Pyridine Synthesis via Directed Aziridination of Phenols in Continuous Flow

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

Project Summary/Abstract The pyridine heterocycle is a privileged motif that appears in countless natural products, drugs, and materials. As the most prevalent heterocyclic aromatic ring in chemical therapeutics, the pyridine motif is featured in a plethora of blockbuster drugs such as Xalkori, Prilosec, and Zytiga. Due to the enormous prevalence of pyridines in human life, new and innovative methodologies to access this motif remain highly sought after. Numerous preparative methods require specialized starting materials and also necessitate strictly defined substitution patterns, which limit structural diversity. Conversely, transforming readily available and inexpensive precursors, that have all substitution intact, directly to the pyridine scaffold would constitute a simple, flexible, and powerful means to access these frameworks. The proposed research aims to develop a directed aziridination methodology in a continuous flow reactor that would allow access to pyridines from readily available phenol starting materials. This transformation has been historically challenging because of the nonregioselective aziridination of the arene ring with nitrene sources, which leads to complex mixtures of products. This powerful new strategy will rely on a directed aziridination to provide regioselectivity in the event. Continuous flow techniques will prove critical to this key transformation in order to avoid various undesired reaction pathways by means that are unparalleled in standard batch synthesis. Finally, a ring contraction process would then furnish libraries of highly valued pyridines in a multi-step, one-flow approach.