Synthesis and Antimicrobial Evaluation of New Pyrrolo-isoxazolidine Derivatives

Article abstract of DOI:10.14233/ajchem.2019.21726

In the present study, pyrrolo-isoxazolidines 3(a-l) and 4(a-e), 4g, 4i, 4j have been synthesized by using the 1,3-dipolar cycloaddition reactions of nitrones 1(a-l) with ester substituted N-aryl maleimide (2b). These heterocycles have been obtained in cis and trans diastereomeric forms. The structures of newly synthesized heterocycles have been confirmed from their spectroscopic parameters such as IR,¹H NMR,¹³C NMR and ESI-MS. The in vitro antimicrobial evaluation of these compounds were also investigated. Most of the prepared heterocycles showed significant antimicrobial properties. C3-phenyl substituted products exhibited the remarkable antibacterial behaviours while C3-thienyl/furyl substituted heterocycles proved themselves potent antifungal agents.

Full text of DOI:10.14233/ajchem.2019.21726

Asian Journal of Chemistry; Vol. 31, No. 1 (2019), 220-228
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21726
Synthesis and Antimicrobial Evaluation of New Pyrrolo-isoxazolidine Derivatives
*
MOHAMAD YUSUF , SHEHNEELA and BALDEV SINGH
Department of Chemistry, Punjabi University, Patiala-147002, India
*Corresponding author: E-mail: yusuf_sah04@yahoo.co.in
Received: 26 September 2018;
Accepted: 20 October 2018;
Published online: 30 November 2018;
AJC-19185
In the present study, pyrrolo-isoxazolidines 3(a-l) and 4(a-e), 4g, 4i, 4j have been synthesized by using the 1,3-dipolar cycloaddition
reactions of nitrones 1(a-l) with ester substituted N-aryl maleimide (2b). These heterocycles have been obtained in cis and trans
diastereomeric forms. The structures of newly synthesized heterocycles have been confirmed from their spectroscopic parameters such as
1
IR, H NMR, 13C NMR and ESI-MS. The in vitro antimicrobial evaluation of these compounds were also investigated. Most of the
prepared heterocycles showed significant antimicrobial properties. C3-phenyl substituted products exhibited the remarkable antibacterial
behaviours while C3-thienyl/furyl substituted heterocycles proved themselves potent antifungal agents.
Keywords: Nitrones, N-Aryl-maleimide, Cycloaddition, Pyrrolo-isoxazolidines, Antimicrobial activities.
The most significant aspect of the above 1,3-dipolar cyclo-
addition reaction is their capability to generate the three adjoining
stereogenic centres through the regioselective and stereoselec-
tive way [12]. These aspects have attracted the much attentions
of the researchers to utilize these reactions in the formation of
five membered heterocyclic products which are realized in
the cis and trans diastereomeric forms [13,14]. The noticeable
characteristic of these processes has been the incorporation of
multiple sterocentres in a single stage reactions [15].
The five membered heterocycles having nitrogen and
oxygen at the adjacent positions are called as isoxazoles while
their half reduced and tetrahydro forms are regarded as isoxazo-
lines and isoxazolidines, respectively [16-18]. The cycloa-
ddition reactions of nitrones with N-aryl-maleimides is an
attractive and versatile protocol for the synthesis of regio and
stereoselective pyrrolo-isoxazolidine scaffolds [19,20]. The
reactions of nitrones with alkene occur via the involvement of
4π and 2π-electrons system which suggested their occurrence
under the thermal modes [5].Pyrrolo-isoxazolidine derivatives
exhibit a wide diversity of biological activities like antibacterial
[21], antifungal [22], anti-inflammatory [23], anticancer [24],
anticonvulsant [25], antitubercular [26], anti-influenza [27],
anti-HIV [28]and antistress [29]. Some of these heterocycles
are also reported as broad spectrum antibiotics due to their
actions against the Gram-positive bacteria [30].
INTRODUCTION
The studies of cycloaddition reactions are concerned with
crucial group of organic processes, which are associated with
immense synthetic applications. These protocols take place by
the involvement of cyclic transition state and proceed through
the concerted mechanism [1]. The [3+2]-cycloaddition reactions
are one of the very important tools for the formation of five
membered heterocycles [2]. Nitrones and azomethine ylides are
the useful 1,3-dipoles as they lead to the generation of numerous
hetrocycles by reacting with variety of dipolarophiles. The gene-
rally used dipolarophiles in these reactions are the activated alkene
and alkyne derivatives [3]. Huisgen has suggested that these
reactions occur through concerted mechanism and they involve
the stereospecificity and regioselectivity in their pathways [4].
The commonly used 1,3-dipoles are nitrones, azomethine imines,
azomethine ylides, diazoalkanes, azides, nitrile oxides, nitrile
imines, nitrile ylides and ozone [5].Among these dipoles, nitrones
are the very important synthones that are found to play a vital
role in the field of heterocyclic synthesis [6]. The important
feature of nitrones is that they may react with variety of dipolaro-
philes to provide various ring sized products from three mem-
bered to macrocycles. These intermediates are prepared by using
the condensation reaction of N-phenylhydroxylamine with appro-
priate carbonyl compounds [7-11].
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Vol. 31, No. 1 (2019)
Synthesis and Antimicrobial Evaluation of New Pyrrolo-isoxazolidine Derivatives 221
In the literature 1,3-dipolar cycloaddition reactions of
N-aryl-maleimide with variety of nitrones have been fully exp-
loited bearing the various substituent upon the N-aryl group of
maleimide as well as on the N-imino aryl/heteroaryl rings of
the nitrone [12-14,31]. Thus, the present study has been taken
up with a view to fill the gap in the literature and to explore
the antimicrobial studies of final heterocyclic products [7].
By considering these aspects in view, we have focused
our present researches upon the extensive 1,3-dipoar cyclo-
addition reactions of ester substituted N-aryl maleimide with
variously substituted N-imino aryl nitrones in order to obtain
new pyrrolo-isoxazolidines. The major interest behind the
synthesis of these hetreocycles was to investigate the effect of
the nature of C3-aryl ring upon the antimicrobial properties of
the proposed heterocycles.
mixture was decomposed by the slow addition to the crushed
ice which upon appropriate shaking provided a light yellow
solid. This product was further crystallized from hexane:ethyl
acetate (1:1) to provide pure compound 2b. White solid; m.p.
150-152 °C; yield: 70 %; IR (KBr, νmax, cm–1): 1696, 1710
(C=O) and 1750 (ester C=O); 1H NMR (400 MHz, CDCl3): δ
8.14 (2H, dd, Jm,o = 1.7, 7.1 Hz, H-3′, 5′), 7.51 (2H, dd, Jm,o
=
2.2, 9.0 Hz, H-2′, 6′), 6.88 (2H, s, H-3, 4), 3.93 (3H, s, OCH3);
ESI-MS: m/z 232 (M+1, 15 %), 231 (M+, 100 %);Anal. calcd.
(%) for C12H9NO4: C, 62.34; H, 3.92; N, 6.06; Found (%): C,
62.09; H, 3.90; N, 6.03.
Synthesis of pyrrolo-isoxazolidines 3a and 4a: A mixture
of nitrone 1a (0.8 g, 0.004 mol) and compound 2b (1.0 g,
0.004 mol) was vigorously refluxed by using dry toluene (25.0
mL) as the solvent. The reaction mixture was allowed to
refluxed for 4 h when whole of the reactant was converted
into products (as checked by TLC). The resulting mixture was
concentrated under vacuum to provide a mass, which was
loaded over a silica-gel column (100-200 mesh) packed in
pure hexane. Further, elution of column with hexane:EtOAc
(2:1) yielded two new products 3a and 4a.
EXPERIMENTAL
The melting points reported are uncorrected and checked
with the open capillary method in paraffin wax. Infrared (IR)
spectra were recorded on a Perkin Elmer FT-IR spectrophoto-
meter with KBr pellets. Waters ESI-MS was used to obtain
the mass spectra of the prepared compounds. Both 1H NMR
and 13C NMR spectra of the given compounds were recorded
on the Bruker Spectrometer at 400 MHz and 100 MHz, respec-
tively. In the NMR scanning tetramethylsilane was added
in the form of standard molecule. The progress of the given
reactions has been monitored with the help of TLC plates,
which were coated with silica gel. The iodine vapours were
used as the visualizing agent for the TLC plates. The nitrones
1(a-l) were prepared and identified according to the literature
methods [32-34].
General procedure for the synthesis of N-aryl nitrones:
A mixture of nitrobenzene (5.0 g, 0.040 mol), ammonium
chloride (2.5 g, 0.046 mol) and H2O (100.0 mL) was mechani-
cally stirrred for 1 h and zinc dust (5.9 g, 0.090 mol) was
slowly added to this mixture. Zinc dust was added in such a
way so that temperature of the reaction mixture could not rise
above the 60-70 °C. The formation of pale yellow reaction
mixture after the addition of whole zinc dust indicated the
complete reduction of nitrobenzene to N-phenylhydroxylamine.
The resulting mixture was filtered and thoroughly washed with
warm water. The equimolar quantity of aromatic aldehydes
(a-l) and chloroform (15 mL) were added to the filtrates and
the mixture was stirred till solids were formed. The crude subs-
tances were purified by their crystallization in MeOH, which
finally yielded the pure nitrones 1(a-l) [32-34].
General procedure for the synthesis of methyl 4-(2,5-
dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate: To a well stirred
solution of maleic anhydride (2.0 g, 0.020 mol) and toluene
(20 mL) was slowly added methyl-4-aminobenzoate (3 g, 0.020
mol). After 1 h a solid substance was separated out which
was filtered and dried under pressure. At the end maleanilic
acid (2a) was realized in the pure form by performing its
crystallization in EtOH (yellow solid; yield: 4.0 g, 80 %, m.p.:
200-202 °C). Further the mixture of maleanilic acid 2a (3.0 g,
0.012 mol), sodium acetate (0.5 g, 0.006 mol) and acetic
anhydride (20.0 mL) was refluxed for 2 h on a water bath.
