Polyethylene glycol-mediated synthesis of decahydroacridine-1,8-diones catalyzed by ceric ammonium nitrate

Article abstract of DOI:10.2478/s11696-010-0070-2

Polyethylene glycol was found to be an inexpensive non-toxic and effective medium for one pot synthesis of high yields of decahydroacridine-1,8-diones in the presence of ceric ammonium nitrate as the catalyst. Moreover, the solvent can be recovered and re

Full text of DOI:10.2478/s11696-010-0070-2

Chemical Papers 64 (6) 825–828 (2010)
DOI: 10.2478/s11696-010-0070-2
SHORT COMMUNICATION
Polyethylene glycol-mediated synthesis
of decahydroacridine-1,8-diones catalyzed
by ceric ammonium nitrate
Mazaahir Kidwai*, Divya Bhatnagar
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, India
Received 13 May 2010; Revised 30 June 2010; Accepted 10 July 2010
Polyethylene glycol was found to be an inexpensive non-toxic and effective medium for one pot
synthesis of high yields of decahydroacridine-1,8-diones in the presence of ceric ammonium nitrate
as the catalyst. Moreover, the solvent can be recovered and reused.
c
ꢀ 2010 Institute of Chemistry, Slovak Academy of Sciences
Keywords: decahydroacridine-1,8-diones, polyethylene glycol, ceric ammonium nitrate, recyclabil-
ity
The wide range of pharmacological properties of
acridine derivatives such as antimalarial (Spalding
et al., 1954) and anticarcinogenic (Lacassagne et al.,
1956) has stimulated investigation of the synthesis of
acridine derivatives. Moreover, the scope of potential
applications for these compounds has dramatically in-
creased due to the discovery of quinacrine and related
compounds (Aguzzi & Heikenwalder, 2003; Korth et
al., 2001; Ryou et al., 2003; Turnbull et al., 2003; Ko-
cisko et al., 2003) which show quite promising activity
in vitro against prion based diseases. Various meth-
ods for the synthesis of these acridine derivatives from
dimedone, aldehyde, and different anilines or ammo-
nium acetate via traditional heating in organic sol-
vents (Martín et al., 1995) and in water catalyzed
by benzyltriethylammonium chloride (TEBAC) under
microwave irradiation (Wang et al., 2004) are available
in literature. Many other methods are also available
in literature (Jin et al., 2004; Wang & Miao, 2006; Shi
et al., 2008, 2009). Most of these reactions use expen-
sive reagents which are difficult to recover and recy-
cle. Moreover, most of these synthetic methodologies
do not meet the requirements of green chemistry. Or-
ganic reactions not using harmful organic solvents are
one of the current focuses especially in this environ-
mentally conscious society. Therefore, to meet the de-
mands of recyclability and environmental concerns, a
more facile way is the use of non-volatile and low toxi-
city liquids, such as polyethylene glycol (PEG), as the
reaction media. Recently, PEG and its monomethyl
ethers have emerged as alternative green reaction me-
dia (Chen et al., 2005; Zhang et al., 2004; Mao et
al., 2008; Jorapur et al., 2008) with unique proper-
ties such as thermal stability, commercial availability,
non-volatility and recyclability. The important differ-
ence between using PEG and other neoteric solvents
is that all toxicological properties, the short and long
term hazards and the biodegradability etc., are es-
tablished and known. Cerium(IV) ammonium nitrate
(CAN) has emerged as an important reagent for the
construction of carbon-carbon and carbon-heteroatom
bonds. In addition, many advantages such as excellent
solubility in water, inexpensiveness, eco friendliness,
easy handling, high reactivity and easy work up pro-
cedures make CAN a potent catalyst in organic syn-
thesis. Besides this, CAN is able to catalyze various
organic transformations not only based on its electron
transfer capacity but also due to its Lewis acid prop-
erty (Nair & Deepthi, 2007; Sridharan & Menéndez,
2008; Chang et al., 2006; Chu et al., 2007; Han et al.,
2006).
Environmentally benign nature of PEG and versa-
*Corresponding author, e-mail: kidwai.chemistry@gmail.com

