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

Abstract

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.

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

“…A potential solution is the coupling of a carboxylic acid ester with an amine-derived (via N -alkyl pyridinium salts) or alcohol-derived (via alkyl halide) alkyl radical source under nickel-catalyzed conditions (Scheme C) . Cross-electrophile coupling reactions of aryl halides with various alkyl radicals to form C­(sp 2 )–C­(sp 3 ) bonds have the broad generality needed, but the use of aryl carboxylic acid esters under these conditions has been demonstrated to make ketone products, not alkylated arenes (Scheme A) .…”

Palladium-Catalyzed Unimolecular Fragment Coupling of N-Allylamides Bearing a Tethered Nucleophile with the Translocation of an Amide Group

“…Our laboratory recently reported the palladium-catalyzed unimolecular fragment coupling (UFC) of amides, in which an amide moiety is deleted from the substrate (Scheme 1b , top). 6e In this reaction, an amide group is eliminated in the form of an isocyanate. In our preliminary study, we also found that when amide substrates bearing an unprotected alcohol group are used, the eliminated isocyanate is trapped by the alcohol moiety (Scheme 1b , bottom).…”

“…In our previous deisocyanative UFC, the trimerization of the eliminated isocyanate to form a stable cyclic trimer (i.e., isocyanurate) serves as one of the driving forces for this reaction. 6e In contrast, in this migratory UFC, the eliminated isocyanate is captured by a tethered nucleophile before it trimerizes. To obtain insights into the thermodynamics of these processes, the free energies of starting thiocarbamate 1a , UFC product 7 , isocyanate 8 , cyclic trimer 9 , and migratory UFC product 2a were estimated by DFT calculations (Figure 1 ).…”

“…Compounds 1a , 1f , and 1g were prepared according to a previously reported procedure. 6e See the Supporting Information (SI) for details.…”

“…In our previous investigation related to the palladium-catalyzed UFC of amides, 6e we found that when an N -allyl­thiocarbamate bearing a primary alcohol group (e.g., 1a ) is used as a substrate, the eliminated isocyanate is trapped by the hydroxy group, resulting in the formation of the carbamate product 2a in 68% yield (Scheme 2 ).…”