Simple and efficient preparation of 2,5-disubstituted oxazoles via a metal-free-catalyzed cascade cyclization

Article abstract of DOI:10.1021/ol101596s

A practical and simple synthesis of 2,5-disubstituted oxazoles was developed via an iodine-catalyzed tandem oxidative cyclization. A wide range of common commercial aromatic aldehydes can be used as reaction substrates, which displayed excellent functional group compatibility in this reaction.

Full text of DOI:10.1021/ol101596s

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3902-3905
Simple and Efficient Preparation of
2,5-Disubstituted Oxazoles via a
Metal-Free-Catalyzed Cascade
Cyclization
Changfeng Wan, Linfeng Gao, Qiang Wang, Jintang Zhang, 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 July 11, 2010
ABSTRACT
A practical and simple synthesis of 2,5-disubstituted oxazoles was developed via an iodine-catalyzed tandem oxidative cyclization. A wide
range of common commercial aromatic aldehydes can be used as reaction substrates, which displayed excellent functional group compatibility
in this reaction.
Oxazoles are an important class of heterocycles which widely
exist in natural compounds, fluorescent dyes, and pharma-
ceuticals.1 Many compounds containing an oxazole motif
exhibit potent biological activities.2 Moreover, they are also
versatile synthetic blocks in organic synthesis.3 Many
strategies were reported for the synthesis of oxazole deriva-
tives.4 Traditionally, substituted oxazoles were accessed via
ring derivatization or cyclization of acyclic precursors.5 For
example, some conventional methods for the preparation of
oxazoles involved the cyclodehydration of R-acylamino-
ketones (Robinson-Gabriel reaction)6 and the oxidation of
oxazolines.7
Recently, direct functionalization of oxazole has been
developed via transition-metal-catalyzed coupling reactions.8
Although these methods provided convenient access to
substituted oxazoles, there are some limitations associated
with them, such as harsh reaction conditions and inaccessible
synthetic precursors. Therefore, the development of more
efficient and practical protocols still is highly desirable.
C-C bond and C-heteroatom bonds have been success-
fully constructed in the presence of a Lewis acid and an
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Moody, C. J. J. Org. Chem. 2009, 75, 152. (e) Pan, Y.-M.; Zheng, F.-J.;
Lin, H.-X.; Zhan, Z.-P. J. Org. Chem. 2009, 74, 3148. (f) Wan, C.; Zhang,
J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338. (g) Saito, A.;
Iimura, K.; Hanzawa, Y. Tetrahedron Lett. 2010, 51, 1471.
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Org. Lett. 2008, 10, 4029. (b) Besselievre, F.; Mahuteau-Betzer, F.; Grierson,
D. S.; Piguel, S. J. Org. Chem. 2008, 73, 3278. (c) Verrier, C. c.; Martin,
T.; Hoarau, C.; Marsais, F. J. Org. Chem. 2008, 73, 7383. (d) Flegeau,
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10.1021/ol101596s  2010 American Chemical Society
Published on Web 08/03/2010

