One-Pot Synthesis of 3-Aryl-5-amino-1,2,4-thiadiazoles from Imidates and Thioureas by I2-Mediated Oxidative Construction of the N–S Bond

Article abstract of DOI:10.1002/ejoc.201800670

A simple and practical method for the one-pot synthesis of 3-aryl-5-amino-1,2,4-thiadiazoles from imidates and thioureas has been developed. The protocol proceeds through sequential base-mediated nucleophilic addition-elimination reactions and an I₂-mediated oxidative coupling for the N–S bond formation. The approach employes readily available and nontoxic substrates and a simple workup to provide 3-aryl-5-amino-1,2,4-thiadiazoles that have a free or substituted amino group.

Full text of DOI:10.1002/ejoc.201800670

A Journal of
Accepted Article
Title: One-Pot Synthesis of 3-Aryl-5-amino-1,2,4-thiadiazoles from
Imidates and Thioureas via I₂-Mediated Oxidative Construction of
N-S Bond
Authors: Ling Chai, Zhenzhen Lai, Qiangqiang Xia, Jiangpei Yuan,
Qilong Bian, Mingjian Yu, Wenkai Zhang, Yuanqing Xu, and
Hao Xu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800670
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800670
Supported by

10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
One-Pot Synthesis of 3-Aryl-5-amino-1,2,4-thiadiazoles from
Imidates and Thioureas via I2-Mediated Oxidative Construction of
N-S Bond
Ling Chai,[a] Zhenzhen Lai,[a] Qiangqiang Xia,[a] Jiangpei Yuan,[a] Qilong Bian,[a] Mingjian Yu,[a] Wenkai
Zhang,[a] Yuanqing Xu*[a] and Hao Xu*[a,b]
Abstract: A simple and practical I2-mediated one-pot synthesis of 3-
aryl-5-amino-1,2,4-thiadiazoles from imidates and thioureas has
been developed. The protocol undergoes sequential process of
base-mediated nuclophilic addition-elimination and I2-mediated
oxidative construction of N-S bond. The merit of this finding is
illustrated by readily available and nontoxic substrates, easy
approach to 3-aryl-5-amino-1,2,4-thiadiazoles with free or
substituted amino group, and I2-mediated oxidative construction of
N-S bond.
prepared beforehand from amidines and isothiocyanates (which
are toxic). Therefore, it is highly desired to develop simpler and
green methods for the synthesis of 3-substituted 5-amino-1,2,4-
thiadiazoles with free or substituted amino group from readily
available and nontoxic substrates.
N-S bond construction through oxidative coupling of N-H
and S-H bonds has attracted much attention for its atom- and
step-economy. Meanwhile hypervalent iodine(Ⅲ) reagents,5a,7
copper salts8 or molecular iodine (I2)6,9 were employed to
promote this transformation. This prompted us to explore the
feasibility of synthesizing
3-substituted 5-amino-1,2,4-
thiadiazoles from simper substrates under I2-mediated oxidative
conditions. In continuation of our endeavors to develop efficient
methods for the synthesis of N-heterocycles from nitriles and
their derivatives,9b,10 herein we report a simple one-pot synthesis
of 3-aryl-5-amino-1,2,4-thiadiazoles with free or substituted
amino group from aromatic imidates and thioureas via I2-
mediated oxidative N-S bond formation.
Introduction
The demand for 1,2,4-thiadiazole derivatives is growing rapidly
in many research fields.1 In the 1,2,4-thiadiazoles, 3-substituted
5-amino-1,2,4-thiadiazoles show wide applications in medicinal
chemistry,2 and they often occur as the basic skeletons of
natural products and pharmaceuticals.3 The importance of this
moiety has prompted the development of many efficient
methods for the synthesis of 3-substituted 5-amino-1,2,4-
thiadiazoles. In the previous methods, 3-substituted 5-amino-
1,2,4-thiadiazoles with free amino group were difficult to be
prepared; and drawbacks of hazardous reagents, tedious
workups, unavailable starting materials and low yields always
existed in the preparation process of such compounds by
previous methods.4 In 2009, a relatively simple method for the
synthesis of 3-aryl-5-amino-1,2,4-thiadiazoles with free amino
group via Pd-catalyzed Suzuki-Miyaura couplings was
developed (Scheme 1A).4e However, the tedious workups and
expensive starting materials still restricted its application.
Furthermore for the synthesis of 3-aryl-5-amino-1,2,4-
thiadiazoles with substituted amino group, the most common
and direct strategy was oxidative heterocyclization of N-
carbamothioylamidines (Scheme 1B).5 Typical oxidants for this
transformation included hypervalentiodine( Ⅲre)agents (such as
PIFA),5a azodicarboxylates (DIAD)5b and Cu(OTf)2/O2.5c
Meanwhile, N-carbamothioylamidines were usually formed from
amidines and isothiocyanates (which are toxic).5 Very recently,
molecular iodine (I2) was also applied in this transformation as a
readily available and eco-friendly oxidants;6 however, the
substrates of N-carbamothioylamidines were still needed to be
work
Previous
N
N
N
S
S
S
NH3
Boc2O/DMAP
THF
(A)
Br
Br
Br
Cl
NH2
NHBoc
EtOH, 70 °C
N
N
N
$19/g
Pd
catalyst
Ar-B(OH)2
N
N
S
S
TFA
Ar
Ar
S
NHBoc DCM
NH2
N
N
,
PIFA, DIAD, Br2
or
NH
S
N
(B)
/O2
I2
Cu(OTf)2
R2
R1
NHR2
R1
N
N
N
H
H
R2 Alkyl
=
N-carbamothioylamidine
or
Aryl
work
This
NH
N
S
S
t-BuOK, DMSO, RT
(1)
(2)
(C)
+
R2
Ar1
R2
NHR2
Aryl
Ar1
OC2H5
H2N
N
N
H
I RT
,
2
2O,
=
H
H,
Alkyl,
Scheme 1. Synthesis of 3-substituted 5-amino-1,2,4-thiadiazoles
Results and Discussion
I2-mediated one-pot reaction of ethyl benzimidate (1a) with
thiourea (2a) was first chosen as the model to optimize the
conditions, which included the bases, solvents and the amount
of molecular iodine. As shown in Table 1,t-BuOK was proved to
be the best base for the first step (entries 1-6), because strong
base was helpful to the formation of N-carbamothioylamidine
intermediate (entry 7; Scheme 1C). However, t-BuOK would not
benefit the I2-mediated oxidative coupling for the second step, so
a small amount of water (0.1 mL) was needed to quench excess
t-BuOK (compare entry 1 with 13). Moreover, the effect of
[a]
[b]
Institute of Functional Organic Molecular Engineering, Henan
University, Kaifeng 475004, P. R. China.
