CN109776388B - Synthetic method of indoline derivative with C2 quaternary carbon center - Google Patents

Abstract

The invention belongs to the field of compound synthesis, and specifically provides a preparation method of an indoline derivative with a C2 quaternary carbon center. The amide is reacted, and then a base is added to the reaction system to continue the reaction to obtain the target product. The technology of the present invention is a brand-new mechanism, based on the insertion reaction of the Kukhtin-Ramirez adduct formed in situ with the polar amino group in the bifunctional compound, and adopts a two-step one-pot synthesis strategy to generate an intramolecular cyclization reaction, with medium to A series of indoline derivatives with C2 quaternary carbon centers were synthesized in high yields.

Description

A kind of synthetic method of indoline derivative with C2 quaternary carbon center

technical field

The invention belongs to the technical field of organic synthesis, and specifically provides a method for synthesizing a class of indoline derivatives with a C2 quaternary carbon center.

Background technique

Indoline derivatives with a C2 quaternary carbon center, as a class of indole alkaloids with special structures, can be used to treat various diseases, such as anti-tumor, anti-bacterial infection, etc., and are very useful pharmacophore groups. Such compounds usually have good biological and pharmacological activities, such as Trigonoliimine C has potential anti-HIV biological activity (J.Am.Chem.Soc.2011,133,10050); Mitragynine pseudoindoxyl in guinea pig ileum and mouse vas deferens Shows strong opioid agonist activity (J.Med.Chem.2002,45,1949); Vallesamidine isolated from Vallesiadichotoma has potential anticancer activity (Helv.Chim.Acta.1965,48,391). The use of cheap and readily available raw materials to efficiently synthesize natural products and their analogs containing such molecular skeletons under mild conditions has always been a research focus and hotspot in the field of organic synthetic chemistry.

Indoline derivatives with C2 quaternary carbon centers have diverse biological activities and pharmacological effects, and related research activities and development of practical applications are based on the effective acquisition of such compounds. However, the methods for separating and extracting such indoline derivatives from animals, plants and microorganisms are not only long-term, high-cost, but also limited in the amount of compounds obtained. Organic synthesis methods have attracted the strong interest of many organic chemists, and some effective synthetic methods have also been established.

In the existing reports, the most commonly used synthetic strategies for indoline derivatives with C2 quaternary carbon centers are all achieved by intramolecular cyclization reactions with diazotium esters as starting materials. In 2013, Liang et al. reported the palladium-catalyzed cross-coupling reaction of aryldiazoformates with N-substituted-2-iodoanilines, and synthesized indoline derivatives with α-quaternary carbon centers in the presence of CO. (Chem. Commun. 2013, 49, 561).

In 2014, Hu et al. reported the Rh2(OAc) ₄ -catalyzed diazolysis reaction of diazotides with ₂ -aminophenyl ketones. The synthesis of indoline derivatives with a C2 quaternary carbon center was achieved through an intramolecular Aldol-type reaction where the ketone carbonyl unit captures nitrogen ylides (Chem. Commun. 2014, 50, 951).

酸共催化的合成策略，从初始原料邻氨基查尔酮出发，分子内捕获氮叶立德完成关环，合成了一系列具有C2季碳中心的吲哚啉衍生(J.Org.Chem.2014,79,8440)。Subsequently, the group utilized Rh(II)/

Acid co-catalyzed synthesis strategy, starting from the initial raw material o-aminochalcone, capturing nitrogen ylide in the molecule to complete the ring closure, and synthesizing a series of indoline derivatives with C2 quaternary carbon center (J.Org.Chem.2014,79 , 8440).

In 2017, Anbarasan et al. started from the nitrogen ylide formed by o-vinylaniline and α-diazoate, realized intramolecular ring closure under palladium catalysis, and synthesized indoline derivatives with α-quaternary carbon center ( ACS Catal. 2017, 7, 6283).

To sum up the above, there are only a few reports on the synthetic methods of indoline derivatives with C Nitrogen compounds and substrates have limited scope of application, and transition metals are required. Existing methods still cannot meet the needs for the synthesis of indoline derivatives with C2 quaternary carbon centers with diverse structures. Therefore, starting from simple and readily available raw materials, development It is still an important topic in organic synthetic chemistry to construct a simple and efficient new method for the synthesis of such compounds.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a new method for efficiently synthesizing indoline derivatives with C2 quaternary carbon centers.

The present invention adopts the following technical scheme to realize:

A preparation method of an indoline derivative having a C2 quaternary carbon center, the bifunctional compound having the structural formula of formula 1 and the α-carbonyl formate of the structural formula of formula 2 are dissolved in an organic solvent, and hexamethylphosphoramidite is added to carry out Reaction, then in the reaction system, add alkali, continue to react to finish, separate and obtain the purpose product of formula 3 structure:

Ar is an aromatic group;

Described X is N or CH; Y is substituted formyl, ester group or phosphono group;

Described A is amino protecting group;

R ₁ is selected from one of aryl and aryl vinyl; R ₂ is selected from one of alkyl and benzyl;

The base is cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene ( at least one of DBN).

The technology of the present invention is a completely new mechanism, based on the insertion reaction of the Kukhtin-Ramirez adduct formed in situ with the polar amino group in the bifunctional compound, and the intramolecular cyclization reaction takes place by a two-step one-pot synthesis strategy. A series of indoline derivatives with C2 quaternary carbon centers were synthesized in high yields. By adopting the preparation method and the new preparation idea of the present invention, the initial raw materials are simple and easy to obtain, the substrate is suitable for a wide range, and the reaction conditions are mild. In the prior art, it is necessary to use α-diazides, which are reacted with the participation of transition metals. However, the types of diazides that are commercially available are limited, and the operation is dangerous.

The inventors of the present invention have found that the target product can be prepared unexpectedly in a one-pot and high-yield manner through the novel mechanism of the present invention through the control of the substrate and the hexamethylphosphoramidite and the alkali species. .

The research found that under the innovative preparation mechanism of the present invention, the further coordinated control of the Ar substituent, X, Y, R ₁ substituent of the substrate, hexamethylphosphoramidite, and base types can further improve the preparation mechanism of the present invention. It can further improve the yield of the product.

In the present invention, Ar is an aryl group, a heterocyclic aryl group, or a combination of at least one aryl group and a heterocyclic aryl group to form a fused-ring aryl group. Preferably, the Ar is benzene, a five-membered or six-membered heterocyclic aryl group, a fused-ring aryl group formed by combining any two or more aromatic rings of a benzene ring and a heterocyclic aryl group. The heteroatom of the heterocyclic aryl group is preferably at least one of O, S or N.

In Ar, the aromatic ring of the aryl group, heterocyclic aryl group or fused-ring aryl group is allowed to carry a substituent; the substituent is preferably halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy.

In the present invention, when X is N, Y is preferably a phosphono group; when X is CH, Y is a substituted formyl group or an ester group. The substituted formyl group (expressed as -CO-R) is preferably an alkyl-substituted formyl group (R is an alkyl group), an aryl-substituted formyl group (R is an aryl group), and the aryl-substituted formyl group is The formyl group is, for example, phenylformyl, substituted phenylformyl. The phosphono group may be a thiohybridized phosphono group. (eg -P(S)RR).

The inventors of the present invention found that X is preferably CH, and Y is a substituted formyl group. This structure can unexpectedly improve product yield relative to other types of bifunctional compounds.

Even more preferably, X is CH and Y is an aryl-substituted formyl group.

The -A can be a group well known in the industry for protecting an amino group, preferably -Ts (p-toluenesulfonyl), -Cbz, -Boc or -Fmoc.

Preferably, the bifunctional compound includes an o-aminobenzaldehyde derivative.

Further preferably, the bifunctional compound has the structural formula of formula 1-A, formula 1-B or formula 1-C:

R ₃ to R ₆ are independently one of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy substituted aryl or heterocyclic aryl kind;

Said R ₇ and R ₈ are independently phenyl;

Described R ₉ is C ₁ -C ₆ alkyl, benzyl;

R ₁₀ to R ₁₄ are independently one of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy substituted aryl or heterocyclic aryl kind.

The inventors of the present invention have found that the compound of formula 1-C can unexpectedly improve the yield of one-pot preparation compared with formula 1-A and formula 1-B.

Further research found that R ₃ is preferably H, and the position of electron withdrawing or electron donating group will affect the yield of the product to a certain extent. When R ₄ is preferably a C ₁ -C ₆ alkyl group, the product yield can be unexpectedly improved. R ₅ can be H, an electron withdrawing group or an electron donating group. R ₆ is preferably H, and the placement of electron-donating and electron-withdrawing groups at this position affects the yield of the product to a certain extent.

Preferably, R ₃ , R ₅ and R ₆ are hydrogen; R ₄ is a C ₁ -C ₆ alkoxy group, more preferably a methoxy group.

The research also found that, among R ₁₀ to R ₁₃ , except when R ₁₃ located in the para position is a strong power supply group, the product yield can be significantly improved.

Preferably, R ₁₀ , R ₁₁ , R ₁₃ and R ₁₄ are hydrogen; R ₁₂ is a C ₁ -C ₆ alkoxy group, more preferably a methoxy group. The study found that under this preferred substrate, it can be unexpectedly as high as 92%.

The α-carbonyl formate of formula 2 of the present invention includes benzoyl formate and β,γ-unsaturated benzoyl formate compounds containing different substituents.

Preferably, the R ₁ is selected from one of aryl and arylvinyl.

It is also found in the research of the present invention that in the compound of formula 2, the choice of R ₁ group also has a great influence on the product yield. Preferably, the R ₁ phenyl or substituted phenyl. The substituent of the substituted phenyl group is, for example, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. It is found that when R ₁ is preferably phenyl or substituted phenyl, the yield of the product can be unexpectedly improved.

R ₂ is selected from C ₁ -C ₆ alkyl or benzyl; preferably ethyl.

More preferably, R ₁ is phenyl and R ₂ is ethyl. This preferred substrate can surprisingly further enhance the yield of the product.

Preferably, the molar ratio of the α-carbonyl formate and the bifunctional compound is 1:(1-1.5).

Preferably, the molar ratio of α-carbonyl formate and hexamethyl phosphoramidite is 1:(1-1.5).

It is found in the research of the present invention that the desired product can be prepared unexpectedly and successfully by using the base required by the present invention.

Preferably, the base is cesium carbonate. The preferred base can further improve the yield of the target product.

Preferably, the molar feeding ratio of the base to the α-carbonyl formate is 1:1 to 2.5:1.

The inventors also found that, on the basis of the control of the substrate, hexamethylphosphoramidite and base, further control of the reaction solvent system is helpful to further improve the preparation advantages of the new mechanism of the present invention, and is helpful to further improve Preparation effect.

The organic solvent is selected from acetonitrile, benzene, toluene, xylene, tetrahydrofuran (THF), dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide ( DMF), any one or more of dimethyl sulfoxide (DMSO).

Preferably, the organic solvent is dichloromethane. The research found that under the preferred organic solvent system, the effect of the innovative preparation mechanism of the present invention can be further improved unexpectedly, and the yield of the target product can be improved.

It is found in the research of the present invention that further controlling the temperature in the preparation process is helpful to further improve the preparation effect.

Preferably, hexamethylphosphoramidite is added at a temperature lower than 0° C., and after the addition is completed, the temperature is raised to the room temperature for reaction; the alkali is added after the reaction is completed at room temperature; and the reaction is continued at this temperature until the end.

Preferably, the room temperature is 10-40°C.

Preferably, the reaction time of the bifunctional compound, α-carbonyl formate and hexamethyl phosphoramidite at room temperature is preferably 0.5-2 h.

After the alkali addition is completed, the reaction time is 2 hours to 20 hours.

Further preferably, in the preparation method of the present invention, the α-carbonyl formate and the bifunctional compound are dissolved in an organic solvent, and then hexamethylphosphoramidite (can be used in advance with the reaction solvent under nitrogen protection at a temperature of -78°C) Dilution) is added dropwise to the reaction system, after the dropwise addition is completed, the reaction is stirred at room temperature for 0.5-2 hours, then the base is added to the reaction system, and the reaction is performed at room temperature for 2 hours to 20 hours; then the desired product is obtained by separation and purification.

