Friedel-Crafts acylation with amides

Abstract

Friedel-Crafts acylation has been known since the 1870s, and it is an important organic synthetic reaction leading to aromatic ketone products. Friedel-Crafts acylation is usually performed with carboxylic acid chlorides or anhydrides, while amides are generally not useful substrates in these reactions. Despite being the least reactive carboxylic acid derivative, we have found a series of amides capable of providing aromatic ketones in good yields (55-96%, 17 examples). We propose a mechanism involving diminished C-N resonance through superelectrophilic activation and subsequent cleavage to acyl cations.

Figure 1

Isolated yields for cyclizations of amide derivatives 1a-d.

Figure 1

Calculated relative free energies (kcal/mol) in solution for M06/6-31G(d) optimized structures of intermediates and transition state (34) for amide 16 cleavage.

Scheme 1

Products and yields from intramolecular reactions.