One-pot synthesis of symmetrical and unsymmetrical acridine sulfonamide derivatives catalyzed by p-TSA

Article abstract of DOI:10.1007/s11164-017-2870-2

Abstract: Synthesis of a series of symmetrical and unsymmetrical 1,8-dioxo-octahydroacridine benzenesulfonamide derivatives has been achieved by one-pot, multicomponent reaction of aromatic aldehydes and sulfanilamide with cyclic 1,3-dicarbonyl compounds by using p-toluenesulfonic acid as an effective, cheap, and efficient catalyst. Reaction progress was monitored by thin-layer chromatography (TLC), and products were analyzed by Fourier-transform infrared (FT-IR), ¹H and ¹³C nuclear magnetic resonance (NMR), and mass spectroscopy (MS). Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-017-2870-2

Res Chem Intermed
DOI 10.1007/s11164-017-2870-2
One-pot synthesis of symmetrical and unsymmetrical
acridine sulfonamide derivatives catalyzed by p-TSA
Cinnathambi Subramani Maheswari1
•
Rathinam Ramesh1 Appaswami Lalitha1
•
Received: 15 November 2016 / Accepted: 10 January 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract Synthesis of a series of symmetrical and unsymmetrical 1,8-dioxo-octahy-
droacridine benzenesulfonamide derivatives has been achieved by one-pot, multicompo-
nent reaction of aromatic aldehydes and sulfanilamide with cyclic 1,3-dicarbonyl
compounds by using p-toluenesulfonic acid as an effective, cheap, and efficient catalyst.
Reaction progress was monitored by thin-layer chromatography (TLC), and products were
analyzed by Fourier-transform infrared (FT-IR), 1H and 13C nuclear magnetic resonance
(NMR), and mass spectroscopy (MS).
Graphical Abstract
CHO
O
CHO
O
O
80 °C
Stirring
R
R
2
O +
NH2
+
NH2
1
O
2
O
3
1
CH3CN
SO2NH2
3
4
SO2NH2
20 mol% p-TSA
R
O
R
O
O
O
N
N
29 examples
12 examples
SO2NH2
SO2NH2
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2870-2)
contains supplementary material, which is available to authorized users.
&
Appaswami Lalitha
lalitha2531@yahoo.co.in
1
Department of Chemistry, Periyar University, Periyar Palkalai Nagar, Salem,
Tamil Nadu 636011, India
123

C. S. Maheswari et al.
Keywords p-Toluenesulfonic acid Á Symmetrical 1,8-dioxo-octahydroacridine
benzenesulfonamide Á Unsymmetrical 1,8-dioxo-octahydroacridine
benzenesulfonamide Á Multicomponent reaction Á One-pot synthesis
Introduction
Acridine and its derivatives are important compounds, and acridine-1,8-diones
containing a 1,4-dihydropyridine parent nucleus have attracted considerable
attention due to their potential pharmacological activities. Acridine and its hydro
derivatives are active against malaria [1], cancer [2], and leishmaniasis [3]. In recent
years, compounds with sulfonamide moiety have been considered an important
group of organic compounds possessing a clinically active pharmacophore [4–9],
exhibiting a wide variety of pharmacological properties, such as antibacterial [10],
hypoglycemic [11], diuretic [12, 13], anti-carbonic anhydrase [12, 14], antithyroid
[15], and anticancer activities [16, 17]. Due to their widespread biological
applications, the present study aimed to develop a new method to synthesize a series
of symmetrical and unsymmetrical 1,8-dioxo-octahydroacridine benzenesulfon-
amide derivatives.
One-pot multicomponent condensation reactions represent effective and efficient
tools to perform better synthesis, because they allow assembly of complex
molecules with maximum simplicity and brevity [18–20]. In recent years, a variety
of synthetic methods for preparation of acridine derivatives by reaction of aldehydes
with two equivalents of 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexane-
dione and different amine sources such as urea [21], methyl amine [22], anilines or
ammonium acetate [23] via conventional heating in organic solvents have been
presented. The yields of these compounds were elevated by use of triethylbenzy-
lammonium chloride (TEBAC) [24], p-dodecylbenzenesulfonic acid (DBSA) [25],
proline [26], Amberlyst-15 [27], tris(pentafluorophenyl)borane [28], and many other
reagents under different conditions. These reported methodologies have their own
advantages but also suffer from one or more disadvantages such as prolonged
reaction time, toxic reagents, expensive metal catalysts, hazardous organic solvents,
harsh reaction conditions, complex processes, low yield, tedious workup conditions,
etc.
Results and discussion
The present study aims to develop a new protocol for one-pot synthesis of a series
of symmetrical 4-(3,3,6,6-tetramethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-octahy-
droacridin-10(9H)-yl)benzenesulfonamide and 4-(1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,
8-octahydroacridin-10(9H)-yl)benzenesulfonamide derivatives from aromatic alde-
hydes and sulfanilamide with 5,5-dimethyl-1,3-cyclohexanedione (dimedone)/1,3-
cyclohexanedione by using p-toluenesulfonic acid (p-TSA) as catalyst.
We chose the reaction of dimedone (1), sulfanilamide (2), and 4-chloroben-
zaldehyde (3) as a model (Scheme 1) and investigated different Lewis and Brønsted
123

One-pot synthesis of symmetrical and unsymmetrical…
Scheme 1 Synthesis of 1,8-dioxo-octahydroacridine benzenesulfonamide derivatives using p-TSA as
catalyst
Table 1 Optimization of reaction conditions for synthesis of symmetrical 1,8-dioxo-octahydroacridine
benzenesulfonamide (4b)
Entry Catalyst
Mol% of catalyst Solvent
Temp. (°C) Time (min) Yielda (%)
1
CAN
CAN
20
20
Ethanol
Methanol
Ethanol
–
Reflux
Reflux
Reflux
80
300
276
420
600
360
600
480
720
180
480
120
15
30
23
10
Trace
–
2
3
Bismuth nitrate 20
4
–
–
5
Oxalic acid
HCl
10
10
10
10
20
–
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Acetic acid
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
6
–
7
H2SO4
HNO3
–
8
–
9
Acetic acid
Acetic acid
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
46
52
66
96
82
88
42
52
49
10
11
12
13
14
15
16
17
a
20
20
10
30
20
20
20
CH3CN/H2O 80
Acetonitrile
Acetonitrile
Acetonitrile
Ethanol
80
80
80
80
80
80
25
15
360
480
138
Water
Methanol
Reaction conditions: Dimedone (2 mmol), sulfanilamide (1 mmol), 4-chlorobenzaldehyde (1 mmol),
CH3CN (3 ml), p-TSA, 80 °C
acid catalysts in polar protic and polar aprotic solvents at different temperatures; the
screening results are presented in Table 1. When the reaction was performed in
absence of catalyst, no product formation was observed even after prolonged
reaction time. The reaction was then attempted with ceric ammonium nitrate and
bismuth nitrate individually, with low product yields even after 6 h (Table 1, entries
1–3). Next, we performed the reaction under similar conditions with different
Brønsted acid catalysts such as oxalic acid, hydrochloric acid, sulfuric acid, nitric
acid, and acetic acid (Table 1, entries 5–10), but the product yields were again not
123

C. S. Maheswari et al.
improved. However, the product yield was greatly improved when using p-TSA as
catalyst (20 mol%). Subsequently, the effect of solvents was explored with ethanol,
methanol, water, acetonitrile, and acetonitrile:water mixture (1:1), among which
acetonitrile gave excellent product yield. We also investigated the quantity of p-
TSA required for this reaction (Table 1, entries 13 and 14), observing that 20 mol%
p-TSA in CH3CN (Table 1, entry 12) was sufficient to drive this reaction
successfully at 80 °C.
Using the above optimized conditions, aromatic aldehydes having both electron-
withdrawing and electron-donating groups were subjected to the reaction, with no
specific substituent effects observed in this conversion. However, the reactivity of
dimedone was found to be higher, providing the product faster, compared with 1,3-
cyclohexanedione (Table 2).
Under the above optimized conditions, we next tried to synthesize unsymmetrical
4-(3,3-dimethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)ben-
zenesulfonamide derivatives (Scheme 2). The pilot reaction was carried out using
dimedone (1 mmol), 1,3-cyclohexanedione (1 mmol), 4-nitrobenzaldehyde (1 mmol),
and sulfonamide (1 mmol) in presence of 20 mol% p-TSA as catalyst in 3 ml
acetonitrile at 80 °C for appropriate time with continuous stirring (Table 3).
In this case, we observed three different products, viz. an unsymmetrical acridine
benzenesulfonamide and two symmetrical xanthenes. Fortunately, we got our
desired products, the unsymmetrical 1,8-dioxo-octahydroacridine benzenesulfon-
amides 10a–l in good yields, along with the symmetrical xanthenes formed in small
quantities; the mixture of these products was purified by column chromatography to
afford the desired product. To the best of our knowledge, no literature method is
available for synthesis of unsymmetrical acridine derivatives. The 1H NMR
spectrum of 4-(3,3-dimethyl-9-(4-nitrophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahy-
droacridin-10(9H)-yl)benzenesulfonamide (10g) showed aromatic protons at d
8.15–7.99 ppm, while the NH2 proton of sulfonamide moiety appeared as singlet at
d 8.05 ppm, merged with the aromatic protons. Next, the peak at d 5.23 ppm
confirms the presence of methine proton, and methylene protons appeared at d
2.24–1.74 ppm. The dimedone diastereomeric protons also mixed with the
methylene protons, showing two singlets at d 2.49 and 2.04 ppm and two singlets
at d 0.89 and 0.76 ppm, indicating presence of geminal methyl protons of dimedone
moiety.
The side product, 3,3,6,6-tetramethyl-9-(4-nitrophenyl)-3,4,5,6,7,9-hexahydro-
1H-xanthene-1,8(2H)-dione (11g) formed was also confirmed by 1H NMR analysis.
1
The H NMR spectrum showed two singlets at d 0.99 and 0.83 ppm, indicating
presence of geminal methyl protons of dimedone moiety, and the singlet observed at
d 4.5 ppm corresponds to presence of methine (–CH–) proton, while another
multiplet appeared at d 7.135–7.013 ppm, indicating presence of aromatic protons.
For synthesis of a series of novel unsymmetrical acridine-1,8-dione benzenesul-
fonamides, we used various substituted aromatic aldehydes (for the cycloconden-
sation reaction) with both electron-donating and withdrawing-groups present in
ortho, para, and meta positions. When either electron-donating or electron-
withdrawing substituents (–F, –Cl, –Br, –NO2 and –OCH3, –CH3, –OH) were
present in para position, our target products were formed in good yields and the
123

One-pot synthesis of symmetrical and unsymmetrical…
Table 2 Synthesis of symmetrical 1,8-dioxo-octahydroacridine benzenesulfonamides using 20 mol% p-
TSA as catalyst
Entry
R3C6H4CHO
R1 and R2
Product
Time (min)
Yielda (%)
M.p. (°C)
1
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4a
4b
4c
4d
4e
4f
23
15
18
16
19
16
25
17
30
15
16
28
91
95
93
93
94
90
86
92
95
95
95
90
197–199
268–270
255–256
284–286
233–236
258–260
290–293
288–289
[300
2
4-ClC6H4
3
2-ClC6H4
4
2,4-ClC6H3
4-OCH3C6H4
4-CH3C6H4
4-OH-3-OCH3C6H3
4-BrC6H4
5
6
7
4g
4h
4i
8
9
4-OHC6H4
4-NO2C6H4
3-NO2C6H4
10
11
12
4j
277–280
217–220
180–182
4k
4l
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
a
3,4-OCH3C6H3
4-FC6H4
CH3
CH3
CH3
H
4m
4n
4o
5a
5b
5c
5d
5e
5f
20
16
40
28
25
47
39
25
26
35
26
30
27
33
35
24
40
88
94
86
90
94
82
85
88
91
83
92
89
91
87
87
93
86
288–290
228–230
266–268
148–150b
290b
1,4-CHOC6H4
C6H5
4-ClC6H4
H
2-ClC6H4
H
286–288b
279–282b
176–178b
172–174b
194–196b
295–298b
274–277b
178–180b
168–170b
227–230b
290–292b
[300b
2,4-ClC6H3
4-OCH3C6H4
4-CH3C6H4
4-OH-3-OCH3C6H3
4-BrC6H4
H
H
H
H
5g
5h
5i
H
4-OHC6H4
4-NO2C6H4
3-NO2C6H4
3,4-OCH3C6H3
4-FC6H4
H
H
5j
H
5k
5l
H
H
5m
5n
1,4-CHOC6H4
H
Reaction conditions: Dimedone or 1,3-cyclohexanedione (2 mmol), sulfanilamide (1 mmol), aromatic
aldehyde (1 mmol), CH3CN (3 ml), p-TSA, 80 °C
b
Novel compounds
xanthenes were formed in lower percentages. However, with aromatic aldehydes
having electron-donating or electron-withdrawing groups in ortho position, there
was a slight decrease in the yield of the desired product and an increase in the
formation of xanthenes, which may be due to steric effects. In the case of aromatic
aldehydes with substituents in meta position, the decrease in the yield of the acridine
product may be attributed to electronic effects.
123

