Reactivity of several deactivated 3-aminobenzo[b]thiophenes in the Buchwald-Hartwig C-N coupling. Scope and limitations

Article abstract of DOI:10.1016/j.tet.2007.10.029

Di(hetero)arylamines were prepared in moderate to high yields by Buchwald-Hartwig C-N coupling of bromobenzenes bearing electron-withdrawing groups and of a bromobiphenyl with several methyl 3-aminobenzo[b]thiophene-2-carboxylates, using the coupling cond

Full text of DOI:10.1016/j.tet.2007.10.029

Available online at www.sciencedirect.com
Tetrahedron 63 (2007) 13000–13005
Reactivity of several deactivated 3-aminobenzo[b]thiophenes in
the Buchwald–Hartwig C–N coupling. Scope and limitations
a,
Maria-Joao R. P. Queiroz, Ricardo C. Calhelha and Gilbert Kirsch
a
b
*
~
aCentro de Quꢀımica, Universidade do Minho, 4710-057 Braga, Portugal
b
´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique,
´
Universite Paul Verlaine, 1, bd Arago Metz Technopole, 57078 Metz, France
Received 27 July 2007; revised 1 October 2007; accepted 4 October 2007
Available online 7 October 2007
Abstract—Di(hetero)arylamines were prepared in moderate to high yields by Buchwald–Hartwig C–N coupling of bromobenzenes bearing
electron-withdrawing groups and of a bromobiphenyl with several methyl 3-aminobenzo[b]thiophene-2-carboxylates, using the coupling
conditions for heteroaromatic amines [Pd(OAc)2, Xantphos, Cs2CO3 in dioxane, 120 ꢀC]. The use of these aminobenzo[b]thiophenes as
coupling components avoids the step of changing the amino group into a bromine atom, like we have done before to perform C–N couplings
using the corresponding 3-bromobenzo[b]thiophenes. Nevertheless, the couplings using the methyl 3-aminobenzo[b]thiophene-2-carboxyl-
ates were only successful with bromobenzenes bearing electron-withdrawing groups and a bromobiphenyl or with electron deficient rings
such us as bromopyridines. Using the latter compounds, different substituted 6H-benzothieno[3,2-d]pyrido[1,2-a]pyrimid-6-ones were
obtained by C–N coupling followed by an intramolecular cyclization. These tetracyclic compounds may have interesting biological activity
like it was already demonstrated by us for the non substituted derivative.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
work using the ethyl 3-bromobenzo[b]thiophene-2-carboxyl-
ate and 2-aminopyridine as coupling components.6 The
6H-benzothieno[3,2-d]pyrido[1,2-a]pyrimid-6-one thus ob-
tained was shown to induce cellular apoptosis in tumoral
cell lines after photoactivation, in very low concentrations.11
The diarylamine skeleton is commonly found in several
compounds with biological activity,1 in materials with inter-
esting electronic properties2 and in ligands for transition
metals.3
For some years now, we have been interested in the synthesis
of diaryl and diheteroarylamines by Buchwald–Hartwig
C–N coupling4 of substituted 3-bromobenzo[b]thiophenes
with anilines and aminopyridines,5,6 and of substituted
bromothiophenes with aliphatic amines or anilines,7 and
with aminopyridines.8 Recently, we were also able to react
substituted aminothiophenes with bromopyridines but the
former did not react with bromobenzenes.9
2. Results and discussion
2.1. Synthesis of 3-aminobenzo[b]thiophene-
2-carboxylates 1–3
The aminated coupling components 1–3 are already
known12,13 and were prepared here in good yields from
2-nitrobenzonitriles, methyl thioglycolate, and aqueous
KOH in DMF at 0 ꢀC (Scheme 1).12
Here we report the C–N coupling of bromobenzenes bearing
electron-withdrawing groups and 2-bromopyridines with
several methyl 3-aminobenzo[b]thiophene-2-carboxylates
using the coupling conditions for heteroaromatic amines.10
When 2-bromopyridines were used as coupling components,
the corresponding benzothienopyridopyrimidones were
obtained. This was already observed by us in an earlier
NH2
CO2Me
CN
KOH/H2O
DMF, 0 °C
1 h
+
HS
CO2Me
R
NO2
S
R
R = H, OMe, NO2
1 R = H, 50%
2 R = OMe, 60%
3 R = NO2, 60%
Scheme 1. Synthesis of 3-aminobenzo[b]thiophene-2-carboxylates 1–3.
Keywords: Buchwald–Hartwig coupling; Palladium; Di(hetero)arylamines;
Methyl 3-aminobenzo[b]thiophene-2-carboxylates; Pyridines; Benzothi-
enopyridopyrimidones.
* Corresponding author. Tel.: +351253604378; fax: +351253604382;
e-mail: mjrpq@quimica.uminho.pt
Compound 2 was first prepared in a very low overall
yield (14%) from 2,4-difluorobenzonitrile. The latter gave
a mixture of 2-fluoro-4-methoxybenzonitrile and 4-fluoro-
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.029

M.-J. R. P. Queiroz et al. / Tetrahedron 63 (2007) 13000–13005
13001
2-methoxybenzonitrile by treatment with sodium meth-
oxide, which was used without purification to obtain com-
pound 2 (Scheme 2).13
presented in Table 1, giving compounds 13–15 after intra-
molecular cyclization (Scheme 4). This was already ob-
served by us in the synthesis of compound 13 from the
ethyl 3-bromobenzo[b]thiophene-2-carboxylate and 2-ami-
nopyridine.6
CN
F
HS
CN
F
CN
NaOMe
MeO
CO2Me
2, 14%
+
10
11
KOt-Bu
DMSO, 25 °C,
under N2
R1
F
OMe
12
9
N
1
F
Pd(OAc)2,
Xantphos,
N
Br
8
2
3
7
1 or 2
+
6
Scheme 2. Earlier synthesis of 3-aminobenzo[b]thiophene 2.13
N
Cs2CO3,
dioxane,
120 °C
O
R1
R2
S
5
4
R1= H or F
13 R1 = R2 = H, 2 h, 80%
In the present work we have prepared in good yield the
4-methoxy-2-nitrobenzonitrile as precursor of compound
2, by reacting 3-nitro-4-bromoanisole with CuCN in DMF
(Scheme 3). This method had already been used by some
of us in the synthesis of 4-cyano-2,5-dimethylacetanilide
from the corresponding brominated compound.14
14 R1 = H, R2 =OMe, 22 h, 40%
15 R1 = F, R2 = H, 22 h, 45%
Scheme 4. Synthesis of benzothieno[3,2-d]pyrido[1,2-a]pyrimid-6-ones by
C–N coupling and intramolecular cyclization.
Compound 13 was obtained in an excellent yield after a short
time of heating and its purification was easier using the
actual starting materials. As this compound had already
shown biological activity,11 the substituted compounds
obtained for the first time in the present work, 14 and 15,
will also be tested.
Br
CN
CuCN
anhyd. DMF
160 °C, 2 h
MeO
NO2
MeO
NO2
71%
Scheme 3. Synthesis of 4-methoxy-2-nitrobenzonitrile from 3-nitro-4-
bromoanisole.
3. Conclusions
The 3-amino-6-nitrobenzo[b]thiophene 3 was prepared
earlier by others in moderate yield from 2-fluoro-4-nitro-
benzonitrile using NEt3 in MeCN.13
We were able to prepare several arylheteroarylamines
and benzothieno[3,2-d]pyrido[1,2-a]pyrimid-6-ones from
methyl 3-aminobenzo[b]thiophene-2-carboxylates by Buch-
wald–Hartwig C–N coupling followed in the latter case by
an intramolecular cyclization. The method has a wide appli-
cation to bromobenzenes bearing electron-withdrawing
groups and electron deficient rings like bromopyridines.
Nevertheless using these conditions, reaction with bromo-
benzenes bearing electron-donating groups did not occur.
2.2. Synthesis of arylheteroarylamines by Buchwald–
Hartwig coupling of bromobenzenes bearing electron-
withdrawing groups with compounds 1–3
The methyl 3-aminobenzo[b]thiophene-2-carboxylates 1–3,
which are precursors by substitutive deamination of the 3-
bromobenzo[b]thiophenes used earlier by us,6 were coupled
with several bromobenzenes bearing electron-withdrawing
groups (CN, CHO, NO2) and with bromobiphenyl under
C–N coupling conditions used for heteroaromatic amines
(Table 1).6,10 The corresponding arylheteroarylamines 4–12
were obtained in moderate to good yields. In the synthesis
of 6a from amine 1 and 4-nitrobromobenzene, triarylamine
6b was also isolated in a very low yield (Table 1). This
may be due to the high reactivity of this bromobenzene as
Buchwald–Hartwig coupling component, which reacts also
with the diarylamine 6a.
The reactions presented here occur with the amino precur-
sors of the corresponding brominated benzo[b]thiophenes,
obtained by substitutive deamination, that we used before
in this type of couplings thus avoiding one step.
