1,3‐Dipolar Cycloaddition of Alkanone Enolates with Azides in Deep Eutectic Solvents for the Metal‐Free Regioselective Synthesis of Densely Functionalized 1,2,3‐Triazoles

Abstract

Dedicated to Professor Cesare Gennari on the occasion of his 70th birthday.An eco-friendly metal-free protocol was developed for the regioselective synthesis of densely functionalized 1,2,3-triazoles through a 1,3-dipolar cycloaddition reaction of alkanone enolates with azides performed in the environmentally responsible choline chloride/urea or choline acetate/urea eutectic mixture. This approach displays a broad substrate scope, straightforwardly furnishing the desired triazoles (including the challenging phenolic derivatives) in yields of up to 98 %, while working at room temperature and under aerobic conditions. The practicability of the method is exemplified by the sustainable synthesis of some pharmaceutically relevant triazole derivatives carried out via telescoped, one-pot cycloaddition/ reduction processes in the same eutectic mixture without any halfway isolation/purification step of intermediates.

N-, O- and S-Heterocycles Synthesis in Deep Eutectic Solvents

“…Recently, Cicco and coworkers described a regioselective synthesis of functionalized 1,2,3-triazole derivatives 41, through a 1,3-dipolar cycloaddition reaction between enolates of alkanones 40 and azides, in environmentally benign urea-based eutectic mixtures [ChCl/urea and choline acetate (ChOAc)/urea], Scheme 14 [33]. This metal-free protocol, performed under mild conditions such as room temperature and aerobic conditions, showed a broad substrate scope, affording the desired triazoles in 40-98% yields, overall, up to 13 h, Scheme 14.…”

“…The eutectic mixture ChOAc/urea was recycled for four runs, showing a decrease in the product yield from 98% (first cycle 66% (fourth cycle). Moreover, one-pot cycloaddition/reduction processes w successfully performed in ChCl/urea DES leading to functionalized triazoles w pharmacological properties [33]. Moreover, the tetrazole ring has been prepared in DES mixtures.…”

Synthesis of N-heterocyclic compounds: A green approach using deep eutectic solvents

“…In addition, one-pot cycloaddition/reduction procedures in ChCl/urea DES were successfully performed to produce functionalized triazoles having a variety of pharmacological properties. [28]…”

A Sustainable Synthetic Approach to Tacrine and Cholinesterase Inhibitors in Deep Eutectic Solvents under Aerobic Conditions

“…DESs have been widely used in organic synthesis [ 9 ], in particular for the preparation of N -containing heterocyclic scaffolds because of their dual solvent–catalyst role [ 10 , 11 , 12 ]. Over the last decade, valuable sustainable methodologies have been introduced in the literature, both by our group and others, for the synthesis of pharmacologically active heterocycles with central nervous system activity or anti-inflammatory or antiproliferative properties (e.g., functionalized triazoles, pyrimidines, imidazoles, pyrazones, benzoxazines, tetrahydrofuran, and tetrahydropyran derivatives) [ 13 , 14 , 15 , 16 , 17 , 18 ] and of Active Pharmaceutical Ingredients (APIs) like COX-1 inhibitors [ 19 ] and antihistamine drugs (e.g., thenfadyl and some analogs, such as dimethindene) [ 20 , 21 ].…”