One-pot approach to construct benzo[4,5]thieno[3,2-b]indoles, pyrido[3′,2’:4,5]thieno[3,2-b]indoles and pyrazino[2′,3’:4,5]thieno[3,2-b]indoles based on the Fischer indole synthesis

Article abstract of DOI:10.1016/j.tet.2020.131723

During this study, series of benzo[4,5]thieno[3,2-b]indoles, pyrido[3′,2’:4,5]thieno[3,2-b]indoles and pyrazino[2′,3’:4,5]thieno[3,2-b]indoles were efficiently synthesized from benzo- and pyrido- or pyrazino-fused 3-aminothiophene-2-carboxylates, respectively, using one-pot two-step strategy based on the Fischer indolization reaction. The essence of this synthetic approach is acid-promoted reaction of the 3-aminothiophene intermediates, in situ generated from the corresponding ring-fused 3-aminothiophene-2-carboxylates, with arylhydrazines to give arylhydrazones of thiophen-3(2H)-ones, followed by their indolization to afford thieno[3,2-b]indole-cored molecules.

Full text of DOI:10.1016/j.tet.2020.131723

Journal Pre-proof
One-pot approach to construct benzo[4,5]thieno[3,2-b]indoles,
pyrido[3',2':4,5]thieno[3,2-b]indoles and pyrazino[2',3':4,5]thieno[3,2-b]indoles based
on the Fischer indole synthesis
Roman A. Irgashev, Alexander S. Steparuk, Gennady L. Rusinov
PII:
S0040-4020(20)30943-1
https://doi.org/10.1016/j.tet.2020.131723
TET 131723
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 August 2020
Revised Date: 21 October 2020
Accepted Date: 23 October 2020
Please cite this article as: Irgashev RA, Steparuk AS, Rusinov GL, One-pot approach
to construct benzo[4,5]thieno[3,2-b]indoles, pyrido[3',2':4,5]thieno[3,2-b]indoles and
pyrazino[2',3':4,5]thieno[3,2-b]indoles based on the Fischer indole synthesis, Tetrahedron, https://
doi.org/10.1016/j.tet.2020.131723.
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Graphical abstract
One-pot approach to construct benzo[4,5]thieno[3,2-b]indoles,
pyrido[3',2':4,5]thieno[3,2-b]indoles
and
pyrazino[2',3':4,5]thieno[3,2-b]indoles based on the Fischer
indole synthesis
Roman A. Irgashev*, Alexander S. Steparuk, Gennady L. Rusinov
Postovsky Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, S. Kovalevskoy Str., 22,
Ekaterinburg, 620990, Russia
Corresponding author. Fax: +7 343 369 30 58;
e-mail: irgashev@ios.uran.ru

One-pot approach to construct benzo[4,5]thieno[3,2-b]indoles,
pyrido[3',2':4,5]thieno[3,2-b]indoles and pyrazino[2',3':4,5]thieno[3,2-
b]indoles based on the Fischer indole synthesis
Roman A. Irgashev,a,b,* Alexander S. Steparuk,a Gennady L. Rusinova,b
a
Postovsky Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, S.
Kovalevskoy Str., 22, Ekaterinburg, 620990, Russia
*Corresponding author, e-mail: irgashev@ios.uran.ru
b Ural Federal University named after the First President of Russia B. N. Yeltsin, Mira Str., 19,
Ekaterinburg, 620002, Russia
Keywords: Benzo[4,5]thieno[3,2-b]indole; Aza-analogue; 3-Aminothiophene; the Fischer indole
synthesis
_____________________________________________________________________________
ABSTRACT
During this study, series of benzo[4,5]thieno[3,2-b]indoles, pyrido[3',2':4,5]thieno[3,2-b]indoles
and pyrazino[2',3':4,5]thieno[3,2-b]indoles were efficiently synthesized from benzo- and pyrido-
or pyrazino-fused 3-aminothiophene-2-carboxylates, respectively, using one-pot two-step
strategy based on the Fischer indolization reaction. The essence of this synthetic approach is
acid-promoted reaction of the 3-aminothiophene intermediates, in situ generated from the
corresponding ring-fused 3-aminothiophene-2-carboxylates, with arylhydrazines to give
arylhydrazones of thiophen-3(2H)-ones, followed by their indolization to afford thieno[3,2-
b]indole-cored molecules.
_____________________________________________________________________________
1

1. Introduction
Benzo[4,5]thieno[3,2-b]indole (BTI), also referred in the literature as [1]benzothieno[3,2-
b]indole and thianaphtheno[3,2-b]indole, has been earlier used for the engineering of substances
which are important both for materials science and medicinal chemistry. BTI framework has
been utilized as electron-rich π-conjugated system in the design of organic semiconductors, such
as 2,2-dicyanovinyl dyes which are shown solvatochromic properties [1], bipolar host materials
[2], e.g. compound mBTITrz (Figure 1), and thermally activated delayed fluorescence emitters
[3] for organic light-emitting diodes. In regard to application of BTI in medicinal chemistry,
some of its derivatives have exhibited potential antihistaminic activity [4] and selective estrogen
receptor modulator properties [5], e.g. compound BTI-1 (Figure 1).
Figure 1. Benzo[4,5]thieno[3,2-b]indole-based functional compounds
Therefore, it is not surprising, that significant efforts of researchers have been focused on the
elaboration of methods for the synthesis of BTI derivatives. Thus, the construction of BTI
scaffolds has been successfully performed using different transition-metal-based strategies,
including Pd- or Cu-catalyzed cyclization of aryl- or arylthio-linked indoles [6,7] as well as aryl-
or arylamino-linked benzo[b]thiophenes [8–15], and Cu-catalyzed cascade double cyclization of
N-protected 2-[(2-bromophenyl)ethynyl]anilines [16] or 2-[(2-halogenbenzyl)thio]benzonitriles
[17]. Moreover, BTI derivatives have also been prepared in accordance with transition-metal-
free methods, such as cyclization of 2-arylbenzo[b]thiophenes 1-3 under the Cadogan reaction
conditions for 1 (X = NO2) [1–3,18–21], thermal [18] or photochemical [22] conditions for 2 (X
= N3), electrochemical conditions for 3 (X = NHSO2Ph) [23], oxidative cyclization of 2-(2-
mercaptophenyl)indoles 4 with elemental iodine [24], three-component reaction of 3-
nitrobenzo[b]thiophenes 5 with amines and cyclohexanones in the presence of 4 Å molecular
sieves, followed by oxidation of the formed intermediates with chloranil [25], and reaction of
benzo[b]thiophen-3(2H)-ones (thioindoxyls) 6 with arylhydrazines according to the Fischer
2

