Highly Fluorescent Pyrido[2,3-b]indolizine-10-Carbonitriles through Pseudo Three-Component Reactions of N-(Cyanomethyl)pyridinium Salts

Article abstract of DOI:10.1002/ejoc.201900995

An interaction of N-(cyanomethyl)pyridinium salts with vinamidinium perchlorates or enaminones proceeds as a pseudo-three component process and results in the formation of 3- or 2-substituted pyrido[2,3-b]indolizine-10-carbonitriles, respectively. Optical properties of these compounds have been evaluated, revealing effective green light emission with fluorescence quantum yields of up to 0.81.

Full text of DOI:10.1002/ejoc.201900995

A Journal of
Accepted Article
Title: Highly Fluorescent Pyrido[2,3-b]indolizine-10-Carbonitriles
through Pseudo Three-Component Reactions of N-
(Cyanomethyl)pyridinium Salts
Authors: Ekaterina A. Sokolova, Alexey A. Festa, Nikita E. Golantsov,
Natalia S. Lukonina, Ilya N. Ioffe, Alexey V. Varlamov, and
Leonid G. Voskressensky
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900995
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900995
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10.1002/ejoc.201900995
European Journal of Organic Chemistry
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Highly Fluorescent Pyrido[2,3-b]indolizine-10-Carbonitriles
through Pseudo Three-Component Reactions of N-
(Cyanomethyl)pyridinium Salts
Ekaterina A. Sokolova,[a] Alexey A. Festa,*[a] Nikita E. Golantsov,[a] Natalia S. Lukonina,[b] Ilya N. Ioffe,[b]
Alexey V. Varlamov[a] and Leonid G. Voskressensky*[a]
Abstract: An interaction of N-(cyanomethyl)pyridinium salts with
vinamidinium perchlorates or enaminones proceeds as a pseudo-
three component process and results in the formation of 3- or 2-
substituted pyrido[2,3-b]indolizine-10-carbonitriles, respectively.
Optical properties of these compounds have been evaluated,
revealing effective green light emission with fluorescence quantum
yields of up to 0.81.
to investigate its potential in the transformations with other 1,3-
difunctionalized compounds. Herein we report a pseudo three-
component reaction of N-(cyanomethyl)pyridinium 1 (2 equiv)
and vinamidinium salts or enaminones, to form hitherto unknown
3- or 2-substituted pyrido[2,3-b]indolizines 3 with prominent
optical properties (fluorescence quantum yields of up to 0.81)
(Scheme 1, eq. 2).
Introduction
Domino and multicomponent reactions allow rapid and efficient
construction of molecular complexity;[1–5] they are widely used for
the synthesis of natural products and analogues,[6,7]
pharmaceutical substances,[8–11] functional materials,[12,13]
macrocyclizations[14,15]. Employing these tools for the preparation
of fluorophores and electrophores emerged as
a useful
technique,[16–19] enabling fast creation of numerous scaffolds with
diverse structure and needful properties. Indolizines are indeed
sought-for heterocycles,[20,21] which have various applications as
biologically active compounds,[22–25] dyes,[26–28] molecular probes
and sensors [29–33]. They are also well-known fluorophores,[34]
with some recent examples of multicomponent syntheses.[35–39]
Pyrido[2,3-b]indolizine-10-carbonitrile scaffold 3 has been firstly
prepared by Proença et al through a domino cyclization of
dimerized pyridinium salts 2 with acetylacetone 4a or chalcones
(Scheme 1, eq. 1),[40,41] although their potential as fluorophores
was not recognized. This method is also limited to the synthesis
of pyridoindolizines, bearing substituents at C(2) and C(4)
positions only. Moreover, the preliminary preparation of
dimerized salt is needed. Following our interest in the chemistry
of N-(cyanomethyl)azinium quaternary salts,[42–47] we have
concurrently discovered, that this reaction might be carried out
without initial dimerization of the pyridinium salts, prompting us
Scheme 1. An outline for the synthesis of pyrido[2,3-b]indolizines.
Results and Discussion
Synthesis of pyrido[2,3-b]indolizines
Firstly, we envisioned 1,3-dialdehydes to work analogously to
acetylacetone (Table 1, entry 1), to give target pyridoindolizines,
unsubstituted at C(2) and C(4) positions. Unfortunately, these
reactions were ineffective, producing target molecule 3b in 5%
yield (Table 1, entry 2). It turned out, that the reaction of
synthetic precursors of malondialdehydes, vinamidinium salts 5,
furnished corresponding pyridoindolizine 3b with 20% yield
(Table 1, entry 3). The reaction conditions optimization allowed
to increase the yield of this pseudo three-component reaction to
30% (Table 1, entry 4). Under standard conditions, the reactants
were refluxed in absolute EtOH for 25 h in the presence of Et3N.
