A catalyst-free reaction in water: Synthesis of benzo[4,5]imidazo[1,2-a] pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives

Article abstract of DOI:10.1039/c2gc35745c

An environmentally benign and efficient method has been developed for the synthesis of a series of benzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)- one derivatives in aqueous media under catalyst-free conditions by simply combining 2-aminobenzimidazole, aldehyde, and cyanoacetamide. The advantages of this method are that it is catalyst-free, has an easy workup, provides excellent yields, and uses water as the solvent which is considered to be relatively environmentally benign.

Full text of DOI:10.1039/c2gc35745c

View Online / Journal Homepage
Dynamic Article Links
Green Chemistry
Cite this: DOI: 10.1039/c2gc35745c
www.rsc.org/greenchem
PAPER
A catalyst-free reaction in water: synthesis of benzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives†
Junhua Liu,a Min Lei*b and Lihong Hu*a,b
Received 16th May 2012, Accepted 27th June 2012
DOI: 10.1039/c2gc35745c
An environmentally benign and efficient method has been developed for the synthesis of a series of benzo-
[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives in aqueous media under catalyst-free
conditions by simply combining 2-aminobenzimidazole, aldehyde, and cyanoacetamide. The advantages
of this method are that it is catalyst-free, has an easy workup, provides excellent yields, and uses water as
the solvent which is considered to be relatively environmentally benign.
Introduction
In today’s world, the development of efficient, practical and
environmentally friendly methods of synthesis is one of the
main priorities for modern organic synthesis.1 Organic solvents
represent the biggest pollution problem in many synthetic
organic processes. Therefore, the elimination of solvents in
chemical processes or the replacement of hazardous solvents
with relatively benign solvents have been one of the key areas of
green chemistry.2 Water as a green reaction medium has gained
considerable interest in view of its low cost, safety, and environ-
mentally benign properties.3 Furthermore, catalyst-free synthetic
methods have attracted much interest not only for laboratory syn-
thesis but also in chemical industry, because of reduced pol-
lution, lower costs, mild conditions, and ease of purification.4
Scheme 1 Synthesis of benzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyri-
Dihydropyrimidine derivatives have attracted much attention
midin-4(1H)-one 4.
as important structural motifs in medical chemistry owing to
their significant therapeutic and biological activities, such as
antineaplastic activity,5 TIE-2 and/or VEGFR2 inhibitory activi-
imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives.
Therefore, we wish to report here a simple but effective pro-
cedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimido-
ties,6 T cell activation,7 lymphocyte specific kinase,8 protein
kinase inhibitor,9 and DNA-topoisomerase I.10 Due to their
importance, we have reported an efficient and green procedure
for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidine and
[1,2,4]triazolo[1,5-a]pyrimidine derivatives.11 As part of a conti-
nuing effort in our laboratory toward the synthesis of dihydro-
pyrimidine derivatives, we accidentally developed a novel and
efficient method for the synthesis benzo[4,5]imidazo[1,2-a]pyri-
mido[4,5-d]pyrimidin-4(1H)-one derivatives via three-com-
ponent condensation reaction of 2-aminobenzimidazole,
aldehyde, and cyanoacetamide. However, to the best of our
knowledge, there is no report on the synthesis of benzo[4,5]-
[4,5-d]pyrimidin-4(1H)-one derivatives from 2-aminobenzimida-
zole, aldehyde, and cyanoacetamide under catalyst-free con-
ditions in water (Scheme 1).
Results and discussion
Optimization of the reaction conditions
Initially, we explored the three-component condensation reaction
of 2-aminobenzimidazole 1 (2 mmol) with benzaldehyde 2a
(2 mmol), and cyanoacetamide 3 (2 mmol) in 2 mL H2O at
reflux temperature for 3 h. Curiously, the product 2,5-diphenyl-
2,3,5,12-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyr-
imidin-4(1H)-one 4a, shown in Scheme 2 and confirmed by
NMR and LC-MS, was obtained in 90% yield based on benz-
aldehyde 2a, while in contrast, the product 2-amino-4-phenyl-
1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxamide
aSchool of Pharmacy, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, P.R. China
bShanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai, 201203, P.R. China. E-mail: mlei@mail.shcnc.ac.cn,
simmhulh@mail.shcnc.ac.cn; Fax: +86 20231965; Tel: +86 20231965
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35745c
This journal is © The Royal Society of Chemistry 2012
Green Chem.