E-mail: xuhao@henu.edu.cn; 18937822307@163.com.
Key Laboratory of Natural Medicine and Immuno-Engineering,
Henan University, Kaifeng 475004, P. R. China.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
solvents was also investigated, and DMSO provided the highest
yield (entries 1, 8-12). When the amount of I2 was reduced to 0.5
mmol (1 equiv.), a lower yield of product 3a was obtained
(compared entry 1 with 14). The reaction was also performed
under I2-catalyzed oxidative conditions (O2 balloon, 1 atm), but
only a 31% yield of 3a was obtained (entry 15). Meanwhile it
was noted that a high yield could still be provided under a
nitrogen atmosphere (entry 17), and the yield of 3a showed no
increasement under an oxygen atmosphere (entry 16). When no
I2 was added in the second step under N2 atmosphere, only
trace amount of 3a was detected (entry 18). Based on these
results (entries 1, 14-18), the main oxidant in this transformation
should be molecular iodine (I2), rather than DMSO or oxygen
(O2).
benzimidates with electron-withdrawing groups showed higher
reactivity (Br, CF3; 3f, 3i, 3n, 3t, 3x), perhaps because electron-
withdrawing groups made benzimidates easier to be attacked by
thiourea; meanwhile the reactivity of benzimidates with electron-
donating groups (CH3, OCH3; 3b, 3c, 3g, 3h) was lower than
others. The position of substituent on the benzyl group (meta
and para position) affected the yields of 3 as well; for the weak
electron-donating group of methyl,
the para-substituted
benzimidates provided higher yields (compare 3b and 3c), due
to lower steric hindrance; however for chlorine atom and
methoxyl group, the opposite case was presented (compare 3d
with 3e, 3g with 3h), maybe because the strong electron-
withdrawing inductive effect of chlorine atom activated the
substrate of imidates, and strong electron-donating conjugative
effect of methoxyl group deactivated the substrate respectively.
Furthermore, the heteroarylimidates were also tolerated well in
this transformation (3j-3l). For the substrate of alkyl-substituted
thioureas, the steric hindrance of substituent groups did not
affect the yield of products 3 significantly, even thioureas with t-
butyl group worked well for this transformation. But there were
still some limitations, for example, the aliphatic imidates like
benzyl and n-butyl imidates failed to provide the intended
products (Scheme S1 in the Supporting Information).
Table 1. I2-mediated one-pot synthesis of 3-phenyl-5-amino-1,2,4-thiadiazole
(3a)
from ethyl benzimidate (1a) with thiourea (2a): optimization of
conditions.[a]
N
S
NH
OC2H5 H2N
,
,
S
ase o ven
1
B
S
l
t RT
(
)
+
NH2
N
,
,
NH2
2
(
H O I RT
)
2
2
a
1
a
2
a
3
Entry
1
2
3
4
5
6
7
8
Base
t-BuOK
EtONa
NaOH
KOH
Cs2CO3
K3PO4
--
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Dioxane
t-BuOCH3
t-BuOH
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Yield (%)[b]
88
39
60
59
Trace
Trace
0
35
49
Trace
Trace
27
47
34
31
85
86
trace
9
10
11
12
13[c]
14[d]
15[e,g]
16[g]
17[h]
18[f,h]
[a] Reaction conditions: without exclusion of air in a sealed Schlenk tube. For
the first step, ethyl benzimidate 1a (0.5 mmol, 75 mg), thiourea 2a (1 mmol, 76
mg), base (1 mmol), anhydrous solvent (1 mL), reaction time (4 h) at room
temperature (~25 oC). For the second step, I2 (1 mmol, 254 mg), H2O (0.1 mL),
reaction time (10 h) at room temperature (~25 oC). [b] Isolated yield. [c]
Without addition of H2O for the second step. [d] I2 (0.5 mmol) for the second
step. [e] I2 (0.25 mmol) for the second step. [f] No I2 was added in the second
step. [g] Under a O2 balloon (1 bar) for the second steps. [h] Under a N2
balloon (1 bar) for the two steps in a Schlenk tube.
