Reactions of 2-lithiated indoles with elemental sulfur. Formation of pentathiepino[6,7-b]indoles and indoline-2-thiones

Article abstract of DOI:10.1016/S0040-4020(01)00660-3

The reactions of 2-lithiated indole and 1-methylindole with elemental sulfur have been studied, leading e.g. to a rational approach to pentathiepino[6,7-b]indoles 5 and 10. Notable amounts of the previously known tetrathiocino[5,6-b:8,7-b′]diindole 11 could be observed as a side reaction in the preparation of 10. Treatment of the anions of indoline-2-thiones 6 or 7 with sulfur also gave the pentathiepins 5 or 10, respectively. In addition, a convenient and clean lithiation route to indoline-2-thione (6) has been developed.

Full text of DOI:10.1016/S0040-4020(01)00660-3

TETRAHEDRON
Pergamon
Tetrahedron 57 ꢀ2001) 7185±7189
Reactions of 2-lithiated indoles with elemental sulfur. Formation
of pentathiepino[6,7-b]indoles and indoline-2-thiones
a,p b,c
Gordon W. Rewcastle, Tomasz Janosik and Jan Bergman
b,c,p
a
Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019,
Auckland, New Zealand
b
Unit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park,
SE-141 57 Huddinge, Sweden
c
S oÈ dert oÈ rn University College, SE-141 04 Huddinge, Sweden
Received 20 April 2001;accepted 14 June 2001
AbstractÐThe reactions of 2-lithiated indole and 1-methylindole with elemental sulfur have been studied, leading e.g. to a rational
0
approach to pentathiepino[6,7-b]indoles 5 and 10. Notable amounts of the previously known tetrathiocino[5,6-b:8,7-b ]diindole 11 could
be observed as a side reaction in the preparation of 10. Treatment of the anions of indoline-2-thiones 6 or 7 with sulfur also gave the
pentathiepins 5 or 10, respectively. In addition, a convenient and clean lithiation route to indoline-2-thione ꢀ6) has been developed. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
S S
S
S
S
H C
3
S
S
S
S
S
X
Y
Several dopamine derived pentathiepins have been isolated
from Lissoclinum tunicates, such as varacin ꢀ1), which was
demonstrated to possess cytotoxic activity against the
NH2
1
1
2
X = Y = OCH3
X = OH, Y = OCH3
3
human colon cancer HCT 116. Likewise, the related
marine compound lissoclinotoxin A ꢀ2), isolated from
Lissoclinum perforatum in 1991, was ascribed antifungal
and antimicrobial activities, but was not assigned a correct
2
3
S
structure until several years later. Additional biologically
S
S
S
S
S
S
S
active metabolites belonging to this class have been isolated
from the Palauan ascidian Lissoclinum japonicum, other
unidenti®ed Lissoclinum species, and also from a Polycitor
NC
S
S
N
S
N
H
4
or a Eudistoma species. These natural products have
attracted considerable interest, in particular varacin ꢀ1) for
which several total syntheses have been developed.
4
5
5
1
1
Interestingly, numerous synthetic pentathiepins have been
known for some time, e.g. 3 which was shown to induce
2-Thioindole derivatives
have, for example, been
demonstrated as useful intermediates in the synthesis of
6
DNA cleavage, and 4 which displays a wide range of anti-
0
12
2,2 -dithiobisindole tyrosine kinase inhibitors. Indoline-
2-thiones 6 and 7 are available via the reaction of the
corresponding oxindoles with P S10 in re¯uxing benzene
4
or xylene, a procedure which works well for the prepara-
tion of 7, however in the case of the parent indoline-2-thione
6, the yield is considerably lower and the product obtained
requires time-consuming puri®cation. Compound 8 has
recently been used as the starting material for the prepara-
tion of the cruciferous phytoalexin sinalexin. Thionation
of amides has also been effected using in situ reagents
prepared from P4S10 and sodium carbonate in THF,
however at that time the method was not applied for the
preparation of indoline-2-thiones.
7
fungal activity. A considerable number of synthetic efforts
7
aiming at non natural pentathiepins as well as acyclic
,8
9
pentasul®des have been reported. In our laboratory,
work in this area has previously resulted in isolation of
13
6
reaction of isatin with P S in re¯uxing pyridine, as well as
H-pentathiepino[6,7-b]indole ꢀ5) in a low yield from the
4
10
a rigorous determination of the structure by X-ray crystal-
lography.
1
0
14
1
5
Keywords: lithiated indole;indole-2-thiones;pentathiepins.
Corresponding authors. Tel.: 146-8-608-9204;fax: 146-8-711-68-69;
e-mail: jabe@cnt.ki.se
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020ꢀ01)00660-3

7186
G. W. Rewcastle et al. / Tetrahedron 57 ꢀ2001) 7185±7189
i
S
S
N
1
0 (13%)
11 (19%)
N
R
CH3
7
6
7
8
R = H
R = CH3
R = OCH3
8
Scheme 3. Reagents and conditions: ꢀi) NaH, THF, rt;then S , 08C.
Although 1-methylindoline-2-thione ꢀ7) was not isolated
from the lithiation and the reaction of 1-methylindole with
sulfur, it probably was still involved in its anionic thienol
form as an intermediate in the formation of the pentathiepin
10. To test this hypothesis, a sample of the thione 7 was
converted into its anion with sodium hydride in THF, and
reacted with sulfur ꢀScheme 3). Compounds 10 and 11 were
obtained as previously as the only major products, thereby
con®rming the intermediacy of the thio anion in their forma-
tion. In both of the above reactions, the proportions of the
two products were found to change with increased time
prior to workup, with the diindole tetrasul®de 11 increasing
at the expense of the pentathiepin 10.
2
. Results and discussion
In connection with attempts to develop a more rational
methodology for preparation of indolo fused pentathiepins
and a milder and cleaner procedure for the synthesis of
indoline-2-thiones, thionations of 2-lithio derivatives of
indoles have now been studied. The lithiation and thionation
of 1-methylindole ꢀ9) using 20 equiv. elemental sulfur gave
6
-methylpentathiepino[6,7-b]indole ꢀ10) together with the
known tetrathiodiindole 11 ꢀScheme 1). The known
compound 1-methylindoline-2-thione ꢀ7) was not observed
in this experiment.
Puri®ed samples of 10 appeared to be relatively stable with
respect to conversion to 11, so to test whether this trans-
formation was a result of the basic medium in the above
reactions, an isolated sample of 10 was heated at re¯ux in
ethanol containing triethylamine. A relatively rapid reaction
was observed and, apart from elemental sulfur, compound
11 was the only major product observed ꢀScheme 4).
The pentathiepin 10 provided elemental analysis and high
resolution mass spectral data which were consistent with the
1 13
formula C H NS , and both H- and C NMR spectra
9
7
5
supported the assigned structure. The presence of sulfur at
both the 2- and 3-positions was con®rmed when reduction
with sodium borohydride in the presence of iodomethane
ꢀ
ꢀ
1
Scheme 2) gave 6the known 1-methyl-2,3-bis-
methylthio)indole ꢀ12). The second product, compound
1, similarly gave data supporting the assigned structure,
1
Although the mechanism of the base induced transformation
of 10 into 11 is uncertain, it possibly involves the inter-
mediacy of dithioisatin ꢀ13), since it is known that 1,2-
dithiones are prone to dimerizations and other secondary
reactions. Two possible routes to 13 can be proposed,
differing only in whether nucleophilic attack by the
base occurs on the 2- ꢀpath A) or 4- ꢀpath B) sulfur atom
and this was con®rmed by direct comparison with an
authentic sample previously prepared by the literature
route.
1
7
18
i, ii
ꢀScheme 5).
N
CH3
In a further development, we have devised a similar synthe-
sis of the parent 6H-pentathiepino[6,7-b]indole ꢀ5) in fair
yield via the reaction of the dianion 14 ꢀprepared according
9
1
9
CH3
to the Katritzky protocol via lithiation of indole, followed
by N-protection and activation of the 2-position using
carbon dioxide, and subsequent lithiation in the 2-position)
with 8 equiv. elemental sulfur as the electrophile ꢀScheme
6). The best yields of 5 were obtained using conditions
where the temperature after the addition of sulfur was
allowed to rise slowly during 10±12 h from 270 to 108C.
When only one equivalent of sulfur was used to effect the
thionation of 14, indoline-2-thione ꢀ6) was isolated as the
major product. The highest yield of 6 ꢀ54%) was obtained
when the temperature was kept at 2708C for 30 min, and
then allowed to rise to room temperature during 1 h.
S
N
S
S
S
S
S
S
S
N
S
CH3
N
CH3
1 (10%)
1
0 (22%)
1
Scheme 1. Reagents and conditions: ꢀi) n-BuLi, THF, 278 to 2108C;ꢀii)
S
8
ꢀ20 equiv.), 2108C, 30 min, then AcOH.
S
S
S
S
SCH3
SCH3
S
i
S
S
S
S
i
N
CH3
N
CH3
S
11 (89%) S (97%)
8
N
CH3
1
0
12
4 3
, CH I, THF, 408C, 30 min,
1
0
Scheme 2. Reagents and conditions: ꢀi) NaBH
4%.
4
3
Scheme 4. Reagents and conditions: ꢀi) Et N, EtOH, re¯ux 30 min.

G. W. Rewcastle et al. / Tetrahedron 57 ꢀ2001) 7185±7189
7187
:B
S
S
S
S
S
S
S
S
S
path A
path B
S
S
S
N
N
:B
N
CH3
CH3
CH3
1
3
10
10
Scheme 5.
that the thienol anion of 6 is an intermediate in the formation
of 5. As anticipated, treatment of the pentathiepin 5 with
bases ꢀe.g. Et N, DBU) in ethanol gave complex mixtures
i
Li
ii
5
6
N
3
OLi
according to TLC. Here the possibility of deprotonation at
the indole nitrogen leads to a wide array of reactions.
O
14
In conclusion, useful routes to pentathiepino[6,7-b]indoles 5
and 10 starting from readily available materials have been
developed, providing the ®rst rational syntheses of
compounds belonging to this class. In addition, alternative
procedures for the synthesis of indoline-2-thiones have been
studied, leading to a useful synthesis of the parent indoline-
2-thione ꢀ6).
Scheme 6. Reagents and conditions: ꢀi) S
10 h), then AcOH, 29%;ꢀii) S ꢀ1 equiv.), THF, 270 to 208C ꢀ1.5 h), then
aq. sat. NH Cl, 54%.
8
ꢀ8 equiv.), THF, 270 to 108C
ꢀ
8
4
However, useful amounts of 6 were also produced when the
reaction mixture was allowed to warm slowly to room
temperature over 12±18 h. Puri®cation of the thione 6
thus obtained proved to be particularly easy, as trituration
of the crude product mixture with diethyl ether gave
material of good quality.
3. Experimental
3.1. General
Some further observations made during the above
mentioned reactions merit some attention. The reaction of
1
small amounts of the expected ꢀvide supra) known side
product 15. Thus prolonged reaction times at room
temperature lead to increasing amounts of 15, which is in
analogy with the behaviour of 6-methylpentathiepino[6,7-
b]indole ꢀ10).
4 with 8 equiv. of sulfur may under some conditions give
NMR spectra were recorded on Bruker DPX 300 ꢀ300 MHz)
or AMX 400 ꢀ400 MHz) spectrometers. IR spectra were
recorded on a Perkin±Elmer 1600 FT-IR instrument. MS
ꢀESI) spectra were obtained using a Perkin±Elmer API
150 EX spectrometer. MS ꢀEI) data were recorded on a
Varian VG 70SE spectrometer. High resolution mass spec-
tra were performed by Sveriges Lantbruksuniversitet ꢀSLU),
Uppsala, Sweden. The elemental analysis was performed by
the Microchemical Laboratory at the University of Otago in
Dunedin, New Zealand. Melting points were taken on a
Reichert Ko¯er hot stage and are uncorrected. Chromato-
graphy was performed on Merck Silica Gel 60. Solvents
were of analytical grade and were used as received. THF
was distilled from sodium and benzophenone.
