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

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 the C–F bond amination of difluoropyridine
in continuous flow. These processes occur at room temperature and
tolerate the presence of air and moisture, without the requirement
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 access
to a wide range of amides with higher conversions and selectivities
than those when working in conventional batch conditions, while working
under quasi-stoichiometric conditions. Notably, the sodium salts (NaOR,
NaF, etc.) formed as byproducts 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.