oxidant in recent years.9 In continuation of our endeavors
to use iodine and TBHP as a catalyst system to construct
heterocycles,10 herein, we report a simple and efficient
iodine-catalyzed synthesis of 2,5-disubstituted oxazoles from
easily available starting materials under mild conditions.
Our investigation began with the reaction of 2-amino-1-
phenylethanone hydrochloride (1a) and 4-chlorobenzalde-
hyde (2h) in the presence of Lewis acid and TBHP11 in
DMF. The results were summarized in Table 1. First, the
different oxidants on the reaction. Different oxidants, such
as t-BuOOt-Bu, H2O2, m-CPBA, were employed in this
reaction respectively (Table 1, entries 5-7). The experi-
mental results indicated that TBHP was the most effective
for the reaction. When the reaction was carried out without
an oxidant, the reaction afforded the desired product with a
low yield of 23% (Table 1, entry 8), which suggested that
the oxidant also played an important role in the reaction.
Then we investigated the influence of base on the reaction
and found that sodium hydrogen carbonate was the most
effective for the reaction (Table 1, entries 9-11). Subse-
quently, the reaction solvent was optimized (Table 1, entries
12-15). When DMF was replaced with THF, no product
was observed (Table 1, entry 13). When ethanol, DCE, or
CH3CN was employed as solvent respectively, low yields
of the product were obtained. After optimization, DMF was
the best solvent for this reaction. Finally, the dosage of 1a
was investigated. When the amount of 1a was increased to
3.0 equiv from 1.5 equiv, the corresponding yield enhanced
from 52% to 65%. While the loading of 1a was continuously
increased to 4.0 equiv, the yield enhanced further to 79%
from 65% (Table 1, entries 16-17). When the reaction was
performed at room temperature, no desired product was
obtained (Table 1, entry 18). As a result, the optimal reaction
conditions were established as follows: 4.0 equiv of 1a and
1.0 equiv of 2h as reaction substrates, 1.0 equiv of sodium
hydrogen carbonate as a base, 0.3 equiv of iodine as a
catalyst, 1.5 equiv of TBHP as an oxidant, and DMF as the
solvent.
Table 1. Optimization of Reaction Conditionsa
entry catalyst
oxidant
TBHP
TBHP
TBHP
TBHP
H2O2
m-CPBA
t-BuOOt-Bu NaHCO3 DMF
-
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
base
solvent yield (%)b
1
2
3
CuCl2
FeCl3
I2
NaHCO3 DMF
NaHCO3 DMF
NaHCO3 DMF
NaHCO3 DMF
NaHCO3 DMF
NaHCO3 DMF
0
0
52
0
4
-
5
I2
19
32
41
23
47
43
18
42
0
6
I2
7
I2
8
I2
NaHCO3 DMF
9
I2
K2CO3
Cs2CO3
-
NaHCO3 C2H5OH
NaHCO3 THF
NaHCO3 DCE
NaHCO3 CH3CN
NaHCO3 DMF
NaHCO3 DMF
NaHCO3 DMF
DMF
DMF
DMF
10
11
12
13
14
15
16c
17d
18e
I2
I2
I2
I2
I2
I2
I2
I2
With the optimal conditions in hand, we then investigated
the substitution effect of the aromatic ring of the aldehydes
on the reaction in order to extend the scope of the reaction
substrates. The results are summarized in Table 2 (entries
1-16). It was found that there was little difference between
the substitution effect of an electron-donating group and that
of an electron-withdrawing group, although it seemed as if
electron-donating substituents favored this reaction more than
the electron-withdrawing substituents. Similarly, the effect
of steric hindrance had little influence on the reaction despite
a slight tendency toward ortho-substitution. Moreover, these
phenyl aldehyde substrates could be replaced with other
aromatic aldehydes. When (Z)-3-phenylacrylaldehyde and
2-naphthaldehyde were chosen as the reactants, for example,
the reactions also gave the corresponding products in 76%
and 75% yields respectively (Table 2, entries 17-18).
Heterocyclic aldehydes can also be the substrates, and the
corresponding products can be obtained with moderate to
good yields (Table 2, entries 19-21). When multisubstituted
aldehydes were employed as the reactants, the reactions also
proceeded smoothly to give the corresponding products with
good yields (Table 2, entries 22-23). When a heterocycle
was chosen as a substituent of the phenyl ring of aldehyde,
the reaction also afforded the corresponding product in 82%
yield (Table 2, entry 24).
39
46
65
79
0
I2
a Reaction conditions: 1a (1.5 equiv), 2h (1.0 equiv, 0.2 mmol), base
(1.0 equiv), catalyst (0.3 equiv), oxidant (1.5 equiv) in solvent (1 mL).
b Isolated yield. c 3.0 equiv of 1a. d 4.0 equiv of 1a. e The reaction was
carried out at room temperature for 10 h.
catalytic activities of different metal salts were examined as
Lewis acids in this reaction; however, no catalytic activity
was observed for this reaction (Table 1, entries 1-2). It was
found that the reaction proceeded smoothly when iodine was
employed as a catalyst (Table 1, entry 3). Without iodine
the reaction did not work and no product was detected (Table
1, entry 4), which indicated that iodine was an essential
catalyst for this reaction. Then we investigated the effect of
(9) (a) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 6968. (b) Basle,
O.; Li, C. J. Org. Lett. 2008, 10, 3661. (c) Basle, O.; Li, C. J. Green Chem.
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42, 335.
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12, 2841.
In order to examine the practicability of this developed
methodology, annuloline (6) was selected as a target
molecule, which was isolated from the roots of ryegrass and
(11) Hill, J. G.; Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1983,
48, 3607.
Org. Lett., Vol. 12, No. 17, 2010
3903

Table 2. Synthesis of 2,5-Disubstituted Oxazolesa
a Reaction conditions: 1a (0.8 mmol), 2 (1.0 equiv, 0.2 mmol), NaHCO3 (0.2 mmol), iodine (0.06 mmol), TBHP (0.3 mmol) in DMF (1 mL). b Isolated yield.
was the first isolated natural product containing an oxazole
substructure. Previous reports on the preparation of annu-
loline generally involved the preparation of building
blocks.8a,12 By using this new method, the preparation of
annuloline (6) was achieved by the reaction of 4 with 5 in
one step, giving the target annuloline (6) with a yield of 75%
(Scheme 1).
Moreover, a possible mechanism of the reaction was
proposed as shown in Scheme 2 according to the results
above. First, the reaction of 1a with 2h formed A, and then
3904
Org. Lett., Vol. 12, No. 17, 2010

Scheme 1. Synthesis of Annuloline
In summary, a practical and efficient synthesis of 2,5-
disubstituted oxazoles was described via an iodine-catalyzed
tandem process. The reaction gave the desired products from
readily accessible substrates under mild conditions. The
reaction did not involve any metal salt, excluding the residue
of a metal ion in the products. Furthermore, the reaction
showed a broad scope of substrates in which a wide range
of common commercial aromatic aldehydes were employed,
and these substrates displayed excellent functional group
compatibility. Further application and limitation of this
procedure are in progress in our laboratory.
Scheme 2. Possible Pathway of the Reaction
Acknowledgment. We are grateful to the Natural Science
Foundation of China (20932002, 20972144, 20628202,
20772188, and 90813008) and the Chinese Academy of
Sciences for support.
B was obtained by the enolization of A. Then an intramo-
lecular attack of the oxygen atom provided C in the presence
of iodine and TBHP. Finally, C gave the product 3h by
deprotonation and oxidation.
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.
(12) (a) Molina, P.; Fresneda, P. M.; Almendros, P. Heterocycles 1993,
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