A simple route to γ-carbolines and indolizino[7,6-b]indoles

Article abstract of DOI:10.1016/j.tet.2015.09.046

We designed and realized for the first time an approach to indolizino[7,6-b]indoles. This approach is based on the Leuckart-Wallach reaction of 2-(2-oxoalkyl)indoles with formamide followed by Bischler-Napieralski cyclization producing γ-carbolines. The alkylation of 3-alkyl-γ-carbolines with phenacyl bromides followed by the treatment of the formed pyridinium salt with base produced the target aromatic tetracyclic system.

Full text of DOI:10.1016/j.tet.2015.09.046

Accepted Manuscript
A simple route to γ-carbolines and indolizino[7,6-b]indoles
Arkady S. Pilipenko, Maxim G. Uchuskin, Igor V. Trushkov, Alexander V. Butin
PII:
S0040-4020(15)30074-0
10.1016/j.tet.2015.09.046
TET 27143
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 June 2015
Revised Date: 8 September 2015
Accepted Date: 21 September 2015
Please cite this article as: Pilipenko AS, Uchuskin MG, Trushkov IV, Butin AV, A simple route to γ-
carbolines and indolizino[7,6-b]indoles, Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.046.
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A simple route to γ-carbolines and
indolizino[7,6-b]indoles
Arkady S. Pilipenko, Maxim G. Uchuskin,* Igor V. Trushkov, Alexander V. Butin

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A simple route to γ-carbolines and indolizino[7,6-b]indoles
Arkady S. Pilipenkoa, Maxim G. Uchuskinb , Igor V. Trushkovc,d and Alexander V. Butin a,b
a Kuban State Technological University
Moskovskaya st. 2, Krasnodar 350072, Russian Federation
,
b Department of Chemistry, Perm State University, Bukireva st. 15, Perm 614990, Russian Federation
c Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russian Federation
d Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, ul. Samory Mashela 1, Moscow 117997,
Russian Federation
Dedicated to the blessed memory of Professor Alexander V. Butin, teacher and friend
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We designed and realized for the first time an approach to indolizino[7,6-b]indoles. This
approach is based on the Leuckart-Wallach reaction of 2-(2-oxoalkyl)indoles with formamide
followed by Bischler-Napieralski cyclization producing γ-carbolines. The alkylation of 3-alkyl-
γ-carbolines with phenacyl bromides followed by the treatment of the formed pyridinium salt
with base produced the target aromatic tetracyclic system.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Indoles
Reductive amination
Bischler-Napieralski cyclization
γ-Carbolines
Indolizino[7,6-b]indoles
———
Maxim G. Uchuskin Tel.: +7-342-239-6401; fax: +7-342-239-6862; e-mail: mu@psu.ru

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Pyrido[x,y-b]indoles (carbolines) are considered as an
important class of organic compounds.1 Among the isomeric
carbolines, pyrido[4,3-b]indoles, or γ-carbolines, occupy the
second place (after β-carbolines) by the state of knowledge.2 γ-
Carboline derivatives, in which one or more rings are annulated
to the pyridine ring, e.g. alkaloid isocryptolepine, related
indolo[3,2-c]quinolines and others demonstrate significant
bioactivity3 (Figure 1).
Along with this, indolizino[7,6-b]indoles (γ-carbolines to the
N(2)–C(3) bond of which the pyrrole ring is annulated) have not
been investigated. However, these compounds should have a
good pharmacological potential, as isomeric indolizinoindoles
have significant cytotoxicity against cancer cells with multiple
modes of action.4 Moreover, hexahydroindolizino[7,6-b]indole
derivatives demonstrate no cytotoxicity5 but show very high
affinity to G protein-coupled receptors, such as histamine,
dopamine, serotonin, adrenergic, melatonin-concentrating
hormone receptors, and can be used for the treatment of
neurodegenerative diseases, allergic reactions, hypertension, type
2 diabetes, obesity, etc.6 Together, these data stimulate the
development of new approaches to the synthesis of the γ-
carboline scaffold as well as the preparation of new γ-carboline
derivatives including the novel aromatic system of
indolizino[7,6-b]indole.
Scheme 1. Synthesis of γ-carbolines 4 (for specification of R1
and R2, see table 1).
Among various procedures for Leuckart-Wallach reaction of
dialkyl ketones, after some experimentation we selected the
simplest one, i.e., heating of the mixture of ketone and
formamide under reflux without solvent.8 Quenching of the
reaction mixture with cold water led to the precipitation of
amides 2 in a sufficiently pure form for introducing them into
further transformations without additional purification.
Unexpectedly, the attempts to perform Bischler-Napieralski
cyclization under the typical reaction conditions (POCl3, P2O5 or
SOCl2 in a benzene/toluene mixture as well as polyphosphoric
acid (PPA) usage) produced only complex mixtures of non-
identified products. Fortunately, the utilization of PPA ethyl ester
solved this problem. Nevertheless, we failed to isolate 3,4-
dihydro-5H-γ-carbolines 3 due to their instability as a result of
both oxidation and disproportionation.9 Therefore, compounds 3
were immediately oxidized with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) furnishing the target γ-carbolines 4 in
moderate yields (Table 1).
Table 1. Synthesis of γ-carbolines 4.
1
a
b
c
d
e
f
R1
R2
4
a
b
c
d
e
f
Yield of 4, %a
Me
H
38
31
30
29
35
36
32
Et
H
Figure 1. Examples of bioactive γ-carboline derivatives.
