Pd-catalyzed Coupling Cyclization Of δ,ε-Alkenyl Oxime Toward Access To 1,2-Oxezapines

Seven-membered heterocycles are receiving increasing attention due to their biological and therapeutic relevance.Azepane and oxzepane,are a class of compounds holding a unique position in heterocyclic compounds.These substances exhibit a variety of biological activities,and have been used as building blocks for the construction of many biological agents.For instance,benzazepine and benzodiazepines are well-known pharmacophores in numerous drugs and natural products;oxazepine derivatives have found use as glycosidase inhibitors;oxepanes are key scaffolds of secondary metabolites found in fungus.In addition,the internal strain of 7-membered ring often confers these compounds with unusual conformational preference that may be harnessed for particular purposes.Although there have been intensive endeavors devoted to their synthesis,such as intramolecular nucleophilic cyclization and C?X（X=N,O）bond formation,ring-closing metathesis etc.,straightforward access to seven-membered heterocycles by direct heterocyclization remains lacking and represents an unmet target.Pd-Catalyzed heterocyclization reaction of alkenyl amides and alcohols with aryl halides is a powerful synthetic tool for the access to various O-and N-heterocycles.In this thesis,the Pd-catalyzed coupling cyclization ofδ,ε-alkenyl oxime with（hetero）aryl and alkenyl halides is investigated.Based on the originally designed model substrate,the reaction conditions were optimized,and the optimal conditions were determined as follows:oxime（0.2 mmol）,halide（1.2 equiv）,Pd（dba）₂（5 mol%）,SPhos（10 mol%）,Cs₂CO₃（1.2 equiv）,m-xylene（2 m L）,150 ^oC,Ar,12 h.Next,under the optimal reaction conditions,the substrate scope of oxime and aryl halide was studied respectively,and a series of seven-membered nitroxide heterocyclic compounds were synthesized in good yields.Two possible cyclization mechanisms were conceived,including the inner-sphere migratory insertion and the outer-sphere aza-Wacker process.We performed DFT calculations to determine the potential energy surface of the two pathways.Our calculation clearly shows that the outer-sphere aza-Wacker type cyclization is favored.