Carbon–nitrogen bonds are important linkages that are widespread throughout natural products, organic intermediates and pharmaceuticals and thus their formation has been an active area of research for over 100 years. Typical reaction conditions feature inorganic bases; however, they lead to a variety of issues, such as problems with reproducibility and the need for higher temperatures, increased catalyst loading, or phase-transfer agents. Looking to address some of these concerns and expand the currently limited use of organic bases, Stephen Buchwald and co-workers (J. Am. Chem. Soc. https://doi.org/cm35; 2018) from the Massachusetts Institute of Technology have developed conditions that use 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base for C–N cross-coupling (pictured, top).
The newly developed conditions — featuring an air-stable palladium pre-catalyst COD(AlPhos-Pd)2 — have been shown to work well for a variety of coupling partners, giving high yields even for base-sensitive substrates that are troublesome to couple under previously studied conditions. Fluoroalkylamines, for example, have been reported to undergo base-promoted decomposition, but this is not the case when coupled using DBU at room temperature (pictured, bottom). Coupling substrates with alkyl halides has also been shown to work well, allowing the C–N coupled product to undergo further synthetic expansion.
In addition to scope, Buchwald and co-workers also investigated the catalytic palladium complex, looking at how ligand size affects the electrophilicity of the palladium atom, and how this in turn affects the base strength required for efficient coupling; this enabled them to explain why AlPhos works well as a ligand in this system. They measured the magnitude of the trans phosphorus–nitrogen coupling constants in several amine-bound palladium complexes featuring ligands of varying size, and out of the ligands investigated, AlPhos led to the smallest coupling constant. This indicates that the complex featuring AlPhos has the most cationic palladium atom and therefore generates a bound amine that is more easily deprotonated — thus leading to efficient coupling even with a weak organic amine base such as DBU.
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Geogheghan, K. All about that base. Nature Chem 10, 487 (2018). https://doi.org/10.1038/s41557-018-0057-0