Reaction of thiosalicylic acid with 1,4-quinones and cyclization of the resulting arylsulfanylbenzoic acids

Article abstract of DOI:10.1134/S1070428009090152

Thiosalicylic acid reacts with 1,4-benzoquinone to give 2-(1,4-dihydroxyphenylsulfanyl)benzoic acid which undergoes intramolecular cyclization to 1,4-dihydroxythioxanthen-9-one in the presence of dehydrating agents. Cyclization of arylsulfanylbenzoic acid

Full text of DOI:10.1134/S1070428009090152

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 9, pp. 1405–1409. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.A. Loskutov, I.V. Beregovaya, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 9, pp. 1418–1422.
Reaction of Thiosalicylic Acid with 1,4-Quinones and Cyclization
of the Resulting Arylsulfanylbenzoic Acids
V. A. Loskutov and I. V. Beregovaya
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: val@nioch.nss.ru
Received January 21, 2009
Abstract—Thiosalicylic acid reacts with 1,4-benzoquinone to give 2-(1,4-dihydroxyphenylsulfanyl)benzoic
acid which undergoes intramolecular cyclization to 1,4-dihydroxythioxanthen-9-one in the presence of dehy-
drating agents. Cyclization of arylsulfanylbenzoic acids obtained by reaction of thiosalicylic acid with
1,4-naphtho- and anthraquinones leads to 1,4-quinone derivatives, benzo- and naphthothioxanthenetriones.
DOI: 10.1134/S1070428009090152
Dihydroxythioxanthene derivatives were found to
exhibit biological activity [1–4] and initiate photo-
chemical polymerization [5]. The most widely known
representative of this series of compounds is 1,4-dihy-
droxythioxanthen-9-one (I) which was synthesized
about 100 years ago [6] by cyclization of 2-[(2,5-di-
hydroxyphenyl)sulfanyl]benzoic acid (II); the latter
was prepared from benzoquinone III and thiosalicylic
acid (IV) in acetic acid (Scheme 1).
1,4-naphthoquinone (VII) in ethanol gave 2-(1,4-di-
oxo-1,4-dihydronaphthalen-2-ylsulfanyl)benzoic acid
(V) and benzothioxanthene VI (Scheme 2). However,
the parameters of the products given in [4] are not fully
consistent with the assumed structures. In particular,
1
the H NMR spectrum of acid V lacks a signal typical
of quinoid compounds which should be located in
a stronger field than signals from aromatic protons [7].
Therefore, the assignment of structures of compounds
I and II made in [4] seems to be insufficiently substan-
tiated. The goal of the present work was to elucidate
the structure of compounds formed by reaction of thio-
salicylic acid (IV) with 1,4-benzo-, 1,4-naphtho-, and
1,4-anthraquinones and of their cyclization products,
thioxanthen-9-one derivatives.
Scheme 1.
O
OH
6
3
COOH
COOH
SH
4'
3'
AcOH
+
S
We have found that acid IV reacts with 1,4-benzo-
quinone (III) at room temperature not only in acetic
acid [6] but also in other solvents (such as diethyl ether
and ethanol) and that the reaction occurs as 1,4-ad-
dition of the nucleophile at the conjugated bond system
of quinone III with participation of one carbonyl group
(which is typical of quinones), followed by rearrange-
ment of the adduct to produce dihydroxy-substituted
O
OH
IV
III
II
O
OH
S
OH
1
diphenyl sulfide II. The H NMR spectrum of the iso-
I
lated product contained signals from aromatic protons
and three signals assignable to hydroxy protons.
A broadened downfield signal at δ 12–14 ppm was as-
signed to proton in the carboxy group, and the position
of the two other OH signals (2′-OH and 5′-OH; δ 8.93
and 9.03 ppm) indicated equal contributions of the cor-
responding protons to exchange processes. In the IR
Tandon et al. [4] recently postulated that the above
reactions does not lead to hydroquinone derivatives I
and II but to their oxidation products, 2-(3,6-dioxo-
cyclohexa-1,4-dien-1-ylsulfanyl)benzoic acid and thio-
xanthene-1,4,9-trione. This assumption was made on
the basis of the fact that the reaction of acid IV with
1405

LOSKUTOV, BEREGOVAYA
1406
Scheme 2.
O
O
O
O
S
O
O
1
4
COOH
COOH
SH
EtOH
+
+
S
O
IV
VII
V
VI
Scheme 3.
OH
OAc
OAc
5'
6
3
COOH
COOH
3'
Et2O
IV
+ VII
S
S
8'
OH
VIII
IX
spectrum of II we observed strong absorption bands in
the regions 2600–3500 and 1685 cm–1, which con-
firmed the presence of hydroxy and carboxy groups in
its molecule.
naphthoquinone VII was carried out in ethanol, acid
VIII was formed as the major product (81%).
Unlike benzo- and naphthoquinones, the reaction of
IV with 1,4-anthraquinone (X) was successful only at
elevated temperature. By heating the reactants in boil-
ing benzene we obtained 2-(1,4-dioxo-1,4-dihydro-
anthracen-2-ylsulfanyl)benzoic acid (XI) (Scheme 4).
The 1H NMR spectrum of XI lacked signals assignable
to OH protons (δ 9–10 ppm).
Likewise, the reaction of thiosalicylic acid (IV)
with 1,4-naphthoquinone (VII) in diethyl ether at room
temperature gave 2-(1,4-dihydroxynaphthalen-2-ylsul-
fanyl)benzoic acid VIII (Scheme 3) whose structure
was confirmed by spectral data (the 1H NMR spectrum
of VIII contained OH proton signals at δ 9.13, 9.74,
and 13.16 ppm) and transformation into di-O-acetyl
derivative IX. Compound VIII was insufficiently
stable, so that we failed to isolate it as analytically pure
substance. On heating for a short time in methanol and
subsequent keeping at room temperature for several
days, dihydroxy acid VIII was gradually converted
into orange 2-(1,4-dioxo-1,4-dihydronaphthalen-2-yl-
sulfanyl)benzoic acid (V). The 1H NMR spectrum of V
differed from that given in [4]. Unlike published data
[4], compound V displayed in the spectrum signals at
δ 6.02 and 13.39 ppm due to protons in the quinoid
ring (3′-H) and carboxy group, respectively. In the
1H NMR spectrum of 2-phenylsulfanyl-1,4-naphtho-
quinone, the 3-H proton resonated in the same region
(δ 6.12 ppm) [4]. When the reaction of acid IV with
In keeping with published data [8], carboxy-substi-
tuted diphenyl sulfides are converted into thioxanthen-
9-ones in the presence of dehydrating agents such as
sulfuric, phosphoric, or polyphosphoric acid. As noted
in [4], there are no examples of formation of cycliza-
tion products in the absence of dehydrating agents.
Acid II was converted into 1,4-dihydroxythioxanthen-
9-one (I) by the action of concentrated sulfuric acid
[6]. We found in [9] that analogous cyclization occurs
in polyphosphoric acid, and the structure of thioxan-
thenone I thus obtained was confirmed by comparison
of its spectral parameters with those reported in [10].
However, our attempts to effect cyclization of
1,4-naphthoquinone and 1,4-anthraquinone derivatives
V, VIII, and XI in concentrated sulfuric acid were
unsuccessful. As a result, poorly soluble dark brown
Scheme 4.
O
O
O
S
O
10'
9'
5'
8'
6
3
1
4
12
7
COOH
3'
Benzene, 80°C
IV +
S
O
O
O
X
XI
XII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

REACTION OF THIOSALICYLIC ACID WITH 1,4-QUINONES
1407
Calculated (B3LYP/6-31G*) total energies (E), electron affinities (EA), and ionization potentials (IP) of quinoid and hydro-
quinone thioxanthene structures
ΔΔE,a
kcal/mol
Quinoid structure
E, a.u.
EA, eV
Hydroquinone structure
E, a.u.
IP, eV
O
O
O
OH
–1122.36541 1.76
–1275.93103 1.67
–1429.47856 1.65
–1123.60426 7.05
–1277.15136 6.70
–1430.69363 6.32
–00.0
S
S
O
O
OH
OH
O
O
–11.6
–14.9
S
S
O
O
OH
OH
O
O
S
S
O
OH
a
Difference in the total energies.
materials were obtained both on heating and at room
temperature. We succeeded in obtaining the corre-
sponding thioxanthenes using a mixture of methane-
sulfonic acid with phosphoric anhydride as dehydrat-
ing agent. Under these conditions, naphthylsulfanyl-
substituted benzoic acids V and VIII were converted
into benzothioxanthenetrione VI, and naphthothioxan-
thenetrione XII was obtained from anthraquinone
derivative XI. The electronic absorption spectra of
compounds VI and XII were similar to the spectrum of
thioxanthene-1,4,9-trione (XIII) which was synthe-
sized by oxidation of dihydroxythioxanthenone I with
ceric ammonium nitrate. In going from xanthenetrione
XIII to benzo- and naphtho-fused derivatives VI and
XII, the long-wave absorption maximum was dis-
placed by 17 and 8 nm, respectively, toward shorter
wavelengths.
droxythioxanthenone I (the total energy of the latter
was taken as zero; absolute energy differences cannot
be used in the calculations, for the quinoid and hydro-
quinone structures have different elemental composi-
tions). The results (see table) showed that increase in
the number of fused aromatic rings is accompanied by
reduction of both electron affinity of the quinoid struc-
ture (i.e., stabilization) and ionization potential of the
hydroquinone structure (i.e., destabilization). The cal-
culated ΔΔE values provide an additional support to
stabilization of the quinoid structure in going from
thioxanthenetrione XIII to benzo- and naphto-fused
analogs VI and XII.
Thus our experimental data and calculation results
indicate that Tandon et al. [4] erroneously assigned
quinoid structure to the product obtained by reaction of
thiosalicylic acid with benzoquinone. In fact, the pri-
mary product is 2-(1,4-dihydroxyphenylsulfanyl)ben-
zoic acid which undergoes intramolecular cyclization
to 1,4-dihydroxythioxanthen-9-one (I) by the action of
dehydrating agents. In going to linearly fused benzo
and naphtho analogs (quinones VII and X), the forma-
tion of the corresponding quinoid compounds becomes
predominating, in keeping with the known [7] relation
between the thermodynamic stability of quinones and
the number of aromatic fragments in their molecules.
Quinones VI, XII, and XIII give rise to redox
equilibrium with the corresponding hydroquinones.
The thermodynamic stability of compounds VI, XII,
and XIII was evaluated by quantum-chemical calcula-
tions of their vertical electron affinities and vertical
ionization potentials of the hydroquinone structures. In
addition, differences in their total energies (ΔΔE) were
calculated for benzo- and naphthothioxanthene deriva-
tives relative to thioxanthenetrione XIII and dihy-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

LOSKUTOV, BEREGOVAYA
tered off. Yield 0.15 g (58%), mp 199–202°C. The IR
1408
EXPERIMENTAL
spectrum was identical to that given above in a.
The IR spectra were recorded in KBr on a Bruker
Vector 22 instrument. The H NMR spectra were
2-(1,4-Dioxo-1,4-dihydronaphthalen-2-ylsulfa-
nyl)benzoic acid (V). A mixture of 1.58 g (10 mmol)
of quinone VII, 1.54 g (10 mmol) of acid IV, and
100 ml of ethanol was stirred for 4 h at room tempera-
ture. The mixture was filtered, the filtrate was evap-
orated to a small volume, and the precipitate was
filtered off. Yield 2.5 g (81%), mp 203–206 °C (from
1
measured on a Bruker AC-200 spectrometer from so-
lutions in DMSO-d6 using the residual proton signal of
the solvent as reference. The UV spectra were obtained
on a Hewlett–Packard 4853 spectrophotometer from
solutions in chloroform. The mass spectra were run on
a Finnigan MAT-8200 instrument; the molecular
weights and elemental compositions were determined
from the high-resolution mass spectra. The progress of
reactions and the purity of products were monitored by
thin-layer chromatography on Silufol UV-254 plates
using methylene chloride–acetone (10:1) as eluent.
1
EtOH); published data [4]: mp 205–207°C. H NMR
spectrum, δ, ppm: 6.02 s (1H, 3′-H); 7.70 m, 7.85 m,
7.95 m, and 8.05 m (8H, Harom); 13.39 br.s (1H,
COOH).
2-(1,4-Dihydroxynaphthalen-2-ylsulfanyl)ben-
zoic acid (VIII). Quinone VII, 0.5 g (3.2 mmol), was
added to a solution of 0.48 g (3.1 mmol) of acid IV in
35 ml of diethyl ether, the mixture was stirred for 2.5 h
at room temperature and evaporated to a small volume,
~10 ml of methylene chloride was added to the resi-
due, and the precipitate was filtered off and washed
with methylene chloride. Yield 0.6 g (62%), mp 260–
265°C (decomp.). IR spectrum, ν, cm–1: 3600–2600
Quantum-chemical calculations were performed at
the B3LYP/6-31G* level of theory using GAMESS
software package [11]. The applicability of the cal-
culation procedure was confirmed by the existence of
a linear correlation between the calculated vertical
electron affinities of a series of benzo-, naphtho-, and
anthraquinones and their experimental redox potentials
[7] (r = 0.99). Extension of the basis set with diffuse
functions did not improve the results appreciably.
1
(O–H), 1680 br (C=O). H NMR spectrum, δ, ppm:
6.68 d (1H, 3-H), 6.73 s (1H, 3′-H), 7.15 t and 7.31 t
(1H each, 4-H, 5-H), 7.55 m (2H, 6′-H, 7′-H), 7.96 d
(1H, 6-H), 8.11 m and 8.18 m (1H each, 5′-H, 8′-H),
9.13 br.s (1H, OH), 9.74 s (1H, OH), 13.16 br.s
(1H, OH).
1,4-Dihydroxythioxanthen-9-one (I) was synthe-
sized by cyclization of acid II in polyphosphoric acid.
mp 288–289°C (from DMSO–EtOH). The IR and
1H NMR spectra of compound I were consistent with
those reported in [10].
2-(1,4-Diacetoxynaphthalen-2-ylsulfanyl)benzoic
acid (IX). A mixture of 1.14 g of acid VIII, 10 ml of
acetic anhydride, and 0.03 ml of concentrated sulfuric
acid was stirred for 1 h at room temperature. The
mixture was poured onto ice, and the precipitate was
filtered off. Yield 1.3 g (89%), mp 208–213°C (from
aqueous EtOH, 1:1). IR spectrum, ν, cm–1: 3400–2500
(O–H); 1760, 1684 (C=O). 1H NMR spectrum, δ, ppm:
2.42 s and 2.43 s (3H each, CH3), 6.83 d (1H, 3-H),
7.25 t and 7.35 t (1H each, 4-H, 5-H), 7.41 s (1H,
3′-H), 7.73 m (2H, 6′-H, 7′-H), 7.93 d (1H, 6-H), 8.02 m
(2H, 5′-H, 8′-H). Found, %: C 63.79; H 4.03; S 7.74.
C21H16O6S. Calculated, %: C 63.64; H 4.04; S 8.08.
2-(2,5-Dihydroxyphenylsulfanyl)benzoic acid
(II). a. 1,4-Benzoquinone (III), 5.5 g (50 mmol), was
added in portions to a solution of 7.5 g (49 mmol) of
thiosalicylic acid (IV) in 300 ml of diethyl ether. The
mixture was stirred for 2 h at room temperature and
filtered, the filtrate was evaporated to a volume of 10–
20 ml, and ~50 ml of methylene chloride was added.
The precipitate was filtered off and washed with meth-
ylene chloride. Yield 9.6 g (75%), mp 202–204°C;
published data [6]: mp 199°C. IR spectrum, ν, cm–1:
3500–2600 (O–H), 1685 br (C=O). 1H NMR spectrum,
δ, ppm: 6.7–6.86 m (4H, 3-H, 3′-H, 4′-H, 6′-H),
7.15 t.d and 7.34 t.d (1H each, 4-H, 5-H, J = 7.5,
1.5 Hz), 7.90 d.d (1H, 6-H, J = 7.5, 1.5 Hz), 8.93 s and
9.03 s (1H each, OH), 13.00 (1H, COOH). Found: m/z
262.03020 [M]+. C13H10O4S. Calculated: M 262.02998.
2-(1,4-Dioxo-1,4-dihydroanthracen-2-ylsulfanyl)-
benzoic acid (XI). A mixture of 0.62 g (4 mmol) of
acid IV, 0.81 g (4 mmol) of quinone X, and 40 ml of
benzene was heated for 4 h under reflux. The mixture
was cooled, and the precipitate was filtered off. Yield
0.9 g (64%), mp 242–249°C (decomp.). IR spectrum,
ν, cm–1: 3600–2700 (O–H); 1731, 1664 (C=O); 1610
b. A mixture of 0.15 g (1 mmol) of acid IV, 0.11 g
(1 mmol) of quinone III, and 5 ml of ethanol was
stirred for 3 h at room temperature. The mixture was
evaporated almost to dryness, the residue was treated
with methylene chloride, and the precipitate was fil-
1
(C=C). H NMR spectrum, δ, ppm: 6.07 s (1H, 3′-H),
7.73 m (5H, 3-H, 4-H, 5-H, 6′-H, 7′-H), 7.95 m (1H,
6-H), 8.28 m (2H, 5′-H, 8′-H), 8.55 s and 8.69 s (1H
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

REACTION OF THIOSALICYLIC ACID WITH 1,4-QUINONES
1409
each, 9′-H, 10′-H), 13.15 br.s (1H, COOH). Found: m/z
360.0452 [M]+. C21H12O4S. Calculated: M 360.0451.
DMSO, the mixture was stirred for 2 h at room tem-
perature and poured into water, and the precipitate was
filtered off. Yield almost quantitative. The product was
purified by passing its solution in chloroform through
a small layer of silica gel. mp 212–214°C (from ben-
zene); published data [12]: mp 237°C. IR spectrum:
ν 1675 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 6.93 d
and 7.13 d (1H each, 2-H, 3-H, J = 10.0 Hz), 7.70 t
and 7.82 t (1H each, 6-H, 7-H, J = 8.0 Hz), 8.02 d and
8.30 d (1H each, 5-H, 8-H, J = 8.0 Hz). UV spectrum,
11H-Benzo[b]thioxanthene-6,11,12-trione (VI).
A mixture of 0.7 g of phosphoric anhydride and 6 ml
of methanesulfonic acid was heated to 70°C, 0.5 g of
acid VIII was added, and the mixture was stirred for
30 min. The mixture was cooled and treated with ice,
and the precipitate was filtered off, washed with water,
dried, and purified by column chromatography on
silica gel using methylene chloride as eluent. Yield
0.2 g (42%), mp 310–313°C (from DMSO); published
data [4]: mp 190–192°C. IR spectrum, ν, cm–1: 1673
λ
max, nm: 305, 458. Found, %: C 64.70; H 2.53;
S 13.17. C13H6O3S. Calculated, %: C 64.46; N 2.48;
S 13.22.
1
(C=O), 1623 (C=C). H NMR spectrum (CDCl3), δ,
ppm: 7.57–7.89 m (5H, 2-H, 3-H, 4-H, 8-H, 9-H);
8.15 d.d, 8.24 d.d, and 8.51 d.d (1H each, 1-H, 7-H,
10-H). UV spectrum, λmax, nm (ε): 314 (8983), 441
(630). Found, %: C 69.98; H 2.78; S 10.95.
m/z 292.0188 [M]+. C17H8O3S. Calculated, %: C 69.86;
H 2.74; S 10.96. M 292.01887.
REFERENCES
1. Walker, E.H., Palomino, E., and Blumenthal, S.L., US
Patent no. 20040116508, 2004; Chem. Abstr., 2004,
vol. 141, no. 33775q.
2. Singh, P., Pardasani, R.T., Prashant, A., and Choud-
Acid V was converted into thioxanthenetrione VI
hary, B., Phosphorus Sulfur, 1994, vol. 86, p. 21.
according to a similar procedure.
3. Kostakis, I.K., Pouli, N., Marakos, P., Mikros, E., Skal-
tsounis, A.-L., Leonce, S., Atassi, G., and Renard, P.,
Bioorg. Med. Chem., 2001, vol. 9, p. 2793.
4. Tandon, V.K., Singh, R.V., and Yadav, D.B., Bioorg.
Med. Chem. Let., 2004, vol. 14, p. 2901.
5. Jiang, X. and Yin, J., Macromol. Rapid Commun., 2004,
vol. 25, p. 748.
6. Clarke, H.T. and Smiles, S., J. Chem. Soc., 1911,
13H-Naphtho[2,3-b]thioxanthene-6,13,14-trione
(XII). A mixture of 0.6 g of phosphoric anhydride and
4 ml of methanesulfonic acid was heated to 70°C,
0.19 g of acid XI was added, and the mixture was
stirred for 50 min. The mixture was cooled and treated
with ice, and the precipitate was filtered off, washed
with water, dried, and purified by column chromatog-
raphy on silica gel using methylene chloride as eluent.
The product was additionally recrystallized from chlo-
roform–ethanol. Yield 0.05 g (28%), mp 344–350°C
(decomp.). IR spectrum, ν, cm–1: 1682 (C=O), 1620
(C=C). 1H NMR spectrum (CDCl3), δ, ppm: 7.6–7.8 m
(5H, 2-H, 3-H, 4-H, 9-H, 10-H), 8.14 m (2H, 8-H,
11-H), 8.57 d (1H, 1-H), 8.77 s and 8.82 s (1H each,
7-H, 12-H). UV spectrum, λmax, nm (ε): 293 (15608),
309 (16245), 433 (7893). Found, %: C 73.48; H 2.90;
S 9.42. m/z 342.0346 [M]+. C21H10O3S. Calculated, %:
C 73.68; H 2.92; S 9.36. M 342.0345.
vol. 99, p. 1535.
7. Gorelik, M.V., Khimiya antrakhinonov i ikh proizvod-
nykh (Chemistry of Anthraquinones and Their Deriva-
tives), Moscow: Khimiya, 1983.
8. Rasanu, N., St. Serc. Chim., 1973, vol. 21, p. 1083.
9. Loskutov, V.A., Gatilov, Yu.V., and Mamatyuk, V.I.,
Russ. J. Org. Chem., 2008, vol. 44, p. 626.
10. Sharghi, H. and Beni, A.R.S., Synthesis, 2004, p. 2900.
11. Schmidt, M.W., Baldridge, K.K., Boatz, J.A., El-
bert, S.T., Gordon, M.S., Jensen, J.H., Koseki, S., Mat-
sunaga, N., Nguyen, K.A., Su, S.J., Windus, T.L.,
Dupuis, M., and Montgomery, J.A., J. Comput. Chem.,
1993, vol. 14, p. 1347.
1H-Thioxanthene-1,4,9-trione (XIII). Ceric am-
monium nitrate, 2.75 g (5 mmol), was added to a so-
lution of 0.6 g (2.5 mmol) of compound I in 25 ml of
12. Konig, H.-B., FRG Patent no. 955510, 1957; Chem.
Abstr., 1958, vol. 52, p. 9220h.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009