Synthesis of thienodolin

Article abstract of DOI:10.1002/ejoc.200400073

We report a total synthesis of the alkaloid thienodolin (1a), as well as its 5-chloro isomer 1b and its unsubstituted analogue 1c, in three steps from the corresponding oxindoles 8a-c. The preparation was achieved through an initial Vilsmeier-Haack-Arnold reaction (chloro-formylation) followed by protection at the indole nitrogen, creation of the fused thiophene ring by nucleophilic substitution at the 2-position and an intramolecular cyclization using mercaptoacetamide. This gave 1a, 1b and 1c in total yields of 42%, 35% and 37%, respectively. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400073

FULL PAPER
Synthesis of Thienodolin
Robert Engqvist,[a,b] Atif Javaid,[b] and Jan Bergman*[a,b]
Keywords: Alkaloid / Total synthesis / Indoles
We report a total synthesis of the alkaloid thienodolin (1a),
as well as its 5-chloro isomer 1b and its unsubstituted ana-
fused thiophene ring by nucleophilic substitution at the 2-
position and an intramolecular cyclization using mercap-
logue 1c, in three steps from the corresponding oxindoles toacetamide. This gave 1a, 1b and 1c in total yields of 42%,
8a−c. The preparation was achieved through an initial
Vilsmeier−Haack−Arnold reaction (chloro-formylation) fol-
lowed by protection at the indole nitrogen, creation of the
35% and 37%, respectively.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Results and Discussion
Thienodolin (1a) was isolated from the culture broth of
Streptomyces albogriseolus MJ286Ϫ76F7 and structurally
elucidated in the early 1990Јs by Nakamura et al.[1Ϫ2] The
alkaloid 1a was shown to have both growth promoting and
inhibiting activities in rice seedlings.
In 1995, Olesen et al. presented a synthetic pathway to
methyl thieno[2,3-b]indole-2-carboxylate (5) starting from
2-chloroindole-3-carbaldehyde (6c) (Scheme 2).[6] The dis-
advantage of this approach, as a prospective way to 1c, lies
in the deprotection step, which should result in an incon-
venient mixture of 5 and the acid 7 in moderate yields.
Despite its relative simplicity, only a few methods are
available for the synthesis of the thieno[2,3-b]indole ring
system[3Ϫ6] and no total synthesis of the alkaloid 1a has
been reported until now. Some aza derivatives, i.e. thi-
azolo[4,5-b]indoles (2), have been synthesized (Scheme 1)
from 1-acetyl-2-bromoindolinone (3) and thioacetamides
4.[7]
Scheme 2. Olesen’s route to thieno[2,3-b]indoles[6]
Subsequently, we contemplated the possibility that the
easily-removable Boc-protecting group would be more suit-
able during any synthesis of 1a since it should activate the
indole ring towards nucleophilic attack.
2,6-Dichloroindole-3-carbaldehyde (6a) has been pre-
pared previously by Acheson and co-workers[8] using a tedi-
ous route. However, the method of choice for the synthesis
of a 2-chloro-3-carboxaldehyde-substituted indole involves
reacting an oxindole with a Vilsmeier reagent generated in
situ from DMF and phosphorus oxychloride (POCl3) i.e.
the VilsmeierϪHaackϪArnold reaction.[9] When we ap-
plied this reaction to the chlorosubstituted oxindoles 8aϪb,
Scheme 1. Synthesis of thiazolo[4,5-b]indoles (2).[7]
[a]
Unit for Organic Chemistry, CNT, Department of Biosciences
at Novum, Karolinska Institute,
Novum Research Park, 141 57 Huddinge, Sweden
Södertörn University College,
[b]
141 04 Huddinge, Sweden
Fax: (internat.) ϩ46-8-6081501
E-mail: jabe@cnt.ki.se
Eur. J. Org. Chem. 2004, 2589Ϫ2592
DOI: 10.1002/ejoc.200400073
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2589

R. Engqvist, A. Javaid, J. Bergman
FULL PAPER
we noticed that a higher yield was obtained if the oxindoles temperatures for a shorter period of time. When 5 was
were pretreated with POCl3 then treated with a fresh solu- treated with ammonia in methanol in a sealed tube at 80
tion of the Vilsmeier reagent at 0 °C, and finally heated at °C for 6 days, 1c was obtained in 27% isolated yield to-
reflux for 20 h. This procedure gave mixtures of the desired gether with 50% of unreacted 5. If the reaction was per-
dichloroindole-3-carbaldehydes 6aϪb and, because of the formed at 120 °C only small amounts of the unsubstituted
excess Vilsmeier reagent, the by-product chloro-3-(dimeth- thieno[2,3-b]indole (12) could be isolated. Compound 12
ylaminomethylene)-1-formyloxindoles 9aϪb. This kind of has been prepared previously by Olesen and co-workers by
transformation has been reported twice previously in the heating 5 in morpholine. This result has been confirmed
literature.[10] The corresponding des-N-formyl enamine am- previously.[6] Additionally, the parent compound 12 has
ides 10a and 10b have been prepared selectively by Sarges been prepared recently by a palladium promoted reductive
et al. by reacting the oxindoles 8a and 8b with N,N-dimeth- cyclization of 3-(2-nitrophenyl)thiophene (13) in the pres-
ylformamide dimethyl acetal (DMF/DMA) in refluxing ence of CO.[12]
chloroform.[11]
Several attempts to react 12 with hydrogen isocyanate
(generated in situ) or chlorosulfonyl isocyanate failed. The
desired thienoindoles 1aϪc, were prepared instead by treat-
ment of 11aϪc with 2-mercaptoacetamide in the presence
of K2CO3 in methanol at reflux for 16 h.
This procedure gave a total yield of 42% for the synthesis
of thienodolin (1a) from the known 6-chloroxindole in three
Scheme 3. Synthesis of 10aϪb from 8aϪb according to Sarges et
al.[11]
Chloro-3-(dimethylaminomethylene)-1-formyloxindoles
9aϪb were easily converted into 6a and 6b in good yields
by refluxing in neat POCl3. The aldehydes 6aϪb were sub-
sequently protected using di-tert-butyl dicarbonate (Boc2O)
Table 1. Yields for the total synthesis of 1aϪc
and 4-(dimethylamino)pyridine (DMAP) in tetrahydrofu- Entry
ran. The protected indole derivative 11c was heated with
methyl thioglycolate and potassium carbonate in methanol
Yields (%)
9 Ǟ 6 10
R1, R2 6, 9
1
Total yield (%)
1
H, Cl 45, 40 85
Cl, H 45, 19 81
63
84 42
89 35
78 37
yielding the ester 5 in 70% yield. The corresponding Boc-
protected methyl thieno[2,3-b]indole-2-carboxylate was ob-
2
66
3
H, H
73,[5]
0
Ϫ
65[7]
tained in a low yield by performing the reaction at lower
Scheme 4. I) i. POCl3, 1,2-dichloroethane, ii. Vilsmeier reagent, reflux, 20 h. II) POCl3, 100 °C, 0.5 h. III) Boc2O, DMAP, THF, 0 °C,
1.5 h. IV) methyl thioglycolate, methanol, reflux, 16 h. V) NH3, methanol. VI) ammonia, methanol, sealed tube, 80 °C, 6 days. VII) 2-
mercaptoacetamide, methanol, reflux, 16 h
2590
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2589Ϫ2592

Synthesis of Thienodolin
FULL PAPER
ppm. MS (ESI): m/z ϭ 212 [M Ϫ H]Ϫ C9H5NO35Cl2, 214 [M Ϫ
steps (Table 1, Scheme 4). The spectroscopic data recorded
H]Ϫ C9H5NO35Cl 37Cl, 216 [M Ϫ H]Ϫ C9H5NO37Cl2.
