Synthesis of δ-Carbolines and the Alkaloid Quindoline through a Molybdenum-Catalyzed Cadogan Cyclization and their Photoluminescent Properties

Article abstract of DOI:10.1055/s-0037-1612416

Cadogan reductive cyclization of substituted 2-aryl-3-nitropyridines to give δ-carbolines was performed under MoO ₂ Cl ₂ (DMF) ₂ catalysis with triphenylphosphine as a ligand. A new approach for the synthesis of the alkalo

Full text of DOI:10.1055/s-0037-1612416

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© Georg Thieme Verlag Stuttgart · New York
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en
V. Y. Shuvalov et al.
Letter
Synlett
Synthesis of -Carbolines and the Alkaloid Quindoline through a
Molybdenum-Catalyzed Cadogan Cyclization and their Photolumi-
nescent Properties
Vladislav Yu. Shuvalova,b
CO2Et
NO2
Anna S. Ruppa
CO2Et
Anna K. Kuratovaa
NH
R1
N
Alexander S. Fisyuka,b
Andrey A. Nefedovc
Galina P. Sagitullina*a
R1
R2
N
R2
R1 = Me, c-Pr; R2 = H, OMe, Me
6 examples
55–71% yield
PPh3 (2.4 equiv),
MoO2Cl2(DMF)2 (5 mol%)
a Department of Organic Chemistry, F. M. Dostoevsky Omsk
State University, 55a Mira Ave., 644077 Omsk, Russian
Federation
NO2
p-cymene, Δ, 3–6 h
H
N
(CH2)n
(CH2)n
sagitullina@chemomsu.ru
N
b Laboratory of New Organic Materials, Omsk State Technical
University, 11 Mira Ave., 644050 Omsk, Russian Federation
c N. N. Vorozhtsov Institute of Organic Chemistry, Siberian
Branch of the Russian Academy of Sciences, 9 Lavrentiev
Ave., 630090 Novosibirsk, Russian Federation
N
R
n = 4, 6, 7, 10
R
16 examples
40–68% yield
R = H, Me, OMe, Cl
H
NO2
N
2 steps
N
N
quindoline
Cryptolepis
sanguinolenta
Received: 02.02.2019
Accepted after revision: 03.03.2019
Published online: 10.04.2019
Malaria is one of the most dangerous infectious diseases
and is the main cause of death (mostly in children under
five years old) in developing countries, where more than a
million people die every year because of it. The appearance
in the 20th century in Thailand and Colombia of a new type
of chloroquine-resistant malarial plasmodium, Plasmodium
falciparum, caused a surge in malarial disease. This resulted
in an emergency situation, as no vaccine or antimalarial
drug active against this P. falciparum strain, the most deadly
malaria parasite, was available and, consequently, efforts
were made to produce them (Figure 1).1 Several scientific
research groups were engaged in antimalarial drug design,
but the only success was achieved by the group of Tu Youy-
ou, who screened 1000 species of wild plants and extracted
artemisinin from Artemisia annua.2 As a result, Tu Youyou,
the program manager for artemisinin, was awarded a half
share in the Nobel Prize in Physiology or Medicine for
2015.3,4
DOI: 10.1055/s-0037-1612416; Art ID: st-2019-u0064-l
Abstract Cadogan reductive cyclization of substituted 2-aryl-3-nitro-
pyridines to give -carbolines was performed under MoO2Cl2(DMF)2 ca-
talysis with triphenylphosphine as a ligand. A new approach for the syn-
thesis of the alkaloid quindoline based on a Mo(VI)-catalyzed Cadogan
reductive cyclization of 2-phenyl-3-nitro-5,6,7,8-tetrahydroquinoline
followed by aromatization of the resulting 2,3,4,10-tetrahydro-1H-in-
dolo[3,2-b]quinoline is proposed. Various о-nitroarylpyridines, obtained
by reacting acylpyruvates and cyclic hydroxymethylene ketones with ni-
troacetophenone enamines, were used as starting compounds for the
preparation of -carbolines. The synthesized -carbolines were found to
act as phosphors; their photophysical properties were studied and a
structure–property relationship was revealed.
