Three-component synthesis of 4-aryl-1H-pyrimido[1,2-a] benzimidazole derivatives in ionic liquid

Article abstract of DOI:10.1002/jhet.215

(Chemical Equation Presented) A green and simple synthesis of 4-ayrl-3,4-dihydro-1H-pyrimido[1,2-a]benzimidazole derivatives was accomplished in excellent yields via the reaction of aryl aldehyde, 1,3-dicarbonyl compounds and 1Hbenzo[ d]imidazol-2-amine in ionic liquid of [bmim⁺][BF ₄^- ]. This protocol has the advantages of easier work-up, mild reaction conditions, high yields, and an environmentally benign procedure compared with the reported methods.

Full text of DOI:10.1002/jhet.215

26
Three-Component Synthesis of 4-Aryl-1H-pyrimido[1,2-a]
Benzimidazole Derivatives in Ionic Liquid
Vol 47
Changsheng Yao,a,b Song Lei,a,b Cuihua Wang,a,b Tuanjie Li,a,b Chenxia Yu,a,b
Xiangshan Wang,a,b and Shujiang Tua,b
*
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China
bKey Laboratory of Biotechnology on Medical Plant, Xuzhou Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China
*E-mail: laotu2001@263.net
Received March 31, 2009
DOI 10.1002/jhet.215
Published online 21 December 2009 in Wiley InterScience (www.interscience.wiley.com).
A green and simple synthesis of 4-ayrl-3,4-dihydro-1H-pyrimido[1,2-a]benzimidazole derivatives was
accomplished in excellent yields via the reaction oþf aryl aldehyde, 1,3-dicarbonyl compounds and 1H-
benzo[d]imidazol-2-amine in ionic liquid of [bmim ][BFꢀ4 ]. This protocol has the advantages of easier
work-up, mild reaction conditions, high yields, and an environmentally benign procedure compared with
the reported methods.
J. Heterocyclic Chem., 47, 26 (2010).
INTRODUCTION
yields. Therefore, the development of simple, convenient,
and environmentally benign approaches for the synthesis
of these compounds is still desirable.
The small organic molecules, such as, the fused nitro-
gen-containing heterocycles receive a large amount of
attention in the literature due to their exciting biological
properties and their roles as pharmacophores of consid-
erable historical importance. For example, the deriva-
tives of pyrimido[1,2-a]benzimidazol-2-one can be used
as inhibitor of cell proliferation [1], lymphocyte specific
kinase [2], DNA-topoisomerase I [3], and protein kinase
[4]. Hence, the preparation of this important heterocyclic
core unit has gained much importance. However, only
one method reported to synthesize these compounds was
via the reaction of a, b-unsaturated esters, which could
be prepared via the condensation reaction, with 1H-benzo
[d]imidazol-2-amine in the presence of organic solvents
or under solvent-free conditions at high temperature [5–
9]. Furthermore, most of the synthetic protocols in litera-
ture so far have many drawbacks, including prolonged
reaction time, drastic reaction conditions, the use of some
toxic organic solvents, such as, nitrobenzene, and low
A multicomponent reaction (MCR) can create highly
complex molecules from readily available starting mate-
rials without the complicated purification operations;
thus, MCRs are resource- and time-effective and eco-
nomically favorable processes in diversity generation
[10–13]. Recently, there have been tremendous develop-
ment in three- and four-component reactions and great
efforts continue to be made to develop new MCRs [14–
19]. Besides, the ionic liquids have been widely used as
environmentally benign reaction media in organic syn-
thesis because of their unique properties of nonvolatility,
nonflammability, and recyclability. Many organic reac-
tions, including MCRs, were carried out efficiently in
ionic liquids [20–28]. To continue our work on the syn-
thesis of heterocyclic compounds via MCR in ionic
liquids [29–31], we report herein the three-component
synthesis of 4-aryl-3,4-dihydro-1H-pyrimido[1,2-a]ben-
zimidazol-2-one in ionic liquid (Scheme 1).
C
V
2009 HeteroCorporation

January 2010
Three-Component Synthesis of 4-Aryl-1H-pyrimido[1,2-a]benzimidazole
Derivatives in Ionic Liquid
27
Scheme 1
Table 2
Temperature optimization for the synthesis of 4a.
Entry
Temperature (ꢁC)
Time (h)
Yield (%)
1
2
3
4
5
6
20
40
10
9
75
80
86
88
90
85
60
80
8
7
90
100
6
6
RESULTS AND DISCUSSION
The effect of solvent on the reaction was initially
examined by reacting phenyl aldehyde (1 mmol), 2,2-di-
methyl-1,3-dioxane-4,6-dione (1 mmol), and 1H-benzo
[d]imidazol-2-amine (1 mmol) at room temperature. The
results in Table 1 show that only in ionic liquids the
expected product 4a was given with moderate yield
(60–75%) by the three-component reaction. Further-
more, the reaction accomplished in [bmimþ][BF4ꢀ]
exhibited higher yield (75%) than other counterparts.
Thereforeþ, we carried out the three-component reaction
in [bmim ][BFꢀ4 ] to synthesize the desired products.
To find the optimal reaction temperature, the synthe-
sis of (4a) was studied at different temperatures. The
results are summarized in Table 2. As shown in Table
2, the reaction at 90ꢁC proceeded in highest yield
among the six reaction temperatures tested. Therefore,
90ꢁC was chosen for this reaction.
clude that the electronic nature of substituents of the ar-
omatic aldehyde had no significant effect on the reac-
tion. Even the heterocyclic aldehyde could be used in
this reaction (4h). However, when the aliphatic aldehyde
was applied to this reaction, no expected product was
obtained.
All of the compounds were characterized by
1
HRMS(ESI), FTIR, and H NMR. To further elucidate
the structure of products, a single crystal of compound
4a was prepared and its structure was determined by X-
ray diffraction (Fig. 1).
The recovery and reuse of solvent and/or catalyst are
highly preferable in terms of green synthetic process.
Therefore, with the success of the above reactions, we
continued our research by studying the reuse of the sol-
vent. It turned out that the recovery and reuse of
[bmimþ][BFꢀ4 ] is not only convenient but also efficient.
Thus, at completion monitored by TLC, the reaction
mixture was cooled to room temperature and poured
into water. The solid product was collected by filtration
and recrystallized from ethanol to give the pure product.
The filtrate was washed with acetic ester, concentrated
under reduced pressure, and dried in vacuo at 100ꢁC for
several hours to give the reusable solvent. Studies by
using phenyl aldehyde, 2,2-dimethyl-1,3-dioxane-4,6-
dione and 1H-benzo[d]imidazol-2-amine as model sub-
strates shows that the recovered solvent could be succes-
sively recycled in subsequent reactions without almost
Based on the optimized reaction conditions, a series
of 4-aryl-3,4-dihydro-1H-pyrimido[1,2-a]benzimidazol-
2-one were synthesized. The results, summarized in
Table 3, show that the three-component reaction in
[bmimþ][BFꢀ4 ] gave the corresponding products in mod-
erate to good yields. This methodology can be applied
to aromatic aldehydes either with electron-withdrawing
groups (such as, a nitro group, halogen) or electron-
donating groups (such as, a methoxy) with excellent
yields under the same conditions. Therefore, we con-
Table 1
Solvent effect on the synthesis of 4a.
Table 3
Synthesis of 4 in ionic liquid ([bmim1][BF4ꢀ]).
Entry
Solventa
Temperature (ꢁC) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
[bypþþ][Brꢀ]
[byp ][BFꢀ4 ]
[bmimþþ][Brꢀ]
[bmim ][BFꢀ4 ]
Ethanol
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
10
10
10
10
10
12
12
12
15
60
62
70
75
Compound
no.
Time Yield
(h) (%)
R1
M.p. (ꢁC)
4a
C6H5
7
90
291–293
(ref. 32, 289–290)
294–296
Trace
Trace
Trace
Trace
Trace
CH3CN
4b
4c
4d
4e
4f
4-BrC6H4
3,4,5-(OCH3)3C6H2
3-NO2C6H4
2-FC6H4
3,4-(OCH2O)C6H3
4-NO2C6H4
7
8
8
7
8
8
85
82
85
88
83
82
CH3COOH
CHCl3
H2O
273–275
283–285
284–285
236–238
>300
(ref. 6, >300)
285–287
a [bypþ][Brꢀ], 1-butylpyridinium bromide; [bypþ][BFꢀ4 ], 1-butylpyridi-
nium tetrafluoroborate;þ[bmimþ][Brꢀ], 3-butyl-1-methyl-1H-imidazol-
3-ium bromide; [bmim ] [BFꢀ4 ], 3-butyl-1-methyl-1H-imidazol-3-ium
tetrafluoroborate.
4g
4h
2-SC4H3
7
80
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

28
C. Yao, S. Lei, C. Wang, T. Li, C. Yu, X. Wang, and S. Tu
Vol 47
Scheme 2
Figure 1. The crystal structure of 4a.
any decrease in its efficiency. The results of the reuse of
the ionic liquid are summarized in Table 4. Even in the
fourth round, the yield of the product 4a is fairly high.
A plausible mechanism of the reaction was presented
in Scheme 2. Product 4 may be synthesized via sequen-
tial Knoevenagel condensation, Michael addition, cycli-
zation, and elimination mechanism (Scheme 2). The
condensation between aldehyde and Meldrum’s acid
gave 5-arylidene substituted Meldrum’s acid 5. Michael
addition between 5 and 1H-benzo[d]imidazol-2-amine 3
then furnished the intermediate 6, which isomerized to
7. After that, intramolecular cyclization of 7 gave 8,
which finally afforded 4 by loosing acetone and carbon
dioxide.
synthesizing
4-aryl-1H-pyrimido[1,2-a]benzimidazole
derivatives in ionic liquid medium [bmimþ][BF4ꢀ].
Meanwhile, the ionic liquid was chosen as a kind of
green solvent, which could be reused for several rounds
without significant loss of activity.
EXPERIMENTAL
Common reagents and materials were purchased from com-
mercial sources and purified by recrystallization or distillation.
NMR spectra were recorded on a Bruker DPX 400; data for
1H are reported as follows: chemical shift (ppm), integration,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet; and br, broad), coupling constant (Hz), and number.
Infrared (IR) spectra were recorded on a TENSOR 27 spectro-
photometer in KBr pellet and are reported in terms of fre-
quency of absorption (cmꢀ1). HRMS (ESI) were determined
by using micrOTOF-QIIHRMS/MS instrument (BRUKER).
Melting points were determined in open capillaries and are
uncorrected. The single crystal diffraction data were gathered
on a Rigaku Saturn diffractometer.
To test the proposed reaction pathway, compound 5a
was synthesized in [bmimþ][BF4ꢀ] and it could react
with 3 smoothly and gave product 4a with yield similar
to the three-component reaction in ionic liquid. The fact
supported the supposed reaction mechanism.
To extend the scope of this protocol for the synthesis
of the derivatives of pyrimido[1,2-a]benzimidazole,
other cyclic 1,3-dicarbonyl compounds (Scheme 3) and
acyclic 1,3-dicarbonyl compounds (Scheme 4) were
applied in the three-component synthesis as the surro-
gates of 2,2-dimethyl-1,3-dioxane-4,6-dione. The results,
listed in Tables 5 and 6, show that these three-compo-
nent reactions in ionic liquid gave the desired products,
10 and 12, successfully.
General procedure for the synthesis of 4-Aryl-1H-pyri-
mido[1,2-a]benzimidazol derivatives. Aryl aldehyde 1 (1.0
mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione
2
3
(0.14 g, 1.0
(0.13 g, 1.0
mmol), and 1H-benzo[d]imidazol-2-amine
mmol) were mixed in 3 mL [bmimþ][BF4ꢀ]. Then, the mixture
was stirred for a certain time (monitored by TLC) at 90ꢁC.
The result mixture was cooled to room temperature and poured
into 20 mL of water. The solid product was collected by
In summary, we have developed an efficient, econom-
ical, safe, and environmentally benign procedure for
Scheme 3
Table 4
Study on the reuse of ionic liquid ([bmim1][BF4ꢀ]).
Round
1
2
3
4
4a Yield (%)
90
88
87
87
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Three-Component Synthesis of 4-Aryl-1H-pyrimido[1,2-a]benzimidazole
Derivatives in Ionic Liquid
29
Scheme 4
4-(3-Nitrophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-
a]pyrimidin-2-one (4d). IR (potassium bromide): 3065, 2866,
2729, 1696, 1637, 1586, 1532, 1506, 1458, 1351, 1284, 1246,
1161, 1130, 1085, 921, 873, 813, 731 cmꢀ1
;
1H NMR
(DMSO-d6): d 11.82 (s, 1H, NH), 8.20 (d, J ¼ 8.0 Hz, 1H,
ArH), 8.02 (s, 1H, ArH), 7.70–7.66 (m, 1H, ArH), 7.50 (d, J
¼ 4.0 Hz, 2H, ArH), 7.13–7.05 (m, 3H, ArH), 6.17 (dd, J1 ¼
3.2 Hz, J2 ¼ 7.2 Hz, 1H, CH), 3.57 (dd, J1 ¼ 7.2 Hz, J2
¼
16.4 Hz, 1H, CH2), 3.03 (dd, J1 ¼ 3.2 Hz, J2 ¼ 16.4 Hz, 1H,
CH2). HRMS (ESI): m/z cal. for: 309.0983 [MþH]þ, found:
309.0985.
filtration and recrystallized from ethanol to give the pure com-
pound 4. The filtrate was washed with acetic ester for several
times, concentrated under reduced pressure, and dried in vacuo
at 100ꢁC for several hours to give the reusable solvent. A sim-
ilar procedure was used in preparing the following compounds
10 and 12.
4-(2-Fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-
a]pyrimidin-2-one (4e). IR (potassium bromide): 3061, 3006,
2923, 2864, 2702, 1687, 1637, 1584, 1486, 1456, 1423, 1377,
1354, 1311, 1286, 1244, 1226, 1160, 1095, 898, 762, 746
cmꢀ1 1H NMR (DMSO-d6): d 11.77 (s, 1H, NH), 7.48 (d, J
;
¼ 8.0 Hz, 1H, ArH), 7.40–7.30 (m, 2H, ArH), 7.13–7.04 (m,
4H, ArH), 6.68 (t, J ¼ 7.6 Hz, 1H, ArH), 6.17 (dd, J1 ¼ 2.8
Hz, J2 ¼ 7.6 Hz, 1H, CH), 3.60 (dd, J1 ¼ 7.6 Hz, J2 ¼ 16.4
Hz, 1H, CH2), 2.86 (dd, J1 ¼ 2.8 Hz, J2 ¼ 16.4 Hz, 1H,
CH2). HRMS (ESI): m/z cal. for: 282.1037 [MþH]þ, found:
282.1034.
4-Phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrimi-
din-2-one (4a). IR (potassium bromide): 3059, 3034, 2912,
1730, 1649, 1590, 1458, 1363, 1323, 1287, 1245, 1168, 926,
890, 766, 743, 700 cmꢀ1 1H NMR (DMSO-d6): dd11.66 (s,
;
1H, NH), 7.83 (d, J ¼ 8.0 Hz, 1H, ArH), 7.46–7.40 (m, 2H,
ArH), 7.35–7.32 (m, 3H, ArH), 7.08–7.03 (m, 3H, ArH), 5.94
(q, J ¼ 4.0 Hz, 1H, CH), 3.52 (dd, J1 ¼ 8.0 Hz, J2 ¼ 16.0
Hz, 1H, CH2), 2.94 (dd, J1 ¼ 3.2 Hz, J2 ¼ 16.4 Hz, 1H,
CH2). HRMS (ESI): m/z cal. for: 264.1131 [MþH]þ, found:
264.1132.
4-Benzo[1,3]dioxol-5-yl-3,4-dihydro-1H-benzo[4,5]imidazo
[1,2-a]pyrimidin-2-one (4f). IR (potassium bromide): 3051,
2888, 2725, 1686, 1639, 1585, 1504, 1490, 1456, 1445, 1350,
1
1241, 1037, 931, 891, 810, 728 cmꢀ1; H NMR (DMSO-d6): d
11.67 (s, 1H, NH), 7.46 (d, J ¼ 8.0 Hz, 1H, ArH), 7.11–7.09
(m, 1H, ArH), 7.03 (d, J ¼ 8.0 Hz, 2H, ArH), 6.86 (d, J ¼ 8.0
Hz, 1H, ArH), 6.77 (s, 1H, ArH), 6.50 (q, J ¼ 4.0 Hz, 1H,
ArH), 6.00 (s, 2H, OCH2O), 5.82 (dd, J1 ¼ 3.6 Hz, J2 ¼ 6.8
Hz, 1H, CH), 3.42 (dd, J1 ¼ 6.8 Hz, J2 ¼ 16.4 Hz, 1H, CH2),
2.94 (dd, J1 ¼ 3.6 Hz, J2 ¼ 16.4 Hz, 1H, CH2). HRMS (ESI):
m/z cal. for: 308.1029 [MþH]þ, found: 308.1029.
4-(4-Bromophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-
a]pyrimidin-2-one (4b). IR (potassium bromide): 3054, 2996,
2929, 2849, 2698, 1694, 1634, 1583, 1505, 1455, 1420, 1359,
1324, 1263, 1239, 1150, 1076, 1010, 974, 894, 843, 817, 759,
741, 677 cmꢀ1
;
1H NMR (DMSO-d6): d 11.74 (s, 1H, NH),
7.56 (d, J ¼ 7.2 Hz, 2H, ArH), 7.47 (d, J ¼ 8.0 Hz, 1H,
ArH), 7.10–7.02 (m, 5H, ArH), 6.00 (dd, J1 ¼ 3.2 Hz, J2
¼
4-(4-Nitrophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-
a]pyrimidin-2-one (4g). IR (potassium bromide): 3050, 2859,
2750, 1702, 1636, 1584, 1524, 1486, 1456, 1412, 1346, 1318,
7.2 Hz, 1H, CH), 3.54 (dd, J1 ¼ 7.2 Hz, J2 ¼ 16.4 Hz, 1H,
CH2), 2.93 (dd, J1 ¼ 3.2 Hz, J2 ¼ 16.4 Hz, 1H, CH2). HRMS
(ESI): m/z cal. for: 342.0237 [MþH]þ, found: 342.0252.
4-(3,4,5-Trimethoxyphenyl)-3,4-dihydro-1H-benzo[4,5]imi-
dazo[1,2-a]pyrimidin-2-one (4c). IR (potassium bromide):
2939, 2846, 2761, 1704, 1633, 1594, 1509, 1460, 1427, 1343,
1331, 1283, 1241, 1129, 1143, 1002, 898, 847, 823, 766, 744,
1286, 1246, 1105, 965, 927, 896, 851, 741, 698 cmꢀ1 1H
;
NMR (DMSO-d6): d 11.82 (s, 1H, NH), 8.22 (d, J ¼ 8.0 Hz,
2H, ArH), 7.50 (d, J ¼ 8.0 Hz, 1H, ArH), 7.33 (d, J ¼ 8.0
Hz, 2H, ArH), 7.14 (d, J ¼ 7.6 Hz, 2H, ArH), 7.05 (d, J ¼
7.6 Hz, 1H, ArH), 6.17 (dd, J1 ¼ 2.4 Hz, J2 ¼ 7.2 Hz, 1H,
CH), 3.60 (dd, J1 ¼ 7.2 Hz, J2 ¼ 16.4 Hz, 1H, CH2), 3.00
(dd, J1 ¼ 2.4 Hz, J2 ¼ 16.4 Hz, 1H, CH2). HRMS (ESI): m/z
cal. for: 309.0982 [MþH]þ, found: 309.0985.
689 cmꢀ1 1H NMR (DMSO-d6): d 11.76 (s, 1H, NH), 7.45
;
(d, J ¼ 8.0 Hz, 1H, ArH), 7.20–6.98 (m, 3H, ArH), 6.50–6.46
(m, 2H, ArH), 5.80 (dd, J1 ¼ 4.4 Hz, J2 ¼ 6.8 Hz, 1H, CH),
3.65 (s, 6H, 2 ꢂ OCH3), 3.63 (s, 3H, OCH3), 3.40 (dd, J1 ¼
6.8 Hz, J2 ¼ 16.4 Hz, 1H, CH2), 3.03 (dd, J1 ¼ 4.4 Hz, J2 ¼
16.4 Hz, 1H, CH2). HRMS (ESI): m/z cal. for: 354.1448
[MþH]þ, found: 354.1439.
4-Thiophen-2-yl-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyr-
imidin-2-one (4h). IR (potassium bromide): 3098, 2996, 2848,
2696, 1699, 1634, 1602, 1587, 1504, 1456, 1410, 1368, 1343,
Table 5
Synthesis of 10 in ionic liquid ([bmim1][BF4ꢀ]).
Compound no.
