Synthesis of 2-arylbenzoxazoles through oxidation of C-H bonds adjacent to oxygen atoms

Article abstract of DOI:10.1002/ejoc.201301504

A practical and simple synthesis of benzoxazoles from easily available substrates was developed. The protocol is triggered by an iron-catalyzed tandem oxidative process from simple ether derivatives. A practical and simple synthesis of benzoxazoles from easily available substrates is developed. The protocol is triggered by an iron-catalyzed tandem oxidative process from simple ether derivatives. Copyright

Full text of DOI:10.1002/ejoc.201301504

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301504
Synthesis of 2-Arylbenzoxazoles through Oxidation of C–H Bonds Adjacent to
Oxygen Atoms
Lijun Gu,*[a] Wei Wang,[a] Yong Xiong,[a] Xiangzhong Huang,[a] and Ganpeng Li*[a]
Keywords: Synthetic methods / C–H activation / Oxidation / Domino reactions / Nitrogen heterocycles / Iron
A practical and simple synthesis of benzoxazoles from easily
available substrates was developed. The protocol is triggered
by an iron-catalyzed tandem oxidative process from simple
ether derivatives.
these advances, versatile and efficient methods for the direct
construction of substituted benzoxazoles that are compati-
ble with various functional groups and that can be per-
formed by using readily available starting materials remain
highly desirable.
Introduction
Benzoxazoles are an important class of nitrogen-contain-
ing heterocycles, as they are the basic constituents of
numerous natural products, biologically active alkaloids,
and pharmaceuticals.[1] These compounds have been exten-
sively studied for their biological and therapeutic activities.
They have been shown to act as cathepsin inhibitors, topo-
isomerase II inhibitors, and PTP-1B inhibitors. In addition,
substituted benzoxazoles are increasingly gaining impor-
tance in materials science, especially in the field of fluores-
cent materials.[2] Consequently, the development of syn-
thetic methods for the preparation of functionalized benz-
oxazoles has received considerable attention.[3] General
methods for the synthesis of benzoxazole derivatives involve
two types of reactions.[4] One is the metal-catalyzed intra-
molecular cyclization of o-haloanilides. The second ap-
proach mainly involves the condensation of 2-aminophenol
with either a carboxylic acid derivative under strong acid/
high temperature conditions or an aromatic aldehyde under
strong oxidative conditions. Recently, the activation of C–H
bonds has received much attention for the straightforward
construction of C–C and C–heteroatom bonds. Various
substituted benzoxazoles have been successfully synthesized
by direct C–H activation and subsequent C–C bond forma-
tion with aryl halides, aromatic carboxylic acids, sodium
sulfinates, aryl triflates, arylsilanes, and aryl boronic acids;
even arene C–H bonds have been activated by double C–H
activation.[5] Recently, Nguyen and co-workers reported an
iron sulfide based catalytic system for the direct condensa-
tion of 2-hydroxynitrobenzenes with activated methyl
groups to construct substituted benzoxazoles.[6] Despite
Transformation of an unactivated C(sp3)–H bond into
more usable compounds has attracted much attention.[7] In
particular, great progress has been achieved in the function-
alization of C–H bonds of ethers.[8] It has been reported
that, for ether derivatives, the C(sp3)–H bonds adjacent to
oxygen atoms have a relatively low bond dissociation en-
ergy, which indicates that homolytic cleavage of these C–H
bonds will easily take place.[9] Therefore, it is possible to
activate this type of compound through a single-electron
transfer process. Recently, Lei and co-workers reported the
nickel-catalyzed oxidative arylation of the ortho-C(sp3)–H
bond adjacent to the oxygen atom of THF and 1,4-diox-
ane.[10] They used arylboronic acids as the nucleophiles, and
a series of α-arylated ethers were prepared. We envisioned
that amino groups might be used as the nucleophiles to
form oxazolidine derivatives that could yield oxazole deriv-
atives by deprotonation and oxidation (Scheme 1). In con-
nection with our broader interest in the synthesis of nitro-
gen-containing heterocycle compounds,[11] herein we dis-
close our preliminary results on the iron/(tBuO)2-mediated
transformation of 2-(aryloxy)anilines for the synthesis of
benzoxazoles under neutral reaction conditions.[12]
[a] Key Laboratory of Chemistry in Ethnic Medicinal Resources,
State Ethnic Affairs, Commission & Ministry of Education,
Yunnan University of Nationalities,
Kunming, Yunnan, P. R. China, 650500
E-mail: gulijun2005@126.com
ganpeng_li@sina.com.cn
www.ynni.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301504.
