A Rapid and Convenient Synthesis of Acridine Derivatives Using Camphor Sulfonic Acid Catalyst

Full text of DOI:10.1080/00304948.2018.1549907

Organic Preparations and Procedures International
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A Rapid and Convenient Synthesis of Acridine
Derivatives Using Camphor Sulfonic Acid Catalyst
D. S. Bhagat, S. U. Tekale, A. K. Dhas, S. U. Deshmukh, R. P. Pawar & P. S.
Kendrekar
To cite this article: D. S. Bhagat, S. U. Tekale, A. K. Dhas, S. U. Deshmukh, R. P. Pawar
&
P. S. Kendrekar (2019): A Rapid and Convenient Synthesis of Acridine Derivatives Using
Camphor Sulfonic Acid Catalyst, Organic Preparations and Procedures International, DOI:
0.1080/00304948.2018.1549907
1
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ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1549907
A Rapid and Convenient Synthesis of Acridine
Derivatives Using Camphor Sulfonic Acid Catalyst
1
1
1
1
D. S. Bhagat, S. U. Tekale, A. K. Dhas, S. U. Deshmukh,
1
2
R. P. Pawar, and P. S. Kendrekar
1
Department of Chemistry, Deogiri College, Station Road, Aurangabad 431
0
05, MS, India
2
Department of Health Sciences, Central University of Technology,
Bloemfontein 9300, Free State, South Africa
th
Acridines were first developed as dyes, and since the early 20 century their varied
properties have continued to be of interested. Derivatives of acridine showed good cyto-
toxic activity against human leukemia cells. They are found to be potent drugs towards
1
–2
3
4
metastatic breast cancer cells. Acridine can be used in chemosensors, dyes, fluores-
5–6
7
8
9
cent probes, anticonvulsant, analgesic, hypertensive, and anti-inflammatory medi-
cations and in chiral optical materials. Proflavin has been used as an antibacterial
and antifungal agent. Acridines such as quinacrine, pyronaridine and acranil have
10
11
1
2
1
3
been used as antimalarial drugs. Acridines have been utilized as single agents or in
combination with other antineoplastic drugs in the treatment of acute non-lymphocytic
1
4,15
16
and lymphocytic leukemia,
synthesis.
and against lung cancer. Acridines inhibit RNA
17
Several catalysts have been used for the synthesis of N-substituted 3,3,6,6-tetra-
methyl-9,10-diphenyl-3,4,6,7,9,10-hexahydroacridine-1,8-(2H,5H)-dione derivatives (4);
1
8
19
20
these include [2-MPyH]OTf, SBA Pr-SO H, DABCO-PEG ionic liquid, SiO /
3
2
24
21
22
23
ZnCl2, Cu doped nano ZnO, SiO2I, silica bonded N-propyl sulfamic acid,
25
26
BNBTS, K CO and Cu Cl . Some of the reported synthetic protocols used expen-
2
3
2
2
sive reagents, extended reaction times, high reaction temperatures or lengthy work-up
procedures. In the present work we describe a fast and green approach for the synthesis
of compounds (4) by using camphor sulfonic acid (CSA) (Scheme 1).
In search of the best experimental reaction conditions, the reaction of dimedone 1,
benzaldehyde 2 and aniline 3 was considered as a model reaction (Scheme 1). The reac-
tion was carried out using CSA and other catalysts as reported in the literature (Table
1). The reaction went smoothly and in high yield by using CSA in ethanol (Table 1,
entry 6). When the reaction was carried out in the absence of catalyst, the product
formed in only a trace amount (Table 2, entry 1). To optimize the concentration of
CSA required to obtain high yields of product in the model reaction, we investigated 2,
4
, 6, 8, 10, 12 and 14 mol % catalyst (Table 2). Optimal results were obtained with
Received August 14, 2017; in final form August 10, 2018.
Address correspondence to R. P. Pawar, Department of Chemistry, Deogiri College, Station
Road, Aurangabad, 431 005, MS, India. E-mail: rppawar@yahoo.com
1

