Study On The New Reaction Based On Benzyne

The chromene derivatives are a class of heterocyclic skeletal compounds in nature and have a wide range of physiological and pharmacological activities.Particularly,2-imine-3-carboxamide-2H-chromene derivatives can be used as good inhibitors of some enzymes and are promising drugs for the treatment of alzheimer’s and cancer.In addition,2-imine-3-carboxamide-2H-chromene derivatives can also be used as small molecule fluorophores with low cytotoxicity and able to selectively stain organelles in living cells.Benzyne is a very active intermediate in organic chemistry.The reaction types consist of nucleophilic addition reaction,σ bonds insertion reaction,cycloaddition reaction and multicomponent coupling reaction and so on.Generally,benzyne is employed in situ generation from precursors.However,limited to its harsh generating conditions,development of benzyne is slow.Until 1983,a new precursor(otrimethylsilyl trifluoromethanesulfonate)was synthesized by kobayashi,from which benzyne can be generated in situ under a very mild condition(in presence of fluorine sources).Then benzyne was widely used as a useful organic synthon in the preparation of natural products and pharmaceutical intermediates.In this paper,a concise and direct synthetic strategy for the construction of 2-aryliminochromene skeleton by cascade three-component coupling reaction of arynes,N,S-keteneacetals,and DMF in good yields has been disclosed.The optimal reaction conditions were confirmed as 2:1 mole ratio of 1a(dropwises in 9 h)and 2a in DMF(c = 0.2 M)in the precence of KF at 90 oC.It is noteworthy that the products were purified by recrystallization from ethanol but siligel columan chromatography.With the optimal conditions in hands,we next successfully explored nineteen substrate scope with yields as high as 96%.Besides,seven substrates with biologically active skeleton have also been synthsis with good yields.Based on the above experimental results,a plausible reaction mechanism was proposed: benzyne is generated from Kobayashi precursor in the presence of KF.Then four-membered intermediate is formed by [2 + 2] π-bond cyclization of benzyne with DMF,which isomerizes to an o-quinone methide(o-QM)via ring-opening.Subsequently,the o-QM is trapped by N,S-keteneacetals to give formal [4 + 2] adduct.Finally,the desired product is afforded with elimination of dimethylamine and methyl mercaptan.The structures of all the synthesized new compounds have been characterized by IR,1H NMR,13 C NMR and HRMS(compounds containing fluorine atom such as 3d,3e,3k and 3l have also been characterized by 19 F NMR),and the target compound structure has been determined by the single crystal of compound 3a.