Selectivity of Aryl and Benzylic Bromination

Ferguson, Douglas (1997) Selectivity of Aryl and Benzylic Bromination. PhD thesis, University of Glasgow.

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Bromination has historically been an important organic transformation. The organic bromides produced are extremely useful as intermediates in synthetic pathways and are utilised widely throughout synthesis for a variety of purposes. Organic bromides are also becoming increasingly important as the end products of synthesis as the field of organohalogen natural products expands and more of these compounds are shown to exhibit potentially useful biological activities. During this research the selectivity of bromination in a variety of aromatic systems was studied. The aim being to build up an understanding of the factors involved such that we would be better able to predict and manipulate the selectivity of bromination. Initial studies centred upon the aryl bromination of anisoles. The aryl bromination of methyl 3,5-dimethoxybenzoate and 3,5-dimethoxytoluene was extensively studied. Conditions were found whereby all the aryl brominated derivatives could be obtained selectively in good yield. For 3,5-dimethoxytoluene (i) these conditions are summarised in the diagram below. [Diagram removed] These results along with those obtained for the bromination of a range of other anisoles, including 3,5-dimethyl anisole (ii) and 6-methoxy-4-methyl-2,3-dihydrobenzofuran (iii), indicate that the most important factors in determining the selectivity of bromination for this type of compound are steric inhibition of resonance hindering bromination ortho to methoxy groups and whether the conditions used and reactivity of the substrate are such that a product distribution that is kinetic or thermodynamic in nature results. [Diagram removed] Another area of research centred upon the bromination steps involved in the synthetic pathway to ZD9331, a potential drug substance currently being developed by Zeneca Pharmaceuticals. In particular, the benzylic bromination of 2,6,7-trimethyl-N3-pivaloyloxymethylquinazolinone (iv) was studied extensively. [Diagram removed] It was demonstrated that the use of more selective benzylic bromination conditions, namely a photo-initiated reaction with NBS in dichloromethane, rather than reaction with NBS in chlorobenzene initiated by the thermal decomposition of AIBN, resulted in an improvement from 47% to 80% in the obtained yield of the desired product, 6-bromomethyl-2,7-dimethyl-N(3)-pivaloyloxymethylquinazolinone (v). The C2-methyl group of quinazolinone (iv) was identified as being brominated via an ionic, rather than radical, route and this, combined with the selective C6-methyl group bromination methodology, allowed a range of brominated derivatives of qainazolinone (iv) to be prepared which aided the identification and quantitation of the brominated side products produced by the bromination of quinazolinone (iv) under various conditions.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: R A Hill
Keywords: Organic chemistry
Date of Award: 1997
Depositing User: Enlighten Team
Unique ID: glathesis:1997-75859
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 17:42
Last Modified: 19 Nov 2019 17:42

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