Efficient synthesis of 1,3,4-thiadiazoles using hydrogen bond donor (thio)urea derivatives as organocatalysts

Article abstract of DOI:10.1002/jhet.367

(Chemical Equation Presented) A simple and efficient procedure for the synthesis of 1,3,4-thiadiazoles has been achieved using thiourea as organocatalyst. In this study, the steric and electronic effects using structurally different derivatives of urea and thiourea in different solvents were evaluated. The best yields and the rate of the reactions were obtained using 30 mol % of thiourea as catalyst in acetonitrile at room temperature. The molecular structures of the products were established by ¹H and ¹³C NMR spectral data.

Full text of DOI:10.1002/jhet.367

616
Efficient Synthesis of 1,3,4-Thiadiazoles Using Hydrogen Bond
Donor (Thio)urea Derivatives as Organocatalysts
Vol 47
Shahnaz Rostamizadeh,* Reza Aryan, Hamid Reza Ghaieni,
and Ali Mohammad Amani
Faculty of Science, Department of Chemistry, K.N. Toosi University of Technology, Tehran, Iran
*E-mail: shrostamizadeh@yahoo.com
Received September 14, 2009
DOI 10.1002/jhet.367
Published online 3 May 2010 in Wiley InterScience (www.interscience.wiley.com).
A simple and efficient procedure for the synthesis of 1,3,4-thiadiazoles has been achieved using thio-
urea as organocatalyst. In this study, the steric and electronic effects using structurally different deriva-
tives of urea and thiourea in different solvents were evaluated. The best yields and the rate of the
reactions were obtained using 30 mol % of thiourea as catalyst in acetonitrile at room temperature. The
1
molecular structures of the products were established by H and 13C NMR spectral data.
J. Heterocyclic Chem., 47, 616 (2010).
¨
losis activity using Bronsted acidic ionic liquid
[Bmim]BF4 as dual solvent and catalyst [17].
INTRODUCTION
1,3,4-Thiadiazoles are a group of heterocyclic build-
ing blocks for which a wide variety of applications have
been reported including dyes [1], lubricating agents [2],
optically active liquid crystals [3], and photographic
materials [4]. In the medicinal field, therapeutic proper-
ties such as antitumor [5], hypoglycemic [6], anticonvul-
sant [7], hypotensive [8], antiproliferative [9] and
antituberculosis [10a,b], antileishmanial [11a,b], and
anti-Helicobacter pylori [12a,b] activities have been
assigned to their various derivatives. Moreover, these
compounds have recently been the subject of some theo-
retical and computational studies because of their signif-
icance [13,14]. Also, the research on the synthesis and
discovery of new 1,3,4-thiadiazole derivatives with spe-
cific medicinal properties is still an active area of
research [15]. Literature survey of synthetic methods for
these interesting compounds indicates that there are
three main categories for the synthesis of 1,3,4-thiadia-
zoles: (1) cyclizations involving one-bond formation
[16a–h], (2) cyclizations involving formation of two
bonds [16a,d–g], and (3) cyclizations involving forma-
tion of three bonds [16a,h]. Very recently, we reported a
new three-bond forming one-pot protocol for the synthe-
sis of some 1,3,4-thiadiazoles with potential antitubercu-
With a view to designing more selective, robust, envi-
ronmentally benign, and functional-group tolerant cata-
lysts, chemists have begun to reconsider using the pro-
ton as the simplest Lewis acid. Therefore, taking their
cue from natural enzymatic systems, chemists have
attempted to explore the development of weak acid–
base interactions/hydrogen bonding which is one of the
most dominant forces in molecular interaction and rec-
ognition in biological systems [18], as a basis for cata-
lyst design and as an impressive option to replace the
¨
proton and other commonly known Lewis and Bronsted
acids. So, small organic molecules called organocata-
lysts [19,20], which can form hydrogen bonds, contain
no metallic atoms and are favorable in terms of environ-
mental viewpoints that can be used as efficient catalysts
for various organic transformations [21]. Recently, thio-
urea derivatives have been the subject of extensive
research in the field of designing hydrogen bond catalyst
and several excellent reviews are available on this sub-
ject (for example see [22]). Various thiourea catalysts
have been utilized to catalyze organic reactions through
hydrogen bonding, either for asymmetric or for nona-
symmetric catalysis. Herein, we only refer to some of
C
V
2010 HeteroCorporation

May 2010
Efficient Synthesis of 1,3,4-Thiadiazoles Using Hydrogen Bond Donor
(Thio)urea Derivatives as Organocatalysts
617
Scheme 1. Model reaction for the organocatalyzed synthesis of 1,3,4-thiadiazoles.
the most recently reported studies such as chlorohydrins
synthesis [23], enantioselective Michael addition [24],
asymmetric Bayliss-Hillman reaction [25], Diels-Alder
reaction [26], acetallization of aldehydes and ketones
[27], nitro-Michael addition [28], nucleophilic addition
to acyl imines [29], and enantioselective tandem Mi-
chael-Knoevenagel reaction [30]. To the best of our
knowledge, there is no report on the role and application
of organocatalysts for the preparation of 1,3,4-thiadia-
zoles in the literature. On the basis of the aforemen-
tioned considerations, we decided to investigate the
steric and electronic effect of urea and thiourea in dif-
ferent solvents to represent a novel efficient catalytic
protocol for the synthesis of some 1,3,4-thiadiazoles
derivatives possessing arylamino and aryl moieties on
positions 3 and 5 of thiadiazole ring.
catalysts in water because the catalysts form very stron-
ger hydrogen bonds with water molecules, especially
since the water molecules are present in such a great
numbers as solvent [31]. In addition, when we chose
ethanol as a hydroxylic solvent capable of forming
hydrogen bonds weaker than water, the process did not
proceed well either (Table 1, entries 2 and 14). In these
two cases, we only obtained the semicarbazone interme-
diate 6 as the only product and not the desired heterocy-
clic compound. With a polar aprotic solvent such as ace-
tonitrile, we managed to obtain the thiadiazole product
with moderate to good yields and in relatively short
reaction times (Table 1, entries 3, 4, and 7–12). This is
undoubtedly due to the effective hydrogen bond forma-
tion between the substrates and the catalyst in acetoni-
trile. Solvents such as dimethylformamide (DMF) and
dimehtylsulfoxide (DMSO) were also effective in the
case of catalysts 5b, 5c, 5d, 5e but the yields were
lower and the reaction times were much longer in these
solvents (Table 1, entries 5 and 6, Table 2, entries 6–
11), whereas in the case of catalysts 5f and 5g, no reac-
tion was observed (Table 2, entries 12–15). Moreover,
when the temperature was changed from 30ꢀC to reflux
condition, no remarkable change in the yield and the
reaction time was observed (Table 1, entries 9–12). It is
RESULTS AND DISCUSSION
At the beginning to determine the appropriate cata-
lyst, we examined the effect of hydrogen bond donor
catalyst structure on the synthesis of 1,3,4-thiadiazoles.
The model reaction is shown in Scheme 1. For this
study, derivatives of urea and thiourea along with two
guanidinium salts are used in different solvents and tem-
peratures (Schemes 1 and 2, Tables 1 and 2). As can be
deduced from Tables 1 and 2, the best results were
obtained when 30 mol % of the thiourea as catalyst was
used relative to reactants at room temperature (Table 1,
entries 4–6).
Scheme 2. Urea, thiourea, and guanidinium salts as organocatalysts
employed in this study.
The results shown in Tables 1 and 2 indicate an im-
portant point about the nature of catalysis and the proper
type of solvent used in the process. In water as solvent,
no reaction was observed for both urea and thiourea as
catalyst (Table 1, entries 1 and 13). So, this solvent was
not tested anymore in the case of other catalysts. This
means that reactants do not form hydrogen bonds with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

618
S. Rostamizadeh, R. Aryan, H. Reza Ghaieni, and A. Mohammad Amani
Vol 47
Table 1
Screening of the effect of temperature and the type solvent for the synthesis of 1,3,4-thiadiazoles using simple thiourea and urea.
Entry
Catalyst type
Catalyst loading (%)
Solvent
Temperature (ꢀC)
Reaction time
Commentsa
1
2
5a
5a
5a
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
30
30
30
30
30
30
20
40
30
30
30
30
30
30
Water
30
30
24 h
24 h
No reaction
Ethanol
CH3CN
CH3CN
DMF
Only intermediate 6, Yield 60%
Product 7, Yield 50%
Product 7, Yield 81%
Product 7, Yield 76%
Product 7, Yield 70%
Product 7, Yield 40%
Product 7, Yield 80%
Product 7, Yield 80%
Product 7, Yield 83%
Product 7, Yield 80%
Product 7, Yield 77%
No reaction
3
4
30
30
4.5 h
75 min
2.5 h
2.5 h
5
30
30
30
30
40
60
70
6
7
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Water
3 h
8
9
70 min
70 min
70 min
70 min
70 min
24 h
10
11
12
13
14
reflux
30
30
Ethanol
24 h
Only intermediate 6, Yield 40%
a Isolated yield.
worth mentioning that the reaction was best performed
at 30ꢀC (Table 1, entry 4).
both steric and electronic. Taking a precise look at the
results in Table 1, upon going from thiourea to N-meth-
ylthiourea, reveals that even a small change in the
structure (replacing H with CH3) has led to a drastic
reduction in the reaction rate and a remarkable decrease
in the yield of formation of thiadiazole (Table 1, entry 4
and Table 2, entry 2). This can be better deduced in the
case of N, N0-diphenylurea and N-phenylthiourea (Table
2, entries 1 and 2) with their unsubstituted analogs (Ta-
ble 1, entries 3 and 4). Observing a longer reaction time
for N-phenylthiourea in comparison with the case of thi-
ourea indicates that steric demands are the major factors
governing the formation of the hydrogen bond between
catalysts and the substrates. With a more sterically hin-
dered catalyst like N-phenylthiourea, the catalyst is not
capable of forming effective hydrogen bridges with
The amount of 30 mol % of the catalyst was found to
be the optimum amount for the present process. When
we applied a lower amount of thiourea (20 mol %, Ta-
ble 1, entry 7), the reaction yield was decreased to
nearly half of that found with 30 mol % of the catalyst.
