Synthesis Of Trifluoromethyl Or Carbonyl-containing N-Heterocycles Through Cascade Cyclization Reactions

The synthesis of N-heterocycles has been regarded as an attractive research topic in the field of organic synthesis.Some N-heterocycles,such as imidazole,pyrrole,and oxindole,commonly exist in the field of biology,pharmaceutical chemistry,and functional materials.For the specifically functionalized N-heterocycles,including trifluoromethyl or carbonyl-containing N-heterocycles,the development of efficient methods for the synthesis of these compounds has aroused extensive interest among organic chemists.Due to the unique property of trifluoromethyl group,the incorporation of trifluoromethyl group into heterocycle molecules could significantly improve the physicochemical property and metabolic stability of the parent molecules,thereby extending the application area of N-heterocycles in various fields.Carbonylative reactions have emerged as a powerful tool for the synthesis of carbonyl-containing N-heterocycles.The presence of carbonyl unit is beneficial to be attacked by nucleophiles,generating more and more structurally diverse N-heterocyclic derivatives.Among these,Heck carbonylative reactions have become a mainstream approach for the assembly of carbonyl-containing N-heterocycles.In general,the introduction of trifluoromethyl or carbonyl groups could increase the structural diversity and application value of N-heterocycles.Our research group devotes ourselves to the investigation on the trifluoromethyl synthon and carbonylative reactions.In this theme,we developed several strategies for the synthesis of trifluoromethyl or carbonyl-containing N-heterocycles through cascade annulation reactions.The main contents are as follows:（1）We have developed a metal-free approach for the rapid and efficient synthesis of2-trifluoromethyl-imidazoline via a cascade coupling/iodoaminocyclization reaction of trifluoroacetimidoyl chlorides,allylamines and N-iodosuccinimide.High efficiency of this transformation is observed,as verified that more than half of the imidazoline products can be isolated in>90%yield.The obtained imidazoline products with a pendent iodomethyl group can be easily transformed into other synthetically useful compounds.（2）We have explored a palladium-catalyzed four-component carbonylative cyclization of alkenyl-tethered aryl iodides,trifluoroacetimidoyl chlorides and propargyl amines for the preparation of structurally diverse carbonyl-bridged bisheterocycles using inexpensive Ac₂O/HCO₂H as a CO surrogate.The reaction proceeds through a cascade intramolecular Heck reaction,carbonylation,nucleopalladation and reductive elimination sequence with the concurrent formation of two C-N bonds and three C-C bonds.Control experiments indicate that carbon monoxide plays a critical role in the reaction.The transformation exhibits excellent chemo-and regioselectivities,providing a facile and effective pathway for the synthesis of functionalized bisheterocycles.（3）We have demonstrated a palladium-catalyzed cascade cyclization of 2-heteroaryl iodobenzene and Na N₃for the synthesis of pyrrolo[1,2-a]quinoxalinones with moderate to excellent yields using TFBen（benzene-1,3,5-triyl triformate）as a convenient CO surrogate.Notable merits of the reaction include a low catalyst loading,a broad substrate scope,no need of CO gas and easy derivatization of the products.