Generation of 500-member library of 10-alkyl-2-R1,3-R 2-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones

Article abstract of DOI:10.3390/molecules14125223

Representative benzimidazopyrimidinones were previously reported to be intercalating antitumor agents. In this work, we used 2-substituted 4,10-dihydrobenzo [4,5]imidazo[1,2-a]pyriminin-4-ones for their diversification by regioselective alkylation. Under

Full text of DOI:10.3390/molecules14125223

Molecules 2009, 14, 5223-5234; doi:10.3390/molecules14125223
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Generation of 500-Member Library of 10-Alkyl-2-R1,3-R2-4,10-
Dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones
Svetlana M. Sirko, Nikolay Yu. Gorobets *, Vladimir I. Musatov and Sergey M. Desenko
Department of Chemistry of Heterocyclic Compounds, SSI “Institute for Single Crystals” of National
Academy of Sciences of Ukraine, Lenin Ave. 60, Kharkiv 61001,Ukraine
* Author to whom correspondence should be addressed: E-Mail: gorobets@isc.kharkov.com.
Received: 4 November 2009; in revised form: 3 December 2009 / Accepted: 14 December 2009 /
Published: 15 December 2009
Abstract: Representative benzimidazopyrimidinones were previously reported to be
intercalating antitumor agents. In this work, we used 2-substituted 4,10-dihydrobenzo
[4,5]imidazo[1,2-a]pyriminin-4-ones for their diversification by regioselective alkylation.
Under the conditions established, the alkylation gave 10-alkyl derivatives which permitted
the parallel generation of a 500-member library of the title compounds.
Keywords: benzimidazole; dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one library;
regioselective alkylation; anti-cancer agents
Introduction
The benzimidazole fragment is a frequent motif in recent publications devoted to drug design and
molecular diversity oriented synthesis [1–9]. Fused polycyclic derivatives of benzimidazo[1,2-a]
pyrimidines are often cited as anti-cancer and cytotoxic agents [10–14]. These molecules bind to DNA
by stacking interactions of their π-electron rich planar fragments with the nucleic acid sandwiching in
two consecutive base pairs of the double helix. This affects the DNA shape eventually prohibiting
replication and causing the cell death [15,16].
Condensed benzimidazoles represent a suitable platform for the construction of such planar
molecules applying the strategy of diversity oriented synthesis. We were interested in the generation of
a library of diverse compounds based on the dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one
core (Figure 1).

Molecules 2009, 14
Figure 1. Dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one core.
5224
7
6
O
8
3
N
9
2
N
N
10 H
We aimed to generate a 500-member library of dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones
by introducing the initial diversity points in the positions C-2 and C-3 and then diversifying the
obtained compounds by regioselective alkylation reactions using alkylating agents of different types in
parallel format. In view of the scaffold structure (Figure 1) there are at least three products of
monoalkylation that can be expected: the N1- and N10-substituted derivatives and the product of
O-alkylation. Thus, uniform conditions for regioselective alkylation of dihydrobenzo[4,5]imidazo[1,2-
a]pyrimidin-4-ones are required.
Results and Discussion
Several synthetic approaches to the dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one scaffold 1
have been found in the literature [17–22]. All of them utilize the reactivity of 2-aminobenzimidazole 2
with 1,3-dielectrophiles of several types. However, because of the commercial ability of different
β-ketoesters 3, we have applied them [23] for the synthesis of starting compounds 1a–p. In contrast to
the original protocol [23] where authors heated a neat mixture of 2-aminobenzimidazole 2 and some
liquid β-ketoesters 3, we applied DMF as a solvent to make the procedure general for different starting
materials including solid esters 3e–h (Table 1). Application of other solvents (EtOH, AcOH, dioxane)
at reflux resulted in lower yields.
In our initial experiments on the alkylation we used the representative 1a in the reaction with
4-methylbenzyl chloride 4a under different reaction conditions. Strong alkali media (NaH or KOH in
DMF, DMSO or dioxane) gave mixtures of alkylation products and therefore were not acceptable.
Milder reaction conditions (NaHCO3 or K2CO3 in acetone, NEt3 in DMF) led to low yields or to
products contaminated with the starting material 4a. However, application of K2CO3 (3 equiv) in DMF
at 90 °C for 2h resulted in the formation of only one isomer 5aa with 81% yield following a simple
aqueous workup (Scheme 1). Application of such conditions is very convenient for parallel synthesis
because the reaction media does not reflux and the reaction can be carried out in a simple sealed
vessel. These conditions were suitable for application of a representative of N-substituted
2-chloroacetamides 4o (Table 2). The product 5ao was obtained in the same manner with 77%
yield (Scheme 1).
Table 1. Synthesis of exampled starting dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones 1a–p.
O
O
R2
R1
R2
R1
Δ
AlkO
N
2
N
+
DMF
N
N
O
NH2
N
H
H
3a-p
1a-p

Molecules 2009, 14
5225
Table 1. Cont.
Code
Structure
Yield,%
Code
Structure
Yield,%
O
O
1a
75
80
71
79
1i
60
47
54
56
N
N
N
N
N
Me
N
H
H
O
N
O
N
1b
1j
1k
1l
N
Cl
N
N
H
N
Me
H
O
O
1c
N
N
Me
OMe
N
H
N
H
N
O
N
O
N
1d
N
N
Me
N
N
H
N
N
O
H
F
O
N
1e
87
1m
73
N
Me
Me
N
H
N
N
H
Me
OMe
O
O
1f
87
77
1n
1o
55
35
N
N
N
N
N
H
N
CF3
N
O
H
N
O
1g
N
OEt
N
N
H
N
O
N
O
H
N
N
O
N
1h
80
1p
67
N
N
N
N
H
N
H

Molecules 2009, 14
Scheme 1. Model alkylation of the 2-phenyl-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one 1a.
5226
6
6
O
O
O
Cl
Δ
N
N
9
9
DMF
+
N
N
N
N
N
K2CO3
N
N
H
O
Me
1a
4a
HN
5aa
Me
5ao
N
O
O
MeO
+
N
Δ
NH2
Me
EtO
DMF
-
Positive NOE
6
3a
Table 2. Selected examples 4a–u of alkylation agents used for the library 5 generation.
Code
4a
Structure
Code
4h
Structure
Code
4o
Structure
Cl
F
Cl
O
Cl
Cl
MeO
MeO
N
H
Me
Cl
Br
Cl
Cl
4b
4c
4d
4i
4j
4p
4q
4r
O
Me
N
H
Me
OMe
F
Me
I
O
Cl
N
H
CF3
O
O
Cl
4k
Cl
F
MeO
O
Me
O
Cl
N
H
Cl
O
O
O
4e
4f
4l
4m
4n
4s
4t
Cl
Cl
Cl
N
Me
Me
N
H
Me
Cl
Cl
Cl
O
Cl
N
H
N
H
O
Me
Cl
O
O
4g
4u
F3C
Cl
Cl
N
N
H
H
OMe

Molecules 2009, 14
5227
The information on alkylation of the dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones 1 turned
out to be absent in the literature, thus it was not possible to predict with certainty which isomer out of
three mentioned above was formed. The NOE experiment, irradiation of the product 5aa with the
resonance frequency of its CH2 protons at 5.58 ppm has demonstrated a close location of the
methylene group and the upfield CH proton of the benzimidazole ring (doublet at 7.63 ppm) which
agrees with either for O-alkylated or N10-alkylated product. To undoubtedly determine the structure of
the product 5aa we have carried out a counter-synthesis (Scheme 1) of this compound starting from
2-amino-1-(4-methylbenzyl)benzimidazole 6 described previously [24]. The products obtained in these
two alternative ways were identical. This means that the upfield doublet (at 7.63 ppm) of the
benzimidazole ring belongs to the 9-C-H proton but not to the 6-C-H. Consequently, the latter gives its
downfield doublet at 8.48 ppm. This alternative synthetic pathway leading to the compound 5aa gives
lower yield (54% isolated yield). Also in this protocol the main diversity point (the alkylation agent)
was introduced not at the last synthetic step, which was less convenient for the library generation.
Alkylation of the starting derivative 1a using a representative of the N-substituted 2-chloroacetamides
4o led to one regioisomer 5ao. The discussed signal assignment for compound 5aa gives opportunity
to determine structure of the product 5ao, the positive NOE between the protons of the CH2 group
(5.29 ppm) and the upfield benzimidazole 9-C-H proton (doublet at 7.71 ppm) fully confirms the
N10-alkylation.
The specified conditions allowed us to perform regioselective alkylation of the
2-(het)arylderivatives 1a–g with all the applied chemotypes of alkylation agents (representatives of
benzyl clorides, 2-chloroacetic acid derivatives and representatives of alkylbromides or iodides, see
Table 2 for selected alkylation agents 4a–u). However, a series of pilot experiments with the alkylation
of 2-methyl-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one 1i by representatives of the
N-substituted 2-chloroacetamides 4l–u led to isolation of a mixture of two isomeric products. At the
same time, the application of other alkylation agents was successful in this case. The same result was
observed for the 2-tert-butyl derivative 1m. Also, in the case of the starting compounds 1o,p, we could
not achieve the regioselectivity with alkylators of all chemotypes. Thus, we had to exclude the 2-alkyl
derivatives 1i–n from the starting set used in the alkylation with the N-substituted
2-chloroacetamides 4l–u, and we did not use the derivatives 1o,p for the library generation.
Scheme 2. Generation of a 500-member library of 10-alkyl-2-R1,3-R2-4,10-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones 5.
O
O
Δ
R2
R2
R1
DMF
N
Hal
N
+
R3
K2CO3
R1
N
N
N
N
R3
H
5
1a-n...
4a-u...
500 members

