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    Home > Green Chemistry: electrochemically initiated cyclization of ketone with 2-aminopyridine to prepare imidazo [1,2-a] pyridine

    Green Chemistry: electrochemically initiated cyclization of ketone with 2-aminopyridine to prepare imidazo [1,2-a] pyridine

    • Last Update: 2019-03-25
    • Source: Internet
    • Author: User
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    Nitrogen heterocycles are the core structures of many drugs and functional materials, and their synthesis has been one of the hotspots in organic synthesis chemistry In recent years, the development of modern organic electrosynthesis provides a new platform for the green synthesis of nitrogen-containing heterocycles Researchers have successively developed a variety of intramolecular electrochemical oxidation amination methods for olefins, alkynes, aromatics and alkanes to construct nitrogen heterocycles However, there are few reports on the construction of nitrogen heterocycles by intermolecular amination Imidazo [1,2-a] pyridine is a kind of important structural framework, which is the core segment of many drug molecules Imidazolylpyridines have many biological activities, such as antipyretic, antiviral, antibacterial, anticancer and anti-inflammatory 2-aminopyridine and ketone are traditionally used as raw materials for the synthesis of these compounds, but stoichiometric oxidants or other toxic reagents and high temperature conditions are usually needed Therefore, it is necessary to develop a green and efficient electrochemical method to construct imidazolidine skeleton (source: Green Chemistry) recently, Professor Yu Xiaoqi and Associate Professor Chen shanyong of Sichuan University developed the first intermolecular electrochemical amination / cyclization reaction without additional metal catalyst or equivalent times of chemical oxidant, which realized the green synthesis of pyridine imidazole skeleton from 2-aminopyridine and ketone Relevant research results were published on Green Chemistry (DOI: 10.1039/c8gc03622e) The first author of this paper is Feng Meilin, a doctoral student of the research group Firstly, the conditions of amination / cyclization of 2-aminopyridine and acetophenone were selected (Table 1) The author found that 25% Nai was used as redox reagent, and the reaction could produce the target product successfully, but the yield was only 7% (entry 2) After further screening of the catalyst, the author found that the catalytic effect of hi is better, and the yield of the product can reach 62% The yield of 3AA can be further increased to 99% by carefully selecting the amount of Hi, the ratio of substrate and other conditions (source: Green Chemistry) after obtaining the optimal reaction conditions, the author investigated the substrate range of the electrochemical reaction (Table 2) Both electron deficient and electron rich acetophenone are suitable substrates, and the products (3ba-3ia, 3ja and 3KA) can be obtained in medium to extremely good yields The reaction can tolerate a variety of functional groups, including nitro group, trifluoromethyl group, cyano group, sulfonyl group, ester group, etc Interestingly, the unstable 2-hydroxyacetophenone in the oxidation system can also react smoothly, and 2-hydroxy-aryl-imidazolyl pyridine (3la, 3Na, 3oa) can be obtained in good yield Heterocyclic ketone and unsaturated ketone are also suitable for this reaction, and the corresponding heterocyclic product (3PA - 3ua) can be obtained in medium yield Under the improved conditions, the alkylketones with lower activity can also effectively carry out the above transformation (3VA - 3YA) Then, the application of 2-aminopyridine was studied The corresponding product (3AB - 3aE) can be obtained from alkyl or phenyl substituted 2-aminopyridine in good yield In addition, although the yield is low, 2-aminoquinoline can react smoothly to get the corresponding products (source: Green Chemistry) then, in order to evaluate the scalability of the electrochemical tandem cyclization under the standard conditions, the author used 10 mmol of 1a (1.20 g) to carry out a gram scale reaction The target product imidazo [1,2-a] pyridine 3AA was obtained with 70% separation yield and acetophenone 1A was recovered with 26% recovery (source: Green Chemistry) N-heterocyclic derivatives of sulfur and selenium widely exist in some bioactive molecules, so the author has further expanded the reaction and developed a "scheme 2" method to construct C-N and C-S / C-Se bonds at the same time Under standard conditions, the target product (5a - 5g) can be obtained in medium to good yield by adding diphenyl disulfide into the reaction system In addition, diphenyl diselenium was also suitable for the three-component reaction, and 3-selenidimidazolopyridine was obtained in 32% yield for 5 h It is speculated that the sulfurization / selenidation reaction is realized by the electrophilic attack of the generated imidazo [1,2-a] pyridine 3 by the phsi or phsei electrophilic substance formed under the electrochemical conditions The first step in the synthesis of imidazo [1,2-a] pyridine by C-H functionalization catalyzed by green chemistry is usually the formation of imine However, the author did not observe the formation of imine in the standard reaction condition without electricity Therefore, the author speculates that the formation of C-N bond between pyridine and ketone should precede the formation of imine Then, the reaction was monitored by LC-MS it was found that a new substance (0.343 min) was formed in the electrolysis process besides reactants and products, and two signal peaks (M / Z 213 and M / Z 195) corresponding to intermediates 6B and 6C were obtained Based on the above results and related literature, the author proposed a possible reaction mechanism (scheme 3) Firstly, the iodide anion is oxidized to molecular iodine on the anode (which may be accompanied by the formation of positive iodide ions) and reacts with ketone to form α - iodo ketone 6A; 2-aminopyridine and intermediate 6A undergo nucleophilic substitution to obtain intermediate 6B, which is then cyclized in the molecule to obtain intermediate 6C The target product 3AA was obtained by deprotonization of 6C (source: Green Chemistry) Summary: the author developed an environmentally friendly intermolecular C-N bond formation / cyclization reaction and synthesized a series of imidazo [1,2-a] pyridine derivatives In this reaction, the catalytic amount of hydroiodic acid is used as the redox catalyst, the low toxic ethanol is used as the solvent, and the diaphragm free electrolyzer is used as the reaction vessel to electrolyze at a constant voltage The reaction substrate has a wide range and can tolerate a variety of functional groups In addition, the electrochemical three component series reaction for the synthesis of 3-sulfinyl imidazolidine was also reported.
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