Synthesis of [1]Benzothieno[2,3- b ]quinolines via Transition-Metal-Free [3+3] Annulation of Nitroarenes and Benzo[ b ]thiophen-3-ylacetonitrile or 3-(Phenylsulfonylmethyl)benzo[ b ]thiophene Carbanions

Article abstract of DOI:10.1055/s-0036-1588426

Benzo[ b ]thiophen-3-ylacetonitriles or 3-(phenylsulfonylmethyl)benzo[ b ]thiophenes react with nitrobenzene derivatives in the presence of potassium tert -butoxide and chlorotrimethylsilane to form, in good yields, 11-cyano- or 11-(phenylsulfonyl)[1]benzothieno[2,3- b ]quinolines, respectively.

Full text of DOI:10.1055/s-0036-1588426

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
M. Nowacki, K. Wojciechowski
Paper
Synthesis
Synthesis of [1]Benzothieno[2,3-b]quinolines via Transition-
Metal-Free [3+3] Annulation of Nitroarenes and Benzo[b]thio-
phen-3-ylacetonitrile or 3-(Phenylsulfonylmethyl)benzo[b]thio-
phene Carbanions
Michał Nowacki
1. t-BuOK, Et3N, THF
2. Me3SiCl
3. NH4Cl (aq)
Z
Z
Y
Krzysztof Wojciechowski*
Y
+
S
S
N
NO2
Institute of Organic Chemistry, Polish Academy of Sci-
ences, ul. Kasprzaka 44/52, 01-224 Warszawa, Poland
krzysztof.wojciechowski@icho.edu.pl
one-pot procedure
transition-metal-free
X
X
22–89%
X = H, Cl
Y = F, Cl, Br, I, SPh
Z = CN, SO2Ph
12 examples
Received: 08.03.2017
Accepted after revision: 22.04.2017
Published online: 30.05.2017
applicable to the synthesis of condensed quinoline deriva-
tives, namely acridines,3 indoloquinolines,4 and other poly-
cyclic azaheteroarenes.5
DOI: 10.1055/s-0036-1588426; Art ID: ss-2017-t0150-op
Here we present an application of our methodology to
the synthesis of [1]benzothieno[2,3-b]quinolines. The
known methods for the synthesis of this heterocyclic sys-
tem are presented in Scheme 2.
Abstract Benzo[b]thiophen-3-ylacetonitriles or 3-(phenylsulfonyl-
methyl)benzo[b]thiophenes react with nitrobenzene derivatives in the
presence of potassium tert-butoxide and chlorotrimethylsilane to form,
in good yields, 11-cyano- or 11-(phenylsulfonyl)[1]benzothieno[2,3-
b]quinolines, respectively.
In the first method, upon treatment of 3-phenylquino-
line with hydrogen sulfide at high temperature, the sulfur
atom was incorporated to form the thiophene ring (Scheme
2, a).6 Both the thiophene and pyridine rings were formed
in a cascade reaction between aryl isothiocyanates and 2-
ethynylaryl radicals generated from the corresponding di-
azonium salts (Scheme 2, b).7 Other methods employed
benzo[b]thiophene derivatives, such as the condensation of
benzo[b]thiophen-2(3H)-one with 2-aminobenzaldehydes
(Scheme 2, c)8 or 2-nitrobenzaldehydes with a subsequent
reduction of the nitro group (Scheme 2, d),9 condensation
of pentafluorobenzaldehyde with 2-aminobenzo[b]thio-
Key words carbanions, nitroarenes, heterocycles, cyclization, quino-
lines, thiophenes
Nucleophilic substitution of hydrogen in nitroarenes
has found numerous applications in the synthesis of het-
erocyclic compounds.1 One of the general approaches uti-
lizes nitrobenzene derivatives formed by replacement of a
hydrogen in the ortho position to the nitro group with car-
bon or nitrogen nucleophiles. These nitrobenzene deriva-
tives are transformed into indole or quinoline derivatives
by various means, mostly by reduction of the nitro group or
by interaction of the introduced substituent with the nitro
group. Less known and widespread, but much more inter-
esting, are reactions in which the σH-adducts formed by ad-
dition of carbanions at the ortho position to the nitro group
of nitroarene are transformed directly into condensed het-
erocycles containing the pyridine ring.2,3 In these processes
the pyridine nitrogen atom of the formed heterocycle origi-
nates from the nitro group of the nitroarene. Such transfor-
mations occur when these σH-adducts are treated with
Lewis acids or silylating agents (Scheme 1). During our
studies on transformations of σH-adducts of carbanions to
nitroarenes, we have developed several efficient methods
R3SiCl
base
NO2
Z
N
Z
NO2
base
X
X
X
H
σH-adduct
Z
H
N
N
=
etc.
Scheme 1 Transformation of σH-adducts into condensed quinolines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
M. Nowacki, K. Wojciechowski
Paper
Synthesis
tert-butoxide was used for the generation of the carbanion.
The starting carbanion precursors nitrile 3a and sulfone 3b
were readily obtained from commercially available ben-
zo[b]thiophene (thionaphthene, 1) in two simple steps
(Scheme 3). Chloromethylation of benzo[b]thiophene (1)
with formaldehyde and HCl provided 3-(chloromethyl)ben-
zo[b]thiophene (2),12 which upon treatment with potassi-
um cyanide furnished the desired nitrile 3a.12 Analogously,
the reaction of 2 with sodium benzenesulfinate provided
the sulfone 3b.
H2S, Al2O3
630 °C
(a)
(b)
(c)
(d)
S
N
N
Ph
Ph
N
–20 °C to r.t.
+
_
+
NCS
O
N2BF4
S
base
H
O
O
+
S
CN
S
H2N
O
N
CO2R
CO2R
KCN
1) piperidine
2) SnCl2
S
Cl
H
3a
CH2O–HCl
+
S
SO2Ph
PhSO2Na
N
NO2
S
S
S
1
2
F
F
O
F
F
F
S
F
F
F
O
145 °C
3b
H
(e)
+
S
Scheme 3 Synthesis of carbanion precursors 3a and 3b
S
N3
N
CN
N
F
1) KOH, MeOH
2) ClCONR2
3) hν
CN
In the elaborated procedure of the synthesis of [1]ben-
zothieno[2,3-b]quinolines, we added a THF solution of po-
tassium tert-butoxide to a mixture of 3-(cyanomethyl)ben-
zo[b]thiophene (3a), 4-chloro-1-nitrobenzene (4b) and tri-
ethylamine in THF at –70 °C and then treated the formed
σH-adduct with chlorotrimethylsilane at this temperature.
After three hours, the reaction mixture was allowed to
reach room temperature and the stirring was continued
overnight. Then the reaction mixture was quenched with
saturated aqueous ammonium chloride and the product
was isolated in 64% yield. Other nitrobenzene derivatives
reacted analogously to give 11-cyanobenzothienoquino-
lines 5aa–af. Similarly, the reactions of sulfone 3b with ni-
trobenzenes 4a–f gave 11-(phenylsulfonyl)[1]benzothie-
no[2,3-b]quinolines 5ba–bf in good yields (Table 1).
A plausible mechanism for the formation of the cya-
no[1]benzothieno[2,3-b]quinolines is shown in Scheme 4.
The first step is addition of the benzothiophen-3-ylacetoni-
trile carbanion to the nitroarene generating σH-adduct A.
Silylation of the σH-adduct A leads to silyl nitronate B.
Deprotonation of the nitronate B followed by elimination of
a siloxide leads to intermediate nitroso compound D. Fur-
ther deprotonation of D, followed by silylation, forms
azaxylylene E that can undergo electrocyclization resulting
in 5a,6-dihydrobenzothienoquinoline F. Similar electrocy-
clizations of aza-ortho-xylylenes leading to condensed het-
erocycles are known processes.13 Elimination of another
molecule of silanol from F provides the final product. Alter-
natively, the intermediate F can be formed by an intramo-
lecular addition of the ambident carbanion G to the nitroso
+
NO2
(f)
S
S
Scheme 2 Known methods for the synthesis of benzothieno[2,3-
b]quinolines
phene generated in situ from the corresponding acyl azide
(Scheme 2, e),10 and reaction of 2-nitrobenzo[b]thiophene
with phenylacetonitrile (Scheme 2, f).11
Our approach to [1]benzothieno[2,3-b]quinolines em-
ploys analogues of the benzyl carbanion, containing the
benzothienyl substituent instead of the benzene ring. Thus,
it can be considered as a method using the reactivity re-
versed (Umpolung) to that in the reaction shown in Scheme
2 (f).
In a preceding paper5 we described reactions of highly
electrophilic 6-nitroquinolines with thienylmethyl carban-
ions, generated from 2- or 3-thienylacetonitriles or ethyl 2-
or 3-thienylacetates, leading to condensed tetracyclic thie-
no[4,7]phenanthrolines. According to the elaborated proto-
col, both reagents were dissolved in acetonitrile and treated
with DBU (a moderately strong base), in the presence of a
silylating agent. The reactions proceeded slowly, giving the
desired products in good yields after 2–7 days. Under these
conditions, benzo[b]thiophen-3-ylacetonitrile (3a) reacted
with the less electrophilic 2,4-dichloronitrobenzene (4e) to
give product 5ae in low yield (22%) after 18 days.5
Now we have found that the reactions of nitrobenzene
derivatives 4 with benzo[b]thiophen-3-ylacetonitrile (3a)
and 3-(phenylsulfonylmethyl)benzo[b]thiophene (3b) pro-
ceed more efficiently when the stronger base potassium
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
M. Nowacki, K. Wojciechowski
Paper
Synthesis
group, followed by silylation and elimination of silanol. The
crucial point of the proposed mechanism seems to be for-
mation of the nitroso intermediate D.
NO2
_
_
O
_
O
S
S
O
R3SiO
+
+
N
N
t-BuO–
R3SiCl
CN
CN
The phenylsulfonyl group in the formed sulfones can be
easily substituted by an alkylamino group. Thus, when we
treated compound 5ba with cyclohexylamine, the corre-
sponding 11-(cyclohexylamino)[1]benzothieno[2,3-b]quin-
oline (6a) was formed in quantitative yield. Similarly, the
reactions of compounds 5bc and 5bd with n-butylamine
and isopropylamine, respectively, gave compounds 6c and
6d, respectively (Scheme 5).
In conclusion, we have developed a simple synthesis of
[1]benzothieno[2,3-b]quinoline derivatives by reaction of
nitroarenes with benzo[b]thiophen-3-ylmethyl carbanions.
