Novel ((3Z,5Z)-3,5-bis(phenylimino)-1,2-dithiolan-4-yl) and 3H-[1,2]dithiolo[3,4-b]quinolin-4(9H)-one heterocycles: An effective and facile green route

Article abstract of DOI:10.1039/b808949c

Two new sulfur heterocycle systems containing a 1,2-dithiole group, have been synthesized and characterized by IR, ¹H NMR and single crystal X-ray crystallography. Optimum conditions for these closed-ring reactions have been studied and the pos

Full text of DOI:10.1039/b808949c

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/greenchem | Green Chemistry
Novel ((3Z,5Z)-3,5-bis(phenylimino)-1,2-dithiolan-4-yl) and
3H-[1,2]dithiolo[3,4-b]quinolin-4(9H)-one heterocycles: an effective
and facile green route†
Fangfang Jian,*a,b Jian Zheng,b Yufeng Lia and Jing Wangb
Received 29th May 2008, Accepted 31st October 2008
First published as an Advance Article on the web 19th November 2008
DOI: 10.1039/b808949c
Two new sulfur heterocycle systems containing a 1,2-dithiole group, have been synthesized and
characterized by IR, 1H NMR and single crystal X-ray crystallography. Optimum conditions for
these closed-ring reactions have been studied and the possible reaction mechanism has been
explored. A simple, fast, inexpensive and clean green synthesis route has been described here. The
anti-cancer activity of these compounds was evaluated in terms of cell growth inhibition against
human liver cancer cells HepG2.
In the field of biological research, cancer prevention and
Introduction
controlling remains an important topic. Since the 1990’s it has
Over recent years great efforts have been made in the field
been discovered that 1,2-dithiole derivatives may be used as
of green chemistry to adopt methods and processes that use
new anti-cancer drugs,11,12 there has been great interest in the
less toxic chemicals, produce smaller amounts of by-products
research of the anti-cancer activity of 1,2-dithiole derivatives
and use less energy.1 As part of this green concept, toxic and
and their related compounds.13 1,2-Dithiole derivatives have a
flammable organic solvents are replaced by alternative non-
gene-repairing function and are capable of repairing damaged
toxic and non-flammable media or the reactions are carried out
DNA.14,15 These compounds are very effective in preventing
without the use of any organic solvent, and the classical sources
and controlling liver, breast and lung cancers.16,17 They may
of heating are replaced or reactions carried out at ambient
also prevent the formation of tumors because of their unique
temperature.2 Organic reactions under solvent-free conditions
electronic structure, and thus induce cancer resistance in the
have attracted significant attention3 for the advantages they
human body.18,19
offer in terms of green chemistry.4 Among various chemical
Quinolone derivatives also exhibit impressive biologi-
methods, ultrasonic treatment has been suggested as a promising
cal activity20 and have been extensively investigated as
technique since it possesses various advantages.5 The ultrasonic
antidiabetic,21 anticancer,22,23 and antiviral24 agents. Some fluo-
method is a fast continuous extrusion process with a residence
roquinolone compounds, such as norfloxacin,25 ciprofloxacin,26
time of a few seconds. The process may not require the use
and levofloxacin,27 have been developed and clinically used for
of any chemical agent and does not generate byproducts. It is
the treatment of various infectious diseases. These compounds
an energy efficient environmentally friendly physical process. In
seem to exert their antitumor effect through inhibition of tubulin
fact, ultrasonic techniques have been employed for the synthe-
polymerization involving binding to the colchicine binding site
sis of cycloadditions,6 methanofullerene derivatives,7 selective
of tubulin.28 The quantitative structure–activity relationships
nitration of phenols,8a and Suzuki cross-coupling reactions,8b
of a variety of antimitotic quinolones have been reported by
etc.9,10 To contribute to the development of environmentally
benign organic chemistry, we are focusing our research on the
replacement of the volatile common organic reaction media
and we are interested in the use of solvent-free conditions and
Weigt.29 Quinolone derivatives are known as broad-range drugs
and have a different anticancer mechanism to 1,2-dithiole.
Taking advantage of the concept of bioisosterism, the novel 3H-
[1,2]dithiolo[3,4-b]quinolin-4(9H)-one compounds containing a
quinolone group and a 1,2-dithiole ring were designed and
ultrasonic methods.
synthesized in order to search for a new drug with higher
bioactivity.
aMicroscale Science Institute, Weifang University, Weifang, 261061,
P. R. China. E-mail: ffj2003@163169.net; Fax: (+)86-536-8785802
In this paper, we describe the solvent-free synthesis and
structure of two new classes of 1,2-dithiole derivatives:
((3Z,5Z)-3,5-bis(phenylimino)-1,2-dithiolan-4-yl) (1) and 3H-
[1,2]dithiolo[3,4-b]quinolin-4(9H)-one (2) (Scheme 1). The
in vitro anti-tumor tests of the two new classes of com-
pounds are also reported. The results demonstrate that
the compound ((3Z,5Z)-3,5-bis (phenylimino)-1,2-dithiolan-
4-yl)(4-fluorophenyl)methanone exhibits excellent anti-cancer
activity and is, potentially, a novel anti-tumor medicine.
bNew Materials and Function Coordination Chemistry Lab, Qingdao
University of Science & Technology, Qingdao, 266042, P. R. China.
