Metal-free Catalyzed Cyanylation Of Quinoline Nitrogen Oxides

Functionalized quinoline derivatives as the important N-containing heterocycle compounds are increasingly utilized in pharmaceutical,particularly in the fields of antimalarial and anticancer activities.The nitrile group also possesses multifunctional applications as intermediates in organic synthesis because it can be easily converted into various functional groups,such as amines,amides and carboxylic acids etc.Some derivatives of 2-cyano quinoline/pyridine are important structural units in pharmaceutical,natural products and preclinical drug candidates.Therefore,synthesis of derivatives of 2-cyano quinoline/pyridine has attracted more attention.A regioselective method for the synthesis of 2-cyanoquinoline derivatives was developed with quinoline N-oxide as substrate and trimethylsilyl cyanide?TMSCN?as the cyano source.The cyanation reaction occurs by activating the reaction substrate in the presence of diacetoxyiodobenzene?PIDA?to cleave the N-O bond.Firstly,the arylamines were used as the starting material to obtain the quinoline compounds through the skraup synthesis method,and the quinoline N-oxides were obtained by the oxidation reaction.Then a highly regioselective cyanation of quinoline N-oxides with trimethylsilyl cyanide was developed by using PIDA as mediated hypervalent iodine?III?reagent under metal-free and base-free reaction conditions to obtain 2-cyanoquinolines.Twenty-two 2-cyano quinolones/pyridines were prepared by this strategy,and the target products were confirmed and characterized by UV spectrum,IR spectrum,¹H-NMR and¹³C-NMR.The method avoided using the transition-metal,phosphorus reagent and base additives.The mechanism of the reaction was verified by control experiments.The reactive ionic intermediates were captured and characterized by ¹H-NMR and ¹³C-NMR,which proving ionic reaction mechanism.Finally,in order to further demonstrate the synthetic utility of this cyanation reaction,a gram-scale reaction was carried out to the synthesis of the TB inhibitor.