CN105085369B - A kind of aryl oxidized indole derivatives of 3- and its synthetic method - Google Patents

Abstract

The invention discloses the synthetic method of 3 aryl oxidized indoles shown in a kind of formula (I), and using 3 diazonium Oxoindoles and aromatic hydrocarbons as raw material, 3 aryl oxidized indoles are prepared through single step reaction using Bronsted acid as catalyst.Method proposed by the present invention avoid using expensive transition-metal catalyst, using aromatic hydrocarbons cheap and easy to get as raw material, reaction condition is gentle, reactions steps are few, reaction is fast, cost is low, the waste of generation is few, Atom economy is high, it is easy to operate securely and reliably.

Description

A kind of 3-aryl oxide indole derivative and its synthetic method

technical field

The invention relates to the fields of synthetic medicine and chemical industry, and mainly relates to a rapid and green p-3-aryloxindole derivative and a chemical synthesis method thereof.

Background technique

3-Aryloxindoles are widely used in the synthesis of 3,3-disubstituted oxindoles and indolines, which are a series of biologically active natural products and synthetic drugs The skeleton structure of such as SM-130686, BMS-204352, hodgkinsine, qudrigemine C, etc. (as shown below). A series of synthetic methods for 3-aryloxindoles have been developed in the past decades, such as strong acid-promoted intramolecular Friedel-Crafts reactions starting from α-haloacetamides, strong bases or light-promoted molecules Internal cyclization reaction, intramolecular coupling reaction catalyzed by divalent palladium; addition of isatin by Grignard reagent and then reductive deoxygenation reaction catalyzed by Lewis acid; molecule of indolinone and aromatic halide catalyzed by divalent palladium Intercoupling reaction; Coupling reaction of 3-diazoindole with arylboron reagent. However, the above methods have defects such as harsh reaction conditions, use of air-sensitive reagents or transition metal catalysts, and mostly involve multi-step reactions, which will generate a large amount of chemical waste in the intermediate process, and are time-consuming and costly. It is beneficial to the application of 3-aryloxindole in organic synthesis and its industrial synthesis.

Biologically Active Molecules Containing 3-Aryloxindole Structural Units

Contents of the invention

The invention overcomes the above-mentioned defects of the prior art, and discloses a synthesis method of 3-aryloxindole with short preparation route, reliable reaction and simple operation. The present invention designs a method for preparing 3-aryloxindole by using 3-diazoindole and aromatic hydrocarbon as raw materials and only one-step reaction. Compared with the reported synthetic methods, this method has the advantages of avoiding the use of expensive transition metal catalysts, using cheap and easily available aromatic hydrocarbons as raw materials, mild reaction conditions, fewer reaction steps, fast reaction, low cost, less waste generated, atom economy Therefore, this method has broad application prospects in the field of drug synthesis.

The 3-aryloxindole derivatives proposed by the present invention are as shown in the following formula (I):

in,

R is hydrogen, alkyl, alkoxycarbonyl, acyl ^;

^R is alkyl, alkoxy, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, iodine;

Ar is phenyl, substituted phenyl, furyl, substituted furyl, thienyl, substituted thienyl, benzofuryl, benzothienyl, naphthyl, anthracenyl, or phenanthrenyl.

Among them, preferably,

^R is hydrogen, benzyl, methyl, allyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzoyl;

^R is alkyl, alkoxy, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, iodine;

Ar is phenyl, substituted phenyl, furyl, substituted furyl, thienyl, substituted thienyl, benzofuryl, benzothienyl, naphthyl, anthracenyl, or phenanthrenyl.

The present invention proposes a method for synthesizing 3-aryl indole derivatives, using 3-diazoindole and aromatic hydrocarbons as raw materials and using protonic acid as a catalyst to prepare 3-aryl indole through one-step reaction. Its reaction equation is as shown in formula (A):

in,

R is hydrogen, alkyl, alkoxycarbonyl, acyl ^;

^R is alkyl, alkoxy, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, iodine;

Ar is phenyl, substituted phenyl, furyl, substituted furyl, thienyl, substituted thienyl, benzofuryl, benzothienyl, naphthyl, anthracenyl, or phenanthrenyl.

Among them, preferably,

^R is hydrogen, benzyl, methyl, allyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzoyl;

^R is alkyl, alkoxy, hydroxyl, nitro, cyano, fluorine, chlorine, bromine, iodine;

Ar is phenyl, substituted phenyl, furyl, substituted furyl, thienyl, substituted thienyl, benzofuryl, benzothienyl, naphthyl, anthracenyl, or phenanthrenyl.

In the method of the present invention, the aromatic hydrocarbon and the protonic acid catalyst are dissolved in a solvent, and the solution of 3-diazoindole is slowly added to the mixed solution of the aromatic hydrocarbon and the protonic acid catalyst at 0°C , while vigorously stirring; after the addition of 3-diazoindole dropwise, continue to stir at room temperature for 10 to 60 minutes until the 3-diazoindole is completely consumed; then add excess NaHCO ₃ solids to the reaction solution to quench The reaction was quenched, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (with ethyl acetate:petroleum ether=1:30～1:10 as eluent) to obtain a pure product.

The synthetic method of the 3-aryloxindole designed by the present invention comprises the following steps:

Weigh the raw materials according to the molar ratio of aromatic hydrocarbons: 3-diazoindole: protonic acid = 5.0: 1.0: (0.1-2.0) (based on the amount of 3-diazoindole). The aromatic hydrocarbon and the protonic acid catalyst are dissolved in a solvent to make a mixed solution of the aromatic hydrocarbon and the protonic acid catalyst; the 3-diazoindole is dissolved in a solvent to make a 3-diazoindole The solution. At 0°C, slowly add the solution of 3-diazoindole to the mixed solution of the aromatic hydrocarbon and protonic acid catalyst while vigorously stirring; after the 3-diazoindole is added dropwise, continue to Stir for 10-60 minutes until the 3-diazoindole is completely consumed. Then in the reaction liquid, add excess NaHCO ₃ solids to quench the reaction, filter off the solids and remove the solvent under reduced pressure; the crude product is subjected to column chromatography (take ethyl acetate:petroleum ether=1:30～1:10 as eluent) to obtain pure product.

In the method of the present invention, the protonic acid catalyst is trifluoromethanesulfonic acid, methanesulfonic acid, concentrated sulfuric acid, fluoboric acid, perchloric acid, or periodic acid.

In the method of the present invention, the 3-diazoindole is unsubstituted or substituted 3-diazoindole on the N atom of the five-membered ring.

In the method of the present invention, the 3-diazoindole has substituents or no substituents at positions 4, 5, 6 and 7.

In the method of the present invention, the aromatic hydrocarbon is benzene, substituted benzene, naphthalene, phenanthrene, anthracene, furan, thiophene, benzofuran, or benzothiophene.

In the method of the present invention, the solvent is dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, tetrahydrofuran, ether, toluene, n-hexane or cyclohexane.

The present invention has the following advantages and effects: avoiding the use of expensive transition metal catalysts, using cheap and easily available aromatic hydrocarbons as raw materials, mild reaction conditions, few reaction steps, short time consumption, low cost, less waste generated, high atom economy, The operation is simple, safe and reliable.

Description of drawings

FIG. 1 is a schematic diagram of ¹ H NMR of the product obtained in Example 1.

FIG. 2 is a schematic diagram of ¹³ C NMR of the product obtained in Example 1.

FIG. 3 is a schematic diagram of ¹ H NMR of the product obtained in Example 2.

FIG. 4 is a schematic diagram of ¹³ C NMR of the product obtained in Example 2.

FIG. 5 is a schematic diagram of ¹ H NMR of the product obtained in Example 3.

FIG. 6 is a schematic diagram of ¹³ C NMR of the product obtained in Example 3.

FIG. 7 is a schematic diagram of ¹ H NMR of the product obtained in Example 4.

FIG. 8 is a schematic diagram of ¹³ C NMR of the product obtained in Example 4.

FIG. 9 is a schematic diagram of ¹ H NMR of the product obtained in Example 5.

FIG. 10 is a schematic diagram of ¹³ C NMR of the product obtained in Example 5.

FIG. 11 is a schematic diagram of ¹ H NMR of the product obtained in Example 6.

FIG. 12 is a schematic diagram of ¹³ C NMR of the product obtained in Example 6.

FIG. 13 is a schematic diagram of ¹ H NMR of the product obtained in Example 7.

FIG. 14 is a schematic diagram of ¹³ C NMR of the product obtained in Example 7.