R1
R2
Time (h)
Yield (%)
M.p. (ꢁC)
10a
10b
10c
10d
10e
10f
C6H5
3-NO2C6H4
3-BrC6H4
H
H
H
7
6
7
7
7
7
6
7
85
82
83
84
86
85
84
83
291–293 (ref. 33, >300)
289–291 (ref. 33, >300)
>300 (ref. 33, >300)
293–295 (ref. 33, >300)
>300 (ref. 34, 368)
294–296 (ref. 33, >300)
294–296 (ref. 33, >300)
>300 (ref. 34, 389)
4-CH3C6H4
C6H5
H
CH3
CH3
CH3
CH3
3,4-(OCH2O)C6H3
3-BrC6H4
4-OCH3C6H4
10g
10h
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

30
C. Yao, S. Lei, C. Wang, T. Li, C. Yu, X. Wang, and S. Tu
Vol 47
Table 6
Synthesis of 12 in ionic liquid ([bmim1][BF4ꢀ]).
Compound no.
R1
R3
Time (h)
Yield (%)
M.p. (ꢁC)
12a
12b
12c
12d
12e
12f
C6H5
3-NO2C6H4
4-OCH3C6H4
4-FC6H4
CH3
CH3
6
5
6
7
6
6
6
6
80
82
83
84
83
84
82
86
294–296 (ref. 35, >300)
287–289 (ref. 35, 290–292)
286–288 (ref. 35, 279–282)
>300 (ref. 35, >300)
294–296 (ref. 35, 294–297)
>300 (ref. 35, >300)
>300 (ref. 35, >300)
CH3
CH3
C6H5
OC2H5
OC2H5
OC2H5
OC2H5
4-NO2C6H4
4-BrC6H4
4-FC6H4
12g
12h
>300 (ref. 35, >300)
1295, 1263, 1235, 1154, 1013, 974, 894, 843, 720 cmꢀ1 1H
;
8,8-Dimethyl-5-phenyl-5,8,9,10-tetrahydro-7H-4b,10,11-tri-
aza-benzo[b]fluoren-6-one (10e). IR (potassium bromide):
NMR (DMSO-d6): d 11.72 (s, 1H, NH), 7.44 (t, J ¼ 7.6 Hz,
2H, ArH), 7.34–7.36 (m, 1H, thiophene-H), 7.12–7.09 (m, 2H,
ArH), 6.99–6.94 (m, 2H, thiophene-H), 6.28 (dd, J1 ¼ 2.0 Hz,
J2 ¼ 6.8 Hz, 1H, CH), 3.58 (dd, J1 ¼ 6.8 Hz, J2 ¼ 16.4 Hz,
1H, CH2), 3.00 (dd, J1 ¼ 2.0 Hz, J2 ¼ 16.4 Hz, 1H, CH2).
HRMS (ESI): m/z cal. for: 270.0696 [MþH]þ, found:
270.0709.
3228, 2956, 1658, 1106, 891, 838, 759 cmꢀ1 1H NMR
;
(DMSO-d6): d 11.13 (s, 1H, NH), 7.38–7.33 (m, 3H, ArH),
7.28–7.23 (m, 3H, ArH), 7.18–7.14 (m, 1H, ArH), 7.05 (t, J ¼
8.0 Hz, 1H, ArH), 6.96 (t, J ¼ 7.6 Hz, 1H, ArH), 6.42 (s, 1H,
CH), 2.67–2.50 (m, 2H, CH2), 2.29–2.04 (m, 2H, CH2), 1.06
(s, 3H, CH3), 0.93 (s, 3H, CH3). HRMS (ESI): m/z cal. for:
344.1757 [MþH]þ, found: 344.1786.
5-Phenyl-5,8,9,10-tetrahydro-7H-4b,10,11-triaza-benzo[b]
fluoren-6-one (10a). IR (potassium bromide): 3226, 3029,
5-Benzo[1,3]dioxol-5-yl-8,8-dimethyl-5,8,9,10-tetrahydro-7H-
4b,10,11-triaza-benzo[b]fluoren-6-one (10f). IR (potassium
1
2957, 1653, 885, 749 cmꢀ1; H NMR (DMSO-d6): d 11.10 (s,
bromide): 3228, 3095, 2966, 1644, 850, 791 cmꢀ1 1H
;
1H, NH), 7.38–7.31 (m, 3H, ArH), 7.25–7.22 (m, 3H, ArH),
7.15 (t, J ¼ 7.6 Hz, 1H, ArH), 7.04 (t, J ¼ 7.6 Hz, 1H, ArH),
6.95 (t, J ¼ 7.6 Hz, 1H, ArH), 6.42 (s, 1H, CH), 2.74–2.70
(m, 2H, CH2), 2.32–2.20 (m, 2H, CH2), 2.00–1.86 (m, 2H,
CH2). HRMS (ESI): m/z cal. for: 316.1444 [MþH]þ, found:
316.1459.
NMR (DMSO-d6): d 11.09 (s, 1H, NH), 7.38–7.31 (m, 2H,
ArH), 7.06 (t, J ¼ 7.2 Hz, 1H, ArH), 6.98 (t, J ¼ 7.6 Hz,
1H, ArH), 6.89 (s, 1H, ArH), 6.82–6.76 (m, 2H, ArH), 6.35
(s, 1H, CH), 5.93 (s, 2H, OCH2O), 2.64–2.53 (m, 2H, CH2),
2.28–2.06 (m, 2H, CH2), 1.06 (s, 3H, CH3), 0.96 (s, 3H,
CH3). HRMS (ESI): m/z cal. for: 388.1656 [MþH]þ, found:
388.1685.
5-(3-Nitrophenyl)-5,8,9,10-tetrahydro-7H-4b,10,11-triaza-
benzo[b]fluoren-6-one (10b). IR (potassium bromide): 3220,
1
3040, 2950, 1652, 1514, 1020, 744 cmꢀ1; H NMR (DMSO-
5-(3-Bromophenyl)-8,8-dimethyl-5,8,9,10-tetrahydro-7H-4b,10,
11-triaza-benzo[b]fluoren-6-one (10g). IR (potassium bromide):
d6): d 11.30 (s, 1H, NH), 8.27 (s, 1H, ArH), 8.04 (d, J ¼ 8.4
Hz, 1H, ArH), 7.70 (d, J ¼ 7.6 Hz, 1H, ArH), 7.55 (t, J ¼
8.0 Hz, 1H, ArH), 7.40 (d, J ¼ 7.6 Hz, 1H, ArH), 7.27 (d, J
¼ 7.6 Hz, 1H, ArH), 7.06 (t, J ¼ 7.2 Hz, 1H, ArH), 6.96 (t,
J ¼ 7.6 Hz, 1H, ArH), 6.67 (s, 1H, CH), 2.73–2.70 (m, 2H,
CH2), 2.36–2.19 (m, 2H, CH2), 1.99–1.85 (m, 2H, CH2).
HRMS (ESI): m/z cal. for: 361.1295 [MþH]þ, found:
361.1298.
3222, 3048, 2944, 1650, 887, 743 cmꢀ1 1H NMR (DMSO-
;
d6): d 11.17 (s, 1H, NH), 7.61 (s, 1H, ArH), 7.38 (t, J ¼ 8.0
Hz, 2H, ArH), 7.31–6.98 (m, 3H, ArH), 7.08 (t, J ¼ 7.6 Hz,
1H, ArH), 7.00 (t, J ¼ 7.6 Hz, 1H, ArH), 6.46 (s, 1H, CH),
2.66–2.50 (m, 2H, CH2), 2.29–2.07 (m, 2H, CH2), 1.07 (s, 3H,
CH3), 0.94 (s, 3H, CH3). HRMS (ESI): m/z cal. for: 422.0845
[MþH]þ, found: 422.0851.
5-(3-Bromophenyl)-5,8,9,10-tetrahydro-7H-4b,10,11-triaza-
benzo[b]fluoren-6-one (10c). IR (potassium bromide): 3220,
5-(4-Methoxyphenyl)-8,8-dimethyl-5,8,9,10-tetrahydro-7H-4b,
10,11-triaza-benzo[b]fluoren-6-one (10h). IR (potassium bro-
3048, 2891, 1647, 1571, 996, 890 cmꢀ1
;
1H NMR (DMSO-
mide): 3231, 3099, 2957, 2866, 1645, 838, 737 cmꢀ1 1H
;
d6): d 11.16 (s, 1H, NH), 7.55 (s, 1H, ArH), 7.36–7.31 (m,
2H, ArH), 7.24–7.13 (m, 3H, ArH), 7.02 (t, J ¼ 7.6 Hz, 1H,
ArH), 6.94 (t, J ¼ 7.6 Hz, 1H, ArH), 6.41 (s, 1H, CH), 2.66–
2.63 (m, 2H, CH2), 2.28–2.18 (m, 2H, CH2), 1.95–1.80 (m,
2H, CH2). HRMS (ESI): m/z cal. for: 394.0531 [MþH]þ,
found: 394.0558.
NMR (DMSO-d6): d 11.08 (s, 1H, NH), 7.36 (d, J ¼ 7.6 Hz,
1H, ArH), 7.28–7.24 (m, 3H, ArH), 7.04 (t, J ¼ 7.6 Hz, 1H,
ArH), 6.96 (t, J ¼ 8.0 Hz, 1H, ArH), 6.76 (d, J ¼ 8.4 Hz, 2H,
ArH), 6.36 (s, 1H, CH), 3.66 (s, 3H, OCH3), 2.65–2.51 (m,
2H, CH2), 2.28–2.03 (m, 2H, CH2), 1.06 (s, 3H, CH3), 0.95 (s,
3H, CH3 ). HRMS (ESI): m/z cal. for: 374.1863 [MþH]þ,
found: 374.1853.
5-p-Tolyl-5,8,9,10-tetrahydro-7H-4b,10,11-triaza-benzo[b]
fluoren-6-one (10d). IR (potassium bromide): 3224, 3038,
1-(2-Methyl-4-phenyl-1,4-dihydro-benzo[4,5]imidazo[1,2-
a]pyrimidin-3-yl)-ethanone (12a). IR (potassium bromide):
2950, 1645, 1514, 977, 829 cmꢀ1 1H NMR (DMSO-d6): d
;
11.04 (s, 1H, NH), 7.31 (d, J ¼ 7.6 Hz, 1H, ArH), 7.20–7.14
(m, 3H, ArH), 7.01–6.98 (m, 3H, ArH), 6.90 (t, J ¼ 7.6 Hz,
1H, ArH), 6.33 (s, 1H, CH), 2.65–2.61 (m, 2H, CH2), 2.29–
2.19 (m, 2H, CH2), 2.17 (s, 3H, CH3), 1.93–1.80 (m, 2H,
CH2). HRMS (ESI): m/z cal. for: 330.1601 [MþH]þ, found:
330.1637.
3273, 3103, 3053, 1645, 1536, 1471, 1292, 1158, 806 cmꢀ1
;
1H NMR (DMSO-d6): d 10.83 (s, 1H, NH), 7.42 (d, J ¼ 8.0
Hz, 3H, ArH), 7.35–7.26 (m, 3H, ArH), 7.20–7.16 (m, 1H,
ArH), 7.06–6.95 (m, 2H, ArH), 6.60 (s, 1H, CH), 2.49 (s, 3H,
CH3), 2.23 (s, 3H, CH3). HRMS (ESI): m/z cal. for: 304.1444
[MþH]þ, found: 304.1471.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Three-Component Synthesis of 4-Aryl-1H-pyrimido[1,2-a]benzimidazole
Derivatives in Ionic Liquid
31
Hz, 1H, ArH), 7.28 (d, J ¼7.6 Hz, 1H, ArH), 7.12–7.03 (m,
3H, ArH), 6.96 (t, J ¼ 7.6 Hz, 1H, ArH), 6.46 (s, 1H, CH),
4.02 (q, J ¼ 7.2 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 1.15 (t, J ¼
7.2 Hz, 3H, CH3). HRMS (ESI): m/z cal. for: 352.1456
[MþH]þ, found: 352.1486.
1-[2-Methyl-4-(3-nitrophenyl)-1,4-dihydro-benzo[4,5] imi-
dazo[1,2-a]pyrimidin-3-yl]-ethanone (12b). IR (potassium bro-
mide): 3215, 3087, 2881, 1649, 1560, 1458, 1267, 1059, 959,
888, 737, 690 cmꢀ1 1H NMR (DMSO-d6): d 11.01 (s, 1H,
;
NH), 8.28 (s, 1H, ArH), 8.05 (d, J ¼ 8.0 Hz, 1H, ArH), 7.81
(d, J ¼ 8.0 Hz, 1H, ArH), 7.58 (t, J ¼ 7.6 Hz, 1H, ArH), 7.45
(d, J ¼ 8.0 Hz, 1H, ArH), 7.37 (d, J ¼ 8.0 Hz, 1H, ArH),
7.06 (t, J ¼ 7.2 Hz, 1H, ArH), 6.99 (t, J ¼ 7.6 Hz, 1H, ArH),
6.77 (s, 1H, CH), 2.53 (s, 3H, CH3), 2.30 (s, 3H, CH3). HRMS
(ESI): m/z cal. for: 349.1295 [MþH]þ, found: 349.1326.
Acknowledgments. We are thankful to the National Natural
Science Foundation of China (No. 20672090), the Nature Science
Foundation of the Jiangsu Province (No. BK2006033), Six Kinds
of Professional Elite Foundation of the Jiangsu Province (No. 06-
A-039), and the Natural Science Foundation of Xuzhou City (No.
XJ07065) for financial support.
1-[4-(4-Methoxyphenyl)-2-methyl-1,4-dihydro-benzo[4,5]imi-
dazo[1,2-a]pyrimidin-3-yl]-ethanone (12c). IR (potassium bro-
mide): 3227, 3099, 3002, 2832, 1654, 1628, 1590, 1514, 1459,
1
1335, 1228, 958, 807, 744, 659 cmꢀ1; H NMR (DMSO-d6): d
10.75 (s, 1H, NH), 7.43 (d, J ¼ 8.0 Hz, 2H, ArH), 7.05–6.97 (m,
4H, ArH), 6.83 (d, J ¼ 8.0 Hz, 2H, ArH), 6.57 (s, 1H, CH), 3.67
(s, 3H, OCH3), 2.47 (s, 3H, CH3), 2.22 (s, 3H, CH3). HRMS
(ESI): m/z cal. for: 334.1550 [MþH]þ, found: 334.1565.
REFERENCES AND NOTES
[1] (a) Whitten, J. P.; Schwaebe, M. WO Pat. 2,008,060,693
(2008); (b) Whitten, J. P.; Schwaebe, M. Chem Abstr 2008, 148,
561911.
1-[4-(4-Fluorophenyl)-2-methyl-1,4-dihydro-benzo[4,5]imi-
dazo[1,2-a]pyrimidin-3-yl]-ethanone (12d). IR (potassium
bromide): 3227, 3100, 3022, 2914, 2840, 1653, 1627, 1565,
[2] Martin, M. W.; Newcomb, J.; Nunes, J. J.; Boucher, C.;
Chai, L.; Epstein, L. F.; Faust, T.; Flores, S.; Gallant, P.; Gore, A.;
Gu, Y.; Hsieh, F.; Huang, X.; Kim, J. L.; Middleton, S.; Morgenstern,
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1459, 1330, 1229, 1006, 954, 854, 747 cmꢀ1 1H NMR
;
(DMSO-d6): d 10.85 (s, 1H, NH), 7.48–7.42 (m, 3H, ArH),
7.35 (d, J ¼ 8.0 Hz, 1H, ArH), 7.12–6.98 (m, 4H, ArH), 6.62
(s, 1H, CH), 2.49 (s, 3H, CH3), 2.24 (s, 3H, CH3). HRMS
(ESI): m/z cal. for: 322.1350 [MþH]þ, found: 322.1389.
2-Methyl-4-phenyl-1,4-dihydro-benzo[4,5]imidazo[1,2-a]py-
rimidine-3-carboxylic acid ethyl ester (12e). IR (potassium
bromide): 3234, 3103, 3026, 2928, 2865, 1698, 1615, 1572,
[3] Zanatta, N.; Amaral, S. S.; Esteves-Souza, A.; Echevarria,
A.; Brondani, P. B.; Flores, D. C.; Bonacorso, H. G.; Flores, A. F. C.;
Martins, M. A. P. Synthesis 2006, 2305.
