Synthesis and crystal structure of 7,8-dihydroquinolino[2,3-a]acridine derivatives

Article abstract of DOI:10.1080/00397910802656042

Novel 9-amino-3-substituted-1,2,3,4-acridin-1-one derivatives and 9,14-diamino-7-substituted-7,8-dihydroquinolino[2,3-a]acridine derivatives were synthesized by the condensation reaction of 5-substituted-1,3-cyclohexanedione with 2-aminobenzonitrile and s

Full text of DOI:10.1080/00397910802656042

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Synthesis and Crystal Structure
of 7,8-Dihydroquinolino[2,3-
a]acridine Derivatives
Guang-Fan Han a , Rui-Hua Wang a , Wen-Tao Zhang a
, Yu-Yuan Zhao a , Zheng Xing a & Wei Dai a
a School of Material Science and Engineering,
Jiangsu University of Science and Technology,
Zhenjiang, Jiangsu, China
Available online: 16 Jun 2009
To cite this article: Guang-Fan Han, Rui-Hua Wang, Wen-Tao Zhang, Yu-Yuan
Zhao, Zheng Xing & Wei Dai (2009): Synthesis and Crystal Structure of 7,8-
Dihydroquinolino[2,3-a]acridine Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:14,
2492-2505
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Synthetic Communications1, 39: 2492–2505, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802656042
Synthesis and Crystal Structure of
7,8-Dihydroquinolino[2,3-a]acridine Derivatives
Guang-Fan Han, Rui-Hua Wang, Wen-Tao Zhang, Yu-Yuan Zhao,
Zheng Xing, and Wei Dai
School of Material Science and Engineering, Jiangsu University of Science
and Technology, Zhenjiang, Jiangsu, China
Abstract: Novel 9-amino-3-substituted-1,2,3,4-acridin-1-one derivatives and
9,14-diamino-7-substituted-7,8-dihydroquinolino[2,3-a]acridine derivatives were
synthesized by the condensation reaction of 5-substituted-1,3-cyclohexanedione
with 2-aminobenzonitrile and substituted 2-aminobenzonitrile using p-toluenesul-
fonic acid, K2CO3, and Cu2Cl2 as catalysts. The structures of all compounds were
characterized by elemental analysis, infrared, mass spectrometry, and 1H and 13
C
NMR spectra. The crystal and molecular structures of 6, 14-diamino-3,4,11,12-
tetramethoxy-7-phenyl-7,8-dihydroquinolino[2,3-a]acridine 5a have been deter-
mined by single-crystal x-ray diffraction analysis. The crystal of compound 5a
belongs to triclinic with space group P-1, a ¼ 1.06168(15) nm, b ¼ 1.16951(17)
nm, c ¼ 1.6020(2) nm, a ¼ 71.380(3)ꢀ, b ¼ 77.686(3)ꢀ, c ¼ 66.743(3)ꢀ, Z ¼ 2,
V ¼ 1.7231(4) nm3, R1 ¼ 0.1060, and wR2 ¼ 0.2192.
Keywords: Acridine derivative, anticancer activity, crystal structure,
5-substituted-1,3-cyclohexanedione, synthesis
The family of acridine derivatives is a class of the oldest bioactive
compounds, which were widely used as antibacterial and antimalarial
agents. The emergence of the penicillin eclipsed the acridines in antisepsis
because of their greater therapeutic efficacy than the former. However,
with the current rapid increase in drug-resistant bacterial infection, novel
Received September 28, 2008.
Address correspondence to Guang-Fan Han, School of Material Science and
Engineering, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu
212003, China. E-mail: gf552002@yahoo.com.cn
2492

Synthesis of Acridine Derivatives
2493
acridine derivatives may be of new use. A great amount of research and
development has been carried out on acridine derivatives.[1–7] In these
areas, recent study has been focused mainly on their function as antican-
cer drugs, because of the ability of the acridine chromophore to interca-
late DNA and inhibit topoisomerase emzyme, which further blocks the
pharmacological action of DNA-metabolizing proteins. These com-
pounds have attracted the interests of biochemists and chemists for 10
years because of the possibilities of their clinical use as intercalating drugs
to inhibit the synthesis of nucleic acids. Many types of drugs are known
to bind to DNA through intercalation between consecutive nucleotides in
the DNA strands.
This class of compounds includes several antitumor agents of clinical
importance such as actinomycin-D, daunomycin, and adriamycin.[8–10]
There has been considerable synthetic attention paid to the substi-
tuted aminoacridines.[11–13] The mode of binding of acridine molecules
involves intercalation of the acridine ring between adjacent base pairs
in the DNA duplex, and acridine moieties are held in place by van der
Waals force supplemented by stronger ionic bonds to the phosphate ions
of the DNA backbone. Herein we report the synthesis of the title
compounds. We hope that these novel acridine derivatives will be have
anticancer activities.
SYNTHESIS AND ANALYSIS OF SPECTRA
The synthetic pathway is shown in Scheme 1. The 5-substituted-1,3-cyclo-
hexanediones 1 were prepared as building block from aromatic aldehyde,
acetone, and dimethyl molanate. The intermediate enamines 2a–d were
obtained by condensation reaction of 5-substituted-1,3-cyclohexanedione
1 with 2-amino-4,5-dimethoxybenzonitrile and 2-aminobenzonitrile using
p-toluenesulfonic acid as a catalyst. 3-Substituted-9-amino-1,2,3,4-acridin-1-
one derivatives 3a–d were synthesized by cyclization of the intermediate
enamines 2a–d in the presence of K2CO3 and Cu2Cl2. The intermediate
enamines 4a–d were obtained by condensation reaction of 3-substituted-9-
amino-1,2,3,4-acridin-1-one derivatives 3a–d with 2-amino-4,5-dimethoxy-
benzonitrile and 2-aminobenzonitrile using p-toluenesulfonic acid as a
catalyst. The quinolino[2,3-a] acridine derivatives 5a–d of new form of
pentacyclic system were obtained by condensation reaction of compounds
3a–d with 4,5-dimethoxyanthranilonitrile and 2-aminobenzonitrile using
p-toluenesulfonic acid, K2CO3, and Cu2Cl2 as catalysts. The quinolino
[2,3-a]acridine derivatives 5a–d of a new form of pentacyclic system were
also synthesized by cyclization of the intermediate enamines 4a–d in the
presence of K2CO3 and Cu2Cl2.

2494
G.-F. Han et al.
Scheme 1. (a) TsOH; (b) K2CO3, Cu2Cl2; (c) TsOH; (d) K2CO3, Cu2Cl2; and (e)
TsOH, K2CO3, Cu2Cl2. (a) R ¼ ꢁOCH3; R1 ¼ phenyl, R2 ¼ H; (b) R ¼ ꢁOCH3;
R1 ¼ R2 ¼ CH3; (c) R ¼ H; R1 ¼ phenyl, R2 ¼ H; (d) R ¼ H; R1 ¼ R2 ¼ CH3.
The 1H NMR, 13C NMR, mass spectral (MS), and infrared (IR) data
shown in the experimental section are in accordance with the chemical
1
structures of the target compounds. In the H NMR spectrum of com-
pound 2, the broad single proton peaks at d 6.56 are the characteristic
absorption proton peaks of the amino group. The single peak at d 5.68
was the typical proton peak of the vinyl group. In the 1H NMR spectrum
of compound 3, the two broad single peaks at d 6.10 and d 10.25 were
observed. They disappeared after D2O exchange and therefore were
attributed to the two N–H of the amino group. Because of the existing
intramolecular hydrogen bond between one proton of the amino group
and the oxygen atom of the carbonyl group nearby, its proton peak
drifted to d 10.25.

Synthesis of Acridine Derivatives
2495
13C NMR signals for the individual sp, sp2, sp3 carbon in these
compounds were observed.
The structures of these compounds were further supported by their
IR spectra. Several typical absorption bands at 2240 cmꢁ1 for 2, 4
(CꢂN), 1730 cmꢁ1 for 3 (C¼O), and 3400 cmꢁ1 for (NꢁH) were observed
respectively.
CRYSTAL STRUCTURE
A summary of the crystal data and structure refinement is presented in
Table 1. A perspective view of compound 5a with atomic numbering
Table 1. Crystal parameters data collections and structure refinements for
compound 5a
Parameter
Value
Empirical formula
Formula weight
Temperature
C36H46N4O7
646.77
293(2) K
0.071073 nm
Triclinic
P ꢁ 1
Wavelength
Crystal system
Space group
Unit cell dimensions
a ¼ 1.06168(15) nm, a ¼ 71.380(3)ꢀ
b ¼ 1.16951(17) nm, b ¼ 77.686(3)ꢀ
c ¼ 1.6020(2) nm, c ¼ 66.743(3)ꢀ
1.7231(4) nm3
Volume
Z
Calculated density
Absorption coefficient
F(000)
2
1.247 mg=m3
0.087 mmꢁ1
692
Crystal size
H range for data collection
Limiting indices
0.511 ꢃ 0.495 ꢃ 0.278 mm
1.96ꢀ to 25.50ꢀ
ꢁ7 ꢄ h ꢄ 12, ꢁ14 ꢄ k ꢄ 14, ꢁ18 ꢄ l ꢄ 19
9109=6313 [R(int) ¼ 0.1508]
98.6%
Reflections collected=unique
Completeness to h ¼ 25.50
Absorption correction
Max. and min. transmission
Refinement method
Data=restraints=parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
Largest diff. peak and hole
Empirical
1.00000 and 0.50505
Full-matrix least-squares on F2
6313=2=479
0.953
R1 ¼ 0.0796, wR2 ¼ 0.1989
R1 ¼ 0.1060, wR2 ¼ 0.2192
477 and ꢁ496 e.nmꢁ3

2496
G.-F. Han et al.
Figure 1. ORTEP plot of compound 5a.
Figure 2. Packing diagram of compound 5a in unit cell.

Synthesis of Acridine Derivatives
2497
˚
Table 2. Inter- and intramolecular interaction distances (A) for the compound 5a
D–HꢅꢅꢅA
D–H
HꢅꢅꢅA
DꢅꢅꢅA
D–HꢅꢅꢅA
Symmetry
N(4)–H(4B)ꢅꢅꢅO(7)
O(6)–H(6)ꢅꢅꢅN(1)
N(2)–H(2B)ꢅꢅꢅN(3)
O(5)–H(5A)ꢅꢅꢅO(6)
0.8600
2.4700
1.90(4)
1.94(4)
1.85(2)
3.061(4)
2.761(4)
2.674(4)
2.716(4)
126.700
163(4)
141(3)
167(4)
x, y, z
x, y, z
x, y, z
x, y, z
0.88(4)
0.87(4)
0.877(19)
scheme is shown in Fig. 1. In compound 5a, the dihedral angle between
the bond lengths and bond angles are generally normal in the phenyl
and quinoline rings and the quinoline ring a [C(1), C(2), C(3), C(4),
C(5), C(6), C(7), C(8), C(9), N(1)] with plane equation ꢁ0.3657
x þ 0.8283 y ꢁ 0.4245 z ¼ 1.2900. The quinoline ring b [C(12), C(13),
C(14), C(15), C(16), C(17), C(18), C(19), C(20), N(3)] with plane equation
ꢁ0.1458x þ 0.9340y ꢁ 0.3263z ¼ 4.8766 is 15.114ꢀ. The benzene ring
[C(21), C(22), C(23), C(24), C(25), C(26)] is coplanar with the conjunction
C(11), whose plane equation is ꢁ0.3087x ꢁ 0.4115y ꢁ 0.8575z ¼ ꢁ7.0254.
The dihedral angles between the benzene ring and two quinoline ring
plane are 86.588ꢀ and 82.179ꢀ, respectively.
The packing diagram of the 5a in a unit cell is shown in Fig. 2. X-ray
analysis reveals that there exist intramolecular and intermolecular
hydrogen bonds in the crystal. The intermolecular hydrogen bonds
˚
N(4)ꢁH(4B)ꢅꢅꢅO(7) and O(6)ꢁH(6)ꢅꢅꢅN(1) are 3.061(4) and 2.761(4) A,
respectively, whereas the intramolecular hydrogen bond N(2)ꢁ
˚
H(2B)ꢅꢅꢅN(3) is 2.674(4) A. Moreover, the structural analysis indicates
that these molecular interactions play the role of further stabilizeing
the structure. The bond lengths and bond angles of primary hydrogen
bonds are listed in Table 2.
CONCLUSION
In summary, the condensation reaction of 5-substituted-1,3-cyclohexane-
dione with 2-aminobenzonitrile and substituted 2-aminobenzonitrile
using p-toluenesulfonic acid, K2CO3, and Cu2Cl2 as catalysts gave a
series of novel 9-amino-3-substituted-1,2,3,4-acridin-1-one derivatives
3a–d. We made the same condensation reaction again with compounds
3a–d, 2-aminobenzonitrile, and substituted 2-aminobenzonitrile, which
gave a series of quinolino[2,3-a] acridine derivatives 5a–d of a new form
of pentacyclic system. They would be expected to be useful anticancer
activity compounds.