The reactions are performed under mild conditions and the
yields are usually high. More importantly, there is no need
to use transition metals at any stage of the elaborated syn-
thesis. This can be a decisive factor if the obtained product
is of potential biomedical or pharmaceutical use. Availabili-
ty of both starting materials, nitroarenes and precursors of
hetero analogues of benzyl carbanions, makes this [3+3] an-
nulation a universal and preparatively useful tool for the
synthesis of condensed polycyclic heteroarenes containing
the pyridine ring.
H
_
H
X
+
CN
B
NR3
X
X
A
Et3N
S
S
R3SiO
O
N
X
– R3SiO–
CN
C
S
S
O
R3SiO
R3SiCl
Et3N
N
X
N
X
CN
CN
D
E
Et3N
S
S
H
O
N
X
_
R3SiO
N
R3SiCl
CN
CN
F
G
X
CN
Table 1 Synthesis of [1]Benzothieno[2,3-b]quinolines 5a
X
Et3N
– R3SiOH
S
Z
N
Z
Y
i–iii
Scheme 4 Plausible mechanism for the formation of [1]benzothie-
no[2,3-b]quinolines from nitroarenes and benzothiophen-3-ylacetoni-
trile
Y
+
S
NO2
S
N
X
X
3a, Z = CN
3b, Z = SO2Ph
4a, X = H, Y = F
4b, X = H, Y = Cl
4c, X = H, Y = Br
4d, X = H, Y = I
4e, X = Y = Cl
5aa–bf
SO2Ph
H
R
N
N
Y
RNH2
Y
4f, X = H, Y = SPh
S
N
S
X
Product 5
X
Y
Z
Yield (%)
X
5ba,5bc, 5bd
6a, X = H, Y = F, R = Cy, 100%
6c, X = H, Y = Br, R = n-Bu, 73%
6d, X = H, Y = I, R = i-Pr, 96%
5aa
5ab
5ac
5ad
5ae
5af
H
H
H
H
Cl
H
H
F
CN
CN
CN
CN
CN
CN
22
64
71
60
46
52
89
69
66
65
25
71
Cl
Br
I
Scheme 5 Transformation of sulfones 5 into amines 6
Cl
SPh
5ba
5bb
5bc
5bd
5be
5bf
F
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
All reactions were performed under argon atmosphere. Melting
points are uncorrected. 1H and 13C NMR spectra were recorded on a
Bruker DRX 500 (500 MHz for 1H and 125 MHz for 13C spectra) or a
Varian VNMRS (500 MHz; compounds 5ae and 5bd) spectrometer.
Chemical shifts δ are expressed in ppm referred to TMS, referencing
via solvent residual peaks. Mass spectra (EI, 70 eV) were obtained on
an AutoSpec Premier (Micromass) spectrometer. ESI mass spectra
were obtained on a SYNAPT G2-S HDMS instrument. IR spectra were
recorded on a JASCO FT/IR-6200 instrument. UV-VIS spectra (λ, nm; ε,
H
H
H
Cl
H
Cl
Br
I
Cl
SPh
a Reaction conditions: (i) t-BuOK, Et3N, THF, –70 °C; (ii) Me3SiCl, –65 °C to
r.t., 24 h; (iii) aq NH4Cl.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
M. Nowacki, K. Wojciechowski
Paper
Synthesis
dm3 mol–1 cm–1) were recorded on a Varian Cary 1E UV-VIS spectrom-
eter. Merck Silicagel 60 F254 plates were used for TLC. Merck Silica gel
60 (230–400 mesh) was used for flash column chromatography.
UV-VIS (MeCN): λmax (ε) = 214 (24182), 238 (43677), 283 (57218), 362
(16626).
2-Bromo[1]benzothieno[2,3-b]quinoline-11-carbonitrile (5ac)
[1]Benzothieno[2,3-b]quinolines 5; General Procedure
A yellow solid was collected by filtration and washed with MeCN; the
product that remained in the filtrate was separated by column chro-
matography (silica gel, toluene–hexane, 1:10, then 2:1) .
Et3N (6 mmol) was added dropwise to a solution of nitrile 3a or sul-
fone 3b (1 mmol) and nitroarene 4 (2 mmol) in anhyd THF (10 mL, in
the case of 4d 20 mL) cooled to –70 °C. Then a 1.5 M solution of t-
BuOK in THF (1.2 equiv) was added dropwise and the temperature
was maintained below –65 °C. After 20 min of stirring of the mixture,
TMSCl (6 mmol) was added dropwise at this temperature. The solu-
tion was stirred for 3 h at –65 to –60 °C, then allowed to reach r.t., and
stirred overnight (18–21 h). The reaction mixture was quenched with
H2O (5 mL) and sat. aq NH4Cl (20 mL). The precipitated product (only
in case of products containing nitrile group) was filtered, washed
with H2O and chilled MeCN, and dried. The remaining mixture was
extracted with EtOAc (5 × 20 mL), and the extract was washed with
brine (50 mL), dried (Na2SO4), and evaporated. The crude product was
purified by column chromatography (silica gel, toluene–hexane). The
products were crystallized from appropriate solvents.
Yield: 240 mg (71%); mp 271–272 °C (MeCN–CH2Cl2).
IR (KBr): 3092, 3058, 3040, 2964, 2226 (CN), 1967, 1930, 1727, 1651,
1603, 1587, 1569, 1538, 1477, 1445, 1420, 1386, 1327, 1305, 1287,
1271, 1253, 1206 cm–1
.
1H NMR (500 MHz, CF3CO2D): δ = 7.86 (t, J = 7.3 Hz, 1 H), 7.91 (t, J = 7.3
Hz, 1 H), 8.05 (d, J = 7.5 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.31 (d, J = 7.0
Hz, 1 H), 8.83 (s, 1 H), 9.08 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CF3CO2D): δ = 114.1, 117.3, 123.3, 126.3, 127.8,
128.2, 128.8, 130.1, 130.6, 130.8, 136.2, 137.4, 137.8, 139.2, 142.0,
163.1.
MS (EI): m/z (%) = 342 (10), 341.31 (31), 340 (100), 339 (31), 338 (97),
260 (10), 259 (33), 258 (31), 233 (10), 232 (12), 231 (6), 216 (5), 215
(30), 209 (11), 189 (9), 188 (16), 170 (12), 169 (12), 130 (16), 129 (5),
116 (11), 115 (7), 103 (5), 102 (6), 81 (6), 69 (12).
2-Fluoro[1]benzothieno[2,3-b]quinoline-11-carbonitrile (5aa)
A yellow solid was collected by filtration and washed with MeCN; the
product that remained in the filtrate was separated by column chro-
matography (silica gel, toluene–hexane, 1:10, then 2:1).
HRMS (EI): m/z calcd for C16H779BrN2S+: 337.9513; found: 337.9519.
UV-VIS (MeCN): λmax (ε) = 213 (21528), 236 (36252), 284 (54232), 363
(15344).
Yield: 61 mg (22%); mp 226–228 °C (MeCN–CH2Cl2).
IR (KBr): 3435, 3061, 2222 (CN), 1624, 1595, 1554, 1494, 1454, 1434,
2-Iodo[1]benzothieno[2,3-b]quinoline-11-carbonitrile (5ad)
1391, 1374, 1326, 1258, 1209 cm–1
.
A yellow solid was collected by filtration and washed with MeCN; the
product that remained in the filtrate was separated by column chro-
matography (silica gel, toluene–hexane, 1:10, then 2:1).
1H NMR (500 MHz, CF3CO2D): δ = 7.84 (t, J = 7.8 Hz, 1 H), 7.90 (t, J = 7.5
Hz, 1 H), 7.99 (td, 8.5, 2.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 8.28 (dd, J =
7.5, 2.0 Hz, 1 H), 8.40 (dd, J = 9.3, 4.3, Hz, 1 H), 9.07 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CF3CO2D): δ = 112.8 (d, JCF = 25 Hz), 114.1, 118.0,
125.0 (d, JCF = 9 Hz), 126.3, 127.8, 128.7 (d, JCF = 28 Hz), 128.9, 130.0,
130.8, 136.1, 136.2, 137.5, 139.3, 162.5, 165.7 (d, JCF = 259 Hz).
Yield: 232 mg (60%); mp 287–288 °C (MeCN–CH2Cl2).
IR (KBr): 3085, 3060, 3032, 2954, 2223 (CN), 1960, 1928, 1834, 1790,
1730, 1691, 1648, 1589, 1566, 1541, 1474, 1443, 1415, 1382, 1324,
1305, 1285, 1253, 1204 cm–1
.
MS (EI): m/z (%) = 280 (13), 279 (30), 278 (100), 277 (10), 251 (7), 233
(9), 209 (12), 206 (6), 139 (16), 125 (6).
HRMS (EI): m/z calcd for C16H7FN2S+: 278.0314; found: 278.0305.
1H NMR (500 MHz, CF3CO2D): δ = 7.85 (t, J = 7.3 Hz, 1 H), 7.90 (t, J = 7.3
Hz, 1 H), 7.99–8.13 (m, 2 H), 8.47 (d, J = 7.5 Hz, 1 H), 8.99–9.13 (m, 2
H).
13C NMR (125 MHz, CF3CO2D): δ = 99.0, 114.1, 117.0, 122.6, 126.2,
127.7, 128.2, 130.1, 130.8, 136.1, 137.0, 137.3, 138.1, 139.1, 147.5,
162.9.
UV-VIS (MeCN): λmax (ε) = 210 (27767), 236 (48634), 279 (46812), 357
(18523), 402 (4756).
2-Chloro[1]benzothieno[2,3-b]quinoline-11-carbonitrile (5ab)
MS (EI): m/z (%) = 388 (13), 387 (30), 386 (100), 260 (15), 259 (38),
258 (23), 233 (8), 232 (9), 215 (23), 193 (14), 189 (7), 188 (12), 129
(17), 116 (8), 73 (6), 71 (8), 69 (9).
HRMS (EI): m/z calcd for C16H7IN2S+: 385.9375; found: 385.9369.
A yellow solid was collected by filtration and washed with MeCN; the
product that remained in the filtrate was separated by column chro-
matography (silica gel, toluene–hexane, 1:10, then 2:1).
Yield: 188 mg (64%); mp 253–254 °C (MeCN–CH2Cl2).
UV-VIS (MeCN): λmax (ε) = 211 (9115), 235 (17805), 286 (29502), 365
IR (KBr): 3074, 3059, 3043, 2972, 2226 (CN), 1970, 1929, 1724, 1605,
1589, 1573, 1545, 1479, 1446, 1421, 1388, 1326, 1305, 1288, 1271,
(7315).
1252, 1206 cm–1
.
2,4-Dichloro[1]benzothieno[2,3-b]quinoline-11-carbonitrile (5ae)
1H NMR (500 MHz, CF3CO2D): δ = 7.83 (t, J = 7.8 Hz, 1 H), 7.89 (t, J = 7.5
Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 8.15 (dd, J = 9.0, 1.0 Hz, 1 H), 8.28 (d,
J = 9.0 Hz, 1 H), 8.61 (d, J = 1.0 Hz, 1 H), 9.05 (d, J = 8.0 Hz, 1 H).
A yellow solid was collected by filtration and washed with MeCN; the
product that remained in the filtrate was separated by column chro-
matography (silica gel, toluene–hexane, 1:10, then 2:1).
13C NMR (125 MHz, CF3CO2D): δ = 114.1, 117.5, 123.5, 126.3, 127.3,
127.8, 128.0, 130.1, 130.9, 136.2, 137.4, 137.5, 139.2, 139.3, 141.4,
163.0.
Yield: 150 mg (46%); mp 280–282 °C.
IR (KBr): 3057, 2994, 2962, 2223 (CN), 1723, 1647, 1587, 1539, 1463,
1443, 1421, 1380, 1355, 1325, 1301, 1250, 1207 cm–1
.
MS (EI): m/z (%) = 297 (11), 296 (55), 295 (31), 294 (100), 259 (12),
258 (13), 232 (5), 215 (10), 188 (7), 147 (11).
HRMS (EI): m/z calcd for C16H735ClN2S+: 294.0018; found: 294.0014.
1H NMR (500 MHz, CF3CO2D): δ = 7.85 (t, J = 7.5 Hz, 1 H), 7.92 (t, J = 7.3
Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 8.23 (s, 1 H), 8.57 (s, 1 H), 9.07 (d, J =
7.9 Hz, 1 H).
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M. Nowacki, K. Wojciechowski
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Synthesis
13C NMR (125 MHz, CF3CO2D): δ = 113.7, 117.5, 126.1, 126.2, 127.8,
128.2, 128.4, 129.4, 130.8, 134.3, 136.5, 138.0, 138.4, 139.4, 140.4,
164.8.
1H NMR (500 MHz, DMSO-d6; 25 °C): δ = 7.45 (td, J = 7.8, 0.5 Hz, 1 H),
7.60 (t, J = 7.8 Hz, 2 H), 7.66 (t, J = 7.8 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H),
7.92–7.97 (m, 3 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.24 (d, J = 9.0 Hz, 1 H),
8.71 (d, J = 8.5 Hz, 1 H), 8.84 (d, J = 2.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6; 70 °C): 115.5, 119.5, 121.9, 123.0,
124.0, 124.1, 124.5, 125.2, 125.3, 127.1, 127.9, 128.5, 130.9, 131.4,
134.8, 138.0, 148.2, 153.1, 171.1.
HRMS (ESI): m/z calcd for C16H6Cl2N2S+: 327.9629; found: 327.9623.
UV-VIS (MeCN): λmax (ε) = 201 (15043), 214 (14835), 237 (24674), 286
(34506), 365 (9489), 409 (3136).
MS (EI): m/z (%) = 412 (8), 411 (34), 410 (19), 409 (67), 347 (6), 346
(12), 345 (16), 344 (26), 312 (10), 311 (36), 310 (100), 309 (23), 286
(9), 285 (14), 284 (21), 270 (12), 269 (15), 268 (29), 267 (6), 258 (7),
256 (19), 234 (12), 233 (62), 232 (7), 226 (6), 224 (20), 206 (5), 189
(10), 188 (15), 155 (8), 77 (12).
2-(Phenylthio)[1]benzothieno[2,3-b]quinoline-11-carbonitrile
(5af)
A yellow solid was collected by filtration and washed with MeCN; the
product that remained in the filtrate was separated by column chro-
matography (silica gel, toluene–hexane, 1:10, then 2:1).
+
HRMS (EI): m/z calcd for
C
21H1235ClNO2S2
:
409.0003; found:
Yield: 190 mg (52%); mp 278–280 °C (MeCN–CH2Cl2).
408.9998.
IR (KBr): 3057, 2224 (CN), 1791, 1587, 1564, 1544, 1474, 1443, 1390,
UV-VIS (MeCN): λmax (ε) = 191 (18735), 215 (10327), 281 (11311), 318
(3274), 409 (3744).
1325, 1307, 1269, 1254, 1204 cm–1
.
1H NMR (500 MHz, CF3CO2D): δ = 7.49–7.56 (m, 3 H), 7.62 (d, J = 7.0
Hz, 2 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.85 (t, J = 7.3 Hz, 1 H), 7.94 (dd, J =
9.0, 0.5 Hz, 1 H ), 7.96–8.01 (m, 2 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.96 (d,
J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CF3CO2D): δ = 114.0, 116.3, 121.8, 121.9, 126.1,
127.4, 128.1, 130.3, 130.6, 130.6, 132.7, 133.0, 135.7, 136.7, 137.3,
137.4, 137.5, 139.2, 151.0, 159.9.
2-Bromo-11-(phenylsulfonyl)[1]benzothieno[2,3-b]quinoline
(5bc)
Column chromatography (silica gel, toluene–hexane, 1:1).
Yellow solid; yield: 285 mg (66%); mp >250 °C (EtOAc).
IR (KBr): 3218, 3164, 3030, 2954, 2880, 2831, 2585, 1895, 1665, 1625,
1601, 1571, 1501, 1470, 1438, 1345, 1321, 1293, 1273, 1231 cm–1
.
MS (EI): m/z (%) = 370 (14), 369 (33), 368 (100), 367 (34), 366 (7), 336
(7), 335 (6), 247 (14), 184 (8).
HRMS (EI): m/z calcd for C22H12N2S2+: 368.0442; found: 368.0432.
1H NMR (500 MHz, DMSO-d6): δ = 7.47 (td, J = 7.8, 0.9 Hz, 1 H), 7.59 (t,
J = 7.9 Hz, 2 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.95 (d,
J = 7.5 Hz, 2 H), 8.05 (dd, J = 9.0, 2.0 Hz, 2 H), 8.14 (d, J = 8.0 Hz, 1 H),
8.18 (d, J = 9.0 Hz, 1 H), 8.72 (d, J = 8.3 Hz, 1 H), 9.00 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 120.8, 122.5, 123.3, 124.9, 125.4,
127.0, 128.0, 129.4, 130.0, 130.4, 130.5, 131.1, 133.4, 134.3, 136.2,
139.4, 141.5, 145.4, 163.5.
UV-VIS (MeCN): λmax (ε) = 212 (30295), 239 (39877), 294 (62746), 371
(13569), 433 (7310).
2-Fluoro-11-(phenylsulfonyl)[1]benzothieno[2,3-b]quinoline
(5ba)
HRMS (ESI): m/z calcd for C21H1379BrNNaO2S2+: 453.9571; found:
453.9558.
Column chromatography (silica gel, toluene–hexane, 1:1).
Yellow solid; yield: 350 mg (89%); mp 216–217 °C (EtOAc).
IR (KBr): 3061, 1917, 1816, 1735, 1679, 1622, 1583, 1552, 1487, 1443,
UV-VIS (MeCN): λmax (ε) = 192 (30960), 215 (13574), 282 (10021).
1378, 1356, 1324, 1254 cm–1
.
2-Iodo-11-(phenylsulfonyl)[1]benzothieno[2,3-b]quinoline (5bd)
Column chromatography (silica gel, toluene–hexane, 1:1).
Yellow solid; yield: 325 mg (65%); mp >250 °C (EtOAc).
1H NMR (500 MHz, DMSO-d6; 60 °C): δ = 7.45 (td, J = 7.8, 1.0 Hz, 1 H),
7.58 (t, J = 7.8 Hz, 2 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.69 (t, J = 7.3 Hz, 1 H),
7.85 (td, J = 8.5, 2.5 Hz, 1 H), 7.93 (dd, J = 8.0, 1.0 Hz, 2 H), 8.09 (d, J =
8.0 Hz, 1 H), 8.30 (dd, J = 5.8, 6.0 Hz, 1 H), 8.58 (dd, J = 12.3, 2.5 Hz, 1
H), 8.80 (d, J = 8.5 Hz, 1 H).
IR (KBr): 3160, 3055, 3027, 2952, 2896, 1620, 1568, 1500, 1469, 1440,
1401, 1366, 1313, 1300, 1228 cm–1
.
13C NMR (125 MHz, DMSO-d6; 60 °C): δ = 108.7 (d, JCF = 27.5 Hz),
120.5 (d, JCF = 26.7 Hz), 122.2 (d, JCF = 11 Hz), 122.9, 124.5, 125.2, 127.6
129.2, 129.6, 130.1, 130.9, 131.1 (d, JCF = 10), 133.9, 136.6 (d, JCF = 6
Hz), 139.2, 141.3, 144.1, 159.6 (d, JCF = 245 Hz), 162.1 (d, JCF = 2.5 Hz).
+
1H NMR (500 MHz, DMSO-d6): δ = 7.43 (td, J = 7.8, 1.1 Hz, 1 H), 7.47 (t,
J = 7.8 Hz, 2 H), 7.57 (td, J = 7.6, 1.2 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 1 H),
7.81–7.82 (m, 1 H), 7.83 (dd, J = 8.5, 0.7 Hz, 1 H), 7.86 (d, J = 8.7 Hz, 1
H), 8.18 (dd, J = 9.0, 1.8 Hz, 1 H), 8.98 (d, J = 8.3 Hz, 1 H), 9.21 (d, J = 1.6
Hz, 1 H).
HRMS (ESI): m/z calcd for
C21H12FNNaO2S2 : 416.0191; found:
416.0182.
13C NMR (125 MHz, DMSO-d6): δ = 93.3, 122.7, 122.9, 124.9, 126.1,
128.3, 129.4, 129.8, 130.1, 130.2, 132.0, 133.8, 134.2, 137.1, 138.7,
140.1, 142.4, 145.9, 164.1.
UV-VIS (MeCN): λmax (ε) = 192 (45118), 237 (34725), 280 (35940), 361
(13680), 409 (3744).
+
HRMS (ESI): m/z calcd for
C
21H13INaNO2S2
:
523.9252; found:
523.9241.
2-Chloro-11-(phenylsulfonyl)[1]benzothieno[2,3-b]quinoline
(5bb)
UV-VIS (MeCN): λmax (ε) = 191 (46756), 236 (24703), 288 (37922), 369
(9398).
Column chromatography (silica gel, toluene–hexane, 1:1).
Yellow solid; yield: 282 mg (69%); mp >250 °C (EtOAc).
2,4-Dichloro-11-(phenylsulfonyl)[1]benzothieno[2,3-b]quinoline
(5be)
IR (KBr): 3221, 3168, 3083, 3033, 2960, 2904, 2880, 2592, 1898, 1629,
1569, 1500, 1473, 1439, 1348, 1322, 1293, 1238 cm–1
.
Column chromatography (silica gel, toluene–hexane, 1:1).
Yellow solid; yield: 110 mg (25%); mp 236–238 °C (EtOAc).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
M. Nowacki, K. Wojciechowski
Paper
Synthesis
IR (KBr): 3089, 3062, 1879, 1732, 1585, 1531, 1475, 1455, 1443, 1412,
1365, 1312, 1243 cm–1
1H NMR (500 MHz, DMSO-d6; 60 °C): δ = 7.47 (td, J = 7.8, 1.0 Hz, 1 H),
7.58 (t, J = 8.0 Hz, 2 H), 7.65–7.72 (m, 2 H), 7.92 (dd, J = 8.0, 1.0 Hz, 2
H), 8.13 (t, J = 7.5 Hz, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 8.77 (d, J = 8.5 Hz, 1
H), 8.81 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6; 60 °C): δ = 122.9, 123.1, 124.7, 125.3,
128.7, 128.9, 129.6, 130.0, 130.6, 130.9, 131.1, 132.9, 134.0, 136.9,
139.4, 141.3, 141.4, 160.2, 164.0.
MS (EI): m/z (%) = 352 (12), 351 (34), 350 (94), 349 (12), 308 (14), 307
(43), 294 (11), 293 (12). 292 (8), 281 (6), 279 (12), 269 (31), 268 (100),
267 (20), 266 (14), 253 (7), 252 (6), 251 (7), 241 (5), 240 (11), 208
(12), 146 (6), 122 (5), 121 (8), 83 (10).
.
HRMS (EI): m/z calcd for C21H19FN2S+: 350.1253; found: 350.1259.
UV-VIS (MeCN): λmax (ε) = 201 (20000), 245 (31452), 278 (39811), 337
(9099), 363 (4870), 380 (5838).
2-Bromo-11-(butylylamino)[1]benzothieno[2,3-b]quinoline (6c)
HRMS (ESI): m/z calcd for C21H1335Cl2NNaO2S2+: 465.9506; found:
465.9495.
Column chromatography (silica gel, toluene–hexane, 1:1, then tolu-
ene).
UV-VIS (MeCN): λmax (ε) = 191 (58501), 236 (37299), 289 (55431), 368
(14031), 417 (4547).
Colorless solid; yield: 320 mg (73%); mp 145.5–147 °C (triturated
with pentane).
IR (KBr): 3453, 3051, 3021, 2955, 2923, 2867, 1931, 1886, 1753, 1671,
1605, 1571, 1546, 1492, 1452, 1424, 1401, 1372, 1338, 1316, 1270,
11-(Phenylsulfonyl)-2-(phenylthio)[1]benzothieno[2,3-b]quino-
line (5bf)
1248 cm–1
.
Column chromatography (silica gel, toluene–hexane, 1:1).
Yellow solid; yield: 345 mg (71%); mp 184–186 °C (EtOAc).
IR (KBr): 3047, 1971, 1903, 1731, 1602, 1582, 1472, 1442, 1401, 1346,
1H NMR (500 MHz, CDCl3): δ = 0.92 (t, J = 7.5 Hz, 3 H), 1.43 (sext, J =
7.4 Hz, 2 H), 1.73 (quin, J = 7.5 Hz, 2 H), 3.51 (q, J = 6.7 Hz, 2 H), 4.72 (s,
1 H), 7.44–7.52 (m, 2 H), 7.74 (dd, J = 9.0, 2.0 Hz, 1 H), 7.83 (dd, J = 7.8,
1.5 Hz, 1 H), 7.91 (d, J = 9.0 Hz, 1 H), 8.16 (dd, J = 7.5, 1 Hz, 1 H), 8.27
(d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.8, 20.1, 33.7, 49. 7, 116.7, 117.5,
121.2, 123.0, 124.1, 124.7, 124.9, 126.8, 130.3, 132.6, 132.7, 137.3,
146.8, 149.2, 164.8.
1321, 1305 cm–1
.
1H NMR (500 MHz, DMSO-d6; 60 °C): δ = 7.41–7.48 (m, 6 H), 7.52 (t,
J = 7.8 Hz, 2 H), 7.62–7.72 (m, 5 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.12 (d, J =
8.5 Hz, 1 H), 8.48 (d, J = 1.5 Hz, 1 H), 8.81 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6; 60 °C): δ = 121.6, 122.8, 122.9, 124.4,
125.1, 127.4, 128.6, 128.9, 129.4, 129.5, 129.6, 129.9, 130.4, 130.9,
131.3, 132.8, 133.6, 136.3, 136.5, 139.0, 141.6, 145.5, 162.2.
+
HRMS (ESI): m/z calcd for C19H1879BrN2S+: 385.0374; found: 385.0365.
UV-VIS (MeCN): λmax (ε) = 248 (32797), 289 (64662), 343 (7024), 380
(5140).
HRMS (ESI): m/z calcd for
C27H17NNaO2S3 : 506.0319; found:
506.0309.