indole synthesis strategy [4,5,26–28] (Scheme 1). It should be noted, that the Fischer indole
synthesis is very convenient method for the construction of thieno[3,2-b]indole-cored molecules,
since, in general, the desired compounds can be directly formed by treatment of thiophen-3(2H)-
one substrates with arylhydrazines in the glacial acetic acid solution without isolation of the
intermediate arylhydrazones. Thus, we have previously described approaches towards 2-
(hetero)arylthieno[3,2-b]indoles[29], and thieno[3,2-b]indole-cored heteroacenes [30–32] based
on the Fischer indole synthesis. At the same time, thioindoxyls 6 have tendency to gradually
oxidize with air oxygen, forming thioindigo derivatives[33,34], and their application as
substrates for the synthesis of BTI derivatives can be limited taking into account this fact.
H
N
Ar
4
SH
1. RNH2,
I2
reaction conditions:
P(OEt)3 for
O
R
1
,
NO2
X
N
2
MS (4 Å)
2. chloranil
h or for
Ar
anodic [O] for 3
Ar
Ar
Ar
Ar
S
S
S
5
1, X = NO2
2, X = N3
R = H, Alk, SO2Ph
3, X = PhSO2NH
ArNHNH2, H+
O
the Fischer indole
synthesis
Ar
S
6
Scheme 1. Transition-metal-free protocols for the preparation of BTI derivatives
Recently, we have also described the Fischer indolization based approach for the preparation of
2-substituted thieno[3,2-b]indoles by reaction of 5-substituted 3-aminothiophenes, acted as
synthetic equivalents of thiophen-3(2H)-ones, with arylhydrazines in glacial acetic acid [35]. In
turn, 3-aminothiophene substrates were in situ generated from methyl 3-aminothiophene-2-
carboxylates. In continuation of our research, we wish to report synthetic protocol for the
preparation of BTI derivatives as well as BTI aza-analogues, namely pyrido[3',2':4,5]thieno[3,2-
b]indole (PyrTI) and pyrazino[2',3':4,5]thieno[3,2-b]indole (PrzTI), illustrated in Figure 2,
starting from benzo-, pyrido- or pyrazino-fused 3-aminothiophene-2-carboxylates, respectively,
and arylhydrazines.
3

Figure 2. Structures of BTI aza-analogues
2. Results and discussion
To evaluate application of our synthetic strategy for the construction of BTI molecules, we
selected methyl 3-aminobenzo[b]thiophene-2-carboxylate 7 as the key precursor. Substrate 7 was
readily formed by reaction of 2-nitrobenzonitrile with methyl thioglycolate in the presence of
KOH in accordance with the literature procedure [36]. Furthermore, alkyl 3-
aminobenzo[b]thiophene-2-carboxylates can also be obtained by condensation of 2-fluoro- [37]
or 2-chloro- [38] benzonitriles with alkyl thioglycolates in the presence of bases. Ester 7 was
saponified with NaOH (4 equiv) in a solution of isopropanol – water (9:1, v/v) at reflux (100 °C)
for 2 h, after that the reaction mixture was concentrated under reduced pressure to give crude
sodium salt of amino acid. This salt was dissolved in glacial acetic acid with addition of formic
acid (4 equiv) to speed up the salt dissolution, and treated with phenylhydrazine hidrochloride 8a
(1.2 equiv) at reflux (130 °C) for 2 h, thus affording compound 9a in 92% yield (Scheme 2). To
note, similar yield of product 9a was obtained using phenylhydrazine free base instead of its
hydrochloric salt. In the same manner, the use of arylhydrazines hydrochlorides 8b-j (see
Experimental) afforded products 9b-i in 29-92% yields (Scheme 2). In the case of 3,5-
difluorophenylhydrazine 8j, we failed to prepare the desired BTI derivative, since complex
mixture of compounds were obtained in this experiment.
1. NaOH (4 equiv) / IPA - H2O,
H
NH2
CO2Me
100 °C, 2 h
N
2. ArNHNH3 Cl 8a-i (1.2 equiv),
Ar
HCO H (4 equiv) / AcOH, 130 °C, 2 h
2
S
S
7
9a-i
H
H
H
N
N
N
t-Bu
F
S
S
S
9a, 92%
9b, 40%
9c, 80%
H
H
N
H
N
N
Me
OMe
CF3
S
S
S
S
9d, 69%
H
N
9e, 54%
9f, 47%
H
N
S
H
N
CN
CO2H
S
9g, 29%
9h, 51%
9i, 57%
Scheme 2. Synthesis of BTI compounds 9, scope and yields of products
4

