Synthesis and antimicrobial evaluations of 1,3,4-thiadiazoline-based bisheterocyclics

Article abstract of DOI:10.1002/jhet.2158

The bisthiadiazolines (4a, 4b, 4c, 4d, 4e, 4f, 4g) were synthesized from the cyclization of bisthiosemicarbazones (3a, 3b, 3c, 3d, 3e, 3f, 3g) by refluxing under Ac₂O medium. The intermediates were obtained from the reactions of dibenzaldehydes

Full text of DOI:10.1002/jhet.2158

Month 2014
Synthesis and Antimicrobial Evaluations of 1,3,4-Thiadiazoline-
based Bisheterocyclics
*
Mohamad Yusuf, Manpreet Kaur, and Payal Jain
Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India
*
E-mail:yusuf_sah04@yahoo.co.in
Received August 22, 2013
DOI 10.1002/jhet.2158
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The bisthiadiazolines 4(a–g) were synthesized from the cyclization of bisthiosemicarbazones 3(a–g) by
refluxing under Ac2O medium. The intermediates were obtained from the reactions of dibenzaldehydes 2
(a–g) with thiosemicarbazide by refluxing in the presence of dry EtOH/HCl. The latter were prepared in
good yields from the O-alkylation of 3-hydroxybenzaldehyde with suitable dibromo derivatives under the
alkaline conditions. The structures of prepared compounds were determined from rigorous analysis of their
spectral parameters (UV–vis, IR, 1H NMR, 13C NMR and ESI-MS). The newly prepared compounds were
screened for their antimicrobial activity against seven bacterial and five fungi strains using serial tube
dilution method.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
thiosemicarbazide by refluxing in the presence of dry EtOH
and catalytic amount of HCl. The dibenaldehydes in turns
were obtained successfully from the reaction of 3-hy
droxybenzaldehyde with suitable dibromo reagents (trans-
1,4-dibromo-2-butene, α,α′-dibromo-o-xylene, α,α′-dibro
mo-p-xylene, α,α′-dibromo-m-xylene, 4,4′-bischlorome
thylbiphenyl, cis-1,4-dibromo-2-butene and 1,4-dich
loro-2-butyne) in the presence of KOH in dry EtOH/
DMF. The structures of the intermediates 2(a–g) and 3
(a–g) and final compounds 4(a–g) were determined with
the help of their spectroscopic parameters (UV–vis, IR,
1H NMR, 13C NMR and ESI-MS). The purity of these
products has also been confirmed with the help of their
elemental analysis results.
Heterocyclic chemistry is an integral part of the
chemical sciences and constitutes a considerable part of
the modern researches that are occurring presently
throughout the world. A wide range of heterocyclic
compounds have been synthesized in order to develop
physiologically and pharmacologically active molecules
[1–4]. Five-membered heterocyclic systems having three
heteroatoms at the symmetrical positions are known as
thiadiazolines, and these compounds have been studied
because of their interesting physiological properties [5].
These heterocyclics are found to exhibit various
biological applications like antitubercular [6], antimicro-
bial [7–9], anti-inflammatory [10–12], antiviral, anticonvul-
sant [13,14], hypertensive [15,16], anesthetic [17],
anticancer [18,19], hypoglycemic [20] and cytotoxic
activities [21–27]. Bisthiadiazolines are the molecules, which
are formed by joining two thiadiazoline moieties together
through the rigid linkers. In continuation of our researches
upon the bisheterocyclic compounds [28], the present investi-
gations have been focused upon the synthesis of new
bisthiadiazolines built around seven rigid spacers.
The IR spectra of 2(a–g) exhibited the strong
absorptions at 1694–1682 cmÀ1 because of the conjugated
C═O group, while the C–H stretching band appeared at
2879–2832 and 2759–2726 cmÀ1. In their 1H NMR
(400 MHz, CDCl3) spectra, the most downfield resonance
placed at δ 9.97–9.95 may be occurring because of the
CHO group proton. The signals resonating at δ 7.74–7.45
(2H, d, J = 3.7–1.2 Hz), 7.49–7.40 (2H, dd, J = 7.4–1.3 Hz),
7.48–7.26 (2H, t, J = 7.3–1.9 Hz) and 7.28–7.20 (2H, dt,
J = 3.6–1.6, 7.1–2.7 Hz) were easily assignable to phenyl
ring protons H-2, 6, 5 and 4, respectively. Further, in the
upfield region, the signal of suitable multiplicity was
observed for four protons of OCH2 group at δ 5.23–4.65
(vide experimental).
RESULTS AND DISCUSSION
The bisthiadiazolines 4(a–g) required for the present study
were synthesized from the reactions of bisthiosemicarbazones
3(a–g) with Ac2O under refluxing conditions (Scheme 1).
The latter were prepared in good yields from the
condensation reactions of dibenzaldehydes 2(a–g) with
In the 13C NMR (100 MHz, CDCl3) spectra of 2(a–g), the
presence of aldehyde group (CHO) was confirmed by the
appearance of signal at δ 192.13–191.15. The resonances
© 2014 HeteroCorporation

M. Yusuf, M. Kaur, and P. Jain
Vol 000
Scheme 1
placed at δ 159.92–159.01, 137.87–136.86, 134.64–129.87,
123.92–122.91, 122.76–121.42 and 113.19–112.80 could
be furnished by the aromatic ring carbon atoms C-3, 1, 2,
6, 5 and 4, respectively. The internal rigid chain OCH2
group also provided suitable signals in the aliphatic region
at δ 69.99–64.38 (vide experimental). The UV–vis spectra
of 2(a–g) had two maxima at 332–320 and 272–261 nm,
which were assignable to n → π* and π → π* transitions,
respectively.
The IR spectra of bisthiosemicarbazones 3(a–g) had
major absorptions at 3449–3400, 3269–3240, 3160–3102
(N–H), 1600–1589 (C═N) and 1180–1162 cmÀ1 (C═S)
and did not reveal any absorption in the carbonyl group
region, which confirms that C═O group has undergone
transformation during the reaction. The n → π* transition
in the UV–vis spectra of 3(a–g) was found to be placed at
328–320 nm.
1
The H NMR (400 MHz, DMSO-d6) spectra of 3(a–g)
showed a singlet at δ 11.43–11.39, which was assignable to
3-NH proton, and two singlets resonating at δ 8.12–8.01
and 7.89–7.70 may be resulted by NH-β and NH-α protons,
respectively. Another sharp singlet at δ 8.04–7.94 (2H) was
easily given by azomethyne hydrogen (H-1). The aromatic
ring protons were found to be placed at their expected
positions (vide experimental).
In the 13C NMR (100 MHz, DMSO-d6) spectra of 3
(a–g), the presence of C═S group was confirmed by
the appearance of a signal at δ 178.01–176.70. The
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Bisheterocyclics
downfield signals placed at δ 158.62–158.27 and 143.01–
142.05 may be assigned to C-3′ and C═N, respectively,
because of their direct linkage to the electronegative
oxygen and nitrogen atom, respectively. The rest of the
carbons C-1′, C-6′, C-5′, C-2′, C-4′ and OCH2 were
found to be resonating at δ 137.39–134.97, 129.81–
128.91, 122.82–120.52, 119.08–116.51, 111.86–111.46
and 69.12–67.18, respectively.
signals were observed in the aliphatic region at δ 69.23–
67.69 (OCH2), 22.75–22.31 (3‴–CH3) and 22.64–20.46
(2″–CH3).
ANTIMICROBIAL EVALUATIONS
Antibacterial activity.
The cultures required for the
biological studies of 3(a–g) and 4(a–g) were obtained from
MTCC (Microbial Type Culture Collection and Gene Bank,
Chandigarh, India). The newly prepared compounds were
screened for their antimicrobial activities against seven
bacterial strains namely Klubsellia pneumoniae (MTCC
3384), Pseudomonas aeruginosa (MTCC 424), Escherichia
coli (MTCC 443), Staphylococcus aureus (MTCC 96),
Bacillius subtilis (MTCC 441), Pseudomonas fluorescens
(MTCC 103) and Streptoccus pyrogens (MTCC 442) using
serial tube dilution method at various concentrations of 128,
64, 32, 16, 8, 4, 2 and 1 μg/ml. In this protocol, weighed
amounts of compounds were dissolved in DMSO to prepare
a stock solution. After that, they were diluted to the final
concentration of 128 μg/ml in nutrient broth medium.
