Synthesis of 2,5-disubstituted oxazoles and oxazolines catalyzed by ruthenium(II) porphyrin and simple copper salts

Article abstract of DOI:10.1021/jo202663n

A novel and moderate synthesis of 2,5-disubstituted oxazoles and oxazolines involving ruthenium(II) porphyrin-copper chloride catalyzed cyclization was developed. These reactions using readily available benzene carboxylic acids and phenylethenes or phenylacetylenes are performed under mild conditions. The reactions proceed in series, giving rise to the formation of an intermolecular C-N bond and an intramolecular C-O bond, which yield oxazole or oxazoline derivatives simultaneously.

Full text of DOI:10.1021/jo202663n

Article
pubs.acs.org/joc
Synthesis of 2,5-Disubstituted Oxazoles and Oxazolines Catalyzed by
Ruthenium(II) Porphyrin and Simple Copper Salts
Chuan Long Zhong,† Bo Yang Tang,† Ping Yin,† Yue Chen,‡ and Ling He*,†
†Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
‡Department of Nuclear Medicine, Affiliated Hospital, Luzhou Medical College, No. 25 Taiping Street, Luzhou, Sichuan, 646000, P.
R. China
S
* Supporting Information
ABSTRACT: A novel and moderate synthesis of 2,5-disubstituted oxazoles and oxazolines involving ruthenium(II) porphyrin−
copper chloride catalyzed cyclization was developed. These reactions using readily available benzene carboxylic acids and
phenylethenes or phenylacetylenes are performed under mild conditions. The reactions proceed in series, giving rise to the
formation of an intermolecular C−N bond and an intramolecular C−O bond, which yield oxazole or oxazoline derivatives
simultaneously.
to access substituted oxazoles and oxazolines is simultaneously
still desirable. Moreover, the use of benzene carboxylic acids as
starting material to give oxazoles and oxazolines has never been
reported in the literature.
INTRODUCTION
■
Oxazoles and oxazolines are attractive heterocyclic compounds
not only because of their unique structures and varied
applications1 but also they serve as structural elements for a
variety of natural products and pharmaceuticals.2 Examples of
these compounds include Texaline and a tubulin polymer-
ization inhibitor (A-289099), two important antimycobacterial
and anticancer agents that comprise 2,5-disubstituted oxazole
and oxazoline elements, respectively.3 Moreover, oxazole and
oxazoline derivatives can also be employed as corrosion
inhibitors in industrial settings4 and as chiral ligands in
asymmetric synthesis.5 Because of the important applications
of oxazole and oxazoline derivatives, various synthetic method-
ologies for the production of these compounds have been
developed. Generally, oxazole derivatives are synthesized by
three typical synthetic methods: cyclization of acyclic
precursors,6 oxidation of oxazolines,7 and coupling of the
prefunctionalized oxazoles with other organometallic reagents.8
Classical procedures for the synthesis of oxazolines include the
thermal cyclization of N-(2-hydroxyethyl) amide intermedia-
tes1c and cyclization prompted by the Burgess reagent,9 PPh3/
DIAD,10 DIC/Cu(OTf)2,11 or DAST/Deoxo-Fluor.12 The
cyclization of β-hydroxy carboxylic acid derivatives can also
yield the corresponding 1,3-oxazolines under certain con-
ditions.13 Although some of these reactions allow convenient
access to substituted oxazoles and oxazolines, challenges
remain, including the limited sources of starting materials and
the need to develop milder reaction conditions. In light of these
requirements, developing a milder and more general procedure
With an interest in identifying an efficient catalyst and an
active nitrogen source for the synthesis of new pharmacolog-
ically active compounds, we focused on using simple low-cost
catalysts and additionally, developing a green transition metal-
catalyzed amidation reaction. Among transition metals, copper
is particularly attractive in organic synthesis because of its low
price, low toxicity, and environmentally benign nature. Thus,
copper is gaining favor for use in C−H bond activation14 and
the formation of C−N bonds to yield oxazole derivatives in the
presence of the corresponding oxidant.6c However, these
reactions have low yields of oxazoles and oxazolines when
using only simple copper salt as the catalyst. In addition, other
materials such as zinc chloride, rhodium chloride, mercuric
acetate, and ruthenium(II) porphyrins15 have been also
employed as catalysts for the production of oxazolines. As
shown in Table 1, ruthenium(II) porphyrin−copper salt was
the most effective catalyst of this reaction due to its high
selectivity and efficiency. Herein, we developed a novel
ruthenium−copper-catalyzed oxidative cyclization based on
easily available benzene carboxylic acids and phenylethenes or
phenylacetylenes, providing the substituted oxazoline and
oxazole derivatives with moderate yields.
Received: January 13, 2012
Published: March 21, 2012
© 2012 American Chemical Society
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Article
synthesis of oxazolines were established as follows: 1.0 equiv of
1 and 5 equiv of 2 as reaction substrates, 0.05 equiv of
Ru(TTP)CO and 0.15 equiv of CuCl2 as the catalysts, 0.3 equiv
of I2 as the oxidant, and toluene as the solvent.
In this work, we also introduced different oxidants into the
reaction system to improve the reaction efficiency. It was noted
that the addition of MnO2 made the reaction less efficient
(Table 1, entry 13), O2 made the reaction faster but did not
improve the yield (Table 1, entry 14), and I2 could enhance the
reaction yield up to 34% (Table 1, entry 15). In addition, the
yield was improved to 40% when we introduced both I2 and O2
together as oxidants (Table 1, entry 16).
RESULTS AND DISCUSSION
■
To initiate our investigate, the reaction of 3-p-tolyl-1,4,2-
dioxazol-5-one (1b) and phenylethene (2a) was chosen as a
model reaction and was performed in the presence of copper
salt, ZnCl2, Hg(OAc)2, Rh2(OAc)4, or RhCl3 in acetonitrile.
Unfortunately, the desired oxazoline products were not
obtained. However, the use of Ru(TTP)CO/CuCl2 (or
CuCl) as a composite catalyst (Table 1) led to the formation
a
Table 1. Optimization of the Reaction Conditions
The reaction temperature also had a great influence on the
reaction. Increasing the temperature to 50 °C could shorten the
reaction time to 3 h and increase the yield by up to 47% (Table
1, entry 17). Higher temperatures, however, did not result in
further improvements (Table 1, entry 19, 29). Meanwhile, we
found that O2 had little influence on the reaction if we raised
the temperature (Table 1, entry 18). Subsequently, the reaction
solvent was optimized (Table 1, entry 20−23). When
acetonitrile was replaced with DMF or 1,4-dioxane, only trace
amounts of product were observed (Table 1, entries 21, 23).
When the solvent was changed from acetonitrile to dichloro-
methane, the desired oxazoline was obtained in a lower yield of
28% (Table 1, entry 22). Finally, it was found that toluene was
the most suitable solvent for this reaction, as it enhanced the
yield to 51% (Table 1, entry 20). With the optimized
conditions in hand, the scope of the reaction substrates was
investigated. The reactions of some phenylethenes with a series
of 3-phenyl-1,4,2-dioxazol-5-one derivatives were investigated.
The results are listed in Table 2.
T
time
yield
(%)
entry
catalyst
oxidant
solvent
(°C) (h)
1
CuCl
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
rt
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
3
0
0
2
CuCl2
3
Cu(acac)2
rt
0
4
Cu(CF3SO3)2
rt
0
5
ZnCl2
rt
0
6
Hg(OAc)2
rt
0
7
CuCl/Cu(acac)2
Ru(TTP)CO
rt
trace
trace
0
8
rt
9
Ru3(CO)12
rt
10
11
12
13
Rh2(OAc)4
rt
0
RhCl3
rt
0
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
Ru(TTP)CO/CuCl
rt
25
trace
23
34
40
47
46
43
51
trace
28
trace
MnO2 CH3CN
rt
b
14
O2
I2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMF
rt
15
rt
b
16
b
I2/O2
I2/O2
I2
rt
However, the reaction gave the product with a low yield
using the phenylacetylenes as the substrate. To further optimize
the reaction conditions, we chose the reaction of 3-p-tolyl-1,4,2-
17
50
50
60
50
50
40
50
18
19
20
21
22
23
3
I2
2.5
3
I2
a
Table 2. Synthesis of Oxazolines
I2
3
I2
CH2Cl2
4
I2
1,4-
dioxane
3
24
25
Ru(TTP)CO/CuCl2
I2
I2
toluene
toluene
50
50
3
3
55
43
Ru(TTP)CO/
Cu(CF3SO3)2
entry
R1
R2
oxazolines yield (%)
26
Ru(TTP)CO/
Cu(OAc)2.H2O
I2
toluene
50
3
27
1
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
53
67
62
72
47
50
42
61
49
65
35
67
55
52
60
56
2
Me
27
Ru(TTP)CO/CuI
Ru(TTP)CO/CuCl2
Ru(TTP)CO/CuCl2
Ru(TTP)CO/CuCl2
I2
I2
I2
I2
toluene
toluene
toluene
toluene
50
50
80
50
3
3
1
3
49
67
55
66
3
2-thienyl
2-furyl
c
28
4
c
29
d
5
p-C2H5OC6H4
p-CH3OC6H4
3,4-di-CH3OC6H4
p-ClC6H4
H
30
6
a
Reaction conditions: 1b (1.0 equiv, 0.17 mmol), 2a (4.0 equiv),
catalysts [Ru(TTP)CO, 0.02 equiv; copper salts, 0.3 equiv], oxidant
(0.3 equiv) in solvent (3 mL). Unless otherwise noted, all reactions
were performed under nitrogen. The reaction was carried out in an
oxygen atmosphere with 0.3 equiv of iodine. Oxygen is not
7
3g
3h
3i
8
b
9
3,4-methylenedioxy
3,4-methylenedioxy
3,4-methylenedioxy
3,4-methylenedioxy
3,4-methylenedioxy
3,4-methylenedioxy
Cl
10
11
12
13
14
15
16
17
Me
3j
c
2-thienyl
p-C2H5OC6H4
p-CH3OC6H4
3,4-di-CH3OC6H4
Me
3k
3m
3n
3o
3p
3q
quantitative. Catalysts: Ru(TTP)CO, 0.05 equiv; copper salt, 0.3
equiv. Catalysts: Ru(TTP)CO, 0.05 equiv; copper salt, 0.15 equiv.
d
of the desired oxazolines (3b). Then the loading of the catalyst
was investigated. When the amount of Ru(TTP)CO was
increased from 0.02 to 0.05 equiv, the yield increased from 55%
to 67% (Table 1, entries 24, 28). Meanwhile, we also found that
the amount of CuCl2 had little influence on this reaction when
it was decreased from 0.3 to 0.15 equiv (Table 1, entries 28,
30). As a result, the optimal reaction conditions for the
Me
Br
Me
cyclohexene
a
Unless otherwise noted, all reactions were carried out with molar
ratio of 1:2:Ru(TTP)CO:CuCl2:I2 = 1:5:0.05:0.15:0.3 at 50 °C for 3−
4 h.
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dioxazol-5-one (1b) and 1-ethoxy-4-ethynylbenzene (4c) as the
model reaction. In this experiment, it is found that 1b
decomposed too quickly to react with the phenylacetylenes.16
Thus, we increased the amount of 1b from 1 to 4 equiv and
decreased the amount of 4c to 1 equiv, which increased the
corresponding yield from 35% to 47%. However, we found that
the speed of the reaction decreased and the reaction was not
complete even after 10 hours. Subsequently, when the reaction
temperature was raised to 80 °C, a higher yield of 70% was
obtained. The influence of the amount of Ru(TTP)CO was
also investigated, and when the loading of Ru(TTP)CO was
increased to 0.1 equiv, the yield increased to 87%. Finally, the
optimal reaction conditions for the synthesis of oxazoles was
obtained: 4.0 equiv of 1 and 1 equiv of 4 as reaction substrates,
0.1 equiv of Ru(TTP)CO and 0.15 equiv of CuCl2 as the
catalysts, 0.3 equiv of I2 as the oxidant, and toluene as the
solvent. Under the optimized reaction conditions, the scope of
synthesis of oxazoles was explored. The results are shown in
Table 3. From these results, we can conclude that this method
improve the reaction efficiency. On the other hand, CuCl2 play
a role in the compound B to compound 3a conversion process
(Scheme 1).
Scheme 1. Synthesis of the Active Intermediate B
To further explore the reaction mechanism of phenyl (2-
phenylaziridin-1-yl) methanone B to oxazolines 3a, the active
intermediate B was synthesized by literature methods.17 With
2-amino-2-phenylethanol as a substrate, the tandem condensa-
tion of esterification−cyclization in ClSO3H and NaOH system
afforded corresponding 2-phenylaziridine. Then the acylation of
2-phenylaziridine was carried out with benzoyl chloride to give
the active intermediate B. Subsequently, we found that B can be
translated to forecast product 3a smoothly at 50 °C by using
CuCl2 (0.15 equiv) as catalyst and 0.3 equiv of I2 as oxidant in
toluene. Besides, through LC-MS, we found that B exists in the
reaction mixture of 1a and phenylethene. On the basis of the
experimental results and previous reports,16,17b,18 a tentative
mechanism was proposed as shown in Scheme 2. First, the
intermediate A was formed from 1a via a thermal
decomposition and iodine making it faster into reactive
intermediates A with the release of CO2 in the reaction
process. Second, intermolecular nitrogen atoms transferred
from ruthenium imido complexes to styrene and phenylethyne
derivatives. Thus the reaction of A with styrene derivatives (or
phenylethyn-1-ide) generates acylaziridine B (or B′). Third,
isomerization allows the interaction of CuCl2 with the unshared
electrons of the amido nitrogen to form C (or C′), C (or C′) is
unstable and followed rearrangement by the formation of the
carbonium ion D (or D′) and subsequent cyclization by the
oxygen to give the oxazolinium salt E (or E′). Finally, with the
regeneration of CuCl2, E (or E′) gave the 2,5-disubstituted
oxazolines 3a (or oxazoles 5m).
a
Table 3. Synthesis of Oxazoles
entry
R1
R3
oxazoles
yield (%)
1
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
H
5a
5b
5c
5d
5e
5f
82
49
53
46
78
66
75
87
60
57
78
52
42
55
73
51
80
48
23
2
Me
3
2-thienyl
4
p-C2H5OC6H4
p-(CH3)3CC6H4
p-ClC6H4
H
5
6
7
5g
5h
5i
8
Me
9
2-thienyl
10
11
12
p-C2H5OC6H4
p-(CH3)3CC6H4
p-ClC6H4
H
5j
5k
5l
b
13
5m
5n
5o
5p
5q
5r
5s
b
14
Me
H
b
CONCLUSION
15
2-thienyl
H
■
b
16
2-furyl
H
In conclusion, a more moderate synthesis of 2,5-disubstituted
oxazolines and oxazoles was developed using a transition-metal
ruthenium−copper-catalyzed tandem process for the first time.
Further study of the asymmetric synthesis of oxazolines using
chiral ruthenium porphyrin catalysts or chiral copper−ligands is
underway and will be reported in due course.
b
17
p-C2H5OC6H4
p-CH3OC6H4
3,4-di-CH3OC6H4
H
b
18
H
b
19
H
a
Unless otherwise noted, all reactions were carried out with the molar
ratio of 1:4:Ru(TTP)CO:CuCl2:I2 = 4:1:0.1:0.15:0.3 at 80 °C for 3−4
b
h. Reaction conditions: 1:4:Ru(TTP)CO:CuCl2:I2
1:5:0.05:0.15:0.3 at 50 °C for 3−4 h.
=
EXPERIMENTAL SECTION
■
General Information. NMR experiments were recorded on a 400
MHz spectrometer. Column chromatography was performed on silica
gel H (300−400 mesh). All reactions were carried out under a
nitrogen atmosphere. The substrates 1 were synthesized in one-pot
reaction from the corresponding carboxylic acids following a published
procedure.19 The catalyst Ru(TTP)CO was prepared from
Ru3(CO)12.20
provides a convenient method for the preparation of
substituted oxazolines and oxazoles from aromatic acids.
To investigate the reaction process, the reaction of 3-phenyl-
1,4,2-dioxazol-5-one 1a was performed in the presence of
Ru(TTP)CO, I2, and using toluene as solvent. After 40−60
min, 3-phenyl-1,4,2-dioxazol-5-one disappeared. Otherwise, the
starting material disappeared after at least 4 h without the
presence of I2. On the basis of this finding, we surmise that the
main effect is to accelerate the decomposition rate of 3-p-tolyl-
1,4,2-dioxazol-5-one, making it faster in the conversion into
reactive intermediates A in the presence of 0.3 equiv of iodine
in the reaction process, thereby shortening the reaction time,
General Procedure for Preparation of 2,5-Disubstituted
Oxazolines 3a−3q and Oxazoles 5m−5s. To a solution of
phenylethene or ethynylbenzene (0.6 mmol, 4 equiv) in dried toluene
(3 mL) was added substrate 1 (0.15 mmol, 1 equiv), Ru(TTP)CO
(0.0075 mmol, 5.7 mg), CuCl2 (0.023 mmol, 3.9 mg), and iodine
(0.045 mmol, 11.4 mg) simultaneously under a nitrogen atmosphere at
room temperature. Then the mixture was stirred at 50 °C for 3−4 h.
On completion of the reaction, as indicated by TLC, the reaction
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Scheme 2. Tentative Reaction Mechanism
mixture was directly purified by flash column chromatography of silica
gel H with petroleum ether and ethyl acetate as eluant to give the final
product.
128.5, 125.9, 114.5, 111.5, 81.3, 62.9. HRMS (ESI) calcd for
C13H12NO2: [M + H]+, 214.0868; found m/z, 214.0866.
2-(4-Ethoxyphenyl)-5-phenyl-4,5-dihydrooxazole (3e; Table 2,
Entry 5). Eluent petroleum ether/ethyl acetate (12:1). Yield, 19 mg,
47%. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 7.34−
7.42 (m, 5H), 6.94 (d, J = 8.8 Hz, 2H), 5.65 (dd, J = 8.0, 10.0 Hz, 1H),
4.47 (dd, J = 10.0, 14.8 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.97 (dd, J =
8.0, 14.8 Hz, 1H), 1.45 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 163.8, 161.5, 141.2, 130.0, 128.8, 128.2, 127.2, 125.7, 114.2,
80.9, 63.5, 63.1, 14.7. HRMS (ESI) calcd for C17H18NO2: [M + H]+,
268.1338; found m/z, 268.1332.
