Senior, Aaron James
(2022)
Bismuth(V) mediated meta-arylation.
PhD thesis, University of Nottingham.
Abstract
Despite offering many options for functionalisation, unattractive synthetic routes have left 2,4-cyclohexadienones relatively unexplored. Reported methods to make these substrates are marred by poor regio- and chemoselectivity, toxic reagents, and inefficient processes. The work detailed in this thesis aims to remove barriers to implementation by presenting a synthetic method for their preparation that is selective and predictive, uses benign reagents, and offers excellent yields. To showcase their applicability in synthetic organic chemistry, they will be used as intermediates in the synthesis of meta-substituted phenols and anilines.
A three-step process was developed to access the elusive meta-position of phenols and is described in Chapter 2. Here, a straightforward procedure was developed to access a 6,6-disubstituted 2,4-cyclohexadienone from a single, universal bismuth precursor and a phenol. Following the isolation and full characterisation of the 2,4-cyclohexadienone, a Lewis acid mediated 1,2-aryl migration was optimised to provide the meta-arylated phenol.
An extensive substrate scope showed that this methodology is applicable to phenols and arylboronic acids bearing a range of electronic descriptors and is permitting of highly functionalised handles poised for subsequent diversification chemistry. In addition to this, the selectivity of the arylation step was assessed and found to be influenced more by electronics than sterics, occurring ipso to the most
electron rich position. A comprehensive mechanistic study was undertaken on the 1,2-aryl migration step: passing through a phenonium ion intermediate. Using this
chemistry to access meta-substituted phenols, analogues of mexiletine, lidocaine, and dimethachlor were synthesised in excellent yield to showcase how this chemistry can be applied to the targeted synthesis of important biologically active molecules.
Chapter 3 builds on this work, developing a route to meta-arylated anilines. Using Bi(V) mediated synthesis of 2,4-cyclohexadienones developed in Chapter 2, a deoxyamination reaction step was implemented to deliver a 2,4-cyclohexadienimine. This was found to be competent in a similar 1,2-aryl migration step, yielding the meta-arylated aniline. This method not only describes a means to access these contra-electronic products, but also a formal phenol to aniline conversion – a highly sought-after transformation.
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