We conditions: Dimedone (2 mmol), benzaldehyde (1 mmol), NH4OAc

We optimized the reaction conditions such as effects
of solvents and catalyst. In order to optimize the reaction conditions, the
reaction of benzaldehyde (1 mmol), dimedone (2 mmol), and ammonium acetate (1.2
mmol) in presence of citric acid (2 mmol) was selected as a model reaction (Scheme
1). In pilot experiment, the reaction was carried out in a variety of solvents
water, ethanol, ethanol:water, methanol, acetonitrile, dichloroethane and toluene
as shown in Table 1. The
best result was obtained by the reaction using ethanol providing excellent
yield (89%) of the desired product (Table
1, entry 2). The reaction proceeded scarcely in water, ethanol:water,
methanol, acetonitrile, dichloroethane and toluene providing moderate yields of
anticipated products in comparatively prolonged reaction time (Table 1, entries 1, 3-7).

Table 1:
Optimization of solvent for synthesis of 1, 8-dioxodecahydroacridinea

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Entry

Reaction
Condition

Time
(min)

Isolated
Yieldb (%)

Water/ Reflux

240

Ethanol/Reflux

150

Ethanol:Water/
Reflux

200

Methanol/
Reflux

300

Acetonitrile/
Reflux

360

Dichloroethane/
Reflux

400

Toulene/
Reflux

390

aReaction
conditions: Dimedone (2 mmol), benzaldehyde (1 mmol), NH4OAc (1.5
mmol) and citric acid monohydrate as green additive in various solvent at reflux.

bIsolated yields.

Our
next task was to optimize the catalyst loading. For this, we have carried the model
reaction under optimized conditions by varying the quantity of citric acid as
summarized in Table 2. It was found
that the quantity of catalyst played crucial role on the product yield. When
the quantity of citric was increased, the yield of target product was elevated
significantly (Table 2, entries 1-3)
and maximum yield of the product obtained when 2 mmol of citric acid was used (Table 2, entry 4) Further increase in
quantity of citric acid did not influence on yield of the product (Table 2, entry 5).

With this result in hand, we have
studied the effect of temperature on model reaction
condition by conducting model reaction at 100°C and at room temperature but the
reaction proceeded long time with unsatisfactory result.

Table
2 Optimization
of catalyst amount for the synthesis of 1, 8-dioxodecahydroacridinea

Entry

Citric Acid
(mmol)

Time (min)

Isolated Yield
(%)

–

150

–

150

1.5

150

2.0

150

3.0

150

aReaction
conditions: Dimedone (2 mmol), benzaldehyde (1 mmol), NH4OAc (1.5
mmol) and citric acid in ethanol at reflux.

Table
3:
synthesis of 1, 8-dioxo-decahydroacridine derivatives.a

Entry

Aldehydes
(2)

Product

Time(min)

Yield (%)

Benzaldehyde

150

4-Nitrobenzaldehyde

100

4-Chlorobenzaldehyde

160

4-Bromobenzaldehyde

180

4-Cyanobenzaldehyde

200

4-Hydroxybenzaldehyde

160

4-Methoxybenzaldehyd

210

4-Methylbenzaldehyde

130

3,4,5-Trimethoxybenzaldehyde

230

Thiophene-2-carbaldehyde

240

Isopropanaldehyde

300

aReaction conditions:
Dimedone (2 mmol), aryl aldehyde (1 mmol), NH4OAc (1.5 mmol) and
citric acid in ethanol at reflux.

After
the optimization of reaction conditions, we evaluate the scope and generality
of protocol by reacting dimedone, NH4OAc with diverse aromatic aldehydes.
The results are shown in Table 3. The
reaction proceeded smoothly in all the cases to afford the desired 1,8-dioxodecahydroacridine
in good to excellent yields. It is worthy to note that both electron rich and
electron deficient aromatic aldehydes reacted efficiently with good chemical
reactivity. However, the reaction with aliphatic aldehyde, the time was
prolonged and the yield of the product was very low.

Fig 1:
Reusability of citric acid synthesis of 1, 8-dioxo-decahydroacridine

We have examined the reusability of citric acid for
the model reaction. After completion of the reaction, the product was separated
and resulting filtrate extracted by chloroform. The catalyst was separated from
aqueous layer and dried under vacuum. The recovered citric acid was used for
similar reaction and as it is shown in graph the catalyst could be reused
without significant loss of activity (Fig 1).

The plausible mechanism for 1,
8-dioxodecahydroacridines is depicted in scheme
2. First the citric acid promote for enolization of 1, 3-diketone molecule
and convert aldehydes into suitable electrophile by protonation and the
knoevengel adduct A formed by
reaction of enol form of 1, 3-diketone and the aldehydes. Then, A may undergo Michael addition with
another molecule of dimedone in its enol form influence by citric acid to yield
intermediate B. The resulting
intermediate reacts with ammonium acetate to yield imine which undergoes
an intramolecular cyclization and dehydration to yield the estimated product C.

Scheme 2: Proposed
reaction mechanism for synthesis of 1,8-dioxodecahydroacridines

Table
4:
Effect of various catalysts on synthesis of 1, 8-dioxodecahydroacridines

Entry

Catalyst

Reaction
Condition

Time
(min)

Yield
(%)

References

Citric
acid (2 mmol)

Ethanol/Reflux

150

This
work

Ni0.5Co0.5Fe2O4
(20 mol %)

EtOH:H2O
(1:1),Reflux

SiO2-ZnCl2
(0.2 g mol %)

100°
C

B
(C6F5)3 (3 mol %)

168

PPA-SiO2
(0.02
gm)

100°C

Ammonium
chloride

120°C

SPNP
(0.03 mmol)

H2O,
reflux

120

In
order to show the efficiency and advantages of citric acid with the reported
catalysts, we have tabulated several results for the synthesis of 1,8-dioxodecahydroacridines in Table 4. It is clear that, citric acid is effective in terms of
yield and reaction times than reported catalysts.

Experimental:

All chemicals were purchase from local supplier and
used without further purification. Melting points were determined by the open
capillary method and are uncorrected. The IR spectra were measured on Bruker
ALPHA FT-IR spectrometer in between the frequency range 500-4000 cm-1.
The NMR spectra were recorded on Bruker AC (400 MHz for 1H NMR and
75 MHz for 13C NMR) spectrometer using TMS as an internal standard.
Chemical shifts (d)
are expressed in ppm.

General
procedure for the synthesis of 1, 8-dioxodecahydroacridine derivatives (4a-k):

A mixture of dimedone (2 mmol), aldehyde (1 mmol),
ammonium acetate (1.2 mmol) and citric acid (2 mmol) in ethanol (4 mL) was
stirred at reflux for appropriate time (Table 3). After complete conversion as
indicated by TLC, the reaction mixture was allowed to cool at room temperature,
poured onto ice-cold water (20 ml) and stirred continuously for 10 minutes. The
formed solid filtered, washed with cold water and then dried. The solid was recrystallized
by in ethanol. All the resulting products were purified and characterized by
spectroscopic techniques.

Selected
spectral data of representative compounds

3, 3, 6, 6-Tetramethyl-9-(phenyl)-1, 8-dioxo-decahydroacridine
(Table 3, entry a):

Mp:
193-195°C, 1H NMR (400 MHz, CDCl3) ? (ppm): 7.45 (s, 1H,
NH), 7.65-7.10 (m, 5H, Ar-H), 5.15 (s, 1H, CH), 2.42-2.17 (m, 8H, CH2),
1.12 (s, 6H, CH3), 0.98 (s, 6H, CH3); 13C NMR
(75 MHZ, CDCl3) ?: 193.8, 148.3, 136.4, 126.8, 128.1, 1256.8, 114.3,
51.1, 41.3, 34.2, 33.6, 29.9, 27.6; IR (KBr, cm-1) ? : 3275, 2959,
1631, 1368.