C. S. Maheswari et al.
Scheme 2 Synthesis
octahydroacridin-10(9H)-yl)benzenesulfonamide derivatives using p-TSA as catalyst
of
unsymmetrical
4-(3,3-dimethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-
Table 3 Synthesis of some novel unsymmetrical 4-(3,3-dimethyl-1,8-dioxo-9-phenyl-octahydroacridin-
10(9H)-yl)benzenesulfonamide derivativesa
Entry
ArCHO 9a–l
Time (min)
Yieldb (%)
M.p. (°C) 10a–l
10a–l
11a–l
12a–l
1
C6H5
70
50
56
55
50
63
56
72
85
52
72
90
74
80
77
78
77
73
78
70
72
77
64
53
20
16
20
19
20
23
18
25
22
19
29
37
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
240–242
272–274
230–233
210
2
4-ClC6H4
3
4-OCH3C6H4
4-CH3C6H4
4-BrC6H4
4
5
278–280
260–262
262–264
189–191
228–231
188–190
222–224
203–206
6
4-OHC6H4
4-NO2C6H4
3-NO2C6H4
3,4-OCH3C6H3
4-FC6H4
7
8
9
10
11
12
a
2,4-ClC6H4
2-ClC6H4
Reaction conditions: Dimedone (1 mmol), 1,3-cyclohexanedione (1 mmol), sulfanilamide (1 mmol),
aromatic aldehyde (1 mmol), CH3CN (3 ml), p-TSA, 80 °C
b
Isolated yield of product using column chromatography
A plausible mechanism is suggested for the above synthesis in Scheme 3. In the
presence of Brønsted acid catalyst, the electrophilicity of the carbonyl carbon of the
aromatic aldehyde would be enhanced to react with one molecule of dimedone via
Knoevenagel condensation to form 2-arlylidinedimedone intermediate I, which
prefers to react with another molecule of dimedone via Michael addition, resulting
in formation of Michael adduct II. Subsequent nucleophilic addition of
123

One-pot synthesis of symmetrical and unsymmetrical…
H
O
R
O
H
R
O
O
O
R
O
Knoevenagal condensation
-H2O
Michael addition
H
3(a-o)
O
O
H
OH
O
O
CH3CN
(I)
(II)
O
NH2
O
SO2NH2
R
O
R
O
R
O
O
O
O
H
-H2O
-H2O
HN
N
HO
OH OH
HN
SO2NH2
SO2NH2
4(a-o)
SO2NH2
(IV)
(III)
Scheme 3 Plausible mechanism for synthesis of 1, 8-dioxo-octahydroacridine benzenesulfonamide
derivatives using p-TSA as catalyst
4-aminosulfanilamide gives intermediate III, which undergoes simultaneous
dehydration followed by intramolecular cyclization to form corresponding acridine
derivatives with elimination of a water molecule.
Experimental
General
Melting points were determined in open capillaries and are uncorrected. IR spectra
of the compounds were recorded on FT-IR Magna 550 instrument using KBr
1
pellets. H and 13C NMR spectra were recorded in Bruker 300 and 400 MHz high-
resolution NMR spectrometers with dimethyl sulfoxide (DMSO-d6) as solvent,
recorded in parts per million with tetramethylsilane (TMS) as internal standard.
Reaction progress was monitored by thin-layer chromatography (TLC) on Merck
precoated aluminum sheets of 60 F-254 silica gel plates using mixture of 95 %
chloroform and 5 % methanol as mobile phase. High-resolution mass spectroscopy
data were recorded on JEOL GC Mate II mass spectrometer.
General procedure for synthesis of symmetrical 1,8-dioxo-octahydroacridine
benzenesulfonamide
A mixture of aromatic aldehyde (1 mmol), sulfanilamide (1 mmol), dimedone
(2 mmol)/1,3-cyclohexanedione (2 mmol), and p-toluenesulfonic acid (p-TSA,
123

C. S. Maheswari et al.
20 mol%) in 3 ml CH3CN was heated with stirring at 80 °C for specified time.
Reaction progress was monitored by TLC. After reaction completion, the solid
products were isolated by simple filtration and washed with water. The products
were purified by recrystallization from ethanol to afford pure products. The
1
recrystallized products were analyzed by FT-IR, H and 13C NMR, and MS.
General procedure for synthesis of unsymmetrical 4-(3,3-dimethyl-1,8-dioxo-9-
phenyl-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)benzenesulfonamide
A mixture of aromatic aldehyde (1 mmol), sulfanilamide (1 mmol), dimedone
(1 mmol), 1,3-cyclohexanedione (1 mmol), and p-toluenesulfonic acid (p-TSA,
20 mol%) in 3 ml CH3CN was heated with stirring at 80 °C for specified time.
Reaction progress was monitored by TLC. Then, the solid products were isolated by
simple filtration and washed with water. After that, the crude products were purified
1
by column chromatography. The derived products were analyzed by FT-IR, H and
13C NMR, and MS.
Conclusions
We introduce an efficient and convenient approach for synthesis of pharmacolog-
ically active symmetrical and unsymmetrical acridinedione sulfonamide derivatives
via condensation of sulfanilamide and dimedone/1,3-cyclohexanedione with various
aromatic aldehydes using a less expensive catalyst, namely p-TSA. High yield in
shorter reaction time with simple work-up are the notable advantages of this
protocol.
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