E-mail: wj-crystal@163.net; Fax: (+)86-532-84023606
† Electronic supplementary information (ESI) available: IR and 1H
NMR spectral data, elemental analysis for compounds (1) and (2),
MTT (methyl thiazolyl tetrazolium) methods and the experiments of
the anti-cancer activity against the human liver cancer cells. CCDC
reference numbers 652761, 652762, 652763 and 652764. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b808949c
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 215–222 | 215
©

View Online
Scheme 1
Result and discussion
Synthesis and crystal structure
By reacting 1-(2,4-dichlorophenyl)ethanone with 1-isothio-
cyanatobenzene under basic conditions, two different products
were isolated. Crystal structure determinations carried out on
both products reveal that they are ((3Z,5Z)-3,5-bis(phenyl-
imino)-1,2-dithiolan-4-yl)(2,4-dichlorophenyl) methanone (1e)
and (3Z)-7-chloro-9-phenyl-3-(phenylimino)-3H-[1,2]dithiolo
[3,4-b]quinolin-4(9H)-one (2e). Thus, we have found the a
method to synthesize compound (1) and (2) derivatives. Fig. 1
and 2 show the molecular structures of compounds (1) (1e, 1h,
1i) and (2) (2e), respectively.‡ In order to expediently compare
‡ Crystal data: 1e, C22H14Cl2N2OS2, Mr = 457.37, Triclinic, space group
◦
˚
˚
˚
P-1, a = 10.084(2) A, b = 10.◦331(2) A, c = 10.414(2) A, a = 87.60(3) ,
◦
3
˚
b = 10.331(2) , g = 78.10(3) , V = 1058.1(4) A , Z = 2, T = 293(K),
rcald = 1.436 mg m-3, m = 0.520 mm-1, F(000) = 468. Intensity data
were collected on a Bruker XSCANS system. The structure was solved
by direct methods. There were 4872 measured reflections of which 4604
reflections (Rint = 0.0464) were independent and all are included in the
refinement. R1 = 0.0668, wR2 = 0.1577 for 263 observed reflections with
I ≥ 2s(I), and R1 = 0.1616, wR2 = 0.2053, GOOF = 0.965 for all data.
Crystal data: 1h, C22H13Cl2FN2OS2, Mr = 475.36, Triclinic, space group
Fig. 1 Molecular structure of compound (1) (top, 1e; middle, 1h,
bottom, 1i) with the atomic numbering scheme.
◦
˚
˚
˚
Fig. 1 and 2, we have chosen a similar numbering system in these
four crystal structures.
P-1, a = 9.896(2) A, b = 10.256(2) A, c = 11.128(2) A, a = 89.64(3) ,
◦
◦
3
˚
b = 73.71(3) , g = 82.42(3) , V = 1074.0(4) A , Z = 2, T = 293(K),
rcald = 1.470 mg m-3, m = 0.522 mm-1, F(000) = 484. Intensity data
were collected on Bruker XSCANS system. The structure was solved
by direct methods. There were 4867 measured reflections of which 4592
reflections (Rint = 0.0286) were independent and all are included in the
refinement. R1 = 0.0482, wR2 = 0.1297 for 271 observed reflections with
I ≥ 2s(I), and R1 = 0.0736, wR2 = 0.1461, GOOF = 1.034 for all data.
Compounds 1e, 1h and 1i are isomorphous and isostructural,
they all have the same triclinic crystal system and P¯ı space group,
and the unit cells all consist of two monomeric units. Compound
2e has the monoclinic crystal system and P21/c space group,
Z = 4. The bond lengths and angles of three phenyl rings in
these four structures are normal. The S(1)–S(2) bond lengths of
Crystal data: 1i, C23H17BrN2OS2, Mr = 481.42, Triclinic, space group
◦
˚
˚
˚
P-1, a = 6.3729(13) A, b = 12.941(3) A, c = 13.413(3) A, a = 108.64(3) ,
◦
◦
3
˚
˚
˚
˚
b = 96.27(3) , g = 96.96(3) , V = 1027.5(4) A , Z = 2, T = 293(K),
rcald = 1.556 mg m-3, m = 2.221 mm-1, F(000) = 488. Intensity data
were collected on a Bruker XSCANS system. The structure was solved
by direct methods. There were 4243 measured reflections of which 3546
reflections (Rint = 0.021) were independent and all are included in the
refinement. R1 = 0.0938, wR2 = 0.2734 for 261 observed reflections
with I ≥ 2s(I), and R1 = 0.1304, wR2 = 0.3077, GOOF = 1.035 for all
data. Crystal data: 2e, C22H13ClN2OS2, Mr = 420.91, Monoclinic, space
2.070(2) A 1e, 2.074(1) A 1h and 2.066 (3) A 1i are all slightly
˚
longer than that of 2.062(2) A for 2e. The bond angles in the
1,2-dithiole ring are also slightly different between compounds
1 and 2 (See Table 1). In compounds 1, the 1,2-dithiole ring
and three conjoint atoms C(6), N(1) and N(2) all lie in the same
˚
˚
plane, with the largest atom deviation 0.052 A for 1e, 0.047 A
˚
˚
˚
˚
group P2(1)/c, a = 11.497(2) A, b = 7.5370(15) A, c = 22.384(5) A,
◦
3
b = 103.64(3) , V = 1884.9(7) A , Z = 4, T = 293(K), rcald = 1.483 mg
m-3, m = 0.440 mm-1, F(000) = 864. Intensity data were collected on a
Bruker XSCANS system. The structure was solved by direct methods.