The scope of I2-mediated one-pot synthesis of 5-amino-
1,2,4-thiadiazoles was investigated under the optimized
condition (t-BuOK as base, DMSO as solvent, 2 equiv. of I2 as
oxidant). As shown in Table 2, a series of 5-amino-1,2,4-
thiadiazole products were synthesized in moderate to good
yields at room temperature. For the substrate of imidates, the
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10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
Table 1. I2-mediated one-pot synthesis of 3-aryl-5-amino-1,2,4-thiadiazoles[a,b]
NH
S
N
S
t-BuOK, DMSO, RT
(1)
R
NH
+
R
Ar
Ar
H5
OC2
H2N
N
N
H
I RT
,
2
2O,
(2)
H
1
3
2
N
N
N S
S
S
N
N
S
N
S
Me
Cl
NH2
NH2
NH2
NH2
NH2
NH2
NH2
N
N
N
N
Cl
Me
3a
88%
3b
74%
3c
59%
3d
75%
3e
89%
N
S
S
N
N
N
N
S
S
S
MeO
NH2
NH2
NH2
NH2
N
N
N
N
N
F
3C
Br
MeO
S
3j
77%
3f
94%
3g
52%
3h
31%
3i
92%
N
S
N
S
N
S
N
S
N
S
Me
Me
N
H
NH2
N
N
N
N
N
N
N
H
H
O
S
F
3C
3n
97%
3o
95%
3k
61%
3l
82%
3m
62%
N
S
N
S
N
S
N
S
N
S
n-Hexyl
N
H
N
H
N
H
N
H
N
H
N
N
N
N
N
Cl
F
3C
3p
72%
3r
73%
3s
65%
3t
90%
3q
88%
N
S
N
S
N
S
S
N
N
S
Bn
Bn
Ph
N
H
N
H
N
N
N
H
N
N
N
N
N
H
H
Br
3u
76%
3v
55%
3w
72%
3x
85%
3y
45%
[a] Reaction conditions: without exclusion of air in a sealed Schlenk tube. For the first step, imidate 1 (0.5 mmol, 75 mg), thiourea 2 (1 mmol, 76 mg), t-BuOK (1
mmol, 112 mg), anhydrous DMSO (1 mL), reaction time (4 h) at room temperature (~25 oC). For the second step, I2 (1 mmol, 254 mg), H2O (0.1 mL), reaction
time (10 h) at room temperature (~25 oC). [b] Isolated yield.
As shown in Table 2, the tolenrance of diverse functional
groups implied the potential for modification for the synthesis of
downstream 3-substituted 5-amino-1,2,4-thiadiazole products
under I2-mediated conditions. To further demonstrate the utility
of this synthetic protocol, we applied it into the preparation of N-
(3-phenyl-1,2,4-thiadiazol-5-yl)-4-methoxybenzamide (LUF5417).
LUF5417 was synthesized from readily available ethyl
benzimidate in 70% yield over two steps (Scheme 2).
Thiourea
-BuOK, DMSO,
(1)
S
NH
N
t
RT
NH2
N
Ph
H5
OC2
H
2O,
I
RT
Ph
,
(2)
2
1a
3a
$49/g
O
In
van
Muijlwijk-Koezen’s
work,
a
series
of
O
MeO
S
N
thiodiazolobenzamide compounds was synthesized as potent
and selective adenosine receptor antagonists, especially
LUF5417 showing a Ki value of 82 nM at the adenosine A3
receptor;11 and the excellent activity of LUF5417 was also
proved in Kim's work.4d But the starting material of 3a, used for
the synthesis of LUF5417, was expensive and hard to be
prepared. By our method, 3a could be prepared easily; and
Cl
N
Ph
N
OMe
H
Pyridine
LUF5417
Total
70%
Ref. 11
yield
Scheme 2. The application of I2-mediated one-pot method in the synthesis of
LUF5417
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10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
reaction time (4 h) at room temperature (~25 oC); Condition B: I-1 (0.5 mmol,
90 mg), I2 (1.1 mmol, 279 mg), base (1 mmol), DMSO (1 mL) as solvent,
reaction time (10 h) at room temperature (~25 oC)].
In order to explore the mechanism for the I2-mediated
synthesis of 5-amino-1,2,4-thiadiazoles, the following control
experiments were performed. Expected intermediate I-1 could
be prepared successfully from 1a and 2a in the presence of t-
BuOK (Scheme 3A); and the strong base was helpful to the
formation of intermediate I-1. For the transformation from I-1 to
3a, the molecular iodine (I2) played a key oxidative role, and a
good yield of 3a could be provided under I2-mediated conditions
(entries 6-7 in Scheme 3B). Interestingly, the addition of base
should have benefitted the transformation by the proposed
reaction mechanism below (Scheme 4). However when the base
was added and only DMSO was used as the solvent, a lower
yield of 3a was obtained (entries 2-4 in Scheme 3B); the results
implied the basicity and nucleophilicity of base in DMSO solution
was much stronger than in the DMSO/H2O solution,12 due to
weak solvation effect of base in DMSO solution; so that the I-1
was destroyed and transformed into other by-products.
Moreover when the DMSO/H2O was used as the solvent, the
base of KOH could dissolve well in the aqueous reaction
solution, and deprotonate I-1; then the addition of base was
beneficial to the transformation (entries 5-7 in Scheme 3B). In
addition, a 76% yield of 3a could be obtained under base-free
conditions in DMSO/H2O solution (entry 5 in Scheme 3B); this
result implied that the transformation from I-1 to 3a could also
proceed under base-free conditions. Nonetheless, the addition
of base could accelerate the reaction obviously [compare entry 5
with 7 in Scheme 3B; 76% (10 h) vs 86% (20 min)]. At last, to
verify the existence of generated iodide, we attempted to
capture the iodide with water solution of AgNO3, then a yellow
deposition could be obtained (please see Figure S1 in the
Supporting Information).
A possible mechanism is suggested for synthesis of 3-aryl-
5-amino-1,2,4-thiadiazoles (Scheme 4). At first, intermolecular
nucleophilic attack of thiourea 2 to imidate 1 in the presence of
base
(t-BuOK)
leads
to
intermediate
I
(N-
carbamothioylamidine),then subsequent oxidative iodination of I
furnishes the iodide II.6,8b Afterword, the S-I bond cleaves under
I2-mediated conditions, and a new N-S bond is formed after
intramolecular nucleophilic attack of imino group to sulfur atom
in iodide II, to afford protonated intermediate III. Finally,
deprotonation of III in the presence of base affords the target
product 5-amino-1,2,4-thiadiazole 3a.
