CN111732545B

CN111732545B - 2, 3-dihydrospiro [ imidazole-4, 1 ′ -indene]Compounds and preparation method thereof

Info

Publication number: CN111732545B
Application number: CN202010515301.3A
Authority: CN
Inventors: 崔秀灵; 宋振宇
Original assignee: Huaqiao University
Current assignee: Huaqiao University
Priority date: 2020-06-08
Filing date: 2020-06-08
Publication date: 2023-03-10
Anticipated expiration: 2040-06-08
Also published as: CN111732545A

Abstract

The invention discloses 2, 3-dihydrospiro [ imidazole-4, 1' -indene]The structural formula of the compound is

Wherein R is ¹ Is H, halogen, alkyl, trifluoromethyl, methoxy or ester group, R ² Is aryl or alkyl, R ³ Is alkyl, R ⁴ Is alkyl or aryl. The invention utilizes the ' C = N ' bond in 2H-imidazole as C-electrophilic reagent, and then undergoes intramolecular cyclization reaction to incorporate a guide group into a target product, so that a novel 2, 3-dihydrospiro [ imidazole-4, 1' -indene ] can be conveniently and efficiently synthesized in one step]The compounds have profound significance from the perspective of medicinal chemistry.

Description

2, 3-dihydrospiro [ imidazole-4, 1' -indene ] compound and preparation method thereof

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a 2, 3-dihydrospiro [ imidazole-4, 1' -indene ] compound and a preparation method thereof.

Background

The spiro compound containing N has important application value in medical molecules, functional materials and ligands. On the other hand, 2H-imidazole compounds are important structural units of a plurality of natural products and pharmaceutically active molecules and are also important intermediates in organic synthesis, but the construction of spiro compounds by using the compounds is rarely reported. Therefore, research on synthesis methods of spiro compounds containing 2H-imidazole structural units has important application value and is concerned by researchers in related fields.

At present, no 2, 3-dihydrospiro [ imidazole-4, 1 '-indene ] derivative is synthesized, and only a few 2',3 '-dihydrospiro [ imidazolidine-4, 1' -indene ] -2, 5-dione derivatives are synthesized. Among them, the 2',3' -dihydrospiro [ imidazolidine-4, 1' -indene ] -2, 5-dione derivative generally needs to be synthesized step by step, and has the disadvantages of complicated steps, low yield and poor reaction selectivity.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a 2, 3-dihydrospiro [ imidazole-4, 1' -indene ] compound.

Another object of the present invention is to provide a process for producing the above 2, 3-dihydrospiro [ imidazole-4, 1' -indene ] compounds.

The technical scheme of the invention is as follows:

2, 3-dihydrospiro [ imidazole-4, 1' -indene]The structural formula of the compound is

Wherein R is ¹ Is H, halogen, alkyl, trifluoromethyl, methoxy or ester group, R ² Is aryl or alkyl, R ³ Is alkyl, R ⁴ Is alkyl or aryl.

The reaction equation of the preparation method of the 2, 3-dihydrospiro [ imidazole-4, 1' -indene ] compound is as follows:

the catalyst is dichloro bis (4-methyl isopropylphenyl) ruthenium (II) dimer, the silver salt is silver hexafluoroantimonate or silver bis (trifluoromethanesulfonyl) imide, the additive is nickel trifluoromethanesulfonate, copper trifluoromethanesulfonate or zinc trifluoromethanesulfonate, the acid is acetic acid, pivalic acid, 1-adamantanecarboxylic acid or benzoic acid, and the solvent is tert-amyl alcohol, trifluoroethanol or 1, 2-dichloroethane.

In a preferred embodiment of the present invention, the method comprises mixing the 2H-imidazole derivative, the 2-alkynoate compound, the catalyst, the silver salt, the additive, the acid and the solvent uniformly, reacting at 60-100 ℃ in an air or nitrogen atmosphere, cooling the reaction product to room temperature, and adding saturated NaHCO ₃ Extracting the solution with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the 2, 3-dihydrospiro [ imidazole-4, 1' -indene]A kind of compound is provided.

In a preferred embodiment of the invention, the silver salt is silver bistrifluoromethanesulfonylimide.

In a preferred embodiment of the invention, the additive is zinc triflate.

In a preferred embodiment of the invention, the acid is benzoic acid.

In a preferred embodiment of the invention, the solvent is 1, 2-dichloroethane.

