Synthesis and electrophilic substitution of pyrido[2,3,4-kl]-acridines

Article abstract of DOI:10.3390/60400300

Several new pyrido[2,3,4-kl]acridines were synthesized by reacting naphthoquinone, juglone or cyclohexan-1,3-dione with β,β'- diaminoketones in a biomimetic reaction. The structure of all new compounds was elucidated by NMR and MS spectroscopy. Electrophi

Full text of DOI:10.3390/60400300

Molecules 2001, 6, 300-322
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis and Electrophilic Substitution of Pyrido[2,3,4-kl]-
acridines‡
Avi Koller1, Amira Rudi1, Marta Garcia Gravalos2 and Yoel Kashman1,*
1 School of Chemistry, Tel Aviv University, Ramat Aviv 69978, Israel
2 PharmaMar, Tres- Cantos, Madrid, Spain
* To whom correspondence should be addressed; E-mail: kashman@post.tau.ac.il; Phone: +972-3-640-
8419. Fax: +972-3-640-9293.
‡ Presented at the 4th Electronic Conference on Synthetic Organic Chemistry, September 1-30, 2000,
(Paper A0029).
Received: 28 February 2001; in revised form 7 March 2001 / Accepted: 7 March 2001 / Published: 31
March 2001
Abstract: Several new pyrido[2,3,4-kl]acridines were synthesized by reacting
naphthoquinone, juglone or cyclohexan-1,3-dione with β,β’-diaminoketones in a biomimetic
reaction. The structure of all new compounds was elucidated by NMR and MS spectroscopy.
Electrophilic substitution, mainly nitration, of the various compounds was undertaken and
the substitution positions determined. A series of derivatives was prepared and their
cytotoxicity towards P-388 mouse lymphoma cells analysed. The most cytotoxic derivatives
were found to have IC50’s of 0.05 and 0.1 ug/ml.
Keywords: Pyrido[2,3,4-kl]acridines; Biomimetic synthesis; NMR; Electrophilic nitration;
Cytotoxicity
Introduction
Over the last 15 years more than 50 pyridoacridine alkaloids, based on the 4H-pyrido[2,3,4-
kl]acridone (1) skeleton (Figure 1), have been isolated from marine organisms [1]. Almost all natural
pyridoacridines have been reported to possess significant cytotoxicity against cultured tumor cells [1].

Molecules, 2001, 6
301
This motivated us to synthesize and study some of the compounds of this group. In 1993 we reported a
biomimetic synthesis of the pyrido[2,3,4-kl]acridine ring system by the reaction of β,β’-diamino-
ketones with a variety of quinones and diketones [2][3]. Using this method we synthesized the marine
alkaloid ascididemin (2)[4], eilatin (3)[3] (Figure 1) and also new pyridoacridine skeletons such as
benzoascididemin and isoeilatin [5].
Here we report a biomimetic synthesis of additional new pyridoacridines and a study of their
reactions with electrophiles or amines (in the case of the quinoneimines). Most of the new
pyridoacridines were tested for in-vitro activity against tumor cells and some of them were found to be
highly cytotoxic.
Figure 1
N
O
N
O
N
N
N
N
N
N
N
1
2
3
Results and Discussion
Several new pyridoacridines were synthesized in a two step reaction of β,β’-diaminoketones with
quinones. Thus, addition of 2,2’-diaminobenzophenone 4a or 4b to 1,4-naphthoquinone afforded in the
first step the arylaminonaphthoquinones 5a and 5b respectively, in approximately 50% yield (Scheme
1).
R
2
Scheme 1
R
R
3
4
1
A
H2N
O
15a
O
O
15N
H2N
O
O
4a
4b
B
14
5
E
8
b
14a
a
4c
8a
14c
13
12
6
7
14b
+
F
C
D
10
9a
10a
NH
R
N
11
H2N
9
O
O
R
R
5a : R=H, 54%
5b : R=OMe, 48%
6a : R=H, 93%
6b : R=OMe, 95%
4a : R=H
4b : R=OMe
TFANH
N
O
O
O
1) a
2) b
O
+
N
H2N
7
8 : 13% overall for
2 steps.
.
Reagents and conditions: (a) CeCl 3 7H2O, Air, E tOH, reflux, 9 h; (b) 25% NH 4OH, MeOH, R.T., 7 days.

Molecules, 2001, 6
302
The reaction took place in the presence of catalytic amounts of cerous chloride while air was
bubbled through the solution to oxidize the intermediate hydroquinone [6-7]. In the second step,
treatment of compounds 5a and 5b in methanol with NH4OH at room temperature for 7 days gave the
corresponding compounds 6a and 6b in over 90% yield (Scheme 1).
The structures of 6a and 6b, possessing the required molecular ions (m/z 332 and 392, respectively)
were confirmed by 1D and mainly COSY, HMQC and HMBC 2D-NMR spectra (See Table 1 for the
HMBC correlations and the Experimental section for the proton and carbon chemical shift
assignments).
Characteristic were the resonances of C-10 and C-14b of the quinoneimine system (ring C) and the
down-field proton resonances of the spatially close protons H-4 and H-5 (δH 9.09 and 9.18 ppm,
respectively, for 6a and δH 8.90 and 8.98 ppm, respectively, for 6b)[5].
Three four-spin systems were observed in the 1H-NMR spectrum of 6a belonging to rings A, E and
F. Rings A and E, bearing the spatially close H-4 and H-5 protons, were distinguished from ring F by
NOE measurements. The differentiation between rings A and E was achieved from an NOE between
H-1 and H-14 (about 3.7Å apart). This NOE was also the key for determining the structure of the
nitration products 21, 23a and 23b, as described below. A second reaction that was performed with
naphthoquinone was its reaction with TFA-kynuramine (7) [4] (Scheme 1). This reaction afforded 9H-
benzo[i]pyrido[2,3,4-kl]acridin-9-one (deaza-ascididemin, 8), earlier synthesized by Zjawiony by a
four step reaction [8]. The structure of compound 8 (m/z 282) was confirmed by its NMR data (see
Experimental) and comparison with the data in the literature [8].
A second naphthoquinone that was tested was juglone. Reacting juglone (5-hydroxy-1,4-
naphthoquinone) with diaminobenzophenone 4a afforded, in a regioselective reaction, a single addition
product 9 in 80% yield (Scheme 2).
Scheme 2
1
H2N
4
N
4a
4b
H2N
O
O
O
O
O
14
5
14a
14c
4c
O
b
a
14b
10
+
N
NH
11
8
9
H2N
OH
O
OR
OH
9 (80%)
10 : R=H, 98%
11 : R=Ac, 95%
4a
c
.
Reagents and conditions: (a) CeCl 3 7H O, Air, E tOH, R.T., 3 days; (b) E t N, MeOH, R.T., 10 days;
3
2
(c) Ac 2O, pyridine, R.T., 24 h.
The orientation of this addition was defined by the structure determination of compound 10,
obtained in a second step by stirring compound 9 in methanol with Et3N. A key HMBC correlation in
the structure elucidation was the one between C-14b (δ=147.5) and H-14 (δ 8.73). For other correlations

Molecules, 2001, 6
303
that assisted with the structure determination see Table 1. The regioselectivity of nucleophilic additions
of amines to juglone was observed before by Thomson [9] in the reactions of aniline with the juglone
derivatives 5-acetoxy or 5-methoxy-1,4-naphthoquinones. Performing the second step of the latter
reaction with ammonia, rather than Et3N, as used for the preparation of compounds 6a and 6b, caused
unexpectedly the disappearance of the C-10 carbonyl group. Moreover, acetylation of the obtained
pyridoacridine (12) (Scheme 3) gave a mono- (13a) and a diacetate (13b). It is suggested that the
carbonyl group of compound 10 is replaced in compound 12 by an imine and indeed, treatment of 10,
obtained with the Et3N, with NH3 gave compound 12. The position of the imine group was defined by
a HMBC experiment of compound 13a namely from correlations between the 11-hydroxylic proton
and carbons C-10a, C-11, and C-12 of ring F (see Table 1).
Table 1. Long-range CH correlations observed in the HMBC experiments
of the benzopyridoacridines
H# of correlated protons
C#
6a
3
6b
10
3
12
3
13a
3
20
23a
23b
3
4, OMe
1
1
2
4
1
4
1
4
1
4
1
4
1
4, OMe 4, OMe
3
2
2
2
2
2
4
1, 3
4, 5
6, 8
7
1, 3
4, 5
6, 8
1, 3
4, 5
6, 8
7
1, 3
4, 5
6, 8
7
1, 3
4, 5
6, 8
7
1
4a
4b
4c
5
4, 5
6, 8
7
4, 5
6
4, 5
6
8
8
8
8
8
8
6
5
5, OMe
5
5
5
5
5, OMe 5, OMe
7
6
5, 7
6
5
6
5, 7
6
5, 7
6
5, 7
6
5, 7
6
5
6
5
8
8a
9a
10
10a
11
12
13
14
14a
14b
14c
15a
11
11
11
11
14
13
14
11
11
12
13
12, 14 12, 14 12, 14 12, 14 12,14,OH 12, 14
13
14
11
12
13
14
11
12
13
14
13
14
13, OH
14, OH
13
14
11
12
11
12
12
13
14
12
13
14
12
13
14
11, 13 11, 13
14
11, 13 11, 13 11, 13
14
14
14
2, 4
4
2, 4
2, 4
2, 4
2, 4
4
4

Molecules, 2001, 6
304
Scheme 3
1
A
4
9
N
N
a
N
B
14
13
5
E
8
14a
10a
c
F
12
C
D
N
+
N
N
10
11
b
NH
NAc
OH
OH
NAc
OAc
10
13b (32%)
12 (85%)
13a (35%)
O
O
O
O
O
8
3'
1
4
OMe
a
8a
4a
OMe
4'
OMe
7
2
3
2'
1'
NH
a
6
NH
NH
5
OH NH
OH
14
15 (100%)
16
Reagents and conditions: (a) 25% NH OH, MeOH, R.T., 7 days; (b) MeOH / NH 3 , R.T., 14 days; (c) Ac 2O,
4
pyridine, R.T., 24 h.
Quinoneacetimide systems such as ring C in compounds 13a and 13b are stable, e.g. the reported
simple acetimides of naphthoquinones and benzoquinones [10]. In contrast, simple quinoneimines are
unstable and were seldom isolated [10]. Thus, it was interesting to find that the quinoneimine moiety
of compound 12 is stable as was also found to be the case of the natural pyridoacridine calliactine [11]
whose structure was determined recently [12]. In both compound 12 and calliactine the hydroxyl group
in the β position relative to the imine group seems to stabilize the quinoneimine by a hydrogen- bond.
Another example for the latter behaviour was seen in compound 14, synthesized from juglone and p-
anisidine (Scheme 3). Compound 14 in methanol with aqueous ammonia, yielded the quinoneimine 15,
while compound 16 [13] without the β-OH group, did not form the quinoneimine under the same
conditions. These results proved the necessity of a hydroxyl group β to the ketone for the imine
formation and also suggest that the quinoneimine ring could be obtained, in the synthesis, before the
rings closure of compound 10.
A major target in the present investigation was the study of the electrophilic substitution reactions of
pyridoacridines and dihydropyridoacridines for the preparation of derivatives for structure activity
relationship studies. It was decided to start with nitration as the nitro groups are easily transformed to
other functional groups. Investigating a variety of nitration conditions (HNO3-TFA, HNO3-H2SO4 and
NO2BF4 in CH3CN) brought to the best conditions, namely, the use of HNO3-H2SO4, 1:1 vide infra.
The first substrate for nitration was dihydropyridoacridine 17a. Compounds 17a and 17b were
obtained in quantitative yields by condensation of compounds 4a or 4b with 1,3-cyclohexanedione
(Scheme 4). Nitration of compound 17a gave, after 1 hour, two mononitro isomers 18a and 18b and
three dinitroisomers 19a, 19b and 19c after 12 hours of reaction at room temperature.

Molecules, 2001, 6
305
Scheme 4
R
N
O
a
+
4a / 4b
O
R
N
17a : R=H, 100%
17b : R=OMe, 100%
R4
N
R3
A
N
c
b
17a
R2
R2
E
N
N
R1
18b (60%)
R1=H
R2=NO2
R1
19a (traces) +
R1=R4=NO2
R2=R3=H
+
19c (20%)
+
19b (15%)
R1=R3=NO2 R1=R4=H
R2=R4=H
18a (26%)
R1=NO2
R2=H
R2=R3=NO2
(sym)
(sym)
Reagents and conditions: (a) AcOH / conc. HCl (99.5:0.05), 3-Nitrobenzenesulfonic acid
Sodium salt, reflux, 2 h.; (b) HNO3 / H2SO4 (1:1), R.T., 1 h.; (c) HNO3 / H2SO4 (1:1), R.T.,
12 h.
The structures of the different isomers were determined by 1H-NMR and COSY experiments. In all
the products the nitro group(s) are in ring A (or E) in positions para or ortho to the nitrogen of the
attached pyridine ring (para or ortho positions). The yields of the nitration products indicate that the
para position in ring A (and E) is more reactive than the ortho one under the conditions used. Nitration
of quinoline with nitric acid in sulphuric acid at 0oC was reported to yield 5- and 8-nitroquinoline in a
ratio of 52% to 48% respectively [14]. The nitration experiments of compound 17a show that the para
position of ring A (and E) in the dihydropyridoacridine is more reactive than position- 6 of quinoline,
under the same conditions [15]. Positions 4 and 5 in the pyridoacridine, which can be compared to the
reactive position- 5 of quinoline, are blocked by steric interference and therefore are not substituted.
The nitration of compound 6a afforded a mono-nitro product 20 in 53% yield after 12 hours at room
temperature. Because of the absence of long range CH-correlations in the NMR experiments between
atoms of rings A or E and F to ring C it was difficult to determine whether the nitro group is attached
to ring A or E. However, the nitration position, C-3 on ring A, could be determined from a NOE
between H-1 and H-14 (2%), which are ca.3.7 Å apart (see Scheme 5). It was found by 1D and 2D
NMR experiments (for HMBC correlations see Table 1) that the nitration went to the para position of
ring A as was found for the nitro derivatives of compound 17a which were obtained in higher yields
(compounds 18b, 19b and 19c).

Molecules, 2001, 6
306
Catalytic hydrogenation of compound 20 with 5% Pd-C in AcOH / TFA afforded the amino
derivative 21.
Scheme 5
6a
6b
a
b
a
OMe
OMe
O2N
N
O2N
N
NOE
NO2
R
E
H1
N
A
H14
R2
B
F
C
D
N
R1
N
OMe
N
OMe
O
NO2
O
NO2
23b
R1=H
R2=NO2
O
+
22 (80%)
23a (20%)
R1=NO2
20 : R=NO2, 53%
21 : R=NH2, 40%
(45%)
c
R2=H
Reagents and conditions: (a) HNO / H2SO4 (1:1), R.T., 12 h.; (b) HNO / H2SO4 (1:1), R.T., 1 h.; (c) AcOH
3
3
/ TFA (1:2), 5% Pd/C, H , 3 Atm, R.T., 1 h.
2
Nitration of compound 6b, the electron richer 2,7-dimethoxy derivative of 6a, gave a dinitro
derivative 22 after 1 hour and two tetra nitro isomers 23a and 23b (Scheme 5) after 12 hours of
reaction at room temperature. That the two nitro groups in 22 substituted C-1 and -8, ortho to the
quinoline-nitrogen, was clear from the two AB- systems seen in the 1H-NMR spectrum along with the
aromatic four- proton system (Experimental).
The structures of 23a and 23b were also determined by 1D and 2D-NMR experiments (for HMBC
correlations see Table 1). In compounds 23a and 23b only one of rings A or E was attacked by the
electrophile at the para position. The structures of compounds 23a and 23b are tentatively suggested
on the basis of the structure of compound 20 as depicted in Scheme 5. Because of the nitro groups at
the ortho positions, it was impossible to prove by NOE that the substitution is at the para position of
ring A (as in the case of compound 20). In addition to the nitration of rings A and E, ring F in 23a and
23b was also substituted due to long range activation by the methoxyl groups.
The second electrophilic substitution undertaken was bromination. Compounds 6a and 8 did not
react with Br2 in CH2Cl2, Br2 in AcOH or NBS in CH2Cl2 and it seems that severe conditions may be
needed in order to brominate these compounds. The use of Lewis acids as catalyst precipitated the
compound. Quinoneimine 24 [2] afforded the dibromo derivative 26 (Scheme 6) by reaction with Br2
in AcOH; a reaction known for quinones [16]. Compound 26 like other dibromoquinones is expected
to afford a variety of derivatives by cycloaddition reactions and by reactions with amines and thiols
[13, 16-17].
Several of the synthesized new pyridoacridines were tested for in-vitro cytotoxicity against P-388
mouse lymphoma cells (Table 2). It was found that compounds 6a and 8 are more cytotoxic than other

Molecules, 2001, 6
307
reported natural pyridoacridines for which IC50 values of 0.1- 0.4 ug/ml were found [1a]. The
cytotoxicity of compound 6a, the electron richer dimethoxy derivative 6b and the electron poorer nitro
derivatives 21 and 23b, as well as compound 12 and its acetate derivatives 13a and 13b is lower.
Table 2. In- vitro cytotoxicity against P-388 mouse lymphoma cells
Compound 6a
IC50
6b
8
12 13a 13b 24
10
25
20
21 23b
0.05 10 0.1 >10
5
1
2.5 0.5 10 2.5
(ug/ml)
Oxidation of compounds 17a and 17b, with cerium ammonium nitrate, afforded
benzopyridoacridones 24 and 25, respectively, in high yields (Scheme 6). Amination of the latter
quinoacridones (24 and 25) with several primary amines in ethanol afforded two kinds of derivatives;
monoamination products (compounds 27a- 32a) and symmetric diamination ones (compounds 27b-
31b and 33b). The diamination products were separated easily from the monoamination products, in
each reaction, by silica gel chromatography (eluting with chloroform- methanol mixtures). The
diamination products are more polar than the monoamination products and the starting material.
Performing the amination in acetonitrile instead of ethanol afforded mainly the monoamination
products 27a and 30a with only traces of the diamination products 27b and 30b (Scheme 6). Another
derivative, prepared from 24, was compound 32a (Scheme 6), which was derived from 24 by hydrazoic
acid in methanol under conditions reported for synthesis of aminonaphthoquinones [18].
Scheme 6
R
2
1
3
4
13a
13N
4a
4b
N
O
5
8
12b
Br
Br
4c
12
11
6
a
b
12a
17a, 17b
24
8a
7
9a N
N
R
10
9
O
24 : R=H, 92%
26 (33%)
25 : R=OMe,90%
c
R
N
R
N
N
N
R'NH
R'NH
R
R
R'N
O
27a - 32a (Table 3)
27b - 31b, 33b (Table 3)
(sym.)
Reagents and conditions: (a) CAN, CHCN, reflux, 10 min.; (b) Br , AcOH, 80oC, 2 h.;
3
2
(c) see Table 3 and Experimental.

Molecules, 2001, 6
308
1
The structures of the diamination products were determined by their H- and 13C-NMR spectra
which indicated symmetric structures (see Experimental). The substitution site in the monoamination
product 27a was determined by a HMBC experiment which showed correlations between proton H-11
and carbons C-9a and C-12a and correlations between the substituent NH- proton and carbons C-12a
and C-11 (Scheme 7). As seen in Table 3, the symmetric diamination products are more cytotoxic than
the monoamination ones and most of the diamination products are more toxic than their parent
compounds 24 and 25 (Table 2). Most active are the symmetric derivatives obtained with
isobutylamine and methylamine (compounds 27b- 29b) while the more lypophilic derivative obtained
with dodecylamine (compound 31a) (as well as 31b) and the more hydrophilic derivative obtained with
serinol (compound 33b) are less active.
Scheme 7. CH correlations in HMBC experiment
of compound 27a
N
H
N
12a
9a
11
N
H
O
27a
Table 3. Amination products of compounds 24 and 25 with amines R’NH2
and their in-vitro cytotoxicity against P-388 mouse lymphoma cells.
Yield (%) IC50 (ug/ml)
Compound
R
R’
a
b
a
0.25
1
0.25
1
b
H
(CH3)2CHCH2 36
OCH3 (CH3)2CHCH2 19
38
37
28
38
18
-
0.1
0.1
0.1
0.5
0.5
-
27
28
H
H
H
H
H
CH3
CH3OC6H4
CH3(CH2)11
H
46
55
24
76
-
29
30
2.5
1
31
32aa
(HOCH2)2CH
50
-
>10
33
a 32a is the reaction product of 24 with hydrazoic acid (see Experimental).

Molecules, 2001, 6
309
Experimental
General
Commercially available reagents were purchased from standard chemical suppliers and were used
without further purification. 2(N)-(4-methoxyaniline)-1,4-naphthoquinone (16) was synthesized by a
literature method [13]. IR spectra (KBr disks) were recorded on a Nicolet 205 FT-IR
1
spectrophotometer. MS and HRMS spectra were recorded on a Fisons Autospec Q instrument. H-
NMR and 13C-NMR spectra were recorded on a Bruker ARX-500 or a Bruker AMX-360 spectrometer.
NOE experiments and 2D NMR spectra (COSY, HMQC and HMBC) were recorded on a Bruker
ARX-500 instrument using standard pulse sequences. TLC was performed on Merck precoated
Kieselgel 60 F254 plates. Column chromatography was performed using Silica gel 60 H (Merck) unless
otherwise stated. The silica was washed with methanol, before use, in a Soxhlet apparatus. In all cases
silica gel chromatography was performed with vacuum.
2,2’-Diaminobenzophenone (4a):
Compound 4a was performed from 2,2’-dinitrobenzophenone by hydrogenation, instead of the
literature method of reduction with iron powder [19]. 2,2’-Dinitrobenzophenone [19] (250 mg, 0.92
mmol) was dissolved in dichloromethane (40 mL), 5% Pd/C (100 mg) was added and the solution was
shaken in a Parr apparatus under H2 (3 atm) for 1 hour. The catalyst was filtered off and the solvent
evaporated to afford 4a (195 mg, quantitative yield), yellow crystals (from 80% aqueous methanol),
m.p. 134oC (lit [19], 134-135 oC).
2,2’-Diamino-4,4’-dimethoxybenzophenone (4b):
4b was prepared from 2,2’-Dinitro-4,4’-dimethoxybenzophenone [20] (250 mg, 0.75 mmol) under
the same conditions as described for the synthesis of 4a. The product was recrystallized from methanol
to afford 4b (185 mg, 90%): m.p. 138oC (lit [20], 137-138oC).
General procedure for the reaction between arylamines and 1,4-naphthoquinones
The procedure of Pratt [7] was adopted. The corresponding amine (1 equiv.) was dissolved in
.
ethanol, CeCl3 7H2O (0.05 equiv.) was added followed by the naphthoquinone (1.5 equiv.). The
resulting red solution was refluxed for 9 h. During this time air saturated with ethanol (prepared by
passage of air through hot ethanol to avoid evaporation of the ethanol) was bubbled through the
reaction mixture. After cooling, the ethanol was evaporated and the residue purified by
chromatography on silica gel (eluting with chloroform/methanol) to afford the desired amination
product.

Molecules, 2001, 6
310
2(N)-(2,2’-diaminobenzophenone)-1,4-naphthoquinone (5a):
4a (450 mg, 2.1 mmol) was dissolved in ethanol (20 mL) and reacted with naphthoquinone (500
mg, 3.2 mmol) by the above described general procedure. The crude mixture containing the product
and starting materials was chromatographed by two subsequent silica gel columns (eluting with
CHCl3/MeOH, 50:1) to afford 5a (420 mg, 54%), red prisms (from EtOH), m.p. 208oC; MS (EI); m/z:
+
-1 1
~
368 (100) [M , C23H16N2O3]; IR: ν == 1667, 1611, 1568, 1512, 1292, 1246 cm ; H-NMR (CDCl3):
δ== 6.56 (s, 1 H, 3-H), 6.59 (t, J=7.5 Hz, 1 H, 12’-H), 6.72 (d, J=7.5 Hz, 1 H, 10’-H), 7.21 (t, J=7.5
Hz, 1 H, 11’-H), 7.29 (t, J=7.5 Hz, 1 H, 4’-H), 7.40 (d, J=7.5 Hz, 1 H, 6’-H), 7.52 (d, J=7.5Hz, 1 H,
13’-H), 7.55 (t, J=7.5 Hz, 1 H, 5’-H), 7.63 (d, J=7.5 Hz, 1 H, 3’-H), 7.65 (t, J=7.6 Hz, 1 H, 7-H), 7.75
(t, J=7.6 Hz, 1 H, 6-H), 8.08 (d, J=7.6 Hz, 1 H, 5-H), 8.09 (d, J=7.6 Hz, 1 H, 8-H), 9.30 (br s, 1 H,
NH).
2(N)-(2,2’-diamino-4,4’-dimethoxybenzophenone)-1,4-naphthoquinone (5b):
4b (200 mg, 0.74 mmol) was dissolved in ethanol (10 mL) and reacted with naphthoquinone (170
mg, 1.1 mmol) by the general procedure described above. After two subsequent silica gel columns
(eluting with CHCl3) compound 5b was isolated (150 mg, 48%): red prisms (from EtOH), m.p. 214oC.
+
-1 1
~
– MS (EI); m/z: 428 (100) [M , C25H20N2O5]; IR: ν == 1658, 1624, 1576, 1521, 1448, 1244 cm ; H-
NMR (CDCl3): δ== 3.81 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 6.14 (s, 1 H, 10’-H), 6.17 (d, J=8.5 Hz,
1 H, 12’-H), 6.62 (s, 1 H, 3-H) , 6.68 (dd, J=8.5, 2.5 Hz, 1 H, 4’-H), 7.11 (d, J=2.5Hz, 1 H, 6’-H), 7.36
(d, J=8.5 Hz, 1 H, 13’-H), 7.44 (d, J=8.5 Hz, 1 H, 3’-H), 7.65 (t, J=7.0 Hz, 1 H, 7-H), 7.74 (t, J=7.0
Hz, 1 H, 6-H), 8.10 (d, J=7.0 Hz, 1 H, 5-H), 8.11 (d, J=7.0 Hz, 1 H, 8-H), 9.90 (br s, 1 H, NH).
10H-benzo[i]quino[2,3,4-kl]acridin-10-one (6a):
5a (400 mg, 1.1 mmol) was added to a solution of 25% aq. ammonia (10mL) in methanol (100mL)
and stirred for 7 days at room temperature. During this time the reaction was monitored by TLC, Rf=
0.7 and 0.5 for 5a and 6a respectively (petroleum ether/ethyl acetate, 1:1). The reaction mixture was
evaporated and the crude product was chromatographed (eluting with CHCl3/MeOH 30:1) to afford 6a
(335 mg, 93%), amorphous powder (CHCl3/MeOH, 9:1), m.p. 255oC; Analysis: C23H12N2O (332.1):
calcd. C 83.1, H 3.64, N 8.43, found C 82.4, H 3.53, N 8.70; HRMS calcd. for C23H12N2O [M+]
-1
1
~
332.0950, found 332.0947; IR: ν = 1678, 1654, 1562, 1396, 1203 cm ; H-NMR (CDCl3): δ== 7.73 (t,
J=7.5 Hz, 1 H, 12-H), 7.83 (t, J=8.0 Hz, 1 H, 3-H), 7.90 (t, J=7.5 Hz, 1 H, 13-H), 7.95 (t, J=8.0 Hz, 1
H, 6-H), 7.95 (t, J=8.0 Hz, 1 H, 2-H), 8.03 (t, J=8.0 Hz, 1 H, 7-H), 8.42 (d, J=8.0 Hz, 1 H, 1-H), 8.52
(d, J=7.5 Hz, 1 H, 11-H), 8.73 (d, J=8.0 Hz, 1 H, 8-H), 9.09 (d, J=8.0 Hz, 1 H, 4-H), 9.11 (d, J=7.5
Hz, 1 H, 14-H), 9.18 (d, J=8.0 Hz, 1 H, 5-H); 13C-NMR (CDCl3): δ== 115.8 (s, C-14c), 122.4 (s, C-4a),
124.2 (s, C-4c), 125.9 (d, C-14) , 127.0 (d, C-5), 127.1 (d, C-4), 127.9 (d, C-11), 128.1 (d, C-3), 129.9
(d, C-6), 130.8 (d, C-2), 130.9 (d, C-7), 131.0 (d, C-1), 131.0 (d, C-12), 132.2 (s, C-10a), 132.4 (d, C-
8), 134.7 (d, C-13), 136.0 (s, C-14a), 136.1 (s, C-4b), 145.4 (s, C-9a), 147.2 (s, C-15a), 147.3 (s, C-8a),
147.7 (s, C-14b), 182.2 (s, C-10).

Molecules, 2001, 6
311
2,7-Dimethoxy-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (6b):
5b (150 mg, 0.35 mmol) was treated with ammonia in methanol by the same procedure described
for the synthesis of 6a. The product (6b) was obtained after chromatography (eluting with
chloroform/methanol, 30:1) (130 mg, 95%): amorphous powder (CHCl3/MeOH, 8:2), m.p. 296oC;
Analysis: C25H16N2O3 (392.4): calcd. C 76.5, H 4.11, N 7.14, found C 76.4, H 3.90, N, 7.84; MS (EI);
+
+
+
~
m/z: 392 (100) [M ], 377 (5) [M - CH3], 361 (14) [(M - CH3O]; IR: ν = 1676, 1611, 1587, 1564,
1415, 1239, 1218 cm-1; 1H-NMR (CDCl3): δ== 4.08 (s, 3 H, OCH3), 4.10 (s, 3 H, OCH3), 7.40 (dd, 1 H,
J=9.5, 2.5 Hz, 3-H), 7.54 (dd, 1 H, J=9.5, 2.5 Hz, 6-H), 7.64 (t, 1 H, J=8.0 Hz, 12-H), 7.77 (d, 1 H,
J=2.5 Hz, 1-H), 7.88 (t, 1 H, J=8.0 Hz, 13-H), 8.04 (d, 1 H, J=2.5 Hz, 8-H), 8.49 (d, 1 H, J=8.0 Hz,
11-H), 8.90 (d, 1 H, J=9.5 Hz, 4-H), 8.98 (d, 1 H, J=9.5 Hz, 5-H), 9.07 (d, 1 H, J=8.0 Hz, 14-H); 13C-
NMR (CDCl3): δ== 55.5 (OCH3), 55.9 (OCH3), 108.7 (d, C-8), 110.3 (d, C-1), 113.1 (s, C-14c), 116.0
(s, C-4a), 118.7 (s, C-4c), 119.8 (d, C-3), 122.5 (d, C-6), 126.0 (d, C-14), 128.0 (d, C-11), 128.2 (d, C-
5), 128.4 (d, C-4), 131.4 (d, C-12), 131.4 (s, C-10a), 135.0 (d, C-13), 135.3 (s, C-14a), 137.0 (s, C-4b),
143.7 (s, C-9a), 147.6 (s, C-14b), 148.0 (s, C-8a), 149.0 (s, C-15a), 159.0 (s, C-7), 159.4 (s, C-2), 182.3
(s, C-10).
9H-benzo[i]pyrido[2,3,4-kl]acridin-9-one (8):
TFA-kynuramine (7)[4] (500 mg, 1.9 mmol), naphthoquinone (330 mg, 2.1 mmol) and CeCl3
7H2O (35 mg, 0.094 mmol) were dissolved in ethanol (25 mL). The reaction mixture was refluxed for
.
9 h. while air was bubbled through it as described above in the general procedure. After evaporation of
the ethanol and chromatography (eluting with CHCl3/MeOH, 50:1) the crude product was added to a
solution of 25% aq. ammonia (10 mL) in methanol (100 mL) and was stirred at room temperature for 7
days. The reaction mixture was evaporated and chromatographed (eluting with chloroform/methanol,
30:1) to afford 8 (70mg, 13%), amorphous powder (chloroform/methanol, 9:1), mp 258oC (lit [8],
260-2620C).
3(N)-(2,2’-diaminobenzophenone)-5-hydroxy-1,4-naphthoquinone (9):
.
4a (100 mg, 0.47 mmol) and CeCl3 7H2O (186 mg, 0.50 mmol) were dissolved in ethanol (10 mL)
and 5-Hydroxy-1,4-naphthoquinone (juglone) (87 mg, 0.50 mmol) was added. The color of the solution
changed immediately from yellow to red. The reaction mixture was stirred at room temperature, with
bubbled air, for 3 days. The solvent was then evaporated and the red product purified by
chromatography (eluting with CHCl3/MeOH, 100:1) (144mg, 80%): red prisms (from EtOH), m.p.
o
+
~
221 C; MS (EI); m/z: 384 (100) [M , C23H16N2O4]; IR: ν == 3450, 1625, 1606, 1572, 1513, 1448,
1273, 1242 cm-1; H-NMR (CDCl3): δ== 6.2 (br s, 2 H, NH2), 6.52 (s, 1 H, H-2), 6.58 (t, J=7.5 Hz, 1
1
H, 12’-H), 6.72 (d, J=7.5Hz, 1 H, 10’-H), 7.16 (dd, J=7.5, 2.0 Hz, 1 H, 6-H), 7.21 (t, J=7.5 Hz, 1 H,
11’-H), 7.30 (t, J=7.5 Hz, 1 H, 4’-H), 7.40 (d, J=7.5 Hz, 1 H, 6’-H), 7.51 (d, J=7.5 Hz, 1 H, 13’-H),
7.54 (t, J=7.5 Hz, 1 H, 5’-H), 7.60 (d, J=7.5 Hz, 1 H, 8-H), 7.61 (d, J=7.5 Hz, 1 H, 3’-H), 7.62 (t,
J=7.5 Hz, 1 H, 7-H), 9.45 (br s, 1 H, NH), 11.60 (s, 1 H, OH).

Molecules, 2001, 6
312
11-Hydroxy-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (10):
9 (70 mg, 0.18 mmol) was added to a solution of Et3N (2 mL) in methanol (20 mL) and the
reaction mixture was stirred at room temperature for 10 days. The solution was evaporated and the
residual solid chromatographed (eluting with CHCl3/MeOH, 100:1) to afford 10 (61 mg, 98%), yellow
needles (CHCl3-MeOH 50:1), m.p. 292oC; HRMS calcd. for C23H12N2O2 [M+] 348.0899, found
-1
1
~
348.0899; IR: ν == 3441, 2924, 1639, 1611, 1567, 1458, 1402, 1277 cm ; H-NMR (CDCl3): δ== 7.30
(d, J=8.0 Hz, 1 H, 12-H), 7.83 (t, J=8.0 Hz, 1 H, 13-H), 7.88 (t, J=8.5 Hz, 1 H, 3-H), 8.00 (t, J=8.5
Hz, 1 H, 6-H), 8.00 (t, J=8.5 Hz, 1 H, 2-H), 8.08 (t, J=8.5 Hz, 1 H, 7-H), 8.67 (d, J=8.5 Hz, 1 H, 1-
H), 8.73 (d, J=8.0 Hz, 1 H, 14-H), 8.83 (d, J=8.5 Hz, 1 H, 8-H), 9.08 (d, J=8.5 Hz, 1 H, 4-H), 9.17 (d,
J=8.5 Hz, 1 H, 5-H), 12.90 (s, 1 H, OH); 13C-NMR (CDCl3/CD3OD, 50:1): δ== 116.9 (s, C-10a), 117.7
(d, C-14), 120.3 (d, C-12), 122.7 (s, C-4a), 124.6 (s, C-4c), 127.2 (d, C-5), 127.3 (d, C-4), 128.4 (d, C-
3), 130.4 (d, C-6), 131.1 (d, C-7), 131.2 (d, C-2), 131.3 (d, C-1), 132.7 (d, C-8), 136.1 (s, C-4b), 136.4
(s, C-14a), 137.8 (d, C-13), 145.3 (s, C-9a), 147.5 (s, C-14b), 147.5 (s, C-8a), 147.5 (s, C-15a), 163.9
(s, C-11), 183.6 (s, C-10); C-14c could not be seen due to a long relaxation time.
11-Acetoxy-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (11):
10 (10 mg, 0.029 mmol) was acetylated with acetic anhydride-pyridine, 1:1 (1 mL), at room
temperature for 24 h. The reaction mixture was evaporated and chromatographed (eluting with
CHCl3/MeOH, 40:1) to give 11 (11 mg, 95%), yellow needles (CHCl3/MeOH, 100:1), m.p. 222oC; MS
+
+
~
(EI); m/z: 390 (5) [M , C25H14N2O3], 348 (100) [M -CH2CO]; IR: ν == 2924, 1765, 1677, 1563, 1401,
1193 cm-1; 1H-NMR (CDCl3/CD3OD, 50:1): δ== 2.52 (s, 3 H, COCH3), 7.28 (d, J=8.0 Hz, 1 H, 12-H),
7.69 (t, J=8.0 Hz, 1 H, 13-H), 7.80 (t, J=8.0 Hz, 1 H, 3-H), 7.80 (t, J=8.0 Hz, 1 H, 2-H), 7.85 (t, J=8.0
Hz, 1 H, 6-H), 7.93 (t, J=8.0 Hz, 1 H, 7-H), 8.23 (d, J=8.0 Hz, 1 H, 1-H), 8.57 (d, J=8.0 Hz, 1 H, 14-
H), 8.89 (d, J=8.0 Hz, 1 H, 8-H), 8.96 (d, J=8.0 Hz, 1 H, 4-H), 9.00 (d, J= 8.0 Hz, 1 H, 5-H).
11-Hydroxy-10-imino-10H-benzo[i]quino[2,3,4-kl]acridine (12):
Method A: 9 (110 mg, 0.28 mmol), was added to a mixture of 25% aq. ammonia (2 ml) and methanol
(20 mL) and stirred at room temperature for 7 days. The reaction mixture was then evaporated and the
residue chromatographed (eluting with CHCl3/MeOH, 30:1) to afford 12 (83 mg, 85%).
Method B: 10 (10 mg, 0.029 mmol) was stirred in a saturated ammonia/methanol solution (2 mL) for
14 days. The solvent was then evaporated and the residue chromatographed using CHCl3/MeOH, 30:1,
as eluant to afford 12 (7 mg, 70%), dark-green needles (CHCl3/MeOH, 20:1), m.p. 266oC; HRMS
+
~
calcd. for C23H13N3O [M ] 347.10586, found 347.10590; IR: ν = 3384, 1615, 1565, 1488, 1472, 1405,
1124, 1048 cm-1; 1H-NMR (CDCl3): δ== 7.11 (d, J=8.0 Hz, 1 H, 12-H), 7.57 (d, J=8.0Hz, 1 H, 13-H),
7.77 (t, J=8.0 Hz, 1 H, 3-H), 7.88 (t, J=8.0 Hz, 1 H, 6-H), 7.89 (t, J=8.0 Hz, 1 H, 2-H), 7.97 (t, J=8.0
Hz, 1 H, 7-H), 8.32 (d, J=8.0 Hz, 1 H, 1-H), 8.37 (d, J=7.5 Hz, 1 H, 14-H), 8.40 (d, J=8.0 Hz, 1 H, 8-
H), 9.00 (d, J=8.0 Hz, 1 H, 4-H), 9.10 (d, J=8.0 Hz, 1 H, 5-H), 10.81 (br s, 1 H), 14.8 (br s, 1 H); 13C-
NMR (CDCl3): δ== 113.5 (s, C-10a), 115.9 (d, C-14), 122.4 (s, C-4a), 123.6 (d, C-12), 124.3 (s, C-4c),

Molecules, 2001, 6
313
127.1 (d, C-4), 127.3 (d, C-5), 127.6 (d, C-3), 129.2 (d, C-6), 130.8 (d, C-7), 130.8 (d, C-2), 131.2 (d,
C-8), 131.3 (d, C-1), 133.3 (s, C-14a), 135.2 (d, C-13), 136.1 (s, C-4b), 143.2 (s, C-9a), 146.7 (s, C-
8a), 147.9 (s, C-15a), 148.8 (s, C-14b), 162.1 (s, C-10), 171.0 (s, C-11); C-14c could not be seen due to
a long relaxation time.
Acetylation of compound 12 to afford compounds 13a and 13b:
12 (10 mg, 0.029 mmol) was added to a mixture of acetic anhydride/pyridine, 1:1 (1 mL), and the
solution was stirred at room temperature for 24 h. The reaction mixture was evaporated and
chromatographed. Elution with CHCl3/MeOH, 200:1, afforded the mono N-acetylated product 13a (4
mg, 35%) and further elution with CHCl3/MeOH, 100:1, afforded the diacetylated product 13b (4 mg,
32%). Acetylation of 13a (1 mg, 2.6 µmol) by the same procedure gave the O,N-diacetate derivative
13b (1 mg). 13a: MS (EI); m/z: 389 (14) [M+, C25H15N3O2], 373 (66) [M+- O], 347 (100) [M+-
-1
1
~
CH2CO]; IR: ν == 3430, 1698, 1615, 1568, 1404, 1241, 1175 cm ; H-NMR (CDCl3): δ== 2.72 (s, 3 H,
NCOCH3), 7.22 (d, J=8.5 Hz, 1 H, 12-H), 7.66 (t, J=8.5 Hz, 1 H, 13-H), 7.76 (t, J=8.5 Hz, 1 H, 3-H),
7.89 (t, J=8.5 Hz, 1 H, 2-H), 7.91 (t, J=8.0 Hz, 1 H, 6-H), 7.97 (t, J=8.0 Hz, 1 H, 7-H), 8.31 (d, J=8.5
Hz, 1 H, 1-H), 8.37 (d, J=8.0 Hz, 1 H, 8-H), 8.61 (d, J=8.5 Hz, 1 H, 14-H), 8.98 (d, J=8.5 Hz, 1 H, 4-
H), 9.09 (d, J=8.5 Hz, 1 H, 5-H); 13C-NMR (CDCl3): δ== 26.6 (NCOCH3), 114.4 (s, C-14c), 114.8 (s,
C-10a), 117.8 (d, C-14), 120.3 (d, C-12), 122.5 (s, C-4a), 123.8 (s, C-4c), 127.1 (d, C-4), 127.3 (d, C-
5), 128.0 (d, C-3), 129.8 (d, C-6), 131.0 (d, C-7), 131.0 (d, C-2), 131.2 (d, C-8), 131.2 (d, C-1), 134.6
(d, C-13), 135.0 (s, C-14a), 136.5 (s, C-4b), 141.8 (s, C-9a), 146.1 (s, C-8a), 147.8 (s, C-15a), 148.4 (s,
C-14b), 153.8 (s, C-10), 161.6 (s, C-11), 183.8 (NCOCH3). 13b: MS (EI); m/z: 433 (17) [(M+2)+,
C27H19N3O3], 389 (15) [M+-CH2CO], 373 (100) [(M+2)+-CH3CO2H], 347 (82) [M+- 2CH2CO]; IR:
-1
1
~
ν == 3430, 1767, 1676, 1640, 1569, 1204 cm ; H-NMR (CDCl3): δ== 2.47 (s, 3 H, OCOCH3), 2.60 (s,
3 H, NCOCH3), 7.35 (dd, J=8.0, 1.5 Hz, 1 H, 12-H), 7.77 (t, J=8.0 Hz, 1 H, 13-H), 7.79 (t, J=8.0 Hz,
1 H, 6-H), 7.88 (t, J=8.0 Hz, 1 H, 3-H), 7.89 (t, J=8.0 Hz, 1 H, 7-H), 7.95 (dt, J=8.0, 1.5 Hz, 1 H, 2-
H), 8.34 (d, J=8.0 Hz, 1 H, 8-H), 8.38 (dd, J=8.0, 1.5 Hz, 1 H, 1-H), 8.98 (d, J=8.0 Hz, 1 H, 14-H),
9.08 (d, J=8.0 Hz, 1 H, 4-H), 9.10 (dd, J=8.0, 1.5 Hz, 1 H, 5-H).
3N-(4-methoxyaniline)-5-hydroxy-1,4-naphthoquinone (14):
p-Anisidine (40 mg, 0.32 mmol) was reacted with juglone (57 mg, 0.33 mmol) in the present of
.
CeCl3 7H2O (122 mg, 0.33 mmol) by the procedure described for the preparation of compound 9. The
red product was purified by chromatography (eluting with CHCl3/MeOH, 100:1) (65 mg, 69%): red
o
+
~
crystals (ethanol), m.p. 211 C. – MS (EI); m/z: 295 (100) [M , C17H13NO4]; IR: ν == 3274, 1627, 1590,
1572, 1516, 1240 cm-1; 1H-NMR (CD3SOCD3): δ = 3.78 (s, 3 H, OCH3), 5.87 (s, 1 H, 2-H), 7.01 (d, J
=8.5 Hz, 2 H, 3’-H), 7.24 (d, J=8.5 Hz, 1 H, 6-H), 7.28 (d, J=8.5 Hz, 2 H, 2’-H), 7.44 (d, J=8.5 Hz, 1
H, 8-H), 7.72 (t, J=8.5 Hz, 1 H, 7-H), 9.18 (s, 1 H, NH), 11.54 (s, 1 H, OH); 13C-NMR (CD3SOCD3): δ
= 55.3 (q, OCH3), 101.3 (d, C-2), 114.3 (s, C-4a), 114.6 (d, C-3’), 117.6 (d, C-8), 122.1 (d, C-6), 125.8

Molecules, 2001, 6
314
(d, C-2’), 130.5 (s, C-1’), 133.1 (s, C-8a), 137.6 (d, C-7), 146.9 (s, C-3), 157.1 (s, C-4’), 160.5 (s, C-5),
181.6 (s, C-1), 185.7 (s, C-4).
3(N)-(4-methoxyaniline)-5-hydroxy-1,4-naphthoquinon-4-imine (15):
14 (20 mg, 0.068 mmol) was added to a mixture of 25% aq. ammonia (2 mL) and methanol (20 mL)
and stirred at room temperature for 7 days. Evaporation of the solvent afforded compound 15 (20 mg,
+
~
100%); HRMS calcd. for C17H14N2O3 [M ] 394.1004, found 294.1008; IR: ν == 3300, 1571, 1535,
1513, 1257 cm-1; H-NMR (CD3SOCD3): δ = 3.77 (s, 3 H, OCH3), 5.66 (s, 1 H, 2-H), 7.04 (d, J=9.0
1
Hz, 2 H, 3’-H), 7.14 (d, J=8.0 Hz, 1 H, 6-H), 7.26 (d, J=9.0 Hz, 2 H, 2’-H), 7.39 (d, J=8.0 Hz, 1 H, 8-
H), 7.49 (t, J=8.0 Hz, 1 H, 7-H); 13C NMR (CD3SOCD3): δ = 54.9 (q, OCH3), 100.5 (d, C-2), 113.4 (s,
C-4a), 114.3 (d, C-3’), 115.5 (d, C-8), 121.8 (d, C-6), 125.5 (d, C-2’), 130.2 (s, C-1’), 131.6 (s, C-8a),
132.7 (d, C-7), 147.1 (s, C-3), 156.6 (s, C-4’), 161.5 (s, C-5), 161.6 (s, C-4), 181.6 (s, C-1).
10H,11H,12H-dihydroquino[2,3,4-kl]acridine (17a):
To a stirred solution of 4a (400 mg, 1.9 mmol) in AcOH (50 mL) and conc.HCl (0.25 mL), 1,3-
cyclohexanedione (425 mg, 3.8 mmol) and sodium m-nitrophenylsulfonate (1.3 g, 5.7 mmol) were
added and the reaction mixture was refluxed for 2 h. After cooling, the mixture was poured onto ice
(100 g), the solution brought to pH 8 with 25% ammonia and then extracted with chloroform (3 x 30
x
mL). The chloroform solution was washed with water (2 50 mL) and evaporated to afford 17a (515
mg, quantitative), amorphous powder (CHCl3/MeOH, 20:1), m.p. 186oC; HRMS calcd. for C19H14N2
+
-1
[M ] 270.1157, found 270.1157; IR: ν == 2940, 1585, 1572, 1488, 1400, 1389 cm ; 1H-NMR
(CDCl3): δ== 2.42 (quintet, J=6.0 Hz, 2 H, 11-H), 3.50 (t, J=6.0 Hz, 4 H, 10-, 12-H), 7.76 (t, J=7.0 Hz,
2 H, 2-, 7-H), 7.89 (t, J=7.0 Hz, 2 H, 3-, 6-H), 8.28 (d, J=7.0 Hz, 2 H, 1-, 8-H), 9.06 (d, J=7.0 Hz, 2 H,
4-, 5-H); 13C-NMR (CDCl3): δ== 22.3 (t, C-11), 34.4 (t, C-10), 116.5 (s, C-12b), 122.4 (s, C-4a), 126.1
(d, C-3), 127.0 (d, C-4), 129.2 (d, C-1), 130.0 (d, C-2), 135.9 (s, C-4b), 146.6 (s, C-8a), 159.5 (s, C-
9a).
~
2,7-Dimethoxy-10H,11H,12H-dihydroquino[2,3,4-kl]acridine (17b):
Reacting 4b (520 mg, 1.9 mmol) with 1,3-cyclohexanedione (425 mg, 3.8 mmol) by the same
procedure described for the synthesis of 17a afforded 17b (625mg, quantitative), amorphous powder
(CHCl3/MeOH, 20:1), mp 218oC; HRMS calcd. for C21H18N2O2 [M+] 330.1368, found 330.1368; IR:
-1
1
~
ν == 2950, 1612, 1583, 1413, 1219, 1033 cm ; H-NMR (CDCl3): δ== 2.57 (quintet, J=6.5 Hz, 2 H,
11-H), 3.90 (t, J=6.5 Hz, 4 H, 10-, 12-H), 4.16 (s, 6 H, OMe), 7.65 (dd, J=9.0, 2.5 Hz, 2 H, 3-, 6-H),
8.15 (d, J=2.5 Hz, 2 H, 1-, 8-H), 8.95 (d, J=9.0Hz, 2 H, 4-, 5-H).

Molecules, 2001, 6
315
General procedure for nitration of compounds 6a, 6b and 17a:
The pyridoacridine (10 mg) was added to a 1:1 mixture of conc.H2SO4/fuming HNO3 (2 mL) at 0oC.
The reaction mixture was then allowed to warm up to room temperature and after 1 h. or 12 h. it was
poured onto ice (10 g). The solution was neutralized with 10% NaOH and extracted with chloroform (4
x
10 mL). The chloroform solution was evaporated and the residue was chromatographed.
8-Nitro-10H,11H,12H-dihydroquino[2,3,4-kl]acridine (18a) and 6-Nitro-10H,11H,12H- dihydroquino
[2,3,4-kl]acridine (18b):
Reaction of 17a (10 mg, 0.037 mmol) by the above described procedure for 1 h. gave two products
that were separated by chromatography. Elution with dichloromethane afforded the less polar isomer
18a (3 mg, 26%) and further elution with CH2Cl2/MeOH, 30:1, afforded the more polar isomer 18b (7
mg, 60%). 18a: MS (EI); m/z: 315 (100) [M+, C19H13N3O2], 285 (37) [M+- NO], 269 (30) [M+- NO2];
-1
1
~
IR: ν ===2925, 1591, 1374, 1139 cm ; H-NMR (CDCl3/CD3OD, 50:1): δ== 2.43 (quintet, J=6.0 Hz, 2
H, 11-H), 3.51 (t, J=6.0 Hz, 2 H, 12a-H), 3.75 (t, J=6.0 Hz, 2 H, 10a-H), 7.94 (t, J=8.0 Hz, 1 H, 6-H),
8.05 (t, J=8.0 Hz, 1 H, 2-H), 8.18 (t, J=8.0 Hz, 1 H, 3-H), 8.25 (d, J=8.0 Hz, 1 H, 7-H), 9.06 (d, J=
8.0 Hz, 1 H, 1-H), 9.07 (d, J=8.0 Hz, 1 H, 4-H), 9.21 (d, J=8.0 Hz, 1 H, 5-H). 18b: HRMS calcd. for
C19H13N3O2 [M+] 315.1008, found 315.1006; MS (EI); m/z: 315 (100) [M+], 269 (33) [M+- NO2]; IR:
-1
1
~
ν == 2927, 1588, 1339 cm ; H-NMR (CDCl3/CD3OD, 50:1): δ== 2.42 (quintet, J=6.0 Hz, 2 H, 11-H),
3.50 (t, J=6.0 Hz, 2 H, 12-H, interchangeable), 3.54 (t, J=6.0 Hz, 2 H, 10a-H), 7.87 (t, J=7.5 Hz, 1 H,
3-H), 7.97 (t, J=7.5 Hz, 1 H, 2-H), 8.32 (d, J=7.5 Hz, 1 H, 1-H), 8.36 (d, J=7.5 Hz, 1 H, 8-H), 8.63
(dd, J=7.5, 2.5 Hz, 1 H, 7-H), 8.95 (d, J=7.5 Hz, 1 H, 4-H), 9.93 (d, J=2.5 Hz, 1 H, 5-H).
1,8-Dinitro-10H,11H,12H-dihydroquino[2,3,4-kl]acridine (19a), 3,8-Dinitro-10H,11H, 12H-dihydro-
quino[2,3,4-kl]acridine (19b) and 3,6-Dinitro-10H,11H,12H-dihydroquino [2,3,4-kl]acridine (19c):
Reaction of 17a (10 mg, 0.037mmol) in conc.H2SO4/fuming HNO3 , 1:1 (2ml), by the general above
procedure for 12 h. gave three products that were separated by chromatography. Elution with
dichloromethane/petroleum ether, 4:1, afforded isomer 19a (0.5 mg). Elution with dichloromethane
afforded isomer 19b (2 mg, 15%) and isomer 19c (3 mg, 20%). 19a: MS (EI); m/z: 360 (47) [M+,
+
+
-1 1
~
C19H12N4O4], 330 (60) [M - NO], 300 (100) [M - 2NO]; IR: ν === 2925, 1620, 1583, 1534 cm ; H-
NMR (CDCl3): δ== 2.39 (quintet, J=7.0 Hz, 2 H, 11-H), 3.50 (t, J=7.0 Hz, 4 H, 10-, 12-H), 7.83 (t, J=
7.5 Hz, 2 H, 3-, 6-H), 8.13 (d, J=7.5 Hz, 2 H, 2-, 7-H), 9.10 (d, J=7.5 Hz, 2 H, 4-, 5-H). 19b: HRMS
calcd. for C19H12N4O4 [M+] 360.0859, found 360.0858; MS (EI); m/z: 360 (100) [M+], 330 (23) [M+-
+
+
-1
~
NO], 302 (29) [(M+2) - 2NO], 267 (31) [(M-1) - 2NO2]; IR: ν == 2925, 1618, 1589, 1535, 1341 cm ;
1H-NMR (CDCl3): δ== 2.43 (quintet, J=7.0 Hz, 2 H, 11-H), 3.52 (t, J=7.0 Hz, 2 H, 12a-H), 3.59 (t, J=
7.0 Hz, 2 H, 10-H, interchangeable), 7.95 (t, J=8.0 Hz, 1 H, 6-H), 8.19 (d, J=8.0 Hz, 1 H, 7-H), 8.55
(d, J=8.0 Hz, 1 H, 1-H), 8.73 (dd, J=8.0, 2.0 Hz, 1 H, 2-H), 9.16 (d, J=8.0 Hz, 1 H, 5-H), 9.90 (d, J=
2.0 Hz, 1 H, 4-H). 19c: MS (EI); m/z: 360 (100) [M+, C19H12N4O4], 315 (49) [(M+1)+- NO2], 267 (53)
+
-1 1
~
[(M-1) - 2NO2]; IR: ν == 2925, 1600, 1588, 1506, 1346 cm ; H-NMR (CDCl3): δ== 2.54 (quintet, J=

Molecules, 2001, 6
316
6.0 Hz, 2 H, 11-H), 3.67 (t, J=6.0 Hz, 4 H, 10-, 12-H), 8.60 (d, J=8.0 Hz, 2 H, 1-, 8-H), 8.79 (dd, J=
8.0, 2.0 Hz, 2 H, 2-, 7-H), 9.96 (d, J=2.0 Hz, 2 H, 4-, 5-H).
3-Nitro-10H-benzo[i]quino [2,3,4-kl]acridin-10-one (20):
Reaction of 6a (80 mg, 0.24 mmol) in conc.H2SO4/fuming HNO3, 1:1 (5mL), for 12 h. by the above
general procedure followed by crystallization of the crude product from pyridine afforded 20 (48 mg,
53%), yellow needles, m.p. 339oC; MS (EI); m/z: 377 (100) [M+, C23H11N3O3], 347 (36) [(M+- NO],
+
-1 1
~
330 (41) [(M-1) - NO2]; IR: ν == 1682, 1513, 1404, 1388, 1340, 1276 cm ; H-NMR (CDCl3): δ==
7.79 (t, J=8.0 Hz, 1 H, 12-H), 7.93 (t, J=8.0 Hz, 1 H, 13-H), 8.12 (t, J=8.0 Hz, 1 H, 7-H), 8.12 (t, J=
8.0 Hz, 1 H, 6-H), 8.50 (d, J=8.0 Hz, 1 H, 11-H), 8.54 (d, J=9.0 Hz, 1 H, 1-H), 8.71 (d, J=8.0 Hz, 1 H,
8-H), 8.72 (dd, J=9.0, 2.5 Hz, 1 H, 2-H), 9.09 (d, J=8.0 Hz, 1 H, 14-H), 9.11 (d, J=8.0 Hz, 1 H, 5-H),
10.01 (d, J=2.5 Hz, 1 H, 4-H); 13C-NMR (CDCl3/CF3CO2D, 100:1): δ== 116.5 (s, C-14c), 121.6 (s, C-
4a), 123.6 (d, C-4),123.7 (s, C-4c), 124.7 (d, C-2), 126.4 (d, C-5), 126.7 (d, C-14), 128.4 (d, C-11),
131.5 (d, C-6), 131.8 (d, C-7), 131.9 (d, C-8), 132.2 (s, C-10a), 132.3 (d, C-12), 132.6 (d, C-1), 134.8
(s, C-14a), 135.3 (d, C-13), 136.8 (s, C-4b), 146.0 (s, C-3), 146.7 (s, C-8a), 149.0 (s, C-9a), 149.8 (s,
C-15a), 151.3 (s, C-14b), 181.1 (s, C-10).
3-Amino-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (21):
20 (40 mg, 0.11 mmol) was dissolved in AcOH (3 mL) and TFA (6mL), 5% Pd-C (25 mg) was
added and the reaction mixture was shaken in a Parr apparatus under H2 (3 atm) for 1 h. The catalyst
was then filtered off, the solution poured onto ice (10 g), brought to pH 8 with 25% ammonia and then
x
extracted with chloroform (3
20 mL). After evaporation of the solvent the residue was
chromatographed (eluting with CHCl3/MeOH, 30:1) to afford 21 (15 mg, 40%); HRMS calcd. for
-1
1
C23H13N3O [M+] 347.1059, found 347.1058; IR: ν = 1677, 1646, 1540, 1515 cm ; H-NMR
(CD3SOCD3):=δ== 7.42 (d, J=8.0 Hz, 1 H, 2-H), 7.71 (t, J=8.0 Hz, 1 H, 12-H), 7.93 (t, J=8.0 Hz, 1 H,
13-H), 8.05 (t, J=8.0 Hz, 1 H, 6-H), 8.09 (t, J=8.0 Hz, 1 H, 7-H), 8.13 (d, J=8.0 Hz, 1 H, 1-H), 8.28
(d, J=2.0 Hz, 1 H, 4-H), 8.30 (d, J=8.0 Hz, 1 H, 11-H), 8.53 (d, J=8.0 Hz, 1 H, 8-H), 8.91 (d, J=8.0
Hz, 1 H, 14-H), 9.31 (d, J=8.0 Hz, 1 H, 5-H).
~
2,7-Dimethoxy-1,8-dinitro-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (22):
Reaction of 6b (10 mg, 0.026 mmol) in conc.H2SO4/fuming HNO3, 1:1 (2ml), by the above general
procedure for 1 hr afforded 22 (10 mg, 80%); HRMS calcd. for C25H14N4O7 [M+] 482.0862, found
+
+
+
~
482.0855, 452 (100) [(M - NO]; MS (EI); m/z: 482 (79) [M ], 452 (100) [M -NO]; IR: ν == 1687,
1617, 1540, 1375, 1290 cm-1; H-NMR (CD3SOCD3):=δ== 4.21 (s, 3 H, OCH3), 4.24 (s, 3H, OCH3),
1
7.85 (t, J=8.5 Hz, 1 H, 12-H), 7.97 (d, J=10.0 Hz, 1 H, 3-H), 7.99 (t, J=8.5 Hz, 1 H, 13-H), 8.13 (d,
J=10.0 Hz, 1 H, 6-H), 8.27 (d, J=8.5 Hz, 1 H, 11-H), 8.66 (d, J=8.5 Hz, 1 H, 14-H), 9.28 (d, J=10.0
Hz, 1 H, 4-H), 9.36 (d, J=10.0 Hz, 1 H, 5-H).

Molecules, 2001, 6
317
2,7- Dimethoxy-1,3,8,12-tetrainitro-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (23a) and 2,7-di-
methoxy-1,3,8,14-tetranitro-10H-benzo[i]quino[2,3,4-kl]acridin-10-one (23b):
Reaction of 6b (10 mg, 0.026 mmol) in conc.H2SO4/fuming HNO3, 1:1 (2 ml), by the above general
procedure for 12 hr gave two products that were separated by chromatography. Elution with
dichloromethane afforded first the less polar isomer 23a (3 mg, 20%) and then the more polar isomer
23b (7 mg, 45%). 23a: MS (EI); m/z: 572 (100) [M+, C25H12N6O11], 542 (45) [M+- NO], 482 (78) [M+-
-1
3NO], 452 (32) [M+- 4NO]; IR: ν == 2925, 1706, 1619, 1547, 1375 cm ; 1H-NMR
~
(CD3SOCD3/CF3CO2D, 100:1):=δ== 4.18 (s, 3 H, OCH3), 4.29 (s, 3 H, OCH3), 8.28 (d, J=10.0 Hz, 1 H,
6-H), 8.82 (dd, J=8.5, 2.5 Hz, 1 H, 13-H), 8.90 (d, J=8.5 Hz, 1 H, 14-H), 8.90 (d, J=2.5 Hz, 1 H, 11-
1
H), 9.48 (d, J=10.0 Hz, 1 H, 5-H), 9.86 (s, 1 H, 4-H); H-NMR (CD3CN):=δ== 4.30 (s, 3 H, OCH3),
4.32 (s, 3 H, OCH3), 8.15 (d, J=10.0 Hz, 1 H, 6-H), 8.70 (dd, J=8.5, 2.0 Hz, 1 H, 13-H), 8.99 (d, J=
8.5 Hz, 1 H, 14-H), 9.05 (d, J=2.0 Hz, 1 H, 11-H), 9.30 (d, J=10.0Hz, 1 H, 5-H), 9.75 (s, 1 H, 4-H).
+
~
23b: HRMS calcd. for C25H12N6O11 [M ] 572.0564, found 572.0562; IR: ν = 2925, 1692, 1629, 1557,
1547, 1376 cm-1; 1H-NMR (CD3SOCD3):=δ== 4.14 (s, 3 H, OCH3), 4.27 (s, 3 H, OCH3), 8.06 (t, J=8.0
Hz, 1 H, 12-H), 8.22 (d, J=8.0 Hz, 1 H, 13-H), 8.26 (d, J=9.5 Hz, 1 H, 6-H), 8.54 (d, J=8.0 Hz, 1 H,
11-H), 9.43 (d, J=9.5 Hz, 1 H, 5-H), 9.79 (s, 1 H, 4-H).
10H-quino[2,3,4-kl]acridin-10-one (24):
To a solution of 17a (300 mg, 1.1 mmol) in acetonitrile (120 mL) cerium ammonium nitrate (2.4 g,
4.4 mmol) was added and the reaction mixture was refluxed for 10 min. The acetonitrile was
x
evaporated and the residue dissolved in chloroform (100 mL), washed with 0.1% aq. ammonia (2 100
mL) and evaporated to afford 24 (290 mg, 92%), amorphous powder (CHCl3/MeOH, 20:1), m.p.
o
+
~
254 C; HRMS calcd. for C19H10N2O [M ] 282.0793, found 282.0799; IR: ν = 1663, 1565, 1493, 1280
cm-1; 1H-NMR (CDCl3): δ== 7.11 (d, J=11.0 Hz, 1 H, 11-H), 7.90 (t, J=8.5 Hz, 1 H, 3-H), 7.98 (t, J=
8.5 Hz, 1 H, 2-H), 7.98 (t, J=8.5 Hz, 1 H, 6-H), 7.99 (d, J=11.0 Hz, 1 H, 12-H), 8.05 (t, J=8.5 Hz, 1 H,
7-H), 8.43 (d, J=8.5 Hz, 1 H, 1-H), 8.73 (d, J=8.5 Hz, 1 H, 8-H), 9.14 (d, J=8.5 Hz, 1 H, 4-H), 9.19 (d,
J=8.5 Hz, 1 H, 5-H).
2,7-Dimethoxy-10H-quino[2,3,4-kl]acridin-10-one (25):
Oxidation of 17b (360 mg, 1.1 mmol) by the same procedure described for the synthesis of 24
afforded 25 (340 mg, 90%), amorphous powder (CHCl3/MeOH, 20:1), m.p. 291oC; HRMS calcd. for
+
-1 1
~
C21H14N2O3 [M ] 342.1004, found 342.1004; IR: ν == 1666, 1608, 1415, 1259, 1225 cm ; H-NMR
(CDCl3/CD3OD, 50:1): δ== 4.03 (s, 3 H, OCH3), 4.04 (s, 3 H, OCH3), 7.02 (d, J=10 Hz, 1 H, 11-H),
7.43 (dd, J=8.5, 2.5 Hz, 1 H, 3-H), 7.51 (dd, J=8.5, 2.5 Hz, 1 H, 6-H), 7.72 (d, J=2.5 Hz, 1 H, 1-H),
7.93 (d, J=10 Hz, 1 H, 12-H), 7.94 (s, 1 H, 8-H), 8.88 (d, J=8.5 Hz, 1 H, 4-H), 8.92 (d, J=8.5 Hz, 1 H,
5-H).

Molecules, 2001, 6
318
11,12-Dibromo-10H-quino[2,3,4-kl]acridin-10-one (26):
24 (30 mg, 0.11 mmol) was dissolved in acetic acid (5 mL) and Br2 (0.2 mL, 3.9 mmol) was added
at room temperature. The mixture was stirred at 80oC for 2 h. and then allowed to cool to room
temperature. Water (25 mL) and chloroform (25 mL) were added. The organic phase was extracted
with 5% NaHSO3 (10 mL) and evaporated. The crude product was chromatographed (eluting with
chloroform) to afford 26 (16 mg, 33%); HRMS calcd. for C19H8Br2N2O [M+] 439.8988, found
-1
1
~
439.9000; IR: ν == 3425, 1669, 1491, 1394, 1242, 767 cm ; H-NMR (CDCl3): δ = 7.86 (t, J=8.0 Hz,
1 H, 3-H), 7.93 (t, J=8.0 Hz, 1 H, 2-H), 7.93 (t, J=8.0 Hz, 1 H, 6-H), 7.99 (t, J=8.0 Hz, 1 H, 7-H), 8.39
(d, J=8.0 Hz, 1 H, 1-H), 8.56 (d, J=8.0 Hz, 1 H, 8-H), 8.97 (d, J=8.0 Hz, 1 H, 4-H), 9.04 (d, J=8.0 Hz,
1 H, 5-H).
12-Isobutylamino-10H-quino[2,3,4-kl]acridin-10-one (27a):
24 (40 mg, 0.14 mmol) and isobutylamine (0.12 mL, 1.2 mmol) in acetonitrile (10 mL) were stirred
at room temperature for 48 h. The reaction mixture was then evaporated and the residue
chromatographed by a silica gel column (eluting with CHCl3/MeOH, 30:1) to afford 27a (18 mg,
36%); HRMS calcd. for C23H19N3O [M+] 353.1528, found 353.1525; MS (EI); m/z: 353 (20) [M+], 310
+
-1 1
~
(100) [M - (CH3)2CH]; IR: ν == 2925, 1609, 1514, 1466, 1258, 761 cm ; H-NMR (CDCl3): δ== 1.15
(d, J=7.0 Hz, 6 H, 3’-H), 2.20 (quintet, J=7.0 Hz, 1 H, 2’-H), 3.31 (t, J=7.0 Hz, 2 H, 1’-H), 6.09 (s, 1
H, 11-H), 7.49 (br s, 1 H, NH), 7.76 (t, J=8.0 Hz, 1 H, 3-H), 7.79 (t, J=8.0 Hz, 1 H, 6-H), 7.86 (t, J=
8.0 Hz, 1 H, 2-H), 7.89 (t, J=8.0 Hz, 1 H, 7-H), 8.21 (d, J=8.0 Hz, 1 H, 1-H), 8.60 (d, J=8.0 Hz, 1 H,
13
8-H), 8.91 (d, J=8.0 Hz, 1 H, 5-H), 8.93 (d, J=8.0 Hz, 1 H, 4-H); C-NMR (CDCl3): δ== 20.5 (q, C-
3’), 28.0 (d, C-2’), 50.5 (t, C-1’), 100.7 (d, C-11), 115.3 (s, C-12b), 123.5 (s, C-4c), 123.8 (s, C-4a),
126.8 (d, C-5), 127.3 (d, C-4), 129.0 (d, C-3), 129.3 (d, C-6), 130.7 (d, C-2), 130.8 (d, C-7), 131.0 (d,
C-1), 132.9 (d, C-8), 134.9 (s, C-4b), 144.6 (s, C-9a), 145.7 (s, C-12a), 147.0 (s, C-13a), 147.6 (s, C-
8a), 152.1 (s, C-12), 180.4 (s, C-10).
10,12-Di(isobutylamino)quino[2,3,4-kl]acridine (27b):
24 (100 mg, 0.36 mmol) and isobutylamine (0.30 mL, 3.0 mmol) in ethanol (25 mL) were stirred at
room temperature for 18 h. The reaction mixture was evaporated and the residue chromatographed by
two subsequent silica gel columns (eluting with CHCl3/MeOH/trifluoroacetic acid, 20:1:0.01) to afford
+
~
27b (56 mg, 38%); HRMS calcd. for C27H26N4 [(M - 2) ] 406.2157, found 406.2156; IR: ν = 3445,
1611, 1559, 1462, 1386, 1125, 766 cm-1; H-NMR (CDCl3/CD3OD, 20:1): δ== 1.13 (d, J=7.0 Hz, 12
1
H, 3’-H), 2.25 (quintet, J=7.0 Hz, 2 H, 2’-H), 3.59 (d, J=7.0 Hz, 4 H, 1’-H), 6.19 (s, 1 H, 11-H), 7.99
(t, J=8.0 Hz, 2 H, 3-, 6-H), 8.05 (t, J=8.0 Hz, 2 H, 2-, 7-H), 8.46 (d, J=8.0 Hz, 2 H, 1-, 8-H), 9.16 (d,
13
J=8.0 Hz, 2 H, 4-, 5-H), 9.49 (br s, 1 H, NH); C-NMR (CDCl3/CD3OD, 20:1): δ== 20.1 (q, C-3’),
28.4 (d, C-2’), 51.1 (t, C-1’), 87.6 (d, C-11), 113.0 (s, C-12b), 124.2 (s, C-4a), 127.4 (d, C-4), 131.1 (d,
C-3), 132.0 (d, C-2), 132.2 (d, C-1), 136.1 (s, C-4b), 141.1 (s, C-9a), 146.2 (s, C-8a), 156.0 (s, C-10).

Molecules, 2001, 6
319
2,7-Dimethoxy-12-isobutylamino-10H-quino[2,3,4-kl]acridin-10-one (28a) and 10,12-Di (isobutyl-
amino)-2,7-dimethoxyquino[2,3,4-kl]acridine (28b):
25 (50 mg, 0.15 mmol) was reacted with isobutylamine (0.20 mL, 2.0 mmol) by the described
procedure for the synthesis of 27b. Two obtained compounds were separated by chromatography;
elution with CHCl3/MeOH, 30:1, afforded the monoamination product (28a) (12 mg, 19%) and further
elution with CHCl3/MeOH, 10:1, afforded the diamination product (28b) (25mg, 37%). 28a: MS (EI);
+
+
~
m/z: 413 (29) [M , C25H23O3N3], 370 (100) [M - (CH3)2CH]; IR: ν == 2959, 1658, 1612, 1562, 1467,
1450, 1422, 1223, 1134 cm-1; H-NMR (CDCl3): δ== 1.11 (d, J=7.0 Hz, 6 H, 3’-H), 2.17 (quintet, J=
1
7.0 Hz, 1 H, 2’-H), 3.25 (t, J=7.0 Hz, 2 H, 1’-H), 4.03 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 6.07 (s, 1
H, 11-H), 7.40 (d, J=10.0 Hz, 1 H, 3-H), 7.42 (d, J=10.0 Hz, 1 H, 6-H), 7.50 (br s, 1 H, NH), 7.58 (s, 1
H, 1-H), 8.00 (s, 1 H, 8-H), 8.83 (d, J=10.0 Hz, 1 H, 5-H), 8.86 (d, J=10.0 Hz, 1 H, 4-H). 28b: MS
+
+
~
(EI); m/z: 466 (61) [(M-2) , C29H30N4O2], 423 (100) [(M-2) - (CH3)2CH]; IR: ν == 2924, 1658, 1612,
1564, 1467, 1412, 1252, 1219, 669 cm-1; H-NMR (CDCl3): δ== 1.14 (d, J=7.0 Hz, 12 H, 3’-H), 2.28
1
(quintet, J=7.0 Hz, 2 H, 2’-H), 3.67 (d, J=7.0 Hz, 4 H, 1’-H), 4.06 (s, 6 H, OCH3), 5.89 (s, 1 H, 11-H),
7.36 (dd, J=9.0, 1.5 Hz, 2 H, 3-, 6-H), 7.70 (d, J=1.5 Hz, 2 H, 1-, 8-H), 8.58 (d, J=9.0 Hz, 2 H, 4-, 5-
13
H), 9.78 (br s, 1 H, NH); C-NMR (CDCl3): δ== 20.6 (q, C-3’), 28.7 (d, C-2’), 51.4 (t, C-1’), 56.2
(OCH3), 87.3 (d, C-11), 110.4 (s, C-12b), 111.3 (d, C-1), 117.6 (s, C-4a), 121.9 (d, C-3), 128.0 (d, C-
4), 134.8 (s, C-4b), 141.5 (s, C-9a), 148.1 (s, C-8a), 155.3 (s, C-10), 161.7 (s, C-2).
12-Methylamino-10H-quino[2,3,4-kl]acridin-10-one (29a):
24 (40 mg, 0.14 mmol), methylamine (0.20 mL of 33% methylamine in ethanol, 1.6 mmol) and
.
CeCl3 7H2O (52 mg, 0.14 mmol) were mixed together in ethanol (10 mL).The reaction mixture was
stirred at room temperature for 15 min. then evaporated and chromatographed by two subsequent silica
gel columns (eluting with CHCl3/MeOH, 30:1) to afford 29a (20 mg, 46%); MS (EI); m/z: 311 (100)
+
-1 1
~
[M , C20H13N3O]; IR: ν == 3430, 1610, 1560, 1419 cm ; H-NMR (CDCl3/CD3OD, 20:1): δ== 3.11 (s,
3 H, NCH3), 5.97 (s, 1 H, 11-H), 7.74 (t, J=8.0 Hz, 1 H, 3-H), 7.78 (t, J=8.0 Hz, 1 H, 6-H), 7.82 (t, J=
8.0 Hz, 1 H, 2-H), 7.89 (t, J=8.0 Hz, 1 H, 7-H), 8.14 (d, J=8.0 Hz, 1 H, 1-H), 8.51 (d, J=8.0 Hz, 1 H,
8-H), 8.90 (d, J=8.0 Hz, 1 H, 5-H), 8.92 (d, J=8.0 Hz, 1 H, 4-H).
10,12-Di(methylamino)quino[2,3,4-kl]acridine (29b):
24 (30 mg, 0.11 mmol) was reacted with methylamine (0.20 mL of 33% methylamine in ethanol, 1.6
mmol) in ethanol (10 mL) at room temperature for 24 h. The product (29b) was purified by silica gel
column chromatography eluting with CHCl3/MeOH, 10:1 (10 mg, 28%); MS (EI); m/z: 322 (100) [(M-
+
+
-1
1
~
2) , C21H14N4], 294 (44) [(M-2) - CH2N]; IR: ν == 3405, 1618, 1564, 1419 cm ; H-NMR
(CDCl3/CD3OD, 20:1): δ== 3.38 (s, 6 H, NCH3), 5.83 (s, 1H, 11-H), 7.83 (t, J=8.0 Hz, 2 H, 3-, 6-H),
7.90 (t, J=8.0 Hz, 2 H, 2-, 7-H), 8.21 (d, J=8.0 Hz, 2 H, 1-, 8-H), 8.79 (d, J=8.0 Hz, 2 H, 4-, 5-H).

Molecules, 2001, 6
320
12-(4-methoxyanilino)-10H-quino[2,3,4-kl]acridin-10-one (30a):
24 (10 mg, 0.036 mmol) and p-anisidine (5 mg, 0.041 mmol) were refluxed in acetonitrile for 48 h.
The solvent was evaporated and the residue chromatographed on a silica gel column (eluting with
CHCl3/MeOH, 50:1) to afford 30a (8 mg, 55%); MS (EI); m/z: 403 (100) [M+, C26H17N3O2], 372 (36)
+
-1 1
~
[M - CH3O]; IR: ν == 3448, 1614, 1556, 1512, 1245 cm ; H-NMR (CDCl3): δ = 3.87 (s, 3 H, OCH3),
6.54 (s, 1 H, 11-H), 7.00 (d, J=9.0 Hz, 2 H, 3’-H), 7.38 (d, J=9.0 Hz, 2 H, 2’-H), 7.88 (t, J=8.5 Hz, 1
H, 3-H), 7.88 (t, J=8.5 Hz, 1 H, 6-H), 7.96 (t, J=8.5 Hz, 1 H, 2-H), 7.96 (t, J=8.5 Hz, 1 H, 7-H), 8.37
(d, J=8.5 Hz, 1 H, 1-H), 8.67 (d, J=8.5 Hz, 1 H, 8-H), 9.07 (d, J=8.5 Hz, 1 H, 5-H), 9.10 (d, J=8.5 Hz,
1 H, 4-H).
10,12-Di(4-methoxyanilino)quino[2,3,4-kl]acridine (30b):
24 (10 mg, 0.036 mmol) and p-anisidine (10 mg, 0.081 mmol) in ethanol (4 mL) were stirred at
50oC for 12 h. The ethanol was then evaporated and the residue chromatographed (eluting with
CHCl3/MeOH, 10:1) to afford 30b (7 mg, 38%); MS (EI); m/z: 509 (100) [(M+1)+], 508 (99) [M+,
-1
1
~
C33H24N4O2]; IR: ν == 3440, 2925, 1607, 1548, 1506, 1460, 1253, 1171, 1105, 1025 cm ; H-NMR
(CDCl3/CD3OD, 20:1): δ== 3.89 (s, 6 H, OCH3), 6.71 (s, 1 H, 11-H), 7.00 (d, J=8.0 Hz, 4 H, 3’-H),
7.47 (d, J=8.0 Hz, 4 H, 2’-H), 7.91 (t, J=8.0 Hz, 2 H, 3-, 6-H), 7.99 (t, J=8.0 Hz, 2 H, 2-, 7-H), 8.53
(d, J=8.0 Hz, 2 H, 1-, 8-H), 8.99 (d, J=8.0 Hz, 2 H, 4-, 5-H).
12-Dodecylamino-10H-quino[2,3,4-kl]acridin-10-one (31a) and 10,12-Di(dodecylamino)quino-
[2,3,4-kl]acridine (31b):
24 (10 mg, 0.036 mmol) and dodecylamine (0.030 mL, 0.13 mmol) were stirred in ethanol (4 mL) at
50oC for 12 h. After evaporation of the ethanol, the two products were separated by silica gel
chromatography; elution with CHCl3/MeOH, 30:1, to afford the monoamination product (31a) (4 mg,
24%) and by elution with CHCl3/MeOH, 10:1, the diamination product (31b) which was further
purified on a Sephadex LH-20 column (eluting with CHCl3/MeOH/petroleum ether, 1:1:2) (4 mg,
+
+
~
18%). 31a: MS (EI); m/z: 465 (64) [M , C31H35N3O], 310 (100) [M - (CH2)10CH3]; IR: ν == 2923,
2852, 1610, 1561, 1466 cm-1; 1H-NMR (CDCl3): δ = 0.90 (t, J=7.5 Hz, 3 H, 12’-H), 1.35 (br m, 14 H,
5’-H - 11’-H), 1.46 (m, 2 H, 4’-H), 1.54 (quintet, J=7.5 Hz, 2 H, 3’-H), 1.91 (quintet, J=7.5 Hz, 2 H,
2’-H), 3.45 (m, 2 H, 1’-H), 6.25 (s, 1 H, 11-H), 7.63 (br s, 1 H, NH), 7.87 (t, J=8.0 Hz, 1 H, 3-H), 7.87
(t, J=8.0 Hz, 1 H, 6-H), 7.96 (t, J=8.0 Hz, 1 H, 2-H), 7.98 (t, J=8.0 Hz, 1 H, 7-H), 8.35 (d, J=8.0 Hz, 1
H, 1-H), 8.68 (d, J=8.0 Hz, 1 H, 8-H), 9.06 (d, J=8.0 Hz, 1 H, 5-H), 9.09 (d, J=8.0 Hz, 1 H, 4-H). 31b:
+
+
~
MS (EI); m/z: 630 (100) [(M- 2) , C43H58N4], 475 (33) [(M- 2) - (CH2)10CH3]; IR: ν == 2922, 2851,
1640, 1611, 1563, 1467, 1442, 1408 cm-1; H-NMR (CDCl3): δ = 0.85 (t, J=7.0 Hz, 6 H, 12’-H), 1.2
1
(br m, 28 H, 5’-H - 11’-H), 1.38 (m, 4 H, 4’-H), 1.55 (m, 4 H, 3’-H), 1.96 (m, 4 H, 2’-H), 3.91 (m, 4 H,
1’-H), 6.22 (s, 1 H, 11-H), 7.92 (t, J=8.0 Hz, 2 H, 3-, 6-H), 8.00 (t, J=8.0 Hz, 2 H, 2-, 7-H), 8.55 (d,
J=8.0 Hz, 2 H, 1-, 8-H), 8.99 (d, J=8.0 Hz, 2 H, 4-, 5-H), 9.83 (br s, 1 H, NH).

Molecules, 2001, 6
321
12-Amino-10H-quino[2,3,4-kl]acridin-10-one (32a):
The procedure of Couladouros [17] was adopted. To a solution of 24 (10 mg, 0.036 mmol) in
methanol (2 mL), under nitrogen, was added a solution of sodium azide (14 mg, 0.22 mmol) in water
(0.5 mL) and the solution was acidified to pH 4 with 1N HCl. After stirring at room temperture for 15
h. the reaction mixture was extracted with chloroform (2 x 10 mL) and the combined organic layer was
washed with water (20 ml) and evaporated to afford 32a (8 mg, 76%); HRMS calcd. for C19H11N3O
-1
[M+] 297.0902, found 297.0901; IR: ν == 3425, 1644, 1616, 1546, 1515 cm ; 1H-NMR
~
(CDCl3/CD3OD, 20:1): δ = 6.23 (s, 1 H, 11-H), 7.77 (t, J=8.0 Hz, 1 H, 3-H), 7.80 (t, J=8.0 Hz, 1 H, 6-
H), 7.86 (t, J=8.0 Hz, 1 H, 2-H), 7.89 (t, J=8.0 Hz, 1 H, 7-H), 8.20 (d, J=8.0 Hz, 1 H, 1-H), 8.49 (d,
J=8.0 Hz, 1 H, 8-H), 8.94 (d, J=8.0 Hz, 1 H, 5-H), 8.96 (d, J=8.0 Hz, 1 H, 4-H).
10,12(N,N)-Di(2-amino-1,3-propanediol)quino[2,3,4-kl]acridine (33b):
24 (10 mg, 0.036 mmol) and 2-amino-1,3-propanediol (serinol) (10 mg, 0.11 mmol) were reacted in
ethanol (5 mL) to afford 33b (8mg, 50%), by the procedure described for the synthesis and purification
+
~
of 30b. MS (FAB); m/z: 445 (100) [(M+1) , C25H25N4O4]; IR: ν == 3332, 1613, 1559, 1415, 1390,
1050 cm-1; H-NMR (CD3SOCD3): δ = 3.84 (m, 8 H, 2’-H), 4.45 (quintet, J=5.0 Hz, 2 H, 1’-H), 5.37
1
(t, J=5.0 Hz, 4 H, OH), 6.91 (s, 1 H, 11-H), 8.08 (t, J=7.5 Hz, 2 H, 3-, 6-H), 8.16 (t, J=7.5 Hz, 2 H, 2,
7-H), 8.47 (d, J=7.5 Hz, 2 H, 1-, 8-H), 9.28 (d, J=7.5 Hz, 2 H, 4-, 5-H).
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Sample availability: Samples not available.
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