A rapid and green method for expedient multicomponent synthesis of N-substituted decahydroacridine-1,8-diones as potential antimicrobial agents

Article abstract of DOI:10.1007/s11164-018-3541-7

Abstract: An efficient, green, high yielding, and quick method for the synthesis of N-substituted decahydroacridine-1,8-diones was achieved by multicomponent reaction between various aromatic aldehydes (1a–q), dimedone (2), and various aromatic amines (2a

Full text of DOI:10.1007/s11164-018-3541-7

Research on Chemical Intermediates
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A rapid and green method for expedient multicomponent
synthesis of N-substituted decahydroacridine-1,8-diones
as potential antimicrobial agents
Manisha R. Bhosle, et al. [full author details at the end of the article]
Received: 24 May 2018 / Accepted: 20 July 2018
Ó Springer Nature B.V. 2018
Abstract
An efficient, green, high yielding, and quick method for the synthesis of N-substituted
decahydroacridine-1,8-diones was achieved by multicomponent reaction between
various aromatic aldehydes (1a–q), dimedone (2), and various aromatic amines (2a–
d) using ChCl:Urea deep eutectic solvent as a recyclable organocatalyst and medium.
The reaction conditions are relatively mild and do not require additional metals, acid
catalysts, or organic solvents. The mild reaction conditions, experimental simplicity,
straightforward purification procedures, excellent yields with short reaction times, as
well as the application of green chemistry principles, are the advantages of this
methodology. This simple ammonium deep eutectic solvent, easily synthesized from
choline chloride and urea, is relatively inexpensive and biodegradable, making it
applicable for industrial use. The deep eutectic solvent was easily separated and reused
without loss of activity, and thus provides a good alternative. The synthesized 10-
(substituted phenyl)-9-(substitutedphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahy-
droacridine-1,8 (2H,5H)-diones (4a–l) were screened for their in vitro antimicrobial
activity against four bacterial Gram-positive bacteria (Staphylococcus aureus and
Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas
aeruginosa) and three fungal strains (Candida albicans, Aspergillus niger and
Aspergillus flavus). Among them, the 9-(N,N-Dimethylphenyl)-3,3,6,6-tetramethyl-
10-(3-pyridyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4f), 10-(4-Bro-
mophenyl)-9-(3-hydroxy-4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (4i) and 9-(4-Nitrophenyl)-3,3,6,6-tetramethyl-10-
phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4k) show good antimicro-
bial activity.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
018-3541-7) contains supplementary material, which is available to authorized users.
123

M. R. Bhosle et al.
Graphical Abstract
Keywords ChCl:Urea Á DES Á Decahydroacridine-1,8-diones Á Multicomponent
reaction Á Antimicrobial screening
Introduction
The development of an environmentally benign and efficient protocol for the
synthesis of privileged molecular skeletons has been a challenging task for synthetic
chemists [1, 2]. Among them, multi-component reactions (MCRs) have been shown
to be a one of the most efficient tools in modern synthetic organic chemistry, since
they have all the features that contribute to an ideal synthesis: high atom efficiency,
quick and simple implementation, time and energy savings, environment-friendly,
and they offer a target and diversity-oriented synthesis [3–5]. Therefore, the
development of new multicomponent reactions towards biomedical and industrial
scaffolds is inevitable at the present time.
In the continuing effort to attain greener synthetic methods, reaction solvents
have attracted a great deal of attention. Certainly this awareness is well justified as
reaction solvents are generally the largest component of a reaction by volume/mass.
They are also typically volatile, flammable, and toxic. A number of alternatives
have been developed over the last two decades, including water, supercritical fluids
and ionic liquids [6]. Each of these alternatives has its own strengths and
weaknesses. Ionic liquids and deep eutectic solvents (DES) have been studied as an
alternative to traditional solvents in many applications. The environmentally
friendly and green, nature of these solvents, together with their tunable properties,
has led to their promotion for use in organic, inorganic and electrochemistry
processes [7, 8]. Very recently, the use of deep eutectic solvents (DES) has been
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A rapid and green method for expedient multicomponent…
explored in organic synthesis as a green alternative to VOCs and some ionic liquids
(ILs).
DESs are commonly prepared from a eutectic mixture of Lewis or Brønsted acids
and bases, which may contain a variety of anionic or cationic species, and possess a
melting point much lower than either of the individual components [9–11]. The
majority studied series of DESs are those prepared using choline chloride as a donor
compound with components including urea, sugars, carboxylic acids, and ethylene
glycol or M2? ions. The most commonly employed is the 1:2 molar mixture of
choline chloride and urea which affords a viscous liquid at room temperature.
Advantages of this solvent are several-fold: it is relatively inexpensive, easily
available; it is non-toxic, exhibits no detectable vapor pressure under ambient
conditions, is based on biorenewable materials and is a recyclable catalyst for
various organic transformations [9–11]. Due to interesting properties such as the
ease of handling, excellent catalytic activity and simplicity in processing,
ChCl:Urea have emerged as a promising green reaction media for organic
transformations [12–19]. Combination of established multicomponent reactions
with a deep eutectic mixture is highly desirable.
Fused polycyclic heterocyclic molecules are an important class of organic
molecule because of their widespread applications as pharmaceutical candidates,
optical materials and sensors [20–22]. Acridine is a fused polycyclic aromatic
molecule, which is exhibited in numerous publications in organic, pharmaceutical
and medicinal chemistry because of its potential biological activities and presence
in a variety of significant natural products and synthetic dye-stuffs [23–26].
Acridines are firstly used as antibacterial and antiparasite agents with planar
aromatic structures that are capable of intercalating into DNA base pairs [27].
Furthermore, acridinedione derivatives are known to be biological agents with
antimalarials [28], anti-fungal [29], anti-tumor [30], anti-cancer [31], cytotoxic [32]
and anti-multidrug-resistant properties [33] (Fig. 1).
Fig. 1 Acridine containing biologically active molecules and synthesized potent antimicrobial acridines
123

M. R. Bhosle et al.
There are various reports in the literature for the three-component Hantzsch-type
condensation of aromatic aldehydes, anilines and dimedone via the traditional
heating in organic solvents [34], under MW irradiation [35], and using catalysts, for
example, p-toluenesulfonic acid [36, 37], p-dodecylbenzenesulfonic acid [38], Ceric
ammonium nitrate (CAN) [39], InCl3-ionic liquid [40], montmorillonite [41],
Fe3O4@SiO2-MoO3H nanoparticles [42], silica-bonded N-propyl sulfamic acid
(SBNPSA) [43], amberlyst-15 [44], and benzyltriethylammonium chloride
(TEBAC) [45], leading to acridines. However, many of these methods suffer from
disadvantages such as low yields, toxic organic solvents, long reaction times,
expensive catalysts, the requirement of special apparatus, laborious workup
procedures, and harsh reaction conditions. Thus, to avoid these limitations and to
improve the reaction conditions available for the synthesis of acridinedione, the
discovery of new methodologies using new green and reusable catalysts is still
needed.
Through the versatility and green features of DES combined with the synthetic,
biological attributes of acridinediones, and as a part of our research aimed at the
development of synthetic methodologies using environmentally benign catalysts
through MCRs [46–50], we decided to explore the use of a 1:2 mixture of choline
chloride (ChCl) and urea as a medium and catalyst in the synthesis of N-substituted
decahydroacridine-1,8-diones for the first time.
Experimental
General All the chemicals used were of laboratory grade. Melting points of all the
synthesized compounds were determined in open capillary tubes and are
1
uncorrected. H and 13C NMR spectra were recorded with a Bruker Avance 400
spectrometer operating at 400 and 75 MHz using DMSO and CDCl3 solvents and
tetramethylsilane (TMS) as the internal standard and chemical shift in d ppm. Mass
spectra were recorded on a Sciex, Model; API 3000 LCMS/MS Instrument. The
elemental analysis was done on a Thermofisher EA1112 series CHNS Elemental
Analyser. The purity of each compound was checked by TLC using silica-gel,
60F254 aluminum sheets as adsorbent and visualization was accomplished by iodine/
ultraviolet light.
Preparation of choline chloride:Urea deep eutectic mixture
A mixture of choline chloride (50 mmol) and urea (100 mmol), that is, in the ratio
of 1:2 was heated at 80 °C with stirring for 2 h. In the resulting eutectic solvent, the
liquid was then allowed to cool to room temperature and was used for the synthesis
of N-substituted decahydroacridine-1,8-diones.
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A rapid and green method for expedient multicomponent…
General procedure for the synthesis of 10-(substituted phenyl)-9-
(substitutedphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8
(2H,5H)-diones 18 compounds
A mixture of substituted benzaldehydes (1a–q) (1 mmol), dimedone (2) (2 mol),
and substituted anilines (2a–d) (1 mol) in Choline chloride:Urea (5 mL) was stirred
at 80 °C. Progress of the reaction was monitored by thin layer chromatography ethyl
acetate:hexane (3:7) as solvent. After 30 min of stirring, the reaction mixture was
allowed to cool to room temperature and poured on crushed ice. The thus obtained
solid was filtered, dried and purified by crystallization using ethanol as solvent.
Synthesized compounds were confirmed by melting point, IR, 1H and 13C NMR and
were in good agreement with those reported in the literature [36, 37, 39].
Spectral analysis of compounds
4-(3,3,6,6-Tetramethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8- octahydroacridin-10 (9H)
yl) benzenesulfonohydrazide (4a) White solid, Yield 91%. Melting point
197–199 °C. IR (ATR tmax cm-1): 737, 864, 1098, 1260, 1369, 1498, 1661,
1
2824, 2957. H NMR (400 MHz, CDCl3 dppm): 0.88 (s, 6H, CH3), 0.99 (s, 6H,
CH3), 2.20–2.28 (m, 4H, CH2), 2.32 (dd, J = 17 Hz, 4H, CH2), 4.90 (s, 1H),
7.08–7.16 (m, 5H, ArH), 7.20–7.39 (m, 4H, ArH); 13C NMR (100 MHz, CDCl3
dppm): 26.92, 28.46, 32.42, 41.88, 50.13, 115.29, 125.36, 125.84 (2C), 127.59,
127.83 (2C), 127.91, 127.98, 128.62, 132.45, 137.07 (2C), 145.80, 150.47 (2C),
195.54 (2C).
4-(9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahy-
droacridin-10(9H)-yl) benzenesulfonohydrazide (4b) White solid, Yield 93%.
Melting point 232–235 °C. IR (ATR tmax cm-1): 738, 864, 1094, 1370, 1664,
1
2297, 2879, 2956. H-NMR (400 MHz, CDCl3 dppm): 0.87 (s, 6H, CH3), 0.94 (s,
6H, CH3), 1.84–2.06 (m, 4H, CH2), 2.10–2.18 (m, 4H, CH2), 3.71 (s, 3H, OCH3),
5.24 (s, 1H), 7.23–7.29 (d, J = 8.8 Hz, 2H, ArH), 7.31–7.38 (m, 4H, ArH),
7.57–7.61 (d, J = 7.6 Hz, 2H, ArH). 13C NMR (100 MHz, CDCl3 dppm): 26.82,
29.79, 32.65, 41.86, 50.27, 57.32, 114.25 (2C), 119.87, 129.62 (4C), 129.89, 131.21,
138.93 (2C), 145.45 (2C), 150.09, 151.67, 195.83 (2C).
10-(4-Methoxyphenyl)-9-(4-flurophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (4c) White solid, Yield 86%. Melting point
223–225 °C. IR (ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879,
1
2956. H-NMR (400 MHz, CDCl3 dppm): 0.84 (s, 6H), 0.97 (s, 6H), 1.80–1.83 (d,
J = 17.4 Hz, 2H, CH2), 2.05–2.21 (m, 6H), 3.51 (s, 3H, OCH3), 5.17 (s, 1H),
7.08–7.23 (m, 4H, ArH), 7.39–7.42 (m, 4H, ArH). 13C NMR(100 MHz, CDCl3
dppm): 23.45, 26.78, 29.64, 32.38, 41.72, 50.17, 56.78, 113.57, 116.59 (2C), 123.52,
128.81 (2C), 129.78, 138.29 (2C), 146.42 (2C), 148.71, 150.39, 152.96 (2C),
195.62(2C).
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4d) White solid, Yield 91%. Melting point 245–246 °C. IR
123

M. R. Bhosle et al.
(ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879, 2956. 1H-NMR
(400 MHz, CDCl3 dppm): 0.83 (s, 6H, CH3), 0.93 (s, 6H, CH3), 1.60–1.98 (m, 4H,
CH2), 2.09–2.15 (m, 4H, CH2), 5.20 (s, 1H), 7.06–7.10 (d, J = 7.2 Hz, 2H, ArH),
7.10–7.28 (m, 5H), 7.39–7.41 (m, 2H, ArH). 13C NMR(100 MHz, CDCl3 dppm):
26.85; 28.91, 32.56, 40.97, 49.99, 115.6 (2C), 120.3, 127.0 (4C), 129.35, 132.2
(2C), 135.8, 143.67 (2C), 150.6, 153.0 (2C), 196.21 (2C).
9-(3,4-Dimethoxyphenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (4e) White solid, Yield 90%. Melting point
231–233 °C. IR (ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879,
1
2956. H-NMR (400 MHz, CDCl3 dppm): 0.84 (s, 6H, CH3), 0.93 (s, 6H, CH3),
1.96–2.01 (m, 4H, CH2), 2.09–2.18 (m, 4H, CH2), 3.74 (s, 6H, OCH3), 5.15 (s, 1H),
7.20–7.38 (m, 6H, ArH), 7.41–7.52 (m, 2H, ArH); 13C NMR(100 MHz, CDCl3
dppm): 27.5, 28.8, 32.6, 40.1, 49.89, 57.29, 114.9 (2C), 116.5, 120.3, 127.7 (2C),
131.49, 132.0, 132.8 (2C), 135.8, 146.87 (2C), 154.36, 158.62, 163.2, 195.95 (2C).
9-(N,N-Dimethylphenyl)-3,3,6,6-tetramethyl-10-(3-pyridyl)-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (4f) White solid, Yield 87%. Melting point
254–255 °C. IR (ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879,
1
2956. H-NMR (400 MHz, CDCl3 dppm):0.89 (s, 6H, CH3), 0.94 (s, 6H, CH3),
1.81–1.86 (m, 4H, CH2), 2.05–2.23 (m, 4H, CH2), 2.79 (s, 6H, CH3), 5.23 (s, 1H),
7.07–7.19 (m, 4H, ArH), 7.27–7.37 (m, 4H, ArH). 13C NMR (100 MHz, CDCl3
dppm): 27.45, 28.17, 32.49, 40.79, 41.72, 49.99, 115.43, 118.37, 123.09, 124.96,
127.17, 128.49 (2C), 135.77 (2C), 135.81 (2C), 149.59, 149.84, 153.46 (2C), 196.67
(2C).
9-(4-Bromophenyl)-3,3,6,6-tetramethyl-10-(3-pyridyl)-3,4,6,7,9,10-hexahy-
droacridine-1,8(2H,5H)-dione (4g) White solid, Yield 90%. Melting point
[ 300 °C. IR (ATR tmax cm-1): 734, 831, 1143, 1498, 1630, 1708, 2326, 2919,
1
3109. H-NMR (400 MHz, CDCl3 dppm): 0.88 (s, 6H, CH3), 0.94 (s, 6H, CH3),
1.80–1.94 (m, 4H, CH2), 2.06–2.22 (m, 4H, CH2), 5.24 (s, 1H), 7.22–7.24 (m, 2H,
ArH), 7.31–7.38 (m, 4H, ArH), 7.56–7.58 (m, 3H, ArH). 13C NMR (100 MHz,
CDCl3 dppm): 26.83, 29.80, 32.48, 41.88, 50.24, 114.23 (2C), 119.81 (2C), 129.61
(4C), 131.20 (2C), 138.97 (2C), 145.40 (2C), 150.04(2C), 195.88 (2C).
9-(2-Furyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-
dione (4h) White solid, Yield 75%. Melting point 245–247 °C. IR (ATR tmax
cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879, 2956. 1H-NMR (400 MHz, CDCl3
d
ppm): 0.88 (s, 6H, CH3), 0.92 (s, 6H, CH3), 1.25–1.46 (m, 4H, CH2), 1.99–2.03 (m,
4H, CH2), 5.70 (s, 1H), 6.83–6.97 (d, J = 8.4 Hz, 2H, ArH), 7.06–7.18 (m, 4H,
ArH), 7.20–7.26 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3 dppm): 27.64, 29.60,
31.92, 40.96, 50.27, 109.34, 112.76, 116.43, 126.05 (2C), 132.17, 132.64, 135.90,
145.91, 148.24, 149.08, 152.98, 154.68 (2C), 195.42 (2C).
10-(4-Bromophenyl)-9-(3-hydroxy-4-methoxyphenyl)-3,3,6,6-tetramethyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4i) White solid, Yield 89%.
Melting point [ 300 °C. IR (ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297,
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A rapid and green method for expedient multicomponent…
1
2879, 2956, 3430. H-NMR (400 MHz, CDCl3 dppm): 0.80 (s, 6H, CH3), 0.94 (s,
6H, CH3), 1.00–1.04 (d, 2H, CH2), 2.06–2.22 (m, 6H, CH2), 3.65 (s, 3H, OCH3),
5.24 (s, 1H, CH), 7.22–7.26 (d, 2H, J = 8 Hz, Ar–H), 7.31–7.38 (m, 3H, Ar–H),
7.56–7.58 (m, 2H, Ar–H). 13C NMR (100 MHz, CDCl3 dppm): 28.09, 29.16, 30.04,
40.42, 50.14, 56.98, 112.91 (2C), 119.07, 124.28 (2C), 128.29, 129.43(2C), 130.46
(2C), 145.81(2C), 150.40 (2C), 153.17 (2C), 194.98 (2C).
9-(4-Flurophenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4j) White solid, Yield 87%. Melting point 272–273 °C. IR
(ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879, 2956. 1H-NMR
(400 MHz, CDCl3 dppm): 0.86 (s, 6H, CH3), 0.92 (s, 6H, CH3), 1.62–1.88 (m, 4H,
CH2), 2.00 2.40 (m, 4H, CH3), 5.06 (s, 1H), 6.63–7.09 (m, 4H, ArH), 7.17–7.37 (m,
5H, ArH); 13C NMR(100 MHz, CDCl3 dppm): 26.89, 29.72, 31.90, 41.87, 50.24,
113.55 (2C), 114.82, 128.85 (2C), 129.48, 138.81, 139.14 (2C), 149.65 (2C), 153.45
(2C), 154.67 (2C), 157.7, 195.92 (2C).
9-(4-Nitrophenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4k) White solid, Yield 89%. Melting point 285–287 °C. IR
(ATR tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879, 2956. 1H-NMR
(400 MHz, CDCl3 dppm): d 0.92 (s, 6H, CH3), 0.98 (s, 6H, CH3), 1.23–1.37 (m, 4H,
CH2), 2.33–2.43 (m, 4H, CH2), 5.54 (s, 1H), 7.08–7.18 (m, 5H, ArH), 7.24–7.29 (m,
4H, ArH). 13C NMR (100 MHz, CDCl3 dppm): 27.68, 29.02, 31.85, 41.34, 51.22,
110.19, 110.85, 116.53, 120.26 (2C), 126.91, 126.34, 125.98, 127.43, 139.88,
148.91, 144.63, 149.76, 155.34, 156.21, 194.37(2C).
9-(4-Hydroxyphenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4l) White solid, Yield 92%. Melting point 284–286 °C. IR (ATR
1
tmax cm-1): 738, 864, 1094, 1370, 1664, 2297, 2879, 2956. H-NMR (400 MHz,
CDCl3 dppm): 0.87 (s, 6H, CH3), 1.61–1.86 (m, 4H, CH2), 2.0–2.17 (m, 4H, CH2),
5.25 (s, 1H), 6.94–7.06 (m, 3H, ArH), 7.23–7.26 (m, 4H, ArH), 7.43–7.49 (d, 2H,
ArH), 9.18 (s, 1H, OH). 13C NMR (100 MHz, CDCl3 dppm): 27.51, 28.93, 31.59,
40.29, 50.94, 116.56 (2C), 118.71, 120.38, 127.81 (2C), 131.97, 133.09, 135.73,
141.67, 145.23, 150.65, 154.45 (2C), 155.23 (2C), 195.08 (2C).
Results and discussion
Optimization of reaction conditions
In search of the best experimental reaction conditions, the reaction of 4-chloro
benzaldehyde (1 mmol), cyclohexadione (2) (2 mmol) and aniline (3a) (1 mmol) in
the presence of ChCl:Urea as a deep eutectic medium was considered as a standard
model reaction (Scheme 1). The reaction conditions were optimized on the basis of
the catalyst, solvent and different temperature for the synthesis of N-substituted
decahydroacridine-1,8-diones. This reaction was firstly examined in different
catalysts and solvents such as CAN, p-TSA, and Acetic acid as reported catalyst. It
was observed that formation of product 4d takes place after a long reaction time and
123

M. R. Bhosle et al.
Scheme 1 Synthesis
hexahydroacridine-1,8(2H,5H)-dione (4d)
of
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10
Table 1 Screening of reaction media and catalyst for the synthesis of compound 4a
Entry Catalystb
Solvent (5 mL)
Temp (°C)
Time
Yield (%)c
1
2
3
4
CAN
EtOH
Reflux
Reflux
80
6 h
6 h
6 h
2 h
34
54
64
52
p-TSA
EtOH
Acetic acid
Acetic acid
N-Methyl pyridinium
tosylate
N-Methyl pyridinium
tosylate
80
5
DIPEAc
DIPEAc
80
2 h
2 h
2 h
2 h
2 h
2 h
2 h
69
67
36
85
75
71
45
6
Dicationinic ionic liquid
ChCl:2Glycerol
ChCl:Urea
Dicationinic ionic liquid
ChCl:2Glycerol
EtOH
80
7
80
8
Reflux
Reflux
Reflux
Reflux
9
ChCl:Urea
MeOH
10
11
12
ChCl:Urea
CH3CN
ChCl:Urea
Water
ChCl:Urea
ChCl:Urea
40, 60, 80,
100
30 min 67, 86, 95,
95
13
–
EtOH
80
6 h
Trace
aReaction conditions: benzaldehyde (1) (1 mmol), Aniline (2) (1 mmol), dimedone (3) (2 mmol)
bCatalyst concentration: 20 mol%
cIsolated yields
obtained with poor yield (Table 1, entries 1–3). Considering the drawbacks of the
volatile hazardous organic solvent, we have screened the model reaction in green
solvents like N-Methyl pyridinium tosylate, DIPEAc, dicationinic ionic liquid,
ChCl:Urea and ChCl:Glycerol (Table 1, entries 4–7). Among these solvents,
ChCl:Urea as a prominent deep eutectic medium was used which fulfilled the
requirements of excellent yields with high purity in short reaction time (30 min)
(Table 1, entry 12).
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A rapid and green method for expedient multicomponent…
To confirm the role of ChCl:Urea as a catalyst, a model reaction was separately
attempted in media, viz., ethanol, methanol, acetonitrile and water in the presence of
20 mol% of ChCl:Urea at reflux temperature (Table 1, entries 7–10). The
compound 4d obtained in good yields 85, 75 and 71% in ethanol, methanol and
acetonitrile respectively. The 20 mol% of ChCl:Urea in water gave the poor yield of
desired product. However, time required for these condensations was 2 h (Table 1,
entries 7–10). It was observed that, in absence of ChCl:Urea, condensation could not
occur in media EtOH (Table 1, entry 13). This observation is in agreement with the
idea that ChCl:Urea plays a role not only as a medium but also as a catalyst in this
cyclocondensation. Therefore, ChCl:Urea was chosen as the medium and
organocatalyst of choice for further optimization studies.
Results obtained indicate that a raised temperature accelerates the reaction rate
and favors the exclusive yield of titled product 4d. Raising the temperature up to
80 °C facilitates the homogenization of the reaction mixture. Due to the viscosity of
the solvent, the reactions at lower temperature gave low poor yields of product.
Accordingly, a set of reactions were conducted at varying the temperatures of 40,
60, 80 and 100 °C and obtained the product yield 67, 86, 95, 95% (Table 1, entry
12). Therefore, further reactions were carried out at 80 °C using 5 mL of
ChCl:Urea.
The scope and limitations of this reaction were explored by utilizing various
aldehydes (1), dimedone (2), and various aniline derivatives (3) Scheme 2
(Table 2). As indicated in Table 2, the aromatic substituted decahydroacridine-
1,8-diones were synthesized in higher yields (75–95%) with shorter reaction times
(30 min) relative to the aliphatic substituted decahydroacridine-1,8-diones (Trace).
Various benzaldehydes containing electron-donating, electron withdrawing, and
halogen substituents were successfully applied to the reaction and afforded the
decahydroacridine-1,8-dione heterocycles in good to excellent yields. Aromatic and
Scheme 2 Synthesis of 10-(substituted phenyl)-9-(substitutedphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
hexahydroacridine-1,8 (2H,5H)-diones (4a–r)
123

M. R. Bhosle et al.
Table 2 Synthesis of N-substituted decahydroacridine-1,8-diones with a wide range of aldehydes and
amines in ChCl:Urea as DESa
Sr.
no.
Yield
(%)b
Aldehydes
Anilines
Productc
NH2
1
4a
91
CHO
SO2NH2
NH2
OCH3
CHO
2
4b
93
SO2NH2
OCH3
CHO
NH2
F
3
86
4c
Cl
NH2
NH2
4d
4e
4
5
95
91
CHO
OCH3
H3CO
CHO
N
6
7
8
4f
4g
4h
87
90
75
CHO
Br
NH2
NH2
CHO
O
CHO
OCH3
OH
NH2
4i
9
89
CHO
123

A rapid and green method for expedient multicomponent…
Table 2 continued
F
NH2
4j
10
11
87
89
CHO
NO2
NH2
NH2
4k
CHO
OH
12
13
4l
92
77
CHO
NH2
NH2
NH2
S
N
4m
CHO
CHO
4n
4o
4p
14
15
16
81
Trace
Trace
CHO
CHO
NH2
SO2NH2
NH2
17
18
4q
Trace
CHO
CHO
SO2NH2
NH2
4r
Trace
SO2NH2
aReaction conditions: substituted aldehydes (1) (1 mmol), dimedone (2) (2 mmol), and substituted ani-
lines (3) (1 mmol) in ChCl:Urea (5 mL) and was stirred at 80 °C for 30 min
bIsolated yields
cMelting points, IR, 1H and 13C NMR are in good agreement with those reported in the literature
[36, 37, 39]
123

M. R. Bhosle et al.
hetryl anilines also show good to excellent yields of the products. The synthesized
compounds were isolated, purified, and characterized by Fourier-transform infrared
(FT-IR), 1H and 13C nuclear magnetic resonance (NMR), spectrometric techniques.
Hydrogen bonding and Bronsted basicity of urea are the main factors that
influence the reactivity and selectivity of the process. We tentatively propose the
mechanism of the present reaction to proceed in a manner similar to that described
in the analogous ChCl:Urea catalyzed reactions outlined in Scheme 3. The
reversible hydrogen bonding between urea and carbonyl groups giving substrate-
solvent complex and activated aldehydes is depicted in Scheme 3. The initial
condensation of carbonyl groups with activated dimedone with urea in the
ChCl:Urea leads to the formation of arylidene dimedone with the loss of a water
molecule. Then Micheal addition of the second molecule of enolizable dimedone to
arylidene dimedone followed by intramolecular cyclization with aniline of the
resulting species produces the N-substituted decahydroacridine-1,8-dione
derivatives.
ChCl:Urea can play a dual role in this reaction: (1) as a medium/solvent and (2)
as an organocatalyst which activates the carbonyl and intermediates functional
groups via hydrogen bonding. The rate acceleration for the formation of
Scheme 3 Plausible mechanism for the synthesis of N-substituted-1,8-dioxo-decahydroacridines
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A rapid and green method for expedient multicomponent…
Yield of 4d
94 94
Catalyst Recovery
95
94
94
92
92 92
Fresh
I
II
III
Fig. 2 Recycle and recovery of ChCl:Urea and its effect on yield
3500
3000
2500
2000
1500
1000
Wavenumber cm-1
Fig. 3 FT-IR spectra of ChCl:Urea. Below pink color: fresh ChCl:Urea, above blue color: after III
recycle recovered ChCl:Urea. (Color figure online)
N-substituted decahydroacridine-1,8-diones have been found to be enhanced by
using ChCl:Urea as medium/solvent. ChCl:Urea might be helping to create a high
initial concentration of the reactants in solvation at 80 °C.
Another advantage of using ChCl:Urea is their ability to act as a recyclable
reaction media/catalyst [51–53]. The reaction mixture, including the ChCl:Urea and
4a, was dissolved in water and the insoluble crude product was filtered off. The
ChCl:Urea was recovered from water by evaporation at 80 °C under vacuum,
recycled, and reused for three reaction runs without a significant loss of catalytic
activity (Fig. 2). Recycled ChCl:Urea was confirmed by a FT-IR spectrum which
123

M. R. Bhosle et al.
123

A rapid and green method for expedient multicomponent…
resolved structural information about the molecule. There is no change observed in
the IR spectra of the ChCl:Urea before the reaction and after third recycle (Fig. 3).
The compound having the covalent bond absorbs various frequencies of electro-
magnetic radiation in the infrared region of the electromagnetic spectrum. The
absorption peak at around 3425 cm-1 and 3325.06 is characteristic of N–H and O–
H stretching vibration, respectively. The bands at 2212.58 and 1238.73 cm-1 result
from the C–N and C–O stretching (Fig. 3).
Biological activity
The in vitro antimicrobial activities for the newly synthesized decahydroacridine-
1,8-dione compounds were evaluated for Gram-positive bacteria (Staphylococcus
aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and
Pseudomonas aeruginosa) and fungal strains (Candida albicans, Aspergillus niger
and Aspergillus flavus). Minimum inhibitory concentration (MIC, mg/mL) values of
all the compounds were determined using the standard agar dilution method as per
CLSI guidelines [54]. All the experiments were performed in triplicate, and the
mean reading was taken as the final reading. The 5% DMSO was used as a negative
control, along with ampicillin and fluconazole as the standard antibacterial and
antifungal drugs, respectively (Table 3).
Antimicrobial activity
The in vitro antibacterial evaluations of decahydroacridine-1,8-diones demonstrated
that many of the synthesized compounds display prominent antibacterial activity
against the tested strains. Some title compounds showed broad-spectrum activity
while some compounds were narrow spectrum active against only one bacterial
strain. As seen in Table 3, all the screened decahydroacridine-1,8-diones (4a–
l) exhibited prominent activity compared to the standard drug ampicillin against
Gram-positive bacteria (S. aureus and B. subtilis). Compound 4f having N,N-
dimethyl substitution at the para position showed good inhibitory activity against
Gram-positive bacteria (S. aureus and B. subtilis) MIC values 100 0.67 and
112.5 0.45, respectively. Among the whole series (4a–l), compound 4i with
3-hydroxy, 4-methoxy substitution exhibited excellent activity against all tested
bacterial strains (E. coli, P. aeruginosa and S. aureus). Compound 4k with nitro
group substitution at the para position showed the antibacterial activity against
Gram-positive bacteria (S. aureus and B. subtilis) MIC values 112.1 0.21 and
137.5 0.43, respectively. According to the in vitro antifungal activity data
(Table 3), most of the decahydroacridine-1,8-diones derivatives from the series (4a–
l) exhibited poor inhibitory activities against A. Niger and A. flavus. All the
synthesized compounds exhibited less antifungal activity against the fungal strain
A. flavus.
123

M. R. Bhosle et al.
Conclusion
In summary, we found ChCl:Urea as an effective and environmentally safe,
recyclable catalyst, which successfully catalyzed to produce N-substituted decahy-
droacridine-1,8-diones from aromatic aldehydes, a dimedone and amines. High
catalytic activity, high yields, a clean process, simple catalyst preparation, easy
workup procedure and green conditions are advantages of these protocols. The
synthesized compounds 10-(substituted phenyl)-9-(substitutedphenyl)-3,3,6,6-te-
tramethyl-3,4,6,7,9,10-hexahydroacridine-1,8 (2H,5H)-diones (4a–l) evaluated for
their in vitro antibacterial and antifungal activities and excellently inhibited the four
bacterial and three fungal strains. Compounds 9-(N,N-Dimethylphenyl)-3,3,6,6-
tetramethyl-10-(3-pyridyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4f),
10-(4-Bromophenyl)-9-(3-hydroxy-4-methoxyphenyl)-3,3,6,6-tetramethyl-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (4i) and 9-(4-Nitrophenyl)-
3,3,6,6-tetramethyl-10-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione
(4k) showed excellent antimicrobial activity.
Acknowledgements The authors are grateful to Professor Ramrao A. Mane for his invaluable discussions
and guidance. The authors are also thankful to Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad and Central Drug Research Institute (CDRI), Lucknow for
providing necessary facilities and spectral analysis, respectively.
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Affiliations
1
1
1
Manisha R. Bhosle1 Dhananjay Nipte Jivan Gaikwad Moseen A. Shaikh
•
•
•
•
Giribala M. Bondle1 Jaiprakash N. Sangshetti2
•
&
1
Manisha R. Bhosle
d.manisha11@gmail.com
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad,
Maharashtra 431004, India
2
Y. B. Chavan College of Pharmacy, Rafiq Zakaria Campus, Aurangabad, Maharashtra, India
123