Synthesis of diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups by Buchwald-Hartwig C-N coupling

Article abstract of DOI:10.1016/S0040-4020(02)01656-3

Diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups, were prepared by Buchwald-Hartwig C-N coupling in moderate to high yields. The conditions used were Pd(OAc)₂ (3mol%), BINAP as ligand (4mol%) and Cs

Full text of DOI:10.1016/S0040-4020(02)01656-3

Tetrahedron 59 (2003) 975–981
Synthesis of diarylamines in the benzo[b]thiophene series bearing
electron donating or withdrawing groups by Buchwald–Hartwig
C–N coupling
b
Isabel C. F. R. Ferreira,a Maria-Joa˜o R. P. Queiroza and Gilbert Kirsch
,
*
a
´
Departamento de Quımica, Universidade do Minho, 4710-057 Braga, Portugal
´ ´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Universite de Metz, Faculte des Sciences,
b
´
Ile du Saulcy, 57045 Metz, France
Received 19 September 2002; revised 6 November 2002; accepted 17 December 2002
Abstract—Diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups, were prepared by Buchwald–
Hartwig C–N coupling in moderate to high yields. The conditions used were Pd(OAc)2 (3 mol%), BINAP as ligand (4 mol%) and Cs2CO3 as
base (1.4 equiv.), in toluene at 1008C, being 6-bromo or amino benzo[b]thiophenes coupled, respectively, with substituted anilines or
phenylbromides. The 6-aminobenzo[b]thiophene derivatives were also prepared by palladium catalyzed C–N coupling of the corresponding
6-bromo compounds with benzophenone imine, followed by acidic hydrolysis of the imino derivatives. When 4-nitrobromobenzene and
4-bromobenzonitrile were used as coupling components, triarylamines were also isolated in small amounts. The presence of a fluorine atom
on the phenylbromide highly increases the diarylamine yields. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
arylamines from aryl bromides using benzophenone imine
as an ammonia surrogate.11
The palladium catalyzed amination of aryl halides has
become an important method for the synthesis of arylamines
found in pharmaceuticals,1,2 materials with important
electronic properties3–5 and ligands for transition metals.6
Here we report the synthesis of diarylamines in the
benzo[b]thiophene series bearing electron donating or
withdrawing groups, by palladium catalyzed amination of
aryl halides using Pd(OAc)2, racemic BINAP as ligand and
Cs2CO3 as base. The benzo[b]thiophenes are important
heterocycles either as biological active molecules or as
electronic or luminescent components used in organic
materials.12 In some cases triarylamines were also obtained
as by-products in a small amount. The triarylamine moiety
is also known by its important electronic properties,
particularly for electron luminescent devices.13
During the past six years extensive research devoted to the
development of palladium catalyzed carbon–nitrogen bond
formation has led to efficient systems that offer considerable
advantages over the classical methods (i.e. non-activated
substrates can be used, and neither highly polar solvents nor
severe reaction conditions are required).7,8 The combination
Pd/racemic BINAP is an excellent catalyst system for the
coupling of primary amines with arylbromides.9,10
Although a general protocol had been developed for the
palladium catalyzed cross coupling of primary and secon-
dary amines with aryl bromides using sodium tert-butoxide
(t-BuONa),9 this base presented problems with a number of
common functional groups such as esters, aldehydes,
enolizable ketones, nitriles and nitro groups. The scope of
this method was further expanded by the use of caesium
carbonate (Cs2CO3),10 allowing the coupling of aryl
bromides which were incompatible with t-BuONa. With
this methodology it is also possible to synthesize primary
The 6-aminobenzo[b]thiophenes coupling components were
also prepared by C–N cross coupling of the corresponding
bromo compounds with benzophenone imine followed by
acidic hydrolysis of the imino derivatives.
2. Results and discussion
The regioselectively obtained 6-bromobenzo[b]thiophenes
114 were coupled using two different catalytic systems, with
benzophenone imine to give after hydrolysis of the imino
derivatives, the corresponding 6-aminobenzo[b]thiophenes
2 (Table 1). As far as our knowledge this is the first time that
aminobenzo[b]thiophenes were prepared using this method-
ology. Amine 2a have already been prepared by us from
Keywords: Buchwald–Hartwig coupling; palladium; amination;
diarylamines; benzo[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.
PII: S0040-4020(02)01656-3

976
Table 1. Synthesis and overall yields of 6-aminobenzo[b]thiophenes 2
Bromo compound Amine
I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 975–981
Catalytic system
a
Time (h)
22
Yield (%)
60
b
16
50
a
20
26
50
71
b
1.2 equiv. of HNvC(Ph)2, dry toluene 1008C, Ar.
a—Pd(OAc)2 (3 mol%), rac.BINAP (4 mol%), Cs2CO3 (1.4 equiv.).11a
b—Pd2(dba)3 (0.25 mol%), BINAP (0.75 mol%), CH3ONa (1.4 equiv.).11c
The imino derivatives were hydrolyzed with HCl 2.0 M in THF at rt.
deprotection of the corresponding acetamide which was
obtained by Beckmann rearrangement of the precursor
oxime.15
ing triarylamines 5b and 6b were also isolated as by-
products (Table 2). Increasing the amount of the amino-
benzo[b]thiophene 2b (1 to 1.2 equiv.) and decreasing the
heating time (17 to 5 h), the diarylamine 6a yield increased
(40 to 51%) with the decrease of triarylamine 6b yield (5 to
2%).
Benzo[b]thiophenes 1 and 2 were coupled with anilines or
phenylbromides bearing methoxy groups or different
electron withdrawing groups to give diarylamines 4–8 in
moderate to high yields using the same conditions (Table 2).
Diarylamine 4a has already been prepared by us in the same
yield using t-BuONa as base.15
Despite we had previously concluded that for the synthesis
of methoxylated diarylacetamides in this series by Goldberg
coupling,16 the amido group should be in the benzo[b]thio-
phene moiety, in this work the amino group may be in both
systems to afford diarylamines in good yields.
In the synthesis of diarylamines 5a and 6a, the correspond-
Table 2. Synthesis of diarylamines 4–8
Aniline or Aryl bromide
Benzo[b]thiophene
Heating time (h)
21
Products and yields
1a
2b
7
1a
1b
16
5

I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 975–981
977
Table 2 (continued)
Aniline or Aryl bromide
Benzo[b]thiophene
Heating time (h)
17
Products and yields
1a
1b
17
1a
17
1.3 equiv.
2a
17
2b 1.2 equiv.
5
2a
2a
21
20
1.1 equiv.
1.1 equiv.
2a
24
Reaction conditions: Pd(OAc)2 (3 mol%), rac.BINAP (4 mol%), Cs2CO3 (1.4 equiv.), dry toluene, 1008C, Ar. Control experiments were performed without
catalyst and no diarylamines were formed.
3. Conclusion
[b]thiophenes. The use of Cs2CO3 proved to be general either
in the synthesis of these compounds or in the synthesis of the
primary benzo[b]thiophene amines, with no need of changing
the catalytic system as some authors have claimed.10a
With this work several diarylamines in the benzo[b]thiophene
series bearing electron donating groups (1 or 2 OMe in
different positions) or withdrawing groups (CN, NO2, CHO
and F) were prepared either from bromo or aminobenzo-
The diarylamines obtained can be very useful for several

978
I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 975–981
applications (biological or in materials with electronic or
luminescent properties) based also on the benzo[b]thio-
phene moiety properties and on the variety of substituents
introduced. They can be cyclized to substituted thieno-
carbazoles, bioisosteres of natural anti-tumoral DNA
intercalating compounds (methylated pyridocarbazoles),
being the fluorodiarylamines, obtained in high yields,
specially interesting for this purpose. The presence of a
fluorine atom, useful for increasing the solubility of the
molecules, is very important for biological applications.
20 ml of NaOH 30% and CHCl3 was added. The phases
were separated, the aqueous phase was extracted with
CHCl3 and the organic phases gave, after drying (MgSO4),
filtration and removal of the solvent the corresponding
amines 2.
4.2.1. 6-Amino-2,3,5-trimethylbenzo[b]thiophene (2a).15
From bromo compound 1a (1.96 mmol), using catalytic
system (a) the corresponding imino derivative was obtained
as a yellow solid (0.700 g, quantitative yield), mp 123–125.
IR: 1663, 1611, 1592, 1571, 1488, 1461, 1445, 1377, 1314,
1
1287, 1246, 1229, 993, 958, 912, 866, 811, 784, 696. H
NMR: (CDCl3) 2.23 (3H, s, Me), 2.34 (3H, s, Me), 2.40 (3H,
s, Me), 6.78 (1H, s, H-7), 7.11–7.18 (2H, m, Ar-H), 7.22–
7.29 (2H, m, Ar-H), 7.31 (1H, s, H-4), 7.41–7.53 (4H, m,
Ar-H), 7.80–7.84 (2H, m, Ar-H). 13C NMR: (CDCl3) 11.36
(CH3), 13.66 (CH3), 18.75 (CH3), 111.82, 121.85, 125.90
(C), 126.34 (C), 127.96, 128.12, 128.57, 128.86, 129.28,
130.54, 131.51 (C), 135.68 (C), 136.30 (C), 137.27 (C),
139.61 (C), 146.97 (C), 167.35 (C). MS m/z: 356 (25,
Mþþ1), 355 (100, Mþ), 298 (30), 278 (60) 263 (12) 86 (38)
84 (57). HRMS C24H21NS: calcd Mþ 355.139472; found
Mþ 355.138947. This solid was submitted to hydrolysis
following the general procedure and amine 2a was obtained
as a white solid (0.230 g, overall yield 60%), mp 96–98
4. Experimental
4.1. Materials and methods
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-
photometer and wavenumbers are given in cm21. H and
13C NMR spectra were recorded on a Varian Unity Plus
(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 were obtained by electronic impact in the mass
spectrometry external service of the University of Vigo
(Spain). Elemental analysis was performed on a LECO
CHNS 932 elemental analyzer.
1
1
[lit.,15 96–98]. H NMR: (CDCl3) 2.20 (3H, s, Me), 2.30
(3H, s, Me), 2.41 (3H, s, Me), 3.60 (2H, s, 2£N–H), 7.04
(1H, s, H-7), 7.26 (1H, s, H-7).
Using catalytic system (b) the overall yield for amine 2a
was 50%.
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 cm plates 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
petroleum ether to mixtures of ether/petroleum ether
increasing 10% of ether until the isolation of the product.
4.2.2. 6-Amino-2,3,4,7-tetramethylbenzo[b]thiophene
(2b). From bromo compound 1b (1.85 mmol) using
catalytic system (b) the corresponding imino derivative
was obtained as a yellow solid (0.690 g, quantitative yield)
mp 145–147. IR: 1667, 1610, 1462, 1377, 1316, 1275,
1
1239, 1123, 1074, 956, 917, 867, 856, 787, 773, 750. H
NMR: (CDCl3) 2.24 (3H, s, Me), 2.41 (3H, s, Me), 2.42 (3H,
s, Me), 2.51 (3H, s, Me), 6.29 (1H, s, H-5) 7.05–7.14 (2H,
m, Ar-H), 7.18–7.26 (2H, m, Ar-H), 7.35–7.50 (4H, m,
Ar-H), 7.75–7.82 (2H, m, Ar-H). MS m/z: 370 (30, Mþþ1),
369 (100, Mþ), 292 (40), 277 (20). HRMS C25H23NS: calcd
Mþ 369.155122; found Mþ 369.153329. This solid was
submitted to hydrolysis following the general procedure and
amine 2b was obtained as a white solid (0.270 g, overall
yield 71%), mp 118–120. IR: 3407, 3328, 1615, 1593,
4.2. General procedure for the synthesis of 6-amino-
benzo[b]thiophenes 2a, b by C–N coupling of
compounds 1a or 1b with benzophenone imine and
hydrolysis of the corresponding imino derivatives
Coupling with benzophenone imine: A dry Schlenk tube was
charged, under Ar, with dry toluene (3–5 ml), the 6-bromo
benzo[b]thiophenes 1a or 1b (0.500 g), benzophenone
imine, the catalytic system (a) or (b) and the mixture was
heated at 1008C for several hours (Table 1). After cooling,
waterandetherwereaddedandthephaseswereseparated.The
aqueous phase was extracted with more ether and the organic
extracts were collected, dried (MgSO4) and filtered. Removal
of the solvent gave the corresponding imine derivative as a
yellow solid after some washes with MeOH to remove the
excess of benzophenone imine and traces of toluene.
1
1573, 1484, 1461, 1377, 1328, 1264. H NMR: (CDCl3)
2.27 (3H, s, Me), 2.40 (3H, s, Me), 2.44 (3H, s, Me), 2.65
(3H, s, Me), 3.55 (2H, s, 2£N–H), 6.50 (1H, s, H-5). 13C
NMR: (CDCl3) d 13.83 (CH3), 14.65 (CH3), 15.20 (CH3),
21.26 (CH3), 112.03 (C), 117.03 (CH), 128.66 (C), 128.97
(C), 131.05 (C), 131.97 (C), 139.50 (C), 140.73 (C). Anal.
Calcd for C12H15NS: C 70.20, H 7.36, N 6.82, S 15.61;
found: C 70.16, H 7.26, N 6.75, S 15.58.
Using catalytic system (a) the amine 2b was obtained in
50% overall yield.
Hydrolysis of the imino derivatives:11 To the imino
derivative (,0.650 mol), THF (15 ml) and HCl 2 M
(3 ml) were added and the mixture was stirred at room
temperature for 15 min. HCl 0.5 M (10 ml) and hexane/
ethyl acetate 2:1 (10 ml) were added. A precipitate came off
and filtration gave a white solid. This solid was stirred with
4.3. General procedure for the synthesis of diarylamines
bearing electron donating or withdrawing groups 4–8
A dry Schlenk tube was charged, under Ar, with dry toluene

I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 975–981
979
(3–5 ml), the aniline or arylhalide, the benzo[b]thiophenes
1 or 2, the catalytic system and the mixture was heated at
1008C for several hours (Table 2). The reaction was
followed by TLC and stopped when no increase of the
product seemed to occur. After cooling water and ether were
added. The phases were separated, the aqueous phase was
extracted with more ether and the organic phases collected,
dried (MgSO4) and filtered. 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. In some cases triarylamines were also isolated as
by-products.
0.590 mmol), 2,4-dimethoxyaniline (0.0910 g, 0.590 mmol)
and using solvent gradient from neat petroleum ether to
10% ether/petroleum ether in the column chromatography,
compound 4d was obtained as a white solid (0.111 g, 55%).
Crystallization from ether/petroleum ether gave colorless
1
crystals, mp 103–105. IR: 3407 (N–H). H NMR: (CDCl3)
2.35 (3H, s, Me), 2.45 (3H, s, Me), 2.48 (3H, s, Me), 2.67 (3H,
s, Me), 3.79 (3H, s, OMe), 3.90 (3H, s, OMe), 5.50 (1H, s,
NH), 6.37 (1H, dd, J¼8.7 and 3 Hz, H-50), 6.55 (1H, d,
J¼3 Hz, H-30), 6.75 (1H, d, J¼8.7 Hz, H-60), 6.93 (1H, s,
H-5). 13C NMR: (CDCl3) 13.97 (CH3), 15.19 (CH3), 15.32
(CH3), 21.39 (CH3), 55.63 (OCH3), 55.72 (OCH3), 99.32,
103.74, 115.17, 120.38 (C), 121.49, 128.88 (C), 129.07 (C),
130.82 (C), 130.88 (C), 134.61 (C), 136.40 (C), 140.45 (C),
149.19 (C), 153.54 (C). MS m/z: 342 (25, Mþþ1) 341 (100,
Mþ), 326 (23, Mþ215), 311 (19), 164 (95), 151 (20), 111
(64), 69 (38). Anal. Calcd for C20H23NO2S: C 70.35, H 6.79,
N 4.10, S 9.39; found: C 70.12, H 7.16, N 4.12, S 9.05.
4.3.1. 6-(4-Methoxyphenyl)amino-2,3,5-trimethylbenzo-
[b]thiophene (4a).15 From arylhalide 1a (0.150 g,
0.590 mmol), 4-methoxyaniline (0.0720 g, 0.590 mmol)
and using solvent gradient from neat petroleum ether to
10% ether/petroleum ether in the column chromatography
compound 4a was obtained as a white solid (0.105 g, 60%).
Crystallization from ether/petroleum ether gave colorless
crystals, mp 130–132 [lit.,15 130–132]. The spectroscopic
properties were identical to those already described by us.
4.3.5. 6-(3,4-Dimethoxyphenyl)amino-2,3,5-trimethyl-
benzo[b]thiophene (4e). From arylhalide 1a (0.150 g,
0.590 mmol), 3,4-dimethoxyaniline (0.0900 g, 0.590 mmol)
and using solvent gradient from neat petroleum ether to
10% ether/petroleum ether in the column chromatography,
compound 4e was obtained as a white solid (0.135 g, 70%).
Crystallization from ether/petroleum ether gave colorless
crystals, mp 140–142. IR: 3380 (N–H). 1H NMR:
([D6]DMSO) 2.19 (3H, s, Me), 2.29 (3H, s, Me), 2.36
(3H, s, Me),0 3.68 (6H, s, 2£OMe), 6.47 (1H, dd, J¼8.4 and
2.4 Hz, H-6 ), 6.65 (1H, d, J¼2.4 Hz, H-20), 6.83 (1H, d,
J¼8.4 Hz, H-50), 7.08 (1H, s, H-7), 7.39 (2H, s, H-4 and
N–H). 13C NMR: ([D6]DMSO) 11.21 (CH3), 13.40 (CH3),
18.47 (CH3), 55.33 (OCH3), 56.11 (OCH3), 104.00, 109.45,
109.51, 113.28, 122.74, 125.52 (C), 126.24 (C), 129.97 (C),
134.88 (C), 135.84 (C), 138.53 (C), 140.26 (C), 142.91 (C),
149.55 (C). MS m/z: 328 (22, Mþþ1), 327 (100, Mþ), 312
(62, Mþ215), 313 (14). Anal. Calcd for C19H21NO2S: C
69.69, H 6.46, N 4.28, S 9.79; found: C 69.77, H 6.76, N
4.42, S 9.78.
4.3.2. 6-(3-Methoxyphenyl)amino-2,3,4,7-tetramethyl-
benzo[b]thiophene (4b). From amine 2b (0.250 g,
1.20 mmol), 3-methoxybromobenzene (0.227 g, 1.20 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 (0.189 g, 50%).
Crystallization from ether/petroleum ether gave colorless
crystals mp 162–164. IR: 3352 (N–H). 1H NMR: (CDCl3)
2.35 (3H, s, Me), 2.46 (3H, s, Me), 2.50 (3H, s, Me), 2.69
(3H, s, Me), 3.75 (30H, s, OMe), 5.42 (1H, s, N–H), 6.31–
6.42 (3H, m, H-20, 4 and 60), 6.99 (1H, s, H-5), 7.11 (1H, t,
J¼8 Hz, H-50). 13C NMR: (CDCl3) 14.01 (CH3), 15.18 (CH3),
15.47 (CH3), 21.32 (CH3), 55.11 (OCH3), 101.05, 104.31,
108.08, 122.40 (C), 123.63, 129.14 (C), 129.94, 131.07 (C),
131.79 (C), 134.74 (C), 135.75 (C), 140.33 (C), 147.37 (C),
160.73 (C). Anal. Calcd for C19H21NOS: C 73.28, H 6.80, N
4.50, S 10.29; found: C 73.04, H 6.62, N 4.58, S 10.25.
4.3.6. 6-(3,4-Dimethoxyphenyl)amino-2,3,4,7-tetra-
methylbenzo[b]thiophene (4f). From arylhalide 1b
(0.200 g, 0.740 mmol), 3,4-dimethoxyaniline (0.114 g,
0.740 mmol) and using solvent gradient from neat petro-
leum ether to 10% ether/petroleum ether in the column
chromatography, compound 4f was obtained as a white solid
(0.132 g, 52%). Crystallization from ether/petroleum ether
4.3.3. 6-(2,4-Dimethoxyphenyl)amino-2,3,5-trimethyl-
benzo[b]thiophene (4c). From arylhalide 1a (0.250 g,
0.980 mmol), 2,4-dimethoxyaniline (0.150 g, 0.980 mmol)
and using solvent gradient from neat petroleum ether to 10%
ether/petroleum ether in the column chromatography,
compound 4c was obtained as a white solid (0.227 g,
71%). Crystallization from ether/petroleum ether gave
colorless crystals, mp 130–132. IR: 3387 (N–H). 1H
NMR: (CDCl3) 2.26 (3H, s, Me), 2.39 (3H, s, Me), 2.43 (3H,
s, Me), 3.82 (3H, s, OMe), 3.87 (3H, s, OMe), 5.55 (1H, s,
NH), 6.46 (1H, dd, J¼8.7 and 3 Hz, H-50), 6.57 (1H, d,
J¼3 Hz, H-30), 7.05 (1H, d, J¼8.7 Hz, H-60), 7.38 (1H, s,
H-7), 7.47 (1H, s, H-4). 13C NMR: (CDCl3) 11.37 (CH3),
13.63 (CH3), 18.34 (CH3), 55.66 (2£OCH3), 99.41, 103.77,
109.29, 118.24, 122.53, 124.92 (C), 126.31 (C), 126.90 (C),
130.57 (C), 135.41 (C), 136.66 (C), 139.62 (C), 150.44 (C),
154.53 (C). MS m/z: 328 (20, Mþþ1), 327 (100, Mþ), 312
(40), 297 (20). HRMS C19H21NO2S: calcd Mþ 327.129301;
found Mþ 327.128560.
1
gave colorless crystals, mp 178–180. IR: 3358 (N–H). H
NMR: ([D6]DMSO) 2.21 (3H, s, Me), 2.37 (3H, s, Me), 2.41
(3H, s, Me), 2.58 (3H, s, Me), 3.65 (3H, s, OMe), 3.66 (3H,
s, OMe), 6.30 (1H, dd, J¼8.6 and 2.5 Hz, H-60), 6.53 (1H, d,
J¼2.5 Hz, H-20), 6.77 (1H, d, J¼8.6 Hz, H-50), 6.87 (1H,
s, H-5), 7.24 (1H, s, N–H). 13C NMR: ([D6]DMSO) 13.67
(CH3), 14.91 (CH3), 15.56 (CH3), 21.02 (CH3), 55.25
(OCH3), 56.21 (OCH3), 102.26, 107.34, 113.52, 118.77 (C),
120.63, 129.02 (C), 129.67 (C), 130.41 (C), 133.46 (C),
137.15 (C), 139.81 (C), 139.92 (C), 142.12 (C), 149.55 (C).
MS m/z: 342 (24, Mþþ1), 341 (100, Mþ), 326 (53,
Mþ215). Anal. Calcd for C20H23NO2S: C 70.35, H 6.79,
N 4.10, S 9.39; found: C 69.95, H 6.73, N 4.10, S 9.02.
4.3.4. 6-(2,4-Dimethoxyphenyl)amino-2,3,4,7-tetramethyl-
benzo[b]thiophene (4d). From arylhalide 1b (0.160 g,
4.3.7. 6-(3,5-Dimethoxyphenyl)amino-2,3,5-trimethyl-
benzo[b]thiophene (4g). From arylhalide 1a (0.150 g,

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0.590 mmol), 3,5-dimethoxyaniline (0.117 g, 0.760 mmol)
and using solvent gradient from petroleum ether to 30%
ether/petroleum ether in the column chromatography,
compound 4g was obtained as a white solid (0.155 g,
80%). Crystallization from ether/petroleum ether gave
colorless crystals, mp 112–114. IR: 3385 (N–H). 1H
NMR: (CDCl3) 2.28 (3H, s, Me), 2.37 (3H, s, Me), 2.46 (3H,
s, Me), 3.750(6H, s, 2£OMe), 5.40 (1H, s, N–H), 6.03–6.08
(3H, m, H-2 , 40 and 60), 7.42 (1H, s, H-7), 7.62 (1H, s, H-4).
13C NMR: (CDCl3) 11.37 (CH3), 13.73 (CH3), 18.42 (CH3),
55.23 (2£OCH3), 92.03, 94.75, 114.54, 122.70, 126.37 (C),
127.51 (C), 132.26 (C), 136.40 (C), 137.14 (C), 137.32 (C),
147.00 (C), 161.65 (C). MS m/z: 328 (25, Mþþ1), 327 (100,
Mþ). Anal. Calcd for C19H21NO2S: C 69.69, H 6.46, N 4.28,
S 9.79; found: C 69.43, H 6.59, N 4.36, S 9.48.
15.53 (CH3), 21.30 (CH3), 100.06 (CuN), 113.63, 120.21
(C), 124.85 (C), 125.25, 129.27 (C), 131.63 (C), 132.04 (C),
133.33 (C), 133.72, 137.36 (C), 140.34 (C), 150.17 (C). MS
m/z: 307 (22, Mþþ1), 306 (100, Mþ). HRMS C19H18N2S:
calcd Mþ 306.119071; found 306.118117. It was also
isolated a less polar product as a white solid which showed
to be triarylamine 6b (3.00 mg, 2%), mp 283–285. IR: 2221
1
(CuN). H NMR: (CDCl3) 2.12 (3H, s, Me), 2.50 (3H, s,
Me), 2.53 (3H, s, Me), 2.70 (3H, s, Me), 6.79 (1H, s, H-5),
7.06 (4H, d, 0 J¼9 Hz, H-20, 200, 60 and 600), 7.51 (4H, d,
J¼9 Hz, H-3 , 300, 50 and 500). 13C NMR: (CDCl3) 14.21
(CH3), 15.17 (CH3), 15.78 (CH3), 21.31 (CH3), 104.87
(CuN), 119.09 (C), 121.04, 127.27 (C), 127.82, 129.43 (C),
133.03 (C), 133.50, 134.70 (C), 136.73 (C), 138.70 (C),
140.87 (C), 149.65 (C). MS m/z: 408 (30, Mþþ1), 407 (100,
Mþ). HRMS C26H21N3S: calcd Mþ 407.145620; found
407.146061.
4.3.8. 6-(4-Nitrophenyl)amino-2,3,5-trimethylbenzo-
[b]thiophene (5a) and 6-bis(4-nitrodiphenyl)amino-
2,3,5-trimethylbenzo[b]thiophene (5b). From amine 2a
(0.170 g, 0.880 mmol) and 4-bromonitrobenzene (0.179 g,
0.880 mmol) and using solvent gradient from neat petro-
leum ether to 50% ether/petroleum ether in the column
chromatography, compound 5a was obtained as an orange
solid (0.111 g, 40%). Crystallization from ether/petroleum
ether gave orange crystals, mp 216–218. IR: 3354 (N–H).
1H NMR: (CDCl3) 2.31 (3H, s, Me), 2.35 (3H, s, Me), 2.50
(3H, s, Me), 6.08 (1H, s, N–H), 6.68 (2H, d, J¼9.3 Hz, H-20
and 60), 7.50 (1H, s, H-7), 7.63 (1H, s, H-4), 8.09 (2H, d,
J¼9.3 Hz, H-30 and 50). 13C NMR: (CDCl3) 11.41 (CH3),
13.88 (CH3), 18.35 (CH3), 112.74, 118.75, 123.15, 126.35,
126.56 (C), 130.10 (C), 133.73 (C), 134.57 (C), 136.40 (C),
139.13 (C), 139.79 (C), 151.85 (C). MS m/z: 313 (22,
Mþþ1), 312 (100, Mþ), 266 (15, Mþ246), 251 (20).
