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CN-121990970-A - Method for synthesizing anti-isoamylene substituted indolone by nickel catalysis

CN121990970ACN 121990970 ACN121990970 ACN 121990970ACN-121990970-A

Abstract

The invention relates to a method for synthesizing anti-isoamylene substituted indolone by using transition metal nickel as a catalyst. Specifically, in the presence of a metallic nickel catalyst (Ni (cod) 2 ) and tricyclohexylphosphine (PCy 3 ) as ligands, C3 unsubstituted indolone is used as a nucleophile to react with isoprene to obtain an inverted isoamylene substituted indolone product. And then, taking the product as a reaction raw material, and carrying out nucleophilic substitution reaction with halogenated alkane under alkaline conditions to obtain the 3, 3-disubstituted indolone with divergent functional groups. The invention uses isoprene as a reaction precursor, obtains the indolone product substituted by the anti-isoamylene group with high activity and selectivity, carries out relay nucleophilic substitution reaction, and provides a new strategy for flexibly and conveniently introducing different steric hindrance and electric functional groups.

Inventors

  • CHEN QINGAN
  • LIU YINGYING

Assignees

  • 中国科学院大连化学物理研究所

Dates

Publication Date
20260508
Application Date
20241108

Claims (9)

  1. 1. A method for synthesizing anti-isoamylene substituted indolone by nickel catalysis is characterized in that: Wherein the indolone skeleton Ar can be one or more than two of groups of 5-methyl, 5-fluoro, 5-chloro, 5-bromo, 5-methoxy, 6-fluoro, 6-chloro, 6-bromo, 6-methoxy, 6-methyl formate, 7-methyl and 7-trifluoromethyl, and the following are preferable: The substituent R 1 on the indolone nitrogen can be one or more than two of ethyl, benzyl, allyl and isopentenyl, and the preferable specific examples are as follows: R 2 is one or more than two of benzyl, 4-tert-butylbenzyl, 4-cyanobenzyl, 4-trifluoromethyl benzyl, isopentenyl, geranyl, propargyl, acetonitrile, methyl, ethyl and isopropyl, and is preferably as follows:
  2. 2. A method according to claim 1, characterized in that: the specific operation steps of the first step are as follows: Under the inert atmosphere (such as nitrogen), a nickel catalyst (Ni (cod) 2 ), tricyclohexylphosphine ligand (PCy 3 ), indolone 1, isoprene 2, an alkaline additive (Cs 2 CO 3 ) and tetrahydrofuran solvent (THF) are added into a reaction container, the reaction is carried out for 24 hours at 60 ℃, the reaction temperature is more preferably 60-100 ℃, the reaction time is 24-48 hours, and the reaction is finished, so that the inverted isopentenyl substituted indolone 3 is obtained by separation.
  3. 3. A method according to claim 1 or 2, characterized in that: The molar use ratio of the indolone 1 to the isoprene 2 is preferably 1.0:1.0-1.0:4.0, and more preferably 1.0:1.0-1.0:2.0.
  4. 4. A method according to claim 1 or 2, characterized in that: The molar ratio of the indolone 1 to the alkaline additive (Cs 2 CO 3 ) is preferably 1.0:0.5-1.0:2.0, more preferably 1.0:0.5-1.0:1.0.
  5. 5. A method according to claim 1 or 2, characterized in that: The molar amount ratio of nickel catalyst (Ni (cod) 2 ) to tricyclohexylphosphine ligand (PCy 3 ) is preferably 1.0:1.0 to 1.0:2.5, more preferably 1.0:1.5 to 1.0:2.0, and the preferable addition amount of nickel catalyst (Ni (cod) 2 ) is 0.01 to 0.05mmol, more preferably 0.02mmol, relative to 0.20mmol of indolone 1.
  6. 6. A method according to claim 1 or 2, characterized in that: the solvent is Tetrahydrofuran (THF), and the amount of the solvent to be used is preferably 1.5 to 2.5mL, more preferably 1.9 to 2.0mL, based on 0.20mmol of indolone 1.
  7. 7. A method according to claim 1, characterized in that: the specific operation steps are as follows: adding the inverted isopentenyl substituted indolone 3, an additive base (NaH) and a solvent of nitrogen, dimethylformamide (DMF) and halogenated alkane (R 2 X) into a reaction container in an inert atmosphere (such as nitrogen) for reaction for 12-16 hours at room temperature, and separating to obtain the 3, 3-disubstituted indolone 4 after the reaction is finished.
  8. 8. A method according to claim 1 or 6, characterized in that: The molar ratio of the anti-isoamylene substituted indolone 3, the additive base (NaH) and the halogenated alkane (R 2 X) is preferably 1.0:1.2:1.5-1.0:1.2:1.5, and more preferably 1.0:1.2:2.0.
  9. 9. A method according to claim 1 or 6, characterized in that: The solvent is nitrogen, nitrogen Dimethylformamide (DMF), and the dosage of the solvent is 0.3-0.7 mL, preferably 0.5mL, relative to 0.10mmol of the anti-isoamylene substituted indolone 3.