Amoxicillin was used as a reference drug for comparison
and DMSO as a negative control. All the bacterial strains
were grown in nutrient broth media at 37 °C, then 100 μl of
the broth containing bacteria were inoculated to the test
compounds in the different dilutions. The inoculated tubes
were incubated for 24 h at 37 °C. The growth of bacteria
cultures was monitored visually after 24 h. The susceptibility
of studied compounds on the bacteria growth was
determined by the appearance of turbidity after 24 h of
incubation at 37°C. The results of antibacterial activity
have been presented in Table 1 (3(a–g)), Figure 1, and
Table 2 (4(a–g)), Figure 2.
The comparison of the 1H NMR spectra (400 MHz,
DMSO-d6) of 3(a–g) and 4(a–g) revealed that signals
present at δ 8.12–8.01 (NH-β) and 7.89–7.70 (NH-α) in
the former were found to be missing in 4(a–g), which
clearly describes that these protons have undergone
transformation during the cyclization reaction. Here, signal
of the 1‴–NH proton was present at δ 11.70–11.05 (2H) as
a sharp singlet. The protons H-2′, 6′, 5′ and 4′ were very
well resonating in the aromatic region at δ 7.38–7.25
(2H, J = 2.6–2.1 Hz), 7.35–7.04 (2H, t, J = 8.0–4.7 Hz),
7.26–6.69 (2H, d, Jo = 7.8–0.7 Hz) and 6.90–6.68 (2H, d,
Jo = 7.7–1.2 Hz), respectively. A singlet integrating for
two hydrogens at δ 6.80–6.68 may be allotted to
thiadiazoline ring proton H-2, and two methyl groups
(3‴ and 2″) also appeared as two sharp singlets at δ
2.28–2.20 and 2.09–2.01, respectively, which were
integrating for six protons each.
The UV–vis spectra of 4(a–g) had n → π* and π → π*
transitions at 327–322 and 279–269 nm, respectively. IR
spectra exhibited strong absorptions at 3161–3154 (N–H),
2951–2928, 2873–2849 (methylene C–H), 1688–1682,
1640–1636 (C═O) and 1610–1606 cmÀ1 (C═N).
In the 13C NMR (100 MHz, DMSO-d6) spectra of 4
(a–g), the downfield signals corresponding to 2‴–C═O
and 1″–C═O were found to be present at δ 169.90–169.02
and 169.30–167.01, respectively. The signal placed at δ
147.87–145.89 could be attributed to C═N group. The
aromatic carbon atoms were found to be resonating at
expected positions (vide experimental). The remaining
Antifungal activity.
The antifungal activity of
synthesized compounds 3(a–g) and 4(a–g) was also
determined in vitro by using the serial tube dilution
method against five fungi strains, namely, Aspergillius
E. coli
80
60
40
20
0
K. pneumoniae
P. aeruginosa
P. fluorescens
S. aureus
B. subtilis
S. pyrogens
A. janus
P. glabrum
Compound No.
Figure 1. In vitro MIC (μg/ml) of bisthiosemicarbazones 3(a–g).
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M. Yusuf, M. Kaur, and P. Jain
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janus (MTCC 2751), Aspergillius niger (MTCC 281),
Fusarium oxysporum (MTCC 2480), Aspergillus
sclerotiorum (MTCC 1008) and Pencillium glabrum
(MTCC 4951). Similar method was used for analysis of
antifungal activity as described earlier for the antibacterial
activity. Fluconazole was used as a reference drug for
comparison and DMSO as a negative control. The fungi
strains were grown in the Malt extract for 3 days, and
100 μl of the strains were inoculated to different dilutions
of the test compounds and incubated for 72 h at 28 °C.
The reference drug was also sustained at similar
conditions for comparison. The susceptibility of the fungal
strain on the studied compounds was determined by the
appearance of turbidity after 72 h of incubation at 28 °C.
The observed antifungal activity values are given in
Table 1 (3(a–g)), Figure 1, and Table 2 (4(a–g)), Figure 2.
It is evident from Table 1 that compound 3(a) exhibited
significant MIC (8 μg/ml) against the bacterial strains
Klubsellia pneumonia, P. aeruginosa, P. fluorescens,
B. subtilis and fungi strain P. glabrum. But the compound
3(b) was found to be active at the same MIC against strains
B. subtilis, A. janus, P. glabrum, A. niger and Fusarium
oxysporum. The compound 3(c) inhibited the growth
of strains Escherichia coli, Klubsellia pneumonia,
P. aeruginosa and P. fluorescens at the MIC of 8 μg/ml.
The compound 3(c) was found to be the most
active against B. subtilis (MIC – 4 μg/ml). The com-
pounds 3(d and e) showed activity against P. aeruginosa,
B. subtilis and P. glabrum at MIC of 8 μg/ml. Compound
3(e) also inhibited the growth of Klubsellia pneumoniae,
Pseudomonas fluoresencens and A. niger, while the
compound 3(f) was active against Staphylococcus
aureus, B. subtilis, A. niger and A. sclerotiorum at MIC
of 8 μg/ml.
Table 2 describes that compounds 4(a–e) displayed
significant activity (MIC – 4 μg/ml) against the strain A.
janus, whereas compounds 4(b and c) also inhibited the
growth of strain Pseudomonas flurescens and P. glabrum, re-
spectively, at the same MIC. The compound 4(e) was found
to be active at MIC of 4 μg/ml against Streptoccus pyrogens
and A. sclerotiorum. The compound 4(g) was significantly
active against the strain P. aeruginosa (MIC – 4 μg/ml).
Most of the compounds exhibited good activity at MIC
of 8 μg/ml against the tested microorganisms.
It was also observed from Tables 1 and 2 that
bisthiadiazolines 4(a–g) were found to be biologically
more active than their corresponding bisthiosemicarbazones
3(a–g). The geometry of internal spacer had significant
effect upon the antimicrobial behavior of the bisthiadiazoline,
and the bisheterocyclics linked through the aromatic moiety
(o-xylene 4(b), p-xylene 4(c) and biphenyl 4(e)) exhibited
better activity as compared to the compounds involving
olefinic and alkynic chain.
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E. coli
35
30
K. pneumoniae
25
20
P. aeruginosa
P. fluorescens
15
10
5
0
S. aureus
B. subtilis
S. pyrogens
A. janus
P. glabrum
Compound No.
Figure 2. In vitro MIC (μg/ml) of bisthidiazolines 4(a–g).
(OCH2); ESI-MS: m/z 319 (M + Na, 50%), 281 (4%), 181
(3%), 173 (29%), 159 (13%), 154 (5%), 131 (8%). Anal. Calc.
CONCLUSION
It may be concluded that this study describes a general and
efficient method for the synthesis of new thiadiazoline-based
symmetrical bisheterocyclic compounds built around the seven
rigid spacers. It was also observed that the bisthidiazolines 4
(a–g) seem to be significant antifungal agents.
for C18H16O4: Calc. C, 73.00%; H, 5.40%. Found: C, 72.70%;
H, 5.12%.
Synthesis of 3,3′-[benzene-1,2-diylbis(methanediyloxy)]dibenza
ldehyde 2b. The compound 2(b) was obtained by reacting 3-hy
droxybenzaldehyde (1.22 g, 0.01 mol) with α,α′-dibromo-o-xylene
(1.32 g, 0.005 mol) under similar conditions as used earlier for 2(a).
