Construction Of Bridged Polycycles Via Dearomatization Of In-situ-activated Azaarenes

Nonaromatic six-membered nitrogen-containing heterocycles are prevalent in biologically active natural products and pharmaceuticals,and they were identified as the most common architectures in FDA approved small molecule drugs.Accordingly,the development of robust and rapid approaches to facilitate the assembly of these valuable molecules with novel and diverse structures is of great importance and has become the research focus of many chemists.The dearomatization of azarenes is one of the most direct and effective strategies for constructing these valuable skeleton compounds.Bridged polycyclic hydrogenated pyridines and(iso)quinolines exhibit significant biological activities,which are important structural units of many natural products and drugs.In the second chapter of this paper,we have developed an unprecedented multi-component one-pot dearomative multi-functionalization of azaarenes with aryne and enaminone through an in situ activation strategy,which not only achieved the first full exploitation of the reactive sites of the azaarenes,but also accomplished the efficient synthesis of bridged polycycles hydrogenated pyridines and(iso)quinolines in a highly regio-and diastereoselective manner.In addition,we could successfully realize the step-controlled dearomative tri-and bi-functionalization of quinolines.These transformations were auto-catalytic processes without additional catalysts.In the third chapter of this paper,the dearomative multi-functionalization of azarenes with aryne precusors and binucleophilic enamine-imine hydrochloride was successfully achieved.In the presence of cesium fluoride,the reactions proceeded smoothly with complete region-and distereocontrols,thus providing an efficient approach to bridged polycycles hydrogenated pyridines and(iso)quinolines.In view of the excellent reactivity of enaminone in the second chapter dealing with the synthesis of bridged azaheterocycles.In the fourth chapter,we have developed a BF3·OEt2-catalyzed Michael addition/cyclization/dehydration sequence of ortho-hydroxyenaminones with aromatic or aliphatic aldehyde-derived β,γ-unsaturated α-ketoesters,which provides an efficient and rapid approach to fused hydrogenated benzoxazolepolycycles in a highly diastereoselective manner in up to 95% yield.By employing isatin-derived β,γ-unsaturated α-ketoesters as substrates,completely different reactivities were observed,delivering an array of newatropisomers with an oxindole-substituted N-C axially chiral backbone in up to 97% yield.To account for the possible reaction pathway,DFT calculations were conducted.