for 1a are in accordance with the literature data.[1,2]
6-Chloro-3-[(dimethylamino)methylene]-1-formyloxindole
(9a):
Yield: 1.26 g (40%). M.p. 158Ϫ160 °C. IR: ν˜ ϭ 3120, 3005, 2965,
2799, 1703, 1685, 1589, 1346, 1113, 1089, 950, 836, 806, 773, 641
cmϪ1. 1H NMR: δ ϭ 9.22 (s, 1 H, CH), 7.93 (s, 1 H, CH), 7.88 (d,
Conclusions
Starting from the corresponding oxindoles 8aϪc, we have J ϭ 1.8Hz, 1 H, CH), 7.44 (d, J ϭ 8.3 Hz, 1 H, CH), 7.16 (dd,
J ϭ 8.3, 1.8 Hz, 1 H, CH), 3.58 (s, 3 H, CH3), 3.37 (s, 3 H, CH3)
ppm. 13C NMR: δ ϭ 162.8 (s), 160.1 (d), 151.9 (d), 131.2 (s), 128.2
(s), 126.2 (s), 123.7 (d), 116.1 (d), 112.8 (d), 88.9 (s), 47.1 (q), 42.9
(q) ppm. MS (ESI): m/z ϭ 251 [M ϩ H]ϩ C12H10N2O235Cl, 253
[M ϩ H]ϩ C12H10N2O237Cl.
prepared the alkaloid thienodolin (1a) as well as the two
analogues 1bϪc in total yields of 35Ϫ42% in three steps.
Experimental Section
2,5-Dichloro-3-formylindole (6b): Yield: 1.20 g (45%). M.p.
266Ϫ267 °C. IR: ν˜ ϭ 3111, 2900, 2831, 1631, 1434, 1369, 1218,
NMR spectra were recorded from [D6]DMSO solutions at room
temperature, using the signal from residual DMSO (1H: δ ϭ
2.50 ppm; 13C: δ ϭ 39.5) as internal standard, on a Bruker DPX
300 (300 MHz) spectrometer. Coupling constants and chemical
shifts are given in Hz and ppm, respectively. IR spectra were re-
corded on a PerkinϪElmer 1600 FTIR. Melting points were taken
on a Büchi Melting Point B-545 apparatus and are uncorrected.
Mass spectra were recorded using an LC/MS system operating in
the electron spray ionisation (ESI) mode at 70 eV. Chromatography
was performed on Merck silica gel 60. Elemental analyses were
performed by H. Kolbe Mikroanalytisches Laboratorium,
Mülheim an der Ruhr, Germany. Solvents were of analytical grade
and were used as received. 2-Chloroindole-3-carboxaldehyde,[9] 1-
(tert-butoxycarbonyl)-2-chloroindole-3-carboxaldehyde,[13] 5-chlo-
roxindole,[14] 6-chloroxindole[15] and 2-mercaptoacetamide[16] were
prepared as described in the literature.
1
1109, 850, 805, 742, 682 cmϪ1. H NMR: δ ϭ 7.30 (dd, J ϭ 8.5,
2.1 Hz, 1 H, ArH), 7.44 (d, J ϭ 8.5 Hz, 1 H, ArH), 8.02 (d, J ϭ
2.1 Hz, 1 H, ArH), 9.97 (s, 1 H, CH), 13.29 (br. s, 1 H, NH) ppm.
13C NMR: δ ϭ 111.6 (s), 113.5 (d), 119.0 (d), 123.9 (d), 125.4 (s),
127.5 (s), 133.1 (s), 135.7 (s), 183.4 (d) ppm. MS (ESI): m/z ϭ 212
[M Ϫ H]Ϫ C9H5NO35Cl2, 214 [M Ϫ H]Ϫ C9H5NO35Cl 37Cl, 216
[M Ϫ H]Ϫ C9H5NO37Cl2. C9H5NOCl2 (214.1): calcd. C 50.50, H
2.35, N 6.54; found C 50.63, H 2.41, N 6.42.
5-Chloro-3-[(dimethylamino)methylene]-1-formyloxindole
(9b):
Yield: 0.60 g (19%). M.p. 202Ϫ204 °C [ref.[10b] m.p. 194Ϫ198 °C].
