A Convenient Approach to 2-Aminobenzo[b]chalcogenophenes Based on Copper-Catalyzed Transformation of 4-(2-Bromophenyl)-1,2,3-chalcogenodiazoles in the Presence of a Base and Amines

Article abstract of DOI:10.1134/S1070363218040126

The reactions of 4-(2-bromophenyl)-1,2,3-thia-and -selenadiazoles with amines in the presence of potassium carbonate and copper(I) iodide afforded 2-aminobenzo[b]chalcogenophenes. The corresponding thiaand selenamides, prepared by interaction of 4-(2-brom

Full text of DOI:10.1134/S1070363218040126

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 4, pp. 689–699. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © E.A. Popova, A.G. Lyapunova, M.L. Petrov, T.L. Panikorovskii, D.A. Androsov, 2018, published in Zhurnal Obshchei Khimii, 2018,
Vol. 88, No. 4, pp. 606–616.
A Convenient Approach to 2-Aminobenzo[b]chalcogenophenes
Based on Copper-Catalyzed Transformation
of 4-(2-Bromophenyl)-1,2,3-chalcogenodiazoles
in the Presence of a Base and Amines
a
b
a
b
a
E. A. Popova *, A. G. Lyapunova , M. L. Petrov , T. L. Panikorovskii , and D. A. Androsov
a
St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: ekaterinaapopova@yandex.ru
*
b
St. Petersburg State University, Universitetskaya nab. 7–9, St. Petersburg, 199034 Russia
Received March 12, 2018
Abstract—The reactions of 4-(2-bromophenyl)-1,2,3-thia- and -selenadiazoles with amines in the presence of
potassium carbonate and copper(I) iodide afforded 2-aminobenzo[b]chalcogenophenes. The corresponding thia-
and selenamides, prepared by interaction of 4-(2-bromophenyl)-1,2,3-thia- and -selenadiazoles with amines in
the absence of copper salt, were transformed into 2-aminobenzo[b]chalcogenophenes by the action of
potassium carbonate and copper(I) iodide in DMF in different yields.
Keywords: benzo[b]thiophene, benzo[b]selenophene, 1,2,3-thiadiazole, 1,2,3-selenadiazole, copper-catalyzed
cyclization
DOI: 10.1134/S1070363218040126
Application of benzo[b]thiophene and its derivatives
in the prepation of bioactive compounds is of great
interest to chemists. As example, they have been used
in the development of acetyl-CoA carboxylase inhibitors
[18–20]. As for 2-aminobenzo[b]selenophene, the only
known method for the synthesis of these compounds is
based on reduction of 2-nitrobenzo[b]selenophene
[21]. The reaction of 2-acetyl-3-phenylbenzo[b]seleno-
phene oxime with polyphosphoric acid gave 2-acetyl-
amino-3-phenylbenzo[b]selenophene [22]. 2-Benzoyl-
amino-3-phenylbenzo[b]selenophene has been prepared
by reacting benzoyl isoselenocyanate with diphenyldi-
azomethane [23]. However, up to the present time
there is no general method for the synthesis of 2-amino-
benzo[b]chalcogenophenes.
[1, 2] and tubulin polymerization inhibitors [3–5].
Among others 2-aminobenzo[b]thiophenes have been
successfully applied to the synthesis of selective estrogen
receptor modulator raloxiphene and its analogues [6, 7].
Also, benzo[b]thiophene, benzo[b]selenophene, and
related fused aromatic compounds are key part of
structural motif in the development of optoelectronic
materials like field-effect transistors, organic semicon-
ductors for optoelectronic devices, etс. [8–14].
Recently we reported that 4-(2-halogenaryl)-1,2,3-
thia- and -selenadiazoles bearing nitro group in the
para-position to the halogen gave 2-aminobenzo[b]chalco-
genophenes when heated in DMF in the presence of
amine and potassium carbonate [24, 25]. But only thia-
and -selenamides were obtained under similar reaction
condition when using the substrates without an acceptor
group [25, 26]. Here we report on the catalytic method
for the synthesis of unsubstituted 2-aminobenzo[b]-
chalcogenophenes in up to 87% yields.
Nowadays several methods for the synthesis of 2-
aminobenzo[b]chalcogenophenes are known. The
unsubstituted 2-aminobenzo[b]thiophene has been
prepared from thiosalicylic acid via five-step synthesis
[15]. Also, 2-aminobenzo[b]thiophene has been obtained
from 1-benzothiophen-2-ylmagnesium chloride [16].
The reaction between diverse (2-bromophenyl)aceto-
nitriles and Na S O in the presence of palladium
2
2
3
catalyst also gave rise to the substituted 2-aminobenzo-
b]thiophenes [18–20]. There are some another examples
of the synthesis of substituted 2-aminobenzo[b]thiophenes
[
The Hurd–Mori reaction was used for the synthesis
of 4-(2-halophenyl)-1,2,3-thiadiazoles 3a and 3b from
6
89

6
90
POPOVA et al.
Fig. 1. General view of the molecule of compound 5a in
the crystal.
Fig. 2. General view of the molecule of compound 5d in
the crystal.
methyl ketones 1a and 1b by reacting thionyl chloride
with the corresponding ethoxycarbonylhydrazones 2a
and 2b [27–29]. The reaction of 2-bromoacetophenone
to the formation of 2-aminobenzo[b]chalcogenophenes
5a–5h in 19–83% yields (Scheme 2, Table 1). In the
case of 3a only thioamide 4a was formed. Structure of
compounds 5a, 5d, and 5g was proved by single-
crystal X-ray diffraction method (Figs. 1–3). The
molecule of 5a was found to have disordered thio-
phene ring in the crystal. Such phenomenon is not
unique, there are some other compounds (like dibenzo-
thiophene) for which disordered thiophene fragment in
crystal is obserwed [30]. The reaction terms were
investigated using the reaction of 4-(2-bromophenyl)-
1,2,3-thiadiazole 3b with morpholine as a model
1
b with semicarbazide hydrochloride gave semi-
carbazone 2c which was converted into 4-(2-bromo-
phenyl)-1,2,3-selenadiazole 3c under the action of
selenium dioxide in acetic acid (Scheme 1).
Compounds 3a–3c were further introduced into the
reaction with amines in DMF medium in the presence
of copper(I) iodide and potassium carbonate in an inert
atmosphere; heating up to 80°С for a different time led
Scheme 1.
H
N
O
a
N
b
Z
Hlg
Hlg
N
Hlg
O
N
X
_
_
1
a, 1b
2a 2c
, Hlg = Br (2c); X = S, Hlg = Cl (3a, 70%); X = S, Hlg = Br
NHC(O)OEt, EtOH, 3 h, 80°C; b, SOCl , 2 h, 80°C; X = Se:
2
, 3 h, 65°C.
3a 3c
Z = OEt, Hlg = Cl (2a); Z = OEt, Hlg = Br (2b); Z = NH
3b, 84%); X = Se, Hlg = Br (3c, 72%). X = S: а, NH
а, NH NHC(O)NH ·HCl, EtOH, 3 h, 80°C; b, SeO
2
(
2
2
2
2
Scheme 2.
S
N
Cl
O
Hlg
N
4a
N
NR R2
1
3
a_3cX
X
a 5g
_
5
X = S, Hlg = Cl (4a); X = S, Hlg = Br (5a–5e); X = Se, Hlg = Br (5f, 5g). Reaction conditions: X = S, Hlg = Br(Cl), K
2
CO
3
,
1
2
1
2
2 3
CuI (20 mol %), HNR R , DMF, inert atmosphere, 1–96 h, 80°C; X = Se, Hlg=Br, K CO , CuI (20 mol %), HNR R , DMF,
inert atmosphere, 8–50 h, 80°C.
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A CONVENIENT APPROACH TO 2-AMINOBENZO[b]CHALCOGENOPHENES
691
Table 1. Reaction conditions and yields of 2-aminobenzo[b]chalcogenophenes 5a–5g
Reaction
time, h
Run no.
1
Amine
Product no.
Reaction product
Yield, %
74
4
4a
S
HN
O
O
N
Cl
O
2
3
4
4
5a
5b
83
49
HN
HN
N
N
O
S
S
4
4
5c
78
HN
HN
N
N
S
S
5
6
4
8
5d
5e
68
46
N
S
N
H
7
8
50
8
5f
35
19
HN
O
N
N
O
Se
Se
5g
HN
(
Scheme 3, Table 2). It was found that copper(I) and
phenes under the action of potassium carbonate and
catalytic amount of copper(I) iodide in DMF (Scheme 5,
Table 3). The structure of thioamide 4b was proved by
single-crystal X-ray diffraction method (Fig. 4).
copper(II) salts can be used in the reaction and the
nature of an anion in copper salt does not affect the
process course. The use of microwave activation made
it possible to reduce the reaction time but it did not
influence the yield. As to the nature of a base, potas-
sium carbonate and cesium carbonate were found to be
appropriate bases, but not the potassium tert-butylate.
According to the experimental data (see Tables 1
and 3), the transformation of 4-(2-halophenyl)-1,2,3-
thia- and -selenadiazoles into 2-aminobenzo[b]chalco-
genophenes has several limitations and specific features.
First of all, only bromo-substituted 4-(2-halophenyl)-
1,2,3-thia- and -selenadiazoles (3b, 3c) can be used for
the complete transformation to compounds 5. In the
case of 3a only the product 4a was obtained under the
The corresponding thio- and selenamides 4b–4f
obtained by reacting 4-(2-bromophenyl)-1,2,3-thia-
and -selenadiazole with various amines (Scheme 4)
can be transformed into 2-aminobenzo[b]chalcogeno-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
92
POPOVA et al.
Scheme 3.
O
base, cat
+
N
O
DMF,
80°С, 4 h
Br
N
S
N
H
5
a
N
S
3b
Scheme 4.
X
Hlg
N
1
2
NR R
N
X
Hlg
a_3c
_
3
4a 4f
1
2
1
2
X = S, Hlg = Cl, NR R = morpholine (4а, 68%); X = S, Hlg = Br, NR R = morpholine (4b, 83%); X = Se, Hlg = Br,
1
2
1
2
1
2
NR R = morpholine (4c, 32%); X = S, Hlg = Br, NR R = piperidinyl (4d, 92%); X = Se, Hlg = Br, NR R = diethylamino
4e, 76%); X = Se, Hlg = Br, NR R = pirrolidinyl (4f, 76%). Reaction conditions: K
1
2
(
2 3
CO , amine, DMF, inert atmosphere,
7
0–85°C, 1–96 h (4a–4d); HNEt , KOH, 3 h, 55°C (4e); pirrolidin, room temperature, 40 min (4f).
2
Scheme 5.
X
K CO ,
2
3
1 2
NR R
DMF,
1
2
X
NR R
_
_
8
0°С, 4 23 h
5
a, 5g 5i
Hlg
a, 4b, 4d 4f
_
4
reaction condition (with the presence of CuI in the
reaction mixture or without it). There is one more
limitation for this method related to the amine nature.
Secondary amines reacted actively to form the
corresponding 2-aminobenzo[b]chalcogenophenes with
various yields. Yet at the use of n-butilamine and
benzylamine the tarring of the reaction mixture oc-
curred. The yields of 2-aminobenzo[b]selenophenes
are a little lower than the yields of the same 2-amino-
benzo[b]thiophenes (Table 1). It may be explained by
the fact that under heating the initial selenadiazoles are
less stable then thiadiazoles and decompose actively at
Table 2. Optimization of the reaction conditions of 4-(2-
bromophenyl)-1,2,3-thiadiazole 3b with morpholine
Run no.
Base
Catalyst
CuI
Yield, %
83
8
0°С without future interaction.