2-(4-Methoxyphenyl)-5-phenyl-4,5-dihydrooxazole (3f; Table 2,
Entry 6). Eluent petroleum ether/ethyl acetate (7:1). Yield, 19 mg,
50%. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.33−
7.41 (m, 5H), 6.94 (d, J = 8.8 Hz, 2H), 5.65 (dd, J = 8.0, 10.0 Hz, 1H),
4.46 (dd, J = 10.0, 14.4 Hz, 1H), 3.97 (dd, J = 8.0, 14.4 Hz, 1H), 3.86
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.9, 162.1, 141.1, 130.0,
128.8, 128.2, 127.2, 125.7, 113.7, 80.9, 63.0, 55.3. HRMS (ESI) calcd
for C16H16NO2: [M + H]+, 254.1181; found, m/z, 254.1185.
2-(3,4-Dimethoxyphenyl)-5-phenyl-4,5-dihydro-oxazole (3g;
Table 2, Entry 7). Eluent petroleum ether/ethyl acetate (5:1). Yield,
18 mg, 42%. 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 1.6, 8.4 Hz,
1H), 7.57 (s, 1H), 7.33−7.42 (m, 5H), 6.91 (d, J = 8.4 Hz, 1H), 5.66
(dd, J = 8.0, 10.0 Hz, 1H), 4.48 (dd, J = 10.0, 14.8 Hz, 1H), 3.98 (dd, J
= 8.0, 14.8 Hz, 1H), 3.94 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
164.0, 151.7, 148.7, 141.0, 128.8, 128.3, 125.8, 121.8, 120.1,
110.7,110.4, 81.1, 63.0, 56.0, 55.9. HRMS (ESI) calcd for
C17H18NO3: [M + H]+, 284.1287; found m/z, 284.1292.
2,5-Diphenyl-4,5-dihydrooxazole (3a; Table 2, Entry 1).21 Eluent
1
petroleum ether/ethyl acetate (12:1). Yield, 18 mg, 53%. H NMR
(400 MHz, CDCl3) δ 8.03−8.05 (m, 2H), 7.32−7.53 (m, 8H), 5.68
(dd, J = 8.0, 10.0 Hz, 1H), 4.50 (dd, J = 10.0, 14.8 Hz, 1H), 4.01 (dd, J
= 8.0, 14.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 164.1, 141.0,
131.5, 128.8, 128.4, 128.3, 128.3, 127.5, 125.7, 81.0, 63.0. HRMS (ESI)
calcd for C15H14NO: [M + H]+, 224.1075; found m/z, 224.1073.
5-Phenyl-2-p-tolyl-4,5-dihydrooxazole (3b; Table 2, Entry 2).
1
Eluent petroleum ether/ethyl acetate (12:1). Yield, 24 mg, 67%. H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 2H), 7.33−7.40 (m,
5H), 7.25 (d, J = 8.0 Hz, 2H), 5.65 (dd, J = 8.0, 10.0 Hz, 1H), 4.47
(dd, J = 10.0, 14.8 Hz, 1H), 3.98 (dd, J = 8.0, 14.8 Hz, 1H), 2.41 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 164.1, 141.8, 141.1, 129.1, 128.8,
128.3, 128.2, 125.7, 124.8, 80.9, 63.1, 21.6. HRMS (ESI) calcd for
C16H16NO: [M + H]+, 238.1232; found m/z, 238.1231.
5-Phenyl-2-(thiophen-2-yl)-4,5-dihydrooxazole (3c; Table 2,
Entry 3). Eluent petroleum ether/ethyl acetate (16:1). Yield, 21 mg,
62%. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 3.2 Hz, 1H), 7.48(d,
J = 4.8 Hz, 1H), 7.32−7.41 (m, 5H), 7.10 (dd, J = 4.0, 4.8 Hz, 1H),
5.66 (dd, J = 8.0, 10.0 Hz, 1H), 4.46 (dd, J = 10.0, 14.8 Hz, 1H), 3.97
(dd, J = 8.0, 14.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 159.8,
140.5, 130.4, 130.1, 130.0, 128.8, 128.4, 127.6, 125.7, 81.5, 63.1.
HRMS (ESI) calcd for C13H12NOS: [M + H]+, 230.0640; found m/z,
230.0634.
2-(Furan-2-yl)-5-phenyl-4,5-dihydrooxazole (3d; Table 2, Entry
2-(4-Chlorophenyl)-5-phenyl-4,5-dihydrooxazole (3h; Table 2,
1
4). Eluent petroleum ether/ethyl acetate (7:1). Yield, 23 mg, 72%. H
Entry 8). Eluent petroleum ether/ethyl acetate (25:1). Yield, 23.6
1
NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.34−7.39 (m, 5H), 7.02 (d,
J = 3.2 Hz, 1H), 6.51 (q, J = 1.6 Hz, 1H), 5.63 (dd, J = 8.0, 10.0 Hz,
1H), 4.47 (dd, J = 10.0, 14.8 Hz, 1H), 4.00 (dd, J = 8.0, 14.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 156.3, 145.3, 144.1, 140.3, 128.8,
mg, 61%. H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 2H),
7.36−7.43 (m, 7H), 5.68 (t, J = 8.8 Hz, 1H), 4.49 (dd, J = 10.4, 14.4
Hz, 1H), 4.01 (dd, J = 8.0, 14.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 163.1, 140.7, 137.6, 130.9, 129.6, 128.8, 128.7, 128.4, 125.7,
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81.2, 63.1. HRMS (ESI) calcd for C15H12ClNO: [M + H]+, 258.0686;
found m/z, 258.0685.
128.8, 128.2, 127.3, 122.1, 80.2, 62.9, 21.6. HRMS (ESI) calcd for
C16H15BrNO: [M + H]+, 316.0337; found m/z, 316.0345.
5-(Benzo[d][1,3]dioxol-5-yl)-2-phenyl-4,5-dihydrooxazole (3i;
2,5-Diphenyloxazole (5m; Table 3, Entry 13).6a Eluent petroleum
1
Table 2, Entry 9). Eluent petroleum ether/ethyl acetate (8:1). Yield,
ether/ethyl acetate (25:1). Yield, 13.9 mg, 42%. H NMR (400 MHz,
1
19.6 mg, 49%. H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz,
CDCl3) δ 8.11−8.13 (m, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.44−7.52 (m,
6H), 7.34−7.37 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 161.1,
151.2, 130.3, 128.9, 128.8, 128.4, 127.9, 127.4, 126.2, 124.2, 123.4.
