Cu(II)-Catalyzed Aminocyclization of N-Propargyl Hydrazones to Substituted Pyrazolines

J Org Chem. 2023 Dec 1;88(23):16340-16351. doi: 10.1021/acs.joc.3c01848. Epub 2023 Nov 10.

Abstract

An efficient route for the copper(II)-catalyzed synthesis of substituted pyrazolines from readily accessible N-propargyl hydrazones has been reported under open flask conditions via intramolecular C-N bond formation. N-acyl and N-tosyl-substituted pyrazolines have been prepared in moderate to excellent yields. Mechanistic investigations using NMR, high-resolution mass spectrometry (HRMS), and Hammett analyses suggest that the Cu(II) catalyst generally acts as a Lewis acid to form an iminium-ion intermediate via cyclization, which afforded the desired pyrazolines upon hydrolysis. One progesterone receptor antagonist has also been synthesized utilizing this reaction methodology.