Research On The Synthesis Of Oxazole, Imidazole, And Pyridine Derivatives By Cascade Reactions

N-containing heterocycles, such as oxazoles, imizoles, and pyridines, are the keystructures of a broad range of pharmacologically active molecules and natural products, aswell as the synthetic intermediates for drugs and alkaloids. Therefore, these compounds arewidely employed in the fields of synthetically organic chemistry, material chemistry,medicinal chemistry, and natural product chemistry. Due to the significantly practicalimplication, the study on synthetic methodology for N-containing heterocycles is still one ofthe hot topics in organic chemistry, and extensive efforts have been directed toward the threeskeletons. While there have been a range of methods bearing certain advantages as well asdrawbacks developed in literature, it is of great significance to develop novel cascadereactions for the synthesis of diversified N-containing heterocycles from readily availablestarting materials. In this context, the present dissertation is mainly focused on cascadereactions for the preparation of oxazoles, imizoles, and pyridine derivatives as follows:(1) Polysubstituted oxazole synthesis via I2/TBHP-mediated oxidative cyclization fromaryl alkenes and benzylamines. Oxidative difunctionalization of alkenes could readily lead toa broad range of organic molecules. From aryl alkenes and benzylamines, we have developeda cascade reaction involving I2/TBHP-initiated oxidative amination and cyclization processes,and prepared a series of2,5-disubstituted and2,4,5-trisubstituted oxazoles. The advantages ofthis reaction include simple and easily available starting materials, facile operation, goodyields of the products, and large functional group tolerance. Besides, the mechanisticinvestigation shows benzylamine C(sp3)-H bond functionalization involved in this reaction,which would inspire other cases toward aza-heterocycle synthesis from benzylamines.(2) I2-catalyzed aerobic cyclization of aryl ketones and benzylamines for the synthesis ofpolysubstituted imidazoles. Based on previous work of oxazole synthesis, a synthetic cascadereaction for1,2,4-trisubstituted imidazoles was developed from aryl ketones andbenzylamines using I2as the catalyst and1atm O2as the oxidant. Different types of imidazoleproducts were selectively obtained from two-component reaction or three-component reactionby controlled reaction conditions, and various1,2,4,5-tetrasubstituted imidazoles wereprepared by further transformation of the resultant products. (3) Copper-catalyzed aerobic C N bond cleavage/condensation/cyclization of aromaticmethylamines and methyl ketones for the assembly of2,4,6-trisubstituted pyridines. Strategiesinvolving oxidative cleavage of benzylamine C N bond were usually utilized in thedeprotection of N-protecting groups, imine synthesis, and cross-coupling reactions. With afragment-assembling strategy, for the first time, we developed a copper-catalyzed C N bondcleavage of aromatic methylamines with molecular oxygen as the oxidant for readygeneration of2,4,6-trisubstituted pyridine derivatives. In contrast with traditional method forthe synthesis of2,4,6-trisubstituted pyridines, the present work features advantages includingatom economy, minimized waste, environmentally friendly oxidant, and nonhazardousbyproduct (water).(4) Copper-catalyzed aerobic oxidative cyclization of ketone oximes and pyridines forimidazo[1,2-a]pyridine synthesis. Direct transformation of unactivated pyridines is still a hottopic in synthetic chemistry, but remains a significant challenge owing to the lower energy ofthe π-system relative to benzene. Copper-initiated aerobic cyclization with oximes realizedpyridine functionalization, providing a convenient access to imidazo[1,2-a]pyridinederivatives, in which isoquinolines were also competent to give corresponding products. Asfor the reaction mechanism, we proposed a highly active intermediate formed from oximesand copper, which could activate pyridine to leave for cyclization, and finally aromatizationreadily occurred under oxygen.(5) Lewis acid/copper co-catalyzed ring-opening/Ritter/cyclization reaction cascade forthe synthesis of fused indolizinones. Ring-opening reactions of donor–acceptor (D–A)cyclopropanes could easily occur under Lewis acid due to the strain structure. A novel relaycatalytic cascade reaction involving Lewis acid-trigged ring-opening of cyclopropyl ketones,copper-assisted Ritter-type process, and Lewis acid-catalyzed N-acyliminium ion cyclizationhas been developed to synthesize fused indolizinones. This ingenious cascade methodprovides an efficient and rapid access to diversified synthesis of complex N-heterocycles fromsimple starting materials.