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 done 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.

Sterically-controlled intermolecular Friedel–Crafts acylation with twisted amides via selective N–C cleavage under mild conditions

“…8 Dication-promoted Friedel-Crafts acylation of secondary amides has been reported; however, these reactions require high reaction temperatures and are limited to superelectrophilic activation. 9 We have recently reported on the graphene-catalyzed Friedel-Crafts alkylation of arenes. 10 We have also developed novel transition metal-catalyzed transformations of amides, in which metal inserts into the inert N-C bond, followed by transmetallation (Suzuki reaction), decarbonylation/olefin insertion (Heck reaction), decarbonylation/C-H activation (direct arylation).…”

“…20 The intermolecular Friedel-Crafts acylation of arenes with amides was first evaluated in the acylation of benzene with amides 1 under Brønsted acid (TfOH) conditions (Scheme 1). [7][8][9] Unsurprisingly, Friedel-Crafts addition products were not detected using moderately distorted anilides (1c), twisted imides (1d-1e), activated Weinreb amides (1f) and pyramidalized amides (1g-1h). We were delighted to find that twisted amides 1a and 1b employing the steric ground-state distortion introduced by our laboratory afforded the ketone product in good to excellent yields.…”

Crystal structure of 3-(4-hydroxy-3-methoxyphenyl)-N-phenylpropanamide, C16H17NO3

“…These compounds serve as starting materials for synthesis of 3-arylpropanols [6], 1,3-diarylpropan-1-ones [7], quinolines [8], β-l lactams [9], 4-aryl-2-quinolinones [10] and 1-indanones [11], as well as ligands in iridium complexes [12]. Despite the wide application of these compounds only few structures have been analyzed by X-ray di raction method: the closest examples include 1,3-di-(3-phenylpropanoylamino)benzene [13], …”

Superelectrophiles: Recent Advances

“…Our work with nitro-substituted urea activation is described in Scheme 24 (vide supra). We have also used this method of superelectrophilic activation to promote acyl transfer reactions with amides [ 99 ]. As in the case of ureas, amides are known as somewhat unreactive carbonyl derivatives.…”