Efficient synthesis of acridinediones in aqueous media

Article abstract of DOI:10.1080/00397911.2017.1304556

An efficient synthesis of acridinediones in two steps have been achieved using water as a reaction media without chromatographic purification. First step involves the reaction of dimedone with ammonium acetate to yield enaminone in water which on further

Full text of DOI:10.1080/00397911.2017.1304556

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An Efficient Synthesis of Acridinediones in
Aqueous Media
Keshri Nath Tiwari, Mane Rajendra Uttam, Puja Kumari, Piyush Vatsa & S. M.
Prabhakaran
To cite this article: Keshri Nath Tiwari, Mane Rajendra Uttam, Puja Kumari, Piyush Vatsa & S.
M. Prabhakaran (2017): An Efficient Synthesis of Acridinediones in Aqueous Media, Synthetic
Communications, DOI: 10.1080/00397911.2017.1304556
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Date: 15 March 2017, At: 19:48

An Efficient Synthesis of Acridinediones in Aqueous Media
Keshri Nath Tiwari1, Mane Rajendra Uttam1, Puja Kumari1, Piyush Vatsa1, S. M.
Prabhakaran1
1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), ITI Compound, Raebareli, India
Keshri Nath Tiwari, Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), ITI Compound, Raebareli – 229010,
India. E-mail: keshri.tiwari@niperraebareli.edu.in
Abstract
An efficient synthesis of acridinediones in two steps have been achieved using water as a
reaction media without chromatographic purification. First step involves reaction of
dimedone with ammonium acetate to yield enaminone in water which on further reaction
with various aldehydes yields acridinedione in aqueous media. The reaction merits use of
water as solvent, no additive catalyst and provides high yield of products with good
purity.
GRAPHICAL ABSTRACT
KEYWORDS: Dimedone, Ammonium acetate, Benzaldehyde, Enaminone,
Acridinedione
1

INTRODUCTION
The acridinedione derivatives are heterocyclic molecules which have been diversely used
in medicinal chemistry. These acridinedione or 1,4-dihydropyridine analogues have
interesting biological properties like nicotinamide adenine dinucleotide (NADH) due to
structural similarity which is an important coenzyme found in cells.[1] Besides, their
biological properties have also been explored as antitumor[2,3] and antimicrobial[4,5]
agents, inhibitors of carbonic anhydrase[6] as well as β–channel opener in cardiovascular
disease.[7]
Many acridinedione derivatives have also been utilized as electroluminescent as laser
dyes.[8-11] Their application and photochemical, physical[12,13] and electrochemical
properties[14] have been investigated in detail by various researchers. Since they exhibit
strong fluorescent properties, acridinedione derivatives are quite good as laser dyes, and
are of great potential to be used as electroluminescence (EL) materials.
The acridinediones are typically synthesized by condensation of cyclohexadiones and
benzaldehydes with ammonium acetate or respective amines as a nitrogen source in the
presence of a catalyst. The use of catalyst plays a crucial role in the synthesis and various
reported catalysts like Amberlyst-15,[15] Amberlite IR-120H,[16] CBSA,[17] CTAB,[18]
DBSA,[19] glucose sulphonic acid,[20] SiO2-Pr-SO3H,[21] and [TBA]2[W6O19].[22] and
vitamin B1[23] have been utilized. However, the catalysts used in these reactions have
many disadvantages like being expensive and toxic in nature, contains acidic residues as
impurities and therefore it limits the synthetic application. There have been continuous
2

efforts made to find alternative cost-effective and greener protocols for the synthesis of
acridinediones where toxic solvents and catalysts can be eliminated to provide high
yielding reactions.
We are currently involved in developing new synthetic methods for generation of
heterocyclic compounds in greener solvents and have successfully demonstrated the use
of water as a efficient and eco-friendly reaction media for various reactions.[24-25] In this
continuation, we wish to report a very convenient, high yielding, catalyst and
chromatography free two step synthesis of acridinedione derivatives using water as
reaction media (Scheme 1).
RESULTS AND DISCUSSION
Initially the synthesis of acridinedione derivatives was planned by heating a mixture of
dimedone (1) (1 equiv.), ammonium acetate (3 equiv.) and benzaldehyde (3a) (0.5 equiv.)
without using any catalyst in water (Scheme 2) as a model reaction. After heating the
reaction mixture for 6 hours at 80 ᴏC, a bluish fluorescent spot was visible in UV lamp
on TLC. After the complete consumption of starting precursors, the reaction mixture was
extracted with ethyl acetate which on purification using silica gel chromatography
provided acridinedione 4a as yellow solid. However the yield of this reaction was found
very low due to absence of catalyst. We realized that the yield of the reaction was low
due to the side reactions frequently observed in three component coupling.
3

Accordingly we planned to perform the synthesis of acridinedione in two steps. In first
step, dimedone (1) (1 equiv.) and ammonium acetate (3 equiv.) was heated in water at 80
ᴏC for 5 hours (Scheme 3). To our satisfaction, we obtained enaminone (2) in almost
quantitative yield by simply extracting the reaction mixture with excess of ethyl acetate
and evaporation of organic solvent. The structure of enaminone (2) was confirmed by
spectral analysis and the data were found in good agreement with the literature report.
Next, the reaction of enaminone (2) (1 equiv.) with benzaldehyde (3a) (0.5 equiv.) was
performed in water at 80 ᴏC without catalyst (Scheme 4). Initially, the reaction mixture
was observed clear but after some time solid started precipitating out of water. After 2
hour when the complete starting material was consumed, the light yellow solid was
filtered off. After checking TLC, the compound showed an intense bluish fluorescent spot
in UV lamp. The structure of this product 4a was confirmed by IR, mass and NMR
spectroscopy and the data was found in good agreement with literature.[26]
The IR spectrum of compound 4a showed peaks at 3424 cm-1 which corresponds to NH
and at 2961 cm-1 for alkane. The 1H NMR spectrum of 4a showed characteristic benzylic
C-H at δ 5.09 ppm. The two methyl were observed as singlet at δ 1.05 ppm and δ 0.94
ppm, five aromatic protons between δ 7.0 ppm to δ 7.31 ppm and N-H was observed as
broad singlet at δ 8.25 ppm. The –CH2 proton of cyclohexene rings were observed
between δ 2.08 ppm to δ 2.40 ppm for most of the derivatives. The 13C spectrum of
compound 4a showed characteristic carbonyl peak at δ 196 ppm. The two cyclohexene
carbons were observed at δ 149 ppm and δ 113 ppm. The structure was further confirmed
4

by performing DEPT spectra of compound 4a where the two –CH2 were confirmed at δ
51 ppm and δ 33 ppm. The high resolution mass spectra (HRMS) of all the compounds
were in compliance with the expected structure.
The reaction was also performed in various organic solvents in order to see the yield and
course of reaction using enaminone (2) and benzaldehyde (3a) as a model substrate. To
our satisfaction, the reaction using water provided better yield than organic solvents.
Interestingly, in the reaction of water, the product precipitated out as solid so no
chromatographic purification was needed. The table 1 shows the optimization of solvents.
In this way a series of 17 acridinedione derivatives 4a-q with aromatic, heteroaromatic
and aliphatic aldehydes was successfully synthesized and characterized by various
spectral analysis. Figure 2 represents some of the synthesized acridinediones.
In order to show the wide applicability, the substrate scope of this reaction was further
explored using aromatic, heteroaromatic and aliphatic aldehyde and to our satisfaction,
all the reactions provided required product in good yield with relatively shorter reaction
time. All aromatic aldehydes attempted were found very reactive with shorter reaction
time. For aliphatic substrate, dimethoxyacetaldehyde and octanal was used as aldehyde
component. However the desired product was obtained with relatively low yield in
comparison to aromatic aldehydes. For heteroaromatic aldehydes, the reaction was tried
with furfural and indole-2-carbaldehyde.The reaction with furfural was found very
effective with excellent yield of desired product but the reaction of indole-3-carbaldehyde
5

provided only trace of product. The table 2 shows the scope of substrate with various
aromatic, aliphatic and heteroaromatic aldehydes.
In order to diversify the scope, the reaction was also performed with various other amines
like aniline and benzyl amine as a nitrogen source but unfortunately the reaction did not
provide the required product in significant yield using water as a reaction media.
CONCLUSIONS
In summary, we have developed a green and efficient catalyst and chromatography-free
method for an easy access of acridinedione derivatives which are used as an intermediate
in medicinal chemistry. The reaction merits use of water as a solvent with shorter
reaction time and high yield of product. The synthesized molecules can be potentially
used as a precursor for derivatization to provide electroluminescent materials which are
widely applied in dye and optics.
EXPERIMENTAL
Synthesis of 3-Amino-5,5-dimethylcyclohex-2-enone (2): A mixture of dimedone (1) (1.0
g, 7.1 mmol) and NH4OAc (1.32 g, 21.4 mmol) was heated in 30 mL of water at 80 ᴏC
for 5 hours. After the TLC indicated the consumption of dimedone (2), the reaction
mixture was extracted with ethyl acetate several times. The combined organic layer was
dried over sodium sulphate and evaporated to provide enaminone (2) as light yellow
solid.
6

Synthesis of 3,3,6,6-Tetramethyl-9-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H, 5H)-
dione (4a): A mixture of enaminone (2) (0.2 g, 1.4 mmol) and benzaldehyde (3a) (74 μL,
0.71 mmol) was heated in 10 mL of water at 80 ᴏC for 2 hours. The solid separated out
was filtered off and dried in to provide light yellow colour solid (4a).
Characterization Data For Selected Compounds
ᴏ
3-Amino-5,5-dimethylcyclohex-2-enone (2). m.p.165-167 C; 90% as white solid; IR
(cm-1) 3414, 3020, 2400, 1712; 1H NMR (CDCl3, 300 MHz) δ = 5.29 (s, 1H), 4.85 (bs,
2H, NH), 2.18 (d, J = 9.1 Hz, 4H), 2.02 (s, 2H), 1.07 (s, 6H) 13C NMR (CDCl3, 75
MHz) 198.0, 165.0, 99.0, 49.3, 43.0, 32.7, 28.7 HRMS (ESI) m/z for C8H13NO [M + H]+,
calcd, 140.1705, found, 140.1715
3,3,6,6-Tetramethyl-9-phenyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H, 5H)-dione (4a)
1
m.p. 190-191 ᴏC; 84% as light yellow solid; IR (cm-1) 3424, 3019, 2961, 1629 ; H
NMR (CDCl3, 300 MHz) δ = 8.25 (bs, 1H, NH), 7.33 (d, J = 6.3 Hz, 2H, Ar-H), 7.18 (t,
J = 6.3 Hz, 2H, Ar-H), 7.05 (t, J = 6.2 Hz, 1H, Ar-H), , 5.10 (s, 1H), 2.24 (m, 4H), 2.12
(m, 4H), 1.05 (s, 6H), 0.94 (s, 6H) 13C NMR (CDCl3, 75 MHz) 195.5, 149.9, 147.0,
128.0, 125.9, 113.2, 51.2, 40.9, 33.7, 32.7, 29.5, 27.4 HRMS (ESI) m/z for C23H27NO2
[M + H]+, calcd, 350.2120, found, 350.2119
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H, 5H)-
dione (4c) m.p. 299-302ᴏC; 90% as light yellow solid; IR (cm-1) 3423, 3285, 3020,
2961, 1637; 1H NMR (CDCl3, 300 MHz) δ = 7.98 (bs, 1H, NH), 7.26 (d, J = 7.8 Hz,
7

2H, Ar.-H), 7.14 (d, J = 7.6 Hz, 2H, Ar-H), 5.03 (s, 1H), 2.25 (m, 4H), 2.12 (m, 4H), 1.05
(s, 6H), 0.93 (s, 6H) 13C NMR (CDCl3, 75 MHz) 196.4, 149.7, 145.2, 131.7, 129.6,
113.0, 50.9, 40.9, 33.7, 32.7, 29.8, 26.9 HRMS (ESI) m/z for C23H26ClNO2 [M + H]+,
calcd., 384.1730, found, 384.1735
9-(4-Fluorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H, 5H)-
dione (4d) m.p. 252-253 ᴏC; 90% as light yellow solid; IR (cm-1) 3293, 2980, 1666,
1602; 1H NMR (CDCl3, 300 MHz) δ = 7.93 (bs, 1H, NH), 7.31 (m, 2H, Ar-H), 7.26 (m,
2H, Ar-H), 5.06 (s, 1H), 2.27 (m, 4H), 2.14 (m, 4H), 1.06 (s, 6H), 0.95 (s, 6H) 13C NMR
(CDCl3, 75 MHz) 196.4, 149.1, 142.3, 129.9, 129.7, 129.6, 115.0, 51.2, 41.1, 33.2, 30.3,
27.4 HRMS (ESI) m/z for C23H27FNO2 [M + H]+, calcd, 368.2025, found, 368.2056
ACKNOWLEDGMENT
We are thankful to Dr. S. J. S. Flora, Director, NIPER, Raebareli for his support and
encouragement in carrying out this research work. M.R.U., P.K., P. V. and P.S.M. are
thankful to Department of pharmaceuticals, Ministry of Chemical and Fertilizers, Govt.
of India for providing fellowship. The authors would also like to thank SAIF-CSIR-
CDRI, Lucknow for providing spectral data. NIPER, Raebareli communication no.
NIPER-RBL-MC-06
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Table 1. Optimization of Solvents
Entry Solvent Time Yield (%)*
(h)
1
2
3
4
5
6
EtOH
CH3CN 3 h
DMF 6 h
CHCl3 5 h
4 h
55
75
No expected product
30
25
84
THF
H2O
6 h
2 h
*Isolated yield
12

Table 2. Substrate scope with reaction time and yield
Entry Aldehyde (R)
Product
4a
Time (h)
Yield (%)*
1
Ph (3a)
2
84
80
78
80
76
72
70
72
70
72
71
74
72
75
75
60
65
2
4-Me-Ph (3b)
4-Cl-Ph (3c)
4-F-Ph (3d)
2.5
3
4b
4c
3
4
3
4d
4e
5
4-Br-Ph (3e)
3-Cl-Ph (3f)
2-Cl-6-F-Ph (3g)
2-Br-5-F-Ph (3h)
2-Br-5-OMe-Ph (3i)
3-Me-Ph (3j)
2-Br-Ph (3k)
3-Br-Ph (3l)
4-OMe-Ph (3m)
2-Me-Ph (3n)
Furyl
2.5
2
6
4f
7
3
4g
8
4
4h
4i
9
4.5
4
10
11
12
13
14
15
16
17
4j
2
4k
4l
2.5
3
4m
4n
4o
3
4
Heptyl
10
9
4p
4q
Dimethoxymethyl
*Isolated yield
13

Scheme 1 Two step synthesis of acridinedione
14

Scheme 2. Three component synthesis of acridinedione without catalyst
15

Scheme 3. Synthesis of enaminone (2)
16

Scheme 4. Synthesis of acridinedione from enaminone and aldehyde
17

Figure 1. Various synthesized acridinediones
18