Concise synthesis of 2, 3-diarylpyrimido[1,2-α]benzimidazole based on isoflavones

Article abstract of DOI:10.1021/cc900064q

The 2,3-diarylpyrimido[1,2-a]benzimidazole derivatives were prepared by one-step cyclocondensation of 2-aminobenzimidazole with isoflavone in methanol. Single-crystal diffraction analysis was performed for 2-(2-hydroxyl-4- isopropoxy-phenyl)-3-phenylpyrimido[1,2-a]benzimidazole. The fluorescence properties of the fused 2, 3-diarylpyrimido[1, 2-a]benzimidazole were evaluated.

Full text of DOI:10.1021/cc900064q

J. Comb. Chem. 2010, 12, 225–230
225
Concise Synthesis of 2, 3-Diarylpyrimido[1,2-a]benzimidazole Based
on Isoflavones
Zun-Ting Zhang,* Li Qiu, Dong Xue, Jing Wu, and Fei-Fei Xu
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical
Chemistry, National Engineering Laboratory for Resource DeVelopment of Endangered Crude Drugs in
Northwest of China, and School of Chemistry and Materials Science, Shaanxi Normal UniVersity, Xi’an
710062, P.R. China
ReceiVed April 21, 2009
The 2,3-diarylpyrimido[1,2-a]benzimidazole derivatives were prepared by one-step cyclocondensation of
2-aminobenzimidazole with isoflavone in methanol. Single-crystal diffraction analysis was performed for
2-(2-hydroxyl-4-isopropoxy-phenyl)-3-phenylpyrimido[1,2-a]benzimidazole. The fluorescence properties of
the fused 2, 3-diarylpyrimido[1, 2-a]benzimidazole were evaluated.
Introduction
tively. Herein, we report a new strategy for the preparation
of 2,3-diarylpyrimido[1,2-a]benzimidazole from isoflavones.
Polysubstituted pyrimido[1,2-a]benzimidazoles have bio-
logical properties such as antiparasitic,1 substance P receptor
binding activity,2 antibacterial drugs,3 antiarrhythmics,4
central nervous system-depressing agents,5 as well as marked
herbicidal activity.6 Meanwhile, the pyrimido[1,2-a]benz-
imidazoles possess fluorescence properties.7 The structural
feature of the pyrimido[1,2-a]benzimidazole nucleus are
similar to that of the purine ring system, and therefore, we
were interested in the synthesis of various substituted 2,3-
diarylpyrimido[1,2-a]benzimidazoles. The existing methods
for building up the pyrimido[1,2-a]benzimidazole core
involve the condensation of 2-aminobenzimidazole with (i)
acetylene esters;8 (ii) enamino esters;9 (iii) 1,3-diketone;3-5,10
(iv) R, ꢀ-unsaturated ketones;11 (v) R-halogenated ketones,12
and (vi) intramolecular condensation of N-(halophenyl)py-
rimidin-2-amine7 (Scheme 1). The common feature of
methods i-v is the use of 2-aminobenzimidazole 2 as the
starting materials. Method vi is an intramolecular condensa-
tion which needs a special molecular structure as N-(halophe-
nyl)pyrimidin-2-amine. Significantly, no syntheses of 2,3-
diarylpyrimido[1,2-a]benzimidazoles were reported in the
literature.
Results and Discussion
Reactions of 2-aminobenzimidazole 2 with isoflavones 1
were carried out in refluxing methanol in the presence of
sodium methoxide as base to promote the ring-opening of
isoflavone. Products 3 were obtained in moderate to excellent
yields after refluxing for 8-15 h (Scheme 2).
The choice of base was very important for the cyclocon-
densations of 2-aminobenzimidazole with isoflavone. It was
reported that isoflavone will undergo ring-opening when
refluxed in the presence of base forming an R,ꢀ-unsaturated
ketone intermediate 4 (Scheme 3).19 Subsequent, attack of
the primary amine group from the 2-aminobenzimidazole on
the ꢀ-carbon in 4, followed by a ring closure reaction
between the secondary amine and the carbonyl carbon to
produce 3. Meanwhile, intermediate 4 with a high concentra-
tion of base may eliminate methylorthofoemate to generate
the byproduct 6.19 To identify the optimal variety of the base
and its equivalency, a mixture of ipriflavone (2 mmol) and
2-aminobenzimidazole 2 (4 mmol) was refluxed in methanol.
Under different equivalency of NaOH and NaOMe, it was
found that that 3 equivalency of NaOMe gave the best results
(Table 1, Entry 5). In the cyclocondensations reaction,
sodium methoxide gave excellent yields, while sodium
hydroxide failed to give high yields or reasonable conversion,
probably because of the presence of water. In the presence
It was reported that the chromone fragment present in
isoflavones can generate a 1,3-diketone equivalent which
readily react with amidines,13 guanidine,14 sulfocarbamides,15
and hydrazine16 to form the corresponding 2-substituted
pyrimidines and diarylpyrazoles. Recently, we have reported
the high-throughput synthesis of 3,4-diarylpyrazoles and 4,5-
biphenyl-2-pyrimidinylguanidine by using a one-pot reaction
of hydrazine17 and bisguanidine18 with isoflavones, respec-
Table 1. Effects of Base and Its Amount on the Condensation
of Ipriflavone with 2-Aminobenzimidazole
entry
base
amount
yield(%)a
1
2
3
4
5
6
5 mol/L NaOH
5 mol/L NaOH
NaOMe
NaOMe
NaOMe
2.5 equiv
5 equiv
1 equiv
2 equiv
3 equiv
4 equiv
43
57
61
79
88
72
NaOMe
* To whom correspondence should be addressed. E-mail: zhangzt@
snnu.edu.cn. Phone: 86-29-85303940. Fax: 86-29-85303774.
a Recrystallized from EtOH.
10.1021/cc900064q  2010 American Chemical Society
Published on Web 12/30/2009

226 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Zhang et al.
Scheme 1. Methods for Building up the Pyrimido[1,2-a]benzimidazole Core
Scheme 2. Synthesis of 2,3-Diarylpyrimido[1,2-a]benzimidazole by the Cyclocondensations of 2-Aminobenzimidazole with
Isoflavone
Scheme 3. Proposed Mechanism for the Formation of 3 and Byproduct
of excess methoxide anions, attack of the methoxide anion
on the ꢀ-carbon in 4 can produce an orthoester intermediate,
which leads to byproduct 5. It would promote 4 the
conversion of 6 instead of 3. On the other hand, it is harder
to open the isoflavone ring and produce intermediate 4 under
the condition of lower concentration base.
In general isoflavone 1 substituted with alkoxy, benzyoxyl
groups gave high yields. In contrast, the presence of the

Synthesis of 2, 3-Diarylpyrimido[1,2-a]benzimidazole
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 227
Table 2. Synthesis of 2, 3-Diarylpyrimido[1,2-a]benzimidazole by the Reaction of Various Isoflavones with 2-Aminobenzimidazole at
65°C in MeOH and Their Isolated Yield (for Details, see Experimental Section)

228 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Table 2. Continued
Zhang et al.
a Recrystallized from EtOH. b Purified by silica gel column chromatography.
hydroxyl groups gave lower yields. As shown in the Table
2, isoflavones 1a, 1c, 1e, 1h, 1i, 1j, 1k, 1m, 1n, 1q, and 1r
(Table 2, Entries 1, 3, 5, 8-14 and 18) which do not contain
hydroxyl groups, gave yields of 3 of about 90%. Isoflavone
with one hydroxyl group, 1b, 1f, 1g, and 1o (Table 2, Entries
2, 6, 7 and 12) only gave yields of 3 of about 80% while
those with two free hydroxyls, 3d, 3l (Table 2, Entries 4
and 12) gave yields of roughly 70%. Condensation of
trihydroxy isoflavone genistein (4′,5,7-trihydroxy-isoflavone)
and irisolidone (4′,6-dimethoxy-5,7-dihydroxy-isoflavone)
with 2 failed to produce product 3. The yields of 3 are
directly dependent on the number of free hydroxyl groups
present on the engaged isoflavone. Because the hydroxyls
of isoflavone 1 under basic condition would be oxygen ions,
which possess stronger electron donability than alkoxy and
benzyoxyl groups of the isoflavone, it is not favorable to
the condensation reaction. Compounds 3 were characterized
by 1H and 13C NMR, HRMS, and IR, and the structure was
further unequivocally confirmed by single crystal X-ray
diffraction of 3a which adds sharp evidence for the proposed
structure (Figure 1).
The synthesized compound possesses excellent fluores-
cence property both in solution and solid. The fluorescence
spectra of 3a in the solution and solid are shown in Figure

Synthesis of 2, 3-Diarylpyrimido[1,2-a]benzimidazole
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 229
fluorescence with λem) 440-445 nm in the range of
390-470 nm when they are irradiated at 350 nm in ethanol.
The structural feature of molecules that fluoresce is that they
possess a first singlet excited state S1(π, π*) in a rigid and
conjugated system. The more rigid the structure and the more
conjugated its system, the stronger its fluorescence.20 That
the fused 2,3-diarylpyrimidine[1,2-a]benzimidazo 3 possesses
excellent property of fluorescence confirms that its structure
meets these requirements of rigidity and conjugation.
Conclusions
In summary, we have developed a useful method for the
construction of fused pyrimido[1,2-a]benzimidazole deriva-
tives by the cyclocondensation of 2-aminobenzimidazole with
isoflavone in methanol and the presence of 3 equiv of sodium
methoxide. It is an efficient and regioselective approach
towards the synthesis 2,3-disubstituted pyrimido[1,2-a]ben-
zimidazole. The yields of pyrimido[1,2-a]benzimidazole
derivatives are excellent, most between 68%-93%. Further-
more, 2,3-diarylpyrimido[1,2-a]benzimidazoles exhibit ex-
cellent fluorescence. When solids of 2,3-diarylpyrimido[1,2-
a]benzimidazoles are irradiated at 390 nm, they emit a green
fluorescence.
Figure 1. Single-Crystal X-ray structure of 3a.
Experimental Section
General Procedure. The corresponding isoflavones 1 (2
mmol), 2-aminobenzimidazole 2 (4 mmol), and sodium
methoxide (6 mmol) were refluxed in methanol (15 mL) for
8-15 h. All reactions were monitored by TLC, which
showed the disappearance of 1 that was indicative of the
reaction being complete. The reaction mixture was added
into water (30 mL) and adjusted to neutrality with a solution
of 5% HCl. A yellow precipitate appeared and was filtered.
The yellow precipitate was dissolved in a solution of 10%
HCl (10 mL) and filtered. The mother liquid was neutralized
with sodium hydroxide until crude product was completely
precipitated. The crude product was filtered and recrystallized
from ethanol or purified by column chromatography on silica
gel using chloroform-methanol (10:1) to give the corre-
sponding pure product.
2-(2-Hydroxyl-4-isopropoxyphenyl)-3-phenyl-pyrimi-
do[1,2-a]benzimidazole (Entry 3a, Table 2). Yellow solid,
M.p.: 289.3-289.7 °C. 1H NMR: 1.30 (s, 6H), 4.60 (t, 1H),
6.51 (s, 1H), 6.60 (d, 1H, J ) 8.4 Hz), 7.08 (t, 1H), 7.11 (s,
1H), 7.36 (m, 5H), 7.47 (t, 1H), 7.88 (d, 1H, J ) 8.1 Hz),
8.89 (s, 1H), 10.14 (s, 1H). 13C NMR: 21.7, 69.6, 103.1,
107.3, 110.6, 114.5, 119.3, 121.2, 121.6, 125.5, 127.4, 127.5,
127.8, 128.2, 129.6, 131.1, 134.7, 144.4, 144.7, 150.6, 157.1,
160.5. IR ν KBr max cm-1: 3419.5, 2959.6, 2924.8, 1599.8,
1489.6, 1448.9, 1387.9, 1349.7, 1254.9, 1175.9, 738.8.
HRMS (ESI-TOF, [M+H]+): calcd for C25H22N3O2, 396.1707;
found, 396.1718; λex/λem ) 372/501(solid); λex/λem ) 396/
512 (in ethanol, c ) 1 × 10-4 mol/L).
Figure 2. Fluorescence spectrum of 3a. (a) Fluorescence spectrum
of 3a in ethanol (c ) 1 × 10-4mol/L). (b) Fluorescence spectrum
of 3a as a solid.
Acknowledgment. This research was supported by the
National Natural Science Foundation of China (No: 20772076),
Science and Innovation Funds of Graduate Programs of
Shaanxi Normal University (No: 2008CXS029) and Science
2. We found that compounds 3 emit fluorescence with
λem ) 490-512 nm in the range of 450-550 nm when they
are irradiated at 390 nm in the solid state, and they emit

230 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Zhang et al.
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CC900064Q