Ligandless microwave-assisted Pd/Cu-catalyzed direct arylation of oxazoles

Article abstract of DOI:10.1021/jo7027135

(Chemical Equation Presented) An efficient microwave-assisted palladium/copper co-mediated direct arylation of oxazoles with aryl bromides under ligandless conditions has been developed. The method is functional group tolerant and provides rapid access to medicinally relevant compounds in good yields. Coupled to the van Leusen oxazole ring synthesis, this methodology is illustrated by an expedient two-step synthesis of the four 2,5-diaryloxazole alkaloids texamine, texaline, balsoxin, and O-Me-halfordinol from commercially available starting materials.

Full text of DOI:10.1021/jo7027135

reactive aryl iodides and, to a lesser extent, aryl bromides in
the presence of a metal catalyst (palladium, rhodium, and/or
copper), an inorganic base, and a phosphine ligand in polar
solvents such as DMF at elevated temperatures and prolonged
reaction times. Importantly, however, this reaction has also been
found to proceed under ligandless and even base-free condi-
tions.4 Furthermore, Bergman and Ellman reported that rhodium
catalyzed arylation of azoles with aryl bromides under micro-
wave irradiation requires significantly shorter reaction times.5
Very recently, Daugulis and co-workers described the use of
aryl chlorides in the direct arylation of electron-rich hetero-
cycles.6 Among the oxazole-type compounds, benzoxazoles and
2-phenyloxazoles are the most frequently encountered sub-
strates.7 Direct arylations at the 2 position of 4/5-mono- or
disubstituted oxazoles with aryl halides are much less well
documented. Hoarau et al. have described a regioselective
palladium-catalyzed C-2 arylation of ethyl 4-oxazolecarboxylate
with iodobenzene, while Li et al. have reported the C-2 arylation
of methyl 4-aryl-5-oxazolecarboxylate with aryl iodides under
classical conditions in the presence of copper(I) iodide.8,9 In
this context, a study of the direct metal-catalyzed arylation of
5-substituted oxazoles with aryl bromides, being both cheaper
and more widely available than the corresponding iodides, was
undertaken.
Ligandless Microwave-Assisted Pd/Cu-Catalyzed
Direct Arylation of Oxazoles
Franc¸ois Besselie`vre,†,‡ Florence Mahuteau-Betzer,†
David S. Grierson,§ and Sandrine Piguel*,†,‡
Institut Curie/CNRS, UMR 176, Baˆt. 110-112, Centre
UniVersitaire, Orsay F-91405, France, UniV Paris-Sud, Orsay
F-91405, France, and Faculty of Pharmaceutical Sciences,
UniVersity of British Columbia, 2146 East Mail, VancouVer, BC
V6T 1Z3, Canada
sandrine.piguel@curie.u-psud.fr
ReceiVed December 20, 2007
An efficient microwave-assisted palladium/copper co-medi-
ated direct arylation of oxazoles with aryl bromides under
ligandless conditions has been developed. The method is
functional group tolerant and provides rapid access to
medicinally relevant compounds in good yields. Coupled to
the van Leusen oxazole ring synthesis, this methodology is
illustrated by an expedient two-step synthesis of the four 2,5-
diaryloxazole alkaloids texamine, texaline, balsoxin, and
O-Me-halfordinol from commercially available starting
materials.
Herein, we report a rapid, efficient, and functional group
tolerant method for the intermolecular C-2 direct arylation of
5-aryloxazoles by aryl bromides under ligandless microwave
conditions. This methodology gives access to a wide variety of
2,5-diaryloxazole derivatives and this is illustrated by the
preparation of four known 2,5-diaryloxazole alkaloids from
commercially available starting materials.
As a test reaction, the coupling of 5-phenyloxazole 1a with
bromobenzene was initially studied. Compound 1a was readily
prepared in one step in 85% yield by the van Leusen reaction
of benzaldehyde with p-toluenesulfonylmethylisocyanide
(TosMIC) and K2CO3 in refluxing MeOH.10 Then, inspired by
the pioneering work of Miura et al. on heteroarene direct
arylations,11 the key coupling was carried out in the presence
of Pd(OAc)2 (5 mol %), PCy3 (10 mol %), CuI (1 equiv), and
Cs2CO3 (2 equiv) in DMF at 150 °C. The target 2,5-dipheny-
loxazole 2a was cleanly obtained in good yield (79%) after 2
h. In control reactions where the copper additive or Pd(OAc)2
were left out, only trace amounts of 2a were formed, even after
prolonged heating (24 h). However, under ligand-free conditions,
A functionalized oxazole motif is found in a wide variety of
natural products, biologically active compounds, and optical
materials such as scintillant molecules and fluorescent dyes.
Many strategies for the synthesis of such molecules have
emerged, involving the construction of the oxazole ring by
nontrivial multistep reaction sequences.1 As part of an ongoing
medicinal chemistry program, we needed a flexible route that
would give high yielding and rapid access to different 2,5-
diaryloxazoles. A method involving a direct intermolecular
arylation at position 2 of a readily available 5-aryloxazole
scaffold was identified as an attractive and more operationally
simple alternative to traditional cross-coupling methods.2 Over
the past decade, direct arylation of heteroaromatics including
pyrroles, indoles, furans, thiophenes, azoles, pyridines, and
purines has been intensively studied as an effective and
straightforward method for creating aryl-heteroaryl linkages.3
Typically, this involves the reaction of the heterocycle with
(4) (a) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron
2007, 63, 1970. (b) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem.
2007, 72, 8543.
(5) Lewis, J. C.; Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem.,
Int. Ed. 2006, 45, 1589.
(6) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
(7) For very recent examples, see: (a) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404 and references cited therein. (b) Turner, G.
L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996
and references cited therein. (c) For a mechanistic discussion, see: Sanchez,
R. S.; Zhuravlev, A. J. Am. Chem. Soc. 2007, 129, 5824.
(8) Hoarau, C.; Du Fou de Kerdaniel, A.; Bracq, N.; Grandclaudon, P.;
Couture, A.; Marsais, F. Tetrahedron Lett. 2005, 46, 8573.
(9) Li, X.; Murray, W. V.; Macielag, M. J.; Guan, Q. U.S. Patent 113522
A1, 2005.
† Institut Curie.
‡ Univ Paris-Sud.
§ University of British Columbia.
(1) Palmer, D. C.; Venkatraman, S. In Oxazoles: Synthesis, Reactions
and Spectroscopy, Part A; J. Wiley & Sons: Hoboken, NJ, 2004.
(2) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991.
(3) For recent reviews of heteroarenes and arenes direct arylation, see:
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b)
Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (c) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (d) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35.
(10) Van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 23, 2369.
(11) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467.
10.1021/jo7027135 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/19/2008
3278
J. Org. Chem. 2008, 73, 3278-3280

TABLE 1. Optimization of the Microwave-Assisted Pd/Cu Direct
Arylation Conditionsa
TABLE 2. Scope of Microwave-Assisted Direct Arylation of
5-Phenyloxazoles with Aryl Bromides
entry
CuI (equiv)
reaction time (min)
yieldb (%)
1
2
3
4
5
6
7
0.5
0.5
1
2
1
15
60
30
30
30
15
15
53
57
70
72
72c
81c
11c,d
1
1
a All reactions were performed at 0.4-0.5 M of 5-phenyloxazole 1a (1
equiv) and bromobenzene (1.2 equiv) in DMF heated at 150 °C in a
microwave reactor. b Isolated yields. c K2CO3 was used as base. d Thermal
heating, 150 °C.
such as those reported by Bellina and co-workers,4 compound
2a was isolated in a comparable yield (80%).
Having determined optimal conditions12 for the formation of
2a using classical heating, attention was turned toward the
possible use of microwave irradiation in order to reduce the
reaction time. Organic reactions assisted by microwave irradia-
tion have attracted considerable attention in recent years for
the efficient, accelerated synthesis of a variety of organic
compounds.13 Direct arylations are ideal candidates for micro-
wave-assisted synthesis as they typically require extended
reaction times at high temperatures.14 To date, only one example
of microwave-assisted direct arylation of benzoxazole has been
reported using a rhodium catalyst.5 We were delighted to find
that direct arylation of 1a under microwave irradiation drastically
reduced the reaction time from hours to just a few minutes
(Table 1). Thus, when 5-phenyloxazole 1a was heated for 30
min at 150 °C in a microwave reactor with 1.2 equiv of
bromobenzene, 1 equiv of CuI, 5 mol % of Pd(OAc)2, and 2
equiv of Cs2CO3 in DMF, product 2a was isolated in 70% yield
(Table 1, entry 3). Interestingly, lower yields of 2a were obtained
using smaller amounts (0.5 equiv) of the CuI additive (entries
1 and 2), and the yield remained unchanged when up to 2 equiv
was employed (entry 4). In addition, replacing Cs2CO3 by the
less expensive K2CO3 had no deleterious effect on the reaction
(entry 5). Screening with respect to the solvent and temperature
showed that the reaction proceed best in DMF at 150 °C with
no reaction in DMF at 110 °C. Moreover, commercial grade
DMF can be used without particular precaution. Finally,
reducing the reaction time from 30 to 15 min led to a significant
improvement in yield, from 72 to 81% (entries 5-6). Control
reactions at 10 and 5 min provided incomplete conversion and
gave 2a in 64% and 50% isolated yields, respectively. Therefore,
15 min was found to be the optimal reaction time.15 For
comparison, for the same reaction carried out for 15 min using
a Isolated yields. b 30 min of heating. c 4 min of heating. d 8 min of
heating.
traditional oil bath heating, 2,5-diphenyloxazole 2a was obtained
in only 11% yield (entry 7).
These conditions were then used to investigate the scope of
the direct arylation with various aryl bromides (Table 2). Both
electron-rich (entries 1-5) and electron-deficient (entries 6-12)
aryl bromides reacted with phenyloxazole 1a in good yields,
with substitution being tolerated at each of the ortho, meta, and
para positions. Importantly, these conditions proved compatible
with the presence of important functional groups such as an
ester, a cyano group and halides on the aromatic bromide, which
may be subject to further synthetic transformations. Sterically
hindered aryl bromides were also reactive (entries 1-3), pro-
(12) Optimal conditions: 5-phenyloxazole (1 equiv), bromobenzene (1.2
equiv), Pd(OAc)2 (5 mol%), and CuI (1 equiv) as the co-catalysts, Cs2CO3
(2 equiv) as the base without ligand in DMF at 150 °C.
(13) Kappe, O. C.; Stadler, A.; Mannhold, R. In MicrowaVes in organic
and medicinal chemistry; Wiley-VCH: Weinheim, Germany, 2006.
(14) During the preparation of this manuscript, a microwave-assisted Pd-
catalyzed direct arylation of triazoles was published: Iwasaki, M.; Yorimitsu,
H.; Oshima, K. Chem. Asian J. 2007, 2, 1430.
(15) No product instability was observed under the reaction conditions.
In fact, exposing product 2a to the reaction conditions for 30 min led to
full recovery.
J. Org. Chem, Vol. 73, No. 8, 2008 3279

TABLE 3. van Leusen/direct Arylation Sequence
MeOH (150 mL) was treated with potassium carbonate (7.8 g, 56.6
mmol) and heated to reflux for 4 h. After being cooled to room
temperature, the solvent was removed under reduced pressure and
the crude product was triturated with water at 0 °C. A white
precipitate appeared and was collected by filtration and dried under
vacuum. The solid was crystallized in petroleum ether to give 3.5
g (85%) of white crystals: mp <40 °C; 1H NMR (300 MHz,
CDCl3) δ 7.30-7.40 (m, 2H), 7.44 (t, J ) 7.7 Hz, 2H), 7.66 (d, J
) 7.2 Hz, 2H), 7.93 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 121.4,
124.3, 127.7, 128.6, 128.8, 150.4, 151.5; MS (electrospray) m/z
146.1 (100) [M + H]+. Spectral data were in agreement with those
previously reported.22
General Procedure for Microwave-Assisted Pd/Cu-Catalyzed
Direct Arylation of 5-Aryloxazoles with Aryl Bromides As
Illustrated by the Synthesis of 2,5-Diphenyloxazole (2a). A tube
was charged with 5-phenyloxazole (100.0 mg, 0.69 mmol), bro-
mobenzene (130.3 mg, 0.83 mmol), potassium carbonate (190.4
mg, 1.36 mmol), Pd(OAc)2 (7.7 mg, 0.03 mmol), and CuI (131.4
mg, 0.69 mmol). The tube was flushed with argon, and DMF (1.5
mL) was added. The tube was sealed with a rubber cap and heated
to 150 °C for 15 min under microwave irradiation (200 W) using
air cooling. The reaction mixture was filtered through Celite, the
Celite washed with CH2Cl2, and the filtrate concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel eluting with cyclohexane/EtOAc (90/10) to afford the
title compound 2a (123 mg, 81%) as white crystals: mp 72-74
°C; 1H NMR (300 MHz, CDCl3) δ 7.35 (t, J ) 7.2 Hz, 1H), 7.40-
7.55 (m, 6H), 7.73 (d, J ) 7.7 Hz, 2H), 8.10-8.15 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 123.4, 124.1, 126.2, 127.4, 127.9, 128.4,
128.8, 128.9, 130.3, 151.2, 161.1; MS (electrospray) m/z 222.2 (100)
[M + H]+, 223.1 (17) [M + H]+, 244.1 (25) [M + Na]+. Spectral
data were in agreement with those previously reported.23
viding the expected products in good yields. Only in the case
where an electron-poor coupling partner is employed, shorter
reaction times gave better yields (entries 9-12). For instance,
compound 2j was obtained in 71% yield after only 4 min,
whereas heating for 15 min resulted in a reduced yield of 48%.16
This methodology, combined with the van Leusen reaction
to obtain the requisite 5-substituted oxazole starting materials,
was subsequently applied to the synthesis of the four natural
2,5-diaryloxazole alkaloids texamine 3a, texaline 3b, balsoxin
3c, and O-Me-halfordinol 3d (Table 3). Texamine 3a has been
isolated from the roots of the plant Amyris texana,17 and a five-
step synthesis has been reported with an overall yield of 36%.18
Balsoxin 3c, isolated from the plant A. plumieri, has also been
synthesized by a seven-step sequence in 10% overall yield.19,20
In the first step, veratraldehyde, piperonal, and p-anisaldehyde
were thus converted with TosMIC into their respective oxazoles
1b-d in high yields.21 Directed C-2 arylation under our opti-
mized conditions with bromobenzene or 3-bromopyridine then
gave the target 2,5-diaryloxazoles 3a-d with an average overall
yield of 53% (Table 3). Importantly, although the electronic
effects of the oxazole substrate had been modified, the direct
arylation was still found to be efficient, albeit in lower yield.
In conclusion, a microwave-enhanced and ligandless direct
arylation of 5-aryloxazoles with various aryl bromides has been
developed to generate 2,5-diaryloxazoles. The high functional
group tolerance and the speed of the reaction render this method
suitable for the combinatorial synthesis of a variety of 2,5-
diarylazoles. Studies on further applications of this direct
arylation protocol with aryl chlorides and other heterocycles
are in progress in our laboratory.
Acknowledgment. F.B. thanks the Re´gion Ile-de-France for
a doctoral grant. We also thank the Agence Nationale de la
Recherche for financial support. Jason Martin is gratefully
acknowledged for proofreading the manuscript.
Experimental Section
General Procedure for the Preparation of 5-Aryloxazole from
Aromatic Aldehydes As Illustrated by the Synthesis of 5-Phe-
nyloxazole (1a). A solution of benzaldehyde (3.0 g, 28.3 mmol)
and p-toluenesulfonylmethyl isocyanide (6.1 g, 31.1 mmol) in
Supporting Information Available: General experimental
procedures and spectral data for compounds 1a-d, 2a-m, and 3a-
d. This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Compounds 2k, 2l, and 2m were obtained in, respectively, 57%,
55%, and 52% yields after 15 min heating.
JO7027135
(17) Dominguez, X. A.; de la Fuente, G.; Gonzalez, A. G.; Reina, M.;
Timon, I. Heterocycles 1988, 27, 35.
(18) Ciddens, A. C.; Boshoff, H. I. M.; Franzblau, S. G.; Barry, C. E.;
Copp, B. R. Tetrahedron Lett. 2005, 46, 7355.
(19) Burke, B.; Parkins, H.; Talbot, A. M. Heterocycles 1979, 12, 349.
(20) Hodgetts, K. J; Kershaw, M. T. Org. Lett. 2002, 4, 2905.
(21) Kozikowski, A. P.; Ames, A. J. Org. Chem. 1980, 45, 2548.
(22) Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633.
(23) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.;
Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone,
N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897.
3280 J. Org. Chem., Vol. 73, No. 8, 2008