2-Iodo-11-(isopropylamino)[1]benzothieno[2,3-b]quinoline (6d)
UV-VIS (MeCN): λmax (ε) = 191 (65386), 241 (30680), 296 (44539), 376
(10300), 363 (15344), 437 (5259).
Column chromatography (silica gel, toluene).
Colorless solid; yield: 400 mg (96%); mp 187–188 °C (triturated with
pentane).
Substitution of the Phenylsulfonyl Group by Amines; General Pro-
cedure
IR (KBr): 3364, 3298, 3048, 2953, 1934, 1892, 1780, 1677, 1634, 1575,
11-(Phenylsulfonyl)[1]benzothieno[2,3-b]quinoline 5ba, 5bc, or 5bd
(0.30 mmol) and the appropriate primary amine (2 mmol) in THF (5
mL) were stirred at r.t. until the starting material disappeared (8–24
h, TLC control). After evaporation of the solvents, the product was
subjected to column chromatography (silica gel, toluene or mixture of
solvents).
1543, 1496, 1478, 1442, 1392, 1317, 1242 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.28 (d, J = 6.5 Hz, 6 H), 3.99 (sept, J =
6.5 Hz, 1 H), 4.37 (d, J = 11.0 Hz, 1 H), 7.44–7.53 (m, 2 H), 7.78 (d, J =
9.0 Hz, 1 H), 7.83 (dd, J = 7.8, 1.5 Hz, 1 H), 7.91 (dd, J = 8.5, 1.5 Hz, 1 H),
8.23 (dd, J = 7.8, 1.5 Hz, 1 H), 8.46 (d, J = 1.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.3, 50.7, 89.2, 118.3, 123.2, 123.4,
124.8, 125.0, 127.2, 130.6, 131.3, 133.1, 137.6, 138.3, 147.1, 148.2,
165.3.
11-(Cyclohexylamino)-2-fluoro[1]benzothieno[2,3-b]quinoline
(6a)
MS (EI): m/z (%) = 420 (10), 419 (33), 418 (100), 417 (7), 403 (14), 377
(8), 376 (44), 375 (8), 276 (37), 275 (18), 262 (9), 261 (44), 250 (8),
249 (27), 248 (33), 257 (9), 234 (7), 233 (9), 223 (7), 222 (37), 221 (9),
220 (10), 190 (5), 188 (5), 177 (9), 92 (6), 91 (9).
Column chromatography (silica gel, toluene).
Colorless solid; yield: 350 mg (100%); mp 180–181 °C (triturated with
pentane).
HRMS (EI): m/z calcd for C18H15IN2S+: 418.000; found: 418.000.
IR (KBr): 3351, 3299, 3061, 2924, 2846, 1901, 1624, 1583, 1559, 1501,
1462, 1442, 1424, 1424, 1399, 1373, 1346, 1324, 1265, 1249, 1207
UV-VIS (MeCN): λmax (ε) = 232 (26998), 250 (32081), 291 (66113), 331
(6483), 344 (7280), 363 (4647), 382 (4502).
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.17–1.29 (m, 3 H), 1.29–1.40 (m, 2 H),
1.57–1.65 (m, 1 H), 1.70–1.80 (m, 2 H), 2.01 (d, J = 12.5 Hz, 2 H), 3.56
(d, J = 10.5 Hz, 1 H), 4.40 (d, J = 10.0 Hz, 1 H), 7.45–7.53 (m, 3 H), 7.73
(dd, J = 10.5, 2.5 Hz, 1 H), 7.83 (dd, J = 7.8, 1.5 Hz, 1 H), 8.06 (dd, J = 9.0,
5.5 Hz, 1 H), 8.25 (dd, J = 7.8, 1.5 Hz, 1 H).
Funding Information
This work was financially supported by National Scientific Center
13C NMR (125 MHz, CDCl3): δ = 25.3, 25.6, 35.0, 57.5, 105.8 (d, JCF
=
grant No 2012/07/B/ST5/00813.
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22.5 Hz), 118.2, 119.5 (d, JCF = 25 Hz), 121.8 (d, JCF = 9 Hz), 122.9,
124.5, 124.7, 126.9, 131.0 (d, JCF = 10 Hz), 132.9, 137.5, 145.1, 148.4 (d,
JCF = 5 Hz), 159.4 (d, JCF = 244 Hz), 163.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
M. Nowacki, K. Wojciechowski
Paper
Synthesis
Supporting Information
(4) Nowacki, M.; Wojciechowski, K. RSC Adv. 2015, 5, 94296.
(5) Nowacki, M.; Wojciechowski, K. ChemistrySelect 2016, 1, 4886.
(6) Klemm, L. H.; McCoy, D. R.; Klopfenstein, C. E. J. Heterocycl.
Chem. 1971, 8, 383.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588426.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(7) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Zanardi, G. J. Org. Chem. 2000, 65, 8669.
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E. J. Heterocycl. Chem. 1981, 18, 1405.
(10) Iaroshenko, V. O.; Wang, Y.; Zhang, B.; Volochnyuk, D.;
Sosnovskikh, V. Y. Synthesis 2009, 2393.
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2015, 80, 7530.
(12) Efange, S. M. N.; Mash, D. C.; Khare, A. B.; Ouyang, Q. J. Med.
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V. H. M.; Bos, H. J. T. J. Chem. Soc., Chem. Commun. 1985, 882.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G