Polyfunctionalised pyrimidines and pyrazines from perhalogenated precursors

Abstract

Chapter 1 introduces the modem pharmaceutical industry in terms of the drug discovery process leading into a discussion of the relevance of heterocyclic compounds with particular focus on the synthesis of multifunctional pyrimidines and pyrazines. An introduction into organofluorine chemistry is included followed by a review of the literature on 5-chloro-trifluoropyrimidine, tetrafluoropyrimidine and tetrafluoropyrazine. Chapter 2 describes a study of the reactivity of 5-chlorotrifluoropyrimidine with mono- and difunctional-nucleophiles. This research demonstrates the former are not selective and in the latter the 5-position chlorine atom is inert to nucleophilic aromatic substitution and cross-coupling methodologies. Chapter 3 explores the reactivity of tetrafluoropyrimidine with nitrogen, sulphur and oxygen containing nucleophiles and describes the development of a methodology for the synthesis of multisubstituted pyrimidines by establishing the regioselectivities of such processes. Chapter 4 investigates the reactivity of tetrafluoropyrimidine with difunctional nucleophiles. This study indicated it was not possible to synthesise [5,6]-ring fused systems and that in some cases dimers were formed owing to the 5-position fluorine atom being inactive substitution. Chapter 5 discusses the use of tetrafluoropyrazine in the syntheses of [5,6] ring-fused systems. The reactivity of the system towards MiV-dinucleophiles and C,0-dinucleophiles was investigated. Further functionalisations by nucleophilic aromatic substitution of the remaining fluorine atoms with nitrogen and oxygen nucleophiles are also discussed. Chapter 6 contains the experimental data for Chapters 2 to 5.