Mono- and bis-pyrimido[1,2-a]benzimidazoles: Alum catalyzed regioselective three- or pseudo five-component reaction of 2-aminobenzimidazole with aldehyde and malononitrile

Article abstract of DOI:10.2174/157017811799304368

A series of mono- and bis-pyrimido-[1,2-a]benzimidazole derivatives is synthesized by the regioselective multicomponent condensation reaction of aldehyde and malononitrile with 2-aminobenzimidazole in the presence of alum as a recyclable and efficient cat

Full text of DOI:10.2174/157017811799304368

Letters in Organic Chemistry, 2011, 8, 631-636
631
Mono- and Bis-Pyrimido[1,2-a]benzimidazoles: Alum Catalyzed Regiose-
lective Three- or Pseudo Five-Component Reaction of 2-Aminobenzimi-
dazole with Aldehyde and Malononitrile
Ali R. Karimi* and Fahimeh Bayat
Department of Chemistry, Arak University, Arak, 38156-8-8349, Iran
Received May 15, 2011: Revised June 27, 2011: Accepted June 29, 2011
Abstract: A series of mono- and bis-pyrimido-[1,2-a]benzimidazole derivatives is synthesized by the regioselective mul-
ticomponent condensation reaction of aldehyde and malononitrile with 2-aminobenzimidazole in the presence of alum as a
recyclable and efficient catalyst for this condensation.
Keywords: 2-Aminobenzimidazole, alum, multicomponent reaction, pyrimido[1,2-a]benzimidazole, regioselectivity,.
INTRODUCTION
or tetramethylguanidinium trifluoroacetate (TMGT) [24].
The known methods suffered from the drawbacks of low
yield, prolonged reaction time and the use of toxic solvents
and catalysts. Consequently, there is a need for milder condi-
tions, increased variation of the substituents in the compo-
nents and better yields.
Multicomponent reaction (MCR) has emerged as a pow-
erful strategy in modern synthetic organic chemistry, which
allows molecular complexity and diversity needed in the
combinatorial chemistry for the preparation of bioactive
compounds [1].
Alum is an inexpensive, water-soluble, non-toxic and
commercially available compound that can be used in the
laboratory without special precautions [25a]. KAl(SO4)2.
12H2O (alum) with mild acidity, involatility, and incorrosi-
tivity, is insoluble in common organic solvents and was used
recently as an easily available acidic catalyst in different
reactions [25b].
Benzimidazole is an important heterocyclic system, hav-
ing become increasingly important in medicinal chemistry
and organic synthesis. The benzo-fused imidazoles are used
as antineoplastic and anti cancer agents [2]. These heterocy-
cles also constitute a structural unit of many drugs such as
mebendazole [3], albendazole [4], astemizole [5] and ome-
prazole [6]. Pyrimido[1,2-a]benzimidazole derivatives ex-
hibit anti-inflammatory [7], macrofilaricidal [8], antibiotic
[9], antiarrythemic [10], anthelmintic [11], antibacterial [12],
antifungal [13], antihistaminic [14] and anticancer [15] prop-
erties and they have attracted strong interest as angiotension
receptor antagonist [16], potent and selective 5-HT4 receptor
antagonist, antitumor, antiviral [17], and antiproliferative
[18].
As a continuation of our research in the selective synthe-
sis of heterocyclic compounds [26] and with the aim of using
alum as a catalyst [27], herein we report a simple one-pot,
multi-component synthesis of potentially biologically impor-
tant scaffold pyrimido[1,2-a]benzimidazoles 4a-j (Schemes
1 and 2). In this work we developed a rapid and efficient
protocol for the solution phase synthesis of mono and bis-
pyrimido[1,2-a]benzimidazole derivatives.
Although there are many reported methods for the syn-
thesis of pyrans by three-component condensation of alde-
hyde, malononitrile or ꢀ–dicarbonyl compounds, only a few
reports are available for the synthesis of pyrimido[1,2-
a]benzimidazoles. A number of efforts have been made to
develop methods for preparation of pyrimido[1,2-
a]benzimidazoles. They are prepared via two-component
condensation of 2-aminobenzimidazole with alkenenitriles
[19] or alkynenitriles [20] and also by three-component con-
densation of 2-aminobenzimidazole with aldehyde and
malononitrile in water [21a-c] under classical heating or mi-
crowave irradiation or in ethanol using amine as a catalyst
[21d]. They are obtained by the reaction of 2-aminoben-
zimidazole, aldehyde and ꢀ–dicarbonyl compounds such as
dimedone, acetylacetone, 1,3-indandione and ethyl acetoace-
tate in the presence of sulfamic acid [22], H6P2W18O62 [23],
RESULTS AND DISCUSSION
The synthesis of mono-pyrimido[1,2-a]benzimidazoles
4a-h was achieved by the three-component condensation of
aldehydes 1a-h, malononitrile 3 and 2-aminobenzimidazole
1 in the presence of 10 mol% alum as a catalyst. The reaction
was carried out in ethanol at 70 °C or room temperature to
give products 4a–h in good to high yields (Scheme 1).
Bis-pyrimido[1,2-a]benzimidazole derivatives 4i-j were
obtained by pseudo five-component reaction of isophthalal-
dehyde 2i or terephthalaldehyde 2j (1 mmol), malononitrile
3 (excess) and 2-aminobenzimidazole 1 (2 mmol) in the
presence of 10 mol% alum in ethanol. First the reaction was
stirred at room temperature for 2h. The reaction mixture is
then refluxed for 3 hours (Scheme 2). In order to optimize
the best possible conditions, a different set of reactions was
carried out with respect to different molar ratios of alum,
temperature, and solvent. The condensation of 3-chloroben-
*Address correspondence to this author at the Department of Chemistry,
Arak University, Arak 38156-8-8349, Iran; Tel: +98 861 4173400; Fax: +98
861 4173406; E-mail: ar_karimi55@yahoo.com
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

632 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Karimi and Bayat
NC
NH2
R1
Alum
CN
CN
R1
N
N
N
CHO
NH2
+
+
HN
N
H
1
2a-h
3
4a-h
Scheme 1. Three-component synthesis of mono-pyrimido[1,2-a]benzimidazoles 4a-h.
N
H2N
CN
NH2
2
NC
HN
NH2
N
CN
Alum
H
N
N
1
+
2
NH
N
CN
OHC
CHO
4i-j
N
3
2i-j
Scheme 2. Pseudo five-component synthesis of bis-pyrimido[1,2-a]benzimidazoles 4i-j.
zaldehyde 2a with malononitrile 3 and 2-aminobenzaldehyde
1 was chosen as a model.
The investigation of solvent effect (Table 1, entries 8-18)
on the reaction at 70 °C and room temperature with optimum
amount of catalyst (10 mol%) indicated that the yield gradu-
ally decreased as we moved from polar (except H2O and
EtOH) to less polar solvents. In H2O medium no reaction
occurred. The reaction hardly performed in EtOH/H2O (3:2).
Side products were obtained when EtOH/H2O (3:2), CH3CN,
THF, and CH2Cl2 were used as solvent. Moreover, the yields
were higher when the reactions were carried out at 70 °C
rather than room temperature. Hence, the best reaction con-
dition was obtained by using 10 mol% of alum in ethanol
medium at 70 °C.
Initially the effect of catalyst quantity on the yield of re-
action was evaluated by varying the amounts of catalyst
from 0 to 15 mol% at 70 °C (Table 1, entries 1-4). However,
the results indicated that in the absence of alum the product
4a was obtained in low yield. In addition, the yield decreased
by using 15 mol% of alum. Thus the best result was achieved
with 10 mol% of alum. Optimization of amounts of catalyst
was repeated for mentioned reaction at room temperature
(Table 1, entries 5-7). After 12 h with 5, 10, and 15 mol% of
alum, yields of 40, 80, and 70% were obtained.
Table 1. Optimization of Reaction for the Synthesis of 4a
Entries
Catalyst
solvent
Temp.
Yield
1a
2a
3a
4a
5b
6b
Alum (5 mol%)
Alum (10 mol%)
Alum (15 mol%)
-
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
70 °C
70 °C
70 °C
70 °C
r.t
60
90
85
trace
40
Alum (5 mol%)
Alum (10 mol%)
r.t
80
7b
Alum (15 mol%)
Alum (10 mol%)
Alum (10mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
Alum (10 mol%)
EtOH
H2O
r.t
r.t.
