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

Synthetic method of indoline derivative with C2 quaternary carbon center Download PDF

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CN109776388B
CN109776388B CN201910223550.2A CN201910223550A CN109776388B CN 109776388 B CN109776388 B CN 109776388B CN 201910223550 A CN201910223550 A CN 201910223550A CN 109776388 B CN109776388 B CN 109776388B
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CN109776388A (en
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刘奕奕
万涛
龚尚昆
吴俊杰
徐松
魏加强
周舟
常燕
王笑
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State Grid Corp of China SGCC
Electric Power Research Institute of State Grid Hunan Electric Power Co Ltd
State Grid Hunan Electric Power Co Ltd
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Electric Power Research Institute of State Grid Hunan Electric Power Co Ltd
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Abstract

The invention belongs to the field of compound synthesis, and particularly provides a preparation method of indoline derivatives with a C2 quaternary carbon center. The technology is a brand new mechanism, based on the insertion reaction of a Kukhtin-Ramirez adduct formed in situ and polar amino in a bifunctional compound, and a two-step one-pot synthesis strategy is adopted to generate intramolecular cyclization reaction, so that a series of indoline derivatives with C2 quaternary carbon centers are synthesized with medium to high yield.

Description

Synthetic method of indoline derivative with C2 quaternary carbon center
Technical Field
The invention belongs to the technical field of organic synthesis; in particular to a synthetic method of indoline derivatives with C2 quaternary carbon centers.
Background
Indoline derivatives with C2 quaternary carbon center are used as indole alkaloids with special structures, can be used for treating various diseases, such as tumor resistance, bacterial infection resistance and the like, and are very useful pharmacophores. Such compounds generally have good biological and pharmacological activities, such as the biological activity of Trigonoliimine C against potential HIV virus (j.am.chem.soc.2011,133, 10050); mitragynine pseudondoxyl exhibits potent opioid agonist activity in guinea pig ileum and mouse vas deferens (j.med.chem.2002,45,1949); vallissamine isolated from the leaf vine Vallisiadoptoma has potential anticancer activity (Helv. Chim. acta.1965,48,391). The method for efficiently synthesizing natural products containing the molecular skeleton and analogues thereof under mild conditions by using cheap and easily available raw materials is always a research focus and a hot spot in the field of organic synthetic chemistry.
Figure BDA0002004380700000011
Indoline derivatives with C2 quaternary carbon center have various biological activities and pharmacological effects, and research activities and development of practical applications related to the indoline derivatives are all established on the basis of effectively obtaining the compounds. However, the methods for separating and extracting such indoline derivatives from animals, plants and microorganisms not only have long period and high cost, but also have limited amount of compounds obtained, so that the organic synthesis method of indoline derivatives having C2 quaternary carbon center attracts great interest of numerous organic chemists, and effective synthesis methods are established.
In the prior reports, the most common synthetic strategies for indoline derivatives having a C2 quaternary carbon center were achieved by intramolecular cyclization starting from diazo esters. Liang et al, 2013, reported that palladium-catalyzed cross-coupling of aryldiazoformate with N-substituted-2-iodoaniline synthesized indoline derivatives with an alpha-quaternary carbon center in the presence of CO (chem.
Figure BDA0002004380700000021
In 2014, Hu et al reported Rh2(OAc)4Catalyzing diazo decomposition reaction of diazo ester and 2-aminophenyl ketone. Synthesis of indoline derivatives with C2 quaternary carbon center was achieved by intramolecular Aldol type reaction, capturing nitrogen ylide by the ketone carbonyl unit (chem.
Figure BDA0002004380700000022
Subsequently, the subgroup utilizes Rh (II)
Figure BDA0002004380700000023
According to the acid co-catalysis synthesis strategy, a series of indoline derivatives (J.Org.chem.2014,79,8440) with C2 quaternary carbon centers are synthesized by capturing nitrogen ylide in a molecule from an initial raw material o-amino chalcone.
Figure BDA0002004380700000024
In 2017, Anbarasan et al, starting from a N-ylide formed by o-vinylaniline and alpha-diazoate, achieved intramolecular ring closure under palladium catalysis, synthesized indoline derivatives with an alpha-quaternary carbon center (ACS Catal.2017,7,6283).
