Palladium-Catalyzed Unimolecular Fragment Coupling of N-Allylamides via Elimination of Isocyanate.

Transition metal-catalyzed unimolecular fragment coupling (UFC) is defined as processes that forge new chemical bonds through the extrusion of molecules, such as CO and CO2, and the subsequent recombination of the remaining fragments. Herein, we report on a new UFC reaction that involves the palladium-catalyzed elimination of an isocyanate fragment from an amide, with the formation of carbon-carbon and carbon-heteroatom bonds. An organometallic intermediate that is relevant to the catalytic reaction was characterized by X-ray crystallography. This UFC reaction enables the late-stage transformation of an amide functionality, allowing amides to be used as a convertible directing or protecting group.

Unimolecular Fragment Coupling: A New Bond-Forming Methodology via the Deletion of Atom(s).

Unimolecular fragment coupling (UFC) is defined as a reaction format, wherein atom(s) located in the middle of a molecule are extruded, and the remaining fragments are coupled. UFC is a potentially powerful strategy that is an alternative to transition-metal-catalyzed cross-coupling because the target chemical bond is formed in an intramolecular fashion, which is inherently beneficial for chemoselectivity and stereoselectivity issues. In this Perspective, we will present an overview of the recent advances in UFC reactions, which encompass those proceeding through the elimination of CO2, CO, SO2, isocyanates, N2, or single atoms primarily via transition metal catalysis.

KOtBu-Catalyzed Synthesis of Isoindole Derivatives from N-Benzyl Amides Bearing an Ortho Alkynyl Group via 1,2-Acyl Shift.

In this study, we present the catalytic conversion of benzylamides featuring an ortho alkynyl moiety into 1-acylisoindole derivatives via a 1,2-acyl shift. Remarkably, this transformation proceeds without the need for transition-metal catalysts; instead, KOtBu alone serves as the catalyst. This method enables the efficient synthesis of isoindoles from easily accessible amides with an atom economy of 100%.

Nickel/Photoredox Dual-Catalyzed Conversion of Allyl Esters to Ketones via the Formal Deletion of Oxygen.

We report herein the catalytic conversion of allylic esters into the corresponding ketones by the formal deletion of an oxygen atom. The key to the success of the reaction is the dual use of nickel and photoredox catalysts; the former mediates C-O bond activation and C-C bond formation, while the latter is responsible for deoxygenation of the acyloxy group using PPh3 as a stoichiometric reductant. Catalytic replacement of an oxygen atom of an allyl ester with a tethered alkene is also accomplished.

Nickel-catalyzed direct methylation of arylphosphines via carbon-phosphorus bond cleavage using AlMe3.

We report herein on the nickel-catalyzed methylation of arylphosphines using AlMe3via the cleavage of unactivated C(aryl)-P bonds. This reaction allows for the direct, catalytic substitution of an aryl group on a phosphorus center with a methyl group. This catalytic methylation can proceed, when phosphine oxides and sulfides are used as a substrate.

Aromatic nitrogen scanning by ipso-selective nitrene internalization.

Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3H-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the ipso carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan.