Domino Aryne Annulation Via A Nucleophilic-Ene Process

Benzocycles,especially those benzoheterocycles,are the ubiquitous core structures of biologically active natural products and medicine molecules.To find ways to easily build these benzo-fused frameworks is one of the important aspects in current chemistry research.Due to their unique structural character,arynes are a kind of highly active intermediate that can concomitantly form two chemical bonds on both alkyne carbons.Consequently,aryne chemistry becomes a convenient tool to build benzocycles.Until present,aryne annulation reactions,such as cycloaddition reactions,insertion reactions,and multi-component reactions to obtain these benzocycles have received intensive reports.Throughout these methods,although almost all kinds of benzo-fused cycles can be built,they are more or less limited in scope.In consideration of the high importance of benzocycle frameworks in synthetic and pharmaceutical chemistry,to find general and efficient ways to build them could be of great interest.This project was inspired by the previous work accomplished in our lab,especially the tandem nucleophilic process on domino aryne precursor(TPBT).Based on these previous study,we obtained a series of new 1,2-benzdiyne equivalents via changing the second leaving group on 1,2-benzdiyne precursor.With these new aryne precursors in hand,we successfully developed a domino aryne annulation protocol that involves a nucleophilic-ene cascade.Through this process,we can build a number of nitrogen-containing benzoheterocycles,such as indoline and tetrahydroquinoline scaffolds,which broadly exist in natural and in medicines.Furthermore,the advantages of introducing ene reaction into this process reside in its excellent diastereoselectivity as well as ease to form quaternary carbon centers.In order to demonstrate the potential values of our annulation approach,we used this method to modify the structure of Androlone,a steroid hormone drug.In addition,we also employed this protocol as the key step in the synthesis of the dwarfism drug Ibutamoren mesylate,showing the practical application value of this method in drug synthesis.