The Development of Pd(II)-Catalysed C–H Activation Cascades for the Synthesis of Polyheterocycles

Abstract

A novel Pd(II)-catalysed C–H activation/aza-Wacker cascade sequence has been optimised for indoles bearing an N-tethered alkene and an N-acyl mesylamide group that serves dual purpose as a directing group and a C–N bond precursor. This optimisation was achieved by a combination of Design of Experiments and traditional reactant screening. The reaction is tolerant to functionalisation on the alkene and tether, as well as substitution at various positions around the indole ring. The methodology can also be applied to pyrrole systems. 24 successful examples of this Pd(II)-catalysed C–H activation methodology are described.

A number of studies have been carried out in order to probe the mechanism of this cascade sequence. As a result of this an oxidative Heck/aza-Wacker mechanism beginning with amide deprotonation can be proposed.
The application of this methodology to non-aromatic substrates, with a view to this being used as a potential key step towards the total synthesis of naturally occurring alkaloids and potential drug discovery scaffolds, was examined. The synthesis of the substrate necessary for the total synthesis of the alkaloid matrine was unsuccessful, so the Pd(II)-catalysed C–H activation of enamine test substrates were instead investigated. These substrates were found to be unsuitable for Pd(II)-catalysed C–H activation due to a lack of aromaticity and a lack of electron density.

Proof of concept for the oxidative Heck/aza-Wacker cascade cyclisation of aniline-derived substrates is also described.

Date of Award	24 Mar 2020
Original language	English
Awarding Institution	University of Bristol
Supervisor	Kevin Booker-Milburn (Supervisor)