8, 139.4, 138.6, 34.8, 132.5, 130.7, 128.2, 127.2, 123.9,122.2, 119.0, 115.3, 108.0, 49.1, 38.8, 26.3, 22.6, 20.3; HRMS (ESI-TOF) m / z :C 19 H 19 N 2 O (M + H) +calcd for 291.1492, found 291.1497.

[0050] Yield: 33.5 mg, 57%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.28-7.26(m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.02-6.95 (m, 2H), 6.86 (t, J = 8.4 Hz,1H), 6.59 (d, J = 7.6 Hz, 1H), 3.34-3.26 (m, 2H), 3.04 (s, 3H), 1.45 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.3, 163.0 (d, J = 256.7 Hz, 1C), 142.7, 142.5,133.4 (d, J = 8.1 Hz, 1C), 131.2, 128.4, 125.6, (d, J = 3.4 Hz, 1C), 124.0,122.7, 114.2 (d, J = 19.4 Hz, 1C), 113.4, 107.8, 103.2 (d, J = 15.0 Hz, 1C),49.9, 41.4, 26.1, 23.4; 19 F NMR (282 MHz, CDCl 3 ) δ: -105.8 (s, 1F); HRMS (ESI-TOF) m / z : C 18 H 16 19 FN 2 O (M + H) + calcd for 295.1241, found 295.1247.

[0051] Yield: 33.5 mg, 54%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.34 (d, J= 7.6 Hz, 1H), 7.30-7.18 (m, 3H), 7.14 (d, J = 7.6 Hz, 1H), 7.08 (t, J =8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 3.40 (s, 2H), 3.11 (s, 3H), 1.52 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.3, 143.0, 142.5, 136.7, 132.4, 131.2,128.4, 128.1, 128.0, 124.1, 122.7, 115.4, 114.7, 107.9, 49.9, 42.0, 26.1,23.3; HRMS (ESI-TOF) m / z : C 18 H 16 35 C1N 2 O (M + H) + calcd for 311.0946, found311.0951.

[0052] Yield: 34.7 mg, 49%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.42-7.40(m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23-7.17 (m, 3H), 7.08 (t, J = 7.6 Hz,1H), 6.67 (d, J = 7.6 Hz, 1H), 3.41 (s, 2H), 3.11 (s, 3H), 1.52 (s, 3H); 13 CNMR (100 MHz, CDCl 3 ) δ: 179.3, 143.3, 142.5, 132.5, 131.2 (2C), 128.6, 128.4,125.3, 124.1, 122.7, 117.1, 116.6, 107.9, 49.9, 42.2, 26.1, 23.3; HRMS (ESI-TOF) m / z : C 18H 16 79 Bn 2 O (M + H) + calcd for 355.0441, found 355.0446.

[0053] Yield: 49.0 mg, 80%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.35 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.70-6.65 (m, 3H), 3.72 (s, 3H), 3.35 (s, 2H), 3.12 (s, 3H),1.52 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.6, 162.1, 142.7, 142.6, 133.8,131.6, 128.1, 124.1, 122.6, 118.7, 114.5, 113.8, 107.7, 105.4, 55.4, 50.0,41.7, 26.1, 23.4; HRMS (ESI-TOF) m / z : C 19 H 19 N 2 O 2 (M + H) + calcd for 3007.1441, found 307.1447.

[0054] Yield: 41.8 mg, 72%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.30 (d, J = 7.6 Hz, 1H), 7.21-7.03 (m, 5H), 6.65 (d, J = 7.6 Hz, 1H), 3.36-3.29 (m,2H), 3.11 (s, 3H), 2.24 (s, 3H), 1.51 (s, 3H);13 C NMR (100 MHz, CDCl 3 ) δ:179.7, 142.6, 137.3, 137.0, 132.9, 132.6, 131.7, 129.9, 128.1, 124.1, 122.5,118.5, 113.5, 107.7, 49.9, 41.3, 26.1, 23.2, 20.6; HRMS (ESI-TOF) m / z :C 19 H 19 N 2 O (M + H) + calcd for 291.1492, found 291.1497.

