Synthesis Of Tetramic Acid Derivatives Via Intramolecular Sp~3C-H Amination Mediated By Hypervalent Iodine(â…¢) Reagents/Br(?)Nsted Acids

Tetramic acid derivatives represent an important class of nitrogen-containing heterocycles with a pyrrolidine-2,4-dione moiety. They are core structural skeletons in a variety of natural products from terrestrial and marine origins exhibiting many biological activities such as antibiotic, antiviral, antifungal, phyto-, cytotoxic and enzyme inhibitory activities against bacterial DNA-directed RNA polymerase. Various synthetic ways to such five-membered nitrogen-containing heterocyles have been developed. This structural core can be constructed either by the C(sp3)-C(sp2) bond formation via Dieckmann condensation of N-alkoxy-carbonylacetyl derivatives, or by the C(sp2)-N bond formation through the condensation of a-amino keto ester derivatives. Recently, Liu and co-workers synthesized the tetramic acid derivatives by constructing C(sp3)-N bond via aza-anti-Michael addition of a,β-unsturated acetamides. Although a considerable amount of effort has been expended in the preparation of tetramic acid derivatives, new and straightforward methods to approach these heterocycles are still highly desirable.Nitrogen functionality is prevalent in synthetic and natural small molecules with high level of biological activities, which motivates the development of methodologies to introduce nitrogen atoms into organic molecules. Among various C-N bonds construction methods, the direct C-N bond formation reaction between C-H and N-H bonds is the most powerful strategy because it avoids prefunctionalization of the substrates, thus minimising its environmentally impact and synthetic steps. Recently, intramolecular metal-free C-H amination has become an appealing strategy to directly construct aza-heterocycles due to the environmental benign and atom-economic character. Compared with sp2C-H amination, sp3C-H amination reactions are rare. Recently, Fan and co-workers synthesized azetidines and3-oxyindoles via hypervalent iodine(Ⅲ) mediated intramolecular a-amination of sp3C-H bond of carbonyl compounds under basic conditions. So far, to the best of our knowledge, the direct construction of the tetramic acid skeleton via intramolecular amination reaction between C-H and N-H bonds has never been realized. Herein, we present the first example for the synthesis of tetramic acids via metal-free intramolecular sp3C-H amination mediated by hypervalent iodine(Ⅲ) reagents/Br(?)nsted acids.