Synthesis and characterization of some 5-substituted 2-thiol/thione-1,3,4-oxadiazoles

Article abstract of DOI:10.14233/ajchem.2016.19899

5-(4-Aminophenyl)-2-thiol-1,3,4-oxadiazole (1) was synthesized via the reaction of carbon disulfide with 4-aminobenzoyl hydrazide. Compound 1 was converted to the corresponding diazonium salt which was introduced in coupling reaction with sodium phenoxide as coupling reagent to give azo-oxadiazole derivative containing aldehyde group 2. The resulting aldehyde 2 was then introduced in acid-catalyzed condensation reactions with both 2-aminobenzothiazole and 2-amino-5-mercapto-1,3,4-thiadiazole to obtain the oxadiazolicimines 3a and 3b, respectively. Treatment of the resulting imines 3a and 3b with each succinic acid, maleic acid, phthalic acid and 3-nitrophthalic anhydrides, respectively, under (2+5) cycloaddition conditions afforded eight new oxadiazoles substituted with 1,3-oxazepane and 1,3-oxazepine moieties 4a-d and 5a-d, respectively. The resulting imines 3a and 3b were also treated with sodium azide under (2+3) cycloaddition conditions to obtain two new oxadiazoles containing tetrazole moiety 4e and 5e, respectively. The newly synthesized oxadiazoles might have some biological, pharmaceutical and medicinal applications.

Full text of DOI:10.14233/ajchem.2016.19899

Asian Journal of Chemistry; Vol. 28, No. 12 (2016), 2582-2588
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19899
Synthesis and Characterization of Some 5-Substituted 2-Thiol/Thione-1,3,4-Oxadiazoles
ZEID HASSAN ABOOD
Chemistry Department, College of Science, University of Kerbala, Kerbala, Iraq
Corresponding author: E-mail: zeid.ab2013@yahoo.com
Received: 9 February 2016;
Accepted: 25 July 2016;
Published online: 1 September 2016;
AJC-18043
5-(4-Aminophenyl)-2-thiol-1,3,4-oxadiazole (1) was synthesized via the reaction of carbon disulfide with 4-aminobenzoyl hydrazide.
Compound 1 was converted to the corresponding diazonium salt which was introduced in coupling reaction with sodium phenoxide as
coupling reagent to give azo-oxadiazole derivative containing aldehyde group 2. The resulting aldehyde 2 was then introduced in acid-
catalyzed condensation reactions with both 2-aminobenzothiazole and 2-amino-5-mercapto-1,3,4-thiadiazole to obtain the oxadiazolic-
imines 3a and 3b, respectively. Treatment of the resulting imines 3a and 3b with each succinic acid, maleic acid, phthalic acid and
3-nitrophthalic anhydrides, respectively, under (2+5) cycloaddition conditions afforded eight new oxadiazoles substituted with 1,3-oxazepane
and 1,3-oxazepine moieties 4a-d and 5a-d, respectively. The resulting imines 3a and 3b were also treated with sodium azide under (2+3)
cycloaddition conditions to obtain two new oxadiazoles containing tetrazole moiety 4e and 5e, respectively. The newly synthesized
oxadiazoles might have some biological, pharmaceutical and medicinal applications.
Keywords: 1,3,4-Oxadiazoles, Imines, 1,3-Oxazepanes, 1,3-Oxazepines, Tetrazoles, Azo.
antihistaminic [18], anti-HIV [19], antidepressant [20] and
antitumor activities [21]. Tetrazole and its derivatives have
attracted much attention because of their unique structure and
applications as antimicriobial activity [22], anti-inflammatory
activity [23], antialergic [24] and anticancer [25].
Thus, in this article, we reported here the synthesis of
new 5-substituted-2-thiol-1,3,4-oxadiazole derivatives bearing
biologically active heterocyclic moieties including benzothia-
zole, thiadiazole, oxazepane, oxazepine, tetrazole in addition
of azo group, which might have some biological activity.
INTRODUCTION
Oxadiazoles are five-membered heteroaromatic compounds
including two nitrogen atoms and one oxygen atom on the
ring. Among heterocyclic compounds, 1,3,4-oxadiazole has
become an important for the development of new drugs [1]
and pharmacological interest [2]. For example Raltegravir [3],
an antiretroviral drug A and Zibotentan [4], an anticancer agent
B currently used in clinical medicine. Compounds containing
1
,3,4-oxadiazole nucleus reported to be anti-inflammatory [5],
anticonvulsive, anticancer [6], depressant activity [7], antibac-
terial [8] and antimicrobial [9] properties. One of the popular
methods for the synthesis of 1,3,4-oxadiazole thione/thiol
derivatives reported by Hosur et al. [10] to synthesize of 2-mer-
capto-5-aryl-1,3,4-oxadiazole C from the properly substituted
acid hydrazides in presence of CS2/KOH. El-Hamouly et al.
EXPERIMENTAL
The chemicals were used as purchased from Fluka, Sigma
Aldrich, GCC and Merck. Benzene and THF were freshly
distilled from appropriate drying agents before use. Analytical
[11] were synthesized some 1,3,4-oxadiazole derivatives and
TLC was performed with silica gel 60 F254 plates The reactions
.
compound D exhibited the highest activity against breast
cancer cell line (MCF7).
were monitored by TLC and visualized by development of the
TLC plates with iodine vapour. Melting points were recorded
on an Electro thermal Stuart SMP: 30 capillary melting point
apparatus and are uncorrected. Infrared spectra were recorded
on SHIMADZU FTIR-8400S infrared spectrophotometer as
Oxazepine compounds have medical and biological
importance and they have medicinal [12,13] and pharma-
ceutical applications [14]. Some oxazepine derivatives are
considered a medical drug against the disease [15] and some
of them act as inhibitors of some enzymes action [16]. Fused
oxazepinone derivatives have attracted considerable attention
owing to their promising biological activities [17], such as
1
potassium bromide discs. H NMR spectra was collected on
NMR spectrometer 400 MHz,Avance III 400 Bruker, Germany
at 400 MHz in DMSO-d
6
as solvent and TMS as an internal
standard at Esfahan University, Iran. (CHNS) Elemental analysis

Vol. 28, No. 12 (2016)
Synthesis and Characterization of Some 5-Substituted 2-Thiol/Thione-1,3,4-Oxadiazoles 2583
O
2-[(Benzo[d]thiazol-2-ylimino)methyl]-4-[(E)-{4-(5-
OH
O
F
mercapto-1,3,4-oxadiazol-2-yl)phenyl}diazenyl]phenol 3a:
IR (KBr, νmax, cm ): 3429br ν(O-H), 3134 ν(N-H) thione form,
3064 ν(C-H) benzene, 2928 and 2746 ν(N-H) intramolecularly
hydrogen bonded, thione form, 2584 ν(S-H) thiol form, 1604s
ν(C=N) oxadiazole and ν(C=N) imine, vib. coupling, 1481s
ν(C=C) benzene and ν(C=N) benzothiazole, vib. coupling,
N
N
N
-1
H
H
N
N
O
N
O
N
A
N
O
1410 ν(N=N), 1064 ν(C=S) thione form, 839, 756 and 694
O
H
N
δo.o.p.(C-H) benzene.
O
O
N
S
N
4
-((E)-(4-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenyl)-
N
diazenyl)-2-(((5-mercapto-1,3,4-thiadiazol-2-yl)imino)-
-1
methyl)phenol 3b: IR (KBr, νmax, cm ): 3259 ν(O-H), 3074
ν(N-H) thione form and ν(C-H) benzene, vib. coupling, 2928
and 2756 ν(N-H) intramolecularly hydrogen bonded, thione
form, 2580 ν(S-H) thiol form, 1602s ν(C=N) oxadiazole and
ν(C=N) imine, vib. coupling, 1498s ν(C=C) benzene and
ν(C=N) thiadiazole, vib. coupling, 1408 ν(N=N), 1064 ν(C=S)
thione form, 840 and 702 δo.o.p.(C-H) benzene.
B
N
N
SH
O
C
General procedure for the synthesis of oxadiazolic-
oxazepanes and oxazepines (4a-d) and (5a-d): A mixture of
imine derivative (3a) (0.458 g, 1 mmol) or imine derivative
NO2
N
O
N
(3b) (0.441 g, 1 mmol) and succinic acid or maleic acid or
N
S
phthalic acid or 3-nitrophthalic anhydride (1 mmol) in dry
benzene (15 mL) was refluxed on a water bath at 70 °C for 24
h. and monitored by TLC. The mixture was then allowed to
cool down to room temperature, the coloured precipitate was
filtered, dried and recrystallized from ethanol.
D
Structures of some bioactive 1,3,4-oxadiazole derivatives
was carried out with Perkin Elmer 300A Elemental Analyzer
at Esfahan University, Iran.
-(4-Aminophenyl)-2-thiol-1,3,4-oxadiazole (1) was
synthesized according to Yong and Wood conditions [26] as
pale yellow crystals, m.p.: 234-236 °C, yield 76 %; IR (KBr,
(E)-3-(Benzo[d]thiazol-2-yl)-2-(2-hydroxy-5-((4-(5-
mercapto-1,3,4-oxadiazol-2-yl)phenyl)diazenyl)phenyl)-
5
-1
1,3-oxazepane-4,7-dione (4a): IR (KBr, νmax, cm ): 3163
ν(O-H) and ν(N-H) thione form, vib. coupling, 3066 ν(C-H)
-1
ν
max, cm ): 3448 νas.(NH
2
), 3352 νs.(NH
2
), 3086 ν(N-H) thione
benzene, 2968 ν(C-H) CH , oxazepane, 2937 and 2764 ν(N-H)
2
form and ν(C-H) benzene, vib. coupling, 2947 and 2764
ν(N-H), intramolecularly hydrogen bonded, thione form, 2590
intramolecularly hydrogen bonded, thione form, 2565 ν(S-H)
thiol form, 1695 ν(C=O, O=C-O and O=C-N) oxazepane,
vib. coupling, 1608 ν(C=N) oxadiazole, 1539, 1510 and 1450
ν(C=C) benzene and ν(C=N) benzothiazole, vib. coupling,
1411 ν(N=N), 1066 ν(C=S) thione form, 840 and 752 δo.o.p.(C-H)
ν(S-H) thiol form, 1604 ν(C=N) oxadiazole and δ(NH
2
) vib.
coupling, 1512 ν(C=C) benzene, 1068 ν(C=S) thione form,
8
35, 731 and 694 δo.o.p.(C-H) benzene.
