Synthesis of 2,5-diaryloxazoles through van Leusen reaction and copper-mediated direct arylation

Article abstract of DOI:10.1016/j.tetlet.2009.02.039

The direct arylation of 5-aryloxazoles, prepared by the van Leusen reaction, with various aryl iodides is effectively promoted by a system of CuI combined with PPh₃ and Na₂CO₃ as a ligand and a base, respectively, in DMF to produce the corresponding 2,5-diaryloxazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2009.02.039

Tetrahedron Letters 50 (2009) 3273–3276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,5-diaryloxazoles through van Leusen reaction
and copper-mediated direct arylation
Tomoki Yoshizumi a, Tetsuya Satoh a, Koji Hirano a, Daisuke Matsuo b, Akihiro Orita b, Junzo Otera b,
,
*
Masahiro Miura a,
*
a Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
b Department of Applied Chemistry, Okayama University of Science, Okayama 700-0005, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct arylation of 5-aryloxazoles, prepared by the van Leusen reaction, with various aryl iodides is
effectively promoted by a system of CuI combined with PPh3 and Na2CO3 as a ligand and a base, respec-
tively, in DMF to produce the corresponding 2,5-diaryloxazoles in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 December 2008
Revised 3 February 2009
Accepted 6 February 2009
Available online 10 February 2009
Keywords:
Arylation
Aryl iodide
Copper
Oxazole
The oxazole nucleus is found in a large number of biologically
active natural and unnatural compounds, and the synthesis of its
derivatives is of considerable importance in organic synthesis.1
Aryalted oxazoles are of interest not only due to their biological
properties, but also due to their importance as organic materials
such as scintillant compounds and fluorescent dyes.1,2 For the syn-
thesis of arylated oxazoles having a variety of aryl functions, tran-
sition-metal-catalyzed aryl–aryl cross-coupling with aryl halides
and arylmetal reagents is one of the most reliable methods,3 and
the reaction has been often employed.
tional groups tolerable in the copper-promoted arylation of
benzazoles including benzoxazole with an almost stoichiometric
amount of aryl iodides.10 Subsequently, as 2,5-diaryloxazoles are
of considerable interest biologically and physically,1,2 we have
undertaken their synthesis with our method in combination with
the van Leusen reaction12 that allows a ready access to 5-aryloxaz-
oles using commercially available TosMIC (p-toluenesulfonylmeth-
yl isocyanide) and the corresponding aromatic aldehydes, and this
has appeared to work effectively. The results as well as optical
properties of some
p-extended products having a phenylethynyl
Meanwhile, recent advances in the metal-mediated direct C–H
arylation of heteroarenes may also allow an efficient access to aryl-
oxazoles.4–7 The direct reaction of oxazoles with aryl halides is
usually carried out by using a palladium catalyst, and often by add-
ing a copper6,7c,e or silver7d,f promoter. The arylation of oxazoles via
C–H bond cleavage with aryl iodides may also be performed with
inexpensive copper alone, and it takes place selectively at the less
electron-rich C-2 position.6,8–11 Recently, Do and Dougulis reported
an effective copper-based catalytic system for the reaction with a
strong base such as t-BuOLi or t-BuOK, while an excess amount
of aryl iodide is required for a high-yield coupling.8 The catalytic
method was extended to the C-2 vinylation with b-styryl bromides
by Piguel and co-workers.9 We also found that the use of a tracta-
ble and mild base such as Na2CO3 or K3PO4 makes various func-
moiety are described herein. It should be cited that the palla-
dium-catalyzed arylation reactions of 5-aryloxazoles with aryl bro-
mides using CuI as a promoter and those with aryl iodides in the
presence of Ag2CO3 have been recently described by Piguel7e and
Greaney,7d respectively.
In an initial experiment, 5-phenyloxazole (1a) (0.5 mmol),
which was prepared by the van Leusen reaction,12 was treated with
iodobenzene (2a) (0.6 mmol) under conditions similar to those
employed for the copper-promoted arylation of benzazoles with-
out employing palladium.10 Gratifyingly, when using CuI
(0.5 mmol), PPh3 (0.1 mmol), and Na2CO3 (1 mmol) in DMF as the
promoting system, the reaction proceeded efficiently to afford
2,5-diphenyloxazole (3a) in 83% isolated yield (entry
1 in
Table 1). With this result in hand, various 5-aryloxazoles were
reacted with aryl iodides as follows.
First, the synthesis of balsoxin (3b) was performed.7e,f The
diaryloxazole is known as a natural product isolated from Amyris
species of plant.13a A related natural 2,5-diaryloxazole having a
* Corresponding authors. Tel.: +81 6 6879 7360; fax: +81 6 6879 7362 (M.M.).
E-mail addresses: otera@high.ous.ac.jp (J. Otera), miura@chem.eng.osaka-u.ac.jp
(M. Miura).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.039

