An efficient synthesis of 2-substituted benzoxazoles using cerium(III) chloride/sodium iodide as catalyst

Article abstract of DOI:10.1515/hc-2012-0054

An efficient and environmentally benign method for the synthesis of 2-substituted benzoxazoles is reported. The condensation of 2-aminophenol with an aldehyde gave an imine intermediate, which was cyclized and dehydrogenated to 2-substituted benzoxazole with good yield in the presence of CeCl ₃ /NaI as catalyst. The one-pot synthesis was carried out in toluene at 100 ° C using O ₂ as the oxidant.

Full text of DOI:10.1515/hc-2012-0054

DOI 10.1515/hc-2012-0054ꢀ
ꢀHeterocycl. Commun. 2012; 18(4): 211–214
XAunn Zheuf*faincd iYeunnyatngsWyein* thesis of 2-substituted
benzoxazoles using cerium(III) chloride/sodium
iodide as catalyst
Abstract: An efficient and environmentally benign carboxylic acid derivatives in the presence of strong acid
method for the synthesis of 2-substituted benzoxazoles under harsh conditions (Pottorf et al., 2003). Another
is reported. The condensation of 2-aminophenol with an traditional method for the preparation of benzoxazoles
aldehyde gave an imine intermediate, which was cyclized includes the condensation of 2-aminophenols with alde-
and dehydrogenated to 2-substituted benzoxazole with hydes and subsequent oxidative cyclization of the imine
good yield in the presence of CeCl3/NaI as catalyst. The intermediate (Osowska and Miljanic, 2011). Recently,
one-pot synthesis was carried out in toluene at 100°C methods using transition metal-catalyzed coupling reac-
using O2 as the oxidant.
tions for the construction of benzoxazole framework were
also reported, including copper (Kidwai et al., 2006; Ueda
Keywords: cerium(III) chloride; Lewis acid one-pot syn- and Nagasawa, 2008, 2009; Guru et al., 2011), palladium
thesis; sodium iodide; 2-substituted benzoxazoles.
(Ackermann et al., 2010), iron (Bonnamour et al., 2008),
ruthenium, iridium (Blacker et al., 2009), nickel (Canivet
et al., 2009), and cobalt-catalyzed (Saha et al., 2010) coup-
lings. Activated carbon (Kawashita et al., 2003) and ZnBr2/
ABM (Riadi et al., 2011) have also been used to promote the
benzoxazole preparation reactions. Marsden et al. (2008)
have reported that 2-arylbenzoxazoles can be synthesized
by aza-Wittig reactions.
*Corresponding authors: Xun Zhu and Yunyang Wei, School of
Chemical Engineering, Nanjing University of Science and
Technology, Nanjing, P.R. China, e-mail: ywei@mail.njust.edu.cn;
zhuxun246@126.com
Xun Zhu: Department of Chemical Engineering, Yancheng Textile
Vocational Technology College, Yancheng, P.R. China
In the course of our studies on the synthesis of 2-sub-
stituted benzoxazoles, it was found that CeCl3/NaI, a
system used by Sabitha et al. (2004) for the synthesis of
1,5-benzodiazepines, is an efficient catalyst for the syn-
thesis of the benzoxazole framework from 2-aminophenol
Introduction
Recently, cerium(III) chloride has become an attrac- and aldehydes (Scheme 1).
tive candidate as a Lewis acid in organic chemistry for
its relative nontoxicity and ready availability (Bartoli
et al., 2007). 2-Substituted benzoxazoles are important
heterocyclic compounds that have received considera- Results and discussion
ble attention in the field of medicinal chemistry. These
heteroaromatic derivatives are commonly encountered The initial experiments were carried out in toluene using
in melatonin receptor agonists (Sun et al., 2004), estro- benzaldehyde as the model substrate. Effects of a range
gen receptor agonists (Manas et al., 2004), 5-HT3 recep- of catalysts on the reaction were tested. It was found that
tor agonists (Yoshida et al., 2005), Rho kinase inhibitors in the presence of 15 mol% of CeCl3 and 10 mol% of NaI
(Sessions et al., 2008), and antitumor agents (Aiello as catalyst, the yield of 2-phenyl benzoxazole was higher
et al., 2008). In addition to their use in pharmaceuticals, than in other cases (Table 1, entries 1–7). Toluene was
benzoxazoles are recognized as an important scaffold in found to be the appropriate solvent. When the reaction
agrochemicals and other fine chemicals (Blacker et al., was carried out in tetrahydrofuran (THF) or 1,4-dioxane,
2009). The widespread interest in benzoxazole-contain- the yield of 2-phenyl-benzoxazole was lower (Table 1,
ing structures has promoted extensive studies for their entries 7–9).
synthesis.
Encouraged by the preliminary results, we then
A conventional method for the synthesis of 2-substi- studied the scope of the reaction. It was found that both
tuted benzoxazoles is the reaction of 2-aminophenol with aliphatic aldehydes and aromatic aldehydes react with
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212ꢀ
ꢀX. Zhu and Y. Wei: Synthesis of benzoxazoles using CeCl3-NaI as catalyst
CeCl3 (15 mol%)
NaI (10 mol%)
NH2
OH
N
O
Conclusion
R
RCHO
Toluene/O2
100°C, 36 h
A new method for the synthesis of 2-substituted benzoxa-
zoles from 2-aminophenol and aldehydes in the presence
of 15 mol% of CeCl3 and 10 mol% of NaI was developed.
The one-pot synthesis is carried out in toluene at 100°C
using molecular oxygen as the oxidant. The procedure is
suitable for the synthesis of 2-aryl and 2-alkyl-substituted
benzoxazoles from 2-aminophenol and aromatic or ali-
phatic aldehydes.
1a-k
2a-k
a: R = H
g: R = 4-CH3C6H4
h: R = C6H5
b: R = CH3(CH2)2
c: R = CH3(CH2)3
d: R = 4-NO2C6H4
e: R = 4-ClC6H4
i: R = 4-CH3OC6H4
j: R = 2-styryl
k: R = 2-furyl
f: R = 4-BrC6H4
Scheme 1
Experimental
All chemicals (AR grade) were obtained from commercial resources
and used without further purification. Gas chromatography (GC) ana-
lysis was performed on an Agilent GC-6820 chromatograph equipped
with HP-Innowax (30 m×0.32 mm×0.5 μm) capillary column and a
flame ionization detector. GC-MS spectra were recorded on Thermo
Trace DSQ GC-MS spectrometer using TRB-5MS (30 m×0.25 mm×0.25
μm) column. Melting points were determined using a Yamato melting
2-aminophenol to form the corresponding 2-substituted
benzoxazoles in the presence of 15 mol% of CeCl3 and
10 mol% of NaI as catalyst (Scheme 1). With aromatic
aldehydes as substrates, the reactions proceed smoothly
at 100°C with easy workup operation and high product
yield (Scheme 1, 2d–j). The electronic properties of the
substituents in the aromatic aldehydes have a remark-
able influence on the reaction. The presence of electron-
withdrawing groups is beneficial for the reaction and
higher yields are obtained. The presence of electron-dona-
ting groups reduce the yield of the product (Scheme 1, 2g
and 2i). With aliphatic aldehydes such as butyraldehyde
or valeraldehyde as substrates, moderate to good yields
of the corresponding benzoxazoles are also obtained
(Scheme 1, 2b,c). With formaldehyde as substrate, a
low yield of benzoxazole was obtained, probably due to
the presence of H2O brought to the reaction system with
aqueous formaldehyde (Scheme 1, 2a). The use of hetero-
aryl aldehydes such as 2-furylcarboxaldehyde also give
low yields (Scheme 1, 2k).
1
point apparatus Model MP-21 and are uncorrected. H NMR spectra
were obtained with TMS as internal standard in CDCl3 using a Bruker
DRX 500 (500-MHz) spectrometer. Progress of the reactions was
monitored by TLC using silica-gel polygrams SIL G/UV 254 plates.
Column chromatography was performed using Silicycle (40–60
mm) silica gel. Products were identified by 1H NMR. All products are
known.
General experimental procedure
A solution of 2-aminophenol (1.2 mmol) and benzaldehyde (1 mmol)
in toluene (5 mL) was stirred for 20 min at room temperature and then
treated with CeCl3 (0.04 g, 0.15 mmol) and NaI (0.015 g, 0.1 mmol).
The mixture was stirred at 100°C under O2 for 36 h. The aqueous solu-
tion was extracted with ethyl acetate (3×10 mL), and the product was
purified on a small silica gel column with EtOA/petroleum ether (1:9)
as eluent.
Entry Catalyst (mol%)
Solvent
Temperature Yield
Benzoxazole (2a)ꢀYield 40%; this compound was obtained as oil
(°C)
(%)b
(Lee et al., 2009, yield 69%).
1
2
3
4
5
6
7
8
9
–
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
100
100
100
100
100
100
100
Reflux
<5
15
20
25
30
45
75
45
40
CuCl2 (10)
2-Propylbenzoxazole (2b)ꢀYield 70%; this compound was obtained
as oil (Cho et al., 2002, yield 59%).
AlCl3 (10)
CeCl3‧7H2O (10)
CeCl3 (10)
2-Butylbenzoxazole (2c)ꢀYield 66%; this compound was obtained
as oil (Blacker et al., 2009, yield 52%).
CeCl3 (20)
CeCl3-NaI (15–10)
CeCl3-NaI (15–10)
CeCl3-NaI (15–10)
2-(4-Nitrophenyl)benzoxazole (2d)ꢀYield 82%; this compound
was obtained as white crystals, mp 271–273°C (Kidwai et al., 2006,
yield 75%; mp 270–272°C).
1,4-Dioxane Reflux
Table 1 Optimization of the synthesis of 2-phenylbenzoxazolea.
aReaction conditions: 2-aminophenol, 1.2 mmol; benzaldehyde,
1 mmol; solvent, 5 mL; 100°C for 36 h under O2.
bGC-MS yield.
2-(4-Chlorophenyl)benzoxazole (2e)ꢀYield 80%; this compound
was obtained as white crystals, mp 152–154°C (Kawashita et al., 2003,
yield 88%; mp 153–154°C).
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X. Zhu and Y. Wei: Synthesis of benzoxazoles using CeCl3-NaI as catalystꢀ
ꢀ213
2-(4-Bromophenyl)benzoxazole (2f)ꢀYield 75%. This compound 2-(2-Styryl)benzoxazole (2j)ꢀYield 89%; this compound was obtain-
was obtained as white crystals, mp 157–158°C (Guru et al., 2011, yield ed as white solid, mp 86–87°C (Kidwai et al., 2006, yield 86%; mp
81%; mp 157–158°C).
86–88°C).
2-(4-Tolyl)benzoxazole (2g)ꢀYield 65%; this compound was obtain- 2-(Furan-2-yl)benzoxazole (2k)ꢀYield 42%; this compound was
ed as white solid, mp 116–117°C (Ackermann et al., 2010, yield 82%;
mp 117–118°C).
obtained as white solid, mp 88–89°C (Tauer et al., 1981, yield 35%;
mp 89–90°C).
2-Phenylbenzoxazole (2h)ꢀYield 73%; this compound was obtain-
ed as white crystals, mp 106–108°C (Kawashita et al., 2003, yield
78%; mp 106–107°C).
Acknowledgments: We are grateful to Nanjing University
of Science and Technology and Yancheng Textile Vocatio-
nal Technology College for financial support.
2-(4-Methoxyphenyl)benzoxazole (2i)ꢀYield 63%; this compound
was obtained as white solid, mp 104–106°C (Guru et al., 2011, yield
76%; mp 103–105°C).
Received April 14, 2012; accepted July 31, 2012; previously published
online September 1, 2012
References
Ackermann, L.; Barfuesser, S.; Pospech, J. Palladium-catalyzed
direct arylations, alkenylations, and benzylations through
C−H bond cleavages with sulfamates or phosphates as
electrophiles. Org. Lett. 2010, 12, 724–726.
2-nitrophenols or 1-aryl-2-nitroethanones. Tetrahedron Lett.
2009, 65, 8821–8831.
Manas, E. S.; Unwalla, R. J.; Xu, Z. B.; Malamas, M. S.; Miller, C. P.;
Harris, H. A.; Hsiao, C.; Akopian, T.; Hum, W.-T.; Malakian, K.;
Wolfrom, S.; Bapat, A.; Bhat, R. A.; Stahl, M. L.; Somers, W. S.;
Alvarez, J. C. Structure-based design of estrogen receptor-β
selective ligands. J. Am. Chem. Soc. 2004, 126, 15106–15119.
Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Catalytic
aza-Wittig cyclizations for heteroaromatic synthesis. Org. Lett.
2008, 10, 2589–2591.
Aiello, S.; Wells, G.; Stone, E. L.; Kadri, H.; Bazzi, R.; Bell, D. R.;
Stevens, M. F. G.; Matthews, C. S.; Bradshaw, T. D.; Westwell,
A. D. Synthesis and biological properties of benzothiazole,
benzoxazole, and chromen-4-one analogues of the potent
antitumor agent 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole
(PMX 610, NSC 721648). J. Med. Chem. 2008, 51, 5135–5139.
Bartoli, G.; Fernández-Bolaños, J. G.; Di Antonio, G.; Foglia, G.;
Giuli, S.; Gunnella, R.; Mancinelli, M.; Marcantoni, E.; Paoletti,
M. SiO2-supported CeCl3·7H2O-NaI Lewis acid promoter:
investigation into the Garcia Gonzalez reaction in solvent-free
conditions. J. Org. Chem. 2007, 72, 6029–6036.
Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.;
Williams, J. M. J. Synthesis of benzazoles by hydrogen-transfer
catalysis. Org. Lett. 2009, 11, 2039–2042.
Bonnamour, J.; Bolm, C. Iron-catalyzed intramolecular O-arylation:
synthesis of 2-aryl benzoxazoles. Org. Lett. 2008, 10,
2665–2667.
Osowska, K.; Miljanic, O. S. Oxidative kinetic self-sorting of a
dynamic imine library. J. Am. Chem. Soc. 2011, 133, 724–727.
Pottorf, R. S.; Chadha, N. K.; Katkevics, M.; Ozola, V.; Suna, E.;
Ghane, H.; Regberg, T.; Player, M. R. Parallel synthesis of
benzoxazoles via microwave-assisted dielectric heating.
Tetrahedron Lett. 2003, 44, 175–178.
Riadi, Y.; Mamouni, R.; Azzalou, R.; Haddad, M. E.; Routier, S.;
Guillaumet, G.; Lazar, S. An efficient and reusable hetero-
geneous catalyst animal bone meal for facile synthesis
of benzimidazoles, benzoxazoles, and benzothiazoles.
Tetrahedron Lett. 2011, 52, 3492–3495.
Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Nickel-catalyzed biaryl
coupling of heteroarenes and aryl halides/triflates. Org. Lett.
2009, 11, 1733–1736.
Cho, C. S.; Kim, D. T.; Zhang, J. Q.; Ho, S.-L.; Kim, T.-J.; Shim, S. C.
Tin(II) chloride-mediated synthesis of 2-substituted
benzoxazoles. J. Heterocyclic Chem. 2002, 39, 421–423.
Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Copper(II)-catalyzed
conversion of bisaryloxime ethers to 2-arylbenzoxazoles via
C−H functionalization/C−N/C−O bonds formation. Org. Lett.
2011, 13, 1194–1197.
Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Direct
and practical synthesis of 2-arylbenzoxazoles promoted by
activated carbon. Org. Lett. 2003, 5, 3713–3715.
Kidwai, M.; Bansal, V.; Saxena, A.; Aerry, S.; Mozumdar, S.
Cu-nanoparticles: efficient catalysts for the oxidative
cyclization of Schiffs’ bases. Tetrahedron Lett. 2006, 47,
8049–8053.
Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Reddy, N. M.; Yadav, J. S.
A new, efficient and environmentally benign protocol for the
synthesis of 1,5-benzodiazepines using cerium(III) chloride/
sodium iodide supported on silica gel. Adv. Synth. Catal. 2004,
346, 921–923.
Saha, P.; Ali, M. A.; Ghosh, P.; Punniyamurthy, T. Cobalt-catalyzed
intramolecular C–N and C–O cross-coupling reactions:
synthesis of benzimidazoles and benzoxazoles. Org. Biomol.
Chem. 2010, 8, 5692–5699.
Sessions, E. H.; Yin, Y.; Bannister, T. D.; Weiser, A.; Griffin, E.; Pocas, J.;
Cameron, M. D.; Ruiz, C.; Lin, L.; Schuerer, S. C.; Schroeter, T.;
LoGrasso, P.; Feng, Y. Benzimidazole- and benzoxazole-based
inhibitors of Rho kinase. Bioorg. Med. Chem. Lett. 2008, 18,
6390–6393.
Sun, L.-Q.; Chen, J.; Bruce, M.; Deskus, J. A.; Epperson, J. R.;
Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.; Ryan, E.;
Xu, C. Synthesis and structure–activity relationship of novel
benzoxazole derivatives as melatonin receptor agonists.
Bioorg. Med. Chem. Lett. 2004, 14, 3799–3802.
Lee, J. J.; Kim, J.; Jun, Y. M.; Lee, B. M.; Kim, B. H. Indium-mediated
one-pot synthesis of benzoxazoles or oxazoles from
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Download Date | 2/21/13 4:49 PM

214ꢀ
ꢀX. Zhu and Y. Wei: Synthesis of benzoxazoles using CeCl3-NaI as catalyst
Tauer, E.; Grellmann, K. H. Photochemical and thermal reactions of
aromatic Schiff bases. J. Org. Chem. 1981, 46, 4252–4258.
Ueda, S.; Nagasawa, H. Synthesis of 2-arylbenzoxazoles by
copper-catalyzed intramolecular oxidative CO coupling of
benzanilides. Angew. Chem. Int. Edit. 2008, 47, 6411–6413.
Ueda, S.; Nagasawa, H. Copper-catalyzed synthesis of
benzoxazoles via a regioselective C−H functionalization/C−O
bond formation under an air atmosphere. J. Org. Chem. 2009,
74, 4272–4277.
Yoshida, S.; Shiokawa, S.; Kawano, K.-I.; Ito, T.; Murakami, H.;
Suzuki, H.; Sato, Y. Orally active benzoxazole derivative
as 5-HT3 receptor partial agonist for treatment of diarrhea-
predominant irritable bowel syndrome. J. Med. Chem. 2005,
48, 7075–7079.
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