I
I
Base
S
(1)
(2)
NH
NH
S
H
2O
R2
R2
+
Ar1
H5
OC2
Ar1
N
N
H
H2N
N
-
Base+H+
I
H
+
H
H5
OC2
I
1
2
Base
H
H
Base
I
I2
R2
N
S
N
S
NH
S
NHR2
NHR2
Ar1
Ar1
H+ Base
Ar1
N
N
N
N
-+I
+
H
I
2
II
III
3
Scheme 4. Possible mechanism for synthesis of 3-aryl-5-amino-1,2,4-
thiadiazoles
NH
NH
S
S
A
Condition
Conclusions
+
OEt
(A)
N
NH2
H2N
NH2
H
We have developed a simple and practical I2-mediated one-
pot method for synthesis of 3-aryl-5-amino-1,2,4-
thiadiazoles. The protocol used readily available imidates
and thioureas as the starting materials, economical and
environmentally friendly molecular iodine (I2) as the oxidant.
The one-pot reactions underwent sequential base-mediated
nuclophilic addition-elimination to form the intermediate of
N-carbamothioylamidines, and I2-mediated oxidative
heterocyclization of N-carbamothioylamidines to give the
corresponding products. 3-Substituted 5-amino-1,2,4-
thiadiazoles with free amino group were difficult to be
prepared by previous methods; and drawbacks of
hazardous reagents, tedious workups, unavailable starting
materials and low yields always existed in the preparation
process of such compounds. Meanwhile for the synthesis of
3-substituted 5-amino-1,2,4-thiadiazoles with substituted
amino group, the oxidative heterocyclization of N-
carbamothioylamidines was the most common and direct
strategy; but the N-carbamothioylamidines were usually
prepared from amidines and isothiocyanates (which are
toxic). In addition, the application of molecular iodine (I2) in
the oxidative cross-coupling of N-H and S-H is rare. Given
this, A simple and green method for the synthesis of 3-aryl-
1a
2a
I-1
of
I-1
Condition
Yield
base 86%
as
A/t-BuOK
Condition
(1)
(2)
(3)
as
Condition A/KOH
Condition A/without base
base
73%
0%
NH
S
S
N
NH2
B
Condition
N
H
NH2
(B)
N
3a
I-1
Condition
Yield 3a
of
0%
I
Condition B/without
(1)
(2)
(3)
(4)
(5)
2
as
B/t-BuOK
B/t-BuOK
as
base
40%
36%
48%
Condition
Condition
mmol) as
base
(1.5
Condition B/KOH
base
as
1.1
1.1
1.1
mL)
solvent 76%
as
solvent 90%
Condition B/without base/DMSO/H O
(1/0.1,
(1/0.1,
(1/0.1,
2
as
mL)
Condition B/KOH
Condition B/KOH
base/DMSO/H O
(6)
(7)
2
as
min
86%
base/DMSO/H O
mL)/20
2
Scheme 3. Control experiments for mechanism study [Condition A: without
exclusion of air in a sealed Schlenk tube. Ethyl benzimidate 1a (3 mmol, 448
mg), thiourea 2a (6 mmol, 457 mg), base (6 mmol), anhydrous DMSO (1 mL),
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10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
148-149 oC. 1H NMR (400 MHz, d6-DMSO, 25 oC) δ 8.03 (s, 2H),
5-amino-1,2,4-thiadiazoles with free or substituted amino
group from readily available and nontoxic substrates has
been developed in this paper. In light of the wide application
of the products and easy workup approach, this method will
attract much attention in relevantly academic and industrial
fields.
7.93-7.82 (m, 2H), 7.39-7.30 (m, 1H), 7.29-7.22 (m, 1H), 2.36
o
(s, 3H). 13C NMR (100 MHz, d6-DMSO, 25 C) δ 183.9, 169.0,
138.1, 133.6, 130.8, 128.9, 128.4, 125.0, 21.5. ESI-HRMS
[M+H]+m/z calcd for C9H10N3S 192.0590, found 192.0604
3-(p-Chlorophenyl)-1,2,4-thiadiazol-5-amine (3d)
:
Eluent:
petroleum ether/ethyl acetate (4:1). Yield 79 mg (75%).
White solid, mp 189.7-190.9 oC. 1H NMR (400 MHz, d6-DMSO,
Experimental Section
o
25 C) δ 8.22-8.05 (m, 4H), 7.57 (d, J = 8.4 Hz, 2H). 13C NMR
o
General experimental procedures: All reactions were carried
out under air. Proton and carbon magnetic resonance spectra
(1H NMR and 13C NMR) were recorded using
tetramethylsilane (TMS) in the solvent of CDCl3 as the
internal standard (1H NMR: TMS at 0.00 ppm,CHCl3 at 7.26
ppm; 13C NMR: CDCl3 at 77.16 ppm) or were recorded using
tetramethylsilane (TMS) in the solvent of DMSO-d6 as the
internal standard (1H NMR: TMS at 0.00 ppm, DMSO at 2.50
ppm; 13C NMR: DMSO at 39.51 ppm).
(100 MHz, d6-DMSO, 25 C) δ 184.1, 167.7, 134.9, 132.38 ,
129.5, 129.2. ESI-HRMS [M+H]+ m/z calcd for C8H7ClN3S
212.0044, found 212.0054.
3-(m-Chlorophenyl)-1,2,4-thiadiazol-5-amine (3e)
: Eluent:
petroleum ether/ethyl acetate (4:1). Yield 94 mg (89%).
White solid, mp 189.7-190.9 oC. 1H NMR (400 MHz, d6-DMSO,
25 oC) δ 8.11 (s, 2H), 8.08-7.91 (m, 2H), 7.58-7.43 (m, 2H). 13
C
NMR (100 MHz, d6-DMSO, 25 oC) δ 183.7, 166.8, 135.0, 133.3,
130.6, 129.5, 127.0, 125.9. ESI-HRMS [M+H]+m/z calcd for
C8H7ClN3S 212.0044, found 212.0052.
