Solvent-Free Synthesis of 6-Arylbenzimidazo[1,2-c]quinazolines under Microwave Irradiation

Article abstract of DOI:10.1055/s-2004-815924

The syntheses of 2-(2-nitrophenyl)-1-benzoyl-1H-benzimidazole derivatives 5-9 and their reduction to the corresponding 2-benzimidazoylbenzamides 10-13 are described. Compounds 10-13 were cleanly and efficiently converted to the corresponding 6-arylbenzimi

Full text of DOI:10.1055/s-2004-815924

436
PAPER
Solvent-Free Synthesis of 6-Arylbenzimidazo[1,2-c]quinazolines under
Microwave Irradiation
S
olvent-Free Synth
e
esis of 6-A
r
rylbenzi
n
midazo[1,2-
c
á
]quinazolin
n
es Pessoa-Mahana,*a C. David Pessoa-Mahana,b Ricardo Salazar,a Jaime A. Valderrama,c Edmundo Saez,b
Ramiro Araya-Maturanaa
a
Departamento de Química Orgánica y Fisicoquímica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Casilla 233,
Santiago 1, Chile
Fax +56(2)6782868; E-mail: hpessoa@ciq.uchile.cl
b
c
Departamento de Farmacia, Pontificia Universidad Católica de Chile, Casilla 306, Santiago, Chile
Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago, Chile
Received 16 October 2003; revised 9 December 2003
using triethylamine for trapping the hydrogen chloride
(Equation 1). This treatment provided the corresponding
amides 5–9 in good yields (Table 1). The numbering of
the general formulas of compounds 5–9, 10–13, and 17–
Abstract: The syntheses of 2-(2-nitrophenyl)-1-benzoyl-1H-benz-
imidazole derivatives 5–9 and their reduction to the corresponding
2-benzimidazoylbenzamides 10–13 are described. Compounds 10–
13 were cleanly and efficiently converted to the corresponding 6-
arylbenzimidazo[1,2-c]quinazolines 17–20 by microwave activa- 20 in Equations 1–3 does not follow IUPAC rules, but
tion using SiO2-MnO2 as solid inorganic support.
makes interpretation of NMR spectra easier.
Key words: benzimidazoles, heterocyclization, microwaves, benz-
imidazoquinazolines, solvent-free reactions
11
R
12
10
9
O
13
H
NO2
O2N
8
14
7
R
COCl
17
19
The synthesis of compounds belonging to benzimida-
zo[1,2-c]quinazoline series1,2 constitutes an important
area of research due to their interesting DNA binding
properties.3–5 In a previous paper we reported that the re-
action of 1-acetyl-2-(2-nitrophenyl)benzimidazole (1)
N
N
1
6
16
15
18
2
N
3
5
N
4
20
4
5-9
with iron in acetic acid–ethanol–water afforded a mixture Equation 1
of benzimidazoquinazoline 2 and 2-arylbenzimidazole 3
(Figure 1).6 The formation of compounds 2 and 3 was in-
Table 1 1-Benzoylbenzoimidazoles 5–9 Prepared by Reaction of 4
with Benzoyl Chlorides
terpreted assuming the participation of an dihydrobenzim-
idazoquinazoline intermediate.
Product
R
Yield (%)
In continuation of our work, we wish to report a novel and
interesting approach for the synthesis of 6-arylbenzimida-
zo[1,2-c]quinazolines 17–20 as sole products, using mi-
crowave activation on the precursor N-[2-(1H-
benzimidazol-2-yl)phenyl]benzamides 10–13. Com-
pounds 10–13 were obtained from the corresponding 5–9
benzoylbenzimidazole derivatives under reductive condi-
tions.
5
6
7
8
9
H
76
92
91
86
77
Cl
F
MeO
NO2
The starting benzimidazole 4 required for the study was
prepared from o-nitrobenzaldehyde by using our previ-
ously reported procedure.6 Compound 4 was reacted with
a range of 4-substituted benzoyl chlorides at 0 °C in THF
Amides 5–9 were subjected to reduction with iron in ace-
tic acid–ethanol–water solution at 45–50 °C (Equation 2).
This afforded the corresponding rearranged products 10–
N
Ac
NHAc
O2N
H
N
N
N
N
N
N
CH3
3
1
2
Figure 1 Compounds 1–3
SYNTHESIS 2004, No. 3, pp 0436–0440
x
x
.
x
x
.2
0
0
4
Advanced online publication: 26.01.2004
DOI: 10.1055/s-2004-815924; Art ID: M04503SS.pdf
© Georg Thieme Verlag Stuttgart · New York

PAPER
Solvent-Free Synthesis of 6-Arylbenzimidazo[1,2-c]quinazolines
437
17
16
18
19
R
NH
O
NO2
N
5
3
6
2
9
10
11
N
N
Feº
1
4
8
R
CONH
H2O/ HOAc/ EtOH
12
13
5-9
10-13
Equation 2
13 in good yields and no benzimidazo[1,2-c]quinazolines
were detected by 1H NMR analysis of the crude reaction
products. Reduction of 9 gave a complex reaction mixture
and no efforts were made to isolate the products. The re-
sults are summarized in Table 2.
Table 3 6-Phenylbenzimidazo[1,2-c]quinazolines Prepared by Mi-
crowave-Induced Cyclization of Benzimidazoles 10–13
Product
17
R
Time (min)
Yield (%)
H
30
40
30
45
41
54
56
37
18
Cl
F
Table 2 Products 10–13 Formed by Reduction of 1-Benzoylbenz-
imidazoles 5–8 with Iron
19
Product
10
R
Yield (%)
20
MeO
H
82
86
90
93
11
Cl
F
The formation of products 10–13 from 5–8 probably in-
volves intermediates 15 and 16, as depicted in Scheme 1.
According to this mechanism, the formation of tetracyclic
compounds by dehydration reaction of 16 could be favor-
able in a nonaqueous medium. Based on this assumption
and on the dipolar transition state7 involved in the forma-
tion of intermediates 16 by cyclization from the respective
precursors 10–13 (Scheme 1), we planned to use micro-
wave stimulation to induce the formation of tetracyclic
compounds 17–20 from 10–13. Heterocyclization of com-
12
13
MeO
The results indicate that cyclization of amides to the cor-
responding benzimidazo[1,2-c]quinazoline derivatives
under reductive conditions is an unfavorable process rela-
tive to the transposition reaction.
R
R
O
HO
NH
NH2
[H]
N
N
N
5-8
N
16
15
-H2O
C-N cleavage
R
O
N
N
HN
H
N
N
N
R
17-20
10-13
Scheme 1
Synthesis 2004, No. 3, 436–440 © Thieme Stuttgart · New York

438
H. Pessoa-Mahana et al.
PAPER
1-Benzoyl-1H-benzimidazole Derivatives 5–9; 1-(4-Fluorobenz-
oyl)-2-(2-nitrophenyl)-1H-benzimidazole (7); Typical Proce-
dure
pounds 10–13 using microwave induction was explored
under solvent-free conditions using a solid inorganic ma-
trix.8 Due to the fact that MnO2 has a large capacity to
transfer the dielectric heating9 we used a 95:5 mixture of
silica gel-manganese dioxide as solid support. Com-
pounds 10–13 were impregnated on the support and then
irradiated at 1000 W for an appropriate time (Table 3).
4-Fluorobenzoyl chloride (330 mg, 2.09 mmol) was slowly added
to a stirred solution of 2-(2-nitrophenyl)-1H-benzimidazole (4; 500
mg, 2.09 mmol), Et3N (210 mg, 2.09 mmol) and anhyd THF (50
mL) under N2 at 0 °C. The mixture was maintained at r.t. with stir-
ring for 4 h and then poured into H2O (100 mL). The mixture was
extracted with EtOAc (3 × 50 mL) and the combined organic layers
were dried (MgSO4). Removal of the solvent afforded 7; yield
(crude): 687 mg (91%); mp 165–166 °C (EtOH).
The treatment of 10–13 under microwave irradiation af-
forded the expected 6-phenylbenzimidazo[1,2-c]quinazo-
lines 17–20 in moderate yields (Equation 3). The reaction
proceeded within 30–45 minutes, meanwhile purely ther-
mal conditions (reflux in anhydrous m-xylene over 15 h)
gave a mixture of starting materials 10–13 and tetracyclic
6-phenylbenzimidazo[1,2-c]quinazolines 17–20. At-
tempts to cyclize compound 11 to the corresponding phe-
nylbenzimidazo[1,2-c]quinazolines 18 using only silica
gel were unsuccessful, indicating therefore the efficiency
of manganese dioxide for the microwave transfer energy.
IR: 3032, 1703, 1534, 1302 cm–1.
1H NMR (300 MHz): = 7.07 (d, 1 H, J = 8.2 Hz, 7-H), 7.23 (t, 2 H,
J = 8.4 Hz, 11-H, 13-H), 7.36 (t, 1 H, J = 7.5 Hz, 6 -H or 5-H), 7.49
(t, 1 H, J = 7.5 Hz, 5-H or 6-H), 7.72–7.92 (m, 5 H, 4-H, 18-H, 19-
H and 10-H, 14-H), 7,96 (d, J = 8.0 Hz, 1 H, 17-H), 8.28 (d, J = 8.0
Hz, 1 H, 20-H).
2
13C NMR (75.47 MHz) : = 113.7, 116.1 (d, 2 C, J = 22.1 Hz)
4
120.7, 124.6 (d, 2 C, 3J = 8.9 Hz), 125.0, 127.3, 128.4 (d, J = 2.9
Hz), 130.8, 132.8, 132.9, 133.0, 133,4 133.6, 142.8, 147.2, 150.3,
165.9 (d, 1J = 257 Hz), 166.6.
11
5-9
10
Anal. Calcd for C20H12 FN3 O3: C, 66.47; H, 3.35; N, 11.63. Found:
C, 66.10; H, 3.46; N, 11.51.
R
O
12
N
9
1
4
8
2
3
7
HN
N
1-Benzoyl-2-(2-nitrophenyl)-1H-benzimidazole (5)
Prepared from 4 (420 mg, 1.75 mmol) and benzoyl chloride (246
mg,1.75 mmol); yield (crude): 457 mg (76%); mp 154.5–155,5 °C
(EtOH).
H
N
14
6
Microwave
1000 Watts
15
N
5
N
18
R
16
IR: 3030, 1697, 1524, 1306 cm–1.
17
17-20
10-13
Equation 3
1H NMR (300 MHz): = 6.93 (d, 1 H, J = 8.2 Hz, 7-H), 7.25 (t, 1
H, J = 8.2 Hz, 5-H or 6-H), 7.37 (t, 1 H, J = 8.2 Hz, 6-H or 5-H),
7.43 (t, 2 H, J = 8.0 Hz, 18-H and 19-H), 7.56–7.76 (m, 6 H, 4-H,
and C6H5CO), 7.85 (d, J = 8.0 Hz, 1 H, 17-H), 8.16 (d, J = 8.2 Hz,
1 H, 20-H).
13C NMR (75 MHz): = 114.0, 120.6, 124.4, 124.6, 124.9, 127.5,
128.7 (2 C), 130.0 (2 C), 130.7, 132.4, 132.9, 133.4, 133.5, 133.8,
142.8, 147.2, 150.4, 167.8.
In summary, the syntheses of 6-arylbenzimidazo[1,2-
c]quinazolines have been accomplished by employing the
reduction of 2-(2-nitrophenyl)-1-(4-substituted benzoyl)-
1H-benzimidazoles followed by heterocyclization of the
corresponding benzimidazoylbenzamides, under solvent-
free microwave irradiation. This new approach firmly
confirms the great utility of microwave stimulation in het-
erocyclization reactions for preparing complex polycyclic
systems.
Anal. Calcd for C20H13N3O3: C, 69.95; H, 3.82; N, 12.24. Found: C,
69.91; H, 3.93; N, 12.11.
1-(4-Chlorobenzoyl)-2-(2-nitrophenyl)-1H-benzimidazole (6)
Prepared from 4 (462 mg, 1.93 mmol) and 4-chlorobenzoyl chloride
(338 mg, 1.93 mmol); yield (crude): 670 mg (92%); mp 278.2–
279.0 °C (EtOH).
All reagents were obtained commercially and used without further
purification. Melting points were determined on a Kofler hot-stage
apparatus and are uncorrected. IR spectra were recorded with a FT
Bruker spectrometer in KBr optics. 1H NMR and 13C NMR spectra
were obtained with a Bruker DRX-300 and a Bruker ACP-200 spec-
trophotometers. The chemical shifts are expressed in ppm ( scale)
downfield from TMS, J values are given in Hertz for solutions in
CDCl3 unless otherwise indicated. Microanalyses were determined
on a Fisons EA 1108 instrument. Silica gel Merck 60 (70–230
mesh) and DC-Alufolien 60 F254 were normally used for column
and TLC chromatography, respectively. The microwave-assisted
procedures were carried out in a domestic microwave oven operat-
ing at 1000 W. MnO2was prepared by our reported procedure.10 The
solid support was preparing by heating a 95:5 mixture of silica gel
(70–230 mesh) and MnO2 at 300 °C for 2 h. Petroleum ether used
had bp 70–90 °C.
IR: 3030, 1710, 1530, 1352 cm–1.
1H NMR (300 MHz): = 6.95 (d, 1 H, J = 8.3 Hz, 7-H), 7,26 (t, 1
H, J = 8.0 Hz, 5-H or 6-H), 7.38–7.42 (m, 3 H, 6-H or 5-H, 11-H
and 13-H), 7.62–7.79 (m, 5 H, 4-H, 18-H, 19-H and 10-H, 14-H),
7.85 (d, J = 8.0 Hz, 1 H, 17-H), 8.17 (d, J = 8.0 Hz, 1 H, 20-H).
13C NMR (75 MHz): = 113.8, 120.7, 124.6, 124.7, 125.0, 127.3,
129.1 (2 C), 130.6, 130.8, 131.5 (2 C), 132.9, 133.3, 133.6, 140.4,
142.8, 147.2, 150.3, 166.7.
Anal. Calcd for C20H12ClN3O3: C, 63.55; H, 3.21; N, 11.14. Found:
C 63.37; H, 3.38; N, 11.16.
1-(4-Methoxybenzoyl)-2-(2-nitrophenyl)-1H-benzimidazole (8)
Prepared from 4 (380 mg, 1.59 mmol) and 4-methoxybenzoyl chlo-
ride (271 mg, 1.59 mmol); yield (crude): 511 mg (86%); mp 128–
129 °C (EtOH).
IR: 3030, 1700, 1525, 1348 cm–1.
1H NMR (300 MHz): = 3.81 (s, 3 H, OCH3), 6.87 (d, 2 H, J = 8.8
Hz, 11-H and 13-H), 7.02 (d, 1 H, J = 8.0 Hz, 7-H), 7,21 (t,1 H,
Synthesis 2004, No. 3, 436–440 © Thieme Stuttgart · New York

PAPER
Solvent-Free Synthesis of 6-Arylbenzimidazo[1,2-c]quinazolines
439
J = 7.7 Hz, 5-H or 6-H), 7.33 (t, 1 H, J = 7.7 Hz, 6-H or 5-H), 7.57
(td, 1 H, J = 7.6, 2.1 Hz, 18-H or 19-H), 7,64–7.76 (m, 4 H, 4-H,
10-H, 14-H and 19-H, or 18-H), 7,84 (d, J = 8.1 Hz, 1 H, 17-H),
8.11 (d, J = 8.0 Hz, 1 H, 20-H).
13C NMR (DMSO-d6, 75 MHz): = 56.2, 114.4, 114.7 (2 C), 120.6,
124.4, 124.8, 124.9, 125.3, 126.8, 131.8, 133.1 (2 C), 133.3, 134.1,
134.3, 142.9, 148.0, 150.1, 164.4, 167.1.
13C NMR (DMSO-d6, 75.47 MHz): = 112.0, 116.2, 119.0, 120.4,
123.0, 123.8, 124.2, 127.8, 129.6 (2 C), 129.7 (2 C), 131.4, 133.8,
134.1, 137.5, 138.8, 142.3, 151.4, 164.3.
Anal. Calcd for C20H14ClN3O: C, 69.15; H, 4.07; N, 12.10. Found:
C, 69.12; H, 4.18; N, 11.93.
N-[2-(1H-Benzimidazol-2-yl) phenyl]-4-fluorobenzamide (12)
Prepared from 7 (382 mg, 1.06 mmol); yield (crude): 314 mg
(90%); mp 301–302 °C (EtOH).
IR: 3295, 3030, 1636, 1602 cm–1.
Anal. Calcd for C21H15N3O4: C, 67.54; H, 4.05; N, 11.26. Found: C,
67.86; H, 4.18; N, 11.34.
1-(4-Nitrobenzoyl)-2-(2-nitrophenyl)-1H-benzimidazole (9)
Prepared from 4 (470 mg, 1.97 mmol) and 4-nitrobenzoyl chloride
(365 mg, 1.97 mmol); yield (crude): 585 mg (77%); mp 178.5–179
°C (EtOH).
1H NMR (DMSO-d6, 300.13 MHz): = 7.26–7.37 (m, 3 H, 18-H,
17-H and 12-H or 11-H), 7.52–7.59 (m, 3 H, 3-H, 5-H, and 11-H or
12-H), 7.61 (d, 1 H, J = 7.1 Hz, 16-H or 19-H), 7.85 (d, 1 H, J = 6.9
Hz, 19-H or 16-H), 8.19 (d, 1 H, J = 7.1 Hz, 13-H), 8.28–8.33 (m,
2 H, 2-H, and 6-H), 8.91 (d, 1 H, J = 7.7 Hz, 10-H), 13.30 (s, 1 H,
NH), 14.10 (s, 1 H, NHCO).
IR: 3030, 1702, 1524, 1306 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 7.29 (d, 1 H, J = 7.7 Hz, 7-H),
7.36 (dt, 1 H, J = 7.6, 1.2 Hz, 5-H or 6-H), 7.43 (dt, 1 H, J = 7.8, 1.2
Hz, 6-H or 5-H), 7.69 (dt, 1 H, J = 7.7, 1,7 Hz, 18-H or 19-H), 7.77
(dt, 1 H, J = 7.5, 1.1 Hz, 19-H or 18-H), 7.82–7.87 (m, 2 H, 17-H
and 4-H), 7,90 (d, 2 H, J = 8.8 Hz, 10-H, and 14-H), 8.11 (dd, 1 H,
J = 8.1, 1.0 Hz, 20-H), 8.21 (d, 2 H, J = 8.8 Hz, 11-H and 13-H).
13C NMR (DMSO-d6, 75 MHz): = 115.3, 120.7, 124.2 (2 C),
125.0, 125.5, 125.9, 126.8, 131.2 (2 C), 132.0, 133.6 (2 C), 134.5,
138.6, 143.0, 147.8, 150.0, 150.2, 166.6.
13C NMR (DMSO-d6, 75 MHz): = 112.0, 116.0, 116.4 (d, 2 C,
2J = 22 Hz), 118.8, 120.3, 122.8, 123.6, 124.0, 127.6, 130.4 (d, 2 C,
4
3J = 9.3 Hz), 131.2, 131.7 (d, J = 2.9 Hz), 133.7, 138.8, 142.2,
151.3, 164.2, 164.7 (d, 1J = 249.7 Hz).
Anal. Calcd for C20H14FN3O: C, 72.48; H, 4.26; N, 12.69. Found:
C, 72.09; H, 4.35; N, 12.36.
N-[2-(1H-Benzimidazol-2-yl)phenyl]-4-methoxybenzamide (13)
Prepared from 8 (523 mg, 1.40 mmol); yield (crude): 446 mg
(93%); mp 257–258 °C (EtOH).
IR: 3277, 3030, 1653, 1595 cm–1.
Anal. Calcd for C20H12N4O5: C, 61.84; H, 3.12; N, 14.43. Found: C,
61.56; H, 3.39; N, 14.40.
N-[2-(1H-Benzimidazol-2-yl)phenyl]benzamides 10–13; N-[2-
(1H-Benzimidazol-2-yl)phenyl]benzamide (10); Typical Proce-
dure
1H NMR (DMSO- d6, 300 MHz): = 3.89 (s, 3 H, OCH3), 7.22 (d,
2 H, J = 8.6 Hz, 3-H and 5-H), 7.27–7.32 (m, 3 H, 18-H, 17-H, and
12-H or 11-H), 7.52 (t, 1 H, J = 7.7 Hz, 11-H, or 12-H), 7.60 (d, 1
H, J = 6.1 Hz, 16-H or 19-H), 7.86 (d, 1 H, J = 6.2 Hz, 19-H or 16-
H), 8.17 (d, 1 H, J = 7.8 Hz, 13-H), 8.22 (d, 2 H, J = 8.6 Hz, 2-H,
and 6-H), 8.92 (d, 1 H, J = 8.3 Hz, 10-H), 13.23 (s, 1 H,NH), 13.93
(s, 1 H, NHCO).
13C NMR (DMSO- d6, 75.47 MHz): = 56.0, 112.0, 114.7 (2 C),
115.9, 118.9, 120.4, 122.9, 123.3, 124.1, 127.4, 127.7, 129.8 (2 C),
131.3, 133.9, 139.2, 142.4, 151.5, 162.8, 165.0.
A stirred suspension of 1-benzoyl-2-(2-nitrophenyl)-1H-benzimi-
dazole (5; 328 mg, 0.96 mmol), powder iron (1 g, 17.86 mmol) and
AcOH–EtOH–H2O (80 mL, 1:1:1) was heated at 50–60 °C for 1 h.
The mixture was then diluted with H2O (30 mL), neutralized with
NaHCO3 and extracted with EtOAc (3 × 70 mL). The combined or-
ganic layers were dried (Na2SO4) and the solvent was evaporated in
vacuo to give 10 as a white pale solid; yield (crude): 246 mg (82%).
Further purification of the crude by column chromatography on sil-
ica gel (CHCl3–EtOACc, 1:1) followed by recrystallization from
EtOAc afforded 10 (207 mg, 69%); mp 257–258 °C (EtOH).
Anal. Calcd for C21H17N3O2: C, 73.44; H, 4.99; N, 12.24. Found: C,
73.23; H, 4.73; N, 12.34.
IR: 3274, 3030, 1634, 1595 cm–1.
Benzimidazo[1,2-c]quinazolines 17–20; 6-Phenylbenzimida-
zo[1,2-c]quinazoline (17); Typical Procedure
1H NMR (DMSO-d6, 300 MHz): = 7.28–7.34 (m, 3 H, 18-H, 17-
H and 12-H or 11-H), 7.55 (t, 1 H, J = 8.0 Hz, 11-H or 12-H), 7.61
(d, 1 H, J = 7.9 Hz, 16-H or 19-H), 7.66–7.72 (m, 3 H, 3-H, 4-H and
5-H), 7.79 (d, 1 H, J = 6.9 Hz, 19-H or 16-H), 8.18 (d, 1 H, J = 7.8
Hz, 13-H), 8.23–8.26 (m, 2 H, 2-H, and 6-H), 8.92 (d, 1 H, J = 8.2
Hz, 10-H), 13.27 (s, 1 H, NH), 14.05 (s, 1 H, NHCO).
13C NMR (DMSO-d6, 75 MHz): = 112.1, 116.1, 118.7, 120.5,
123.0, 123.6, 124.1, 127.8 (3 C), 129.5 (2 C), 131.3, 132.6, 133.9,
135.3, 138.9, 142.4, 151.4, 166.5.
To a solution of N-[2-(1H-benzimidazol-2-yl)phenyl]benzamide
(10; 70.4 mg, 0.225 mmol) in CH2Cl2 (15 mL) was added the inor-
ganic support (55 g) and the suspension was vigorously stirred for
15 min at r.t. The solvent was removed in vacuo and the solid was
irradiated at 1000 W for an appropriate time (Table 3), until TLC
showed the disappearance of the starting material. The solid was
thoroughly washed with acetone followed by removal of the solvent
to afford 17; yield (crude): 27 mg (41%). A pure sample of 17 was
obtained by column chromatography on silica gel eluting with
CH2Cl2 (21 mg, 32%); mp 231–233 °C (EtOH–petroleum ether,
2:1).
Anal. Calcd for C20H15N3O: C, 76.65; H, 4.83; N, 13.42. Found: C,
76.42; H, 4.84; N, 13.48.
N-[2-(1H-Benzimidazol-2-yl)phenyl]-4-chlorobenzamide (11)
Prepared from 6 (361 mg, 0.96 mmol); yield (crude): 285 mg
(86%); mp 337–338 °C (EtOH).
IR: 3296, 3030, 1636, 1593 cm–1.
