Development of new classes of aza-Heck cyclisation for the synthesis of nitrogen heterocycles

  • Ian Hazelden

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Two novel classes of aza-Heck reactions have been developed. These processes generate 2-alkenyl-N-heterocycles through the palladium-catalysed cyclisation of substrates containing an activated N–O bond and a pendant olefin. The first of these, based on the cyclisation of N-acyloxysulfonamides, is only the second reported class of aza-Heck reaction and is effective for the synthesis of complex bicyclic N-heterocycles commonly found in the core structures of natural products. Subsequently, an aza-Heck reaction of N-acyloxycarbamates was developed that provides considerable improvements in terms of efficiency compared to the sulfonamide-based reaction. Through the cyclisation of N-acyloxycarbamates, pyrrolidines and piperidines, as well as related 5- and 6-membered N-heterocycles, can be prepared in good to excellent yields. Furthermore, the diastereoselectivities achieved in these processes are generally much greater than those observed with aza-Heck cyclisations of N-acyloxysulfonamides. A number of mechanistic experiments have validated the aza-Heck pathway proposed for these transformations.
A highly asymmetric variant of the aza-Heck reaction was also developed, based on the cyclisation of N-sulfonyloxycarbamates. Through the use of SPINOL-based phosphoramidite ligands, pyrrolidines and piperidines can be prepared in good yields and with high enantioselectivities from substrates containing a diverse range of alkenes.
Additionally, palladium(0)-catalysed cascade reactions using the previously developed N–O bond donors have been demonstrated. These processes initiate with N–O oxidative addition and aminopalladation of a pendant alkene but terminate with trapping of the resulting organopalladium(II) intermediate, as opposed to -hydride elimination. In collaboration with co-workers, a variety of alkene 1,2-aminofunctionalisation cascades have been achieved using this strategy. The application of these cascade reactions to the total synthesis of natural products has also been attempted.
Date of Award23 Jan 2019
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorJohn Bower (Supervisor)

Cite this

'