Synthesis and characterization of 5-substituted novel isoxazolidines derived from 1,3-dipolar cycloaddition of nitrones with olefins: Studies of antibacterial and antifungal activities

Article abstract of DOI:10.1081/SCC-120018773

The synthesis, antibacterial and antifungal activities of a novel series of 5-substituted isoxazolidine derivatives [3a,b(i-viii)] were described. The synthesis of title compounds was achieved via a 1,3-dipolar cycloaddition of C-(4-biphenyl)-N-(4-methylphenyl)nitrone, C-(4-biphenyl)-N-(4-chlorophenyl) nitrone with monosubstituted alkenes.

Full text of DOI:10.1081/SCC-120018773

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Synthesis and Characterization of 5-Substituted Novel
Isoxazolidines Derived from 1,3-Dipolar Cycloaddition
of Nitrones with Olefins: Studies of Antibacterial and
Antifungal Activities
K. R. Ravi Kumar a , H. Mallesha a & K. S. Rangappa a
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, India
Published online: 16 Aug 2006.
To cite this article: K. R. Ravi Kumar , H. Mallesha & K. S. Rangappa (2003) Synthesis and Characterization of 5-Substituted
Novel Isoxazolidines Derived from 1,3-Dipolar Cycloaddition of Nitrones with Olefins: Studies of Antibacterial and Antifungal
Activities, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:9, 1545-1555, DOI: 10.1081/SCC-120018773
To link to this article: http://dx.doi.org/10.1081/SCC-120018773
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1545–1555, 2003
Synthesis and Characterization of 5-Substituted
Novel Isoxazolidines Derived from 1,3-Dipolar
Cycloaddition of Nitrones with Olefins: Studies of
Antibacterial and Antifungal Activities
*
K. R. Ravi Kumar, H. Mallesha, and K. S. Rangappa
Department of Studies in Chemistry, University of
Mysore, Manasagangotri, Mysore, India
ABSTRACT
The synthesis, antibacterial and antifungal activities of a novel
series of 5-substituted isoxazolidine derivatives [3a,b(i–viii)] were
described. The synthesis of title compounds was achieved via a 1,3-
dipolar cycloaddition of C-(4-biphenyl)-N-(4-methylphenyl)nitrone,
C-(4-biphenyl)-N-(4-chlorophenyl) nitrone with monosubstituted
alkenes.
*Correspondence: K. S. Rangappa, Department of Studies in Chemistry,
University of Mysore, Manasagangotri, Mysore 570 006, India; E-mail:
rangappaks@yahoo.com.
1545
DOI: 10.1081/SCC-120018773
Copyright & 2003 by Marcel Dekker, Inc.
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1546
Kumar, Mallesha, and Rangappa
Key Words: Nitrones; Isoxazolidines; Cycloaddition; Antibacterial;
Antifungal.
Nitrones are attractive class of 1,3-dipoles, because of their
versatile synthetic applications in organic synthesis.[1–4] Recently, we
showed that nitrones are convenient class of compounds used for the
synthesis of ultimate carcinogens,[5,6] which are biologically interesting
species. The nitrone addition to unsaturated substrate has been
utilized to develop a synthesis of b-lactams,[7,8] natural products,
versatile synthetic intermediates,[9] and biologically interesting
compounds.[10]
In the interest of the above, we herein reported the synthesis and
characterization of some novel aryl nitrones. The nitrones obtained
were used to synthesize biologically interesting novel isoxazolidines,
which were tested for antibacterial and antifungal activities.
Nitrones were synthesized by the reduction of a mixture of nitro
compounds and 4-biphenyl carboxaldehyde with zinc dust using histidine
as catalyst.[11] The nitrones were found to be light sensitive and hygro-
scopic. Hence they were stored in the dark until further use, the obtained
nitrones were structurally characterized by using 1H NMR, IR, and C, H,
N, analysis.
