Copper-Catalyzed Conjugation between Nitrile Imines and Terminal Alkynes

Nitrile imines and nitrile oxides are both 1,3-dipoles and for this reason are often considered to have similar reactivity. Yet, in this study, nitrile imines do not undergo the copper-catalyzed formal cycloaddition with terminal alkynes to directly afford pyrazoles, as nitrile oxides are reported to do to produce isoxazoles. The copper-catalyzed conjugation between nitrile imines and terminal alkynes instead delivers alkynyl hydrazones, which can be transformed to 1,3,5-trisubstituted pyrazoles. The use of copper acetylides, which are easily prepared from terminal alkynes, and the inclusion of 1,10-phenanthroline (phen) as a ligand for copper result in a rapid and clean reaction to afford alkynyl hydrazones (21 examples). The use of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as the lone enabler of the 5-endo-dig cyclization from alkynyl hydrazones to 1,3,5-trisubstituted pyrazoles (22 examples) may be considered as an improvement over the existing, metal-catalyzed methods without compromising the efficiency and the scope of the reaction. Additionally, evidence shows that the cyclization of an alkynyl hydrazone to a pyrazole can be intercepted by electrophiles to afford either <i>N</i>-allylated, <i>N</i>-propargylated, or alkylated alkynyl hydrazones or tetrasubstituted pyrazoles (15 examples).