Next, we also utilized this synthetic strategy for the construction of BTI aza-analogues. To
prepare PyrTI compounds, we used methyl 3-aminothieno[2,3-b]pyridine-2-carboxylates 10a,b
as the key precursors. These substrates were obtained by treatment of 2-chloronicotinonitrile
with methyl thioglycolate in the presence of NaOMe, affording 10a [39], and 6-(thien-2-yl)-
substituted 3-cyanopyridine-2(1H)-thione with methyl bromoacetate in the presence of KOH,
affording 10b [40]. Saponification of ester 10a was performed under the same reaction
conditions as for ester 7. Further treatment of the formed amino acid sodium salt with
arylhydrazines hydrochlorides 8a-j gave the desired products 11a-j in 57-93% yields (Scheme
3). In the same manner, 2-(thien-2-yl)-substituted PyrTI derivatives 11k-m were prepared in 56-
79% yields starting from ester 10b (Scheme 3). To note, we used 2-methoxyethanol as the
solvent for saponification step of ester 10b, since this compound was poorly soluble in
isopropanol and the reaction proceeded extremely slow.
Scheme 3. Synthesis of PyrTI compounds 11, scope and yields of products.
In turn, 7-aminothieno[2,3-b]pyrazine-6-carboxylate 12, obtained by reaction of 3-
chloropyrazine-2-carbonitrile with methyl thioglycolate in the presence of Et3N [41], was used as
5

the key precursor to construct PrzTI molecules. Similar to esters 7 and 10a, ester 12 was
smoothly converted to the sodium salt of amino acid, and its further treatment with
arylhydrazines hydrochlorides 8a-f in glacial acetic acid solution afforded PrzTIs 13a-f in 36-
53% yields (Scheme 4). Unfortunately, the products 13 were not obtained when arylhydrazines
8g-i, bearing CN, CO2H or CF3 groups at C-4 position, respectively, as well as 3,5-
difluorophenylhydrazine 8j were used for this reaction. It should be noted that compounds 13a-f
were also isolated only in moderate yields, which, for instance, were noticeably lower that the
yields of PyrTIs 11a-f (57-93%, Scheme 2). We assume that this peculiarity for PrzTI series can
be associated with a more pronounced destruction of the intermediate thieno[2,3-b]pyrazine
during the reaction as compared to the similar thieno[2,3-b]pyridine in the case of PyrTI series.
Scheme 4. Synthesis of PrzTI compounds 13, scope and yields of products.
Taking into account that 3-aminothiophene-2-carboxylates are unusual substrates for the
synthesis of thieno[3,2-b]indoles, we assume a possible mechanism of this reaction based on our
findings (Scheme 5). Initially, sodium salt i-1 converts to 3-aminothiophene i-2 under acidic
conditions by decarboxylation of the freed amino acid. Then, intermediate i-2 protonated at C-2
position to give thiophen-3(2H)-iminium cation i-3, which reacts with arylhydrazine affording
arylhydrazone of thiophen-3(2H)-one i-4. The latter one finally undergoes the Fischer
indolization forming the desired thieno[3,2-b]indole product.
6

Scheme 5. Possible mechanism of thieno[3,2-b]indole core construction
We also studied alkylation of PyrTI and PrzTI compounds, since alkylation of pyrrole-containing
ring-fused compounds in general is an important direction of their modification for different
purposes. However, alkylation of PyrTIs and PrzTIs can be ambiguous since these molecules
have nitrogen atoms of both pyrrole and pyridine types. Nevertheless, we were able to obtain N-
benzyl derivatives 14 and 15 in 50% and 63% yields by treatment of compounds 11a and 13a,
respectively, with benzyl chloride in the presence of NaH in DMF solution (Scheme 6).
N
X
N
X
PhCH2Cl
(1.2 equiv),
NaH (4 equiv)
Ph
S
S
N
NH
DMF, 24 h, rt
11a
13a
14
15
( X = CH)
( X = N)
, 50%
, 63%
Scheme 6. Alkylation of PyrTI and PrzTI compounds
3. Conclusion
In summary, we have developed a convenient approach to the synthesis of benzo[4,5]thieno[3,2-
b]indole derivatives and their aza-analogues, such as pyridine and pyrazine annulated thieno[3,2-
b]indoles PyrTIs and PrzTIs, from the ring-fused 3-aminothiophene-2-carboxylates by the one-
pot procedure based on the Fischer indolization reaction. In turn, the starting substrates were
readily obtained by reaction of (hetero)aryl nitriles, bearing a good leaving group in ortho-
position to the cyano function, with methyl thioglycolate in the presence of bases. It should be
noted, that PyrTI and PrzTI, similar in structure to the BTI, are potentially interesting scaffolds
for the design of biologically active compounds and optoelectronic materials.
4. Experimental
7

Analytical studies were carried out using equipment of the Center for Joint Use “Spectroscopy
and Analysis of Organic Compounds” at the Postovsky Institute of Organic Synthesis of the
Russian Academy of Sciences (Ural Division). Melting points were determined on combined
heating stages and are uncorrected. NMR measurements were performed on NMR spectrometers
in DMSO-d6 with tetramethylsilane as an internal standard for 1H, 13C spectra and
perfluorobenzene for 19F ones. Mass spectrometry was performed using a high resolution Q-TOF
LC-MS/MS spectrometer. The literature procedures were used to prepare the key precursors 7
[36], 10a [39], 10b [40] and 12 [41]. Phenylhydrazine (8a), 4-fluorophenylhydrazine (8b), 4-
(tert-butyl)phenylhydrazine (8c), 4-methylphenylhydrazine (8d), naphthalen-1-ylhydrazine (8e),
4-methoxyphenylhydrazine (8f), 4-cyanophenylhydrazine (8g), 4-hydrazinobenzoic acid (8h), 4-
(trifluoromethyl)phenylhydrazine (8i) and 3,5-difluorophenylhydrazine (8j) (hydrochlorides)
have been used in this study. Unless otherwise stated, all reagents were purchased from
commercial sources and used without further purification.
4.1 General procedure for the preparation of benzo[4,5]thieno[3,2-b]indoles (9a-i)
Methyl 3-aminobenzo[b]thiophene-2-carboxylate 7 (207 mg, 1 mmol) was immersed in IPA (9
ml) and suspended. Then, a solution of NaOH (160 mg, 4 mmol) in water (1 ml) was added in
one portion, and the resulting mixture was stirred and heated at reflux (100 °C) for 2 h. The
obtained solution was evaporated to dryness under reduced pressure, and the residue was
dissolved in AcOH (7 ml) with addition of HCO2H (0.15 ml, 4 mmol). An appropriate
arylhydrazine hydrochloride 8a-i (1.2 mmol) was added, and the reaction mixture was stirred and
heated at reflux (130 °C) for 2 h. After that the obtained mixture was cooled to ambient
temperature and diluted with MeOH (14 ml). The formed precipitate was filtered off, washed
with a 50% aqueous MeOH (3 × 4 ml) and dried at 120 °C to afford product 9 in an analytically
pure form.
4.1.1 10H-Benzo[4,5]thieno[3,2-b]indole (9a)
1
Light beige powder, yield 205 mg (92%), m.p. 255-256 °C. H NMR (500 MHz, DMSO-d6) δ
12.12 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.59
(d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.32 – 7.25 (m, 1H), 7.15 (t, J
= 7.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 142.0, 140.6, 137.5, 126.7, 124.5, 124.4,
124.3, 122.8, 121.5, 120.2, 119.4, 118.8, 113.8, 112.6. HRMS (APCI) calcd for C14H10NS m/z
224.0528 [M+H]+, found m/z 224.0528 [M+H]+.
4.1.2 3-Fluoro-10H-benzo[4,5]thieno[3,2-b]indole (9b)
8

White powder, yield 96 mg (40%), m.p. 257-258 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.21 (s,
1H), 8.07 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 9.7, 2.5 Hz, 1H), 7.59 (dd, J
= 8.9, 4.5 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.43 – 7.38 (m, 1H), 7.12 (td, J = 9.2, 2.6 Hz, 1H); 19F
13
NMR (471 MHz, DMSO-d6) δ 38.80 (td, J = 9.6, 4.6 Hz); C NMR (126 MHz, DMSO-d6) δ
156.8 (d, JCF = 232.6 Hz), 142.3, 139.2, 137.2, 126.5, 124.7, 124.6, 124.4, 121.6 (d, JCF = 11.0
Hz), 120.4, 113.7 (d, JCF = 4.5 Hz), 113.5 (d, JCF = 9.7 Hz), 110.8 (d, JCF = 26.1 Hz), 104.0 (d,
JCF = 24.7 Hz). HRMS (APCI) calcd for C14H8FNS m/z 241.0356 [M]+, found m/z 241.0356
[M]+.
4.1.3 3-(tert-Butyl)-10H-benzo[4,5]thieno[3,2-b]indole (9c)
1
Light beige crystals, yield 233 mg (80%), m.p. 217-218 °C. H NMR (500 MHz, DMSO-d6) δ
11.96 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.51
(d, J = 8.6 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.40 – 7.33 (m, 2H), 1.38 (s, 9H); 13C NMR (126 MHz,
DMSO-d6) δ 141.9, 138.7, 137.6, 126.8, 124.5, 124.4, 124.1, 121.3, 121.0, 120.0, 114.6, 113.9,
112.1, 34.4, 31.8. HRMS (APCI) calcd for C18H17NS m/z 279.1076 [M]+, found m/z 279.1080
[M]+.
4.1.4 3-Methyl-10H-benzo[4,5]thieno[3,2-b]indole (9d)
1
Light beige crystals, yield 164 mg (69%), m.p. 263-264 °C. H NMR (500 MHz, DMSO-d6) δ
11.97 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.51 – 7.45 (m,
2H), 7.41 – 7.33 (m, 1H), 7.10 (dd, J = 8.3, 0.9 Hz, 1H), 2.44 (s, 3H); 13C NMR (126 MHz,
DMSO-d6) δ 141.9, 138.9, 137.6, 128.1, 126.8, 124.5, 124.40, 124.39, 124.2, 121.7, 120.1,
118.4, 113.4, 112.3, 21.1. HRMS (APCI) calcd for C15H11NS m/z 237.0607 [M]+, found m/z
237.0607 [M]+.
4.1.5 12H-Benzo[g]benzo[4,5]thieno[3,2-b]indole (9e)
Pink powder, yield 147 mg (54%), m.p. 211-212 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.93 (s,
1H), 8.48 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.08 – 7.99 (m, 2H), 7.90 (d, J = 8.6 Hz,
1H), 7.68 – 7.58 (m, 2H), 7.56 – 7.49 (m, 2H), 7.42 – 7.35 (m, 1H); 13C NMR (126 MHz,
DMSO-d6) δ 141.7, 136.0, 135.3, 130.3, 128.7, 126.9, 125.8, 124.7, 124.48, 124.46, 124.0,
122.5, 120.9, 120.2, 119.8, 118.9, 117.1, 115.7. HRMS (APCI) calcd for C18H11NS m/z
273.0607 [M]+, found m/z 273.0606 [M]+.
4.1.6 3-Methoxy-10H-benzo[4,5]thieno[3,2-b]indole (9f)
9

Orange powder, yield 119 mg (47%), m.p. 201-202 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.93
(s, 1H), 8.06 – 7.98 (m, 2H), 7.50 – 7.44 (m, 2H), 7.40 – 7.34 (m, 1H), 7.30 (d, J = 2.4 Hz, 1H),
6.91 (dd, J = 8.8, 2.5 Hz, 1H), 3.82 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 153.5, 141.9,
138.0, 135.5, 126.8, 124.5, 124.4, 124.2, 121.8, 120.0, 113.5, 113.3, 112.9, 100.7, 55.5. HRMS
(APCI) calcd for C15H11NOS m/z 253.0556 [M]+, found m/z 253.0556 [M]+.
4.1.7 10H-Benzo[4,5]thieno[3,2-b]indole-3-carbonitrile (9g)
1
Yellowish powder, yield 72 mg (29%), m.p. >350 °C. H NMR (500 MHz, DMSO-d6) δ 12.76
(s, 1H), 8.45 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H),
13
7.63 (dd, J = 8.5, 1.6 Hz, 1H), 7.57 – 7.51 (m, 1H), 7.49 – 7.41 (m, 1H); C NMR (126 MHz,
DMSO-d6) δ 142.7, 142.3, 139.3, 126, 125.4, 125.2, 124.8, 124.6, 124.5, 121.4, 120.6, 120.4,
114.4, 113.7, 101.3. HRMS (ESI) calcd for C15H8N2S m/z 248.0403 [M]+, found m/z 248.0403
[M]+.
4.1.8 10H-Benzo[4,5]thieno[3,2-b]indole-3-carboxylic acid (9h)
1
Light orange powder, yield 137 mg (51%), m.p. 344-345 °C. H NMR (500 MHz, DMSO-d6) δ
12.61 (s, 1H), 12.53 (s, 1H), 8.47 – 8.43 (m, 1H), 8.12 – 8.03 (m, 2H), 7.89 (dd, J = 8.6, 1.6 Hz,
13
1H), 7.66 (d, J = 8.6 Hz, 1H), 7.55 – 7.49 (m, 1H), 7.45 – 7.40 (m, 1H); C NMR (126 MHz,
DMSO-d6) δ 168.0, 143.0, 142.3, 138.7, 126.4, 124.8, 124.7, 124.5, 124.0, 121.9, 121.3, 121.1,
120.3, 114.9, 112.3. HRMS (APCI) calcd for C15H9NO2S m/z 267.0349[M]+, found m/z
267.0350 [M]+.
4.1.9 3-(Trifluoromethyl)-10H-benzo[4,5]thieno[3,2-b]indole (9i)
1
Light beige powder, yield 166 mg (57%), m.p. 257-258 °C. H NMR (500 MHz, DMSO-d6) δ
12.62 (s, 1H), 8.30 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.6 Hz,
1H), 7.57 (dd, J = 8.6, 1.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.47 – 7.41 (m, 1H); 19F NMR (471
MHz, DMSO-d6) δ 104.16; 13C NMR (126 MHz, DMSO-d6) δ 142.6, 142.0, 139.2, 126.2, 125.4
(q, J = 271.3 Hz), 125.0, 124.7, 124.5, 120.9, 120.5, 120.4 – 119.7 (m), 119.1 – 118.9 (m), 116.8
(q, J = 4.2 Hz), 114.6, 113.2. HRMS (ESI) calcd for C15H8F3NS m/z 291.0324 [M]+, found m/z
291.0328 [M]+.
4.2 General procedure for the preparation of pyrido[3',2':4,5]thieno[3,2-b]indoles (11a-m)
Methyl 3-aminothieno[2,3-b]pyridine-2-carboxylate 10a (208 mg, 1 mmol) or methyl 3-amino-
6-(thiophen-2-yl)thieno[2,3-b]pyridine-2-carboxylate 10b (290 mg, 1 mmol) was immersed in
IPA (9 ml) (for ester 10a) or 2-methoxyethanol (9 ml) (for ester 10b), and suspended. Then, a
10

solution of NaOH (160 mg, 4 mmol) in water (1 ml) was added in one portion to this suspension,
and the resulting mixture was stirred and heated at reflux (100 °C) for 2 h. The obtained solution
was evaporated to dryness under reduced pressure, and the residue was dissolved in AcOH (7
ml) with addition of HCO2H (0.15 ml, 4 mmol). An appropriate arylhydrazine hydrochloride 8a-
i (1.2 mmol) was added, and the reaction mixture was stirred and heated at reflux (130 °C) for 2
h. After that the obtained mixture was cooled to ambient temperature and diluted with MeOH
(14 ml). The formed precipitate was filtered off, washed with a 50% aqueous MeOH (3 × 4 ml)
and dried at 120 °C to afford product 11 in an analytically pure form.
4.2.1 5H-Pyrido[3',2':4,5]thieno[3,2-b]indole (11a)
Orange powder, yield 177 mg (79%), m.p. 299-300 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.25
(s, 1H), 8.54 (dd, J = 4.6, 1.3 Hz, 1H), 8.40 (dd, J = 7.9, 1.3 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H),
7.64 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 7.9, 4.7 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.5
13
Hz, 1H); C NMR (126 MHz, DMSO-d6) δ 163.3, 145.6, 140.0, 133.8, 127.6, 123.5, 121.52,
121.47, 119.9, 119.7, 119.2, 112.7, 112.2. HRMS (APCI) calcd for C13H9N2S m/z 225.0481
[M+H]+, found m/z 225.0485 [M+H]+.
4.2.2 8-Fluoro-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11b)
1
Light beige powder, yield 225 mg (93%), m.p. 314-315 °C. H NMR (500 MHz, DMSO-d6) δ
12.34 (s, 1H), 8.56 (dd, J = 4.6, 1.6 Hz, 1H), 8.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (dd, J = 9.7, 2.5
Hz, 1H), 7.64 (dd, J = 8.9, 4.5 Hz, 1H), 7.55 (dd, J = 7.9, 4.6 Hz, 1H), 7.17 (td, J = 9.2, 2.6 Hz,
1H); 19F NMR (471 MHz, DMSO-d6) δ 39.24 (td, J = 9.6, 4.6 Hz); 13C NMR (126 MHz, DMSO-
d6) δ 163.4, 156.8 (d, JCF = 233.1 Hz), 145.9, 136.6, 135.5, 127.9, 121.6 (d, JCF = 11.0 Hz),
121.2, 119.8, 113.7 (d, JCF = 9.6 Hz), 112.0 (d, JCF = 4.7 Hz), 111.5 (d, JCF = 26.1 Hz), 104.3 (d,
JCF = 24.8 Hz). HRMS (APCI) calcd for C13H8FN2S m/z 243.0387 [M+H]+, found m/z 243.0390
[M+H]+.
4.2.3 8-(tert-Butyl)-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11c)
1
White powder, yield 237 mg (83%), m.p. 272-273 °C. H NMR (400 MHz, DMSO-d6) δ 12.08
(s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H),
13
7.58 – 7.49 (m, 2H), 7.41 (dd, J = 8.7, 1.9 Hz, 1H), 1.38 (s, 9H); C NMR (126 MHz, DMSO-
d6) δ 163.2, 145.3, 142.2, 138.2, 133.8, 127.4, 121.7, 121.6, 121.3, 119.8, 114.9, 112.4, 112.2,
34.4, 31.7. HRMS (APCI) calcd for C17H17N2S m/z 281.1107 [M+H]+, found m/z 281.1102
[M+H]+.
11