[4] (a) Nunes, J. J.; Zhu, X. T.; Ermann, M.; Ghiron, C.; John-
ston, D. N.; Saluste, C.-G. P. WO Pat. 2,005,021,551 (2005); (b)
Nunes, J. J.; Zhu, X. T.; Ermann, M.; Ghiron, C.; Johnston, D. N.; Sal-
uste, C.-G. P. Chem Abstr 2005, 142, 298123.
1
1365, 1255, 1092, 893, 794, 730 cmꢀ1; H NMR (DMSO-d6):
d 10.82 (s, 1H, NH), 7.35 (t, J ¼ 6.8 Hz, 3H, ArH), 7.27 (t, J
¼ 8.0 Hz, 3H, ArH), 7.20–7.16 (m, 1H, ArH), 7.04 (t, J ¼ 8.0
Hz, 1H, ArH), 6.95 (t, J ¼ 7.6 Hz, 1H, ArH), 6.43 (s, 1H,
CH), 4.02 (q, J ¼ 7.2 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 1.14
(t, J ¼ 7.2 Hz, 3H, CH3). HRMS (ESI): m/z cal. for: 334.1550
[MþH]þ, found: 334.1607.
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2-Methyl-4-(4-nitrophenyl)-1,4-dihydro-benzo[4,5]imidazo
[1,2-a]pyrimidine-3-carboxylic acid ethyl ester (12f). IR (po-
tassium bromide): 3234, 3105, 2978, 2861, 1697, 1619, 1572,
1
1518, 1458, 1235, 870, 755, 715, 608 cmꢀ1; H NMR (DMSO-
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d6): d 10.99 (s, 1H, NH), 8.15 (d, J ¼ 8.4 Hz, 2H, ArH), 7.66
(d, J ¼ 8.8 Hz, 2H, ArH), 7.37 (d, J ¼ 7.6 Hz, 1H, ArH), 7.28
(d, J ¼ 7.6 Hz, 1H, ArH), 7.06 (t, J ¼ 7.2 Hz, 1H, ArH), 6.96
(t, J ¼ 7.2 Hz, 1H, ArH), 6.62 (s, 1H, CH), 4.03 (q, J ¼ 7.2
Hz, 2H, CH2), 2.48 (s, 3H, CH3), 1.16 (t, J ¼ 7.2 Hz, 3H, CH3).
HRMS (ESI): m/z cal. for: 379.1401 [MþH]þ, found: 379.1422.
4-(4-Bromophenyl)-2-methyl-1,4-dihydro-benzo[4,5]imidazo
[1,2-a]pyrimidine-3-carboxylic acid ethyl ester (12g). IR (po-
tassium bromide): 3233, 3101, 3023, 2978, 2849, 1698, 1618,
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1
1571, 1487, 1385, 1234, 1010, 893, 801, 730 cmꢀ1; H NMR
(DMSO-d6): d 10.87 (s, 1H, NH), 7.47 (d, J ¼ 8.4 Hz, 2H,
ArH), 7.36–7.32 (m, 3H, ArH), 7.26 (d, J ¼ 8.0 Hz, 1H,
ArH), 7.06 (t, J ¼ 7.6 Hz, 1H, ArH), 6.96 (t, J ¼ 8.0 Hz, 1H,
ArH), 6.45 (s, 1H, CH), 4.02 (q, J ¼ 7.2 Hz, 2H, CH2), 2.46
(s, 3H, CH3), 1.16 (t, J ¼ 7.2 Hz, 3H, CH3). HRMS (ESI): m/
z cal. for: 412.0655 [MþH]þ, found: 412.0663.
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dazo[1,2-a]pyrimidine-3-carboxylic
(12h). IR (potassium bromide): 3235, 3039, 2929, 1697, 1617,
1458, 1303, 1096, 792, 637 cmꢀ1 1H NMR (DMSO-d6): d
10.84 (s, 1H, NH), 7.43–7.40 (m, 2H, ArH), 7.35 (d, J ¼ 8.0
acid
ethyl
ester
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

32
C. Yao, S. Lei, C. Wang, T. Li, C. Yu, X. Wang, and S. Tu
Vol 47
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[36] The single-crystal growth was carried out in ethanol at
room temperature. X-ray crystallographic analysis was performed
using a Rigaku Saturn diffractometer. Crystal data for 4a: C16H13N3O,
crystal dimension 0.18 mm ꢂ 0.16 mm ꢂ 0.12 mm, Orthorhombic,
[29] Wang, X. S.; Zhang, M. M.; Zeng, Z. S.; Shi, D. Q.; Tu,
S. J.; Wei, X. Y.; Zong, Z. M. J Heterocycl Chem 2008, 45, 71.
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X. Y.; Wang, X. S. J Heterocycl Chem 2008, 45, 653.
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X. Y.; Wang, X. S.; Ji, S. J. J Heterocycl Chem 2008, 45, 653.
˚
space group Pbca, a ¼ 13.606(3), b ¼ 7.5674(15), c ¼ 24.578(5) A, V
3
3
˚
¼ 2530.6(9) A , Mr ¼ 263.29, Z ¼ 8, Dc ¼ 1.382 g/cm , k ¼ 0.71073
A, l (Moka) ¼ 0.090 mmꢀ1, F(000) ¼ 1104, S ¼ 1.151, R1
¼
˚
0.0366, wR2 ¼ 0.0976.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet