Novel synthesis of o-naphthothiophenequinone derivatives via regioselective Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2005.07.036

A novel procedure to construct o-naphthothiophenequinones has been achieved from readily available o-benzothiophenquinones and N-dienes via Diels-Alder reaction-aromatization sequence as key steps. The absolute regioselectivity was established via Diels-A

Full text of DOI:10.1016/j.tet.2005.07.036

Tetrahedron 61 (2005) 9097–9101
Novel synthesis of o-naphthothiophenequinone derivatives
via regioselective Diels–Alder reaction
a
Yu-Dong Shen,a,b Hai-Qiang Wu,b Sheng-Ling Zhang,b Xian-Zhang Bu,a, Lin-Kun An,
*
Zhi-Shu Huang,a Pei-Qing Liu,a Lian-Quan Gu,a,b, Yue-Ming Li and Albert S. C. Chan
c
c
*
aSchool of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510275, China
bSchool of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
cDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
Received 20 May 2005; revised 11 July 2005; accepted 13 July 2005
Available online 1 August 2005
Abstract—A novel procedure to construct o-naphthothiophenequinones has been achieved from readily available o-benzothiophenquinones
and N-dienes via Diels–Alder reaction-aromatization sequence as key steps. The absolute regioselectivity was established via Diels–Alder
reaction of o-benzothiophenquinones with rich electron N-dienes.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
novel derivatives were characterized as 3-aryl and 6-acyl-
amino substituted o-naphthothiophenquinones I (Fig. 1).
The derivatives of synthetic and natural polycyclic quinoid
structure are a large category of very significative
compounds, which possess a broad spectrum of biological
activities.1–7 Among heterocyclic quinones with a variety of
bioactivities, those containing a thiophene ring fused to a
quinone system have received an increasing attention.8
However, efficient methods for the synthesis of o-naphtho-
thiophenequinones could be seldom found.11 Furthermore,
the reported synthetic procedure11 was unapplicable for us
to prepare the proposed derivatives I for unavailable starting
materials.
As part of our ongoing research for hetero polycyclic
o-quinones,9 more structurally diversified o-quinoid deriva-
tives were called for. In contrast to extensive study of
oxoheterocyclic-fused o-quinones, that of thioheterocyclic-
fused o-quinones was quite scarce.8c,10 Therefore, synthesis
of novel thiophen-fused o-quinones was proposed, these
In this paper, we described a novel and regiospecific
procedure to synthesize the target substrates I. The
retrosynthetic analysis (Scheme 1) showed that compounds
I could be achieved facilely from inexpensive and easily
available starting materials II, III, VI, VII via conden-
sation, intramolecularly cyclization, deprotection, IBX
Figure 1.
Keywords: o-Naphthothiophenequinone; IBX; Diels–Alder; Regio-
selectivity.
*
Corresponding authors. Tel.: C86 20 87331215; fax: C86 20 87331215
(X.-Z.B); tel.: C86 20 84110272; fax: C86 20 84110272 (L.-Q.G.);
e-mail addresses: phsbxzh@zsu.edu.cn; cedc42@zsu.edu.cn
Scheme 1. Retrosynthesis route of target compounds I.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.036

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Y.-D. Shen et al. / Tetrahedron 61 (2005) 9097–9101
oxidation, and then Diels–Alder reaction-aromatization
sequence.
2.3. Synthesis of target o-quinones (7a–f)
After the completion of IBX oxidation, the reaction mixture
was first diluted with water, and then extracted with
benzene. The extraction containing benzothiophen-4,5-
diones was dried with anhydrous sodium sulfate and
N-diene II or III16 was added for cycloaddition. The
reaction was carried out at 45 8C and monitored by TLC
(noticeably, only one new fluorescent substance was found,
which indicated that the single regiomer was produced).
About 16 h later, the reaction mixtures were subsequently
aromatized into the final products by refluxing with DDQ.
After purification by chromatography on silica gel (CHCl3/
MeOH), regiospecific compounds 7a–f were obtained in
78–86% yields (Scheme 4).
2. Results and discussion
2.1. Synthesis of benzothiophen-5-ols (5a–d)
Our strategies were started from synthesis of benzothio-
phen-5-ol moieties detailed in Scheme 2. Compounds 3a–d
were prepared in MeOH/H2O by condensing 4-methoxy-
phenylthiol 1 with an equiv of 2-bromo-1-arylyethanones
2a–d at 5–10 8C in the presence of an equiv of KOH.12
Compounds 3a–d were then cyclized into 3-aryl-5-
methoxybenzothiophenes 4a–d in refluxing toluene by
using PPA.13 Finally, benzothiophene-5-ols 5a–d were
achieved in moderate to good overall yield (see Section 4)
after deprotection of 4a–d by refluxing in a mixture of Ac2O
and 48% HBr (1:1 v/v).
Scheme 4. Conditions: (i) benzene, 45 8C, 16 h; (ii) DDQ, benzene, RF,
10 h.
Structures of all final products were assigned according to
1H NMR, 13C NMR, DEPT, HMQC, HMBC, ESI-MS and
element analysis data. The structure of 7a was also proved
unanimously by X-ray crystal structure analysis17 (Fig. 2).
Scheme 2. Conditions: (i) MeOH, equiv KOH, 5–10 8C; (ii) PPA, toluene,
RF, 6 h; (iii) AC2O–HBr (48%) (1:1, v/v), 140 8C, 4 h.
2.2. Synthesis of benzothiophen-4, 5-diones (6a–d)
The next step was to convert benzothiophen-5-ols 5a–d into
benzothiophen-4,5-diones 6a–d. Fremy’s salt is well known
for its application in transforming single phenolic hydroxyl
group into o-quinone group.14 Our first attempt was focused
on the oxidation of benzothiophen-5-ols 5a–d to produce
o-quinones 6a–d. However, most of the reaction failed to
give the desired products in satisfactory yield. After an
in-depth screening of mild oxidants, we found that
o-iodoxybenzoic acid (IBX) could be a good choice in
these reactions, as it was reported that IBX was a good
oxidant for transforming phenols to o-quinones.15 However,
few reports on transformation of hetero biscyclic phenolic
hydroxyl group into o-quinone by IBX could be found. Our
results indicated that IBX worked very well in our system,
the desired product benzothiophen-4,5-diones 6a–d were
obtained regioselectively (Scheme 3) in almost quantitative
yields. The isolation of the diquinone intermediates was
not pursued as most of these o-quinone compounds were
volatile and highly reactive.
Figure 2. X-ray crystal structure for 7a (CCDC no. 267293).
It is interesting that the cycloaddition reactions of our
procedure were essentially regiospecific and high reactive,
which was reasoned that an intermolecular hydrogen bond
(HB) would form between the amide group (NH) of the
N-dienes and the oxygen atom of carbonyl groups in
o-quinones. The role of intermolecular hydrogen bonding in
the regio and stereo-chemical outcome of Diels–Alder
reactions has been well recognized.18
3. Conclusions
In summary, we developed a novel route to prepare
thiophen-fused o-naphthoquinone derivatives via the key
IBX oxidation–cycloaddition–aromatization sequence.
Noticeably, the cycloaddition was regiospecific and highly
efficient. To the best of our knowledge, none relative reports
have surfaced. Furthermore, this work produced a series of
novel thiophene fused o-quinoid derivatives. Studies on the
bioactivities and further synthesis of these compounds are
well under way.
Scheme 3.

Y.-D. Shen et al. / Tetrahedron 61 (2005) 9097–9101
9099
4. Experimental
7.05 (dd, 1H, JZ2.4, 8.6 Hz), 6.46 (br s, 1H); 13C NMR
(75 MHz, CDCl3): d 108.0, 114.3, 123.6, 124.8, 127.2,
128.2, 128.4, 133.0, 135.6, 137.1, 138.8, 152.7.
4.1. General
4.2.2. 3-(4-Chlorophenyl)benzo[b]thiophene-5-ol (5b).
