Synthesis of novel isoxazolidine derivatives and studies for their antifungal properties

Article abstract of DOI:10.1016/S0223-5234(03)00077-1

A series of novel 5-substituted isoxazolidine derivatives 3a(i-viii), 3b(i-viii) and 3c(i-viii) have been prepared and their antifungal activity on Aspergillus flavus, Fusarium moniliforme and Botrydiplodia theobromae have been evaluated.

Full text of DOI:10.1016/S0223-5234(03)00077-1

European Journal of Medicinal Chemistry 38 (2003) 613Á619
/
www.elsevier.com/locate/ejmech
Short communication
Synthesis of novel isoxazolidine derivatives and studies for their
antifungal properties
Kodagahally R. Ravi Kumar, Honnaiah Mallesha, Basappa,
Kanchugarakoppal S. Rangappa *
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
Received 30 September 2002; received in revised form 3 March 2003; accepted 3 March 2003
Abstract
A series of novel 5-substituted isoxazolidine derivatives 3a(iÁ
activity on Aspergillus flavus, Fusarium moniliforme and Botrydiplodia theobromae have been evaluated.
/
viii), 3b(iÁ
/
viii) and 3c(iÁviii) have been prepared and their antifungal
/
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Antifungal properties; Synthesis; Isoxazolidine derivatives; Cycloaddition
1. Introduction
2. Chemistry
Compounds 2(aÁc) were prepared by the reduction of
nitro compounds and 4-biphenyl carboxaldehyde with
zinc dust using histidine as catalyst as shown in Fig. 1
[4]. The nitrones were found to be light sensitive [5] and
hygroscopic [6]. Hence, they were stored in the dark
until further use. The nitrones are versatile synthetic
intermediates in organic synthesis [7,8]. Recently, we
reported that nitrones are convenient class of com-
Over the past two decades the frequency of systematic
fungal infection in man has increased dramatically.
Ketoconazole was the first orally active antifungal agent
that was effective against a broad array of systematic
and superficial fungal infections [1]. In addition to azole
derivatives, a number of antifungal agents having
chemical structures other than azoles have recently
been introduced to the clinic.
In previous studies [2,3], we have described the
application of 1,3-dipolar cycloaddition reaction to the
synthesis of biologically active compounds. We recog-
nized an opportunity to apply our knowledge of 1,3-
dipolar species to the synthesis of a series of 5-
substituted isoxazolidine compounds through the 1,3-
dipolar cycloaddition reaction of a-substituted aldoni-
trones and monosubstituted alkenes. The resulting 5-
substituted isoxazolidines were expected to differ in their
chemical and antifungal properties from the known
azole derivatives, thus providing valuable information
of a new generation of antifungal agents.
/
pounds used for synthesis of ultimate carcinogens [9Á
which are biologically interesting molecules. The novel
isoxazolidines 3(aÁc) were obtained by refluxing the
nitrones 2(aÁc) with equimolar amount of monosub-
stituted alkene in tolueneÁxylene. The cycloaddition of
/11]
/
/
/
all monosubstituted olefins with nitrone showed high
regioselectivity and gave 5-substituted derivatives pre-
dominantly major products [12] for both electron
donating and electron withdrawing groups.
3. Results and discussion
The major products of 5-substituted isoxazolidine
derivatives 3(aÁc) were separated on silica gel column
/
using appropriate combination of chloroform, hexane,
benzene and petroleum ether as eluent. The reaction
condition and the physical data of cycloadducts are
* Corresponding author.
E-mail address: rangappaks@yahoo.com (K.S. Rangappa).
´
0223-5234/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0223-5234(03)00077-1

614
K.R. Ravi Kumar et al. / European Journal of Medicinal Chemistry 38 (2003) 613Á619
/
increasing the antifungal activity and the introduction of
methylene hydroxy group in 3b(vi) and 3c(vi) of
isoxazolidine enhancing the antifungal activity.
4. Conclusion
We prepared a novel series of 5-substituted isoxazo-
lidines. Some of these compounds possessed good
antifungal activities against the fungus Aspergillus
flavus, Fusarium moniliforme and Botrydiplodia theo-
bromae.
5. Experimental
Fig. 1.
