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

## TL;DR

This paper explores using sodium amides in deep eutectic solvents for efficient amidation reactions under mild conditions in continuous flow.

## Contribution

The study pioneers the use of sodium amides in deep eutectic solvents for amidation and C–F bond amination in continuous flow.

## Key findings

- Sodium amides in deep eutectic solvents enable amidation at room temperature without strict drying requirements.
- The DES forms a biphasic system that improves conversions and selectivities in continuous flow compared to batch methods.
- In situ synthesis of sodium amide reagents using NaN(SiMe3)2 is demonstrated to address reagent availability.

## 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 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.