In a preferred embodiment of the invention, the silver salt is silver bistrifluoromethanesulfonylimide, the additive is zinc trifluoromethanesulfonate, the acid is benzoic acid, and the solvent is 1, 2-dichloroethane.

In a preferred embodiment of the present invention, the molar ratio of the 2H-imidazole derivative, the 2-alkynoate compound, the catalyst, the silver salt, the additive and the acid is 1: 1.0-2.0: 0.025-0.05: 0-0.2-0.5.

Further preferably, the reaction temperature is 100 ℃, and the molar ratio of the 2H-imidazole derivative, the 2-alkynoate compound, the catalyst, the silver salt, the additive and the acid is 1:1.5:0.05:0.2: 0.5.

The beneficial effects of the invention are:

1. the invention utilizes the ' C = N ' bond in 2H-imidazole as a C-electrophilic reagent, and then undergoes intramolecular cyclization reaction to incorporate a guide group into a target product, so that a novel 2, 3-dihydrospiro [ imidazole-4, 1' -indene ] compound can be conveniently and efficiently synthesized in one step, and has profound significance from the pharmaceutical chemistry perspective.

2. The preparation method of the invention has the advantages of easily obtained raw materials, good regioselectivity, wide substrate range, strong reaction specificity and simple and convenient post-treatment.

Detailed Description

The technical solution of the present invention is further illustrated and described by the following detailed description.

EXAMPLE 1 Effect of additives on the reaction

To a 25mL dry standard reaction tube equipped with a magnetic rotor were added sequentially 0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium, 0.1mmol of benzoic acid, 0.05mmol of various types of additives (as in Table 1), 0.02mmol of silver hexafluoroantimonate, 0.15mmol of ethyl 2-butynoate, and 2mL of solvent 2, 2-trifluoroethanol. Sealing the reaction system in air atmosphere, stirring at 100 ℃ for 12h, stopping the reaction, cooling to room temperature, and adding 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography to give 2,3 '-trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene-]-2' -Carboxylic acid Ethyl ester, the specific results are shown in Table 1.

TABLE 1

Example 2 Effect of solvent on the reaction

To a 25mL dry standard reaction tube equipped with a magnetic rotor were added sequentially 0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium, 0.1mmol of benzoic acid, 0.05mmol of zinc triflate, 0.02mmol of silver hexafluoroantimonate, 0.15mmol of ethyl 2-butynoate, and 2mL of various solvents (see Table 2). Sealing the reaction system in air atmosphere, stirring at 100 ℃ for 12h, stopping the reaction, cooling to room temperature, and adding 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography to give 2,3 '-trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene-]-2' -Carboxylic acid Ethyl ester, the specific results are shown in Table 2.

TABLE 2

Example 3 Effect of acid on the reaction

To a 25mL dry standard reaction tube equipped with a magnetic rotor were added sequentially 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole 0.1mmol, dichlorobis (4-methylisopropylphenyl) ruthenium 0.005mmol, various acids 0.1mmol (as in Table 3), zinc triflate 0.05mmol, silver hexafluoroantimonate 0.02mmol, ethyl 2-butynoate 0.15mmol, and 2mL solvent 1, 2-dichloroethane. Sealing the reaction system in air atmosphere, stirring at 100 ℃ for 12h, stopping the reaction, cooling to room temperature, and adding 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 2,3' -trimethyl-5-phenyl-2,3-dihydrospiro [ imidazole-4, 1' -indene]-2' -carboxylic acid ethyl ester, the specific results are shown in table 3.

TABLE 3

Example 4 Effect of reaction temperature on the reaction

To a 25mL dry standard reaction tube equipped with a magnetic rotor were added, in order, 2-dimethyl-4, 5-diphenyl-2H-imidazole 0.1mmol, dichlorobis (4-methylisopropylphenyl) ruthenium 0.005mmol, benzoic acid 0.1mmol, zinc triflate 0.05mmol, silver hexafluoroantimonate 0.02mmol, ethyl 2-butynoate 0.15mmol, and 2mL solvent 1, 2-dichloroethane. The reaction system was then sealed in an air atmosphere, stirred at different temperatures (as in Table 4) for 12h, stopped and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to column chromatography to give 2,3 '-trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene]-2' -carboxylic acid ethyl ester, the specific results are shown in table 4.

TABLE 4

Example 5 Effect of catalyst on reaction

To a 25mL dry standard reaction tube equipped with a magnetic rotor were added sequentially 0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of the different catalysts (as in Table 5), 0.1mmol of benzoic acid, 0.05mmol of zinc triflate, 0.02mmol of silver bis (trifluoromethanesulfonyl) imide, 0.15mmol of ethyl 2-butynoate, and 2mL of 1, 2-dichloroethane as solvent. Sealing the reaction system in air atmosphere, stirring at 100 ℃ for 12h, stopping the reaction, cooling to room temperature, and adding 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure,separating the crude product by column chromatography to obtain 2,3 '-trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene]-2' -Carboxylic acid Ethyl ester, the specific results are shown in Table 5.

TABLE 5

Example 6

Preparation of ethyl 2,3' -trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of ethyl 2-butynoate and 2mL of 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 25.1mg of the objective product in 69%. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz， CDCl ₃ )δ7.46(d，J＝7.0Hz，1H)，7.40-7.33(m，3H)，7.23-7.17(m，3H)，7.12-7.06 (m，2H)，4.30-4.20(m，1H)，4.13-4.04(m，1H)，2.67(s，1H)，2.50(s，3H)，1.74 (s，3H)，1.71(s，3H)，1.19(t，J＝7.1Hz，3H). ¹³ C NMR(100MHz，CDCl ₃ )6167.0， 164.2，153.6，149.3，142.0，133.3，132.3，129.9，129.8，128.6，127.9，127.2，123.1，121.9，89.5， 84.8，60.0，31.8，29.4，14.0，12.8.HRMS(ESI)Calcd for C ₂₃ H ₂₄ N ₂ O ₂ [M+H] ⁺ 361.1911； found 361.1912.

example 7

Preparation of 2,3', 5-tetramethyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene ] -2' -carboxylic acid ethyl ester

2, 4-trimethyl-5-phenyl-2H-imidazole 0.1mmol, dichlorobis (4-methylisopropylphenyl) ruthenium (II) 0.005mmol, benzoic acid 0.05mmol, zinc trifluoromethanesulfonate 0.05mmol, silver bistrifluoromethanesulfonylimide 0.02mmol, ethyl 2-butynoate 0.15mmol and 2mL 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 20.9mg of the objective product in a yield of 70%. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz， CDCl ₃ )δ7.43-7.32(m，3H)，7.31-7.26(m，1H)，4.40-4.29(m，1H)，4.27-4.17(m， 1H)，2.63(s，1H)，2.48(s，3H)，1.64(s，3H)，1.60(s，3H)，1.50(s，3H)，1.33 (t，J＝7.1Hz，1H). ¹³ C NMR(100MHz，CDCl ₃ )δ168.4，164.6，153.0，148.1，142.3，132.5， 129.5，128.5，122.7，121.4，90.2，86.5，60.2，32.1，29.2，14.3，13.9，12.8.HRMS(ESI)Calcd for C ₁₈ H2 ₂ N ₂ O ₂ [M+H] ⁺ 299.1754；found 299.1757.

example 8

Preparation of ethyl 3' -methyl-5 ' -phenyl-3 ' H-dispiro [ cyclohexyl-1, 2' -imidazole-4 ',1' -indene ] -2' -carboxylate

0.1mmol of spirocyclohexyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide,ethyl 2-butynoate 0.15mmol and 2mL of 1, 2-dichloroethane were charged to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 24.2mg of the objective product in a yield of 60%. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz， DMSO-d ₆ )67.59(d，J＝7.2Hz，1H)，7.44-7.35.(m，2H)，7.27-7.24(m，2H)，7.19-7.12 (m，4H)，4.17-4.09(m，1H)，4.05-3.96(m，1H)，3.23(s，1H)，2.47(s，3H)，1.98 (dd，J＝14.6，7.9Hz，2H)，1.83-1.68(m，4H)，1.65-1.43(m，4H)，1.11(t，J＝7.1Hz， 3H). ¹³ C NMR(100MHz，DMSO-d ₆ )6166.0，164.5，151.6，150.0，142.2，135.3，133.2， 130.3，130.1，128.9，128.5，127.4，123.6，122.4，91.3，84.1，60.1，41.5，38.9，25.8，23.8，23.6， 14.3，13.0.HRMS(ESI)Calcd for C ₂₆ H ₂₈ N ₂ O ₂ [M+H] ⁺ 401.2224；found 401.2227.

