An Expeditious and Greener Synthesis of 2-Aminoimidazoles in Deep Eutectic Solvents

Martina Capua,Serena Perrone,Filippo Perna,Luigino Troisi,Antonio Salomone,Paola Vitale,Vito Capriati

doi:10.3390/molecules21070924

Abstract

A high-yield one-pot two-step synthesis of 2-aminoimidazoles (2-AI), exploiting an under-air heterocyclodehydration process between α-chloroketones and guanidine derivatives, and using deep eutectic solvents (DESs) as nonconventional, “green” and “innocent” reaction media, has been accomplished successfully. The combination of either glycerol or urea with choline chloride (ChCl) proved to be effective for decreasing the reaction time to about 4–6 h in contrast to the 10–12 h usually required for the same reaction run in toxic and volatile organic solvents and under an argon atmosphere. In addition, the use of the ChCl–urea as a DES also enables the direct isolation of triaryl-substituted 2-AI derivatives by means of a simple work-up procedure consisting in filtration and crystallization, and allows the recycle of the DES mixture. A plausible mechanism highlighting the potential role played by hydrogen bonding catalysis has also been illustrated.

Highlights

The American Chemical Society1 s (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR), founded in 2005 with the aim of catalyzing the integration of green chemistry and engineering into the pharmaceutical industry, strives for the need to replace conventional hazardous volatile organic solvents (VOCs) in favor of safe, green and biorenewable reaction media that are not based on crude petroleum
In this paper we have described the first “green” and efficient condensation-mediated synthesis of 2-AIs successfully run in choline chloride (ChCl)-based deep eutectic solvents (DESs) as environmentally friendly, safe, and nonconventional reaction media
The scope of the reaction is broad in terms of the α-chloroketones employed, and both mono- and diphenyl-substituted guanidines proved to be competent partners

Summary

Introduction

2-Aminoimidazole (2-AI) derivatives are an extremely important class of substituted nitrogen-containing heterocycles whose core has been recognized as a key and essential structural element in a wide range of bioactive molecules such as the antibiotic 1 belonging to the family of cephalosporins [3], the α2 -receptor agonist 2 [4], and the naturally-occurring sponge metabolites bromoageliferin 3 and oroidin 4, which are known for their anti-biofilm activity [5,6] (Figure 1) They have found wide application in coordination chemistry [7,8], in organocatalysis [9], and proven to be either valuable pharmacophores in medicinal chemistry for the development of high value-added molecules for discovery based research [10] or Molecules 2016, 21, 924; doi:10.3390/molecules21070924 www.mdpi.com/journal/molecules blocks for the design modulators smallofmolecule drugsmolecule being bioisosteres of bioisosteres guanidine, useful building blocksoffor the designof ofvarious modulators various small drugs being benzamidine and triazole rings [11].

Methods

Discussion

Conclusion