Copper-catalyzed synthesis of 3-substituted-5-amino-1,2,4-thiadiazoles via intramolecular N-S bond formation

Article abstract of DOI:10.1016/j.tet.2014.09.023

A copper-catalyzed N-S bond formation was utilized to produce 3-substituted-5-amino-1,2,4-thiadiazoles from imidoyl thioureas obtained by reaction of amidine hydrochlorides with isothiocyanates. Moreover, the 1,2,4-thiadiazoles were generated through a on

Full text of DOI:10.1016/j.tet.2014.09.023

Tetrahedron xxx (2014) 1e7
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Copper-catalyzed synthesis of 3-substituted-5-amino-1,2,4-
thiadiazoles via intramolecular NeS bond formation
y
y
*
Ha-Young Kim , Se Hun Kwak , Gee-Hyung Lee, Young-Dae Gong
Department of Chemistry, Dongguk University-Seoul, Pil-dong 3-ga, Jung-gu, Seoul 100715, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A
copper-catalyzed NeS bond formation was utilized to produce 3-substituted-5-amino-1,2,4-
Received 12 August 2014
Received in revised form 4 September 2014
Accepted 8 September 2014
Available online xxx
thiadiazoles from imidoyl thioureas obtained by reaction of amidine hydrochlorides with iso-
thiocyanates. Moreover, the 1,2,4-thiadiazoles were generated through a one-pot protocol without the
isolation of the intermediates. This new method is highly efficient and convenient because it employs the
cheap and environmentally friendly copper salt and can be conducted under air.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thiadiazoles
Nitrogenesulfur bond formation
Imidoyl thioureas
Copper
Oxidative cyclization
1. Introduction
heterocycles possessing heteroatomeheteroatom bonds by the
copper-catalyzed dehydrogenative transformation, there are a few
Copper-catalyzed dehydrogenative heteroatomeheteroatom
bond formation using molecular oxygen as the oxidant is highly
attractive since copper catalysts are inexpensive, have low toxicity,
and are readily available. Molecular oxygen is also a highly atom-
economical and environmentally benign oxidant, producing wa-
ter as the single byproduct.1 Motivated by these advantages, con-
siderable effort has been invested in this catalytic transformation
for the synthesis of heterocyclic compounds and other related
useful materials. For example, both 1,2,4-triazoles2 and 2-H-inda-
zoles3 were generated through a Cu(I) catalyzed CeN/NeN bond
formation, and pyrazoles4 were prepared through a Cu(OAc)2 me-
diated CeC/NeN bond formation cascade. Additionally, a novel
copper-catalyzed approach to aromatic azo compounds from ani-
lines has been developed.5 Recently, copper(II)-catalyzed oxidative
NeN bond formation was used for the synthesis of [1,2,3]triazolo
[1,5-a]pyridines.6 Furthermore, copper salts were successfully
exploited to yield benzo[d]isothiazole-3(2H)-ones and 1,2,4-
thiadiazoles through intramolecular NeS bond formation,7 and to
make intermolecular NeS bond between thiols and amines or
diaryl disulfides and alkylamines, respectively.8 Although sub-
stantial effort has been devoted to exploring the synthesis of
examples employing the transition metal catalyzed NeS bond
formation for the synthesis of heterocycles.7
The 1,2,4-thiadiazole moiety is encountered in a myriad of bi-
ologically active compounds.9 For the purpose of building druglike
libraries, our laboratory has put effort into synthesizing 3-
substituted-5-amino-1,2,4-thiadiazole derivatives 2 using both
solution-phase and solid-phase syntheses.10 Common approaches
to the 1,2,4-thiadiazole skeleton 2 from the imidoyl thiourea 1
employed p-toluenesulfonyl chloride,10 diethyl azodicarboxylate
(DEAD),11 diisopropyl azodicarboxylate (DIAD),12 bromine,13 io-
dine,14 N-chlorosuccinimide,15 hydrogen chloride and hydrogen
peroxide as either a coupling reagent or an oxidant.16 However,
these classical methods would produce undesired byproducts or
wastes that also complicate the process of purification. With these
limitations in mind, we envisioned a copper-catalyzed intra-
molecular NeS bond formation for the synthesis of 3-substituted-
5-amino-1,2,4-thiadiazoles
oxidant.
2 using molecular oxygen as the
2. Results and discussion
At the outset, we chose imidoyl thiourea 1a as a model sub-
strate, which was readily available from the reaction of benzami-
dine hydrochloride with phenyl isothiocyanate (Table 1). We began
our investigation by examining Cu(I) salts such as CuI and CuCN as
* Corresponding author. Fax: þ82 2 2268 8204; e-mail address: ydgong@dong-
guk.edu (Y.-D. Gong).
y
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tet.2014.09.023
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim, H.-Y.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.023

2
H.-Y. Kim et al. / Tetrahedron xxx (2014) 1e7
Table 1
Table 2 (continued)
Optimization of Cu-catalyzed NeS bonda
Entry
2
Time [h]
12
Yieldb [%]
77
8d
2h
2i
Entry
Catalyst
Base
Solvent
Time [h]
Yield 1a/2ab [%]
1
2
3
4
5
6
7
8
CuI
CuI
CuCN
CuBr2
Cu(OAc)2$H2O
CuSO4
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cs2CO3
d
THF
THF
THF
THF
THF
THF
THF
CH3CN
DMF
THF
THF
THF
16
16
16
16
16
16
16
1
1
1
6
1
3:54
9
12 (1)f
34e (72)f
34:35
21:42
0:65
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
d
10c
2j
3
61
0:72
25:52
0:91
0:81
0:85
0:86
0:84
11c
2k
2l
1
6
1
81
71
79
9
10c
11c
12c,d
Cs2CO3
45:36
12c,d
a
Reaction condition: 1a (0.5 mmol), base (2 equiv), cat. (5 mol %), and solvent
(10 mL) under air at 25 ꢀC.
b
Isolated yield.
The reactions were carried out at 50 ꢀC.
Under a nitrogen atmosphere.
c
13
2m
d
14
15
2n
2o
3
3
72
73
catalysts (entries 1 and 3). Fortunately, the desired product 2a was
obtained, but the yield was unsatisfactory.
To enhance the yield, we screened other copper catalysts (en-
tries 4e7). Among them, Cu(OTf)2 showed the best result (entry 7).
It was effective in reducing the reaction time by switching solvent
or increasing the temperature (entries 8e10). Adding a base
seemed to be non-essential, but it evidently facilitated the reaction
(entry 1 vs 2 or 10 vs 11). As expected, the reaction did not proceed
well under a nitrogen atmosphere (entry 12).17
16g
17g
2p
2q
2
1
55
30
With the data in hand, we next tried to explore the scope and
limitations of the optimized reaction conditions (Table 2). Imidoyl
thioureas 1 from benzamidine hydrochloride 3 with various iso-
thiocyanates 4 bearing electron-withdrawing (eCN, eNO2, eCl,
18g
2r
3
20
a
Table 2
Reaction condition: 1a (0.5 mmol), Cs2CO3 (2 equiv), Cu(OTf)2 (5 mol %), and
Synthesis of 3-substituted-5-amino-1,2,4-thiadiazolesa
solvent (10 mL) under air at 50 ꢀC.
b
Isolated yield.
Cu(OTf)2 (0.5 mol %).
Cu(OTf)2 (10 mol %).
The imidoyl thiourea 1i was recovered (23%).
CH3CN was used.
The reaction was carried out at 25 ꢀC.
c
d
e
f
g
Entry
1
2
Time [h]
1 (2)c
Yieldb [%]
86 (85)c
CF3) or electron-donating groups (eOCH3, eCH3) were cyclized to
the corresponding 1,2,4-thiadiazoles (entries 2e7). Substrates from
benzyl or c-pentyl isothiocyanate required more of the copper
catalyst or changing the solvent from THF to CH3CN to complete the
reaction (entries 8 and 9). Other intermediates 1 from acetamidine
hydrochloride, amidinopyridine hydrochlorides, and S-benzyliso-
thiouronium chloride also gave the desired products (entries
10e18). Finally, we reduced the catalyst loading from 5 to 0.5 mol %.
The similar yield demonstrated the high efficiency of the catalyst
(entry 1).
2a
2
3
4
2b
2c
2d
2
3
3
79
60
80
A
one-pot
synthesis
of
3-substituted-5-amino-1,2,4-
thiadiazoles 2 from amidine hydrochlorides 3 and isothiocyanates
4 was reported by Wu and Zhang.12b They achieved the reaction by
a one-pot two-step process. First, imidoyl thioureas 1 were con-
5
6
2e
2f
2
3
87
67
€
structed with Hunig’s base in DMF, and then DIAD was employed to
form NeS bond. Instead of using this procedure, we attempted the
reaction without separating the addition step and the coupling
step, which could not be performed with electrophilic DIAD or
DEAD. This would be feasible because the copper catalyst could not
seriously hamper the reaction in the addition step, and engage in
the coupling of NeS bond of the imidoyl thiourea 1 formed in the
7
2g
3
57
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H.-Y. Kim et al. / Tetrahedron xxx (2014) 1e7
3
mixture. Six selected substrates were tested, which gave the de-
sired products with moderate yields (Table 3). Noteworthy, the fact
that 2n can be obtained from this one-pot protocol shows it is more
versatile for producing the thiadiazoles than the previous method,
which failed to render them from acetamidine hydrochloride.12b
literature reports,2b,4,7a,8 a plausible mechanism for the Cu(II)-
catalyzed formation of NeS bond is depicted in Scheme 3. A radi-
cal pathway could be ruled out because stoichiometric radical
scavenger (TEMPO) did not inhibit the reaction at all (Scheme 2).7c
Initially, a copper catalyst coordinates with imidoyl thiourea 1a.
Subsequently, an oxidative CueS and CueN bond formation would
occur, and a reductive elimination of the copper species 6 makes
NeS bond, affording the thiadiazole 2 and a reduced copper.
Table 3
One-pot synthesis of 3-substituted-5-amino-1,2,4-thiadiazolesa
Entry
1
2
Solvent
THF
Time [h]
6
Yieldb [%]
83
Scheme 2. NeS bond formation in the presence of TEMPO.
2a
2
3
2b
2f
THF
THF
6
6
47
72
4
5
2h
2n
CH3CN
CH3CN
2
6
63
58
Scheme 3. Proposed mechanism for the NeS bond formation of the imidoyl thiourea.
6
2p
THF
3
45
a
Reaction condition: 3 (0.5 mmol), 4 (0.5 mmol), Cs2CO3 (3 equiv), Cu(OTf)2
(5 mol %), and solvent (10 mL) under air at 50 ꢀC.
3. Conclusion
b
Isolated yield.
In summary, we have developed the copper-catalyzed synthesis
of 3-substituted-5-amino-1,2,4-thiadiazoles 2 via intramolecular
NeS bond formation of imidoyl thiourea 1 or directly from ami-
dines 3 and isothiocyanates 4. This method could be an appealing
alternative strategy to substitute the prevalent methods, as it is
economical, easy to handle, and requires environmentally friendly
reagents.
As noted in the Introduction, copper salts can be applied to
connect nitrogen atom to nitrogen atom. Therefore, we suspected
that 1a could be transformed to the triazole under the optimized
condition. But we observed only one spot being the thiadiazole in
the mixture by TLC. Further, 1a of the sulfur atom protected with
methyl 5 was conducted under the condition to investigate
whether 6 could be formed, but no reaction took place (Scheme 1).
This NeN oxidative coupling reaction of the substrates is currently
under investigation in our laboratory.
4. Experimental
4.1. General
All reactions were carried out under open-flask conditions in
which no precautions were taken to exclude air and moisture
from the reaction mixture. All commercial reagents and solvents
were used as received without further purification. The reactions
were monitored by thin-layer chromatography (TLC). Column
chromatography was performed with silica gel (230e400 mesh).
1H NMR and 13C NMR spectra were recorded on a 500 MHz
spectrometer. Proton chemical shift values (d) are given in parts
per million and referenced to tetramethylsilane at 0.00 ppm as
an internal standard. Carbon chemical shifts are reported to the
residual peak of CDCl3 at 77.2 ppm and DMSO-d6 at 39.5 ppm.
Low-resolution mass spectra were obtained on a Triple Quadru-
pole Mass spectrometer using a technique of electronspray ion-
ization. IR spectra were recorded on an FTIR-ATR spectrometer
and are reported in terms of frequency of absorption (cmꢁ1).
High-resolution mass spectra were obtained using a TOF LC/MS
system.
Scheme 1. Attempted NeN bond formation of 5.
Copper-catalyzed reaction can be occurred via a single electron
transfer process or an organometallic pathway.1,14 Based on
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4
H.-Y. Kim et al. / Tetrahedron xxx (2014) 1e7
4.2. Preparation of imidoyl thioureas (1)
d
11.43 (s, 1H), 9.22e7.76 (m, 4H), 7.71e7.29 (m, 5H), 7.07e6.11 (m,
1H); LC/MS (ESI) m/z 324 [MþH]þ.
4.2.1. N-(Phenylcarbamothioyl)benzimidamide (1a). To a suspen-
sion of benzamidine hydrochloride (10.0 mmol) in dichloro-
methane were added phenyl isothiocyanate (10.0 mmol) and
triethylamine (30.0 mmol), and stirred for 24 h at room tempera-
ture. The reaction mixture was concentrated under reduced pres-
sure. Water was added to the crude mixture, and extracted with
ethyl acetate. The combined organic layer was dried over MgSO4
and filtered. After removal of the solvent in vacuum, the resulting
solid was washed with the solvent (diethyl ether/hexane, v/v¼1:3)
to afford the product (1.89 g, 74%). Light yellow solid; mp
4.2.6. N-((2-Methoxyphenyl)carbamothioyl)benzimidamide (1f). To
a suspension of benzamidine hydrochloride (4.0 mmol) in aceto-
nitrile were added 2-methoxyphenyl isothiocyanate (4.0 mmol)
and triethylamine (8.8 mmol), and stirred for 24 h at room tem-
perature. The reaction mixture was concentrated under reduced
pressure. Water was added to the crude mixture, and extracted
with ethyl acetate. After removal of the solvent in vacuum, the
residue was purified by column chromatography to afford the
product as a light yellow oil (924 mg, 81%). The oily compound
became a light yellow solid after two days. Light yellow solid; mp
118e120 ꢀC; 1H NMR (500 MHz, CDCl3)
d 11.64e10.70 (m, 1H),
8.86e7.30 (m, 9H), 7.26e7.09 (m, 1H), 6.91e5.93 (m, 1H); LC/MS
99e101 ꢀC; 1H NMR (500 MHz, CDCl3)
d 11.61e10.40 (m, 1H),
(ESI) m/z 256 [MþH]þ.
9.27e8.53 (m, 1H), 8.21e7.72 (m, 2H), 7.66e7.33 (m, 3H), 7.24e6.04
(m, 4H), 4.11e3.75 (m, 3H); LC/MS (ESI) m/z 286 [MþH]þ.
4.2.2. N-((3-Cyanophenyl)carbamothioyl)benzimidamide
(1b). To
a
suspension of benzamidine hydrochloride (2.0 mmol) in
4.2.7. N-(o-Tolylcarbamothioyl)benzimidamide (1g). To a suspen-
sion of benzamidine hydrochloride (3.0 mmol) in acetonitrile were
added o-tolyl isothiocyanate (3.0 mmol) and triethylamine
(7.5 mmol), and stirred for 24 h at room temperature. The reaction
mixture was concentrated under reduced pressure. Water was
added to the crude mixture, and extracted with ethyl acetate. The
combined organic layer was dried over MgSO4 and filtered. After
removal of the solvent in vacuum, the resulting solid was washed
with diethyl ether to afford the product (480 mg, 59%). Pale yellow
dichloromethane were added 3-cyanophenyl isothiocyanate
(2.0 mmol) and triethylamine (6.0 mmol), and stirred for 24 h at
room temperature. The reaction mixture was concentrated under
reduced pressure. Water was added to the crude mixture, and
extracted with ethyl acetate. After removal of the solvent in vac-
uum, the resulting solid was washed with diethyl ether to afford
the product (477 mg, 85%). Light yellow solid; mp 151e153 ꢀC; 1H
NMR (500 MHz, DMSO-d6) d 11.12e9.91 (m, 2H), 9.64e8.64 (m, 1H),
8.48e7.37 (m, 8H); LC/MS (ESI) m/z 281 [MþH]þ.
solid; mp 116e117 ꢀC; 1H NMR (500 MHz, CDCl3)
d 11.93e10.62 (m,
1H), 8.68e8.02 (m, 1H), 7.97e7.04 (m, 9H), 6.87e5.96 (m, 1H),
4.2.3. N-((4-Nitrophenyl)carbamothioyl)benzimidamide
a
(1c). To
2.57e2.10 (m, 3H); LC/MS (ESI) m/z 270 [MþH]þ.
suspension of benzamidine hydrochloride (4.0 mmol) in
dichloromethane were added 4-nitrophenyl isothiocyanate
(4.0 mmol) and triethylamine (8.8 mmol), and stirred for 12 h at
room temperature. The reaction mixture was concentrated under
reduced pressure. Water was added to the crude mixture, and
extracted with ethyl acetate. The combined organic layer was dried
over MgSO4 and filtered. After removal of the solvent in vacuum,
the resulting solid was washed with diethyl ether to afford the
product (1.081 g, 90%). Yellow solid; mp 161e163 ꢀC; 1H NMR
4.2.8. N-(Benzylcarbamothioyl)benzimidamide (1h). To a suspen-
sion of benzamidine hydrochloride (3.0 mmol) in acetonitrile were
added benzyl isothiocyanate (3.0 mmol) and triethylamine
(6.6 mmol), and stirred for 12 h at room temperature. The reaction
mixture was concentrated under reduced pressure. Water was
added to the crude mixture, and extracted with ethyl acetate. The
combined organic layer was dried over MgSO4 and filtered. After
removal of the solvent in vacuum, the solvent (diethyl ether/hex-
ane, v/v¼2:1) was poured to the residue. The precipitated solid was
collected and washed with the solvent (445 mg, 55%). Pale yellow
(500 MHz, DMSO-d6)
d 11.01 (br s, 1H), 10.55 (br s, 1H), 9.43 (br s,
1H), 8.22 (d, J¼9.1 Hz, 2H), 8.08e7.87 (m, 4H), 7.63 (t, J¼7.3 Hz, 1H),
7.56 (t, J¼7.5 Hz, 2H); LC/MS (ESI) m/z 301 [MþH]þ.
solid; mp 104e106 ꢀC; 1H NMR (500 MHz, CDCl3)
d 11.74e10.59 (m,
1H), 8.35e7.75 (m, 2H), 7.62e7.27 (m, 8H), 7.08e5.98 (m, 1H),
4.2.4. N-((4-Chlorophenyl)carbamothioyl)benzimidamide (1d). To
5.11e4.67 (m, 2H); LC/MS (ESI) m/z 270 [MþH]þ.
a
suspension of benzamidine hydrochloride (2.0 mmol) in
dichloromethane were added 4-chlorophenyl isothiocyanate
(2.0 mmol) and triethylamine (4.4 mmol), and stirred for 16 h at
room temperature. The reaction mixture was concentrated under
reduced pressure. Water was added to the crude mixture, and
extracted with ethyl acetate. The combined organic layer was dried
over MgSO4 and filtered. After removal of the solvent in vacuum,
the resulting solid was washed with diethyl ether to afford the
product (435 mg, 75%). White solid; mp 156e158 ꢀC; 1H NMR
4.2.9. N-(Cyclopentylcarbamothioyl)benzimidamide (1i). To a sus-
pension of benzamidine hydrochloride (1.7 mmol) in acetonitrile
were added cyclopentyl isothiocyanate (1.7 mmol) and triethyl-
amine (3.74 mmol), and stirred for 12 h at room temperature. The
reaction mixture was concentrated under reduced pressure. Water
was added to the crude mixture, and extracted with ethyl acetate.
The combined organic layer was dried over MgSO4 and filtered.
After removal of the solvent in vacuum, the residue was purified by
column chromatography to afford the product (219 mg, 52%). Col-
orless solid; mp 133e135 ꢀC; 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d 11.80e10.87 (m, 1H), 8.99e8.15 (m, 1H),
8.10e7.12 (m, 8H), 6.94e6.17 (m, 1H); LC/MS (ESI) m/z 290 [MþH]þ.
d
12.38e10.32 (m, 2H), 8.13e7.77 (m, 2H), 7.63e7.38 (m, 3H),
4.2.5. N-((3-(Trifluoromethyl)phenyl)carbamothioyl)benzimidamide
(1e). To a suspension of benzamidine hydrochloride (2.0 mmol) in
dichloromethane were added 3-(trifluoromethyl)phenyl iso-
thiocyanate (2.0 mmol) and triethylamine (4.4 mmol), and stirred
for 12 h at room temperature. The reaction mixture was concen-
trated under reduced pressure. Water was added to the crude
mixture, and extracted with ethyl acetate. The combined organic
layer was dried over MgSO4 and filtered. After removal of the sol-
vent in vacuum, the resulting solid was washed with the solvent
(diethyl ether/hexane, v/v¼1:2) to afford the product (453 mg,
70%). White solid; mp 154e156 ꢀC; 1H NMR (500 MHz, CDCl3)
6.88e5.94 (m, 1H), 4.75e4.44 (m, 1H), 2.34e1.95 (m, 2H), 1.84e1.29
(m, 6H); LC/MS (ESI) m/z 248 [MþH]þ.
4.2.10. N-(Phenylcarbamothioyl)pyridine-2-carboximidamide
(1j). To a solution of 2-amidinopyridine hydrochloride (1.58 mmol)
in solvent (acetonitrile/MeOH, v/v¼1:1) were added phenyl iso-
thiocyanate (1.58 mmol) and triethylamine (3.48 mmol), and stir-
red for 2 h at 50 ꢀC. The reaction mixture was concentrated under
reduced pressure. Water was added to the crude mixture, and
extracted with ethyl acetate. The combined organic layer was dried
over MgSO4 and filtered. After removal of the solvent in vacuum,
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H.-Y. Kim et al. / Tetrahedron xxx (2014) 1e7
5
diethyl ether was added to the residue. The oily compound be-
comes solid. The resulting solid was collected and washed with the
solvent (140 mg, 35%). White solid; mp 120e122 ꢀC; 1H NMR
potassium carbonate (6 mmol), and stirred for 0.5 h at room tem-
perature. The reaction mixture was concentrated under reduced
pressure. Water was added to the crude mixture, and extracted
with ethyl acetate. The combined organic layer was dried over
MgSO4 and filtered. After removal of the solvent in vacuum, the
resulting solid was collected and washed with diethyl ether
(304 mg, 46%). Pale yellow solid; mp 122e124 ꢀC; 1H NMR
(500 MHz, CDCl3)
d 11.48e10.69 (m, 1H), 8.83e7.61 (m, 5H),
7.53e7.10 (m, 5H); LC/MS (ESI) m/z 257 [MþH]þ.
4.2.11. N-(Phenylcarbamothioyl)pyridine-3-carboximidamide
(1k). To
a
suspension of 3-amidinopyridine hydrochloride
(500 MHz, CDCl3) d 11.37e7.89 (m, 2H), 7.66e7.53 (m, 1H),
(2 mmol) in acetonitrile were added phenyl isothiocyanate
(2 mmol) and triethylamine (6 mmol), and stirred for 24 h at room
temperature. The reaction mixture was concentrated under re-
duced pressure. Water was added to the crude mixture, and
extracted with ethyl acetate. The combined organic layer was dried
over MgSO4 and filtered. After removal of the solvent in vacuum,
diethyl ether and dichloromethane were added to the residue. The
oily compound becomes solid. The resulting solid was collected and
washed with diethyl ether (420 mg, 82%). Light yellow solid; mp
7.48e7.29 (m, 3H), 7.25e7.17 (m, 1H), 6.10 (br s, 1H), 2.60e1.79 (m,
3H); LC/MS (ESI) m/z 228 [MþH]þ.
4.2.16. Benzyl N-(phenylcarbamothioyl)carbamimidothioate (1p). To
a solution of S-benzylisothiourea hydrochloride (2.6 mmol) in the
solvent (acetone/water, 8:1¼v/v, 18 mL) were added phenyl iso-
thiocyanate (2 mmol) and potassium hydroxide (1 mmol), and
refluxed for 1 h. Acetone was removed under reduced pressure.
Water was added to the crude mixture, and extracted with ethyl
acetate. The combined organic layer was dried over MgSO4 and
filtered. The precipitated solid was collected by filtration, and
washed with water and the solvent (diethyl ether/methanol, v/
v¼2:1) (362 mg, 60%). White solid; mp 114e116 ꢀC; 1H NMR
131e133 ꢀC; 1H NMR (500 MHz, CDCl3)
d 11.97e10.49 (m, 1H),
9.20e8.40 (m, 3H), 8.30e7.59 (m, 2H), 7.52e7.15 (m, 5H), 7.03e6.03
(m, 1H); LC/MS (ESI) m/z 257 [MþH]þ.
4.2.12. N-(Benzylcarbamothioyl)pyridine-3-carboximidamide
(1l). To a suspension of 3-amidinopyridine hydrochloride (2 mmol)
in acetonitrile were added benzyl isothiocyanate (2 mmol) and
triethylamine (6 mmol), and stirred for 24 h at room temperature.
The reaction mixture was concentrated under reduced pressure.
Water was added to the crude mixture, and extracted with ethyl
acetate. The combined organic layer was dried over MgSO4 and
filtered. After removal of the solvent in vacuum, diethyl ether and
dichloromethane were added to the residue. After heating the so-
lution at 50 ꢀC, diethyl ether was added. After repeating it twice, the
resulting solid was collected and washed with diethyl ether
(438 mg, 81%). Pale yellow crystalline solid; mp 97e99 ꢀC; 1H NMR
(500 MHz, CDCl3) d 8.45e8.07 (m, 1H), 7.70e6.99 (m, 10H),
4.38e4.01 (m, 2H); LC/MS (ESI) m/z 302 [MþH]þ.
4.2.17. Benzyl N-{[3-(trifluoromethyl)phenyl]carbamothioyl}-carba-
mimidothioate (1q). To a suspension of S-benzylisothiourea hydro-
chloride (2 mmol) in dichloromethane were added 3-
(trifluoromethyl)phenyl isothiocyanate (2 mmol) and triethylamine
(2.4 mmol), and stirred for 12 h at room temperature. The reaction
mixture was concentrated under reduced pressure. Water was added
to the crude mixture, and extracted with ethyl acetate. The combined
organic layer was dried over MgSO4 and filtered. After removal of the
solvent in vacuum, the residue was purified by column chromatog-
raphy to afford the product (517 mg, 70%). White solid; mp
(500 MHz, CDCl3)
d 11.21 (br s, 1H), 9.17e8.90 (m, 1H), 8.81e8.60
(m, 1H), 8.36e7.91 (m, 1H), 7.81e7.07 (m, 7H), 6.41 (br s, 1H),
112e114 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.62e8.06 (m, 1H),
4.96e4.70 (m, 2H); LC/MS (ESI) m/z 271 [MþH]þ.
8.00e6.98 (m, 9H), 4.63e3.73 (m, 2H); LC/MS (ESI) m/z 370 [MþH]þ.
4.2.13. N-(Phenylcarbamothioyl)pyridine-4-carboximidamide
4.2.18. Benzyl N-(benzylcarbamothioyl)carbamimidothioate (1r). To
a suspension of S-benzylisothiourea hydrochloride (3 mmol) in ace-
tonitrile were added benzyl isothiocyanate (3 mmol) and triethyl-
amine (6.6 mmol), and stirred for 16 h at room temperature. The
reaction mixture was concentrated under reduced pressure. Water
was added to the crude mixture, and extracted with ethyl acetate. The
combined organic layer was dried over MgSO4 and filtered. After re-
moval of the solvent in vacuum, the residue was purified by column
chromatography to afford the product (871 mg, 92%). Pale yellow oil;
(1m). To
a suspension of 4-amidinopyridine hydrochloride
(2 mmol) in acetonitrile were added phenyl isothiocyanate
(2 mmol) and triethylamine (6 mmol), and stirred for 24 h at room
temperature. The reaction mixture was concentrated under re-
duced pressure. Water was added to the crude mixture, and
extracted with ethyl acetate. The combined organic layer was dried
over MgSO4 and filtered. After removal of the solvent in vacuum,
the resulting solid was collected and washed with diethyl ether
(410 mg, 80%). Yellow solid; mp 161e162 ꢀC; 1H NMR (500 MHz,
1H NMR (500 MHz, CDCl3)
d 7.48e7.19 (m, 9H), 7.14e6.79 (m, 1H),
CDCl3)
d
11.77e10.70 (m, 1H), 8.98e7.99 (m, 4H), 7.52e7.29 (m, 4H),
4.91e4.57 (m, 2H), 4.34e4.03 (m, 2H). LC/MS (ESI) m/z 316 [MþH]þ.
7.24e7.15 (m, 1H), 6.88e6.08 (m, 1H); LC/MS (ESI) m/z 257 [MþH]þ.
4.3. General procedure for the synthesis of 3-substituted-5-
amino-1,2,4-thiadiazoles from imidoyl thioureas (2)
4.2.14. N-(Phenylcarbamothioyl)acetimidamide (1n). To a solution
of acetamidine hydrochloride (3.7 mmol) in methanol were added
phenyl isothiocyanate (3.7 mmol) and potassium hydroxide
(7.4 mmol), and stirred for 0.5 h at room temperature. The reaction
mixture was concentrated under reduced pressure. Water was
added to the crude mixture, and extracted with ethyl acetate. The
combined organic layer was dried over MgSO4 and filtered. After
removal of the solvent in vacuum, the residue was purified by
column chromatography to afford the product (222 mg, 31%). Pale
Imidoyl thiourea 1 (0.5 mmol) and Cs2CO3 (1.0 mmol) were
dissolved in THF or CH3CN (10 mL), and Cu(OTf)2 was added to the
solution with stirring (the amount of Cu cat. is described in Table 2).
The mixture was stirred at the temperature described in Table 2.
After completion of the reaction as indicated by TLC, the solvent
was evaporated and quenched with water, extracted with EtOAc.
The organic layer was dried over MgSO4 and filtered. The residue
(or the resulting solid) was either purified by column chromatog-
raphy using ethyl acetate and hexanes as eluents (2a, 2d, 2e, 2f, 2g,
2h, 2i, 2n, 2o, 2p, 2q, 2r) or washed with diethyl ether to give the
product (2b, 2c, 2j, 2k, 2l, 2m).
yellow solid; mp 89e91 ꢀC; 1H NMR (500 MHz, CDCl3)
d 11.30e7.87
(m, 1H), 7.72e7.53 (m, 1H), 7.51e7.28 (m, 3H), 7.26e7.08 (m, 1H),
6.06 (br s, 1H), 2.26e2.06 (m, 3H); LC/MS (ESI) m/z 194 [MþH]þ.
4.2.15. N-((4-Chlorophenyl)carbamothioyl)acetimidamide (1o). To
a suspension of acetamidine hydrochloride (2.9 mmol) in acetoni-
trile were added 4-chlorophenyl isothiocyanate (3 mmol) and
4.3.1. N,3-Diphenyl-1,2,4-thiadiazol-5-amine (2a). White solid
(109 mg, 86%); mp 174e176 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.26 (s,
Please cite this article in press as: Kim, H.-Y.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.023

6
H.-Y. Kim et al. / Tetrahedron xxx (2014) 1e7
1H), 8.21 (dd, J¼6.6, 3.0 Hz, 2H), 7.49e7.38 (m, 5H), 7.24 (d,
J¼7.9 Hz, 2H), 7.16 (t, J¼7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)
HRMS (ESI) m/z calcd for C15H12N3S [MꢁH]ꢁ 266.0757, found
266.0780.
d
180.8, 169.6, 139.3, 133.1, 130.3, 130.1, 128.8, 128.2, 124.5, 118.6. LC/
MS (ESI) m/z 254 [MþH]þ; IR (ATR):
n
¼3225, 2965, 1598, 1556,
4.3.8. N-Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine
(2h). White
1449, 1442, 1348, 751, 710, 690; HRMS (ESI) m/z calcd for C14H10N3S
[MꢁH]ꢁ 252.0601, found 252.0584.
solid (103 mg, 77%); mp 103e105 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.17e8.12 (m, 2H), 7.46e7.30 (m, 8H), 6.61 (s, 1H), 4.51 (d,
J¼5.6 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 184.6, 170.1,136.3,133.4,
4.3.2. 3-[(3-Phenyl-1,2,4-thiadiazol-5-yl)amino]benzonitrile
130.1, 129.1, 128.7, 128.4, 128.1, 127.8, 50.6; LC/MS (ESI) m/z 268
(2b). Pale yellow solid (110 mg, 79%); mp 221e223 ꢀC; 1H NMR
[MþH]þ; IR (ATR):
¼3208, 3126, 1592, 1574, 1343, 1291, 1067, 1023,
n
(500 MHz, CDCl3)
d
8.23 (dd, J¼6.6, 3.0 Hz, 2H), 7.94 (s, 1H), 7.75 (s,
979, 779, 736, 700; HRMS (ESI) m/z calcd for C15H12N3S [MꢁH]ꢁ
1H), 7.60 (dd, J¼8.3, 1.5 Hz, 1H), 7.54 (t, J¼7.9 Hz, 1H), 7.50e7.46 (m,
266.0757, found 266.0754.
3H), 7.44 (d, J¼7.6 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d 178.7,
168.5, 140.4, 132.5, 130.8, 130.3, 128.8, 127.5, 126.2, 122.2, 120.2,
4.3.9. N-Cyclopentyl-3-phenyl-1,2,4-thiadiazol-5-amine (2i). White
solid (88 mg, 72%); mp 101e102 ꢀC; 1H NMR (500 MHz, CDCl3)
118.7, 112; LC/MS (ESI) m/z 279 [MþH]þ; IR (ATR):
¼3289, 2239,
n
1599, 1526,1424,1334, 783, 703; HRMS (ESI) m/z calcd for C15H9N4S
[MꢁH]ꢁ 277.0553, found 277.0539.
d
8.26e8.08 (m, 2H), 7.48e7.36 (m, 3H), 6.01 (d, J¼6.0 Hz, 1H),
3.83e3.68 (m, 1H), 2.14e2.00 (m, 2H), 1.78e1.53 (m, 6H); 13C NMR
(125 MHz, CDCl3)
d 184.1, 170.1, 133.5, 130.0, 128.6, 128.1, 58.5, 33.1,
4.3.3. N-(4-Nitrophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
23.8; LC/MS (ESI) m/z 246 [MþH]þ; IR (ATR):
¼3184, 1573, 1467,
n
(2c). Yellow solid (89 mg, 60%); mp 216e218 ꢀC; 1H NMR (500 MHz,
1347,1287, 1101,1024, 785, 704; HRMS (ESI) m/z calcd for C13H14N3S
[MꢁH]ꢁ 244.0914, found 244.0909.
DMSO-d6)
d
11.68 (s, 1H), 8.34 (d, J¼9.2 Hz, 2H), 8.24 (dd, J¼7.2,
2.3 Hz, 2H), 7.95 (d, J¼9.2 Hz, 2H), 7.60e7.49 (m, 3H); 13C NMR
(125 MHz, DMSO-d6)
d
178.5, 168.7, 145.3, 141.5, 132.4, 130.5, 128.9,
4.3.10. N-Phenyl-3-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine
127.7, 125.7, 117.4; LC/MS (ESI) m/z 299 [MþH]þ; IR (ATR):
n
¼3225,
(2j). White solid (78 mg, 61%); mp 239e241 ꢀC; 1H NMR (500 MHz,
3218, 3063, 1615, 1563, 1521, 1330, 1244, 1109, 847, 819, 704; HRMS
CDCl3)
7.80 (td, J¼7.7, 1.6 Hz, 1H), 7.43 (t, J¼7.9 Hz, 2H), 7.34 (dd, J¼6.9,
5.0 Hz, 1H), 7.26e7.14 (m, 3H); 13C NMR (125 MHz, CDCl3)
181.7,
d
8.65 (d, J¼4.4 Hz, 1H), 8.57 (s, 1H), 8.26 (d, J¼7.9 Hz, 1H),
(ESI) m/z calcd for C14H9N4O2S [MꢁH]ꢁ 297.0452, found 297.0457.
d
4.3.4. N-(4-Chlorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
168.8, 150.9, 150.0, 139.3, 137.0, 130.1, 124.9, 124.7, 123.2, 119.1; LC/
(2d). White solid (115 mg, 80%); mp 196e198 ꢀC; 1H NMR
MS (ESI) m/z 255 [MþH]þ; IR (ATR):
¼3261, 3200, 1621, 1592, 1511,
n
(500 MHz, CDCl3)
d
8.20 (d, J¼3.6 Hz, 2H), 7.98 (s, 1H), 7.54e7.44 (m,
1493, 1432, 1348, 1243, 1136, 746, 696; HRMS (ESI) m/z calcd for
3H), 7.39 (d, J¼8.2 Hz, 2H), 7.30e7.21 (m, 2H); 13C NMR (125 MHz,
C
13H9N4S [MꢁH]ꢁ 253.0553, found 253.0567.
CDCl3)
d 180.2, 169.6, 137.7, 132.8, 130.3, 129.9, 129.5, 128.6, 128.0,
119.7; LC/MS (ESI) m/z 288 [MþH]þ; IR (ATR):
n
¼3129, 1600, 1526,
4.3.11. N-Phenyl-3-(pyridin-3-yl)-1,2,4-thiadiazol-5-amine
1427, 1347, 1156, 828, 713; HRMS (ESI) m/z calcd for C14H9ClN3S
[MꢁH]ꢁ 286.0211, found 286.0221.
(2k). White solid (103 mg, 81%); mp 238e240 ꢀC; 1H NMR
(500 MHz, DMSO-d6) d 11.15 (s, 1H), 9.35 (s,1H), 8.71 (s, 1H), 8.49 (d,
J¼7.8 Hz, 1H), 7.67 (d, J¼7.9 Hz, 2H), 7.63e7.52 (m, 1H), 7.45 (t,
4.3.5. 3-Phenyl-N-[3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-
amine (2e). White solid (140 mg, 87%); mp 124e126 ꢀC; 1H NMR
J¼7.7 Hz, 2H), 7.12 (t, J¼7.3 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
179.4, 166.3, 150.9, 148.5, 139.7, 134.8, 129.5, 128.4, 124.0, 123.1,
(500 MHz, CDCl3)
d
8.74 (s, 1H), 8.21 (dd, J¼6.6, 3.1 Hz, 2H),
117.8; LC/MS (ESI) m/z 255 [MþH]þ; IR (ATR):
¼3191, 2745, 1569,
n
7.59e7.40 (m, 6H), 7.38 (d, J¼7.5 Hz, 1H); 13C NMR (125 MHz,
1456, 1443, 1396, 1359, 1117, 818, 751, 717; HRMS (ESI) m/z calcd for
C
CDCl3)
d
180.3, 169.9, 139.8, 132.8,f 132.4 (q, JCeF¼32.7 Hz), 130.6,
13H9N4S [MꢁH]ꢁ 253.0553, found 253.0569.
130.5, 128.9, 128.3, 123.7 (q, JCeF¼275.1 Hz), 121.2, 120.8 (q,
JCeF¼3.7 Hz), 115.4 (q, JCeF¼3.9 Hz); LC/MS (ESI) m/z 322 [MþH]þ;
4.3.12. N-Benzyl-3-(pyridin-3-yl)-1,2,4-thiadiazol-5-amine
IR (ATR):
n
¼3207, 3087, 1607, 1526, 1459, 1331, 1153, 1111, 895, 700;
(2l). White solid (95 mg, 71%); mp 169e171 ꢀC; 1H NMR (500 MHz,
HRMS (ESI) m/z calcd for C15H9F3N3S [MꢁH]ꢁ 320.0475, found
CDCl3)
d
9.79 (s, 1H), 8.47 (d, J¼7.9 Hz, 1H), 8.30 (d, J¼3.2 Hz, 2H),
320.0495.
7.47e7.26 (m, 6H), 4.51 (d, J¼5.3 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d
185.1, 167.6, 150.0, 149.9, 136.3, 135.3, 129.1, 129.1, 128.4, 128.2,
4.3.6. N-(2-Methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
123.5, 50.8; LC/MS (ESI) m/z 269 [MþH]þ; IR (ATR):
¼3062, 1578,
n
(2f). White solid (95 mg, 67%); mp 96e98 ꢀC; 1H NMR (500 MHz,
1452, 1400, 1191, 1027, 758, 700; HRMS (ESI) m/z calcd for
CDCl3)
7.52e7.40 (m, 3H), 7.13e7.03 (m, 2H), 6.99e6.91 (m, 1H), 3.91 (s,
3H); 13C NMR (125 MHz, CDCl3)
179.6, 169.6, 148.1, 133.2, 130.3,
d
8.42 (s, 1H), 8.30e8.19 (m, 2H), 7.66e7.57 (m, 1H),
C
14H11N4S [MꢁH]ꢁ 267.0710, found 267.0709.
d
4.3.13. N-Phenyl-3-(pyridin-4-yl)-1,2,4-thiadiazol-5-amine
128.9, 128.7, 128.2, 123.7, 121.4, 116.3, 110.8, 56.0; LC/MS (ESI) m/z
(2m). White solid (100 mg, 79%); mp 215e217 ꢀC; 1H NMR
284 [MþH]þ; IR (ATR):
n
¼3378, 1601, 1512, 1459, 1421, 1296, 1247,
(500 MHz, DMSO-d6)
d
11.17 (s, 1H), 8.77 (s, 2H), 8.07 (d, J¼5.3 Hz,
1025, 745, 702; HRMS (ESI) m/z calcd for C15H14N3OS [MþH]þ
2H), 7.67 (d, J¼7.9 Hz, 2H), 7.45 (t, J¼7.9 Hz, 2H), 7.13 (t, J¼7.4 Hz,
284.0852, found 284.0854.
1H); 13C NMR (125 MHz, DMSO-d6)
d 179.6, 166.6, 150.6, 139.6,
139.2, 129.5, 123.2, 121.5, 117.8. LC/MS (ESI) m/z 255 [MþH]þ; IR
4.3.7. N-(2-Methylphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine
(ATR):
n
¼3190, 2761, 1622, 1461, 1362, 1003, 822; HRMS (ESI) m/z
(2g). White solid (76 mg, 57%); mp 171e173 ꢀC; 1H NMR (500 MHz,
calcd for C13H9N4S [MꢁH]ꢁ 253.0553, found 253.0555.
CDCl3)
7.44e7.36 (m, 3H), 7.36e7.24 (m, 2H), 7.18 (t, J¼7.5 Hz, 1H), 2.34 (s,
3H); 13C NMR (125 MHz, CDCl3)
182.8, 169.8, 137.9, 133.1, 131.7, 130.3,
d
8.15 (dd, J¼7.4,1.9 Hz, 2H), 8.02 (s,1H), 7.46 (d, J¼7.9 Hz,1H),
4.3.14. 3-Methyl-N-phenyl-1,2,4-thiadiazol-5-amine (2n). Pale yel-
low solid (69 mg, 72%); mp 112e114 ꢀC; 1H NMR (500 MHz, CDCl3)
d
130.2, 128.7, 128.1, 127.8, 126.2, 120.8, 17.9; LC/MS (ESI) m/z 268
d
9.16 (s, 1H), 7.47e7.39 (m, 2H), 7.26e7.22 (m, 2H), 7.21e7.16 (m,
[MþH]þ; IR (ATR):
n¼3182, 1563, 1425, 1337, 1281, 1070, 766, 702;
1H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
181.6, 169.8, 139.5,
Please cite this article in press as: Kim, H.-Y.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.023

H.-Y. Kim et al. / Tetrahedron xxx (2014) 1e7
7
130.1, 124.8, 119.1, 19.2; LC/MS (ESI) m/z 192 [MþH]þ; IR (ATR):
purified by column chromatography to give the product using
hexanes and ethyl acetate as eluents.
n
¼3225, 2960, 1598, 1545, 1453, 1197, 1001, 807, 746, 715; HRMS
(ESI) m/z calcd for C9H8N3S [MꢁH]ꢁ 190.0444, found 190.0443.
Acknowledgements
4.3.15. N-(4-Chlorophenyl)-3-methyl-1,2,4-thiadiazol-5-amine
(2o). Pale yellow solid (82 mg, 73%); mp 166e168 ꢀC; 1H NMR
This research was financially supported by the Ministry of Trade,
Industry & Energy (MOTIE), and the Korea Institute for Advance-
ment of Technology (KIAT) through the Inter-ER Cooperation Pro-
jects (Grant number R0002016) and the industrial infrastructure
program for fundamental technologies (Grant number M0000338).
We are grateful to Dr. Jun Hee Lee for his critical reading of the
manuscript.
(500 MHz, CDCl3)
d
9.12 (s, 1H), 7.39 (d, J¼8.6 Hz, 2H), 7.22 (d,
J¼8.7 Hz, 2H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 181.4, 170.0,
138.1, 130.1, 130.0, 120.6, 19.3; LC/MS (ESI) m/z 226 [MþH]þ; IR
(ATR):
n
¼3229, 2810, 2101, 1604, 1560, 1429, 1334, 1301, 1089, 805,
746; HRMS (ESI) m/z calcd for C9H7ClN3S [MꢁH]ꢁ 224.0055, found
224.0075.
4.3.16. 3-(Benzylthio)-N-phenyl-1,2,4-thiadiazol-5-amine
Supplementary data
(2p). White solid (82 mg, 55%); mp 148e150 ꢀC; 1H NMR
Copies of 1H spectra for 1, copies of 1H and 13C NMR spectra for 2
and optimization of reaction conditions for the synthesis of 2p.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2014.09.023.
(500 MHz, CDCl3)
d
8.48 (s, 1H), 7.41 (dd, J¼13.2, 7.4 Hz, 4H), 7.31 (t,
J¼7.4 Hz, 2H), 7.28e7.24 (m, 1H), 7.22 (d, J¼7.8 Hz, 2H), 7.18 (t,
J¼7.4 Hz, 1H), 4.45 (s, 2H); 13C NMR (125 MHz, CDCl3)
d 181.0, 167.5,
139.0, 137.3, 130.1, 129.2, 128.7, 127.6, 125.0, 119.1, 36.3; LC/MS (ESI)
m/z 300 [MþH]þ; IR (ATR):
¼3229, 3081, 1598, 1541, 1414, 1218,
n
747, 683; HRMS (ESI) m/z calcd for C15H12N3S2 [MꢁH]ꢁ 298.0467,
References and notes
found 298.0468.
1. (a) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev.
2013, 113, 6234; (b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
2. (a) Kuang, J.; Chen, B.; Ma, S. Org. Chem. Front. 2014, 1, 186; (b) Ueda, S.;
Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
3. Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett. 2011, 13, 3542.
4. Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 7790.
5. Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 6174.
6. Hirayama, T.; Ueda, S.; Okada, T.; Tsurue, N.; Okuda, K.; Nagasawa, H. Chem.
dEur. J. 2014, 20, 4156.
7. (a) Wang, Z.; Kuninobu, Y.; Kanai, M. J. Org. Chem. 2013, 78, 7337; (b) Paul, R.;
Punniyamurthy, T. RSC Adv. 2012, 2, 7057; (c) Sun, Y.; Wu, W.; Jiang, H. Eur. J.
Org. Chem. 2014, 4239.
8. (a) Taniguchi, N. Eur. J. Org. Chem. 2010, 2670; (b) .Taniguchi, N. Synlett 2007,
1917.
4.3.17. 3-(Benzylthio)-N-[3-(trifluoromethyl)phenyl]-1,2,4-
thiadiazol-5-amine (2q). Pale yellow solid (55 mg, 30%); mp
123e125 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.33 (s, 1H), 7.56 (s, 1H),
7.55e7.45 (m, 2H), 7.42 (d, J¼7.3 Hz, 3H), 7.31 (t, J¼7.4 Hz, 2H),
7.28e7.24 (m, 1H), 4.45 (s, 2H); 13C NMR (125 MHz, CDCl3)
180.9,
d
167.6, 139.7, 137.0, 132.5 (q, JCeF¼32.9 Hz), 130.7, 129.2, 128.7, 127.7,
123.7 (q, JCeF¼272.6 Hz), 122.0, 121.4 (q, JCeF¼3.7 Hz), 116.2 (q,
JCeF¼3.9 Hz), 36.3; LC/MS (ESI) m/z 368 [MþH]þ; IR (ATR):
n
¼3209, 3084, 1573, 1459, 1335, 1217, 1169, 1115, 967, 793, 695;
HRMS (ESI) m/z calcd for C16H11F3N3S2 [MꢁH]ꢁ 366.0341, found
9. For examples, see: (a) . Gupta, A.; Mishra, P.; Kashaw, N. S. K.; Kashaw, V.;
366.0318.
€
Stables, J. P. Eur. J. Med. Chem. 2009, 44, 1100; (b) Castro, A.; Gil, C.; Brase, S.;
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(2r). White solid (31 mg, 20%); mp 106e107 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
7.46e7.09 (m, 11H), 4.44 (d, J¼5.7 Hz, 2H), 4.38 (s, 2H); 13
C
NMR (126 MHz, CDCl3) d 184.4, 167.4, 137.4, 136.1, 129.2, 129.1, 128.7,
128.4, 128.0, 127.5, 50.5, 36.1; LC/MS (ESI) m/z 314 [MþH]þ; IR
(ATR):
n
¼3201, 3113, 1596, 1430, 1258, 1195, 1189, 1063, 767, 692;
HRMS (ESI) m/z calcd for C16H14N3S2 [MꢁH]ꢁ 312.0635, found
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amino-1,2,4-thiadiazoles (2)
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17. Under O2 (ballon), 2a was produced in 81% yields in an hour.
Amidine hydrochloride
3 (0.5 mmol), isothiocyanate 4
(0.5 mmol) and Cs2CO3 (1.5 mmol), and solvent (10 mL) were added
to a flask. With stirring, Cu(OTf)2 (5 mol %) was added to the so-
lution. After completion of the reaction as indicated by TLC, the
solvent was evaporated and quenched with water, and extracted
with EtOAc. The organic layer was dried over MgSO4, filtered, and
Please cite this article in press as: Kim, H.-Y.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.023