Scheme 1. Our strategy to substituted benzoxazoles (DTBP = di-
tert-butyl peroxide).
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L. Gu, W. Wang, Y. Xiong, X. Huang, G. Li
SHORT COMMUNICATION
substituents on the methylene-bridged phenyl ring, such as
halogen, cyano, alkyl, and ether groups, were well tolerated
under the optimal conditions. Generally, an electron-donat-
ing substituent on the methylene-bridged phenyl ring
caused a considerable increase in the yield (e.g., see prod-
ucts 2ba–2ha). A substituent at the para position of the
methylene-bridged phenyl ring afforded desired product 2ba
smoothly. However, a substituent at the ortho position of
the methylene-bridged phenyl ring gave corresponding
product 2ca in a lower yield. These results indicate that
steric effects have an impact on the efficiency of the reac-
tions. Notably, the introduction of heterocycles into this
system made this method more useful for the preparation
of pharmaceuticals and materials (e.g., see product 2ia).
Interestingly, the polysubstituted ether derivative gave de-
sired oxidative product 2ja in moderate yield. Unfortu-
nately, 2-butoxyaniline did not deliver the desired product
(Table 2, entry 4).
Results and Discussion
In the initial phase of this study, we investigated the reac-
tion of 2-(benzyloxy)aniline in the presence of FeCl2
(10 mol-%), 1,2-dichloroethane [DCE (1.0 mL)], and
(tBuO)2 [DTBP (3.0 equiv.)] at 110 °C with stirring for 18 h.
To our delight, the desired product, 2-phenylbenzoxazole
(2aa), was isolated in 56% yield (Table 1, entry 1). It was
found that FeBr2 was superior to other iron sources
(Table 1, entries 1–6). Variation of the peroxide showed that
DTBP provided the best results (Table 1, entries 7–12). Of
the solvents tested, benzene proved particularly suitable
(Table 1, entries 13–15). With regard to the optimal amount
of the peroxide, the reaction with 3.0 equiv. of DTBP pro-
vided the best results (Table 1, entries 13, 16, 17). Without
DTBP, none of the desired product was obtained (Table 1,
entry 18). In the absence of FeBr2, this reaction did not
work (Table 1, entry 19). Notably, other metal salts such as
CuBr2, PdBr2, and NiBr2 were all ineffective (Table 1, en-
tries 20–22).
Table 2. Synthesis of substituted benzoxazoles with a variety of
ether derivatives 1.
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Peroxide (4.0 equiv.)
Yield[b] [%]
1
2
3
4
5
6
7
FeCl2
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
benzoyl peroxide
TBHP (5 m in decane)
TBHP (70% in H2O)
H2O2
Oxone
O2 (1 atm)
DTBP
DTBP
DTBP
DTBP
DTBP
none
DTBP
56
79
42
51
63
49
19
72
trace
n.d.
n.d.
n.d.
84
32
48
71
84
n.d.
n.d.
11
trace
trace
FeBr2
Fe(OAc)2
Fe(acac)2
FeBr3
Fe(acac)3
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
none
8[c]
9[c]
10[d]
11
12
13[e]
14[f]
15[g]
16[h]
17[i]
18
19
20
21
22
CuBr2
PdBr2
NiBr2
DTBP
DTBP
DTBP
[a] Reaction conditions: 1a (0.3 mmol), solvent/DCE (1.5 mL), cat-
alyst (10 mol-%), peroxide (3.0 equiv.), 110 °C, under an argon at-
mosphere. [b] Yield of isolated product. [c] TBHP = tert-butyl hy-
droperoxide. [d] H2O2 = 30% in water. [e] PhH as a solvent.
[a] Reaction conditions: 1a (0.3 mmol), benzene (1.5 mL), FeBr2
(10 mol-%), DTBP (3.0 equiv.), 110 °C, under an argon atmo-
sphere. [b] Yield of isolated product.
[f] EtOAc as
a solvent. [g] MeNO2 as a solvent. [h] DTBP
(2.0 equiv.). [i] DTBP (4.0 equiv.).
Of equal importance is the observation that significant
With the optimal reaction conditions established, we structural variation of the amino group substituted phenyl
next investigated the substrate scope of the reaction by em- ring is possible. As shown in Table 3. Substituents at the
ploying a variety of 2-(aryloxy)anilines. As summarized in amino group substituted phenyl ring did not affect the effi-
Table 2, various ether derivatives 1 were found to partici- ciency of this transformation, and the desired benzoxazole
pate in this cascade process. Screening showed that several products were produced in good yields. It was found that
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2-Arylbenzoxazoles through Oxidation of C–H Bonds
reactions of 2-(benzyloxy)aniline derivatives 1 bearing elec-
tron-donating groups proceeded well and gave the desired
benzoxazole derivatives 2la, 2ma, and 2na in 77, 74, and
70% yield, respectively. Also, halo-substituted 2-(benz-
yloxy)aniline derivatives were well tolerated (Table 3 en-
tries 4 and 5). 3-(Benzyloxy)naphthalen-2-amine was also
used in this reaction to afford the corresponding benz-
oxazole in a good yield (Table 3 entry 6).
Scheme 2. Control experiment.
On the basis of observations and previous studies,[10,13]
a
plausible mechanism is proposed, as shown in Scheme 3.
Initially, DTBP is split by Fe2+ into a tert-butoxyl radical,
which results in the oxidation of Fe2+ to Fe3+. A carbon-
centered radical species adjacent to oxygen A could be
formed from 1a, which could be further oxidized to form
cation B through an initial single-electron-transfer (SET)
step. Then, intramolecular attack of the nitrogen atom pro-
vides C, which gives product 2aa by deprotonation and oxi-
dation.
Table 3. Synthesis of substituted benzoxazoles with a variety of 2-
(benzyloxy)aniline derivatives 1.
Scheme 3. Proposed reaction mechanism.
Conclusions
In summary, we have developed a unique method for the
construction of substituted benzoxazoles from 2-(aryloxy)-
anilines. The utilization of inexpensive, readily available
starting materials and catalysts provides significant advan-
tages that lead to increased usefulness of the reaction. Dur-
ing this transformation, four hydrogen atoms were removed.
In addition, at least four bonds were cleaved and one C=N
bond was constructed in one pot. In addition, high func-
tional-group tolerance under relatively mild conditions and
great regioselectivity were exhibited.
[a] Reaction conditions: 1a (0.3 mmol), benzene (1.5 mL), FeBr2
(10 mol-%), DTBP (3.0 equiv.), 110 °C, under an argon atmo-
sphere. [b] Yield of isolated product.
Finally, we examined the scalability of this iron-catalyzed
methodology. Thus, the standard reaction of 2-(benzyloxy)-
aniline was scaled up to a 5 mmol scale by using 10 mol-%
FeBr2, DTBP (4.0 equiv.), and benzene (4.0 mL) at 110 °C
with stirring for 18 h, and the product was delivered in up
to 78% yield.
To gain some understanding of the reaction, 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO, 1.0 equiv.), a radi-
cal-trapping reagent, was added into the reaction mixture
under the standard conditions. No benzoxazole product
was obtained. These results indicate that a radical interme-
diate is most likely involved in the initial steps of this trans-
formation. Furthermore, the reaction of 2-phenyl-2,3-di-
hydrobenzoxazole (C) under the standard conditions was
investigated. Desired product 2-phenylbenzoxazole (2aa)
was obtained in 94% yield (Scheme 2). This result indicates
that intermediate C might be involved in this process.
Experimental Section
Representative Procedure (3aa in Table 1): A Schlenk tube was
charged with 2-(benzyloxy)aniline (1a, 0.3 mmol), FeBr2 (10 mol-
%), and DTBP (3.0 equiv.). Then, the tube was charged with argon,
and the mixture was stirred at 110 °C for about 18–22 h. Upon
completion of the reaction, the mixture was diluted with ethyl acet-
ate (30 mL), washed with a saturated solution of brine (8 mL),
washed with a saturated solution of NaHCO3 (8 mL), washed with
a saturated solution of brine (8 mL), dried (Na2SO4), and concen-
trated in vacuo. The resulting residue was purified by silica gel col-
umn chromatography (hexane/ethyl acetate) to afford substituted
benzoxazoles 3aa.
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L. Gu, W. Wang, Y. Xiong, X. Huang, G. Li
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[5]
a) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom,
R. D. Larsen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 3674;
b) F. Zhang, M. Greaney, Angew. Chem. 2010, 122, 2828; An-
gew. Chem. Int. Ed. 2010, 49, 2768; c) L. Ackermann, A. Al-
thammer, S. Fenner, Angew. Chem. 2009, 121, 207; Angew.
Chem. Int. Ed. 2009, 48, 201; d) H. Hachiya, K. Hirano, T.
Satoh, M. Miura, Angew. Chem. 2010, 122, 2248; Angew.
Chem. Int. Ed. 2010, 49, 2202; e) S. Ranjit, X. Liu, Chem. Eur.
J. 2011, 17, 1105; f) Z. Wang, K. Li, D. Zhao, J. Lan, J. You,
Angew. Chem. 2011, 123, 5477; Angew. Chem. Int. Ed. 2011,
50, 5365; g) C. Li, P. Li, J. Yang, Lei, Wang, Chem. Commun.
2012, 48, 4214.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR and 13C NMR spectra of all key intermediates and final
products.
Acknowledgments
The authors are grateful for financial support from the Educational
Bureau of Yunnan Province (grant number 2010Y431) and the
State Ethnic Affairs Commission (grant number 12YNZ05).
[6]
T. B. Nguyen, L. Ermolenko, A. A. Mourabit, J. Am. Chem.
Soc. 2013, 135, 118.
O. Baudoin, Chem. Soc. Rev. 2011, 40, 4902.
a) S. Zhang, F. Zhang, Y. Tu, Chem. Soc. Rev. 2011, 40, 1937.
a) S. Pan, J. Liu, H. Li, Z. Wang, X. Guo, Z. Li, Org. Lett.
2010, 12, 1932; b) X. Guo, S. Pan, J. Liu, Z. Li, J. Org. Chem.
2009, 74, 8848; c) Z. Li, R. Yu, H. Li, Angew. Chem. 2008, 120,
7607; Angew. Chem. Int. Ed. 2008, 47, 7497.
[1] a) H. Takuzo, I. Masataka, T. Konosuke, T. Masanobu, Chem.
Pharm. Bull. 1982, 30, 2996; b) L. Q. Sun, J. Chen, K. Takaki,
G. Johnson, L. Iben, C. D. Mahle, E. Ryan, C. Xu, Bioorg.
Med. Chem. Lett. 2004, 14, 1197; c) M. L. McKee, S. M. Ker-
win, Bioorg. Med. Chem. 2008, 16, 1775; d) L. Xiao, Chin. J.
Org. Chem. 2011, 31, 878; e) S. M. Johnson, S. Connelly, I. A.
Wilson, J. W. Kelly, J. Med. Chem. 2008, 51, 260; f) D. R.
[7]
[8]
[9]
Chancellor, K. E. Davies, O. D. Moor, C. R. Dorgan, P. D. [10] a) D. Liu, C. Liu, H. Li, A. Lei, Angew. Chem. 2013, 125, 4549;
Johnson, A. G. Lambert, D. Lawrence, C. Lecci, C. Maillol,
P. J. Middleton, G. Nugent, S. D. Poignant, A. C. Potter, P. D.
Price, R. J. Pye, R. Storer, J. M. Tinsley, R. van Well, R. Vick-
ers, J. Vile, F. J. Wilkes, F. X. Wilson, S. P. Wren, G. Wynne, J.
Med. Chem. 2011, 54, 3241; g) S. Vodela, R. V. R. Mekala,
R. R. Danda, V. Kodhati, Chin. Chem. Lett. 2013, 24, 625; h)
H. Ma, Z. Zha, Z. Zhang, L. Meng, Z. Wang, Chin. Chem.
Lett. 2013, 24, 780.
