Facile synthesis of 3-aryl-5-(2-oxopyrrolidin-1-yl)-and 5-(pyridin-4-yl)-4,5-dihydroisoxazoles via 1,3-dipolar cycloaddition under mild conditions

Article abstract of DOI:10.3184/174751913X13735527483211

A convenient and efficient synthetic approach for the synthesis of 5-substituted 3-aryl-4,5-dihydroisoxazoles is reported. In the presence of triethylamine, a series of hydroximoyl chlorides were transformed into nitrile oxides, followed by reaction with N-vinyl-2-pyrrolidinone (or 4-vinylpyridine) by a 1,3-dipolar cycloaddition to give novel 4,5-dihydroisoxazole derivatives.

Full text of DOI:10.3184/174751913X13735527483211

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 499
AUGUST, 499–502
Facile synthesis of 3-aryl-5-(2-oxopyrrolidin-1-yl)- and 5-(pyridin-4-yl)-4,5-
dihydroisoxazoles via 1,3-dipolar cycloaddition under mild conditions
Yan Gong, Yong Wang, Wen-Tao Zhao and Xiang-Yang Tang*
Department of Chemistry, Tianjin University, Tianjin 300072, P. R. China
A convenient and efficient synthetic approach for the synthesis of 5-substituted 3-aryl-4,5-dihydroisoxazoles is
reported. In the presence of triethylamine, a series of hydroximoyl chlorides were transformed into nitrile oxides,
followed by reaction with N-vinyl-2-pyrrolidinone (or 4-vinylpyridine) by a 1,3-dipolar cycloaddition to give novel
4,5-dihydroisoxazole derivatives.
Keywords: 1,3-dipolarcycloaddition,3-aryl-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazoles,3-aryl-5-(pyridin-4-yl)-4,5-dihydro-
isoxazoles, nitrile oxides
Isoxazoline derivatives have attracted considerable interest
because of their biological activities as receptor antagonists,1
selective inhibitors,2 and as potential pharmaceutical agents. It
is reported that small pharmaceutical compounds with substi-
tuted isoxazoline rings could act as inhibitors or fibrinogen
receptor antagonists for the treatment of thromboembolic dis-
orders. Specifically, such compounds are useful for preventing
infectious diseases or for treating a variety of diseases involv-
ing inflammatory activity.3–8 For instance, some phenylisoxa-
zolines have been reported as a class of antibacterial agents
with high activity against gram-positive pathogens.9 Further-
more several 3-substituted-5-pyridinyl-isoxazolines could act
as protein tyrosine phosphatase (PTPases) 1B inhibitors.10,11
Hence, the development of novel 4,5-dihydroisoxazole deriva-
tives was of great interest, which might contribute to the
synthesis of some pharmaceuticals.
Among the classic synthetic methodologies, 1,3-dipolar
cycloaddition reaction represents an important strategy for the
construction of five-membered carbocycles and heterocy-
cles.12,13 Nitrile oxides are one kind of the most reactive 1,3-
dipoles which can undergo reactions smoothly with substituted
alkenes to give substituted 4,5-dihydroisoxazoles.14 More
importantly, 4,5-dihydroisoxazole heterocycles are known to
be versatile intermediates for the synthesis of medicines and
biologically active compounds.15 Generally, 4,5-dihydroisoxa-
zole derivatives have been synthesised via 1,3-dipolar cycload-
dition between alkenes and nitrile oxides,16,17 however, there
are few reports of the synthesis of 4,5-dihydroisoxazoles via
1,3-dipolar cycloaddition between dipolarophilic N-vinyl-
2-pyrrolidinone/4-vinylpyridine and nitrile oxides. Here we
report a facile protocol for the preparation of new 3-aryl-5-(2-
oxopyrrolidin-1-yl)- and 5-(pyridin-4-yl)-4,5-dihydroisoxa-
zoles via 1,3-dipolar cycloaddition between mono-substituted
alkenes and nitrile oxides. With this method, a wide range of
cycloaddition products were obtained in high yields, and which
might find potential application in pharmaceutical field.
Results and discussion
The three-step synthetic procedure used to synthesise 3,5-
disubstituted-4,5-dihydroisoxazoles shown in Scheme 1. Aryl
aldehydes were treated with hydroxylamine hydrochloride and
sodium hydroxide to give the aldoxime, followed by chlorina-
tion with N-chlorosuccinimide (NCS) to give hydroximoyl
chlorides. Without any further purification, hydroximoyl
chlorides were reacted with mono-substituted alkenes in the
presence of triethylamine (Et3N) to give the crude products
that were purified by flash chromatography.
Initially, the cycloaddition reaction was carried out by
adding Et3N into the mixture of hydroximoyl chlorides and
mono-substituted alkene. However, it was found that the alka-
line pyridine moiety of 4-vinylpyridine reacted with hydroxi-
moyl chloride leading to the formation of nitrile oxide dimer
by-product.18 In order to minimise the generation of the nitrile
dimer, hydroximoyl chlorides were added in portions to the
Et3N and mono-substituted alkenes mixture. The quantity
of Et3N and temperature are other important factors for the
1,3-dipolar cycloaddition of nitrile oxides in our experiments
and the results are summarised in Table 1. From Table 1, we
find that the reaction can give the highest yield with 1.5 equiv.
Scheme 1 R=H, p-CH3, 3,4-(OCH2O), p-Cl, m-Cl, o-Cl, p-NO2, m-NO2, m-CF3.
* Correspondent. E-mail: txy@tju.edu.cn

500 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Optimisation studies for 1,3-dipolar cycloaddition of
nitrile oxides (compound 4a as an example)a
Table 3 Synthesis of 3-aryl-substituted-5-(pyridin-4-yl)-4,5-
dihydroisoxazoles 5a
Entry
R
Product 5
Yield/%b
Entry
Solvent
T/°C
Et3N/equiv.
Yield/%b
1
2
3
4
5
6
7
8
H
p-CH3
p-CH3
5a
5b
5c
5d
5e
5f
49
52
50
45
46
35
33
28
1
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
1.0
1.3
1.5
1.7
2.0
1.5
1.5
1.5
78
86
91
90
89
73
88
64
rt
3,4-(OCH2O)
p-Cl
rt
rt
m-Cl
p-NO2
m-NO2
–10
0
5g
5h
reflux
a Hydroximoyl chlorides (1.0 equiv.), vinylpyridine (1.1 equiv.),
Et3N (1.5 equiv.) in CH2Cl2 at room temperature for 12 h. All
products were characterised by 1H NMR, 13C NMR, IR, and mass
spectroscopy.
a Benzohydroximoyl chloride (1.0 equiv.), N-vinyl-2-pyrrolidi-
none (1.1 equiv.) for 12 h.
b Isolated yield.
b Isolated yield.
of Et3N and at room temperature. Since the cycloaddition reac-
tion leads to a maximum yield of 91% (Table 1, entry 4) and
operations are easy to handle, all of the following reactions
were implemented under the selected conditions.
of the phenyl ring, yields are higher than o- and m-positions
(Table 2, entries 4–6), which might be due to the steric hin-
drance. Next, several 3-aryl-5-(pyridin-4-yl)-4,5-dihydroisox-
azoles were tested (Table 3, entries 1–8). The same result
was found in Table 3 that 5b (Table 3, entry 2) gained the
maximum yield and, in contrast, minimum yield was with 5h
(Table 3, entry 8). In addition, 4-vinylpyridine can get a slightly
higher yield than 2-vinylpyridine (Table 3, entries 2, 3). Our
experimental results revealed that the steric and electronic
effects of the substituents extensively influence the reaction
activity.
Meanwhile, the yields of 3-aryl-5-(2-oxopyrrolidin-1-yl)-
4,5-dihydroisoxazoles are higher than those of 3-aryl-5-
(pyridin-4-yl)-4,5-dihydroisoxazoles, which indicated that
the pyrrolidone alkenes are more beneficial to the 1,3-dipolar
cycloaddtion reaction than are the pyridine alkenes.
In conclusion, 17 novel 4,5-dihydroisoxazole derivatives
have been synthesised via 1,3-dipolar cycloaddition under
mild conditions. Aryl nitrile oxides with a high electron
density on the phenyl ring favours the cycloaddition reaction.
In addition, alkenes with neutral moieties are better than
alkaline alkenes for this reaction. Further investigation of their
biological activity is underway and will be reported in due
course.
Using the optimal conditions, we investigated the substrate
scope of hydroximoyl chlorides for the reaction with N-vinyl-
2-pyrrolidinone (Table 2). The results revealed that the sub-
stituents on the phenyl ring have an obvious influence on the
yields of the products. The electron donating ability of –R on
the phenyl ring is –CH3> –H> –Cl, 3,4–(OCH2O)> –NO2, –CF3
due to the inductive effect combined with conjugated effect.
For a series of benzohydroximoyl chloride and hydroximoyl
chlorides with electron-donating groups on the aromatic rings,
1,3-dipolar cycloaddition reactions proceeded smoothly to
give the desired products 4a and 4b in 91–93% yields (Table 2,
entries 1, 2). However, the reduced yields were achieved
with regard to the electron-withdrawing groups on aromatic
substrates (Table 2, entries 3–9). Additionally, with –NO2 and
–CF3 substituted phenyl rings, the desired products were also
obtained, albeit in relatively lower yields (Table 2, entries 7–
9). Furthermore, it was found that substitution at the p-position
Table 2 Synthesis of 3-aryl-substituted-5-(2-oxopyrrolidin-1-
yl)-4,5-dihydroisoxazoles 4a
Experimental
The melting points were determined with an X-6 micro melting-point
apparatus. IR spectra were registered on Bruker ALPHA FT-IR
1
Spectrometer. H NMR (400 MHz) and 13C NMR (100 MHz) were
on Bruker AVANCE III 400MHz spectrometers recorded in CDCl3
solvent with tetramethylsilane (TMS) as internal standard; chemical
shifts were quoted in ppm and J values were given in Hz. HRMS was
performed on Agilent 6520B Q-TOF with Dual ESI as ion source.
Entry
R
Product 4
Yield/%b
1
2
3
4
5
6
7
8
9
H
p-CH3
3,4-(OCH2O)
p-Cl
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
93
88
90
64
72
61
43
47
Synthesis of 3-aryl-5-(2-oxopyrrolidin-1-yl)- and 5-(pyridin-4-yl)-
4,5-dihydroisoxazoles; general procedure
A solution of hydroxamoyl chloride (1.0 mmol) in 5 mL of CH2Cl2
was added dropwise to a stirred solution of Et3N (1.5 mmol), N-vinyl-
2-pyrrolidinone or 4-vinylpyridine (1.1 mmol) in 5 mL of CH2Cl2 at
0 °C. Then the mixture was stirred under nitrogen at room temperature
for 12 h, quenched with saturated solution of NH4Cl, extracted with
CH2Cl2, dried over MgSO4, and evaporated. The crude product was
purified by silica gel column to give the desired product.
3-Phenyl-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole (4a): White
solid, m.p. 110–111 °C; IR (KBr) v 2960, 2874, 1726, 1695, 1412,
1358, 1287, 881, 802, 692 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.78–
7.65 (m, 2H), 7.54–7.34 (m, 3H), 6.69 (dd, J = 9.9, 3.4 Hz, 1H), 3.58
m-Cl
o-Cl
p-NO2
m-NO2
m-CF3
a Hydroximoyl chlorides (1.0 equiv), N-vinyl-2-pyrrolidinone
(1.1 equiv.), Et3N (1.5 equiv.) in CH2Cl2 at room temperature for
12 h. All products were characterised by 1H NMR, 13C NMR, IR,
and mass spectroscopy.
b Isolated yield.

JOURNAL OF CHEMICAL RESEARCH 2013 501
(dd, J = 17.6, 9.9 Hz, 1H), 3.39 (dd, J = 15.6, 8.6 Hz, 1H), 3.28–3.11
(m, 2H), 2.44 (t, J = 8.5 Hz, 2H), 2.17–1.91 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 175.4, 155.4, 130.6, 128.9, 128.7, 126.8, 82.0,
41.6, 37.3, 31.0, 17.8; HRMS calcd for C13H14N2O2 m/z 253.0953
[M+Na+], found 253.0951 [M+Na+].
(400 MHz, CDCl3) δ 8.02–7.82 (m, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.59
(t, J = 7.8 Hz, 1H), 6.73 (dd, J = 10.0, 3.4 Hz, 1H), 3.59 (dd, J = 17.6,
10.0 Hz, 1H), 3.38 (dd, J = 15.6, 8.5 Hz, 1H), 3.29–3.12 (m, 2H), 2.46
(t, J = 8.4 Hz, 2H), 2.21–1.92 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 175.4, 154.4, 131.5 (q, JC-F = 33 Hz), 129.8, 129.7, 129.5, 127.0
(q, JC-F = 3 Hz), 123.7 (q, JC-F = 271 Hz), 123.5 (q, JC-F = 4 Hz), 82.6,
41.6, 36.7, 31.0, 17.7; HRMS calcd for C14H13F3N2O2 m/z 321.0827
[M+Na+], found 321.0820 [M+Na+].
3-(4-Methylphenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole
(4b): White solid, m.p. 124–125 °C; IR (KBr) v 3034, 2928, 1689,
1
1606, 1411, 1355, 1228, 882, 823, 778 cm−1; H NMR (400 MHz,
CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.67 (dd,
J = 9.8, 3.3 Hz, 1H), 3.57 (dd, J = 17.6, 9.8 Hz, 1H), 3.38 (dd, J = 15.5,
8.8 Hz, 1H), 3.24–3.10 (m, 2H), 2.47–2.39 (m, 5H), 2.14–1.94
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.4, 155.4, 140.9, 129.6,
126.7, 125.8, 81.8, 41.5, 37.4, 31.1, 21.5, 17.8; HRMS calcd for
C14H16N2O2 m/z 267.1109 [M+Na+], found 267.1103 [M+Na+].
3-(3,4-Methylenedioxyphenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihy-
droisoxazole (4c): White solid, m.p. 161–162 °C; IR (KBr) v 3004,
3-Phenyl-5-(pyridin-4-yl)-4,5-dihydoisoxazole (5a): White solid,
m.p. 96–98 °C; IR (KBr) v 3062, 2919, 1597, 1415, 1353, 1221, 858,
755, 685 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 5.8 Hz, 2H),
7.70 (dd, J = 7.2, 2.1 Hz, 2H), 7.52–7.37 (m, 3H), 7.35 (d, J = 5.8 Hz,
2H), 5.76 (dd, J = 11.2, 7.3 Hz, 1H), 3.88 (dd, J = 16.6, 11.2 Hz, 1H),
3.33 (dd, J = 16.6, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 155.9,
150.3, 149.9, 130.5, 128.9, 128.8, 126.8, 120.4, 80.6, 43.1; HRMS
calcd for C14H12N2O m/z 225.1028 [M+H+], found 225.1020 [M+H+].
3-(4-Methylphenyl)-5-(pyridin-4-yl)-4,5-dihydoisoxazole (5b): White
solid, m.p. 107–109 °C; IR (KBr) v 3035, 2880, 1601, 1558, 1348,
1
2091, 1697, 1607, 1498, 1420, 1251, 892, 720, 616 cm−1; H NMR
(400 MHz, CDCl3) δ 7.29 (dd, J = 9.3, 0.6 Hz, 1H), 7.07 (d, J =
8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.64 (dd, J = 9.8, 3.3 Hz, 1H),
6.04 (s, 2H), 3.53 (dd, J = 17.5, 9.8 Hz, 1H), 3.37 (dd, J = 15.7,
8.6 Hz, 1H), 3.26–3.03 (m, 2H), 2.43 (t, J = 8.5 Hz, 2H), 2.20–1.91
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.3, 155.0, 149.7, 148.3,
122.8, 121.6, 108.3, 106.4, 101.6, 82.0, 41.6, 37.5, 31.0, 17.8; HRMS
calcd for C14H14N2O4 m/z 297.0851 [M+Na+], found 297.0837
[M+Na+].
1
1218, 894, 819, 541 cm−1; H NMR (400 MHz, CDCl3) δ 8.63 (d,
J = 6.0 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 6.0 Hz, 2H), 7.24
(d, J = 8.1 Hz, 2H), 5.74 (dd, J = 11.1, 7.3 Hz, 1H), 3.86 (dd, J = 16.6,
11.1 Hz, 1H), 3.30 (dd, J = 16.6, 7.3 Hz, 1H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.9, 150.3, 150.0, 140.8, 129.5, 126.8, 126.0,
120.5, 80.4, 43.2, 21.5; HRMS calcd for C15H14N2O m/z 239.1184
[M+H+], found 239.1182 [M+H+].
3-(4-Chlorophenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole
3-(4-Methylphenyl)-5-(pyridin-2-yl)-4,5-dihydoisoxazole (5c): White
(4d): White solid, m.p. 170–171 °C; IR (KBr) v 2991, 2892, 1689,
solid, m.p. 104–106 °C; IR (KBr) v 3062, 2927, 1590, 1513, 1354,
1
1594, 1459, 1355, 1289, 891, 826, 746 cm−1; H NMR (400 MHz,
1
1290, 899, 825, 777 cm−1; H NMR (400 MHz, CDCl3) δ 8.60 (d,
CDCl3) δ 7.64 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.68 (dd,
J = 9.9, 3.5 Hz, 1H), 3.55 (dd, J = 17.6, 9.9 Hz, 1H), 3.36 (dd, J = 15.5,
8.7 Hz, 1H), 3.26–3.07 (m, 2H), 2.44 (t, J = 7.8 Hz, 2H), 2.18–1.91
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.4, 154.6, 136.6, 129.2,
128.0, 127.2, 82.3, 41.6, 37.0, 31.0, 17.8; HRMS calcd for
C13H13ClN2O2 m/z 287.0563 [M+Na+], found 287.0553 [M+Na+].
3-(3-Chlorophenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole
(4e): White solid, m.p. 103–104 °C; IR (KBr) v 3066, 2871, 1696,
J = 4.6 Hz, 1H), 7.78–7.68 (m, 1H), 7.61 (d, J = 8.1 Hz, 3H), 7.23 (t,
J = 8.6 Hz, 3H), 5.85 (dd, J = 11.1, 6.8 Hz, 1H), 3.84 (dd, J = 16.7,
11.1 Hz, 1H), 3.70 (dd, J = 16.7, 6.8 Hz, 1H), 2.39 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.8, 156.7, 145.5, 141.6, 141.5, 129.6, 127.1,
125.5, 125.0, 123.8, 77.3, 43.8, 21.5; HRMS calcd for C15H14N2O m/z
261.1004 [M+Na+], found 261.0997 [M+Na+].
3-(3,4-Methylenedioxyphenyl)-5-(pyridin-4-yl)-4,5-dihydoisoxa-
zole (5d): Light yellow solid, m.p. 127–129 °C; IR (KBr) v 2981,
2787, 1602, 1501, 1453, 1216, 912, 804, 600 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.64 (d, J = 5.7 Hz, 2H), 7.33 (dd, J = 5.6,
3.6 Hz, 3H), 7.04 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.04
(s, 2H), 5.73 (dd, J = 11.1, 7.3 Hz, 1H), 3.82 (dd, J = 16.5, 11.1 Hz,
1H), 3.26 (dd, J = 16.5, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 155.5, 150.3, 149.9, 149.6, 148.2, 123.0, 121.7, 120.4, 108.3, 106.6,
101.6, 80.5, 43.2; HRMS calcd for C15H12N2O3 m/z 269.0926 [M+H+],
found 269.0923 [M+H+].
1
1558, 1413, 1342, 1261, 913, 825, 736 cm−1; H NMR (400 MHz,
CDCl3) δ 7.70 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.48–7.33 (m, 2H),
6.70 (dd, J = 9.9, 3.4 Hz, 1H), 3.55 (dd, J = 17.6, 10.0 Hz, 1H), 3.36
(dd, J = 15.6, 8.6 Hz, 1H), 3.27–3.08 (m, 2H), 2.45 (t, J = 7.8 Hz, 2H),
2.19–1.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.4, 154.5,
135.0, 130.5, 130.5, 130.2, 126.7, 124.8, 82.4, 41.6, 36.9, 31.0, 17.8;
HRMS calcd for C13H13ClN2O2 m/z 287.0563 [M+Na+], found
287.0561 [M+Na+].
3-(2-Chlorophenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole
3-(4-Chlorophenyl)-5-(pyridin-4-yl)-4,5-dihydoisoxazole(5e):White
solid, m.p. 93–95 °C; IR (KBr) v 3031, 2940, 1597, 1494, 1349, 1221,
886, 827, 797 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 5.4 Hz,
2H), 7.63 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.33 (d, J =
5.4 Hz, 2H), 5.77 (dd, J = 11.3, 7.5 Hz, 1H), 3.85 (dd, J = 16.6,
11.3 Hz, 1H), 3.29 (dd, J = 16.6, 7.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 155.0, 150.3, 149.6, 136.5, 129.1, 128.0, 127.4, 120.4, 80.8,
42.9; HRMS calcd for C14H11ClN2O m/z 259.0638 [M+H+], found
259.0628 [M+H+].
(4f): White solid, m.p. 79–80 °C; IR (KBr) v 3066, 2891, 1704, 1588,
1
1410, 1316, 1260, 905, 877, 766 cm−1; H NMR (400 MHz, CDCl3)
δ 7.68 (dd, J = 7.6, 1.4 Hz, 1H), 7.49–7.33 (m, 3H), 6.71 (dd, J = 9.9,
3.0 Hz, 1H), 3.71 (dd, J = 18.1, 9.9 Hz, 1H), 3.51–3.16 (m, 3H), 2.45
(t, J = 8.4 Hz, 2H), 2.17–1.93 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 175.4, 155.3, 132.8, 131.3, 130.8, 130.6, 128.3, 127.2, 82.5, 41.9,
39.6, 31.0, 17.8; HRMS calcd for C13H13ClN2O2 m/z 287.0563
[M+Na+], found 287.0569 [M+Na+].
3-(4-Nitrophenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole
3-(3-Chlorophenyl)-5-(pyridin-4-yl)-4,5-dihydoisoxazole (5f): Light
yellow solid, m.p. 67–69 °C; IR (KBr) v 3063, 2880, 1595, 1556,
1417, 1302, 889, 787, 680 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.65
(d, J = 5.8 Hz, 2H), 7.68 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.48–7.30
(m, 4H), 5.79 (dd, J = 11.3, 7.4 Hz, 1H), 3.86 (dd, J = 16.6, 11.3 Hz,
1H), 3.30 (dd, J = 16.6, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 154.9, 150.4, 149.6, 134.9, 130.7, 130.4, 130.1, 126.9, 124.9, 120.4,
80.9, 42.8; HRMS calcd for C14H11ClN2O m/z 259.0638 [M+H+],
found 259.0640 [M+H+].
3-(4-Nitrophenyl)-5-(pyridin-4-yl)-4,5-dihydoisoxazole (5g): Light
yellow solid, m.p. 188–190 °C; IR (KBr) v 3085, 2840, 1600, 1574,
1342, 1246, 937, 851, 749 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67
(d, J = 5.8 Hz, 2H), 8.30 (d, J = 8.9 Hz, 2H), 7.87 (d, J = 8.9 Hz, 2H),
7.34 (d, J = 5.8 Hz, 2H), 5.86 (dd, J = 11.3, 7.5 Hz, 1H), 3.91 (dd,
J = 16.6, 11.3 Hz, 1H), 3.36 (dd, J = 16.6, 7.5 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 154.5, 150.5, 149.1, 148.7, 134.9, 127.5, 124.1,
120.3, 81.6, 42.4; HRMS calcd for C14H11N3O3 m/z 270.0879 [M+H+],
found 270.0883 [M+H+].
(4g): White solid, m.p. 201–202 °C; IR (KBr) v 3082, 2973, 1683,
1
1517, 1422, 1348, 1288, 961, 855, 785 cm−1; H NMR (400 MHz,
CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 6.74 (dd,
J = 10.1, 3.6 Hz, 1H), 3.60 (dd, J = 17.6, 10.1 Hz, 1H), 3.37 (dd,
J = 15.6, 8.5 Hz, 1H), 3.29–3.15 (m, 2H), 2.46 (t, J = 7.8 Hz, 2H),
2.20–1.96 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.5, 154.0,
148.8, 134.8, 127.5, 124.2, 83.2, 41.8, 36.4, 31.0, 17.8; HRMS calcd
for C13H13N3O4 m/z 298.0804 [M+Na+], found 298.0796 [M+Na+].
3-(3-Nitrophenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihydroisoxazole
(4h): White solid, m.p. 171–172 °C; IR (KBr) v 3062, 2899, 1689,
1
1527, 1460, 1345, 1279, 910, 829, 718 cm−1; H NMR (400 MHz,
CDCl3) δ 8.48 (s, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 7.8 Hz,
1H), 7.66 (t, J = 8.0 Hz, 1H), 6.75 (dd, J = 10.0, 3.6 Hz, 1H), 3.62 (dd,
J = 17.6, 10.1 Hz, 1H), 3.38 (dd, J = 15.4, 8.5 Hz, 1H), 3.30–3.14 (m,
2H), 2.47 (t, J = 7.9 Hz, 2H), 2.20–1.96 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 175.5, 153.9, 148.5, 132.2, 130.6, 130.1, 125.0, 121.6, 83.0,
41.7, 36.6, 31.0, 17.8; HRMS calcd for C13H13N3O4 m/z 298.0804
[M+Na+], found 298.0799 [M+Na+].
3-(3-Nitrophenyl)-5-(pyridin-4-yl)-4,5-dihydoisoxazole (5h): Light
yellow solid, m.p. 92–94 °C; IR (KBr) v 3069, 2951, 1597, 1531,
1353, 1241, 918, 842, 673 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67
(d, J = 5.9 Hz, 2H), 8.45 (s, 1H), 8.31 (d, J = 9.2 Hz, 1H), 8.13 (d,
3-(3-Trifluoromethylphenyl)-5-(2-oxopyrrolidin-1-yl)-4,5-dihy-
droisoxazole (4i): White solid, m.p. 119–120 °C; IR (KBr) v 3063,
1
2897, 1691, 1607, 1462, 1375, 1251, 894, 858, 693 cm−1; H NMR

502 JOURNAL OF CHEMICAL RESEARCH 2013
3
4
5
6
7
E.F. Kleinman, and S. Conn, US 5716967 (1998).
J. Wityak, C.B. Xue, T.M. Sielecki-Dzurdz, et al., US 5849736 (1998).
M.R. Barbachyn, J. Morris, D.O. Wishka, et al., US 6069141 (2000).
H.K. Chang, WO 2005021516 (2005).
J.I. Andrés-Gil, M.J. Alcázar-Vaca, M.E. Matesanz-Ballesteros, et al.
US 7462717 (2008).
Y. Al-Abed, US 7662843 (2010).
M.R. Barbachyn, G.J. Cleek, L.A. Dolak, S., et al., J. Med. Chem., 2003,
46, 284.
J = 7.8 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 5.6 Hz, 2H), 5.86
(dd, J = 11.3, 7.5 Hz, 1H), 3.94 (dd, J = 16.7, 11.3 Hz, 1H), 3.38 (dd,
J = 16.7, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.4, 150.4,
149.2, 148.5, 132.3, 130.8, 123.0, 124.9, 121.7, 120.3, 81.3, 42.5;
HRMS calcd for C14H11N3O3 m/z 270.0879 [M+H+], found 270.0884
[M+H+].
8
9
The financial support from the National Natural Science Foun-
dation of China (No. 21205086) is gratefully acknowledged.
We are grateful for the help of Prof. Jun-An Ma and Prof.
Qing-Zhi Gao in revising the manuscript.
10 R. Maurya, P. Gupta, G. Ahmad, et al., Med. Chem. Res., 2008, 17, 123.
11 G. Ahmad, P.K. Mishra, P. Gupta, et al., Bioorg. Med. Chem. Lett., 2006,
16, 2139.
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Wiley, Interscience Publishers, New York, 1962.
13 A. Padwa, 1,3-Dipolar cycloaddition chemistry. Wiley, New York, 1984.
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VCH Publishers: New York, 1988.
15 D. Simoni, M. Roberti, F.P. Invidiata, et al., J. Med. Chem., 2001, 44,
2308.
Received 3 May 2013; accepted 4 June 2013
Paper 1301926 doi: 10.3184/174751913X13735527483211
Published online: 9 August 2013
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