Electrochemically enabled chemoselective sulfonylation and hydrazination of indoles

Article abstract of DOI:10.1039/c9gc01201j

Environmentally benign electrochemically enabled chemoselective sulfonylation and hydrazination of C2,C3-unsubstituted indoles with arylsulfonyl hydrazide in the presence of ammonium bromide as a redox catalyst and electrolyte have been demonstrated in this work. Under mild electro-oxidation conditions, a series of indole hydrazination products with pharmacological activity were obtained. In vitro, the hydrazination products exhibited a better anti-cancer activity compared with the diazotization products. Further mechanistic studies showed that compound 3ae inhibits cell migration and tubulin aggregation in T-24 cells, thereby leading to cell apoptosis.

Full text of DOI:10.1039/c9gc01201j

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DOI: 10.1039/C9GC01201J
Journal Name
COMMUNICATION
Electrochemically Enabled Chemoselective Sulfonylation and
Hydrazination of Indoles
Received 00th January 20xx,
Accepted 00th January 20xx
Yu-Zhen Zhang, ‡ Zu-Yu Mo, ‡ Heng-Shan Wang, Xiao-An Wen, Hai-Tao Tang*, and
DOI: 10.1039/x0xx00000x
Ying-Ming Pan*
www.rsc.org/
An
environmentally
benign
electrochemically
enabled and S-O bonds (Scheme 1, path a).15 The palladium-catalyzed C-2
/TBHP-mediated C-2 sulfonylation of
chemoselective sulfonylation and hydrazination of C2,C3- arylation of indoles and the I
2
unsubstituted indoles with arylsulfonyl hydrazide in the presence indoles with sulfonylhydrazines were also reported (Scheme 1, paths
of ammonium bromide as redox catalyst and electrolyte was b and c).16 Tu et al. recently performed a selective diazotization and
demonstrated in this work. Under mild electro-oxidation sulfonylation of indoles through TBAI/TBHP-mediated oxidative
conditions, a series of indole hydrazination products with reactions (Scheme 1, path d).17 However, all these methods need use
pharmacological activity were obtained. In vitro, the of stoichiometric amounts of oxidants or transition metal catalysts.
hydrazination products exhibited a better anti-cancer activity Organic electrosynthesis is an atom-economic and eco-friendly
compared with the diazotization products. Further mechanistic synthetic tool that realizes redox reaction via electron transfer and
studies showed that the compound 3ae inhibits cell migration and can be used to replace traditional oxidants.18 This strategy has also
tubulin aggregation in T-24 cells, thereby leading to cell apoptosis. been applied by Lei to achieve an electrochemical oxidative radical
C-H sulfonylation of benzofuran.19 Inspired by these works and our
The indole moiety is probably the most common heterocycle in
electrosynthesis,20
previous study on
we examined the
1
natural and pharmaceutical agents. Substituted indole derivatives
electrochemically initiated reaction between sulfonylhydrazines and
indoles to obtain sulfonylation and hydrazination products under
mild electro-oxidation conditions. These products are part of a new
are considered “privileged structures” as they tend to combine with
many receptors. Since the development of synthetic chemistry, the
functionalization and synthesis of indole derivatives has aroused
2
much interest from synthetic organic chemists, and numerous class of compounds with better antitumor activity compared with
3
effective methods for preparing indoles have been developed.
Unlike azo compounds that are widely used in the dyestuff industry,
traditional diazotization products.
4
5
Previous work:
R2
S
many marketed drugs, including isoniazid,
mildronate,
I2 (10 mol%)
EtOH, 70 o
6
7
R1
hydralazine, and benserazide, contain hydrazine functional groups.
The hydrazine skeleton also displays a variety of bio-activities, such
C
N
H
Pd, additive
O2 (1 atm)
solvent, 70oC, 20 h
8
9
10
a
as
anti-schistosomal,
anti-cancer,
anti-bacterial,
anti-
R1
R1
R2
1
1
12
inflammatory, and anti-oxidant activities. Therefore, introducing
this group into the indole ring presents an attractive research
direction, but only few chemists have undertaken such activity.
N
b
H
O
I2 (20 mol%)
TBHP (2 equiv)
O
S
R1
R2
S
NHNH2
c
d
R2
DCE, rt, 2 h
X
O
N
H
O
X= N, O
R2
TBAI (30 mol%)
TBHP (4 equiv)
O
S
O
As a valuable synthon, sulfonylhydrazines have attracted much
attention due to their different reactivities. They can be used as
sulfonylation reagents13 and transformed into various bioactive
products.14 Much attention has also been paid to the sulfonylation
and sulfuration of indoles with sulfonylhydrazines. For example,
Tian reported a sulfenylation reaction at the C-3 position of indoles
e
O
S
CH3CN, 40 o
C
R1
N
N
R2
N
O
H
RVC
Ni
Ph
Bu4NBF4( 0.1 mmol)
O
K CO (1.5 equiv)
2
3
R1
R2
S
CH3CN/H2O, rt, N2, 3 h
O
O
This work:
R2
O
S
Pt
RVC
O
with sulfonyl hydrazides through the I
2
-catalysed cleavage of S-N
O
S
H
H
O
S
R1
R2
NH4Br (2 equiv)
R1
N
N
R2
NHNH2
N
CH OH, 65 oC, Ar, 5 h
3
N
O
O
H
H
Better pharmacological activity
with hydrazine functional groups
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.
Scheme 1. Coupling reaction of indoles with sulfonyl hydrazides
E-mail: panym@mailbox.gxnu.edu.cn; httang@gxnu.edu.cn
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
‡These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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COMMUNICATION
Journal Name
We began our investigation with indole 1a and p-toluenesulfonyl obtain the corresponding products 3ab-3am (SchemeVie2w).ArBticelnezOennlinee-
hydrazide 2a as substrates. The effects of different reaction sulfonylhydrazide as well as 2- and 3-mDeOtIh:y10l-.b10e3n9z/eCn9eGsuCl0f1o2n0y1lJ-
conditions on the reaction results, including solvent, temperature, hydrazide (2b, 2c, and 2d) reacted with 1a to produce the products
electrolyte, were investigated by using the above model reaction. 3ab, 3ac, and 3ad with 78%, 45%, and 78% yields, respectively.
The results are shown in Table 1. In our previous work, ammonium The product 3ac was then characterized by X-ray diffraction.
2
0
iodide was used as electrolyte to obtain high-yield products.
Similarly, electron donating substituents, such as 4-methoxy- and 4-
Therefore, we used iodide as an electrolyte for our current tert-butylbenzenesulfonohydrazide (2h and 2i), produced
investigation. However, when using sodium iodide or potassium sulfonylation and hydrazination products 3ah and 3ai with 72% and
iodide as electrolyte, the required product 3aa was observed in trace 63% yields, respectively. Moreover, the benzenesulfonylhydrazides
amounts (entries 1 and 2). A similar result was observed when using bearing halide substituents, including F, Cl, and Br, showed good
tetra-butylammonium iodide as electrolyte, with ammonium iodide
reaction efficiency, thereby generating the corresponding products
with yields ranging from 60% to 75% (3ae to 3ag). Notably,
biphenylsulfonyl hydrazide (2j) formed the corresponding product
Table 1. Optimization of the reaction conditionsa,b
3
aj with a 60% yield, whereas naphthalene-2 sulfonohydrazide (2k)
and thio-phene-2-sulfonylhydrazine (2l), showed good reactivity
with 1a and obtained the corresponding products 3ak and 3al with
65% and 86% yields, respectively. Aliphatic sulfonylhydrazides
were also suitable for this transformation. Phenylmethyl
sulfonylhydrazine (2m) reacted with 1a to generate the desired
product 3am with a 40% yield.
Ts
Ts
Pt
RVC
conditions
H
TsNHNH2
N
NHTs
N NTs
N
undivided cell
N
N
H
H
H
1a
2a
3aa
3aa'
Yield (%)b
Entry
Electrolyte
NaI
Solvent
3aa
trace
trace
40
3aa'
R2
O
S
Pt
RVC
O
O
S
H
H
O
S
R2
NHNH2
NH4Br (2 equiv)
N
N
R2
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
OH
OH
OH
OH
OH
OH
OH
OH
trace
CH3OH, 65oC, Ar
undivided cell
N
O
N
O
H
H
3
aa-3am
1
a
2a-2m
KI
trace
O
O
S
NH
n-Bu
NH
NH
n-Bu
4
I
15
S
O
O
O
S
O
H
O
O
H
H
H
N
O
S
N
N
S
N
S
H
H
N
N
N
O
N
O
4
NI
23
trace
N
O
H
H
H
3ac, 45%
3
aa, 85%
3ab, 78%
F
4
Cl
0
0
0
0
0
0
0
0
0
O
S
O
S
O
4
Br
85
O
O
H
N
H
H
O
S
N
N
S
H
N
F
N
O
H
N
H
3ae,
O
4
NBr
trace
0
3
ad, 78%
The X-ray structure of
Br
3ad
65%
Cl
O
n-Bu
NH
NH
NH
NH
4 6
NPF
O
S
O
S
O
S
O
O
O
O
4
4
4
4
Br
Br
Br
Br
H
2
O
20
O
H
H
O
S
H
N
H
H H
N
N
S
Br
N
S
Cl
N
N
O
N
O
N
H
O
N
H
O
H
1
1
1
0
1
2
CH
3
CN
30
3
ag, 60%
3ah, 72%
3
af, 75%
DMSO
CH CH OH
0
3
2
trace
O
S
O
S
O
S
O
O
O
O
O
H
H
O
S
H
N
H
H
H
N
N
S
N
S
N
N
N
O
N
H
O
N
O
H
aReaction conditions: Pt plate as anode (1 cm × 1 cm), reticulated vitreous carbon
H
3
ai, 63%
3ak, 65%
3
aj, 60%
(
RVC) as cathode (100 PPI, 1 cm × 1 cm × 1.2 cm), undivided cell, constant
current = 20 mA , 1a (0.5 mmol), 2a (1 mmol), electrolyte (2 equiv), solvent (8
mL), under Ar at 65 C for 5 h. Isolated yields.
S
O
S
o
b
O
O
S
O
S
O
H
H
O
N
N
H
H
N
O
S
N
N
S
H
N
O
H
producing 3aa with a 40% yield (entries 3 and 4). Meanwhile,
ammonium chloride did not show any progress (entry 5), ammonium
bromide produced 3aa with a 80% yield (entry 6), and replacing
3al, 86%
3am, 40%
Scheme 2. Substrate scope of aryl/heteroarylsulfonyl hydrazides. Reaction
conditions: Pt plate as anode (1 cm × 1 cm), reticulated vitreous carbon (RVC) as
cathode (100 PPI, 1 cm × 1 cm × 1.2 cm), undivided cell, constant current = 20
mA, 1a (0.5 mmol), 2 (1 mmol), electrolyte (2 equiv), solvent (8 mL), under Ar at
ammonium
bromide
with
tetra-butylammonium
hexafluorophosphate and tetra-butylammonium bromide did not
produce any product (entries 7 and 8). Different solvents, such as
o
condition 65 C for 5 h. Isolated yields.
H
2
O, CH
identical conditions. However, none of these solvents was identified
as the best response option (entries 9 to 12). Therefore, with NH Br
as the electrolyte, CH OH as the solvent, platinum as the anode, and
reticulated vitreous carbon (RVC) as the cathode, the desired C-H
sulfonylated 3aa was obtained at a constant current of 20 mA in an
undivided cell with a better yield.
3 2 3
CH OH, DMSO, and CH CN, were then examined under
To further study the substrate scope of this reaction, we
investigated the substrate scope of indoles under standard conditions.
As shown in Scheme 3, those indoles bearing electron-donating
groups, such as 5-Me and 6-Me, demonstrated favorable reactivity
and reaction efficiency with 77% and 67% yields, respectively (3ba
and 3ca). However, those indoles bearing 7-Me and 4-OMe groups
produced the corresponding product with low yields (3da and 3ea).
In addition, the halide substituents, such as 4-chloro/fluoroindoles,
can smoothly react with 2a under optimized reaction conditions and
4
3
After establishing the optimal reaction conditions established, we
next subjected various aryl/heteroarylsulfonohydrazides 2b-2m and
indole 1a into a selective C3-sulfonylation and C2- hydrazination to
2
| J. Name., 2012, 00, 1-3
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Journal Name COMMUNICATION
2
produce the corresponding products 3fa and 3ga with 75% and 55% the presence of I , but the desired product 3aa was not observed,
View Article Online
yields.
thereby suggesting that I
2
DOI: 10.1039/C9GC01201J
was not involved in the reaction and that
the iodine radical was responsible for the oxidative coupling
(Scheme 4, eq. e).
RVC
O
S
O
S
Pt
O
NHNH2
NH4Br ( 2equiv)
H
H
O
S
Based on the above experimental results and cyclic voltammetry
experiments (Figure S2), we propose a reasonable reaction
R1
R1
O
N N
N
H
CH3OH, 65 oC, Ar
N
O
H
1b-1g
2a
3ba-3ga
mechanism in Scheme 5. At the anode, bromine ions were oxidized
to bromine radicals. Sulfonyl hydrazide 1 was oxidized by one
molecular of bromine radical to produce radical intermediate A. The
radical A was further oxidized by the bromine radicals in two steps
followed by the elimination of nitrogen to produce the sulfonyl
radical D, this process was demonstrated by the CV experiments.
Similarly, indole 2 can be oxidized by the bromine radicals to
produce the indole radical-cation intermediate E, which can undergo
radical coupling reaction with the sulfonyl radical D to produce the
sulfonated indole intermediate F. The final nucleophilic addition and
selective oxidative aromatization of the cation intermediate F leads
O
S
O
S
O
O
O
S
O
S
O
O
S
H
H
O
H
H
N
N
N
H
H
N
N
N
S
N
H
O
N
H
N
O
O
H
3ba, 77%
3
ca, 67%
3da, 58%
O
S
O
O
S
O
O
S
O
O
O
O
H
N
H
H
H
O
H
N
H
N
S
N
N
S
N
S
N
H
O
Cl
N
O
H
F
N
H
O
3
ea, 54%
3fa, 75%
3ga, 55%
2
2
to the formation of the sulfonated indole derivative 3. At the
cathode, protons are reduced to hydrogen to complete the reaction
cycle.
Scheme 3. Substrate scope of indoles. Reaction conditions: Pt plate as anode (1
cm × 1 cm), reticulated vitreous carbon (RVC) as cathode (100 PPI, 1 cm × 1 cm
1.2 cm), undivided cell, constant current = 20 mA, 1 (0.5 mmol), 2a (1 mmol),
electrolyte (2 equiv), solvent (8 mL), under Ar at 65 C for 5h. Isolated yields.
×
o
4e
We performed some experiments to reveal the mechanism for this
reaction (Scheme 4). When 4 equivalent of the radical scavenger
TEMPO was added, the reaction between 1a and 2a was not
achieved. The reaction mixture was analyzed by using HRMS and
4e
cathode
2
Br
2H2
4H
-
2e
R2
R2
2
Br
O
N
O
H
O
S
S
O
S
O
R2
O
anodic
oxidation
O
Br
NHNH2
NNH2
R1
NHNHS R2
R1
H
H
S
R2
O
1
O
N
O
N
S
O
O
H
O
S
O
S
- e
H
Pt
RVC
H
H
H
H
3
N
N
O
N
N
N
O
S
O
G
NH4Br(2 equiv)
TEMPO (4 equiv)
O
S
O
N
O
R2
R2 S
R2
NH
N
N
(
a) 1a
2a
2a
H
Br
Br
CH3OH, 65 o
C
4a
3
aa
O
A
O
Br
HBr
O
B
Br
HBr
C
O
(
M + Na+) 364.1671
Detected in HRMS)
Not observed
H
R2
S
NHNH2
(
O
R1
N2
Pt
RVC
1
N
NH4Br (2 equiv)
BHT (3 equiv)
H
O
3aa
Trace
2
R2
D
(
b) 1a
-
e
S
R2
S
CH3OH, 65oC, Ar
O
O
R1
O
O
H
O
Br
S
O
N
N
R1
N
H
H
E
N
Pt
RVC
NH4Br (2 equiv)
6a
H
(c)
(M + H+) 305.0996
(Detected in HRMS)
F
2a
CH3OH, 65oC, Ar
O
O
Scheme 5. Proposed mechanism.
S
O
7
a
+
(
M + H ) 275.0767
(Detected in HRMS)
Sulfonyl hydrazine compounds have anti-tumor activities. To
investigate the anti-tumor activity of these sulfonylation and
hydrazination products, the in vitro cytotoxicities of compounds
3aa-3am and 3ba-3ga and those of sulfonylation and diazotization
product 3ae' against four cancer cell lines (MGC-803, T-24, HepG-2,
O
EtO
P
OEt
Pt
RVC
3aa
Not observed
NH4Br (2 equiv)
P(OEt)3 (10 equiv)
N
H
(
d) 1a
2a
CH3OH, 65oC, Ar
5a
M + H+) 254.0941
Detected in HRMS)
(
(
23
and SK-OV-3) and one human normal cell line (WI-38) were
screened by using the MTT assay with 5-FU as a positive control.
Interestingly, compound 3ae demonstrated a higher in vitro anti-
cancer activity to all cell lines compared with the sulfonylation and
diazotization compound 3ae'. This finding may be attributed to the
I2 (2 equiv)
(e) 1a
2a
3aa
CH3OH, 65oC, Ar
Not observed
Scheme 4. Control experiments.
showed the presence of the TEMPO trapped radicals 4a (Scheme 4,
eq. a). When 3.0 equivalent of 2,6-di-tert-butyl-4-methylphenol
Table 2. IC50 (μM) values for compounds 3ae and 3ae＇.
F
F
(BHT) was added to the system, the product 3aa was observed only
in trace amounts as expected (Scheme 4, eq. b). In addition, a
reaction of hydrazide 2a with styrene was performed under standard
conditions (Scheme 4, eq. c), the desired products 6a and 7a were
detected by HRMS, the above results confirmed the radical
mechanism. Furthermore, we added 10.0 equivalent of triethyl
phosphite to the system to trap any radical intermediates. To our
delight, the indole-phosphorylation product 5a was obtained, which
indicated that an indole radical was produced during the reaction
O
O
S
S
O
O
O
S
O
S
H
H
N
N
F
N
N
F
N
O
N
O
H
H
3ae
3ae'
2
1
(Scheme 4, eq. d). Finally, a reaction of 1a with 2a was achieved in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Green Chemistry
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COMMUNICATION
Journal Name
MGC-803
20.7 ± 0.7
38.9 ± 1.9
35.2 ± 0.8
T-24
HepG-2
15.3 ± 0.9
26.8 ± 1.5
>40
SK-OV-3
25.1 ± 2.3
>40
WI-38
>40
The compound 3ae presented higher in vitro anticancerViaewctAivrtiictlye Otonlainlel
cell lines compared with the sulfonylation and diazotization
DOI: 10.1039/C9GC01201J
3
ae
ae'
-FU
12.4 ± 1.4
>40
compound 3ae'. Moreover, the preliminary analysis of the
mechanism of action studies revealed that the compound 3ae
inhibited cell migration and tubulin polymerization in T-24 cells,
thereby leading to cell cycle apoptosis.
3
>40
5
38.4 ± 1.1
>40
>40
better pharmacological activity of the sulfonyl hydrazide group
compared with the sulfonyl diazo group. As shown in Table 2, the
compound 3ae exhibited a favorable anti-cancer activity to the T-24 The authors declare no competing financial interest.
and HepG-2 cell lines with IC50 values of 12.4 ± 1.4 and 15.3 ± 0.9
Notes
Acknowledgment
μM, respectively. In addition, the inhibitory effect of compound 3ae
on tumor cells was more obvious than that on the human normal cell
We thank the National Natural Science Foundation of China
line WI-38.
(
(
21861006), Guangxi Natural Science Foundation of China
2016GXNSFEA380001, AA17204058 and AB18221005),
BAGUI Scholar Program of Guangxi Province of China
2016A13), Guangxi Funds for Distinguished Experts, State
(
Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources (CMEMR2019-A03) and Innovation
Project of Guangxi Graduate Education (YCBZ2019030) for
financial support.
References
(
1) (a) M. Somei and F. Yamada, Nat. Prod. Rep., 2005, 22, 73; (b) A.
Figure 1. Assessment of nuclear morphological changes via Hoechst
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489; (c) M.-Z. Zhang, Q. Chen and G.-F. Yang, Eur. J. Med. Chem.,
015, 89, 421.
3
3342 staining in T-24 cells after 24 h.
4
2
Detailed studies via acid staining, intracellular ROS detecting,
microfilaments inhibition, and wound healing assay were carried out
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Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson, R.
to further investigate the anti-cancer effects of the compound 3ae on S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A.
T-24 cells. The Hoechst 33342 staining assay revealed that the Kunkel, J. P. Springer and J. Hirshfield, J. Med. Chem., 1988, 31, 2235;
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calcium ion levels in T-24 cells (Figures S3 to S4). The compound
ae also inhibited tubulin aggregation (Figure S5) and cell migration
in T-24 cells (Figure 2).
(3) (a) M. Bandini and A. Eichholzer, Angew. Chem. Int. Ed., 2009,
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Green Chemistry
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View Article Online
DOI: 10.1039/C9GC01201J
RVC
Pt
R2
O
S
O
O
S
NH4Br (2 equiv)
H
H
O
S
R1
R2
NHNH2
R1
N
N
R2
N
O
CH3OH, 65
oC, Ar
N
O
H
undivided cell
H
R1, R2 = Aryl, alkyl
19 examples
0-86% yield
4
F
O
S
O
O
H
H
N
N
S
F
N
H
O
Nuclearmor
Increased concentration
phological changs of reactive oxygen species
IC50
= 12.4 ± 1.4 µM (T-24)
We have developed an electrochemically enabled chemoselective sulfonylation and hydrazination
of C2,C3-unsubstituted indoles with arylsulfonyl hydrazide