Angew. Chem. Int. Ed. 2013, 52, 4453.
[11] a) L. Gu, X. Li, J. Braz. Chem. Soc. 2011, 22, 2036; b) L. Gu,
C. Jin, Org. Biomol. Chem. 2012, 10, 7089; c) L. Gu, R. Wang,
X. Huang, C. Jin, Chin. J. Chem. 2012, 30, 2483; d) L. Gu, X.
Li, J. Heterocycl. Chem. 2013, 50, 408.
[12] For selected examples on Fe-catalyzed reactions, see: a) Y. Li,
L. Ma, F. Jia, Z. Li, J. Org. Chem. 2013, 78, 5638; b) X. Guo,
R. Yu, H. Li, Z. Li, J. Am. Chem. Soc. 2009, 131, 17387; c) H.
Li, Z. He, X. Guo, W. Li, X. Zhao, Z. Li, Org. Lett. 2009, 11,
4176; d) Z. Li, L. Cao, C. Li, Angew. Chem. 2007, 119, 6625;
Angew. Chem. Int. Ed. 2007, 46, 6505; e) H. Egami, R. Shimizu,
Y. Usui, M. Sodeoka, Chem. Commun. 2013, 49, 7346; f) S.
Luo, D. Yu, R. Zhu, X. Wang, L. Wang, Z. Shi, Chem. Com-
mun. 2013, 49, 7794; g) D. H. Dethe, G. M. Murhade, Chem.
Commun. 2013, 49, 8051; h) Z. Huang, L. Jin, Y. Feng, P. Peng,
H. Yi, A. Lei, Angew. Chem. 2013, 125, 7292; Angew. Chem.
Int. Ed. 2013, 52, 7151; i) S. Pan, J. Liu, Y. Liu, Z. Li, Chin.
Sci. Bull. 2012, 57, 2382; j) K. Junge, B. Wendt, S. Zhou, M.
Beller, Eur. J. Org. Chem. 2013, 2061.
[2] a) Y. Sato, M. Yamada, S. Yoshida, T. Soneda, M. Ishikawa,
T. Nizato, K. Suzuki, F. Konno, J. Med. Chem. 1998, 41, 3015;
b) I. H. Leaver, B. Milligan, Dyes Pigm. 1984, 5, 109; c) J.
Boyer, E. Arnoult, M. Médebielle, J. Guillemont, J. Unge, D.
Jochmans, J. Med. Chem. 2011, 54, 797.
[3] a) Y. Cho, C. Lee, C. Cheon, Tetrahedron 2013, 69, 6565; b)
R. D. Viirre, G. Evinder, R. A. Batey, J. Org. Chem. 2008, 73,
3452; c) F. Su, S. C. Mathew, L. Mohlmann, M. Antonietti, X.
Wang, S. Blechert, Angew. Chem. 2011, 123, 683; Angew. Chem.
Int. Ed. 2011, 50, 657; d) G. Altenhoff, F. Glorius, Adv. Synth.
Catal. 2004, 346, 1661; e) C. Sheng, X. Che, W. Wang, S. Wang,
Y. Cao, J. Yao, Z. Miao, W. Zhang, Eur. J. Med. Chem. 2011,
46, 1706.
[13] a) Y. Zhang, C. Li, Angew. Chem. 2006, 118, 1983; Angew.
Chem. Int. Ed. 2006, 45, 1949; b) C. Li, Acc. Chem. Res. 2009,
42, 335; c) W. Wei, M. Zhou, J. Fan, W. Liu, R. Song, J. Li,
Angew. Chem. 2013, 125, 3726; Angew. Chem. Int. Ed. 2013,
52, 3638.
[4] a) D. W. Hein, R. J. Alheim, J. J. Leavitt, J. Am. Chem. Soc.
1957, 79, 427; b) P. Saha, T. Ramana, N. Purkait, M. A. Ali,
R. Paul, T. Punniyamurthy, J. Org. Chem. 2009, 74, 8719; c) S.
Ueda, H. Nagasawa, Angew. Chem. 2008, 120, 6511; Angew.
Chem. Int. Ed. 2008, 47, 6411.
Received: October 3, 2013
Published Online: December 2, 2013
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