Fig. 15 is a schematic diagram of ¹ H NMR of the product obtained in Example 8.

FIG. 16 is a schematic diagram of ¹³ C NMR of the product obtained in Example 8.

FIG. 17 is a schematic diagram of ¹ H NMR of the product obtained in Example 9.

FIG. 18 is a schematic diagram of ¹³ C NMR of the product obtained in Example 9.

FIG. 19 is a schematic diagram of ¹ H NMR of the product obtained in Example 10.

20 is a schematic diagram of ¹³ C NMR of the product obtained in Example 10.

21 is a schematic diagram of ¹ H NMR of the product obtained in Example 11.

Fig. 22 is a schematic diagram of ¹³ C NMR of the product obtained in Example 11.

23 is a schematic diagram of ¹ H NMR of the product obtained in Example 12.

24 is a schematic diagram of ¹³ C NMR of the product obtained in Example 12.

Fig. 25 is a schematic diagram of ¹ H NMR of the product obtained in Example 13.

Fig. 26 is a schematic diagram of ¹³ C NMR of the product obtained in Example 13.

Fig. 27 is a schematic diagram of ¹ H NMR of the product obtained in Example 14.

Fig. 28 is a schematic diagram of ¹³ C NMR of the product obtained in Example 14.

29 is a schematic diagram of ¹ H NMR of the product obtained in Example 15.

30 is a schematic diagram of ¹³ C NMR of the product obtained in Example 15.

Fig. 31 is a schematic diagram of ¹ H NMR of the product obtained in Example 16.

Fig. 32 is a schematic diagram of ¹³ C NMR of the product obtained in Example 16.

Detailed ways

The present invention will be further described in detail in conjunction with the following specific embodiments and accompanying drawings. The process, conditions, reagents, experimental methods, etc. for implementing the present invention are general knowledge and common knowledge in the art except for the content specifically mentioned below, and the present invention has no special limitation content.

Example 1

At 0°C, a solution of N-benzyl-3-diazoindole (1.50 g, 6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoromethanesulfonate over 60 minutes Acid (53uL, 10mol%) mixed solution, while stirring vigorously. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-tolyl)oxindole (1.41 g, 85%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.31–7.24(m,5H),7.21–7.09(m,6H),7.02–6.98(m,1H),6.77(d,J＝7.8Hz 1H), 4.99(d, J＝15.6Hz 1H), 4.88(d, J＝15.6Hz 1H), 4.66(s, 1H), 2.33(s, 3H). ¹³ C NMR(100MHz, CDCl ₃ ): δ176.3, 143.6, 137.3,136.0,133.8,129.7,129.2,128.8,128.3,128.2,127.6,127.4,125.1,122.7,109.2,51.8,44.0,21.1.FTIR(KBr):3050,2922,1711,1612,3487,13 ,1347,1177,1083,1030,1008,890,753,733,698cm ^-1 .HRMS(ESI):calcd for C ₂₂ H ₁₉ NNaO[M+Na] ⁺ ＝336.1364,found 336.1348.

Example 2

At 0°C, a solution of N-methyl-3-diazoindole (1.07g, 6.0mmol) in toluene (12mL) was slowly dropped into toluene (10mL) and trifluoromethanesulfonate over 60 minutes Acid (53uL, 10mol%) mixed solution, while stirring vigorously. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-methyl-3-(p-tolyl)oxindole (1.04 g, 73%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.33–7.29 (m, 1H), 7.16–7.03 (m, 6H), 6.88 (d, J=8.0Hz 1H), 4.56 (s, 1H), 3.24 ( s,3H),2.31(s,3H). ¹³ C NMR(100MHz,CDCl ₃ ):δ176.2,144.5,137.3,133.6,129.6,129.1,128.3,128.3,125.0,122.7,108.1,51.7,26.4,21.1. FTIR(KBr):3054,2922,1693,1607,1495,1468,1376,1344,1086,748,693cm ^-1 .HRMS(ESI):calcd for C ₁₆ H ₁₅ NNaO[M+Na] ⁺ ＝260.1051,found260 .1051.

Example 3

At 0°C, a solution of N-ethoxycarbonyl-3-diazoindole (6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoromethanesulfonic acid ( 53uL, 10mol%) in the mixed solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-ethoxycarbonyl-3-(p-tolyl)oxindole (1.38 g, 78%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.97 (d, J=8.2Hz 1H), 7.38–7.34 (m, 1H), 7.21–7.06 (m, 6H), 4.71 (s, 1H), 4.45 ( q, J=7.1Hz 2H), 2.32(s, 3H), 1.42(t, J=7.1Hz 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ174.0, 151.1, 140.2, 137.7, 133.2, 130.0, 128.7 ,128.4,127.8,125.1,124.9,115.2,63.4,52.2,21.1,14.2.FTIR(KBr):2986,2924,1776,1723,1480,1465,1373,1344,1287,1236,1150,1089,1048, 764cm ^-1 .HRMS(ESI): calcd for C ₁₈ H ₁₇ NNaO ₃ [M+Na] ⁺ ＝318.1106, found 318.1091.

Example 4

At 0°C, a solution of 4-chloro-N-benzyl-3-diazoindole (6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoromethane over 60 minutes Sulfonic acid (53uL, 10mol%) mixed solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product 4-chloro-N-benzyl-3-(p-tolyl)oxindole (1.54 g, 74%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.31–7.24(m,5H),7.17–7.13(m,3H),7.06(d,J=7.9Hz,2H),6.97(d,J=8.2Hz ,1H),6.68(d,J=7.8Hz,1H),4.97(d,J=15.6Hz,1H),4.82(d,J=15.6Hz,1H),4.68(s,1H),2.33(s ,3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ175.5, 145.3, 137.4, 135.6, 131.8, 131.6, 129.7, 129.7, 128.9, 128.0, 127.8, 127.3, 126.6, 123.3, 107.5, 51.7, 44.2, 2 FTIR(KBr):3408,3024,2919,1711,1606,1460,1334,1232,1161,1142,1025,802,774,724,699,503cm ^-1 .HRMS(ESI):calcd for C ₂₂ H ₁₈ ClNNaO[M+Na] ⁺ =370.0975, found 370.0974.

Example 5

At 0°C, a solution of 5-chloro-N-benzyl-3-diazoindole (6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoromethane over 60 minutes Sulfonic acid (53uL, 10mol%) mixed solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product 5-chloro-N-benzyl-3-(p-tolyl)oxindole (1.42 g, 68%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.31–7.23(m,5H),7.17–7.12(m,4H),7.08(d,J＝8.0Hz2H),6.67(d,J＝8.3Hz 1H) ,4.97(d,J=15.6Hz 1H),4.86(d,J=15.6Hz 1H),4.64(s,1H),2.33(s,3H). ¹³ C NMR(100MHz,CDCl ₃ ):δ175.8,142.1 ,137.7,135.5,133.0,130.9,129.8,128.9,128.3,128.2,128.2,127.8,127.3,125.5,110.1,51.8,44.1,21.1.FTIR(KBr):3031,2922,1722,1711,1607, 1427,1340,1160,1113,804,744,700cm ^-1 .HRMS(ESI):calcd for C ₂₂ H ₁₈ ClNNaO[M+Na] ⁺ ＝370.0975,found 370.0962.

Example 6

At 0°C, a solution of 6-chloro-N-benzyl-3-diazoindole (6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoromethane over 60 minutes Sulfonic acid (53uL, 10mol%) mixed solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product 6-chloro-N-benzyl-3-(p-tolyl)oxindole (1.25 g, 60%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.33–7.24(m,5H),7.15(d,J=7.9Hz 2H),7.08–7.04(m,3H),6.98(d,J=7.9,1.5 Hz 1H), 6.77(d, J=1.3Hz 1H), 4.95(d, J=15.6Hz 1H), 4.84(d, J=15.6Hz 1H), 4.62(s, 1H), 2.33(s, 3H) . ¹³ C NMR (100MHz, CDCl ₃ ): δ176.2, 144.8, 137.6, 135.4, 134.0, 133.2, 129.8, 128.9, 128.2, 127.9, 127.5, 127.3, 126.0, 122.7, 109.7, 51.3, 44.1IR (21K.1 ):3411,3030,2923,1711,1609,1490,1336,1183,1080,798,698cm ^{- 1} .HRMS(ESI):calcd for C ₂₂ H ₁₈ ClNNaO[M+Na] ⁺ ＝370.0975,found 370.0972.

Example 7

At 0°C, a solution of 5-bromo-N-benzyl-3-diazoindole (6.0 mmol) in toluene (122 mL) was slowly dropped into toluene (10 mL) and trifluoromethane over 60 minutes Sulfonic acid (53uL, 10mol%) mixed solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product 5-bromo-N-benzyl-3-(p-tolyl)oxindole (2.0 g, 85%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.31–7.24(m, 7H), 7.16(d, J=8.0Hz 2H), 7.07(d, J=8.0Hz 2H), 6.63(d, J=8.3 Hz 1H), 4.97(d, J=15.6Hz 1H), 4.86(d, J=15.6Hz 1H), 4.65(s, 1H), 2.34(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ175.7, 142.6, 137.7, 135.5, 133.0, 131.3, 131.1, 129.8, 128.9, 128.3, 128.2, 127.8, 127.3, 115.5, 110.6, 51.7, 44.0, 21.1. ,1484,1423,1347,1184,1159,1112,1023,803,739,698cm ^-1 .HRMS(ESI):calcd for C ₂₂ H ₁₈ BrNNaO[M+Na] ⁺ ＝414.0469,found414.0465.

Example 8

At 0°C, a solution of 5-methyl-N-benzyl-3-diazoindole (6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoro methanesulfonic acid (53uL, 10mol%) in the mixed solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product 5-methyl-N-benzyl-3-(p-tolyl)oxindole (1.45 g, 74%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.30–7.22(m, 5H), 7.15(d, J=8.0Hz 2H), 7.10(d, J=8.0Hz 2H), 6.97(d, J=8.7 Hz 2H), 6.65(d, J=7.7Hz 1H), 4.97(d, J=15.6Hz 1H), 4.86(d, J=15.6Hz 1H), 4.62(s, 1H), 2.33(s, 3H) ,2.24(s,3H). ¹³ C NMR(100MHz,CDCl ₃ ):δ176.3,141.2,137.3,136.1,134.0,132.3,129.7,129.3,128.8,128.5,128.4,127.6,127.4,125.9,108.9,51.9 44.0,21.2,21.0.FTIR(KBr):3028,2918,1709,1600,1494,1346,1186,1022,890,818,758,732,694,653cm ^-1 .HRMS(ESI):calcd for C ₂₃ H ₂₁ NNaO[M+Na] ⁺ =350.1521, found 350.1536.

Example 9

At 0°C, a solution of 6-fluoro-N-benzyl-3-diazoindole (6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and trifluoromethane over 60 minutes Sulfonic acid (53uL, 10mol%) mixed solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product 6-fluoro-N-benzyl-3-(p-tolyl)oxindole (1.39 g, 70%). ¹ H NMR (400MHz, CDCl ₃ ): δ7.34–7.24(m,5H),7.15(d,J=7.9Hz2H),7.09–7.05(m,3H),6.72–6.64(m,1H),6.51 (dd,J ₁ =8.9Hz,J ₂ =2.2Hz 1H),4.95(d,J=15.6Hz 1H),4.84(d,J=15.6Hz 1H),4.62(s,1H),2.33(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ176.6, 163.0 (d, J _CF = 245.0 Hz), 145.0 (d, J _CF = 11.5 Hz), 137.5, 135.5, 133.5, 129.7, 128.9, 128.2, 127.9, 127.4, 126.0(d, J _CF ＝9.6Hz), 124.4(d, J _CF ＝3.0Hz), 108.9(d, J _CF ＝22.4Hz), 98.0(d, J _CF ＝27.7Hz), 51.2, 44.1, 21.1.FTIR(KBr):3400,3067,2923,1710,1605,1497,1453,1374,1342,1167,1079,939,697cm ^-1 .HRMS(ESI):calcd for C ₂₂ H ₁₈ FNNaO[M+Na ] ⁺ ＝354.1270,found354.1259.

Example 10

At 0°C, a solution of N-benzyl-3-diazoindole (1.50g, 6.0mmol) in 1,2-dichloroethane (12mL) was slowly dropped into isobutylene over 60 minutes Benzene (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (10mL) while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(isobutylphenyl)oxindole (1.07 g, 50%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.32–7.12(m,11H),7.02–6.98(m,1H),6.77(d,J=7.8Hz 1H),4.98(d,J=15.6Hz 1H ),4.90(d,J=15.6Hz 1H),4.67(s,1H),2.45(d,J=7.1Hz 2H),1.90–1.80(m,1H),0.90(d,J=6.6Hz 6H) . ¹³ C NMR (100MHz, CDCl ₃ ): δ176.4, 143.6, 141.1, 136.0, 133.9, 129.7, 129.2, 128.8, 128.2, 128.1, 127.6, 127.4, 125.1, 122.7, 109.2, 51.8, 45.1, 44.0, 2 ,22.4.FTIR(KBr):3411,3056,2948,2922,1711,1609,1488,1466,1357,1199,1165,748,731,699cm ^-1 .HRMS(ESI):calcdfor C ₂₅ H ₂₅ NNaO[M+Na ] ⁺ ＝378.1270,found378.1287.

Example 11

At 0°C, a solution of N-benzyl-3-diazoindole (1.50 g, 6.0 mmol) in 1,2-dichloroethane (12 mL) was slowly dropped into biphenyl over 60 minutes (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (10mL) solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(biphenyl)oxindole (1.28 g, 57%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.56 (d, J=8.1Hz4H), 7.44–7.40 (m, 2H), 7.35–7.23 (m, 8H), 7.23–7.19 (m, 2H), 7.05 –7.01(m, 1H), 6.80(d, J＝7.7Hz 1H), 5.00(d, J＝15.6Hz 1H), 4.91(d, J＝15.6Hz 1H), 4.74(s, 1H). ¹³ C NMR (100MHz, CDCl ₃ ): δ176.1, 143.7, 140.8, 140.7, 135.9, 135.8, 128.9, 128.8, 128.8, 128.4, 127.8, 127.7, 127.4, 127.6, 127.1, 125.20, 122.6, 109.3, 4.5 (IR KBr):3411,3031,2923,1711,1608,1487,1466,1354,1197,1007,762,750,695cm ^-1 .HRMS(ESI):calcd for C ₂₇ H ₂₁ NNaO[M+Na] ⁺ ＝398.1521,found398 .1520.

Example 12

At 0°C, a solution of N-benzyl-3-diazoindole (1.50 g, 6.0 mmol) in 1,2-dichloroethane (12 mL) was slowly dropped into p-methanol over 60 minutes Oxybenzene (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (10mL) solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-methoxyphenyl)oxindole (1.60 g, 81%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.32–7.13(m,9H),7.02–6.99(m,1H),6.88(d,J＝8.6Hz 2H),6.77(d,J＝7.7Hz 1H ), 4.98(d, J=15.6Hz 1H), 4.88(d, J=15.6Hz 1H), 4.64(s, 1H), 3.78(s, 3H). ¹³ C NMR(100MHz, CDCl ₃ ): δ176. 5,159.1,143.6,136.0,129.5,129.2,128.8,128.7,128.3,127.6,127.4,125.1,122.8,114.4,109.2,55.3,51.3,43.9.FTIR(KBr):3025,2923,191,410,165 ,1467,1346,1255,1180,1023,752,696cm ^-1 .HRMS(ESI):calcd for C ₂₂ H ₁₉ NNaO ₂ [M+Na] ⁺ ＝352.1313,found352.1300.

Example 13

At 0°C, a solution of N-benzyl-3-diazoindole (1.50 g, 6.0 mmol) in 1,2-dichloroethane (12 mL) was slowly dropped into acetanilide over 60 minutes (30mmol) and trifluoromethanesulfonic acid (1.06mL, 200mol%) in 1,2-dichloroethane (10mL) solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-acetamidophenyl)oxindole (1.29 g, 60%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.96(s, 1H), 7.38(d, J=8.3Hz 2H), 7.30–7.19(m, 6H), 7.13(d, J=7.3Hz 1H), 7.08(d,J=8.3Hz 2H),7.04–7.00(m,1H),6.80(d,J=7.8Hz 1H),4.99(d,J=15.6Hz 1H),4.90(d,J=15.6Hz 1H), 4.65(s, 1H), 2.10(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ ): δ176.5, 168.6, 143.4, 137.7, 135.8, 132.0, 128.9, 128.9, 128.4, 127.7, 127.3, 125.2 . ^-1 .HRMS(ESI): calcd for C ₂₃ H ₂₁ N ₂ O ₂ [M+H] ⁺ ＝357.1603, found 357.1615.

Example 14

At 0°C, a solution of N-benzyl-3-diazoindole (1.50g, 6.0mmol) in 1,2-dichloroethane (12mL) was slowly dropped into o-dichloroethane over 60 minutes Toluene (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (10mL) solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(3,4-dimethylphenyl)oxindole (1.41 g, 72%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.33–7.13(m,7H),7.09(d,J=7.7Hz 1H),7.01–6.98(m,2H),6.92(d,J=7.7Hz 1H ),6.77(d,J=7.8Hz 1H),4.98(d,J=15.6Hz 1H),4.88(d,J=15.6Hz 1H),4.62(s,1H),2.23(s,3H),2.22 (s,3H). ¹³ CNMR (100MHz, CDCl ₃ ): δ176.5, 143.6, 137.2, 136.1, 136.0, 134.2, 130.2, 129.7, 129.7, 128.8, 128.2, 127.7, 127.4, 125.8, 125.1, 121.8, 108.9 ,44.0,19.9,19.5.FTIR(KBr):3032,2921,1711,1611,1486,1466,1346,1181,1081,751,697cm ^-1 .HRMS(ESI):calcdfor C ₂₃ H ₂₁ NNaO[M+Na ] ⁺ ＝350.1521,found350.1511.

Example 15

At 0°C, a solution of N-benzyl-3-diazoindole (1.50g, 6.0mmol) in 1,2-dichloroethane (12mL) was slowly dropped into m-benzene over 60 minutes Dimethyl ether (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (10mL) solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(2,4-dimethoxyphenyl)oxindole (1.94 g, 90%). ¹ H NMR (CDCl ₃ , 400MHz): δ7.39–7.24(m,5H), 7.15–7.11(m,1H), 7.04–7.02(m,2H), 6.04–6.90(m,1H), 6.74( d, J＝7.8Hz 1H), 6.47–6.45(m, 2H), 5.10(d, J＝15.6Hz 1H), 4.85(d, J＝15.6Hz 1H), 4.82(s, 1H), 3.78(s ,3H),3.59(s,3H). ¹³ C NMR(100MHz,CDCl ₃ ):δ177.0,160.6,158.5,143.3,136.3,130.9,130.1,128.7,127.6,127.6,127.5,124.0,122.4,118.2,108.7 ^. .HRMS(ESI): calcd for C ₂₃ H ₂₁ NNaO ₃ [M+Na] ⁺ ＝382.1419, found 382.1434.

Example 16

At 0°C, a solution of N-benzyl-3-diazoindole (1.50g, 6.0mmol) in 1,2-dichloroethane (12mL) was slowly added dropwise to the H3 Toluene (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (10mL) solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(2,4,6-trimethylphenyl)oxindole (1.80 g, 88%). ¹ H NMR(CDCl ₃ ,400MHz):δ7.40(d,J=7.2Hz2H),7.33–7.30(m,1H),7.27–7.24(m,1H),7.19–7.15(m,1H),6.96 –6.93(m,3H),6.82(d,J=7.8Hz 2H),6.75(s,1H),5.08(s,1H),5.06(d,J=15.4Hz 1H),4.91(d,J= 15.4Hz 1H), 2.52(s, 3H), 2.25(s, 3H), 1.60(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ): δ176.5, 143.2, 137.9, 137.1, 137.0, 136.1, 130.5, 130.3, 129.1, 128.8, 127.9, 127.80, 127.7, 123.7, 122.7, 108.8, 48.2, 44.3, 21.3, 20.9, 19.3. FTIR (KBr): 3426, 3055, 2922, 1723, 1611, 1485, 1465, 1995 ,1164,1096,1011,922,885,859,748,727,697cm ^-1 .HRMS(ESI):calcd for C ₂₄ H ₂₄ NO[M+H] ⁺ ＝342.1858,found342.1861.

Example 17

At 0°C, a solution of N-benzyl-3-diazoxindole (1.50 g, 6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and methanesulfonic acid ( 100mol%) in the mixed solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-tolyl)oxindole (1.10 g, 77%).

Example 18

At 0°C, a solution of N-benzyl-3-diazoindole (1.50 g, 6.0 mmol) in toluene (12 mL) was slowly dropped into toluene (10 mL) and perchloric acid ( 50mol%) in the mixed solution while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-tolyl)oxindole (1.18 g, 83%).

Example 19

At 0°C, a solution of N-benzyl-3-diazoindole (1.50g, 6.0mmol) in toluene (12mL) was slowly dropped into toluene (10mL) and fluoroboric acid (50mol %) in the mixed solution while stirring vigorously. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-tolyl)oxindole (1.02 g, 72%).

Example 20

At 0°C, a cyclohexane (12 mL) solution of N-benzyl-3-diazoindole (1.50 g, 6.0 mmol) was slowly dropped into toluene (30 mmol) and trifluoro Methanesulfonic acid (53uL, 10mol%) in cyclohexane (10mL) solution, while vigorously stirring. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until the 3-diazoindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain Pure product N-benzyl-3-(p-tolyl)oxindole (0.95 g, 67%).

Example 21

At 0°C, a solution of 6-trifluoromethyl-3-diazoindole (1.36g, 6.0mmol) in 1,2-dichloroethane (15mL) was slowly dropped into the 4-Chloroanisole (30mmol) and trifluoromethanesulfonic acid (106uL, 20mol%) in 1,2-dichloroethane (12mL) solution, while stirring vigorously. After the dropwise addition was completed, stirring was continued at room temperature for 60 minutes until 6-trifluoromethyl-3-diazoxindole was completely consumed. Then, excess _NaHCO3 solid was added to the reaction solution to quench the reaction, the solid was filtered off and the solvent was removed under reduced pressure; the crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:10～1:4) to obtain Pure product 6-trifluoromethyl-3-(2-methoxy-5-chlorophenyl)oxindole (1.23 g, 60%). ¹ H-NMR(400MHz,d ₆ -DMSO):δ10.79(s,1H),7.34–7.37(m,2H),7.22(d,J=7.1Hz,1H)7.06–7.10(m,2H) , 7.02(d, J=8.8Hz, 1H), 4.92(s, 1H), 3.57(s, 3H). ¹³ C NMR (100MHz, d ₆ -DMSO): δ176.7, 156.1, 143.6, 134.4, 130.6, 128.7 ^.

The 6-trifluoromethyl-3-(2-methoxy-5-chlorophenyl)oxindole prepared in this example is subjected to an asymmetric fluorination reaction to obtain the drug BMS-204352 (MaxiPost) for treating cerebral apoplexy , the detailed preparation method can refer to the literature: (a) Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.; Feng, X.J.Org.Chem.,2012,77,9148– 9155.; (b) Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk, K.L.J.Org.Chem., 2003, 68, 2494–2497.

The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Claims (3)

1. A synthesis method of 3-aryl oxindole derivatives is characterized in that 3-diazo oxindole and aromatic hydrocarbon are used as raw materials, protonic acid is used as a catalyst, and the 3-aryl oxindole is prepared through one-step reaction, wherein the reaction equation is shown as the formula (A):

wherein,

R¹hydrogen, benzyl, methyl, ethoxycarbonyl;

R²hydroxyl, nitro, cyano, fluorine, chlorine and bromine;

ar is phenyl, naphthyl, anthryl or phenanthryl;

dissolving the aromatic hydrocarbon and the protonic acid catalyst in a solvent, slowly adding the solution of 3-diazo oxoindole into the mixed solution of the aromatic hydrocarbon and the protonic acid catalyst at 0 ℃, and stirring vigorously; after the 3-diazooxindole is dripped, continuously stirring at room temperature for 10-60 minutes until the 3-diazooxindole is completely consumed; then adding excess NaHCO into the reaction solution₃The solid was quenched with water, filtered off and the solvent removed under reduced pressure; carrying out column chromatography on the crude product by using ethyl acetate and petroleum ether as an eluent at a ratio of 1: 30-1: 10 to obtain a pure product;

the protonic acid catalyst is trifluoromethanesulfonic acid, methanesulfonic acid, fluoroboric acid, perchloric acid or periodic acid.

2. The method of synthesizing a 3-aryloxindoles derivative of claim 1 wherein the aromatic hydrocarbon: 3-diazoxyindole: molar ratio of protic acid 5.0: 1.0: (0.1-2.0).

3. The method of synthesizing a 3-aryloxindoles derivative of claim 1 wherein the solvent is dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride, tetrahydrofuran, diethyl ether, toluene, n-hexane, or cyclohexane.