One-pot synthesis of 12-hydroxy-12H-benzo[6]thioxanthene-6,11-diones from 1,4-naphthoquinone and o-acylbenzenethiols

Article abstract of DOI:10.1246/bcsj.77.2095

The title benzo[b]thioxanthenequinone derivatives could be prepared in one-pot via a sequential conjugate addition and an aldol-type reaction between 1,4-naphthoquinone and o-acylbenzenethiols, followed by oxidation with 1,4-naphthoquinone or air.

Full text of DOI:10.1246/bcsj.77.2095

Short Articles
Bull. Chem. Soc. Jpn., 77, 2095–2096 (2004) 2095
One-Pot Synthesis of 12-Hydroxy-
12H-benzo[b]thioxanthene-6,11-
diones from 1,4-Naphthoquinone
and o-Acylbenzenethiols
ꢀ
Akihiro Matsunaga, Miyuki Tanmatsu,
Kazuhiro Kobayashi, Hironobu Umakoshi,
Osamu Morikawa, and Hisatoshi Konishi
Scheme 1.
Department of Materials Science, Faculty of Engineering,
Tottori University, Koyama-minami, Tottori 680-8552
Received April 30, 2004; E-mail: kkoba@chem.tottori-u.ac.jp
The title benzo[b]thioxanthenequinone derivatives
could be prepared in one-pot via a sequential conjugate addi-
tion and an aldol-type reaction between 1,4-naphthoquinone
and o-acylbenzenethiols, followed by oxidation with 1,4-
naphthoquinone or air.
In recent years, we have been developing convenient meth-
ods to prepare biologically interesting heterocycle-fused qui-
none derivatives.1 Compounds having the 12H-benzo[b]thiox-
anthene-6,11-dione skeleton are potentially interesting from
biological and synthetic points of view. However, there have
been few reports on methods for constructing this thioxanthe-
nequinone derivative, though Chuang et al. have described a
synthesis of diethyl 6,11-dihydro-6,11-dioxo-12H-benzo[b]-
thioxanthene-12,12-dicarboxylates by a free radical reaction
between 2-phenylthio-1,4-naphthoquinones with diethyl malo-
nate initiated by manganese(III) acetate.2 In this paper, we
wish to report on a method for the synthesis of new thioxanthe-
nequinone derivatives, 12-hydroxy-12H-benzo[b]thioxan-
thene-6,11-diones 3 and 5, from 1,4-naphthoquinone (1) and
o-acylbenzenethiols (2 and 4). The method is very simple; a
sequential conjugate addition and aldol-type reaction between
these starting materials takes place without any catalyst or ini-
tiator to give the desired products in one-pot.
Scheme 2.
nol at room temperature under argon. The mixtures were heat-
ed at reflux temperature for 8 h, and then the cooled reaction
mixtures were exposed to air overnight. The precipitated
desired benzothioxanthenequinone derivatives 5a–5f and 5h
were collected by suction in moderate-to-good yields. The se-
quence between 1 and 20-mercaptoacetophenone (4g) under
the same conditions resulted in the formation of an intractable
mixture, from which no more than a trace of the desired prod-
uct was obtained. Using THF instead of ethanol as a solvent,
the desired benzoxanthenequinone derivative 5g was isolated
from a rather complex reaction mixture by preparative TLC
on silica gel in lower yield.
First, in order to prepare 12-hydroxy-12H-benzo[b]thioxan-
thene-6,11-dione (3), 1,4-naphthoquinone (1) was allowed to
react with 2-mercaptobenzaldehyde (2) (2:1 molar ratio) in
ethyl alcohol at room temperature. The precipitated desired
product 3 was collected by filtration in fair yield, as shown
in Scheme 1.
Next, the reaction of 1,4-naphthoquinone (1) with 2-mer-
captobenzophenone (4a) was carried out under the same con-
ditions as described above. However, no reaction occurred.
Heating of the mixture at reflux temperature resulted in the for-
mation of an intractable mixture of products. Later, we found
that the sequence leading to the desired 12-aryl-12-hydroxy-
12H-benzo[b]thioxanthene-6,11-dione (5) could be accom-
plished as illustrated in Scheme 2. Thus, 1 and 2-mercaptoben-
zophenones 4 (an equimolar amount each) were mixed in etha-
Experimental
Starting Materials. 2-Mercaptobenzaldehyde (2),3 2-mercap-
tobenzophenone (4a),4 and 20-mercaptoacetophenone (4g)5 were
prepared by appropriate literature methods. 2-Mercaptobenzophe-
nones 4b–f were prepared by the action of appropriate substituted
phenyllithiums on 2-mercaptobenzoic acid according to a proce-
dure in Ref. 5.
2-Mercapto-30-methylbenzophenone (4b): mp 97–98 ꢁC; IR
(KBr disk) 2544, 1652 cmꢂ1; 1H NMR (270 MHz, CDCl3) ꢀ 2.41
(3H, s), 4.21 (1H, s), 7.18 (1H, dt, J ¼ 7:3, 1.3 Hz), 7.3–7.5 (5H,
m), 7.54 (1H, d, J ¼ 7:3 Hz), 7.61 (1H, s). Found: C, 73.52; H,
5.40; S, 14.02%. Calcd for C14H12OS: C, 73.65; H, 5.30; S,
14.04%.
2-Mercapto-40-methylbenzophenone (4c): mp 83–84 ꢁC; IR
(KBr disk) 2541, 1652 cmꢂ1; 1H NMR (270 MHz, CDCl3) ꢀ 2.44
Published on the web November 11, 2004; DOI 10.1246/bcsj.77.2095

2096 Bull. Chem. Soc. Jpn., 77, No. 11 (2004)
Ó 2004 The Chemical Society of Japan
(3H, s), 4.16 (1H, s), 7.18 (1H, td, J ¼ 7:3, 1.3 Hz), 7.25–7.45
(5H, m), 7.69 (2H, d, J ¼ 8:2 Hz). Found: C, 73.51; H, 5.40; S,
13.86%. Calcd for C14H12OS: C, 73.65; H, 5.30; S, 14.04%.
40-Chloro-2-mercaptobenzophenone (4d): mp 73–74 ꢁC; IR
(KBr disk) 2534, 1657 cmꢂ1; 1H NMR (270 MHz, CDCl3) ꢀ 4.17
(1H, s), 7.19 (1H, td, J ¼ 7:6, 1.3 Hz), 7.36 (1H, td, J ¼ 7:6, 1.3
Hz), 7.4–7.5 (4H, m), 7.72 (2H, d, J ¼ 8:9 Hz). Found: C, 62.53;
H, 3.73; S, 12.62%. Calcd for C13H9ClOS: C, 62.77; H, 3.65; S,
12.89%.
6.48 (1H, s), 6.97 (1H, d, J ¼ 7:4 Hz), 7.1–7.35 (6H, m), 7.65–
7.8 (3H, m), 8.0–8.05 (1H, m), 8.1–8.2 (1H, m). Found: C,
74.97; H, 4.44; S, 8.36%. Calcd for C24H16O3S: C, 74.98; H,
4.19; S, 8.34%.
12-Hydroxy-12-(4-methylphenyl)-12H-benzo[b]thioxanth-
ene-6,11-dione (5c): mp 215 ꢁC (decomp); IR (KBr disk) 3434,
1657, 1633 cmꢂ1 1H NMR (270 MHz, CDCl3) ꢀ 2.25 (3H, s),
;
6.53 (1H, s), 7.08 (2H, d, J ¼ 7:9 Hz), 7.2–7.35 (3H, m), 7.37
(2H, d, J ¼ 7:9 Hz), 7.7–7.8 (3H, m), 8.0–8.05 (1H, m), 8.1–
8.15 (1H, m). Found: C, 75.13; H, 4.46; S, 8.25%. Calcd for
C24H16O3S: C, 74.98; H, 4.19; S, 8.34%.
2-Mercapto-30-methoxybenzophenone (4e): Rf 0.18 (1:10
AcOEt–hexane); IR (neat) 2548, 1651 cmꢂ1 1H NMR (270
;
MHz, CDCl3) ꢀ 3.86 (3H, s), 4.19 (1H, s), 7.1–7.55 (8H, m).
Found: C, 68.55; H, 5.02; S, 12.87%. Calcd for C14H12O2S: C,
68.83; H, 4.95; S, 13.13%.
