A four-component synthesis of novel spiro[pyrazoloquinoline-oxindoles] under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2014.01.025

A domino reaction for the rapid and diverse synthesis of spiro[1H-pyrazolo[3,4-b]benzo[h]dihydroquinolin-4,3-indolin-2-ones] is reported. The synthesis represents a thermodynamically-favored four-component reaction between phenylhydrazine, isatins, naphthylamines, and 3-ketoesters giving the novel products in excellent yields under solvent-free conditions. Similar applications of anilines in place of naphthylamines have not led to formation of the expected 4-substituted pyrazolo[3,4-b]quinoline derivatives. The difference was ascribed to lower aromatic character of naphthylamines, with respect to anilines, which enables them to act easier as enamines in reaction with the postulated intermediates formed from condensation of isatins and the in situ generated pyrazolones. Surprisingly, 6-aminouracils in despite of their known enamine properties did not participate in reaction with isatins and pyrazolones, the merit of naphthylamines for this synthesis seems to be met by the favorable balance of their N- and C-nucleophilicity.

Full text of DOI:10.1016/j.tet.2014.01.025

Tetrahedron 70 (2014) 1780e1785
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A four-component synthesis of novel spiro[pyrazoloquinoline-
oxindoles] under solvent-free conditions
,
b
Hamide Hosseinjani-Pirdehi a, Kurosh Rad-Moghadam a , Leila Youseftabar-Miri
*
a Chemistry Department, University of Guilan, P.O. Box 41335-19141, Rasht, Iran
b Chemistry Department, Izeh Branch, Islamic Azad University, Izeh, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A
domino reaction for the rapid and diverse synthesis of spiro[1H-pyrazolo[3,4-b]benzo[h]dihy-
Received 16 October 2013
Received in revised form 27 December 2013
Accepted 14 January 2014
Available online 18 January 2014
droquinolin-4,3-indolin-2-ones] is reported. The synthesis represents a thermodynamically-favored
four-component reaction between phenylhydrazine, isatins, naphthylamines, and 3-ketoesters giving
the novel products in excellent yields under solvent-free conditions. Similar applications of anilines in
place of naphthylamines have not led to formation of the expected 4-substituted pyrazolo[3,4-b]quin-
oline derivatives. The difference was ascribed to lower aromatic character of naphthylamines, with re-
spect to anilines, which enables them to act easier as enamines in reaction with the postulated
intermediates formed from condensation of isatins and the in situ generated pyrazolones. Surprisingly, 6-
aminouracils in despite of their known enamine properties did not participate in reaction with isatins
and pyrazolones, the merit of naphthylamines for this synthesis seems to be met by the favorable balance
of their N- and C-nucleophilicity.
Keywords:
Spiro[pyrazoloquinoline-oxindole]
Four-component reaction
Solvent-free conditions
Domino reactions
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
catalysts or solvents is another existing strategy of laboratories
researching the green feature of MCRs.6
Multicomponent reactions are elaborate combinations of com-
patible chemical transformations into convergent and concise
syntheses of complex molecules from simple starting materials.1
Nature, after several millions years of evolution, exploits many
such reactions, enabling the living systems to efficiently assemble
diverse functional molecules. Attempts of chemists to mimic na-
ture’s synthetic strategy without employing the enzymes have
been so far limited to combining the operationally consistent in-
dividual transformations.2 Recent developments in this discipline
suggest that MCRs are not just a sequential occurrence of kinetically
diverse events but may involve complex equilibriums, which bias
toward formation of single products or key intermediates.3 Both the
kinetic and thermodynamic-based MCRs are cost-effective strate-
gies that bring three or more simple and flexible molecules to-
gether to rapidly introduce structural complexity and diversity via
minimal operations.4 Typically, purification of the products
resulting from MCRs is simple, since the incorporation of all the
employed reactants into molecular structure of the product usually
offers very different physical properties relative to the starting
materials.5 The implementation of MCRs without using toxic
In this view and in line with our interest in synthesis of spi-
rooxindole heterocycles,7 we report an expedient synthesis of
some novel spiro[1H-pyrazolo[3,4-b]benzo[h]dihydroquinolin-4,3-
indolin-2-ones] under solvent-free conditions. The heterocyclic
spirooxindole ring systems are widely spread structural frame-
works present in numerous pharmaceuticals and natural prod-
ucts.8,9 Similarly, heterocycles containing the pyrazole ring are
important targets in synthetic and medicinal chemistry because
this nucleus is the main substructure in numerous biologically ac-
tive compounds10,11 and prominent drugs, such as celecoxib, pyr-
azofurine, celebrex, allopurinol, zaleplon, and many others.12
1H-Pyrazolo[3,4-b]quinolines constitute an important class of
pyrazolo-annelated compounds, owing to their actions as possible
antiviral agents inducing the formation of interferon,13 antiviral
properties,14 and potential antimalarials.15 They are also known for
antibacterial, antitumor, hypotensive, and vasodilation activities.16
Several derivatives of this ring system fluorescence in the blue re-
gion and due to their large electron charge transfer are considered
as promising materials for application in optoelectronic devices and
light emitting diodes.17e19
Upon these salient aspects, incorporation of the two pharma-
cophoric, pyrazolo[3,4-b]quinoline and oxindole, motifs into a sin-
gle molecule via efficient and environmentally benign synthetic
methods would be beneficial.
* Corresponding author. E-mail addresses: radmm@guilan.ac.ir, radmm880@
gmail.com (K. Rad-Moghadam).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.025

H. Hosseinjani-Pirdehi et al. / Tetrahedron 70 (2014) 1780e1785
1781
€
Friedlander condensation of 2-acylanilines with 1H-pyrazolin-
After this preliminary success, our study was followed for fur-
ther advancements by using simpler trial starting materials. In this
regard, we planned to carry out the synthesis via in situ preparation
of 1H-phenylpyrazolin-5-one from condensation of 3-ketoesters
and phenylhydrazine. This proposal was successfully testified for
the synthesis of 4a using the new model reaction involving ethyl
acetoacetate, phenylhydrazine, isatin, and naphthalene-1-amine
(Table 2). The viability of this four-component route seems to be
relied on the consistence of 1H-phenylpyrazolin-5-one formation
with the optimal conditions already set up for the three-
component synthesis.
5-ones is the first and the most widely used route for synthesis of
pyrazolo[3,4-b]quinoline backbone.20 An alternative variant of this
reaction was later developed wherein aldehydes and anilines were
used as separate partners instead of 2-acylanilines to make the
synthesis more flexible with respect to its prototype version.21 This
three-component method in spite of extending the scope of pyr-
azolo[3,4-b]quinoline synthesis suffers from low yields and re-
quires prolonged heating; this may be ascribed to the relatively
high activation energy associated with reaction of anilines as car-
bon-nucleophiles.22 In such conditions, the [2þ1]-condensation of
1H-pyrazolin-5-ones and aldehydes usually predominates over the
main synthesis to afford the relevant bis-pyrazolylmethane
byproducts. Quiroga, Nageswar, and Shi have established im-
proved three-component syntheses of pyrazolo[3,4-b]quinolines
by employing 5-aminopyrazoles in place of anilines.23 The signifi-
cant enamine character of 5-aminopyrazoles makes these com-
pounds useful precursors for the annelation of quinoline rings via
reaction with aldehydes and 1,3-dicarbonyl compounds. In this
context and based on recent recognition of naphthylamines as el-
igible enamines,24,7a we envisaged that spiro[1H-pyrazolo[3,4-b]
benzo[h]dihydroquinolin-4,3-indolin-2-ones] could be synthesized
via a domino reaction between 1H-pyrazolin-5-ones, isatins, and
naphthylamines.
Table 2
Optimizations for the model four-component reactiona
Ph
N
N
NH2
O
H
O
O
N
H
N
O
+
+
NH2
+
OEt
Ph
N
H
O
N
H
5
6
2
3
4a
Entry
Solvent
EtOH
H2O/EtOH (1:1)
d
d
d
d
d
Catalyst
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
p-TSA$H2O (20 mol %)
p-TSA$H2O (20 mol %)
p-TSA$H2O (20 mol %)
d
120
120
120
120
120
150
120
61
65
79
Trace
69
LiClO4 (20 mol %)
p-TSA$H2O (10 mol %)
p-TSA$H2O (30 mol %)
2. Results and discussion
54
79
We commenced our experiments by examining the model re-
action of 1H-phenyl-3-methylpyrazolin-5-one, isatin, and naph-
thalene-1-amine in various temperatures, solvents, and presence of
varying catalysts. The results are summarized in Table 1.
a
Equal amounts (1 mmol) of the reactants were used at 80 ꢀC.
Isolated yields of 4a.
b
Monitoring the model reaction by thin layer chromatography
(TLC) on silica gel revealed the formation of 1H-phenyl-3-
methylpyrazolin-5-one 1 as the initial event, preceding the pro-
duction of 4a. A correlation between the consumption of 1H-phe-
nyl-3-methylpyrazolin-5-one 1 and the formation of 4a is evident
when the reaction is followed by TLC. This observation led us to
explore the limitation and scope of applicable substrates for this
synthetic route by testifying diverse reactants under the optimal
conditions.
Table 1
Optimizations for the model three-component reactiona
Ph
N
N
NH2
O
Ph
H
N
N
N
O
+
+
O
N
O
N
H
H
1
2
3
4a
As shown in Table 3, this protocol is efficient for a variety of
substrates, affording the corresponding spiro-products 4aeh and
7a,b, mostly in high yields. The reaction tolerates various sub-
stituents reside on the aromatic ring of indolin-2-one entity as well
Entry Solvent
Catalystc
Temperature Time
Yieldb (%)
(ꢀC)
(min)
1
EtOH
p-TSA$H2O
80
80
80
80
80
50
100
80
80
80
80
100
100
100
100
100
170
75
100
100
100
100
65
68
44
Trace
81
76
79
d
2
H2O/EtOH (1:1) p-TSA$H2O
3
4
5
CH3CN
C6H12
d
p-TSA$H2O
p-TSA$H2O
p-TSA$H2O
p-TSA$H2O
p-TSA$H2O
d
Table 3
Synthesis of spiro[1H-pyrazolo[3,4-b]benzodihydroquinolin-4,3-indolin-2-ones]
4aeh and 7a,b under the optimized conditions
6
d
7
d
8
d
Ph
Ph
O
O
N
N
N
N
9
d
CAN
LiClO4
Zn(L-proline)2
20
74
23
X
O
H
H
R
R
10
11
d
R
OEt
Z
N
Y
Z
Z
N
d
O
or
+
+
p-TSA
H
N
O
a
N
O
N
H
N
H
Equal amounts (1 mmol) of the reactants were used.
Isolated yields of 4a.
Catalysts (20 mol %).
Ph
NH
H
b
c
4a-h
7a-b
Product
R
X
Y
Z
Time (min)
Yieldsa (%)
4a
4b
4c
4d
4e
4f
4g
4h
7a
7b
Me
Me
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
H
H
H
H
H
H
H
H
H
H
Cl
H
CH3O
Cl
NO2
H
Cl
120
120
140
150
120
100
270
210
140
210
79
84
75
53
81
92
65
76
81
78
As this Table shows, the trial reaction gives the best yield under
solvent-free conditions and proceeds smoothly at 80 ꢀC (oil bath)
with catalytic p-toluenesulfonic acid-monohydrate (p-TSA$H2O) to
afford the desired product, spiro[1H-pyrazolo[3,4-b]benzo[h]qui-
nolin-4,3-indoline]-4,11-dihydro-3-methyl-1-phenyl-20-one 4a, in
100 min (entry 5). Note that no product is formed within a rea-
sonable time in the absence of any catalyst. With other selected
catalysts and solvents (Table 1) the reaction gave rather lower
yields within comparable reaction times.
n-Pr
n-Pr
n-Pr
n-Pr
Ph
Ph
n-Pr
Ph
NH2
NH2
H
H
H
a
Isolated yields.

1782
H. Hosseinjani-Pirdehi et al. / Tetrahedron 70 (2014) 1780e1785
as the steric demands imposed by the residues of naphthalen-2-
amine and 3-ketoesters. It is also noticeable that the presence of
an electron-withdrawing nitro group at the 5-position of isatin
increases the rate and yield of the reaction; in contrast, the rate and
yield of the reaction are decreased when there is an electron-
donating methoxy group at the same position.
Attempts to use anilines instead of naphthylamines, in the ex-
pectation to synthesize spiro[1H-pyrazolo[3,4-b]quinolin-4,3-
indolines] under identical reaction conditions, was met with fail-
ure. These applications led to complex reaction mixtures in which
the anilines remained largely unreacted, presumably due to their
higher aromatic character and so to their weak enamine-like be-
havior. Surprisingly, our efforts to extend the scope of this reaction
for synthesis of spiro[pyrazolo[3,4-b]pyrimido[4,5-f]quinoline-4,3-
indoline]-5,7,20-triones 8 under similar conditions by employing 6-
aminouracils 9, which are known for their enamine behavior,
remained entirely unsuccessful (Scheme 1). In all of these attempts
the 6-aminouracils were recovered unreacted.
through a cascade of reactions initiating with parallel formation of
1H-phenylpyrazolin-5-ones and isatin imines. Knoevenagel con-
densation of these two intermediates, while liberating the naph-
thylamine, results in formation of the key diazafulvalene
intermediate 10. This reactive intermediate subsequently un-
dergoes twice nucleophilic additions by the naphthylamine, at
both the C- and N-termini of its enamine functionality, followed
by elimination of water to give the product (Scheme 2). There is an
alternative pathway for the reaction in which the intermediate 11,
formed from N-nucleophilic addition of naphthylamine onto the
hydrazidic carbonyl group of the intermediate 10, undergoes
a [3,3]-sigmatropic rearrangement followed by intramolecular
imination and then tautomerization to give the product (Scheme
3). The diazafulvalene intermediate 10 consists of a zwitterionic
mesomeric form in which the oxindole ring gains aromatic sta-
bilization energy in expense of charging the pyrazole ring with an
Ph
Ph
N
N
Z
N
N
Ph
[3,3]-sigmatropic
rearrangement
R
OH
NH
OH
NH
N
N
R
NH2
Z
O
H
H
N
Ph
p-TSA
N
R
N
N
N
N
H
O
R
O
+
+
O
O
N
H
H3C
N
O
O
N
R
11
O
O
H
N
H
8
N
R
O
Ph
Ph
9
R = H, Me
N
N
N
N
OH
O
NH2
Scheme 1. The reaction of 6-amino-1,3-dimethyluracil with isatin and 3-methyl-1H-
phenylpyrazolin-5-one in the presence of p-TSA.
R
R
NH
Z
Z
O
O
N
H
N
H
While, we have not performed special experiments to de-
termine the mechanism of this four-component synthesis, a rea-
sonable sequence of events leading to formation of the products
was suggested in Scheme 2. It is likely that the synthesis proceeds
-H2O
Ph
N
N
R
H
N
Z
4
Ph
N
O
O
H
N
N
O
1
N
H
O
+
R
OEt
Ph
NH2
R
5
6
Scheme 3. An alternative proposal for the mechanism of the synthesis.
