Suzuki coupling of oxazoles

Article abstract of DOI:10.1021/ol060591j

A protocol for the functionalization of the oxazole 2- and 4-positions using the Suzuki coupling reaction is described. 2-Aryl-4-trifloyloxazoles undergo rapid, microwave-assisted coupling with a range of aryl and heteroaryl boronic acids in good to excel

Full text of DOI:10.1021/ol060591j

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2495-2498
Suzuki Coupling of Oxazoles
Emmanuel Ferrer Flegeau,† Matthew E. Popkin,‡ and Michael F. Greaney*,†
UniVersity of Edinburgh, School of Chemistry, Joseph Black Building,
King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, U.K., and
GlaxoSmithKline, Chemical DeVelopment, Old Powder Mills,
Tonbridge, Kent, TN11 9AN, U.K.
Michael.Greaney@ed.ac.uk
Received March 10, 2006
ABSTRACT
A protocol for the functionalization of the oxazole 2- and 4-positions using the Suzuki coupling reaction is described. 2-Aryl-4-trifloyloxazoles
undergo rapid, microwave-assisted coupling with a range of aryl and heteroaryl boronic acids in good to excellent yields. The methodology
is similarly effective using 4-aryl-2-chlorooxazoles as the coupling partner and has been extended to the synthesis of a novel class of homo-
and heterodimeric 4,4-linked dioxazoles.
The oxazole heterocycle is a fundamental ring system found
throughout chemistry in areas such as natural products,
pharmaceuticals, agrochemicals, peptidomimetics, and poly-
mers.1 Naturally occurring oxazoles are usually found with
a 2,4-substitution pattern,2 a consequence of their biosynthetic
assembly from serine residues, although 2,5-substituted
oxazole natural products are known.3
A variety of venerable condensation methods are known
for oxazole synthesis, often involving the preparation of
appropriately substituted acyclic amides and their subsequent
dehydrative cyclization.4 Although tried and tested, the
frequently harsh reaction conditions characteristic of the
classical methods can make them unsuitable for the synthesis
of multifunctional oxazoles of the type found in natural
products. From a lead discovery perspective in medicinal
chemistry, which frequently requires the rapid synthesis of
diverse heterocycles, the preparation of oxazoles using
condensation reactions can be a drawback, as it necessitates
the synthesis of diversified acyclic precursors prior to
cyclization, i.e., early stage rather than late stage diversifica-
tion. An alternative strategy is to prepare the oxazole
heterocycle at an early stage and carry out subsequent
functionalizations at each position using palladium cross-
coupling chemistry. This idea has been exemplified in the
development of Stille,5 Sonogashira,6 Negishi,7 and direct
(5) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
Synthesis 1987, 693-696. (b) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995,
415-416. (c) Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 5319-
5322. (d) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623-4633. (e)
Boto, A.; Ling, M.; Meek, G.; Pattenden, G. Tetrahedron Lett. 1998, 39,
8167-8170. (f) Jeong, S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998, 63,
8640-8641. (g) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469-471.
(h) Smith, A. B., III; Minbiole, K. P.; Freeze, S. Synlett 2001, 11, 1739-
1742. (i) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 10942-10953.
(6) (a) Sakamoto, T.; Nagata, H.; Kondo, Y.; Shiraiwa, M.; Yamanaka,
H. Chem. Pharm. Bull. 1987, 35, 823-828. (b) Langille, N. F.; Dakin, L.
A.; Panek, J. S. Org. Lett. 2002, 4, 2485-2488. (c) Dakin, L. A.; Langille,
N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812-6815. (d) Su, Q.; Panek,
J. S. Angew. Chem., Int. Ed. 2005, 48, 1223-1225.
(7) (a) Harn, N. K.; Gramer, C. J.; Anderson, B. A. Tetrahedron Lett.
1995, 36, 9453-9456. (b) Anderson, B. A.; Harn, N. K. Synthesis 1996,
583-585. (c) Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M.
F.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. J. Org. Chem.
1997, 62, 8634-8639. (d) Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999,
64, 1011-1014. (e) Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.;
Imbordino, H. R.; Pangborn, J. J. Org. Process Res. DeV. 2003, 7, 696-
699.
† University of Edinburgh.
‡ GlaxoSmithKline.
(1) Palmer, D. C.; Taylor, E. C. The Chemistry of Heterocyclic
Compounds. Oxazoles: Synthesis, Reactions, and Spectroscopy, Parts A
& B; Wiley: New Jersey, 2004; Vol. 60.
(2) Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.; Walsh, C.
T. Nat. Prod. Rep. 1999, 16, 249-263.
(3) O’Donovan, D. G.; Horan, H. J. Chem. Soc. C 1971, 331-334.
(4) For a recent review, see: Yeh, V. Tetrahedron 2004, 60, 11995-
12042.
10.1021/ol060591j CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/11/2006

arylation methods8 for the functionalization of oxazoles in
recent years. The Suzuki coupling, by contrast, has seen
relatively little application:9 Hodgetts described the coupling
of phenyl boronic acid to 2-, 4-, and 5-halo-oxazoles,10 of
2-aminophenyl boronic acid to 5-halo-oxazoles, and of 3,4-
dimethoxyphenyl boronic acid to 2-bromooxazole; Taylor
has examined the coupling of phenyl and 3-thiophene boronic
acid to two 2-chloro oxazoles.11 We chose to examine the
functionalization of the oxazole 2- and 4-positions with a
view of developing a versatile Suzuki methodology for the
generation of a range of arylated and heteroarylated oxazoles.
We began by preparing 2-phenyl-4-trifloyloxazole, 2a,
from oxazolone 1 to study Suzuki coupling at the oxazole
4-position (Scheme 1). The synthesis of trifloyl oxazoles
Table 1. Optimization of Suzuki Coupling of Triflate 2a with
Tolylboronic Acida
entry
catalyst
base
K3PO4
NaOH
KOtBu
NaOH
NaOH
time
48 h
20 h
20 h
16 h
16 h
solvent
yieldg
1
2
3
4
5
6
7
8
9
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
dioxane
dioxane
dioxane
traces
0%
0%
aq dioxane traces
CH3CN
THFd
dioxane
THF
traces
16%
48%
traces
36%
Na2CO3, 2 M 48 h
Na2CO3, 2 M 16 h
Scheme 1. Synthesis of 2-Phenyl-4-trifloyloxazole
b
Pd(OAc)2, PCy3 KF
Pd(OAc)2, PCy3 KF
72 h
72 h
c
THF
10 PdCl2(PPh3)2
11 PdCl2(PPh3)2
Na2CO3, 2 M 20 min dioxanee
Na2CO3, 2 M 40 min dioxanee
94%
67%
f
a Conditions: 5 mol % catalyst loading, 3 equiv of base, reflux. b 1% of
Pd(OAc)2 and 1.2% of PCy3. c 5% of Pd(OAc)2 and 6% of PCy3. d Reaction
was carried out at 60 °C. e Microwave irradiation at 150 °C for 20 min.f 1
mol % catalyst loading. g Isolated yield after SiO2 chromatography.
from oxazolones, first introduced by Barrett5b and Kelly5c
in the context of the Stille reaction, enables the regiocon-
trolled installation of an electrophile functional group for
subsequent palladium cross-coupling. This strategy avoids
potential regioselectivity problems inherent to direct halo-
genation at the oxazole 4-position and has been employed
successfully in several Stille and Sonagashira oxazole cross-
coupling reactions.5g-i,6b-d Triflate 2 is a crystalline solid that
can be stored for several months at -20 °C.
A range of conditions were examined for the Suzuki
coupling of 2a with tolylboronic acid (Table 1). It was
immediately clear that the substrate could not tolerate strong
bases such as KOtBu or NaOH often employed in the reaction
(Table 1, entries 1-5), as they caused extensive degradation
of the triflate with very little coupled product (3a) being
observed. Use of a weaker base with PdCl2(PPh3)2 as catalyst
provided the first signs of a successful reaction; refluxing
in THF for 2 days using aqueous Na2CO3 as base produced
3a in 16% yield (Table 1, entry 6), which could be improved
to 48% by switching to the higher-boiling solvent dioxane
(Table 1, entry 7).
Suzuki coupling of aryl triflates under mild conditions,12
proved ineffective with the oxazole substrate producing a
low yield of coupled product after prolonged reflux (Table
1, entries 8 and 9). The beneficial effect of combining a weak
base with higher reaction temperatures led us to examine
the reaction under microwave heating. We were pleased to
observe that irradiation in dioxane for 20 min at 150 °C
(Table 1, entry 10) produced the desired 4-tolyl oxazole in
an excellent 94% yield. The catalyst loading could be reduced
to 1% but at the expense of a longer reaction time and a
decrease in yield (Table 1, entry 11).
The methodology was extended to the synthesis of a range
of 2,4-disubstituted oxazoles (Table 2). We were pleased to
observe excellent reactivity for a variety of electron-deficient
and electron-rich aryl boronic acids (Table 2, entries 1-12),
ortho-substituted aryl boronic acids (Table 2, entry 4), as
well as heteroaromatic pinacol boronic esters (Table 2, entries
8-10) with yields being uniformly good to excellent. The
reaction was tolerant of alternative aryl groups in the
2-position, with electron-donating (Table 2, entries 7, 10,
and 12) and electron-withdrawing groups (Table 2, entry 5)
producing high yields of 4-substituted oxazoles.
The combination of a PCy3/Pd(OAc)2 catalyst system with
potassium fluoride as base, reported to be effective for the
(8) (a) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga,
K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma,
R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257-272. (b) Pivsa-Art, S.;
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn.
1998, 71, 467-473. (c) Hoarau, C.; Du Fou de Kerdaniel, A.; Bracq, N.;
Grandclaudon, P.; Couture, A.; Marsais, F. Tetrahedron Lett. 2005, 46,
8573-8577.
(9) (a) Maekawa, T.; Sakai, N.; Tawada, H.; Murase, K.; Hazama, M.;
Sugiyama, Y.; Momose, Y. Chem. Pharm. Bull. 2003, 51, 565-573. (b)
Buzon, R. A., Sr.; Castaldi, M. J.; Li, Z. B.; Ripin, D. H. B.; Tao, Y. PCT
Int. Appl. WO 2004020438 A2 20040311, 2004; Chem. Abstr. 2004, 140,
235721. (c) Tanaka, T.; Hirai, K.; Takemura, C.; Kita, H. Japanese Patent
JP 2005223238 A2 20050818, 2005; Chem. Abstr. 2005, 143, 239833.
(10) (a) Hodgetts K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905-2907.
(b) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911-2914.
(11) Young, G. L.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2004,
45, 3797-3801.
Having established a robust protocol for Suzuki coupling
at the 4-position, we then turned our attention to the
2-position. We initially investigated a similar strategy for
the preparation of the Suzuki electrophile by synthesizing
4-phenyl-4-oxazalin-2-one 46b and attempting to convert it
to the known 2-trifloyl oxazole 5 (Scheme 2). Although the
triflate could be prepared and isolated as described by
Panek,6b it was quite thermally unstable and decomposed
(12) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
2496
Org. Lett., Vol. 8, No. 12, 2006

Table 2. Suzuki Coupling of Oxazolyl 4-Triflates
a Isolated yield after SiO2 chromatography. b Pinacolato boronic ester used in coupling.
immediately when exposed to the high temperatures of our
Suzuki reactions.
to the triflate group at the 2-position, we decided to prepare
2-chloro oxazoles, readily synthesized by Vedejs’ protocol
of oxazole lithiation and subsequent trapping with hexachlo-
roethane, a method that avoids ring-opening complications
of the lithiooxazole.13 The 2-chloro-4-phenyloxazole 8 proved
to be an excellent substrate for Suzuki coupling under our
optimized conditions. A range of boronic acids could be
coupled to the chloride in generally excellent yields (Table
3, entries 1-5).
The nonaflate 6 proved slightly more robust and could be
isolated and purified by column chromatography. However,
when subjected to the reaction conditions for Suzuki
coupling, it likewise rapidly decomposed. Efforts to trans-
form 4 into alternative Suzuki electrophiles using POBr3,
(Ph)3PBr2, or (Ph)2POCl were unsuccessful. As an alternative
With an arylation methodology in place for the oxazole
2- and 4-positions, we were interested in extending the
reaction to the coupling of two oxazole units to make a
dioxazole. This reaction would represent the first steps in
the development of a general Suzuki coupling strategy for
the synthesis of polyoxazoles. The challenge here is to
successfully synthesize an oxazole boronic acid, a class of
compound rarely described in the literature.9c,14 The carbon-
boron bond can be susceptible to protonolysis when adjacent
to a heteroatom, leading to stability problems and handling
Scheme 2. Activation of the Oxazole 2-Position
(13) Atkins, J. M.; Vedejs, E. Org. Lett. 2005, 7, 3351-3354.
Org. Lett., Vol. 8, No. 12, 2006
2497

Scheme 3. Synthesis of 4,4-Dioxazoles Using the
Suzuki-Miyaura Reaction
Table 3. Synthesis of 2,4-Disubstituted Oxazoles from 8
pleased to observe that microwave heating to 150 °C for 20
min produced the novel homodimeric dioxazole 10 in 58%
yield.
The Suzuki-Miyaura reaction could also be applied to
the 2-(p-fluorophenyl)- and 2-(p-methoxyphenyl)-substituted
oxazole triflates 2b and 2c producing the homodimers 11
and 12 in good yield, as well as the cross-coupling of triflates
2a and 2b to give the heterodimer 13 in 39% yield.
To conclude, we have developed a protocol for the
arylation of the oxazole 2- and 4-positions using the Suzuki
coupling. The method is quick, versatile, works in high yield,
and has been applied to the preparation of a new class of
dimeric 4,4-linked dioxazoles. Future work will develop
Suzuki coupling strategies for polyoxazole synthesis.
Acknowledgment. We thank GSK and the University of
Edinburgh for funding, Prof Mark Bradley and Biotage for
the use of a Smith synthesizer, and the EPSRC mass
spectrometry service at the University of Swansea.
a Isolated yield after SiO2 chromatography. b Pinacolato boronic ester
used in coupling.
difficulties.15,16 As a result, we decided to examine the in
situ generation of boronic esters and their subsequent one-
pot Suzuki coupling. Accordingly, we treated triflate 2a with
bispinacolatodiboron under microwave-accelerated Miyaura
conditions until the starting material had disappeared by TLC
(Scheme 3). The same reaction vessel was then recharged
with 5 mol % of PdCl2(PPh3)2, aqueous sodium carbonate,
and an additional equivalent of the triflate 2a. We were
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.
OL060591J
(15) (a) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447-3450. (b) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron
2001, 57, 9813-9816 and references therein.
(16) Attempted Miyaura borylation of 4-phenyl-2-chlorooxazole, 8, gave
a quantitative yield of 4-phenyloxazole, indicating that rapid protodebor-
onation may restrict the use of 2-halo-oxazoles as nucleophiles in the
Suzuki-Miyara reaction under these reaction conditions.
(14) During the preparation of this paper, a protocol for the synthesis
and Suzuki coupling of oxazol-4-ylboronates was reported: Araki, H.;
Katoh, T.; Inoue, M. Synlett 2006, 555-558.
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Org. Lett., Vol. 8, No. 12, 2006