Angewandte
Chemie
DOI: 10.1002/anie.200801240
Homogeneous Catalysis
Synthesis of 2-Arylbenzoxazoles by Copper-Catalyzed Intramolecular
À
Oxidative C O Coupling of Benzanilides**
Satoshi Ueda and Hideko Nagasawa*
The benzoxazole moiety is an important structural motif in
many biologically active natural products and pharmaceutical
compounds.[1] Development of efficient methods to construct
functionalized benzoxazole scaffolds is thus highly relevant
for drug discovery. Traditional methods for the preparation of
the benzoxazole framework include condensation reactions
of 2-aminophenols with carboxylic acids in the presence of
acid or the reaction of 2-aminophenols with aldehydes and
subsequent oxidative cyclization of the imine intermediate.[2]
Recently, general methods for the copper-catalyzed intra-
molecular C–O coupling reaction of 2-haloanilides were
reported.[3] Although these approaches provide efficient
access to benzoxazoles, they each require ortho-substituted
anilines as starting material. We report herein the develop-
ment of a straightforward and versatile method to obtain
functionalized benzoxazoles by copper-catalyzed intramolec-
were then explored to optimize the yields. These investiga-
tions revealed that 2a could be obtained in 81% yield in the
presence of Cu(OTf)2 (20 mol%) at 1408C in o-xylene under
an atmosphere of O2 (Table 1, entry 1).[8] During the course of
Table 1: Copper-catalyzed cyclization of N-phenylbenzamide.[a]
[b]
Entry
Cu catalyst [mol%]Gas
T [8C]Yield [%]
(1 atm)
1
2
3
4
5
6
7
8
9
Cu(OTf)2 [20]O
Cu(OTf)2 [20]Air
Cu(OTf)2 [20]Air
Cu(OTf)2 [10]O
Cu(OTf) [20]O
Cu(OAc)2 [20]O
Cu(ClO4)2·6H2O [20]O
CuCl2 [20]O
140
39
89
140
140
140
140
140
140
81 (77)[c]
(86)[c–e]
2
140
160
[d]
50
22
11
2
2
2
2
2
2
À
ular oxidative aromatic C O bond formation in readily
available benzanilides.
Over the past decade, extensive efforts have been made to
develop methodologies that directly functionalize aromatic
38[f]
0[g]
[4]
[5]
CuBr2 [20]O
0[h]
À
À
À
C H bonds to construct C C or C N/O bonds using
transition-metal catalysis. Many of these reactions were aided
by directing groups which typically possess a lone pair that
can coordinate to the transition-metal catalyst to direct ortho
[a]The reaction was carried out in 0.25 mmol scale, unless otherwise
noted. [b]Yields of isolated product. [c]Gram-scale reaction in paren-
thesis (6.0 mmol scale). [d]1,2-Dichlorobenzene was used as solvent.
[e]Reaction time =48 h. [f] N-(2-chlorophenyl)benzamide was also
formed in 14% yield. [g] N-(2-chlorophenyl)benzamide was formed in
10% yield. [h] N-(2-cromophenyl)benzamide was formed in 6% yield.
[6]
functionalization via a five-or six-membered metallacycle.
The aminoacyl group has served as the directing group in
several ortho C–H functionalization reactions of anilides.[7]
Therefore, we reasoned that, with an appropriate catalytic
À
system, benzoxazoles could be produced through C H bond
activation and subsequent intramolecular coupling with the
amide oxygen of the anilides. To develop this idea, we first
optimized conditions for the conversion of benzanilide 1a
into 2-phenylbenzoxazole 2a. Preliminary screening of a
range of transition-metal catalysts (containing palladium,
rhodium, or copper) showed that only the copper catalysts
gave the cyclized product, albeit in small amounts. Variations
in the nature of the copper catalyst, solvents, and temperature
our present work, Buchwald and Brasche have reported
impressive results on the development of intramolecular
oxidative C–N coupling reactions for the synthesis of
benzimidazoles using a catalytic system of CuII/O2.[5a] How-
ever, to our knowledge, there is no precedent for amide
oxygen functioning as a nucleophile in catalytic oxidative
coupling reactions. Using an atmosphere of air in place of O2
reduced the yield of 2a to 39% (Table 1, entry 2). However,
the reaction at 1608C in 1,2-dichlorobenzene achieved the
best yield, even in an atmosphere of air (Table 1, entry 3).[8]
On reducing the amount of catalyst to 10 mol% and reacting
under an O2 atmosphere, the yield was reduced to 50%
(Table 1, entry 4). The reaction also proceeded employing
Cu(OTf), Cu(OAc)2 or Cu(ClO4)2 as catalysts, albeit in lower
yield (Table 1, entries 5–7). The use of CuCl2 and CuBr2 gave
small amounts of o-halogenated products and none of the
desired product (Table 1, entries 8 and 9).
[*]Dr. S. Ueda, Prof. H. Nagasawa
Laboratory of Medicinal and Pharmaceutical Chemistry
Gifu Pharmaceutical University
5-6-1 Mitahora-higashi, Gifu 502-8585 (Japan)
Fax: (+81)58-237-8571
E-mail: hnagasawa@gifu-pu.ac.jp
[**]This work was supported in part by a Grant from The Saijiro Endo
Memorial Foundation for Science & Technology and a Grant-in-Aid
for Young Scientists (Start-up) (19890179) from Japan Society for
the Promotion of Science (JSPS). We thank Dr. K. L. Kirk (NIDDK,
NIH) for helpful suggestions.
Substituent diversity was achieved using a variation on the
optimized reaction conditions with a catalytic system of
Cu(OTf)2/O2 (Table 2). Reaction of benzanilides substituted
at the meta or para position with electron-donating alkyl or
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 6411 –6413
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6411
Ueda, Satoshi