After the completion of reaction (as checked by TLC), the
cis-Methyl-4-[(3H,3aH,6aH)-4,6-dioxo-2,3-diphenyl-
hexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl]benzoate (3a):
Off white solid; m.p. 186-188 °C; yield: 37 %; IR (KBr, νmax
,
cm–1): 1691, 1716 (C=O), 1739 (ester C=O), 2951 (aliphatic
C-H) and 3290 (aromatic C-H); 1H NMR (400 MHz, DMSO-
d6): δ 7.87 (2H, dt, Jp,o = 1.1, 7.3 Hz, H-3′″, 5′″), 7.66 (2H, d,
Jo = 7.9 Hz, H-2′″, 6′″), 7.46 (2H, d, Jo = 7.5 Hz, H- 2″, 6″),
7.21 (3H, m, H-3″, 4″, 5″), 6.98 (3H, m, H-3′, 4′, 5′), 6.81
(2H, dd, Jm,o = 2.1, 7.3 Hz, H-2′, 6′), 5.17 (1H, d, J3,3a = 8.0
Hz, H-3), 5.06 (1H, d, J6a,3a = 6.80 Hz, H-6a), 3.93 (1H, dd,
J3a,3 = 8.0 Hz, J3a,6a = 6.4 Hz, H-3a), 3.88 (3H, s, OCH3); 13C
NMR (100 MHz, DMSO-d6): δ 169.91, 168.32 (C=O), 167.34
(ester C=O), 147.96 (C-1′″), 145.42 (C-1′), 131.66 (C-4′″),
128.64 (C-1″), 128.41 (C-3′″, 5′″), 127.58 (C-2′″, 6′″), 126.38
(C-3″, 5″), 124.59 (C-2″, 6″), 123.07 (C-3′, 5′), 121.79 (C-
4″), 119.54 (C-4′), 116.84 (C-2′, 6′), 76.82 (C-6a), 64.39 (C-
3), 51.86 (OCH3), 48.56 (C-3a); ESI-MS: m/z 429 (M+1, 27
%), 428 (M+, 100 %); Anal. calcd. (%) for C25H20N2O5: C,
70.09; H, 4.71; N, 6.54; Found (%): C, 69.81; H, 4.73; N,
6.51.
trans-Methyl-4-[(3H,3aH,6aH)-4,6-dioxo-2,3-diphenyl-
hexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl]benzoate (4a):
Off white solid; m.p. 168-170 °C; yield: 20 %; IR (KBr, νmax
,
cm–1): 1696, 1714 (C=O), 1740 (ester C=O), 2957 (aliphatic
C-H) and 3288 (aromatic C-H); 1H NMR (400 MHz, DMSO-
d6): δ 7.84 (2H, dd, Jp,o = 0.8, 7.6 Hz, H-3′″, 5′″), 7.62 (2H, d,
Jo = 8.1 Hz, H-2′″, 6′″), 7.43 (2H, d, Jo = 7.7 Hz, H- 2″, 6″),
,
7.23 (3H, m, H-3″, 4″ 5″), 6.94 (3H, m, H- 3′, 4′, 5′), 6.89
(2H, dd, Jm,o = 2.8, 7.2 Hz, H-2′, 6′), 5.78 (1H, s, H-3), 5.23
(1H, d, J6a,3a = 6.7 Hz, H-6a), 4.13 (1H, d, J3a,6a = 6.7 Hz), 3.89
(3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ 168.32,
167.68 (C=O), 166.82 (ester C=O), 149.23 (C-1′″), 143.16
(C-1′), 130.51 (C-4′″), 130.13 (C-1″), 129.17 (C-3′″, 5′″),
128.24 (C-2′″, 6′″), 125.09 (C-3″, 5″), 124.47 (C-2″, 6″),
123.27 (C-3′, 5′), 120.46 (C-4″), 118.13 (C-4′), 116.96 (C-2′,
6′), 77.89 (C-6a), 64.78 (C-3), 51.35 (OCH3), 49.26 (C-3a);
ESI-MS: m/z 451 (M+Na, 98 %), 429 (M+1, 32 %); Anal.

222 Yusuf et al.
Asian J. Chem.
calcd. (%) for C25H20N2O5: C, 70.09; H, 4.71; N, 6.54; Found
(%): C, 70.37; H, 4.69; N, 6.49.
1H NMR (400 MHz, DMSO-d6): δ 10.37 (1H, s, OH), 7.86
(2H, dd, Jp,o = 0.6, 7.9 Hz, H-3′″, 5′″), 7.63 (2H, d, Jo = 7.2 Hz,
H-2′″, 6′″), 7.47 (2H, d, Jo = 7.5 Hz, H-5″, 6″), 7.18 (2H, t, Jo
= 7.0 Hz, H-2″, 4″), 6.91 (3H, m, H- 3′, 4′, 5′), 6.78 (2H, dd,
Jm,o = 2.4, 7.7 Hz, H-2′, 6′), 5.23 (1H, d, J3,3a = 8.2 Hz, H-3),
5.16 (1H, d, J6a,3a = 6.2 Hz, H-6a), 3.88 (1H, dd, J3a,3 = 8.2 Hz,
J3a,6a = 6.2 Hz, H-3a), 3.85 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO-d6): δ 168.96, 167.20 (C=O), 166.78 (ester C=O),
153.82 (C-3″), 148.08 (C-1′″), 144.64 (C-1′), 131.81 (C-4′″),
129.73 (C-1″), 129.03 (C-3′″, 5′″), 128.46 (C-2′″, 6′″), 125.63
(C-5″), 124.84 (C-3′, 5′), 123.34 (C-4′), 120.68 (C-6″), 119.03
(C-2′, 6′), 117.87 (C-2″), 114.71 (C-4″), 76.84 (C-6a), 64.86
(C-3), 52.09 (OCH3), 49.08 (C-3a); ESI-MS: m/z 445 (M+1,
27 %), 444 (M+, 100 %); Anal. calcd. (%) for C25H20N2O6: C,
67.56; H, 4.54; N, 6.30; Found (%): C, 67.83; H, 4.52; N,
6.33.
trans-Methyl-4-[(3H,3aH,6aH)-3-(3-hydroxyphenyl)-
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl]benzoate (4c): Off white solid; m.p. 145-147 °C; yield:
26 %; IR (KBr, νmax, cm–1): 1698, 1714 (C=O), 1742 (ester
C=O), 2950 (aliphatic C-H), 3289 (aromatic C-H) and 3409
(O-H); 1H NMR (400 MHz, DMSO-d6): δ 10.49 (1H, s, OH),
7.82 (2H, dd, Jp,o = 0.8, 7.1 Hz, H-3′″, 5′″), 7.67 (2H, d, Jo =
7.6 Hz, H-2′″, 6′″), 7.42 (2H, d, Jo = 7.8 Hz, H- 5″, 6″), 7.19
(2H, t, Jo = 7.2 Hz, H-2″, 4″), 6.92 (3H, m, H- 3′, 4′, 5′), 6.75
(2H, dd, Jm,o = 2.5, 7.1 Hz, H-2′, 6′), 5.80 (1H, s, H-3), 5.30
(1H, d, J6a,3a = 6.4 Hz, H-6a), 4.10 (1H, d, J3a,6a = 6.4 Hz, H-
3a), 3.86 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ
168.02, 167.43 (C=O), 166.01 (ester C=O), 154.43 (C-3″),
148.94 (C-1′″), 144.08 (C-1′), 132.63 (C-4′″), 129.05 (C-1″),
128.84 (C-3′″, 5′″), 128.32 (C-2′″, 6′″), 126.20 (C-5″), 124.17
(C-3′, 5′), 123.79 (C-4′), 121.26 (C-6″), 120.06 (C-2′, 6′),
118.09 (C-2″), 114.22 (C-4″), 76.13 (C-6a), 65.94 (C-3), 51.34
(OCH3), 48.65 (C-3a); ESI-MS: m/z 446 (M+2, 12 %), 445
(M+1, 100 %); Anal. calcd. (%) for C25H20N2O6: C, 67.56; H,
4.54; N, 6.30; Found (%): C, 67.35; H, 4.56; N, 6.26.
Synthesis of pyrrolo-isoxazolidines 3b and 4b: The
compounds 3b and 4b were prepared by treating nitrone 1b
(0.9 g, 0.004 mol) with maleimide 2b (1.0 g, 0.004 mol) by
following the similar protocol as given earlier for 3a and 4a.
cis-Methyl-4-[(3H,3aH,6aH)-3-(2-hydroxyphenyl)-4,6-
dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl]benzoate (3b): Off white solid; m.p. 133-135 °C; yield: 38
%; IR (KBr, νmax, cm–1): 1699, 1713 (C=O), 1741 (ester C=O),
2952 (aliphatic C-H), 3285 (aromatic C-H) and 3405 (O-H);
1H NMR (400 MHz, DMSO-d6): δ 10.39 (1H, s, OH), 7.88
(2H, dt, Jp,o = 1.0, 7.1 Hz, H-3′″, 5′″), 7.65 (2H, d, Jo = 8.8 Hz,
H-2′″, 6′″), 7.43 (1H, dd, Jm,o = 1.4, 7.7 Hz, H-6″), 7.20 (2H, t,
Jo = 7.7 Hz, H-4″, 5″), 7.11 (1H, td, Jm,o = 1.6, 8.2 Hz, H-3″),
6.94 (3H, m, H- 3′, 4′, 5′), 6.81 (2H, m, H-2′, 6′), 5.19 (1H, d,
J3,3a = 8.2 Hz, H-3), 5.10 (1H, d, J6a,3a = 6.5 Hz, H-6a), 3.91
(1H, dd, J3a,3 = 8.2 Hz, J3a,6a = 6.5 Hz, H-3a), 3.82 (3H, s,
OCH3); 13C NMR (100 MHz, DMSO-d6): δ 168.46, 168.18
(C=O), 165.76 (ester C=O), 154.71 (C-2″), 148.93 (C-1′″),
143.10 (C-1′), 130.27 (C-4′″), 128.75 (C-1″), 128.37 (C-3′″,
5′″), 127.68 (C-2′″, 6′″), 125.09 (C-6″), 124.26 (C-4″), 122.59
(C-3′, 5′), 119.38 (C-5″), 118.65 (C-4′), 116.88 (C-2′, 6′),
115.40 (C-3″), 76.94 (C-6a), 65.70 (C-3), 51.83 (OCH3), 48.58
(C-3a); ESI-MS: m/z 467 (M+Na, 14 %), 444 (M+, 100 %);
Anal. calcd. (%) for C25H20N2O6: C, 67.56; H, 4.54; N, 6.30;
Found (%): C, 67.28; H, 4.51; N, 6.27.
