Efficient method for the synthesis of benzimidazoquinazoline derivatives with three-point diversity

Article abstract of DOI:10.1080/00397910701489453

An efficient strategy for the preparation of a novel heterocyclic ring system of benzimidazoquinazolines with three-point diversity has been described. The compounds were obtained by treating o-phenylene diamines with o-nitrobenzaldehyde to give benzimidazoles, followed by reduction of the nitro group to give an amine. Derivatization of the resulting amine with isothiocyanates followed by in situ cyclodesulfurization at rt furnished the title compounds in high yields and purities. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701489453

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Efficient Method for the Synthesis of
Benzimidazoquinazoline Derivatives with
Three‐Point Diversity
Biswajit Saha a , Sunil Sharma a & Bijoy Kundu a
a Medicinal Chemistry Division, Central Drug Research Institute, Lucknow,
India
Version of record first published: 05 Oct 2007
To cite this article: Biswajit Saha, Sunil Sharma & Bijoy Kundu (2007): Efficient Method for the Synthesis of
Benzimidazoquinazoline Derivatives with Three‐Point Diversity , Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 37:19, 3455-3470
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Synthetic Communicationsw, 37: 3455–3470, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701489453
Efficient Method for the Synthesis of
Benzimidazoquinazoline Derivatives with
Three-Point Diversity
Biswajit Saha, Sunil Sharma, and Bijoy Kundu
Medicinal Chemistry Division, Central Drug Research Institute,
Lucknow, India
Abstract: An efficient strategy for the preparation of a novel heterocyclic ring system
of benzimidazoquinazolines with three-point diversity has been described. The
compounds were obtained by treating o-phenylene diamines with o-nitrobenzaldehyde
to give benzimidazoles, followed by reduction of the nitro group to give an amine.
Derivatization of the resulting amine with isothiocyanates followed by in situ cyclode-
sulfurization at rt furnished the title compounds in high yields and purities.
Keywords: benzimidazoquinazoline, o-phenylene diamines, prototropic tautomerism,
quinazoline ring
INTRODUCTION
The quinazoline skeleton, when selectively functionalized, is a building block
for the preparation of numerous alkaloids[1] and substances capable of exhibit-
ing a wide spectrum of biological activities, ranging from anticancer[2] and
anticonvulsant[3] to antidiabetic activities.[4] Quinazolines are also among
the most potent of the protein kinase inhibitors that compete for binding at
the ATP site.[5] As part of our continuing effort[6–9] to develop new strategies
for synthesizing nitrogen-rich heterocyclic compounds based on quinazolines,
we required compounds based on benzimidazoquinazolines (I). We argued
Received February 15, 2007
CDRI Communication No. 7150.
Address correspondence to Bijoy Kundu, Medicinal Chemistry Division, Central
Drug Research Institute, Lucknow 226 001, India. E-mail: bijoy_kundu@yahoo.com
3455

3456
B. Saha, S. Sharma, and B. Kundu
Figure 1. Structures of the two clinically used drugs based on imidazoquinazolines.
that because two of the imidazoquinazoline-based drugs, anagrelide[10] and
quazinone[11] (Fig. 1) are used clinically as antithrombotic and cardiotonic
agents, benzoannelated derivatives would furnish novel privileged structures
for generating new leads against variety of biological targets. Benzoannelation
is a well-known method for the diversification of heterocycles of biological
value.[12] Methods of I involved treatment of 6-mercaptobenzimidazo-quina-
zoline with amines[13] and aza-Wittig reaction of iminophosphoranes derived
from 2-(o-azido) phenyl benzimidazole with isocyanates.[14] We directed our
efforts toward the development of a novel strategy that would avoid the
reliance of iminophosphoranes in favor of cyclodesulfurization from
thioureas.
We proposed to realize this by fusing the benzimidazole moiety with the
quinazoline ring. For our target structure I, the most efficient route would
employ condensation of 2-(1H-benzoimidazol-2-yl)-phenylamine (2) with
isothiocyanates (Fig. 2). Intermediate 2 can be obtained from the correspond-
ing nitro derivative 3, and the latter can be obtained by the literature procedure
for benzimidazole formation.[15] In this communication, we report a versatile
method for the synthesis of benzimidazoquinazolines (I) using o-phenylene
diamines, o-nitrobenzaldehyde, and isothiocyanates.
Figure 2. Retrosynthetic pathway for the synthesis of benzoimidazoquinazolines (I).

Benzimidazoquinazoline Derivatives
RESULTS AND DISCUSSION
3457
The synthesis of benzimidazoquinazolines I is outlined in Scheme 1. The
synthesis commenced with the preparation of five o-phenylene diamines
5(a–e) by reducing the corresponding o-nitroaniline derivatives 4(a–e) via
hydrogenation in the presence of Pd/C in methanol. The o-phenylene
diamines 5 were then subjected to two sequential cyclizations to give the
title compounds. Initially, intermediates 5 were treated with o-nitrobenzale-
hyde in DMF in the presence of oxonew to give benzimidazole 6.[15] The
nitro groups in 6 were then reduced to NH2 by catalytic hydrogenation to
give 7. This was followed by a second cyclization wherein intermediates
7 were treated with isothiocyanates to give benzimidazoquinazolines I via
cyclodesulfurization of thioureas generated in situ. Initially, we effected the
cyclodesulfurization by carrying out the reaction in either dichloromethane
(DCM) or N,N-dimethylformamide (DMF) both at rt and at high temperature;
however, the title compounds I were obtained in poor yields (Table 1). We
then effected cyclodesulfurization by using HgCl2, which is one of the most
widely used reagents for this purpose.[16] The best results were obtained
when the reaction was carried out in two steps. Initially, 7 was treated with
isothiocyanates for 2 h at rt in DMSO, then HgCl2 was added in situ for the
cyclodesulfurization of the resulting thiourea (8). The method worked
equally well with both aryl and alkyl isothiocyanates.
The scope and limitation of our strategy for I was established by using
structurally diverse isothiocyanates and o-nitrobenzadehydes. The final
Scheme 1. Reagents and conditions: a) 10% Pd/C, MeOH, H2 30 psi, 2 h, rt;
b) o-nitrobenzaldehyde, DMF, oxone, 2 h, rt; c) 10% Pd-C, MeOH, H2 30 psi, 2 h,
rt; d) aryl/benzyl isothiocyanate, DMSO, rt, 2 h, then HgCl2, 2 h.

3458
Table 1. Formation of I from 7
B. Saha, S. Sharma, and B. Kundu
Reaction condition
I
7 þ Benzyl isothiocyanate, DCM, rt, 12 h
7 þ Benzyl isothiocyanate DCM, 408C, 12 h
7 þ Benzyl isothiocyanate DMF, rt, 12 h
7 þ Benzyl isothiocyanate DMF, 808C, 24 h
No product
No product
30%
65%
7 þ Benzyl isothiocyanate DMSO, rt, HgCl2, 4 h
77%
92%
7 þ Benzyl isothiocyanate DMSO, rt, 2 h, then HgCl2 2 h
compounds (Table 2) were obtained in greater than 85% purity, and after puri-
fication on column chromatography were characterized using electron spray
ionization mass spectroscopy (ESMS) and NMR. Interestingly, the title
compounds I derived from o-phenylene diamines with unsymmetrical substi-
tution (4c, 4d, and 4e) exhibited two peaks of equal intensities on high per-
formance liquid chromatography (HPLC) with a difference in the retention
time of less than a minute, and the NMR data exhibited signals for two sets
of compounds. The spectroscopic data for products obtained as isomeric
mixtures are presented as such, and no attempts were made to separate
them. A similar phenomenon was also observed for intermediates 6c, 6d,
and 6e derived from o-phenylene diamines with unsymmetrical substitution
(4c, 4d, and 4e). However, after the conversion of nitro groups in 6 to
amines 7 by catalytic hydrogenation, HPLC and NMR confirmed the
presence of a single compound. Prototropic tautomerism[17] is well known
in imidazoles, arising because of the rapid exchange of protons between
N-1 and N-3. Presence of the two tautomeric forms in intermediates 6
derived from unsymmetrical o-phenylene diamines can be attributed to the
strong intramolecular hydrogen bonding between the NH and the oxygen
atom of the nitro group, thereby resulting in a mixture of two distinct
compounds (Fig. 3) in about equal quantities. These two forms are indistin-
guishable on a thin-layer chromatography (TLC) plate, but with the use of
HPLC they can be resolved as two distinct compounds. By NMR, we were
able to observe two sets of signals for each proton, thereby suggesting slow
interconversion of tautomers. However, intermediates 7 derived from unsym-
metrical o-phenylene diamines showed the existence of a single compound
both by HPLC and NMR due to the rapid prototropic tautomerism between
N-1 and N-3. Furthermore, when the NH2 and NH of 2-(1H-benzoimidazol-
2-yl)-phenylamine 7 derived from unsymmetrical o-phenylene diamines 4c,
4d, and 4e gets involved in cyclization with phenylisothiocyanates to
furnish I, the blockade of prototropy resulted in a mixture of two distinct
compounds in about equal quantities (Fig. 4). Attempts to separate the two
isomers by column chromatography were not successful. NMR exhibited
two sets of signals for protons arising from two isomers. In contrast, benzimi-
dazoquinazolines (I) obtained from o-phenylenediamines with symmetrical

Table 2. Physicochemical characteristics of compounds based on I
Number Comp. number R1
R2
n
R3
ESMS (Mþ þ 1) HPLCa tR (min)b Yield (%) Purityc (%)
1
2
Ia
Ib
Ic
Id
Ie
If
H 4,5 di-OCH3
4,5 di -CH3 4,5 di-OCH3
1
1
0
1
1
1
1
1
1
1
0
2
1
0
0
1
H
4-F
385.07
431.33
373.93
355.73
339.13
352.20
373.00
413.00
387.20
381.07
353.20
367.20
373.93
414.00
385.33
418.67
18.14
14.51
82
77
72
84
72
88
80
79
82
77
84
73
74
82
78
87
92
88
90
85
87
91
86
85
90
86
87
88
86
89
87
91
3
2-CH3
4-OCH3
4-CH3
5-Cl
H
4- CH3
H
15.20, 15.41
15.82, 6.24
14.70, 14.80
18.16
4
5
H
H
6
4,5 di -CH3
4-CH3
4,5 di -CH3 4,5 di-OCH3
H
H
4-Cl
7
Ig
Ih
Ii
H
16.91, 17.0
14.97
18.16
8
H
4-Cl
9
4,5 di -CH3
4-di -CH3
4,5 di -CH3
4,5 di -CH3
2-CH3
H
H
10
11
12
13
14
15
16
Ij
H
2,6-di-C2H5
4-CH3
H
15.9, 16.0
18.89
20.77
Ik
Il
H
H
5 -Cl
Im
In
Io
Ip
H
14.7, 14.9
15.35
17.78
4,5 di-OCH3
4,5 di-OCH3
4,5 di-OCH3
3-COCH3
2-CH3
4-Cl
H
H
19.24
aC18 reverse phase column (250 ꢀ 4.6 mm; 10 mm) with a linear gradient 10–100% CH3CN in water over 30 min, flow rate 1.0 mL/min and UV
detection 220/254 nm.
bRetention time on HPLC.
cPurity of crude products based on RP-HPLC chromatograms.

3460
B. Saha, S. Sharma, and B. Kundu
Figure 3. Structures of prototropic tautomers in intermediate 6c.
Figure 4. HPLC of two isomers for benzimidazoquinazolines Id derived from
unsymmetrical o-phenylene diamine.
substitutions (4b) or without any substitution (4a) exhibited a single peak on
HPLC despite the blockade of prototropy. The two isomers, although not
identical, appear to behave as a single compound.
CONCLUSION
In summary, we have developed a versatile approach for the synthesis of ben-
zimidazoquinazolines with three-point diversity from o-phenylene diamines
in excellent yields and purities. The limitation of our methodology is that
the title compounds I derived from o-phenylene diamines with unsymmetrical
substitution(s) will give rise to two isomers approximately in equal quantities
and may be difficult to separate by column chromatography.
EXPERIMENTAL
General
Melting points are uncorrected and were determined in capillary tubes on a
hot-stage apparatus containing silicon oil. IR spectra were recorded using a
Perkin-Elmer RX I FTIR spectrophotometer. 1H NMR and 13C NMR
spectra were recorded on either a 300- or 200-MHz FT spectrometer,
using TMS as an internal standard (chemical shifts in d values, J in
Hertz). The ESMS was recorded through direct flow injections in a
Merck M-8000 LCMS system. Elemental analyses were performed on a

Benzimidazoquinazoline Derivatives
3461
Carlo Erba 1108 microanalyzer or Elementar’s Vario EL III microanalyzer.
RP-HPLC analysis of products was carried out on Agilent liquid chromato-
graph using a 5-mm, 4.8- ꢀ 150-mm C-18 reverse-phase column with a
linear gradient of 10–100% acetonitrile in water (v/v) having 0.05%
TFA over 30 min. The flow rate was 1.0 mL/min, and UV detection was
observed at 220/254 nm.
Synthesis of 2-(2-Nitro-phenyl)-1H-benzimidazoles, Representative
Procedure
To the methanolic solution of compound 4b (1.00 g, 6.01 mmol), 200 mg of
10% Pd/C was added under a nitrogen atmosphere. The atmosphere of the
vessel was replaced by hydrogen gas. The reaction was carried out on a
Parr assembly at 30 psi at rt. After completion of the reaction, the
reaction mixture was filtered over a pad of Celitew and the solvent was con-
centrated under reduced pressure to obtain solid 5b. To a solution of 5b
(500 mg, 3.67 mmol) in DMF, 6-nitro 3,4-dimethoxy nitrobelzaldehyde
(852 mg, 4.03 mmol, 1.1 equiv) was added followed by Oxonew
(1353.7 mg, 2.20 mmol, 0.65 equiv). The mixture was stirred for 2 h at rt
and then added dropwise with vigorous stirring into a mixture of K2CO3
(1M, 10 mL) and H2O (100 mL). The precipitate was extracted into
EtOAc, and the extract was washed successively with H2O and brine.
After drying over Na2SO4, the solvent was evaporated under reduced
pressure to give a brown solid residue. This residue, upon column chrom-
atography over silica gel (100–200 mesh) using chloroform as eluent,
furnished compound 6b as a yellow solid.
Data
2-(4,5-Dimethoxy-2-nitro-phenyl)-1H-benzim-idazole (6a): Yield 86%;
yellow solid; mp 149–1518C; IR nmax (KBr) 1523 (NO2), 3421 (br, NH)
cm21
;
1H NMR (300 MHz, DMSO-d6) d ¼ 3.93 (s, 3H, OCH3), 3.94
(s, 3H, OCH3), 7.18–7.27 (m, 2H, J ¼ 8.1 Hz, ArH), 7.41 (s, 1H, ArH),
7.54 (d, 1H, J ¼ 7.5 Hz, ArH), 7.64 (d, 1H, J ¼ 9.0 Hz, ArH), 7.67 (s, 1H,
ArH). 13C NMR (50.3 MHz, DMSO-d6) d ¼ 56.7, 56.8, 79.5, 108.4, 111.7,
113.6, 119.0, 119. 3, 122.1, 123.0, 134.9, 142.0, 143.8, 148.5, 152.0. Mass
(ES þ ) m/z 300.12 (Mþ þ 1). Anal. calcd. for C15H13N3O4: C, 60.20; H,
4.38; N, 14.04. Found: C, 60.45; H, 4.49; N, 14.51.
2-(4,5-Dimethoxy-2-nitro-phenyl)-5,6-dimethyl-1H-benzim-idazole (6b):
Yield 82%; yellow solid; mp 165–1678C; IR nmax (KBr) 1521 (NO2),
3395 (br, NH) cm21
;
1H NMR (300 MHz, DMSO-d6) d ¼ 2.31 (s, 6H,
2 ꢀ CH3), 3.91 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 7.34 (s, 2H, ArH), 7.37

3462
B. Saha, S. Sharma, and B. Kundu
(s, 1H, ArH), 7.62 (s, 1H, ArH). Mass (ES þ ) m/z 328.32 (Mþ þ 1). Anal.
calcd. for C17H17N3O4: C, 62.38; H, 5.23; N, 12.84. Found: C, 62.51; H,
5.12; N, 13.02.
5-Methoxy-2-(2-nitro-phenyl)-1H-benzimidazole and 6-methoxy-2-(2-
nitro-phenyl)-1H-benzimidazole (6d): Yield 85%; yellow solid; mp
1
155–1578C; IR nmax (KBr) 1527 (NO2), 3429 (br, NH) cm21; H NMR
(300 MHz, DMSO-d6) d ¼ 3.78 (s, 3H, OCH3), 3.81 (s, 3 H, OCH3),
6.82–6.90 (m, 2 H, ArH), 7.01 (s, 1H. ArH), 7.18 (s, 1H. ArH), 7.43
(d, 1H, J ¼ 8.7 Hz, ArH), 7.53 (d, 1H, J ¼ 8.7 Hz, ArH), 7.71 (t, 2H,
J ¼ 7.5 Hz, ArH), 7.83 (t, 2 H, J ¼ 7.5 Hz, ArH), 7.93–7.99 (overlapped,
4H, ArH). Mass (ES þ ) m/z 270.24 (Mþ þ 1). Anal. calcd. for
C14H11N3O3: C, 62.45; H, 4.12; N, 15.61. Found: C, 62.40; H, 4.49; N,
15.36.
5-Methyl-2-(2-nitro-phenyl)-1H-benzimidazole and 6-methyl-2-(2-nitro-
phenyl)-1H-benzimidazole (6e): Yield 82%; yellow solid; mp 145–1478C;
IR nmax (KBr) 1525 (NO2), 3435 (br, NH) cm21 1H NMR (300 MHz,
;
DMSO-d6) d ¼ 2.29 (s, 3H, CH3), 2.35 (s, 3H, CH3), 6.34 (m, 2H, ArH),
6.44–6.89 (overlapped, 5H, ArH), 7.02–7.24 (overlapped, 5H, ArH), 7.30
(d, 1H, J ¼ 7.5 Hz, ArH), 7.33 (d, 1H, J ¼ 7.5 Hz, ArH). Mass (ES þ ) m/z
254.27 (Mþ þ 1). Anal. calcd. for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59.
Found: C, 66.79; H, 4.49; N, 16.36.
5,6-Dimethyl-2-(2-nitro-phenyl)-1H-benzim-idazole (6f): Yield 87%;
yellow solid; mp 175–1778C; IR nmax (KBr) 1523 (NO2), 3452 (br, NH)
cm21
;
1H NMR (300 MHz, DMSO-d6) d ¼ 2.31 (s, 3H, CH3), 2.34
(s, 3H, CH3), 7.32 (s, 1H, ArH), 7.42 (s, 1H, ArH), 7.71 (t, 1H, J ¼ 7.5
Hz, ArH), 7.83 (t, 1H, J ¼ 7.5 Hz ArH), 7.94 (d, 1H, J ¼ 9.0 Hz, ArH),
7.98 (d, 1 H, J ¼ 8.7 Hz ArH); 13C NMR (50.3 MHz, DMSO) d ¼ 20.3,
97.5, 111.9, 119.5, 124.5, 124.7, 130.8, 131.0, 132.2, 132.7, 133.6, 142.8,
146.6, 149.3. Mass (ES þ ) m/z 268.21 (Mþ þ 1). Anal. calcd. for
C15H13N3O2: C, 67.40; H, 4.90; N, 15.72. Found: C, 67.22; H, 4.81; N,
15.60.
Synthesis of 2-(1H-benzimidazol-2-yl)-phenyl-amines from 2-(2-
nitro-phenyl)-1H-benzimidazoles, Representative Procedure
To the methanolic solution of compounds 6b (500 mg, 1.52 mmol), 100 mg of
10% Pd/C was added under a nitrogen atmosphere. The atmosphere of the
vessel was replaced by hydrogen gas. The reaction was carried out on a
Parr assembly at 30 psi at rt. After completion, the reaction mixture was
w
filtered over a bed of Celite, and the solvent was concentrated under
reduced pressure to obtain solid 7b as a pure product.

Benzimidazoquinazoline Derivatives
Data
3463
2-(1H-Benzimidazol-2-yl)-4,5-dimethoxy-phenyl-amine (7a): Yield 96%;
1
yellow solid; mp 155–1578C; IR nmax (KBr) 3423 (br, NH) cm21; H NMR
(300 MHz, DMSO-d6) d ¼ 3.78 (s, 3H, OCH3), 3.82 (s, 3 H, OCH3), 6.45
(s, 1H, NH), 7.16 (t, 1H, J ¼ 7.5 Hz, ArH), 7.32–7.34 (m, 2H, ArH), 7.58
(s, 1H, ArH), 7.66 (d, 1H, J ¼ 7.2 Hz, ArH), 7.85 (d, 1H, J ¼ 7.2 Hz, ArH).
Mass (ES þ ) m/z 270.26 (Mþ þ 1). Anal. calcd. for C15H15N3O2: C, 66.90;
H, 5.61; N, 15.60. Found: C, 66.45; H, 5.49; N, 15.36.
2-(5,6-Dimethyl-1H-benzimidazol-2-yl)-4,5-dimethoxy-phenylamine (7b):
Yield 93%; pale yellow solid; mp 140–1428C; IR nmax (KBr) 3450 (br, NH)
cm21; 1H NMR (300 MHz, DMSO-d6) d ¼ 2.50 (s, 6 H, 2 ꢀ CH3), 3.94 (s, 6
H, 2 ꢀ OCH3), 6.62 (s, 1 H, ArH), 7.47 (s, 1H. ArH), 7.57 (s, 2H. ArH). Mass
(ES þ ) m/z 298.29 (Mþ þ 1). Anal. calcd. for C17H19N3O2: C, 68.67; H,
6.44; N, 14.13. Found: C, 68.63; H, 6.32; N, 13.96.
2-(6-Methoxy-1H-benzimidazol-2-yl)-phenylamine (7d): Yield 95%; pale
yellow solid; mp 145–1478C; IR nmax (KBr) 3448 (br, NH) cm21; 1H NMR
(300 MHz, DMSO-d6) d ¼ 3.86 (s, 3 H, OCH3), 6.74 (t, 1H, J ¼ 7.5 Hz,
ArH), 6.81 (d, 1H, J ¼ 8.1 Hz, ArH), 6.90 (d, 1H, J ¼ 8.7 Hz, ArH), 7.07
(s, 1H, ArH), 7.20 (t, 1H, J ¼ 7.5 Hz. ArH), 7.50 (d, 2H, J ¼ 7.8 Hz, ArH).
Mass (ES þ ) m/z 240.11 (Mþ þ 1). Anal. calcd. for C14H13N3O: C, 70.28;
H, 5.48; N, 17.56. Found: C, 69.93; H, 5.51; N, 17.36.
2-(6-Methyl-1H-benzimidazol-2-yl)-phenylamine (7e): Yield 87%; pale
yellow solid; mp 157–1588C; IR nmax (KBr) 3450 (br, NH) cm21; 1H NMR
(300 MHz, DMSO-d6) d ¼ 2.20 (s, 3H, CH3), 6.12 (m, 2H, ArH), 6.33
(t, 2H, J ¼ 7.5 Hz, ArH), 6.54–6.89 (m, 2H, ArH), 7.16 (d, 1H. J ¼ 7.5 Hz,
ArH). Mass (ES þ ) m/z 224.29 (Mþ þ 1). Anal. calcd. for C14H13N3: C,
75.31; H, 5.87; N, 18.82. Found: C, 75.45; H, 6.09; N, 18.96.
2-(5,6-Dimethyl-1H-benzimidazol-2-yl)-phenylamine (7f): Yield 93%; pale
yellow solid; mp 135–1378C; IR nmax (KBr) 3370 (br, NH) cm21; 1H NMR (300
MHz, DMSO-d6) d ¼ 3.60 (s, 6 H, 2 ꢀ CH3), 7.98 (t, 1 H, J ¼ 7.5 Hz, ArH), 8.14
(d, 1H, J ¼ 8.1 Hz, ArH), 8.50 (t, 1H, J ¼ 7.5 Hz, ArH), 8.69 (s, 2H, ArH), 8.97
(d, 1H, J ¼ 7.8 Hz, ArH). Mass (ES þ ) m/z 238.23 (Mþ þ 1). Anal. calcd. for
C15H15N3: C, 75.92; H, 6.37; N, 17.71. Found: C, 76.01; H, 6.79; N, 17.35.
Synthesis of Imidazoquinazoline from 2-(1H-Benzimidazol-2-yl)-
phenylamines, Representative Procedure
To a solution of 7b (250 mg, 0.84 mmol) in dry DMSO (5 mL), 4-fluorobenzy-
lisothiocyanate (230 mL, 1.68 mmol) was added. The mixture was stirred at rt for

3464
B. Saha, S. Sharma, and B. Kundu
2 h. Next, triethylamine (91 mL, 0.66 mmol) and HgCl2 (90 mg, 0.33mmol) was
added to the reaction mixture and again stirred for 1 h. The mixture was then
treated with EtOAc (5 mL) and stirred for an additional 5 min. After this, the
mixture was poured in cold water, followed by addition of more EtOAc
w
(100 mL). The resulting mixture was filtered through a bed of Celite, and the
organic layer was separated and washed with water. The organic layer was
dried over Na2SO4 and evaporated to obtain a solid residue. The residue upon
column chromatography over silica gel (100 mesh) using hexane–ethylacetate
(80:20, v/v) as the eluent furnished compound Ib as off-white solid.
Data
Benzyl-(2,3-dimethoxy-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-amine
(Ia): Yield 82%; off-white solid; mp 222–2258C; IR nmax (KBr) 3423 (br,
1
NH) cm21; H NMR (300 MHz, CDCl3) d ¼ 4.02 (s, 3H, OCH3), 4.04
(s, 3H, OCH3), 4.93 (d, 2H, J ¼ 8.7 Hz, CH2), 5.47 (s, 1H, NH), 7.13
(s, 1H, ArH), 7.25–7.37 (m, 2H. ArH), 7.39–7.46 (m, 3H, ArH), 7.52
(t, 2H, J ¼ 7.5 Hz, ArH), 7.73 (d, 1H, J ¼ 8.1 Hz, ArH), 7.87 (s, 1H, ArH),
7.96 (d, 1 H, J ¼ 8.1 Hz, ArH); 13C NMR (50.3 MHz, CDCl3 þ TFA)
d ¼ 47.1, 56.7, 56.9, 101.4, 102.9, 106.6, 114.3, 114.9, 124.0, 125.7, 126.3,
128.4, 128.7, 129.3, 129.5, 131.9, 136.9, 143.6, 145.3, 149.5, 158.2. Mass
(ES þ ) m/z 385.07 (Mþ þ 1). Anal. calcd. for C23H20N4O2: C, 71.86; H,
5.24; N, 14.57. Found: C, 71.58; H, 5.49; N, 14.36.
(2,3-Dimethoxy-9,10-dimethyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-
(4-fluoro-benzyl)-amine (Ib): Yield 77%; off-white solid; mp 258–2608C;
1
IR nmax (KBr) 3403 (br, NH) cm21; H NMR (300 MHz, CDCl3) d ¼ 2.38
(s, 3H, CH3) 2.40 (s, 3H, CH3), 4.02 (s, 3H, OCH3), 4.04 (s, 3H, OCH3),
4.92 (d, 2H, J ¼ 4.8 Hz, CH2), 5.50 (s, 1H, NH), 7.10 (t, 3H, J ¼ 7.8 Hz,
ArH), 7.47 (s, 1H. ArH), 7.52 (t, 2H, J ¼ 6.0 Hz, ArH), 7.69 (s, 1H, ArH),
7.84 (s, 1H, ArH); 13C NMR (75.4 MHz, CDCl3 þ TFA) d ¼ 20.4,
20.7, 45.4, 56.1, 56.3, 103.8, 106.7, 108.3, 112.4, 115.5, 115.8, 119.6,
126.2, 129.5, 129.6, 131.1, 134.3, 139.6, 142.9, 144.5, 147.1, 148.3, 152.9,
160.7, 163.9. Mass (ES þ ) m/z 431.33 (Mþ þ 1). Anal. calcd. for
C25H23FN4O2: C, 69.75; H, 5.39; N, 13.02. Found: C, 69.73; H, 5.21; N,
13.21.
(2-Chloro-8-methyl-benzo[4,5]imidazo[1,2-c] quinazolin-6-yl)-p-tolyl-
amine and (2-chloro-11-methyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-
yl)-phenyl-amine (Ic): Yield 72%; yellow solid; mp 247–2498C; IR
1
n
max(KBr) 3460 (NH) cm21; H NMR (300 MHz, CDCl3) d ¼ 2.35 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 2.77 (s, 3H, CH3), 2.83 (s, 3H, CH3), 7.02
(d, 2H, J ¼ 7.8 Hz, ArH), 7.13 (d, 1H, J ¼ 8.7 Hz, ArH), 7.24 (d, 4H,
J ¼ 8.7 Hz, ArH), 7.34–7.38 (overlapped, 4H, ArH), 7.51–7.57 (m, 2H,

Benzimidazoquinazoline Derivatives
3465
ArH), 7.63 (d, 2 H, J ¼ 8.1 Hz, ArH), 7.76 (s, 1H, ArH), 7.90 (s, 1H, ArH),
8.42 (d, 1H, ArH), 8.56 (d, 2H, J ¼ 5.4 Hz, ArH); 13C NMR (75.4 MHz,
CDCl3 þ TFA) d ¼ 16.2, 16.5, 20.3, 110.8, 112.7, 113.6, 114.3, 116.2,
116.8, 117.2, 121.2, 121.6, 122.2, 122.7, 123.2, 123.5, 124.6, 125.2, 126.0,
126.8, 127.2, 128.4, 129.8, 130.7, 130.9, 131.1, 131.5, 131.9, 133.1, 135.0,
135.4, 137.8, 141.5, 142.9, 143.5, 144.4, 146.7. Mass (ES þ ) m/z 372.93
(Mþ þ 1). Anal. calcd. for C22H17ClN4: C, 70.87; H, 4.60; N, 15.03. Found:
C, 70.45; H, 4.49; N, 15.26.
Benzyl-(9-methoxy-benzo[4,5]imidazo[1,2-c]quin- azolin-6-yl)-amine and
benzyl-(10-methoxy-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-amine (Id):
Yield 84%; pale yellow solid; mp 145–1478C; IR nmax (KBr) 3408
1
(br, NH) cm21; H NMR (300 MHz, CDCl3) d ¼ 3.84 (s, 3 H, OCH3), 3.89
(s, 3H, OCH3), 4.96–5.47 (m, 4H, 2 x CH2), 5.49 (s, 2H, 2 ꢀ NH), 6.96
(dd, 1H, J ¼ 1.8 Hz, J ¼ 9.0 Hz, ArH), 7.13 (d, 1H, J ¼ 9.0 Hz, ArH),
7.26 (overlapped, 1H, ArH), 7.33–7.44 (m, 9H, ArH), 7.53 (d, 4H, J ¼ 7.5
Hz, ArH), 7.66 (m, 5H, ArH), 7.88 (d, 1H, J ¼ 9.0 Hz, ArH), 8.49
(t, 2H, J ¼ 9.0 Hz, ArH) 13C NMR (75.4 MHz, CDCl3) d ¼ 46.3, 55.6,
55.9, 97.8, 112.2, 112.4, 112.7, 120.3, 122.1, 123.8, 124.0, 125.5, 127.3,
127.9, 128.0, 128.1, 128.5, 128.9, 131.4, 131.6, 138.0, 143.8, 144.1, 144.8,
145.1, 149.6, 155.9, 157.8. Mass (ES þ ) m/z 355.73 (Mþ þ 1). Anal. calcd.
for C22H18N4O: C, 74.56; H, 5.12; N, 15.81. Found: C, 74.52; H, 5.23; N,
15.73.
Benzyl-(9-methyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-amine and
benzyl-(10-methyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-amine (Ie):
Yield 72%; white solid; mp 227–2298C; IR nmax (KBr) 3438 (br, NH)
cm21
;
1H NMR (300 MHz, CDCl3) d ¼ 2.55 (s, 6H, 2 ꢀ CH3), 4.99
(m, 4 H, 2 ꢀ CH2), 5.54 (s, 1H, NH), 5.64 (s, 1H, NH), 7.21–7.36 (over-
lapped, 9H, ArH), 7.39–7.42 (m, 5H, ArH), 7.53 (d, 3H, J ¼ 7.2 Hz, ArH),
7.62–7.70 (m, 4H, ArH), 7.78 (s, 1H, ArH), 8.54 (d, 2H, J ¼ 8.1 Hz, ArH).
Mass (ES þ ) m/z 339.13 (Mþ þ 1). Anal. calcd. for C22H18N4: C, 78.08;
H, 5.36; N, 16.56. Found: C, 78.28; H, 5.49; N, 16.36.
Benzyl-(9,10-dimethyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-amine (If):
Yield 88%; off-white solid; mp 240–2428C, IR nmax (KBr) 3370 (br, NH)
1
cm21; H NMR (300 MHz, CDCl3 þ TFA) d ¼ 2.48 (s, 3H, CH3), 2.51
(s, 3H, CH3), 5.13 (s, 2H, CH2), 7.27 (s, 1H, ArH), 7.49 (overlapped, 3
H, ArH), 7.72–7.80 (m, 4 H, ArH), 7.86 (d, 1 H, J ¼ 8.4 Hz, ArH), 8.03
(t, 1H, J ¼ 7.8 Hz, ArH), 8.48 (d, 1H, J ¼ 8.1 Hz, ArH); 13C NMR (75.4
MHz, CDCl3 þ TFA) d ¼ 20.3, 20.8, 46.8, 107.0, 112.1, 113.2, 114.0,
114.9, 117.0, 124.4, 126.2, 126.6, 127.5, 128.4, 128.6, 129.2, 130.2,
136.6, 137.1, 140.0, 145.3. Mass (ES þ ) m/z 353.20 (Mþ þ 1). Anal.
calcd. for C23H20N4: C, 78.38; H, 5.72; N, 15.90. Found: C, 78.49; H,
5.49; N, 15.97.

3466
B. Saha, S. Sharma, and B. Kundu
(4-Chloro-benzyl)-(9-methyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-
amine and (4-Chloro-benzyl)-(10-methyl-benzo[4,5]imidazo[1,2-c]quina-
zolin-6-yl)-amine (Ig): Yield 80%; pale yellow solid; mp 239–2418C; IR
1
nmax (KBr) 3442 (br, NH) cm21; H NMR (300 MHz, CDCl3) d ¼ 2.54
(s, 3H, CH3), 2.55 (s, 3H, CH3), 4.96 (m, 4H, CH2), 5.63 (brs, 1H, NH),
5.65 (brs, 1H, NH), 7.18 (d, 1H, J ¼ 8.4 Hz, ArH), 7.33–7.42 (m, 7H,
ArH), 7.47 (d, 2H, J ¼ 3.0 Hz, ArH), 7.50 (d, 2H, J ¼ 3.0 Hz, ArH), 7.56
(s, 1H, ArH), 7.65 (m, 5H, ArH), 7.78 (s, 1H, ArH), 7.89 (d, 1H, J ¼ 5.4
Hz, ArH), 8.52 (d, 2H, J ¼ 4.8 Hz, ArH). Mass (ES þ ) m/z 373.00
(Mþ þ 1). Anal. calcd. for C22H17ClN4: C, 70.87; H, 4.60; N, 15.03. Found:
C, 70.98; H, 4.49; N, 15.16.
Benzyl-(2,3-dimethoxy-9,10-dimethyl-benzo[4,5]imidazo[2,1-a]isoquinolin-
6-yl)-amine (Ih): Yield 79%; pale yellow solid; mp 213–2158C; IR nmax(KBr)
3427 (br, NH) cm21; 1H NMR (300 MHz, CDCl3) d ¼ 2.40 (s, 6H, 2 ꢀ CH3),
4.03 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 4.98 (d, 2H, J ¼ 5.4 Hz, CH2), 5.63
(brs, 1H, NH), 7.12 (s, 1H, ArH), 7.29–7.43 (m, 3H, ArH), 7.54 (d, 2H, J ¼ 3.9
Hz, ArH), 7.57 (s, 1H, ArH), 7.69 (s, 1H, ArH), 7.87 (s, 1H, ArH). Mass (ES þ )
m/z 413.00 (Mþ þ 1). Anal. calcd. for C25H24N4O2: C, 72.79; H, 5.86; N, 13.58.
Found: C, 72.89; H, 5.49; N, 13.78.
(4-Chloro-benzyl)-(9,10-dimethyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-
yl)-amine (Ii): Yield 82%; light brown solid; mp 258–2608C; IR nmax (KBr)
3450 (br, NH) cm21; 1H NMR (300 MHz, CDCl3) d ¼ 2.44 (s, 3 H, CH3), 2.47
(s, 3H, CH3), 4.76 (d, 2H, J ¼ 6.0 Hz, CH2), 6.48 (br, 1H, NH), 7.28–7.42
(overlapped, 4H, ArH), 7.51 (d, 1H, J ¼ 8.4 Hz, ArH), 7.57 (d, 2H, J ¼ 8.7
Hz, ArH), 7.72 (s, 1H, ArH), 7.83 (s, 1H, ArH), 8.48 (d, 1H, J ¼ 7.8 Hz,
ArH). Mass (ES þ ) m/z 387.20 (Mþ þ 1). Anal. calcd. for C23H19ClN4: C,
71.40; H, 4.95; N, 14.48. Found: C, 71.25; H, 4.67; N, 14.06.
(2,6-Diethyl-phenyl)-(9-methyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-
amine and (2,6-diethyl-phenyl)-(10-methyl-benzo[4,5]imidazo[1,2-c]qui-
nazolin-6-yl)-amine (Ij): Yield 77%; white solid; mp 268–2708C; IR nmax
1
(KBr) 3424 (br, NH) cm21; H NMR (300 MHz, CDCl3) d ¼ 1.26 (s, 6H,
2 ꢀ CH3), 1.34 (s, 3H, CH3), 1.51 (s, 3H, CH3), 2.53 (s, 6H, 2 ꢀ CH3),
4.08–4.15 (m, 8H, 4 ꢀ CH2), 6.89 (d, 2H, J ¼ 8.1 Hz, ArH), 7.05 (over-
lapped, 3H, ArH), 7.10–7.29 (overlapped, 7H, ArH), 7.41 (t, 2H, J ¼ 4.5
Hz, ArH), 7.70 (s, 1H. ArH), 7.79 (d, 1H, J ¼ 7.8 Hz, ArH), 8.41 (d, 2H,
J ¼ 7.5 Hz, ArH), 8.63 (d, 1H, J ¼ 5.1 Hz, ArH), 8.66 (d, 1H, J ¼ 7.2 Hz,
ArH). Mass (ES þ ) m/z 381.07 (Mþ þ 1). Anal. calcd. for C25H24N4: C,
78.92; H, 6.36; N, 14.73. Found: C, 78.80; H, 6.46; N, 14.98.
(9,10-Dimethyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-p-tolyl-amine (Ik):
Yield 87%; off-white solid; mp 250–2528C; IR nmax (KBr) 3420 (br, NH)
1
cm21; H NMR (300 MHz, CDCl3 þ TFA) d ¼ 2.34 (s, 3H, CH3), 2.47

Benzimidazoquinazoline Derivatives
3467
(s, 3H, CH3), 2.51(s, 3H, CH3), 7.18-7.36 (m, 4H, ArH), 7.47 (d, 1H, J ¼ 7.8
Hz, ArH), 7.57 (t, 1H, J ¼ 7.8 Hz, ArH), 7.73 (d, 1H, J ¼ 10.8 Hz, ArH), 7.80
(t, 1H, J ¼ 7.5 Hz, ArH), 8.20 (s, 1H, ArH), 8.50 (d, 1H, J ¼ 8.1 Hz, ArH).
Mass (ES þ ) m/z 353.20 (Mþ þ 1). Anal. calcd. for C23H20N4: C, 78.38;
H, 5.72; N, 15.90. Found: C, 78.45; H, 5.49; 15.66.
(9,10-Dimethyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-phenethyl-amine
(Il): Yield 82%; off-white solid; mp 240–2428C; IR nmax (KBr) 3431 (br, NH)
cm21; 1H NMR (300 MHz, CDCl3 þ TFA) d ¼ 2.19 (s, 6H, 2 ꢀ CH3), 3.20 (t, 2
H, J ¼ 6.0 Hz, CH2), 4.12 (t, 2H, J ¼ 6.0 Hz, CH2), 7.13 (s, 1H, ArH), 7.29–
7.39 (m, 5 H, ArH), 7.51 (s, 2H, ArH), 7.75 (d, 1H, J ¼ 8.1 Hz, ArH), 7.86
(t, 1H, J ¼ 7.5 Hz, ArH), 8.39 (d, 1H, J ¼ 4.8 Hz, ArH); 13C NMR (75.4
MHz, CDCl3 þ TFA) d ¼ 20.2, 20.3, 35.1, 44.0, 108.2, 114.1, 114.3, 123.4,
124.7, 125.8, 126.2, 127.0, 129.1, 129.7, 136.0, 136.2, 138.7, 138.9, 143.4,
144.9, 146.0, 161.1, 161.6. Mass (ES þ ) m/z 367.20 (Mþ þ 1). Anal. calcd.
for C24H22N4: C, 78.66; H, 6.05; N, 15.29. Found: C, 78.87; H, 6.39; N, 15.58.
Benzyl-(2-chloro-8-methyl-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-amine
and benzyl-(2-chloro-11-methyl-benzo[4,5]imidazo[1,2-c] quinazolin-6-
yl)-amine (Im): Yield 74%; off-white solid; mp 247–2498C; IRnmax (KBr)
3448 (br, NH) cm21
;
1H NMR (300 MHz, CDCl3) d ¼ 2.82 (s, 6H,
2 ꢀ CH3); 4.96 (d, 4H, J ¼ 6.0 Hz, 2 ꢀ CH2), 5.65 (s, 2H, 2 ꢀ NH), 7.25–
7.29 (overlapped, 3H, ArH), 7.30–7.42 (m, 5H, ArH), 7.43–7.47 (overlapped,
3H, ArH), 7.51–7.54 (overlapped, 4H, ArH), 7.57–7.59 (overlapped, 5H,
ArH), 8.58 (s, 2H, ArH); 13C NMR (75.4 MHz, CDCl3 þ TFA) d ¼ 17.3,
29.9, 46.5, 109.7, 117.0, 123.2, 123.8, 126.0, 127.1, 127.7, 128.2, 128.3,
129.2, 129.5, 131.1, 132.1, 138.0, 142.7, 145.0, 147.5. Mass (ES þ ) m/z
372.93 (Mþ þ 1). Anal. calcd. for C22H17ClN4: C, 70.87; H, 4.60; N, 15.03.
Found: C, 70.67; H, 4.70; N, 15.19.
1-[3-(2,3-Dimethoxy-benzo[4,5]imidazo[1,2-c]quinazolin-6-ylamino)-
phenyl]-ethanone (In): Yield 82%; yellow solid; mp 257–2598C; IRnmax
1
(KBr) 3448 (br, NH) cm21. H NMR (300 MHz, CDCl3 þ TFA) d ¼ 2.63
(s, 3H, CH3), 4.03 (s, 6H, 2 ꢀ OCH3), 7.13 (s, 1H, ArH), 7.65–7.73
(m, 2H. ArH), 7.80 (d, 2H, J ¼ 7.8 Hz, ArH); 7.88–7.99 (m, 3H, ArH); 8.13
(s, 1H, ArH); 8.39 (d, 1H, J ¼ 8.4 Hz, ArH); 13C NMR (75.4 MHz,
CDCl3 þ TFA) d ¼ 26.8, 55.6, 56.7, 100.8, 102.8, 104.9, 113.5, 114.1, 116.2,
117.3, 121.2, 125.4, 126.0, 126.4, 126.9, 128.9, 130.1, 131.4, 138.0, 140.1,
144.9, 149.2, 200.3. Mass (ES þ ) m/z 414.00 (Mþ þ 1). Anal. calcd.s for
C24H20N4O3: C, 69.89; H, 4.89; N, 13.58. Found: C, 69.45; H, 4.49; N, 13.96.
(2,3-Dimethoxy-benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-o-tolyl-amine
(Io): Yield 78%; yellow solid; mp 242–2448C; IR nmax (KBr) 3440 (br, NH)
cm21; 1H NMR (300 MHz, CDCl3 þ TFA) d ¼ 2.40 (s, 3H, CH3), 4.00 (s, 3H,
OCH3), 4.03 (s, 3H, OCH3), 7.06 (s, 1H, ArH), 7.33–7.45 (m, 3H, ArH), 7.68

3468
B. Saha, S. Sharma, and B. Kundu
(t, 1H, J ¼ 7.5 Hz, ArH), 7.65–7.91 (m, 3H, ArH), 8.01 (d, 1H, J ¼ 8.1 Hz,
ArH), 8.27 (d, 1H, J ¼ 8.4 Hz, ArH); 13C NMR (75.4 MHz, CDCl3 þ TFA)
d ¼ 18.3, 56.6, 56.7, 97.5, 103.6, 113.8, 114.1, 114.4, 116.2, 117.7, 118.4,
126.0, 126.2, 126.9, 127.3, 128.9, 131.5, 131.8, 134.5, 145.2, 148.6, 157.5.
Mass (ES þ ) m/z 385.33 (Mþ þ 1). Anal. calcd. for C23H20N4O2: C, 71.86;
H, 5.24; N, 14.57. Found: C, 71.59; H, 5.39; N, 14.37.
(4-Chloro-benzyl)-(2,3-dimethoxy-benzo[4,5]imidazo[1,2-c]quinazolin-6-
yl)-amine (Ip): Yield 87%; pale yellow solid; mp 237–2398C; IR (KBr) 3423
1
(br, NH) cm21. H NMR (300 MHz, CDCl3) d ¼ 4.02 (s, 3H, OCH3), 4.05
(s, 3H, OCH3), 4.91 (d, 2H, J ¼ 5.4 Hz, CH2), 5.49 (brs, 1H, NH), 7.11
(s, 1H, ArH), 7.31–7.40 (m, 3H. ArH), 7.46–7.54 (m, 3H, ArH), 7.76
(d, 1H, J ¼ 8.7 Hz, ArH), 7.88 (s, 1H, ArH), 7.96 (d, 1H, J ¼ 7.8 Hz,
ArH); 13C NMR (75.4 MHz, CDCl3 þ TFA) d ¼ 46.0, 56.3, 56.6, 101.0,
102.5, 106.1, 112.9, 113.9, 114.6, 116.7, 125.4, 126.1, 129.2, 129.4, 131.5,
134.3, 134.9, 143.0, 143.3, 145.0, 149.3, 157.9. Mass (ES þ ) m/z 418.67
(Mþ þ 1). Anal. calcd. for C23H19ClN4O2: C, 65.95; H, 4.57; N, 13.38.
Found: C, 65.79; H, 4.49; N, 13.76.
ACKNOWLEDGMENT
B. Saha and S. Sharma are grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial support.
REFERENCES
1. Michael, P. J. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2005,
22, 627–646.
2. (a) Ciardiello, F. Epidermal growth factor receptor tyrosine kinase inhibitors as
anti-cancer agents. Drugs 2000, 60 (suppl. 1), 25–32; (b) Tsou, H. R.;
Mamuya, N.; Johnson, B. D.; Reich, M. F.; Gruber, B. C.; Ye, F.;
Nilakantan, R.; Shen, R.; Discafani, C.; DeBlanc, R.; Davis, R.; Koehn, F. E.;
Greenberger, L. M.; Wang, Y. F.; Wissner, A. 6-Substituted-4-(3-bromophenyl-
amino)quinazolines as putative irreversible inhibitors of the epidermal growth
factor receptor (EGFR) aand human epidermal growth factor receptor (HER-2)
tyrosine kinases with enhanced antitumor activity. J. Med. Chem. 2001, 44,
2719–2734; (c) Smaill, J. B.; Rewcastle, G. W.; Loo, J. A.; Greis, K. D.;
Chan, O. H.; Reyner, E. L.; Lipka, E.; Showalter, H. D.; Vincent, P. W.;
Elliott, W. L.; Denny, W. A. Tyrosine kinase inhibitors. 17. Irreversible inhibitors
of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phe-
nylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing
functions. J. Med. Chem. 2000, 43, 1380–1397.
3. Mannschreck, A.; Koller, H.; Stuhler, G.; Davies, M. A.; Traber, J. The enantio-
mers of methaqualone and their unequal anticonvulsive activity. Eur. J. Med.
Chem. 1984, 19, 381–383.

Benzimidazoquinazoline Derivatives
3469
4. Molamas, M. S.; Miller, J. Quinazolineacetic acids and related analogs as aldose
reductase inhibitors. J. Med. Chem. 1991, 34, 1492–1503.
5. (a) Fry, D. W. Protein tyrosine kinases as therapeutic targets in cancer chemother-
apy and recent advances in the development of new inhibitors. Expert Opin. Invest.
Drugs 1994, 3, 577–595; (b) Gibson, K. H.; Grundy, W.; Godfrey, A. A.;
Woodburn, J. R.; Asthon, S. E.; Curry, B. J.; Scarlett, L.; Barker, A. J.;
Brown, D. S. Epidermal growth factor receptor tyrosine kinase: Structure-
activity relationships and antitumour activity of novel quinazolines. Bioorg.
Med. Chem. Lett. 1997, 7, 2723–2728; (c) Myers, M. R.; Setzer, N. N.;
Spada, A. P.; Zulli, A. L.; Hsu, C. Y. J.; Zilberstein, A.; Johnson, S. E.;
Hook, L. E.; Jacoski, M. V. The preparation and SAR of 4-(anilino),
4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56lck and EGF-R
tyrosine kinase activity. Bioorg. Med. Chem. Lett. 1997, 7, 417–420.
6. (a) Grover, R.; Kesarwani, A. P.; Srivastava, G. K.; Kundu, B.; Roy, R. Base
catalyzed intramolecular transamidation of 2-aminoquinazoline derivatives on
solid phase. Tetrahedron 2005, 61, 5011–5018; (b) Kesarwani, A. P.;
Grover, R.; Roy, R.; Kundu, B. Solid-phase synthesis of imidazoquinazolinone
derivatives with three-point diversity. Tetrahedron 2005, 61, 629–635.
7. Srivastava, G. K.; Kesarwani, A. P.; Grover, R. K.; Srinivasan, T.; Roy, R.;
Kundu, B. Solid phase synthesis of 2-aminoquinazoline-based compounds.
J. Comb. Chem. 2003, 5, 769–774.
8. Kesarwani, A. P.; Srivastava, G. K.; Rastogi, S. K.; Kundu, B. Solid-phase
synthesis of quinazolin-4(3H)-ones with three-point diversity. Tetrahedron Lett.
2002, 43, 5579–5581.
9. Kundu, B.; Partani, P.; Duggineni, S.; Sawant, D. Solid-phase synthesis of 2-ami-
noquinazolinone derivatives with two- and three-point diversity. J Comb. Chem.
2005, 7, 909–915.
10. Spence, C. M.; Bergden, R. N. Anagrelide a review of its pharmacodynamic and
pharmacokinetic properties and therapeutic potential in the treatment of thrombo-
cythaemia. Drugs 1994, 47, 809–822.
11. Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M.
Inhibitors of cyclic AMP phosphodiesterase 3. Synthesis and biological evaluation
of pyrido and imidazolyl analogs of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quina-
zoline. J. Med. Chem. 1988, 31, 2136–2145.
12. Katritzky, A. R.; Tymoshenko, D. O.; Monteux, D.; Vvedensky, V.; Nikonov, G.;
Cooper, C. B.; Deshpande, M. A new three-carbon synthon for efficient synthesis
of benzannelated and 1-(2-arylethenyl) heterocycles. J. Org. Chem. 2000, 65,
8059–8062.
13. Perron, D.; Conlon, D.; Bousquet, P. F.; Robinson, S. P. Benzimidazo[1,2-c]quinazo-
line dimers as potential antitumor agent. J. Heterocycl. Chem. 1997, 34, 807–812.
14. (a) Molina, P.; Alajarin, M.; Vidal, A. Heterocyclic synthesis via a tandem aza-
Wittig reaction/heterocumulene-mediated annulation reaction. New methodology
for the preparation of quinazoline derivatives. Tetrahedron Lett. 1988, 29,
3849–3852; (b) Molina, P.; Alajarin, M.; Vidal, A. New methodology for the prep-
aration of quinazoline derivatives via tandem aza-wittig/heterocumulene-
mediated annulation. Synthesis of 4(3H)-quinazolinones, benzimidazo[1,2-c] qui-
nazolines, quinazolino[3,2-a]quinazolines and benzothiazolo[3,2-c]quinazolines.
Tetrahedron 1989, 45, 4263–4286.
´
w
15. Beaulieu, P. L.; Hache, B.; Moos, E. V. A practical Oxone -mediated, high-
throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines

3470
B. Saha, S. Sharma, and B. Kundu
and aldehydes and its application to preparative scale synthesis. Synthesis 2003,
1683–1692.
16. (a) Nicolaou, K. C.; Trujillo, J. I.; Jandeleit, B.; Chibale, K.; Rosenfed, M.;
Diefenbach, B.; Cheresh, D. A.; Goodman, S. L. Design, synthesis and biological
evaluation of nonpeptide integrin antagonists. Bioorg. Med. Chem. 1998, 6,
ˇ ˇ
1185–1208; (b) Peterlin-Masic, L.; Kikelj, D. Arginine mimetics. Tetrahedron
2001, 57, 7073–7105; (c) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.;
Gu, Z. A mild and efficient method for the preparation of guanidines. Tetrahedron
Lett. 1992, 33, 5933–5936; (d) Iwanowicz, E.; Poss, M. A.; Lin, J. Preparation of
N,N0-bis-tert-butoxycarbonylthiourea. Synth. Commun. 1993, 23, 1443–1445;
´ ´
(e) Cherkaoui, O.; Essassi, E. M.; Zniber, R. Heterocyclisation des 2-aminoalkyl
(et aryl) benzimidazoles en catalyse par transfert de phase. Bull. Soc. Chim. Fr.
1991, 255–259.
17. Grimmett, M. R. Imidazoles and their benzo derivatives. Comprehensive
Heterocyclic Chemistry; Pergamon: New York, 1984, Vol. 5, p. 345.