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M. Kidwai, D. Bhatnagar/Chemical Papers 64 (6) 825–828 (2010)
O
O
R3
O
O
CH
+
NH4OAc
+
R1
R1
R1
O
N
H
R3
II
R2
R2
R2
I
III
Fig. 1. Synthesis of decahydroacridine-1,8-diones (III). Reaction conditions: active methylene compound I (2 mmol), aldehyde II
(1 mmol), ammonium acetate (1 mmol), CAN (5 mole %), PEG 400 as a solvent, 25◦C, 10–25 min (see Table 4).
Table 1. Spectral data of novel decahydroacridine-1,8-diones
Compound
Spectral data
IR, ν˜/cm−1: 3432 (NH), 1637 (C O), 1462 (C C)
—
—
—
—
IIIb
1H NMR (CDCl3), δ: 11.47 (s, 1H, NH), 6.97–6.45 (m, 4H, Haryl), 5.55 (s, 1H), 3.76 (s, 3H, OCH3), 2.37–1.84 (m,
12H, CH2)
13C NMR (CDCl3), δ: 196.2, 161.8, 148.7, 132.2, 129.5, 125.7, 123.4, 113.8, 110.7, 55.4, 42.5, 36.9, 21.3, 17.8
HRMS, m/z (found/calc.): 323.1519/323.1521 (M+, C20H21NO3)
IR, ν˜/cm−1: 3305 (NH), 1601 (C O), 1434 (C C)
—
—
—
—
IIIe
1H NMR (CDCl3), δ: 11.82 (s, NH), 6.82–6.21 (m, 4H, Haryl), 5.47 (s, 1H), 4.30 (s, 1H, OH), 2.42–1.96 (m, 12H,
CH2)
13C NMR (CDCl3), δ: 196.7, 158.0, 139.3, 130.2, 116.2, 113.8, 43.9, 36.9, 28.6, 17.2
HRMS, m/z (found/calc.): 309.1384/309.1365 (M+, C19H19NO3)
—
—
IIIh
IIIj
IR, ν˜/cm−1: 3424 (NH), 1631 (C O), 1433 (C C)
—
—
1H NMR (CDCl3), δ: 11.92 (s, 1H, NH), 6.98–6.50 (m, 3H, Hthiophene), 5.40 (s, 1H), 2.67–1.74 (m, 12H, CH2)
13C NMR (CDCl3), δ: 197.2, 148.7, 139.4, 140.5, 126.4, 124.2, 113.7, 42.7, 36.2, 28.9, 17.2
HRMS, m/z (found/calc.): 299.0972/299.0980 (M+, C17H17NO2S)
IR, ν˜ /cm−1: 3430 NH), 1587 (C O), 1462 (C C)
—
—
—
—
1H NMR (CDCl3), δ: 11.87 (s, 1H, NH), 6.90–6.61 (m, 4H, Haryl), 5.61 (s, 1H), 3.72 (s, 3H, OCH3), 2.35–2.21 (m,
8H, CH2), 1.13 (m, 12H, CH2)
13C NMR (CDCl3), δ: 191.5, 162.8, 149.2, 132.2, 129.5, 124.6, 123.2, 113.2, 110.7, 56.3, 42.7, 26.3, 17.2
HRMS, m/z (found/calc.): 379.2152/379.2147 (M+, C24H29NO3)
tility of CAN encouraged their coupling and the study
of their utility in the synthesis of decahydroacridine-
1,8-diones. In continuation of our studies in develop-
ing cheap and environmentally benign methodologies
for organic synthesis (Kidwai et al., 2008a, 2008b,
2007) we present here for the first time the synthe-
sis of decahydroacridine-1,8-diones using PEG-400 as
the solvent and applying CAN as the catalyst (Fig. 1).
Melting points were determined using a Thomas
Hoover melting point apparatus and are uncorrected.
IR spectra were recorded on a Perkin–Elmer FTIR-
1710 spectrophotometer using KBr as pellets. 1H
NMR and 13C NMR were recorded on a Bruker Avance
Spectrospin at 300 MHz and 75 MHz, respectively,
using CDCl3 as a solvent and TMS as the internal
standard. EIMS spectra (75 eV) were obtained on
a KC455 Waters TOF-MS spectrometer. Analytical
TLC was performed on pre-coated Merck silica gel 60
F254 plates; the spots were detected either under UV
light or by placing them in a iodine chamber. Tem-
perature of the reaction mixture was measured by a
non-contact mini gun thermometer (AZ minigun type,
model 8868).
In a 50 mL round bottom flask, cyclohexane-1,3-dione
(2 mmol), aromatic aldehyde (1 mmol) and ammo-
nium acetate (1 mmol) in PEG 400 (0.2 mL) were
mixed and stirred at room temperature. To this so-
lution, CAN (5 mole %) was added. Progress of the
reaction mixture was monitored by TLC. After the
completion of the reaction, the reaction mixture was
cooled in a dry ice-acetone bath to freeze the PEG and
the product was extracted with ether (PEG being in-
soluble in ether). The ether layer was decanted, dried
and concentrated under reduced pressure to give the
crude product (single compound according to TLC).
Purification by silica gel column chromatography us-
ing ethyl acetate/hexane (ϕr = 1 : 4) as an eluent af-
forded pure compounds IIIa–IIIp. The recovered PEG
can be reused in consecutive runs. The structures of
all products were unambiguously confirmed by spec-
1
tral data (IR, H and 13C NMR, MS) (Table 1).
In the initial studies, the reaction of cyclohexane-
1,3-dione (2 mmol), benzaldehyde (1 mmol), and am-
monium acetate (1 mmol) was performed in a tradi-
tional organic solvent (EtOH, Table 2, entry 1). The
reaction mixture was stirred for 4 h at room temper-
ature to obtain 60 % of decahydroacridine-1,8-dione
(IIIa), whereas the same reaction in the presence of
Decahydroacridine-1,8-diones (IIIa–IIIp) were pre-
pared according to the following general procedure:

