2-Methyltetrahydrofuran (2-MeTHF): A Green Solvent for Pd-NHC-Catalyzed Amide and Ester Suzuki-Miyaura Cross-Coupling by N-C/O-C Cleavage

The palladium-NHC-catalyzed (NHC=N-heterocyclic carbene) Suzuki-Miyaura cross-coupling of amides and esters via highly chemoselective N-C(O) and O-C(O) cleavage with aryl boronic acids using green, sustainable and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) is reported. A variety of amides and aryl esters were coupled with aryl boronic acids in high to excellent yields. This method employs commercially-available, air- and moisture-stable Pd(II) -NHC precatalysts. Crucially, the use of 2-MeTHF leads to the highest TON reported to date in amide N-C(O) bond cross-coupling. This operationally-simple protocol was utilized in the synthesis a bioactive ketone intermediate, emphasizing the potential of 2-MeTHF as a green solvent in unconventional amide bond disconnection. Given the tremendous importance of amide bond cross-coupling strategies and the drive to maintain full sustainability in cross-coupling processes, we expect that the synthetic method will be of broad interest.