Skeletal Metalation of Lactams through Carbonyl-to-Nickel Exchange Logic

Abstract

Classical metalation reactions such as the metal-halogen exchange are powerful tools to construct chemical bonds between two molecules. An analogous metal-carbon exchange strategy would provide a new entry into the direct structural remodeling of core carbon frameworks, yet its development has remained highly challenging. Here we introduce a skeletal metalation strategy that enables lactams, a highly prevalent motif in bioactive molecules, to be readily converted into well-defined, synthetically useful organonickel reagents. The reaction features a selective activation of unstrained CN bonds mediated by an easily prepared Ni(0) reagent, followed by CO deinsertion and dissociation under mild room temperature conditions in a formal carbonyl-to-nickel exchange process. The underlying principles of this unique reactivity was rationalized by organometallic and computational studies. The skeletal metalation was further applied to a direct CO excision reaction and a carbon isotope exchange reaction of lactams, underscoring the synthetic potential of metal-carbon exchange logic for skeletal modifications of complex molecules.

Formation of C(sp2)–C(sp3) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

“…This demonstrates that the decarbonylation and oxidative addition steps are fast and reversible at rt . This finding implies that 1) CO must be efficiently removed from the system to avoid ketone formation and 2) nickel(0) binds CO with high affinity . We surmised that heating the reaction and maximizing reaction headspace may be required to liberate bound CO from the nickel catalyst and to dilute the concentration of CO in the reaction flask, respectively…”

“…25 This finding implies that 1) CO must be efficiently removed from the system to avoid ketone formation and 2) nickel(0) binds CO with high affinity. 26 We surmised that heating the reaction and maximizing reaction headspace may be required to liberate bound CO from the nickel catalyst and to dilute the concentration of CO in the reaction flask, respectively. 27 Third, to study the reactivity of the new pyridone-ligated arylnickel(II) species in cross-electrophile coupling, we combined 3 with protected alkyl iodide 6 (1 equiv) under reducing conditions at rt, 60 °C, and 110 °C (Scheme 2D).…”

Formation of C(sp2)–C(sp3) Bonds Instead of Amide C–N Bonds from Carboxylic Acid and Amine Substrate Pools by Decarbonylative Cross-Electrophile Coupling

“…27 This finding implies that 1) CO must be efficiently removed from the system to avoid ketone formation and 2) nickel(0) binds CO with high affinity. 28 We surmised that heating the reaction and maximizing reaction headspace may be required to liberate bound CO from the nickel catalyst and to dilute the concentration of CO in the reaction flask, respectively. 29 Third, to study the reactivity of the new pyridone-ligated arylnickel(II) species in cross-electrophile coupling, we combined 3 with protected alkyl iodide 6 (1 equiv) under reducing conditions at rt, 60 °C, and 110 °C (Scheme 2D).…”

“…Very hindered carboxylic acids, such as 2,4,6-trimethylbenzoic acid, provided only ketone product. The abundance of amines, carboxylic acids, and alcohols allowed for easy access to products derived from complex starting materials, such as advanced pieces of mosapride ( 17), an atorvastatin side chain (21), and substrates derived from glucose (30), uridine (31), hydroxyproline (29,32), telmisartan (27) and febuxostat (28)(29)(30). Major side products observed in cases with lower yields were aryl dimer and ketone.…”

Distinguishing Competing Mechanistic Manifolds for C(acyl)–N Functionalization by a Ni/N-Heterocyclic Carbene Catalyst System

“…While the geometric parameters for 8b , c were near-identical, complex 8d demonstrated a six-membered chelate with the two carbamate directing groups. Although such chelates have been described for phosphine-based catalyst systems, computational studies of NHC-based catalyst systems have instead invoked three-centered oxidative addition with disagreement over the role of directing-group assistance or chelation post-oxidative addition. , Other chelating groups are expected to perform similarly; see the Supporting Information for the oxidative addition product derived from a 2-pyridyl substituted benzamide.…”