Novel one-pot synthesis of aziridines carrying sydnone moiety and their biological studies

Article abstract of DOI:10.1080/00397911.2011.599102

A novel series of 5-(3-arylsydnon-4-yl)-7-aryl-1,4-diazabicyclo[4,1,0]hept- 4-enes 3a-l were prepared in a one-pot synthesis by the reaction of 2,3-dibromo-1-(3-arylsydnon-4-yl)-3-arylpropan-1-one 1a-l and 1,2-diaminoethane. The newly synthesized compounds were screened for their antibacterial and antifungal activity.

Full text of DOI:10.1080/00397911.2011.599102

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Novel One-Pot Synthesis of Aziridines
Carrying Sydnone Moiety and Their
Biological Studies
Jyothi C. Hegde a , K. S. Girish a , Adithya Adhikari a & Balakrishna
Kalluraya a
a Department of Studies in Chemistry, Mangalore University,
Mangalagangthri, Karnataka, India
Accepted author version posted online: 01 Feb 2012.Published
online: 18 Oct 2012.
To cite this article: Jyothi C. Hegde , K. S. Girish , Adithya Adhikari & Balakrishna Kalluraya (2013)
Novel One-Pot Synthesis of Aziridines Carrying Sydnone Moiety and Their Biological Studies, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:2, 301-308, DOI: 10.1080/00397911.2011.599102
To link to this article: http://dx.doi.org/10.1080/00397911.2011.599102
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Synthetic Communications1, 43: 301–308, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.599102
NOVEL ONE-POT SYNTHESIS OF AZIRIDINES
CARRYING SYDNONE MOIETY AND THEIR
BIOLOGICAL STUDIES
Jyothi C. Hegde, K. S. Girish, Adithya Adhikari, and
Balakrishna Kalluraya
Department of Studies in Chemistry, Mangalore University,
Mangalagangthri, Karnataka, India
GRAPHICAL ABSTRACT
Abstract A novel series of 5-(3-arylsydnon-4-yl)-7-aryl-1,4-diazabicyclo[4,1,0]hept-4-enes
3a–l were prepared in a one-pot synthesis by the reaction of 2,3-dibromo-1-
(3-arylsydnon-4-yl)-3-arylpropan-1-one 1a–l and 1,2-diaminoethane. The newly synthe-
sized compounds were screened for their antibacterial and antifungal activity.
Keywords Aziridine; biological activity; one-pot synthesis; sydnone derivatives
INTRODUCTION
Aziridines are simple nitrogen-containing three-membered heterocycles, one of
the most valuable classes in organic chemistry, because of their use in syntheses of
many nitrogen-containing biologically active molecules.[1–3] Many naturally occur-
ring aziridine derivatives exhibit antitumor and antibiotic activity.[4,5]
Sydnones are a well-defined novel class of mesoionic compounds consisting of
a 1,2,3-oxadiazole ring system and are valuable synthetic intermediates.[6] Because of
their mesoionic character, they have been widely studied since their discovery.
Interest in sydnone derivatives has been encouraged by the discovery that they exhi-
bit various pharmacological activities.[7,8]
Received March 10, 2011.
Address correspondence to Balakrishna Kalluraya, Department of Studies in Chemistry,
Mangalore University, Mangalagangthri, Karnataka, India. E-mail: bkalluraya@gmail.com
301

302
J. C. HEGDE ET AL.
Scheme 1.
Scheme 2.
Prompted by these observations and in continuation of our research in syd-
none chemistry,[9–12] we studied the mode of addition between 2,3-dibromo-1-
(3-arylsydnone-4-yl)-3-arylpropane-1-ones 1 with ethylen diamine. Surprisingly,
such reactions resulted in the formation of a hitherto-unreported novel series of
aziridines containing a sydnone moiety (Scheme 1). A probable mechanism for the
formation of aziridines is outlined in Scheme 2.
RESULTS AND DISCUSSION
The starting material, 2,3-dibromo-1-(3-arylsydnon-4-yl)-3-arylpropan-1-one
1a–l, was prepared by the bromination of 1-(3-arylsydnone-4-yl)-3-aryl-2-propene-1-
one.[12] These propenones were in turn prepared by the condensation of appropriate

303

304
J. C. HEGDE ET AL.
aldehydes with 3-substituted-4-acetylsydnones.[12] 3-Substituted-4-acetylsydnone
was prepared according to the procedure reported in the literature.[13]
The reaction between 2,3-dibromo-1-(3-arylsydnon-4-yl)-3-arylpropan-1-one
1a–l with ethylene diamine 2 in the presence of triethyl amine in ethanol medium
resulted in the formation of 5-(3-arylsydnon-4-yl)-7-aryl-1,4-diazabicyclo[4,1,0]hept-4-
enes 3a–l. All the newly synthesized compounds were characterized by spectral and ana-
lytical data. The characterization data of the newly synthesized compounds are given in
Table 1.
The infrared (IR) spectra of these compounds showed an absorption band
1
around 1754–1765 cmꢁ1 for the carbonyl group of sydnone moiety. The H NMR
spectra (300 MHz) (CDCl3) of aziridine 3g showed a singlet at d 2.35 integrating
for three protons for the methyl group. The methylene protons at C-2 are found
to be magnetically nonequivalent as they are prochiral. The signals corresponding
to these two protons appeared as multiplets centered at d 2.70 and d 3.44, integrating
for one proton each. The methylene protons at C-3 also appeared to be magnetically
nonequivalent (diastereotopic) because of the restricted rotation and the signals due
to these protons also appeared as multiplets centered at d 3.21 and d 3.80, integrating
for one proton each. The two methine protons at C-7 and C-6 appeared as two
doublets at d 2.90 and d 3.30, each integrating for one proton. The ortho- and
meta-protons of p-tolyl group appeared as two doublets centered at d 7.03 and d
7.21, integrating for two protons each. Similarly the ortho- and meta-protons of
p-bromophenyl group appeared as two doublets centered at d 7.34 and d 7.40, each
integrating for two protons.
Further the mass spectrum [liquid chromatography–mass spectrometry
(LCMS)] of this compound showed the Mþ þ 1 peak and the corresponding isotopic
peak at m=z 425=427, consistent with the molecular formula C20H17BrN4O2.
Fragment peak at m=z 367 is due to the loss of -NO and -CO from the molecular
ion, which is characteristic of sydnone-containing molecule. Base peak was observed
at m=z 91 because of the formation of tropylium cation.
BIOLOGICAL ACTIVITY
The newly synthesized compounds 3a–l were subjected for in vitro antibacterial
and antifungal studies by the cup–plate[14] method against both Gram-positive and
Gram-negative bacteria. Antibacterial activity was determined against S. aureus
(ATCC-25923) and K. pneumoniae and antifungal activity was studied against A. niger
and C. albicans (NCIM-NO. 3100). Ciprofloxacin and ciclopiroxolamine were employed
as standard drugs. Dimethyl formamide (DMF) was used as solvent control. Among
them, compounds 3c, 3d, and 3l showed considerable antibacterial and antifungal
activities. The results of antibacterial and antifungal studies are summarized in Table 2.
CONCLUSION
In conclusion, we studied the reaction of sydnone dibromides with ethylene
dibromides to get a novel series of aziridines, namely 5-(3-arylsydnon-4-yl)-7-aryl-
1,4-diazabicyclo[4,1,0]hept-4-enes 3a–l, in a one-pot reaction, and the yields ranged
from 53% to 69%.

AZIRIDINES CARRYING SYDNONE MOIETY
305
Table 2. Antibacterial and antifungal activity data of 5-(3-arylsydnon-4-yl)-7-aryl-1,4-diazabicyclo
[4,1,0]hept-4-enes 3a–l
Antibacterial activitiesa
(diameter of zone of
inhibition in mm)
Antifungal activitiesb
(diameter of zone of
inhibition in mm)
Compound
S. aureus
K. pneumoniae
A. niger
C. albicans
3c
3d
20
18
14
15
—
12
—
20
—
20
—
18
22
10
12
09
18
—
22
—
22
—
20
26
10
—
10
20
—
18
—
—
24
24
26
14
10
16
18
—
24
—
—
26
3f
3g
3h
3j
3k
3l
Solvent control DMF
Ciprofloxacin
Ciclopiroxolamine
Notes. Diameter of the cup, 5 mm; amount of the sample used, 25 mg=cup; and solvent control, dimethyl
formamide.
aCiprofloxacin used as standard.
bCiclopiroxolamine used as standard.
EXPERIMENTAL
Melting points were determined using the open capillary method and are
uncorrected. All compounds were analyzed satisfactorily for C, H, N (Vairo-EL
Elementar III model analyzer). Infrared (IR) spectra (KBr pellet) were recorded
on a Perkin-Elmer 983 or Jasco Fourier transform (FT) IR 430 spectrophotometer.
1
The H NMR spectra were recorded on a Bruker AC 300 F (300-MHz) NMR spec-
trometer using dimethylsulfoxide (DMSO-d6) as solvent and tetramethylsilane
(TMS) as an internal standard. The chemical shift values are expressed in d scale
downfield from TMS, and proton signals are indicated as s, singlet; d, doublet;
and m, multiplet. Mass spectra of synthesized compounds were recorded on a Jeol
JMS-D 300 mass spectrometer or LC=MS (API 3000, Applied Bio systems) operat-
ing at 70 eV.
Preparation of 2,3-Dibromo-1-(3-arylsydnon-4-yl)-3-arylpropan-1-one
1a–l
1-(3-Arylsydnon-4-yl)-3-aryl-2-propen-1-ones (0.01 mol) was dissolved in gla-
cial acetic acid (20 ml) by gentle warming. A solution of bromine in glacial acetic acid
(30% w=v) was added to it with constant stirring until the yellow color of the bro-
mine persisted. The reaction mixture was stirred at room temperature for 1–2 h.
The solid separated was filtered, washed with methanol, and dried. It was then
recrystallized from ethanol.

