I2/CuCl2-promoted one-pot three-component synthesis of aliphatic or aromatic substituted 1,2,3-thiadiazoles

Article abstract of DOI:10.1039/c9cc04254g

An efficient I₂/CuCl₂-promoted one-pot three-component strategy for the construction of 1,2,3-thiadiazoles from aliphatic- or aromatic-substituted methyl ketones, p-toluenesulfonyl hydrazide, and potassium thiocyanate has been develo

Full text of DOI:10.1039/c9cc04254g

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
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I /CuCl -Promoted One-Pot Three-Component Synthesis of
2
2
Aliphatic or Aromatic Substituted 1,2,3-Thiadiazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Can Wang,‡ Xiao Geng,‡ Peng Zhao, You Zhou, Yan-Dong Wu, Yan-Fang Cui* and An-Xin Wu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
-promoted one-pot three-component strategy electrochemical method to afford such structures (Scheme 1c).12
Although hydrazones can be obtained from the dehydration
An efficient I
for the construction of 1,2,3-thiadiazoles from aliphatic- or
aromatic-substituted methyl ketones, p-toluenesulfonyl
2 2
/CuCl
1
3
condensation of hydrazines and ketones , significant progress in
this area is still limited by the use of pre-prepared N-
tosylhydrazones and poor substrate scope, such as aliphatic
hydrazide, and potassium thiocyanate has been developed. Simple
and commercially available starting materials, a broad substrate
scope, and excellent functional group tolerability make this
strategy practical for applications. Furthermore, 1,2,3-thiadiazoles
synthesis was realized by using potassium thiocyanate as an
odorless sulfur source.
analogues being incompatible.
Remarkably, many bioactive
1
g-
compounds with 1,2,3-thiadiazole skeleton are aliphatic products.
h,2b-c,4a
Therefore, a more efficient and straightforward strategy to
obtain 1,2,3-thiadiazoles that remedies these deficiencies is greatly
needed and remains a significant challenge. Herein, we have
disclosed an alternative three-component strategy to access 1,2,3-
thiadiazoles that avoids using pre-prepared substrates. Notably,
aliphatic methyl ketones react smoothly in this reaction to afford
the corresponding thiadiazole products (Scheme 1d). Furthermore,
this protocol is the first example of cheap and readily available
1
,2,3-Thiadiazoles are important N,S-heterocyclic moiety,
which are ubiquitous in natural products and pharmaceutical
molecules. They have widespread applications in medicines and
1
pesticides owing to their various biological activities, including
2
3
4
antiviral , anticancer , and antifungal activities. 1,2,3-Thiadiazoles
can also serve as versatile intermediates for the synthesis of various
14
potassium thiocyanate being used as an odorless sulfur source for
the efficient construction of 1,2,3-thiadiazole frameworks.
5
organic compounds.
Previous works :
Owing to their significance, much effort has been made to
construct 1,2,3-thiadiazole skeletons. Conventional synthetic
a) TBAI / K S O
8
2
2
NNHTs
N
N
S8
6
7
S
protocols, including the Hurd–Mori synthesis , Wolff synthesis , and
b) flavin / NH4I / O2
c) electrosynthesis
Ar
Ar
8
9
Pechmann synthesis, among others , have been reported.
Nevertheless, these reported protocols generally require the use of
highly reactive reagents or pre-functionalized substrates, reaction
safety should be considered. Pleasingly, several elegant
methodologies using preprepared N-tosylhydrazones as substrates
have emerged recently, which overcome these known deficiencies
This work :
O
N
N
S
I2, CuCl2
DMSO, 100 o
R
TsNHNH2
KSCN
R
(d)
n
C
n
1
0–12
R = Aliphatic, Aromatic
to some extent.
For example, the Cheng’s group developed a
Scheme 1. Previous and present approaches to 1,2,3-thiadiazoles.
TBAI-catalyzed reaction between pre-prepared N-tosylhydrazones
1
0
and sulfur to access 1,2,3-thiadiazoles (Scheme 1a). In 2017, Iida
and co-workers developed an unusual flavin–iodine-catalyzed
First, we selected acetophenone (1a), p-toluenesulfonyl
hydrazide (2), and potassium thiocyanate (3) as model substrates to
evaluate suitable reaction conditions. Pleasingly, in the presence of
2
in DMSO at 100 C for 1 h, target product 4-phenyl-
,2,3-thiadiazole (4a) was obtained in 75% yield (Table 1, entry 1).
1
1
reaction to obtain 1,2,3-thiadiazoles (Scheme 1b). More recently,
Tang et al. reported an admirable metal- and oxidant-free
1
1
.6 equiv. of I
Motivated by this result, we examined the effect of reaction
temperature, with 100 C found to be optimal (Table 1, entries 1–5).
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, P. R. China. E-mail:
yfcui@mail.ccnu.edu.cn.
Next, the iodine loading was investigated, with 2.0 equiv. of I
2
affording the optimum yield (Table 1, entries 6–9). Furthermore,
the reaction yield was not improved by increasing the amount of
potassium thiocyanate to 2.0 equiv., while further increasing the
amount to 3.0 equiv. afforded a lower yield (Table 1, entries 10–11).
Various solvents were screened to further improve the yield, with
DMSO found to most suitable for this reaction (Table 1, entries 12–
chwuax@mail.ccnu.edu.cn.
†
Electronic Supplementary Information (ESI) available: CCDC 1919871. For ESI and
crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
These authors made equal contributions.
‡
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
1
5). Additives also significantly affected the reaction results, with (Scheme 2). To our delight, various chained alipVhieawtAicrticmle Oetnhlinyel
CuCl found to give the best reaction promotion, affording 4a in 86% ketones, including long or short, and straighDtOoIr: b10r.a1n0c3h9/eCd9sCtCru0c4t2u5r4eGs,
yield (Table 1, entries 16–19). Based on this excellent result, we afforded corresponding compounds 6a–6l in 54%–72% yields.
tested different amounts of CuCl additive, with 0.5 equiv. found to Furthermore, cyclic aliphatic methyl ketones also reacted smoothly
2
2
be the optimal loading (Table 1, entries 20–21).
Table 1. Optimization of the Reaction Conditionsa
to give 6m–6o in 62%–73% yields. Pleasingly, α- and β-ionone also
delivered corresponding 1,2,3-thiadiazoles 6p and 6q in 72% and 74%
yields, respectively. Hexane-2,5-dione (5r) bearing two acetyl
groups was also suitable substrate for this transformation, affording
N
O
N
S
4
8% product yield. To our disappointment, α-substituted aryl
ketones are not compatible with this reaction (see Supporting
Information).
conditions
TsNHNH2
KSCN
1a
2
3
4a
O
N
N
I2, CuCl2
S
TsNHNH2
KSCN
R
R
DMSO, 100 ℃
Temp
I
2
KSCN
Additive
(1.0 eq.)
Yieldb
(%)
75
trace
44
67
71
14
29
51
79
68
57
R = Aryl, Alkyl
R = Aryl, Alkyl
Entry
Solvent
1, 5
2
3
4, 6
o
(
C)
(eq.)
1.6
1.6
1.6
1.6
1.6
0.4
0.8
1.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
(eq.)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3.0
1.0
1.0
1.0
1.0
1
2
3
4
5
6
7
8
9
100
rt
60
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DIOX
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4a R = H, 89%
4b R = Me, 83%
c R = OMe, 81%
4e R = 3-OMe, 82%
4f R = 2-OMe, 87%
N
N
N
N
N
N
S
N
S
S
O
4
R
4g R= 3,4-di-OMe, 81%
4h R = 2-OH, 71%
O
R
4d R = OEt, 86%
80
4i 85%
120
100
100
100
100
100
100
100
100
100
100
4k R = 4-F, 84%
4l R = 4-Cl, 85%
4m R= 3-Br, 81%
N
N
N
N
N
4o R = 4-CN, 76%
p R = 4-SO2CH3, 75%
4q R = 3-NO2, 73%
S
S
S
O
O
4
R
4
n R= 3,4-di-Cl, 79%
R
4j 87%
N
N
N
N
N
N
N
N
N
N
S
S
S
S
S
1
1
1
1
1
1
0
1
2
3
4
5
S
13
4r 74%
4s 71%
N
4t 85%
4u 81%
DMF
NMP
DMAC
trace
NR
trace
N
N
S
N
S
N
N
N
N
S
S
6
a 62%
6b 54%
6c 56%
6d 59%
Cu(OAc)
2
1
6
100
2.0
1.0
DMSO
74
.
2
H O
N
N
S
N
N
N
N
S
S
1
1
1
7
8
9
100
100
100
100
100
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
DMSO
DMSO
DMSO
DMSO
DMSO
CuCl
Cu(OTf)
CuBr
2
86
84
83
81
89
2
6e 61%
6f 60%
6g 63%
2
N
N
N
N
N
N
S
c
S
S
2
0
CuCl
CuCl
2
d
2
1
2
6h 58%
6i 61%
6j 69%
a
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), 3 (x mmol),
2
were heated in 2 mL of solvent within 1 h.
N
N
S
N
N
N
N
S
N
N
S
b
c
d
S
2
(0.25 mmol).
HO
6k 71%
6l 72%
6m 62%
6n 73%
The optimized reaction conditions were then applied to
various aromatic methyl ketone substrates (Scheme 2). As shown in
Scheme 2, aryl methyl ketones bearing electron-rich (4-Me, 4-OMe,
N
N
S
N
N
N
N
N
N
S
S
S
N
4
2 2
-OEt, etc), electron-deficient (4-CN, 4-SO Me, and 3-NO ), and
O
N
S
halogenated (4-F, 4-Cl, 3-Br, etc) groups reacted smoothly with p-
toluenesulfonyl hydrazide (2) and potassium thiocyanate (3) under
the optimum reaction conditions to afford the corresponding
products in good yields (71%–89%, 4a–4q). Notably, 2-naphthyl
methyl ketone and 1-naphthyl methyl ketone were also tolerated in
this transformation, giving corresponding products 4r and 4s in 74%
and 71% yields, respectively. Furthermore, this protocol exhibited
commendable compatibility with heteroaryl ketones, such as 1-(2,5-
dimethylthiophen-3-yl)ethanone (1t), with the corresponding
product obtained 85% yield. Pleasingly, when 1,1'-(1,3-
phenylene)diethanone (1u) bearing two acetyl groups was used as
substrate, corresponding product 4u was obtained in 81% yield. To
examine the generality of this reaction, we also tested aliphatic
methyl ketones as substrates. Surprisingly, various aliphatic methyl
ketones (5) reacted smoothly with p-toluenesulfonyl hydrazide (2)
and potassium thiocyanate (3) in this reaction. Accordingly, we next
investigated the scope of aliphatic methyl ketone substrates
6
o 69%
6p 72%
6q 74%
6r 48%
Scheme 2. Scope of methyl ketones. Reaction conditions: 1.0 mmol
scale. Isolated yields.
To further demonstrate the synthetic practicability of this
strategy, a 10-mmol scale synthesis of 4-phenyl-1,2,3-thiadiazole
4a) was conducted, with the product obtained in 62% yield
Scheme 3a). Furthermore, the reaction was also applicable to
natural product pregnenolone acetate (5s), affording the
corresponding 1,2,3-thiadiazole product 6s in 71% yield (Scheme
(
(
3
b). The structure of 6s was unambiguously determined by X-ray
crystallographic analysis (see Supporting Information).
To further understand the reaction mechanism of this three-
component reaction process, several control experiments were
conducted. First, based on our previous work, we reacted
1
5
hydrated phenylglyoxal (1ac) as substrate with p-toluenesulfonyl
2
| J. Name., 2012, 00, 1-3
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hydrazide (2) and potassium thiocyanate (3) under the optimized
In conclusion, we have developed an effViiceiwenArtticlethOrnelinee-
conditions for 1 h, with no target product 4-phenyl-1,2,3-thiadiazole component strategy for preparing 1,2,3-thDiOadI:ia10z.o1l0e3s9/fCro9mCC0m4e25th4yGl
O
N
N
ketones, p-toluenesulfonyl hydrazide, and potassium thiocyanate
that avoids using highly reactive or pre-prepared substrates. This
strategy has excellent substrate compatibility, especially for
aliphatic substrates, and enriches the substrate diversity of 1,2,3-
thiadiazoles synthesis. Further studies toward other applications of
this strategy are currently underway in our laboratory.
standard
conditions
S
TsNHNH2
KSCN
gram-scale
(a)
10 mmol
1a
2
3
4a 62%
N
S
O
N
TsNHNH2
2
I2, CuCl2
DMSO, 100 ℃
(b)
O
N
N
O
S
O
KSCN
TsNHNH2 (2) , KSCN (3)
O
3
CCDC 1919871
O
6s 71%
5s
I2 , CuCl2 , DMSO, 100 o
C
1a
4a
Scheme 3. Gram-scale Experiments and Further Conversion of
Pregnenolone Acetate.
path a
path b
I2/CuCl2
2
2
- H O
- HTs
H
N
(4a) detected (Scheme 4a). This result demonstrated that 1ac was
N
Ts
Ts
not the intermediate in this reaction. Furthermore, α-
iodoacetophenone (1aa) and 1-phenyl-2-thiocyanatoethanone (A)
were reacted as substrates under the optimized conditions to
obtain the corresponding target compound in 76% and 78% yields,
respectively. However, in the absence of iodine, the yield of 4a
decreased obviously (Scheme 4b and 4c). These results showed that
N
N
O
S
I
B
H
1
aa
E
I2
H
N
N
Ts
I
1
aa and A were pivotal intermediates in this process, and that
3
-
CN
iodine also played a significant role. Furthermore, 4a was also
obtained in 81% yield when using acetophenone tosylhydrazone (B)
as substrate. Meanwhile, no target product formation occurred in
the absence of iodine, proving that B was a pivotal intermediate in
the reaction and further confirming the importance of the
iodination process in the reaction (Scheme 4d).
O
C
3
Ts
NH
SCN
N
S
CN
A
2
D
-
H2O
O
N
N
Scheme 5. Proposed mechanism
OH
OH
I2, CuCl2
S
TsNHNH2
KSCN
(a)
DMSO, 100 o
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21472056, 21602070, and 21772051) and the
Fundamental Research Funds for the Central Universities
(CCNU15ZX002 and CCNU18QN011) for financial support. This work
was also supported by the 111 Project B17019.
C
1ac
2
3
4a ND
O
N
N
S
I
CuCl2
TsNHNH2
KSCN
(b)
DMSO, 100 o
C
1aa
2
3
4a
Conditions
with I2
Yields of 4a
76%
Conflicts of interest
without I2
45%
There are no conflicts to declare.
O
N
N
S
SCN
CuCl2
DMSO, 100 o
Conditions
with I2
Yields of 4a
78%
TsNHNH2
(c)
C
A
2
4a
without I2
42%
Notes and references
H
N
1
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Ts
N
N
S
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with I2
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81%
CuCl2
DMSO, 100 o
KSCN
(d)
C
without I2
ND
B
3
4a
Scheme 4. Control Experiments
From the above control experiments, we proposed a possible
reaction process, as shown in Scheme 5. First, acetophenone 1a
transforms into intermediate D via two possible reaction paths. In
path a, acetophenone 1a is first iodinated and then reacts with
KSCN (3) to give intermediate A. Next, A and p-toluenesulfonyl
hydrazide (2) undergo dehydration condensation to give
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1
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2 to obtain intermediate B, followed by
iodination and then react with 3 to obtain intermediate D.
Intermediate D further undergoes an intramolecular nucleophilic
substitution process to give intermediate E. Finally, HTs elimination
delivers 4-phenyl-1,2,3-thiadiazole 4a.
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C9CC04254G
Graphic Abstract
O
N
N
I2, CuCl2
S
R
R
TsNHNH2
KSCN
n
DMSO, 100 o
n
C
R = Aliphatic, Aromatic
40 examples
up to 89% yield
N
S
N
O
O
CCDC 1919871