Arylated pyridines: Suzuki reactions of O-substituted
2,6-dihalogenated-3-hydroxypyridines
Glen M. Chapman,a Stephen P. Stanforth,*a Brian Tarbitb and Michael D. Watsona
1
a School of Applied and Molecular Sciences, University of Northumbria, Newcastle upon Tyne,
UK NE1 8ST. E-mail: steven.stanforth@unn.ac.uk
b Seal Sands Chemicals Ltd., Seal Sands Road, Seal Sands, Middlesbrough, UK TS2 1UB
Received (in Cambridge, UK) 21st December 2001, Accepted 24th January 2002
First published as an Advance Article on the web 1st February 2002
2-Bromo-6-iodo-3-methoxypyridine 5b yielded mono-
arylated derivatives 6b–9b and teraryls 10b–14b in selective
Suzuki reactions.
Pd(PPh3)4 catalysed Suzuki reactions of compounds 1d and 1e
with phenylboronic acid in a mixture of boiling dimethoxy-
ethane and 2 M sodium carbonate solution, loss of the
O-substituent was observed. Mono-phenylation reactions of
1b,c and f were also disappointing and a complex mixture
of products was always obtained (by proton NMR spec-
troscopy). For example, the mixture obtained from the
Suzuki reaction of compound 1b with one mol equivalent of
phenylboronic acid showed four methoxy signals attributed to
unreacted starting material 1b, diphenylated product 4 and pre-
sumably both regioisomers 2 and 3 of mono-phenylated
material. An authentic sample of the diphenylated compound 4
(73% yield, mp 76–78 ЊC) was readily prepared from compound
1b using an excess of phenylboronic acid.
We next turned our attention to the chemoselective
mono-arylation reactions of O-substituted 2-bromo-3-hydroxy-
6-iodopyridine derivatives 5b and 5c. These compounds were
prepared by iodination of 2-bromo-3-hydroxypyridine8 giving
compound 5a followed by either O-methylation yielding com-
pound 5b (mp 99–100 ЊC) or O-benzylation yielding compound
5c (mp 81–82 ЊC). In the mono-arylation reactions of com-
pounds 5b and 5c with a series of boronic acids (Scheme 2)
Aryl-substituted pyridine derivatives have recently attracted
considerable synthetic attention in natural product chemistry,
materials chemistry and other areas. The macrocycles Nosi-
heptide1 and Promothiocin A2 are both tri-arylated pyrid-
ine derivatives bearing three pendant thiazole substituents
and these compounds are representative examples from the
natural product arena whereas poly(thienopyridines) and
related compounds3 are well known examples from the
materials chemistry field. Bryce and co-workers have recently
reported the synthesis of a range of 2-aryl-3-hydroxypyridine
derivatives from furan precursors.4 In view of the current
general interest in arylated pyridine derivatives,5–7 we have been
interested in exploring methods for preparing these types of
heterocycle from commercially available and inexpensive
3-hydroxypyridine.
Our preliminary investigations focused on the O-substituted
2,6-diiodo compounds 1b–f (Scheme 1) which were prepared
Scheme 1
from 2,6-diiodo-3-hydroxypyridine 1a using standard pro-
cedures for protecting phenolic groups. Compound 1a was
readily prepared from 3-hydroxypyridine following a literature
procedure.8 We anticipated that the two iodo-substituents
might be replaced sequentially by two aryl groups and that the
protected 3-hydroxy group might also be replaced at a later
stage (e.g. as its trifluoromethanesulfonate) by an additional
group since trifluoromethanesulfonates and other groups are
well known substrates for the Suzuki and other cross-coupling
reactions.9,10
The Suzuki reactions of compounds 1b–f with one mol
equivalent of phenylboronic acid were investigated with the
expectation that cross-coupling would occur regioselectively at
the least sterically crowded 6-position leaving the 2-iodo group
free for a subsequent coupling reaction. However, in the
Scheme 2
excellent chemoselectivity was observed and the arylated
products 6b–9b and 6c indicated in Table 1 were isolated in
moderate to good yields (57–96%). The mono-arylated com-
pounds 6b–9b were then subjected to a second Suzuki reaction
(Scheme 2) giving the 2,6-diarylated products 10b–14b in
moderate–good yields (43–87%) as depicted in Table 1. With
the exception of the electron-deficient 3-nitrophenyl group, the
yields for the introduction of the second aryl group were
generally not as good as for the first arylation reaction. This
is presumably a consequence of the less reactive bromine atom
and greater steric hindrance at the 2-position.
In summary, compound 5b has been shown to undergo
DOI: 10.1039/b111620g
J. Chem. Soc., Perkin Trans. 1, 2002, 581–582
This journal is © The Royal Society of Chemistry 2002
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