PhI-Catalyzed Intramolecular Oxidative Coupling Toward Synthesis of 2-Amino-1,3,4-Thiadizoles

Article abstract of DOI:10.1007/s10562-018-2541-y

A highly efficient method for the synthesis of thiadiazole derivatives via intramolecular oxidative coupling of thiosemicarbazide, using the in situ generated hypervalent iodine(III) reagents is developed. The protocol can be carried out smoothly and provides a variety of thiadiazole derivatives in moderate to excellent yields. Graphical Abstract: A highly efficient method for the synthesis of thiadiazole derivatives via PhI-catalyzed intramolecular oxidative coupling of thiosemicarbazide has been developed.

Full text of DOI:10.1007/s10562-018-2541-y

Catalysis Letters
https://doi.org/10.1007/s10562-018-2541-y
PhI-Catalyzed Intramolecular Oxidative Coupling Toward Synthesis
of 2-Amino-1,3,4-Thiadizoles
Yingzhi Han1 · Yadong Sun1 · Ablimit Abdukader1 · Bifu Liu2 · Duozhi Wang1
Received: 25 June 2018 / Accepted: 3 September 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
A highly efficient method for the synthesis of thiadiazole derivatives via intramolecular oxidative coupling of thiosemicar-
bazide, using the in situ generated hypervalent iodine(III) reagents is developed. The protocol can be carried out smoothly
and provides a variety of thiadiazole derivatives in moderate to excellent yields.
Graphical Abstract
A highly efficient method for the synthesis of thiadiazole derivatives via PhI-catalyzed intramolecular oxidative coupling of
thiosemicarbazide has been developed.
8
, alkyl
Keywords Catalytic oxidation · Hypervalent iodine · Aromatic aldehydes · Thiadizole · Metal-free
1 Introduction
azidobenziodoxole (IBA-N3) [16], [hydroxy(sulfonyloxy)
iodo]arenes [17], [hydroxyl(tosyloxy)iodo]benzene (HTIB,
Koser’s reagent) [18] and so on. More importantly, hyper-
valent iodine reagents are able to activate C-hetero bond
[19–21], C–C bond [1, 22, 23] and hetero–hetero bond [24]
in oxidizing reactions, and in these processes it avoids pre-
functionalization of the substrates, thus reducing the impact
of the environment and the number of synthetic steps [25].
However, with the development of new, cost-effective, and
environmentally benign metal-free catalysis processes, the
hypervalent iodine catalytic oxidation system remains a sig-
nificant challenge. In recent years, the in situ generation of
iodine has attracted more and more attention of the scientific
community. Recently, the groups of Ochiai and Kita inde-
pendently reported the oxidative coupling reactions using
iodosoarene as catalysts and meta-chloroperbenzoic acid as
cooxidant [26–28]. More recently, Ishihara and co-workers
successfully developed the α-oxyacetylation of ketones cata-
lyzed by the in situ generated iodine(III) in the presence of
iodosobenzene (PhI) [29].
In recent decades, hypervalent iodine(III) reagents have
played a vital role in organic synthesis on account of its mild
oxidation performance, low toxicity, easy recyclability, easy
handling, and having the same effect as heavy metal reagents
[1–14]. Considerable research efforts have been devoted to
the efficient introduction of hypervalent iodine(III) reagents
into organic compounds, such as the Togni reagents [15],
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-018-2541-y) contains
supplementary material, which is available to authorized users.
* Yadong Sun
syd19791016@163.com
* Duozhi Wang
xjwangdz@sina.com
1
College of Chemistry and Chemical Engineering, Xinjiang
University, Ürümqi 830046, China
2
School of Chemistry and Material Engineering, Huizhou
University, Huizhou 516007, China
Vol.:(0123456789)
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Y. Han et al.
Thiadiazole derivatives are known to exhibit prominent
biological and therapeutic activities in many pharmaceuti-
cals, which are widely used for antimicrobial [30–32], anti-
inflammatory [33], anticonvulsant [34, 35], antituberculosis
[36–38], anticancer [39–41] and antihyperlipidemic [42]
activities. Moreover, they can also be proverbially used as
ratiometric fluorescent pH indicators and diversity ligands
for catalytic reactions [43], and they are an important five-
membered sulfur-containing and nitrogen-containing hetero-
cycles regarding as ligands with metals to form polymers
[44]. Therefore, inspired by glamorous biological profiles
and extensive applications, a large number of researchers
focused on exploring efficient methods for the synthesis of
thiadiazoles and their structural analogues. Generally, tran-
sition metal-catalyzed addition of 2-benzylidenehydrazine-
carbothioamides has been considered to be the conventional
method for the synthesis of 5-aryl-1,3,4-thiadiazol-2-amines
(Scheme 1a) [45–48]. In 2015, Francis and co-workers
assumed a reusable silica-bound ruthenium complex as
catalysts to synthesize 2-amino-5-(substituted)-1,3,4-thia-
diazoles in photoredox catalysis. Despite the efficiency of
these reactions, the use of transition metal is not friendly for
the environment, which limits their practicability in phar-
maceutical industry. Hence, the development of a cheap
and practical approach for the synthesis of thiadizole under
metal-free conditions is extremely challenging (Scheme 1b)
[49–52]. Recently, Chang and co-workers used I2-mediated
oxidative C–S bond formation to obtain the 2-amino-
5-(substituted)-1,3,4-thiadizole products, which needs the
equivalent of iodine oxidant. On the basis of our recent
development of catalytic oxidative C–S bond formation for
the construction of thiadiazole heterocycles and our con-
tinuing interest in developing C–Het bond formation reac-
tions [53, 54]. Herein, we reported a novel and an efficient
protocol for the synthesis of 2-amino-5-(substituted)-1,3,4-
thiadizole via oxidative cyclization of C–S bonds. Especially
,the in situ generation of hypervalent iodine(III) is the key
for the success of the reaction (Scheme 1c).
2 Results and Discussion
In this work, the reaction of 2aa and 3 was used as sub-
strates to screen the optimal reaction conditions. As shown
in Table 1, the screening of different solvents and additives
was carried out. The results indicated that dimethyl sul-
phoxide (DMSO) was proved to be the best solvent com-
pared to 1,4-dioxane, ethanol, dichloromethane and so on
in the TBAI–H2O2 system (Table 1, entries 1–10). When
K2CO3 was used as an additive, the yield was basically
unchanged in different solvents (Table 1, entries 11–14).
Under similar conditions, when acetic acid was used as an
additive, the yield was significantly increased with DMSO
as solvents (Table 1, entries 15–18). After catalytic oxida-
tion system evaluation, we found that the PhI–H2O2 sys-
tem provided the best yield (Table 1, entries 18–20). As
to the reaction temperature, 60 °C was the best (Table 1,
entries 20–24), and the yield was not changed at room
temperature with extension of the time (Table 1, entry 25).
More importantly, after doing the blank control study, we
found that the yield was < 50% (Table 1, entry 26–27).
Therefore, the optimal reaction conditions were employ-
ing 10 mol% of PhI as a catalyst, two equivalents of H2O2
as an external oxidant and two equivalents of AcOH as an
additive in DMSO at 60 °C for 4 h.
With the optimized conditions in hand, we explored
the substrate scope of 1aa and the results are illustrated
in Table 2. From Table 2, the 2-amino-5-phenyl-1,3,4-
thiadizole (1aa) was successfully obtained in 88% yield
under the optimized conditions. To our delight, various
aryl-substituted aldehyde were well proceeded smoothly
under the optimized conditions and provided desired thi-
adizoles 1ab–bb in moderate to excellent yields (49–90%).
For example, halogen groups substituted at the ortho, meta
or para position of the aromatic aldehydes, such as fluoro
(1ab–ac), chloro (1ad–af), and bromo (1ag–ai), were
well tolerated, affording the corresponding 2-amino-
5-(substituted)-1,3,4-thiadiazoles in good to excellent
yields (76–90%). Additionally, 5-(3-nitrophenyl)-1,3,4-thi-
adiazol-2-amine (3aj) and 5-(4-nitrophenyl)-1,3,4-thiadia-
zol-2-amine (3ak) were investigated, and they transferred
to the products in 79 and 84% yields, respectively. Fur-
thermore, the process exhibited compatibility with several
electron-donating groups at the ortho, meta or para posi-
tion of the aromatic aldehydes, such as methyl (1al–an),
methoxy (1ao–aq), and isopropyl (1ar). According to the
above results, the substituents in the ortho, meta or para
position have little effect on the desired product yields.
On the other hand, some disubstituted aromatic aldehydes
such as 3,4-dichlorobenzaldehyde, 2,4-dinitrobenzalde-
hyde, 2,5-dimethoxybenzaldehyde and 3,4-dimethylben-
zaldehyde were investigated, which could be well tolerated
Scheme 1 A variety of methods for the synthesis of 2-amino-
5-(substituted)-1,3,4-thiadizole
1 3

PhI-Catalyzed Intramolecular Oxidative Coupling Toward Synthesis of…
Table 1 Screening of the reaction conditions
Entry
Cat. (10 mol%)
Oxidant (2
equiv)
Additive (2 equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
KI
PhI
PhI
PhI
PhI
PhI
PhI
–
–
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
–
–
–
–
–
–
–
–
DMSO
1,4-Dioxane
EtOH
CH2Cl2
Toluene
CH3CN
DMF
THF
AcOEt
AcOH
DMSO
1,4-Dioxane
EtOH
CH2Cl2
1,4-Dioxane
EtOH
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
80
100
40
rt
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
24
4
4
40
23
15
20
n.p
n.p
30
n.p
n.p
n.p
40
33
25
22
30
17
20
61
n.p
88
50
48
46
42
42
20
38
9
–
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
K2CO3
K2CO3
K2CO3
K2CO3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
–
rt
60
60
AcOH
Reaction conditions: 2aa (0.5 mmol), 3 (0.5 mmol), catalyst (10 mol%), H2O2 (30% in water, 2 equiv), additive (2 equiv), solvent (3 mL); n.p. =
no product
aIsolated yield
to synthesize the corresponding products in good to excel-
lent yields (55–84%, 1as–av). Other aromatic aldehydes
and heterocyclic aldehydes, such as α-naphthaldehyde
and thiophene aldehyde, also gained the target products in
good to satisfactory yields (79–86%, 1aw–ax). In addition,
cinnamic aldehydes was used to form the target products
in moderate yield (50%, 1ay) as well. Interestingly, 2-phe-
nylacetaldehyde and cyclohexanecarbaldehyde were also
suitable substrates for the reaction to give the correspond-
ing products in excellent yields (85–89%, 1az–ba). It is
also worth noting that the desired product (75%, 1bb) was
smoothly obtained from the reaction by N-phenylhydrazi-
necarbothioamide and benzaldehyde (2aa).
To further clarify the reaction mechanism, the fol-
lowing experiments were conducted (Scheme 2). Com-
pound 2aa was used as the reaction substrate to explore
control experiments. When 1.5 equivalents of TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl) as a radical scav-
enger was introduced into the reaction mixture under the
optimal conditions, the desired product 1aa was obtained
in 70% yield (Scheme 2(1)). This result suggested that the
existence of TEMPO had no inhibiting effect on the reaction
absolutely. Meanwhile, 1.5 equivalents of BHT (2,6-di-tert-
butyl-4-methylphenol) was added into the reaction system
under the optimal conditions, the yield of 1aa was increased
to 85% (Scheme 2(2)). This result further indicated that the
1 3

Y. Han et al.
Table 2 Scope of substituents (R) on the aromatic compounds
Table 2 (continued)
15
77
16
17
18
19
79
84
49
84
entry aldehyde (2)
product (1)
yield (%)
1
2
3
88
88
90
4
5
76
79
20
21
80
81
6
7
83
87
22
23
55
79
8
9
76
82
24
86
50
25
10
79
26
27
89
85
75
11
12
13
14
84
82
83
89
28a
Reaction conditions: 2 (0.5 mmol), 3 (0.5 mmol), PhI (10 mol%),
H2O2 (2 equiv), AcOH (2 equiv), DMSO (3 mL), 60 °C, 4 h
aN-phenylhydrazinecarbothioamide
reaction can fulfill smoothly in the presence of BHT. Hence,
a free-radical pathway is not most likely involved in this
transformation. It is worth noting that the 1.5 equivalents
of PhI(OAc)2 instead of the system of PhI–H2O2 was added
to the reaction mixture at 60 °C for 4 h, the yield was 82%
(Scheme 2(3)). Similarly, in the presence of PhI(OAc)2
(10%), H2O2 (2 equiv) and DMSO at 60 °C for 4 h, the yield
was 81% (Scheme 2(4)). Therefore, this result suggested that
hypervalent iodine (PhI(OAc)2) was in situ produced by PhI
and the catalytic process was crucial for this transformation.
On the basis of the above experimental results and
related literature reports [55–62], a plausible mechanism is
outlined in Scheme 3. The active PhI(OAc)2, which is gen-
erated in situ from the PhI as a catalyst, H2O2 as an oxidant
and AcOH as an additive, and the simultaneous loss of one
water molecule. After that, intermediate B is generated from
the reaction of intermediate A with PhI(OAc)2, which can
be promoted C–S bond formation in order to generate the
cationic species C and the simultaneous formation of PhI.
Subsequently, the cationic species C will loss hydrogen ions
to give the desired product D and obtain AcOH. Finally,
PhI was oxidized to PhI(OAC)2 by H2O2 to complete the
catalytic cycle.
1 3

PhI-Catalyzed Intramolecular Oxidative Coupling Toward Synthesis of…
Scheme 2 Mechanism studies
1
purification. H NMR and 13C NMR spectra were meas-
ured on a 400 MHz spectrometer (1H 400 MHz, 13C
100 MHz), using DMSO-d6 as the solvent with tetra-
methylsilane (TMS) as the internal standard at room tem-
perature. Chemical shifts (δ) are given in ppm relative to
TMS, the coupling constants J are given in Hz. Melting
points were determined on a micromelting point apparatus
without corrections.
3.2 General Procedure for the Synthesis
of 2‑Amino‑1,3,4‑Thiadiazoles
To a mixture of thiosemicarbazide (3, 0.5 mmol), sodium
acetate (0.5 mmol), aldehyde (2, 0.5 mmol), 3 mL of solvent
(vH2O:vEtOH = 1:1) was successively added into the tube and
stirred for 15 min at room temperature. After the reaction
was completed, the solvent was evaporated under reduced
pressure and the residue was redissolved in DMSO (3 mL),
followed by addition of acetic acid (2 equiv), PhI (10 mol%)
and H2O2 (2 equiv) in sequence, and then stirred at 60 °C
for 4 h (monitored by TLC). After allowing to attain room
temperature, the saturated solution of Na2S2O3 (5 mL) was
added to the reaction mixture in order to quench and then the
mixture was extracted with ethyl acetate (3×10 mL). The
combined organic layer was dried over anhydrous MgSO4
and concentrated. Finally, the residue was purified by flash
column chromatography on silica gel using a mixture of ethyl
acetate and petroleum ether as eluent to give the products.
Scheme 3 Plausible reaction mechanism
In summary, we have developed a PhI-catalyzed intra-
molecular oxidative coupling of thiosemicarbazide to
form 2-amino-1,3,4-thiadizole by using a simple catalytic
system consisting of PhI, H2O2 and AcOH. A series of
thiadiazole derivatives were obtained in moderate to good
yields. This protocol is associated with easily available
starting materials, mild conditions, good yields, which
makes the reactions more friendly to the environment for
the use of in situ generated hypervalent iodine(III) rea-
gents rather than transition metals in the operation.
Acknowledgements We thank the National Natural Science Founda-
tion of China (21662032, 21562039, 21502066), Xinjiang Natural Sci-
ence Foundation (2015211C264), Guangzhou Natural Science Foun-
dation (2014A030310113) and Xinjiang University Doctoral Science
Foundation (BS150225) for financial support.
3 Experimental
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1 3