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

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dc.contributor.authorAnderson, Ryan Gerald, author
dc.contributor.authorMcNally, Andrew, advisor
dc.contributor.authorPaton, Robert S., committee member
dc.contributor.authorChatterjee, Delphi, committee member
dc.date.accessioned2019-01-07T17:19:08Z
dc.date.available2019-01-07T17:19:08Z
dc.date.issued2018
dc.description.abstractNitrogen 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.
dc.format.mediumborn digital
dc.format.mediummasters theses
dc.identifierAnderson_colostate_0053N_15124.pdf
dc.identifier.urihttps://hdl.handle.net/10217/193102
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.subjectkinase inhibitors
dc.subjectpyridines
dc.subjectphosphonium salts
dc.subjectheteroatom coupling
dc.titleSelective functionalization of pyridines and diazines via nucleophilic addition to heterocyclic phosphonium salts
dc.typeText
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineChemistry
thesis.degree.grantorColorado State University
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (M.S.)

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