Copper(I) iodide-catalyzed synthesis of 1-benzothiophen-2-amines from 4-(2-bromophenyl)-1,2,3-thiadiazole

Full text of DOI:10.1134/S1070428015070283

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 7, pp. 1040–1042. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © M.L. Petrov, E.A. Popova, D.A. Androsov, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 7, pp. 1057–1059.
SHORT
COMMUNICATIONS
Copper(I) Iodide-Catalyzed Synthesis of 1-Benzothiophen-
2-amines from 4-(2-Bromophenyl)-1,2,3-thiadiazole
M. L. Petrov, E. A. Popova, and D. A. Androsov
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: mLpetrov@lti-gti.ru
Received April 15, 2015
DOI: 10.1134/S1070428015070283
2-Dimethylamino-1-benzothiophen-6-ol is the key
intermediate product in the synthesis of the known
selective estrogen receptor modulator Raloxifene and
its analogs [1, 2]. However, procedures for the synthe-
sis of 2-amino-1-benzothiophenes have been poorly
explored. Nowadays, three methods for the preparation
of 2-amino-1-benzothiophene are known: (1) five-step
synthesis from thiosalicylic acid [3], (2) from 1-benzo-
thiophen-2-ylmagnesium chloride [4], and (3) reaction
of (2-bromophenyl)acetonitrile with Na2S2O3 in the
presence of palladium catalyst [5]. 2-(Morpholin-4-yl)-
1-benzothiophene was synthesized by addition of mor-
pholine to the C2–C3 bond of 1-benzothiophene with
subsequent aromatization by the action of sulfur [6].
2-(Piperidin-1-yl)-1-benzothiophene was prepared by
heating a mixture of 2-bromo-1-benzothiophene with
piperidine in a sealed ampule [7]. 6-Benzyloxy-N,N-di-
methyl-1-benzothiophen-2-amine was obtained in two
steps by treatment of a mixture of 4-benzyloxybenzal-
dehyde and N,N-dimethylthioformamide with lithium
diisopropylamide, followed by cycloaromatization
with methanesulfonic acid [8].
5-unsubstituted 4-(2-halophenyl)-1,2,3-thiadiazoles
with a base generates very unstable acetylenic thiolate
which react with nucleophiles like HNR2. The subse-
quent 5-exo-trig-cyclization of intermediate enethio-
lates should produce 2-amino-1-benzothiophenes.
We previously showed that 4-(2-chlorophenyl)- and
4-(2-bromophenyl)-1,2,3-thiadiazoles in the presence
of potassium carbonate and excess morpholine in
dimethylformamide lose nitrogen molecule to give
potassium 2-(2-halophenyl)ethynethiolates. Further
reaction with morpholine afforded the corresponding
potassium 2-(2-halophenyl)-1-(morpholin-4-yl)ethene-
thiolates which did not undergo intramolecular cycliza-
tion regardless of the halogen nature. The subsequent
acidification led to the formation of 2-(2-halophenyl)-
thioacetic acid morpholides. However, introduction of
a nitro group into the para position with respect to the
chlorine atom in 4-(2-chlorophenyl)-1,2,3-thiadiazole
resulted in successful synthesis of 2-dialkylamino-1-
benzothiophenes [10].
Herein we describe a new method for the prepara-
tion of 2-amino-1-benzothiophenes from 4-(2-bromo-
phenyl)-1,2,3-thiadiazole (1) [10] and secondary
amines (morpholine and piperidine) in the presence of
potassium carbonate and a catalytic amount of copper
We have recently proposed a new procedure for
the preparation of 2-amino-1-benzothiophenes from
4-(2-halophenyl)-1,2,3-thiadiazoles [9]. Treatment of
Scheme 1.
NR2
H+
HNR2
S– K+
S
HNR2, K2CO3
DMF, Δ
NR2
S– K+
Br
4a
N
–N2
N
Br
CuI
Br
S
Br
NR2
1
2
3a, 3b
S
5a, 5b
R2N = morpholin-4-yl (a), piperidin-1-yl (b).
1040

COPPER(I) IODIDE-CATALYZED SYNTHESIS OF 1-BENZOTHIOPHEN-2-AMINES
1041
Scheme 2.
O
O
K2CO3, CuI
DMF, Δ
N
N
N
O
–N2
S
S
S– K+
Br
Br
4a
3a
5a
(I) iodide. The amount of the latter was 20 mol % with
respect to thiadiazole 1. Decomposition of 4-(2-bromo-
phenyl)-1,2,3-thiadiazole (1) by the action of potas-
sium carbonate and excess secondary amine in di-
methylformamide with liberation of nitrogen gave
potassium 2-(2-bromophenyl)ethynethiolate (2) which
then reacted with secondary amine to produce potas-
sium 2-(2-bromophenyl)-1-aminoethenethiolate 3a or
3b. The subsequent intramolecular cyclization via nu-
cleophilic replacement of the bromine atom by thiolate
sulfur in the presence of copper(I) iodide afforded
2-(morpholin-4-yl)- and 2-(piperidin-1-yl)-1-benzo-
thiophenes 5a and 5b (Scheme 1).
8.0 Hz), 7.64 d (7-H, J = 8.0 Hz). 13C NMR spectrum
(DMSO-d6), δC, ppm: 50.8 (NCH2), 66.0 (CH2O), 99.3
(C3), 121.3 (C4), 121.7 (C7), 122.1 (C6), 125.0 (C5),
132.3 (C9), 140.8 (C8), 157.9 (C2).
b. Likewise, the reaction of 0.1 g (0.333 mmol) of
thiomorpholide 4a with 0.07 g (0.5 mmol) of K2CO3
and 0.014 mg (0.067 mmol) of CuI in 3 mL of DMF
gave 0.052 g (71%) of 5a.
2-(Piperidin-1-yl)-1-benzothiophene (5b). A mix-
ture of 0.2 g (0.828 mmol) of thiadiazole 1, 0.344 g
(2.49 mmol) of K2CO3, 0.21 g (2.49 mmol) of piperi-
dine, and 0.032 g (0.165 mmol) of copper(I) iodide in
3 mL of DMF was stirred for 4 h at 80°C under argon.
The mixture was cooled and poured into 50 mL of
a saturated solution of ammonium chloride. The pre-
cipitate was filtered off, washed with a saturated solu-
tion of ammonium chloride (3×10 mL) and water
(3×10 mL), and dissolved in 30 mL of chloroform. The
solution was washed with brine (2×20 mL) and water
(2×20 mL) and dried over calcined Na2SO4, the sol-
vent was distilled off under reduced pressure, and the
residue was purified by chromatography in a 3×10-cm
column charged with silica gel L (100–160 μm) using
hexane–ethyl acetate (4:1) as eluent. A fraction with
Rf 0.54 (hexane–ethyl acetate, 5:1) was collected.
Yield 0.088 g (49%), fine colorless crystals, mp 98.5–
The intermediate formation of potassium 2-(2-bro-
mophenyl)-1-aminoethenethiolates 3a was proved by
the synthesis of compound 5a from 2-(2-bromophe-
nyl)thioacetic acid morpholide (4a), which was accom-
plished under the same conditions, by heating in di-
methylformamide in the presence of potassium carbon-
ate and copper(I) iodide (Scheme 2).
The structure of 5a and 5b was confirmed by the
1H and 13C NMR and mass spectra, as well as by com-
parison with published data [6, 7].
2-(Morpholin-4-yl)-1-benzothiophene (5a).
a. A mixture of 0.1 g (0.414 mmol) of thiadiazole 1,
0.174 g (0.5 mmol) of potassium carbonate, 0.075 g
(0.828 mmol) of morpholine, and 0.016 g (0.083 mmol)
of copper(I) iodide in 3 mL of dimethylformamide was
stirred for 4 h at 80°C under argon. The mixture was
cooled and poured into water, the precipitate was
filtered off, washed with a saturated solution of ammo-
nium chloride (3×10 mL) and water (3×10 mL), and
dissolved in chloroform. The solution was dried over
calcined Na2SO4, the solvent was distilled under
reduced pressure, and the residue was purified by
chromatography in a 3×10-cm column charged with
silica gel L (100–160 μm) using hexane–ethyl acetate
(4:1) as eluent. A fraction with Rf 0.55 (hexane–ethyl
acetate, 2:1) was collected. Yield 0.075 g (82%), fine
1
100°C [7]. H NMR spectrum (DMSO-d6), δ, ppm:
1.53–1.61 m (2H, NCH2CH2CH2), 1.61–1.71 m (4H,
NCH2CH2), 3.17–3.27 m (4H, NCH2), 6.26 s (3-H),
6.98–7.07 m (6-H), 7.15–7.24 m (5-H), 7.43 d (4-H,
J = 7.0 Hz), 7.65 d (7-H, J = 8.0 Hz). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 23.9 (NCH2CH2CH2), 25.1
(NCH2CH2), 51.7 (NCH2), 98.4 (C3), 120.8 (C4), 121.2
(C7), 122.0 (C6), 124.9 (C5), 132.1 (C9), 141.3 (C8),
158.3 (C2). Mass spectrum, m/z (Irel, %): 218.0997
[M + H]+. C13H16NS. Calculated: M 218.1003.
The melting points were measured on a Boetius
1
melting point apparatus. The H and 13C NMR spectra
were recorded on a Bruker DPX-400 spectrometer at
400.13 and 100.16 MHz, respectively. The high-reso-
lution mass spectrum of 5b (electrospray ionization)
was obtained on a Micromass 70-VSE instrument. The
progress of reactions was monitored by TLC on
1
colorless crystals, mp 179–181°C [6]. H NMR spec-
trum (CDCl3), δ, ppm: 3.27 t (4H, NCH2, J = 5.0 Hz),
3.90 t (4H, CH2O, J = 5.0 Hz), 6.26 s (3-H), 7.09–
7.17 m (6-H), 7.23–7.32 m (5-H), 7.51 d (4-H, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015

PETROV et al.
1042
3. Stacy, G.W., Wollner, T.E., and Villaescusa, F.W.,
Silicagel 60 F254 plates; spots were visualized under
UV light or by treatment with iodine vapor. The
solvents used were purified and dried according to
standard procedures.
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p. 7838.
This study was performed in the framework of
a state contract of the Ministry of Education and
Science of the Russian Federation.
5. Hou, C., He, Q., and Yang, C., Org. Lett., 2014, vol. 16,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015