One-pot synthesis of 2-oxazolines from ethyl α-cyanocinnamate derivatives with n-bromoacetamide

Article abstract of DOI:10.1002/jhet.1902

An efficient method for the one-pot synthesis of 2-oxazolines from ethyl α-cyanocinnamate derivatives with N-bromoacetamide in the presence of K₃PO₄ has been developed. The reaction performed smoothly and cleanly to give 2-oxazolines in good to excellent yields (up to 98%) within 4.5 h in acetone at room temperature without protection of inert gases. A total of 13 examples have been investigated. A possible nucleophilic addition reaction mechanism is proposed.

Full text of DOI:10.1002/jhet.1902

794
One-Pot Synthesis of 2-Oxazolines from Ethyl a-Cyanocinnamate Derivatives
with N-Bromoacetamide
Vol 51
a
a
a
a
a
a
*
Zhanguo Chen, Hua Wen, Wenli Li, Jimei Zhou, Junli Hu, and Wei Xia
Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering
Science, Shaanxi Normal University, Xi’an, Shannxi 710062, China
*
E-mail: chzhg@snnu.edu.cn
Received June 7, 2012
DOI 10.1002/jhet.1902
Published online 6 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
An efficient method for the one-pot synthesis of 2-oxazolines from ethyl a-cyanocinnamate derivatives
with N-bromoacetamide in the presence of K3PO4 has been developed. The reaction performed smoothly
and cleanly to give 2-oxazolines in good to excellent yields (up to 98%) within 4.5 h in acetone at room
temperature without protection of inert gases. A total of 13 examples have been investigated. A possible
nucleophilic addition reaction mechanism is proposed.
J. Heterocyclic Chem., 51, 794 (2014).
INTRODUCTION
On the basis of the effort of many scientist and our group
to study the aminobromination for the electron-deficient
olefins,[15] we discovered that the N-bromoacetamide (NBA)
could expediently converted the ethyl a-cyanocinnamates
(electron-deficient olefins) into the corresponding 2-oxazoline
in the presence of base. Under optimized reaction conditions,
a very simple and efficient one-pot synthesis of 2-oxazolines
from ethyl a-cyanocinnamate derivatives with NBA in the
presence of K3PO4 has been developed. The reaction was
performed handily in acetone at room temperature without
protection of inert gases and gave the corresponding products
in good to excellent yields (up to 98%, Scheme 1). Herein,
we wish to report the detailed study of the reaction.
2-Oxazoline belongs to an important class of heterocyclic
compound and a versatile intermediate in organic synthesis
because it can be easily converted into numerous useful func-
tional derivatives via regioselective and stereoselective ring-
opening process.[1] Many of the synthetic compounds and
natural products possess the 2-oxazoline unit that exhibit
potent biological activity.[2] Furthermore, the chiral 2-
oxazolines as the ligand were also used in the many catalytic
asymmetric synthesis process.[3] Because of its important
applications in the various regions mentioned earlier, many
organic chemists and biologists have paid attention to the
synthesis of 2-oxazolines for a long time.[1–4] In the past
two decades, numerous reports had described their synthesis
including condensation of carboxylic acids,[5] esters,[6]
nitriles,[7] aldehydes,[8] imino-ether hydrochlorides,[9]
Vilsmeier reagent with vicinal amino alcohols,[10] and cycli-
zation of b-hydroxy amides.[11] However, each method has
its disadvantages in any given situation, such as harsh reaction
condition, longer reaction time, and harmful to the environ-
ment. Thus, the efficient and the one-pot method for the
synthesis of the multifunctional group’s 2-oxazolines from
new substrates under mild reaction conditions are still desired.
Although 2-oxazolines were also directly synthesized
from olefins, the substrates were limited in a certain range,
and the available substrates were mainly simple olefins.