View Online
2-aminobenzimidazole 1, two molecules of benzaldehyde 2a,
and cyanoacetamide 3 was stirred under reflux temperature or
100 °C for 5 h in THF, toluene, DCM, MeCN, DMSO, and
DMF (Table 1, entries 1–6). The reaction using EtOH (80%) or
H2O (90%) as the solvents gave the corresponding product 4a in
high yields (Table 1, entries 7–8). From the economical and
environmental point of view, H2O was chosen as the reaction
medium for all further reactions. Furthermore, the relation
between the yields of the model reaction and temperature was
also studied. We carried out the reaction at temperatures ranging
from 40 °C to reflux temperature using water as the reaction
medium (Table 1, entries 8–11), finding that the yields of the
desired product 4a were improved as the temperature was
increased. Therefore, the best reaction conditions were obtained
in water under reflux temperature.
The scope of the substrates
To further explore the scope of this protocol, we decided to
investigate the condensation reaction of 2-aminobenzimidazole
1, aromatic aldehyde 2, and cyanoacetamide 3 in water as
solvent under catalyst-free conditions (Table 2).
Scheme 2 Condensation of 2-aminobenzimidazole 1, benzaldehyde
2a, and cyanoacetamide 3.
Table 2 Synthesis
of
benzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]-
pyrimidin-4(1H)-one 4 in watera
5a was not obtained. The probable reason for this phenomenon
was that 5a was able to easily react with the aldehyde to form 4a
under these reaction conditions. Encouraged by this result, we
further investigated the effect of solvent and temperature on the
model reaction of 2-aminobenzimidazole 1, two molecules of
benzaldehyde 2a, and cyanoacetamide 3 (Table 1).
As shown in Table 1, low yields of the target product
4a (25–50%) were obtained when the mixture of
Table 1 Optimization of condensation of 2-aminobenzimidazole 1,
two molecules of benzaldehyde 2a, and cyanoacetamide 3a
Entry Ar
Product 4 Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
C6H5 2a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
3
3
2
2
2
2
2
2
2
2
8
8
8
5
5
5
6
6
90
85
92
90
91
92
89
90
89
90
Trace
Trace
Trace
85
86
83
83
80
4-CH3OC6H4 2b
4-CH3C6H4 2c
4-ClC6H4 2d
4-NCC6H4 2e
4-CH3OOCC6H4 2f
4-FC6H4 2g
4-F3CC6H4 2h
3-ClC6H4 2i
3-CH3C6H4 2j
2-CH3C6H4 2k
2-ClC6H4 2l
2-CH3OC6H4 2m
4-Pyridyl 2n
4-Pyridyl 2n
3,4-(CH3O)2C6H3 2o
3-OH-4-CH3OC6H3 2p 4q
4-OH-3-CH3OC6H3 2q 4r
Entry
Solvent
Temp. (°C)
Time (h)
Yield of 4ab (%)
1
2
3
4
5
6
7
8
THF
Reflux
100
Reflux
Reflux
100
5
5
5
5
5
5
3
3
3
3
3
40
50
25
45
50
50
80
90
0
Toluene
DCM
MeCN
DMSO
DMF
EtOH
H2O
H2O
H2O
H2O
9
10
11
12
13
14
15
16
17
18
100
Reflux
Reflux
40
60
80
9
10
11
10
20
a Conditions: 2-aminobenzimidazole 1 (2 mmol), benzaldehyde 2a
(4.4 mmol), and cyanoacetamide 3 (2 mmol), solvent (2 mL). b Isolated
yields.
a Conditions: aminobenzimidazole 1 (2 mmol), aldehyde 2 (4.4 mmol),
and cyanoacetamide 3 (2 mmol), H2O (2 mL), reflux. b Isolated yields.
Green Chem.
This journal is © The Royal Society of Chemistry 2012

View Online
As shown in Table 2, the electronic effect from the substrate
had no significant impact on the overall yields of the products 4.
For example, aromatic aldehydes carrying either electron-donat-
ing or electron-withdrawing substituents, including a CF3 group,
could react efficiently to give the corresponding products
without significant difference (Table 2, entries 2–10). Moreover,
hetero-aromatic aldehyde could also react smoothly to give the
corresponding product in good yield (Table 2, entry 14).
However, the steric hindrance effect from the substrate had a
major impact on the overall yields of the products 4. For
instance, para- or meta-substituted benzaldehydes (Table 2,
entries 2–10) could react smoothly to give the desired products
in excellent yields (85–92%). Whereas, only trace amounts of
desired products were observed when using the ortho-substituted
benzaldehydes as the substrates under the same reaction con-
ditions (Table 2, entries 11–13). Only trace amounts of 4k (m/z
422.19, [M + H]+), 4l (m/z 462.22, [M + H]+), and 4m (m/z
454.18, [M + H]+) were detected by LCMS. Furthermore, we
also found that 3,4-substituted benzaldehydes (Table 2, entries
15–17) were well tolerated, furnishing good yields of expected
products.
The structures of the benzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]-
pyrimidin-4(1H)-ones 4 were established from one-dimensional
(1H NMR, 13C NMR, and DEPT), two-dimensional (ROESY,
HMQC, and HMBC) NMR spectral data, and HRESIMS data.
As shown in Fig. 1–3, compound 4d was chosen as a representa-
tive example. Compound 4d had the molecular formula
C24H17Cl2N5O, deduced from its HRMS (m/z 462.0886, [M +
H]+), indicated eighteen degrees of unsaturation. In the 1H NMR
Fig. 3 Important ROESY correlations for compound 4d.
spectrum, three active hydrogen signals at 8.51 ppm (brs),
7.84 ppm (brs), and 7.45 ppm (brs) were ascribed to the three
NH groups. The singlet at 5.29 ppm is assigned to H-2, and has
HMB correlation contours with 134.4 ppm (Fig. 2). The H-5
proton appears as a singlet at 6.12 ppm, which shows (i) HMB
correlation contours with C-4 at 163.9, C-4a at 115.7, and C-12a
at 153.4 (Fig. 2), and (ii) a H,H-ROESY correlation with the
doublet at 5.83 ppm (J = 7.7 Hz), assignable to H-7 (Fig. 3).
H-7 and H-10 occur as doublets, respectively, at 5.83
(J = 7.7 Hz) and 7.17 (J = 7.7 Hz) ppm (Fig. 1). H-7 shows a H,
H-ROESY correlation with H-8, which appears as a triplet at
6.69 ppm (J = 7.7 Hz), which, in turn, shows a H,H- ROESY
correlation with the triplet due to H-9 at 6.97 ppm (J = 7.7 Hz)
(Fig. 3).
Probable mechanism for the condensation
A plausible mechanism for the formation of benzo[4,5]imidazo-
[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-ones 4 is depicted in
Scheme 3. In the initial step, this reaction may proceed via inter-
mediate 6, formed by the Knoevenagel condensation of aldehyde
2 and cyanoacetamide 3. Then, Michael addition between 6 and
1 leads to the formation of intermediate 7, followed by intra-
molecular cyclization to afford the intermediate 9 which is iso-
merized to 5. Ultimately, the expected products 4 is formed by
the condensation of intermediate 5 with aldehyde 2 (Scheme 3).
Conclusions
In summary, we have demonstrated a novel protocol for the prep-
aration of benzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4-
(1H)-ones 4 via the three-component condensation reactions of
2-aminobenzimidazole 1, aldehyde 2, and cyanoacetamide 3 in
water under catalyst-free conditions. This procedure offers
several notable advantages including the operational simplicity,
mild reaction conditions, high yields, without catalyst, and little
environmental impact. Hence, it is a useful method for the syn-
thesis of these heterocyclic compounds.
Fig. 1 1H- and 13C-NMR assignments for compound 4d.
Experimental
Melting points were measured by a WRS-1B micromelting point
apparatus and are uncorrected. NMR spectra were recorded on a
Bruker AMX 300 instrument or Bruker AMX 400 instrument
Fig. 2 Key HMBC correlations of compound 4d.
This journal is © The Royal Society of Chemistry 2012
Green Chem.

View Online
1H, CH); 13C NMR (100 MHz, DMSO-d6) δC: 164.2, 153.6,
143.3, 135.6 133.3, 133.2, 130.2, 129.7, 128.9, 128.8, 128.7,
121.6, 118.7, 116.2, 116.0, 111.0, 62.5, 59.6; ESI-MS m/z 394
[M + H]+; HRMS (ESI) calc. for C24H20N5O [M + H]+
394.1662, found 394.1665.
2,5-Bis(4-methoxyphenyl)-2,3,5,12-tetrahydrobenzo[4,5]imidazo-
[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4b)
Isolated as a white powder; m.p. 236.2–236.7 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.23 (brs, 1H, NH), 7.74 (brs, 1H,
NH), 7.44 (d, J = 8.7 Hz, 2H, ArH), 7.38 (brs, 1H, NH), 7.22 (d,
J = 8.7 Hz, 2H, ArH), 7.21 (d, J = 7.7 Hz, 1H, ArH), 7.01 (d,
J = 8.7 Hz, 4H, ArH), 6.94 (t, J = 7.7 Hz, 1H, ArH), 6.64 (t, J =
7.7 Hz, 1H, ArH), 5.99 (s, 1H, CH), 5.77 (d, J = 7.7 Hz, 1H,
ArH), 5.18 (s, 1H, CH), 3.80 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3); 13C NMR (100 MHz, DMSO-d6) δC: 164.4, 160.5,
160.3, 153.6, 133.4, 129.9, 127.5, 125.0, 121.5, 118.7, 116.3,
116.2, 114.3, 114.1, 111.1, 61.9, 59.1, 55.6; ESI-MS m/z 454
[M + H]+; HRMS (ESI) calc. for C26H24N5O3 [M + H]+
454.1874, found 454.1877.
