Concise route to 4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylates

Article abstract of DOI:10.3987/COM-05-10545

Reactions of 3-acyl-1,2-naphthoquinones with ethyl mercaptoacetate followed by protection of the resulting hydroxyl groups and thiophene ring formation using 1-trimethylsilylimidazole, deprotection with hydrochloric acid, and oxidation with cerium(IV) amm

Full text of DOI:10.3987/COM-05-10545

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Received, 24th August, 2005, Accepted, 26th September, 2005, Published online, 27th September, 2005
CONCISE
ROUTE
TO
4,5-DIOXO-4,5-DIHYDRONAPHTHO[1,2-
b]THIOPHENE-2-CARBOXYLATES
Kazuhiro Kobayashi,* Satoshi Yamane, Kazuna Miyamoto, Osamu Morikawa, and
Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University,
Koyama-minami, Tottori 680-8552, Japan
Abstract- Reactions of 3-acyl-1,2-naphthoquinones with ethyl mercaptoacetate
followed by protection of the resulting hydroxyl groups and thiophene ring
formation using 1-trimethylsilylimidazole, deprotection with hydrochloric acid,
and oxidation with cerium(IV) ammonium nitrate (CAN) gave, in one-pot, the title
thienonaphthoquinone derivatives in moderate to good yields.
In continuation of our interest in the development of simple and general methods for the preparation of
heterocycle-fused quinone derivatives,1 we recently reported a one-pot synthesis of 4,7-dioxo-4,7-
dihydrobenzo[b]thiophene-2-carboxylates
and
4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophene-2-
carboxylates from 2-acyl-1,4-quinones and mercaptoacetates, via 1-trimethylsilylimidazole-induced
thiophene ring formation.2a We also reported a one-pot synthesis of 4,8-dioxo-4,8-dihydrobenz[1,2-b:5,4-
b’]dithiophene-2,6-dicarboxylates as an extension of this thiophene ring formation. 2b In this paper we
reports a further attempt to extend this method to a new synthesis of 4,5-dioxo-4,5-dihydronaphtho[1,2-
b]thiophene-2-carboxylates (4) starting from readily available 3-acyl-1,2-naphthoquinones (1). Although
a number of synthetic methods of naphtho[1,2-b]thiophenes have been devised,3 there are few reports on
the synthesis of naphtho[1,2-b]thiophene-4,5-dione derivatives,4 which are of interest from a biological
point of view, because some naphtho[2,3-b]thiophene-4,9-dione derivatives have been reported to exhibit
biological activities.5
Our synthesis was conducted as illustrated in the Scheme. Thus, reactions of 3-acyl-1,2-naphthoquinones
(1) with ethyl mercaptoacetate in THF at room temperature gave 4-sulfenylated hydroquinones (2). After
removal of THF, protection of hydroxyl groups of these hydroquinones (2) and thiophene ring formation
were accomplished by treating with 5 molar amounts of 1-trimethylsilylimidazole at 90 ˚C to lead to
naphthothiophenes (3). After cooling to 0 ˚C, deprotection with hydrochloric acid followed by CAN
oxidation gave rise to the expected naphtho[1,2-b]thiophene-4,5-diones (4). These one-pot syntheses were
achieved generally in good yields as depicted in the Scheme. The use of 3-(2-methylpropanoyl)-1,2-

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HETEROCYCLES, Vol. 65, No. 12, 2005
O H
O H
O
OTMS
OTMS
O
R
HSCH C O Et
2
1-TMS-imidazole
90 ˚C
2
O
O
THF, rt
R
EtOCOCH S
2
R
S
1
2
C O Et
2
3
a R = Me
b R = Et
c R = n-Pr
d R = i-Pr
e R = n-Bu
f R = n-Pent
g R = n-Hex
h R = c-Hex
O
4a 76%
4b 73%
4c 70%
4d 41%
4e 66%
4f 62%
4g 59%
4h 44%
O
aq. HCl, 0 ˚C
CAN, MeCN
R
S
C O Et
2
naphthoquinone (1d) and 3-cyclohexanecarbonyl-1,2-naphthoquinone (1h) somewhat diminished the
yields of the corresponding desired products (4d and 4h), probably due to their bulky substituents.
The method appears to be considerably general. Unfortunately, however, 4,5-dioxo-4,5-
dihydronaphtho[1,2-b]thiophene-2-carboxylates carrying an aromatic substituent at the 3-positions cannot
be obtained, because the photoacylation of 1,2-naphthoquinone with aromatic aldehydes, such as
benzaldehyde or 4-methylbenzaldehyde, did not gave the desired benzoylated hydroquinones.
In summary, we have shown that 4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylates can be
obtained in one-pot from readily available starting materials. The method may be of value in heterocyclic
quinone synthesis.
EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are
uncorrected. IR spectra were determined with a Perkin-Elmer 1600 Series FT IR spectrophotometer as
1
KBr disk. The H NMR spectra were determined in CDCl3 using TMS as an internal reference with a
JEOL JNM-GX270 FT NMR spectrometer operating at 270 MHz. J values are given in Hz. Low-
resolution MS spectra were measured by a JEOL AUTOMASS 20 spectrometer (Center for Joint
Research and Development, this University). TLC was carried out on a Merck Kieselgel 60 PF254. All of
the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. 3-Acyl-1,2-naphthoquinones (1)6b were prepared by reductive photoacylation of 1,2-
naphthoquinone with aldehydes by the method of Takuwa et al.,6b followed by oxidation of the resulting
3-acyl-1,2-naphthalenediol6 with Ag2O7 (almost quantitative). Data for new products are as follows. 3-(2-
Methylpropanoyl)-1,2-naphthoquinone (1d): a red solid; mp 102–106 ˚C (decomp) (benzene–hexane);
νmax/cm–1 1708, 1682; δH 1.15 (6H, d, J 6.9), 3.59 (1H, septet, J 6.9), 7.56 (1H, d, J 7.6), 7.62 (1H, td, J

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7.6, 1.3), 7.73 (1H, td, J 7.6, 1.3), 8.11 (1H, s), 8.14 (1H, dd, J = 7.6 and 1.3 Hz). Anal. Calcd for
C14H12O3: C, 73.67; H, 5.30. Found; C, 73.57; H, 5.30. 3-Hexanoyl-1,2-naphthoquinone (1f): a red solid;
mp 108–112 ˚C (decomp) (benzene–hexane); νmax/cm–1 1695, 1675; δH 0.90 (3H, t, J 6.9), 1.3–1.4 (4H, m),
1.55–1.75 (2H, m), 3.00 (2H, t, J 7.3), 7.57 (1H, dd, J 7.6, 1.3), 7.62 (1H, td, J 7.6, 1.3), 7.73 (1H, td, J
7.6, 1.3), 8.14 (1H, dd, J 7.6, 1.3), 8.16 (1H, s). Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found; C,
74.94; H, 6.39. 3-Heptanoyl-1,2-naphthoquinone (1g): a red solid; mp 103–108 ˚C (decomp)
(benzene–hexane); νmax/cm–1 1682, 1652; δH 0.89 (3H, t, J 6.6), 1.3–1.45 (6H, m), 1.6–1.7 (2H, m), 3.00
(2H, t, J 7.3), 7.57 (1H, d, J 7.6), 7.62 (1H, td, J 7.6, 1.3), 7.73 (1H, td, J 7.6, 1.3), 8.15 (1H, d, J 7.6),
8.17 (1H, s). Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found; C, 75.51; H, 6.79. (Cyclohexyl)(1,2-
dihydroxynaphthalen-3-yl)methanone: 33%; a yellow solid; mp 189–193 ˚C (decomp) (hexane); νmax/cm–1
3481, 1651; δH 1.2–1.7 (6H, m), 1.75–2.0 (4H, m), 3.45–3.6 (1H, m), 6.05 (1H, s), 7.36 (1H, ddd, J 8.2,
7.9, 1.3), 7.54 (1H, ddd, J 8.2, 7.9, 1.3), 7.81 (1H, d, J 8.2), 7.98 (1H, s), 8.10 (1H, dd, J 8.2, 1.3), 11.90
(1H, s). Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found; C, 75.50; H, 6.74. 3-Cyclohexanecarbonyl-
1,2-naphthoquinone (1h): a red solid; mp 110–113 ˚C (decomp) (benzene–hexane); νmax/cm–1 1682, 1673,
1659; δH 0.95–1.45 (6H, m), 1.5–1.95 (4H, m), 3.3–3.4 (1H, m), 7.54 (1H, d, J 7.6), 7.61 (1H, td, J 7.6,
1.3), 7.72 (1H, td, J 7.6, 1.3), 8.08 (1H, s), 8.14 (1H, d, J 7.6). Anal. Calcd for C17H16O3: C, 76.10; H, 6.01.
Found; C, 76.07; H, 6.24.
Ethyl
3-Methyl-4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate
(4a).
Typical
Procedure for the Preparation of Thienonaphthoquinones (4). To a stirred solution of 3-acetyl-1,2-
naphthoquinone (1a) (0.12 g, 0.61 mmol) in THF (1.8 mL) under argon was added ethyl mercaptoacetate
(73 mg, 0.61 mmol); the mixture was stirred for 1 h at rt. After removal of THF under reduced pressure,
1-trimethylsilylimidazole (0.43 g, 3.1 mmol) was added to the residue. The mixture was then heated at 90
˚C for 2 h under stirring. The cooled resulting mixture was dissolved in acetonitrile (2.6 mL) and 10%
hydrochloric acid (1.3 mL) was added to this solution at 0 ˚C. After this solution was stirred for 1 h at the
same temperature, a solution of CAN (0.67 g, 1.2 mmol) in water (2.6 mL) was added. The orange-red
precipitate appeared immediately and it was collected by suction and recrystallized from hexane-CHCl3 to
give 4a (0.46 g, 76%) as red needles; mp 258–261 ˚C; νmax/cm–1 1707, 1665, 1652; δH 1.42 (3H, t, J 7.3),
2.88 (3H, s), 4.40 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.6–7.7 (2H, m), 8.12 (1H, d, J 7.9); MS m/z 300 (M+,
100). Anal. Calcd for C16H12O4S: C, 63.99; H, 4.03; S, 10.68. Found: C, 63.88; H, 4.19; S, 10.46.
Ethyl 3-Ethyl-4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4b): red needles; mp
203–205 ˚C (hexane–CHCl3); νmax/cm–1 1712, 1667, 1652; δH 1.23 (3H, t, J 7.3), 1.42 (3H, t, J 7.3), 3.42
(2H, q, J 7.3), 4.40 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.6–7.7 (2H, m), 8.12 (1H, d, J 7.9); MS m/z 314
(M+, 100). Anal. Calcd for C17H14O4S: C, 64.95; H, 4.49; S, 10.20. Found: C, 64.66; H, 4.39; S, 10.36.
Ethyl 4,5-Dioxo-3-propyl-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4c): orange needles;
mp 166–167 ˚C (hexane–CHCl3); νmax/cm–1 1716, 1674, 1655; δH 1.03 (3H, t, J 7.3), 1.42 (3H, t, J 7.3),

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1.60 (2H, sextet, J 7.3), 3.37 (2H, t, J 7.3), 4.39 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.65–7.7 (2H, m), 8.12
(1H, d, J 7.9); MS m/z 328 (M+, 100). Anal. Calcd for C18H16O4S: C, 65.84; H, 4.91; S, 9.76. Found: C,
65.59; H, 5.00; S, 9.72.
Ethyl 3-(1-Methylethyl)-4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4d): orange
needles; mp 194–197 ˚C (hexane–CHCl3); νmax/cm–1 1716, 1679, 1650; δH 1.38 (6H, d, J 7.3), 1.42 (3H, t,
J 7.3), 4.39 (2H, q, J 7.3), 4.50 (1H, septet, J 7.3), 7.45–7.55 (1H, m), 7.6–7.7 (2H, m), 8.12 (1H, d, J
7.3); MS m/z 328 (M+, 31), 282 (100). Anal. Calcd for C18H16O4S: C, 65.84; H, 4.91; S, 9.76. Found: C,
65.74; H, 5.00; S, 9.52.
Ethyl 3-Butyl-4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4e): orange needles; mp
169–170 ˚C (hexane–CHCl3); νmax/cm–1 1713, 1668, 1652; δH 0.96 (3H, t, J 7.3), 1.42 (3H, t, J 7.3),
1.45–1.65 (4H, m), 3.39 (2H, t, J 6.9), 4.40 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.6–7.7 (2H, m), 8.12 (1H,
d, J 7.6); MS m/z 342 (M+, 100). Anal. Calcd for C19H18O4S: C, 66.65; H, 5.30; S, 9.36. Found: C, 66.49;
H, 5.31; S, 9.32.
Ethyl 4,5-Dioxo-3-pentyl-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4f): orange needles;
mp 150–152 ˚C (hexane–CHCl3); νmax/cm–1 1712, 1673, 1652; δH 0.91 (3H, t, J 7.3), 1.35–1.6 (8H, m),
3.38 (3H, t, J 7.6), 4.40 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.65–7.7 (2H, m), 8.12 (1H, d, J 7.6); MS m/z
356 (M+, 93), 273 (100). Anal. Calcd for C20H20O4S: C, 67.39; H, 5.66; S, 9.00. Found: C, 67.21; H, 5.67;
S, 8.91.
Ethyl 3-Hexyl-4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4g): orange needles; mp
133–135 ˚C (hexane–CHCl3); νmax/cm–1 1716, 1674, 1652; δH 0.89 (3H, t, J 6.9), 1.3-1.65 [11H, m
including t (J 7.3) at 1.42], 3.38 (2H, t, J 7.3), 4.40 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.65–7.7 (2H, m),
8.12 (1H, dd, J 7.6, 1.0); MS m/z 370 (M+, 76), 273 (100). Anal. Calcd for C21H22O4S: C, 68.08; H, 5.99;
S, 8.66. Found: C, 67.83; H, 6.12; S, 8.62.
Ethyl 3-Cyclohexyl-4,5-dioxo-4,5-dihydronaphtho[1,2-b]thiophene-2-carboxylate (4h): orange
needles; mp 161–164 ˚C (hexane–CHCl3); νmax/cm–1 1711, 1674, 1646; δH 1.25–1.85 [13H, m including t
(J 7.3) at 1.43], 2.15–2.2 (1H, m), 4.39 (2H, q, J 7.3), 7.45–7.55 (1H, m), 7.65–7.7 (2H, m), 8.11 (1H, d, J
7.9); MS m/z 368 (M+, 100). Anal. Calcd for C21H20O4S: C, 68.46; H, 5.47; S, 8.70. Found: C, 68.38; H,
5.67; S, 8.48.
ACKNOWLEDGEMENTS
We thank Mrs. Miyuki Tanmatsu of this Department for her assistance in determining the mass spectra
and performing combustion analyses. This research was partially supported by a Grand-in-Aid for
Scientific Research (C) 15550092 from Japan Society for the Promotion of Science.
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