Chemoselective synthesis of 4-oxo-2-aryl-4,10-dihydropyrimido [1,2-a][1,3]benzimidazol-3-yl cyanides via [3+3] atom combination of 2-aminobenzimidazole with ethyl-α-cyanocinnamoates

Article abstract of DOI:10.1002/jhet.640

Figure represented. Chemoselective synthesis of 4-oxo-2-aryl-4,10- dihydropyrimido[1,2-a][1,3]benzimidazol-3-yl cyanides from three-component reactions of 2-aminobenzimidazole, aldehydes, and ethyl cyanoacetate via [3+3] atom combination is reported. The

Full text of DOI:10.1002/jhet.640

July 2011
Chemoselective Synthesis of 4-Oxo-2-aryl-4,10-dihydropyrimido
[1,2-a][1,3]benzimidazol-3-yl Cyanides via [3þ3] Atom
Combination of 2-Aminobenzimidazole
915
with Ethyl-a-Cyanocinnamoates
Hassan Sheibani* and Fahimeh Hassani
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran
*E-mail: hsheibani@mail.uk.ac.ir
Received May 5, 2010
DOI 10.1002/jhet.640
Published online 21 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
This article is dedicated in the memory of Mr. Alireza Afzalipour, founder of Kerman University, on the occasion of the centenary of his birth.
Chemoselective synthesis of 4-oxo-2-aryl-4,10-dihydropyrimido[1,2-a][1,3]benzimidazol-3-yl cyanides
from three-component reactions of 2-aminobenzimidazole, aldehydes, and ethyl cyanoacetate via [3þ3]
atom combination is reported. The effect of different base catalysts such as sodium acetate, triethyl-
amine, and magnesium oxide MgO on the product yield has also been investigated under conventional
heating.
J. Heterocyclic Chem., 48, 915 (2011).
INTRODUCTION
conjugate addition of 2-aminobenzothiazole 1a to the
acetylenic acids in butanol, followed by cyclocondensa-
tion, gave the corresponding 2H-pyrimido[2,1-b]benzo-
thiazol-2-ones, which is due to Michael addition of the
endocyclic nitrogen centre on acetylenic carbon. More
recently, we have reported nucleophilic addition of 2-
minobenzimidazole 1a to an enone type of 3-benzyli-
dene-2,4-pentane-dione I in the presence of catalysts
such as magnesium oxide MgO and 12-tungstophos-
phoric acid (PW) followed by cyclization, leads to 4H-
pyrimido[2,1-b]benzimidazole derivatives II. In this
case, the endocyclic nitrogen of the 2-minobenzimida-
zole 1a is the most reactive [13]. However, in the case
of Michael addition of 2-aminobenzothiazole 1b on bis
(methylthio)methyllene malononitrile nitrile IIIa or
ethyl-2-cyano-3,3-bismethyl thioacrylate IIIb afforded
2-Aminobenzimidazole 1a or 2-aminobenzothiazole
1b have three sites of electron rich sites, at the nitrogen
and sulfur atoms. Nucleophilic reactions on these com-
pounds can take place on either of the exocyclic or the
endocyclic nitrogen centre, depending on the nature of
the electro phile and the reaction conditions [1,2]. Benz-
imidazole derivatives are known as intermediates for the
synthesis of molecules exhibit a number of important
pharmacological properties, such as antihistaminic [3],
antiallergic [4], and antipyretic [5]. In addition, these
compounds are effective against the human cytomegalo-
virus (HCMV) [6] and several viruses such as HIV
[7,8], herpes (HSV-1) [9], RNA [10], influenza [11],
and human cytomegalovirus (HCMV) [8].
The widespread interest in benzimidazole containing
systems has promoted extensive studies of their synthe-
ses. Substituted 2-aminobenzimidazoles are useful inter-
mediates for the syntheses of fused heterocyclic ring
systems [12]. Nucleophilic reactions of 2-aminobenzimi-
dazole 1a can take place on either of the exocyclic or
the endocyclic nitrogen centre, depending on the nature
of the electrophile and the reaction conditions [1,2]. The
3-cyano-4-imino-2-methyl-thio-4H-pyrimido
[2,1-b]
[1,3] benzothiazoles IVa and 4H-pyrimido[2,1-b]benzo-
thiazole-2-thiome-thyl-3-cyano-4-one derivatives IVb,
respectively, the exocyclic nitrogen being the most reac-
tive for these reactions (Scheme 1) [14,15].
