Copper-catalyzed synthesis of benzoxazoles via a regioselective C-H functionalization/C-O bond formation under an air atmosphere

Article abstract of DOI:10.1021/jo900513z

(Chemical Equation Presented) An efficient method for the synthesis of functionalized benzoxazoles is described that involves a copper(II)-catalyzed regioselective C-H functionalization/C-O bond formation protocol. The use of dichlorobenzene as a solvent at 160°C allows the use of air as the terminal oxidant in the catalytic synthesis of benzoxazoles in a process that has high functional group tolerance. The presence of a directing group at the meta position markedly improves the reaction efficacy and a variety of 7-substituted benzoxazoles are selectively produced under mild reaction conditions. The mechanism of the reaction is also discussed in this report.

Full text of DOI:10.1021/jo900513z

Copper-Catalyzed Synthesis of Benzoxazoles via a Regioselective
C-H Functionalization/C-O Bond Formation under an Air
Atmosphere
Satoshi Ueda and Hideko Nagasawa*
Laboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical UniVersity,
5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
hnagasawa@gifu-pu.ac.jp
ReceiVed March 10, 2009
An efficient method for the synthesis of functionalized benzoxazoles is described that involves a copper(II)-
catalyzed regioselective C-H functionalization/C-O bond formation protocol. The use of dichlorobenzene
as a solvent at 160 °C allows the use of air as the terminal oxidant in the catalytic synthesis of benzoxazoles
in a process that has high functional group tolerance. The presence of a directing group at the meta
position markedly improves the reaction efficacy and a variety of 7-substituted benzoxazoles are selectively
produced under mild reaction conditions. The mechanism of the reaction is also discussed in this report.
Introduction
tumor agents.7 In addition to their use in medicinal chemistry,
benzoxazoles are recognized as an important scaffold in
fluorescent probes such as anion and metal cation sensors.8
Because of these and other applications, much attention has been
paid to the development of efficient methods for the preparation
of benzoxazoles.
A number of methods for the synthesis of benzoxazoles have
been reported. Among these, two classical approaches that start
from 2-aminophenol precursors have often been applied for the
elaboration of the benzoxazole moiety. The first approach
involves a condensation reaction of the 2-aminophenols with
acid chlorides in the presence of strong acid under heat or
microwave irradiation.9 The second involves the reaction of the
2-aminophenols with aldehydes in the presence of a stoicheo-
metric or catalytic amount of an oxidant.10 Recently, several
Benzoxazoles are an important class of heterocyclic com-
pounds that have many applications in medicinal chemistry. For
example, benzoxazole derivatives have been characterized as
estrogen receptor agonists,1 5-HT3 receptor agonists,2 melatonin
receptor agonists,3 HIV-1 reverse transcriptase inhibitors,4
amyloidogenesis inhibitors,5 Rho kinase inhibitors,6 and anti-
(1) (a) 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. J. Am.
Chem. Soc. 2004, 126, 15106. (b) Malamas, M. S.; Manas, E. S.; McDevitt,
R. E.; Gunawan, I.; Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson,
R. A.; Keith, J. C., Jr.; Harris, H. A. J. Med. Chem. 2004, 47, 5021.
(2) Yoshida, S.; Shiokawa, S.; Kawano, K.; Ito, T.; Murakami, H.; Suzuki,
H.; Sato, Y. J. Med. Chem. 2005, 48, 7075–7079.
(3) (a) Sun, L.-Q.; Chen, J.; Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.;
Ryan, E.; Xu, C. Bioorg. Med. Chem. Lett. 2004, 14, 1197. (b) 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. Bioorg. Med. Chem. Lett. 2004, 14, 3799.
(4) (a) Saari, W. S.; Hoffman, J. M.; Wai, J. S.; Fisher, T. E.; Rooney, C. S.;
Smith, A. M.; Thomas, C. M.; Goldman, M. E.; O’Brien, J. A. J. Med. Chem.
1991, 34, 2922. (b) Goldman, M. E.; Nunberg, J. H.; O’Brien, J. A.; Quintero,
J. C.; Schleif, W. A.; Freund, K. F.; Gaul, S. L.; Saari, W. S.; Wai, J. S.; Hoffman,
J. M. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 6863.
(6) 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. Bioorg. Med. Chem. Lett. 2008, 18, 6390.
(7) (a) 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. J. Med.
Chem. 2008, 51, 5135. (b) Rida Samia, M.; Ashour Fawzia, A.; El-Hawash Soad,
A. M.; ElSemary Mona, M.; Badr Mona, H.; Shalaby Manal, A. Eur. J. Med.
Chem. 2005, 40, 949.
(8) (a) Taki, M.; Wolford, J. L.; O’Halloran, T. V. J. Am. Chem. Soc. 2004,
126, 712. (b) Tanaka, K.; Kumagai, T.; Aoki, H.; Deguchi, M.; Iwata, S. J.
Org. Chem. 2001, 66, 7328. (c) Wu, Y.; Peng, X.; Fan, J.; Gao, S.; Tian, M.;
Zhao, J.; Sun, S. J. Org. Chem. 2007, 72, 62.
(5) (a) Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman, R. L.;
Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit, S.; Chiang, K. P.;
Dendle, M. T. A.; Sacchettini, J. C.; Kelly, J. W. Angew. Chem., Int. Ed. 2003,
42, 2758. (b) Johnson, S. M.; Connelly, S.; Wilson, I. A.; Kelly, J. W. J. Med.
Chem. 2008, 51, 260.
4272 J. Org. Chem. 2009, 74, 4272–4277
10.1021/jo900513z CCC: $40.75 2009 American Chemical Society
Published on Web 04/21/2009

Copper-Catalyzed Synthesis of Benzoxazoles
SCHEME 1. Copper-Catalyzed Intramolecular Oxidative
C-O Coupling
groups reported transition-metal-catalyzed C-N and/or C-O
coupling approaches for the synthesis of benzoxazoles using
halogenated arene precusors. For example, Glorius reported the
copper-catalyzed domino C-N/C-O bond forming reaction
between 1,2-dihaloarenes and primary amides.11 Batey and Bolm
reported copper-12 or iron-catalyzed13 intramolecular O-arylation
of 2-haloanilides for the synthesis of benzoxazoles. Although
these approaches provide an efficient access to functionalized
benzoxazoles, development of new and effective synthetic
approaches with high atom economy is still desired.
imidazoles.21 In a recent report, we also described a related
Cu(OTf)2/O2 catalytic system for intramolecular oxidative C-O
coupling of anilides in the synthesis of 2-arylbenzoxazoles
(Scheme 1).22,23 In this paper, we report a detailed investigation
of the scope and limitations of the intramolecular C-O coupling
process under an air atmosphere. We also disclose the results
of directing group assisted regiocontrolled C-H functionaliza-
tion/C-O bond formation for the efficient construction of
7-substituted benzoxazoles.
In recent years, transition metal-catalyzed C-H functional-
ization/C-heteroatom bond formation has emerged as a power-
ful method for the direct conversion of arenes and alkanes into
functionalized products.14 An intramolecular version of this
process has been successfully applied to the direct construction
of benzo-fused heterocyclic compounds from simple precusors.
In 2005, pioneering work by the Buchwald group15a afforded
efficient synthetic approaches to functionalized carbazoles by
palladium-catalyzed aromatic C-H activation followed by
intramolecular C-N bond formations.15 Subsequently, Yu and
Inamoto expanded the scope of the palladium-catalyzed C-H
functionalization/C-heteroatom bond forming reaction to in-
clude a variety of substrates thereby providing straightforward
access to other classes of benzo-fused heterocycles such as
indazoles,16 indolines,17 oxindoles,18 benzothiazoles,19 and
benzothiophenes.20 More recently, Buchwald has reported the
use of a novel Cu(OAc)2/O2 catalytic system for C-H func-
tionalization/C-N bond formation for the synthesis of benz-
Results and Discussion
Substrate Scope and Limitation. In our earlier work, a
number of 2-arylbenzoxazoles were successfully synthesized
from benzanilides utilizing 20 mol % of Cu(OTf)2 and 1 atm
of O2 gas as terminal oxidant in o-xylene at 140 °C (method
A). In a subsequent exploration, it became apparent that the
reactions in o-dichlorobenzene (o-DCB) at 160 °C under an
atmosphere of air gave superior results in most cases (method
B).
Table 1 summarizes the scope and limitation of the oxidative
C-O coupling reaction. Reactions of benzanilide 1a and
p-halogen-substituted derivatives 1b and 1c gave the corre-
sponding benzoxazoles in good yield (entries 1-3). The
reactions of substrates with a halogen or methoxy substituent
at the meta position proceeded regioselectively at the less
sterically hindered 6-position of the anilide to produce the
corresponding 5-substituted benzoxazoles 2d-f,i (entries 4-6
and 9). The m-halogen-substituted substrates 1d and 1e showed
lower reactivities than the corresponding p-halogen-substituted
substrates 1b and 1c (entries 2-5). Reaction of a substrate with
the strongly electron-withdrawing nitro group did not proceed
at all, even at elevated temperature (entry 7). Similarly, the
electron-deficient 4-pyridinyl derivative 1h failed to react and
starting material was recovered (entry 8). On the other hand,
substrates with an electron-donating alkoxy group at the 3- or
4-position gave the corresponding benzoxazoles in high yield
(entries 9 and 10). The strong dependence of the reaction
efficacy on the electronic nature of the arene ring indicates the
involvement of an electrophilic aromatic substitution process
in the cyclization reactions (see the later mechanistic discussion).
The use of method B provided an increase in yield for the
reactions of sterically demanding ortho-substituted substrates
1m and 1n (entries 13 and 14).
(9) (a) Hein, D. W.; Alheim, R. J.; Leavitt, J. J. J. Am. Chem. Soc. 1957, 79,
427. (b) Pottorf, R. S.; Chadha, N. K.; Katkevics, M.; Ozola, V.; Suna, E.; Ghane,
H.; Regberg, T.; Player, M. R. Tetrahedron Lett. 2002, 44, 175.
(10) For stoicheometric reactions, see: (a) Varma, R. S.; Saini, R. K.; Prakash,
O. Tetrahedron Lett. 1997, 38, 2621. (b) Srivastava, R. G.; Venkataramani, P. S.
Synth. Commun. 1988, 18, 1537. For catalytic reactions, see: (c) Kawashita, Y.;
Nakamichi, N.; Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5, 3713. (d) Chen,
Y.-X.; Qian, L.-F.; Zhang, W.; Han, B. Angew. Chem., Int. Ed. 2008, 47, 9330.
(11) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661.
(12) (a) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (b) Viirre,
R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452. (c) Barbero, N.;
Carril, M.; San Martin, R.; Dominguez, E. Tetrahedron 2007, 63, 10425.
(13) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665.
(14) For reviews, see: (a) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem.
2006, 4, 4041. (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. For
C-N bond formation, see: (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2006, 128, 9048. (d) Olson, D. E.; Du Bois, J. J. Am. Chem. Soc. 2008,
130, 11248. (e) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562. (f)
Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274. (g)
Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316. For C-O
bond formation, see: (h) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org.
Lett. 2006, 8, 3387. (i) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am.
Chem. Soc. 2008, 130, 13285. (j) Dick, A. R.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 2300. (k) Desai, L. V.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 9542. (l) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L.
J. Org. Chem. 2008, 73, 4717. (m) Kalyani, D.; Sanford, M. S. Org. Lett. 2005,
7, 4149. For C-halogen bond formation see: (n) Mei, T.-S.; Giri, R.; Maugel,
N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215. (o) Hull, K. L.; Anani,
W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. (p) Wan, X.; Ma, Z.;
Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128,
7416. (q) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112.
(r) Giri, R.; Wasa, M.; Breazzano, S. P.; Yu, J.-Q. Org. Lett. 2006, 8, 5685.
(15) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (c) Jordan-Hore, J. A.; Johansson,
C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130,
16184.
In contrast to the syntheses of 2-arylbenzoxazoles, the
developed procedures were not effective for the preparation of
simple 2-alkylbenzoxazoles. For example, the reaction of
pivalanilide 1o gave the desired product in only 19% yield.
Cyclohexane-substituted substrate 1p gave no desired product
and instead the aromatized product 2a was formed as a major
product.
(16) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org.
Lett. 2007, 9, 2931.
(17) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452.
(18) (a) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058. (b) Miura,
T.; Ito, Y.; Murakami, M. Chem. Lett. 2009, 38, 328.
(19) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10,
5147.
(21) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932.
(22) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411.
(23) For relevant copper-mediated C-H functionalization, see: (a) Chen, X.;
Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (b)
Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett. 2006, 35, 842.
(20) Inamoto, K.; Arai, Y.; Hiroya, K.; Doi, T. Chem. Commun. 2008, 5529.
J. Org. Chem. Vol. 74, No. 11, 2009 4273

Ueda and Nagasawa
TABLE 1. Scope of the Copper-Catalyzed Oxidative Cyclizationa
a Reaction conditions: method A: Cu(OTf)2 (20 mol %), o-xylene, O2 (1 atm), 140 °C, 28 h; method B: Cu(OTf)2 (20 mol %), o-DCB, air (1 atm),
160 °C, 28 h. b Not tested.
TABLE 2. Optimization of Directed Cyclization of 3aa
SCHEME 2. Directed Cyclization of 3a
Cu(OTf)2
entry (mol %)
solvent temp (°C) gas (1 atm) yield of 4a (%)
1
2
3
4
20
20
20
10
o-xylene
o-xylene
o-DCB
140
110
110
110
O2
air
air
air
82b
72
89
73
o-DCB
a Reaction run with 0.25 mmol substrate for 12 h. b Reaction time )
28 h.
A Directed Cyclization Approach to 7-Substituted Ben-
zoxazoles. Next, we focused our attention on the regioselectivity
of the C-H functionalization/cyclization.24 As discussed above,
cyclization of m-halogen- or m-methoxy-substituted substrates
cyclized at a less sterically hindered site. In contrast, m-
pyrrolidinone-substituted substrate 3a cyclized exclusively at
the more sterically hindered 2 position to afford 7-substituted
benzoxazole 4a (Scheme 2). This regioselectivity can be ascribed
to the formation of the doubly coordinated intermediate 5. In
addition to regiocontrol, the presence of the pyrrolidinone
directing group at the meta position seems to improve the
reaction efficacy (Table 2). The cyclization of 3a proceeds under
an atmosphere of air at 110 °C without significant drop in yield
(entry 2). The use of o-DCB as a solvent at 110 °C gave the
best result (entry 3). When the catalyst loading was lowered to
10 mol %, the yield of 4a dropped to 73% yield.
The relatively mild conditions as well as the high yield of
the directed cyclization of 3a encouraged us to extend this
methodology to the synthesis of a series of 7-substituted
benzoxazoles. To our knowledge, there are no reports on the
systematic evaluation of directed cyclization by aromatic C-H
functionalization/C-heteroatom bond formation. As shown in
Table 3, a broad range of functional groups can be utilized as
directing group in the directed C-O coupling reactions.
The reaction of oxazolidinone-substituted substrates 3b gave
the desired 7-substituted benzoxazole 4b in good yield (entry
1). A similar result was obtained with the acyclic carbamate-
substituted substrate 3c (entry 2). The reaction of the m-
acetamide-substituted substrate 3d gave a mixture of 2-phenyl-
benzoxazole 4da and 2-methylbenzoxazole 4db in 7:3 ratio,
suggesting that the N-benzoyl group is more prone to cyclize
as compared to the N-acetyl group (entry 3). In contrast, the
m-trifluoroacetamide-substituted substrate 3e cyclized exclu-
sively at the N-benzoyl group to produce the corresponding
7-substituted 2-phenylbenzoxazole 4e (entry 4). The reaction
of phenyl dimethylcarbamate derivative 3f gave the desired
(24) For intramolecular hydroarylation of alkenes by directed aromatic C-
H functionalization/C-C bond formation, see: (a) Harada, H.; Thalji, R. K.;
Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772. (b) Thalji, R. K.;
Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2005, 70, 6775.
(c) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2001, 123, 9692.
4274 J. Org. Chem. Vol. 74, No. 11, 2009

Copper-Catalyzed Synthesis of Benzoxazoles
TABLE 3. Scope of Directed Cyclizationa
a Reaction conditions: Cu(OTf)2 (20 mol %), o-DCB, air, 110 °C, 12 h. b Reaction conducted at 140 °C. c Reaction conducted at 130 °C;
6-chlorinated 4k was obtained (39% yield) as byproduct. d Reaction conducted at 125 °C in chlorobenzene.
SCHEME 3. Synthesis of 5- and 7-Hydroxybenzoxazoles
good substrates for the directed cyclization providing the
corresponding 7-substituted products in 74-80% yields (entries
6-8). An N-acetyl group on indole also served as directing
group to afford the tricyclic product 4j in high yield (entry 9).
Interestingly, the reaction of pyrazole-substituted substrate 3k
in o-DCB at 130 °C afforded the desired product 4k (44% yield)
and 6-chlorinated compound 4k as a byproduct (39% yield)
(entry 10).25 When the reaction was conducted in chlorobenzene
at 125 °C, 4k was obtained in 92% yield and no chlorinated
byproduct was observed. Although the mechanism for the
formation of the chlorinated byproduct is uncertain, o-DCB
would be a source of Cl required for formation of the
6-chlorinated byproduct in the reaction of the pyrazole-
substituted substrate 3k. Introduction of substituents into the
ortho position of the pyrrolidinone directing group did not affect
regioselectivity of the cyclization (entry 11 and 12). However,
the methyl-substituted substrate showed lower reactivity as
compared with 3b or 3l. One might predict this result because
the steric bulk of the methyl substituent of 3m would direct the
7-substituted product 4f in moderate yield (entry 5). This product
can be readily converted to 7-hydroxybenzoxazole 6a by
treatment with KOH in MeOH. On the other hand, the
5-hydroxy-substituted regioisomer 6b can be obtained by
deprotection of 2i with BBr3 (Scheme 3). The results described
above demonstrate that ortho- and meta-substituted anilides can
be converted to two different regioisomeric benzoxazoles
respectively by changing the nature of the protecting groups of
the intended substituent. Benzamides with electron-withdrawing
directing groups such as acetyl, benzoyl, and formyl (3g-i) are
(25) Reaction of 3k in o-DCB at 110 °C resulted in incomplete reaction and
4k was obtained in 24% yield with a trace amount of chlorinated byproduct.
The formation of chlorinated byproduct was not observed for the reaction of
other substrates.
J. Org. Chem. Vol. 74, No. 11, 2009 4275

Ueda and Nagasawa
TABLE 4. Synthesis of 2-Alkyl-/2-Alkenylbenzoxazolesa
pyrrolidinone carbonyl group away from the plane of the
aromatic ring, thus disturbing effective formation of a doubly
coordinated intermediate such as 5.
Directed Cyclizations toward 2-Alkyl- and 2-Alkenylben-
zoxazoles. The successful formation of 7-substituted 2-aryl-
benzoxazoles under relatively mild conditions led us to reex-
amine the synthesis of 7-substituted 2-alkylbenzoxazoles by
means of directed cyclization. Although copper-catalyzed cy-
clizations of simple alkyl-substituted anilides were unsuccessful
(Table 1, entries 15 and 16), the use of the directed cyclization
approach resulted in successful formation of 2-alkyl-substituted
benzoxazoles. Although the yields are generally lower than the
directed cyclizations of benzanilides (Table 3), a variety of
7-substituted 2-alkyl- and 2-alkenylbenzoxazoles can be syn-
thesized in synthetically acceptable yields (Table 4). The
prrolidinone-substituted substrates 7a-c provided the corre-
sponding 2-alkylbenzoxazoles in moderate to good yields
(entries 1-3). Cinnamoylanilide 7d provided 8d without
isomerization of olefin geometry (entry 4). Other directing
groups were also effective for the directed cyclizations of alkyl-
substituted substrates. These reactions demonstrate that the
directed intramolecular C-O coupling reaction should be a
useful methodology for generating medicinally important 7-sub-
stituted benzoxazoles and their derivatives.1b,3,26
Mechanistic Consideration. During our studies of the scope
of the reaction, we had noticed that electron-rich anilides showed
higher reactivities than electron-deficient anilides. This was
confirmed by the time dependence curve for the oxidative
coupling reactions of unsubstituted anilide 1a and anilides with
either an electron-donating methoxy substitution (1i) or an
electron-withdrawing chloro substitution (1e) (Figure 1). This
result is consistent with the findings of Buchwald et al., who
observed that more electron-rich benzamidines reacted faster
than electron-deficient benzamidines in the copper-catalyzed
oxidative synthesis of benzimidazoles.21 Furthermore, an electron-
withdrawing halogen substituent at the meta position resulted
in lower relativities as compared to p-halogen-substituted
substrates with a halogen reactivity order of F > Cl > Br (Table
1). These observations suggest the involvement of an electro-
philic aromatic substitution process in the reaction. In conjunc-
tion with the observed regioselectivity in the directed cycliza-
tions, we currently believe an electrophilic metalation process
is involved in the oxidative C-O coupling reaction (Scheme
4).27 In this model, initial coordination of benzanilide to
Cu(OTf)2 would lead to directed ortho metalation by electro-
philic aromatic substitution at the Cu center. The presence of a
directing group at the meta position of the anilide would promote
this process by the formation of doubly coordinated intermediate.
The formation of a six-membered metallacycle and subsequent
a Reaction conditions: Cu(OTf)2 (20 mol %), o-DCB, air 120 °C,
12 h. b Reaction conducted at 130 °C.
(26) (a) Terasaka, T.; Tsuji, K.; Kato, T.; Nakanishi, I.; Kinoshita, T.; Kato,
Y.; Kuno, M.; Inoue, T.; Tanaka, K.; Nakamura, K. J. Med. Chem. 2005, 48,
4750. (b) Harikrishnan, L. S.; Kamau, M. G.; Herpin, T. F.; Morton, G. C.; Liu,
Y.; Cooper, C. B.; Salvati, M. E.; Qiao, J. X.; Wang, T. C.; Adam, L. P.; Taylor,
D. S.; Chen, A. Y. A.; Yin, X.; Seethala, R.; Peterson, T. L.; Nirschl, D. S.;
Miller, A. V.; Weigelt, C. A.; Appiah, K. K.; O’Connell, J. C.; Lawrence, M. R.
Bioorg. Med. Chem. Lett. 2008, 18, 2640.
(27) We have reported in our previous communication that no kinetic isotope
effect was observed in an intramolecular competition experiment using ortho
deuterium labeled substrate (see ref 22). This suggests that a hydrogen abstraction
step is not involved in the rate determining step and other metalation mechanisms
such as σ-bond metathesis might be eliminated. Intramolecular isotope effects
are sometimes observed in palladium-catalyzed C-H functionalizations, see:
(a) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084. (b)
Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew.
Chem., Int. Ed. 2007, 46, 5554. (c) Campeau, L.-C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
reductive elimination affords benzoxazole and a reduced copper
species that is then reoxidized by molecular oxygen to complete
the catalytic cycle. A different mechanism, which involves
electrophilic aromatic substitution at the amide oxygen with
concurrent leaving of the reduced copper species, seems
unlikely, since favorable geometry of copper coordination for
such a process would be hard to align in the doubly coordinated
intermediate of directed cyclizations. Although there is no clear
evidence for the formation of an ortho-metalated intermediate,
experimental observations do not contradict the electrophilic
metalation mechanism.
4276 J. Org. Chem. Vol. 74, No. 11, 2009

Copper-Catalyzed Synthesis of Benzoxazoles
were then purged under oxygen and o-xylene (0.5 mL) was added
via syringe. The reaction mixture was then heated with stirring at
140 °C for 28 h under an oxygen atmosphere (balloon). After
cooling to room temperature, a small amount of methanol was added
to dissolve insoluble materials and the mixture was purified by
preparative TLC.
General Procedure for the Synthesis of Benzoxazoles under
Air (Method B). To a dried Schlenk tube was added the anilide
(0.25 mmol), Cu(OTf)2 (0.05 mmol), and o-dichlorobenzene (0.5
mL). The reaction mixture was then heated with stirring at 160 °C
for 28 h under atmospheric air (balloon). After cooling to room
temperature, a small amount of methanol was added to dissolve
insoluble materials and the mixture was purified by preparative
TLC.
2-Phenylbenzoxazole (2a). According to the general procedures
described above with benzanilide 1a, the product 2a was obtained
by preparative TLC (EtOAc-hexane 1:9) as a white solid (method
A: 39.5 mg, 81%; method B: 43.3 mg, 89%). Mp 102-103 °C
(lit.12a mp 101-102 °C); 1H NMR (400 MHz, CDCl3) δ 8.20 (dd,
2H, J ) 2.2 Hz, J ) 5.6 Hz), 7.69 (m, 1H), 7.43-7.57 (m, 4H),
7.25-7.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 163.0, 150.7,
142.1, 131.5, 128.9, 127.6, 127.1, 125.1, 124.6, 120.0, 110.6; MS
(EI) m/z 195 (M+).
FIGURE 1. Time-dependent production of 2a, 2e, and 2i.
SCHEME 4. Plausible Mechanism of Oxidative Cyclization
General Procedure for the Directed Cyclization. To a dried
Schlenk tube was added the anilide (0.25 mmol), Cu(OTf)2 (0.05
mmol), and o-dichlorobenzene (0.5 mL). The reaction mixture was
then heated with stirring at 110 °C for 12 h under atmospheric air
(balloon). After cooling to room temperature, a small amount of
methanol was added to dissolve insoluble materials and the mixture
was purified by preparative TLC.
3-(2-Phenylbenzoxazol-7-yl)oxazolidin-2-one (4b). According
to the general procedure described above with anilide 3b, the
product 4b was obtained by preparative TLC (EtOAc-hexane 2:1)
as a white solid (57.4 mg, 82%). Mp 173-174 °C; 1H NMR (400
MHz, CDCl3) δ 8.25-8.20 (m, 2H), 7.73 (d, 1H, J ) 8.4 Hz),
7.62 (d, 1H, J ) 8.0 Hz), 7.60-7.50 (m, 3H), 7.38 (t, 1H, J ) 8.0
Hz), 4.65-4.50 (m, 2H), 4.82-4.42 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 162.8, 155.6, 143.6, 142.6, 131.9, 129.0, 127.7, 126.6,
125.1, 122.4, 118.7, 117.2, 62.3, 46.5; HRMS (EI), m/z calcd for
C16H12N2O3 (M+) 280.0848, found 280.0855.
Conclusion
A variety of benzoxazoles have been obtained by the copper-
catalyzed intramolecular oxidative C-O coupling of anilides
that are synthesized from readily available anilines. This study
has proven that O2 gas can be successfully replaced with
atmospheric air without affecting the efficiency of the reaction.
Furthermore, the optimized directed cyclization conditions are
mild enough to allow for the use of a range of directing groups
and functional groups providing a variety of 7-substituted
benzoxazoles. The directed cyclization approach should provide
opportunities for further derivatization since many directing
groups used in the present study can be converted into other
functionalities after copper-catalyzed reactions. Overall, we
believe that the described chemistry will give access to
differently substituted benzoxazole skeletons in a simple and
straightforward way.
Acknowledgment. We thank Dr. K. L. Kirk (NIDDK, NIH)
for very helpful suggestions and Ms. Emi Inaba for her technical
assistance. This research was supported in part by a Grant-in-
Aid for Young Scientists (Start-up) (19890179) from the Japan
Society for the Promotion of Science (JSPS), by the Japan
Science and Technology Agency (JST) in Research for Promot-
ing Technological Seeds (08-119), and by a Grant from The
Saijiro Endo Memorial Foundation for Science & Technology.
Supporting Information Available: Full experimental details
of the preparation and characterization of the starting materials
and characterization data for all known products and for all new
compounds (including copies of 1H and 13C NMR spectra). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Procedure for the Synthesis of Benzoxazoles under
O2 (Method A). To a dried Schlenk tube was added the anilide
(0.25 mmol) and Cu(OTf)2 (0.05 mmol). The tube and its contents
JO900513Z
J. Org. Chem. Vol. 74, No. 11, 2009 4277