Synthesis of fluorinated heterocycles by electrophilic cyclisations of alkynes

• Main Author: He, Jinglei
• Format: Dissertation
• Language: English
• Published: University of Leicester 2016

Fluorinated heterocyclic compounds are a highly desirable target for the pharmaceutical industry because heterocyclic compounds often form the core structure in drug candidate molecules and the incorporation of fluorine often enhances their biological activity. The aim of this project was to design new and efficient procedures to fluorinated heterocycles using aromatic alkynes containing internal nucleophiles. In Chapter 2 a series of known and new alkynes were synthesised by Sonagashira reactions of terminal alkynes with aryl iodides and the reactivity of these alkynes with electrophilic fluorinating reagents was studied. The alkynes were reacted with Selectfluor to generate difluorinated ketones and a diketone byproduct was also produced in some of the reactions. The introduction of an ortho-substituent (-NO2, -CH2OH, -CHO, -CH2OAc) on the aryl rings had a significant impact on these reactions and, in most cases, no difluoroketone products could be isolated. In Chapter 3 iodocyclisations of the alkynes with internal nucleophiles were studied as the model reactions for electrophilic cyclisation. When Py2I+BF4- was used as the electrophilic iodinating reagent, 6-membered rings were normally obtained. However, when iodine was used as the electrophilic iodinating reagent, either 6- or 5-membered rings could be obtained as the main products depending on the internal nucleophile. For example, the fluoroalkylated secondary alcohols underwent 6-endo-dig cyclisations with Py2I+BF4-, whilst the reaction of the same substrate with iodine gave predominately the (E) 5-exo-dig iodocyclised products. Palladium-catalysed protocyclisations with a range of aromatic alkyne substrates, including secondary and tertiary alcohols, carboxylic acid and secondary amine, are described in Chapter 4. A new fluorocyclisation for tertiary alcohols using N-fluorobenzenesulfonimide and silver nitrate was developed successfully and three different types of fluorinated products (monofluorinated alcohol, difluorinated alcohol and monofluorinated alkene) were obtained depending upon the tertiary alcohol and the amount of N-fluorobenzenesulfonimide.