Determination of the R → S enantiomerization barrier in 5,6-dihydrobenzoimidazo[1,2-c]quinazolines

Article abstract of DOI:10.1007/s10593-012-1054-7

Chiral imidazoquinazolines undergoing thermally induced reversible R → S enantiomerization have been synthesized by the interaction of 2-(o-aminophenyl)benzimidazoles with aldehydes and ketones. The benzimidazole fragment has been used for the first time

Full text of DOI:10.1007/s10593-012-1054-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
DETERMINATION OF THE R
S ENANTIOMERIZATION
BARRIER IN 5,6-DIHYDROBENZOIMIDAZO[1,2-c]QUINAZOLINES
P. G. Morozov1 and S. V. Kurbatov1*
Chiral imidazoquinazolines undergoing thermally induced reversible R
S enantiomerization have
been synthesized by the interaction of 2-(o-aminophenyl)benzimidazoles with aldehydes and ketones.
The benzimidazole fragment has been used for the first time as an indicator group in temperature-
1
dependent H NMR spectra for determining the energy barrier of this rearrangement. The effects of
nearby substituents on the kinetic and activation parameters, and on the recyclization mechanism have
been investigated.
Keywords: benzimidazole, quinazoline, enantiomerization, rearrangement, dynamic 1H NMR.
It is known that azomethines of type 1, formed on interacting 2-(o-aminophenyl)benzimidazole with
aromatic aldehydes, are spontaneously cyclized into chiral imidazoquinazolines of type 2 [1].
Ar
Ar
H
H
H
Ar
H
N
N
H
N
N
N
N
N
N
N
H
S-2
R-2
1
1
If the energy barrier of intramolecular conversion (such as R-2
S-2) falls into the time scale of H
NMR (ΔG≠ 30-125 kJ/mol) and is accompanied by a change in configuration of the chiral center, then it is
298
possible to determine it without a prior separation of the R- and S-enantiomers. For this, it is necessary to
introduce a diastereotopic label, such as a benzyl or isopropyl group, into the near environment of the
stereogenic center and to follow the evolution of its signal in temperature-dependent NMR spectra. Similar
methods of studying stereoconversions, proceeding through dissociation–recombination of bonds formed by the
stereogenic center, have been successfully used for carbon and other elements [2, 3]. However, the introduction
of a diastereotopic label is synthetically difficult and/or affects the kinetics and mechanism of the intramolecular
reaction being studied.
_______
*To whom correspondence should be addressed, kurbatov@sfedu.ru.
1Southern Federal University, 7 Zorge St., Rostov-on-Don 344090, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 815-823, May, 2012. Original
article submitted August 15, 2011.
758
0009-3122/12/4805-0758©2012 Springer Science+Business Media, Inc.

The aim of our work was the investigation of the kinetic stability and the mechanism of cleavage–
formation of the C–N bond in the quinazoline ring by using a benzimidazole fragment as indicator group. On
interacting 2-(2-aminophenyl)-5,6-dimethylbenzimidazole (3), synthesized by us, with aldehydes the 9,10-di-
methyl substituted analogs of quinazolines of type 2 are formed. We introduced two indicator methyl groups, in
order to simplify the appearance of the benzimidazole fragment signals and to facilitate analysis of the dynamic
1
NMR spectra. It is necessary to emphasize that in the H NMR spectrum of the starting benzimidazole 3, the
H-4 and H-7 proton signals are displayed as a two-proton singlet, while the methyl group signals appear as a
six-proton singlet [3].
