The Study On Arene Trifunctionalization Via A Domino Aryne Nucleophilic-[4+2] Cascade

Polysubstituted arenes are the core skeletons of various natural products,pharmaceutical molecules,and organic functional materials.The means for the rapid construction of their frameworks has always been a research focus among synthetic chemists.Arynes are highly reactive intermediates derived from aromatic systems by the formal abstraction of two hydrogen atoms from adjacent positions,which can be used to readily prepare various vicinal difunctionalized arenes and offer numerous applications in organic synthesis.The extensive applications of mild methods for the generation of arynes and the development of novel reaction types have led to aryne chemistry becoming a blossoming area in recent decades.In addition,polysubstituted arenes have been synthesized by using benzdiyne and benztriyne equivalents.In view of the prevailing presence of polysubstituted arenes,especially those with highly fused heterocyclic aromatic ring systems,more efficient and practical aryne multifunctionalization maneuvers are still highly desired and valuable.Recently,our group successively developed two generations of domino aryne precursors(TPBT,TTPM),and obtained several multisubstituted arenes through a tandem nucleophilic process on 1,2-benzdiyne precursor(TPBT).Furthermore,a domino aryne nucleophilic-ene reaction was realized by combining two different types of arynophiles in the same cascade process,hence,a variety of nitrogen-containing benzoheterocycles were achieved.Based on the previous work,we developed a convenient and efficient domino aryne process to generate a range of[6,n,6,6]-polycyclic ring systems,which was realized via a 1,2-benzdiyne through a nucleophilic and Diels-Alder reaction cascade using styrene as the 2,3-aryne reaction partner,three new chemical bonds,namely one C-N and two C-C bonds,and two benzofused rings could be constructed concomitantly in this process.The reaction has a wide range of substrate scope.Particularly,the [6,5,6,6,6]-pentacyclic architectures contain three consecutive chiral centers with exclusive diastereoselectivity.In addition,we employed this protocol as the key step in the synthesis of ergot alkaloid skeleton,showing the potential application value of this method in the construction of natural products.Moreover,we further studied the leaving-ability and reactivity of the second leaving group on the 1,2-benzdiyne precursors.It was found that the domino aryne precursor with two ortho-fluoro substituted phenyl sulfonates was superior to other analogues,and it could fill the leaving-ability gap between the highly active OTf group and the comparatively inert OTs group.