Convenient one-pot synthesis of 2,5-disubstituted oxazoles via a catalytic oxidative dehydrogenation of F3CSO3H·SiO 2-DDQ/CuCl2/LiCl

Article abstract of DOI:10.1002/jhet.1637

A facile one-pot synthesis of 2,5-disubstituted oxazoles was developed via cyclization of aldoximes and phenylacetylene then dehydrogenation oxidation. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was studied for the selective oxidation of oxazolines using Cu²⁺/Li⁺ as catalyst and O₂ as indirect oxidant. The reaction results showed that this catalyst system can effectively catalyze the oxidation of oxazolines to the corresponding oxazoles. Thus, a variety of polysubstituted oxazoles was easily synthesized in high yields by catalytic oxidation of 2,3-dichloro-5,6-dicyano-1, 4-benzoquinone/CuCl₂/LiCl/O₂.

Full text of DOI:10.1002/jhet.1637

Month 2013
Convenient One-Pot Synthesis of 2,5-Disubstituted Oxazoles via a
Catalytic Oxidative Dehydrogenation of F3CSO3HÁSiO2-DDQ/CuCl2/LiCl
*
Shizhen Yuan, Zhen Li, and Ling Xu
Department of Chemistry, Anhui University of Architecture, Hefei, Anhui 230022, China
*
E-mail: yuanshzh3@hotmail.com
Received November 18, 2011
DOI 10.1002/jhet.1637
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
F3CSO3H.SiO2, 50-70 oC
OH
N
N
+
Ph
R
DDQ/CuCl2/LiCl/O2
Dioxane/n-propanol
O
R
1a-n
3aa-3na
2a
R=C6H5, 4-CH3C6H4, 4-CH OC H , 3-CH OC H , 2-CH OC H , 4-ClC6H4, 3-ClC6H4, 2-ClC6H4, 4-O NC H , α-Naphthyl,
β-Naphthyl, 2-Furan, 2-Thiophene, n-C3H7.
A facile one-pot synthesis of 2,5-disubstituted oxazoles was developed via cyclization of aldoximes and
phenylacetylene then dehydrogenation oxidation. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was studied
for the selective oxidation of oxazolines using Cu2+/Li+ as catalyst and O2 as indirect oxidant. The reaction
results showed that this catalyst system can effectively catalyze the oxidation of oxazolines to the
corresponding oxazoles. Thus, a variety of polysubstituted oxazoles was easily synthesized in high yields
by catalytic oxidation of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone/CuCl2/LiCl/O2.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a
highly active and selective oxidant and is widely used to
the dehydrogenation and aromatization in organic synthesis,
especially suitable for the dehydrogenation of benzylic
and allylic oxidations. In oxidation reaction, DDQ is reduced
to DDQH2 (2,3-dichloro-5,6-dicyano-1,4-hydroquinone).
However, DDQH2 is reductant; the oxidation capacity of
DDQ gradually decreases with increasing concentration
of DDQH2, so decreasing the concentration of DDQH2
will help to enhance the oxidation capacity of DDQ. Undoubt-
edly, the best way to decrease the concentration of DDQH2 is
that DDQH2 could be oxidized to DDQ by desired oxidant.
To initiate our study, we have optimized the reaction
conditions for the formation of oxazole with benzaldoxime
(1a) and phenylacetylene (2a) as substrates (Scheme 1).
The results are listed in Table 1.
Oxazoles are well known as important structural units in a
wide variety of biologically active natural products as well as
useful synthetic intermediates [1]. In particular, many efforts
have been focused for the synthesis of 2,5-substituted
oxazoles because of their existence in substructures of many
pharmaceuticals [2]. Classical procedure for the synthesis of
them includes two steps: (1) cyclization of acyclic precursors
and (2) dehydrogenation oxidation of oxazolines.
Now, major cyclizations have the reaction of amide with
olefinic bond [3] or acetylene bond [4] and amine with car-
bonyl compounds [5]. The main dehydrogenation oxida-
tion methods are (1) direct halogenation with a halogen
then dehydrohalogenation [6], (2) bromination with NBS
[7] then eliminating hydrogen bromide, and (3) direct
dehydrogenation with specific oxidation [8].
As shown in Table 1, we could have access to optimum
conditions of synthesis:
However, these methods always suffered from the limi-
tation of utilization of the toxic transition-metal catalysts,
such as Pd(OAc)2 [9], Ru(PPh)3 [10], PbCl2(PPh3)2 [11],
or inaccessible starting materials [12]. Therefore, the
development of more efficient and practical protocols still
would be highly desirable.
1. Influence of catalysts
First, various catalysts were examined; it has been
observed that heterogeneous catalysts (Table 1,
entries 4–8) were more effective than homo-
geneous catalysts (Table 1, entries 1–3). The
mixture of trifluoromethanesulfonic acid and
silica [F3CSO3HÁSiO2 (0.15 + 0.15 g)] was the
most efficient catalyst for synthesis of substituted
oxazoles (Table 1, entries 8–10).
RESULTS AND DISCUSSION
Herein, we report a novel tandem synthetic method for prep-
aration of 2,5-substituted oxazoles from facile aldoximes and
phenylacetylene with effective catalytic oxidation reaction.
As is well known that oxazole ring is readily oxidized and
leads to open in the presence of oxidants, so only specific
oxidants could be qualified for dehydrogenation oxidation.
2. Influence of oxidants
In the absence of Cu2+ and only by using DDQ, DDQ/
O2, and DDQ/LiCl/O2 as the oxidants, the yields of
© 2013 HeteroCorporation

S. Yuan, Z. Li, and L. Xu
Vol 000
Scheme 1
Catalyst
N
N
OH
+
O
Oxidant, Solvent
1a
2a
3aa
Table 1
Optimization of reaction conditions.a,b
Entry
Catalyst
H2SO4 (98%)
Oxidant
Yield (3aa, %)c
1
2
3
4
DDQ
36
41
43
47
46
47
51
55
57
56
59
67
63
65
69
62
71
78
84
82
57
63
81
4-CH3C6H4SO3H(0.1 g)
Sulfamic acid (0.1 g)
Phosphotungstic acid (0.1 g)
Montmorillonite (0.1 g)
ASR (D001, 0.1 g)
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
5
6d
7
F3CSO3H(0.1 g)
8
9
F3CSO3HÁSiO2(0.1 + 0.1 g)
F3CSO3HÁSiO2(0.15 + 0.15 g)
F3CSO3HÁSiO2(0.2 + 0.2 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
F3CSO3HÁSiO2(0.3 g)
10
11e
12
13
14
15
16
17f
18
19
20
21
22
23
DDQ
DDQ/O2
DDQ/CuCl2(1:1)/O2
DDQ/CuSO4(1:1)/O2
DDQ/Cu(NO3)2(1:1)/O2
DDQ/CuCl2/NaCl (1:1:1)/O2
DDQ/CuCl2/MgCl2(1:1:1)/O2
DDQ/CuCl2/LiCl(1:1:1)/O2
DDQ/CuCl2/LiCl (1:1:2)/O2
DDQ/CuCl2/LiCl (1:1:3)/O2
DDQ/CuCl2/LiCl (1:1:4)/O2
DDQ/LiCl(1:1)/O2
DDQ/CuSO4/LiCl(1:1:3)/O2
DDQ/Cu(NO3)2/LiCl (1:1:3)/O2
aReaction conditions: 1a (1.0 equiv, 5.0 mmol), 2a (1.2 equiv), oxidant (1.0 equiv), solvent = dioxane : n-propanol (V:V = 2:1, 20.0 mL), reaction tem-
perature (50–70ꢀC), and reaction time (8 h). bOne-pot synthesis. cDetermined by GC. dASR, acidic styrol resin (D001), DDQ, 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone. eDDQ (1.0 equiv), O2 (1.3 MPa). fDDQ/CuCl2/LiCl (1.0 equiv).
oxazoles were not high (Table 1, entries 9, 10, 11, 21).
From Table 1, Cu2+ is a highly efficient oxidation
catalyst (Table 1, entries 12–14), and LiCl is the pref-
erable excitation reagent (Table 1, entries 15–17). It is
known that the ratio of CuCl2 to LiCl could affect
reaction severely. The yields were the highest when
LiCl/CuCl2 mole ratio was 3(Table 1, entries 19).