Molecules 2009, 14
Figure 2. Selected members of the generated library 5 and their isolated yields.
5228
O
O
O
O
N
N
N
N
Me
N
N
N
N
N
N
N
Me
N
CF3
N
O
O
Me
5ia
5gk
5nj
5kc
F
65%
Me
43%
67%
51%
Me
N
O
O
O
O
N
N
N
N
Me
F
OMe
N
N
N
N
N
N
N
Me
O
Me
Me
N
HN
5jg
79%
5ch
90%
5fl
73%
5me
75%
Me
Cl
Cl
N
F3C
O
N
O
O
N
N
N
N
OMe
Cl
N
N
N
O
O
O
OMe
5er
97%
NH
5bl
94%
NH
NH
O
5ct
87%
MeO
O
Me
Figure 3. Distribution of different congener’s chemotypes in the generated 500-member library 5.
Number of
Compounds
300
250
200
150
100
50
Р2
1a-h
0
1Рi-1n
4a-1h
42i-k
3
4l-u
The library was generated in parallel format (Scheme 2, Figure 2) and the structure and purity of
1
every congener were checked by H-NMR. In about 85% cases the products were isolated with very
good average yield (about 70%) and met the purity requirements (maximal total level of impurities less
then 10% as determined by 1H-NMR). In those cases (about 10%) where the impurity level was higher
than 10% the product purity was improved by heating in EtOH to remove soluble remains of the

Molecules 2009, 14
5229
starting materials. In about 5% of cases the products did not satisfy the purity requirements either after
the simple workup or after the additional purification.
As a result, the desired 500-member library contained different compound chemotypes whose
distribution is illustrated in Figure 3. As one can see, the starting 2-(het)arylderivatives 1a–g
contributed much more significantly to the total number of compounds because of their selectivity in
the reaction with the diverse N-substituted 2-chloroacetamides 4l–u.
In summary, a 500-member library of 10-Alkyl-2-R1,3-R2-4,10-dihydrobenzo[4,5]imidazo[1,2-
a]pyrimidin-4-ones was quickly generated under uniform conditions in liquid phase parallel format.
Structural diversity of the library members was achieved by application of two rows of starting
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones containing different 2-(het)aryl (1a–h) or 2-alkyl
(1i–n) substituents as well as three types of alkylation agents. The major part of congeners comprises
conjugated planar molecules derived from 2-(het)aryldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-
ones 1a–h that makes them potential anti-cancer DNA intercalators.
Experimental
General
The starting dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones 1a [25], 1e [26], 1i [25], 1o [27],
1p [27] have been previously described. The starting sets of ß-ketoesters and alkylation agents were
supplied by Chemical Diversity Research Institute, Chimki, Moscow, Russia. All other reagents and
1
13
solvents are commercially available and were used without additional purification. H, C and NOE
NMR experiments were recorded at 200 MHz (50 MHz for 13C NMR) in DMSO-d6 solutions.
Dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-ones (1a–p). An equimolar mixture of 2-amino-
benzimidazole 2 and corresponding β-ketoester 3a–p (0.04 mol) in DMF (4 mL) was refluxed for
20–60 min. If a precipitate was formed or the mixture was solidified at heating, the mixture was kept at
mild heating for another 5 min and then cooled down to the room temperature. In the cases when no
precipitate was formed, the mixture was refluxed for 60 min and then cooled down to the room
temperature. The solid reaction mixture was fluidized with EtOH, the precipitated was separated by
filtration, washed with EtOH and dried on air. The products 1a-p obtained in this manner had adequate
1H NMR spectra and used for the next reaction step without additional purification.
1
2-(3-Chlorophenyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1b). H-NMR δ 6.70 (s, 1H),
7.31 (m, 1H), 7.41-7.62(m, 4H), 8.05(m, 1H), 8.14 (m, 1H), 8.44 (dd, J = 1.2 Hz, J = 7.9 Hz, 1H),
13.12 (br. s, 1H).
1
2-(3-Methoxyphenyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1c). H-NMR δ 3.83 (s, 3H),
6.64 (s, 1H), 7.06 (m, 1H), 7.20-7.57 (m, 4H), 7.57-7.83 (m, 2H), 8.46 (d, J = 7.9 Hz, 1H), 13.06 (br. s,
1H).
1
2-(4-Fluorophenyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1d). H-NMR δ 6.61 (s, 1H),
7.22-7.42 (m, 3H), 7.47 (d, J = 4.0 Hz, 2H), 8.16 (m, 2H), 8.45 (dd, J = 0.7 Hz, J = 7.8 Hz, 1H),
13.10 (br. s, 1H).

Molecules 2009, 14
5230
1
2-(4-Metoxyphenyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1e). H-NMR δ 3.82 (s, 3H),
6.50 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 7.17-7.60 (m, 3H), 8.07 (d, J = 8.7 Hz, 2H), 8.44 (d, J = 7.9 Hz,
13
1H), 12.95 (br. s, 1H); C NMR δ 56.1, 96.6, 111.8, 114.8, 116.3, 122.4, 126.6, 126.8, 129.3, 130.2,
131.8, 150.3, 160.4, 161.1, 162.0.
1
2-(Pyridin-4-yl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1f). H-NMR δ 6.80 (s, 1H), 7.36
(m, 1H), 7.50 (d, J = 4.0 Hz, 2H), 8.04 (dd, J = 1.7 Hz, J = 5.2 Hz, 2H), 8.47 (d, J = 7.9 Hz, 1H), 8.71
(dd, J = 1.7 Hz, J = 5.2 Hz, 2H), 13.10 (br. s, 1H).
1
2-(Pyridin-3-yl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1g). H-NMR δ 6.73 (s, 1H), 7.33
(m, 1H), 7.42-7.60 (m, 3H), 8.33-8.56 (m, 2H), 8.66 (dd, J = 1.7 Hz, J = 4.7 Hz, 1H), 9.27 (dd,
J = 0.8 Hz, J = 2.3 Hz, 1H).
1
2-(Pyridin-2-yl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1h). H-NMR δ 7.03 (s, 1H), 7.35
(m, 1H), 7.41-7.63 (m, 3H), 7.98 (td, J = 0.8 Hz, J = 7.9 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H),
8.47 (d, J = 7.9 Hz, 1H), 8.70 (d, J = 0.5 Hz, 1H), 13.17 (br. s, 1H).
3-Benzyl-2-methyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1j). 1H-NMR δ 2.30 (s, 3H), 3.88
(s, 2H), 7.03-7.35 (m, 6H), 7.35-7.60 (m, 2H) 8.39 (d, J = 7.8 Hz, 1H), 12.32 (br. s, 1H).
1
2-Ethyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1k). H-NMR δ 1.20 (t, J = 7.5 Hz, 3H),
2.56 (q, J = 7.5 Hz, 2H), 5.83 (s, 1H), 7.26 (td, J = 1.5 Hz, J = 7.9 Hz, 1H), 7.34-7.59 (m, 2H),
8.35 (d, 7.8 Hz, 1H), 12.66 (br. s, 1H).
1
2-Propyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1l). H-NMR δ 0.90 (t, J = 7.2 Hz, 3H),
1.67 (hexet, J = 7.2 Hz, 2H), 2.42-2.55 (m, 2H), 5.82 (s, 1H), 7.25 (td, J = 1.5 Hz, J = 7.9 Hz, 1H),
7.33-7.60 (m, 2H), 8.35 (d, 7.9 Hz, 1H), 12.67 (br. s, 1H); 13C-NMR δ 14.0, 21.7, 38.1, 98.9, 113.8,
115.9, 122.0, 126.2, 127.5, 135.2, 149.4, 160.0, 164.1.
1
2-tert-Butyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1m). H-NMR δ 1.27 (s, 9H), 5.95 (s,
1H), 7.27 (m, 1H), 7.33-7.53 (m, 2H), 8.37 (d, 7.9 Hz, 1H), 12.85 (br. s, 1H).
1
2-Trifluoromethtyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (1n). H-NMR δ 6.43 (s, 1H),
7.36 (m, 1H), 7.47-7.58 (m, 2H), 8.44 (dd, J = 0.8 Hz, J = 7.9 Hz, 1H).
Generation of 500-member Library 5 of 10-Alkyl-2-R1,3-R2-4,10-Dihydrobenzo[4,5]imidazo[1,2-
a]pyrimidin-4-ones
The equimolar mixture (0.6 mmol) of starting dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one
(1a–n...) and corresponding alkylation agent (4a–u…) was dissolved in DMF (2 mL) with mild
heating. Then K2CO3 (1.8 mmol) was added and the reaction mixture was stirred at 90-100 °C for 2h.
The mixture was cooled down and diluted with 50% aqueous EtOH (4 mL). The formed precipitate
was removed by filtration, washed with H2O and 50% aqueous EtOH and dried on air at 90 °C. In
1
those cases where H-NMR demonstrated more than 10 mol.% total impurity level, the product was

Molecules 2009, 14
5231
additionally purified by heating in 1-2 mL of EtOH for 3-5 min, then cooling to rt, and isolation by
filtration.
10-(4-Methylbenzyl)-2-phenyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (5aa). 1H-NMR δ
2.22 (s, 3H, Me), 5.58 (s, 2H, CH2), 6.72 (s, 1H, 3-CH), 7.13 (d, J = 8.1 Hz, 2H, Ar), 7.29-7.43 (m,
3H, Ar), 7.43-7.58 (m, 4H, Ar), 7.63 (d, J = 7.9 Hz, 1H, 9-CH), 8.07-8.33 (m, 2H, 7-CH and 8-CH),
8.48 (d, J = 7.9 Hz, 1H, 6-CH); 13C-NMR δ 21.2, 45.9, 98.4, 110.8, 116.4, 123.1, 125.9, 126.8, 127.8,
128.4, 129.3, 129.9, 131.0, 131.7, 133.5, 137.7, 137.9, 149.6, 160.4, 161.2.
2-(4-Oxo-2-phenylpyrimido[1,2-a]benzimidazol-10(4H)-yl)-N-(3-methoxyphenyl)acetamide
(5ao).
1H-NMR δ 3.68 (s, 3H, OMe), 5.29 (s, 2H, CH2), 6.65 (dd, J = 1.7 Hz, J = 7.9 Hz, 1H, Ar),
6.73 (s, 1H, 3-CH), 6.98-7.34 (m, 3H, Ar), 7.34-7.62 (m, 5H, Ar), 7.71 (d, J = 8.1 Hz, 1H, 9-CH),
8.00-8.27 (m, 2H, 7-CH and 8-CH), 8.51 (d, J = 8.1 Hz, 1H, 6-CH), 10.52 (s, 1H, NH).
2-[4-Oxo-2-(3-chlorophenyl)pyrimido[1,2-a]benzimidazol-10(4H)-yl]-N-(3-methylphenyl)acetamide
(5bl). 1H-NMR δ 2.25 (s, 3H), 5.29 (s, 2H), 6.76 (m, 1H), 6.89 (d, J = 7.3 Hz, 1H), 7.18 (t, J = 8.2 Hz,
1H), 7.27-7.64 (m, 6H), 7.70 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 6.4 Hz, 1H), 8.20 (s, 1H), 8.53 (d, J = 7.9
Hz, 1H), 10.40 (br. s, 1H); 13C-NMR δ 21.6, 45.9, 99.1, 110.8, 116.2, 117.7, 121.0, 123.3, 125.1,
125.7, 126.3, 127.0, 127.5, 129.2, 130.7, 131.0, 131.1, 132.5, 134.4, 138.7, 139.0, 139.7, 149.6, 159.4,
160.2, 165.2.
10-(2-Chloro-6-fluorobenzyl)-2-(3-methoxyphenyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one
1
(5ch). H-NMR δ 3.84 (s, 3H), 5.74 (s, 2H), 6.71 (s, 1H), 7.04 (m, 1H), 7.19-7.78 (m, 9H),
8.50 (d, J = 7.9 Hz, 1H).
N-(Furan-2-ylmethyl)-2-[4-Oxo-2-(3-methoxyphenyl)pyrimido[1,2-a]benzimidazol-10(4H)-yl]-
1
acetamide (5ct). H-NMR δ 3.83 (s, 3H), 4.30 (d, J = 5.5 Hz, 1H), 5.11 (s, 2H), 6.23 (dd, J = 0.7 Hz,
J = 3.3 Hz, 1H), 6.32 (dd, J = 1.8 Hz, J = 3.3 Hz, 1H), 6.75 (s, 1H), 7.07 (m, 1H), 7.31-7.47 (m, 2H),
7.47-7.59 (m, 2H), 7.59-7.79 (m, 3H), 8.49 (d, J = 8.1 Hz, 1H), 8.86 (t, J = 5.5 Hz, 1H).
N-(4-Carbomethoxyphenyl)-2-[4-oxo-2-(4-methoxyphenyl)pyrimido[1,2-a]benzimidazol-10(4H)-yl]-
acetamide (5er). 1H-NMR δ 3.78 (s, 6H), 5.31 (s, 2H), 6.63 (s, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.37 (t, J
= 7.3 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.62-7.79 (m, 3H), 7.89 (d, J = 8.9 Hz, 2H), 8.09 (d,
J = 8.9 Hz, 2H), 8.48 (d, J = 7.8 Hz, 1H), 10.70 (br. s, 1H); 13C-NMR δ 46.0, 52.4, 56.1, 97.2, 110.7,
114.8, 116.2, 119.8, 123.1, 125.4, 125.9, 126.7, 129.4, 129.8, 130.9, 132.5, 143.8, 149.6, 160.3, 160.9,
162.1, 166.0, 166.5.
N-(3-Methylphenyl)-2-[4-oxo-2-(pyridin-4-yl)pyrimido[1,2-a]benzimidazol-10(4H)-yl]-acetamide
(5fl). 1H-NMR δ 2.23 (s, 3H), 5.31 (s, 2H), 6.88 (d, J = 7.3 Hz, 1H), 6.93 (s, 1H), 7.18 (t, J = 7.8 Hz,
1H), 7.28-7.51 (m, 3H), 7.57 (t, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 6.1 Hz, 2H),
8.52 (d, J = 7.8 Hz, 1H), 8.69 (d, J = 6.1 Hz, 2H), 10.49 (br. s, 1H).