HRMS (ESI) calcd for C15H12NO: [M + H]+, 222.0919; found m/z,
222.0920.
2H), 7.44−7.54 (m, 3H), 6.81−6.86 (m, 3H), 5.99 (s, 2H), 5.60 (dd, J
= 8.0, 10.0 Hz, 1H), 4.46 (dd, J = 10.0, 14.8 Hz, 1H), 3.99 (dd, J = 8.0,
14.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 164.0, 148.2, 147.7,
134.7, 131.5, 128.4, 128.3, 127.5, 119.7, 108.3, 106.2, 101.2, 81.2, 62.9.
HRMS (ESI) calcd for C16H14NO3: [M + H]+, 268.0974; found m/z,
268.0967.
5-Phenyl-2-p-tolyloxazole (5n; Table 3, Entry 14).6a Eluent
petroleum ether/ethyl acetate (20:1). Yield, 19.4 mg, 55%; mp 69−
6b
1
5-(Benzo[d][1,3]dioxol-5-yl)-2-p-tolyl-4,5-dihydro-oxazole (3j;
71 °C (lit.72−73 °C ). H NMR (400 MHz, CDCl3) δ 8.00 (d, J =
8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.43−7.46 (m, 3H), 7.28−7.36
(m, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.3, 150.9,
140.6, 129.5, 128.9, 128.3, 128.0, 126.2, 124.7, 124.1, 123.3, 21.5.
HRMS (ESI) calcd for C16H14NO: [M + H]+, 236.1075; found m/z,
236.1078.
Table 2, Entry 10). Eluent petroleum ether/ethyl acetate (10:1).
1
Yield, 27.4 mg, 65%; mp 81−82 °C. H NMR (400 MHz, CDCl3) δ
7.89 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.78−6.83 (m, 3H),
5.96 (s, 2H), 5.57 (dd, J = 8.0, 10.0 Hz, 1H), 4.42 (dd, J = 10.0, 14.8
Hz, 1H), 3.95 (dd, J = 8.0, 14.8 Hz, 1H), 2.41 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 164.1, 148.2, 147.6, 141.9, 134.9, 129.1, 128.2, 124.7,
119.7, 108.3, 106.2, 101.2, 81.0, 62.9, 21.6. HRMS (ESI) calcd for
C17H16NO3: [M + H]+, 282.1130; found m/z, 282.1129.
5-Phenyl-2-(thiophen-2-yl)oxazole (5o; Table 3, Entry 15).23
Eluent petroleum ether/ethyl acetate (20:1). Yield, 25.2 mg, 73%.
1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 2.8 Hz, 1H), 7.70 (d, J =
7.6 Hz, 2H), 7.42−7.46 (m, 3H), 7.40 (s, 1H), 7.32−7.36 (m, 1H),
7.13−7.15 (dd, J = 4.0, 5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
157.3, 150.8, 129.9, 128.9, 128.5, 128.3, 128.0, 127.7, 127.6, 124.1,
123.2. HRMS (ESI) calcd for C13H10NOS: [M + H]+, 228.0483;
Found m/z, 228.0484.
5-(Benzo[d][1,3]dioxol-5-yl)-2-(thiophen-2-yl)-4,5-dihydrooxa-
zole (3k; Table 2, Entry 11). Eluent petroleum ether/ethyl acetate
1
(8:1). Yield, 14.3 mg, 35%. H NMR (400 MHz, CDCl3) δ 7.70 (s,
1H), 7.50 (d, J = 4.8 Hz, 1H), 7.10−7.12 (m, 1H), 6.81−6.84 (m,
3H), 5.98 (s, 2H), 5.57−5.62 (m, 1H), 4.42 (dd, J = 10.0, 14.8 Hz,
1H), 3.95 (dd, J = 8.0, 14.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
159.7, 148.2, 147.7, 134.3, 130.4, 130.0, 127.6, 119.8, 111.2, 108.3,
106.2, 101.2, 81.6, 63.0. HRMS (ESI) calcd for C14H12NO3S: [M +
H]+, 274.0538; found m/z, 274.0537.
5-(Benzo[d][1,3]dioxol-5-yl)-2-(4-ethoxyphenyl)-4,5-dihydrooxa-
zole (3m; Table 2, Entry 12). Eluent petroleum ether/ethyl acetate
(5:1). Yield, 31.3 mg, 67%; mp 96−99 °C. 1H NMR (400 MHz,
CDCl3) δ 7.93 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.78−6.83
(m, 3H), 5.96 (s, 2H), 5.55 (dd, J = 8.0, 10.0 Hz, 1H), 4.40(dd, J =
10.0, 14.8 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.93 (dd, J = 8.0, 14.8 Hz,
1H), 1.44 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.7,
161.5, 148.1, 147.5, 134.9, 129.9, 119.7, 119.6, 114.1, 108.2, 106.2,
101.1, 80.9, 63.5, 62.9, 14.7. HRMS (ESI) calcd for C18H18NO4: [M +
H]+, 312.1236; found m/z, 312.1244.
5-(Benzo[d][1,3]dioxol-5-yl)-2-(4-methoxyphenyl)-4,5-dihydroox-
azole (3n; Table 2, Entry 13). Eluent petroleum ether/ethyl acetate
(5:1). Yield, 24.5 mg, 55%. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J =
8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.78−6.83 (m, 3H), 5.97 (s,
2H), 5.55 (dd, J = 8.0, 10.0 Hz, 1H), 4.41 (dd, J = 10.0, 14.8 Hz, 1H),
3.90−3.96 (dd, J = 8.0, 14.8 Hz, 1H), 3.86 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 163.7, 162.1, 148.1, 147.6, 135.0, 130.0, 120.1, 119.6,
113.7, 108.3, 106.2, 101.2, 81.0, 63.0, 55.4. HRMS (ESI) calcd for
C17H16NO4: [M + H]+, 298.1079; found m/z, 298.1071.
