Catalyst-free rapid synthesis of benzo[4,5]imidazo[1,2-a]-pyrimidine-3- carboxamides via four-component coupling in one pot

Article abstract of DOI:10.1007/s13738-013-0321-6

Abstract: A new class of fused tricyclic benzo[4,5]imidazo[1,2-a]- pyrimidine-3-carboxamide derivatives was synthesized via an environmentally benign one pot sequential four-component condensation reaction of an amine, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, an aldehyde and 1H-benzo[d]imidazol-2-amine without using catalyst in good yields.

Full text of DOI:10.1007/s13738-013-0321-6

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0321-6
ORIGINAL PAPER
Catalyst-free rapid synthesis of benzo[4,5]imidazo[1,2-a]-
pyrimidine-3-carboxamides via four-component coupling
in one pot
•
Ahmad Shaabani Mozhdeh Seyyedhamzeh
•
•
Nasim Ganji Seik Weng Ng
Received: 12 June 2013 / Accepted: 27 July 2013
Ó Iranian Chemical Society 2013
Abstract A new class of fused tricyclic benzo[4,5]imi-
dazo[1,2-a]-pyrimidine-3-carboxamide derivatives was
synthesized via an environmentally benign one pot
sequential four-component condensation reaction of an
amine, 2,2,6-trimethyl-4H-1,3-dioxin-4-one, an aldehyde
and 1H-benzo[d]imidazol-2-amine without using catalyst
in good yields.
pyrimidines are known for their important biological
activities [8]. Benzo[4,5]imidazo[1,2-a]pyrimidine deriva-
tives can be used as inhibitor of cell proliferation [9],
lymphocyte specific kinase [10], DNA-topoisomerase and
protein kinase [11, 12].
The rapid assembly of molecular diversity and com-
plexity is widely regarded as one of the most important
aspects in modern organic synthesis, and is also a key
paradigm in the design of libraries of bioactive molecules
(for selected reviews of diversity-oriented synthesis and its
impact in the discovery of bioactive compounds, see: [13–
19]). One approach to address this challenge involves the
development of multicomponent reactions (MCRs), in
which three or more reactants are combined sequentially
together in a single reaction flask to generate a product in
such a way that all the starting materials significantly
contribute atoms to the newly formed product, are partic-
ularly promising for the construction of libraries of com-
pounds (for selected recent reviews on multicomponent
reactions, see: [20–26]). Another two important aspects are
the development the catalyst-free synthesis in a greener
solvent such as water or under solvent-free conditions [27–
34]. The combination of these three aspects is highly
challenging and will provide the more benefits for chemical
transformations.
Keywords Catalyst-free Á Multicomponent
reaction Á 2,2,6-Trimethyl-4H-1,3-dioxin-4-one Á
1H-Benzo[d]imidazol-2-amine
Introduction
Recently, much attention has been devoted towards dihy-
dropyrimidine derivatives due to their significant thera-
peutic and medicinal properties [1–3]. Several marine
alkaloids having the dihydropyrimidine core unit were
found to show interesting biological activities such as
antiviral, antibacterial and anti-inflammatory activities [4,
5]. Many functionalized derivatives are used as calcium
channel blockers, antihypertensive agents and a-la antag-
onists [6, 7]. Numerous heterocyclic systems fused with
In continuing of our studies toward the synthesis of
organic compounds via multicomponent reactions (MCRs)
[35–39], we report an environmentally friendly synthesis of
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0321-6) contains supplementary
material, which is available to authorized users.
various
dihydrobenzo[4,5]imidazo[1,2-a]-pyrimidine-3-
A. Shaabani (&) Á M. Seyyedhamzeh Á N. Ganji
Department of Chemistry, Shahid Beheshti University,
G. C., P.O. Box 19396-4716, Tehran, Iran
e-mail: a-shaabani@sbu.ac.ir
carboxamide derivatives 5 via a one pot sequential four-
component condensation of amines 1, 2,2,6-trimethyl-4H-
1,3-dioxin-4-one 2, aldehydes 3 and 1H-benzo[d]imidazol-
2-amine 4 in good yields under solvent-free and in water as
a green solvent without using any catalyst within
35–60 min, respectively (Scheme 1).