2498
G.-F. Han et al.
EXPERIMENTAL
Melting points were determined on an electrothermal apparatus, and the
temperature was not calibrated. Microanalysis was performed by the
Perkin-Elmer 2400 Microanalytical Service, and elemental analysis for
C, H, and N were within ꢆ0.3% of the calculated value. IR spectra were
recorded as thin films on KBr using a Perkin-Elmer 1700 spectrophot-
ometer. The NMR spectra were recorded by a Bruker ARX-300 spectro-
meter. Sample solutions were prepared in CDCl3 containing
tetramethysilane (TMS) as an internal reference. Mass spectra were
recorded by JMS-DX300 at 70 eV.
All chemical reagents were commercially available and purified
with standard methods before use. Solvents were dried in routine ways
and redistilled. 5-Substituted-1,3-cyclo-hexanediones 1 were obtained
from aromatic aldehyde, acetone, and dimethyl molanate according to
the literature[14] method with slightly modification.
N-(5-Phenyl-3-oxo-cyclohexen-1-yl)-2-amino-4,5-dimethoxy
benzonitrile 2a
2-Amino-4,5-dimethoxybenzonitrile (8.9 g, 0.050 mol) and 5-phenyl-1,
3-cyclohexanedione 1a (9.4 g, 0.050 mol) were suspended in toluene
(100 mL) containing p-toluenesulfonic acid monohydrate (1 g,
0.005 mol). The mixture was refluxed for 6 h, and the water was collected
in a Dean–Stark water separator. At the end of the reaction, the reaction
mixture was chilled to room temperature, and the product was filtered
off. The yellow powder was recrystallized from ethanol to afford 13.5 g
of the title compound as yellow crystals in 77.6% yield. Mp 205–206ꢀC;
1H NMR (CDCl3, 500 MHz) d: 2.50–3.54 (m, 2H, 60-H), 2.88–2.90 (m,
2H, 40-H), 3.39–3.41 (m, 1H, 50-H), 3.86, 3.87 (each s, each 3H, 6H,
OMe-H), 5.41 (s, 1H, vinyl-H), 6.69 (br s, 1H, exchanges with D2O,
NH), 6.88 (s, 1H, Ph-H), 6.97 (s, 1H, Ph-H), 7.21–7.23 (m, 2H, Ph-H),
7.38–7.40 (m, 3H, Ph-H); 13C NMR (CDCl3, 125 MHz) d: 40.2, 41.6,
46.8, 56.2, 56.2 (5C, sp3-C), 99.9, 105.9, 110.1, 117.3, 126.7 (2C), 127.8,
128.0 (2C), 143.3, 146.6, 149.3, 154.4, 155.3, 160.3 (15C, sp þ sp2-C),
198.6 (1C, C¼O); IR (KBr) t: 3412, 2230, 1638, 1513 cmꢁ1. Anal.
calcd. for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04; found: C, 72.26; H,
5.68; N, 8.16.
The compound 2b was obtained from 2-amino-4,5-dimetho-
xybenzonitrile and 5,5-dimethy-1,3-cyclohexanedione in
manner.
a similar

Synthesis of Acridine Derivatives
2499
N-(5,5-Dimethy-3-oxo-cyclohexen-1-yl)-2-amino-4,5-
dimethoxybenzonitrile 2b
Yield: 78.6%; mp 192–194ꢀC; 1H NMR (CDCl3, 500 MHz) d: 1.13 (s, 6H,
Me-H), 2.48 (s, 2H, 60-H), 3.12 (s, 2H, 40-H), 3.87 (s, 3H, OMe-H), 3.97
(s, 3H, OMe-H), 5.27 (s, 1H, vinyl-H), 6.23 (br s, 1H, 1H, exchanges with
D2O, NH), 7.21 (s, 1H, ph-H), 7.51 (s, 1H, ph-H); IR (KBr) t: 3451,
2226, 1608, 1538 cmꢁ1; MS (70 eV) m=z (%): 301.3 (Mþ þ 1,100).
The compound 2c was obtained from 2-aminobenzonitrile and
5-phenyl-1,3-cyclohexanedione in a similar manner.
N-(5-Phenyl-3-oxo-cyclohexen-1-yl)-2-amino-benzonitrile 2c
Yield: 75%; mp 199–200ꢀC; 1H NMR (CDCl3, 500 MHz) d: 2.59–2.61 (m,
2H, 60-H), 2.66–2.68 (m, 1H, 40-H), 2.88 (m, 1H, 40-H), 3.42–3.43 (m, 1H,
50-H), 5.68 (s, 1H, vinyl-H), 6.56 (br s, 1H, exchanges with D2O, NH),
7.23–7.28 (m, 3H, Ph-H), 7.35–7.38 (m, 2H, Ph-H), 7.50–7.51 (m, 2H,
Ph-H), 7.57 (t, J ¼ 7.8 Hz, 1H, Ph-H), 7.64 (d, J ¼ 7.8 Hz, 1H, Ph-H);
13C NMR (CDCl3, 125 MHz) d: 37.3, 39.7, 43.4 (3C, sp3-C), 124.7,
125.6, 125.7, 126.7 (2C), 127.2, 128.7, 128.9 (2C), 133.4 (2C), 133.9
(2C), 140.9, 142.4 (15C, sp þ sp2-C), 197.5 (1C, C¼O); IR (KBr) t:
3450, 2225, 1639, 1529 cmꢁ1. Anal. calcd. for C19H16N2O: C, 79.14; H,
5.59; N, 9.72; found: C, 79.18; H, 5.65; N, 9.59.
The compound 2d was obtained from 2-aminobenzonitrile and
5,5-dimethy-1,3-cyclo-hexanedione in a similar manner.
N-(5,5-Dimethy-3-oxo-cyclohexen-1-yl)-2-aminobenzonitrile 2d
Yield: 86.5%; mp 210–212ꢀC; 1H NMR (CDCl3, 500 MHz) d: 1.17 (s, 6H,
Me-H), 2.58 (s, 2H, 60-H), 3.07 (s, 2H, 40-H), 5.49 (s, 1H, vinyl-H), 6.37
(br s, 1H, exchanges with D2O, NH), 7.52 (t, J ¼ 7.5 Hz, 1H, Ph-H), 7.77
(t, J ¼ 7.5 Hz, 1H, Ph-H), 7.86 (d, J ¼ 8.0 Hz, 1H, Ph-H), 7.93 (s, 1H,
Ph-H); IR (KBr) t: 3415, 2223, 1621, 1524 cmꢁ1; MS (70 eV) m=z (%):
241.3 (Mþ þ 1, 100).
9-Amino-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroacridin-1-one 3a
N-(5-Phenyl-3-oxo-cyclohexen-1-yl)-2-amino-4,5-dimethoxybenzonitrile
2a (10.44 g, 0.030 mol) was added to tetrahydrofuran (100 mL) containing
potassium carbonate (1.38 g, 0.010 mol) and cuprous chloride (0.45 g,