306
J. C. HEGDE ET AL.
Preparation of 5-(3-Arylsydnon-4-yl)-7-aryl-1,4-diazabicyclo[4,1,0]
hept-4-enes 3a–l
A
mixture of 2,3-dibromo-1-(3-arylsydnon-4-yl)-3-arylpropan-1-one 1a–l
(0.01 mol), ethylenediamine (0.01 mol), and triethylamine (0.05 mol) was dissolved
in 15 ml ethanol by heating. The clear solution was allowed to stand at room tempera-
ture for 4–6 days. The progress of the reaction was monitored by thin-layer chroma-
tography (TLC). The solid separated was collected by filtration and recrystallized
from ethanol to get pure 5-(3-arylsydnon-4-yl)-7-aryl-1,4-diazabicyclo[4,1,0]hept-4-
enes 3a–l in 53–69% yield.
The characterization data of compounds 3a–l are given in Table 1.
Compound 3a. IR (KBr disc): c(C¼O sydnone) 1761 cmꢁ1, c(C¼N) 1605 cmꢁ1
.
1H NMR (300 MHz) CDCl3, d, 2.61 (m, 1H, C2-H); d 3.05 (d, 1H, C7-H); d 3.31
(m, 1H, C3-H); d 3.42 (d, 1H, C6-H); d 3.48–3.60 (m, 1H, C2-H); d 3.68–3.78 (m,
1H, C3-H); d 7.1–7.4 (m, 10H, Ar-H). Mass: m=z, 333 (Mþ þ 1) (MF: C19H16N4O2).
Compound 3b. IR (KBr disc): c(C¼O sydnone) 1764 cmꢁ1, c(C¼N) 1602 cmꢁ1
.
1H NMR (300 MHz) CDCl3, d, 2.65–2.71 (m, 1H, C2-H); d 2.78 (d, 1H, C7-H); d
3.08 (m, 1H, C3-H); d 3.28 (d, 1H, C6-H); d 3.41–3.48 (m, 1H, C2-H); d 4.23–4.54
(m, 1H, C3-H); d 6.91 (d, 2H, ortho protons of p-chlorophenyl); d 7.28 (d, 2H, meta
protons of p-chlorophenyl); d 7.05–7.40 (m, 5H, Ar-H). Mass: m=z, 367=369 (Mþ þ 1
& Mþ þ 3 peak) (MF: C19H15ClN4O2).
Compound 3c. IR (KBr disc): c(C¼O sydnone) 1760 cmꢁ1, c(C
1594 cmꢁ1
.
=
N)
1H NMR (300 MHz) DMSO-d6, d, 2.65–2.74 (m, 1H, C2-H); d 2.81 (d, 1H, C7-H);
d 3.06–3.18 (m, 1H, C3-H); d 3.28 (d, 1H, C6-H); d 3.35–3.47 (m, 1H, C2-H); d
4.31–4.64 (m, 1H, C3-H); d 6.91 (d, 2H, ortho protons of p-bromophenyl); d 7.32
(d, 2H, meta protons of p-bromophenyl); d 7.10–7.30 (m, 5H, Ar-H). Mass: m=z,
411=413 (Mþ þ 1 & Mþ þ 3 peak) (MF: C19H15BrN4O2).
Compound 3d. IR (KBr disc): c(C¼O sydnone) 1758 cmꢁ1, c(C¼N) 1598 cmꢁ1
.
1H NMR (300 MHz) DMSO-d6, d 2.58–2.66 (m, 1H, C2-H); d 2.71 (d, 1H, C7-H);
d 2.96–3.18 (m, 1H, C3-H); d 3.31 (d, 1H, C6-H); d 3.50–3.60 (m, 1H, C2-H); d
4.10–4.35 (m, 1H, C3-H); d 4.54 (s, 2H, O-CH2-O); d 6.96–7.41 (m, 8H, Ar-H). Mass:
m=z, 377 (Mþ þ 1) (MF: C20H16ClN4O4).
Compound 3e. IR (KBr disc): c(C¼O sydnone) 1756 cmꢁ1, c(C¼N) 1595 cmꢁ1
.
1H NMR (300 MHz) CDCl3, d, 2.32 (s, 3H, CH3); d, 2.70 (m, 1H, C2-H); d, 2.97
(d, 1H, C7-H); d, 3.24 (m, 1H, C3-H); d, 3.33 (d, 1H, C6-H); d, 3.38-3.52 (m, 1H,
C2-H); d, 3.76–3.84 (m, 1H, C3-H); d, 7.19 (d, 2H, ortho-protons of p-tolyl); d, 7.34
(d, 2H, meta-protons of p-tolyl); d, 7.12–7.28 (m, 5H, Ar-H). Mass: m=z, 347
(Mþ þ 1) (MFC20H18N4O2).
Compound 3f. 1H NMR (300 MHz) CDCl3, d, 2.28 (s, 3H, CH3); d 2.46 (m,
1H, C2-H); d 2.80 (d, 1H, C7-H); d 3.15 (m, 1H, C3-H); d 3.30 (d, 1H, C6-H); d
3.46–3.59 (m, 1H, C2-H); d 3.60–3.69 (m, 1H, C3-H); d 7.15 (d, 2H, o-protons of
p-tolyl); d 7.26 (d, 2H, m-protons of p-tolyl); d 7.34 (d, 2H, o-protons of p-chlorophe-
nyl); d 7.54 (d, 2H, m-protons of p-chlorophenyl). Mass: m=z, 381=383 (Mþ þ 1 and
Mþ þ 3 peaks) (MFC20H17ClN4O2).

AZIRIDINES CARRYING SYDNONE MOIETY
307
Compound 3h. IR spectra (KBr disc): c(C¼O
1749 cmꢁ1, c(C¼N)
sydnone)
1605 cmꢁ1. H NMR (300 MHz) CDCl3, d, 2.25 (s, 3H, CH3); d 2.48–2.56 (m, 1H,
C2-H); d 2.75 (d, 1H, C7-H); d 2.90–3.10 (m, 1H, C3-H); d 3.40 (d, 1H, C6-H); d
3.49–3.68 (m, 2H, C2-H & C3-H); d 4.49 (s, 2H, -O-CH2-O); d 7.10 (d, 2H,o-protons
of p-tolyl); d 7.25–7.52 (m, 5H, remaining aromatic protons). Mass: m=z, 391 (Mþ þ 1)
(MF C21H18N4O4).
1
Compound 3i. IR spectra (KBr disc): c(C¼O
1753 cmꢁ1, c(C¼N)
sydnone)
1589 cmꢁ1. H NMR (300 MHz) CDCl3, d, 2.61–2.68 (m, 1H, C2-H); d 2.83 (d,
1H, C7-H); d 3.23–3.36 (m, 1H, C3-H); d 3.41 (d, 1H, C6-H); d 3.52–3.58 (m, 1H,
C2-H); d 3.83 (s, 3H, -OCH3); d 4.32–4.65 (m, 1H, C3-H); d, 7.06 (d, 2H, ortho pro-
tons of p-anisyl); d 7.28 (d, 2H, meta-protons of p-anisyl); d 7.31–7.53 (m, 5H, Ar-H).
Mass: m=z, 363 (Mþ þ 1) (MF C20H18N4O3).
1
Compound 3j. IR spectra (KBr disc): c(C¼O
1759 cmꢁ1, c(C¼N)
sydnone)
1
1593 cmꢁ1. H NMR (300 MHz) CDCl3, d, 2.70–2.74 (m, 1H, C2-H); d, 2.86 (d,
1H, C7-H); d, 3.17–3.20 (m, 1H, C3-H); d, 3.31 (d, 1H, C6-H); d 3.45–3.50 (m, 1H,
C2-H); d 3.79 (s, 3H, -OCH3); d 4.43–4.79 (m, 1H, C3-H); d 6.87 (d, 2H, o-protons
of p-chlorophenyl); d 7.07 (d, 2H, ortho-protons of p-anisyl); d 7.24 (d, 2H, meta-pro-
tons of p-anisyl); d 7.38 (d, 2H, m-protons of p-chlorophenyl). Mass: m=z, 397=399
(Mþ þ 1 and Mþ þ 3 peak) (MF C20H17ClN4O3).
Compound 3k. IR spectra (KBr disc): c(C¼O
1757 cmꢁ1, c(C¼N)
sydnone)
1
1604 cmꢁ1. H NMR (300 MHz) CDCl3, d, 2.58–2.64 (m, 1H, C2-H); d 2.86 (d,
1H, C7-H); d 3.21–3.34 (m, 1H, C3-H); d 3.41 (d, 1H, C6-H); d 3.48–3.71 (m, 2H,
C2-H & C3-H); d 3.91 (s, 3H, -OCH3); d 6.90 (d, 2H, ortho-protons of p-bromophe-
nyl); d 7.10 (d, 2H, ortho-protons of p-anisyl); d 7.31 (d, 2H, meta-protons of p-
anisyl); d 7.42 (d, 2H, meta-protons of p-bromophenyl). Mass: m=z, 441=443
(Mþ þ 1 and Mþ þ 3 peak) (MF C20H17BrN4O3).
Compound 3l. IR spectra (KBr disc): c(C¼O
1758 cmꢁ1, c(C¼N)
sydnone)
1
1595 cmꢁ1. H NMR (300 MHz) CDCl3, d, 2.68–2.70 (m, 1H, C2-H); d 2.89 (d,
1H, C7-H); d 3.01–3.21 (m, 1H, C3-H); d 3.34 (d, 1H, C6-H); d 3.42–3.54 (m, 1H,
C2-H); d 3.94 (s, 3H, -OCH3); d 4.21–4.54 (m, 1H, C3-H); d 4.61 (s, 2H, O-CH2-
O); d 7.14 (d, 2H, ortho-protons of p-anisyl); d 7.42–7.61 (m, 5H, meta-protons of
p-anisyl & Ar-H). Mass: m=z, 407 (Mþ þ 1) (MF C21H18N4O5).
ACKNOWLEDGMENTS
The authors thank the head, RSIC, Chandigarh, and CDRI, Lucknow, for
spectral and analytical data.
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