Key words quindoline, carbolines, Cadogan cyclization, nitro com-
pounds, acylpyruvates, cyclic hydroxymethylene ketones
Me
H
O
O
Me
N
N
HN
O
H
N
O
Me
Me
Cl
N
O
Cryptolepis
sanguinolenta
cryptolepine
artemisinin
chloroquine
Figure 1 Antimalarial drugs
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
V. Y. Shuvalov et al.
Letter
Synlett
The development of new antimalarial drugs is an urgent
task, because artemisinin-resistant strains of P. falciparum
have already been found in Cambodia, Myanmar, Thailand,
Vietnam, and Madagascar.5 Mutations in one of the genes of
the malaria plasmodium are the cause of drug resistance.6
Quindoline and cryptolepine are major alkaloids, and
isocryptolepine is a minor alkaloid of the Cryptolepis san-
guinolenta, a plant that grows in West and Central Africa.
The root-bark extract of this plant is used in traditional
medicine to treat various types of fever, including tubercu-
losis and malaria.7 Quindoline is a synthetic precursor of
cryptolepine, which is an anhydro base of a quaternary
quindolinium salt in structure.
Most -carbolines have been synthesized from substi-
tuted pyridines and indoles.12a–с Crucially, new methods for
the synthesis of -carbolines by the Pd-catalyzed reaction
of 2-iodoanilines with N-tosylenynamines include a Larock
indolization stage, a Ts group elimination, electrocycliza-
tion, and oxidative aromatization; the compounds can also
be prepared by Ni-catalyzed or metal-free [2+2+2] cycload-
dition
reactions
of
N-(2-cyanophenyl)-N-(phenyl-
ethynyl)methanesulfonamide with internal alkynes.12d–e
Here, we report, for the first time, a synthesis of -car-
bolines through a MoO2Cl2(DMF)2-catalyzed Cadogan reac-
tion, together with a new method for obtaining the alkaloid
quindoline. In addition, the photophysical properties of the
resulting -carbolines were studied. The dioxomolybde-
num(VI)-catalyzed Cadogan reaction has recently been suc-
cessfully used for the synthesis of indoles and carbazoles.13
First, we optimized the conditions for the reductive cy-
clization of 2-aryl-3-nitropyridines 3 to -carbolines 4.
Heating pyridine 3a in the presence of ethane-1,2-diyl-
bis(diphenylphosphine) (DPPE) under solvent-free condi-
tion afforded -carboline 4a in trace amounts. The optimal
conditions for the synthesis of 4a involve the use of PPh3 as
a reducing agent and MoO2Cl2(DMF)2 as a catalyst (Table 1).
3-Nitropyridines 3a–f were obtained by cyclocondensa-
tion of acylpyruvate 1a (R2 = Me) or 1b (R2 = cyclopropyl)
with nitroenamines 2a–c (R1 = H, OMe, Me). A one-pot syn-
thesis of pyridines 3 was performed in acetic acid at 35 °C.
-Carbolines 4a–f were synthesized by reductive Cadogan
cyclization under Mo(VI) catalysis with triphenylphosphine
as a reducing agent [Scheme 1; see Supporting Information
(SI) for details].
Over the past 40 years, many structural analogues of
natural quindoline and cryptolepine have been synthe-
sized; the biological activities of these analogues is often
higher than that of the natural alkaloids.8
-Carbolines (5H-indolo[3,2-b]pyridines) exhibit anti-
malarial activity and extremely high antifungal and anti-
bacterial activity, as well as inhibitory activity against the
kinesin protein (KSP) involved into the proliferation of can-
cer cells, cytotoxicity to HeLa cells, and affinity for adenos-
ine A3 receptors.9 -Carbolines and benzo--carbolines
show fluorescent properties, which permits the use of fluo-
rescence spectroscopy and microscopy to quantify their an-
timalarial activity and to determine their subcellular local-
ization in DNA-containing parasite structures.10
In two reviews, 15 methods for the synthesis of quindo-
line have been reported.11 The most effective was the syn-
thesis of quindoline through the reduction of 1,3-bis(2-ni-
trophenyl)propan-2-one to a diamino ketone that under-
goes spontaneous cyclization to form 2-(2-aminobenzyl)-
1H-indole, which undergoes oxidative cyclization to form
quindoline.11 The reviews cites no examples of the synthe-
sis of quindoline from 2-arylnitropyridines.
Cyclocondensation of cyclic hydroxymethylene ketones
5 with nitroacetophenone enamines 2a–d resulted in the
formation of 3-nitropyridines 6a–p. Subsequent Mo(VI)-
catalyzed Cadogan reaction afforded a series of -carbolines
7a–p with a fused pyridine ring (Scheme 2, see SI).
Table 1 Optimization of the Cadogan Reactiona
CO2Et
NO2
CO2Et
Reductive cyclization
NH
Me
N
Me
N
3a
4a
Entry
Reductant
DPPEd
Solvent
–
Temp (°C)
Сatalystb
Time (h)
Yieldc (%)
1
2
3
4
150
177
110
177
–
5
10
24
3
traces
34
e
PPh3
p-cymene
toluene
–
e
PPh3
MoO2Cl2(DMF)2
MoO2Cl2(DMF)2
15
e
PPh3
p-cymene
71
a All reactions were conducted with 1 mmol of 3a under N2.
b 5 mol%.
с Isolated yield after column chromatography.
d 1.1 mmol.
e 2.4 mmol.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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V. Y. Shuvalov et al.
Letter
Synlett
CO2Et
O
CO2Et
N
CO2Et
PPh3 (2.4 equiv),
MoO2Cl2(DMF)2 (5 mol%)
NO2
NO2
NH
AcOH, 35 °C
+
R2
R2
p-cymene, 177 °C, 3 h
O
72 h, 54–72%
R1
H2N
R2
N
R1
1a–b
2a–c
4a–f
3a–f
R1
CO2Et
NH
CO2Et
NH
CO2Et
NH
CO2Et
NH
CO2Et
NH
CO2Et
NH
Me
Me
Me
N
N
N
N
N
N
OMe
OMe
Me
Me
4a, 71%
4b, 64%
4c, 58%
4d, 68%
4e, 60%
4f, 55%
Scheme 1 Mo-catalyzed Cadogan cyclization of 3-nitropyridines 3 to 4-ethoxycarbonyl--carbolines 4
The final stage of the synthesis of the alkaloid quindo-
line involved aromatization of the cyclohexane ring of the
-carboline 7a (Scheme 3).
(see Table S1 in the SI). In the case of compounds 4b,e,
which have a methoxy group on the benzene ring, the last
two bands overlapped to form a strong broad band at 370–
377 nm, while the attenuation coefficient increased to
13.6 × 103 to 14.4 × 103 L × mol−1 × cm−1 (Table S1 in the SI).
Compounds 4a–f are phosphors, emitting light in the 450–
460 nm region (Figure 2); however, they are characterized
by low quantum yields (0.05–0.18).
Absorption spectra of 4-ethoxycarbonyl--carbolines
4a–f in ethanol solution showed four bands with max
=
250–264, 277–280, 331–340 (4a,c,d,f), and 378–388 nm
(4a,c,d,f). The molar attenuation coefficients of these com-
pounds were in the range 6.2 × 103 to 9.3 × 103 L × mol−1
×
cm−1
OH
H
NO2
AcOH
NO2
MoO2Cl2(DMF)2 (5 mol%)
N
(CH2)n
(CH2)n
(CH2)n
85 °C
PPh3 (2.4 equiv),
p-cymene, 177 °C, 6 h
H2N
2a–d
N
N
R
O
6a–p
7a–p
5
R
R
n = 4, 6, 9, 10
H
N
H
N
H
H
N
N
N
N
N
N
7c, 53%
7d, 57%
7b, 43%
7a, 52%
H
N
H
N
H
H
N
N
N
N
Me
N
N
Me
OMe
Cl
Me
OMe
Cl
Me
OMe
Cl
7g, 60%
7h, 44%
7e, 53%
7f, 42%
H
N
H
N
H
N
H
N
N
N
OMe
N
N
7k, 64%
7l, 53%
7i, 40%
7j, 68%
H
N
H
N
H
N
H
N
N
N
Cl
N
N
7m, 41%
7p, 56%
7o, 60%
7n, 40%
Scheme 2 Dioxomolybdenum-catalyzed reductive cyclization of 3-nitro-o-pyridinophanes to form -carbolines with a lipophilic bridge
N
H
H
N
N
Pd/C
1. MeHal
2. :B
N
Ph2O, 5 h, Δ
N
N
Me
7a
quindoline
cryptolepine
Scheme 3 Synthesis of alkaloid quindoline by aromatization of 7a; :B = Base (OH-).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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V. Y. Shuvalov et al.
Letter
Synlett
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612416.
S
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References and Notes
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Figure 2 Normalized absorption and fluorescence spectra of dilute
solutions of compounds 4a–f in EtOH
The absorption spectra of -carbolines 7a–p, recorded
under the same conditions, showed two main bands at
261–264 and 311–316 nm. The band in the long-wave-
length region of the spectrum had a shoulder, which was
most pronounced for compounds 7a–d, which contain no
substituents on the benzene core. In the case of the me-
thoxy-substituted derivatives 7i–l, the shoulder overlapped
with the main band to give a broad signal with a maximum
at 316–330 nm. The molar attenuation coefficients for
compounds 7a–p were in the range 14.6 × 103 to 20.3 × 103
L × mol−1 × cm−1 (Table S2 in the SI).
A comparison of the absorption spectra of tetra-, hexa-,
nona-, and decamethylene-substituted -carbolines
showed that the positions of the absorption maxima for
compounds 7a–d (261, 311–312 nm), 7e–h (262–264, 315–
323 nm), 7i–l (264, 323–330 nm), and 7m–p (263–264,
314–316 nm) do not depend on the size of the methylene
chain. Upon excitation with UV light, ethanolic solutions of
compounds 7a–p produced a strong photoluminescence,
emitting blue light (368–389 nm) with a quantum yield of
0.11–0.54. Introduction of the methoxy group to the C(7)
atom of the benzene ring of compounds 7i–l led to an in-
crease in the quantum yield (0.45–0.54) and to a hyp-
sochromic shift (maxem = 368–372 nm) in the luminescence
spectrum. For the chlorine-substituted carbolines 7m–p, a
hypsochromic shift was also observed (maxem = 369–373
nm); however, the quantum yield decreased (0.11–0.12).
In summary, we have developed, for the first time, a cat-
alytic two-step synthesis of substituted -carbolines14 and
a three-step synthesis of quindoline alkaloid from available
starting compounds. We also studied the photophysical
properties of the products and we revealed a structure–
property relationship.
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Funding Information
This work was financially supported by the Russian Foundation for
Basic Research and Ministry of Education of Omsk Region (grant 16-
43-550144/16 r_a) and the Ministry of Education and Science of the
Russian Federation (the project 4.1657.2017/4.6).
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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V. Y. Shuvalov et al.
Letter
Synlett
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(14) Ethyl 5H-Pyrido[3,2-b]indole-4-carboxylates 4a–j; General
Procedure
A solution of the appropriate ethyl 3-nitroisonicotinate 3a–f (1
mmol), PPh3 (0.629 g, 2.4 mmol), and MoO2Cl2(DMF)2 (0.017 g,
0.05 mmol) in p-cymene (10 mL) was refluxed with constant
stirring under N2. The solvent was removed under reduced pres-
sure, and the residue was purified by column chromatography
[silica gel, toluene then PE–EtOAc (1:1)], followed by crystalliza-
tion from i-PrOH.
Ethyl 2-Methyl-5H-pyrido[3,2-b]indole-4-carboxylate (4a)
Light-yellow crystals; yield: 180 mg (71%); mp 130–131 °C (i-
PrOH). IR (KBr): 3391, 2985, 1687, 1475, 1240, 1212, 1097, 730
cm–1. 1H NMR (400 MHz, CDCl3):  = 1.48 (t, J = 7.1 Hz, 3 H), 2.80
(s, 3 H), 4.50 (q, J = 7.1 Hz, 2 H), 7.30 (ddd, J = 7.9, 6.8, 1.4 Hz, 1
H), 7.45–7.55 (m, 2 H), 7.69 (s, 1 H), 8.40 (d, J = 7.9 Hz, 1 H), 9.50
(br s, 1 H). 13C NMR (100 MHz, CDCl3):  = 14.3, 24.1, 61.7, 111.4,
118.4, 118.6, 120.6, 121.2, 121.5, 128.4, 130.5, 141.0, 144.0,
149.9, 166.4. Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N,
11.02. Found: C, 70.89; H, 5.57; N, 10.96.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E