Moreover, using higher amounts of catalyst (40 mol %,
Table 1, entry 8) did not make any remarkable differ-
ence in the yield and the reaction time.
To find out which catalyst could be the most benefi-
cial one for our purpose and what would be the nature
of the catalytic effect, we examined five derivatives of
urea and thiourea along with two guanidinium salts in
this process (Tables 1 and 2, Scheme 2). The chemical
nature of catalyst effect here in this process could be
Table 2
Comparison of the urea and thiourea derivatives as organocalysts in the synthesis of 1,3,4-thiadiazoles.
Entry
Catalyst type
Catalyst loading (%)
Solvent
Temperature (ꢀC)
Reaction time (h)
Commentsa
1
2
3
5b
5d
5e
5f
5g
5b
5b
5d
5d
5e
5e
5f
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
24
4.5
24
24
24
24
24
24
24
24
24
24
24
24
24
Trace of intermediate 6
Product 7, Yield 45%
Product 7, Yield 40%
No reaction
4
5
No reaction
6
7
Trace of product 7
Trace of product 7
Product 7, Yield 30%
Product 7, yield 25%
Product 7, Yield 36%
Product 7, Yield 27%
No reaction
DMSO
DMF
8
9
DMSO
DMF
10
11
12
13
14
15
DMSO
DMF
5f
5g
5g
DMSO
DMF
DMSO
No reaction
No reaction
No reaction
a Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Efficient Synthesis of 1,3,4-Thiadiazoles Using Hydrogen Bond Donor
(Thio)urea Derivatives as Organocatalysts
619
Scheme 3. Resonance structures of urea and thiourea.
pounds 7a–n). Both the reaction times and isolated
yields in Table 2 indicate no general pattern for deriva-
tives with electron withdrawing or electron donating
substituents. Reaction times are in the range of 30–75
min for all products and the yields vary between 81%
and 95%. Taking these facts into consideration, we can
only lay emphasis on the role of steric, and not, elec-
tronic effects on the preparation of 1,3,4-thiadiazoles
using (thio)urea organocatalysts. Then, we performed
some control experiments to confirm the role of thiourea
as catalyst in this process. Primarily we performed the
process by using equivalent amounts of phenylisothio-
cyanate, hydrazine hydrate, and benzaldehyde and the
use of thiourea (30 mol % relative to reactants) in dry
acetonitrile as solvent under N2 inert atmosphere. As
expected, we observed the formation of intermediate 6
(Scheme 1) as the only product and no sign of the
desired thiadiazole product was observed. When we per-
formed the test experiment in EtOH as solvent and in
the absence of any catalyst, only trace amounts of inter-
mediate 6 were obtained. These control experiments
show that hydrogen bonds of thiourea are necessary to
promote the reaction and solvents such as water and
ethanol cannot play the role of a hydrogen bond donor
to catalyze this process. According to these results, we
proposed a reasonable reaction pathway for the prepara-
tion of 1,3,4-thiadiazoles using thiourea as catalyst
(Scheme 5).
substrates. This will result in a decrease in the reactivity
of the substrate, much longer reaction time, and much
lower yield of the product (Table 2, entry 3). Moreover,
the application of N,N0-diphenylurea, as a catalyst with
two very bulky substituents on nitrogen atoms, led to
the formation of the intermediate 6 (Scheme 1) in trace
amounts and no sign of formation of thiadiazole ring
(Table 2, entry 1).
The difference in catalytic activity of thiourea and
urea can be clearly seen in Table 1 (entries 3 and 4) as
one of the most interesting points of this study. Thiourea
has catalyzed the reaction faster than urea in acetonitril
as solvent at room temperature. The possible reason for
this observation is the fact that in thiourea the sulfur
heteroatom has more polarizability in comparison to ox-
ygen. So, when drawing the resonance structures for
urea and thiourea, the 50 contribution in the resonance
structure is higher for thiourea because the negative
charge could be better stabilized on sulfur than on oxy-
gen atom (Scheme 3). Accordingly, more positive
charge on nitrogen and on the hydrogen atom in 50 reso-
nance structure has lead to stronger hydrogen bonding
with the reactants and a more catalytic effect. Moreover,
the pKa value for thiourea is less than the one for urea
[32] which means thiourea is more acidic than urea.
Therefore, thiourea should be able to catalyze the cycli-
zation step better than urea.
The main interesting point that can be observed
through this proposed reaction pathway is that when one
of the hydrogen on nitrogen atom of thiourea (nitrogen
atom on the left side of thiourea) is replaced with a
more sterically hindered substituent like methyl and phe-
nyl, one of the hydrogen bond connections has actually
been removed which prevents self formation of the tem-
plate between the catalyst with the two reactants. In the
case of thiourea as catalyst, this template of hydrogen
bridges facilitates the approaching of 4-phenylthiosemi-
carbazide to benzaldehyde and the formation of 4-phe-
nylthiosemicarbazone intermediate. The ease of hydro-
gen bond formation also facilitates the cyclization to
2,3-dihydrothiadiazoline intermediate in the second step.
To prove that the electronic effects do not play a dis-
tinct role in hydrogen bond catalyzed synthesis of 1,3,4-
thiadiazoles, we repeated this process using various phe-
nylisothiocyanate and benzaldehyde derivatives with
different electron demands (Scheme 4, Table 3, com-
Scheme 4. General reaction pattern used for the synthesis of substituted 1,3,4-thiadiazoles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

620
S. Rostamizadeh, R. Aryan, H. Reza Ghaieni, and A. Mohammad Amani
Vol 47
Table 3
Organocatalytic synthesis of 1,3,4-thiadiazoles using thiourea as hydrogen bond catalyst.
Entry
R1
R2
Reaction time (min)
Yielda (%)
M. P. (ꢀC) (Lit.) [ref.]
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
H
H
H
4-Br
4-Cl
4-F
75
60
45
45
30
30
40
35
40
60
50
60
65
60
81
95
92
87
93
90
95
92
90
80
89
86
90
95
200–202 (199–200) [10]
320–323 (338–339) [10]
217–219 (216–217) [10]
252–254 (258–262) [10]
267–269 (275–277) [10]
207–211 (216–220) [10]
281–284 (293–294) [10]
288–290 (300–302) [10]
343–347 (368) [10]
H
H
H
4-NO2
H
4-Br
4-Cl
4-NO2
H
4-NO2
4-NO2
4-NO2
4-NO2
4-Me
4-Me
4-Me
4-Me
3-Me
177–179 (176–180) [10]
220–224 (213–214) [10]
203–207 (210–214) [10]
270–273 (280–284) [10]
180–182 (176) [33]
4-Cl
4-F
4-NO2
H
a Isolated yield.
The hydrogen bonding in this step of the reaction is re-
sponsible for the activation of C¼¼N double bond and
the motivation for cyclization. Herein, the existence of
more bulky groups like methyl and phenyl also will
result in improper hydrogen bonding of the catalyst to
4-phenylthiosemicarbazone.
yields, thiourea derivatives have been used which are
cheaper than ionic liquids [bmim]. In addition, ionic
liquids [bmim] BF4 may release HF and decompose af-
ter some time, whereas thiourea derivatives do not have
such a problem and can also be handled and kept more
easily than ionic liquids. The only difference with this
study is slightly longer reaction times.
The case of guanidinium salts with no catalytic activ-
ity can simply be explained in another way. The guani-
dinium cations strongly form hydrogen bonds with their
counterions carbonates or nitrates, and, consequently
will not be able to form such bonds with the substrates
in the reaction (Table 1, entries 18 and 19).
CONCLUSIONS
In summary, we have developed a study on hydro-
gen bond catalysis in the synthesis of 1,3,4-thiadiazoles
In comparison to our previous work [15], this study
has several advantages. Apart from the similarity in
as
a group of medicinally important heterocyclic
Scheme 5. The proposed reaction pathway for the formation of 1,3,4-thiadiazole in which a template of hydrogen bond thiourea organocatalyst has
the main role.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Efficient Synthesis of 1,3,4-Thiadiazoles Using Hydrogen Bond Donor
(Thio)urea Derivatives as Organocatalysts
621
(s, 1H, para to thiadiazole ring), 10.33 (1H, NH), 11.62 (1H,
NH). (Presence of two tautomeric isomers [34].)
compounds. We examined several urea, thiourea, and
gunidinium compounds to realize the major factors
governing the catalytic activity of these compounds
and realized that the true feature of the catalytic effect
is steric, and not, electronic effect because the rates
and yields of the reaction are strongly dependent
on the steric bulk of the catalyst. Application of
N-methyl- and N-phenylthiourea resulted in lower
yields and slower reaction rates in comparison with
thiourea. Finally, this process provides easy access to
important thiadiazole heterocyclic building block in rel-
atively short reaction times and various derivatives
with different electron demands on substituents were
prepared. We think that this process has a great poten-
tial to be applied for the catalytic purposes of synthetic
protocols for other important heterocycles and we are
working to develop this idea for the purpose of organic
and heterocyclic synthesis.
