Electrochemical sulfonylation of thiols with sulfonyl hydrazides: A metal- and oxidant-free protocol for the synthesis of thiosulfonates

Article abstract of DOI:10.1039/c8gc02143k

An efficient electrochemical transformation of structurally diverse sulfonyl hydrazides and thiols into thiosulfonates in the presence of ammonium iodide as redox catalyst and electrolyte in acetonitrile at ambient temperature is reported. Transition metal- and oxidant-free conditions are the striking features of this protocol. The in vitro cytotoxicity of all compounds is evaluated by MTT assay against four human cancer cell lines. The results reveal that 3ac and 3ag exhibit potential inhibitory activity against tumor cells. Furthermore, 3ag inhibits cell migration ability and tubulin polymerization in T-24 cells, leading to cell cycle arrest and apoptosis.

Full text of DOI:10.1039/c8gc02143k

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Electrochemical sulfonylation of thiols with sulfonyl hydrazides: a
metal- and oxidant-free protocol for the synthesis of
thiosulfonates
Received 00th January 20xx,
Accepted 00th January 20xx
Zu-Yu Mo, Toreshettahally R Swaroop, Wei Tong, Yu-Zhen Zhang, Hai-Tao Tang*, Ying-Ming Pan*,
Hong-Bin Sun and Zhen-Feng Chen*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient electrochemical transformation of structurally diverse
sulfonyl hydrazides and thiols into thiosulfonates in the presence
of ammonium iodide as redox catalyst and electrolyte in
acetonitrile at ambient temperature is reported. Transition metal-
and oxidant-free conditions are the striking features of this
protocol. The in vitro cytotoxicity of all compounds is evaluated
by MTT assay against four human cancer cell lines. The results
reveal that 3ac and 3ag exhibit potential inhibitory activity against
tumor cells. Furthermore, 3ag inhibits cell migration ability and
tubulin polymerization in T-24 cells, leading to cell cycle arrest and
apoptosis.
Scheme 1. Synthesis of unsymmetrical thiosulfonates from sulfonyl hydrazides.
transition metal catalysts, stoichiometric amounts of oxidants,
important class of compounds in medicinal chemistry and drug elevated temperatures, or formation of undesirable side-
Organosulfur compounds with sulfonyl motif represent an
discovery for having wide range of biological activities.1 In
products. Hence, a mild, transition metal and oxidant-free,
particular, thiosulfonates are reported as anti-microbial, anti-
fungal, insecticidal, cytotoxic, and anti-viral agents.2 They also
have widespread applications in polymer production,
photographic processes, and bioanalytical and biomedical
fields as biosensors,3 and they are used as electrophilic
sulfenylating reagents in organic synthesis over sulfenyl
halides because of their superior reactivity and stability.4
In general, symmetric thiosulfonates can be synthesized by
the oxidation of thiols or disulfides.5 Many approaches are
reported for the synthesis of unsymmetrical thiosulfonates
including sulfenylation of sodium sulfinates with disulfides in
the presence of metal catalysts or halogen-based oxidants6
and coupling of thiols with sulfonyl chlorides.7 Sulfonyl
hydrazides are actually commercial sulfonyl sources showing
widespread application in the synthesis of sulfonyl organic
products.8 Recently, cross-coupling of sulfonyl hydrazides with
thiols catalyzed by CuBr2 in tert-butyl hydroperoxide (TBHP)
media (Scheme 1a),8a disulfides mediated by H2O2 (Scheme
1b)8b and thiols in NaI/TBHP media (Scheme 1c)8c are reported.
All of these methods suffer from demerits, such as the use of
green, and sustainable synthetic method that overcomes these
limitations is in demand.
The applications of electricity in organic synthesis are well
documented.9 The replacement of the stoichiometric amounts
of chemical reagents or oxidants in cross-coupling reactions
with electrons as mass free reagents prevents waste, making
electro-synthesis an eco-friendly and atom-economic synthetic
tool. The use of transition metal catalysts may lead to its
presence in final products in trace amounts, which restricts
their application in pharmaceutical chemistry. Therefore, the
replacement of transition metals by iodine has emerged as a
powerful strategy in recent years.10 In electro-organic
synthesis, the anodic oxidation of iodide generates iodine,
which can be interconverted during the cycle of the reaction.
Thus, the catalytic or sub-stoichiometric amounts of iodide
salts are enough to achieve chemical transformation. Recently,
Lei and co-workers11 have reported the electro-oxidative
synthesis of unsymmetrical disulfides, which is the only
method that uses electricity to form S-S bond. To the best of
our knowledge, synthesis of unsymmetrical thiosulfonates
using electricity has not been reported. As a part of our efforts
in developing new reactions in organic synthesis,12 we now
disclose an electrochemical cross-coupling of sulfonyl
hydrazides with thiols in the presence of catalytic amount of
NH4I in acetonitrile at ambient temperature (Scheme 1d).
State Key Laboratory for the 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: 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
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Table 1. Optimization of reaction conditions.a,b
Scheme 2. Substrate scope of mercaptansa,b
RVC
NH4I (10 mol %)
Pt
O
S
O
+
HS
R
NHNH2
S
S R
CH3CN, r.t.
undivided cell
O
O
1a
2a-m
3aa-3am
O
O
S
O
S
Entry
1
Solvent
CH3CN
Electrolyte
NaI
Yield (%)b
S
S
S
S
O
O
O
3ac, 75%
3aa
3ab
, 82%
, 78%
c
trace
trace
0
76%
O
O
S
O
2
CH3CN
KI
S
Cl
O
S
S
Br
S
O
S
F
O
O
3
CH3CN
NH4Br
NH4I
3ad
3ae
3af
, 72%
, 65%
, 70%
O
O
S
O
S
4
CH3CN
S
S
S
CF3
S
t-Bu
82
0
O
O
O
5
CH3CN
n-Bu4NPF6
n-Bu4NI
NH4I
3ag, 85%
3ah, 83%
3ai, 78%
O
O
O
S
6
CH3CN
S
S
S
S Bn
50
20
0
S
S
O
O
O
7
CH3OH
3ak
3al
, 72%
3aj, 60%
, 76%
O
8
DMSO
NH4I
S
S
O
3am, 78%
9
H2O
NH4I
0
10
11
12
13
1,4-dioxane
CH3OH/CH3CN
CH3CN
NH4I
0
aReaction conditions: Reticulated vitreous carbon (RVC) as anode (100 PPI, 1 cm ×
1 cm × 1.2 cm), Pt plate as cathode (1 cm × 1 cm), undivided cell, constant current
= 10 mA, 1a (0.3 mmol), 2a (0.3 mmol), catalyst (10 mol%), solvent (6 mL), under
atmospheric air at room temperature for 3 h. bIsolated yields. c4 mmol of 1a
reacted with 4 mmol of 2b to afford 3ab in 76% yield.
NH4I
40
50 c
80 d
NH4I
CH3CN
NH4I
Under optimized reaction conditions, we next subjected
various mercaptans 2b-2m to sulfonylation with
benzenesulfonohydrazide 1a to obtain the desired
thiosulfonates 3ab-3am (Scheme 2). Thus, 3- and 2-
aReaction conditions: Reticulated vitreous carbon (RVC) as anode (100 PPI, 1 cm ×
1 cm × 1.2 cm), Pt plate as cathode (1 cm × 1 cm), undivided cell, constant current
= 10 mA, 1a (0.3 mmol), 2a (0.3 mmol), catalyst (10 mol%), solvent (6 mL), under
atmospheric air at room temperature for 3 h. bIsolated yields. cCatalyst (5 mol%).
dCatalyst (20 mol%).
