Selective Functionalization of Pyridines and Diazines via Heterocyclic Phosphonium Salts

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Project Abstract. The aim of this proposal is to develop a general process to functionalize pyridines and diazines so that biologically active molecules can be accessed in an accelerated fashion. Pyridines are the second most common nitrogen heterocycle observed in FDA approved drugs and related diazines (pyrimidines, pyrazines and pyridazines) are also widely found. Traditional methods to functionalize these heterocycles are limited by functional group tolerance, poor regiocontrol and lack of applicability to complex substrates. Our strategy to functionalize these heterocycles will install a versatile functional group that enables a number of subsequent bond-forming reactions. Specifically, we will transform pyridines and diazines into phosphonium salts and use the unique reactivity of the phosphonium ion to make medicinally relevant derivatives. The 4-selective reaction to make phosphonium salts will use common reagents, be trivial to perform and have a broad substrate scope. We also propose to use this approach for late-stage functionalization of pharmaceuticals. Transforming phosphonium salts into important pyridine and diazine derivatives will occur through distinct mechanistic pathways. Direct reactions with nucleophiles will form C–C, C–O, C–S, C–N, and C–Hal bonds that occur via SNAr processes or ligand coupling at the phosphorus center. Metal-catalyzed cross-coupling, using nickel and cobalt catalysts, will be exploited for arylation and alkylation reactions. Base-mediated fragmentation reactions form heteroaryl anions that will be used to install deuterium and tritium isotopes and form organometallics. A conceptually new approach to make important bis-heterobiaryls will be developed base on phosphorus ligand coupling processes. Collectively, this program will provide rapid access to pyridine and diazine derivatives that have multiple applications in the pharmaceutical sciences. The long-term objective is for these methods to be used as routine tools by medicinal chemists.