Ultrasound-assisted synthesis of pyrazolo[1,2-b]phthalazines and dihydrospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazines] using TBAF as an efficient phase-transfer catalyst

Article abstract of DOI:10.1134/S107036321607032X

Tetrabutylammonim fluoride has been used as an efficient catalyst for synthesis of pyrazolo[1,2-b]-phthalazine-5,10-diones and dihydrospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazines] by one-pot three-component reaction of phthalhydrazide, aromatic aldehyd

Full text of DOI:10.1134/S107036321607032X

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 7, pp. 1735–1740. © Pleiades Publishing, Ltd., 2016.
Ultrasound-Assisted Synthesis
of Pyrazolo[1,2-b]phthalazines
and Dihydrospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazines]
Using TBAF as an Efficient Phase-Transfer Catalyst1
H. Kefayati, A. Delafrooz, and S. Homayoon
Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
e-mail: kefayati@iaurasht.ac.ir
Received March 12, 2016
Abstract—Tetrabutylammonim fluoride has been used as an efficient catalyst for synthesis of pyrazolo[1,2-b]-
phthalazine-5,10-diones and dihydrospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazines] by one-pot three-component
reaction of phthalhydrazide, aromatic aldehydes or isatin derivatives, with malononitrile in water under
ultrasond irradiation. This rapid method gave the products in high yield.
Keywords: tetrabutylammonim fluoride, ultrasound, pyrazolo[1,2-b]phthalazine, phthalhydrazide, dihydro-
spiro(indoline-3,1'-pyrazolo[1,2-b]phthalazines)
DOI: 10.1134/S107036321607032X
INTRODUCTION
RESULTS AND DISCUSSION
Pyrazoles are important componds in new drugs
development, including blockbuster drugs such as
celecoxib, viagra, pyrazofurine, and many others [1,
2]. Heterocycles containing a phthalazine moiety are of
certain interest due to their pronounced pharma-
cological and biological activities [3–8].
The primary appoach to optimization of synthesis
of pyrazolo[1,2-b]phthalazine-5,10-dione 4a by the
reaction of phthalhydrazide 1 with 4-chlorobenzal-
dehyde 2a and malononitrile 3 in water was initiated
by various basic catalysts such as NaOH, KOH,
Na2CO3, and TBAF. The experiments were carried out
by two method: (1) Ultrasonic irradiation in water bath
at 60°C; (2) Conventional heating in an oil bath at 60°C
(Table 1). It was determined that all above bases
promoted the reaction, but most promicing results were
obtained for sonication of the reaction mixture in the
presence of TBAF.
Synthesis of pyrazolo[1,2-b]phthalazine-5,10-diones
via three-component reaction of phthalhydrazid, malo-
nonitrile or ethyl cyanoacetate with aromatic aldehydes
[9–12] or isatin derivatives [13–16] by various
methods were developed. The above synthetic methods
have certain limitations such as use of expensive
catalysts, long reaction times, difficult work-up, and
tough reaction conditions.
Application of tetrabutylammonium chloride or bromide
proved to be less efficient than the corresponding
fluoride (Table 2) which could be justified by higher
strength of the H–F bond.
The development of our research efforts in MCR
chemistry [17, 18] was directed towards application of
tetrabutylammonim fluoride (TBAF) catalysis in the
synthesis of pyrazolo[1,2-b]phthalazine-5,10-diones
derivatives by one pot three-component reaction of
phthalhydrazide 1 with aromatic aldehydes 2 and
malononitrile 3 in water under ultrasound irradiation.
This rapid, 20–45 min, method gave the products with
excellent yields (86–95%) (Scheme 1).
Catalysis of the reaction by other fluorides, such as
NaF, CsF and NH4F, under the same conditions
demonstrated that TBAF was the most efficient
catalyst (Table 2).
According to the experimental data (Table 2),
heating from 50 to 75°C induced higher yield of the
products (95%) accumulated in shorter reaction time.
Amount of TBAF 0.4 mmol was determined to be the
optimum (Table 2) for the further study.
1 The text was submitted by the authors in English.
1735

1736
KEFAYATI et al.
Scheme 1. TBAF catalyzed synthesis of pyrazolo[1,2-b]phthalazine-5,10-diones.
O
O
Ar
TBAF
))))))
CN
CN
N
N
NH
NH
+ ArCH2O +
CN
H2O
NH2
O
O
1
2
3
4a−4k
Ar = 4-Cl-phenyl (a); 3-Cl-phenyl (b); 2-Cl-phenyl (c); 4-Br-phenyl (d); 2,4-di-Cl-phenyl (e); 3-NO2-phenyl (f); 4-NO2-
phenyl (g); 3-OMe-phenyl (h); 2-OMe-phenyl (i); H (j); 2-naphtyl, l,3-pyridyle (k).
The optimized reaction conditions supported the
reaction of both electron-rich and electron deficient
aryl aldehydes (Table 3).
were measured on an Electrothermal IA 9100
apparatus in open capillary tubes. Elemental analysis
for new compounds was carried out on a Thermo
Finnigan Flash EA 1112 series instrument. IR spectra
were recorded for KBr pellets on a Shimadzu FT-IR
Besides aromatic aldehydes isatin derivatives 5
were introduced in the reaction under similar con-
ditions (Scheme 2). Sonication of solutions of isatin
derivatives with phthalhydrazide 1 and malononitrile 3
in H2O led to dihydrospiro(indoline-3,1'-pyrazolo[1,2-
b]phthalazines) 6a–6c with high yield.
1
8600 spectrophotometer. H and 13C NMR spectra
were measured for DMSO-d6 solutions on a Bruker
DRX-400 Avance spectrometer at 400 and 100 MHz
respectively. Ultrasonication was performed in an
ASTRA 3-D ultrasound cleaner with a frequency of
45 kHz and an output power of 350 W.
The exact mechanism of formation of pyrazolo[1,2-
b]phthalazine-5,10-diones 4 was not established,
however, a probable one is presented in Scheme 3. The
general Knoevenagel condensation of arylaldehydes 2
with malononitrile 3 in the presence of catalytic
amount of TBAF led to benzylidene malononitrile 7.
TBAF promoted Michael addition of phthalhydrazide
1 to electron deficient Knoevenagel adduct 7 was
followed by cyclization and tautomeric transformation
into the corresponding pyrazolo[1,2-b]phthalazine-
5,10-diones 4a–4l (Scheme 3).
General procedure for compounds 4a–4l and 5a–
5c. A mixture of phthalhydrazide (1.0 mmol), an aryl
aldehyde (1.0 mmol) or isatin derivative
Table 2. Catalysis by halides in the synthesis of 4aa
Catalyst
T, ºC Time, min
Yield, %
79
TBACl (0.4 mmol)
TBABr (0.4 mmol)
TBAF (0.4 mmol)
NaF (0.4 mmol)
CsF (0.4 mmol)
60
60
60
60
60
60
50
75
75
75
75
75
75
110
120
50
71
EXPERIMENTAL
91
All reagents were purchased from Merck and Fluka
and used without further purification. Melting points
140
120
120
90
84
80
NH4F (0.4 mmol)
TBAF (0.4 mmol)
TBAF (0.4 mmol)
TBAF (0.3 mmol)
TBAF (0.2 mmol)
TBAF (0.1 mmol)
TBAF (0.5 mmol)
TBAF (0.6 mmol)
65
Table 1. Catalysis by basic compounds in the synthesis of
4aa at 60ºC
80
Ultrasonic
Reflux
20
95
Catalyst
time, min
120
yield, % time, min yield, %
35
91
NaOH
KOH
75
70
68
91
180
180
180
100
67
70
60
74
60
88
120
100
20
82
Na2CO3
120
95
TBAF
50
20
95
a
a
Reaction conditions: phthalhydrazide (1.0 mmol), 4-chloro-
benzaldehyde (1.0 mmol), malononitrile (1.0 mmol), catalyst
(0.4 mmol), water (5 mL).
Reaction condition: Phthalhydrazide (1.0 mmol), 4-chloro-
benzaldehyde (1.0 mmol), malononitrile (1.0 mmol), ultrasonic
irradiation (45 kHz), water (5 mL).
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ULTRASOUND-ASSISTED SYNTHESIS OF PYRAZOLO[1,2-b]PHTHALAZINES
1737
Scheme 2. TBAF catalyzed synthesis of dihydrospiro(indoline-3,1'-pyrazolo[1,2-b]phthalazine).
R
N
O
O
O
O
TBAF
))))))
NH
NH
CN
CN
N
+
+
O
CN
N
H2O
N
R
NH2
O
O
1
5
3
6a−6c
R = 4-Cl-phenyl (a); 3-Cl-phenyl (b); 2-Cl-phenyl (c).
Scheme 3. A proposed mechanism for the formation of pyrazolo[1,2-b]phthalazine-5,10-diones 4a–4l.
O
NC
NC
H
CN
F(Bu)4N
+
−H2O
Ar
H
CN
3
Ar
7
O
O
2
H
N
F(Bu)4N
HN
Micheal addition
1
O
O
NH2
Ar
N
NH
O
O
O
C
CN
N
N
N
NH
N
CN
CN
N
H
Ar
Ar
O
4a−4l
Ar = 4-Cl-phenyl (a); 3-Cl-phenyl (b); 2-Cl-phenyl (c); 4-Br-phenyl (d); 2,4-di-Cl-phenyl (e); 3-NO2-phenyl (f); 4-NO2-
phenyl (g); 3-OMe-phenyl (h); 2-OMe-phenyl (i); H (j); 2-naphtyl (k), 3-pyridyle (l).
(1.0 mmol), and malononitrile (1.0 mmol) in 5 mL of
water was subjected to ultrasound irradiation (45 kHz)
in the presence of TBAF (0.4 mmol) at 75°C for the
appropriate time (Table 3). Upon completion of the
reaction (monitored by TLC), the reaction mixture was
cooled down to room temperature. The precipitate was
filtered off and washed with ethanol to yield pure
products 4a–4l and 5a–5c.
3-Amino-1-(2-chlorophenyl)-5,10-dioxo-5,10-di-
hydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
(4c). Yellow powder, mp 259–261°C. IR spectrum, ν,
1
cm–1: 3367, 3232, 3171, 2206, 1655, 1568, 1379. H
NMR spectrum, δ, ppm: 8.29–8.27 m (1H), 8.14 br.s
(2H, NH2), 8.11–8.07 m (1H), 8.01–7.96 m (2H), 7.60
d.d (J = 7.0, 2.0 Hz, 1H), 7.48–7.46 m (1H), 7.38–7.31
m (2H), 6.46 s (1H). 13C NMR spectrum, δ, ppm:
157.1, 154.0, 151.6, 135.8, 135.2, 134.3, 131.7, 130.4,
130.2, 129.5, 129.2, 128.8, 128.3, 127.8, 127.2, 116.2,
61.1, 60.2 ppm.
3-Amino-1-(4-chlorophenyl)-5,10-dioxo-5,10-dihyd-
ro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (4a).
Yellow powder, mp 270–272°C. IR (KBr) spectrum, ν,
cm–1: 3371, 3257, 3114, 2196, 1656, 1566. 1H NMR
spectrum, δ, ppm: 8.27–8.24 m (1H), 8.13 br.s (2H,
NH2), 8.10–8.06 m (1H), 7.99–7.94 m (2H), 7.52 d
(J = 8.8 Hz, 2H), 7.43 d (J = 8.8 Hz, 2H), 6.15 s (1H).
13C NMR spectrum, δ, ppm: 157.1, 154.1, 151.2,
137.1, 135.1, 134.2, 133.3, 129.3, 129.4, 129.0, 128.1,
127.7, 127.1, 116.4, 60.3, 62.7.
3-Amino-1-(4-bromophenyl)-5,10-dioxo-5,10-di-
hydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
(4d). Yellow powder, mp 267–268°C. IR spectrum, ν,
1
cm–1: 3371, 3257, 3193, 2194, 1655, 1560. H NMR
spectrum, δ, ppm: 8.27–8.25 m (1H), 8.13 br.s (2H,
NH2), 8.10–8.07 m (1H), 7.98–7.96 m (2H), 7.56 d
(J = 8.8 Hz, 2H), 7.46 d (J = 8.8 Hz, 2H), 6.13 s (1H).
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KEFAYATI et al.
Table 3. Synthesis of pyrazolo[1,2-b]phthalazine derivativesa
mp, °C
mp, °C
Structure
found
Structure
found
Cl
NO2
4a
20 95 270–272 270–272 4g
25 94 278–280 228–229
O
O
N
N
N
N
CN
NH2
CN
NH2
O
O
O
O
Cl
OMe
4h
32 92 248–250 248–251
4b
4c
25 93 265–267 266–268
N
N
N
N
CN
NH2
CN
NH2
O
O
O
O
OMe
CN
45 90 259–261 257–259 4i
40 95 259–261 259–260
Cl
N
N
N
N
CN
NH2
Br
NH2
O
O
O
O
4j
20 95 276–278 275–276
N
N
4d
4e
25 91 262–264 263–264
CN
NH2
N
N
CN
O
O
NH2
Cl
O
O
25 93 259–260 259–261 4k
20 92 276–277
–
Cl
CN
N
N
N
N
CN
NH2
NH2
O
O
O
O
N
4f
40 90 269–270 269–271
NO2
4l
30 86 266–268
–
N
N
N
N
CN
NH2
CN
NH2
O
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 7 2016

ULTRASOUND-ASSISTED SYNTHESIS OF PYRAZOLO[1,2-b]PHTHALAZINES
1739
Table 3. (Contd.)
mp, °C
mp, °C
Structure
Structure
found
found
H
N
O
O
CH2
N
5a
45 84 267–269 269–270 5c
60 81 264–266 266
N
N
O
O
O
CN
NH2
N
N
CN
NH2
O
H3C
N
O
O
5b
60 88 281–283 282–284
N
N
CN
NH2
O
a
Reaction condition: phthalhydrazide (1.0 mmol), aryl aldehyde or isatin derivatives (1.0 mmol), and malononitrile (1 mmol), TBAF
(0.4 mmol), water (5 mL), T = 75ºC, ultrasonic irradiation (45 kHz).
13C NMR spectrum, δ, ppm: 157.1, 154.1, 151.2,
138.4, 135.1, 134.2, 131.9, 129.6, 129.3, 129.0, 127.7,
127.1, 121.9, 116.4, 62.8, 61.3.
(4i). Yellow powder, mp 259–261°C. IR spectrum, ν,
1
cm–1: 3380, 3250, 3184, 2199, 1657, 1564, 1379. H
NMR spectrum, δ, ppm: 8.30–8.27 m (1H), 8.11–8.09
m (1H), 8.02 br.s (2H, NH2), 8.01–7.97 m (2H), 7.32–
7.27 m (2H), 7.04 d (J = 7.6 Hz, 1H), 6.91 d.t (J = 7.6,
0.8 Hz, 1H), 6.35 s (1H), 3.74 s (3H, OCH3). 13C NMR
spectrum, δ, ppm: 157.1, 156.9, 153.7, 151.5, 135.2,
134.2, 129.8, 129.1, 129.0, 127.9, 127.8, 127.2, 126.3,
121.2, 116.5, 112.1, 61.1, 59.4, 56.3.
3-Amino-1-(4-nitrophenyl)-5,10-dioxo-5,10-di-
hydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
(4g). Yellow powder, mp 278–280°C. IR spectrum, ν,
cm–1: 3433, 3321, 3076, 2160, 1658, 1558, 1352, 1515.
1H NMR spectrum, δ, ppm: 8.27–8.29 m (1H), 8.22 d
(J = 8.6 Hz, 2H), 8.20 br.s (2H, NH2), 8.08–8.10 m
(1H), 7.97–7.99 m (2H), 7.81 d (J = 8.6 Hz, 2H), 6.30
s (1H). 13C NMR spectrum, δ, ppm: 157.2, 154.2,
151.4, 147.8, 146.3, 135.1, 134.3, 129.4, 128.9, 128.5,
127.8, 127.2, 124.2, 116.3, 61.8, 59.8.
3-Amino-1-(naphthalen-2-yl)-5,10-dioxo-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
(4k). Yellow powder, mp 276–278°C. IR spectrum, ν,
1
cm–1: 3365, 3255, 3193, 2190, 1652, 1560. H NMR
spectrum, δ, ppm: 8.30–8.28 m (1H), 8.16 br.s (2H,
NH2), 7.89–8.08 m (7H), 7.53–7.60 m (3H), 6.30 s
(1H). 13C NMR spectrum, δ, ppm: 157.2, 154.2, 151.1,
136.3, 135.1, 134.2, 133.3, 133.1, 129.3, 129.1, 128.9,
128.3, 128.1, 127.8, 127.1, 126.9, 126.8, 126.5, 124.8,
116.6, 63.7, 61.8. Found, %: C 72.71; H 3.50; N 15.52.
C22H14N4O2. Calculated, %: C 72.12; H 3.85; N 15.29.
3-Amino-1-(3-methoxyphenyl)-5,10-dioxo-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
(4h). Yellow powder, mp 248–250°C. IR spectrum, ν,
1
cm–1: 3361, 3259, 3056, 2190, 1654, 1566. H NMR
spectrum, δ, ppm: 8.25–8.27 m (1H), 8.08–8.10 m
(3H, NH2, CH), 7.95–7.99 m (2H), 7.28 t (J = 7.6 Hz,
1H), 6.99–7.01 m (2H), 6.89 d.d (J = 8.0,1.6 Hz, 1H),
6.10 s (1H), 3.74 s (3H). 13C NMR spectrum, δ, ppm:
159.8, 157.1, 154.1, 151.1, 138.1, 134.2, 130.1, 129.5,
129.3, 129.1, 127.3, 127.1, 124.2, 119.2, 113.8, 113.1,
64.0, 63.3, 55.6.
3-Amino-5,10-dioxo-1-(pyridin-3-yl)-5,10-dihyd-
ro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (4l).
Yellow powder, mp 266–268°C. IR spectrum, ν, cm–1:
1
3364, 3259, 3193, 2189, 1652, 1569, 1383. H NMR
3-Amino-1-(2-methoxyphenyl)-5,10-dioxo-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
spectrum, δ, ppm: 8.73 d (J = 1.6 Hz, 1H), 8.54 d.d
(J = 4.8, 1.2 Hz, 1H), 8.27–8.25 m (1H), 8.17 br.s (2H,
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KEFAYATI et al.
NH2), 8.10–8.08 m (1H), 7.99–7.96 m (2H), 7.94–7.92
m (1H), 7.40 d.d (J = 7.8, 4.4 Hz, 1H), 6.22 s (1H). 13C
NMR spectrum, δ, ppm: 159.1, 158.1, 156.1, 148.1,
134.7, 130.6, 129.7, 129.3, 128.1, 127.3, 126.1, 124.2,
120.2, 112.8, 113.1, 64.5, 61.3. Found, %: C 64.66; H
3.27; N 21.55. C17H11N5O2. Calculated, %: C 64.35; H
3.49; N 22.07.
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spectrum, δ, ppm: 10.88 s (1H, NH), 8.28 br.s (2H,
NH2), 8.26 d (J = 7.7 Hz, 1H), 7.99 m (3H), 7.44 d
(J = 7.7 Hz, 1H), 7.30 m (1H), 6.96 m (1H), 6.82 d
(J = 7.7 Hz, 1H).
(R)-3'-Amino-1-methyl-2,5',10'-trioxo-5',10'-di-
hydrospiro(indoline-3,1'-pyrazolo[1,2-b]phthalazine)-
2'-carbonitrile (5b). Yellow powder, mp 281–283°C.
IR spectrum, ν, cm–1: 3441, 3311, 2189, 1721, 1669.
1H NMR spectrum, δ, ppm: 8.31 br.s (2H, NH2), 8.22 d
(J = 7.9 Hz, 1H), 7.91 m (3H), 7.47 d (J = 7.0 Hz, 1H),
7.36 m (1H), 7.14 d (J = 7.4 Hz, 1H), 7.06 m (1H),
3.25 s (3H).
(R)-3'-Amino-1-benzyl-2,5',10'-trioxo-5',10'-dihyd-
rospiro(indoline-3,1'-pyrazolo[1,2-b]phthalazine)-2'-
carbonitrile (5c). Yellow powder, mp 264–266°C. IR
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spectrum, δ, ppm: 8.37 br.s (2H, NH2), 8.26 d (J =
8.1 Hz, 1H), 8.05 d (J = 6.45 Hz, 1H), 7.95 m (2H),
7.54–7.45 m (3H), 7.32 m (2H), 7.26 d (J = 6.45 Hz,
2H), 7.00–6.91 m (2H), 4.91 d.d (J = 16.07 Hz, 2H).
CONCLUSIONS
Tetrabutylammonium fluoride can act as an
efficient catalyst of condensation of phthalhydrazide
and aryl aldehyde or isatin derivatives with malono-
nitrile under ultrasound irradiation in water leading to
the corresponding pyrazolo[1,2-b]phthalazine-5,10-
diones and dihydrospiro(indoline-3,1'-pyrazolo[1,2-b]-
phthalazines). The use of TBAF has the advantages of
being economically viable and more efficient for the
multicomponent reaction. The method can be
successfully applied to a variety of aryl aldehydes in
rapid synthesis of a variety of heterocycles with
excellent yields.
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ACKNOWLEDGMENTS
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DOI: 10.2174/157017810791130577.
Financial support by Rasht Branch, Islamic Azad
University (grant no. 4.5830) is gratefully acknowledged.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 7 2016