1
7
HN
NH
S
S
S
S
15
Quenching of the reaction mixture of 14 and sulfur with
dilute aqueous sulfuric acid after allowing the temperature
to quickly ꢀ,30 min) attain room temperature lead to the
isolation of the expected intermediate indoline-2-thione
3.1.1. Lithiation and reaction of 1-methylindole with
sulfur. To a solution of 1-methylindole ꢀ3.28 g, 25 mmol)
in THF ꢀ50 mL) at 2788C under an atmosphere of dry
nitrogen, was added n-BuLi in hexanes ꢀ2.5 M, 13.0 mL,
1
3
ꢀ
6). Longer reaction times at 2708C ꢀ,18 h) followed
by quenching at 2708C produced only low yields of the
previously observed compounds, indicating that the reaction
is slow at low temperatures. The indoline-2-thione 6 could
also be converted into the pentathiepin 5 in 42% yield via
treatment with sodium hydride in THF, followed by addi-
tion of sulfur ꢀScheme 7), thus also in this case suggesting
33 mmol) and the resulting mixture was allowed to warm
to 2108C ꢀice±salt bath) to give a white precipitate. After a
further 30 min at 2108C the slurry was added, via a double
ended needle, to a stirred suspension of sulfur ꢀ16 g,
0
.5 mol) in THF ꢀ100 mL) at 2108C, to give a deep red
colour. The reaction mixture was stirred for a further
0 min at 2108C and acetic acid ꢀ2.5 mL) was added.
3
S
After ®ltering to remove excess sulfur, the solvent was
removed under reduced pressure and the residue was
extracted into ethyl acetate ꢀ200 mL) and washed with sat.
aq. NaHCO ꢀ50 mL). After drying ꢀNa SO ), the solvent
S
S
S
i
S
S
N
N
3
2
4
H
H
was evaporated and the residue was puri®ed by chromato-
graphy. Residual sulfur was removed by elution with
hexane, followed by subsequent elution with hexane±
dichloromethane ꢀ95:5) to give, as a yellow solid, 6-methyl-
6
5
Scheme 7. Reagents and conditions: ꢀi) NaH, THF, 2108C, then S
208C, 4 h, 42%.
8
, 210 to

7188
G. W. Rewcastle et al. / Tetrahedron 57 ꢀ2001) 7185±7189
pentathiepino[6,7-b]indole ꢀ10) ꢀ1.61 g, 22%);mp
dichloromethane±hexane) 124±1258C;IR ꢀKBr) nmax
044 ꢀw), 2932 ꢀw), 1459, 1442, 1349, 1330, 1233,
2708C under nitrogen atmosphere. n-BuLi in hexanes
ꢀ1.6 M, 7.6 mL, 12.2 mmol) was added at 2708C and the
mixture was stirred for 30 min, followed by introduction of
carbon dioxide during 10 min. The solvent was removed at
reduced pressure ꢀduring that time the temperature was
allowed to rise to 208C). Nitrogen was introduced into the
reaction vessel, and the residue was dissolved in THF
ꢀ30 mL), thereafter t-BuLi in pentane ꢀ1.7 M, 7.1 mL,
12.1 mmol) was added at 2708C, and the mixture was stir-
red for 30 min. Sulfur ꢀ3.08 g, 96 mmol) was thereafter
added at 2708C, producing a dark red mixture. The
temperature was allowed to rise to 108C over 10 h. Acetic
acid ꢀ2 mL) was added and stirring was continued for
ꢀ
3
7
7
2
1
1
40 cm ; H NMR ꢀ400 MHz, CDCl ) d 3.85 ꢀs, 3H),
3
1
3
.22±7.29 ꢀm, 3H), 7.63±7.68 ꢀm, 1H);
C NMR
ꢀ
100.6 MHz, CDCl ) d 31.5 ꢀq), 110.5 ꢀd), 119.1 ꢀs),
3
1
ꢀ
20.5 ꢀd), 122.1 ꢀd), 124.6 ꢀd), 128.9 ꢀs), 136.5 ꢀs), 141.3
s);MS ꢀEI) m/z 289 ꢀM , 20%), 225 ꢀM2S , 100);HRMS
1
2
ꢀ
Anal. calcd for C H NS C, 37.3;H, 2.4;N, 4.8;S,
EI) Found m/z 288.9174, calcd for C H NS 288.9182.
