Reaction of N-(phenyl and methyl)-C-arylnitrones with DMAD in ionic liquid: Efficient synthesis of Δ4-isoxazolines

Article abstract of DOI:10.1002/jhet.682

Facile synthesis of N-(methyl and phenyl)-Δ⁴-isoxazolines via the reaction of (Z)-N-(methyl and phenyl)- C-arylnitrones with dimethyl acethylenedicarboxylate, DMAD, in ionic liquid is described. (Z)-Nmethyl- C-arylnitrones afforded the high yie

Full text of DOI:10.1002/jhet.682

106
Reaction of N-(Phenyl and methyl)-C-arylnitrones with DMAD in
Ionic Liquid: Efficient Synthesis of D4-Isoxazolines
Vol 49
Hassan Valizadeh,a,* Esmail Vesally,b and Leila Dinparastc
aDepartment of Chemistry, Islamic Azad University, Myianeh Branch, Myianeh, Iran
bPayame Noor University (PNU), Zanjan, Iran
cDepartment of Chemistry, Faculty of Science, Azarbaijan University of Tarbiat Moallem, P. O.
Box 53714-161, Tabriz, Iran
*E-mail: hvalizadeh2@yahoo.com
Received June 20, 2010
DOI 10.1002/jhet.682
Published online 13 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
Facile synthesis of N-(methyl and phenyl)-D4-isoxazolines via the reaction of (Z)-N-(methyl and phe-
nyl)-C-arylnitrones with dimethyl acethylenedicarboxylate, DMAD, in ionic liquid is described. (Z)-N-
methyl-C-arylnitrones afforded the high yield of N-methyl-D4-isoxazolines 4a-4e in ionic liquid,
[bmim]BF4, at room temperature. However, the reaction of (Z)-N-phenyl-C-arylnitrones with DMAD
afforded the mixtures of cis and trans isomers of related N-phenyl-D4-isoxazolines (5a–j, 6a–j) under
these conditions.
J. Heterocyclic Chem., 49, 106 (2012).
INTRODUCTION
Nitrone 1,3-dipoles have been used for the synthesis
of isoxazoline derivatives by 1,3-dipolar cycloaddition
reactions [11–21]. Despite the other 1,3-dipoles, nitrones
are stable compounds and do not require an in situ for-
mation. In continuation of our interest to use ionic
liquids (ILs), water or solvenless systems as green reac-
tion medium [22–29], in this report, we wish to high-
light our results on cycloaddition reactions of (Z)-nitro-
nes, 1a–e and 2a–j, with DMAD to produce related
D4-isoxazoline derivatives in good to excellent yields
(Scheme 1).
Nitrogen and oxygen containing heterocyclic com-
pounds are very important organic compounds because
of their wide range of pharmacological activity. Isoxazo-
lines represent one of the active classes of compounds
possessing a wide spectrum of biological activities such
as antidiabetic [1], diuretic [2], analgesic [3], antheli-
mentic [4], hypolipaemic [5] and antimicrobial activity
[6]. One of the most common procedures for the synthe-
sis of these compounds is cycloaddition reaction of 1,3-
dipoles to olefins. The 1,3-diolar cycloaddition, also
known as the Huisgen cycloaddition, is a well-known
reaction in organic chemistry consisting of the reaction
of alkenes with a 1,3-dipolar compounds that allows the
synthesis of various heterocycles such as isoxazolines
[7]. A range of different substituents can be included in
the dipole and the dipolarophile, resulting in a broad
range of possible cycloadducts, which can serve as use-
ful synthetic building blocks. These reactions are syn-
thetically very useful because of their high stereospeci-
ficity and stereoselectivity [8–10].
RESULTS AND DISCUSSION
In a typical experiment, N-methyl-C-phenylnitrone 1a
(15 mmol) and DMAD (15 mmol) were charged into a
10-mL flask containing [bmim]Cl (2 mL) and mixed
thoroughly. Then, the mixture was stirred at room tem-
perature. The whole reactions were monitored by TLC
using (EtOAc/petroleum 1:6) as eluent and found that
the reaction was completed to afford N-methyl-D4-
C
V
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January 2012
Efficient Synthesis of D4-Isoxazolines
107
Scheme 1. Reaction of N-(methyl and phenyl)nitrones with DMAD in
[bmim] BFꢀ4
This reaction led to formation of the diastereomeric
mixture of 2,3-diphenyl-D4-isoxazoline (5a and 6a) in
82% yield. The structures of two diastereomers were
1
confirmed on the basis of IR and H NMR spectroscopic
data. The IR spectrum of the mixture of two diastereom-
ers exhibited two sharp bands at 1741 and 1719
cmꢀ1(C¼¼O) and a series of bands in the region of
1640–1560 cmꢀ1(C¼¼C). In the 1H NMR spectrum
(CDCl3), two singlets at d 3.63 and 3.65 (CO2Me), two
singlets at d 5.14 and 5.13 (benzylic proton), and mul-
tiplet at d 7.20–8.12 (Ar-H) were observed. The ratio of
two diastereomers was evaluated from the 1H NMR
spectroscopic data.
To examine the versatility of the procedure, the reac-
tion of N-methyl-C-arylnitrones 1a–e and N-phenyl-C-
arylnitrones 2a–j containing electron-rich, electron-poor,
or electron-neutral substituents with DMAD were exam-
ined and high yields (>82% yields) of related D4-isoxa-
zolines were synthesized (Table 2).
As it can see from Table 2, the reaction of N-methyl
nitrones was occurred faster and in higher yields in
comparison with N-phenyl nitrones. This different
behavior is probably due to the resonance of double
bond, C¼¼N of nitrones 2a–j with phenyl substituent on
N atom. Interesting results were found by comparison of
the 1H NMR spectroscopic data of products from the
reaction of N-methyl and N-phenyl nitrones with
DMAD. These data showed that the reaction of N-phe-
nyl nitrones with DMAD afforded diastereomeric mix-
ture of D4-isoxazolines. However, in the case of N-
methyl nitrones with DMAD, only one product was iso-
lated. These results showed that inversion energy barrier
of nitrogen atom in N-phenyl-D4-isoxazolines are higher
than N-methyl-D4-isoxazolines due to higher steric strain
between larger phenyl groups during inversion was
occurred in the compounds 4a–e in comparison with
products 5a–j and 6a–j. Hartree Fock (HF) with STO-
3G basis set were used to calculate the inversion energy
barrier for typical compounds 4a and 5a. The calcula-
tions were clarified a larger inversion energy for 5a
isoxazoline 4a after 22 min in 80% yield. Several butyl-
methylimidazolium-based ILs, [bmim]X, with varying
anions such as PF6ꢀ, Brꢀ, and BFꢀ4 , were screened for
this reaction for complete conversions as monitored by
TLC to afford product (Table 1).
Evidently, [bmim] BF4ꢀ was found to be superior in
terms of yield (92%) and reaction time (15 min) as com-
pared with other ILs (entries 2–5). For optimizing the
conditions, we used the substrates in different ratios. It
was found that the best results were obtained using 1:1
reactants ratio. The reaction in [bmim] BFꢀ4 was con-
ducted at higher temperatures for optimizing the condi-
tions and no significant improvements were observed in
yields or reaction times. We examined the reaction
under neat conditions, without using ionic liquid, to
demonstrate the catalytic ability of [bmim] BFꢀ4 (Table
1). This result clearly indicates that [bmim] BFꢀ4 has
significant catalytic role in this reaction (entry 1). When
optimizing the reaction conditions, we extended this
procedure to N-phenyl-C-phenylnitrone 2a to obtain the
corresponding N-phenyl-D4-isoxazoline (Scheme 1).
Table 1
Reaction of N-(methyl and phenyl)-C-phenylnitrones (1a and 2a) with DMAD under different conditions.
Entry
Nitrone
Ar
Reaction medium
Product
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
2a
2b
Ph
Ph
Ph
Ph
Neat
4a
4a
4a
4a
4a
4b
5a, 6a
5b, 6b
45
22
25
20
16
16
25
27
45
80
82
83
92
93
82
86
[bmim]Cl
[bmim]Br
[bmim]PF6
[bmim]BF4
[bmim]BF4
[bmim]BF4
[bmim]BF4
Ph
4-Me-Ph
Ph
2-OH-Ph
a Isolated yield of products after flash chromatography.
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108
H. Valizadeh, E. Vesally, and L. Dinparast
Vol 49
Table 2
Synthesis of N-(methyl and phenyl)-3-aryl-D4-isoxazolines in [bmim]BF4 at room temperature.
L(þ)-Diethyl
Time
(min)
Product(s)
(ratio of isomers)
Entry
Nitrone
Ar
tartrate (mol %)
Yielda (%)
1
2
3
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
0
0
0
25
27
22
19
20
25
18
25
20
24
20
22
23
25
15
16
16
14
15
5a, 6a (55/45)
5b, 6b (57/43)
5c, 6c (54/46)
5d, 6d (55/45)
5e, 6e (53/47)
5f, 6f (57/43)
5g, 6g (55/45)
5h, 6h (58/42)
5i, 6i (53/47)
5j, 6j (56/44)
5a, 6a (82/18)
5b, 6b (85/15)
5c, 6c (88/12)
5d, 6d (80/20)
4a
83
86
85
90
82
86
87
91
85
86
82
80
82
81
94
91
90
93
95
2-OH-Ph
5-Br-Ph
5-NO2-Ph
2-Cl-Ph
2-NO2-Ph
3-OMe-Ph
3-NO2-Ph
2-OMe-Ph
3-Cl-Ph
Ph
4
0
5
6
0
0
7
8
0
0
9
0
0
10
11
12
13
14
15
16
17
18
19
2j
2a
2b
2c
2d
1a
1b
1c
1d
1e
10
10
10
10
–
2-OH-Ph
5-Br-Ph
5-NO2-Ph
Ph
4-Me-Ph
3-NO2-Ph
2-OMe
–
–
4b
4c
4d
–
2-Cl
–
4e
a Isolated yield of products.
(16.56 kcal molꢀ1) respect to 4a (16.56 kcal molꢀ1).
The diagram of energy versus torsional angle was pre-
sented (Fig. 1). Another HF calculation was done for
acetyl rotation in the mentioned molecules 4a and 5a.
However, lower rotation energies (2.24 and 2.03 kcal
molꢀ1) were obtained for molecules 4a and 5a, respec-
tively (Fig. 2).
(Table 2). To assign the compounds 5a–b and 6a–b, nu-
clear Overhauser effects (NOE) have been used to estab-
lish a space proximity relation between H-3 and N-phe-
nyl substituent. On irradiation of proton H-3 in isomers
5a–j, the NOE induced the enhancement of the signals
of protons at the ortho position of phenyl substituent.
On the other hand, no effect on the signal of N-phenyl
protons of isomers 6a–j was observed by irradiation of
the H-3 proton. This lack of effect proves that in prod-
ucts 6a–j, the H-3 proton exists on opposite side of N-
phenyl substituent. As shown in Table 2, in all cases the
In the case of N-phenyl nitrones with DMAD, prod-
ucts 5a–j and 6a–j were isolated by column chromatog-
raphy and the ratios of diastereoisomers were calculated
Figure 1. Inversion energy barrier diagram for typical compounds 4a
and 5a.
Figure 2. Acetyl group rotation diagram of typical compounds 4a and 5a.
Journal of Heterocyclic Chemistry
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Efficient Synthesis of D4-Isoxazolines
109
162.71. Anal. Calcd. (%) for C14H15NO5: C, 60.64; H, 5.45;
N, 5.05. Found (%): C, 60.87; H, 5.37; N, 4.90.
yields of isomers 5a–j are higher than yields of isomers
6a–j.
2-Methyl-3-(4-methylphenyl)-4,5-dicarbomethoxy-D4-isoxa-
zoline(4b) White crystals; mp 50–51ꢁC; IR (KBr): 1750, 1711,
For comparison, we also examined the reaction of
nitrones 2a–d with DMAD in chiral medium containing
L(þ)-diethyl tartrate and the ratio of diastereoisomers
were evaluated under these conditions (entries 11–14,
Table 2). As it can be seen from Table 2, the selectivity
of the reaction was increased under these conditions.
1648, 1110 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d ¼ 7.31–
7.25 (m, 4H, Ar-H), 5.11 (s, 1H, CH), 3.88 (s, 3H, Me), 3.69
(s, 3H, Me), 3.05 (s, 3H, Me), 2.38 (s, 3H, Me). 13C NMR
(CDCl3. 100 MHz) d ¼ 24.12, 33.95, 52.40, 50.72, 87.98,
111.64, 119.72, 124.44, 126.36, 129.96, 135.55, 159.58,
162.71. Anal. Calcd. (%) for C15H17NO5: C, 61.85; H, 5.88;
N, 4.81. Found (%): C, 62.02; H, 5.67; N, 4.62.
2-Methyl-3-(3-nitrophenyl)-4,5-dicarbomethoxy-D4-isoxa-
zoline(4c) White crystals; mp 78–79ꢁC; IR (KBr): 1752,
CONCLUSIONS
1709, 1638,1535, 1356,1120 cmꢀ1 1H NMR (400 MHz,
.
In summary, we have developed a convenient and ef-
ficient synthetic approach to synthesize N-(methyl and
phenyl)-D4-isoxazolines via the 1,3-dipolar cycloaddition
reaction of (Z)-N-(methyl and phenyl) nitrone deriva-
tives with DMAD in [bmim] BFꢀ4 at room temperature.
(Z)-N-phenyl nitrones afforded good to high yield of the
diastereomeric mixture of related D4-isoxazolines in this
procedure. Moreover, fast reaction times, simple experi-
mental procedure and good yields of the products are
the advantages. We believe our procedure will find im-
portant applications in the synthetic organic chemistry.
CDCl3): d ¼ 7.21–7.05 (m, 4H, Ar-H), 4.95 (s, 1H, CH), 3.80
(s, 3H, Me), 3.61 (s, 3H, Me), 3.05 (s, 3H, Me). 13C NMR
(CDCl3 100 MHz) d ¼ 32.95, 51.43, 50.32, 86.18, 113.64,
120.12, 121.26, 123.98, 125.65, 127.87, 128.90, 133.33,
160.18, 164.11. Anal. Calcd. (%) for C14H14N2O7: C, 52.18;
H, 4.38; N, 8.69. Found (%): C, 52.25; H, 4.23; N, 8.50.
2,3-Diphenyl-4,5-dicarbomethoxy-D4-isoxazoline (5a, 6a) Col-
orless liquid; IR (KBr): 1771, 1718, 1654, 1114 cmꢀ1 1H
.
NMR (400 MHz, CDCl3): d ¼ 7.20–8.12 (m, 10H, Ar-H),
5.14 and 5.13 (two singlets, 1H, CH), 3.80 and 3.82 (two sin-
glets, 3H, CO2Me), 3.63 and 3.65 (two singlets, 3H, CO2Me).
Anal. Calcd. (%) for C19H17NO5: C, 67.25; H, 5.05; N, 4.13.
Found (%): C, 68.11; H, 5.10; N, 4.15.
2-Phenyl-3-(5-bromophenyl)-4,5-dicarbomethoxy-D4-isoxa-
zoline (5c,6c) Colorless liquid; IR (KBr): 1746, 1718, 1610,
1
1118 cmꢀ1. H NMR (400 MHz, CDCl3): d ¼ 7.62–7.28 (m,
EXPERIMENTAL
9H, Ar-H), 5.18 and 5.16 (two singlets, 1H, CH), 3.81 and
3.79 (two singlets, 3H, CO2Me), 3.70 and 3.68 (two singlets,
3H, CO2Me). Anal. Calcd. (%) for C19H16BrNO5: C, 54.56; H,
3.86; N, 3.35. Found (%): C, 55.12; H, 3.88; N, 3.34.
General information. All reagents were purchased from
Merck (Germany) company and used without further purifica-
tion. Infrared spectra were recorded in KBr and were deter-
1
2-Phenyl-3-(2-chlorophenyl)-4,5-dicarbomethoxy-D4-isoxa-
zoline (5e, 6e) Colorless liquid; IR (KBr): 1732, 1721, 1618,
mined on a Perkin Elmer FTIR spectrometer. H NMR spectra
were obtained in CDCl3 solution from Bruker Avance AC-400
MHz and 13C NMR spectra at 100 MHz on the aforemen-
tioned instruments. Elemental analyses were carried out on a
Perkin-Elmer 240C elemental analyzer and are reported in per-
cent atomic abundance. Analytical thin-layer chromatography
was performed using precoated silica gel 60 F254 plates
(Merck, Darmstadt), and the spots were visualized with UV
light at 254 nm. Merck silica gel 60 (230–400 mesh) was used
for flash chromatography.
Synthesis of 2-(methyl and phenyl)-3-aryl-D4-isoxasolines,
general p procedure. Nitrone (15 mmol) and DMAD (15
mmol) were added to [bmim] BFꢀ4 (2 mL) in a 10-mL conical
flask, and the mixture was shaken for a period of time at room
temperature (TLC) as listed in Table 2. After completion of
the reaction, the mixture was extracted three times with 7 mL
of ethyl acetate. The combined organic layers were dried over
anhydrous sodium sulphate and evaporated under reduced pres-
sure. Then, the crud mixture was purified by flash chromatog-
raphy on silica gel to afford corresponding cycloadduct (Table
2).
1
1115 cmꢀ1. H NMR (400 MHz, CDCl3): d ¼ 7.15–7.29 (m,
9H, Ar-H), 5.24 and 5.22 (two singlets, 1H, CH), 4.03 and
3.99 (two singlets, 3H, CO2Me), 3.58 and 3.56 (two singlets,
3H, CO2Me). Anal. Calcd. (%) for C19H16ClNO5: C, 61.05; H,
4.31; N, 3.75. Found (%): C, 61.94; H, 4.37; N, 3.73.
2-Phenyl-3-(3-methoxyphenyl)-4,5-dicarbomethoxy-D4-isoxa-
zoline (5g, 6g) Colorless liquid; IR (KBr): 1742, 1713, 1612,
1114 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d ¼ 7.42-7.28 (m,
9H, Ar-H), 5.15 and 5.13 (two singlets, 1H, CH), 3.95 (s, 3H,
OMe), 3.79 and 3.76 (two singlets, 3H, CO2Me). Anal. Calcd.
(%) for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found (%): C,
66.01; H, 5.20; N, 3.81.
Acknowledgments. The offices of the Research Vice Chancellor
of Myianeh Branch of Islamic Azad University and Azarbaijan
University of Tarbiat-Moallem are gratefully acknowledged.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
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