Synthesis, characterization and biological activity studies on 6-p-dimethylaminophenyl-5,6-dihydrobenzoimidazo [1,2-c]quinazoline: Crystal structure of the title compound and comparative study with related derivatives

Article abstract of DOI:10.1007/s10870-011-0243-z

Reaction of o-aminophenylbenzimidazole with p-dimethylaminobenzaldehyde yielded 6-p-dimethylamin-ophenyl-5,6-dihydrobenzoimidazo[ 1,2-c]quinazoline, which was characterized by elemental analysis, IR, UV-Vis, ¹H NMR, ¹³C NMR, mass spectral studies and X-ray crystal structure analysis. Studies on the antimicrobial activity of the compound revealed that it is active against fungus Yeast but not Bacillus subtilis. The compound crystallized in the space group P2₁/n with the unit cell parameters a = 10.652(2) A, b = 11.002(2) A, c = 15.753(2) A, β = 109.29(2)° and the structure was refined to an R-factor of 0.0479. The hydropyrimidine ring in the quinazoline moiety is in skew-boat conformation. The dimethylamino group attached to phenyl ring is in conjugation with it. The structure was stabilized by intermolecular C-H-N interactions. A few of the related quinazolines (6-p-hydroxyphenyl-5,6-dihydrobenzoimidazo [1,2-c]quinazoline; 6-phenyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline; 6-pyridyl-5,6- dihydrobenzoimidazo[1,2-c]quinazoline; 6-furyl-5,6-dihydrobenzoimidazo[1,2-c] quinazoline) were also examined for their biological activity, in addition to their characterization by IR, UV-Vis, JH and ¹³C NMR spectral studies along with structural comparison. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s10870-011-0243-z

J Chem Crystallogr (2012) 42:305–312
DOI 10.1007/s10870-011-0243-z
ORIGINAL PAPER
Synthesis, Characterization and Biological Activity Studies
on 6-p-Dimethylaminophenyl-5,6-dihydrobenzoimidazo
[1,2-c]quinazoline: Crystal Structure of the Title Compound
and Comparative Study with Related Derivatives
•
S. G. Bubbly S. B. Gudennavar N. M. Nanje Gowda
•
•
•
•
Rita Bhattacharjee V. Gayathri S. Natarajan
Received: 14 April 2011 / Accepted: 3 December 2011 / Published online: 14 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Reaction of o-aminophenylbenzimidazole with
p-dimethylaminobenzaldehyde yielded 6-p-dimethylamin-
ophenyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline, which
were also examined for their biological activity, in addition
1
to their characterization by IR, UV–Vis, H and 13C NMR
spectral studies along with structural comparison.
1
was characterized by elemental analysis, IR, UV–Vis, H
NMR, 13C NMR, mass spectral studies and X-ray crystal
structure analysis. Studies on the antimicrobial activity of the
compound revealed that it is active against fungus Yeast but
not Bacillus subtilis. The compound crystallized in the space
Keywords X-ray crystal structure ꢀ NMR ꢀ
p-Dimethylaminobenzaldehyde ꢀ
o-Aminophenylbenzimidazole ꢀ
Benzoimidazo[1,2-c]quinazoline ꢀ Biological activity
˚
group P21/n with the unit cell parameters a = 10.652(2) A,
˚
˚
b = 11.002(2) A, c = 15.753(2) A, b = 109.29(2)° and the
structure was refined to an R-factor of 0.0479. The hydro-
pyrimidine ring in the quinazoline moiety is in skew-boat
conformation. The dimethylamino group attached to phenyl
ring is in conjugation with it. The structure was stabilized by
intermolecular C–H–N interactions. A few of the related
quinazolines (6-p-hydroxyphenyl-5,6-dihydrobenzoimidazo
[1,2-c]quinazoline; 6-phenyl-5,6-dihydrobenzoimidazo[1,2-
c]quinazoline; 6-pyridyl-5,6-dihydrobenzoimidazo[1,2-c]qui-
nazoline; 6-furyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline)
Introduction
Quinazolines and their derivatives are of significant focus in
the field of medicinal chemistry owing to their broad spectrum
of biological properties. They are potent cytotoxic agents
[1–4]. Substituted quinazolines exhibit fungicidal, anti-
microbial, CNS stimulant, diuretic, anti-inflammatory, anti-
cancer, anti-hypertensive, anti-analgesic, antitumour and
anti-HIV properties [5–7]. Some of the derivatives of
indole[1,2-c]quinazoline show cataleptogenic activity [8].
Imidazole and their derivatives are widely used as ligating
groups to transition metal ions [9, 10]. Multidentate N-hetero-
cycles on coordination to metal ions produce organized
supramolecules and they appear quite promising for the design
of stable light conversion devices [11]. The application of
imidazoles in medicinal chemistry [12] and chemistry of nat-
ural products/alkaloids [13, 14] are also well known. Hetero-
cycles containing the imidazole moiety are of biological
significance and display antibacterial, antifungal activities [15],
leukotriene B4 receptor antagonist properties [16], and potas-
sium channel openers [17]. Benzimidazole and their derivatives
as well as their metal complexes exhibit antibacterial, anti-
fungal, veterinary, anthelmintic, insecticidal and virucidal
activities [18, 19]. It is likely that the introduction of benz-
imidazole group into the quinazoline system would appreciably
S. G. Bubbly (&) ꢀ S. B. Gudennavar
Department of Physics, Christ University, Hosur Road,
Bangalore 560029, Karnataka, India
e-mail: bubbly.sg@christuniversity.in;
bubblysg@rediffmail.com
N. M. Nanje Gowda
Dean of Science, Christ University, Bangalore 560 029,
Karnataka, India
R. Bhattacharjee ꢀ V. Gayathri
Department of Chemistry, Bangalore University, Central College
Campus, Bangalore 560001, Karnataka, India
S. Natarajan
School of Physics, Madurai Kamaraj University, Madurai
625021, Tamilnadu, India
123

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J Chem Crystallogr (2012) 42:305–312
influence the biological activity of the latter. Benzimidazo-
quinazolines have been reported to exhibit virucidal properties
and antifungal effects against dermatophytes [20]. Benzimi-
dazo[1,2-c]quinazolines with 6-alkyl substitution have been
evaluated for their bronchodilator activity [21].
was separated and recrystallized from ethanol to get
6-p-dimethylaminophenyl-5,6-dihydrobenzoimidazo[1,2-c]
quinazoline (I) as a cream crystalline solid. Compounds II
through V were prepared as reported earlier [24–27].
Elemental analysis for 6-p-dimethylaminophenyl-
5,6-dihydrobenzoimidazo[1,2-c]quinazoline (I) having the
molecular formula C22H20N4 requires C 77.63, H 5.92, N
16.45%. Found: C 76.78, H 6.16, N 15.87%. Yield: 60%;
mp: 201°C. dH (400 MHz, DMSO-d6) {7.4 (s, NH), 6.86 (s,
CH), 7.96 (d, J = 8.0, H-7), 7.24 (t, J = 7.60, H-8), 6.81
(t, J = 0.8, H-9), 6.87 (d, J = 8.0, H-10), quinazoline ring
protons}, {7.62 (s, H-20), 7.06 (t, J = 7.2, H-30), 7.02
(t, J = 7.2, H-40), 7.12 (d, J = 1.2, H-50), benzimidazole
ring protons}, {7.15 (d, J = 8.4, H-200/600), 6.63 (d,
J = 8.8, H-300/500), phenyl ring protons}, 2.82 (s, 2CH3). dC
(400 MHz, DMSO-d6) {147.15 (C-2), 143.61 (C-3), 110.68
(C-4), 68.23 (CH), 127.25 (C-7), 131.39 (C-8), 117.88
(C-9), 114.66 (C-10), quinazoline ring carbons}, {118.47
(C-20) 121.86 (C-30), 121.71, (C-40), 111.88 (C-50), 132.92
(C-60), 143.88 (C-70), benzimidazole ring carbons}, 124.54
(C-100), 127.07 (C-200/600), 111.92 (C-300/500), 150.75 (C-400),
phenyl ring carbons}, 40.12 (2CH3).
Presumably, the biological activity of 6-phenyl-5,6-di-
hydrobenzimidazo[1,2-c]quinazoline is related to its
structure and electron donor/acceptor substituents. For
instance, the introduction of electron-withdrawing substit-
uents such as Cl, Br, F and NO2 on the 6-phenyl ring
rendered compounds devoid of antifungal activity [22]. On
the contrary, an electron donor substituent such as OCH3
group enhanced the activity of the compound by nearly five
times as in T. mentagrophytes, E. floccosum and T. rubrum.
A detailed analysis of the structure of a compound
would provide an opportunity to understand the biological
function and its implication in the structural ramifications
needed for binding to the receptors. In the present
study, we have made an attempt to understand the influence
of the substituent groups on the conformation of the
dihydrobenzoimidazo[1,2-c]quinazoline ring system. With
this in view, herein we report the synthesis, characteriza-
tion, crystal structure and biological activity of 6-p-dim-
ethylaminophenyl-5,6-dihydrobenzoimidazo[1,2-
6-p-Hydroxyphenyl-5,6-dihydrobenzoimidazo
[1,2-c]quinazoline (II)
c]quinazoline.
White solid; Yield: 60%; mp: 295°C. dH (400 MHz,
DMSO-d6) 7.46 (s, NH), 6.89 (s, CH), {7.96 (d, J = 5.6,
H-7), 7.25 (t, J = 5.60, H-8), 6.83 (t, J = 6.0, H-9), 6.87
(d, J = 6.8, H-10), quinazoline ring protons}, {7.64 (d,
J = 6.4, H-20), 7.16 (t, J = 6.4, H-30), 7.06 (t, J = 6.0,
H-40), 6.96 (d, J = 6.4, H-50), benzimidazole ring protons},
{7.19(d, J = 6.8, H-200/600), 6.74 (d, J = 6.8, H-300/500),
phenyl ring protons}, 9.65 (s, OH). dC (400 MHz, DMSO-
d6) {147.04 (C-2), 143.50 (C-3), 111.70 (C-4), 68.10 (CH),
121.90 (C-7), 131.50 (C-8), 117.90 (C-9), 114.60 (C-10),
quinazoline ring carbons}, {118.50 (C-20) 121.90 (C-30),
121.70, (C-40), 110.60(C-50), 132.80 (C-60), 143.80 (C-70),
benzimidazole ring carbons}, {130.50 (C-100), 127.70
(C-200/600), 115.30 (C-300/500), 158.00 (C-400), phenyl ring
carbons}.
Experimental
Apparatus
The electronic spectra of the N-heterocycles (I–V) were
recorded in DMF using Shimadzu UV3101 PC. The IR
spectra of the compounds were recorded as Nujol mulls
using Shimadzu FTIR 8400S spectrometer. 1H and 13C
NMR spectra of the N-heterocycles were recorded on
Bruker av 400 MHz instrument using DMSO-d6 as solvent.
1
The H and 13C NMR chemical shifts are reported as d in
parts per million relative to tetramethylsilane as an internal
reference and coupling constants (J) are in Hz. The mass
spectrum of I was recorded on Shimadzu GCMS QP5050.
Synthesis and Spectroscopic Characterization
6-Phenyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline (III)
6-p-Dimethylaminophenyl-5,6-dihydrobenzoimidazo
[1,2-c]quinazoline (I)
White solid; Yield: 70%; mp: 199°C. dH (400 MHz,
DMSO-d6) 7.62 (s, NH), 7.08 (s, CH), {7.95 (d, J = 6.7,
H-7), 7.27 (m, H-8), 6.82 (t, J = 7.4, H-9), 6.86
(d, J = 8.1, H-10), quinazoline ring protons}, {7.65 (d,
J = 7.95, H-20), 7.25 (m, H-30), 7.18 (m, H-40),7.10(d,
J = 7.2, H-50), benzimidazole ring protons}, {7.29 (m,
H-200/600), 7.33 (m, H-300/500), 7.15 (m, H-400), phenyl ring
protons}. dC (400 MHz, DMSO-d6) {146.80 (C-2), 143.11
(C-3), 111.80 (C-4), 67.80 (CH), 124.59 (C-7), 131.61
o-Aminophenylbenzimidazole was prepared by adopting a
literature method [23]. A mixture of o-aminophenylbenz-
imidazole (0.05 mol, 10.45 g) and p-dimethylamino benzal-
dehyde (0.05 mol, 6.66 g) in 200 ml of ethanol was refluxed
for 5 h. The resulting solution was evaporated under reduced
pressure to a small volume to obtain a yellow compound. It
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J Chem Crystallogr (2012) 42:305–312
307
(C-8), 118.13 (C-9), 114.76 (C-10), quinazoline ring car-
bons}, {118.55 (C-20) 122.13 (C-30), 121.98 (C-40), 110.47
(C-50), 140.31 (C-60), 143.80 (C-70), benzimidazole ring
carbons},{132.78 (C-100), 128.88 (C-200/400/600), 125.94
(C-300/500), phenyl ring carbons}.
Table 1 Crystal data, intensity collection conditions and refinement
parameters for compound I
CCDC No.
742983
Empirical formula
Formula weight
Temperature (K)
C22H20N4
340.42
293(2)
6-Pyridyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline (IV)
˚
Wavelength (A)
1.54180
Crystal system, space group
Monoclinic, P21/n
a = 10.652(2), b = 11.002(2),
c = 15.753(3), b = 109.29(2)
1742.5(6)
White solid; Yield: 60%; mp: 230°C. dH (400 MHz,
DMSO-d6) {5.4 (s, NH), 7.72 (s, CH), 7.64 (d, J = 9.4,
H-7), 7.24 (m, H-8), 7.24 (m, H-9), 7.32 (d, J = 9.4, H-10),
quinazoline ring protons}, {7.16 (d, J = 7.02, H-20), 7.06
(m, H-30), 6.80 (m, H-40), 6.83 (d, J = 9.4, H-50), benz-
imidazole ring protons}, {7.94 (d, J = 9.4, H-300), 7.74
(m, H-400), 7.03 (t, J = 9.4, H-500), 8.4(d, J = 4.7, H-600),
pyridyl ring protons}. dC (400 MHz, DMSO-d6)
{158.40(C-2), 112.10(C-3), 133.00 (C-4), 67.50 (CH),
123.90 (C-7), 122.00 (C-8), 122.20 (C-9), 124.60 (C-10),
quinazoline ring carbons}, {110.70 (C-20) 114.70 (C-30),
118.10, (C-40), 118.60 (C-50), 143.80 (C-60), 142.90 (C-70),
benzimidazole ring carbons}, {146.9 (C-100), 137.40
(C-300), 120.20 (C-400), 131.50 (C-500), 149.4 (C-600), pyridyl
ring carbons}.
˚
Unit cell dimensions (A, °)
3
˚
Volume (A )
Z, Calculated density (Mg/m3)
4, 1.298
Absorption coefficient
(mm-1
0.616
)
Absorption correction
Max. and min. transmission
Crystal size (mm)
F(000)
Psi-scan [29]
0.98 and 0.97
0.13 9 0.11 9 0.10
720
h range for data collection (°)
Index ranges
4.42–66.32
0 B h B 12, -1 B k B 13,
-18 B l B 17
Reflections collected/unique
Completeness to
3586/3051 [R(int) = 0.0194]
2h = 66.32, 94.4%
Refinement method
Full-matrix least-squares on F2
1.031
Goodness-of-fit on F2
Data/restraints/parameters
Final R indices (I [ 2r(I))
R indices (all data)
6-Furyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline (V)
3051/0/300
Cream solid; Yield: 60%; mp: 211°C. dH (400 MHz,
DMSO-d6){7.63 (s, NH), 7.54 (s, CH), 7.94 (d, J = 6.76,
H-7), 7.29 (t, J = 8.38, H-8), 6.87 (t, J = 7.2, H-9), 6.94
(d, J = 8.0, H-10), quinazoline ring protons}, {7.66 (m,
H-20), 7.24 (m, H-30), 7.22 (m, H-40), 7.46 (m, H-50),
benzimidazole ring protons}, {6.34 (H-300), 6.36 (m, H-400),
7.46 (m, H-500), furyl ring protons}. dC (400 MHz, DMSO-
d6) {147.18 (C-2), 143.4 (C-3), 112.29 (C-4), 61.83 (CH),
125.14 (C-7), 132.19 (C-8), 118.94 (C-9), 110.62 (C-10),
quinazoline ring carbons}, {119.14 (C-20), 122.93 (C-30),
122.83 (C-40), 108.40 (C-50), 132.9 (C-60), 143.2 (C-70),
benzimidazole ring carbons},{152.40 (C-200), 110.80
(C-300), 110.80 (C-400), 115.42 (C-500), furyl ring carbons}.
R1 = 0.0479, wR2 = 0.1307
R1 = 0.0869, wR2 = 0.1763
0.482 and -0.232
Largest diff. peak
-3
˚
and hole (e A
)
methods and refined by full-matrix least squares method
using SHELX97 [28]. The non-hydrogen atoms were
refined anisotropically and the hydrogen atoms were
refined isotropically. The refinement was continued until
the maximum shift/e.s.d was zero. Crystal data, intensity
collection conditions and refinement parameters are pre-
sented in Table 1.
X-ray Crystallography
Antimicrobial Activity
Suitable single crystals of I for X-ray diffraction study
were grown by slow evaporation from concentrated ethanol
solution. Measurements were made using graphite mono-
The antimicrobial activity of the N-heterocycles, I, II and
III against the bacterial strain Bacillus subtilis and the
fungus Yeast was investigated. The test solutions (50 ppm
concentration) were prepared in DMSO for evaluating the
biological activity. Cup-plate method was employed and
the tests were carried out at room temperature. The
experimental plates were incubated for 24 h and the zone
of inhibition was measured. The drug action was estimated
on the basis of percentage growth inhibition of the cultures.
˚
chromated CuKa radiation (k = 1.54180 A) on an Enraf-
Nonius CAD-4 diffractometer using x-2h scan mode. The
crystals of compound I belong to the monoclinic space
˚
group P21/n with unit cell parameters a = 10.652(2) A,
˚
˚
b = 11.002(2) A, c = 15.753(2) A, b = 109.00(2)°. The
intensities were corrected for Lorentz, polarization and
absorption. The crystal structure was solved by direct
123

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J Chem Crystallogr (2012) 42:305–312
Percentage inhibition was calculated with standard antibi-
otic Septran and standard antifungal agent Grissoflumin as
reference.
formation of the quinazoline derivative. However the IR
spectrum of I showed N–H stretching and in-plane bending
vibrations of quinazoline ring at 3182 and 1589 cm-1
respectively. The tC=N coupled with tC=C of the phenylene
rings was observed at 1612 cm-1. The assignments of the
other bands along with the spectral data which have not been
reported earlier of the related quinazoline derivatives, II–V
arelistedinTable 2[30]. TheUV–VisspectrumofI exhibited
absorption bands assignable to p ! pꢁ transitions and these
are listed in Table 3 along with the spectral data of related
quinazoline derivatives.
Results and Discussion
o-Aminophenylbenzimidazole reacts with p-dimethyl-
amino benzaldehyde in ethanol to produce 6-p-dimethyl-
aminophenyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline
(I). The reaction may occur in two steps, the first one being
the nucleophilic attack of amine, o-aminophenylbenzimi-
dazole on the aldehyde, p-dimethylamino benzaldehyde
leading to the formation of carbinolamine by coupling. In
the second step, the carbinolamine undergoes cyclisation
followed by the loss of a molecule of water to produce the
product (I) as illustrated in Scheme 1.
The mass spectrum of I showed a parent ion peak at m/z
340. The compound undergoes fragmentation and the
resultant pattern along with m/z values are depicted in
Scheme 2.
The 1H NMR spectrum of o-aminophenylbenzimidazole
exhibited resonance peaks due to NH2 of the amino group
and NH of benzimidazole at 6.97 and 6.75 d respectively.
When this heterocycle was reacted with p-dimethylamino
benzaldehyde the NH resonance peak was observed at 7.4 d
and the NH2 resonance disappeared in the spectrum. The
aldehydic proton resonance of p-dimethylamino benzalde-
hyde, observed at 9.66 d, after condensation has undergone
upfield shift and it was observed at 6.86 d. The 13C NMR
spectrum of p-dimethylamino benzaldehyde exhibited a
resonance at 189.72 d due to aldehydic CH and this has
shifted to 68.23 d in the spectrum of I (dihydropyrimidine
carbon 6).
The 1H NMR spectrum of I exhibited resonances due to
NH and CH of dihydropyrimidine ring at 7.40 and 6.86 d
respectively. A peak at 2.58 d is assigned to CH3 protons of
N–Me2 moiety. The resonances due to phenyl ring protons
200, 600 and 300, 500 (Scheme 1) are observed at 7.15 and 6.63
d as doublets. The protons 20, 30, 40 and 50 of benzimidazole
moiety displayed peaks at 7.62, 7.06, 7.02 and 7.12 d
respectively. The protons 7, 8, 9 and 10 of benzoquinazo-
line ring displayed peaks at 7.96, 7.24, 6.81 and 6.87 d
respectively.
The IR spectrum of o-aminophenylbenzimidazole exhib-
ited two bands, one at 3380 cm-1 due to tN–H of benzimid-
azole group and another split band at 3160 and 3130 cm-1
assignable to tN–H of NH2 group of phenylene ring. The
spectrum of p-dimethylamino benzaldehyde displayed a band
at 1740 cm-1 due to tC=O. The spectrum of I did not show any
peak around 3380 and 1740 cm-1 implying condensation and
N
N
C2H5OH
O
C
R
+
Reflux, 5h
N
H
N
..
H
H
H
N
N:
HO
H
R
H
H
2'
5'
1'
7
8
Cyclisation
H2O
7'
N
3'
4'
2
6
3
9
+
N1
6'
10
5
N
4
H
H
R
Product
R
Name (R)
6"
5"
CH3
CH3
1"
1"
4"
I
6-p-dimethylaminophenyl
N
3"
5"
2"
6"
The 13C NMR spectrum of I exhibited methyl carbon
resonance at 40.12 d. The resonances due to quaternary
carbons 2, 3, 4, 60, 70, 100 and 400 are observed at 147.15,
143.61, 110.6, 143.88, 132.92, 124.54 and 150.75 d
respectively. The peaks due to carbons 20, 30, 40 and 50 of
benzimidazole moiety are at 118.47, 121.86, 121.71 and
111.88 d respectively. The carbons 7, 8, 9 and 10 of
benzimidazole ring exhibited the corresponding peaks at
127.25, 131.39, 117.88 and 114.66 d. The phenyl ring
carbons 200 & 600 and 300 & 500 displayed peaks at 127.07 and
111.92 d respectively.
4"
II
III
IV
6-p-hydroxyphenyl
6-phenyl
OH
3"
2"
6"
1"
5"
4"
2"
3"
1"
N
2"
6"
6-pyridyl
6-furyl
5"
3"
4"
1"
O
2"
5"
V
The 1H and 13C NMR spectral data of I along with those of
II to V are listed under experimental section. Compounds I, II
and III possess N–Me2, OH and H groups in the para position
ofthephenylring. Inthedihydropyrimidineringall thecarbon
3" 4"
Scheme 1 Reaction mechanism of o-aminophenylbenzimidazole
with substituted benzaldehyde
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J Chem Crystallogr (2012) 42:305–312
Table 2 Infrared spectral data (cm-1
309
)
I
II
III
IV
V
Assignments
3182
1612
1589
1527
1321
1284,
1008,
937,
862
3205
1614
1587
1531
1321
1280,
1007,
928,
880
3252
1616
1582
1528
1319
1296,
1007,
930,
891
3275
1621
1595
1538
1326
1284,
1020,
933,
876
3251
1614
1585
1529
1330
1263,
1007,
932,
891
tN–H of quinazoline ring
tC=N and tC=C of benzimidazole and tC=C of quinazoline.
tN–H in-plane bending vibration
tC=C and dCH
tC–N and dNH
Benzimidazole ring vibrations
1226
1168
752
1245
1161
748
1261
1157
741
1222
1154
750
1230
1148
748
In-plane CH deformation and ring breathing modes
CH out-of-plane deformation of quinazoline ring vibrations
NH out-of-plane deformation
820
831
829
809
825
CH out-of-plane bending
653
659
674
674
651
Skeletal frequency of quinazoline
Table 3 Electronic spectral
data (cm-1
Ligand
Electronic transitions (cm-1 a
)
)
I
34317 (14542)
34352 (11876)
36390 (6968)
27933 (11342)
36417 (5379)
33025 (16200)
27886 (8373)
27996 (9264)
33036 (8551)
34388 (18322)
33091 (9181)
II
III
IV
V
33003 (14590)
34364 (7042)
33069 (18222)
34495 (10479)
27996 (5521)
28777 (10267)
a
e values in cm2 mol-1 are
given in parentheses
resonances of I and II have undergone downfield shifts except
that of C-4. The electron donating ability of the substituents is
in the order N–Me2 [ OH [ H and thus the proton and car-
bon resonances of phenyl ring of I and II have undergone
upfield shifts as compared to those of compound III.
X-ray Crystallography of Compound I
The X-ray crystallographic study on I has shown that the
fused benzimidazole ring is roughly planar with a maxi-
˚
mum deviation of 0.015(3) A for atom C9 (Fig. 1). The
geometrical parameters of the imidazole ring system are
consistent with those reported in the literature [31]. The
bond lengths and angles within the central dihydropyrim-
idine ring are affected by conjugation. The formal single
Fig. 1 Single crystal X-ray structure of I with thermal ellipsoids at
50% probability
rings indicates that the latter is nearly orthogonal to the
former. A study of the torsion angles, asymmetric param-
eters and least squares plane calculations reveal that the
dihydropyrimidine ring is in the skew-boat conformation,
which is confirmed by the puckering parameters [33],
˚
bonds N1–C9 [1.377(3) A], N1–C2 [1.394(3) A] and N16–
˚
˚
C15 [1.389(3) A] possess values of a partial double bond
2
(standard: Csp –N = 1.39 A) [32]. The quinazoline ring
˚
˚
has deviated from planarity with deviation of 0.272(3) A at
˚
C17 from the least squares plane defined by atoms N1/C9/
C10/C15/N16/C17. The imidazole and dihydropyrimidine
rings are nearly co-planar as indicated by the dihedral angle
of 5.05(2)°. The dihedral angle of 84.85(2)° between the
planes of dimethylaminophenyl and the dihydropyrimidine
Q = 0.402 A, h = 60.1° and / = 286.99°. Similar skew
boat conformations were reported in 5,6-dihydroimi-
dazo[1,2-c]quinazolines [26, 34, 35]. There are several
reported structures where the dihydropyrimidine ring
existed in half chair/flat boat type conformation [36–43].
123

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J Chem Crystallogr (2012) 42:305–312
Scheme 2 Mass spectral
fragmentation of I
-
N
N
+ 2H
N
N
CH
N
N
-
H
-
H
192
N
194
- C7H4N2(C6H4)
- C6H4N(CH3)2CNH2
H3C
147
CH3
N
- C6H4N(CH3)2
N
H
N
H
N
- C6H4CHN
H
-
N
H
220
- C7H4N2
N
N
H3C
CH3
H3C
CH3
-
340
44
N
H
H
104
˚
Table 4 Comparison of bond lengths (A) and angles (°) in 6-phenyl
groups
Bonds/angle
Compound
I
II
III
C22–C23
C21–C22
C20–C21
C19–C20
C18–C19
C18–C23
C20–C21–C22
1.399(4)
1.399(4)
1.398(4)
1.370(4)
1.364(4)
1.379(4)
116.4(3)
1.386(3)
1.386(3)
1.386(3)
1.374(3)
1.390(3)
1.382(3)
119.0(2)
1.385(2)
1.374(3)
1.374(3)
1.381(3)
1.383(2)
1.387(2)
119.9(2)
Fig. 2 Packing of molecules down a-axis of I
8
6
3
11 12
7
2
N
5
9
10
Thetorsionanglesof63.0(3)°and-55.5(4)°forN16–C17–
C18–C23 and N1–C17–C18–C23 respectively determine the
inter-ring conformation of the junction between dimethylam-
inophenyl ring and the dihydrobenzimidazoquinazoline ring.
This value being close to 60° indicates that the dimethylam-
inophenyl ring bisects the plane of the dihydrobenzimidazo
quinazoline ring. The molecule possesses a chiral center at
C17. The dimethylamino group is essentially planar (sum of
the bond angles at N24 is 358°) and nearly coplanar with the
adjacent phenyl ring C18/C19/C20/C21/C22/C23 (dihedral
angles 170.6(3)° and 11.1(4)°). The atoms N24, C25 and C26
13
4
N1
14
15
16
N
17
18
H
H
R
Fig. 3 I: R = dimethylaminophenyl; II: R = hydroxyphenyl; III:
R = phenyl
clearly conjugated with phenyl ring as indicated by the N24–
˚
C21 bond length [1.377(4) A] and the bond angles around
˚
of the dimethylamino group have deviations of 0.051(3) A,
˚
˚
N24. Thepackingofmoleculesdowna-axis is shown in Fig. 2.
The structure exhibits intermolecular hydrogen bonds of the
type C–H–N. The intermolecular hydrogen bonds are between
the nitrogen of the imidazole ring of one molecule and the
-0.059(3) A and -0.150(3) A respectively from the least
squares plane of the phenyl ring C18/C19/C20/C21/C22/C23.
The planarity of the dimethylamino group may increase the
conjugation with the phenyl ring. The dimethylamino group is
123

J Chem Crystallogr (2012) 42:305–312
311
Table 5 Comparison of bond
˚
Compound
rC–NH
rC–C(R)
rC–N(ring)
N–C–N
C–NH–C
lengths (A) and angles (°) of
dihydropyrimidine ring
I
1.446(4)
1.459(3)
1.452(2)
1.462(5)
1.450(3)
1.510(4)
1.514(3)
1.521(2)
1.525(5)
1.490(3)
1.476(4)
1.459(3)
1.457(2)
1.456(5)
1.453(3)
105.2(2)
106.5(2)
106.6(1)
107.4(3)
107.2(2)
120.5(2)
122.6(2)
121.4(2)
123.7(3)
121.0(2)
II
III
IV
V
donating and do not show any bacterial growth inhibition.
These substituents show appreciable growth inhibition as
compared to the standards in the case of the fungus Yeast. The
substituent in III (phenyl) which has hydrogen in the para
position shows moderate antimicrobial activity for both the
microbes as compared to I and II.
Table 6 Percentage inhibition shown against Bacillus subtilis and
Yeast
Compound
Bacillus subtilis
Yeast
I
Nda
Nda
46
70
70
40
67
II
III
Standard
76
Conclusion
a
Not detected
In conclusion, the reaction of o-aminophenyl benzimidazole
with substituted aldehydes has resulted in the formation of
quinazoline derivatives via cyclisation with the elimination of
water molecule(s). 1H and 13C NMR spectral data have sup-
ported the formation of cyclised products. X-ray crystallo-
graphic studies have confirmed the cyclisation and have
revealed the influence of the substituent R on the dihydrop-
ryrimidine ring with respect to bond lengths and bond angles.
The dihydropyrimidine ring is in a skew-boat conformation in
I and the dimethylamino group is clearly conjugated with the
phenyl ring which it is attached to. Antimicrobial activity of I,
II and III against the bacterial strain Bacillus subtilis and the
fungus Yeast reveal that I and II are slightly more toxic as
compared to the standard with respect to Yeast but showed no
toxicity against Bacillus subtilis.
hydrogen of phenylene ring of adjacent molecule. The
hydrogen bonding parameters are given below.
DꢂH ꢀ ꢀ ꢀ A
Symm
Cð6ÞꢂHð6Þ ꢀ ꢀ ꢀ Nð8Þ ꢂx; 1 ꢂ y; ꢂ z 2:6029 A 3:5977A 171ꢃ
H ꢀ ꢀ ꢀ A
D ꢀ ꢀ ꢀ A
DꢂH ꢀ ꢀ ꢀ A
˚
˚
The bond lengths in the 6-phenyl group of I have changed
compared with other derivatives due to the para substitu-
tion of the dimethylamino group (Table 4). While the bond
lengths C22–C23, C21–C22 and C20–C21 (Fig. 3) are
elongated, the bond lengths C19–C20, C18–C19 and C18–
C23 are shortened (Table 4) as compared to para OH
substituted phenyl group in 6-p-hydroxyphenyl-5,6-
dihydrobenzoimidazo[1,2-c]quinazoline (II) [24] and
the non-substituted phenyl group in 6-phenyl-5,6-di-
hydrobenzoimidazo[1,2-c]quinazoline (III) [25]. The N1–
C17 bond in the dihydropyrimidine ring of compound I is
Supplementary Material
˚
lengthened (1.477(4) A) when compared to the respective
˚
bond lengths in II: 1.459(3) A, III: 1.457(2) A, IV:
˚
Crystallographic data for the structural analysis of com-
pound I have been deposited with the Cambridge Crys-
tallographic Data Centre (CCDC) as 742983. Copies of the
data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge,
CB2 1EZ, U.K.; Fax: ?44 1223 336033; e-mail: deposit@
ccdc.cam.ac.uk).
˚
˚
1.453(3) A [26] and V: 1.456(5) A [27]. The N1–C17–N16
bond angle (105.0(2)°) has decreased as compared to
106.5(2)°, 106.6(1)°, 107.2(2)° and 107.4(3)° respectively
in compounds II, III, IV and V. The dihedral angle
between dimethyl aminophenyl ring and the dihy-
drobenzoimidazoquinazoline plane in compound I is
80.9(2)° whereas the corresponding angle is 86.26(1)° and
87.4(2)° in compounds IV and V respectively. Bond
lengths and bond angles of dihydropyrimidine ring of
compounds I–V are compiled in Table 5.
Acknowledgements The authors are thankful to Mr. Kalyan Sundar
and Mr. Pandiaraman, School of Physics, Madurai Kamaraj Univer-
sity for single crystal data collection.
The antimicrobial activity of I, II and III against the bac-
terial strain Bacillus subtilis and the fungus Yeast reveal that
I and II are slightly more toxic as compared to the standard
with respect to Yeast but showed no toxicity against Bacillus
subtilis (Table 6). The substituents in para positions (dime-
thyl amino group in I and hydroxyl group in II) are electron
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