There were 4160 measured reflections of which 3966 reflections
(Rint = 0.0332) were independent and all are included in the refinement.
R1 = 0.0536, wR2 = 0.1404 for 253 observed reflections with I ≥ 2s(I),
and R1 = 0.1159, wR2 = 0.1700, GOOF = 1.013 for all data.
216 | Green Chem., 2009, 11, 215–222
This journal is
The Royal Society of Chemistry 2009
©

View Online
◦
˚
Table 1 Selected band (A) and angle ( )
1e 1h
1i
2e
S(1)–C(9)
S(1)–S(2)
S(2)–C(7)
O(1)–C(16)
N(1)–C(7)
N(1)–C(6)
N(2)–C(9)
N(2)–C(10)
C(7)–C(8)
C(8)–C(9)
1.804(4)
2.070(2)
1.747(4)
1.233(5)
1.323(5)
1.437(5)
1.270(5)
1.418(5)
1.399(6)
1.446(5)
1.798(2)
2.074(1)
1.751(2)
1.241(3)
1.336(3)
1.436(3)
1.269(3)
1.421(3)
1.401(3)
1.463(3)
1.788(6)
2.066(3)
1.736(6)
1.234(9)
1.327(8)
1.433(9)
1.271(1)
1.421(9)
1.428(9)
1.461(9)
1.815(3)
2.062 (2)
1.745(3)
1.235(4)
1.358(4)
1.456(3)
1.277(4)
1.409(4)
1.384(4)
1.455(5)
C(9)–S(1)–S(2)
C(7)–S(2)–S(1)
C(7)–N(1)–C(6)
96.46(2)
95.11(2)
124.0(4)
96.36(8)
95.43(8)
123.74(2)
119.7(2)
126.0(2)
116.06(2)
117.92(2)
116.9(2)
126.4(2)
120.31(2)
113.35(2)
96.8(2)
95.3(2)
97.28(1)
94.38(1)
118.8(2)
126.2(3)
124.6(3)
116.3(2)
119.1(3)
117.5(3)
124.5(3)
123.8(3)
111.6(2)
125.3(5)
120.1(6)
124.7(6)
116.8(5)
118.4(5)
115.3(5)
125.4(6)
120.6(5)
114.0(5)
C(9)–N(2)–C(10) 119.8(4)
N(1)–C(7)–C(8)
N(1)–C(7)–S(2)
C(8)–C(7)–S(2)
C(7)–C(8)–C(9)
N(2)–C(9)–C(8)
N(2)–C(9)–S(1)
C(8)–C(9)–S(1)
126.3(4)
115.7(3)
118.0(3)
117.2(4)
127.0(4)
120.0(3)
113.0(3)
Scheme 2
Fig. 2 Molecular structure of compound (2e) with the atomic number-
ing scheme.
1,2-dithiolan-4-yl) compounds 1a–1j and five 3H-[1,2]dithiolo
[3,4-b]quinolin-4(9H)-one compounds (2a, 2e, 2f, 2h and 2i),
and their structures were characterized by elemental analysis,
IR and 1H NMR spectroscopy, and 1e, 1h, 1i and 2e were also
characterized by X-ray diffraction.
˚
for 1h, and 0.055 A for 1i, respectively. For compound 2e, the
atoms in the 1,2-dithiole ring and quinoline ring neatly define a
˚
plane, with the largest atom deviation being 0.145 A for C(20),
and the dihedral angles between the two phenyl rings and above
We have initially optimized the reaction conditions by study-
ing the influence of the solvent, the alkalinity and reaction tem-
perature as well as the various 1-(substituted-phenyl)ethanone
for compounds (1), and the results of the effects of the solvent
are reported in Table 2. It can be seen from the Table 2 that
the choice of solvent is of great importance. Dioxane as solvent
gave the best yield. An absolutely anhydrous solvent improves
the yield and reduces by-products. In addition, the presence
and concentration of base has a dominating effect; potassium
hydroxide, due to its high solubility in dioxane, gave high yields.
The synthesis of 3H-[1,2]dithiolo[3,4-b] quinolin-4(9H)-one
derivatives (2) using a catalyst was also studied. It could be
shown that (2) could be obtained by the catalyzed reaction
of compounds (1) with HX (X = Br,Cl) being eliminated. By
examining the effects of different catalysts it can be seen from
Table 3 that the choice of anion has little effect on the reactions
but that the cation is critical. The trivalent cerium and yttrium
ions lead to acceptable reaction rates while the quadrivalent
cerium and bivalent Cu and Pb do not catalyse the reaction.
Trivalent Fe ion is a catalyst but the reaction rate is low. The
the plane are 85.85◦ and 33.30◦, respectively.
Further
investigation
revealed
that
((3Z,5Z)-3,5-
bis(phenylimino)-1,2-dithiolan-4-yl) derivatives (1) could
be synthesized directly in very high yields simply using air as
oxidant under basic conditions. In addition, it was discovered in
our experiments that although 3H-[1,2]dithiolo[3,4-b] quinolin-
4(9H)-one derivatives (2) may be directly obtained by making
1-(2-chlorophenyl)ethanone or 1-(2-bromophenyl) ethanone
react with 1-isothiocyanatobenzene in one-pot, compound (2)
can also be obtained from compound (1). The latter, catalyzed
by cerous nitrate, can undergo ring closing to turn into (2).
From this we infer that the possible reaction mechanism may
be as shown in Scheme 2.
From the possible reaction mechanism in Scheme 2 it can
be seen that an oxidative cyclization occurs as step (6). Other
oxidants, such as H2O2 and MnO2, did not give the expected
results and we thus suggest that the mild oxidation by oxygen
in the air is most efficacious for the closed-ring reaction. In this
way, we have synthesized ten ((3Z,5Z)-3,5-bis(phenyl-imino)-
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 215–222 | 217
©

View Online
Table 2 The effects of solvent for synthesis compounds (1)
3,5-bis(phenylamino) 1,2-dithiole derivatives, are stable in the
solid state and in all organic solvents tested. We have only
repeated the synthesis of compounds (1a), (1b), (1e), (1f) and
(1j) using ultrasonic reaction conditions to compare with the
general method, and found (1a), (1b) and (1j) had an improved
yield, but (1e) and (1f) did not. Table 6 shows the compar-
ative results of the two different synthesis methods at room
temperature.
Using solvent-free synthesis, the compounds (2) are more
easily obtained in one-pot. If the 1-(2-chlorophenyl) ethanone or
1-(2-bromophenyl) ethanone derivatives were liquid, they were
first mixed with 1-isothiocyanato-benzene in a 50 mL round
bottomed flask in 1:2 molar ratio, then 4 mole ratio of solid
KOH and a little metal K were added. The ultrasonic reactions
lasted 30 minutes. The products were dissolved in water and
aqueous Ce(NO3)3 added while stirring. The yellow precipitation
formed was isolated by filtration and recrystallized from acetic
ether. The pure compounds (2) could be obtained in satisfying
yield. Although the compounds (2) were stable in air, they all
decompose before their melting point.
Solvent
Yield(%)
Solvent
Yield(%)
1,4-Dioxane
Tetrahydrofuran
Ethyl ether
Ethanol
Methanol
Water
91.5
71.0
65.5
0
0
0
Cyclohexane
Petroleum ether
Pyridine
Benzene
Toluene
n-Hexane
Ethyl acetate
40.0
25.9
45.8
42.4
40.7
35.5
0
DMF
12.7
Table 3 The effects of catalyst to the reaction
Catalyst
Yield(%)
Catalyst
Yield(%)
Ce(NO3)3
Ce(NO3)4
CeCl3
GdCl3
NaNO3
63.0
0
59.0
56.3
4.6
CuCl2
FeCl3
H2O2
Pb(NO3)4
air
0
15
0
0
4.3
mechanism of the catalysis by Ce3+, Yb3+ and Fe3+ is not yet clear.
Additionally, by adopting the “one-pot approach” in which the
1-(2-chlorophenyl) ethanone or 1-(2-bromophenyl) ethanone
derivatives react with 1-isothio-cyanatobenzene, together with
potassium hydroxide and cerous nitrate, (2) can also be obtained
directly. Table 4 shows the effect of different 1-(substituted-
phenyl)ethanones and the yields obtained. Table 5 shows the
obtained compounds (2) and yields.
Up to now, we have only been able to synthesise the
compounds (1) when electron-withdrawing groups, such as
chlorine or bromine, are attached to the benzene ring of
the 1-(substituted-phenyl)ethanone. Using these 1-(substituted-
phenyl) ethanones, the reaction and product isolation are
facile. However, if the benzene ring of the 1-(substituted-
phenyl)ethanone have an –NO2 substituent, the reaction pro-
ceeds very rapidly but numerous by-products are formed and
product isolation becomes difficult. As an exception, the reaction
of acetyl pyridine is very fast and product isolation easy. So far,
we have not obtained compound (1) when there are electron
contributing groups such as alkyl or alkoxy attached to the
benzene ring of the acetophenone. We are continuing to explore
further variations of this reaction.
Ultrasonic treatment can produce a localized and transient
high temperature and pressure as high as ~5000 K and
~300 atm,30 respectively. Chemical effects may be induced
by ultrasonic techniques through direct formation of cav-
itation micro-bubbles. Considering 1-isothio-cyanatobenzene
was liquid and some 1-(substitutedphenyl)ethanone deriva-
tives also were liquid, solvent-free conditions might be re-
alized by ultrasound. With this idea in mind, we mixed 1-
(2-chlorophenyl) ethanone and 1-isothio-cyanatobenzene with
solid KOH under ultrasonic conditions using ultrasonic in-
strument JCX-600G, and allowed them to react for 10 min-
utes, the compound (1a) could be obtained with 96% yield.
Hence, an effective and facile green route to synthesize
these novel (3Z,5Z)-3,5-bis(phenyl-imino)-1,2-dithiolan-4-yl)
(1) and 3H-[1,2]dithiolo[3,4-b]quinolin-4(9H)-one (2) deriva-
tive heterocycle systems were formed. If the 1-(substituted-
phenyl)ethanone was liquid, we first mixed 0.01 mol of 1-
(substituted-phenyl)ethanone and 0.02 mol 1-isothiocyanato-
benzene in a 50 mL round bottomed flask with stirring.
We then added milled solid KOH in small amounts. The
ultrasonic reaction lasted 10–15 minutes, the reactants were fully
changed to a dope or light-yellow solid. We let the obtained
products (dopes or light-yellow solid) dry in air for more than
24 hours under room temperature; or 8–10 hours at temperature
60–70 ◦C. The yellow solid was obtained by washing the
above products with water several times. If the 1-(substituted-
phenyl)ethanone was solid, we first ground it with solid KOH
together, then added it to liquid 1-isothiocyanato-benzene with
stirring. The other processes were the same as above. Yellow
single crystals, suitable for X-ray measurements, were obtained
by recrystallization from acetic ether. The compounds (1),
Biological results
The basic 1,2-dithiole structure in both classes of compounds
(1) and (2) suggested that these compounds might exhibit anti-
cancer activity. Thus, samples of some compounds (1) and (2)
were given to the anti-cancer medicine laboratory of the China
Pharmaceutical University for further research. Adopting the
MTT (methyl thiazolyl tetrazolium) method for the in vitro
research of antitumor drugs, experiments were carried out to
examine anti-cancer activity against human liver cancer cells
(HepG2 and SMMC-7721). The preliminary in vitro anti-tumor
tests show that the compounds (1) have good anti-cancer activity
and are potentially a new group of anti-tumor medicines, the
IC50 values of compounds (1c) and (1d) are about 1.36 mM and
0.984 mM on HepG2, which is lower than that of the positive
control drug, gambogic acid (about 1.55 mM). But, neither (1)
nor (2) is effective against human liver cancer cells SMMC-7721.
Table 7 list the results of 13 compounds which were compared
with the positive control drug, gambogic acid on HepG2 (IC50
half inhibition concentration of drug).
=
Compounds (1d), (1h) and (2d), having a fluorin substituent
on the phenyl ring, showed strong HepG2 inhibitory activity
(IC50 < 10-5M). Substituents at the para- position of the phenyl
ring seem to be more effective than those at the ortho-position.
218 | Green Chem., 2009, 11, 215–222
This journal is
The Royal Society of Chemistry 2009
©

View Online
Table 4 Products and yields from the different 1-(substituted-phenyl)ethanones
Entry
Starting Materials
Products
Mp (◦C)
171
Yield (%)
1a
73.0
1b
149
91.5
1c
1d
1e
155
145
165
93.0
56.0
73.5
1f
174
171
75.0
95.0
1g
1h
1i
169
173
78.5
71.0
1j
146
91.5
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 215–222 | 219
©

View Online
Table 5 Products and yields for compounds (2)
Entry
Starting Materials
Products
Mp (◦C)
254
Yield (%)
2a
50.0
2e
2f
275
271
63.0
60.0
2h
2i
289
261
70.5
85.5
Table 6 The comparing result of general and ultrasonic treatment
Table 7 The inhibition effects of tested drugs on in vitro growth of
HepG-2a
Entry
1a
Condition
Reaction time
Yield%
Concentration
Dioxane
Solvent-free
Dioxane
Solvent-free
Dioxane
Solvent-free
Dioxane
Solvent-free
Dioxane
Solvent-free
6 hour
10 minutes
6 hour
10 minutes
6 hour
15 minutes
6 hour
15 minutes
6 hour
15 minutes
73.0
96.0
91.5
88.0
73.5
68.0
75.0
65.0
91.5
86.0
b
Entry
10-5
M
10-6
M
10-7
M
IC50
1b
1a
1b
1c
1d
1e
1f
14.51%
50.54%
62.72%
83.65%
11.94%
11.36%
19.10%
23.11%
9.63%
50.72%
10.91%
14.45%
11.68%
93.96%
6.32%
29.46%
53.54%
59.75%
6.40%
10.07%
6.88%
16.43%
8.10%
26.20%
3.65%
4.75%
8.85%
2.22%
16.04%
3.20%
0.03%
0.31%
14.14%
5.15%
8.04%
3.33%
3.15%
2.46%
0.8%
nd
1.02 ¥ 10-5