[12] When electron-deficient olefins reacted with MeCN
and 4-TsNCl2 or 2-NsNCl2, the imidazoline products were
obtained.[13] Ethyl a-cyanocinnamates are believed to be
the useful substrates in organic synthesis.[14] However,
the successful one-pot synthesis of 2-oxazolines from ethyl
a-cyanocinnamate derivatives has not been reported so far.
RESULT AND DISCUSSION
The initial experiment was carried out by using the ethyl
a-cyanocinnamate 1a as model substrate and NBA as a
reagent in the presence of 50% anhydrous K3PO4 in acetone.
When a mixture of ethyl a-cyanocinnamate (1.0equiv),
NBA (1.1 equiv), and K3PO4 (0.5 equiv) was stirred at room
temperature for 24h, to our delight, the reaction proceeded
smoothly, and the reaction afforded the corresponding
product 3a in 40% yield (Scheme 2).
Encouraged by this result, a systematic study was under-
taken for the optimization of the reaction conditions. Firstly,
the category and amount of base were investigated, and the
results are listed in Table 1. As shown in the Table 1, anhy-
drous K3PO4 is an efficient base for this reaction. When the
loading of K3PO4 was increased, the yield of corresponding
product was improved (Table 1, entries 1–3). However,
when the loading of K3PO4 was increased up to 2.0 equiv,
© 2013 HeteroCorporation

One-Pot Synthesis of 2-Oxazolines from Ethyl a-Cyanocinnamate Derivatives with
N-Bromoacetamide
May 2014
795
Scheme 1. One-pot synthesis of 2-oxazolines from ethyl a-cyanocinnamate
derivatives with N-bromoacetamide (NBA).
that the reaction failed to give any product in the absence
of base that indicates that the base is a key role for this
reaction (Table 1, entry 9). For the K3PO4, the best base
was chosen; a little excess of stoichiometric loading was
found to be necessary for ensuring the reaction to work well.
Further study showed that the solvent affected this reaction,
too. As shown in Table 1 (entries 1–15), acetone is a best
solvent for the reaction among the investigated solvents.
Besides acetone, THF and toluene were also found to be
efficient solvents for this reaction (entries 10 and 11).
However, DMF, CHCl3, CH2Cl2, and CH3CN were less
efficient (Table 1, entries 12–15).
Scheme 2. One-pot synthesis of 2-oxazoline (3a) from ethyl a-cyanocinnamate
(1a) in the present of 50 mol% K3PO4.
It was discovered that the mole ratio of the substrate,
reagent, and K3PO4 also affected the yield of the product,
and the outcomes are listed in Table 2. As shown in
Table 2, the most reasonable mole ratio of the substrate,
NBA, and K3PO4 is 1a:NBA:K3PO4 = 1.0:1.5:1.2 (mol)
in which the highest chemical yield (96%) was achieved
when the reaction was carried out at room temperature in
acetone within 2.5 h (Table 2, entry 6).
To explore the scope and the limitation of the one-pot
synthesis of 2-oxazolines from ethyl a-cnayocinnamate
derivatives and gain an insight into the reaction mecha-
nism, a series of the ethyl a-cyanocinnamate derivatives
bearing electron-donating groups (EDG) and/or electron-
withdrawing groups (EWG) on the benzene ring have been
investigated. The results are summarized in Table 3.
the yield of corresponding product was decreased although the
starting material was consumed in short period (Table 1,
entry 4). It was discovered that anhydrous K2CO3 was also
an efficient base for this reaction (Table 1, entry 5). However,
when the stronger bases were subjected to this reaction,
such as KOH and NaOH, the reactions did not work well
(Table 1, entries 6 and 7). These outcomes indicate that
stronger bases are not suitable promoting reagents for this
reaction. The anhydrous NaOAc was discovered to be not
an effective reagent, too, even though reaction time was
prolonged up to 48 h (Table 1, entry 8). It is worthy to note
Table 1
The influence of base and solvent to the reaction.a
Entry
Substrate
Product
Solvent
Base (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
THF
Toluene
DMF
CHCl3
CH2Cl2
CH3CN
K3PO4(50)
K3PO4(70)
K3PO4(110)
K3PO4(200)
K2CO3(110)
KOH(110)
NaOH(110)
NaOAc(110)
0
K3PO4(110)
K3PO4(110)
K3PO4(110)
K3PO4(110)
K3PO4(110)
K3PO4(110)
b
24
18
2.0
0.5
5.5
10
48
48
48
4.5
24
48
48
24
10
40
80
93
84
90
20
Trace
Trace
0
90
83
Trace
Trace
25
57
aConditions: substrate (2.0 mmol), NBA (2.2 mmol), solvent (10 mL), at room temperature. Isolated yield.