4.2.4 8-Methyl-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11d)
1
Beige powder, yield 190 mg (80%), m.p. 283-284 °C. H NMR (400 MHz, DMSO-d6) δ 12.09
(s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (s, 1H), 7.55 – 7.50
13
(m, 2H), 7.14 (dd, J = 8.4, 1.3 Hz, 1H), 2.44 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 163.2,
145.4, 138.3, 133.9, 128.5, 127.5, 125.1, 121.7, 121.6, 119.8, 118.7, 112.4, 111.7, 21.1. HRMS
(APCI) calcd for C14H11N2S m/z 239.0637 [M+H]+, found m/z 239.0641 [M+H]+.
4.2.5 12H-Benzo[g]pyrido[3',2':4,5]thieno[3,2-b]indole (11e)
Yellow powder, yield 173 mg (63%), m.p. >350 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s,
1H), 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.50 – 8.45 (m, 2H), 8.04 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 8.7
13
Hz, 1H), 7.72 – 7.62 (m, 2H), 7.60 – 7.50 (m, 2H); C NMR (126 MHz, DMSO-d6) δ 162.9,
145.1, 135.0, 132.3, 130.5, 128.7, 127.3, 126.0, 124.8, 122.3, 121.7, 121.0, 120.6, 120.0, 119.0,
117.2, 114.0. HRMS (APCI) calcd for C17H11N2S m/z 275.0637 [M+H]+, found m/z 275.0637
[M+H]+.
4.2.6 8-Methoxy-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11f)
1
Deep orange powder, yield 145 mg (57%), m.p. 250-251 °C. H NMR (500 MHz, DMSO-d6) δ
12.06 (s, 1H), 8.52 (dd, J = 4.6, 1.6 Hz, 1H), 8.36 (dd, J = 7.9, 1.6 Hz, 1H), 7.55 – 7.49 (m, 2H),
7.36 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.9, 2.5 Hz, 1H), 3.83 (s, 3H); 13C NMR (126 MHz,
DMSO-d6) δ 163.3, 153.7, 145.4, 134.9, 134.3, 127.5, 121.8, 121.6, 119.8, 113.8, 113.5, 111.9,
100.9, 55.5. HRMS (APCI) calcd for C14H11N2OS m/z 255.0587 [M+H]+, found m/z 255.0590
[M+H]+.
4.2.7 5H-Pyrido[3',2':4,5]thieno[3,2-b]indole-8-carbonitrile (11g)
Pink powder, yield 164 mg (66%), m.p. 328-329 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.85 (s,
1H), 8.60 (dd, J = 4.6, 1.6 Hz, 1H), 8.50 (d, J = 0.7 Hz, 1H), 8.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.79
(d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 1.6 Hz, 1H), 7.57 (dd, J = 8.0, 4.6 Hz, 1H); 13C NMR (126
MHz, DMSO-d6) δ 163.6, 146.5, 141.6, 135.7, 128.3, 125.9, 125.0, 121.4, 120.8, 120.3, 120.1,
113.8, 112.7, 101.6. HRMS (APCI) calcd for C14H8N3S m/z 250.0433 [M+H]+, found m/z
250.0434 [M+H]+.
4.2.8 5H-Pyrido[3',2':4,5]thieno[3,2-b]indole-8-carboxylic acid (11h)
1
White powder, yield 201 mg (75%), m.p. >350 °C. H NMR (500 MHz, DMSO-d6) δ 12.66 (s,
1H), 12.63 (s, 1H), 8.58 (dd, J = 4.6, 1.5 Hz, 1H), 8.51 (s, 1H), 8.43 (dd, J = 8.0, 1.5 Hz, 1H),
7.92 (dd, J = 8.6, 1.5 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.0, 4.6 Hz, 1H); 13C NMR
12

(126 MHz, DMSO-d6) δ 168.0, 163.5, 146.1, 142.4, 135.1, 128.0, 124.5, 122.2, 121.7, 121.20,
121.16, 120.0, 113.3, 112.5. HRMS (APCI) calcd for C14H9N2O2S m/z 269.0379 [M+H]+, found
m/z 269.0377 [M+H]+.
4.2.9 8-(Trifluoromethyl)-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11i)
Pink powder, yield 178 mg (61%), m.p. 292-293 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.73 (s,
1H), 8.60 (dd, J = 4.6, 1.6 Hz, 1H), 8.46 (dd, J = 8.0, 1.6 Hz, 1H), 8.38 (s, 1H), 7.83 (d, J = 8.6
19
Hz, 1H), 7.61 (dd, J = 8.7, 1.7 Hz, 1H), 7.58 (dd, J = 8.0, 4.7 Hz, 1H); F NMR (471 MHz,
DMSO-d6) δ 104.04; 13C NMR (126 MHz, DMSO-d6) δ 163.6, 146.3, 141.4, 135.5, 128.1, 125.3
(q, JCF = 271.5 Hz), 121.0, 121.0, 120.8 – 120.0 (m), 119.98, 119.7 – 119.4 (m), 117.2 (q, JCF
=
4.2 Hz), 113.3, 112.9. HRMS (ESI) calcd for C14H8F3N2S m/z 293.0355 [M+H]+, found m/z
293.0352 [M+H]+
4.2.10 7,9-Difluoro-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11j)
Pink fleecy crystals, yield 187 mg (72%), m.p. >350 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.70
(s, 1H), 8.58 (dd, J = 4.7, 1.6 Hz, 1H), 8.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (dd, J = 8.0, 4.7 Hz,
1H), 7.39 (dd, J = 9.6, 2.0 Hz, 1H), 7.07 (td, J = 10.4, 2.0 Hz, 1H); 19F NMR (376 MHz, DMSO-
d6) δ 46.95 (td, J = 9.9, 4.4 Hz), 43.58 (ddd, J = 10.5, 4.4, 2.3 Hz); 13C NMR (126 MHz, DMSO-
d6) δ 163.1, 159.2 (dd, JCF = 239.0, 12.1 Hz), 154.3 (dd, JCF = 246.7, 15.9 Hz), 145.9, 141.2 (dd,
JCF = 15.0, 12.6 Hz), 134.2 (d, JCF = 2.8 Hz), 128.0, 120.8, 120.1, 108.7, 107.7 (d, JCF = 22.6
Hz), 95.8 (dd, JCF = 26.5, 4.3 Hz), 95.2 (dd, JCF = 29.7, 22.8 Hz). HRMS (APCI) calcd for
C13H7F2N2S m/z 261.0293 [M+H]+, found m/z 261.0289 [M+H]+.
4.2.11 2-(Thiophen-2-yl)-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11k)
1
Yellowish powder, yield 242 mg (79%), m.p. 290-291 °C. H NMR (500 MHz, DMSO-d6) δ
12.22 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 3.6 Hz, 1H), 7.84
(d, J = 7.9 Hz, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H),
7.24 – 7.15 (m, 2H); 13C NMR (126 MHz, DMSO-d6) δ 163.1, 148.3, 144.2, 140.0, 134.0, 128.6,
128.5, 128.3, 125.7, 123.5, 121.6, 120.0, 119.8, 119.1, 115.4, 112.7, 112.2. HRMS (APCI) calcd
for C17H11N2S2 m/z 307.0358 [M+H]+, found m/z 307.0356 [M+H]+.
4.2.12 8-Fluoro-2-(thiophen-2-yl)-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11l)
1
Yellowish powder, yield 217 mg (67%), m.p. 308-309 °C. H NMR (500 MHz, DMSO-d6) δ
12.30 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 3.7, 0.9 Hz, 1H),
7.72 – 7.67 (m, 2H), 7.63 (dd, J = 8.9, 4.5 Hz, 1H), 7.21 (dd, J = 5.0, 3.7 Hz, 1H), 7.16 (td, J =
13

