Research On Regioselective Cyanoalkoxylation And Cyanoalkylation Of 8-Aminoquinoline Derivatives

Cyano-containing compounds have been widely applied in natural products,pharmaceutical and material chemistry.Cyano group could be converted into many different functional groups,such as aldehyde group,carboxylic acid,ester group,ketone group,amide,primary amine and so on.The earliest used cyanide sources were metal cyanation reagents such as Cu CN,Na CN and Zn?CN?₂ etc,and its disadvantages were relatively large toxicity and could cause metal waste.In this context,organic chemists have explored a series of less toxic,mild and friendly organic cyanation reagents,for example,N-cyano-N-phenyl-p-toluenesulfonamide?NCTS?,trimethylsilylcyanide?TMSCN?,acetonitrile and azobisisobutyronitrile?AIBN?etc.It is worth noting that AIBN could generate three kinds of cyano-containing radicals under different conditions,namely cyano radical,cyanopropyl radical and cyanopropoxyl radical.The cyano source and cyanopropyl source provided by AIBN have effectively synthesized cyano-containing aromatic compounds through the C-H bond activation strategy.Due to the importance of quinoline structure in natural products,materials and bioactive molecules.Therefore,the modification of quinoline ring has been a research hotspot in organic synthetic chemistry.Our laboratory has achieved transition-metal-catalyzed C5 halogenation of 8-amidoquinoline,and also reported efficient nickel-catalyzed or metal-free system fluorination of 8-amidoquinoline at the C5 position for the first time.This paper contains three parts:In the first part,we choose 8-amidoquinoline as substrate,cheap and readily available AIBN to provide cyanopropoxyl source,and cheap copper acetate as the catalyst,and we have realized a novel C5cyanoalkoxylation of 8-amidoquinoline under oxygen atmosphere for the first time.After obtaining the optimized reaction conditions through experimental screening,we carried out the substrate exploration of the derivatives of 8-amidoquinoline,and AIBN analogues were also suitable for this reaction,providing the corresponding cyanoalkoxylation products.C-O ether bond was formed at the C5 position of the quinoline ring.The isotope labeling experiment we conducted also effectively verified that the oxygen atom of the ether bond in the cyanoalkoxylation product comes from oxygen.In the second part,we continued to use 8-amidoquinoline as substrate,AIBN as cyanopropyl source,and have achieved the cyanoalkylation at the C5 position catalyzed by nickel sulfate.This reaction required to be performed under nitrogen atmosphere at high temperature.It also forms the construction of the C-C bond.The reaction was also compatible with various substituted functional groups on the aromatic ring,and had good compatibility with different AIBN analogues,obtaining the corresponding C5 cyanoalkylated products.In the third part,we studied the mechanism of cyanoalkoxylation and cyanoalkylation in detail.According to free radical inhibition experiments and free radical capture experiments,it could be concluded that cyanoalkoxylation reaction was a free radical mechanism via single electron transfer.Similar to the cyanoalkoxylation reaction mechanism,the cyanoalkylation mechanism also underwent a single electron transfer process,and the generated cyanopropyl radical was highly directed to realize the remote C5 addition of 8-amidoquinoline.In addition,chelation of Cu?OAc?₂ with cyano and carbonyl would stabilize the transition state of proton transfer and promote the addition of cyanopropyl radical with large steric hindrance.