S. W. Ng
Department of Chemistry, University of Malaya,
50603 Kuala Lumpur, Malaysia
123

J IRAN CHEM SOC
R2
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H
N
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R1
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min
min
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-
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H
1
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1= benzyl, 4-Me-benzyl, phenyl, allyl or n-propyl
R
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=
-
-
-
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-
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C6
-
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,
4
e 4 or n-propyl
H
C6
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Scheme 1 Synthesis of dihydrobenzo[4,5]imidazo[1,2-a]-pyrimidine-3-carboxamides 5a–l
N-Benzyl-2-methyl-4-(2-nitrophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5b)
Experimental
Melting points were measured on an Electrothermal 9200
apparatus and are uncorrected. IR spectra were recorded on a
Shimadzu IR-470 spectrometer. 1H NMR spectra were
recorded on a Bruker DRX-300 Avance spectrometer at
300.13 MHz; 13C NMR spectra were recorded on a Bruker
DRX-400 Avance spectrometer at 100.65 MHz, respec-
tively. The elemental analyses were performed with an
Elementar Analysensysteme GmbH VarioEL. All the prod-
ucts are new compounds, which were characterized byIR, 1H
NMR and 13C NMR spectra and elemental analyses data.
Yellow powder (0.37 g, 85%): mp 249 °C (dec.). IR (KBr)
cm-1: 3,246, 3,063, 2,918, 1,673, 1,628, 1,579, 1,531,
1
1,461. H NMR (300.13 MHz, DMSO-d6) d: 2.23 (3H, s,
CH3), 4.18 (Ha, br s, CHaHb), 4.35 (Hb, br s, CHaHb), 6.75
(1H, s, CH), 6.86–8.20 (13H, m, H-Ar), 8.33 (1H, br s,
NHCO), 10.29 (1H, br s, NH). 13C NMR (100.65 MHz,
DMSO-d6) d: 13.8, 38.3, 52.4 (CH3, CH2, and CH), 99.3,
105.7, 112.7, 116.1, 117.9, 118.1, 119.3, 122.8, 123.0,
124.1, 124.4, 124.9, 126.6, 127.7, 130.0, 131.8, 135.5,
138.6, 139.1, 142.4, 143.9 (C-Ar and C=C, C=N), 162.1
(CO). Anal. Calcd for C25H21N5O3: C, 68.33; H, 4.82; N,
15.94; found C, 68.29; H, 4.89; N, 15.99.
Typical procedure for the synthesis of N-benzyl-2-
methyl-4-(2-nitrophenyl)-1,4-dihydrobenz[4,
5]imidazo[1,2-a]pyrimidine-3-carboxamide (5a)
N-Benzyl-2-methyl-4-(4-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5c)
A solution of benzylamine (0.11 g, 1.0 mmol) and 2,2,6-
trimethyl-4H-1,3-dioxin-4-one (0.14 g, 1.0 mmol) was
heated under solvent-free conditions at 150 °C for 30 min.
Then, 2-nitrobenzaldehyde (0.15 g, 1.0 mmol) and 1H-
benzo[d]imidazol-2-amine (0.13 g, 1.0 mmol) in 5 ml H2O
were added simultaneously. The reaction mixture was
allowed to reflux for 15 min until the precipitate was
appeared. After completion of the reaction, as indicated by
TLC (EtOAc:n-hexane, 1:2), the reaction mixture was fil-
tered off and the residue was washed with ethanol and then
with ethanol to give 5a as a pure product. Yellow powder
(0.39 g, 89%): mp 260–262 °C. IR (KBr) cm-1: 3,270,
White powder (0.37 g, 86%): mp 280–282 °C. IR (KBr)
cm-1: 3,307, 3,027, 2,918, 1,670, 1,627, 1,579, 1,512,
1
1,451. H NMR (300.13 MHz, DMSO-d6) d: 2.17 (3H, s,
CH3), 4.12 (Ha, m, CHaHb), 4.38 (Hb, m, CHaHb), 6.54
(1H, s, CH), 6.84–7.32 (13H, m, H-Ar), 8.27 (1H, br s,
NHCO), 10.14 (1H, s, NH). 13C NMR (100.65 MHz,
DMSO-d6) d: 13.8, 38.3, 52.6 (CH3, CH2, and CH), 99.8,
105.6, 112.6, 115.8, 117.8, 122.7, 123.0, 124.2, 124.8,
125.3, 127.8, 128.8, 131.1, 135.6, 135.9, 138.6, 142.6,
144.4 (C-Ar, C=C and C=N), 162.3 (CO). Anal. Calcd for
C25H21ClN4O: C, 70.01; H, 4.93; N, 13.06; found C, 70.09;
H, 4.86; N, 13.13.
