Synthesis of benzothiopyrano[2,3-b]indol-11-one and benzopyrano[2,3-b] indol-11-one

Article abstract of DOI:10.1016/j.tet.2003.09.084

The fused heterocycles benzothiopyrano[2,3-b]indol-11-one and benzopyrano[2,3-b]indol-11-one, have been prepared from methyl 3-indole carboxylate in two steps.

Full text of DOI:10.1016/j.tet.2003.09.084

Tetrahedron 59 (2003) 9649–9653
Synthesis of benzothiopyrano[2,3-b]indol-11-one
and benzopyrano[2,3-b]indol-11-one
Robert Engqvista,b and Jan Bergmana,b
,
*
aUnit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park,
SE-141 57 Huddinge, Sweden
¨ ¨
Sodertorn University College, SE-141 04 Huddinge, Sweden
b
Received 16 July 2003; revised 4 September 2003; accepted 25 September 2003
Abstract—The fused heterocycles benzothiopyrano[2,3-b]indol-11-one and benzopyrano[2,3-b]indol-11-one, have been prepared from
methyl 3-indole carboxylate in two steps.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Certain tetracyclic ring systems such as ellipticine (1) are
powerful intercalators of DNA and derivatives of 1 have
been used in cancer chemotherapy.1 Unfortunately 1 is also
very toxic. Therefore considerable efforts have been
invested in attempts to develop active compounds with
reduced toxicity. In this context we are interested in
tetracyclic heterocycles containing indole cores such as
indolo[2,3-b]quinoxaline (2). Unfortunately derivatives of 2
were inactive against most types of cancer except against
Burkitt’s lymfoma. Because of its viral relationship several
derivatives of 2 were tested on a number of virus. In these
tests e.g. the derivative 3 showed high activities against
HSV-1, CMV and VZV. In contrast to 1 derivatives of 2
have low toxicity2 (Fig. 1).
Quinolino[2,3-b] indol-11-one (4) has recently been pre-
pared for the first time,3 whereas its angular isomer 5 has
been known for a long time and a large number of syntheses
are known4 (Fig. 2).
Figure 2.
The synthesis of 4 available is out-lined in Scheme 1.3 The
crucial intermediate 7 was generated from 6 and N-chloro-
succinimide (NCS) in the presence of N,N-dimethylpi-
perazine and (without isolation) reacted with aniline giving
the corresponding 2,3-disubstituted indole, which were
subsequently easily cyclized to 4 in hot diphenyl ether in a
high yield (Scheme 1).
By using thiophenol and phenol as partners to 7 it is possible
to introduce sulfur and oxygen functionalities in the
2-position of the indole, thus yielding 8a and 8b,
respectively. Unfortunately, diphenyl disulfide was formed
as a side product in the reaction with thiophenol decreasing
the yield of 8a. Attempts to increase the yield by additional
equivalents of thiophenol failed. However, 8a could be
made in 69% yield by reacting 6 with phenylsulfenyl
chloride (9). This was done easily by adding sulfuryl
chloride to a mixture of diphenyl disulfide and 6 in
chloroform, thereby generating the sulfenyl chloride 9 in
situ. A plausible mechanism is that 9 reacts at the 3-position
Figure 1.
Keywords: indoles; benzopyranones; benzothiopyranones.
*
Corresponding author. Tel.: þ46-8-6089204; fax: þ46-8-6081501;
e-mail: jabe@cnt.ki.se
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.084

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R. Engqvist, J. Bergman / Tetrahedron 59 (2003) 9649–9653
Scheme 1. (a) NCS, 1,4-dimethylpiperazine, CH2Cl2, 08C, 2 h. (b) Trichloroacetic acid, aniline, room temperature, 2 h. (c) Diphenyl ether, reflux, 30 min to 3 h
30 min.
Scheme 2. (a)
(9), CHCl3, room temperature, 3 h 30 min.
of 6 and thereafter migrates to the 2-position (Scheme 2).
Hamel has discussed similar mechanisms in the formation
of 2,3-bisphenylthioindoles from 3-phenylthioindole.5
was prepared in good yield, but the cyclization in PPA at
1608C gave a mixture of benzothiopyrano[3,2-b]indol-11-
one (12) and ethyl indole-2-carboxylate. When the reaction
was performed at 2058C only 12 was obtained in a moderate
yield (27%) (Scheme 4).
It was not possible to cyclize either 8a, or 8b by heating in
diphenyl ether as it was in the case of 4 (Scheme 1). Instead
compounds 8a–b were cyclized in hot polyphosphoric acid
(PPA) to benzothiopyrano[2,3-b]indol-11-one (10a) and
benzopyrano[2,3-b]indol-11-one (10b) in good yields
(Scheme 3).
Compound 10a has been described in the literature and was
first synthesized by Hamel from indole and o-carbomethox-
ybenzenesulfenyl chloride in three steps giving a mixture of
10a and 12.6 We have recently shown that a molecule
originally published as having the linear structure 4, is in
fact the angular isomer 5,3 which was prepared as outlined
In a similar manner to 8a, the 2,3-disubstituted indole 11
Scheme 3. (a) (i) NCS, N,N-dimethylpiperazine, CH2Cl2, 08C, 2 h; (ii) trichloroacetic acid, phenol or thiophenol, 258C, 2–2.5 h; (b) diphenyl disulfide,
SO2Cl2, 0–258C, 4 h; (c) PPA, 1608C, 2 h.
Scheme 4. (a) 9, CHCl3, room temperature, 2 h; (b) PPA, 2058C, 1 h.

R. Engqvist, J. Bergman / Tetrahedron 59 (2003) 9649–9653
9651
Scheme 5. (a) HCl, methanol, reflux, 15 h.8
in Scheme 5. The corresponding chromone derivative was
similarly prepared and assigned a linear structure 10b by
Eiden et al.,7,8 which has now also been shown to be
incorrect. As indicated in Scheme 5, ring opening of the
intermediate, probably after protonation of the anilinic
nitrogen atom in the tetrahedral intermediate, takes
preference over elimination of water.
angular products 5 and 13, respectively. In contrast,
cyclization of the thiol 16 mainly gave the linear isomer
(10a).8 Only traces of the angular isomer (17) could be
detected (Scheme 7). This may occur because the C–S
bondlength is longer than both the C–N and the C–O and
hence would favour elimination of water from the
tetrahedral intermediate because of the more flexible ring.
The angular regioisomeric product (13) obtained from 3-(2-
hydroxybenzoyl)-oxindole according to Scheme 5 is in fact
identical with a product previously prepared by Stadlbauer
and Kappe from 4-amino-3-phenylbenzopyran-2-one.4c–e
The angular isomer could also be prepared from 2-(2-
hydroxyphenyl)indole and triphosgene, a reaction that also
yielded the isomer 14 as a minor product (Scheme 6). Base-
induced cyclization of 15a and 15b invariably produced the
In summary, the 2,3-disubstituted indoles 8a–b were
readily formed from methyl indole-3-carboxylate and
subsequently easily cyclized in hot PPA to benzothiopyrano-
[2,3-b]indol-11-one (10a) and benzopyrano[2,3-b]indol-11-
one (10b), respectively. We could thereby conclude that
the molecule previously reported7,8 as benzopyrano[2,3-b]-
indol-11-one is in fact the angular regioisomeric structure
i.e. benzopyrano[3,2-c]indol-6-one (13).
Scheme 6. (a) Triphosgene, acetic acid, reflux, 1 h.
Scheme 7. (a) HCl, methanol, reflux, 15 h.8

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R. Engqvist, J. Bergman / Tetrahedron 59 (2003) 9649–9653
3. Experimental
mixture was washed with aq. NaHCO3 (10%), aq. HCl
(1 M) and water. The organic layer was dried with MgSO4.