12-(4-Chlorophenyl)-12-hydroxy-12H-benzo[b]thioxanth-
ene-6,11-dione (5d): mp 216 ꢁC (decomp); IR (KBr disk) 3438,
1658, 1631 cmꢂ1 1H NMR (270 MHz, CDCl3) ꢀ 6.56 (1H, s),
;
2-Mercapto-40-methoxybenzophenone (4f): mp 87–88 ꢁC;
7.2–7.4 (5H, m), 7.43 (2H, d, J ¼ 8:6), 7.65–7.8 (3H, m), 7.95–
8.05 (1H, m), 8.1–8.2 (1H, m). Found: C, 68.08; H, 3.17; S,
8.05%. Calcd for C23H13ClO3S: C, 68.23; H, 3.24; S, 7.92%.
12-Hydroxy-12-(3-methoxyphenyl)-12H-benzo[b]thioxanth-
ene-6,11-dione (5e): mp 235 ꢁC (decomp); IR (KBr disk) 3438,
1
IR (KBr disk) 2538, 1645 cmꢂ1; H NMR (270 MHz, CDCl3) ꢀ
3.89 (3H, s), 4.09 (1H, s), 6.95 (2H, d, J ¼ 8:9 Hz), 7.19 (1H,
td, J ¼ 7:3, 1.6 Hz), 7.33 (1H, td, J ¼ 7:3, 1.6 Hz), 7.35–7.45
(2H, m), 7.79 (2H, d, J ¼ 8:9 Hz). Found: C, 68.72; H, 5.02; S,
13.00%. Calcd for C14H12O2S: C, 68.83; H, 4.95; S, 13.13%.
5-Chloro-2-mercaptobenzophenone (4h) was synthesized by
the action of phenyllithium on 5-chloro-2 mercaptobenzoic acid,6
which was prepared from 2-amino-5-chlorobenzoic acid accord-
ing to a method by Allen and MacKay.7 4h: Rf 0.36 (1:5
1670, 1632 cmꢂ1 1H NMR (270 MHz, CDCl3) ꢀ 3.76 (3H, s),
;
6.51 (1H, s), 6.70 (1H, dd, J ¼ 7:9, 2.3 Hz), 7.05–7.35 (6H, m),
7.65–7.8 (3H, m), 8.0–8.05 (1H, m), 8.1–8.2 (1H, m). Found: C,
72.00; H, 4.04; S, 8.02%. Calcd for C24H16O4S: C, 71.98; H,
4.03; S, 8.01%.
AcOEt–hexane); IR (neat) 2555, 1652 cmꢂ1
;
1H NMR (270
12-Hydroxy-12-(4-methoxyphenyl)-12H-benzo[b]thioxanth-
ꢁ
MHz, CDCl3) ꢀ 4.15 (1H, s), 7.3–7.55 (5H, m), 7.62 (1H, t, J ¼
7:6 Hz), 7.78 (2H, d, J ¼ 8:3 Hz). Found: C, 62.50; H, 3.74; S,
12.72%. Calcd for C13H9ClOS: C, 62.77; H, 3.65; S, 12.89%.
12-Hydroxy-12H-benzo[b]thioxanthene-6,11-dione (3). To
a stirred solution of 1,4-naphthoquinone (1) (0.47 g, 3.0 mmol)
in EtOH (15 mL) at room temperature was added dropwise an
EtOH (5 mL) solution of 2-mercaptobenzaldehyde (2) (0.21 g,
1.5 mmol). Stirring was continued for 4 h at the same temperature.
Filtration and washing with ethanol of the resulting precipitate
ene-6,11-dione (5f): mp 216 C (decomp); IR (KBr disk) 3466,
1684, 1658 cmꢂ1 1H NMR (270 MHz, CDCl3) ꢀ 3.72 (3H, s),
;
6.60 (1H, s), 6.79 (2H, d, J ¼ 8:9 Hz), 7.15–7.35 (3H, m), 7.39
(2H, d, J ¼ 8:9 Hz), 7.65–7.8 (3H, m), 8.0–8.05 (1H, m), 8.1–
8.15 (1H, m). Found: C, 71.87; H, 4.12; S, 7.98%. Calcd for
C24H16O4S: C, 71.98; H, 4.03; S, 8.01%.
12-Hydroxy-12-methyl-12H-benzo[b]thioxanthene-6,11-di-
one (5g): mp 148 ꢁC (decomp); IR (KBr disk) 3374, 1660, 1624
1
cmꢂ1; H NMR (270 MHz, CDCl3) ꢀ 1.67 (3H, s), 6.65 (1H, s),
ꢁ
gave pure 3 (0.29 g, 65%) as a red solid: mp 254 C (decomp);
7.25–7.45 (3H, m), 7.7–7.85 (2H, m), 7.96 (1H, dd, J ¼ 7:9, 1.3
Hz), 8.05–8.2 (2H, m). Found: C, 70.12; H, 4.22; S, 10.37%.
Calcd for C18H12O3S: C, 70.11; H, 3.92; S, 10.40%.
2-Chloro-12-hydroxy-12-phenyl-12H-benzo[b]thioxanth-
ene-6,11-dione (5h): mp 237 ꢁC (decomp); IR (KBr disk) 3400,
1663, 1631 cmꢂ1 1H NMR (270 MHz, CDCl3) ꢀ 6.59 (1H, s),
;
IR (KBr disk) 3416, 1671, 1652 cmꢂ1 1H NMR (270 MHz,
;
CDCl3) ꢀ 2.79 (1H, d, J ¼ 5:3 Hz), 6.39 (1H, d, J ¼ 5:3 Hz),
7.35–7.55 (3H, m), 7.65–7.85 (3H, m), 8.1–8.25 (2H, m). Found:
C, 69.19; H, 3.50; S, 10.90%. Calcd for C17H10O3S: C, 69.37; H,
3.42; S, 10.89%.
Typical Procedure for the Preparation of Benzothioxanth-
enediones 5. 12-Hydroxy-12-phenyl-12H-benzo[b]thioxanth-
ene-6,11-dione (5a): To a stirred solution of 1,4-naphthoquinone
(1) (0.16 g, 1.0 mmol) in EtOH (10 mL) at room temperature un-
der argon was added a solution of 2-mercaptobenzophenone (4a)
(0.21 g, 1.0 mmol) in EtOH (10 mL). After stirring for 5 min, the
mixture was refluxed for 8 h. The cooled resulting mixture was ex-
posed to the atmosphere and stirring was continued overnight. The
red precipitate was collected by suction and recrystallized from
hexane–CH2Cl2 to give pure 5a (0.22 g, 60%) as a red solid;
7.15–7.35 (5H, m), 7.45–7.5 (2H, m), 7.7–7.8 (3H, m), 8.0–8.05
(1H, m), 8.1–8.15 (1H, m). Found: C, 67.88; H, 3.34; S, 7.76%.
Calcd for C23H13ClO3S: C, 68.23; H, 3.24; S, 7.92%.
References
1
K. Kobayashi, K. Nomura, T. Ogata, M. Tanmatsu, O.
Morikawa, and H. Konishi, Synthesis, 2003, 673; K. Kobayashi,
T. Ogata, K. Miyamoto, O. Morikawa, and H. Konishi, Hetero-
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mp 208 ꢁC (decomp); IR (KBr disk) 3415, 1658, 1630 cmꢂ1
;
2 C.-P. Chuang and S.-F. Wang, Heterocycles, 43, 2215
(1996).
1H NMR (270 MHz, CDCl3) ꢀ 6.56 (1H, s), 7.1–7.4 (6H, m),
7.49 (2H, dd, J ¼ 7:9, 1.3 Hz), 7.65–7.8 (3H, m), 7.95–8.05
(1H, m), 8.1–8.15 (1H, m). Found: C, 74.52; H, 3.78; S, 8.43%.
Calcd for C23H14O3S: C, 74.58; H, 3.81; S, 8.66%.
3
4
H. S. Kasmai and S. G. Miscke, Synthesis, 1989, 763.
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which was obtained after the usual workup, followed by purifica-
tion using preparative TLC on SiO2 (1:3 AcOEt–hexane).
12-Hydroxy-12-(3-methylphenyl)-12H-benzo[b]thioxanth-
ene-6,11-dione (5b): mp 220 ꢁC (decomp); IR (KBr disk) 3392,
5
6
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7
580 (1966).
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;