Synthesis of benzoxazoles via intramolecular cyclization of ortho-halobenzanilides using copper fluorapatite catalyst

Article abstract of DOI:10.1055/s-0029-1217381

An efficient method for the synthesis of benzoxazoles via intramolecular cyclization of ortho-haloanilides using heterogeneous copper fluorapatite catalyst is described. A variety of orthohaloanilides (iodo-, bromo- and chloroanilides) were cyclized to the corresponding benzoxazoles, demonstrating the versatility of the reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217381

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LETTER
1753
Synthesis of Benzoxazoles via Intramolecular Cyclization of
ortho-Halobenzanilides using Copper Fluorapatite Catalyst
S
ynthesisof Benzoxaz
.
ole
s
Lakshmi Kantam,*a G. T. Venkanna,a K. B. Shiva Kumar,a V. Balasubrahmanyam,a Suresh Bhargavab
a
Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
School of Applied Sciences, RMIT University, Melbourne, Australia
Fax +91(40)27160921; E-mail: mlakshmi@iict.res.in
b
Received 28 October 2008
recyclable heterogeneous copper-exchanged fluorapatite
and copper-exchanged tert-butoxyapatite catalysts for the
N-arylation of imidazoles and other heterocycles with
iodo-, bromo-, chloro- and fluoro-arenes, with good to ex-
Abstract: An efficient method for the synthesis of benzoxazoles
via intramolecular cyclization of ortho-haloanilides using heteroge-
neous copper fluorapatite catalyst is described. A variety of ortho-
haloanilides (iodo-, bromo- and chloroanilides) were cyclized to the
corresponding benzoxazoles, demonstrating the versatility of the cellent yields.17a–17c In addition, we reported Suzuki and
reaction.
Heck coupling reactions using a Pd-FAP catalyst (fluora-
patite-supported palladium catalyst).17d In a continuation
Key words: copper fluorapatite catalyst, ortho-haloanilides, in-
tramolecular cyclization, heterogeneous catalyst
of our work with fluorapatite, we herein report the synthe-
sis of benzoxazoles via intramolecular cyclization of
ortho-haloanilides using a copper fluorapatite catalyst
(Cu-FAP; Scheme 1).
Benzoxazoles are an important class of heterocyclic com-
pounds which are found in a variety of natural products.
They have wide application in the treatment of stroke, de-
pression, immune diseases, cerebral ischaemia1 and are
important targets in drug discovery.2
X
O
O
N
CuFAP
N
K2CO3, DMF, 110 °C
H
Conventional synthesis of benzoxazoles involves the use
of 2-aminophenol as a starting material, which is reacted
with an aldehyde via oxidative cyclization of the imine in-
termediate or coupling with carboxylic acid derivatives.
The former method involves the use of strong oxidants
X = I, Br, Cl
Scheme 1 Synthesis of benzoxazole catalyzed by Cu-FAP
In an effort to evolve a better catalytic system, various re-
action parameters were studied for the synthesis of 2-phe-
nylbenzoxazole via intramolecular cyclization of N-(2-
bromophenyl)benzamide, which was prepared by acyla-
tion of 2-bromoaniline at 90–110 °C. The results are pre-
sented in Table 1. The solvent was found to have a
pronounced effect in these reactions; thus DMF and
DMSO were good solvents whereas DME provided mod-
erate yields. The reaction, when conducted in either 1,4-
dioxane or toluene, gave poor yields of the desired prod-
uct (Table 1, entries 4 and 5). A variety of bases were
screened and it was found that Cu-FAP catalyst in combi-
nation with K2CO3 (2 equiv), afforded good yields of the
desired product in DMF at 110 °C. Other bases such as
Cs2CO3, Na2CO3 and K3PO4 produced moderate yields of
the desired product.
– 6
such as DDQ,3 PhI(OAc)2,4 Mn(OAc)3,5 Th+ClO4 ,
Ba(MnO4)2,7 NiO2,8 or Pb(OAc)4,9 whereas the latter
method requires the use of strong acids under elevated
temperatures.10 Recently, an efficient synthesis of ben-
zoxazoles was reported by Batey et al., which involved an
intramolecular C–O cross-coupling of ortho-haloanilides
using CuI and 1,10-phenanthroline in DME under reflux
conditions.11 Later, Dominguez and co-workers explored
the use of ortho-haloanilides as starting materials for the
synthesis of benzoxazoles using CuCl or Cu(OTf)2 in
combination with diamine ligands.12 Very recently, Bolm
and co-workers reported an efficient synthesis of benzox-
azoles using sub-stoichiometric amounts of FeCl3 and
2,2,6,6-tetramethyl-3,5-heptanedione in DMF and
Cs2CO3 as base at 120 °C.13
Apatites are metal basic phosphates for which the chemi-
cal formula is M10(PO4)6(X)2 [M = divalent metal,
X = monovalent anion]. Various kinds of cations and an-
ions can be readily introduced into their framework due to
their large ion-exchange ability and such exchanged apa-
tites are already in use in several organic transforma-
tions.14–16 Very recently, we reported the preparation of
A control reaction conducted under identical conditions
but without Cu-FAP catalyst did not yield the cyclized
product. The Cu-FAP catalyst can be recovered quantita-
tively by simple filtration and reused. Consistent activity
was observed even after the fourth cycle (Table 1, entry
1). Moreover, the absence of copper in the filtrate was
confirmed by atomic absorption spectroscopy, confirming
that no leaching of copper occurred during the reaction
and providing evidence for heterogeneity throughout the
reaction. Various other heterogeneous copper-supported
catalysts such as Cu-HAP (copper hydroxyapatite), Cu/
SYNLETT 2009, No. 11, pp 1753–1756
x
x
.x
x
.2
0
0
9
Advanced online publication: 16.06.2009
DOI: 10.1055/s-0029-1217381; Art ID: D37408ST
© Georg Thieme Verlag Stuttgart · New York

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1754
M. L. Kantam et al.
LETTER
Table 1 Screening Reaction Parameters for the Synthesis of 2-Phe-
Table 2 Synthesis of 2-Phenylbenzoxazole using Different Hetero-
nylbenzoxazolea
geneous Copper Catalystsa
Br
Br
O
N
O
O
O
CuFAP
catalyst
base, solvent, 110 °C
base, solvent, 110 °C
N
N
N
H
H
Entry
Base
Solvent
DMF
Yield (%)b
Entry
Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
Catalyst
Cu-FAP
Cu-HAP
Cu/Al2O3
Cu/TiO2
Cu/SiO2
Cu/NaY
Yield (%)b
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
95, 90c
90
1
2
3
4
5
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
95
80
70
72
51
65
DMSO
DME
86
Dioxane
Toluene
DMF
30
38
89
DMF
86
a Reaction conditions: haloanilides (1 mmol), and K2CO3 (2 mmol),
catalyst (7.3 mol% ) in DMF (4 mL) at 110 °C.18,
b Isolated yield.
DMF
78
a Reaction conditions: haloanilides (1 mmol), base (2 mmol), catalyst
(0.1 g), solvent (4 mL), 110 °C.
NaY, Cu/SiO2, Cu/Al2O3, and Cu/TiO2 were screened and
their efficiency determined to be Cu-FAP > Cu-HAP >
Cu/Al2O3 > Cu/TiO2 > Cu/NaY > Cu/SiO2 (Table 2).
b Isolated yield.
c Yield after the fourth cycle.
Table 3 Synthesis of Benzoxazoles using Cu-FAP Catalysta
Entry
1
Substrate
Product
Time (h)
16
Yield (%)b
95, 90c
Br
O
N
O
O
O
N
H
Br
2
3
16
16
93
90
O
N
N
H
Br
O
N
OMe
N
H
OMe
4
5
15
18
89
90
Br
O
N
O
O
Br
N
H
Br
Br
O
N
N
H
MeO
MeO
Br
6
15
80
O
N
O
NO2
N
H
NO2
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LETTER
Synthesis of Benzoxazoles
1755
Table 3 Synthesis of Benzoxazoles using Cu-FAP Catalysta (continued)
Entry
7
Substrate
Product
Time (h)
15
Yield (%)b
91
Br
O
N
O
Cl
N
H
Cl
8
9
18
15
87
95
Br
O
N
O
O
N
H
Br
O
N
CN
N
H
CN
10
15
85
Br
O
N
O
F
N
H
F
11
12
13
14
15
14
10
10
10
10
94
96
96
93
90
O
N
Br
O
O
O
N
H
I
O
N
N
H
I
O
N
N
H
O
N
I
O
O
N
H
I
O
N
OMe
N
H
OMe
16
17
10
20
90
85
I
O
N
O
O
Br
N
H
Br
O
N
Cl
N
H
a Reaction conditions: haloanilides (1 mmol), and K2CO3 (2 mmol), Cu-FAP (0.1g), DMF (4 mL), 110 °C.
b Isolated yield.
c Yield after fourth cycle.
Synlett 2009, No. 11, 1753–1756 © Thieme Stuttgart · New York