O
Z
R
N
Z
Ph
N
O
N
NH2
antiaromatic electronic configuration.25 This perturbation of
electronic energy across the molecule would make the carbonyl
group of pyrazolone ring system more reactive toward additions
O
3
H
N
H
O
10
2
(Fig. 1). Addition to this group interrupts the cyclic
p-system in
Z
the pyrazolone ring and thereby offers the diazafulvalene 10-II to
relief from the local antiaromaticity. Usually, the addition of
amines to carbonyl groups is kinetically more favored than addi-
tion of carbon nucleophiles under similar conditions. This seems
to be the case for naphthylamines, which prefer to add at nitrogen
atom onto the carbonyl group of the pyrazolone ring. The
resulting adduct then undergoes cyclization through an intra-
molecular conjugate addition associated with elimination of
water.
NH2
N
N
H
O
2
Ph
N
Ph
N
Z
N
H
R
OH
NH
N
O
R
1
N
H
O
11
Ph
Ph
R
R
N
N
N
N
Z
Z
N
N
Ph
Ph
N
N
R
R
H
H
N
N
Z
Z
NH2
H
O
O
N
H
N
O
10-I
O
4
O
O
N
H
N
H
10-II
H
Scheme 2. A proposed mechanism for the synthesis of products.
Fig. 1. Stabilization of indole and partial destabilization of pyrazolone ring created via
resonance across the diazafulvalene.

H. Hosseinjani-Pirdehi et al. / Tetrahedron 70 (2014) 1780e1785
1783
The presence of the electron-donating methoxy group at the 5-
position of oxindole ring enhances the extent of amidic resonance
of this ring system and thus interrupts the resonance between the
two heterocyclic rings in diazafulvalene 10. In contrast, participa-
tion of the oxindole nitrogen in the amidic resonance is weakened
by its cross-conjugation with the nitro substituent present at the 5-
position of this ring whereby the resonance between the two
heterocyclic rings makes a greater contribution to the electronic
configuration of the molecule and hence facilitates the synthesis
(Fig. 2).
determinant of selectivity and efficiency of the syntheses presented
here. This route offers additional advantages, such as mild and
solvent-free conditions, reasonable reaction times, fairly high
yields, and simple isolation procedures.
4. Experimental
4.1. General
All of the solvents and reagents were purchased from Fluka or
Merck chemical companies. Melting points were measured on an
Electrothermal apparatus and are uncorrected. IR spectra were
obtained in KBr discs on a Shimadzu IR-470 spectrometer. 1H and
13C NMR spectra were measured with Bruker DRX-400 AVANCE
spectrometer. Chemical shifts of 1H and 13C NMR spectra were
expressed in parts per million downfield from tetramethylsilane.
Mass spectra were recorded on an Agilent Technology 5973 Net-
work MSD mass spectrometer operating at an ionization potential
of 70 eV. Elemental analyses for C, H, and N were performed using
a Foss Heraus CHNeO-rapid analyzer.
4.2. Typical procedure for preparation of spiro[1H-pyrazolo
[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-dihydro-3-methyl-
1-phenyl-20-one (4a)
Fig. 2. Enhanced cross-resonances and their effects on reactivity of diazafulvalenes.
The structures of all the products 4aeh and 7a,b are consistent
with their elemental analyses, IR, 1H- and 13C NMR as well as mass
spectral data. For example, the IR spectrum of 4a showed distinct
absorptions at 3345, 3261, and 1689 cmꢁ1 corresponding to vi-
brations of its eNH and C]O groups. A relatively wide range of
A mixture of isatin (0.147 g, 1 mmol), phenylhydrazine (0.11 g,
1 mmol), ethyl acetoacetate (0.130 g, 1 mmol), and naphthalen-1-
amine (0.144 g, 1 mmol) was added to a vial containing a mag-
netic stirring bar. The reaction mixture was sealed and stirred at
80 ꢀC until disappearance of the starting materials (monitored by
TLC on silica gel using a 1:1 mixture of ethyl acetate/n-hexane).
After completion of the reaction, the solid residue was washed with
water (10 mL) and ethanol (95%, 10 mL) to obtain the pure product
4a (0.34 g, 79% yield).
chemical shifts, i.e.,
d 6.00e8.26, were observed for the aromatic
protons of these products, suggesting that they experience diverse
anisotropic effects of the rings. 1H NMR spectra of the products
displayed characteristic upfield shifts for 40-H proton at about
d
6.50 due to anisotropic shielding effect of 1H-pyrazolo[3,4-b]
benzoquinoline backbone orienting roughly perpendicular to the
plane of oxindole ring (Fig. 3).
4.2.1. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-3-methyl-1-phenyl-20-one (4a). White powder, Yield,
0.34 g (79%). Mp 255e258 ꢀC, IR (KBr), nmax: 3445 (NH), 3261 (NH),
3230, 3062, 2920, 1689 (C]O), 1610, 1550, 748 cmꢁ1 1H NMR
.
(400.22 MHz, DMSO) d: 11.35 (1H, s, NH), 9.39 (1H, s, NH), 8.24 (1H,
d, J 8.0 Hz), 7.95 (1H, d, J 8.0 Hz), 7.66e7.55 (7H, m), 7.42 (1H, t, J
7.2 Hz, Ph 4-H), 7.22e7.13 (3H, m), 6.73 (1H, t, J 7.5 Hz, 50-H), 6.54
(1H, d, J 7.5 Hz, 40-H), 1.44 (3H, s, CH3). 13C NMR (100.63 MHz,
DMSO) d: 11.9, 53.1, 96.7, 117.8, 119.6, 120.8, 121.8, 122.9, 123.0,
123.2, 123.3, 126.5, 126.7, 127.1, 128.1, 128.5, 129.0, 130.0, 131.8,
133.7, 137.4, 138.9, 139.0, 140.3, 145.8, 181.5. MS (EI) m/z (%)¼428
(Mþ, 12), 426 (Mþꢁ2H, 100), 400 (MþꢁHCO, 45), 384 (16), 368 (12),
313 (8), 274 (21), 257 (43), 174 (82), 112 (76). Anal. Calcd for
Fig. 3. Anisotropic shielding effects of the crossed rings on the incident protons.
The mass spectra of all the products exhibited the molecular ion
peaks at appropriate m/z values. Loss of two hydrogen atoms and
extrusion of CO from the molecular ions are the prevalent frag-
mentation patterns of these spectra.
C28H20N4O: C, 78.49; H, 4.70; N, 13.08%. Found: C, 78.36; H, 4.63; N,
13.29%.
4.2.2. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-3-methyl-50-chloro-1-phenyl-20-one (4b). White powder,
Yield, 0.39 g (84%). Mp 264e267 ꢀC, IR (KBr), nmax: 3379 (NH), 3181
3. Conclusion
In summary, an efficient route for synthesis of novel spiro[1H-
(NH), 3060, 1688 (C]O), 1614, 1573, 1483, 778 cmꢁ1 1H NMR
.
pyrazolo[3,4-b]benzoquinolin-4,3-indolin-2-ones] via
a
four-
(400.22 MHz, DMSO) d: 11.28 (1H, s, NH), 11.12 (1H, s, NH), 8.14 (1H,
component reaction between isatins, 3-ketoesters, naphthyl-
amines, and phenylhydrazine was reported here. The high con-
vergence of this synthetic method was attributed to intermediacy
of the diazafulvalenes derived from condensation of isatins and the
in situ generated pyrazolones. Neither anilines nor the enaminic 6-
aminouracils gave the corresponding products when used in place
of naphthylamines. A favorable balance of N- and C-nucleophilic
reactivity is considered for naphthylamines and suggested to be the
d, J 7.6 Hz), 7.96 (1H, d, J 7.2 Hz), 7.70e7.54 (5H, m), 7.38 (3H, m),
7.26 (1H, d, J 8.4 Hz), 7.15e7.09 (2H, m), 6.81 (1H, d, J 8.8 Hz), 6.48
(1H, d, J 2.0 Hz, 40-H), 1.86 (3H, s, CH3). 13C NMR (100.63 MHz,
DMSO) d: 12.0, 56.0, 102.8, 118.3, 118.6, 119.8, 120.0, 122.1, 122.7,
122.8, 123.8, 124.8, 125.9, 126.4, 126.8, 128.1, 128.9, 129.3, 133.7,
137.4, 138.4, 138.5, 148.7, 149.1, 162.2, 180.7. MS (EI) m/z (%)¼462
(Mþꢁ2H, 37Cl, 4), 460 (Mþꢁ2H, 35Cl, 9), 436 (MþꢁCO, 37Cl, 6), 434
(MþꢁCO, 35Cl, 6), 339 (7), 337 (11), 310 (37), 308 (85), 273 (77), 264

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H. Hosseinjani-Pirdehi et al. / Tetrahedron 70 (2014) 1780e1785
(36), 229 (21), 174 (87), 77 (100). Anal. Calcd for C28H19ClN4O: C,
72.65; H, 4.14; N, 12.10%. Found: C, 72.73; H, 4.11; N, 12.06%.
(Mþꢁ2O, 21), 443 (11), 407 (7), 382 (7), 363 (5), 308 (7), 69 (n-
PreCN, 62), 77 (78). Anal. Calcd for C30H23N5O3: C, 71.84; H, 4.62; N,
13.96%. Found: C, 71.79; H, 4.58; N, 14.07%.
4.2.3. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-1-phenyl-3-propyl-20-one (4c). White powder, Yield, 0.34 g
(75%). Mp 304e307 ꢀC, IR (KBr), nmax: 3433 (NH), 3215 (NH), 3057,
4.2.7. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-1,3-diphenyl-20-one (4g). White powder, Yield, 0.32
g
2967, 1702 (C]O), 1600, 1542, 1478, 802, 741 cmꢁ1
.
1H NMR
(65%). Mp 307e310 ꢀC, IR (KBr), nmax: 3379 (NH), 3218 (NH), 3105,
2956, 1701 (C]O), 1606, 1546, 1490, 752 cmꢁ1 1H NMR
(400.22 MHz, DMSO) : 11.15 (1H, s, NH), 9.52 (1H, s, NH), 8.06 (1H,
(400.22 MHz, DMSO)
d
: 11.37 (1H, s, NH), 9.38 (1H, s, NH), 8.25 (1H,
.
d, J 8.4 Hz), 7.95 (1H, d, J 8.0 Hz), 7.67e7.51 (7H, m), 7.42 (1H, t, J
d
7.2 Hz), 7.22e7.12 (3H, m), 6.72 (1H, t, J 7.4 Hz, 50-H), 6.53 (1H, d, J
d, J 8.0 Hz), 7.88 (1H, d, J 7.6 Hz), 7.76 (2H, d, J 7.7 Hz, Ph 2-H), 7.65
(2H, t, J 7.7 Hz, Ph 3-H), 7.56e7.47 (4H, m), 7.23 (1H, d, J 8.4 Hz), 7.17
(1H, d, J 8.0 Hz), 7.16 (1H, t, J 8.4 Hz), 7.03e6.98 (1H, m), 6.88e6.78
(4H, m), 6.72 (1H, t, J 8.0 Hz, 60-H), 6.55 (1H, d, J 8.0 Hz, 40-H). 13C
7.4 Hz, 40-H), 1.83e1.71 (2H, m,
a
-H), 1.24e1.16 (1H, m,
-HB), 0.46 (3H, t, J 7.4 Hz, CH3). 13C NMR
: 14.4, 21.5, 28.7, 53.2, 96.3, 117.7, 119.6, 120.9,
b-HA),
1.07e0.97 (1H, m,
b
(100.63 MHz, DMSO)
d
121.8, 122.8, 122.98, 123.01, 123.3, 126.6, 126.7, 127.1, 128.0, 128.5,
129.0, 129.9, 132.2, 133.7, 137.4, 138.9, 139.0, 140.1, 149.9, 181.8. MS
(EI) m/z (%)¼457 (Mþþ1, 11), 456 (Mþ, 33), 454 (Mþꢁ2H, 44), 428
(64), 427 (MþꢁCO, 66), 413 (MþꢁHNCO, 43), 384 (30), 257 (20), 228
(19), 202 (26), 77 (100). Anal. Calcd for C30H24N4O: C, 78.92; H, 5.30;
N, 12.27%. Found: C, 79.03; H, 5.37; N, 12.18%.
NMR (100.63 MHz, DMSO) d: 53.5, 96.2, 117.7, 119.8, 121.1, 121.9,
122.7, 122.8, 122.9, 123.8, 123.9, 126.4, 126.5, 127.7, 127.8, 127.9,
128.0, 128.1, 128.5, 128.8, 130.1, 133.50, 133.53, 137.4, 138.4, 138.7,
140.9, 149.9, 181.8. MS (EI) m/z (%)¼491 (Mþþ1, 8), 490 (Mþ, 22),
488 (Mþꢁ2H, 20), 462 (MþꢁCO, 51), 461 (MþꢁHCO, 100), 385 (7),
369 (7), 358 (7), 257 (23), 245 (16), 230 (13), 112 (37). Anal. Calcd for
C33H22N4O: C, 80.80; H, 4.52; N, 11.42%. Found: C, 80.87; H, 4.49; N,
4.2.4. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-50-methoxy-1-phenyl-3-propyl-20-one (4d). White powder,
Yield, 0.26 g (53%). Mp 294e296 ꢀC, IR (KBr), nmax: 3358 (NH), 3250
11.36%.
4.2.8. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-50-chloro-1,3-diphenyl-20-one (4h). White powder, Yield,
0.40 g (76%). Mp 295e298 ꢀC, IR (KBr), nmax: 3393 (NH), 3221 (NH),
(NH), 2933, 1719 (C]O), 1570, 1512, 1380, 1231 cmꢁ1 1H NMR
.
(400.22 MHz, DMSO) d: 11.35 (1H, s, NH), 9.14 (1H, s, NH), 8.24 (1H,
d, J 8.4 Hz), 7.96 (1H, d, J 8.0 Hz), 7.67e7.55 (5H, m), 7.42 (1H, t, J
3049, 1709 (C]O), 1612, 1548, 1467 cmꢁ1 1H NMR (400.22 MHz,
.
7.2 Hz), 7.19e7.15 (2H, m), 6.85 (1H, dd, J 8.8 and 2.4 Hz, 60-H), 6.00
DMSO) d: 11.22 (1H, s, NH), 9.71 (1H, s, NH), 8.08 (1H, d, J 7.6 Hz),
(1H, d, J 2.4 Hz, 40-H), 3.50 (3H, s, OCH3), 1.82e1.72 (2H, m,
a
-H),
-HB), 0.45 (3H, t, J
: 14.4, 21.5, 28.7, 53.5,
7.90 (1H, d, J 7.6 Hz), 7.76 (2H, d, J 7.6 Hz, Ph 2-H), 7.65 (2H, t, J
7.6 Hz, Ph 3-H), 7.60e7.48 (4H, m), 7.30e7.21 (3H, m), 7.02e6.98
(1H, m), 6.85e6.80 (4H, m), 6.46 (1H, d, J 1.6 Hz, 40-H). 13C NMR
1.24e1.14 (1H, m,
b-HA), 1.04e0.97 (1H, m, b
7.2 Hz, CH3). 13C NMR (100.63 MHz, DMSO)
d
55.7, 95.7, 113.0, 114.2, 118.8, 119.6, 121.9, 122.8, 122.9, 123.0, 126.6,
126.7,126.9,129.0,129.8,129.9,131.8,133.0,133.7,137.6,139.1,140.7,
149.8, 154.4, 181.8. MS (EI) m/z (%)¼486 (Mþ, 3), 458 (MþꢁCO, 5),
457 (MþꢁEt, 9), 443 (MþꢁPr, 6), 307 (2), 279 (3), 77 (100). Anal.
Calcd for C31H26N4O2: C, 76.52; H, 5.39; N, 11.51%. Found: C, 76.59;
H, 5.43; N, 11.43%.
(100.63 MHz, DMSO) d: 53.6, 97.0, 119.5, 119.9, 122.6, 122.9, 123.0,
123.2, 124.0, 125.1, 126.5, 126.8, 126.9, 127.7, 127.8, 128.0, 128.1,
128.6, 128.9, 130.1, 132.7, 133.3, 133.7, 137.6, 137.9, 138.6, 140.6,
149.9, 181.6. MS (EI) m/z (%)¼524 (Mþ, 35Cl, 5), 522 (Mþꢁ2H, 35Cl,
13), 498 (MþꢁH2CO, 37Cl, 1), 496 (MþꢁH2CO, 35Cl, 3), 308 (5), 236
(47), 194 (10), 103 (PheCN, 59), 77 (100). Anal. Calcd for
C
33H21ClN4O: C, 75.50; H, 4.03; N, 10.67%. Found: C, 75.44; H, 4.09;
4.2.5. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-50-chloro-1-phenyl-3-propyl-20-one (4e). White powder,
Yield, 0.40 g (81%). Mp 298e301 ꢀC, IR (KBr), nmax: 3362 (NH), 3221
(NH), 3058, 2947, 1689 (C]O), 1582, 1532, 1467, 795 cmꢁ1. 1H NMR
N, 10.59%.
4.2.9. Spiro[1H-pyrazolo[3,4-b]benzo[f]quinolin-4,3-indoline]-4,11-
dihydro-1-phenyl-3-propyl-20-one (7a). Cream powder, Yield,
0.40 g (81%). Mp>310 ꢀC, IR (KBr), nmax: 3384 (NH), 3247 (NH),
(400.22 MHz, DMSO)
J 8.0 Hz), 7.97 (1H, d, J 8.0 Hz), 7.65e7.56 (7H, m), 7.43 (1H, t, J 7.2 Hz),
7.27e7.20 (3H, m), 6.44 (1H, d, J 1.6 Hz, 40-H),1.82e1.68 (2H, m,
-H),
1.23e1.14 (1H, m, -HA),1.05e0.96 (1H, m, -HB), 0.44 (3H, t, J 7.2 Hz,
CH3). 13C NMR (100.63 MHz, DMSO)
: 14.3, 21.5, 28.7, 53.3, 96.0,
d: 11.44 (1H, s, NH), 9.56 (1H, s, NH), 8.26 (1H, d,
3036, 2959, 1697 (C]O), 1599, 1546, 1482, 816, 753 cmꢁ1 1H
.
a
NMR (400.22 MHz, DMSO) d: 1080 (1H, s, NH), 9.70 (1H, s, NH),
b
b
7.95 (1H, d, J 8.8 Hz), 7.90e7.87 (1H, m), 7.68 (2H, d, J 7.4 Hz, Ph
2-H), 7.60 (2H, t, J 7.4 Hz, Ph 3-H), 7.42 (1H, t, J 7.4 Hz, Ph 4-H),
7.38e7.32 (2H, m), 7.27e7.22 (3H, m), 7.12 (1H, t, J 7.6 Hz), 6.68
(1H, t, J 7.6 Hz, 50-H), 6.52 (1H, d, J 7.6 Hz, 40-H), 1.84e1.77 (1H, m,
d
119.5, 119.7, 122.7, 122.8, 122.9, 123.2, 123.4, 124.9, 126.7, 126.9, 127.1,
127.2, 128.6, 129.1, 130.0, 131.5, 133.8, 137.7, 138.2, 138.8, 139.8, 149.8,
181.5. MS (EI) m/z (%)¼490 (Mþꢁ2H, 35Cl, 6), 489 (4), 488 (Mþꢁ2H,
35Cl, 9), 464 (MþꢁCO, 37Cl, 4), 463 (6), 462 (MþꢁCO, 35Cl,11), 461 (12),
418 (7), 265 (4), 69 (n-PreCN, 81). Anal. Calcd for C30H23ClN4O: C,
73.39; H, 4.72; N, 11.41%. Found: C, 73.46; H, 4.75; N, 11.35%.
a
-HA), 1.74e1.67 (1H, m,
0.90e0.81 (1H, m,
-HB), 0.45 (3H, t, J 7.4 Hz, CH3). 13C NMR
(100.63 MHz, DMSO) : 14.3, 21.4, 28.6, 52.6, 96.8, 111.9, 117.7,
a-HB), 1.14e1.05 (1H, m, b-HA),
b
d
121.7, 121.8, 123.1, 123.2, 123.7, 127.0, 127.4, 127.5, 128.4, 128.5,
129.2, 129.9, 130.0, 130.4, 130.6, 138.95, 139.04, 139.7, 149.8,
153.6, 181.5. MS (EI) m/z (%)¼457 (Mþþ1, 11), 456 (Mþ, 33), 428
(MþꢁH2CO, 74), 413 (MþꢁPr, 86), 385 (Mþꢁ2HꢁC3H7CN, 15), 368
(10), 351 (9), 308 (17), 192 (20), 55 (100). Anal. Calcd for
4.2.6. Spiro[1H-pyrazolo[3,4-b]benzo[h]quinolin-4,3-indoline]-4,11-
dihydro-50-nitro-1-phenyl-3-propyl-20-one (4f). White powder,
Yield, 0.46 g (92%). Mp 295e298 ꢀC, IR (KBr), nmax: 3372 (NH), 3223
(NH), 3025, 2942,1705 (C]O), 1614,1547, 1509, 1434, 1320 cmꢁ1. 1H
C
30H24N4O: C, 78.92; H, 5.30; N, 12.27%. Found: C, 78.96; H, 5.34;
NMR (400.22 MHz, DMSO)
d
: 11.54 (1H, s, NH), 1040 (1H, s, NH),
N, 12.25%.
8.28 (1H, d, J 8.4 Hz), 8.07 (1H, dd, J 8.8 and 2.4 Hz, 60-H), 8.00 (1H, d,
J 8.0 Hz), 7.69e7.60 (7H, m), 7.49e7.46 (1H, m), 7.40 (1H, d, J 9.2 Hz),
4.2.10. Spiro[1H-pyrazolo[3,4-b]benzo[f]quinolin-4,3-indoline]-4,11-
dihydro-1,3-diphenyl-20-one (7b). Cream powder, Yield, 0.39 g
(79%). Mp>310 ꢀC, IR (KBr), nmax: 3436 (NH), 3264 (NH), 1706
(C]O), 1605, 1553, 1489, 759 cmꢁ1. 1H NMR (400.22 MHz, DMSO)
7.31 (1H, d, J 2.4 Hz, 40-H), 7.29 (1H, d, J 8.4 Hz), 1.84e1.70 (2H, m,
a-
H), 1.24e1.15 (1H, m,
b
-HA), 1.08e0.98 (1H, m,
b-HB), 0.45 (3H, t, J
7.4 Hz, CH3). 13C NMR (100.63 MHz, DMSO)
d: 14.3, 21.4, 28.6, 53.2,
96.8, 117.8, 119.7, 121.4, 122.8, 122.9, 123.6, 124.1, 124.2, 124.8, 126.9,
127.2, 127.8, 129.1, 130.1, 131.4, 134.0, 137.7, 138.4, 138.7, 141.0, 144.9,
149.7, 181.2. MS (EI) m/z (%)¼501 (Mþ, 2), 499 (Mþꢁ2H, 16), 469
d: 10.59 (1H, s, NH), 9.64 (1H, s, NH), 7.85 (2H, t, J 7.0 Hz), 7.80 (2H,
d, J 7.6 Hz), 7.66 (2H, t, J 7.6 Hz), 7.51e7.45 (2H, m), 7.32e7.22 (3H,
m), 7.17e7.10 (3H, m), 7.01 (2H, t, J 7.6 Hz), 6.72e6.66 (3H, m), 6.55

H. Hosseinjani-Pirdehi et al. / Tetrahedron 70 (2014) 1780e1785
1785
(1H, d, J 8.0 Hz, 40-H). 13C NMR (100.63 MHz, DMSO)
d: 52.7, 96.8,
6. (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta, N.; Bonacorso, H.
Chem. Rev. 2008, 108, 2015; (b) Holbrey, J. D.; Turner, M. B.; Reichert, W. M.;
Rogers, R. D. Green Chem. 2003, 5, 731.
7. (a) Rad-Moghadam, K.; Youseftabar-Miri, L. Synlett 2010, 1969; (b) Rad-Mog-
hadam, K.; Youseftabar-Miri, L. Tetrahedron 2012, 67, 5693.
112.0, 117.7, 121.3, 121.6, 122.0, 123.6, 123.8, 127.1, 127.2, 127.6,
127.7, 127.8, 128.1, 128.5, 129.0, 129.7, 129.8, 130.1, 130.3, 130.4,
133.5, 138.5, 138.8, 139.6, 140.7, 150.0, 181.5. MS (EI) m/z (%)¼491
(Mþþ1, 7), 490 (Mþ, 21), 462 (58), 461 (MþꢁHCO, 100), 385
(Mþꢁ2HꢁPhCN, 13), 265 (8), 245 (25), 178 (12). Anal. Calcd for
8. Smith, W. P.; Sollis, L. S.; Howes, D. P.; Cherry, C. P.; Starkay, D. I.; Cobley, N. K. J.
Med. Chem. 1998, 41, 787.
9. (a) Ma, J.; Hecht, S. M. Chem. Commun. 2004, 1190; (b) Edmondson, S.; Dani-
shefsky, S. J.; Sepp-Lorenzinol, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147.
10. (a) Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6,
1819; (b) Singh, S. K.; Reddy, P. G.; Rao, K. S.; Lohray, B. B.; Misra, P.; Rajjak, S. A.;
Rao, Y. K.; Venkatewarlu, A. Bioorg. Med. Chem. Lett. 2004, 14, 499.
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Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034.
C
33H22N4O: C, 80.80; H, 4.52; N, 11.42%. Found: C, 80.93; H, 4.45;
N, 11.34%.
Acknowledgements
12. (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Careter, J. S.; Collins, P. W.;
Graneto, S. M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.;
Rogier, D. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
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Supports of this work from Research Council of University of
Guilan are gratefully acknowledged.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.01.025.
13. Crenshaw, R. R.; Luke, G. M.; Smirnoff, P. J. Med. Chem. 1976, 19, 262.
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