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Alkynylated imidazo [1, 5-a] indole compound and preparation method thereof

A technology of indole compounds and alkynyl imidazoles, applied in the direction of organic chemistry, etc., can solve the problems of narrow substrate application range, harsh reaction conditions, low yield, etc., and achieve high chemical selectivity and regioselectivity, mild and moderate Sexual reaction conditions, economic effects of reaction steps

Active Publication Date: 2021-10-08
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, the currently reported methods for the construction of imidazo[1,5-a]indoles through C–H cyclization reactions between indole substrates and various reagents all have some obvious disadvantages, such as the need to use dangerous heavy Nitrogen compounds or malodorous isonitriles are used as reaction reagents, need to use exogenous metal or non-metal oxidants, narrow substrate scope, low yield, harsh reaction conditions, etc.
In addition, searching the existing literature, did not find the method for preparing alkynylated imidazo[1,5-a]indole compounds

Method used

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  • Alkynylated imidazo [1, 5-a] indole compound and preparation method thereof
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  • Alkynylated imidazo [1, 5-a] indole compound and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0029] Optimization of reaction conditions: According to the following reaction formula, with compounds 1aa and 2aa as template substrates, the reaction conditions were optimized according to the steps shown in Table 1, including sequential optimization of catalysts, solvents and additives.

[0030]

[0031] First, with NaOAc as an additive, 1aa and 2aa were reacted in methanol at 60°C for 9h under the catalysis of a series of metal catalysts (No. 1-5). The results show that using [Cp*RhCl 2 ] 2 When used as a catalyst, the target [4+1] cyclization / alkynyl migration cascade reaction product 3aa was obtained with a yield of 69% and good chemoselectivity and regioselectivity (No. 5).

[0032] Next, respectively [Cp*RhCl 2 ] 2 and NaOAc as catalysts and additives to investigate the effects of different solvents on the yield of the target product (No. 6-13). The results revealed that the C–H olefination / directing group migration by-product 4aa was favored over 3aa in aproti...

Embodiment 2

[0040] Under the optimal reaction conditions mentioned above (No. 22), the applicable range of substrates for the Rh(III)-catalyzed [4+1] cyclization / alkynyl transfer cascade reaction was explored, and the results are shown in Table 2.

[0041] Table 2. Applicable substrate scope of Rh(III)-catalyzed [4+1] cyclization / alkynyl transfer cascade reaction a,b

[0042]

[0043] a Reaction conditions: Unless otherwise specified, 1 (0.25mmol), 2 (0.325mmol), [Cp*RhCl 2 ] 2 (5mol%) and KF (0.25mmol) were placed in MeOH (4.0mL) and reacted at 60°C for 9h; b Refers to the isolated yield.

[0044]First, 2aa was used as a template alkyne substrate to investigate the scope of application of indole substrates. For example, indole substituted with halogen (F, Cl, Br, I) can react smoothly and obtain the product 3ab-3ah with a yield of 53-71%; The indole can also react smoothly, and the product 3ai-3ao is obtained with a yield of 68-76%. electron-withdrawing CO 2 Me-substituted ind...

Embodiment 3

[0050] Gram scale-up reaction experiment: Carry out gram-scale scale-up reaction according to the following reaction conditions, when reacting with 1aa (6mmol) and 2aa (7.8mmol), the target product 3aa can be obtained with a yield of 73%. This demonstrates that the reaction between 1aa and 2aa can be scaled up to the gram scale without loss of efficiency, indicating the practicality and industrial application prospects of this reaction.

[0051]

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Abstract

The invention provides an alkynylated imidazo [1, 5-a] indole compound and a preparation method thereof, and belongs to the technical field of organic synthesis. A series of alkynylated imidazo [1, 5-a] indole compounds are synthesized through [4+1] cyclization / alkynyl migration cascade reaction between rhodium catalyzed indole and alpha, alpha-difluoromethylene alkyne, a catalyst is [Cp*RhCl2]2, an additive is potassium fluoride, and a solvent is methanol; the molar ratio of the indole to the alpha, alpha-difluoromethylene alkyne is 1: 1.3, the addition amount of the catalyst is 5% of the molar amount of the indole, and the molar ratio of the additive to the indole is 1: 1. The synthesis method provided by the invention has the advantages of wide substrate application range, high chemical selectivity and regioselectivity, good yield, good functional group tolerance, economic reaction steps, mild neutral reaction conditions and the like. The structural formula of the alkynylated imidazo [1, 5-a] indole compound is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to an alkynylated imidazo[1,5-a]indole compound and a preparation method. Background technique [0002] Indole fused ring compounds widely exist in active natural products and drug molecules, and have shown important application value. Therefore, the methods of constructing compounds with such structures have attracted extensive attention of chemists. Most of the traditional methods for constructing such structures involve multi-step functional group conversion reactions, and require multiple separations and purifications, which have the disadvantages of cumbersome steps and low overall yields. In recent years, directing group-assisted and transition metal-catalyzed C–H activation reactions have been rapidly developed. Compared with traditional synthetic methods, transition metal-catalyzed C–H activation reactions do not require prefunctionalization of substrat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 赵飞刘思宇乔进张小宁卢杨斌龚鑫戴龙芦世尧
Owner CHENGDU UNIV