5.1. Chemistry
given in Table 1. All the synthesized isoxazolidines were
structurally characterized by IR, 1H-NMR and C, H, N
analysis. The antifungal activity of these new com-
pounds were evaluated in solid agar media, and their
antifungal activity are summarized in Table 2. Some
compounds 3b(ii), 3b(iv), 3b(vi) 3c(ii), and 3c(vi) were
The melting points were determined on SELACO-650
hot stage apparatus and are uncorrected. IR (Nujol)
spectra were measured on shimadzu 8300 IR spectro-
photometer, 1H-NMR were recorded on Shimadzu
AMX 400-Bruker, 400 MHz spectrophotometer by
using CDCl3 as solvent and TMS as an internal
standard (chemical shift in d ppm). Elemental analyses
(C, H, N) were obtained on a Vario-EL instrument. The
shown more potent than nystatin. In general, 3c(iÁ
/
viii)
showed better activity than 3a(iÁviii) and 3b(iÁviii). The
/
/
introduction of fluorine to the phenyl ring enhanced the
antifungal activity. However, introduction of one more
phenyl ring to the isoxazolidine ring in 3b(ii) and 3c(ii)
results were within 9
Column and TLC were done with silica gel BDH 60Á
120 mesh and pre-coated silica gel plates.
/
0.4% of the theoretical values.
/
Table 1
Reaction condition and physical data of isoxazolidines 3a(iÁ
/
vii), 3b(iÁ
/
vii) and 3c(i-viii) series
Isoxazolidines Solvent used for reaction Time taken to complete the reaction (h) Rf value Eluent used in separation
% Yield M.p. (8C)
3a(i)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
17
17
18
18
31
22
20
18
19
24
19
20
24
17
22
18
20
19
20
22
24
24
23
22
0.61
0.63
0.58
0.54
0.68
0.58
0.62
0.64
0.62
0.64
0.61
0.58
0.67
0.69
0.62
0.66
0.77
0.86
0.63
0.71
0.69
0.68
0.79
0.66
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
CHCl3ꢀ
/
hexane 1:2
57
61
oily
141
oily
oily
oily
oily
oily
oily
oily
134
oily
oily
oily
oily
oily
oily
oily
132
oily
oily
oily
oily
oily
oily
3a(ii)
3a(iii)
3a(iv)
3a(v)
/hexane 1:2
/
petroleum ether 2:1 54
petroleum ether 2:1 84
petroleum ether 2:1 69
petroleum ether 2:1 58.6
petroleum ether 2:1 62
/
/
3a(vi)
3a(vii)
3a(viii)
3b(i)
/
/
/
hexane 1:2
hexane 1:2
hexane 1:2
hexane 1:2
68
/
69.5
71.5
65
3b(ii)
3b(iii)
3b(iv)
3b(v)
/
/
/
petroleum ether 1:1 84
petroleum ether 2:1 80
petroleum ether 2:1 65.5
petroleum ether 2:1 61.5
petroleum ether 2:1 64
/
3b(vi)
3b(vii)
3b(viii)
3c(i)
/
/
/
/
benzene (2:1)
benzene (2:1)
benzene (3:1)
65
60
59
3c(ii)
3c(iii)
3c(iv)
3c(v)
xylene
xylene
xylene
/
/
/petroleum ether (3:1) 61
xylene
/benzene (2:1)
62.8
3c(vi)
3c(vii)
3c(viii)
xylene
xylene
xylene
/petroleum ether (2:1) 59.6
/benzene (1:1)
66.4
58
/benzene (3:1)

K.R. Ravi Kumar et al. / European Journal of Medicinal Chemistry 38 (2003) 613Á
/619
615
Table 2
The minimum inhibitory concentrations (MIC) a of isoxazolidines 3a(iÁ
/
viii), 3b(iÁ
/
viii) and 3c(iÁviii) for antifungal activity
/
Isoxazolidines
Tested fungus
A. flavus (MIC in mM)
F. moniliforme (MIC in mM)
B. theobromae (MIC in mM)
Nystatin
3a(i)
3
5
2.5
11.5
5.5
9.5
5.5
11.0
12.0
5.5
11.5
7.5
5.0
7.0
9.0
7.5
5.5
7.5
6.5
8.5
5.0
6.0
7.5
9.0
6.0
7.5
8.0
12.0
5.5
7.0
10.5
8.0
12.0
5.5
11.5
8.5
2.5
4.5
2.5
6.5
3.0
7.5
5.5
9.0
2.5
5.5
4.0
8.0
3.0
5.0
8.0
12.0
10.5
5.0
10.5
8.0
3.5
10.5
5.5
8.5
5.0
6.5
6.0
7.5
3.0
10.0
9.0
7.5
5.5
7.0
5.5
6.5
3.0
5.5
6.5
3a(ii)
3a(iii)
3a(iv)
3a(v)
3a(vi)
3a(vii)
3a(viii)
3b(i)
3b(ii)
3b(iii)
3b(iv)
3b(v)
3b(vi)
3b(vii)
3b(viii)
3c(i)
3c(ii)
3c(iii)
3c(iv)
3c(v)
3c(vi)
3c(vii)
3c(viii)
a
Average of atleast three determinations.
