Photocatalytic Strategies for the Functionalization of Pyridines

Pyridines and other azaarenes are ubiquitous in pharmaceuticals, with pyridine being the most frequent moiety within all nitrogen-containing heterocycles in FDA approved drugs. The discovery and development of new drugs relies heavily on chemists’ ability to modify/diversify these commonly occurring structures. Developing new catalytic pyridine functionalization processes which expand upon known methodologies and overcome current limitations is of extreme value.

In the first project, we developed a switchable photocatalytic system that granted access to C4 and C2 benzylated cyanopyridines. The two processes used the same reaction conditions and photoredox catalysts, and differed only in the nature of the photochemical quencher which allowed us to select at will between mechanistically divergent processes. The two reaction manifolds, an ipso-substitution path proceeding via radical coupling and a Minisci-type addition, enabled selective access to regioisomeric C4 or C2 benzylated pyridines, respectively.

In a second project, we devised a new photocatalytic procedure for the C-H allylation of pyridines. This method overcame several of the current methodologies’ limitations, including the need for the prefunctionalization of the pyridine substrates. The method allows the functionalization of pyridines with radicals derived from allylic C-H bonds. Overall, two substrates undergo C-H functionalization to form a new C(sp²)-C(sp³) bond. A dithiophosphoric acid organocatalyst was crucial to master three catalytic functions, sequentially acting as: i) a Brønsted acid, ii) a single electron reductant, and iii) a hydrogen atom abstractor for the activation of allylic C-H bonds. The resulting pyridinyl and allylic radicals then couple with high regioselectivity.

Taken together, these methodologies offer new strategies for the selective functionalization of pyridines and have been successfully applied for the late-stage diversification of valuable molecules, including marketed drugs. These strategies require mild operational conditions and simple visible light illumination; thus, they have the potential to be quickly adopted by chemists.

If you would like to follow the ceremony on Zoom, please register here.