[0055] Yield: 38.8 mg, 66%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.27 (d, J = 7.6 Hz, 1H), 7.15-7.11 (m, 2H), 7.02-6.98 (m, 3H), 6.58 (d, J = 7.6 Hz,1H), 3.28 (s, 2H), 3.03 (s, 3H), 1.45 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ:179.3, 160.6 (d, J = 247.7 Hz, 1C), 136.5 (d, J = 3.8 Hz, 1C), 132.0, 131.9,131.3, 128.3, 124.1, 122.6, 119.7 (d, J = 20.8 Hz, 1C), 118.9(d, J = 24.1 Hz,1C), 117.2, 114.8 (d, J = 9.2 Hz, 1C), 107.8, 50.0, 41.0, 26.1, 23.2; 19 F NMR (282 MHz, CDCl 3 ) δ: -113.2 (s, 1F); HRMS (ESI-TOF) m / z : C 18 H16 19 FN 2 O (M + H) + calcd for 295.1241, found 295.1247.

[0056] Yield: 35.1 mg, 51%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.65 (s,1H), 7.60 (d, J = 8.4 Hz, 1H), 7.40-7.33 (m, 2H), 7.24-7.19 (m, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 3.44 (s, 2H), 3.11 (s, 3H), 1.55(s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.0, 144.4, 142.4, 131.0, 130.8, 129.2(q, J = 3.0 Hz, 1C), 128.5 (t, J = 3.7 Hz, 1C), 126.9 (d, J = 3.3 Hz, 1C),126.5, 124.2, 122.8 (q, J = 270.7 Hz, 1C), 122.7, 116.9, 114.6, 49.9, 41.5,26.1, 23.4; 19 F NMR (282 MHz, CDCl 3 ) δ: -63.0 (s, 3F); HRMS (ESI-TOF) m / z :C 19 H 16 19 F 3 N 2 O (M + H) + calcd for 345.1209, found 345.1215.

[0057] Yield: 36.0 mg, 56%; yellow oily liquid; 1 H NMR (400 MHz, CDCl3 ) δ: 8.25 (s,1H), 8.19 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.2 Hz,1H), 7.22 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz,1H), 3.49 (s, 2H), 3.11 (s, 3H), 1.57 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ:178.8, 147.5, 146.4, 142.3, 131.3, 130.7, 128.7, 127.3, 126.4, 124.0, 122.9,116.2, 115.1, 108.1, 50.0, 41.6, 26.1, 13.5; HRMS (ESI-TOF) m / z : C 18 H 16 N 3 O 3 (M+H) + calcd for 322.1186, found 322.1192.

[0058] Yield: 38.9 mg, 67%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.30-7.25(m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.06-7.03 (m, 2H), 6.97 (d, J = 8.0 Hz,1H), 6.64 (d, J = 8.0 Hz, 1H), 3.36-3.28 (m, 2H), 3.11 (s, 3H), 2.28 (s, 3H),1.52 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ: 179.6, 142.8, 142.5, 140.2, 132.2,131.6, 130.7, 128.1, 127.9, 124.1, 122.4, 118.6, 110.7, 107.6, 49.9, 41.7,26.0, 23.0, 21.6; HRMS (ESI-TOF) m / z : C 19 H 19 N 2 O (M + H) + calcd for 291.1492, found 291.1497.

[0059] Yield: 37.5 mg, 53%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.39 (s,1H), 7.32-7.30 (m, 2H), 722-7.17 (m, 2H), 7.0 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 3.33 (s, 2H), 3.14 (s, 3H), 1.53 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.2, 142.5, 142.2, 133.3, 133.1, 131.1, 130.5, 128.3, 127.0,124.0, 122.6, 117.6, 112.5, 107.9, 49.8, 41.6, 26.0, 22.9; HRMS (ESI-TOF) m / z : C 18 H 16 79 Bn 2 O (M + H) + calcd for 355.0441, found 355.0446.

[0060] Yield: 29.0 mg, 41%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.77 (d, J = 8.0 Hz, 1H), 7.59 (d,J = 7.6 Hz, 1H), 7.28-27 (m, 1H), 7.20 (t, J = 8.0Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.87-6.85 (m, 2H), 3.49-3.42 (m, 2H), 3.24(s, 3H), 1.56 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.0, 142.8, 140.0, 137.4,132.9, 132.0, 128.5, 128.2, 127.1, 123.3, 122.2, 117.6, 116.4, 108.2, 48.7,41.7, 26.3, 22.7; HRMS (ESI-TOF) m / z : C 18 H 16 79 Bn 2 O (M + H) + calcd for 355.0441, found 355.0446.

[0061] Yield: 47.3 mg, 70%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.50-7.44(m, 3H), 7.42-7.36 (m, 3H), 7.31 (d, J = 7.2 Hz, 1H), 7.23-7.19 (m, 1H), 7.16-7.07 (m, 4H), 6.57-6.54 (m, 1H), 3.49 (s, 2H), 1.67 (s, 3H); 13 C NMR (100MHz, CDCl 3 ) δ: 178.9, 142.6, 140.3, 134.2, 132.5, 132.1, 131.2, 130.3, 129.5,128.1, 128.0, 127.2, 126.4, 124.6, 123.0, 118.4, 113.7, 109.0, 50.2, 42.2,23.6; HRMS (ESI-TOF) m / z : C 23 H 19N 2 O (M + H) + calcd for 339.1492, found339.1497.

[0062] Yield: 53.5 mg, 76%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.41-7.38(m, 2H), 7.23-7.17 (m, 6H), 7.08-7.00 (m, 4H), 6.54-6.52 (m, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 16.0 Hz, 1H), 3.50-3.42 (m, 2H), 1.58 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.5, 141.9, 140.3, 135.5, 132.5, 132.2, 131.5,130.4, 128.6, 128.1, 127.4, 127.1, 127.0, 124.3, 122.5, 118.3, 113.7, 108.8,50.1, 43.6, 41.4, 24.4; HRMS (ESI-TOF) m / z : C 21 H 21 N 2 O (M + H) + calcd for353.1648, found 353.1654.

[0063] Yield: 45.4 mg, 62%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.39-7.37(m, 2H), 7.22-7.18 (m, 3H), 7.07-7.01 (m, 4H), 6.90 (d, J = 8.0 Hz, 2H), 6.53(d, J = 8.0 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.68 (d, J= 15.6 Hz, 1H), 3.49-3.41 (m, 2H), 2.30 (s, 3H), 1.57 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ:179.5, 141.9, 140.4, 137.1, 132.5, 132.5, 132.2, 131.5, 130.4, 129.2, 128.1,127.1, 127.0, 124.2, 122.5, 118.4, 113.6, 108.9, 50.0, 43.4, 41.4, 24.4,21.0; HRMS (ESI-TOF) m / z : C 25 H 23 N 2 O (M + H) + calcd for 367.1805, found367.1810.

[0064] Yield: 39.2 mg, 53%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.42-7.40(m, 2H), 7.23-7.17 (m, 3H), 7.10-7.05 (m, 2H), 7.00-7.96 (m, 2H), 6.90 (t, J = 8.8 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 4.66 (d, J = 15.6 Hz, 1H), 3.48-3.41 (m, 2H), 1.58 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ:179.4, 162.0 (d, J = 244.5 Hz, 1C), 141.6, 140.3, 132.6, 132.1, 131.5, 131.3(d, J = 3.2 Hz, 1C), 130.4, 128.9, 128.8, 128.1, 127.1, 124.4, 122.7, 116.0(d, J= 455.8 Hz, 1C), 115.5 (d, J = 21.4 Hz, 1C), 108.7, 50.0, 42.9, 41.4,24.3; 19 F NMR (282 MHz, CDCl 3 ) δ: -114.8 (s, 1F); HRMS (ESI-TOF) m / z :C 24 H 20 19 FN 2 O (M + H) + calcd for 371.1554, found 371.1560.

[0065] Yield: 56.0 mg, 76%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.43-7.30(m, 4H), 7.24-7.21 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.93-6.88 (m, 4H), 6.65-6.63 (m, 1H), 3.36-3.29 (m, 2H), 3.13 (s, 3H), 1.49 (s, 3H); 13 C NMR (100MHz, CDCl 3 ) δ: 179.4, 158.2, 152.4, 140.1, 138.6, 133.3, 132.4, 132.0, 130.2,129.6, 127.2, 122.7, 119.4, 118.0, 117.9, 116.7, 113.9, 108.5, 50.0, 41.6,26.2, 22.8; HRMS (ESI-TOF) m / z : C 21 H 21 N 2 O 2 (M + H) + calcd for 369.1598, found369.1603.

[0066] Yield: 47.0 mg, 81%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3) δ: 7.38-7.35(m, 2H), 7.23 (d J = 8.8 Hz, 1H), 7.18-7.14 (m, 2H), 6.96 (d, J = 8.0 Hz,1H), 6.49 (d, J = 8.0 Hz, 1H), 3.35 (s, 2H), 3.06 (s, 3H), 2.34 (s, 3H), 1.52(s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.4, 140.4, 140.1, 132.4, 130.1, 131.8,131.4, 130.1, 128.2, 127.0, 125.2, 118.3, 113.7, 107.3, 50.0, 41.9, 26.3,23.1, 21.0; HRMS (ESI-TOF) m / z : C 19 H 19 N 2 O (M + H) + calcd for 291.1492, found291.1497.

[0067] Yield: 46.5 mg, 79%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.36 (t, J = 8.0 Hz, 2H), 7.25-7.23 (m, 2H), 7.21-7.16 (m, 2H), 6.57 (d, J = 8.4 Hz,1H), 3.42-3.31 (m, 2H), 3.11 (s, 3H), 1.52 (s, 3H), 1.30 (s, 9H); 13 C NMR (100MHz, CDCl 3 ) δ: 179.8, 145.6, 140.6, 140.1, 132.2, 131.9, 131.1, 130.1, 127.1,124.8, 121.3, 118.3, 113.9, 107.2, 50.1, 41.8, 34.6, 31.5, 26.1, 23.1; HRMS(ESI-TOF) m / z : C22 H 25 N 2 O (M + H) + calcd for 333.1961, found 333.1967.

[0068] Yield: 37.1 mg, 63%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.44-7.36(m, 2H), 7.24-7.19 (m, 2H), 7.05-7.02 (m, 1H), 6.91-6.86 (m, 1H), 6.58-6.55(m, 1H), 3.36 (s, 2H), 3.09 (s, 3H), 1.52 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ:179.1, 159.1 (d, J = 239.8 Hz, 1C), 139.9, 138.5, 133.2 (d, J = 7.9 Hz, 1C),132.5, 132.1, 130.1, 127.3, 118.2, 114.4 (d, J = 23.3 Hz, 1C), 112.4 (d, J =24.8 Hz, 1C), 108.2 (d, J = 8.1 Hz, 1C), 50.3, 50.3, 41.6, 26.2, 23.0; 19 F NMR (282 MHz, CDCl 3 ) δ: -120.1 (s, 1F); HRMS (ESI-TOF) m / z : C 18 H 16 19 FN 2 O (M + H) + calcd for 295.1241, found 295.1247.

[0069] Yield: 36.6 mg, 59%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3) δ: 7.44-7.39(m, 2H), 7.27-7.15 (m, 4H), 6.57 (d, J = 8.4 Hz, 1H), 3.39-3.31 (m, 2H), 3.08(s, 3H), 1.52 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 178.9, 141.2, 139.8, 133.2,132.5, 132.0, 130.1, 128.1, 127.9, 127.3, 124.7, 118.1, 113.8, 108.6, 50.1,41.7, 26.2, 22.8; HRMS (ESI-TOF) m / z : C 18 H 16 35 C1N 2 O (M + H) + calcd for 311.0946, found 311.0951.

[0070] Yield: 40.4 mg, 57%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.45-7.37(m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 6.8 Hz, 2H), 6.52 (d, J = 8.0Hz, 1H), 3.38-3.31 (m, 2H), 3.08 (s, 3H), 1.52 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 178.8, 141.6, 139.8, 133.6, 132.5, 132.0, 131.0, 130.1, 127.5,127.3, 118.0, 115.2, 113.8, 109.1, 50.1, 41.7, 26.1, 22.8; HRMS (ESI-TOF) m / z : C 18 H 16 79 Bn 2 O (M + H)+ calcd for 355.0441, found 355.0446.

[0071] Yield: 41.0 mg, 51%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.54-7.50(m, 2H), 7.46-7.43 (m, 1H), 7.41-7.37 (m, 1H), 7.24-7.20 (m, 2H), 6.43 (d, J = 8.0 Hz, 1H), 3.37-3.29 (m, 2H), 3.07 (s, 3H), 1.51 (s, 3H); 13 C NMR (100MHz, CDCl 3 ) δ: 178.7, 142.3, 139.8, 137.0, 133.9, 133.1, 132.5, 132.0, 130.2,127.4, 118.1, 113.8, 109.7, 85.1, 50.0, 41.7, 26.1, 22.8; HRMS (ESI-TOF) m / z :C 18 H 16 79 IN 2 O (M + H) + Calcd for 403.0302, found 403.0307.

[0072] Yield: 33.7 mg, 49%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.49 (d, J = 8.0 Hz, 1H), 7.44-7.41 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 6.74 (d, J =8.4 Hz, 1H), 3.42-3.31 (m, 2H), 3.15 (s, 3H), 1.55 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.5, 145.6, 139.6, 132.5, 132.1 (d, J= 3.4 Hz, 1C), 130.2,128.3, 127.5, 126.0 (t, J = 4.0 Hz, 1C), 124.3 (q, J = 270.0 Hz, 1C), 121.3(q, J = 3.6 Hz, 1C), 117.8, 113.9, 107.5, 49.7, 41.7, 26.3, 22.6; 19 F NMR (282MHz, CDCl 3 ) δ: -61.6 (s, 3F), HRMS (ESI-TOF) m / z : C 19 H 16 19 F 3 N 2 O (M + H) + calcdfor 345.1209, found 345.1215.

[0073] Yield: 27.6 mg, 43%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.54-7.50(m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.40-7.37 (m, 1H), 7.22 (d, J = 8.0 Hz,2H), 6.42 (d, J = 8.0 Hz, 1H), 3.37-3.29 (m, 2H), 3.06 (s, 3H), 1.51 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 178.7, 142.3, 139.8, 137.0, 133.9, 133.1, 132.5,132.0, 130.2, 127.4, 118.1, 113.8, 109.7, 85.1, 50.0, 41.8, 26.1, 22.8; HRMS(ESI-TOF) m / z : C 18 H 16 N 3 O 3 (M + H) +calcd for 322.1186, found 322.1192.

[0074] Yield: 31.3 mg, 45%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.98-7.96(m, 1H), 7.89 (s, 1H), 7.41-7.27 (m, 2H), 7.21-7.19 (m, 2H), 6.71 (d, J = 8.0Hz, 1H), 4.45-4.30 (m, 2H), 3.41-3.32 (m, 2H), 3.14 (s, 3H), 1.55 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.8, 166.3, 146.7,139.8, 132.6, 131.9, 130.9, 130.1, 127.3, 125.2, 117.9, 114.0, 107.4, 60.9,49.5, 41.7, 26.3, 22.7, 14.3; HRMS (ESI-TOF) m / z : C 21 H 21 C1N 2 O 3 (M + H) + calcdfor 349.1547, found 349.1552.

[0075] Yield: 37.3 mg, 61%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.38 (d, J = 7.6 Hz, 1H), 7.31-7.27 (m, 1H), 7.17-7.12 (m, 3H), 6.58 (d, J = 8.4 Hz,1H), 6.26 (d, J = 7.6 Hz, 1H), 3.89 (s, 3H), 3.63 (d, J = 13.2 Hz, 1H), 3.35(d, J= 13.2 Hz, 1H), 3.02 (s, 3H), 1.61 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ:179.8, 156.2, 143.9, 140.9, 132.6, 131.6, 130.0, 129.4, 126.8, 117.9, 117.1,113.3, 105.6, 100.8, 55.1, 50.2, 40.0, 26.2, 21.1; HRMS (ESI-TOF) m / z :C 19 H 19 N 2 O 2 (M + H) + calcd for 307.1441, found 307.1447.

[0076] Yield: 30.4 mg, 49%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.48 (d, J = 8.0 Hz, 1H), 7.29-7.27 (m, 1H), 7.20-7.16 (m, 2H), 7.04-7.00 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 3.50 (d, J = 14.0 Hz,1H), 3.02 (s, 3H), 1.70 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 178.2, 144.7,139.8, 132.8, 131.7, 131.2, 130.0, 129.5, 128.5, 127.2, 123.8, 117.8, 113.6,106.4, 50.8, 39.3, 26.2, 20.5; HRMS (ESI-TOF) m / z : C 18 H 16 35 C1N 2 O (M + H) +calcdfor 311.0946, found 311.0951.

[0077] ': Yield: 30.4 mg, 49%; Yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.42-7.35 (m, 2H), 7.27-7.18 (m, 3H), 7.03 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 3.37(s, 2H), 3.07 (s, 3H), 1.51 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.5, 143.8,140.1, 133.9, 132.5, 132.1, 129.9, 129.8, 127.3, 125.1, 122.3, 118.3, 113.7,108.5, 49.9, 41.9, 26.2, 23.3; HRMS (ESI-TOF) m / z : C 18 H 16 35 C1N 2 O (M + H) + calcdfor 311.0946, found 311.0951.

[0078] Yield: 45.8 mg, 65%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.45-7.43(m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.33-7.30 (m, 1H), 7.26-7.25 (m, 1H), 7.16-7.12 (m, 1H), 7.06-7.00 (m, 5H), 6.86-6.83 (m, 2H), 6.36-6.34 (m, 1H),3.61-3.53 (m, 2H), 3.37 (d, J = 12.8 Hz, 1H), 3.21 (d, J = 12.8 Hz, 1H), 2.83(s, 3H); 13 C NMR (100 MHz, CDCl3 ) δ: 178.0, 143.1, 140.4, 135.2, 132.4, 132.1,130.1, 129.8, 128.7, 128.1, 127.5, 127.0, 126.5, 124.9, 122.1, 118.5, 113.7,107.4, 56.4, 43.8, 40.5, 25.7; HRMS (ESI-TOF) m / z : C 24 H 21 N 2 O (M + H) + calcd for353.1648, found 353.1654.

[0079] Yield: 39.4 mg, 59%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.40-7.34(m, 3H), 7.24-7.19 (m, 3H), 7.05 (t, J = 8.0 Hz, 1H), 6.64 (d, J = 7.6 Hz,1H), 4.65 (d, J = 10.8 Hz, 1H), 4.30 (d, J = 11.2 Hz, 1H), 3.53 (d, J = 13.6Hz, 1H), 3.40 (d, J = 13.6 Hz, 1H), 3.11 (s, 3H), 1.97 (s, 3H); 13 C NMR (100MHz, CDCl 3 ) δ: 176.3, 170.3, 143.3, 139.1, 132.5, 132.1, 130.1, 128.8, 127.4,127.3, 125.0, 122.6, 118.1, 113.9, 107.8, 66.4, 53.7, 37.2, 26.2, 20.6; HRMS(ESI-TOF) m / z : C 20 H 19 N 2 O 3 (M + H) +calcd for 335.1390, found 335.1396.

[0080] Yield: 31.5 mg, 47%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.27 (s,1H), 8.21-8.19 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H),7.01-6.93 (m, 2H), 3.50-3.42 (m, 2H), 3.40 (s, 3H), 2.44 (s, 3H), 1.53 (s,3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 179.5, 147.6, 146.4, 140.1, 132.4, 131.5,131.4, 127.4, 126.4, 122.8, 121.8, 119.7, 116.3, 115.2, 49.3, 41.8, 29.5,24.0, 18.9; HRMS (ESI-TOF) m / z : C 19 H 18 N 3 O 3 (M + H) + calcd for 336.1343, found336.1348.

