Synthesis of sulfur-sulfur bond formation from thioamides promoted by 2,3-dichloro-5,6-dicyanobenzoquinone

Article abstract of DOI:10.1021/ol102455x

A mild and efficient synthesis of sulfur-sulfur bond formation from thioformanilides with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is described. Functionality on the aromatic ring plays a key role in the formation of a sulfur-sulfur bond.

Full text of DOI:10.1021/ol102455x

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5570-5572
Synthesis of Sulfur-Sulfur Bond Formation
from Thioamides Promoted by
2,3-Dichloro-5,6-dicyanobenzoquinone
Wei-Sheng Lo,† Wan-Ping Hu,‡ Hsiao-Ping Lo,† Chung-Yu Chen,§ Chai-Lin Kao,†
Jaya Kishore Vandavasi,† and Jeh-Jeng Wang*,†
Department of Medicinal and Applied Chemistry, Department of Biotechnology, and
Department of Pharmacy, Kaohsiung Medical UniVersity, Kaohsiung City 807, Taiwan
jjwang@kmu.edu.tw
Received October 11, 2010
ABSTRACT
A mild and efficient synthesis of sulfur-sulfur bond formation from thioformanilides with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is
described. Functionality on the aromatic ring plays a key role in the formation of a sulfur-sulfur bond.
Molecules containing a disulfide moiety play a vital role in
chemistry and biochemistry.1 In particular, disulfide-contain-
ing molecules appeared in a variety of biologically active
target molecules such as anticancer activity.2 A number of
synthetic strategies have been discovered and reported on
sulfur-sulfur bond formation.3-5 Among them, oxidation
evaluation of 2-phenylbenzothiazole derivatives 4 as pho-
tosensitizing agents.8 The results showed that most of 4,
under UVA light exposure, induced basal cell carcinoma
(BCC) all apoptosis. These results encouraged us to design
and synthesize a larger diversity of 2-phenylbenzothiazoles
4. Our initial attempt was to synthesize benzothiazole
scaffolds from thioformanilides with 2,3-dichloro-5,6-dicy-
anobenzoquinone (DDQ) for SAR studies. Surprisingly, the
dimerized products with “-S-S-” bond linkage resulted
instead of the expected benzothiazoles 4 (Scheme 1). These
results showed the difference in reactivity followed by
outcome of the products as compared to the reaction pattern
observed by Bose.9-11 Presumably, this might be the
substituent effect on both the rings A and B of thioforma-
nilides 2. We then switched our attention to sulfur-sulfur
bond formation from thioformanilides bearing different
substituent groups on aromatic rings. S-S bond formation
7
of thiols with halogens6 and H2O2 is the most common.
Recently, we reported an efficient synthesis and biological
† Department of Medicinal and Applied Chemistry.
‡ Department of Biotechnology.
§ Department of Pharmacy.
(1) (a) Shinkai, H.; Maeda, K.; Yamasaki, T.; Okamoto, H.; Uchida, I.
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Montero, J.; Supuran, C. Med. Res. ReV. 2008, 28, 445. (c) Atkinson, A.;
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S. M.; Tsai, F. Y.; Shen, H. C.; Chang, L. S.; Wang, J. J. Bioorg. Med.
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.
10, 1358.
10.1021/ol102455x
.
 2010 American Chemical Society
Published on Web 11/10/2010

benzothiazole 4a (entry 3, Table 1), whereas reaction in
methanol gave 3a in 57% and 4a in 33% yield (entry 4, Table
1). Since hypervalent iodo reagents such as DMP16 and PIFA17
are notable oxidants, we then examined their dimerization abi-
lity on 2a. Interestingly, benzothiazole 4a was obtained as a
major product (entries 5-8). Treatment of substrate 2a with
K3Fe(CN)68,18 in acetonitrile at 0 °C for 2 h gave exclusively
benzothiazole 4a in 72% yield (entry 9, Table 1). Increasing
the solvent polarity and reaction temperature with K3Fe(CN)6,
no reaction was observed, and the starting material was
recovered (entry 10). The structure of 3a was confirmed by
single-crystal X-ray crystallographic analysis (Figure 1).
Scheme 1
.
Optimization of Reaction Conditions to Synthesize
Disulfides 3
reactions may be of interest to chemists working in the field
of dynamic combinatorial chemistry.12
Furthermore, we also explored the dimerization activity
with a variety of oxidative reagents13 viz., DDQ, cerium(IV)
ammonium nitrate (CAN), Dess-Martin periodinane (DMP),
phenyliodine(III) bis(trifluoroacetate) (PIFA), and potassium
ferricyanide K3Fe(CN)6. Herein, we describe our studies by
general investigations of the sulfur-sulfur bond formation
of thioformanilides 2.
Initially, a reaction of N-(phenyl)-3-methyl-4-nitrothioben-
zamide 2a, generated by sulfonation of the corresponding
benzamides with Lawesson’s reagent,8 was examined. These
results are summarized in Table 1. The reaction of 2a and
Figure 1. ORTEP diagram of 3a.
Table 1. Optimization of S-S Bond Formation with Various
With optimized conditions in hand (Table 1, entry 1), we
explored the scope and limitations of this process. We designed
and synthesized various substituents on ring A and ring B of
thioformanilides with an electron-donating group (EDG), with an
electron-withdrawing group, (EWG) and without any substituent
(Table 2). Aromatic ring A without substituent and ring B bearing
strong EWG (-NO2) of compound 2a was smoothly converted
to 3a in high yield (entry 1, Table 2), while ring A with strong
EWG (-NO2) and ring B with strong EDG (-OMe) could also
be dimerized in good yields (entries 2 and 3). Ring A bearing
relatively less EWG (Cl or CF3) and ring B with strong EWG
(-NO2) were generated to disulfide compound in 74-82% yield
(entries 4-7, Table 2). Having a strong electron-withdrawing nitro
group on ring A and less electron-withdrawing halide or trifluoro-
methyl gave desired product in good to high yields (entries 8-15).
When the nitro group was on the para or meta position of ring A,
the corresponding products were obtained in good to high yields
(entries 16-24, Table 2).
Oxidizing Reagents
temp time yield
yield
entry reagent equiv solvent (°C) (min) 3a (%) 4a (%)
1
2
DDQ
1.2
1.2
4.2
4.2
1.2
2.2
1.2
2.2
4
CH2Cl2 0-28
MeOH 0-28
20
20
88
62
43
57
42
12
17
14
0
0
31
55
33
46
54
58
64
72
0
DDQ
3
CAN
CH3CN
MeOH
CH2Cl2
MeOH
0
0
0
0
30
4
CAN
30
40
30
30
90
120
90
5
DMP
6
DMP
7
PIFA
CH2Cl2 28
8
PIFA
CH3CN
CH3CN
EtOH
0
0
9
K3Fe(CN)6
K3Fe(CN)6
10
4
reflux
0
the commercially available DDQ (1.2 equiv) was first
conducted in dichloromethane at 0 °C.14 The reaction was
performed at room temperature for 20 min to furnish
dimerized compound 3a with 88% yield (entry 1, Table 1).
However, reaction in methanol solvent furnished 3a in 62%
yield along with intramolecular cyclization product 4a in
31% yield (entry 2, Table 1).
Benzothiazole formation occurred without substituent on
ring A and with EDG on ring B in 76% yield. Functionality
By using 4.2 equiv of CAN15 in acetonitrile at 0 °C for 30
min, the reaction produced almost a 1:1 ratio of dimer 3a and
(16) Arun, P. T.; Vinod, T. K. Tetrahedron Lett. 2002, 43, 569.
(17) (a) Pohnert, G. J. Prakt. Chem. 2000, 342, 731. (b) Moreno, I.;
Tellitu, I.; Etayo, J.; Sanmartin, R.; Dominguez, E. Tetrahedron 2001, 57,
5403. (c) Hata, K.; Hamamoto, H.; Shiozaki, Y.; Kita, Y. Chem. Commun.
2005, 2465. (d) Downer-Riley, N. K.; Jackson, Y. A. Tetrahedron 2008,
64, 7741.
(12) Dolle, R. E. J. Comb. Chem. 2002, 4, 5.
(13) Oxidations in organic chemistry by Milos Hudlicky. ACS Monog-
raphy 186, 1990.
(14) Back, T. G.; Clary, K. N.; Gao, D. Chem. ReV. 2010, 110, 4498.
(15) Sridharan, V.; Menedez, J. C. Chem. ReV. 2010, 110, 3805. (b)
Nair, V.; Augustine, A. Org. Lett. 2003, 5, 543.
(18) Serdons, K.; Vanderghinste, D.; Eeckhoudt, M. V.; Cleynhens, J.;
Groot, T. D.; Bormans, G.; Verbruggen, A. J. Labelled Comp. Radiopharm.
2009, 52, 227
.
Org. Lett., Vol. 12, No. 23, 2010
5571

Table 2. Reaction of Various Thioformanilides 2 with DDQ to
Form Dimerized Products 3
Table 3. In Vitro Cytotoxicity of Compound 3l in Selected
Cancer Cell Linesa
cell line
GI50 (µM)
Non-Small Cell Lung Cancer
HOP-92
NCI-H226
0.175
0.427
Colon Cancer
HCT-15
0.388
0.141
CNS Cancer
SNB-75
entry
3
R1
R2
R3
R4
R5
R6
yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
H
Me
OMe
OMe
H
NO2
H
H
NO2
NO2
NO2
NO2
CF3
F
Cl
Br
CF3
F
Cl
88
74
74
76
74
82
77
75
76
72
72
81
79
83
71
72
72
83
74
86
84
81
78
82
Melanoma
LOX MVI
MALME-3M
SK-MEL-5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
CF3
Cl
CF3
Cl
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
0.304
0.252
0.262
H
Ovarian Cancer
IGROV1
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.217
Breast Cancer
T-47D
Mean
9
0.221
0.372
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3j
3k
3l
H
H
Me
a Data obtained from NCI’s in vitro disease-oriented tumor cells screen.
3m Me
3n
3o
3p
3q
3r
3s
Me
Me
H
Br
NO2 Cl
NO2 Me
CF3
CF3
F
Cl
CF3
F
Cl
CF3
CF3
Scheme 2
.
Plausible Mechanism for the DDQ-Mediated Dimer
Formation with Disulfide Bond
H
Me NO2
Me NO2
Me
Me
Me
H
H
H
H
H
H
F
3t
H
H
H
NO2
3u
3v
3w
3x
H
H
Me NO2
H
H
on aromatic ring plays a key role in the formation of
sulfur-sulfur bonds. Compound 3l was selected by the U.S.
National Cancer Institute for evaluation in the in vitro
preclinical antitumor screening program against 60 human
tumor cell lines derived from nine cancer cell19 types. The
selected biological evaluation results for the dimerization
compound are presented in Table 3. The mean GI50 value
for dimerization of 3l was 0.372 µM, indicating that this
agent has the potential for use as a highly potent broad-
spectrum anticancer compound to inhibit the growth of a
variety of cancer cell lines.
A plausible mechanism for the synthesis of disulfides by
DDQ is depicted in Scheme 2. Arylthioformanilide 2 can
form as thioiminol 5, which reacts with DDQ to generate
thiyl radical intermediate 6. If EWG is present on ring A or
ring A with hydrogen and ring B bearing EWG, the
dimerization reaction is predominant rather than cyclization.
The presence of EDG on ring A would stabilize the radical
intermediate that leads to the formation of the cyclized
product 4. In contrast, the stability of the radical intermediate
by the substituents on the ring system directs the formation
of either cyclized product or dimerized product.
In summary, we have developed a mild and efficient synthetic
route for sulfur-sulfur bond formation reactions with DDQ in
high yields. This methodology may be applicable for other
sulfur-sulfur bond formations of different thio substituent
molecules and various analogues. Further biological activities
of these compounds are under investigation.
Acknowledgment. We thank the National Science Council
of the Republic of China and KMU Center of Excellence
for Environmental Medicine for financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds and
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(19) Plowman, J.; Dykes, D. J.; Hollingsdead, M.; Simpson-Herren, L.;
Alley, M. C. Human Tumor Xenograft Models in NCI Drug Development.
In Anticancer Drug DeVelopment guide: Preclinical Screening, Clinical
Trials, and ApproVal; Teicher, B., Ed.; Humana Press Inc.: Totowa, NJ,
1997; p 101.
OL102455X
5572
Org. Lett., Vol. 12, No. 23, 2010