E)-2-Hydroxy-5-[{4-(5-mercapto-1,3,4-oxadiazol-
yl)phenyl}diazenyl]benzaldehyde (2) was synthesized
1
(
benzene; H NMR: δ = 2.51 (DMSO solvent), 2.58-2.62 (t,
2
2
J = 6.8 Hz, 2H, CH –CO–O, oxazepane), 2.73–2.76 (t, J = 6.9
following the method described by Acton [27] as red solid,
Hz, 2H, CH –CO–N, oxazepane), 2.90 (s, 1H, S–H), 3.38 (H O
2
2
-1
m.p.: 196-198 °C, yield 78 %; IR (KBr, νmax, cm ): 3402br
ν(O-H), 3190 ν(N-H), thione form, 3095 ν(C-H) benzene,
in DMSO), 6.98–7.98 (Ar–H and C–H, oxazepane), 6.98–7.02
(t, J = 8.3 Hz, 1H, Ha), 7.18–7.22 (t, J = 8.3 Hz, 1H, Hb), 7.25
(s, 1H, Hc), 7.28–7.30 and 7.32–7.34 (dd, J = 7.2, 9.9 Hz,
2H, Hd; He), 7.41–7.43 and 7.45–7.48 (dd, J = 8.2, 11.7 Hz,
3H, 2×Hf; Hg), 7.64 (s, 1H, C–H, oxazepane), 7.73–7.75 (d, J
= 8.1 Hz, 2H, 2×Hh). 7.96–7.98 (d, J = 7.8 Hz, 1H, Hi), 9.40
(s, N–H, thione form), 10.39 (s, 1H, O–H). Anal. calcd. for
2
937 and 2748 ν(N-H) intramolecularly hydrogen bonded,
thione form, 2885 ν(C-H) aldehyde, 2580 ν(S-H) thiol
form, 1662 ν(C=O) aldehyde, 1604 ν(C=N) oxadiazole, 1477
ν(C=C) benzene, 1411 ν(N=N), 1068 ν(C=S) thione form,
842 and 721 δo.o.p.(C-H) benzene.
General procedure for the synthesis of oxadiazolic-
C
26
H
18
N
6
O
5
S : C, 55.91; H, 3.25; N, 15.05; S, 11.48 Found C,
2
imines (3a and 3b): Azo-oxadiazolic aldehyde (2) (1.63 g, 5
mmol) was dissolved in 15 mL of absolute ethanol containing
two drops of glacial acetic acid, then 2-aminobenzothiazole
0.75 g, 5 mmol) or 2-amino-5-mercapto-1,3,4-thiadiazole
0.665 g, 5 mmol) was dissolved in 10 mL of absolute ethanol
and added drop wise. The reaction mixture was refluxed with
stirring on a water bath at 70 °C for 9 to 11 h, respectively and
monitored by TLC. The mixture was then allowed to cool down
to room temperature, the coloured precipitate was filtered and
recrystallized from ethanol.
56.18; H, 3.36; N, 15.13; S, 11.17.
(E)-3-(Benzo[d]thiazol-2-yl)-2-(2-hydroxy-5-((4-(5-
mercapto-1,3,4-oxadiazol-2-yl)phenyl)diazenyl)phenyl)-
2,3-dihydro-1,3-oxazepine-4,7-dione (4b): IR (KBr, νmax, cm ):
3068 ν(O-H), ν(N-H) thione form and ν(C-H) benzene, vib.
coupling, 2935 and 2754 ν(N-H) intramolecularly hydrogen
bonded, thione form, 1703 ν(C=O, O=C-O) oxazepine, 1653
ν(C=O, O=C-N) oxazepine, 1604 ν(C=N) oxadiazole, 1475br
ν(C=C) benzene and ν(C=N) benzothiazole, vib. coupling,
1411 ν(N=N), 1068 ν(C=S) thione form, 852 and 750 δo.o.p.(C-H)
-1
(
(

2584 Abood
Asian J. Chem.
1
benzene; H NMR: δ = 2.51 (DMSO solvent), 3.35 (H
2
O in
forms, 1695s ν(C=O, O=C-O and O=C-N) oxazepane, vib.
coupling, 1604 ν(C=N) oxadiazole, 1510 and 1487 ν(C=C)
benzene and ν(C=N) thiadiazole, vib. coupling, 1417 ν(N=N),
DMSO), 6.10 (s, 2H, 2×olefinic =CH, oxazepine), 6.99–8.07
Ar–H and C–H, oxazepine), 6.99–7.03 (t, J = 8.2 Hz, 1H,
Ha), 7.19–7.23 (t, J = 8.2 Hz, 1H, Hb), 7.25 (s, 1H, Hc), 7.30–
(
1
1064 ν(C=S) thione form, 842 δo.o.p.(C-H) benzene; H NMR:
7.32 and 7.34–7.36 (dd, J = 9.5, 8.9 Hz, 2H, Hd; He), 7.48 (s,
1H, C–H, oxazepine), 7.62–7.64 (d, J = 10.4 Hz, 1H, Hf),
7.68–7.70 (d, J = 8.8 Hz, 2H, 2×Hg), 7.82–7.84 (d, J = 8.8
δ = 2.51 (DMSO solvent), 2.57–2.60 (t, J = 5.0 Hz, 2H, CH
CO–O, oxazepane), 2.73–2.74 (d, J = 5.4 Hz, 2H, CH –CO–
N, oxazepane), 2.86 and 2.90 (ss, 2H, 2×S–H), 3.35 (H O in
2
–
2
2
Hz, 2H, 2×Hh), 8.05–8.07 (d, J = 11.1 Hz, 1H, Hi), 9.39 (s,
H, N–H, thione form), 10.39 (s, 1H, O–H); Anal. calcd. for
: C, 56.11; H, 2.90; N, 15.10; S, 11.52; Found
C, 56.42; H, 3.06; N, 15.01; S, 11.73.
E)-4-(Benzo[d]thiazol-2-yl)-3-(2-hydroxy-5-((4-(5-
mercapto-1,3,4-oxadiazol-2-yl)phenyl)diazenyl)phenyl)-
DMSO), 7.12–7.84 (Ar–H and C–H, oxazepane), 7.12 (s, 1H,
Ha), 7.24–7.26 (d, J = 8.9 Hz, 1H, Hb), 7.52–7.54 (d, J = 8.5
Hz, 1H, Hc), 7.68–7.70 (d, J = 8.8 Hz, 2H, 2×Hd), 7.81 (s,
1H, C–H, oxazepane), 7.82–7.84 (d, J = 8.7 Hz, 2H, 2×He),
9.54 (s, 2H, 2×N–H, thione forms), 10.39 (s, 1H, O–H); Anal.
1
C
26
H
16
6 5 2
N O S
(
calcd. for C21
H
15
N
7
O
5
S : C, 46.57; H, 2.79; N, 18.10; S, 17.76;
3
3
ν
,4-dihydrobenzo[e][1,3]oxazepine-1,5-dione (4c): IR (KBr,
max, cm ): 3171 ν(O-H) and ν(N-H) thione form, vib. coupling,
Found C, 46.88; H, 2.96; N, 17.92; S, 17.98.
-1
(E)-2-(2-Hydroxy-5-((4-(5-mercapto-1,3,4-oxadiazol-
2-yl)phenyl)diazenyl)phenyl)-3-(5-mercapto-1,3,4-
thiadiazol-2-yl)-2,3-dihydro-1,3-oxazepine-4,7-dione (5b):
3061 ν(C-H) benzene, 2966 and 2806 ν(N-H) intramolecularly
hydrogen bonded, thione form, 2636 ν(S-H) thiol form, 1689
ν(C=O, O=C-O) and ν(C=O, O=C-N) oxazepine, vib. coupling,
-1
IR (KBr, νmax, cm ): 3269 ν(O-H), 3169 ν(N-H) thione form,
3072 ν(C-H) benzene, 2935 and 2789 ν(N-H) intramolecularly
hydrogen bonded, thione form, 2582 ν(S-H) thiol forms, 1707
ν(C=O, O=C-O and O=C-N) oxazepine, vib. coupling, 1604
ν(C=N) oxadiazole, 1537 and 1508 ν(C=C) benzene and ν(C=N)
thiadiazole, vib. coupling, 1411 ν(N=N), 1066 νν(C=S) thione
1600 ν(C=N) oxadiazole, 1554, 1487 and 1450 ν(C=C) benzene
and ν(C=N) benzothiazole, vib. coupling, 1411 ν(N=N), 1070
ν(C=S) thione form, 758 and 731 δo.o.p.(C-H) benzene; H
NMR: δ = 2.51 (DMSO solvent), 3.36 (H
1
2
O in DMSO), 6.98–
7
1
7
7
.84 (Ar–H and C–H, oxazepine), 6.98–7.02 (t, J = 8.0 Hz,
1
H, Ha), 7.19–7.22 (t, J = 7.4 Hz, 1H, Hb), 7.26 (s, 1H, Hc),
.30–7.32 and 7.34–7.36 (dd, J = 9.7, 7.0 Hz, 2H, Hd; He),
.47 (s, 1H, C–H, oxazepine), 7.52–7.60 (m, 6H, Hf; Hg; Hh;
form, 842 and 696 δo.o.p.(C-H, benzene); H NMR: δ = 2.51
(DMSO solvent), 3.36 (H O in DMSO), 6.64–6.67 (d, J = 11.8
2
Hz, 2H, 2×olefinic =CH, oxazepine), 7.12–7.84 (Ar–H and
C–H, oxazepine), 7.12 (s, 1H, Ha), 7.23–7.25 (d, J = 8.9 Hz,
1H, Hb), 7.51 (s, 1H, C–H, oxazepine), 7.52–7.54 (d, J = 7.2
Hi; Hj; Hk), 7.68–7.70 (d, J = 8.8 Hz, 2H, 2×Hl), 7.81–7.84
d, J = 8.6 Hz, 2H, 2×Hm), 9.60 (s,1H, N–H, thione form),
0.39 (s, 1H, O–H); Anal. calcd. for C30 : C, 59.40;
(
1
H
18
N O
6 5
S
2
Hz, 1H, Hc
(d, J = 8.9 Hz, 2H, 2×He), 9.39 and 9.40 (ss, 2H, 2×N–H,
thione forms), 10.39 (s, 1H, O–H);Anal. calcd. for C21 S :
)
, 7.68–7.70 (d, J = 8.2 Hz, 2H, 2×Hd), 7.82–7.84
H, 2.99; N, 13.85; S, 10.57; Found C, 59.72; H, 3.24; N, 13.91;
S, 10.33.
H N O
13 7 5
3
(
E)-4-(Benzo[d]thiazol-2-yl)-3-(2-hydroxy-5-((4-(5-
C, 46.75; H, 2.43; N, 18.17; S, 17.83; Found C, 46.93; H,
2.52; N, 18.26; S, 18.11.
mercapto-1,3,4-oxadiazol-2-yl)phenyl)diazenyl)phenyl)-6-
nitro-3,4-dihydrobenzo[e][1,3]oxazepine-1,5-dione (4d): IR
(E)-3-(2-Hydroxy-5-((4-(5-mercapto-1,3,4-oxadiazol-2-
yl)phenyl)diazenyl)phenyl)-4-(5-mercapto-1,3,4-thiadiazol-
2-yl)-3,4-dihydrobenzo[e][1,3]oxazepine-1,5-dione(5c): IR
(KBr, νmax, cm ): 3074 ν(O-H), ν(N-H) thione form and ν(C-
H) benzene, vib. coupling, 2962 and 2897 ν(N-H) intramole-
cularly hydrogen bonded, thione form, 2654 and 2528 ν(S-
H) thiol forms, 1689 ν(C=O, O=C-O and O=C-N) oxazepine,
vib. coupling, 1589 ν(C=N) oxadiazole, 1539 and 1508
ν(C=C) benzene and ν(C=N) thiadiazole, vib. coupling, 1408
-1
(KBr, νmax, cm ): 3282 ν(O-H), 3076 ν(N-H) thione form and
ν(C-H) benzene, vib. coupling, 2929 and 2760 ν(N-H) intra-
molecularly hydrogen bonded, thione form, 2596 ν(S-H) thiol
form, 1707 ν(C=O, O=C-O) and ν(C=O, O=C-N), oxazepine,
-1
vib. coupling, 1602 ν(C=N) oxadiazole, 1533 νas.(NO
2
), 1489br
ν(C=C) benzene and ν(C=N) benzothiazole, vib. coupling,
1
7
413 ν(N=N), 1313 νs.(NO
50 and 698 δo.o.p.(C-H) benzene; H NMR: δ = 2.51 (DMSO
O in DMSO), 6.99–8.26 (Ar–H and C–H,
oxazepine), 6.99–7.03 (t, J = 6.9 Hz, 1H, Ha), 7.22–7.25 (t, J
3.7 Hz, 1H, Hb), 7.26 (s, 1H, Hc), 7.30–7.32 (d, J = 8.2 Hz,
2
), 1068 ν(C=S) thione form, 840,
1
solvent), 3.34 (H
2
ν(N=N), 1068 ν(C=S) thione form, 839, 796 and 734 δo.o.p.(C-H)
1
benzene; H NMR: δ= 2.51 (DMSO solvent), 3.39 (H
2
O in
=
DMSO), 7.24–8.10 (Ar–H and C–H, oxazepine), 7.24–7.26
1
8
1
8
H, Hd), 7.43–7.45 (d, J = 8.5 Hz, 1H, He), 7.60–7.62 (d, J =
.5 Hz, 1H, Hf), 7.68–7.70 (d, J = 8.4 Hz, 2H, 2×Hg), 7.76 (s,
H, C–H, oxazepine), 7.96–8.06 (m, 3H, Hh; Hi; Hj), 8.09–
.11 (d, J = 8.4 Hz, 2H, 2×Hk), 8.24–8.26 (d, J = 7.9 Hz, 1H,
(d, J = 8.9 Hz, 1H, Ha), 7.53–7.55 (d, J = 9.1 Hz, 1H, Hb),
7.60 (s, 1H, Hc), 7.68–7.70 (d, J = 8.5 Hz, 2H, 2×Hd , 7.78 (s,
)
1H, C–H, oxazepine), 7.83–7.85 (d, J = 8.1 Hz, 2H, 2×He),
8.03–8.10 (m, 4H, Hf; Hg; Hh; Hi), 9.44 and 9.48 (ss, 2H,
2×N–H, thione forms), 10.39 (s, 1H, O–H); Anal. calcd. for
Hl), 9.44 (s, 1H, N–H, thione form), 10.38 (s, 1H, O–H);Anal.
calcd. for C30 : C, 55.30; H, 2.63; N, 15.05; S, 9.84;
Found C, 55.63; H, 2.54; N, 15.14; S, 9.65.
E)-2-(2-Hydroxy-5-((4-(5-mercapto-1,3,4-oxadiazol-
-yl)phenyl)diazenyl)phenyl)-3-(5-mercapto-1,3,4-
thiadiazol-2-yl)-1,3-oxazepane-4,7-dione (5a): IR (KBr, νmax
H
17
N
7
O S
7 2
C
25
H
15
N
7
O
5
S : C, 50.93; H, 2.56; N, 16.63; S, 16.31; Found
3
C, 51.15; H, 2.66; N, 16.86; S, 16.01.
(
(E)-3-(2-Hydroxy-5-((4-(5-mercapto-1,3,4-oxadiazol-
2-yl)phenyl)diazenyl)phenyl)-4-(5-mercapto-1,3,4-
thiadiazol-2-yl)-6-nitro-3,4-dihydrobenzo[e][1,3]-
2
,
-1
-1
cm ): 3101 ν(O-H) and ν(N-H) thione form, vib. coupling,
057 ν(C-H) benzene, 2933 and 2758 ν(N-H) intramolecularly
hydrogen bonded, thione form, 2656 and 2551 ν(S-H) thiol
oxazepine-1,5-dione (5d): IR (KBr, νmax, cm ): 3221 ν(O-H),
3
3113 ν(N-H) thione form, 3076 ν(C-H) benzene, 2924 and
2794 ν(N-H) intramolecularly hydrogen bonded, thione form,

Vol. 28, No. 12 (2016)
Synthesis and Characterization of Some 5-Substituted 2-Thiol/Thione-1,3,4-Oxadiazoles 2585
-
1
2
634 ν(S-H) thiol form, 1718 ν(C=O, O=C-O) oxazepine, 1683
ν(C=O, O=C-N) oxazepine, 1606 ν(C=N) oxadiazole, 1537
), 1568, 1510 and 1475 ν(C=C) benzene and ν(C=N)
thiadiazole, vib. coupling, 1408 ν(N=N), 1315 νs.(NO ), 1062
ν(C=S) thione form, 750 and 690 δo.o.p.(C-H) benzene; H
NMR: δ = 2.51 (DMSO solvent), 3.34 (H O in DMSO), 7.23-
.09 (Ar–H and C–H, oxazepine), 7.23–7.25 (d, J = 8.7 Hz,
H, Ha), 7.53–7.55 (d, J = 5.8 Hz, 1H, Hb), 7.64 (s, 1H, Hc),
.68–7.70 (d, J = 8.7 Hz, 2H, 2×Hd , 7.77 (s, 1H, C–H,
tetrazol-5-yl)phenol (5e): IR (KBr, νmax, cm ): 3259br ν(O-
H), ν(N-H) thione form and ν(C-H) benzene, vib. coupling,
2941 and 2881 ν(N-H) intramolecularly hydrogen bonded,
thione form, 1591 ν(C=N) tetrazole and ν(C=N) oxadiazole,
vib. coupling, 1506 ν(C=C) benzene and ν(C=N) thiadiazole,
vib. coupling, 1400ss ν(N=N), 1028 ν(C=S) thione form, 837
ν
as.(NO
2
2
1
2
1
8
1
7
and 742 δo.o.p(C-H) benzene; H NMR: δ= 2.51 (DMSO solvent),
3.29 (H O in DMSO), 3.60 and 3.71 (ss, 2H, 2×S-H), 7.18–
7.71 (Ar–H), 7.18 (s, 1H, Ha), 7.42–7.44 (d, J = 8.5 Hz, 1H,
Hb), 7.51–7.53 (d, J = 8.1 Hz, 1H, Hc), 7.67–7.68 and 7.70–
7.71 (dd, J = 3.7, 6.7 Hz, 4H, 2×Hd; 2×He), 8.45 and 8.70 (ss,
2×N–H, thione forms), 9.36 (s, 1H, O–H); Anal. calcd. for
2
)
oxazepine), 7.83–7.85 (d, J = 8.5 Hz, 2H, 2×He), 7.99–8.09
m, 3H, Hf; Hg; Hh), 9.32 and 9.36 (ss, 2H, 2×N–H, thione
forms), 10.39 (s, 1H, O–H); Anal. calcd. for C25 : C,
7.32; H, 2.22; N, 17.66; S, 15.16; Found C, 47.64; H, 2.15; N,
(
H
14
N
8
O S
7 3
4
1
C
17
H
10
N
10
O S
2 3
: C, 42.32; H, 2.09; N, 29.03; S, 19.94; Found
7.96; S, 15.07.
C, 42.55; H, 2.01; N, 29.22; S, 19.80.
General procedure for the synthesis of oxadiazolic-
RESULTS AND DISCUSSION
tetrazoles 4e and 5e: A mixture of imine derivative 3a (0.458
g, 1 mmol) or imine derivative 3b (0.441 g, 1 mmol) and sodium
azide (0.065 g, 1 mmol) in tetrahydrofuran (20 mL) was
refluxed with stirring on a water bath at 70 °C for 24 h. TLC
showed that the reactions were completed. The reaction
mixture was then allowed to cool down to room temperature.
The solvent was removed by evaporation under reduced
pressure and the coloured precipitate was recrystallized from
ethanol.
4-Aminobenzoic hydrazide was converted to 5-(4-amino-
phenyl)-2-thiol-1,3,4-oxadiazole (1) by treating it with carbon
disulfide in presence of potassium hydroxide as catalyst in
absolute ethanol [26]. Diazotization of amino group in compound
1 using sodium nitrite and hydrochloric acid generated the
corresponding diazonium salt which was directly introduced
in coupling reaction with 2-hydroxybenzaldehyde dissolved
in sodium hydroxide solution to give azo-oxadiazole derivative
(2) containing aldehyde group [27]. Aldehyde group of azo-
oxadiazole derivative (2) was condensed with two selected
amines including 2-aminobenzothiazole (ABT) and 2-amino-
5-mercapto-1,3,4-thiadiazole (AMT) in the presence of glacial
acetic acid as catalyst in absolute ethanol to yield the azo-
imine derivatives of 1,3,4-oxadiazole (3a and 3b), respectively
(Schemes I and II). A concerted reactions involving (2+5)
cycloadditions of imine group of oxadiazolic-imines (3a and
3b) with succinic acid, maleic acid, phthalic acid and 3-nitro-
phthalic anhydrides, as five-membered components, in dry
benzene at 70 °C for 24 h gave the seven-membered 1,3-
oxazepane and 1,3-oxazepine derivatives of 1,3,4-oxadiazole
4a-d and 5a-d, respectively in good yields (Table-1). Moreover,
a concerted reactions involving the (2+3) cycloadditions of
imine group of the oxadiazolic-imines (3a and 3b) with sodium
azide in tetrahydrofuran at 70 °C for 24 h afforded 1,5-disubs-
tituted tetrazole derivatives of 1,3,4-oxadiazole 4e and 5e,
respectively in good yields (Table-1).
(
E)-2-(1-(Benzo[d]thiazol-2-yl)-1H-tetrazol-5-yl)-4-
(
(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)diazenyl)-
-1
phenol (4e): IR (KBr, νmax, cm ): 3290br ν(O-H), ν(N-H)
thione form and ν(C-H) benzene, vib. coupling, 2941 and 2877
ν(N-H) intramolecularly hydrogen bonded, thione form, 1597
ν(C=N) tetrazole and ν(C=N) oxadiazole, vib. coupling, 1543
ν(C=C) benzene and ν(C=N) benzothiazole, vib. coupling,
1
410 ν(N=N), 1043 ν(C=S) thione form, 840 and 748 δo.o.p(C-H)
1
benzene; H NMR: δ = 2.51 (DMSO solvent), 3.34 (H O in
2
DMSO), 3.76 (s,1H, S-H), 6.99–7.73 (Ar–H), 6.99–7.01 (t,
J = 5.1 Hz, 1H, Ha), 7.05–7.08 (t, J = 7.4 Hz, 1H, Hb), 7.19
s, 1H, Hc), 7.23–7.24 and 7.26–7.28 (dd, J = 3.4, 7.7 Hz, 2H,
Hd; He), 7.45–7.47 (d, J = 8.0 Hz, 1H, Hf), 7.52–7.54 (d, J =
.4 Hz, 2H, 2×Hg), 7.64–7.66 (d, J = 8.2 Hz, 2H, 2×Hh),
.71–7.73 (d, J = 9.7 Hz, 1H, Hi), 8.60 (s, N–H, thione form),
(
8
7
9
.36 (s, 1H, O–H); Anal. calcd. for C22
H
13
N
9
O
2
S : C, 52.90;
2
H, 2.62; N, 25.24; S, 12.84; Found C, 53.23; H, 2.54; N, 25.41;
S, 12.62.
(
E)-4-((4-(5-Mercapto-1,3,4-oxadiazol-2-yl)phenyl)-
The chemical structures of the target compounds synthe-
sized were deduced from IR, H NMR spectral measurements
1
diazenyl)-2-(1-(5-mercapto-1,3,4-thiadiazol-2-yl)-1H-
TABLE-1
PHYSICAL PROPERTIES OF THE SYNTHESIZED COMPOUNDS
Product
Physical state
Orange solid
Red solid
Orange solid
Orange solid
Red solid
R (developer)
m.p. (°C)
Weight (g)/Yield (%)
1.626/71
f
3a
0.75 (n-hexane/EtOAc, 3:1)
0.84 (n-hexane/EtOAc, 2:1)
0.52 (n-hexane/EtOAc, 1:1)
0.49 (n-hexane/EtOAc, 1:1)
0.46 (n-hexane/EOAc, 1:1)
0.40 (n-hexane/EtOAc, 1:1)
0.50 (n-hexane/EtOAc, 1:1)
0.68 (n-hexane/EtOAc, 1:1)
0.66 (n-hexane/EtOAc, 1:1)
0.61 (n-hexane/EtOAc, 1:1)
0.55 (n-hexane/EtOAc, 1:1)
0.60 (n-hexane/EtOAc, 1:1)
238-240
251-252
260-262
243-245
252-254
264-266
153-155
176-178
183-185
231-233
240-242
135-137
3b
1.698/77
0.452/81
0.440/79
0.436/72
0.508/78
0.374/75
0.444/82
0.431/80
4a
4b
4c
4d
Red solid
4e
Light purple solid
Dark orange solid
Dark Orange solid
Dark orange solid
Red solid
5a
5b
5c
0.418/71
0.488/77
0.395/82
5d
5e
Dark purple solid

2586 Abood
Asian J. Chem.
O
C
N
N
1
2
) i
) ii
NH2
N N
1) iii
2) iv
N
OH
NH2
H N
2
N
HS
O
N
HS
H
1
O
CHO
2
v
N
N
N
OH
N
N
HS
N
N
O
N
OH
Ar
Ar
Ar
vi
N
N
S
O
O
HS
O
4
a= Ar
a= Ar
HC
N
Ar
N N
S
O
N
S
5
SH
3a = Ar
3b = Ar
N N
S
vii
N
N
N
OH
N
SH
N
HS
O
N
S
O
O
N
N
N
OH
4
5
b= Ar
b= Ar
N
HS
N N
S
O
O
N
N
Ar
SH
N
N
N
N
N
OH
N
N
N
4e= Ar
HS
S
O
N N
S
5
e= Ar
O
O
SH
N
S
4
c= Ar
c= Ar
O
N N
S
5
SH
N
N
N
OH
N
N
HS
O
Ar
O
O
N
S
4
5
d= Ar
d= Ar
NO
2
O
N N
S
SH
Scheme-I: Synthesis of 1,3,4-oxadiazoles, Reagents and conditions (i) CS
°C; (iv) 2-hydroxybenzaldehyde, NaOH 10 %, 5 °C; (v) ABT or AMT, EtOH, 70 °C, 11 to 9 h, respectively; (vi) succinic acid
or maleic acid or phthalic acid or 3-nitrophthalic anhydrides, dry benzene, 70 °C, 24 h; (vii) NaN , THF, 70 °C, 24 h
2
, KOH, EtOH, 70 °C, 7 h; (ii) Conc. HCl; (iii) NaNO , HCl, 0-
2
5
3
and (CHNS) elemental analysis and were in good agreement
with the proposed structures.
IR spectra of azo-oxadiazole derivative (2) indicated the
-1
absence of a doublet band at 3448 and 3352 cm for (-NH
2
)
1
The IR and H NMR spectra of the desired compounds
str. and appearance of the following characteristic bands: the
-1
4
a-e and 5a-e were described previously. The IR spectrum of
oxadiazole derivative (1) showed the disappearance of the
sharp doublet band for hydrazide group (-NHNH ) at (3307,
236) cm and the strong band at 1627 cm due to (C=O) str.,
additionally the appearance of the following characteristic
weak band at 1411 cm attributed to azo group (N=N) str.,
-1
the broad band at 3402 cm assigned to (O-H) str., the sharp-
-1
2
strong band at 1662 cm belong to aldehydic (C=O) str., the
-
1
-1
-1
3
oxadiazolic (C=N) str. appeared as weak band at 1604 cm
due to disappearance of the bending vibration of (-NH
2
) group.
-1
bands: the doublet band at 3448 and 3352 cm assigned to
-NH ) str. that substituted in benzene ring, the strong band at
604 cm attributed to the oxadiazolic (C=N) str. and (-NH
bend. due to the vibration coupling interaction. The weak and
IR spectra of oxadiazolic-imines (3a and 3b) showed the
-
1
(
1
2
disappearance of the sharp-strong band at 1662 cm for
aldehydic (C=O) str., also disappearing the sharp doublet band
-1
2
)
for (-NH
2
) str. in 2-aminobenzothiazole and 2-amino-5-
-1
-1
strong bands at 2590 and 1068 cm belong to (S-H) str. and
C=S) str. in thioenol and thioketone forms, respectively. The
mercapto-1,3,4-thiadiazole at (3398, 3273) cm and (3336,
-
1
(
3267) cm , respectively and appearance of sharp-strong band

Vol. 28, No. 12 (2016)
Synthesis and Characterization of Some 5-Substituted 2-Thiol/Thione-1,3,4-Oxadiazoles 2587
C
N
C
N
C
+
O
N
O
C
C O
O
C
O
O
C
O
O
O
T.S
Na
N
Na
N
N
C
Na
N
N
N
N
N
C
N
N
N
N
C
N
N
N
N
+
+ NaH
Ar`
H
H
H
Ar`
C
Ar`
Ar`
Ar
Ar
Ar
Ar
T.S
Scheme-II: Proposed mechanisms for the addition of cyclic anhydrides and sodium azide to imine
-1
at 1604 and 1602 cm , respectively, attributed to iminic and
oxadiazolic (C=N) str. due to the vibration coupling interaction.
The IR spectra of the oxadiazolic-oxazepanes and oxazepines
showed (N-H) protons for thione forms as singlet at 9.54 ppm
and (S-H) protons for thiol forms as a singlet signals at δ 2.86
and 2.90 ppm, respectively, also the triplet at δ 2.57-2.60 ppm
(
4a-d and 5a-d) showed the appearance of one or two bands
(J = 5.0 Hz, 2H) assigned to methylene group protons (CH
CO–O), the doublet signal at 2.73-2.74 ppm (J = 5.4 Hz, 2H)
belong to methylene group protons (CH –CO–N) of the oxaze-
2
–
-1
at the range 1718-1653 cm attributed to the stretching vibra-
tions of carbonyl groups (N-C=O and O-C=O) of the oxazepane
and oxazepine rings. The spectra also showed the disappea-
2
pane ring. The singlet signal for (C-H) proton of the oxazepane
and oxazepine rings in compounds 4a-d appeared at δ 7.81,
7.51, 7.78 and 7.77 ppm, respectively; additionally the olefinic
(=CH) protons of the oxazepine ring in compound 4b showed
doublet at 6.64–6.67 (J = 11.8 Hz, 2H). The (Ar–H) protons
of compounds 5a-d appeared at δ 7.12-8.10 ppm and were
described in details in the experimental section. It should be
-1
rance of the sharp-strong band at 1604 and 1602 cm for iminic
(C=N) str. and appearance of weak-medium band at the range
-
1
1
608-1600 cm assigned to oxadiazolic (C=N) str. The IR
spectra of the oxadiazolic-tetrazoles 4e and 5e showed the
absence of the sharp-strong band at 1604 and 1602 cm for
iminic (C=N) str. and appearance of medium band at 1597
cm and 1591 cm , respectively assigned to tetrazolic and
oxadiazolic (C=N) str. due to the vibration coupling interaction.
-1
-
1
-1
1
noted that the H NMR spectra of compounds 4a-d and 5a-d
showed the (C-H) proton in the oxazepane and oxazepine rings
at lower field due to the high deshielding affect caused by
oxygen and nitrogen atoms.
The structures of oxazepane and oxazepine compounds
1
4
a-d were established by their H NMR spectra (400 MHz,
DMSO-d
6
) which showed the phenolic (O-H) proton as a singlet
Moreover, the (CHNS) elemental analysis results were
all in good agreement with the proposed chemical structures
for compounds 4a-d and 5a-d.
at δ 10.39, 10.39, 10.39 and 10.38 ppm, respectively. The spectra
of oxazepine compounds 4b-d appeared (N-H) proton for thione
form as a singlet at 9.39, 9.60 and 9.44 ppm, respectively,
while spectrum of oxazepane compound 4a showed both (S-H)
and (N-H) protons for thiol and thione forms as a singlet signals
at δ 2.90 and 9.40 ppm, respectively and two triplets at δ 2.58-
1
H NMR spectra of the synthesized tetrazoles 4e and
5e showed the (O-H) proton as a singlet at δ 9.36 ppm. The
(N-H) and (S-H) protons for thioketone and thioenol forms in
compound 4e as a singlet signals at δ 8.60 and 3.76 ppm,
respectively, while in compound 5e the two singlets at δ 8.45
and 8.70 ppm assigned to two (N-H) groups protons found in
two thione forms, also the two singlets at δ 3.60 and 3.71 ppm
attributed to two (S-H) groups protons present in two thiol
forms. The (Ar–H) protons of compounds 4e and 5e appeared
at δ 6.99-7.73 ppm.
2.62 (J = 6.8 Hz, 2H) and 2.73–2.76 (J = 6.9 Hz, 2H) ppm
assigned to methylene groups protons (CH –CO–O) and (CH –
2
2
CO–N) of the oxazepane ring, respectively. The C-H proton
of oxazepane and oxazepine rings in compounds 4a-d appeared
as singlet at δ 7.64, 7.48, 7.47 and 7.76 ppm, respectively.
Moreover, the olefinic (=CH) protons of the oxazepine ring in
compound 4b appeared as singlet at 6.10 ppm. The signals of
aromatic protons (Ar–H) of compounds 4a-d appeared at δ
Elemental analysis results were within ± 0.4 % of the
theoretical values and in good agreement with the proposed
chemical structures for compounds 4e and 5e.
6.98-8.26 ppm. The structures of the prepared oxazepane and
1
oxazepine compounds 5a-d, were confirmed by their H NMR
spectra which appeared singlet signal at δ 10.39 ppm belong
to the phenolic (O-H) proton. The spectra of oxazepine com-
pounds 5b-d showed two singlet signals at δ (9.39, 9.40), (9.44,
ACKNOWLEDGEMENTS
The authors thank to the staff of Central Lab., University
1
9.48) and (9.32, 9.36) ppm for two (N-H) groups protons in
of Esfahan, Iran for their significant assistance in H NMR and
thione forms, while spectrum of oxazepane compound 5a
elemental analysis measurements of the synthesized compounds.

2588 Abood
Asian J. Chem.
1
4. M. Sahu, A.G. Nerkar, H.U. Chikhale and S.D. Sawant, J. Young
Pharmacists, 7, 21 (2015).
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1