Poly(ethyleneglycol): A versatile and recyclable reaction medium in gaining access to benzo[4,5]imidazo[1,2-a]pyrimidines under microwave heating

Article abstract of DOI:10.1002/jhet.132

(Chemical Equation Presented) Polyethylene glycol is found to be a nontoxic and recyclable reaction medium for the microwave-assisted, one-pot, multicomponent reactions of aromatic aldehydes with 2-aminobenzimidazole and 1,2-diphenylethanone in the presen

Full text of DOI:10.1002/jhet.132

664
Poly(ethyleneglycol): A Versatile and Recyclable Reaction
Medium in Gaining Access to Benzo[4,5]imidazo[1,
2-a]pyrimidines Under Microwave Heating
Vol 46
Shu-Liang Wang, Wen-Juan Hao, Shu-Jiang Tu,* Xiao-Hong Zhang, Xu-Dong
Cao, Shu Yan, Shan-Shan Wu, Zheng-Guo Han, and Feng Shi
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, Jiangsu,
221116, People’s Republic of China
*E-mail: laotu2001@263.net
Received March 10, 2009
DOI 10.1002/jhet.132
Published online 9 July 2009 in Wiley InterScience (www.interscience.wiley.com).
Polyethylene glycol is found to be a nontoxic and recyclable reaction medium for the microwave-
assisted, one-pot, multicomponent reactions of aromatic aldehydes with 2-aminobenzimidazole and
1,2-diphenylethanone in the presence of potassium carbonate. This environmentally friendly microwave
protocol offers ease of operation and enables recyclability of reaction media and synthesis of a variety
of substituted benzo[4,5]imidazo[1,2-a]pyrimidine derivatives. It is an efficient, promising, and green
synthetic strategy to construct benzo[4,5]imidazo[1,2-a]pyrimidine skeleton.
J. Heterocyclic Chem., 46, 664 (2009).
INTRODUCTION
homogeneous and allow molecular interactions to be
more efficient [6].
The search for alternative reaction media to replace
volatile and often toxic solvents commonly used in or-
ganic synthetic procedures is an important objective of
significant environmental consequence [1]. Media con-
sidered include (a) the use of supercritical fluids [2] that
have the advantage of facile solvent removal and easy
recyclability but require high pressure; (b) fluorous-
based systems [3] that have the advantage of being
highly hydrophobic but expensive and for which the sol-
vents are probably innocuous but have the disadvantage
of being volatile; (c) more recently, environmentally be-
nign solvents such as ionic liquids [4] and water [5].
Ionic liquids have a particularly useful set of properties,
being nonvolatile and readily dissolving many transition
metal catalysts but their preparation was not convenient,
and volatile organic solvents were also used for the
preparation. The use of water as solvent is probably the
most desirable approach, but this is often not possible
due to the hydrophobic nature of the reactants. It is cus-
tomary to measure the efficiency of a catalyst by the
number of cycles for which it can be reused. Similarly,
the value of a new solvent medium primarily depends
on its environmental impact, the ease with which it can
be recycled, low vapor pressure, nonflammability, and
high polarity for solubilization. In performing the major-
ity of organic transformations, solvents play an impor-
tant role in mixing the ingredients to make the system
Recently, using polyethylene glycol (PEG) as a green
reaction medium has become an important research area
[7]. In addition to be a safe, readily available, and envi-
ronmentally friendly solvent [8], PEG has also been rec-
ognized as an effective and recyclable reaction medium
with unique properties and potentials for many organic
reactions such as substitution, oxidation, and reduction.
Under microwave irradiation (MW), PEG is rapidly
heated to high temperature, enhancing molecular interac-
tions more efficiently. Thus, it is clear that the combined
approach of microwave superheating and PEG as a reac-
tion medium could be considered a promising and green
synthetic strategy for the construction of important het-
erocyclic skeleton.
