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DOI: 10.1039/C8CC06649C
Chemical Science
ARTICLE
Pleasingly,
this
process
is
compatible
with
various(hetero)arylboronic acids, and pyrroles 3ab–3aj were
obtained in 63–90% yield from alkynyamide 1a (Table 3). The
scope includes paraꢀ (3ab), metaꢀ (3ac and 3ad), orthoꢀ (3ae), and
disubstituted phenylboronic acids (3af–3ah) with methyl (3ab and
3ah), halide (3ad, 3ae, and 3ag), or alkoxy groups (3ac, 3af, and
3ag). 2ꢀNaphthylboronic acid (3ai) and various heteroarylboronic
acids that include 5ꢀindolylboronic acid (3aj), 3ꢀfuranylboronic acid
(3ak), and 3ꢀthienylboronic acid (3al) are also tolerated. No reaction
was observed when 4ꢀpyridinylboronic acid, methylboronic acid, or
cyclopropylboronic acid were used.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the European Union’s Horizon 2020
research and innovation programme [grant number 702386] through
a Marie SkłodowskaꢀCurie Individual Fellowship to S.N.K.; the
University of Nottingham; and GlaxoSmithKline.
To illustrate its utility, this methodology was applied to the
preparation of pyrroles that have been used in the synthesis of 4,4ꢀ
difluoroꢀ4ꢀboraꢀ3a,4aꢀdiazaꢀsꢀindacene
(BODIPY)
derivatives
(Scheme 2).3a,b,d Removal of the tosyl group from 3aa with KOH in
MeOH/TFH (1:1) at 70 °C gave pyrrole 6 in >99% yield, which has
previously been converted into BODIPY derivative 7.16
Alternatively, treatment of 3aa with POCl3 in DMF at 100 °C in a
microwave reactor resulted in formylation with concomitant removal
of the tosyl group to give pyrrole 8, which has been used in the
synthesis of BODIPY derivative 9.16
Notes and references
1
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Scheme 2 Synthesis of precursors to BODIPY derivatives
In a further application, removal of the tosyl group of 3ia with
KOH was followed by immediate alkylation with nꢀhexyl bromide
as described previously to give pyrrole 10 in 56% yield over two
steps (Scheme 3).17 Pyrrole 10 was previously converted in two steps
into 11, a known inhibitor of bovine cyclooxygenase and 5ꢀ
lipoxygenase.17
7
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Scheme 3 Formal synthesis of bovine cyclooxygenase and 5-lipoxygenase
inhibitor 11
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In conclusion, we have developed a synthesis of diverse 2,3,4ꢀ
trisubstituted pyrroles by the nickelꢀcatalyzed reaction of Nꢀtosyl
alkynamides with arylboronic acids. These reactions rely upon the
reversible E/Z isomerization of alkenylnickel species as a key step to
enable cyclization to take place. This method was applied to the
synthesis of pyrroles that are precursors to BODIPY derivatives, as
well as an inhibitor of bovine cyclooxygenase and 5ꢀlipoxygenase.
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