Suzuki-Miyaura mediated biphenyl synthesis: a spotlight on the boronate coupling partner

Baltus, Christine B. (2011) Suzuki-Miyaura mediated biphenyl synthesis: a spotlight on the boronate coupling partner. PhD thesis, University of Greenwich.

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Abstract

The biaryl motif is found in many natural and synthetic products that display a wide range of biological activities. This explains why biphenyls are widely encountered in medicinal chemistry as a privileged scaffold. The palladium-catalysed Suzuki-Miyaura (SM) coupling is one of the most important and efficient strategies for the synthesis of symmetrical and unsymmetrical biaryl compounds; the arylboronic acid or ester is a key partner in this coupling reaction.
This work presents the synthesis of a library of new molecules containing the biphenyl scaffold; o-, m- and p-(bromomethyl)phenylboronic acid pinacol esters, 2a-c, were selected as coupling partners. Nucleophilic substitution of the bromide was carried out with amine, thiol, alcohol or phenol nucleophiles. Supported reagents and microwave assisted organic synthesis conditions were employed to enhance this chemistry and made it amenable to parallel synthesis. The resulting arylboronates were used in SM coupling reactions in order to obtain a range of biphenyls.
The use of Boc-piperazine as a nucleophile in the SN2 reaction, with 2a-c, and 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nitropyridine as aryl halides in the SM coupling reaction, allowed two other points of functionalisation to be added to the biaryl motif.
The conditions for the SM coupling of mercaptomethylphenylboronic esters and orthosubstituted methylphenylboronic esters were optimised in order to broaden the scope of the biaryl library.
Phosphines were found to be good nucleophiles in the SN2 reaction with 2a-c. A Wittig reaction was performed with the resulting phosphonium arylboronates in order to synthesise arylboronic esters containing an alkene function prior the reduction of the resulting double bond of the stilbene derivatives and realising a SM coupling to synthesise arylethylbiphenyls.
The stilbene derivatives were also synthesised by using the olefin cross-metathesis reaction of 4-vinylphenylboronic acid pinacol ester.
A solid state crystallographic study was undertaken on a small library of methylbiphenylamides to compare the crystal structures of isomers or biphenyls with different functional groups.

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