Imidazo[1,2-a]pyrimidines are well-known com-
pounds because of their pharmacological profiles as anti-
cytomegalo-zoster and antivaricella-zoster virus [9]. The
chemical modification of the imidazopyrimidine ring
such as the introduction of different substituents or het-
eroatoms have allowed expansion of the research to
structure–activity relationship to afford new insight into
the molecular interaction at the receptor level. With an
imidazo[1,2-a]pyrimidine parent nucleus, benzo[4,5]
imidazo[1,2-a]pyrimidine derivatives showed a diverse
range of biological properties such as antineoplastic ac-
tivity [10], and acted as C3a receptor antagonists [11]
C
V
2009 HeteroCorporation

July 2009
Poly(ethyleneglycol): A Versatile and Recyclable Reaction Medium in Gaining
Access to Benzo[4,5]imidazo[1,2-a]pyrimidines Under Microwave Heating
665
Scheme 1
Scheme 2
and new calcium antagonists [12]. Because of a range
of biological activity they exhibited, these compounds
have distinguished themselves as heterocycles of pro-
found chemical and biological significance. Thus, the
synthesis of these molecules has attracted considerable
attention [13]. Recently, the synthesis of benzo[4,5] imi-
dazo[1,2-a]pyrimidine derivatives were reported by
Alvarez-Builla and coworkers via the reaction of an
requisite arylmethyleneacetoacetate with 2-aminobenzi-
midazole [14]. The improved procedure for benzo[4,5]-
imidazo[1,2-a]pyrimidines in ionic liquid through the
condensation of aldehydes with b-ketoester and 2-ami-
nobenzimidazole was described by Shaabani et al. [15].
However, the synthesis of new heterocyclic compounds
containing benzoimidazopyrimidine scaffold and devel-
opment of more rapid and efficient entry to this hetero-
cycles are strongly desired. In connection with our pre-
vious studies [16], to modify benzoimidazopyrimidine
scaffold, in this article we report a practical, inexpen-
sive, rapid, and green microwave-promoted method for
the synthesis of new heterocyclic compounds containing
benzoimidazopyrimidine unit in PEG-300 using 1,2-
diphenylethanone as potent precursor (Scheme 1).
ranging from 90 to 130ꢀC, with an increment of 10ꢀC
each time. The yield of product 4a was increased and
the reaction time was shortened as the temperature was
increased from 90 to 120ꢀC (Table 1, entries 5ꢁ8).
However, further increase of the temperature to 130ꢀC
failed to improve the yield of product 4a (Table 1, entry
9). Therefore, 120ꢀC was chosen as the reaction temper-
ature for all further microwave-assisted reactions.
The use of these optimal microwave experimental
conditions [PEG-300, 120ꢀC] to the reactions of differ-
ent aromatic aldehydes afforded good yields of ben-
zo[4,5]imidazo[1,2-a]pyrimidines, with two phenyl
groups presenting in positions 4 and 5 of the new form-
ing pyrimidine nucleus, respectively. To test the scope
of aromatic aldehydes, 2-aminobenzimidazole and 1,2-
diphenylethanone were used as model substrates, and
the results (Table 2, entries 1–11) indicated that aro-
matic aldehydes bearing functional groups such as
chloro, bromo, or methoxy are suitable for the reaction.
We have also observed electronic effects, that is, aro-
matic aldehydes with electron-withdrawing groups (Ta-
ble 2, entries 1ꢁ4) reacted rapidly, while electron-rich
groups (Table 2, entries 6ꢁ11) decreased the reactivity,
requiring longer reaction times.
RESULTS AND DISCUSSION
2-Aminobenzimidazole is a versatile and readily
obtainable reagent, and its chemistry has received con-
siderable attention in recent years due to the high nucle-
ophilic reactivity of two nitrogen atoms [17]. Our strat-
egy synthesizing the poly-substituted benzo[4,5]imi-
dazo[1,2-a]pyrimidines was that 2-aminobenzimidazole
was examined as starting material to react with aromatic
aldehydes and 1,2-diphenylethanone under microwave
heating. Initially, we screened various conditions for the
one-pot, three-component reaction of equimolar amount
of 2-aminobenzimidazole with 4-chlorobenzaldehyde
and 1,2-diphenylethanone at 100ꢀC in the presence of
potassium carbonate under microwave irradiation
(Scheme 2 and Table 1). Among various polar solvents
tested, glacial acetic acid (HOAc), acetonitrile, ethanol,
and water gave poor to moderate yields of the expected
product (Table 1, entries 1ꢁ4). The best solvent was
found to be PEG-300. In this solvent, benzo[4,5]imi-
dazo[1,2-a]pyrimidines (4a) was obtained with the best
yield (Table 1, entry 5). To further optimize the reaction
conditions, the reaction was carried out at temperatures
The use of PEG as a recyclable reaction medium in
these reactions avoids the use of volatile and toxic or-
ganic solvents. In addition to the often referred advan-
tages of using PEG-300 as solvent, this procedure has
following remarkable features when compared to con-
ventional method: (1) short reaction time, (2) clean reac-
tion protocol, (3) high yielding.
Table 1
Optimization for the synthesis of 4a under MW.
Entry
Solvent
T (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
HOAc
100
100
100
100
100
90
10
10
10
10
10
14
12
12
12
46
34
57
41
68
60
76
87
83
CH3CN
Ethanol
Water
PEG-300
PEG-300
PEG-300
PEG-300
PEG-300
110
120
130
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

666
S.-L. Wang, W.-J. Hao, S.-J. Tu, X.-H. Zhang, X.-D. Cao, S. Yan, S.-S. Wu, Z.-G. Han,
and F. Shi
Vol 46
Table 2
Synthesis of compounds 4 under microwave irradiation.
Entry
Product
Ar
Time (min)
Yield (%)
mp (ꢀC)
1
2
4a, 4-Chlorophenyl (1a)
4b, 4-Bromophenyl (1b)
4c, 2-Chlorophenyl (1c)
4d, 2,4-Dichlorophenyl (1d)
4e, Phenyl (1e)
12
12
10
10
14
14
16
14
14
16
18
87
85
86
84
82
80
78
80
79
75
76
284–286
>300
>300
3
4
>300
5
274–276
295–297
>300
6
7
4f, 4-Tolyl (1f)
4g, 4-Dimethylaminophenyl (1g)
4h, Benzo[d][1,3]dioxol-5-yl (1h)
4i, 4-Methoxyphenyl (1i)
4j, 3,4-Dimethoxyphenyl (1j)
4k, 3,4,5-Trimethoxyphenyl (1k)
8
9
>300
250–252
267–268
296–298
10
11
To prove that the use of PEG as solvent is practical,
it has to be conveniently recyclable with minimal loss
and decomposition. Because PEG is immiscible with
aliphatic hydrocarbons, the desired product may be
extracted with compounds such as cyclohexane [18],
and the retained PEG phase may be reused. In the recy-
cling study, the reaction between 4-chlorobenzaldehyde,
1,2-diphenylethanone, and 2-aminobenzimidazole in the
presence of potassium carbonate could be repeated three
times without reduction of the yield (84% ꢂ 3%),
although a weight loss of ꢃ10% PEG was observed
from cycle to cycle.
none and 2-aminobenzimidazole in PEG-300, which
provides a rapid and efficient route for the construction
of benzo[4,5]imidazo[1,2-a]pyrimidine skeleton. This
protocol offers a rapid and clean alternative and reduces
reaction time. The recyclability of the reaction media
makes reaction economically and potentially viable for
commercial applications.
EXPERIMENTAL
Microwave irradiation was carried out with a microwave
oven EmrysTM Creator from Personal Chemistry, Uppsala,
Sweden. Melting points were determined in the open capilla-
ries and were uncorrected. IR spectra were taken on a FT-IR-
The formation of 4 is likely to proceed via initial con-
densation of aromatic aldehydes 1 with 1,2-diphenyle-
thanone 2 to afford 3-aryl-1,2-diphenylprop-2-en-1-one
A, which further undergoes in situ Michael addition
reaction with 2-aminobenzimidazole 3 to yield interme-
diate B. The intermediate B is upon intramolecular cy-
clization and dehydration to generate final products 4
(Scheme 3).
Tensor 27 spectrometer in KBr pellets and reported in cmꢁ1
.
1H NMR spectra were measured on a Bruker DPX 400 MHz
spectrometer using TMS as an internal standard and DMSO-d6
as solvent. Elemental analysis was determined by using a Per-
kin-Elmer 240c elemental analysis instrument.
General procedure for the one-pot synthesis of ben-
zo[4,5]imidazo[1,2-a]pyrimidine derivatives under micro-
wave irradiation conditions. Typically, in a 10-mL EmrysTM
reaction vial, aromatic aldehyde 1 (1 mmol), 1,2-diphenyletha-
none 2 (1 mmol), 2-aminobenzimidazole 3 (1 mmol), potas-
sium carbonate (0.4 mmol), and PEG-300 (2 mL) were mixed
and then capped. The mixture was irradiated for a given time
at 120ꢀC under microwave irradiation (initial power 100 W
and maximum power 250 W). Upon completion, monitored by
TLC, the reaction mixture was cooled to room temperature.
The precipitated product was filtered off and the filter liquor
was extracted by diethyl ether. The residue left after evapora-
tion of the solvent was added to the solid product isolated by
filtration, and purified by flash chromatography (silica gel, pe-
troleum ether: acetone ¼ 10:1) to give rise to the pure product
4. The recovered PEG can be reused for a number of cycles
without significant loss of activity.
In this study, all the products were characterized by
1
melting point, IR, and H NMR spectral data, as well as
elemental analysis.
In conclusion, we have demonstrated that PEG is a
convenient, inexpensive, nonionic liquid, nontoxic, and
recyclable reaction medium for the efficient synthesis of
4,5-bis-aryl substituted benzo[4,5]imidazo[1,2-a]pyrimi-
dines. Interestingly, we found a new multicomponent
reaction of aromatic aldehydes with 1,2-diphenyletha-
Scheme 3
4-(4-Chlorophenyl)-2,3-diphenyl-4,10-dihydrobenzo[4,5]-
imidazo[1,2-a]pyrimidine (4a). ir (potassium bromide):
3055, 3025, 2820, 1625, 1578, 1408, 1279, 1088, 1011, 830,
;
774, 698 cmꢁ1 1H NMR (DMSO-d6): d 10.22 (s, 1H, NH),
7.40 (d, 2H, J ¼ 8.4 Hz, ArH), 7.31 (d, 2H, J ¼ 8.8 Hz,
ArH), 7.26–7.24 (m, 6H, ArH), 7.15 (d, 1H, J ¼ 8.0 Hz,
ArH), 7.07–7.00 (m, 4H, ArH), 6.91–6.88 (m, 3H, ArH), 6.66
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Poly(ethyleneglycol): A Versatile and Recyclable Reaction Medium in Gaining
Access to Benzo[4,5]imidazo[1,2-a]pyrimidines Under Microwave Heating
667
(s, 1H, CH). Anal. calcd. for C28H20ClN3: C, 77.50; H, 4.65;
N, 9.68. Found: C, 77.31; H, 4.67; N, 9.55.
calcd. for C29H21N3O2: C, 78.54; H, 4.77; N, 9.47. Found: C,
78.62; H, 4.75; N, 9.53.
4-(4-Bromophenyl)-2,3-diphenyl-4,10-dihydrobenzo[4,5]-
imidazo[1,2-a]pyrimidine (4b). ir (potassium bromide):
3054, 3024, 2820, 1626, 1579, 1403, 1286, 1071, 1009, 841,
4-(4-Methoxyphenyl)-2,3-diphenyl-4,10-dihydrobenzo[4,5]-
imidazo[1,2-a]pyrimidine (4i). ir (potassium bromide): 3048,
3016, 2834, 1628, 1580, 1418, 1264, 1028, 856, 777, 701
1
774, 699 cmꢁ1
;
1H NMR (DMSO-d6): d 10.19 (s, 1H, NH),
cmꢁ1; H NMR (DMSO-d6): d 10.14 (s, 1H, NH), 7.35 (d, 2H,
7.45 (d, 2H, J ¼ 8.0 Hz, ArH), 7.33 (d, 2H, J ¼ 8.4 Hz,
ArH), 7.30–7.27 (m, 6H, ArH), 7.15 (d, 1H, J ¼ 8.0 Hz,
ArH), 7.07–7.00 (m, 4H, ArH), 6.92–6.89 (m, 3H, ArH), 6.65
(s, 1H, CH). Anal. calcd. for C28H20BrN3: C, 70.30; H, 4.21;
N, 8.78. Found: C, 70.46; H, 4.19; N, 8.69.
J ¼ 8.8 Hz, ArH), 7.29–7.26 (m, 5H, ArH), 7.25–7.20 (m, 2H,
ArH), 7.06–6.98 (m, 4H, ArH), 6.91–6.87 (m, 3H, ArH), 6.81
(d, 2H, J ¼ 8.8 Hz, ArH), 6.51 (s, 1H, CH), 3.65 (s, 3H,
OCH3). Anal. calcd. for C29H23N3O: C, 81.09; H, 5.40; N,
9.78. Found: C, C, 81.01; H, 5.43; N, 9.69.
4-(2-Chlorophenyl)-2,3-diphenyl-4,10-dihydrobenzo[4,5]-
imidazo[1,2-a]pyrimidine (4c). ir (potassium bromide): 3051,
3023, 2822, 1627, 1579, 1459, 1283, 1034, 913, 783, 697
4-(3,4-Dimethoxyphenyl)-2,3-diphenyl-4,10-dihydrobenzo
[4,5]imidazo[1,2-a]pyrimidine (4j). ir (potassium bromide):
3048, 3016, 2834, 1628, 1580, 1418, 1264, 1028, 856, 777, 701
cmꢁ1; 1H NMR (DMSO-d6): d 10.09 (s, 1H, NH), 7.29–7.25 (m,
7H, ArH), 7.07–7.01 (m, 4H, ArH), 7.00–6.96 (m, 2H, ArH),
6.95–6.93 (m, 1H, ArH), 6.90 (d, 2H, J ¼ 8.0 Hz, ArH), 6.84 (d,
1H, J ¼ 8.4 Hz, ArH), 6.48 (s, 1H, CH), 3.65 (s, 3H, OCH3),
3.62 (s, 3H, OCH3). Anal. calcd. for C30H25N3O2: C, 78.41; H,
5.48; N, 9.14. Found: C, 78.52; H, 5.46; N, 9.20.
cmꢁ1 1H NMR (DMSO-d6): d 10.25 (s, 1H, NH), 7.52 (dd,
;
1H, J1 ¼ 7.6 Hz, J2 ¼ 1.6 Hz, ArH), 7.28–7.24 (m, 8H, ArH),
7.18 (dd, 1H, J1 ¼ 7.6 Hz, J2 ¼ 1.6 Hz, ArH), 7.03–6.96 (m,
5H, ArH), 6.92–6.87 (m, 3H, ArH), 6.85 (s, 1H, CH). Anal.
calcd. for C28H20ClN3: C, 77.50; H, 4.65; N, 9.68. Found: C,
77.59; H, 4.64; N, 9.74.
4-(2,4-Dichlorophenyl)-2,3-diphenyl-4,10-dihydrobenzo [4,5]-
imidazo[1,2-a]pyrimidine (4d). ir (potassium bromide): 3055,
3024, 2816, 1626, 1580, 1459, 1282, 1102, 1010, 843, 772,
4-(3,4,5-Trimethoxyphenyl)-2,3-diphenyl-4,10-dihydrobenzo
[4,5]imidazo[1,2-a]pyrimidine (4k). ir (potassium bromide):
3050, 3018, 2834, 1651, 1571, 1418, 1251, 1125, 1011, 828,
779, 701 cmꢁ1; 1H NMR (DMSO-d6): d 10.13 (s, 1H, NH), 7.41
(d, 1H, J ¼ 7.6 Hz, ArH), 7.30–7.28 (m, 6H, ArH), 7.08–7.01
(m, 4H, ArH), 6.96 (d, 1H, J ¼ 7.6 Hz, ArH), 6.91 (d, 2H, J ¼
7.6 Hz, ArH), 6.78 (s, 2H, ArH), 6.47 (s, 1H, CH), 3.66 (s, 6H,
OCH3), 3.56 (s, 3H, OCH3). Anal. calcd. for C31H27N3O3: C,
76.05; H, 5.56; N, 8.58. Found: 76.13; H, 5.54; N, 8.63.
696 cmꢁ1 1H NMR (DMSO-d6): d 10.25 (s, 1H, NH), 7.54
;
(d, 1H, J ¼ 8.4 Hz, ArH), 7.45 (s, 1H, ArH), 7.34 (d, 1H, J ¼
8.0 Hz, ArH), 7.29 (d, 1H, J ¼ 8.0 Hz, ArH), 7.24 (s, 5H,
ArH), 7.04–6.97 (m, 5H, ArH), 6.93–6.89 (m, 3H, ArH),
6.88(s, 1H, CH). Anal. calcd. for C28H19Cl2N3: C, 71.80; H,
4.09; N, 8.97. Found: C, 71.72; H, 4.11; N, 8.90.
