Amine Protection by In Situ Formation of Deep Eutectic Solvents

In recent years, there have been many governmental and industrial efforts to replace, eliminate or reduce the use of solvents in pharmaceutical and chemical industries. This effort has been driven by the need to reduce any possible human health impact, process safety risks, and negative effects to the environment. The use of ‘‘green’’ solvents is the aim to minimize the environmental impact resulting from their use in chemical production. Since amines are noteworthy functionality present in a wide range of biologically active compounds, their protection is an important and a frequently required exercise in synthetic organic and medicinal chemistry owing to their high nucleophilicity and basicity. Various methods for the protection of amine groups have been reported in which hazardous, toxic, and volatile organic solvents have been replaced by the use of green solvents such as water, or ionic liquids. Recently, deep eutectic solvents (DESs) have begun to be evaluated as superior green, biorenewable, and biodegradable reaction media to perform chemical transformations. DESs are generally obtained by the complexation of a quaternary ammonium salt such as choline chloride with a metal salt or hydrogen bond donor like urea, carboxylic acid, sugar and amide.6 Herein we report a novel procedure for the amino group protection in which a DES is formed consisting of choline chloride and the amine. As a consequence, the amine is not only a reactant, but simultaneously part of the solvent (Figure 1). Figure 1: Amine protection by in situ formed DES. The method is quite general for all the relevant amino protecting groups such as Fmoc, Boc, Cbz, Tosyl and acetyl groups. Various aromatic, aryl and alkyl amines were converted to their N-protected derivatives in excellent yields. Selective protection of amines in the presence of other functional groups was also achieved by this method.