2(b): Light brown solid; Yield 74%; m.p.: 57–59 °C; IR (KBr):
ν
max (cmÀ1): 3064 (aromatic C–H), 2920, 2826 (methylene C–H),
EXPERIMENTAL
2877, 2758 (aldehyde C–H), 1684 (C═O), 1261, 1038 (C–O);
UV–vis (MeOH): λmax (nm): 328, 264; 1H NMR (400 MHz,
CDCl3): δ 9.97 (2H, s, CHO), 7.53 (2H, dd, J = 3.5, 6.9 Hz, H-
4′, 5′), 7.45 (2H, d, Jm = 2.2 Hz, H-2), 7.43 (2H, d, J = 4.0 Hz,
H-6), 7.41 (2H, d, J = 4.0 Hz, H-3′, 6′), 7.38 (2H, t, J = 3.4 Hz,
H-5), 7.23 (2H, td, J = 1.6, 2.7 Hz, H-4), 5.23 (4H, s, OCH2);
13C NMR (100 MHz, CDCl3): δ 191.98 (C═O), 159.14 (C-3),
137.86 (C-1), 134.64 (C-2), 130.22 (C-1′, 2′), 129.32 (C-4′, 5′),
128.83 (C-3′, 6′), 123.92 (C-6), 122.07 (C-5), 113.19 (C-4),
68.31 (OCH2); ESI-MS: m/z 369 (M + Na, 53%), 347 (M + 1,
100%), 302 (3%), 301 (4%), 225 (12%), 210 (8%), 209 (40%),
181 (11%). Anal. Calc. for C22H18O4: Calc. C, 76.30%; H,
Melting points reported are uncorrected. IR spectra were
scanned in KBr pellets on a Perkin Elmer (Buckinghamshire,
England) RXIFT Infrared spectrophotometer. 1H NMR spectra
(Fallanden, Switzerland) were recorded on a 400 MHz Bruker
spectrometer using TMS as the internal standard. The mass
spectra (Vernon Hills, USA) have been scanned on the Waters
Micromass Q-T of Micro (ESI) spectrometer. TLC plates were
coated with silica gel suspended in MeOH-CHCl3, and iodine
vapors were used as visualizing agent.
Synthesis of 3,3′-[but-2-ene-1,4-diylbis(oxy)]dibenzaldehyde
2a.3-ydroxybenzaldehyde (1.22 g, 0.01 mol) and KOH (0.55 g,
0.01 mol) were dissolved in alcohol (100 ml), and then solvent
was removed under vacuum. The residue was dissolved in DMF
(25 ml), and trans-1,4-dibromo-2-butene (1.07 g, 0.005 mol) was
added slowly. The reaction mixture was refluxed for 4 h, during
which KBr was separated out. The solvent was removed under
vacuum, and the remaining mixture was poured into iced HCl to
give a solid substance, which was filtered under suction and
thoroughly washed with water. The crude product thus obtained
was crystallized from MeOH to yield pure compound 2(a).
2(a): light brown solid; yield 71%; m.p.: 70–72 °C; IR
(KBr): νmax (cmÀ1): 3070 (aromatic C–H), 2910, 2832 (methy-
lene C–H), 2864, 2751 (aldehyde C–H), 1686 (C═O), 1258,
1025 (C–O); UV–vis (MeOH): λmax (nm): 324, 261; 1H
NMR (400 MHz, CDCl3): δ 9.97 (2H, s, CHO), 7.48 (2H, d,
J = 1.2 Hz, H-2), 7.46 (2H, dd, J = 2.3, 4.9 Hz, H-6), 7.39
(2H, t, J = 7.3 Hz, H-5), 7.20 (2H, dt, J = 2.3, 4.9 Hz, H-4),
6.12 (2H, t, Jvic = 1.6 Hz, CH═), 4.65 (4H, dd, J = 1.2,
2.3 Hz, OCH2); 13C NMR (100 MHz, CDCl3): δ 192.13
(C═O), 159.09 (C-3), 137.87 (C-1), 130.22 (C-2), 128.17
(CH═), 123.90 (C-6), 122.18 (C-5), 112.97 (C-4), 67.83
5.40%. Found: C, 76.60%; H, 5.42%.
Synthesis of 3,3′-[benzene-1,4-diylbis(methanediyloxy)]diben
zaldehyde 2c. The compound 2(c) was prepared by reacting
3-hydroxybenzaldehyde (1.22 g, 0.01 mol) with α,α′-dibromo-
p-xylene (1.32 g, 0.005 mol) under similar conditions as
discussed for 2(a).
2(c): Off white solid; Yield 88%; m.p.: 122–124 °C; IR (KBr):
ν
max (cmÀ1): 3065 (aromatic C–H), 2929, 2834 (methylene C–H),
2832, 2742 (aldehyde C–H), 1694 (C═O), 1254, 1037 (C–O);
UV–vis (MeOH): λmax (nm): 322, 269; 1H NMR (400 MHz,
CDCl3): δ 9.97 (2H, s, CHO), 7.48 (2H, brs, H-2), 7.47 (4H, s,
H-2′, 3′, 5′, 6′), 7.45 (2H, brs, H-6), 7.26 (2H, t, J = 3.1 Hz, H-
5), 7.24 (2H, t, Jm = 2.2 Hz, H-4), 5.14 (4H, s, OCH2); 13C
NMR (100 MHz, CDCl3): δ 192.04 (C═O), 159.24 (C-3),
137.86 (C-1), 136.37 (C-1′, 4′), 130.17 (C-2), 127.85 (C-2′, 3′,
5′, 6′), 123.84 (C-6), 122.14 (C-5), 113.18 (C-4), 69.99
(OCH2); ESI-MS: m/z 369 (M + Na, 100%), 347 (M + 1, 41%),
270 (29%), 225 (19%), 211 (16%), 121 (65%), 106 (43%). Anal.
Calc. for C22H18O4: Calc. C, 76.30%; H, 5.20%. Found: C,
76.00%; H, 5.17%.
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Synthesis of 3-(3-(3-formylbenzyloxy)benzyloxy)benzaldehyde 2d.
The compound 2(d) was synthesized by reacting 3-hydrox
ybenzaldehyde (1.22 g, 0.01 mol) with α,α′-dibromo-m-xylene (1.32 g,
0.005 mol) under similar conditions as described earlier for 2(a).
2(d): light brown solid; yield 69%; m.p.: 63–65 °C; IR (KBr):
C–H), 2879, 2757 (aldehyde C–H), 1682 (C═O), 1260, 1040
(C–O); UV–vis (MeOH): λmax (nm): 332, 269; 1H NMR
(400 MHz, CDCl3): δ 9.95 (2H, s, CHO), 7.56 (2H, d,
J = 3.7 Hz, H-2), 7.47 (4H, d, J = 3.8 Hz, H-6), 7.43 (2H, t,
J = 3.9 Hz, H-5), 7.25 (2H, td, J = 1.6, 2.7 Hz, H-4), 5.15 (4H,
s, OCH2); 13C NMR (100 MHz, CDCl3): δ 191.15 (C═O),
159.01 (C-3), 137.80 (C-1), 130.36 (C-2), 123.79 (C-6),
122.14 (C-5), 113.19 (C-4), 83.07 (C-2′), 68.31 (OCH2);
ESI-MS: m/z 317 (M + Na, 32%), 295 (M + 1, 45%), 284
(4%), 262 (100%), 158 (17%), 106 (67%). Anal. Calc. for
C18H14O4: Calc. C, 73.46%; H, 4.70%. Found: C, 73.24%;
ν
max (cmÀ1): 3348 (aromatic C–H), 2927, 2837 (methylene C–H),
2871, 2759 (aldehyde C–H), 1682 (C═O), 1253, 1039 (C–O);
UV–vis (MeOH): λmax (nm): 326, 270; 1H NMR (400 MHz,
CDCl3): δ 9.96 (2H, s, CHO), 7.53 (2H, brs, H-2), 7.48 (2H, d,
Jm = 1.5 Hz, H-6), 7.44 (2H, brs, H-5), 7.42 (1H, brs, H-6′),
7.36 (1H, d, J = 1.1 Hz, H-5′), 7.26 (2H, d, J = 4.5 Hz, H-2′, 4′),
7.23 (2H, t, J = 2.2 Hz, H-4), 5.13 (4H, s, OCH2); 13C NMR
(100 MHz, CDCl3): δ 192.06 (C═O), 159.18 (C-3), 137.79 (C-
1′), 136.86 (C-1), 130.32 (C-2), 129.16 (C-6′), 128.84 (C-4′),
127.49 (C-3′), 126.72 (C-2′), 126.50 (C-5′), 123.80 (C-6),
122.76 (C-5), 113.19 (C-4), 69.94 (OCH2); ESI-MS: m/z 369
(M + Na, 100%), 347 (M + 1, 59%), 268 (12%), 214 (6%), 213
(19%), 109 (24%), 104 (32%). Anal. Calc. for C22H18O4: Calc.
