Site-Selective Functionalization of Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with Quinolinone

The
selective installation of phosphinoyl and carbamoyl moieties
on the pyridine scaffold is an important transformation in synthetic
and medicinal chemistry. By employing quinolinone as an efficient
organic photocatalyst, we developed a catalytic system driven by visible
light that forms phosphinoyl and carbamoyl radicals, which react with
various heteroarenium derivatives under mild, transition-metal-free
conditions. This straightforward and environmentally friendly synthetic
method represents a new approach to site-divergent pyridine functionalization
that offers considerable advantages in both simplicity and efficiency.
Ambient temperature is sufficient for the formation of the reactive
radicals, and the site-selectivity can be switched from C2 to C4 by
changing the radical coupling sources. Under standard reaction conditions,
phosphinoyl radicals give access to C4 products, while carbamoyl radicals
selectively give C2 products. We found that the carbamoyl radical
overcomes the intrinsic preference for forming the ortho-product by
allowing the oxo functionality of the carbamoyl radical to electrostatically
engage the nitrogen of the pyridinium substrate, which preferentially
gives the ortho-product. The phosphinoyl radical cannot engage in
the same interaction, because the phosphorus is too large. This novel
synthetic route tolerates a broad range of substrates and provides
a convenient and powerful synthetic tool for accessing the core structures
of numerous privileged scaffolds.