Metal-Catalysed Electrophilic Ring Closing Strategies to Organic Heterocycles

Oxygen and nitrogen heterocycles are well-known classes of compounds due to their excellent biological activity. Halogenated compounds are very useful synthetic intermediates and can function as suitable building blocks for pharmaceutical products. Thus, halocyclisation reactions to deliver fluorine and iodine into oxygen and nitrogen heterocycles have been investigated using electrophilic reagents N-fluorobenzensulfonimide and iodine with alkyne-containing tertiary alcohol substrates and alkyne-containing amides.

Chapter 2 describes the synthesis and characterisation of a series of alkyne-containing tertiary alcohol substrates that have been targeted as starting materials to allow an investigation of iodocyclisation/fluorocyclisation reactions in order to generate cyclised products. Complications caused by protocyclisation reactions to give undesired dihydroisobenzofuran products have been overcome by using the different reaction sequences. In Chapter 3, a new fluorocyclisation methodology for Ag-catalysed electrophilic fluorination of alkynes to give monofluorinated or difluorinated dihydroisobenzofuran products has been designed, including avenues for regiospecific control to expand both the utility and substrate scope of the reaction. Chapter 4 shows divergent behaviour in the iodocyclisation reactions of the same alkyne substrates in different solvents where different regioselectivity for the (E)/(Z) 5-exo-dig product has been demonstrated. This regioselectivity depends on the functional groups present and the reaction conditions. Finally, Chapter 5 describes the synthesis of terminal alkynes containing benzyl or aryl amides which have been prepared in excellent yields. The amide groups have been used as internal nucleophiles for iodocyclisation reactions using the methods outlined in Chapter 4. It was found that the aryl amide (5.62e) gave oxygen-heterocyclic product mixtures in both CH2Cl2 and MeCN solvents. However, the benzyl amides (5.62a,b) gave oxygen-heterocycles in MeCN and nitrogen-heterocycles in DCM. It is presumed that the relative nucleophilicities of the oxygen and nitrogen centres in these amides are influenced by both the electronic influence of the N-substituent and interactions with the solvent.