Studies On The Asymmetric Alkylation Of Pyrazolone Derivatives

Pyrazolin-5-ones, a class of important aza-heterocycles, have a range of applications as pharmaceutical agents, photographic couplers, chelating agents in coordination chemistry, synthetic scaffolds in combinatorial and medicinal chemistry, and agrochemical products. Particularly,4-substituted-pyrazolin-5-ones frequently act as the core frame of many pharmaceutical compounds. Hence, the synthesis of chiral4-substituted-pyrazolin-5-ones has potential pharmaceutical application value. However, a thorough survey of relevant literature shows that the asymmetric alkylation for the synthesis of optically active4-substituted-pyrazolin-5-one derivatives has been never explored before. Therefore, study of the highly effective approaches to access enantioenriched4-substitued-pyrazolin-5-one derivatives should be of great value.The last decade has witnessed a rapid development of organocatalysis. Organometallic catalysts, often expensive, toxic and with harsh reactions conditions, can mediate a wide range of substrates with variable ligands. Enzymatic catalysis has relatively high selectivity and reactivity, but the scope of substrates is limited. In comparison, organocatalysts can be obtained from a variety of sources and in most cases are non-toxic. They also have a diversity of structures and mild reaction conditions. Therefore, to expand its application in the asymmetric catalysis has become a focus of attention. As an important member of organocatalysts, chiral phase-transfer catalyst has become a powerful tool in the construction of complex molecular skeletons, and they have wild applications in organic synthesis, especially in the synthesis of natural and non-natural amino acids.In this dissertation, we focus on the asymmetric alkylation of pyrazolone derivatives catalyzed by phase-transfer catalysis derived from cinchona alkaloid. Based on the available resources in the group, several catalysts were synthesized through the simple one-step reaction and their application in the asymmetric alkylation reaction was also studied. Reaction conditions (base, catalyst, solvent, and temperature) were optimized. The results show that catalyst c-5performs best. With the optimal reaction conditions in hand,20examples of catalytic enantioselective alkylation reaction are presented. The reaction does not need protection against oxygen and moisture. Although reactivity was relatively low at0℃, yield and enantiomeric excess were reasonable (up to82%and72%, respectively).