Aryne Trifunctionalization Enabled By A New 1,2-Benzdiyne Equivalent

Aromatic compounds bearing multiple substituents broadly exist in numerous biologically active natural products,medicines,and functional materials.Consequently,the preparation of arenes with multiple substituents by simple and highly efficient approaches has become one of the important research areas in synthetic organic chemistry.As one of the most active organic intermediates,arynes have been utilized in many chemical transformations.However,aryne intermediates are extremely unstable and cannot be separated from the reaction,which then only allow in situ generation from the reactions.Currently,Kobayashi aryne generation method has become one of the most popular aryne formation way under mild condition,the aryne generation rate of which could be efficitively tuned by temperature,solvent,and the concentration of fluoride.This Kobayashi approach greatly propels the recent development of aryne chemistry.Although aryne chemistry has achieved rapid progress,how to achieve substitution more than two on a benzene ring remains one of the challenges.The research content of our group is to prepare multisubstituted arenes through aryne intermediates and look for their applications in the synthesis of natural products as well as drug molecules.Along with our study,our group has achieved: aryne multisubstitution through the usage of 1,2-benzdiyne equivalent,namely TPBT reagent;arene 1,2,3-trisubstitution through a cascade benzyne difunctionalization and C-H bond functionalization;Grob fragmentation of a benzobutanol species with concomitant formation of 2,3-aryne species.My project was inspired by our prevous work,especially the development and application of our TPBT reagent,developed a class of a new 1,2-benzdiyne precursors,all the tranditional 1,2-benzdiyne equivalents have two leaving groups and one accepting group;whereas,our 1,2-benzdiyne equivalent is composed by two accepting groups and one leaving group.By using 2,6-bis(trimethylsilyl)phenyl trifluoromethanesulfonate as such an new 1,2-benzdiyne precursor to react with pyridine-N-oxide,a 2,3-aryne precursor with 3-pyridyl group was successfully synthesized after consequent OH group protection with OTf by a one-pot process.In this transformation,the 3-TMS group serves as an electron-donating group to direct the formation of C-O bond preferentially on its ortho-position.Futher transformations of the generated 2,3-aryne precursors exhibit excellent reaction efficiency with good to high regioselectivity,affording various polysubtituted arenes.By changing the structures of both pyridine-N-oxides and aryne precursors,we could prepare a family of analogs,showing a great potential of our method.Mechanistically,the overall process of our method can be seen as a process of 1,2-benzdiyne chemistry.In this project,we used this new 1,2-benzdiyne equivalent to prepare a series of polysubstituted arenes bearing pyridyl functionality,showing great potential of our approach.Moreover,we also examined the substrates with N-hydroxyl amides,sulfoxide,and DMF in an expection to obtain the corresponding products.The reaction with N-hydroxyl amides could give us the desired 2,3-aryne precrusors with an amido substituent;unfortunately,both sulfoxide and DMF gave no desired products.Further study on these substrates are still undergoing in our group.