1H NMR (DMSO-d6, 300 MHz): = 7.28–7.35 (m, 3 H, 18-H, 17-
H and 12-H or 11-H), 7.54 (td, 1 H, J = 7.9, 1.2 Hz, 11-H or 12-H),
7.62–7.59 (m, 1 H, 16-H, or 19-H), 7.78 (d, 2 H, J = 8.6 Hz, 3-H and
5-H), 7.84–7.87 (m, 1 H, 19-H or 16-H), 8.18 (dd, 1 H, J = 7.9, 1.2
Hz, 13-H), 8.24 (d, 2 H, J = 8.6 Hz, 2-H, and 6-H), 8.92 (dd, 1 H,
J = 8.4, 0.8 Hz, 10-H), 13.26 (s, 1 H, NH), 14.11 (s, 1 H, NHCO).
IR: 3056, 1626, 1592 cm–1.
1H NMR (200 MHz): = 6.62 (d, 1 H, J = 8.4 Hz, 8-H), 7.12 (td, 1
H, J = 7.8, 1.2 Hz, 9-H or 10-H), 7.48 (td, 1 H, J = 7.8, 1.1 Hz, 10-
H or 9-H), 7.62–7.86 (m, 7 H, C6H5, and 2-H, 3-H), 7.96–8.04 (m,
2 H, 4-H and 11-H), 8.77 (dd, 1 H, J = 7.7 Hz, 1.4 Hz, 1-H).
13C NMR (50 MHz): = 114.7, 120.2, 122.9, 124.5, 125.9, 127.4,
128.5, 128.6 (2 C), 128.9, 129.6 (3 C), 131.3, 132.1, 134.5, 142.7,
144.6, 148.3, 148.8.
Synthesis 2004, No. 3, 436–440 © Thieme Stuttgart · New York

440
H. Pessoa-Mahana et al.
PAPER
Anal. Calcd for C20H13N3: C, 81.34; H, 4.44; N, 14.23. Found: C,
81.62; H, 4.60; N, 14.56.
and 2-H, 3-H), 8.0 (d, 2 H, J = 8.1 Hz, 4-H and 11-H), 8.75 (dd, 1
H, J = 7.8, 1.3 Hz, 1-H).
13C NMR (50 MHz): = 55.6, 114.5, 114.6 (2 C), 118.3, 120.0,
122.5, 124.2, 125.6, 126.7, 128.1 (2 C), 129.4, 130.0 (2 C), 131.8,
142.5, 144.4, 148.3, 148.5, 161.6.
6-(4-Chlorophenyl)benzimidazo[1,2-c]quinazoline (18)
Prepared from 11 (66.6 mg, 0.202 mmol); yield (crude): 34.1 mg
(54%); mp 240–241.5 °C (EtOH–petroleum ether, 2:1).
IR: 3060, 1635, 1592 cm–1.
1H NMR (200 MHz): = 6.75 (d, 1 H, J = 8.4 Hz, 8-H), 7.17 (td, 1
H, J = 7.3, 1.2 Hz, 9-H or 10-H), 7.50 (dt, 1 H, J = 7.2, 1.2 Hz, 10-
H or 9-H), 7.63–7.85 (m, 6 H, 14-H, 15-H, 17-H, 18-H and 2-H, 3-
H), 7.98–8.03 (m, 2 H, 4-H and 11-H), 8.75 (dd, 1 H, J = 7.8, 1.5
Hz, 1-H).
13C NMR (50 MHz): = 114.2, 118.5, 120.2, 122.7, 124.3, 125.8,
128.2, 128.5, 129.1, 129.6 (2 C), 130.0 (2 C), 132.0, 132.7, 137.3,
142.3, 144.5, 147.4, 148.0.
Anal. Calcd for C21H15N3O: C, 77.52; H, 4.65; N, 12.91. Found: C,
77.20; H, 4.92; N, 12.73.
Acknowledgment
We thank FONDECYT 1030916 and CEPEDEQ of Facultad de
Ciencias Químicas y Farmacéuticas, Universidad de Chile for
microanalytical and NMR facilities.
References
Anal. Calcd for C20H12ClN3: C, 72.93; H, 3.68; N, 12.77. Found: C,
72.82; H, 3.62; N, 12.56.
(1) Khajavi, M. S.; Rad-Moghadam, K.; Hazarkhani, H.
Synth.Commun. 1999, 29, 2617.
6-(4-Fluorophenyl)benzimidazo[1,2-c]quinazoline (19)
Prepared from 12 (100 mg, 0.30 mmol); yield (crude): 52.4 mg
(56%); mp 223–223.5 °C (EtOH–petroleum ether, 2:1).
(2) Soukri, M.; Guillaumet, G.; Besson, T.; Aziane, D.; Aadil,
M.; Essassi, E. M.; Akssira, M. Tetrahedron Lett. 2000, 41,
5857.
IR: 3070, 1628, 1597 cm–1.
(3) Lamazzi, C.; Léonce, S.; Pfeiffer, B.; Renard, P.;
Guillaumet, G.; Rees, C. W.; Besson, T. Bioorg. Med. Chem.
Lett. 2000, 10, 2183.
(4) Dalla, V. i. a. L.; Gia, O.; Marciani Magno, S.; Da Settimo,
A.; Primofiore, G.; Da Settimo, F.; Simorini, F.; Marini, A.
M. Eur. J. Med. Chem. 2002, 37, 475.
(5) Dalla, V. i. a. L.; Gia, O.; MarcianiMagno, S.; Da Settimo,
A.; Marini, A. M.; Primofiore, G.; Da Settimo, F.; Salerno,
S. Farmaco 2001, 56, 159.
(6) Valderrama, J. A.; Pessoa-Mahana, H.; Sarrás, G.; Tapia, R.
Heterocycles 1999, 51, 2193.
1H NMR (200 MHz): = 6.69 (d, 1 H, J = 8.4 Hz, 8-H), 7.17 (td, 1
H, J = 7.9, 1.2 Hz, 9-H or 10-H), 7.32–7.41 (m, 2 H, 15-H, 17-H),
7.50 (td, 1 H, J = 7.7, 1.1 Hz, 10-H or 9-H), 7.68–7.86 (m, 4 H, 14-
H, 18-H and 2-H, 3-H), 7.96–8.03 (m, 2 H, 4-H and 11-H), 8.75
(ddd, 1 H, J = 7.6, 1.3, 0.7 Hz, 1-H).
13C NMR (50 MHz): = 114.1, 116.6 (d, 2 C, 2J = 21.6 Hz), 118.5,
120.2, 122.7, 124.3, 125.8, 128.2, 128.5, 129.2, 130.5, 130.7 (d, 2
C, 3J = 9.3 Hz), 132.0, 142.3, 144.4, 147.5, 148.1, 164.2 (d,
1J = 248.5 Hz).
(7) For precedents on microwave effects on cyclization
reactions involving transition states more polar than the
ground states, see: (a) Bougrin, K.; Loupy, A.; Petit, A.;
Daou, B.; Soufiaoui, M. Tetrahedron 2001, 57, 163.
(b) Dandia, A.; Sati, M.; Arya, K.; Loupy, A. Heterocycles
2003, 60, 563.
(8) For a review on solvent-free organic synthesis using
microwaves, see: Loupy, A.; Petit, A.; Hamelin, J.; Texier-
Boullet, F.; Jacquault, P.; Mathé, D. Synthesis 1998, 1213.
(9) Walkiewicz, J. W.; Kazonich, G.; McGill, J. L. Miner.
Metall. Proc. 1988, 5, 39.
Anal. Calcd for C20H12FN3: C, 76.24; H, 3.86; N, 13.41. Found: C,
76.37; H, 3.78; N, 13.34.
6-(4-Methoxyphenyl)benzimidazo[1,2-c]quinazoline (20)
Prepared from 13 (69.2 mg, 0.20 mmol); yield (crude): 24.4 mg
(37%); mp 255–256 °C (EtOH–petroleum ether, 2:1).
IR: 3060, 1628, 1590,1451, 1361 cm–1.
1H NMR (200 MHz): = 3.97 (s, 3 H, OCH3), 6.81 (d, 1 H, J = 8.4
Hz, 8-H), 7.11–7.18 (m, 3 H, 15-H, 17-H and 9-H or 10-H), 7.48 (td,
1 H, J = 7.7, 1.0 Hz, 10-H or 9-H), 7.66–7.84 (m, 4 H, 14-H, 18-H
(10) Cassis, R.; Valderrama, J. A. Synth. Commun. 1983, 13, 347.
Synthesis 2004, No. 3, 436–440 © Thieme Stuttgart · New York