methylbenzenethiol
(
2b and 2c
)
benzenesulfonothioates 3ab and 3ac with 78% and 75% yield,
formed S-m/o-tolyl
respectively. In addition, 4-chloro/bromo/fluorobenzenethiols
(
First, the coupling of benzenesulfonohydrazide 1a with 4-
methylbenzenethiol 2a was conducted by using reticulated
vitreous carbon (RVC) as anode and platinum as cathode at a
constant current of 10 mA in acetonitrile. With sodium iodide
as a catalyst and electrolyte, the required product S-p-tolyl
benzenesulfonothioate 3aa was observed in trace amount
(Table 1, entry 1). A similar trend was observed with potassium
iodide (Table 1, entry 2). Unfortunately, no progress was
observed in the reaction with ammonium bromide (Table 1,
entry 3). Delightedly, 3aa was isolated with 82% yield by using
ammonium iodide (Table 1, entry 4). Replacement of
2d-f
)
afforded
S-(4-chloro/bromo/fluorophenyl)
benzenesulfonothioates 3ad-af with 65%-72% yield. Then, 4-
methoxy- and 4-tert-butylbenzenethiol (2g and 2h) gave
corresponding sulfonothioates 3ag and 3ah with 85% and 83%
yield, respectively. Besides, 4-trifluoromethylbenzenethiol (2i
)
bearing strong electron-withdrawing group also underwent
smooth reaction to give S-(4-(trifluoromethyl)phenyl)
benzenesulfonothioate 3ai with 78% yield. Even bicyclic-thiol
like naphtha-lene-2-thiol (2j) also formed the desired thioate
3aj with 60% yield. Interestingly, heteroaryl mercaptan such as
thiophene-2-thiol (2k) afforded corresponding thioate 3ak
with 76% yield. Finally, alkyl thiols phenylmethanethiol (2l) and
pentane-1-thiol (2m) also formed their corresponding S-alkyl
benzenesulfonothioates 3al and 3am with 72% and 78% yield,
respectively.
ammonium
iodide
by
tetra-butylammonium
hexafluorophosphate did not furnish any product (Table 1,
entry 5), but tetra-butylammonium iodide gave 3aa a 50%
yield (Table 1, entry 6), which indicates that iodide is essential
+
for this reaction. NH4 gave a superior result to K+ or n-Bu4N+,
To demonstrate the further generality of the protocol, we
focused on the sulfonylation of 4-methylbenzenethiol 2a with
various aryl/heteroarylsulfonohydrazides 1b-n under optimal
perhaps due to the good solubility of NH4I in acetonitrile. Using
ammonium iodide as catalyst and electrolyte, we replaced
acetonitrile with other solvents, such as methanol, DMSO,
water, and dioxane. However, none of them were optimal for reaction conditions (Scheme 3). Thus, 4-, 3-, and 2-
the reaction (Table 1, entries 7-10). It can be explained by the
fact that acetonitrile has good solubility as well as excellent
electrical conductivity. Methanol/acetonitrile solvent mixture
formed 3aa with 40% yield (Table 1, entry 11). The variation of
catalyst quantity from 10 mol% to 5 mol% and to 20 mol%
decreased the yield to 50% and 80%, respectively (Table 1,
entries 12 and 13).
methylbenzenesulfonohydrazides (1b-d) reacted with 2a to
give S-p-tolyl 4/3/2-methylbenzenesulfonothioate 3ba-da with
70%-85% yield. Similarly, 2a was successfully sulfonylated with
4-fluoro/chloro/bromobenzenesulfonohydrazides
(1e-g), to
form their corresponding products 3ea-ga with 70%-78% yield.
Also, 4-methoxy- and 4-tert-butylbenzenesulfonohydrazide (1h
and 1i
)
afforded S-p-tolyl 4-methoxy- and 4-tert-butyl
2 | J. Name., 2012, 00, 1-3
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benzenesulfonothioate (3ha and 3ia) with 68% and 78% yield,
respectively. Sulfonohydrazide bearing electron-withdrawing
nitro group (1j) also underwent smooth reaction to give
desired product 3ja with 70% yield. Notably, biphenylsulfonyl
hydrazide (1k) and naphthalene-2-sulfonohydrazide (1l) also
formed their corresponding products 3ka and 3la with 75%
RVC
Pt
NH4I (10 mol%)
TEMPO (4 equiv)
O
S
N
O
S
O
N
(a)
1a
2a
2a
CH3CN, r.t.
undivided cell
O
4a
4b
(M+H+) 298.1477
(M+H+) 280.1735
(Detected in HRMS)
I2 (2 equiv.)
CH3CN, r.t.
(b)
(c)
3aa
1a
1a
trace
and
80%
yield
respectively.
Finally,
pyridine-3-
RVC
Pt
sulfonohydrazide (1m) and thio-phene-2-sulfonohydrazide (1n
)
NH4I (10 mol%)
S
S
3aa
Not observed
CH3CN, r.t.
undivided cell
also underwent sulfonylation with 2a to give desired products
3ma and 3na with 72% and 78% yield, respectively. Replacing
the aryl group with a n-pentyl group failed to form the product
5
O
O
S
3oa
.
O
S
O
Scheme 3. Substrate scope of aryl/heteroarylsulfonyl hydrazidesa,b
6a
Detected in
HRMS
Optimal conditions
1b
(d)
RVC
NH4I (10 mol %)
Pt
O
O
S
O
O
S
O
S
Ar(Het)
NHNH2
HS
Ar(Het)
S
+
CH3CN, r.t.
undivided cell
O
O
6b
Detected in HRMS
3ba-3na
1b-n
2a
O
S
O
S
O
S
S
S
S
Scheme 4. Control experiments.
O
O
O
3da, 70 %
3ca, 80%
3ba
, 85%
O
O
S
O
confirmed the involvement sulfonyl radical intermediates
(Scheme 4d).
Br
S
S
F
S
Cl
S
S
O
O
O
3ga
3ea, 70%
3fa, 73%
, 78%
O2
N
Finally, to determine the redox behavior of the reactants
and their mixtures, we carried out cyclic voltammetry (CV)
experiments. The cyclic voltagrams are shown in Figure 1. 4-
Methylbenzenethiol 2a showed an oxidation peak at 1.31 V
(curve b), which might be due to the oxidation of thiol 2a to
corresponding thiyl radical followed by its dimerization to give
O
O
O
S
S
S
O
S
S
S
O
O
O
3ja, 70%
3ha
3ia
, 68%
, 78 %
O
O
O
S
S
S
S
S
S
N
O
O
O
3ma, 72 %
3ka
, 75 %
S
3la
, 80%
O
S
O
S
disulfane 5 11
. Similarly, 1a exhibited oxidation at 1.30 V (curve
S
S
O
O
c). The CV of NH4I displays two oxidation peaks at 0.44 and
0.69 V (curve d), which correspond to the oxidation of iodide
3na, 78 %
3oa, 0 %
aReaction conditions: Reticulated vitreous carbon (RVC) as anode (100 PPI, 1 cm ×
1 cm × 1.2 cm), Pt plate as cathode (1 cm × 1 cm), undivided cell, constant current
= 10 mA, 1a (0.3 mmol), 2a (0.3 mmol), catalyst (10 mol%), solvent (6 mL), under
(I−) to I3 and I3 to iodine (I2) respectively.13 In the mixture of
2a with NH4I, the oxidation peak of 2a significantly shifted
from 1.31 V to 0.83 V, and the oxidation peak of NH4I, 0.44 V is
visible (curve e). Thus, the generated iodine (I2) is oxidizing the
thiol 2a to its corresponding thiyl radical. However, one of the
control experiments (Scheme 3b) suggests that I2 is not
involved in the reaction. Hence, we postulate that, molecular
−
−
atmospheric air at room temperature for 3 h. bIsolated yields
.
To understand the mechanism of this reaction, we
conducted some control experiments (Scheme 4). A reaction
between 1a and 2a was performed in the presence of TEMPO
under standard conditions to trap radicals (Scheme 4a). The
analysis of the reaction mixture by HRMS showed the presence
of TEMPO trapped radicals 4a and 4b, indicating that sulfonyl-
and methylbenzene sulfur radicals are the reaction
intermediates. To determine the involvement of molecular
iodine, a reaction of 1a with 2a was conducted in the presence
of I2, in which the desired product 3aa was observed only in
trace amount (Scheme 4b). This observation substantiates that
I2 is not involved in the reaction, but the iodine atom is
responsible for oxidative coupling. Furthermore, one cannot
rule out the formation of disulfides by electrochemical
oxidation from thiols and their participation in the reaction.11
Thus, the reaction of 1a with 1,2-di-p-tolyldisulfane
5 was
Figure 1. Cyclic voltammograms of reactants and their mixtures in 0.1
M
carried out under optimized conditions, and did not produce
the desired product 3aa (Scheme 4c), indicating that disulfanes
are not the intermediate reactive species. In addition, when 1b
was reacted with styrene under our optimal conditions,
products 6a and 6b were detected by HRMS, these results also
LiClO4/CH3CN using a glassy carbon disk working electrode (diameter, 3 mm), Pt
disk and Ag/AgCl (0.1 M in CH3CN) as counter and reference electrode at 100
mV/s scan rate: (a) background, (b) 2a (10 mmol/L), (c) 1a (10 mmol/L), (d) NH4I
(2 mmol/L), (e) 2a (10 mmol/L) + NH4I (2 mmol/L), (f) 1a (10 mmol/L) + NH4I (2
mmol/L), (g) 1a (10 mmol/L) + 2a (10 mmol/L) + NH4I (2 mmol/L).
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Table 2. IC50 (µM) values for compounds 3ac and 3ag against
different cell lines.
iodine and iodine atoms exist in equilibrium, and the iodine
atom is responsible for oxidation of 2a to thiyl radical. A
parallel analysis of a mixture of 1a and NH4I, displayed
oxidation peaks at 0.39 and 0.67 V for NH4I and at 1.27 V for
1a (curve f) with slight enhancement in the oxidation peak of
1a, indicating its oxidation by iodine atom. At last, the CV of a
compo
unds
HL-7402
MGC-803
T-24
SK-OV-3
WI-38
3ac
3ag
5-FU
10.3 ± 1.2
12.1 ± 0.9
>40
8.5 ± 0.9
9.4 ± 1.5
>40
8.7 ± 0.7
8.0 ± 0.5
39.4 ± 0.5
12.1 ± 0.5
10.7 ± 1.1
>40
>40
39.8 ± 0.4
>40
mixture of 1a, 2a, and NH4I showed a dramatic increase in
Compound 3ag was evaluated for its inhibitory activity for tubulin
polymerization and cell migration. The results revealed that the
treatment of T-24 cells with 3ag inhibited cell migration and tubulin
polymerization. Detailed studies such as Hoechst 33342 staining
assay suggested that the compound 3ag induced apoptosis in T-24
cells. Its influence on the cell cycle distribution was assessed on the
T-24 cell line. The results suggested that 3ag caused the G2/M-
phase arrest in T-24 cells. In addition, treatment with 3ag elevated
intracellular ROS and calcium ion levels in T-24 cells. (supporting
information Fig. S1-S6.)
current from 250 μA to 325 μA at 0.8 V, which indicates the
catalytic activity of NH4I and the intermediate thiyl radical
(curve g), which are regenerated over the span of CV scan.
Also, no change in oxidation potential of 1a (1.30 V) in curve g
indicates that neither NH4I nor thiyl radical directly affects it.
Based on our preliminary mechanistic studies and literature
reports,8 a probable mechanism for the electrochemical
synthesis of thiosulfonates is given in Scheme 5. At the anode,
the oxidation of iodides would yield iodine atoms through the
−
formation of I3 . Iodine atoms could oxidize thiols
In summary, we have developed a new metal- and oxidant-
free method for the synthesis of unsymmetrical thiosulfonates
with high yields via sulfonylation of thiols with sulfonyl
hydrazides, which overcomes all the limitations of the existing
methods. The versatility of the reaction has been
demonstrated by using various aryl/heteroaryl/alkyl thiols and
aryl/heteroarylsulfonyl hydrazides. The reaction proceeds
through a radical pathway, which is evident from the radical
trapping experiment and CV studies. The compounds 3ac and
3ag exhibited potential inhibitory activity against tumor cells.
Moreover, compound 3ag inhibited cell migration and tubulin
polymerization in T-24 cells, leading to cell cycle arrest and
apoptosis. Further efforts on electrochemical transformations
are currently under way in our laboratory.
2 to thiyl
radicals with the regeneration iodides. In parallel, the anodic
oxidation of sulfonyl hydrazide gives sulfonyl hydrazide
1
radical, which undergoes further oxidation by iodine and thiyl
radicals in a series of steps, followed by the elimination of
nitrogen to give sulfonyl radical. Finally, sulfur-sulfone bond is
formed by the combination of sulfonyl radical and thiyl radical
to furnish thiosulfonates 3. At the cathode, reduction takes
place to liberate hydrogen, which completes the
electrochemical cycle.
We thank the National Natural Science Foundation of China
(21362002), Guangxi Natural Science Foundation of China
(2016GXNSFEA380001 and 2016GXNSFGA380005), Ministry of
Education of China (IRT_16R15), State Key Laboratory for
Chemistry and Molecular Engineering of Medicinal Resources
(Guangxi Normal University) (CMEMR2017-A02 and
CMEMR2017A-07) and BAGUI Scholar Program of Guangxi
Province of China (2016A13) for their financial support.
Scheme 5. Proposed mechanism.
To explore the biological significance of these series of
thiosulfonates, the in vitro antitumor activities of 3ab-3an and
3ba-3na against four human tumor cell lines, human liver (HL-
7402), human gastric (MGC-803), human bladder (T-24),
human ovarian (SK-OV-3), and normal liver cell lines (WI-38)
were determined by methylthiazoltetrazolium assay. 5-
Notes and references
1
(a) E. Goffin, T. Drapier, A. P. Larsen, P. Geubelle, C. P. Ptak,
S. Laulumaa, K. Rovinskaja, J. Gilissen, P. Tullio, L. Olsen, K.
Frydenvang, B. Pirotte, J. Hanson, R. E. Oswald, J. S. Kastrup
and P. Francotte, J. Med. Chem., 2018, 61, 251. (b) W. Dohle,
F. L. Jourdan, G. Menchon, A. E. Prota, P. A. Foster, P.
Mannion, E. Hamel, M. P. Thomas, P. G. Kasprzyk, E.
Ferrandis, M. O. Steinmetz, M. P. Leese and B. V. L. Potter, J.
Med. Chem., 2018, 61, 1031. (c) Q. Liu, F. Huang, X. Yuan, K.
Fluorouracil (5-FU) was used as
a
positive control.
Interestingly, compounds 3ac and 3ag exhibited preferential
anticancer activity toward four human tumor cell lines (Table
2). The compound 3ac exhibited good inhibitory activity
toward HL-7402, MGC-803, and T-24 cell lines with IC50 values
of 10.3 ± 1.2, 8.5 ± 0.9 and 8.7 ± 0.7 μM respectively.
Compound 3ag was a powerful cytotoxic against MGC-803, T-
24, and SK-OV-3 cell lines with IC50 values of 9.4 ± 1.5, 8.0 ± 0.5
and 10.7 ± 1.1 μM respectively. In addition, compounds 3ac
and 3ag have more obvious inhibitory effect on tumor cells
than WI-38. Then, the lead compound 3ag was selected for
further anti-tumor mechanism study on T-24 cells.
Wang, Y. Zou, J. Shen and Y. Xu, J. Med. Chem., 2017, 60
,
10231. (d) M. Bonnet, C. R. Hong, W. W. Wong, L. P. Liew, A.
Shome, J. Wang, Y. Gu, R. J. Stevenson, W. Qi, R. F. Anderson,
F. B. Pruijn, W. R. Wilson, S. M. F. Jamieson, K. O. Hicks and
M. P. Hay, J. Med. Chem., 2018, 61, 1241.
2
(a) J. P. Weidner and S. S. Block, J. Med. Chem. 1964, 7, 671.
(b) M.-L. Alcaraz, S. Atkinson, P. Cornwall, A. C. Foster, D. M.
Gill, L. A. Humphries, P. S. Keegan, R. Kemp, E. Merifield, R.
A. Nixon, A. J. Noble, D. O’Beirne, Z. M. Patel, J. Perkins, P.
Rowan, P. Sadler, J. T. Singleton, J. Tornos, A. J. Watts and I.
A. Woodland, Org. Process Res. Dev., 2005, 9, 555. (c) E. A.
Santos, F. Gonçalves, P. C. Prado, D. Y. Sasaki, D. P. de Lima
4 | J. Name., 2012, 00, 1-3
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Green Chemistry
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DOI: 10.1039/C8GC02143K
We have developed a new metal- and oxidant-free method for the synthesis of anticancer
thiosulfonates via sulfonylation of thiols.