70
N.R.
15
8b
9b
EtOH-H2Of
CH3CN
THF
r.t.
10b
11b
12b
13c
14d
15e
16a
17a
18a
r.t
60
r.t
52
CH2Cl2
EtOH
r.t
45
r.t
70
EtOH
r.t
65
EtOH
r.t.
22
CH3CN
THF
70 °C
70 °C
70 °C
70
60
EtOH-H2Of
22
areaction time =2h,b reaction time =12h,c reaction time = 7h,d reaction time = 5h,e reaction time = 3h, fEtOH-H2O (3:2).

Mono- and Bis-Pyrimido[1,2-a]benzimidazoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
633
Table 2. Alum Catalyzed Synthesis of Mono- and Bis-Pyrimido[1,2-a]benzimidazoles
Entry
Aldehyde
product
Yieldb
Yieldc
M.p. (°C)
Lit. M.p. (°C)d
1
2
3-chlorobenzaldehyde
4-chlorobenzaldehyde
3-bromobenzaldehyde
3-methoxybenzaldehyde
4-methoxybenzaldehyde
2-chloro-6-fluorobenzaldehyde
benzaldehyde
4a
4b
4c
4d
4e
4f
90% (2h)
86% (3.5h)
87% (2h)
86% (2h)
70% (6h)
90% (1.5 h)
88% (2.5h)
83% (5h)
73% (5h)
70% (5h)
78%
73%
70%
71%
-
222 dec
230 dec
217 dec
216 dec
224 dec
227 dec
219 dec
236 dec
235 dec
237 dec
-
238 dec [20]
3
240 dec [20]
4
-
5
-
6
79%
72%
-
-
7
4g
4h
4i
235-236 [20]
8a
9a
10a
4-pyridinecarbaldehyde
isoterephthalaldehyde
terphthaldehyde
-
-
-
-
-
4j
a2 h at room temperature and then 3h at 70 oC. byields refer to isolated products at 70 °C. cyields refer to isolated products at room temperature for 12h. dLit. M.p. for 4' isomer.
Alum
N
NC
C
H
NH
NC
NH2
Alum
NC
NC
R
CN
H
N
R
N
Path A
R
N
N
R
N
N
HN
HN
H2N
Alum
N
HN
Alum
R
CN
C
N
N
O
H
H
4
+
H
Alum
NC
CN
N
C
N
NH2
H
H
N
HN
N
2
3
N
N
H2N
Alum
Path B
HN
NH
R
H
N
NH
NC
N
N
R
NC
5
1
H
H
CN
R
4'
R
Scheme 3. Plausible mechanism of the Alum-catalyzed synthesis of 4.
We next examined a wide variety of aldehydes to estab-
lish the scope of this catalytic transformation. It is notewor-
thy that for mono aldehydes 2a-g the reaction mixture was
refluxed at 70 °C in ethanol for appropriate time (Table 2)
but for 4-pyridine carbaldehyde 2h and dialdehydes 2i-j the
reaction mixture was stirred at room temperature for 2h and
then it was refluxed for 3h. Furthermore, for mono aldehydes
all of the reactants are used in stoichiometric amounts al-
though for dialdehydes excess malononitrile is necessary to
achieve complete reaction (Table 2).
The reaction presumably proceeds in two steps: initial
condensation of aldehyde 2 and malononitrile 3 by standard
Knoevenagel reaction takes place to form an intermediate
called arylidene malononitrile 5. Then the reaction of 2-
aminobenzimidazole 1 with arylidene malononitrile 5 may
proceed by two possible mechanistic pathways depending on
whether the initial attack of the alkenenitrile is by the nitro-
gen of the side chain (path A) or by the ring nitrogen (path
B) to give the isomeric pyrimido[1,2-a]benzimidazoles 4 or
4' (Scheme 3).
Fig. (1). NOE spectra of 4c. Solvent: DMSO-d6.
Although three component condensation of 2-
aminobenzimidazole and malononitrile and aldehyde has
been reported by Shaabani et. al. in H2O medium without
catalyst, but the reaction led to the formation of 4' isomer.
The mentioned reaction was heated at 90 °C for 7-12 h.
[21a]. Nonetheless S. A. Komykhov [19a] and M. B.
Deshmukh [21d] and co-workers reported the reaction of
N,N-unsaturated nitrile with 2-aminobenzimidazole in etha-
nol with amine catalyst to get 1,2-dihydro-benzo[4,5]
imidazo[1,2-a]-pyrimidine-3-carbonitrile derivatives, but it
suffers from the drawbacks of low yield and the use of toxic
catalyst while alum which is used in our article is a co-
friendly catalyst [27].
In order to distinguish between the isomeric pyrimido[1,
1
2-a]benzimidazoles 4c and 4c', H nuclear overhauser effect
(NOE) experiment was used. No enhancement of the H-b
signal was observed when the methine proton (H-a) was ir-
radiated in compound 4c. These results confirm that the
pyrimido[1,2-a]benzimidazoles obtained in this work are of
structure 4c (Fig. 1).

634 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Karimi and Bayat
N
NC
3
NH2
NH2
N
CN
NC
Cl
Alum
H
1
N
N
+
+
and/or
HN
N
S
CHO
Cl
Only
NH2
6
2a
4a
Scheme 4. 2-aminobenzothioazole has not participated in this reaction.
Under the same conditions this reaction almost could not
be observed when 2-aminobenzothiazole 6 was used as a
starting material (Scheme 4). It is noticeable that when 2-
aminobenzimidazole 1, 2-aminobenzothioazole 6, 3-
chlorobenzaldehyde 2a and malononitrile 3 in the presence
of alum were heated for 2 h, the reaction led to the formation
of only 4a. It means that the 2-aminobenzothioazole 6 has
not participated in this reaction. Therefore, the alum is a se-
lective catalyst for the synthesis of pyrimido[1,2-
a]benzimidazoles by reaction of 2-aminobenzimidazole, al-
dehyde and malononitrile in the presence of 2-
aminobenzothiazole (Scheme 4).
filtered off and washed with hot ethanol and hot water to
give the desired products.
Spectral Data
(4a): IR (KBr) (vmax, cm-1): 3448, 3319, 3213, 3059,
1
2914, 2197, 1682, 1639, 1602, 1471. H NMR (DMSO-d6,
300 MHz) ꢀH: 5.29 (1H, s, CH), 6.93 (2H, s, NH2), 7.00 (1H,
t, J=7.66 Hz, Harom), 7.12 (1H, t, J=7.42 Hz, Harom), 7.24 (2H,
d, J=7.57 Hz, Harom), 7.35-7.45 (3H, m, Harom), 7.64 (1H, d,
J=7.82 Hz, Harom), 8.67 (1H, s, NH). 13C NMR (DMSO-d6,
75 MHz) ꢀC: 52.97, 61.52, 112.97, 116.63, 119.55, 120.47,
123.7, 125.11, 126.48, 128.29, 129.68, 131.24, 133.66,
143.97, 145.83, 149.83, 152.
In this study, the products were characterized by melting
point, IR, 1H NMR and 13C NMR spectral data, as well as by
elemental analyses.
(4b): IR (KBr) (vmax, cm-1): 3447, 3310, 3211, 3059,
1
2916, 2197, 1682, 1637, 1602, 1471. H NMR (DMSO-d6,
300 MHz) ꢀH: 5.26 (1H, s, CH), 6.89 (2H, s, NH2), 7.00 (1H,
t, J=7.64 Hz, Harom), 7.12 (1H, t, J=7.28 Hz, Harom), 7.23 (1H,
d, J=7.72 Hz, Harom), 7.31 (2H, d, J=8.16 Hz, Harom), 7.43
(2H, d, J=8.06 Hz, Harom), 7.64 (1H, t, J=7.85 Hz, Harom),
8.16 (1H, s, NH). Anal. Calcd for C17H12ClN5: C, 63.46; H,
3.76; N, 21.77. Found: C, 64.01; H, 3.91; N, 22.03.
CONCLUSION
In conclusion, we have described an efficient, one-pot,
and three- or pseudo five-component method for the synthe-
sis of Mono- and Bis-pyrimido[1,2-a]benzimidazoles cata-
lyzed by alum as a co-friendly catalyst. Short reaction times,
regioselectivity, high yields and easy workup are the advan-
tages of this protocol. The reaction is also performed at room
temperature with desirable yield.
(4c): IR (KBr) (vmax, cm-1): 3448, 3319, 3213, 3059 ,
1
2914, 2197, 1682, 1639, 1602, 1471. H NMR (DMSO-d6,
300 MHz) ꢀH: 5.28 (1H, s, CH), 6.91 (2H, s, NH2), 7.01 (1H,
m, Harom), 7.12 (1H, m, Harom), 7.22-7.38 (3H, m, Harom),
7.49-7.63 (3H, m, Harom), 8.64 (1H, s, NH). Anal. Calcd for
C17H12BrN5: C, 55.75; H, 3.30; N, 19.12. Found: C, 55.84;
H, 3.21; N, 19.51.
EXPERIMENTAL
IR spectra were obtained on a Unicom Galaxy Series
FTIR 5000 Spectrophotometer. 1H NMR and 13C NMR spec-
tra were determined on a Bruker Avance 300 MHz spec-
trometer. Elemental analyses were performed using a Vario
EL III elemental analyzer.
(4d): IR (KBr) (vmax, cm-1): 3429, 3317, 3217, 3065,
2937, 2193, 1680, 1637, 1601, 1469. H NMR (DMSO-d6,
1
300 MHz) ꢀH: 3.71 (3H, s, CH3), 5.17 (1H, s, CH), 6.83-6.87
(5H, m, NH2 and Harom), 7.02 (1H, t, J=7.62 Hz, Harom), 7.12
(1H, t, J=7.41 Hz, Harom), 7.21-7.29 (2H, m, Harom), 7.62 (1H,
d, J=7.91 Hz, Harom), 8.58 (1H, s, NH). 13C NMR (DMSO-d6,
75 MHz) ꢀC: 53.46, 55.48, 62.24, 112.57, 112.87, 113.1,
116.55 118.38, 119.69, 120.36, 123.81, 129.72, 130.39,
144.02, 144.97, 149.65, 152.26, 159.82.
(4e): IR (KBr) (vmax, cm-1): 3448, 3323, 3217, 2916,
2187, 1680, 1601, 1465. 1H NMR (DMSO-d6, 300 MHz) ꢀH:
3.71 (3H, s, CH3), 5.14 (1H, s, CH), 6.81 (2H, s, NH2), 6.91
(2H, d, J=8.43 Hz, Harom), 6.99 (1H, t, J=7.65 Hz, Harom),
7.11 (1H, t, J=7.57 Hz, Harom), 7.18-7.23 (3H, m, Harom), 7.62
(1H, d, J=7.93 Hz, Harom), 8.51 (1H, s, NH). Anal. Calcd for
C18H15N5O: C, 68.13; H, 4.76; N, 22.07. Found: C, 67.87; H,
4.60; N, 22.21.
General Procedure for the Preparation of Products 4a-h
A mixture of aldehyde 2a-h (1mmol), malononitrile 3 (1
mmol), 2-aminobenzimidazole 1 (1 mmol), and alum (10
o
mol%) in EtOH was stirred at r.t or 70 C for several hours
(Table 2). Upon completion of the reaction as monitored by
TLC, the reaction was filtered off and washed with hot etha-
nol and hot water to give the desired products.
General Procedure for the Preparation of Products 4i-j
A mixture of aldehyde 2i-j (1mmol), malononitrile 3 (3
mmol), 2-aminobenzimidazole 1 (2 mmol), and alum (10
mol% with respect to aldehyde) in EtOH was stirred at r.t for
2h and then refluxed at 70 oC for 3h (Table 2). Upon comple-
tion of the reaction as monitored by TLC, the reaction was
(4f): IR (KBr) (vmax, cm-1):3450, 3315, 3082, 2183, 1672,
1
1631, 1601, 1446. H NMR (DMSO-d6, 300 MHz) ꢀH: 5.96
(1H, s, CH), 6.85 (2H, s, NH2), 6.99 (1H, t, J=7.62 Hz, Ha-

Mono- and Bis-Pyrimido[1,2-a]benzimidazoles
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
635
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rom), 7.1 (1H, t, J=7.53 Hz, Harom), 7.19-7.25 (2H, m, Harom),
7.35-7.45 (2H, m, Harom), 7.53 (2H, d, J=7.94 Hz, Harom,), 8.5
(1H, s, NH). 13C NMR (DMSO-d6, 75 MHz) ꢀC: 48.73,
59.09, 112.6, 115.91, 116.30, 118.91, 120.21, 123.69,
126.51, 127.69, 127.87, 129.76, 131.06, 131.19, 132.96,
133.04, 144.01, 149.96, 151.72, 160.73, 164.04.
(4g): IR (KBr) (vmax, cm-1): 3448, 3313, 3211, 2191,
1683, 1639, 1602, 1469. 1H NMR (DMSO-d6, 300 MHz) ꢀH:
5.20 (1H, s, CH), 6.82 (1H, s, NH2), 7.0 (1H, t J=7.89 Hz,
Harom), 7.12 (2H, t, J=7.49 Hz, Harom), 7.37-7.21(6H, m, Ha-
rom), 7.62 (1H, d, J=8.03 Hz, Harom), 8.58 (1H, s, NH). Anal.
Calcd for C17H13N5: C, 71.06; H, 4.56; N, 24.37. Found: C,
71.33; H, 4.41; N, 24.44.
(4h): IR (KBr) (vmax, cm-1): 3367, 2931, 2204, 1628,
1606, 1485. 1H NMR (DMSO-d6, 300 MHz) ꢀH: 5.29 (1H, s,
CH), 6.97 (2H, s, NH2), 7.01 (1H, t, J=7.76 Hz, Harom), 7.13
(1H, t, J=7.58 Hz, Harom), 7.25-7.3 (3H, m, Harom), 7.62 (1H,
d, J=7.93 Hz, Harom), 8.45 (2H, d, J=5.98 Hz, Harom), 8.73
(1H, s, NH). Anal. Calcd for C16H12N6: C, 66.66; H, 4.20; N,
29.15. Found: C, 67.05; H, 4.24; N, 29.50.
(4i): IR (KBr) (vmax, cm-1): 3485, 3373, 3169, 2191,
1678, 1633, 1602, 1475. 1H NMR (DMSO-d6, 300 MHz) ꢀH:
5.35 (2H, s, CH), 6.91 (4H, s, NH2), 7.0 (2H, t, J=7.62 Hz,
Harom), 7.12 (2H, t, J=7.53 Hz, Harom), 7.23 (2H, d, J=7.63
Hz, Harom), 7.64 (4H, d, J=5.29 Hz, Harom), 7.87 (2H, bs,
Harom), 8.58 (2H, s, NH). Anal. Calcd for C28H22N10: C,
67.46; H, 4.45; N, 28.10. Found: C, 67.88; H, 4.61; N, 27.81.
[8]
[9]
[10]
[11]
[12]
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[13]
[14]
(4j): IR (KBr) (vmax, cm-1): 3412, 3288, 3086, 2185,
1682, 1631, 1589, 1473. 1H NMR (DMSO-d6, 300 MHz) ꢀH:
5.36 (2H, s, CH), 6.93 (4H, s, NH2), 7.0 (2H, t, J=7.5 Hz,
Harom), 7.13 (2H, t, J=7.53 Hz, Harom), 7.25 (2H, d, J=8.09
Hz, Harom), 7.51 (2H, d, J=8.28 Hz, Harom), 7.62 (2H, d,
J=7.96 Hz, Harom), 7.93 (2H, d, J=8.29 Hz, Harom), 8.51 (2H,
s, NH). Anal. Calcd for C28H22N10: C, 67.46; H, 4.45; N,
28.10. Found: C, 67.79; H, 4.32; N, 28.30.
[15]
[16]
[17]
[18]
ACKNOWLEDGEMENT
We gratefully acknowledge the financial support from
the Research Council of Arak University.
SUPPLEMENTARY MATERIAL
[19]
[20]
Supplementary material is available on the publishers
Web site along with the published article.
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