A New General Strategy for Pyridine Functionalization via Dearomatized Intermediates

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Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, an unsurprising fact because of their propensity for hydrogen bonding and suite of valuable physiochemical properties such as aqueous solubility, net polarity, and resistance to oxidative metabolism. Synthetic methods to directly and selectively functionalize pyridines are critical in drug discovery efforts because drug-developers require variation in positional selectivity, various carbon- and heteroatom bearing groups on the scaffold a wide variance in their steric and electronic properties. However, general approaches to transform pyridine C–H bonds into valuable derivatives are lacking. In this proposal, we outline a dearomatization strategy by converting pyridines into Zincke imine and iminium adducts. In effect, these adducts make pyridines react like a series of alkenes rather than an aromatic system and thus open up the plethora of reactions associated with olefins that were previously ineffective on pyridines themselves. We will show that pyridines can now participate in numerous processes, such as halogenation, reaction with sp2-carbon electrophiles radical reactions that were either not viable or operated under extreme reaction conditions. The processes will occur with exclusive control of regioselectivity for the 3-position of Zincke intermediates and are also switchable to the 5-position based on the Zincke adduct's structure. The ring-opening-functionalization-ring-closing is sequencable into one-pot processes in many cases. We will also use the Zincke platform to access pyridine isotopologs for ADME studies and new methods to form N–oxides. We plan to employ this strategy for simple building block pyridines, drug-like intermediates and for late-stage functionalization of complex pyridine-containing drugs.