Reported herein is an investigation into palladium-catalysed -allylation employing sulfonamide nucleophiles. Anions of benzylsulfonamides have been shown to react with a series of allyl acetates in the presence of Pd0 catalysts, phosphine ligands and base at room temperature, enabling the synthesis of sp3-functionalised sulfonamides. The developed methodology has allowed access to a library of novel allylated sulfonamides, varying both amine substituent and allylic functionality. In addition, we have applied our methodology to a series of known sulfonamide drug targets, to demonstrate our reaction as a useful late-stage functionalisation tool, whilst populating chemical space. The performed mechanistic study using a stereospecific electrophile confirms benzylsulfonamides behave as soft carbon nucleophiles in the Tsuji-Trost reaction, as a ‘net retention’ of stereochemistry is observed (confirmed by X-ray crystallography). Moreover, the asymmetric synthesis of allylated sulfonamides is probed, although obtaining enantioselectivity a- to SO bonds is naturally difficult, due to the conformational preferences of sulfonamide carbanions. Traditional methods for direct -alkylation of sulfonamides require strong bases, reactive electrophiles, low temperatures and use of stoichiometric amounts of additives. Therefore, in addition to a catalytic method, we report an alternative method reacting benzylsulfonamides with allyl bromide electrophiles via a nucleophilic substitution reaction, using mild conditions (LDA, THF at –20 °C).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:732914 |
| Date | January 2017 |
| Creators | Walton, Scarlett Maria |
| Contributors | Sweeney, Joe ; Gill, Duncan |
| Publisher | University of Huddersfield |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.hud.ac.uk/id/eprint/34344/ |
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