Figure BDA0002004380700000031
In view of the above, only a few reports have been made on the synthesis of indoline derivatives having a quaternary carbon center of C2, and these methods still suffer from the following disadvantages: the prior method can not meet the synthesis requirement of indoline derivatives with various structures and C2 quaternary carbon centers, so that a simple and efficient new synthesis method for constructing the compounds is developed from simple and easily available raw materials and is still an important subject in organic synthetic chemistry.
Disclosure of Invention
The invention aims to provide a novel method for efficiently synthesizing indoline derivatives with C2 quaternary carbon centers.
The invention is realized by adopting the following technical scheme:
a preparation method of indoline derivative with C2 quaternary carbon center comprises the steps of dissolving bifunctional compound with a structural formula 1 and alpha-carbonyl formic ether with a structural formula 2 in an organic solvent, adding hexamethylphosphoramidite for reaction, adding alkali into a reaction system, continuing the reaction until the reaction is finished, and separating to obtain the target product with a structure of a formula 3:
Figure BDA0002004380700000032
Figure BDA0002004380700000041
ar is an aromatic group;
x is N or CH; y is substituted formyl, ester or phosphonyl;
a is an amino protecting group;
R1one selected from aryl and aryl vinyl; r2One selected from alkyl and benzyl;
the base is at least one of cesium carbonate, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN).
The technology is a brand new mechanism, based on the insertion reaction of a Kukhtin-Ramirez adduct formed in situ and polar amino in a bifunctional compound, and a two-step one-pot synthesis strategy is adopted to generate intramolecular cyclization reaction, so that a series of indoline derivatives with C2 quaternary carbon centers are synthesized with medium to high yield. By adopting the preparation method and the brand-new preparation idea, the initial raw materials are simple and easy to obtain, the substrate application range is wide, and the reaction conditions are mild. In the prior art, alpha-diazo compounds are required to react in the presence of transition metals, however, diazo compounds are available in limited commercial varieties and are hazardous to handle.
Figure BDA0002004380700000042
The inventor researches and discovers that the target product can be prepared in high yield through a novel mechanism and one pot surprisingly by the substrate and further by the control of the hexamethylphosphoramidite and the alkali species.
The research finds that the Ar substituent of the substrate, X, Y, R, is further added under the innovative preparation mechanism of the invention1The substituent, hexamethylphosphoramidite and alkali are cooperatively controlled, so that the advantages of the preparation mechanism can be further improved, and the yield of the product can be further improved.
In the invention, Ar is aryl, heterocyclic aryl or at least one aryl and heterocyclic aryl are merged to form fused ring aryl. Preferably, Ar is benzene, five-membered or six-membered heterocyclic aryl, or fused ring aryl formed by the union of any two or more aromatic rings in benzene ring and heterocyclic aryl. 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, the heterocyclic aryl or the condensed ring aryl is allowed to have a substituent; the substituent is preferably halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl or C1-C6An alkoxy group.
In the present invention, when X is N, Y is preferably a phosphono group; when X is CH, Y is substituted formyl or ester. The substituted formyl group (the expression is-CO-R), preferably alkyl substituted formyl group (R is alkyl), aryl substituted formyl group (R is aryl), and the aryl substituted formyl group is, for example, phenyl formyl group and substituted phenyl formyl group. The phosphono group may be a sulphur hybridized phosphono group. (e.g., -P (S) RR).
The inventor researches to find that X is preferably CH, and Y is substituted formyl. This structure unexpectedly increases product yield relative to other types of difunctional compounds.
Still more preferably, X is CH and Y is aryl-substituted formyl.
the-A may be a group for protecting an amino group, which is well known in the industry, and is preferably-Ts (p-toluenesulfonyl), -Cbz, -Boc or-Fmoc.
Preferably, the bifunctional compound comprises an anthranilic aldehyde derivative.
Further preferably, the difunctional compound has the structural formula 1-A, formula 1-B or formula 1-C:
Figure BDA0002004380700000051
R3～R6independently of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl radical, C1-C6One of alkoxy-substituted aryl or heterocyclic aryl;
said R7、R8Independently is phenyl;
said R9Is C1-C6Alkyl, benzyl;
R10～R14independently of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl radical, C1-C6One of an alkoxy-substituted aryl or a heterocyclic aryl.
The research of the inventor finds that the compound with the structure of formula 1-C can unexpectedly improve the yield of one-pot preparation compared with the compounds with the structures of formula 1-A and formula 1-B.
Further research shows that R3Preferably H, which is either an electron-withdrawing or electron-donating group, to some extent affects product yield. R4Preferably C1-C6When alkyl is used, the yield of the product can be unexpectedly improved. R5May be H, an electron withdrawing group or an electron donating group. R6Preferably H, in which the electron-donating and electron-withdrawing groups are located, the uniformity affects the yield of the product.
Preferably, R3、R5、R6Is hydrogen; r4Is C1-C6The alkoxy group of (3) is more preferably a methoxy group.
It has also been found that R10～R13In (c) except for R at para position13When the compound is a strong power supply group, the product yield can be obviously improved.
Preferably, R10、R11、R13、R14Is hydrogen; r12Is C1-C6The alkoxy group of (3) is more preferably a methoxy group. It was found that with this preferred substrate, unexpectedly up to 92% can be achieved.
The alpha-carbonyl formate of the formula 2 of the present invention includes benzoyl formate, beta, gamma-unsaturated benzoyl formate compounds having various substituents.
Preferably, R is1Is selected from aryl and aryl vinyl.
The research of the invention also discovers that in the compound of the formula 2, R1The choice of group also has a large influence on the product yield. Preferably, R is1Phenyl or substituted phenyl. The substituent of the substituted phenyl is, for example, halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl or C1-C6An alkoxy group. Found that R1Preferably phenyl or substituted phenyl, the yield of the product is unexpectedly improved.
R2Is selected from C1-C6Alkyl or benzyl; preferably ethyl.
Further preferably, R1Is phenyl, R2Is ethyl. This preferred substrate surprisingly further increases the yield of the product.
Preferably, the molar ratio of the alpha-carbonyl formate to the bifunctional compound is 1: (1-1.5).
Preferably, the molar amount of α -carbonylformate and hexamethylphosphoramidite is 1: (1-1.5).
The present inventors have found that the desired products can be prepared unexpectedly successfully using the bases claimed in the present invention.
Preferably, the base is cesium carbonate. Preferred bases may further enhance the yield of the desired product.
Preferably, the molar charge ratio of the alkali to the alpha-carbonyl formate is 1: 1-2.5: 1.
The research of the inventor also finds that the reaction solvent system is further controlled on the basis of controlling the substrate, the hexamethylphosphoramidite and the alkali, so that the preparation advantage of the brand new mechanism is further promoted, and the preparation effect is further promoted.
The organic solvent is selected from any one or more of acetonitrile, benzene, toluene, xylene, Tetrahydrofuran (THF), dioxane, dichloromethane, chloroform, 1, 2-dichloroethane, N-Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
Preferably, the organic solvent is dichloromethane. Researches show that under the preferable organic solvent system, the effect of the innovative preparation mechanism of the invention can be unexpectedly further improved, and the yield of the target product is improved.
The research of the invention finds that the temperature in the preparation process is further controlled, which is beneficial to further improving the preparation effect.
Preferably, hexamethylphosphoramidite is added at the temperature lower than 0 ℃, and the temperature is raised to room temperature for reaction after the addition is finished; after the reaction is finished at room temperature, adding the alkali; the reaction was continued to the end while maintaining the temperature.
Preferably, the room temperature is 10-40 ℃.
Preferably, the reaction time of the bifunctional compound, the alpha-carbonyl formate and the hexamethylphosphoramidite at room temperature is preferably 0.5-2 h.
The reaction is continued for 2 to 20 hours after the alkali addition is completed.
Further preferably, the preparation method comprises the steps of dissolving alpha-carbonyl formate and a bifunctional compound in an organic solvent, then dropwise adding hexamethylphosphoramidite (which can be diluted by the reaction solvent in advance) into a reaction system at the temperature of-78 ℃ under the protection of nitrogen, stirring and reacting at room temperature for 0.5-2 hours after dropwise adding, adding alkali into the reaction system, and reacting at room temperature for 2-20 hours; then separating and purifying to obtain the target product.
The preparation method comprises a preferable synthesis method of indoline derivatives with C2 quaternary carbon centers (see synthesis line B), wherein reaction substrates alpha-carbonyl formate of formula 1-A, formula 1-B or formula 1-C structural formula and bifunctional compounds are dissolved in an organic solvent, hexamethylphosphoramidite is dropwise added into a reaction system at-78 ℃ under the protection of nitrogen, the molar feeding ratio of the compounds is 1 (1-1.5) to (1-1.5), and the obtained reaction mixture is removed from a low-temperature reactor after dropwise addition is finished and is placed in a room temperature reactor for stirring reaction for 2 hours. After the reaction is finished, adding a certain amount of alkali into the reaction system, and reacting for 2 to 20 hours at room temperature. And then removing the solvent under reduced pressure, and purifying the crude product by 200-300-mesh silica gel column chromatography to obtain an indoline target compound (formula 3-A, formula 3-B or formula 3-C) with a C2 quaternary carbon center. The eluting agent adopts a petroleum ether-ethyl acetate mixed solvent, and the volume ratio is 15: 1-5: 1; the yield was calculated from the pure product obtained. The yield can reach 92% according to different target compounds. The amount of the target compound to be prepared and the volume of the reaction vessel can be enlarged or reduced in a corresponding ratio.
Figure BDA0002004380700000081
Line B
Has the advantages that:
1. the invention provides a brand new preparation mechanism for preparing indoline derivatives with C2 quaternary carbon centers;
2. under the brand-new preparation mechanism, the substrate substituent, the alkali and the reaction solvent in the preparation process are further controlled, so that the preparation effect is further improved, and the yield of the target product is improved.
3. The indoline derivative I with the C2 quaternary carbon center has potential biological activity and pharmacological action; the provided synthesis method has the advantages of easily available raw materials, mild reaction conditions and wide substrate adaptability, and belongs to a brand-new synthesis strategy. The invention provides a new method for synthesizing the compound.
The specific implementation mode is as follows:
the invention further specifically describes a method for synthesizing an indoline derivative i having a C2 quaternary carbon center by using specific preparation examples, which are only used for specifically describing the invention, and particularly, the experimental conditions of specific implementation are only examples, and do not limit the actual protection scope of the invention at all. The specific implementation mode is as follows:
the reaction substrate I adopted in the following examples is alpha-carbonyl formate, and is prepared by a known synthesis method (see Zhang, X., et al. org. Lett.2015,17,3782; Ayyampillai, M., et al. tetrahedron Lett.2014,55,3503), and the general structural formula of the reaction substrate I is as follows:
Figure BDA0002004380700000091
the reaction substrate I is a bifunctional compound, and is prepared by a known synthesis method (see Huang, Y., et al. org. Lett.2009,11,991; Micheline, G., et al. tetrahedron Lett.1985,26,53), and the general structural formula of the compound is as follows:
Figure BDA0002004380700000092
the circuit of the indoline derivative I with the C2 quaternary carbon center synthesized by the invention is as follows:
Figure BDA0002004380700000093
in the above general structural formula:
in formula II: r1One selected from phenyl and phenyl vinyl; r2Is selected from C1-C6One of alkyl and benzyl;
in formulas III and I: raSelected from halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl or C1-C6One of alkoxy groups;
dissolving a reaction substrate alpha-carbonyl formate I and a bifunctional compound I in an organic solvent, then dropwise adding hexamethylphosphoramidite into a reaction system under the protection of nitrogen at-78 ℃, wherein the molar feeding ratio of the compounds is 1 (1-1.5) to 1-1.5, and after dropwise adding, removing the obtained reaction mixture from a low-temperature reactor, and placing the reaction mixture in a room-temperature stirring reactor for reaction for 2 hours. After the reaction is finished, adding a certain amount of alkali into the reaction system, and reacting for 2 to 20 hours at room temperature. And then removing the solvent under reduced pressure, and purifying the crude product by 200-300 mesh silica gel column chromatography to obtain the target compound I. The eluting agent adopts a petroleum ether-ethyl acetate mixed solvent, and the volume ratio is 15: 1-5: 1; the yield was calculated from the pure product obtained.