4. Experimental
4.1. Materials and methods
Melting points (ꢀC) were determined in a Stuart SMP3 appa-
1
ratus and are uncorrected. H and 13C NMR spectra were
recorded on a Varian Unity Plus (300 and 75.4 MHz,
Attempts to perform the C–N couplings with bromobenz-
enes bearing methoxy groups even in the meta position
were unsuccessful. This constitutes a limitation for the use
of the amino compounds 1–3 as coupling components and
it may be due to the deactivation of the amine by the methyl
carboxylate of position 2.
1
respectively). H–1H spin–spin decoupling, DEPT q 45ꢀ
and bidimensional heterocorrelation 1H–13C techniques
(HMQC and HMBC) were used to attribute some signals.
Chemical shifts are given in parts per million and coupling
constants in hertz. The mass spectra were obtained by elec-
tronic impact unless stated in the mass spectrometry external
service of the University of Vigo (Spain). Elemental analysis
was performed on a LECO CHNS 932 elemental analyzer.
2.3. Synthesis of tetracyclic compounds by Buchwald–
Hartwig coupling of 2-bromopyridines with methyl
3-aminobenzo[b]thiophene-2-carboxylates 1 and 2
followed by intramolecular cyclization
The reactions were monitored by thin layer chromatography
(TLC). Column chromatography was performed on
Macherey-Nagel silica gel 230–400 mesh. Preparative thin
layer chromatography (PLC) was performed in 20ꢁ20 cm
The aminobenzo[b]thiophenes 1 and 2 reacted with 2-bro-
mopyridines, using the same C–N coupling conditions

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M.-J. R. P. Queiroz et al. / Tetrahedron 63 (2007) 13000–13005
Table 1. Buchwald–Hartwig coupling components and arylheteroarylamines products 4–12
Amino compound
Bromobenzene
Time (h)
Arylheteroarylamine (%)
CN
H
N
Br
3
CO2Me
CN
S
4, 65%
CHO
H
N
Br
2
CO2Me
CHO
S
5, 70%
NO2
H
N
CO2Me
6a, 61%
S
+
Br
NH2
O2N
3
NO2
CO2Me
S
1
NO2
N
CO2Me
S
6b, 3%
O2N
H
N
Br
1
3
1
3
CO2Me
O2N
S
7, 83%
H
N
CO2Me
S
8, 63%
Br
CN
H
N
Br
CO2Me
CN
S
MeO
9, 30%
NH2
CO2Me
S
MeO
2
CHO
H
N
Br
CO2Me
CHO
S
MeO
10, 30%
(continued)

M.-J. R. P. Queiroz et al. / Tetrahedron 63 (2007) 13000–13005
13003
Table 1. (continued)
Amino compound
Bromobenzene
Time (h)
Arylheteroarylamine (%)
CN
H
N
Br
5
CO2Me
CN
S
O2N
11, 35%
NH2
CHO
H
N
CO2Me
S
O2N
Br
3
CO2Me
3
S
CHO
O2N
12, 76%
(i) Pd(OAc)2 (10 mol %), Xantphos (12 mol %), Cs2CO3 (2.8 equiv), dry dioxane, 120 ꢀC (silicone bath), 1–5 h.
plates Macherey-Nagel, Layer 2 mm SIL G-200 UV254. Pe-
troleum ether refers to the boiling range 40–60 ꢀC. Ether re-
fers 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.
0.796 mmol), amine 1 (150 mg, 0.724 mmol), heating for
3 h. Compound 4 was isolated by column chromatography
using solvent gradient till 20% ether/petroleum ether as a
white solid (145 mg, 65%), mp 139–141 ꢀC, after some
1
washes with petroleum ether. H NMR (CDCl3): 3.94 (3H,
s, OMe), 7.00 (2H, d, J¼8.7 Hz, 20 and 60-H), 7.27–7.33
(1H, m, Ar–H), 7.47–7.54 (4H, m, Ar–H), 7.81–7.85 (1H,
m, ArH), 8.59 (1H, br s, N–H) ppm. 13C NMR (CDCl3):
52.23 (OCH3), 104.37 (C), 112.41 (C), 118.63 (20 and
60-CH), 119.31 (C), 123.47 (CH), 124.11 (CH), 124.99
(CH), 127.95 (CH), 132.09 (C), 133.31 (30 and 50-CH),
139.67 (C), 142.43 (C), 146.74 (C), 165.08 (C]O) ppm.
Anal. Calcd for C17H12N2O2S: C 66.22, H 3.92, N 9.08, S
10.40; found: C 66.29, H 4.07, N 9.15, S 10.01.
