Three-component synthesis of 4-amino-2-aryl-2H-pyrimido-[1,2-b][1,3] benzazole-3-carbonitriles and 4H-pyrimido-[2,1-b][1,3]benzazoles in the presence of magnesium oxide and 12-tungstophosphoric acid as catalysts

Article abstract of DOI:10.1007/s11172-013-0319-3

A simple and convenient approach was suggested for the synthesis of 4-amino-2-aryl-2H-pyrimido[1,2-b][1,3]benzimidazole-3-carbonitriles or -benzothiazole-3-carbonitriles through a three-component reaction of 2-aminobenzimidazole or 2-aminobenzothiazole, a

Full text of DOI:10.1007/s11172-013-0319-3

Russian Chemical Bulletin, International Edition, Vol. 62, No. 10, pp. 2202—2208, October, 2013
2202
Threeꢀcomponent synthesis of 4ꢀaminoꢀ2ꢀarylꢀ2Hꢀpyrimidoꢀ
[1,2ꢀb][1,3]benzazoleꢀ3ꢀcarbonitriles and 4Hꢀpyrimidoꢀ
[2,1ꢀb][1,3]benzazoles in the presence of magnesium oxide
and 12ꢀtungstophosphoric acid as catalysts*
H. Sheibani and M. Babaie
Department of Chemistry, Shahid Bahonar University of Kerman,
76169 Kerman, Iran.
Eꢀmail: hsheibani@mail.uk.ac.ir
A simple and convenient approach was suggested for the synthesis of 4ꢀaminoꢀ2ꢀarylꢀ2Hꢀ
pyrimido[1,2ꢀb][1,3]benzimidazoleꢀ3ꢀcarbonitriles or ꢀbenzothiazoleꢀ3ꢀcarbonitriles through
a threeꢀcomponent reaction of 2ꢀaminobenzimidazole or 2ꢀaminobenzothiazole, aldehyde,
and malononitrile in the presence of magnesium oxide (MgO) and 12ꢀtungstophosphoric acid
as catalysts. Threeꢀcomponent reactions of aldehyde, ꢀketoester, and 2ꢀaminobenzimidazole
or 2ꢀaminobenzothiazole with the formation of 4Hꢀpyrimido[2,1ꢀb]benzimidazole or 4Hꢀpyꢀ
rimido[2,1ꢀb]benzothiazole derivatives, respectively, were also studied. These approaches have
the advantage of high yields, rapid and pure course of the reactions, as well as the use of cheap
and available catalysts.
Key words: threeꢀcomponent reaction, 4Hꢀpyrimido[2,1ꢀb]benzimidazole, magnesium
oxide, 12ꢀtungstophosphoric acid.
Polyfunctional heterocycles are principal structural
2ꢀaminobenzothiazole 1b was found to be the most acꢀ
tive.13 However, addition of 2ꢀaminobenzothiazole 1b to
bis(methylthio)methylenemalononitrile (IIIa) or ethyl
2ꢀcyanoꢀ3,3ꢀbis(methylthio)acrylate (IIIb) gives 3ꢀcyanoꢀ
4ꢀiminoꢀ2ꢀmethylthioꢀ4Hꢀpyrimido[2,1ꢀb][1,3]benzoꢀ
thiazole (IVa) and 3ꢀcyanoꢀ2ꢀmethylthioꢀ4Hꢀpyrimidoꢀ
[2,1ꢀb][1,3]benzothiazolꢀ4ꢀone (IVb), respectively, i.e.,
the exocyclic nitrogen atom is the most active in these
reactions (Scheme 1).14,15
Dihydropyrimidine derivatives frequently exhibit valuꢀ
able therapeutic and medicinal properties.16,17 In particuꢀ
lar, dihydropyrimidine derivatives, viz., benzo[4,5]imidꢀ
azo[1,2ꢀa]pyrimidines, because of their biological activity
are widely used as antineoplastics18 and proteinꢀkinase
inhibitors.19 These agents were synthesized by the Knoevꢀ
enagel reaction between an aldehyde and a ꢀketoester.20
It should be noted that the indicated compounds were
obtained by a threeꢀcomponent reaction. Despite simꢀ
plicity, the known methods have a number of disadvanꢀ
tages, such as low yields, the use of toxic, expensive, and
environmentally unfriendly solvents.21—24 The disadvanꢀ
tages of the already existing methods prompted us to search
for alternative approaches to the synthesis of 4Hꢀpyrimiꢀ
do[2,1ꢀb]benzimidazole and 4Hꢀpyrimido[2,1ꢀb]benzoꢀ
thiazole derivatives. We have developed threeꢀcomponent
reactions of malononitrile or ethyl cyanoacetate with alꢀ
dehydes and 1,3ꢀbinucleophiles, such as amidines,25—27
fragments of many medicines.1,2 That is why, much attenꢀ
tion is paid to their synthesis. Earlier, it was found3,4 that
pyrimidines fused to fiveꢀmembered aromatic heterocyꢀ
cles containing two heteroatoms (such as benzimidazoles
or benzothiazoles) possess interesting pharmacological
properties. These compounds are characterized by a wide
range of biological and pharmacological activity due to
the presence in their structure of a "fold" passing through
the nitrogen and sulfur atoms, which is believed to be one
of the structural features responsible for their activity.5,6
Analysis of literature data showed that there are only sevꢀ
eral works7—10 devoted to the synthesis of pyrimidobenzꢀ
imidazoles and pyrimidobenzothiazoles. There are three
electronꢀenriched positions in 2ꢀaminobenzimidazole (1a)
or 2ꢀaminobenzothiazole (1b): the nitrogen and sulfur atꢀ
oms. Reactions of these compounds with electrophiles can
take place either at exocyclic or endocyclic nitrogen atom,
depending on the nature of the electrophile and reaction
conditions.11,12 Nucleophilic addition of 2ꢀaminobenzoꢀ
thiazole to acetylenic esters I with subsequent cyclization
leads to 2Hꢀpyrimido[2,1ꢀb]benzothiazolꢀ2ꢀone derivaꢀ
tives II. In this case, the endocyclic nitrogen atom of
* Dedicated to the memory of Alirez Alfzalipur, the founder of
the University of Kerman, in connection with the 100th anniꢀ
versary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2202—2208, October, 2013.
1066ꢀ5285/13/6210ꢀ2202 © 2013 Springer Science+Business Media, Inc.

4HꢀPyrimido[1,2ꢀb][1,3]benzazoles
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2203
Scheme 1
Z = CN (IIIa), CO2Et (IIIb); X = NH (IVa), O (IVb)
ꢀhydroxyꢀ or ꢀaminoꢀsubstituted activated C—Hꢀacꢀ
ids,28 ꢀoxohydrazones,29 3ꢀalkylꢀ1ꢀphenylꢀ2ꢀpyrazolinꢀ
5ꢀones.30
The target compounds, 4ꢀaminoꢀ2ꢀarylꢀ2Hꢀpyrimiꢀ
do[1,2ꢀb]benzimidazoleꢀ3ꢀcarbonitriles or ꢀbenzothiꢀ
azoleꢀ3ꢀcarbonitriles32 2a—f were obtained by a threeꢀ
component the reaction of 2ꢀaminobenzimidazole 1a or
2ꢀaminobenzothiazole 1b, aldehydes 3a—c, and malonoꢀ
nitrile (4) in the presence of catalysts, magnesium oxide
and PW, in excellent yields (Scheme 2). These reactions
were carried out in the presence of two forms of magneꢀ
sium oxide crystals: commercial MgO (CMꢀMgO) and
MgO with highly developed surface (HSAꢀMgO). It was
found that HSAꢀMgO is more active than CMꢀMgO. We
also used PW in the presence of a catalytic amount of
triethylamine as a highly efficient heterogeneous catalyst.
The experimental results are given in Table 1.
Heteropolyacids (HPA) are stronger acids than homoꢀ
geneous acid catalysts, such as sulfuric acid or ionꢀexꢀ
change resins. As catalysts, they have a number of advanꢀ
tages, which make them economically and environmenꢀ
tally more preferable. The use of HPA as heterogeneous
acid catalysts is important for the development of "green"
catalysts, since they make it possible to avoid pollution of
environment and prevent corrosion unavoidable in conꢀ
ventional technologies.33
Results and Discussion
In the present work, we developed an efficient threeꢀ
component oneꢀpot method for the preparation of 4ꢀaminoꢀ
2ꢀarylꢀ2Hꢀpyrimido[1,2ꢀb][1,3](benzimidazole or benzoꢀ
thiazole)ꢀ3ꢀcarbonitriles and triheterocyclic 4Hꢀpyrꢀ
imido[2,1ꢀb]benzazoles by the condensation of 2ꢀaminoꢀ
benzimidazole (1a) or 2ꢀaminobenzothiazole (1b) with
aldehydes and malononitrile or ꢀketoester, respectively,
in the presence of catalysts, viz., MgO or 12ꢀtungstophosꢀ
phoric acid (PW). These heterogeneous catalysts can be
easily regenerated from the reaction mixture by filtration
and reused after activation. This is their advantage over
common homogeneous catalysts. Magnesium oxide is
a universal compound used as a heterogeneous basic cataꢀ
lyst for a number of the baseꢀcatalyzed organic reactions,
as well as an additive in production of refractory materiꢀ
als, dyes, and superconductors.31
Scheme 2
Cat is catalyst
X = NH (1a), S (1b)

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Sheibani and Babaie
Table 1. Synthesis of compounds 2a—f in the presence of catalysts
double bond with the formation of the intermediate 7
(this differs from the mechanism for the preparation of
compound 5, where the endocyclic nitrogen atom of
2ꢀaminobenzimidazole 1a or 2ꢀaminobenzothiazole 1b reꢀ
acts with the C=C double bond). Then, the endocyclic
nitrogen atom acts as nucleophile and rapidly intramolecꢀ
ularly reacts with the CN fragment to form the final
product 2. We also studied a reaction between benzꢀ
ylidenemalononitrile 6 (obtained earlier by the reacꢀ
tion of benzaldehyde with malononitrile) and 2ꢀaminoꢀ
benzimidazole or 2ꢀaminobenzothiazole in the presence
of MgO with the highly developed surface, which
gave 4ꢀaminoꢀ2ꢀarylꢀ2Hꢀpyrimido[1,2ꢀb]benzimidazoleꢀ
Comꢀ
pound
Ar
X
CM/HSA(MgO)
PW
t/min
Yield
(%)
t/min Yield
(%)
2a
2b
2c
2d
2e
2f
Ph
4ꢀClC6H4
2,4ꢀCl2C6H3 NH
Ph
4ꢀClC6H4
4ꢀMeC6H4
NH
NH
90/10
45/5
45/8
60/12
45/8
75/12
80/92
75/95
75/90
70/91
80/93
80/90
15
10
15
22
15
18
91
94
89
91
92
90
S
S
S
For oneꢀpot reactions with sequential steps, usually
called tandem or cascade reactions, it is essential to select
such reaction conditions that the mixing the reagents and
catalysts would trigger a required cascade of transformaꢀ
tions. For example, benzylidenemalononitrile (6) containꢀ
ing an electronꢀpoor carbon—carbon double bond, is
formed quantitatively in the course of the rapid Knoeveꢀ
nagel reaction of malononitrile with the aromatic aldeꢀ
hyde. As we reported earlier,27 this reaction readily occurs
in the presence of MgO. In the second step, the exocyclic
amino group of 2ꢀaminobenzimidazole 1a or 2ꢀaminoꢀ
benzothiazole 1b attacks the electrophilic carbon—carbon
3ꢀcarbonitriles or ꢀbenzothiazoleꢀ3ꢀcarbonitriles
(Scheme 3).
2
It should be noted that the reaction is highly regioꢀ
selective and leads only to one out of two possible isomers.
The structure of products 2 was confirm by the study of
the reaction of Nꢀ(benzimidazoleꢀ or 1,3ꢀbenzothiazolꢀ2ꢀ
yl)ꢀNꢀ(alkylidene)amines 8a—d (obtained by the reaction
of aldehydes with 2ꢀaminobenzazoles) with malononitrile,
which in the presence of MgO with highly developed surꢀ
face led to the same 4ꢀaminoꢀ2ꢀarylꢀ2Hꢀpyrimido[1,2ꢀb]ꢀ
benzimidazoleꢀ3ꢀcarbonitrile or ꢀbenzothiazoleꢀ3ꢀcarboꢀ
nitriles 2a—d (Scheme 4).
Scheme 3
Scheme 4
Ar = Ph (8a, 8c), 4ꢀClC6H4 (8b, 8d)
X = NH (8a, 8b), S (8c, 8d)
i. Reflux, 1 h.

4HꢀPyrimido[1,2ꢀb][1,3]benzazoles
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2205
4ꢀAminoꢀ2ꢀ(4ꢀmethylphenyl)ꢀ2Hꢀ[1,3]thiazino[3,2ꢀa]ꢀ
benzimidazoleꢀ3ꢀcarbonitrile (10) was similarly syntheꢀ
sized in excellent yield by the threeꢀcomponent reaction
of benzimidazoleꢀ2ꢀthiol (9), 4ꢀmethylbenzaldehyde, and
malononitrile in the presence of MgO with highly develꢀ
oped surface as a highly efficient heterogeneous catalyst
(Scheme 5).
tanedione type undergo condensation with 2ꢀaminothiꢀ
azole or various aminoheterocycles like in the general proꢀ
cedure for the synthesis of monocyclic compounds by the
Biginelli reaction.
To develop this strategy, we studied a threeꢀcompoꢀ
nent reactions of aldehyde, ethyl acetoacetate (or dimeꢀ
done), and 2ꢀaminobenzimidazole (or 2ꢀaminobenzothiꢀ
azole) leading to 4Hꢀpyrimido[2,1ꢀb]benzimidazole and
4Hꢀpyrimido[2,1ꢀb]benzothiazole derivatives (11 and 12,
respectively) in the presence of the PW, commercial
CMꢀMgO, and HSAꢀMgO catalysts (Scheme 7). The catꢀ
alysts were found to greatly affect the rates and the yields
of the reactions. The results obtained are summarized
in Table 2.
Scheme 5
Though we did not yet establish the mechanism of the
formation of 4Hꢀpyrimido[2,1ꢀb]benzoazoles, a probable
pathway of the reaction is shown in Scheme 8. Apparentꢀ
ly, the reaction takes place in two steps: the Knoevenagel
condensation of aldehyde and ꢀketoester gives 2ꢀbenzꢀ
ylideneꢀ3ꢀoxobutanoate (13); then, the Michael addition
of 2ꢀaminobenzimidazole 1a or 2ꢀaminobenzothiazole 1b
to compound 13 leads to compound 14, cyclization of
which results in 4Hꢀpyrimido[2,1ꢀb]benzoazoles 11.
The structures of compounds 2a—f were established
1
Bicyclic dihydropyrimidines (DHP), such as thiazoloꢀ
pyrimidines and imidazopyrimidines possessing a powerꢀ
ful vasorelaxant activity were obtained in two steps by the
Biginelli reaction (Atwal modification) (Scheme 6). In
this approach,19 enones of the 3ꢀbenzylideneꢀ2,4ꢀpenꢀ
based on elemental analysis, IR spectroscopy, H and
13C NMR spectroscopy, as well as mass spectrometry.
The IR spectra of these compounds exhibit an absorption
band of the CN group in the region 2235—2238 cm–1 and
two sharp bands at 3450—3400 and 3370—3300 cm–1
,
Scheme 6
i. 12 h.
Scheme 7

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Sheibani and Babaie
Scheme 8
Table 2. Synthesis of compounds 11a—f and 12a—c in the presence of various catalysts
Comꢀ
pound
Ar
X
M.p./C
[Ref.]
CM/HSA(MgO)
PW
t/min
Yield
(%)
t/min
Yield
(%)
11a
11b
11c
11d
11e
11f
12a
12b
12c
Ph
S
S
S
N
N
N
S
172—175 [21]
140—143 [21]
150—152 [21]
291—293 [22]
270—272 [22]
40/5
45/95
35/93
55/89
50/90
55/85
45/87
55/90
40/87
40/86
7
95
90
79
85
87
84
85
67
80
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
55/10
63/12
45/10
70/14
12
12
15
20
10
17
20
40
225 (decomp.) [21] 43/10
226—227 [10]
236—240 [10]
241—243 [10]
35/5
50/10
75/22
2ꢀMeOC6H4
3ꢀMeOC6H4
S
S
1100 EX mass spectrometer (70 eV). Elemental analysis was perꢀ
formed on a Heraeus CHNꢀOꢀRapid analyzer.
Preparation of MgO with highly developed surface. The cataꢀ
lysts used in this work were obtained by calcination of Mg(OH)2
hydrate at 450 C for 2 h.
corresponding to the asymmetric and symmetric vibration
of the NH2 group. Compounds 11a—f and 12a—c are
described in the literature.21—24 The IR spectra and meltꢀ
ing points of all the known compounds agree with those
described in the literature.
Nꢀ(Benzimidazolꢀ2ꢀylꢀ or benzothiazolꢀ2ꢀyl)ꢀNꢀalkylideneꢀ
amines 8a—d. The reactions were carried out in a standard roundꢀ
bottom flask equipped with a reflux condenser with heating.
A mixture of aldehyde 3 (2 mmol) and 2ꢀaminobenzazole 1a or 1b
(2 mmol) in acetonitrile (40 mL) was refluxed with stirring for
1 h. Then, the reaction mixture was cooled, a precipitate of
product 8 was filtered off and recrystallized from ethanol.34
Synthesis of 4ꢀaminoꢀ2ꢀarylꢀ2Hꢀpyrimido[1,2ꢀb][1,3]benzꢀ
imidazoleꢀ3ꢀcarbonitriles or ꢀbenzothiazoleꢀ3ꢀcarbonitriles 2a—f
(general procedure). Method A. A mixture of 2ꢀaminobenzimidꢀ
azole or 2ꢀaminobenzothiazole 1 (2 mmol), aldehyde (2 mmol),
and malononitrile (2 mmol) in MeCN (25 mL) was refluxꢀ
ed with stirring in the presence of commercial MgO or MgO
with highly developed surface (0.25 g). The reaction of was
carried out until completion (TLC monitoring). The solvent
was allowed to evaporate at ~20 C, then ethanol (30 mL)
was added, and the reaction mixture was stirred. The undisꢀ
solved catalyst was filtered off, the filtrate was concentratꢀ
In conclusion, we described threeꢀcomponent reacꢀ
tions of 2ꢀaminobenzimidazole or 2ꢀaminobenzothiazole
as a 1,3ꢀbinucleophiles, aldehydes, and malononitrile (or
ꢀketoesters) in the presence of catalysts, MgO and PW,
which rapidly and in high yields furnish 4ꢀaminoꢀ2ꢀarylꢀ
2Hꢀpyrimido[1,2ꢀb][1,3]benzazoleꢀ3ꢀcarbonitriles and
4Hꢀpyrimido[2,1ꢀb][1,3]benzazole derivatives, respectively.
Experimental
Melting points were determined on a Gallencamp apparatus
and were not corrected. IR spectra were recorded on a Mattson
1000 FTꢀIR spectrometer, 1H and 13C NMR spectra were reꢀ
corded on a Bruker DRXꢀ500 Avance spectrometer (500 and
125.77 MHz, respectively) in DMSOꢀd6, using Me4Si as an inꢀ
ternal standard. Mass spectra were obtained on Shimadzu QP

4HꢀPyrimido[1,2ꢀb][1,3]benzazoles
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2207
ed. The product obtained was purified by crystallization from
ethanol.
Method B. The synthesis was carried out similarly to method
A in the presence of PW (0.25 g).
4ꢀAminoꢀ2ꢀ(4ꢀmethylphenyl)ꢀ2Hꢀpyrimido[2,1ꢀb][1,3]ꢀ
benzothiazoleꢀ3ꢀcarbonitrile (2f). Method A. The yield was 0.57 g
(90%), light green crystals, m.p. 199—200 C. IR (KBr), max/cm–1
:
3320, 3210 (br, NH2); 2178 (CN); 1632, 1618 (C=N). MS, m/z
(Irel (%)): 318 [M]+, (10), 316 (100); 290 (36); 251 (45); 199 (12);
140 (14); 134 (20); 109 (11); 91 (22); 69 (15); 65 (18); 58 (11);
43 (52); 41 (12). Found (%): C, 67.63; H, 4.33; N, 17.38.
C18H14N4S. Calculated (%): C, 67.90; H, 4.43; N, 17.60.
1H NMR, : 8.10—6.82 (m, 10 H, Ar, NH2); 4.58 (s, 1 H, CH);
2.38 (s, 3 H, Me). 13C NMR, : 160.59, 156.55, 154.31, 141.63,
137.06, 132.24, 130.81, 129.94, 129.05, 128.25, 124.05, 122.26,
116.54, 89.46, 55.08, 20.99 (Me).
4ꢀAminoꢀ2ꢀ(4ꢀmethylphenyl)ꢀ4Hꢀ[1,3]thiazino[3,2ꢀa]benzꢀ
imidazoleꢀ3ꢀcarbonitrile (10). A mixture of 1Hꢀbenzimidazoleꢀ
2ꢀthiol 9 (2 mmol), 4ꢀmethylbenzaldehyde (2 mmol), and malꢀ
ononitrile (2 mmol) in MeCN (25 mL) was refluxed with stirring
in the presence of MgO with highly developed surface (0.25 g).
The reaction of was carried out until completion (15 min, TLC
monitoring), then the solvent was allowed to evaporate at ~20 C,
ethanol (30 mL) was added, and the reaction mixture was stirred.
The undissolved catalyst was filtered off, the filtrate was conꢀ
centrated. The product obtained was purified by crystallization
from ethanol. The yield was 0.57 g (90%), yellow crystals, m.p.
220—222 C. IR (KBr), max/cm–1: 3282, 2941 (br, NH2); 2176
(CN); 1581, 1520 (C=N). MS, m/z (Irel (%)): 318 [M]+, (23),
306 (8); 185 (12); 157 (12); 136 (8); 119 (100); 111 (23); 91 (60);
77 (12); 65 (19); 43 (38); 41 (22); 150 (54); 134 (78); 108 (33);
90 (38); 58 (35); 43 (42). Found (%): C, 67.71; H, 4.30; N, 17.34.
C18H14N4S. Calculated (%): C, 67.90; H, 4.43; N, 17.60.
1H NMR, : 7.66—6.85 (m, 10 H, Ar, NH2); 5.15 (s, 1 H, CH);
2.33 (s, 3 H, Me). 13C NMR, : 160.61, 160.15, 139.38, 138.89,
138.29, 132.88, 131.97, 130.73, 129.17, 128.66, 127.64, 121.21,
113.71, 112.64, 49.88, 20.68 (CH3).
4ꢀAminoꢀ2ꢀphenylꢀ2,10ꢀdihydropyrimido[1,2ꢀa][1,3]benzꢀ
imidazoleꢀ3ꢀcarbonitrile (2a). Method A. The yield was 0.52 g
(94%), m.p. 201—203 C. IR (KBr), max/cm–1: 3350, 3110 (br,
NH2, NH); 2175 (CN), 1650, 1620 (C=N). MS, m/z (Irel (%)):
287 [M]+, (30), 286 (30); 210 (100); 133 (90); 105 (17); 90 (20);
77 (28); 51 (18); 43 (27). Found (%): C, 70.75; H, 4.38; N, 24.06.
C17H13N5. Calculated (%): C, 71.07; H, 4.56; N, 24.37. 1H NMR,
: 8.57 (s, 1 H, NH); 8.07—6.99 (m, 9 H, Ar); 6.78 (s, 2 H,
NH2); 5.20 (s, 1 H, CH). 13C NMR, : 151.70, 149.06 (C=N);
143.60, 142.89, 129.26, 128.63, 127.77, 125.86, 123.26, 119.79,
119.07 (CN), 116.02, 112.34, 61.98 (C(3)), 53.23 (C(2)).
4ꢀAminoꢀ2ꢀ(4ꢀchlorophenyl)ꢀ2,10ꢀdihydropyrimido[1,2ꢀa]ꢀ
[1,3]benzimidazoleꢀ3ꢀcarbonitrile (2b). Method A. The yield was
0.6 g (95%), m.p. 209—210 C. IR (KBr), max/cm–1: 3438,
3336, 3100 (br, NH2, NH); 2187 (CN); 1676, 1651 (C=N). MS,
m/z (Irel (%)): 321 [M]+, (8), 306 (12); 230 (32); 216 (30); 188
(35); 171 (15); 119 (23); 105 (100); 91 (85); 77 (45); 57 (27);
51 (18); 43 (84); 41 (19). Found (%): C, 63.20; H, 3.39; N, 12.43.
C17H12ClN5. Calculated (%): C, 63.46; H, 3.76; N, 21.77.
1H NMR, : (s, 1 H, NH); 7.64—6.98 (m, 8 H, Ar); 6.83 (s, 2 H,
NH2); 5.25 (s, 1 H, CH). 13C NMR, : 151.54, 149.18 (C=N);
143.55, 141.77, 132.39, 129.23, 128.63, 127.89, 123.32, 119.87,
118.93 (CN); 118.08, 112.39, 61.51 (C(3)); 52.59 (C(2)).
4ꢀAminoꢀ2ꢀ(2,4ꢀdichlorophenyl)ꢀ2,10ꢀdihydropyrimido[1,2ꢀa]ꢀ
[1,3]benzimidazoleꢀ3ꢀcarbonitrile (2c). Method A. The yield was
0.64 g (90%), light yellow crystals, m.p. 212—214 C. IR (KBr),

max/cm–1: 3412, 3310, 3210 (br, NH2, NH); 2187 (CN); 1676,
1627 (C=N). MS, m/z (Irel (%)): 356 [M]+, (10), 396 (33);
119 (30); 111 (35); 91 (20); 77 (15); 58 (30); 43 (100). Found (%):
C, 56.96; H, 3.00; N, 19.43. C17H11Cl2N5. Calculated (%):
C, 57.32; H, 3.11; N, 19.66. 1H NMR, : 8.48 (s, 1 H, NH);
7.67—6.99 (m, 7 H, Ar); 6.88 (s, 2 H, NH2); 5.64 (s, 1 H, CH).
13C NMR,  151.50, 149.55 (C=N); 143.49, 138.33, 133.31,
132.42, 129.96, 129.23, 129.08, 128.05, 123.37, 119.98, 118.29
(CN); 119.09, 112.41, 60.36 (C(3)); 50.54 (C(2)).
Synthesis of 4Hꢀpyrimido[2,1ꢀb]benzimidazole or 4Hꢀpyrꢀ
imido[2,1ꢀb]benzothiazole derivatives 11a—f and 12a—c (general
procedure). Compounds 11a—f and 12a—c were obtained acꢀ
cording to the procedure described for the synthesis of 2a—f with
the replacement of malononitrile with ethyl acetoacetate or
dimedone.
4ꢀAminoꢀ2ꢀphenylꢀ2Hꢀpyrimido[2,1ꢀb][1,3]benzothiazoleꢀ3ꢀ
carbonitrile (2d). Method A. The yield was 0.55 g (91%), light
brown crystals, m.p. 197—199 C. IR (KBr), max/cm–1: 3344,
3204 (br, NH2); 2174 (CN); 1612 (C=N); 1542 (C=C). MS, m/z
(Irel (%)): 304 [M]+, (10), 286 (100); 206 (11); 149 (8); 111 (7);
91 (5); 58 (9); 43 (32). Found (%): C, 66.89; H, 3.75; N, 18.11.
C17H12N4S. Calculated (%): C, 67.09; H, 3.97; N, 18.41.
1H NMR, : 7.75—6.96 (m, 11 H, Ar, NH2); 4.75 (s, 1 H, CH).
13C NMR, : 160.63, 160.18, 136.03, 135.86 134.89, 133.61,
128.92, 128.63, 113.74, 113.59, 113.48, 112.56 (CN), 92.03, 80.28
(C(3)); 60.47 (C(2)).
The authors are grateful to the Departmental Research
Committee of the Shahid Bahonar University of Kerman
for the financial support of this work.
References
1. A. Dömling, I. Ugi, Angew Chem., Int. Ed., 2000, 39, 3168.
2. A. Dömling, Chem Rev., 2006, 106, 17.
3. A. Burger, Medicinal Chemistry, 3th ed., WileyꢀInterscience,
New York, 1970, p. 72; p. 544; p. 719.
4 I. Hutchinson, S. A. Jennings, B. R. Vishnuvajjala, A. D.
Westwell, M. F. G. Stevens, J. Med. Chem., 2002, 45, 744.
5. N. Denora, V. Laquintana, M. G. Pisu, R. Dore, L. Murru,
A. Latrofa, G. Trapani, E. Sanna, J. Med. Chem., 2008,
51, 6876.
6. J. J. Wade, C. B. Toso, C. J. Matson, V. L. Stelzer, J. Med.
Chem., 1983, 26, 608.
7. J. J. Wade, R. F. Hegel, C. B. Toso, J. Org. Chem., 1979,
44, 1811.
4ꢀAminoꢀ2ꢀ(4ꢀchlorophenyl)ꢀ2Hꢀpyrimido[2,1ꢀb][1,3]benzoꢀ
thiazoleꢀ3ꢀcarbonitrile (2e). Method A. The yield was 0.62 g
(93%), yellow crystals, m.p. 215—217 C. IR (KBr), max/cm–1
:
3361, 3208 (br, NH2); 2184 (CN); 1636, 1620 (C=N). MS, m/z
(Irel (%)): 338 [M]+, (54), 336 (100); 310 (49); 271 (59); 150 (54);
134 (78); 108 (33); 90 (38); 58 (35); 43 (42). Found (%): C, 59.97;
H, 3.05; N, 16.24. C17H11ClN4S. Calculated (%): C, 60.27;
H, 3.27; N, 16.54. 1H NMR, : 8.33—6.89 (m, 10 H, Ar, NH2);
4.03 (s, 1 H, CH). 13C NMR, : 159.69, 158.53, 158.40, 153.00,
135.98, 134.49, 133.17, 130.88, 129.78, 128.42, 127.99, 123.83,
117.74, 91.00, 80.14.
8. C. Hulme, Y. S. Lee, Mol. Divers., 2008, 12, 1.

2208
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Sheibani and Babaie
9. [V. D. Dyachenko, R. P. Tkachev, Russ. J. Org. Chem.
(Engl. Transl.), 2003, 39, 757 [Zh. Org. Khim., 2003, 39, 807].
10. A. Shaabani, E. Farhangi, A. Rahmati, Comb. Chem. High.
T. Scr., 2006, 9, 771.
11. A. Miloudi, D. ElꢀAbed, G. Boyer, J. P. Finet, J. P. Galy,
D. Siri, Eur. J. Org. Chem., 2004, 1509.
12. L. Jin, B. Song, G. Zhang, R. Xu, S. Zhang, X. Gao, D. Hu,
S. Yang, Bioorg. Med. Chem. Lett., 2006, 16, 1537.
13. H. Wahea, J. T. Mbaforb, A. E. Nkengfackb, Z. T. Fomumb,
R. A. Cherkasova, O. Sternerc, D. Doepp, ARKIVOC, 2003,
xv, 107.
23. A. A. Pavlenko, Kh. S. Shikhaliev, A. Yu. Potapov, D. V.
Krylsky, Chem. Heterocycl. Compd., 2005, 41, 689 [Khim.
Geterotsikl. Soedin, 2005, 641].
24. K. B. Sharma, P. K. Sharma, M. Kumar, Synth. Commun.,
2010, 40, 2347.
25. H. Sheibani, K. Saidi, A. S. Saljooghi, J. Chem. Res.,
2008, 390.
26. H. Sheibani, A. S. Saljooghi, A. Bazgir, ARKIVOC, 2008,
ii, 115.
27. H. Sheibani, M. Seifi, A. Bazgir, Synth. Commun., 2009,
39, 1055.
14. M. S. Pinglea, S. P. Vartale, V. N. Bhosale, S. V. Kuberkar,
ARKIVOC, 2006, x, 190.
15. K. G. Baheti, S. B. Kapratwar, S. V. Kuberkar, Synth. Comꢀ
mun., 2002, 32, 2237.
16. H. Khabazzadeh, K. Saidi, H. Sheibani, Bioorg. Med. Chem.
Lett., 2008, 18, 278.
28. M. Seifi, H. Sheibani, Catal. Lett., 2008, 126, 275.
29. H. Sheibani, M. A. Amrollahi, Z. Esfandiarpoor, Mol.
Divers., 2010, 14, 277.
30. H. Sheibani, M. Babaie, Synth. Commun., 2010, 40, 257.
31. C. Xu, J. K. Bartley, D. I. Enache, David, W. Knight, G. J.
Hutchings, Synthesis, 2005, 10, 3468.
17. C. M. Wright, R. J. Chovatiya, N. E. Jameson, D. M. Turnꢀ
er, G. Zhu, S. Werner, D. M. Huryn, J. M. Pipas, B. W.
Day, P. Wipf, J. L. Brodsky, Bioorg. Med. Chem., 2008,
16, 3291.
32. A. Dandia, S. Khaturia, P. Sarawgi, A. Jain, Phosphorus,
Sulfur, Silicon Relat. Elem., 2007, 182, 1529.
33. H. Khabazzadeh, K. Saidi, H. Sheibani, ARKIVOC, 2008,
xv, 34.
18. A. A. M. AbdelꢀHafez, Arch. Pharmacal. Res., 2007, 30, 678.
19. K. S. Atwal, S. Moreland, Bioorg. Med. Chem. Lett., 1991,
1, 291.
34. M. Krasavin, S. Tsirulnikov, M. Nikulnikov, V. Kysil,
A. Ivachtchenko, Tetrahedron Lett., 2008, 49, 5241.
20. R. Alajarin, P. Jordan, J. J. Vaquero, J. AlvarezꢀBuilla, Synꢀ
thesis, 1995, 389.
21. A. Shaabani, A. Rahmati, S. Naderi, Bioorg. Med. Chem.
Lett., 2005, 15, 5553.
22. Y. ChangꢀSheng, L. Song, W. CuiꢀHua, Y. ChenꢀXia,
S. QingꢀQing, T. ShuꢀJaing, Chin. J. Chem., 2008, 26.
Received February 8, 2011;
in revised form September 21, 2012