H
N
H2N
H2N
4
(1)
(2)
Me
Me
(1)
(2)
Me
Me
5
N
N
N
6
7
H
3
H2N
(2)
(1)
Me
Me
N
N
H
The methyl groups (and also the H-4 and H-7 protons) undergo rapid positional exchange, caused by
N-3 transfer of a proton and rotation around the benzimidazolyl–phenyl bond. In the 1H NMR spectra
N-1
of the obtained dimethylimidazoquinazolines 4a-i, the signals of the methyl groups at room temperature are
anisochronous and are displayed as two three-proton singlets in the 2.1-2.3 ppm region. On heating solutions of
compounds 4a-i in deuterated nitrobenzene, positional exchange of the methyl groups was observed in a series
of cases, reflecting the thermally induced reversible recyclization of the pyrimidine ring. The signals of the
methyl groups were broadened, then coalesced and were transformed into a broad six-proton singlet, narrowing
on further increasing of the ampoule temperature in the NMR spectrometer. Cleavage of the quinazoline ring
C–N bond was accompanied by a rotation of the benzimidazole fragment in the "open" intermediate state of
type 5 and by R
S inversion of the chiral spiro carbon configuration. The kinetic and activation parameters
of these rearrangements are given in Table 1.
Ar
H
H
H
Ar
H
5
N
N
6
8
4
(2)
(1)
(1)
(2)
Me
Me
Me
Me
9
N
N
N
3
N
10
2
1
11
S-4a–i
R-4a–i
Ar
H
Ar
H
N
N
H
N
(2)
(1)
Me
Me
Me
Me
N
N
H
N
(1)
(2)
5a–i
5'a–i
a Ar = Ph, b Ar = 4-Me2NC6H4, c Ar = 4-MeOC6H4, d Ar = 3,4-(MeO)2C6H3,
e Ar = 3,4,5-(MeO)3C6H2, f Ar = 4-ClC6H4, g Ar = 4-O2NC6H4, h Ar = 2-furyl, i Ar = 2-thienyl
759

TABLE 1. Kinetic and Activation Parameters of the R
Rearrangement of 5,6-Dihydrobenzoimidazo[1,2-c]quinazolines 4a-i
S
Com-
pound
Ar
G298, kJ/mol
H, kJ/mol
S, J/molK
k298, sec–1
Ph
>125
78.2
83.3
77.8
>125
>125
>125
80.3
—
48
66
55
—
—
—
43
—
—
-103
-59
-77
—
<1·10–9
1.1·10–1
1.4·10–2
1.4·10–1
<1·10–9
<1·10–9
<1·10–9
5.2·10–2
<1·10–9
4a
4b
4c
4d
4e
4f
4-Ме2NC6H4
4-МеOC6H4
3,4-(МеO)2C6H3
3,4,5-(МеO)3C6H2
4-ClC6H4
—
4-O2NC6H4
2-Furyl
—
4g
4h
4i
-125
—
2-Thienyl
>125
It follows from the data of Table 1, that the phenyl substituent and its derivatives containing electron-
withdrawing groups (compounds 4a,f,g) sharply increase the activation barrier, moving it beyond the limits of
determination by the NMR method. The most probable explanation of such a substituent effect seems to be the
following. The rate of the R-4
S-4 rearrangement is determined by the stability of the intermediate of type
5. Electron-donating substituents reduce the electron deficit on the azomethine carbon atom and stabilize the
open structure 5, but electron-withdrawing substituents destabilize it.
The activation barrier is significantly reduced for derivatives of π-electron-rich aldehydes (compounds
4b-d,h). The greatest effect is shown by the dimethylamino group and two methoxy groups. It should be noted
that the introduction of a third methoxy group (compound 4e) already sharply increases ΔG≠. This is linked to
the fact that as a result of steric crowding, the lone pair of the p-methoxy group oxygen atom is not effectively
conjugated with the π-system of the benzene ring and the C=N bond, and the electron-withdrawing inductive
effect of the three methoxy groups thus predominates.
It is known, that by their ability of stabilizing electron-deficient centers, heteroatoms are arranged in the
sequence –NH– > –O– > –Te– ≈ –Se- > –S– [4]. This explains the higher kinetic mobility of the furan
derivative 4h in comparison with the thiophene derivative 4i.
The recyclization R-4
S-4 is apparently accompanied by proton transfer from the amino group to
the benzimidazole group and the formation of intermediate structures of type 5, and is not simply a case of a
reversible heterolysis of the C–N bond. To verify this hypothesis we synthesized N-alkylated quinazolines of
type 6. The introduction of a diastereotopic benzyl group into the near environment of the chiral center allows,
apart from clarifying the role of the N–H fragment, the use of an additional indicator group for studying the
stereodynamics in quinazolines of type 6. However imidazoquinazolines 6a-c, even containing electron-
donating substituents, unlike those type 4 compounds lacking an N-alkyl group, were not recyclized upon
heating in deuterated nitrobenzene solutions up to 180oC (ΔG≠ > 125 kJ/mol). The signals of the H-8,11 and
298
H-9,10 protons of the benzimidazole moiety remained anisochronous and were not broadened, but the
methylene group signal was retained as an AB quartet.
In difference from N-alkylation sharply increasing the activation barrier of recyclization, C-alkylation of
the chiral center predictably reduces the activation barrier as a result of the electron-donating effect of the
methyl group (compounds 4c and 7b, Tables 1 and 2).
H
R
CH2Ph
H
Ar
Me
N 5
5
N
6
8
6
8
4
4
Me
Me
9
9
N
N
3
3
10
N
10
N
2
1
11
1
2
11
6a–c
7a–e
6 a Ar = 4-MeOC6H4, b Ar = 4-Me2NC6H4, c Ar = 2-furyl;
7 a R = Ph, b R = 4-MeOC6H4, c R = Me, d R = Et, e R = Pr
760

TABLE 2. Kinetics and Activation Parameters of the Rearrangements of
5,6-Dihydrobenzoimidazo[1,2-c]quinazolines 7a-e
Com-
pound
H,
kJ/mol
S,
J/molК
R
G298, kJ/mol
k
298, sec–1
Ph
>125
78.2
—
72
—
-22
119
-53
-78
<1·10–9
7a
7b
7c
7d
7e
4-МеOC6H4
1.2·10–1
1.5·10–8
2.7·10–4
2.6·10–3
Me
Et
117.5
93.3
153
77
Pr
87.4
64
In the series of derivatives 7c-e synthesized from benzimidazole 3 and the corresponding ketones, the
activation barrier of thermally induced recyclization is also progressively reduced (Table 2).
Introduction of methyl groups into the benzimidazole fragment simplified spectral investigation of
compounds of types 4 and 7, but hindered the preparation of monocrystals suitable for investigation by X-ray
structural analysis. We successfully grew a monocrystal of the unmethylated benzimidazole derivative – quinazoline
8. According to the data of X-ray structural analysis (Fig. 1) molecules of compound 8 were packed in the crystal as
racemate (space group P) due to an intermolecular hydrogen bond N(16)–H···N-8 between the R- and S-enantiomers.
Me
O
H
H
N
N
N
8
Fig. 1. Molecular structure of the quinazoline 8 with atoms represented by thermal vibrations ellipsoids with
50% probability.
In conclusion, it is necessary to mention that the new approach proposed by us using a benzimidazole
fragment as an indicator label enables processes of bond cleavage–formation to be investigated even for achiral
structures, for which known approaches using a diastereotopic label are not applicable in principle. Thus, the
kinetic stability of any interaction (covalent, coordination, hydrogen bonding), affecting azole or azine nitrogen
atoms in a benzimidazole fragment and inhibiting free rotation as a result, may be investigated.
761

TABLE 3. Physicochemical Characteristics of the Synthesized
Compounds 4a-i, 6a-c, 7a-e and 8
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °C
Yield, %
C
H
N
C22H19N3
81.23
81.20
5.97
5.89
12.99
12.91
260-262
226-228
224-226
212-214
196-198
264-266
314-316
220-222
238-240
162-164
220-222
170-172
210-212
232-234
202-204
218-220
206-208
150-152
61
84
66
95
86
73
96
63
62
85
80
50
56
63
63
49
70
55
4a
4b
4c
4d
4e
4f
C24H24N4
78.36
78.23
6.70
6.57
15.31
15.20
C23H21N3O
C24H23N3O2
C25H25N3O3
C22H18ClN3
C22H18N4O2
C20H17N3O
C20H17N3S
C28H23N3O
C29H26N4
77.85
77.72
6.04
5.96
11.91
11.82
74.90
74.78
6.11
6.01
10.12
10.90
72.40
72.27
6.16
6.06
10.20
10.11
73.55
73.43
5.16
5.04
11.80
11.68
71.47
71.34
5.01
4.90
15.22
15.13
4g
4h
4i
76.30
76.17
5.55
5.43
13.45
13.32
72.62
72.48
5.28
5.17
12.80
12.68
80.71
80.55
5.66
5.55
10.17
10.06
6a
6b
6c
7a
7b
7c
7d
7e
8
81.16
80.90
6.20
6.09
13.13
13.01
C25H19N3O
C23H21N3
79.70
79.55
5.13
5.06
11.20
11.13
81.53
81.39
6.45
6.24
12.48
12.38
C24H23N3O
C18H19N3
78.15
78.02
6.37
6.27
11.48
11.37
78.11
77.95
7.01
6.90
15.27
15.15
C19H21N3
78.48
78.32
7.37
7.26
14.52
14.42
C20H23N3
78.82
78.65
7.70
7.59
13.84
13.76
C19H15N3O
75.96
75.73
5.28
5.02
13.80
13.94
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker DPX-250 (250 MHz) instrument in CDCl3 (for
compound 4g in DMSO-d6), temperature-dependent spectra were recorded in C6D5NO2, internal standard was
TMS. Computer modelling of spectra and calculation of rate constants were carried out with the aid of program
gNMR 5.1 [5]. Values of the Gibbs free energy (ΔG≠) were calculated according to the Arrhenius equation for
each rate constant. Enthalpies (ΔH≠) and entropies (ΔS≠) of activation with a correlation coefficient of at least
0.98 were found by linearization using the least squares method.
Physicochemical characteristics of the synthesized compounds 4a-i, 6a-c. 7a-e and 8 are given in Table 3,
and the 1H NMR spectroscopy data are in Table 4.
9,10-Dimethyl-5,6-dihydrobenzoimidazo[1,2-c]quinazolines 4a-i, 6-(5-Methylfuran-2-yl)-5,6-di-
hydrobenzoimidazo[1,2-c]quinazoline (8) (General Method). An aldehyde (1.27 mmol) and AcOH (0.01 ml)
were added to a solution of 2-(2-aminophenyl)benzimidazole (1.27 mmol) or its 5,6-dimethyl derivative 3 [6]
(1.27 mmol) in MeOH (5 ml). The reaction mixture was refluxed for 2 h and left overnight for complete
precipitation of solid. The solid was filtered off, washed with cold MeOH, and air-dried at 50oC.
762

TABLE 4. 1H NMR Spectra of the Synthesized Imidazoquinazolines 4a-i,
6a-c, 7a-e and 8
Com-
Chemical shifts, , ppm (J, Hz)
pound
1
2
2.15 (3H, s) and 2.28 (3H, s, 9,10-CH3); 4.94 (1Н, br. s, NH); 6.30 (1H, s) and
7.50 (1H, s, H-8,11); 6.55 (1H, s, H-6); 6.66 (1H, d, J = 8.1, H-4);
6.91 (1H, dd, J = 7.3, J = 7.7, H-2); 7.19 (1H, dd, J = 7.3, J = 8.1, H-3);
7.27-7.43 (5H, m, H Ph); 8.15 (1H, d, J = 7.7, H-1)
4a
2.15 (3H, s) and 2.28 (3H, s, 9,10-CH3); 2.93 (6H, s, N(CH3)2); 4.64 (1H, s, NH);
4b
4c
6.28 (1H, s) and 7.50 (1H, s, H-8,11); 6.43 (1H, s, H-6); 6.59-6.69 (3H, m, H-4,3',5');
6.90 (1H, dd, J = 7.3, J = 7.7, H-2); 7.18 (1H, dd, J = 7.3, J = 8.0, H-3);
7.25 (2H, d, J = 8.7, H-2',6'); 8.16 (1H, d, J = 7.7, H-1)
2.15 (3H, s) and 2.28 (3H, s, 9,10-CH3); 3.76 (3H, s, OCH3); 4.85 (1H, s, NH);
6.27 (1H, s) and 7.49 (1H, s, H-8,11); 6.48 (1H, s, H-6); 6.66 (1H, d, J = 8.0, H-4);
6.84 (2H, d, J = 8.7, Н Ar); 7.30 (2H, d, J = 8.7, Н Ar);
6.91 (1H, dd, J = 7.4, J = 7.8, H-2); 7.19 (1H, dd, J = 7.4, J = 8.0, H-3);
8.15 (1H, d, J = 7.8, H-1)
2.13 (3H, s) and 2.28 (3H, s, 9,10-CH3); 3.72 (3H, s) and 3.88 (3H, s, 3',4'-OCH3);
4.66 (1H, s, NH); 6.20 (1H, s) and 7.50 (1H, s, H-8,11); 6.47 (1H, s, H-6);
6.69 (1H, d, J = 8.6, H-4); 6.80-7.03 (4H, m, Н-2,2',5',6'); 7.22 (1H, dd, J = 7.6, J = 8.6, H-3);
8.16 (1H, d, J = 7.7, H-1)
4d
4e
2.14 (3H, s) and 2.28 (3H, s, 9,10-CH3); 3.68 (6H, s, 3',5'-OCH3); 3.82 (3H, s, 4'-OCH3);
5.02 (1H, s, NH); 6.22 (1H, s) and 7.49 (1H, s, H-8,11);
6.38 (1H, s, H-6); 6.61 (2H, s, H-2',6'); 6.74 (1H, d, J = 7.9, H-4);
6.92 (1H, dd, J = 7.6, J = 7.8, H-2); 7.22 (1H, dd, J = 7.6, J = 7.9, H-3);
8.14 (1H, d, J = 7.8, H-1)
2.19 (3H, s) and 2.30 (3H, s, 9,10-CH3); 4.77 (1H, s, NH); 6.39 (1H, s) and
7.51 (1H, s, H-8,11); 6.58 (1H, s, H-6); 6.69 (1H, d, J = 7.3, H-4);
4f
6.94 (1H, dd, J = 7.6, J = 7.6, H-2); 7.17-7.34 (5H, m, H-3, H Ar); 8.15 (1H, d, J = 7.6, H-1)
2.24 (3H, s) and 2.29 (3H, s, 9,10-CH3); 6.78-6.89 (2H, m, Н-2,4); 7.16 (1H, s) and
7.47 (1H, s, H-8,11); 7.18-7.29 (2H, m, Н-3,6); 7.39 (2H, d, J = 8.7, H-2',6');
7.73 (1H, s, NH); 7.95 (1H, d, J = 8.1, H-1); 8.16 (2H, d, J = 8.7, H-3',5')
4g
2.30 (3H, s) and 2.33 (3H, s, 9,10-CH3); 5.23 (1H, s, NH); 6.00 (1H, d, J = 3.4, H-3');
6.18 (1H, dd, J = 1.8, J = 3.2, H-4'); 6.68 (1H, d, J = 1.8, H-6); 6.74 (1H, d, J = 8.3, H-4);
6.80 (1H, s) and 7.52 (1H, s, H-8,11); 6.92 (1H, dd, J = 7.6, J = 7.9, H-2);
4h
4i
7.20 (1H, dd, J = 7.6, J = 8.3, H-3); 7.28 (1H, d, J = 1.8, H-5'); 8.11 (1H, d, J = 7.9, H-1)
2.25 (3H, s) and 2.31 (3H, s, 9,10-CH3); 4.99 (1H, s, NH); 6.62 (1H, s) and
7.50 (1H, s, H-8,11); 6.74 (1H, d, J = 8.3, H-4); 6.86-6.92 (2H, m, H-6,4');
6.95 (1H, dd, J = 7.3, J = 7.6, H-2); 7.04 (1H, d, J = 3.4, H-3'); 7.18-7.28 (2H, m, H-3,5');
8.14 (1H, d, J = 7.6, H-1)
3.68 (3H, s, OCH3); 4.28 (1H, d, J = 15.6) and 4.64 (1H, d, J = 15.6, СН2);
6.51 (1H, s, H-6); 6.71 (2H, d, J = 8.5, H-3',5'); 6.80 (1H, d, J = 8.5, H-4);
6.91-7.44 (12H, m, Н Ar); 7.80 (1H, d, J = 8.1, H-11); 8.31 (1H, d, J = 7.7, H-1)
6a
6b
6c
2.84 (6H, s, N(CH3)2); 4.28 (1H, d, J = 16.0) and 4.64 (1H, d, J = 16.0, СН2);
6.45-6.54 (3H, m, Н-6,3',5'); 6.75 (1H, d, J = 8.4, H-4); 6.92-7.38 (12H, m, Н Ar);
7.78 (1H, d, J = 8.1, H-11); 8.30 (1H, d, J = 7.7, H-1)
4.46 (1H, d, J = 15.4) and 4.80 (1H, d, J = 15.4, СН2); 5.89 (1H, d, J = 3.7, H-3');
6.13 (1H, dd, J = 1.8, J = 3.7, H-4'); 6.59 (1H, s, H-6); 6.86 (1H, d, J = 8.4, H-4);
7.02 (1H, dd, J = 7.3, J = 7.7, H-2); 7.14-7.40 (10H, m, Н Ar);
7.81 (1H, d, J = 8.1, H-11); 8.27 (1H, d, J = 7.7, H-1)
2.10 (3H, s), 2.12 (3H, s) and 2.28 (3H, s, 6,9,10-CH3); 4.64 (1H, s, NH); 6.11 (1H, s) and
7.50 (1H, s, H-8,11); 6.67 (1H, d, J = 8.1, H-4); 6.91 (1H, dd, J = 7.3, J = 7.7, H-2);
7.21 (1H, dd, J = 7.3, J = 8.1, H-3); 7.33-7.44 (3H, m, H-3',4',5');
7a
7b
7c
7.54-7.66 (2H, m, H-2',6'); 8.16 (1H, d, J = 7.7, H-1)
2.06 (3H, s, 6-CH3); 2.12 (3H, s) and 2.26 (3H, s, 9,10-CH3); 3.80 (3Н, s, OCH3);
4.63 (1H, s, NH); 6.12 (1H, s) and 7.49 (1H, s, H-8,11); 6.67 (1H, d, J = 8.1, H-4);
6.83-6.94 (3H, m, H-2,3',5'); 7.20 (1H, dd, J = 7.7, J = 8.1, H-3);
7.55 (2H, d, J = 8.5, H-2',6'); 8.15 (1H, d, J = 7.7, H-1)
1.88 (6H, s, 6-C(CH3)2); 2.35 (3H, s) and 2.38 (3H, s, 9,10-CH3); 4.60 (1H, s, NH);
6.71 (1H, d, J = 8.1, H-4); 6.89 (1H, dd, J = 7.3, J = 7.7, H-2);
7.20 (1H, dd, J = 7.3, J = 8.1, H-3); 7.30 (1H, s) and 7.56 (1H, s, H-8,11);
8.13 (1H, d, J = 7.7, H-1)
763

TABLE 4 (continued)
1
2
0.93 (3H, t, J = 7.3, CH2CH3); 1.89 (3H, s, 6-CH3); 2.28-2.52 (8H, m, CH2CH3, 9,10-CH3);
4.24 (1H, s, NH); 6.67 (1H, d, J = 8.1, H-4); 6.83 (1H, dd, J = 7.3, J = 7.7, H-2);
7.18 (1H, dd, J = 7.3, J = 8.1, H-3); 7.24 (1H, s) and 7.54 (1H, s, H-8,11);
8.09 (1H, d, J = 7.7, H-1)
7d
7e
0.82 (3H, t, J = 7.3, CH2CH2CH3); 1.13-1.37 (1H, m) and 1.39-1.63 (1H, m, CH2CH2CH3);
1.74-1.96 (4H, m, 6-СН3, CH2CH2CH3); 2.23-2.51 (7H, m, 9,10-СН3, CH2CH2CH3);
4.40 (1H, s, NH); 6.67 (1H, d, J = 8.1, H-4); 6.84 (1H, dd, J = 7.3, J = 7.7, H-2);
7.18 (1H, dd, J = 7.3, J = 8.1, H-3); 7.23 (1H, s) and 7.54 (1H, s, H-8,11);
8.09 (1H, d, J = 7.7, H-1)
2.13 (3Н, s, СН3); 5.13 (1H, s, NH); 5.70 (1H, d, J = 3.4, H-4'); 5.76 (1H, d, J = 3.4, H-3');
6.54 (1H, s, H-6); 6.83 (1H, d, J = 8.4, H-4); 6.98 (1H, dd, J = 7.4, J = 7.6, H-2);
7.14-7.38 (4H, m, Н Ar); 7.80 (1H, d, J = 7.6, H-11); 8.25 (1H, d, J = 7.6, H-1)
8
TABLE 5. Basic Bond Lengths (l) in the Molecule of Imidazoquinazoline 8
Bond
l
, Å
Bond
l, Å
O(1)–C(18)
O(1)–(21)
N(1)–C(9)
N(1)–C(2)
N(1)–C(17)
C(2)–C(3)
C(2)–C(7)
C(3)–C(4)
C(4)–C(5)
C(6)–C(7)
C(7)–N(8)
N(8)–C(9)
C(9)–C(10)
1.3688(14)
1.3806(16)
1.3716(15)
1.3878(16)
1.4549(14)
1.3851(19)
1.4017(17)
1.381(2)
C(10)–C(11)
C(10)–C(15)
C(11)–C(12)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
C(15)–N(16)
N(16)–C(17)
C(17)–C(18)
C(18)–C(19)
C(19)–C(20)
C(20)–C(21)
C(21)–C(22)
1.3977(18)
1.4079(16)
1.381(2)
1.388(2)
1.377(2)
1.4000(18)
1.3862(16)
1.4536(16)
1.5030(17)
1.3347(18)
1.425(2)
1.395(2)
1.3929(18)
1.3982(16)
1.3208(15)
1.4451(17)
1.339(2)
1.485(2)
TABLE 6. Basic Valence Angles (ω) in the Molecule of Imidazoquinazoline 8
Bond
ω, deg.
Bond
ω, deg.
C(18)–O(1)–C(21)
C(9)–N(1)–C(2)
C(9)–N(1)–C(17)
C(2)–N(1)–C(17)
C(3)–C(2)–N(1)
C(3)–C(2)–C(7)
N(1)–C(2)–C(7)
C(4)–C(3)–C(2)
C(3)–C(4)–C(5)
C(6)–C(5)–C(4)
C(5)–C(6)–C(7)
C(6)–C(7)–N(8)
C(6)–C(7)–C(2)
N(8)–C(7)–C(2)
C(9)–N(8)–C(7)
N(8)–C(9)–N(1)
106.34(10)
107.16(10)
124.50(10)
126.52(10)
132.39(12)
122.62(12)
104.96(11)
116.50(13)
121.53(15)
121.91(14)
117.40(13)
129.77(12)
120.04(12)
110.16(10)
104.86(10)
112.76(11)
N(8)–C(9)–C(10)
N(1)–C(9)–C(10)
C(11)–C(10)–C(15)
C(11)–C(10)–C(9)
C(15)–C(10)–C(9)
C(12)–C(11)–C(10)
C(11)–C(12)–C(13)
C(14)–C(13)–C(12)
C(13)–C(14)–C(15)
N(16)–(15)–C(14)
N(16)–C(15)–C(10)
C(14)–C(15)–C(10)
C(15)–N(16)–C(17)
N(16)–C(17)–N(1)
N(16)–C(17)–C(18)
N(1)–C(17)–C(18)
128.46(11)
118.69(10)
120.14(12)
122.52(11)
117.30(11)
120.44(13)
119.22(14)
121.39(14)
120.23(13)
121.25(11)
120.11(11)
118.56(12)
120.15(10)
108.44(10)
114.10(10)
108.50(10)
764

5,6-Dihydrobenzoimidazo[1,2-c]quinazolines 6a-c, 7a,b,d,e (General Method). A solution of the
corresponding 2-(2-aminophenyl)benzimidazole (4.2 mmol) or its N-benzyl derivative [6] (4.2 mmol), carbonyl
compound (8.4 mmol) and p-toluenesulfonic acid (5 mg) in butanol (5 ml) was refluxed for 21 h. The solid was
filtered off, washed first with a butanol–petroleum ether 1:2 mixture (5 ml), then with petroleum ether (10 ml),
and air-dried at 80oC.
6,6,9,10-Tetramethyl-5,6-dihydrobenzoimidazo[1,2-c]quinazoline (7c). 2-(2-Aminophenyl)-5,6-di-
methylbenzimidazole (1 g, 4.2 mmol) was dissolved with heating in acetone (10 ml). AcOH (0.1 ml) was added
to the obtained solution, and the mixture was refluxed for 14 h. The precipitated solid was filtered off and
washed with acetone (5 ml).
X-Ray Structural Investigation of Compound 8. Monocrystals of quinazoline 8 were obtained from
methyl alcohol. The crystals of compound 8 (C19H15N3O3, M 301.34) were monoclinic, space group P at 293 K:
a 8.9393(18), b 12.798(3), c 13.361(3) Å; β 92.90(3)o; V 1526.6(5) Å3; Z 4 (Z' 1; dcalc 1.311 g/cm3; μ(MoKα)
3.57 cm-1; F(000) 632. The intensities of 5613 reflections (λ(MoKα) 0.71073 Å, ω scanning, 2θ < 58o) and 5327
independent reflections (Rint 0.0424) were determined on a Bruker SMART 1000 CCD diffractometer and used
in the subsequent refinement. The structure was solved by the direct method and refined by least squares in an
anisotropic-isotropic full-matrix approximation on F2. The positions of hydrogen atoms were calculated
geometrically and refined in an isotropic approximation according to the "rider" model. Final values of the
probability factors for compound 8 were wR2 0.1030 and GOOF 1.012 for all independent reflections
(R1 0.1405 calculated on F for 2620 fixed reflections with I > 2σ(I). All calculations were carried out with the
SHELXTL PLUS 5.0 set of programs [7].
The basic geometric parameters of a monocrystal of 8 are given in Tables 5, 6.
The data of the X-ray structural analysis of quinazoline 8 have been deposited in the Cambridge
Crystallographic Data Center (CCDC 846361).
The authors are grateful to Z. A. Starikova (INEOS RAN) for carrying out the X-ray structural study.
The work was carried out with the financial support of the Russian Foundation for Basic Research
(project No. 09-03-00726-a) and the Ministry of Education and Science of the Russian Federation (AVTsP RNP
VSh 3.6.11).
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P. H. M. Budzelaar, http://home.cc.umanitoba.ca/~budzelaa/gNMR/gNMR.html
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G. M. Sheldrick, SHELXTL v. 5.10, Structure Determination Software Suit, Bruker AXS (1998).
765