Molecules 2009, 14
5232
Ethyl N-(3-methylphenyl)-2-[4-oxo-2-(pyridin-3-yl)pyrimido[1,2-a]benzimidazol-10(4H)-yl]acetate
1
(5gk). H-NMR δ 1.21 (t, J = 7.0 Hz, 3H), 4.19 (q, 7.0 Hz, 2H), 5.36 (s, 2H), 6.87 (s, 1H), 7.32-7.66
(m, 3H), 7.74 (d, J = 7.9 Hz, 1H), 8.49 (d, J = 8.1 Hz, 2H), 8.67 (dt, J = 1.7 Hz, J = 4.7 Hz, 1H),
9.33 (m, 1H).
1
2-Methyl-10-(4-methylbenzyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (5ia). H-NMR δ 2.23
(s, 3H), 2.33 (s, 3H), 5.45 (s, 2H), 5.96 (s, 1H), 7.11 (d, J = 7.1 Hz, 2H), 7.19-7.66 (m, 5H),
8.45 (d, J = 7.9 Hz, 1H)
3-Benzyl-2-methyl-10-(3-trifluoromethylbenzyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one
1
(5jg). H-NMR δ 2.33 (s, 3H), 3.93 (s, 2H), 5.59 (s, 2H), 7.04-7.79 (m, 11H), 7.91 (s, 1H), 8.50 (d,
J = 7.8 Hz, 1H).
1
10-(2-Fluorobenzyl)-2-ethyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (5kc). H NMR δ 1.19
(t, J = 7.5 Hz, 3H), 2.56 (q, J = 7.5 Hz, 2H), 5.55 (s, 2H), 5.97 (s, 1H), 7.11 (m, 1H), 7.19-7.41 (m,
13
4H), 7.41-7.65 (m, 2H), 8.45 (dq, J = 0.7 Hz, J = 7.9 Hz, 1H); C-NMR δ 13.0, 31.1, 100.3, 110.4,
116.0, 116.4, 123.0, 125.3, 125.4, 126.0, 126.7, 130.7, 130.8, 131.4, 149.4, 160.0, 163.4, 170.0.
1
2-tert-Butyl-10-(4-clorobenzyl)dihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (5me). H-NMR δ
1.27 (s, 9H), 5.48 (s, 2H), 6.03 (s, 1H), 7.13-7.59 (m, 6H), 7.66 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 8.1
Hz, 1H).
1
10-Butyl-2-trifluoromethyldihydrobenzo[4,5]imidazo[1,2-a]pyrimidin-4-one (5nj). H-NMR δ 0.88 (t,
J = 7.2 Hz, 3H), 1.31 (hexet, J = 7.5 Hz, 2H), 1.79 (pentet, J = 7.5 Hz, 2H), 4.32 (t, J = 7.2 Hz, 2H),
6.51 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 8.50 (d, J = 8.0
Hz, 1H); 13C-NMR δ 13.9, 19.9, 30.2, 42.8, 100.1, 111.0, 116.6, 123.6, 124.6, 125.5, 127.6, 131.8,
149.6, 159.5, 160.2.
Acknowledgements
We thank ChemDiv, Inc. San Diego, CA, USA for supporting this work.
References and Notes
1. Charifson, P.S.; Grillot, A.L.; Grossman, T.H.; Parsons, J.D.; Badia, M.; Bellon, S. Deininger,
D.D.; Drumm, J.E.; Gross, C.H.; Letiran, A.; Liao, Y.; Mani, N.; Nicolau, D.P.; Perola, E.;
Ronkin, S.; Shannon, D.; Swenson, L.L.; Tang, Q.; Tessier, P.R.; Tian, S.K.; Trudeau, M.; Wang,
T.; Wei, Yu.; Zhang, H.; Stamos, D. Novel dual-targeting benzimidazole urea inhibitors of DNA
gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and
evolution through the judicious use of structure-guided design and stucture-activity relationships.
J. Med. Chem. 2008, 51, 5243–5263.
2. Hasegawa, M.; Nishigaki, N.; Washio, Y.; Kano, K.; Harris, P.A.; Sato, H.; Mori, I.; West, R.I.;
Shibahara, M.; Toyoda, H.; Wang, L.; Nolte, R.T.; Veal, J.M.; Cheung, M. Discovery of novel

Molecules 2009, 14
5233
benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors. J. Med.
Chem. 2007, 50, 4453–4470.
3. Kumar, A.; Maurya, R.A.; Ahmad, P. Diversity oriented synthesis of benzimidazole and
benzoxa/(thia)zole libraries through polymer-supported hypervalent iodine reagent. J. Comb.
Chem. 2009, 11, 198–201.
4. Podunavac-Kuzmanović, S.O.; Cvetković, D.D.; Barna, D.J. QSAR Analysis of 2-amino or 2-
methyl-1-substituted benzimidazoles against Pseudomonas aeruginosa. Int. J. Mol. Sci. 2009, 10,
1670–1682.
5. Algul, O.; Kaessler, A.; Apcin, Y.; Yilmaz, A.; Jose, J. Comparative studies on conventional and
microwave synthesis of some benzimidazole, benzothiazole and indole derivatives and testing on
inhibition of hyaluronidase. Molecules 2008, 13, 736–748.
6. Xu, Y.S.; Zeng, C.C.; Jiao, Z.G.; Hu, L.M.; Zhong, R.G. Design, synthesis and anti-HIV integrase
evaluation of 4-oxo-4H-quinolizine-3-carboxylic acid derivatives. Molecules 2009, 14, 868–883.
7. Madhav, J. V.; Suresh, B. K.; Rajitha, B. Dipyridine copper chloride as a mild and efficient
catalyst for the solid state synthesis of 2-substituted benzimidazoles. ARKIVOC 2008, xiii,
145–150.
8. Vinodkumar, R.; Vaidya, S. D.; Kumar, B.V.; Bhise, U.N.; Bhirud, S.B.; Mashelkar, U.C.
Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N-substituted 2-(4-
styrylphenyl)-1H-benzimidazole and N- substituted-3[4-(1H-benzimidazole-2-yl)-phenyl]-acrylic
acid tert-butyl ester. ARKIVOC 2008, xiv, 37–49.
9. Martínez-Palou, R.; Zepeda, L.G; Höpfl, H; Montoya1, A.; Guzmán-Lucero D.J.; Guzmán J.
Parallel and automated library synthesis of 2-long alkyl chain benzoazoles and azole[4,5-
b]pyridines under microwave irradiation. Mol. Divers. 2009, 9, 361–369.
10. Abdel-hafez, A.A.M. Benzimidazole condensed ring systems: new synthesis and antineoplastic
activity of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo[4,5]imidazo[1,2-a]pyrimidine
derivatives. Arch. Pharm. Res. 2007, 30, 678–684.
11. Via, L.D.; Gia, O.; Magno, S.M.;. Da Settimo, A.; Marini, A.M.; Primofiore, G.; Da Settimo, F.;
Salerno, S. Synthesis, in vitro antiproliferative activity and DNA-interaction of
benzimidazoquinazoline derivatives as potential anti-tumor agents. Il. Farmaco. 2001, 56,
159–167.
12. Starčević K.; Kralj, M.; Ester, K.; Karminski-Zamola, G. Synthesis and cytostatic evaluation of
pyridopyrimidobenzimidazole derivatives. Heterocycles 2007, 3, 647–656.
13. Vaidyanathan, V.G.; Villalta, P.W.; Sturla, S.J. Nucleobase-dependent reactivity of a quinone
metabolite of pentachlorophenol. Chem. Res. Toxicol. 2007, 20, 913–919.
14. Chiba, T.; Shigeta, S.; Numazaki, Y. Inhibitory effekt of piridobenzazoles on replication in Vitro.
Biol. Pharm. Bull. 1995, 18, 1081–1083.
15. Gupta, S.P. Quantitative structure-activity relationship studies on anticancer drugs. Chem. Rev.
1994, 94, 1507–1551.
16. Gago, F. Stacking Interactions and Intercalative DNA Binding. Methods 1998, 14, 277–292.
17. Papadopoulos, K.; Young W.D. Versatile synthesis of ibotenic acid analogues with potential for
activity at glutamate receptors by use of a homochiral β-lactam template in our ‘ring switching’
strategy. Tetrahedron Lett. 2002, 43, 3951–3955.

Molecules 2009, 14
5234
18. Toche, R.B.; Ghotekar, B.K.; Muddassar A. Kazi, M.A.; Kendre, D.B.; Jachak, M.N. Synthesis of
fused pyrimidines from amines and cyclic β-formylesters. Tetrahedron 2007, 63, 8157–8163.
19. Al-Awadi, N.A.; Abdelhamid, I.A.; Al-Etaibi, A.M.; Elnagdi, M.H. Gas-phase pyrolysis in
organic synthesis: rapid green synthesis of 4-quinolinones. Synlett 2007, 14, 2205–2208.
20. Carpenter, R.D.; Lam K.S.; Kurth, M.J. Microwave-mediated heterocyclization to
benzimidazo[2,1-b]quinazolin-12(5H)-ones. J. Org. Chem. 2007, 72, 284–287
21. Metwally, M.A.; Desoky, E.I.; Fawzy, R.; Etman H. A. Ketene S,S-Acetals in the synthesis of
some new fused pyrimidine derivatives. Chem. Heterocycl. Comp. 2007, 43, 382–386.
22. Wahe, H.; Asobo, P.F.; Cherkasov, R.A.; Fomum, Z.T.; Doepp, D. Heterocycles of biological
importance: Part 8. Formation of pyrimido[1,2-a]benzimidazoles and oxazolo[3,2-
a]benzimidazoles by conjugate addition of 2-aminobenzimidazoles to 4-hydroxy-2-alkynenitriles.
ARKIVOC 2004, i, 130–137.
23. Antaki, H.; Petrow V. New syntheses of heterocyclic compounds. Part XII. The condensation of
ethyl β-aminocrotonate with some cyclic amidines. J. Chem. Soc. 1951, 551–555.
24. Ramström, H.; Bourotte, M.; Philippe, C.; Schmitt, M.; Haiech, J.; Bourguignon, J.-J.;
Heterocyclic bis-cations as starting hits for design of inhibitors of the bifunctional enzyme
histidine-containing protein kinase/phosphatase from Bacillus subtilis. J. Med. Chem. 2004, 47,
2264–2275.
25. Ogura, H.; Kawano, M.; Itoh, T. Studies on heterocyclic compounds. XIII. Reaction of 2-amino-
benzazoles with acetylenic compounds. Chem. Pharm. Bull. 1973, 21, 2019–2025.
26. Niwa, R.; Katagiri, N.; Kato, T. Studies on ketene and its derivatives. CXXII. Reaction of
haloketenes with 1,3-diaza-1,3-diene compounds. Chem. Pharm. Bull. 1984, 32, 4149–4153.
27. De Cat, A.; van Dormael, A. Heterocyclic derivatives of pyrimidobenzimidazoles. Bull. Soc.
Chim. Belg. 1950, 59, 573–587.
Sample Availability: Samples of all the compounds described are available from authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).