2,3,4-Triphenyl-4,10-dihydrobenzo[4,5]imidazo[1,2-a]-py-
rimidine (4e). ir (potassium bromide): 3053, 3023, 2823,
Acknowledgment. The authors are grateful for financial support
from the National Science Foundation of China (Nos. 20672090
and 200810102050), Natural Science Foundation of the Jiangsu
Province (No. BK2006033), Six Kinds of Professional Elite
Foundation of the Jiangsu Province (No. 06-A-039), the Qing
Lan Project (No. 08QLT001), and Graduate Foundation of Xuz-
hou Normal University (No. 08YLB031).
1
1626, 1509, 1458, 1284, 1073, 829, 782, 700 cmꢁ1; H NMR
(DMSO-d6): d 10.14 (s, 1H, NH), 7.39(d, 2H, J ¼ 7.2 Hz,
ArH), 7.29–7.27 (m, 3H, ArH), 7.26–7.23 (m, 5H, ArH), 7.17
(d, 2H, J ¼ 7.2 Hz, ArH), 7.05–6.98 (m, 4H, ArH), 6.90–6.87
(m, 3H, ArH), 6.57 (s, 1H, CH). Anal. calcd. for C28H21N3: C,
84.18; H, 5.30; N, 10.52. Found: C, 84.24; H, 5.33; N, 10.49.
4-p-Tolyl-2,3-diphenyl-4,10-dihydrobenzo[4,5]imidazo-[1,2-
a]pyrimidine (4f). ir (potassium bromide): 3051, 3022, 2825,
1
1626, 1574, 1459, 1282, 1179, 1009, 826, 774, 698 cmꢁ1; H
REFERENCES AND NOTES
NMR (DMSO-d6): d 10.12 (s, 1H, NH), 7.29 (d, 2H, J ¼ 8.0
Hz, ArH), 7.28–7.21 (m, 6H, ArH), 7.18 (d, 1H, J ¼ 8.0 Hz,
ArH), 7.06 (d, 2H, J ¼ 7.6 Hz, ArH), 7.03–6.98 (m, 4H,
ArH), 6.90–6.87 (m, 3H, ArH), 6.53 (s, 1H, CH), 2.18 (s, 3H,
CH3). Anal. calcd. for C29H23N3: C, 84.23; H, 5.61; N, 10.16.
Found: C, 84.31; H, 5.59; N, 10.21.
4-(4-Dimethylaminophenyl)-2,3-diphenyl-4,10-dihydro-benzo
[4,5]imidazo[1,2-a]pyrimidine (4g). ir (potassium bromide):
3053, 3023, 2802, 1625, 1575, 1444, 1234, 1165, 1073, 827,
777, 698 cmꢁ1 1H NMR (DMSO-d6): d 10.05 (s, 1H, NH),
;
7.26–7.23 (m, 9H, ArH), 7.05–6.97 (m, 4H, ArH), 6.91–6.87
(m, 3H, ArH), 6.58 (d, 2H, J ¼ 8.4 Hz, ArH), 6.39 (s, 1H,
CH), 2.81 (s, 6H, CH3). Anal. calcd. for C30H26N4: C, 81.42;
H, 5.92; N, 12.66. Found: C, 81.34; H, 5.95; N, 12.72.
4-Benzo[1,3]dioxol-5-yl-2,3-diphenyl-4,10-dihydrobenzo[4,5]-
imidazo[1,2-a]pyrimidine (4h). ir (potassium bromide): 3051,
3018, 2824, 1627, 1573, 1460, 1237, 1039, 935, 853, 777, 698
;
cmꢁ1 1H NMR (DMSO-d6): d 10.13 (s, 1H, NH), 7.29–7.27
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(m, 2H, ArH), 7.26–7.23 (m, 5H, ArH), 7.07–6.99 (m, 4H,
ArH), 6.94–6.89 (m, 5H, ArH), 6.78 (d, 1H, J ¼ 8.4 Hz,
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