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T. Yoshizumi et al. / Tetrahedron Letters 50 (2009) 3273–3276
Table 1
Reaction of 5-aryloxazoles (1) with aryl iodides (2)a
N
I
N
CuI/PPh3
+
Ar
Ar
O
Na2CO3, DMF
O
X
X
1
2
3
Entry
1
1
2: X
3, % Yieldb
N
N
O
O
2a: X = H
3a, 83
1a
N
N
O
MeO
O
MeO
MeO
X
MeO
1b
2
3
4
5
6
2a: X = H
3b: X = H, 94
2b: X = OMe
2c: X = CO2Me
2d: X = CN
2e: X = Br
3c: X = OMe, 91
3d: X = CO2Me, 85
3e: X = CN, 87
3f: X = Br, 77
N
N
O
7
2c: X = CO2Me
O
MeO
CO2Me
MeO
1c
3g, 86
N
N
O
O
X
1d
8
9
10
11
2a: X = H
3h: X = H, 93
3i: X = OMe, 59
3j: X = CN, 84
3k: X = CF3, 74
2b: X = OMe
2d: X = CN
2f: X = CF3
N
N
12c
2a: X = H
O
Br
O
Br
X
1e
3l: X = H, 64
13c
14
2c: X = CO2Me
2a: X = H
3m: X = CO2Me, 70
N
N
O
O
X
N
N
1f
3n: X = H, 91
15
2c: X = CO2Me
3o: X = CO2Me, 55
a
Reaction conditions: [1]:[2]:[CuI]:[PPh3]:[Na2CO3] = 0.5:0.6:0.5:0.1:1.0 (in mmol), in DMF (1 mL) under N2 at 160 °C for 2 h.
b
c
Isolated yield.
CuBr was used in place of CuI.
pyridyl group from the species, texalin,13b and its analogs have
electron-donating or withdrawing substituent 2b–e effectively
proceeded to give the corresponding products 3c–f in good yields.
Thus, methoxy, methoxycarbonyl, cyano, and bromo functions
were tolerable under the reaction conditions (entries 3–6). 5-(4-
Methoxyphenyl) (1c), 5-(2-naphthyl) (1d), 5-(4-bromophenyl)
(1e), and 5-(3-pyridyl)oxazoles (1f) were also suitable substrates
for the direct arylation (entries 7–15). It should be noted that in
been reported to show antimycobacterial activity.14a,b Some syn-
thetic balsoxin analogs having a sulfonamide group were also
claimed as MMP inhibitors.14c Treatment of 5-(3,4-dimethoxy-
phenyl)oxazole (1b) with 2a under the standard conditions affor-
ded the expected product, balsoxin (3b), in 94% yield (entry 2).
Then, the reactions of 1b with various iodobenzenes having an

T. Yoshizumi et al. / Tetrahedron Letters 50 (2009) 3273–3276
3275
Table 2
Reaction of 5-aryloxazoles 1b–d and benzoxazole 1g with 1-iodo-4-(2-phenylethynyl)benzene (2g)a and optical properties of products 3p–s
3, % Yieldb
kabs
log
e
kem
Ufe
c
d
Entry
1
N
N
O
MeO
MeO
1
1b
352
4.66
4.67
4.72
4.81
442
429
418
380
0.93
O
2
3
1c
1d
1g
MeO
347
355
333
0.93
0.97
0.90
3q, 70
N
O
3r, 66
N
O
4
3s, 90
a
Reaction conditions: [1]:[2g]:[CuI]:[PPh3]:[Na2CO3] = 0.5:0.6:0.5:0.1:1.0 (in mmol), in DMF (1 mL) under N2 for 4 h.
Isolated yield.
b
c
Absorption maximum in CH2Cl2.
d
e
Fluorescence maximum in CH2Cl2 (5.0 Â 10À6 M) exited at 350 nm for 3p–r and 325 nm for 3s.
Absolute quantum yield determined by an integrating sphere system.
the reactions of 1e (entries 12 and 13), CuBr was used in place of
Consequently, we examined the reactions of 5-aryloxazoles 1b–
d as well as benzoxazole (1g) with 1-iodo-4-(2-phenyleth-
ynyl)benzene (2g) prepared by our method. The results as well
as optical properties of the products are summarized in Table 2,
and the fluorescence spectra are shown in Figure 1. As is seen,
the triple bond in 2g was tolerable, and the reaction took place
CuI, as the bromo function was partly replaced by iodo one when
using CuI.15
On the other hand, we are interested in the synthesis and phys-
ical properties of 4-(phenylethynyl)phenyl-substituted heteroare-
nes as triple-bond containing
p
-conjugated organic materials.16
We also developed a facile method, utilizing a double elimination
effectively to afford the p-conjugated compounds 3p–s in good
strategy, for preparing 4-(phenylethynyl)phenyl halides, which are
yields. They were found to show strong fluorescence in a range
of kem 380–442 nm with high absolute quantum yields more than
0.90. The di- and mono-methoxy substitutions in compounds 3p
useful building blocks for constructing the p
-conjugated systems.17
Meanwhile,
a literature search indicates that 2-[4-(phenyl-
ethynyl)phenyl]-substituted 5-phenyloxazole18a,b and benzoxaz-
ole18c–e may act as efficient violet to blue fluorophores.
and 3q appear to induce the larger red shifts than the p-extension
by the naphthalene ring of 3r. While compound 3s shows two
accompanied shoulder peaks, they are not clear or do not appear
in the case of compounds 3p–r.
In summary, we have demonstrated that the combination of
readily available and tractable reagents CuI/PPh3/Na2CO3 can act
as an effective promoter system for the direct arylation of 5-arylox-
azoles with aryl iodides.19 It has also been utilized for the synthesis
3p
3q
3r
3s
of a natural product, balsoxin and its analogs and of
p-extended
compounds having a phenylethynyl moiety that exhibits strong
fluorescence.20
Acknowledgments
Inom
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformations of
Carbon Resources’ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We thank Dr. Y. Tachibana of Osaka
University for the measurement of fluorescence spectra.
Supplementary data
330
380
430
480
λ / nm
530
580
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.039.
Figure 1. Normalized fluorescence spectra of compounds 3p–s.

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T. Yoshizumi et al. / Tetrahedron Letters 50 (2009) 3273–3276
Watanabe, F.; Tamura, Y. PCT Int. Appl., 2003, WO2003035610; Chem. Abstr.
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19. The copper-mediated arylation reaction of 1,3-azoles may be considered to
proceed via the initial cupration of C-2 with the aid of a base.8b,10 In the case
using a mild base, pre-coordination of the copper promoter to the azole
nitrogen would be required to abstract the C-2 hydrogen.6
20. Typical procedure [reaction of 5-(3,4-dimethoxyphenyl)oxazole (1b) with
iodobenzene (2a) or 1-iodo-4-(2-phenylethynyl)benzene (2 g), entry 2 in Table 1
and entry 1 in Table 2]: In a 20 mL two-necked flask, 1b (103 mg, 0.5 mmol), 2a
(123 mg, 0.6 mmol) or 2 g (182 mg, 06 mmol), CuI (95 mg, 0.5 mmol), PPh3
(26.2 mg, 0.1 mmol), Na2CO3 (106 mg, 1 mmol), 1-methylnaphthalene (ca.
50 mg, internal standard), and DMF (1 mL) were added. The resulting mixture
was stirred under N2 (with balloon) for 2 h at 160 °C (bath temperature). After
cooling, the mixture was poured into water containing ethylenediamine (ca.
1 mL), extracted with dichloromethane, and dried over sodium sulfate. Product
3b (132 mg, 94%) was isolated by column chromatography on silica gel using
hexane–ethyl acetate (80:20, v/v). The spectroscopic data of 3b were in
agreement with those reported previously.7e In the case using 2 g, after
evaporation of the solvent, product 3p (168 mg, 88%) was obtained by
recrystallization from toluene–hexane: mp 183–185 °C; 1H NMR (400 MHz,
CDCl3) d 3.92 (s, 3H), 3.98 (s, 3H), 6.93 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H),
7.30 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.35–7.38 (m, 4H), 7.54–7.57 (m, 2H), 7.63 (d,
J = 8.1 Hz, 2H), 8.07 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 57.91,
57.99, 90.93, 93.50, 109.50, 113.49, 119.31, 122.84, 124.45, 124.87, 126.92,
127.91, 128.86, 130.30, 130.44, 133.57, 133.88, 151.32, 151.54, 153.51,
162.00; HRMS (EI) calculated for C25H19NO3 [M]+: 381.1365. Found: 381.
1356.
13. (a) Burke, B.; Parkins, H.; Talbot, A. M. Heterocycles 1979, 12, 349; (b)
Domínguez, X. A.; de la Fuenta, G.; González, A. G.; Reina, M.; Timón, I.
Heterocycles 1988, 27, 35.
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FEMS Immunol. Med. Mic. 1998, 20, 267; (b) Giddens, A. C.; Boshoff, H. I. M.;
Franzblau, S. G.; Barry, C. E., III; Copp, B. R. Tetrahedron Lett. 2005, 46, 7355; (c)