9
7
5
9
7
5
5
5.4%. Found C, 37.6;H, 2.3;N, 4.8;S, 55.4.
Further elution with hexane±dichloromethane ꢀ9:1) gave
5
7
2
,10-dihydro-5,10-dimethyl[1,2,3,4]-tetrathiocino[5,6-b:8,
0
558C ꢀdec) ꢀlit. , 252±2548C);IR ꢀKBr) n
15 min, followed by addition of sat. aq. NH Cl ꢀ50 mL).
4
-b ]diindole ꢀ11) ꢀ0.48 g, 10%);mp ꢀethyl acetate) 250±
3049 ꢀw),
The mixture was ®ltered and diluted with ethyl acetate
ꢀ50 mL). The organic phase was washed with brine
ꢀ50 mL), dried ꢀNa SO ) and the solvent was thereafter
1
7
max
2
934 ꢀw), 1449, 1328, 1306, 1226, 1155, 1006, 742 cm ;
1
2
2
4
1
H NMR ꢀ400 MHz, CDCl ) d 4.01 ꢀs, 6H), 7.10 ꢀddd,
3
evaporated. The residue was subjected to column chromato-
graphy initially using hexane, followed by 5±20% dichloro-
methane in hexane which afforded 6H-pentathiepino[6,7-
b]indole ꢀ5) as a yellow crystalline material ꢀ960 mg,
29%). An analytical sample was obtained after recrystalli-
Jˆ8.0, 6.9, 1.0 Hz, 2H), 7.37 ꢀddd, Jˆ8.2, 6.9, 1.2 Hz,
1
3
2
NMR ꢀ100.6 MHz, CDCl ) 30.7 ꢀq), 110.3 ꢀd), 120.4 ꢀd),
H), 7.43 ꢀd, Jˆ8.2 Hz, 2H), 7.46 ꢀd, Jˆ8.0 Hz, 2H);
C
3
120.9 ꢀs), 121.3 ꢀd), 124.8 ꢀd), 126.7 ꢀs), 128.0 ꢀs), 137.5 ꢀs).
MS ꢀESI) m/z 387 [M1H] .
1
10
zation from acetonitrile, mp ꢀacetonitrile) 169±1708C ꢀlit.
3355, 1466, 1417, 1388, 1343,
max
1
70±1718C);IR ꢀKBr) n
2
1 1
3
.1.2. Reduction and methylation of 6-methylpenta-
1224, 846, 815, 747 cm ; H NMR ꢀ300 MHz, CDCl ) d
3
13
7.24±7.33 ꢀm, 3H), 7.67±7.70 ꢀm, 1H), 8.53 ꢀbr s, 1H); C
thiepino[6,7-b]indole ꢀ10). To a mixture of 6-methyl-
pentathiepino[6,7-b]indole ꢀ10) ꢀ217 mg, 0.75 mmol) and
iodomethane ꢀ1 mL) in ethanol ꢀ30 mL) was added sodium
borohydride ꢀ0.28 g, 7.5 mmol) in portions. The resulting
solution was stirred at 408C for 30 min and the solvent
was removed under vacuum. After workup in ethyl acetate
as before, the product was puri®ed by preparative layer
chromatography on silica gel eluting with hexane±dichloro-
NMR ꢀ75.4 MHz, CDCl ) d 111.8 ꢀd), 120.6 ꢀs), 120.8 ꢀd),
3
122.6 ꢀd), 125.3 ꢀd), 130.1 ꢀs), 135.2 ꢀs), 138.0 ꢀs). MS ꢀESI)
m/z 274 ꢀ[M2H] , 100%), 210 ꢀ[M2S ±H] , 48), 178
2
2
2
2
ꢀ[M2S ±H] , 53). HRMS ꢀEI) Found m/z 274.9025, calcd
3
for C H NS 274.9025.