5-(Benzo[d][1,3]dioxol-5-yl)-2-(3,4-dimetho-xyphenyl)-4,5-dihy-
drooxazole (3o; Table 2, Entry 14). Eluent petroleum ether/ethyl
acetate (3:1−2:1). Yield, 25.5 mg, 52%. 1H NMR (400 MHz, CDCl3)
δ 7.58 (dd, J = 1.6, 8.4 Hz, 1H), 7.53 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H),
6.78−6.84 (m, 3H), 5.96 (s, 2H), 5.53−5.58 (m, 1H), 4.40 (dd, J =
10.0, 14.4 Hz, 1H), 3.91−3.96 (m, 7H). 13C NMR (100 MHz, CDCl3)
δ 163.8, 151.7, 148.7, 148.2, 147.7, 134.9, 121.7, 120.2, 119.7, 110.7,
110.4, 108.3, 106.2, 101.2, 81.1, 63.0, 56.0, 55.9. HRMS (ESI) calcd for
C18H18NO5: [M + H]+, 328.1185; found m/z, 328.1181.
2-(Furan-2-yl)-5-phenyloxazole (5p; Table 3, Entry 16).6b Eluent
1
petroleum ether/ethyl acetate (13:1). Yield, 16.2 mg, 51%. H NMR
(400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 0.8 Hz,
1H), 7.42−7.46 (m, 3H), 7.33−7.37 (m, 1H), 7.08 (d, J = 3.6 Hz,
1H), 6.57 (q, J = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 153.9,
150.8, 144.4, 142.9, 128.9, 128.6, 127.6, 124.2, 123.2, 111.9, 111.4.
HRMS (ESI) calcd for C13H10NO2: [M + H]+, 212.0712; found m/z,
212.0713.
2-(4-Ethoxyphenyl)-5-phenyloxazole (5q; Table 3, Entry 17).
1
Eluent petroleum ether/ethyl acetate (15:1). Yield, 31.8 mg, 80%. H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 7.2
Hz, 2H), 7.41−7.46 (m, 3H), 7.31−7.35 (m, 1H), 6.99 (d, J = 8.8 Hz,
2H), 4.11 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 161.2, 160.7, 150.6, 128.8, 128.1, 127.9, 126.1, 123.9,
123.2, 120.0, 114.6, 63.5, 14.7. HRMS (ESI) calcd for C17H16NO2: [M
+ H]+, 266.1181; found m/z, 266.1186.
2-(4-Methoxyphenyl)-5-phenyloxazole (5r; Table 3, Entry 18).6a
Eluent petroleum ether/ethyl acetate (12:1). Yield, 18.1 mg, 48%; mp
95−98 °C (lit. 97−99 °C6b). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J
= 8.8 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.41−7.47 (m, 3H), 7.32−
7.35 (m, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 161.3, 161.2, 150.7, 128.9, 128.2, 127.9, 126.1, 124.0,
123.2, 120.2, 114.2, 55.4. HRMS (ESI) calcd for C16H14NO2: [M +
H]+, 252.1025; found m/z, 252.1018.
2-(3,4-Dimethoxyphenyl)-5-phenyloxazole (5s; Table 3, Entry
19). Eluent petroleum ether/ethyl acetate (6:1). Yield, 9.7 mg, 23%.
1H NMR (400 MHz, CDCl3) δ 7.71−7.75 (m, 4H), 7.45−7.48 (m,
3H), 7.35−7.38 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.97
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.6, 151.0, 150.9, 149.1,
128.9, 128.3, 128.1, 124.1, 123.2, 119.5, 111.0, 110.4, 109.0, 56.1, 56.0.
HRMS (ESI) calcd for C17H16NO3: [M + H]+, 282.1130; found m/z,
282.1131.
5-(4-Chlorophenyl)-2-p-tolyl-4,5-dihydrooxazole (3p; Table 2,
General Procedure for Preparation of 2,5-Disubstituted
Oxazoles 5a−5l. To a solution of ethynylbenzene (0.12 mmol, 1
equiv) in dried toluene (3 mL) was added substrate 1 (0.48 mmol, 4
equiv), Ru(TPP)CO (0.006 mmol, 4.6 mg), CuCl2 (0.018 mmol, 3.1
mg), and iodine (0.036 mmol, 9.1 mg) simultaneously under a
nitrogen atmosphere at room temperature. Then the mixture was
stirred at 80 °C for 3−4 h. On completion of the reaction, as indicated
by TLC, the reaction mixture was directly purified by flash column
chromatography on silica gel H with petroleum ether and ethyl acetate
as eluant to give the product.
Entry 15). Eluent petroleum ether/ethyl acetate (18:1). Yield, 24.5
1
mg, 60%. H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H),
6.24−7.38 (m, 6H), 5.62 (dd, J = 8.0, 10.0 Hz, 1H), 4.47 (dd, J = 10.0,
14.8 Hz, 1H), 3.93 (dd, J = 8.0, 14.8 Hz, 1H), 2.41 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 162.5, 140.6, 132.8, 131.7, 129.4, 128.9,
128.8, 128.0, 127.7, 79.3, 62.7, 21.3. HRMS (ESI) calcd for
C16H15ClNO: [M + H]+, 272.0842; found m/z, 272.0835.
5-(4-Bromophenyl)-2-p-tolyl-4,5-dihydrooxazole (3q; Table 2,
Entry 16). Eluent petroleum ether/ethyl acetate (18:1). Yield, 26.6
1
mg, 56%. H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.6 Hz, 2H),
7.49 (d, J = 8.0 Hz, 2H), 7.20−7.25 (m, 4H), 5.58−5.62 (m, 1H), 4.45
(dd, J = 10.0, 14.8 Hz, 1H), 3.91 (dd, J = 8.0, 14.8 Hz, 1H), 2.40 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 164.1, 142.1, 140.1, 131.9, 129.1,
5-(4-Methoxyphenyl)-2-phenyloxazole (5a; Table 3, Entry 1).6a
1
Eluent petroleum ether/ethyl acetate (30:1). Yield, 24.7 mg, 82%. H
NMR (400 MHz, CDCl3) δ 8.07−8.14 (m, 2H), 7.66 (d, J = 8.0 Hz,
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2H), 7.47 (s, 3H), 7.38 (s, 1H), 6.98 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 160.5, 159.7, 151.3, 130.1, 128.7,
127.5, 126.1, 125.7, 121.9, 120.8, 114.3, 55.3. HRMS (ESI) calcd for
C16H14NO2: [M + H]+, 252.1025; found m/z, 252.1026.