The preparation method of the present invention includes a preferred method for synthesizing an indoline derivative with a C2 quaternary carbon center (see synthesis route B). The reaction substrate α-carbonyl formate and the bifunctional compound are dissolved in an organic solvent, and then hexamethylphosphoramidite is added dropwise to the reaction system under nitrogen protection at a temperature of -78 ° C, and the molar feeding ratio of the above compounds is 1 :(1～1.5):(1～1.5), after the dropwise addition, the obtained reaction mixture was removed from the low-temperature reactor, and was stirred at room temperature for 2 hours. After the reaction is completed, a certain amount of base is added to the reaction system, and the reaction is carried out at room temperature for 2 to 20 hours. Then the solvent is removed under reduced pressure, and the crude product is purified by 200-300 mesh silica gel column chromatography to obtain the indoline target compound (formula 3-A, formula 3-B or formula 3-C) with a C2 quaternary carbon center ). The eluent adopts petroleum ether-ethyl acetate mixed solvent, and the volume ratio is 15:1 to 5:1; the yield is calculated based on the obtained pure product. Depending on the target compound, yields can be as high as 92%. The amount of the target compound prepared and the volume of the reaction vessel can be scaled up or down accordingly.

line B

Beneficial effects:

1. The present invention provides a new preparation mechanism for preparing indoline derivatives with C2 quaternary carbon centers;

2. Under the new preparation mechanism of the present invention, the substrate substituent, base and reaction solvent in the preparation process are further controlled, which helps to further improve the preparation effect and improve the yield of the target product.

3. The provided indoline derivative I with a C2 quaternary carbon center has potential biological activity and pharmacological action; the provided synthetic method has easily available raw materials, mild reaction conditions, wide substrate adaptability, and belongs to a brand-new synthetic strategy. The present invention provides a new method for the synthesis of such compounds.

Detailed ways:

In the present invention, the synthesis method of the indoline derivative I with a C2 quaternary carbon center is described in more detail through specific preparation examples. The purposes of the examples are only used to specifically illustrate the present invention. It is an example, and does not constitute any limitation to the actual protection scope of the present invention. The specific implementation is as follows:

The reaction substrate III used in the following examples is α-carbonyl formate, prepared by known synthetic methods (see Zhang, X., et al. Org. Lett. 2015, 17, 3782; Ayyampillai, M., et al.TetrahedronLett.2014,55,3503), its general structural formula is:

The adopted reaction substrate III is a bifunctional compound, prepared by known synthetic methods (see Huang, Y., et al. Org. Lett. 2009, 11, 991; Micheline, G., et al. Tetrahedron Lett. 1985, 26 ,53), and its general structural formula is:

The route of the indoline derivative I with C2 quaternary carbon center synthesized by the present invention is:

In the above structural formula:

In formula II: R ₁ is selected from a kind of phenyl group and phenylvinyl group; R ₂ is selected from a kind of C ₁ -C ₆ alkyl group and benzyl group;

In formula III and I: R _a is selected from one of halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

The reaction substrate α-carbonyl formate 11 and the bifunctional compound 111 are dissolved in the organic solvent, and then under nitrogen protection, at -78 ° C, hexamethylphosphoramidite is added dropwise to the reaction system, and the above-mentioned compound molar feeding ratio is 1: (1-1.5): (1-1.5), after the dropwise addition, the obtained reaction mixture was removed from the low-temperature reactor, and the reaction mixture was placed at room temperature and stirred for 2 hours. After the reaction is completed, a certain amount of base is added to the reaction system, and the reaction is carried out at room temperature for 2 to 20 hours. Then the solvent was removed under reduced pressure, and the crude product was purified by 200-300 mesh silica gel column chromatography to obtain the target compound I. The eluent adopts petroleum ether-ethyl acetate mixed solvent, and the volume ratio is 15:1 to 5:1; the yield is calculated based on the obtained pure product.

Example 1

Synthesis and structural identification of indoline compound IP1 with C2 quaternary carbon center, in the general structural formula (formula II and III), R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y=COPh .