The novel 5-substituted isoxazolidines were obtained by refluxing the
nitrones 2a and 2b with equimolar amount of monosubstituted alkenes in
toluene/xylene. The cycloaddition of all monosubstituted olefins with
nitrone showed high regioselectivity and gave 5-substituted derivatives
predominantly (Sch. 1).[3]
The major products of 5-substituted isoxazolidine derivatives were
separated on silica gel column using appropriate combination of
chloroform, hexane, benzene, and petroleum ether as eluents. The
reaction condition and the physical data of cycloadducts are given in
Table 1. All synthesized isoxazolidines were structurally characterized
1
by using IR, H NMR, and C, H, N analysis.
The results of antibacterial and antifungal activities of the mole-
cules are summarized in Tables 2 and 3. Introduction of chlorine
substituent into phenyl ring proved to be very beneficial for activity,
thus 3b(i–viii) series showed better Minimum Inhibition Concentration
(MIC) values against all tested fungi and bacteria compared to 3a(i–viii)
series.
Compounds 3a(iv), 3a(vii), 3b(iv), 3b(vi), and 3b(vii) showed better
antifungal activity compared to standard drug Nystatin against
Botrydiplodia theobromae.

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Synthesis and Characterization of Novel Isoxazolidines
1547
Scheme 1.
EXPERIMENTAL SECTION
Melting points were determined on SELACO-650 hot stage
apparatus and are uncorrected. IR (nujol) spectra were measured on
Shimadzu 8300 IR spectrophotometer, 1H NMR were recorded on
Shimadzu AMX 400-Bruker, 400 MHz spectrometer by using CDCl3 as
solvent and TMS as an internal standard (chemical shift in ꢀ ppm).
Elemental analyses were obtained on a Vario-EL instrument. Column
and TLC were done with silica gel BDH 60–120 mesh and pre-coated
silica gel plates.
Procedure for the Synthesis of C-(4-Biphenyl)-
N-(4-methylphenyl) and C-(4-Biphenyl)-
N-(4-chlorophenyl) Nitrones, 2a and 2b
Nitrones were synthesized according to the procedure we reported
earlier.[11]
Synthesis of C-(4-biphenyl)-N-(4-methylphenyl) nitrone, 2a: This was
obtained from 4-methyl nitrobenzene and 4-biphenyl carboxaldehyde as
a white crystalline solid; yield 813 mg (91%), m.p. 225ꢀC. 1H NMR
(Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.42 (s, 3H, Ar-CH3);
7.25–7.29 (d, 2H, Ar-H); 7.38–7.51 (m, 3H, Ar-H); 7.64–7.74 (m, 6H,
Ar-H); 7.95 (s, 1H, CH¼N); 8.45–8.50 (d, 2H, Ar-H). Anal. calcd.

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1548
Kumar, Mallesha, and Rangappa

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Synthesis and Characterization of Novel Isoxazolidines
1549
Table 2. The minimum antibacterial and antifungal inhibitory concentrations
(mgm/mL) of isoxazolidines 3a(i–viii).
Tested bacteria
Tested fungus
Isoxazolidines E. coli B. cereus S. aureus
A. flavus
F. moniliforme B. theobromae
Ampicillin
3a(i)
3a(ii)
5.0
70.0
50.0
70.0
50.0
60.0
70.0
50.0
70.0
3.0
70.0
2.5
100
Nystatin 12.0
40.0
20.0
14.0
60.0
50.0
20.0
40.0
40.0
60.0
40.0
20.0
21.0
60.0
50.0
40.0
20.0
40.0
40.0
20.0
40.0
110
100
70.0
100
50.0
70.0
60.0
50.0
70.0
70.0
50.0
50.0
3a(iii)
3a(iv)
30.0
40.0
3a (v)
3a(vi)
30.0
40.0
3a(vii)
3a(viii)
60.0
50.0
20.0
40.0
Table 3. The minimum antibacterial and antifungal inhibitory concentrations
(mgm/mL) of isoxazolidines 3b(i–viii).
Tested bacteria
Tested fungus
Isoxazolidines E. coli B. cereus S. aureus
A. flavus
F. moniliforme B. theobromae
Ampicillin
3b(i)
3b(ii)
5.0
60.0
50.0
60.0
70.0
70.0
50.0
60.0
70.0
3.0
100
2.5
120
100
70.0
Nystatin 12.0
30.0
20.0
14.0
40.0
30.0
40.0
30.0
40.0
50.0
30.0
20.0
21.0
40.0
30.0
40.0
20.0
40.0
20.0
20.0
30.0
120
100
3b(iii)
3b(iv)
3b(v)
30.0
40.0
50.0
110
70.0
50.0
80.0
70.0
50.0
50.0
20.0
50.0
3b(vi)
3b(vii)
3b(viii)
60.0
50.0
40.0
20.0
C20H17NO: C, 83.62; H, 5.92; N, 4.88. Found: C, 83.32; H, 5.48; N, 4.94.
IR (Nujol): ꢁ (cmÀ1): 1548 (C¼N); 1140 (NO).
Synthesis of C-(4-biphenyl)-N-(4-chlorophenyl) nitrone, 2b: This was
obtained from 4-chloronitrobenzene and 4-biphenyl carboxaldehyde as a
white crystalline solid; yield: 812 mg (96%), m.p. 307ꢀC. 1H NMR
(Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 7.44–7.49 (m, 5H,
Ar-H); 7.65–7.79 (m, 6H, Ar-H); 7.94 (s, 1H, CH¼N); 8.44–8.48 (d, 2H,
Ar-H). Anal. calcd. C19H14NOCl: C, 74.27; H, 4.56; N, 4.56. Found: C,
74.14; H, 4.72; N, 4.68. IR (Nujol): ꢁ (cmÀ1): 1572 (C¼N); 1152 (NO).

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1550
Kumar, Mallesha, and Rangappa
General Procedure for the Synthesis of
Novel Isoxazolidines, [3a,b (i–viii)]
Equimolar mixture of nitrones 2a and 2b and differentalkenes were
dissolved in 10 mL of toluene/xylene. The reaction mixture was refluxed
till the reaction completes which was monitored by TLC. The pure
products were separated by using silica gel column.
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-cyano isoxazolidines,
3a(i): Itwas obatined from equimolar mixutre of C-(4-biphenyl)- N-(4-
1
methylphenyl) nitrone 2a (500 mg) and acrylonitrile (0.31 mL). H NMR
(Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.28 (s, 3H, Ar-CH3);
2.66–2.82 (q, 2H, H4); 4.45 (t, 1H, H5); 5.08 (t, 1H, H3); 6.92 (d, 2H,
Ar-H); 7.42 (d, 2H, Ar-H (BP); 7.52 (t, 1H, Ar-H (BP); 7.56 (d, 2H,
Ar-H); 7.63 (t, 2H, Ar-H (BP); 7.69 (d, 4H, Ar-H (BP). Anal. calcd.
for C23H20N2O: C, 81.18; H, 5.88; N, 8.23. Found: C, 81.08; H, 5.92;
N, 8.08. IR (Nujol): ꢁ (cmÀ1): 1748 (CO); 1278 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-phenyl isoxazoli-
dines, 3a(ii): It was obtained from equimolar mixture of C-(4-biphenyl-
N-(4-methylphenyl) nitrone 2a (500 mg) and styrene (0.25 mL). 1H NMR
(Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.28 (s, 3H, Ar-CH3);
2.69–2.85 (q, 2H, H4); 5.03 (t, 1H, H5); 5.12 (t, 1H, H3); 6.92 (d, 2H,
Ar-H); 7.29–7.41 (m, 5H, Ar-H); 7.42 (d, 2H, Ar-H (BP)); 7.52 (t, 1H, Ar-H
(BP); 7.55 (d, 2H, Ar-H); 7.64 (t, 2H, Ar-H (BP)); 7.69 (d, 4H, Ar-H
(BP)). Anal. calcd. for C28H25NO: C, 85.93; H, 6.39; N, 3.58. Found: C,
85.68; H, 6.26; N, 3.72. IR (Nujol): ꢁ (cmÀ1): 1712 (CO); 1246 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-benzoate isoxazoli-
dines, 3a(iii): Itwas obatined from equimolar mixutre of C-(4-biphe-
nyl)-N-(4-methylphenyl) nitrone 2a (500 mg) and vinyl benzoate
(0.26 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm):
2.29 (s, 3H, Ar-CH3); 2.65–2.84 (q, 2H, H4); 4.72 (t, 1H, H5); 5.12 (t,
1H, H3); 6.93 (d, 2H, Ar-H); 7.28–7.50 (m, 3H, Ar-H); 7.42 (d, 2H, Ar-H,
BP); 7.52 (t, 1H, Ar-H, BP); 7.55 (d, 2H, Ar-H); 7.64 (t, 2H, Ar-H, BP);
7.79 (d, 4H, Ar-H, BP). 7.81 (d, 2H, Ar-H). Anal. calcd. for C29H25NO3:
C, 80; H, 5.75; N, 3.22. Found: C, 80.08; H, 5.62; N, 3.14. IR (Nujol):
ꢁ (cmÀ1): 1752 (C¼O); 1732 (CO); 1270 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-ethylate isoxazoli-
dines, 3a(iv): Itwas obatined from equimolar mixutre of C-(4-biphe-
nyl)-N-(4-methylphenyl) nitrone 2a (500 mg) and ethyl acrylate
(0.17 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm):
0.93 (t, 3H, CH3); 2.28 (s, 3H, Ar-CH3); 2.66–2.84 (q, 2H, H4); 3.62
(q, 2H, CH2); 4.46 (t, 1H, H5); 5.12 (t, 1H, H3); 6.92 (d, 2H, Ar-H);
7.42 (d, 2H, Ar-H, BP); 7.52 (t, 1H, Ar-H, BP); 7.55 (d, 2H, Ar-H);

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Synthesis and Characterization of Novel Isoxazolidines
1551
7.64 (t, 2H, Ar-H, BP); 7.79 (d, 4H, Ar-H, BP). Anal. calcd. for
C25H25NO3: C, 77.52; H, 6.46; N, 3.62. Found: C, 77.46; H, 6.36; N,
3.44. IR (Nujol): ꢁ (cmÀ1): 1726 (C¼O); 1708 (CO); 1240 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-methylene acetate
isoxazolidine, 3a(v): It was obtained from equimolar mixture of
C-(4-biphenyl)-N-(4-methylphenyl) nitrone 2a (500 mg) and allyl acetate
(0.23 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.28
(s, 3H, Ar-CH3); 2.42 (d, 2H, CH2); 2.64–2.82 (q, 2H, H4); 3.42 (s, 3H,
OCH3); 4.25 (t, 1H, H5); 5.12 (t, 1H, H3); 6.92 (d, 2H, Ar-H); 7.42
(d, 2H, Ar-H, BP); 7.52 (t, 1H, Ar-H, BP); 7.53 (d, 2H, Ar-H); 7.64 (t,
2H, Ar-H, BP); 7.79 (d, 4H, Ar-H, BP). Anal. calcd. for C25H25NO3: C,
77.72; H, 6.22; N, 3.62. Found: C, 77.58; H, 6.16; N, 3.58. IR (Nujol): ꢁ
(cmÀ1): 1720 (CO); 1250 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-methylene hydroxy
isoxazolidines, 3a(vi): It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methylphenyl) nitrone 2a (500 mg) and allyl alcohol
(0.24 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm):
2.28 (s, 3H, Ar-CH3); 2.66–2.85 (q, 2H, H4); 3.64 (d, 2H, CH2); 4.76
(t, 1H, H5); 5.15 (t, 1H, H3); 5.25 (s, 1H, OH); 6.92 (d, 2H, Ar-H);
7.42 (d, 2H, Ar-H, BP); 7.52 (t, 1H, Ar-H, BP); 7.55 (d, 2H, Ar-H);
7.63 (t, 2H, Ar-H, BP); 7.79 (d, 4H, Ar-H, BP). Anal. calcd. for
C23H23NO2: C, 80; H, 6.66; N, 4.06. Found: C, 80.04; H, 6.52; N, 4.12.
IR (Nujol): ꢁ (cmÀ1): 1728 (CO); 1262 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-(3-cyclohexene)
isoxazolidines, 3a(vii): It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-methylphenyl) nitrone 2a (500 mg) and 4-vinyl-1-cyclo-
hexene (0.21 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3);
ꢀ (ppm): 1.38–1.42 (m, 2H, CH2, cyclohexene); 1.52 (s, 1H, cyclohexene);
2.26 (s, 3H, Ar-H); 2.28–2.31 (m, 2H, cyclohexene); 2.33–2.38 (m, 2H,
cyclohexene); 2.65–2.83 (q, 2H, H4); 4.82 (m, 1H, CH); 5.12 (t, 1H, CH);
5.6–5.66 (m, 2H, cyclohexene); 6.92 (d, 2H, Ar-H); 7.42 (d, 2H, Ar-H, BP);
7.52 (t, 1H, Ar-H, BP); 7.55 (d, 2H, Ar-H); 7.63 (t, 2H, Ar-H, BP); 7.74
(d, 4H, Ar-H, BP). Anal. calcd. for C28H29NO: C, 85.06; H, 7.34; N,
3.54. Found: C, 85.12; H, 7.18; N, 3.48. IR (Nujol): ꢁ (cmÀ1): 1744 (CO);
1270 (NO).
Synthesis of 2-(4-methylphenyl)-3-(4-biphenyl)-5-methylate isoxazoli-
dines, 3a(viii): Itwas obatined from equimolar mixutre of C-(4-biphe-
nyl)-N-(4-methylphenyl) nitrone 2a (500 mg) and methyl acrylate
(0.17 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm):
2.28 (s, 3H, Ar-CH3); 2.67–2.85 (q, 2H, H4); 3.41 (s, 3H, OCH3); 4.44
(t, 1H, CH); 5.14 (t, 1H, CH); 6.92 (d, 2H, Ar-H); 7.43 (d, 2H, Ar-H, BP);
7.53 (t, 1H, Ar-H, BP); 7.55 (d, 2H, Ar-H); 7.64 (t, 2H, Ar-H, BP); 7.73

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Kumar, Mallesha, and Rangappa
(d, 4H, Ar-H, BP). Anal. calcd. for C24H23NO3: C, 77.2; H, 6.17; N, 3.75.
Found: C, 77.12; H, 6.12; N, 3.58. IR (Nujol): ꢁ (cmÀ1): 1726 (C¼O);
1708 (CO); 1240 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-cyano isoxazolidines,
3b(i): Itwas obatined from equimolar mixutre of C-(4-biphenyl)- N-(4-
1
chlorophenyl) nitrone 2b (500 mg) and acrylonitrile (0.30 mL). H NMR
(Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.83–3.01 (q, 2H, H4);
4.46 (t, 1H, H5); 5.10 (t, 1H, H3); 7.28 (d, 2H, Ar-H); 7.41 (d, 2H, Ar-H
(BP)); 7.52 (t, 1H, Ar-H (BP)); 7.64 (t, 2H, Ar-H (BP)); 7.77 (d, 2H,
Ar-H); 7.69 (d, 4H, Ar-H (BP)). Anal. calcd. C22H17N2OCl: C, 73.3;
H, 4.72; N, 7.28. Found: C, 73.08; H, 4.88; N, 7.64. IR (Nujol): ꢁ
(cmÀ1): 1734 (CO); 1274 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-phenyl isoxazolidines,
3b(ii): Itwas obatined from equimolar mixut re of C-(4-biphenyl)- N-(4-
chlorophenyl) nitrone 2b (500 mg) and styrene (0.25 mL). 1H NMR
(Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.88–3.06 (q, 2H, H4);
5.05 (t, 1H, H5); 5.14 (t, 1H, H3); 7.29 (d, 2H, Ar-H); 7.29–7.41 (m, 5H,
Ar-H); 7.42 (d, 2H, Ar-H (BP)); 7.52 (t, 1H, Ar-H (BP)); 7.64 (t, 2H,
Ar-H (BP)); 7.77 (d, 2H, Ar-H); 7.79 (d, 4H, Ar-H (BP)). Anal. calcd.
