Copper(II)-catalyzed conversion of bisaryloxime ethers to 2-arylbenzoxazoles via C-H functionalization/C-N/C-O bonds formation

Article abstract of DOI:10.1021/ol2000809

A copper(II)-catalyzed conversion of bisaryloxime ethers to 2-arylbenzoxazoles has been developed. The reaction involves a cascade C-H functionalization and C-N/C-O bond formation under oxygen atmosphere.(Figure Presented)

Full text of DOI:10.1021/ol2000809

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1194–1197
Copper(II)-Catalyzed Conversion
of Bisaryloxime Ethers to
2-Arylbenzoxazoles via C-H
Functionalization/C-N/C-O Bonds
Formation
Murali Mohan Guru, Md Ashif Ali, and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039,
India
tpunni@iitg.ernet.in
Received January 11, 2011
ABSTRACT
A copper(II)-catalyzed conversion of bisaryloxime ethers to 2-arylbenzoxazoles has been developed. The reaction involves a cascade C-H
functionalization and C-N/C-O bond formation under oxygen atmosphere.
Recent advances in cross-coupling reactions by transi-
tionmetal catalysishaveled tothe development of effective
methods for the construction of carbon-carbon and
carbon-heteroatom bonds.1 Among these, the direct func-
tionalization of aryl C-H bonds is a particularly valuable
tool in synthetic chemistry.2-4 These reactions are usually
aided by the directing groups that can coordinate to the
catalyst to direct ortho functionalization via a five- or six-
membered metallocycle. Herein, we wish to report a new
copper(II)-catalyzed rearrangement of bisaryloxime ethers
to 2-arylbenzoxazoles in the presence of molecular oxygen.
This process involves a cascade C-H functionalization
and C-N/C-O bond formation.
Benzoxazoles are an important class of heterocycles that
are encountered in a number of biologically active natural
products and medicinally significant compounds.5 The
common classical methods used for the construction of
the benzoxazole framework start from 2-aminophenols,
and often theyare limited duetononavailabilityof suitably
substituted starting precursors and, sometimes, the require-
ment of harsh reaction conditions such as involvement of
(1) For some recent reviews, see: (a) Monnier, F.; Taillefer, M.
Angew. Chem., Int. Ed. 2009, 48, 6954. (b) Corbet, J.-P.; Mignani, G.
Chem. Rev. 2006, 106, 2651. (c) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (d) Correa, A.; Mancheno, O. G.; Bolm, C.
Chem. Soc. Rev. 2008, 37, 1108. (e) Wurtz, S.; Glorius, F. Acc. Chem.
Res. 2008, 41, 1523. (f) Hartwig, J. F. Synlett 2006, 1283. (g) Beletskaya,
I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.
(2) For some examples on C-C cross-coupling, see: (a) Ackermann,
L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627. (b) Nishikata,
T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem., Int. Ed. 2010, 49, 781. (c)
Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.;
Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew.
Chem., Int. Ed. 2009, 48, 1830. (d) Norinder, J.; Matsumoto, A.;
Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 5858. (e)
Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (f) Zhao,
J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007, 129,
5288. (g) Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int.
Ed. 2009, 48, 201. (h) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 9982. (i) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am.
Chem. Soc. 2010, 132, 9602.
(4) For examples on C-O cross-coupling, see: (a) Ueda, S.; Nagasa-
wa, H. J. Org. Chem. 2009, 74, 4272. (b) Wang, W.; Luo, F.; Zhang, S.;
Cheng, J. J. Org. Chem. 2010, 75, 2415.
(5) For some examples, see: (a) Rodriguez, A. D.; Ramirez, C.;
Rodriguez, I. I.; Gonzalez, E. Org. Lett. 1999, 1, 527. (b) 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. (c) Taki, M.; Wolford, J. L.; O’Halloran, T. V. J. Am. Chem. Soc.
2004, 126, 712.
(3) For some examples on C-N cross-coupling, see: (a) Brasche, G.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (b) Tsang,
W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
14560. (c) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya,
K. Org. Lett. 2007, 9, 2931.
r
10.1021/ol2000809
Published on Web 02/10/2011
2011 American Chemical Society

strong acids in combination with elevated temperature.6
Some of these drawbacks have been recently overcome by
using the cross-coupling reactions that allow the construc-
tion of the target heterocycles under relatively milder
conditions.2g,4,7
copper(II) salts under oxygen atmosphere. Screening of
copper sources revealed Cu(OTf)2 as the most effective
catalyst, while other copper sources afforded inferior
results. With Cu(OTf)2 as the catalyst, we went on to
screen other reaction parameters. The reaction was found
to proceed more selectively in nonpolar solvents than in
polar solvents, and toluene was found to be the solvent
of choice (entries 1-6). The reaction in xylene required
slightly longer reaction time to afford similar results.
The effect of temperature was studied, and 80 °C affor-
ded the best results. Lower catalyst loading (10 mol %)
led to a slower rate of the target reaction along with in-
crease in the yield of the byproduct (entry 9). A control
experiment confirmed that in the absence of copper
catalyst, for 5 h, a trace of nitrile A and phenol B were
obtained along with starting material 1a. These results
reveal that the formation of A and B takes place
independently due to cleavage of the N-O bond under
heating and not by the copper-catalysis.8
With the optimized conditions, the scope of the reaction
with various bisaryloxime ethers 1b-n was next explored
(Table 2, Scheme 1). The substrates bearing electron-with-
drawing or -donating groups in the phenyl rings proceeded
to react smoothly to provide the corresponding benzox-
azoles 2b-j in 80-88% yield. The structure of compound
2h was confirmed by X-ray analysis (see the Supporting
Information). Benzoxazoles 2k-n having 2-thiophenyl-,
2-naphthyl-, and 2-quinolidinyl units could be prepared in
80-85% yield.
Table 1. Screening of Reaction Conditionsa
yield
(%)c
time convb
entry
[Cu]
solvent
toluene
(h)
(%)
2a
A þ B
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
3
4
100
100
90
88
40
45
35
37
30
35
80
55
-
trace
5
xylene
DMSO
DMF
0.5 100
1.5 100
50
43
1,4-dioxane 12
70
32
THF
12
24
24
8
80
35
Cu(OAc)2 H2O toluene
50
16
3
CuSO4 5H2O toluene
47
12
5d
tracee
trace
3
Cu(OTf)2
toluene
toluene
toluene
100
60
10 Cu(OTf)2
11
4
-
5
trace
Using these conditions, the reaction of alkyl aryloxime
ether 1p was further studied (see below). However, no
desired rearrangement was observed and the substrate
underwent decomposition to give cyclohexanecarbonitrile
and phenol in quantitative yield.
a Reaction conditions: bisaryloxime ether 1a (0.5 mmol) and [Cu] (20
mol %) were stirred in solvent (2 mL) at 80 °C under oxygen balloon.
b Determined by 400 MHz 1H NMR. c Isolated yield. d Cu(OTf)2 (10 mol
%) used. e Reaction temperature = 70 °C.
Bisaryloxime ethers were prepared from arylaldehydes
and aryloxyamines.8 The latter could be obtained by cross-
coupling of arylboronic acids with N-hydroxyphthalimide
followed by treatment with hydrazine monohydrate. The
rearrangement of the aryloxime ethers was optimized by
using bisaryloxime ether 1a as a model substrate (Table 1).
To our delight, the substrate readily underwent conversion
to give 2-arylbenzoxazole 2a along with a trace of 4-meth-
ylbenzonitrile A and phenol B in the presence of 20 mol %
To reveal the practical utility of the protocol, the reac-
tion of bisaryloxime ether 1a was studied on a 10 mmol
scale and the rearrangement readily occurred to give the
desired 2a in 86% yield.
Regarding the mechanism, the bisaryloxime ether 1o
having an R-methyl group does not undergo any reaction,
which suggests that the imine C-H is crucial for this
process. Furthermore, benzonitrile showed no reaction
with phenol under similar conditions suggesting that the
reaction does not involve an oxonium intermediate 3.9 In
addition, the crossover experiment with a mixture of 1a
and 1m afforded 2a and 2m as the only products, which
suggests that the reaction involves an intramolecular
(6) For examples, see: (a) Dopp, H.; Dopp, D. In Houben-Weyl:
Methoden der Organischen Chemie; Schumann, E., Ed.; Thieme: Stuttgart,
Germany, 1993; Vol. E8a, p 1020. (b) Boyd, G. V. In Science of Synthesis;
Houben-Weyl Methods of Molecular Transformations; Schaumann, E.,
Ed.; Thieme: Stuttgart, Germany, 2002; Vol. 11, p 481. (c) Boyd, G. V. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W.;
Potts, K. T., Eds.; Pergamon Press: New York, 1984; Vol. 6, p 177.
(7) Benzoxazole synthesis: From 1,2-dihaloarenes, see: (a) Altenhoff,
G.; Glorius, F. Adv. Synth. Catal. 2004, 346, 1661. (b) Viirre, R. D.;
Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452. From 2-haloa-
nilides, see:(c) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665. (d)
Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy,
T. J. Org. Chem. 2009, 74, 8719. (e) Barbero, N.; Carril, M.; SanMartin,
R.; Dominguez, E. Tetrahedron 2007, 63, 10425. (f) Evindar, G.; Batey,
R. A. J. Org. Chem. 2006, 71, 1802. (g) Saha, P.; Ali, M. A.; Ghosh, P.;
Punniyamurthy, T. Org. Biomol. Chem. 2010, 8, 5692.
(8) For the synthesis and N-O cleavage of oxime ether, see: Johnson,
S. M.; Petrassi, H. M.; Palaninathan, S. K.; Mohamedmohaideen,
N. N.; Purkey, H. E.; Nochols, C.; Chiang, K. P.; Walkup, T.;
Sacchettini, J. C.; Sharpless, K. B.; Kelly, J. W. J. Med. Chem. 2005,
48, 1576.
(9) Abramovitch, R. A.; Inbasekaran, M.; Kato, S. J. Am. Chem.
Soc. 1973, 95, 5428.
Org. Lett., Vol. 13, No. 5, 2011
1195

Table 2. Cu(OTf)2-Catalyzed Conversion of Bisaryloxime Ethers to Benzoxazoles
a Reaction conditions: substrate 1a-n (0.5 mmol) and Cu(OTf)2 (20 mol %) were stirred in toluene (2 mL) at 80 °C under oxygen balloon. b Isolated
yield. c A ∼2-5% of nitrile and phenol were obtained as determined by 1H NMR of the crude reaction mixture.
process. These experimental results reveal that the reaction
might involve a Lewis acid catalyzed cascade rearrangement
with C-H functionalization and C-N/C-O bond forma-
tion. Thus, the substrates 1a-n may undergo chelation with
Cu(OTf)2 to give an intermediate a that could rearrange to
provide c via b. The intermediate c can provide the target
molecules 2a-n by reductive elimination.4a Alternatively, c
may be oxidized by another equivalent of Cu(OTf)2, form-
ing a copper(III) intermediate d that may undergo reductive
elimination to give the target products 2a-n.4b The reduced
copper species may be oxidized by oxygen to compelete the
catalytic cycle.4,10
In conclusion, a copper(II)-catalyzed rearrangement of
bisaryloxime ethers to substituted 2-arylbenzoxazoles has
been developed by using molecular oxygen under neutral
(10) For example, see: Punniyamurthy, T.; Rout, L. Coord. Chem.
Rev. 2008, 252, 134.
1196
Org. Lett., Vol. 13, No. 5, 2011

Scheme 1. Proposed Catalytic Cycle
conditions. The reaction affords a new route for the synth-
esis of substituted 2-arylbenzoxazoles. The detailed study
on the mechanism is currently under investigation.
and IndustrialResearch, New Delhi, forgenerousfinancial
support.
Supporting Information Available. Experimental pro-
cedure, X-ray data and structure, characterization data,
and NMR (1H and 13C) spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Department of Science
and Technology, New Delhi, and the Council of Scientific
Org. Lett., Vol. 13, No. 5, 2011
1197