1
2
3
4
5
6
7
8
K
K
K
K
K
2
2
2
2
2
CO
3
3
3
3
3
The structure of the target compounds was
CO
CO
CO
CO
CuCl
CuBr
83
1
confirmed by NMR spectra. In the H NMR spectrum
of compound 5d six signals related to the protons of
piperidine ring and to the protons of methyl group
were observed in the range of 0.8–6.6 ppm. Such
spectral pattern indicates that the pyrrolidine ring is
present in a definite conformation and the conforma-
tions interconvertin time exceeds the time if the
spectrum recording (otherwise, we would expect the
appearance of four signals: one for each methylene
group as they are symmetric, one for the single proton,
and one for the methyl group). The COSY and HSQC
spectra proved that 2.88 and 3.58 ppm signals belong
82
CuCl
2
87
Cu(OAc)
CuI
2
92
Cs
2
CO
3
77
t-BuOK–DMF
t-BuOK–THF
CuI
22
CuI
31
а
9
K
2
CO
3
CuI
82
a
The reaction mixture was subjected to microwave irradiation
600 W) at 80°C for 90 min.
(
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

A CONVENIENT APPROACH TO 2-AMINOBENZO[b]CHALCOGENOPHENES
693
Fig. 3. General view of the molecule of compound 5g in
the crystal.
Fig. 4. General view of the molecule of compound 4b in
the crystal.
2
6
to H and H at the C and C atoms of the piperidine
ring systems), it may be stated that the signal at 3.07–
ax
eq
6
ring, respectively. The signals at 1.28 and 1.70 ppm
correspond to Hax and Heq at the C and C atoms,
respectively. In this case the spin-spin coupling constants
3.20 ppm belongs to C H of the piperidine ring, the
ax
3
5
6
gem
signal at 3.47 ppm belongs to C H (J
=
eq
НН
12.05 Hz), and the signal at 3.54–3.64 ppm belongs to
2
(6)
2(6)
3(5)
3(5)
2
Jgem for the protons Hax –Heq
and Hax –Heq
C H .
ax
equal 13.1 and 12.1 Hz, respectively.
The presumable reaction mechanism was proposed
and outlined in Scheme 6 by the example of 4-(2-
bromophenyl)-1,2,3-thiadiazole. We made the conclu-
sion that 3→5 transformation in the presence of copper(I)
iodide includes the decomposition of compound 3
1
.28
3
.58
H
1.70
H
H
H
N
H
S
H
CH3
H
H
0.94
H
Table 3. The reaction conditions and yields of 2-amino-
benzo[b]chalcogenophenes 5a, 5g–5i
1
.55
2
.88
1
In the H NMR spectra of compound 5e there were
three separate signals of the protons which are located
two bonds away from the nitrogen atom, ppm: 3.07–
Reaction
Amide time,
h
Run
no.
Yield,
%
Reaction product
–
3
.20 (1H), 3.47 br.d (1H, J = = 12.05 Hz), 3.54–3.64 m
1
2
4a
4b
12
4
–
2
6
(
1H) (these signals correspond to C H , C H and
ax ax
6
88
C H of the piperidine ring). The presence of such
eq
N
S
O
signals in the spectrum indicates the staggered
conformation of the piperidine ring with the ethyl
substituent playing an anchor role. However, an
unambiguous correlation of the signals was possible
due to the COSY spectral method. The COSY spectra
contained the following cross-peaks, ppm: 3.63↔1.73
5a
3
4
4d
4e
33
43
39
50
N
Se
5g
3
4
5
(
1.60–1.90 ppm, C , C , C methylene groups and
СH CH ), 3.47↔1.76 (1.60–1.90 ppm), 3.47↔3.16
2
3
N
(
3.09–3.23 ppm, 1H). Due to the presence of the
Se
corresponding cross-peaks and the fact that the signal
at 3.47 ppm was registered as a broad doublet (J =
5h
1
2.05 Hz) and the signal at 3.07–3.20 ppm was
5
4f
28
32
recorded as a multiplet with several spin-spin coupling
constants of more than 10 Hz (it is typical for axial-
axial and geminal interaction between the protons in
N
Se
5i
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
94
POPOVA et al.
Scheme 6.
_
B
_HB
_N2
Br
N
Br
N
Br
_
N
N
_
S
S
S
3
b
6
7
_B_
BH
1
2
HNR R
Br
1
2
Br
CH
Br
NR R
C
SH
S
S
4
_
9
8
B
R1
R2
N
R1
R2
I
1
2
Cu
N
NR R
Br
S
_
1
0
S
Br
_
_I
NR R2
1
1
1
R1
R2
_
R1
R1
HN
N
N
R2
R2
Cu
Br
III
Cu
I (or)
13
R1
S
+
2
HN
R2
NR R2
1
12
NR R2
1
S
5
under the action of a base followed by transformation
in thioketene 9. Further addition of amine to thioketene
followed by cyclization under the action of copper(I)
salt gives the desired 2-aminobenzo[b]thiophene. The
possibility of using copper(I) and copper(II) salts
suggests that the process includes catalytic cycle with
one-electron transfer. As the reaction rate decreases
twice when using 2-ethylpiperidine instead of
piperidine (8 h vs 4 h), it means that amine nature
plays an important role in the rate-determining step. If
the nucleophilic substitution of the halogen in aromatic
ring is the rate-determining step, then the decrease in
the reaction rate, when using sterically hindered amine,
can prove that copper is not only electron-carrier in the
reaction course but forms directly a complex with
amine. The presence of a substituent near the reaction
site in amine makes the complex formation difficult.
In summary, we developed a catalytic method of the
synthesis of unsubstituted 2-aminobenzo[b]chalcogeno-
phenes from 4-(2-bromophenyl)-1,2,3-thia- and -selena-
diazoles as well as the corresponding thio- and selenamides.
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A CONVENIENT APPROACH TO 2-AMINOBENZO[b]CHALCOGENOPHENES
695
1
1
1
1
13
EXPERIMENTAL
Table 4. Н, Н– Н COSY and Н– С HSQC NMR spectral
data for compound 5d
Melting points were measured on a Boetius melting
δ, ppm
С
δ , ppm
1
13
point apparatus. H and C NMR spectra were
recorded on a Bruker DPX-400 spectrometer at 400.13
and 100.16 MHz, respectively. High-resolution mass
spectra (electrospray ionization) were taken on a
Micromass 70-VSE instrument. The reaction progress
was monitored by TLC on Silica gel 60 F254 plates;
spots were visualized under UV light or by treatment
with iodine vapor. Single-crystal X-ray diffraction
analysis was performed on a Xcalibur Agilent
Technologies instrument (Oxford Diffraction). X-ray
diffraction data were deposited at the Cambridge
Crystallographic Data Centre [CCDC 1449609 (5a),
1
1
1
1
13
Н
Н– Н COSY
Н– С HSQC
22.08
0
1
.94
1.55 (1.48–1.62)
.28 (1.20–1.36) 1.70, 2.88, 3.58
33.32
1.55 (1.48–1.62) 0.94, 1.28
30.19
1
2
.70
.88
1.28 (1.20–1.36), 2.88, 3.58
1.28 (1.20–1.36), 1.70, 3.58
1.28 (1.20–1.36), 1.70, 2.88
–
33.32
51.14
3.58
51.14
6
7
7
7
7
.25
98.51
.02 (6.98–7.06) 7.19 (7.15–7.24), 7.64
.19 (7.15–7.24) 7.02 (6.98–7.06), 7.42
121.16
124.90
120.78
121.93
1
449608 (5d), 1047330 (5g), 1433686 (4b)].
The solvents used were purified and dried accord-
ing to standard procedures. All chemicals were used as
purchased.
.42
.64
7.19 (7.15–7.24)
7.02 (6.98–7.06)
Ethyl 2-(1-(2-chlorophenyl)ethylidene)hydrazino-
carboxylate (2a). A mixture of 1-(2-chlorophenyl)-
ethanone 1a (15.45 g, 0.1 mol), ethyl carbazate
4-(2-Chlorophenyl)-1,2,3-thiadiazole (3a). A solu-
tion of 3.05 g (12.7 mmol) of compound 2a in 7 mL of
(
10.4 g, 0.1 mol), and three drops of H SO in 50 mL
SOCl was refluxed within 2 h, then cooled, and
2
4
2
of EtOH was refluxed for 3 h and left overnight at
room temperature. The precipitate was filtered off,
poured into water. The precipitate was filtered off,
washed thoroughly with water, and crystallized from
washed with EtOH–H O (1 : 1), and dried. Yield 21.90 g
СHCl –MeOH. Yield 1.72 g (70%), white crystals, mp
2
3
1
1
(
89%), white crystals, mp 131–132°C. H NMR
34–35°C. H NMR spectrum (CDCl ), δ, ppm: 7.37–
3
spectrum (CDCl ), δ, ppm: 1.34 t (3H, J = 7.1 Hz),
7.47 m (2H), 7.53–7.57 m (1H), 8.12–8.16 m (1H),
3
1
3
2
.22 s (3H), 4.33 q (2H, J = 7.1 Hz), 7.26–7.30 m (2H),
.35–7.38 m (1H), 7.41–7.44 m (1H), 7.93 br.s (1H, NH).
C NMR spectrum (CDCl ), δ , ppm: 14.6, 16.8, 62.2,
9.05 s (1H). C NMR spectrum (CDCl ), δ , ppm:
3 С
7
127.4, 129.6, 130.4, 130.6, 131.9, 132.3, 134.6, 159.1.
13
+
3
С
Mass spectrum (HRMS-EI), m/z: 195.9935 [M + H]
126.9, 129.7, 129.9, 130.5, 132.3, 138.8, 149.5. The
(calculated for C H ClN S: 196.9940). The spectral
8
5
2
spectral data correspond to those described in [24].
data correspond to those described in [24].
Ethyl 2-(1-(2-bromophenyl)ethylidene)hydrazino-
4-(2-Bromophenyl)-1,2,3-thiadiazole (3b) was
carboxylate (2b) was prepared similarly from 29.4 g
prepared similarly. Yield 3.58 g (84%), pale yellow
1
(
0.15 mol) of 1-(2-bromophenyl)ethanone 1b and
crystals, mp 41.5–42.5°С. H NMR spectrum (CDCl ),
3
1
2
5.35 g (0.15 mol) of ethyl carbazate; the reaction time
h. Yield 36.23 g (86%), white crystals, mp 139–140°С.
δ, ppm: 7.27–7.35 m (1Н), 7.42–7.50 m (1Н), 7.73 d
(1H, J = 8.1 Hz), 7.94 d (1H, J = 8.0 Hz), 9.01 s
1
13
H NMR spectrum (CDCl ), δ, ppm: 1.36 t (3H, J =
(1H ). С NMR spectrum (CDCl ), δ , ppm: 122.3,
3
Het
3
С
6
7
7
.8 Hz), 4.34 q (2H, J = 6.8 Hz), 2.24 s (3H), 7.17–
.26 m (1Н), 7.29–7.36 m (1Н), 7.39 d (1H, J =
.1 Hz), 7.57 d (1H, J = 8.2 Hz), 7.94 s (1Н, NH). С
127.9, 130.6, 131.7, 132.2, 133.9, 134.7, 160.5. Mass
spectrum (HRMS-EI), m/z: 240.9430 [M + H]
+
1
3
(calculated for C H BrN S: 240.9435). The spectral
8
5
2
NMR spectrum (CDCl ), δ , ppm: 14.6, 17.1, 62.2,
data correspond to those described in [33].
3
С
1
21.6, 127.5, 130.0, 130.6, 132.9, 140.8, 150.5, 154.0.
4
-(2-Bromophenyl)-1,2,3-selenadiazole (3c). Sele-
+
Mass spectrum (HRMS-EI), m/z: 285.0233 [M + H]
calculated for C H BrN O : 285.0239).
nium dioxide (0.31 g, 2.80 mmol) was added with
stirring to a suspension of semicarbazone 2c (0.64 g,
2.5 mmol) in glacial acetic acid (6 mL). The mixture
was stirred at 30°C for 4 h and then at 47°C for 22 h,
cooled to room temperature, poured into water
(50 mL), and extracted with chloroform (3×15 mL).
(
1
1
13
2
2
2
-[1-(2-Bromophenyl)ethylidene]hydrazinocar-
boxamide (2c) was prepared as described in [31].
Yield 88%, white crystals, mp 175–177°С (mp 175–
1
77°С [32].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
96
POPOVA et al.
8.0 Hz). C NMR spectrum (DMSO-d ), δ , ppm:
13
The extract was washed with an aqueous solution of
sodium carbonate (3×10 mL), brine (3×10 mL) and
dried over anhydrous Na SO . The solvent was
6
С
49.2, 50.2, 50.9, 66.2, 66.2, 124.6, 128.3, 129.2, 130.6,
13
132.9, 136.9, 198.3. C NMR spectrum (CDCl ), δ ,
2
4
3
С
removed at a reduced pressure to yield the crude
product. Purification of the crude product by column
chromatography using ethyl acetate–petroleum ether
ppm: 50.0, 50.1, 50.9, 66.2, 66.2, 66.4, 124.0, 128.0,
128.8, 129.2, 132.9, 135.5, 199.5. Mass spectrum
(HRMS-ESI), m/z: 323.9859 [M + Na] (calculated for
+
(
1 : 10) as the eluent gave 3c (0.52 g, 72%) as pale
C H BrNNaOS: 323.9857).
1
2
14
1
orange crystals, mp 37–38°C. H NMR spectrum
CDCl ), δ, ppm: 7.31 t (1H, J = 8.0 Hz), 7.45 t (1H,
2
-(2-Bromophenyl)-1-(morpholin-1-yl)ethane-
(
3
selenone (4c). Yield 0.05 s (32%), pale orange
J = 7.5 Hz), 7.74 d (1H, J = 8.0 Hz), 7.88 d (1H, J =
7
NMR spectrum (CDCl ), δ , ppm: 122.4, 127.6, 130.2,
1
m/z (I, %): 260 (34) [M – N ] , 181 (60) [M – N – Se] ,
1
(
[
1
crystals, mp 135–136°С. H NMR spectrum (CDCl ),
1
3
3
.5 Hz), 9.65 s (1H + HSe satellite, J = 41.0 Hz). C
δ, ppm: 3.46 br.s (4H), 3.82 t (2H, J = 5.2 Hz), 4.46–
3
С
4
.55 m (2H), 4.51 s (2H), 7.15 t (1H, J = 7.9 Hz), 7.31
32.4, 132.7, 133.7, 142.1, 160.3. Mass spectrum (EI),
t (1H, J = 7.9 Hz), 7.52 d (1H, J = 7.9 Hz), 7.56 d.d
+
+
2
2
13
(
1H, J = 7.9, 0.9 Hz). C NMR spectrum (CDCl ), δ ,
3 С
+
01 (63) [M – N – Se – Br] , 89 (65), 75 (100), 50
2
ppm: 51.9, 53.8, 54.7, 65.8, 66.3, 123.8, 128.0, 128.8,
28.9, 132.9, 134.6, 203.7. Mass spectrum (HRMS-
66). Mass spectrum (HRMS-ESI), m/z: 310.8700
1
+
M + Na] (calculated for С Н BrN NaSe: 310.8699).
+
8
5
2
ESI), m/z: 369.9358 [M + Na] (calculated for
С Н BrNOSe: 369.9322).
General procedure for the synthesis of amides 4a–
1
2
14
4
d. A mixture of 3 (1 equiv), K CO (2.5–3 equiv),
2
3
2
-(2-Bromophenyl)-1-(piperidin-1-yl)ethane-
and amine (4.4–27 equiv) in DMF (3–10 mL) was
stirred at 70–85°C for 4–96 h under argon atmosphere.
After cooling to room temperature, the solvent was
evaporated in a vacuum. The residue was dissolved in
chloroform and thoroughly washed with water, dried
over anhydrous Na SO . The solvent was evaporated at
selenone (4d). Yield 0.22 g (92%), orange crystals, mp
5–77°С. H NMR spectrum (CDCl ), δ, ppm: 1.37
br.s (2H), 1.47–1.90 m (5H), 3.43 br.s (2H), 4.19–4.77
m (4H), 7.13 br.s (1H), 7.27 br.s (1H), 7.41–7.76 m
2H). C NMR spectrum (CDCl ), δ , ppm: 23.8,
5.5, 26.2, 52.7, 54.3, 56.5, 124.0, 128.0, 128.7, 129.2,
32.9, 135.1, 201.5. Mass spectrum (HRMS-ESI), m/z:
83.9273 [M + K] (calculated for С Н BrKNSe:
1
7
3
13
(
2
1
3
3
С
2
4
a reduced pressure. The crude product was purified by
recrystallization or column chromatography.
+
1
3
16
2
-(2-Chlorophenyl)-1-(morpholin-1-yl)ethanethione
383.9268).
(
(
4a). Yield 0.88 g (68%), white crystals, mp 119–120°C
hexane–petroleum ether–chloroform, 50 : 5 : 3). H
N,N-Diethyl-2-(2-bromophenyl)ethaneseleno-
amide (4e). A mixture of compound 3c (0.3 g,
1
NMR spectrum (CDCl ), δ, ppm: 3.45 m (2H), 3.53 m
(
3
1
.05 mmol), KOH (0.12 g, 2.1 mmol) and diethyl-
2H), 3.75 m (2H), 4.37 m (2H), 4.35 s (2H), 7.18–
amine (1.5 mL, 1.07 g, 1.5 mmol) was stirred at 55°C
until nitrogen evolution сeased. The mixture was
cooled to room temperature, poured into water
7
6
5
1
2
2
.26 m (2H), 7.36 d (1H, J = 8.0 Hz), 7.41 d (1H, J =
1
3
.6 Hz). C NMR spectrum (CDCl ), δ , ppm: 47.1,
3
С
0.0, 50.7, 66.1, 66.3, 127.2, 128.5, 129.1, 129.5,
(
75 mL), neutralized with dilute acetic acid, and
33.1, 133.7, 199.4. Mass spectrum (HRMS-EI), m/z:
extracted with chloroform (3×10 mL). The extract was
dried over anhydrous Na SO ; the solvent was
+
56.0557 [M + Н] (calculated for C H ClNOS:
1
2
14
2
4
56.0563). The spectral data correspond to those
evaporated at a reduced pressure. The residue was
chromatographed using ethyl acetate–petroleum ether
(1 : 10) as the eluent. Yield 0.26 g (76%), bright
described in [34].
-(2-Bromophenyl)-1-(morpholin-1-yl)ethanethione
4b). Yield 1.03 g (83%), white crystals, mp 115–117°С
2
1
(
(
yellow crystals, mp 69–70°C. H NMR spectrum
1
Et O). H NMR spectrum (DMSO-d ), δ, ppm: 3.53 t
(CDCl ), δ, ppm: 1.16 t (3H, J = 7.1 Hz), 1.34 t (3H,
2
6
3
(
(
7
8
2H, J = 4.5 Hz), 3.66–3.76 m (4H), 4.23 s (2H), 4.28 t
4H, J = 5.0 Hz), 7.18–7.24 m (1Н), 7.26 d (1H, J =
J = 7.1 Hz), 3.37 q (2H, J = 7.1 Hz), 4.12 q (2H, J =
7.1 Hz), 4.39 s (2H), 7.11 t (1H, J = 7.5 Hz), 7.25 t
(1H, J = 7.5 Hz), 7.47 d (1H, J = 7.5 Hz), 7.52 d (1H,
.0 Hz), 7.34–7.41 m (1Н), 7.62 d (1H, J =
1
13
.0 Hz). H NMR spectrum (CDCl ), δ, ppm: 3.49 t
J = 7.5 Hz). C NMR spectrum (CDCl ), δ , ppm:
3
3
С
(
2H, J = 4.5 Hz), 3.56 t (2H, J = 4.5 Hz), 3.79 t (2H,
J = 4.5 Hz), 4.34–4.44 m (4Н), 7.12–7.20 m (1Н), 7.29–
.36 m (1Н), 7.44 d (1H, J = 7.5 Hz), 7.59 d (1H, J =
10.9, 12.6, 47.4, 51.6, 53.6, 124.2, 127.8, 128.5, 129.1,
132.6, 135.3, 201.9. Mass spectrum (EI), m/z (I, %):
+
7
254 (42) [M – Br] , 183 (16), 169 (24), 158 (13), 89
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

A CONVENIENT APPROACH TO 2-AMINOBENZO[b]CHALCOGENOPHENES
697
(
18), 72 (26), 29 (100). Mass spectrum (HRMS-ESI),
mixture was stirred at 80°С for 4–23 h. In the case of
compounds 5g–5i an additional amount of CuI (0.2–
0.3 equiv) was added and the reaction flask was
evacuated, flushed with argon again, and stirred at 80–
+
m/z: 333.9712 [M + Н] (calculated for С Н BrNSe:
3
С Н BrNNaSe: 355.9529).
1
2
16
+
33.9710), 355.9532 [M + Na] (calculated for
1
2
16
8
5°С for 13–24 h. After cooling, the reaction mixture
2
-(2-Bromophenyl)-1-(pirrolidin-1-yl)ethane-
was poured into a saturated aqueous solution of NH Cl
4
selenone (4f). A solution of selenadiazole 3c (0.3 g,
.04 mmol) in pyrrolidine (3 mL, 2.58 g, 36 mmol)
(
50 mL), extracted with chloroform (3×10 mL). The
1
extract was filtered, washed with saturated aqueous
solution of NH Cl (2×20 mL), brine (2×20 mL), water
was stirred at room temperature for 40 min and then
poured into water (75 mL). The solution was extracted
with chloroform (3×10 mL), the extract was washed
with the diluted solution of acetic acid and brine, dried
over anhydrous Na SO , and concentrated under
reduced pressure. The residue was purified by column
chromatography using ethyl acetate–petroleum ether
1 : 10) as the eluent. Yield 0.26 g (76%), orange
4
(
2×20 mL), dried over anhydrous Na SO , and
2 4
concentrated at a reduced pressure. The crude product
was purified by column chromatography [SiO , eluent
ethyl acetate–hexane (1 : 4), or ethyl acetate–
petroleum ether (1 : 25)] affording the target com-
pounds 5a, 5g–5i with 32–88% yields.
2
2
4
(
1
crystals, mp 70–71°С. H NMR spectrum (CDCl ), δ,
ppm: 2.05 sextet (4H, J = 6.7 Hz), 3.34 t (2H, J =
.7 Hz), 3.91 t (2H, J = 6.7 Hz), 4.32 s (2H), 7.13 t
4-(Benzo[b]thiophen-2-yl)morpholine (5a). Yield
0.075 g (82%, method a), 0.052 g (71%, method b),
white crystals, mp 179–181°С. H NMR spectrum
3
1
6
(
1H, J = 7.5 Hz), 7.29 t (1H, J = 7.5 Hz), 7.47 d (1H,
(CDCl ), δ, ppm: 3.27 t (4Н, J = 5.0 Hz), 3.89 t (4Н,
3
1
3
J = 7.5 Hz), 7.56 d (1H, J = 7.5 Hz). C NMR
spectrum (CDCl ), δ , ppm: 24.3, 26.6, 51.9, 54.2,
5
J = 5.0 Hz), 6.25 s (1H), 7.09–7.17 m (1Н), 7.23–7.32
m (1Н), 7.50 d (1H, J = 8.0 Hz), 7.64 d (1H, J =
3
С
1
3
8.0, 124.7, 127.8, 128.6, 129.6, 132.7, 134.9, 199.0.
8.0 Hz). C NMR spectrum (CDCl ), δ , ppm: 51.0,
3 С
+
Mass spectrum (HRMS-ESI), m/z: 331.9533 [M + Н]
calculated for С Н BrNSe: 331.9553).
66.3, 99.5, 121.0, 121.6, 121.7, 124.6, 132.7, 140.3,
(
157.8. Mass spectrum (HRMS-ESI), m/z: 204.0841
1
2
15
+
[
M + Н] (calculated for C H NS: 204.0841).
1
2
13
General procedures for the synthesis of 2-amino-
1
449609. The spectral data correspond to those
benzo[b]thiophenes and 2-amino-benzo[b]seleno-
phenes (5a–5j). a. A suspension of 3b or 3c (1 equiv),
K CO (3 equiv) in amine (2 equiv) and DMF (3 mL)
described in [35].
1-(Benzo[b]thiophen-2-yl)piperidine (5b). Yield
2
3
was flushed with argon and degassed for three times,
then CuI (0.2 equiv) was added. The reaction flask was
evacuated, flushed with argon, degassed once more
and the reaction mixture was stirred at 70–85°С for 4–
0.088 g (49%, method a), white crystals, mp 98.5–
1
100°С. H NMR spectrum (DMSO-d ), δ, ppm: 1.53–
6
1.61 m (2Н), 1.61–1.71 m (4Н), 3.17–3.27 m (2Н),
6.26 s (1H), 6.98–7.07 m (1Н), 7.15–7.24 m (1Н), 7.43
1
3
5
0 h. After cooling the reaction mixture was poured
d (1Н, J = 7.0 Hz), 7.65 d (1Н, J = 8.0 Hz). C NMR
spectrum (DMSO-d ), δ , ppm: 23.9, 25.1, 51.7, 98.4,
into a saturated aqueous solution of NH Cl (50 mL)
4
6
С
and extracted with ethyl acetate (2×20 mL). The
extract was filtered, washed with saturated aqueous
120.8, 121.2, 122.0, 124.9, 132.1, 141.3, 158.3. Mass
spectrum (HRMS-ESI), m/z: 218.0997 [M + Н]
+
solution of NH Cl (2×20 mL), brine (2×20 mL), water
(calculated for C H NS: 218.0998). The spectral data
4
13 15
(
2×20 mL), dried over anhydrous Na SO , and
correspond to those described in [35].
2
4
concentrated at a reduced pressure. The crude product
1
-(Benzo[b]thiophen-2-yl)pyrrolidine (5c). Yield
was purified by column chromatography [SiO , ethyl
2
0
.135 g (78%, method a), white crystals, mp 87–89°С.
H NMR spectrum (CDCl ), δ, ppm: 1.90–2.19 m
4Н), 3.30–3.55 m (4Н), 5.87 s (1H), 6.98–7.06 m
1Н), 7.19–7.27 m (1Н), 7.44 d (1Н, J = 8.0 Hz), 7.60
acetate–hexane (1 : 4, 1 : 5), or ethyl acetate–
petroleum ether (1 : 8, 1 : 25)] affording the cor-
responding 2-amino-benzo[b]thiophenes and 2-amino-
benzo[b]selenophenes with yields of 19–93%.
1
3
(
(
13
d (1Н, J = 8.0 Hz). C NMR spectrum (CDCl ), δ ,
3
С
b. A suspension of 4 (1 equiv) and K CO3
ppm: 25.8, 50.5, 94.0, 119.7, 121.4, 124.5, 131.8,
2
(
1.5 equiv) in DMF (3 mL) was flushed with argon and
141.8, 153.9. Mass spectrum (EI), m/z (I, %): 204 (16)
[M + 1] , 203 (100) [M] , 202 (54), 175 (6), 160 (30),
+
+
degassed for three times, then CuI (0.2 equiv) was
added. The reaction flask was evacuated and flushed
with argon, degassed once more and the reaction
147 (35), 134 (14), 121 (10), 89 (28), 41 (28), 27 (23).
+
Mass spectrum (HRMS-ESI), m/z: 204.0841 [M + Н]
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
98
POPOVA et al.
(
calculated for C H NS: 204.0841). The spectral data
J = 5.7 Hz), 1.74 quintet (4Н, J = 5.7 Hz), 3.24 t (4H,
J = 5.7 Hz), 6.24 s (1H), 7.00 t (1H, J = 7.1 Hz), 7.23 t
1
2
13
correspond to those described in [36].
-(Benzo[b]thiophen-2-yl)-4-methylpiperidine (5d).
Yield 0.195 g (68%, method a), yellow crystals, mp
1
1
(
1H, J = 7.1 Hz), 7.43 d (1H, J = 7.7 Hz), 7.64 d (1H,
1
1
3
J = 7.8 Hz). C NMR spectrum (CDCl ), δ , ppm:
3
С
1
23.8, 25.2, 53.0, 101.0, 121.1, 122.1, 124.6, 124.7,
01–102.5°С. H NMR spectrum (CDCl ), δ, ppm:
3
1
2
2
34.0, 143.5, 160.6. Mass spectrum (HRMS-ESI), m/z:
.02 d (3Н, J = 7.0 Hz), 1.34–1.50 m (2Н), 1.51–1.63
+
66.0456 [M + Н] (calculated for C H NSe:
1
3
16
m (1H), 1.76 d (2H, J = 13.1 Hz), 2.92 m (2H), 3.66
br.d (2H, J = 12.1 Hz), 6.18 s (1H), 7.03–7.14 m (1Н),
66.0448).