M. Kidwai, D. Bhatnagar/Chemical Papers 64 (6) 825–828 (2010)
827
Table 2. Synthesis of decahydroacridine-1,8-diones: effect of
increase in the quantity of CAN from 2 mole % to 5
mole % not only decreased the reaction time from 25
min to 15 min but also increased the product yield
from 95 % to 98 %. This showed that the catalyst
concentration plays a major role in the optimization
of the product yield. The use of 10 mole % of CAN
decreased the yield of the product to 65 %. The rea-
son for the low product yield is the starting material
or the product decomposition in the course of the re-
action when excess amount (10 mole %) of CAN was
used. Thus, 5 mole % CAN was found to be the best
choice for the optimum yield of decahydroacridine-1,8-
diones (Table 3).
solventa
Entry
Solvent
Time/h
Yield/%b
1
2
3
4
5
6
Ethanol
Acetonitrile
Toluene
PEG 200
PEG 400
PEG 600
4
4
5
1
1
1
60
62
60
90
91
91
a) Reaction conditions: cyclohexane-1,3-dione (2 mmol), ben-
zaldehyde (1 mmol), ammonium acetate (1 mmol), 25◦C; b)
isolated and unoptimized yields.
The effect of temperature on the reaction rate as
well as on the yields of products was also investigated.
Faster reactions occurred on increasing the reaction
temperature; however, the product yield decreased at
high temperatures as one of the reactants oxidizes at
high temperature in the presence of CAN (Table 3).
In order to extend the range of substrates, the pre-
sented methodology was applied to a wide range of
aldehydes in the presence of 5 mole % of CAN un-
der similar conditions. As expected, satisfactory re-
sults were obtained (Table 4).
PEG 400 as an eco friendly medium provided 91 % of
IIIa in only 1 h (Table 2, entry 5).
To further improve the yield and to optimize the
reaction conditions, the same reaction was carried out
in the presence of 2 mole % of CAN under similar con-
ditions. A tremendous improvement was observed and
the yield of IIIa was increased up to 95 % after stir-
ring the mixture for only 25 min. With this optimistic
result in hand, the best reaction conditions were fur-
ther investigated using different amounts of CAN. An
To check the eco friendliness of PEG, PEG 400 was
Table 3. Synthesis of decahydroacridine-1,8-diones: catalytic activity and temperature effecta
Catalytic effecta,b
Time/min
Temperature effecta,c
Entry
CAN/mole %
Yield/%d
Temperature/◦C
Time/min
Yield/%d
1
2
3
4
0
2
5
60
25
15
10
91
98
98
67
25
45
60
80
15
12
10
8
98
98
93
78
10
a) Reaction conditions: cyclohexane-1,3-dione (2 mmol), benzaldehyde (1 mmol), ammonium acetate (1 mmol), PEG 400 as a
solvent; b) reactions performed at 25◦C; c) 5 mole % of CAN was used; d) isolated and unoptimized yields.
Table 4. Synthesis of various decahydroacridine-1,8-diones using CAN and PEGa
Compd.
R1
R2
R3
m.p./◦C
m.p./◦Cb
Time/min
Yield/%c
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
phenyl
279–281
301–302
304–306
298–299
307–309
302–304
282–284
276–278
279–280
293–295
269–270
297–299
302–304
310–312
284–285
306–308
279–281
–
304–306
298–299
–
303–305
282–284
–
278–280
–
270–272
297–299
302–304
310–312
285–287
306–308
15
20
20
25
20
20
10
15
15
20
20
25
20
20
10
15
98
98
98
92
97
97
93
90
98
96
92
92
97
96
94
91
2-methoxyphenyl
4-methoxyphenyl
4-chlorophenyl
4-hydroxyphenyl
2-hydroxyphenyl
3-nitrophenyl
2-thienyl
phenyl
2-methoxyphenyl
4-methoxyphenyl
4-chlorophenyl
4-hydroxyphenyl
2-hydroxyphenyl
3-nitrophenyl
2-thienyl
a) Reaction conditions: see Fig. 1; b) m.p. given in literature; c) isolated and unoptimized yields.

828
M. Kidwai, D. Bhatnagar/Chemical Papers 64 (6) 825–828 (2010)
recycled for several times using reaction conditions
given for compound IIIa (see Fig. 1 and Table 4). The
yield for three subsequent runs was almost identical
with the yield obtained with fresh PEG (∼ 98 %). The
reaction proceeded cleanly with consistent results, al-
though a mass loss of about 5 % of PEG 400 was
observed from cycle to cycle due to mechanical loss.
In conclusion it was found that PEG 400 as a sol-
vent and CAN as a catalyst are useful for effective syn-
thesis of decahydroacridine-1,8-diones. The methodol-
ogy is simple, efficient and environment friendly with
a simple work up. The solvent system could be reused
for several times. All the mentioned characteristics of
our protocol make the reaction suitable for scale up
and commercialization.
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