This compound was obtained as a yellow oil in 58% overall
yield (eluent: EtOAc/Petroleum-II 1:8). Anal. Calcd for
C14H9ClOS: C, 64.49; H, 3.48; S, 12.30; Found: C, 64.47;
All reagents were available commercially. Solvents were
purified using standard techniques. Reactions were moni-
tored by TLC. Separation by vacuum chromatographic
1
column were performed on Silica gel H. H NMR, 13C
1
H, 3.52; S, 12.27; H NMR (300 MHz, CDCl3): d 7.72 (d,
NMR, DEPT, HMQC and HMBC spectra were measured on
a Varian UNITY INOVA 500 or 300 MHz spectrometer
using TMS as an internal standard. For the electrospray
(ESI) MS analysis, a Finnigan LCQ Deca XP ion trap mass
spectrometer was equipped with a Microsoft Windows NT
data system and an ESI interface was used. Elementary
analysis was recorded on an Elementar Vario EL elementary
analysis device. N-Dienes II, III are prepared by using the
reported method.16
1H, JZ8.6 Hz), 7.31–7.41 (m, 6H), 7.00 (dd, 1H, JZ2.0,
8.6 Hz); 13C NMR (75 MHz, CDCl3): d 107.7, 114.6, 123.6,
125.1, 128.6, 129.5, 132.7, 133.1, 134.1, 135.9, 138.6,
153.4.
4.2.3. 3-(4-Fluorophenyl)benzo[b]thiophene-5-ol (5c).
This compound was obtained as a yellow oil in 60% overall
yield (eluent: EtOAc/Petroleum-II 1:8). Anal. Calcd for
C14H9FOS: C, 68.84; H, 3.71; S, 13.12; Found: C, 68.79; H,
3.74; S, 13.09; 1H NMR (300 MHz, CDCl3): d 7.75 (d, 1H,
JZ8.6 Hz), 7.49 (dd, 1H, JZ5.5, 8.5 Hz), 7.37 (s, 1H), 7.29
(d, 1H, JZ2.3 Hz), 7.14 (t, 2H, JZ8.6 Hz), 6.99 (dd, 1H,
JZ2.3, 8.6 Hz), 5.65 (br s, 1H); 13C NMR (75 MHz,
CDCl3): d 107.7, 114.5, 115.6 (d, JZ21.0 Hz), 123.7, 124.9,
130.0 (d, JZ7.3 Hz), 131.8, 132.8, 136.2, 139.0, 153.3,
162.1 (d, JZ245.6 Hz).
4.2. General procedure for 3-arylbenzothiophen-5-ols
(5a–d)
To a freshly prepared solution of 70 mL of MeOH, 30 mL of
water, and 3.3 g of KOH (85% purity; 0.05 mol) at room
temperature was added 4-methoxybenzenethiol 1 (7.0 g,
0.05 mol) in one portion, and the solution was cooled to
between 5 and 10 8C. A saturated solution of 2-bromo-1-
arylyethanones (2a–d) (0.05 mol) in MeOH was added at a
rate that the temperature did not exceed 15 8C. The reaction
was continued for further 1 h at 15 8C, and then was allowed
to stir overnight at room temperature. The reaction was
diluted with water and extracted with ether. The organic
layers were washed with 1 M HC1 solution, water, saturated
aqueous NaHCO3, and saturated aqueous NaCl. The
organics were dried over anhydrous Na2SO4, filtered, and
evaporated to give crude products (3a–d) as yellow oils.
4.2.4. 3-(2-Methylphenyl)benzo[b]thiophene-5-ol (5d).
This compound was obtained as a yellow oil in 62% overall
yield (eluent: EtOAc/Petroleum-II 1:8). Anal. Calcd for
C15H12OS: C, 74.97; H, 5.03; S, 13.34; Found: C, 74.94; H,
5.28; S, 13.29; 1H NMR (300 MHz, CDCl3): d 7.74 (d, 1H,
JZ8.6 Hz), 7.28–7.33 (m, 5H), 6.95 (dd, 1H, JZ2.4,
8.6 Hz), 6.84 (d, 1H, JZ2.4 Hz), 2.20 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 20.2, 108.0, 114.3, 123.4, 125.0, 125.6,
127.8, 130.1, 130.3, 132.1, 135.2, 136.7, 136.9, 140.2,
153.2.
A mixture of 2-(4-methoxyphenylthio)-1-arylethanones
(3a–d), polyphosphoric acid (40 g), and toluene (100 mL)
was refluxed for 6 h. The reaction mixture was cooled to
room temperature, poured into water, and extracted with
ether. The organic extracts were dried over Na2SO4.
Evaporation gave crude compounds (4a–d), which were
used directly for the next reaction without further
purification.
4.3. General procedure for substituted naphtho [1,2-b]
thiophene-4,5-diones (7a–f)
Compound 5a–d (1 mmol) and IBX (1.2 mmol) were added
to dry DMF (5 mL) and then stirred at the room temperature
for 6 h. The reaction mixture was diluted with water
(120 mL), extracted with benzene, washed with saturated
aqueous sodium chloride, dried over Na2SO4, and con-
centrated to 50 mL, N-dienes II or III (1 mmol) was added
and then the mixture was stirred at 45 8C for 16 h. The
solution containing cycloaddition products was added DDQ
(0.75 mmol) and refluxed for further 16 h. Evaporation and
purification by chromatography on silica gel (CHCl3/
MeOH) gave 7a–f in good yields.
Unpurified 3-aryl-5-methoxybenzo[b]thiophenes (4a–d)
were added to mixed solution (40 mL) of 48% HBr and
acetic anhydride (1:1, v/v). The mixture was refluxed at
140 8C for 4 h. The reaction mixture was cooled to room
temperature, neutralized with saturated sodium bicarbonate
solution and extracted with ether. The organic extracts were
washed with saturated aqueous sodium chloride and dried
over anhydrous Na2SO4. Evaporation and purification by
chromatography on silica gel (eluent: EtOAc/Petroleum-II
1:8) gave 3-arylbenzo[b]thiophene-5-ols (5a–d) in moder-
ate to good overall yields.
4.3.1. 7,9-Dimethyl-3-phenyl-6-acetamidonaphtho[1,2-b]
thiophene-4,5-dione (7a). This compound was obtained as
a red solid in 86% yield (eluent: MeOH/CHCl3 1:50). Anal.
Calcd for C22H17NO3S: C, 70.38; H, 4.56; N, 3.73; S, 8.54;
Found: C, 70.35; H, 4.61; N, 3.70; S, 8.49; MS (ESI) m/z:
1
4.2.1. 3-Phenylbenzo[b]thiophene-5-ol (5a). This com-
pound was obtained as a yellow oil in 53% overall yield
(eluent: EtOAc/Petroleum-II 1:8). Anal. Calcd for
C14H10OS: C, 74.31; H, 4.45; S, 14.17; Found: C, 74.27;
374 (MKH)K; H NMR (300 MHz, CDCl3): d 10.0 (br s,
1H), 7.35–7.43 (m, 6H), 7.18 (s, 1H), 2.65 (s, 3H), 2.25
(s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3): d 19.4,
24.2, 24.33, 122.0, 125.0, 127.8, 128.1, 128.7, 129.9, 131.6,
132.9, 134.4, 136.8, 139.6, 142.4, 144.4, 151.5, 168.8,
174.9, 185.4.
1
H, 4.48; S, 14.14; H NMR (300 MHz, CDCl3): d 7.76
(d, 1H, JZ8.7 Hz), 7.55–7.58 (m, 2H), 7.41–7.48 (m, 5H),

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Y.-D. Shen et al. / Tetrahedron 61 (2005) 9097–9101
4.3.2. 7,9-Dimethyl-3-(4-chlorophenyl)-6-acetamido-
naphtho [1,2-b]thiophene-4,5-dione (7b). This compound
was obtained as a red solid in 83% yield (eluent: MeOH/
CHCl3 1:50). Anal. Calcd for C22H16ClNO3S: C, 64.47; H,
3.93; N, 3.42; S, 7.82; Found: C, 64.44; H, 3.96; N, 3.39; S,
28.8, 122.8, 125.0, 128.0, 129.1, 130.1, 131.6, 132.8, 134.0,
138.2, 138.6, 139.3, 142.7, 142.9, 150.9, 169.4, 175.4,
185.8.
1
7.78; MS (ESI) m/z: 408 (MKH)K; H NMR (500 MHz,
Acknowledgements
CDCl3): d 2.25 (s, 3H), 2.26 (s, 3H), 2.68 (s, 3H), 7.20 (s,
1H), 7.36 (s, 4H), 7.40 (s, 1H), 10.03 (br s, 1H); 13C NMR
(125 MHz, CDCl3): d 19.3, 24.1, 24.3, 122.2, 125.2, 127.9,
128.2, 129.9, 130.3, 130.6, 131.7, 133.0, 133.1, 134.3,
137.2, 140.0, 142.7, 143.3, 152.0, 169.0, 175.1, 185.5.
We are indebted to the National Natural Science Foundation
of China (20472117, 20272085), the Guangdong Provincial
Natural Science Foundation, Government Science-Tech-
nology Program Foundation of Guangzhou, and The Hong
Kong Polytechnic University Area of Strategic Develop-
ment Fund for financial support of this study.
4.3.3. 7,9-Dimethyl-3-(4-fluorophenyl)-6-acetamido-
naphtho [1,2-b]thiophene-4,5-dione (7c). This compound
was obtained as a red solid in 85% yield (eluent: MeOH/
CHCl3 1:50). Anal. Calcd for C22H16FNO3S: C, 67.16; H,
4.10; N, 3.56; S, 8.15; Found: C, 67.13; H, 4.14; N, 3.54; S,
1
8.11; MS (ESI) m/z: 392 (MKH)K; H NMR (300 MHz,
References and notes
CDCl3): d 2.24 (s, 3H), 2.25 (s, 3H), 2.67 (s, 3H), 7.06 (t,
2H, JZ8.6 Hz), 7.17 (s, 1H), 7.36–7.41 (m, 3H), 10.01 (br s,
1H); 13C NMR (75 MHz, CDCl3): d 19.4, 24.3, 24.4, 114.9
(d, JZ21.6 Hz), 122.0, 125.0, 129.8, 130.4, 130.6 (d, JZ
7.9 Hz), 131.5, 133.0, 137.0, 139.7, 142.5, 143.3, 151.8,
162.5 (d, JZ247.4 Hz), 168.9, 174.9, 185.4.
1. (a) Zhou, G. Y.; Zhao, B. L.; Hou, J. W.; Ma, G. E.; Xin, W. J.
Pharmacol. Res. 1999, 40, 487–491. (b) Zhou, W.; Ruigrok,
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4.3.4. 7,9-Dimethyl-3-(2-methylphenyl)-6-acetamido-
naphtho [1,2-b]thiophene-4,5-dione (7d). This compound
was obtained as red solid in 80% yield (eluent: MeOH/
CHCl3 1:20). Anal. Calcd for C23H19NO3S: C, 70.93; H,
4.92; N, 3.60; S, 8.23; Found: C, 70.89; H, 4.95; N, 3.57; S,
3. (a) Ryu, S. Y.; Lee, C. O.; Choi, S. U. Planta Med. 1997, 63,
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Z. P.; Lee, C. M.; Sham, H. L.; Wong, N. C. J. Med. Chem.
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1
8.25; MS (ESI) m/z: 388 (MKH)K; H NMR (300 MHz,
CDCl3): d 2.10 (s, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 7.10
(s, 1H), 7.13–7.31 (m, 4H), 7.37 (s, 1H), 9.98 (br s, 1H); 13C
NMR (75 MHz, CDCl3): d 19.7, 20.3, 24.5, 24.6, 122.7,
125.2, 125.6, 128.4, 129.3, 129.9, 130.3, 133.2, 133.3,
135.1, 136.9, 137.2, 140.1, 142.7, 143.7, 151.1, 169.3,
174.5, 185.2.
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Patent no. US005969163A. (b) Carvalho, C. E.M; Ferreira,
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4.3.5.
7,9-Diethyl-3-(4-fluorophenyl)-6-acetamido-
naphtho [1,2-b]thiophene-4,5-dione (7e). This compound
was obtained as a red solid in 78% yield (eluent: MeOH/
CHCl3 1:200). Anal. Calcd for C24H20FNO3S: C, 68.39; H,
4.78; N, 3.32; S, 7.61; Found: C, 68.36; H, 4.82; N, 3.30; S,
1
7.58; MS (ESI) m/z: 420 (MKH)K; H NMR (500 MHz,
CDCl3): d 1.24 (t, 3H, JZ7.5 Hz), 1.42 (t, 3H, JZ7.4 Hz),
2.24 (s, 3H), 2.66 (q, 2H, JZ7.5 Hz), 3.11 (q, 2H, JZ
7.4 Hz), 7.07 (t, 2H, JZ8.7 Hz), 7.16 (s, 1H), 7.40 (dd, 2H,
JZ5.3, 8.7 Hz), 7.48 (s, 1H), 9.81 (br s, 1H); 13C NMR
(125 MHz, CDCl3): d 13.5, 14.3, 24.2, 24.7, 28.8, 114.9
(d, JZ21.7 Hz), 122.9, 124.8, 129.3, 130.6, 130.7 (d, JZ
8.3 Hz), 131.9, 138.4, 138.8, 139.4, 143.0, 143.2, 150.9,
162.7 (d, JZ247.5 Hz), 169.5, 175.7, 186.2.
4.3.6. 7,9-Diethyl-3-(4-chlorophenyl)-6-acetamido-
naphtho [1,2-b]thiophene-4,5-dione (7f). This compound
was obtained as red solid in 80% yield (eluent: MeOH/
CHCl3 1:200). Anal. Calcd for C24H20ClNO3S: C, 65.82; H,
4.60; N, 3.20; S, 7.32; Found: C, 65.78; H, 4.65; N, 3.21; S,
8. (a) Krapcho, A. P.; Petry, M. E.; Hacker, M. P. J. Med. Chem.
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1
7.34; MS (ESI) m/z: 436 (MKH)K; H NMR (300 MHz,
CDCl3): d 1.24 (t, 3H, JZ7.5 Hz), 1.40 (t, 3H, JZ7.4 Hz),
2.23 (s, 3H), 2.64 (q, 2H, JZ7.5 Hz), 3.08 (q, 2H, JZ
7.4 Hz), 7.15 (s, 1H), 7.32 (s, 4H), 7.45 (s, 1H), 9.78 (br s,
1H); 13C NMR (75 MHz, CDCl3): d 13.6, 14.3, 24.3, 24.7,

Y.-D. Shen et al. / Tetrahedron 61 (2005) 9097–9101
9101
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¨
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´
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˚
monoclinic, space group P2(1)/c, aZ17.413(6) A, bZ
˚
˚
16.235(5) A, cZ8.054(3) A, aZ90.008, bZ95.706(6)8, gZ
3
3
˚
90.008, VZ2265.8(13) A , ZZ4, DcZ1.451 g/m , F(000)Z
1016, 1.188!q!27.138, K22%h%22, K20%k%14,
K10%l%10, TZ293 K, colorless red, 0.54!0.42!0.21.
R1Z0.0595 ([IO2s(I)]), 0.1040 (all data), uR2Z0.1817
([IO2s(I)]), 0.2224 (all data). Crystallographic data for the
structures in this paper have been deposited with the
Cambridge crystallographic data centre as supplementary
publication numbers CCDC 267293. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: C44 1223 336033 or
e-mail: eposit@ccdc.cam.ac.uk].
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