Me
Cl
In this work we report a new simple approach to γ-carbolines
as well as indolizino[7,6-b]indoles starting from 2-(2-
oxoalkyl)indoles 1 the preparation of which by the furan ring
opening—indole ring closure domino reaction of 2-(2-
aminophenyl)furans was recently developed by us.7
Et
Me
Cl
Me
OMe
H
Me
g
4-MeC6H4CH2
g
a Overall isolated yield of 4 from 2-(2-oxoalkyl)indoles 1.
2. Results and discussion
Earlier it was shown that N-unsubstituted γ-carbolines
demonstrate significant antiviral activity.10 We demonstrated that
the developed method can be applied for the synthesis of these
and related NH-γ-carbolines 5 in a straightforward manner by the
detosylation of compounds 4 with KOH in aqueous DMSO
(Table 2).
Our approach to γ-carbolines is based on the transformation
of 2-(2-oxoalkyl)indoles 1 into amides 2 using the Leuckart-
Wallach reaction with HCONH2 followed by Bischler-
Napieralski
cyclization
of
N-[1-alkyl-2-(2-
indolyl)ethyl]formamides 2 and the oxidation of the formed
dihydro-γ-carbolines 3 (Scheme 1).
Table 2. Synthesis of NH-γ-carbolines 5.

3
4
c
R1
Me
Et
R2
Cl
5
a
b
c
Yield of 5, %
4. Experimental section
ACCEPTED MANUSCRIPT
87
4.1. General
d
e
Cl
85
NMR spectra were acquired on Bruker Avance 300
spectrometer at room temperature; the chemical shifts δ were
measured in ppm with respect to solvent (1Н: CDCl3, δ = 7.26
Me
Me
88
ppm; 13C: CDCl3, δ = 77.0 ppm; Н: DMSO-d6, δ = 2.50 ppm;
1
13C: DMSO-d6, δ = 39.5 ppm). Splitting patterns are designated
as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
double doublet. Coupling constants (J) are given in Hertz. IR
spectra were measured as KBr plates on InfraLUM FT-02 and
InfraLUM FT-801 instruments. Mass spectra were recorded on a
Kratos MS-30 instrument with 70 eV electron impact ionization
at 200 C. Elemental analyses were performed with Fisons EA-
1108 CHNS elemental analyser instrument. Melting points (mp)
were measured on Electrothermal 9100 capillary melting point
apparatus. Column chromatography was performed using silica
gel KSK (50–160 ꢀm, LTD Sorbpolymer). All the reactions were
carried out using freshly distilled and dry solvents.
Moreover, we showed that the obtained γ-carbolines 4 can be
used as starting compounds for the first synthesis of the fully
aromatic indolizino[7,6-b]indole system. The reaction of γ-
carbolines
corresponding ammonium salt, treatment of which with NaHCO3
solution in aqueous dioxane led to the deprotonation of the acidic
CH-moiety in ortho-position to the pyridinium nitrogen. The
intramolecular aldol condensation accomplished the formation of
the target tetracyclic framework (Table 3).
4
with phenacyl bromides
6
afforded the
Table 3. Synthesis of indolizino[7,6-b]indoles 8.
4.2. Synthesis of 3-alkyl-5-tosyl-5H-pyrido[4,3-b]indoles 4a-g
Mixture of 2-(2-oxoalkyl)indole 1 (15 mmol) and formamide
(100 mL) was refluxed for 40 min and poured into cold water (1
L). To the filtered precipitate of amide 2 polyphosphoric acid
ethyl ester (60 mL) was added. The reaction mixture was
refluxed for 4 h, poured into cold water (400 mL) and neutralized
with NaHCO3. Intermediate 3 was extracted with EtOAc (3×75
mL). The combined extracts were dried with Na2SO4 and filtered
with charcoal. Solvent was evaporated. The residue was
dissolved in benzene (25 mL). To this solution DDQ (2.27 g, 10
mmol) was added. The mixture was refluxed for 5–7 min and
poured into water (100 mL). Product was extracted with EtOAc
(3×50 mL). The combined extracts were dried with Na2SO4.
Solvent was evaporated. Residue was purified by column
chromatography on silica gel (eluent: benzene-hexane, 1:3).
4
a
b
b
c
e
e
f
R1
H
R2
H
6
a
a
b
a
a
b
b
Ar
Ph
8
a
b
c
d
e
f
Yield of 8, %a
82
77
79
80
85
73
71
4.2.1. 3-Methyl-5-tosyl-5H-pyrido[4,3-b]indole (4a).
Me
Me
H
H
Ph
Yield 1.92 g (38%); pale beige crystals; mp 173–174°C;
[Found: C, 67.98; H, 4.68; N, 8.34. C19H16N2O2S requires C,
67.84; H, 4.79; N, 8.33%]; Rf (acetone/petroleum ether 1:1) 0.44;
νmax (KBr) 1596, 1456, 1366, 1189, 1175, 1153, 980, 708, 665,
585, 569, 543 cm-1; δH (CDCl3) 9.26 (s, 1H, HAr), 8.23–8.19 (m,
H
4-ClC6H4
Ph
Cl
H
Me
Me
OMe
Ph
3
H
4-ClC6H4
4-ClC6H4
2H, HAr), 8.05 (s, 1H, HAr), 7.87 (d, 2H, J = 8.1 Hz, HTs3), 7.61–
H
g
7.56 (m, 1H, HAr), 7.48–7.43 (m, 1H, HAr), 7.33 (d, 2H, J = 8.1
Hz, HTs), 2.68 (s, 3H, CH3), 2.26 (s, 3H, CH3); δC (CDCl3) 156.5,
146.2, 143.4, 142.5, 137.1, 133.6, 130.4 (2C), 128.2, 126.5 (2C),
124.7, 123.5, 120.9, 119.4, 114.3, 107.8, 24.8, 21.0; m/z (EI, 70
eV) 336 (58) [M+], 182 (85), 181 (87), 155 (23), 154 (23), 128
(31), 127 (70), 126 (20), 91 (100), 65 (59), 43 (39), 41 (20).
a Isolated yield
Unfortunately, we failed to remove the tosyl group from the
synthesized indolizino[7,6-b]indoles 8. We found that these
compounds are stable under typical conditions for detosylation
(K2CO3 in aqueous MeOH under reflux; ethanolic NaOH at
various temperatures; Mg, NH4Cl, MeOH/H2O at room
temperature and under heating). Full conversion of 8 under
treatment with NaOH in DMSO was observed, however only
products of decomposition were formed in this case.
4.2.2. 3-Ethyl-5-tosyl-5H-pyrido[4,3-b]indole (4b).
Yield 1.63 g (31%); beige needles; mp 144–145°C; [Found:
C, 68.39; H, 5.16; N, 8.01. C20H18N2O2S requires C, 68.55; H,
5.18; N, 7.99%]; Rf (acetone/petroleum ether 1:1) 0.54; νmax
(KBr) 1596, 1490, 1457, 1406, 1373, 1201, 1179, 1147, 1091,
989, 867, 812 cm-1; δH (CDCl3) 9.28 (s, 1H, HAr), 8.23–8.19 (m,
3. Conclusions
3
2H, HAr), 8.03 (s, 1H, HAr), 7.85 (d, 2H, J = 8.4 Hz, HTs3), 7.62–
In summary, we have developed a simple route to γ-carbolines
7.56 (m, 1H, HAr), 7.48–7.43 (m, 1H, HAr), 7.32 (d, 2H, J = 8.4
from 2-(2-oxoalkyl)indoles consisting of Leuckart-Wallach and
Bischler-Napieralski
carbolines were further transformed into indolizino[7,6-b]indoles
in high yields. This is the first example of the synthesis of this
aromatic tetracyclic system.
3
Hz, HTs), 2.96 (q, 2H, J = 7.5 Hz, CH2), 2.25 (s, 3H, CH3), 1.32
reactions. The obtained 3-alkyl-γ-
(t, 3H, 3J = 7.5 Hz, CH3); δC (CDCl3) 161.6, 146.2, 143.4, 142.6,
137.2, 133.5, 130.4 (2C), 128.2, 126.4 (2C), 124.8, 123.5, 120.9,
119.6, 114.3, 106.8, 31.3, 20.9, 14.3; m/z (EI, 70 eV) 350 (31)
[M+], 196 (26), 195 (100), 167 (26), 140 (16), 91 (20), 43 (27).
4.2.3. 7-Chloro-3-methyl-5-tosyl-5H-pyrido[4,3-b]indole (4c).

4
Tetrahedron
ACCEPTED MANUSCRIPT
Yield 1.67 g (30%); white solid; mp 242–243°C; [Found: C,
CH2), 2.34 (s, 3H, CH3), 2.28 (s, 3H, CH3); δC (CDCl3) 159.5,
61.40; H, 4.11; N, 7.69. C19H15ClN2O2S requires C, 61.53; H,
4.08; N, 7.55%]; Rf (acetone/petroleum ether 1:1) 0.41; νmax
(KBr) 1598, 1458, 1377, 1176, 1155, 1091, 987, 814 cm-1; δH
(CDCl3) 9.03 (s, 1H, HAr), 8.28 (d, 1H, 4J = 1.8 Hz, HAr), 8.01 (s,
1H, HAr), 7.85 (d, 1H, 3J =8.4 Hz, HAr), 7.74 (d, 2H, 3J = 8.1 Hz,
145.4, 144.2, 142.0, 138.2, 136.7, 135.8, 134.4, 129.8 (2C), 129.2
(2C), 128.9 (2C), 127.9, 126.5 (2C), 124.4, 123.9, 120.4, 120.2,
114.7, 108.7, 44.7, 21.5, 21.0; m/z (EI, 70 eV) 426 (43) [M+], 271
(80), 270 (100), 256 (93), 105 (16), 91 (70), 76 (20), 65 (27), 43
(38).
3
4
3
HTs), 7.36 (dd, 1H, J = 8.4, J = 1.8 Hz, HAr), 7.20 (d, 2H, J =
8.1 Hz, HTs), 2.74 (s, 3H, CH3), 2.32 (s, 3H, CH3); δC (CDCl3)
156.8, 145.8, 144.5, 141.8, 138.4, 134.4, 133.6, 130.1 (2C), 126.5
(2C), 124.9, 122.5, 120.8, 119.2, 114.9, 108.4, 25.2, 21.6; m/z
(EI, 70 eV) 372/370 (17/51) [M+], 217/215 (33/100), 195 (22),
155 (42), 139 (57), 127 (26), 126 (49), 91 (65), 65 (34), 43 (27).
4.3. Synthesis of 5H-pyrido[4,3-b]indoles 5a-c
The mixture of compound 4 (1.5 mmol) and DMSO (20 mL)
was heated until full dissolution. Then 50% aq. NaOH (1.5 mL)
was added. The reaction mixture was stirred at 45°C for 5 h and
poured into water (300 mL). The formed precipitate was
recrystallized from 1,4-dioxane–hexane mixture. See table 2
4.2.4. 7-Chloro-3-ethyl-5-tosyl-5H-pyrido[4,3-b]indole (4d).
4.3.1. 7-Chloro-3-methyl-5H-pyrido[4,3-b]indole (5a).
Yield 1.67 g (29%); beige solid; mp 178–179°C; [Found: C,
62.40; H, 4.38; N, 7.18. C20H17ClN2O2S requires C, 62.41; H,
4.45; N, 7.28%]; Rf (acetone/petroleum ether 1:1) 0.56; νmax
(KBr) 1595, 1448, 1394, 1371, 1201, 1190, 1176, 1152, 1090,
989, 950, 816 cm-1; δH (CDCl3) 9.08 (s, 1H, HAr), 8.28 (d, 1H, 4J
Yield 0.28 g (87%); white solid; mp 310°C (dec.); [Found: C,
66.54; H, 4.42; N, 12.91. C12H9ClN2 requires C, 66.52.; H, 4.19;
N, 12.93]; Rf (acetone/petroleum ether 2:1) 0.38; νmax (KBr)
3424, 1604, 1460, 1448, 1320, 1244, 1232, 1160, 1064, 808 cm-1;
δH (CDCl3) 11.71 (br.s, 1H, NH), 9.20 (s, 1H, HAr), 8.18 (d, 1H,
3
= 1.8 Hz, HAr), 8.03 (s, 1H, HAr), 7.86 (d, 1H, J = 8.4 Hz, HAr),
4
3J = 8.4 Hz, HAr), 7.56 (d, 1H, J = 1.8 Hz, HAr), 7.33 (s, 1H,
7.73 (d, 2H, 3J = 8.7 Hz, HTs), 7.36 (dd, 1H, 3J = 8.4, 4J = 1.8 Hz,
HAr), 7.25 (dd, 1H, 3J = 8.4, 4J = 1.8 Hz, HAr), 2.59 (s, 3H, CH3);
δC (CDCl3) 153.2, 145.2, 141.8, 140.4, 130.5, 121.7, 120.0,
119.8, 116.9, 111.1, 105.0, 24.3; m/z (EI, 70 eV) 218/216
(33/100) [M+], 181 (14), 154 (17), 127 (15), 76 (16), 43 (45).
3
3
1HAr), 7.19 (d, 2H, J = 8.7 Hz, HTs), 2.99 (q, 2H, J = 7.5 Hz,
3
CH2), 2.31 (s, 3H, CH3), 1.39 (t, 3H, J = 7.5 Hz, CH3); δC
(CDCl3) 162.1, 145.8, 144.6, 141.8, 138.5, 134.4, 133.6, 130.0
(2C), 126.5 (2C), 124.9, 122.5, 120.9, 119.4, 114.9, 107.3, 31.9,
21.5, 14.4; m/z (EI, 70 eV) 386/384 (19/57) [M+], 231/229
(33/100), 91 (75), 65 (37), 43 (26).
4.3.2. 7-Chloro-3-ethyl-5H-pyrido[4,3-b]indole (5b).
Yield 0.29 g (85%); white solid; mp 243–244°C; [Found: C,
67.79; H, 4.97; N, 12.15. C13H11ClN2 requires C, 67.68; H, 4.81;
N, 12.14]; Rf (acetone/petroleum ether 2:1) 0.58; νmax (KBr)
3420, 1616, 1576, 1560, 1452, 1324, 1240, 840, 800 cm-1; δH
(CDCl3) 11.69 (br.s, 1H, NH), 9.22 (s, 1H, HAr), 8.17 (d, 1H, 3J =
4.2.5. 3,7-Dimethyl-5-tosyl-5H-pyrido[4,3-b]indole (4e).
Yield 1.84 g (35%); beige needles; mp 211–212°C; [Found:
C, 68.56; H, 5.29; N, 8.01. C20H18N2O2S requires C, 68.55; H,
5.18; N, 7.99%]; Rf (acetone/petroleum ether 1:1) 0.41; νmax
(KBr) 1597, 1464, 1373, 1226, 1188, 1177, 1142, 1092, 988, 806
cm-1; δH (CDCl3) 9.01 (s, 1H, HAr), 8.08 (d, 1H, 4J = 1.5 Hz, HAr),
8.02 (s, 1H, HAr), 7.82 (d, 1H, 3J = 7.8 Hz, HAr), 7.73 (d, 2H, 3J =
4
8.4 Hz, HAr), 7.56 (d, 1H, J = 2.1 Hz, HAr), 7.31 (s, 1H, HAr),
7.25 (dd, 1H, 3J = 8.4, 4J = 2.1 Hz, HAr), 2.85 (q, 2H, 3J = 7.5 Hz,
3
CH2), 1.29 (t, 1H, J = 7.5 Hz, CH3); δC (CDCl3) 158.7, 145.2,
3
4
142.1, 140.4, 130.4, 121.7, 120.0, 119.8, 117.0, 111.1, 103.8,
31.0, 14.3; m/z (EI, 70 eV) 232/230 (33/100) [M+], 202 (60),
195/193 (9/27), 168/166 (9/27), 140 (27), 59 (18), 43 (13).
8.4 Hz, HTs), 7.21 (dd, 1H, J = 7.8, J = 1.5 Hz, HAr), 7.17 (d,
3
2H, J = 8.4 Hz, HTs), 2.73 (s, 3H, CH3), 2.54 (s, 3H, CH3), 2.30
(s, 3H, CH3); δC (CDCl3) 155.9, 145.4, 144.3, 141.4, 138.4,
138.3, 134.8, 129.9 (2C), 126.4 (2C), 125.7, 121.5, 120.1, 119.7,
114.9, 108.4, 25.1, 22.2, 21.5; m/z (EI, 70 eV) 350 (100) [M+],
196 (47), 195 (100), 153 (18), 91 (20), 59 (21), 43 (39).
4.3.3. 3,7-Dimethyl-5H-pyrido[4,3-b]indole (5c).
Yield 0.26 g (88%); white solid; mp 278–279°C; [Found: C,
79.54; H, 6.16; N, 14.23. C13H12N2 requires C, 79.56; H, 6.16; N,
14.27]; Rf (acetone/petroleum ether 2:1) 0.30; νmax (KBr) 3410,
1604, 1464, 1452, 1324, 1240, 1196, 808 cm-1; δH (CDCl3) 11.43
4.2.6. 7-Methoxy-3-methyl-5-tosyl-5H-pyrido[4,3-b]indole (4f).
Yield 1.98 g (36%); beige solid; mp 208–209°C; [Found: C,
65.63; H, 4.78; N, 7.82. C20H18N2O3S requires C, 65.55; H, 4.95;
N, 7.64%]; Rf (acetone/petroleum ether 1:1) 0.34; νmax (KBr)
1603, 1465, 1373, 1314, 1282, 1187, 1174, 1147, 1115, 1091,
1037, 990, 809 cm-1; δH (CDCl3) 8.95 (s, 1H, HAr), 7.99 (s, 1H,
3
(br.s, 1H, NH), 9.11 (s, 1H, HAr), 8.01 (d, 1H, J = 8.1 Hz, HAr),
7.30 (s, 1H, HAr), 7.25 (s, 1H, HAr), 7.04 (d, 1H, 3J = 8.1 Hz, HAr),
2.57 (s, 3H, CH3), 2.47 (s, 3H, CH3); δC (CDCl3) 152.4, 144.7,
141.2, 140.1, 135.7, 121.2, 120.0, 118.5, 117.5, 111.3, 104.6,
24.4, 21.6; m/z (EI, 70 eV) 196 (100) [M+], 168 (13), 76 (13), 75
(18), 51 (16), 43 (20).
3
4
HAr), 7.80 (d, 1H, J = 8.4 Hz, HAr), 7.78 (d, 1H, J = 2.1 Hz,
3
3
HAr), 7.72 (d, 2H, J = 8.4 Hz, HTs), 7.16 (d, 2H, J = 8.4 Hz,
3
4
HTs), 6.96 (dd, 1H, J = 8.4, J = 2.1 Hz, HAr), 3.93 (s, 3H,
OCH3), 2.72 (s, 3H, CH3), 2.30 (s, 3H, CH3); δC (CDCl3) 159.9,
155.2, 145.5, 144.4, 140.8, 139.3, 134.6, 129.9 (2C), 126.4 (2C),
120.7, 120.1, 117.2, 112.3, 108.4, 99.6, 55.8, 25.0, 21.5; m/z (EI,
70 eV) 366 (100) [M+], 211 (15), 43 (16).
4.4. Synthesis of 2-aryl-10-tosyl-1H-indolizino[7,6-b]indoles
8a-h
The mixture of pyrido[4,3-b]indole 4 (1.5 mmol), phenacyl
bromide 6 (1.7 mmol), benzene (10 mL) and toluene (7 mL) was
heated under reflux for 72 h. After cooling to room temperature,
the precipitate was filtered. The formed salt 7 was mixed with
NaHCO3 (3 mmol), water (10 mL), and 1,4-dioxane (7 mL). The
mixture was refluxed after dissolution of the solid for 5-7 min.
The reaction mixture was cooled to room temperature. The
formed precipitate was filtered and recrystallized from
CH2Cl2/hexane mixture.
4.2.7. 3-(4-Methylbenzyl)-5-tosyl-5H-pyrido[4,3-b]indole (4g).
Yield 2.04 g (32%); beige solid; mp 153–154°C; [Found: C,
73.22; H, 5.11; N, 6.73. C26H22N2O2S requires C, 73.21; H, 5.20;
N, 6.57]; Rf (acetone/petroleum ether 1:1) 0.59; νmax (KBr) 1597,
1460, 1372, 1200, 1186, 1173, 985 cm-1; δH (CDCl3) 9.08 (s, 1H,
HAr), 8.30–8.27 (m, 1H, HAr), 8.00 (s, 1H, HAr), 7.95–7.92 (m,
1H, HAr), 7.59 (d, 2H, 3J = 8.4 Hz, HT3s), 7.53–7.48 (m, 1H, HAr),
7.41–7.36 (m, 1H, HAr), 7.20 (d, 2H, J = 8.1 Hz, HAr), 7.14 (d,
2H, 3J = 8.1 Hz, HAr), 7.08 (d, 2H, 3J = 8.4 Hz, HTs), 4.29 (s, 2H,
4.4.1. 2-Phenyl-10-tosyl-10H-indolizino[7,6-b]indole (8a).

5
Yield 0.54 g (82%); yellow crystals; mp 212–213°C; [Found:
C, 74.05; H, 4.77; N, 6.32. C27H20N2O2S requires C, 74.29; H,
4.62; N, 6.42]; Rf (acetone/petroleum ether 1:2) 0.55; νmax (KBr)
1656, 1596, 1368, 1340, 1204, 1192, 1172, 1148, 1128, 1092,
800 cm-1; δH (CDCl3) 8.37 (s, 1H, HAr), 8.18–8.15 (m, 1H, HAr),
8.11 (s, 1H, HAr), 7.70–7.65 (m, 5H, 3HAr+2HTs), 7.44–7.38 (m,
3H, HAr), 7.30–7.24 (m, 3H, HAr), 7.09 (d, 2H, 3J = 8.1 Hz, HTs),
6.83 (s, 1H, HAr), 2.25 (s, 3H, CH3); δC (CDCl3) 144.9, 140.4
(2C), 135.0, 134.3, 133.4, 132.5, 131.0, 129.6 (2C), 128.8 (2C),
128.1, 126.7 (2C), 126.2 (2C), 124.8, 124.4, 119.7, 116.8, 116.5,
115.5, 108.1, 102.1, 96.3, 21.4; m/z (EI, 70 eV) 436 (44) [M+],
281 (100), 139 (16), 91 (35), 65 (32), 59 (28), 43 (63).
2.1 Hz, HAr), 7.99 (s, 1H, HAr), 7.89 (s, 1H, HAr), 7.81 (d, 1H, 3J
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= 8.1 Hz, HAr), 7.76–7.69 (m, 4H, 2HAr+2HTs), 7.44–7.38 (m, 2H,
3
4
HAr), 7.30–7.23 (m, 3H, HAr+2HTs), 7.18 (dd, 1H, J = 8.1, J =
2.1 Hz, HAr), 6.95 (s, 1H, HAr), 2.49 (s, 3H, CH3), 2.23 (s, 3H,
Me); δC (CDCl3) 145.4, 139.8, 138.3, 134.7, 133.2, 132.2, 131.8,
130.0 (2C), 129.8, 128.8 (2C), 126.6, 126.4 (2C), 125.8, 125.7
(2C), 121.9, 120.3, 117.8, 115.7, 115.1, 108.9, 101.1, 96.2, 21.7,
20.9; m/z (EI, 70 eV) 450 (12) [M+], 296 (100), 202 (37), 115
(42), 59 (71), 42 (43).
4.4.6. 2-(4-Chlorophenyl)-8-methyl-10-tosyl-10H-indolizino[7,6-
b]indole (8f).
Yield 0.53 g (73%); yellow crystals; mp 250°C (dec.);
[Found: C, 69.46; H, 4.37; N, 5.63. C28H21ClN2O2S requires C,
69.34; H, 4.36; N, 5.78]; Rf (acetone/petroleum ether 1:2) 0.62;
νmax (KBr) 1652, 1596, 1420, 1360, 1340, 1204, 1172, 1152,
1136, 1128, 1088, 828, 816, 800 cm-1; δH (CDCl3) 8.99 (s, 1H,
HAr), 8.06 (s, 1H, HAr), 7.99 (s, 1H, HAr), 7.90 (s, 1H, HAr), 7.84
(d, 1H, 3J = 7.8 Hz, HAr), 7.77 (d, 2H, 3J = 8.7 Hz, HAr), 7.72 (d,
2H, 3J = 8.4 Hz, HTs), 7.47 (d, 2H, 3J = 8.7 Hz, HAr), 7.28 (d, 2H,
4.4.2. 1-Methyl-2-phenyl-10-tosyl-10H-indolizino[7,6-b]indole
(8b).
Yield 0.52 g (77%); yellow crystals; mp 198–199°C; [Found:
C, 74.60; H, 5.07; N, 6.24. C28H22N2O2S requires C, 74.64; H,
4.92; N, 6.22.]; Rf (acetone/petroleum ether 1:2) 0.60; νmax (KBr)
1652, 1600, 1428, 1360, 1348, 1248, 1208, 1168, 1108, 1088,
944, 812 cm-1; δH (CDCl3) 9.01 (s, 1H, HAr); 8.08–8.05 (m, 1H,
HAr), 7.93 (s, 1H, HAr), 7.93–7.90 (m, 1H, HAr), 7.79 (s, 1H, HAr),
7.71 (d, 2H, 3J = 8.4 Hz, HTs), 7.59–7.55 (m, 2H, HAr3), 7.51–7.44
(m, 3H, HAr), 7.37–7.30 (m, 2H, HAr), 7.26 (d, 2H, J = 8.4 Hz,
HTs), 2.49 (s, 3H, CH3), 2.23 (s, 3H, CH3); δC (CDCl3) 145.3,
139.5 (2C), 135.2, 133.2, 130.6, 130.0 (2C), 129.9, 129.6, 128.5
(2C), 128.2 (2C), 128.1, 126.4 (2C), 124.8, 124.7, 120.5, 118.1,
115.4, 114.9, 109.4, 104.2, 99.5, 20.8, 9.7; m/z (EI, 70 eV) 450
(21) [M+], 296 (100), 140 (17), 105 (18), 91 (62), 59 (33), 43
(43).
3
3J = 8.4 Hz, HTs), 7.19 (d, 1H, J = 7.8 Hz, HAr), 6.97 (s, 1H,
HAr), 2.49 (s, 3H, CH3), 2.24 (s, 3H, CH3); δC (CDCl3) 145.6,
139.8, 138.5, 133.7, 133.2, 132.4, 131.9, 131.1, 130.1 (2C), 128.9
(2C), 128.5, 127.4 (2C), 126.5 (2C), 125.9, 121.9, 120.5, 118.0,
115.9, 115.2, 109.2, 101.2, 96.3, 21.8, 21.0; m/z (EI, 70 eV)
486/484 (7/21) [M+], 332/330 (33/100), 282 (34), 165 (16), 101
(23), 91 (43), 65 (21), 59 (52), 43 (51).
4.4.7.
2-(4-Chlorophenyl)-8-methoxy-10-tosyl-10H-
indolizino[7,6-b]indole (8g).
4.4.3. 2-(4-Chlorophenyl)-1-methyl-10-tosyl-10H-indolizino[7,6-
b]indole (8c).
Yield 0.53 g (71%); yellow solid; mp 250°C (dec.); [Found:
C, 67.22; H, 4.26; N, 5.57. C28H21ClN2O3S requires C, 67.13; H,
4.22; N, 5.59]; Rf (acetone/petroleum ether 1:2) 0.53; νmax (KBr)
1612, 1492, 1376, 1368, 1284, 1264, 1204, 1188, 1172, 1156,
1140, 1108, 1092, 832, 816, 808 cm-1; δH (CDCl3) 8.89 (s, 1H,
HAr), 8.02 (s, 1H, HAr), 7.98 (s, 1H, HAr), 7.85 (d, 1H, 3J = 8.4 Hz,
Yield 0.73 g (79%); yellow crystals; mp 250°C (dec.);
[Found: C, 69.23; H, 4.35; N, 5.89. C28H21ClN2O2S requires C,
69.34; H, 4.36; N, 5.78.]; Rf (acetone/petroleum ether 1:2) 0.63;
νmax (KBr) 1652, 1456, 1436, 1368, 1348, 1208, 1172, 1088, 948,
840, 812 cm-1; δH (CDCl3) 9.02 (s, 1H, HAr), 8.07–7.27 (m, 14H,
HAr), 3.38 (s, 3H, CH3), 2.50 (s, 3H, CH3); δC (CDCl3) 145.4,
139.5, 134.2, 133.1, 131.2, 130.7, 130.0 (2C), 129.8 (2C), 129.7,
128.6 (2C), 128.5, 128.3, 126.4 (2C), 124.8, 124.6, 120.6, 118.2,
115.6, 114.9, 109.6, 104.3, 99.5, 20.9, 9.8; m/z (EI, 70 eV)
331/329 (33/100), 196 (44), 101 (38), 91 (78), 59 (27), 43 (71).
3
3
HAr), 7.76 (d, 2H, J = 8.7 Hz, HAr), 7.72 (d, 2H, J = 8.1 Hz,
4
3
HTs), 7.59 (d, 1H, J = 2.1 Hz, HAr), 7.46 (d, 2H, J = 8.7 Hz,
3
3
4
HAr), 7.30 (d, 2H, J = 8.1 Hz, HTs), 6.97 (dd, 1H, J = 8.4, J =
2.1 Hz, HAr), 6.95 (s, 1H, HAr), 3.89 (s, 3H, OCH3), 2.25 (s, 3H,
CH3); δC (CDCl3) 159.8, 145.5, 140.8, 133.7, 133.1, 132.1, 131.9,
130.9, 130.0 (2C), 128.7 (2C), 128.2, 127.3 (2C), 126.4 (2C),
121.5, 117.1, 117.0, 115.8, 111.6, 109.0, 101.1, 100.5, 96.2, 55.6,
20.9; m/z (EI, 70 eV) 502/500 (5/15) [M+], 347/345 (33/100), 302
(20), 91 (16), 59 (18), 43 (32).
4.4.4. 8-Chloro-2-phenyl-10-tosyl-10H-indolizino[7,6-b]indole
(8d).
Yield 0.56 g (80%); yellow crystals; mp 230°C (dec.);
[Found: C, 68.70; H, 4.22; N, 5.98. C27H19ClN2O2S requires C,
68.86; H, 4.07; N, 5.95]; Rf (acetone/petroleum ether 1:2) 0.60;
νmax (KBr) 1652, 1604, 1452, 1416, 1376, 1360, 1340, 1208,
1188, 1172, 1144, 1088, 1076, 968, 904, 816 cm-1; δH (CDCl3)
9.10 (s, 1H, HAr), 8.08–7.99 (m, 4H, HAr), 7.78–7.74 (m, 4H,
HAr), 7.47–7.40 (m, 3H, HAr), 7.34–7.27 (m, 3H, HAr), 7.01 (s,
1H, HAr), 2.26 (s, 3H, CH3); δC (CDCl3) 146.0, 140.2, 134.5,
132.9, 132.4, 132.3, 131.5, 130.3 (2C), 128.9 (2C), 126.9 (2C),
126.6 (2C), 125.8 (2C), 125.1, 123.7, 122.2, 119.1, 114.7, 114.6,
109.2, 101.1, 96.4, 21.0; m/z (EI, 70 eV) 472/470 (5/15) [M+],
318/316 (33/100), 252 (14), 232 (32), 91 (28), 65 (17), 59(30), 43
(57).
Acknowledgments
We thank the Ministry of Education and Science of Russian
Federation (project 4.246.2014/K) for support of this work.
Supplementary data
1
Copies of H and 13C NMR spectra for all compounds can be
found with this article in the online version.
References and notes
1. a) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem., 2007,
14, 479-500. b) Edwankar, C.R.; Edwankar, R.V.; Namjoshi,
O.A.; Rallapappi, S.K.; Yang, J.; Cook, J.M. Curr. Opin. Drug
Discov. Devel., 2009, 12, 752-771. c) Gupta, A.; Kamble, B.;
Nanjan, M. J.; Nanjan, C. M. J. Curr. Org. Synth. 2012, 9, 377-
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J.; Brimble, M. A. Eur. J. Med. Chem., 2015, doi:
10.1016/j.ejmech.2014.11.038.
4.4.5. 8-Methyl-2-phenyl-10-tosyl-10H-indolizino[7,6-b]indole
(8e).
Yield 0.57 g (85%); yellow crystals; mp 210°C (dec.);
[Found: C, 74.83; H, 4.76; N, 6.30. C28H22N2O2S requires C,
74.64; H, 4.92; N, 6.22]; Rf (acetone/petroleum ether 1:2) 0.56;
νmax (KBr) 1656, 1598, 1367, 1341, 1224, 1203, 1172, 1128,
4
1091, 801 cm-1; δH (CDCl3) 8.96 (s, 1H, HAr), 8.01 (d, 1H, J =

6
Tetrahedron
2. a) Alekseyev R. S.; Kurkin A. V.; Yurovskaya M. A. Chem.
ACCEPTED MANUSCRIPT
Heterocycl. Comp., 2009, 45, 889-925; Khim. Geterotsikl. Soedin.,
2009, 1123-1166. b) Alekseyev R. S.; Kurkin A. V.; Yurovskaya
M. A. Chem. Heterocycl. Comp., 2010, 46, 777-821; Khim.
Geterotsikl. Soedin., 2010, 963-1018. c) Alekseyev R. S.; Kurkin
A. V.; Yurovskaya M. A. Chem. Heterocycl. Comp., 2011, 46,
1169-1198; Khim. Geterotsikl. Soedin., 2010, 1447-1484.
3. a) Van Baelen, G.; Hostyn, S.; Dhooghe, L.; Tapolcsanyi, P.;
Matyus, P.; Lemiere, G.; Dommisse, R.; Kaiser, M.; Brun, R.;
Cos, P.; Maes, L.; Hajos, G.; Riedl, Z.; Nagy, I.; Maes, B. U. W.;
Pieters, L. Bioorg. Med. Chem. 2009, 17, 7209-7217. b) Whittell,
L. R.; Batty, K. T.; Wong, R. P. M.; Bolitho, E. M.; Fox, S. A.;
Davis, T. M. E.; Murray, P. E. Bioorg. Med. Chem., 2011, 19,
7519-7525. c) Uchuskin, M. G.; Pilipenko, A. S.; Serdyuk, O. V.;
Trushkov, I. V.; Butin, A. V. Org. Biomol. Chem., 2012, 10, 7262-
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T,-C.; Shah, A.; Su, T.-L. J. Med. Chem., 2013, 56, 1544-1563. b)
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2012/112966. c) Jain, R. P.; Chakravarthy, S. WO Patent
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Jiang, M. X. US Patent 2011/0003738.
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Soedin., 2009, 774-776. b) McNamara, Y. M.; Cloonan, S. M.;
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M. J.; Williams, D. C. Bioorg. Med. Chem., 2011, 19, 1328-1348.
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3790.

ACCEPTED MANUSCRIPT
A simple route to γ-carbolines and indolizino[7,6-b]indoles
Arkady S. Pilipenkoa, Maxim G. Uchuskin*b, Igor V. Trushkovc,d, and Alexander V.
Butina,b
aKuban State Technological University, Moskovskaya st. 2, Krasnodar 350072, Russian
b
Federation; Department of Chemistry, Perm State University, Bukireva st. 15, Perm 614990, Russian
c
Federation; Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie gory 1-3,
d
Moscow 119991, Russian Federation; Laboratory of Chemical Synthesis, Federal Research Center of
Pediatric Hematology, Oncology and Immunology, ul. Samory Mashela 1, Moscow, 117997, Russian
Federation
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e
M
N
l
C
H
5b
12.5
11.5
10.5
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
мд
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRIPT
N
e
M
N
e
M
H
c
5
12.5
11.5
10.5
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
мд
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRIPT
Ph
N
N
s
T
a
8
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
мд
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCPRhIPT
N
e
M
N
s
T
8b
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
мд
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRIPT
l
C
N
e
M
N
s
T
c
8
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
мд
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRPIPh T
N
N
l
C
s
T
8d
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
мд
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRIPT
Ph
N
N
e
M
s
T
e
8
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
мд
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRIPTl
C
N
N
e
M
s
T
8f
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
мд
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
f1 (
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0

ACCEPTED MANUSCRIPT l
C
N
N
e
M
O
s
T
8
g
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
мд
)
190
180
170
160
150
140
130
120
110
100
мд
f1 (
90
)
80
70
60
50
40
30
20
10
0