Abstract
Acridinediones were synthesized by the one-pot Hantzsch condensation of an aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione, and aniline/4-methylaniline in refluxing water. This method has then been extended to the four-component reaction of an aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione, ethyl acetoacetate and ammonium acetate for the synthesis of polyhydroquinoline derivatives. This is an environmentally friendly and efficient procedure providing good to excellent yields.
Keywords: acridinedione, polyhydroquinoline, one-pot reaction, water
1. Introduction
1,4-Dihydropyridines as analogues of nicotinamide adenine dinucleotide (NADH) coenzymes exhibit a wide range of biological activities, such as calcium channel blocking, and today they are widely used in pharmacology [1]. Acridines which possess the 1,4-dihydropyridine parent nucleus have interesting pharmaceutical properties such as a positive iontropic effects promoting the entry of calcium to the intracellular space [2], and 1,8-(2H,5H)-acridinediones are known as laser dyes [3].
1,8-(2H,5H)-Acridinediones were synthesized by the adoption of the Hantzsch procedure, i.e., by the thermal reaction of 5,5-dimethyl-1,3-cyclohexanedione (dimedone) with an aldehyde and ammonia. Most of the methods reported previously usually require long reaction times, afford 1,4-dihydropyridines in relatively low yield, and suffer from utilizing harmful organic solvents in most cases [4,5,6,7,8,9,10,11].
On the other hand, with the increasing environmental concerns, green chemistry has attracted intensive attention in recent years. Multicomponent one-pot reactions as a kind of economical and efficient procedure has been widely used for the synthesis of heteroatom-containing compounds [12,13,14]. Moreover, organic reactions in water as the reaction medium, which represents a clean, economical, and environmental-safe protocol, has attracted considerable attention. We have already reported the one-pot synthesis of 10-unsubstituted 1,8-(2H,5H)-acridinediones by the thermal reaction of 5,5-dimethyl-1,3-cyclohexanedione (dimedone) with an aldehyde and ammonium acetate in pure water without any additives [15]. In this paper, ammonium acetate has been replaced by aniline and 4-methylaniline for the synthesis of N-substituted 1,8-(2H,5H)-acridinediones by the Hantzsch reaction in refluxing water.
2. Results and Discussion
1,8-(2H,5H)-Acridinediones were synthesized by the one-pot three-component Hantzsch condensation for a designated time of paraformaldehyde, dimedone and NH4HCO3, or NH4OAc, or aniline, or 4-methyl-aniline in refluxing water without any additives. The reaction times and yields are listed in Table 1.
Table 1.
Reaction time and yield for the reaction of different amines/ammonium salts.
| Entry | Amine | Reaction time/min | Product | R | Yield / % a |
|---|---|---|---|---|---|
| 1 | NH4OAc | 40 min | 4a | H | 86 |
| 2 | NH4HCO3 | 40 min | 4b | H | 83 |
| 3 | C6H5-NH2 | 90 min | 4c | C6H5 | 71 |
| 4 | 4-CH3-C6H5-NH2 | 90 min | 4d | 4-CH3-C6H4 | 69 |
a Isolated yield of the pure product recrystallized from 75% aqueous ethanol.
From Table 1, one can see that the reaction yields of ammonium compounds (entry 1 and 2) are higher than for aromatic amines (entry 3 and 4). This is probably due to the lower solubility of the aromatic amines in water and lower reactivity than that of the ammonium compounds. It should be mentioned that the amount of the amine in the reactions was different. When an aromatic amine was used (entry 3 and 4), the molar ratio of 1, 2, and 3 was 1:2:1; when an ammonium compound was used (entry 1 and 2), the molar ratio of 1, 2, and 3 was 1:2:4. The increasing of the dosage of ammonium compound is because of the easy resolvability.
In order to obtain a higher yield, we tried to add a phase-transfer catalyst (PTC) to the reaction mixtures. Cetyltrimethylammonium bromide (CTAB) was previously applied by us to the aqueous Michael reaction of dimedone with chalcones [16], and now in this Hantzsch condensation of aldehyde, dimedone and aniline, addition of 10% mol of CTAB produced N-substituted 1,8-(2H,5H)-acridinediones in much better yield. The reaction yields, as well as the melting points for the Hantzsch reactions with the molar ratio of aromatic aldehydes 1, dimedone (2), and aniline or 4-methylaniline 3, and CTAB as 1:2:1:0.1 in refluxing water are listed in Table 2. Reaction times are all 90 min. In our protocol, no organic solvents were used during the reaction process. Furthermore, since the product is solid and precipitates out from the reaction mixtures, the work-up procedure involves simple filtration. The desired products of high purity were obtained by column chromatography or recrystallization.
Table 2.
Yields and melting points for the one-pot synthesis of N-substituted acridinediones.
| Entry | R | R’ | Product | Yield / % a | m.p. (lit.) / °C |
|---|---|---|---|---|---|
| 1 | C6H5 | C6H5 | 5a | 80 | 220–222 (200–205) [17] |
| 2 | 4-Cl-C6H4 | C6H5 | 5b | 86 | 243–245 (233–235) [18] |
| 3 | 4-CN-C6H4 | C6H5 | 5c | 88 | 265–267 |
| 4 | 4-NO2-C6H4 | C6H5 | 5d | 85 | 281–282 (216–218) [17] |
| 5 | 3- NO2-C6H4 | C6H5 | 5e | 84 | 272–274 (276–278) [19] |
| 6 | 3,4- Cl2-C6H3 | C6H5 | 5f | 90 | 274–275 |
| 7 | 4-CH3O-C6H4 | C6H5 | 5g | 70 | 291–293 (290–291) [20] |
| 8 | C6H5 | 4-CH3-C6H4 | 5h | 81 | 261–263 (264–266) [21] |
| 9 | 4-Cl-C6H4 | 4-CH3-C6H4 | 5i | 85 | 270–272 (271–272) [21] |
| 10 | 4-CN-C6H4 | 4-CH3-C6H4 | 5j | 88 | 268–270 (273–275) [21] |
| 11 | 4-NO2-C6H4 | 4-CH3-C6H4 | 5k | 83 | >300 (>300) [22] |
| 12 | 3-NO2-C6H4 | 4-CH3-C6H4 | 5l | 85 | 281–283 (283–284) [23] |
| 13 | 3,4-Cl2-C6H3 | 4-CH3-C6H4 | 5m | 88 | 253–255 (250–252) [23] |
| 14 | 4-CH3O-C6H4 | 4-CH3-C6H4 | 5n | 72 | 280–282 (281–283) [23] |
a Isolated yield of the pure product recrystallized from 75% aqueous ethanol.
From Table 2, one can see that all these reactions gave good to excellent yields, reflecting that dimedone has high solubility in water and high reactivity. The yields of N-substituted acridinediones for the aromatic aldehydes with an electron-withdrawing group are higher than those for aromatic aldehydes with electron-donating groups. We also tried 3,4-dimethoxybenzaldehyde, but the reaction yield is lower than 50%.
We have attempted to extend the above methods to different 1,3-dicarbonyl compounds for the synthesis of unsymmetrically substituted 1,4-dihydropyridines such as polyhydroquinoline derivatives. Ethyl acetoacetate and 1,3-cyclohexanedione smoothly undergo a four-component reaction with aromatic aldehyde and ammonium acetate to produce polyhydroquinoline derivatives in refluxing water catalyzed by CTAB. Because of the lower activity for the synthesis of unsymmetrically substituted 1,4-dihydropyridines than the symmetrically substituted 1,4-dihydropyridines, ammonium acetate was used to replace the aromatic amines. The reaction yields, as well as the melting points for the Hantzsch reaction with the molar ratio of aromatic aldehydes 1, dimedone (2), ethyl acetoacetate (6), ammonium acetate (3), and CTAB as 1:1:1:4:0.1 in refluxing water are listed in Table 3. Reaction times are all 90 min.
Table 3.
Yields and melting points for the one-pot synthesis of polyhydroquinoline derivatives.
| Entry | R | Product | Yield / % a | m.p. (lit.) / °C |
|---|---|---|---|---|
| 1 | C6H5 | 7a | 85 | 224–226 (228–229) [24] |
| 2 | 4-CH3O-C6H4 | 7b | 81 | 257–259 (260–262) [24] |
| 3 | 4-Cl-C6H4 | 7c | 90 | 244–266 (245–246) [24] |
| 4 | 4-NO2-C6H4 | 7d | 88 | 242–244 (241–242) [24] |
a Isolated yield of the pure product recrystallized from 75% aqueous ethanol.
Among the acridinediones and polyhydroquinoline products 5c and 5f were unknown compounds and were characterized by their melting point, IR, 1H-NMR, 13C-NMR spectra and elemental analysis. Structures of known compounds were confirmed by comparison of their melting points and 1H-NMR spectra with the reported data. It should be mentioned that the melting point of 5d was obviously higher than the reported in the literature [17]. However, our measured IR, 1H-NMR, 13C-NMR spectral data and elemental analysis are consistent with the series of acridinediones products, exhibiting the same identities. The different mp might be ascribed to the presence of an impurity or solvent in product 5d from the reported literature, because even a trace amount could have a great effect on the m.p. of a compound with high m.p.
3. Experimental
3.1. General
1H-NMR spectra were recorded on a Bruker Avance-400 (400 MHz) spectrometer (Bruker, Switzerland), and chemical shifts (δ) are reported in parts per million relative to tetramethylsilane and coupling constants (J) in Hz. Splitting patterns are designated as s, singlet; d, doublet; br, broad. 13C-NMR spectra were recorded on the same spectrometer (at 100 MHz) with complete proton decoupling, and chemical shifts are reported in parts per million relative to the solvent resonance used as the internal standard (CDCl3, δ 77.16 ppm; DMSO-d6, δ 39.52 ppm). IR spectra were taken on a Bruker Vector-22 spectrometer (Bruker, Switzerland) in KBr pellets and are reported in cm−1. Melting points were determined on an XT-4 apparatus (Beijing Tech Instrument Co., Beijing, China). Analytical TLC and column chromatography were performed on silica gel GF254 and silica gel H60, respectively.
3.2. Typical Procedure for the Synthesis of Acridinediones: 3,3,6,6-Tetramethyl-9,10-diphenyl-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (5a)
A mixture of 1a (106.1 mg, 1 mmol), 2 (280.4 mg, 2 mmol), 3c (93.1 mg, 1 mmol) and CTAB (36.4 mg, 0.1 mmol) in water (4 mL) was vigorously stirred under reflux. The reaction was completed after 90 min, as monitored by TLC. Due to the high yields of 5a, the work-up procedure involved simple filtration and washing twice with water (10 mL). The obtained solid products were nearly pure. The desired product of high purity were further achieved by column chromatography with petroleum ether/ethyl acetate or recrystallization from 75% aqueous ethanol.
3,3,6,6-Tetramethyl-9-(4-cyanophenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (5c). IR (KBr): υ 2956 (s), 2872 (m), 2223 (m), 1643 (s), 1576 (s), 1492 (m), 1362 (s), 1297 (w), 1262 (m), 1174 (w), 1144 (m), 1122 (w), 1000 (m), 851 (s), 704 (s), 569 (s) cm−1; 1H-NMR (CDCl3): δ 0.79 (s, 6H, CH3), 0.95 (s, 6H, CH3), 1.85 (d, J = 17.5 Hz, 2H, CH2), 2.11 (d, J = 17.5 Hz, 2H, CH2), 2.12 (d, J = 16.2 Hz, 2H, CH2), 2.21 (d, J = 16.2 Hz, 2H, CH2), 5.31 (s, 1H, CH), 7.25 (d, J = 8.0 Hz, 2H, ArH), 7.54 (d, J = 8.6 Hz, 2H, ArH), 7.58 (d, J = 8.0 Hz, 2H, ArH), 7.59 (m, 3H, ArH); 13C-NMR (CDCl3): δ 195.8, 151.6, 150.6, 138.6, 131.9, 129.7, 128.8, 119.3, 113.4, 109.5, 50.1, 41.8, 33.7, 32.4, 29.6, 26.7; Anal. Calcd. for C30H30N2O2: C, 79.97; H, 6.71; N, 6.22; Found: C, 79.97; H, 6.80; N, 6.17.
3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (5d). IR (KBr): υ 2956 (m), 1635 (s), 1594 (w), 1514 (m), 1349 (s), 1224 (m), 1176 (w), 1144 (w), 1113 (w), 1003 (m), 864 (w), 830 (w), 703 (m), 572 (w), 513 (w) cm−1; 1H-NMR (CDCl3): δ 0.72 (s, 6H, CH3), 0.88 (s, 6H, CH3), 1.77 (d, J = 17.5 Hz, 2H, CH2), 2.03 (d, J = 17.5 Hz, 2H, CH2), 2.04 (d, J = 16.3 Hz, 2H, CH2), 2.14 (d, J = 16.3 Hz, 2H, CH2), 5.28 (s, 1H, CH), 7.18 (d, J = 8.2 Hz, 2H, ArH), 7.53 (d, J = 8.2 Hz, 2H, ArH), 7.54 (s, 1H, ArH), 7.55 (d, J = 8.8 Hz, 2H, ArH), 8.05 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (CDCl3): δ 195.6, 153.6, 150.4, 146.2, 138.7, 129.7, 128.8, 123.5, 113.6, 50.1, 41.9, 33.6, 32.4, 29.6, 26.7; Anal. Calcd. for C29H30N2O4: C, 74.02; H, 6.43; N, 5.95; Found: C, 73.63; H, 6.43; N, 5.91.
3,3,6,6-Tetramethyl-9-(3,4-dichlorophenyl)-10-phenyl-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridine-dione (5f). IR (KBr): υ 2962 (m), 2948 (m), 1650 (s), 1638 (s), 1573 (m), 1471 (m), 1360 (s), 1224 (s), 1143 (m), 1027 (w), 1002 (w), 878 (m), 704 (s), 574 (m) cm−1; 1H-NMR (CDCl3): δ 0.80 (s, 6H, CH3), 0.93 (s, 6H, CH3), 1.83 (d, J = 17.6 Hz, 2H, CH2), 2.08 (d, J = 17.6 Hz, 2H, CH2), 2.17 (m, 4H, CH2), 5.21 (s, 1H, CH), 7.22 (m, 2H, ArH), 7.28 (m, 2H, ArH), 7.50 (s 1H, ArH), 7.56 (m, 3H, ArH); 13C-NMR (CDCl3): δ 195.7, 150.3, 146.6, 138.7, 131.9, 130.0, 129.9, 129.6, 127.6, 113.8, 50.1, 41.8, 32.4, 29.7, 26.8; Anal. Calcd. for C29H29Cl2NO2: C, 70.44; H, 5.91; N, 2.83; Found: C, 70.40; H, 6.01; N, 2.78.
4. Conclusions
In summary, acridinediones and polyhydroquinoline derivatives were synthesized by the one-pot Hantzsch condensation of an aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione, ethyl acetoacetate and amine. It represents a straightforward protocol for the eco-friendly and efficient synthesis of a series of 1,4-dihydropyridines with potential biological activities.
Acknowledgments
We are grateful for financial support from the Natural Science Foundation of Anhui Province Education Department (KJ2010B049) and Anhui Provincial Natural Science Foundation (1208085QB24).
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/5/5339/s1.
Footnotes
Sample Availability: Samples of the compounds 5a–n, 7a–d are available from the authors.
References and Notes
- 1.Stilo A.D., Visentin S., Cena C., Gasco A.M., Ermondi G., Gasco A. New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities. J. Med. Chem. 1998;41:5393–5401. doi: 10.1021/jm9803267. [DOI] [PubMed] [Google Scholar]
- 2.Janis R.A., Triggle D.J. New developments in Ca2+ channel antagonists. J. Med. Chem. 1993;26:775–785. doi: 10.1021/jm00360a001. [DOI] [PubMed] [Google Scholar]
- 3.Kaya M., Yıldırır Y., Türker L. Synthesis and laser activity of halo-acridinedione derivatives. J. Heterocyclic Chem. 2009;46:294–297. doi: 10.1002/jhet.45. [DOI] [Google Scholar]
- 4.Dabiri M., Baghbanzadeh M., Arzroomchilar E. 1-Methylimidazolium triflouroacetate ([Hmim]TFA): An efficient reusable acidic ionic liquid for the synthesis of 1,8-dioxo-octahydroxanthenes and 1,8-dioxo-decahydroacridines. Catal. Commun. 2008;9:939–942. doi: 10.1016/j.catcom.2007.09.023. [DOI] [Google Scholar]
- 5.Shi D.Q., Ni S.N., Yang F., Shi J.W., Dou G.L., Li X.Y., Wang X.S. An efficient synthesis of polyhydroacridine derivatives by the three-component reaction of aldehydes, amines and dimedone in ionic liquid. J. Heterocycl. Chem. 2008;45:653–660. doi: 10.1002/jhet.5570450303. [DOI] [Google Scholar]
- 6.Kumara D., Sandhu J.S. Efficient, solvent-free, microwave-enhanced condensation of 5,5-dimethyl-1,3-cyclohexanedione with aldehydes and imines using libr as inexpensive, mild catalyst. Synth. Commun. 2010;40:510–517. doi: 10.1080/00397910902987792. [DOI] [Google Scholar]
- 7.Venkatesan K., Pujari S.S., Srinivasan K.V. Proline-catalyzed simple and efficient synthesis of 1,8-dioxo-decahydroacridines in aqueous ethanol medium. Synth. Commun. 2009;39:228–241. doi: 10.1080/00397910802044306. [DOI] [Google Scholar]
- 8.Niknam K., Panahi F., Saberi D., Mohagheghnejad M. Silica-bonded S-sulfonic acid as recyclable catalyst for the synthesis of 1,8-dioxo-decahydroacridines and 1,8-dioxo-octahydroxanthenes. J. Heterocycl. Chem. 2010;47:292–300. [Google Scholar]
- 9.Kidwai M., Bhatnagar D. Ceric ammonium nitrate (CAN) catalyzed synthesis of n-substituted decahydroacridine-1,8-diones in PEG. Tetrahedron Lett. 2010;51:2700–2703. doi: 10.1016/j.tetlet.2010.03.033. [DOI] [Google Scholar]
- 10.Shi D.Q., Shi J.W., Yao H. Clean synthesis of 9,10-diarylacridine derivatives in aqueous media. Chin. J. Org. Chem. 2009;29:239–244. [Google Scholar]
- 11.Shi D.Q., Mou J., Zhuang Q.Y., Wang X.S. Synthesis of ethyl 2,7,7-trimethyl-5-oxo-4-aryl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate in water. Chin. J. Org. Chem. 2004;24:1569–1572. [Google Scholar]
- 12.Ramazani A., Rezaei A. Novel one-pot, four-component condensation reaction: An efficient approach for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives by a Ugi-4CR/aza-wittig sequence. Org. Lett. 2010;12:2852–2855. doi: 10.1021/ol100931q. [DOI] [PubMed] [Google Scholar]
- 13.Ramazani A., Karimi Z., Souldozi A., Ahmadi Y. Four-component synthesis of 1,3,4-oxadiazole derivatives from n-isocyaniminotriphenylphosphorane, aromatic carboxylic acids, aromatic bis-aldehydes, and secondary amines. Turk. J. Chem. 2012;36:81–91. [Google Scholar]
- 14.Ramazani A., Rouhani M., Rezaei A., Shajari N., Souldozi A. The reaction of (n-isocyanimino)triphenylphosphorane with biacetyl in the presence of aromatic carboxylic acids: Efficient one-pot three-component reaction for the synthesis of 3-(5-aryl-1,3,4-oxadiazol-2-yl)-3-hydroxybutan-2-one derivatives. Helv. Chim. Acta. 2011;94:282–288. doi: 10.1002/hlca.201000219. [DOI] [Google Scholar]
- 15.Wang G.W., Xia J.J., Miao C.B., Wu X.L. Environmentally friendly and efficient synthesis of various 1,4-dihydropyridines in pure water. Bull. Chem. Soc. Jpn. 2006;79:454–459. doi: 10.1246/bcsj.79.454. [DOI] [Google Scholar]
- 16.Wang G.W., Lu Q.Q., Xia J.J. Three types of products obtained unexpectedly from the reaction of dimedone with chalcones. Eur. J. Org. Chem. 2011:4429–4438. doi: 10.1002/ejoc.201100374. [DOI] [Google Scholar]
- 17.Luo H., Kang Y., Nie H., Yang L. Fe3+-montmorillonite: An efficient solid catalyst for one-pot synthesis of decahydroacridine derivatives. J. Chin. Chem. Soc. 2008;55:1280–1285. doi: 10.1002/jccs.200800191. [DOI] [Google Scholar]
- 18.Shi D.Q., Shi J.W., Yao H. Three-component one-pot synthesis of polyhydroacrodine derivatives in aqueous media. Synth. Commun. 2009;39:664–675. doi: 10.1080/00397910802431057. [DOI] [Google Scholar]
- 19.Das B., Thirupathi P., Mahender I., Saidi Reddy V., Rao Y.K. Amberlyst-15: An efficient reusable heterogeneous catalyst for the synthesis of 1,8-dioxo-octahydroxanthenes and 1,8-dioxo-decahydroacridines. J. Molecular Catal. A: Chem. 2006;247:233–239. doi: 10.1016/j.molcata.2005.11.048. [DOI] [Google Scholar]
- 20.Tang Z.Q., Chen Y., Liu C.N., Cai K.Y., Tu S.J. A green procedure for the synthesis of 1,8-dioxodecahydroacridine derivatives under microwave irradiation in aqueous media without catalyst. J. Heterocycl. Chem. 2010;47:363–367. [Google Scholar]
- 21.Shen Y.B., Wang G.W. Solvent-free synthesis of xanthenediones and acridinediones. ARKIVOC. 2008;xvi:1–8. [Google Scholar]
- 22.Tu S., Li T., Zhang Y., Shi F., Xu J., Wang Q., Zhang J., Zhu X., Jiang B., Jia R., Zhang J. New reaction of schiff base with dimedone: New method for the acridine derivatives under microwave irradiation. J. Heterocycl. Chem. 2007;44:83–88. doi: 10.1002/jhet.5570440114. [DOI] [Google Scholar]
- 23.Shen W., Wang L.M., Tian H., Tang J., Yu J.J. Brønsted acidic imidazolium salts containing perfluoroalkyl tails catalyzed one-pot synthesis of 1,8-dioxo-decahydroacridines in water. J. Fluorine Chem. 2009;130:522–527. doi: 10.1016/j.jfluchem.2009.02.014. [DOI] [Google Scholar]
- 24.Bandgar B.P., More P.E., Kamble V.T., Totre J.V. Synthesis of polyhydroquinoline derivatives under aqueous media. ARKIVOC. 2008;xv:1–8. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.