Direct arylations on water: Synthesis of 2,5-disubstituted oxazoles balsoxin and texaline

Article abstract of DOI:10.1039/b719466h

An efficient two-step palladium catalysed synthesis of 2,5-disubstituted oxazoles is reported. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719466h

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Direct arylations on water: synthesis of 2,5-disubstituted oxazoles
balsoxin and texalinewz
Stephan A. Ohnmacht,a Patrizia Mamone,a Andrew J. Culshawb and
Michael F. Greaney*a
Received (in Cambridge, UK) 18th December 2007, Accepted 18th January 2008
First published as an Advance Article on the web 5th February 2008
DOI: 10.1039/b719466h
An efficient two-step palladium catalysed synthesis of 2,5-
disubstituted oxazoles is reported.
has widespread application in medicinal, agrochemical,
natural products and materials chemistry.5
Taking commercially available oxazole as our starting
point, we functionalised the 2-position using a Negishi cross-
coupling protocol developed by Reeder and co-workers.6
Following lithiation with n-BuLi at ꢀ78 1C, solid ZnCl2 is
added to form the zincate, which subsequently undergoes Pd-
catalysed coupling with aryl iodides at 60 1C. The procedure
proved very effective for the preparation of the four 2-arylated
oxazoles 6a–d, 6b having been exemplified in Reeder’s work
and 6a, c, d being newly prepared using this method. With
these substrates in hand, we turned our attention to the direct
arylation of the oxazole 5-position. We have recently devel-
oped an effective on water7 method for the direct arylation of
heteroarenes;8 high yields of arylated products are produced
under far milder conditions than those typically employed in
literature heteroarene arylations.
The functionalisation of heteroaromatic compounds by tran-
sition metal (TM) catalysed C–C bond formation comple-
ments classic condensation chemistry as a strategy for poly-
functional heteroaromatic synthesis.1 Whereas classic hetero-
cyclic synthesis frequently involves the preparation of appro-
priately substituted acyclic precursors which undergo cyclo-
condensation as a final step, TM-catalysed cross couplings
offer the possibility of taking the parent, commercially avail-
able heteroarenes and selectively functionalising the C–H
bonds around the heteroarene nucleus. The two approaches
are illustrated in Scheme 1 for a 2,5-disubstituted azole synth-
esis. Whilst the condensation route is generally reliable and
built upon many years of literature precedent, the preparation
of the appropriately substituted precursor 1 is necessarily
multi-step and the subsequent condensation is usually carried
out under forcing conditions. The TM-catalysed approach
offers significant advantages of speed and synthetic expediency
in comparison, along with the potential for mild C–C bond
forming reaction conditions.
We were pleased to observe that the on water direct aryla-
tion is effective across a wide range of aryl iodides (Table 1),
with yields being good to excellent for the 2-substituted
oxazoles 6a–c. The scope of aryl iodide covers electron rich
(entries 5 and 6), electron poor (entries 3, 4, 7 and 9), sterically
hindered (entries 2 and 10) as well as aryl iodides which
contain additional functional handles for further elaboration
such as aryl halide (entries 7 and 8) and acyl (entry 9). The
process was poorly effective for pyridyl iodides,9 producing
very slow reactions with low yields of the oxazoyl pyridines
(30–36%), with homocoupling of the oxazole being the
dominant side-reaction.10
Importantly, the cross-coupling route enables the introduc-
tion of diversity at a late stage, rather than the early stage
mandated by the condensation approach, a strategic advan-
tage2 in the type of intensive analog synthesis required by
contemporary medicinal and agrochemical chemistry.
The TM-catalysed approach becomes even more attractive
if direct arylation can be incorporated as a C–C bond forming
reaction.3 Here, the stoichiometric metallation required for
classic cross-couplings such as the Suzuki–Miyaura, Stille and
Negishi reactions is dispensed with, in favour of direct C–H
bond functionalisation.4 We now report the preparation of
assorted 2,5-diaryloxazoles using TM-catalysed chemistry:
Negishi coupling at the 2-position using a stoichiometric
zincate followed by direct arylation at the 5-position under
mild ‘on water’ conditions. The oxazole heteroarene structure
The average yield across the 30 examples in Table 1 was
85%, illustrating the power of the direct arylation method for
the rapid assembly of functionalised heteroarenes. This is the
first study of oxazole arylation that examines substrate range;
a University of Edinburgh, School of Chemistry, Joseph Black
Building, King’s Buildings, West Mains Rd, Edinburgh, UK EH9 3JJ
b Global Discovery Chemistry, Novartis Horsham Research Centre,
Wimblehurst Road, Horsham, West Sussex, UK RH12 5AB
w CCDC 671459. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b719466h
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. See
DOI: 10.1039/b719466h
Scheme 1 Heteroarene synthesis via condensation and TM-catalysed
methods.
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Table 1
Scheme 2 2-Aryloxazole synthesis via Negishi cross-coupling.
Entry
1
Products
Yield (%)
92
83
92
2
83
98
90
3
4
5
6
7
8
9
80
98
90
Scheme 3 Synthesis of balsoxin and texaline.
84
85
80
texaline are 2,5-diaryloxazoles isolated from Amyris species of
plant in the Caribbean,12,13 with texaline reported to have
antimycobacterial activity against Mycobacterium tuberculo-
sis, M. avium and M. kansasii.14
75
84
97
The aforementioned Negishi coupling of aryl iodides with
oxazole introduced the requisite 2-aryl substituent. A direct
arylation at the 5-position with the electron rich aryl iodides
3,4-dimethoxyiodobenzene and 3,4-methylenedioxyiodoben-
zene afforded balsoxin, 18, and texaline, 19, respectively, in
good yield (Scheme 3). The power of the direct arylation
approach can be appreciated in comparison to literature
preparations of these two natural products. Hodgetts and
Kershaw synthesised balsoxin in 7 steps, 40% overall yield
in a Suzuki–Miyaura approach, starting from ethyl 2-amino
oxazole carboxylate,15 whilst Copp and co-workers synthe-
sised texaline in 6 steps, 4% overall yield using a condensation
approach.16
76
89
79
90
87
92
68
83
70
86
89
93
In conclusion, we have developed a mild direct arylation
method for the synthesis of 2,5-disubstituted oxazoles and
applied it to the two-step assembly of balsoxin and texaline.
We thank Novartis, The EU and the University of Edin-
burgh for funding. The EPSRC mass spectrometry service at
the University of Swansea is acknowledged and Prof. Simon
Parsons (School of Chemistry, University of Edinburgh) is
thanked for assistance with X-ray crystallography.
10
85
76
81
previous arylations of the oxazole 5-position having been
confined to individual substrates and uniformly taking place
at elevated temperatures.11 Preliminary results suggest that the
on water arylation will be effective for the acidic azole 2-
position; treatment of 5-phenyloxazole with p-chloroiodoben-
zene afforded the 2,5-diaryloxazole product in a good 71%
yield.9
Notes and references
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Having established the method for the 2-step synthesis of
2,5-diaryloxazoles, we applied the chemistry to the rapid
construction of two oxazole natural products. Balsoxin and
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