Direct Amidation of Esters via Ball Milling

Abstract

<p><i>The direct mechanochemical amidation of esters – enabled by ball-milling – is herein described. The operationally simple procedure requires inputs of ester, amine, and sub-stoichiometric KOtBu and is applicable to a preparation of 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 API’s, agrochemicals, and its ability to deliver gram-scale synthesis of active pharmaceuticals and building blocks is demonstrated, all in the absence of a reaction solvent.</i></p>

Mechanochemical techniques for the activation and use of zero-valent metals in synthesis

“…More recently, such devices have been investigated for use in chemistry, with earlier applications being in the areas of formulation science, polymorphism, and crystal engineering, before moving into chemical synthesis applications such as the preparation of metal-organic frameworks (MOFs) and the construction of organic molecules. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In recent years, research endeavours in these latter applications of ball mills have intensified, highlighting the minimisation of reaction solvent, and enabling alternative selectivity and reactivity to solvent-based approaches as significant drivers for continual development. A similar pattern can be found for the use of ball mills in the activation of zero-valent metals.…”

Green metrics in mechanochemistry

“…Browne et al developed an original and efficient ball milling method for direct amide bond formation using methyl or ethyl esters as starting materials (from reagents 21 and 24), 84 circumventing the need of any activating reagent, usually needed when using carboxylic acids as starting materials. The solventfree reaction was carried out using an amine (from 22 and 25), 1.2 equivalent of ester, and a substoichiometric amount of potassium tert-butoxide (0.85 mol%) as a base.…”

Atom-efficient direct amidation by thermo-mechanochemistry

“…[21][22][23] Solvent-free or minimum-solvent mechanochemical reaction environment is known to have tremendous sustainability benefits 24 and is known to be effective in the synthesis of amides. [25][26][27][28][29][30][31][32][33][34][35] Here we present a conceptually different approach, which involves the thermo-mechanochemical treatment of carboxylic acids and amines for the quantitative conversion to amides without additives. Moreover, we managed to observe and characterise ammonium carboxylate salts as crystalline reaction intermediates preceding the amide bond formation.…”