General procedure for the synthesis of isoxazolidines,
crystalline solid is obtained in ethanol; yield 815 mg
(95%), m.p. 178 8C.
3a(iÁ
nitrones 2a, 2b and 2c and different alkenes were
dissolved in 10 mL of tolueneÁxylene. The reaction
mixture was refluxed for 18Á20 h to complete the
/
viii), 3b(iÁ
/
vii) and 3c(iÁ/viii): Equimolar mixture of
1H-NMR d (ppm): 3.82 (s, 3H, ArÃ
/
OCH3); 7.20Á
7.46 (m, 3H, ArÃH), 7.62Á
H), 7.92 (s, 1H, CHÄN), 8.24Á
/
7.24
/
(d, 2H, ArÃ
(m, 6H, ArÃ
ArÃH).
IR (Nujol): n (cmꢁ1): 1572 (CÄ
/
H); 7.34Á
/
/
/7.72
/
/
/
/
8.28 (d, 2H,
reaction, which was monitored by TLC. The pure
products were separated by using appropriate mixture
of chloroform, hexane, petroleum ether and benzene as
eluent in silica gel column.
/
/
N); 1152 (NO).
5.1.3. Synthesis of C-biphenyl-N-(4-
fluorophenyl)nitrone (2c)
This was obtained from the reduction of a mixture of
4-fluoronitrobenzene and 4-biphenyl carboxaldehyde
with zinc dust using histidine as catalyst [4]. A white
crystalline solid is obtained in ethanol; yield 812 mg
(96%), m.p. 307 8C.
5.1.1. Synthesis of C-biphenyl-N-phenyl nitrone (2a)
This was obtained from the reduction of a mixture of
nitrobenzene and 4-biphenyl carboxaldehyde with zinc
dust using histidine as catalyst [4]. A white crystalline
solid is obtained in ethanol; yield 748 mg (80%), m.p.
203 8C.
1H-NMR d (ppm): 7.44Á
7.79 (m, 6H, ArÃH), 7.94 (s, 1H, CHÄ
2H, ArÃH).
IR (Nujol): n (cmꢁ1): 1572 (CÄ
/
7.49 (m, 5H, ArÃ
/
H), 7.65Á
/
/
/
N), 8.44Á
/
8.48 (d,
1H-NMR d (ppm): 7.39Á
7.48 (m, 6H, ArÃH), 7.97 (s, 1H, CHÄ
(dd, 2H, ArÃH).
IR (Nujol): n (cmꢁ1): 1584 (CÄ
/
7.51 (m, 6H, ArÃ
/
H), 7.65Á
/
/
/
/
N), 8.46Á
/
8.51
/N); 1152 (NO).
/
/N); 1168 (NO).
5.1.4. Synthesis of 2-phenyl-3-biphenyl-5-cyano
isoxazolidine (3a(i))
5.1.2. Synthesis of C-biphenyl-N-(4-
methoxyphenyl)nitrone (2b)
This was obtained from the reduction of a mixture of
4-methoxynitrobenzene and 4-biphenyl carboxaldehyde
with zinc dust using histidine as catalyst. A white
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (2a) (500 mg) and acryloni-
trile (0.10 mL).
1H-NMR d (ppm): 2.65Á
1H, H5); 5.08 (t, 1H, H3); 6.91 (t, 1H, ArÃ
/
2.81 (dd, 2H, H4); 4.45 (t,
H); 7.2 (t, 2H,
/

616
K.R. Ravi Kumar et al. / European Journal of Medicinal Chemistry 38 (2003) 613Á619
/
ArÃ
7.64 (t, 2H, ArÃ
H(BP).
/
H); 7.41 (d, 2H, ArÃ
/
H(BP); 7.52 (t, 1H, ArÃ
/
H(BP);
5.1.9. Synthesis of 2-phenyl-3-biphenyl-5-methelene
hydroxy isoxazolidine (3a(vi))
/
H(BP); 7.72 (d, 2H, ArÃ
/
H); 7.69 (d, 4H,
ArÃ
/
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (2a) (500 mg) and allyl
alcohol (0.12 mL).