The product was isolated as a white solid by chromato-
graphy (20% ethyl acetate in n-hexane). Yield: 1.67 g
(52%). Mp: 161–1628C; IR nmax: 3196, 1679, 1666, 1473,
1371, 1211, 1095, 736; 1H NMR d: 12.27 (1H, s, NH), 8.00
(1H, m, ArH), 7.42–7.34 (3H, m, ArH), 7.21–7.05 (5H, m,
ArH), 3.68 (3H, s, OCH3); 13C NMR d: 163.4 (s), 156.9 (s),
151.3 (s), 130.7 (s), 130.0 (d, 2C), 125.3 (s), 123.7 (d), 122.1
(d), 121.5 (d), 120.4 (d), 116.6 (d, 2C), 111.6 (d), 91.7 (s),
50.4 (t). Anal. calcd for C16H13NO3 C, 71.90; H, 4.90; N,
5.24. Found C, 72.06; H, 4.88; N, 5.20.
3.1. General
NMR spectra were recorded in DMSO-d6 solutions at room
temperature and using the signal from DMSO-d6 (1H:
d¼2.50 ppm; 13C: d¼39.5 ppm) as internal standard, on a
Bruker DPX 300 (300 MHz) spectrometer. J values are
given in Hz and d values are given in ppm. IR spectra are
recorded on a Perkin–Elmer 1600 FTIR. Melting points
were taken on a Bu¨chi Melting Point B-545 apparatus and
are uncorrected. Chromatography was performed on Merck
silica gel 60, TLC analyses were run on Merck silica gel
F254 plates. The elemental analyses were performed by
H. Kolbe Mikroanalytisches Laboratorium, Mu¨lheim an der
Ruhr, Germany. Solvents were of analytical grade and were
used as received.
3.1.3. Ethyl 3-phenylthio indole-2-carboxylate (11).
Sulfuryl chloride (0.68 g; 5.0 mmol) was added to a solution
diphenyl disulfide (1.10 g; 5.0 mmol) in chloroform
(10 mL) at 08C under argon and the reaction was stirred at
room temperature for 30 min. This solution was added to
ethyl indole-2-carboxylate (0.94 g; 5.0 mmol) in chloro-
form (10 mL) at 08C and the reaction mixture was stirred in
room temperature for 2 h 30 min. The reaction mixture was
washed aq. NaHCO3 (sat.) and water. The organic layer was
dried with MgSO4. The product was isolated by chroma-
tography (10% acetone in n-hexane). Yield: 0.98 g (66%).
Mp: 135–1368C [Lit.,9 mp: 1358C]; The spectral data were
in agreement with those published.9
3.1.1. Methyl 2-phenylthio indole-3-carboxylate (8a).
Method A. A suspension of methyl indole-3-carboxylate
(0.52 g; 3.0 mmol) in dichloromethane (20 mL) was cooled
to 08C under argon and treated sequentially with N,N-di-
methylpiperazine (0.23 g; 2.0 mmol) and N-chlorosuccini-
mide (0.44 g; 3.3 mmol) in one portion. The resulting
solution was stirred for 2 h at 08C whereupon a solution
of thiophenol (0.70 g; 6.4 mmol) and trichloroacetic acid
(0.12 g; 0.73 mmol) in dichloromethane (10 mL) was added
and the solution stirred at room temperature for 2.5 h. The
reaction mixture was washed with aq. NaHCO3 (10%), aq.
HCl (1 M) and water. The organic layer was dried with
MgSO4. The product was isolated by chromatography (20%
ethyl acetate in n-hexane). Yield: 0.31 g (37%).
3.1.4. Benzothiopyrano[2,3-b]indol-11-one (10a). Com-
pound 8a (0.100 g; 0.35 mmol) was heated in PPA (1 g) at
1608C for 2 h. The reaction mixture was allowed to cool to
808C and water (80 mL) was added. The solid thus formed
was isolated by filtration, washed with water and dried.
The product was purified by chromatography with 40%
acetone in n-hexane giving 10a as a white solid. Yield:
65 mg (73%). Mp: 330–3378C (decomp.) [Lit.,6 mp:
.3008C]; The spectral data were in agreement with those
published.6
Method B. Sulfuryl chloride (0.71 g; 5.25 mmol) was added
to a solution of methyl indole-3-carboxylate (0.88 g;
5 mmol) and diphenyl disulfide (1.10 g; 5 mmol) in dry
chloroform (25 mL) at 08C under argon. The solution was
stirred at 08C for 30 min and thereafter at room temperature
for 3.5 h. The reaction mixture was washed with aq.
NaHCO3 (10%) and brine. The organic layer was dried
with MgSO4. The product was isolated as a white solid by
chromatography (15% ethyl acetate in n-hexane). Yield:
0.98 g (69%).
3.1.5. Benzopyrano[2,3-b]indol-11-one (10b). Compound
8b (0.200 g; 0.75 mmol) was heated in PPA (2 g) at 1608C
for 2 h. The reaction mixture was allowed to cool to 808C
and water (80 mL) was added. The solid thus formed was
isolated by filtration, washed with water and dried. The
product was purified by chromatography with 40% acetone
in n-hexane giving 10b as a white solid. Yield: 147 mg
(84%). Mp: 344–3498C (decomp.); IR nmax: 3018, 2740,
1624, 1604, 1519, 1198, 749; 1H NMR d: 12.87 (1H, s, NH),
8.25 (1H, dd, 7.8, 1.4, ArH), 8.11 (1H, m, ArH), 7.80–7.70
(2H, m, ArH), 7.55–7.48 (2H, m, ArH), 7.34–7.28 (2H, m,
ArH); 13C NMR d: 171.6 (s), 155.8 (s), 153.5 (s), 132.8 (d),
131.9 (s), 125.6 (d), 125.0 (d), 123.6 (d), 123.5 (s), 122.0
(d), 121.9 (s), 120.4 (d), 117.7 (d), 111.8 (d), 98.8 (s). Anal.
calcd for C15H9NO2 C, 76.59; H, 3.86; N, 5.95. Found C,
76.69; H, 3.88; N, 5.92.
Mp: 133–1348C; IR nmax: 3280, 1667, 1496, 1465, 1439,
1194, 1067, 750; 1H NMR d: 11.58 (1H, s, NH), 7.92 (1H, m,
ArH), 7.47–7.34 (6H, m, ArH), 7.18–7.14 (2H, m, ArH),
3.83 (3H, s, OCH3); 13C NMR d: 164.3 (s), 137.9 (s), 136.5
(s), 131.7 (d, 2C), 131.5 (s), 129.9 (d, 2C), 128.5 (d), 126.5
(s), 122.5 (d), 121.5 (d), 120.2 (d), 111.7 (d), 105.9 (s), 50.8
(t). Anal. calcd for C16H13NO2S C, 67.82; H, 4.62; N, 4.94.
Found C, 67.94; H, 4.55; N, 4.83.
3.1.2. Methyl 2-phenoxy indole-3-carboxylate (8b). A
suspension of methyl indole-3-carboxylate (2.08 g;
11.9 mmol) in dichloromethane (50 mL) was cooled to
08C under argon and treated sequentially with N,N-di-
methylpiperazine (0.75 g; 6.6 mmol) and N-chlorosuccini-
mide (1.75 g; 13.1 mmol) in one portion. The resulting
solution was stirred for 2 h at 08C and then a solution of
phenol (2.30 g; 24.5 mmol) and trichloroacetic acid (0.50 g;
3.1 mmol) in dichloromethane (50 mL) was added and the
solution stirred at room temperature for 2 h. The reaction
3.1.6. Benzothiopyrano[3,2-b]indol-11-one (12). Ethyl
3-thiophenyl indole-2-carboxylate (0.150 g; 0.505 mmol)
was heated in PPA (1.5 g) at 2058C for 50 min. The reaction
mixture was allowed to cool to room temperature and water
was added. The solid thus formed was isolated by filtration,
washed with water and dried. The blackish solid was
purified by sublimation (2008C, 0.35 mbar) to give a white
solid. Yield: 34 mg (27%). Mp: 300–3258C (decomp.)

R. Engqvist, J. Bergman / Tetrahedron 59 (2003) 9649–9653
9653
[Lit.,6 mp: .3008C]; The spectral data were in agreement
with those published.6
˚
2. (a) Harmenberg, J.; Wahren, B.; Bergman, J.; Akerfeldt, S.;
Lundblad, L. Antimicrob. Agents Chemother. 1988, 32, 1720.
˚
(b) Harmenberg, J.; Akesson-Johansson, A.; Graslund, A.;
¨
˚
Malmfors, T.; Bergman, J.; Wahren, B.; Akerfeldt, S.;
Lundblad, L.; Cox, S. Antivir. Res. 1991, 15, 193.
3.1.7. Reaction of 2-(2-hydroxyphenyl)indole and tri-
phosgene. Triphosgene (0.99 g; 3.33 mmol) was added to a
solution of 2-(2-hydroxyphenyl) indole9 in acetic acid
(10 mL). The reaction mixture was heated to reflux for 1 h
and thereafter filtrated while it was hot and washed with
acetic acid and ethanol to give benzopyrano[4,3-b]indol-6-
one (10b). Yield: 0.55 g (46%). Mp: .3608C [Lit.,4e mp:
3158C]; The spectral data were in agreement with those
published.4e
˚
3. Bergman, J.; Engqvist, R.; Stalhandske, C.; Wallberg, H.
Tetrahedron 2003, 59, 1033.
4. (a) Dave, V.; Warnhoff, E. W. Tetrahedron 1975, 31, 1255.
(b) Winterfeldt, E.; Altmann, H. J. Angew. Chem. 1968, 80, 486.
(c) Stadlbauer, W.; Karem, A.-S.; Kappe, T. Monatsh. Chem.
1984, 115, 467. (d) Stadlbauer, W.; Karem, A.-S.; Kappe, T.
Monatsh. Chem. 1986, 117, 1305. (e) Stadlbauer, W.; Karem,
A.-S.; Kappe, T. Monatsh. Chem. 1987, 118, 81. (f) De
Diesbach, H. Helv. Chim. Acta 1951, 34, 1050.
5. Hamel, P. J. Org. Chem. 2002, 67, 2854.
The mother liquor was poured into water and the solid thus
formed was isolated by filtration and washed with water
to give 14. An analytical sample was recrystallized from
6. Hamel, P.; Girard, M.; Tsou, N. N. J. Heterocycl. Chem. 1999,
36, 643.
2-propanol. Yield: 0.42 g (36%). Mp: 153–1548C; IR nmax
:
7. (a) Eiden, F.; Dobinsky, H. 1970, German Patent 2,037,047.
(b) Eiden, F.; Dobinsky, H. Justus Liebigs Ann. Chem. 1970,
365.
1756, 1468, 1447, 1354, 1340, 1216, 1202, 1132, 997, 748;
1H NMR d: 8.34 (1H, m, ArH), 8.14 (1H, m, ArH), 7.77
(1H, m, ArH), 7.53–7.40 (6H, m, ArH); 13C NMR d: 148.1
(s), 143.5 (s), 133.7 (s), 132.1 (s), 130.2 (d), 130.0 (s), 125.5
(d), 124.5 (d), 124.5 (d), 123.8 (d), 120.9 (d), 116.5 (d),
115.0 (d), 113.9 (s), 101.0 (d); Anal. calcd for C15H9NO2 C,
76.59; H, 3.86; N, 5.95. Found C, 76.68; H, 3.77; N, 5.83.
8. Eiden, F.; Dobinsky, H. Justus Liebigs Ann. Chem. 1974, 1981.
9. Gairns, R. S.; Moody, C. J.; Rees, C. W.; Tsoi, S. C. J. Chem.
Soc., Perkin Trans. 1 1986, 3, 497.
References
1. (a) Gribble, G. W. The Alkaloids 1990, 39, 239. (b) Potier, P.
Chem. Soc. Rev. 1992, 113.