Ethyl-a-cyanocinnamoates have three electron defi-
cient centers at Cb and carbons of nitryl and carboxylate
C
V
2011 HeteroCorporation

916
H. Sheibani and F. Hassani
Vol 48
Scheme 1
groups. Thus, they can react with binucleophiles to pre-
pare heterocyclic compounds. These processes are
highly regioselective, and chemoselective synthesis of
these compounds depend on the reactivity of binucleo-
philes [16–18].
MgO (HSA-MgO)]. We have found that 2-aminobenzo-
thiazole 1a acts as a binucleophile toward the deficient
centers at Cb and nitryl group of ethyl-a-cyanocinna-
moates to release 4-oxo-2-aryl1,4-dihydropyrimido[1,2-
a][1,3]benzimidazol-3-yl cyanides as only product. This
fact represents a distinct advantage in terms of chemose-
lectivity synthesis of these compounds (Scheme 2).
To optimize the reaction conditions for preparing
compounds 3 and 4, the effect of base catalyst for pre-
paring compounds 3 and 4 under different reaction con-
ditions were investigated.
RESULTS AND DISCUSSION
To study the regioselectivity of the 2-aminobenzothia-
zole 1a with ethyl-a-cyanocinnamoates, we have investi-
gated three-component reaction of 2-aminobenzimida-
zole 1a, aldehydes 2a–c and ethyl cyanoacetate or
malononitrile 3 in the presence of base catalysts such as
sodium acetate, triethylamine, and magnesium oxide
[commercial MgO (CM-MgO) and high surface area
First, we examined three-component reactions of 2-
aminobenzimidazole 1a, aldehydes 2a–f, and ethyl cya-
noacetate or malononitrile in an organic solvent (tolu-
ene) at reflux in the presence of triethylamine as base
catalyst. The reactions were too slow, and the yields
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Chemoselective Synthesis of 4-Oxo-2-aryl-4,10-dihydropyrimido [1,2-a][1,3]benzimidazol-3-yl
cyanides via [3þ3] Atom Combination of 2-Aminobenzimidazole with Ethyl-a-cyanocinnamoates
Table 1
917
Synthesis of compounds 3a-f and 4a,b in the presence of base catalysts.
Base catalyst:
triethylamine
Base catalyst: sodium
acetate
Base catalyst: CMa/HSAb
(MgO)
Compound Number
R
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (min)
Yield (%)
3a
3b
3c
3d
3e
3f
C6H5
10
18
16
11
15
12
10
8
58
36
35
40
47
52
65
75
9
70
42
36
44
53
68
80
85
73/40
90/57
98/85
90/80
80/64
50/45
90/10
45/5
36/96
28/72
26/60
26/64
25/78
34/92
80/92
75/95
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2,4-ClC6H3
4-CF3C6H4
C6H5
12
11
10
10
10
8
4a
4b
4-ClC6H4
6
a Commercial MgO.
b High surface area MgO.
were not high. Second, other reactions were performed
in water and ethanol at reflux and in the presence of an
equivalent amount of sodium acetate. Finally, the three-
component reaction was carried out in the presence of
two types of magnesium crystals [commercial MgO
(CM-MgO) and high surface area MgO (HSA-MgO)].
High surface area MgO was found to be more active
than CM-MgO, and the results of these methods are pre-
sented in Table 1.
