Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones

Article abstract of DOI:10.3390/molecules25184059

Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn, the microwave-assisted interaction of N-(cyanomethyl)-2-alkylpyridinium salts with enaminones unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions, instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as base and employs benign solvents. The optical properties of the resulting pyrido[2,3-b]indolizines were studied, showing green light emission with high fluorescence quantum yields.

Full text of DOI:10.3390/molecules25184059

molecules
Article
Microwave-Assisted Synthesis of Fluorescent
Pyrido[2,3-b]indolizines from Alkylpyridinium Salts
and Enaminones
1
1
1
, Victor B. Rybakov 2,
Ekaterina A. Sokolova , Alexey A. Festa , Karthikeyan Subramani
Alexey V. Varlamov , Leonid G. Voskressensky and Erik V. Van der Eycken 1,3,
1
1
*
1
Organic Chemistry Department, Science Faculty, RUDN University, Miklukho-Maklaya st., 6,
17198 Moscow, Russia; soko-katya@mail.ru (E.A.S.); festa_aa@pfur.ru (A.A.F.);
1
subramanikarthikeya91@gmail.com (K.S.); avarlamov@sci.pfu.edu.ru (A.V.V.);
lvoskressensky@sci.pfu.edu.ru (L.G.V.)
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1–3,
2
3
1
19991 Moscow, Russia; rybakov20021@yandex.ru
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry,
University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
Correspondence: erik.vandereycken@kuleuven.be
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Alessandro Ponti and Giorgio Molteni
Received: 1 August 2020; Accepted: 3 September 2020; Published: 5 September 2020
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn,
the microwave-assisted interaction of N-(cyanomethyl)-2-alkylpyridinium salts with enaminones
unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions,
instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as
base and employs benign solvents. The optical properties of the resulting pyrido[2,3-b]indolizines
were studied, showing green light emission with high fluorescence quantum yields.
Keywords: pyridinium ylide; indolizine; domino reaction; fluorescence
1
. Introduction
Indolizines, and in particular the annulated ones, are frequently found to exhibit useful
biological [1–6] and optical properties [
of pyridinium ylides, which can undergo cycloaddition reactions with alkenes [15
In some cases, interaction of ylides with alkenes or alkynes leads to a different outcome [24
7
–
14]. The synthesis of indolizines usually relies on the reactivity
18] or alkynes [19 23].
26]. Another
–
–
–
approach towards the indolizine scaffold is based on intramolecular cyclization of 2-alkylpyridinium
ylides. For instance, Opatz et al. used 2-alkyl-1-(cyanomethyl)pyridinium salts to prepare
aminoindolizines [27]. Following our interest in the chemistry of cyanomethylpyridinium salts [28–30],
we recently showed that the interaction of N-(cyanomethyl)pyridinium chlorides with enaminones
under basic conditions proceeds as a pseudo-three-component reaction, resulting in the formation of
pyridoindolizine-10-carbonitriles [31].
In this work we discovered that the reactions of 2-alkyl-N-(cyanomethyl)pyridinium salts
enaminones proceed unexpectedly as a two-component domino sequence of cycloisomerization and
cyclocondensation reactions, while cycloaddition processes were not observed (Scheme 1).
1 with
2
Molecules 2020, 25, 4059; doi:10.3390/molecules25184059
www.mdpi.com/journal/molecules

Molecules 2020, 25, 4059
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Scheme 1. General representation of the current work.
2
. Results
Based on the previously investigated reaction [31], we started optimization of the conditions with
the use of sodium acetate as base and an iso-propanol/water mixture as solvent (Table 1, entries 1–6).
Varying the ratio of the starting materials and the base, the target compound 3a was obtained with 50%
yield (Table 1, entry 5). The use of other bases such as Et N, DIPEA, or NH OAc did not improve the
3
4
yield (Table 1, entries 7–9). Inorganic bases did not ameliorate the process either (Table 1, entries 10
and 11). The variation of reaction time or temperature commonly led to diminished yields (Table 1,
entries 12–14).
Table 1. Reaction conditions optimization.
Entry a
Base
1a: 2a: Base
3: 1: 5
Yield, % b
1
2
3
4
5
6
7
8
9
34
40
46
12
50
44
31
25
34
5
3: 1: 1
3: 1: 0.5
NaOAc
3: 1: 0.1
1.5: 1: 0.5
1: 1: 0.5
Et N
3
1.5: 1: 0.5
1.5: 1: 0.5
1.5: 1: 0.5
1.5: 1: 0.5
1.5: 1: 0.5
1.5: 1: 0.5
1.5: 1: 0.5
1.5: 1: 0.5
DIPEA
NH OAc
4
1
1
0
K CO
2 3
1
Cs CO
2
21
47
33
37
3
1
2 c
3 d
4 e
NaOAc
NaOAc
NaOAc
1
1
a
A mixture of pyridinium salt
1
(0.591 mmol), enaminone
2 and the corresponding base in isopropyl alcohol (3 mL)
and water (1 mL) was irradiated in a closed vessel in a microwave reactor Monowave 300 (Anton Paar GmbH) at
50 C for 30 min. Isolated yield. c The reaction time was prolonged from 30 to 60 min. The reaction temperature
◦
b
d
1
◦
e
◦
was 120 C. The reaction temperature was 180 C.

Molecules 2020, 25, 4059
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With the optimized conditions in hand, we went on to investigate the reaction scope. It turned out
that the reaction of N-cyanomethyl-2,3-dimethylpyridinium salt with enaminone was more effective,
and the target product 3b was isolated with 82% yield (Scheme 2). On the contrary, the interaction
of 2,5-dimethylpyridinium salt with the enaminone delivered product 3c with 27% yield. When
p-methylphenyl-substituted enaminone was used, the compounds 3d–f were isolated with 21–37%
yield. Bromo-substituted enaminones could be also used with various pyridinium salts to give
indolizines 3g–i with 19–62% yield. Pyridoindolizines 3j–l with a phenol moiety were prepared
with 24–66% yield. Moreover, we were pleased to find the pyridyl-containing enaminones to work
successfully, producing the corresponding compounds 3m–r with poor to moderate yields. It is worth
noting that taking N-cyanomethyl-2,3-dimethylpyridinium bromide in a large excess increased the
yield of the compound 3n from 33% to 85%. Unfortunately, increasing the loading of the pyridinium
3
salts in other cases did not result in yield improvement. The use of aliphatic enaminones (R = Me or
Et) in the reactions with N-cyanomethyl-2,3-dimethylpyridinium bromide generated complex mixtures,
and no target product could be isolated. As a rule, the use of 2,3-dimethylpyridiniums resulted in
greater yields of the target pyridoindolizines 3. The scope of the enaminones included various aryl
groups, even phenols and heterocycles, while the use of aliphatic enaminones was found to be a
limitation of the method.
Scheme 2. The scope of the reaction between N-cyanomethyl-2-methylpyridinium bromides and
a
a
various enaminones . General conditions: a mixture of pyridinium salt
1 (0.591 mmol), enaminone
2
(0.394 mmol), and sodium acetate (0.197 mmol) in isopropyl alcohol (3 mL) and water (1 mL) was
◦
b
placed into the microwave reactor and irradiated at 150 C for 30 min. The reaction was performed
on 1.182 mmol scale of N-cyanomethyl-2,3-dimethylpyridinium salt.

Molecules 2020, 25, 4059
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The structure of pyridoindolizine 3b was unambiguously determined by a single crystal X-ray
diffraction study (Figure 1, CCDC 1922817).
Figure 1. Crystal structure of 3b (CCDC 1922817).
The reaction presumably starts with the intramolecular cyclization of a deprotonated
group on a nitrile moiety, eventually giving an aminoindolizine intermediate 27] (Scheme 3).
The interaction of the latter with enaminone produces an intermediate . The cyclocondensation of
completes the reaction sequence, delivering pyridoindolizine 3a. The intermediate is evidently
-extensive pyrrole fragment combined with an amino
α-methyl
A
[
B
B
A
a highly nucleophilic species, containing a
π
group, readily reacting with the present electrophiles. Unfortunately, our attempts to isolate this
intermediate failed. Even experiments in the absence of the enaminone generated multicomponent
mixtures, pointing out the possibility for A to interact with the starting salt 1a.
Scheme 3. Proposed mechanism for pyrido[2,3-b]indolizine formation.
The optical properties of the synthesized compounds were evaluated and all the spectra were
measured in toluene solutions (Figure 2, Table 2, separate images are available in Supplementary
Materials). Indolizines 3a–c, m–q exhibited absorption peak maxima at 403–420 nm. The emission
−
1
peak maxima lay in the green region 505–528 nm, and the largest Stokes shift 4950 cm was registered
for compound 3b. The fluorescence quantum yields (FQYs) were determined using coumarin 153
as a standard [32]. The lowest FQY values of 55–63% were measured for 4-pyridyl-substituted
pyridoindolizines 3m–o, while the phenyl-substituted pyridoindolizine 3b demonstrated the highest
FQY, 82%. This optical behavior is in accordance with the literature. For instance, indolizines,
condensed with isoindole [33], quinoline [34
,35] or dihydropyrrole [36] cycles also emit in the blue to
green region 410–556 nm with FQYs up to 77%.

Molecules 2020, 25, 4059
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(
a)
(b)
) and emission (b) spectra of the above synthesized compounds in toluene.
Figure 2. The absorbance (
a
Table 2. Photophysical properties of the synthesized compound.
Abs [a]
ε
[b]
Emission [a]
[nm]
FQY [c]
[%]
Stokes Shift
Compound
−1
9
−1
[cm ]
[nm]
[(M cm) (10 )]
3
a
413
404
414
418
410
420
416
409
1.652
1.616
1.656
1.672
1.640
1.680
1.664
1.636
511
505
520
519
513
528
516
512
77
82
64
57
63
55
64
77
4643
4950
4923
4655
4897
4870
4658
4918
3
b
3
c
3
m
3
n
3
3
3
o
p
q
[a]
Peak maximum. [b] Molar extinction coefficient. [c] Fluorescence quantum yield.
3
. Materials and Methods
3
.1. General Information
Starting reagents were purchased from commercial sources and were used without any additional
purification. Enaminones were prepared according to the literature procedures [37]. Microwave
2
reactions were conducted in a Monowave 300 Microwave Reactor (Anton Paar GmbH, Graz, Austria).
Column chromatography was performed using silica gel (230–400 mesh) and mixtures in different
proportions of ethyl acetate with hexane as the mobile phase. Melting points were determined on a
1
SMP-10 apparatus (Barloworld Scientific Limited, Stone, UK). H NMR spectra were recorded on a
1
3
4
00 MHz spectrometer (Bruker, 100 MHz for C NMR) and referenced to the residual signals of the
solvent (for H and 13C). Chemical shifts are reported in parts per million (
1
δ/ppm). Coupling constants
are reported in Hertz (J/Hz). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet;
q, quadruplet; m, multiplet; dd, doublet of doublets and td, triplet of doublets. Low resolution mass
spectra were recorded with an LCMS-8040 triple quadrupole liquid chromatograph mass-spectrometer
(Shimadzu corp., Tokyo, Japan). The reaction progress was monitored by TLC and the spots were
visualized under UV light (254 or 365 nm). Elemental analysis was performed on a EuroVector EA-3000
instrument (EuroVector S.p.A., Milan, Italy).
3
.2. General Procedure for the Synthesis of Salts 1a–c
Bromoacetonitrile (0.026 mol) was added to a stirred solution of corresponding pyridine (0.022 mol)
in acetonitrile (10 mL). The reaction mixture was heated at reflux for 4 h. The precipitate was filtered,
washed with acetonitrile, and dried in vacuum over P O .
2
5

Molecules 2020, 25, 4059
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◦
N-(Cyanomethyl)-2-methylpyridinium bromide (1a). White powder; m.p. 195–196 C (decomp.); yield,
1
3
.56 g (76%); H NMR (400 MHz, CDCl )
δ
9.16 (1H, d, J = 6.1 Hz, H-6), 8.59–8.62 (1H, m, H-4), 8.16
3
(
1H, d, J = 7.6 Hz, H-3), 8.06–8.08 (1H, m, H-5), 6.11 (2H, d, J = 1.5 Hz, CH -CN), 2.90 (3H, s, C -CH ).
2 2 3
C NMR (100 MHz, CDCl3) δ 156.2, 147.3, 146.1, 130.2, 126.1, 113.5, 45.1, 20.0. ESI MS: m/z 133 [M] .
1
3
+
Elemental analysis calcd (%) for C H BrN : C 45.10; H 4.26; N 13.15; found: C 45.02; H 4.29; N 13.26.
8
9
2
◦
N-(Cyanomethyl)-2,3-dimethylpyridinium bromide (1b). Light beige powder; m.p. 175–177 C (decomp.);
−1
1
yield, 3.60 g (72%); IR (cm ): 2256 (CN); H NMR (400 MHz, CDCl )
δ
9.05 (1H, d, J = 6.1 Hz, H-6),
3
8
.53 (1H, d, J = 8.1 Hz, H-4), 7.98–8.01 (1H, m, H-5), 6.20 (2H, s, CH -CN), 2.83 (3H, s, C -CH ), 2.52
2
2
3
13
(
3H, s, C -CH ). C NMR (100 MHz, CDCl )
δ
155.5, 147.3, 143.9, 139.2, 125.1, 113.7, 45.9, 19.3, 17.3.
3
3
3
+
ESI MS: m/z 147 [M] . Elemental analysis calcd (%) for C H BrN : C 47.60; H 4.88; N 12.34; found: C
9
11
2
4
7.56; H 4.87; N 12.43.
◦
N-(Cyanomethyl)-2,5-dimethylpyridinium bromide (1c). Light beige powder; m.p. 168–169 C (decomp.);
1
yield, 2.90 g (58%); H NMR (400 MHz, CDCl )
δ
9.11 (1H, s, H-6), 8.49 (1H, d, J = 8.3 Hz, H-3), 8.08
1H, d, J = 8.3 Hz, H-4), 6.07 (2H, s, CH -CN), 2.88 (3H, s, C -CH ), 2.46 (3H, s, C -CH ). C NMR
2 2 3 5 3
3
13
(
(
+
100 MHz, CDCl3)
δ 153.2, 147.9, 145.3, 136.5, 129.5, 113.5, 44.9, 19.4, 17.4. ESI MS: m/z 147 [M] .
Elemental analysis calcd (%) for C H BrN : C 47.60; H 4.88; N 12.34; found: C 47.57; H 4.91; N 12.45.
9
11
2
3
.3. General Procedure for the Synthesis of Enaminones 2
A mixture of dimethylformamide dimethylacetal (14.8 mmol) and methyl ketone (14.8 mmoL)
◦
was placed into the microwave reactor and irradiated at 150 C for 15 min, then left to cool to room
temperature. After cooling, the precipitate was filtered-off, washed twice with toluene and dried on air.
◦
(
E)-3-(Dimethylamino)-1-phenylprop-2-en-1-one (2a). Yellow powder; m.p. 91–92 C; yield, 1.17 g (45%);
1H NMR (400 MHz, CDCl3)
.39–7.45 (3H, m, Ph-H), 5.70 (1H, d, J = 12.4 Hz, CH=CH-NMe ), 3.11 (3H, s, N-CH ), 2.90 (3H, s,
δ 7.88 (2H, d, J = 6.9 Hz, Ph-H), 7.78 (1H, d, J = 12.4 Hz, CH=CH-NMe2),
7
2
3
13
N-CH3). C NMR (100 MHz, CDCl )
ESI MS: m/z 176 [M + H] .
δ
188.8, 154.4, 140.7, 131.0, 128.2 (2C), 127.6 (2C), 92.3, 45.1, 37.4.
3
+
◦
(
E)-3-(Dimethylamino)-1-(p-tolyl)prop-2-en-1-one (2b). Yellow powder; m.p. 88–89 C; yield, 0.62 g (24%);
H NMR (400 MHz, CDCl3)
1
δ 7.80 (2H, d, J = 8.1 Hz, Ph-H), 7.77 (1H, d, J = 12.3 Hz, CH=CH-NMe2),
7
.19 (2H, d, J = 8.1 Hz, Ph-H), 5.70 (1H, d, J = 12.3 Hz, CH=CH-NMe ), 3.09 (3H, s, N-CH ), 2.89 (3H, s,
2
3
13
N-CH ), 2.37 (3H, s, Ph-CH ). C NMR (100 MHz, CDCl )
δ
188.2, 153.9, 141.1, 137.7, 128.7 (2C), 127.5
3
3
3
+
(2C), 92.0, 44.8, 37.1, 21.3. ESI MS: m/z 190 [M + H] .
◦
(
1
E)-3-(Dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (2d). Orange powder; m.p. 133–135 C; yield,
1
.58 g (56%); H NMR (400 MHz, CDCl )
δ
13.98 (1H, s, C -OH), 7.87 (1H, d, J = 12.3 Hz, CH=CH-NMe ),
3
2
2
7
.69 (1H, dd, J = 8.1, 1.1 Hz, Ph-H), 7.35 (1H, m, Ph-H), 6.93 (1H, d, J = 8.1, Ph-H), 6.80 (1H, m, Ph-H),
13
5
.77 (1H, d, J = 12.3 Hz, CH=CH-NMe ), 3.18 (3H, s, N-CH ), 2.96 (3H, s, N-CH ). C NMR (100 MHz,
2 3 3
+
CDCl3)
δ
191.6, 163.0, 154.9, 134.0, 128.3, 120.4, 118.3, 118.1, 90.1, 45.5, 37.5. ESI MS: m/z 192 [M + H] .
◦
(
0
E)-3-(Dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (2e). Yellow powder; m.p. 115–116 C; yield,
1
.886 g (34%); H NMR (400 MHz, CDCl ) δ 8.67 (2H, d, J = 5.6, Ar-H), 7.82 (1H, d, J = 11.9 Hz,
3
CH=CH-NMe ), 7.67 (2H, d, J = 5.6 Hz, Ar-H), 5.63 (1H, d, J = 11.9 Hz, CH=CH-NMe ), 3.16 (3H, s,
2
2
13
N-CH ), 2.93 (3H, s, N-CH ). C NMR (100 MHz, CDCl )
1.6, 45.2, 37.4. ESI MS: m/z 177 [M + H] .
δ
186.4, 155.2, 149.9 (2C), 147.3, 121.2 (2C),
3
3
3
+
9
3
.4. General Procedure for the Synthesis of Compounds 3a–r
Method A (for 3a–g, 3i, 3m–r): A mixture of pyridinium salt 1 (0.591 mmol), enaminone 2
(
0.394 mmol), and sodium acetate (0.197 mmol) in isopropyl alcohol (3 mL) and water (1 mL) was
◦
placed into the microwave reactor and irradiated at 150 C for 30 min. After cooling to room temperature,

Molecules 2020, 25, 4059
7 of 12
the solvent was then evaporated under reduced pressure. The products were isolated by column
chromatography on silica gel, eluting with ethyl acetate-hexane mixture in different proportions.
Method B (for 3h, 3k): A mixture of pyridinium salt 1 (0.591 mmol), enaminone 2 (0.394 mmol),
and sodium acetate (0.197 mmol) in isopropyl alcohol (3 mL) and water (1 mL) was placed into
◦
the microwave reactor and irradiated at 150 C for 30 min and left to cool to room temperature.
After cooling, the precipitate was filtered-off and washed with ethanol, water (2 times) and ethanol
again, then dried in air.
Method C (for 3j, 3l): A mixture of pyridinium salt 1 (0.591 mmol), enaminone 2 (0.394 mmol),
and sodium acetate (0.197 mmol) in isopropyl alcohol (3 mL) and water (1 mL) was placed into the
◦
microwave reactor and irradiated at 150 C for 30 min and left to cool to room temperature. The reaction
mixture was diluted with water (70 mL) and extracted with DCM. The combined organic layer was
dried over Na SO . After filtration, the solvent was evaporated under reduced pressure. The residue
2
4
was recrystallized from the isopropyl alcohol-DCM 3-1 mixture. The precipitate was filtered-off and
washed with isopropyl alcohol for 3 times, then dried in air.
2
-Phenylpyrido[2,3-b]indolizine (3a). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 10.
◦
1
Light brown powder; m.p. 178–180 C (decomp.); yield, 48 mg (50%); H NMR (400 MHz, CDCl )
δ
8.25
d, J = 7.1 Hz, 1H, H-6), 8.15 (d, J = 8.6 Hz, 1H, H-3), 8.11 (d, J = 7.6 Hz, 2H, Ph-H), 7.61 (d, J = 8.6 Hz, 1H,
H-4), 7.50–7.52 (m, 3H, H-9, Ph-H), 7.42–7.44 (m, 1H, Ph-H), 6.95–6.98 (m, 1H, H-7), 6.90 (s, 1H, H-10),
.53–6.55 (m, 1H, H-8). 13C NMR (100 MHz, CDCl3)
154.9, 146.3, 140.7, 139.2, 128.6 (2C), 128.4, 127.5
2C), 124.6, 123.4, 121.7, 119.4, 118.0, 112.2, 108.7, 92.5. ESI MS: m/z 245 [M + H] . Elemental analysis calcd
3
(
6
(
δ
+
(
%) for C H N : C 83.58; H 4.95; N 11.47; found: C 83.54; H 4.98; N 11.59.
17 12 2
9
-Methyl-2-phenylpyrido[2,3-b]indolizine (3b). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 5. Yellow powder; m.p. 143–146 C (decomp.); yield, 83 mg (82%); H NMR
400 MHz, CDCl3) 8.16–8.20 (m, 2H, H-3, H-6), 8.12 (d, J = 7.6 Hz, 2H, Ph-H), 7.62 (d, J = 8.6 Hz, 1H,
H-4), 7.50–7.53 (m, 2H, Ph-H), 7.41–7.44 (m, 1H, m, Ph-H), 6.88 (s, 1H, H-10), 6.80 (d, J = 6.1 Hz, 1H, H-8),
(
δ
13
6.52–6.55 (m, 1H, H-7), 2.51 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3)
δ
154.7, 146.2, 140.6 (2C), 128.7
9
3
+
(3C), 128.4, 127.5 (2C), 122.3 (2C), 122.0, 118.3, 112.2, 109.0, 91.1, 18.5. ESI MS: m/z 259 [M + H] . Elemental
analysis calcd (%) for C H N : C 83.69; H 5.46; N 10.84; found: C 83.66; H 5.51; N 10.95.
18
14
2
7
-Methyl-2-phenylpyrido[2,3-b]indolizine (3c). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 5. Dark yellow powder; m.p. 175–176 C (decomp.); yield, 27 mg (27%); H NMR
(400 MHz, CDCl3)
δ 8.15 (d, J = 8.6 Hz, 1H, H-3), 8.10 (d, J = 7.6 Hz, 2H, Ph-H), 8.08 (s, 1H, H-6), 7.59
(
d, J = 8.6 Hz, 1H, H-4), 7.49–7.52 (m, 2H, Ph-H), 7.41–7.46 (m, 2H, H-9, Ph-H), 6.86–6.87 (m, 2H, H-8,
13
H-10), 2.31 (3H, c, C -CH ). C NMR (100 MHz, CDCl3) δ 154.5, 146.0, 140.7, 138.3, 128.6 (2C), 128.3,
1
7
3
+
27.5 (2C), 127.1, 121.8, 121.6, 119.0, 118.1 (2C), 112.0, 91.9, 18.3. ESI MS: m/z 259 [M + H] . Elemental
analysis calcd (%) for C H N : C 83.69; H 5.46; N 10.84; found: C 83.62; H 5.48; N 10.99.
18
14
2
2
-(p-Tolyl)pyrido[2,3-b]indolizine (3d). Prepared according to the Method A. Eluent ethyl acetate-hexane
◦
1
1
: 10. Bright yellow powder; m.p. 181–182 C (decomp.); yield, 29 mg (29%); H NMR (400 MHz,
8.90 (d, J = 7.1 Hz, 1H, H-6), 8.67 (d, J = 8.6 Hz, 1H, H-3), 8.09 (d, J = 8.1 Hz, 2H, Ph-H), 7.80
d, J = 8.6 Hz, 1H, H-4), 7.61 (d, J = 9.6 Hz, 1H, H-9), 7.30 (d, J = 8.1 Hz, 2H, Ph-H), 7.09–7.11 (m, 1H,
H-7), 6.78 (s, 1H, H-10), 6.68–6.70 (m, 1H, H-8), 2.37 (s, 3H, Ph-CH3). 13C NMR (100 MHz, CDCl3)
CDCl3)
(
δ
δ
1
2
53.2, 145.4, 138.7, 137.9, 137.2, 129.3 (2C), 126.8 (2C), 126.3, 124.1, 121.5, 119.6, 118.7, 111.3, 108.8, 91.5,
+
0.8. ESI MS: m/z 259 [M + H] . Elemental analysis calcd (%) for C H N : C, 83.69; H, 5.46; N, 10.84;
18 14 2
found: C 83.65; H 5.49; N 10.96.
9
-Methyl-2-(p-tolyl)pyrido[2,3-b]indolizine (3e). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 15. Yellow powder; m.p. 174 C (decomp.); yield, 87 mg (81%); H NMR (400 MHz,
CDCl3) 8.79 (d, J = 6.6 Hz, 1H, H-6), 8.66 (d, J = 8.6 Hz, 1H, H-3), 8.09 (d, J = 8.1 Hz, 2H, Ph-H), 7.80
d, J = 8.6 Hz, 1H, H-4), 7.31 (d, J = 7.6 Hz, 2H, Ph-H), 6.93 (d, J = 6.1 Hz, 1H, H-8), 6.77 (s, 1H, H-10),
δ
(
13
6
.65–6.67 (m, 1H, H-7), 2.46 (s, 3H, C -CH ), 2.37 (s, 3H, Ph-CH ). C NMR (100 MHz, CDCl3) δ 153.1,
9 3 3

Molecules 2020, 25, 4059
8 of 12
1
45.4, 139.7, 137.8, 137.2, 129.2 (2C), 127.2, 126.8 (2C), 123.9, 122.5, 122.1, 119.8, 111.4, 108.9, 90.3, 20.8,
+
18.0. ESI MS: m/z 273 [M + H] . Elemental analysis calcd (%) for C H N : C, 83.79; H, 5.92; N, 10.29;
19 16 2
found: C 83.72; H 5.89; N 10.43.
7
-Methyl-2-(p-tolyl)pyrido[2,3-b]indolizine (3f). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 15. Dark yellow powder; m.p. 173–174 C (decomp.); yield, 23 mg (21%); H NMR
(400 MHz, CDCl3)
δ 8.73 (s, 1H, H-6), 8.60 (d, J = 8.6 Hz, 1H, H-3), 8.08 (d, J = 8.1 Hz, 2H, Ph-H), 7.77
(
d, J = 8.6 Hz, 1H, H-4), 7.55 (d, J = 9.3, 1H, H-9), 7.30 (d, J = 7.6 Hz, 2H, Ph-H), 6.98 (d, J = 9.3 Hz, 1H,
13
H-8), 6.73 (s, 1H, H-10), 2.37 (s, 3H, Ph-CH ), 2.28 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3) δ 152.9,
3
7
3
1
45.3, 137.8, 137.6, 137.2, 129.2 (2C), 127.5, 126.7 (2C), 123.2, 121.3, 119.4, 118.3, 117.7, 111.1, 91.0, 20.8,
+
17.7. ESI MS: m/z 273 [M + H] . Elemental analysis calcd (%) for C H N : C, 83.79; H, 5.92; N, 10.29;
19
16
2
found: C 83.84; H 5.90; N 10.33.
2
-(4-Bromophenyl)pyrido[2,3-b]indolizine (3g). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 15. Brown powder; m.p. 215–217 C (decomp.); yield, 33 mg (26%); H NMR
400 MHz, CDCl3) 8.93 (d, J = 7.1 Hz, 1H, H-6), 8.72 (d, J = 9.1 Hz, 1H, H-3), 8.15 (d, J = 8.6 Hz, 2H,
Ph-H), 7.86 (d, J = 9.1 Hz, 1H, H-4), 7.69 (d, J = 8.6 Hz, 2H, Ph-H), 7.62 (d, J = 9.1 Hz, 1H, H-9), 7.11–7.14
m, 1H, H-8), 6.80 (s, 1H, H-10), 6.70–6.73 (m, 1H, H-7). 13C NMR (100 MHz, CDCl3)
151.9, 145.5,
39.1, 139.0, 131.6 (2C), 128.9 (2C), 126.4, 124.5, 122.1, 121.8, 119.9, 118.7, 111.3, 108.9, 91.6. ESI MS: m/z
(
δ
(
δ
1
3
3
+
24 [M + H] . Elemental analysis calcd (%) for C H BrN : C 63.18; H 3.43; N 8.67; found: C 63.25; H
17
11
2
.40; N 8.63.
2
-(4-Bromophenyl)-9-methylpyrido[2,3-b]indolizine (3h). Prepared according to the Method B. Gold
◦
1
powder; m.p. 192–193 C (decomp.); yield, 82 mg (62%); H NMR (400 MHz, CDCl )
δ 8.80 (d,
3
J = 7.1 Hz, 1H, H-6), 8.70 (d, J = 8.6 Hz, 1H, H-3), 8.16 (d, J = 8.3 Hz, 2H, Ph-H), 7.85 (d, J = 8.6 Hz, 1H,
H-4), 7.69 (d, J = 8.3 Hz, 2H, Ph-H), 6.95 (d, J = 6.6 Hz, 1H, H-8), 6.79 (s, 1H, H-10), 6.66–6.69 (m, 1H,
1
3
H-7), 2.46 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3) δ 151.8, 145.5, 140.0, 139.1, 131.5 (2C), 128.9
(
9
3
+
2C), 127.2, 124.0, 122.7, 122.4, 122.0, 119.9, 111.4, 109.0, 90.4, 18.0. ESI MS: m/z 338 [M + H] . Elemental
analysis calcd (%) for C H BrN : C 64.11; H 3.89; N 8.31; found: C 64.01; H 3.91; N 8.36.
18
13
2
2
-(4-Bromophenyl)-7-methylpyrido[2,3-b]indolizine (3i). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 15. Light brown powder; m.p. 177–178 C (decomp.); yield, 25 mg (19%); H NMR
(400 MHz, CDCl3)
δ 8.72 (s, 1H, H-6), 8.61 (d, J = 8.1 Hz, 1H, H-3), 8.14 (d, J = 7.6 Hz, 2H, Ph-H), 7.79
(
1
d, J = 8.1 Hz, 1H, H-4), 7.67 (d, J = 7.6 Hz, 2H, Ph-H), 7.55 (d, J = 9.1 Hz, 1H, H-9), 6.99 (d, J = 9.1 Hz,
13
H, H-8), 6.74 (s, 1H, H-10), 2.27 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3)
δ
151.5, 145.3, 139.1,
7
3
1
3
37.9, 131.5 (2C), 128.9 (2C), 127.7, 123.2, 121.9, 121.5, 119.5, 118.3, 117.9, 111.1, 91.1, 17.7. ESI MS: m/z
38 [M + H] . Elemental analysis calcd (%) for C H BrN : C 64.11; H 3.89; N 8.31; found: C 64.17; H
18 13 2
+
3
.92; N 8.34.
2
-(Pyrido[2,3-b]indolizin-2-yl)phenol (3j). Prepared according to the Method C. Dark brown powder;
◦
1
m.p. 230–232 C (decomp.); yield, 38 mg (37%); H NMR (400 MHz, CDCl )
δ
15.09 (s, 1H, OH), 8.99
3
(
d, J = 6.6 Hz, 1H, H-6), 8.85 (d, J = 8.9 Hz, 1H, H-3), 8.13 (d, J = 7.6 Hz, 1H, Ph-H), 8.06 (d, J = 8.9 Hz,
1
2
H, H-4), 7.65 (d, J = 9.1 Hz, 1H, H-9), 7.29–7.31 (m, 1H, Ph-H), 7.18–7.20 (m, 1H, H-8), 6.92–6.96 (m,
H, Ph-H), 6.84 (s, 1H, H-10), 6.78–6.80 (m, 1H, H-7). 13C NMR (100 MHz, CDCl3)
159.5, 154.4, 141.6,
δ
1
39.3, 130.8, 127.3, 126.3, 125.1, 121.6, 121.5, 119.7, 118.7, 118.6, 117.8, 110.2, 109.5, 90.3. ESI MS: m/z 261
+
[M + H] . Elemental analysis calcd (%) for C H N O: C 78.44; H 4.65; N 10.76; found: C 78.39; H
17
12
2
4
.62; N 10.82.
2
-(9-Methylpyrido[2,3-b]indolizin-2-yl)phenol (3k). Prepared according to the Method B. Gold powder;
◦
1
m.p. 179 C (decomp.); yield, 71 mg (66%); H NMR (400 MHz, CDCl ) δ 15.10 (s, 1H, OH), 8.87 (d,
3
J = 6.6 Hz, 1H, H-6), 8.84 (d, J = 8.6 Hz, 1H, H-3), 8.13 (d, J = 7.6 Hz, 1H, Ph-H), 8.06 (d, J = 8.6 Hz, 1H,
H-4), 7.29–7.31 (m, 1H, Ph-H), 7.01 (d, J = 6.6 Hz, 1H, H-8), 6.92–6.96 (m, 2H, Ph-H), 6.84 (s, 1H, H-10),
13
6
.73–6.76 (m, 1H, H-7), 2.47 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3)
δ
159.5, 154.3, 141.5, 140.3,
9
3
130.8, 127.3, 127.2, 123.9, 123.4, 122.1, 121.6, 119.7, 118.6, 117.9, 110.3, 109.6, 89.2, 17.9. ESI MS: m/z 275

Molecules 2020, 25, 4059
9 of 12
+
[
M + H] . Elemental analysis calcd (%) for C H N O: C 78.81; H 5.14; N 10.21; found: C 78.77; H
18
14
2
5
.16; N 10.30.
2
-(7-Methylpyrido[2,3-b]indolizin-2-yl)phenol (3l). Prepared according to the Method C. Brown powder;
◦
1
m.p. 226–227 C (decomp.); yield, 26 mg (24%); H NMR (400 MHz, CDCl )
δ
15.13 (s, 1H, OH), 8.81 (s,
H, H-6), 8.78 (d, J = 8.9 Hz, 1H, H-3), 8.11 (d, J = 7.1 Hz, 1H, Ph-H), 8.03 (d, J = 8.9 Hz, 1H, H-4), 7.60
d, J = 9.1 Hz, 1H, H-9), 7.28–7.30 (m, 1H, Ph-H), 7.07 (d, J = 9.1 Hz, 1H, H-8), 6.91–6.95 (m, 2H, Ph-H),
3
1
(
13
6
.78 (s, 1H, H-10), 2.30 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3)
δ
159.5, 154.1, 141.4, 138.3, 130.7,
9
3
+
1
28.4, 127.2, 123.2, 121.3, 121.2, 119.7, 118.6 (2C), 118.3, 117.8, 110.0, 89.8, 17.7. ESI MS: m/z 275 [M + H] .
Elemental analysis calcd (%) for C H N O: C 78.81; H 5.14; N 10.21; found: C 78.83; H 5.11; N 10.28.
18
14
2
2
-(Pyridin-4-yl)pyrido[2,3-b]indolizine(3m). PreparedaccordingtotheMethodA. Eluentethylacetate-hexane
◦
1
1
: 5. Orange powder; m.p. 196–199 C (decomp.); yield, 30 mg (31%); H NMR (400 MHz, CDCl )
δ
8.73
d, J = 5.9 Hz, 2H, Py-H), 8.29 (d, J = 6.6 Hz, 1H, H-6), 8.21 (d, J = 8.6 Hz, 1H, H-3), 8.01 (d, J = 5.9 Hz, 2H,
Py-H), 7.66 (d, J = 8.6 Hz, 1H, H-4), 7.52 (d, J = 9.6 Hz, 1H, H-9), 7.00–7.03 (m, 1H, H-7), 6.90 (s, 1H, H-10),
.58–6.60 (m, 1H, H-8). 13C NMR (100 MHz, CDCl3)
151.7, 150.2 (2C), 147.7, 146.5, 139.9, 124.7, 124.0,
22.4, 121.7 (2C), 119.6, 118.2, 111.8, 109.2, 92.7. ESI MS: m/z 246 [M + H] . Elemental analysis calcd (%)
for C H N : C 78.35; H 4.52; N 17.13; found: C 78.31; H 4.55; N 17.20.
3
(
6
1
δ
+
16
11
3
9
-Methyl-2-(pyridin-4-yl)pyrido[2,3-b]indolizine (3n). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 5. Light beige powder; m.p. 173–174 C (decomp.); yield, 34 mg (33%); H NMR
400 MHz, CDCl3) 8.72 (d, J = 5.8 Hz, 1H, Py-H), 8.18–8.20 (m, 2H, H-3, H-6), 8.01 (d, J = 5.8 Hz,
H, Py-H), 7.65 (d, J = 8.6 Hz, 1H, H-4), 6.86 (s, 1H, H-10), 6.82 (d, J = 6.6 Hz, 1H, H-8), 6.54–6.56 (m,
(
2
δ
13
1
1
H, H-7), 3.18 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3) δ 151.5, 150.5, 150.2 (2C), 147.7, 141.1,
9 3
28.5, 123.6, 122.5, 122.3, 121.6 (2C), 118.3, 111.8, 109.3, 91.2, 18.5. ESI MS: m/z 260 [M + H] . Elemental
+
analysis calcd (%) for C H N : C 78.74; H 5.05; N 16.20; found: C 78.71; H 5.09; N 16.29.
17
13
3
7
-Methyl-2-(pyridin-4-yl)pyrido[2,3-b]indolizine (3o). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 5. Light beige powder; m.p. 223–225 C (decomp.); yield, 27 mg (26%); H NMR
(400 MHz, CDCl3)
δ 8.73 (d, J = 5.8 Hz, 2H, Py-H), 8.21 (d, J = 8.6 Hz, 1H, H-3), 8.11 (s, 1H, H-6), 8.03
(
1
1
d, J = 5.8 Hz, 2H, Py-H), 7.66 (d, J = 8.6 Hz, 1H, H-4), 7.47 (d, J = 8.9 Hz, 1H, H-9), 6.90 (d, J = 8.9 Hz,
13
H, H-8), 6.87 (s, 1H, H-10), 2.33 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3)
δ
151.3, 150.1 (2C), 147.9,
7
3
+
46.4, 139.0, 127.6, 122.2, 121.9, 121.7 (2C), 119.1, 118.6, 118.1, 111.6, 92.2, 18.3. ESI MS: m/z 260 [M + H] .
Elemental analysis calcd (%) for C H N : C 78.74; H 5.05; N 16.20; found: C 78.69; H 5.06; N 16.32.
17
13
3
2
-(Pyridin-2-yl)pyrido[2,3-b]indolizine (3p). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 10. Yellow powder; m.p. 159–162 C (decomp.); yield, 27 mg (28%); H NMR
400 MHz, CDCl3) 8.72 (d, J = 4.0 Hz, 1H, Pyr-H), 8.60 (d, J = 8.1 Hz, 1H, Py-H), 8.38 (d, J = 8.6 Hz, 1H,
H-3), 8.33 (d, J = 7.1 Hz, 1H, H-6), 8.28 (d, J = 8.6 Hz, 1H, H-4), 7.86 (m, 1H, Py-H), 7.52 (d, J = 9.1 Hz,
H, H-9), 7.31–7.33 (m, 1H, Py-H), 6.99–7.01 (m, 1H, H-7), 6.91 (s, 1H, H-10), 6.58–6.60 (1H, m, H-8),
.58–6.60 (m, 1H, H-8). 13C NMR (100 MHz, CDCl3)
157.2, 153.4, 149.0, 145.9, 139.5, 136.9, 124.7,
23.6, 123.3, 122.8, 121.5, 119.5, 118.2, 112.5, 108.9, 92.5. ESI MS: m/z 246 [M + H] . Elemental analysis
calcd (%) for C H N : C 78.35; H 4.52; N 17.13; found: C 78.32; H 4.57; N 17.14.
(
δ
1
6
1
δ
+
16
11
3
9
-Methyl-2-(pyridin-2-yl)pyrido[2,3-b]indolizine (3q). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 10. Lime-green powder; m.p. 124–127 C (decomp.); yield, 71 mg (70%); H NMR
400 MHz, CDCl3) 8.71 (d, J = 4.0 Hz, 1H, Py-H), 8.61 (d, J = 7.6 Hz, 1H, Py-H), 8.37 (d, J = 8.6 Hz,
H, H-3), 8.25 (d, J = 8.6 Hz, 1H, H-4), 8.22 (d, J = 7.1 Hz, 1H, H-6), 7.84–7.87 (m, 1H, Py-H), 7.30–7.32
m, 1H, Py-H), 6.88 (s, 1H, H-10), 6.80 (d, J = 6.1 Hz, 1H, H-8), 6.53–6.55 (m, 1H, H-7), 2.51 (s, 3H,
(
1
(
δ
13
C -CH ). C NMR (100 MHz, CDCl3)
δ
157.2, 153.3, 149.0, 145.9, 140.7, 136.8, 128.4, 123.4, 123.2, 122.4,
9
3
+
1
22.1, 121.5, 118.3, 112.5, 109.1, 91.1, 18.5. ESI MS: m/z 260 [M + H] . Elemental analysis calcd (%) for
C H N : C 78.74; H 5.05; N 16.20; found: C 78.70; H 5.07; N 16.25.
17
13
3

Molecules 2020, 25, 4059
10 of 12
7
-Methyl-2-(pyridin-4-yl)pyrido[2,3-b]indolizine (3r). Prepared according to the Method A. Eluent ethyl
◦
1
acetate-hexane 1: 7. Brown powder; m.p. 74–79 C (decomp.); yield, 39 mg (38%); H NMR (400 MHz,
CDCl3) 8.71 (d, J = 4.0 Hz, 1H, Py-H), 8.59 (d, J = 8.1 Hz, 1H, Py-H), 8.35 (d, J = 8.6 Hz, 1H, H-3), 8.25
d, J = 8.6 Hz, 1H, H-4), 8.13 (s, 1H, H-6), 7.83–7.86 (m, 1H, Py-H), 7.47 (d, J = 9.1 Hz, 1H, H-9), 7.30–7.32
δ
(
13
(m, 1H, Py-H), 6.86–6.89 (m, 2H, H-8, H-10), 2.33 (s, 3H, C -CH ). C NMR (100 MHz, CDCl3) δ 157.4,
7 3
1
53.2, 149.0, 146.0, 138.5, 136.8, 127.1, 123.2, 122.6, 121.9, 121.5, 119.0, 118.2, 118.0, 112.3, 92.1, 18.3. ESI
+
MS: m/z 260 [M + H] . Elemental analysis calcd (%) for C H N : C 78.74; H 5.05; N 16.20; found: C
17
13
3
7
8.71; H 5.09; N 16.33.
4
. Conclusions
In conclusion, we discovered a novel domino route to condensed indolizines—pyrido[2,3-b]
indolizines, containing various aromatic or heteroaromatic moieties at C(2) and alkyl groups at C(7) or
C(9). The route is based on the interaction of 2-alkyl-N-(cyanomethyl)pyridinium salts with enaminones.
The synthesized compounds are effective fluorophores, emitting green light with FQYs up to 82%.
Supplementary Materials: The supplementary materials are available online.
Author Contributions: Conceptualization, L.G.V. and E.V.V.d.E.; methodology, E.A.S., A.V.V. and A.A.F.; X-ray
analysis, V.B.R.; optical studies, K.S.; writing—original draft preparation, A.A.F.; writing—review and editing,
L.G.V. and E.V.V.d.E. All authors have read and agreed to the published version of the manuscript.
Funding: The publication was prepared with the support of the “RUDN University Program 5–100” and RFBR
Grant 18-33-20101 (Sokolova E.A.). Funding for optical studies was provided by the Ministry of Science and
Higher Education of the Russian Federation (award no. 075-03-2020-223 (FSSF-2020-0017)).
Acknowledgments: The research is carried out using the equipment of the shared research facilities of HPC
computing resources at Lomonosov Moscow State University.
Conflicts of Interest: The authors declare no conflict of interest.
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