Synthesis of a novel structural variant of imidazoquinazoline with three-point diversity

Article abstract of DOI:10.1055/s-2006-926467

An efficient strategy for the preparation of a novel structural variant of imidazoquinazolines with three-point diversity has been described. The compounds were obtained by treating benzil with o-nitrobenzaldehyde to give imidazoles, followed by reduction

Full text of DOI:10.1055/s-2006-926467

PAPER
1841
Synthesis of a Novel Structural Variant of Imidazoquinazoline with
Three-Point Diversity1
A
N
ovel Struc
u
tural
V
ariant
n
of
I
midazoq
i
uinazol
l
ine Sharma, Biswajit Saha, Devesh Sawant, Bijoy Kundu*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Fax +91(522)2623405; E-mail: bijoy_kundu@yahoo.com
Received 27 October 2005; revised 20 December 2005
evaluation against a variety of biological targets. Fusing
the imidazo moiety with the 2-amino quinazoline ring at
different positions could furnish structural variants of imi-
dazoquinazolines. The three possible routes that can effect
Abstract: An efficient strategy for the preparation of a novel struc-
tural variant of imidazoquinazolines with three-point diversity has
been described. The compounds were obtained by treating benzil
with o-nitrobenzaldehyde to give imidazoles, followed by reduction
of the nitro group to give an aryl amine. Condensation–cyclization this fusion have been depicted in Scheme 1.
of the resulting intermediate with isothiocyanates in the presence of
Recently, we reported the use of the 2-aminoquinazoline
DBU for 45 minutes at room temperature furnished the title com-
template for the synthesis of imidazoquinazolines 1 and 2.
pounds in high yields and purities.
For the synthesis of 1, 2-aminoquinazolines were treated
Key words: imidazoquinazoline, imidazole, DBU
with phenacyl bromides via condensation–cyclization6
using the procedure described by Gueiffier et al. for imi-
dazopyridines.7 For the synthesis of compounds based on
2, the amino group of a polymer-linked amino acid was
The quinazoline nucleus present in imidazoquinazolines
is an attractive target because it forms an important com-
first derivatized with 2-nitrobenzaldehyde followed by re-
ponent of pharmacologically active compounds and is as-
duction of the nitro group to an amine. Next, the resulting
sociated with a wide range of biological activities ranging
aryl amine was functionalized with isothiocyanates fol-
from anticonvulsant2 and antibacterial to antidiabetic.3
lowed by cyclization of the resulting thioureas with diiso-
Two imidazoquinazoline-based drugs, anagrelide4 and propylcarbodiimide (DIC), then acidolytic cleavage from
quazinone,5 are used clinically as anti-thrombotic and car- the resin yielded 2.8 However, for the synthesis of imida-
diotonic agents (Figure 1), structural variants of imidazo- zoquinazolines 3 based on option 3, there was no report
quinazolines are quite likely to provide structures for available in the literature. Interestingly, a careful survey
of the literature revealed two papers for the synthesis of
Cl
Cl
H3C
benzimidazoquinazolines, a benzoannelated derivative of
3. The first method involved treatment of 6-mercaptoben-
zimidazo-quinazoline with amines9 and the second meth-
od involved an aza-Wittig reaction of iminophosphoranes
derived from 2-(o-azido)phenylbenzimidazole with iso-
cyanates.10 For our target structure 3, the most efficient
route would require the condensation of 2-(1H-imidazol-
H
Cl
N
N
O
O
N
N
N
N
H
H
anagrelide
quazinone
Figure 1 Structure of the two clinically used drugs based on imida-
zoquinzolines 2
N
N
OPTION 3
HN
R
N
3
N
N
ref. 8
ref. 6
OPTION 2
O
N
N
H
H2N
N
2
R
N
OPTION 1
N
N
1
Ph
Scheme 1 Three different options for fusing imidazo moiety with 2-aminoquinazoline
SYNTHESIS 2006, No. 11, pp 1841–1847
x
x.
x
x
.
2
0
0
6
Advanced online publication: 27.04.2006
DOI: 10.1055/s-2006-926467; Art ID: P17205SS
© Georg Thieme Verlag Stuttgart · New York

1842
S. Sharma et al.
PAPER
2-yl)-phenylamine derivatives 5 with isothiocyanate procedure.11 Attempts to reduce the nitro group in 9 by
(Scheme 2). Intermediate 5 can be obtained from the cor- catalytic hydrogenation led to incomplete reduction even
responding nitro derivative 6; the latter can be readily pre- after 48 hours. HPLC analysis showed that the ratio of re-
pared by literature procedures.11 The proposed synthetic duced product to precursor was approximately 60:40. In
strategy for 3 is distinctly different from the strategies re- contrast, when tin(II) chloride was used for reduction of
ported earlier by us for 1 and 2. In this communication, we the nitro group in 9, HPLC showed complete reduction to
report for the first time an efficient strategy for the synthe- give 10.
sis of a new structural variant of imidazoquinazoline
based on 3 with three-point diversity derived from benzil,
2-nitrobenzaldehydes, and isothiocyanates.
With compound 10 in hand we then looked at the intramo-
lecular cyclization between the NH of imidazole and aryl
NH2 with phenylisothiocyanates to give imidazoquinazo-
The synthesis of 3 is depicted in Scheme 3. Imidazole 9 lines 3. Initially, we attempted the cyclization by simply
was prepared from benzil and o-nitrobenzaldehyde in ace- heating 10 with isothiocyanates for 24 hours in DMF;
tic acid in the presence of ammonium acetate by a known however, the title compounds 3 were obtained in poor
N
N
N
N
N
H
RNCS
+
N
H
N
HN
HN
R
H2N
NH
R
S
5
4
N
O
O
OHC
O2N
N
+
+
NH4OAc
H
O2N
6
Scheme 2 Retrosynthetic pathway for the synthesis of imidazoquinazolines based on prototype 3
R1
R1
CHO
O
NO2
a
N
R3
R2
+
O
R3
R1
N
R2
8a–d
H
R1
O2N
7a,b
9a–e
R1
H
R2
H
R3
9,10
a
b
c
d
e
H
OMe
Cl
OMe OMe
b
H
H
H
H
H
R1
F
OMe
Cl
R1
N
N
R3
R2
R1
c
N
N
R3
R2
R1
N
HN
R4
H
H2N
3a–r
10a–e
Scheme 3 Reagents and conditions: a) NH4OAc, AcOH, reflux, 5 h; b) SnCl2·2H2O, MeOH, reflux; 1 h, c) aryl/alkylisothiocyanate, DBU,
MeCN, r.t., 1 h.
Synthesis 2006, No. 11, 1841–1847 © Thieme Stuttgart · New York

PAPER
A Novel Structural Variant of Imidazoquinazoline
1843
Table 1 Formation of 3a from 10a Using Lewis Acids and Bases
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. H
1
Lewis acid Base
CuCl i-Pr2EtN
Solvent Temp Time
Yield (%)
50
NMR and 13C NMR spectra were recorded on either a 300 MHz or
a 200 MHz FT spectrometer, with TMS as an internal standard. The
electrospray MS was recorded through direct flow injections on a
Merck M-8000 LCMS system. Elemental analyses were performed
on a Carlo Erba 1108 microanalyzer or Elementar’s Vario EL III
microanalyzer. RP-HPLC analysis of products was performed on an
Agilent liquid chromatograph using a 5 mm, 4.8 × 150 mm, C-18 re-
verse-phase column with a linear gradient of 10–100%, MeCN–
H2O containing 0.05% TFA over 30 min. The flow rate was 1.0 mL/
min, and UV detection was observed at 220/254 nm.
MeCN
MeCN
MeCN
MeCN
DMF
80 °C 6 h
80 °C 6 h
80 °C 1.5 h
(1.5 equiv)
Yb(OTf)3 i-Pr2EtN
60
90
65
75
70
92
90
(1.5 equiv)
InCl3
i-Pr2EtN
(1.5 equiv)
InCl3
i-Pr2EtN
r.t.
r.t.
r.t.
6 h
(1.5 equiv)
2-(2-Nitrophenyl)-4,5-diphenyl-1H-imidazole (9a); Typical
Procedure
–
–
–
–
–
–
DABCO
(1.5 equiv)
6 h
A solution of compound 7a (1.00 g, 4.76 mmol) in AcOH was treat-
ed with 2-nitrobenzaldehyde (0.719 g, 4.76 mmol) and NH4OAc
(2.93 g, 38.08 mmol). The reaction mixture was refluxed for 4 h,
then AcOH was evaporated, and the residue was treated with a 10%
aq solution of NaHCO3 (pH 8). The mixture was extracted with
EtOAc (2 × 25 mL), washed with brine (25 mL), and dried over
Na2SO4. The solvent was evaporated under reduced pressure to give
a yellow solid.
DABCO
(0.5 equiv)
DMF
6 h
DBU
(0.5 equiv)
CH2Cl2 r.t.
2.5 h
1.5 h
DBU
(0.5 equiv)
THF
r.t.
r.t.
r.t.
Yield: 82%; yellow solid; mp 142–144 °C.
IR (KBr): 1352, 1526, 1591, 3436 cm–1.
1H NMR (200 MHz, DMSO): d = 7.32–7.47 (m, 10 H, ArH), 7.61–
7.68 (m, 1 H, ArH), 7.76–7.81 (m, 1 H, ArH), 7.93 (d, J = 8.0 Hz,
1 H, ArH), 7.99 (d, J = 8.0 Hz, 1 H, ArH), 12.98 (br s, 1 H, NH).
DBU
(0.5 equiv)
MeCN
DMF
45 min 93
DBU
3 h
90
(0.5 equiv)
13C NMR (50.32 MHz, DMSO): d = 123.85, 124.39, 127.41,
128.64, 129.08, 129.88, 130.17, 132.48, 135.11, 137.96, 141.43,
148.71. 186.27.
yields. DIC also failed to induce dehydrative cycliza-
tion.12 Recently Wang et al.13 reported copper(I) chloride
promoted intramolecular cyclization of N-(2-amino-
aryl)thioureas. We subjected intermediate 10 to copper(I)
chloride promoted cyclization in the presence of phenyl-
isothiocyanates. Unfortunately, we observed only 50%
conversion of 10 into the desired product 3. We then opti-
mized the cyclization of 10 using a variety of Lewis acids
and bases as catalysts (Table 1). Amongst the Lewis acids
tested, indium trichloride (10 mol%) at 80 °C led to the
complete conversion of 10 into the desired product 3.
However, the best results were obtained when DBU (0.5
equiv) was used as a catalyst in acetonitrile, as it resulted
in complete cyclization in less than one hour at room tem-
perature. The method worked equally well with both aryl-
and alkylisothiocyanates. The scope and limitation of our
strategy for 3 was established by using two benzil, four o-
nitrobenzadehyde, and eight isothiocyanates. The crude
products obtained after the completion of the synthesis
were purified by column chromatography to furnish 3.
The compounds were obtained in excellent isolated yields
ranging from 77–85% (Table 2). The electron-withdraw-
ing and electron-donating substituents on aldehydes and
isothiocyanates had no significant affect on the yield and
purity of the final compounds.
MS (ES+): m/z = 342.36 (M+ + 1).
Anal. Calcd for C21H15N3O2: C, 73.89; H, 4.43; N, 12.31. Found: C,
73.99; H, 4.73; N, 12.11.
2-(4,5-Dimethoxy-2-nitrophenyl)-4,5-bis-(4-methoxyphenyl)-
1H-imidazole (9b)
Yield: 98%; orange solid; mp 204–205 °C.
IR (KBr): 1336, 1587, 1591, 2836, 2938, 3436 cm–1.
1H NMR (200 MHz, DMSO): d = 3.92 (s, 3 H,OCH3), 3.95 (s, 3
H,OCH3), 3.99 (s, 3 H,OCH3), 4.01 (s, 3 H,OCH3), 6.83 (d, J = 8.0
Hz, 2 H, ArH), 6.96 (d, J = 8.0 Hz, 1 H, ArH), 7.34 (s, 1 H, ArH),
7.43–7.46 (m, 4 H, ArH), 7.65 (s, 1 H, ArH), 7.94 (d, J = 8.0 Hz, 1
H, ArH), 12.59 (br s, 1 H, NH).
13C NMR (50.32 MHz, DMSO): d = 55.37, 55.55, 56.18, 56.66,
108.27, 112.65, 114.02, 114.55, 118.55, 123.70, 127.51, 127.98,
128.49, 129.86, 136.79, 148.75, 151.70, 158.37, 159.21, 165.15,
193.94.
MS (ES+): m/z (%) = 462.47 (M+ + 1).
Anal. Calcd for C25H23N3O6: C, 65.07; H, 5.02; N, 9.11. Found: C,
65.29; H, 5.43; N, 9.31.
2-(5-Chloro-2-nitrophenyl)-4,5-diphenyl-1H-imidazole (9c)
Yield: 92%; yellow solid; mp 224–225 °C.
IR (KBr): 1351, 1597, 3460 cm–1.
1H NMR (200 MHz, DMSO): d = 7.11 (d, J = 8.0 Hz, 2 H, ArH),
7.30–7.35 (m, 8 H, ArH), 7.51 (d, J = 2.0 Hz, 1 H, ArH), 7.77–7.84
(m, 1 H, ArH), 7.99 (d, J = 2.0 Hz, 1 H, ArH), 12.93 (br s, 1 H, NH).
13C NMR (50.32 MHz, DMSO): d = 125.19, 126.28, 127.41,
128.64, 129.39, 129.85, 129.95, 130.73, 132.63, 134.74, 135.87,
136.79, 138.22, 139.97, 147.05, 195.17.
In summary we have developed a versatile approach for
the synthesis of a novel structural variant of imidazo-
quinazolines with three-point diversity from imidazoles in
excellent yields and purities.
Synthesis 2006, No. 11, 1841–1847 © Thieme Stuttgart · New York

1844
S. Sharma et al.
PAPER
Table 2 Physical Characteristics of Compounds 3
Compd R1
R2
R3
R4
MS (M+ + 1)
413.07
447.98
445.07
516.33
507.13
507.60
522.80
547.07
568.08
487.06
515.77
461.56
427.55
393.61
461.21
365.88
496.31
427.70
HPLC tR (min)b Yield (%)
Purityc (%)
3a
3b
3c
3d
3e
3f
H
H
H
Ph
22.218
22.363
24.529
24.624
23.714
23.985
26.085
23.241
23.284
19.185
20.525
24.847
21.256
23.333
22.236
20.558
29.062
18.446
82
80
85
80
80
84
80
83
82
79
80
82
77
78
81
77
82
79
92
88
92
88
87
91
86
89
90
87
87
89
85
86
90
88
91
87
H
H
H
2-ClC6H4
3-Tol
H
H
F
H
H
F
2,6-[i-Pr]2C6H3
2-ClC6H4
Ph
H
OMe
H
OMe
Cl
OMe
OMe
OMe
OMe
H
3g
3h
3i
H
Cl
3-Tol
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
Cl
3-Tol
2-ClC6H4
3-Tol
3j
3k
3l
H
3-AcC6H4
3-Tol
H
3m
3n
3o
3p
3q
3r
H
H
H
Bn
H
H
H
Bu
H
H
H
4-ClCH2C6H4
Et
H
H
H
H
H
Cl
4-ClCH2C6H4
Bu
H
H
Cl
a C18 reverse-phase column (250 × 4.6 mm; 10 mm) with a linear gradient 10–100%, MeCN–H2O over 30 min, flow rate 1.0 mL/min, and UV
detection 220/254nm.
b Purity of crude products based on RP-HPLC chromatograms.
MS (ES+): m/z = 376.81 (M+ + 1).
2-[4,5-Bis(4-methoxyphenyl)-1H-imidazol-2-yl]-4,5-dimethoxy-
phenylamine (10b)
Yield: 85%; white solid; mp 144–145 °C.
IR (KBr): 2934, 2936, 1595, 3462 cm–1.
Anal. Calcd for C21H14ClN3O2: C, 67.12; H, 3.75; N, 11.18. Found:
C, 67.51; H, 3.43; N, 11.11.
