Assessing Sodium Amide Reagents for Ester Amidations in Deep Eutectic Solvents in Continuous Flow

ABSTRACT: Advancing the synthetic applications of sodium amides, this study pioneers their use in Deep Eutectic Solvents (DES) for efficient amidation of a range of esters and for C-F bond amination of difluoropyridine in continu-ous flow. These processes occur at room temperature and tolerate the presence of air and moisture, without the re-quirement for strictly dried organic solvents, conditions typically disallowed in sodium amide chemistry. Reactivity studies demonstrate that the DES plays a key role, by facilitating the formation of a unique biphasic system with the organic solvents employed, which can operate under segmented flow in a coiled reactor. These conditions allow ac-cess to a wide range of amides with higher conversions and selectivities than when working in conventional batch conditions while working under quasi-stoichiometric conditions. Notably, the sodium salts (NaOR, NaF, etc) formed as by-products from these reactions can be finely dispersed through the DES, preventing clogging of the flow reactor. To address the limited availability of commercially viable sodium amide reagents, we demonstrate their in-situ flow synthesis using NaN(SiMe3)2 as a precursor. Combining X-ray crystallographic and spectroscopic studies, a closer look into the constitution of these powerful amidation reagents is provided, uncovering their tendency to form kinetically activated monomeric/dimeric species in THF solutions.