Challenging cross couplings in micellar media

Pyridines are among the most common heterocyclic motifs in medicinal chemistry, with substitution at the 2-position being the most abundant. However, methods to access 2-aryl pyridines are severely limited by the instability and difficulty of synthesis of 2-pyridyl boronic acids and related organometallics. Synthesis of drug candidates containing this motif thus relies on either (1) acceptance that yields will be poor, to the detriment of process sustainability, or (2) use of the pyridyl fragment as the electrophile, which inherently limits the flexibility of viable synthesis strategies, and which may require costly and wasteful route redevelopment.

Attempts to address the poor stability of 2-pyridyl boron reagents by using stoichiometric amounts of a copper salt have met with some limited success, but at the expense of atom efficiency and environmental impact. In contrast, while the cross coupling of 2-pyridylstannanes is general, complications around the use of organotin reagents including their toxicity and difficulty of separation have limited recent investigations into cross coupling of 2-pyridylstannane nucleophiles.

A general and robust approach to the cross coupling of 2-pyridyl organometallics would therefore enable the efficient synthesis of drug candidates, reducing waste and accelerating the development of new medicines