The action of excitation is not obvious when there is
only a small amount of LiCl. However, too much LiCl
also was disadvantageous to the reaction, probably
because the relative concentration of Cu2+ is lower,
and Cu2+ and O2 could not contact abundantly
(Table 1, entries 17–20). Unexpectedly, the complex
catalyst with CuSO4/LiCl failed to give the ideal yield
(Table 1, entries 22).
temperature (50–70ꢀC), overall reaction time (8 h), and
dioxane : n-propanol (V:V = 2:1, 20 mL) as the solvent.
Subsequently, we further investigated the scope of a
one-pot synthesis of 2,5-disubstituted oxazoles by using
different aldoximes and phenylacetylene as the substrates
under the optimal conditions (Scheme 2). The results are
summarized in Table 2.
It was found that all of substituted benzaldoxime
proceeded smoothly to afford the expected 2,5-diaryl
oxazoles (59–91%). Generally, the benzaldoxime-bearing
electron-donating group gave poly-substituted oxazoles
in higher yields (Table 2, entries 2–5), lower yields
were obtained with electron-withdrawing substituents on
the benzene ring (Table 2, entries 6–9). Moreover,
when fused-ring and heterocyclic aldoximes were
chosen as the substrates, the reaction also afforded the
corresponding products in high yields (Table 2, entries
10–13). However, aliphatic aldoxime almost failed to
yield the desired product (Table 2, entries 14). All com-
pounds obtained were consistent with authentic ones in lit-
erature [5,6,13,14].
As a result, the optimal reaction conditions were
established as follows: 1.0 equiv (5 mmol) of 1a, 1.2 equiv
of 2a as reaction substrates, F3CSO3HÁSiO2 (0.3 g) as cycli-
zation catalyst, 1.0 equiv of DDQ/CuCl2/LiCl (1:1:3)/O2 as
a complex oxidant, pressure of oxygen (1.3 MPa), reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Oxazole, Aldoximes, Cyclization, DDQ, Catalytic Oxidation
Scheme 2
F3CSO3H.SiO2, 50-70 oC
OH
N
N
+
Ph
R
DDQ/CuCl2/LiCl/O2
Dioxane/n-propanol
O
R
1a-n
3aa-3na
2a
R=C6H5, 4-CH3C6H4, 4-CH OC H , 3-CH OC H , 2-CH OC H , 4-ClC6H4, 3-ClC6H4, 2-ClC6H4, 4-O NC H , α-Naphthyl,
β-Naphthyl, 2-Furan, 2-Thiophene, n-C3H7.
Table 2
One-pot synthesis of 2,5-substituted oxazoles.a,b,c
Entry
1
R
Product 3
Entry
8
R
Product 3
C6H5
2-ClC6H4
2
3
4
4-CH3C6H4
4-CH3O6H4
3-CH3O6H4
9
O2N
10
11
b-Naphthyl
a-Naphthyl
5
6
7
2-CH3O6H4
4-ClC6H4
3-ClC6H
12
13
14
2-Furan
2-Thiophene
n-C3H7
aReaction conditions: 1a (1.0 equiv, 5.0 mmol), 2a (1.2 equiv), oxidant (1.0 equiv), and reaction time (8 h). bOne-pot synthesis. cIsolated yield.
constants (J) were expressed in ppm and Hz,respectively. HRMS was
recorded on a “MS-GC (HP5890 (II)/HP 5972, EI) spectrometer” is
reworded to “MS-GC (HP5890 (II)/HP 5972, EI) spectrometer
(Hewlett-Packard, USA)”. TLC was purchased from “Anhui
Liangchen Silicon Material Co., Ltd.,” is reworded to “Anhui
Liangchen Silicon Material Co., Ltd. (Hefei, China),” and all material
were from Aldrich (Shanghai, China) and used directly as received.
General procedure for the synthesis of 2,5-substituted
EXPERIMENTAL
On the basis of our experimental results and previous reports,
we propose the following possible mechanism (Scheme 3).
“IR (Perkin-Elmer, 2000 FTIR)” is reworded to “IR (Perkin-
Elmer, 2000 FTIR, Tianjin China)”, 1H and 13C NMR spectra
were recorded on a “Bruker AC-300 FT spectrometer” is
reworded to “Bruker AC-300 FT spectrometer (Switzerland)”
using TMS as internal standard. The chemical shifts (d) and coupling
oxazoles.
The mixture of substituted benzaldoximes (1.0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Yuan, Z. Li, and L. Xu
Vol 000
Scheme 3
H+
-H2O
+
OH2
OH
+
R
R
N
N
R
N
+
Ph
Ph
OH2
-H+
+
R
Ph
H2O
R
N
N
OH
N
OH
Ph
Ph
Ph
H+
+
R
R
OH
+
R
N
H
N
H
Ph
Ph
-H+
O
O
H
DDQ
-
-DDQH
R
N
H
R
N
H
N
-
DDQH
-DDQH2
R
Ph
O
O
N
Cl
CN
+
Cu
O2
Cl
CN
Ar
Ph
O
(DDQ)
O
OH
N
Cl
Cl
CN
CN
2+
Cu
Ar
Ph
O
(DDQH2)
OH
equiv, 5.0 mmol), F3CSO3HÁSiO2 (0.3 g), and toluene (5 mL)
was stirred for 0.5 h at 50ꢀC. Then, phenylacetylene was
added dropwise to the mixture. After the reaction mixture was
stirred for 3.5 h at 70ꢀC, the mixture of DDQ (1.0 equiv),
CuCl2Á2H2O (1.0 equiv), LiClÁH2O (3.0 equiv), and
dioxane : n-propanol (V:V = 2:1, 20 mL) was added to
the reactor. The reaction was sequentially stirred for 4 h
at 60ꢀC under reaction pressure of oxygen (1.3 MPa). After
the reaction, the mixture was extracted with CH2Cl2 and
separated, the organic phase was washed with saturated
brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The pure products were obtained by
flash chromatography on silica gel eluting with petroleum
ether/EtOAc (1:6, V: V) and identified by IR, 1H, 13C NMR
and HRMS.
150.87, 133.32, 128.94, 128.47, 128.28, 127.98, 127.81,
127.65, 124.18, 123.36.; HRMS Calcd C13H9NO2 (M+):
211.0633, found: 211.0639.
2-(Thiophen-2-yl)-5-phenyl-oxazole (3ma).
White solid.
mp: 62–65ꢀC.; IR: 1648, 1586, 1247 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d: 7.74–7.71 (dd, J = 8.0, 1.8 Hz, 1H), 7.69–
7.51 (dd, J = 2.7, 1.2 Hz, 2H), 7.49–7.45 (m, 3H), 7.42–7.38
(d, J = 5.1 Hz, 1H), 7.35–7.32 (d, J = 5.1 Hz, 1H), 7.14–7.11
(s, 1H); 13C NMR (75 MHz, CDCl3): d 157.72, 151.31, 130.51,
129.37, 129.04, 127.59, 127.13, 126.46, 124.72, 123.23,
120.81.; HRMS: Calcd for C13H9NOS (M+): 227.2115, found:
227.1892.
In summary, we have developed a novel tandem one-pot
synthetic method for preparation of 2,5-substituted oxazoles
from substituted benzaldoximes and phenylacetylene. In
contrast to the synthetic methods reported for oxazoles, it is
featured as accessible raw materials and as a high-efficiency
2-(Furan-2-yl)-5-phenyl-oxazole (3la).
White solid, mp:
57–61ꢀC.; IR: 1662, 1585, 756 cmÀ1
;
1H NMR (300 MHz,
CDCl3) d 7.78–7.67 (m, 2H), 7.54–7.51 (s, 1H), 7.44–7.35 (m,
3H), 7,34–7.43 (m, 1H), 7.07–7.04 (d, J = 1.4 Hz, 1H), 6.54–
6.52 (d, J = 1.2 Hz, 1H).; 13C NMR (75 MHz, CDCl3) d 153.41,
catalytic oxidation. Therefore, this method is a useful
complement to the existing methods for the synthesis of the
2,5-disubstituted oxazoles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Oxazole, Aldoximes, Cyclization, DDQ, Catalytic Oxidation
[6] Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org Lett
2010, 12, 3902.
[7] Murai, K.; Takahara, Y.; Matsushita, T.; Komatsu, H.;
Fujioka, H. Org Lett 2010, 12, 3456.
[8] Jiang, H. F.; Huang, H. W.; Cao, H.; Qi, C. R. Org Lett 2010,
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Acknowledgments. We appreciate the Natural Science Fund of
Anhui Province Education Office (KJ2011z050), the Natural
Science Foundation of China (20771004/B0101), and the Anhui
Key Laboratory of Advanced Building Materials.
[9] Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J.
E. Org Lett 2010, 12, 3578.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet