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.

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 ].…”

Azide–Enolate Cycloaddition‐Rearrangement Enables Direct α‐Amination of Amides and Enelactam Synthesis from Esters**

“…Formal (3 + 2) cycloaddition of organic azides and enolisable carbonyl compounds has been widely investigated since the initial reports of Olsen and Pedersen (A1, Figure 1). [1][2][3][4] Important later contributions from Ramachary, [5][6][7][8][9][10][11] among others [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] have firmly established the utility of the transformation for triazole synthesis (A1, Figure 1), identified secondary and tertiary amines as effective organocatalysts, and further defined the substrate scope to include most commonly aldehydes, but also ketones and malonates, among others. In 2015-16, Yan [31] demonstrated that it was possible to directly obtain amides (A2, Figure 1) under mild conditions from urea-promoted aldehyde-azide cycloadditions, by rearrangement of the initially formed hydroxy triazoline Chemistry-A European Journal www.chemeurj.org cycloadducts, a finding followed up by Yuan [32] in the same year using the ionic liquid [bmim]OH as catalyst.…”