Synthesis Of Quinolones By One-pot Tandem "Carbonylative Sonogashira Coupling- Nucleophilic Addition" Over Bifunctional Ligand Based Pd-catalyst

Quinolones are a kind of N-containing heterocyclic keto-compounds.In many bioactive substances,natural products and pharmaceuticals contain the parent-structures of quinolones.For example,quinolones exhibited potential bio-activity against malaria,cancer,viral ect.,which are widely applicable in the field of medicine.In addition,quinolones possess several reactive sites,which can be modified by variety of functional groups as the building blocks to develop many important organic intermediates in organic synthesis.Quinolones are usually synthesized via intramolecular nucleophilic addition of meta-NH2-susbstituted aryl-?,?-acetyenic ketones,which can be prepared via from carbonylative Sonogashira coupling of 2-NH2-substituted aryl iodides,CO and terminal alkynes.Accordingly,the synthesis of quinolones is sequentially related to the two key reactions including carbonylative Sonogashira coupling and intramolecular nucleophilic addition of-NH2 group to C?C triple bond.In this thesis,a protocol for the one-pot synthesis from 2-iodoaniline,CO and terminal alkynes has been established via one-pot tandem “carbonylative Sonogashira coupling-nucleophilic addition”.In order to fulfill this one-pot synthesis,the unique functional ligand of L3 containing phosphino-fragement and Lewis basic piperidyl group was synthesized and then was applied to coordinate with Pd-center to develop a bifunctional Pd-complex catalyst for the above mentioned tandem “carbonylative Sonogashira coupling-nucleophilic addition”.The factors in terms of ligand effect,the molar ratio of P/Pd,reaction temperature and solvent effect were investigated initially.Under the optimized conditions,the production 2-substituted quinolones with the isolated yields of 48%-85% through the one-pot tandem "carbonylative Sonogashira coupling-nucleophilic addition" was successfully obtained over L3-based bifunctioanl Pd-complex system.It was found that the bi-functionalities in L3 played the indispensable roles in improving the co-catalytic performance of Pd-catalyst for this tandem reaction.The phosphino-fragment in L3 could coordinate with Pd to efficiently catalyze the first-step carbonylative Sonogashira coupling.The piperidinyl group in L3 could serve as a Lewis base catalyst responsible for the intramolecular nucleophilic addition between the alkynyl and amino-groups in the second step.In addition,the synergistic co-catalysis of L3-based bifunctional Pd-complex catalyst proved more efficient than that of mechanically mixtures containing individual Pd-complex and Lewis base of N-methyl piperidine.Scheme 1 Synthesis of quinolone compounds via one-pot tandem “carbonylative Sonogashira coupling-nucleophilic addition” over L3-based bifunctional Pd-complex catalyst...