Study On Synthesis Of 4H-Chromene Derivatives Based On Thioamide And Paraquinone Methides

The chromene derivatives are an important class of bicyclic compounds.Chromenes?2H-chromene or 4H-chromene?skeleton are widely found in natural products and drugs and have a variety of biological and pharmacological activities.For example,HA14-1 is an inducer that induces apoptosis of tumor cells;Rhodomyrtone has a good inhibitory activity against staphylococcus aureus.The structure of?-ketothioamides?KTAs?uniquely contains multiple reactive sites,including the carbonyl group,the conjugated effect of the carbonyl group and the double bond,which makes it a versatile 1,3-electrophilic equilibrium.It is an extremely important multifunctional synthon for building heterocyclic compounds.The para-quinone methides have a carbonyl-containing cyclohexadiene as the core and an exocyclic alkylene disposed on the para-position.The strong conjugated system makes it have strong polarity and high reactivity.In this paper,A novel NEt₃-promoted synthesis of highly substituted 4H-chromene derivatives 3 from KTAs 1 and ortho-hydroxyphenyl-substituted para-quinone methides2 at 70^oC via substituted chroman intermediate has been developed.The optimal reaction conditions were confirmed as 1:1.2 mole ratio of KTAs 1 and ortho-hydroxyphenyl-substituted para-quinone methides 2 in EtOH?c=0.1 M?in the precence of NEt₃?0.5equiv?at 70 ^oC.With the optimal conditions in hands,28 substrates scope were explored with good yields successfully.The intermediate compound 5 was captured through designed control experiments and confirmed that the intermediate compound 5 can be converted to the target compound 3aa under optimal reaction conditions.Finally,we proposed a possible mechanism including 1,6-conjugated addition/O-cyclization/alkaline heating ring-opening/isomerization/O-cyclization.The structures of all the synthesized new compounds have been characterized by IR,¹H NMR,¹³C NMR and HRMS,and the structure of target compounds have been determined by X-ray the single crystal of compound 3aa.