Nickel chloride-catalyzed one-pot three-component synthesis of pyrazolophthalazinyl spirooxindoles

Article abstract of DOI:10.1016/j.tet.2011.07.002

A direct and efficient approach for the preparation of pyrazolophthalazinyl spirooxindoles has been developed through one-pot three-component reaction of easily available isatin, malononitrile or cyanoacetic ester, and phthalhydrazide catalyzed by nickel chloride in polyethylene glycol 600. Desired products were obtained in high to excellent yields using a simple workup procedure.

Full text of DOI:10.1016/j.tet.2011.07.002

Tetrahedron 67 (2011) 7426e7430
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nickel chloride-catalyzed one-pot three-component synthesis of
pyrazolophthalazinyl spirooxindoles
*
Xiao-Nan Zhang, Yong-Xiao Li, Zhan-Hui Zhang
The College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050016, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2011
Received in revised form 26 June 2011
Accepted 1 July 2011
Available online 7 July 2011
A direct and efficient approach for the preparation of pyrazolophthalazinyl spirooxindoles has been
developed through one-pot three-component reaction of easily available isatin, malononitrile or cya-
noacetic ester, and phthalhydrazide catalyzed by nickel chloride in polyethylene glycol 600. Desired
products were obtained in high to excellent yields using a simple workup procedure.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Nickel chloride
Pyrazolophthalazinyl spirooxindoles
Multicomponent reaction
One-pot
Polyethylene glycol
1. Introduction
reported for the preparation of pyrazolophthalazinyl spiroox-
indoles.6 Considering the above reports, the development of new
Multicomponent coupling reactions (MCRs), with high-
throughput generate structurally complex molecules by the re-
action of three or more readily accessible starting materials via
a one-pot methodology, have become powerful tools in organic,
combinatorial, and medicinal chemistry. They offer significant ad-
vantages over conventional stepwise strategies, by reducing waste
production, saving energy, shortening reaction periods, and
avoiding protectionedeprotection of functional groups thus
resulting in both economical and environmental benefits.1
Heterocyclic chemistry is one of the most important disciplines
in organic synthesis and pharmaceutical chemistry.2 Among the
various heterocyclic systems discovered and developed, the
nitrogen-containing heterocycles play a fundamental role in the
context of both chemistry and biology. Spirooxindole is one of
prevalent heterocycles found in numerous natural and synthetic
products along with useful bio-, physio-, and pharmaceutical ac-
tivities.3 In addition, heterocyclic fused phthalazines have been
found to posses cytotoxic, antimicrobial, anticonvulsant, antifungal,
anticancer, anti-inflammatory, and cardiotonic activities.4 They also
exhibited good feature as new luminescence material or fluores-
cence probe.5 Consequently, great efforts have been made to find
efficient synthetic methods to gain access to spirooxindole and
phthalazine derivatives. So far, only a few methods have been
synthetic methodologies for the construction of pyrazoloph-
thalazinyl spirooxindole scaffold will be a beneficial and interesting
challenge.
In recent years, the use of polyethylene glycol as a reaction
medium has gained considerable interest in organic synthesis due
to its many advantages from environmental, economical, and safety
standpoints.7 It is non-toxic, inexpensive, non-volatile, thermally
stable, biologically acceptable, and eco-friendly, and allows many
useful organic transformations to be performed under mild re-
action conditions, such as coupling,8 addition,9 substitution,10
condensation,11 oxidation,12 reduction,13 and multicomponent re-
action.14 In a continuation of our interest in developing more effi-
cient and environmental benign methodologies,15 we report herein
a simple and facile procedure for the synthesis of pyrazoloph-
thalazinyl spirooxindoles through one-pot three-component re-
action of isatin, malononitrile or cyanoacetic ester and
phthalhydrazide catalyzed by NiCl2 in PEG 600 (Scheme 1).
Scheme 1. Synthesis of pyrazolophthalazinyl spirooxindoles catalyzed by NiCl2 in PEG
* Corresponding author. E-mail address: zhanhui@mail.nankai.edu.cn (Z.-H.
600.
Zhang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.002

X.-N. Zhang et al. / Tetrahedron 67 (2011) 7426e7430
7427
2. Results and discussion
electron-withdrawing groups on the aromatic ring, were reacted
with malononitrile and phthalhydrazide to generate pyrazoloph-
thalazinyl spir-30-oxindoles (4) in good to high yields. In general,
isatins with electron-withdrawing group on the aromatic ring
reacted rapidly, while isatins bearing electron-donating group de-
creased the reactivity, requiring longer reaction times. In addition,
the reactions were also found to be effective when less reactive
cyanoacetic esters were employed in place of malononitrile. How-
ever, it is observed that the corresponding products were obtained
in slightly lower yields than malononitrile.
First of all, the model reaction of isatin (1.0 mmol), malononitrile
(1.0 mmol), and phthalhydrazide (1.0 mmol) was conducted to
screen the optimal reaction conditions and the results were listed
in Table 1. We attempted various conditions and found that the
reaction gave satisfying result in the presence of NiCl2 in PEG 600 at
100 ꢀC (Table 1, entry 15). Other Lewis acids, such as FeCl3, ZnCl2,
InBr3, CoCl2, Cu(NO3)2, and Cu(SO4)2, afforded 4a in lower yields
along with recovery of the starting material (Table 1, entries 9e14).
Moreover, the results indicated that the yield was decreased to
some extent when 10 mol % of NiCl2 was used (Table 1, entry 21),
and no reaction was observed even for longer time in the absence of
a catalyst (Table 1, entry 1). No substantial improvement in the
yield was observed by increasing the amount of NiCl2 to 30 mol %.
Also, the effect of the solvents on the reaction was investigated. As
could be seen in Table 1, the solvent played a crucial role for this
reaction. Water, acetonitrile, N,N-dimethyl formamide (DMF), and
1,4-dioxane (Table 1, entries 16e19) were found not suitable for this
reaction, since no reaction took place. The target product was
obtained in 60% yield in refluxing ethanol. To our surprise, we
found that the yield of the desired product 4a could be improved to
90% when PEG 600 was employed. Besides, the effect of tempera-
ture was studied by carrying out the model reaction in PEG 600 at
different temperatures in the presence of NiCl2. The results sug-
gested that the optimized reaction temperature was 100 ꢀC.
The scope and limitations of this new MCR process were further
evaluated under optimized reaction conditions and the results are
shown in Table 2. A variety of isatin, both electron-donating and
The products were characterized by IR, 1H NMR and 13C NMR
spectra, and by elemental analysis. The structure of 4i was further
confirmed by X-ray diffraction analysis of single crystal and is
shown below in Fig. 1.
In order to elucidate the reaction mechanism, we also conducted
the reaction of 2-(2-oxoindolin-3-ylidene)malononitrile (5)17 with
phthalhydrazide in the presence of NiCl2 under same condition.
Interestingly, 4a was obtained in high yield. In addition, when we
tried to perform the reaction of phthalhydrazide with isatin or
malononitrile in the above reaction conditions, no reaction was
observed. On the basis of these findings, we propose a plausible
mechanism for this three-component reaction (Scheme 2). The
reaction may proceed in a stepwise manner. Firstly, we assume that
the initial step is a Knoevenagel condensation between isatin and
malononitrile, resulting the adduct 5, which suffers a Michael ad-
dition of phthalhydrazide to the C]C bond of 5, followed by cy-
cloaddition and isomerization to afford the target product 4a. The
role of NiCl2 probably would be Lewis acid for the activation of the
nitrile to transform into amine.
Finally, the present route to pyrazolophthalazinyl spirooxindole
was successfully applied to a large scale process. A typical reaction
was performed for synthesis of 4a with tenfold amounts of re-
actants and catalyst with respect to the one mentioned in the
Experimental section. The result showed that the desired product
4a was obtained in 88% yield.
Table 1
Screening on the reaction conditions for the synthesis of 4aa
3. Conclusion
In summary, we have developed a new strategy that provides an
efficient synthesis of a class of structurally unique pyrazoloph-
thalazinyl spirooxindoles via NiCl2-catalyzed one-pot three-com-
ponent condensation reaction from simple and readily available
precursors. The simplicity, high yields of products, easy workup
procedure, and avoidance of hazardous organic solvents are the
major features of this methodology.
Entry Catalyst
Solvent
Temp (ꢀC) Time (h) Yieldb (%)
1
No
PEG 600
EtOH
H2O
EtOH
EtOH
PEG 600
EtOH
H2O
PEG 600
PEG 600
PEG 600
PEG 600
100
5.0
2.5
4.0
5.5
2.0
2.0
5.5
2.0
3.0
3.5
2.5
3.5
3.0
3.0
1.3
3.0
3.5
3.5
3.0
2.5
3.0
1.0
5.0
3.0
3.5
1.5
0
0
2
3
4
5
6
7
NaHCO3 (20 mol %)
NaOAc (20 mol %)
MgO (20 mol %)
CuO (20 mol %)
NaOAc (20 mol %)
K2CO3 (20 mol %)
Reflux
Reflux
Reflux
Reflux
100
0
0
0
0
4. Experimental section
4.1. General
Reflux
Reflux
100
12
15
8
8
b-CD (20 mol %)
9
FeCl3 (20 mol %)
ZnCl2 (20 mol %)
InBr3 (20 mol %)
CoCl2 (20 mol %)
Cu(NO3)2 (20 mol %) PEG 600
Cu(SO4)2 (20 mol %) PEG 600
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (10 mol %)
NiCl2 (30 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
NiCl2 (20 mol %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
100
100
18
0
All solvents and chemicals were obtained commercially and
were used as received. Melting points were determined using an X-
4 apparatus and are uncorrected. IR spectra were recorded using
a Bruker-TENSOR 27 spectrometer instrument. NMR spectra were
taken with a Bruker DRX-500 spectrometer at 500 MHz (1H) and
125 MHz (13C) using DMSO-d6 as the solvent. Elemental analyses
were obtained on a Vario EL III CHNOS elemental analyzer.
100
100
100
100
Reflux
Reflux
Reflux
12
20
10
90
0
PEG 600
H2O
CH3CN
DMF
1,4-Dioxane Reflux
EtOH
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
PEG 600
0
0
0
Reflux
100
100
25
60
21
90
0
4.2. General procedure for synthesis of pyrazolophthalazinyl
spirooxindoles
60
0
A mixture of isatin 1 (1.0 mmol), malononitrile or cyanoacetic
80
110
40
85
ester
2 (1.0 mmol), phthalhydrazide (1.0 mmol), and NiCl2
(0.2 mmol) in PEG 600 (5 mL) was stirred at 100 ꢀC for the ap-
propriate time (Table 2). After complete conversion as indicated by
TLC, water was added and the product was extracted with ethyl
a
All reactions were run with isatin (1.0 mmol), malononitrile (1.0 mmol), and
phthalhydrazide (1.0 mmol) in solvent (5 mL).
b
Isolated yields.

7428
X.-N. Zhang et al. / Tetrahedron 67 (2011) 7426e7430
Table 2
Synthesis of pyrazolophthalazinyl spirooxindoles catalyzed by NiCl2 in PEG 600
Entry
R
R1
R2
X
Products
Time (h)
Yielda (%)
Mp (ꢀC)
lit. Mp (ꢀC)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
CN
CN
CN
CN
CN
CN
CN
CN
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
1.3
1.2
1.3
1.1
1.0
2.3
2.5
1.2
1.0
1.0
0.8
2.5
2.3
2.0
3.0
1.5
2.0
2.1
2.2
2.5
2.0
2.0
2.3
1.7
3.5
3.5
90
88
85
86
83
84
80
91
92
93
95
82
80
85
90
93
83
84
85
86
84
88
83
91
82
84
268e270
283e285
223e224
278e279
265e266
278e279
>350
269e2706
282e2846
222e2236
276e2776
2666
CH2CH2CH2CH3
CH2]CHCH3
PhCH2
H
H
H
H
H
H
H
H
H
H
H
H
CH2CH2CH2CH3
CH2]CHCH3
PhCH2
H
H
H
H
H
H
H
Me
Me
Cl
Br
I
NO2
H
Cl
Br
I
NO2
H
H
H
H
325e327
>350
9
CN
CN
CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
348e350
280e281
318e320
288e290
305e307
308e310
340e342
285e286
259e260
255e256
291e292
332e334
331e333
340e342
320e322
322e323
308e309
280e2826
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOiPr
COOiPr
284e2866
258e2606
254e2566
290e2916
4s
4t
Cl
Br
I
NO2
Cl
Br
4u
4v
4w
4x
4y
4z
a
Yields refer to pure isolated products.
Scheme 2. A possible mechanism for the one-pot reaction for synthesis of 4a.
Fig. 1. X-ray crystal structure of 4i (CCDC 825902).16
acetate (2ꢁ10 ml). The organic phase was dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude
product was recrystallized from ethanol to afford the pure product.
solid; IR (KBr)
1558, 1545, 1533, 1497, 1437, 1375, 1261, 1203, 1167, 1144, 824,
700 cmꢂ1; 1H NMR (DMSO-d6, 500 MHz)
2.22 (s, 3H, CH3), 6.81 (d,
n 3353, 3315, 2208, 1747, 1719, 1692, 1659, 1624, 1601,
d
J¼8.0 Hz, 1H, ArH), 7.11 ( d, J¼8.0 Hz, 1H, ArH), 7.32 (s, 1H, ArH),
7.98e8.03 (m, 2H, ArH), 8.06 (d, J¼7.5 Hz, 1H, ArH), 8.30 (d,
J¼8.0 Hz, 1H, ArH), 8.34 (s, 2H, NH2), 10.83 (br s, 1H, NH); 13C NMR
4.3. Characterization data
4.3.1. 30-Amino-5-methyl-2,50,100-trioxo-50,100-dihydrospiro [indo-
line-3,10-pyrazolo[1,2-b]phthalazine]-20-carbonitrile
(DMSO-d6, 125 MHz) d 20.6, 60.3, 69.9, 110.0, 114.5, 125.1, 125.5,
(4f). Yellow
127.0, 127.6, 127.9, 128.7, 130.7, 131.8, 134.3, 135.0, 139.8, 151.7, 152.5,

X.-N. Zhang et al. / Tetrahedron 67 (2011) 7426e7430
7429
156.3, 172.4; Anal. Calcd for C20H13N5O3: C, 64.69; H, 3.53; N, 18.86;
found: C 64.85; H 3.38; N, 19.02.