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Table 2
The influence of mol ratio of the starting material, reagent, and K3PO4 to reaction.a
Entry
Substrate
Product
1a:NBA:K3PO4 (mole ratio)
Time (h)
Yield (%)b
1
1a
1a
1a
1a
1a
1a
1a
1a
3a
3a
3a
3a
3a
3a
3a
3a
1:1.1:1.1
1:1.5:1.1
1:2.0:1.1
1:1.5:0.5
1:1.5:0.7
1:1.5:1.2
1:1.5:1.5
1:1.5:2.0
2.0
5.5
12
24
24
2.5
1.5
0.5
93
95
88
39
61
96
90
86
2
3
4
5
6
7
8
aConditions: substrate 1a (2.0mmol), acetone (10 mL), at room temperature. bIsolated yield.
All ethyl a-cyanocinnamate derivatives reacted with
NBA successfully to give the corresponding 2-oxazolines
in good to excellent yields (72–98%). Both EDG and EWG
on the phenyl ring were compatible to the reaction system.
As shown in Table 3, the reaction activity of ethyl
a-cyanocinnamate derivatives depends greatly on the
substituent groups of benzene ring, especially those
on the 4-position of the phenyl ring. For the ethyl
a-cyanocinnamate derivatives that bearing stronger EDGs
or no any substituent group on the benzene ring
(Table 3, 1a–1e), the reaction gave the expected products
in high yields up to 90–98% (Table 3, entries 1–5). However,
when the ethyl a-cyanocinnamate derivatives bearing
stronger EWGs on the phenyl ring (1g–1j), the reaction
afforded the corresponding products in slightly lower yields
of 79–85% (Table 3, entries 7–10). Other substrates such
as 1k and 1l could give the expected products in the excellent
yields of 90% and 93%, respectively (entries 11 and 12).
Herein, the substrates of 1f and 1m also afforded the
corresponding products in good yields of 85% and 72%,
respectively (Table 3, entries 6 and 13). The results
mentioned earlier indicate that the EDGs and EWGs on the
phenyl ring could affect the reaction activity of substrates.
We realized that the formation process of 2-oxazoline was
via an aminobrominated intermediate. To confirm the hypoth-
esis of the 2-oxazoline formation from an aminobrominated
intermediate, the following experiment was carried out:
Ethyl a-cyanocinnamate 1a was reacted with NBA in acetone
promoted by K3PO4 at room temperature. When the substrate
1a was justly consumed, the reaction was stopped and the
solvent was concentrated under reduced pressure to give a
The aminobrominated intermediate (ethyl b-acetamide-b-
benzyl-a-bromo-a-cyanopropionate) as well as corresponding
2-oxazoline 3a were simultaneously observed (shown in
Fig. 1). Furthermore, the HRMS analysis of the mixture
indicated that the aminobrominated intermediate and the
product 3a were clearly identified. HRMS-ESI (m/z): Calcd
for C14H15BrNaN2O3[M + Na]+ 361.0164 (aminobrominated
intermediate), found 361.0195; Calcd for C14H14NaN2O3
[M + Na]+ 281.0897 (3a), found 281.0892. Indeed, during
the course of our reaction, a phenomenon was obviously
observed that the spot of aminobrominated intermediate was
disappeared when the reaction time was extended for a while
monitored by TLC.
We found that the reaction has high regiospecificity. To
further seek the evidence of regiospecificity of the reaction,
a single crystal of one product, 5-cyano-5-ethoxyformacyl-
2-methyl-4-(naphthalen-1-yl)-4,5-dihydrooxazole 3l, was
cultured. The regiospecificity of this 2-oxazoline was
confirmed by its X-ray crystallographic analysis (Fig. 2,
CCDC-873424). The result showed that the nitrogen atom
in 2-oxazoline ring is connected to b-carbon of the substrate.
On the basis of the very electron deficient property of
the substrates, the presence of the intermediate of amino-
brominated product during reaction progress monitored
1
by H NMR analysis and the evidence of regiospecificity
of the reaction, the plausible reaction mechanism involving
the aminobromination and the cyclization reaction
processes is proposed (Scheme 3). The first step was a
deprotonation reaction of NBA by K3PO4 to generate a
Hofmann species AcNBr- (Hs), which in turn attacks
the benzylic position of ethyl a-cyanocinnamate to
generate a Michael intermediate (G). A carbanion in this
1
mixture. The reaction mixture was analyzed by H NMR.
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One-Pot Synthesis of 2-Oxazolines from Ethyl a-Cyanocinnamate Derivatives with
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Table 3
The reaction results of various ethyl a-cyanocinnamate derivatives with N-bromoacetamide.a
Entry
1
Substrate
Product
Time (h)
2.5
Yield (%)b
96
2
2.0
91
3
4
2.2
1.5
98
96
5
1.5
90
6
4.5
85
(Continued)
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Z. Chen, H. Wen, W. Li, J. Zhou, J. Hu, and W. Xia
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Table 3
(Continued)
Entry
Substrate
Product
Time (h)
Yield (%)b
7
1.5
85
8
9
1.5
1.4
82
82
10
1.7
79
11
2.0
93
12
0.5
90
(Continued)
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One-Pot Synthesis of 2-Oxazolines from Ethyl a-Cyanocinnamate Derivatives with
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Table 3
(Continued)
Entry
13
Substrate
Product
Time (h)
4.5
Yield (%)b
72
aConditions: substrate (2.0 mmol), NBA (3.0 mmol), K3PO4 (2.4 mmol), acetone (10 mL), at room temperature.
bIsolated yield.
Figure 1. The 1H NMR spectrum of reaction mixture.
Michael intermediate (G) was formed, and it was
stabilized by the inductive effect from two EWGs
(CN and COOEt). In the second step, Br+ ion migrated
to the carbanion from NBr of the amide and then created
an acetamido anion (H).[15] In this stage, the acetamido
anion (H) accepted a proton from another NBA molecule
and gave a aminobrominated product (E) and a new AcNBr-
ion (Hs). The latter, as a stronger base than NBA, would
participate in the next cycle. Herein, an intermediate M
was formed via intramolecular rearrangement of compound
E. The final step was an intramolecular nucleophilic
substitution reaction of intermediate M that afforded
2-oxazoline with assistance of the base. The
regioselectivity could be explained by the fact that
the b-position of the substrate is loaded more positive
charge related to its a-position because of inductive
effect from two EWGs (CN and COOEt).
Briefly, the present one-pot synthesis of 2-oxazolines
essentially consists of two key reactions: nucleophilic
conjugate addition of electron-deficient olefines and
intramolecular nucleophilic substitution reaction of inter-
mediate M.[15,16]
P
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Vol 51
EXPERIMENTAL
General information. Unless otherwise stated, all reagents
were purchased from commercial sources and without further
purification. Reaction progress was monitored by TLC using
Merck silica gel 60F-254 with detection by UV. Flash
chromatography was performed using Merck silica gel 60 with
freshly distilled solvents. Columns were typically packed as slurry
and equilibrated with the appropriate solvent system prior to use.
