Photoredox-catalyzed Ring-opening Pyridinization Of Cyclic Oximes

Objective:Pyridine is the heterocyclic structure with the highest frequency in the drug molecules approved by FDA;On the other hand,cyanoalkyl groups are not only very useful active intermediates in the field of synthetic chemistry,but also widely exist in natural products and drug molecules.It is very challenging to introduce cyanoalkyl group directly into pyridine ring in a simple and efficient way.At present,only four free radical-mediated ring-opening pyridylation studies of cyclic oxime derivatives have been reported.However,these methods require the introduction of appropriate functional groups on the oxygen atoms in the oxime,and also have the disadvantages of poor reaction site selectivity,intense reaction conditions or the need for external additives（acid,base,oxidant）to assist.Therefore,the purpose of this project is to develop a mild,universal and highly selective ring-opening pyridylation method of cyclic oxime using the photocatalytic phosphonyl radical mediated deoxidation strategy.Methods:In this experiment,2-（[1,1’-biphenyl]-4-yl）cyclobutan-1-one oxime and 4-cyanopyridine were used as template substrates,and the optimum reaction conditions for the preparation of cyanoalkylated pyridine derivatives were selected through the screening of phosphine,photosensitizer and solvent.Then,under this reaction condition,explore the universality of different reaction substrates,explore the reaction mechanism through free radical capture experiment,free radical clock experiment and cyclic voltammetry,and propose a possible reaction mechanism.Finally,the model reaction was amplified and the product was applied to explore its application value.Results:Through the screening of the reaction system,the optimum reaction conditions were obtained:cyclohexanone oxime（0.15 mmol）and cyanopyridine（0.1 mmol）as substrates,fac-Ir（ppy）₃（2 mol%）as photocatalyst,CH₂Cl₂（2 m L）as solvent,PPh₃（0.3 mmol）as phosphine source,reaction at room temperature and argon atmosphere,under 30W blue light irradiation for18 hours.Under these reaction conditions,36 pyridine derivatives were obtained in 20%–95%yield.The reaction was amplified to obtain the target product with 81%yield.Three application products were obtained by transforming the cyano functional group of the template substrate.Conclusion:In this paper,we developed a new method of N-O/C-C bond cleavage mediated by phosphonyl radical,and realized the ring-opening pyridylation of cyclic oxime through the free radical-free radical coupling.This mild,acid-free,alkali-free and oxidation-free method is applicable to a series of cyclic oximes and cyanopyridine.The mechanism of the reaction was studied.It was found that the reaction was further converted into structurally attractive cyanalkyl pyridine derivatives by photo-catalyzed phosphonyl-mediated N-O/C-C bond cleavage followed by free-radical coupling.The application study of the obtained products found that the cyanalkyl pyridine products can be amplified and easily converted into compounds with a variety of skeletons,including pyridine amide,pyridine carbamate and pyridine carboxylic acid,which has certain application value.