Facile and simple route to the synthesis of condensed acridine systems

Article abstract of DOI:10.1081/SCC-200063947

Condensation of cyclohexane-1,3-dione or dimedone with o-nitrobenzaldehyde and ammonium acetate/acetic anhydride furnished the corresponding acridinedione/xanthene derivatives. The middle ring aromatization followed by reductive cyclization afforded the r

Full text of DOI:10.1081/SCC-200063947

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Facile and Simple Route to
the Synthesis of Condensed
Acridine Systems
a
a
Periyasamy Murugan , Kuo Chu Hwang
,
b
Dhakshanamurthy Thirumalai & Vayalakavoor T.
b
Ramakrishnan
a
Department of Chemistry, National Tsing Hua
University, Hsinchu, Taiwan, China
b
Department of Organic Chemistry, University of
Madras, Chennai, India
Published online: 15 Aug 2006.
To cite this article: Periyasamy Murugan , Kuo Chu Hwang , Dhakshanamurthy
Thirumalai & Vayalakavoor T. Ramakrishnan (2005) Facile and Simple Route to the
Synthesis of Condensed Acridine Systems, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:13, 1781-1788,
DOI: 10.1081/SCC-200063947
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Synthetic Communications , 35: 1781–1788, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063947
Facile and Simple Route to the Synthesis
of Condensed Acridine Systems
Periyasamy Murugan and Kuo Chu Hwang
Department of Chemistry, National Tsing Hua University, Hsinchu,
Taiwan, China
Dhakshanamurthy Thirumalai and Vayalakavoor T. Ramakrishnan
Department of Organic Chemistry, University of Madras, Chennai, India
Abstract: Condensation of cyclohexane-1,3-dione or dimedone with o-nitrobenzalde-
hyde and ammonium acetate/acetic anhydride furnished the corresponding acridine-
dione/xanthene derivatives. The middle ring aromatization followed by reductive
cyclization afforded the respective condensed acridine systems.
Keywords: Acridinedione, reductive cyclization, xanthene
The acridine skeleton fused with a five- or six-membered heterocyclic ring
[1]
plays a vital role as a DNA-intercalating anticancer drug. Pyridoacridine
alkaloids are an important class of marine natural products with interesting
[
2,3]
biological properties.
activity against L1210 leukemia cells and powerful calcium-releasing
Compounds of this class show both cytotoxic
[
4,5]
activity in the sarcoplasmic reticulam.
structures have enhanced selectivity for cerebral coronary and peripheral
Other compounds with similar
[6]
blood vessels. The synthesis and biological evaluation of a number of
condensed acridines has been extensively studied by Antonini and his
Received in India March 3, 2005
Address correspondence to Vayalakavoor T. Ramakrishnan, Department of Organic
Chemistry, University of Madras, Guindy Campus, Chennai-600 025, India. Tel.: þ91-
4
4-24414247; Fax: þ91-44-22352494; E-mail: vtrk28@yahoo.com
1
781

1782
P. Murugan et al.
[7]
coworkers. Moreover, the synthesis of a number of quino and pyrano
[
8]
acridine derivatives has been reported.
In continuation with our interest in the acridinedione ring system,
[9–11]
we
focused our attention on the synthesis of condensed acridine systems. Because
of their biological importance, we report a simple and facile synthesis of
quinoline, pyridine-containing condensed acridine systems. Condensation of
dimedone 1 and o-nitrobenzaldehyde 2 in aq. ethanol furnished the tetraketone
[12,13]
3
,
which was then refluxed with ammonium acetate (excess) in acetic
acid to give 9-(2-nitrophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-
[
14]
1
,8-(2H,5H) acridinedione 4 in 82% yield. Aromatization of the compound
with active MnO afforded 9-(2-nitrophenyl)-3,3,6,6-tetramethyl-3,4,5,6-
4
2
tetrahydro-1,8-(2H, 7H)acridinedione 5 in 80% yield. Reductive cyclization
of compound 5 with Fe/HCl in ethanol at 908C for 4 h furnished 3,3,7,7-tetra-
methyl-1,3,4,5,5a,6,7,8-octahydroquino[2,3,4-kl]acridin-1-one 6 (Scheme 1).
Similarly, condensation of cyclohexane-1,3-dione 7 with o-nitrobenzal-
[
12,13]
dehayde 2 afforded the teraketone 8,
which was then refluxed in acetic
anhydride to give the xanthene derivative 9. Reductive cyclization of the
compound 9 with Fe/HCl in ethanol furnished 13-oxo-6,7,8,10,11,12,13,13b-
octahydro-benzopyrano[2,3,4-kl]acridine 10 (Scheme 2).
Scheme 1.

Condensed Acridine Systems
1783
Scheme 2.
Next, the hexahydroquinoline derivative 11 was synthesized according to
[
15]
the literature procedure
active MnO to afford methyl 2-methyl-4-(o-nitrophenyl)-5-oxo-5,6,7,8-teter-
and then was subjected to aromatization with
2
ahydroquinoline-3-carboxalate 12. Treatment of 12 with Fe/HCl in ethanol
at 908C for 4 h furnished methyl 2-methyl-4,5-dihydro-6H-pyrido[4,3,2-
mn]acridin-1-carboxylate 13 (Scheme 3).
[16]
Similarly, the reductive cyclization of the naphthyl derivative 14
with
con. H SO at 908C for 4 h furnished 4-amino-7,12-dihydrobenzo[c]acridin-7-
2
4
one 15 (Scheme 4).
In summary, we have reported the synthesis of acridine derivatives fused
with quinoline, pyran, pyridine, and benzene ring systems using a simple and
convenient methodology. Also, in the case of reductive cyclization of the
compounds 5, 9, and 12 to give the corresponding cyclized compounds 6,
1
0, and 13, the use of other reducing agents such as SnCl /HCl, Sn/HCl,
2
and Raney Ni results in the formation of an inseparable mixture. Thus,
Fe/HCl in ethanol was found to be an efficient reagent for the reductive
cyclization.
Scheme 3.

1784
P. Murugan et al.
Scheme 4.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded on a Perkin Elmer
1
2
58 spectrophotometer. H NMR spectra were recorded on JEOL GSX 400
400 MHz) instrument. Mass spectra were measured on Hewlett-Packard
985 GC/MS instrument. HRMS data was recorded on a Thermo Finnigan
MAT 95XL instrument.
(
5
9
-(o-Nitrophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)
acridinedione (4). A solution of tetraketone 3 (1.5 g, 3.6 mmol) and
ammonium acetate (excess) in acetic acid (25 mL) was refluxed for 8 h. The
reaction mixture was then cooled and poured onto crushed ice; the yellow
solid obtained was filtered, dried, and recrystallized from a mixture of
methanol and chloroform (1:2). Yield: 1.25 g (82%); mp 298–3008C; IR
2
1 1
(
KBr): 1630, 1509, 1350 cm ; H NMR (400 MHz, CDCl ): d 0.93 and
.08 (2s, 12H, gem-dimethyl), 2.01–2.22 (2d, 4H, C4 and C -CH ,
5 2
3
1
J ¼ 16.2Hz), 2.34–2.46 (2d, 4H, C and C -CH , J ¼ 16.9Hz), 5.75 (s, 1H,
2
7
2
C -H), 7.29–7.70 (m, 4H, Ar-H), and 8.8 (bs, 1H, NH, exchangeable
9
þ
with D O); MS (EI) m/z (%): 394 (M , 8), 393 (6), 347 (3), 378 (4), 335
2
(2), 307 (3), 272 (4), 271 (2), 236 (5), 194 (100), 180 (26), 152 (10), 112
(
12), 83 (9). Anal. calcd. for C H N O (394.46): C, 70.03; H, 6.64; N,
2
3 26 2 4
7
.10. Found: C, 70.12; H, 6.42; N, 7.29.
9-(o-Nitrophenyl)-3,3,6,6-tetramethyl-3,4,5,6-tetrahydro-1,8(2H,5H)acri
dinedione (5). The acridinedione 4 (1.5 g, 3.38 mmol) was dissolved in
chloroform (150 mL) with a few drops of DMSO and stirred at room tempera-
ture with active MnO (6.0 g) for 12 h. The residue was filtered off and the
2
filtrate was concentrated. The solid obtained was recrystallized from
methanol to afford the compound 5. Yield: 1.2 g (80%); mp 248–2508C;
2
IR (KBr): 1698, 1509, 1350 cm ; H NMR (400 MHz, CDCl ): d 1.08
1
1
3
(
s, 12H, gem-dimethyl), 2.39 and 3.11 (2s, 8H, C , C , C , C -CH ), 6.89–
2 4 5 7 2
þ
.20 (m, 4H, Ar-H). MS: m/z (%): 392 (M , 1), 377 (2), 347 (100), 346
100), 300 (11), 316 (5), 290 (30), 262 (6), 247 (8), 232 (6), 204 (5), 83
8
(

Condensed Acridine Systems
1785
(
12), 55 (16). Anal. calcd. for C H N O (392.44): C, 70.40; H, 6.16; N,
2
3 24 2 4
7
.13. Found: C, 70.49; H, 6.28; N, 7.28.
3
1
,3,7,7-Tetramethyl-1,3,4,5,5a,6,7,8-octahydro-2H-quino[2,3,4-kl]acridin-
-one (6). To a mixture of acridinedione 5 (2.5 g, 6.3 mmol) and iron powder
(
3.5 g) in ethanol (20 mL), a solution of con. HCl (1.8 mL) in ethanol (10 mL)
was added slowly and the reaction mixture was refluxed for 4 h. The reaction
mixture was filtered and the filtrate was concentrated to afford a solid, which
was then purified by column chromatography over neutral alumina using a 1:1
mixture of chloroform methanol as eluant. Yield: 1.72 g (78%); mp 272–
2
748C; UV (lmax): 361, 310 nm (MeOH); fluorescence (lmax): 462 nm
21 1
(
MeOH). IR (KBr): 3250, 1610, 1580 cm ; H NMR (400 MHz, CDCl ): d
3
0
.99, 1.15, 1.16, 1.20 (4s, 12H gem-dimethyl), 1.95–2.05 (m, 2H, C -CH ),
6 2
2
C -CH ), 2.50 (bs, 2H, C -CH ), 4.31–4.40 (m, 1H, C -CH), 5.81 (bs, 1H,
.45–2.60 (2d, 2H, J ¼ 17.5 Hz, C -CH ), 2.75–2.95 (2d, 2H, J ¼ 17.5 Hz,
2
2
4
2
8
2
5a
1
3
NH, exchangeable with D O), 7.31–7.92 (m, 4H, Ar-H); C NMR
2
(
100 MHz, CDCl ): d 191.87, 164.74, 154.20, 148.37, 136.33, 128.76,
3
1
3
28.40, 127.80, 124.13, 122.08, 119.80, 109.97, 51.42, 51.07, 46.31, 40.49,
1.72, 31.31, 30.37, 29.85, 26.92, 24.87. MS, m/z (%): 346 (100), 345
(
45), 344 (40), 343 (30), 316 (10), 290 (50), 189 (10), 288 (25), 246 (10).
Anal. calcd. for C H N O (346.46): C, 79.73; H, 7.56; N, 8.08. Found: C,
2
3 26 2
7
9.89; H, 7.68; N, 8.22.
9
-(2-Nitrophenyl)-3,4,6,7-tetrahydro-9H-xanthene-1,8(2H, 5H)-dione (9).
A solution of the tetraketone 7 (1.0 g, 2.8 mmol) in acetic anhydride
20 mL) was refluxed for 7 h. After completion of the reaction, the reaction
mixture was concentrated. The solid material obtained was recrystallized
(
from methanol to give the xanthene derivative 9. Yield: 0.85 g (78%); mp
2
1 1
2
CDCl ): d 1.92–2.10 (m, 4H), 2.30–2.32 (m, 4H), 2.56–2.67 (m, 4H),
48–2508C; IR (KBr): 1670, 1530, 1358, 1335 cm . H NMR (400 MHz,
3
5
Ar-H). Anal. calcd. for C H NO (339.34): C, 67.25; H, 5.04; N, 4.12.
.41(s, 1H, C -H), 7.40–7.63 (m, 3H, Ar-H), 7.79–7.81 (d, 1H, J ¼ 8.0 Hz,
9
1
9
17
5
Found: C, 67.52; H, 5.10; N, 4.29.
3
(
-Oxo-6,7,8,10,11,12,13,13b-octahydro-benzopyrano[2,3,4-kl]
acridine
10). To a mixture of xanthene derivative 9 (1.0 g, 2.9 mmol) and iron
powder (1.4 g) in ethanol (20 mL), a solution of con. HCl (0.6 mL) in
ethanol (5 mL) was added slowly and refluxed for 5 h. The reaction mixture
was concentrated and the residue was purified by column chromatography
over neutral alumina using a mixture of chloroform and methanol (3:1) as
eluant. Yield: 0.52 g (60%); mp 220–2228C; IR (KBr): 1706, 1601,
2
1 1
1
588 cm . H NMR (400 MHz, DMSO-d ): d 1.78–1.86 (m, C -CH , 2H),
.89–1.96 (m, C -CH , 2H), 2.14–2.20 (m, C -CH , 2H), 2.23–2.30
6 7 2
1
1
1
2
6
2
(
m, C -CH , 2H), 2.55–2.66 (m, C and C -CH , 4H), 5.38 (s, C13b, 1H),
12 2 8 10 2
1
3
7
.31–7.76 (m, 4H, Ar-H); C NMR (100 MHz, DMSO-d ): d 190.82,
6

1786
P. Murugan et al.
1
1
63.72, 162.17, 151.11, 148.27, 147.18, 136.32, 128.34, 127.18, 127.01,
18.48, 109.86, 51.27, 50.89, 41.98, 40.11, 34.07, 33.78, 31.61. MS, m/z
(%): 291 (51), 262 (10), 260 (20), 236 (40), 235 (100), 217 (60), 197 (45),
1
9
83 (40), 180 (40), 168 (35), 167 (50), 141 (30), 140 (30), 108 (60),
1 (70), 83 (55). HRMS calcd. for C H NO : 291.3438. Found: 291.3441.
1
9
17
2
Methyl 2-methyl-4-(o-nitrophenyl)-5-oxo-5,6,7,8-tetrahydroquinoline-3-
carboxylate (12). Aromatization of 11 was carried out by following the
procedure described in the synthesis of the compound 5 to afford the ester
1
1
2
2. Yield: 0.98 g (65%); mp 154–1568C; IR (KBr): 1729, 1690, 1510,
21 1
369 cm . H NMR (400 MHz, CDCl ): d 2.14–2.18 (m, 2H, C -CH ),
3
7
2
.52–2.55 (m, 2H, C -CH ), 2.60 (s, 3H, CH ), 3.15–3.20 (m, 2H,
3
8
2
C -CH ), 3.39 (s, 3H, OCH ), 7.02–7.04 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.50–
6
2
3
1
3
7
.61 (m, 2H, Ar-H), 8.21–8.23 (d, J ¼ 8.0 Hz, 2H, Ar-H). C NMR
(
100 MHz, CDCl ): d 197.21, 164.37, 152.65, 146.18, 141.08, 140.2,
3
1
3
4
34.07, 131.29, 129.11, 125.65, 124.48, 122.30, 115.18, 52.80, 32.68,
2.56, 22.89, 22.76. Anal. calcd. for C H N O (340.33): C, 63.52; H,
1
8 16 2 5
.74; N, 8.23. Found: C, 63.45; H, 4.82; N, 8.18.
Methyl 2-methyl-4,5-dihydro-6H-pyrido[4,3,2-mn]acridin-1-carboxylate
13). Reductive cyclization of 12 was carried out by following the
procedure described for the synthesis of the compound 6 to afford the ester
(
2
1
1
3. Yield: 0.21 g (4%); mp 225–2278C; IR (KBr): 1725, 1610, 1522 cm
;
H NMR (400 MHz, CDCl ): d 2.19–2.22 (m, C -CH , 2H), 2.57 (s, 3H,
1
3
5
2
CH ), 3.15–3.2 (m, C and C -CH , 4H), 4.07 (s, 3H, CH ), 7.67–7.88 (2t,
3
3
4
6
2
1
H, Ar-H), 8.04–8.06 (m, 2H, Ar-H). C NMR (100 MHz, CDCl ): d
3
2
1
1
3
70.46, 162.46, 160.53, 153.59, 145.45, 133.60, 131.15, 129.72, 126.87,
24.14, 120.56, 119.83, 115.72, 53.40, 33.88, 33.54, 22.62, 22.14; MS, m/z
(
%): 292 (100), 277 (10), 261 (80), 260 (30), 233 (30), 232 (54), 231 (28),
18 (36), 217 (24), 216 (64), 206 (23), 192 (45), 191 (34), 189 (61), 164
10), 140 (63), 130 (63), 102 (32), 95 (45), 88 (42). Anal. calcd. for
C H N O (292.33): C, 73.94; H, 5.51; N, 9.58. Found: C, 73.65; H, 5.87;
2
(
1
8 16 2 2
N, 10.33.
4-Amino-7,12-dihydrobenzo[c]acridin-7-one (15). In a 50-mL round
bottomed flask, a solution of 14 (0.5 g, 1.7 mmol) in con. H SO (5 mL) was
2
4
heated to 908C for 5 h. Then, the reaction mixture was poured into boiling
water (20 mL). The yellow solid obtained was filtered, dried, and purified
by column chromatography over neutral alumina using a mixture of
methanol and chloroform (1:3) as eluant. Yield: 0.24 g (52%); mp . 3208C;
2
1 1
IR (KBr): 3410, 3369, 3120, 1640 cm ; H NMR (400 MHz, CDCl ): d
3
5
7
1
.92 (bs, NH , exchanged with D O), 6.93–6.95 (d, J ¼ 8.0 Hz, 1H), 7.30–
2
2
.33 (m, 1H), 7.42–7.46 (m, 1H), 7.72–7.784 (m, 2H), 7.99–8.25 (m, 4H),
1
3
1.47 (bs, NH, exchanged with D O). C NMR (100 MHz, DMSO-D6)
2
d: 176.18, 145.78, 138.53, 132.70, 127.11, 125.43, 123.17, 121.87, 121.50,

Condensed Acridine Systems
1787
1
21.48, 121.20, 119.35, 118.36, 116.73, 116.13, 115.50, 110.04; MS, m/z
%): 260 (100), 232 (5), 231 (6), 204 (8), 203 (5). Anal. calcd. for
C H N O (260.29): C, 78.44; H, 4.64; N, 10.77. Found: C, 78.69; H,
(
1
7 12 2
4
.49; N, 10.51.
ACKNOWLEDGMENT
The authors are grateful to National Science Council, Taiwan, ROC,
Department of Science and Technology and UGC (Government of India,
New Delhi, India) for financial support.
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