2
Pawar et al.
Scheme 1. Standard model reaction.
Table 1
Effect of Catalyst and Solvents
ꢀ
Entries
Catalysts
Solvent Time (h/ min) Temp. ( C) Yield (%)
Ref.
1
2
3
4
5
6
SBA-Pr-SO H
–
5 min
2–5 h
10–12 h
2 h
0.5–2 h
30 min
140
80
100
140
90
69
40–90
90
60–75
80
19
23
28
24
25
3
SiO -I
Ethanol
Water
Ethanol
–
2
TEBAC
NH SO H
2
3
BNBTS
CSA
Ethanol
60
90–94 Present work
Table 2
Effect of Concentration of Catalyst
ꢀ
Entries
Mol %
Solvent
Time (min)
Temp ( C)
Yield (%)
1
2
3
4
5
6
7
8
No catalyst
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
30
30
30
30
30
30
30
30
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Trace
30
50
60
80
90
90
90
2
4
6
8
10
12
14
1
0 mol % of catalyst (Table 2, entry 6). In order to evaluate the effect of solvent, reac-
tions were carried out as listed in Table 3. Toluene, acetonitrile, DMF and DCM
afforded moderate yields. Methanol and DMSO resulted in good yields; but ethanol fur-
nished the product in 90% yield (Table 3, entry 6), making it the most favorable solv-
ent. To explore the scope of the method, different aldehydes and anilines were treated
with dimedone in the presence of 10 mol % of CSA using ethanol as a solvent. All the

Acridine Derivatives
3
Table 3
Screening of Solvent
ꢀ
Entries
Solvent
CSA mol %
Time (min)
Temp ( C)
Yield (%)
1
2
3
4
5
6
7
Toluene
Acetonitrile
DMF
10
10
10
10
10
10
10
30
30
30
30
30
30
30
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
60
70
75
70
80
90
78
DCM
Methanol
Ethanol
DMSO
Table 4
Synthesis of Acridine Derivatives
o
MP ( C)
Entry Aldehyde (R ) Amine (R ) Time (Min.) Yield (%) Observed Reported Ref. No.
1
2
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
4-Cl
4-Cl
4-Cl
4-NO2
4-OH
3-NO2
4-Me
4-Cl
4-Me
4-Me
-H
4-Me
4-Me
4-Me
4-Me
3-NO2
-H
30
30
30
30
30
30
30
30
30
30
30
30
30
90
91
92
90
91
90
93
92
90
90
93
93
90
303–305 303–305
273–275 273–275 18, 27
18
242–245 243–245
278–280 281–282
284–287 347–349
280–284 279–282
296–298 295–297
272–274 273–275
275–277 276–278
278–280 278–280
276–278 277–279
217–219 222–224
252–254 255–257
27
27
18
27
18
18
19
26
18
18
18
4-OH, 3-OMe
4-OMe
4-NO2
j
k
l
3-NO2
4-OMe
-H
-H
-H
-H
m
Reaction conditions: Dimedone (2 mmol), aromatic amine (1 mmol), aldehyde derivatives
1 mmol), CSA catalyst (10 mol %), ethanol solvent (2 mL).
(
substrates were well tolerated under the optimized conditions, furnishing the product in
uniformly high yields. The results are compiled in Table 4. Formation of the desired
product was confirmed by comparing the melting points with the literature values and
1
13
by IR, H NMR, C NMR and mass spectroscopic data.
In summary, we have developed a practical approach for the synthesis of compounds
4
via the multicomponent reaction of substituted amines, aldehydes and dimedone using
CSA catalyst in ethanol. This procedure is rapid and greener than some of the previous
methods, in that it avoids the use of more toxic solvents and requires less heating.
Experimental Section
Chemicals were purchased from SD Fine or Sigma Aldrich and used without further
purification. Melting points of the products were recorded on a digital melting point

4
Pawar et al.
apparatus (Optics Technology). The reactions were monitored using thin layer chroma-
tography (TLC) in 40% ethyl acetate:n-hexane on silica gel precoated aluminum foil
(
Merck). FT-IR (KBr) spectra were recorded at room temperature on a Varian Inova
1
spectrometer, and H NMR spectra in CDCl using tetramethylsilane (TMS) as internal
3
standard on a Brucker Vector spectrometer.
General Procedure for the Synthesis of 3,3,6,6-Tetramethyl-9,10-diphenyl-
3
,4,6,7,9,10-hexahydroacridine-1,8-(2H,5H)-diones (4)
In a round bottom flask were placed cyclohexanedione 1 (2 mmol), an aromatic alde-
hyde 2 (1 mmol), an aniline 3 (1 mmol) and CSA (10 mol %) in ethanol (2 mL) and the
ꢀ
reaction mixture was stirred at 60 C. The progress of reaction was monitored using
TLC. The reaction mixture was quenched with crushed ice and extracted with ethyl
acetate (2 ꢁ 15 mL). The organic extract was washed with brine solution (2 ꢁ 15 mL)
and dried over anhydrous sodium sulfate, then filtered. The solvent was evaporated
under reduced pressure to afford the corresponding crude compounds. The obtained
crude compounds were recrystallized from ethanol (Table 4).
Representative Compound Data
9
,10-bis(4-Chlorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-4-chlorophenylacridine-
ꢀ
1
1,8(2H, 5H, 9H, 10H)-dione (4a): Off white solid; mp. 303–305 C. H NMR
(
7
6
400 MHz, CDCl , ppm): d 0.74 (s, 6H), 0.89 (s, 6H), 1.95–2.14 (m, 8H), 5.15 (s, 1H),
3
ꢂ1
.08–7.15 (m, 5H), 7.20 (s, 1H), 7.46–7.50 (d, 2H). IR (cm ) 2950, 1680, 1577, 1491,
þ
50. MS: 492.14 (M -1).
9
-(4-Chlorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-10-p-tolylacridine-1,8(2H,
ꢀ
H, 9H, 10H-dione (4b): Off white solid; mp. 273–275 C. H NMR (400 MHz, CDCl ,
3
1
5
ppm): d 0.8. (s, 6H), 0.94 (s, 6H), 1.87 (s, 1H), 2.03–2.17 (m, 7H), 2.49 (s, 3H), 5.23
ꢂ1
(
1
s, 1H), 7.06–7.10 (d, 2H), 7.18–7.23 (m, 2H), 7.33–7.39 (m, 4H). IR (cm ) 2958,
639, 1574, 1360, 1221, 840; MS: 472.20 (M -1).
þ
9
-(4-Chlorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-10-m-tolylacridine-1,8(2H,
ꢀ
H, 9H, 10H)-dione (4c): Yellow solid; mp. 242–245 C. H NMR (400 MHz, CDCl ,
3
1
5
ppm): d 0.73 (s, 6H), 0.88 (s, 6H), 1.79 (s, 1H), 1.96–1.99 (m, 2H), 2.05–2.18 (m, 5H),
2
.41 (s, 3H) 5.16 (s, 1H), 6.92–6.95 (m, 1H), 7.12–7.19 (m, 3H), 7.25–7.37 (m, 4H);
þ
MS: 472.20 (M -1).
3
,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-10-phenylacridine-1,8(2H,
ꢀ
1
5
H, 9H, 10H)-dione (4k): Faint yellow solid; mp. 278–280 C. H NMR (400 MHz,
CDCl , ppm): d 0.79 (s, 6H), 0.96–0.99 (s, 6H), 2.05–2.33 (m, 8H), 5.34 (s, 1H),
3
7
.35–7.39 (d, 2H), 7.50 (d, 1H), 7.58–7.62 (d, 2H), 8.05–8.15 (m, 3H); MS: 469.28
þ
(M -1).
Acknowledgments
We thank the Council of Scientific and Industrial Research, New Delhi (110012), for
financial support under a Junior Research Fellowship. We are thankful to the
Principal, Deogiri College, Aurangabad, India, for providing laboratory facilities and
the permission to use the Central Research Laboratories facility.

Acridine Derivatives
5
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