trans-Methyl-4-[(3H,3aH,6aH)-3-(2-hydroxyphenyl)-
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl]benzoate (4b): Off white solid; m.p. 115-117 °C; yield:
20 %; IR (KBr, νmax, cm–1): 1699, 1712 (C=O), 1743 (ester
C=O), 2954 (aliphatic C-H), 3281 (aromatic C-H) and 3404
(O-H); 1H NMR (400 MHz, DMSO-d6): δ 10.52 (1H, s, OH),
7.85 (2H, dd, Jp,o = 0.9, 7.5 Hz, H-3′″, 5′″), 7.64 (2H, d, Jo =
7.8 Hz, H-2′″, 6′″), 7.48 (1H, dd, Jm,o = 2.1, 8.0 Hz, H-6″),
7.22 (2H, t, Jo = 7.9 Hz, H-4″, 5″), 7.16 (1H, dd, Jm,o = 1.8, 8.0
Hz, H-3″), 6.98 (3H, m, H- 3′, 4′, 5′), 6.80 (2H, m, H-2′, 6′),
5.80 (1H, s, H-3), 5.25 (1H, d, J6a,3a = 6.8 Hz, H-6a), 4.15 (1H,
d, J3a,6a = 6.8 Hz, H-3a), 3.84 (3H, s, OCH3); 13C NMR (100
MHz, DMSO-d6): δ 169.85, 169.01 (C=O), 167.24 (ester
C=O), 155.01 (C-2″), 149.84 (C-1′″), 145.41 (C-1′), 132.20
(C-4′″), 130.02 (C-1″), 128.94 (C-3′″, 5′″), 128.02 (C-2′″, 6′″),
126.78 (C-6″), 125.04 (C-4″), 122.82 (C-3′, 5′), 120.04 (C-
5″), 118.98 (C-4′), 117.82 (C-2′, 6′), 115.10 (C-3″), 77.45 (C-
6a), 66.08 (C-3), 51.57 (OCH3), 49.13 (C-3a); ESI-MS: m/z
468 (M+Na+1, 60 %), 467 (M+Na, 100 %), 445 (M+1, 50
%); Anal. calcd. (%) for C25H20N2O6: C, 67.56; H, 4.54; N,
6.30; Found (%): C, 67.32; H, 4.57; N, 6.32.
Synthesis of pyrrolo-isoxazolidines 3d and 4d: Hetero-
cycles 3d and 4d could become available from the dipolar
cycloaddition reaction of 1d (0.9 g, 0.004 mol) and 2b (1.0 g,
0.004 mol) under the usual reaction conditions.
cis-Methyl-4-[(3H,3aH,6aH)-3-(4-hydroxyphenyl)-4,6-
dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl]benzoate (3d): Off white solid; m.p. 210-212 °C; yield: 55
%; IR (KBr, νmax, cm–1): 1696, 1718 (C=O), 1741 (ester C=O),
2952 (aliphatic C-H), 3285 (aromatic C-H) and 3402 (O-H);
1H NMR (400 MHz, DMSO-d6): δ 10.36 (1H, s, OH), 7.82
(2H, dt, Jp,o = 0.9, 7.3 Hz, H-3′″, 5′″), 7.62 (2H, d, Jo = 8.0 Hz,
H-2′″, 6′″), 7.45 (2H, d, Jo = 7.1 Hz, H-2″, 6″), 7.24 (2H, t, Jo
= 7.7 Hz, H-3″, 5″), 6.93 (3H, m, H- 3′, 4′, 5′), 6.71 (2H, dd,
Jm,o = 2.5, 7.3 Hz, H-2′, 6′), 5.18 (1H, d, J3,3a = 8.4 Hz, H-3),
5.11 (1H, d, J6a,3a = 6.6 Hz, H-6a), 3.94 (1H, dd, J3a,3 = 8.4 Hz,
J3a,6a = 6.6 Hz, H-3a), 3.86 (3H, s, OCH3); 13C NMR (100 MHz,
DMSO-d6): δ 169.15, 168.32 (C=O), 165.81 (ester C=O),
155.08 (C-4″), 147.18 (C-1′″), 144.47 (C-1′), 130.87 (C-4′″),
130.04 (C-1″), 128.05 (C-3′″, 5′″), 127.14 (C-2′″, 6′″), 125.42
(C-2″, 6″), 124.31 (C-3′, 5′), 122.79 (C-4′), 119.55 (C-2′, 6′),
118.78 (C-3″, 5″), 77.58 (C-6a), 66.34 (C-3), 51.90 (OCH3),
48.74 (C-3a); ESI-MS: m/z 468 (M+Na+1, 35 %), 444 (M+,
Synthesis of pyrrolo-isoxazolidines 3c and 4c: The
reaction of compounds 1c (0.9 g, 0.004 mol) and 2b (1.0 g,
0.004 mol) in the same manner as described above for 3a and
4a resulted in the formation of two new diastereomers 3c and
4c.
cis-Methyl-4-[(3H,3aH,6aH)-3-(3-hydroxyphenyl)-4,6-
dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl]benzoate (3c): Off white solid; m.p. 160-162 °C; yield: 50
%; IR (KBr, νmax, cm–1): 1696, 1715 (C=O), 1740 (ester C=O),
2953 (aliphatic C-H), 3283 (aromatic C-H) and 3408 (O-H);

Vol. 31, No. 1 (2019)
Synthesis and Antimicrobial Evaluation of New Pyrrolo-isoxazolidine Derivatives 223
100 %); Anal. calcd. (%) for C25H20N2O6: C, 67.56; H, 4.54;
N, 6.30; Found (%): C, 67.34; H, 4.51; N, 6.27.
(100 MHz, DMSO-d6): δ 169.22, 168.32 (C=O), 165.98 (ester
C=O), 148.29 (C-1′″), 143.31 (C-1′), 130.59 (C-4′″), 129.13
(C-1″), 128.29 (C-4″), 127.33 (C-3′″, 5′″), 125.94 (C-2′″, 6′″),
124.22 (C-2″, 6″), 123.52 (C-3′, 5′), 119.38 (C-4′), 118.97
(C-3″, 5″), 116.44 (C-2′, 6′), 76.93 (C-6a), 64.05 (C-3), 51.77
(OCH3), 48.30 (C-3a), 21.6 (C4″-CH3); ESI-MS: m/z 443 (M+1,
28 %), 442 (M+, 100 %); Anal. calcd. (%) for C26H22N2O5:
C, 70.58; H, 5.01; N, 6.33; Found (%): C, 70.31; H, 4.99;
N, 6.36.
Synthesis of pyrrolo-isoxazolidine (3f): The reaction of
nitrone 1f (0.9 g, 0.004mol) and compound 2b (1.0 g, 0.004
mol) could be able to provide 3f under the conditions as given
above (3a and 4a).
trans-Methyl-4-[(3H,3aH,6aH)-3-(4-hydroxyphenyl)-
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl]benzoate (4d): Off white solid; m.p. 193-195 °C; yield:
24 %; IR (KBr, νmax, cm–1): 1695, 1721 (C=O), 1742 (ester
C=O), 2953 (aliphatic C-H), 3286 (aromatic C-H) and 3406
(O-H); 1H NMR (400 MHz, DMSO-d6): δ 10.53 (1H, s, OH),
7.84 (2H, dt, Jp,o = 0.8, 7.9 Hz, H-3′″, 5′″), 7.65 (2H, d, Jo =
7.7 Hz, H-2′″, 6′″), 7.43 (2H, d, Jo = 7.6 Hz, H- 2″, 6″), 7.28
(2H, t, Jo = 7.2 Hz, H-3″, 5″), 6.96 (3H, m, H- 3′, 4′, 5′), 6.74
(2H, dd, Jm,o = 2.1, 7.8 Hz, H-2′, 6′), 5.83 (1H, s, H-3), 5.26
(1H, d, J6a,3a = 6.9 Hz, H-6a), 4.10 (1H, d, J3a,6a = 6.9 Hz, H-
3a), 3.82 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6): δ
168.34, 168.03 (C=O), 166.39 (ester C=O), 153.93 (C-4″),
148.07 (C-1′″), 145.87 (C-1′), 132.02 (C-4′″), 130.40 (C-1″),
129.95 (C-3′″, 5′″), 128.34 (C-2′″, 6′″), 126.16 (C-2″, 6″),
125.48 (C-3′, 5′), 123.47 (C-4′), 120.47 (C-2′, 6′), 119.43 (C-
3″, 5″), 77.23 (C-6a), 65.78 (C-3), 52.16 (OCH3), 49.32 (C-
3a); ESI-MS: m/z 467 (M+Na, 100 %), 445 (M+1, 26 %);
Anal. calcd. (%) for C25H20N2O6: C, 67.56; H, 4.54; N, 6.30;
Found (%): C, 67.28; H, 4.52; N, 6.28.
