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.

Public Health Relevance

. The aim of this project is to develop new chemical methods that will provide access to chemical motifs commonly found in small-molecule drugs. Specifically, pyridines and diazines are widespread components in therapeutic compounds and our proposed methods will directly transform these heterocycles into molecules of significance interest in medicinal chemistry. The methods will also be simple and practical and amenable to use by scientists in the pharmaceutical and biomedical sciences.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Yang, Jiong
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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Anderson, Ryan G; Jett, Brianna M; McNally, Andrew (2018) Selective formation of heteroaryl thioethers via a phosphonium ion coupling reaction. Tetrahedron 74:3129-3136
Patel, Chirag; Mohnike, Margaret; Hilton, Michael C et al. (2018) A Strategy to Aminate Pyridines, Diazines, and Pharmaceuticals via Heterocyclic Phosphonium Salts. Org Lett 20:2607-2610
Anderson, Ryan G; Jett, Brianna M; McNally, Andrew (2018) A Unified Approach to Couple Aromatic Heteronucleophiles to Azines and Pharmaceuticals. Angew Chem Int Ed Engl 57:12514-12518
Dolewski, Ryan D; Fricke, Patrick J; McNally, Andrew (2018) Site-Selective Switching Strategies to Functionalize Polyazines. J Am Chem Soc 140:8020-8026
Hilton, Michael C; Zhang, Xuan; Boyle, Benjamin T et al. (2018) Heterobiaryl synthesis by contractive C-C coupling via P(V) intermediates. Science 362:799-804