New Chemical Process to Selectively Functionalize Pyridines, Diazines and Pharmaceuticals

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Project Abstract. The goal of this project is to introduce a new synthetic strategy to functionalize pyridine and diazine heterocycles. Pyridines are the second most common nitrogen heterocycle found in FDA approved drugs, and there are numerous examples of diazines in these structures. The widespread occurrence arises because of a combined effect of the heterocycle and its substituents. The key drug-receptor interaction is often comprised of a hydrogen bond between the heterocycles N-lone pairs and the biological target. These heterocycles are also polar, can engage in p-stacking interactions and are resistant to oxidative metabolism. The substituents enable tuning of the steric and electronic environment of the heterocycle as well as serving as additional binding sites. As such, medicinal chemists require chemical process that can directly and selectively install a range of substituents at various stages of drug discovery from C–H precursors. In this proposal we will develop three different approaches for azine functionalization. First, we will install heterocyclic phosphonium salts and exploit their unique reactivity to develop coupling reactions with amines, thiophenols, cysteine containing molecules and alkynes. Using phosphines with pendant functional groups will enable coupling with water and ammonia. Second, direct coupling reactions between NTf-pyridinium salts and nucleophiles will be exploited for C–Heteroatom bond formation. additionsThis platform will enable direct coupling with aliphatic amines, anilines, amides and sulfonamides. Third, we will use sulfur nucleophile to change the regioselectivity of nucleophilic addition from the 4-position of pyridines to the 2-position of the scaffold. Once embedded in the substrate, these sulfur nucleophiles also serve as versatile functional group the enable other transformations to make C–N, C–O and C–F bonds.