Method for synthesizing cyanoalkyl indoline by cyano-alkylation of N-allylaniline

A technology for synthesizing cyanoalkyl indolines and allylaniline cyanoanes, which is applied in organic chemistry, bulk chemical production, etc., can solve the problems of product limitation, limitation, and high cost, and achieve wide substrate range and high reaction efficiency. The effect of mild conditions and simple operation

Active Publication Date: 2019-05-31
KUNMING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Both of these reactions use acetonitrile as the source of cyanoalkyl groups, but in order to activate the C-H bond of acetonitrile, a combination of palladium catalyst, a large excess of AgF and a high iodine reagent is required, which is very costly
In addition, in the 3-cyanoalkylindoline synthesis reaction of this method, since only acetonitrile is an available cyanoalkyl source, the product is limited to the primary nitrile; meanwhile, the sulfonyl protecting group is not compatible in this reaction.
Chinese patent CN108440373A has reported the reaction of iron-catalyzed azobisisobutyronitrile (AIBN) as cyanoalkylation reagent to synthesize 3-cyanoalkyl indoline, but limited by the structure of azo reagent, this reaction can only be used for the synthesis of tertiary nitriles
Although some progress has been made in the synthesis of high-value nitrile molecules such as cyanoalkylindolines, the direct synthesis of high-value nitrile molecules such as cyanoalkylindolines from inexpensive alkylnitriles via C–H bond functionalization reactions is still Relies mainly on strong bases or specific expensive metal catalysts

Method used

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  • Method for synthesizing cyanoalkyl indoline by cyano-alkylation of N-allylaniline
  • Method for synthesizing cyanoalkyl indoline by cyano-alkylation of N-allylaniline
  • Method for synthesizing cyanoalkyl indoline by cyano-alkylation of N-allylaniline

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Experimental program
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Effect test

Embodiment 1

[0038] Synthesis of non-activated olefins formula I compound (taking 1a2 synthesis as an example), the reaction scheme is as follows:

[0039]

[0040] Operation steps: Add p-toluidine (1.607g, 15.0mmol), CH 2 Cl 2 (50.0 mL), and Et 3N (4.170 mL, 30.0 mmol) and finally acetyl chloride (1.273 mL, 18.0 mmol) was added. The reaction mixture was stirred at room temperature with a magnetic stirrer. After TLC showed that the p-toluidine of the raw material was consumed, the 3 solution (100 mL), the reaction was quenched with CH 2 Cl 2 (100.0 mL) was extracted 3 times. The combined organic phases were washed twice with brine (50 mL). The solid obtained by distilling off the organic solvent was washed with a mixture of petroleum ether / ethyl acetate (5:1, volume ratio) to obtain p-methylacetanilide (2.104 g, 94% yield) as a white solid. To a stirred solution of p-methylacetanilide (1.492 g, 10.0 mmol) and NaOH (600 mg, 15.0 mmol) in DMF (30 mL) was added 2-methyl-3-bromoprop...

Embodiment 2

[0046] N-allyl aniline cyanoalkylation synthesis cyanoalkyl indoline (taking the synthesis of 2a1 as an example), the reaction scheme is as follows:

[0047]

[0048] Operation steps: Add N-allylaniline derivative 1a1 (57mg, 0.3mmol), catalyst DTBP (88mg, 0.6mmol) and acetonitrile solvent (3.0mL) to a Schlenk tube equipped with a magnetic stirrer under argon protection . The mixture was heated and stirred at 140°C for 6h, cooled with saturated Na 2 S 2 o 3 Quenched with aqueous solution (1.0 mL) and water (10.0 mL). The resulting mixture was extracted three times with dichloromethane (10.0 mL), and the organic phases were combined. The organic solvent was evaporated, and the residue was subjected to column chromatography using 300-400 mesh silica gel (petroleum ether and ethyl acetate as eluents) to obtain 3-cyanoalkylindoline product 2a1.

[0049] With reference to above-mentioned embodiment 2, investigate catalyst, the impact of temperature on reaction, specific situ...

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Abstract

The invention provides a method for synthesizing cyanoalkyl indoline by cyano-alkylation of N-allylaniline. The method includes using cheap alkyl nitrile and specific non-activated olefin to perform an exo selective cyano-alkylation/cyclization cascade reaction on the N-allylaniline compound under the conditions of no metal and neutrality to generate 3-cyanoalkyl indoline. The reaction of the method does not need metal and strong alkali, has a wide substrate range, and can smoothly occur even when sulfonyl protecting groups exist in the compound; and in addition, by using the method, primary,secondary and tertiary nitrile products can be successfully synthesized, and meanwhile, the reaction conditions are mild, the operation is simple, so that the method is suitable for industrial popularization.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing cyanoalkyl indolines by cyanoalkylation of N-allyl aniline. Background technique [0002] Indoline is a very important class of nitrogen-containing heterocyclic compounds, which are commonly found in alkaloids and other natural products, and have great applications in the dye industry, spices, organic intermediate synthesis, medicine, and pesticide synthesis. Due to the diverse biological activities and clinical applications of compounds with indoline as the core structure, scientists are required to synthesize more structurally diverse indoline derivatives as drug lead molecules. The direct synthesis of high-value cyanoalkylindolines from inexpensive alkylnitriles using C–H bond functionalization reactions is attractive because such processes avoid the pre-halogenation of reaction starting materials and the use of highly toxic cyan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/18C07D409/12
CPCY02P20/55
Inventor 梁德强宋雪梅王宝玲李维莉马银海
Owner KUNMING UNIV
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