Acid-Mediated Synthesis Of Nitrogen Heterocycles Via Ynamides And Synthetic Studies Towards Precursor Of (-)-Actinophyllic Acid

Ynamides,which can be considered as nitrogen atom-substituted alkynes,have a unique structure with a nitrogen directly attached to the triple bond.The most important feature of the ynamides leads to a special performance at regioselectivity and stereoselectivity.Recent the development of these substrates have stimulated the enthusiasm of research of many scholars.The thesis summarizes the major development of ynamide chemistry contained the preparation methods,various types of reactions and an application in natural product total synthesis recently.The main content of this thesis include the acid-mediated synthesis methodology of nitrogen heterocycles via ynamides and synthetic studies towards precursor of（-）-actinophyllic acid.Firstly,the thesis describes an efficient and atom-economical[2+2+2]cycloaddition of ynamides with two discrete nitriles catalyzed by TfOH to form multi-substituted 4-aminopyrimidine.Various functional groups,such as halides,ester,nitro,and ether,are tolerated.This transformation employs mild conditions,good to excellent yields,and a broad range of substrate scopes.On the basis of the reaction results,a possible mechanism is illustrated,ynamide was activated with acid yielding a highly reactive keteniminium ion intermediate,followed by nitriles attack,cyclization and alkalization to obtained the desired products.Furthermore,we synthesized the correspongding products with different nitriles in good total yield with moderate regioselectivity via a diversity oriented approach for structural optimization.Secondly,[4+2]cycloaddition reaction mediated by TfOH proceeds smoothly to afford quinazoline derivatives in good yield when the equivalent amounts of the nitrile and ynamide was used in the optimized reaction conditions.This part work is ongoing in our laboratories currently.Finally,during our research on（-）-Actinophyllic acid,the key intermediate pyrrolidine derivative was obtained by a Et₂AlI-mediated halo-mannich-type reaction using cyclopropyl carbonyl-derived enolates and sulfonyl-protected imines,which structure and absolute configuration the same as natural product confirmed by ¹H NMR,¹³C NMR,NOE,HRMS and X-ray diffraction.But we have a lot of trouble in consequent acylation and oxidation,numerous attempts to stop the leak had failed or not yielded the desired results.Our further synthetic stratigies involve activated/non-activated cyclopropane ring-opening by nitrogen nucleophiles and Dieckmann cascade reactions.This part work is ongoing in our laboratories currently.