The use of different bases or solvents, as far as varying reaction
time or performing the reaction under MW conditions did not
improve the yield of product 3b.
[a]
Dr. E.A. Sokolova, Dr. A.A. Festa, Dr. N.E. Golantsov, Prof. A.V.
Varlamov, Prof. L.G. Voskressensky
Organic Chemistry Department
Science Faculty, Peoples’ Friendship University of Russia (RUDN
University)
Moscow, Russia, Miklukho-Maklaya st., 6
E-mail: festa_aa@pfur.ru; lvoskressensky@sci.pfu.edu.ru
Dr. N.S. Lukonina, Dr. I.N Ioffe
[b]
Department of Chemistry
Lomonosov Moscow State University
Leninskie Gory, 1-3, 119991, Moscow (Russia)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900995
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Figure 1. Scope of pseudo three-component reaction of vinamidinium and N-
(cyanomethyl)pyridinium (2 equiv) salts. Reaction conditions: Table 1, Entry 4.
In search for a better coupling partner, we put our attention to
another well-known 1,3-dielectrophiles
– enaminones. The
interaction of enaminone 6a with pyridinium salt under standard
conditions furnished target indolizine 7a with negligible 4% yield
(Table 2, Entry 1). Carrying out the reaction in ethanol-water
mixture raised the yield to 31% (Table 2, Entry 2), while
changing the alcohol to i-PrOH resulted in 44% of the target
product (Table 2, Entry 3). Screening of the bases (Table 2,
Entries 4-8) revealed sodium acetate to be the best choice,
delivering compound 7a with 51% yield (Table 2, Entry 6). The
structure of compound 7a was determined by single crystal X-
ray diffraction study (CCDC #1938369), displaying the process
to be regioselective.
Table 1. Reaction Optimization.
Entry
Substrate
Base
Conditions
Product,
Yield, %
1
2
3
4a
4b
5
K2CO3 (3 equiv)
K2CO3 (3 equiv)
K2CO3 (3 equiv)
MeOH-H2O (3:1), 3a, 91
reflux, 3 h
MeOH-H2O (3:1), 3b, 5
reflux, 3 h
MeOH, reflux, 18
h
3b, 20
4[a]
5
5
5
5
Et3N
EtOH, reflux, 25 h
EtOH, reflux, 25 h
3b, 30
3b, 21
3b, 28
NH4OAc
NH4OAc
6[b]
EtOH, MW, 150
oC, 30 min
[a] Reaction conditions: N-(cyanomethyl)pyridinium chloride 1 (1.19 mmol),
vinamidinium perchlorate 5 (0.40 mmol), NEt3 (1.98 mmol), EtOH (9 mL).
[b] Reactions were run in microwave reactor Monowave 300 (Anton Paar
GmbH) in a closed vial, and the reaction temperature was monitored by an IR
sensor.
Despite high reactivity of vinamidinium perchlorates, and
consequent formation of complex mixtures, the reaction scope
investigation showed the possibility to employ vinamidinium salts
with various aryl substituents. Thus, phenyl, p-chlorophenyl, p-
fluorophenyl pyridoindolizines were obtained with poor to
moderate yields (Figure 1). Besides N-(cyanomethyl)pyridinium
chloride, 4-substituted pyridinium salts were tested. The reaction
worked for 4-methyl, ethyl, and phenyl-substituted pyridinium
salts. The structure of compound 3l was unambiguously
determined by X-ray diffraction study (CCDC #1938370). The
use of 3-substituted pyridinium salts resulted in the formation of
isomeric mixtures and were not listed in the scheme.
Table 2. Enaminone 6a in a reaction with pyridinium salt[b]
Entry
Base
Solvent
Yield, %
1
Et3N
EtOH
4
2
Et3N
EtOH-H2O (3:1)
i-PrOH-H2O (3:1)
i-PrOH-H2O (3:1)
i-PrOH-H2O (3:1)
i-PrOH-H2O (3:1)
i-PrOH-H2O (3:1)
i-PrOH-H2O (3:1)
31
44
36
43
51
5
3
Et3N
4
DIPEA
NH4OAc
NaOAc
K2CO3
Cs2CO3
5
6[a]
7
8
21
[a] Reaction conditions: N-(cyanomethyl)pyridinium chloride 1 (1.19 mmol),
vinamidinium perchlorate 5 (0.40 mmol), NEt3 (1.98 mmol), EtOH (9 mL).
[b] Reactions were run in microwave reactor Monowave 300 (Anton Paar
GmbH) in a closed vial, and the reaction temperature was monitored by an IR
sensor.
The selected conditions were used to perform the scope studies.
Enaminone 6a reacted with unsubstituted, 4-ethyl-, 4-phenyl-N-
(cyanomethyl)pyridinium chlorides to produce target molecules
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10.1002/ejoc.201900995
European Journal of Organic Chemistry
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7b-d with moderate yields (Figure 2). Phenyl substituent could
be successfully installed on a pyridoindolizine moiety with the
help of the corresponding enaminone, producing compounds 7e-
h. Aliphatic enaminones could also be used to generate 2-
methyl and 2-ethyl substituted pyridoindolizines 7i-l, and 7m, n,
respectively. We were also happy to find that pyridine rings
could be also incorporated in pyridoindolizine scaffolds 7o-s with
moderate yields.
Scheme 2. Proposed mechanism for the formation of pyridoindolizines 3 and
7.
Optical
properties
of
pyrido[2,3-b]indolizines.
The
fluorophoric indolizine system offers versatile possibilities for
construction of various derivatives with intense emission in the
desired ranges of the visible spectrum.[48] The above
synthesized compounds exhibit a visibly strong green-light
fluorescence with quantum yields of 0.4–0.8 determined with
respect to coumarin 153 in ethanol as the reference (quantum
yield of 0.546[49]). In Figure 3, we present UV/Vis absorption and
emission spectra for a representative selection of pyrido[2,3-
Figure 2. Reaction scope for enaminones and pyridinium salts. Reaction
conditions: Table 2, Entry 6.
According to the literature,[40,41] the following pathway for the
formation of pyrido[2,3-b]indolizines can be suggested. At first,
the base-promoted dimerization of pyridinium salt 1 takes place.
The dimerized salt 2 undergoes a cyclization to an intermediate
A, which can aromatize through the elimination of pyridinium
hydrochloride. The formed aminoindolizine 8 can condense with
1,3-dielectophiles, forming pyridoindolizines 3 or 7 (Scheme 2).
This key intermediate 8 might be isolated from the reaction
mixture and transformed into corresponding product in a two-
component manner, providing evidence for the suggested
reaction pathway. It needs to be noted that four new bonds and
two rings are formed in one synthetic operation, supporting high
effectiveness of the discovered process.
b]indolizines. The parent compound 7m shows
a strong
absorption band with partial vibrational resolution in the region of
350–470 nm. Extension of the π-system of 7m with various
phenyl substituents leads to a red shift of the absorption
spectrum. The effect is more pronounced when there is a phenyl
moiety at the position 8 of the core pyridoindolizine (3i and 7n)
while in the 2- and 3-sustituted compounds 3b and 7g it is
weaker. The lowest excitation energy is observed in the 3,8-
substituted 3i where the absorption threshold emerges at 2.4 eV.
(Figure 3 and Table 3).
Figure 3. UV/Vis absorption (left) and fluorescence (right, excitation
wavelength 400 nm) spectra for the selected pyrido[2,3-b]indolizines in
dichloromethane.
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10.1002/ejoc.201900995
European Journal of Organic Chemistry
FULL PAPER
can induce some 2-3-fold increase in the oscillator strength
(compare, e.g., 7m, 7n, and 3i).
Fluorescence of eleven compounds was measured mostly in
ethanol with the excitation at 400 nm (Table 3). For five selected
compounds (3b, 3i, 7g, 7m and 7n), the absorption and
emission spectra were also measured in dichloromethane and
toluene. The partly resolved vibrational progressions allow for
certain liberty in defining the Stokes shift. Measuring it between
the first vibrational peaks yields rather small values of 600–1200
cm–1 while the distance between the center-of-mass of the
absorption and emission bands reaches several thousands of
cm–1. Both in the ground and the excited states, the compounds
are polar, the dipole moment of ca. 8-9 D in S0 and ca. 6-7 D S1
being oriented more or less parallel to the nitrile moiety. As a
result, the emission band shifts to the red in the less polar
solvents together with a drop in the fluorescence quantum yield.
Introduction of a fluorine atom into a peripheral phenyl ring (3j,
3k) has no effect on the emission properties while the chlorine
substituents can cause significant fluorescence quenching. Thus,
compound 3g demonstrates the lowest quantum yield in ethanol
of 0.46.
TDDFT-PBE0 optimization of the S1 state shows good
agreement with experimental emission wavelength (see Table 3).
The stationary point of S1 reveals, together with anticipated
redistribution of the bond lengths in the conjugated system,
certain decrease in the dihedral angles between the
pyridoindolizine and its phenyl substituents. The computational
estimates of the 0-0 transition energy taken as the difference
between the stationary points of the S0 and S1 agrees quite well
with the experimental estimates obtained as the crossing point
of the normalized absorption and emission spectra.
Figure 4. Frontier molecular orbitals in the compounds 3b, 7m and 7l show
relatively limited effect of the phenyl substituents.
To rationalize the observed spectra, we have performed
geometry optimization of the compounds synthesized at the
PBE0/Def2-TZVPP level and calculated the vertical excitation
spectra using the TDDFT-PBE0/Def2-TZVPP approach. The
calculations were carried out with the use of the Firefly v. 8.2
software[50] which is partly based on the GAMESS(US)
package.[51] It was found that the observed absorption
corresponds to the S1 state dominated by the HOMO→LUMO
excitation, and the calculated vertical absorption wavelengths
are in a reasonable agreement with the measured spectra. The
structures of the HOMO and the LUMO in the selected
compounds are shown on Fig. 4. One can see that the frontier
orbitals only moderately vary upon addition of the phenyl
substituents. Yet, as can be seen from Table 3, the substituents
Table 3. Experimental absorption (wavelength and absorption edge) and fluorescence (emission wavelength, quantum yield, Stokes shift) data together with the
respective TD-DFT estimates for a series of pyrido[2,3-b]indolizines.
opt
Compound
solvent
abs
nm
,
em
nm
,
f
Stokes
shift,
cm–1
Eg
,
TDDFT
absorption
wavelength,
nm
f01
(TDDFT)
TDDFT
emission
wavelength,
nm
f01
(TDDFT)
0-0
TDDFT
0-0
transition
energy,
cm–1
eV
transition
energy
exp., cm–1
3b
EtOH
443
447
454
438
440
461
467
473
443
438
459
460
465
462
463
487
490
471
459
462
0.66
0.69
0.47
0.81
0.46
0.74
0.74
0.52
0.65
0.68
790
630
2.6
405
0.09
501
0.07
22200
22100
21800
22200
22100
21100
20900
21200
22200
22200
22300
DCM
Toluene
EtOH
EtOH
EtOH
DCM
520
3c
3g
3i
1190
1130
1160
1010
0
2.6
2.6
2.4
399
401
429
0.11
0.12
0.26
494
495
528
0.08
0.08
0.21
22600
22600
21100
Toluene
EtOH
EtOH
3j
790
2.6
2.6
406
400
0.09
0.11
502
495
0.07
0.08
22300
22600
3k
1190
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10.1002/ejoc.201900995
European Journal of Organic Chemistry
FULL PAPER
7f
EtOH
431
431
435
442
446
422
426
435
447
450
458
456
456
460
466
471
448
450
457
472
475
482
0.74
0.64
0.66
0.48
0.69
0.58
0.64
0.44
0.75
0.76
0.56
1270
1270
1250
1170
1190
1380
1250
1110
1190
1170
1090
2.6
2.6
394
392
0.08
0.09
508
483
0.05
0.06
22500
22500
22300
22000
21800
23000
22800
22400
21800
21600
21300
22500
23100
7g
EtOH
DCM
Toluene
EtOH
7l
2.6
2.7
410
388
0.18
0.08
518
488
0.14
0.05
21900
23100
7m
EtOH
DCM
Toluene
EtOH
7n
2.6
415
0.17
520
0.14
21700
DCM
Toluene
.
3-Phenylpyrido[2,3-b]indolizine-10-carbonitrile (3b). Yellow
solid; 32 mg; 30% yield, m.p. 208-209 (dec); 1H NMR (400 MHz,
DMSO-d6): δ = 7.16 (t, J = 6.8 Hz, 1H; H-7); 7.44 (t, J = 7.4 Hz,
1H; Ph-H); 7.55 (t, J = 7.4 Hz, 2H; Ph-H); 7.62-7.64 (m, 1H; H-
8); 7.86-7.87 (m, 3H; H-9, Ph-H); 9.10 (d, J = 1.7 Hz,1H; H-4);
9.15 (d, J = 1.7 Hz, 1H; H-2); 9.30 (d, J = 6.8 Hz,1H; H-6); 13C
NMR (100 MHz, DMSO-d6): δ = 73.5; 112.5; 115.4; 117.1;
118.4; 123.4; 127.1 (3C); 127.7; 128.4; 129.2 (2C); 130.4; 137.5;
143.0; 144.2; 147.6; IR (KBr): ν = 2205 cm-1 (C≡N); ESI MS:
m/z 270 [M+H]+; elemental analysis calcd (%) for C18H11N3: C
80.28; H 4.12; N 15.60; found: C 80.22; H 4.07; N 15.73.
Conclusions
We have revealed that the interaction of readily available
starting materials: N-(cyanomethyl)pyridinium salts and
vinamidinium perchlorates or enaminones, leads to the
formation of 3-substituted or 2-substituted pyrido[2,3-
b]indolizine-10-carbonitriles, respectively. The synthesized
indolizines are prominent fluorophores with emission ranging
from blue to green regions and f from 0.46 to 0.81. We believe
these compounds to find interesting applications in biology in the
nearest future, as well as in the fabrication of OLED devices.
Representative procedure for the synthesis of 2-substituted
pyrido[2,3-b]indolizine-10-carbonitriles (7a-f, 7p-s)
Experimental Section
A mixture of pyridinium salt 1 (1.19 mmol), enaminone 6 (0.40
mmol), and sodium acetate (1.98 mmol) in isopropyl alcohol (3
ml) and water (1 mL) was heated to 150 °C for 30 min in a
closed vial in the microwave reactor Monowave 300. After
cooling to rt, the precipitate was filtered-off and washed with
isopropyl alcohol, water (2 times) and isopropyl alcohol again;
dried on air.
General details can be found in the online Supporting Information. This
document also contains detailed procedures and analytical data for novel
compounds as well as copies of NMR spectra.
Representative procedure for the synthesis of 3-substituted
pyrido[2,3-b]indolizine-10-carbonitriles (3b, 3j, 3l)
To a stirred solution of a pyridinium salt 1 (1.19 mmol) and
vinamidinium perchlorate 5 (0.40 mmol) in dry ethanol (9 ml),
NEt3 (1.98 mmol) was added in five portions over 2 hours at
reflux. The reaction mixture was heated at reflux for 25-30 hours.
The reaction mixture was diluted with water (75 ml) and
extracted with DCM. The combined organic layer was dried over
Na2SO4. After filtration, the solvent was then evaporated under
reduced pressure. Products were isolated by column
chromatography on neutral aluminium oxide, eluent ethyl
acetate-hexane 1:5.
2-(2-Hydroxyphenyl)-8-methylpyrido[2,3-b]indolizine-10-
carbonitrile (7a). Brown solid; 61 mg; 51% yield, m.p. > 300°С
1
(dec); H NMR (400 MHz, DMSO-d6): δ = 2.44 (s, 3H; C8-CH3);
6.94-6.97 (m, 2H; Ph-H); 7.00 (d, J = 6.6 Hz, 1H; H-7); 7.33 (t, J
= 7.5 Hz, 1H; Ph-H); 7.60 (s, 1H; H-9); 8.11 (d, J = 7.5 Hz, 1H;
Ph-H); 8.15 (d, J = 8.8 Hz, 1H; H-4); 8.85 (d, J = 8.8 Hz, 1H; H-
3); 9.10 (d, J = 6.6 Hz, 1H; H-6); 14.04 (s, 1H; OH); 13C NMR
(100 MHz, DMSO-d6): δ = 21.3; 71.3; 112.8; 115.0; 115.1;
115.6; 118.0; 119.0; 119.5; 122.0; 122.6; 127.5; 127.8; 131.4;
142.4; 142.6; 143.3; 155.8; 159.0; IR (KBr): ν = 2203 cm-1
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10.1002/ejoc.201900995
European Journal of Organic Chemistry
FULL PAPER
(C≡N); ESI MS: m/z 300 [M+H]+; elemental analysis calcd (%)
for C19H13N3O: C 76.24; H 4.38; N 14.04; found: C 76.19; H
4.32; N 14.17.
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The publication has been prepared with the support of the
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Keywords: indolizine • multicomponent reaction • fluorescence •
pyridinium salt • heterocycles
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European Journal of Organic Chemistry
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10.1002/ejoc.201900995
European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Ekaterina A. Sokolova, Alexey A. Festa,
Nikita E. Golantsov, Natalia S. Lukonina,
Ilya N. Ioffe, Alexey V. Varlamov and
Leonid G. Voskressensky*
Page No. – Page No.
Highly Fluorescent Pyrido[2,3-
Text for Table of Contents
b]indolizine-10-Carbonitriles through
Pseudo Three-Component Reactions
of N-(Cyanomethyl)pyridinium Salts
TOC text: A novel class of effective fluorophores, incorporating pyrido[2,3-b]indolizine scaffold, has
been discovered. The synthesis of pyridoindolizines involves one synthetic step from readily available
starting materials.
KEY topic: Multicomponent reactions
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