Structural Evidence for Aromatic Heterocycle N–O Bond Activation via Oxidative Addition

Abstract

Many methods report the scission of N−O bonds of aromatic heterocycles and their subsequent functionalization. Oxidative addition is one of the presumed pathways through which aromatic N−O bond activation with transition metals is achieved. We report the first well-defined pathway of (benz)isoxazole's aromatic N−O bond activation through oxidative addition. We also provide control experiments, which show that aromatic N−O bonds may be broken by strong inorganic reductants. These results highlight that N−O bonds are susceptible to both reduction and oxidative addition, which has important implications for catalysis. Exploring the reactivity of one of these complexes toward a series of electrophiles leads to the discovery of a Staudingertype β-lactam synthesis upon the reaction with a ketene. Finally, we demonstrate that the choice of different metal/ligand combinations allows for selective oxidative addition into either C−I bonds or N−O bonds in the presence of the other.

Activation of N−O σ Bonds with Transition Metals: A Versatile Platform for Organic Synthesis and C−N Bonds Formation**

“…recently demonstrated the ability of the nickel(0) complex [(dcype)Ni] (dcype=1,2‐bis(dicyclohexylphosphino)ethane) to insert in the N−O bond of benzoxazole 18 . X‐ray, NMR, and HRMS analyses confirmed the structure of the resulting Ni(II) complex 19 (Scheme 3g) [15] …”

“…X-ray, NMR, and HRMS analyses confirmed the structure of the resulting Ni(II) complex 19 (Scheme 3g). [15] These selected examples evidence the possibility to activate NÀ O bonds with transition metals via oxidative addition. Based on these seminal examples, the ability of hydroxylamine derivatives to undergo oxidative addition to transition metals was utilized to develop metal-catalyzed CÀ N bond formations.…”

Activation of N–O σ Bonds with Transition Metals: a Versatile Platform for Organic Synthesis and C–N Bonds Formation

“…The structure of the resulting Ni(II) complex 18 was confirmed by X-ray, NMR and HRMS analysis (Scheme 3g). [15] These selected examples showcase the propensity of transition metals to activate N-O bonds via oxidative addition. However, X-Ray structures are not giving any information on the mechanistic pathway followed, and more investigations are required to distinguish between pure oxidative addition and single electron pathways.…”

Late-Stage C(sp3)–H Methylation of Drug Molecules

“…Pleasingly, the C­( sp 3 )-methylations of these rings with varying 4- substitutions proceeded efficiently ( 26 – 28 , 44%–70% yield). Notably, the benzisoxazole moiety of 27 , which typically undergoes oxidative addition into Ni(0), was stable under our reaction conditions. The core of lifitegrast, a benzoyl-substituted tetrahydroquinoline, was functionalized at two α-amino positions ( 29 , 55% yield, 1:1 r.r.).…”