CN105085369A - 3-aryloxoindole derivative and synthetic method thereof - Google Patents

Abstract

The invention discloses a method for synthesizing 3-aryloxindole represented by formula (I). The 3-aryloxindole and aromatic hydrocarbon are used as raw materials and protonic acid is used as catalyst to prepare 3-aryloxindole through one-step reaction. oxindole. The method proposed by the present invention avoids the use of expensive transition metal catalysts, uses cheap and easily available aromatic hydrocarbons as raw materials, has mild reaction conditions, few reaction steps, fast reaction, low cost, less waste generated, high atom economy, simple, safe and reliable operation .

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, for example, SM-130686, BMS-204352, hodgkinsine, qudrigemineC, etc. (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 indolone and aromatic halide catalyzed by divalent palladium Intercoupling reaction; Coupling reaction of 3-diazoindole with aryl boron 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 lot 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 synthetic method of 3-aryl oxide indole derivatives, using 3-diazoindole and aromatic hydrocarbons as raw materials, using protonic acid as a catalyst, and preparing 3-aryl oxide 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 pure product.

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

The raw materials are weighed according to the molar ratio of aromatic hydrocarbon: 3-diazoindole: protonic acid = 5.0: 1.0: 0.1 to 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 add excess NaHCO ₃ solids to quench the reaction in the reaction solution, 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 HNMR of the product obtained in Example 1.

Fig. 2 is a schematic diagram of ¹³ CNMR of the product obtained in Example 1.

Fig. 3 is a schematic diagram of ¹ HNMR of the product obtained in Example 2.

Fig. 4 is a schematic diagram of ¹³ CNMR of the product obtained in Example 2.

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

Fig. 6 is a schematic diagram of ¹³ CNMR of the product obtained in Example 3.

7 is a schematic diagram of ¹ HNMR of the product obtained in Example 4.

Fig. 8 is a schematic diagram of ¹³ CNMR of the product obtained in Example 4.

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

Fig. 10 is a schematic diagram of ¹³ CNMR of the product obtained in Example 5.

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

Fig. 12 is a schematic diagram of ¹³ CNMR of the product obtained in Example 6.

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

14 is a schematic diagram of ¹³ CNMR of the product obtained in Example 7.

FIG. 15 is a schematic diagram of ¹ HNMR of the product obtained in Example 8.

16 is a schematic diagram of ¹³ CNMR of the product obtained in Example 8.

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

Fig. 18 is a schematic diagram of ¹³ CNMR of the product obtained in Example 9.

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

Fig. 20 is a schematic diagram of ¹³ CNMR of the product obtained in Example 10.

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

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

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

Fig. 24 is a ¹³ CNMR schematic diagram of the product obtained in Example 12.

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

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

27 is a schematic diagram of ¹ HNMR of the product obtained in Example 14.

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

Fig. 29 is a schematic diagram of ¹ HNMR of the product obtained in Example 15.

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

31 is a schematic diagram of ¹ HNMR of the product obtained in Example 16.

32 is a schematic diagram of ¹³ CNMR 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%) in a 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 HNMR (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=7.8Hz1H), 4.99 ( d, J=15.6Hz1H), 4.88(d, J=15.6Hz1H), 4.66(s, 1H), 2.33(s, 3H). ¹³ CNMR (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. 1177, 1083, 1030, 1008, 890, 753, 733, 698cm ^-1 . HRMS (ESI): calcdforC 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%) in a 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 HNMR (CDCl ₃ , 400MHz): δ7.33-7.29(m, 1H), 7.16-7.03(m, 6H), 6.88(d, J=8.0Hz1H), 4.56(s, 1H), 3.24(s, 3H), 2.31(s, 3H). ¹³ CNMR (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): calcdforC 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 HNMR (CDCl ₃ , 400MHz): δ7.97(d, J=8.2Hz1H), 7.38-7.34(m, 1H), 7.21-7.06(m, 6H), 4.71(s, 1H), 4.45(q, J=7.1Hz2H), 2.32(s, 3H), 1.42(t, J=7.1Hz3H). ¹³ CNMR (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): calcdfor C ₁₈ H ₁ 7NNaO 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 HNMR (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 CNMR (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): calcdforC 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 HNMR (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=8.3Hz1H), 4.97 (d, J=15.6Hz1H), 4.86(d, J=15.6Hz1H), 4.64(s, 1H), 2.33(s, 3H). ¹³ CNMR (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, 14784, 14 , 1160, 1113, 804, 744, 700cm ^-1 .HRMS (ESI): calcdforC ₂₂ H ₁₈ ClNNaO[M+Na] ⁺ =370.0975, found370.0962.

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 HNMR (400MHz, CDCl ₃ ): δ7.33-7.24(m, 5H), 7.15(d, J=7.9Hz2H), 7.08-7.04(m, 3H), 6.98(d, J=7.9, 1.5Hz1H) , 6.77(d, J=1.3Hz1H), 4.95(d, J=15.6Hz1H), 4.84(d, J=15.6Hz1H), 4.62(s, 1H), 2.33(s, 3H). ¹³ CNMR(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, 44.1, 21.1. FTIR (KBr): 334011, 3 , 2923, 1711, 1609, 1490, 1336, 1183, 1080, 798, 698cm ^-1 . HRMS (ESI): calcdforC ₂₂ H ₁₈ ClNNaO[M+Na] ⁺ =370.0975, found370.0972.

Example 7

At 0°C, a solution of 5-bromo-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-bromo-N-benzyl-3-(p-tolyl)oxindole (2.0 g, 85%). ¹ HNMR (400MHz, CDCl ₃ ): δ7.31-7.24(m, 7H), 7.16(d, J=8.0Hz2H), 7.07(d, J=8.0Hz2H), 6.63(d, J=8.3Hz1H), 4.97(d, J=15.6Hz1H), 4.86(d, J=15.6Hz1H), 4.65(s, 1H), 2.34(s, 3H). ¹³ CNMR(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. 1347, 1184, 1159, 1112, 1023, 803, 739, 698cm ^-1 . HRMS (ESI): calcdforC 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 a 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 HNMR (400MHz, CDCl ₃ ): δ7.30-7.22(m, 5H), 7.15(d, J=8.0Hz2H), 7.10(d, J=8.0Hz2H), 6.97(d, J=8.7Hz2H), 6.65(d, J=7.7Hz1H), 4.97(d, J=15.6Hz1H), 4.86(d, J=15.6Hz1H), 4.62(s, 1H), 2.33(s, 3H), 2.24(s, 3H) . ¹³ CNMR (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, 10.2, FTIR (KBr): 3028, 2918, 1709, 1600, 1494, 1346, 1186, 1022, 890, 818, 758, 732, 694, 653cm ^-1 .HRMS (ESI): calcdforC 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 HNMR (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 =2.2Hz1H), 4.95(d, J=15.6Hz1H), 4.84(d, J=15.6Hz1H), 4.62(s, 1H), 2.33(s, 3H). ¹³ CNMR (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 _{FTIR _ _ _} (KBr): 3400, 3067, 2923, 1710, 1605, 1497, 1453, 1374, 1342, 1167, 1079, 939, 697cm ^-1 .HRMS (ESI): calcdforC ₂₂ H ₁₈ FNNaO[M+Na] ⁺ ＝354.1270 , found 354.1259.

Example 10

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 isobutylene over 60 minutes phenylbenzene (30 mmol) and trifluoromethanesulfonic acid (106 uL, 20 mol%) in 1,2-dichloroethane (10 mL) 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-(isobutylphenyl)oxindole (1.07 g, 50%). ¹ HNMR (CDCl ₃ , 400MHz): δ7.32-7.12 (m, 11H), 7.02-6.98 (m, 1H), 6.77 (d, J=7.8Hz1H), 4.98 (d, J=15.6Hz1H), 4.90 (d, J=15.6Hz1H), 4.67(s, 1H), 2.45(d, J=7.1Hz2H), 1.90-1.80(m, 1H), 0.90(d, J=6.6Hz6H). ¹³ CNMR(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, 30.2, 22.4, 22. KBr): 3411, 3056, 2948, 2922, 1711, 1609, 1488, 1466, 1357, 1199, 1165, 748, 731, 699cm ^-1 .HRMS (ESI): calcdforC ₂₅ H ₂₅ NNaO[M+Na] ⁺ = 378.1270, found 378.1287.

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) 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 HNMR (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=7.7Hz1H), 5.00(d, J=15.6Hz1H), 4.91(d, J=15.6Hz1H), 4.74(s, 1H). ¹³ CNMR(100MHz, CDCl ₃ ). 3411, 3031, 2923, 1711, 1608, 1487, 1466, 1354, 1197, 1007, 762, 750, 695cm ^-1 .HRMS (ESI): calcdforC ₂₇ H ₂₁ NNaO[M+Na] ⁺ =398.1521, found3981520

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 (30 mmol) and trifluoromethanesulfonic acid (106 uL, 20 mol%) in 1,2-dichloroethane (10 mL) 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 HNMR (CDCl ₃ , 400MHz): δ7.32-7.13 (m, 9H), 7.02-6.99 (m, 1H), 6.88 (d, J=8.6Hz2H), 6.77 (d, J=7.7Hz1H), 4.98 (d, J=15.6Hz1H), 4.88(d, J=15.6Hz1H), 4.64(s, 1H), 3.78(s, 3H). ¹³ CNMR (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, 1710, 1609, 1515, 14786, 14 , 1255, 1180, 1023, 752, 696cm ^-1 .HRMS (ESI): calcdforC ₂₂ H ₁₉ NNaO ₂ [M+Na] ⁺ = 352.1313, found 352.1300.

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) 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-acetamidophenyl)oxindole (1.29 g, 60%). ¹ HNMR (CDCl ₃ , 400MHz): δ7.96(s, 1H), 7.38(d, J=8.3Hz2H), 7.30-7.19(m, 6H), 7.13(d, J=7.3Hz1H), 7.08(d , J=8.3Hz2H), 7.04-7.00(m, 1H), 6.80(d, J=7.8Hz1H), 4.99(d, J=15.6Hz1H), 4.90(d, J=15.6Hz1H), 4.65(s, 1H), 2.10(s, 3H). ¹³ CNMR (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, 123.0, 120.6, 109.3 ^of ESI): calcdfor 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 (1.50 g, 6.0 mmol) in 1,2-dichloroethane (12 mL) was slowly dropped into the o Toluene (30 mmol) and trifluoromethanesulfonic acid (106 uL, 20 mol%) in 1,2-dichloroethane (10 mL) were stirred 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-(3,4-dimethylphenyl)oxindole (1.41 g, 72%). ¹ HNMR (CDCl ₃ , 400MHz): δ7.33-7.13(m, 7H), 7.09(d, J=7.7Hz1H), 7.01-6.98(m, 2H), 6.92(d, J=7.7Hz1H), 6.77 (d, J=7.8Hz1H), 4.98(d, J=15.6Hz1H), 4.88(d, J=15.6Hz1H), 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, 122.8, 109.4, 51.8, , 19.5. FTIR (KBr): 3032, 2921, 1711, 1611, 1486, 1466, 1346, 1181, 1081, 751, 697cm ^-1 .HRMS (ESI): calcdforC ₂₃ H ₂₁ NNaO[M+Na] ⁺ ＝350.1521 , found 350.1511.

Example 15

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 m-benzene over 60 minutes Dimethyl ether (30 mmol) and trifluoromethanesulfonic acid (106 uL, 20 mol%) in 1,2-dichloroethane (10 mL) were stirred 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-(2,4-dimethoxyphenyl)oxindole (1.94 g, 90%). ¹ HNMR (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=7.8Hz1H), 6.47-6.45(m, 2H), 5.10(d, J=15.6Hz1H), 4.85(d, J=15.6Hz1H), 4.82(s, 1H), 3.78(s, 3H), 3.59(s, 3H). ¹³ CNMR (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, 104.7 99.5, 55.6, 55.4, 48.0, 43.9. FTIR (KBr): 3410, 3024, 2923, 1711, 1611, 1487, 1466, 1347, 1209, 1160, 1129, 1082, 1047, 1025, 750, 699cm ^-1 .HRMS (ESI): calcdfor C ₂₃ H ₂₁ NNaO ₃ [M+Na] ⁺ = 382.1419, found 382.1434.

Example 16

At 0°C, a solution of N-benzyl-3-indole diazoxindole (1.50 g, 6.0 mmol) in 1,2-dichloroethane (12 mL) was slowly dripped into the H3 Toluene (30 mmol) and trifluoromethanesulfonic acid (106 uL, 20 mol%) in 1,2-dichloroethane (10 mL) were stirred 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-(2,4,6-trimethylphenyl)oxindole (1.80 g, 88%). ¹ HNMR (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=7.8Hz2H), 6.75(s, 1H), 5.08(s, 1H), 5.06(d, J=15.4Hz1H), 4.91(d, J=15.4Hz1H) , 2.52(s, 3H), 2.25(s, 3H), 1.60(s, 3H). ¹³ CNMR (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. 1096, 1011, 922, 885, 859, 748, 727, 697cm ^-1 .HRMS(ESI): calcdforC ₂₄ H ₂₄ NO[M+H] ⁺ = 342.1858, found 342.1861.

Example 17

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 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) 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 (30 mmol) and trifluoromethanesulfonic acid (106 uL, 20 mol%) in 1,2-dichloroethane (12 mL) while vigorously stirring. 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 CNMR (100MHz, d ₆ -DMSO): δ176.7, 156.1, 143.6, 134.4, 130.6, 128.7, 128.6(q), 127.4, 126.0, 124.2, 122.4, 118.3, 113.6, 105.1, 56.1, 48.3.FTIR(KBr): 3200, 1710, 1320, 1250, 1170, 1120, 1050cm ^-1 .

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 , detailed preparation method can refer to 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 (9)

1. A 3-aryl oxide indole derivative, characterized in that, as shown in 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. 2. A 3-aryl oxide indole derivative, characterized in that, as shown in formula (I), in, ^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. 3. A synthetic method for 3-aryl oxide indole derivatives, characterized in that, with 3-diazoindole oxide and aromatic hydrocarbons as raw materials, with protonic acid as catalyst, through one-step reaction to prepare 3-aryl oxide Indole, its reaction equation is 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, benzo Thienyl, naphthyl, anthracenyl, phenanthrenyl; Dissolving the aromatic hydrocarbon and the protonic acid catalyst in a solvent, slowly adding a solution of 3-diazoindole 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 solid to the reaction solution to quench the reaction, filter out solid 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 pure product. 4. The synthetic method of 3-aryloxindole derivatives as claimed in claim 3, characterized in that, arene: 3-diazoindole: the molar ratio of protonic acid=5.0/1.0/0.1～2.0. 5. the preparation method of 3-hydroxyindole according to claim 1, is characterized in that, described protonic acid catalyst is trifluoromethanesulfonic acid, methanesulfonic acid, the vitriol oil, fluoboric acid, perchloric acid or periodic acid. 6. the preparation method of 3-aryl oxide indole according to claim 1, is characterized in that, described 3-diazo indole is unsubstituted or substituted 3-diazo on the five-membered ring N atom Oxindole. 7. The preparation method of 3-aryloxindole according to claim 6, characterized in that, the 3-diazoindole has substituents or no substituents at positions 4, 5, 6, and 7. 8. the preparation method of 3-aryl oxide indole according to claim 1 is characterized in that, described aromatic hydrocarbon is benzene, substituted benzene, naphthalene, phenanthrene, anthracene, furan, thiophene, benzofuran or benzofuran Thiophene. 9. the preparation method of 3-aryl oxide indole according to claim 1 is characterized in that, described solvent is methylene dichloride, chloroform, 1,2-ethylene dichloride, carbon tetrachloride, tetrahydrofuran, Diethyl ether, toluene, n-hexane or cyclohexane.