Synthesis Of1,3,5-Trisubstituted Pyrazoles By Cope-Type Hydroamination Of1,3-Dialkynes

Substituted pyrazoles have been widely used in organic synthesis and biochemistry because of their structural motif frequently found in various bioactive molecules and natural products. Particularly, the1,3,5-trisubstituted pyrazoles constitute the core structures of commercial drugs (for example:Acomplia, Viagra, and Celebrex). Thus, the development of convenient methods for1,3,5-trisubstituted pyrazoles synthesis has been attracted considerable attention. However, synthesis of1,3,5-trisubstituted pyrazoles frequently suffers from some drawbacks, such as multistep reactions, harsh reaction conditions, the use of transition-metal catalysts, special starting materials or poor selectivity.In this paper, a simple method for synthesis of1,3,5-trisubstituted pyrazoles via intermolecular Cope-type hydroamination reaction of1,3-dialkynes with substituted hydrazine (NH2NHR) was described. The main contents were summarized below:1. Initially, the reaction of1,4-diphenylbuta-1,3-diyne (la) with methylhydrazine sulfate was chosen as a model reaction to optimize the reaction conditions. It was found that the reaction of1,4-diphenylbuta-1,3-diyne (0.4mmol) with methylhydrazine sulfate (1.6mmol) and Et2NH (1.6mol) in DMSO at110℃for20h gave the best result. Under the optimized reaction conditions, Various of1,3,5-trisubstituted pyrazoles were obtained in good yields (62%-89%).2. The reactions of symmetric1,3-dialkynes with methylhydrazine sulfate procced smoothly to afford1,3,5-trisubstituted pyrazoles in good yields (71-89%). The1,3-dialkynes Bearing an electron-withdrawing group got higher yield than those bearing an electron-donating groups. The reactions of unsymmetric1,3-dialkynes with methylhydrazine sulfate were also examined, and region-isomers of pyrazoles will be obtained. When Ri and R2having big different push-pull electronic abilities, single products would be formed in good yields.