cis-Methyl-4-((3H,3aH,6aH)-3-(4-methoxyphenyl)-
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl)benzoate (3f): Off white solid; m.p. 190-192 °C; yield:
45 %; IR (KBr, νmax, cm–1): 1693, 1712 (C=O), 1742 (ester
C=O), 2952 (aliphatic C-H) and 3281 (aromatic C-H); 1H NMR
(400 MHz, DMSO-d6): δ 7.83 (2H, dd, Jp,o = 1.0, 7.8 Hz, H-
3′″, 5′″), 7.69 (2H, d, Jo = 7.6 Hz, H-2′″, 6′″), 7.41 (2H, d, Jo =
7.9 Hz, H- 2″, 6″), 7.20 (2H, t, Jo = 7.5 Hz, H-3″, 5″), 6.95
(3H, m, H- 3′, 4′, 5′), 6.79 (2H, dd, Jm,o = 2.4, 8.0 Hz, H-2′,
6′), 5.20 (1H, d, J3,3a = 8.3 Hz, H-3), 5.09 (1H, d, J6a,3a = 6.1
Hz, H-6a), 3.92 (1H, dd, J3a,3 = 8.3 Hz, J3a,6a = 6.1 Hz, H-3a),
3.90 (3H, s, C4″-OCH3), 3.81 (3H, s, C4′″-OCH3); 13C NMR
(100 MHz, DMSO-d6): δ 168.58, 167.43 (C=O), 166.41 (ester
C=O), 155.41 (C-4″), 149.19 (C-1′″), 143.84 (C-1′), 130.24
(C-4′″), 130.81 (C-1″), 129.06 (C-3′″, 5′″), 128.87 (C-2′″, 6′″),
126.22 (C-2″, 6″), 124.33 (C-3′, 5′), 123.53 (C-4′), 120.84
(C-2′, 6′), 119.45 (C-3″, 5″), 75.06 (C-6a), 66.28 (C-3), 55.9
(C4″-OCH3) 51.58 (C4′″-OCH3), 48.23 (C-3a); ESI-MS: m/z
481 (M+Na, 100 %), 459 (M+1, 25 %); Anal. calcd. (%) for
C26H22N2O6: C, 68.11; H, 4.84; N, 6.11; Found (%): C, 67.84;
H, 4.82; N, 6.08.
Synthesis of pyrrolo-isoxazolidines 3g and 4g: The
products 3g and 4g were synthesized from the reaction of nitrone
1g (0.9 g, 0.004 mol) and maleimide 2b (1.0 g, 0.004 mol) by
following the usual protocols as stated above for 3a and 4a.
cis-Methyl-4-((3H,3aH,6aH)-3-(4-chlorophenyl)-4,6-
dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl)benzoate (3g): Off white solid; m.p. 202-204 °C; yield: 51
%; IR (KBr, νmax, cm–1): 1691, 1714, (C=O), 1741 (ester C=O),
2954 (aliphatic C-H) and 3285 (aromatic C-H); 1H NMR (400
MHz, DMSO-d6): δ 7.90 (2H, dt, Jp,o = 0.8, 7.2 Hz, H-3′″,
5′″), 7.60 (2H, d, Jo = 7.6 Hz, H-2′″, 6′″), 7.48 (2H, d, Jo = 8.0
Hz, H- 2″, 6″), 7.28 (2H, t, Jo = 7.4 Hz, H-3″, 5″), 6.91 (3H,
m, H- 3′, 4′, 5′), 6.82 (2H, dd, Jm,o = 2.5, 7.6 Hz, H-2′, 6′), 5.17
(1H, d, J3,3a = 7.9 Hz, H-3), 5.02 (1H, d, J6a,3a = 6.2 Hz, H-6a),
3.89 (1H, dd, J3a,3 = 7.9 Hz, J3a,6a = 6.2 Hz, H-3a), 3.84 (3H, s,
OCH3); 13C NMR (100 MHz, DMSO-d6): δ 168.08, 167.91
(C=O), 165.75 (ester C=O), 149.91 (C-1′″), 143.80 (C-1′),
131.71 (C-4′″), 129.69 (C-1″), 128.56 (C-4″), 127.54 (C-3′″,
5′″), 125.44 (C-2′″, 6′″), 124.64 (C-2″, 6″), 122.33 (C-3′, 5′),
119.56 (C-4′), 118.68 (C-3″, 5″), 116.15 (C-2′, 6′), 75.64 (C-
6a), 64.91 (C-3), 52.29 (OCH3), 49.15 (C-3a); ESI-MS: m/z
464 (M+2, 32 %), 462 (M+, 94 %); Anal. calcd. (%) for
C25H19N2O5Cl: C, 64.87; H, 4.14; N, 6.05; Found (%): C, 64.61;
H, 4.12; N, 6.02.
Synthesis of pyrrolo-isoxazolidines 3e and 4e: The com-
pounds 3e and 4e were realized easily from the cycloaddition
reaction of 1e (0.8 g, 0.004 mol) and 2b (1.0 g, 0.004 mol) by
following the similar protocol as depicted above for 3a and
4a.
cis-Methyl-4-((3H,3aH,6aH)-4,6-dioxo-2-phenyl-3-(p-
tolyl)hexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)benzoate
(3e): Off white solid; m.p. 176-178 °C; yield: 44 %; IR (KBr,
ν
max, cm–1): 1698, 1720 (C=O), 1738 (ester C=O), 2959 (aliphatic
C-H) and 3282 (aromatic C-H); 1H NMR (400 MHz, DMSO-
d6): δ 7.89 (2H, dd, Jp,o = 0.7, 7.8 Hz, H-3′″, 5′″), 7.66 (2H, d,
Jo = 7.0 Hz, H-2′″, 6′″), 7.40 (2H, d, Jo = 7.5 Hz, H- 2″, 6″),
7.30 (2H, t, Jo = 7.2 Hz, H-3″, 5″), 6.98 (3H, m, H- 3′, 4′, 5′),
6.75 (2H, dd, Jm,o = 2.4, 7.8 Hz, H-2′, 6′), 5.20 (1H, d, J3,3a
=
8.3 Hz, H-3), 5.08 (1H, d, J6a,3a = 6.0 Hz, H-6a), 3.92 (1H, dd,
J3a,3 = 8.3 Hz, J3a,6a = 6.0 Hz, H-3a), 3.82 (3H, s, OCH3), 2.5
(3H, s, CH3); 13C NMR (100 MHz, DMSO-d6): δ 168.82,
168.18 (C=O), 167.24 (ester C=O), 148.52 (C-1′″), 145.21
(C-1′), 132.98 (C-4′″), 128.71 (C-1″), 128.03 (C-4″), 127.54
(C-3′″, 5′″), 126.11 (C-2′″, 6′″), 125.38 (C-2″, 6″), 122.47
(C-3′, 5′), 121.66 (C-4′), 119.48 (C-3″, 5″), 116.89 (C-2′, 6′),
77.34 (C-6a), 65.64 (C-3), 52.32 (OCH3), 49.42 (C-3a), 21.4
(C4″-CH3); ESI-MS: m/z 465 (M+Na, 98 %), 443 (M+1, 40
%); Anal. calcd. (%) for C26H22N2O5: C, 70.58; H, 5.01; N,
6.33; Found (%): C, 70.29; H, 4.98; N, 6.30 %.
trans-Methyl-4-((3H,3aH,6aH)-4,6-dioxo-2-phenyl-3-
(p-tolyl)hexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)benzo-
ate (4e): Off white solid; m.p. 161-163 °C; yield: 32 %; IR
(KBr, νmax, cm–1): 1699, 1718 (C=O), 1741 (ester C=O), 2956
(aliphatic C-H) and 3284 (aromatic C-H); 1H NMR (400 MHz,
DMSO-d6): δ 7.86 (2H, dd, Jp,o = 1.0, 8.0 Hz, H-3′″, 5′″), 7.63
(2H, d, Jo = 7.4 Hz, H-2′″, 6′″), 7.42 (2H, d, Jo = 7.8 Hz, H- 2″,
6″), 7.23 (2H, t, Jo = 7.0 Hz, H-3″, 5″), 6.95 (3H, m, H- 3′, 4′,
5′), 6.72 (2H, dd, Jm,o = 2.6, 7.3 Hz, H-2′, 6′), 5.86 (1H, s, H-
3), 5.29 (1H, d, J6a,3a = 6.7 Hz, H-6a), 4.08 (1H, d, J3a,6a = 6.7
Hz, H-3a), 3.87 (3H, s, OCH3), 2.5 (3H, s, CH3); 13C NMR

224 Yusuf et al.
Asian J. Chem.
trans-Methyl-4-((3H,3aH,6aH)-3-(4-chlorophenyl)-
dd, J3a,3 = 8.1 Hz, J3a,6a = 6.5 Hz, H-3a), 3.86 (3H, s, OCH3);
13C NMR (100 MHz, DMSO-d6): δ 169.82, 167.83 (C=O),
166.72 (ester C=O), 148.19 (C-1′″), 145.09 (C-1′), 144.56 (C-
2″), 131.72 (C-4′″), 130.58 (C-5″), 129.84 (C-3′″, 5′″), 128.95
(C-2′″, 6′″), 125.11 (C-3′, 5′), 122.64 (C-4′), 1l20.78 (C-3″),
119.94 (C-4″), 117.34 (C-2′, 6′), 77.78 (C-6a), 64.53 (C-3),
51.38 (OCH3), 48.62 (C-3a); ESI-MS: m/z 436 (M+2, 5 %),
435 (M+1, 24 %), 434 (M+, 100); Anal. calcd. (%) for
C23H18N2O5S: C, 63.58; H, 4.18; N, 6.45 %, S, 7.38; Found
(%): C, 63.83; H, 4.16; N, 6.42 %, S, 7.35.
trans-Methyl-4-((3H,3aH,6aH)-4,6-dioxo-2-phenyl-3-
(thiophen-2-yl)hexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl)benzoate (4i): Off white solid; m.p. 199-202 °C; yield: 22
%; IR (KBr, νmax, cm–1): 1696, 1716 (C=O), 1744 (ester C=O),
2955 (aliphatic C-H) and 3282 (aromatic C-H); 1H NMR (400
MHz, DMSO-d6): δ 7.83 (2H, dd, Jp,o = 0.7, 7.9 Hz, H-3′″,
5′″), 7.76 (1H, d, J3″,4″ = 3.8 Hz, H-3″),7.67 (2H, d, Jo = 7.5
Hz, H-2′″, 6′″), 7.63 (1H, d, J5″,4″ = 5.1 Hz, H-5″), 7.23 (1H,
dd, J4″,3″ = 3.6 Hz, J4″,5″ = 5.1 Hz, H-4″), 6.95 (3H, m, H- 3′, 4′,
5′), 6.73 (2H, dd, Jm,o = 2.4, 7.7 Hz, H-2′, 6′), 5.81 (1H, s, H-
3), 5.31 (1H, d, J6a,3a = 6.8 Hz, H-6a), 4.16 (1H, d, J3a,6a = 6.8
Hz, H-3a), 3.88 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-
d6): δ 169.04, 168.94 (C=O), 167.18 (ester C=O), 147.55 (C-
1′″), 144.52 (C-1′), 143.07 (C-2″), 132.23 (C-4′″), 130.22 (C-
5″), 129.37 (C-3′″, 5′″), 127.28 (C-2′″, 6′″), 126.85 (C-3′, 5′),
123.06 (C-4′), 121.27 (C-3″), 120.29 (C-4″), 117.76 (C-2′,
6′), 75.89 (C-6a), 66.91 (C-3), 52.58 (OCH3), 49.12 (C-3a);
ESI-MS: m/z 458 (M+Na+1, 24 %), 457 (M+Na, 48 %), 435
(M+1, 8 %); Anal. calcd. (%) for C23H18N2O5S: C, 63.58; H,
4.18; N, 6.45; S, 7.38; Found (%): C, 63.32; H, 4.20; N, 6.40;
S, 7.41.
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl)benzoate (4g): Off white solid; m.p. 183-185 °C; yield:
27 %; IR (KBr, νmax, cm–1): 1698, 1713 (C=O), 1744 (ester
C=O), 2951 (aliphatic C-H) and 3284 (aromatic C-H); 1H NMR
(400 MHz, DMSO-d6): δ 7.88 (2H, dt, Jp,o = 1.0, 7.3 Hz, H-
3′″, 5′″), 7.61 (2H, d, Jo = 7.1 Hz, H-2′″, 6′″), 7.43 (2H, d, Jo =
7.8 Hz, H- 2″, 6″), 7.21 (2H, t, Jo = 7.9 Hz, H-3″, 5″), 6.94
(3H, m, H- 3′, 4′, 5′), 6.80 (2H, dd, Jm,o = 2.3, 7.4 Hz, H-2′,
6′), 5.84 (1H, s, H-3), 5.30 (1H, d, J6a,3a = 6.6 Hz, H-6a), 4.14
(1H, d, J3a,6a = 6.6 Hz, H-3a), 3.90 (3H, s, OCH3); 13C NMR
(100 MHz, DMSO-d6): δ 169.71, 167.88 (C=O), 166.08 (ester
C=O), 147.83 (C-1′″), 144.37 (C-1′), 130.60 (C-4′″), 130.34
(C-1″), 129.16 (C-4″), 128.88 (C-3′″, 5′″), 126.68 (C-2′″, 6′″),
124.87 (C-2″, 6″), 123.58 (C-3′, 5′), 120.85 (C-4′), 118.05
(C-3″, 5″), 117.26 (C-2′, 6′), 76.48 (C-6a), 66.45 (C-3), 51.89
(OCH3), 48.70 (C-3a); ESI-MS: m/z 464 (M+2, 12 %), 462
(M+, 33 %); Anal. calcd. (%) for C25H19N2O5Cl: C, 64.87; H,
4.14; N, 6.05; Found (%): C, 64.59; H, 4.16; N, 6.03.
Synthesis of pyrrolo-isoxazolidine (3h): The heterocycle
3h was obtained from the reaction of 1h (1.0 g, 0.004 mol)
and 2b (1.0 g, 0.004 mol) by following the above described
procedures.
cis-Methyl-4-((3H,3aH,6aH)-3-(4-nitrophenyl)-4,6-
dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl)benzoate (3h): Off white solid; m.p. 220-222 °C; yield: 48
%; IR (KBr, νmax, cm–1): 1346, 1518 (NO2), 1699, 1715 (C=O),
1739 (ester C=O), 2956 (aliphatic C-H) and 3280 (aromatic
C-H); 1H NMR (400 MHz, DMSO-d6): δ 7.89 (2H, dt, Jp,o
=
1.0, 7.8 Hz, H- 3′″, 5′″), 7.78 (2H, d, Jo = 7.8 Hz, H-3″, 5″),
7.68 (2H, d, Jo = 8.0 Hz, H-2′″, 6′″), 7.52 (2H, d, Jo = 7.4 Hz,
H-2″, 6″), 6.99 (3H, m, H- 3′, 4′, 5′), 6.88 (2H, dd, Jm,o = 2.2,
8.1 Hz, H-2′, 6′), 5.21 (1H, d, J3,3a = 8.1 Hz, H-3), 5.12 (1H, d,
J6a,3a = 6.3 Hz, H-6a), 3.90 (1H, dd, J3a,3 = 8.1 Hz, J3a,6a = 6.3
Hz, H-3a), 3.80 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-
d6): δ 169.43, 168.75 (C=O), 165.74 (ester C=O), 148.76 (C-
1′″), 144.67 (C-1′), 132.17 (C-4′″), 129.44 (C-1″), 128.46 (C-
4″), 127.98 (C-3′″, 5′″), 125.87 (C-2′″, 6′″), 125.81 (C-3′, 5′),
122.61 (C-2″, 6″), 119.03 (C-4′), 118.83 (C-3″, 5″), 117.51
(C-2′, 6′), 77.46 (C-6a), 65.18 (C-3), 51.05 (OCH3), 49.38
(C-3a); ESI-MS: m/z 475 (M+2, 3 %), 474 (M+1, 27 %), 473
(M+, 100);Anal. calcd. (%) for C25H19N3O7: C, 63.42; H, 4.05;
N, 8.88; Found (%): C, 63.16; H, 4.02; N, 8.84.
Synthesis of pyrrolo-isoxazolidines 3j and 4j: The usual
reaction of 1j (0.7 g, 0.004 mol) and 2b (1.0 g, 0.004 mol)
under the above described conditions furnished two new pro-
ducts 3j and 4j.
cis-Methyl-4-((3H,3aH,6aH)-3-(furan-2-yl)-4,6-dioxo-
2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-yl)-
benzoate (3j): Off white solid; m.p. 218-220 °C; yield: 35 %;
IR (KBr, νmax, cm–1): 1692, 1710 (C=O), 1741 (ester C=O),
2953 (aliphatic C-H) and 3283 (aromatic C-H); 1H NMR (400
MHz, DMSO-d6): δ 7.85 (2H, dd, Jp,o = 0.8, 7.1 Hz, H-3′″,
5′″), 7.66 (2H, d, Jo = 7.9 Hz, H-2′″, 6′″), 7.52 (1H, d, J3″,4″
1.7 Hz, H-3″), 6.93 (3H, m, H- 3′, 4′, 5′), 6.88 (1H, d, J5″,4″
=
=
Synthesis of pyrrolo-isoxazolidines 3i and 4i: The hetero-
cycles 3i and 4i were obtained in the pure by using the cyclo-
addition process of 1i (0.8 g, 0.004mol) and 2b (1.0 g, 0.004
mol) under the above described conditions.
3.4 Hz, H-5″), 6.76 (2H, dd, Jm,o = 2.3, 7.3 Hz, H-2′, 6′), 6.68
(1H, dd, J4″,3″ = 1.7 Hz, J4″,5″ = 3.4 Hz, H-4″), 5.16 (1H, d, J3,3a
= 8.3 Hz, H-3), 5.06 (1H, d, J6a,3a = 6.3 Hz, H-6a), 3.91 (1H,
dd, J3a,3 = 8.3 Hz, J3a,6a = 6.3 Hz, H-3a), 3.87 (3H, s, OCH3);
13C NMR (100 MHz, DMSO-d6): δ 168.44, 167.05 (C=O),
165.49 (ester C=O), 155.96 (C-2″), 149.40 (C-1′″), 143.23
(C-1′), 130.58 (C-4′″), 129.74 (C-5″), 128.44 (C-3′″, 5′″),
127.50 (C-2′″, 6′″), 125.86 (C-3′, 5′), 123.51 (C-4′), 116.19
(C-2′, 6′), 109.75 (C-3″), 106.17 (C-4″), 75.99 (C-6a), 66.18
(C-3), 52.36 (OCH3), 48.25 (C-3a); ESI-MS: m/z 441 (M+Na,
38 %), 419 (M+1, 26 %); Anal. calcd. (%) for C23H18N2O6: C,
66.03; H, 4.34; N, 6.70; Found (%): C, 65.77; H, 4.30; N,
6.67.
