Investigation into the synthetic potential of ethenesulfonyl fluoride via homogenous catalysis.

Abstract

Sulfonyl fluorides are becoming increasingly attractive in both chemistry and biology. Not only does this functional group inhibit several proteins, but several advantages over its Br and Cl counterparts, makes it a useful synthon and “click reagent” for organic synthesis. Despite this, there are very few methods to easily obtain various sulfonyl fluoride derivatives. One particular sulfonyl fluoride containing compound that has received considerable attention in recent literature is ethenesulfonyl fluoride (ESF). This molecule has been used to attach the sulfonyl fluoride moiety onto larger, more complex molecules. Thus, the main objective of this thesis was to investigate some unexplored avenues of the application of ESF in homogenous catalysis in order to easily prepare sulfonyl fluoride derivatives. The transformations and target materials selected would thus be both versatile and indispensable tools for organic synthesis. To achieve this aim, the use of a transition metal catalyzed reaction was first employed. A palladium catalyzed oxidative Heck coupling reaction was developed using ESF as the substrate. After screening various palladium catalysts, oxidants and bases, a mixture of Pd(OAc)2, Cu(OAc)2 and LiOAc resulted in an effective combination that provided the desired products in good yields (up to 80 %) under mild conditions. The generality of this method was demonstrated by the effective reactivity maintained when screened against a diversity of boronic acids. The usefulness of the products generated from this method was demonstrated by the subsequent development of a novel one-pot preparation of β-sultams. These motifs have otherwise remained elusive to organic synthesis emphasizing the importance of this new approach (Chapter 2). The application of the oxidative Heck method was further investigated as a key step in the preparation of Naratriptan, an effective and popular drug for the treatment of migraines. The attachment of ESF onto the desired indole scaffold was successful, however the remaining proposed steps proved to require additional optimization. It was found that when the β-sultam was treated under basic conditions, a novel ring opening reaction of the β-sultam occurred, which resulted in the formation of vinyl sulfonamides. It was concluded that as a future prospect, hydrogenation of the vinyl sulfonamides be carried out prior to the Aldol condensation in the preparation of Naratriptan (Chapter 3). To fully apply the ESF to homogenous catalysis and to obtain more sulfonyl fluoride derivatives, it’s amiability to organocatalysis was also explored. ESF was used as a substrate in a number of Michael reactions in which organocatalysts with various modes of action were applied. It was found that reacting the ESF with methyl 2-oxocyclopentanecarboxylate in the presence of a chiral thiourea catalyst (hydrogen bonding catalysis), showed the best reactivity and yield (96 %). Determining the enantioselectivity of the reaction proved difficult by chiral HPLC, however when the optical rotation was measured, it was found that the reaction was enantioselective (Chapter 4). A crystal of the product was grown and analysed, which confirmed the synthesis of the racemate (Chapter 5). This proved to be the first instance of an organocatalyzed reaction where ESF was used as a substrate. These results have confirmed the hypothesis of using ESF within organocatalysis and has led to new opportunities in the search for new sulfonyl fluoride derivatives.