A novel method for the synthesis of 1(2H)-phthalazinones using silica-supported perchloric acid

Article abstract of DOI:10.1002/jhet.77

A simple and efficient synthesis of 1(2H)-phthalazinone derivatives was achieved via reaction of phthalaldehydic acid and various phenyl hydrazines in acetonitrile using HClO₄-SiO₂ as a catalyst in very good yields.

Full text of DOI:10.1002/jhet.77

March 2009
A Novel Method for the Synthesis of 1(2H)-Phthalazinones Using
Silica-Supported Perchloric Acid
351
Majid M. Heravi,* Bita Baghernejad, and Hossein A. Oskooie
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
*E-mail: mmh1331@yahoo.com
Received March 31, 2008
DOI 10.1002/jhet.77
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
A simple and efficient synthesis of 1(2H)-phthalazinone derivatives was achieved via reaction of
phthalaldehydic acid and various phenyl hydrazines in acetonitrile using HClO4-SiO2 as a catalyst in
very good yields.
J. Heterocyclic Chem., 46, 351 (2009).
INTRODUCTION
of HClO4-SiO2 [13]. We have recently used HClO4–
SiO2 for the synthesis of 14-aryl or alkyl-14-H-diben-
zoxanthenes [14]. As part of our program aimed at
developing new selective and environmental friendly
methodologies for the preparation of fine chemicals [15–
18], herein we report an efficient and convenient proce-
dure for the synthesis of 1(2H)-phthalazinones using
HClO4-SiO2 as a reusable and heterogeneous catalyst in
good yields (Scheme 1).
Heterocyclic compounds occur very widely in nature
and are essential to life. Nitrogen-containing heterocy-
clic molecules constitute the largest portion of chemical
entities, which are part of many natural products, fine
chemicals, and biologically active pharmaceuticals vital
for enhancing the quality of life [1]. Phthalazine scaf-
fold have shown its potential as a privileged structure
for the generation of drug-like libraries in drug-discov-
ery process [2]. 2H-Phthalazin-1-ones are of consider-
able interest due to their antidiabatic [3] and antiallergic
activities [4], and its bioactivity has been researched
extensively [5–8]. They are also useful intermediates
for the synthesis of inhibitors of the VEGF (vascular
endothelial growth factor) receptor tyrosine kinases for
the treatment of cancer [9]. However, phthalazinone
derivatives have attracted considerable attention in the
development of novel antiasthmatic agents with dual
activities of thromboxane A2 (TXA2) synthetase inhibi-
tion and bronchodialation [10]. Consequently, there is a
need to develop new methods to synthesis of these
compounds.
RESULTS AND DISCUSSION
1(2H)-Phthalazinone were obtained by phthalaldehy-
dic acid and various phenyl hydrazines in CH3CN using
HClO4-SiO2 as a reusable catalyst (Scheme 1) in good
yields (Table 1). It has been proven recently that
HClO4-SiO2 is a mild, worthwhile heterogeneous cata-
lyst, which efficiently and selectively catalyzes various
organic transformations and synthesis. The effect of
temperature was studied by carrying out the reactions at
different temperature (25ꢀC), 50ꢀC and under refluxing
temperature (82ꢀC). As it shown in Table 1, the yields
of reactions increased as the reaction temperature was
raised. These results showed that refluxing temperature
would be the temperature of choice for all reactions.
The reaction proceeded very cleanly under reflux condi-
tion and were free of side products.
Solid-supported reagents are unique catalysts that
have become popular over the last 2 decades [11]. The
high catalytic activity, low toxicity, moisture, and air
tolerance, their recyclability and particularly low price
make the use of solid supported reagents attractive alter-
natives to conventional Lewis acids and triflates [12].
Although the catalytic applications of solid supported
reagents for organic synthesis have been well estab-
lished, relatively few examples are reported on the use
Influences of solvents are the important parameter for
the determination of yield of the products. The reaction
was conducted in various solvents on the synthesis of 3a
using HClO4-SiO2 as a reusable catalyst.
C
V
2009 HeteroCorporation

352
M. M. Heravi, B. Baghernejad, and H. A. Oskooie
Vol 46
Scheme 1
As shown in Table 2, the performance of various sol-
vents are in the following order: acetonitrile > ethyl
acetate > THF > toluene > dichloromethane.
Acetonitrile shows better yields, when compared with
other solvents. In addition, the time required for
Table 1
Synthesis of 2,4,5-triaryl-imidazoles using various heteropolyacids under refluxing condition.
Mp (ꢀC)
Yield (%)a
50ꢀC
Entry
Substrate
Product
Time (h)
1
Observed
104
Reported
25ꢀC
50
82ꢀC
95
1
104–105 [19]
85
2
3
1.5
206
176
204–206 [20]
175–177 [21]
43
40
76
63
92
80
2
4
5
2
170
121
168–169 [22]
45
50
70
79
81
90
1.5
120.5–121.5 [19]
6
7
1.5
136
127
135 [23]
50
43
75
70
90
80
2
126–127 [24]
a Yields were analyzed by GC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
A Novel Method for the Synthesis of 1(2H)-Phthalazinones
Using Silica-Supported Perchloric Acid
353
Table 2
ured by using the capillary tube method with an electro ther-
mal 9200 apparatus. 1H NMR spectra were recorded on a
Bruker AQS AVANCE-300 MHz spectrometer using TMS as
an internal standard (CDCl3 solution). IR spectra were
recorded from KBr disk on the FTIR Bruker Tensor 27. GC/
MS spectra were recorded on an Agilent Technologies 6890
network GC system and an Agilent 5973 network Mass selec-
tive detector. Thin layer chromatography (TLC) on commer-
cial aluminum-backed plates of silica gel, 60 F254 was used to
monitor the progress of reactions. All products were character-
ized by spectra and physical data.
Synthesis of 3a with HClO4-SiO2 in the
presence of different solvents.
Entry
Solvent
Temperature Time (min) Yield (%)a
1
2
3
4
5
Acetonitrile
Ethyl acetate
THF
reflux
reflux
reflux
reflux
reflux
1
95
92
90
90
89
1
1.20
2
Toluene
Dichloromethane
2
a Yields were analyzed by GC.
Preparation of 2-phenyl-2H-phthalazin-1-one (3a): A
typical procedure. To a mixture of phthalaldehydic acid
(1 mmol, 15 g) and phenylhydrazine (1 mmole, 1 mL) in ace-
catalytic amount of HClO4–SiO2
completion of the reaction was found to be less in aceto-
nitrile. This is due to higher solvent polarity of acetoni-
trile when compared with that of other solvents. We
expect that the solvent removes products from the active
surface of the catalyst. Therefore, more polar solvents
may remove the product better and thus regenerate the
catalyst active sites allowing continuation of the cata-
lytic reaction.
tonitrile (5 mL),
a
(0.01 mmol) was added and refluxing was continued for 1 h.
The reaction progress was monitored by TLC. After comple-
tion of the reaction, the mixture was then filtrated (in order to
separation of catalyst from the mixture). The filtrate was then
diluted with 5% NaHCO3 (5 mL) and the product was
extracted with diethyl ether (2 ꢁ 5 mL) and dried over
MgSO4. The solvent was evaporated under reduced pressure
and the crude product was obtained. The resulting solid prod-
uct was recrystallized from ethanol to give the pure product.
The reactions proceeded efficiently at mild conditions
and are completed within 1–2 h, in contrast to conven-
tional methods that require long reaction times. This
method not only affords the products in good yields but
also avoids the problems associated with catalyst cost,
handling, safety, and pollution. This catalyst is eco-
friendly for a variety of organic transformations. It is
nonvolatile, nonexplosive, easy to handle, and thermally
robust. The time required for completion of the reaction
was found to be less for phenyl hydrazine when com-
pared with substrates bearing electron withdrawing
groups (Table 1, entries 2–7). Moreover, the steric hin-
drance seems to have significant effects on reaction
times and yields (Table 2, entries 3, 4, 7).
3a: mp. 104ꢀC; IR: 1620 (C¼¼N), 1670 (C¼¼O) cmꢂ1
;
1H
NMR:d 7.59–8.27 (m, 9H, ArAH), 8.8 (s, 1H); ms: m/z 222
(Mþ).
3c: mp. 176ꢀC; IR: 1633 (C¼¼N), 1674 (C¼¼O) cmꢂ1
;
1H
NMR:d 7.61–8.43 (m, 7H, ArAH); ms: m/z 301 (Mþ).
Preparation of the HClO4–SiO2 catalyst [13]. HClO4
(1.8 g, 12.5 mmol, as a 70% aq. solution) was added to a sus-
pension of SiO2 (230–400 mesh, 23.7 g) in Et2O (70.0 mL).
The mixture was concentrated and the residue was heated
at 100ꢀC for 72 h under vacuum to furnish HClO4–SiO2
(0.5 mmol/g) as a free flowing powder (50 mg ¼ 0.025 mmol
of HClO4).
Caution. Although no explosions were reported under these
conditions, extreme care has to be taken for large scale reac-
tions. The preparation of the catalyst should be performed with
special care and in a safe environment.
Reusability of catalyst. Next, we investigated the reusabil-
ity of HClO4–SiO2. When the reaction was completed, the cat-
alyst was separated by simple filtration and recovered with
CHCl3 (2 ꢁ 5 mL) and subsequently dried at 80ꢀC in order
to be. HClO4–SiO2 can be reused in subsequent reactions with-
out significant decrease in activity even after five runs
(Table 3).
In conclusion, we are reporting an efficient process
for the synthesis of biologically interesting functional-
ized 1(2H)-phthalazinone derivatives starting from read-
ily available and inexpensive reagents. It can be con-
cluded that HClO4-SiO2 is an efficient and excellent cat-
alyst for the synthesis of these compounds in high yields
and mild conditions in short reaction times. This method
offers some advantages in terms of simplicity of per-
formance. The low cost of the catalyst, low toxicity of
the catalyst, fast reaction times, recyclability of the cata-
lyst, and high yields of the products are the other advan-
tages for this synthesis. We believe our procedure will
find important applications in the synthesis of 1(2H)-
phthalazinones. The method is also relatively environ-
mentally benign.
Table 3
Reuse of the HClO4-SiO2 for synthesis
of 2-phenyl-2H-phthalazin-l-one (3a).
Entry
Time (h)
Yield (%)a
1
2
3
4
5
1
1
95
93
92
90
90
1.20
2
EXPERIMENTAL
2.20
All products are known compounds and were characterized
1
by mp, IR, H NMR, and GC/MS. Melting points were meas-
a Yields were analyzed by GC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

354
M. M. Heravi, B. Baghernejad, and H. A. Oskooie
Vol 46
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet