Sustainable mechanochemical synthesis of functionalisable fluorinated scaffolds for drug discovery using green LAG

Abstract

Fluoroarenes have become widely recognised as useful building blocks in medicinal chemistry, and manipulation of these compounds can be achieved readily using nucleophilic aromatic substitution (S_NAr) to introduce a diverse range of functionality for drug development. A more sustainable mechanochemical approach to S_NAr of fluoroarenes using planetary ball milling with a range of aliphatic and aromatic amines as nucleophiles has been investigated with 20 examples described. An efficient set of milling conditions using liquid assisted grinding (LAG) employing the bio-solvent Cyrene or water, and short reaction times (30 minutes) has been developed. Yields were consistently higher when using Cyrene or water as LAG agent rather than DMF. The method provides a useful alternative to the dipolar aprotic solvents DMF and DMSO and high temperatures commonly used in S_NAr. Ethyl acetate is employed in the extractive work-up, but is recyclable and considered a green solvent. The method reduces or obviates bulk reaction solvent and aqueous waste streams containing dipolar aprotic solvents.