5-(4-Bromopheny)-N-phenyl-1,3,4-thiadiazol-2-amine
(7b). This compound was obtained as white crystalline solid,
mp 320–323ꢀC (Lit. mp 338–339ꢀC [10]), ir: 3302, 3122 (NH)
1595 (C¼¼N) 679 cmꢁ1 (CASAC); 1H NMR (300 MHz,
DMSO-d6): d 7.06 (t, 1H, J ¼ 6.5 Hz), 7.29 (t, 2H, J ¼ 6.5
Hz, ortho to thiadiazole ring on phenyl), 7.49 (m, 4H, 2H
meta to thiadiazole ring and 2H on phenylamino group), 7.76
(m, 2H), 8.04 (s, 2H), 10.21 (1H, NH), 11.79 (1H, NH). (Pres-
ence of two tautomeric isomers [34].)
5-(4-Chlorophenyl)-N-phenyl-1,3,4-thiadiazol-2-amine
(7c). This compound was obtained as white crystalline solid,
mp 217–219ꢀC (Lit. mp 216–217ꢀC [10]), ir 3306, 3132 (NH)
1586 (C¼¼N) 690 cmꢁ1 (CASAC); 1H NMR (300 MHz,
DMSO-d6): d 7.21 (t, 1H, J ¼ 6.9 Hz), 7.35 (m, 4H), 7.54
(t, 4H, J ¼ 7.5 Hz, meta to thiadiazole ring on phenyl group),
10.39 (s, 1H, NH).
5-(4-Fluorophenyl)-N-phenyl-1,3,4-thiadiazol-2-amine
(7d). This compound was obtained as white crystalline solid,
mp 252–254ꢀC (Lit. mp 258–262ꢀC [10]), ir: 3322, 3132 (NH)
1606 (C¼¼N) 690 cmꢁ1 (CASAC); 1H NMR (300 MHz,
DMSO-d6): d 7.25 (t, 1H, J ¼ 6.0 Hz), 7.31 (t, 2H, J ¼ 6.0
Hz), 7.44 (t, 2H, J ¼ 9.0 Hz, ortho to thiadiazole ring on phe-
nyl group), 7.66 (d, 2H, J ¼ 6.0 Hz, meta to thiadiazole ring
on phenyl group), 8.11 (m, 2H), 10.23 (s, 1H, NH).
EXPERIMENTAL
Melting points were measured on a Bu¨chi B-540 apparatus
and are uncorrected. IR spectra were measured on Bomem
FTIR ABB FTLA200-100 spectrometer. 1H and 13C NMR
spectra were measured with a Bruker DRX-300 Avance
spectrometer at 300 and 75 MHz using TMS as an internal
standard. Chemical shifts are reported (d) relative to TMS,
and coupling constants (J) are reported in hertz (Hz).
Mass spectra were recorded on a High Resolution Agilent
Technology EX mass spectrometer. Chemicals were obtained
from Merck, Darmstadt, Germany and Sigma-Aldrich Saint
Quentin Falavier, Cedex, France and used without further
purification.
5-(4-Nitrophenyl)-N-phenyl-1,3,4-thiadiazol-2-amine (7e). This
compound was obtained as light yellow crystalline solid, mp
267–269ꢀC (Lit. mp 275–277ꢀC [10]), ir: 3347, 3137 (NH)
1
2978 (CH) 1596 (C¼¼N) 695 cmꢁ1 (CASAC); H NMR (300
MHz, DMSO-d6): d 7.19 (t, 1H, J ¼ 7.5 Hz), 7.51 (t, 2H, J ¼
7.5 Hz), 7.86 (d, 2H, J ¼ 8.4 Hz), 8.21 (d, 2H, J ¼ 8.4 Hz,
ortho to thiadiazole ring on phenyl group), 8.44 (d, 2H, J ¼
8.4 Hz, meta to thiadiazole ring on phenyl group).
N-(4-nitrophenyl)-5-phenyl-1,3,4-thiadiazol-2-amine (7f). This
compound was obtained as light yellow crystalline solid, mp
207–211ꢀC (Lit. mp 216–220ꢀC [10]), ir: 3311, 3154 (NH)
1
2980 (CH) 1601 (C¼¼N) 690 cmꢁ1 (CASAC); H NMR (300
Typical experimental procedure for organocatalytic
preparation
MHz, DMSO-d6): d 7.56 (m, 3H), 7.83 (m, 2H), 8.15 (d, 2H,
J ¼ 9.0 Hz, meta to thiadiazole ring on phenyl group), 8.49
(d, 2H, J ¼ 9.0 Hz), 10.66 (s, 1H, NH).
of
1,3,4-thiadiazoles
using
(thio)urea
derivatives. To a round bottomed flask was added phenyliso-
thiocyanate derivative (0.24 mL, 2 mmoles), acetonitrile as
solvent (2 mL), and hydrazine hydrate (0.1 mL, 2 mmoles)
(Scheme 3). This mixture was stirred at 25–30ꢀC for 10 min,
Then thiourea (0.045 g, 0.6 mmoles, 30 mol %) and substi-
tuted benzaldehyde (2 mmoles) were added to the reaction ves-
sel. The reaction mixture was then stirred for the specified
time at 30ꢀC (Table 2). After completion of reaction (as moni-
tored by TLC, ethyl acetate:petroleum ether, 1:4), the resulting
precipitates were vacuum filtered using a Bu¨chi funnel. The
results are shown in Table 2. The precipitates were further
purified with either ethanol or ethanol/water and were further
characterized by mp, IR, NMR, and MS spectroscopy. This
procedure was repeated the same in the case of other urea or
thiourea derivatives (Table 1).
