Dithiocarbamates as an efficient intermediate for the synthesis of symmetrical substituted 2,5-diamino-1,3,4-thiadiazoles in water

Article abstract of DOI:10.1002/jhet.871

Synthesis of symmetrical substituted 2,5-diamino-1,3,4-thiadiazoles is described. Reaction of easily prepared dithiocarbamates with hydrazine gives the corresponding thiadiazoles in moderate to good yields. This method is new, efficient, and simple especi

Full text of DOI:10.1002/jhet.871

July 2012
Dithiocarbamates as an Efficient Intermediate for the Synthesis of
939
Symmetrical Substituted 2,5-Diamino-1,3,4-thiadiazoles in Water
*
*
Azim Ziyaei Halimehjani, Akram Ashouri, and Katayoun Marjani
Faculty of Chemistry, Tarbiat Moallem University, Tehran 11365, Iran
*
E-mail: ziyaei@tmu.ac.ir or marjani _katy@yahoo. com
Received October 20, 2010
DOI 10.1002/jhet.871
View this article online at wileyonlinelibrary.com.
Synthesis of symmetrical substituted 2,5-diamino-1,3,4-thiadiazoles is described. Reaction of easily pre-
pared dithiocarbamates with hydrazine gives the corresponding thiadiazoles in moderate to good yields. This
method is new, efficient, and simple especially in the work-up procedure.
J. Heterocyclic Chem., 49, 939 (2012).
INTRODUCTION
Although there are many reports for the synthesis of
thiadiazoles, few reports are available for the synthesis
of symmetrical 2,5-disubstituted amino-1,3,4-thiadia-
zoles in the literatures. Okuma et al. reported synthesis
of the symmetrical 2,5-di (p-tolyl)-1,3,4-thiadiazole by
the reaction of disulfur dichloride and p-tolylaldehyde
hydrazone in the presence of 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) [21]. Thompson and coworkers also
have synthesized symmetrical thiadiazoles and used
these compounds as ligand in the coordination chemistry
[22]. Hassan et al. have found the 2,5-disubstituted
amino-1,3,4-thiadiazoles as byproduct [23].
Heterocyclic compounds constitute a large family of
organic compounds, which include many biological
materials in life. Especially five-membered ring hetero-
cyclic compounds serve as the core compound of a large
number of substances that have interesting biological
activities [1]. One class of this family is 1,3,4-thiadia-
zoles, which due to its heteroaromatic characters and bi-
ological properties have been of special interested in
recent years. 1,3,4-thiadiazoles have been used in
numerous therapeutic areas such as antimicrobial [2,3],
antitumor [2], antibacterial [4,5], anticonvulsant and
antiangiogenic [6], antihypertensive [7], hypoglycemic
activity [8], and are key intermediates in the preparation
of various biologically active compounds such as mega-
zol [9], acetazolamide [10], antitubercular [11], antifun-
gal [12], anti-inflammatory [13], analgesic activity, and
lower ulcerogenic potential [14]. Substituted 1, 3, 4-thia-
diazoles are also useful compounds in agriculture (as
herbicides, fungicides, bactericides, and plant growth
regulator) [15] and in many other fields of technology
such as dyes, lubricating compositions, optically active
liquid crystals, and photographic materials [16].
Synthesis of 1,3,4-thiadiazoles usually involves multi-
step procedures such as cyclization of thiosemicarbazide
with di-(2-pyridyl)thionocarbonate (DPT), dicyclohexyl-
carbodiimide (DCC), [17] or concentrated strong
mineral acids [18], or cyclodehydration reaction of
acylthiosemicarbazate bounded to a resin with 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide (EDC), TMSCl,
PPh3, SOCl2, PCl5, and diphenylchlorophosphate [1,19].
A few publications have reported the synthesis of these
compounds under milder conditions, such as oxidative
cyclization of thiosemicarbazone with FeCl3 [16], or
reaction of thiosemicarbazide, and CS2 under reflux
condition [20].
RESULTS AND DISSCUSION
Recently, we have reported a one-pot procedure for
the synthesis of 2-amino-5-substituted-1,3,4-thiadiazoles
in water by using dithiocarbamates and acid hydrazides
[24]. As the biological activity of thiadiazoles are
depending on the type of modification in the ring, and
in continuation of our research on dithiocarbamates, we
were interested in the synthesis of a range of symmetri-
cal 2,5-disubstituted amino-1,3,4- thiadiazoles under
mild reaction conditions with the reaction of dithiocar-
bamates with hydrazine salt (Scheme 1). For this pur-
pose, we have synthesized the starting materials by the
reaction of aromatic amines, carbon disulfide, alkyl ha-
lide or acrylonitrile in the presence of triethylamine
[25]. After synthesizing of the starting materials, we
focused on the optimization of the reaction conditions
by varying the ratio of the starting materials, pyridine
or triethyl amine as promoter, temperature, and the solvent.
We have found that the best condition was when two
equivalents of dithiocarbamate, one equivalent of hydra-
zine sulfate, and 2-3 equiv. of pyridine were used in
© 2012 HeteroCorporation

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A. Z. Halimehjani, A. Ashouri, and K. Marjani
Vol 49
Scheme 1. Reaction of dithiocarbamates with hydrazine salt to prepare thiadiazole rings.
water under reflux condition. Under these optimal condi-
tions 2,5-disubstituted amino-1,3,4-thiadiazoles 2 were
obtained as the major products.
reaction condition is not efficient for primary and second-
ary aliphatic amines. The structure of the products was
elucidated by their 1H and 13C nuclear magnetic resonance
(NMR), and carbon-hydrogen-nitrogen analysis (CHN) ele-
mental analysis. The 1H NMR of the products show a broad
peaks at 8.5–11 ppm in DMSO as NMR solvent, whereas
the uncyclized products show two broad peaks at 8–12
ppm for the N―H groups. The carbon NMR shows a peak
at 155–165 ppm, which is related to the thiadiazole ring.
Proposed mechanism for the synthesis of substituted 2,
5-diamino-1,3,4-thiadiazoles is shown in Scheme 2.
Mixture of pyridine and water give a mild basic media in
which the hydrazine sulfate was converted to hydrazine.
As shown in Table 1, dithiocarbamates prepared with
ethyl iodide, allyl chloride, and acrylonitrile gave the
thiadiazole ring as the only product in good yields.
Although the reaction of benzyl dithiocarbamates with
hydrazine sulfate gave the uncyclized product 3 under
the same conditions, but by using the 1:1 ratio of water
and dimethyl sulfoxide (DMSO) as solvent, the thiadia-
zole rings were obtained in moderate yields. Electron-
donating and withdrawing groups on the aromatic ring
of amine did not affect the reaction condition. This
Table 1
Synthesis of substituted 2, 5-diamino-1,3,4-thiadiazoles using dithiocarbamates and hydrazine sulfate in water.a
Entry
Ar
R
Product-2b (Mp)
Product-3b
1
2
3
4
Ph
―CH2CH2CN
―CH2CH2CN
―CH2CH2CN
―CH2CH2CN
―CH2CH3
62 (244–7)[26]c
82 (256–8)[27]
95 (251–3)[28]
66 (263–5)
–
–
–
–
4-ClC6H4
4-BrC6H4
C10H7
5
Ph
42
–
6
7
8
4-ClC6H4
4-BrC6H4
C10H7
―CH2CH3
―CH2CH3
―CH2CH3
61
45
84
–
–
–
9
4-MeOC6H4
4-MeC6H4
3,4-Cl2C6H3
Ph
4-ClC6H4
4-BrC6H4
C10H7
―CH2CH3
―CH2CH3
―CH2CH3
60 [27]
61 (252–6)[27b]
62 (260––3)
–
–
–
–
–
–
–
10
11
12
13
14
15
16
17
18
19
―CH2CH═CH2
―CH2CH═CH2
―CH2CH═CH2
―CH2CH═CH2
―CH2C6H5
―CH2C6H5
―CH2C6H5
―CH2C6H5
50
28
40
75
Ph
25d
50d
29d
66d
25[29]
10[27]
40[28]
–
4-ClC6H4
4-BrC6H4
C10H7
aReaction conditions: dithiocarbamate (2 mmole), hydrazine sulfate (1 mmol), pyridine (2–3 mmol), and water (5 mL) for 20 h at reflux.
bIsolated yields.
cReferences for the known compounds.
dThe reaction was carried out in 1:1 portion of water and DMSO at reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Dithiocarbamates as an Efficient Intermediate for the Synthesis of Symmetrical
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Substituted 2,5-Diamino-1,3,4-thiadiazoles in Water
Scheme 2. Proposed mechanism for synthesis of thiadiazole ring.
Evaporation of the solvent gives the crude product that was
purified by recryctalization in ethanol. Structure of the products
characterized with their IR, 1HNMR, 13CNMR, and CHN
analysis. spectroscopic data for selected compounds: N2,N5-bis
So it can attack dithiocarbamate 1 to prepare compound 3.
In basic media, compound 3 was converted to the anion 4.
Cyclization via nucleophilic attack of sulfur on the thiocar-
bonyl group produced anion 5, which was converted to 6
by absorbing a proton from water. Aromatization of 5 pro-
ceeded by elimination of H2S [24].
(4-chlorophenyl)-1,3,4-thiadiazole-2,5-diamine:
(Table
1,
Entries 2, 6, 13, and 17) mp 256–258ꢀC; IR (KBr) υmax 3212,
1
3112, 1598, 1546, 1482, 1444, 1189, 746, 693 cmÀ1; H NMR
(300 MHz, DMSO-d6): d (ppm) = 7.35 (d, J = 8.8 Hz, 4H),
7.59 (d, J = 8.8 Hz, 4H), 10.05 (s, 2H, ―NH). 13C NMR (125
MHz, DMSO-d6): d (ppm) = 119.2, 125.3, 129.6, 140.8, 156.5.
Anal. Calcd. for C14H10Cl2N4S: C, 49.85; H, 2.96; N, 16.61.
Found: C, 49.52; H, 2.91; N, 16.27. N2,N5-bis (naphthalen-2-
yl)-1,3,4-thiadiazole-2,5-diamine (Table 1, entries 4, 8, 15, 19):
mp 263–265ꢀC; IR (KBr) υmax 3196, 1581, 1541, 1469, 1396,
CONCLUSIONS
In conclusion, we have shown a new protocol for the
synthesis of 2,5-disubstituted amino-1,3,4-thiadiazoles
with the reaction of dithiocarbamates prepared with aro-
matic amines and hydrazine sulfate in water. The proce-
dure is mild, efficient, and gives good yields. It avoids
hazardous organic solvents and toxic catalysts, especially
in the cyclization step. The work-up is simple and the pro-
ducts were obtained by simple filtration.
1
1251, 790, 765, 619 cmÀ1; H NMR (500 MHz, DMSO-d6): d
(ppm) = 7.49-7.60 (m, 8H), 7.83 (d, J = 8.0 Hz, 2H), 7.95 (d, J
= 7.9 Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 9.79 (s, 2H, ―NH).
13C NMR (125 MHz, DMSO-d6): d (ppm) = 114.9, 121.9,
122.4, 125.1, 125.6, 126.1, 128.3, 133.8, 136.8, 143.6, 157.9.
Anal. Calcd. for C22H16N4S: C, 71.73; H, 4.35; N, 15.21.
Found: C, 71.06; H, 4.17; N, 15.01. N2,N5-bis(3,4-
dichlorophenyl)-1,3,4-thiadiazole-2,5-diamine (Table 1, entry
11): mp 260–263ꢀC; IR (KBr) υmax 3391, 3248, 1625, 1596,
EXPERIMENTAL
Genaral. All reactions were carried out in an atmosphere of
1
1536, 1475, 1131, 810 cmÀ1; H NMR (300 MHz, DMSO-d6):
air. Chemicals and solvents were purchased from Merck and
d (ppm) = 7.37 (dd, J = 8.8 and 2.2 Hz, 2H), 7.50 (d, J = 8.8
Hz, 2H), 8.04 (d, J = 2.2 Hz, 2H), 10.3 (s, 2H, ―NH). 13C
NMR (75 MHz, DMSO-d6): d (ppm) = 117.1, 117.9, 122.3,
130.7, 131.2, 140.7, 155.6. Anal. Calcd. for C14H8Cl4N4S: C,
41.37; H, 1.97; N, 13.38. Found: C, 41.43; H, 1.96; N, 13.93.
1
Fluka and used as received. The H and 13C NMR spectra were
recorded on a Brucker 300-MHz spectrometer. Chemical shifts
are reported in (ppm) relative to tetramethylsilane (TMS) or
CDCl3 as internal. Dithiocarbamates were prepared according to
the reported procedures.
General procedure for the preparation of 2,5- disubstituted
amino-1,3,4-thiadiazole. 2 mmol of dithiocarbamate, 1 mmol
of hydrazine sulfate salt, and 2–3 mmol pyridine were added to 5-
mL water. The mixture was heated under reflux condition for 20
h with vigorous stirring until reaction was complete. Then, the
mixture was cooled to room temperature, and the product was
filtered and washed with water and petroleum ether to obtain
the pure 2,5-disubstituted amino-1,3,4-thiadiazoles. In the case
of entries 16–18, the filtrate was extracted with ethyl acetate to
give the uncyclized products. The organic layer was washed
with water (three times) and then treated with sodium sulfate.
Acknowledgments. We are grateful to the faculty of chemistry of
Tarbiat Moallem University for supporting this work.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet