Aobha Hickey

The quinoline nucleus occurs in many natural and synthetic pharmacologically active compounds, and is ranked 22^nd in the top 100 most frequently used ring systems present in FDA approved drugs. Thus, the quinoline motif is considered a privileged biological scaffold, utilised by synthetic chemists to build molecular complexity, and ultimately improve biological activity. As a versatile heterocycle, it displays reactivity similar to that of other aromatic (inter alia pyridine) analogues, and thus can undergo a wide range of synthetic transformations, in addition to acting as a ligand for transition metal-catalysed reactions.

Our laboratory recently reported a palladium‐catalysed, phosphine‐free, direct arylation of 4‐phenoxyquinolines, in air resulting in the synthesis of a range of benzofuroquinolines. Subsequent mechanistic investigations involving ¹H-¹⁵N HMBC spectroscopy led us to propose that the quinoline moiety present in the starting material may be acting as a ligand for this transformation.

Through careful optimisation, 6-methoxyquinoline, a relatively inexpensive and stable ligand, was found to catalyse the intramolecular direct arylation of diaryl ethers, furnishing a range of dibenzofurans under much milder conditions than those previously reported, using air as an oxidant. The synthesis of dibenzofurans through a direct arylation approach has received little attention in the literature. Typically, forcing conditions are required to achieve appreciable yields of the dibenzofuran products and consequently they have proven to be a challenging synthetic target in this space. Applications of the chemistry described herein include the concise preparation of analogues of the naturally occurring dibenzofuran, Ruscodibenzofuran, and the synthesis of novel fluorescent quinoline molecules.

References:

Shanahan, R. M.; Hickey, A.; McGlacken, G. Eur. J. Org. Chem. 2018, 44, 6140-6149