Direct Amidation of Esters by Ball Milling**

Abstract

The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram‐scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

“…Owing to the omnipresent nature of the amide bond in nature as well as in synthetic compounds such as pharmaceuticals and agrochemicals, the development of amide bond formation (ABF) methods has stimulated chemists for well over a century . Notably, with the increasing emphasis on the advancement of more sustainable strategies for ABF in recent years, , ample more-benign protocols based on, e.g., non-classical, aqueous, and catalytic ABF have been reported.…”

Plasma flow chemistry for direct N-acylation of amines by esters

“…Recently, a new technique, such as ball-milling, was used to achieve the N-acylation of amines, however a base was necessary to perform the reaction. 32,33 Nevertheless, for all these methods, the use of coupling agents, additives, acids, bases, metal catalysts or photocatalysts was necessary.…”