Polyethylene glycol-promoted synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives in water

Article abstract of DOI:10.1080/00397911.2017.1278774

Synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives were achieved using polyethylene glycol (PEG-400) as promoting reaction medium in water under catalyst-free conditions at reflux and room temperature, respectively. The structure of pyrimido[1,2-a]benzimidazole was confirmed using ¹H NMR, ¹³C NMR, DEPT, and HMBC experiments. The promising points for the present methodology are efficiency, generality, high yield, short reaction time, cleaner reaction profile, ease of product isolation, simplicity, potential of recycling reaction medium, and finally agreement with green chemistry protocols.

Full text of DOI:10.1080/00397911.2017.1278774

Polyethylene Glycol Promoted Synthesis of Pyrimido[1,2-a]benzimidazole and
Pyrano[2,3-c]pyrazole Derivatives in Water
Dattatray Survase1, Babasaheb Bandgar2, Vasant Helavi1,
1Organic chemistry Research Laboratory, Department of chemistry, Rajaram College
Kolhapur (MS) India
2School of chemical science, Solapur University Solapur, (MS) India
Abstract
Synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives were
achieved using polyethylene glycol (PEG-400) as promoting reaction medium in water
under catalyst-free conditions at reflux and room temperature respectively. The structure
1
of pyrimido[1,2-a]benzimidazole was confirmed using HNMR, 13CNMR, DEPT and
HMBC experiments. The promising point for present methodology are efficiency,
generality, high yield, short reaction time, cleaner reaction profile, ease of product
isolation, simplicity, potential of recycling reaction medium and finally agreement with
green chemistry protocols.
Graphical Abstract
1

KEYWORDS: Catalyst-free synthesis, pyrimido[1,2-a]benzimidazole, PEG-Water,
pyrano[2,3-c]pyrazole
1. INTRODUCTION
The discovery of new synthetic methodologies that facilitate the preparation of
organic compound is a focal point of research activity in field of modern organic, bio-
organic and medicinal chemistry [1]. Benzimidazole is a class of heterocyclic aromatic
organic compound which share a fundamental structural characteristic of six membered
benzene fused to the 4 and 5-position of five membered imidazole ring system. The
heterocyclic benzimidazole scaffold is a useful structural motif for the development of
molecules of pharmaceutical or biological interest. In 1872, Hobrecker reported the first
benzimidazole synthesis of 2,5- and 2,6-dimethylbenzimidazole and he never suspected
that benzimidazole scaffold would become such a preeminent structure [2]. The interest in
benzimidazole chemistry has been spawned by the discovery of N-ribosyl-dimethyl
benzimidazole. The N-ribosyl-dimethyl benzimidazole was found to be most prominent
benzimidazole compound in nature serves as an axial ligand for cobalt in vitamin B12 [3]
Over the years of active research, benzimidazole and its derivatives have evolved as
important privileged structures in medicinal chemistry encompassing a diverse range of
biological activities including antiparasitic (specifically anthelmintics, e.g., albendazole,
mebendazole), Antiulcer (proton pump inhibitors (PPIs), e.g., omeprazole),
.
antihypertensive (angiotensin II receptor blockers, e.g., candesartan, telmisartan),
antihistaminic (H1-receptor antagonists, e.g., Bilastine), anti-cancer (nitrogen mustard
alkylating agents, e.g., bendamustine), antiemetic/antipsychotics (e.g., droperidol) [4-6]
.
2

The fused pyrimido[1,2-a]benzimidazole ring system with phenyl sulfonyl moiety
exhibited comparable analgesic and anti-inflammatory activity to indomethacin [7] and
The tricyclic benzimidazole compounds having potent anti-inflammatory activity
comparable to standard ibuprofen [8-10]. A number of drugs like albendazole,
mebendazole, thiabendazole as anthelmintics; omeprazole, lansoprazole, pantoprazole as
proton pump inhibitors; astemizole as antihistaminic; enviradine as antiviral; candesarten
cilexitil and telmisartan as antihypertensive contains benzimidazole were already well
established and successfully used in the treatment of multiple ailments. Therefore
development of an efficient, one pot and chemo selective procedure synthesis of
pyrimido[1,2-a]benzimidazole in green reaction medium without catalyst is of
considerable interest. PEGs are green, non-volatile, recyclable, stable to acid, base, and
also to high temperature. Recently reported in many reactions, PEG and its aqueous
solutions were acting as promoting reaction medium [11-16]. Here we were report a facile
and convenient way to create diversely substituted medicinally privileged 2-amino
pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole scaffold. The new simple green
non catalytic multicomponent process in PEG-Water as a solvent can produce an
effective transformation of aromatic aldehyde, malononitrile and 2-amino benzimidazole
into heterocyclic pyrimido[1,2-a]benzimidazole at reflux without addition of catalyst.
2. RESULT AND DISCUSSION
A catalyst free condensation of p-chloro benzaldehyde, 2-amino benzimidazole and
malononitrile were studied in different solvents at various temperature conditions. It was
observed that only trace amount of product formed in DMF, DMSO and Toluene while it
3

furnished moderate yield in water. In polyethylene glycol reaction proceeded at reflux
giving 60% yield. We observed that knoevenagel condensation requires more time (~2 h)
in PEG 400 so only small amount of water in PEG is essential to catalyze knoevenagel
condensation with faster rate. The best results were obtained in PEG: Water (8:2) by
optimizing reaction conditions at different PEG: water ratio shown in table 1.
Interestingly we found that knoevenagel condensation proceeds within 5-10 min in
presence of PEG: water. Water catalyses knoevenagel condensation [17, 21] and hence
cyclocondensation reaction completes within 6 h with good to excellent yields. Initially
all starting materials were soluble in aqueous PEG solution so at the start of the reaction a
solution was observed to be nearly transparent. Almost all products were found to be
insoluble in PEG solution, so with the progress of reaction products sediments slowly
from reaction mixture. Due to high hydrophilicity of PEG, separation of the products
from reaction mixture could be realized by adding water. This simple procedure allowed
easy scale up of our methodology. We extended the reaction towards synthesis of
pyrano[2,3-c]pyrazole Surprisingly we found that the reaction completes within short
reaction time without use of catalyst at room temperature.
All synthesized compounds were characterised by IR, 1H and 13CNMR and
Mass spectroscopy and found to be well matching with that reported in the literature [18-
20]. We observed that aldehydes having electron donating or electron withdrawing groups
does not affect reaction rate considerably. However steric effect from the substrate had a
major impact on the overall yield of product (Table 2 entry 4e and 4g). After reaction,
the polyethylene glycol was easily separated from the reaction medium by washing with
4

distilled water (PEG is soluble in water). The washed PEG is distilled under vacuum to
recover solvent for reuse in subsequent reactions. After three successive runs, recycled
PEG showed no loss of efficiency with regard to reaction time and yield.
3. CONCLUSION
The new, simple, green and non-catalytic multicomponent process offers a
facile and convenient way to create substituted medicinally relevant pyrimido[1,2-
a]benzimidazoles and its derivatives approved basis for the generation of molecules
having promising biological activity. The promising point for present methodology are
efficiency, generality, high yield, short reaction time, cleaner reaction profile, ease of
product isolation, simplicity, potential of recycling reaction medium and finally
agreement with green chemistry protocols, making it a useful and attractive process for
the synthesis of pyrimido[1,2-a]benzimidazole derivatives. Application of PEG-water as
a solvent system not only makes product separation much easier, but also shows higher
environmental compatibility and sustainability due to the avoidance of quenching steps,
reduced reliance on toxic organic solvents and minimization of waste and convenience of
non-catalytic chain ‘green’ processes in water. Therefore this type of MCR brings us a
closer to the notion of ‘ideal synthesis’ [11]
.
4. EXPERIMENTAL
All chemicals were obtained from commercial suppliers and were used
without further purification. Melting points were determined in open capillaries and were
uncorrected. All reactions were monitored by thin layer chromatography (TLC) with 0.2
5