Xantphos refers to 4,5-bis(diphenylphosphane)-9,9-di-
methylxanthene.
2-Nitrobenzonitrile and 2,4-dinitrobenzonitrile were purchased
from Sigma–Aldrich.
4.1.1. 4-Methoxy-2-nitrobenzonitrile. 3-Nitro-4-bromo-
anisole (2.50 g, 0.0110 mol) was dissolved in anhyd DMF
and CuCN (1.5 equiv) was added. The mixture was heated
at 160 ꢀC for 2 h. After cooling it was poured into crushed
ice and a precipitate was formed, which was filtered and
dried under vacuum. The greenish solid obtained was dis-
solved in CHCl3 and the solution was filtered. The solvent
removal of the filtrate gave a yellow solid (1.36 g, 71%),
4.2.2. Methyl 3-(4-formylphenylamino)benzo[b]thio-
phene-2-carboxylate (5). 4-Bromobenzaldehyde (147 mg,
0.796 mmol), amine 1 (150 mg, 0.724 mmol), heating for
2 h. Compound 5 was isolated using column chromato-
graphy and 50% ether/petroleum ether as a yellow solid
(158 mg, 70%), mp 139–140 ꢀC, after some washes with
1
1
mp 129–131 ꢀC. H NMR (CDCl3): 3.99 (3H, s, OMe),
petroleum ether. H NMR (CDCl3): 3.94 (3H, s, OMe),
7.28 (1H, dd, J¼9 and 2.4 Hz, 5-H), 7.79–7.84 (2H, m, 3
and 6-H) ppm. 13C NMR (CDCl3): 56.52 (OCH3), 99.40
(C), 111.06 (CH), 115.24 (C), 119.94 (CH), 136.59 (CH),
150.09 (C), 163.18 (C) ppm.
7.06 (2H, d, J¼8.4 Hz, 20 and 60-H), 7.25–7.32 (1H, m,
Ar–H), 7.46–7.56 (2H, m, Ar–H), 7.77–7.85 (3H, m,
ArH), 8.63 (1H, br s, N–H), 9.89 (1H, s, CHO) ppm. 13C
NMR (CDCl3): 52.22 (OCH3), 112.20 (C), 118.35 (20 and
60-CH), 123.42 (CH), 124.06 (CH), 125.20 (CH), 127.93
(CH), 130.45 (C), 131.38 (30 and 50-CH), 132.25 (C),
139.69 (C), 142.66 (C), 148.38 (C), 165.13 (C]O),
190.69 (CHO) ppm. Anal. Calcd for C17H13NO3S: C
65.68, H 4.21, N 4.50, S 10.30; found: C 65.85, H 4.35, N
4.69, S 9.94.
4.2. General procedure for the C–N coupling
In a dry Schlenk tube, dry dioxane (3–5 mL), the arylhalide
(1.1 equiv), Pd(OAc)2 (10 mol %), Xantphos (12 mol %),
Cs2CO3 (2.8 equiv), and the methyl 3-aminobenzo[b]thio-
phene-2-carboxylates 1–3 were added under argon and the
mixture was heated with stirring at 120 ꢀC (silicone bath)
for some hours (following the reaction by TLC). After cool-
ing, ethyl acetate was added and the mixture was filtered un-
der vacuum. The filtrate was evaporated under reduced
pressure to give a residue, which was submitted to column
chromatography (silica 230–400 mesh) using solvent gradi-
ent from neat petroleum ether to mixtures of diethyl ether/
petroleum ether, increasing 10% of ether till the isolation
of the product, unless stated otherwise.
4.2.3. Methyl 3-(4-nitrophenylamino)benzo[b]thiophene-
2-carboxylate (6a) and methyl 3-(bis(4-nitrophenyl)-
amino)benzo[b]thiophene-2-carboxylate (6b). 1-Bromo-4-
nitrobenzene (161 mg, 0.796 mmol), amine 1 (150 mg,
0.724 mmol), heating for 3 h. Compound 6b was isolated
by column chromatography using solvent gradient till 20%
ether/petroleum ether as a yellow solid (17.0 mg, 3%), mp
1
201–203 ꢀC, after some washes with petroleum ether. H
NMR (CDCl3): 3.76 (3H, s, OMe), 7.17 (4H, d, J¼9.3 Hz,
20,60,200 and 600-H), 7.34–7.46 (2H, m, Ar–H), 7.54–7.60
(1H, m, Ar–H), 7.95 (1H, d, J¼9 Hz, Ar–H), 8.16 (4H, d,
J¼9.3 Hz, 30,50,300 and 500-H) ppm. 13C NMR (CDCl3):
4.2.1. Methyl 3-(4-cyanophenylamino)benzo[b]thio-
phene-2-carboxylate (4). 4-Bromobenzonitrile (145 mg,

13004
M.-J. R. P. Queiroz et al. / Tetrahedron 63 (2007) 13000–13005
52.62 (OCH3), 120.88 (4ꢁCH), 123.12 (CH), 123.64 (CH),
125.50 (4ꢁCH), 126.03 (CH), 128.44 (CH), 128.48 (C),
135.41 (C), 139.49 (C), 140.04 (C), 142.96 (C), 150.49 (C),
160.60 (C]O) ppm. MS (EI): m/z (%) 449.07 (M+, 6),
389.12 (M+ꢂCO2Me, 100). HRMS [M+] calcd for
C22H15N3O6S 449.0682, found 449.0683.
