Electrochemical Synthesis of 3,5-Disubstituted-1,2,4-thiadiazoles through NH4I-Mediated Dimerization of Thioamides

Article abstract of DOI:10.1002/adsc.201800871

A electrochemical method for the synthesis of 3,5-disubstituted-1,2,4-thiadiazoles through NH₄I-mediated dimerization of thioamides is reported. Using the inexpensive NH₄I as electrolyte and catalyst, this electrosynthesis approach requires no oxidizing agents and enables the convenient production of diverse 1,2,4-thiadiazoles products. The approach is an example of S?N bond construction through the electrochemical method. (Figure presented.).

Full text of DOI:10.1002/adsc.201800871

Title: Electrochemical Synthesis of 3,5-Disubstituted-1,2,4-thiadiazoles
through NH4I-Mediated Dimerization of Thioamides
Authors: Zi-Qiang Wang, Xiu-Jin Meng, Qian-yu Li, Hai-Tao Tang,
Heng-shan Wang, and Ying-ming Pan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800871
Link to VoR: http://dx.doi.org/10.1002/adsc.201800871

10.1002/adsc.201800871
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Electrochemical
Synthesis
of
3,5-Disubstituted-1,2,4-
thiadiazoles through NH4I-Mediated Dimerization of
Thioamides
Zi-Qiang Wang, Xiu-Jin Meng, Qian-Yu Li, Hai-Tao Tang,* Heng-Shan Wang, Ying-
Ming Pan*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China. E-mail:
httang@gxnu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A electrochemical method for the synthesis of
3,5-disubstituted-1,2,4-thiadiazoles through NH4I-mediated
dimerization of thioamides is reported. Using the
inexpensive NH4I as electrolyte and catalyst, this
electrosynthesis approach requires no oxidizing agents and
enables the convenient production of diverse 1,2,4-
thiadiazoles products. The approach is an example of S–N
bond construction through the electrochemical method.
Keywords: electrochemical synthesis; S–N bond
construction; NH4I-mediated; thiadiazoles; thioamides
1,2,4-Thiadiazole is an important five-membered
heterocyclic unit because of its ubiquity in
numerous bioactive molecules.[1] For example,
cefozopran (SCE-2787), which is one of the
many compounds containing a 1,2,4-thiadiazole
Figure 1. Bioactive molecules containing a thiadiazole
moiety.
unit (Figure 1), is a commercially available drug
oxidizing agents (Scheme 1). Other substrates, such
as aryl nitriles,[7] aryl amidines,[8] and 3,5-dichloro-
1,2,4-thiadiazole,[9] have also been reported for the
synthesis of thiadiazoles. However, these methods
typically require stoichiometric amounts of oxidizing
agents,[7] excessive amounts of sulfur[8a] and
LiOtBu,[8b] or expensive palladium catalyst[9].
Therefore, a green, facile, and sustainable approach
for 1,2,4-thiadiazoles synthesis is urgently needed.
[2]
with
potent
antibiotic
activity.
Polycarpathiamine A, which was isolated by
Proksch’s group from the ascidian Polycarpa
aurata, displays an excellent cytotoxic activity
against the murine lymphoma cell line L5178Y.[3]
The aromatase inhibitory activities of compounds
I and II, both of which possess pyridyl groups,
are 30–125 times higher than that of trans-
resveratrol. Replacing the pyridyl group in these
compounds with a 3-methoxyphenyl group yield
confers compound III with an intense NF-κB
inhibitory activity.[4] The indole-containing
thiadiazole derivative (compound IV) exhibits a
potent anticancer activity.[5] In view of the
importance of 1,2,4-thiadiazoles, numerous
methods that utilize thioamides as starting
materials have been developed for the synthesis
of 1,2,4-thiadiazole derivatives.[6] However, all of
these methods require stoichiometric amounts of
The formation of carbon-heteroatom and
heteroatom-heteroatom bonds is one of the most
significant transformations in modern organic
chemistry. Direct X-H/X-H (X=C, N, S, O) oxidative
coupling have been widely explored due to the
simplicity of the method.[10] However, traditional
cross-coupling reactions require precious metals as
catalysts or stoichiometric amounts of oxidants. Thus,
the development of a metal-free and oxidizing-agent-
free X-H/X-H (X=C, N, S, O) oxidative coupling
would represent a major advancement toward achiev-
1
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10.1002/adsc.201800871
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions. a
Entry
1
Solvent
Electrolyte
Yield (%)b
63%
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:CH3CN (1:1)
CH3OH:H2O (1:1)
n-Bu4NI
2
KI
71%
3
NH4I
94%d
20%
4
NaI
NH4Br
Scheme 1. Synthesis of 1,2,4-thiadiazoles from thioamides
through C-N and S-N bond formation.
5
69%
6
NH4I (10 mol %)
NH4I (2 mol %)
-
92%
7
40%
ing lower cost and greater environmental
sustainability in the preparation of heterocyclic
compounds.
8
Trace
76%
9c
10
11
NH4I
NH4I
60%
Electroorganic synthesis is an ideal alternative
approach for synthesizing various heterocyclic
structures through X-H/X-H oxidative coupling.[11-12]