We have recently reported the three-component reac-
tion of malononitrile or ethyl cyanoacetate with (phenyl-
hydrazono)-propan-2-one 7 or amidine systems as1,3-
dinucleophile and aldehydes in the presence of MgO
afforded only 3-amino-2,5-dihydropyridazine and 4-
amino-5-pyrimidine carbonitrile or pyrimidinone deriva-
tives respectively [20,21]. In these protocols as exhibited
in Scheme 4, we have investigated reactions of ethyl-a-
cyanocinnamoates 6 which have three electron deficient
centers at carbons of nitryl and carboxylate groups and
carbon of Cb with 1,3-dinucleophile such as (phenylhy-
drazono)propan-2-one 7 or phenylamidine 8 afforded
only 2,5-diaryl ethyl -6-acetyl-3-amino-2,5-dihydro-4-
pyridazinecarboxylate and 4-diaryl-6-oxo-1,6-dihydro-5-
pyrimidinecarbonitrile derivatives, respectively, in the
presence of magnesium oxide MgO as a highly effective
heterogeneous base catalyst in excellent yields. In these
reactions 1,3-dinucleophiles act via regioselective on Cb
and carbon of carboxylate group of ethyl-a-cyanocinna-
moates which have three electron deficient centers
(Scheme 4).
2-Aminobenzimidazole 1a and ethyl-a-cyanocinna-
moates or a-cyanocinnamonitrile have several sites of
electron rich sites or electron defision sites, respectively.
Thus these reaction are highly regioselective, leading to
only one of the some possible isomers that can be
formed in different conditions [19]. To confirm the
structure of products 3 and 4, reaction of N-(1,3-benzoi-
midazol-2-yl)-N-(alkylidene)-amines 5a,b (which pre-
pared by reaction of aldehydes with 1a) with ethyl cya-
noacetate or malononitrile were studied, which afforded
the same product of 4-oxo-2-aryl-4,10-dihydropyri-
mido[1,2-a][1,3]benzimidazol-3-yl cyanid es (3a,b) or
4-amino-2-aryl-2H-pyrimido[1,2-b][1,3]benzi midazol-3-
yl cyanide derivatives (4a,b) respectively in the pres-
ence of high surface area MgO (Scheme 3).
The structures of compounds 3a–f and 4a,b were elu-
cidated and assigned from their elemental analyses and
1
their IR, H NMR, 13C NMR, and mass spectra. The IR
Scheme 3
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918
H. Sheibani and F. Hassani
Vol 48
Scheme 4
gress of the reaction being monitored by TLC and unsing n-
hexane/ethyl acetate as an eluent). The product 3 precipitated
from the reaction mixture after cooling and the solid was fil-
tered and recrystallized from ethanol.
Method II. A mixture of the 2-aminobenzimidazole 1a (2
mmol), aldehyde 2 (2 mmol), and ethyl cyanoacetate or malo-
nonitrile (2 mmol) in ethanol (25 mL) was refluxed with stir-
ring in the presence of triethylamine (0.5 mL). The reactions
were continued until completion, as monitored by TLC. After
completion of the reaction, the product was purified as in
method I.
Method III. A mixture of the 2-aminobenzimidazole 1a (2
mmol), aldehyde (2 mmol), and ethyl cyanoacetate or malono-
nitrile (2 mmol) in CH3CN (25 mL) was refluxed with stirring
in the presence of commercial MgO or high surface area MgO
(0.25 g). The reactions were continued until completion, as
monitored by TLC. After completion of the reaction, the cata-
lyst was removed by filtration, and the filtrate was concen-
trated to obtain the crude product. The crude product was crys-
tallized from ethanol.
4-Oxo-2-phenyl-4,10-dihydropyrimido[1,2-a][1,3] benzimi-
dazol-3-yl cyanide (3a). Pale yellow crystals. mp 300–303ꢁC.
IR (KBr, mmax/cmꢀ1): 3295 (broud, NH), 2207 (CN), 1695
(C¼¼O), 1641 (C¼¼N), 1603 (C¼¼C). 1H NMR (500 MHz,
DMSO-d6): 8.37 (d, 1H, Ar); 7.86 (d, 2H, Ar); 7.76 (s, 1H,
NH);7.58–7.07 (m, 6H, Ar). 13C NMR (125 MHz, DMSO-d6)
166.3 (C), 160.5 (C), 152.0 (C), 138.3 (C), 129.8 (CH),
128.4(CH), 128.0 (CH), 127.4 (C), 124.8 (CH), 121.7 (CH),
120.7 (CH), 115.5 (CH), 115.0 (C), 111.0 (CH), 79.0 (C3).
MS (m/z): 286 (10) (Mþ), 277(35), 236 (15), 207 (20), 186
(23), 133 (100), 115 (18),105 (80), 97 (27),91 (40), 83 (34),77
(45), 69(42),63 (29),55 (61), 43 (92). Anal. Calcd. For
C17H10N4O: C, 71.32; H, 3.52; N, 19.57%. Found: C, 71.15;
H, 3.21; N,19.19.
spectra of compounds 3a–f and 4a,b showed the pres-
ence of CN at a region of 2240–2230 cmꢀ1, and a sharp
band at 1700–1650 cmꢀ1 which is due to the amide
groups.
In summary, we have described chemoselective
synthesis of 4-oxo-2-aryl-4,10-dihydropyrimido[1,2-a]
[1,3]benzimidazol-3-yl cyanides from three-component
reactions of 2-aminobenzimidazole, aldehydes, and ethyl
cyanoacetate in the peresence of base catalysts such as
triethylamine, sodium acetate, and magnesium oxide
(MgO). The advantage of these procedures reported here
are: high selectivity, high purity of products, and easy
workup.
EXPERIMENTAL
Melting points were measured on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were measured
on a Mattson 1000 FTIR spectrometer. The proton and carbon
NMR spectra were recorded with a BRUKER DRX-500
AVANCE spectrometer at 500 and 125.77 MHz, respectively.
Mass spectra were recorded on a MS-QP2000A Shimadzu
mass spectrometer operating at an ionization potential of 70
eV. Elemental analyses were performed using a Heracus CHN-
O-Rapid analyzer.
Preparation of high surface area MgO. The catalysts used
in this study were obtained by calcinations of rehydrated
Mg(OH)2. The experimental results showed that an optimal
calcination temperature in the range 400–500ꢁC gives poorly
crystalline, high surface area MgO that can be regenerated by
washing, and then reused. After separation of the product by
filtration, the recovered solvent containing MgO was reused
twice without loss of activity of the catalyst [22].
General procedure for the preparation of 4-oxo-2-aryl-
1,4-dihydropyrimido[1,2-a][1,3]benzimidazol-3-yl cyanides
(3a–f) and 4-amino-2-aryl-2H-pyrimido[1,2-b][1,3] benzimi-
dazol-3-yl cyanides (4a,b). Method I A mixture of the 2-
aminobenzimidazole 1a (2 mmol), aldehyde 2 (2 mmol) and
ethyl cyanoacetate or malononitrile (2 mmol) and sodium ace-
tate (2 mmol) in H2O (50 mL) and ethanol (5 mL) was
refluxed with stirring for the time reported in Table 1 (the pro-
2-(4-Methylphenyl)-4-oxo-4,10-dihydropyrimido
[1,2-a]
[1,3]benzimidazol-3-yl cyanide (3b). Yellow crystals. mp
300–302ꢁC. IR (KBr, mmax/cmꢀ1): 3291–2770 (broud, NH),
2208 (CN), 1698 (C¼¼O), 1637 (C¼¼N), 1605 (C¼¼C). 1H
NMR (500 MHz, DMSO-d6): 8.37 (d, 1H, Ar); 7.77 (d, 1H,
Ar); 7.73 (s, 1H, NH); 7.56(d, 1H, Ar); 7.38(t, 1H, Ar);
7.32(d, 1H, Ar); 7.26–7.06 (m, 2H, Ar) 2.38 (s, 3H, CH3). 13C
NMR (125 MHz, DMSO-d6) 166.3 (C), 160.5 (C), 162.7 (C),
152.2 (C), 139.7 (C), 135.4 (C), 128.6 (CH), 128.4 (CH),
124.8 (CH), 121.5 (CH), 120.8 (C), 115.3 (C), 115.0 (CH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Chemoselective Synthesis of 4-Oxo-2-aryl-4,10-dihydropyrimido [1,2-a][1,3]benzimidazol-3-yl
cyanides via [3þ3] Atom Combination of 2-Aminobenzimidazole with Ethyl-a-cyanocinnamoates
919
111.3 (CH), 75.4 (C3), 20.9 (CH3). MS (m/z): 300 (25) (Mþ),
272(20), 234 (8), 133 (100), 105 (80), 90 (15), 79 (35), 63
(20), 52 (28), 43 (18). Anal. Calcd. For C18H12N4O: C, 71.99;
H, 4.03; N, 18.66%. Found: C, 71.67; H, 4.15; N, 18.28.