5-H), 7.00 (2H, d, J¼8.7 Hz, 20 and 60-H), 7.23 (1H, d, J¼
2.4 Hz, 7-H), 7.36 (1H, d, J¼9.0 Hz, 4-H), 7.52 (2H, d, J¼
8.7 Hz, 30 and 50-H), 8.62 (1H, br s, N–H) ppm. 13C NMR
(CDCl3): 52.05 (OCH3), 55.64 (OCH3), 104.39 (C),
104.85 (7-CH), 109.52 (C), 114.94 (5-CH), 118.75 (20 and
60-CH), 119.32 (C), 125.77 (C), 125.86 (4-CH), 133.32 (30
and 50-CH), 141.93 (C), 142.61 (C), 146.72 (C), 160.08
(C), 165.12 (C]O) ppm. MS (EI): m/z (%) 338.07 (M+,
40), 306.05 (M+ꢂOMe, 100). HRMS [M+] calcd for
C18H14N2O3S 338.0725, found 338.0736.
Compound 6a was isolated as the major product using 15%
ether/petroleum ether as a yellow solid (143 mg, 61%), mp
133–135 ꢀC, after some washes with petrol. 1H NMR
(CDCl3): 3.95 (3H, s, OMe), 6.99 (2H, d, J¼9 Hz, 20 and
60-H), 7.27–7.35 (1H, m, Ar–H), 7.49–7.55 (2H, m,
Ar–H), 7.85 (1H, d, J¼8.7 Hz, ArH), 8.15 (2H, d, J¼
9.3 Hz, 30 and 50-H), 8.66 (1H, br s, N–H) ppm. 13C NMR
(CDCl3): 52.34 (OCH3), 113.50 (C), 117.50 (20 and
60-CH), 123.54 (CH), 124.30 (CH), 124.93 (CH), 125.47
(30 and 50-CH), 128.06 (CH), 132.14 (C), 139.67 (C),
141.73 (C), 141.84 (C), 148.72 (C), 164.98 (C]O) ppm.
MS (EI): m/z (%) 328.05 (M+, 5), 298.08 (M+ꢂ30, 31),
266.04 (100). HRMS [M+] calcd for C16H12N2O4S
328.0518, found 328.0527.
4.2.7. Methyl 3-(4-formylphenylamino)-6-methoxybenzo-
[b]thiophene-2-carboxylate (10). 4-Bromobenzaldehyde
(122 mg, 0.660 mmol), amine 2 (120 mg, 0.500 mmol), heat-
ing for 3 h. Compound 10 was isolated by column chromato-
graphy using solvent gradient till 30% ether/petroleum ether as
a yellow solid (55.0 mg, 30%), mp 169–171 ꢀC, after washes
with petroleum ether. 1H NMR (CDCl3): 3.91 (3H, s, OMe),
3.92 (3H, s, OMe), 6.89 (1H, dd, J¼9.0 and 2.4 Hz, 5-H),
7.06 (2H, d, J¼8.7 Hz, 20 and 60H), 7.23 (1H, d, J¼2.4 Hz,
7-H), 7.41 (1H, d, J¼9.0 Hz, 4-H), 7.78 (2H, d, J¼8.7 Hz,
30 and 50H), 8.68 (1H, br s, N–H), 9.88 (1H, s, CHO) ppm.
13C NMR (CDCl3): 52.04 (OCH3), 55.62 (OCH3), 104.73
(CH), 109.27 (C), 114.87 (CH), 118.42 (20 and 60-CH),
125.89 (C), 126.05 (CH), 130.41 (C), 131.37 (30 and 50-CH),
141.90 (C), 142.79 (C), 148.30 (C), 160.03 (C), 165.13
(C]O), 190.71 (CHO) ppm. MS (EI): m/z (%) 341 (M+,
65), 281 (M+ꢂCO2Me, 100). HRMS [M+] calcd for
C18H15NO4S 341.0722, found 341.0722.
4.2.4. Methyl 3-(2-nitrophenylamino)benzo[b]thiophene-
2-carboxylate (7). 1-Bromo-2-nitrobenzene (166 mg,
0.800 mmol), amine 1 (170 mg, 0.800 mmol), heating for
1 h. Compound 7 was isolated as a yellow solid (218 mg,
1
83%), mp 207–209 ꢀC, after some washes with ether. H
NMR (CDCl3): 3.96 (3H, s, OMe), 6.85–6.98 (2H, m, ArH),
7.29–7.38 (2H, m, ArH), 7.48–7.54 (2H, m, ArH), 7.85–7.88
(1H, m, ArH), 8.24 (1H, dd, J¼8.4 and 1.5 Hz, ArH), 10.33
(1H, br s, NH) ppm. 13C NMR (CDCl3): 52.46 (OCH3),
118.33 (C), 118.70 (CH), 119.48 (CH), 123.46 (CH), 124.46
(CH), 124.59 (CH), 126.41 (CH), 127.80 (CH), 133.27 (C),
134.83 (CH), 135.63 (C), 138.86 (C), 139.45 (C), 140.26
(C), 163.59 (C]O) ppm. MS (EI): m/z (%) 328.05 (M+, 7),
298.08 (M+ꢂ30, 7), 266.01 (100). HRMS [M+] calcd for
C16H12N2O4S 328.0518, found 328.0524.
4.2.8. Methyl 3-(4-cyanophenylamino)-6-nitrobenzo[b]-
thiophene-2-carboxylate (11). 4-Bromobenzonitrile (107 mg,
0.590 mmol), amine 3 (150 mg, 0.590 mmol), heating for
5 h. The crude was submitted to a dry flash column using
silica (150–230 mesh)/ether and compound 11 was isolated
as a red solid (81.0 mg, 35%), mp 194–196 ꢀC, after some
washes with petrol. 1H NMR (CDCl3): 3.98 (3H, s, OMe),
6.99 (2H, d, J¼8.4 Hz, 20 and 60-H), 7.53–7.63 (3H, m,
ArH), 8.11 (1H, dd, J¼9.0 and 2.1 Hz, 5-H), 8.59 (1H, br
s, N–H), 8.76 (1H, d, J¼2.1 Hz, 7-H) ppm. 13C NMR
(CDCl3): 52.72 (OCH3), 105.48 (C), 117.41 (C), 118.90
(5-CH), 118.95 (20 and 60-CH), 119.78 (7-CH), 125.62
(4-CH), 133.38 (C), 133.57 (30 and 50-CH), 136.04 (C),
139.28 (C), 141.64 (C), 146.08 (C), 146.92 (C), 164.22
(C]O) ppm. MS (FAB): m/z (%) 354 (M++H, 54), 353
(M+, 70). HRMS [M++H] calcd for C17H12N3O4S
354.0549, found 354.0551.
4.2.5. Methyl 3-(biphenyl-4-ylamino)benzo[b]thiophene-
2-carboxylate (8). 4-Bromobiphenyl (169 mg, 0.724 mmol),
amine 1 (150 mg, 0.724 mmol), heating for 3 h. Compound
8 was isolated by column chromatography using solvent gra-
dient till 5% ether/petroleum ether as a yellow solid (163 mg,
63%), mp 158–159 ꢀC, after some washes with petroleum
ether. 1H NMR (CDCl3): 3.94 (3H, s, OMe), 7.12–7.22 (3H,
m, ArH), 7.31–7.37 (1H, m, ArH), 7.40–7.57 (6H, m, ArH),
7.59–7.64 (2H, m, ArH), 7.79 (1H, m, ArH), 8.79 (1H, br s,
NH) ppm. 13C NMR (CDCl3): 51.92 (OCH3), 106.99 (C),
121.62 (2ꢁCH), 123.26 (CH), 123.49 (CH), 125.71 (CH),
126.70 (2ꢁCH), 126.94 (CH), 127.64 (2ꢁCH), 127.69
(CH), 128.78 (2ꢁCH), 131.97 (C), 136.12 (C), 140.04 (C),
140.52 (C), 141.61 (C), 145.86 (C), 165.76 (C]O) ppm.
MS (EI): m/z (%) 359.10 (M+, 41), 327.07 (100). HRMS
[M+] calcd for C22H17NO2S 359.0980, found 359.0973.
4.2.9. Methyl 3-(4-formylphenylamino)-6-nitrobenzo[b]-
thiophene-2-carboxylate (12). 4-Bromobenzaldehyde
(48.0 mg, 0.260 mmol), amine 3 (66.0 mg, 0.260 mmol),
heating for 3 h. Compound 12 was isolated washing the
crude with ether as a yellow solid (70.0 mg, 76%), mp
1
180–182 ꢀC, after some washes with petroleum ether. H
NMR (CDCl3): 3.99 (3H, s, OMe), 7.05 (2H, d, J¼8.7 Hz,
20 and 60-H), 7.64 (1H, d, J¼9.0 Hz, 4-H), 7.82 (2H, d, J¼
8.7 Hz, 30 and 50-H), 8.10 (1H, dd, J¼9.0 and 2.1 Hz,
5-H), 8.66 (1H, br s, N–H), 8.76 (1H, d, J¼2.1 Hz, 7-H),
9.91 (1H, s, CHO) ppm. 13C NMR (CDCl3): 52.68
(OCH3), 118.70 (20 and 60-CH), 118.79 (5-CH), 119.73
(7-CH), 125.83 (4-CH), 128.24 (C), 131.17 (40-C), 131.50
(30 and 50-CH), 136.21 (C), 139.28 (C), 141.91 (C), 146.90
(C), 147.60 (10-C), 164.25 (C]O), 190.53 (CHO) ppm.
4.2.6. Methyl 3-(4-cyanophenylamino)-6-methoxybenzo-
[b]thiophene-2-carboxylate (9). 4-Bromobenzonitrile
(98.0 mg, 0.500 mmol), amine 2 (120 mg, 0.500 mmol),
heating for 1 h. Compound 9 was isolated by column chro-
matography using solvent gradient till 30% ether/petroleum
ether as a yellow solid (51.0 mg, 30%), mp 205–207 ꢀC,
after washes with petrol. H NMR (CDCl3): 3.91 (3H, s,
OMe), 3.92 (3H, s, OMe), 6.90 (1H, dd, J¼9.0 and 2.4 Hz,
1

M.-J. R. P. Queiroz et al. / Tetrahedron 63 (2007) 13000–13005
13005
MS (FAB): m/z (%) 357 (M++H, 100). HRMS [M++H] calcd
for C17H13N2O5S 357.0545, found 357.0550.
Acknowledgements
~
Thanks are due to Fundac¸ao para a Ciencia e Tecnologia (Por-
tugal) and FEDER (European Communautaire fund) for
^
4.3. Synthesis of 6H-benzothieno[3,2-d]pyrido-
[1,2-a]pyrimid-6-ones
ꢀ
financial support through Centro de Quımica -Univ. do
Minho, project POCI/QUI/59407/2004 and for PhD grant
awarded to R. C. Calhelha (SFRH/BD/29274/2006).
The same procedure as described above (Section 4.2) was used.
4.3.1. 6H-Benzothieno[3,2-d]pyrido[1,2-a]pyrimid-6-one
(13). Amine 1 (100 mg, 0.483 mmol), 2-bromopyridine
(76.2 mg, 0.483 mmol), heating for 2 h. The crude was sub-
mitted to a dry flash column using silica (150–230 mesh)/
ether and compound 13 was isolated as a light yellow solid
References and notes
1. Thomas, G. Medicinal Chemistry; Wiley-VCH: Weinheim,
2000.
1
(98 mg, 80%), H and 13C spectra confer with the ones
presented in our earlier work.6
2. (a) Bellmann, E.; Shaheen, S. E.; Thayumanavan, S.;
Barlow, S.; Grubbs, R. H.; Marder, S. R.; Kippelen, B.;
Peyghambarian, N. Chem. Mater. 1998, 10, 1668–1676; (b)
Goodson, F. E.; Hartwig, J. F. Macromolecules 1998, 31,
1700–1703; (c) Zhang, X.-X.; Sadighi, J. P.; Mackewitz,
T. W.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 7606–
7607.
4.3.2. 6H-3-Methoxybenzothieno[3,2-d]pyrido[1,2-a]pyri-
mid-6-one (14). 2-Bromopyridine (54.0 mg, 0.340 mmol),
amine 2 (75.0 mg, 0.340 mmol), heating for 22 h. Com-
pound 14 was isolated using preparative thin layer chroma-
tography (PLC)/CHCl3 as light yellow solid (43.0 mg, 40%),
mp 284–286 ꢀC. 1H NMR (DMSO-d6, T¼70 ꢀC): 3.92 (3H,
s, OMe), 7.20 (1H, dd, J¼8.7 and 2.4 Hz, 2-H), 7.28–7.34
(1H, m, ArH), 7.69 (1H, d, J¼2.4 Hz 4-H), 7.78 (1H, d, J¼
8.7 Hz, ArH), 7.86–7.93 (1H, m, ArH), 8.25 (1H, d, J¼
8.7 Hz, 1-H), 9.00 (1H, br d, J¼8 Hz, ArH) ppm. 13C
NMR (DMSO-d6, T¼70 ꢀC): 55.60 (OCH3), 106.51 (CH),
111.25 (C), 114.76 (CH), 114.85 (CH), 124.38 (CH), 125.43
(CH), 125.95 (CH), 127.05 (C), 135.44 (CH), 143.34 (C),
149.14 (C), 153.21 (C), 153.30 (C), 161.14 (C) ppm. MS
(EI): m/z (%) 282 (M+, 100). HRMS [M+] calcd for
C15H10N2O2S 282.0463, found 282.0460.
3. Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett.
1998, 39, 2367–2370.
4. For C–N coupling reviews see: (a) Hartwig, J. F. Synlett 1997,
329–340; (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046–2067; (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818; (d)
Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125–146; (e) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131–209.
5. Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G.
Tetrahedron 2003, 59, 3737–3743.
6. Queiroz, M.-J. R. P.; Begouin, A.; Ferreira, I. C. F. R.; Kirsch,
G.; Calhelha, R. C.; Barbosa, S.; Estevinho, L. M. Eur. J. Org.
Chem. 2004, 3679–3685.
7. Begouin, A.; Hesse, S.; Queiroz, M.-J. R. P.; Kirsch, G.
Synthesis 2005, 2373–2378.
8. Begouin, A.; Hesse, S.; Queiroz, M.-J. R. P.; Kirsch, G.
Synthesis 2006, 2794–2798.
9. Begouin, A.; Hesse, S.; Queiroz, M.-J. R. P.; Kirsch, G. Eur. J.
Org. Chem. 2007, 1678–1682.
4.3.3. 6H-9-Fluoro-benzothieno[3,2-d]pyrido[1,2-a]pyri-
mid-6-one (15). 2-Bromo-5-fluoropyridine (131 mg,
0.724 mmol), amine 1 (150 mg, 0.724 mmol), heating for
22 h. The crude was submitted to column chromatography
from neat petroleum ether till 20% ethyl acetate/petroleum
ether and compound 15 was isolated as a light yellow solid
(79.0 mg, 45%), mp 277–279 ꢀC, after some washes with pe-
1
troleum ether. H NMR (DMSO-d6, T¼60 ꢀC): 7.60–7.66
10. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org.
Lett. 2002, 4, 3481–3484.
(1H, m, ArH), 7.69–7.75 (1H, m, ArH), 7.88–7.94 (1H,
m, ArH), 7.99–8.06 (1H, m, ArH), 8.16 (1H, d, J¼8.1 Hz,
ArH), 8.38 (1H, br d, J¼7.8 Hz, ArH), 8.94–8.97 (1H, m,
ꢁ
11. Viola, G.; Salvador, A.; Vedalvi, D.; Fortunato, E.; Disaro, S.;
13
ArH) ppm. C NMR (DMSO-d6, T¼60 ꢀC): 109.02 (C),
Basso, G.; Queiroz, M.-J. R. P. J. Photochem. Photobiol., B:
Biol. 2006, 82, 105–116.
12. Beck, J. R. J. Org. Chem. 1972, 37, 3224–3225.
13. Bridges, A. J.; Zhou, H. J. Heterocycl. Chem. 1997, 34, 1163–
1172.
111.95 (d, J¼42 Hz, CH), 123.49 (CH), 123.69 (CH),
125.29 (CH), 127.88 (d, J¼11.46 Hz, CH), 128.11 (d, J¼
6.64 Hz, CH), 129.81 (CH), 133.59 (C), 140.92 (C),
147.23 (C), 153.24 (d, 241.58 Hz, C–F), 152.88 (C),
153.33 (C) ppm. MS (EI): m/z (%) 270 (M+, 100). HRMS
[M+] calcd for C14H7FN2OS 270.0263, found 270.0262.
14. Oliveira-Campos, A. M. F.; Queiroz, M.-J. R. P.; Raposo,
M.M. M.;Shannon,P. V. R.Tetrahedron Lett. 1995, 36, 133–134.