One-pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives under solvent-free conditions

Article abstract of DOI:10.1039/c4ra08617a

A series of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones were obtained from aldehydes, phthalhydrazide and malononitrile in good to excellent yields at 80-100 °C under solvent-free conditions by proceeding through a simple, mild and efficient procedure utilizing N,N,N′,N′-tetrabromobenzene-1,3-disulfonamide [TBBDA] and poly(N-bromo-N-ethylbenzene-1,3-disulfonamide) [PBBS] as catalysts. This journal is

Full text of DOI:10.1039/c4ra08617a

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One-pot synthesis of 1H-pyrazolo[1,2-b]
phthalazine-5,10-dione derivatives under solvent-
Cite this: RSC Adv., 2014, 4, 47925
free conditions†
*
Ramin Ghorbani-Vaghei, Samira Noori, Zahra Toghraei-Semiromi and Zahra Salimi
Received 13th August 2014
Accepted 22nd September 2014
A series of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones were obtained from aldehydes, phthalhydrazide and
malononitrile in good to excellent yields at 80–100 ꢀC under solvent-free conditions by proceeding
through a simple, mild and efficient procedure utilizing N,N,N0,N0-tetrabromobenzene-1,3-disulfonamide
[TBBDA] and poly(N-bromo-N-ethylbenzene-1,3-disulfonamide) [PBBS] as catalysts.
DOI: 10.1039/c4ra08617a
www.rsc.org/advances
widely in nature and are essential to life.3–5 Amongst a large variety
of heterocyclic compounds, heterocycles containing phthalazine
Introduction
moiety are of interest because they show some pharmacological
and biological activities.6–8 Phthalazine derivatives were reported to
possess anticonvulsant,9 cardiotonic,10 vasorelaxant,11 cytotoxic,12
antimicrobial,13 antifungal,14 anticancer15 and anti-inammatory
activities.16 Recently, 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives have been synthesized by using p-toluenesulfonic acid
(p-TSA) in ionic liquid, 1-butyl-3-methylimidazolium bromide
[bmim]Br, as solvent at 100 ꢀC,17 triethylamine (0.02 g, 20% mol) as
catalyst in EtOH under ultrasonication18 and 1-butyl-3-
methylimidazolium hydroxide ([Bmim]OH) under irradiation,19
CuI nanoparticles as catalyst under solvent-free conditions,20
Indium chloride(InCl3) as catalyst under solvent-free conditions,21
and Fe3O4 nanoparticles coated by (3-aminopropyl)-triethoxysilane
as catalyst under solvent-free conditions.22 Due to the interesting
properties of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones, the
development of synthetic methods which create a facile access to
this heterocycle compounds is desirable.‡
Multi-component reactions (MCRs) are considered to be important
concepts of organic chemistry. MCRs have great advantages over
classic reaction strategies, such as greater efficiency, more irre-
versible product, and shorter reaction time. Multi-component
reactions have now been well established as a powerful synthetic
tool to produce Heterocyclic components.1,2 Organic reactions
under solvent-free conditions are not only of interest from an
environmental view point, but also offer considerable advantages
in terms of yield, selectivity, and simplicity of the reaction proce-
dures. Organic solvents, due to the high toxicity of the chemical
industry, are a source of chemical contamination and the removal
or replacement is of great help to the environment. In most cases,
the reaction was performed under solvent-free conditions, better
and faster than the conventional methods. The synthesis of new
heterocyclic compounds has always been a subject of great interest
due to their wide applicability. Heterocyclic compounds occur very
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University,
65174, Hamedan, Iran. E-mail: rgvaghei@yahoo.com; Fax: +98 (81)38380709;
Tel: +98 (81)38380709
acetate/n hexane (3 : 10)], the reaction mixture was cooled, and was acetone added
to it (15 mL). The insoluble phthalhydrazide was removed by ltration and washed
with acetone (15 mL). Removal of the solvent under reduced pressure gave the
catalyst. The crude product was recrystallized from ethyl acetate/n hexane (1 : 3) to
afford the pure product.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra08617a
3-Amino-5,10-dioxo-1-pentyl-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile 11: MS: m/z: 310, 239, 232, 184, 162, 155, 132, 119, 104,
76, 57, 51. Anal. calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.69;
H, 5.73; N, 17.47.
‡ Materials and Equipment.
All commercially available chemicals were obtained from Merck and Fluka and
used without further purication unless otherwise stated. 1H and 13C-NMR spectra
were recorded on Bruker Avance 300 FT NMR spectrometers (undertaken at
Kharazmi University, Iran), 400 FT NMR spectrometers (undertaken at University of
Isfahan, Iran) and Jeol FT-90 NMR spectrometers (undertaken at Bu-Ali Sina
University, Iran). Mass spectra were recorded on a 5973 Network Mass selective
Detector Mass Spectrometer (undertaken at University of Tehran, Iran). Elemental
analyses (CHN) were performed with a Elemental Combustion System 4010
(undertaken at University of Tehran, Iran).
3-Amino-1-hexyl-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile 13: MS: m/z: 324, 239, 184, 162, 130, 119, 104, 76, 50.
Anal. calcd for C18H20N4O2: C, 66.65; H, 6.21; N, 17.27. Found: C, 66.64; H, 6.17; N,
17.13.
3-Amino-1-heptyl-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile 14: MS: m/z: 338, 239, 184, 162, 130, 104, 76, 50. Anal.
calcd for C19H22N4O2: C, 67.44; H, 6.55; N, 16.56. Found: C, 67.03; H, 6.24; N, 16.83.
3-Amino-5,10-dioxo-1-phenethyl-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile 12: MS: m/z: 344, 329, 239, 184, 162, 155, 130, 104, 91, 76,
50. Anal. calcd for C20H16N4O2: C, 69.76; H, 4.68; N, 16.27. Found: C, 69.55; H, 4.38;
N, 16.64.
Typical experimental procedure for the synthesis of 1H-pyrazolo[1,2-b]
phthalazine-5,10-dione derivatives using TBBDA and PBBS catalysts:
A mixture of malononitrile (2 mmol), phthalhydrazide (2 mmol), aldehyde (2.2
mmol), and TBBDA (0.09 mmol) or PBBS (0.1 g) was heated at 80 ꢀC. Aer
completion of the reaction by TLC [chamber containing iodine crystals and ethyl
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tetrabromobenzene-1,3-disulfonamide [TBBDA] (15 min, 89%,
Table 1, entry 6). In the light of this fact, subsequent studies were
carried out under the following optimized conditions, that is, with
0.05 g TBBDA at 100 ꢀC. Using a catalytic amount of aqueous 48%
HBr instead of TBBDA gave lower yields (38%). This result indi-
cates that the generation of the protic acid HBr may not be the
only factor responsible for the catalytic activity of TBBDA. It is
possible that the positive sulfonium moiety also has some role
in facilitating. We next examined a wide variety of aldehydes
containing either electron-withdrawing or electron-donating
substituents successfully reacted with phthalhydrazide and
malononitrile to establish the scope of catalysts (Table 1). These
results encouraged us to investigate the scope and generality of
this new protocol for various aliphatic and aromatic aldehydes
under optimized conditions, as shown in Table 2. It is worth
mentioning that there are no reports of the synthesis of 1H-pyr-
azolo[1,2-b]phthalazine-5,10-diones from aliphatic aldehydes. The
nature and electronic properties of the aldehyde substrates affect
the conversion rate and yield. Aromatic aldehydes (Table 2, entries
1–10) react faster and in higher yield than the aliphatic aldehydes
(Table 2, entries 11–14).