example 9

Preparation of ethyl 2,3',5' -tetramethyl-5- (p-tolyl) -2, 3-dihydrospiro [ imidazole-4, 1 '-indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-di-p-tolyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of ethyl 2-butynoate and 2mL of 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 27.7mg of the objective product in 71% yield. TheNuclear magnetic characterization of the compounds is as follows: ¹ H NMR(400 MHz，CDCl ₃ )δ7.27(d，J＝4.9Hz，1H)，7.21(d，J＝7.6Hz，1H)，7.13(dd，J＝15.4， 7.9Hz，3H)，6.91(d，J＝8.1Hz，2H)，4.30-4.21(m，1H)，4.13-4.04(m，1H)，2.50(s， 3H)，2.46(s，1H)，2.41(s，3H)，2.22(s，3H)，1.72(s，3H)，1.70(s，3H)，1.20 (t，J＝7.1Hz，3H). ¹³ C NMR(100MHz，CDCl ₃ )6167.1，164.4，153.7，146.7，142.3，140.1， 138.5，133.8，130.6，129.6，128.7，127.3，122.9，122.6，89.3，84.5，60.0，31.9，29.5，21.5，21.2， 14.1，12.8.HRMS(ESI)Calcd for C ₂₅ H ₂₈ N ₂ O ₂ [M+H] ⁺ 389.2224；found 389.2226.

example 10

Preparation of ethyl 2,3 '-trimethyl-5' -chloro-5- (4-chlorophenyl) -2, 3-dihydrospiro [ imidazole-4, 1 '-indene ] -2' -carboxylate

2, 2-dimethyl-4, 5-bis (4-chlorophenyl) -2H-imidazole 0.1mmol, dichlorobis (4-methylisopropylphenyl) ruthenium (II) 0.005mmol, benzoic acid 0.05mmol, zinc trifluoromethanesulfonate 0.05mmol, silver bistrifluoromethanesulfonylimide 0.02mmol, ethyl 2-butynoate 0.15mmol, and 2mL of 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 30.6mg of the objective product in 71% yield. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz，CDCl ₃ )δ7.44(d，J＝1.6Hz，1H)，7.33(dd，J＝8.0，1.8Hz，1H)， 7.26-7.23(m，1H)，7.16-7.10(m，4H)，4.31-4.23(m，1H)，4.16-4.08(m，1H)，2.48 (s，3H)，2.19(s，1H)，1.70(s，3H)，1.69(s，3H)，1.22(t，J＝7.1Hz，3H). ¹³ C NMR (100MHz，CDCl ₃ )6165.4，164.0，152.0，147.3，143.9，136.3，135.0，134.9，130.6，129.7， 128.6，128.5，124.2，122.4，89.9，84.4，60.5，32.0，29.4，14.1，12.9.HRMS(ESI)Calcd for C ₂₃ H ₂₂ Cl ₂ N ₂ O ₂ [M+H] ⁺ 429.1131；found 429.1134.

example 11

Preparation of ethyl 2,3 '-trimethyl-6' - (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -2, 3-dihydrospiro [ imidazole-4, 1 '-indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-bis (3- (trifluoromethyl) phenyl) -2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of ethyl 2-butynoate and 2mL of 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 32.8mg of the objective product in 66% yield. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ7.86-7.79(m，2H)，7.65(d，J＝7.8Hz，1H)， 7.51(s，1H)，7.47-7.39(m，2H)，7.32(d，J＝7.9Hz，1H)，4.23-4.14(m，1H)，4.09-4.00 (m，1H)，3.78(s，1H)，2.48(s，3H)，1.63(s，3H)，1.56(s，3H)，1.11(t，J＝7.1 Hz，3H). ¹³ C NMR(100MHz，DMSO-d ₆ )δ164.1，164.0，149.8，149.7，146.1，146.1，137.9， 133.5，130.9，130.2，130.1(q，J _C-F ＝31.8Hz)，129.5(q，J _C-F ＝31.9Hz)，127.1(q，J _C-F ＝ 3.5Hz)，124.5(q，J _C-F ＝272.4Hz)，124.1(q，J _C-F ＝272.3Hz)，123.7(q，J _C-F ＝4.0Hz)， 123.4，119.8(q，J _C-F ＝3.8Hz)，90.1，85.0，60.5，32.5，30.0，14.2，12.7. ¹⁹ F NMR(376MHz， DMSO-d ₆ )δ-60.9，-62.0.HRMS(ESI)Calcd for C ₂₅ H ₂₂ F ₆ N ₂ O ₂ [M+H] ⁺ 497.1658；found 497.1657.

example 12

Preparation of ethyl 2,3 '-trimethyl-4' -fluoro-5- (3-fluorophenyl) -2, 3-dihydrospiro [ imidazole-4, 1 '-indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-bis (3-fluorophenyl) -2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of ethyl 2-butynoate and 2mL of 1, 2-dichloroethane were charged into a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 32.6mg of the objective product in 82% yield. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz，CDCl ₃ )δ7.36-7.29(m，1H)，7.15-7.01(m，4H)，7.00-6.92(m，2H)， 4.32-4.23(m，1H)，4.17-4.07(m，1H)，2.67(s，3H)，2.25(s，1H)，1.71(s，3H)， 1.69(s，3H)，1.22(t，J＝7.1Hz，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ165.5(d，J _C-F ＝2.6Hz)，164.1，162.4(d，J _C-F ＝245.9Hz)，158.7(d，J _C-F ＝255.5Hz)，151.7(d，J _C-F ＝7.0Hz)，151.7(d，J _C-F ＝7.9Hz)，151.7，134.4(d，J _C-F ＝7.7Hz)，133.5，131.7(d，J _C-F ＝7.5Hz)，129.8(d，J _C-F ＝8.1Hz)，128.5(d，J _C-F ＝12.0Hz)，122.9(d，J _C-F ＝3.0Hz)， 119.2(d，J _C-F ＝3.3Hz)，117.2(d，J _C-F ＝21.3Hz)，116.6(d，J _C-F ＝21.3Hz)，114.4(d， J _C-F ＝23.1Hz)，89.9，85.2，60.4，31.8，29.4，15.4(d，J _C-F ＝4.3Hz)，14.1. ¹⁹ F NMR(376 MHz，CDCl ₃ )δ-112.7，-118.9.HRMS(ESI)Calcd for C ₂₃ H ₂₂ F ₂ N ₂ O ₂ [M+H] ⁺ 397.1722； found 397.1724.

example 13

Preparation of ethyl 2,3 '-trimethyl-7' -fluoro-5- (2-fluorophenyl) -2, 3-dihydrospiro [ imidazole-4, 1 '-indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-bis (2-fluorophenyl) -2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of ethyl 2-butynoate and 2mL of 1, 2-dichloroethane were charged into a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 21.0mg of the objective product in 53% yield. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz，CDCl ₃ )δ7.33-7.27(m，1H)，7.21-7.15(m，1H)，7.12(d，J＝7.4 Hz，1H)，7.07-6.95(m，2H)，6.93-6.83(m，2H)，4.38-4.29(m，1H)，4.27-4.18(m，1H)， 2.54(s，1H)，2.38(s，3H)，1.75(s，3H)，1.73(s，3H)，1.30(t，J＝7.1Hz，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ164.4，161.9(d，J _C-F ＝3.2Hz)，160.1(d，J _C-F ＝253.2Hz)， 157.9(d，J _C-F ＝251.3Hz)，151.4(d，J _C-F ＝2.4Hz)，145.3(d，J _C-F ＝5.1Hz)，134.2，132.4 (d，J _C-F ＝13.2Hz)，131.0(d，J _C-F ＝8.4Hz)，130.9(d，J _C-F ＝7.7Hz)，129.61(d，J _C-F ＝2.8Hz)，123.43(d，J _C-F ＝3.7Hz)，120.90(d，J _C-F ＝13.7Hz)，117.5(d，J _C-F ＝3.1Hz)， 117.0(d，J _C-F ＝21.8Hz)，116.0(d，J _C-F ＝22.5Hz)，91.8，85.1，60.4，29.8，28.9(d，J _C-F ＝9.0Hz)，14.1，13.0. ¹⁹ F NMR(376MHz，CDCl ₃ )δ-111.5，-117.1.HRMS(ESI)Calcd for C ₂₃ H ₂₂ F ₂ N ₂ O ₂ [M+H] ⁺ 397.1722；found 397.1726.