1477, 1448, 1394, 1315, 1267, 1168, 1145, 1116, 823, 700 cmꢂ1
1H NMR (DMSO-d6, 500 MHz)
3.47 (s, 3H, CH3), 6.79e6.85
;
d
(m, 1H, ArH), 7.25e7.40 (m, 1H, ArH), 7.52e7.64 (m, 1H, ArH),
8.00e8.05 (m, 3H, ArH), 8.30e8.32 (m, 1H, ArH), 10.89 (s, 1H,
4.3.2. 30-Amino-5,7-dimethyl-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carbonitrile (4g). Yellow
NH); 13C NMR (DMSO-d6, 125 MHz)
d 51.1, 70.2, 70.3, 111.2,
solid; IR (KBr)
1490, 1419, 1382, 1271, 1205, 1147, 1033, 866, 694 cmꢂ1
(DMSO-d6, 500 MHz) 2.18 (s, 1H, CH3), 2.23 (s, 3H, CH3), 6.94 (s,
n
3465, 3404, 2194, 1743, 1683, 1652, 1604, 1558,
111.8, 113.9, 124.2, 126.2, 127.3, 127.5, 127.9, 128.4, 129.2, 129.8,
134.7, 135.5, 152.6, 157.2, 173.2, 173.3; Anal. Calcd for
C20H13ClN4O5: C, 56.55; H, 3.08; N, 13.19; found: C 56.72; H
2.90; N, 13.02.
;
1H NMR
d
1H, ArH), 7.12 (s,1H, ArH), 8.00e8.07 (m, 3H, ArH), 8.31 (d, J¼8.0 Hz,
1H, ArH), 8.32 (s, 2H, NH2), 10.86 (s, 1H, NH); 13C NMR (DMSO-d6,
125 MHz)
d
16.1, 20.4, 60.4, 70.1, 114.5, 119.1, 122.3, 125.1, 126.9,
4.3.8. Methyl 30-amino-5-bromo-2,50,100-trioxo-50,100-dihydrospiro[in-
127.6,127.9,128.9, 131.3,132.1,134.3,135.0,138.3, 151.6,152.4, 156.2,
172.8; Anal. Calcd for C21H15N5O3: C, 65.45; H, 3.92; N, 18.17; found:
C 65.58; H 4.10; N, 17.98.
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate
(4n). Yellow
3404, 3292, 1751, 1705, 1670, 1647, 1618, 1533, 1477,
1448,1382,1309,1265,1217, 1168,1143,1116,1031, 810, 704 cmꢂ1; 1H
NMR (DMSO-d6, 500 MHz)
solid; IR (KBr)
n
d
3.47 (s, 3H, CH3), 6.80 (d, J¼8.5 Hz, 1H,
4.3.3. 30-Amino-5-chloro-2,50,100-trioxo-50,100-dihydrospiro
line-3,10-pyrazolo[1,2-b]phthalazine]-20-carbonitrile
(4h). Yellow
solid; IR (KBr) 3358, 3249, 2208, 1762, 1705, 1662, 1643, 1622,
1558, 1473, 1411, 1363, 1257, 1167, 1134, 1115, 1029, 827, 698 cmꢂ1
1H NMR (DMSO-d6, 500 MHz)
[indo-
ArH), 7.39 (dd, J¼8.5, 2.0 Hz,1H, ArH), 7.64 (s,1H, ArH), 8.00e8.07 (m,
3H, ArH), 8.30e8.32 (m,1H, ArH),10.89 (s,1H, NH); 13C NMR (DMSO-
n
d6, 125 MHz) d 50.5, 69.7, 80.3, 111.2, 113.4, 126.8, 126.9, 127.4, 128.0,
;
128.7, 129.0, 132.1, 134.2, 134.9, 142.6, 152.1, 156.7, 163.1, 163.1, 172.6;
Anal. Calcd for C20H13BrN4O5: C, 51.19; H, 2.79; N, 11.94; found: C
51.02; H 2.98; N, 12.13.
d
6.94 (d, J¼8.0 Hz,1H, ArH); 7.36 (dd,
J¼8.5, 2.0 Hz, 1H, ArH), 7.71 (d, J¼2.0 Hz, 1H, ArH), 8.00e8.08 (m,
3H, ArH), 8.31 (d, J¼8.0 Hz, 1H, ArH), 8.39 (s, 2H, NH2), 11.07 (s, 1H,
NH); 13C NMR (DMSO-d6, 125 MHz)
d
59.5, 69.5, 111.7, 114.3, 124.9,
4.3.9. Methyl 30-amino-5-iodo-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4o). Yellow
126.5, 127.0, 127.5, 127.6, 127.7, 128.8, 130.2, 134.4, 135.0, 141.0, 151.9,
152.5, 156.4, 172.2; Anal. Calcd for C19H10ClN5O3: C, 58.25; H, 2.57;
N, 17.88; found: C 58.06; H 2.75; N, 17.70.
solid; IR (KBr)
1602, 1521, 1473, 1394, 1313, 1267, 1217, 1168, 1143, 1118, 823,
698 cmꢂ1 1H NMR (DMSO-d6, 500 MHz)
3.47 (s, 3H, CH3), 6.68
n 3446, 3354, 1739, 1701, 1666, 1647, 1635, 1616,
;
d
4.3.4. 30-Amino-5-bromo-2,50,100-trioxo-50,100-dihydrospiro [indo-
(d, J¼8.0 Hz, 1H, ArH), 7.54 (dd, J¼8.0, 1.5 Hz, 1H, ArH), 7.75 (d,
line-3,10-pyrazolo[1,2-b]phthalazine]-20-carbonitrile
(4i). Yellow
3394, 3354, 2212, 1751, 1693, 1658, 1618, 1602, 1577,
1558, 1477, 1440, 1379, 1272, 1257, 1166, 1147, 1122, 819, 800,
702 cmꢂ1 1H NMR (DMSO-d6, 500 MHz)
J¼1.5 Hz, 1H, ArH), 8.00e8.07 (m, 3H, ArH), 8.30e8.32 (m, 1H,
solid; IR (KBr)
n
ArH), 10.87 (s, 1H, NH); 13C NMR (DMSO-d6, 125 MHz)
d 50.6, 69.6,
80.4, 84.5, 111.8, 127.0, 127.4, 128.0, 128.8, 129.2, 132.1, 134.2, 135.0,
137.9, 143.1, 150.6, 152.1, 156.7, 163.2, 172.4; Anal. Calcd for
C20H13IN4O5: C, 46.53; H, 2.54; N, 10.85; found: C 46.35; H 2.72; N,
10.68.
;
d
6.89 (d, J¼8.5 Hz, 1H,
ArH); 7.49 (dd, J¼8.5, 2.0 Hz, 1H, ArH), 7.82 (d, J¼2.0 Hz, 1H, ArH),
8.00e8.08 (m, 3H, ArH), 8.32 (dd, J¼8.5, 2.0 Hz,1H, ArH), 8.39 (s, 2H,
NH), 11.08 (s, 1H, NH); 13C NMR (DMSO-d6, 125 MHz)
d 59.5, 69.4,
112.2, 114.2, 114.3, 127.0, 127.5, 127.6, 127.7, 127.8, 128.8, 133.0, 134.4,
135.0, 141.4, 151.9, 152.5, 156.3, 172.1; Anal. Calcd for C19H10BrN5O3:
C, 52.31; H, 2.31; N, 16.05; found: C 52.15; H 2.50; N, 15.88.
4.3.10. Methyl 30-amino-5-nitro-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate
(4p). Yellow
3421, 3313, 1751, 1701, 1662, 1608, 1558, 1473, 1456,
1382, 1338, 1309, 1265, 1211, 1141, 1083, 1033, 839, 774, 702 cmꢂ1; 1H
NMR (DMSO-d6, 500 MHz)
solid; IR (KBr)
n
4.3.5. 30-Amino-5-iodo-2,50,100-trioxo-50,100-dihydrospiro [indoline-
3,10-pyrazolo[1,2-b]phthalazine]-20-carbonitrile (4j). Yellow solid; IR
d
3.46 (s, 3H, CH3), 7.05 (d, J¼7.5 Hz, 1H,
ArH), 7.73(brs,2H, NH2),8.00e8.03(m, 3H, ArH), 8.20(d,J¼8.0Hz,1H,
(KBr)
1473, 1440, 1379, 1274, 1257, 1291, 1166, 1147, 1124, 815, 800,
702 cmꢂ1 1H NMR (DMSO-d6, 500 MHz)
n 3392, 3303, 3180, 2212, 1751, 1691, 1658, 1616, 1602, 1577,
ArH), 8.32 (d, J¼7.5 Hz,1H, ArH), 8.46 (s,1H, ArH),11.49 (s,1H, NH); 13C
NMR (DMSO-d6, 125 MHz) d 51.0, 70.6, 81.2, 109.9, 122.2, 124.2, 127.1,
;
d
6.77 (d, J¼8.0 Hz, 1H,
127.4, 127.9, 128.6, 129.0, 130.0, 134.6, 135.5, 143.8, 151.0, 152.5, 157.1,
163.8, 173.4; Anal. Calcd for C20H13N5O7: C, 55.18; H, 3.01; N, 16.09;
found: C 54.99; H 2.83; N, 16.25.
ArH), 7.64 (d, J¼8.5 Hz,1H, ArH), 7.93 (s, 1H, ArH), 8.01e8.08 (m, 3H,
ArH), 8.31 (d, J¼8.0 Hz, 1H, ArH), 8.39 (s, 2H, NH2), 11.05 (s, 1H, NH);
13C NMR (DMSO-d6, 125 MHz)
d 59.6, 69.3, 85.4, 112.6, 114.3, 127.0,
127.5,127.7, 127.9, 128.8, 133.0, 134.4, 135.0,138.8, 141.8, 151.8, 152.4,
156.3, 171.9; Anal. Calcd for C19H10IN5O3: C, 47.23; H, 2.09; N, 14.49;
found: C 47.40; H 1.92; N, 14.66.
4.3.11. Ethyl 30-amino-5-chloro-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4u). Yellow
solid; IR (KBr)
1400, 1298, 1265, 1164, 1145, 1112, 819, 773, 698 cmꢂ1
(DMSO-d6, 500 MHz)
n
3442, 3332, 1751, 1705, 1662, 1647, 1602, 1533, 1481,
;
1H NMR
4.3.6. Methyl 30-amino-2,50,100-trioxo-50,100-dihydrospiro [indoline-
3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4l). Yellow solid; IR
d
0.92 (t, J¼7.0 Hz, 3H, CH3), 3.84e3.94 (m, 2H,
CH2), 6.84 (d, J¼8.5 Hz, 1H, ArH), 7.27 (dd, J¼8.5, 2.0 Hz, 1H, ArH),
(KBr)
1305,1290,1290,1267,1240,1164,1139,1095, 779, 698cmꢂ1; 1H NMR
(DMSO-d6, 500 MHz)
n 3415, 3352,1758,1701,1670,1652,1616,1508,1465,1407,1382,
7.51 (d, J¼2.0 Hz, 1H, ArH), 8.00e8.06 (m, 3H, ArH), 8.31e8.32 (m,
1H, ArH), 10.86 (s, 1H, NH); 13C NMR (DMSO-d6, 125 MHz)
d 13.7,
d
3.44 (s, 3H, CH3), 6.83 (d, J¼7.5 Hz, 1H, ArH),
58.8, 69.8, 80.3, 110.6, 124.1, 125.7, 127.0, 127.4, 128.0, 128.7, 128.9,
129.2, 134.2, 135.0, 142.3, 150.8, 152.2, 156.6, 163.0, 172.8; Anal. Calcd
for C21H15ClN4O5: C, 57.48; H, 3.45; N, 12.77; found: C 57.65; H 3.28;
N, 12.60.
6.88 (t, J¼7.5 Hz,1H, ArH), 7.21 (t, J¼7.5 Hz,1H, ArH), 7.30 (d, J¼7.0 Hz,
1H,ArH), 7.98e8.06 (m, 3H,ArH), 8.30e8.32(m,1H, ArH),10.74 (s,1H,
NH); 13C NMR (DMSO-d6, 125 MHz)
d 51.0, 70.6, 81.2, 109.9, 122.2,
124.2, 127.1, 127.4,127.9, 128.6, 129.0,130.0, 134.6,135.5, 143.8,150.9,
151.0,152.5,157.1,163.8,173.8;Anal. Calcd forC20H14N4O5:C, 61.54;H,
3.62; N, 14.35; found: C 61.38; H 3.45; N, 14.52.
4.3.12. Ethyl 30-amino-5-bromo-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4v). Yellow
solid; IR (KBr)
1398, 1300, 1265, 1219, 1167, 1145, 1118, 1064, 821, 702 cmꢂ1
NMR (DMSO-d6, 500 MHz)
0.92 (t, J¼6.5 Hz, 3H, CH3), 3.84e3.94
(m, 2H, CH2), 6.80 (d, J¼8.0 Hz, 1H, ArH), 7.40 (dd, J¼8.0, 2.0 Hz, 1H,
n
3438, 3330, 1747, 1705, 1662, 1620, 1602, 1529, 1477,
4.3.7. Methyl 30-amino-5-chloro-2,50,100-trioxo-50,100-dihydrospiro[in-
;
1H
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4m). Yellow
d
solid; IR (KBr)
n 3454, 3350, 1751, 1701, 1666, 1647, 1602, 1521,

7430
X.-N. Zhang et al. / Tetrahedron 67 (2011) 7426e7430
ArH), 7.63 (d, J¼2.0 Hz, 1H, ArH), 7.98e8.08 (m, 3H, ArH), 8.30e8.32
(m, 1H, ArH),10.86 (s, 1H, NH); 13C NMR (DMSO-d6, 125 MHz)
13.7,
C22H17BrN4O5: C, 53.13; H, 3.45; N, 11.27; found: C 52.96; H 3.62;
N, 11.08.
d
58.9, 69.8, 80.3, 111.2, 113.3, 126.8, 127.0, 127.4, 128.0, 128.7, 129.2,
132.0, 134.2, 134.9, 142.7, 150.8, 152.1, 156.6, 163.0, 172.7; Anal. Calcd
for C21H15BrN4O5: C, 52.19; H, 3.13; N, 11.59; found: C 52.01; H 2.98;
N, 11.76.
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (20872025 and 21072042) and the Nature Science
Foundation of Hebei Province (B2011205031) for the financial
support.
4.3.13. Ethyl 30-amino-5-iodo-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4w). Yellow
solid; IR (KBr)
1429, 1398, 1386, 1357, 1299, 1265, 1165, 1145, 1120, 821, 777,
700 cmꢂ1 1H NMR (DMSO-d6, 500 MHz)
n 3439, 3331, 1739, 1701, 1662, 1616, 1604, 1525, 1473,
References and notes
;
d
0.92 (t, J¼7.5 Hz, 3H,
CH3), 3.85e3.94 (m, 2H, CH2), 6.69 (d, J¼8.0 Hz, 1H, ArH), 7.55 (dd,
J¼8.0, 2.0 Hz,1H, ArH), 7.74(d, J¼2.0 Hz,1H, ArH), 8.00e8.06 (m, 3H,
ArH), 8.30e8.32 (m,1H, ArH), 10.84 (s, 1H, NH); 13C NMR (DMSO-d6,
1. (a) Ganem, B. Acc. Chem. Res. 2009, 42, 463e472; (b) Kumaravel, K.; Vasuki, G.
Curr. Org. Chem. 2009, 13, 1820e1841; (c) Jiang, B.; Shi, F.; Tu, S. J. Curr. Org.
Chem. 2010, 14, 357e378.
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Chem. 2004, 12, 2483e2488; (b) Dandia, A.; Singh, R.; Khaturia, S.; Merienne,
C.; Morgant, G.; Loupy, A. Bioorg. Med. Chem. 2006, 14, 2409e2417; (c) Ding, K.;
Lu, Y. P.; Nikolovska-Coleska, Z.; Wang, G. P.; Qiu, S.; Shangary, S.; Gao, W.; Qin,
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covery Dev. 2010, 13, 758e776; (f) Antonchick, A. P.; Gerding-Reimers, C.; Cat-
arinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat.
Chem. 2010, 2, 735e740.
4. (a) Rodriguez-Ciria, M.; Sanz, A. M.; Yunta, M. J. R.; Gomez-Contreras, F.; Navarro,
P.; Sanchez-Moreno, M.; Boutaleb-Charki, S.; Osuna, A.; Castineiras, A.; Pardo, M.;
Cano, C.; Campayo, L. Bioorg. Med. Chem. 2007, 15, 2081e2091; (b) Wang, H. J.;
Zhang, X. N.; Zhang, Z. H. Monatsh. Chem. 2010,141, 425e430; (c) De, P.; Baltas, M.;
Lamoral-Theys, D.; Bruyere, C.; Kiss, R.; Bedos-Belval, F.; Saffon, N. Bioorg. Med.
Chem. 2010, 18, 2537e2548; (d) Galisteo, J.; Navarro, P.; Campayo, L.; Yunta, M. J.
R.; Gomez-Contreras, F.; Villa-Pulgarin, J. A.; Sierra, B. G.; Mollinedo, F.; Gonzalez,
J.; Garcia-Espana, E. Bioorg. Med. Chem. 2010, 18, 5301e5309.
125 MHz)
d 14.2, 59.3, 70.1, 80.9, 84.9, 112.2, 127.5, 127.9, 128.5,
129.2, 129.9, 132.6, 134.7, 135.4, 138.3, 143.6, 151.3, 152.6, 157.1,
163.5, 172.9; Anal. Calcd for C21H15IN4O5: C, 47.57; H, 2.85; N, 10.57;
found: C 47.38; H 3.01; N, 10.60.
4.3.14. Ethyl 30-amino-5-nitro-2,50,100-trioxo-50,100-dihydrospiro[in-
doline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate (4x). Yellow
solid; IR (KBr)
1429, 1400, 1382, 1340, 1296, 1265, 1211, 1145, 1085, 702 cmꢂ1
NMR (DMSO-d6, 500 MHz)
n
3442, 3330, 1757, 1708, 1664, 1652, 1612, 1533, 1481,
;
1H
d
0.89 (t, J¼7.5 Hz, 3H, CH3), 3.86 (q,
J¼7.5 Hz, 2H, CH2), 7.03 (d, J¼8.5 Hz, 1H, ArH), 7.96e8.04 (m, 3H,
ArH), 8.20 (dd, J¼8.5, 2.0 Hz, 1H, ArH), 8.31 (d, J¼7.0 Hz, 1H, ArH),
8.44 (d, J¼2.0 Hz, 1H, ArH), 11.48 (s, 1H, NH); 13C NMR (DMSO-d6,
125 MHz)
d 13.7, 59.0, 69.3, 79.8, 109.5, 120.2, 126.8, 127.0, 127.5,
127.8, 128.0, 128.9, 134.3, 134.9, 142.5, 149.6, 151.1, 152.3, 156.7,
162.9, 173.8; Anal. Calcd for C21H15N5O7: C, 56.13; H, 3.36; N, 15.58;
found: C 55.98; H 3.52; N, 15.40.
5. Wu, H.; Chen, X. M.; Wan, Y.; Xin, H. Q.; Xu, H. H.; Ma, R.; Yue, C. H.; Pang, L. L.
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Huddleston, J. G.; Rogers, R. D. Green Chem. 2005, 7, 64e82; (c) Zhou, H. F.; Fan,
Q. H.; He, Y. M.; Gu, L. Q.; Chan, A. S. C. Prog. Chem. 2007, 19, 1517e1528.
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(b) de Souza, A. L. F.; Silva, A. D.; Antunes, O. A. C. Appl. Organomet. Chem. 2009,
23, 5e8; (c) Kidwai, M.; Mishra, N. K.; Bhardwaj, S.; Jahan, A.; Kumar, A.; Mo-
zumdar, S. ChemCatChem 2010, 2, 1312e1317.
9. Reddy, B. V. S.; Somashekar, D.; Reddy, A. M.; Yadav, J. S.; Sridhar, B. Synthesis
2010, 2069e2074.
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Aust. J. Chem. 2008, 61, 700e703.
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3623e3625.
13. (a) Chandrasekhar, S.; Narsihmulu, C.; Chandrashekar, G.; Shyamsunder, T.
Tetrahedron Lett. 2004, 45, 2421e2423; (b) Zhou, H. F.; Fan, Q. H.; Tang, W. J.; Xu,
L. J.; He, Y. M.; Deng, G. J.; Zhao, L. W.; Gu, L. Q.; Chan, A. S. C. Adv. Synth. Catal.
2006, 348, 2172e2182.
4.3.15. Isopropyl
drospiro[indoline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate
(4y). Yellow solid; IR (KBr) 342, 3313.5, 2980, 2853, 1751, 1701,
1662, 1647, 1622, 1558, 1533.3, 1481, 1398, 1296, 265.2, 1166.9, 1145,
1105, 1076, 1043, 896, 700 cmꢂ1 1H NMR (DMSO-d6, 500 MHz)
30-amino-5-chloro-2,50,100-trioxo-50,100-dihy-
n
;
d
0.78 (d, J¼6.5 Hz, 3H, CH3), 1.09 (d, J¼6.5 Hz, 3H, CH3), 4.76e4.83
(m, 1H, CH), 6.90 (d, J¼8.5 Hz, 1H, ArH), 7.34 (dd, J¼8.5, 2.0 Hz, 1H,
ArH), 7.57 (d, J¼2.0 Hz, 1H, ArH), 8.05e8.09 (m, 2H, ArH), 8.12e8.14
(m, 1H, ArH), 8.37e8.39 (m, 1H, ArH), 10.95 (s, 1H, NH); 13C NMR
(DMSO-d6, 125 MHz) d 21.2, 21.5, 66.1, 70.0, 80.6, 110.7, 124.2, 125.8,
127.1, 127.5, 128.1, 128.8, 129.2, 129.2, 134.3, 135.1, 142.4, 151.0, 152.3,
156.6, 162.9, 173.0; Anal. Calcd for C22H17ClN4O5: C, 58.35; H, 3.78;
N, 12.37; found: C 58.52; H 3.96; N, 12.20.
14. (a) Guchhait, S. K.; Madaan, C. Synlett 2009, 628e632; (b) Zhang, Q. A.; Chen, J.
X.; Gao, W. X.; Ding, J. C.; Wu, H. Y. Appl. Organomet. Chem. 2010, 24, 809e812.
15. (a) Liu, Y. H.; Zhang, Z. H.; Li, T. S. Synthesis 2008, 3314e3318; (b) Liu, Y. H.; Liu,
4.3.16. Isopropyl
drospiro[indoline-3,10-pyrazolo[1,2-b]phthalazine]-20-carboxylate
(4z). Yellow solid; IR (KBr) 3751, 3425, 3313, 2852, 1747, 1701,
1683, 1662, 1647, 1618, 1604, 1570, 1533, 1508, 1400, 1296, 1265,
1222, 1167, 1145, 1103, 1031, 821, 775, 702 cmꢂ1 1H NMR (DMSO-
d6, 500 MHz)
30-amino-5-bromo-2,50,100-trioxo-50,100-dihy-
€
Q. S.; Zhang, Z. H. J. Mol. Catal. A: Chem. 2008, 296, 42e46; (c) Lu, H. Y.; Li, J. J.;
Zhang, Z. H. Appl. Organomet. Chem. 2009, 23, 165e169; (d) Liu, Y. H.; Liu, Q. S.;
n
€
Zhang, Z. H. Tetrahedron Lett. 2009, 50, 916e921; (e) Lu, H. Y.; Yang, S. H.; Deng,
€
J.; Zhang, Z. H. Aust. J. Chem. 2010, 63, 1290e1296; (f) Zhang, Z. H.; Lu, H. Y.;
;
Yang, S. H.; Gao, J. W. J. Comb. Chem. 2010, 12, 643e646; (g) Hou, J. T.; Gao, J. W.;
Zhang, Z. H. Appl. Organomet. Chem. 2011, 25, 47e53; (h) Wang, H. J.; Mo, L. P.;
Zhang, Z. H. ACS Comb. Sci. 2011, 13, 181e185.
d
0.72 (d, J¼6.0 Hz, 3H, CH3), 1.03 (d, J¼6.0 Hz, 3H,
CH3), 4.69e4.77 (m, 1H, CH), 6.80 (d, J¼8.0 Hz, 1H, ArH), 7.41 (dd,
J¼8.5, 2.0 Hz, 1H, ArH), 7.63 (d, J¼2.0 Hz, 1H, ArH), 8.00e8.03 (m,
2H, ArH), 8.06e8.08 (m, 1H, ArH), 8.31e8.32 (m, 1H, ArH), 10.89 (s,
16. The single-crystal growth was carried out in tetrahydrofuran at room tem-
perature. CCDC 825902 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via http://www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi
or e-mail: deposit@ccdc.cam.ac.uk.
17. GrRedkin, R.; Shemchuk, L. A.; Chernykh, V. P.; Shishkin, O. V.; Shishkina, S. V.
Tetrahedron 2007, 63, 11444e11450.
1H, NH); 13C NMR (DMSO-d6, 125 MHz)
d 21.2, 21.5, 66.1, 69.9,
111.3, 113.4, 126.9, 127.1, 127.6, 128.1, 128.8, 129.5, 132.1, 134.4,
135.1, 142.8, 151.0, 152.3, 152.5, 156.7, 162.9, 172.9; Anal. Calcd for