Example 1
Figure BDA0002004380700000101
Synthesis and structural identification of indoline compound IP1 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝COPh。
Figure BDA0002004380700000102
In a 25mL Schlenk flask equipped with a magnetic stir bar, ethyl benzoylformate (in formula II, R) was added sequentially1＝Ph，R2Et 36mg (0.2mmol), o-aminochalcone (in formula III, R)aH, X ═ CH, Y ═ COPh)83mg (0.22mmol), 1.5mL of dichloromethane, and then a dichloromethane solution of hexamethylphosphoramidite (36mg, dissolved in 0.5mL of dichloromethane) was added dropwise to the reaction system at a temperature of-78 ℃ under nitrogen atmosphere, and after completion of the addition, the resulting reaction mixture was removed from the low-temperature reactor and allowed to stir at room temperature for 2 hours. After completion of the reaction, 98mg of cesium carbonate (Cs) was directly added2CO30.30mmol) was added to the reaction system and left to react at room temperature for 2 hours. After the reaction is finished, the solvent is removed under reduced pressure, the crude product is purified by 200-300 mesh silica gel column chromatography, wherein the eluent is adoptedUsing petroleum ether-ethyl acetate mixed solvent with the volume ratio of 15: 1-5: 1 to obtain 47mg of a cis-product which is a white solid pure product and 34mg of a trans-product which is a white solid pure product, wherein the total yield is 75%, and the cis/trans ratio is 1.4: 1. The preparation amount of the target compound IP-1 and the volume of the reaction vessel can be enlarged or reduced according to the corresponding proportion; the physicochemical parameters of the target compound IP-1 are shown in Table 1.
Compared with the example 1, the difference is only that NaOH and Na are adopted2CO3、K2CO3、Et3When N, imidazole, piperidine, DABCO are used as bases, the reaction cannot obtain the target product. Thus, it was confirmed that the substrate was involved in hexamethylphosphoramidite, Cs2CO3DBU and DBN can be used as alkali to successfully implement the brand-new preparation mechanism of the invention and prepare the target product with high yield by one pot. On the basis, a reaction solvent system and reaction temperature in the reaction process are further reasonably controlled, and the yield of the prepared target product can be further improved.
Example 2
Synthesis and structural identification of indoline compound IP-1 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝COPh。
The raw materials, synthesis steps and process parameters used were essentially the same as in example 1, except as listed below:
the alkali used in the second step is DBU, and the dosage is 46mg (0.30 mmol); the cis-product is 16mg of white solid pure product, the trans-product is 34mg of white solid pure product, the total yield is 46 percent, and the cis/trans ratio 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, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝CO-3-OMe-C6H4(3-methoxybenzoyl).
Figure BDA0002004380700000111
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (Y is CO-3-MeO-C)6H4) In an amount of 90mg (0.22 mmol); the cis-form product is 40mg of a light yellow solid pure product, the trans-form product is 24mg of the light yellow solid pure product, 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 structural identification of indoline compound IP-3 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝CO-4-Cl-C6H4(4-chlorobenzoyl).
Figure BDA0002004380700000121
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the bifunctional compound I is o-aminochalcone (Y is CO-4-Cl-C)6H4) In an amount of 91mg (0.22 mmol); the cis-form product is 34mg of a light yellow solid pure product, the trans-form product is 31mg of a yellow solid pure product, the total yield is 57 percent, and the cis/trans ratio is 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 in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝CO-4-OMe-C6H4(4-methoxybenzoyl).
Figure BDA0002004380700000122
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the I of the double functional group compound of the used raw materials is adjacentAminochalcone (Y ═ CO-4-OMe-C6H4) In an amount of 90mg (0.22 mmol); the cis-form product is 42mg of a light yellow solid pure product, the trans-form product is 55mg of the light yellow solid pure product, the total yield is 85 percent, 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 in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝CO-4-Me-C6H4(4-methylbenzoyl).
Figure BDA0002004380700000131
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (Y is CO-4-Me-C)6H4) In an amount of 86mg (0.22 mmol); the cis-form product is 19mg of yellow solid pure product, the trans-form product is 34mg of yellow solid pure product, the total yield is 48 percent, and the cis/trans ratio is 1: 1.8. The physical and chemical parameters are shown in Table 1.
Example 7
Synthesis and structural identification of indoline compound IP-6 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra4-Me, X ═ CH, Y ═ COPh (benzoyl).
Figure BDA0002004380700000132
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a4-Me) in an amount of 86mg (0.22 mmol); the cis-form product is 38mg of yellow solid pure product, the trans-form product is 20mg of yellow solid pure product, the total yield is 52 percent, and the cis/trans ratio is 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 in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝4-OMe，X＝CH，Y＝COPh。
Figure BDA0002004380700000141
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a4-OMe) in an amount of 90mg (0.22 mmol); the cis-form product is 55mg of a light yellow solid pure product, the trans-form product is 50mg of a white solid pure product, the total yield is 92%, and the cis/trans ratio is 1.1: 1. The physical and chemical parameters are shown in Table 1.
Example 9
Synthesis and structural identification of indoline compound IP-8 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝4-Cl，X＝CH，Y＝COPh。
Figure BDA0002004380700000142
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a4-Cl) in an amount of 91mg (0.22 mmol); the cis-product is 50mg of an orange solid pure product, the trans-product is 28mg of a light yellow solid pure product, the total yield is 68%, and the cis/trans ratio is 1.8: 1. 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 in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝4-CF3，X＝CH，Y＝COPh。
Figure BDA0002004380700000143
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a＝4-CF3) In an amount of 98mg (0.22 mmol); the cis-form product is 57mg of white solid pure product, the trans-form product is 28mg of yellow solid pure product, the total yield is 70 percent, and the cis/trans ratio is 2: 1. The physical and chemical parameters are shown in Table 1.
Example 11
Synthesis and structural identification of indoline compound IP-10 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝5-Cl，X＝CH，Y＝COPh。
Figure BDA0002004380700000151
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a5-Cl) in an amount of 91mg (0.22 mmol); the cis-form product is 53mg of a light yellow solid pure product, the trans-form product is 31mg of the light yellow solid pure product, the total yield is 74 percent, and the cis/trans ratio is 1.7: 1. The physical and chemical parameters are shown in Table 1.
Example 12
Synthesis and structural identification of indoline compound IP-11 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝5-Br，X＝CH，Y＝COPh。
Figure BDA0002004380700000152
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a5-Br) in an amount of 100mg (0.22 mmol); obtaining cis-product59mg of a light yellow solid pure product, 42mg of a trans-product, 82% of total yield and 1.4:1 of 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 in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝6-Cl，X＝CH，Y＝COPh。
Figure BDA0002004380700000161
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the compound I of the double functional groups of the raw materials is o-amino chalcone (R)a6-Cl) in an amount of 91mg (0.22 mmol); the cis-form product is 22mg of a light yellow solid pure product, the trans-form product is 47mg of the light yellow solid pure product, the total yield is 60 percent, and the cis/trans ratio is 1: 2.1. The physical and chemical parameters are shown in Table 1.
Example 14
Synthesis and structural identification of indoline compound IP-13 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝Ph，R2＝Et，Ra＝H，X＝CH，Y＝CO2Et。
Figure BDA0002004380700000162
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the double functional group compound I is an anthranilic aldehyde derivative (R)a＝H，X＝CH，Y＝CO2Et) in an amount of 76mg (0.22 mmol); the cis-product was found to be 26mg of pure white solid, the trans-product was found to be 23mg of pure white solid, the total yield was 48%, and cis/trans was 1.1: 1. The physical and chemical parameters are shown in Table 1.
Example 15
Synthesis and structural identification of indoline compound IP-14 with C2 quaternary carbon centerR in the formulae (formulae II and III)1＝Ph，R2＝Et，Ra＝H，X＝N，Y＝-P(S)Ph2。
Figure BDA0002004380700000163
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the double functional group compound I is an anthranilic aldehyde derivative (R)a＝H，X＝N，Y＝P(S)Ph2) In an amount of 108mg (0.22 mmol); the single trans-product is 57mg of a light yellow solid pure product, and the yield is 44%. The physical and chemical parameters are shown in Table 1.
Example 16
Synthesis and structural identification of indoline compound IP-15 with C2 quaternary carbon center, R in structural general formula (formula II and III)1＝—CH＝CHPh，R2＝Et，Ra＝H，X＝CH，Y＝COPh。
Figure BDA0002004380700000171
The synthesis procedure and process parameters were essentially the same as in example 1, except as listed below:
the raw material alpha-carbonyl formate I is styryl ethyl formate (R)1＝—CH＝CHPh，R2Et) in an amount of 41mg (0.20 mmol); the compound I of the double functional groups of the raw materials is o-amino chalcone (R)aH, X ═ CH, Y ═ COPh), in an amount of 91mg (0.22 mmol); the alkali used in the second step is DBU, and the dosage is 46mg (0.30 mmol); 13mg of a cis-product and 23mg of a trans-product are obtained, 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 chemical Structure and physicochemical parameters of indoline derivatives I of the invention having a C2 quaternary carbon center
Figure BDA0002004380700000172
Figure BDA0002004380700000181
Figure BDA0002004380700000191
Figure BDA0002004380700000201
Figure BDA0002004380700000211
Figure BDA0002004380700000221
According to the invention, under the action of the substrate, hexamethylphosphoramidite and the alkali, a target product can be synthesized based on a Kukhtin-Ramirez adduct formed in situ by a one-pot method, and the yield can reach 92% by adopting the optimized substrate and matching preparation conditions.

Claims (11)

1. A preparation method of indoline derivatives with C2 quaternary carbon center is characterized in that bifunctional compounds and alpha-carbonyl formic ether are dissolved in an organic solvent, hexamethylphosphoramidite is added at the temperature lower than 0 ℃, and the temperature is raised to room temperature for reaction after the addition is finished; after the reaction is finished at room temperature, adding the alkali; the reaction is continued to the end while keeping the temperature, and the target product is obtained:
the bifunctional compound has a structural formula of 1-A, 1-B or 1-C:
Figure FDA0002557994360000011
the alpha-carbonyl formate has a structural formula of formula 2:
Figure FDA0002557994360000012
the target product has the structural formula 3-A, 3-B or 3-C:
Figure FDA0002557994360000013
Figure FDA0002557994360000021
R1one selected from aryl and aryl vinyl;
R2one selected from alkyl and benzyl;
R3～R6independently of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl radical, C1-C6One of alkoxy-substituted aryl or heterocyclic aryl;
said R7、R8Independently is phenyl;
said R9Is C1-C6Alkyl or benzyl;
R10～R14independently of hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C6Alkyl radical, C1-C6One of alkoxy-substituted aryl or heterocyclic aryl;
the protecting group A is-Ts, -Cbz, -Boc or-Fmoc;
the alkali 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.
2. The method of claim 1, wherein the difunctional compound has the formula 1-C.
3. The method of claim 1, wherein R is10、R11、R13、R14Is hydrogen, R12Is C1-C6Alkoxy group of (2).
4. The method of claim 3, wherein R is3、R5、R6Is hydrogen, R4Is C1-C6Alkoxy group of (2).
5. The method of claim 1, wherein R is1Is selected from aryl and aryl vinyl.
6. The method of claim 1, wherein R is1Selected from phenyl or substituted phenyl.
7. The method of claim 1, wherein R is2Is selected from C1-C6One of alkyl and benzyl.
8. The process according to any one of claims 1 to 7, wherein the molar ratio of the α -carbonylformate to the bifunctional compound is 1: (1-1.5).
9. The method of claim 1, wherein the molar ratio of α -carbonylformate to hexamethylphosphoramidite is 1: (1-1.5).
10. The method according to claim 1, wherein the organic solvent is one or more selected from acetonitrile, benzene, toluene, xylene, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1, 2-dichloroethane, N-dimethylformamide, and dimethylsulfoxide.
11. The process according to claim 1, wherein the α -carbonylformate and the bifunctional compound are dissolved in an organic solvent, hexamethylphosphoramidite is added dropwise to the reaction system at a temperature of-78 ℃ under the protection of nitrogen, and after the addition, the reaction system is stirred at room temperature for 0.5 to 2 hours, the base is added to the reaction system, and the reaction system is further reacted at room temperature for 2 to 20 hours; then separating and purifying to obtain the target product.
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