Scholarly article on topic 'Synthesis of N-substituted Acridinediones and Polyhydroquinoline Derivatives in Refluxing Water'

Synthesis of N-substituted Acridinediones and Polyhydroquinoline Derivatives in Refluxing Water Academic research paper on "Chemical sciences"

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Academic research paper on topic "Synthesis of N-substituted Acridinediones and Polyhydroquinoline Derivatives in Refluxing Water"

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molecules

ISSN 1420-3049

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Synthesis of ^-substituted Acridinediones and Polyhydroquinoline Derivatives in Refluxing Water

Jing-Jing Xia * and Ke-Hua Zhang

School of Materials and Chemical Engineering, Anhui University of Architecture, Hefei 230601, China; E-Mail: zhangkehua@aiai.edu.cn

* Author to whom correspondence should be addressed; E-Mail: xiajj@aiai.edu.cn; Tel.: +86-551-382-8100.

Received: 13 March 2012; in revised form: 24 April 2012 / Accepted: 28 April 2012 / Published: 7May 2012

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-(2#,5#)-acridinediones are known as laser dyes [3].

1,8-(2#,5#)-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 [4-11].

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 [12-14]. 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 ^-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.

O OO JI 11

HCHO + ^ . refluxing | | + amine ---- " water -

1 2 3a-d 4a-d

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 ^-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 ^-substituted acridinediones.

O O R O

RCHO +

+ R'NH2

CTAB H2O

R' 5a-n

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 ^-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.

RCHO +

+ NH4OAc + CH3COCH2COOEt

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, 'H-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 (5) 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 (CDCh, 5 77.16 ppm; DMSO-d6, 5 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): u 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 (CDCh): 5 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 (CDQ3): 5 195.8, 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): u 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 (CDO3): 5 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 (CDO3): 5 195.6, 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): u 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 (CDQ3): 5 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): 5 195.7, 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 C29H29ChNO2: 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.

Supplementary Materials

Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/5/5339/s1.

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).

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Sample Availability : Samples of the compounds 5a-n, 7a-d are available from the authors.

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