HRMS C17H16N2O2S: calcd Mþ 312.093250; found
312.093531. It was also isolated a less polar product as a
yellow solid which showed to be triarylamine 5b (0.0460 g,
12%), mp 118–120. IR: 1596, 1580, 1493, 1462, 1377,
1339, 1299, 1280, 1178, 1150, 1109, 873, 843, 750, 739,
4.3.10. 6-(2-Fluorophenyl)amino-2,3,5-trimethylbenzo-
[b]thiophene (7a). From amine 2a (0.150 g, 0.785 mmol)
and 2-bromofluorobenzene (0.1 ml, 0.915 mmol), com-
pound 7a was obtained as a brown solid (0.220 g,
quantitative yield). Crystallization from ether/petroleum
ether gave colorless crystals, mp 119–121. IR: 3383 (N–H).
1H NMR: (CDCl3) 2.29 (3H, s, Me), 2.40 (3H, s, Me), 2.48
(3H, s, Me), 5.60 (1H, s, N–H), 6.75–6.85 (1H, m, Ar-H),
6.94–7.02 (2H, m, Ar-H), 7.06–7.15 (1H, m, Ar-H), 7.45
(1H, s, H-7), 7.62 (1H, s, H-4). 13C NMR: (CDCl3) 11.38
(CH3), 13.73 (CH3), 18.29 (CH3), 114.03 (CH), 115.18 (d,
J¼19 Hz, CH), 116.16 (d, J¼2.3 Hz, CH), 119.33 (d, J¼
7.2 Hz, CH), 122.80 (CH), 124.34 (d, J¼3.5 Hz, CH),
126.41 (C), 127.61 (C), 132.38 (C), 133.32 (d, J¼11.2 Hz,
C(F)CN), 136.42 (C), 136.48 (C), 137.48 (C), 152.44 (d,
J¼239.9 Hz, CF). MS m/z: 286 (20, Mþþ1), 285 (100, Mþ),
284 (16, Mþ21), 270 (16, Mþ215). Anal. Calcd for
C17H16FNS: C 71.55, H 5.65, N 4.91, S 11.23; found: C
71.34, H 6.00, N 5.01, S 10.98.
1
722, 699, 685, 514, 507. H NMR: (CDCl3) 2.14 (3H, s,
Me), 2.33 (03H0,0 s,0Me), 2.52 (3H, s, Me), 7.11 (4H, d, J¼
4.3.11. 6-(4-Fluorophenyl)amino-2,3,5-trimethylbenzo-
[b]thiophene (7b). From amine 2a (0.150 g, 0.785 mmol)
and 4-bromofluorobenzene (0.12 ml, 0.942 mmol), com-
pound 7b was obtained as a light brown solid (0.200 g,
90%). Crystallization from ether/petroleum ether gave
9.3 Hz, H-2 , 2 , 6 and 600), 7.54 (1H, s, H-7 or04), 7.56 (1H,
s, H-4 or 7), 8.14 (4H, d, J¼9.3 Hz, H-30, 300, 5 and 500). 13
C
NMR: (CDCl3) 11.41 (CH3), 13.99 (CH3), 18.51 (CH3),
120.63, 122.95, 124.26, 125.57, 126.68 (C), 132.01 (C),
136.44 (C), 137.29 (C), 138.64 (C), 141.36 (C), 142.23 (C),
151.25 (C). MS m/z: 434 (27, Mþþ1), 433 (100, Mþ). Anal.
Calcd for C23H19N3O4S: C 63.73, H 4.42, N 9.69, S 7.40;
found: C 63.40, H 4.89, N 9.34, S 7.97.
1
beige crystals, mp 159–160. IR: 3382 (N–H). H NMR:
([D6]DMSO) 2.21 (3H, s, Me), 2.28 (3H, s, Me), 2.38 (3H, s,
Me), 6.84–6.90 (2H, m, Ar-H), 6.99–7.05 (2H, m, Ar-H),
7.37 (1H, s, N–H), 7.44 (1H, s, H-7 or H-4), 7.45 (1H, s, H-4
or H-7). 13C NMR: ([D6]DMSO) 11.15 (CH3), 13.40 (CH3),
18.37 (CH3), 111.78 (CH), 115.58 (d, J¼22.2 Hz, 2£CH),
117.79 (d, J¼7.5 Hz, 2£CH), 122.84 (CH), 126.24 (C),
126.91 (C), 130.82 (C), 135.71 (C), 135.91 (C), 139.00 (C),
141.72 (d, J¼1.96 Hz, C), 155.93 (d, J¼234.6 Hz, CF).
Anal. Calcd for C17H16FNS: C 71.55, H 5.65, N 4.91, S
11.23; found: C 71.55, H 5.80, N 5.00, S 11.25.
4.3.9. 6-(4-Cyanophenyl)amino-2,3,4,7-tetramethylbenzo-
[b]thiophene (6a) and 6-bis(4-cyanodiphenyl)amino-
2,3,4,7-tetramethylbenzo[b]thiophene (6b). From amine
2b (0.110 g, 0.530 mmol) and 4-bromobenzonitrile
(0.0810 g, 0.440 mmol), heating for 5 h, and using solvent
gradient from neat petroleum ether to 50% ether/petroleum
ether in the column chromatography, compound 6a was
obtained as a white solid (0.0700 g, 51%). Crystallization
from ether/petroleum ether gave colorless crystals, mp
230–232. IR: 3307 (N–H), 2216 (CuN). 1H NMR:
(CDCl3) 2.32 (3H, s, Me), 2.48 (3H, s, Me), 2.52 (3H, s,
Me), 2.71 (3H, s, Me), 5.83 (1H, s, N–H), 6.65 (2H, d,
J¼9 Hz, H-20 and 60), 6.93 (1H, s, H-5), 7.43 (2H, d, J¼9 Hz
H-30 and 50). 13C NMR: (CDCl3) 14.12 (CH3), 15.19 (CH3),
4.3.12. 6-(4-Formylphenyl)amino-2,3,5-trimethylbenzo-
[b]thiophene (8). From amine 2a (0.0900 g, 0.470 mmol)
and 4-bromobenzaldehyde (0.0870 g, 0.470 mmol) and
after PLC 70% ether/petroleum ether (several elutions),
compound 8 was obtained as a yellow solid (0.0410 g,
30%). Crystallization from ether/petroleum ether gave
yellow crystals, mp 191–193. IR: 3321 (N–H), 1662
1
(CvO). H NMR: (CDCl3) 2.30 (3H, s, Me), 2.36 (3H, s,

I. C. F. R. Ferreira et al. / Tetrahedron 59 (2003) 975–981
981
N. Chem. Mater. 1998, 10, 1668–1676. (b) Thayumanavan,
S.; Barlow, S.; Marder, S. R. Chem. Mater. 1997, 9,
3231–3235. (c) Kanbara, T.; Miyazaki, Y.; Hasegawa, K.;
Yamamoto, T. J. Polym. Sci. Part A: Polym. Chem. 2000, 38,
4194–4199.
Me), 2.49 (3H, s, Me), 5.94 (1H, s, N–H), 6.79 (2H, d,
J¼9 Hz, H-20 and 60), 7.49 (1H, 0s, H-7), 7.66 (1H, s, H-4),
7.72 (2H, d, J¼9 Hz, H-30 and 5 ), 9.78 (1H, s, CHO). 13C
NMR: (CDCl3) 11.39 (CH3), 13.84 (CH3), 18.37 (CH3),
113.59, 118.14, 123.01, 126.52 (C), 127.81 (C), 129.80 (C),
132.22, 134.06 (C), 134.36 (C), 136.33 (C), 139.30 (C),
151.55 (C), 190.33 (C¼O). MS m/z: 296 (20, Mþþ1), 295
(100, Mþ), 280 (15, Mþ215). HRMS C18H17NOS: calcd
Mþ 295.103086; found 295.103345.
6. Greco, G. E.; Popa, A. I.; Schrock, R. R. Organometallics,
1998, 17, 5591–5593.
7. (a) Hartwig, J. F. Synlett. 1997, 329–340. (b) Hartwig, J. F.
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Acc. Chem. Res. 1998, 31, 805–818. (b) Yang, B. H.;
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Acknowledgements
Thanks are due to Foundation for the Science and
Technology-IBQF-Univ. Minho (Portugal) for financial
support, to the Research Incitement Programme of the
Calouste Gulbenkian Foundation (Portugal) and to Escola
10. (a) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6359–6362. (b) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
2000, 65, 1144–1157.
´
Superior Agraria-Instituto Politecnico de Braganc¸a for
supporting in part Isabel C. F. R. Ferreira’s PhD.
´
11. (a) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.;
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367–6370.
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(b) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas,
C. J. Am. Chem. Soc. 1998, 120, 827–828. (c) Prashad, M.;
Hu, B.; Lu, Y.; Draper, R.; Har, D.; Repic, O.; Blacklock, T. J.
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