mm Merck silica gel F254 plates. NMR spectra were recorded on Bruker Avance III FT
NMR at 400 MHz spectrometer in DMSO-d6 using TMS as internal standard (chemical
shifts are expressed as δ values relative to TMS as internal standard). IR spectra were
recorded on a Perkin Elmer FTIR spectrophotometer.
General one-pot procedure for synthesis of pyrimido[1,2-a]benzimidazoles : A
mixture of aldehyde (1 mmol), 2-amino benzimidazole (1 mmol) and malononitrile (1
mmol) in PEG 400 (4 ml) and water (1 ml) solution were refluxed for 6-8 h. The progress
of reaction was monitored by TLC using petroleum ether: ethyl Acetate (6:4) as solvent
system. After completion of the reaction, H2O (200 ml) was added and stirred for 2-3 h,
the solid product separate out which was filtered to give the corresponding product with
high purity without the need of column chromatography for purification.
General one-pot procedure for synthesis of pyrano[2,3-c]pyrazole derivatives: A
mixture of ethyl acetoacetate (1.2 mmol) and hydrazine hydrate (1.2 mmol) was taken in
dry reaction flask, The flask was stirred till the solid separate out within 1-2 min. To this
flask Aldehyde (1 mmol), malononitrile (1 mmol) and PEG 400 (4 ml): water (1 ml)
solution was added and continued the stirring for 2-3 h at room temperature. The progress
of reaction was monitored by TLC using petroleum ether: ethyl Acetate (6:4) as solvent
system. After completion of the reaction the reaction mass was poured over ice, 200 ml
water was added to solution and solution was stirred for 2 hr. The obtained solid was
filtered, washed with water and crude solid was crystallized from methanol.
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SUPPORTING INFORMATION
Supplementary material, which includes some of the scan copies of IR, 1H-NMR,
13CNMR and Mass analysis, for this article can be accessed on the publisher’s website
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Table 1 Optimisation of reaction conditions for a catalyst-free synthesis of 4b in different
solvent and at temperature conditions respectively.
Entry Solvent
Temp (oC)
Time(h)
Yield (%)b
1
2
3
4
5
6
7
8
9
Toluene
90
7
7
7
7
7
7
7
7
7
Trace
Trace
Trace
60
DMF
90
DMSO
90
Water
90
PEG-600
reflux
reflux
reflux
reflux
reflux
65
PEG: Water (5:5)
PEG: Water (7:3)
PEG: Water (8:2)
PEG: Water (9:1)
74
80
86
82
Reaction Condition: p-chloro benzaldehyde (1 mmol), 2-amino benzimidazole (1 mmol)
and malononitrile (1 mmol), Solvent (5 ml), b isolated yield.
9

Table 2 The reaction between aromatic aldehyde, 2-amino benzimidazole / (Ethyl
acetoacetate and hydrazine hydrate) (1mmol each) and malononitrile in PEG: Water at
reflux and room temperature respectively.
Entry
Aldehyde
Producta
Time ( hr)
Yield
(%)b
84
Ref
18
1
7
2
7
86
18
3
4
5
6
7.5
7
75
80
72
80
18
18
18
18
7.5
7.5
10

7
8
9
2.0
2.0
2.0
77
90
91
18
19
19
10
11
2.0
2.5
88
81
19
20
12
13
2.0
2.0
86
87
19
19
11

14
2.5
80
20
Reaction Condition: Aromatic aldehyde (1 mmol), 2-amino benzimidazole / (Ethyl
acetoacetate and hydrazine hydrate) (1 mmol each) and malononitrile (1 mmol) in PEG:
Water (4:1) at reflux.
aAll the products are known and were identified by their comparison of their IR and
NMR spectra [18-20], b isolated Yields.
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Scheme 1 A catalyst-free synthesis of 4b and 6e using PEG-H2O as aqueous reaction
medium.
13

Scheme 2 A catalyst-free synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-
c]pyrazole derivatives using PEG-H2O as aqueous reaction medium.
14