Synthesis of 3,4,5-trisubstituted isoxazoles by the 1,3-dipolar cycloaddition reaction of α-azido acrylates and aromatic oximes

Article abstract of DOI:10.1055/s-0033-1340470

A novel, one-pot, cascade reaction sequence featuring the 1,3-dipolar cycloaddition reaction of α-azido acrylates and aromatic oximes was developed. This procedure provides an efficient, straightforward and metal-free method for the synthesis of 3,4,5-trisubstituted isoxazoles under mild reaction conditions.

Full text of DOI:10.1055/s-0033-1340470

510▌
PAPER
paper
Synthesis of 3,4,5-Trisubstituted Isoxazoles by the 1,3-Dipolar Cycloaddition
Reaction of α-Azido Acrylates and Aromatic Oximes
Trisubstituted Isoxazoles by 1,3-Dipolar Cycloaddition
Manman Hu, Xinwei He, Zhiqiang Niu, Zhenglei Yan, Fuyin Zhou, Yongjia Shang*
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Key Laboratory of Molecule-Based Materials,
College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, P. R. of China
Fax +86(553)5910126; E-mail: shyj@mail.ahnu.edu.cn
Received: 23.10.2013; Accepted after revision: 25.11.2013
R3
Abstract: A novel, one-pot, cascade reaction sequence featuring
the 1,3-dipolar cycloaddition reaction of α-azido acrylates and aro-
matic oximes was developed. This procedure provides an efficient,
straightforward and metal-free method for the synthesis of 3,4,5-tri-
substituted isoxazoles under mild reaction conditions.
COOR2
N3
H
R3
COOR2
O
NCS, DMF
r.t., 5–8 h
2
NOH
N
R1
Et3N, 90 °C, 8 h
Key words: 1,3-dipolar cycloaddition, α-azido acrylates, aromatic
oximes, isoxazoles, one-pot synthesis
R1
1
3
Scheme 1 Synthesis of 3,4,5-trisubstituted isoxazoles by the 1,3-di-
polar cycloaddition reaction of α-azido acrylates and aromatic oximes
Isoxazoles have attracted a great deal of interest as syn-
thetic targets because they are easily transformed into var-
ious biodynamic agents,1,2 including those with
antithrombotic,3 PAF antagonist4 and hypolipidemic
properties.5 Recently, 3,4,5-trisubstituted isoxazoles were
found to be novel PPARδ agonists.6 The traditional meth-
od for isoxazole core synthesis is the 1,3-dipolar cycload-
dition of alkynes with nitrile oxides generated from the
dehydrohalogenation of hydroximoyl chlorides in the
presence of triethylamine.7 This method is limited by the
availability of the alkynes. Other methods for isoxazole
synthesis include palladium-catalyzed cascade cycliza-
tion–alkenylation,8 copper-catalyzed cascade cycliza-
tion–migration,9 iodocyclization10 and metalative
cyclization;11 however, these strategies either require
multiple steps or employ metal catalysts. Consequently,
the development of practical and flexible synthetic meth-
ods for isoxazoles is still desirable.
of triethylamine. NCS was added to a solution of 1a in
DMF and the mixture was stirred at room temperature for
5 hours. Successively, 1.0 equivalent of triethylamine and
of α-azido acrylate 2a were added, and the resulting reac-
tion mixture was stirred at 90 °C to give the product 3a in
75% yield.
Based on this outcome, the reaction conditions were opti-
mized with regard to solvent, base, temperature and reac-
tion time; the results are summarized in Table 1. Similar
results were observed when CH2Cl2, MeCN, DMF,
DMSO, THF or toluene was used as the solvent (Table 1,
entries 1–9). Notably, raising the temperature at the sec-
ond step improved the yield, with 90 °C as the apparent
optimum reaction temperature (Table 1, entries 4–6, 20
and 21). Neither changing the base from triethylamine to
DMAP, DABCO, K2CO3, AcONa or KOH, nor using 2.0
equivalents of the triethylamine base, led to an enhanced
yield (Table 1, entries 14–19). Besides these variations, a
change in the reaction time also failed to improve the yield
(Table 1, entries 10–13). Thus, the reaction is best per-
formed with 1.0 equivalent of triethylamine in DMF at
90 °C for 8 hours (Table 1, entry 6).
2-Azido acrylates are versatile building blocks in organic
synthesis. In recent years, much attention has been fo-
cused on applying 2-azido acrylates as a pivotal three-
atom synthon for the formation of diverse nitrogen-con-
taining heterocycles.12–14 As a part of an ongoing research
into the development of efficient syntheses of isoxazoles,
herein we report a general, straightforward and metal-free
procedure for the synthesis of 3,4,5-trisubstituted isoxa-
zoles by the triethylamine-promoted 1,3-dipolar cycload-
dition reaction of α-azido acrylates and aromatic oximes
(Scheme 1).
To test the scope of this reaction, various aromatic oximes
1a–j and α-azido acrylates 2a–h were subjected to the
above optimized reaction conditions (Table 2). For the
different aromatic oximes 1, both the electronic nature
and steric requirements of the substituents on the benzene
ring influence the reaction yield. Specifically, aromatic
oximes bearing a strongly electron-withdrawing group
(NO2) or a strongly electron-donating group (OMe) gave
relatively lower yields (Table 2, entries 3 and 4). When
the substituent is at the ortho position of the benzene ring
(Table 2, entries 8 and 9), significantly reduced yields
were also observed, which might be ascribed to steric rea-
sons. When various α-azido acrylates 2 were examined,
We began our investigation by performing the 1,3-dipolar
cycloaddition reaction of α-azido acrylate 2a, 4-methyl-
benzaldehyde oxime (1a) and N-chlorosuccinimide
(NCS) in N,N-dimethylformamide (DMF) in the presence
SYNTHESIS 2014, 46, 0510–0514
Advanced online publication: 02.01.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340470; Art ID: SS-2013-H0695-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Trisubstituted Isoxazoles by 1,3-Dipolar Cycloaddition
511
acterized by 1H NMR, 13C NMR, IR and HRMS spectra.
In addition, the structure of product 3i was unambiguous-
ly confirmed by X-ray diffraction analysis (Figure 1).
Table 1 Optimization of the Reaction Conditionsa
H
N3
COOEt
O
NOH
COOEt
Table 2 Study of the Reaction Scopea
NCS, DMF
2a
N
solvent, base
3
r.t., 5 h
N3 R
COOR2
R3
H
COOR2
1a
3a
NOH
NCS, DMF
r.t., 5–8 h
2
R1
O
N
Entry
Base
Solvent
Temp
(°C)
Time
(h)
Yieldb
(%)
Et3N, 90 °C, 8 h
1
3
R1
1
2
Et3N
CH2Cl2
CH2Cl2
MeCN
DMF
DMF
DMF
DMSO
toluene
THF
r.t.
35
r.t.
50
70
90
90
90
90
90
90
90
90
90
90
90
90
90
90
100
110
8
8
30
45
41
45
55
75
69
63
43
75
74
69
50
73
74
73
71
72
75
75
74
Entry
R1
R2, R3
Product Yieldb (%)
Et3N
3
Et3N
8
1
2
4-Me (1a)
H (1b)
4-OMe (1c)
4-NO2 (1d)
4-F (1e)
4-Cl (1f)
3-Cl (1g)
2-Cl (1h)
2-Br (1i)
4-Br (1j)
1a
Et, H (2a)
3a
3b
3c
3d
3e
3f
75
76
55
65
81
75
70
59
60
70
75
73
71
69
61
63
65
4
Et3N
8
2a
5
Et3N
8
3
2a
6
Et3N
8
4
2a
7
Et3N
8
5
2a
8
Et3N
8
6
2a
9
Et3N
8
7
2a
3g
3h
3i
10
11
12
13
14
15
16
17
18
19c
20
21
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
10
18
24
6
8
2a
Et3N
9
2a
Et3N
10
11
12
13
14
15
16
17
2a
3j
Et3N
Me, H (2b)
Pr, H (2c)
n-Bu, H (2d)
Bn, H (2e)
Me, 4-Cl (2f)
Et, 4-NO2 (2g)
Et, 4-Me (2h)
3k
3l
DMAP
DABCO
K2CO3
AcONa
KOH
Et3N
8
1a
8
1a
3m
3n
3o
3p
3q
8
1a
8
1a
8
1a
8
1f
Et3N
8
a Reaction conditions: (1) 1 (1.0 mmol), NCS (1.1 mmol), DMF (5
mL), r.t., 5–8 h; (2) 2 (1.0 mmol), Et3N (1.0 mmol), 90 °C, 8 h.
b Yields of isolated products after flash column chromatography.
Et3N
8
a Reaction conditions: (1) 1a (1.0 mmol), NCS (1.1 mmol), DMF (5
mL), r.t., 5 h; (2) 2a (1.0 mmol), base (1.0 mmol), solvent (5 mL).
b Yields of isolated products after flash column chromatography.
c Base (2 equiv) was used.
those with an alkyl (R2) group (Table 2, entries 11–13) re-
sulted in higher yields than when R2 is a benzyl group (Ta-
ble 2, entry 14). Notably, α-azido acrylate 2h bearing an
electron-donating group (R3) gave a higher yield than 2g
with an electron-withdrawing group on the benzene ring
(Table 2, entries 16 and 17). Also notably, these [3+2] cy-
cloadditions are regioselective, in that only isoxazoles
were isolated. The structures of products 3a–q were char-
Figure 1 X-ray crystal structure of 3i15
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 510–514

512
M. Hu et al.
PAPER
H
Cl
O–
N
Et3N
NOH
NCS
DMF
NOH
R1
R1
R1
– Et3N⋅HCl
1
A
B
O
N3
N
Ar
Ar
EtOOC
H
COOEt
N3
R1
COOEt
R1
R1
Et3N
Ar
2
O
O
– Et3N⋅HN3
N
N
3
C
Scheme 2 Proposed mechanism for the formation of 3,4,5-trisubstituted isoxazoles 3
Et3N (0.143 g, 1.0 mmol) were added, and the resulting mixture was
stirred in an oil bath at 90 °C for 8 h. Upon the completion of this
reaction, the mixture was cooled to r.t. and extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with H2O
(25 mL), dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The resulting residue was purified by flash
column chromatography on silica gel [200–300 mesh; EtOAc–pe-
troleum ether, 1:100 (v/v)] to give the desired product 3a.
Based on our experimental results and previous studies on
similar 1,3-cycloaddition reactions,16,17 a plausible mech-
anism for this 1,3-dipolar cycloaddition reaction is pro-
posed, as shown in Scheme 2. Initially, the aromatic
oxime 1 reacts with N-chlorosuccinimide to form the ald-
oxime chloride A. Intermediate B, generated in situ from
A by treatment with triethylamine, reacts with the α-azido
acrylate 2 to form intermediate C via a 1,3-dipolar cyclo-
addition reaction. Then, a base-assisted aromatization of
intermediate C would furnish the final product 3.
Yield: 230 mg (75%); white solid; mp 111–113 °C.
IR (KBr): 2983, 1730, 1612, 1442, 1203, 1099, 1018, 929, 825, 765,
694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.40 (m, 3 H, CH3C6H4,
C6H5), 7.26–7.30 (m, 4 H, CH3C6H4, C6H5), 7.13 (d, J = 8.4 Hz, 2
H, CH3C6H4), 4.33 (q, J = 7.5 Hz, 2 H, CH2), 2.34 (s, 3 H, CH3),
1.28 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.4, 157.1, 155.6, 139.9, 130.1,
129.2, 128.6, 128.3, 128.1, 124.8, 124.1, 61.9, 29.6, 21.3, 13.8.
In summary, we have developed a straightforward and
metal-free method for the synthesis of 3,4,5-trisubstituted
isoxazoles in good to excellent yields from easily avail-
able α-azido acrylates and aromatic oximes. This mild an-
nulation strategy may offer a protocol for synthesizing
other azaheterocycles in medicinal chemistry.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NO3: 308.1287; found:
308.1286.
NMR spectra were recorded in CDCl3 on a Bruker Avance 300
1
Ethyl 3,4-Diphenylisoxazole-5-carboxylate (3b)
Yield: 222 mg (76%); white solid; mp 86–88 °C.
MHz instrument. H NMR chemical shifts are reported as δ (parts
per million) relative to the signal of CHCl3 at 7.26 (s) ppm, and 13
C
NMR shifts as δ (parts per million) relative to the CDCl3 triplet at
76.0 ppm. HRMS were obtained using an Agilent 6200 LC/MS
mass spectrometer (TOF-ESI). IR spectra of solid compounds were
recorded as KBr plates on a Prestige-21 FTIR spectrophotometer.
All solvents were purified and dried by following standard proce-
dures, unless otherwise stated.
IR (KBr): 2983, 1730, 1625, 1458, 1433, 1319, 1240, 1099, 837,
769, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.25–7.40 (m, 10 H, 2 × C6H5),
4.33 (q, J = 7.2 Hz, 2 H, CH2), 1.27 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.4, 157.1, 156.0, 130.1, 129.8,
129.5, 128.6, 128.5, 128.2, 127.9, 127.5, 124.2, 61.9, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3: 294.1130; found:
294.1130.
(Z)-Ethyl 2-Azido-3-phenylacrylate (2a); Typical Procedure
To a deoxygenated solution of ethyl cinnamate (176 mg, 1 mmol)
and NaN3 (98 mg, 1.5 mmol) in anhydrous MeCN, a deoxygenated
solution of CAN (1.370 g, 2.5 mmol) in the same solvent (10 mL)
was added dropwise at 0 °C and stirred well. H2O (400 mL) was
added to the reaction mixture and the aqueous layer was extracted
with CH2Cl2 (4 × 150 mL). The combined organic extracts were
washed with H2O (2 × 100 mL), and dried over anhydrous Na2SO4.
The crude residue, on treatment with anhydrous NaOAc (123 mg,
1.5 mmol) in anhydrous acetone (5 mL), followed by usual workup
and purification by silica gel column chromatography using petro-
leum ether–EtOAc (98:2) as eluent, afforded 2a as a pale yellow
viscous liquid.
Ethyl 3-(4-Methoxyphenyl)-4-phenylisoxazole-5-carboxylate
(3c)
Yield: 177 mg (55%); yellow solid; mp 87–88 °C.
IR (KBr): 2943, 1732, 1602, 1517, 1446, 1313, 1207, 1016, 831,
763, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.49 (m, 5 H, C6H5), 7.19 (d,
J = 7.8 Hz, 2 H, CH3OC6H4), 6.82 (d, J = 8.7 Hz, 2 H, CH3OC6H4),
4.31 (q, J = 7.2 Hz, 2 H, CH2), 3.86 (s, 3 H, CH3O), 1.25 (t, J = 7.2
Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.0, 157.1, 156.2, 130.1, 130.0,
128.8, 128.3, 128.0, 123.8, 122.5, 120.9, 111.6, 61.9, 56.0, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NO4: 324.1236; found:
324.1231.
Ethyl 4-Phenyl-3-(p-tolyl)isoxazole-5-carboxylate (3a); Typical
Procedure
A mixture of 4-methylbenzaldehyde oxime (1a; 0.135 g, 1.0 mmol)
and NCS (0.1469 g, 1.1 mmol) in DMF (5 mL) was stirred for 5 h
at r.t. Then, ethyl α-azidocinnamate (2a; 0.217 g, 1.0 mmol) and
Synthesis 2014, 46, 510–514
© Georg Thieme Verlag Stuttgart · New York

PAPER
Trisubstituted Isoxazoles by 1,3-Dipolar Cycloaddition
513
Ethyl 3-(4-Nitrophenyl)-4-phenylisoxazole-5-carboxylate (3d)
1H NMR (300 MHz, CDCl3): δ = 7.54 (d, J = 7.5 Hz, 2 H, BrC6H4),
7.23–7.34 (m, 7 H, BrC6H4, C6H5), 4.37 (q, J = 6.9 Hz, 2 H, CH2),
1.31 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 163.3, 157.1, 155.0, 133.0, 131.8,
131.2, 130.6, 129.8, 129.4, 128.5, 127.8, 127.5, 127.3, 125.3, 123.3,
62.1, 13.9.
Yield: 219 mg (65%); yellow solid; mp 69–71 °C.
IR (KBr): 2983, 1728, 1604, 1525, 1348, 1311, 1234, 1199, 1016,
860, 761, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.44 (d, J = 8.4 Hz, 2 H,
NO2C6H4), 8.17 (d, J = 9.0 Hz, 2 H, NO2C6H4), 7.60 (d, J = 8.4 Hz,
2 H, C6H5), 7.40–7.43 (m, 3 H, C6H5), 4.34 (q, J = 7.2 Hz, 2 H,
CH2), 1.27 (t, J = 7.2 Hz, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H15BrNO3: 372.0235;
found: 372.0235.
13C NMR (75 MHz, CDCl3): δ = 156.6, 151.9, 148.8, 134.2, 133.4,
130.0, 129.4, 129.2, 128.6, 127.4, 124.2, 123.7, 62.2, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2O5: 339.0981;
found: 339.0980.
Ethyl 3-(4-Bromophenyl)-4-phenylisoxazole-5-carboxylate (3j)
Yield: 259 mg (70%); yellow solid; mp 101–103 °C.
IR (KBr): 2983, 2378, 1730, 1647, 1448, 1307, 1238, 937, 829, 765,
698 cm–1.
Ethyl 3-(4-Fluorophenyl)-4-phenylisoxazole-5-carboxylate (3e)
1H NMR (300 MHz, CDCl3): δ = 7.34–7.41 (m, 5 H, BrC6H4,
C6H5), 7.21–7.23 (m, 4 H, C6H5), 4.28 (q, J = 7.2 Hz, 2 H, CH2),
1.22 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.4, 156.9, 156.2, 132.3, 131.8,
130.0, 129.9, 128.8, 128.3, 128.0, 127.9, 126.8, 124.4, 123.8, 61.9,
13.8.
Yield: 251 mg (81%); yellow solid; mp 63–65 °C.
IR (KBr): 2981, 2308, 1728, 1606, 1523, 1454, 1313, 1018, 852,
761, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.96–7.52 (m, 9 H, FC6H4, C6H5),
4.32 (q, J = 6.9 Hz, 2 H, CH2), 1.26 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 165.3 (1JCF = 249 Hz), 161.9,
161.5, 156.9, 156.2, 131.3, 131.1, 130.5, 130.4, 129.4, 129.2, 129.0,
128.7, 128.5, 128.3, 128.1, 124.0, 116.3, 115.8, 115.5, 62.0, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H15BrNO3: 372.0235;
found: 372.0235.
Methyl 4-Phenyl-3-(p-tolyl)isoxazole-5-carboxylate (3k)
Yield: 219 mg (75%); yellow solid; mp 81–83 °C.
HRMS (ESI): m/z [M + H]+ calcd for C18H15FNO3: 312.1036;
found: 312.1035.
IR (KBr): 2947, 1728, 1614, 1498, 1446, 1303, 1209, 1014, 827,
769, 731, 646 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.38 (m, 7 H, CH3C6H4,
C6H5), 7.11 (d, J = 7.8 Hz, 2 H, CH3C6H4), 3.85 (s, 3 H, CH3), 2.31
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.4, 157.5, 155.4, 140.0, 130.1,
129.2, 128.6, 128.3, 128.2, 127.5, 124.8, 124.3, 52.5, 21.3.
Ethyl 3-(4-Chlorophenyl)-4-phenylisoxazole-5-carboxylate (3f)
Yield: 245 mg (75%); yellow solid; mp 107–109 °C.
IR (KBr): 2981, 2378, 1738, 1600, 1450, 1311, 1234, 1016, 839,
769, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.21–7.37 (m, 9 H, ClC6H4,
C6H5), 4.29 (q, J = 7.5 Hz, 2 H, CH2), 1.23 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.4, 156.9, 156.1, 136.1, 130.1,
129.7, 129.3, 129.2, 128.9, 128.8, 128.4, 126.3, 124.2, 62.0, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3: 294.1130; found:
294.1130.
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO3: 328.0740;
found: 328.0740.
Propyl 4-Phenyl-3-(p-tolyl)isoxazole-5-carboxylate (3l)
Yield: 234 mg (73%); red solid; mp 86–88 °C.
IR (KBr): 3138, 2449, 1732, 1618, 1448, 1317, 1240, 1008, 823,
763, 698 cm–1.
Ethyl 3-(3-Chlorophenyl)-4-phenylisoxazole-5-carboxylate (3g)
Yield: 229 mg (70%); yellow solid; mp 63–65 °C.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.37 (m, 7 H, CH3C6H4,
C6H5), 7.10 (d, J = 7.8 Hz, 2 H, CH3C6H4), 4.20 (t, J = 6.6 Hz, 2 H,
CH2CH2CH3), 2.31 (s, 3 H, CH3), 1.58–1.75 (m, 2 H, CH2CH2CH3),
0.82 (t, J = 7.2 Hz, 3 H, CH2CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 162.4, 157.2, 155.8, 139.9, 130.1,
129.2, 128.5, 128.3, 128.2, 124.9, 123.9, 67.4, 21.6, 21.2, 10.1.
IR (KBr): 2976, 2380, 1728, 1620, 1433, 1319, 1240, 1099, 837,
761, 702, 613 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.21–7.47 (m, 9 H, ClC6H4,
C6H5), 4.34 (q, J = 6.9 Hz, 2 H, CH2), 1.27 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.2, 156.9, 156.2, 134.5, 130.0,
129.9, 129.7, 128.8, 128.4, 128.3, 127.8, 126.6, 124.0, 62.0, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO3: 322.1443; found:
322.1443.
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO3: 328.0740;
found: 328.0740.
Butyl 4-Phenyl-3-(p-tolyl)isoxazole-5-carboxylate (3m)
Ethyl 3-(2-Chlorophenyl)-4-phenylisoxazole-5-carboxylate (3h)
Yield: 237 mg (71%); red solid; mp 120–121 °C.
Yield: 192 mg (59%); yellow solid; mp 77–79 °C.
IR (KBr): 2962, 2360, 2341, 1728, 1654, 1452, 1317, 1238, 1006,
825, 765, 694 cm–1.
IR (KBr): 2911, 2380, 1732, 1614, 1433, 1317, 1259, 1022, 837,
763, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.21–7.38 (m, 9 H, ClC6H4,
C6H5), 4.37 (q, J = 7.5 Hz, 2 H, CH2), 1.32 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.3, 157.2, 154.8, 133.6, 131.7,
131.1, 129.8, 129.7, 128.5, 127.8, 127.6, 126.8, 125.6, 62.1, 13.9.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.38 (m, 7 H, CH3C6H4,
C6H5), 7.10 (d, J = 7.5 Hz, 2 H, CH3C6H4), 4.24 (t, J = 6.3 Hz, 2 H,
CH2CH2CH2CH3), 2.31 (s, 3 H, CH3), 1.52–1.68 (m, 2 H,
CH2CH2CH2CH3), 1.16–1.26 (m, 2 H, CH2CH2CH2CH3), 0.85 (t,
J = 6.9 Hz, 3 H, CH2CH2CH2CH3).
13C NMR (75 MHz, CDCl3): δ = 162.4, 157.2, 155.8, 139.9, 130.1,
129.5, 128.5, 128.3, 128.2, 124.9, 123.9, 65.7, 30.2, 21.3, 18.8,
13.5.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO3: 336.1600; found:
336.1600.
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO3: 328.0740;
found: 328.0740.
Ethyl 3-(2-Bromophenyl)-4-phenylisoxazole-5-carboxylate (3i)
Yield: 222 mg (60%); yellow solid; mp 97–100 °C.
IR (KBr): 2981, 2378, 1730, 1610, 1429, 1319, 1190, 1020, 860,
763, 698 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 510–514

514
M. Hu et al.
PAPER
Benzyl 4-Phenyl-3-(p-tolyl)isoxazole-5-carboxylate (3n)
Yield: 254 mg (69%); red solid; mp 126–128 °C.
Acknowledgment
This work was partially supported financially by the National Natu-
ral Science Foundation of China (No. 21172001, 21372008), the
Program for the NCET (NCET-10-0004) and the Anhui Provincial
Natural Science Foundation (No. 1308085QB39).
IR (KBr): 2378, 1728, 1637, 1508, 1448, 1313, 1230, 1006, 825,
748, 669 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.21–7.40 (m, 12 H, CH3C6H4,
C6H5, C6H5), 7.11 (d, J = 7.5 Hz, 2 H, CH3C6H4), 5.29 (s, 2 H, CH2),
2.32 (s, 3 H, CH3).
Supporting Information for this article is available online at
13C NMR (75 MHz, CDCl3): δ = 162.4, 156.9, 155.5, 140.0, 134.5,
130.1, 129.3, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.5, 126.9,
124.8, 124.3, 67.3, 21.3.
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (ESI): m/z [M + H]+ calcd for C24H20NO3: 370.1443; found:
370.1443.
References
(1) (a) Rajanarendar, E.; Shaik, F. P.; Reddy, A. S. R. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2008, 47,
1753. (b) Rajanarendar, E.; Murthy, K. R.; Reddy, M. N.;
Shaik, F. P. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 2011, 50, 1658.
(2) Rajanarendara, E.; Ramesha, P.; Srinivasa, M.; Shaik, F. P.
Phosphorus, Sulfur Silicon Relat. Elem. 2009, 184, 733.
(3) Batra, S.; Srinivasan, T.; Rastogi, S. K.; Kundu, B.; Patra,
A.; Bhaduri, A. P.; Dixit, M. Bioorg. Med. Chem. Lett. 2002,
12, 1905.
Methyl 4-(4-Chlorophenyl)-3-(p-tolyl)isoxazole-5-carboxylate
(3o)
Yield: 199 mg (61%); yellow solid; mp 125–126 °C.
IR (KBr): 2951, 2378, 1730, 1647, 1490, 1446, 1319, 1249, 1211,
1008, 925, 823, 734, 669 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.33 (d, J = 8.1 Hz, 2 H, ClC6H4),
7.16–7.22 (m, 4 H, ClC6H4, CH3C6H4), 7.10 (d, J = 7.8 Hz, 2 H,
CH3C6H4), 3.85 (s, 3 H, CH3), 2.30 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.4, 157.7, 155.5, 140.2, 134.9,
131.5, 129.4, 128.6, 128.4, 126.6, 124.5, 123.2, 52.7, 21.3.
(4) Hamama, W. S.; Ibrahim, M. E.; Zoorob, H. H. Synth.
Commun. 2013, 43, 2393.
(5) Kaur, A.; Singh, B.; Jaggi, A. S. Bioorg. Med. Chem. Lett.
2013, 23, 797.
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO3: 328.0740;
found: 328.0740.
(6) Avupati, V. R.; Kurre, P. N.; Bagadi, S. R.; Muthyala, M. K.;
Yejella, R. P. Chem-Bio. Inform. J. 2010, 10, 74.
(7) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.; Naito, T.;
Miyata, O. Org. Lett. 2010, 12, 2594.
(8) She, Z.; Niu, D.; Chen, L.; Gunawan, M. A.; Shanja, X.;
Hersh, W. H.; Chen, Y. J. Org. Chem. 2012, 77, 3627.
(9) Ueda, M.; Sugita, S.; Sato, A.; Miyoshi, T.; Miyata, O.
J. Org. Chem. 2012, 77, 9344.
(10) Waldo, J. P.; Mehta, S.; Neuenswander, B.; Lushington, G.
H.; Larock, R. C. J. Comb. Chem. 2008, 10, 658.
(11) Gayon, E.; Quinonero, O.; Lemouzy, S.; Vrancken, E.;
Campagne, J. M. Org. Lett. 2011, 13, 6418.
(12) Hong, D.; Chen, Z.-B.; Lin, X.-F.; Wang, Y.-G. Org. Lett.
2010, 12, 4608.
Ethyl 4-(4-Nitrophenyl)-3-(p-tolyl)isoxazole-5-carboxylate (3p)
Yield: 221 mg (63%); yellow solid; mp 87–89 °C.
IR (KBr): 2981, 2378, 1734, 1600, 1448, 1319, 1244, 1205, 1029,
829, 756, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.23 (d, J = 8.1 Hz, 2 H,
NO2C6H4), 7.48 (d, J = 8.1 Hz, 2 H, NO2C6H4), 7.21 (d, J = 8.1 Hz,
2 H, CH3C6H4), 7.13 (d, J = 8.1 Hz, 2 H, CH3C6H4), 4.34 (q, J = 6.9
Hz, 2 H, CH2), 2.33 (s, 3 H, CH3), 1.29 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 162.2, 156.5, 156.2, 147.6, 140.5,
135.3, 131.1, 129.5, 128.3, 128.0, 124.0, 123.3, 122.0, 62.3, 21.2,
13.8.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O5: 353.1137;
found: 353.1137.
(13) (a) Hong, D.; Zhu, Y.; Lin, X.; Wang, Y. Tetrahedron 2011,
67, 650. (b) Ng, E. P. J.; Wang, Y.-F.; Hui, B. W.-Q.;
Lapointe, G.; Chiba, S. Tetrahedron 2011, 67, 7728.
(14) Dinda, B. K.; Jana, A. K.; Mal, D. Chem. Commun. 2012, 48,
3999.
(15) The crystal data of compound 3i have been deposited with
the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 940588. Copies of the
data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk] or via
www.ccdc.cam.ac.uk/data_request/cif. Compound 3i: space
group P2(1)/c, a = 7.918(2) Å, b = 11.326(3) Å,
c = 18.103(6) Å, α = 90°, β = 100.868°, γ = 90°,
V = 1594.4(8) Å3, T = 293(2) K, Z = 4. More data are given
in the Supporting Information.
Ethyl 3-(4-Chlorophenyl)-4-(p-tolyl)isoxazole-5-carboxylate
(3q)
Yield: 221 mg (65%); yellow solid; mp 106–108 °C.
IR (KBr): 2962, 2926, 1728, 1610, 1475, 1238, 1012, 825, 748, 694
cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.20 (d, J = 7.8 Hz, 2 H, ClC6H4),
8.07 (d, J = 8.1 Hz, 2 H, CH3C6H4), 7.53 (d, J = 8.1 Hz, 2 H,
CH3C6H4), 7.33 (d, J = 7.8 Hz, 2 H, ClC6H4), 4.46 (q, J = 6.9 Hz, 2
H, CH2), 2.45 (s, 3 H, CH3), 1.44 (t, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 161.0, 158.7, 148.0, 139.8, 137.7,
133.6, 129.3, 129.1, 128.9, 128.8, 128.6, 127.4, 124.9, 61.3, 21.4,
14.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H17ClNO3: 342.0897;
found: 342.0896.
(16) Zhu, S.-R.; Shi, S.-H.; Gerritz, S. W. Tetrahedron Lett.
2011, 52, 4001.
(17) Li, Y.; Hong, D.; Lu, P.; Wang, Y.-G. Tetrahedron Lett.
2011, 52, 4161.
Synthesis 2014, 46, 510–514
© Georg Thieme Verlag Stuttgart · New York