C27H22NOCl: C, 78.83; H, 5.35; N, 3.41. Found: C, 78.68; H, 5.52; N,
3.28. IR (Nujol): ꢁ (cmÀ1): 1700 (CO); 1240 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-benzoate isoxazoli-
dines, 3b(iii): It was obtained from equimolar mixture of C-(4-biphenyl)-
N-(4-chlorophenyl) nitrone 2b (500 mg) and vinyl benzoate (0.15 mL).
1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.85–3.03 (q,
2H, H4); 4.72 (t, 1H, H5); 5.15 (t, 1H, H3); 7.28 (d, 2H, Ar-H); 7.29–7.50
(m, 3H, Ar-H); 7.42 (d, 2H, Ar-H, BP); 7.53 (t, 1H, Ar-H, BP); 7.64 (t, 2H,
Ar-H, BP); 7.78 (d, 2H, Ar-H); 7.79 (d, 4H, Ar-H, BP). 7.81 (d, 2H, Ar-H).
Anal. calcd. C28H22NO3Cl: C, 73.85; H, 4.86; N, 3.1. Found: C, 73.58; H,
4.58; N, 3.08. IR (Nujol): ꢁ (cmÀ1): 1738 (C¼O); 1730 (CO); 1268 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-ethylate isoxazoli-
dines, 3b(iv): It was obtained from equimolar mixture of C-(4-biphenyl)-
N-(4-chlorophenyl) nitrone 2b (500 mg) and ethyl acrylate (0.21 mL).
1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 0.93 (t, 3H,
CH3); 2.84–3.02 (q, 2H, H4); 3.62 (q, 2H, CH2); 4.44 (t, 1H, H5); 5.13
(t, 1H, H3); 7.28 (d, 2H, Ar-H); 7.41 (d, 2H, Ar-H, BP); 7.52 (t, 1H, Ar-H,
BP); 7.64 (t, 2H, Ar-H, BP); 7.77 (d, 2H, Ar-H); 7.79 (d, 4H, Ar-H, BP).
Anal. calcd. C24H22NO3Cl: C, 70.76; H, 5.41; N, 3.44. Found: C, 70.62; H,
5.36; N, 3.38. IR (Nujol): ꢁ (cmÀ1): 1722 (C¼O); 1700 (CO); 1232 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-methylene acetate iso-
xazolidines, 3b(v): It was obtained from equimolar mixture of C-(4-biphe-
nyl)-N-(4-chlorophenyl) nitrone 2b (500 mg) and allyl acetate (0.1 mL).

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Synthesis and Characterization of Novel Isoxazolidines
1553
1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.42 (d, 2H,
CH2); 2.84–3.02 (q, 2H, H4); 3.42 (s, 3H, OCH3); 4.26 (t, 1H, H5); 5.12 (t,
1H, H3); 7.26 (d, 2H, Ar-H); 7.41 (d, 2H, Ar-H, BP); 7.52 (t, 1H, Ar-H,
BP); 7.64 (t, 2H, Ar-H, BP); 7.77 (d, 2H, Ar-H); 7.79 (d, 4H, Ar-H, BP).
Anal. calcd. C24H22NO3Cl: C, 70.76; H, 5.40; N, 3.44. Found: C, 70.58;
H, 5.38; N, 3.38. IR (Nujol): ꢁ (cmÀ1): 1740 (CO); 1266 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-methylene hydroxy
isoxazolidine, 3b(vi): It was obtained from equimolar mixture of C-(4-
biphenyl)-N-(4-chlorophenyl)nitrone 2b (500 mg) and allyl alcohol
(0.15 mL). 1H NMR (Bruker-AMX-400, 400 MHz, CDCl3; ꢀ (ppm):
2.74–2.92 (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, Ar-H); 7.41 (d, 2H, Ar-H, BP); 7.52 (t,
1H, Ar-H, BP); 7.64 (t, 2H, Ar-H, BP); 7.77 (d, 2H, Ar-H); 7.79 (d, 4H,
Ar-H, BP). Anal. calcd. C22H20NO2Cl: C, 72.33; H, 5.48; N, 3.84. Found:
C, 72.18; H, 5.38; N, 3.72. IR (Nujol): ꢁ (cmÀ1): 1720 (CO); 1248 (NO).
Synthesis
of
2-(4-chlorophenyl)-3-(4-biphenyl)-5-(3-cyclohexene)
isoxazolidines, 3b(vii): It was obtained from equimolar mixture of
C-(4-biphenyl)-N-(4-chlorophenyl) nitrone 2b (500 mg) and 4-vinyl-1-
1
cyclohexene (0.25 mL). H NMR (Bruker-AMX-400, 400 MHz, CDCl3);
ꢀ (ppm): 1.38–1.42 (m, 2H, CH2, cyclohexene); 1.52 (s, 1H, cyclohexene);
2.28–2.31 (m, 2H, cyclohexene); 2.33–2.38 (m, 2H, cyclohexene);
2.85–3.03 (q, 2H, H4); 4.82 (m, 1H, CH); 5.14 (t, 1H, H3); 5.6–5.66 (m,
2H, cyclohexene); 7.28 (d, 2H, Ar-H); 7.41 (d, 2H, Ar-H, BP); 7.52 (t, 1H,
Ar-H, BP); 7.63 (t, 2H, Ar-H, BP); 7.77 (d, 2H, Ar-H); 7.79 (d, 4H, Ar-H,
BP). Anal. calcd. C27H26NOCl: C, 78.07; H, 6.26; N, 3.37. Found: C,
78.14; H, 6.18; N, 3.18. IR (Nujol): ꢁ (cmÀ1): 1730 (CO); 1260 (NO).
Synthesis of 2-(4-chlorophenyl)-3-(4-biphenyl)-5-methyl isoxazolidines,
3b(viii): Itwas obtained from equimolar mixture of C-(4-biphenyl)-N -(4-
chlorophenyl) nitrone 2b (500 mg) and methyl acrylate (0.35 mL).
1H NMR (Bruker-AMX-400, 400 MHz, CDCl3); ꢀ (ppm): 2.87–3.05 (q,
2H, H4); 3.41 (s, 3H, OCH3); 4.45 (t, 1H, H5); 5.12 (t, 1H, H3); 7.28 (d,
2H, Ar-H); 7.41 (d, 2H, Ar-H, BP); 7.52 (t, 1H, Ar-H, BP); 7.64 (t, 2H,
Ar-H, BP); 7.77 (d, 2H, Ar-H); 7.79 (d, 4H, Ar-H, BP). Anal. calcd.
C23H20NO3Cl: C, 70.23; H, 5.09; N, 3.56. Found: C, 70.14; H, 5.12; N,
3.42. IR (Nujol): ꢁ (cmÀ1): 1745 (CO); 1278 (NO).
Microorganisms Used for the Antimicrobial Activity
Bacteria: Escherichia coli, Bacillus cereus, and Staphylococcus aureus.
Fungus: Aspergillus flavus, Fusarium moniliforme and Botrydiplodia
theobromae.

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1554
Kumar, Mallesha, and Rangappa
Determination of Antibacterial Activity
The isoxazolidines were tested for antibacterial activity by serial
tube dilution technique[12,13] at different concentrations (10, 20. . . . . .
150 mg/mL) against E. coli (Gram-negative), B. cereus (Gram-positive)
and S. aureus (Gram-positive) microbes. Ampicillin 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 calibrated to 0.1 mL. After incubat-
ing all the tubes at 37ꢀC for 24 h, their absorbance was recorded at
640 nm along with ampicillin. Percentage of inhibition was calculated
as follows,
100ðP À QÞ
% Inhibition ¼
P
where P ¼ absorbance without the test sample and Q ¼ absorbance with
test sample. Then the minimum inhibitor concentration (MIC) was
recorded in mg/mL.
REFERENCES
1. Black, D.St.C.; Crozier, R.F.; Davis, V.C. 1,3-Dipolar cycloaddition
reactions of nitrones. Synthesis 1975, 4, 205–221.
2. Banerji, A.; Sahu, A.J. Recent advances in cycloaddition reactions of
nitrones. Scient. Indus. Res. 1986, 45, 355–369.
3. Torsell, K.B.G. Nitrile Oxides, Nitrone and Nitronates in Organic
Synthesis; VCH: New York, Weinheim, 1988.
4. Banerji, A.; Basu, S. Cycloaddition of C,N-diarylnitrones to 2-bute-
nolide; synthesis of 2,3,6,6a-tetrahydrofuro[3,4-d ]-isoxazol-4-(3aH)-
one. Tetrahedron 1992, 48, 3335–3344.
5. Mallesha, H.; Ravikumar, K.R.; Mantelingu, K.; Rangappa, K.S.
Synthesis and characterization of model ultimate carcinogens/
metabolites derived from lead tetracetate oxidation of arylnitrones;
20-deoxyguanosin adducts. Synthesis 2001, 10, 1459–1461.
6. Mallesha, H.; Ravikumar, K.R.; Rangappa, K.S. Synthesis of
N-acetoxy-N-benzoyl-2-aminofluorene, an ultimate carcinogens by
LTA oxidation of a-phenyl-N-(2-aminofluorenyl) nitrone, and
N-(20-deoxyguanosin-8-yl)-2-aminofluorene. Synthesis 2001, 16,
2415–2418.

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Synthesis and Characterization of Novel Isoxazolidines
1555
7. Padwa, A.; Koehler, K.F.; Rodringuez, A. Nitrone cycloaddition.
A new approach to b-lactams. J. Am. Chem. Soc. 1981, 103,
4974–4975.
8. Padwa, A.; Koehler, K.F.; Rodringuez, A. New synthesis of b-lac-
tams based on nitrone cycloaddition to nitroalkenes. J. Org. Chem.
1984, 49, 282–288.
9. Padwa, A. 1,3-Dipolar Cycloadditon Chemistry; John Wiley and
Sons: New York, 1984; Vol. 1 and 2.
10. Ochiai, M.; Obayashi, M.; Morita, K. A new 1,3-dipolar cycloaddi-
tion reaction synthesis of some isoxazolidines derivatives.
Tetrahedron 1967, 23, 2641–2648.
11. Mallesh, H.; Ravikumar, K.R.; Vishukumar, B.K.; Mantelingu, K.;
Rangappa, K.S. Histidine as a catalyst in organic synthesis: a facile
in situ synthesis of a,N-diaryl nitrones. Proc. Indian. Acad. Sci.
(Chem. Sci.). 2001, 1113 (4), 291.
12. Collins, C.H.; Lyne, P.M. Microb. Methods; Butterworth: London,
1970; 414–419.
13. Mullen, G.B.; Decory, T.R.; Mitchell, J.T.; Allen, S.D.; Kinsolving,
C.R.; Gergiev, V.St. Studies on antifungal agents. Novel substituted
3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-alkylisoxazolidine deri-
vatives. J. Med. Chem. 1988, 31, 2008–2014.
Received in the UK April 17, 2002

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