example 14

Preparation of methyl 2, 2-dimethyl-3 ' -hexyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of methyl 2-nonynoate and 2mL of 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 27.1mg of the objective product in 65% yield. The nuclear magnetic characterization of the compound is as follows: ¹ H NMR(400MHz， CDCl ₃ )δ7.48(dd，J＝6.4，1.6Hz，1H)，7.42-7.35(m，3H)，7.25-7.16(m，3H)，7.09 (t，J＝7.6Hz，2H)，3.71(s，3H)，3.06-2.98(m，1H)，2.97-2.88(m，1H)，2.27(s， 1H)，1.76(s，3H)，1.71(s，3H)，1.65-1.53(m，2H)，1.42-1.34(m，2H)，1.31-1.25 (m，4H)，0.88(t，J＝7.0Hz，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ167.3，164.6，158.7， 149.7，141.6，132.7，132.4，130.0，129.9，128.7，128.0，127.3，123.4，122.2，89.8，85.1，50.9， 32.0，31.6，29.6，29.5，28.65，26.9，22.5，14.1.HRMS(ESI)Calcd for C ₂₇ H ₃₂ N ₂ O ₂ [M+H] ⁺ 417.2537；found 417.2535.

example 15

Preparation of p-methylphenyl 2,3' -trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene ] -2' -carboxylate

0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of p-methylphenyl 2-butynoate and 2mL of 1, 2-dichloroethane were charged into a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 23.4mg of the objective product in 55% yield. The nuclear magnetism of the compound is characterized as follows: ¹ H NMR(400 MHz，DMSO-d ₆ )δ7.68(dd，J＝6.2，2.1Hz，1H)，7.50-7.43(m，2H)，7.35-7.29(m，2H)， 7.23-7.20(m，4H)，7.17(d，J＝8.3Hz，2H)，6.83(d，J＝8.4Hz，2H)，3.83(s，1H)，2.56 (s，3H)，2.28(s，3H)，1.61(s，3H)，1.47(s，3H). ¹³ CNMR(100MHz，DMSO-d ₆ ) δ166.0，162.9，155.0，150.3，148.2，141.8，135.3，133.8，132.9，130.7，130.6，130.2，129.0， 128.7，127.3，123.7，122.8，121.9，89.6，85.0，32.8，30.0，20.8，13.2.HRMS(ESI)Calcd for C ₂₈ H ₂₆ N ₂ O ₂ [M+H] ⁺ 423.2067；found 423.2069.

example 16

Preparation of 2,3' -trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene ] -2' -carboxylic acid m-fluorophenyl ester

0.1mmol of 2, 2-dimethyl-4, 5-diphenyl-2H-imidazole, 0.005mmol of dichlorobis (4-methylisopropylphenyl) ruthenium (II), 0.05mmol of benzoic acid, 0.05mmol of zinc trifluoromethanesulfonate, 0.02mmol of silver bistrifluoromethanesulfonylimide, 0.15mmol of m-fluorophenyl 2-butynoate and 2mL of 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL of saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 30.0mg of the objective product in 70% yield. The nuclear magnetism of the compound is characterized as follows: ¹ H NMR(400 MHz，CDCl ₃ )67.57(dd，J＝5.2，2.5Hz，1H)，7.49-7.42(m，3H)，7.33-7.26(m，2H)， 7.23(t，J＝4.3Hz，2H)，7.16(t，J＝7.6Hz，2H)，6.95-6.88(m，1H)，6.79-6.70(m，2H)，3.05(s，1H)，2.61(s，3H)，1.78(s，3H)，1.66(s，3H). ¹³ CNMR(100MHz， CDCl ₃ )δ166.8，162.8(d，J _C-F ＝247.6Hz)，162.2，157.2，150.7(d，J _C-F ＝10.9Hz)，149.4， 141.7，132.4，132.1，130.7，130.3，130.1(d，J _C-F ＝9.4Hz)，129.0，128.2，127.3，123.3，122.4， 117.5(d，J _C-F ＝3.3Hz)，112.8(d，J _C-F ＝21.1Hz)，109.8(d，J _C-F ＝24.4Hz)，89.8，84.8， 31.9，29.7，13.2. ¹⁹ F NMR(376MHz，CDCl ₃ )δ-110.9.HRMS(ESI)Calcd for C ₂₇ H2 ₃ FN ₂ O ₂ [M+H] ⁺ 427.1816；found 427.1820.

example 17

Preparation of o-bromophenyl 2,3' -trimethyl-5-phenyl-2, 3-dihydrospiro [ imidazole-4, 1' -indene ] -2' -carboxylate

2, 2-dimethyl-4, 5-diphenyl-2H-imidazole 0.1mmol, dichloro-bis (4-methyl-isopropyl) -lPhenyl) ruthenium (II) 0.005mmol, benzoic acid 0.05mmol, zinc triflate 0.05mmol, silver bistrifluoromethanesulfonylimide 0.02mmol, o-bromophenyl 2-butynoate 0.15mmol, and 2mL 1, 2-dichloroethane were added to a 25mL reaction tube. The reaction mixture was stirred in air at 100 ℃ for 12h, quenched and cooled to room temperature, followed by the addition of 10mL saturated NaHCO ₃ The solution was extracted with ethyl acetate (10 mL. Times.3), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by column chromatography to give 27.1mg of the objective product in 55% yield. The nuclear magnetism of the compound is characterized as follows: ¹ H NMR(400 MHz，CDCl ₃ )δ7.61-7.54(m，2H)，7.49-7.44(m，3H)，7.34-7.26(m，2H)，7.25-7.22 (m，2H)，7.17-7.08(m，3H)，6.95(dd，J＝8.0，1.5Hz，1H)，2.66(s，3H)，2.30(s， 1H)，1.77(s，3H)，1.69(s，3H). ¹³ C NMR(100MHz，CDCl ₃ )δ166.6，161.7，157.8， 150.1，147.8，141.8，133.3，132.3，131.3，130.7，130.2，128.9，128.5，128.1，127.5，127.4，123.9， 123.5，122.5，116.4，90.1，85.0，32.0，29.4，13.5.HRMS(ESI)Calcd for C ₂₇ H2 ₃ BrN ₂ O ₂ [M+H] ⁺ 487.1016；found 487.1018.

the above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, and all equivalent variations and modifications made within the scope of the present invention and the content of the description should be included in the scope of the present invention.

Claims

1. 2, 3-dihydrospiro [ imidazole-4, 1' -indene]The preparation method of the compound is characterized by comprising the following steps: the reaction equation is as follows:

the catalyst is dichlorobis (4-methylisopropylphenyl) ruthenium (II) dimer, the silver salt is silver hexafluoroantimonate or silver bistrifluoromethanesulfonylimide, the additive is nickel trifluoromethanesulfonate, copper trifluoromethanesulfonate or zinc trifluoromethanesulfonate, and the acid is acetic acid, pivalic acid, 1-adamantanecarboxylic acid or benzeneFormic acid, the solvent is tert-amyl alcohol, trifluoroethanol or 1, 2-dichloroethane, wherein R is ¹ Is H, halogen, alkyl, trifluoromethyl, methoxy or ester group, R ² Is aryl or alkyl, R ³ Is alkyl, R ⁴ Is an alkyl or aryl group.

2. The method of claim 1, wherein: comprises the steps of uniformly mixing the 2H-imidazole derivative, the 2-alkynoate compound, the catalyst, the silver salt, the additive, the acid and the solvent, reacting at 60-100 ℃ in the air or nitrogen atmosphere, cooling the reaction product to room temperature, and then adding saturated NaHCO ₃ Extracting the solution with ethyl acetate, drying the organic layer with anhydrous sodium sulfate, concentrating, and purifying by column chromatography to obtain the 2, 3-dihydrospiro [ imidazole-4, 1' -indene]A compound of the class.

3. The method of claim 1 or 2, wherein: the silver salt is bis (trifluoromethanesulfonyl) imide silver.

4. The method of claim 1 or 2, wherein: the additive is zinc trifluoromethanesulfonate.

5. The production method according to claim 1 or 2, characterized in that: the acid is benzoic acid.

6. The method of claim 1 or 2, wherein: the solvent is 1, 2-dichloroethane.

7. The method of claim 1 or 2, wherein: the silver salt is bis (trifluoromethanesulfonyl) imide silver, the additive is zinc trifluoromethanesulfonate, the acid is benzoic acid, and the solvent is 1, 2-dichloroethane.

8. The method of claim 1 or 2, wherein: the molar ratio of the 2H-imidazole derivative, the 2-alkynoate compound, the catalyst, the silver salt, the additive and the acid is 1.0-2.0.

9. The method of claim 8, wherein: the reaction temperature is 100 ℃, and the molar ratio of the 2H-imidazole derivative, the 2-alkynoate compound, the catalyst, the silver salt, the additive and the acid is 1.