Use Trifluoromethyl Group As CO Surrogate For The Synthesis Of 1,3-oxazin-6-ones

The 1,3-oxazin-6-one frameworks have been recognized as important building blocks in a number of pharmaceuticals and biologically active molecules,as exemplified by a novel lipase inhibitor cetilistat(ATL-962),salinazinone A,and salinazinone B.Toward this end,much attention has been recently paid to the development of new methods for their syntheses.The selective incorporation of a CF3 group into drug molecules may give rise to significant improvement in the drug’s pharmacokinetic properties,binding selectivity,and metabolic stability.Among the most direct approaches for the construction of C-CF3 bonds is the direct radical C-H trifluoromethylation of various types of organic molecules by using Togni’s reagent as the CF3 radical source.On the contrary to the C-F or C-CF3 bond formations,the development of novel synthetic methods for the activation or cleavage of C-F bonds has also received much attention owing to the importance of the resulting more valuable partially fluorinated or non-fluorinated organic compounds from readily available per or oligofluorinated starting materials.However,the elegant combination of direct radical C-H trifluoromethylation and selective cleavage of C-F bonds for the construction of functionally diverse heterocycles,to the best of our knowledge,still remain elusive.Encouraged by our group recent success in direct radical trifluoromethylation of β-C-H of α,β-unsaturated amides and β-Csp3-H bond of amides and inspired by base-mediated C-F bond activation and cleavage,This paper mainly explore a new and efficient protocol using Togni’s reagent as a CO surrogate for carbonylation reactions.And mainly synthesis 30 novel 1,3-Oxazin-6-ones molecular.This thesis includes the following two aspects:1.Use enamine and Togni reagent as reaction reagent,potassium phosphate as catalyst,acetonitrile and water as solvent,under mild transition-metal-free conditions using CF3 as a new and benign CO surrogates for carbonylation reactions and constructed a series of multifunctional 1,3-oxazine-6-ketone compounds.The method is simple,high yield and wide applicability and easy handing.2.Remote β-C-H carbonylation of amines triggered by trifluoromethylation of alkenes in one pot to produce novel 1,3-oxazin-6-ketones containing CF3 functional groups.The overall process serves as a novel,efficient,and safe approach to synthetically valuable 1,3-oxazin-6-one motifs in satisfactory yields,featuring a broad substrate scope with a high degree of skeletal and functional diversity.Furthermore,the newly developed one-pot protocol from alkenyl N-ethyl-amides by simultaneous functionalization of one Csp2-H,one Csp3-H,one Csp2-H,and three Csp3-F bonds provides a facile and step-economical access to valuable CF3-containing 1,3-oxazin-6-ones.