2-(4,5-Diphenyl-1H-imidazol-2-yl)phenylamine (10a); Typical
Procedure
1H NMR (200 MHz, CDCl3): d = 3.08 (s, 3 H, OCH3), 3.12 (s, 3 H,
OCH3), 3.65 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 6.73 (s, 1 H,
ArH), 7.30–7.35 (m, 5 H, ArH), 7.58–7.61 (m, 3 H, ArH), 8.10 (s,
1 H, ArH), 11.96 (br s, 1 H, NH).
13C NMR (50.32 MHz, CDCl3): d = 55.45, 55.65, 56.06, 57.37,
101.59, 102.14, 105.26, 110.51, 114.3, 126.11, 129.41, 134.36,
141.45, 141.67, 146.17, 151.00, 159.15.
To a solution of 6a (1.00 g, 2.93 mmol) in MeOH (15 mL),
SnCl2·2H2O (3.30 g, 14.66 mmol) was added. The reaction mixture
was refluxed under nitrogen for 1.5 h. The MeOH was evaporated
and then a 10% aq solution of NaOH was added (pH 8). EtOAc (2
× 25 mL) was added and the resulting mixture was filtered through
a plug of celite. The organic layer was washed with H2O (25 mL),
dried over Na2SO4, and concentrated to dryness under reduced pres-
sure to afford 10a.
MS (ES+): m/z = 432.48 (M+ + 1).
Anal. Calcd for C25H25N3O4: C, 69.59; H, 5.84; N, 9.74. Found: C,
69.21; H, 5.79; N, 9.98.
Yield: 85%; white solid; mp 136–138 °C.
IR (KBr): 1601, 3359, 3462 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.39–6.43 (m, 1 H, ArH), 6.58 (d,
J = 8.0 Hz, 1 H, ArH), 6.78 (br s, 2 H, NH2), 6.82–6.86 (m, 1 H,
ArH), 7.01–7.34 (m, 10 H, ArH), 7.62 (d, J = 7.1 Hz, 1 H, ArH),
12.26 (br s, 1 H, NH).
5-Chloro-2-(4,5-diphenyl-1H-imidazol-2-yl)phenylamine (10c)
Yield: 87%; white solid; mp 187–188 °C.
IR (KBr): 3426 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.71 (d, J = 8.0 Hz, 1 H, ArH),
7.08 (dd, J = 6.0, 2.0 Hz, 1 H, ArH), 7.30–7.53 (m, 7 H, ArH), 7.53–
7.58 (m, 4 H, ArH), 12.01 (br s, 1 H, NH).
13C NMR (50.32 MHz, CDCI3): d = 111.46, 115.37, 116.20,
126.75, 127.62, 128.83, 129.34, 132.01, 135.46, 147.08, 147.16.
13C NMR (50.32 MHz, CDCl3): d = 118.13, 118.42, 121.15, 122.66,
125.21, 131.01, 132.34, 133.22, 133.51, 133.95, 134.24, 134.93,
138.37, 150.36, 150.88.
MS (ES+): m/z = 312.38 (M+ + 1).
Anal. Calcd for C21H17N3: C, 81.00; H, 5.50; N, 13.49. Found: C,
81.19; H, 5.73; N, 13.11.
Synthesis 2006, No. 11, 1841–1847 © Thieme Stuttgart · New York

PAPER
A Novel Structural Variant of Imidazoquinazoline
1845
MS (ES+): m/z 346.82 (M+ + 1).
7.51–7.60 (m, 5 H, ArH), 7.68–7.69 (m, 2 H, ArH), 8.16–8.21 (m,
1 H, ArH).
13C NMR (75.4 MHz, CDCl3): d = 23.1, 24.6, 28.6, 28.9, 108.0,
117.24, 118.55, 120.8, 123.7, 127.7, 127.8, 128.1, 128.2, 128.5,
129.7, 130.8, 131.7, 132.4, 133.7, 139.2, 142.5, 142.6, 144.8, 146.6,
157.8, 161.1.
Anal. Calcd for C21H16ClN3: C, 72.93; H, 4.66; N, 12.15. Found: C,
72.79; H, 4.54; N, 12.08.
(2,3-Diphenylimidazo[1,2-c]quinazolin-5-yl)phenylamine (3a);
Typical Procedure
To a solution of imidazole 10a (100 mg, 0.32mmol) and phenyl-
isothiocyanate (39 mL, 0.32 mmol) in CH3CN (15 mL), DBU (24
mL, 0.16mmol) was added. The resulting mixture was stirred at r.t.
for 45 min. The solvent was evaporated under reduced pressure, the
residue was extracted with EtOAc (2 × 20 mL), washed with H2O
(20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to
obtain a solid residue. Column chromatography of the residue (sili-
ca gel; CHCl3–MeOH, 99:1) furnished 3a as a white solid.
Anal. Calcd for C34H31FN4: C, 79.35; H, 6.07; N, 10.89. Found: C,
79.10; H, 6.24; N, 10.71.
2-Chlorophenyl(8,9-dimethoxy-2,3-diphenylimidazo[1,2-
c]quinazolin-5-yl)amine (3e)
Yield: 80%; white solid; mp 249–250 °C.
IR (KBr): 1592, 3419 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.02 (s, 3 H,OCH3), 4.10 (s, 3
H,OCH3), 6.94–7.01 (m, 1 H, ArH), 7.13 (br s, 1 H, NH), 7.20 (s, 1
H, ArH), 7.24–7.37 (m, 2 H, ArH), 7.49–7.66 (m, 10 H, ArH), 7.96
(s, 1 H, ArH), 8.58 (d, 1 H, J = 8.0 Hz, ArH).
13C NMR (50.32 MHz, CDCl3): d = 56.6, 56.8, 103.5, 107.4, 110.6,
121.0, 122.67, 123.5, 124.1, 127.6, 128.0, 128.5, 128.7, 129.5,
130.1, 130.8, 133.2, 134.07, 135.6, 137.1, 139.9, 141.3, 143.0,
145.5, 148.0, 152.4.
Yield: 82%; white solid; mp 200–201 °C.
IR (KBr): 1625, 3400 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.76 (br s, 1 H, NH), 7.01–6.97
(m, 1 H, ArH), 7.23–7.25 (m, 6 H, ArH), 7.37–7.42 (m, 1 H, ArH),
7.53–7.70 (m, 10 H, ArH), 8.55 (d, J = 9.0 Hz, 1 H, ArH).
13C NMR (75.4 MHz, CDCl3): d = 116.8, 119.4, 120.4, 123.1,
123.4, 124.8, 125.8, 127.8, 128.0, 128.5, 129.0, 129.8, 130.7, 130.8,
132.8, 133.7, 138.2.
Anal. Calcd for C30H23ClN4O: C, 71.07; H, 4.57; N, 11.05. Found:
C, 71.27; H, 4.49; N, 11.41
Anal. Calcd for C28H20N4: C, 81.53; H, 4.89; N, 13.58. Found: C,
81.73; H, 5.01; N, 13.37.
{9-Chloro-2,3-bis(4-methoxyphenyl)imidazo[1,2-c]quinazolin-
5-yl}phenylamine (3f)
Yield: 84%; white solid; mp 206–207 °C.
2-Chlorophenyl(2,3-diphenylimidazo[1,2-c]quinazolin-5-
yl)amine (3b)
Yield: 80%; white solid; mp 176–177 °C.
IR (KBr): 1593, 3358 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.93–6.98 (m, 1 H, ArH), 7.18–
7.31 (m, 6 H, NH, ArH), 7.41–7.68 (m, 10 H, ArH), 8.56–8.62 (m,
2 H, ArH).
IR (KBr): 1623, 3390 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H,OCH3), 4.07 (s, 3
H,OCH3), 6.92 (d, J = 9.0 Hz, 2 H, ArH), 7.11–7.17 (m, 2 H, NH,
ArH), 7.26 (d, J = 9.0 Hz, 2 H, ArH), 7.36–7.42 (m, 4 H, ArH),
7.57–7.74 (m, 6 H, ArH), 8.63 (d, J = 3.0 Hz, 1 H, ArH).
13C NMR (75.4 MHz, CDCl3): d = 116.7, 120.9, 122.6, 123.1,
123.2, 124.2, 125.3, 125.7, 127.2, 127.8, 128.3, 128.3, 129.1, 129.3,
129.8, 130.5, 130.7, 132.8, 133.3, 134.8, 140.0, 141.3, 142.5, 145.2.
13C NMR (75.4 MHz, CDCl3): d = 55.4, 55.8, 114.0, 115.3, 117.8,
119.7, 121.7, 122.0, 122.4, 123.7, 124.5, 126.2, 127.2, 129.1, 130.0,
130.5, 134.2, 138.1,140.2, 140.6, 143.7, 159.4, 161.5.
Anal. Calcd for C28H19ClN4: C, 75.25; H, 4.28; N, 12.54. Found: C,
75.20; H, 4.49; N, 12.91.
Anal. Calcd for C30H23ClN4O2: C, 71.07; H, 4.57; N, 11.05. Found:
C, 71.37; H, 4.39; N, 11.45.
(9-Fluoro-2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)-m-tolyl-
amine (3c)
Yield: 85%; white solid; mp 178–179 °C.
{9-Chloro-2,3-bis(4-methoxyphenyl)imidazo[1,2-c]quinazolin-
5-yl}-m-tolylamine (3g)
Yield: 80%; white solid; mp 185–186 °C.
IR (KBr): 1605, 3385 cm–1.
IR (KBr): 1600, 3381 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 6.71 (br s, 1 H,
NH), 6.84 (d, 1 H, J = 9.0 Hz, ArH), 7.05 (s, 1 H, ArH), 7.13 (m, 1
H, ArH), 7.25–7.33 (m, 3 H, ArH), 7.58–7.75 (m, 10 H, ArH), 8.22
(dd, 1 H, J = 3.0 Hz, J = 6.0 Hz, ArH).
1H NMR (200 MHz, CDCl3): d = 2.31 (s, 3 H, CH3), 3.78 (s, 3 H,
OCH3), 3.96 (s, 3 H, OCH3), 6.80 (d, J = 8.0 Hz, 2 H, ArH), 6.90
(br s, 1 H, NH), 7.06–7.17 (m, 4 H, ArH), 7.45–7.62 (m, 8 H, ArH),
8.50 (d, J = 2.0 Hz, 1 H, ArH).
13C NMR (75.4 MHz, CDCl3): d = 21.7, 109.0 (d, J = 22.62 Hz),
116.5, 117.5 (d, J = 7.54 Hz), 118.6 (d, J = 22.0 Hz), 120.0, 120.7,
124.3, 127.7, 127.8, 127.9, 128.4, 128.8, 129.8, 130.5, 130.8, 132.7,
133.5, 137.9, 138.2, 138.8, 139.7, 142.1, 158.1, 161.4.
13C NMR (75.4 MHz, CDCl3): d = 21.8, 55.3, 55.8, 113.9, 115.3,
116.8, 117.7, 119.6, 120.4, 122.0, 122.3, 122.5, 126.2, 127.2, 128.1,
128.9, 129.8, 134.1, 137.9, 138.9, 140.2, 140.2, 140.6, 142.1, 143.7,
159.3, 161.5.
Anal. Calcd for C29H21FN4: C, 78.36; H, 4.76; N, 12.60. Found: C,
78.58; H, 4.49; N, 12.91.
Anal. Calcd for C31H25ClN4O2: C, 71.46; H, 4.84; N, 10.75. Found:
C, 71.35; H, 4.49; N, 10.61.
2,6-Diisopropylphenyl(9-fluoro-2,3-diphenylimidazo[1,2-c]-
quinazolin-5-yl)amine (3d)
Yield: 80%; white solid; 214–216 °C.
{8,9-Dimethoxy-2,3-bis(4-methoxyphenyl)imidazo[1,2-c]-
quinazolin-5-yl}-m-tolylamine (3h)
Yield: 83%; white solid; mp 218–219 °C.
IR (KBr): 1624, 3390 cm–1.
IR (KBr): 1594, 3387 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.98 (d, J = 6.0 Hz, 6 H, 2 × CH3),
1.13 (d, J = 6.0 Hz, 6 H, 2 × CH3), 2.83–2.93 (m, 2 H, 2 × CH), 5.91
(br s, 1 H, NH), 7.14–7.18 (m, 3 H, ArH), 7.25–7.28 (m, 5 H, ArH),
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3 H, CH3), 3.78 (s, 3 H,
OCH3), 3.95 (s, 3 H, OCH3), 4.01 (s, 3 H, OCH3), 4.06 (s, 3 H,
OCH3), 6.80–6.83 (m, 4 H, ArH), 6.94 (br s, 1 H, NH), 7.11–7.18
(m, 5 H, ArH), 7.53–7.58 (m, 4 H, ArH), 7.90 (s, 1 H, ArH) .
Synthesis 2006, No. 11, 1841–1847 © Thieme Stuttgart · New York

1846
S. Sharma et al.
PAPER
13C NMR (50.32 MHz, CDCl3): d = 22.0, 55.6, 56.0, 57.0, 56.8,
103.5, 107.4, 110.2, 114.2, 115.4, 116.9, 119.1, 120.4, 122.8, 124.4,
126.8, 129.2, 129.5, 134.4, 137.6, 138.6, 139.1, 140.3, 142.1, 145.2,
147.9, 152.3, 159.5, 161.6.
7.11 (d, 1 H, J = 8.0 Hz, ArH), 7.24–7.27 (m, 2 H, ArH), 7.50–7.67
(m, 11 H, ArH), 8.53 (d, 1 H, J = 2.0 Hz, ArH).
13C NMR (50.32 MHz, CDCl3): d = 22.0, 117.0, 117.3, 120.5,
121.0, 122.7, 124.8, 127.5, 128.3, 128.7, 129.2, 130.2, 130.3, 130.8,
130.9, 131.2, 133.0, 133.7, 138.0, 139.2, 140.5, 140.7, 142.7, 144.3.
Anal. Calcd for C33H30N4O4: C, 72.51; H, 5.53; N, 10.25. Found: C,
72.31; H, 5.49; N, 10.01.
Anal. Calcd for C29H21ClN4; C, 75.56; H, 4.59; N, 12.15. Found: C,
75.78; H, 4.49; N, 12.51.
2-Chlorophenyl{8,9-dimethoxy-2,3-bis(4-methoxyphenyl)imi-
dazo[1,2-c]quinazolin-5-yl}amine (3i)
Yield: 82%; white solid; mp 260–261 °C.
IR (KBr): 1593, 3345 cm–1.
Benzyl(2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)amine (3m)
Yield: 77%; white solid; mp 156–158 °C.
IR (KBr): 1612, 3397 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 3 H,OCH3), 3.90 (s, 3
H,OCH3), 4.00 (s, 3 H,OCH3), 4.09 (s, 3 H,OCH3), 6.80 (d, J = 9.0
Hz, 2 H, ArH) 6.94–6.99 (m, 1 H, ArH), 7.05 (d, J = 6.0 Hz, 2 H,
ArH), 7.11 (s, 1 H, ArH), 7.21 (br s, 1 H, NH), 7.25 (d, 1 H, J = 9.0
Hz, ArH), 7.31 (m, 1 H, ArH), 7.47 (d, J = 9.0 Hz, 2 H, ArH), 7.54
(d, J = 6.0 Hz, 2 H, ArH), 7.94 (s, 1 H, ArH), 8.58 (d, J = 9.0 Hz, 1
H, ArH).
13C NMR (75.4 MHz, CDCl3): d = 55.4, 55.7, 56.3, 56.6, 103.2,
107.1, 110.4, 113.9, 115.4, 119.2, 121.9, 122.5, 123.3, 123.8, 126.6,
127.3, 129.3, 129.4, 134.4, 135.5, 136.8, 139.8, 142.4, 145.0, 148.1,
152.1, 159.3, 161.4
1H NMR (200 MHz, CDCl3): d = 4.56 (d, 2 H, J = 4.0 Hz, CH2),
4.88 (t, 1 H, J = 4.0 Hz, NH), 6.98– 7.02 (m, 1 H, ArH), 7.21–7.24
(m, 5 H, ArH), 7.33 (d, J = 8.0 Hz, 1 H, ArH), 7.38–7.45 (m, 4 H,
ArH), 7.48–7.64 (m, 7 H, ArH), 8.53 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 46.4, 116.6, 120.9, 123.5,
124.1, 125.3, 125.5, 127.9, 128.0, 128.3, 128.7, 128.9, 129.6, 130.5,
130.6, 131.0, 132.6, 134.1, 137.8, 142.0, 143.0, 143.9, 145.3.
Anal. Calcd for C29H22N4: C, 81.66; H, 5.20; N, 13.14. Found: C,
81.78; H, 5.49; N, 13.42.
Butyl(2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)amine (3n)
Yield: 78%; white solid; mp 127–129 °C.
IR (KBr): 1625, 3433 cm–1.
Anal. Calcd for C32H27ClN4O4: C, 67.78; H, 4.80; N, 9.88. Found:
C, 67.89; H, 4.57; N, 9.91.
1H NMR (200 MHz, CDCl3): d = 0.81 (t, J = 8.0 Hz, 3 H, CH3),
1.00–1.07 (m, 2 H, CH2), 1.20–1.29 (m, 2 H, CH2), 3.34–3.44 (m, 2
H, CH2), 4.59 (t, J = 4.0 Hz, 1 H, NH), 7.22–7.30 (m, 2 H, ArH),
7.35 (dd, J = 2.0, 6.0 Hz, 1 H, ArH), 7.52–7.58 (m, 10 H, ArH), 8.52
(d, J = 8.0 Hz, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 14.0, 20.3, 31.1, 41.6, 116.4,
120.8, 123.4, 123.8, 125.3, 125.3, 127.8, 128.3, 128.6, 129.6, 130.5,
131.3, 132.7, 134.2, 142.0, 143.2, 144.3, 145.3.
(8,9-Dimethoxy-2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)-
m-tolylamine (3j)
Yield: 79%; white solid; mp 252–253 °C.
IR (KBr): 1630, 3402 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 4.02 (s, 3 H,
OCH3), 4.07 (s, 3 H, OCH3), 6.66 (br s, 1 H, NH), 6.83 (m, 1 H,
ArH), 6.94 (s, 1 H, ArH), 7.12–7.14 (m, 2 H, ArH), 7.25–7.28 (m,
3 H, ArH), 7.57–7.70 (m, 8 H, ArH), 7.93 (s, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 22.0, 56.5, 56.8, 103.5, 107.4,
110.2, 116.8, 120.2, 124.4, 128.0, 128.4, 128.7, 129.7, 130.0, 130.9,
131.2, 133.1, 134.1, 137.6, 138.5, 139.1, 140.1, 142.2, 145.5, 148.0,
152.4.
Anal. Calcd for C26H24N4: C, 79.56; H, 6.16; N, 14.27. Found: C,
79.20; H, 6.24; N, 14.31
4-Chlorobenzyl(2,3-diphenylimidazo[1,2-c]quinazolin-5-
yl)amine (3o)
Yield: 81%; white solid; mp 164–166 °C.
IR (KBr): 1623, 3416 cm–1.
Anal. Calcd for C31H26N4O2: C, 76.52; H, 5.39; N, 11.51. Found: C,
76.20; H, 5.49; N, 11.91.
1H NMR (200 MHz, CDCl3): d = 4.53 (d, J = 4.0 Hz, 2 H, CH2),
4.84 (t, J = 4.0 Hz, 1 H, NH), 6.97 (d, J = 8.0 Hz, 2 H, ArH), 7.20–
7.26 (m, 5 H, ArH), 7.42–7.62 (m, 10 H, ArH), 8.54 (d, J = 8.0 Hz,
1 H, ArH).
3-Acetylphenyl(8,9-dimethoxy-2,3-diphenylimidazo[1,2-c]-
quinazolin-5-yl)amine (3k)
Yield: 80%; white solid; mp 163–164 °C.
IR (KBr): 1595, 3387 cm–1.
13C NMR (50.32 MHz, CDCl3): d = 45.6, 116.6, 117.4, 120.8,
123.5, 124.2, 125.5, 127.9, 128.2, 128.7, 129.1, 129.4, 129.6, 130.6,
131.1, 132.6, 133.6, 134.1, 136.5, 142.1, 142.8, 143.7, 145.3.
1H NMR (200 MHz, CDCl3): d = 2.57 (s, 3 H, COCH3), 4.03 (s, 3
H,OCH3), 4.10 (s, 3 H,OCH3), 6.81 (br s, 1 H, NH), 7.15 (s, 1 H,
ArH), 7.24–7.29 (m, 2 H, ArH), 7.36 (m, 1 H, ArH), 7.56–7.72 (m,
11 H, ArH), 7.95 (s, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 27.0, 56.5, 56.8, 103.5, 107.4,
110.4, 119.1, 120.1, 123.2, 123.7, 128.1, 128.4, 128.7, 129.4, 129.6,
130.1, 131.1, 133.1, 133.9, 137.3, 138.2, 139.1, 139.7, 142.3, 145.2,
148.3, 152.5, 197.5.
Anal. Calcd for C29H21ClN4: C, 75.56; H, 4.59; N, 12.15. Found: C,
75.20; H, 4.49; N, 12.31
Ethyl(2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)amine (3p)
Yield: 77%; white solid; mp 149–150 °C.
IR (KBr): 1600, 3422 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.90 (t, J = 8.0 Hz, 3 H, CH3),
3.49 (m, 2 H, CH2), 4.49 (br s, 1 H, NH), 7.22–7.25 (m, 2 H, ArH),
7.35 (d, J = 8.0 Hz, 1 H, ArH), 7.53–7.57 (m, 10 H, ArH), 8.52 (d,
J = 8.0 Hz, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 14.3, 36.8, 112.6, 116.4, 120.9,
123.4, 123.9, 125.3, 127.9, 128.2, 128.6, 128.8, 129.5, 130.6, 131.2,
132.8, 134.1, 142.0, 143.2, 144.1.
Anal. Calcd for C32H26N4O3: C, 74.69; H, 5.09; N, 10.89. Found: C,
74.77; H, 4.89; N, 10.99.
(9-Chloro-2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)-m-tolyl-
amine (3l)
Yield: 82%; white solid; mp 192–193 °C.
IR (KBr): 1595, 3399 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.29 (s, 3 H, CH3), 6.74 (br s, 1 H,
NH), 6.84 (d, 1 H, J = 8.0 Hz, ArH), 7.03 (d, 1 H, J = 2.0 Hz, ArH),
Synthesis 2006, No. 11, 1841–1847 © Thieme Stuttgart · New York

PAPER
A Novel Structural Variant of Imidazoquinazoline
1847
Anal. Calcd for C24H20N4: C, 79.10; H, 5.53; N, 15.37. Found: C,
79.20; H, 5.24; N, 15.81.
References
(1) CDRI Communication No. 6900.
(2) Mannschreck, A.; Koller, H.; Stuhler, G.; Davies, M. A.;
Traber, J. Eur. J. Med. Chem. 1984, 19, 381.
4-Chlorobenzyl(9-chloro-2,3-diphenylimidazo[1,2-c]quinazo-
lin-5-yl)amine (3q)
(3) Molamas, M. S.; Miller, J. J. Med. Chem. 1991, 34, 1492.
(4) Spence, C. M.; Bergden, R. N. Drugs 1994, 47, 809.
(5) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.;
Strosberg, A. M. J. Med. Chem. 1988, 31, 2136.
(6) Kundu, B. presented at IUPAC-BNP-2004, New Delhi,
India, 26th–31st January 2004.
(7) Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, A.;
Snoeck, R.; Andrei, G.; Chavignon, O.; Teulade, J. C.;
Witvrouw, M.; Balzarini, J.; Clercq, E. D. C. J. Med. Chem.
1998, 41, 5108.
(8) (a) Kesarwani, A. P.; Grover, R.; Roy, R.; Kundu, B.
Tetrahedron 2005, 61, 629. (b) Srivastava, G. K.;
Kesarwani, A. P.; Grover, R. K.; Srinivasan, T.; Roy, R.;
Kundu, B. J. Comb. Chem. 2003, 5, 769. (c) Grover, R.;
Kesarwani, A. P.; Srivastava, G. K.; Kundu, B.; Roy, R.
Tetrahedron 2005, 61, 5011.
(9) Perron, D.; Conlon, D.; Bousquet, P. F.; Robinson, S. P. J.
Heterocycl. Chem. 1997, 34, 807.
(10) (a) Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett.
1988, 29, 3849. (b) Molina, P.; Alajarin, M.; Vidal, A.
Tetrahedron 1989, 45, 4263.
(11) Krieg, B.; Manecke, G. Z. Naturforsch., B 1967, 22, 132.
(12) (a) Krchank, V.; Smith, J.; Vagner, J. Tetrahedron Lett.
2001, 42, 1627. (b) Smith, J.; Liras, J.; Schneider, S. E.;
Anslyn, E. V. J. Org. Chem. 1996, 61, 8811. (c) Li, M.;
Wilson, J.; Protlock, D. E. Tetrahedron Lett. 2001, 42,
2273. (d) Song, A.; Marik, J.; Lam, K. S. Tetrahedron Lett.
2004, 45, 2727.
Yield: 82%; white solid; mp 184–185 °C.
IR (KBr): 1617, 3414 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.50 (d, J = 4.0 Hz, 2 H, CH2),
4.86 (t, J = 4.0 Hz, 1 H, NH), 6.96 (d, J = 8.0 Hz, 2 H, ArH), 7.20–
7.26 (m, 4 H, ArH), 7.46–7.57 (m, 10 H, ArH), 8.50 (d, J = 2.0 Hz,
1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 45.4, 116.8, 117.4, 121.1,
122.5, 124.0, 127.0, 128.0, 128.6, 128.9, 129.3, 129.6, 130.5, 130.6,
132.4, 133.5, 133.6, 136.2, 141.2, 142.5, 143.7, 143.9.
Anal. Calcd for C29H20Cl2N4: C, 70.31; H, 4.07; N, 11.31. Found:
C, 70.20; H, 4.24; N, 11.51.
Butyl(9-chloro-2,3-diphenylimidazo[1,2-c]quinazolin-
5-yl)amine (3r)
Yield: 79%; white solid; mp 164–166 °C.
IR (KBr): 1597, 3431 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.80 (t, 3 H, J = 6.0 Hz, CH3),
0.96–1.06 (m, 2 H, CH2), 1.10–1.25 (m, 2 H, CH2), 3.32–3.41 (m, 2
H, CH2), 4.62 (br s, 1 H, NH), 7.23 (dd, 1 H, J = 2.0, 6.0 Hz, ArH),
7.51 (d, J = 8.0 Hz, 1 H, ArH), 7.58–7.68 (m, 10 H, ArH), 8.49 (d,
1 H, J = 2.0 Hz, ArH).
13C NMR (50.32 MHz, CDCl3): d = 14.0, 20.2, 31.0, 41.7, 116.6,
117.2, 121.1, 122.7, 123.9, 126.8, 128.0, 128.2, 128.9, 129.0, 129.7,
130.69, 130.71, 132.7, 133.8, 136.6, 141.6, 144.4.
Anal. Calcd for C26H23ClN4: C, 73.14; H, 5.43; N, 13.12. Found: C,
73.50; H, 5.24; N, 13.91.
(13) Wang, J. X.; Zhang, L.; Xu, Y.; Krishnamurthy, D.;
Sananayake, C. H. Tetrahedron Lett. 2004, 45, 7167.
Acknowledgment
S. Sharma, B. Saha and D. Sawant are grateful to CSIR New Delhi
for financial support.
Synthesis 2006, No. 11, 1841–1847 © Thieme Stuttgart · New York