Results and discussion
In a continuation of our interest in the application of N,N,N0,N0-
tetrabromobenzene-1,3-disulfonamide [TBBDA] and poly(N-
bromo-N-ethylbenzene-1,3-disulfonamide) [PBBS],23 in organic
synthesis,23–33 we report a new and efficient method for the one-
pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione deriv-
atives by the condensation of various aliphatic and aromatic
aldehydes with phthalhydrazide and malononitrile in the pres-
ꢀ
ence of TBBDA and PBBS as efficient catalysts at 80–100 C in
good to excellent yields. The route for the synthesis of 1H-pyr-
azolo[1,2-b]phthalazine-5,10-dione is shown in Scheme 1.
The advantages of TBBDA and PBBS are as follows:
1. The preparation of TBBDA and PBBS are easy.
2. TBBDA and PBBS are stable under atmospheric conditions
for two months.
3. Aer completion of the reaction, the catalysts are recov-
ered and can be reused several times without decreasing the
yield.
Initially, we decided to explore the role of our catalyst in various
conditions for the synthesis of 3-amino-5,10-dioxo-1-phenyl-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile as a model
compound (Table 2, entry 1). In the ethanol system, the best
results were achieved using 0.1 g of N,N,N0,N0-tetrabromobenzene-
1,3-disulfonamide [TBBDA] (90 min, 71%, Table 1, entry 2).
Therefore, we decided to test this solvent-free reaction with
various ratios of TBBDA. We found that the reaction was rapid and
gave excellent yield of the product while using N,N,N0,N0-
Mechanistically, it is likely that these catalysts release
Br+ in situ, which can act as an electrophilic species and
Scheme 1 One-pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-
Scheme 2 Suggested mechanism for synthesis of 1H-pyrazolo[1,2-b]-
dione derivatives.
phthalazine-5,10-dione derivatives.
Table 1 Optimization of reaction conditions for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Entry
Solvent
Catalyst
Amount of catalyst
Time (min)
Yield (%)
Tempe (ꢀC)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
Solvent-free
Solvent-free
Solvent-free
Solvent-free
TBBDA/PBBS
TBBDA/PBBS
TBBDA/PBBS
HBr (48%)
TBBDA/PBBS
TBBDA/PBBS
TBBDA/PBBS
None
0.05 g
0.1 g
0.1 g
5 mol%
0.03 g
0.05 g
0.07 g
—
120
90
90
120
35
15
62/40
71/54
—
Reux
Reux
rt
Reux
100
100
100
100
38
78/61
89/65
89/65
29
15
120
47926 | RSC Adv., 2014, 4, 47925–47928
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Table
derivatives
2 Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
the mechanism shown in Scheme 2 is proposed for the
synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione deriv-
atives.23,32 According to this mechanism, TBBDA can be
activated the carbonyl group to formation of an alkene
(a) and then cation (b) as intermediates. Intramolecular
cyclization lead to the 1H-pyrazolo[1,2-b]phthalazine-5,10-
dione derivatives.
In recent years, synthesis of organic compounds in the
absence of solvents has attracted much interest from chemists
from the view point of reduced pollution, low cost, simplicity in
process and handling.
TBBDA time
PBBS time
Entry Substrate
(min)/yield (%) [Lit.] (min)/yield (%) Ref.
1
2
3
4
15/89[87]
20/84[81]
15/83[82]
15/85[92]
40/65
50/72
40/69
40/70
34
34
34
34
Conclusions
We have developed a simple procedure for the synthesis of
novel 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
from the reaction of various aliphatic and aromatic aldehydes
with phthalhydrazide and malononitrile in the presence of
TBBDA and PBBS as catalysts under solvent-free conditions.
Moreover, the method has advantages in terms of product
yields, recyclable catalyst, operational simplicity (easy work-up
of reactions), environmental friendliness (non-corrosive cata-
lyst), inexpensive catalyst and short reaction times.
5
15/87
40/64
—
Acknowledgements
6
7
15/90[91]
15/83
45/63
40/69
36
The authors are thankful to the Center of Excellence in Devel-
opment of Environmentally Friendly Methods for Chemical
Synthesis (CEDEFMCS), Bu-Ali Sina University, for nancial
support.
—
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9
10/89[90]
15/90[94]
10/85
15/83
35
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47928 | RSC Adv., 2014, 4, 47925–47928
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