3, 3, 6, 6-Tetramethyl-9-(4-chlorophenyl)-1, 8-dioxo-decahydroacridine
(Table 3, entry c):

Mp:
295-297 °C, 1H NMR (400 MHz, CDCl3) ? (ppm): 7.66 (s, 1H, NH), 7.48 (d, J = 9, 2H), 7.38 (d, J = 9, 2H), 5.16 (s, 1H, CH), 2.30-2.13 (m, 8H, CH2), 1.17 (s, 6H, CH3), 0.95 (s, 6H, CH3);
13C
NMR (75 MHZ, CDCl3) ?: 196.1, 150.1, 144.9, 132.0, 130.1, 127.9, 113.2,
51.5, 41.1, 34.4, 33.6, 30.5, 26.8; IR (KBr, cm-1): 3436, 2954, 1647, 1612, 1365.

3, 3, 6, 6-Tetramethyl-9-(4-cynophenyl)-1, 8-dioxo-decahydroacridine
(Table 3, entry e):

Mp:
324-326°C, 1H NMR (400 MHz, CDCl3)
? (ppm): 0.96 (s, 6H, CH3), 1.13 (s, 6H, CH3), 2.19 (d, J?16.5 Hz, 2H), 2.28 (d, J?16.5 Hz, 2H), 2.26(d, J?16.5 Hz, 2H), 2.43 (d, J?16.5 Hz, 2H), 5.11 (s, 1H, CH), 5.91 (s, 1H, NH),
7.46 (d, J?8.3
Hz, 2H, Ar-H), 7.52 (d, J?8.3
Hz, 2H, Ar-H); 13C NMR (75 MHZ, CDCl3) ?: 194.8, 148.7, 146.1, 130.2,
129.5, 120.7, 112.9, 50.4, 32.9, 32.0, 30.5, 29.1, 26.6; ); IR (KBr): 3321, 2955, 2233, 1631, 1491 cm-1

3, 3, 6, 6-Tetramethyl-9-(4-methoxyphenyl)-1, 8-dioxo-decahydroacridine
(Table 3, entry g):

Mp:
270-272°C, 1H NMR (400 MHz, CDCl3)
? (ppm): 8.82 (s, 1H, NH), 7.12 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.83(s, 1H, CH), 3.65 (s, 3H,
O-CH3), 2.35 (d, J
= 17.0 Hz, 1H), 2.24 (d, J = 16.3 Hz, 1H), 2.10 (d, J =15.9, 1H), 1.98 (d, J = 16.2 Hz, 1H), 1.01 (s, 6H, CH3),
0.98 (s, 6H, CH3);
13C
NMR (75 MHZ, CDCl3)
?:
192.4, 154.6, 149.1, 138.9, 128.6, 112.8, 111.8, 54.6, 51.8, 32.2, 30.3, 28.9,
26.5.; IR (KBr, cm-1): 3448, 2954, 1643, 1612, 1365, 1141.

3, 3, 6, 6-Tetramethyl-9-(4-methylphenyl)-1, 8-dioxo-decahydroacridine
(Table 3, entry 1):

Mp: 271-273°C, 1H NMR (400 MHz, CDCl3)
? (ppm): 11.9 (s, 1H, NH), 7.09 (d, J = 9, 2H), 6.98 (d, J = 9, 2H), 5.50 (s,
1H, CH), 2.29 (s, 3H, CH3), 2.19-2.47 (m, 8H, CH2), 1.22 (s, 6H, CH3),
1.09 (s, 6H, CH3); 13C NMR (75 MHZ, CDCl3) ?:
190.6, 135.5, 135.1, 129.3, 128.9, 126.5, 117.7, 47.2, 46.6, 32.5, 31.3, 29.8,
27.4; 20.9; IR (KBr, cm-1) : 2958, 2877, 1569, 1369.

Conclusion:

In this work,
the reported method offers simple, and economically viable one-pot method for synthesis
of decahydroacridine-1, 8-diones derivatives via Hantzsch condensation
of various aldehydes, ammonium acetate with cyclic 1, 3-dicarbonyl compound using commercially available, inexpensive
citric acid as a green additive. Some important superiorities of this method
are use of inexpensive reagents, absence of toxic effluents, use of green
solvent, easy workup and operational simplicity In addition, employment of
green, inexpensive, eco-friendly and commercially available additive make this
procedure very attractive in modern synthetic methodologies.

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