Analytical data for substituted 1,3,4-thiadiazoles. N,5-
diphenyl-1,3,4-thiadiazol-2-amine (7a). This compound was
obtained as white crystalline solid, mp 200–202ꢀC (Lit. mp
199–200ꢀC [10]), ir: 3297, 3148 (NH) 1606 (C¼¼N) 680 cmꢁ1
(CASAC), 1H NMR (300 MHz, DMSO-d6): d 7.06 (t, 1H,
J ¼ 9.0 Hz), 7.31 (m, 4H), 7.46 (d, 2H, J ¼ 9.0 Hz, ortho to
thiadiazole ring), 7.81 (m, 2H, meta to thiadiazole ring), 8.31
5-(4-Bromophenyl)-N-(4-nitrophenylamino)-1,3,4-thiadia-
zol-2-amine (7g). This compound was obtained as light yꢀel-
low crystalline solid, mp 281–284ꢀC (Lit. mp 293–294 C
[10]), ir: 3301 3147 (NH) 3003 (CH) 1598 (C¼¼N) 695 cmꢁ1
(CASAC); 1H NMR (300 MHz, DMSO-d6): d 7.66 (d, 2H,
J ¼ 8.1 Hz, ortho to thiadiazole ring on phenyl group), 7.89
(d, 2H, J ¼ 8.1 Hz), 8.21 (m, 2H, meta to thiadiazole ring on
phenyl group), 8.77 (br. s, 2H), 10.59 (br. s, 1H, NH).
5-(4-Chlorophenyl)-N-(4-nitrophenyl)-1,3,4-thiadiazol-2-
amine (7h). This compound was obtained as light yellow
crystalline solid, mp 288–290ꢀC (Lit. mp 300–302ꢀC [10]), ir:
3311, 3167 (NH) 3014 (CH) 1611 (C¼¼N) 690 cmꢁ1
(CASAC); 1H NMR (300 MHz, DMSO-d6): d 7.59 (d, 2H,
J ¼ 9.0 Hz, ortho to thiadiazole ring on phenyl group), 7.88
(d, 2H, J ¼ 9.0 Hz, meta on thiadiazole ring), 8.11 (d, 2H,
J ¼ 9.0 Hz), 8.31 (d, 2H, J ¼ 9.0 Hz), 10.52 (s, 1H, NH).
N-(4-nitrophenyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine
(7i). This compound was obtained as reddish yellow crystal-
line solid, mp 343–347ꢀC (Lit. mp 368ꢀC [10]), ir: 3302, 3128
1
(NH) 2990 (CH) 1596 (C¼¼N) 695 cmꢁ1 (CASAC); H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

622
S. Rostamizadeh, R. Aryan, H. Reza Ghaieni, and A. Mohammad Amani
Vol 47
[3] Choi, U. S.; T Kim, W.; Jung, S. W.; Kim, C. J. Bull Ko-
rean Chem Soc 1998, 19, 299.
(300 MHz, DMSO-d6): d 8.12 (d, 2H, J ¼ 9.0 Hz), 8.26 (d,
2H, J ¼ 9.0 Hz), 8.33 (d, 2H, J ¼ 4.2 Hz, ortho to thiadiazole
ring on phenyl group), 8.41 (d, 2H, J ¼ 4.2 Hz, meta to thia-
diazole ring on phenyl group), 10.53 (br. s, 1H, NH).
[4] Chen, S. L.; Ji, S. X.; Zhu, Z. H.; Yao, Z. G. Dyes Pig
1993, 23, 275.
[5] Miyamoto, K.; Koshiura, R.; Mori, M.; Yokoi, H.; Mori,
C.; Hasegawa, T.; Takatori, K. Chem Pharm Bull 1985, 33, 5126.
[6] Mhasalkar, M. Y.; Shah, M. H.; Pilankar, P. D.; Nikam, S.
T.; Anantarayanan, K. G.; Deliwala, C. V. J Med Chem 1971, 14,
1000.
N-(4-methylphenyl)-5-phenyl-1,3,4-thiadiazol-2-amine (7j). This
compound was obtained as white crystalline solid, mp 177–
179ꢀC (Lit. mp 176–180ꢀC [10]), ir: 3260, 3200 (NH) 1615
1
(C¼¼N) 699 cmꢁ1 (CASAC); H NMR (300 MHz, DMSO-d6):
d 2.33 (s, 3H, CH3), 2.39 (s, 3H, CH3), 7.22 (m, 2H), 7.52 (m,
4H, meta to thiadiazole ring), 7.97 (m, 2H, ortho to thiadiazole
ring), 8.29 (s, 1H, ortho to thiadiazole ring), 10.19 (1H, NH).
(Presence of two tautomeric isomers [34].)
[7] Chapleo, C. B.; Myres, P. L.; Smith, A. C. B.; Stillings, M.
R.; Tulloch, I. F.; Walter, D. S. J Med Chem 1988, 31, 7.
[8] Grant, A. M.; Krees, S. V.; Mauger, A. B.; Rzezotarski, W.
J.; Wolff, F. W. J Med Chem 1972, 15, 1082.
5-(4-Chlorophenyl)-N-(4-methylphenyl)-1,3,4-thiadiazol-2-
amine(7k). This compound was obtained as white crystalline
solid, mp 220–224ꢀC (Lit. mp 213–214ꢀC [10]), ir: 3342, 3142
[9] Matysiak, J.; Opolski, A. Bioorg Med Chem 2006, 14,
4483.
[10] (a) Oruc, E. E.; Rollas, S.; Kandemirli, F.; Shvets, N.;
Dimoglo, A. S. J Med Chem 2004, 47, 6760; (b) Mahdiuni, H.;
Mobasheri, H.; Shafiee, A.; Foroumadi, A. Biochem Biophys Res
Commun 2008, 376, 174.
1
(NH) 2978 (CH) 1596 (C¼¼N) 685 cmꢁ1 (CASAC); H NMR
(300 MHz, DMSO-d6): d 2.34 (s, 3H, CH3), 7.27 (d, 2H, J ¼
8.1), 7.51 (d, 2H, J ¼ 8.1), 7.63 (d, 2H, J ¼ 6.9, ortho to thia-
diazole ring on phenyl group), 8.09 (d, 2H, J ¼ 6.9, meta to
thiadiazole ring on phenyl group), 10.22 (s, 1H, NH).
[11] (a) Poorrajab, F.; Kabudanian Ardestani, S.; Emami, S.;
Behrouzi-Fardmoghadam, M.; Shafiee, A.; Foroumadi, A. Eur J Med
Chem 2009, 44, 1758; (b) Poorrajab, F.; Ardestani, S. K.; Foroumadi,
A.; Emami, S.; Kariminia, A.; Behrouzi-Fardmoghadam, M.; Shafiee,
A. Exp Parasitol 2009, 121, 2323.
5-(4-Fluorophenyl)-N-(4-methylphenyl)-1,3,4-thiadiazol-2-
amine (7l). This compound was obtained as white crystalline
solid, mp 203–207ꢀC (Lit. mp 210–214ꢀC [10]), ir: 3322,
1
3132 (NH) 1606 (C¼¼N) 690 cmꢁ1 (CASAC); H NMR (300
[12] (a) Mirzaei, J.; Siavoshi, F.; Emami, S.; Safari, F.; Khosh-
ayand, M. R.; Shafiee, A.; Foroumadi, A. Eur J Med Chem 2008, 43,
1575; (b) Mohammadhosseini, N.; Letafat, B.; Siavoshi, F.; Emami,
S.; Safari, F.; Shafiee, A.; Foroumadi, A. Med Chem Res 1.578, 17,
2008; DOI 10.1007/s00044–008-9099-y.
MHz, DMSO-d6): d 2.34 (s, 3H, CH3), 7.27 (d, 2H, J ¼ 8.1
Hz), 7.48 (d, 2H, J ¼ 8.1 Hz), 7.61 (d, 2H, J ¼ 6.0 Hz, ortho
to thiadiazole ring on phenyl group) 8.09 (m, 2H, meta to thia-
diazole ring on phenyl group), 10.30 (s, 1H, NH).
[13] Feki, H.; Fourati, N.; Abid, Y.; Minot, C. J Mol Struct
(THEOCHEM) 2008, 852, 87.
N-(4-methylphenyl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine
(7m). This compound was obtained as light yellow crystalline
solid, mp 270–273ꢀC (Lit. mp 280–284ꢀC [10]), ir: 3306,
[14] Yakuphanoglua, F.; Atalay, Y.; Sekercic, M. J Mol Struct
2005, 779, 72.
1
3126 (NH) 2988 (CH) 1591 (C¼¼N) 690 cmꢁ1 (CASAC); H
[15] Radi, M.; Crespan, E.; Botta, G.; Falchi, F.; Maga, G.;
Manetti, F.; Corradi, V.; Mancini, M.; Santucci, M. A.; Schenoned, S.;
Botta, M. Bioorg Med Chem Lett 2008, 18, 1207.
NMR (300 MHz, DMSO-d6): d 2.31 (s, 3H, CH3), 7.21 (d,
2H, J ¼ 8.4 Hz), 7.44 (d, 2H, J ¼ 8.4 Hz), 8.28 (d, 2H, J ¼
9.0 Hz, ortho to thiadiazole ring on phenyl group), 8.34 (d,
2H, J ¼ 9.0 Hz, meta to thiadiazole ring on phenyl group).
N-(3-methylphenyl)-5-phenyl-1,3,4-thiadiazol-2-amine (7n). This
compound was obtained as white crystalline soꢁli1d, mp 180–
182ꢀC, ir: 3312, 3163 (NH) 1602 (C¼¼N) 699 cm (CASAC),
1H NMR (300 MHz, DMSO-d6): d 2.35 (s, 3H, CH3), 7.12 (d,
1H, J ¼ 6.9 Hz), 7.33 (t, 1H, J ¼ 6.9 Hz), 7.52 (m, 4H), 8.08
(m, 2H, meta to thiadiazole ring on phenyl group), 8.25 (s,
1H, para to thiadiazole ring on phenyl group), 10.15 (1H,
NH); 13C NMR (75 MHz, DMSO-d6): d 23.34, 123.76,
126.77, 127.24, 128.11, 128.35, 129.21, 130.66 (C-para to thia-
diazole ring on phenyl group), 134.75 (quaternary carbon on
phenyl ring), 137.81, 139.41, 144.11 (C-2 in thiadiazole ring),
178.33 (C-5 in thiadiazole ring); ms m/z ¼ 267; Anal. Calcd.
For C15H13N3S (267.08): C, 67.39; H, 4.90; N, 15.72; S,
11.99; Found: C, 67.69; H, 4.69; N, 15.32; S, 11.72.
[16] (a) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. In
Comprehensive Heterocyclic Chemistry; Pergamon Press, 1996; Vol.II,
p. 379 and the references cited therein; (b) Okawara, T.; Tateyama,
Y.; Yamasaki, T.; Furukawa, M. J Heterocycl Chem 1988, 25, 1071;
(c) Li, C. K.; Cao, L. H. J Chin Chem Soc 2008, 55, 1313; (d)
Elmoghayar, M. R. H.; Abdalla, S. O.; Abdel-Samad Nasr, M. Y. J
Heterocycl Chem 1984, 21, 781; (e) Flowers, W. T.; Robinson, J. F.;
Taylor, D. R.; Tipping, A. E. J Chem Soc Perkin Trans 1 356, 1981;
(f) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett 2008, 49, 879; (g)
Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron Lett 2003, 44,
´
7825; (h) Lebrini, M.; Bentiss, F.; Lagrenee, M. J Heterocycl Chem
2005, 42, 991.
[17] Rostamizadeh, Sh.; Aryan, R.; Ghaieni, H. R.; Amani, A.
M. Heteroatom Chem 2008, 19, 320.
[18] Silverman, R. B. The Organic Chemistry of Enzyme-Cata-
lyzed Reactions; Academic Press:San Diego, 2002.
[19] Schreiner, P. R. Chem Soc Rev 2003, 32, 289.
[20] Pihko, P. M. Angew Chem Int Ed 2004, 43, 2062.
[21] Notz, W.; Tanaka, F.; Barbas, C. F. Acc Chem Res 2004,
37, 580.
Acknowledgments. The authors gratefully acknowledge partial
financial support of this work by Research Council of K. N. Toosi
University of Technology, Tehran, Iran and Dr. Khosrow Jadidi
from Shahid Beheshti University for his helpful consultations.
[22] (a) Connon, S. J. Chem Eur J 2006, 12, 5418; (b) Doyle,
A. G.; Jacobsen, E. N. Chem Rev 2007, 107, 5713.
[23] Bentley, P. A.; Mei, Y.; Du, J. Tetrahedron Lett 2008, 49,
1425.
REFERENCES AND NOTES
[24] Gu, C.-L.; Liu, L.; Sui, Y.; Zhao, J.-L.; Wanga, D.; Chen,
Y.-J. Tetrahedron Asymmetry 2007, 18, 455.
[25] Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett 2004, 45, 5589.
[1] Zareba, S. Pharmazie 1993, 48, 782.
[2] Gao, Y. L.; Zhang, Z. J.; Xue, Q. Mater Res Bull 1999, 34,
1867.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Efficient Synthesis of 1,3,4-Thiadiazoles Using Hydrogen Bond Donor
(Thio)urea Derivatives as Organocatalysts
623
[26] Wittkopp, A.; Schreiner, P. R. Chem Eur J 2003, 9, 407.
[31] Stahl, N.; Jencks, W. P. J Am Chem Soc 1986, 108,
4196.
[27] Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434.
[28] Wei, S.; Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Catal
Today 2007, 121, 151.
[32] Hodgman, C. D. In Handbook of Chemistry and Physics;
Chemical Rubber Publishing Company:Cleveland, OH, 1951; p 1636–
1637.
[29] Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006, 62,
11499.
[33] De, S. C.; Roy-Choudhury, S. K. J Indian Chem Soc 1928,
5, 269.
[30] Dodda, R.; Mandal, T.; Zhao, C.-G. Tetrahedron Lett 2008,
49, 1899.
[34] Stanovnik, B.; Tisler, M. J Org Chem 1960, 25, 2234.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet