Ethyl α-nitrocinnamates in the synthesis of highly functionalized isoxazoles

Article abstract of DOI:10.1002/ejoc.201000401

An effective method for the synthesis of highly functionalized isoxazoles from readily available starting ethyl α-nitrocinnamates has been developed. Ethyl α-nitrocinnamates react smoothly with α-nitro carbonyl compounds to produce isoxazoles in good yiel

Full text of DOI:10.1002/ejoc.201000401

FULL PAPER
DOI: 10.1002/ejoc.201000401
Ethyl α-Nitrocinnamates in the Synthesis of Highly Functionalized Isoxazoles
Kuang-Po Chen,[a] Yu-Jyun Chen,[a] and Che-Ping Chuang*[a]
Keywords: Nitrogen heterocycles / Michael addition / Alkylation / Multicomponent reactions
An effective method for the synthesis of highly functionalized
azoles effectively. These pyridinium salts can be generated
isoxazoles from readily available starting ethyl α-nitrocinna- in situ from the corresponding alkyl bromides. The one-pot
mates has been developed. Ethyl α-nitrocinnamates react
smoothly with α-nitro carbonyl compounds to produce
isoxazoles in good yields. Michael addition of pyridinium
ylides to ethyl α-nitrocinnamates can also produce these isox-
multicomponent process was also developed. Isoxazoles can
be produced directly from readily available aromatic alde-
hydes, ethyl nitroacetate, and pyridinium salts.
Introduction
Results and Discussion
The initial study started with the reaction between ethyl
α-nitrocinnamate (1A, Ar = Ph) and ethyl nitroacetate (2a;
Scheme 1). Treatment of 1A with 2a and triethylamine in
acetonitrile at 60 °C furnished isoxazole 3Aa exclusively in
93% yield (Table 1, Entry 1). The structure of 3Aa was
Isoxazoles have long been targeted in synthetic investi-
gations for their known biological activities and pharmaco-
logical properties, which include antibacterial, COX-2 in-
hibitory, GABAA antagonist, antinociceptive, and antican-
cer activity.[1] The development of new and efficient meth-
ods for their syntheses remains an area of current interest,
and many synthetic methods have been employed in the
synthesis of isoxazoles including oximation of 1,3-dicar-
bonyl compounds or α,β-unsaturated compounds,[2] con-
densation of oxime dianions,[3] and cycloaddition of nitrile
oxides to alkynes.[4] The reaction of activated acetylenes
and alkyl nitroacetates in the presence of triphenylphos-
phane also provided isoxazoles.[5] Nitro compounds can be
considered as versatile building blocks in organic synthesis,
as both the activating effect of the nitro group and its facile
transformation into various functionalities have extended
the importance of nitro compounds in the preparation of
complex molecules.[6] Although a number of methods are
available as cited above, the search for newer methods for
the synthesis of isoxazoles is continuously being pursued.
Nitronate anions can be generated from α-nitro carbonyl
compounds by using a wide range of bases and act as car-
bon nucleophiles with common electrophiles, including al-
dehydes and electron-poor alkenes, leading to carbon–
carbon bond formation.[6a–6d] Ethyl α-nitrocinnamates are
readily accessible from aromatic aldehydes and ethyl nitro-
acetate.[7] As part of our study on the development of new
routes to heterocyclic systems,[8–10] we now report a new
method for the synthesis of highly functionalized isoxazoles
from ethyl α-nitrocinnamates.
1
clearly assigned by H NMR and 13C NMR spectroscopy.
A plausible reaction mechanism is shown in Scheme 2. De-
protonation of 2a forms nitronate anion 7a and then
Michael addition of 7a to 1A afforded enolate anion 8Aa.
Intramolecular nucleophilic O-alkylation[11] of 10Aa gave
11Aa. Finally, isoxazoline N-oxide 11Aa was converted into
cycloadduct 3Aa via N-hydroxy compound 12Aa by elimi-
nation of H2O (Scheme 2, path a). In this reaction, the for-
mation of cyclopropane 9Aa derived from intramolecular
nucleophilic C-alkylation[12] of 8Aa was not observed
(Scheme 2, path b). In an attempt to investigate the range
of solvents compatible with this reaction, ethyl α-nitro-
cinnamate (1a) and ethyl nitroacetate (2a) were chosen as
model compounds, and this reaction was performed in vari-
ous solvents. The results are summarized in Table 1 (En-
tries 2–4). A change in the solvent to chloroform, ethanol,
and DME gave isoxazole 3Aa in 88–65% yield. In chloro-
form and DME, the reaction proceeds at a much slower
rate. Further studies showed that bases influenced strongly
the reaction yields. As shown in Table 1, DABCO gave 60%
yield of 3Aa, and 3Aa was not isolated when DBU was
employed as the base (Table 1, Entries 5 and 6). With piper-
idine, instead of expected product 3Aa, 4Aa derived from
the selective amidation of 3Aa was obtained in 89% yield,
and isomeric product 6Aa was not isolated (Table 1, En-
try 7). The reason for this interesting selective amidation is
not clear. On the basis of these results, by choosing acetoni-
trile as solvent, triethylamine and piperidine as bases, the
generalities of this reaction were examined with α-nitrocin-
namates 1B and 1C (Table 1, Entries 8–11). The reaction
worked well, and isoxazoles 3 and4 were formed selectively
[a] Department of Chemistry, National Cheng Kung University,
Tainan, Taiwan 70101, Republic of China
Fax: +886-6-2740552
E-mail: cpchuang@mail.ncku.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000401.
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Ethyl α-Nitrocinnamates in the Synthesis of Highly Functionalized Isoxazoles
depending on the base used. The structure of 4 was revealed
1
by H NMR and 13C NMR spectroscopy. In addition, the
structure of 4Ba was confirmed by single-crystal X-ray
analysis (Figure 1).[13] Diamides 5 can be formed as the
major products by prolonging the reaction time and in-
creasing the amount of piperidine (Table 1, Entries 12–14).
The best yield of 5 was obtain when the reaction was car-
ried out by using piperidine (7 equiv.) at 60 °C for 56 h. As
shown in Table 1 (Entries 13 and 14), under these condi-
tions, diamides
5
were formed predominantly ac-
companying a small amount of 4.
Scheme 2. Plausible reaction mechanism for the reaction between
ethyl α-nitrocinnamates 1 and ethyl nitroacetate (2a).
Scheme 1. Reactions with ethyl nitroacetate (2a).
Table 1. Reactions with ethyl nitroacetate (2a).
Entry
1
Solvent
Base
Time [h] Product, % yield[a]
1
2
3
4
5
6
7
8
1A CH3CN
1A CHCl3
Et3N[b]
Et3N[b]
4
24
4
48
4
4
4
4
4
4
4
56
56
56
3Aa, 93
3Aa, 88
3Aa, 74
3Aa, 65
3Aa, 60
3Aa, 0
4Aa, 89
3Ba, 90
3Ca, 75
1A
1A
EtOH
DME
Et3N[b]
Et3N[b]
Figure 1. The molecular structure of 4Ba.
1A CH3CN
1A CH3CN
DABCO[b]
DBU[b]
1A CH3CN piperidine[b]
1
as its H NMR and 13C NMR spectroscopic data are iden-
1B CH3CN
1C CH3CN
Et3N[b]
Et3N[b]
tical to those for the product obtained by the reaction of
1A with 15b (Scheme 4; Table 3, Entry 1). The high regiose-
lectivity for the formation of 3Ab can be rationalized by
considering that the stronger electron-withdrawing effect of
the benzoyl group over that of the carbethoxy group makes
the nitronate intermediate undergo intramolecular nucleo-
philic O-alkylation mainly via 10Ab. We next applied the
Et3N/CH3CN reaction conditions to α-nitrocinnamates 1B
and 1C (Table 2, Entries 2 and 3). The reaction worked
9
10
11
12
13
14
1B CH3CN piperidine[b]
1C CH3CN piperidine[b]
4Ba, 87
4Ca, 76
1A CH3CN
piperidine[c]
4Aa, 28; 5Aa, 53
4Aa, 12; 5Aa, 75
4Ba, 8; 5Ba, 75
1A CH3CN piperidine[d]
1B CH3CN piperidine[d]
[a] Isolated yield based on ethyl α-nitrocinnamates 1. [b] 3 equiv. of
base was used. [c] 5 equiv. of base was used. [d] 7 equiv. of base was
used.
For the formation of isoxazoles 3 bearing a 5-keto group, well, and isoxazoles 3Bb and 3Cb were formed predomi-
the reaction between ethyl α-nitrocinnamates 1 and α-nitro- nantly in 78 and 69% yield, respectively. This method
acetophenone (2b) was also studied (Scheme 3). Treatment proved to be of general applicability on ethyl α-nitro-
of 1A with 2b and triethylamine in acetonitrile at 60 °C fur- cinnamates 1 and α-nitro carbonyl compounds 2. In all
nished isoxazole 3Ab in 76% yield (Table 2, Entry 1). Isox- cases, isoxazoles 3, 4, and 5 were obtained effectively.
azole 3Ab was produced by intramolecular nucleophilic O-
Pyridinium ylides have found wide application in the syn-
alkylation of 10Ab. In addition to 3Ab, a small amount thesis of tetrahydroindolizine and pyridine derivatives.[14,15]
(5%) of 13Ab was formed by similar O-alkylation of 14Ab. Because pyridinium salts are more accessible than the cor-
The structure of 3Ab was confirmed by NMR spectroscopy, responding α-nitro carbonyl compounds, we continued to
Eur. J. Org. Chem. 2010, 5292–5300
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K.-P. Chen, Y.-J. Chen, C.-P. Chuang
Table 3. Reactions with preformed pyridinium salts 15.
FULL PAPER
Entry
1
15 Solvent
Base[a]
Time [h] Product, % yield[b]
1
2
3
4
5
6
7
8
1A 15b CH3CN
1A 15b CHCl3
1A 15b EtOH
1A 15b CH3CN DABCO
1A 15b CH3CN DBU
1A 15b CH3CN piperidine
1B 15b CH3CN
1C 15b CH3CN
1A 15a CH3CN
1B 15a CH3CN
1C 15a CH3CN
1A 15c CH3CN
Et3N
Et3N
Et3N
2
2
2
2
2
2
2
2
3
4
3
2
3Ab, 92
3Ab, 92
3Ab, 84
3Ab, 92
3Ab, 37
3Ab, 92
3Bb, 94
3Cb, 91
3Aa, 75
3Ba, 68
3Ca, 53
3Ac, 64
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
9
10
11
12
[a] 3 equiv. of base was used. [b] Isolated yield based on ethyl α-
nitrocinnamates 1.
reaction condition to α-nitrocinnamates 1B and 1C
(Table 3, Entries 7 and 8). The reaction worked well, and
isoxazoles 3Bb and 3Cb were formed in 94 and 91% yield,
respectively. Pyridinium salts 15a and 15c bearing other car-
bonyl groups were also investigated, and isoxazoles 3 were
produced in moderate yields (Table 3, Entries 9–12). This
reaction provides an efficient method for the formation of
isoxazoles 3 from ethyl α-nitrocinnamates 1 and pyridinium
salts 15.
Scheme 3. Reactions with α-nitroacetophenone (2b).
Table 2. Reactions with α-nitroacetophenone (2b).
Entry
1
Base
Time [h]
Product, % yield[a]
1
2
3
1A
1B
1C
Et3N[b]
Et3N[b]
Et3N[b]
5
4
4
3Ab, 76; 13Ab, 5
3Bb, 78; 13Bb, 6
3Cb, 69
[a] Isolated yield based on ethyl α-nitrocinnamates 1. [b] 3 equiv. of
base was used.
The pyridinium salts are readily accessible from pyridines
and alkyl halides.[16] To enhance the efficiency of this reac-
tion, we next investigated the process in which pyridinium
salts 15 and hence the ylides were generated in situ from
the corresponding alkyl halides. Phenacylpyridinium chlo-
ride (15d, R = Ph, X = Cl) was formed by the reaction
of pyridine and phenacyl chloride in acetonitrile at room
temperature for 16 h. Subsequent addition of triethylamine
and ethyl α-nitrocinnamate (1A) and stirring the reaction
mixture at 60 °C for another 2 h produced isoxazole 3Ab
in 59% yield (Table 4, Entry 1). This poor reaction yield is
presumably due to the slow reaction rate between phenacyl
chloride and pyridine. Phenacyl bromide was next used as
the in situ precursor of pyridinium salt 15b and the reaction
yield (93%) of desired isoxazole 3Ab was dramatically in-
creased (Table 4, Entry 2). Analogous results were obtained
with α-nitrocinnamates 1 and α-bromo carbonyl com-
Scheme 4. Reactions with pyridinium salts 15.
report the synthesis of isoxazoles via pyridinium ylides. The pounds and are summarized in Table 4 (Entries 3–10).
reaction between ethyl α-nitrocinnamate (1A, Ar = Ph) with When pyridinium salts 15 were generated in situ from the
preformed phenacylpyridinium bromide (15b, R = Ph, X = corresponding bromides, isoxazoles were obtained in a bet-
Br) was first examined (Scheme 4). Treatment of pyridinium ter reaction yield than those with preformed pyridinium
salt 15b with triethylamine and 1A in acetonitrile at 60 °C salts. This modified process offers significant advantages, as
for 2 h gave isoxazole 3Ab as the only product in 92% yield it precludes the necessity to generate and isolate pyridinium
(Table 3, Entry 1). Isoxazole 3Ab was formed presumably salts 15 in a separate step.
through a reaction route similar to that outlined in
One-pot multicomponent reactions have attracted con-
Scheme 1, by intramolecular nucleophilic O-alkylation of siderable attention in organic synthesis, as they can produce
16Ab. Again, the formation of cyclopropane 9Ab was not target products from readily available starting materials in
detected. Various solvents such as chloroform and ethanol a single operation without isolating the intermediates, thus
could also be useful for this reaction (Table 3, Entries 2 and reducing reaction times, labor, cost, and waste production.
3). In acetonitrile, different bases were next screened for this In an attempt to enhance the efficiency of the synthesis of
reaction. Replacement of triethylamine with other bases ex- isoxazoles, we then turned our attention to the development
cept DBU also led to 3Ab in a similar reaction yield of a one-pot process, in which ethyl α-nitrocinnamates 1
(Table 3, Entries 4–6). We next applied the Et3N/CH3CN could be generated in situ from aromatic aldehydes 17 and
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Ethyl α-Nitrocinnamates in the Synthesis of Highly Functionalized Isoxazoles
Table 4. Reactions with pyridinium salts 15 generated in situ from
the corresponding alkyl halides.
Entry
1
15
Base[a]
Time [h] Product, % yield[b]
1
2
3
4
5
6
7
8
9
1A
1A
1B
1C
1A
1B
1C
1A
1B
1C
15d[c]
15b[d]
15b[d]
15b[d]
15a[d]
15a[d]
15a[d]
15c[d]
15c[d]
15c[d]
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
2
2
2
2
3
3
3
2
2
4
3Ab, 59
3Ab, 93
3Bb, 94
3Cb, 93
3Aa, 85
3Ba, 80
3Ca, 60
3Ac, 68
3Bc, 63
3Cc, 48
Scheme 5. One-pot synthesis of isoxazoles with ethyl nitroacetate
(2a).
Table 5. One-pot synthesis of isoxazoles with ethyl nitroacetate
(2a).
10
[a] 3 equiv. of base was used. [b] Isolated yield based on ethyl α-
nitrocinnamates 1. [c] The pyridinium salt was generated in situ
from pyridine and phenacyl chloride. [d] The pyridinium salt was
generated in situ from pyridine and the corresponding alkyl bro-
mides.
Entry
17
Base
Time [h]
Product, % yield[a]
1
2
3
4
5
6
7
8
17B[b]
17B[b]
17B[b]
17B[c]
17A[c]
17C[c]
17D[c]
17E[c]
17F[c]
17A[c]
17B[c]
17C[c]
17D[c]
17E[c]
17F[c]
17G[c]
17A[c]
17B[c]
17E[c]
17F[c]
17G[c]
Et3N[d]
24
36
36
36
36
72
54
36
14
14
14
14
14
10
10
10
48
56
56
56
56
3Ba, 60
3Ba, 63
Et3N[d]
Et3N[e]
3Ba, 68
Et3N[e]
3Ba, 75
Et3N[e]
3Aa, 74
Et3N[e]
3Ca, 46
ethyl nitroacetate (2a). The transformation of p-bro-
mobenzaldehyde (17B, Ar = p-BrPh) and ethyl nitroacetate
(2a) into isoxazole 3Ba was first studied (Scheme 5). Under
the optimal conditions shown in Table 1, that is, triethyl-
amine (3 equiv.) as base and acetonitrile as solvent, 60%
yield of isoxazole 3Ba was obtained from 2a and 17B
(1 equiv.) after heating at 60 °C for 24 h. (Table 5, Entry 1).
The reaction yield of 3Ba could be improved to 75% when
the reaction was performed with 2 equiv. of 17B and
5 equiv. of triethylamine at 60 °C for 36 h (Table 5, Entry 4).
Investigation of the scope of this triethylamine-initiated
one-pot reaction revealed that aromatic aldehydes 17 (bear-
ing electron-withdrawing and electron-donating groups)
could be utilized in this protocol (Table 5, Entries 1–9). The
reaction of ethyl nitroacetate (2a) with electron-deficient
aromatic aldehydes was faster than with electron-rich aro-
matic aldehydes. In contrast, when piperidine (3 equiv.) was
employed as base, reaction of benzaldehyde (17A, Ar = Ph)
Et3N[e]
3Da, 65
Et3N[e]
3Ea, 77
9
Et3N[e]
3Fa, 60
10
11
12
13
14
15
16
17
18
19
20
21
piperidine[d]
piperidine[d]
piperidine[d]
piperidine[d]
piperidine[d]
piperidine[d]
piperidine[d]
piperidine[e]
piperidine[e]
piperidine[e]
piperidine[e]
piperidine[e]
4Aa, 73
4Ba, 71; 5Ba, 6
4Ca, 64
4Da, 71
4Ea, 66; 5Ea, 5
4Fa, 54; 5Fa, 12
4Ga, 64; 5Ga, 9
4Aa, 22; 5Aa, 54
4Ba, 4; 5Ba, 72
4Ea, 4; 5Ea, 69
4Fa, 0; 5Fa, 57
4Ga, 7; 5Ga, 64
[a] Isolated yield based on ethyl nitroacetate (2a). [b] Reactions
were carried out with 1 equiv. of 17. [c] Reactions were carried out
with 2 equiv. of 17. [d] 3 equiv. of base was used. [e] 5 equiv. of base
was used.
and ethyl nitroacetate (2a) produced 4Aa (73%) derived action of aromatic aldehydes 17, ethyl nitroacetate (2a), and
from the selective amidation of 3Aa (Table 5, Entry 10). A pyridinium salts 15 (Scheme 6). Indeed, using triethylamine
variety of aromatic aldehydes 17 was also employed under as base, benzaldehyde (17A, Ar = Ph), ethyl nitroacetate
piperidine-initiated one-pot reaction conditions. As shown (2a) and preformed phenacylpyridinium bromide (15b)
in Table 5 (Entries 10–16), not only electron-rich aromatic were transformed into isoxazole 3Ab in 50% yield after
aldehydes but also electron-deficient aromatic aldehydes af- heating at 60 °C for 24 h (Table 6, Entry 1). When piperid-
forded desired isoxazole derivatives 4 in moderate yields ine was employed, desired product 3Ab was obtained in a
with high regioselectivity. With electron-deficient aromatic much better reaction yield (92%) and the reaction time was
aldehydes, small amounts of diamides 5 were also formed shortened to 2 h (Table 6, Entry 2). A similar result was ob-
(Table 5, Entries 11, 14–16). By prolonging the reaction tained when phenacylpyridinium bromide (15b) was gener-
time and increasing the amount of piperidine (5 equiv.), di- ated in situ from pyridine and phenacyl bromide (Table 6,
amides 5 became the major products (Table 5, Entries 17– Entry 3). Using these piperidine/acetonitrile conditions, we
21). In this one-pot process between aromatic aldehydes 17 examined the generality of this three-component process
and ethyl nitroacetate (2a), isoxazoles 3, 4, and 5 could be with various aromatic aldehydes 17 and pyridinium salts 15.
formed selectively depending on the base used and the reac- As shown in Table 6 (Entries 3–12), isoxazoles 3 bearing a
tion time. These results demonstrate that a one-pot process 5-keto group were obtained in moderate to good yields.
for the efficient synthesis of highly functionalized isoxazole This one-pot three-component process offers significant ad-
derivatives has been successfully established.
vantages, as it precludes the necessity to prepare ethyl α-
In view of the good results on the one-pot process be- nitrocinnamates 1 in a separate step and 5-ketoisoxazoles
tween aromatic aldehydes 17 and ethyl nitroacetate (2a), we were produced effectively from readily available aromatic
reasoned that it might be possible to form isoxazole deriva- aldehydes 17, ethyl nitroacetate (2a), and pyridinium salts
tives bearing a 5-keto group through a three-component re- 15.
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K.-P. Chen, Y.-J. Chen, C.-P. Chuang
FULL PAPER
HRMS were recorded with a JEOL JMS-SX 102A mass spectrom-
eter. X-ray diffraction structure analyses were performed with a
Nonius Kappa CCD diffractometer. Structure analysis was made
by using the SHELXTL program on a personal computer. Analyti-
cal thin-layer chromatography was performed with precoated silica
gel 60 F-254 plates (0.25 mm thick) and visualized by UV light.
The reaction mixture was purified by column chromatography over
silica gel (70–230 mesh).
Typical Procedure for the Reactions with α-Nitro Carbonyl Com-
pounds 2: A solution of ethyl α-nitrocinnamate (1A, 142 mg,
0.64 mmol), ethyl nitroacetate (2a, 128 mg, 0.96 mmol), and trieth-
ylamine (195 mg, 1.93 mmol) in CH3CN (6 mL) was heated at
60 °C for 4 h. The reaction mixture was diluted with EtOAc
(100 mL), washed with H2O (3ϫ50 mL), dried (Na2SO4), and con-
centrated in vacuo. The residue was chromatographed over silica
gel (20 g; hexane/EtOAc, 8:1) followed by crystallization (hexane/
EtOAc) to give 3Aa (173 mg, 93%).
Scheme 6. One-pot synthesis of isoxazoles 3 with pyridinium salts
15.
Table 6. One-pot synthesis of isoxazoles 3 with pyridinium salts 15.
Entry
17
15
Base[a]
Time [h] Product, % yield[b]
1
2
17A 15b
17A 15b
17A 15b
17B 15b
17C 15b
17D 15b
17E 15b
17F 15b
17G 15b
17A 15c
17B 15c
17C 15c
Et3N
16
2
2
2
2
2
2
2
2
2
2
2
3Ab, 50
3Ab, 92
3Ab, 90
3Bb, 85
3Cb, 58
3Db, 90
3Eb, 85
3Fb, 81
3Gb, 83
3Ac, 67
3Bc, 71
3Cc, 53
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
Piperidine
piperidine
piperidine
piperidine
piperidine
Typical Procedure for the Reactions with Pyridinium Salts 15: A
solution of ethyl α-nitrocinnamate (1A, 152 mg, 0.69 mmol), phen-
acylpyridinium bromide (15b, 288 mg, 1.04 mmol), and triethyl-
amine (209 mg, 2.07 mmol) in CH3CN (6 mL) was heated at 60 °C
for 2 h. The reaction mixture was diluted with EtOAc (100 mL),
washed with H2O (3ϫ50 mL), dried (Na2SO4), and concentrated
in vacuo. The residue was chromatographed over silica gel (20 g;
hexane/EtOAc, 8:1) followed by crystallization (hexane/EtOAc) to
give 3Ab (204 mg, 92%).
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9[c]
10[c]
11[c]
12[c]
Typical Procedure for the One-pot Reactions between Aromatic Al-
dehydes 17 and Ethyl Nitroacetate (2a): A solution of benzaldehyde
(17A, 137 mg, 1.29 mmol), ethyl nitroacetate (2a, 172 mg,
1.29 mmol), and triethylamine (653 mg, 6.47 mmol) in CH3CN
(5 mL) was stirred at 60 °C for 36 h. The reaction mixture was di-
luted with EtOAc (100 mL), washed with H2O (3ϫ50 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was chromato-
graphed over silica gel (20 g; hexane/EtOAc, 8:1) followed by
crystallization (hexane/EtOAc) to give 3Aa (138 mg, 74%).
[a] 5 equiv. of base was used. [b] Isolated yield based on ethyl nitro-
acetate (2a). [c] Pyridinium salts 15 were generated in situ by the
reaction of pyridine and the corresponding alkyl bromides.
Conclusions
We have developed a new reaction for the synthesis of
highly functionalized isoxazoles from readily available start-
ing ethyl α-nitrocinnamates. Ethyl α-nitrocinnamates react
smoothly with α-nitro carbonyl compounds to produce
isoxazoles in good yields. This protocol provides novel and
effective methodology for the preparation of isoxazoles. The
reaction is applicable to a range of ethyl α-nitrocinnamates
and α-nitro carbonyl compounds with a variety of versatile
functional groups. Conjugate addition of pyridinium ylides
to ethyl α-nitrocinnamates can also generate these isox-
azoles. These pyridinium salts can be generated in situ from
the corresponding alkyl bromides. To increase the efficiency
of this reaction, the one-pot multicomponent process was
also developed. Isoxazoles can be produced directly from
Typical Procedure for the One-Pot Reactions between Aromatic Al-
dehydes 17, Ethyl Nitroacetate (2a), and Pyridinium Salts 15: A
solution of benzaldehyde (17A, 114 mg, 0.93 mmol), ethyl nitro-
acetate (2a, 102 mg, 0.77 mmol), phenacylpyridinium bromide
(15b, 315 mg, 1.13 mmol), and piperidine (319 mg, 3.75 mmol) in
CH3CN (5 mL) was stirred at 60 °C for 2 h. The reaction mixture
was diluted with EtOAc (100 mL), washed with H2O (3ϫ50 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was chro-
matographed over silica gel (20 g; hexane/EtOAc, 8:1) followed by
crystallization (hexane/EtOAc) to give 3Ab (228 mg, 92%).
Diethyl 4-Phenylisoxazole-3,5-dicarboxylate (3Aa): White crystals;
m.p. 51–52 °C. IR (KBr): ν = 2985, 1735, 1235, 1200, 1025 cm–1.
˜
readily available aromatic aldehydes and ethyl nitroacetate. 1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H, CH3),
1.27 (t, J = 7.1 Hz, 3 H, CH3), 4.32 (q, J = 7.1 Hz, 2 H, OCH2),
4.33 (q, J = 7.1 Hz, 2 H, OCH2), 7.34–7.39 (m, 2 H, ArH), 7.40–
7.45 (m, 3 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 13.78
(q), 13.81 (q), 62.3 (t), 62.4 (t), 125.5 (s), 126.8 (s), 127.8 (2 d),
129.0 (d), 129.9 (2 d), 155.5 (s), 156.4 (s), 157.1 (s), 159.1 (s) ppm.
C15H15NO5 (289.10): calcd. C 62.28, H 5.23, N 4.84; found C
62.11, H 5.28, N 4.83.
In this one-pot process, isoxazoles 3, 4, and 5 were formed
selectively depending on the base used and the reaction
time. 5-Ketoisoxazoles can also be produced directly from
readily available aromatic aldehydes, ethyl nitroacetate, and
pyridinium salts.
Diethyl 4-(4-Bromophenyl)isoxazole-3,5-dicarboxylate (3Ba): White
Experimental Section
crystals; m.p. 90–91 °C. IR (KBr): ν = 2985, 1740, 1260, 1205,
˜
1
General Considerations: The NMR spectra were recorded with a
Bruker Avance 300 or AMX-400 spectrometer. Chemical shifts are
reported in ppm relative to TMS as internal reference. Elemental
analyses were performed with a Heraeus CHN-Rapid Analyzer.
1020 cm–1. H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.0 Hz,
3 H, CH3), 1.30 (t, J = 7.0 Hz, 3 H, CH3), 4.34 (q, J = 7.0 Hz, 2
H, OCH2), 4.35 (q, J = 7.0 Hz, 2 H, OCH2), 7.25 (d, J = 8.4 Hz,
2 H, ArH), 7.57 (d, J = 8.4 Hz, 2 H, ArH) ppm. 13C NMR
5296
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5292–5300

Ethyl α-Nitrocinnamates in the Synthesis of Highly Functionalized Isoxazoles
(75.4 MHz, CDCl3): δ = 13.82 (q), 13.85 (q), 62.5 (2 t), 123.4 (s),
J = 7.9 Hz, 1 H, ArH), 7.95 (d, J = 7.9 Hz, 2 H, ArH) ppm. 13C
124.4 (s), 125.8 (s), 131.0 (2 d), 131.7 (2 d), 155.1 (s), 156.2 (s), NMR (75.4 MHz, CDCl3): δ = 13.9 (q), 62.6 (t), 123.5 (s), 123.9
157.1 (s), 158.9 (s) ppm. C15H14BrNO5 (367.01): calcd. C 48.93, H
3.83, N 3.80; found C 48.92, H 3.89, N 3.76.
(s), 125.7 (s), 128.8 (2 d), 130.1 (2 d), 131.3 (2 d), 131.7 (2 d), 134.5
(d), 135.2 (s), 154.9 (s), 159.2 (s), 163.4 (s), 182.0 (s) ppm. HRMS
(EI): calcd. for C19H14BrNO4 399.0109; found 399.0106.
Diethyl 4-(Thiophen-2-yl)isoxazole-3,5-dicarboxylate (3Ca): White
crystals; m.p. 42–43 °C. IR (KBr): ν = 2985, 1735, 1235, 1020,
˜
Ethyl 5-Benzoyl-(4-thiophen-2-yl)isoxazole-3-carboxylate (3Cb):
1
715 cm–1. H NMR (400 MHz, CDCl3): δ = 1.326 (t, J = 7.2 Hz,
Pale-yellow crystals; m.p. 55–56 °C. IR (KBr): ν = 2980, 1740,
˜
1
1235, 1180, 1010 cm–1. H NMR (400 MHz, CDCl3): δ = 1.38 (t,
3 H, CH3), 1.329 (t, J = 7.2 Hz, 3 H, CH3), 4.38 (q, J = 7.2 Hz, 2
H, OCH2), 4.39 (q, J = 7.2 Hz, 2 H, OCH2), 7.11 (dd, J = 5.0,
3.6 Hz, 1 H, ArH), 7.28 (dd, J = 3.6, 0.8 Hz, 1 H, ArH), 7.49 (dd,
J = 5.0, 0.8 Hz, 1 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ
= 13.8 (2 q), 62.5 (t), 62.6 (t), 118.5 (s), 125.7 (s), 126.8 (d), 128.1
(d), 130.6 (d), 155.7 (s), 156.2 (s), 157.1 (s), 159.0 (s) ppm.
C13H13NO5S (295.31): calcd. C 52.87, H 4.44, N 4.74, S 10.86;
found C 52.78, H 4.46, N 4.73, S 10.98.
J = 7.1 Hz, 3 H, CH3), 4.45 (q, J = 7.1 Hz, 2 H, OCH2), 7.03 (dd,
J = 5.1, 3.7 Hz, 1 H, ArH), 7.33 (dd, J = 3.7, 1.0 Hz, 1 H, ArH),
7.42 (dd, J = 5.1, 1.0 Hz, 1 H, ArH), 7.48 (t, J = 7.6 Hz, 2 H,
ArH), 7.63 (t, J = 7.6 Hz, 1 H, ArH), 7.93 (d, J = 7.6 Hz, 2 H,
ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 13.9 (q), 62.7 (t),
117.7 (s), 125.9 (s), 127.0 (d), 128.3 (d), 128.7 (2 d), 130.0 (2 d),
130.8 (d), 134.5 (d), 135.2 (s), 155.1 (s), 159.4 (s), 163.1 (s), 182.3
(s) ppm. C17H13NO4S (327.06): calcd. C 62.37, H 4.00, N 4.28, S
9.80; found C 62.46, H 3.97, N 4.26, S 9.89.
Diethyl 4-(4-Methoxyphenyl)isoxazole-3,5-dicarboxylate (3Da):
White crystals; m.p. 60–61 °C. IR (KBr): ν = 2985, 1740, 1615,
˜
1515, 1230 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J =
7.1 Hz, 3 H, CH3), 1.31 (t, J = 7.1 Hz, 3 H, CH3), 3.85 (s, 3 H,
OCH3), 4.34 (q, J = 7.1 Hz, 2 H, OCH2), 4.35 (q, J = 7.1 Hz, 2 H,
OCH2), 6.95 (d, J = 8.8 Hz, 2 H, ArH), 7.32 (d, J = 8.8 Hz, 2 H,
ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 13.7 (2 q), 55.1
(q), 62.1 (t), 62.2 (t), 113.1 (2 d), 118.5 (s), 125.2 (s), 131.3 (2 d),
155.4 (s), 156.4 (s), 156.6 (s), 159.2 (s), 160.0 (s) ppm. C16H17NO6
(319.11): calcd. C 60.18, H 5.37, N 4.39; found C 60.08, H 5.36, N
4.30.
Ethyl 5-Benzoyl-4-(4-methoxyphenyl)isoxazole-3-carboxylate (3Db):
Yellow crystals; m.p. 58–59 °C. IR (KBr): ν = 2975, 1735, 1665,
˜
1510, 1235 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J =
7.1 Hz, 3 H, CH3), 3.81 (s, 3 H, OCH3), 4.40 (q, J = 7.1 Hz, 2 H,
OCH2), 6.90 (d, J = 8.8 Hz, 2 H, ArH), 7.35 (d, J = 8.8 Hz, 2 H,
ArH), 7.46 (t, J = 7.7 Hz, 2 H, ArH), 7.61 (t, J = 7.7 Hz, 1 H,
ArH), 7.93 (d, J = 7.7 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 13.6 (q), 54.8 (q), 62.1 (t), 113.2 (2 d), 118.3 (s), 124.2
(s), 128.3 (2 d), 129.6 (2 d), 131.2 (2 d), 133.9 (d), 135.1 (s), 154.9
(s), 159.2 (s), 159.8 (s), 162.5 (s), 182.1 (s) ppm. C20H17NO5
(351.11): calcd. C 68.37, H 4.88, N 3.99; found C 68.12, H 4.92, N
3.89.
Diethyl 4-(4-Chlorophenyl)isoxazole-3,5-dicarboxylate (3Ea): White
crystals; m.p. 75–76 °C. IR (KBr): ν = 2985, 1740, 1495, 1450,
˜
1
1235 cm–1. H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.1 Hz,
3 H, CH3), 1.30 (t, J = 7.1 Hz, 3 H, CH3), 4.34 (q, J = 7.1 Hz, 2
H, OCH2), 4.35 (q, J = 7.1 Hz, 2 H, OCH2), 7.31 (d, J = 8.6 Hz,
2 H, ArH), 7.41 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 13.7 (2 q), 62.3 (2 t), 124.2 (s), 125.2 (s),
127.9 (2 d), 131.3 (2 d), 135.0 (s), 155.1 (s), 156.0 (s), 157.1 (s),
158.8 (s) ppm. C15H14ClNO5 (323.06): calcd. C 55.65, H 4.36, N
4.33; found C 55.69, H 4.40, N 4.27.
Ethyl 5-Benzoyl-4-(4-chlorophenyl)isoxazole-3-carboxylate (3Eb):
White crystals; m.p. 59–60 °C. IR (KBr): ν = 2985, 1740, 1670,
˜
1450, 1230 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J =
7.1 Hz, 3 H, CH3), 4.39 (q, J = 7.1 Hz, 2 H, OCH2), 7.33–7.38 (m,
4 H, ArH), 7.49 (t, J = 7.7 Hz, 2 H, ArH), 7.64 (t, J = 7.7 Hz, 1 H,
ArH), 7.95 (d, J = 7.7 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 13.9 (q), 62.5 (t), 123.8 (s), 125.2 (s), 128.3 (2 d), 128.7
(2 d), 130.0 (2 d), 131.4 (2 d), 134.5 (d), 135.1 (2 s), 154.9 (s), 159.2
(s), 163.3 (s), 182.0 (s) ppm. C19H14ClNO4 (355.06): calcd. C 64.14,
H 3.97, N 3.94; found C 64.14, H 3.98, N 3.89.
Diethyl 4-(4-Nitrophenyl)isoxazole-3,5-dicarboxylate (3Fa): White
crystals; m.p. 112–113 °C. IR (KBr): ν = 2985, 1740, 1735, 1520,
˜
1
1255 cm–1. H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.1 Hz,
3 H, CH3), 1.31 (t, J = 7.1 Hz, 3 H, CH3), 4.35 (q, J = 7.1 Hz, 2
H, OCH2), 4.36 (q, J = 7.1 Hz, 2 H, OCH2), 7.57 (d, J = 8.8 Hz,
2 H, ArH), 8.30 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 13.81 (q), 13.84 (q), 62.73 (t), 62.77 (t),
123.0 (2 d), 123.6 (s), 131.3 (2 d), 133.8 (s), 148.1 (s), 154.8 (s),
155.9 (s), 157.7 (s), 158.7 (s) ppm. C15H14N2O7 (334.08): calcd. C
53.89, H 4.22, N 8.38; found C 53.89, H 4.23, N 8.35.
Ethyl 5-Benzoyl-4-(4-nitrophenyl)isoxazole-3-carboxylate (3Fb):
White crystals; m.p. 89–90 °C. IR (KBr): ν = 2995, 1740, 1660,
˜
1520, 1240 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.34 (t, J =
7.2 Hz, 3 H, CH3), 4.40 (q, J = 7.2 Hz, 2 H, OCH2), 7.52 (t, J =
7.7 Hz, 2 H, ArH), 7.61 (d, J = 8.8 Hz, 2 H, ArH), 7.68 (t, J =
7.7 Hz, 1 H, ArH), 8.00 (d, J = 7.7 Hz, 2 H, ArH), 8.27 (d, J =
8.8 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 13.8
(q), 62.7 (t), 123.1 (2 d), 128.8 (2 d), 130.0 (2 d), 131.2 (2 d), 133.8
(s), 134.8 (d), 134.9 (s), 147.9 (s), 154.6 (s), 158.8 (s), 163.9 (s),
181.5 (s) ppm. C19H14N2O6 (366.09): calcd. C 62.30, H 3.85, N
7.65; found C 62.28, H 3.84, N 7.64.
Ethyl 5-Benzoyl-4-phenylisoxazole-3-carboxylate (3Ab): White crys-
tals; m.p. 71–72 °C. IR (KBr): ν = 2985, 1735, 1230, 1180,
˜
1
1015 cm–1. H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz,
3 H, CH3), 4.38 (q, J = 7.1 Hz, 2 H, OCH2), 7.33–7.42 (m, 5 H,
ArH), 7.45 (t, J = 7.6 Hz, 2 H, ArH), 7.60 (t, J = 7.6 Hz, 1 H,
ArH), 7.93 (d, J = 7.6 Hz, 2 H, ArH) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 13.8 (q), 62.4 (t), 124.8 (s), 126.7 (s), 128.0 (2 d), 128.6
(2 d), 128.9 (d), 130.00 (2 d), 130.01 (2 d), 134.3 (d), 135.3 (s), 155.1
(s), 159.4 (s), 163.2 (s), 182.3 (s) ppm. C19H15NO4 (321.10): calcd.
C 71.02, H 4.71, N 4.36; found C 71.06, H 4.71, N 4.33.
Ethyl 5-Benzoyl-4-(4-cyanophenyl)isoxazole-3-carboxylate (3Gb):
White crystals; m.p. 98–99 °C. IR (KBr): ν = 2990, 2230, 1740,
˜
1660, 1240 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.33 (t, J =
7.2 Hz, 3 H, CH3), 4.40 (q, J = 7.2 Hz, 2 H, OCH2), 7.51 (t, J =
7.3 Hz, 2 H, ArH), 7.54 (d, J = 8.4 Hz, 2 H, ArH), 7.67 (t, J =
7.3 Hz, 1 H, ArH), 7.70 (d, J = 7.3 Hz, 2 H, ArH), 7.98 (d, J =
Ethyl 5-Benzoyl-4-(4-bromophenyl)isoxazole-3-carboxylate (3Bb): 8.4 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 13.8
Yellow oil. IR (KBr): ν = 2925, 1740, 1230, 1180, 1010 cm–1. 1H (q), 62.7 (t), 112.7 (s), 118.2 (s), 123.4 (s), 128.8 (2 d), 130.0 (2 d),
˜
NMR (400 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H, CH3), 4.39 130.9 (2 d), 131.6 (2 d), 131.8 (s), 134.7 (d), 134.9 (s), 154.6 (s),
(q, J = 7.2 Hz, 2 H, OCH2), 7.29 (d, J = 8.5 Hz, 2 H, ArH), 7.49
158.8 (s), 163.7 (s), 181.6 (s) ppm. C20H14N2O4 (346.10): calcd. C
(t, J = 7.9 Hz, 2 H, ArH), 7.52 (d, J = 8.5 Hz, 2 H, ArH), 7.64 (t, 69.36, H 4.07, N 8.09; found C 69.36, H 4.10, N 8.11.
Eur. J. Org. Chem. 2010, 5292–5300
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5297

K.-P. Chen, Y.-J. Chen, C.-P. Chuang
FULL PAPER
Ethyl 5-Acetyl-4-phenylisoxazole-3-carboxylate (3Ac): White crys-
Ethyl
4-(4-Methoxyphenyl)-5-(piperidine-1-carbonyl)isoxazole-3-
tals; m.p. 78–79 °C. IR (KBr): ν = 2985, 1735, 1200, 1020,
carboxylate (4Da): Light-yellow powder; m.p. 61–62 °C. IR (KBr):
˜
˜
1
695 cm–1. H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3
ν = 2940, 1730, 1645, 1515, 1255 cm–1. 1H NMR (400 MHz,
H, CH3), 2.53 (s, 3 H, CH3), 4.33 (q, J = 7.1 Hz, 2 H, OCH2), CDCl3): δ = 1.15–1.28 (m, 2 H, CH2), 1.35 (t, J = 7.1 Hz, 3 H,
7.34–7.39 (m, 2 H, ArH), 7.40–7.47 (m, 3 H, ArH) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 13.8 (q), 28.5 (q), 62.4 (t), 123.8 (s), 126.8
CH3), 1.49–1.61 (m, 4 H, 2 CH2), 3.11 (t, J = 5.6 Hz, 2 H, NCH2),
3.57–3.65 (m, 2 H, NCH2), 3.84 (s, 3 H, OCH3), 4.39 (q, J = 7.1 Hz,
(s), 128.1 (2 d), 129.2 (d), 129.8 (2 d), 155.8 (s), 159.2 (s), 162.2 (s), 2 H, OCH2), 6.94 (d, J = 8.8 Hz, 2 H, ArH), 7.37 (d, J = 8.8 Hz,
186.5 (s) ppm. C14H13NO4 (259.08): calcd. C 64.86, H 5.05, N 5.40; 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 13.9 (q), 24.1
found C 64.80, H 5.06, N 5.34.
(t), 25.1 (t), 25.9 (t), 43.1 (t), 47.7 (t), 55.2 (t), 62.3 (t), 113.8 (2 d),
118.6 (s), 119.3 (s), 130.8 (2 d), 153.7 (s), 157.2 (s), 159.7 (s), 160.0
(s), 161.4 (s) ppm. C19H22N2O5 (358.15): calcd. C 63.67, H 6.19, N
7.82; found C 63.47, H 6.24, N 7.70.
Ethyl 5-Acetyl-4-(4-bromophenyl)isoxazole-3-carboxylate (3Bc):
White needles; m.p. 88–89 °C. IR (KBr): ν = 1750, 1700, 1215,
˜
1020, 830 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J =
7.1 Hz, 3 H, CH3), 2.59 (s, 3 H, CH3), 4.35 (q, J = 7.1 Hz, 2 H,
OCH2), 7.25 (d, J = 8.5 Hz, 2 H, ArH), 7.57 (d, J = 8.5 Hz, 2 H,
ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 13.8 (q), 28.4 (q),
62.5 (t), 122.7 (s), 123.6 (s), 125.6 (s), 131.2 (2 d), 131.6 (2 d),
155.4 (s), 159.0 (s), 162.2 (s), 186.5 (s) ppm. C14H12BrNO4 (336.99):
calcd. C 49.73, H 3.58, N 4.14; found C 49.76, H 3.66, N 4.14.
4-(4-Chlorophenyl)-5-(piperidine-1-carbonyl)isoxazole-3-carboxylate
(4Ea): White powder; m.p. 74–75 °C. IR (KBr): ν = 2940, 1740,
˜
1650, 1445, 1255 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.25–1.32
(m, 2 H, CH2), 1.35 (t, J = 7.2 Hz, 3 H, CH3), 1.51–1.65 (m, 4 H,
2 CH2), 3.14 (t, J = 5.6 Hz, 2 H, NCH2), 3.62 (t, J = 5.6 Hz, 2 H,
NCH2), 4.39 (q, J = 7.2 Hz, 2 H, OCH2), 7.39 (s, 4 H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 13.9 (q), 24.1 (t), 25.2 (t), 26.1
(t), 43.2 (t), 47.7 (t), 62.4 (t), 118.7 (s), 125.1 (s), 128.6 (2 d), 131.0
(2 d), 135.0 (s), 153.6 (s), 156.7 (s), 159.4 (s), 162.0 (s) ppm.
C18H19ClN2O4 (362.10): calcd. C 59.59, H 5.28, N 7.72; found C
59.53, H 5.29, N 7.66.
Ethyl 5-Acetyl-4-(thiophen-2-yl)isoxazole-3-carboxylate (3Cc): Yel-
low oil. IR (KBr): ν = 2980, 1740, 1205, 1015, 710 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.34 (t, J = 7.1 Hz, 3 H, CH3), 2.59 (s, 3
H, CH3), 4.40 (q, J = 7.1 Hz, 2 H, OCH2), 7.12 (dd, J = 5.2, 3.7 Hz,
1 H, ArH), 7.36 (dd, J = 3.7, 1.2 Hz, 1 H, ArH), 7.50 (dd, J = 5.2,
1.2 Hz, 1 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 13.8
(q), 28.4 (q), 62.6 (t), 116.8 (s), 125.8 (s), 127.0 (d), 128.3 (d), 130.9
(d), 155.8 (s), 159.2 (s), 161.9 (s), 186.4 (s) ppm. HRMS (EI): calcd.
for C12H11NO4S 265.0425; found 265.0417.
4-(4-Nitrophenyl)-5-(piperidine-1-carbonyl)isoxazole-3-carboxylate
(4Fa): Light-yellow crystals; m.p. 79–80 °C. IR (KBr): ν = 2940,
˜
1740, 1650, 1520, 1255 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.36 (t, J = 7.1 Hz, 3 H, CH3), 1.38–1.45 (m, 2 H, CH2), 1.59–1.70
(m, 4 H, 2 CH2), 3.22 (t, J = 5.6 Hz, 2 H, NCH2), 3.64 (t, J =
5.6 Hz, 2 H, NCH2), 4.41 (q, J = 7.1 Hz, 2 H, OCH2), 7.66 (d, J
= 8.8 Hz, 2 H, ArH), 8.28 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 13.8 (q), 24.0 (t), 25.2 (t), 26.3 (t),
43.3 (t), 47.7 (t), 62.6 (t), 118.3 (s), 123.3 (2 d), 130.8 (2 d), 133.5 (s),
147.8 (s), 153.4 (s), 156.2 (s), 159.1 (s), 162.7 (s) ppm. C18H19N3O6
(373.13): calcd. C 57.90, H 5.13, N 11.25; found C 57.85, H 5.12,
N 11.25.
Ethyl
4-Phenyl-5-(piperidine-1-carbonyl)isoxazole-3-carboxylate
(4Aa): White crystals; m.p. 89–90 °C. IR (KBr): ν = 1735, 1645,
˜
1255, 1180, 1015 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.12–1.22
(m, 2 H, CH2), 1.33 (t, J = 7.1 Hz, 3 H, CH3), 1.48–1.59 (m, 4 H,
2 CH2), 3.10 (t, J = 5.6 Hz, 2 H, NCH2), 3.57–3.67 (m, 2 H,
NCH2), 4.39 (q, J = 7.1 Hz, 2 H, OCH2), 7.38–7.46 (m, 5 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 13.9 (q), 24.1 (t), 25.1
(t), 25.9 (t), 43.1 (t), 47.7 (t), 62.4 (t), 119.5 (s), 126.6 (s), 128.4 (2
d), 128.9 (d), 129.6 (2 d), 153.7 (s), 157.1 (s), 159.6 (s), 161.8 (s)
ppm. C18H20N2O4 (328.14): calcd. C 65.84, H 6.14, N 8.53; found
C 65.84, H 6.15, N 8.56.
Ethyl 4-(4-Cyanophenyl)-5-(piperidine-1-carbonyl)isoxazole-3-carb-
oxylate (4Ga): White needles; m.p. 87–88 °C. IR (KBr): ν = 1740,
˜
1650, 1225, 1180, 1030 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.35 (t, J = 7.1 Hz, 3 H, CH3), 1.31–1.42 (m, 2 H, CH2), 1.54–1.69
(m, 4 H, 2 CH2), 3.20 (t, J = 5.5 Hz, 2 H, NCH2), 3.63 (t, J =
5.5 Hz, 2 H, NCH2), 4.40 (q, J = 7.1 Hz, 2 H, OCH2), 7.59 (d, J
= 8.6 Hz, 2 H, ArH), 7.71 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C
NMR (75.4 MHz, CDCl3): δ = 13.7 (q), 23.8 (t), 25.0 (t), 26.0 (t),
43.1 (t), 47.6 (t), 62.4 (t), 112.4 (s), 118.1 (s), 118.3 (s), 130.3 (2 d),
131.4 (s), 131.8 (2 d), 153.2 (s), 156.1 (s), 158.9 (s), 162.4 (s) ppm.
C19H19N3O4 (353.14): calcd. C 64.58, H 5.42, N 11.89; found C
64.60, H 5.46, N 11.93.
Ethyl 4-(4-Bromophenyl)-5-(piperidine-1-carbonyl)isoxazole-3-carb-
oxylate (4Ba): White needles; m.p. 105–106 °C. IR (KBr): ν = 2940,
˜
1725, 1255, 1200, 990 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.25–
1.37 (m, 2 H, CH2), 1.33 (t, J = 7.1 Hz, 3 H, CH3), 1.49–1.64 (m,
4 H, 2 CH2), 3.13 (t, J = 5.6 Hz, 2 H, NCH2), 3.56–3.66 (m, 2 H,
NCH2), 4.38 (q, J = 7.1 Hz, 2 H, OCH2), 7.31 (d, J = 8.5 Hz, 2 H,
ArH), 7.54 (d, J = 8.5 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 13.9 (q), 24.1 (t), 25.2 (t), 26.2 (t), 43.3 (t), 47.8 (t),
62.5 (t), 118.8 (s), 123.3 (s), 125.6 (s), 131.3 (2 d), 131.6 (2 d), 153.6
(s), 156.8 (s), 159.5 (s), 162.0 (s) ppm. C18H19BrN2O4 (406.05):
calcd. C 53.08, H 4.70, N 6.88; found C 53.09, H 4.70, N 6.86.
4-Phenyl(isoxazole-3,5-dicarbonyl)bispiperidine (5Aa): White crys-
tals; m.p. 164–165 °C. IR (KBr): ν = 2940, 1645, 1505, 1450,
˜
1255 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.09–1.18 (m, 2 H,
CH2), 1.18–1.26 (m, 2 H, CH2), 1.46–1.58 (m, 8 H, 4 CH2), 3.12
(t, J = 5.5 Hz, 2 H, NCH2), 3.13 (t, J = 5.5 Hz, 2 H, NCH2), 3.59–
3.72 (m, 4 H, 2 NCH2), 7.32–7.44 (m, 3 H, ArH), 7.53 (dd, J =
7.6, 1.8 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
24.1 (2 t), 25.2 (2 t), 25.8 (t), 25.9 (t), 42.8 (t), 43.1 (t), 47.78 (t),
47.83 (t), 117.0 (s), 126.8 (s), 128.4 (2 d), 128.9 (3 d), 157.2 (s),
157.8 (s), 159.3 (s), 159.4 (s) ppm. C21H25N3O3 (367.19): calcd. C
68.64, H 6.86, N 11.44; found C 68.67, H 6.90, N 11.46.
Ethyl 5-(Piperidine-1-carbonyl)-4-(thiophen-2-yl)isoxazole-3-carb-
oxylate (4Ca): White needles; m.p. 64–65 °C. IR (KBr): ν = 2945,
˜
1740, 1255, 1180, 1010 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.30–1.43 (m, 2 H, CH2), 1.39 (t, J = 7.1 Hz, 3 H, CH3), 1.55–1.68
(m, 4 H, 2 CH2), 3.17 (t, J = 5.5 Hz, 2 H, NCH2), 3.57–3.75 (m, 2
H, NCH2), 4.45 (q, J = 7.1 Hz, 2 H, OCH2), 7.09 (t, J = 4.3 Hz, 1
H, ArH), 7.35 (d, J = 4.3 Hz, 1 H, ArH), 7.43 (d, J = 4.3 Hz, 1 H,
ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 14.0 (q), 24.2 (t),
25.2 (t), 26.1 (t), 43.2 (t), 47.8 (t), 62.6 (t), 113.2 (s), 126.1 (s), 127.3
(d), 127.7 (d), 129.7 (d), 153.5 (s), 156.9 (s), 159.5 (s), 161.8 (s)
ppm. C16H18N2O4S (334.10): calcd. C 57.47, H 5.43, N 8.38; found
C 57.36, H 5.40, N 8.35.
4-(4-Bromophenyl)(isoxazole-3,5-dicarbonyl)bispiperidine
(5Ba):
White crystals; m.p. 221–222 °C. IR (KBr): ν = 2950, 1640, 1635,
˜
1
1450, 1255 cm–1. H NMR (400 MHz, CDCl3): δ = 1.20–1.28 (m,
2 H, CH2), 1.28–1.37 (m, 2 H, CH2), 1.50–1.62 (m, 8 H, 4 CH2),
5298
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5292–5300

Ethyl α-Nitrocinnamates in the Synthesis of Highly Functionalized Isoxazoles
3.07–3.22 (m, 4 H, 2 NCH2), 3.58–3.74 (m, 4 H, 2 NCH2), 7.45 (d, Supporting Information (see footnote on the first page of this arti-
1
J = 8.5 Hz, 2 H, ArH), 7.53 (d, J = 8.5 Hz, 2 H, ArH) ppm. 13C cle): Copies of the H and 13C NMR spectra of the isoxazoles.
NMR (100.6 MHz, CDCl3): δ = 24.0 (2 t), 25.15 (t), 25.18 (t), 25.96
(t), 26.06 (t), 42.8 (t), 43.1 (t), 47.7 (t), 47.8 (t), 116.1 (s), 123.1 (s),
125.7 (s), 130.0 (2 d), 132.0 (2 d), 156.8 (s), 157.4 (s), 158.9 (s),
Acknowledgments
159.7 (s) ppm. C21H24BrN3O3 (445.10): calcd. C 56.51, H 5.42, N
We are grateful to the National Science Council of ROC for finan-
9.41; found C 56.47, H 5.37, N 9.23.
cial support. (Grant No. NSC-98–2113-M-006–003-MY2)
4-(4-Chlorophenyl)(isoxazole-3,5-dicarbonyl)bispiperidine
(5Ea):
White crystals; m.p. 193–194 °C. IR (KBr): ν = 2945, 1630, 1620,
˜
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1
1445, 1250 cm–1. H NMR (400 MHz, CDCl3): δ = 1.17–1.28 (m,
2 H, CH2), 1.28–1.37 (m, 2 H, CH2), 1.43–1.72 (m, 8 H, 4 CH2),
3.03–3.24 (m, 4 H, 2 NCH2), 3.55–3.80 (m, 4 H, 2 NCH2), 7.38 (d,
J = 8.4 Hz, 2 H, ArH), 7.51 (d, J = 8.4 Hz, 2 H, ArH) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 24.0 (2 t), 25.2 (2 t), 26.0 (t), 26.1
(t), 42.8 (t), 43.1 (t), 47.7 (t), 47.8 (t), 116.1 (s), 125.2 (s), 129.0 (2
d), 129.8 (2 d), 134.9 (s), 156.9 (s), 157.4 (s), 159.0 (s), 159.7 (s)
ppm. C21H24ClN3O3 (401.15): calcd. C 62.76, H 6.02, N 10.46;
found C 62.66, H 6.06, N 10.42.
4-(4-Nitrophenyl)(isoxazole-3,5-dicarbonyl)bispiperidine
(5Fa):
White needles; m.p. 180–181 °C. IR (KBr): ν = 2950, 1650, 1520,
˜
1
1345, 1255 cm–1. H NMR (400 MHz, CDCl3): δ = 1.26–1.35 (m,
2 H, CH2), 1.35–1.42 (m, 2 H, CH2), 1.58–1.69 (m, 8 H, 4 CH2),
3.20 (t, J = 5.5 Hz, 2 H, NCH2), 3.24 (t, J = 5.5 Hz, 2 H, NCH2),
3.63–3.73 (m, 4 H, 2 NCH2), 7.79 (d, J = 8.8 Hz, 2 H, ArH), 8.26
(d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 24.0 (2 t), 25.20 (t), 25.25 (t), 26.17 (t), 26.25 (t), 43.0 (t), 43.3
(t), 47.8 (t), 48.0 (t), 115.7 (s), 123.9 (2 d), 129.4 (2 d), 133.5 (s),
147.6 (s), 156.6 (s), 156.9 (s), 158.5 (s), 160.8 (s) ppm. C21H24N4O5
(412.17): calcd. C 61.15, H 5.87, N 13.58; found C 61.11, H 5.86,
N 13.61.
4-(4-Cyanophenyl)(isoxazole-2,5-dicarbonyl)bispiperidine
(5Ga):
White needles; m.p. 187–188 °C. IR (KBr): ν = 2945, 1645, 1255,
˜
1
1215, 1025 cm–1. H NMR (400 MHz, CDCl3): δ = 1.23–1.42 (m,
4 H, 2 CH2), 1.51–1.70 (m, 8 H, 4 CH2), 3.18 (t, J = 5.6 Hz, 2 H,
NCH2), 3.22 (t, J = 5.6 Hz, 2 H, NCH2), 3.64–3.72 (m, 4 H, 2
NCH2), 7.69 (d, J = 8.7 Hz, 2 H, ArH), 7.72 (d, J = 8.7 Hz, 2 H,
ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 24.1 (2 t), 25.29 (t),
25.33 (t), 26.2 (t), 26.3 (t), 43.1 (t), 43.4 (t), 47.9 (t), 48.0 (t), 112.6
(s), 116.0 (s), 118.2 (s), 129.2 (2 d), 131.7 (s), 132.6 (2 d), 156.7 (s),
157.1 (s), 158.7 (s), 160.7 (s) ppm. C22H24N4O3 (392.18): calcd. C
67.33, H 6.16, N 14.28; found C 67.08, H 6.12, N 14.29.
Ethyl 3-Benzoyl-4-phenylisoxazole-5-carboxylate (13Ab): White
powders; m.p. 74–75 °C. IR (KBr): ν = 2980, 1740, 1230, 1210,
˜
1
1015 cm–1. H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz,
3 H, CH3), 4.37 (q, J = 7.1 Hz, 2 H, OCH2), 7.29–7.44 (m, 5 H,
ArH), 7.49 (t, J = 7.5 Hz, 2 H, ArH), 7.64 (t, J = 7.5 Hz, 1 H,
ArH), 8.05 (d, J = 7.5 Hz, 2 H, ArH) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 13.9 (q), 62.4 (t), 125.8 (s), 126.7 (s), 128.1 (2 d), 128.7
(2 d), 129.0 (d), 129.9 (2 d), 130.5 (2 d), 134.6 (d), 135.7 (s), 156.0
(s), 156.7 (s), 160.4 (s), 185.9 (s) ppm. C19H15NO4 (321.10): calcd.
C 71.02, H 4.71, N 4.36; found C 70.97, H 4.68, N 4.30.
Ethyl 3-Benzoyl-4-(4-bromophenyl)isoxazole-5-carboxylate (13Bb): [8] a) C.-P. Chuang, A.-I. Tsai, Synthesis 2006, 675–679; b) C.-P.
Yellow oil. IR (KBr): ν = 2925, 1735, 1230, 1180, 1005 cm–1. 1H
Chuang, K.-P. Chen, Y.-L. Hsu, A.-I. Tsai, S.-T. Liu, Tetrahe-
dron 2008, 64, 7511–7516.
[9] a) Y.-L. Wu, C.-P. Chuang, P.-Y. Lin, Tetrahedron 2000, 56,
6209–6217; b) Y.-J. Liao, Y.-L. Wu, C.-P. Chuang, Tetrahedron
2003, 59, 3511–3520.
[10] a) C.-P. Chuang, Y.-L. Wu, M.-C. Jiang, Tetrahedron 1999, 55,
11229–11236; b) M.-C. Jiang, C.-P. Chuang, J. Org. Chem.
2000, 65, 5409–5412; c) Y.-L. Wu, C.-P. Chuang, P.-Y. Lin, Tet-
rahedron 2001, 57, 5543–5549; d) C.-C. Tseng, Y.-L. Wu, C.-P.
Chuang, Tetrahedron 2002, 58, 7625–7633; e) Y.-L. Wu, C.-P.
˜
NMR (400 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H, CH3), 4.38
(q, J = 7.1 Hz, 2 H, OCH2), 7.27 (d, J = 8.3 Hz, 2 H, ArH), 7.50
(t, J = 7.8 Hz, 2 H, ArH), 7.51 (d, J = 8.3 Hz, 2 H, ArH), 7.66 (t,
J = 7.8 Hz, 1 H, ArH), 8.06 (d, J = 7.8 Hz, 2 H, ArH) ppm. 13C
NMR (75.4 MHz, CDCl3): δ = 13.9 (q), 62.5 (t), 123.5 (s), 124.7
(s), 125.7 (s), 128.8 (2 d), 130.5 (2 d), 131.3 (2 d), 131.6 (2 d), 134.7
(d), 135.5 (s), 156.1 (s), 156.4 (s), 160.0 (s), 185.6 (s) ppm. HMRS
(EI): calcd. for C19H14BrNO4 399.0109; found 399.0108.
Eur. J. Org. Chem. 2010, 5292–5300
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5299

K.-P. Chen, Y.-J. Chen, C.-P. Chuang
FULL PAPER
Chuang, Tetrahedron 2004, 60, 1841–1847; f) C.-M. Tseng, Y.-
L. C.-P. Chuang, Tetrahedron 2004, 60, 12249–12260; g) C.-Y.
Lin, Y.-C. Cheng, A.-I. Tsai, C.-P. Chuang, Org. Biomol. Chem.
2006, 4, 1097–1103; h) A.-I. Tsai, C.-P. Chuang, Tetrahedron
2006, 62, 2235–2239; i) C.-P. Chuang, A.-I. Tsai, Tetrahedron
2007, 63, 11911–11919; j) K.-P. Chen, H.-Q. Lee, Y.-C. Cheng,
C.-P. Chuang, Org. Biomol. Chem. 2009, 7, 4074–4081.
[11] Simililar O-alkylation with a nitro group as leaving group has
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1825.
[12] Similar three-membered ring C-alkylation has been reported.
See: a) N. Ono, T. Yanai, I. Hamamoto, A. Kamimura, A.
Kaji, J. Org. Chem. 1985, 50, 2806–2807; b) C. M. Moorhoff,
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finement method, full-matrix least-squares on F2, goodness-of-
fit on F2 1.203, final R indices [IϾ2σ (I)] R1 = 0.0306, wR2 =
0.0791, R indices (all data) R1 = 0.0372, wR2 = 0.0962, largest
diff. peak and hole 0.284 and –0.451 eÅ–3. CCDC-764659 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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[14]
[15]
[13] Crystal data for 4Ba: C18H19BrN2O4, M = 407.26, T =
200(2)°K, λ = 0.71073 Å, triclinic, space group P1, a =
9.4050(2) Å,
b = 9.5540(3) Å, c = 10.8065(3) Å, α =
[16] O. Tsuge, S. Kanemasa, S. Takenaka, Bull. Chem. Soc. Jpn.
1985, 58, 3137–3157.
91.0610(10)°, β = 113.5600(10)°, γ = 91.2630(10)°, V =
889.47(4) Å3, Z = 2, Dcalcd. = 1.521 mgm–3, µ = 2.336 mm–1,
F (000) = 416, crystal size 0.41ϫ0.37ϫ0.35 mm3, reflections
collected 9345, independent reflections 3110 (Rint= 0.0394), re-
Received: March 24, 2010
Published Online: August 3, 2010
5300
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5292–5300