2,5-Di-p-tolyl-2,3,5,12-tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-one (4c)
Isolated as a white powder; m.p. 231.5–232.0 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.39 (brs, 1H, NH), 7.75 (brs, 1H,
NH), 7.47 (d, J = 8.0 Hz, 2H, ArH), 7.36 (brs, 1H, NH), 7.25 (d,
J = 8.0 Hz, 4H, ArH), 7.19 (d, J = 8.0 Hz, 2H, ArH), 7.12 (d, J
= 7.6 Hz, 1H, ArH), 6.92 (t, J = 7.6 Hz, 1H, ArH), 6.62 (t, J =
7.6 Hz, 1H, ArH), 6.02 (s, 1H, CH), 5.77 (d, J = 7.6 Hz, 1H,
ArH), 5.21 (s, 1H, CH), 2.36 (s, 1H, CH3), 2.34 (s, 1H, CH3);
13C NMR (100 MHz, DMSO-d6) δC: 164.3, 153.6, 143.2, 139.6,
139.0, 133.3, 132.6, 130.2, 129.5, 129.4, 128.6, 121.5, 118.7,
116.1, 111.1, 62.3, 59.4, 21.3, 21.2; ESI-MS m/z 422 [M + H]+;
HRMS (ESI) calc. for C26H24N5O [M + H]+ 422.1975, found
422.1973.
Scheme 3 A plausible mechanistic pathway to explain the formation
of compounds 4.
using solvent peaks as DMSO-d6 solutions. HRESIMS were
determined on a Micromass Q-Tif Global mass spectrometer and
ESIMS were run on a Bruker Esquire 3000 Plus Spectrometer.
TLC was performed on GF254 silica gel plates (Yantai Huiyou
Inc., China).
2,5-Bis(4-chlorophenyl)-2,3,5,12-tetrahydrobenzo[4,5]imidazo-
[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4d)
General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-ones 4
Isolated as a white powder; m.p. 229.7–229.8 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.51 (brs, 1H, NH), 7.84 (brs, 1H,
NH), 7.65–7.55 (m, 6H, ArH), 7.45 (brs, 1H, NH), 7.38–7.27
(m, 2H, ArH), 7.17 (d, J = 7.7 Hz, 1H, ArH), 6.97 (t, J =
7.7 Hz, 1H, ArH), 6.69 (t, J = 7.7 Hz, 1H, ArH), 6.12 (s, 1H,
CH), 5.83 (d, J = 7.7 Hz, 1H, ArH), 5.29 (s, 1H, CH); 13C NMR
(100 MHz, DMSO-d6) δC: 163.9, 153.4, 143.1, 134.9, 134.5,
134.4, 133.1, 132.1, 130.6, 129.2, 128.9, 121.8, 119.1, 116.3,
115.7, 111.1, 61.6, 58.9; ESI-MS m/z 462 [M + H]+; HRMS
(ESI) calc. for C24H18Cl2N5O [M + H]+ 462.0883, found
462.0886.
A mixture of 2-aminobenzimidazole 1 (2 mmol), aldehyde 2
(4.4 mmol), and cyanoacetamide 3 (2 mmol) in water (2 mL)
was refluxed for 2–6 h. After completion of the reaction (TLC),
the solid was filtered off, washed with water and further purified
by recrystallisation from ethanol (5 mL) to yield pure products 4.
2,5-Diphenyl-2,3,5,12-tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-one (4a)
Isolated as a white powder; m.p. 224.4–225.5 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.38 (brs, 1H, NH), 7.77 (brs, 1H,
NH), 7.62–7.58 (m, 2H, ArH), 7.52–7.44 (m, 6H, ArH), 7.40
(brs, 1H, NH), 7.34–7.28 (m, 2H, ArH), 7.18 (d, J = 7.8 Hz, 1H,
ArH), 6.94 (t, J = 7.8 Hz, 1H, ArH), 6.61 (t, J = 7.8 Hz, 1H,
ArH), 6.08 (s, 1H, CH), 5.71 (d, J = 7.8 Hz, 1H, ArH), 5.27 (s,
4,4′-(4-Oxo-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidine-2,5-diyl)dibenzonitrile (4e)
Isolated as a white powder; m.p. 229.4–229.6 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.52 (brs, 1H, NH), 7.99 (d, J =
Green Chem.