1H (300 MHz) and 13C (75.5MHz) NMR spectra were recorded
using CDCl3 as a solvent. Chemical shifts (d) are reported in ppm,
using TMS as an internal standard. Data are presented as follows:
chemical shift (ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, sept= septet, m = multiplet), coupling
constant J (Hz), and integration. HRMS was recorded on a
commercial apparatus (ESI). The crystal structure was recorded on
an X-ray diffraction spectrometer. Melting point was uncorrected.
Preparation of N-bromoacetamide.
N-Bromoacetamide
Figure 2. X-ray crystal structure of product 3l.
Scheme 3. The plausible reaction mechanism.
was prepared according to the reference with slight modification.
[15] Acetamide (5.0 g, 85 mmol) and liquid bromine (13.5 g,
170 mmol) were added into a 150 mL round-bottomed flask
immersed in an ice-water bath and stirred electromagnetically at
0–5ꢀC until the solid dissolved completely. The ice-cooled 50%
KOH solution (10mL) was dropped while stirring at 0–5ꢀC, and a
large amount of light yellow solid was precipitated. The mixture
was allowed to stand in the ice-water bath for 2–3 h to complete
the reaction. Upon addition of 10g of NaCl and 125mL of
CHCl3, the suspension was heated on a hot-water bath to dissolve
the precipitate with vigorous stirring. Then, the organic layer was
separated and dried with anhydrous Na2SO4. After the solid was
filtrated off, 125mL of hexane was added to the filtrate and the
solution was placed in a refrigerator overnight. The white needles
were collected by filtration, and dried in vacuum: yield 5.72 g
(49.1%). mp 90.5–91.5ꢀC.
General experimental procedure. Into a dried vessel were
added substrate (2.0mmol), NBA (3.0mmol), anhydrous K3PO4
(2.4mmol), and acetone (10 mL). The mixture was stirred at room
temperature in air until the reaction was completed. The reaction
was monitored by TLC up to the aminobrominated intermediate
was disappeared completely. Ethyl acetate (20mL) was added
into the reaction mixture to quench the reaction. The solution
was washed with brine (3 Â 10 mL) and water (3 Â 10 mL). The
organic solution was dried by anhydrous Na2SO4 and
concentrated under reduced pressure to give crude product that
was purified by column chromatography with silica gel using
petroleum ether and EtOAc as eluent to afford the pure product.
5-Cyano-5-ethoxyformacyl-2-methyl-4-phenyl-4,5-dihydrooxazole
(3a). Following general experimental procedure, a white solid (495 mg,
96% yield) was obtained. mp: 50–52ꢀC.1H NMR(300 MHz, CDCl3) d
7.44–7.28 (m, 5H, Ar-H), 5.53 (s, 1H, Ar-CH-), 4.45 (q, 2H, CH2CH3),
2.25 (s, 3H, CH3), 1.41 (t, J=7.1Hz,3H, CH2CH3); 13C NMR
(75.5 MHz, CDCl3) d 165.0, 164.1, 135.5, 129.4, 128.9 (2), 127.1
(2), 113.0, 82.1, 79.7, 64.3, 14.0, 13.6; HRMS-ESI (m/z): Calcd for
C14H14NaN2O3 [M + Na]+ 281.0897, found: 281.0892.
CONCLUSION
A one-pot method for the synthesis of 2-oxazoline deriva-
tives using ethyl a-cyanocinnamate derivatives with NBA
in the presence of K3PO4 has been developed. This new
protocol can conveniently and efficiently converts the ethyl
a-cyanocinnamate derivatives into 2-oxazolines at room
temperature in good to excellent yields with the extensive
range of a-cyanocinnamate derivatives. Both EDG and
EWG on the phenyl ring are compatible to the reaction
system. The proposed plausible reaction mechanism
involving aminobromination process and cyclization process
can explain well the regiospecificity of the reaction.
5-Cyano-5-ethoxyformacyl-2-methyl-4-(4-methylphenyl)-4,
5-dihydrooxazole (3b).
Following general experimental
procedure, a white solid (469 mg, 91% yield) was obtained. mp:
53–55ꢀC. 1H NMR(300 MHz, CDCl3) d 7.34–7.18 (m, 4H, Ar-H),
5.49 (s, 1H, ArCH), 4.45 (d, J=2.88Hz, 2H, CH2CH3), 2.37
(s, 3H, Ar-CH3), 2.25 (s, 3H, CH3) 1.42 (d, J=1.17Hz, 3H,
CH2CH3); 13C NMR(75.5 MHz, CDCl3) d 165.0, 163.9, 139.2,
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One-Pot Synthesis of 2-Oxazolines from Ethyl a-Cyanocinnamate Derivatives with
N-Bromoacetamide
May 2014
801
7.57
mp: 86–88ꢀC. 1H NMR (300 MHz, CDCl3)
d
132.6, 129.6 (2), 127.0 (2), 113.1, 82.1, 79.6, 64.2, 21.3, 14.0, 13.5;
HRMS-ESI (m/z): Calcd for C15H16NaN2O3 [M + Na]+ 295.1053,
found: 295.1054.
(d, J = 8.2 Hz, 2H, Ar-H), 7.17 (d, J = 8.1 Hz, 2H, Ar-H), 5.49
(s, 1H, ArCH), 4.45 (q, 2H, CH2CH3), 2.25 (s, 3H, CH3),
1.42 (t, J = 7.1Hz,3H, CH2CH3); 13C NMR (75.5 MHz,
CDCl3) d 164.7, 164.5, 134.6, 132.1 (2), 128.8 (2), 123.6,
112.9, 81.9, 79.0, 64.5, 14.0, 13.6; HRMS-ESI (m/z): Calcd
for C14H13BrNaN2O3 [M + Na]+ 359.0001, found:359.0000.
5-Cyano-5-ethoxyformacyl-2-methyl-4-(4-nitrophenyl)-4,5-
dihydrooxazole (3j). Following general experimental procedure,
the white solid (481mg, 79% yield) was obtained. mp: 99–101ꢀC.
1H NMR(300 MHz, CDCl3) d 8.31 (d, J = 8.5Hz, 2H, Ar-H), 7.52
(d, J = 8.4Hz, 2H, Ar-H), 5.65 (s, 1H, ArCH), 4.49 (q, 2H,
CH2CH3), 2.29 (s, 3H, CH3), 1.45 (t, J = 7.1Hz, 3H, CH2CH3);
13C NMR (75.5 MHz, CDCl3) d 165.1, 164.3, 148.5, 142.5,
129.5, 128.3 (2), 124.1, 112.7, 81.7, 78.6, 64.8, 14.0, 13.6;
HRMS-ESI (m/z): Calcd for C14H13NaN3O5 [M + Na]+ 326.0747,
found: 326.0751.
5-Cyano-5-ethoxyformacyl-2-methyl-4-(4-methoxyphenyl)-4,
5-di-hydrooxazol (3c). Following general experimental procedure,
the colorless oil (564 mg, 98% yield) was obtained. 1H NMR
(300 MHz, CDCl3) d 7.20 (d, J = 8.4 Hz, 2H, Ar-H), 6.94
(d, J = 8.5 Hz, 2H, Ar-H), 5.47 (s, 1H, ArCH), 4.44 (q, 2H,
CH2CH3), 3.82 (s, 3H, OCH3), 2.25 (s, 3H, CH3), 1.41
(t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR(75.5 MHz, CDCl3) d
165.0, 163.8, 160.3, 128.4 (2), 127.6, 114.3 (2), 113.2, 82.2, 79.4,
64.2, 55.2, 14.0, 13.5; HRMS-ESI (m/z): Calcd for
C15H16NaN2O4 [M + Na]+ 311.1002, found 311.1002.
