3/4-phenylene bisheterocycles from ring transformation reaction of sydnone derivatives: Synthesis of 3-[3/4-heterocyclyl]phenyl-5-methyl-3H-[1,3,4]- oxadiazol-2-ones from 3/4-acetylphenylsydnones and their biological properties

Article abstract of DOI:10.1002/hc.20255

The bifunctional 3/4-[acetyl]phenyl-sydnones 1a, 1b were subjected to a one-pot ring conversion to 3-[3/4-acetyl]phenyl-5-methyl-3H-[1,3, 4]-oxadiazol-2-ones 2a, 2b, which on further bromination yielded the 3-[3/4-bromoacyl]phenyl-5-methyl-3H-[1,3,4]-oxad

Full text of DOI:10.1002/hc.20255

Heteroatom Chemistry
Volume 18, Number 1, 2007
3/4-Phenylene Bisheterocycles from Ring
Transformation Reaction of Sydnone Derivatives:
Synthesis of 3-[3/4-Heterocyclyl]phenyl-5-
methyl-3H-[1,3,4]-oxadiazol-2-ones from
3/4-Acetylphenylsydnones and Their
Biological Properties
Ravindra R. Kamble,1 Prashant R. Latthe,2 and Bharati V. Badami2
1Yuvaraja’s College, University of Mysore, Mysore 570005, India
2P.G. Department of Chemistry, Karnatak University, Dharwad 580003, India
Received 6 August 2005; revised 29 December 2005
benzaldehyde. Most of these compounds exhibited
ABSTRACT: The bifunctional 3/4-[acetyl]phenyl-
antifungal activity greater than the reference drugs
sydnones 1a, 1b were subjected to a one-pot ring
ꢀ
C
used.
2007 Wiley Periodicals, Inc. Heteroatom Chem
conversion to 3-[3/4-acetyl]phenyl-5-methyl-3H-[1,3,
4]-oxadiazol-2-ones 2a, 2b, which on further bromi-
nation yielded the 3-[3/4-bromoacyl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-ones 3a, 3b. Reaction of these
compounds with thiourea yielded the 3-[3/4-(2-
aminothiazol-4-yl)]phenyl-5-methyl-3H-[1,3,4]-
oxadiazol-2-ones 4a, 4b. The other thiazole deriva-
tives 5a, 5b–7a, 7b were prepared by using thiosemi-
carbazide, thioacetamide, and thiobenzamide,
respectively. In another reaction of the bromoacetyl
compounds (3a, 3b) with 2-aminopyridine and
2-aminothiazole, the fused biheterocyclic compounds
3-[3/4-imidazo-[1,2-a]pyridine-2-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-ones 8a, 8b and 3-[3/4-
imidazo-[2,1-b]-thiazol-6-yl]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-ones 9a, 9b were obtained. The
3-[3/4-(benzofuran-2-carbonyl)]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-ones 10a, 10b were obtained
by treatment of compounds 3a, 3b with o-hydroxy
18:50–54, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20255
INTRODUCTION
Sydnones readily undergo one-step ring conversion
to a variety of heterocycles by 1,3-dipolar cycload-
dition reactions [1], and a few such reactions utiliz-
ing this latent functionality of sydnones have been
reported from our laboratory [2–5]. Sydnones con-
taining appropriate functional groups can act as
bifunctional systems, serving as important precur-
sors for the synthesis of bisheterocycles. The syn-
thetic method of bisheterocycles, which is lengthy
and affected sequentially, requires bifunctional pre-
cursors, which in turn are not readily accessible. In
an attempt to exploit the synthetic utility of some
bifunctional sydnones and to develop simple, con-
cise, and convenient method for the bisheterocycles,
we now report the synthesis of the title compounds
from 3/4-[acetyl]phenylsydnones 1a, 1b using the
one-pot 1,3-dipolar cycloaddition reaction. We have
Correspondence to: Bharati V. Badami; e-mail: bbadami@
rediffmail.com.
c
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2007 Wiley Periodicals, Inc.
50

3/4-Phenylene Bisheterocycles from Ring Transformation Reaction of Sydnone Derivatives 51
earlier reported [5] the facile one-pot synthesis of
not be separated. The mixture of the acetyl and
bromoacetyl derivatives was apparent in the 1H
NMR spectrum by the presence of CH3 protons
of the acetyl group at δ 2.60 and also the CH2
protons of the bromoacetyl compound at δ 4.62.
This mixture on further bromination using bromine
in acetic acid converted the acetyl compounds
2a, 2b, also to the bromoacetyl derivatives 3a,
3b. These compounds serve as key intermediates
for the preparation of various bisheterocycles 5a,
5b–10a, 10b. Compounds 3a, 3b on reaction
with thiourea yielded 3-[3/4-(2-aminothiazol-4-
yl)]phenyl-5-methyl-3H-[1,3,4]-oxadiazol-2-ones 5a,
5b, which are bisheterocycles containing a biologi-
cally potent thiazole ring. Similarly, other thiazole
derivatives 6a, 6b–8a, 8b were prepared by using
thiosemicarbazide, thioacetamide, and thiobenza-
mide, respectively. In another reaction of the bro-
moacetyl compounds 3a, 3b with 2-aminopyridine
and 2-aminothiazole, the fused bisheterocyclic
compounds 3-[3/4-imidazo-[1,2-a]pyridine-2-yl]-
9a, 9b and -[3/4-imidazo-[2,1-b]thiazol-6-yl]phenyl-
5-methyl-3H-[1,3,4]-oxadiazol-2-ones 10a, 10b were
obtained. Another bisheterocyclic system, 3-[3/4-
(benzofuran-2-carbonyl)]phenyl-5-methyl-3H-[1,3,
4]-oxadiazol-2-ones 10a, 10b, where the two het-
erocyclic rings are separated by a benzoyl group,
was prepared by the reaction of the bromoacetyl
compounds 3a, 3b with o-hydroxy benzaldehyde
in the presence of anhydrous K2CO3 (Scheme 1).
3-aryl-5-methyl-3H-[1,3,4]-oxadiazol-2-ones from 3-
arylsydnones, and this was the first documenta-
tion of their spectral and biological studies. In
continuation of this work and to carry out struc-
tural modifications, we thought of combining some
heterocycles with these oxadiazolinones. Initially,
we have selected the thiazole, imidazopyrimidine,
imidazothiazole, and the benzofuran heterocycles,
not only because of their pronounced biological
activities[6–9] but also because of their ease of syn-
thesis from the bromoacetyl moiety. Bisheterocy-
cles, which are mainly of synthetic origin, have
received great deal of attention in recent years, as
they can form useful molecular models to compare
the reactivities of the heterocyclic rings and to eval-
uate their biological properties.
RESULTS AND DISCUSSION
In the present work, 3/4-[acetyl]phenylsydnones
1a, 1b were first subjected to ring conversion to
3-[3/4-acetyl]phenyl-5-methyl-3H-[1,3,4]-oxadiazol-
2-ones 2a, 2b by one-pot reaction with bromine
in acetic anhydride. The formation of these acetyl
compounds was accompanied by bromination of the
acetyl group to give the 3-[3/4-bromoacyl]phenyl-
5-methyl-3H-[1,3,4]-oxadiazol-2-ones 3a, 3b, and
the product obtained was a mixture of the acetyl
and the bromoacetyl compounds, which could
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

52 Kamble, Latthe, and Badami
All these compounds were characterized by their
spectral and analytical data. All the 1H NMR spectra
of the 4,4ꢁ-disubstituted phenyl compounds 2a–10a
exhibited the AAꢁBBꢁ splitting pattern for the phenyl
ring protons.
temperature. After complete addition, stirring was
continued for 30 min. The reaction mixture was
poured into ice water, the solid separated was fil-
tered, dried, and crystallized from methanol to ob-
tain compounds 3a, 3b.
3-[3-Bromoacyl]phenyl-5-methyl-3H-[1,3,4]-oxa-
diazol-2-one 3a. White crystals, m.p. 141–143◦C,
yield 81%. 1H NMR (CDCl3, 300 MHz): δ 7.83–7.60
(m, 4H, Ar-H), 4.60 (s, 2H, CH2), 2.35 (s, 3H, oxadi-
azolinone CH3); IR 1770 (lactone νC O), 1675 (acetyl
νC O). Calculated for C11H9N2O3Br(297): C, 44.46%;
H, 3.03%; N, 9.48%. Found: C, 44.08%; H, 2.98%;
N, 9.01%.
Antimicrobial Activity
All the newly synthesized compounds were evaluated
for their antibacterial activity against Gram nega-
tive (Escherichia coli) and Gram positive (Bacillus
cirroflagellosus) bacteria and their antifungal activ-
ity against Aspergillus niger and Fusarium poa, with
Ciprofloxacin and Griseofulvin as reference drugs,
respectively. Only the p-bromoacetyl compound 3a
showed growth-inhibitory action two times more
than the reference drug against E. coli, A. niger,
and F. poa, while the corresponding m-isomer (3b)
was weak to moderately active against all these mi-
crobes. The 2-aminothiazole derivative (5a) ex-
hibited considerable selective bacterial growth in-
hibition only against E. coli and moderate activity
against both the fungi. In contrast, the presence of
a 2-hydrazine group (6a) reduced the antibacterial
activity against both the strains, while the 2-methyl-
(6a) and the 2-phenyl- (7a) substituted compounds
showed weak antibacterial activity. All the corre-
sponding m-isomers were weakly active against all
the microbes. In view of the variation of the biolog-
ical activity observed for the isomeric compounds,
the synthesis of structurally modified systems is con-
tinued and is in progress.
3-[4-Bromoacyl]phenyl-5-methyl-3H-[1,3,4]-oxa-
diazol-2-one 3b. White crystals, m.p. 162–64◦C,
yield 85%. 1H NMR (CDCl3, 300 MHz): δ 8.12–8.00
(4H, Ar-H), 4.44 (s, 2H, CH2), 2.39 (s, 3H, oxadia-
zolinone CH3); IR 1776 (lactone νC O), 1671 (acetyl
νC O). Calculated for C11H9N2O3Br(297): C, 44.46%;
H, 3.03%; N, 9.48%. Found: C, 44.06%; H, 3.00%;
N, 9.00%.
3-[3/4-(2-Substituted-thiazol-4-yl)]phenyl-5-
methyl-3H-[1,3,4]-oxadiazol-2-ones 4a,
4b–7a, 7b
General Procedure. 3-[3/4-Bromoacyl]phenyl-5-
methyl-3H-[1,3,4]-oxadiazol-2-one 3a/3b (0.01 mol)
was dissolved in ethanol (10 mL), and thiourea (0.5 g,
0.01 mol) was added with stirring at room temper-
ature. The mixture was stirred for 30 min and the
solution was made alkaline with sodium bicarbonate
solution. The solid separated was filtered, dried, and
crystallized from ethanol to get compounds 4a/4b.
Similarly, compounds 5a/5b, 6a/6b, and 7a/7b were
prepared using thiosemicarbazide, thioacetamide,
and thiobenzamide, respectively.
EXPERIMENTAL
IR spectra were recorded on a Nicolet-Impact 410
FT-IR spectrophotometer in KBr pellets. 1H NMR
spectra were recorded on a Brucker-Varian 300 MHz
FT-NMR spectrophotometer in CDCl3 using TMS as
an internal standard. Purity of the compounds was
checked by TLC on silica gel plates.
3-[3-(2-Aminothiazol-4-yl)]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-one 4a. Yellow crystals, m.p.
151–154◦C, yield 81%. 1H NMR (CDCl3, 300 MHz):
δ 8.01–7.80 (4H, Ar-H), 7.82 (s, 1H, thiazole C5-H),
5.01 (s, 2H, NH2, D2O exchanged), 2.35 (s, 3H, oxadi-
The synthesis of 3-[3/4-acetyl]phenyl sydnones
1a, 1b [10] and the sydnone ring transformation
of these compounds to the 3-[3/4-acetyl]-/3-[4-
bromoacyl]phenyl-5-methyl-3H-[1,3,4]-oxadiazol-2-
ones 2a, 2b and 3a, 3b was carried out by literature
methods [11].
azolinone CH3); IR 3370–3350 (br, νNH of thiazole),
2
1760 (lactone νC O), 1648 (νC N). Calculated for
C12H10N4O2S(274): C, 52.55%; H, 3.64%; N, 20.43%.
Found: C, 52.08%; H, 3.21%; N, 20.01%.
3-[3/4-Bromoacyl]phenyl-5-methyl-3H-[1,3,4]-
oxadiazol-2-ones 3a, 3b
The above mixture of compounds 2a/2b and 3a/3b
(0.01 mol) was suspended in glacial acetic acid
(10 mL), and bromine (0.5 mL, 0.11 mol) in acetic
acid (5 mL) was added with stirring at room
3-[4-(2-Aminothiazol-4-yl]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-one 4b. Yellow crystals, m.p.
170–172◦C, yield 89%. 1H NMR (CDCl3, 300 MHz):
δ 8.12–8.01 (4H, Ar-H), 7.8 (s, 1H, thiazole C5-H),
Heteroatom Chemistry DOI 10.1002/hc

3/4-Phenylene Bisheterocycles from Ring Transformation Reaction of Sydnone Derivatives 53
4.93 (s, 2H, NH2, D2O exchanged), 2.33 (s, 3H, oxa-
C16H15N3O2S(377): C, 67.90%; H, 3.97%; N, 11.40%.
Found: C, 67.68%; H, 3.49%; N, 11.01%.
diazolinone CH3); IR 3375–3350 (νNH of thiazole),
2
1757 (lactone νC O), 1652 (νC N). Calculated for
C12H10N3O2(260): C, 52.55%; H, 3.64%; N, 20.43%.
Found: C, 52.15%; H, 3.20%; N, 20.00%.
3-[4-(2-Phenylthiazol-4-yl]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-one 7b. Colorless crystals, m.p.
184–186◦C, yield 73%. 1H NMR (CDCl3, 300 MHz):
δ 8.15–7.60 (m, 9H, Ar-H), 7.85 (s, 1H, thiazole
C5-H), 2.39 2.32 (s, 3H, oxadiazolinone CH3); IR
1768 (lactone νC O), 1645 (νC N). Calculated for
C16H15N3O2S(377): C, 67.90%; H, 3.97%; N, 11.40%.
Found: C, 67.50%; H, 3.55%; N, 11.02%.
3-[3-(2-Hydrazinothiazol-4-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-one 5a. Yellow crystals, m.p.
191–194◦C, yield 74%. 1H NMR (CDCl3, 300 MHz):
δ 8.91 (br, 2H, NH2, D2O exchanged), 8.15–8.01 (4H,
Ar-H), 7.82 (s, 1H, thiazole C5-H), 4.82 (br, 1H, NH,
D2O exchanged), 2.32 (s, 3H, oxadiazolinone CH3);
IR 3375–3350 (br, νNHNH ), 1751 (lactone νC O), 1647
(νC N). Calculated for C122H11N5O2S(289): C, 49.82%;
H, 3.80%; N, 24.22%. Found: C, 49.40%; H, 3.31%;
N, 23.77%.
3-[3/4-Imidazo-[1,2-a]pyridine-2-yl]phenyl-5-
methyl-3H-[1,3,4]-oxadiazol-2-ones 8a, 8b
A mixture of compound 3a/3b (0.01 mol) and 2-
aminopyridine (0.01 mol) in methanol (20 mL) was
refluxed on a water bath for 2 h. The reaction was fol-
lowed by TLC. After the completion of the reaction,
the solution was diluted with water and the result-
ing mixture, containing a yellow solid, was cooled
in an ice bath. The solid separated was filtered,
washed thoroughly with water, and dried to obtain
compounds 8a, 8b.
3-[4-(2-Hydrazinothiazol-4-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-one 5b. Yellow crystals,
m.p. 157–159◦C, yield 80%. 1H NMR (CDCl3,
300 MHz): δ 8.90 (br, 2H, NH2, D2O exchanged),
8.15–8.01 (4H, Ar-H), 7.85 (s, 1H, thiazole C5-H),
4.82 (br, 1H, NH, D2O exchanged), 2.32, 7.85 (s, 1H,
thiazole C5-H), 2.32 (s, 3H, oxadiazolinone CH3);
IR 3375–3350 (br, νNHNH2), 1751 (lactone νC O), 1647
(νC N). Calculated for C12H11N5O2S(289): C, 49.82%;
H, 3.80%; N, 24.22%. Found: C, 49.51%; H, 3.42%;
N, 23.97%.
3-[3-Imidazo-[1,2-a]pyridine-2-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-one 8a. Yellow crystals, m.p.
191–193◦C, yield 61%. 1H NMR (CDCl3, 300 MHz):
δ 8.15–7.60 (m, 9H, Ar-H), 7.85 (s, 1H, thiazole
C5-H), 2.39 2.32 (s, 3H, oxadiazolinone CH3); IR
1777 (lactone νC O), 1623 (νC N). Calculated for
C16H12N4O2(292): C, 65.75%; H, 4.11%; N, 19.17%.
Found: C, 65.71%; H, 4.06%; N, 19.12%.
3-[3-(2-Methylthiazol-4-yl]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-one 6a. White crystals, m.p.
191–193◦C, yield 71%. 1H NMR (CDCl3, 300 MHz):
δ 8.10–8.00 (4H, Ar-H), 7.80 (s, 1H, thiazole C5-H),
4.24 (s, 3H, thiazole CH3), 2.33 (s, 3H, oxadiazoli-
none CH3); IR 1755 (lactone νC O), 1648 (νC N).
Calculated for C13H13N3O2S(275): C, 56.72%; H,
4.72%; N, 15.27%. Found: C, 56.28%; H, 4.28%; N,
14.724%.
3-[4-Imidazo-[1,2-a]pyridine-2-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-one 8b. Yellow crystals, m.p.
176–178◦C, yield 78%. 1H NMR (CDCl3, 300 MHz):
δ 8.35 (s, 1H, imidazo CH), 7.90–7.65 (8H, Ar-H),
2.31 (s, 3H, oxadiazolinone CH3); IR 1770 (lactone
νC O), 1603 (νC N). Calculated for C16H12N4O2(292):
C, 65.75%; H, 4.11%; N, 19.17%. Found: C, 65.47%;
H, 3.85%; N, 18.71%.
3-[4-(2-Methylthiazol-4-yl]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-one 6b. White crystals, m.p.
180–182◦C, yield 87%. 1H NMR (CDCl3, 300 MHz):
δ 7.95–7.65 (4H, Ar-H), 7.80 (s, 1H, thiazole C5-H),
4.22 (s, 3H, thiazole CH3), 2.33 (s, 3H, oxadiazoli-
none CH3); IR 1764 (lactone νC O), 1648 (νC N).
Calculated for C13H13N3O2S(275): C, 56.72%; H,
4.72%; N, 15.27%. Found: C, 56.45%; H, 4.38%; N,
14.84%.
3-[3/4-Imidazo-[2,1-b]thiazol-6-yl]phenyl-5-
methyl-3H-[1,3,4]-oxadiazol-2-ones 9a, 9b
A mixture of compound 3a/3b (0.01 mol) and 2-
aminothiazole (0.01 mol) in methanol (20 mL) was
refluxed on a water bath for 2 h. After the completion
of the reaction, the solution was diluted with water
and the resulting mixture, containing a white solid,
was cooled in an ice bath. The solid separated was
filtered, washed thoroughly with water and dried to
obtain compounds 9a, 9b.
3-[3-(2-Phenylthiazol4-yl]phenyl-5-methyl-3H-[1,
3,4]-oxadiazol-2-one 7a. Colorless crystals, m.p.
151–153◦C, yield 67%. 1H NMR (CDCl3, 300 MHz):
δ 7.90–8.10 (m, 9H, Ar-H), 7.85 (s, 1H, thiazole
C5-H), 2.33 (s, 3H, oxadiazolinone CH3); IR
1777 (lactone νC O), 1643 (νC N). Calculated for
Heteroatom Chemistry DOI 10.1002/hc

54 Kamble, Latthe, and Badami
3-[3-Imidazo-[2,1-b]thiazol-6-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-one 9a. White crystals, m.p.
179–181◦C, yield 86%. 1H NMR (CDCl3, 300 MHz):
δ 8.35 (s, 1H, imidazo CH), 7.91–7.53 (4H, Ar-H),
6.81 (d, 1H, J = 7.9 Hz, thiazole C4-H), 6.72 (d, 1H,
J = 7.9 Hz, thiazole C5-H), 2.41 (s, 3H, oxadiazoli-
none CH3); IR 1770 (lactone νC O), 1647 (νC N).
Calculated for C14H10N4O2S(298): C, 56.38%; H,
3.55%; N, 18.79%. Found: C, 56.02%; H, 2.94%; N,
18.16%.
8.30–8.21 (4H, Ar-H), 7.77–7.30 (m, 4H, benzofuran
Ar-H), 7.30 (s, 1H, benzofuran C2-H), 2.59 (s, 3H,
oxadiazolinone CH3); IR 1782 (lactone νC O), 1634
(νC flanked by benzofuran and phenyl ring), 1597
O
(νC N). Calculated for C18H12N2O4(320): C, 67.51%;
H, 3.75%; N, 8.75%. Found: C, 67.15%; H, 3.22%;
N, 8.33%.
ACKNOWLEDGMENTS
We thank Dr. G. S. Puranik, retired Professor of
Organic Chemistry and former Chairman, Depart-
ment of Chemistry, Karnatak University, Dharwad,
for encouragement and suggestions. The authors
also wish to thank SIF, Indian Institute of
Science, Bangalore, and USIC, Karnatak University,
Dharwad, for providing spectral data.
3-[4-Imidazo-[2,1-b]thiazol-6-yl]phenyl-5-methyl-
3H-[1,3,4]-oxadiazol-2-one 9b. White crystals, m.p.
192–195◦C, yield 81%. 1H NMR (CDCl3, 300 MHz):
δ 8.50, (s, 1H, imidazo CH), 7.91–7.53 (4H, Ar-H),
6.85 (d, 1H, J = 8 Hz, thiazole C4-H), 6.75 (d, 1H,
J = 8 Hz, thiazole C5-H), 2.41 (s, 3H, oxadiazolinone
CH3); IR 1770 (lactone νC O), 1647 (νC N). Calcu-
lated for C14H10N4O2S(298): C, 56.38%; H, 3.55%;
N, 18.79%. Found: C, 56.00%; H, 2.85%; N, 18.46%.
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[1,3,4]-oxadiazol-2-one 10a. Yellow crystals, m.p.
1
154–156◦C, yield 72%. H NMR (CDCl3, 300 MHz): δ
8.22–8.15 (4H, Ar-H), 7.77–7.30 (m, 4H, benzofuran
Ar-H), 7.25 (s, 1H, benzofuran C2-H), 2.59 (s, 3H,
oxadiazolinone CH3); IR 1782 (lactone νC O), 1634
(νC flanked by benzofuran and phenyl ring), 1597
O
(νC N). Calculated for C18H12N2O4(320): C, 67.51%;
H, 3.75%; N, 8.75%. Found: C, 67.04%; H, 3.28%;
N, 8.11%.
3-[4-(Benzofuran-2-carbonyl]phenyl-5-methyl-3H-
[1,3,4]-oxadiazol-2-one 10b. Yellow crystals, m.p.
1
167–169◦C, yield 72%. H NMR (CDCl3, 300 MHz): δ
[11] Stansfield, F. J Chem Soc 1958, 4781.
Heteroatom Chemistry DOI 10.1002/hc