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1756
M. L. Kantam et al.
LETTER
Johnson, G.; Iben, L.; Mahle, C. D.; Ryan, E.; Xu, C. Bioorg.
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1996, 37, 8869.
A variety of structurally divergent ortho-halobenzanilides
possessing a wide range of functional groups was chosen,
in order to ascertain the scope and the generality of the
Cu-FAP-promoted intramolecular cyclization reaction
and the results are summarized in Table 3.18 Ortho-
halobenzanilides with electron-withdrawing and electron-
donating substituents on the phenyl ring reacted similarly
to provide the corresponding benzoxazoles in excellent
yields. Aliphatic ortho-haloanilides such as cyclohexane
carboxylic acid (2-halophenyl)amide also underwent in-
tramolecular cyclization to give the corresponding benz-
oxazoles in excellent yields (Table 3, entries 11 and 12).
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In order to explore the potential activity of such a highly
active Cu-FAP catalyst, the catalyst was used in the
cyclization of various ortho-halobenzanilides such as
2-iodo-, 2-bromo- and 2-chlorobenzanilides to give the
corresponding benzoxazoles. The results are summarized
in Table 3.
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2008, 73, 3452.
The intramolecular cyclization of 2-iodobenzanilides was
rapid compared to those of 2-bromo- and 2-chlorobenz-
anilides, which may be attributed to the greater ease of
oxidative addition of iodoarenes over bromo- and chloro-
arenes.
(12) Barbero, N.; Carril, M.; SanMartin, R.; Dominguez, E.
Tetrahedron 2007, 63, 10425.
(13) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665.
(14) Elliott, J. C. Structure and Chemistry of the Apatites and
Other Calcium Orthophosphates; Elsevier: Amsterdam,
1994, 111.
(15) Sugiyama, S.; Minami, T.; Hayashi, H.; Tanaka, M.;
Shigemoto, N.; Moffat, J. B. J. Chem. Soc., Faraday Trans.
1996, 92, 293.
In conclusion, a convenient, simple and efficient method
has been developed for the preparation of benzoxazoles,
via intramolecular cyclization of ortho-haloanilides, us-
ing heterogeneous copper fluorapatite catalyst. A variety
of ortho-haloanilides was converted into the correspond-
ing benzoxazoles, demonstrating the versatility of the re-
action. The catalyst can be readily recovered and reused.
This methodology may find widespread use for the prep-
aration of benzoxazole derivatives.
(16) (a) Yamaguchi, K.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2000, 122, 7144. (b) Mori,
K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Chem. Commun. 2001, 461. (c) Mori, K.; Yamaguchi, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. New J. Chem. 2002,
26, 1536. (d) Mori, K.; Yamaguchi, K.; Hara, T.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2002, 124,
11572. (e) Mori, K.; Hara, T.; Oshiba, M.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. New J. Chem. 2005, 29, 1174.
(17) (a) Choudary, B. M.; Sridhar, Ch.; Kantam, M. L.;
Venkanna, G. T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127,
9948. (b) Kantam, M. L.; Venkanna, G. T.; Sridhar, Ch.;
Shiva Kumar, K. B. Tetrahedron Lett. 2006, 47, 3897.
(c) Kantam, M. L.; Venkanna, G. T.; Sridhar, Ch.; Sreedhar,
B.; Choudary, B. M. J. Org. Chem. 2006, 71, 9522.
(d) Kantam, M. L.; Shiva Kumar, K. B.; Srinivas, P.;
Sreedhar, B. Adv. Synth. Catal. 2007, 349, 1141.
(18) Synthesis of Benzoxazoles; Typical Procedure: Catalyst
Cu-FAP (100 mg) was added to a mixture of ortho-
haloanilide (1 mmol), and K2CO3 (2 mmol) in DMF (4 mL)
at 110 °C, and the mixture was stirred for 10–20 h. The
progress of the reaction was monitored by TLC and on
completion of the reaction, the mixture was centrifuged, the
centrifugate was treated with ethyl acetate (20 mL) and
washed with water. After removing the solvent, the crude
material was purified by chromatography on silica gel (60–
120 mesh) to afford 2-phenylbenzoxazole (Table 3, Entry
1)11a as a white solid. Mp 101–102 °C; 1H NMR (CDCl3, 300
MHz): d = 8.25–8.10 (m, 2 H), 7.76–7.70 (m, 1 H), 7.57–
7.48 (m, 4 H), 7.33–7.27 (m, 2 H); EI-MS: m/z (%) = 195
[M+], 167 (28), 149 (17), 105 (27), 83 (59), 63 (52), 41 (42).
Acknowledgment
G.T.V wishes to thank CSIR, India for SRF fellowship. M.L.K.
thanks Rosemary Wilson from RMIT University for manuscript
proof reading.
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Synlett 2009, No. 11, 1753–1756 © Thieme Stuttgart · New York