1.36 ¥ 10-6
9.84 ¥ 10-7
nd
M
M
M
1e
1f
nd
nd
1j
1g
1h
1i
9.1 ¥ 10-5
nd
M
1j
1.00 ¥ 10-5
3.11 ¥ 10-4
nd
M
M
2a
2c
2d
GAc
However, multi-substituted compounds showed decreased
anti-cancer activity, and compounds (1e), (1f), (1g) and (1i)
lacked anticancer activity against HepG2. The reason for these
results is not clear. In order to understand the relationship of
the anti-cancer activity of a drug with time, further tests on
the in vitro growth of HepG-2 over longer time periods were
carried out. Table S18 in the ESI† lists the results. Our results
demonstrated that the extent of inhibition depends on both the
length of reaction time and the concentration of compounds
applied. The compound (1d) is given as an example: at 48 h, when
the concentration of (1d) is increased from 10-7 M to 10-4 M,
the inhibitory rate reaches to 93.69% from 16.04%; at 12h,
if the concentration of (1d) is increased from 10-7 M to 10-4 M,
the inhibitory rate reaches 71.55% from 10.37%. It is suggested
5.07%
10.70%
69.89%
1.66 ¥ 10-4
1.55 ¥ 10-6
M
M
a nd = not determined. b IC50 = half inhibition concentration of drug.
c GA = gambogic acid.
there exists the obvious relationship between inhibitory rate,
time and concentration.31
Conclusions
In summary, we have discovered two new closed-ring reactions
and developed a convenient, solvent-free and environmentally
220 | Green Chem., 2009, 11, 215–222
This journal is
The Royal Society of Chemistry 2009
©

View Online
benign one-pot method for the synthesis of various substituted
(3Z,5Z)-3,5-bis(phenylimino)-1,2-dithiolan-4-yl) (1) and 3H-
[1,2]dithiolo [3,4-b]quinolin-4(9H)-one (2) derivatives. Starting
from commercially available 1-isothiocyanatobenzene and 1-
(substituted- phenyl) ethanone derivatives, a range of pharma-
ceutically relevant compounds (1) or (2) are obtained selectively.
The compounds (2), 3H-[1,2]dithiolo [3,4-b]quinolin-4(9H)-
ones, are a new class of heterocyclic systems. The reported
ultrasonic method is shown to be very flexible; the reaction
conditions can be easily controlled to obtain (1) or (2) in most
cases. Mild reaction conditions, high yield, simple purification,
short reaction period and the stability and cheapness of the
reagents are features of this new procedure. The work-up
procedure is simple and green: the all steps reaction processes are
carried out in water or under solvent free conditions, washing
of the reaction mixture is with water and all the steps of the
reaction are carried out at ambient temperature. All of these
features make this synthesis a promising method in industrial
applications. Moreover, extrapolation of this method to the
application to the methylene cyanide, [CH2(CN)2], malonic ester,
[CH2(COOR)2], or other compounds containing active a-H is
currently under investigation. Additionally, the preliminary ex-
perimental results indicate that ((3Z,5Z)-3,5-bis (phenylimino)-
1,2-dithiolan-4-yl)(4-fluorophenyl)methanone is an anti-cancer
medicine of great potential. Of those compounds, the most
potent HepG2 inhibitors were those (1d, 1h and 2d) having a
fluorin substituent on the phenyl ring. The substituents at the
para- position of the phenyl ring exhibited greater anti-cancer
activity than those at the ortho- or meta-positions. Further
design and chemical modifications to synthesis compounds (1)
containing a fluorine atom are in progress.
during which a light yellow precipitate formed. The precipitation
was filtered, washed with diethyl ether, dissolved in water
and Ce(NO3)3 aq. added while stirring. The precipitation was
isolated by filtration. Yellow single crystals suitable for X-ray
measurements were obtained from
ether:petroleum ether (1:2).
a mixture of acetic
Representative experimental procedure for compounds (1a)
under solvent-free conditions was as follows. The ultrasonic
treatment was conducted with an Ultrasonic Generator JCX-
600G (100 kHz, 600 W, Shangdong Ultrasonic Co. Ltd., China)
in a temperature controlled container, in which a 50 mL flask
is placed in a water bath and ultrasonically treated from under-
neath. At ambient temperature, the mixture of 0.01 mol of 1-(2-
chlorophenyl)ethanone and 0.02 mol 1-isothiocyanatobenzene
was put into the above flask, then the milled solid KOH
(0.02 mol) was added in the flask. The ultrasonic reaction was
carried out for 10 minutes, the reactants were changed to a light-
yellow solid. We let the obtained light-yellow solid dry in air for
more than 24 hours under room temperature. The yellow solid
(1a) was obtained by washing with water several times.
The original IR and 1H NMR spectral data, elemental analysis
for compounds (1) and (2), crystal data for compounds 1e, 1h,
1i and 2e, MTT (methyl thiazolyl tetrazolium) methods and
the experiments of the anti-cancer activity against the human
liver cancer cells, etc. are given in the ESI.† CCDC-652764
for compound 1e, CCDC-652761 for compound 1h, CCDC-
652762 for compound 1i, and CCDC-652763 for compound 2e,
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data-
request/cif.
Experimental
Acknowledgements
Because all compounds reported in this manuscript were synthe-
sized by a general method, and not all by a solvent-free method,
we should first introduce the general synthesis procedure below.
General procedure for (3Z,5Z)-3,5-bis(phenyl-imino)-1,2-
dithiolan-4-yl) derivatives (1a–1j): 0.01 mol of acetophenone
(or its derivative) in 20 mL of dioxane was placed in a 50 mL
round bottomed flask. 0.02 mol (1.12 g) of KOH was then
added while stirring at room temperature. 0.02 mol 1-isothio-
cyanatobenzene was then added dropwise over three hours.
The reaction was stirred for a further six hours, and a yellow
precipitate formed. The precipitate was then filtered, washed
with diethyl ether and dried in air. Yellow single crystals, suitable
for X-ray measurements, were obtained by recrystallization
from a mixture of acetic ether:cyclohexane (1:3). Compounds
1 are stable in the solid state and in all organic solvents
tested.
The example for synthesis of (3Z)-7-chloro-9-phenyl-3-
(phenylimino)-3H-[1,2]dithiolo[3,4-b]quinolin-4(9H)-one 2e is
given to illustrate the general procedure for compounds (2a,
2e, 2f, 2h and 2i). To a 50 mL flask 0.01 mol of 1-(2,4-
dichloro-phenyl)ethanone in 20 mL of anhydrous dioxane was
added. Then 0.04 mol (1.75 g) KOH and a little metal K was
added while stirring and the mixture refluxed for 10 min.
1-isothio-cyanatobenzene (0.02 mol) was then added dropwise
over three hours. The reaction was stirred for a further six hours,
This work was supported by Natural Science Foundation
of Shandong Province (No.Y2005B04 and No. Z2007B01),
P. R. China.
Notes and references
1 A. Matlack, Green Chem., 2003, 5, G7–G12.
2 (a) K. Tanaka, Solvent-free Organic Synthesis, Wiley-VCH,
Weinheim, 2003; (b) Ionic Liquids in Synthesis, ed. P. Wasserscheid,
and T. Welton, Wiley-VCH, Weinheim, 2003; (c) Chemical Synthesis
Using Supercritical Fluids, ed. P. G. Jessop, and W. Leitner, Wiley-
VCH, Weinheim, 1999.
3 (a) J. Zhang, Z. Cui, F. Wang, Y. Wang, Z. Miao and R. Chen, Green
Chem., 2007, 9, 1341–1345; (b) R. S. Varma, Green Chem., 1999, 1,
43; (c) G. W. V. Cave, C. L. Raston and J. L. Scott, Chem. Commun.,
2001, 2159.
4 P. T. Anastas, J. C. Warner, Green Chemistry–Theory and Practice,
Oxford University Press, New York, 1998.
5 S. E. Shim, V. V. Yashin and A. I. Isayev, Green Chem., 2004, 6,
291–294.
6 (a) J. L. Bravo, I. Lo´pez, P. Cintas, G. Silvero and M. J. Are´valo,
Ultrason. Sonochem., 2006, 13, 408; (b) D. J. Flannigan, S. D. Hopkins
and K. S. Suslick, J. Organomet. Chem., 2005, 690, 3513.
7 Y. Zhu, J. Phys. Chem. Solids, 2004, 65, 349.
8 (a) R. Rajagopal and K. V. Srinivasan, Ultrason. Sonochem., 2003,
10, 41; (b) R. Rajagopal, D. V. Jarikote and K. V. Srinivasan, Chem.
Commun., 2002, 616.
9 D. S. Jacob, V. Kahlenberg, K. Wurst, L. A. Solovyov, I. Felner, L.
Shimon, H. E. Gottlieb and A. Gedanken, Eur. J. Inorg. Chem., 2005,
3, 522–528.
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 215–222 | 221
©

View Online
10 X. Li, J. Zhao, Q. Li, L. Wang and S. C. Tsang, Dalton Trans., 2007,
1875–1880.
11 (a) C. W. Rees and D. J. Williams, J. Org. Chem., 1996, 61, 9178;
(b) C. W. Rees, J. P. Andrew and D. J. White, J. Org. Chem., 1998, 63,
2189.
12 J. S. Wang, X. Shen, X. He, Y. R. Zhu, B. C. Zhang, J. B. Wang, G.-S.
Qian, S. Y. Kuang, A. Zarba, P. A. Egner, L. P. Jacobson, A. Munoz,
K. J. Helzlsouer, J. D. Groopman and T. W. Kensler, J. Natl. Cancer
Inst., 1999, 91, 347.
13 (a) T. Chatterji, M. Kizil, K. Keerthi, G. Chowdhury, T. Pospisil and
K. S. Gates, J. Am. Chem. Soc., 2003, 125, 4996; (b) L. Breydo and
K. S. Gates, J. Org. Chem., 2002, 67, 9054.
22 Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Nakanishi, P.
Nampoothiri, E. Hamel, A. Brossi and K.-H. Lee, Bioorg. Med.
Chem. Lett., 2003, 13, 2891–2893.
23 S. Nakamura, M. Kozuka, K. F. Bastow, H. Tokuda, H. Nishino, M.
Suzuki, J. Tatsuzaki, S. L. M. Natschke, S.-C. Kuo and K.-H. Lee,
Bioorg. Med. Chem., 2005, 13, 4396–4401.
24 B. d’A. Lucero, C. R. B. Gomes, I. C. de P. P. Frugulhetti,
L. V. Faro, L. Alvarenga, M. C. B. V. Souza, T. M. L. de Souza
and V. F. Ferreira, Bioorg. Med. Chem. Lett., 2006, 16, 1010–
1013.
25 H. Koga, A. Itoh, S. Murayama, S. Suzue and T. Irikura, J. Med.
Chem., 1980, 23, 1358–1363.
14 A. Asai, M. Hara, S. Kakita, Y. Kanda, M. Yoshida, H. Saito and Y.
Saitoh, J. Am. Chem. Soc., 1996, 118, 6802.
15 P. J. O’Dwyer, S. W. Johnson and C. Khater, Cancer Res., 1997, 1,
1050.
26 (a) R. Wise, J. M. Andrews and L. J. Edwards, Antimicrob. Agents
Chemother., 1983, 23, 559–564; (b) K. Grohe and H. Heitzer, Liebigs
Ann. Chem., 1987, 29–37.
27 (a) S. Atarashi, S. Yokohama, K. Yamamzaki, K. Sakano, M.
Imamura and I. Hayakawa, Chem. Pharm. Bull., 1987, 35, 1896–
1902; (b) T. Une, T. Fujimoto, K. Sato and Y. Osada, Antimicrob.
Agents Chemother., 1988, 32, 559–564.
28 (a) Y. Xia, Z.-Y. Yang, S. L. Morris-Natschke and K.-H. Lee, Curr.
Med. Chem., 1999, 6, 179–194; (b) Y. Xia, Z.-Y. Yang, P. Xia, T.
Hackel, E. Hamel, A. Mauger, J.-H. Wu and K.-H. Lee, J. Med.
Chem., 2001, 44, 3932–3936.
29 M. Weigt and M. A. Wiese, Quant. Struct.-Act. Relat., 2000, 19,
142–148.
30 (a) E. B. Flint and K. S. Suslick, Science, 1991, 253, 1397; (b) C.
Sehgal, R. P. Steer, R. G. Sutherland and R. E. Verrall, J. Phys.
Chem., 1977, 81, 2618.
31 W. Wang, Q. Guo, Q. You, K. Zhang, Y. Yang, J. Yu, W. Liu, L.
Zhao, H. Hu, Y. Hu, Z. Tan and X. Wang, Anti-cancer Drugs, 2006,
17(7), 797–805.
16 M. K. Kwak, N. Wakabayashi and K. Itoh, J. Bio. Chem., 2003,
278(8), 8135.
17 (a) K. Mitra, W. Kim, J. S. Daniels and K. S. Gates, J. Am. Chem.
Soc., 1996, 119, 11691; (b) S. B. Behroozi, W. Kim, J. Dannaldson
and K. S. Gates, Biochemistry, 1996, 35, 1768.
18 (a) T. W. Kensier and P. A. Egner, Cancer Res., 1987, 47, 427; (b) N. E.
Davidson and P. A. Egner, Cancer Res., 1990, 50, 22551.
19 Y. Y. Maxuitenko, A. H. Libby, H. H. Joyner, T. J. Curphey, D. L.
M acMillan, T. W. Kensier and B. D. Roebuck, Carcinogenesis, 1998,
19, 1609.
20 (a) A. F. Pazharskii, A. T. Soldatenkov, A. R. Katritzky, Heterocycles
in Life and Society, John Wiley & Sons, Chichester, 1997, pp. 147–
148; (b) L. A. Mitscher, Chem. Rev., 2005, 105, 559–592.
21 D. Edmont, R. Rocher, C. Plisson and J. Chenault, Bioorg. Med.
Chem. Lett., 2000, 10, 1831–1834.
222 | Green Chem., 2009, 11, 215–222
This journal is
The Royal Society of Chemistry 2009
©