Domino Cyclization/cyanation Reaction Of B,?-Unsaturated Hydrazones And Its Synthetic Applications

Pyrazolines represent an important class of N-heterocycles that are widely found in natural products,bioactive molecules and pharmaceuticals.Cyano group is a very important organic functional group,which can be effectively converted into carboxylic acids,aldehydes,ketones,amides,amines,and nitrogen-containing heterocycles.Furthermore,cyano group is a ubiquitous structural motif frequently found in many marketed drugs.The introduction of cyano group into drug molecules can adjust the physicochemical and pharmacokinetic properties,and thus enhance their biological activities.Therefore,the introduction of cyano group into small molecule drugs is one of the important strategies for the chemical structure modification of drugs.Olefins are a class of ubiquitous,cheap,and readily available organic compounds that generally exhibit rich chemical reactivities.Difunctionalization of olefins can efficiently synthesize multi-site reaction products in a single step,which is characterized by high atom and step economy,good synthetic efficiency,and structure-diverse products.Therefore,alkene difunctionalization represents a powerful synthetic strategy in modern organic synthesis.We report the first copper-catalyzed domino cyclization/cyanation of ?,?-unsaturated hydrazones to deliver a variety of cyano-featured pyrazolines under mild conditions.The optimized reaction conditions were established by sreening cyano sources,catalysts,oxitants,base,and solvents.The optimized product yields can be obtained by treating ?,?-unsaturated hydrazones and Zn(CN)2 in the presence of Cu(acac)2,K2S2O8,and NaHCO3 in DMSO at ambient temperature for 12 h.With the optimal conditions in hand,we next investigated the substrate scopes.All 22 new compounds were obtained with good yields and characterized by using 1H NMR,13C NMR,and HRMS.The present method features mild conditions,easy operation,broad substrate scope,the use of commercially available and inexpensive copper catalysts and cheap cyano source.This method can construct the pyrazoline skeleton with the simultaneous incorporation of a cyano group and the formation of C(sp3)-CN and C-N bonds in a single step.To further demonstrate the potential synthetic applications,we performed the gram-scale synthesis and the related chemical transformation for products.Based on control experiments and the radical-trapping experiment,a possible catalytic pathway was proposed.