This journal is © The Royal Society of Chemistry 2012

View Online
8.4 Hz, 4H, ArH), 7.90 (brs, 1H, NH), 7.74 (d, J = 8.4 Hz, 2H,
ArH), 7.49 (d, J = 8.4 Hz, 2H, ArH),7.48 (brs, 1H, NH), 7.29
(d, J = 7.8 Hz, 1H, ArH), 7.00 (t, J = 7.8 Hz, 1H, ArH), 6.70 (t,
J = 7.8 Hz, 1H, ArH), 6.25 (s, 1H, CH), 5.80 (d, J = 7.8 Hz, 1H,
ArH), 5.40 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6) δC:
163.6, 153.1, 140.6, 138.3, 133.0, 132.9, 132.8, 129.8, 121.9,
119.2, 118.9, 118.7, 116.5, 115.4, 113.1, 112.6, 111.1, 61.7,
59.1; ESI-MS m/z 444 [M + H]+; HRMS (ESI) calc. for
C26H18N7O [M + H]+ 444.1567, found 444.1569.
2.2 Hz), 125.64 and 123.47 (1JCF = 216.7 Hz), 125.52 and
123.35 (1JCF = 216.7 Hz), 121.9, 119.2, 116.5, 115.5, 110.9,
61.8, 59.1; ESI-MS m/z 530 [M + H]+; HRMS (ESI) calc. for
C26H18F6N5O [M + H]+ 530.1410, found 530.1413.
2,5-Bis(3-chlorophenyl)-2,3,5,12-tetrahydrobenzo[4,5]imidazo-
[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4i)
Isolated as a white powder; m.p. 235.8–236.5 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.46 (brs, 1H, NH), 7.92 (brs, 1H,
NH), 7.60 (d, J = 5.8 Hz, 2H, ArH), 7.56–7.48 (m, 4H, ArH),
7.45 (brs, 1H, NH), 7.26 (s, 2H, ArH), 7.25 (d, J = 7.8 Hz, 1H,
ArH), 6.99 (t, J = 7.8 Hz, 1H, ArH), 6.69 (t, J = 7.8 Hz, 1H,
ArH), 6.13 (s, 1H, CH), 5.82 (d, J = 7.8 Hz, 1H, ArH), 5.30 (s,
1H, CH); 13C NMR (100 MHz, DMSO-d6) δC: 163.8, 153.2,
143.1, 137.7, 135.4, 133.6, 133.4, 133.0, 131.0, 130.8, 130.3,
129.8, 128.5, 127.6, 121.9, 119.1, 116.4, 115.6, 110.9, 61.6,
58.9; ESI-MS m/z 462 [M + H]+; HRMS (ESI) calc. for
C24H18Cl2N5O [M + H]+ 462.0883, found 462.0880.
Dimethyl 4,4′-(4-oxo-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo-
[1,2-a]pyrimido[4,5-d]pyrimidine-2,5-diyl)dibenzoate (4f)
Isolated as a white powder; m.p. 229.1–229.5 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.48 (brs, 1H, NH), 8.04 (d, J = 8.4
Hz, 4H, ArH), 7.83 (brs, 1H, NH), 7.72 (d, J = 8.4 Hz, 2H,
ArH), 7.41 (d, J = 8.4 Hz, 2H, ArH), 7.27 (d, J = 7.7 Hz, 1H,
ArH), 6.98 (t, J = 7.7 Hz, 1H, ArH), 6.66 (t, J = 7.7 Hz, 1H,
ArH), 6.22 (s, 1H, CH), 5.77 (d, J = 7.7 Hz, 1H, ArH), 5.38 (s,
1H, CH), 3.88 (s, 3H, OCH3), 3.87 (s, 3H, OCH3); 13C NMR
(100 MHz, DMSO-d6) δC: 166.4, 166.2, 163.8, 153.3, 140.5,
138.2, 133.1, 131.3, 130.9, 129.8, 129.6, 129.2, 121.8, 119.0,
116.4, 115.6, 111.0, 61.9, 59.3, 52.8, 52.7; ESI-MS m/z 510
[M + H]+; HRMS (ESI) calc. for C28H24N5O5 [M + H]+
510.1772, found 510.1775.
2,5-Di-m-tolyl-2,3,5,12-tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-one (4j)
Isolated as a white powder; m.p. 232.3–232.5 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.30 (brs, 1H, NH), 7.77 (brs, 1H,
NH), 7.45–7.29 (m, 5H, ArH), 7.22 (d, J = 7.6 Hz, 1H, ArH),
7.20–7.10 (m, 4H, ArH), 6.94 (t, J = 7.6 Hz, 1H, ArH), 6.62 (t,
J = 7.7 Hz, 1H, ArH), 6.02 (s, 1H, CH), 5.73 (d, J = 7.7 Hz, 1H,
ArH), 5.21 (s, 1H, CH), 2.35 (s, 3H, CCH3), 2.30 (s, 3H,
CCH3); 13C NMR (100 MHz, DMSO-d6) δC: 164.2, 153.6,
143.2, 138.0, 137.7, 135.6, 133.3, 133.2, 130.8, 130.3, 129.3,
128.8, 128.7, 125.9, 121.6, 118.7, 116.2, 116.1, 111.0, 62.5,
59.6, 21.7, 21.6; ESI-MS m/z 422 [M + H]+; HRMS (ESI) calc.
for C26H24N5O [M + H]+ 422.1975, found 422.1977.
2,5-Bis(4-fluorophenyl)-2,3,5,12-tetrahydrobenzo[4,5]imidazo-
[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4g)
Isolated as a white powder; m.p. 230.2–230.4 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.41 (brs, 1H, NH), 7.82 (brs, 1H,
NH), 7.65–7.55 (m, 2H, ArH), 7.43 (brs, 1H, NH), 7.35–7.28
(m, 6H, ArH), 7.23 (d, J = 7.8 Hz, 1H, ArH), 6.96 (t, J =
7.8 Hz, 1H, ArH), 6.66 (t, J = 7.8 Hz, 1H, ArH), 6.11 (s, 1H,
CH), 5.77 (d, J = 7.7 Hz, 1H, ArH), 5.28 (s, 1H, CH); 13C NMR
(100 MHz, DMSO-d6) δC: 164.64 and 162.18 (1JCF
=
2,5-Di(pyridin-4-yl)-2,3,5,12-tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-one (4n)
246.5 Hz), 164.14 and 162.14 (1JCF = 250.0 Hz),164.1, 153.4,
143.21 and 143.17 (4JCF = 3.7 Hz), 133.2, 131.7, 130.91 and
130.84 (3JCF = 7.0 Hz), 130.84 and 130.77 (3JCF = 7.0 Hz),
129.42 and 129.38 (4JCF = 3.7 Hz), 121.7, 118.9, 116.3, 116.16
Isolated as a white powder; m.p. 232.2–233.4 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.70 (d, J = 6.1 Hz, 4H, ArH), 8.52
(brs, 1H, NH), 7.94 (brs, 1H, NH), 7.55 (d, J = 6.1 Hz, 2H,
ArH), 7.54 (brs, 1H, NH), 7.28 (d, J = 6.1 Hz, 2H, ArH), 7.27
(d, J = 7.7 Hz, 1H, ArH), 7.01 (t, J = 7.7 Hz, 1H, ArH), 6.70 (t,
J = 7.7 Hz, 1H, ArH), 6.17 (s, 1H, CH), 5.86 (d, J = 7.7 Hz, 1H,
ArH), 5.33 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6) δC:
163.5, 153.1, 150.6, 150.3, 143.9, 141.7, 132.9, 123.9, 123.7,
122.0, 119.2, 116.5, 115.2, 110.9, 61.2, 58.6; ESI-MS m/z 396
[M + H]+; HRMS (ESI) calc. for C22H18N7O [M + H]+
396.1567, found 396.1564.
and 115.99 (2JCF = 17.0 Hz), 115.9, 115.82 and 115.65 (2JCF
=
17.0 Hz), 111.0, 61.7, 58.8; ESI-MS m/z 430 [M + H]+; HRMS
(ESI) calc. for C24H18F2N5O [M + H]+ 430.1474, found 430.1477.
2,5-Bis(4-(trifluoromethyl)phenyl)-2,3,5,12-tetrahydrobenzo[4,5]-
imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4h)
Isolated as a white powder; m.p. 241.0–241.6 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.55 (brs, 1H, NH), 7.89 (d, J = 8.3 Hz,
4H, ArH), 7.88 (brs, 1H, NH), 7.80 (d, J = 8.3 Hz, 2H,
ArH), 7.49 (brs, 1H, NH), 7.48 (d, J = 8.3 Hz, 2H, ArH), 7.24
(d, J = 7.7 Hz, 1H, ArH), 6.98 (t, J = 7.7 Hz, 1H, ArH), 6.69 (t,
J = 7.7 Hz, 1H, ArH), 6.27 (s, 1H, CH), 5.78 (d, J = 7.7 Hz, 1H,
ArH), 5.42 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6) δC:
163.7, 153.3, 143.2, 139.9, 137.6, 133.1, 130.65 and 130.39
(2JCF = 25.3 Hz), 130.35 and 130.09 (2JCF = 25.3 Hz), 129.73
and 129.73 (4JCF = 1.0 Hz), 129.73 and 129.72 (4JCF = 1.0 Hz),
2,5-Di(pyridin-3-yl)-2,3,5,12-tetrahydrobenzo[4,5]imidazo[1,2-a]-
pyrimido[4,5-d]pyrimidin-4(1H)-one (4o)
Isolated as a white powder; m.p. 221.3–222.0 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.70–8.69 (m, 2H, ArH), 8.63 (dd,
J = 4.7, 1.6 Hz, 1H, ArH), 8.57 (brs, 1H, NH), 8.50 (brs, 1H,
NH), 7.98 (dd, J = 8.1, 2.0 Hz, 1H, ArH), 7.93 (s, 1H, ArH),
7.62 (s, 1H, ArH), 7.53 (brs, 1H, NH), 7.52–7.49 (m, 2H, ArH),
126.10 and 126.07 (3JCF = 2.2 Hz), 125.86 and 125.83 (3JCF
=
This journal is © The Royal Society of Chemistry 2012
Green Chem.

View Online
7.21 (d, J = 7.8 Hz, 1H, ArH), 6.97 (t, J = 7.8 Hz, 1H, ArH), 6.66
(t, J = 7.8 Hz, 1H, ArH), 6.21 (s, 1H, CH), 5.79 (d, J = 7.8 Hz,
1H, ArH), 5.38 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6)
δC: 163.7, 153.3, 151.5, 151.0, 149.9, 149.8, 143.1, 136.3,
132.9, 131.2, 129.0, 124.1, 121.9, 119.1, 116.5, 115.6, 111.0,
60.2, 57.4; ESI-MS m/z 396 [M + H]+; HRMS (ESI) calc. for
C22H18N7O [M + H]+ 396.1567, found 396.1569.
62.3, 59.4, 56.1, 55.9; ESI-MS m/z 486 [M + H]+; HRMS (ESI)
calc. for C26H24N5O5 [M + H]+ 486.1772, found 486.1774.
Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (grants 30925040, 81102329) and the Chinese
National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program” (grant 2011ZX09307-
002-03).
2,5-Bis(3,4-dimethoxyphenyl)-2,3,5,12-tetrahydrobenzo[4,5]-
imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4p)
Isolated as a white powder; m.p. 229.0–229.8 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 8.23 (brs, 1H, NH), 7.73 (brs, 1H,
NH), 7.35 (brs, 1H, NH), 7.21 (d, J = 7.6 Hz, 1H, ArH), 7.21 (s,
1H, ArH), 7.10–6.93 (m, 4H, ArH), 6.99 (t, J = 7.6 Hz, 1H,
ArH), 6.85 (s, 1H, ArH), 6.66 (t, J = 7.6 Hz, 1H, ArH), 5.96 (s,
1H, CH), 5.86 (d, J = 7.6 Hz, 1H, ArH), 5.17 (s, 1H, CH), 3.78
(s, 12H, OCH3); 13C NMR (100 MHz, DMSO-d6) δC: 164.5,
153.5, 149.8, 148.6, 143.3, 133.4, 127.6, 125.1, 121.6, 121.2,
118.7, 116.1, 111.9, 111.7, 111.1, 62.3, 59.4, 56.0, 55.9, 55.8,
55.7; ESI-MS m/z 514 [M + H]+; HRMS (ESI) calc. for
C28H28N5O5 [M + H]+ 514.2085, found 514.2083.
Notes and references
1 (a) T. H. Istvan and T. A. Paul, Chem. Rev., 2007, 107, 2167;
(b) I. T. Horvath, Chem. Rev., 2002, 35, 685; (c) R. T. Baker and
W. Tumas, Science, 1999, 284, 1477; (d) P. T. Anastas and J. C. Warner,
Green Chemistry: Theory and Practice, Oxford University Press, Oxford,
1998; (e) P. Anastas and T. Williamson, Green Chemistry, Frontiers in
Benign Chemical Synthesis and Procedures, Oxford Science Publications,
Oxford, 1998; (f) J. Haggin, Chem. Eng. News, 1994, 72, 22;
(g) E. M. Kirschner, Chem. Eng. News, 1994, 72, 13; (h) D. L. Illman,
Chem. Eng. News, 1994, 72, 22.
2 (a) S. Kobayashi and K. Manabe, Acc. Chem. Res., 2002, 35, 209;
(b) U. K. Lindström, Chem. Rev., 2002, 102, 2751; (c) C. J. Li, Chem.
Rev., 2005, 105, 3095; (d) U. M. Lindstrom, Organic Reactions in Water,
Blackwell Publishing, Oxford, UK, 2007; (e) V. K. Ahluwalia and
R. S. Varma, Green Solvents for Organic Synthesis, Alpha Science Inter-
national, Abingdon, UK, 2009; (f) J. N. Tan, H. Li and Y. Gu, Green
Chem., 2010, 12, 1772; (g) D. Bradley, G. Williams, A. Cullen,
A. Fourie, H. Henning, M. Lawton, W. Mommsen, P. Nangu, J. Parker
and A. Renison, Green Chem., 2010, 12, 1919; (h) A. Solhy,
A. Elmakssoudi, R. Tahir, M. Karkouri, M. Larzek, M. Bousmina and
M. Zahouily, Green Chem., 2010, 12, 2261.
3 (a) C. J. Li, Chem. Rev., 1993, 93, 2023; (b) M. C. Pirrung, Chem.–Eur.
J., 2006, 12, 1312; (c) S. Chitra, N. Paul, S. Muthusbramanian and
P. Manisankar, Green Chem., 2011, 13, 2777.
4 (a) G. Choudhary and R. K. Peddinti, Green Chem., 2011, 13, 276;
(b) S. Kumar, P. Sharma, K. K. Kapoor and M. S. Hundal, Tetrahedron,
2008, 64, 536; (c) J. Zhang, Z. Cui, F. Wang, Y. Wang, Z. Miao and
R. Chen, Green Chem., 2007, 9, 1341.
5 (a) Abdel-Hafez and A. M. Atef, Pharmacal Res., 2007, 30, 678;
(b) J. P. Whitten and M. Schwaebe, WO. Pat., 2008060693, 2008.
6 M. Cheung, P. A. Harris, M. Hasegawa, S. Ida, K. Kano, N. Nishigaki,
H. Sato, J. M. Veal, Y. Washio and R. I. West, WO. Pat., 2002044156,
2002.
2,5-Bis(3-hydroxy-4-methoxyphenyl)-2,3,5,12-tetrahydrobenzo-
[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4q)
Isolated as a white powder; m.p. 229.6–231.1 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 9.16 (brs, 2H, OH), 8.20 (brs, 1H,
NH), 7.71 (brs, 1H, NH), 7.36 (brs, 1H, NH), 7.15 (d, J =
7.6 Hz, 1H, ArH), 7.01 (s, 2H, ArH), 7.00–6.90 (m, 5H, ArH),
6.64 (t, J = 7.6 Hz, 1H, ArH), 5.85 (s, 1H, CH), 5.83 (d, J =
7.6 Hz, 1H, ArH), 5.05 (s, 1H, CH), 3.80 (s, 3H, OCH3), 3.79
(s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δC: 164.4,
153.7, 148.8, 146.6, 143.1, 133.4, 128.0, 125.3, 121.4, 119.7,
118.7, 116.4, 115.9, 115.8, 112.2, 111.1, 62.3, 59.4, 56.1, 55.9;
ESI-MS m/z 486 [M + H]+; HRMS (ESI) calc. for C26H24N5O5
[M + H]+ 486.1772, found 486.1774.
7 J. J. Nunes, X. T. Zhu, P. Amouzegh, C. Ghiron, D. N. Johnston and E.
C. Power, WO. Pat., 2005009443, 2005.
2,5-Bis(4-hydroxy-3-methoxyphenyl)-2,3,5,12-tetrahydrobenzo-
[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one (4r)
8 M. W. Martin, J. Newcomb, J. J. Nunes, C. Boucher, L. Chai,
L. F. Epstein, T. Faust, S. Flores, P. Gallant, A. Gore, Y. Gu, F. Hsieh,
X. Huang, J. L. S. Kim, Middleton, K. Morgenstern, A. Oliveira-
dos-Santos, V. F. Patel, D. Powers, P. Rose, Y. Tudor, S. M. Turci,
A. A. Welcher, D. Zack, H. L. Zhao, L. Zhu, X. T. Zhu, C. Ghiron,
M. Ermann, D. Johnston and C. G. P. Saluste, J. Med. Chem., 2008, 51,
1637.
9 J. J. Nunes, X. T. Zhu, M. Ermann, C. Ghiron, D. N. Johnston and
C. G. P. Saluste, WO. Pat., 2005021551, 2005.
10 N. Zanatta, S. S. Amaral, A. Esteves-Souza, A. Echevarria,
P. B. Brondani, D. C. Flores, H. G. Bonacorso, A. F. C. Flores and
M. A. P. Martins, Synthesis, 2006, 2305.
Isolated as a white powder; m.p. 233.0–233.1 °C; 1H NMR
(400 MHz, DMSO-d6) δH: 9.16 (brs, 2H, OH), 8.25 (brs, 1H,
NH), 7.71 (brs, 1H, NH), 7.36 (brs, 1H, NH), 7.11 (d, J = 7.6 Hz,
1H, ArH), 7.07 (s, 1H, ArH), 7.00–6.89 (m, 4H, ArH),
6.85–6.70 (m, 2H, ArH), 6.64 (t, J = 7.6 Hz, 1H, ArH), 5.84 (s,
1H, CH), 5.83 (d, J = 7.6 Hz, 1H, ArH), 5.06 (s, 1H, CH), 3.80
(s, 3H, OCH3), 3.79 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6) δC: 164.4, 153.6, 148.8, 146.6, 143.2, 133.4, 128.0,
125.3, 121.4, 119.7, 118.7, 116.3, 115.9,115.8, 112.1, 111.1,
11 J. H. Liu, M. Lei and L. Hu, Green Chem., 2012, 14, 840.
Green Chem.
This journal is © The Royal Society of Chemistry 2012