8
5
5
3.3.2. Indoline-2-thione ꢀ6). Indole ꢀ5.86 g, 50 mmol) in
THF ꢀ45 mL) was treated with n-BuLi in hexanes ꢀ2.5 M,
21 mL, 52.5 mmol) at 2708C under N during 15±20 min.
methane ꢀ9:1), to give 1-methyl-2,3-bisꢀmethylthio)indole
ꢀ
d 2.37 ꢀs, 3H), 2.40 ꢀs, 3H), 3.86 ꢀs, 3H), 7.17±7.33 ꢀm, 3H),
1
12) ꢀ73 mg, 44%) as an oil; H NMR ꢀ400 MHz, CDCl )
3
2
The mixture was kept at 2708C for 30 min, followed by
introduction of carbon dioxide during 15 min at 2708C.
The solvent was removed at reduced pressure ꢀduring that
time the temperature was allowed to rise to 208C). Nitrogen
was introduced into the system, and the white residue was
dissolved in THF ꢀ60 mL), and after cooling to 2708C,
t-BuLi in pentane ꢀ1.7 M, 31 mL, 52.7 mmol) was added
during 15±20 min. After stirring at 2708C for 30 min,
sulfur ꢀ1.6 g, 51.3 mmol) was quickly added in one portion
and the resulting yellow mixture was stirred at 2708C for
30 min, and was thereafter allowed to warm to 208C during
7.76 ꢀbr d, Jˆ8.0 Hz, 1H). The spectral data were in agree-
ment with those already reported.
1
6
3.2. Reaction of 1-methyl-2-indolinethione ꢀ7) with
sulfur
A
6
solution of 1-methylindoline-2-thione ꢀ7) ꢀ1.0 g,
.1 mmol) in dry THF ꢀ10 mL) was treated with sodium
hydride ꢀ0.3 g of a 60% dispersion in mineral oil,
.4 mmol) at room temperature under nitrogen, and the
resulting mixture was added to a stirred suspension of sulfur
2 g, 62 mmol), in THF ꢀ20 mL) at 08C. The mixture was
7
1 h, followed by quenching with sat. aq. NH Cl ꢀ100 mL).
4
ꢀ
Stirring was continued for 5 min, the mixture was thereafter
diluted with water ꢀ100 mL) and extracted with ethyl acetate
ꢀ100 mL). The organic layer was washed with brine ꢀ50 mL)
allowed to warm to room temperature with stirring over-
night. Standard workup and chromatography as before
gave 10 ꢀ0.23 g, 13%) and 11 ꢀ0.22 g, 19%).
and dried over Na SO . Evaporation of the solvent gave a
2 4
greenish-beige residue, which was treated with diethyl ether
ꢀ,20 mL), producing a pale beige precipitate, which was
collected by ®ltration, washed with diethyl ether and dried
to give 6 ꢀ4.00 g, 54%) as a pale beige solid;mp ꢀdiethyl
3
.3. Reaction of 10with triethylamine
A suspension of 10 ꢀ0.29 g, 1 mmol) and triethylamine
1 mL) in ethanol ꢀ20 mL) was heated under re¯ux for
0 min, cooled and diluted with water. The solid was
1
3
ꢀ
3
ether) 146±1488C ꢀlit. , 147±1498C);IR ꢀKBr) nmax 3092,
2987 ꢀw), 2920 ꢀw), 2877 ꢀw), 1618, 1505, 1467, 1447,
2
1
1
collected by ®ltration, dried, and ®nally puri®ed by chroma-
tography as above, to give sulfur ꢀ93 mg, 97% of theoreti-
cal) and 11 ꢀ172 mg, 89%).
1341, 1296, 1178, 1116, 750 cm ; H NMR ꢀ300 MHz,
DMSO-d
) d 4.01 ꢀs, 2H), 6.96 ꢀd, Jˆ7.7 Hz, 1H), 7.04
ꢀddd, Jˆ8.4, 7.6, 1.0 Hz, 1H), 7.19±7.26 ꢀm, 2H), 12.59
6
1
3
ꢀ
br s, 1H); C NMR ꢀ75.4 MHz, DMSO-d ) d 49.1 ꢀt),
6
3.3.1. 6H-Pentathiepino[6,7-b]indole ꢀ5). A solution of
indole ꢀ1.40 g, 12 mmol) in THF ꢀ30 mL) was cooled to
109.9 ꢀd), 123.2 ꢀd), 124.0 ꢀd), 127.7 ꢀd), 130.8 ꢀs), 145.2
ꢀs), 203.1 ꢀs). MS ꢀESI) m/z 148 [M2H] .
2

G. W. Rewcastle et al. / Tetrahedron 57 ꢀ2001) 7185±7189
7189
3.4. Transformation of indoline-2-thione ꢀ6) into 6H-
pentathiepino[6,7-b]indole ꢀ5)
8. ꢀa) Feh e r, F.;Langer, M. Tetrahadron Lett. 1971, 12, 2125.
ꢀb) Feh e r, F.;Langer, M.;Volkert, R. Z. Naturforsch 1972,
2
7b, 1006. ꢀc) Chenard, B. L.;Miller, T. J. J. Org. Chem.
A solution of indoline-2-thione ꢀ6) ꢀ745 mg, 5 mmol) in
THF ꢀ20 mL) was added during 15 min to a suspension of
sodium hydride ꢀ0.44 g of a 60% dispersion in mineral oil,
1984, 49, 1221. ꢀd) Chenard, B. L.;Harlow, R. L.;Johnson,
A. L.;Vladuchick, S. A. J. Am. Chem. Soc. 1985, 107, 3871.
ꢀe) Sato, R.;Saito, S.;Chiba, H.;Goto, T.;Saito, M.
Chem.
1
1 mmol) in THF ꢀ20 mL) at 2108C under N . After stirring
2
Lett. 1986, 349. ꢀf) Sato, R.;Kimura, T.;Goto, T.;Saito, M.
Tetrahedron Lett. 1988, 29, 6291. ꢀg) Sato, R.;Saito, S.;
Chiba, H.;Goto, T.;Saito, M. Bull. Chem. Soc. Jpn 1988,
61, 1647. ꢀh) Sato, R.;Kimura, T.;Goto, T.;Saito, M.;
Kabuto, C. Tetrahedron Lett. 1989, 30, 3453. ꢀi) Sato, R.;
at 2108C for 15 min, sulfur ꢀ0.8 g, 25 mmol) was quickly
added in one portion at 2108C. The mixture was thereafter
allowed to slowly warm to room temperature during 4 h.
After quenching with acetic acid ꢀ1 mL), sat. aq. NH Cl
4
ꢀ
50 mL) was added, and the resulting mixture was ®ltered
Ohyama, T.;Ogawa, S.
Heterocycles 1995, 41, 893.
and diluted with ethyl acetate ꢀ50 mL). The organic layer
was washed with brine ꢀ50 mL), dried ꢀNa SO ) and the
ꢀj) Perregaard, J.;Scheibye, S.;Meyer, H. J.;Thomsen, I.;
Lawesson, S.-O. Bull. Soc. Chim. Belg. 1977, 86, 679.
ꢀk) Earle, M. J.;Massey, A. G.;Al-Soudani, A.-R.;Zaidi, T.
Polyhedron 1989, 8, 2817. ꢀl) Nakayama, J.;Kashiwagi, M.;
Yomoda, R.;Hoshino, M. Nippon Kagaku Kaishi 1987, 1424.
ꢀm) Sato, R.;Ohyama, T.;Kawagoe, T.;Baba, M.;Nakayo, S.;
Kimura, T.;Ogawa, S. Heterocycles 2001, 55, 145.
2
4
solvents were evaporated to give a yellow residue, which
was subjected to column chromatography initially using
hexane, followed by 10±40% dichloromethane in hexane,
to give 6H-pentathiepino[6,7-b]indole ꢀ5) as a yellow
crystalline solid ꢀ580 mg, 42%).
9
. Hou, Y.;Abu-Yousef, I. A.;Harpp, D. N. Tetrahedron Lett.
2000, 41, 7809 and references cited therein.
0. Bergman, J.;Sta lhandske, C. Tetrahedron Lett. 1994, 35,
Ê
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