Description

Method for synthesizing anti-isoamylene substituted indolone by nickel catalysis Technical Field The invention relates to a method for synthesizing anti-isoamylene substituted indolone by nickel catalysis, and relates to the field of synthesis of anti-isoamylene substituted indolone. Background Indolones are common framework structures in a variety of drug molecules and natural alkaloids, and in particular indolones bearing an anti-isopentenyl substitution at the C3 position have been of great interest for their broad biological activity. In the traditional strategy of constructing pentenyl substituted indolones by transition metal catalyzed allylic alkylation, the substituent at position 3 of indolone participates in the formation of reactive intermediates, playing a key role in controlling the activity and selectivity of the chemical reaction of the reaction. Thus, when these substituents are removed, not only the reactivity is inhibited, but also various byproducts are difficult to control. And the direct assembly of isoprene onto indolones is more challenging than common pre-activated pentenyl precursors. The result describes a functionalization reaction of isoprene catalyzed by transition metal nickel, which realizes the anti-isopentenyl of C3 unsubstituted indolone. This process has not only high activity and economy of the reacting atoms, but also high chemical and regioselectivity. In addition, the C-H bond exposed at the alpha position of the carbonyl enables the obtained anti-isopentenyl substituted indolone product to generate nucleophilic substitution reaction with various electrophiles under alkaline conditions, thereby realizing the synthesis of 3, 3-disubstituted indolone and providing a new strategy for introducing different steric hindrance and electrical functional groups more flexibly and conveniently in chemical reaction. In summary, the present results describe innovative methods for synthesizing trans-isopentenyl substituted indolones with high activity and selectivity using the reaction of unactivated indolones with isoprene under nickel catalysis. Disclosure of Invention The invention aims to provide a method for synthesizing anti-isoamylene substituted indolone by nickel catalysis. The specific operation steps are as follows: Reaction equation 1: To the reaction flask, 0.02mmol of nickel catalyst (Ni (cod) 2), 0.04mmol of tricyclohexylphosphine ligand (PCy 3), 0.20mmol of indolone 1, 0.40mmol of isoprene 2, 0.20mmol of alkaline additive (Cs 2CO3) and 2.0mL of tetrahydrofuran solvent (THF) were sequentially added under nitrogen atmosphere, reacted at 60℃for 24 hours, and after completion of the reaction, the antiprenyl-substituted indolone 3 was isolated. Reaction equation 2: Under nitrogen atmosphere, 0.10mmol of the anti-isopentenyl substituted indolone 3, 0.12mmol of additive base (NaH), 0.5mL of nitrogen as a solvent, dimethylformamide (DMF) and 0.20mmol of halogenated alkane (R 2 X) are sequentially added into a reaction bottle to react for 12 hours at the temperature of 0 ℃ to room temperature, and the reaction is finished, so that the 3, 3-disubstituted indolone 4 is obtained by separation. In the invention, metal nickel catalyst (Ni (cod) 2) and tricyclohexylphosphine (PCy 3) are used as ligands, C3 unsubstituted indolone is used as nucleophilic reagent to react with isoprene, thus obtaining the product of the inverted isoamylene substituted indolone. And then, taking the product as a reaction raw material, and carrying out nucleophilic substitution reaction with halogenated alkane under alkaline conditions to obtain the 3, 3-disubstituted indolone with divergent functional groups. The invention uses isoprene as a reaction precursor, obtains the indolone product substituted by the anti-isoamylene group with high activity and selectivity, carries out relay nucleophilic substitution reaction, and provides a new strategy for flexibly and conveniently introducing different steric hindrance and electric functional groups. The invention has the following advantages: First, in the nickel-catalyzed functionalization of isoprene, the anti-isopentenyl of the C3 unsubstituted indolone is achieved. This process has not only high activity and economy of the reacting atoms, but also high chemical and regioselectivity. In addition, the C-H bond exposed at the alpha position of the carbonyl enables the obtained product of the inverted isopentenyl substituted indolone to generate nucleophilic substitution reaction with various electrophiles, thereby realizing the synthesis of 3, 3-disubstituted indolone and providing a new strategy for introducing different steric hindrance and electrical functional groups more flexibly and conveniently in chemical reaction. Detailed Description For a better understanding of equation one in the present invention, it is illustrated by the following examples. The starting materials and results for the reactions of examples 1-18 are shown in Table 1, where start