5-Cyano-5-ethoxyformacyl-2-methyl-4-(3-methoxyphenyl)-4,
5-dihydrooxazole (3d). Following general experimental procedure,
the colorless oil (553 mg, 96%yield) was obtained. 1H NMR
(300 MHz, CDCl3) d 7.37–7.32 (m, 1H, Ar-H), 6.94–6.82
(m, 3H, Ar-H), 5.50 (s, 1H, ArCH), 4.44 (q, 2H, CH2CH3),
3.82 (s, 3H, -OCH3), 2.25 (s, 3H, CH3), 1.41(t, J = 6.9 Hz, 3H,
CH2CH3); 13C NMR (75.5 MHz, CDCl3) d 164.9, 164.1,
159.9, 137.1, 130.0, 119.4 (2), 114.6, 113.0, 82.0, 79.5, 64.3,
55.3, 14.0, 13.5; HRMS-ESI (m/z): Calcd for C15H16NaN2O4
[M + Na]+ 311.1002, found: 311.1006.
5-Cyano-5-ethoxyformacyl-4-(furan-2-yl)-2-methyl-4,5-dihy
drooxazole(3k).
Following general experimental procedure,
the white solid (461mg, 93% yield) was obtained. mp: 65–67ꢀC.
1H NMR (300 MHz, CDCl3) d 7.50 (s, 1H, furyl-H), 6.44
(d, J = 6.30 Hz, 2H, furyl-H), 5.57 (s, 1H, furylCH), 4.42
(q, 2H, CH2CH3), 2.22 (s, 3H, CH3), 1.40 (t, J = 7.0 Hz, 3H,
CH2CH3); 13C NMR (75.5 MHz, CDCl3) d 164.8, 164.4,
148.0, 144.0, 112.8, 110.8, 109.9, 80.0, 74.1, 64.4, 13.9,
13.5; HRMS-ESI (m/z): Calcd for C12H12NaN2O4 [M + Na]+
271.0689, found: 271.0692.
5-Cyano-5-ethoxyformacyl-2-methyl-4-(3,4,5-trimethoxyphenyl)-
4,5-dihydrooxazole (3e).
Following general experimental
1
procedure, the colorless oil (627 mg, 90% yield) was obtained. H
NMR (300 MHz, CDCl3) d 6.50 (s, 2H, Ar-H), 5.47 (s, 1H, ArCH),
4.45 (q, 2H, CH2CH3), 3.88 (s, 9H, OCH3), 2.26 (s, 3H, CH3), 1.43
(t, J=7.1Hz, 3H, CH2CH3); 13C NMR(75.5 MHz, CDCl3) d 164.8,
163.9, 153.4 (2), 138.7, 131.0, 113.1, 104.3 (2), 82.1, 79.6, 64.3,
60.7, 56.1 (2), 13.9, 13.5; HRMS-ESI (m/z): Calcd for
C17H20NaN2O6 [M + Na]+ 371.1214, found: 371.1218.
5-Cyano-5-ethoxyformacyl-2-methyl-4-(naphthalen-1-yl)-
4,5-dihydrooxazole (3l).
Following general experimental
procedure, the white crystal (552 mg, 90% yield) was obtained.
mp: 112–114ꢀC. 1H NMR (300MHz, CDCl3) d 7.92–7.52
(m, 7H, Naphthyl-H), 6.43 (s, 1H, NaphthylCH), 4.47 (q, 2H,
CH2CH3), 2.32 (s, 3H, CH3), 1.42 (t, J = 7.1 Hz,3H, CH2CH3);
13C NMR(75.5 MHz, CDCl3) d 165.3, 164.2, 133.9, 130.8, 130.0,
129.4, 126.7, 126.0 (2), 125.6, 125.5, 122.1, 112.9, 82.3, 75.6,
64.5, 13.9, 13.6; HRMS-ESI (m/z): Calcd for C18H16NaN2O3
[M+ Na]+ 331.1053, found: 331.1056.
5-Cyano-5-ethoxyformacyl-4-(3,5-dimethoxyphenyl)-2-methyl-4,
5-dihydrooxazole (3f). Following general experimental procedure, the
1
white solid (540 mg, 88% yield) was obtained. mp: 60–62ꢀC. H
NMR (300 MHz, CDCl3) d 6.47(s, 1H, Ar-H), 6.41 (s, 2H, Ar-H),
5.45 (s, 1H, ArCH), 4.44 (q, 2H, CH2CH3), 3.80 (s, 6H, OCH3),
2.24 (s, 3H, CH3), 1.42 (t, J=7.1Hz, 3H, CH2CH3); 13C NMR
(75.5 MHz, CDCl3) d 164.9, 164.1, 161.1, 137.7, 113.0, 105.3 (2),
100.9 (2), 82.0, 79.5, 64.3, 55.3 (2), 13.9, 13.5; HRMS-ESI (m/z):
Calcd for C16H18NaN2O5 [M + Na]+ 341.1108, found: 341.1113.
5-Cyano-5-ethoxyformacyl-4-(4-fluorophenyl)-2-methyl-4,
5-dihydrooxazole (3g). Following general experimental
procedure, the white solid (469 mg, 85% yield) was obtained.
mp:58.6–61ꢀC. 1H NMR (300MHz, CDCl3) d 7.30–7.09 (m, 4H,
Ar-H), 5.51 (s, 1H, ArCH), 4.45 (q, 2H, CH2CH3), 2.25 (s, 3H,
CH3), 1.42 (t, J = 7.1Hz, 3H, CH2CH3); 13C NMR(75.5 MHz,
CDCl3) d 164.9, 164.2, 161.6, 131.5, 129.0 (2), 116.5, 116.1,
113.0, 82.0, 79.0, 64.4, 13.9, 13.5; HRMS-ESI (m/z): Calcd for
C14H13FNaN2O3 [M + Na]+ 299.0802, found: 299.0804.
4-(4-Chlorophenyl)-5-cyano-5-ethoxyformacyl-2-methyl-4,5-
dihydrooxazole (3h). Following general experimental procedure,
the white solid (479 mg, 82% yield) was obtained. mp: 78–80ꢀC.
1H NMR (300 MHz, CDCl3) d 7.42–7.22 (m, 4H, Ar-H), 5.51
(s, 1H, ArCH), 4.46(q, 2H, CH2CH3), 2.26 (s, 3H, CH3), 1.42
(t, J = 7.0 Hz, 3H, CH2CH3); 13C NMR(75.5 MHz, CDCl3) d
164.7, 164.4, 135.3, 134.2, 129.1 (2), 128.5 (2), 112.9, 81.9,
79.0, 64.3, 14.0, 13.5; HRMS-ESI (m/z): Calcd for
C14H13ClNaN2O3[M + Na]+ 315.0507, found: 315.0523.
(Æ)-5-Cyano-5-ethoxyformacyl-2-methyl-4-styryl-4, 5-
dihydrooxazole (3m).
Following general experimental
1
procedure, the yellow oil (408 mg, 72% yield) was obtained. H
NMR (300 MHz, CDCl3) d7.46–7.31 (m, 5H, Ar-H), 6.77
(d, J = 15.69 Hz, 1H, ArCH), 6.30–6.22 (m, 1H, CH), 5.04 (d, J
=7.2 Hz, 1H, CHCH), 4.41 (q, 2H, CH2CH3), 2.17 (s, 3H,
CH3), 1.38 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR(75.5 MHz,
CDCl3) d 164.6, 163.6, 135.6, 128.6 (3), 126.8 (2), 123.3,
121.3, 113.3, 80.8, 77.6, 64.3, 13.9, 13.5; HRMS-ESI (m/z):
Calcd for C16H16NaN2O3 [M + Na]+ 307.1053, found 307.1053.
Acknowledgments. The authors are grateful to the Natural Science
Foundation of Shaanxi Province (2009JM2011) and the Innovation
Foundation of Postgraduate Cultivation of Shaanxi Normal
University (2008CXB009).
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