19
13
9.2, 2.6 Hz, 1H); F NMR (471 MHz, DMSO-d6) δ 39.32 (td, J = 9.5, 4.5 Hz); C NMR (126
MHz, DMSO-d6) δ 163.3, 156.9 (d, JCF = 233.2 Hz), 148.7, 144.0, 136.6, 135.7, 128.7, 128.6,
128.5, 125.8, 121.7 (d, JCF = 11.1 Hz), 119.7, 115.4, 113.6 (d, JCF = 9.6 Hz), 112.0 (d, JCF = 4.6
Hz), 111.5 (d, JCF = 26.1 Hz), 104.2 (d, JCF = 24.8 Hz). HRMS (APCI) calcd for C17H10FN2S2
m/z 325.0264 [M+H]+, found m/z 325.0259 [M+H]+.
4.2.13 8-(tert-Butyl)-2-(thiophen-2-yl)-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (11m)
1
Beige powder, yield 203 mg (56%), m.p. 261-262 °C. H NMR (500 MHz, DMSO-d6) δ 12.06
(s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 3.2 Hz, 1H), 7.79 (s, 1H),
7.68 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.6, 1.5 Hz, 1H), 7.22 – 7.19 (m,
13
1H), 1.39 (s, 9H); C NMR (126 MHz, DMSO-d6) δ 163.0, 148.1, 144.2, 142.3, 138.2, 134.0,
128.6, 128.4, 128.1, 125.6, 121.7, 121.4, 120.1, 115.4, 114.9, 112.4, 112.2, 34.5, 31.7. HRMS
(APCI) calcd for C21H19N2S2 m/z 363.0984 [M+H]+, found m/z 363.0979 [M+H]+.
4.3 General procedure for the preparation of pyrazino[2',3':4,5]thieno[3,2-b]indoles (13a-f)
A solution of NaOH (160 mg, 4 mmol) in water (1 ml) was added to methyl 7-aminothieno[2,3-
b]pyrazine-6-carboxylate 12 (209 mg, 1 mmol) dissolved in IPA (9 ml). The reaction mixture
was stirred and heated at (100 °C) reflux for 2 h, and then evaporated to dryness under reduced
pressure. The residue was dissolved in AcOH (7 ml) with addition of HCO2H (0.15 ml, 4 mmol),
and an appropriate arylhydrazine hydrochloride 8a-f (1.2 mmol) was added. The reaction
mixture was stirred and heated at reflux (130 °C) for 2 h, then it was cooled to ambient
temperature and diluted with 50% aqueous MeOH (14 ml), and filtrated to remove a small
amount of impurities. The main precipitate was formed at standing filtrate for 1 h at ambient
temperature. The solid was filtrated, washed with a 50% aqueous MeOH (3 × 4 ml) and dried at
120 °C to give product 13 in an analytically pure form.
4.3.1 10H-Pyrazino[2',3':4,5]thieno[3,2-b]indole (13a)
1
Light beige powder, yield 110 mg (49%), m.p. 234-235 °C. H NMR (500 MHz, DMSO-d6) δ
12.63 (s, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.63
(d, J = 8.3 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.26 – 7.19 (m, 1H); 13C NMR (126 MHz, DMSO-d6) δ
157.9, 141.0, 140.9, 139.1, 138.5, 132.4, 124.9, 121.3, 120.1, 119.8, 116.6, 113.1. HRMS
(APCI) calcd for C12H8N3S m/z 226.0433 [M+H]+, found m/z 226.0435 [M+H]+.
4.3.2 7-Fluoro-10H-pyrazino[2',3':4,5]thieno[3,2-b]indole (13b)
14

1
Light brown powder, yield 87 mg (36%), m.p. 301-302 °C. H NMR (500 MHz, DMSO-d6) δ
12.71 (s, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 9.6, 2.4 Hz, 1H),
7.62 (dd, J = 8.9, 4.4 Hz, 1H), 7.25 (td, J = 9.2, 2.5 Hz, 1H); 19F (471 MHz, DMSO-d6) δ 39.81
(td, J = 9.4, 4.5 Hz); 13C NMR (126 MHz, DMSO-d6) δ 158.1, 156.9 (d, JCF = 234.0 Hz), 141.1,
139.5, 138.3, 137.5, 134.1, 121.3 (d, JCF = 11.2 Hz), 116.1 (d, JCF = 4.8 Hz), 114.2 (d, JCF = 9.6
Hz), 113.2 (d, JCF = 26.3 Hz), 104.8 (d, JCF = 24.8 Hz). HRMS (APCI) calcd for C12H7FN3S m/z
244.0339 [M+H]+, found m/z 244.0340 [M+H]+.
4.3.3 7-(tert-Butyl)-10H-pyrazino[2',3':4,5]thieno[3,2-b]indole (13c)
1
Light brown powder, yield 149 mg (53%), m.p. 211-212 °C. H NMR (500 MHz, DMSO-d6) δ
12.47 (s, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.90 (s, 1H), 7.55 (d, J = 8.7 Hz,
1H), 7.49 (dd, J = 8.7, 1.6 Hz, 1H), 1.38 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 157.9,
142.7, 140.9, 139.1, 138.8, 138.6, 132.5, 123.3, 121.1, 116.7, 115.4, 112.7, 34.5, 31.7. HRMS
(APCI) calcd for C16H16N3S m/z 282.1059 [M+H]+, found m/z 282.1056 [M+H]+.
4.3.4 7-Methyl-10H-pyrazino[2',3':4,5]thieno[3,2-b]indole (13d)
1
Light brown powder, yield 120 mg (50%), m.p. 249-250 °C. H NMR (500 MHz, DMSO-d6) δ
12.48 (s, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J = 8.4 Hz,
1H), 7.22 (dd, J = 8.4, 1.4 Hz, 1H), 2.45 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 157.9,
141.0, 139.3, 139.0, 138.6, 132.5, 129, 126.6, 121.4, 119.1, 116.0, 112.9, 21.1. HRMS (APCI)
calcd for C13H10N3S m/z 240.0590 [M+H]+, found m/z 240.0594 [M+H]+.
4.3.5 12H-Benzo[g]pyrazino[2',3':4,5]thieno[3,2-b]indole (13e)
1
Light beige powder, yield 124 mg (45%), m.p. 297-298 °C. H NMR (500 MHz, DMSO-d6) δ
13.58 (s, 1H), 8.78 (d, J = 2.5 Hz, 1H), 8.70 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.04
(d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.59 – 7.54 (m, 1H); 13C NMR
(126 MHz, DMSO-d6) δ 157.8, 140.8, 138.7, 138.6, 136.5, 131.2, 130.9, 128.7, 126.2, 125.5,
122.5, 121.8, 121.2, 118.9, 118.2, 117.1. HRMS (APCI) calcd for C16H10N3S m/z 276.0590
[M+H]+, found m/z 276.0591 [M+H]+.
4.3.6 7-Methoxy-10H-pyrazino[2',3':4,5]thieno[3,2-b]indole (13f)
1
Brownish powder, yield 119 mg (45%), m.p. 275-276 °C. H NMR (500 MHz, DMSO-d6) δ
12.44 (s, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.46
(d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.9, 2.5 Hz, 1H), 3.84 (s, 3H); 13C NMR (126 MHz, DMSO-d6)
15

δ 157.9, 153.9, 140.9, 138.9, 138.6, 135.9, 132.8, 121.5, 116.0, 115.6, 113.9, 100.9, 55.5. HRMS
(APCI) calcd for C13H10N3OS m/z 256.0539 [M+H]+, found m/z 256.0535 [M+H]+.
4.4 General procedure for the preparation of compounds 14 and 15
PyrTI derivative 11a (224 mg, 1 mmol) or PrzTI derivative 13a (225 mg, 1 mmol) was dissolved
in dry DMF (7 ml), then NaH (96 mg, 4 mmol) was added in one portion, and the obtained
suspension was stirred for 30 min at ambient temperature under an argon atmosphere. Benzyl
chloride (0.14 ml, 1.2 mmol) was added, and the resulted mixture was stirred at ambient
temperature for 24 h. Then, the reaction mixture was diluted with H2O (7 ml), and the formed
precipitate was filtered off, washed with H2O (2 × 10 ml) and dried on air. The crude product
was crystallized from acetonitrile (5 ml) to afford N-benzyl derivative 14 or 15 in an analytically
pure form.
4.4.1 5-Benzyl-5H-pyrido[3',2':4,5]thieno[3,2-b]indole (14)
1
Light beige powder (MeCN), yield 157 mg (50%), m.p. 184-185 °C. H NMR (500 MHz,
DMSO-d6) δ 8.52 (dd, J = 4.5, 1.3 Hz, 1H), 8.42 (dd, J = 8.1, 1.3 Hz, 1H), 7.92 (d, J = 7.9 Hz,
1H), 7.81 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.1, 4.6 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.28 – 7.18 (m,
4H), 7.11 (d, J = 7.3 Hz, 2H), 5.99 (s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 163.2, 145.5,
140.9, 137.8, 133.8, 128.8, 128.0, 127.4, 126.2, 123.9, 121.12, 121.10, 120.2, 119.7, 119.6,
112.7, 111.1, 47.5. HRMS (ESI) calcd for C20H15N2S m/z 315.0950 [M+H]+, found m/z
315.0956 [M+H]+.
4.4.2 10-Benzyl-10H-pyrazino[2',3':4,5]thieno[3,2-b]indole (15)
Yellowish powder (MeCN), yield 200 mg (63%), m.p. 154-155 °C. 1H NMR (500 MHz, DMSO-
d6) δ 8.78 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.4
Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.32 – 7.11 (m, 6H), 6.05 (s, 2H); 13C NMR (126 MHz,
DMSO-d6) δ 158.1, 141.0, 139.3, 138.7, 137.7, 132, 128.6, 127.5, 127, 125.1, 121.3, 120.5,
120.2, 116.3, 111.7, 47.5. HRMS (ESI) calcd for C19H14N3S m/z 316.0903 [M+H]+, found m/z
316.0898 [M+H]+
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
16

This research study was supported by the Russian Foundation for Basic Research (research
project No. 18-33-20083).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
17

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19

HIGHLIGHTS
•
•
•
Ring-annulated thieno[3,2-b]indoles were readily synthesized by one-pot procedure
The synthesis was performed using easily accessible starting materials
The Fischer indolization reaction is a key transformation of the current approach

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: