CN106423281A - Application of tris(bis(trimethylsilyl)amino)lanthanum to catalyzed preparation of spiro[cyclopropane-1,3'-indole] compound - Google Patents

Abstract

The invention discloses application of tris(bis(trimethylsilyl)amino)lanthanum to catalyzed preparation of a spiro[cyclopropane-1,3'-indole] compound. The chemical formula of tris(bis(trimethylsilyl)amino)lanthanum is [(Me3Si)2N]3Ln(Mu-Cl)Li(THF)3, and can be taken as a catalyst for catalyzing substitution of isatin, phosphite ester and olefin to prepare the spiro[cyclopropane-1,3'-indole] compound through a one-pot reaction; in the catalyst, (Me3Si)2N represents trimethylsilylamino; Ln represents positive trivalent rare earth metal ions, and is selected from one of lanthanum, samarium, gadolinium, erbium or ytterbium; Mu- represents a bridged bond; THF represents tetrahydrofuran. In the method, a catalyst synthesizing method is simple, reaction raw materials are simple and readily available, a substrate has a wide application range, the one-pot reaction has high efficiency, reaction conditions are mild, and the yields of most target products are 85 percent or more.

Description

The role of rare earth silamide in the catalytic preparation of spiro[cyclopropane-1,3′-indole] compounds application

technical field

The invention belongs to the technical field of preparation of isatin derivatives, and specifically relates to the application of a rare earth silamide in the catalytic preparation of spiro[cyclopropane-1,3'-indole] compounds.

Background technique

The spiro[cyclopropane-1,3′-indole] skeleton widely exists in many natural products and drug molecules, and some herbicides, inhibitors and antagonists that have been applied use it as the main structural unit. In addition, the spiro[cyclopropane-1,3′-indole] skeleton is also used as an intermediate for the synthesis of some important alkaloids. Therefore, it is of great theoretical and practical significance to study the efficient synthesis technology of spiro[cyclopropane-1,3′-indole] skeleton.

In the prior art, the reported synthetic routes of the spiro[cyclopropane-1,3′-indole] skeleton are relatively limited, mainly including four types of methods. First, Pd catalyzes the direct arylation reaction of cyclopropane (see Ladd, CL; Roman, DS; Charette, AB Org. Lett. 2013, 15 , 1350.); second, the activation of sulfur and phosphorus ylides under stoichiometric alkali conditions Reaction of double bonds (see Ranieri, B.; Sartori, A.; Curti, C.; Battistini, L.; Rassu, G.; Pelosi, G.; Casiraghi, G.; Zanardi, F. Org. Lett. 2014 , 16 , 932.); third, the reaction of diazo compounds with activated double bonds (see Karthik, G.; Rajasekaran, T.; Sridhar, B.; Reddy, BVS Tetrahedron Lett. 2014, 55 , 7064.); Fourth, the reaction of halogenated hydrocarbons with activated double bonds under stoichiometric alkali conditions (see Zhao, B.; Du, D. Eur. J. Org. Chem. 2015, 5350.). The above methods can produce spiro[cyclopropane-1,3′-indole] compounds, but there are some defects generally, such as the complex structure of the reaction raw materials requires pre-synthesis, the use of diazonium reagents, the presence of metered bases or noble metal catalysis, the reaction The conditions are harsh, and so on. In view of the good biological activity of spiro[cyclopropane-1,3′-indole] compounds, it is necessary to find a synthetic method with simple source of raw materials, high activity, mild reaction conditions and good universality to effectively prepare spiro[ Cyclopropane-1,3'-indole] compounds are necessary.

Contents of the invention

The purpose of the present invention is to provide the application of a rare earth silamide in catalytic preparation of spiro[cyclopropane-1,3'-indole] compound. Synthesis of spiro[cyclopropane-1,3'-indole] compounds through the reaction of rare earth silamide catalyzed substitution of isatin, phosphite and activated alkenes, which is a kind of simple raw material source, high activity, mild reaction conditions and universal application Sexy way.

In order to achieve the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is:

The application of silicon amino rare earth compounds as catalysts to catalyze the reaction of replacing isatin, diethyl phosphite and olefins;

The chemical structural formula of described silicon amino rare earth compound is as follows:

Wherein, Ln is positive trivalent rare earth metal ion.

The silicon amino rare earth compound of the present invention is used as a catalyst to catalyze the reaction of substituted isatin, diethyl phosphite and alkene to prepare spiro [cyclopropane-1,3'-indole] compound. According to molar ratio, catalyst: substituted isatin : phosphite: olefin=(0.33～0.50): 1: (1～1.5): (2～5); the reaction temperature is room temperature～50°C; the reaction time is 3～10 hours.

In the above-mentioned technical scheme, the chemical structure general formula of described substituted isatin is as follows:

Wherein, R ¹ is selected from one of allyl, benzyl, ethyl; R ² is selected from hydrogen, 4-chloro, 5-chloro, 4-bromo, 5-methyl, 5-fluoro, 7-fluoro one of

The general chemical structure formula of described olefin is as follows:

Wherein, ^R3 is selected from one of methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, acetyl, benzoyl, thiophene- ² -formyl, dimethoxyphosphoryl; R4 is selected from hydrogen, One of methyl and ethoxycarbonyl; R5 is selected from one of hydrogen, phenyl, ethoxycarbonyl, p ^- methylphenyl, p-methoxyphenyl, and p-trifluoromethylphenyl.

In the above technical solution, the reaction is carried out in an organic solvent; the organic solvent is one or more of acetonitrile, dichloromethane, ethylene glycol dimethyl ether, tetrahydrofuran, and ethylene glycol diethyl ether; preferably acetonitrile. The solvent has an important influence on the organic synthesis reaction, especially for the one-pot reaction of many raw materials, the solvent will affect the reaction environment, thereby affecting the target product and yield; the preferred acetonitrile of the present invention has good solubility to catalysts and all substrates, and Acetonitrile has the appropriate polarity, which can induce the reaction to generate active intermediates in situ and quickly initiate a series of cyclization processes to generate the target product; it can well disperse the reaction raw materials and provide a good reaction environment. Under the same conditions, the yield in acetonitrile 84%, much higher than other solvents, and achieved the next technical effect.

The chemical formula of the catalyst of the present invention: [(Me ₃ Si) ₂ N] ₃ Ln( μ -Cl)Li(THF) ₃ , where (Me ₃ Si) ₂ N represents trimethylsilylamino, and Ln represents positive trivalent Rare earth metal ions, selected from one of lanthanum, samarium, gadolinium, erbium or ytterbium; μ - represents bridge bond; THF represents tetrahydrofuran.

In the present invention, the phosphite is diethyl phosphite; the general chemical structure formula of the reaction product spiro[cyclopropane-1,3'-indole] compound is as follows:

.

In the above technical solution, the said condition of anhydrous and oxygen-free is preferably in an inert atmosphere.

In the above technical scheme, the general formula of the catalyst is: [(Me ₃ Si) ₂ N] ₃ Ln( μ -Cl)Li(THF) ₃ ; wherein, Ln represents a positive trivalent rare earth metal ion selected from the group consisting of lanthanum, One of samarium, gadolinium, erbium or ytterbium, preferably ytterbium, under the same conditions, compared to the other four metals, the reaction catalyzed by it has a higher yield for spiro[cyclopropane-1,3'-indole] compound formation higher. The preparation method of above-mentioned catalyst is as follows:

(1) At -10°C, slowly add n -BuLi hexane solution (60 mmol, 2.52 M) into a 100 mL Schlenk reaction flask filled with (Me ₃ Si) ₂ NH (60 mmol), and react at room temperature 30 minutes;

(2) Add the above reaction solution to anhydrous LnCl ₃ (20 mmol) in THF (30 mL) suspension, and stir overnight at room temperature;

(3) The solvent was removed under reduced pressure, and the obtained solid powder was extracted with hot toluene to remove LiCl, concentrated, placed at 0°C, and a large number of crystals were precipitated, which was the desired silicon amino rare earth compound.

In the above-mentioned technical scheme, the consumption of described catalyst is 33～50% of the molar number of substituting isatin, preferably 40%; The consumption of catalyst of the present invention makes reaction carry out efficiently, avoids increasing reaction cost simultaneously and simplifies the aftertreatment of reaction system .

In the above-mentioned technical scheme, the consumption of described diethyl phosphite is 1～1.5 times of the molar quantity of substituted isatin; The consumption of preferred phosphite is 1.2 times of the molar quantity of substituted isatin; Diethyl phosphite of the present invention The amount of ester is conducive to the complete reaction, while avoiding the waste caused by diethyl phosphite being unable to react completely, and also beneficial to post-processing.

In the above technical scheme, the amount of the olefin is 2 to 5 times the molar amount of the substituted isatin; the preferred amount of the olefin is 3 times the molar amount of the substituted isatin; the amount of the olefin of the present invention is conducive to the improvement of the reaction yield , avoiding waste, and also beneficial to post-processing.

In the above technical scheme, the reaction temperature is room temperature to 50°C, preferably room temperature; the reaction time is 3 to 10 hours, preferably 5 hours; the reaction conditions disclosed in the present invention are mild, and the room temperature operation is conducive to industrial production. In the case of low yield, reduce production requirements and avoid potential safety hazards.

In the above technical scheme, the reaction process includes under anhydrous and oxygen-free conditions, the silicon amino rare earth compound [(Me ₃ Si) ₂ N] ₃ Ln( μ -Cl)Li(THF) ₃ , substituted isatin, phosphite , activated olefins and organic solvents were mixed, stirred at room temperature to 50°C for 3 to 10 hours, the reaction was terminated, extraction was performed, the extract was dried with a desiccant, filtered, the solvent was removed under reduced pressure, and finally obtained by flash column chromatography [Cyclopropane-1,3'-indole] compound. In the preferred technical scheme, water is used to terminate the reaction, the extractant is ethyl acetate, the desiccant is anhydrous sodium sulfate, and the eluent is ethyl acetate/petroleum ether system (volume ratio is 1: 7), and the post-treatment of the present invention is simple , the pure product can be effectively obtained after post-treatment without causing waste.

The present invention further discloses the application of the silicon amino rare earth compound in the catalytic preparation of spiro[cyclopropane-1,3'-indole] compounds; when spiro[cyclopropane-1,3'-indole] compounds are preferably prepared, The reaction temperature is from room temperature to 50°C, and the reaction time is from 3 to 10 hours.

Above-mentioned technical scheme can be expressed as follows:

Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art:

1. The present invention uses the silicon amino rare earth compound [(Me ₃ Si) ₂ N] ₃ Ln( μ -Cl)Li(THF) ₃ as a catalyst to catalyze the reaction of replacing isatin, phosphite and olefin for the first time, and can prepare spiro[cyclopropane -1,3'-indole] compound, the raw materials are simple and easy to obtain, the reaction conditions are mild (room temperature), the reaction time is short (5 hours), and the yield of the target product is high, which can reach more than 90%.

2. The application disclosed by the invention adopts a one-pot reaction method, adding catalyst, substituted isatin, phosphite and olefin into the solvent for one-step reaction, high reaction efficiency, simple and controllable reaction conditions, and simple post-treatment, which overcomes the existing technology The disadvantages of pre-synthesizing raw materials, multi-step operations, and complex post-processing are required to prepare products.

3. The application method disclosed in the present invention has universal applicability to various substituted isatins and activated alkenes, not only can obtain the carbocycle-linked carbonyl structure, but also obtain the spiro[cyclopropane-1,3′ with carbocycle-linked phosphate ester structure for the first time. -indole] compound greatly enriches the structure of spiro[cyclopropane-1,3'-indole] compound, expands its application, and achieves unexpected technical effects.

4. The method disclosed by the invention does not use a noble metal catalyst, does not use a metered strong base, the reaction cost is low, and it is also beneficial to protect the environment; at the same time, the catalyst used in the invention has a simple synthesis method and a high yield, and the entire preparation of spiro[cyclopropane-1, The process of the 3'-indole] compound is controllable, and the reaction conditions are mild, which is beneficial to industrial production.

detailed description

The present invention will be further described below in conjunction with embodiment:

Example 1: Synthesis of catalyst [(Me ₃ Si) ₂ N] ₃ La( μ -Cl)Li(THF) ₃

At -10°C, a hexane solution of n-BuLi (60 mmol, 2.52 M) was slowly added into a 100 mL Schlenk reaction flask filled with (Me ₃ Si) ₂ NH (60 mmol), and reacted at room temperature for 30 minutes. The above reaction solution was added to a suspension of anhydrous LaCl ₃ (20 mmol) in THF (30 mL), and stirred overnight at room temperature. The solvent was removed under reduced pressure, and the obtained solid powder was extracted with hot toluene to remove LiCl, concentrated, placed at 0°C, and a large number of crystals were precipitated, which was the desired lanthanum siliconamide compound, with a yield of 85%.

Other catalysts can refer to the preparation method of Example 1.

Example 2: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 84%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.25 (t, J = 6.8 Hz, 1H), 7.03 (t, J = 7.6Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.85 ( d, J = 6.8 Hz, 1H), 5.89–5.80 (m,1H), 5.26–5.20 (m, 2H), 4.39 (d, J = 5.2 Hz, 2H), 3.74 (s, 3H), 2.67 (t , J =8.4 Hz, 1H), 2.40 (dd, J = 8.0, 4.8 Hz, 1H), 1.83 (dd, J = 8.4, 4.8 Hz, 1H).

Example 3: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Er( μ -Cl)Li(THF) ₃ (0.1497 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 68%.

Example 4: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Gd( μ -Cl)Li(THF) ₃ (0.1480 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 62%.

Example 5: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Sm( μ -Cl)Li(THF) ₃ (0.1469 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 68%.

Example 6: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ La( μ -Cl)Li(THF) ₃ (0.1450 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 81%.

Example 7: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 91%.

Example 8: Preparation of spiro[cyclopropane-1,3′-indole] compound by reaction of N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.2282 g, 0.25 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 92%.

Example 9: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.5 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 69%.

Example 10: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.75 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 85%.

Example 11: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.0 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 78%.

Example 12: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 ml), methyl acrylate (2.0 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 85%.

Example 13: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (2.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 83%.

Example 14: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Then, stir at room temperature for 3 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 78%.

Example 15: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 8 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 81%.

Example 16: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1506 g, 0.165 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 10 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a colorless oily product with a yield of 80%.

Example 17: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and n-butyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), n-butyl acrylate (1.5 mmol) in turn, mix After uniformity, stir at room temperature for 5 hours, add water to terminate the reaction, extract with ethyl acetate three times, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate Ester:petroleum ether=1:7) to obtain a colorless oily product with a yield of 88%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.25 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.85 ( d, J = 7.6 Hz, 1H), 5.89–5.79 (m,1H), 5.25–5.20 (m, 2H), 4.45–4.33 (m, 2H), 4.21–4.05 (m, 2H), 2.66 (t, J =8.4 Hz, 1H), 2.39 (dd, J = 8.0, 4.8 Hz, 1H), 1.82 (dd, J = 8.4, 4.8 Hz, 1H),1.64–1.57 (m, 2H), 1.40–1.31 (m , 2H), 0.91 (t, J = 7.2 Hz, 3H).

Example 18: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl methacrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , followed by adding acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl methacrylate (1.5 mmol), After mixing, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: acetic acid Ethyl ester:petroleum ether=1:7) to obtain a white solid product with a yield of 93%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.27 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.2Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.91 ( d, J = 7.6 Hz, 1H), 5.89–5.79 (m,1H), 5.25–5.19 (m, 2H), 4.44–4.30 (m, 2H), 3.73 (s, 3H), 2.48 (d, J = 5.2 Hz, 1H), 1.61 (s, 3H), 1.60 (d, J = 5.2 Hz, 1H).

Example 19: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and methyl cinnamate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), methyl cinnamate (1.5 mmol) in turn, mix After homogenization, stir at 50°C for 5 hours, add water to terminate the reaction, extract with ethyl acetate three times, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: acetic acid Ethyl ester:petroleum ether=1:7) to obtain a yellow solid product with a yield of 60%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.33–7.28 (m, 3H), 7.19–7.12 (m, 3H), 6.86(d, J = 7.6 Hz, 1H), 6.70 (t, J = 7.6 Hz , 1H), 5.98 (d, J = 7.6 Hz, 1H), 5.93–5.84 (m, 1H), 5.26–5.22 (m, 2H), 4.49–4.37 (m, 2H), 3.95 (d, J = 8.0 Hz,1H), 3.79 (s, 3H), 3.09 (d, J = 8.0 Hz, 1H).

Example 20: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and ethyl cinnamate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), ethyl cinnamate (1.5 mmol) successively, mix After homogenization, stir at 50°C for 5 hours, add water to terminate the reaction, extract with ethyl acetate three times, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: acetic acid Ethyl ester:petroleum ether=1:7) to obtain a yellow solid product with a yield of 71%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.33–7.29 (m, 3H), 7.20–7.12 (m, 3H), 6.85(d, J = 7.6 Hz, 1H), 6.70 (t, J = 7.6 Hz , 1H), 5.99 (d, J = 8.0 Hz, 1H), 5.93–5.84 (m, 1H), 5.25–5.21 (m, 2H), 4.51–4.35 (m, 2H), 4.30–4.21 (m, 2H ), 3.94 (d, J = 8.0 Hz, 1H), 3.08 (d, J = 8.4 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H).

Example 21: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and diethyl benzylidene malonate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), diethyl benzylidene malonate ( 1.5 mmol), mixed and stirred at room temperature for 5 hours, adding water to terminate the reaction, extracted three times with ethyl acetate, dried the extract with anhydrous sodium sulfate, filtered, removed the solvent under reduced pressure, and finally passed through silica gel column flash column chromatography (washing Removal agent: ethyl acetate:petroleum ether=1:7) to obtain a white solid product with a yield of 85%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29–7.23 (m, 4H), 7.11–7.09 (m, 2H), 6.92–6.84 (m, 3H), 5.93–5.84 (m, 1H), 5.30–5.23 (m, 2H), 4.62–4.56 (m, 1H), 4.32–4.03 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H).

Example 22: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and benzylidene acetone

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), benzylidene acetone (1.5 mmol) in sequence, and mix well Afterwards, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate : Petroleum ether=1:7) to obtain a yellow oily product with a yield of 62%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.33–7.28 (m, 3H), 7.18–7.13 (m, 3H), 6.87(d, J = 7.6 Hz, 1H), 6.71 (t, J = 7.6 Hz , 1H), 6.01 (d, J = 7.2 Hz, 1H),5.93–5.83 (m, 1H), 5.26–5.21 (m, 2H), 4.50–4.36 (m, 2H), 3.98 (d, J = 8.4 Hz,1H), 3.12 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H).

Example 23: Spiro[cyclopropane-1, 3'-indole] compound

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), 3-phenyl-1-(2- Thiophene)-2-propen-1-one (0.321 g, 1.5 mmol), after mixing, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, reduce The solvent was removed under pressure, and finally the off-white solid product was obtained by flash column chromatography on a silica gel column (eluent: ethyl acetate:petroleum ether=1:7), with a yield of 94%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (dd, J = 5.2, 1.2 Hz, 1H), 7.44 (dd, J = 4.0, 1.2 Hz, 1H), 7.36–7.31 (m, 3H), 7.26– 7.24 (m, 2H), 7.20 (t, J = 8.0Hz, 1H), 7.00 (dd, J = 5.2, 4.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.14 (d, J = 7.2 Hz, 1H), 5.76–5.67 (m, 1H), 5.14–5.07 (m,2H), 4.46–4.21 (m, 2H), 4.14 (d, J = 8.4 Hz, 1H), 3.61 (d, J = 8.4 Hz, 1H).

Example 24: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and chalcone

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , followed by adding acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), chalcone (0.312 g, 1.5 mmol) , after mixing, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: Ethyl acetate:petroleum ether=1:7) to obtain a yellow solid product with a yield of 91%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl _{3 )} δ: 7.80 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.2Hz, 1H), 7.37–7.31 (m, 5H), 7.26–7.19 (m , 3H), 6.88 (d, J = 8.0 Hz, 1H), 6.79(t, J = 7.6 Hz, 1H), 6.17 (d, J = 7.6 Hz, 1H), 5.70–5.61 (m, 1H), 5.08 –5.01(m, 2H), 4.44–4.19 (m, 2H), 4.16 (d, J = 8.4 Hz, 1H), 3.64 (d, J = 8.4 Hz, 1H).

Example 25: Spiro[cyclopropane -1,3′-indole] compound

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , followed by adding acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), 3-(4-methylphenyl) -1-Phenyl-2-propen-1-one (0.333 g, 1.5 mmol), mix well and stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, and dry the extract with anhydrous sodium sulfate, Filtration, removal of the solvent under reduced pressure, and finally silica gel column flash column chromatography (eluent: ethyl acetate:petroleum ether=1:7) yielded an off-white solid product with a yield of 95%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.2Hz, 1H), 7.35–7.31 (m, 2H), 7.24–7.18 (m, 2H), 7.11–7.09 (m, 2H), 7.02 (d, J= 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.22 ( d, J= 7.2 Hz, 1H), 5.69–5.60 (m, 1H), 5.08–5.00 (m, 2H), 4.43–4.15 (m, 2H), 4.12(d, J = 8.4 Hz, 1H), 3.63 (d, J = 8.4 Hz, 1H), 2.31 (s, 3H).

Example 26: Spiro[cyclo propane-1,3′-indole] compound

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), 3-(4-methoxyphenyl )-1-phenyl-2-propen-1-one (0.357 g, 1.5 mmol), mix well and stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, and dry the extract with anhydrous sodium sulfate , filtered, and the solvent was removed under reduced pressure. Finally, flash column chromatography on silica gel (eluent: ethyl acetate:petroleum ether=1:7) gave off-white solid product with a yield of 94%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.8 Hz, 2H), 7.32–7.18 (m, 6H), 6.88 (d, J = 8.0 Hz, 1H), 6.83–6.76 (m, 3H), 6.16 (d, J = 7.2 Hz, 1H), 5.73–5.63 (m, 1H), 5.10–5.04 (m, 2H), 4.44–4.16 (m, 2H), 4.13 (d, J = 8.0 Hz , 1H), 3.80 (s, 3H), 3.60 (d, J = 8.4 Hz, 1H).

Example 27: Spiro[ Cyclopropane-1,3′-indole] compound

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), 3-(4-trifluoromethylbenzene Base)-1-phenyl-2-propen-1-one (0.414 g, 1.5 mmol), mix well and stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, and extract with anhydrous sodium sulfate Dry, filter, and remove the solvent under reduced pressure. Finally, flash column chromatography on silica gel (eluent: ethyl acetate:petroleum ether=1:7) gave a white solid product with a yield of 71%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.6Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.39–7.32 (m, 4H), 7.25 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.17 (d, J = 7.6 Hz ,1H), 5.69–5.60 (m, 1H), 5.08–5.00 (m, 2H), 4.43–4.18 (m, 2H), 4.15 (d, J =7.6 Hz, 1H), 3.67 (d, J = 8.4 Hz, 1H).

Example 28: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and diethyl maleate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , followed by adding acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), diethyl maleate (1.5 mmol) , after mixing, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: Ethyl acetate:petroleum ether=1:7) to obtain a white solid product with a yield of 89%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.26 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.80 ( d, J = 7.2 Hz, 1H), 5.90–5.81 (m,1H), 5.27–5.20 (m, 2H), 4.41–4.39 (m, 2H), 4.28–4.20 (m, 4H), 2.86 (s, 2H), 1.28 (s, 6H).

Example 29: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting N-allyl isatin, diethyl phosphite and diethyl fumarate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , followed by adding acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), diethyl fumarate (1.5 mmol) , after mixing, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: Ethyl acetate:petroleum ether=1:7) to obtain a white solid product with a yield of 85%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.26 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.80 ( d, J = 7.2 Hz, 1H), 5.90–5.81 (m,1H), 5.27–5.20 (m, 2H), 4.41–4.39 (m, 2H), 4.28–4.20 (m, 4H), 2.86 (s, 2H), 1.28 (s, 6H).

Example 30: Preparation of spiro[cyclopropane-1,3′-indole] compound by reaction of N-allyl isatin, diethyl phosphite and dimethyl vinyl phosphate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , followed by adding acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.5 mL), vinyl dimethyl phosphate (1.5 mmol) , after mixing, stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: Ethyl acetate:petroleum ether=1:7) to obtain a yellow oily product with a yield of 66%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.80 (d , J = 7.6 Hz, 1H), 5.92–5.82 (m,1H), 5.27–5.21 (m, 2H), 4.49–4.36 (m, 2H), 3.83 (d, J = 10.8 Hz, 3H), 3.77( d, J = 11.2 Hz, 3H), 2.30–2.24 (m, 1H), 1.99–1.91 (m, 2H).

Example 31: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting 4-chloro-N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), 4-chloro-N-allyl isatin (0.111 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol ), stirred at room temperature for 5 hours after mixing, adding water to terminate the reaction, extracted three times with ethyl acetate, dried the extract with anhydrous sodium sulfate, filtered, removed the solvent under reduced pressure, and finally passed through silica gel column flash column chromatography (eluent : ethyl acetate:petroleum ether=1:7) to obtain a yellow solid product with a yield of 72%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.87–5.77 (m, 1H), 5.23–5.19 (m, 2H),4.38–4.36 (m, 2H), 3.74 (s, 3H), 3.48 (t, J = 8.4 Hz, 1H), 2.53 (dd, J = 8.8 ,4.8 Hz, 1H), 2.21 (dd, J = 8.0, 4.8 Hz, 1H).

Example 32: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting 4-bromo-N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), 4-bromo-N-allyl isatin (0.133 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol ), stirred at room temperature for 5 hours after mixing, adding water to terminate the reaction, extracted three times with ethyl acetate, dried the extract with anhydrous sodium sulfate, filtered, removed the solvent under reduced pressure, and finally passed through silica gel column flash column chromatography (eluent : ethyl acetate:petroleum ether=1:7) to obtain a yellow solid product with a yield of 80%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.13–7.07 (m, 2H), 6.84 (dd, J = 7.2, 2.0Hz, 1H), 5.86–5.77 (m, 1H), 5.23–5.18 (m, 2H ), 4.38–4.36 (m, 2H), 3.74 (s,3H), 3.56 (t, J = 8.4 Hz, 1H), 2.60 (dd, J = 9.2, 4.8 Hz, 1H), 2.16 (dd, J = 8.4, 4.8 Hz, 1H).

Example 33: Preparation of spiro[cyclopropane-1,3′-indole] compound by reacting 5-chloro-N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), 5-chloro-N-allyl isatin (0.111 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol ), stirred at room temperature for 5 hours after mixing, adding water to terminate the reaction, extracted three times with ethyl acetate, dried the extract with anhydrous sodium sulfate, filtered, removed the solvent under reduced pressure, and finally passed through silica gel column flash column chromatography (eluent : ethyl acetate:petroleum ether=1:7) to obtain a yellow oily product with a yield of 92%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.22 (d, J = 8.4 Hz, 1H), 6.84–6.79 (m,2H), 5.87–5.77 (m, 1H), 5.24–5.19 (m, 2H) , 4.38–4.36 (m, 2H), 3.74 (s, 3H),2.68 (t, J = 8.4 Hz, 1H), 2.42 (dd, J = 8.0, 5.2 Hz, 1H), 1.85 (dd, J = 8.4 ,5.2 Hz, 1H).

Example 34: Preparation of spiro[cyclopropane-1,3′-indole] compound by reaction of 5-methyl-N-allyl isatin, diethyl phosphite and methyl acrylate

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), 5-methyl-N-allyl isatin (0.101 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol), mix well and stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally pass through silica gel column flash column chromatography (elution Agent: ethyl acetate:petroleum ether=1:7) to obtain a yellow oily product with a yield of 86%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.04 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 7.6Hz, 1H), 6.67 (s, 1H), 5.88–5.78 (m, 1H) , 5.24–5.18 (m, 2H), 4.37–4.35 (m,2H), 3.73 (s, 3H), 2.64 (t, J = 8.4 Hz, 1H), 2.38 (dd, J = 8.0, 5.2 Hz, 1H ), 2.32 (s, 3H), 1.80 (dd, J = 8.8, 4.8 Hz, 1H).

Example 35: [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ catalyzed 5-fluoro-N-allyl isatin, diethyl phosphite and methyl acrylate Preparation of spiro[cyclopropane-1,3'-indole] compounds by reaction

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), 5-fluoro-N-allyl isatin (0.103 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol ), stirred at room temperature for 5 hours after mixing, adding water to terminate the reaction, extracted three times with ethyl acetate, dried the extract with anhydrous sodium sulfate, filtered, removed the solvent under reduced pressure, and finally passed through silica gel column flash column chromatography (eluent : ethyl acetate:petroleum ether=1:7) to obtain a yellow oily product with a yield of 90%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.97–6.92 (m, 1H), 6.80 (dd, J = 8.4, 4.0Hz, 1H), 6.62 (dd, J = 8.0, 2.4 Hz, 1H), 5.88– 5.78 (m, 1H), 5.24–5.21 (m,2H), 4.38–4.37 (m, 2H), 3.75 (s, 3H), 2.67 (t, J = 8.4 Hz, 1H), 2.42 (dd, J = 8.0, 5.2 Hz, 1H), 1.83 (dd, J = 8.4, 5.2 Hz, 1H).

Example 36: [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ catalyzed 7-fluoro-N-allyl isatin, diethyl phosphite and methyl acrylate Preparation of spiro[cyclopropane-1,3'-indole] compounds by reaction

In the reaction flask treated with dehydration and deoxygenation, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.1826 g, 0.20 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), 7-fluoro-N-allyl isatin (0.103 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol ), stirred at room temperature for 5 hours after mixing, adding water to terminate the reaction, extracted three times with ethyl acetate, dried the extract with anhydrous sodium sulfate, filtered, removed the solvent under reduced pressure, and finally passed through silica gel column flash column chromatography (eluent : ethyl acetate:petroleum ether=1:7) to obtain a yellow oily product with a yield of 86%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.02–6.94 (m, 2H), 6.64 (d, J = 6.8 Hz, 1H),5.96–5.87 (m, 1H), 5.22–5.15 (m, 2H), 4.52–4.50 (m, 2H), 3.74 (s, 3H), 2.68(t, J = 8.4 Hz, 1H), 2.42 (dd, J = 8.1, 5.2 Hz, 1H), 1.85 (dd, J = 8.4, 5.2Hz, 1H).

Example _{37 :} Preparation _of spiro _[ cyclo propane-1,3′-indole] compound

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.2282 g, 0.25 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-benzyl isatin (0.119 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate: Petroleum ether = 1:7) to obtain a yellow oily product with a yield of 88%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.30–7.24 (m, 5H), 7.16 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.95 (s, 2H), 3.76 (s, 3H), 2.69 (t, J = 8.4 Hz, 1H), 2.44 (dd, J = 8.0,5.2 Hz, 1H), 1.85 (dd, J = 8.4, 5.2 Hz, 1H).

Example 38: [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ catalyzes the reaction of N-ethyl isatin, diethyl phosphite and methyl acrylate to prepare spiro[cyclo propane-1,3′-indole] compound

In the reaction flask that has been dehydrated and deoxygenated, weigh [(Me ₃ Si) ₂ N] ₃ Yb( μ -Cl)Li(THF) ₃ (0.2282 g, 0.25 mmol) in the reaction flask under argon protection , add acetonitrile (0.5 mL), diethyl phosphite (0.6 mmol), N-ethyl isatin (0.088 g, 0.5 mmol), acetonitrile (0.5 mL), methyl acrylate (1.5 mmol) in sequence, and mix well Stir at room temperature for 5 hours, add water to terminate the reaction, extract three times with ethyl acetate, dry the extract with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and finally perform flash column chromatography on a silica gel column (eluent: ethyl acetate: Petroleum ether = 1:7) to obtain a yellow solid product with a yield of 81%.

The theoretical molecular formula of the obtained product and the main NMR test data are as follows. It can be seen from the analysis that the actual synthesized product is consistent with the theoretical analysis.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28 ((t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.84 ( d, J = 7.2 Hz, 1H), 3.86–3.78 (m,2H), 3.75 (s, 3H), 2.65 (t, J = 8.4 Hz, 1H), 2.38 (dd, J = 8.0, 4.8 Hz, 1H ), 1.80 (dd, J = 8.4, 4.8 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H).

Claims (10)

1. silicon base rare earth compound replaces the application of the reaction of isatin, phosphite ester and alkene as catalyst；

The chemical structural formula of described silicon base rare earth compound is as follows：

Wherein, Ln is the rare earth ion of positive trivalent；

The chemical structure of general formula of described replacement isatin is as follows：

Wherein, R¹Selected from one of pi-allyl, benzyl, ethyl；R²Selected from hydrogen, 4- chlorine, 5- chlorine, 4- bromine, 5- methyl, 5- fluorine, 7- One of fluorine；

The chemical structure of general formula of described alkene is as follows：

Wherein, R³Selected from methoxycarbonyl group, carbethoxyl group, positive butoxy carbonyl, acetyl group, benzoyl, thiophene -2- formoxyl, diformazan One of epoxide phosphoryl；R⁴Selected from one of hydrogen, methyl, carbethoxyl group；R⁵Selected from hydrogen, phenyl, carbethoxyl group, to first One of base phenyl, p-methoxyphenyl, p-trifluoromethyl phenyl.

2. application according to claim 1 is it is characterised in that described application comprises the following steps：In anhydrous and oxygen-free condition Under, to replace isatin, phosphite ester and alkene as reactant, with silicon base rare earth compound as catalyst, in organic solvent Spiral shell [cyclopropane -1,3 '-indoles] compound is prepared in reaction.

3. according to claim 2 application it is characterised in that：Described organic solvent is acetonitrile, dichloromethane, ethylene glycol two One or more of methyl ether, oxolane, ethylene glycol diethyl ether.

4. according to claim 3 application it is characterised in that：Described organic solvent is acetonitrile；Described Ln is ytterbium；Described Asia Phosphate is diethyl phosphite；It is inert atmosphere conditions under the conditions of described anhydrous and oxygen-free.

5. according to claim 1 application it is characterised in that：According to molar ratio computing, catalyst: replace isatin: phosphorous acid Ester：Alkene=(0.33～0.50): 1:（1～1.5）∶（2～5）；Described reaction temperature is room temperature～50 DEG C；Reaction time be 3～ 10 hours.

6. according to claim 5 application it is characterised in that：According to molar ratio computing, catalyst: replace isatin: phosphorous acid Ester：Alkene=0.4: 1: 1.2: 3；Described reaction temperature is room temperature；Reaction time is 5 hours.

7. according to claim 2 application it is characterised in that：Application process includes under the conditions of anhydrous and oxygen-free, by silicon ammonia Base rare earth compound, replacement isatin, phosphite ester, alkene and organic solvent mix, and stir 3 ~ 10 hours at room temperature～50 DEG C, Terminating reaction, is extracted, and filters after extract desiccant dryness, and filtrate decompression obtains spiral shell through column chromatography after removing solvent [cyclopropane -1,3 '-indoles] compound.

8. according to claim 7 application it is characterised in that：Using water terminating reaction；Extractant is ethyl acetate；It is dried Agent is anhydrous sodium sulfate；Eluant, eluent is ethyl acetate/petroleum ether system.

9. silicon base rare earth compound prepares the application in spiral shell [cyclopropane -1,3 '-indoles] compound in catalysis；

The chemical structural formula of described silicon base rare earth compound is as follows：

Wherein, Ln is the rare earth ion of positive trivalent.

10. according to claim 9 application it is characterised in that：When preparing spiral shell [cyclopropane -1,3 '-indoles] compound, instead Temperature is answered to be room temperature～50 DEG C, the reaction time is 3～10 hours.