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Selective functionalization of pyridines and diazines via nucleophilic addition to heterocyclic phosphonium salts




Anderson, Ryan Gerald, author
McNally, Andrew, advisor
Paton, Robert S., committee member
Chatterjee, Delphi, committee member

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Nitrogen heterocycles, specifically pyridines and pyrimidines, are common motifs found in pharmaceuticals, agrochemicals and materials. Site-selective functionalization of these azines are highly sought after for medicinal chemistry purposes. It has previously been found in our lab that heterocyclic phosphonium salts can potentially serve as a useful functional handle to selectively functionalize these valuable scaffolds. This work describes the utility of heterocyclic phosphonium salts as electrophiles to selectively form C-O, C-S, C-N and C-Se bonds in a diverse range of pyridines and diazines. First, the addition of thiolate nucleophiles to heterocyclic phosphonium salts to selectively form heteroaryl thioethers is described. This coupling reaction proceeds through deprotonation of the alkyl thiol followed by addition of the heterocyclic phosphonium salt under mild conditions. The reaction scope was tested for a variety of alkyl thiol nucleophiles as well as different pyridine phosphonium salts. The extent of the method's utility was demonstrated through late-stage functionalization of some complex pharmaceuticals. Additionally, initial results on the reactivity of sulfinate nucleophiles with heterocyclic phosphonium salts is communicated. Second, aromatic heteronucleophiles were explored for reactivity with heterocyclic phosphonium salts. Aromatic heteronucleophiles can be classified as either exocyclic or endocyclic. Exocyclic aromatic heteronucleophiles, such as phenols, thiophenols and anilines, were able to be selectively coupled to azines and pharmaceuticals. Endocyclic aromatic heteronucleophiles, such as pyrroles, pyrazoles and imidazoles, also proved to be compatible. All these nucleophiles were able to be coupled to complex drug-like fragments as well as other bioactive molecules via the phosphonium ion. The method also enabled a convergent coupling reaction between two elaborate coupling partners to form a novel tyrosine kinase inhibitor that would be difficult to access using conventional methods.


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kinase inhibitors
phosphonium salts
heteroatom coupling


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