General procedure for synthesis of compounds (3a-3y):
Thiourea
mL) were added into a 10 mL reaction tube charged with a
magnetic stirrer. Then the aromatic imidate (0.5 mmol) was
2 (1 mmol), t-BuOK (1 mmol, 112 mg) and DMSO (1
3-(p-Bromophenyl)-1,2,4-thiadiazol-5-amine (3f):[13] Eluent:
1
petroleum ether/ethyl acetate (4:1). Yield 120 mg (94%).
o
o
1
White solid, mp 202-203 C ( lit.[13] mp 197.9-199.1 C). H
added into the tube,and the tube was sealed and stirred for 4
h under room temperature for the first step. After that, 100
uL water and iodine (1 mmol, 254 mg) was added into the
tube; the mixture was stirred for 10 h at room temperature
for the second step. The resulting solution was quenched
with saturated aqueous solution of Na2S2O3. The organic and
aqueous layers were separated, and the aqueous layer was
extracted with EtOAc (3×15 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated and
purified by column chromatography on silica gel employing
petroleum ether/ EtOAc as eluent to afford target product
o
NMR (400 MHz, d6-DMSO, 25 C) δ 8.09 (s, 2H), 7.98 (d, J =
8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, d6-
o
DMSO, 25 C) δ 184.1, 167.8, 132.7, 132.1, 129.8, 123.7. ESI-
MS [M+H]+m/z 255.90.
3-(m-Methoxyphenyl)-1,2,4-thiadiazol-5-amine (3g): Eluent:
petroleum ether/ethyl acetate (4:1). Yield 54 mg (52%).
White solid, mp 124.1-126.4 oC. 1H NMR (400 MHz, d6-DMSO,
o
25 C) δ 8.04 (s, 2H), 7.69-7.62 (m, 1H), 7.62-7.57 (m, 1H),
7.37 (t, J = 7.9 Hz, 1H), 7.06-6.97 (m, 1H), 3.80 (s, 3H). 13C
NMR (100 MHz, d6-DMSO, 25 oC) δ 183.5, 168.2, 159.3, 134.5,
129.7, 119.7, 115.7, 112.2, 55.1. ESI-HRMS [M+H]+ m/z calcd
for C9H10N3OS 208.0539, found 208.0533.
(3a-3y).
3-Phenyl-1,2,4-thiadiazol-5-amine (3a):[6c] Eluent: petroleum
ether/ethyl acetate (4:1). Yield 78 mg (88%). White solid, mp
155-156 oC ( lit.[6c] m.p. 155-156 C). 1H NMR (400 MHz, d6-
o
3-(p-Methoxyphenyl)-1,2,4-thiadiazol-5-amine
(3h):[6d]
DMSO, 25 oC) δ 8.27-7.90 (m, 4H), 7.63-7.26 (m, 3H). 13C NMR
(100 MHz, d6-DMSO, 25 oC) δ 184.0, 168.8, 133.6, 130.2,
129.0, 127.8. ESI-MS [M+H]+ m/z 178.13.
Eluent: petroleum ether/ethyl acetate (3:1). Yield 32 mg
(31%). White solid, mp 185.5-187.1 oC. 1H NMR (400 MHz, d6-
o
DMSO, 25 C) δ 8.16-7.82 (m, 4H), 7.08-6.87 (m, 2H), 3.80 (s,
3H). 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 183.3, 168.2,
160.4, 128.9, 126.1, 113.9, 55.2. ESI-HRMS [M+H]+ m/z calcd
for C9H10N3OS 208.0539, found 208.0550.
3-(p-Tolyl)-1,2,4-thiadiazol-5-amine (3b): Eluent: petroleum
ether/ethyl acetate (4:1). Yield 71 mg (74%). White solid, mp
167-168 oC. 1H NMR (400 MHz, d6-DMSO, 25 oC) δ 8.01 (s, 2H),
7.95 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.34 (s, 3H).
3-[p-(Trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-amine
(3i):[13] Eluent: petroleum ether/ethyl acetate (4:1). Yield 113
mg (92%). White solid, mp 166-168 oC (lit.[13] mp 149.8-151.9
13C NMR (100 MHz, d6-DMSO, 25 C) δ 183.8, 168.9, 139.8,
o
131.1, 129.6, 127.8, 21.4. ESI-HRMS [M+H]+ m/z calcd for
o
oC). 1H NMR (400 MHz, d6-DMSO, 25 C) δ 8.27 (d, J = 8.1 Hz,
C11H12N2S 192.0590, found 192.0585.
2H), 8.17 (s, 2H), 7.84 (d, J = 8.2Hz, 2H). 13C NMR (100 MHz,
d6-DMSO, 25 oC) 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 183.9,
3-(m-Tolyl)-1,2,4-thiadiazol-5-amine (3c): Eluent: petroleum
ether/ethyl acetate (4:1). Yield 56 mg (59%). White solid, mp
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10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
167.0, 136.6, 129.7 (q, J = 31.6 Hz), 128.9, 128.0, 125.6 (q, J = N-(n-Hexyl)-3-phenyl-1,2,4-thiadiazol-5-amine (3p): Eluent:
3.7 Hz), 124.2 (q, J = 272.0 Hz). ESI-MS [M+H]+ m/z 246.20.
petroleum ether/ethyl acetate (15:1). Yield 63 mg (72%).
o
1
White solid, mp 46.6-48.3 C. H NMR (400 MHz, d6-DMSO,
o
3-(Thiophen-2-yl)-1,2,4-thiadiazol-5-amine (3j)
:
Eluent: 25 C) δ 8.54 (s, 1H), 8.24-7.94 (m, 2H), 7.61-7.32 (m, 3H),
petroleum ether/ethyl acetate (4:1). Yield 71 mg (77%). 1.71-1.52 (m, 2H), 1.45-1.17 (m, 6H), 0.97-0.76 (m, 3H). 13C
White solid, mp 193.3-194.9 oC. 1H NMR (400 MHz, d6-DMSO, NMR (100 MHz, d6-DMSO, 25 oC) δ 183.6, 169.0, 133.7, 130.2,
25 oC) δ 8.10 (s, 2H), 7.68-7.57 (m, 2H), 7.26-7.01 (m, 1H). 13
C
129.0, 127.9, 45.7, 31.4, 28.9, 26.4, 22.5, 14.4. ESI-HRMS
NMR (100 MHz, d6-DMSO, 25 oC) δ 183.7, 164.2, 137.5, 129.0, [M+H]+ m/z calcd for C14H20N3S 262.1372, found 262.1366.
128.4, 127.9. ESI-HRMS [M+H]+ m/z calcd for C6H6N3S2
183.9998, found 183.9990.
N-Isopropyl-3-phenyl-1,2,4-thiadiazol-5-amine
Eluent: petroleum ether/ethyl acetate (15:1). Yield 96 mg
Eluent: (88%). Colorless oil. H NMR (400 MHz, d6-DMSO, 25 C) δ
(3q):[15]
1
o
3-(Thiophen-3-yl)-1,2,4-thiadiazol-5-amine (3k)
:
petroleum ether/ethyl acetate (4:1). Yield 56 mg (61%). 8.48 (d, J = 6.8 Hz, 1H), 8.17-8.02 (m, 2H), 7.57-7.35 (m, 3H),
White solid, mp 192.8-195.0 oC. 1H NMR (400 MHz, d6-DMSO, 3.83 (s, 1H), 1.25 (d, J = 6.5 Hz, 6H). 13C NMR (100 MHz, d6-
o
25 C) δ 8.13-7.87 (m, 3H), 7.64-7.52 (m, 2H). 13C NMR (100 DMSO, 25 oC) δ 182.5, 169.0, 133.7, 130.2, 129.0, 127.9, 48.0,
o
MHz, d6-DMSO, 25 C) δ 183.7, 165.5, 136.4, 127.4, 127.2, 22.6. ESI-MS [M+H]+ m/z 220.05.
126.8. ESI-HRMS [M+H]+ m/z calcd for C6H6N3S2183.9998,
found 184.0000.
N-Isopropyl-3-(p-chlorophenyl)-1,2,4-thiadiazole (3r): Eluent:
petroleum ether/ethyl acetate (10:1). Yield 93 mg (73%).
3-(Furan-3-yl)-1,2,4-thiadiazol-5-amine
(3l)
:
Eluent: White solid, mp 134.2-136.1 oC. 1H NMR (400 MHz, d6-DMSO,
o
petroleum ether/ethyl acetate (2:1). Yield 69 mg (82%). 25 C) δ 8.51 (d, J = 7.2 Hz, 1H), 8.19-8.00 (m, 2H), 7.62-7.43
White solid, mp 175.1-176.3 oC. 1H NMR (400 MHz, d6-DMSO, (m, 2H), 3.83 (s, 1H), 1.25 (d, J = 6.5 Hz, 6H). 13C NMR (100
25 oC) δ 8.06 (s, 2H), 7.80 (s, 1H), 6.99-6.83 (m, 1H), 6.68-6.54 MHz, d6-DMSO, 25 C) δ 182.5, 167.8, 134.9, 132.4, 129.6,
o
(m, 1H). 13C NMR (100 MHz, d6-DMSO, 25 C) δ 183.7, 160.9, 129.1, 48.0, 22.6. ESI-HRMS [M+H]+ m/z calcd for C11H13ClN3S
o
148.9, 144.8, 112.2, 111.7. ESI-HRMS [M+H]+ m/z calcd for 254.0513, found 254.0504.
C6H6N3OS 168.0226, found 168.0221.
N-(tert-Butyl)-3-phenyl-1,2,4-thiadiazol-5-amine (3s): Eluent:
N-Methyl-3-phenyl-1,2,4-thiadiazol-5-amine (3m):[6a] Eluent: petroleum ether. Yield 76 mg (65%). White solid, mp 108.9-
1
o
petroleum ether/ethyl acetate (5:1). Yield 59 mg (62%). 109.9 oC. H NMR (400 MHz, d6-DMSO, 25 C) δ 8.34 (s, 1H),
White solid, mp 141-143 oC (lit.[6a] mp 155 C). 1H NMR (400 8.22-8.02 (m, 2H), 7.56-7.38 (m, 3H), 1.45 (s, 9H). 13C NMR
o
MHz, d6-DMSO, 25 oC) δ 8.46 (s, 1H), 8.21-7.98 (m, 2H), 7.56- (100 MHz, d6-DMSO, 25 oC) δ 181.1, 168.6, 133.8, 130.2,
7.40 (m, 3H), 2.97 (d, J = 4.7 Hz, 3H). 13C NMR (100MHz, d6- 129.0, 127.9, 53.7, 28.7. ESI-HRMS [M+H]+ m/z calcd for
DMSO, 25 oC) δ 184.4, 169.1, 133.7, 130.2, 129.0, 128.0, 32.0. C12H16N3S 234.1059, found 234.1096.
ESI-MS [M+H]+ m/z 191.98.
N-(tert-Butyl)-3-[p-(trifluoromethyl)phenyl]-1,2,4-
N-Methyl-3-[p-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-
thiadiazol-5-amine (3t): Eluent: petroleum ether/ethyl
amine (3n): Eluent: petroleum ether/ethyl acetate (10:1). acetate (10:1). Yield 136 mg (90%). White solid, mp 117.4-
o
1
o
Yield 126 mg (97%). White solid, mp 160.2-162.8 oC. 1H NMR 118.3 C. H NMR (400 MHz, d6-DMSO, 25 C) δ 8.46 (s, 1H),
o
(400 MHz, d6-DMSO, 25 C) δ 8.56 (s, 1H), 8.30 (d, J = 8.1 Hz, 8.29 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 1.46 (s, 9H).
2H), 7.84 (d, J = 8.2 Hz, 2H), 3.01 (d, J = 4.8 Hz, 3H). 13C NMR 13C NMR (100 MHz, d6-DMSO, 25 C) δ 181.9, 166.6, 136.7,
o
o
(100 MHz, d6-DMSO, 25 C) δ 184.6, 167.6, 137.0, 130.2 (q, J 129.6 (q, J = 31.2, 30.6 Hz), 128.0, 125.6 (q, J = 3.8 Hz), 125.5
= 31.7 Hz), 128.7, 128.6, 126.0 (q, J = 3.7 Hz), 123.3, 120.6, (q, J = 272.1 Hz), 53.3, 28.1. ESI-HRMS [M+H]+ m/z calcd for
32.0. ESI-HRMS [M+H]+ m/z calcd for C10H9F3N3S 260.0464, C13H15F3N3S 302.0933, found 302.0940.
found 260.0468.
N-Cyclohexyl-3-phenyl-1,2,4-thiadiazol-5-amine
3-Phenyl-N-(n-propyl)-1,2,4-thiadiazol-5-amine
(3o):[14] (3u):[5]Eluent: petroleum ether/ethyl acetate (20:1). Yield 99
o
Eluent: petroleum ether/ethyl acetate (50:1). Yield 104 mg mg (76%). White solid, mp 127.9-128.8 oC(lit.[5] 126-127 C).
o
1
(95%). White solid, mp 84.4-85.3 C. H NMR (400 MHz, d6- 1H NMR (400 MHz, d6-DMSO, 25 oC) δ 8.64-8.40 (m, 1H),
o
DMSO, 25 C) δ 8.56 (s, 1H), 8.20-7.98 (m, 2H), 7.60-7.28 (m, 8.18-8.02 (m, 2H), 7.57-7.35 (m, 3H), 3.52 (s, 1H), 2.11-1.91
3H), 3.30 (d, J = 6.9 Hz, 2H), 1.78-1.48 (m, 2H), 0.95 (t, J = 7.4 (m, 2H), 1.82-1.63 (m, 2H), 1.64-1.50 (m, 1H), 1.45-1.13 (m,
o
Hz, 3H). 13C NMR (100 MHz, d6-DMSO, 25 C) δ 183.7, 169.0, 5H). 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 182.5, 169.0,
133.7, 130.2, 129.0, 127.9, 47.6, 22.3, 11.8. ESI-MS [M+H]+ 133.7, 130.2, 129.0, 127.9, 45.2, 32.4, 25.6, 24.7. ESI-MS
m/z 220.07.
[M+H]+ m/z 260.11.
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10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
o
N-Cyclopropyl-3-phenyl-1,2,4-thiadiazol-5-amine
(3v):[14] (m, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, d6-DMSO, 25 C) δ
Eluent: petroleum ether/ethyl acetate (10:1). Yield 60 mg 177.0, 167.3, 166.4, 163.8, 133.3, 131.2, 130.7, 129.3, 127.9,
(55%). White solid, mp 183.2-183.8 oC. 1H NMR (400 MHz, d6- 123.1, 114.6, 56.1. ESI-MS [M-H]- m/z 310.08.
o
DMSO, 25 C) δ 9.04 (s, 1H), 8.19-7.87 (m, 2H), 7.60-7.30 (m,
3H), 2.73-2.60 (m, 1H), 0.86-0.72 (m, 2H), 0.68-0.55 (m, 2H). Synthesis of N-carbamothioylbenzimidamide (I-1): Thiourea
o
13C NMR (100 MHz, d6-DMSO, 25 C) δ 186.1, 169.6, 133.7, 2a (6 mmol, 457 mg), t-BuOK (6 mmol, 673 mg) and DMSO (6
130.3, 129.1, 127.9, 27.3, 7.1. ESI-MS [M+H]+ m/z 218.06.
mL) were added into a 25 mL round-bottom flask charged
with a magnetic stirrer. Then the benzoimidate 1a (3 mmol,
N-Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine (3w):[4c] Eluent: 448 mg) was added into the flask; and the flask was sealed
petroleum ether/ethyl acetate (10:1). Yield 96 mg (72%). and stirred for 4 h under room temperature. After that, the
White solid, mp 109.3-110.8 oC (lit.[4c] mp 103-105 oC). 1H resulting solution was quenched with saturated aqueous
o
NMR (400 MHz, d6-DMSO, 25 C) δ 8.99 (s, 1H), 8.09 (m, J = solution of Na2S2O3. The organic and aqueous layers were
6.9, 2.2 Hz, 2H), 7.54-7.33 (m, 7H), 7.33-7.24 (m, 1H), 4.60 (d, separated, and the aqueous layer was extracted with EtOAc
o
J = 5.7 Hz, 2H). 13C NMR (100 MHz, d6-DMSO, 25 C) δ 183.7, (3×20 mL). The combined organic layers were dried over
168.8, 138.5, 133.6, 130.3, 129.0, 129.0, 128.1, 128.0, 127.8, anhydrous Na2SO4, concentrated and purified by column
49.0. ESI-MS [M+H]+ m/z 268.08.
chromatography on silica gel employing petroleum ether/
EtOAc (2:1) as eluent to afford target product N-
N-Benzyl-3-(p-bromophenyl)-1,2,4-thiadiazol-5-amine (3x): carbamothioylbenzimidamide (I-1). Yield 462 mg (86%). Pale
Eluent: petroleum ether/ethyl acetate (10:1). Yield 147 mg green solid, mp 150.9-152.1 oC. 1H NMR (400 MHz, d6-DMSO,
o
(85%). White solid, mp 132.8-134.0 oC. 1H NMR (400 MHz, d6- 25 C) δ 10.29 (s, 1H), 8.73 (s, 1H), 8.43-8.29 (m, 1H), 8.28-
o
DMSO, 25 C) δ 9.03 (s, 1H), 8.19-7.83 (m, 2H), 7.72-7.61 (m, 8.12 (m, 1H), 8.02-7.90 (m, 2H), 7.61-7.39 (m, 3H). 13C NMR
2H), 7.46-7.33 (m, 4H), 7.33-7.24 (m, 1H), 4.60 (d, J = 5.8 Hz, (100 MHz, d6-DMSO, 25 oC) δ 192.1, 162.5, 135.7, 132.0,
2H). 13C NMR (100 MHz, d6-DMSO, 25 oC) δ 183.8, 167.8, 128.7, 127.9. ESI-HRMS [M+H]+ m/z calcd for C8H10N3S
138.4, 132.6, 132.1, 129.9, 129.0, 128.1, 127.8, 123.8, 49.0. 180.0590, found 180.0584.
ESI-HRMS [M+H]+ m/z calcd for C15H13BrN3S 346.0008, found
346.0000.
Synthesis of 3a from I-1: I-1 (0.5 mmol, 90 mg), DMSO (1 mL),
H2O (0.1 mL), KOH (1 mmol, 56 mg) and iodine (1.1 mmol,
Eluent: 279 mg) were sequentially added into a 10 mL reaction tube
N,3-Diphenyl-1,2,4-thiadiazol-5-amine
(3y):[6a]
petroleum ether/ethyl acetate (20:1). Yield 57 mg (45%). charged with a magnetic stirrer. The mixture was stirred for
1
White solid, mp 176-179 oC (lit.[6a] mp 172 °C). H NMR (400 10 h at room tempereture. The resulting solution was
MHz, d6-DMSO, 25 oC) δ 11.07 (s, 1H), 8.30-8.05 (m, 2H), quenched with saturated aqueous solution of Na2S2O3. The
7.73-7.61 (m, 2H), 7.58-7.49 (m, 3H), 7.48-7.39 (m, 2H), 7.16- organic and aqueous layers were separated, and the aqueous
o
7.05 (m, 1H). 13C NMR (100 MHz, d6-DMSO, 25 C) δ 179.6, layer was extracted with EtOAc (3×15 mL). The combined
169.0, 140.3, 133.2, 130.7, 129.9, 129.2, 128.0, 123.4, 118.1. organic layers were dried over anhydrous Na2SO4,
ESI-MS [M-H]- m/z 252.33.
concentrated and purified by column chromatography on
silica gel employing petroleum ether/ EtOAc (4:1) as eluent
Synthesis of 4-methoxy-N-(3-phenyl-1,2,4-thiadiazol-5- to afford target product 3a (80 mg, 90%).
yl)benzamide (LUF5417) from 3a[11]: 5-Amino-3-phenyl-1,2,4-
thiadiazole 3a (4 mmol, 709 mg) was dissolved in dry pyridine
(1.8 mL) at a 10 mL three-neck flask. The mixture was cooled
to 0 °C, and 4-methoxybenzoyl chloride (5.9 mmol, 1.0 g) was
Acknowledgements
dropwise added. The solution solidified gradually within 0.5 h. This work was supported by National Natural Science
Foundation of China (Grant No. 21502042, 51403051),
Scientific Research Key Project Fund of Henan Provincial
Education Department (Grant No. 15A150041, 16A150003),
Scientific Research Fund of Henan University (No.
2013YBZR008).
And then the solid was dissolved in a mixture of EtOAc/water
(1/1, 80 mL). The water layer was removed, and the organic
layer was washed subsequently with 40 mL of 1 M HCl, 40 mL
of 5% NaHCO3 solution and 40 mL of brine. The organic layer
was dried over anhydrous MgSO4 and concentrated under
reduced pressure. The oily residue was purified by column
chromatography on silica gel employing petroleum ether/
EtOAc (10:1) as eluent, and white crystal of 4-methoxy-N-(3-
Keywords: I2-mediated • one-pot synthesis • oxidative
construction of N-S bond • 5-amino-1,2,4-thiadiazole • imidate
phenyl-1,2,4-thiadiazol-5-yl)benzamide
(LUF5417)
was
obtained. Yield 984 mg (79%). White solid, mp 174.7-176.0 oC
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201800670
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
I -mediated oxidative
coupling
2
Heterocycles*
Ling Chai, Zhenzhen Lai, Qiangqiang
Xia, Jiangpei Yuan, Qilong Bian,
Mingjian Yu, Wenkai Zhang, Yuanqing
Xu*, Hao Xu*
NH
S
N
S
t-BuOK, DMSO, RT
(1)
(2)
+
R2
NHR2
Ar1
Ar
H5
OC2
H2N
N
N
H
I RT
,
2
2O,
H
addition-elimination
nucleophilic
=
R2
Aryl
H,
Alkyl,
Page No. – Page No.
25
31-97
%
examples,
One-Pot Synthesis of 3-Aryl-5-amino-
1,2,4-thiadiazoles from Imidates and
Thioureas via I2-Mediated Oxidative
Construction of N-S Bond
♦
and
readily avillable
harmfuless substrates
♦
♦
♦
easy
to
and
unfunctionalized
construction
functionalized
N-S
bond
approach
3-aryl-5-amino-1,2,4-thiadiazoles
I
2-mediated oxidative
of
and
access to
LUF5417
fast
inexpensive
A simple and practical I2-mediated one-pot synthesis of 3-aryl-5-amino-1,2,4-thiadiazoles from imidates and thioureas has
been developed. The protocol undergoes sequential process of base-mediated nuclophilic addition-elimination and I2-
mediated oxidative construction of N-S bond.
This article is protected by copyright. All rights reserved.