This approach utilizes electrons as “reagents” to
accomplish the redox process and is a powerful tool
for synthesizing organic compounds. Zeng[11e]
provided an overview of previous works that
synthesized heterocyclic structures through an
electrochemical method. Baran[11d] comprehensively
summarized the electrochemical methods for organic
synthesis that have been reported since 2000. Lei[11f]
recently outlined the application of electrochemical
oxidative cross-coupling in C−C, C−O, C−N, N–N,
and C–S bond construction.
Although considerable efforts have been
directed toward the construction of C–C, C–N,
C–O, and heteroatom-heteroatom bonds through
electrochemical methods, to the best of our
knowledge, the electrochemical construction of
S–N bond has not been reported. We have
demonstrated a consistent continuous interest in
the synthesis of functionalized heterocycles.[13]
Herein, we report an attractive method for the
synthesis of 1,2,4-thiadiazoles through the
electrochemical construction of the S–N bond
from thioamides bearing aryl and alkyl
substituents under transition-metal-free and
oxidizing-agent-free conditions.
We selected thiobenzamide 1a as the model
substrate for the optimization of the reaction
conditions (Table 1). We treated thiobenzamide
1a at a constant current (10 mA) in the presence
of 5 mol % n-Bu4NI at room temperature for 4 h
in an undivided cell containing a mixed solvent of
methanol and acetonitrile (1:1). Consequently, we
isolated the target product 2a with a yield of 63%
(Table 1, entry 1). We identified NH4I as the
optimal electrolyte (Table 1, entries 2–5) by
screening various types of electrolytes (KI, NH4I,
NaI, and NH4Br). The use of NaI (Table 1, entry
4) as electrolyte markedly decreased the yield of
CH3CN:H2O (1:1)
NH4I
64%
a) Reaction conditions: Reticulated vitreous carbon (RVC)
anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1
cm × 1 cm), undivided cell, constant current = 10 mA, 1a
(0.5 mmol), NH4I (5 mol %), solvents (6 mL), under air
c)
atmosphere at room temperature for 4 h. b) Isolated yield.
d)
Constant current = 5 mA. we can get the same yield
under Ar or air atmosphere.
product 2a to 20%. The yield of 2a was
unaffected when the reaction was performed after
the NH4I loading was increased to 10 mol %
(Table 1, entry 6). Reducing the amount of NH4I
to 2 mol % resulted in low product yield (Table 1,
entry 7). Moreover, conducting electrolysis
without NH4I (Table 1, entry 8) yielded only
trace amounts of product 2a, indicating that NH4I
was crucial for reaction efficiency. The yield
decreased when the current density was adjusted
to 5 mA (Table 1, entry 9). The use of other
solvents, such as methanol and water (1:1) or
acetonitrile and water (1:1), decreased the yields
(Table 1, entries 10 and 11). Furthermore, we
examined other cheaper electrodes and mediators
(Table S1), and the interesting finding was that
electricity was indispensable (Table S1, entry 10).
Therefore, the optimized reaction conditions for
this transformation involved electrolysis with 5
mol % NH4I in MeOH:MeCN (1:1) under air
atmosphere at room temperature for 4 h.
After the optimized reaction conditions were
defined, we investigated the substrate scope of
the electrolytic dimerization by varying the
thioamide substituents of the substrates. The
corresponding products were easily obtained with
moderate to excellent yields (63%–94%), as
shown in Scheme 2. We found that electrolysis
was compatible with different alkyl groups of
thiobenzamides (products 2b–2f). Performing the
2
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10.1002/adsc.201800871
Advanced Synthesis & Catalysis
respectively.[4] Furthermore, 1,2,4-thiadiazole
derivatives 2c and 2h, which were easily obtained
through this method, displayed a potent NF-κB
Scheme 2. Substrate scope.a,b
inhibitory activity with IC50 values of 0.8 and 0.4
[4]
μM, respectively.
Overall, our experimental
results indicated that the electrochemical reaction
is compatible with aromatic and aliphatic
thioamides.
To demonstrate our method’s potential for
application, we performed the reaction at a gram
scale level in a beaker-type cell with the same
electrode and the same current density at room
temperature for 70 h to afford corresponding
products with satisfactory yields (Scheme 3).
a) Reaction conditions: Reticulated vitreous carbon (RVC)
anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt plate cathode (1
cm × 1 cm), undivided cell, constant current = 10 mA, 1
(0.5 mmol), NH4I (5 mol%), solvent (6 mL), under air
atmosphere at room temperature for 4 h. b) Isolated yield.
reaction with ortho-, meta-, or para-substituted
thiobenzamides produced the corresponding
products 2b–2d with excellent yields. This result
indicated that electrolytic dimerization was
unaffected by the steric properties of the
substrate. In addition, the reaction exhibited an
excellent tolerance against the presence of
various electron-donating groups (including –
OMe, –OCF3, and –OH) and electron-
withdrawing groups (such as –F, –Cl, –CF3, and –
NO2) at different positions of the reacting phenyl
ring (products 2g–2n). The ring fusion of
thioamide (R = 1-naphthyl) proceeded smoothly
with a good yield (product 2o). All thioamides
containing heterocyclic groups (R = 4-pyridyl, 3-
pyridyl, -furyl, and -thienyl) were suitable
substrates (products 2p–2s) for this reaction. This
reaction was also applicable to thioamides
bearing benzyl (product 2t) or tert-butyl (product
2u). Products 2p and 2q were effective aromatase
inhibitors with IC50 values of 0.8 and 0.2 μM,
Scheme 4. Controlled experiments.
To investigate the possible pathways, we
performed some control experiments. 1a was
initially reacted with I2 (2 equiv.) in the mixed
CH3CN:CH3OH
(1:1) solvent
at
room
temperature for 4 h in the absence of a current,
and product 2a was afforded with 51% isolated
yield (Scheme 4, Eq. 1). Subsequently, TEMPO/1,
1-diphenylethylene, and 1a were performed under
standard conditions, and the target product 2a
was obtained with 86/84% isolated yield (Scheme
4, Eq. 2). These results might exclude the
possibility of a radical mechanism. To explore the
substrate structure-reactivity relationship, we
performed
a
crossover experiment using
equimolar amounts of reactants 1a and 1u, which
yielded the corresponding products A and B (A:B
= 100:52, Scheme 4, Eq 3, determined by LC-
MS). This result indicated that the aryl substrate
1a was more convenient for this transformation.
Next, we conducted cyclic voltammetry (CV)
experiments to determine the role of NH4I. As
depicted by curve c in Figure 2, substrate 1a had
no obvious oxidation peak without NH4I in the
range of 0.0−1.0 V vs Ag/AgCl, implying that 1a
cannot be oxidized within the range. The CV of
NH4I (curve b) exhibited two oxidation peaks at
0.48 (Ox1) and 0.68 V (Ox2) vs Ag/AgCl, which
Scheme 3. Gram-scale reaction.
3
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10.1002/adsc.201800871
Advanced Synthesis & Catalysis
In conclusion, we developed
a
novel
electrochemical method for the synthesis of
various
3,5-disubstituted-1,2,4-
thiadiazoles
through the NH4I-mediated dimerization of
thioamides under mild conditions. The synthetic
utility of our method was demonstrated through
the synthesis of several bioactive compounds
including 2p, 2q
presented the first example of S–N bond
construction through an electrochemical
, 2c, and 2h. Our approach
approach. Our electrochemical methodology
offers notable advantages over other methods,
such as high conversion efficiency, broad
substrate scope, and inexpensive electrolyte
requirement. This reaction can be easily scaled up
with an excellent yield, indicating its potential for
practical applications.
Figure 2. Cyclic voltammograms of NH4I and related
compounds in 0.1 M LiClO4/CH3CN/MeOH (1/1 v/v)
using a glassy carbon disk working electrode (diameter, 3
mm), Pt disk, and Ag/AgCl (0.1 M in CH3CN) as counter
a)
and reference electrodes at 100 mV/s scan rate:
d)
background, b) NH4I (3 mmol/L), c) 1a (8 mmol/L), and
NH4I (3 mmol/L) and 1a (8 mmol/L).
Experimental Section
attributed to the oxidation of the I anion to form
the I3 anion and the I3 anion to form I2. [14] The
CV of the mixture of NH4I (3 mmol/L) and
compound 1a (8 mmol/L) exhibited an additional
marked increase in catalytic current (curve d),
suggesting that NH4I was the catalyst for the
electrochemical process.
The thioamides (0.5 mmol, 1.0 equiv) and NH4I (0.025
mmol, 0.05 equiv) were placed in a 10 mL three-necked
round-bottomed flask. The flask was equipped with a RVC
(100 PPI, 1 cm x 1 cm x 1.2 cm) anode and a platinum
plate (1 cm x 1 cm) cathode. MeOH (3.0 mL) and MeCN
(3.0 mL) were added. The electrolysis was carried out at
RT using a constant current of 10 mA until complete
consumption of the substrate (monitored by TLC, about 4
h). The reaction mixture was concentrated and the residue
was chromatographed through silica gel eluting with ethyl
acetate/petroleum ether to give the products.
Acknowledgements
We thank the National Natural Science Foundation of China
(21362002), Guangxi Natural Science Foundation of China
(2016GXNSFEA380001 and 2016GXNSFGA380005) and State
Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources (CMEMR2017-A02 and CMEMR2017-A07)
for financial support.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800871
Advanced Synthesis & Catalysis
COMMUNICATION
Electrochemical Synthesis of 3,5-Disubstituted-
1,2,4-thiadiazoles through NH4I-Mediated
Dimerization of Thioamides
Adv. Synth. Catal. Year, Volume, Page – Page
Zi-Qiang Wang, Xiu-Jin Meng, Qian-Yu Li, Hai-
Tao Tang,* Heng-Shan Wang, Ying-Ming Pan*
6
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