IR (Nujol): n (cmꢁ1): 1742 (CO); 1280 (NO).
5.1.5. Synthesis of 2-phenyl-3-biphenyl-5-phenyl
isoxazolidine (3a(ii))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (2a) (500 mg) and styrene
(0.25 mL).
1H-NMR d (ppm): 2.65Á
/
2.80 (dd, 2H, H4); 3.64 (d,
2H, CH2); 4.76 (m, 1H, H5); 5.14 (t, 1H, H3); 5.25 (s,
1H, OH); 6.92 (t, 1H, ArÃH); 7.2 (t, 2H, ArÃH); 7.41 (d,
2H, ArÃH, BP); 7.52 (t, 1H, ArÃH, BP); 7.64 (t, 2H,
ArÃH, BP); 7.72 (d, 2H, ArÃH); 7.69 (d, 4H, ArÃH,
BP).
/
/
/
/
/
/
/
1H-NMR d (ppm): 2.72Á
1H, H5); 5.12 (t, 1H, H3); 6.91 (t, 1H, ArÃ
ArÃH); 7.29Á7.41 (m, 5H, ArÃH); 7.42 (d, 2H, ArÃ
H(BP); 7.52 (t, 1H, ArÃH(BP); 7.64 (t, 2H, ArÃ
/2.88 (dd, 2H, H4); 5.05 (t,
/H); 7.2 (t, 2H,
IR (Nujol): n (cmꢁ1): 1710 (CO); 1242 (NO).
/
/
/
/
/
/
H(BP); 7.72 (d, 2H, ArÃ
/
H); 7.69 (d, 4H, ArÃ/H(BP).
5.1.10. Synthesis of 2-phenyl-3-biphenyl-5-(3-
cyclohexene) isoxazolidine (3a(vii))
IR (Nujol): n (cmꢁ1): 1712 (CO); 1240 (NO).
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (3a) (500 mg) and 4-vinyl-1-
cyclohexene (0.25 mL).
5.1.6. Synthesis of 2-phenyl-3-biphenyl-5-benzoate
isoxazolidine (3a(iii))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (2a) (500 mg) and vinyl
benzoate (0.25 mL).
1H-NMR d (ppm): 1.38Á
ene); 1.52 (s, 1H, cyclohexene); 2.27Á
cyclohexene); 2.33Á2.38 (m, 2H, cyclohexene); 2.6Á
2.65Á2.80 (dd, 2H, H4); 3.64 (d, 2H, CH2); 4.76 (t,
1H, H5); 5.14 (t, 1H, H3); 4.82 (m, 1H, CH); 5.12 (t, 1H,
CH); 5.6Á5.66 (m, 2H, cyclohexene); 6.92 (t, 1H, ArÃ
H); 7.2 (t, 2H, ArÃH); 7.41 (d, 2H, ArÃH, BP); 7.52 (t,
1H, ArÃH, BP); 7.64 (t, 2H, ArÃH, BP); 7.72 (d, 2H,
/1.42 (m, 2H, CH2, cyclohex-
/2.31 (m, 2H,
/
/
1H-NMR d (ppm): 2.70Á
1H, H5); 5.13 (t, 1H, H3); 6.91 (t, 1H, ArÃ
2H, ArÃH); 7.28Á7.50 (m, 3H, ArÃH); 7.41 (d, 2H, ArÃ
H(BP); 7.52 (t, 1H, ArÃH(BP); 7.72 (d, 2H, ArÃH); 7.64
(t, 2H, ArÃH(BP); 7.79 (d, 4H, ArÃH(BP); 7.81 (d, 2H,
ArÃH).
IR (Nujol): n (cmꢁ1): 1748 (CÄ
(NO).
/2.86 (dd, 2H, H4); 4.72 (t,
/
/H); 7.20 (t,
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
ArÃ
/
H); 7.79 (d, 4H, ArÃ
/
H, BP).
IR (Nujol): n (cmꢁ1): 1730 (CO); 1262 (NO).
/
O); 1730 (CO); 1260
5.1.7. Synthesis of 2-phenyl-3-biphenyl-5-ethylate
isoxazolidine (3a(iv))
5.1.11. Synthesis of 2-phenyl-3-biphenyl-5-methylate
isoxazolidine (3a(viii))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (2a) (500 mg) and ethyl
acrylate (0.20 mL).
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (3a) (500 mg) and methyl
acrylate (0.17 mL).
1H-NMR d (ppm): 0.94 (t, 3H, CH3); 2.68Á
/
2.86 (dd,
2H, H4); 3.62 (q, 2H, CH2); 4.43 (t, 1H, H5); 5.12 (t, 1H,
H3); 6.91 (t, 1H, ArÃH); 7.2 (t, 2H, ArÃH); 7.41 (d, 2H,
ArÃH, BP); 7.52 (t, 1H, ArÃH, BP); 7.64 (t, 2H, ArÃH,
BP); 7.72 (d, 2H, ArÃH); 7.79 (d, 4H, ArÃH, BP).
IR (Nujol): n (cmꢁ1): 1720 (CÄ
O); 1722 (CO); 1234
(NO).
1H-NMR d (ppm): 2.6Á
/
2.9 (dd, 2H, CH2); 3.41 (s,
3H, OCH3); 4.45 (t, 1H, CH); 5.12 (t, 1H, CH); 6.92 (t,
1H, ArÃH); 7.2 (t, 2H, ArÃH); 7.41 (d, 2H, ArÃH, BP);
7.52 (t, 1H, ArÃH, BP); 7.64 (t, 2H, ArÃH, BP); 7.72 (d,
/
/
/
/
/
/
/
/
/
/
/
/
2H, ArÃ
/
H); 7.79 (d, 4H, ArÃ
/
H, BP).
/
IR (Nujol): n (cmꢁ1): 1742 (CO); 1280 (NO).
5.1.8. Synthesis of 2-phenyl-3-biphenyl-5-methylene
acetate isoxazolidine (3a(v))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-phenylnitrone (2a) (500 mg) and allyl
acetate (0.2 mL).
5.1.12. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
cyano isoxazolidine (3b(i))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and acrylonitrile (0.31 mL).
1H-NMR d (ppm): 2.42 (d, 2H, CH2) 2.62Á
2H, H4); 3.42 (s, 3H, OCH3); 2.70Á
5.06 (t, 1H, H3) 6.91 (t, 1H, ArÃH); 7.2 (t, 2H, ArÃ
7.41 (d, 2H, ArÃH, BP); 7.52 (t, 1H, ArÃH, BP); 7.64 (t,
2H, ArÃH, BP); 7.72 (d, 2H, ArÃH); 7.69 (d, 4H, ArÃH,
BP).
IR (Nujol): n (cmꢁ1): 1745 (CO); 1270 (NO).
/
2.78 (dd,
4.25 (m, 1H, H5);
H);
/
1H-NMR d (ppm): 2.82Á
ArÃ
2H, ArÃ
H(BP); 7.63 (t, 2H, ArÃ
(d, 4H, ArÃH(BP).
IR (Nujol): n (cmꢁ1): 1748 (CO); 1278 (NO).
/
3.0 (dd, 2H, H4); 3.76 (s, 3H,
OCH3); 4.44 (t, 1H, H5); 5.06 (t, 1H, H3); 7.28 (d,
H); 7.42 (d, 2H, ArÃH(BP); 7.52 (t, 1H, ArÃ
H(BP); 7.68 (d, 2H, ArÃH); 7.74
/
/
/
/
/
/
/
/
/
/
/
/
/
/

K.R. Ravi Kumar et al. / European Journal of Medicinal Chemistry 38 (2003) 613Á
/619
617
5.1.13. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
phenyl isoxazolidine (3b(ii))
5.1.17. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-
5metylene hydroxy isoxazolidine (3b(vi))
This was obtained from equimolar mixture of C-(4-
biphenyl-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and styrene (0.25 mL).
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and allyl alcohol (0.24 mL).
1H-NMR d (ppm): 2.74Á
3H, ArÃ
7.40 (m, 5H, ArÃ
ArÃH); 7.42 (d, 2H, ArÃ
7.64 (t, 2H, ArÃH(BP); 7.72 (d, 4H, ArÃ
IR (Nujol): n (cmꢁ1): 1712 (CO); 1246 (NO).
/2.92 (dd, 2H, H4); 3.80 (s,
1H-NMR d (ppm): 2.66Á
2H, CH2); 3.78 (s, 3H, ArÃ
(t, 1H, H3); 5.25 (s, 1H, OH); 7.26 (d, 2H, ArÃ
(d, 2H, ArÃH(BP); 7.52 (t, 1H, ArÃH(BP); 7.63 (t, 2H,
ArÃH(BP); 7.68 (d, 2H, ArÃH); 7.74 (d, 4H, ArÃH(BP).
IR (Nujol): n (cmꢁ1): 1728 (CO); 1262 (NO).
/
2.84 (dd, 2H, H4); 3.63 (d,
OCH3); 4.74 (t, 1H, H5); 5.12
H); 7.42
/
OCH3); 5.04 (t, 1H, H5); 5.13 (t, 1H, H3); 7.28Á
/
/
/
H); 7.28 (d, 2H, ArÃ
/
H); 7.68 (d, 2H,
/
/
/
H(BP); 7.54 (t, 1H, ArÃ
/
H(BP);
/
/
/
/
H(BP).
/
/
/
5.1.18. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
(3-cyclohexene) isoxazolidine (3b(vii))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and 4-vinyl-1-cyclohexene (0.21 mL).
5.1.14. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
benzoate isoxazolidine (3b(iii))
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and vinyl benzoate (0.26 mL).
1H-NMR d (ppm): 1.37Á
ene); 1.52 (s, 1H, cyclohexene); 2.26Á
cyclohexene); 2.32Á2.36 (m, 2H, cyclohexene); 2.68Á
2.86 (dd, 2H, H4); 3.76 (s, 3H, ArÃOCH3) 4.82 (m,
1H, H5); 5.12 (t, 1H, H3); 5.60Á5.68 (m, 2H, cyclohex-
ene); 7.28 (d, 2H, ArÃH); 7.42 (d, 2H, ArÃH, BP); 7.52
(t, 1H, ArÃH, BP); 7.63 (t, 2H, ArÃH, BP); 7.68 (d, 2H,
/1.41 (m, 2H, CH2, cyclohex-
1H-NMR d (ppm): 2.74Á
3H, ArÃ
7.50 (m, 3H, ArÃ
ArÃH(BP) 7.70 (d, 2H, ArÃ
7.52 (t, 1H, ArÃH(BP); 7.68 (d, 2H, ArÃ
ArÃH(BP).
IR (Nujol): n (cmꢁ1): 1752 (CÄ
(NO).
/
2.92 (dd, 2H, H4); 3.78 (s,
/2.30 (m, 2H,
/
/
/
OCH3); 4.74 (t, 1H, H5); 5.14 (t, 1H, H3); 7.26Á
/
/
/
H); 7.28 (d, 2H, ArÃ
/H); 7.63 (t, 2H,
/
/
/
H); 7.42 (d, 2H, ArÃ
/H(BP);
/
/
/
/H); 7.74 (d, 4H,
/
/
/
ArÃ
/
H); 7.79 (d, 4H, ArÃ
/
H, BP).
/
O); 1732 (CO); 1270
IR (Nujol): n (cmꢁ1):1744 (CO); 1270 (NO).
5.1.19. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
methylate isoxazolidine (3b(viii))
This was obtained from equimolar mixture of C-(4-
biphenyl-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and methyl acrylate (0.17 mL).
5.1.15. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
ethylate isoxazolidine (3b(iv))
This was obtained from equimolar mixture of C-(4-
biphenyl-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and ethyl acrylate (0.17 mL).
1H-NMR d (ppm): 2.66Á
3H, OCH3); 3.80 (s, 3H, ArÃ
5.14 (t, 1H, H3); 7.28 (d, 2H, ArÃ
BP); 7.52 (t, 1H, ArÃH, BP); 7.63 (t, 2H, ArÃ
7.68 (d, 2H, ArÃH); 7.79 (d, 4H, ArÃH, BP).
IR (Nujol): n (cmꢁ1): 1726 (CÄ
O); 1708 (CO); 1240
(NO).
/
2.84 (dd, 2H, H4); 3.42 (s,
OCH3); 4.44 (t, 1H, H5);
H); 7.42 (d, 2H, ArÃH,
H, BP);
/
1H-NMR d (ppm): 0.94 (t, 3H, CH3); 2.68Á
/
2.85 (dd,
2H, H4); 3.62 (q, 2H, CH2); 3.78 (s, 3H, ArÃOCH3);
4.45 (t, 1H, H5); 5.13 (t, 1H, H3); 7.28 (d, 2H, ArÃH);
7.42 (d, 2H, ArÃH(BP); 7.52 (t, 1H, ArÃH(BP); 7.63 (t,
2H, ArÃH(BP); 7.68 (d, 2H, ArÃH); 7.74 (d, 4H, ArÃ
H(BP).
IR (Nujol): n (cmꢁ1): 1726 (CÄ
(NO).
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
O); 1708 (CO); 1240
5.1.20. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
cyano isoxazolidines (3c(i))
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
acrylonitrile (0.30 mL).
5.1.16. Synthesis of 2-(4-methoxyphenyl)-3-biphenyl-5-
methylene acetate isoxazolidine (3b(v))
1H-NMR d (ppm): 2.83Á
H5); 5.10 (t, 1H, H3); 7.28 (d, 2H, ArÃ
ArÃH(BP); 7.52 (t, 1H, ArÃH(BP); 7.64 (t, 2H, ArÃ
/3.01 (q, 2H, H4); 4.46 (t, 1H,
This was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methoxyphenyl)nitrone (2b) (500 mg)
and allyl acetate (0.23 mL).
/H); 7.41 (d, 2H,
/
/
/
H(BP); 7.77 (d, 2H, ArÃ
/
H); 7.69 (d, 4H, ArÃ
/
H(BP).
1H-NMR d (ppm): 2.42 (d, 2H, CH2); 2.67Á
/
2.85 (dd,
2H, H4); 3.42 (s, 3H, OCH3); 3.76 (s, 3H, ArÃOCH3);
4.26 (t, 1H, H5); 5.12 (t, 1H, H3); 7.26 (d, 2H, ArÃH);
7.42 (d, 2H, ArÃH(BP); 7.50 (t, 1H, ArÃH(BP); 7.62 (t,
2H, ArÃH(BP); 7.68 (d, 2H, ArÃH); 7.70 (d, 4H, ArÃ
H(BP).
IR (Nujol): n (cmꢁ1): 1720 (CO); 1250 (NO).
IR (Nujol): n (cmꢁ1): 1734 (CO); 1274 (NO).
/
/
5.1.21. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
/
/
phenyl isoxazolidines (3c(ii))
/
/
/
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
styrene (0.25 mL).

618
K.R. Ravi Kumar et al. / European Journal of Medicinal Chemistry 38 (2003) 613Á619
/
1H-NMR d (ppm): 2.88Á
H5); 5.14 (t, 1H, H3); 7.29 (d, 2H, ArÃ
5H, ArÃH); 7.42 (d, 2H, ArÃH(BP); 7.52 (t, 1H, ArÃ
H(BP); 7.64 (t, 2H, ArÃH(BP); 7.77 (d, 2H, ArÃH); 7.79
/
3.06 (q, 2H, H4); 5.05 (t, 1H,
5.1.26. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-(3-
cyclohexene) isoxazolidines (3c(vii))
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
4-vinyl-1-cyclohexene (0.25 mL).
/
H); 7.29Á7.41 (m,
/
/
/
/
/
/
(d, 4H, ArÃ
/H(BP).
IR (Nujol): n (cmꢁ1): 1700 (CO); 1240 (NO).
1H-NMR d (ppm): 1.38Á
ene); 1.52 (s, 1H, cyclohexene); 2.28Á
cyclohexene); 2.33Á2.38 (m, 2H, cyclohexene); 2.85Á
3.03 (q, 2H, H4); 4.82 (m, 1H, CH); 5.14 (t, 1H, H3);
5.6Á5.66 (m, 2H, cyclohexene); 7.28 (d, 2H, ArÃH); 7.41
(d, 2H, ArÃH, BP); 7.52 (t, 1H, ArÃH, BP); 7.63 (t, 2H,
ArÃH, BP); 7.77 (d, 2H, ArÃH); 7.79 (d, 4H, ArÃH,
BP).
/1.42 (m, 2H, CH2, cyclohex-
/2.31 (m, 2H,
5.1.22. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
/
/
benzoate isoxazolidines (3c(iii))
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
vinyl benzoate (0.15 mL).
/
/
/
/
/
/
/
1H-NMR d (ppm)): 2.85Á
1H, H5); 5.15 (t, 1H, H3); 7.28 (d, 2H, ArÃ
(m, 3H, ArÃH); 7.42 (d, 2H, ArÃH, BP); 7.53 (t, 1H,
ArÃH, BP); 7.64 (t, 2H, ArÃH, BP); 7.78 (d, 2H, ArÃ
H); 7.79 (d, 4H, ArÃH, BP). 7.81 (d, 2H, ArÃH).
IR (Nujol): n (cmꢁ1): 1738 (CÄ
O); 1730 (CO); 1268
(NO).
/
3.03 (q, 2H, H4); 4.72 (t,
/
H); 7.29Á7.50
/
IR (Nujol): n (cmꢁ1): 1730 (CO); 1260 (NO).
/
/
/
/
/
5.1.27. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
ethyl isoxazolidines (3c(viii))
/
/
/
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
methyl acrylate (0.35 mL).
1H-NMR d (ppm): 2.87Á
/
3.05 (q, 2H, H4); 3.41 (s, 3H,
OCH3); 4.45 (t, 1H, H5); 5.12 (t, 1H, H3); 7.28 (d, 2H,
ArÃH); 7.41 (d, 2H, ArÃH, BP); 7.52 (t, 1H, ArÃH,
BP); 7.64 (t, 2H, ArÃH, BP); 7.77 (d, 2H, ArÃH); 7.79
H, BP).
5.1.23. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
ethylate isoxazolidines (3c(iv))
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
ethyl acrylate (0.21 mL).
/
/
/
/
/
(d, 4H, ArÃ
/
1H-NMR d (ppm): 0.93 (t, 3H, CH3); 2.84Á
/
3.02 (q,
2H, H4); 3.62 (q, 2H, CH2); 4.44 (t, 1H, H5); 5.13 (t, 1H,
H3); 7.28 (d, 2H, ArÃH); 7.41 (d, 2H, ArÃH, BP); 7.52
(t, 1H, ArÃH, BP); 7.64 (t, 2H, ArÃH, BP); 7.77 (d, 2H,
ArÃH); 7.79 (d, 4H, ArÃH, BP).
IR (Nujol): n (cmꢁ1): 1722 (CÄ
(NO).
IR (Nujol): n (cmꢁ1): 1745 (CO); 1278 (NO).
/
/
5.2. Determination of antifungal activity
/
/
/
/
Fungus used for the antifungal activity: Aspergillus
(ATCC76087)
/
O); 1700 (CO); 1232
flavus
Fusarium
moniliforme
(ATCC5342) Botrydiplodia theobromae (ATCC76087)
The isoxazolidines were tested for antifungal activity
by serial tube dilution technique [13,14] at different
concentrations (0.5, 1, 1.5, . . ., 12 mM) against A.
flavus, F. moniliforme and B. theobromae. Nystatin
was used as reference standard and CHCl3 as control.
To the culture tubes containing 1.9 mL of media, 0.1 mL
of test solution was added at sterile conditions. To all
the tubes including standard and controls, the fresh
inoculum was added using Himedia flexiloop 4 cali-
brated to 0.001 mL. After incubating all the tubes at
37 8C for 24 h, their absorbance was recorded at 640 nm
along with Nystatin. Percentage of inhibition was
calculated as by the following equation,
5.1.24. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
methylene acetate isoxazolidines (3c(v))
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
allyl acetate (0.1 mL).
1H-NMR d (ppm): 2.42 (d, 2H, CH2); 2.84Á
/
3.02 (q,
2H, H4); 3.42 (s, 3H, OCH3); 4.26 (t, 1H, H5); 5.12 (t,
1H, H3); 7.26 (d, 2H, ArÃH); 7.41 (d, 2H, ArÃH, BP);
7.52 (t, 1H, ArÃH, BP); 7.64 (t, 2H, ArÃH, BP); 7.77 (d,
/
/
/
/
2H, ArÃ
/
H); 7.79 (d, 4H, ArÃ
/
H, BP).
IR (Nujol): n (cmꢁ1): 1740 (CO); 1266 (NO).
5.1.25. Synthesis of 2-(4-fluorophenyl)-3-biphenyl-5-
methylene hydroxy isxazolidine (3c(vi))
100 (P ꢁ Q)
% Inhibitionꢂ
P
It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-fluorophenyl)nitrone (2c) (500 mg) and
allyl alcohol (0.15 mL).
where Pꢂ
/
absorbance without the test sample and Qꢂ
absorbance with test sample.
/
1H-NMR d (ppm): 2.74Á
/
2.92 (q, 2H, H4); 3.64 (d,
2H, CH2); 4.76 (t, 1H, H5); 5.12 (t, 1H, H3); 5.25 (s, 1H,
OH); 7.28 (d, 2H, ArÃH); 7.41 (d, 2H, ArÃH, BP); 7.52
(t, 1H, ArÃH, BP); 7.64 (t, 2H, ArÃH, BP); 7.77 (d, 2H,
ArÃH); 7.79 (d, 4H, ArÃH, BP).
IR (Nujol): n (cmꢁ1): 1720 (CO); 1248 (NO).
/
/
References
/
/
/
/
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