Regioselective C-C cross-coupling of 1,2,4-thiadiazoles with maleimides through iridium-catalyzed C-H activation

Article abstract of DOI:10.1039/c9ob01539f

A regioselective C-C cross-coupling of 1,2,4-thiadiazoles with maleimides through iridium catalysis was developed. This transformation tactically linked the 1,2,4-thiadiazoles and succinimides together, and the novel molecules formed may have potential biological activity.

Full text of DOI:10.1039/c9ob01539f

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DOI: 10.1039/C9OB01539F
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Regioselective C-C cross-coupling of 1,2,4-thiadiazoles with
Received 00th January 20xx,
Accepted 00th January 20xx
maleimide through iridium-catalyzed C-H activation†
Ting Tian,a‡ An-Shun Dong,a‡ Dan Chen, Xian-Ting Caoa* and Guannan Wanga, b
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) Previous work:
A regioselective C-C cross-coupling of 1,2,4-thiadiazoles with
maleimide through iridium catalysis was developed. This
transformation tactically linked the 1,2,4-thiadiazoles and
succinimides together, and the novel molecules formed may has
potential biological activity.
O
N
OMe
O
N
O
N
N
N
H
ref 9
N
O
Introduction
O
ref 10
N
N
O
O
O
In recent years, the application of 1,2,4-thiadiazoles derivatives in
pharmaceutical chemistry has attracted extensive attention
because of the unique biological activity of 1,2,4-thiadiazole ring.1
For instance, the molecular structures of antibiotics Cefozopran and
cephalosporins Ceftaroline all contain 1,2,4-thiadiazole ring (Figure
1a). In 2012, Cushman group screened a series of 3,5-diaryl-1,2,4-
thiadiazole and found they have potential antitumor activity.2
However, the structure of these 1,2,4-thiadiazole compounds is
relatively simple, which limits the further screening and
optimization of their activities. Based on this background, the
development of simple and efficient approaches for the synthesis of
this class of compounds is of great significance.
On the other hand, the molecular structure of succinyl imide is
widely found in natural products or drug molecules.4 For example,
some drugs including Phensuximide and Thalidomide contain the
framework of succinyl imide (Figure 1b).5 For this reason, succinyl
imide is widely utilized as raw materials in many organic reactions.6
In 2016, Kim and coworkers reported rhodium-catalyzed C(sp3)-H
ref 8
N
ref 11,12
O
O
O
N
N
ref 7
O
O
ref 13
N
O
N
N
O
N
N
N
N
O
b) This work:
O
N
O
H
O
N
S
[Ir]
N
S
N
+
N
N
O
H
1a
2a
3a
Scheme 1 N-containing directing groups promoted C-H alkylations
using maleimides.
alkylation of 8‑methylquinolines with maleimides (Scheme 1a).7 In
2017, Chatani group developed rhodium-catalyzed alkylation of
ortho C−H bonds in aromatic amides with maleimides.8 In addition,
Wu and coworkers described the cobalt-catalyzed 1,4-addition of C-
H bonds of oximes with maleimides.9 Prabhu et al. demonstrated
azo directed selective 1,4-addition of ortho C−H bond to maleimides
by cobalt catalysis.10 The alkylation reactions using N-substituted
indole and maleimides were achieved under manganese and cobalt
catalysis by Song11 and Li,12 respectively. Recently, Wu group also
achieved rhodium-catalyzed direct C-H alkylation of 2-aryl-1,2,3-
triazole N-oxides with maleimides.13 These methods were achieved
by rhodium, ruthenium and cobalt catalysis represent very inspring
progress. Moreover, further developments on this theme towards
wide substrates scope are still highly desirable. In this respect, we
demonstrated an iridium-catalyzed regioselective C-C cross-
coupling of 1,2,4-thiadiazoles with maleimide through C-H
activation (Scheme 1b).
O
N
H
N
S
N
N
S
S
N
N
N
O
N
O
N
N
R
(a)
(b)
O
R
H2N
O
anticancer activity
O
Cefozopran
O
N
O
N
O
NH
O
O
Phensuximide
Thalidomide
Figure 1 The structure of Cefozopran and Ceftaroline.
a. The Key Laboratory for Medical Tissue Engineering, College of Medical
Engineering, Jining Medical University. E-mail: chemcxt@mail.jnmc.edu.cn
b. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration（Tongji
University），Ministry of Education, 389 Xincun Road, 200065 Shanghai, P. R.
China
c. ‡ Ting Tian and An-Shun Dong contributed equally.
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Initial studiesa,b,c
View Article Online
O
N
a,b
Table 2 Substrate scope of compounds 1 wDithOIm: 1a0l.e1i0m3i9d/eCs9OB01539F
H
O
O
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
N
S
R'
O
N
N
S
N
+
N
H
AgSbF6 (20 mol %)
O
O
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
N
N
S
DCE, 120 °C 24 h
,
O
N
S
AcOH (20 L)
μ
N
R'
+
1a
2a
3a
N
AgSbF6 (20 mol %)
R
R
N
DCE, 120 °C 24 - 40 h
,
R
O
Yield
[%]
78
0
R
Entry
Deviation from initial conditions
AcOH (20 L)
μ
1
2
3
R'
R'
R'
1
2
None
O
O
O
N
N
O
N
O
O
No [Cp*IrCl2]2
N
N
S
N
S
S
3
No Cu(OAc)2
0
R
R
N
N
N
4
No AgSbF6
0
R
R
3m
3n
3o
3p
3q
3a
3b
3c
3d
3e
, R' = Me, 78%
, R' = Et, 62%
, R' = t-Bu, 65%
, R' = Ph, 47%
, R' = Bn, 80%
, R = Me, R' = Me, 63%
, R = Me, R' = Et, 53%
, R = t-Bu, R' = Me, 71%
, R = t-Bu, R' = Et, 67%
, R = F, R' = Me, 69%
, R = F, R' = Et, 70%
5
No AcOH
45
0
3f
, R = Me, R' = Me, 79%
3g
3h
, R = Me, R' = Et, 80%
, R = Me, R' = t-Bu, 68%
, R = Cl, R' = Me, 62%
, R = Cl, R' = Et, 75%
6
Dioxane
3i
3j
7
MeCN
0
3r
3s, R = F, R' = t-Bu, 50%
3t
3k
, R = Cl, R' = t-Bu, 67%
8
DMF
0
, R = CF3, R' = Me, 26%
c
3l
, R = F, R' = Me, 60%
3u
3v
, R = CF3, R' = Et, 28%
, R = CN, R' = Me, trace
9
DMSO
H2O
0
R'
3v'
, R = NO2, R' = Me, trace
R'
O
N
10
11
12
13
14
0
O
O
N
O
Cu(OAc)2 was replaced with AgOAc
75
trace
trace
trace
N
S
N
S
[Cp*IrCl2]2 was replaced with [Cp*RhCl2]2
[Cp*IrCl2]2 was replaced with [Cp*Co(CO)I2]
[Cp*IrCl2]2 was replaced with [Cp*CoI2]2
N
N
3w
3x
, R' = Me, 51%
, R' = Et, 48%
3y
3z
, R' = Me, 46%
, R' = Et, 44%
a Optimization reactions performed using 0.2 mmol of 1a for 24
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Cp*IrCl2]2 (2.5
mol %), Cu(OAc)2 (20 mol %), AgSbF6 (20 mol %), AcOH (20 μL),
DCE (1 mL), 120 oC, 24 h. b Isolated yields. c Reaction time: 40 h.
h at 120 o C. b Isolated yields. c DCE = 1,2-dichloroethane.
The 1,2,4-thiadiazole scafflod contains nitrogen-atoms, which are
commonly used as directing group in C-H activation reactions.3 In
this case, we assumed that an straightforward route to access 1,2,4-
thiadiazoles derivatives would be the direct C-H bond activation of
arenes.
and then fluoro substituted substrate. This phenomenon showed
that the reactivity of these substrates was influenced by the
electronic effect of substitute groups. However, for the substrates
that with para-substituents, there is no obvious trend (3m-s). When
1,2,4-thiadiazoles has -CF3, CN, NO2 in the p-position, it could be
found that the yield with electron withdrawing groups were lower
to that of the electron donating group (Table 2, 3t- 3v’). Especially,
many byproducts were formed when substituent was CN or NO2.
When the substituent was in the o- positions, the target product
can be found to be lower than the m- and p-positions because of
the steric hindrance effect(Table 2, 3w- 3z).
Results and discussion
Model investigations focused on the C-C cross-coupling of 3,5-
diphenyl-1,2,4-thiadiazole 1a and N-methylmaleimide 2a. The
desired product 3a was isolated in 78% yield under standard
conditions (Table 1, entry 1). Control experiments demonstrated
that all the components of the reaction were indispensable to
ensure C-C cross-coupling (Table 1, entries 2-4). It was worth noting
that in the absence of AcOH, The yield of product was decreased to
45% (Table 1, entry 5). Afterwards, other solvents such as dioxane,
MeCN, DMF, DMSO and H2O were examined, the results revealed
that DCE was the best solvent to promote the reaction with 78%
yield (Table 1, entries 6-10). After the further screening of additive
and catalysts, when AgOAc as additive did not improve the yield
(Table 1, entry 11), and other catalysts such as [Cp*RhCl2]2,
[Cp*Co(CO)I2] and [Cp*CoI2]2 were found to be less effective (Table
1, entries 12-14).
Table 3 Substrate scope of compounds 1 with dimethyl fumarate a,b
H
MeO2C
CO2Me
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
N
S
CO2Me
CO2Me
4
N
S
R
+
CO2Me
R
N
AgSbF6 (20 mol %)
DCE, 120 °C 40 h
N
R
,
R
R
AcOH (20 L)
μ
1
3
MeO2C
N
S
3aa
3ab
3ac
3ad
, R = H, 60%
R
, R = Me, 80%
, R = F, 55%
, R = Cl, 57%
N
a
With the suitable reaction conditions in hand, we next explored
the scope of the transformation (Table 2). Firstly, Numerous 1,2,4-
thiadiazoles and methylmaleimides derivatives were investigated
(Table 2). The 1,2,4-thiadiazoles derivatives with both electron-
withdrawing group and electron-donating group can react with
different maleimides smoothly, providing desired products in
moderate to good yields (3a-s). When the substituent was in the m-
positions (3f-l), we can find that the reactivity of methyl substituted
substrate was the best, followed by chloro substituted substrate,
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Cp*IrCl2]2 (2.5
mol %), Cu(OAc)2 (20 mol %), AgSbF6 (20 mol %), AcOH (20 μL), DCE
(1 mL), 120 oC, 40 h. b Isolated yields.
In addition, we found that there are some structural similarities
between dimethyl fumarate and maleimide. In this case, we
employed dimethyl fumarate as substrate to replace maleimide
(Table 3). As expected, dimethyl fumarate can undergo this
reaction smoothly, giving the corresponding products in moderate
2 | J. Name., 2017, 00, 1-3
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revealed that a reversible C-H cleavage step can be considered for
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Table 4 Substrate scope of compounds 5 with maleimides a,b
(Scheme 2b).14 Furthermore, an intermoDleOcuI:l1a0r.10k3in9e/Cti9cOBis0o1t5o3p9eF
experiment of 1a and 1a-d10 with methylmaleimide was performed,
and an intermolecular kinetic isotope effect (KIE) of 2 was obtained
(Scheme 2c), clarifying that the cleavage of C-H bond may play a
significant role in the reaction.15
R''
O
N
O
O
H
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
N
S
N
N
R''
S
+
R
AgSbF6 (20 mol %)
N
N
R
R'
N
H
N
DCE, 120 °C 40 h
,
O
2
R'
H
AcOH (20 L)
Based on the experimental results and previous literature
μ
5
6
reports,7-13,16
a possible reaction mechanism was discussed
R''
R''
R''
O
O
O
N
N
N
(Scheme 3). First of all, the catalytic species (A) was generated from
[Cp*IrCl2]2 in the presence of AgSbF6 and Cu(OAc)2. Then, catalytic
species (A) coordinates with the nitrogen atom of 1,2,4-thiadiazoles
(1) and then undergo C-H metalation process to form intermediate
(B). After that, the catalyst in intermediate B coordinates with
maleimides (2) to form complex C, which subsequently go through
migratory insertion to generate a seven-membered cyclometalated
complex D. Finally, desired product (3) is obtained through
protonation and the catalytic species (A) is released to continue the
catalytic cycle.
O
O
O
N
N
N
S
S
S
N
N
N
N
N
N
H
H
H
6a
6b
6c
6d
6e, R'' = Me, 53%
6f, R'' = Et, 63%
R''
, R'' = Me, 57%
, R'' = Et, 59%
R''
, R'' = Me, 55%
, R'' = Et, 57%
R''
O
N
O
N
O
N
O
O
O
F
N
S
N
S
N
S
N
N
N
N
N
N
H
H
H
6g
6h
6i
6j
6k
6l
, R'' = Me, 58%
, R'' = Et, 55%
, R'' = Me, 50%
, R'' = Et, 51%
, R'' = Me, 65%
, R'' = Et, 52%
O
N
O
a
[Cp*IrCl2]2 + AgSbF6 + Cu(OAc)2
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Cp*IrCl2]2 (2.5
N
S
mol %), Cu(OAc)2 (20 mol %), AgSbF6 (20 mol %), AcOH (20 μL), DCE
(1 mL), 120 oC, 40 h. b Isolated yields.
N
[Cp*IrOAc]SbF6
3
1
A
to good yields. Same thing as above, the reactivity was also
influenced by the electronic effect of substitute groups (3aa-ad).
Moreover, the molecular structure of product 3aa was further
confirmed by X-ray crystallography.
To further investigate the applicability of the reaction system, we
next utilized N,3-diphenyl-1,2,4-thiadiazol-5-amine derivatives as
substrates to react with different maleimides (Table 4). To our
delight, corresponding products also can be isolated in moderate
yields through extending the reaction time (6a-l).
A series of control experiments were further carried out to study
the reaction mechanism. First, the yield of the product 3a has no
obvious change when 2 equiv. of TEMPO was added, which
suggested that a radical pathway should not be involved in the
reaction (Scheme 2a). Next, with the excess introduction of D2O,
the deuterated product 1aa was obtained. These observations
H
protonation
HOAc
C-H metalation
O
N
*Cp
S
*Cp
Ir
O
Ir
N
N
S
N
N
B
D
O
migratory insertion
*Cp
O
coordination
N
N
Ir
O
O
N
S
2
N
C
Scheme 3 Proposed mechanism
O
TEMPO (2.0 equiv)
N
H
O
O
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
N
S
Conclusions
N
S
(a)
N
+
N
AgSbF6 (20 mol %)
N
DCE, 120 °C 24 h
,
O
In summary, we have developed an iridium-catalyzed direct C-C
cross-coupling of 1,2,4-thiadiazoles with maleimide, opening a
access for the synthesis of 1,2,4-thiadiazoles derivatives and the
reaction showed excellent regioselectivity. Substituent groups
including methyl, ethyl, tert-butyl, phenyl, benzyl and halo were all
compatible, generating the corresponding products in moderate to
good yields. Further efforts on iridium-catalyzed C-H activation
reactions are currently underway in our laboratory.
AcOH (20 L)
μ
1a
2a
3a, 75%
94% D
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
AgSbF6 (20 mol %)
55% D
S
N
N
S
(b)
N
N
D O (150 L)
μ
2
55% D
DCE, 120 °C 3 h
,
94% D
AcOH (20 L)
μ
1aa
1a
O
N
O
N
S
N
S
S
N
Conflicts of interest
There are no conflicts to declare
N
3a
[Cp*IrCl2]2 (2.5 mol %)
Cu(OAc)2 (20 mol %)
AgSbF6 (20 mol %)
O
N
O
1a
N
N
O
+
(c)
DCE, 120 °C 6 h
,
AcOH (20 L)
μ
N
S
O
N
D5
KH/KD = 2
Acknowledgements
This work was supported by the Doctoral Scientific Research
2a
N
D4
1a-d10
D5
3a-d9
D5
Foundation of Jining Medical University (NO. 6001/600763002).
Scheme 2 Mechanism studies
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