Decarboxylative cross-coupling of azoyl carboxylic acids with aryl halides

Article abstract of DOI:10.1021/ol1019597

Decarboxylative cross-coupling of thiazole and oxazole-5-carboxylic acids with aryl halides is reported. Under a bimetallic system of catalytic palladium and a stoichiometric silver carbonate, a variety of (hetero)arylated azoles can be prepared in excell

Full text of DOI:10.1021/ol1019597

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4745-4747
Decarboxylative Cross-Coupling of
Azoyl Carboxylic Acids with Aryl
Halides
Fengzhi Zhang and Michael F. Greaney*
School of Chemistry, UniVersity of Edinburgh, Joseph Black Building,
King’s Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
michael.greaney@ed.ac.uk
Received August 18, 2010
ABSTRACT
Decarboxylative cross-coupling of thiazole and oxazole-5-carboxylic acids with aryl halides is reported. Under a bimetallic system of catalytic
palladium and a stoichiometric silver carbonate, a variety of (hetero)arylated azoles can be prepared in excellent yield.
The decarboxylative cross-coupling of aryl carboxylic acids with
aryl halides is a recently established method for biaryl synthe-
sis.1 Carboxylic acids represent a powerful alternative to the
conventional organometallic building blocks used as nucleo-
philes in sp2 C-C bond formation, conferring advantages of
cost, availability, and ease of use. The transformation typically
employs bimetallic catalysis;a conventional palladium cycle
to activate the electrophile plus a second copper or silver-
mediated process to effect decarboxylation (Scheme 1).
scope, but significant challenges remain in establishing this
exciting transformation as a general method for biaryl
synthesis.3 Heterocyclic acids, in particular, remain under-
exploited in this method.
Pioneering work from Forgione and Bilodeau established
the viability of decarboxylative coupling for pyrrole and furan
substrates,4 and work from our own laboratory has demon-
strated decarboxylative coupling of azoyl acids with C-H
components.5 Outside of these contributions there have been
no focused efforts on heteroaryl carboxylic acid coupling.
Given the stability and tremendous accessibility of heteroaryl
carboxylic acids relative to heteroaryl organometallics, the
reaction has great potential for the synthesis of multihet-
eroaryl compounds integral to medicinal chemistry. We wish
to report our efforts in this area using decarboxylative
coupling to prepare arylated thiazoles and oxazoles, com-
pounds of fundamental importance in medicinal, agro, and
natural products chemistry.6
Scheme 1. The Decarboxylative Cross-Coupling Reaction
The canonical substrate for a decarboxylative coupling is
a σ electron poor benzoic acid, with much of the ground-
breaking work being carried out with o-nitrobenzoic acid.2
Recent work has concentrated on expanding this substrate
(1) (a) Bonesi, S. M.; Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed.
2008, 47, 10022–10025. (b) Goossen, L. J.; Rodriguez, N.; Goossen, K.
Angew. Chem., Int. Ed. 2008, 47, 3100–3120. (c) Baudoin, O. Angew.
Chem., Int. Ed. 2007, 46, 1373–1375.
(2) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664.
10.1021/ol1019597  2010 American Chemical Society
Published on Web 09/24/2010

We began by examining the cross-coupling of iodobenzene
with 4-methyl-2-phenylthiazole-5-carboxylic acid 1a as a test
reaction (Table 1). Using a simple catalyst system of PdCl2
improve efficiencies, however, so was maintained in the
optimized procedure. We could reduce the stoichiometry of
Ag2CO3 and still observe successful coupling (entry 6),
although yields dropped roughly in line with the amount of
Ag+ present in the reaction. Control experiments in the
absence of either Pd or silver were negative for arylated
product 3a.
Table 1. Reaction Optimizationa
With this optimized procedure in hand we applied it to
a range of aryl halides (Scheme 2). Yields were generally
Scheme 2
.
Decarboxylative Cross-Coupling of Thiazole 1a with
entry
base
solvent
toluene
yield (%)b
Aryl Halides
1
2
CuCO3 (1 equiv)
Ag2CO3 (1 equiv)
Ag2CO3 (1 equiv)
Ag2CO3 (1 equiv)
Ag2CO3 (1 equiv)
0
74
81
96
81
57
DMA
3c
4d
DMA/toluene (1:10)
DMA/toluene (1:10)
DMA/toluene (1:10)
5d e
,
6d
Ag2CO3 (0.3 equiv) DMA/toluene (1:10)
a Conditions: thiazole 1a (1 equiv), iodobenzene 2a (2 equiv), PdCl2 (5
mol %), triphenylphosphine (10 mol %) plus base and solvent as shown in
the table. Reactions were carried out on a 0.3 mmol scale and heated to
135 °C for 16 h in a sealed tube under air. b Isolated yield. c Reaction was
conducted with Dean-Stark apparatus under N2 atmopshere. d Thiazole 1a
(1.5 equiv), iodobenzene 2a (1 equiv). e No triphenylphosphine.
and PPh3, we were surprised to observe no cross-coupling
at all in the presence of stoichiometric CuCO3 (entry 1), a
reagent we have used previously for decarboxylation.5 By
contrast, stoichiometric Ag2CO3 proved very effective,
affording the phenylated thiazole 3a in 74% yield in DMA,
and 81% yield with toluene/DMA (10:1) (entries 2 and 3).
A further jump in yield could be attained by varying the
stoichiometry such that the aryl iodide was the limiting
reagent (entry 4), affording an excellent 96% yield of 3a.
This stoichiometry is a common feature of decarboxylative
cross-coupling with aryl halides;3 the acid component can
undergo proto-decarboxylation to varying degrees and is
often used in small excess. The phosphine ligands were not
essential for coupling, with ligand free conditions affording
3a in high yield (entry 5). Triphenylphosphine did generally
excellent for a variety of simple aryl bromides and iodides.
Electron-rich (3b-e) and electron-poor (3f-i) halides
were equally successful in the reaction. Halogenated
functionality was tolerated (3f and 3g), with 3g displaying
an o-fluoro group. We were pleased to find the reaction
was effective for heteroaryl halides. 4-Iodopyridine was
coupled in excellent yield (3j), along with 5- and 3-halo
indoles in somewhat reduced yields (3k and 3l). Synthesis
of products 3j-l in one step illustrates the power of
disconnecting through the biaryl bond for multiheteroaro-
matic compounds. Classic approaches would require
longer sequences whereby the heteroaromatic is formed
through condensation of acyclic precursors. Finally, we
performed a double coupling using o-bromomethyliodo-
benzene, isolating the novel sp2 and sp3 coupled product
3m in 80% yield.
(3) Recent examples: (a) Li, M.; Ge, H. Org. Lett. 2010, 12, 3464–
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Goossen, L. J.; Rodriguez, N.; Lange, P. P.; Linder, C. Angew. Chem., Int.
Ed. 2010, 49, 1111–1114. (f) Shang, R.; Xu, Q.; Jiang, Y.-Y.; Wang, Y.;
Liu, L. Org. Lett. 2010, 12, 1000–1003. (g) Sun, Z.-M.; Zhang, J.; Zhao,
P. Org. Lett. 2010, 12, 992–995. (h) Kim, H.; Lee, P. H. AdV. Synth. Catal.
2009, 351, 2827–2832. (i) Shang, R.; Fu, Y.; Wang, Y.; Xu, Q.; Yu, H.-Z.;
Liu, L. Angew. Chem., Int. Ed. 2009, 48, 9350–9354. (j) Goossen, L. J.;
Zimmermann, B.; Linder, C.; Rodriguez, N.; Lange, P. P.; Hartung, J. AdV.
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To fully establish the scope of the arylation we prepared
a range of thiazole and oxazole-5-carboxylic acids and
´
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4746
Org. Lett., Vol. 12, No. 21, 2010

subjected them to the coupling protocol with 4-iodopyridine
and benzene derivatives (Scheme 3). A variety of para-
Scheme 4. Synthesis of Pimprinine
Scheme 3
.
Decarboxylative Cross-Coupling of Thiazole 1a with
Aryl Halides
Pimprinine displays a range of biological activities such
as monoamine oxidase inhibition, antiplatelet aggregation,
and anticonvulsant activity,9 and has been the subject of
several syntheses that use 3-acyl indole derivatives as starting
materials.10 The decarboxylative cross-coupling offers a more
modular approach: Starting from 2-methyloxazole-5-car-
boxylic acid 6, available through simple hydrolysis of the
known ethyl ester,11 coupling with the commercially avail-
able indole 7 under our standard conditions proceeded in
63% yield. Basic hydrolysis removed the tosyl group
quantitatively, producing the natural product in a short and
efficient sequence.
In conclusion, we have developed a decarboxylative cross-
coupling method for the (het)arylation of thiazoles and
oxazoles. The reaction employs a very simple catalyst system
and delivers excellent yields of a wide variety of bromide
and iodide coupling partners.
substituted aryl substituents in the 2-position all gave
excellent yields for thiazoles (5a-e) and oxazoles (5f-i).
In each case the heterocyclic iodide was equally as effective
as the phenyl iodide. The 2-methyl thiazole was a good
substrate, producing the 2,4-dialkyl-5-aryl thiazoles 5j and
5k in high yield. Importantly, we found that 4-unsubstituted
oxazoles were productive in the reaction, affording the 2,5-
disubstituted products 5l and 5m, again in good yield. In
contrast, azole-4-carboxylic acids were not good substrates
for the cross-coupling under these reaction conditions.
The success of decarboxylative coupling with azoles
having a vacant 4-position prompted us to conclude our
studies with a short synthesis of the alkaloid pimprinine.
Originally isolated in 1960 from Streptomyces pimprina,7
pimprinine was characterized as the oxazolylindole 8, and
is part of a wider class of 5-(3-indolyl)oxazole alkaloids that
have been subsequently discovered (Scheme 4).8
Acknowledgment. We thank the EPSRC for funding
(Leadership Fellowship to M.F.G.) and the EPSRC mass
spectrometry service at the University of Swansea.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1019597
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