2,5-Bis(4-ethoxyphenyl)oxazole (5j; Table 3, Entry 10). Eluent
petroleum ether/ethyl acetate (15:1). Yield, 21.2 mg, 57%. H NMR
1
(400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz,
2H), 7.27 (s, 1H), 6.94−6.98 (m, 4H), 4.05−4.13 (m, 4H), 1.43−1.47
(m, 6H). 13C NMR (100 MHz, CDCl3) δ 160.7, 160.5, 159.0, 150.7,
127.7, 125.5, 121.6, 120.9, 120.2, 114.8. 114.6, 63.6, 63.5, 14.8, 14.7.
HRMS (ESI) calcd for C19H20NO3: [M + H]+, 310.1443; found m/z,
310.1447.
2-(4-tert-Butylphenyl)-5-(4-ethoxyphenyl)oxazole (5k; Table 3,
Entry 11). Eluent petroleum ether/ethyl acetate (30:1). Yield, 30.3 mg,
78%. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.64 (d,
J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 6.96 (d, J = 8.8
Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.36 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 160.7, 159.1, 153.4, 151.0, 127.6,
125.9, 125.7, 125.6, 121.7, 120.8, 114.8, 63.5, 34.9, 31.1, 14.7. HRMS
(ESI) calcd for C21H24NO2: [M + H]+, 322.1807; found m/z,
322.1802.
2-(4-Chlorophenyl)-5-(4-ethoxyphenyl)oxazole (5l; Table 3, Entry
12). Eluent petroleum ether/ethyl acetate (30:1). Yield, 18.7 mg, 52%.
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 2H), 7.63 (d, J =
8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 6.96 (d, J = 8.8 Hz,
2H), 4.08 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 159.5, 159.3, 151.6, 136.1, 129.1, 127.3, 126.0, 125.7,
121.9, 120.4, 114.9, 63.6, 14.8. HRMS (ESI) calcd for C17H15ClNO2:
[M + H]+, 300.0791; found m/z, 300.0798.
5-(4-Methoxyphenyl)-2-p-tolyloxazole (5b; Table 3, Entry 2).22
1
Eluent petroleum ether/ethyl acetate (25:1). Yield, 15.6 mg, 49%. H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.8
Hz, 2H), 7.30 (s,1H), 7.28 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.8 Hz,
2H), 3.86 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
160.8, 159.7, 150.9, 140.4, 129.5, 126.1, 125.6, 124.8, 121.8, 120.9,
114.3, 55.4, 21.5. HRMS (ESI) calcd for C17H16NO2: [M + H]+,
266.1181; found m/z, 266.1174.
5-(4-Methoxyphenyl)-2-(thiophen-2-yl)oxazole (5c; Table 3,
Entry 3).23 Eluent petroleum ether/ethyl acetate (20:1). Yield, 16.4
1
mg, 53%. H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 3.6 Hz, 1H),
7.63 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 5.2 Hz, 1H), 7.27 (s, 1H), 7.12−
7.14 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H). 13C NMR (100
MHz, DMSO) δ 159.8, 156.1, 150.6, 131.7, 129.6, 128.9, 128.0, 125.8,
122.5, 120.1, 114.8, 55.5. HRMS (ESI) calcd for C14H12NO2S: [M +
H]+, 258.0589; found m/z, 258.0582.
2-(4-Ethoxyphenyl)-5-(4-methoxyphenyl)oxazole (5d; Table 3,
Entry 4). Eluent petroleum ether/ethyl acetate (15:1). Yield, 16.3
1
mg, 46%. H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 2H),
7.64 (d, J = 8.8 Hz, 2H), 7.28 (s, 1H), 6.98 (d, J = 3.2 Hz, 2H), 6.96
(d, J = 3.2 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.45 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 160.6, 159.6,
150.7, 127.7, 125.5, 121.7, 121.0, 120.2, 114.6, 114.3, 63.6, 55.3, 14.7.
HRMS (ESI) calcd for C18H18NO3: [M + H]+, 296.1287; found m/z,
296.1290.
2-(4-tert-Butylphenyl)-5-(4-methoxyphenyl)oxazole (5e; Table 3,
Entry 5). Eluent petroleum ether/ethyl acetate (30:1). Yield, 28.8 mg,
78%. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.65 (d,
J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 6.97 (d, J = 8.8
Hz, 2H), 3.85 (s, 3H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
160.7, 159.7, 153.4, 151.0, 127.9, 125.9, 125.7, 125.6, 121.8, 120.9,
114.3, 55.3, 34.9, 31.1. HRMS (ESI) calcd for C20H22NO2: [M + H]+,
308.1651; found m/z, 308.1652.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*lhe2001@sina.com
Notes
2-(4-Chlorophenyl)-5-(4-methoxyphenyl)oxazole (5f; Table 3,
The authors declare no competing financial interest.
Entry 6).24 Eluent petroleum ether/ethyl acetate (30:1). Yield, 22.6
1
mg, 66%. H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H),
ACKNOWLEDGMENTS
7.65 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 6.98
(d, J = 8.8 Hz, 2H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
159.9, 159.6, 151.6, 136.1, 129.1, 128.0, 127.3, 125.8, 122.0, 120.6,
114.4, 55.4. HRMS (ESI) calcd for C16H13ClNO2: [M + H]+,
286.0635; found m/z, 286.0631.
■
This work was financially supported by the National Science
Foundation of China (no. 21072131).
REFERENCES
■
5-(4-Ethoxyphenyl)-2-phenyloxazole (5g; Table 3, Entry 7).
Eluent petroleum ether/ethyl acetate (30:1). Yield, 23.9 mg, 75%;
(1) (a) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389.
(b) Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467. (c) Frump,
J. A. Chem. Rev. 1971, 71, 483.
1
mp 74−76 °C. H NMR (400 MHz, CDCl3) δ 8.09−8.11 (m, 2H),
7.65 (d, J = 8.4 Hz, 2H), 7.45−7.50 (m, 3H), 7.32 (s, 1H), 6.97 (d, J =
8.4 Hz, 2H), 4.08 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 6.8 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 160.5, 159.2, 151.3, 130.1, 128.8, 127.5,
126.1, 125.7, 121.8, 120.6, 114.9, 63.6, 14.8. HRMS (ESI) calcd for
C17H16NO2: [M + H]+, 266.1181; found m/z, 266.1173.
(2) (a) Jin, Z. Nat. Prod. Rep. 2009, 26, 382. (b) Onishi, H.; Pelak, B.
A.; Gerckens, L. S.; Silver, L. L.; Kahan, F. M.; Chen, M. H.; Patchett,
A. A.; Galloway, S. M.; Hyland, S. A.; Anderson, M. S.; Raetz, C. R. H.
Science 1996, 274, 980. (c) Wang, W. L.; Yao, D. Y.; Gu, M.; Fan, M.
Z.; Li, J. Y.; Xing, Y. C.; Nan, F. J. Bioorg. Med. Chem. Lett. 2005, 15,
5284.
5-(4-Ethoxyphenyl)-2-p-tolyloxazole (5h; Table 3, Entry 8). Eluent
1
petroleum ether/ethyl acetate (25:1). Yield, 29.1 mg, 87%. H NMR
(3) (a) Giddens, A. C.; Boshoff, H. I. M.; Franzblau, S. G.; Berry, C.
E., III; Copp, B. R. Tetrahedron Lett. 2005, 46, 7355. (b) Tahir, S. K.;
Nukkala, M. A.; Mozny, N. A. Z.; Credo, R. B.; Warner, R. B.; Li, Q.;
Woods, K. W.; Claiborne, A.; Gwaltney, S. L., II; Frost, D. J.; Sham, H.
L.; Rosenberg, S. H.; Ng, S. C. Mol. Cancer. Ther. 2003, 2, 227.
(4) Palmer, D. C.; Venkatraman, S. Oxazoles: Synthesis, Reactions and
Spectroscopy, Part A; J. Wiley & Sons: Hoboken, NJ, 2004.
(5) (a) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505.
(b) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106,
3561.
(6) (a) Jiang, H.; Huang, H.; Cao, H.; Qi, C. Org. Lett. 2010, 12,
5561. (b) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett.
2010, 12, 3902. (c) Wan, C.; Zhang, J.; Wang, S.; Fan, J.; Wang, Z.
Org. Lett. 2010, 12, 2338. (d) Pan, Y. M.; Zheng, F. J.; Lin, H. X.;
Zhan, Z. P. J. Org. Chem. 2009, 74, 3148. (e) Kumar, M. P.; Liu, R. S. J.
(400 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 8.4 Hz,
2H), 7.27−7.29 (m, 3H), 6.95 (d, J = 8.4 Hz, 2H), 4.07 (q, J = 6.8 Hz,
2H), 2.41(s, 3H), 1.44 (t, J = 6.8 Hz,3H). 13C NMR (100 MHz,
CDCl3) δ 160.7, 159.1, 151.0, 140.3, 129.4, 126.0, 125.6, 124.8, 121.7,
120.7, 114.8, 63.5, 21.5, 14.7. HRMS (ESI) calcd for C18H18NO2: [M
+ H]+, 280.1338; found m/z, 280.1334.
5-(4-Ethoxyphenyl)-2-(thiophen-2-yl) oxazole (5i; Table 3, Entry
9). Eluent petroleum ether/ethyl acetate (20:1). Yield, 19.5 mg, 60%;
1
mp 68−71 °C. H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 3.2 Hz,
1H), 7.62 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 4.4 Hz, 1H), 7.26 (s, 1H),
7.13 (dd, J = 3.6, 4.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 4.08 (q, J = 6.8
Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
159.1, 156.7, 150.8, 133.9, 130.1, 127.9, 127.2, 125.6, 121.6, 120.3,
114.8, 63.5, 14.7. HRMS (ESI) calcd for C15H14NO2S: [M + H]+,
272.0745; found m/z, 272.0758.
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The Journal of Organic Chemistry
Article
Org. Chem. 2006, 71, 4951. (f) Lee, J. C.; Kim, S.; Lee, Y. C. Synth.
Commun. 2003, 33, 1611.
(7) (a) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207.
(b) Meyers, A. I.; Tavares, F. X. Tetrahedron Lett. 1994, 35, 2481.
(8) (a) Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48,
9553. (b) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006,
8, 2495. (c) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009,
11, 1457.
(9) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907.
(10) Roush, D. M.; Patel, M. M. Synth. Commun. 1985, 15, 675.
(11) Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett. 2004,
45, 9611.
(12) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165.
(13) Badiang, J. G.; Aube, J. J. Org. Chem. 1996, 61, 2484.
(14) (a) Boldron, C.; Gamez, P.; Tooke, D. M.; Spek, A. L.; Reedijk,
J. Angew. Chem., Int. Ed. 2005, 44, 3585. (b) Borduas, N.; Powell, D. A.
J. Org. Chem. 2008, 73, 7822. (c) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.;
Zhao, Y. J. Org. Chem. 2008, 73, 3961.
(15) (a) Simonneaux, G.; Montigny, F. D.; Paul-Roth, C.; Gulea, M.;
Masson, S. Tetrahedron Lett. 2002, 43, 3685. (b) Lo, W. C.; Che, M.
C.; Cheng, K. F.; Mak, T. C. W. Chem. Commun. 1997, 1205.
(c) Galardon, E.; Maux, P. L.; Simonneaux, G. Tetrahedron Lett. 2000,
56, 615.
(16) Cadogan, J. I. G.; Gosney, I. Chem. Commun. 1973, 586.
(17) (a) Li, X.; Chen, N.; Xu, J. Synthesis 2010, 3423. (b) Ferraris, D.;
Drury, W. J., III; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 4568.
(18) (a) Heine, H. W.; Proctor., Z. J. Org. Chem. 1958, 23, 1554.
(b) Nabeya, A.; Shigemoto, T.; Iwakura, Y. J. Org. Chem. 1975, 40,
3536.
(19) Geffken, D. Liebigs Ann. Chem. 1982, 211.
(20) Hu, W. H.; Li, P. R.; Jiang, J.; Che, C. M.; Chen, J. Adv. Synth.
Catal. 2010, 352, 3190.
(21) Kuwano, R.; Kameyama, N.; Ikeda, R. J. Am. Chem. Soc. 2011,
133, 7312.
(22) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. ChemCatChem
2010, 2, 1403.
(23) Cano, I.; Alvarez, E.; Nicasio, M. C.; Perez, P. J. J. Am. Chem.
Soc. 2011, 133, 191.
(24) Pulici, M.; Quartieri, F.; Felder, E. R. J. Comb. Chem. 2005, 7,
463.
4277
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