Research On The Construction Of Novel Nitrogen-containing Noncyclic Or Heterocyclic Compounds Through Multicomponent Reactions Of Isocyanides

Isocyanide is isoelectronic with CO,which contains the extraordinary divalent carbon atom.It is an important synthon in organic synthesis reactions,and can participate in a variety of reactions,especially in a wide variety of isocyanide-based multicomponent reactions.This paper is devoted to the developmentof multicomponent reactions involving isonitriles.Under the catalysis of Pd/Cu or rare earth metals,new strategies for the synthesis of many important nitrogen-containing noncyclic or nitrogen-containing heterocyclic compounds,such as acylisoureas,imides,polysubstituted oxazoles and oxazole-triazole bicyclics,were developed.Forthernore,the antitumor activity of some nitrogen-containing heterocyclic compounds was preliminarily investigated.These research results will be introduced one by one in three parts.Part 1,a highly selective synthesis of acyl isoureas and imides from readily accessible amides,isocyanides and carboxylates based on reaction solvent selection is described.Inthepresenceofacatalyticamountof[1,1'-bis?diphenylphosphino?ferrocene]dichloropalladium?II?and cupric acetate,treatment of amides and isocyanides in alcohols at 60 ^oC provided acyl isoureas in high yields.Interestingly,when other solvents such as acetonitrile was used instead of alcohols,imides were exclusively produced in good to excellent yields via direct N-acylation of amides with carboxylates as the acyl sources.Reaction products were determined by the solvent alcohol and acetonitrile through the influence on reaction mechanism.Good yields,high regioselectivity,easily available starting materials and experimentally convenient catalytic process make it an attractive alternative toward isoureas and imides.Part 2,due to their relatively high efficiency,water compatibility,mild conditions,and eco-friendly catalytic reactions,the use of rare earth catalysts in organic synthesis has received increasing attention from chemists in recent years.In this chapter,the triple insertion reaction of alkynic acid with tert-butylisonitrile in the presence of the rare earth metal Ce?OTf?₃is studied.The reaction mechanism is proved by deuterium labeling experiments.The method has mild conditions and simple operation.It only needs a catalytic amount?10 mol%?of rare earth trifluormesylate and can obtain a variety of polysubstituted oxazole derivatives containing alkynyl groups.the in vitro cytotoxic potency of target compounds were evaluated by MTT assay against the human gastric cancer cell?MGC803?,human bladder tumor cell?T24?,human liver hepatocellular cancer cell?Hep G2?and A549?human non-small cell lung cancer cells?.The results show that the target compounds have certain anti-tumor activity and have the value of further research.Part 3,oxazole and 1,2,3-triazole are heterocyclic matrix with wide biological activity.In this chapter,based on the two-component reaction of alkynyl carboxylic acid and tert-butyl isocyanide,the multi-component reaction of alkynyl carboxylic acid,tert-butyl isocyanide and organic azides catalyzed by rare earth metals was developed.In the presence of Ce?OTf?₃?10 mol%?,the cascade reaction of one molecule of alkynyl carboxylic acid with three molecules of tert-butyl isocyanides proceeds chemoselectively and regioselectively via a triple and ordered isocyanide insertion process at room temperature,and then the Cesium-catalyzed[3+2]cycloaddtion reaction between the resulted alkynyl oxazole and organic azides was further initiated by the temperature elevation?100 ^oC?,thereby leading to multi-substituted triazole-oxazole derivatives in practical,time-saving,one-pot operations.An nucleophilic mechanism is proposed for the transformation.Furthermore,some of the synthesized target compounds showed potential anticancer activities against MGC803?human gastric cancer cell?with IC₅₀values below 20?mol.L^-1.