cis-Methyl-4-((3H,3aH,6aH)-4,6-dioxo-2-phenyl-3-
(thiophen-2-yl)hexahydro-5H-pyrrolo[3,4-d]isoxazol-5-
yl)benzoate (3i): Off white solid; m.p. 214-216 °C; yield: 31
%; IR (KBr, νmax, cm–1): 1695, 1711 (C=O), 1740 (ester C=O),
2957 (aliphatic C-H) and 3285 (aromatic C-H); 1H NMR (400
MHz, DMSO-d6): δ 7.86 (2H, dd, Jp,o = 1.0, 7.2 Hz, H-3′″,
5′″), 7.72 (1H, d, J3″,4″ = 3.7 Hz, H-3″),7.68 (2H, d, Jo = 7.9
Hz, H-2′″, 6′″), 7.61 (1H, d, J5″,4″ = 5.0 Hz, H-5″), 7.21 (1H,
dd, J4″,3″ = 3.7 Hz, J4″,5″ = 5.0 Hz, H-4″), 6.91 (3H, m, H- 3′, 4′,
5′), 6.74 (2H, dd, Jm,o = 2.5, 7.8 Hz, H-2′, 6′), 5.22 (1H, d, J3,3a
= 8.1 Hz, H-3), 5.13 (1H, d, J6a,3a = 6.5 Hz, H-6a), 3.95 (1H,
trans-Methyl-4-((3H,3aH,6aH)-3-(furan-2-yl)-4,6-
dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-5-

Vol. 31, No. 1 (2019)
Synthesis and Antimicrobial Evaluation of New Pyrrolo-isoxazolidine Derivatives 225
yl)benzoate (4j): Off white solid; m.p. 205-207 °C; yield: 20
%; IR (KBr, νmax, cm–1): 1694, 1718, (C=O), 1742 (ester C=O),
2950 (aliphatic C-H) and 3286 (aromatic C-H); 1H NMR (400
MHz, DMSO-d6): δ 7.88 (2H, dd, Jp,o = 0.9, 7.3 Hz, H-3′″,5′″),
7.64 (2H, d, Jo = 7.6 Hz, H-2′″, 6′″), 7.53 (1H, d, J3″,4″ = 1.6
Hz, H-3″), 6.96 (3H, m, H- 3′, 4′, 5′), 6.86 (1H, d, J5″,4″ = 3.5
Hz, H-5″), 6.75 (2H, dd, Jm,o = 2.0, 7.8 Hz, H-2′, 6′), 6.64 (1H,
dd, J4″,3″ = 1.6 Hz, J4″,5″ = 3.5 Hz, H-4″), 5.85 (1H, s, H-3),
5.21 (1H, d, J6a,3a = 6.7 Hz, H-6a), 4.11 (1H, d, J3a,6a = 6.7 Hz,
H-3a), 3.81 (3H, s, OCH3); 13C NMR (100 MHz, DMSO-d6):
δ 168.95, 168.74 (C=O), 167.09 (ester C=O), 154.28 (C-2″),
147.22 (C-1′″), 144.31 (C-1′), 132.18 (C-4′″), 129.14 (C-5″),
128.96 (C-3′″, 5′″), 128.01 (C-2′″, 6′″), 126.37 (C-3′, 5′),
122.76 (C-4′), 117.78 (C-2′, 6′), 110..04 (C-3″), 106.68 (C-
4″), 76.35 (C-6a), 65.89 (C-3), 51.93 (OCH3), 49.87 (C-3a);
ESI-MS: m/z 441 (M+Na, 12 %), 418 (M+, 30 %);Anal. calcd.
(%) for C23H18N2O6: C, 66.03; H, 4.34; N, 6.70; Found (%): C,
66.29; H, 4.32; N, 6.73.
OCH3), 2.24 (3H, s, C5″-CH3); 13C NMR (100 MHz, DMSO-
d6): δ 168.23, 168.01 (C=O), 165.50 (ester C=O), 153.89 (C-
2″), 148.72 (C-1′″), 145.13 (C-1′), 142.86 (C-5″), 132.36 (C-
4′″), 129.11 (C-3′″, 5′″), 128.34 (C-2′″, 6′″), 126.06 (C-3′,
5′), 123.59 (C-4′), 121.95 (C-3″), 116.89 (C-2′, 6′), 107.88
(C-4″), 76.12 (C-6a), 65.88 (C-3), 51.67 (OCH3), 48.93 (C-
3a), 13.8 (C5″-CH3); ESI-MS: m/z 434 (M+2, 3 %), 433 (M+1,
26 %), 432 (M+, 100 %); Anal. calcd. (%) for C24H20N2O6: C,
66.66; H, 4.66; N, 6.48; Found (%): C, 66.39; H, 4.64; N,
6.51.
RESULTS AND DISCUSSION
The syntheses of pyrrolo-isoxazolidines 3(a-l) and 4(a-
e), 4g, 4i, 4j was initiated from the reaction of nitrobenzene
with zinc dust in the presence of NH4Cl/H2O to provide nitrones
1(a-l). The N-aryl maleimide (2b) required for these reactions
was prepared in two steps starting from the reaction of maleic
anhydride with methyl-4-aminobenzoate which led to the
formation of N-aryl maleanilic acid (2a) [4,35]. The latter was
cyclized by refluxing under CH3COO–Na+/Ac2O conditions
to yield product 2b. The extensive 1,3-dipolar cycloaddition
reactions of prepared nitrones 1(a-l) were carried out by reflu-
xing with 2b in the presence of dry toluene. After the comple-
tion of these reactions, the mixtures were concentrated under
the reduced pressure (Scheme-I). The resulting masses were
purified by using the silica-gel column chromatography which
provided two types of diastereomeric products 3(a-l) and 4(a-
e), 4g, 4i, 4j. The elemental analysis results were helpful to
confirm the purity of prepared heterocycles and their structures
were characterized on the basis of their spectral data (IR, 1H
NMR, 13C NMR, and ESI-MS).
IR spectra of 3(a-l) and 4(a-e), 4g, 4i, 4j showed intense
absorptions in the carbonyl group region at 1744-1738, 1721-
1710 and 1699-1691 cm-1 which suggested the presence of
three C=O groups in their structures (two of succinimide moiety
and one belonging to ester). The aromatic and aliphatic C-H
stretching frequencies were observed in 3290-3280 and 2959-
2950 cm-1 region, respectively. In the heterocycle 3h two addi-
tional bands were observed at 1518 and 1346 cm-1 which proved
the presence of NO2 group in this molecules. The appearance
of broad bands at 3409-3402 cm-1 in the IR spectra of 3(b-d)
and 4(b-d) indicated the presence of O-H group in their mole-
cular structures.
Synthesis of pyrrolo-isoxazolidines (3k): The product
3k was obtained by treating nitrone 1k (0.9 g, 0.004 mol) with
maleimide 2b (1.0 g, 0.004mol) under the similar conditions
as explained earlier for 3a and 4a.
cis-Methyl-4-((3,3aH,6aH)-3-(5-methylthiophen-2-yl)-
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl)benzoate (3k): Off white solid; m.p. 216-218 °C; yield:
38 %; IR (KBr, νmax, cm–1): 1690, 1710 (C=O), 1741 (ester
C=O), 2953 (aliphatic C-H) and 3285 (aromatic C-H); 1H NMR
(400 MHz, DMSO-d6): δ 7.90 (2H, dd, Jp,o = 0.7, 7.8 Hz, H-
3′″, 5′″), 7.68 (2H, d, Jo = 7.5 Hz, H-2′″, 6′″), 7.59 (1H, d, J3″,4″
= 3.7 Hz, H-3″), 6.91 (3H, m, H-3′, 4′, 5′), 6.83 (2H, dd, Jm,o
=
2.2, 7.9 Hz, H-2′, 6′), 6.76 (1H, d, J4″,3″ = 3.6 Hz, H-4″), 5.28
(1H, d, J3,3a = 8.2 Hz, H-3), 5.02 (1H, d, J6a,3a = 6.2 Hz, H-6a),
3.97 (1H, dd, J3a,3 = 8.2 Hz, J3a,6a = 6.2 Hz, H-3a), 3.80 (3H, s,
OCH3), 2.50 (3H, s, CH3); 13C NMR (100 MHz, DMSO-d6): δ
168.71, 167.99 (C=O), 166.89 (ester C=O), 148.12 (C-1′″),
144.19 (C-1′), 143.18 (C-2″), 136.23 (C-5″), 132.93 (C-4′″),
128.92 (C-3′″, 5′″),127.32 (C-2′″, 6′″), 125.84 (C-3′, 5′),
122.46 (C-4′), 120.75 (C-3″), 120.69 (C-4″), 117.93 (C-2′,
6′), 77.93 (C-6a), 64.54 (C-3), 52.07 (OCH3), 49.28 (C-3a),
15.4 (C5″-CH3); ESI-MS: m/z 450 (M+2, 12 %), 449 (M+1,
30 %); Anal. calcd. (%) for C24H20N2O5S: C, 64.27; H, 4.50;
N, 6.25; S, 7.15; Found (%): C, 64.01; H, 4.47; N, 6.22; S,
7.12.
1H NMR spectra (400 MHz, DMSO-d6) of the newly
prepared diastereomers 3(a-l) and 4(a-e), 4g, 4i, 4j were very
helpful to confirm their structures. The p-disubstituted benzene
ring present on the N-atom of succinimide moiety provided
appropriate doublet of triplets and doublet of doublets at δ
7.90-7.82 (H-3′″, 5′″) and 7.71-7.60 (H-2′″, 6′″), respectively
having coupling values of Jp,o = 1.1-0.6, 8.0-7.1 and Jo = 8.8-
7.0 Hz, respectively. Three hydrogens H-3′, 4′, 5′ belonging
to the N-phenyl ring of isoxazolidine moiety were respon-
sible to generate mutiplets at δ 6.99-6.91 (3H) while H-2′, 6′
associated to the same ring were found to be centred at δ 6.89-
Synthesis of pyrrolo-isoxazolidines (3l): The heterocycle
3l was prepared from the reaction of nitrone 1l (0.8 g, 0.004
mol) and maleimide 2b (1.0 g, 0.004 mol) under the same
conditions as discussed formerly for 3a and 4a.
cis-Methyl-4-((3H,3aH,6aH)-3-(5-methylfuran-2-yl)-
4,6-dioxo-2-phenylhexahydro-5H-pyrrolo[3,4-d]isoxazol-
5-yl)benzoate (3l): Off white solid; m.p. 208-210 °C; yield:
40 %; IR (KBr, νmax, cm–1): 1697, 1719 (C=O), 1743 (ester
C=O), 2958 (aliphatic C-H) and 3287 (aromatic C-H); 1H NMR
(400 MHz, DMSO-d6): δ 7.84 (2H, dt, Jp,o = 1.0, 7.4 Hz, H-
3′″, 5′″), 7.69 (2H, d, Jo = 7.1 Hz, H-2′″, 6′″), 7.60 (1H, d, J3″,4″
= 3.5 Hz, H-3″), 6.98 (3H, m, H- 3′, 4′, 5′), 6.84 (2H, dd, Jm,o
= 2.5, 7.6 Hz, H-2′, 6′), 6.60 (1H, d, J4″,3″ = 3.5 Hz, H-4″), 5.24
(1H, d, J3,3a = 8.0 Hz, H-3), 5.11 (1H, d, J6a,3a = 6.1 Hz, H-6a),
3.85 (1H, dd, J3a,3 = 8.0 Hz, J3a,6a = 6.1 Hz, H-3a), 3.89 (3H, s,
6.71 in the form of well defined doublet of doublets (Jm,o
=
2.8-2.0, 8.1-7.1). Many substituted C3-aryl rings furnished the
signals of appropriate multiplicity at the suitable positions in
the aromatic region. The singlets integrating for three protons

226 Yusuf et al.
Asian J. Chem.
NHOH
NO2
O
H
N
Zn dust/ NH4Cl
Ar-CHO/ CHCl3
(i)
H2O/mech. stirring
Ar
1 (a-l)
NH
2
O
O
O
OH
O
C
3'
2'
2
toluene/ stirring
O
(CH3COO)2O/
CH3COONa/
3
(ii)
1
N
O
NH
1'
C
4'
+
OMe
4
∆
5
OMe
6'
5'
O
O
O
2a
2b
O
OMe
O
H
6a
1
O
3'
5'
2'
2''' 3'''
O
6
5
1'''
2N
3
N
1'
4'
C
4'''
4
OMe
3a
6'
6'''
5'''
H
H
O
Ar
O
O
3(a-l)
H
N
O
toluene/
∆
(iii)
N
C
+
+
Ar
OMe
O
H
2''' 3'''
1O 6a
3'
2'
1 (a-l)
6
O
2b
OMe
O
5
N
2 N
1'
4'''
1'''
4'
C
3
4
3a
5'
6'
6'''
5'''
H
H
Ar
O
4(a-e), 4g, 4i, 4j
OH
3''
3''
3''
3''
3''
OH
OMe
4''
CH
3''
HO
3
2''
1''
2''
1''
2''
1''
4''
5''
4''
5''
2''
1''
2''
4''
5''
4''
5''
2''
4''
5''
,
,
,
,
,
,
5''
1''
6''
1''
6''
6''
6''
6''
6''
d
4''
b
c
e
4''
f
3''
a
3''
Ar =
4''
3''
3''
3''
4''
3''
Cl
NO
2
2''
2''
4''
5''
4''
5''
5''
5''
CH
3
5''
,
5'' CH
3
2''
,
2''
,
2''
,
2''
S
1''
O
,
O
S
1''
1''
1''
1''
1''
6''
6''
k
g
i
j
l
h
Scheme-I: Synthesis of pyrrolo-isoxazolidines 3(a-l) and 4(a-e), 4g, 4i, 4j
at δ 3.89-3.80 were easily assignable to COOCH3 group
present at the para position of the 5-N aromatic ring. In com-
pounds 3(b-d) and 4(b-d), O-H substituents belonging to C3-
aromatic ring were fully confirmed by the appearance of the
D2O exchangeable singlets at δ 10.36-10.53. Three protons
singlets located at δ 3.90 and 2.50 could be easily allotted to
OCH3 (3f) and CH3 (3e-4e) group, respectively. Similarly,
methyl group belonging to C3-thienyl (3k) and C3-furyl (3l)
rings were able to produce three protons singlets at δ 2.50-
direct bonding with electronegative nitrogen atom while its
benzylic nature also seems to be contributing to its downfield
appearance. The inter-relationship between these hydrogens
was established on the basis of their mutual coupling constants.
The coupling values of J3,3a = 8.4-7.9 Hz and J6a,3a = 6.6-6.0 Hz
in heterocycles 3(a-l) describe the cis relationship between
H-3 and H-3a as well as H-6a and H-3a. This observation
certainly proves that all the three protons H-3, H-6a and H-3a
are cis among to each other and present on the same side of
molecular framework.
1
2.24. The interesting feature of the H NMR spectra of the
prepared diastereomers was the signal of H-3, H-6a and H-3a.
In 3(a-l), doublets at δ 5.28-5.16, doublets at δ 5.16-5.02 and
well splitted doublet of doublets at δ 3.97-3.85 were easily
assigned to H-3, H-6a and H-3a, respectively. The proton H-3
appeared more downfield than H-6a and H-3a owing to its
Similarly, three noticeable hydrogens H-3, H-6a and H-
3a in 4(a-e), 4g, 4i 4j were found to be resonating at δ 5.86-
5.78 (s), 5.31-5.21 (d) and 4.16-4.08 (d), respectively. The
singlet appearance of H-3 in these heterocycles suggested that
this hydrogen has not been able to couple with adjacent proton

Vol. 31, No. 1 (2019)
Synthesis and Antimicrobial Evaluation of New Pyrrolo-isoxazolidine Derivatives 227
and it has trans relationship with H-3a. Coupling values of
6.9-6.4 Hz between H-3a and H-6a certainly established their
cis dispositions with respect to each other.
against the three fungal and four bacterial species (two Gram-
negative and two Gram-positive) such as Aspergillius janus,
Penicillium glabrum, Aspergillus niger, Escherichia coli,
Klubsellia pneumonia, Bacillius subtilis, Staphylococcus aureus,
respectively. Serial tube dilution method was applied for the
MIC evaluation of these compounds [36-38]. Amoxicillin has
been used as the standard drug for antibacterial analysis while
antifungal study was carried out against the fluconazole. The
lowest concentration of the given compound required to control
the growth of microorganisms after overnight incubation was
considered as minimum inhibitory concentrations (MIC). The
MIC of the tested compounds was determined at the concen-
trations of 128, 64, 32, 16, 8 and 4 µg/mL against the above
said microorganisms. DMSO was used for preparing the stock
solutions. Standard drug and DMSO were used as positive
and negative control, respectively.
It is evident from the above discussion that stereochemical
relationship between H-6a and H-3a is similar in the both
diastereomers while H-3 and H-3a are cis in 3(a-l) but these
hydrogens are found to be trans oriented to each other in 4(a-
e), 4g, 4i and 4j. It may easily described that cycloadducts
3(a-l) and 4(a-e), 4g, 4i, 4j have similar configurations at C-
3a and C-6a while it seems to be opposite at C-3 position.
13C NMR spectra (100 MHz, DMSO-d6) of the both types
of diastereomers 3(a-l) and 4(a-e), 4g, 4i, 4j were very instru-
mental to confirm their carbon skeletons. The location of three
downfield signals at δ169.91-168.02, 169.01-167.05 and 167.34-
165.49 were able to confirm the presence of three C=O groups
in these molecules. Three appropriate signals were easily
resonating at δ 149.91-147.18 (C-1′″), 145.87-143.10 (C- 1′)
and132.98-130.24 (C- 4′″). The isoxazolidine ring carbon C-
3 revealed the signals at δ 66.91-64.05 while carbon atoms C-
6a and C-3a present at the junction of the two heterocyclic
rings yielded two appropriate resonances at δ 77.93-75.06 and
49.87-48.23, respectively. The methyl group of ester moiety
(COOCH3)furnished suitable signals at δ 52.58-51.05. In the
compounds 3e, 4e and 3(k-l) addional signals were also located
at δ 21.6-21.4 due to the presence of CH3 group at the C3-
aromatic/hetero aromatic ring. The OCH3 group located at the
same aromatic ring (3f) also generated an appropriate signal
at δ 55.9. The resonances of the remaining aromatic ring carbon
atoms were centered at the suitable δ values.
The bacterial and fungal susceptibility of the tested
compounds were examined through the appearance of turbidity
after the above mentioned durations.The observed MIC values
were compared with positive controls, which are presented in
Table-1.
It is evident from Table-1 that heterocycles 3b, 4b, 3c,
4c, 3d and 4d displayed potent behaviours against Escherichia
coli, Klubsellia pneumonia, Bacillius subtilis, Staphylococcus
aureus at the MIC of 8 µg/mL while compounds 3i, 4i, 3j, 4j,
3k and 3l were found to be significantly active (MIC-8 µg/mL)
against Aspergillius janus, Penicillium glabrum, Aspergillus
niger. Products 3e and 4e showed MIC of 8 µg/mL against
Klubsellia pneumonia and Bacillius subtilis, respectively. The
product 3f was also found to inhibit the growth of Escherichia
coli and Staphylococcus aureus at the MIC of 8 and 16 µg/mL,
respectively. The diastereomers3g and 4g could provide noticeable
activity (MIC-8 µg/mL) against Aspergillius janus and Peni-
cillium glabrum, respectively. The product 3h demonstrated
The proposed structures of 3(a-l) and 4(a-e), 4g, 4i, 4j
were further corroborated from their ESI-MS spectral data.
Antimicrobial activity of 3(a-l) and 4(a-e), 4g, 4i, 4j:
The in vitro antifungal and antibacterial activities of the newly
prepared products 3(a-l) and 4(a-e), 4g, 4i, 4j were attempted
TABLE-1
MIC (µg/mL) DATA OF PYRROLO-ISOXAZOLIDINES 3(a-l) AND 4(a-e), 4g, 4i, 4j
Gram-negative bacteria Gram-positive bacteria
B. subtilis S. aureus
Fungi
Compd. No.
E. coli
32
16
8
K. pneumonia
A. janus
64
16
32
32
16
64
32
32
32
16
32
8
32
32
8
8
16
8
P. glabrum
A. niger
64
32
8
16
8
16
8
8
32
64
16
8
16
8
32
32
16
64
32
16
32
16
64
32
32
64
8
16
8
8
8
16
8
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
3g
4g
3h
3i
4i
16
32
16
8
16
32
32
32
64
32
16
64
16
32
16
32
64
8
16
8
8
8
8
8
–
2
8
8
16
8
8
16
16
8
16
8
16
64
32
8
32
8
64
32
16
16
32
16
32
64
32
32
16
32
2
8
32
32
16
32
32
32
16
32
32
16
64
4
32
64
16
32
32
32
16
64
32
32
2
64
32
16
64
32
64
16
32
16
4
3j
4j
3k
16
8
–
3l
16
–
2
Amoxicillin
Fluconazole
–
–
–
–
2

228 Yusuf et al.
Asian J. Chem.
11. A. Zeghdaoui, B. Tuccio, J.-P. Finet, V. Cerri and P. Tordo, J. Chem.
Soc. Perkin Trans. II, 2087 (1995);
https://doi.org/10.1039/P29950002087.
12. A. Kaur and B. Singh, J. Heterocycl. Chem., 51, 1421 (2014);
https://doi.org/10.1002/jhet.1838.
13. A. Kaur, B. Singh andA.S. Jaggi, Bioorg. Med. Chem. Lett., 23, 797 (2013);
https://doi.org/10.1016/j.bmcl.2012.11.080.
14. R. Badru, S. Shah and B. Singh, J. Heterocycl. Chem., 49, 336 (2012);
https://doi.org/10.1002/jhet.794.
15. T.B. Nguyen, A. Martel, C. Gaulon, R. Dhal and G. Dujardin, Org. Prep.
Proced. Int., 42, 387 (2010);
https://doi.org/10.1080/00304948.2010.513886.
16. B. Cottineau, P. Toto, C. Marot, A. Pipaud and J. Chenault, Bioorg. Med.
Chem. Lett., 12, 2105 (2002);
remarkable results against Aspergillus niger at the MIC of 8
µg/mL. Table-1 clearly describes that compounds 3a and 4a
exhibited moderate level of actions against Escherichia coli,
Staphylococcus aureus, Aspergillius janus and Aspergillus
niger at the MIC of 16 µg/mL. It is also clear from these results
that most of the prepared compounds exhibited moderate
activity against the tested microorganisms (MIC-16 µg/mL).
It may be derived from the above mentioned antimicrobial
evaluation results that the thiophene/furan based pyrroloiso-
xazolidines 3(i-l), 4i and 4j revealed better antifungal properties
whereas phenyl substituted products 3(a-h) and 4(a-e), 4g were
able to exhibit the promising antibacterial properties.
https://doi.org/10.1016/S0960-894X(02)00380-3.
17. F.A.-K. Amer, M. Hammouda, A.-A.S. El-Ahl and B.F. Abdel-Wahab,
J. Chin. Chem. Soc., 54, 1543 (2007);
Conclusion
https://doi.org/10.1002/jccs.200700217.
18. A.O. Abdelhamid, A.H. El-Ghandour and A.A.M. El-Reedy, J. Chin.
Chem. Soc., 55, 406 (2008);
https://doi.org/10.1002/jccs.200800060.
19. B. Chakraborty, M.S. Chhetri, S. Kafley andA. Samanta, Indian J. Chem.,
49B, 209 (2010).
20. M. Kaur, B. Singh, B. Singh and A. Arjuna, J. Heterocycl. Chem., 54,
1848 (2017);
https://doi.org/10.1002/jhet.2712.
21. A. Kaur and B. Singh, J. Heterocycl. Chem., 51, 482 (2014);
https://doi.org/10.1002/jhet.1730.
22. Basappa, M.P. Sadashiva, K. Mantelingu, S.N. Swamy and K.S.
Rangappa, Bioorg. Med. Chem., 11, 4539 (2003);
https://doi.org/10.1016/j.bmc.2003.08.007.
23. A.G. Habeeb, P.N. Praveen Rao and E.E. Knaus, J. Med. Chem., 44,
2921 (2001);
It may be concluded that in the present study we have
investigated the applications of 1,3-dipolar cycloaddition
reactions for the synthesis of new pyrrolo-isoxazolidines which
have been realized in the two diastereomeric forms (cis and
trans). The stereochemistry of prepared products has been
ascertained on the basis of the coupling values. Most of the
prepared diastereomeric heterocycles exhibited significant
antimicrobial activites. C3-phenyl substituted products exhi-
bited the noticeable antimicrobial behaviours while C3-thienyl/
furyl substituted heterocycles proved themselves potent anti-
fungal agents. Thus, nature of the C3-aryl group has been found to
affect the antimicrobial activities of the prepared heterocycles.
https://doi.org/10.1021/jm0101287.
ACKNOWLEDGEMENTS
24. A. Kamal, J.S. Reddy, M.J. Ramaiah, D. Dastagiri, E.V. Bharathi, M.A.
Azhar, F. Sultana, S.N.C.V.L. Pushpavalli, M. Pal-Bhadra and A.
Juvekar, Eur. J. Med. Chem., 45, 3924 (2010);
https://doi.org/10.1016/j.ejmech.2010.05.047.
25. H. Uno, M. Kurokawa, Y. Masuda and H. Nishimura, J. Med. Chem.,
22, 180 (1979);
The authors express their gratitude to The Head, Depart-
ment of Chemistry, Punjabi University, Patiala, India for provi-
ding the necessary laboratory facilities for this work.
https://doi.org/10.1021/jm00188a011.
26. A. Lilienkampf, M. Pieroni, B. Wan, Y. Wang, S.G. Franzblau and A.P.
Kozikowski, J. Med. Chem., 53, 678 (2010);
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
https://doi.org/10.1021/jm901273n.
27. H. Kai, H. Matsumoto, N. Hattori, A. Takase, T. Fujiwara and H.
Sugimoto, Bioorg. Med. Chem. Lett., 11, 1997 (2001);
https://doi.org/10.1016/S0960-894X(01)00362-6.
28. T. Ichiba, P.J. Scheuer and M. Kelly-Borges, J. Org. Chem., 58, 4149
(1993);
https://doi.org/10.1021/jo00067a062.
29. R. Badru, P. Anand and B. Singh, Eur. J. Med. Chem., 48, 81 (2012);
https://doi.org/10.1016/j.ejmech.2011.11.037.
30. P. Anand and B. Singh, Mini Rev. Med. Chem., 14, 623 (2014);
https://doi.org/10.2174/1389557514999140728102737.
31. O. Bortolini, I. Mulani, A. De Nino, L. Maiuolo, M. Nardi, B. Russo
and S. Avnet, Tetrahedron, 67, 5635 (2011);
https://doi.org/10.1016/j.tet.2011.05.098.
32. S.Yavuz, H. Ozkan, N. Colak andY.Yildirir, Molecules, 16, 6677 (2011);
https://doi.org/10.3390/molecules16086677.
REFERENCES
1. N.L.S. Johari, S.N.M. Poad, N.H. Hassan and N.I. Hassan, Malays. J.
Anal. Sci., 20, 1241 (2016);
https://doi.org/10.17576/mjas-2016-2006-02.
2. N.A. Bokach, M.L. Kuznetsov andV.Y. Kukushkin, Coord. Chem. Rev.,
255, 2946 (2011);
https://doi.org/10.1016/j.ccr.2011.07.001.
3. M. Al-Ghorbani, U. Al-Timari and T.F.S.A. Khanum, Res. J. Chem. Sci.,
4, 60 (2014).
4. J. Kaur, B. Singh and K.K. Singal, Indian J. Chem., 44B, 1476 (2005).
5. Y. Xing and N.X. Wang, Coord. Chem. Rev., 256, 938 (2012);
https://doi.org/10.1016/j.ccr.2012.01.002.
33. P. Roy and R.K. De, Indian J. Chem., 50B, 1513 (2011).
34. P. Anand and B. Singh, Bioorg. Med. Chem., 20, 521 (2012);
https://doi.org/10.1016/j.bmc.2011.05.027.
35. N.P. Shetgiri and B.K. Nayak, Indian J. Chem., 44B, 1933 (2005).
36. P.K. Sarvesh and K. Nizamuddin, Arch. Pharm. Chem. Life Sci., 341,
418 (2008);
https://doi.org/10.1002/ardp.200700197.
37. M. Yusuf and I. Solanki, J. Saudi Chem. Soc., 21, 251 (2017);
https://doi.org/10.1016/j.jscs.2015.02.002.
6. S. Shah, R. Badru and B. Singh, Synth. Commun., 43, 1073 (2013);
https://doi.org/10.1080/00397911.2011.622063.
7. F.A. Almashal, J. Basrah. Res. Sci., 37, 128 (2011).
8. R.D. Hinton and E.G. Janzen, J. Org. Chem., 57, 2646 (1992);
https://doi.org/10.1021/jo00035a020.
9. M. Thirumalaikumar, S. Sivasubramanian,A. Ponnuswamy and P. Mohan,
Eur. J. Med. Chem., 31, 905 (1996);
https://doi.org/10.1016/S0223-5234(97)89854-6.
10. G. Broggini, C. La Rosa, T. Pilati,A. Terraneo and G. Zecchi, Tetrahedron,
57, 8323 (2001);
38. M. Yusuf and M. Kaur, J. Heterocycl. Chem., 54, 735 (2017);
https://doi.org/10.1002/jhet.2583.
https://doi.org/10.1016/S0040-4020(01)00785-2.