An improved procedure for the three-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives using basic ionic liquid

Article abstract of DOI:10.3184/174751916X14627996968714

An efficient and green method for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives has been achieved through the one-pot, three-component condensation of aromatic aldehydes, malononitrile or ethyl cyanoacetate, and phthalhydrazide in

Full text of DOI:10.3184/174751916X14627996968714

354 RESEARCH PAPER
VOL. 40 JUNE, 354–357
JOURNAL OF CHEMICAL RESEARCH 2016
An improved procedure for the three-component synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives using basic ionic liquid
Wang Wang, Li Cong-Hao, Yu Yi, Li Xiao-Jun and Guo Hong-Yun*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P.R. China
An efficient and green method for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives has been achieved through the
one-pot, three-component condensation of aromatic aldehydes, malononitrile or ethyl cyanoacetate, and phthalhydrazide in the presence
of 1-butyl-3-methyl imidazolium hydroxide ([bmim]OH) as catalyst in EtOH. This reaction does not involve any hazardous organic solvent
and toxic catalyst. The ionic liquid can be recovered and recycled for subsequent reactions. Moreover, this protocol has the advantages of
easy work-up, short reaction time, mild reaction conditions and environmentally benign procedures compared with the reported methods.
Keywords: one-pot, three-component condensation, ionic liquid
Multicomponent reactions (MCRs) can be used to produce
elaborate biologically active compounds and have become
an important area of research in organic, combinatorial, and
medicinal chemistry.1–4 The MCR strategy offers significant
advantages over conventional linear-type synthesis because of its
flexible, convergent, and atom efficient nature.5,6 In recent years,
the synthesis of combinatorial small-molecule heterocyclic
libraries has emerged as a valuable tool in the search for novel
lead structures.7–9 Thus, the success of combinatorial chemistry
in the drug discovery process considerably depends on further
advances in the synthesis of heterocyclic compounds using
MCR methodology and environmentally benign procedures.
In the past few decades, the synthesis of new heterocyclic
compounds has been a subject of great interest due to their wide
applicability. Heterocyclic compounds occur widely in nature
and are essential to life. Among a large variety of heterocyclic
compounds, those containing a pyrazole ring are of interest
because they show some pharmacological and biological
activities,10–13 and phthalazine derivatives have been reported
to possess anticonvulsant,14 cardiotonic,15 and vasorelaxant16
activities. In order to synthesise new biologically active
compounds, our plan was to target compounds in which both
ring systems were present and fused together.
efficient, convenient, and facile method for the synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives using an
ionic liquid as the basic catalyst.
Results and discussion
We chose [bmim]OH as the ionic liquid, and our method
of synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives 4 is shown in Scheme 1. In order to optimise the
conditions, we used as a simple model, the three-component
reaction of benzaldehyde (1, Ar = Ph) (1 mmol), malononitrile
(2, X = CN) (1 mmol) and phthalhydrazide 3 (1 mmol) in the
presence of [bmim]OH (10 mol%). The reaction was carried out
in six different solvents and at different temperatures and the
results are shown in Table 1. Ethanol gave the best yield (entry 8)
and after evaluating various temperatures (entries 6–11), 60 °C
was found to be optimal. We also investigated the effect of
lowering and raising the mol% of the catalyst. The yield using
5 mol% dropped to 79% and there was no improvement in the
yield when 15 and 20 mol% was used. The optimum conditions
were thus to heat a 1:1:1 ratio of reactants in EtOH at 60 °C in
the presence of 10 mol% [bmim]OH.
Based on the optimised reaction conditions, a series of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives were
synthesised. The results, summarised in Table 2, show that the
three-component reaction in the presence of 10 mol% [bmim]
OH at 60 °C gave the corresponding products in moderate to
very good yields. It is clear that this method can be applied to
aromatic aldehydes with either electron-withdrawing groups or
electron-donating groups, but those substrates bearing electron-
withdrawing groups have higher reactivity (higher yields and
shorter reaction time) than those bearing electron-donating
groups. So, it is concluded that the electronic nature of the
To the best of our knowledge, only a few methods are available
for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives,17,18 most of which have various drawbacks. They
require long reaction times, harsh reaction conditions, and use
toxic and non-recyclable catalysts. It is thus desirable to develop
more efficient methods for the synthesis of such heterocycles.
Our recent interest has been in the development of new
synthetic methods using ionic liquids as reaction media
and catalyst.19–21 Herein, we would like to report a highly
Ar
O
O
X
CN
[bmim]OH
Solvent, heat
N
N
NH
NH
+
ArCHO +
X
NH
2
O
O
2
3
4
1
X = CN,COOEt
Scheme 1
* Correspondent. E-mail: guohy63@163.com

JOURNAL OF CHEMICAL RESEARCH 2016 355
Table 1 Optimisation of the reaction conditions for the [bmim]OH-
catalysed synthesis of a 1-phenyl-1H-pyrazolo[1,2-b]phthalazine-5,10-
dione derivative (4, Ar = Ph, X = CN) using a three-component model
reaction (Scheme 1)a
Table 2 Synthesis of 1-aryl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione
derivatives 4a–l via a three-component reaction using [bmim]OH as
catalyst in ethanol (Scheme 1)a
Entry Ar
X
Products
Time/h Yield/%b
Entry
1
2
3
4
Solvent
CHCl3
CH3CN
DMF
CH3OH
H2O
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
Temperature/°C
Time/h
8
8
8
8
Yield/%b
28
75
70
61
Trace
85
1
2
3
4
5
6
7
8
C6H5–
CN
CN
CN
CN
CN
CN
CN
CN
CN
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.5
1
2.0
1
1
2
0.8
1
0.8
1.5
3
93
97
88
95
95
86
97
94
98
90
84
90
Reflux
Reflux
Reflux
Reflux
Reflux
80
4-Cl–C6H4–
4-MeO–C6H4–
4-F–C6H4–
2-Cl–C6H4–
4-CH3–C6H4–
3-Br–C6H4–
2,4-Cl2–C6H3–
4-NO2–C6H4–
5
6
12
3
7
70
3
88
8
9
60
50
1.5
4
93
82
9
10
11
12
4-isopropyl–C6H4– CN
4-CH3–C6H4–
4-NO2–C6H4–
4j
4k
4l
10
11
40
25
4
12
65
35
COOEt
COOEt
2.5
aReaction conditions: a mixture of benzaldehyde (1, Ar = Ph) (1.0 mmol), malononitrile (2,
X = CN) (1.0 mmol) and phthalhydrazide (3) (1.0 mmol) was stirred in various solvents
for various times and heated at various temperatures in the presence of 10 mol%[bmim]
OH (Scheme 1).
aReaction conditions: a mixture of araldehyde (1) (1.0 mmol), malononitrile or ethyl
cyanoacetate (2, X = CN, COOEt) (1.0 mmol) and phthalhydrazide (3) (1.0 mmol) was
stirred in EtOH and heated at 60 °C for various times in the presence of 10 mol%[bmim]
OH (Scheme 1).
bIsolated yields.
bIsolated yields.
O
NH
3
Ar
O
O
NH
X
CN
N
N
-H2O
O
+
ArCHO
NH
CHAr
X
N
X
5
1
2
6
Ar
Ar
O
O
O
X
X
N
N
N
N
NH
NH
2
O
4
7
X= CN,COOEt
Scheme 2
substituents on aldehydes has some effect on this reaction.
These three-component condensation reactions also proceeded
with ethyl cyanoacetate (Table 2, entries 11 and 12), but in
these cases the reaction times are longer. It may be due to
the lower reactivity of ethyl cyanoacetate compared to that of
malononitrile. When an aliphatic aldehyde was subjected to
this reaction, no product was obtained. We attribute this to the
slow formation and unstable nature of the alkylidenemalonitrile
formed from the aliphatic aldehydes examined. In a further
study, alkylidenemalonitrile and phthalhydrazide were reacted
under the same conditions, but no product was obtained. This
may be due to an electronic effect. In this study, all the products
were characterised by their m.p., IR, 1H NMR, 13C NMR, mass
spectroscopy and elemental analyses.
A reasonable mechanism for the formation of the product 4 is
outlined in Scheme 2. The reaction occurs via initial formation
of intermediate 5 by the Knoevenagel addition of malononitrile
or ethyl cyanoacetate 2 to the aldehyde 1 followed by loss of
H2O. Then, Michael-type addition of the phthalhydrazide 3 to
5 yields 6, which after cyclisation and tautomerisation, affords
the corresponding products 4.
Experimental
Melting points were determined with an X-4 microscopic melting-
point apparatus and are uncorrected. IR spectra were recorded on a
Nexus 670 spectrometer in KBr. 1H NMR and 13C NMR spectra were
measured on a Bruker Avance-II 500 MHz spectrometer using TMS
as internal standard and DMSO-d6 as solvent. NMR spectra were
obtained on a Bruker Avance-II 500 MHz spectrometer (1H NMR at
500 Hz, 13C NMR at 125 Hz) in DMSO-d6 using TMS as an internal
standard. Chemical shifts (δ) are given in ppm and coupling constants
(J) in Hz.
