Facile synthesis of polysubstituted oxazoles via A copper-catalyzed tandem oxidative cyclization

Article abstract of DOI:10.1021/ol100688c

A highly efficient synthesis of polysubstituted oxazoles was developed via a copper-catalyzed tandem oxidative cyclization. The desired products can be obtained from readily available starting materials under mild conditions. This is an attractive alterna

Full text of DOI:10.1021/ol100688c

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2338-2341
Facile Synthesis of Polysubstituted
Oxazoles via A Copper-Catalyzed
Tandem Oxidative Cyclization
Changfeng Wan, Jintang Zhang, Sujing Wang, Jinmin Fan, and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory
of Soft Matter Chemistry and Department of Chemistry, UniVersity of Science and
Technology of China, Hefei, 230026, P. R. China
zwang3@ustc.edu.cn
Received March 24, 2010
ABSTRACT
A highly efficient synthesis of polysubstituted oxazoles was developed via a copper-catalyzed tandem oxidative cyclization. The desired
products can be obtained from readily available starting materials under mild conditions. This is an attractive alternative method for the
synthesis of oxazole derivatives.
The ubiquitous oxazoles have attracted more and more
attention in both industrial and academic fields for decades.1
This interest arises from the fact that a variety of natural
and synthetic compounds which contain the oxazole sub-
structure exhibit significant biological activities such as
anticancer, antifungal, antitumor, anti-inflammatory, and
antiviral properties.2 For instance, Leucamide A and its
analogues, which are very important anticancer reagents,3
are mainly composed of several oxazole moieties. Moreover,
oxazole derivatives can also be employed as organic materi-
als, such as a corrosion inhibitor.4 Owing to their important
applications, various synthetic methodologies of oxazole
derivatives have been developed.5 Classical procedures for
the synthesis of oxazoles include a cyclodehydration of
acyclic precursors,6,7 the coupling of the prefunctionalized
oxazoles with organometallic reagents,8 and the oxidation
of oxazolines.9 However, these methods always suffered from
the limitation of harsh conditions and tedious synthetic
procedures. As far as we know, the reports for the direct
(4) (a) Palmer, D. C.; Venkatraman, S. Oxazoles: Synthesis, Reactions
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60, 3967.
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Soc. 1998, 120, 5597. (b) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (c) Burgett,
A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem., Int. Ed. 2003, 42,
4961. (d) Wipf, P. Chem. ReV. 1995, 95, 2115. (e) Riego, E.; Hernandez,
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73, 7383. (e) Young, G. L.; Smith, S. A.; Taylor, R. J. K. Tetrahedron
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D.; Albericio, F.; Alvarez, M. Synthesis 2005, 1907. (f) Kende, A. S.;
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E.; Barda, D. A. Org. Lett. 2000, 2, 1033.
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Lett. 2004, 45, 3797
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10.1021/ol100688c  2010 American Chemical Society
Published on Web 04/15/2010

approach to the highly functionalized oxazoles are rare.10
Therefore, developing a milder and more general procedure
to access polysubstituted oxazole derivatives is still highly
desirable.
Table 1. Optimization of the Reaction Conditionsa
Copper, among transition metals, is particularly attractive
in organic synthesis because of its low price, slight toxicity,
and environmentally benign feature.11 Collectively, there are
many reports on copper-catalyzed oxidative C-H bond
activation.12 For example, the Li group has reported a cross
dehydrogenative coupling (CDC) reaction in the presence
of copper and the corresponding oxidant.13 Herein, we
developed a novel and efficient copper-catalyzed oxidative
tandem cyclization from easily available benzylamines and
1,3-dicarbonyl derivatives, providing the polysubstituted
oxazole derivatives with moderate to good yields.
To initiate our study, the reaction of ethyl acetoacetate
with benzylamine was chosen as a model reaction in the
presence of a copper source and t-BuOOH (TBHP) solution
in n-hexane at room temperature.14 It was found that the
reaction led to the desired product ethyl 5-methyl-2-phenyl-
oxazole-4-carboxylate with a yield of 9% (Table 1, entry
1). Then we optimized the reaction conditions further to
increase the reaction yield. However, changing the reaction
temperature or modulating the reaction time had no positive
influence on this reaction. The addition of benzylamine in
two portions can increase the yield (Table 1, entry 2) and
avoid the oxidation of benzylamine. After a series of tries,
we introduced different additives to the reaction system to
improve the reaction efficiency. It was noted that the addition
of 1.2 equiv of NBS or iodine could enhance the reaction
yield up to 35% and 56% respectively (Table 1, entries 3
and 4). Following these results, the other oxidants, such as
t-BuOOt-Bu, TBHP, and air, were tested for this reaction in
the presence of molecular iodine. Among them, TBHP
solution in n-hexane gave the best result (Table 1, entries
entry
catalyst
oxidant
TBHP
TBHP
TBHP
TBHP
Air
additive solvent yield (%)b
1c CuI
-
-
CH3CN
CH3CN
9
15
35
56
17
34
29
32
53
61
57
0
2
3
4
5
6
CuI
CuI
CuI
CuI
CuI
NBS CH3CN
I2
I2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
THF
t-BuOOt-Bu I2
7d CuI
8
TBHP
TBHP
TBHP
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
-
9
10
11
12
13
14
15
16
CuCl
Cu(OAc)2·H2O TBHP
CuBr TBHP
Cu(OAc)2·H2O TBHP
Cu(OAc)2·H2O TBHP
Cu(OAc)2·H2O TBHP
Cu(OAc)2·H2O TBHP
Cu(OAc)2·H2O TBHP
39
43
93
0
EtOH
DMF
dioxane
17e Cu(OAc)2·H2O TBHP
DMF
73
a Reaction conditions: benzylamine (2 equiv, addition in two portions),
ethyl acetoacetate (1 equiv, 0.5 mmol), catalyst (0.05 mmol, 10 mmol %),
oxidant (2 equiv), additive (1.2 equiv), solvent (3 mL). The reaction was
performed for 6 h. b Determined by GC-MS with internal standard.
c Addition of benzylamine in one portion. d Aqueous TBHP (70%) was used
as oxidant. e The reaction was carried out at 60 °C.
4-6). Aqueous TBHP disfavored this reaction, nevertheless,
resulting in a poor yield of 29% (Table 1, entry 7).
Subsequently, different copper salts were examined in the
reaction. Without copper catalysts, the reaction was carried
out inefficiently, and the desired product was obtained with
a poor yield of 32% (Table 1, entry 8). Normally, all of these
copper salts can catalyze this reaction and improve the reaction
yields. Among these different copper salts, Cu(OAc)2·H2O was
the best catalyst for this reaction, and the corresponding yield
was enhanced up to 61% (Table 1, entries 9-11). Afterward,
various solvents were screened for this reaction. When the
reaction solvent was changed from acetonitrile to toluene or
dioxane, no product was observed. When THF or ethanol was
employed as the reaction solvent, the desired oxazole was
obtained in a lower yield of 43% and 39%, respectively (Table
1, entries 12-16). Finally, it was found that DMF was the most
suitable solvent for this reaction, with which the highest yield
of 93% was obtained (Table 1, entry 15). The reaction
temperature also had great influence on the reaction. Raising
the reaction temperature incurred a lower yield, while reducing
the reaction temperature led to a slower reaction rate (Table 1,
entry 17). In compromise, room temperature should be the
optimized reaction temperature.
(7) (a) Lister, J.; Robinson, R. J. Chem. Soc. 1912, 1297. (b) Keni, M.;
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Finally, the optimal reaction condition was obtained, that
is, 2 equiv of benzylamine (1a) and 1 equiv of ethyl
acetoacetate (2a) as substrates, 0.01 equiv of copper acetate
as catalyst, 2 equiv of TBHP as oxidant, and 1.2 equiv of
(14) Hill, J. G.; Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1983,
48, 3607.
Org. Lett., Vol. 12, No. 10, 2010
2339

iodine as additive; DMF was the reaction solvent at room
temperature. With the optimized conditions in hand, the
scope of the reaction substrates was investigated. First, we
examined the reaction with a series of 1,3-dicarbonyl
compounds, and the results are listed in Scheme 1. From
tanamide), the reaction gave the product with a lower yield
of 38% (Scheme 1, 3k).
Next, different benzylamine derivatives were investigated
as the reaction substrates (Scheme 2).
Scheme 2. Copper-Catalyzed Oxidative Cyclization with
Different Benzylamine Derivativesa b c
,
,
Scheme 1. Copper-Catalyzed Oxidative Cyclization with
Different 1,3-Dicarbonyl Compoundsa
a Reaction conditions: benzylamine (2 equiv), 1,3-dicarbonyl compounds
(1 equiv, 1 mmol), Cu(OAc)2·H2O (0.1 mmol, 10 mmol %), TBHP (2 euqiv),
I2 (1.2 equiv), DMF (3 mL). Isolated yield was given.
Scheme 1 it was found that various substrates were converted
into the corresponding products with moderate to good yields
under the conditions. For example, ꢀ-keto esters with
different alkyl substituents could provide the corresponding
products with high yields regardless of the difference of the
substituent (Scheme 1, 3a-3g). This meant that steric effect
and electronic effect had little influence on the reaction. The
reaction condition was so mild that the unsaturated functional
group can survive the reaction. For example, 3h was obtained
smoothly in a yield of 78% (Scheme 1, 3h) without any
change of styrene group, whose structure was also confirmed
by X-ray crystallography.15 When the reaction substrates
were switched from ꢀ-keto esters to ꢀ-diketones, the reac-
tions can be carried out smoothly to give the corresponding
products with good yields (Scheme 1, 3i-3j). When ꢀ-keto
ester was replaced with ꢀ-keto amide (3-oxo-N-phenylbu-
a Reaction conditions: benzylamine derivatives (2 equiv), ethyl aceto-
acetate (1 equiv, 1 mmol), Cu(OAc)2·H2O (0.1 mmol, 10 mmol %), TBHP
(2 euqiv), I2 (1.2 equiv), DMF (3 mL). Isolated yield was given. b Ethyl
3-oxohexanoate as substrate. c Butylamine as substrate.
Electron-withdrawing substituents on the aromatic ring
were more beneficial for this transformation, while the
electron-donating group decreased the reaction yields (Scheme
2, 3l-3q). Steric effect also had a slightly adverse influence
on the reaction. For instance, (2-chlorophenyl)methanamine
gave a lower reaction yield (Scheme 2, 3r). Then several
heterocyclic amines were employed as the reaction substrates
and the corresponding reactions afforded the oxazoles with
moderate to good yields (Scheme 2, 3s-3u). However,
butylamine failed to yield the desired product (Scheme 2,
2340
Org. Lett., Vol. 12, No. 10, 2010

3v). This perhaps implied that it was necessary for a weak
C-H bond to be adjacent to the amino group for this
reaction.
Scheme 4
.
Possible Mechanism for the Copper-Catalyzed
Formation of Oxazoles
To explore the reaction process, the reaction of ethyl
2-iodo-3-oxobutanoate with benzylamine was performed in
the presence of copper acetate and TBHP. It was found that
the reaction can give the oxazole product with a yield of
53%, as shown in Scheme 3. On the basis of the experimental
Scheme 3
.
Reaction of Benzylamine with Ethyl
2-Iodo-3-oxobutanoate
results and the previous reports,13,16 we proposed a tentative
mechanism, as shown in Scheme 4. First, 4 is formed from
1a and 2a in the presence of iodine. The oxidation of 4 and
coordination of copper ions provides 5, which undergoes an
intramolecular cyclization via an oxygen atom attacking to
double bonds and gives the intermediate 6 in a tandem
process. Further oxidation of 6 affords the product 3a.
In summary, we developed a facile and efficient oxidative
synthesis of polysubstituted oxazoles from readily available
starting materials. This transformation from benzylamine and
ꢀ-diketone derivatives into oxazoles was achieved involving
a tandem oxidative cyclization. In contrast to the traditional
synthetic methods for oxazoles, the reaction condition was
much milder, and the reaction substrates were extended.
Therefore, this method is an attractive alternative to synthe-
size oxazoles. The investigation of the reaction mechanism
is in process in our laboratory.
Acknowledgment. We are grateful to the Natural Science
Foundation of China (20932002, 20972144, 20628202,
20772188, and 90813008) and the support from the Chinese
Academy of Sciences.
(15) Crystallographic data of compound 3h: C22H21NO3, MW ) 347.40,
monoclinic, space group P21/n; a ) 6.715, b ) 17.086, c ) 16.786 Å, R
) 90.000°, ꢀ ) 95.5°, µ ) 90.000°, V ) 1917.1 Å3, Z ) 4, Dc ) 1.204
g/cm3, F(000) ) 736, µ ) 0.080 mm-1, crystal dimensions 0.30 × 0.24 ×
0.20 mm was used for measurement on a CrysAlis RED, Oxford Diffraction
Ltd. diffractometer with a graphite monochromater. I > 2σ(I). Final indices:
R1 ) 0.0384, wR2 ) 0.0595. The crystal structure of compound 3h was
solved by direct method SHLXS-97 (Sheldrick, 1990) and expanded using
difference Fourier technique, refined by the program SHLXL-97 (Sheldrick,
1997) and the full-matrix least-squares calculations. CCDC 756060.
Supporting Information Available: Typical procedure
for the reaction and characterization data for products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Kumler, W. D. J. Am. Chem. Soc. 1938, 60, 855
.
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