Diaza-nazarov cyclization: an umpolung approach to access multi-substituted pyrazoles

Abstract

The Nazarov reaction is a 4 thermal conrotatory electrocyclization reaction which is used to obtain five-membered ring structures.1 Among the heterocyclic variants for this pericyclic reaction is the aza-Nazarov reaction, which was previously studied by the Türkmen Research Group2,3 which incorporates a nitrogen atom into the ring, making it possible to access heterocyclic structures. To elaborate this concept, this project focuses on the development of a variant of the Nazarov reaction, which is scarcely studied on, namely the diaza-Nazarov reaction that yields a 3-hydroxypyrazole motif with a substituent at the N1 position. The substrate for the electrocyclization is prepared in 5 steps to construct an N-acyl azo derivative, and it was discovered that the treatment of this compound with 1-1.5 equivalents of TFA at room temperature gives the corresponding pyrazole derivative in high yields. In this project, the diaza-Nazarov reaction was developed, the conditions were optimized, substrate scope studies were conducted, a reaction mechanism was proposed, a control experiment was done to inquire about the β silicon effect, and further transformations were done on the diaza-Nazarov product to demonstrate that it is possible to do functionalization at later stages.