[0081] Yield: 37.9 mg, 54%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.26 (s,1H), 8.21-8.18 (m, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.06-7.00 (m, 2H), 6.79-6.74 (m, 1H), 3.78 (s, 3H), 3.51-3.43 (m, 2H), 3.38 (s, 3H), 1.53 (s, 3H); 13 CNMR (100 MHz, CDCl 3) δ: 179.0, 147.6, 146.4, 145.1, 132.4, 131.4, 130.0,128.7, 127.4, 126.5, 123.5, 116.5, 115.0, 112.2, 55.7, 50.1, 41.6, 29.5,24.0; HRMS (ESI-TOF) m / z : C 19 H 18 N 3 O 4 (M + H) + calcd for 352.1292, found352.1297.

[0082] Yield: 45.3 mg, 61%; yellow oily liquid; 1 H NMR (400 MHz, CDCl 3 ) δ: 8.17 (s,1H), 8.04 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.59-7.55 (m, 2H),7.49 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H),6.82 (d, J = 7.6 Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 3.50 (s, 3H), 3.46 (d, J = 14.0 Hz, 1H), 1.94 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 171.3, 148.0, 146.2,135.8, 135.0, 133.1, 131.3, 127.3, 127.2, 127.1, 126.5, 126.1, 123.8, 122.9,119.4, 115.7, 115.0, 108.8, 48.8, 47.9, 29.8, 28.2; HRMS (ESI-TOF) m / z :C 22 H 18 N 3 O3 (M + H) + calcd for 372.1343, found 372.1348.

[0083] The above-described embodiments are only preferred embodiments of the present invention, and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious changes made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing 3-(o-cyanobenzyl)indole-2-one compounds, characterized in that: The steps include: The N-aryl acrylamide compound represented by Formula 1, the 3-aminoindazole compound represented by Formula 2, a copper catalyst, an oxidant and an organic solvent are sequentially added to a Schlenk sealed reactor, and the atmosphere in the reactor is replaced with an inert atmosphere, followed by heating and stirring for reaction. After the reaction is complete, a 3-(o-cyanobenzyl)indole-2-one compound represented by Formula 3 is obtained by post-treatment; the reaction formula is as follows: ； R 1 Selected from methyl and phenyl; R 2 is selected from hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, bromine, iodine, -CF3, -NO2, phenoxy; R 3 Selected from benzyl; R 4 Selected from hydrogen; R 5 is selected from hydrogen, methyl, fluorine, chlorine, bromine and iodine; The copper catalyst is Cu(OAc)2; the oxidant is TBHP (tert-butyl peroxide); and the organic solvent is acetonitrile.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the N-aryl acrylamide compound shown in Formula 1, the 3-aminoindazole compound shown in Formula 2, the copper catalyst, and the oxidant is 1: (1-3): (0.01-0.04): (1-5).

3. The preparation method according to claim 2, characterized in that: The molar ratio of the N-aryl acrylamide compound shown in Formula 1, the 3-aminoindazole compound shown in Formula 2, the copper catalyst, and the oxidant is 1: 2: 0.02: 2.

5.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The inert atmosphere is a nitrogen atmosphere or an argon atmosphere.

5. The preparation method according to claim 4, characterized in that: The inert atmosphere is argon atmosphere.

6. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of the heating and stirring reaction is 110-130° C.; the reaction time of the heating and stirring reaction is 12-48 hours.

7. The preparation method according to claim 6, characterized in that: The reaction temperature of the heating and stirring reaction is 120° C.; the reaction time of the heating and stirring reaction is 24 hours.

8. The preparation method according to any one of claims 1 to 3, characterized in that: The post-processing operation is as follows: The reaction mixture was washed with brine, the aqueous phase was extracted three times with EtOAc, the organic phases were combined and dried over anhydrous Na2SO4, and concentrated in vacuo to obtain a residue, which was separated by silica gel column chromatography to obtain a pure 3-(o-cyanobenzyl)indole-2-one compound of formula 3.

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