H, 4.68%.
Synthesis of 2,2′-(3,3′-(but-2-ene-1,4-diylbis(oxy))bis(3,1-pheny
lene))bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide) 3a. A
mixture of 2(a) (1.1 g, 0.005 mol) and thiosemicarbazide (0.91 g,
0.01 mol) in dry EtOH (20 ml) and HCl (1.0 ml) was refluxed for 4 h.
The progress of the reaction was monitored by TLC. After the
completion of the reaction, the resulting mixture was cooled in an ice
bath to give a solid substance. The crude product thus obtained was
filtered under suction, dried and crystallized from MeOH to yield
pure compound 3(a).
C, 76.30%; H, 5.40%. Found: C, 76.58%; H, 5.43%.
Synthesis of 3,3′-(biphenyl-4,4′-diylbis(methylene))bis(oxy)dibe
nzaldehyde 2e. The compound 2(e) was prepared by reacting 3-hy
droxybenzaldehyde (1.22 g, 0.01 mol) with 4,4′-bis-chloromethyldiphenyl
(1.25 g, 0.005 mol) under similar conditions as given earlier for 2(a).
3(a): off white solid; yield 87%; m.p.: 110–112 °C; IR (KBr):
υmax (cmÀ1) 3447, 3267, 3156 (N–H), 3026 (aromatic C–H),
2984, 2865 (methylene C–H), 1599 (C═N), 1261, 1082 (C–O),
1180 (C═S); UV–vis (MeOH): λmax (nm): 320; 1H NMR
(400 MHz, DMSO-d6): δ 11.42 (2H, s, 3-NH), 8.01 (2H, s, NH-
β), 7.99 (2H, s, H-1), 7.70 (2H, brs, NH-α), 7.40 (2H, t,
J = 2.2 Hz, H-2′), 7.27 (2H, t, J = 7.8 Hz, H-5′), 7.26 (2H, d, Jo =
7.6 Hz, H-6′), 6.93 (2H, ddd, J = 0.8, 2.6, 3.4 Hz, H-4′), 6.11
(2H, t, Jvic = 2.4 Hz, CH═), 4.65 (4H, d, Jvic = 1.1 Hz,
2(e): light brown solid; yield 67%; m.p.: 119–121 °C; IR
(KBr): νmax (cmÀ1): 3063 (aromatic C–H), 2924, 2820 (methy-
lene C–H), 2870, 2726 (aldehyde C–H), 1693 (C═O), 1261,
1
1027 (C–O); UV–vis (MeOH): λmax (nm): 320, 262; H NMR
(400 MHz, CDCl3): δ 9.97 (2H, s, CHO), 7.74 (2H, s, H-2),
7.63 (4H, d, Jo = 8.0 Hz, H-3′, 5′), 7.53 (4H, d, Jo = 8.0 Hz, H-
2′, 6′), 7.49 (4H, brs, H-6), 7.48 (2H, brs, H-5), 7.28 (2H, dd,
Jm,o = 3.6, 7.1 Hz, H-4), 5.18 (4H, s, OCH2); 13C NMR (100 MHz,
CDCl3): δ 191.58 (C═O), 159.24 (C-3), 139.74 (C-4′), 137.31 (C-
1), 135.21 (C-1′), 129.87 (C-2), 127.72 (C-3′, 5′), 126.69 (C-2′,
6′), 122.91 (C-6), 121.42 (C-5), 113.16 (C-4), 69.28 (OCH2); ESI-
MS: m/z 445 (M + Na, 9%), 423 (M + 1, 2%), 413 (8%), 359
(12%), 302 (23%), 301 (100%), 273 (4%), 219 (26%), 180 (42%),
149 (52%), 104 (8%). Anal. Calc. for C28H22O4: Calc. C, 79.62%;
H, 5.21%. Found: C, 79.93%; H, 5.23%.
Synthesis of 3,3′-(but-2-ene-1,4-diylbis(oxy))dibenzaldehyde
2f. The compound 2(f) was obtained by reacting 3-hydroxybenza
ldehyde (0.01 mol, 1.22 g) with cis-1,4-dichloro-2-butene (1.07 g,
0.005 mol) under similar conditions as used earlier for 2(a).
2(f): light brown solid; yield 70%; m.p.: 52–54 °C; IR (KBr):
νmax (cmÀ1): 3073 (aromatic C–H), 2909, 2838 (methylene C–H),
2868, 2754 (aldehyde C–H), 1689 (C═O), 1257, 1024 (C–O);
UV–vis (MeOH): λmax (nm): 324, 272; 1H NMR (400 MHz,
CDCl3): δ 9.97 (2H, s, CHO), 7.49 (2H, d, J= 1.2 Hz, H-2), 7.44
(2H, d, J= 1.9 Hz, H-5), 7.40 (2H, t, J= 1.3, 7.4 Hz, H-6), 7.22
(2H, m, H-4), 5.98 (2H, t, Jvic =3.4Hz, CH═), 4.76 (4H, d, Jvic =4.0
Hz, OCH2); 13C NMR (100 MHz, CDCl3): δ 192.05 (C═O),
158.92 (C-3), 137.83 (C-1), 130.23 (C-2), 128.39 (CH═),
123.90 (C-6), 122.11 (C-5), 112.80 (C-4), 64.38 (OCH2);
ESI-MS: m/z 319 (M + Na, 29%), 297 (M + 1, 100%), 276
(23%), 240 (8%), 194 (43%), 147 (12%), 129 (37%). Anal. Calc.
for C18H16O4: Calc. C, 73.00%; H, 5.40%. Found: C, 73.29%;
OCH2); 13C NMR (100 MHz, DMSO-d6):
δ 177.97
(C═S), 158.27 (C-3′), 142.24 (C═N), 135.33 (C-1′),
129.30 (C-6′), 127.95 (CH═), 120.52 (C-5′), 116.51
(C-2′), 111.46 (C-4′), 67.18 (OCH2); ESI-MS: m/z 465
(M + Na, 59%), 443 (M + 1, 23%), 426 (4%), 395 (27%),
389 (100%), 369 (6%), 354 (12%), 352 (21%), 324
(22%), 323 (63%), 313 (30%), 308 (23%), 224 (7%), 179
(7%). Anal. Calc. for C20H22N6O2S2: Calc. C, 54.29%, H,
4.97%; N, 19.00%; S, 14.47%. Found: C, 54.50%; H,
4.99%; N, 18.96%; S, 14.38%.
Synthesis of 2,2′-(3,3′-(1,2-phenylenebis(methylene))bis(oxy)bis(3,1-
phenylene)) bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide)
3b. The compound 3(b) was obtained by reacting 2(b) (0.5 g,
0.001445 mol) with thiosemicarbazide (0.26 g, 0.00289 mol)
under the same conditions as given earlier for 3(a).
3(b): off white solid; yield 82%; m.p.: 218–220 °C; IR (KBr):
υmax (cmÀ1) 3425, 3262, 3152 (N–H), 3027 (aromatic C–H),
2974, 2881 (methylene C–H), 1589 (C═N), 1257, 1097 (C–O),
1171 (C═S); UV–vis (MeOH): λmax (nm): 322; 1H NMR
(400 MHz, DMSO-d6): δ 11.41 (2H, s, 3-NH), 8.09 (2H, brs,
NH-β), 8.01 (2H, s, H-1), 7.81 (2H, brs, NH-α), 7.53 (2H,
d, J = 3.3 Hz, H-4″, 5″), 7.51 (2H, brs, H-2′), 7.36 (2H,
d, J = 3.2 Hz, H-3″, 6″), 7.27 (2H, t, J = 7.7 Hz, H-5′), 7.22
(2H, d, Jo = 7.3 Hz, H-6′), 6.99 (2H, d, Jo = 7.7 Hz, H-4′), 5.26
(4H, s, OCH2); 13C NMR (100 MHz, DMSO-d6): δ 178.01
(C═S), 158.46 (C-3′), 142.05 (C-1), 135.45 (C-4″, 5″), 134.97
(C-1′), 129.41 (C-6′), 128.66 (C-1″, 2″), 127.96 (C-3″, 6″),
120.73 (C-5′), 116.55 (C-2′), 111.86 (C-4′), 67.33 (OCH2);
ESI-MS: m/z 515 (M + Na, 5%), 493 (M + 1, 4%), 491 (6%),
476 (20%), 475 (62%), 453 (100%), 436 (7%), 432 (10%), 417
(6%), 402 (9%), 383 (8%), 374 (11%), 373 (19%), 369 (20%),
359 (13%). Anal. Calc. for C24H24N6O2S2: Calc. C, 58.53%; H,
H, 5.38%.
Synthesis of 3,3′-[but-2-yne-1,4-diylbis(oxy)]dibenzaldehyde
2g. The compound 2(g) was synthesized by reacting 3-hy
droxybenzaldehyde (1.22 g, 0.01 mol) with 1,4-dichloro-2-butyne
(1.47 g, 0.005 mol) under similar conditions as used earlier for 2(a).
2(g): brown solid; yield 64%; m.p.: 184–186 °C; IR (KBr):
νmax (cmÀ1): 3059 (aromatic C–H), 2923, 2832 (methylene
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Antimicrobial Evaluations of 1,3,4-Thiadiazoline-based
Bisheterocyclics
4.88%; N, 17.07%; S, 13.00%. Found: C, 58.76%; H, 4.90%; N,
17.13%; S, 13.05%.
brs, H-2′), 7.67 (4H, d, Jo = 8.1 Hz, H-3″, 5″), 7.55 (4H, d, Jo =
8.0 Hz, H-2″, 6″), 7.30 (2H, t, J = 7.7 Hz, H-5′), 7.21 (2H, d, Jo =
6.8 Hz, H-6′), 7.01 (2H, d, Jo = 7.0 Hz, H-4′), 5.18 (4H, s,
OCH2); 13C NMR (100 MHz, DMSO-d6): δ 176.83 (C═S),
158.62 (C-3′), 142.12 (C-1), 139.39 (C-4″), 137.39 (C-1′),
135.71 (C-1″), 129.62 (C-6′), 128.03 (C-3″, 5″), 126.59 (C-2″,
6″), 122.82 (C-5′), 119.08 (C-2′), 114.56 (C-4′), 68.20 (OCH2);
ESI-MS: m/z 559 (M + Na, 100%), 537 (M + 1, 46%), 455
(39%), 419 (35%), 403 (4%), 375 (27%), 374 (100%), 338
(18%), 298 (31%), 257 (4%), 245 (21%), 197 (6%), 180 (23%),
140 (61%), 105 (4%). Anal. Calc. for C30H28N6S2: Calc. C,
63.38%; H, 4.93%; N, 14.78%. Found: C, 63.63%; H, 4.95%;
N, 14.83%.
Synthesis of 2,2′-(3,3′-(1,4-phenylenebis(methylene))bis(oxy)bis(3,1-
phenylene))bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide) 3c.
The compound 3(c) was prepared by reacting 2(c) (0.5 g, 0.001445 mol)
with thiosemicarbazide (0.15 g, 0.00173 mol) under the same conditions
as described previously for 3(a).
3(c): off white solid; yield 85%; m.p.: 209–211 °C; IR (KBr):
υmax (cmÀ1) 3427, 3240, 3102 (N–H), 3023 (aromatic C–H),
2975, 2883 (methylene C–H), 1589 (C═N), 1262, 1098 (C–O),
1162 (C═S); UV–vis (MeOH): λmax (nm): 323; 1H NMR
(400 MHz, DMSO-d6): δ 11.42 (2H, s, 3-NH), 8.12 (2H, s, NH-
β), 8.03 (2H, s, H-1), 7.89 (2H, brs, NH-α), 7.53 (2H, brs, H-
2′), 7.48 (4H, s, H-2″, 3″, 5″, 6″), 7.30 (2H, t, J = 7.8 Hz, H-6′),
7.22 (2H, t, J = 7.4 Hz, H-5′), 7.04 (2H, dd, J = 1.5, 6.4 Hz, H-
4′), 5.14 (4H, s, OCH2); 13C NMR (100 MHz, DMSO-d6): δ
177.99 (C═S), 158.54 (C-3′), 142.08 (C-1), 136.44 (C-1′),
135.49 (C-1″, 4″), 129.42 (C-6′), 127.65 (C-2″, 3″, 5″, 6″),
120.73 (C-5′), 116.66 (C-2′), 111.67 (C-4′), 69.12 (OCH2);
ESI-MS: m/z 515 (M + Na, 14%), 493 (M + 1, 54%), 476
(18%), 475 (23%), 445 (27%), 432 (16%), 418 (4%), 417
(11%), 404 (14%), 374 (20%), 373 (53%), 344 (8%), 343
(13%), 300 (7%), 299 (20%), 298 (100%), 179 (14%), 147
(17%), 104 (8%). Anal. Calc. for C24H24N6O2S2: Calc. C,
58.53%; H, 4.87%; N, 17.07%; S, 13.00%. Found: C, 58.29%;
H, 4.85%; N, 17.00%, S, 12.94%.
Synthesis of 2,2′-(3,3′-(but-2-ene-1,4-diylbis(oxy))bis(bis(3,1-phen
ylene)) bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide)
3f. The compound 3(f) was obtained by reacting 2(f) (1.1 g,
0.005 mol) with thiosemicarbazide (0.91 g, 0.01 mol) under
the same conditions as described previously for 3(a).
3(f): off white solid; yield 87%; m.p.: 168–170 °C; IR (KBr):
υmax (cmÀ1) 3449, 3269, 3154 (N–H), 3027 (aromatic C–H),
2981, 2867 (methylene C–H), 1598 (C═N), 1261, 1082 (C–O),
1178 (C═S); UV–vis (MeOH): λmax (nm): 323; 1H NMR
(400 MHz, DMSO-d6): δ 11.39 (2H, s, 3-NH), 8.07 (2H, s, NH-
β), 8.02 (2H, s, H-1), 7.77 (2H, brs, NH-α), 7.42 (2H, t,
J = 2.2 Hz, H-2′), 7.27 (2H, d, Jo = 7.4 Hz, H-6′), 7.25 (2H, t,
J = 7.6 Hz, H-5′), 6.93 (2H, ddd, J = 0.7, 3.2, 2.6 Hz, H-4′), 6.09
(2H, t, Jvic = 2.1 Hz, CH═), 4.62 (4H, d, Jvic = 1.2 Hz, OCH2);
13C NMR (100 MHz, DMSO-d6): δ 177.97 (C═S), 158.27 (C-
3′), 142.42 (C-1), 136.83 (C-1′), 129.30 (C-6′), 127.95 (CH═),
120.52 (C-5′), 116.51 (C-2′), 111.46 (C-4′), 67.18 (OCH2);
ESI-MS: m/z 465 (M + Na, 100%), 443 (M + 1, 100%), 414
(24%), 378 (5%), 377 (8%), 364 (52%), 349 (16%), 348 (76%),
329 (19%), 321 (4%), 300 (6%), 279 (11%), 267 (7%), 248
(27%), 154 (10%). Anal. Calc. for C20H22N6O2S2: Calc. C,
54.29%, H, 4.97%; N, 19.00%; S, 14.47%. Found: C, 54.50%;
H, 5.00%; N, 19.07%; S, 14.53%.
Synthesis of 2-(3-(3-(3-((2-carbamothioylhydrazono)methyl)ben
zyloxy)benzylidene) hydrazinecarbothioamide of 3d.
The
compound 3(d) was synthesized by reacting 2(d) (0.5g,
0.001445 mol) with thiosemicarbazide (0.26 g, 0.00289 mol) under
the same conditions as used in 3(a).
3(d): light brown solid; yield 88%; m.p.: 63–65 °C; IR (KBr):
υmax (cmÀ1) 3428, 3260, 3154 (N–H), 3025 (aromatic C–H),
2973, 2883 (methylene C–H), 1591 (C═N), 1256, 1095 (C–O),
1175 (C═S); UV–vis (MeOH): λmax (nm): 321; 1H NMR
(400 MHz, DMSO-d6): δ 11.39 (2H, s, 3-NH), 8.05 (2H, brs,
NH-β), 8.03 (2H, s, H-1), 7.80 (2H, brs, NH-α), 7.55 (2H, d,
J = 3.1 Hz, H-6″), 7.52 (1H, d, J = 2.9 Hz, H-5″), 7.49 (2H, brs,
H-2′), 7.37 (2H, d, J = 3.0 Hz, H-2″, 4″), 7.26 (2H, t, J = 7.5 Hz,
H-5′), 7.21 (2H, d, Jo = 7.3 Hz, H-6′), 7.01 (2H, d, Jo = 7.6 Hz,
H-4′), 5.13 (4H, s, OCH2); 13C NMR (100 MHz, DMSO-d6): δ
177.98 (C═S), 158.60 (C-3′), 142.08 (C-1), 136.83 (C-1′),
136.43 (C-1″, 3″), 135.45 (C-4″, 6″), 129.81 (C-6′), 127.96 (C-
2″), 121.09 (C-5″), 120.68 (C-5′), 118.01 (C-2′), 111.67 (C-4′),
68.04 (OCH2); ESI-MS: m/z 515 (M + Na, 100%), 493 (M + 1,
78%), 478 (12%), 477 (6%), 423 (41%), 421 (9%), 419 (11%),
417 (43%), 399 (60%), 380 (28%), 371 (5%), 370 (9%), 368
(7%), 359 (12%). Anal. Calc. for C24H24N6O2S2: Calc. C,
58.53%; H, 4.88%; N, 17.07%; S, 13.00%. Found: C, 58.31%;
H, 4.85%; N, 17.05%; S, 12.96%.
Synthesis of 2,2′-(3,3′-(but-2-yne-1,4-diylbis(oxy))bis(3,1-phenyle
ne))bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide) 3g. The
compound 3(g) was prepared by reacting 2(g) (0.5 g, 0.00170 mol)
with thiosemicarbazide (0.30 g, 0.00340 mol) under the same
conditions as used in 3(a).
3(g): light brown solid; yield 71%; m.p.: 209–211 °C; IR (KBr):
υmax (cmÀ1) 3429, 3257, 3160 (N–H), 3025 (aromatic C–H),
2982, 2879 (methylene C–H), 1600 (C═N), 1256, 1084 (C–O),
1178 (C═S); UV–vis (MeOH): λmax (nm): 328; 1H NMR
(400 MHz, DMSO-d6): δ 11.39 (2H, s, 3-NH), 8.07 (2H, s, NH-
β), 7.94 (2H, s, H-1), 7.79 (2H, brs, NH-α), 7.38 (2H, t, J=1.8Hz,
H-2′), 7.29 (2H, t, J=6.7Hz, H-5′), 7.25 (2H, d, Jo =7.1Hz, H-
6′), 6.89 (2H, dd, J= 0.9, 2.3 Hz, H-4′), 4.72 (4H, s, OCH2); 13C
NMR (100 MHz, DMSO-d6): δ 176.70 (C═S), 158.50 (C-3′),
143.01 (C-1), 136.07 (C-1′), 128.91 (C-6′), 127.89 (C-2″), 121.86
(C-5′), 117.68 (C-2′), 111.86 (C-4′), 67.80 (OCH2); ESI-MS: m/z
463 (M + Na, 51%), 441 (M + 1, 12%), 426 (7%), 416 (100%),
412 (43%), 406 (20%), 405 (62%), 381 (17%), 346 (44%), 342
(16%), 310 (3%), 282 (19%), 163 (4%). Anal. Calc. for
C20H20N6O2S2: Calc. C, 54.54%; H, 4.54%; N, 19.09%; S,
14.54%. Found: C, 54.32%; H, 4.52%; N, 19.08%; S, 14.46%.
Synthesis of N,N′-(5,5′-(3,3′-(but-2-ene-1,4-diylbis(oxy))bis(3,1-
phenylene))bis(4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5,2-diyl))di
acetamide 4a. A mixture of 3(a) (0.5 g, 0.00113 mol) and
acetic anhydride (25 ml) was refluxed for 10 h, and the progress
Synthesis of 2,2′-(3,3′-(1,2-phenylenebis(methylene))bis(oxy)bis(3,1-
phenylene)) bis(methan-1-yl-1-ylidene)bis(hydrazinecarbothioamide)
3e.
The compound 3(e) was synthesized by reacting 2(e) (0.5g,
0.00118 mol) with thiosemicarbazide (0.214 g, 0.00236 mol) under the
similar conditions as described earlier for 3(a).
3(e): light brown solid; yield 88%; m.p.: 218–220 °C; IR
(KBr): νmax (cmÀ1): 3400, 3243, 3155 (N–H), 3026 (aromatic
C–H), 2982, 2862 (methylene C–H), 1599 (C═N), 1264, 1087
(C–O), 1176 (C═S); UV–vis (MeOH): λmax (nm): 318; 1H
NMR (400 MHz, DMSO-d6): δ 11.43 (2H, s, 3-NH), 8.10 (2H,
s, NH-β), 8.04 (2H, s, H-1), 7.82 (2H, brs, NH-α), 7.69 (2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Yusuf, M. Kaur, and P. Jain
Vol 000
of reaction was monitored by TLC. The resulting reaction
mixture was poured over ice to obtain a solid product, which
was filtered under suction and finally crystallized from MeOH
to yield pure compound 4(a).
527 (8%), 526 (22%), 425 (5%), 386 (4%), 372 (7%), 368 (35%),
344 (92%), 340 (11%), 268 (15%), 238 (11%), 162 (13%). Anal.
Calc. for C32H32N6O6S2: Calc. C, 58.18%; H, 4.84%; N, 12.72%;
S, 9.69%. Found: C, 57.95%; H, 4.86%; N, 12.66%; S, 9.75%.
Synthesis of N,N′-(5,5′-(3,3′-(1,3-phenylenebis(methylene))bis
(oxy)bis3,1-phenylene))bis(4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5
4(a): creamish solid; yield 85%; m.p.: 69–71 °C; IR (KBr): νmax
(cmÀ1): 3159 (N–H), 3062 (aromatic C–H), 2934, 2861 (methylene
C–H), 1685, 1638 (C═O), 1607 (C═N), 1239, 1015 (C–O); UV–vis
,2-diyl))diacetamide 4d.
The compound 4(d) was prepared by
1
reacting 3(d) (0.5 g, 0.00101 mol) with acetic anhydride (25 ml)
under the same conditions as described for 4(a).
(MeOH): λmax (nm): 324, 279; H NMR (400 MHz, DMSO-d6): δ
11.62 (2H, s, 1‴–NH), 7.27 (2H, brs, H-2′), 7.21 (2H, t,
J=7.2Hz, H-6′), 6.85 (2H, d, Jo =7.3Hz, H-5′), 6.79 (2H, d, Jo =
7.6 Hz, H-4′), 6.76 (2H, s, H-2), 6.04 (2H, t, Jvic =1.8Hz, CH═),
4.57 (4H, d, Jvic =1.4Hz, OCH2), 2.28 (6H, s, 3‴–CH3), 2.01
(6H, s, 2″–CH3); 13C NMR (100 MHz, DMSO-d6): δ 169.67 (2‴–
C═O), 169.30 (1″–C═O), 158.88 (C-3′), 147.35 (C═N), 141.89
(C-1′), 130.06 (C-6′), 128.30 (OCH2CH═), 118.09 (C-5′), 114.26
(C-2′), 112.37 (C-4′), 67.69 (OCH2), 67.15 (C-2), 22.75 (3‴–
CH3), 22.64 (2″–CH3); ESI-MS: m/z 633 (M + Na, 100%), 578
(5%), 533 (6%), 532 (11%), 476 (4%), 344 (37%). Anal. Calc. for
C28H30N6O6S2: Calc. C, 55.08%; H, 4.92%; N, 13.77%; S,
10.49%. Found: C, 55.30%; H, 4.94%; N, 13.82%; S, 10.38%.
Synthesis of N,N′-(5,5′-(3,3′-(1,2-phenylenebis(methylene))bis(oxy)
bis(3,1-phenylene))bis(4-acetyl-4, 5-dihydro-1,3,4-thiadiazole-5,2-diyl))
diacetamide 4b. The compound 4(b) was prepared by reacting 3(b)
(0.5 g, 0.00101 mol) with acetic anhydride (25 ml) under the same
conditions as used for earlier for 4(a).
4(d): light brown solid; yield 75%; m.p. 86–88 °C; IR(KBr): νmax
(cmÀ1): 3158 (N–H), 3059 (aromatic C–H), 2937, 2849 (methylene
C–H), 1684, 1637 (C═O), 1609 (C═N), 1237, 1034 (C–O); UV–
1
vis (MeOH): λmax (nm): 326, 276; H NMR (400 MHz, DMSO-
d6): δ 11.05 (2H, s, 1‴–NH), 7.89 (2H, s, H–6′′′′, 4′′′′), 7.76 (1H,
s, H-2′′′′), 7.31 (2H, d, J=2.3Hz, H-2′), 7.09 (1H, s, H-5′′′′),7.04
(2H, td, J=4.7, 7.9Hz, H-6′), 7.02 (2H, t, J=7.4Hz, H-5′), 6.90
(2H, d, Jo =7.3Hz, H-4′), 6.80 (2H, s, H-2), 5.14 (4H, s, OCH2),
2.25 (6H, s, 3‴–CH3), 2.09 (6H, s, 2″–CH3); 13C NMR (100 MHz,
DMSO-d6): δ 169.90 (2‴–C═O), 167.01 (1″–C═O), 158.13 (C-3′),
146.80 (C═N), 142.09 (C-1′), 137.48 (C-1′′′′, 3′′′′), 135.45 (C-2′′′
′), 134.09 (C-4′′′′, 6′′′′), 131.89 (C-5′′′′), 129.05 (C-6′), 115.39 (C-
5′), 113.47 (C-4′), 111.58 (C-2′), 69.23 (OCH2), 67.21 (C-2), 22.31
(3‴–CH3), 21.80 (2″–CH3); ESI-MS: m/z 683 (M + Na, 32%), 661
(M + 1, 19%), 627 (23%), 579 (7%), 558 (12%), 519 (10%), 431
(6%), 430 (7%), 376 (4%), 375 (46%), 363 (31%), 344 (81%), 342
(16%), 243 (18%), 169 (28%). Anal. Calc. for C32H32N6O6S2: C,
58.18%; H, 4.84%; N, 12.72%; S, 9.69%. Found: C, 57.94%; H,
4.86%; N, 12.76%; S, 9.62%.
4(b): off white solid; yield 66%; m.p.: 108–110 °C; IR (KBr): νmax
(cmÀ1): 3154 (N–H), 3068 (aromatic C–H), 2951, 2862 (methylene C–H),
1682, 1640 (C═O), 1610 (C═N), 1240, 1034 (C–O); UV–vis (MeOH):
1
Synthesis of N,N′-(5,5′-(3,3′-(biphenyl-4,4′-diylbis(methylene))bis
(oxy)bis(3,1-phenylene)) bis(4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5,2-
diyl))diacetamide 4e. The compound 4(e) was synthesized by reacting
3(e) (0.5 g, 0.0012 mol) with acetic anhydride (25 ml) under the same
conditions as used in 4(a).
λmax (nm): 323, 269; H NMR (400MHz, DMSO-d6): δ 11.68 (2H, s,
1‴–NH), 7.36 (2H, m, H-2′), 7.30 (2H, brs, H-6′), 7.26 (2H, t, J=0.7Hz,
H-5′), 7.06 (2H, d, Jp=0.4Hz, H-4′′′′, 5′′′′), 6.93 (2H, d, Jp=0.3Hz, H-3′
′′′, 6′′′′), 6.90 (2H, d, J=1.2Hz, H-4′), 6.68 (2H, s, H-2), 5.22 (4H, s,
OCH2), 2.25 (6H, s, 3‴–CH3), 2.08 (6H, s, 2″–CH3); 13C NMR
(100 MHz, DMSO-d6): δ 169.04 (2‴–C═O), 167.18 (1″–C═O), 159.01
(C-3′), 145.89 (C═N), 143.87 (C-1′), 137.43 (C-1′′′′, 2′′′′), 136.34 (C-4′′′′,
5′′′′), 135.02 (C-3′′′′, 6′′′′), 129.53 (C-6′), 115.65 (C-5′), 113.58 (C-4′),
111.61 (C-2′), 69.20 (OCH2), 67.08 (C-2), 22.43 (3‴–CH3),
20.46 (2″–CH3); ESI-MS: m/z 683 (M + Na, 100%), 661
(M + 1, 71%), 617 (18%), 526 (9%), 491 (4%), 476 (14%), 475
(40%). Anal. Calc. for C32H32N6O6S2: Calc. C, 58.18%; H,
4.84%; N, 12.72%; S, 9.69%. Found: C, 58.41%; H, 4.86%; N,
4(e): light brown solid; yield 78%; m.p.: 98–100 °C; IR (KBr): νmax
(cmÀ1): 3160 (N–H), 3057 (aromatic C–H), 2928, 2873 (methylene
C–H), 1686, 1639 (C═O), 1606 (C═N), 1237, 1056 (C–O); UV–
vis (MeOH): λmax (nm): 327, 278; 1H NMR (400 MHz, DMSO-d6):
δ 11.61 (2H, s, 1‴–NH), 7.63 (4H, d, Jo =8.0Hz, H-3′′′′, 5′′′′), 7.50
(4H, d, Jo =7.7Hz, H-2′′′′, 6′′′′), 7.25 (2H, t, J=8.0Hz, H-6′), 7.21
(2H, d, J=5.3Hz, H-5′), 7.32 (2H, d, J=2.1Hz, H-2′), 6.86 (2H, t,
J=7.6Hz, H-4′), 6.73 (2H, s, H-2), 5.11 (4H, d, J=1.4Hz, OCH2),
2.24 (6H, s, 3‴–CH3), 2.06 (6H, s, 2″–CH3); 13C NMR (100 MHz,
DMSO-d6): δ 169.06 (2‴–C═O), 167.38 (1″–C═O), 158.50 (C-3′),
146.12 (C═N), 142.58 (C-1′), 139.57 (C-4′′′′), 135.70 (C-1′′′′),
129.59 (C-6′), 127.97 (C-3′′′′, 5′′′′), 126.63 (C-2′′′′, 6′′′′), 117.34
(C-5′), 113.71 (C-2′), 111.63 (C-4′), 69.09 (OCH2), 65.83 (C-2),
22.39 (3‴–CH3), 21.79 (2″–CH3,); ESI-MS: m/z 759 (M + Na,
31%), 737 (M + 1, 19%), 679 (45%), 540 (8%), 475 (32%), 453
(100%), 369 (3%), 344 (18%), 238 (9%), 149 (41%), 102 (4%). Anal.
Calc. for C38H36N6O6S2: Calc. C, 61.95%; H, 4.89%; N, 11.41%; S,
8.69%. Found: C, 61.70%; H, 4.87%; N, 11.46%; S, 8.74%.
12.64%; S, 9.73%.
Synthesis of N,N′-(5,5′-(3,3′-(1,4-phenylenebis(methylene))bis
(oxy)bis(3,1-phenylene)) bis(4-acetyl-4,5-dihydro-1,3,4-thiadiazole-
5,2-diyl))diacetamide 4c.
The compound 4(c) was synthesized
by reacting 3(c) (0.5 g, 0.00101 mol) with acetic anhydride (25 ml)
under the similar conditions as used for 4(a).
4(c): off white solid; yield 80%; m.p.: 96–98 °C; IR(KBr): νmax
(cmÀ1): 3161 (N–H), 3061 (aromatic C–H), 2934, 2852 (methylene
C–H), 1687, 1639 (C═O), 1606 (C═N), 1239, 1035 (C–O); UV–vis
1
(MeOH): λmax (nm): 322, 278; H NMR (400 MHz, DMSO-d6): δ
Synthesis of N,N′-5,5′-(3,3′-(but-2-ene-1,4-diylbis(oxy))bis(3,1-
phenylene))bis(4-acetyl À4,5-dihydro-1,3,4-thiadiazole-5,2-diyl))
diacetamide 4f. The compound 4(f) was obtained by reacting 3
(f) (0.5 g, 0.00113 mol) with acetic anhydride (25 ml) under the
same conditions as described earlier for 4(a).
11.70 (2H, s, 1‴–NH), 7.52 (4H, s, H-2′′′′, 3′′′′, 5′′′′, 6′′′′), 7.38
(2H, d, J=2.6Hz, H-2′), 7.35 (2H, td, J= 4.9, 8.3 Hz, H-6′), 7.24
(2H, t, J=7.8Hz, H-5′), 6.83 (2H, d, Jo =7.7Hz, H-4′), 6.75 (2H,
brs, H-2), 5.20 (4H, s, OCH2), 2.20 (6H, s, 3‴–CH3), 2.04 (6H, s,
2″–CH3); 13C NMR (100 MHz, DMSO-d6): δ 169.09 (2‴–C═O),
167.29 (1″–C═O), 158.48 (C-3′), 146.07 (C═N), 142.78 (C-1′),
137.48 (C-1′′′′, 4′′′′), 135.65 (C-2′′′′, 3′′′′, 5′′′′, 6′′′′), 129.50 (C-
6′), 115.63 (C-5′), 113.58 (C-4′), 111.62 (C-2′), 69.21 (OCH2),
67.08 (C-2), 22.42 (3‴–CH3), 20.45 (2″–CH3); ESI-MS: m/z 683
(M + Na, 100%), 661 (M + 1, 3%), 629 (4%), 583 (9%), 569 (14%),
4(f): off white solid; yield 85%; m.p.: 120–122 °C; IR (KBr): νmax
(cmÀ1): 3157 (N–H), 3061 (aromatic C–H), 2935, 2862 (methylene
C–H), 1683, 1638 (C═O), 1607 (C═N), 1237, 1017 (C–O); UV–vis
1
(MeOH): λmax (nm): 323, 279; H NMR (400 MHz, DMSO-d6): δ
11.09 (2H, s, 1‴–NH), 7.25 (2H, brs, H-2′), 7.19 (2H, t,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis and Antimicrobial Evaluations of 1,3,4-Thiadiazoline-based
Bisheterocyclics
[2] Temple, C. 1,2,4-Triazoles, Montegomery, J. A., Ed.; Willy
Interscience: New York, 1981.
[3] Hetzhein, A.; Mockel, K. Adv Heterocycl Chem 1996, 7, 183.
[4] Sandstrom, J. Adv Heterocycl Chem 1968, 9, 165.
[5] Kornis G. I. Comprehensive Heterocyclic Chemistry II;
Storr, R. C., Ed.; Pergamon: Oxford, 1996; 4, 379.
J=7.2Hz, H-6′), 6.79 (2H, d, Jo =7.3Hz, H-5′), 6.69 (2H, s, H-2),
6.68 (2H, d, Jo =7.5Hz, H-4′), 6.08 (2H, t, Jvic =1.7Hz, CH═),
5.08 (4H, d, J=1.4Hz, OCH2), 2.26 (6H, s, 3‴–CH3), 2.08 (6H,
s, 2″–CH3); 13C NMR (100 MHz, DMSO-d6): δ 169.81 (2‴–
C═O), 169.12 (1″–C═O), 158.79 (C-3′), 147.08 (C═N), 141.78
(C-1′), 130.08 (C-6′), 128.27 (CH═), 118.23 (C-5′), 114.09 (C-2′),
112.34 (C-4′), 68.01 (OCH2), 65.93 (C-2), 22.69 (3‴–CH3), 21.68
(2″–CH3); ESI-MS: m/z 633 (M + Na, 68%), 611 (M + 1, 100%),
569 (15%), 543 (23%), 502 (16%), 434 (11%), 344 (8%). Anal.
Calc. for C28H30N6O6S2: Calc. C, 55.08%; H, 4.92%; N, 13.77%;
S, 10.49%. Found: C, 54.86%; H, 4.86%; N, 13.71%; S, 10.44%.
Synthesis of N,N′-(5,5′-(3,3′-(but-2-yne-1,4-diylbis(oxy))bis(3,1-
phenylene))bis(4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5,2-diyl))diac
etamide 4g. The compound 4(g) was prepared by reacting 3(g)
(0.5 g, 0.00113 mol) with acetic anhydride (25 ml) under the similar
conditions as discussed previously for 4(a).
[6] Shucla, H. K.; Desai, N. C.; Astik, R. R., Thaker, K. A. J Ind
Chem Soc 1984, 455.
[7] Desai, K.; Baxi, A. J Ind J Pharm Sci 1992, 54, 183.
[8] Gawande, N. G.; Shingare, M. S. Ind J Chem 1987, 26B, 387.
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[10] Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Konstlan, C.
R.; Schrier, D. J.; Dyer, R. D. J Med Chem 1993, 61, 1090.
[11] Song, Y.; Cornor, D. T.; Sercel, A. D.; Sorenson, R. J.;
Doubleday, R.; Unangst, P. C.; Roht, B. D.; Beylin, V. G.; Gilbertsen,
R. B.; Chan, K.; Schrier, D. J.; Guglietta, A.; Bornemerier, D. A.; Dyer,
R. D. J Med Chem 1999, 42, 1161.
[12] Abanauskas, L.; Kalcas, V.; Udrenait, E.; Gaidelis, P.;
Brukstus, A.; Dauksas, A. Pharmazie 2001, 56, 617.
[13] Chapleo, C. B.; Myers, M.; Myers, P. L.; Saville, J. F.; Smith,
A. C. B.; Stilling, M. R.; Tulloch, I. F.; Walter, D. S.; Welbourn, A. D. J
Med Chem 1986, 29, 2273.
4(g): light brown solid; yield 70%; m.p.: 102–104 °C; IR (KBr):
ν
max (cmÀ1): 3156 (N–H), 3061 (aromatic C–H), 2931, 2862 (meth-
ylene C–H), 1688, 1636 (C═O), 1609 (C═N), 1237, 1014 (C–O);
UV–vis (MeOH): λmax (nm): 325, 278; 1H NMR (400 MHz,
DMSO-d6): δ 11.59 (2H, s, 1‴–NH), 7.25 (2H, brs, H-2′), 7.20
(2H, t, J=7.4Hz, H-6′), 6.80 (2H, d, Jo =7.1Hz, H-5′), 6.79 (2H,
d, Jo =7.3Hz, H-4′), 6.73 (2H, s, H-2), 4.49 (4H, d, J=1.9Hz,
OCH2), 2.27 (6H, s, 3‴–CH3), 2.07 (6H, s, 2″–CH3); 13C NMR
(100 MHz, DMSO-d6): δ 169.02 (2‴–C═O), 168.00 (1″–C═O),
159.01 (C-3′), 147.87 (C═N), 141.99 (C-1′), 130.86 (C-6′),
128.01 (C-2′′′′), 117.89 (C-5′), 114.67 (C-2′), 112.03 (C-4′), 68.03
(OCH2), 65.89 (C-2), 22.68 (3‴–CH3), 22.61 (2″–CH3); ESI-MS:
m/z 631 (M + Na, 100%), 609 (M + 1, 43%), 586 (5%), 582 (5%),
526 (11%), 476 (4%), 344 (3%). Anal. Calc. for C28H28N6O6S2:
Calc. C, 55.26%; H, 4.61%; N, 13.81%; S, 10.52%. Found: C,
55.48%; H, 4.59%; N, 13.78%; S, 10.56%.
[14] Chapleo, C. B.; Myers, P. L.; Smith, A. C.; Stilling, M. R.;
Tulloch, I. F.; Walter, D. S. J Med Chem 1988, 31, 7.
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[18] Chou, J. Y.; Lai, S. H.; Pan, S. L.; Jow, G. M.; Chern, J. W.;
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[19] Hana, M. A.; Girges, M. M.; Rasala, D.; Gawinecki, R.
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Acknowledgments. Authors are highly thankful to DST (SERB,
Fast Track Scheme no. SR/FT/CS-041/2010), New Delhi, for
providing the financial support for this research work.
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REFERENCES AND NOTES
[1] (a) Kornis G. I. In Comprehensive Heterocyclic Chemistry I;
Katritzky, A. R., Rees, C. W., Ed.; Pergamon: Oxford, 1984; Vol 4,
Ch. 4.27, p 545 (b). Kornis, G. I. In Comprehensive Heterocyclic
Chemistry II, Storr, R. C., Ed.; Pergamon: Oxford, 1996, Vol 4, Ch.
4.10, 379.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet