A new synthesis of cytotoxic thiosulfonates and the first synthesis of deuterated thiosulfonates

Article abstract of DOI:10.1055/s-0031-1260252

A new synthesis of thiosulfonates starting from thiophenols and cyanuric chloride activated dimethyl sulfoxide is reported herein. Although the yields of the reactions are moderate, this method enables the incorporation of the SCD₃ group of dimethyl sulfoxide-d₆ into thiosulfonates. This is the first synthesis of deuterated thiosulfonates with a labeling purity above 99%. In addition, the cytotoxicity of the thiosulfonates is reported for the first time. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1260252

PAPER
3635
A New Synthesis of Cytotoxic Thiosulfonates and the First Synthesis of
Deuterated Thiosulfonates
Synthesis of
C
e
ytotoxic
T
h
n
iosulfonates
g
andDeuteratedTh
G
iosulfonate
s
ao,a Huiyuan Zhai,b Meina Jin,b Guobiao Chu,a Hongquan Duan,b Chunbao Li*a
a
Department of Chemistry, College of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27403475; E-mail: lichunbao@tju.edu.cn
b
School of Pharmaceutical Science, Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070,
P. R. of China
Received 12 July 2011; revised 8 September 2011
nuric chloride and two equivalents of dimethyl sulfoxide
in acetonitrile, toluene, N,N-dimethylformamide, ethyl
acetate, or dimethyl sulfoxide. Only in neat dimethyl sulf-
oxide at 80 °C for 13 hours did the reaction lead to thio-
Abstract: A new synthesis of thiosulfonates starting from thiophe-
nols and cyanuric chloride activated dimethyl sulfoxide is reported
herein. Although the yields of the reactions are moderate, this meth-
od enables the incorporation of the SCD3 group of dimethyl sulfox-
ide-d6 into thiosulfonates. This is the first synthesis of deuterated sulfonate 2a (Scheme 1).
thiosulfonates with a labeling purity above 99%. In addition, the cy-
totoxicity of the thiosulfonates is reported for the first time.
O
Me
O
Me
S
S
S
Key words: thiols, esterification, sulfoxides, cytotoxicity, thiosul-
fonates
SH
S
O
O
TCT (2.0 equiv), DMSO
80 °C, 13 h
or
R
R
R
Thiosulfonates are useful sulfenylating reagents in organ-
ic synthesis. They have been reported to display antimi-
crobial and fungicidal activity.1 The following methods
are used for their preparation: the reaction of alkyl halides
with thiosulfonates,2 silver sulfonates with sulfonyl chlo-
rides,2 sulfonic acid with thiols in the presence of cyanuric
chloride,3 sulfonic anhydrides with thiols, or sulfinates
with disulfides;4 the oxidation of thiols and disulfides by
peroxymonosulfonate, singlet oxygen, dinitrogen tetrox-
ide, or zinc dichromate;5 the oxidation of disulfides by
ammonium cerium nitrate/iodine, peroxy acid, phenyliod-
ine(III), sodium periodate, or Selectfluor;6 the reduction
of sulfonyl chloride by samarium or potassium iodide/ac-
etone.7 To investigate the mechanism of thiosulfonates as
antibiotics and cytotoxins, which will be reported herein,
we need highly pure deuterated compounds. These com-
pounds are essential to reaction mechanism studies, en-
zyme studies, and drug metabolism studies. However, the
reported procedures utilized thiols, disulfides, and sulfo-
nyl chlorides as starting materials, none of which are com-
mercially available as deuterated compounds. The only
available deuterated sulfur compound is dimethyl sulfox-
ide-d6. If dimethyl sulfoxide could be transferred into
thiosulfonates, it would be feasible to prepare the deuter-
ated compounds urgently needed for biochemical experi-
ments.
1
2a–i
3
Scheme 1
Table 1 Reaction of Thiophenols and Cyanuric Chloride Activated
Dimethyl Sulfoxidea,b
Entry
Substrate
R
Product
Yieldc
(%)
1
2
1a
1b
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
47
55
51
62
57
74
42
48
41
59
4-i-Pr
3
4-Me
4
2,4-Me2
2,5-Me2
2,4,6-Me3
4-MeO
4-Cl
5
6
7
1g
1h
1i
8
9
4-Br
10
1j
4-MeO2C
3
a Reaction conditions: thiophenol 1 (1.0 equiv), TCT (2.0 equiv),
DMSO (solvent), 80 °C, 13 h.
b When substrates BuSH, BnSH, or 4-chlorobenzyl mercaptan were
used as the substrate, a complicated mixture resulted with none of the
desired products isolated.
It is known that dimethyl sulfoxide can be activated by
cyanuric chloride to form electrophilic sulfur-containing
species.8 If these species can be captured by thiophenol, it
would be possible to form disulfur-containing com-
pounds. Therefore, thiophenol (1a) was treated with cya-
c Isolated yield.
A series of thiophenol 1a–j were subjected to these condi-
tions and the results are summarized in Table 1. The reac-
tion times are roughly the same, which suggests that the
sulfur-containing electrophile shows no discrimination to-
wards the mercapto group. The substituents on the phenyl
SYNTHESIS 2011, No. 22, pp 3635–3638
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.10.2011
DOI: 10.1055/s-0031-1260252; Art ID: H68911SS
© Georg Thieme Verlag Stuttgart · New York

3636
F. Gao et al.
PAPER
rings, which range from electron-donating to slightly elec- Now it is possible to synthesize deuterium-labeled thio-
tron-withdrawing groups, show scarce influence on the re- sulfonate. Four thiophenols 1d–f,j were treated with cya-
action rates. However, the yields changed with the nuric chloride and dimethyl sulfoxide-d6 (Scheme 3). The
number of the substituents. The trisubstituted 2,4,6-tri- results are summarized in Table 2. The yields and reaction
methylthiolphenol 1f gave the corresponding product 2f rates are similar to the reactions above. The deuterium-
in the highest yield (entry 6). The disubstituted dimethyl- labeling purities are above 99% as indicated in the 1H and
thiophenols 1d,e yielded the corresponding products 2d,e 13C NMR spectra.
in better yields than monosubstituted thiophenols (entries
4, 5 vs. 2, 3). This is probably caused by the sulfur-con-
taining electrophile, which can attack the phenyl ring to
O
D3C
CD3
S
S
SH
S
O
S
O
O
form side products. It is obvious that the multisubstituted
ring can hinder the attack of the sulfur-containing electro-
phile on the phenyl ring. In most cases (entries 1–9),
methanethiosulfonates 2 are the major products. Howev-
er, for methoxycarbonyl-substituted thiophenol 1j, the
product is S-methyl (methoxycarbonyl)benzenethiosul-
fonate 3 (entry 10). This is attributed to the strong elec-
tron-withdrawing effect of the methoxycarbonyl group.
The reactions led to complicated products when thiols
such as butanethiol, benzyl mercaptan, and 4-chloroben-
zyl mercaptan were used as the substrates, probably be-
cause thiols are better nucleophiles toward cyanuric
chloride than thiophenols and might form a thiol-substi-
tuted cyanuric chloride.
TCT (2.0 equiv), DMSO-d6
80 °C, 13 h
or
R
R
R
1
4a–c
5
Scheme 3
Table 2 Reaction of Thiophenols and Cyanuric Chloride Activated
a
Dimethyl Sulfoxide-d6
Entry
Substrate
R
Product Yieldb (%)
1
2
3
4
1d
1e
1f
2,4-Me2
2,5-Me2
2,4,6-Me3
4-MeO2C
4a
4b
4c
5
62
54
72
58
Following mechanism is proposed for this reaction
(Scheme 2). The rearrangement of vic-disulfoxides A to
thiosulfonates 2 has been previously reported9 and it is
also expected to occur under the cyanuric chloride activat-
ed dimethyl sulfoxide reaction conditions. To prove the
mechanism, we trapped chloromethane gas from the reac-
tion with 1,4-diazabicyclo[2.2.2]octane (DABCO) in eth-
anol to produce the DABCO ammonium salt.
1j
a Reaction conditions: thiophenol 1 (1.0 equiv), TCT (2.0 equiv),
DMSO-d6 (solvent), 80 °C, 13 h.
b Isolated yield.
Cytotoxicity of the thiosulfonates against suspended tu-
mor cells was determined by the MTT [3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide] method.10
Briefly, cells were seeded onto 96-well culture plates at
1 × 104 cells/180 mL/well. After incubation with various
concentrations of compounds for 48 hours, MTT (20 mL,
5 mg/mL) was added to each well. After four hours incu-
bation, the culture medium was removed, and cells were
Cl
N
O
Cl
Cl
N
O
Cl
Cl
N
Cl
DMSO
– MeCl
N
N
N
N
N
N
Me
Cl
S
S
Cl–
Me
Me
Cl
N
Cl
Cl
N
Cl
Cl
N
TCT
ArSH
N
N
N
O
N
N
N
N
Cl-
O
S
S
Cl
Me
Me
O
S
Cl
N
S
Cl
O
Ar
O
S
TCT
S
Me
DMSO
Ar
N
S
Me
Me
O
S
Cl– Me
Ar
S
Me
O
S
O
O
– ClMe2S+
ref. 9
or
Ar
S
S
S
Me
S
Ar
Me
Ar
S
Me
O
O
O
A
2
3
Figure 1 Cytotoxic activities of products 2a–i and 3 against two tu-
mor cell lines (MDA-MB-231 is a type of human breast cancer cell,
A549 is a type of human lung cancer cell)11
Scheme 2 A plausible mechanism for the reaction of TCT-activated
DMSO and thiophenols
Synthesis 2011, No. 22, 3635–3638 © Thieme Stuttgart · New York

PAPER
Synthesis of Cytotoxic Thiosulfonates and Deuterated Thiosulfonates
3637
1H NMR (400 MHz, CDCl3): d = 7.57 (d, J = 8.0 Hz, 1 H), 7.22 (s,
1 H), 7.12 (d, J = 8.0 Hz, 1 H), 3.20 (s, 3 H), 2.57 (s, 3 H), 2.39 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 143.8, 143.0, 137.6, 132.4, 128.2,
123.8, 47.5, 21.4, 21.3.
MS (ESI): m/z (%) = 239 [M + Na]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C9H12NaO2S2: 239.0171;
dissolved in dimethyl sulfoxide. The optical densities
(OD) at 570 nm were measured using a microplate reader.
The results are summarized in Figure 1. Although the cy-
totoxicities are moderate, this is the first report that thio-
sulfonates are cytotoxic. The biochemistry research using
these deuterated compounds will be reported in due
course.
found: 239.0174.
In conclusion, a new method for the synthesis of thiosul-
fonates has been developed that is operationally simple
and the yields are moderate. This reaction makes it possi-
ble to incorporate the SCD3 group of dimethyl sulfoxide-
d6 into the thiosulfonate with excellent labeling purity.
This represents the first synthesis of deuterated thiosul-
fonates. The cytotoxicity of the thiosulfonate is reported
for the first time. Improving the cytotoxicity of these com-
pounds is underway.
S-2,5-Dimethylphenyl Methanesulfonothioate (2e)
IR (KBr): 2923, 1490, 1451, 1410, 1312, 1135, 946, 814, 745 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.52 (s, 1 H), 7.28 (m, 2 H), 3.21
(s, 3 H), 2.56 (s, 3 H), 2.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 140.7, 138.0, 137.2, 133.1, 131.4,
126.8, 47.7, 20.9, 20.7.
MS (ESI): m/z (%) = 216 [M]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C9H12NaO2S2: 239.0171;
found: 239.0167.
All chemicals were obtained from commercial sources or prepared
according to standard methods. 1H (400 MHz) and 13C NMR (100
MHz) were recorded on a Bruker AM-400 spectrometer relative to
TMS (1H) or CDCl3 (13C). IR spectra were recorded on BIO-RAD
FTS 3000 spectrophotometer. MS (ESI) were obtained on a Finni-
gan LCQ Advantage MAX spectrometer. HRMS (ESI) were ob-
tained on Bruker micrOTOF-QII. All new compounds were fully
characterized, known compounds (Table 1, 2a,12 2h13) were charac-
terized and the data compared to the literature.
S-2,4,6-Trimethylphenyl Methanesulfonothioate (2f)
IR (KBr): 2927, 1464, 1378, 1310, 1131, 952, 862, 744 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.06 (s, 2 H), 3.21 (s, 3 H), 2.59
(s, 6 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 144.7, 142.4, 130.0, 123.5, 48.8,
22.3, 21.3.
MS (ESI): m/z (%) = 230 [M]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C10H14NaO2S2: 253.0327;
found: 253.0327.
S-4-Isopropylphenyl Methanesulfonothioate (2b); Typical Pro-
cedure
4-Isopropylthiophenol (200 mg, 1.31 mmol) was added to a soln of
TCT (604 mg, 3.27 mmol) in anhyd DMSO (2.5 mL). The mixture
was stirred at 80 °C and until completion (13 h, TLC monitoring).
Then, the mixture was extracted with CH2Cl2 (3 × 15 mL). The sol-
vent was concentrated in vacuo to give crude product, which was
further purified by column chromatography (silica gel, petroleum
ether–EtOAc, 12:1) to afford 2b (167 mg, 55%).
S-4-Methoxyphenyl Methanesulfonothioate (2g)
IR (KBr): 2924, 1589, 1494, 1318, 1254, 1131, 1021, 953, 835
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 8.8 Hz, 2 H), 7.00 (d,
J = 8.8 Hz, 2 H), 3.88 (s, 3 H), 3.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.5, 138.1, 118.5, 115.5, 55.6,
46.9.
In the reaction of TCT-activated DMSO-d6, DMSO-d6 was used to
replace DMSO.
IR (KBr): 2964, 1482, 1463, 1320, 1132, 948, 834, 740 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 8.0 Hz, 2 H), 7.36 (d,
J = 8.0 Hz, 2 H), 3.20 (s, 3 H), 3.02-2.95 (m, 1 H), 1.29 (d, J = 6.8
Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 153.1, 136.3, 128.1, 124.7, 47.3,
34.1, 23.7.
MS (ESI): m/z (%) = 219 [M + H]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C8H10NaO3S2: 240.9964;
found: 240.9972.
S-4-Bromophenyl Methanesulfonothioate (2i)
IR (KBr): 2925, 1472, 1389, 1314, 1135, 1064, 1005, 950, 828, 741
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.62 (dd, J = 8.0 Hz, 4 H), 3.22 (s,
MS (ESI): m/z (%) = 231 [M + H]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C10H14NaO2S2: 253.0327;
3 H).
13C NMR (100 MHz, CDCl3): d = 137.6, 133.2, 127.0, 126.9, 47.7.
MS (ESI): m/z (%) = 267 [M + H]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C7H7BrNaO2S2: 290.8941;
found: 253.0330.
S-4-Methylphenyl Methanesulfonothioate (2c)
IR (KBr): 2928, 1591, 1486, 1400, 1309, 1133, 946, 817, 740 cm–1.
found: 290.8940.
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 8.0 Hz, 2 H), 7.31 (d,
J = 8.0 Hz, 2 H), 3.19 (s, 3 H), 2.44 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 142.5, 136.2, 130.8, 124.5, 47.2,
21.5.
Methyl 4-[(Methylsulfanyl)sulfonyl]benzoate (3)
IR (KBr): 2923, 1716, 1432, 1396, 1280, 1110, 759 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01 (d, J = 8.4 Hz, 2 H), 7.59 (d,
J = 8.4 Hz, 2 H), 3.93 (s, 3 H), 2.47 (s, 3 H).
MS (ESI): m/z (%) = 203 [M + H]+ (100).
13C NMR (100 MHz, CDCl3): d = 166.6, 143.3, 130.1, 128.1, 125.6,
52.1, 22.8.
HRMS (ESI): m/z [M + Na]+ calcd for C8H10NaO2S2: 225.014;
found: 225.0015.
MS (ESI): m/z (%) = 246 [M]+ (100).
S-2,4-Dimethylphenyl Methanesulfonothioate (2d)
IR (KBr): 2926, 1476, 1375, 1313, 1311, 945, 821, 740 cm–1.
Synthesis 2011, No. 22, 3635–3638 © Thieme Stuttgart · New York

3638
F. Gao et al.
PAPER
HRMS (ESI): m/z [M + Na]+ calcd for C9H10NaO4S2: 268.9912;
found: 268.9915.
idue was purified by bulb-to-bulb distillation to yield N-methyldi-
azabicyclo[2.2.2]octane chloride (126 mg).14
S-2,4-Dimethylphenyl Trideuteromethanesulfonothioate (4a)
IR (KBr): 2924, 1450, 1376, 1322, 1139, 1017, 818, 773 cm–1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1H NMR (400 MHz, CDCl3): d = 7.57 (s, 1 H), 7.22 (s, 1 H), 7.12
(s, 1 H), 2.57 (s, 3 H), 2.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 143.8, 142.9, 137.6, 132.4, 128.2,
Acknowledgment
123.8, 21.4, 21.3.
We thank NSFC for financial support.
MS (ESI): m/z (%) = 219 [M]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C9H9D3NaO2S2: 242.0359;
found: 242.0363.
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IR (KBr): 2923, 1455, 1380, 1323, 1140, 1017, 774 cm–1.
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(s, 3 H), 2.39 (s, 3 H).
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found: 242.0366.
S-2,4,6-Trimethylphenyl Trideuteromethanesulfonothioate
(4c)
IR (KBr): 2924, 1464, 1378, 1311, 1137, 1011, 890, 774 cm–1.
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(s, 3 H).
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MS (ESI): m/z (%) = 233 [M]+ (100).
HRMS (ESI): m/z [M + Na]+ calcd for C10H11D3NaO2S2: 256.0516;
found: 256.0518.
Methyl 4-[(Trideuteromethylsulfanyl)sulfonyl]benzoate (5)
IR (KBr): 2954, 1711, 1341, 1395, 1280, 1186, 1109, 1007, 845,
756 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.01 (d, J = 8.0 Hz, 2 H), 7.59 (d,
J = 8.4 Hz, 2 H), 3.93 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.6, 143.3, 130.1, 128.1, 125.6,
52.1.
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HRMS (ESI): m/z [M + Na]+ calcd for C9H7D3NaO4S2: 272.0101;
found: 272.0105.
N-Methyldiazabicyclo[2.2.2]octane Chloride; Trapping MeCl
from the Reaction by DABCO
In a 50-mL flask, a stirred mixture of 4-isopropylthiophenol (400
mg, 2.63 mmol) and TCT (1208 mg, 6.55 mmol) in DMSO (5 mL)
was heated to 80 °C. The gas generated from the flask was intro-
duced into a soln of DABCO (295 mg, 2.63 mmol) in EtOH (5 mL).
After 20 h, EtOH was evaporated under reduced pressure. The res-
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Synthesis 2011, No. 22, 3635–3638 © Thieme Stuttgart · New York