CN111187198B - Preparation method of 3,3' -disubstituted indol-2-one compound - Google Patents

Abstract

The application discloses a novel 3,3' -disubstituted indole-2-ketone compound substituted by cyanoalkyl sulfonyl and a synthesis method thereof. The method is carried out under the catalysis condition of an iron catalyst,Naryl alkene amidificationThe compound and the cyclobutanone oxime ester compound are broken by C-C bond and inserted into SO ₂ To construct cyanoalkylsulfonyl substituted 3,3' -disubstituted indol-2-ones. The olefin double-functionalization of the method relates to a free radical mechanism, namely the generation of an imino radical, the cleavage of a C-C bond and SO ₂ Serial processes of insertion, sulfonyl radical addition and cyclization. The method is novel and convenient, has good functional group adaptability and does not need to use additional alkali and oxidant.

Description

A kind of preparation method of 3,3'-disubstituted indole-2-one compounds

Technical field

The present application belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 3,3’-disubstituted indole-2-one compounds.

Background technique

Sulfur-containing derivatives are important structural units in organic synthesis and drug synthesis. Sulfone is a useful organosulfur derivative that has been widely used in the chemical industry, agricultural chemicals, pharmaceuticals, organic synthesis and flame retardant materials. With the widespread application of sulfones, the preparation methods of sulfones have attracted the attention of organic chemists, and many novel strategies have been established. Among them, inserting sulfur dioxide is the simplest method to synthesize sulfones. DABSO [DABCO·(SO ₂ ) ₂ ], sodium sulfite and thiourea dioxide are usually used as sulfur dioxide sources to prepare sulfones.

Alkyl nitriles are also important structural units in many cyano-containing drug molecules and natural products, and the cyanoalkyl structure can also be easily converted into other functional groups. Therefore, the development of synthetic strategies for the efficient and convenient preparation of alkyl nitriles has also attracted the attention of organic chemists. Traditional methods for synthesizing alkyl nitriles include dehydrogenation of amines, dehydration of aldoximes or amides, and cyanation of alkyl halides. In recent years, carbon-carbon σ bond cleavage of cyclobutanone oxime esters has also appeared, which is a convenient way to introduce cyanoalkyl groups with longer aliphatic chains into organic molecules. Most of these methods involve the formation of cyanoalkyl radicals, which react with another substrate. The inventor's research team disclosed a method using MCPs, cyclobutanone oxime ester compounds and K ₂ S ₂ O ₅ as raw materials to construct a 2-cyanoalkylsulfonyl-substituted 3,4-dihydronaphthalene compound through visible light catalysis Synthetic strategy, this method breaks two carbon-carbon σ bonds in a one-pot reaction to form one carbon-carbon bond and two carbon-sulfur bonds. This method captures SO ₂ through the formation of cyanoalkyl radicals and subsequent formation of sulfonate Acyl radicals cause ring opening and cyclization of MCPs. Nonetheless, methods to capture SO ₂ via the formation of cyanoalkyl radicals and subsequent formation of sulfonyl radicals are still very rare (see Scheme 1).

Indolinones are important synthetic intermediates and the structural unit skeletons of many drugs and natural product molecules. Due to their widespread use, many organic chemists have devoted themselves to developing new methods for the preparation of indolinones. In recent years, a series of strategies to construct indolinones via ORC (oxidative radical coupling) have been developed. In the present invention, we propose an iron-catalyzed cyanoalkylsulfonylation/arylation reaction between N -aryl enamides and cyclobutanone oxime esters, inserting sulfur dioxide to construct cyanoalkylsulfonyl groups. of indolinone compounds.

Contents of the invention

The object of the present invention is to provide a new cyanoalkylsulfonyl-substituted 3,3'-disubstituted indol-2-one compound and its synthesis method. In this method, under iron catalyst catalytic conditions, N -aryl enamide compounds and cyclobutanone oxime ester compounds break through CC bonds and insert SO ₂ to construct cyanoalkylsulfonyl-substituted 3,3'-disubstituted Indole-2-one compounds. The olefin bifunctionalization of the method of the present invention involves a free radical mechanism, through a series process of imine radical generation, CC bond cleavage, SO ₂ insertion, sulfonyl radical addition and cyclization. The method of the present invention is novel and convenient, has good functional group adaptability and does not require the use of additional bases and oxidants.

The invention provides a method for preparing 3,3’-disubstituted indole-2-one compounds, which includes the following steps:

Add the N -aryl enamide compound represented by Formula 1, the cyclobutanone oxime ester compound represented by Formula 2, iron catalyst, K ₂ S ₂ O ₈ and organic solvent into the reactor. Then, the reactor is placed in an oil bath under an inert atmosphere to heat and stir the reaction. The complete reaction of the raw materials is monitored by TLC or GC-MS. After post-processing, the target product shown in Formula 3 is obtained. The reaction formula is as follows:

In the above reaction formula, R ₁ is selected from a C _1-20 alkyl group, a C _6-20 aryl group-C _1-20 alkyl group, and a substituted or unsubstituted C _6-20 aryl group. Wherein, the substituent in the "substituted or unsubstituted" is selected from halogen, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group.

Preferably, R ₁ is selected from C _1-6 alkyl, C _6-14 aryl-C _1-6 alkyl, substituted or unsubstituted C _6-14 aryl. Wherein, the substituent in the "substituted or unsubstituted" is selected from halogen, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group.

Most preferably, _R1 is selected from methyl, benzyl, phenyl or substituted benzyl, wherein the substituent in the substituted benzyl is selected from fluorine, bromine, bromine, iodine, methyl, methoxy.

R ₂ is selected from C _1-20 alkyl, C _6-20 aryl-C _1-20 alkyl, C _1-20 alkyl-C(O)OC _1-20 alkyl.

Preferably, R ₂ is selected from C _1-6 alkyl, C _6-14 aryl-C _1-6 alkyl, C _1-6 alkyl-C(O)OC _1-6 alkyl.

Most preferably, _R2 is selected from methyl, benzyl, _CH3C (O)O- _CH2- .

R ₃ represents one, two or three substituents at the meta or para position of N on the connected benzene ring. Each R ₃ substituent is independently selected from hydrogen, halogen, C _1-20 alkyl, C _{1 -20} haloalkyl group, C _1-20 alkoxy group, C _6-20 aryl group, C _6-20 aryloxy group, C _1-20 alkyl -OC(O)-.

Preferably, R ₃ represents one, two or three substituents at the meta or para position of N on the connected benzene ring, and each R ₃ substituent is independently selected from hydrogen, halogen, and C _1-6 alkyl group. , C _1-6 haloalkyl group, C _1-6 alkoxy group, C _6-14 aryl group, C _6-14 aryloxy group, C _1-6 alkyl-OC(O)-.

Most preferably, R ₃ represents one, two or three substituents at the meta or para position of N on the attached benzene ring, and each R ₃ substituent is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, Methyl, tert-butyl, trifluoromethyl, methoxy, phenoxy, EtOC(O)-.

R is selected from substituted or unsubstituted C ₆ -C ₂₀ arylformyl. Wherein, the substituent in the "substituted or unsubstituted" is selected from halogen, trifluoromethyl, and nitro.

Preferably, R is selected from substituted or unsubstituted C ₆ -C ₁₄ arylformyl. Wherein, the substituent in the "substituted or unsubstituted" is selected from halogen, trifluoromethyl, and nitro.

Further preferably, R is selected from any one of substituted or unsubstituted benzoyl groups. Wherein, the substituent in the "substituted or unsubstituted" is selected from halogen, trifluoromethyl, and nitro.

Most preferably, R is selected from 4-trifluoromethylbenzoyl.

X selected from O or C (R ₄ R ₅ ); of which, R ₄ , R ₅ independently selects alkyl groups from hydrogen, C ₁ -C ₂₀ , replaced or unsubspreaded C ₆ -C ₂₀ arcanel, and C ₆ -C ₂₀ aryl - C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ alkoxy, C ₆ -C ₂₀ aryl - C ₁ -C ₂₀ alkoxy, C ₆ -C ₂₀ Aryl - C ₁ -C ₂₀ alkoxyformyl. The substituent in "substituted or unsubstituted" is selected from the group consisting of halogen, C ₁ -C ₆ alkyl group, and C ₁ -C ₆ alkoxy group.

Preferably, R ₄ and R ₅ are independently selected from hydrogen, C ₁ -C ₆ alkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ aryl-C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₄ aryl group - C ₁ -C ₆ alkoxy group, C ₆ -C ₁₄ aryl group - C ₁ -C ₆ alkoxy group formyl. The substituent in "substituted or unsubstituted" is selected from the group consisting of halogen, C ₁ -C ₆ alkyl group, and C ₁ -C ₆ alkoxy group.

Further preferably, R ₄ and R ₅ are independently selected from hydrogen, methyl, benzyl, benzyloxy, substituted or unsubstituted phenyl, and benzyloxyformyl. The substituent in "substituted or unsubstituted" is selected from chlorine, bromine, fluorine, methyl, and tert-butyl.

According to the aforementioned preparation method of the present invention, the compound of formula 1 is selected from one of the compounds represented by the following formulas 1a-1r:

According to the aforementioned preparation method of the present invention, the compound of formula 2 is selected from one of the compounds represented by the following formulas 2a-2j:

According to the aforementioned preparation method of the present invention, the iron catalyst is selected from any one of FeCl ₂ , Fe(OAc) ₂ , Fe(OTf) ₂ , Fe(acac) ₂ and FeCl ₃ . FeCl ₂ is preferred.

According to the aforementioned preparation method of the present invention, the organic solvent is selected from any one of acetonitrile, DCE, toluene, and tert-butyl acetate. Acetonitrile is preferred.

According to the aforementioned preparation method of the present invention, the inert atmosphere is selected from an argon atmosphere or a nitrogen atmosphere, preferably an argon atmosphere.

According to the aforementioned preparation method of the present invention, the reaction temperature of the heating and stirring reaction is 60-100°C, preferably 80°C; the reaction time of the heating and stirring reaction is 4 to 48 hours, preferably 12 hours.

According to the aforementioned preparation method of the present invention, the molar ratio of the N -aryl enamide compound represented by Formula 1, the cyclobutanone oxime ester compound represented by Formula 2, the iron catalyst and K ₂ S ₂ O ₈ is 1: (1~2): (0.01~0.2): (1~3). Preferably, the molar ratio of the N -aryl enamide compound shown in Formula 1, the cyclobutanone oxime ester compound shown in Formula 2, the iron catalyst and K ₂ S ₂ O ₈ is 1: 1.5: 0.1: 2.

According to the aforementioned preparation method of the present invention, the post-treatment includes the following steps: filtering the reaction mixture, washing, drying the organic phase with anhydrous sodium sulfate, distilling the solvent under reduced pressure to obtain a residue, and coating the residue with a silica gel column The target product 3 was obtained by analytical separation (elution solvent was petroleum ether/ethyl acetate).

The method of the present invention achieves the following beneficial effects:

The invention provides a new cyanoalkylsulfonyl-substituted 3,3'-disubstituted indole-2-one compound and its synthesis method. In this method, under the catalytic conditions of an economical and cheap iron catalyst, N -aryl enamide compounds and cyclobutanone oxime ester compounds are broken through CC bonds and inserted into SO ₂ to construct cyanoalkylsulfonyl-substituted 3,3' - Disubstituted indole-2-one compounds. The olefin bifunctionalization of the method of the present invention involves a free radical mechanism, through a series process of imine radical generation, CC bond cleavage, SO ₂ insertion, sulfonyl radical addition and cyclization. The method of the present invention is novel and convenient, has good functional group adaptability and does not require the use of additional bases and oxidants.

Detailed ways

The present invention will be further described in detail below with reference to specific examples. In the following, unless otherwise specified, the method operations involved are routine methods in the art, and the reagents used can be obtained through commercial sources and/or prepared using synthetic methods known in the art.

Example 1-20 Reaction condition optimization test

Using N -phenyl enamide compounds represented by Formula 1a and cyclobutanone oxime ester compounds represented by Formula 2a as raw materials, the effects of different preparation process conditions on the yield of the target product 3aa were discussed. Representative examples are as follows: As shown in Example 1-20.

The reaction formula is as follows:

Example 1

Add the N-aryl enamide compound shown in formula 1a (0.2 mmol, 0.1M), the cyclobutanone oxime ester compound shown in formula 2a (0.3 mmol, 1.5 equiv), and FeCl ₂ to the Schlenk sealed tube reactor. (2.6 mg, 10 mol%), K ₂ S ₂ O ₈ (88.8 mg, 2 equiv) and acetonitrile (2 mL), then the reactor was placed in an 80°C oil bath under argon protection for stirring reaction 12 Hours, the reaction raw materials are completely consumed by TLC or GC-MS. The reaction mixture is filtered, washed, and the organic phase is dried with anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain a residue. The residue is separated by silica gel column chromatography (washed). The solvent was removed (petroleum ether/ethyl acetate) to obtain the target product 3aa. Yield: 36.7 mg, 62%; white solid; mp 147.8-148.5 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) d: 7.39-7.35 (m, 2H),7.14 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.72 (d, J = 14.4 Hz,1H), 3.60 (d, J = 14.8 Hz, 1H), 3.27 (s, 3H), 2.93- 2.86 (m, 1H), 2.82-2.75(m, 1H), 2.52-2.46 (m, 2H), 2.10-2.02 (m, 2H), 1.46 (s, 3H); ¹³ C{ ¹ H}NMR (100MHz , CDCl ₃ ) δ: 177.6, 143.2, 129.9, 129.1, 123.3, 122.7, 118.1, 108.9, 59.4,52.8, 45.4, 26.6, 25.0, 17.9, 16.1.

Example 2

The catalyst FeCl ₂ is not added, and the remaining conditions and operations are the same as in Example 1. The yield of the target product of Formula 3aa is 0%.

Example 3

The catalyst Fe(OAc) ₂ was used instead of FeCl ₂ . The remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 31%.

Example 4

Catalyst Fe(OTf) ₂ was used instead of FeCl ₂ . The remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 18%.

Example 5

Catalyst Fe(acac) ₂ was used instead of FeCl ₂ , and other conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 26%.

Example 6

Catalyst FeCl ₃ was used instead of FeCl ₂ . The remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 20%.

Example 7

The input amount of catalyst FeCl ₂ is 20 mol%. The remaining conditions and operations are the same as in Example 1. The yield of the target product of Formula 3aa is 61%.

Example 8

Na ₂ S ₂ O ₅ was used instead of K ₂ S ₂ O _5. The remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 40%.

Example 9

Thiourea dioxide was used instead of K ₂ S ₂ O ₅ . The remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 37%.

Example 10

DABSO replaced K ₂ S ₂ O ₅ , and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 24%.

Example 11

The feeding amount of K ₂ S ₂ O ₅ is 3 equivalents. The remaining conditions and operations are the same as in Example 1. The yield of the target product of Formula 3aa is 60%.

Example 12

The solvent DCE was used instead of acetonitrile, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 30%.

Example 13

The solvent THF was used instead of acetonitrile, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 0%.

Example 14

The solvent toluene was used instead of acetonitrile, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 34%.

Example 15

The solvent DMF was used instead of acetonitrile, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 0%.

Example 16

The solvent DMSO was used instead of acetonitrile, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 0%.

Example 17

The solvent tert-butyl acetate was used instead of acetonitrile, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 41%.

Example 18

The reaction temperature was replaced with 60°C, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 50%.

Example 19

The reaction temperature was replaced with 100°C, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 43%.

Example 20

The reaction time was replaced with 48 h, and the remaining conditions and operations were the same as in Example 1. The yield of the target product of Formula 3aa was 63%.

Substrate expansion test:

According to the reaction condition optimization test results of the present invention, the inventor selected the reaction conditions of Example 1 as the best reaction conditions, and further expanded various types of reaction substrates to investigate the best reaction conditions (i.e., the reaction of Example 1 Conditions) adaptability to different types of reaction substrates, the results are as follows:

Product characterization:

3af: Yield: 40.4 mg, 51%; white solid; mp 138.6-139.1 ^o C (uncorrected); ¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.38-7.27 (m, 2H), 7.19-7.15 (m, 2H), 7.11-7.03 (m,3H), 6.95-6.89 (m, 1H), 3.62-3.15 (m, 7H), 3.07-3.01 (m, 1H), 2.82-2.75 (m,2H), 2.34 ( s, 1.6H), 2.33 (s, 1.4H), 1.42 (s, 1.6H), 1.37 (s, 1.4H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.6 (d, J = 17.2 Hz, 1C), 143.4, 138.3 (d, J = 2.8Hz, 1C), 135.9 (d, J = 28.8 Hz, 1C), 130.2-129.8 (m, 1C), 129.3, 129.0,127.8, 126.9 (d, J = 10.6 Hz, 1C), 123.4, 122.7 (d, J = 16.5 Hz, 1C), 117.1,109.0 (d, J = 15.8 Hz, 1C), 60.3 (d, J = 14.4 Hz, 1C) , 58.4 (d, J = 62.8 Hz, 1C), 45.5 (d, J = 13.3 Hz, 1C), 35.2 (d, J = 53.0 Hz, 1C), 26.2 (d, J = 2.0Hz, 1C), 24.8 (t, J = 21.9 Hz, 1C), 21.1 (d, J = 1.8 Hz, 1C).

Yield: 42.3 mg, 46%; gray solid; mp 70.2-70.7 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.50-7.48 (m, 2H), 7.4 1-7.27 (m, 2H), 7.13-7.02 (m 3H), 7.00-6.90 (m, 1H), 3.67-3.44 (m, 3H), 3.29-3.25 (m, 3.4H), 3.05-3.00 (m, 1.6H), 2.83 -2.74 (m, 2H), 1.44 (s, 1.6H), 1.41 (s, 1.4H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.6 (d, J = 14.7 Hz, 1C ), 143.3 (d, J = 20.2 Hz, 1C), 137.9 (d, J = 20.0 Hz, 1C), 132.4, 130.1, 129.2 (d, J = 23.4 Hz, 1C), 128.8 (d, J = 9.8Hz , 1C), 127.8, 125.7 (d, J = 3.7 Hz, 1C), 123.3, 122.6 (t, J = 13.4 Hz, 1C), 116.8, 109.1 (d, J = 15.9 Hz, 1C), 60.4 (d, J = 3.6 Hz, 1C), 57.8 (d, J =51.3 Hz, 1C), 45.5 (d, J = 14.4 Hz, 1C), 34.8 (d, J = 43.5 Hz, 1C), 26.6,24.7 (t, J = 29.7 Hz, 1C).

Yield: 36.3 mg, 44%; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.44-7.25 (m, 7H), 7.16-7.1 3 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.71-4.52 (m,2H), 4.23-4.18 (m, 1H), 3.79-3.67 (m, 1.6H), 3.52 (d, J = 14.4 Hz, 0.4H), 3.24 (t , J = 6.4 Hz, 3.3H), 3.07-3.00 (m, 1H), 2.74-2.62 (m, 2H), 2.45-2.40(m, 0.7H), 1.32 (s, 1.3H), 1.23 (s, 1.7H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ:177.8 (d, J = 3.4 Hz, 1C), 143.3 (d, J = 27.9 Hz, 1C), 136.1 (d, J = 17.9 Hz, 1C), 130.2, 129.1 (t, J = 22.3 Hz, 1C), 128.8-128.2 (m, 1C), 127.8, 124.0,123.4, 122.6 (d, J = 14.6 Hz, 1C), 115.9 (d , J = 39.3 Hz, 1C), 108.8 (d, J =6.9 Hz, 1C), 72.7 (d, J = 30.9 Hz, 1C), 70.0 (d, J = 69.3 Hz, 1C), 60.8 (d, J = 30.6 Hz, 1C), 58.2 (d, J = 73.8 Hz, 1C), 45.3 (d, J = 6.7 Hz, 1C), 26.5,24.9 (d, J = 27.1 Hz, 1C), 22.7 (d, J = 45.8 Hz, 1C).

Yield: 41.4 mg, 47%; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.40-7.30 (m, 7H), 7.11-7.06 (m, 1H), 6.90 (t, J = 8.0 Hz, 1H), 5.21-5.13 (m, 2H), 3.76 (d, J = 14.4 Hz, 1H), 3.65-3.59 (m, 1H), 3.44-3.33 (m, 0.5H), 3.32-3.12(m , 5H), 2.88-2.79 (m, 2.5H), 1.44 (s, 1.5H), 1.44 (s, 1.5H); ¹³ C{ ¹ H}NMR (100MHz, CDCl ₃ ) δ: 177.6 (d, J = 5.6 Hz, 1C), 169.2 (d, J = 8.2 Hz, 1C), 143.3 (d, J = 11.6 Hz, 1H), 134.5 (d, J = 3.1 Hz, 1C), 129.3 (d, J = 15.4 Hz, 1C),128.8-128.7 (m, 1C), 128.6, 127.8, 125.7 (d, J = 3.7 Hz, 1C), 123.4, 122.8,116.3 (d, J = 18.5 Hz, 1C), 109.0 (d, J = 9.3 Hz, 1C), 68.4 (d, J = 5.4 Hz, 1C), 60.5 (d, J = 11.7 Hz, 1C), 53.9 (d, J = 4.0 Hz, 1C), 45.5 (d, J = 6.3Hz, 1C), 35.7 (d, J = 1.9 Hz, 1C), 26.6 (d, J = 1.4 Hz, 1C), 25.0 (d, J = 9.4Hz, 1C), 19.3 (d, J = 3.4 Hz , 1C).

Yield: 33.9 mg, 55%; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.32-7.28 (m, 1H), 7.19-7.17 (m, 1H), 7.11-7.07 (m, 1H ), 6.88 (d, J = 7.6 Hz, 1H), 4.03-3.94 (m, 2H), 3.40-3.33 (m, 1H), 3.28-3.22 (m, 4H), 2.41-2.37 (m, 1H), 2.03-1.99 (m, 1H), 1.39 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 180.2, 143.2,132.6, 128.1, 122.5, 122.5, 115.6, 108.3, 68.1, 55.8, 46.3, 36.7, 26.2, 24.4.

Yield: 44.2 mg, 60%; white solid; mp 165.0-165.5 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.56-7.52 (m, 2H), 7.47-7.38 (m, 4H ), 7.28 (d, J = 0.8Hz, 1H), 7.18 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.84 (d, J =14.8 Hz, 1H), 3.67 (d, J = 14.4 Hz, 1H), 2.98-2.91 (m, 1H), 2.86-2.79 (m ,1H), 2.53- 2.44 (m, 2H), 2.13-2.07 (m, 2H), 1.57 ( s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.3, 143.6, 134.2, 129.7, 129.6, 129.1, 128.4, 126.7, 123.5,123.1, 118.1, 110.2, 59.9 , 53.1, 45.6 , 25.5, 18.1, 16.2.

Yield: 50.4 mg, 66 %; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.36-7.27 (m, 6H), 2.26-7.22 (m, 1H), 7.12-7.10 (m, 1H) ), 6.80 (d, J = 7.6 Hz, 1H), 5.05 (d, J = 15.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 3.78 (d, J = 14.8Hz, 1H), 3.62 (d, J = 14.8 Hz, 1H), 2.93-2.88 (m, 1H), 2.86-2.78 (m, 1H), 2.47-2.43 (m, 2H), 2.10-2.02 (m, 2H), 1.51 ( s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.8, 142.3, 135.5, 130.1, 129.0, 128.8, 127.7, 127.3, 123.4,122.8, 118.1, 110.0, 59.1 , 52.9, 45.6 , 44.2, 25.8, 18.0, 16.1.

Yield: 40.4 mg, 51%; colorless oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.36-7.34 (m, 1H), 7.25-7.21 (m, 3H), 7.14-7.07 (m, 3H), 6.81 (d, J = 8.0 Hz, 1H), 5.00 (d, J = 15.6 Hz, 1H), 4.8 3 (d, J = 15.6 Hz, 1H), 3.77 (d, J = 14.8 Hz, 1H ), 3.61 (d, J = 14.8 Hz, 1H), 2.92-2.84 (m, 1H), 2.83-2.79 (m, 1H), 2.46-2.42 (m, 2H), 2.32 (s, 3H), 2.09- 2.04 (m, 2H), 1.50 (s, 3H); ¹³ C{ ¹ H}NMR (100MHz, CDCl ₃ ) δ: 177.7, 142.4, 137.4, 132.4, 130.1, 129.4, 129.0, 127.3, 123.3,122.7, 1 18.1 , 110.0, 59.1, 52.9, 45.5, 44.0, 25.7, 21.1, 18.0, 16.1.

Yield: 34.4 mg, 43%; green oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.36-7.31 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.04-7.00(m, 2H), 6.77 (d, J = 7.6 Hz, 1H), 4.98-4.87 (m, 2H), 3.79 (d, J = 14.4 Hz,1H), 3.63 (d, J = 14.4 Hz, 1H), 2.97-2.90 (m, 1H), 2.87-2.79 (m, 1H), 2.50-2.46 (m, 2H), 2.11-2.06 (m, 2H), 1.50 ( s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.8, 162.2 (d, J = 244.6 Hz, 1C), 142.2, 131.2 (d, J = 3.1 Hz, 1C), 130.0 ,129.1 (t, J = 5.5 Hz, 1C), 123.4, 122.9, 118.0, 115.8, 115.6, 109.9, 59.1,53.0, 45.5, 43.6, 25.9, 18.0, 16.2; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ : -114.6 (s,1F).

Yield: 16.8 mg, 25%; white solid; mp 90.6-91.2 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.24 (s, J = 8.0 Hz, 1H), 6.64-6. 62 (m, 1H), 6.50 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 3.69 (d, J = 14.8 Hz, 1H), 3.53 (d, J = 14.4 Hz, 1H), 3.24 (s, 3H), 2.92-2.86 (m, 1H), 2.83-2.78 (m, 1H), 2.53-2.49 (m, 2H), 2.12-2.07 (m, 2H), 1.44 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 178.3, 160.9,144.6, 124.1, 121.6, 118.0, 106.6, 96.9, 59.7, 55.5, 52.8, 45.0, 26.7, 25.2,18.0, 16.2.

': Yield: 21.5 mg, 32%; white solid; mp 156.0-156.5 ^o C (uncorrected); ¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.34 (t, J = 8.0 Hz, 1H), 6.68 (d , J = 8.4 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 3.94 (d, J = 15.2 Hz, 4H), 3.67 (d, J = 14.4 Hz, 1H), 3,25 (s ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 178.0, 155.9,144.7, 130.6, 118.1, 115.4, 105.8, 102.4, 58.1, 55.6, 52.0, 45.1, 26.8, 22.7,17.8, 16.3 .

Yield: 13.6 mg, 20%; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.32 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 4.10 (d, J = 14.8 Hz, 1H), 3.73 (d, J = 14.4 Hz, 1H), 3.27 (s, 3H), 2.99-2.92 (m,1H) , 2.81-2.74 (m, 1H), 2.49 (t, J = 7.2 Hz, 2H), 2.12-2.07 (m, 2H), 1.56 (s,3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.1, 145.3, 130.7, 130.5, 126.1, 123.5,118.0, 107.5, 57.3, 52.2, 46.2, 26.9, 22.0, 17.9, 16.1.

': Yield: 21.1 mg, 31%; yellow solid; mp 135.9-136.6 ^o C (uncorrected); ¹ HNMR (400 MHz, CDCl ₃ ) δ: 7.29 (s, 1H), 7.12-7.10 (m, 1H) , 6.92 (d, J = 2.4 Hz, 1H), 3.72 (d, J = 14.8 Hz, 1H), 3.56 (d, J = 14.4 Hz, 1H), 3.25 (s, 3H), 3.04-2.90 (m, 2H), 2.55-2.50 (m, 2H), 2.16-2.08 (m, 2H), 1.45 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.8, 144.4, 135.0, 128.4, 124.4, 122.7, 118.0,109.7, 59.1, 53.0, 45.2, 26.8, 25.2, 18.0, 16.2.

Yield: 47.7 mg, 71%; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.97 (d, J = 2.4 Hz, 1H), 6.89-6.82 (m, 2H), 3.81 (s, 3H), 3.70 (d, J = 14.8 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 3.26 (s, 3H), 2.98-2.83 (m, 2H), 2.51 (t, J = 6.8 Hz, 2H), 2.13-2.06 (m, 2H), 1.45 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ:177.3, 156.0, 136.6, 131.4, 118.1, 112.9, 111.1 , 109.2, 59.4, 55.8, 52.9,45.9, 26.7, 25.1, 18.0, 16.1.

Yield: 54.1 mg, 68%; colorless oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.35-7.30 (m, 2H), 7.10-7.00 (m, 5H), 6.88 (d, J = 8.4 Hz, 1H), 3.72 (d, J = 14.4Hz, 1H), 3.51 (d, J = 14.4 Hz, 1H), 3.02( s , 3H), 3.00-2.89 (m, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.15-2.08 (m, 2H), 1.44 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ )δ: 177.6, 158.0, 152.5, 139.0, 131.6, 129.7, 122.8, 120.1, 118.0, 117.8,116.1, 109.6, 59.1, 52.9, 45.8, 26.8, 25.2, 18.0, 16.2.

Yield: 47.4 mg, 74%; white solid; mp 123.9-124.6 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.15 (d, J = 4.8 Hz, 2H), 6.82-6.80 ( m, 1H), 3.71 (d, J =14.8 Hz. 1H), 3.55 (d, J = 14.8 Hz, 1H), 3.25 (s, 3H), 2.96-2.89 (m, 1H),2.86-2.79 (m , 1H), 2.51-2.48 (m, 2H), 2.37 (s, 3H), 2.12-2.05 (m, 2H), 1.45(s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.6, 140.8, 132.4, 130.1, 129.4,124.1, 118.0, 108.7, 59.6, 52.9, 45.6, 26.7, 25.2, 21.2, 18.0, 16.2.

Yield: 52.9 mg, 73%; yellow solid; mp 107.2-107.8 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.39-7.36 (m, 2H), 6.86-6.84 (m, 1H ), 3.70 (d, J = 14.8Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 3.25 (s, 3H), 2.93-2.86 (m, 1H), 2.76-2.68 (m, 1H) , 2.53-2.44 (m, 2H), 2.11-2.04 (m, 2H), 1.48 (s, 3H), 1.33 (s,9H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.8 , 146.0, 140.8, 129.6, 125.7, 120.8,118.0, 108.3, 59.8, 52.8, 45.7, 34.6, 31.5, 26.6, 25.0, 17.9, 16.2.

Yield: 42.8 mg, 66%; white solid; mp 160.1-160.7 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.14-7.12 (m, 1H), 7.09-7.04 (m, 1H ), 6.87-6.83 (m, 1H), 3.72 (d, J = 14.8 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 3.26 (s, 3H), 3.05-2.91(m, 2H) , 2.54 (t, J = 6.8 Hz, 2H), 2.17-2.10 (m, 2H), 1.46 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.4, 159.2 (d , J = 240 Hz, 1C), 139.1, 131.7 (d, J =8.0 Hz, 1C), 118.0, 115.4 (d, J = 23.3 Hz, 1C), 111.8 (d, J = 24.9 Hz, 1C), 109.4 (d, J = 8.1 Hz, 1C), 59.1, 53.0, 45.9 (d, J = 1.7 Hz, 1C), 26.8, 25.1,18.0, 16.2; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ: -119.5 ( s, 1F).

Yield: 43.5 mg, 64%; gray solid; mp 156.0-156.5 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.32 (t, J = 8.8 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 3.72(d, J = 14.8 Hz, 1H), 3.56 (d, J = 14.4 Hz, 1H), 3.25 (s, 3H), 3.04-2.90 (m,2H), 2.53 ( t, J = 7.2 Hz, 2H), 2.16-2.08 (m, 2H), 1.46 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.3, 141.7, 131.8, 129.0, 128.2, 124.0, 118.0, 109.8,59.1, 53.0, 45.7, 26.8, 25.1, 18.0, 16.2.

Yield: 46.1 mg, 60%; gray oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.49-7.47 (m, 2H), 6.81-6.79 (m, 1H), 3.72 (d, J = 14.8 Hz, 1H), 3.56 (d, J = 14.4Hz, 1H), 3.23 (s, 3H), 3.03-2.90 (m, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.16-2.08(m , 2H), 1.46 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.2, 142.2, 132.2,131.9, 126.7, 118.0, 115.4, 110.3, 59.1, 53.0, 45.6, 26 .7 , 25.1, 18.0, 16.2.

Yield: 43.2 mg, 55%; yellow solid; mp 108.2-108.7 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.68 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 3.71 (d, J = 14.4Hz, 1H), 3.56 (d, J = 14.4 Hz, 1H), 3.24 (s, 3H), 2.98-2.91 (m, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.15-2.07 (m, 2H), 1.45 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ )δ: 177.0, 142.9, 137.8, 132.6, 132.2, 118.0, 110.9 , 85.0, 59.1, 53.0, 45.4,26.7, 25.1, 18.0, 16.2.

Yield: 37.4 mg, 50%; yellow solid; mp 59.8-60.3 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.63 (t, J = 8.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 3.76(d, J = 14.4 Hz, 1H), 3.66 (d, J = 14.4 Hz, 1H), 3.30 (s, 3H), 3.03-2.87 (m,2H), 2.50 ( t, J = 7.2 Hz, 2H), 2.13-2.06 (m, 2H), 1.48 (s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 177.8, 146.2, 130.7, 126.7 ( q, J = 3.9 Hz, 1C), 124.8 (q, J = 32.6 Hz, 1C), 124.2 (q, J = 270 Hz, 1C), 120.7 (q, J = 3.7 Hz, 1C), 118.1, 108.6, 58.8, 53.0, 45.3, 26.8, 25.0, 17.9, 16.0; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ: -61.3 (s, 3F).

Yield: 33.3 mg, 44%; white solid; mp 80.1-80.6 ^o C (uncorrected); ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.12-8.10 (m, 1H), 8.01 (d , J = 1.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.42-4.34 (m, 2H), 3.77 (d, J = 14.8 Hz, 1H), 3.65 (d, J =14.4 Hz, 1H), 3.30 (s, 3H), 2.99-2.83 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.13-2.05 (m, 2H), 1.47 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); ¹³ C{ ¹ H}NMR (100MHz, CDCl ₃ ) δ: 178.1, 166.1, 147.3, 131.7, 130.1, 125.1, 124.5, 118.0, 108.4,61.1, 59.2, 53.0, 45.3 , 26.9, 25.2 , 18.0, 16.1, 14.3.

Yield: 45.8 mg, 60%; yellow oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.31-7.28 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.15-7.07 ( m, 4H), 6.80 (d, J = 6.8Hz, 2H), 6.68 (d, J = 8.0 Hz, 1H), 3.88 (d, J = 14.4 Hz, 1H), 3.67 (d, J =14.4 Hz, 1H), 3.07 (t, J = 4.8 Hz, 2H), 3.02 (s, 3H), 2.92-2.90 (m, 1H), 2.87-2.80 (m, 1H), 2.49 (t, J = 4.8 Hz, 2H ), 2.12-2.05 (m, 2H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 176.5, 143.8, 133.2, 130.1, 129.3, 127.7, 127.3, 127.2,124.5, 122.2, 118.0, 108.6 , 58.5, 53.1, 50.8, 44.6, 26.3, 18.0, 16.2.

Yield: 39.3 mg, 54%; colorless oily liquid; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.43-7.38 (m, 2H), 7.16-7.12 (m, 1H), 6.95 (d, J = 7.6 Hz, 1H), 4.39 (d, J = 10.8Hz, 1H), 4.08 (d, J = 11.2 Hz, 1H), 3.82-3.75 (m, 2H), 3.23 (s, 3H), 3.01-2.94 ( m, 1H), 2.90-2.83 (m, 1H), 2.55-2.49 (m, 2H), 2.13-2.06 (m, 2H), 2.04(s, 3H); ¹³ C{ ¹ H}NMR (100 MHz, CDCl ₃ ) δ: 174.4, 169.9, 143.9, 130.0, 125.9, 124.6, 122.8, 118.0, 109.1, 66.9, 55.9, 53.2, 49.1, 26.8, 20.6, 18.0, 16.2.

The above-described embodiments are only preferred embodiments of the present invention, and are not an exhaustive list of possible implementations of the present invention. For those skilled in the art, any obvious modifications made without departing from the principle and spirit of the present invention should be considered to be included in the scope of the claims of the present invention.

Claims (10)

1. A preparation method of 3,3’-disubstituted indole-2-one compounds, comprising the following steps: Add the N-aryl enamide compound shown in Formula 1, the cyclobutanone oxime ester compound shown in Formula 2, iron catalyst, K ₂ S ₂ O ₈ and organic solvent into the reactor, and then place the reactor in Under an inert atmosphere, heat and stir the reaction in an oil bath, monitor the complete reaction of the raw materials by TLC or GC-MS, and obtain the target product shown in Formula 3 after post-processing; ; Among them, the N-aryl enamide compound represented by Formula 1 is selected from one of the compounds represented by the following formulas 1a-1r: ; The cyclobutanone oxime ester compound represented by formula 2 is selected from one of the compounds represented by the following formulas 2a-2j: ; And wherein, the iron catalyst is selected from any one of FeCl ₂ , Fe(OAc) ₂ , Fe(OTf) ₂ , Fe(acac) ₂ and FeCl ₃ ; the organic solvent is selected from acetonitrile, DCE, Either toluene or tert-butyl acetate. 2. The preparation method according to claim 1, characterized in that: the iron catalyst is selected from FeCl ₂ . 3. The preparation method according to claim 1, characterized in that: the organic solvent is selected from acetonitrile. 4. The preparation method according to any one of claims 1 to 3, characterized in that the inert atmosphere is selected from an argon atmosphere or a nitrogen atmosphere. 5. The preparation method according to claim 4, characterized in that the inert atmosphere is an 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 60-100°C; the reaction time of the heating and stirring reaction is 4 to 48 hours. 7. The preparation method according to claim 6, characterized in that the reaction temperature of the heating and stirring reaction is 80°C, and the reaction time of the heating and stirring reaction is 12 hours. 8. The preparation method according to any one of claims 1-3, characterized in that: N-aryl enamide compounds shown in formula 1, cyclobutanone oxime ester compounds shown in formula 2, iron catalyst The feeding molar ratio of K ₂ S ₂ O ₈ is 1: (1~2): (0.01~0.2): (1~3). 9. The preparation method according to claim 8, characterized in that N-aryl enamide compounds shown in formula 1, cyclobutanone oxime ester compounds shown in formula 2, iron catalyst and K ₂ S ₂ The feeding molar ratio of O ₈ is 1: 1.5: 0.1: 2. 10. The preparation method according to any one of claims 1-3, characterized in that: the post-treatment includes the following steps: filtering the reaction mixture, washing, drying the organic phase with anhydrous sodium sulfate, and distilling under reduced pressure. The solvent was used to obtain a residue, which was separated by silica gel column chromatography to obtain the target product 3.