In a 25mL Schlenk flask equipped with a magnetic stirrer, 36 mg (0.2 mmol) of ethyl benzoylformate (in formula II, R ₁ =Ph, R ₂ =Et), o-aminochalcone (in formula III) were successively added. , _Ra =H, X=CH, Y=COPh) 83 mg (0.22 mmol), 1.5 mL of dichloromethane, then under nitrogen protection, at -78 ℃ temperature, was added dropwise a solution of hexamethylphosphoramide in dichloromethane ( 36 mg, dissolved in 0.5 mL of dichloromethane) into the reaction system, after the dropwise addition was completed, the resulting reaction mixture was removed from the low temperature reactor, and was placed at room temperature for stirring for 2 hours. After the reaction was completed, 98 mg of cesium carbonate (Cs ₂ CO ₃ , 0.30 mmol) was directly added to the reaction system, and the reaction was continued at room temperature for 2 hours. After the reaction is completed, the solvent is removed under reduced pressure, and the crude product is purified by 200-300 mesh silica gel column chromatography, wherein the eluent is a mixed solvent of petroleum ether-ethyl acetate, and the volume ratio is 15:1-5:1. The formula product is 47 mg of pure white solid, the trans product is 34 mg of pure white solid, the total yield is 75%, and the cis/trans ratio is 1.4:1. The amount of the target compound IP-1 prepared and the volume of the reaction vessel can be expanded or reduced according to the corresponding proportion; the physicochemical parameters of the target compound IP-1 are shown in Table 1.

Compared with Example 1, the only difference is that when NaOH, Na ₂ CO ₃ , K ₂ CO ₃ , Et ₃ N, imidazole, piperidine and DABCO are used as bases, the desired product cannot be obtained in the reaction. Therefore, it is confirmed that the substrate can successfully implement the new preparation mechanism of the present invention under the condition that hexamethylphosphoramidite is involved and Cs ₂ CO ₃ , DBU, and DBN are used as bases, and the purpose is to be prepared in one pot with high yield. product. On this basis, by further reasonably controlling the reaction solvent system and the reaction temperature in the reaction process, the yield of the obtained target product can be further improved.

Example 2

Synthesis and structural identification of indoline compound IP-1 with C2 quaternary carbon center, in the general structural formula (formula II and III), R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y =COPh.

Raw materials used, synthesis steps and process parameters are basically the same as Example 1, and the differences are listed as follows:

The base used in the second step is DBU, and the consumption is 46mg (0.30mmol); The cis product is 16mg of pure white solid, and the trans product is 34mg of pure white solid, and the total yield is 46%, and cis/trans is 1: 2.1. The physical and chemical parameters are shown in Table 1.

Example 3

Synthesis and structural identification of indoline compound IP-2 with C2 quaternary carbon center, in the general structural formula (formula II and III), R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y =CO-3-OMe- _C6H4 ( ₃ -methoxybenzoyl).

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (Y=CO-3-MeO-C ₆ H ₄ ), and the consumption is 90 mg (0.22 mmol); the cis product is 40 mg of pure light yellow solid, and the trans product is 40 mg. It is 24 mg of pure light yellow solid, the total yield is 56%, and the cis/trans ratio is 1.7:1. The physical and chemical parameters are shown in Table 1.

Example 4

Synthesis and structure identification of indoline compound IP-3 with C2 quaternary carbon center, in the general structural formula (formula II and III), R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y =CO-4-Cl- _C6H4 ( ₄ -chlorobenzoyl).

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (Y=CO-4-Cl-C ₆ H ₄ ), and the consumption is 91 mg (0.22 mmol); the cis product is 34 mg of pure light yellow solid, and the trans product is 34 mg. It was 31 mg of pure yellow solid, the total yield was 57%, and the cis/trans ratio was 1.1:1. The physical and chemical parameters are shown in Table 1.

Example 5

Synthesis and structural identification of indoline compound IP-4 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y= CO-4-OMe- _C6H4 ( ₄ -methoxybenzoyl).

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The raw material bifunctional compound 111 used is o-aminochalcone (Y=CO-4-OMe-C ₆ H ₄ ), and the consumption is 90 mg (0.22 mmol); the cis product is 42 mg of pure light yellow solid, and the trans product is 42 mg. It is 55 mg of pure light yellow solid, the total yield is 85%, and the cis/trans ratio is 1:1.3. The physical and chemical parameters are shown in Table 1.

Example 6

Synthesis and structural identification of indoline compound IP-5 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y= CO-4-Me- _C6H4 ( ₄ -methylbenzoyl).

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (Y=CO-4-Me-C ₆ H ₄ ), and the consumption is 86 mg (0.22 mmol); the cis product is 19 mg of pure yellow solid, and the trans product is The pure yellow solid was 34 mg, the total yield was 48%, and the cis/trans ratio was 1:1.8. The physical and chemical parameters are shown in Table 1.

Example 7

Synthesis and structure identification of indoline compound IP-6 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =4-Me, X =CH Y=COPh (benzoyl).

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (R _a =4-Me), and the consumption is 86mg (0.22mmol); the cis product is 38mg of pure yellow solid, and the trans product is 20mg of pure yellow solid, The overall yield was 52% with a cis/trans of 1.9:1. The physical and chemical parameters are shown in Table 1.

Example 8

Synthesis and structural identification of indoline compound IP-7 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =4-OMe, X=CH in the general structural formula (formula II and III), Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (R _a =4-OMe), and the consumption is 90 mg (0.22 mmol); the cis product is 55 mg of pure light yellow solid, and the trans product is 50 mg of pure white solid , the overall yield was 92%, and the cis/trans ratio was 1.1:1. The physical and chemical parameters are shown in Table 1.

Example 9

Synthesis and structure identification of indoline compound IP-8 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =4-Cl, X =CH in the general structural formula (formula II and III), Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The raw material bifunctional compound 111 used is o-aminochalcone (R _a =4-Cl), and the consumption is 91mg (0.22mmol); the cis product is a pure orange solid product 50mg, and the trans product is a pure light yellow solid product 28 mg, 68% overall yield, 1.8:1 cis/trans. The physical and chemical parameters are shown in Table 1.

Example 10

Synthesis and structural identification of indoline compound IP-9 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =4-CF ₃ , X=CH in the general structural formula (formula II and III) , Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (R _a =4-CF ₃ ), and the consumption is 98mg (0.22mmol); the cis product is 57mg of pure white solid, and the trans product is 28mg of pure yellow solid , the overall yield was 70%, and the cis/trans ratio was 2:1. The physical and chemical parameters are shown in Table 1.

Example 11

Synthesis and structure identification of indoline compound IP-10 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =5-Cl, X = CH in the general structural formula (formula II and III), Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (R _a =5-Cl), and the consumption is 91 mg (0.22 mmol); the cis product is 53 mg of light yellow solid pure product, and the trans product is light yellow solid pure product 31 mg, 74% overall yield, cis/trans 1.7:1. The physical and chemical parameters are shown in Table 1.

Example 12

Synthesis and structure identification of indoline compound IP-11 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =5-Br, X = CH, Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The raw material bifunctional compound III1 used is o-aminochalcone (R _a =5-Br), and the consumption is 100mg (0.22mmol); the cis product is 59mg of pure light yellow solid, and the trans product is pure light yellow solid 42 mg, 82% overall yield, 1.4:1 cis/trans. The physical and chemical parameters are shown in Table 1.

Example 13

Synthesis and structural identification of indoline compound IP-12 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =6-Cl, X=CH in the general structural formula (formula II and III), Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is o-aminochalcone (R _a =6-Cl), and the consumption is 91mg (0.22mmol); the cis product is 22mg of pure light yellow solid, and the trans product is pure light yellow solid 47 mg, 60% overall yield, cis/trans 1:2.1. The physical and chemical parameters are shown in Table 1.

Example 14

Synthesis and structure identification of indoline compound IP-13 with C2 quaternary carbon center, in the general structural formula (formula II and III), R ₁ =Ph, R ₂ =Et, R _a =H, X=CH, Y= CO ₂ Et.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is an o-aminobenzaldehyde derivative (R _a =H, X=CH, Y=CO ₂ Et), and the consumption is 76 mg (0.22 mmol); the cis product is 26 mg of pure white solid, and the reverse The product of formula is 23 mg of pure white solid, the total yield is 48%, and the cis/trans ratio is 1.1:1. The physical and chemical parameters are shown in Table 1.

Example 15

Synthesis and structure identification of indoline compound IP-14 with C2 quaternary carbon center, R ₁ =Ph, R ₂ =Et, R _a =H, X=N, Y= -P(S) _Ph2 .

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The used raw material bifunctional compound III is an o-aminobenzaldehyde derivative (R _a =H, X=N, Y=P(S)Ph ₂ ), and the consumption is 108 mg (0.22 mmol); the single trans product is a pale yellow solid The pure product was 57 mg, and the yield was 44%. The physical and chemical parameters are shown in Table 1.

Example 16

Synthesis and structure identification of indoline compound IP-15 with C2 quaternary carbon center, R ₁ =—CH=CHPh, R ₂ =Et, R _a =H, X=CH in the general structural formula (formula II and III) , Y=COPh.

Synthesis step and process parameter are basically identical with embodiment 1, and difference is listed as follows:

The raw material α-carbonyl formate III used is ethyl styryl formate (R ₁ =—CH=CHPh, R ₂ =Et), and the consumption is 41 mg (0.20 mmol); the raw material bifunctional compound III is an o-amino group Chalcone (R _a =H, X=CH, Y=COPh), the dosage is 91mg (0.22mmol); the base used in the second step is DBU, the dosage is 46mg (0.30mmol); the cis product is a pale yellow oily The liquid pure product is 13 mg, and the trans product is 23 mg of light yellow oily liquid pure product. The total yield is 32%, and the cis/trans ratio is 1:1.8. The physical and chemical parameters are shown in Table 1.

Table 1. The chemical structure and physicochemical parameters of the indoline derivative I with C2 quaternary carbon center of the present invention

In the present invention, the target product can be synthesized by one-pot method based on the Kukhtin-Ramirez adduct formed in situ under the action of the substrate, hexamethylphosphoramidite and the base, and by adopting the preferred substrate, With the preparation conditions, a yield as high as 92% can be obtained.

Claims (11)

1. a preparation method of the indoline derivative with C2 quaternary carbon center is characterized in that, bifunctional compound, α-carbonyl formate are dissolved in organic solvent, add hexamethyl at lower than 0 ℃ Phosphoramidite, after the addition is completed, it is warmed up to react at room temperature; after the reaction is completed at room temperature, the alkali is added; keep at this temperature and continue to react to the end to obtain the target product: The bifunctional compound has the structural formula of formula 1-A, formula 1-B or formula 1-C:

Described alpha-carbonyl formate has formula 2 structural formula:

The target product has the structural formula of formula 3-A, formula 3-B or formula 3-C:

R ₁ is selected from one of aryl and aryl vinyl; R ₂ is selected from one of alkyl and benzyl; R ₃ to R ₆ are independently one of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy substituted aryl or heterocyclic aryl kind; Said R ₇ and R ₈ are independently phenyl; Described R ₉ is C ₁ -C ₆ alkyl or benzyl; R ₁₀ to R ₁₄ are independently one of hydrogen, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy substituted aryl or heterocyclic aryl kind; Described protecting group A is -Ts, -Cbz, -Boc or -Fmoc; The base is at least one of cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,5-diazabicyclo[4.3.0]non-5-ene. kind. 2 . The preparation method of claim 1 , wherein the bifunctional compound has a structural formula of formula 1-C. 3 . 3 . The preparation method according to claim 1 , wherein R ₁₀ , R ₁₁ , R ₁₃ , and R ₁₄ are hydrogen, and R ₁₂ is a C ₁ -C ₆ alkoxy group. 4 . The preparation method of claim 3, wherein R ₃ , R ₅ and R ₆ are hydrogen, and R ₄ is a C ₁ -C ₆ alkoxy group. 5. The preparation method of claim 1, wherein the R ₁ is selected from the group consisting of aryl and arylvinyl. 6. The preparation method of claim 1, wherein the R ₁ is selected from phenyl or substituted phenyl. 7. The preparation method of claim 1, wherein R ₂ is selected from one of C ₁ -C ₆ alkyl and benzyl. 8 . The preparation method according to claim 1 , wherein the molar ratio of the α-carbonyl formate and the bifunctional compound is 1:(1-1.5). 9 . 9 . The preparation method according to claim 1 , wherein the molar ratio of α-carbonyl formate and hexamethylphosphoramidite is 1:(1-1.5). 10 . 10. The preparation method of claim 1, wherein the organic solvent is selected from the group consisting of acetonitrile, benzene, toluene, xylene, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloromethane Any one or more of ethane, N,N-dimethylformamide and dimethylsulfoxide. 11. The preparation method according to claim 1, wherein the α-carbonyl formate and the bifunctional compound are dissolved in an organic solvent, and then the hexamethylphosphoramidite is dropped under nitrogen protection at a temperature of -78° C. Add to the reaction system, place the mixture at room temperature for 0.5-2 hours after the dropwise addition is completed, add the base to the reaction system, and react at room temperature for 2 hours to 20 hours; then separate and purify to obtain the desired product.