HETEROCYCLES

Note | Regular issue | Vol. 78, No. 5, 2009, pp. 1271-1279
Received, 2nd December, 2008, Accepted, 26th January, 2009, Published online, 29th January, 2009.
DOI: 10.3987/COM-08-11614

■ Synthesis of Quinolizino[3,2-a]quinolizine Derivatives and Their Fluorescence

Kenichirou Yokota, Masayori Hagimori, Yasuhiro Shigemitsu, Naoko Mizuyama, Bo-Cheng Wang, and Yoshinori Tominaga*

School of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Polycyclic quinolizine derivatives, quinolizino[3,2-a]quinolizines (4a–c), were synthesized in moderate yields by a one-pot method using ketene dithioacetal, methyl bis(methylsulfanyl)methylene-cyanoacetate (2), alkyl 2-pyridylacetates (1a, b), and 2-pyridylacetonitrile (1c). Compounds 4a, b exhibited red fluorescence (Em max: 576 nm) in solid state.

Recently, organic electroluminescent (OEL) materials that exhibit fluorescence in solid state have gained considerable attention. OELs are now fast replacing liquid crystal displays (LCDs). Fluorescent dyes can be used as emitters in electroluminescence devices and as solar energy accumulators; they are also used to prepare fluorescent greenhouse films, copy-preventing inks, and fluorescent colorants.1 Heteroaromatic compounds have attracted particular interest because most heterocyclic compounds contain a variety of fluorescent pigment molecules. We have synthesized many heterocyclic compounds from ketene dithioacetals, some of which exhibit fluorescence.2 In general, chemical compounds that display fluorescence are mostly polycyclic aromatic and polyaryl-substituted compounds, such as rubulene derivatives. Recently, we found that 2-pyrone derivatives are potential electroluminescent materials.3 The fused 2-pyrone derivative, the pyranoquinolizine derivative A4 exhibits red fluorescence in solid state, which is an important and desired feature in the field of OEL research. Certain types of quinolizines have attracted significant attention owing to their possible applications as photographic materials and dyes.5–7 In particular, the fluorescence properties of fused quinolizine derivatives such as pyrroloquinolizine derivative B and quinolizino[3,2-a]quinolizine C are of interest to us.2a-d,8 In this paper, we report the synthesis of fused quinolizine derivatives, quinolizino[3,2-a]quinolizines, by a one-pot synthesis method using a ketene dithioacetal.

4H-Quinolizine derivatives are usually synthesized by the condensation of alkyl 2-pyridylacetates (1a, b) or 2-pyridylacetonitrile (1c) with ethoxymethylene compounds and ketene dithioacetals.7 During their study on [3.3.3]cyclazine derivatives, Schwarz et al. synthesized 4H-quinolizines and analyzed their ultraviolet-visible (UV-Vis) spectra7b in detail;8 however, they did not investigate the fluorescence properties of these compounds. In our previous research, we synthesized 2-methylsulfanyl-4-oxo-4H-quinolizine-3-carbonitriles (3a, b) in 48–50% yield by direct heating of a mixture of ketene dithioacetal (2) and 1a or 1b without any solvent or catalyst (base or acid).6 Since the yield of the products formed under these reaction conditions was unexpectedly low (48–50%), we carried
out the above-mentioned reaction under basic conditions. We carried out the condensation of methyl 2-pyridylacetate (1a) with methyl bis(methylsulfanyl)methylene-cyanoacetate (2) in the presence of potassium carbonate at room temperature for 4–5 h and obtained methyl 3-cyano-4-oxo -4H-quinolizine-1-carboxylate (3a) in 84% yield. With 3 equiv of 1a, we could isolate methyl 7-cyano-6,14-dioxo-6H,14H-quinolizino[3,2-a]quinolizine-8-carboxylate (4a) in 68% yield. In this case, we carried out the reaction at room temperature for 1 h, after which we heated the reaction mixture at 50–60 °C for 20 min (short reaction time) and then stirred it at room temperature for 3 h. We synthesized 4b (57% yield) in a similar manner from 2 and 1b. We also obtained 4c from 1a, 2, and 1c by a one-pot reaction (Scheme 1). These quinolizino[3,2-a]quinolizine derivatives were presumably formed via the addition-elimination and cyclization mechanism shown in Scheme 2.

Treatment of 4a with polyphosphoric acid (PPA) at 100°C for 30 min afforded a five-ring system, 7-Hydroxy-6,9,15-trioxo-6H,9H,15H-pyrido[3,4,5-g.h]quinolizino[3,2-a]quinolizine (5), in 54% yield (mp > 300°C) (Scheme 3). The structure of 5 was established on the basis of its spectroscopic data.

FLUORESCENCE
Research on 2-pyrone derivatives revealed that pyrano[3,4-d]quinolizine derivatives emit red fluorescence in solid state.4 Further research on the fluorescence of chemical compounds with a fused quinolizine skeleton is expected to be carried out in the future. We focused our research on the fluorescence properties of 6H,14H-quinolizino[3,2-a]quinolizine-6,14-dione derivatives synthesized. We analyzed the room-temperature fluorescence emission spectra of 3a, 3b, 4a–c, and 5 in their solid states. The fluorescence maxima (Em max) and relative fluorescent intensities (RI) of these compounds are listed in Table 1. The Em max and RIs of 3a, b, 4a–c, and 5 ranged from 541 to 576 nm and 0.01 to 0.44, respectively. Among these compounds, 4a and 4b showed red fluorescence similar to DCM: [4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran], which is a red laser dye (Em max: 577 nm)1b,9. The implications of the present results are discussed on the fluorescence of 4H-quinolizine derivatives as a basic structure in the field of organic electroluminescent materials. Currently, we are in the process of evaluating the relationship between structure and fluorescence properties of these compounds.

In conclusion, polycyclic quinolizine derivatives, 6H,14H-quinolizino[3,2-a]quinolizines (4a–c), were synthesized in moderate yields by a one-pot method using a ketene dithioacetal, methyl bis(methylsulfanyl)methylene-cyanoacetate (2), alkyl 2-pyridylacetates (1a, b), and 2-pyridylacetonitrile (1c). These compounds exhibited red fluorescence (4a, Em max: 576 nm; 4b, Em max: 576 nm) similar to DCM.

EXPERIMENTAL
Identifications of compounds and measurements of properties were carried out by general procedures using the following equipment. All melting points were determined in a capillary tube and uncorrected. Infrared (IR) spectra were recorded in potassium bromide pellets on JASCO 810 or Shimazu IR-460 spectrometer and ultraviolets (UV) absorption spectra were determined in 95% ethanol on a Hitachi 323 spectrometer. Fluorescence spectra were determined on Shimazu RF-5300pc. Nuclear magnetic resonance (NMR) spectra were obtained on Gemini 300NMR (300MHz), JEOL-GX-400 (400MHz), and Varian UNITYplus 500NMR (500MHz) spectrometers with tetramethylsilane as an internal standard. Mass spectra (MS) were recorded on JEOL-DX-303 mass spectrometers. Microanalyses were performed by K.Yoshida on a Perkin Elmer at Nagasaki University. All compounds were reagent grade and used without further purification unless otherwise specified.

Method of Measurement of Fluorescence.
A powder sample of subject compound is heaped in a tray. After covering the sample with a quartz plate, this part was fixed in fluorescence spectrometer. After fixing the fluorescent wavelength, the excitation spectrum was determined by the scanning with the fluorescent wavelength. Similarly, Fluorescent spectrum was obtained after scanning with the excitation wavelength. After obtaining these results, the excitation wavelength was decided and the fluorescence spectrum was measured. The fluorescent relative intensity was determined by using DMPC: [6-(4-N,N-dimethylaminophenyl)-4-methylsulfanyl-2-oxo-2H- pyran-3-carbonitrile]3g as standard sample. Fluorescence of standard sample and all subject compounds were measured on 345 nm excitation.

Methyl 3-Cyano-2-methylsulfanyl-4-oxo-4H-quinolizine-1-carboxylate (3a)
A mixture of 0.76 g (5.00 mmol) of methyl 2-pyridylacetate (1a), 1.0 g (5.0 mmol) of 2, and 1.38 g (10.0 mmol) of potassium carbonate in 15 mL of DMSO was stirred for 2 h at rt. This mixture was stirred and heated for 20 min at 50-60°C and for additional 2 h at rt. The reaction mixture was poured into 300 mL of ice water and then neutralized with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried by air to give yellow products. The products was collected by filtration to give 1.15 g (4.19 mmol, 84% yield). Analytical sample was recrystallized from MeOH to give dark red crystals, mp 131-132°C (Lit.,6c 133-134°C). IR (KBr, cm-1): 2217 (CN), 1734 (CO), 1671 (CO), 1625, 1509, 1467. 1H NMR (CDCl3) δ: 2.75 (3H, s, SMe), 4.00 (3H, s, OMe), 7.31 (1H, m, 7-H), 7.78 (1H, dd, J=1.4, 5.5 Hz, 9-H), 7.78 (1H, m, 8-H), 9.26 (1H, ddd, J=1.2, 1.2, 9.3 Hz, 6-H). 13C NMR (100 MHz, CDCl3) δ: 19.11, 53.01, 93.71, 112.01, 115.77, 117.60, 123.13, 129.22, 136.53, 141.70, 153.57, 156.22, 165.70. Fluoresence (solid): Ex max, 337 nm; Em max, 568 nm; RI=0.43.
Ethyl 3-Cyano-2-methylsulfanyl-4-oxo-4H-quinolizine-1-carboxylate (3b)
This compound was prepared in 71% yield from, 1.65 g (10.0 mmol) of ethyl 2-pyridylacetate (1b), 2.44 g (12.0 mmol) of 2 and 2.76 g (20.0 mmol) of potassium carbonate in a manner similar to that described for synthesis of 3a. In this case, an insoluble side product in EtOH was obtained 0.042 g (1.2%) as orange needles, mp 311-312°C. This product was compound 4a. An analytical sample was recrystallized from EtOH to give yellow needles, mp 126-128°C (Lit.,6c mp 128-129°C). IR (KBr, cm-1): 2202 (CN) 1666 (CO), 1623, 1459 1223. 1H NMR (CDCl3) δ: 1.44 (3H, t, J=7.3 Hz, O-CH2-CH3), 2.75 (3H, s, SMe), 4.48 (2H, q, J=7.3 Hz, O-CH2-), 7.30 (1H, m, 7-H), 7.74-7.84 (2H, m, 8, 9-H), 9.26 (1H, J=7.2 Hz, 6-H). 13C NMR (100 MHz, CDCl3) δ: 14.08, 19.15, 62.59, 93.84, 112.52, 115.80, 117.53, 123.11, 129.22, 136.39, 141.63, 153.35, 156.27, 165.26. Fluoresence (solid): Ex max, 341 nm; Em max, 541 nm; RI=0.44.
Methyl 7-Cyano-6,14dioxo-6H,14H-quinolizino[3,2-a]quinolizine-8-carboxylate (4a)
Method A: A mixture of, 2.27 g (15.0 mmol) of methyl 2-pyridylacetate (1a), 1.0 g (5.0 mmol) of 2, and 2.76 g (20.0 mmol) of potassium carbonate in 15 mL of DMSO was stirred for 2 h at rt. This mixture was stirred and heated for 30 min at 50-60°C and stirred for additional 2 h at rt. The reaction mixture was poured into 300 mL of ice water and then neutralized with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried by air to give dark red products. A mixture of this compounds and 50 mL of MeOH was refluxed for 1 h. After cooling, the product was collected by filtration to give 1.17 g (3.39 mmol, 68% yield). Analytical sample was recrystallized from DMF to give orange red crystals, mp 311-313°C. Method B: A mixture of, 0.302 g (2.0 mmol) of methyl 2-pyridylacetate (1a), 0.332 g (2.2 mmol) of 3a, and 0.552 g (4.0 mmol) of potassium carbonate in 10 mL of DMSO was stirred for 2 h at rt. This mixture was stirred and heated for 30 min at 50-60°C and stirred for additional 2 h at rt. The reaction mixture was poured into 300 mL of ice water. The precipitate was collected by filtration, washed with water, and dried by air to give dark red products. A mixture of this compounds and 50 mL of MeOH was refluxed for 1 h. After cooling, the product was collected by filtration to give 0.409 g (1.14 mmol, 57% yield). IR (KBr, cm-1): 3094, 2206 (CN), 1720 (CO), 1683, 1653, 1551, 1517, 1498. UV (EtOH) λ nm (log ε): 270 (4.10), 377 (4.23), 429 (3.93). 1H NMR (DMSO-D6) δ: 3.94 (3H, s, OMe), 7.19 (1H, ddd, J=1.4, 6.6, 7.1 Hz, 11-H), 7.67 (1H, dd, J=1.4, 8.9 Hz, 9-H), 7.74 (1H, ddd, J=1.4, 6.6, 8.9 Hz, 10-H), 7.90 (1H, ddd, J=1.4, 6.0, 7.1 Hz, 3-H), 8.53 (1H, ddd, J=1.4, 7.1, 8.5 Hz, 2-H), 9.08 (1H, d, J=7.1 Hz, 12-H), 9.62 (1H, d, J=6.0 Hz, 4-H), 10.18 (1H, d, J=8.5 Hz, 1-H). 13C NMR (100 MHz, DMSO-D6) δ: 51.95, 75.52, 95.29, 95.65, 114.66, 117.30, 120.73, 121.07, 124.59, 128.25, 131.83, 135.80, 139.94, 141.27, 142.38, 146.38, 155.64, 156.45, 166.62. Fluoresence (solid): Ex max, 336 nm; Em max, 576 nm; RI=0.12. Ms: m/z 346 (M++1, 36), 345 (M+, 100), 319 (15), 317 (57), 314 (40), 302 (13), 287 (24), 286 (69), 259 (48), 230 (49), 78 (26). Anal. Calcd for C19H11N3O4=345.3085: C, 66.09; H, 3.21; N, 12.17. Found: C, 65.81; H, 3.21; N, 12.09.
Ethyl 7-Cyano-6,14-dioxo-6H,14H-quinolizino[3,2-a]quinolizine-8-carboxylate (4b)
This compound (0.51 g, 1.43 mmol) was prepared in 57% yield from 1.24 g (7.5 mmol) of ethyl 2-pyridylacetate (1b), 0.51 g (2.5 mmol) of 2, and 1.38 g (10.0 mmol) of potassium carbonate in a manner similar to that described for synthesis of 4a. This compound (4b) was also prepared from 3b and 1b under the same reaction condition in 57% yield (Method B). An analytical sample was recrystallized from DMF to give dark red needles, mp 305-306°C. IR (KBr, cm-1): 3092, 2203 (CN), 1723 (CO), 1681 (CO), 1645, 1556, 1520, 1498. UV (EtOH) λ nm (log ε): 270 (4.24), 273 (4.10), 346 (4.25), 364 (4.32), 378 (4.34), 430 (4.03). 1H NMR (CDCl3) δ: 1.42 (3H, t, OCH2-CH3), 4.61 (2H, q, O-CH2-Me), 6.96 (1H, m, 11-H), 7.52 (1H, m, 10-H), 7.67 (1H, m, 3-H), 7.81 (1H, d, J=9.2 Hz, 9-H), 8. 27 (1H, m, 2-H), 9.10 (1H, d, J=7.8 Hz, 12-H), 9.78 (1H, d, J=7.7 Hz, 4-H), 10.37 (1H, d, J=9.7 Hz, 1-H). 13C NMR (100 MHz, CDCl3) δ: 13.53, 64.81, 92.72, 110.02, 112.85, 115.69, 118.52, 120.13, 122.03, 124.21, 125.90, 131.91, 133.20, 141.91, 143.06, 145.74, 146.99, 147.94, 154.85, 156.19, 166.59. Fluoresence (solid): Ex max, 328 nm; Em max, 576 nm; RI= 0.13. Ms: m/z 360 (M++1, 23), 359 (M+, 100), 331 (29), 314 (29), 303 (18), 287 (30), 286 (20), 260 (11), 259 (54), 230 (63). Anal. Calcd for C20H13N4O4=359.355: C, 66.85; H, 3.65; N, 11.69. Found: C, 66.73; H, 3.41; N, 11.61.
6,14-Dioxo-6H,14H-quinolizino[3,2-a]quinolizine-7, 8-dicarbonitrile (4c)
A mixture of 0.76 g (5.0 mmol) of methyl 2-pyridylacetate (1a), 1.0 g (5.0 mmol) of 2 and 1.38 g (10.0 mmol) of potassium carbonate in 15 mL of DMSO was stirred for 2 h at rt. This mixture was stirred and heated for 10 min at 50-60°C and stirred for additional 2 h at rt. 0.71 g (6.0 mmol) of 2-pyrdylacetonitrile (1c) and 1.38 g (10.0 mmol) of potassium carbonate were added to the reaction mixture. After stirring for 4 h at rt, the reaction mixture was poured into 300 mL of ice water and then neutralized with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried by air to give dark red product. A mixture of this compounds and 50 mL of MeOH was refluxed for 1 h. After cooling, the products were collected by filtration to give 1.15 g (3.69 mmol, 74% yield). This compound (4c) was also synthesized from 3a and 1c in 62% yield (Method B). Analytical sample was recrystallized from DMF to give brown yellow crystals, mp > 300°C. IR (KBr, cm-1): 3100, 2210 (CN), 1691 (CO), 1655 (CO), 1617, 1561, 1515. UV (EtOH) λ nm (log ε): 269 (4.35), 309 (4.30), 341 (4.37), 358 (4.35), 373 (4.32), 426 (4.18). 1H NMR (CDCl3) δ: 7.42 (1H, m, 11-H), 7.88 (2H, m, 10-H), 8.03 (1H, m, 3-H), 8.14 (1H, d, J=8.8 Hz, 9-H), 8.48 (1H, m, 2-H), 9.37 (1H, d, J=6.8 Hz, 12-H), 9.79 (1H, d, J=6.8 Hz, 4-H), 10.31 (1H, d, J=8.8 Hz, 1-H). 13C NMR (100 MHz, CDCl3) δ: 96.35, 110.01, 112.84, 115.67, 117.41, 118.50, 121.63, 122.71, 125.75, 130.00, 132.46, 139.71, 142.10, 143.30, 146.61, 147.92, 155.63, 158.75. Fluoresence (solid): Ex max, 329 nm; Em max, 563 nm; RI=0.01. Ms: m/z 313 (M++1, 5), 312 (M+, 21), 284 (27), 255 (12), 44 (00). HRMS (EI): 312.0629 (Calcd. 312.0647 for C18H8N4O2).
7-Hydroxy-6,9,15-trioxo-6H,9H,15H-pyrido[3,4,5-g.h]quinolizino[3,2-a]quinolizine (5)
A mixture of 4a (0.39 g, 1.1 mmol) was heated at 100°C for 1 h. After cooling, the mixture was poured into 100 mL of water and stand over for 2 h. The precipitate was collected by the filtration to give 0.20 g (0.59 mmol, 54% yield) of yellow brown crystals which was recrystalized from DMF to give yellow crystals, mp > 300°C. IR (KBr, cm-1): 2537 (br), 3128, 3002, 1731 (CO), 1667 (CO), 1623, 1560, 1519. UV (EtOH) λ nm (log ε): 285 (4.09), 305 (4.06), 332 (4.08), 431 (3.98). 1H NMR (CDCl3 + CF3COOH 0.04 ml) δ: 7.85 (1H, m, 12-H), 7.94 (1H, m, 11-H), 8.46 (1H, m, 3-H), 8.62 (1H m, 2-H), 9.70 (1H, d, J=7.3 Hz, 10-H), 9.81 (1H, d, J=8.3 Hz, 13-H), 10.02 (1H, d, J=8.9 Hz, 4-H), 10.25 (1H, d, J=8.6 Hz, 1-H). 13C NMR (100 MHz, CDCl3 + CF3COOH 0.04 mL) δ: 110.08, 112.91, 115.75, 118.58, 120.97, 121.86, 124.80, 126.04, 132.35, 139.99, 143.60, 145.77, 146.67, 148.19, 155.00, 159.83, 160.60, 167.10. Fluoresence (solid): Ex max, 343 nm; Em max, 569 nm; RI=0.04. Ms: m/z 332 (M++1, 28), 331 (M+, 100), 303 (38), 232 (15), 231 (12), 230 (17), 204 (15), 203 (18). HRMS (EI): 331.0578 (Calcd. 331.0593 for C18H9N3O4).

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10. Compound 2 is commercially available reagent.