We studied the reuse of [bmim]OH using the model reaction
(Scheme 1) and found that it could be successively recovered
and reused five times (93, 93, 91, 92 and 90%) without much
loss in its catalytic activity.

356 JOURNAL OF CHEMICAL RESEARCH 2016
The synthesis of this task-specific ionic liquid has been carried out
from a similar method in the literature.22 The ionic liquid was formed
quantitatively and in high purity as assessed by H NMR. All other
chemicals (AR grade) were commercially available and used without
further purification.
128.6, 128.7, 129.0, 133.6, 134.6, 135.3, 137.6, 150.5, 153.5, 156.6; MS
(EI, 70 eV) m/z (%): 330 (M+, 20.0), 313 (48.6), 239 (100), 140 (37.8).
Anal. calcd for C19H14N4O2: C, 69.08; H, 4.27; N, 16.96; found: C,
69.01; H, 4.24; N, 16.92%.
3-Amino-1- (3-bromophenyl) -5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4g): Yellow powder, m.p.
273−275 °C (EtOH) (lit.17 270−272 °C). IR vmax (KBr): 3369, 3261,
2194, 1656, 1566, 1470, 1381, 1277 cm–1; 1H NMR: δ 6.14 (1H, s, CH),
7.32−8.27 (10H, m, ArH and NH2); 13C NMR: δ 60.8, 62.3, 115.9, 121.8,
126.0, 126.6, 127.2, 128.5, 129.0, 129.5, 130.6, 131.1, 133.7, 134.5,
141.2, 150.7, 153.7, 156.7; MS (EI, 70 eV) m/z (%): 394 (M+, 2.7), 239
(27.3), 234 (32.4), 153 (100). Anal. calcd for C18H11BrN4O2: C, 54.70;
H, 2.81; N, 14.18; found: C, 54.62; H, 2.79; N, 14.22%.
3-Amino-1-(2,4-dichlorophenyl)-5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4h): Yellow powder, m.p.
257−258 °C (EtOH). IR vmax (KBr): 3366, 3243, 2202, 1663, 1564,
1471, 1377, 1279 cm–1; 1H NMR: δ 6.45 (1H, s, CH), 7.41−8.29 (9H, m,
ArH and NH2); 13C NMR: δ 59.3, 60.1, 115.6, 126.7, 127.4, 128.0, 128.3,
128.8, 129.1, 130.6, 132.3, 133.6, 133.9, 134.5, 134.8, 151.3, 153.6,
156.7; MS (EI, 70 eV) m/z (%): 384 (M+, 9.7), 239 (100), 222 (24.8),
187 (45.5). Anal. calcd for C18H10Cl2N4O2: C, 56.12; H, 2.62; N, 14.54;
found: C, 56.07; H, 2.59; N, 14.59%.
1
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives 4
A mixture of the aromatic aldehyde 1 (1 mmol), malononitrile or ethyl
cyanoacetate 2 (1 mmol), phthalhydrazide 3 (1 mmol), [bmim]OH (0.1
mmol) in EtOH (5 mL) was stirred at 60 °C for the appropriate time
(monitored by thin-layer chromatography [TLC]). After completion of
the reaction, the mixture was cooled to room temperature and poured
into water (10 mL). The solid product was collected by filtration and
recrystallised from ethanol to give the pure compound 4. The filtrate
was extracted with diethyl ether several times to remove unreacted
starting materials and other organic contaminations. Then the water
was evaporated under reduced pressure and dried to recover the ionic
liquid for subsequent use.
3-Amino-5,10-dihydro-5,10-dioxo-1-phenyl-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile (4a): Yellow powder, m.p. 282−283 °C
(EtOH) (lit.18 276−278 °C). IR vmax (KBr): 3360, 3259, 2197, 1660,
1566, 1438, 1382, 1297 cm–1; 1H NMR: δ 6.13 (1H, s, CH), 7.32−8.27
(11H, m, ArH and NH2); 13C NMR: δ 61.4, 62.9, 116.0, 126.6, 126.7,
127.2, 128.2, 128.5, 128.6, 128.8, 133.7, 134.6, 138.4, 150.6, 153.6,
156.6; MS (EI, 70 eV) m/z (%): 316 (M+, 13.9), 299 (28.1), 239 (100).
Anal. calcd for C18H12N4O2: C, 68.35; H, 3.82; N, 17.71; found: C,
68.29; H, 3.78; N, 17.75%.
3-Amino-1- (4-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4b): Yellow powder, m.p.
269−271 °C (EtOH) (lit.18 270−272 °C). IR vmax (KBr): 3376, 3265,
2200, 1661, 1564, 1437, 1380, 1277 cm–1; 1H NMR: δ 6.15 (1H, s, CH),
7.42−8.27 (10H, m, ArH and NH2); 13C NMR: δ 60.9, 62.3, 115.9, 126.6,
127.2, 128.4, 128.5, 128.8, 132.8, 133.7, 134.6, 137.4, 150.7, 153.6,
156.6; MS (EI, 70 eV) m/z (%): 350 (M+, 6.9), 333 (17.6), 239 (50.1),
188 (45.3), 153 (100). Anal. calcd for C18H11ClN4O2: C, 61.64; H, 3.16;
N, 15.97; found: C, 61.55; H, 3.11; N, 15.92%.
3-Amino-5,10-dihydro-1- (4-nitrophenyl) -5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4i): Yellow powder, m.p.
272−274 °C (EtOH). IR vmax (KBr): 3433, 3324, 2197, 1679, 1660, 1604,
1
1558, 1517, 1379, 1276 cm–1; H NMR: δ 6.30 (1H, s, CH), 7.80−8.29
(10H, m, ArH and NH2); 13C NMR: δ 60.4, 62.1, 115.7, 123.8, 126.7,
127.3, 128.0, 128.4, 128.9, 133.9, 134.7, 145.8, 147.4, 150.9, 153.8, 156.7;
MS (EI, 70 eV) m/z (%): 361 (M+, 11.1), 344 (32.5), 239 (100), 114
(22.6). Anal. calcd for C18H11N5O4: C, 59.84; H, 3.07; N, 19.38; found:
C, 59.78; H, 3.03; N, 19.34%.
3-Amino-5,10-dihydro-1-(4-isopropylphenyl)-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4j): Yellow powder, m.p.
277−278 °C (EtOH). IR vmax (KBr): 3368, 3265, 2193, 1660, 1567, 1467,
1381, 1277 cm–1; 1H NMR: δ 1.18 (6H, d, J = 7.0 Hz, CH3), 2.85−2.90 (1H,
m, CH), 6.10 (1H, s, CH), 7.22−8.27 (10H, m, ArH and NH2); 13C NMR:
δ 23.7, 23.8, 33.1, 61.4, 62.7, 116.1, 126.4, 126.6, 126.8, 127.2, 128.7, 133.7,
134.6, 135.7, 148.4, 150.6, 153.6, 156.6; MS (EI, 70 eV) m/z (%): 358 (M+,
18.1), 341 (52.1), 239 (100), 154 (22.7). Anal. calcd for C21H18N4O2: C,
70.38; H, 5.06; N, 15.63; found: C, 70.30; H, 5.02; N, 15.68%.
Ethyl 3-amino-5,10-dihydro-5,10-dioxo-1-p-tolyl-1H-pyrazolo[1,2-b]
phthalazine-2-carboxylate (4k): Yellow powder, m.p. 208−210 °C
(EtOH) (lit.18 204−206 °C). IR vmax (KBr): 3438, 3331, 1714, 1657, 1620,
1493, 1344, 1265 cm–1; 1H NMR: δ 1.25 (3H, t, J = 7.5 Hz, CH3), 2.30
(3H, s, CH3), 4.29 (2H, q, J = 7.0 Hz, OCH2), 6.06 (1H, s, CH), 7.56−8.27
(10H, m, ArH and NH2); 13C NMR: δ 14.2, 20.5, 59.1, 62.6, 106.8, 126.8,
127.2, 128.4, 128.9, 129.1, 133.9, 134.8, 136.6, 136.9, 150.1, 153.1, 157.3,
162.8; MS (EI, 70 eV) m/z (%): 377 (M+, 19.8), 286 (100), 240 (32.1), 162
(55.8). Anal. calcd for C21H19N3O4: C, 66. 83; H, 5.07; N, 11.13; found: C,
66.76; H, 5.02; N, 11.17%.
Ethyl 3-amino-5,10-dihydro-1-(4-nitrophenyl)-5,10-dioxo-1H-pyrazolo-
[1,2-b]phthalazine-2-carboxylate (4l): Yellow powder, m.p. 240−242 °C
(EtOH) (lit.18 241−243 °C). IR vmax (KBr): 3426, 3223, 1722, 1657, 1614,
1494, 1348, 1265 cm–1; 1H NMR: δ 1.31 (3H, t, J = 7.5 Hz, CH3), 4.34
(2H, q, J = 7.0 Hz, OCH2), 6.19 (1H, s, CH), 7.74−8.56 (10H, m, ArH
and NH2); 13C NMR: δ 13.9, 58.8, 62.5, 62.7, 106.7, 114.9, 123.1, 124.1,
125.1, 126.7, 128.7, 131.6, 132.5, 133.7, 137.3, 149.2, 152.6, 161.1; MS
(EI, 70 eV) m/z (%): 408 (M+, 7.8), 286 (100), 240 (28.1), 162 (72.7), 104
(74.7). Anal. calcd for C20H16N4O6: C, 58. 82; H, 3.95; N, 13.72; found: C,
58.76; H, 3.90; N, 13.76%.
3-Amino-5,10-dihydro-1-(4-methoxyphenyl)-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4c): Yellow powder, m.p.
264−266 °C (EtOH). IR vmax (KBr): 3369, 3264, 2193, 1660, 1566,
1
1438, 1380, 1276 cm–1; H NMR: δ 3.75 (3H, s, OCH3), 6.10 (1H, s,
CH), 6.91−8.26 (10H, m, ArH and NH2); 13C NMR: δ 18.5, 61.4, 62.6,
113.8, 116.1, 126.6, 127.2, 128.4, 128.7, 130.1, 133.6, 134.6, 150.5,
153.5, 156.6, 159.2; MS (EI, 70 eV) m/z (%): 346 (M+, 11.2), 329 (43.9),
184 (100), 133 (35.4), 114 (62.0). Anal. calcd for C19H14N4O3: C, 65.89;
H, 4.07; N, 16.18; found: C, 65.81; H, 4.02; N, 16.12%.
3-Amino-1- (4-fluorophenyl) -5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4d): Yellow powder, m.p.
267−268 °C (EtOH) (lit.17 263−265 °C). IR vmax (KBr): 3367, 3264,
2192, 1659, 1566, 1512, 1440, 1380, 1278 cm–1; 1H NMR: δ 6.16 (1H, s,
CH), 7.18−8.27 (10H, m, ArH and NH2); 13C NMR: δ 61.1, 62.3, 115.1,
115.3, 116.0, 126.6, 127.2, 128.6, 128.8, 129.1, 129.2, 133.7, 134.6,
150.6, 153.6, 156.6, 160.9, 162.9; MS (EI, 70 eV) m/z (%): 334 (M+,
16.9), 317 (45.2), 239 (100). Anal. calcd for C18H11FN4O2: C, 64.67; H,
3.32; N, 16.76; found: C, 64.58; H, 3.28; N, 16.69%.
3-Amino-1- (2-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4e): Yellow powder, m.p.
261−262 °C (EtOH) (lit.18 259−262 °C). IR vmax (KBr): 3375, 3245,
2205, 1662, 1564, 1471, 1380, 1279 cm–1; 1H NMR: δ 6.46 (1H, s, CH),
7.33−8.30 (10H, m, ArH and NH2); 13C NMR: δ 59.8, 60.6, 115.6, 126.7,
127.3, 127.8, 128.3, 128.7, 129.7, 129.9, 131.2, 133.8, 134.7, 151.1, 153.5,
156.6; MS (EI, 70 eV) m/z (%): 350 (M+, 10.6), 239 (100), 188 (20.9),
153 (67.2). Anal. calcd for C18H11ClN4O2: C, 61.64; H, 3.16; N, 15.97;
found: C, 61.56; H, 3.12; N, 15.98%.
Received 29 January 2016; accepted 25 March 2016
Paper 1603882 doi: 10.3184/174751916X14627996968714
Published online: 17 May 2016
3-Amino-5,10-dihydro-5,10-dioxo-1-p-tolyl-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile (4f): Yellow powder, m.p. 254−256 °C.
IR vmax (KBr): 3364, 3263, 2197, 1659, 1565, 1467, 1380, 1278 cm–1;
1H NMR: δ 2.30 (3H, s, CH3), 6.09 (1H, s, CH), 7.16−8.26 (10H, m,
ArH and NH2); 13C NMR: δ 20.7, 61.5, 62.8, 116.0, 126.6, 126.8, 127.2,
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