Facile and green method for the synthesis of 4-amino-1,2-dihydrobenzo [4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles catalysed by ammonium Acetate

Article abstract of DOI:10.3184/174751912X13528011362074

A facile and green method for the synthesis of 4-amino-1,2-dihydrobenzo[4, 5]imidazo[1,2-a]pyrimidine-6-carbonitrile derivatives has been developed by one-pot condensation of 2-aminobenzimidazole, aldehydes, and malononitrile catalysed by ammonium acetate

Full text of DOI:10.3184/174751912X13528011362074

738 RESEARCH PAPER
DECEMBER, 738–739
JOURNAL OF CHEMICAL RESEARCH 2012
Facile and green method for the synthesis of 4-amino-1,2-dihydrobenzo
[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles catalysed by ammonium
acetate
Lingjun Hua, Zhajun Zhana, Min Leib* and Lihong Hua,b
aCollege of Pharmaceutical Science, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
bShanghai Research Center for Modernization ofTraditional Chinese Medicine, Shanghai Institute of Materia Medica, Shanghai 201203,
P. R. China
A facile and green method for the synthesis of 4-amino-1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-6-carbonitrile
derivatives has been developed by one-pot condensation of 2-aminobenzimidazole, aldehydes, and malononitrile
catalysed by ammonium acetate in ethanol. The inexpensive and readily available catalyst and easy workup is
environmentally friendly.
Keywords: 2-aminobenzimidazole, aldehydes, malononitrile, green chemistry, muti-component reactions
Multi-component reactions (MCRs) are significant and useful
organic reactions, which refer to a chemical reaction where
three or more compounds react to form a single product.1–5
Recently, MCRs have become powerful tools in modern syn-
thetic chemistry due to their efficiency and convenience in the
construction of multiple new bonds in one-pot processes.6–8
Efforts are being made to find and develop new MCRs.
Imidazo[1,2-a]pyrimidines and their analogues have a wide
range of applications, such as benzodiazepine receptor
agonists,9 antiviral,10 antitumor,11 and antimicrobial agents.12,13
Moreover, pyrimido[1,2-a]benzimidazoles represent a pharma-
ceutically important class of compounds because of their
diverse range of biological activities.14–16 Therefore, prepara-
tion of these heterocyclic compounds has gained great
importance in organic synthesis.
In recent years, several methods have been reported for the
synthesis of benzo[4,5]imidazo[1,2-a]pyrimidine derivatives
via multi-component condensations of 2-aminobenzimidazole,
aldehydes, and malononitrile.14–16 To improve the yields of this
three-component condensation reaction, a number of catalysts
and techniques, such as microwaves,17–19 MgO,20 C5H5N,21
Et3N,22–24 Me2NH,23 and N2H4,26 have been used. However,
these methods are limited by drawbacks, such as long reaction
times, poor yields, harsh reaction conditions or the use of toxic
catalysts. Consequently, better conditions are required.
NH4OAc is cheap, nontoxic, and stable and it is used widely
in organic synthesis. Earlier work in our laboratory established
that NH4OAc can efficiently catalyse the multi-component
condensation reaction of 4-hydroxyquinolin-2(1H)-one,
aldehydes, and malononitrile.27 Therefore, we investigated
whether NH4OAc could catalyse the condensation of 2-amino-
benzimidazole, aldehydes, and malononitrile. Preliminary
experiments revealed that the condensation of 2-aminobenz-
imidazole, aldehyde, and malononitrile can react smoothly
to give benzo[4,5]imidazo[1,2-a]pyrimidine products in the
presence of NH4OAc in good yields. Hence, we now report a
green, efficient, and rapid procedure for the one-pot synthesis
of 4-amino-1,2-dihydro-benzo[4,5]imidazo[1,2-a]pyrimidine-
6-carbonitrile derivatives by using NH4OAc as the catalyst in
excellent yields (Scheme 1).
Firstly, the mixture of 2-aminobenzimidazole 1, benzalde-
hyde 2a, and malononitrile 3 was chosen as the model reaction
to detect whether the use of NH4OAc was efficient and the
results are summarised in Table 1.
As shown in Table 1, only 35% yield of the corresponding
product 4a was obtained when the mixture of 2-aminobenz-
imidazole 1, benzaldehyde 2a, and malononitrile 3 was stirred
under reflux temperature for 120 min in the absence of NH4OAc
(Table 1, entry 1). However, the yield was improved greatly
(83%) when the reaction was carried out under similar
conditions in the presence of 5 mol% NH4OAc. This study
demonstrated that NH4OAc could catalyse the condensation of
2-aminobenzimidazole 1, benzaldehyde 2a, and malononitrile
3 for the synthesis of 4-amino-2-phenyl-1,2-dihydrobenzo[4,5]
imidazo[1,2-a]pyrimidine-3-carbonitrile 4a efficiently. Then,
the amount of NH4OAc was changed from 0 to 30 mol%,
showing that yields of 4a were improved as the amount of
NH4OAc increased from 0 to 10 mol%, and the yields were
maintained as the amount of NH4OAc increased from 10 to
30 mol%. Therefore, 10 mol% of NH4OAc was considered to
be the most suitable for efficient reaction.
Having established the optimised reaction conditions, we
thensuccessfullysynthesisedavarietyof4-amino-1,2-dihydro-
benzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitrilederivatives
4 (Table 2). A series of aromatic aldehydes were selected
to undergo the reaction in the presence of 10 mol% NH4OAc
in EtOH at the reflux temperature. As shown in Table 2,
benzaldehydes carrying either electron-donating or electron-
withdrawing substituents could react efficiently with excellent
Table 1 Optimisation of the condensation of 2-aminobenz-
imidazole 1, benzaldehyde 2a, and malononitrile 3a
Entry
NH4OAc/mol%)
Time/min
Yield of 4a/%b
1
2
3
4
5
6
none
3
120
60
40
30
30
30
35
60
83
91
91
88
5
10
20
30
a Conditions: 2-aminobenzimidazole 1 (5 mmol), benzaldehyde
2a (5.5 mmol), malononitrile 3 (5.5 mmol), EtOH (10 mL), reflux
temperature.
Scheme 1
* Correspondent. E-mail: mlei@mail.shcnc.ac.cn
b Isolated yield.

JOURNAL OF CHEMICAL RESEARCH 2012 739
Table 2 Synthesis of 4-amino-1,2-dihydrobenzo[4,5]imidazo
[1,2-a]pyrimidine-3-carbonitrile derivatives 4a
4-Amino-2-(4-cyanophenyl)-1,2-dihydrobenzo[4,5]imidazo[1,2-a]
pyrimidine-3-carbonitrile (4h):Yield: 92%; yellow solid; m.p. 215 °C
(Dec.). 1H NMR (300 MHz, DMSO-d6): δ = 5.36 (s, 1H), 6.94 (s, 2H),
6.99 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.7 Hz,
1H), 7.45 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 7.7 Hz, 1H), 7.83 (d, J =
8.2 Hz, 2H), 8.71 (brs, 1H). 13C NMR (75 MHz, DMSO-d6): δ = 52.70,
60.73, 110.57, 112.50, 116.18, 118.58, 118.93, 120.02, 123.44,
126.87, 129.20, 132.80, 143.48, 148.23, 149.37, 151.47. MS (ESI):
m/z = 313 ([M + H]+). HRMS (ESI) calcd for C18H13N6 [M + H]+
313.1196; found 313.1189.
4-Amino-2-(pyridin-4-yl)-1,2-dihydrobenzo[4,5]imidazo[1,2-a]
pyrimidine-3-carbonitrile (4i): Yield: 88%; yellow solid; m.p. 215 °C
(Dec.). 1H NMR (300 MHz, DMSO-d6): δ = 5.28 (s, 1H), 6.95 (s, 2H),
6.99 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.21–7.27 (m, 3H),
7.61 (d, J = 7.8 Hz, 1H), 8.49–8.55 (m, 2H), 8.72 (s, 1H). 13C NMR
(75 MHz, DMSO-d6): δ = 52.04, 60.35, 112.52, 116.22, 118.96,
120.05, 120.79, 123.46, 129.20, 143.48, 149.48, 150.09, 151.31,
151.39. MS (ESI): m/z = 289 ([M + H]+). HRMS (ESI) calcd for
C16H13N6 [M + H]+ 289.1196, found 289.1192.
Entry
R1
Time/min Product 4 Yield/%b
1
2
3
4
5
6
7
8
9
C6H5 2a
30
30
60
20
20
20
60
20
20
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
88
86
93
94
94
80
92
88
4-MeC6H4 2b
4-MeOC6H4 2c
4-ClC6H4 2d
3-ClC6H4 2e
2-ClC6H4 2f
4-HOC6H4 2g
4-NCC6H4 2h
4-Pyridyl 2i
a Conditions: 2-aminobenzimidazole 1 (5 mmol), aldehyde 2
(5.5 mmol), malononitrile 3 (5.5 mmol), EtOH (10 mL), reflux
temperature.
This work was supported by the National Natural Science
Foundation of China (grants 30925040, 81102329), the
Chinese National Science & Technology Major Project “Key
New Drug Creation and Manufacturing Program” (grant
2011ZX09307-002-03), and the Science Foundation of
Shanghai (grant 12XD14057).
b Isolated yield.
yields (80–94%) (Table 2, entries 1–8). Therefore, the effect of
the substituents on the benzene ring showed no obvious effect
on this conversion. As shown in Table 2, this experimental pro-
cedure has the ability to tolerate a variety of functional groups,
such as methyl, methoxyl, hydroxyl, cyano, and halides.
Furthermore, 4-pyridinecarboxaldehyde could react smoothly
to give the corresponding products 4i in good yields (88%)
(Table 2, entry 9). Note that all of the condensations were
complete within 60 min and the products 4 could be obtained
simply by filtration from the reaction medium.
In conclusion, a NH4OAc-catalysed synthesis of 4-amino-
1,2-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbo-
nitrile derivatives 4 from 2-aminobenzimidazole 1, aldehydes 2,
and malononitrile 3 has been described. The catalyst NH4OAc
is not only readily available and cheap, but also much safer
and more practical in comparison to the reported catalysts.
Undoubtedly, all the advantages of the reactions make this
procedure a useful addition to the present methodologies for
heterocyclic synthesis.
Received 13 September 2012; accepted 26 October 2012
Paper 1201514 doi: 10.3184/174751912X13528011362074
Published online: 5 December 2012
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1
(Dec.). H NMR (300 MHz, DMSO-d6): δ = 5.07 (s, 1H), 6.70 (d,
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