2500
G.-F. Han et al.
0.005 mol). The reaction mixture was refluxed for 12 h, and the hot
mixture was filtered into hexane (200 mL). The precipitated 3a was
filtered off and washed with water. The yellow powder was recrystallized
from ethanol to afford 6.2 g 3a as yellow crystals in 59.4% yield. Mp
1
221–222ꢀC; H NMR (CDCl3, 500 MHz) d: 2.94 (dd, J ¼ 16.9, 12.00 Hz,
1H, 4-H), 3.01 (dd, J ¼ 16.9, 4.3 Hz, 1H, 4-H), 3.28 (dd, J ¼ 16.1, 11.9 Hz,
1H, 2-H), 3.39 (dd, J ¼ 16.1, 3.9 Hz, 1H, 2-H), 3.53–3.54 (m, 1H, 3-H),
4.02 (s, 6H, OMe-H), 6.04 (br s, 1H, NH), 6.99 (s, 1H, Ph-H), 7.25 (s,
1H, Ph-H), 7.27 (d, J ¼ 7.8 Hz, 2H, Ph –H), 7.39 (t, J ¼ 7.8 Hz, 3H,
Ph-H), 10.15 (br s, 1H, exchanges with D2O, hydrogen bonded NH);
13C NMR (CDCl3, 125 MHz) d: 39.2, 41.7, 46.8, 56.2, 56.2 (5C, sp3-C),
99.8, 105.9, 108.7, 111.1, 126.7 (2C), 126.9, 128.8 (2C), 143.1, 145.6,
148.5, 153.1, 154.1, 161.3 (total 15C, sp2-C), 200.6 (1C, C¼O); IR
(KBr) t: 3423, 1742, 1607, 1519 cmꢁ1; MS (70 eV) m=z (%): 348 (100),
319 (18.37), 244 (15.11), 229 (10.90). Anal. calcd. for C21H20N2O3: C,
72.40; H, 5.79; N, 8.04; found: C, 72.34; H, 5.78; N, 8.08.
The other compounds 3b–d were obtained from enamines 2b–d in a
similar manner.
9-Amino-6,7-dimethoxy-3,3-dimethy-1,2,3,4-tetrahydroacridin-
1-one 3b
1
Yield: 70%; mp 196–198ꢀC; H NMR (CDCl3, 500 MHz) d: 1.10 (s, 6H,
Me-H), 2.54 (s, 2H, 4-H), 3.00 (s, 2H, 2-H), 3.97 (s, 3H, OMe-H), 4.07 (s,
3H, OMe-H), 6.36 (br s, 1H, NH2), 7.25 (s, 1H, 8-H), 7.42 (s, 1H, 5-H),
10.24 (br s, 1H, hydrogen bonded NH2); IR (KBr) t: 3451, 1732, 1608,
1538 cmꢁ1; MS (70 eV) m=z (%): 301.3 (Mþ þ 1, 100).
9-Amino-3-phenyl-1,2,3,4-tetrahydroacridin-1-one 3c
Yield: 75%; mp 212–213ꢀC; 1H NMR (CDCl3, 500 MHz) d: 2.92–2.93 (m,
2H, 4-H), 3.29–3.30 (m, 1H, 2-H), 3.43–3.44 (m, 1H, 2-H), 3.52–3.54 (m,
1H, 3-H), 6.10 (br s, 1H, NH2), 7.24–7.36 (m, 5H, Ph-H), 7.42 (t,
J ¼ 8.3 Hz, 1H, Ph-H), 7.70 (t, J ¼ 8.3 Hz, 1H, Ph-H), 7.82 (d, J ¼ 8.3 Hz,
1H, Ph-H), 7.86 (d, J ¼ 8.3 Hz, 1H, Ph-H), 10.25 (br s, 1H, exchanges
with D2O, hydrogen bonded NH2); 13C NMR (CDCl3, 125 MHz) d: 39.0,
41.8, 46.8 (3C, sp3-C), 106.0, 117.6, 120.9, 125.0, 126.7 (2C), 126.9, 128.8
(2C), 129.3, 132.2, 143.0, 148.4, 154.3, 162.8 (total 15C, sp2-C), 200.7 (1C,
C¼O); IR (KBr) t: 3489, 1732, 1616, 1516 cmꢁ1; MS (70 eV) m=z (%):
289.3 (Mþ þ 1, 100), 273 (85), 195 (12), 154 (98). Anal. calcd. for
C19H16N2O: C, 79.14; H, 5.59; N, 9.72; found: C, 78.98; H, 5.58; N 9.64.

Synthesis of Acridine Derivatives
2501
9-Amino-3,3-dimethy-1,2,3,4-tetrahydroacridin-1-one 3d
1
Yield: 78%; mp 226–227ꢀC; H NMR (CDCl3, 500 MHz) d: 1.15 (s, 6H,
Me-H), 2.60 (s, 2H, 4-H), 3.05 (s, 2H, 2-H), 5.23 (br s, 1H, NH2), 7.49 (t,
J ¼ 7.5 Hz, 1H, Ph-H), 7.75 (t, J ¼ 7.5 Hz, 1H, Ph-H), 7.85 (d, J ¼ 8.3 Hz,
1H, Ph-H), 7.96 (s, 1H, Ph-H), 10.25 (br s, 1H, NH2); IR (KBr) t: 3415,
1721, 1584, 15411 cmꢁ1; MS (70 eV) m=z (%): 241.3 (Mþ þ 1, 100).
N-(4,5-Dimethoxybenzo-2-nitrile)-1,9-diamino-3-phenyl-
1,2,3,4-tetrahydroacridine 4a
9-Amino-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroacridin-1-one 3a (6.96 g,
0.020 mol) and 2-amino-4,5-dimethoxybenzonitrile (3.56 g, 0.020 mol)
were added to toluene (100 mL) containing p-toluenesulfonic acid mono-
hydrate (1 g, 0.005 mol). The mixture was refluxed for 6 h, and the water
was collected in a Dean–Stark water separator. At the end of the reac-
tion, the reaction mixture was chilled to room temperature, and the pro-
duct was filtered off. The yellow powder was recrystallized from ethanol
to afford 5.54 g of the title compound as yellow crystals in 54.5% yield.
1
Mp > 300ꢀC; H NMR (CDCl3, 500 MHz) d: 2.45 (d, J ¼ 15.0 Hz, 2H,
4-H), 3.27 (d, J ¼ 15.0 Hz, 2H, 2-H), 3.35 (dd, J ¼ 15.0, 6.0 Hz, 1H,
3-H), 3.79, 3.81, 3.89, 3.91 (each s, each 3H, 12H, OMe-H), 6.27 (br s,
1H, NH2), 7.01–7.12 (m, 5H, Ph-H), 7.18 (s, 1H, 8-H), 7.25 (s, 1H,
30-H), 7.61 (s, 1H, 5-H), 7.71 (s, 1H, 60-H), 10.09 (br s, 1H, NH2); IR
(KBr) t: 3468, 2226, 1607, 1503 cmꢁ1; MS m=z (%): 509.4 (Mþ þ 1,
100), 349.3 (25). Anal. calcd. for C30H28N4O4: C, 70.85; H, 5.55; N,
11.02; found: C, 70.68; H, 5.49; N, 11.13.
The compound 4b was obtained from 3b and 2-amino-4,5-dimethox-
ybenzonitrile in a similar manner.
N-(4,5-Dimethoxybenzo-2-nitrile)-1,9-diamino-6,7-dimethoxy-
3,3-dimethy-1,2,3,4-tetrahydroacridine 4b
1
Yield: 65.5%; mp 220–221ꢀC; H NMR (DMSO, 500 MHz) d: 0.98 (s,
6H, Me-H), 2.46 (s, 2H, 4-H), 2.83 (s, 2H, 2-H), 3.84 (each s, each 3H,
12H, OMe-H), 6.67 (br s, 1H, NH2), 7.14 (s, 1H, 5-H), 7.36 (s, 1H,
30-H), 7.68 (s, 1H, 8-H), 8.18 (s, 1H, 60-H), 10.52 (br s, 1H, NH2); IR
(KBr) t: 3423, 2224, 1610, 1501 cmꢁ1; MS (70 eV) m=z (%): 461.2
(Mþ þ 1, 100).
The other compound 4c were obtained from 3c and 2-aminobenzoni-
trile in a similar manner.

2502
G.-F. Han et al.
N-(2-Benzonitrile)-1,9-diamino-3-phenyl-1,2,3,4-tetrahydroacridine 4c
1
Yield: 71.2%; mp > 300ꢀC; H NMR (CD3OD, 500 MHz) d: 2.84 (dd,
J ¼ 8.30 Hz, 1H, 4-H), 2.97 (d, J ¼ 21.1 Hz, 1H, 4-H), 3.47 (m, 3H,
2-H þ 3-H), 6.28 (br s, 1H, NH2), 6.98 (d, J ¼ 8.0 Hz, 1H, 3-Ph-H),
7.19 (t, J ¼ 7.6 Hz, 1H, 3-Ph-H), 7.27 (m, 3H, 3-Ph-H), 7.37 (t, J ¼ 7.5 Hz,
2H, 40-H þ 50-H), 7.49 (t, J ¼ 7.20 Hz, 1H, 5-H), 7.57 (t, J ¼ 7.80 Hz, 1H,
6-H), 7.68 (d, J ¼ 7.8 Hz, 1H, 7-H), 7.74 (t, J ¼ 7.7 Hz, 1H, 60-H), 7.88 (d,
J ¼ 8.3 Hz, 1H, 8-H), 7.92 (d, J ¼ 8.8 Hz, 1H, 30-H), 10.86 (br s, 1H,
NH2); IR (KBr) t: 3466, 2223, 1615, 1506 cmꢁ1; MS (70 eV) m=z (%):
389.3 (Mþ þ 1, 100).
The compound 4d was obtained from 3d and 2-aminobenzonitrile in
a similar manner.
N-(2-Benzonitrile)-1,9-diamino-3,3-dimethy-1,2,3,4-tetrahydroacridine 4d
1
Yield: 63%; mp 256–258ꢀC; H NMR (CDCl3, 500 MHz) d: 1.08 (s, 6H,
Me-H), 2.46 (s, 2H, 4-H), 3.04 (s, 2H, 2-H), 6.15 (br s, 1H, NH2), 6.96 (d,
J ¼ 8.1 Hz, 1H, 40-H), 7.23 (t, J ¼ 18.7 Hz, 1H, 8-H), 7.47 (d, J ¼ 7.6 Hz,
1H, 60-H), 7.62 (t, J ¼ 7.7 Hz, 1H, 6-H), 7.72 (t, J ¼ 6.6 Hz, 2H,
7-H þ 5-H), 7.87 (d, J ¼ 8.3 Hz, 1H, 50-H), 7.95 (d, J ¼ 8.0 Hz, 1ꢁH1,
30-H), 10.92 (br s, 1H, NH2); IR (KBr) t: 3455, 2223, 1602, 1501 cm
MS (70 eV) m=z (%): 341.3 (Mþ þ 1, 100).
;
6,14-Diamino-3,4,11,12-tetramethoxy-7-phenyl-
7,8-dihydroquinolino[2,3-a]acridine 5a
9-Amino-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroacridin-1-one
3a
(6.96 g, 0.020 mol) and 2-amino-4,5-dimethoxybenzonitrile (3.6 g,
0.020 mol) were added to toluene (100 mL) containing p-toluenesulfonic
acid monohydrate (1 g, 0.005 mol). The mixture was refluxed for 6 h,
and the water was collected in a Dean–Stark water separator. K2CO3
(0.7 g, 0.005 mol) and Cu2Cl2 (0.45 g, 0.005 mol) were added to the mix-
ture. The reaction mixture was refluxed for 12 h and was chilled to room
temperature. The precipitated 5a was filtered off and washed with water.
The yellow powder was recrystallized from ethanol to afford 5.5 g of 5a in
1
54.1% yield. Mp 202–203ꢀC; H NMR (CDCl3, 500 MHz) d: 3.35 (d,
J ¼ 15.0 Hz, 1H, 8-H), 3.47 (dd, J ¼ 15.0, 6.0 Hz, 1H, 7-H), 3.82, 3.88,
3.90, 3.94 (each s, each 3H, 12H, OMe-H), 4.64 (s, 1H, 8-H), 6.01 (br
s, 1H, NH2), 6.57 (br s, 2H, NH2), 7.00–7.15 (m, 5H, Ph-H), 7.00
(s, 1H, 13-H), 7.22 (s, 1H, 5-H), 7.53 (s, 1H, 10-H), 7.56 (s, 1H, 2-H),

Synthesis of Acridine Derivatives
2503
11.08 (br s, 1H, hydrogen bonded NH2); IR (KBr) t: 3468, 1607,
1503 cmꢁ1; MS m=z (%): 509.4 (Mþ þ 1, 100), 349.3 (25), Anal. calcd.
for C30H28N4O4: C, 70.85; H, 5.55; N, 11.02; found: C, 70.68; H, 5.49;
N, 11.13.
The compound 5b were obtained from 3b and 2-amino-4,5-dimethoxy-
benzonitrile in a similar manner.
6,14-Diamino-3,4,11,12-tetramethoxy-7,7-dimethy-7,8-dihydroquinolino
[2,3-a]acridine 5b
1
Yield: 51.2%; mp > 300ꢀC; H NMR (DMSO, 500 MHz) d: 1.26 (s, 6H,
Me-H), 3.01 (s, 2H, 8-H), 3.96 (each s, each 3H, 12H, OMe-H), 6.27
(br s, 2H, NH2), 6.93 (br s, 1H, NH2), 7.29 (s, 1H ,13-H), 7.46 (s, 1H,
5-H), 7.75 (s, 1H, 10-H), 8.20 (s, 1H, 2-H), 10.91 (br s, 1H, hydrogen
bonded NH2); IR (KBr) t: 3422, 1610, 1505 cmꢁ1; MS (70 eV) m=z
(%): 461.2 (Mþ þ 1, 100).
The compound 5c were obtained from 3c and 2-aminobenzonitrile in
a similar manner.
6,14-Diamino-7-phenyl-7,8-dihydroquinolino[2,3-a]acridine 5c
1
Yield: 53.2%; mp 250–252ꢀC; H NMR (DMSO, 500 MHz) d: 3.51 (d,
J ¼ 16.5 Hz, 1H, 8-H), 3.75 (dd, J ¼ 6.5 Hz, 15.7 Hz, 1H, 7-H), 4.83 (s,
1H, 8-H), 6.23 (br s, 2H, NH2), 6.79 (br s, 1H, NH2), 7.09–7.17 (m,
5H, 3-Ph-H), 7.50 (t, J ¼ 6.7 Hz, 1H, 4-H), 7.64 (d, J ¼ 6.7 Hz, 1H,
12-H), 7.68 (d, J ¼ 10 Hz, 1H, 11-H), 7.71 (d, J ¼ 6.7 Hz, 1H, 10-H),
7.85 (t, J ¼ 6.7 Hz, 1H, 3-H), 7.96 (d, J ¼ 8.0 Hz, 1H, 2-H), 8.11 (d,
J ¼ 8.1 Hz, 1H, 9-H), 8.41 (d, J ¼ 8.4 Hz, 1H, 5-H), 10.67 (br s, 1H,
hydrogen bonded NH2); IR (KBr) t: 3452, 1603, 1502 cmꢁ1; MS
(70 eV) m=z (%): 389.3 (Mþ þ 1,100).
The compound 5d was obtained from 3d and 2-aminobenzonitrile in
a similar manner.
6,14-Diamino-7,7-dimethy-7,8-dihydroquinolino[2,3-a]acridine 5d
1
Yield: 58.5%; mp > 300ꢀC; H NMR (DMSO, 500 MHz) d: 2.50 (s, 6H,
Me-H), 3.16 (s, 2H, 8-H), 6.61 (br s, 2H, NH2), 7.02 (br s, 1H, NH2),
7.48 (d, J ¼ 7.0 Hz, 1H , 4-H), 7.69 (d, J ¼ 7.5 Hz, 1H, 11-H), 7.72 (d,
J ¼ 8.0 Hz, 1H, 2-H), 7.85 (d, J ¼ 4.5 Hz, 1H, 12-H), 7.87 (d, J ¼ 8.5 Hz,
1H, 11-H), 7.95 (t, J ¼ 8.0 Hz, 1H, 13-H), 8.35 (d, J ¼ 7.5 Hz, 1H, 3-H),

2504
G.-F. Han et al.
8.64 (d, J ¼ 7.5 Hz, 1H, 5-H), 12.96 (br s, 1H, hydrogen bonded NH2);
IR (KBr) t: 3431, 1612, 1511 cmꢁ1; MS (70 eV) m=z (%): 341.3
(Mþ þ 1, 100).
Determination of Crystal Structure
A yellowish transparent crystal 0.511 mmꢃ 0.495 mm ꢃ 0.278 mm was
selected for the crystal structure measurements. The x-ray diffraction inten-
sities were recorded by a Bruker Smart 1000 CCD automatic diffractometer
with graphite-monochromatized Mo Ka radiation (k ¼ 0.071073 nm) at
293(2) K. In the range of 1.96 <h < 25.50, 6313 independent reflections were
obtained. The structures were solved by direct methods using the
SHELXL-97 program. All the nonhydrogen atoms were refined on F2
anisotropically with the full-matrix least squares method. Hydrogen atoms
were added according to the theoretical methods. The final convergence
indices were R1 ¼ 0.1060, wR2 ¼ 0.2192 (w ¼ 1=[S2 ðF02Þ þ (0.1186P)2], and
P ¼ ðF02 þ 2F02Þ=3, S ¼ 0.953. The maximum and the minimum difference
peak holes were 477 and ꢁ496 e=nm3 respectively.
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