Synthesis of tetra- and pentaaza heterocyclic systems and benzimidazo[1,2-c]quinazoline derivatives

Article abstract of DOI:10.1134/S1070428014010187

5,6-Dihydropyrimido[5′,4′: 5,6]pyrido[1,2-a]benzimidazole and pyrimido[4′,5′: 4,5]pyrimido[1,6-a]-benzimidazole derivatives were synthesized starting from 3-[4-hydroxy-6-methyl(hydroxy)-2-phenylpyrimidin-5-yl] propanoic and 4-hydroxy-2-phenylpyrimidine-5-carboxylic acids. New 6-sulfanyl-substituted benzimidazo-[1,2-c]quinazolines were also prepared.

Full text of DOI:10.1134/S1070428014010187

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 94–99. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.A. Harutyunyan, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 1, pp. 100–105.
Synthesis of Tetra- and Pentaaza Heterocyclic Systems
and Benzimidazo[1,2-c]quinazoline Derivatives
A. A. Harutyunyan
Mndzhoyan Institute of Fine Organic Chemistry, Research Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: harutyunyan.arthur@yahoo.com
Received June 7, 2013
Abstract—5,6-Dihydropyrimido[5′,4′:5,6]pyrido[1,2-a]benzimidazole and pyrimido[4′,5′:4,5]pyrimido[1,6-a]-
benzimidazole derivatives were synthesized starting from 3-[4-hydroxy-6-methyl(hydroxy)-2-phenylpyrimidin-
5-yl]propanoic and 4-hydroxy-2-phenylpyrimidine-5-carboxylic acids. New 6-sulfanyl-substituted benzimidazo-
[1,2-c]quinazolines were also prepared.
DOI: 10.1134/S1070428014010187
Heteroannulated benzimidazoles constitute an ex-
tensively explored class of polyazaheterocyclic com-
pounds many of which are increasingly used in biology
and medicine [1, 2]. Ninety five years after the first
synthesis of the benzimidazo[1,2-c]quinazoline system
[3], some compounds of this series were found to
exhibit high cytotoxicity against tumor cells in vitro
[4, 5]. Their activity is determined by the ability of
fused benzimidazoles having a planar structure to
intercalate DNA between neighboring nucleobases and
thus interfere replication and transcription [2, 4].
ence of sodium ethoxide (Scheme 1). Acids Ia–Ig re-
acted with o-phenylenediamine in polyphosphoric acid
(PPA) along different pathways, depending on the
substituent in position 2 of the pyrimidine ring. The
condensation with 2-phenyl-substituted pyrimidinyl-
propanoic acids Ia, Ib [8], and Ic [6] afforded
4-hydroxy-6-methyl-2-phenyl-, 4-methyl-2-phenyl-,
and 4,6-dimethyl-2-phenyl-5,6-dihydropyrimido-
[5′,4′:5,6]pyrido[1,2-a]benzimidazoles IIa–IIc [6].
However, the reactions with 2-methyl, 2-amino,
2-hydroxy, and 2-sulfanyl derivatives Id–Ig lead to the
formation of benzimidazole derivatives IIIa–IIId
which did not undergo further cyclization to tetracyclic
structure II. Compound IIIa readily reacted with
4-nitrobenzaldehyde in the presence of ZnCl2 ac-
cording to Claisen to give styrylpyrimidine IV as the
only product.
The reactions with 2-phenylpyrimidinyl derivatives
Ia–Ic are likely to include two steps with initial forma-
tion of benzimidazole derivatives which then undergo
cyclization to compounds IIa–IIc. Replacement of the
methyl group in position 6 of the pyrimidine ring by
hydroxy (acid Ia) does not prevent this reaction
pathway. If the 2-position in the pyrimidine ring is
replaced by Me, NH2, OH, or SH group, the second
step is not accomplished.
Derivative of a new heterocyclic system, 3-phenyl-
pyrimido[4′,5′:4,5]pyrimido[1,6-a]benzimidazole-
6(5H)-thione (IX), was synthesized according to the
classical approach developed for the synthesis of benz-
imidazo[1,2-c]quinazolines from anthranilic acid and
Taking into account the above stated, in continua-
tion of studies directed toward search for new biologi-
cally active derivatives of pyrimidines and other aza
heterocycles [6, 7], the present article reports on the
synthesis of new 2-(pyrimidin-5-yl)benzimidazoles
and tetracyclic compounds that are derivatives of tetra-
and pentaaza heterocyclic systems, pyrimido[5′,4′:5,6]-
pyrido[1,2-a]benzimidazole and pyrimido[4′,5′:4,5]-
pyrimido[1,6-a]benzimidazole (pyrimidine isostere of
benzimidazo[1,2-c]quinazoline). Also, new 6-benzyl-
sulfanyl derivatives of benzimidazo[1,2-c]quinazoline
and dimeric structures were synthesized.
Pyrimidinylbenzimidazoles and 5,6-dihydropyrim-
ido[5′,4′:5,6]pyrido[1,2-a]benzimidazole derivatives
were prepared starting from 2-substituted 3-(pyrimi-
din-5-yl)propanoic acids Ia–Ig which were obtained in
turn by reaction of the corresponding amidines,
guanidine, or thiourea with adducts derived from ethyl
acetoacetate or diethyl malonate and ethyl acrylate or
methyl methacrylate in anhydrous ethanol in the pres-
94

SYNTHESIS OF TETRA- AND PENTAAZA HETEROCYCLIC SYSTEMS
95
Scheme 1.
O
N
O
H2N
H2N
HN
R3
OH
+
R2
R1
Ia–Ig
OH
HN
N
Ph
N
N
N
N
R2
N
Ph
N
R1
R2
R1
IIa–IIc
O
N
HN
O
N
HN
N
HN
N
HN
Me
R
Me
IIIa–IIId
NO2
IV
I, R3 = Ph: R1 = OH, R2= Me (a); R1 = Me, R2 = H (b); R1 = R2 = Me (c); R1 = Me, R2 = H, R3 = Me (d), NH2 (e), OH (f), SH (g);
II, R1 = OH, R2 = Me (a); R1 = Me, R2 = H (b); R1 = R2 = Me (c); III, R = Me (a), NH2 (b), OH (c), SH (d).
o-phenylenediamine [3]. Following this approach,
initial 2-phenyl-4-oxo-3,4-dihydropyrimidine-5-car-
boxylic acid (V) [9] was treated with POCl3, and the
resulting 4-chloro derivative VI was brought into reac-
tion with alcoholic ammonia. Heating of 4-aminopy-
rimidine VII with o-phenylenediamine in polyphos-
phoric acid afforded key benzimidazole VIII, and the
latter reacted with carbon disulfide in the presence of
potassium hydroxide, yielding target product IX
(Scheme 2). The average yield of IX was 34%; neither
variation of the reaction conditions and solvent nor the
use of tetrabutylammonium bromide improved the
yield of IX. Identification of other possible reaction
products was not performed.
Taking into account intercalating and antitumor
activity of substituted benzimidazo[1,2-c]quinazolines,
benzimidazo[1,2-c]quinazoline-2-thiol (X) [3] was al-
kylated with benzyl chlorides, 4-methyl-6-chloropy-
rimidin-2-amine, and o- and p-xylylene dichlorides in
the presence of sodium hydroxide to obtain new sul-
fanyl derivatives XIa–XIf and dimeric structures XIg
and XIh (Scheme 3).
Scheme 2.
O
N
O
O
O
HN
OH
N
OH
N
OH
NH2
Ph
Ph
N
Cl
Ph
N
V
VI
VII
N
N
N
H
N
N
N
Ph
N
NH2
VIII
Ph
N
N
S
H
IX
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HARUTYUNYAN
96
Scheme 3.
N
N
N
N
Me
N
N
N
N
SR
N
SH
N
S
N
NH2
XIa–XIe
X
XIf
N
N
N
N
S
N
N
S
N
N
N
N
S
N
S
N
XIg
XIh
XI, R = 2-ClC6H4CH2 (a), 4-MeO-3-O2NC6H3CH2 (b), 2,4-Me2C6H3CH2 (c), 2,4,6-Me3C6H2CH2 (d), 4-FC6H4CH2 (e).
Rf 0.55 (ethanol–dichloroethane, 1:10). IR spectrum,
EXPERIMENTAL
1
ν, cm–1: 1706, 1660 (C=O), 1618 (C=N). H NMR
The IR spectra were recorded on a Nicolet Avatar
330 spectrometer from samples dispersed in mineral
oil. The H NMR spectra were measured on a Varian
Mercury-300 spectrometer at 300 MHz using tetra-
methylsilane as internal reference. Thin-layer chro-
matography was performed on Silufol UV-254 plates;
spots were visualized by treatment with iodine vapor.
The elemental compositions of the isolated compounds
were consistent with the calculated values.
3-(4-Hydroxy-6-oxo-2-phenyl-1,6-dihydropy-
rimidin-5-yl)-2-methylpropanoic acid (Ia). Metallic
sodium, 2.3 g (0.1 mol), was dissolved in 640 g
(4 mol) of diethyl malonate, 100 g (1 mol) of methyl
methacrylate was added, and the solution was heated
for 24 h at 70–80°C. The mixture was neutralized with
10% aqueous HCl, and the oily material was separated,
washed with water, dried over Na2SO4, and distilled
under reduced pressure to collect a fraction boiling at
200–210°C (110 mm). The product, 26.0 g (0.1 mol),
was added to a suspension of 15.7 g (0.1 mol) of benz-
amidine hydrochloride in a solution of 4.6 g (0.2 mol)
of sodium in 250 mL of anhydrous ethanol. The mix-
ture was heated for 5 h under reflux and evaporated to
dryness, a solution of 4 g (0.1 mol) of sodium hydrox-
ide in 100 mL of water was added, and the mixture
was heated for 4 h under reflux and acidified to pH 3
with aqueous HCl. The precipitate was filtered off and
dried. Yield 70%, mp >320°C (decomp.; from DMF),
spectrum (DMSO-d6), δ, ppm: 1.09 d (3H, CH3, J =
6.8 Hz), 2.65–2.78 m (3H, CHCH2), 7.37–7.51 m (3H)
and 8.12–8.16 m (2H) (C6H5), 11.58 br (3H, NH, OH,
COOH). Found, %: N 10.52. C14H14N2O4. Calculated,
%: N 10.21.
1
Condensation of 3-(pyrimidin-5-yl)propanoic
acids with o-phenylenediamine (general procedure).
A mixture of 1.08 g (0.01 mol) of o-phenylenediamine
and 0.01 mol of acid Ia–Ig in 10.0 g of polyphosphoric
acid was heated for 3 h at 210–220°C. The mixture
was cooled and treated with excess aqueous ammonia,
and the precipitate was filtered off and dried.
(RS)-6-Methyl-2-phenyl-5,6-dihydropyrimido-
[5′,4′:5,6]pyrido[1,2-a]benzimidazole-4-ol (IIa).
Yield 72%, yellow powder, mp >340°C (from DMF),
Rf 0.64 (ethanol–dichloroethane, 1:10). IR spectrum,
1
ν, cm–1: 1643 (C=O), 1611 (C=N). H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 1.57 d (3H, CH3, J =
6.8 Hz), 2.52 d.d (1H, CH2, J = 16.4, 11.2 Hz),
3.16 d.d (1H, CH2, J = 16.4, 6.6 Hz), 3.32 m (1H, CH);
7.25 m, 7.30 m, 7.62 m, 8.45 m (1H each, C6H4); 7.53–
7.65 m (3H) and 8.28 m (2H) (C6H5), 12.95 br (1H,
OH). Found, %: N 17.25. C20H16N4O. Calculated, %:
N 17.06.
4-Methyl-2-phenyl-5,6-dihydropyrimido-
[5′,4′:5,6]pyrido[1,2-a]benzimidazole (IIb) and
(RS)-4,6-dimethyl-2-phenyl-5,6-dihydropyrimido-
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SYNTHESIS OF TETRA- AND PENTAAZA HETEROCYCLIC SYSTEMS
97
[5′,4′:5,6]pyrido[1,2-a]benzimidazole (IIc) were
synthesized from acids Ib [8] and Ic [6], respectively,
and o-phenylenediamine according to the procedure
described in [6].
5-[2-(1H-Benzimidazol-2-yl)ethyl]-2-methyl-
6-[(E)-2-(4-nitrophenyl)-1-ethenyl]pyrimidin-4(3H)-
one (IV). A mixture of 2.68 g (0.01 mol) of pyrimidine
IIIa, 1.51 g (0.01 mol) of 4-nitrobenzaldehyde, and
1.36 g (0.01 mol) of ZnCl2 was fused for 2 h at 150–
160°C on a Wood bath. The mixture was cooled and
treated with water, and the product was recrystallized
from DMF. Yield 65%, mp 297–298°C, Rf 0.54
(ethanol–dichloroethane, 1:10). IR spectrum, ν, cm–1:
3623 (OH), 3364 (NH), 1648 (C=O), 1600 (C=N).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
2.13 s (3H, CH3), 2.93 t and 3.09 t (2H each, CH2CH2,
J = 7.5 Hz), 7.06 d (1H, =CH, J = 16.1 Hz), 7.13–
7.19 m and 7.48–7.64 m (2H each, C6H4), 7.87 m and
8.27 m (2H each, C6H4NO2), 7.89 d (1H, =CH, J =
16.1 Hz), 12.52 br.s (2H, NH, OH). Found, %:
N 17.34. C22H19N5O3. Calculated, %: N 17.45.
5-[2-(1H-Benzimidazol-2-yl)ethyl]-2,6-dimethyl-
pyrimidin-4(3H)-one (IIIa) was synthesized from
acid Id [8] and o-phenylenediamine. Yield 75%,
mp 306–307°C (from DMF), Rf 0.67 (ethanol–di-
chloroethane, 1:10). IR spectrum, ν, cm–1: 3350 (NH),
1
1652 (C=O), 1610 (C=N). H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 2.07 s and 2.30 s (3H
each, CH3), 2.82–2.96 m (4H, CH2CH2), 7.07–7.13 m
and 7.42–7.48 m (2H each, C6H4), 12.20 br.s and
12.24 br.s (1H each, OH, NH). Found, %: N 20.62.
C15H16N4O. Calculated, %: N 20.88.
2-Amino-5-[2-(1H-benzimidazol-2-yl)ethyl]-
6-methylpyrimidin-4(3H)-one (IIIb) was synthesized
from acid Ie [10] and o-phenylenediamine. Yield 68%,
mp 223–225°C (from EtOH), Rf 0.69 (ethanol–di-
chloroethane, 1:10). IR spectrum, ν, cm–1: 3340, 3180
4-Chloro-2-phenylpyrimidine-5-carboxylic acid
(VI). A mixture of 2.16 g (0.01 mol) of acid V and
5.0 mL of POCl3 was heated for 2 h under reflux,
excess POCl3 was distilled off, and the oily residue
was poured onto 50 g of ice. After 1 h, the precipitate
was filtered off, washed with cold water, and dried.
Yield 87%, mp 114–115°C (from dioxane), Rf 0.80
1
(NH2, NH), 1656 (C=O), 1608 (C=N). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 2.04 s (3H, CH3),
2.76–2.83 m (2H, CH2), 2.88–2.95 m (2H, CH2),
6.24 br.s (2H, NH2), 7.00–7.05 m and 7.36–7.42 m
(2H each, C6H4), 11.07 br.s and 11.86 br.s (1H each,
NH). Found, %: N 26.30. C14H15N5O. Calculated, %:
N 26.01.
1
(ethyl acetate–octane, 1 : 2). H NMR spectrum
(DMSO-d6–CCl4, 1 :3), δ, ppm: 7.49–7.56 m (2H,
3′-H, 5′-H, C6H5), 7.58–7.64 m (1H, 4′-H, C6H5), 8.24–
8.29 m (2H, 2′-H, 6′-H, C6H5), 8.78 s (1H, N=CH),
13.73 br.s (1H, OH). Found, %: N 11.70. C11H7ClN2O2.
Calculated, %: N 11.94.
5-[2-(1H-Benzimidazol-2-yl)ethyl]-6-methyl-
1,2,3,4-tetrahydropyrimidine-2,4-dione (IIIc) was
synthesized from acid If [11] and o-phenylenediamine.
Yield 63%, mp 200–202°C, Rf 0.49 (ethanol–di-
chloroethane, 1:10). IR spectrum, ν, cm–1: 3400 (NH),
4-Amino-2-phenylpyrimidine-5-carboxylic acid
(VII). A solution of 2.35 g (0.01 mol) of 4-chloro-
pyrimidine VI in 50 mL of a saturated alcoholic
solution of ammonia was heated for 4 h at 120–130°C
in a high pressure reactor. The solvent was distilled off,
the residue was treated with 30 mL of water, and the
precipitate was filtered off and dried. Yield 82%,
mp 273–274°C (from 1,2-dimethoxyethane), Rf 0.59
(ethanol–dichloroethane, 1:10). IR spectrum, ν, cm–1:
3484, 3309, 3170 (NH2), 1683 (C=O), 1620 (C=N).
1H NMR spectrum (DMSO-d6–CCl4, 1 :3), δ, ppm:
7.07 br.s, 7.68 br.s, and 7.91 br.s (1H each, NH2,
COOH), 7.36–7.43 m (3H, 3′-H, 4′-H, 5′-H, C6H5),
8.33–8.40 m (2H, 2′-H, 6′-H, C6H5), 8.78 s (1H,
N=CH). Found, %: N 19.81. C11H9N3O2. Calculated,
%: N 19.53.
1
1651 (C=O), 1572 (C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 1.87 s (3H, CH3), 2.69 m (2H,
CH2), 2.87 m (2H, CH2), 7.07–7.13 m and 7.35–
7.53 m (2H each, C6H4), 10.54 s and 10.94 s (1H each,
CONH), 12.17 br.s (1H, NH). Found, %: N 20.47.
C14H14N4O2. Calculated, %: N 20.73.
5-[2-(1H-Benzimidazol-2-yl)ethyl]-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidin-4-one (IIId) was
synthesized from acid Ig [10] and o-phenylenedi-
amine. Yield 82%, mp 325–327°C (from EtOH),
Rf 0.78 (ethanol–dichloroethane, 1:10). IR spectrum,
ν, cm–1: 3440 (NH), 1660–1575 (C=O, C=N,
1
NH–C=S). H NMR spectrum (DMSO-d6–CCl4, 1:3),
δ, ppm: 1.96 s (3H, CH3), 2.73–2.82 m (2H, CH2),
2.89–2.97 m (2H, CH2), 7.01–7.07 m and 7.36–7.43 m
(2H each, C6H4); 11.84 br.s, 11.92 br.s, and 12.03 br.s
(1H each, NH). Found, %: N 19.30. C14H14N4OS. Cal-
culated, %: N 19.57.
5-(1H-Benzimidazol-2-yl)-2-phenylpyrimidin-
4-amine (VIII). A mixture of 2.15 g (0.01 mol) of acid
VII, 1.19 g (0.011 mol) of o-phenylenediamine, and
10.0 g of polyphosphoric acid was heated for 2 h at
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HARUTYUNYAN
98
220–230°C on a Wood bath. The mixture was cooled
to room temperature and neutralized with aqueous am-
monia, and the precipitate was filtered off and dried.
Yield 85%, mp >330°C (from dioxane), Rf 0.68 (etha-
nol–dichloroethane, 1:10). IR spectrum, ν, cm–1: 3379,
compound X and 4-methoxy-3-nitrobenzyl chloride.
Yield 82%, mp 253–255°C (from DMF), Rf 0.54 (etha-
nol–dichloroethane, 1:10). IR spectrum: ν 1621 cm–1
1
(C=N). H NMR spectrum (DMSO-d6–CCl4, 1:3), δ,
ppm: 3.93 s (3H, OCH3), 4.82 s (2H, CH2), 7.21 d (1H,
6′-H, J = 8.7 Hz), 7.42 d.d.d (1H, C6H4, J = 8.2, 7.2,
1.5 Hz), 7.51 d.d.d (1H, C6H4, J = 8.0, 7.2, 1.2 Hz),
7.60 d.d.d (1H, C6H4, J = 7.9, 7.2, 1.2 Hz), 7.77 d.d.d
(1H, C6H4, J = 8.7, 7.2, 1.7 Hz), 7.83–7.90 m (2H,
1
3268 (NH2, NH), 1625 (C=N). H NMR spectrum
(DMSO-d6–CCl4, 1:3), δ, ppm: 7.12–7.22 m (2H),
7.39–7.55 m (4H), 7.59–7.66 m (1H), 8.40–8.46 m
(2H) (Harom); 9.05 s (1H, N=CH), 9.28 br.s (2H, NH2),
12.76 br.s (1H, NH). Found, %: N 24.58. C17H13N5.
Calculated, %: N 24.37.
Harom), 7.85 d.d (1H, 5′-H, J = 8.7, 2.3 Hz), 8.15 d (1H,
3′-H, J = 2.3 Hz), 8.40 br.d (1H, C6H4, J = 8.2 Hz),
8.56 d.d (1H, C6H4, J = 8.0, 1.7 Hz).
3-Phenylpyrimido[4′,5′:4,5]pyrimido[1,6-a]-
benzimidazole-6(5H)-thione (IX). A mixture of
1.44 g (5 mmol) of amine VIII, 1.4 g (25 mmol) of
potassium hydroxide, 0.76 g (0.6 mL, 10 mmol) of
carbon disulfide, 5 mL of water, and 35 mL of dioxane
was heated for 24 h under reflux. The mixture was
evaporated to dryness, 50 mL of water was added to
the residue, and the mixture was heated to the boiling
point, filtered, and acidified to pH 5 with aqueous HCl.
The mixture was kept in the cold, and the precipitate
was filtered off and dried. Yield 0.56 g (34%),
mp >340°C (from 1,2-dimethoxyethane), Rf 0.61 (etha-
nol–dichloroethane, 1:10). IR spectrum: ν 1596 cm–1
6-(2,4-Dimethylbenzylsulfanyl)benzimidazo-
[1,2-c]quinazoline (XIc) was synthesized from com-
pound X and 2,4-dimethylbenzyl chloride. Yield 74%,
mp 155–156°C (from EtOH), Rf 0.61 (ethanol–di-
chloroethane, 1:10). IR spectrum: ν 1620 cm–1 (C=N).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.31 s (3H,
CH3), 2.48 s (3H, CH3), 4.80 s (2H, CH2), 6.96 d.d
(1H, 5′-H, J = 7.9, 1.9 Hz), 7.01 d (1H, 3′-H, J =
1.9 Hz), 7.35–7.41 m (2H, C6H4), 7.50 d.d.d (1H,
C6H4, J = 8.1, 7.3, 1.0 Hz), 7.60 d.d.d (1H, C6H4, J =
7.9, 7.1, 1.3 Hz), 7.76 d.d.d (1H, C6H4, J = 8.2, 7.1,
1.5 Hz), 7.83–7.90 m (2H, C6H4), 8.38 br.d (1H, C6H4,
J = 8.3 Hz), 8.57 d.d (1H, C6H4, J = 7.9, 1.5 Hz).
Found, %: N 11.08. C23H19N3S. Calculated, %: N 11.37.
1
(NHC=S). H NMR spectrum (DMSO-d6–CCl4, 1:3),
δ, ppm: 7.11–7.18 m and 7.58–7.65 m (2H each,
C6H4), 7.47–7.56 m (3H) and 8.28–8.34 m (2H)
(C6H5), 9.14 br.s (1H, =CH), 12.54 br.s (1H, NH).
Found, %: N 21.40. C18H11N5S. Calculated, %: N 21.26.
6-(2,4,6-Trimethylbenzylsulfanyl)benzimidazo-
[1,2-c]quinazoline (XId) was synthesized from com-
pound X and 2,4,6-trimethylbenzyl chloride. Yield
67%, mp 186–187°C (from EtOH), Rf 0.76 (ethanol–
dichloroethane, 1:10). IR spectrum: ν 1621 cm–1
Benzimidazo[1,2-c]quinazolines XIa–XIi (gen-
eral procedure). Compound X, 2.51 g (0.01 mol), was
dissolved in 50 mL of 0.2 N aqueous sodium hydrox-
ide, 0.011 mol of substituted benzyl chloride or
2-amino-4-chloro-6-methylpyrimidine or 0.005 mol of
o- or p-xylylene dihalide was added, and the resulting
suspension was heated for 24 h on a water bath. The
precipitate was filtered off, washed with water, and
dried.
1
(C=N). H NMR spectrum (DMSO-d6–CCl4, 1:3), δ,
ppm: 2.29 s (3H, CH3), 2.46 s (6H, CH3), 4.81 s (2H,
CH2), 6.87 s (2H, 3′-H, 5′-H), 7.35 d.d.d (1H, C6H4,
J = 8.3, 7.3, 1.2 Hz), 7.49 d.d.d (1H, C6H4, J = 8.0, 7.1,
1.0 Hz), 7.60 d.d.d (1H, C6H4, J = 8.0, 7.0, 1.2 Hz),
7.75 d.d.d (1H, C6H4, J = 8.1, 7.1, 1.5 Hz), 7.84 d.d
(1H, C6H4, J = 8.1, 1.0 Hz), 7.89 br.d (1H, C6H4, J =
8.1 Hz), 8.35 br.d (1H, C6H4, J = 8.3 Hz), 8.59 d.d
(1H, C6H4, J = 8.0, 1.4 Hz). Found, %: N 11.17.
C24H21N3S. Calculated, %: N 10.96.
6-(2-Chlorobenzylsulfanyl)benzimidazo[1,2-c]-
quinazoline (XIa) was synthesized from compound X
and 2-chlorobenzyl chloride. Yield 79%, mp 205–
207°C (from dioxane), Rf 0.59 (ethanol–dichloro-
ethane, 1:10). IR spectrum: ν 1615 cm–1 (C=N).
1H NMR spectrum (DMSO-d6), δ, ppm: 4.94 s (2H,
CH2), 7.23–7.32 m (2H), 7.38–7.63 m (4H), 7.73–
7.81 m (2H), 7.86–7.90 m (2H), 8.39 br.d (1H, J =
8.2 Hz), 8.56 d.d (1H, J = 8.0, 1.4 Hz). Found, %:
N 11.42. C21H14ClN3S. Calculated, %: N 11.18.
6-(4-Fluorobenzylsulfanyl)benzimidazo[1,2-c]-
quinazoline (XIe) was synthesized from compound X
and 4-fluorobenzyl chloride. Yield 80%, mp 160–
161°C (from EtOH), Rf 0.50 (ethanol–dichloroethane,
1
1:10). IR spectrum: ν 1618 cm–1 (C=N). H NMR
spectrum (DMSO-d6), δ, ppm: 4.82 s (2H, CH2),
7.04 m (2H, 3′-H, 5′-H), 7.41 d.d.d (1H, C6H4, J = 8.3,
7.2, 1.4 Hz), 7.51 d.d.d (1H, C6H4, J = 8.0, 7.3,
1.2 Hz), 7.57–7.63 m (3H, 2′-H, 6′-H, C6H4),
6-(4-Methoxy-3-nitrobenzylsulfanyl)benzimid-
azo[1,2-c]quinazoline (XIb) was synthesized from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

SYNTHESIS OF TETRA- AND PENTAAZA HETEROCYCLIC SYSTEMS
99
7.76 d.d.d (1H, C6H4, J = 8.2, 7.1, 1.6 Hz), 7.83–
7.90 m (2H, C6H4), 8.40 br.d (1H, C6H4, J = 8.3 Hz),
8.57 d.d (1H, C6H4, J = 8.0, 1.2 Hz). Found, %:
N 11.52. C21H14FN3S. Calculated, %: N 11.69.
292°C (from DMF), Rf 0.62 (ethanol–dichloroethane,
1
1:10). IR spectrum: ν 1620 cm–1 (C=N). H NMR
spectrum (DMSO-d6), δ, ppm: 4.84 s (4H, CH2), 7.37–
7.67 m (6H, Harom), 7.62 s (4H, C6H4), 7.79–7.96 m
(6H, Harom), 8.41 br.d (2H, Harom, J = 8.2 Hz), 8.51 br.d
(2H, Harom, J = 7.7 Hz). Found, %: N 13.65.
C36H24N6S2. Calculated, %: N 13.90.
4-(Benzimidazo[1,2-c]quinazolin-6-ylsulfanyl)-6-
methylpyrimidin-2-amine (XIf) was synthesized
from compound X and 4-chloro-6-methylpyrimidin-2-
amine. Yield 85%, mp 305–307°C (from H2O), Rf 0.74
(ethanol–dichloroethane, 1:10). IR spectrum, ν, cm–1:
REFERENCES
1
3416, 3309 (NH2), 1628 (C=N). H NMR spectrum
1. Rohini, R., Shanker, K., Reddy, P.M., Ho, Y.P., and
(DMSO-d6), δ, ppm: 2.24 s (3H, CH3), 6.38 s (1H,
5′-H), 6.54 br.s (2H, NH2); 7.34–7.40 m (2H),
7.47 d.d.d (1H, J = 8.0, 7.3, 1.2 Hz), 7.56–7.64 m
(2H), 7.80 br.d (1H, J = 7.9 Hz), 8.41 br.d (1H, J =
8.0 Hz), and 9.49 br.d (1H, J = 8.2 Hz) (C6H4). Found,
%: N 23.63. C19H14N6S. Calculated, %: N 23.45.
Ravinder, V., Eur. J. Med. Chem., 2009, vol. 44, p. 3330.
2. Lyakhova, E.A., Guseva, Yu.A., Lyakhov, S.A., and
Andronati, S.A., Zh. Org. Farm. Khim., 2010, vol. 8,
no. 30, p. 3.
3. Von Niementowski, S., Ber., 1899, vol. 32, p. 1456.
4. Brana, M.F., Castellano, J.M., Keilhauer, G.,
Machuca, A., Martin, Y., Redondo, C., Schlick, E., and
Walker, N., Anti-Cancer Drug Des., 1994, vol. 9,
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5. Brana, M.F., De Vega, M.J.P., Perron, D., Conlon, D.,
Bousquet, P.F., and Robinson, S.P., J. Heterocycl.
Chem., 1997, vol. 34, p. 807.
6-[2-(Benzimidazo[1,2-c]quinazolin-6-ylsulfanyl-
methyl)benzylsulfanyl]benzimidazo[1,2-c]quinaz-
oline (XIg) was synthesized from compound X and
1,2-bis(bromomethyl)benzene. Yield 52%, mp 288–
290°C (from DMF), Rf 0.60 (ethanol–dichloroethane,
1
1:10). IR spectrum: ν 1620 cm–1 (C=N). H NMR
6. Arutyunyan, A.A., Khim. Zh. Arm., 2012, vol. 65,
spectrum (DMSO-d6), δ, ppm: 5.18 s (4H, CH2),
7.21 d.d.d (2H, Harom, J = 8.4, 7.2, 1.2 Hz), 7.36–7.58 m
(10H, Harom), 7.69–7.74 m (2H, Harom), 7.84 br.d (2H,
p. 257.
7. Arutyunyan, A.A., Khim. Zh. Arm., 2012, vol. 65,
p. 317.
Harom, J = 8.1 Hz), 8.23 br.d (2H, Harom, J = 8.4 Hz),
8. Hullar, T.L. and French, W.C., J. Med. Chem., 1969,
vol. 12, p. 424.
9. Ruhemann, S., Ber., 1897, vol. 30, p. 821.
8.27 d.d (2H, Harom, J = 7.5, 1.8 Hz). Found, %:
N 13.72. C36H24N6S2. Calculated, %: N 13.90.
6-[4-(Benzimidazo[1,2-c]quinazolin-6-ylsulfanyl-
methyl)benzylsulfanyl]benzimidazo[1,2-c]quinazo-
line (XIh) was synthesized from compound X and
1,4-bis(chloromethyl)benzene. Yield 52%, mp 290–
10. Baker, B.R. and Almaula, P.I., J. Heterocycl. Chem.,
1964, vol. 1, p. 263.
11. Ge, X. and Roux, B., J. Phys. Chem. B, 2010, vol. 114,
p. 9525.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014