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Article

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

by
Ekaterina A. Sokolova
1,
Alexey A. Festa
1,
Karthikeyan Subramani
1,
Victor B. Rybakov
2,
Alexey V. Varlamov
1,
Leonid G. Voskressensky
1 and
Erik V. Van der Eycken
1,3,*
1
Organic Chemistry Department, Science Faculty, RUDN University, Miklukho-Maklaya st., 6, 117198 Moscow, Russia
2
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1–3, 119991 Moscow, Russia
3
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(18), 4059; https://doi.org/10.3390/molecules25184059
Submission received: 1 August 2020 / Revised: 24 August 2020 / Accepted: 3 September 2020 / Published: 5 September 2020
(This article belongs to the Special Issue Advances in Cycloadditions: Theory, Practice, and Applications)
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Versions Notes

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.

Graphical Abstract

1. Introduction

Indolizines, and in particular the annulated ones, are frequently found to exhibit useful biological [1,2,3,4,5,6] and optical properties [7,8,9,10,11,12,13,14]. The synthesis of indolizines usually relies on the reactivity of pyridinium ylides, which can undergo cycloaddition reactions with alkenes [15,16,17,18] or alkynes [19,20,21,22,23]. In some cases, interaction of ylides with alkenes or alkynes leads to a different outcome [24,25,26]. 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 [28,29,30], 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 1 with enaminones 2 proceed unexpectedly as a two-component domino sequence of cycloisomerization and cyclocondensation reactions, while cycloaddition processes were not observed (Scheme 1).

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 Et3N, DIPEA, or NH4OAc did not improve the 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).
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 salts in other cases did not result in yield improvement. The use of aliphatic enaminones (R3 = 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.
The structure of pyridoindolizine 3b was unambiguously determined by a single crystal X-ray diffraction study (Figure 1, CCDC 1922817).
The reaction presumably starts with the intramolecular cyclization of a deprotonated α-methyl group on a nitrile moiety, eventually giving an aminoindolizine intermediate A [27] (Scheme 3). The interaction of the latter with enaminone produces an intermediate B. The cyclocondensation of B completes the reaction sequence, delivering pyridoindolizine 3a. The intermediate A is evidently a highly nucleophilic species, containing a π-extensive pyrrole fragment combined with an amino 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.
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 peak maxima lay in the green region 505–528 nm, and the largest Stokes shift 4950 cm−1 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%.

3. Materials and Methods

3.1. General Information

Starting reagents were purchased from commercial sources and were used without any additional purification. Enaminones 2 were prepared according to the literature procedures [37]. Microwave 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 SMP-10 apparatus (Barloworld Scientific Limited, Stone, UK). 1H NMR spectra were recorded on a 400 MHz spectrometer (Bruker, 100 MHz for 13C NMR) and referenced to the residual signals of the solvent (for 1H and 13C). Chemical shifts are reported in parts per million (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 P2O5.
N-(Cyanomethyl)-2-methylpyridinium bromide (1a). White powder; m.p. 195–196 °C (decomp.); yield, 3.56 g (76%); 1H NMR (400 MHz, CDCl3) δ 9.16 (1H, d, J = 6.1 Hz, H-6), 8.59–8.62 (1H, m, H-4), 8.16 (1H, d, J = 7.6 Hz, H-3), 8.06–8.08 (1H, m, H-5), 6.11 (2H, d, J = 1.5 Hz, CH2-CN), 2.90 (3H, s, C2-CH3). 13C 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]+. Elemental analysis calcd (%) for C8H9BrN2: C 45.10; H 4.26; N 13.15; found: C 45.02; H 4.29; N 13.26.
N-(Cyanomethyl)-2,3-dimethylpyridinium bromide (1b). Light beige powder; m.p. 175–177 °C (decomp.); yield, 3.60 g (72%); IR (cm−1): 2256 (CN); 1H NMR (400 MHz, CDCl3) δ 9.05 (1H, d, J = 6.1 Hz, H-6), 8.53 (1H, d, J = 8.1 Hz, H-4), 7.98–8.01 (1H, m, H-5), 6.20 (2H, s, CH2-CN), 2.83 (3H, s, C2-CH3), 2.52 (3H, s, C3-CH3). 13C NMR (100 MHz, CDCl3) δ 155.5, 147.3, 143.9, 139.2, 125.1, 113.7, 45.9, 19.3, 17.3. ESI MS: m/z 147 [M]+. Elemental analysis calcd (%) for C9H11BrN2: C 47.60; H 4.88; N 12.34; found: C 47.56; H 4.87; N 12.43.
N-(Cyanomethyl)-2,5-dimethylpyridinium bromide (1c). Light beige powder; m.p. 168–169 °C (decomp.); yield, 2.90 g (58%); 1H NMR (400 MHz, CDCl3) 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, CH2-CN), 2.88 (3H, s, C2-CH3), 2.46 (3H, s, C5-CH3). 13C NMR (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 C9H11BrN2: C 47.60; H 4.88; N 12.34; found: C 47.57; H 4.91; N 12.45.

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) δ 7.88 (2H, d, J = 6.9 Hz, Ph-H), 7.78 (1H, d, J = 12.4 Hz, CH=CH-NMe2), 7.39–7.45 (3H, m, Ph-H), 5.70 (1H, d, J = 12.4 Hz, CH=CH-NMe2), 3.11 (3H, s, N-CH3), 2.90 (3H, s, N-CH3). 13C NMR (100 MHz, CDCl3) δ 188.8, 154.4, 140.7, 131.0, 128.2 (2C), 127.6 (2C), 92.3, 45.1, 37.4. ESI MS: m/z 176 [M + H]+.
(E)-3-(Dimethylamino)-1-(p-tolyl)prop-2-en-1-one (2b). Yellow powder; m.p. 88–89 °C; yield, 0.62 g (24%); 1H NMR (400 MHz, CDCl3) 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-NMe2), 3.09 (3H, s, N-CH3), 2.89 (3H, s, N-CH3), 2.37 (3H, s, Ph-CH3). 13C NMR (100 MHz, CDCl3) δ 188.2, 153.9, 141.1, 137.7, 128.7 (2C), 127.5 (2C), 92.0, 44.8, 37.1, 21.3. ESI MS: m/z 190 [M + H]+.
(E)-3-(Dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (2d). Orange powder; m.p. 133–135 °C; yield, 1.58 g (56%); 1H NMR (400 MHz, CDCl3) δ 13.98 (1H, s, C2-OH), 7.87 (1H, d, J = 12.3 Hz, CH=CH-NMe2), 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), 5.77 (1H, d, J = 12.3 Hz, CH=CH-NMe2), 3.18 (3H, s, N-CH3), 2.96 (3H, s, N-CH3). 13C NMR (100 MHz, 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]+.
(E)-3-(Dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (2e). Yellow powder; m.p. 115–116 °C; yield, 0.886 g (34%); 1H NMR (400 MHz, CDCl3) δ 8.67 (2H, d, J = 5.6, Ar-H), 7.82 (1H, d, J = 11.9 Hz, CH=CH-NMe2), 7.67 (2H, d, J = 5.6 Hz, Ar-H), 5.63 (1H, d, J = 11.9 Hz, CH=CH-NMe2), 3.16 (3H, s, N-CH3), 2.93 (3H, s, N-CH3). 13C NMR (100 MHz, CDCl3) δ 186.4, 155.2, 149.9 (2C), 147.3, 121.2 (2C), 91.6, 45.2, 37.4. ESI MS: m/z 177 [M + H]+.

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, 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 Na2SO4. After filtration, the solvent was evaporated under reduced pressure. The residue 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. Light brown powder; m.p. 178–180 °C (decomp.); yield, 48 mg (50%); 1H NMR (400 MHz, CDCl3) 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), 6.53–6.55 (m, 1H, H-8). 13C NMR (100 MHz, CDCl3) δ 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 (%) for C17H12N2: C 83.58; H 4.95; N 11.47; found: C 83.54; H 4.98; N 11.59.
9-Methyl-2-phenylpyrido[2,3-b]indolizine (3b). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 5. Yellow powder; m.p. 143–146 °C (decomp.); yield, 83 mg (82%); 1H NMR (400 MHz, CDCl3) δ 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), 6.52–6.55 (m, 1H, H-7), 2.51 (s, 3H, C9-CH3). 13C NMR (100 MHz, CDCl3) δ 154.7, 146.2, 140.6 (2C), 128.7 (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 C18H14N2: C 83.69; H 5.46; N 10.84; found: C 83.66; H 5.51; N 10.95.
7-Methyl-2-phenylpyrido[2,3-b]indolizine (3c). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 5. Dark yellow powder; m.p. 175–176 °C (decomp.); yield, 27 mg (27%); 1H 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, H-10), 2.31 (3H, c, C7-CH3). 13C NMR (100 MHz, CDCl3) δ 154.5, 146.0, 140.7, 138.3, 128.6 (2C), 128.3, 127.5 (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 C18H14N2: C 83.69; H 5.46; N 10.84; found: C 83.62; H 5.48; N 10.99.
2-(p-Tolyl)pyrido[2,3-b]indolizine (3d). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 10. Bright yellow powder; m.p. 181–182 °C (decomp.); yield, 29 mg (29%); 1H NMR (400 MHz, CDCl3) δ 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) δ 153.2, 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, 20.8. ESI MS: m/z 259 [M + H]+. Elemental analysis calcd (%) for C18H14N2: C, 83.69; H, 5.46; N, 10.84; 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 acetate-hexane 1: 15. Yellow powder; m.p. 174 °C (decomp.); yield, 87 mg (81%); 1H NMR (400 MHz, CDCl3) δ 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), 6.65–6.67 (m, 1H, H-7), 2.46 (s, 3H, C9-CH3), 2.37 (s, 3H, Ph-CH3). 13C NMR (100 MHz, CDCl3) δ 153.1, 145.4, 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 C19H16N2: C, 83.79; H, 5.92; N, 10.29; 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 acetate-hexane 1: 15. Dark yellow powder; m.p. 173–174 °C (decomp.); yield, 23 mg (21%); 1H 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, H-8), 6.73 (s, 1H, H-10), 2.37 (s, 3H, Ph-CH3), 2.28 (s, 3H, C7-CH3). 13C NMR (100 MHz, CDCl3) δ 152.9, 145.3, 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 C19H16N2: C, 83.79; H, 5.92; N, 10.29; 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 acetate-hexane 1: 15. Brown powder; m.p. 215–217 °C (decomp.); yield, 33 mg (26%); 1H NMR (400 MHz, CDCl3) δ 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) δ 151.9, 145.5, 139.1, 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 324 [M + H]+. Elemental analysis calcd (%) for C17H11BrN2: C 63.18; H 3.43; N 8.67; found: C 63.25; H 3.40; N 8.63.
2-(4-Bromophenyl)-9-methylpyrido[2,3-b]indolizine (3h). Prepared according to the Method B. Gold powder; m.p. 192–193 °C (decomp.); yield, 82 mg (62%); 1H NMR (400 MHz, CDCl3) δ 8.80 (d, 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, H-7), 2.46 (s, 3H, C9-CH3). 13C NMR (100 MHz, CDCl3) δ 151.8, 145.5, 140.0, 139.1, 131.5 (2C), 128.9 (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 C18H13BrN2: C 64.11; H 3.89; N 8.31; found: C 64.01; H 3.91; N 8.36.
2-(4-Bromophenyl)-7-methylpyrido[2,3-b]indolizine (3i). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 15. Light brown powder; m.p. 177–178 °C (decomp.); yield, 25 mg (19%); 1H 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 (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, 1H, H-8), 6.74 (s, 1H, H-10), 2.27 (s, 3H, C7-CH3). 13C NMR (100 MHz, CDCl3) δ 151.5, 145.3, 139.1, 137.9, 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 338 [M + H]+. Elemental analysis calcd (%) for C18H13BrN2: C 64.11; H 3.89; N 8.31; found: C 64.17; H 3.92; N 8.34.
2-(Pyrido[2,3-b]indolizin-2-yl)phenol (3j). Prepared according to the Method C. Dark brown powder; m.p. 230–232 °C (decomp.); yield, 38 mg (37%); 1H NMR (400 MHz, CDCl3) δ 15.09 (s, 1H, OH), 8.99 (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, 1H, 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, 2H, Ph-H), 6.84 (s, 1H, H-10), 6.78–6.80 (m, 1H, H-7). 13C NMR (100 MHz, CDCl3) δ 159.5, 154.4, 141.6, 139.3, 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 C17H12N2O: C 78.44; H 4.65; N 10.76; found: C 78.39; H 4.62; N 10.82.
2-(9-Methylpyrido[2,3-b]indolizin-2-yl)phenol (3k). Prepared according to the Method B. Gold powder; m.p. 179 °C (decomp.); yield, 71 mg (66%); 1H NMR (400 MHz, CDCl3) δ 15.10 (s, 1H, OH), 8.87 (d, 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), 6.73–6.76 (m, 1H, H-7), 2.47 (s, 3H, C9-CH3). 13C NMR (100 MHz, CDCl3) δ 159.5, 154.3, 141.5, 140.3, 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 [M + H]+. Elemental analysis calcd (%) for C18H14N2O: C 78.81; H 5.14; N 10.21; found: C 78.77; H 5.16; N 10.30.
2-(7-Methylpyrido[2,3-b]indolizin-2-yl)phenol (3l). Prepared according to the Method C. Brown powder; m.p. 226–227 °C (decomp.); yield, 26 mg (24%); 1H NMR (400 MHz, CDCl3) δ 15.13 (s, 1H, OH), 8.81 (s, 1H, 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), 6.78 (s, 1H, H-10), 2.30 (s, 3H, C9-CH3). 13C NMR (100 MHz, CDCl3) δ 159.5, 154.1, 141.4, 138.3, 130.7, 128.4, 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 C18H14N2O: C 78.81; H 5.14; N 10.21; found: C 78.83; H 5.11; N 10.28.
2-(Pyridin-4-yl)pyrido[2,3-b]indolizine (3m). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 5. Orange powder; m.p. 196–199 °C (decomp.); yield, 30 mg (31%); 1H NMR (400 MHz, CDCl3) 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), 6.58–6.60 (m, 1H, H-8). 13C NMR (100 MHz, CDCl3) δ 151.7, 150.2 (2C), 147.7, 146.5, 139.9, 124.7, 124.0, 122.4, 121.7 (2C), 119.6, 118.2, 111.8, 109.2, 92.7. ESI MS: m/z 246 [M + H]+. Elemental analysis calcd (%) for C16H11N3: C 78.35; H 4.52; N 17.13; found: C 78.31; H 4.55; N 17.20.
9-Methyl-2-(pyridin-4-yl)pyrido[2,3-b]indolizine (3n). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 5. Light beige powder; m.p. 173–174 °C (decomp.); yield, 34 mg (33%); 1H NMR (400 MHz, CDCl3) δ 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, 2H, 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, 1H, H-7), 3.18 (s, 3H, C9-CH3). 13C NMR (100 MHz, CDCl3) δ 151.5, 150.5, 150.2 (2C), 147.7, 141.1, 128.5, 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 C17H13N3: C 78.74; H 5.05; N 16.20; found: C 78.71; H 5.09; N 16.29.
7-Methyl-2-(pyridin-4-yl)pyrido[2,3-b]indolizine (3o). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 5. Light beige powder; m.p. 223–225 °C (decomp.); yield, 27 mg (26%); 1H 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 (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, 1H, H-8), 6.87 (s, 1H, H-10), 2.33 (s, 3H, C7-CH3). 13C NMR (100 MHz, CDCl3) δ 151.3, 150.1 (2C), 147.9, 146.4, 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 C17H13N3: C 78.74; H 5.05; N 16.20; found: C 78.69; H 5.06; N 16.32.
2-(Pyridin-2-yl)pyrido[2,3-b]indolizine (3p). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 10. Yellow powder; m.p. 159–162 °C (decomp.); yield, 27 mg (28%); 1H NMR (400 MHz, CDCl3) δ 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, 1H, 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), 6.58–6.60 (m, 1H, H-8). 13C NMR (100 MHz, CDCl3) δ 157.2, 153.4, 149.0, 145.9, 139.5, 136.9, 124.7, 123.6, 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 C16H11N3: C 78.35; H 4.52; N 17.13; found: C 78.32; H 4.57; N 17.14.
9-Methyl-2-(pyridin-2-yl)pyrido[2,3-b]indolizine (3q). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 10. Lime-green powder; m.p. 124–127 °C (decomp.); yield, 71 mg (70%); 1H NMR (400 MHz, CDCl3) δ 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, 1H, 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, C9-CH3). 13C 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, 122.1, 121.5, 118.3, 112.5, 109.1, 91.1, 18.5. ESI MS: m/z 260 [M + H]+. Elemental analysis calcd (%) for C17H13N3: C 78.74; H 5.05; N 16.20; found: C 78.70; H 5.07; N 16.25.
7-Methyl-2-(pyridin-4-yl)pyrido[2,3-b]indolizine (3r). Prepared according to the Method A. Eluent ethyl acetate-hexane 1: 7. Brown powder; m.p. 74–79 °C (decomp.); yield, 39 mg (38%); 1H NMR (400 MHz, CDCl3) δ 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 (m, 1H, Py-H), 6.86–6.89 (m, 2H, H-8, H-10), 2.33 (s, 3H, C7-CH3). 13C NMR (100 MHz, CDCl3) δ 157.4, 153.2, 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 C17H13N3: C 78.74; H 5.05; N 16.20; found: C 78.71; 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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Sample Availability: Not available.
Molecules 25 04059 sch001
Scheme 1. General representation of the current work.
Scheme 1. General representation of the current work.
Molecules 25 04059 sch001
Molecules 25 04059 sch002
Scheme 2. The scope of the reaction between N-cyanomethyl-2-methylpyridinium bromides and various enaminones a. a 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 placed into the microwave reactor and irradiated at 150 °C for 30 min. b The reaction was performed on 1.182 mmol scale of N-cyanomethyl-2,3-dimethylpyridinium salt.
Scheme 2. The scope of the reaction between N-cyanomethyl-2-methylpyridinium bromides and various enaminones a. a 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 placed into the microwave reactor and irradiated at 150 °C for 30 min. b The reaction was performed on 1.182 mmol scale of N-cyanomethyl-2,3-dimethylpyridinium salt.
Molecules 25 04059 sch002
Molecules 25 04059 g001
Figure 1. Crystal structure of 3b (CCDC 1922817).
Figure 1. Crystal structure of 3b (CCDC 1922817).
Molecules 25 04059 g001
Molecules 25 04059 sch003
Scheme 3. Proposed mechanism for pyrido[2,3-b]indolizine formation.
Scheme 3. Proposed mechanism for pyrido[2,3-b]indolizine formation.
Molecules 25 04059 sch003
Molecules 25 04059 g002
Figure 2. The absorbance (a) and emission (b) spectra of the above synthesized compounds in toluene.
Figure 2. The absorbance (a) and emission (b) spectra of the above synthesized compounds in toluene.
Molecules 25 04059 g002
Table 1. Reaction conditions optimization.
Table 1. Reaction conditions optimization.
Molecules 25 04059 i001
Entry aBase1a: 2a: BaseYield, % b
1NaOAc3: 1: 534
23: 1: 140
33: 1: 0.546
43: 1: 0.112
51.5: 1: 0.550
61: 1: 0.544
7Et3N1.5: 1: 0.531
8DIPEA1.5: 1: 0.525
9NH4OAc1.5: 1: 0.534
10K2CO31.5: 1: 0.55
11Cs2CO31.5: 1: 0.521
12 cNaOAc1.5: 1: 0.547
13 dNaOAc1.5: 1: 0.533
14 eNaOAc1.5: 1: 0.537
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 150 °C for 30 min. b Isolated yield. c The reaction time was prolonged from 30 to 60 min. d The reaction temperature was 120 °C. e The reaction temperature was 180 °C.
Table 2. Photophysical properties of the synthesized compound.
Table 2. Photophysical properties of the synthesized compound.
Compound Abs [a]ε [b]Emission [a]FQY [c]Stokes Shift
[nm][(M cm)−1 (109)][nm][%][cm−1]
3a4131.652511774643
3b4041.616505824950
3c4141.656520644923
3m4181.672519574655
3n4101.640513634897
3o4201.680528554870
3p4161.664516644658
3q4091.636512774918
[a] Peak maximum. [b] Molar extinction coefficient. [c] Fluorescence quantum yield.

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MDPI and ACS Style

Sokolova, E.A.; Festa, A.A.; Subramani, K.; Rybakov, V.B.; Varlamov, A.V.; Voskressensky, L.G.; Van der Eycken, E.V. Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones. Molecules 2020, 25, 4059. https://doi.org/10.3390/molecules25184059

AMA Style

Sokolova EA, Festa AA, Subramani K, Rybakov VB, Varlamov AV, Voskressensky LG, Van der Eycken EV. Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones. Molecules. 2020; 25(18):4059. https://doi.org/10.3390/molecules25184059

Chicago/Turabian Style

Sokolova, Ekaterina A., Alexey A. Festa, Karthikeyan Subramani, Victor B. Rybakov, Alexey V. Varlamov, Leonid G. Voskressensky, and Erik V. Van der Eycken. 2020. "Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones" Molecules 25, no. 18: 4059. https://doi.org/10.3390/molecules25184059

APA Style

Sokolova, E. A., Festa, A. A., Subramani, K., Rybakov, V. B., Varlamov, A. V., Voskressensky, L. G., & Van der Eycken, E. V. (2020). Microwave-Assisted Synthesis of Fluorescent Pyrido[2,3-b]indolizines from Alkylpyridinium Salts and Enaminones. Molecules, 25(18), 4059. https://doi.org/10.3390/molecules25184059

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