7
.20–7.27 m (1Н), 7.46 d (1Н, J = 8.0 Hz), 7.61 d (1Н,
N,N-Diethylbenzo[b]selenophene-2-amine (5h) was
1
J = 8.0 Hz). H NMR spectrum (DMSO-d ), δ, ppm:
0
m (1H), 1.70 br.d (2H, J = 13.1 Hz), 2.88 m (2H), 3.58
br.d (2H, J = 12.1 Hz), 6.25 s (1H), 6.98–7.06 m (1Н),
prepared by method b. CuI was added to the reaction
mixture twice: 0.012 g (0.064 mmol) at the beginning
of the reaction, 0.012 g (0.064 mmol) after 23 h. The
6
.94 d (3Н, J = 7.0 Hz), 1.20–1.36 m (2Н), 1.48–1.62
mixture was stirred at 85°С for another 20 h. Yield
1
7.15–7.24 m (1Н), 7.42 d (1H, J = 8.0 Hz), 7.64 d (1H,
0.032 g (39%), yellow oil. H NMR spectrum (CDCl ),
3
13
J = 8.0 Hz). C NMR spectrum (CDCl ), δ , ppm: 21.8,
δ, ppm: 1.26 t (6Н, J = 7.1 Hz), 3.36 q (4H, J =
7.1 Hz), 6.13 br.s (1H), 6.96 t (1H, J = 7.5 Hz), 7.21 t
(1H, J = 7.5 Hz), 7.39 d (1H, J = 7.8 Hz), 7.61 d (1H,
3
С
3
1
2
1
2
0.4, 33.4, 51.5, 98.5, 120.5, 120.9, 121.5, 124.4, 132.6,
40.9, 158.3. C NMR spectrum (DMSO-d ), δ , ppm:
2.0, 30.2, 33.3, 51.1, 98.5, 120.8, 121.2, 121.9, 124.9,
32.2, 141.3, 158.0. Mass spectrum (HRMS-ESI), m/z:
13
6
С
1
3
J = 7.8 Hz). C NMR spectrum (CDCl ), δ , ppm:
3 С
12.7, 48.4, 98.4, 120.4, 121.5, 124.6, 125.0, 133.4, 144.4,
+
32.1157 [M + Н] (calculated for C H NS: 232.1154).
157.3. Mass spectrum (HRMS-ESI), m/z: 254.0444
14
17
+
[
M + Н] (calculated for C H NSe: 254.0442).
1
2
16
1
-(Benzo[b]thiophen-2-yl)-2-ethylpiperidine (5e).
1
Yield 0.122 g (60%, method a), yellow oil. H NMR
1-(Benzo[b]seleniphen-2-yl)pyrrolidine (5i) was
spectrum (CDCl ), δ, ppm: 0.97 t (3Н, J = 7.0 Hz),
prepared by method b. CuI was added to the reaction
mixture twice: 0.015 g (0.08 mmol) at the beginning of
the reaction, 0.015 g (0.08 mmol) after 4 h. The
mixture was stirred at 85°С for another 24 h. Yield
3
1
.60–1.91 m (8Н), 3.07–3.20 m (1H), 3.47 br.d (1H,
J = 12.1 Hz), 3.54–3.64 m (1Н), 6.10 br.s (1H), 7.00–
7
8
.11 m (1Н), 7.19–7.27 m (1Н), 7.43 d (1H, J =
.0 Hz), 7.59 d (1H, J = 8.0 Hz). C NMR spectrum
1
3
1
0.032 g (32%), beige crystals, mp 89–90°C. H NMR
(
CDCl ), δ , ppm: 11.5, 18.9, 20.6, 25.0, 26.6, 45.9,
spectrum (DMSO-d ), δ, ppm: 1.99 quintet (4H, J =
3
С
6
6
1
0.4, 97.6, 120.1, 120.5, 121.4, 124.4, 132.3, 141.3,
3.5 Hz), 3.26 q (4H, J = 7.1 Hz), 5.87 s (1H), 6.85 t
(1H, J = 7.4 Hz), 7.15 t (1H, J = 7.4 Hz), 7.34 d (1H,
J = 7.7 Hz), 7.68 d (1H, J = 7.7 Hz). C NMR
58.0. Mass spectrum (HRMS-ESI), m/z: 246.1299
+
13
[
M + Н] (calculated for: C H NS 246.1311).
1
5
19
spectrum (DMSO-d ), δ , ppm: 25.5, 51.2, 95.7, 119.4,
6
С
1
-(Benzo[b]selenophen-2-yl)morpholine (5f). Yield
1
20.9, 124.8 (2C), 132.7, 144.3, 154.8. Mass spectrum
0
1
(
(
7
.060 g (35%, method a), pale orange crystals, mp 174–
76°C. H NMR spectrum (CDCl ), δ, ppm: 3.23 t
4H, J = 4.5 Hz), 3.86 t (4Н, J = 4.5 Hz), 6.33 br.s
1H), 7.04 t (1H, J = 7.4 Hz), 7.25 t (1H, J = 8.2 Hz),
.47 d (1H, J = 7.8 Hz), 7.66 d (1H, J = 7.8 Hz). C
NMR spectrum (CDCl ), δ , ppm: 52.0, 66.3, 102.4,
21.8, 122.8, 124.7, 125.0, 134.2, 142.8, 159.9. Mass
spectrum (HRMS-ESI), m/z: 268.0252 [M + Н]
calculated for С Н NOSe: 268.0241).
+
1
(HRMS-ESI), m/z: 252.0296 [M + Н] (calculated for
С Н NSe: 252.0291).
3
1
2
14
ACKNOWLEDGMENTS
This work was financially supported by the Ministry
of Education and Science of the Russian Federation
within the framework of the state project (project no.
1
3
3
С
1
+
(
1
2
14
4
.5554.2017/8.9) using the equipment of the X-ray
1
-(Benzo[b]selenophen-2-yl)piperidine (5g). In
Diffraction Center of St. Petersburg State University
and the Engineering Center of the St. Petersburg State
Institute of Technology (Technical University).
the case of the synthesis by method b CuI was added
trice: 0.022 g (0.116 mmol) at the beginning of the
reaction, 0.022 g (0.116 mmol) after 7 h, and 0.011 g
(
0.058 mmol) after 13 h. The mixture was stirred at
REFERENCES
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0
0°С for another 13 h. Yield 0.030 g (19%, method a),
.077 g (50%, method b), white crystals, mp 97–98°С.
1
. Chonan, T., Wakasusugi, D., Yamamoto, D., Yashiro, M.,
Oi, T., Tanaka, H., Ohoka-Sugita, A., Io, F., Koretsune, H.,
and Hiratate, A., Bioorg. Med. Chem., 2011, vol. 19,
1
H NMR spectrum (CDCl ), δ, ppm: 1.61 sextet (2H,
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

A CONVENIENT APPROACH TO 2-AMINOBENZO[b]CHALCOGENOPHENES
699
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