2-(4-Methoxyphenyl)-4-oxo-4,10-dihydropyrimido[1, [1,2-
a][1,3]benzimidazol-3-yl cyanide (3c). Yellow crystals. mp
291–294ꢁC. IR (KBr, mmax/cmꢀ1): 3303–2773 (broud, NH),
2206 (CN), 1698 (C¼¼O), 1640 (C¼¼N), 1606 (C¼¼C). 1H
NMR (500 MHz, DMSO-d6): 8.37 (d, 1H, Ar); 7.87 (d, 2H,
Ar); 7.56 (s, 1H, NH); 7.62(d, 1H, Ar); 7.36(t, 1H, Ar); 7.24–
7.04 (m, 3H, Ar); 3.83 (s, 3H, OCH3). 13C NMR (125 MHz,
DMSO-d6) 165.5 (C), 160.6 (C), 152.85 (C), 152.55 (C),
130.04 (CH), 127.38 (C), 124.59 (CH), 121.13 (CH), 120.51
(C), 119.38 (C), 115.42 (C), 114.88 (CH), 113.38 (CH),
111.28 CH), 78.45 (C3), 55.22 (CH3). MS (m/z): 316 (12)
(Mþ), 301(5), 133 (100), 105 (90), 90 (18), 79 (42), 63 (28),
50 (35), 43 (40). Anal. Calcd. For C18H12N4O2: C, 68.35; H,
3.82; N, 17.71%. Found: C, 68.09; H, 3.55; N, 17.34.
2-(4-Chlorophenyl)-4-oxo-4,10-ihydropyrimido[1,2-a][1,3
]benzimidazol-3-yl cyanide (3d). Pale yellow crystals. mp
304–306ꢁC. IR (KBr, mmax/cmꢀ1): 3295–2769 (broud, NH), 2207
(CN), 1700 (C¼¼O), 1639 (C¼¼N),1604 (C¼¼C). 1H NMR (500
MHz, DMSO-d6): 8.37 (d, 1H, Ar); 7.87 (d, 2H, Ar); 7.80 (s, 1H,
NH); 7.57(d, 2H, Ar); 7.37(t, 1H, Ar); 7.26–7.09 (m, 2H, Ar). 13C
NMR (125 MHz, DMSO-d6) 164.8 (C), 160.5 (C), 162.9 (C),
151.8 (C), 137.2 (C), 134.5 (C), 130.3 (CH), 128.1 (CH), 124.7
(C), 121.8 (CH), 120.7 (CH), 115.8 (C), 114.9 (CH), 111.3 (CH),
79.0 (C3). MS (m/z): 322 ( 5) (Mþ2), 320 (9) (Mþ), 316 (15), 282
(50), 277 (100), 201 (27), 183 (30), 152 (20), 77 (37), 51 (30).
Anal. Calcd. For C17H9ClN4O: C, 63.66; H, 2.83; Cl, 11.05; N,
17.47 %. Found: C, 63.30; H, 2.52; Cl, 10.73; N, 17.05.
1650, 1620(C¼¼N) cmꢀ1; dH (500 MHz, DMSO -d6): 8.57(1H,
s, NH), 8.07–6.99(9H, m, Ar), 6.78(2H, s, NH2), 5.20(1H, s,
CH). dC (125 MHz, DMSO-d6): 151.7 (C), 149.1(C), 143.6
(C), 142.8 (CH), 129.3 (C), 128.6 (CH), 127.8 (CH), 125.8
(CH), 123.3 (C), 119.8 (CH), 119.1(C), 116.0 (CH), 112.3
(CH), 61.9 (C3), 53.2 (C2). MS, m/z (%): 287 (Mþ, 30), 286
(30), 210 (base beak, 100), 133 (90), 105 (17), 90(20), 77(28),
51(18), 43(27). Anal.Calcd. For C17H13N5: C, 71.07; H, 4.56;
N, 24.37 %. Found: C, 70.75; H, 4,38; N, 24.06.
4-Amino-2-(4-chlorophenyl)-2,10-dihydropyrimido [1,2-
a][1,3]benzimidazol-3-yl cyanide (4b). White crystals, mp
209–210ꢁC; mmax(KBr): 3438, 3336, 3100 (broad, NH2, NH),
2187(CN), 1676, 1651(C¼¼N) cmꢀ1; dH (500 MHz, DMSO-
d6):8.58(1H, s, NH), 7.64–6.98 (8H, m, Ar), 6.83(2H, s, NH2),
5.25(1H, s, CH). dC (125 MHz, DMSO-d6): 151.5 (C),
149.2(C), 143.5 (C), 141.7 (C), 132.4 (CH), 129.2 (CH), 128.6
(CH), 127.9 (C), 123.3 (CH), 119.9 (CH), 118.9 (C), 118.1
(CH), 112.4 (C), 61.5 (C3), 52.6 (C2). MS, m/z (%): 321(Mþ,
8), 306(12), 230(32), 216(30), 188(35), 171(15), 119(23),
105(base beak, 100), 91(85), 77(45), 57(27), 51(18), 43(84),
41(19). Anal.Calcd. For C17H12ClN5: C, 63.46; H, 3.76; N,
21.77 %. Found: C, 63.20; H, 3.39; N, 21.43.
General procedure for the preparation of N-(1,3-benzoi-
midazol-2-yl)-N-(alkylidene)amines (5a,b). The reactions
were carried out in a standard round bottom glass flask
equipped with a vertical condenser under thermal conditions.
Reactions were performed with arylaldehydes 2 (2 mmol), 2-
aminobenzoles 1a, b (2 mmol) in acetonitrile (40 mL) under
stirring at refluxing temperature for 1 hr. The final reaction
mixture was cooled, the precipitate was filtered and recrystal-
lized from ethanol to afford desired product 5 [23].
2-(2,4-Dichlorophenyl)-4-oxo-4,10-dropyrimido[1,2-a][1,3]
benzimidazol-3-yl cyanide (3e). Yellow crystals. mp 298–
300ꢁC. IR (KBr, mmax/cmꢀ1): 3282–2726 (broud, NH), 2218
Acknowledgment. The authors express appreciation to the Sha-
hid Bahonar University of Kerman Faculty Research Committee
for its support of this investigation.
1
(CN), 1698 (C¼¼O), 1661 (C¼¼N), 1604 (C¼¼C). H NMR (500
MHz, DMSO-d6): 8.38 (d, 1H, Ar); 8.13 (s, 1H, NH); 7.76 (s,
1H, Ar); 7.61–7.14 (m, 5H, Ar). 13C NMR (125 MHz, DMSO-
d6) 164.3 (C), 159.8 (C), 153.3 (C), 151.3 (C), 137.0 (C), 134.2
(C), 131.4 (CH), 128.9 (CH), 127.3 (CH), 124.6 (C), 122.3
(CH), 120.6 (CH), 116.4 (C), 114.9 (C), 111.3 (CH), 80.7 (C3).
MS (m/z): 355 (8) (Mþ), 354 (29), 277 (38), 264 (32), 148 (20),
133 (100), 105 (90), 91 (30), 79 (60), 69 (43), 57 (66), 43 (84).
Anal. Calcd. For C17H8Cl2N4O: C, 57.49; H, 2.27; Cl, 19.96; N,
15.77 %. Found: C, 57.18; H, 2.05; Cl, 19.58; N, 15.43.
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1
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1
), 129.6 (CH), 127.66 (C), 126.32 (q, JC–F 287.50 Hz, CF3),
125,2 (CH), 124.53 (CH), 121.85 (CH), 120.54 (C), 114.96 (CH),
111.29 (CH), 78.42 (C3). MS (m/z): 354 (80) (Mþ), 326(15), 300
(15), 159 (25), 133 (100), 105 (38), 90 (25), 79 (18), 63 (15), 51
(15), 43 (24). Anal. Calcd. For C18H9F3N4O: C, 61.02; H, 2.56;
N, 15.81%. Found: C, 60.79; H, 2.25; N, 15.45.
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