1
3,051, 2,930, 1,670, 1,626, 1,580, 1,512, 1,459. H NMR
(300.13 MHz, DMSO-d6) d: 2.15 (3H, s, CH3), 3.96 (Ha, d,
2
2JHH = 14.7 Hz, CHaHb), 4.42 (Hb, dd, JHH = 14.9 Hz,
3JHH = 6.5 Hz, CHaHb), 6.87–6.91 (3H, m, CH, H-Ar),
3
7.05 (1H, t, JHH = 6.5 Hz, H-Ar), 7.10–7.20 (5H, m,
3
H-Ar), 7.27 (1H, d, JHH = 7.3 Hz, H-Ar), 7.36 (1H, d,
N-Benzyl-2-methyl-4-(4-methylphenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5d)
3JHH = 7.3 Hz, H-Ar), 7.49–7.59 (2H, m, H-Ar), 7.91 (1H,
3
d, JHH = 7.4 Hz, H-Ar), 8.12 (1H, br s, NHCO), 10.26
(1H, s, NH). 13C NMR (100.65 MHz, DMSO-d6) d: 13.9,
38.3, 48.4 (CH3, CH2, and CH), 99.9, 105.3, 112.8, 116.2,
118.1, 120.3, 122.8, 123.1, 124.3, 125.4, 125.6, 128.0,
130.0, 131.0, 131.7, 135.5, 138.6, 142.7, 144.4 (C-Ar, C=C
and C=N), 162.3 (CO). Anal. Calcd for C25H21N5O3: C,
68.33; H, 4.82; N, 15.94; found C, 68.39; H, 4.76; N, 15.86.
White powder (0.32 g, 79%): mp 292–294 °C. IR (KBr)
cm-1: 3,307, 3,039, 2,918, 1,671, 1,626, 1,582, 1,514,
1
1,449. H NMR (300.13 MHz, DMSO-d6) d: 2.18 (3H, s,
CH3), 2.25 (3H, s, CH3), 4.16 (Ha, dd, JHH = 15.1 Hz,
2
2
3JHH = 4.7 Hz, CHaHb), 4.37 (Hb, dd, JHH = 15.4 Hz,
123

J IRAN CHEM SOC
3
6.76–7.05 (9H, m, H-Ar), 7.22 (2H, d, JHH = 8.4 Hz,
3JHH = 6.6 Hz, CHaHb), 6.50 (1H, s, CH), 6.83–7.32
(13H, m, H-Ar), 8.27 (1H, br s, NHCO), 10.06 (1H, s, NH).
13C NMR (100.65 MHz, DMSO-d6) d: 13.7, 16.9, 38.3,
52.9 (CH3, CH2, and CH), 100.2, 105.7, 112.4, 115.7,
117.6, 122.7, 123.1, 123.3, 124.2, 125.3, 127.9, 130.9,
133.4, 134.0, 135.6, 138.7, 142.8 (C-Ar, C=C and C=N),
162.4 (CO). Anal. Calcd for C26H24N4O: C, 76.45; H, 5.92;
N, 13.72; found C, 76.53; H, 5.86; N, 13.65.
