Waste minimized one-pot synthesis of azido- or triazole-pyrazolines using polarclean as reaction medium

Abstract

Herein, we report a sustainable, atom and step-efficient protocol for the one-pot preparation of azido and triazole-functionalized pyrazoline employing a non-toxic, biodegradable, and industrial production waste-derived Polarclean:H2O (4:1) mixture as safer dipolar aprotic reaction medium. The cyclization and di-functionalization of N-tosyl β,γ-unsaturated hydrazones in the presence of a cost-effective CuSO4 catalyst and NaN3 results in high-yield formation of azido-functionalized pyrazolines, easily isolated through simple filtration. The introduction of an azido group to the pyrazoline scaffold allows for the design of a mild, atom-economical one-pot multi-step procedure for the synthesis of triazole-decorated pyrazolines that were isolated in high yield and purity (up to 99%) through straightforward filtration. Both the CuSO4 catalyst and the Polarclean:H2O (4:1) medium proved to be optimal for promoting the one pot Cu(II) cyclization/azidation of β,γ-unsaturated hydrazones in the presence of K2S2O8 as oxidant and then, without isolating the azido-derivative intermediates, the Cu(I) azido-alkynes cyclization by simply adding a stoichiometric amount of an alkyne and 10 mol% of a biocompatible reductant, such as sodium ascorbate. The current protocol, characterized by mild reaction conditions and simple products isolation, shows above all low E-factor values and exceptional Environmental and Safety Hazard Scores (ES and SHZS), confirming its overall sustainability and benignity.