Abstract
Ball milling of aromatic, heteroaromatic, vinylic, and aliphatic esters with ethanol and calcium nitride afforded the corresponding primary amides in a transformation that was compatible with a variety of functional groups and maintained the integrity of a stereocenter α to carbonyl. This methodology was applied to α-amino esters and N-BOC dipeptide esters and also to the synthesis of rufinamide, an antiepileptic drug.
Highlights
Mechanochemistry involves chemical transformations induced by the direct absorption of mechanical energy, normally arising from grinding or milling processes
A number of mechanochemical approaches to amide synthesis from amines and carboxylic acids have been developed on the basis of the use of coupling reagents such as EDC,[7] EDC/ HOBt in the presence of Mg−Al hydrotalcite,[8] EDC in the presence of nanocrystalline hydroxyapatite,[9] carbonyldiimidazole,10 2,4,6-trichloro-1,3,5-triazine/triphenylphosphine,[11] uronium-based reagents,[12] and hydrolytic enzymes.[13]
We first optimized the mechanochemical transformation of ethyl 3-fluorobenzoate 1a into primary amide 2a with magnesium nitride, which has been employed as a source of ammonia in several transformations, harsh reaction conditions were required.[23]
Summary
Mechanochemistry involves chemical transformations induced by the direct absorption of mechanical energy, normally arising from grinding or milling processes. Solvation phenomena are not significant, often leading to accelerated reactions and alterations in product selectivity, which may lead to the discovery of new chemical transformations.[3] the use of solvent-free conditions is relevant in the context of green chemistry, since volatile organic solvents are the vast majority of residues from synthetic activities.[4] there is a growing interest in the application of mechanochemistry to the synthesis of active pharmaceutical ingredients (APIs).[5]
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