3
H-Ar), 7.29 (2H, d, JHH = 7.8 Hz, H-Ar), 8.22 (1H, t,
3JHH = 5.6 Hz, NHCO), 10.03 (1H, s, NH). 13C NMR
(100.65 MHz, DMSO-d6) d: 13.7, 16.9, 38.0, 51.2, 52.6
(CH3, CH2, and CH), 100.4, 105.7, 110.0, 112.4, 115.6,
117.6, 123.1, 124.6, 124.8, 127.9, 129.0, 130.7, 131.6,
132.6, 138.7, 142.8, 155.0 (C-Ar, C=C and C=N), 162.3
(CO). Anal. Calcd for C26H23ClN4O: C, 70.50; H, 5.23; N,
12.65; found C, 70.59; H, 5.26; N, 12.73.
N-Benzyl-2-methyl-4-(4-methoxyphenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-]pyrimidine-3-
carboxamide (5e)
ORTEP diagram for 5g; summary of data: The Cam-
bridge Crystallographic Data Center (CCDC) no.: 907238;
unit cell parameters: a 13.5701(5) b 8.9746(5) c 18.6211(9)
beta 99.062(4); space group P 21/n.
White powder (0.32 g, 76%): mp 290–292 °C. IR (KBr)
cm-1: 3,295, 3,051, 2,918, 1,672, 1,623, 1,584, 1,512,
N-Phenyl-2-methyl-4-(4-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5h)
1
1,459. H NMR (300.13 MHz, DMSO-d6) d: 2.19 (3H, s,
CH3), 3.71 (3H, s, OCH3), 4.16 (Ha, m, CHaHb), 4.35 (Hb,
dd,, 2JHH = 15.0 Hz, 3JHH = 5.7 Hz, CHaHb), 6.50 (1H, s,
CH), 6.86–8.20 (13H, m, H-Ar),.8.33 (1H, br s, NHCO),
10.29 (1H, br s, NH). 13C NMR (100.65 MHz, DMSO-d6)
d: 13.7, 38.3, 51.3, 52.6 (CH3, CH2, and CH), 100.4, 105.7,
110.0, 112.4, 115.7, 117.6, 122.7, 123.1, 124.2, 124.7,
128.0, 129.1, 130.8, 135.7, 138.7, 142.8, 155.1 (C-Ar, C=C
and C=N), 162.4 (CO). Anal. Calcd for C26H24N4O2: C,
73.56; H, 5.70; N, 13.20; found C, 73.49; H, 5.76; N, 13.25.
White powder (0.34 g, 83%): mp 258–260 °C. IR (KBr)
cm-1: 3,319, 3,015, 2,942, 1,667, 1,626, 1,600, 1,514,
1
1,442. H NMR (300.13 MHz, DMSO-d6) d: 2.22 (3H, s,
CH3), 6.68 (1H, s, CH), 6.90–7.57 (13H, m, H-Ar), 9.77
(1H, br s, NHCO), 10.36 (1H, s, NH). 13C NMR
(100.65 MHz, DMSO-d6) d: 13.7, 52.6 (CH3 and CH),
100.4, 105.9, 112.4, 115.9, 116.4, 118.2, 119.6, 124.9,
125.6, 127.4, 128.8, 132.2, 135.1, 135.7, 137.5, 142.3 (C-
Ar, C=C and C=N), 161.0 (CO). MS m/z: 417 (M??1,
37Cl, 4), 416 (M?, 37Cl, 18), 415 (M??1, 35Cl, 16), 414
(M?, 35Cl, 46), 399 (3), 322 (100), 294 (32), 184 (80), 158
(52), 119 (31), 65 (39). Anal. Calcd for C24H19ClN4O: C,
69.48; H, 4.62; N, 13.50; found C, 69.41; H, 4.66; N, 13.57.
N-Benzyl-2-methyl-4-(4-ethyl)-1,4-dihydrobenzo[4,
5]imidazo[1,2-a]pyrimidine-3-carboxamide (5f)
White powder (0.27 g, 80%): mp 275–277 °C. IR (KBr)
cm-1: 3,308, 3,060, 2,968, 1,677, 1,638, 1,614, 1,517,
1
1,459. H NMR (300.13 MHz, DMSO-d6) d: 0.56 (3H, t,
3JHH = 7.1 Hz, CH3), 1.49–1.59 (1H, m, CH2), 1.98–2.10
(1H, m, CH2), 2.13 (3H, s, CH3), 4.38 (2H, m, CH2), 5.64
(1H, br s, CH),.6.97–7.37 (9H, m, H-Ar), 8.40(1H, t,
3JHH = 5.0 Hz, NHCO), 9.75 (1H, s, NH). 13C NMR
(100.65 MHz, DMSO-d6) d: 3.1, 13.5, 22.0, 38.6, 49.4
(CH3, CH2, and CH), 97.7, 105.2, 112.5, 115.7, 117.6,
122.9, 123.5, 124.5, 127.7, 133.0, 136.0, 138.6, 144.0 (C-
Ar, C=C and C=N), 163.0 (CO). Anal. Calcd for
C21H22N4O: C, 72.81; H, 6.40; N, 16.17; found C, 72.89;
H, 6.46; N, 16.25.
N-Phenyl-2-methyl-4-(phenyl)-1,4-dihydrobenzo[4,
5]imidazo[1,2-a]pyrimidine-3-carboxamide (5i)
Yellow powder (0.31 g, 81%): mp 266–268 °C. IR (KBr)
cm-1: 3,246, 3,051, 2,918, 1,670, 1,620, 1,578, 1,516,
1
1,441. H NMR (300.13 MHz, DMSO-d6) d: 2.22 (3H, s,
CH3), 6.66 (1H, s, CH), 6.86–7.57 (14H, m, H-Ar), 9.75
(1H, s, NHCO), 10.28 (1H, s, NH). 13C NMR
(100.65 MHz, DMSO-d6) d: 13.7, 53.2 (CH3 and CH),
100.5, 105.7, 112.6, 115.8, 115.9, 117.8, 119.5, 122.9,
124.2, 124.8, 124.9, 127.9, 132.4, 135.3, 137.0, 138.7,
142.9 (C-Ar, C=C and C=N), 161.2 (CO). Anal. Calcd for
C24H20N4O: C, 75.77; H, 5.30; N, 14.73; found C, 75.71;
H, 5.36; N, 14.67.
N-(4-Methylbenzyl)-2-methyl-4-(3-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5g)
White powder (0.38 g, 87%): mp 271–273 °C. IR (KBr)
N-Phenyl-2-methyl-4-(3-nitrophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5j)
cm-1: 3,319, 3,051, 2,918, 1,671, 1,635, 1,579, 1,512,
1
1,457. H NMR (300.13 MHz, DMSO-d6) d: 2.18 (3H, s,
CH3), 2.25 (3H, s, CH3), 3.71 (3H, s, CH3), 4.12 (Ha, dd,
3
2JHH = 15.2 Hz, JHH = 4.6 Hz, CHaHb), 4.32 (Hb, dd,
Yellow powder (0.36 g, 85%): mp 245–247 °C. IR (KBr)
3
2JHH = 15.3 Hz, JHH = 6 Hz, CHaHb), 6.49 (1H, s, CH),
cm-1: 3,426, 3,051, 2,923, 1,661, 1,628, 1,594, 1,527,
123

J IRAN CHEM SOC
1
1,439. H NMR (300.13 MHz, DMSO-d6) d: 2.22 (3H, s,
precipitate was appeared. After completion of the reaction,
as indicated by TLC (EtOAc:n-hexane, 1:2), the reaction
mixture was filtered off and the residue was further purified
by recrystallization from ethanol to give 7b as a pure
product. Yellow powder (0.26 g, 97%): mp 177–179 °C.
1H NMR (300.13 MHz, DMSO-d6) d: 7.17–7.22 (2H, m,
H-Ar), 7.46 (1H, br s, H-Ar), 7.60 (1H, br s, H-Ar), 7.83
CH3), 6.66 (1H, s, CH), 6.86–7.57 (14H, m, H-Ar), 9.75
(1H, s, NHCO), 10.28 (1H, s, NH). 13C NMR
(100.65 MHz, DMSO-d6) d: 13.9, 52.4 (CH3 and CH),
99.7, 105.7, 112.8, 115.9, 116.2, 117.4, 118.1, 119.3,
119.6, 124.8, 126.6, 127.6, 129.6, 133.1, 135.1, 138.6,
139.3, 142.6, 144.1 (C-Ar, C=C and C=N), 161.1 (CO).