IR: ν˜ ϭ 3034, 2927, 2901, 2803, 1697, 1681, 1613, 1589, 1389, 1139,
1
798, 783, 761, 666 cmϪ1. H NMR: δ ϭ 9.20 (s, 1 H, CH), 7.94 (s,
1 H, CH), 7.82 (d, J ϭ 8.4 Hz, 1 H, CH), 7.52 (d, J ϭ 1.8 Hz, 1
H, CH), 7.00 (dd, J ϭ 8.4, 1.8 Hz, 1 H, CH), 3.59 (s, 3 H, CH3),
3.37 (s, 3 H, CH3) ppm. 13C NMR: δ ϭ 163.0 (s), 159.9 (d), 152.2
(d), 131.5 (s), 129.2 (s), 128.7 (s), 121.6 (d), 114.8 (d), 114.2 (d),
88.8 (s), 47.2 (q), 42.9 (q) ppm.
Methyl Thieno[2,3-b]indole-2-carboxylate (5): A mixture of 11c[13]
(1.12 g; 4.0 mmol), methyl 2-mercaptoacetate (0.50 g; 4.4 mmol),
K2CO3 (0.61 g; 4.4 mmol) and methanol (16 mL) was refluxed for
16 h. Thereafter, the reaction mixture was allowed to cool to room
temperature and poured into water (160 mL). The resulting precipi-
tate was collected by filtration, washed with water and dried. Yield:
0.70 g (70%). M.p. 201Ϫ202 °C [ref.[6] m.p. 201Ϫ209 °C].
General Procedure for the Synthesis of Dichloroindole-3-carbal-
dehydes 6a؊b from Chloro-3-[(dimethylamino)methylene]oxindoles
9a؊b: A mixture of the appropriate chloro-3-[(dimethylamino)me-
thylene]-1-formyloxindole (0.445 g; 1.78 mmol) and POCl3
(1.533 g; 10 mmol) was heated at 100 °C for 30 min. Ice-water
(50 mL) was added to the reaction mixture, which was then stirred
for 1 h then extracted with ethyl acetate. The organic phase was
washed with NaHCO3 (sat.), brine, and dried with Na2SO4. The
solvent was removed at reduced pressure to give a solid, which was
purified by column chromatography on silica gel eluting with ethyl
acetate/hexane, 1:1.
Synthesis of Dichloroindole-3-carbaldehydes 6a؊b and Chloro-3-
[(dimethylamino)methylene]oxindoles 9a؊b. General Procedure:
POCl3 (3.83 g; 25 mmol) was added to a solution of the appropriate
chloroxindole (2.10 g; 12.5 mmol) and dry 1,2-dichloroethane
(100 mL) at room temperature under argon. The reaction mixture
was heated at reflux for 30 min and was then stirred at room tem-
perature for 90 min. Simultaneously, a solution of the Vilsmeier’s
salt in 1,2-dichloroethane was prepared as follows: POCl3 (5.75 g,
37.5 mmol) was added dropwise to a solution of dry 1,2-dichloro-
ethane (20 mL) and dry DMF (2.74 g, 37.5 mmol) over 30 min at 0
°C under argon, followed by stirring for 90 min at room tempera-
ture. This solution was then added to the reaction mixture, which
was subsequently heated at reflux for 20 h. The solvent was then
removed at reduced pressure, ice-water was added, and the mixture
was allowed to stand for 3 h. The resulting precipitate was collected
by filtration, washed with water, and purified by column chroma-
2,6-Dichloro-3-formylindole (6a): Yield: 0.325 g (85%). M.p.
240Ϫ241 °C [ref.[8] m.p. 238Ϫ239 °C].
2,5-Dichloro-3-formylindole (6b): Yield: 0.308 g (81%). M.p.
266Ϫ267 °C.
Synthesis of 11a؊b. General Procedure: DMAP (0.024 g, 0.1 equiv.)
was added to a reaction mixture containing Boc2O (0.655 g,
3.0 mmol) and the appropriate dichloro-3-formylindole (0.428 g;
2.0 mmol) in THF (10 mL) at 0 °C and then stirred at 0 °C for
tography on silica gel eluting with hexane/ethyl acetate, 6:4 then 90 min. The solvent was removed under reduced pressure, and the
methanol/chloroform, 1:9.
resulting precipitate was dissolved in ethyl acetate and washed with
HCl (1M), NaHCO3 (sat.) and brine. The organic phase was dried
with Na2SO4 and the solvent was removed under reduced pressure.
White needles were obtained by recrystallisation from 2-propanol.
2,6-Dichloro-3-formylindole (6a): Yield: 1.19 g (45%). M.p.
240Ϫ241 °C [ref.[8] m.p. 238Ϫ239 °C]. IR: ν˜ ϭ 3085, 3037, 2838,
1630, 1573, 1421, 1371, 1061, 852, 806, 755, 688 cmϪ12. 1H NMR:
δ ϭ 7.26 (dd, J ϭ 8.5, 1.8 Hz, 1 H, ArH), 7.45 (d, J ϭ 1.8 Hz, 1 1-(tert-Butoxycarbonyl)-2,6-dichloroindole-3-carboxaldehyde (11a):
H, ArH), 8.02 (d, J ϭ 8.5 Hz, 1 H, ArH), 9.97 (s, 1 H, CH), 13.23
Yield: 0.395 g (63%). M.p. 127Ϫ128 °C. IR: ν˜ ϭ 3009, 2979, 1759,
(br. s, 1 H, NH) ppm. 13C NMR: δ ϭ 111.5 (d), 112.0 (s), 121.3
1664, 1304, 1139, 1112, 836, 817, 758 cmϪ1 1H NMR (CDCl3):
.
(d), 123.0 (s), 123.1 (d), 128.3 (s), 135.0 (s), 135.5 (s), 183.3 (d) δ ϭ 1.74 (s, 9 H, CH3), 7.34 (dd, J ϭ 8.5, 1.8 Hz, 1 H, ArH), 8.11
Eur. J. Org. Chem. 2004, 2589Ϫ2592
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R. Engqvist, A. Javaid, J. Bergman
FULL PAPER
(d, J ϭ 1.8 Hz, 1 H, ArH), 8.20 (d J ϭ 8.5 Hz, 1 H,, ArH), 10.24 ArH), 11.83 (s, 1 H, NH) ppm. 13C NMR: δ ϭ 111.9 (d), 118.8
(s, 1 H, CH) ppm. 13C NMR (CDCl3) δ ϭ 28.0 (q), 87.4 (s), 115.2 (d), 119.6 (d), 120.1 (d), 121.7 (s), 122.6 (d), 123.7 (s), 131.5 (s),
(d), 117.2 (s), 121.9 (d), 122.9 (s), 125.6 (d), 131.9 (s), 135.5 (s),
141.9 (s), 144.3 (s), 164.3 (s) ppm. MS (ESI): m/z ϭ 217 [M ϩ
135.7 (s), 147.6 (s), 185.4 (d) ppm. MS (ESI): m/z ϭ 314 [M ϩ H]ϩ, H]ϩ. C11H8N2OS (216.3): calcd. C 61.09, H 3.73, N 12.95; found
C14H13NO335Cl2, 316 [M ϩ H]ϩ C14H13NO335Cl 37Cl, 318 [M ϩ
H]ϩ C14H13NO337Cl2. C14H13NO3Cl2 (314.2): calcd. C 53.52, H
4.17, N 4.46; found C 53.61, H 4.23, N 4.32.
C 61.02, H 3.88, N 12.87.
Synthesis of Thieno[2,3-b]indole-2-carboxamide (1c) from 5: Com-
pound 5 (0.120 g, 0.52 mmol) and methanol saturated with am-
monia (at 0 °C) were heated in a sealed tube at 80 °C for 6 days.
The solvent was removed under reduced pressure and the solid was
purified by chromatography on silica gel eluting with ethyl acetate/
hexane, 1:1 then ethyl acetate, 100%. Yield: 30 mg (27%); M.p.
291Ϫ292 °C (dec.).
1-(tert-Butoxycarbonyl)-2,5-dichloroindole-3-carboxaldehyde (11b):
Yield: 0.415 g (66%). M.p. 143Ϫ144 °C. IR: ν˜ ϭ 3113, 2973, 1751,
1662, 1441, 1302, 1121, 1068, 1013, 874, 818, 799, 728 cmϪ1 1H
.
NMR (CDCl3): δ ϭ 1.73 (s, 9 H, CH3), 7.33 (dd, J ϭ 9.0, 2.0 Hz,
1 H, ArH), 7.97 (d, J ϭ 9.0 Hz, 1 H, ArH), 8.28 (d, J ϭ 2.0 Hz,
1 H, ArH), 10.21 (s, 1 H, CH) ppm. 13C NMR (CDCl3) δ ϭ 28.0
(q), 87.3 (s), 115.9 (d), 116.6 (s), 120.5 (d), 125.3 (s), 126.0 (d),
130.8 (s), 133.4 (s), 136.1 (s), 147.5 (s), 185.1 (d) ppm. MS (ESI):
[1]
K. Kanbe, H. Naganawa, M. Okamura, Y. Okami, T. Takeuchi,
S. Hattori, M. Hamada, Biosci. Biotech. Biochem. 1993, 57,
m/z
ϭ
314 [M
ϩ
H]ϩ, C14H13NO335Cl2, 316 [M
ϩ
H]ϩ
632Ϫ635.
C14H13NO335Cl 37Cl, 318 [M
ϩ
H]ϩ C14H13NO337Cl2.
[2]
K. Kanbe, H. Naganawa, T. Nakamura, Y. Okami, T. Takeu-
C14H13NO3Cl2 (314.2): calcd. C 53.52, H 4.17, N 4.46; found
C 53.44, H 4.25, N 4.39.
chi, Biosci. Biotech. Biochem. 1993, 57, 636Ϫ637.
J. Levy, D. Royer, J. Guilhem, M. Cesario, C. Pascard, Bull.
[3]
Soc. Chim. France 1987, 193Ϫ198.
Synthesis of 1a؊c. General Procedure: A mixture of 11aϪc
(4.0 mmol), 2-mercaptoacetamide (0.40 g; 4.4 mmol), K2CO3
(0.61 g; 4.4 mmol) and methanol (16 mL) was refluxed for 16 h.
Thereafter, the reaction mixture was allowed to cool to room tem-
perature and poured into water (160 mL). The resulting precipitate
was collected by filtration, washed with water and dried.
[4]
G. Kobayashi, Y. Matsuda, Japanese Patent 47036757 B4,
1972, Chem. Abstr. 1972, 77, 140005.
G. Kobayashi, S. Furukawa, Y. Matsuda, R. Natsuki, Yaku-
[5]
guku Zasshi 1969, 89, 58Ϫ63.
[6] [6a]
P. Olesen, J. Hansen, M. Engelstoft, J. Heterocycl. Chem.
1995, 32, 1641Ϫ1642. [6b] P. Jakobsen, A. Kanstrup, P. Faarup,
P. Olesen, J. Lundbech, (Novo Nordisk A/S, Den.), US. Pat.
[6c]
6-Chlorothieno[2,3-b]indole-2-carboxamide
(Thienodoline,
1a):
5536721, 1998 [Chem. Abstr. 1998, 129, 148909].
P.
Yield: 0.210 g [84%, (1/4 scale)]. M.p. 311Ϫ312 °C [ref.[2] m.p.
249Ϫ250 °C]. IR: ν˜ ϭ 3457, 3307, 3174, 1644, 1581, 1510, 1490,
Jakobsen, A. Kanstrup, P. Faarup, P. Olesen, (Novo Nordisk
A/S, Den.), WO. Pat. 9525110, 1995 [Chem. Abstr. 1995, 124,
117290].
1394, 1373, 1244, 1087, 1064, 871, 804 cmϪ1. H NMR: δ ϭ 7.16
1
[7]
[8]
V. Velezheva, A. Lepeshkin, O. Fedotova, V. Shvedov, K. Tur-
chin, A. Sedov, O. Anisimova, Pharm. Chem. J. (Engl. Transl.)
1996, 30, 643Ϫ647.
(d, J ϭ 8.4 Hz, 1 H, ArH), 7.30 (br. s, 1 H, NH), 7.58 (s, 1 H,
ArH), 7.76 (d, J ϭ 8.4 Hz, 1 H, ArH), 7.93 (br. s, 1 H, NH), 8.12
(s, 1 H, CH), 11.93 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ 111.7
(d), 119.7 (d), 119.9(d), 120.0 (d), 120.5 (s), 123.4 (s), 127.1 (s),
132.4 (s), 142.2 (s), 145.0 (s), 164.2 (s) ppm. MS (ESI): m/z ϭ 251
[M ϩ H]ϩ C11H7N2OS35Cl, 253 [M ϩ H]ϩ C11H7N2OS37Cl.
M. Acheson, P. Hunt, D. Littlewood, B. Murrer, H. Rosenberg,
J. Chem. Soc., Perkin Trans. 1 1978, 1117Ϫ1125.
[9] [9a]
U. Stoess, PhD thesis, Münster, 1967. [9b]K. Shulze, J. Re-
isch, U. Stoess, Arch. Pharm. (Weinheim, Ger.) 1972, 305,
523Ϫ533.
[9c]
H. Showalter, A. Sercel, B. Leja, C. Wolfangel,
5-Chlorothieno[2,3-b]indole-2-carboxamide (1b): Yield: 0.224 g
[89%, (1/4 scale)]. M.p. 289Ϫ290 °C. IR: ν˜ ϭ 3489, 3432, 3372,
3155, 1660, 1598, 1445, 1417, 1387, 1246, 752, 736 cmϪ1. 1H NMR:
δ ϭ 7.23 (d, J ϭ 8.6 Hz, 1 H, ArH), 7.25 (br. s, 1 H, NH), 7.51 (d,
J ϭ 8.6 Hz, 1 H, ArH), 7.80 (s, 1 H, ArH), 7.94 (br. s, 1 H, NH),
8.10 (s, 1 H, CH), 11.98 (br. s, 1 H, NH) ppm. 13C NMR: δ ϭ
113.3 (d), 118.3 (d), 120.0 (d), 122.4 (d), 122.8 (s), 123.0 (s), 124.1
(s), 132.3 (s), 140.3 (s), 145.5 (s), 164.2 (s) ppm. MS (ESI): m/z ϭ
251 [M ϩ H]ϩ C11H7N2OS35Cl, 253 [M ϩ H]ϩ C11H7N2OS37Cl.
C11H7N2OSCl (250.7): calcd. C 52.70, H 2.81, N 11.17; found
C 52.61, H 2.88, N 11.03.
L. Ambroso, W. Elliott, D. Fry, A. Kraker, C. Howard, G. Lu,
C. Moore, J. Nelson, B. Roberts, P. Vincent, W. Denny, A.
Thompson, J. Med. Chem. 1993, 40, 413Ϫ426.
[10] [10a]
S. Seshadri, M. Sardessai, A. Betrabet, Indian J. Chem.
[10b]
1969, 7, 662Ϫ666.
G. Hardtmann (Sandoz AG), Ger. Pat.
2338668, 1974 [Chem. Abstr. 1974, 80, 133063].
[11]
R. Sarges, H. Howard, K. Koe, A. Weissman, J. Med. Chem.
1989, 32, 437Ϫ444.
J. Smitrovich, I. Davies, Org. Lett. 2004, 6, 533Ϫ535.
P. Kutschy, M. Suchy, A. Andreani, M. Dzurilla, V. Kovacik,
J. Alfoeldi, M. Rossi, M. Gramatova, Tetrahedron 2002, 58,
9029Ϫ9040.
S. Kadin (Pfizer Inc.), US. Pat. 4569942, 1986 [Chem. Abstr.
1986, 105, 42644].
E. Kraynack, J. Dalgard, F. Gaeta, Tetrahedron Lett. 1998,
39, 7679Ϫ7682.
[12]
[13]
[14]
[15]
[16]
Thieno[2,3-b]indole-2-carboxamide (1c): Yield: 0.67 g (78%). M.p.
290Ϫ291 °C (dec.). IR: ν˜ ϭ 3366, 3179, 1640, 1595, 1515, 1419,
1
1400, 1247, 743 cmϪ1. H NMR: δ ϭ 7.14 (t, J ϭ 7.65 Hz, 1 H,
ArH), 7.20 (m, 2 H, ArH), 7.49 (d, J ϭ 8.1 Hz, 1 H, ArH), 7.75
(d, J ϭ 7.65 Hz, 1 H, ArH), 7.89 (br. s, 1 H, NH), 8.13 (s, 1 H,
W. Ried, D. Kuhnt, Liebigs Ann. Chem. 1986, 780Ϫ784.
Received February 4, 2004
2592
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2589Ϫ2592