Palladium-catalyzed amination and cyclization to heteroannellated indoles and carbazoles

Article abstract of DOI:10.1016/S0040-4020(03)00552-0

New ortho-bromodiarylamines in the benzo[b]thiophene series were prepared by palladium-catalyzed amination, either in the benzene or in the thiophene ring. These were submitted to palladium-catalyzed cyclization, under different required conditions, to give several differently substituted thieno[3,2-c] or [2,3-b]carbazoles and indolo[3,2-b]benzo[b]thiophenes. This constitutes a novel synthetic route to both tetracyclic systems.

Full text of DOI:10.1016/S0040-4020(03)00552-0

Tetrahedron 59 (2003) 3737–3743
Palladium-catalyzed amination and cyclization to
heteroannellated indoles and carbazoles
b
Isabel C. F. R. Ferreira,a Maria-Joa˜o R. P. Queiroza and Gilbert Kirsch
,
*
a
´
Departamento de Quımica, Campus de Gualtar, Universidade do Minho, 4710-057 Braga, Portugal
´
b
´ ´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Universite de Metz Faculte des Sciences, Ile du Saulcy,
57045 Metz, France
Received 23 January 2003; revised 19 March 2003; accepted 1 April 2003
Abstract—New ortho-bromodiarylamines in the benzo[b]thiophene series were prepared by palladium-catalyzed amination, either in the
benzene or in the thiophene ring. These were submitted to palladium-catalyzed cyclization, under different required conditions, to give
several differently substituted thieno[3,2-c] or [2,3-b]carbazoles and indolo[3,2-b]benzo[b]thiophenes. This constitutes a novel synthetic
route to both tetracyclic systems. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
reoxidation of Pd(0) formed by Cu(OAc)2, allowed also
the synthesis of a ring A methoxylated thienocarbazole.5
Heteroannellated indole and carbazole alkaloids constitute
an important class of natural compounds due to their
biological activities mostly based on their special affinity
toward DNA.1 Therefore, these compounds play a crucial
role as potential leads for the discovery of antitumor active
drugs using bioisosteric replacements.2 The use of classical
isosteres as benzene, thiophene and pyridine resulted in
analogues with biological activity retention among different
series of pharmacological agents with changes in selectivity,
toxicity and metabolic stability. However there are many
examples where this methodology has resulted in the
preparation of molecules with marked increases in potency
as well as efficacy.3 With this in mind, recently we have
studied several convergent ring B routes for the synthesis of
methylated thienocarbazoles, bioisosteres of pyridocarba-
zoles (ellipticines and olivacines), from precursors obtained
either by C–C4 or C–N5 palladium or copper catalyzed
cross couplings followed by intramolecular cyclizations. In
particular, using the Sakamoto’s palladium-catalyzed cycli-
zation conditions, described for the convergent ring B
synthesis of carbazoles and carbolines from ortho-bromo-
diarylamine precursors,6 we were not able to obtain the
corresponding thienocarbazole from an ortho-bromo-
diarylamine. Under the same conditions this was possible
from the ortho-bromodiarylacetamide occurring cyclization
with N-deprotection.5 In the same work another method
based on the palladium electrophilic attack on both aromatic
rings of ortho-unhalogenated diarylamines and on the
Herein we describe the synthesis of several differently
substituted thieno[3,2-c] and [2,3-b]carbazoles and
indolo[3,2-b]benzo[b]thiophenes via ortho-bromodiaryl-
amines. The latter were obtained by palladium-catalyzed
amination5,7 performed on both rings of the benzo[b]thio-
phene moiety and were submitted to palladium-catalyzed
intramolecular cyclization under Sakamoto’s6 or Jeffery’s8
conditions as required. The tetracyclic compounds prepared
may have biological activity or/and may be used as
biomarkers due to their fluorescence already studied by
us9 and possible DNA intercalation which is in study. The
presence of methoxy groups in this type of compounds
showed to be important for biological activity, the
9-methoxyellipticine10 being much more active than the
ellipticine itself. The ortho-bromodiarylamines obtained
may be interesting either for biological or for electro-
luminescent devices, in this latter case not only by their own
properties but also by allowing polymerization to poly-
arylamines, using the same type of palladium-catalyzed
amination.11
2. Results and discussion
2.1. Synthesis of ortho-bromodiarylamines and intra-
molecular cyclization to thienocarbazoles
6-Bromo and 6-amino 2,3,5-trimethylbenzo[b]thiophenes
14 and 2a5,7 were coupled respectively with ortho-bromo
anilines 3 or 1,2,4-tribromobenzene under Buchwald–
Hartwig palladium-catalyzed amination12 conditions to
Keywords: palladium; amination; ortho-bromodiarylamines; cyclization;
thienocarbazoles; indolobenzo[b]thiophenes.
*
Corresponding author. Tel.: þ351-253604378; fax: þ351-253678983;
e-mail: mjrpq@quimica.uminho.pt
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00552-0

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I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 3737–3743
give ortho-bromodiarylamines 4 which were submitted to
intramolecular cyclization under Jeffery’s conditions8
(Scheme 1). Aniline 3a was prepared by bromination of
(Scheme 1). This is in agreement with other authors who
had already observed that these conditions were not
effective for substrates having electron withdrawing
groups.8b
p-anisidine
(Bu4NBr3) following the literature procedure for the
using
tetrabutylammoniumtribromide
synthesis of 3b.13
Following the same methodology the linear thieno[2,3-b]-
carbazole 6d was obtained from the ortho-bromodiaryl-
amine 4e, which was prepared from the coupling of
2-bromo-iodobenzene with 6-amino-2,3,4,7-tetramethyl-
benzo[b]thiophene 2b7 (Scheme 2). No dehalogenation
was observed either in the coupling or in the cyclization
reaction. In the synthesis of 6d higher amounts of catalyst
and Bu4NBr were needed together with longer time and
higher temperature, the additions being made after 24 h of
heating at 858C. The reaction was heated for more 24 h at
958C in the new conditions, as shown in Scheme 2.
The yields of 4a–d were in the range of 30–35% in the best
case, after choosing the right base. During the synthesis of
4a and 4b, ortho-dehalogenation to the corresponding
diarylamines 5a and 5b also occurred (10–15%).
The methoxylated ortho-bromodiarylamines 4a and 4b
were obtained using t-BuONa as the base, while for the
synthesis of 4d, Cs2CO3 was the most effective base.
We had previously reported the preparation of the
diarylamine 4c, but the cyclization under Sakamoto’s
conditions (Pd(OAc)2, Na2CO3 in DMF) didn’t afford the
corresponding thienocarbazole.5 These conditions were also
not effective when applied to the new substituted ortho-
bromodiarylamines 4a, 4b and 4d obtained in the present
work. The use of Jeffery’s conditions with tetrabutyl-
ammonium bromide (Bu4NBr),8 allowed the cyclization of
4a–c to afford the thienocarbazoles 6a–c in moderate to
quantitative yields (Scheme 1). Some dehalogenation
occurred in the synthesis of thienocarbazole 6b depending
on the temperature. In the synthesis of 6c no dehalogenation
occurred and the unreacted diarylamine was recovered.
The cyclization of ortho-bromodiarylamines 4 in the
presence of Bu4NBr may be due to the coordination and
thereby solvation of the palladium intermediates by the
bromide ions present in the reaction mixture. Once the
‘locked’ palladium catalyst is released from the substrates,
the catalytic cycle continues smoothly as claimed by
others.8b
2.2. Synthesis of ortho-bromodiarylamines and
intramolecular cyclization to indolobenzo[b]thiophenes
3-Bromobenzo[b]thiophene was coupled with ortho-bromo-
anilines 3a–c to give the corresponding ortho-bromo-
diarylamines 7a–c (30–40%) (Scheme 3). The use of
t-BuONa as the base and higher amounts of Pd(OAc)2 and
When applied to ortho-bromodiarylamine 4d, the same
conditions didn’t afford the corresponding thienocarbazole
Scheme 1. Synthesis of o-bromodiarylamines 4 and intramolecular cyclization to thienocarbazoles 6. (i) Pd(OAc)2(3 mol%), BINAP(4 mol%). t-BuONa or
Cs2CO3 (1.4 equiv.) toluene 908C or 1008C, under Ar; (ii) Pd(OAc)2 (50 mol%), K2CO3(2.5 equiv.), Bu4NBr(Stoichi.), DMF 75 or 858C, under Ar.

I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 3737–3743
3739
Scheme 2. Synthesis of o-bromodiarylamine 4e and intramolecular cyclization to thienocarbazoles 6d. (i) Pd(OAc)2(3 mol%), BINAP(4 mol%). t-BuONa
(1.4 equiv.) toluene 22 h, 1008C, under Ar; (ii) Pd(OAc)2 (50þ50 mol%), k2CO3(2.5 equiv.), Bu4NBr (Stoichi.þ0.5 equiv.), DMF 24 h, 858C,þ24 h, 958C
under Ar.
BINAP were necessary for the coupling in these cases. The
diarylamines 7 were cyclized to the corresponding indolo-
benzo[b]thiophenes 8 in good to high yields, under
Sakamoto’s conditions and without the need of Bu4NBr
(Scheme 3). This is due to the fact that the cyclization in this
case is toward a more reactive heterocyclic ring instead of a
benzene ring.
used, following Jeffery’s conditions, while the indolo-
benzo[b]thiophenes were obtained simply by the application
of the Sakamoto’s conditions.
Both tetracyclic heteroaromatic systems being bioisosteres
of natural anti-tumor pyridocarbazoles can act as DNA-
binding agents which may be used as medical or relevant
probes or drugs due to their fluorescence properties. The
presence of methoxy groups in the molecules can be very
important for the biological activity of this type of
compounds as observed for 9-methoxyellipticine. The
ortho-bromodiarylamines could also find application either
in biology or in materials science due not only to their
properties of diarylamine moiety but also by allowing
polymerization to polyarylamines.
Unexpectedly when 1.2 equiv. of 2-bromoaniline were used
in the coupling reaction, it was possible to obtain compound
8c directly in 20% yield together with diarylamine 7c in
16% yield. Attempts to obtain also the methoxylated
compounds 8a and 8b in a one pot procedure using the
latter conditions, were not successful. Indolobenzo[b]thio-
phene 8c had already been prepared by other authors using a
different method.14
4. Experimental
3. Conclusion
4.1. Materials and methods
A novel synthetic route to thienocarbazoles and indolo-
benzo[b]thiophenes is presented via ortho-bromodiaryl-
amines obtained by palladium-catalyzed amination on both
rings of the benzo[b]thiophene moiety. The palladium-
catalyzed intramolecular cyclization to thienocarbazoles
was successful when tetrabutylammonium bromide was
Melting points (8C) were determined in a Gallenkamp
apparatus and are uncorrected. IR spectra were recorded as
nujol mulls on a Perkin–Elmer 1600-FTIR spectro-
1
photometer and wavenumbers are given in cm21. H and
13C NMR spectra were recorded on a Varian Unity Plus
Scheme 3. Synthesis of o-bromodiarylamines 7 and intramolecular cyclization to indolobenzo[b]thiophenes 8. (i) Pd(OAc)2(5 mol%), BINAP(7.5 mol%).
t-BuONa (1.4 equiv.) toluene 1008C, under Ar; (ii) Pd(OAc)2 (10 mol%), Na2CO3(1.4 equiv.), reflux DMF.

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(300 and 75.4 MHz, respectively). 1H–1H spin–spin
decoupling and DEPT u 458 were used. Chemical shifts
are given in ppm and coupling constants in Hz. The mass
spectra (EI) and the HRMS were obtained from the mass
spectrometry external service of the University of Vigo
(Spain). Elemental analysis was performed on a LECO
CHNS 932 elemental analyser.
Removal of the solvent gave an oil, after removal of traces
of toluene with MeOH, which was submitted to column
chromatography to give the product and in some cases the
correponding dehalogenated diarylamine.
4.2.1. 6-(2-Bromo-4-methoxyphenyl)amino-2,3,5-tri-
methylbenzo[b]thiophene (4a). From 6-bromobenzo-
[b]thiophene 1 (0.49 g, 1.9 mmol), 2-bromo-4-methoxy-
aniline 3a (0.46 g, 2.3 mmol) and using petroleum ether in
the column chromatography, compound 4a was obtained as
a white solid (0.22 g, 30%). Crystalization from ether/
petroleum ether gave colourless crystals, mp 120–122. IR:
3413 (N–H). 1H NMR: (CDCl3) 2.29 (3H, s, Me), 2.40 (3H,
s, Me), 2.47 (3H, s, Me), 3.80 (3H, s, OMe), 5.61 (1H, s,
N–H), 6.81 0(1H, dd, J¼9 and 3 Hz, H-50), 6.98 (1H, d,
J¼9 Hz, H-6 ), 7.18 (1H, d, J¼3 Hz, H-30), 7.44 (2H, s, H-4
and 7). 13C NMR: (CDCl3) 11.35 (CH3), 13.67 (CH3), 18.29
(CH3), 55.83 (OCH3), 112.05, 113.71 (C), 114.45, 118.02,
118.93, 122.73, 126.29 (C), 126.35 (C), 131.69 (C), 135.83
(C), 136.57 (C), 136.68 (C) 138.26 (C), 153.92 (C). MS: 377
(100, Mþ 81Br), 375 (97, Mþ 79Br), 362 (28, Mþ 81Br215),
360 (26, Mþ 79Br215), 298 (21, Mþ280), 281 (28). HRMS
C18H18BrNOS: calcd Mþ 79Br 375.02925; found
375.02964.
The reactions were monitored by thin layer chromatography
(TLC). Column chromatography was performed on
Macherey–Nagel silica gel 230–400 mesh. Preparative
Layer Chromatography (PLC) was performed in 20£20 cm2
Plate Macherey–Nagel, Layer 2 mm SIL G-200 UV254
.
Petroleum ether refers to the boiling range 40–608C. Ether
refers to diethylether. When solvent gradient was used, the
increase of polarity was made gradually from neat
petroleum ether to mixtures of ether/petroleum ether
increasing 10% of ether until the isolation of the product.
Compounds 1 and 2 were prepared by methods already
described by us.4,5,7 Compound 3b was prepared as already
described by others.13 Compound 4c was already prepared
by us from compound 1 or 2a.5
4.1.1. 2-Bromo-4-methoxyaniline (3a). To a solution of
p-anisidine (1.0 g, 8.1 mmol) in CH2Cl2 (27 ml) and MeOH
(13 ml) was added Bu4NBr3 (3.6 g, 7.5 mmol) and the
mixture was stirred at r.t. for 2 h. Ether (15 ml) and sat.
Na2SO3 solution (30 ml) were added and the phases were
separated. The organic phase was washed with water
(20 ml), dried (MgSO4) and filtered. Removal of the solvent
gave an oil which was submitted to column chromatography
using solvent gradient from neat petroleum ether to 50%
ether/petroleum ether to give compound 3a (0.69 g, 42%) as
As a slightly more polar product the corresponding
dehalogenated amine 5a was also isolated (82 mg, 15%)
with identical properties to a sample prepared by us from
other starting materials.7
4.2.2. 6-(2-Bromo-4,5-dimethoxyphenyl)amino-2,3,5-tri-
methylbenzo[b]thiophene (4b). From 6-bromobenzo-
[b]thiophene 1 (0.40 g, 1.6 mmol), 2-bromo-4,5-dimethoxy-
aniline 3b13 (0.44 g, 1.9 mmol) and using solvent gradient
from neat petroleum ether to 10% ether/petroleum ether in
the column chromatography, compound 4b was obtained as
a white solid (0.22 g, 35%). Crystallization from ether/
petroleum ether gave colourless crystals, mp 125–127. IR:
3377 (N–H). 1H NMR: (CDCl3) 2.29 (3H, s, Me), 2.40 (3H,
s, Me), 2.46 (3H, s, Me), 3.72 (3H, s, OMe), 3.87 (3H, s,
OM0e), 5.59 (1H, s, N–H), 6.61 (1H, s, H-60), 7.07 (1H, s,
H-3 ), 7.44 (1H, s, H-4 or 7), 7.47 (1H, s, H-7 or 4). 13C
NMR: (CDCl3) 11.36 (CH3), 13.69 (CH3), 18.35 (CH3),
55.99 (OCH3), 56.56 (OCH3), 102.32, 102.42 (C), 112.54,
115.83, 122.80, 126.40 (C), 126.67 (C), 131.95 (C), 135.99
(C), 136.53 (C), 136.89 (C), 137.98 (C), 143.53 (C), 149.17
(C). MS: 407 (100, Mþ 81Br), 405 (98, Mþ 79Br), 392 (35,
Mþ 81Br215), 390 (33, Mþ 79Br215). HRMS C19H20-
BrNO2S: calcd Mþ 79Br 405.03981; found 405.04168.
1
a purple oil. H NMR: (CDCl3) 3.69 (2H, s, 2£NH), 3.73
(3H, s, OMe), 6.72–6.74 (2H, m, 2£Ar-H), 7.01 (1H, broad
s, Ar-H). 13C NMR: (CDCl3) 55.85 (OCH3), 109.56 (C),
114.97, 116.60, 117.39, 137.81 (C), 152.60 (C). MS: 203
(97, Mþ 81Br), 201 (100, Mþ 79Br), 188 (90, Mþ 81Br215),
186 (92, Mþ 79Br215). HRMS C7H8BrNO: calcd Mþ 79Br
201.98228; found 201.98365.
As a less polar product, 2,6-dibromo-4-methoxyaniline was
also isolated as white crystals (0.45 g, 20%), mp 81–83. 1H
NMR: (CDCl3) 3.73 (3H, s, OMe), 4.20 (2H, s, 2£N–H),
7.03 (2H, s, H-3 e 5). MS: 283 (39, Mþ 81Br, 81Br) 281 (79,
M
þ 79Br, 81Br), 279 (41, Mþ 79Br, 79Br), 268 (47, 283215),
266 (100, 281215), 264 (50, 279215). Anal. Calcd for
C7H7Br2NO: C 29.93, H 2.51, N 4.99; found: C 30.10, H
2.62, N 4.98.
As a slightly more polar product the corresponding
dehalogenated amine 5b was also isolated (50 mg, 10%)
with identical properties to a sample prepared by us from
other starting materials.7
4.2. General procedure for the synthesis of ortho-
bromodiarylamines precursors of thienocarbazoles
A dry Schlenk tube was charged, under Ar, with dry toluene
(3–5 ml), the aniline or aryl halide, the benzo[b]thiophene 1
or 2, Pd(OAc)2 (3 mol%), racemic BINAP (4 mol%),
t-BuONa or Cs2CO3 as base (1.4 equiv.), and the mixture
was heated at 908C or 1008C respectively, for several hours
(Scheme 1 or 2). The reaction was followed by TLC. After
cooling water and ether were added. The phases were
separated, the aqueous phase was extracted with more ether
and the organic phase was dried (MgSO4) and filtered.
4.2.3. 6-(2,4-Dibromophenyl)amino-2,3,5-trimethyl-
benzo[b]thiophene (4d). From 6-aminobenzo[b]thiophene
2a (0.15 g, 0.78 mmol), 1,2,4-tribromobenzene (0.21 g,
0.65 mmol) and using petroleum ether in the column
chromatography, compound 4d was obtained as a white
solid (0.10 g, 35%). Crystallization from petroleum ether
gave colourless crystals, mp 156–158. IR: 3408 (N–H). 1H
NMR: (CDCl3) 2.29 (3H, s, Me), 2.33 (3H, s, Me), 2.47 (3H,

I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 3737–3743
3741
s, Me), 5.44 (1H, s, N–H), 6.64 0(1H, dd, J¼9 and 3 Hz,
H-500), 7.05 (1H, d, J¼3 Hz, H-3 ), 7.38 (1H, d, J¼9 Hz,
H-6 ), 7.44 (1H, s, H-7), 7.55 (1H, s, H-4). 13C NMR:
(CDCl3) 11.39 (CH3), 13.79 (CH3), 18.36 (CH3), 112.84
(C), 115.79, 115.91, 119.83, 122.99, 125.17 (C), 126.45 (C),
128.52 (C), 133.24 (C), 133.74, 135.77 (C), 136.44 (C),
138.37 (C), 145.82 (C). MS: 427 (57, Mþ 81Br, 81Br), 425
(100, Mþ 79Br, 81Br), 423 (53, Mþ 79Br, 79Br). Anal. Calcd
for C17H15Br2NS: C 48.02, H 3.56, N 3.29, S 7.54; found: C
48.27, H 3.79, N 3.30, S 7.29.
NMR: (CDCl3) 2.39 (3H, s, Me), 2.58 (3H, s, Me), 2.64 (3H,
s, Me), 3.98 (3H, s, OMe), 4.09 (3H, s, OMe), 7.03 (1H, s,
H-7), 7.37 (1H, s, H-10), 7.57 (1H, s, H-4), 8.01 (1H, s,
N–H). 13C NMR: (CDCl3) 11.77 (CH3), 13.74 (CH3), 17.13
(CH3), 55.16 (OCH3), 56.56 (OCH3), 94.45, 103.61, 115.11
(C), 116.35 (C), 117.14 (C), 118.04, 127.07 (C), 127.48 (C),
129.22 (C), 133.73 (C), 134.82 (C), 136.23 (C), 144.72 (C),
148.84 (C). MS: m/z 325 (100, Mþ). HRMS C19H19NO2S:
calcd Mþ 325.11365; found 325.11520.
The corresponding dehalogenated diarylamine 5b was also
isolated as a more polar product (16 mg, 15%) with identical
properties to a sample prepared by other method.7
4.2.4. 6-(2-Bromophenyl)amino-2,3,4,7-tetramethyl-
benzo[b]thiophene (4e). From 6-aminobenzo[b]thiophene
2b (0.15 g, 0.73 mmol), 2-bromo-iodobenzene (0.21 g,
0.73 mmol) and using neat petroleum ether to 10% ether/
petroleum ether in the column chromatography purification,
compound 4e was obtained as a white solid (0.17 g, 65%).
Crystallization from ether/petroleum ether gave colourless
crystals, mp 148–150. IR: 3384 (N–H). 1H NMR: (CDCl3)
2.34 (3H, s, Me), 2.47 (3H, s, Me), 2.52 (3H, s, Me), 02.71
(3H, s, Me), 5.91 (1H, s, N–H), 6.59–6.67 (2H, m, H-4 and
60), 6.97 (1H, s, H-5), 7.07 (1H, td, J¼0 7.8 and 1.5 Hz, H-50),
7.50 (1H, dd, J¼7.8 and 1.5 Hz, H-3 ). 13C NMR: (CDCl3)
14.09 (CH3), 15.20 (CH3), 15.49 (CH3), 21.30 (CH3),
110.08 (C), 113.93, 119.12, 124.26 (C), 125.11, 128.15,
129.20 (C), 131.31 (C), 132.53, 132.57 (C), 133.65 (C),
136.64 (C), 140.29 (C), 143.64 (C). Anal. Calcd for
C18H18BrNS: C 60.00, H 5.04, N 3.89, S 8.90; found: C
60.23, H 5.03, N 3.95, S 8.90.
4.3.3. 2,3,5-Trimethyl-6H-thieno-[3,2-c]carbazole (6c).5
From ortho-bromodiarylamine 4c (85 mg, 0.25 mmol) the
thienocarbazole 6c was obtained as a white solid after PLC
(19 mg, 30%). Crystallization from ether/petroleum ether
gave colourless crystals, with identical properties to a
sample prepared by other method.5
4.3.4. 2,3,4,7-Tetramethyl-9H-thieno-[2,3-b]carbazole
(6d). From ortho-bromodiarylamine 4e (0.12 g,
0.33 mmol), following the general procedure described
above but increasing the amounts of the catalyst and of
Bu4NBr and the temperature after 24 h (like shown in
Scheme 2) and heating for more 24 h, the thienocarbazole
6d was obtained after column chromatography using
petroleum ether to 30% ether/petroleum ether as a white
solid (33 mg, 35%). Crystallization from ether/petroleum
ether gave colourless crystals, mp 232–234. IR: 3414
4.3. General procedure for the intramolecular
cyclization of ortho-bromodiarylamines 4 to thieno-
[3,2-c]carbazoles 6a–c
1
(N–H). H NMR: (CDCl3þDMSO-d6) 2.28 (3H, s, Me),
2.42 (3H, s, Me), 2.45 (3H, s, Me), 3.05 (3H, s, Me), 6.98
(1H, t, J¼8 Hz, ArH), 7.18 (1H, t, J¼8 Hz, ArH), 7.29 (1H,
d, J¼8 Hz, H-8), 8.05 (1H, d, J¼8 Hz, H-5) 9.80 (1H, s,
N–H). 13C NMR: (CDCl3þDMSO-d6) 13.87 (CH3), 14.63
(CH3), 16.04 (CH3), 16.60 (CH3), 108.46 (C), 110.03,
117.84, 120.99 (C), 122.36, 124.05 (C), 124.25, 124.86 (C),
128.14 (C), 128.62 (C), 131.90 (C), 136.04 (C), 136.65 (C),
140.67 (C). Anal. Calcd for C18H17NS: C 77.38, H 6.13, N
5.01, S 11.47; found: C 77.52, H 6.09, N 5.03, S 11.52.
A dry Schlenk tube was charged, under Ar, with dry DMF
(3–4 ml), the ortho-bromodiarylamine 4, Pd(OAc)2
(50 mol%), K2CO3 as base (2.5 equiv.), Bu4NBr (stoich.)
and the mixture was heated at 758C or 858C for several
hours (Scheme 1). The reaction was followed by TLC. After
cooling CHCl3 was added. The phases were separated, the
aqueous phase was extracted with more CHCl3 and the
organic phase was dried (MgSO4) and filtered. Removal of
the solvent gave an oil, which was submitted to PLC (50%
ether/petroleum ether) unless stated, to give the product and
in some cases the corresponding dehalogenated
diarylamine.
4.4. General procedure for the synthesis of ortho-
bromodiarylamines 7 precursors of indolobenzo[b]-
thiophenes
A dry Schlenk tube was charged, under Ar, with dry toluene
(3–5 ml), 3-bromobenzo[b]thiophene (1.1 equiv.), the
ortho-bromoaniline 3, Pd(OAc)2 (5 mol%), racemic
BINAP (7.5 mol%) and t-BuONa (1.4 equiv.) as base and
the mixture was heated at 1008C for several hours
(Scheme 3). The reaction was followed by TLC. After
cooling water and ether were added. The organic phase was
separated, dried (MgSO4) and solvent removed to give an
oil which was submitted to chromatographic purification
using solvent gradient from petroleum ether to 30% ether/
petroleum ether to give the product and starting materials.
4.3.1. 9-Methoxy-2,3,5-trimethyl-6H-thieno-[3,2-c]car-
bazole (6a). From ortho-bromodiarylamine 4a (0.11 g,
0.29 mmol) and heating for 5 h at 858C, following the
general procedure, the thienocarbazole 6a was obtained as a
white solid (86 mg, quantitative yield), which after
crystalization from ether/petroleum ether gave colourless
crystals, with identical properties to a sample prepared by
other method.5
4.3.2. 8,9-Dimethoxy-2,3,5-trimethyl-6H-thieno-[3,2-
c]carbazole (6b). From ortho-bromodiarylamine 4b
(0.13 g, 0.32 mmol) and heating for 9 h at 758C, following
the general procedure, the thienocarbazole 6b was obtained
as a white solid (30 mg, 30%), after PLC (50% ether/
petroleum ether). Crystallization from ether/petroleum ether
gave colourless crystals, mp 210–212. IR: 3438 (N–H). 1H
4.4.1. 3-(2-Bromo-4-methoxyphenyl)aminobenzo[b]thio-
phene (7a). From 2-bromo-4-methoxyaniline 3a (0.50 g,
2.5 mmol), compound 7a was obtained as a rosed solid after
chromatographic purification (0.24 g, 30%). Crystallization
from ether/petroleum ether gave rosed crystals, mp 85–87.

3742
I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 3737–3743
IR: 3395 (N–H). 1H NMR: (CDCl3) 3.79 (3H, s, OMe), 6.00
(1H, broad s, N–H), 6.79 (1H, dd, J¼9 and 2.7 Hz, H-50),
6.95 (1H, s, H-2), 7.05 (1H, d, J¼9 Hz, H-60), 7.16 (1H, d,
J¼2.7 Hz, H-30), 7.38–7.42 (2H, m, 2£ArH), 7.66–7.69
(1H, m, ArH), 7.83–7.87 (1H, m, ArH). 13C NMR: (CDCl3)
55.88 (OCH3), 109.39, 112.02 (C), 114.57, 117.44, 117.91,
120.62, 123.20, 124.01, 124.95, 134.45 (C), 135.16 (C),
135.99 (C), 138.89 (C), 153.63 (C). MS: 335 (100, Mþ
81Br), 333 (96, Mþ 79Br), 320 (42, Mþ 81Br215), 318 (42,
N–H). 13C NMR: (CDCl3) 55.88 (OCH3), 101.16, 112.91,
113.36, 116.18 (C), 119.36, 122.78 (C), 124.13, 124.25,
124.41, 126.74 (C), 135.47 (C), 137.60 (C), 142.76 (C),
154.32 (C). MS: 253 (100, Mþ), 238 (20, Mþ215), 210
(48). Anal. Calcd for C15H11NOS: C 71.42, H 4.38, N 5.53,
S 12.66; found: C 71.09, H 4.31, N 5.55, S 12.30.
4.5.2. 8,9-Dimethoxy-6H-indolo[3,2-b]benzo[b]thiophene
(8b). From ortho-diarylamine 7b (0.10 g, 0.28 mmol)
compound 8b was obtained as a beje solid (46 mg, 60%),
mp 120–122. IR: 3406 (N–H). 1H NMR: (CDCl3
þ([D6]DMSO) 3.82 (3H, s, OMe), 3.83 (3H, s, OMe),
6.91 (1H, s, H-7), 7.03 (1H, s, H-10), 7.10–7.16 (1H, m, H-3
or 4), 7.21–7.27 (1H, m, H-4 or 3), 7.70 (1H, broad d,
J¼8 Hz, H-2 or 5), 7.79 (1H, broad d, J¼8 Hz, H-5 or 2),
10.60 (1H, s, N–H). 13C NMR: ([D6]DMSO) 55.79 (OCH3),
55.92 (OCH3), 95.44, 100.39, 114.45 (C), 114.74 (C),
119.03, 122.78, 123.67, 123.73, 126.99 (C), 134.99 (C),
136.13 (C), 141.55 (C), 144.22 (C), 147.01 (C). MS: 283
(100, Mþ), 268 (35, Mþ215). Anal. Calcd for C16H13NO2S
calcd C 67.82, H 4.62, N 4.94, S 11.31; found: C 67.44, H
4.94, N 4.95, S 10.88.
M
þ 79Br215), 254 (25, Mþ280), 239 (23), 223 (25), 210
(32). HRMS C15H12BrNOS calcd Mþ 79Br 333.98565;
found 333.98695.
4.4.2. 3-(2-Bromo-3,4-dimethoxyphenyl)aminobenzo-
[b]thiophene (7b). From 2-bromo-4,5-dimethoxyaniline
3b13 (0.50 g, 2.2 mmol), heating for 16 h and following
the general procedure, compound 7b was obtained as a
rosed solid after chromatographic purification (0.23 g,
30%). Crystallization from ether/petroleum ether gave
1
rosed crystals, mp 100–102. IR: 3413 (N–H). H NMR:
(CDCl3) 3.71 (3H, s, OMe), 3.87 (3H, s, OMe), 5.99 (1H, s,
N–H), 6.76 (1H, s, H-60), 6.97 (1H, s, H-2), 7.06 (1H, s,
H-30), 7.39–7.43 (2H, m, 2£ArH), 7.68–7.73 (1H, m, ArH),
7.84–7.88 (1H, m, ArH). 13C NMR: (CDCl3) 56.03
(OCH3), 56.59 (OCH3), 100.99 (C), 101.41, 109.19,
115.78, 120.66, 123.21, 124.05, 125.07, 134.40 (C),
135.12 (C), 135.99 (C), 138.89 (C), 143.38 (C), 149.26
(C). Anal. Calcd for C16H14BrNO2S: C 52.76, H 3.87, N
3.85, S 8.80; found: C 52.70, H 4.16, N 3.97, S 8.86.
4.5.3. 6H-Indolo[3,2-b]benzo[b]thiophene (8c). From
ortho-bromodiarylamine 7c (80 mg, 0.26 mmol) compound
8c was obtained as a white solid (58 mg, quantitative yield).
Crystallization from ether/petroleum ether gave colourless
1
crystals, mp 251–253 (lit14 250–252). H NMR: (CDCl3)
7.22–7.50 (4H, m, H-3,4, 8 and 9), 7.55 (1H, broad d,
J¼8 Hz, ArH), 7.79(1H, broad d, J¼8 Hz, ArH), 7.88 (1H,
broad d, J¼8 Hz, ArH), 7.92 (1H, broad d, J¼8 Hz, ArH),
8.60 (1H, s, N–H). 13C NMR: (CDCl3) 112.15, 116.59 (C),
119.33, 119.36, 120.22, 122.50 (C), 123.34, 124.14, 124.25,
124.43, 126.63 (C), 136.82 (C), 140.54 (C), 142.87 (C). MS:
223 (100, Mþ), 121 (11). HRMS C14H9NS: calcd Mþ
223.045571; found 223.045592.
4.4.3. 3-(2-Bromophenyl)aminobenzo[b]thiophene (7c).
From 2-bromoaniline 3c (0.50 g, 2.9 mmol), compound 7c
was obtained as an oil after chromatographic purification
(0.35 g, 40%). 1H NMR: (CDCl3) 6.30 (1H, s, N–H), 6.65–
6.75 (1H, m, ArH), 6.98 (1H, dd, J¼8.1 and 1.5 Hz, H-60),
7.10–7.17 (1H, m, ArH),7.18 (1H, s, H-2) 7.36–7.43 (2H,
m, 2£ArH), 7.55 (1H, dd, J¼8.1 and 1.5 Hz, H-30), 7.64–
7.67 (1H, m, ArH), 7.85–7.89 (1H, m, ArH). 13C NMR:
(CDCl3) 110.45 (C), 113.63, 114.78, 120.12, 120.90,
123.15, 124.11, 124.97, 128.31, 132.62, 133.51 (C),
134.84 (C), 138.74 (C), 142.37 (C). MS: 305 (70, Mþ
81Br), 303 (69, Mþ 79Br), 224 (75), 223 (100). HRMS
C14H10BrNS: calcd Mþ 81Br 305.97425; found 305.97304.
Acknowledgements
Thanks are due to Foundation for the Science and
Technology-IBQF-Univ. Minho (Portugal), to the Research
Incitment Programme of the Calouste Gulbenkian
Foundation (Portugal) for financial support and to Escola
4.5. General procedure for the intramolecular
cyclisation of ortho-bromodiarylamines 7 to indolo-
[3,2-b]benzo[b]thiophenes 8
´
Superior Agraria-Instituto Politecnico de Braganc¸a for
supporting in part Isabel C. F. R. Ferreira PhD.
´
ortho-Bromodiarylamines 7, Pd(OAc)2 (10%) and Na2CO3
(1.4 equiv.) were refluxed in dry DMF (4–5 ml), for 2 h.
The reaction was followed by TLC. After cooling, CHCl3
was added. The organic phase was separated, dried
(MgSO4), filtered and the solvent removed to give the
product which was submitted to crystallization using ether/
petroleum ether.
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