Anal. Calcd for C24H19N5O3: C, 67.76; H, 4.50; N, 16.46;
found C, 67.71; H, 4.46; N, 16.51.
3
(1H, t, JHH = 7.9 Hz, H-Ar), 8.37–8.46 (2H, m, H-Ar),
8.85 (1H, s, H-Ar), 9.59 (1H, s, CH), 12.85 (1H, s, NH).
Anal. Calcd for C14H10N4O2: C, 63.15; H, 3.79; N, 21.04;
found C, 63.11; H, 3.72; N, 21.01.
N-Propyl-2-methyl-4-(4-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5k)
Results and discussion
White powder (0.33 g, 87%): mp 292–294 °C. IR (KBr)
cm-1: 3,331, 3,064, 2,955, 2,877, 1,676, 1,627, 1,512,
In a pilot experiment, the reaction of N-alkyl-3-oxobu-
tanamide 6, which was derived from the nucleophilic
reaction of benzyl amine 1 with 2,2,6-trimethyl-4H-1,3-
dioxin-4-one under solvent-free conditions at 150 °C for
30 min, with 2-nitrobenzaldehyde and 1H-benzo[d]imida-
zol-2-amine 4 without addition of catalyst proceeds in
water at reflux temperature. The progress of the reaction
was monitored by TLC. After completion of the reaction,
the product N-benzyl-2-methyl-4-(2-nitrophenyl)-1,4-di-
hydrobenz[4,5]imidazo[1,2-a]pyrimidine-3-carboxamide
5a was obtained in 89% yield.
1
1,457. H NMR (300.13 MHz, DMSO-d6) d: 0.70 (3H, t,
3JHH = 7.2 Hz, CH3), 1.27–1.37 (2H, m, CH2), 2.15 (3H,
s, CH3), 2.96–3.01 (2H, m, CH2), 6.52 (1H, s, CH),
6.84–6.92 (1H, m, H-Ar), 6.97–7.05 (2H, m, H-Ar),
7.22–7.37 (5H, m, H-Ar), 7.77 (1H, br s, NHCO), 10.10
(1H, s, NH). 13C NMR (100.65 MHz, DMSO-d6) d: 7.5,
13.6, 18.5, 36.7, 52.4 (CH3, CH2, and CH), 100.1, 105.6,
112.5, 115.8, 117.8, 124.7, 124.9, 127.8, 128.6, 130.7,
136.0, 138.7, 142.9 (C-Ar, C=C and C=N), 162.0 (CO).
Anal. Calcd for C21H21ClN4O: C, 66.22; H, 5.56; N, 14.71;
found C, 66.16; H, 5.48; N, 14.66.
We have shown that the use of a wide diversity of
substituents in amines 1 and aldehydes 3 in this four-
component reaction makes possible the synthesis of
libraries under similar circumstances. The results revealed
that not only electron-deficient and electron-rich aryl
aldehydes but also aliphatic aldehydes in the multi-com-
ponent reaction afforded the corresponding product effi-
ciently under the same conditions. The results are shown in
Table 1. As anticipated from our original results, these
reactions proceeded very cleanly and no undesirable side
reactions were observed. All compounds, described in the
paper, were synthesized for the first time. The structures of
products 5a–l are shown in Fig. 1.
N-Allyl-2-methyl-4-(4-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-
carboxamide (5l)
White powder (0.32 g, 84%): mp 295–297 °C. IR (KBr)
1
cm-1: 3,331, 3,039, 2,917, 1,676, 1,615, 1,514, 1,458. H
NMR (300.13 MHz, DMSO-d6) d: 2.18 (3H, s, CH3), 3.68
(2H, br s, CH2), 4.85 (Ha, d, JHH(trans) = 17.2 Hz,
3
CH=CHaHb),
4.94
(Hb,
d,
3JHH(cis) = 10.2 Hz,
CH = CHaHb), 5.61–5.77 (1H, m, CH=CH2) 6.54 (1H, s,
CH), 6.85–6.93 (1H, m, H-Ar), 6.98–7.05 (2H, m, H-Ar),
7.24–7.37 (5H, m, H-Ar), 7.94 (1H, br s, NHCO), 10.12
(1H, s, NH). 13C NMR (100.65 MHz, DMSO-d6) d: 13.7,
37.3, 52.3 (CH3, CH2, and CH), 99.8, 105.6, 111.1, 112.6,
115.9, 117.8, 124.8, 124.9, 127.7, 128.7, 131.4, 136.0,
138.7, 142.8 (C-Ar, C=C and C=N), 162.0 (CO). Anal.
Calcd for C21H19ClN4O: C, 66.58; H, 5.05; Cl, 9.36; N,
14.79; found C, 66.51; H, 5.12; N, 14.72.
The nature of these compounds as 1:1:1:1 adducts was
apparent from their mass spectra, which displayed, in each
case, the molecular ion peak at appropriate m/z values.
Compounds 5a–l are stable solids whose structures are
1
fully supported by IR, H, and 13C NMR spectroscopies
1
and elemental analysis. For example, the H NMR spec-
trum of 5a exhibited a singlet for the methyl group
(d = 2.15), a doublet at 3.96 ppm (2JHH = 14.7 Hz) and a
doublet of doublet at 4.42 ppm (2JHH = 14.9 Hz,
3JHH = 6.5 Hz) for the methylene group. One multiplet
(d = 6.87–6.91) was attributed to methine group (CHN)
and phenyl moiety. Other 11 aromatic hydrogens gave rise
to characteristic signals in the aromatic region of the
spectrum. The spectrum also contains a broad singlet
Synthesis of N-(3-nitrobenzylidene)-1H-
benzo[d]imidazol-2-amine (7b)
The mixture of 3-nitrobenzaldehyde (0.15 g, 1.0 mmol)
and 1H-benzo[d]imidazol-2-amine (0.13 g, 1.0 mmol) in
5 ml H2O was allowed to reflux for 5 min until the
123

J IRAN CHEM SOC
Table 1 Synthesis of
dihydrobenzo[4,5]imidazo[1,2-
a]-pyrimidine-3-carboxamides
5a–l
Entry
R1
Aldehyde
Product
Time (min)
Yielda (%)
1
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
4-Methylbenzyl
Phenyl
2-Nitrobenzaldehyde
3-Nitrobenzaldehyde
4-Chlorobenzaldehyde
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
Propionaldehyde
5a
5b
5c
5d
5e
5f
45
35
50
55
60
60
40
50
60
45
60
55
89
85
86
79
76
80
87
83
81
85
82
84
2
3
4
5
6
7
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
Benzaldehyde
5g
5h
5i
8
9
Phenyl
10
11
12
Phenyl
3-Nitrobenzaldehyde
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
5j
n-Propyl
Allyl
5k
5l
a
Isolated yield
Fig. 1 The structures of
products 5a–l
Cl
NO2
NO2
O
O
O
N
H
N
N
N
N
H
N
H
N
N
N
H
N
N
N
H
H
a
5
5b
c
5
e
M
O
O
O
O
N
N
H
N
H
N
N
H
N
N
N
N
H
N
N
N
H
5f
H
e
5
5d
Cl
Cl
O
O
O
N
H
N
N
H
N
N
N
H
N
N
N
H
N
H
N
N
5
g
5i
5h
H
Cl
Cl
NO2
O
O
O
N
N
N
N
H
HN
N
H
N
N
N
N
H
N
5j
N
5l
H
H
5k
(d = 8.12) which is attributed NHCO group. The signal
corresponding to the NH group appears as a singlet at
Two suggested pathways for the formation of compound
5 are presented in Scheme 2. It is conceivable in pathway I,
so that the initial event is the formation of Schiff base 7 by
the condensation of an aldehyde 3 and 1H-benzo[d]imi-
dazol-2-amine 4. In the next step, intermediate 8 is
obtained via Michael addition reaction between 7 and N-
alkyl-3-oxobutanamide 6, which derived from the reaction
1
10.26 ppm. The H-decoupled 13C NMR spectrum of 5a
showed 23 distinct resonances in agreement with the
product structure. Furthermore, the structure of the product
5g was confirmed unambiguously by single-crystal X-ray
analysis (Fig. 2).
123

J IRAN CHEM SOC
of an amine 1 with 2,2,6-trimethyl-4H-1,3-dioxin-4-one 2.
Then, the intermediate 9 is produced by an elimination
reaction. Finally, Michael addition between 9 and 1H-
benzo[d]imidazol-2-amine 4 afforded the intermediate 10,
which upon isomerization, intramolecular cyclization and
dehydration gave the product 5. In the case of pathway II, a
reaction between compound 6 and aldehyde 3 produces the
intermediate 9, which after reaction with 4 affords product
5.
To distinguish the preferred pathway (pathway I or II),
we carried out the condensation reaction between 3-nitro-
benzaldehyde 3b with N-alkyl-3-oxobutanamide 6 and the
desired intermediate 9 was not obtained under reflux con-
ditions in water. However, the intermediate N-(3-nitro-
benzylidene)-1H-benzo[d]imidazol-2-amine 7b was easily
prepared via the condensation of 3-nitrobenzaldehyde 3b
and 1H-benzo[d]imidazol-2-amine 4 under the same reac-
tion conditions (Scheme 3). This finding leads us to con-
clude that the preferred pathway to produce 5 is via route I.
In conclusion, we demonstrated an environmentally
efficient four-component approach for the synthesis of
dihydrobenzo[4,5]imidazo[1,2-a]-pyrimidine-3-carbox-
amide derivatives via cyclocondensation reaction of pri-
mary aliphatic or aromatic amines, 2,2,6-trimethyl-4H-1,3-
dioxin-4-one, 1H-benzo[d]imidazol-2-amine and aliphatic
or aromatic aldehydes under catalyst-free conditions and in
water. To the best of our knowledge, this new procedure
provides the first example of the efficient synthetic method
Fig. 2 ORTEP diagram for 5g
H
N
R2
H
C O
NH2
N
3
4
-
H
2O
H
N
O
O
HR2
NHR1
N
C
H
N
N
7
N
H
R2
N
8
I
O
O
H
O
O
O
-acetone
R1NH2
NHR1
O
O
H
N
R1HN
1
6
N
H
R2
2
II
N
O
O
R2
H
C O
3
R1HN
R2
9
N
H2N
N
H
4
H
O
O
O
O
O
R1HN
R1HN
R1HN
NH
-
H
2O
NH
NH
R2
NH2
R2
R2
N
N
N
N
10
N
5
Scheme 2 Proposed mechanism for the synthesis of dihydrobenzo[4,5]imidazo[1,2-a]-pyrimidine-3-carboxamides 5
123

J IRAN CHEM SOC
Scheme 3 Synthesis of N-(3-
nitrobenzylidene)-1H-
benzo[d]imidazol-2-amine 7b
O
O
R1HN
6
II
(No reaction)
24 h
H
C O
reflux
H
O
,
2
N
O2
H
N
N
O2
3b
NH2
H
N
N
4
N
I
5 min
N
7b
14. D.R. Spring, Org. Biomol. Chem. 1, 3867 (2003)
15. M.D. Burke, E.M. Berger, S.L. Schreiber, Science 302, 5645
(2003)
16. M.D. Burke, S.L. Schreiber, Angew. Chem. Int. Ed. 43, 46 (2004)
17. D.S. Tan, Nat. Chem. Biol. 1, 74 (2005)
18. L.A. Wessjohann, E. Ruijter, Top. Curr. Chem. 243, 137 (2005)
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cycl. Compd. 48, 584 (2012)
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for dihydrobenzo[4,5]imidazo[1,2-a]-pyrimidine-3-car-
boxamides by a four-component reaction. The operational
simplicity, short reaction time, high purity and good yield
of products and minimal environmental impact are notable
features of this procedure.
Acknowledgments We gratefully acknowledge financial support
from the Iran National Elites Foundation (INEF), Research Council of
Shahid Beheshti University and Ministry of Higher Education of
Malaysia (Grant No. UM.C/HIR/MOHE/SC/12).
´
22. D.J. Ramon, M. Yus, Angew. Chem. Int. Ed. 44, 1602 (2005)
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¨
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