Resonance Destabilization in N-Acylanilines (Anilides): Electronically-Activated Planar Amides of Relevance in N–C(O) Cross-Coupling

Abstract

Transition-metal-catalyzed activation of amide N-C(O) bonds proceeds via selective metal insertion into the carbon-nitrogen amide bond. Herein, we demonstrate that N-acylanilines (anilides), the first class of planar amides that have been shown to undergo selective amide N-C cross-coupling reactions, feature a significantly decreased barrier to rotation around the amide N-C(O) bond. Most significantly, we demonstrate that amide n → π* resonance in simple anilides can be varied by as much as 10 kcal/mol. The data have important implications for the design of N-C(O) amide cross-coupling reactions and control of the molecular conformation of anilides by resonance effects.

N‐Boc‐Amides in Cross‐Coupling Reactions

“…They applied their catalytic system involving Ni 0 /NHC to Suzuki–Miyaura‐type coupling reactions . N ‐Methylbenzanilide showed poor reactivity in this type of coupling compared with amide‐to‐ester conversion, whereas N ‐Boc‐benzamides led to a significantly better reactivity as well as boronic ester compared with boronic acid. With these optimized coupling partners, the conditions were optimized and a mixture of inorganic base (K 3 PO 4 ) and water is required to activate the boronic ester and thus obtain the corresponding ketone in almost quantitative yield.…”

“…Different nonplanar amides, all destabilized electronically and/or sterically, have been designed and used in cross‐coupling reactions …”

“…Different nonplanar amides, all destabilized electronically and/or sterically,h ave been designed and used in cross-coupling reactions. [29,41] In this review we will focus on the N-Boc-protected amide family, [42] which are, from our point of view,astrategic and useful tooli nt otal synthesis. Indeed, an unprotected amide does not react with transition metals,a nd remains unreactive towardss everal reaction conditions, which allows high chemoselectivity [43] over several synthesis steps.…”

Ligand Effect on Iron‐Catalyzed Cross‐Coupling Reactions: Evaluation of Amides as O‐Coordinating Ligands

“…As major design criteria, the ideal ligands would be (1) readily synthesized or commercially available, (2) low costing, (3) modular, and (4) general . The selected amide ligands are divided into five classes: (a) commercially‐available TMU ( 1 ) and N‐methyl‐succinimide ( 2 ); (b) N‐sterically‐differentiated benzamide derivatives in the series Me ( 3 ), Et ( 4 ), i ‐Pr ( 5 ) as well as their N‐alicyclic morpholinyl ( 6 ), pyrrolidinyl ( 7 ) and piperidinyl ( 8 ) analogues; (c) electronically‐varied 4‐MeO‐ ( 9 ) and 4‐CF 3 ‐benzamides ( 10 ), sterically‐varied 2‐Me‐benzamide ( 11 ), chelating 2‐carboxamido‐benzamide ( 12 ); (d) aliphatic amides in the dimethylacetamide series, including DMAC ( 13 ), DEAC ( 14 ) as well as sterically‐varied 1° (C 9 H 19 ‐, 15 ), 2° ( i ‐Pr, 16 ), and 3° (ad, 17 ) analogues; (e) chelating aliphatic morpholinyl amide ( 18 ) and 2‐methoxyethylbenzamide ( 19 ) as well as resonance reduced N−Me‐anilide ( 20 ) and N,N‐dimethylbenzenesulfonamide ( 21 ). Our previous studies identified cyclic ureas DMPU ( 23 ) and DMI ( 24 ) as O‐coordinating amide‐type donors due to increased N lp to C=O conjugation (O‐basicity) from both nitrogen atoms as well as ring‐expanded N‐methyl‐caprolactam ( 25 ) adopting sterically‐minimized chair‐like conformation (Figure f).…”

“…ligand effect on iron-catalyzed cross-coupling. [a] (entries[15][16][17] with gradually decreasing reactivity. (6) Finally, a screen of chelating morpholinyl (18) and 2-methoxyethyl amides(19) (entries[18][19] and less basic NÀ Me-anilide(20) and DMBS (21) identified 2-methoxyethylbenzamide (entry19) as the most reactive in this series.…”