Ultrasound-promoted catalyst-free one-pot four component synthesis of 2H-indazolo[2,1-b]phthalazine-triones in neutral ionic liquid 1-butyl-3-methylimidazolium bromide

Article abstract of DOI:10.1016/j.ultsonch.2011.07.011

A catalyst-free one-pot four component methodology for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones under ultrasonic irradiation at room temperature using 1-butyl-3-methylimidazolium bromide, [Bmim]Br, as a neutral reaction medium is described. A broad range of structurally diverse aldehydes (aromatic aldehydes bearing electron withdrawing and/or electron releasing groups as well as heteroaromatic aldehydes) were applied successfully, and corresponding products were obtained in good to excellent yields without any byproduct.

Full text of DOI:10.1016/j.ultsonch.2011.07.011

Ultrasonics Sonochemistry 19 (2012) 307–313
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound-promoted catalyst-free one-pot four component synthesis
of 2H-indazolo[2,1-b]phthalazine-triones in neutral ionic liquid
1-butyl-3-methylimidazolium bromide
b
Mohsen Shekouhy a, , Alireza Hasaninejad
⇑
a College of Chemistry, Islamic Azad University, Bandar Abbas Branch, Hormozgan, Iran
b Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2011
Received in revised form 14 July 2011
Accepted 25 July 2011
Available online 30 July 2011
A catalyst-free one-pot four component methodology for the synthesis of 2H-indazolo[2,1-b]phthalazine-
triones under ultrasonic irradiation at room temperature using 1-butyl-3-methylimidazolium bromide,
[Bmim]Br, as a neutral reaction medium is described. A broad range of structurally diverse aldehydes
(aromatic aldehydes bearing electron withdrawing and/or electron releasing groups as well as heteroar-
omatic aldehydes) were applied successfully, and corresponding products were obtained in good to
excellent yields without any byproduct.
Keywords:
1-Butyl-3-methylimidazolium bromide
Ultrasound
Ó 2011 Elsevier B.V. All rights reserved.
2H-Indazolo[2,1-b]phthalazine-trione
Catalyst-free reaction
Multi-component reaction
Combinatorial chemistry
1. Introduction
derivatives [9], 3,4-dihydropyrimidin-2-ones [10], 1,3,5-thiadiazole
and bi(1,3,5-thiadiazole) [11], benzoacridinones [12], 2-(3,5-diaryl-
The efficient high-throughput synthesis of organic compounds is
one of the most important objectives in modern drug discovery.
Organic reactions should be fast and facile, and the target products
should be easily separated and purified in high yields. From this
point of view, there is much interest in the implementation of new
processes and new synthetic strategies. In this regard, nonclassical
methods, microwave-assisted synthesis, ultrasonic irradiation, and
supercritical fluids, find application as appealing methods to achieve
these goals [1]. Ultrasonic activation, based on cavitation effects
leading to mass transfer improvement, is widely used today to pro-
mote numerous organic reactions [2]. A survey of literature shows
that the synthesis of heterocyclic compounds has been accelerated
by ultrasound irradiation. Compared with traditional methods, this
technique is more convenient and easily controlled and is more
appropriate in the consideration of green chemistry concepts [3].
In this way, Cella and Stefani have recently published an important
review concerningto the use of ultrasound in heterocyclic chemistry
[4]. Ultrasound irradiation have also been used for the synthesis of a
wide variety of heterocycles such as tetrahydropyrimidines [5],
4H-benzo[b]pyran derivatives [6], 1,8-dioxooctahydroxanthene
derivatives [7], 1,5-benzodiazepines [8], pyrido[2,3-d]pyrimidine
4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles [13]. In all cases,
the reactions occurred under mild conditions with good to excellent
yields and in a few minutes.
In the other hand multi-component reactions (MCRs) play an
important role in combinatorial chemistry because of the ability
to synthesize target compounds with greater efficiency and atom
economy by generating structural complexity in a single step from
three or more reactants. Moreover, MCRs offer the advantage of
simplicity and synthetic efficiency over conventional chemical
reactions [14].
Moreover one of the most important aspects in green chemistry
is the use of ionic liquids (ILs) as greener solvents in organic reac-
tions that is in combination with some advantages such as control
of product distribution [15], enhanced rate [16] and/or reactivity
[17], ease of product recovery [18], catalyst immobilization [19],
and recycling [20]. Since ILs are neither completely nonvolatile
nor non-flammable, use of ILs omits the risk of combustion by
replacement of volatile organic compounds widely used as sol-
vents in organic reactions.
In combination with the use of ILs in organic transformations,
catalyst-free methodologies for the synthesis of organic com-
pounds have attracted much interest because of their ease of
experimental procedures as well as workup, low cost, possibility
of using acid or base sensitive substrates, and environmentally
⇑
Corresponding author. Tel.: +98 (761)6665501; fax: +98 (761)6670243.
E-mail address: m.shekouhy@gmail.com (M. Shekouhy).
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.07.011

308
M. Shekouhy, A. Hasaninejad / Ultrasonics Sonochemistry 19 (2012) 307–313
benign nature [21]. Many organic transformations were studied
under catalyst-free conditions such as synthesis of 2-amino thiaz-
ols,[22] N-benzyloxycarbonylation of amines,[23] synthesis of ben-
zoic and benzyl esters,[24] gembisillylation of carboxylic acids,[25]
synthesis of polyorganosyloxanes [26] and one-pot four compo-
nent synthesis of poly substituted imidazoles [27].
added to [Bmim]Br (0.5 g) in a 25 mL Pyrex flask. The mixture
was continuously irradiated for the appropriate time (Table 2) at
room temperature. The reactions were followed by thin layer chro-
matography (TLC) using hexane/ethyl acetate (3:1) as an eluent.
The ultrasonic apparatus used showed the temperature automati-
cally so the temperature was controlled and fixed at room temper-
ature by pouring cold water in the bath in the case of any elevation
of temperature. After completion of the reaction, water (20 mL)
was added and stirred magnetically for 5 min. Insoluble crude
products were filtered, dried, and recrystallized from ethanol. To
recover the [Bmim]Br, after the isolation of insoluble products,
water was evaporated, and the remaining viscous liquid was
washed with ethyl acetate (5 mL) and dried under reduced pres-
sure ([Bmim]Br was recovered in 97% yield).
Nitrogen heterocycles containing a phthalazine moiety are
important because they show biological and pharmacological
activities such as anticonvulsant, cardiotonic, and vasorelaxant,
and also unique electrical and optical properties [28]. Despite
many methods being available for the synthesis of phthalazine
derivatives,[29–33] their broad utility has accentuated the need
to develop new synthetic routes for these compounds. Recent pro-
tocols have employed three-component condensations of alde-
hydes and dimedone (5,5-dimethylcyclohexane-1,3-dione) with
2,3-dihydro-1,4-phthalazinedione (phthalhydrazide) and/or one-
pot four component reaction between aldehydes and dimedone
(5,5-dimethylcyclohexane-1,3-dione), hydrazinium hydroxide and
phthalic anhydride using various catalytic systems such as p-tolu-
enesulfonic acid (p-TSA) [34a], H2SO4 [34b], heteropoly acids
(HPAs) [34c], starch sulfate [35a], CeSO4Á4H2O [35b] and silica sup-
ported poly phosphoric acid [35c]. These protocols have limitations
such as the formation of by-products and the use of toxic organic
solvents, acidic conditions, large amounts of catalyst, and tedious
work-up procedures. According to the principle of safe chemistry,
synthetic methods should be designed to use substances that exhi-
bit little or no toxicity to human health and the environment [36].
As a part of our continuing studies in developing efficient cata-
lyst-free synthetic methodologies in organic preparations,[27,37]
we found that synthesis of 2H-indazolo [2,1-b] phthalazine-triones
via a one-pot four component reaction can be efficiently achieved
without any catalyst with the use of neutral ILs under ultrasonic
irradiation at room temperature.
2.3. Selected Spectral data
2.3.1. 3,3-dimethyl-13-phenyl-3,4-dihydro-1H-indazolo[1,2-b]
phthalazine-1,6,11(2H,13H)-trione (Compound 5a)
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.23 (s, 6H),
2.33 (Distorted AB system, 2H), 3.25 (AB System, J = 18.0 Hz, 1H),
3.48 (AB System, J = 18.0 Hz, 1H), 6.44 (s, 1H), 7.41–8.42 (m, 9H).
13C NMR (125 MHz, CDCl3): d (ppm) 28.2, 28.4, 34.3, 38.0, 50.4,
64.5, 118.6, 127.0, 127.5, 127.7, 128.3, 128.6, 129.1, 133.4, 134.2,
136.3, 150.9, 151.7, 154.2, 156.8, 192.3. Anal. Calcd for
C23H20N2O3: C, 74.18; H, 5.41; N, 7.52%, Found: C, 74.23; H, 5.40;
N, 7.61%.
2.3.2. 13-(4-chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-indazolo
[1,2-b]phthalazine-1,6,11(2H,13H)-trione (Compound 5b)
White powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.21 (s, 3H),
1.23 (s, 3H), 2.33 (Distorted AB System, 2H), 3.26 (AB System,
J = 18.5 Hz, 1H), 3.44 (AB System, J = 18.5 Hz, 1H), 6.45 (s,1H),
7.33–8.42 (m, 8H). 13C NMR (125 MHz, CDCl3): d (ppm) 28.3,
28.4, 34.5, 38.1, 50.6, 64.4, 118.2, 127.7, 128.0, 128.4, 128.5,
128.7, 129.0, 133.3, 134.4, 134.6, 134.9, 151.0, 154.2, 156.0,
192.2. Anal. Calcd for C23H19ClN2O3: C, 67.90; H, 4.71; N, 6.89%,
Found: C, 67.81; H, 4.77; N, 6.95%.
2. Methods
2.1. Apparatus and analysis
Reagents and solvents were purchased from Merck, Fluka or
Aldrich. The IL was prepared according to the reported method
[38]. Melting points were determined in capillary tubes in an elec-
tro-thermal C14500 apparatus. The progress of the reaction and
the purity of compounds were monitored by TLC analytical silica
gel plates (Merck 60 F250). All known compounds were identified
by comparison of their melting points and 1H NMR data with those
in the authentic samples. The 1H NMR (500 MHz) and 13C NMR
(125 MHz) were run on a Bruker Avance DPX-250, FT-NMR spec-
trometer. Chemical shifts are given as d values against tetrameth-
ylsylane as the internal standard and J values are given in Hz.
Microanalysis was performed on a Perkin–Elmer 240-B microana-
lyzer. The ultrasound apparatus was cleaning bath Wiseclear
770 W (Seoul, Korea). The operating frequency was 40 kHz and the
output power was 200 W, estimated calorimetrically. The reaction
flasks were located in the maximum energy area in the water bath,
where the surface of reactants (reaction vessel) is slightly lower than
the level of the water, and the addition or removal of water
controlled the temperature of the water bath. The temperature of
the water bath was controlled at 25–30 °C. All experiments per-
formed in this work were repeated three times. The yield reported
represents the average of the values obtained for each reaction.
2.3.3. 13-(4-fluorophenyl)-3,3-dimethyl-3,4-dihydro-1H-indazolo
[1,2-b]phthalazine-1,6,11(2H,13H)-trione (Compound 5d)
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.23 (s, 6H),
2.35 (Distorted AB System, 2H), 3.22 (AB System, J = 18.5 Hz, 1H),
3.43 (AB System, J = 18.0 Hz, 1H), 6.41 (s, 1H), 7.01–8.44 (m, 8H).
13C NMR (125 MHz, CDCl3): d (ppm) 28.5, 28.6, 34.8, 38.1, 50.5,
1
64.2, 115.6, 115.9 (d, JC–F = 275 Hz), 118.0, 127.3, 128.0, 128.9,
129.0, 132.4, 133.5, 134.6, 151.1, 152.0, 154.3, 156.0, 192.1. Anal.
Calcd for C23H19FN2O3: C, 70.76; H, 4.91; N, 7.18%, Found: C,
70.82; H, 4.85; N, 7.29%.
2.3.4. 3,3-dimethyl-13-p-tolyl-3,4-dihydro-1H-indazolo[1,2-b]
phthalazine-1,6,11(2H,13H)-trione (Compound 5h)
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.25 (s, 6H),
2.31 (s, 3H), 2.38 (Distorted AB System, 2H), 3.22 (AB System,
J = 18.0 Hz, 1H), and 3.45 (AB System, J = 18.0 Hz, 1H), 6.43 (s,
1H), 7.16–8.42 (m, 8H). 13C NMR (125 MHz, CDCl3): d (ppm) 21.3,
28.5, 28.9, 34.6, 38.1, 50.6, 64.6, 118.3, 127.0, 127.7, 127.9, 128.8,
129.3, 129.5, 133.4, 133.6, 134.2, 138.5, 150.9, 154.3, 156.3,
192.1. Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25%,
Found: C, 74.66; H, 5.71; N, 7.39%.
2.2. General procedure for the synthesis of 2H-indazolo[2,1-b]
phthalazine-triones
2.3.5. 13-(4-isopropylphenyl)-3,3-dimethyl-3,4-dihydro-1H-indazolo
[1,2-b]phthalazine-1,6,11(2H,13H)-trione (Compound 5o)
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.22 (s, 3H),
1.25 (s, 6H), 1.27 (s, 3H), 2.37–2.38 (Distorted AB System, 2H),
2.89–2.94 (m, 3H), 6.24 (s, 1H), 7.24 (t, J = 8.0 Hz, 2H), 7.38 (d,
Dimedone (1 mmol), aromatic aldehyde (1 mmol), hydrazinium
hydroxide (1.2 mmol) and phthalic anhydride (1 mmol) were

M. Shekouhy, A. Hasaninejad / Ultrasonics Sonochemistry 19 (2012) 307–313
309
J = 8.5 Hz, 2H), 7.43–7.48 (m, 1H), 7.52–8.35 (m, 4H). 13C NMR
(125 MHz, CDCl3): d (ppm) 24.3, 28.8, 29.1, 34.2, 35.1, 35.9, 51.7,
64.3, 120.5, 126.0, 127.44, 127.48, 129.1, 129.7, 131.2, 134.5,
149.4, 149.9, 151.0, 151.3, 154.3, 156.3, 191.3. Anal. Calcd for
125.6, 126.6, 127.0, 127.4, 128.5, 128.9, 132.1, 132.5, 135.7,
139.0, 155.4, 158.6, 191.3. Anal. Calcd for C21H18N2O3S: C, 66.65;
H, 4.79; N, 7.40%, Found: C, 66.78; H, 4.86; N, 7.49%.
C
26H26N2O3: C, 75.34; H, 6.32; N, 6.76%, Found: C, 75.43; H, 6.33;
2.3.8. 3,3-dimethyl-13-(naphthalen-2-yl)-3,4-dihydro-1H-indazolo
[1,2-b]phthalazine-1,6,11(2H,13H)-trione (Compound 5r)
N, 6.85%.
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.24 (s, 3H),
1.25 (s, 3H), 2.37 (Distorted AB System, 2H), 2.97 (AB System,
J = 15.0 Hz, 1H), 3.01 (AB System, J = 15.0 Hz, 1H), 6.41 (s, 1H),
7.42–7.56 (m, 8H), 7.85–7.86 (m, 1H), 7.88–8.29 (m, 3H). 13C
NMR (125 MHz, CDCl3): d (ppm) 28.7, 29.1, 35.2, 36.0, 51.7, 64.8,
120.6, 124.5, 126.0, 126.8, 126.9, 127.2, 128.1, 128.7, 131.1,
133.6, 133.8, 134.5, 135.7, 137.1, 138.2, 149.5, 151.1, 151.5,
154.3, 156.3, 192.3. Anal. Calcd for C27H22N2O3: C, 76.76; H, 5.25;
N, 6.63%, Found: C, 76.83; H, 5.32; N, 6.70%.
2.3.6. 13-(1H-indol-3-yl)-3,3-dimethyl-3,4-dihydro-1H-indazolo[1,2-b]
phthalazine-1,6,11(2H,13H)-trione (Compound 5p)
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.23 (s, 6H),
2.33 (Distorted AB System, 2H), 3.24 (AB System, J = 18.5 Hz, 1H),
3.43 (AB System, J = 18.0 Hz, 1H), 6.43 (s, 1H), 7.32–8.46 (m, 9H),
9.87 (brs, 1H). 13C NMR (125 MHz, CDCl3): d (ppm) 24.2, 28.5,
29.0, 34.1, 35.3, 35.9, 51.9, 64.8, 111.3, 112.0, 114.6, 118.3, 119.2,
121.4, 123.0, 123.9, 127.2, 127.5, 128.35, 128.39, 132.21, 132.29,
135.5, 136.8, 156.4, 158.8, 191.3. Anal. Calcd for C25H21N3O3: C,
72.98; H, 5.14; N, 10.21%, Found: C, 72.82; H, 5.19; N, 10.29%.
3. Results and discussions
2.3.7. 3,3-dimethyl-13-(thiophen-2-yl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (Compound 5q)
To find an appropriate reaction medium for the catalyst-free
synthesis of the titled compounds, one-pot four component reac-
tion between dimedone (1) (1 mmol), benzaldehyde (2a) (1 mmol),
hydrazinium hydroxide (3) (1.2 mmol) and phthalic anhydride (4)
(1 mmol) was selected as a model reaction (Scheme. 1) and was
examined in several reaction medium (0.5 g) and the yield and
reaction times were monitored in the presence of ultrasonic irradi-
ation at room temperature. The obtained results are summarized in
Table 1.
Yellow powder, 1H NMR (500 MHz, CDCl3): d (ppm) 1.22 (s, 6H),
2.34 (Distorted AB System, 2H), 3.25 (AB System, J = 18.5 Hz, 1H),
3.46 (AB System, J = 18.0 Hz, 1H), 6.24 (s, 1H), 6.79 (d, J = 9.0 Hz,
1H), 6.98 (t, J = 9.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.68 (d,
J = 8.0 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H). 13C NMR (125 MHz, CDCl3):
d (ppm) 24.4, 28.1, 29.3, 34.4, 35.0, 35.6, 51.9, 64.7, 116.0, 123.5,
Table 1
Catalyst-free one-pot four component reaction between dimedone (1) (1 mmol),
benzaldehyde (2a) (1 mmol), hydrazinium hydroxide (3) (1.2 mmol) and phthalic
anhydride (4) (1 mmol) in several reaction medium in the presence of ultrasonic
irradiation at room temperature.
CHO
O
(2a)
Yield (%)a
O
O
Entry
Reaction medium
Time (min)
O
O
N
1
2
3
4
H2O (0.5 mL)
60
60
60
60
60
60
10
31
63
44
31
77
79
93
O
N
EtOH (0.5 mL)
CH3CN (0.5 mL)
CHCl3 (0.5 mL)
PEG 400 (0.5 mL)
SiO2 (0.5 g)
O
O
(4)
(1)
5
(5a)
.H2O
H2N NH2
6b
7
(3)
[Bmim]Br (0.5 g)
a
Isolated yield.
Scheme. 1. The one-pot four component reaction between dimedone (1) (1 mmol),
benzaldehyde (2a) (1 mmol), hydrazinium hydroxide (3) (1.2 mmol) and phthalic
anhydride (4) (1 mmol).
b
Reaction conditions: substrates were mixed with SiO2 truly and the obtained
mixture was irradiated under the neat condition.
Table 2
Catalyst-free one-pot four component synthesis of 2H-indazolo[2,1-b]phthalazine-triones in [Bmim]Br in the presence of ultrasonic irradiation at room temperature.
Entry
R
Compound
Time (min)
Yield (%)a
M.P. (°C)
Found
Reported
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
4-BrC6H4
4-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
10
7
7
10
3
10
5
10
14
8
15
5
15
12
10
15
8
93
91
92
93
95
91
94
91
90
92
90
92
90
89
93
92
90
93
206–208
260–262
262–263
222–223
215–217
266–267
272–274
227–229
239–241
206–207
242–243
215–217
218–220
183–185
230–232
248–250
232–234
240–242
207–209[35c]
259–261[35c]
258–260[35c]
224–226[35c]
217–219[35c]
264–266[35c]
270–272[35c]
226–228[35c]
241–243[35c]
204–206[35c]
240–241[35a]
214–216[35a]
216–217[35a]
180–182[35a]
-
4-NO2C6H4
2-ClC6H4
3-NO2C6H4
4-CH3C6H4
2-CH3C6H4
3-ClC6H4
2-CH3OC6H4
4-CF3C6H4
4-CH3OC6H4
3-PhOC6H4
4-isoC3H7C6H4
3-indolyl
9
10
11
12
13
14
15
16
17
18
-
-
-
2-thienyl
2-naphthyl
15
a
Isolated yield.

310
M. Shekouhy, A. Hasaninejad / Ultrasonics Sonochemistry 19 (2012) 307–313
Table 3
As it is clear form Table 1, the best results were obtained in the
Catalyst-free one-pot four component reaction between dimedone (1) (1 mmol),
benzaldehyde (2a) (1 mmol), hydrazinium hydroxide (3) (1.2 mmol) and phthalic
anhydride (4) (1 mmol) in the presence of [Bmim]Cl, [Bmim]Br and [Bmim]I under
ultrasonic irradiation at room temperature.
presence of [Bmim]Br as a reaction medium.
In the next step the scope and efficiency of the process was ex-
plored under the optimized conditions. For this purpose, a broad
range of structurally diverse aromatic aldehydes (2) were con-
densed with dimedone (1), hydrazinium hydroxide (3) and phtha-
lic anhydride (4) in the presence of ultrasonic irradiation at room
temperature (Scheme. 2), and the results are displayed in Table 2.
The yields obtained were good to excellent without formation
of any side-products and all reactions proceed rapidly in short
times. Aromatic aldehydes having electron withdrawing groups
(Table 2, entries 5, 7, 12) reacted at faster rate compared with
aromatic aldehydes substituted with electron releasing groups
(Table 2, entries 11, 13, 14, 16). Beside this, our methodology has
been used successfully for heteroaromatic aldehydes, and corre-
sponding products were obtained in excellent yields and without
any byproduct. (Table 2, entries 16, 17). All the products obtained
were fully characterized by 1H NMR and 13C NMR spectroscopy and
by comparison with the reported spectral data.
Entry
Reaction medium
Time (min)
Yield (%)a
1
2
3
[Bmim]Cl (0.5 g)
[Bmim]Br (0.5 g)
[Bmim]I (0.5 g)
20
10
25
93
93
91
a
Isolated yield.
According to these observations, we suggest a mechanism for
this reaction in which the IL serves two catalytic functions; first,
to electrophilically activate the aldehyde carbonyl through hydro-
gen-bonding to the carbonyl oxygen, and second, to enhance the
nucleophilicity of the hydrazinium hydroxide through deprotona-
tion of the N–H bond, as shown in the Scheme. 3. Our proposed
mechanism contains two steps. Initial formation of the phthalhyd-
razide (6) by nucleophilic addition of hydrazinium hydroxide (3) to
phthalic anhydride (4) followed by dehydration occurs.
Many recent studies have established that hydrogen bonding
can occur between the solute and the cationic or anionic compo-
nent of ILs [39]. Based on these facts, Deb and Bhuyan have sug-
gested for the synthesis of bis(indolyl)methanes via condensation
of indoles with aldehydes that hydrogen bond formation between
a carbonyl group and solvent leads to activation of aldehydes [40].
Moreover, Crowhurts et al. demonstrated that imidazolium ILs are
able to act as strong hydrogen bond acids as well as hydrogen bond
bases at the same time [39c]. They shown that acidity of ILs is
determined by the cation and it has been suggested that the hydro-
gen bond acidity is controlled by the ability of cation to act as a
hydrogen bond acceptor; so a strong anion–cation interaction re-
duces the ability of the cation to hydrogen bond with the substrate.
In the other hand hydrogen bond basicity of ILs was dominated by
the choice of anion. It is well known that the hydrogen bonding be-
tween cationic component of an IL and negatively charged parts of
electrophiles (hydrogen bond acidity) in combination with the
hydrogen bonding between anionic component of the applied IL
with the positively charged polar hydrogens of nucleophiles
(hydrogen bond basicity) obviously enhance the reaction rate
and yields. Accordingly we think that in the case of buthyl methyl-
imidazolium based ILs ([Bmim]X, X = ClÀ, BrÀ and IÀ) the best re-
sults in order of reaction rate an yields most be obtained in the
presence of [Bmim]Br as a reaction medium for the synthesis of
titled compounds due to the moderate interaction between cat-
ionic component (buthyl methylimidazolium) and the anionic
component (Br-) that leads to the sufficient hydrogen bond acidity
and hydrogen bond basicity of the IL. In order to establish the our
theory in this case, the model reaction was examined in the pres-
ence of three ILs ([Bmim]Cl, [Bmim]Br and [Bmim]I) and the ob-
tained results are summarized in Table 3. As it is clear form
Table 3, the best results were obtained in the presence of [Bmim]Br
as we expected.
The second step involves initial formation of heterodiene (7) by
standard Knoevenagel condensation of dimedone (1) and aldehyde
(2). Subsequent Michael-type addition of the phthalhydrazide fol-
lowed by cyclization affords the corresponding product (5).
(Scheme. 3)
To investigate the role of ultrasonic irradiation in this method,
the reactions were carried out in the presence of the same amount
of [Bmim]Br under stirring condition at room temperature. The re-
sults are summarized in Table 4. It is clear that, under the same
reaction conditions, reactions under ultrasonic irradiation led to
relatively higher yields and shorter reaction times.
It is presumed that the efficiency using ultrasound irradiation is
due to the cavitation phenomena. An ultrasonic wave is a pressure
wave with alternate compressions and rarefactions which is able to
break the intermolecular forces maintaining the cohesion of the li-
quid and produces a cavity in the rarefaction section of the wave.
The chemical and physical effects of ultrasound derive primarily
from acoustic cavitation which includes formation, growth and col-
lapse of the cavity [41–43]. Bubble collapse in liquids results in an
enormous concentration of energy from the conversion of kinetic
energy of liquid motion into heating of the contents of the bubble.
The high local temperatures and pressures produced by cavitation
lead to a diverse set of applications of ultrasound [44]. As it is
Table 4
Catalyst-free one-pot four component synthesis of 2H-indazolo[2,1-b]phthalazine-
triones in [Bmim]Br under stirring condition at room temperature.
Entry
R
Compound
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
4-BrC6H4
4-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
180
180
180
180
180
180
180
180
180
180
180
180
180
180
180
180
180
180
31
36
33
39
55
25
49
21
4-NO2C6H4
2-ClC6H4
3-NO2C6H4
4-CH3C6H4
2-CH3C6H4
3-ClC6H4
2-CH3OC6H4
4-CF3C6H4
4-CH3OC6H4
3-PhOC6H4
4-isoC3H7C6H4
3-Indolyl
R
CHO
(2)
O
R
9
Trace
22
Trace
46
Trace
No reaction
Trace
No reaction
22
O
O
10
11
12
13
14
15
16
17
18
O
O
[Bmim]Br 0.5g
N
N
O
Sonication ))))))
r.t
O
O
(4)
3-15 min 89-95%
(1)
(5a-5r)
.H2O
H2N NH2
(3)
2-Thienyl
2-Naphthyl
Scheme. 2. Catalyst-free one-pot four component synthesis of 2H-indazolo[2,1-
b]phthalazine-triones in [Bmim]Br in the presence of ultrasonic irradiation at room
temperature.
25
a
Isolated yield.

M. Shekouhy, A. Hasaninejad / Ultrasonics Sonochemistry 19 (2012) 307–313
311
Step 1:
Br
Me
N
H
H
H2N N
(3)
N
Bu
Br
H
O
O
O
O
O
H
N
H
- H2O
N
H
NH
NH
O
OH
(4)
O
Bu
N
(6)
H
N
Me
Step 2:
N
N
H
Me
Bu
Bu
N
H
Me
H
O
N
N
R
Me
Br
O
Br
O
N
Bu
H
H
H
O
O
O
O
O
H
R
H
(2)
(1)
Me
H
-H2O
N
N
Bu
O
O
R
O
O
O
N
N
H
R
N
NH
O
Br
(7)
(5)
O
Scheme. 3. Suggested mechanism for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones in the presence of [Bmim]Br.
shown in Scheme. 3 our proposed mechanism for the one-pot four
components synthesis of 2H-indazolo[2,1-b]phthalazine-triones in
the presence of ultrasonic irradiation in [Bmim]Br consist of two
steps contain the nucleophilic addition of hydrazinium hydroxide
to phthalic anhydride, Knoevenagel condensation between dime-
done and carbonyl compounds and Michael-type addition of the
phthalhydrazide. It is well known that all of these reactions have
negative activation volumes owing to the condensation of the mol-
ecules into a reactive intermediate. In this regard, it is well-known
that reactions with negative activation volumes are accelerated
with pressure [45]. On the other hand, ultrasound irradiation
[46,47] as well as solvophobic interactions of ionic liquids gener-
ates a microscopic internal pressure in the solvent cavity [48]. So
owning to the ultrasonic cavitations, microscopic internal high
pressures and high temperatures have been generated in reaction
media [49]. Accordingly, it is reasonable to assume that these ef-
fects should accelerate this type of four components condensation
reaction.
cost efficiency, and use of [Bmim]Br as a solvent, and thus signifi-
cantly contributes to the practice of green chemistry. The use of
[Bmim]Br as a nonvolatile medium, simple workup, neutral reac-
tion conditions, and high yields of the products make our method-
ology a valid contribution to the existing processes in the field of
2H-indazolo[2,1-b]phthalazine-triones synthesis.
Acknowledgment
We appreciate Islamic Azad University (Bandar Abbas branch)
Research Councils for the financial support of this work.
References
[1] M. Nuchter, B. Ondruschka, A. Jungnickel, U. Muller, Organic processes
initiated by non-classical energy sources, J. Phys. Org. Chem. 13 (2000) 579–
586.
[2] [a] T.J. Mason, J.P. Lorimer, Sonochemistry. Part 1. The physical aspects, Chem.
Soc. Rev. 16 (1987) 239–274;
[b] J.T. Li, S.X. Wang, G.F. Chen, T.S. Li, Some applications of ultrasound
irradiation in organic synthesis, Curr. Org. Synth. 2 (2005) 415–436;
[C] G. Cravotto, P. Cintas, Power ultrasound in organic synthesis: moving
cavitational chemistry from academia to innovative and large-scale
applications, Chem. Soc. Rev. 35 (2006) 180–196.
4. Conclusion
In conclusion, an extremely efficient method has been devel-
oped for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones
in [Bmim]Br under ultrasonic irradiation and catalyst-free condi-
tions at room temperature. This method is bestowed with several
unique merits, such as high conversions, simplicity in operation,
[3] T.J. Mason, P. Cintas, in: J. Clark, D. Macquarrie (Eds.), Handbook of Green
Chemistry and Technology, Blackwell Science, Oxford, 2002, p. 372.
[4] R. Cella, H. Stefani, Ultrasound in heterocycles chemistry, Tetrahedron 65
(2009) 2619–2641.
[5] E.A. Muravyova, S.M. Desenko, V.I. Musatov, I.V. Knyazeva, S.V. Shishkina, O.V.
Shishkin, V.A. Chebanov, Ultrasonic-promoted three-component synthesis of

312
M. Shekouhy, A. Hasaninejad / Ultrasonics Sonochemistry 19 (2012) 307–313
some biologically active 1,2,5,6-tetrahydropyrimidines, J. Comb. Chem.
(2007) 797–803.
[6] J.T. Li, W.Z. Xu, L.C. Yang, T.S. Li, One-pot synthesis of 2-amino-4-aryl-3-
carbalkoxy- 7,7-dimethyl-5,6,7,8-tetrahydrobenzo[b]pyran derivatives
9
[26] T. Ogawa, J. Watanabe, Y. Oshima, Catalyst-free synthesis of
polyorganosiloxanes by high temperature & pressure water, Supercrit. Fluids
45 (45) (2008) 80–87.
[27] A. Hasaninejad, A. Zare, M. Shekouhy, J. Ameri-Rad, Catalyst-free one-pot four
component synthesis of polysubstituted imidazoles in neutral ionic liquid 1-
butyl-3-methylimidazolium bromide, J. Comb. Chem. 12 (2010) 844–849.
[28] [a] F.W. Lichtenthaler, Unsaturated O- and N-Heterocycles from carbohydrate
feedstocks, Acc. Chem. Res. 35 (2002) 728–737;
catalyzed by KF/basic Al2 O3 under ultrasound irradiation, Synth. Commun.
34 (2004) 4565–4571.
[7] T.S. Jin, J.S. Zhang, A.Q. Wang, T.S. Li, Ultrasound-assisted synthesis of 1,8-
dioxoocta hydroxanthene derivatives catalyzed by p-dodecylbenzenesulfonic
acid in aqueous media, Ultrason. Sonochem. 13 (2006) 220–224.
[8] K.P. Guzen, R. Cella, H.A. Stefani, Ultrasound enhanced synthesis of 1,5-
benzodiazepinic heterocyclic rings, Tetrahedron Lett. 47 (2006) 8133–8136.
[9] S. Tu, L. Cao, Y. Zhang, Q. Shao, D. Zhou, C. Li, An efficient synthesis of
pyrido[2,3-d]pyrimidine derivatives and related compounds under ultrasound
irradiation without catalyst, Ultrason. Sonochem. 15 (2008) 217–221.
[10] J.T. Li, J.F. Han, J.H. Yang, T.S. Li, An efficient synthesis of 3,4-dihydropyrimidin-
2-ones catalyzed by NH2SO3H under ultrasound irradiation, Ultrason.
Sonochem. 10 (2003) 119–121.
[11] N.M.A. El-Rahman, T.S. Saleh, M.F. Mady, Ultrasound assisted synthesis of
some new 1,3,4-thiadiazole and bi(1,3,4-thiadiazole) derivatives incorporating
pyrazolone moiety, Ultrason. Sonochem. 16 (2009) 70–74.
[12] H. Zang, Y. Zhang, Y. Zhang, B.W. Cheng, An efficient ultrasound promoted
method for the one-pot synthesis of 7,10,11,12-tetrahydrobenzo[c]acridin-
8(9H)-one derivatives, Ultrason. Sonochem. 17 (2010) 495–499.
[13] D. Venzke, A.F.C. Flores, F.H. Quina, L. Pizzuti, C.M.P. Pereira, Ultrasound
promoted greener synthesis of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-
phenylthiazoles, Ultrason. Sonochem 18 (2011) 370–374.
(b) V.P. Litvinov, Multi-component cascade heterocyclisation as a promising
route to targeted synthesis of polyfunctional pyridines, Russ. Chem. Rev. 72
(72) (2003) 69–85.
[29] E. Mosaddegh, A. Hassankhani, A rapid, one-pot, four-component route to 2H-
indazolo[2,1-b]phthalazine-triones, Tetrahedron Lett. 52 (2011) 488–490.
[30] T. Sheradsky, R. Moshenberg, Bridgehead hydrazines. 3. Unusual
photorearrangement
of
1,4-diphenylpyridazino[1,2-b]phthalazine-6,11-
dione, J. Org. Chem. 51 (1986) 3123–3125.
[31] Y.K. Ramtohup, M.N.G. James, J.C. Vederas, Synthesis and evaluation of keto-
glutamine analogues as inhibitors of hepatitis A virus 3C proteinase, J. Org.
Chem. 67 (2002) 3169–3178.
[32] A. Csampai, K. Kormendy, F. Ruff, Highly regioselective ring opening of
epoxides and aziridines using (bromodimethyl)sulfonium bromide,
Tetrahedron 47 (1991) 4457–4460.
[33] L.P. Liu, J.M. Lu, M. Shi, PhI(OAc)2-Mediated novel 1,3-dipolar cycloaddition of
methylenecyclopropanes (MCPs) vinylidenecyclopropanes (VCPs) and
methylenecyclobutane (MCB) with phthalhydrazide, Org. Lett.
1303–1306.
9 (2007)
[14] H. Bienayme, C. Hulme, G. Oddon, P. Schmitt, Maximizing synthetic efficiency:
multi-component transformations lead the way, Chem. Eur. J. 6 (2000) 3321–
3329.
[34] [a] M. Sayyafi, M. Seyyedhamzeh, H.R. Khavasi, A. Bazgir, One-pot, three-
component route to 2H-indazolo[2,1-b]phthalazine-triones, Tetrahedron 64
(2008) 2375–2378;
[15] M.J. Earle, S.P. Katdare, K.R. Seddon, Paradigm confirmed: the first use of ionic
liquids to dramatically influence the outcome of chemical reactions, Org. Lett.
6 (2004) 707–710.
(b) J.M. Khurana, D. Magoo, Efficient one-pot syntheses of 2H-indazolo[2,1-b]
phthalazine-triones by catalytic H2SO4 in water-ethanol or ionic liquid,
Tetrahedron Lett. 50 (2009) 7300–7303;
[16] [a] M.J. Earle, P.B. McCormac, K.R. Seddon, Diels–Alder reactions in ionic
(c) R. Fazaeli, H. Aliyan, N. Fazaeli, Heteropoly Acid in ionic liquid – an efficient
catalyst for the preparation of 2H-Indazolo[2,1-b]phthalazine-triones, The
Open Cat. J. 3 (2010) 14–16.
liquids.
A safe recyclable alternative to lithium perchlorate-diethyl ether
mixtures, Green Chem. 1 (1999) 23–25;
(b) R. Vijayaraghavan, D.R. MacFarlane, Charge transfer polymerization in
ionic liquids, Aust. J. Chem. 57 (2004) 129–133;
[35] [a] H. Shaterian, F. Rigi, Starch sulfate as an efficient and biodegradable
polymer catalyst for one-pot, four-component reaction of 2H-indazolo[2,1-
b]phthalazine-triones, Starch 00 (2011) 1–7;
(c) J.N. Rosa, C.A.M. Afonso, A.G. Santos, Ionic liquids as a recyclable reaction
medium for the Baylis–Hillman reaction, Tetrahedron 57 (2001) 4189–4193.
[17] Y. Chauvin, L. Mussmann, H. Olivier, A novel class of versatile solvents for two-
phase catalysis: Hydrogenation, isomerization, and hydroformylation of
alkenes catalyzed by rhodium complexes in liquid 1,3-aialkylimidazolium
salts, Angew. Chem., Int. Ed. Engl. 34 (1995) 2698–2700.
(b) E. Mosaddegh, A. Hassankhani, A rapid, one-pot, four-component route to
2H-indazolo[2,1-b]-phthalazine-triones, Tetrahedron Lett. 52 (2011) 488–490;
(c) H. Shaterian, A. Hosseinian, M. Ghashang, Reusable silica supported poly
phosphoric acid catalyzed three-component synthesis of 2H-indazolo[2,1-
b]phthalazine-trione derivatives, Arkivoc ii (2009) 59–67.
[18] [a] M.A. Klingshirn, R.D. Rogers, K.H. Shaughnessy, Palladium-catalyzed
hydroesterification of styrene derivatives in the presence of ionic liquids, J.
Organomet. Chem. 690 (2005) 3620–3626;
(b) E. Mizushima, T. Hayashi, M. Tanaka, Palladium-catalysed carbonylation of
aryl halides in ionic liquid media: high catalyst stability and significant rate-
enhancement in alkoxycarbonylation, Green Chem. 3 (2001) 76–79.
[19] [a] J.S. Yadav, B.V.S. Reddy, G. Baishya, K.V. Reddy, A.V. Narsaiah, Conjugate
[36] [a] P.T. Anastas, J.C. Warner, In Green Chemistry: Theory and Practice, Oxford
University Press, Oxford, UK, 1998;
(b) P.T. Anastas, T. Williamson, In Green Chemistry: Frontiers in Benign
Chemical Synthesis and Process, Oxford University Press, Oxford, UK, 1998.
[37] [a] A. Hasaninejad, A. Zare, M. Shekouhy, N. Golzar, Efficient synthesis of 4,4a-
(arylmethylene)-bis(3-methyl-1-phenylpyrazol-5-ol) derivatives in PEG-400
under catalyst-free conditions, Org. Prep. Proc. Int. 43 (2011) 131–137;
(b) A. Zare, A. Parhami, A.R. Moosavi-Zare, A. Hasaninejad, A. Khalafi-Nezhad,
M.H. Beyzavi, A catalyst-free protocol for the green and efficient condensation
of indoles with aldehydes in ionic liquids, Can. J. Chem. 87 (2009) 416–421.
[38] J. Dupont, C.S. Consorti, P.A.Z. Suarez, R.F. de Souza, Preparation of 1-butyl-3-
methyl imidazolium-based room temperature ionic liquids, Org. Synth. Coll.
10 (2004) 184–187.
addition of indoles to a,b-unsaturated ketones using Cu(OTf)2 immobilized in
ionic liquids, Tetrahedron 61 (2005) 9541–9544;
(b) M. Johansson, A.A. Linden, J.E. Baeckvall, Osmium-catalyzed
dihydroxylation of alkenes by H2O2 in room temperature ionic liquid co-
catalyzed by VO(acac)2 or MeReO3, J. Organomet. Chem. 690 (2005) 3614–
3619;
(c) A. Serbanovic, L.C. Branco, M. Nunes da Ponte, C.A.M. Afonso, Osmium
catalyzed asymmetric dihydroxylation of methyl trans-cinnamate in ionic
liquids followed by supercritical CO2 product recovery, J. Organomet. Chem.
690 (2005) 3600–3608.
[39] [a] J.L. Anderson, J. Ding, T. Welton, D.W. Armstrong, Characterizing ionic
liquids on the basis of multiple solvation interactions, J. Am. Chem. Soc. 124
(2002) 14247–14254;
(b) Q. Liu, M.H.A. Jonssen, F. Rantwijk, R.A. Sheldon, Room-temperature ionic
liquids that dissolve carbohydrates in high concentrations, Green Chem. 7
(2005) 39–42;
(c) L. Crowhurst, P.R. Mawdsley, J.M. Perez-Arlandis, P.A. Salter, T. Welton,
Solvent–solute interactions in ionic liquids, Phys. Chem. Chem. Phys. 5 (2003)
2790–2794.
[20] [a] (M. Picquet, S. Stutzmann, I. Tkatchenko, I. Tommasi, J. Zimmermann, P.
Wasserscheid, Selective palladium-catalysed dimerisation of methyl acrylate
in ionic liquids: towards a continuous process, Green Chem. 5 (2003) 153–162;
(b) S.A. Forsyth, H.Q.N. Gunaratne, C. Hardacre, A. McKeown, D.W. Rooney,
K.R. Seddon, Utilisation of ionic liquid solvents for the synthesis of Lily-of-the-
Valley fragrance {b-Lilial; 3-(4-t-butylphenyl)-2-methylpropanal}, J. Mol.
Catal. A: Chem. 231 (2005) 61–66;
(c) M.T. Reetz, W. Wiesenhoefer, G. Francio, W. Leitner, Biocatalysis in ionic
liquids: batchwise and continuous flow processes using supercritical carbon
dioxide as the mobile phase, Chem. Commun. (2002) 992–993.
[21] J.J. Schneider, N.I. Maksim, J. Engstler, R. Joshi, R. Schierholz, R. Feile, Catalyst
free growth of a carbon nanotube-alumina composite structure, Inorg. Chim.
Acta 361 (2008) 1770–1778.
[40] M.L. Deb, P.J. Bhuyan, An efficient and clean synthesis of bis(indolyl)methanes
in a protic solvent at room temperature, Tetrahedron Lett. 47 (2006) 1441–
1443.
[41] P.R. Gogate, S. Mujumdar, A.B. Pandit, Sonochemical reactors for waste water
treatment: comparison using formic acid degradation as a model reaction,
Adv. Environ. Res. 7 (2003) 283–299.
[42] T.J. Mason, Sonochemistry sonoprocessing: the link the trends and (pobably)
the future, Ultrason. Sonochem. 10 (2003) 175–179.
[22] T.M. Potewar, S.A. Ingale, K.V. Srinivasan, Catalyst-free efficient synthesis of 2-
aminothiazoles in water at ambient temperature, Tetrahedron 64 (2008)
5019–5022.
[43] T.J. Mason, L. Paniwnyk, J.P. Lorimer, The uses of ultrasound in food
technology, Ultrason. Sonochem. 3 (1996) S253–S260.
[44] M.H. Entezari, A. Asghari, F. Hadizadeh, Sono-synthesis of imidazolidine-2-
[23] J.J. Shrikhande, M.B. Gawande, R.V. Jayaram,
A
catalyst-free N-
thione as a base compound of some pharmaceutical products, Ultrason.
benzyloxycarbonylation of amines in aqueous micellar media at room
temperature, Tetrahedron Lett. 49 (2008) 4799–4803.
[24] X. Li, W. Eli, G. Li, Solvent-free synthesis of benzoic esters and benzyl esters in
novel Brønsted acidic ionic liquids under microwave irradiation, Catal.
Commun. 9 (2008) 2264–2268.
[25] Y. Wei, H. Ren, J. Wang, Solvent- and catalyst-free gem-bisallylation of
carboxylic acid derivatives with allylzinc bromide, Tetrahedron Lett. 49 (2008)
5697–5699.
Sonochem. 15 (2008) 119–123.
[45] A. Shaabani, A.H. Rezayan, A. Rahmati, M. Sharifi, Ultrasound-accelerated
synthesis of 1,4-dihydropyridines in an ionic liquid, Monatsh Chem. 137
(2006) 77–81.
[46] T.J. Manson, Ultrasound in synthetic organic chemistry, Chem. Soc. Rev. 26
(1997) 443–451.
[47] P. Cintas, J.L. Luche, Green chemistry. The sonochemical approach, Green
Chem. 1 (1999) 115–125.

M. Shekouhy, A. Hasaninejad / Ultrasonics Sonochemistry 19 (2012) 307–313
313
[48] (a) A. Kumar, Salt effects on Diels–Alder reaction kinetics, Chem. Rev. 101
(2001) 1–20;
[49] [a] J.T. Li, W.Z. Yang, S.X. Wang, S.H. Li, T.S. Li, Improved synthesis of chalcones
under ultrasound irradiation, Ultrason. Sonochem. 9 (2002) 237–239;
(b) S.X. Wang, J.T. Li, W.Z. Yang, T.S. Li, Synthesis of ethyl a-cyanocinnamates
catalyzed by KF-Al2O3 under ultrasound irradiation, Ultrason. Sonochem. 9
(2002) 159–161;
(b) T. Welton, Room-temperature ionic liquids. Solvents for synthesis and
catalysis, Chem. Rev. 99 (1999) 2071–2084;
(c) P. Wasserscheid, W. Keim, Ionic liquids – new ‘‘solutions’’ for transition
metal catalysis, Angew. Chem. Int. Ed. 39 (2000) 3772–3789;
(d) R. Sheldon, Catalytic reactions in ionic liquids, Chem. Commun. (2001)
2399–2407.
(c) S.X. Wang, X.W. Li, J.T. Li, Synthesis of N-alkoxyphthalimides under
ultrasound irradiation, Ultrason. Sonochem. 15 (2008) 33–36.