Microwave-assisted, montmorillonite K-10 catalyzed three-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2012.06.045

An efficient, rapid, and green synthesis of 2H-indazolo[2,1-b]phthalazine- triones has been accomplished under solvent-free conditions by the reaction of phthalhydrazide, aldehydes and 5,5-dimethylcyclohexane-1,3-dione. This approach exploits the synthetic potential of microwave irradiation and Montmorillonite K-10 combination and offers many advantages, such as excellent product yields, shorter reaction time, reusable catalyst, easy isolation of products, and environmentally benign reaction conditions.

Full text of DOI:10.1016/j.tet.2012.06.045

Tetrahedron 68 (2012) 6820e6828
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted, montmorillonite K-10 catalyzed three-component synthesis
of 2H-indazolo[2,1-b]phthalazine-triones under solvent-free conditions
,
Mudumala Veeranarayana Reddy a, Gangireddy Chandra Sekhar Reddy b, Yeon Tae Jeong a
*
a Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
b The WCU Center for Synthetic Polymer Bio-conjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Busan 609-735,
Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2012
Received in revised form 6 June 2012
Accepted 9 June 2012
Available online 15 June 2012
An efficient, rapid, and green synthesis of 2H-indazolo[2,1-b]phthalazine-triones has been accomplished
under solvent-free conditions by the reaction of phthalhydrazide, aldehydes and 5,5-
dimethylcyclohexane-1,3-dione. This approach exploits the synthetic potential of microwave irradia-
tion and Montmorillonite K-10 combination and offers many advantages, such as excellent product
yields, shorter reaction time, reusable catalyst, easy isolation of products, and environmentally benign
reaction conditions.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
2H-indazolo[2,1-b]phthalazine-triones
Montmorillonite K-10
Microwave irradiation
Solvent-free reaction
1. Introduction
calculations have also suggested that reactions with high activation
energies can be performed under microwave irradiation without
Green chemistry approaches are significant due to the reduction
in by-products, reaction waste, and reduction of energy cost. Or-
ganic reactions under solvent-free conditions have attracted much
interest from chemists particularly from the viewpoint of green
chemistry.1e3In recent times, exploration of solvent-free reactions
has gained importance due to several advantages, such as experi-
mental simplicity, less energy requirement, and almost quantitative
reactivity of the substrates due to intimacy of the reagents. Im-
proving the substrates reactivity and product formation efficiency
by energising the reactions with microwave irradiation is another
development in organic green chemical synthesis. Microwave-
assisted organic synthesis is characterized by spectacular acceler-
ations in many reactions as a consequence of three dimensional
heating of the reaction mass, which cannot be produced by classical
heating. Simple workup, high yields, improved selectivity and clean
reaction pathways are additional advantages with microwave-
assisted preparation of organic compounds. Indeed, even re-
actions that do not occur by conventional heating can be effectively
performed using microwaves. In particular, microwave heating
when coupled with solvent-free strategy, presents a powerful and
green alternative to conventional synthesis. Theoretical
the use of harsh reaction conditions.
Recently, numerous important heterocycles have been synthe-
sized under solvent-free conditions accelerated by microwave
irradiation.4e9
Nitrogen-containing heterocyclic compounds are widespread
in nature, and their applications to pharmaceuticals, agrochemi-
cals, and functional materials are becoming more and more im-
portant.10 Among a large variety of N-containing heterocyclic
compounds, those containing hydrazine moiety as ’fusion site’
have received considerable attention because of their pharmaco-
logical properties and clinical applications.11 Moreover, fused
phthalazines were found to possess multiple biological activities,
such as antimicrobial,12 anticonvulsant,13 antifungal,14 antican-
cer,15 and anti-inflammatory activities.16 Nevertheless the de-
velopment of new synthetic methods for the efficient preparation
of heterocycles containing phthalazine ring fragment is an in-
teresting challenge. Recently, several elegant multicomponent
strategies for the synthesis of 2H-indazolo[2,1-b]phthalazine-tri-
ones by the cyclocondensation of phthalhydrazide, aldehydes, and
1,3-diketones utilizing different types of catalysts have been
reported.17e25 The reported methods show varying degrees of
successes as well as limitations, such as harsh reaction conditions,
expensive catalyst/reagent, toxic organic solvents, low product
yields, long reaction times, and co-occurrence of several side
products. Thus, a simple, rapid and efficient procedure is still
* Corresponding author. Tel.: þ82 51 629 6411; fax: þ82 51 629 6408; e-mail
address: ytjeong@pknu.ac.kr (Y.T. Jeong).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.045

M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
6821
Table 1
strongly desired for the synthesis of these important fused het-
erocyclic compounds.
Effect of temperature on the synthesis of 13-(3-fluorophenyl)-3,4-dihydro-3,3-
dimethyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione(4b)
Solid acids catalysts have gained much importance in recent
years due to economic by reusability and environmental benefits by
non-toxic.26e29 Recently, the use of environmentally friendly and
economically viable solid acids is increasing continuously owing to
their ease of handling and high catalytic activities. Among them,
montmorillonite K-10 is a well-known and widely used solid acid
catalyst in synthetic organic chemistry. It has received considerable
attention due to its non-toxicity, cost effectiveness, air and water
compatibility, ease of handling, good reactivity, recyclability, ex-
perimental simplicity, commercially availability, green catalyst re-
markable ability to suppress side reactions in acid sensitive
substrates and supports for a wide variety of reactions. Microwave-
promoted solvent-free solid acid reactions are well known as en-
vironmentally benign methods that also usually provide improved
selectively, enhanced reaction rates, cleaner products and manip-
ulative simplicity.26e29 It is also an excellent catalyst for
microwave-assisted organic synthesis.30e33 This area has also
attracted considerable attention in recent years.
Our literature survey at this stage revealed that there are no
reports on the synthesis of 2H-indazolo[2,1-b]phthalazine-triones
under microwave-assisted in solvent-free at 80 ꢀC mediated by K-
10. Our main target is to develop a green organic reaction meth-
odology, which is relatively faster and cleaner than conventional
reactions. As part of our ongoing research program on the de-
velopment of clean protocols34,35 herein, we report a facile one-pot
synthesis of 2H-indazolo[2,1-b]phthalazine-triones via three-
component coupling of phthalhydrazide, aldehydes and 5,5-
dimethylcyclohexane-1,3-dione in the presence of catalytic
amount (5 mol %) of K-10 under solvent-free microwave irradiation
at 80 ꢀC (Scheme 1).
Entry
Temperature (ꢀC)
Time (min)
Yielda (%)
1
2
3
4
40
60
80
100
120
80
30
30
30
30
30
5
30
50
75
70
60
96
5
6b
a
Isolated yield.
Reaction was carried out by microwave irradiation.
b
Next the effect of catalyst plays an important role in the for-
mation of 2H-indazolo[2,1-b]phthalazine-triones derivatives. 3-
Fluorobenzaldehyde (2b, 1 mmol), phthalhydrazide (1, 1 mmol),
and 5,5-dimethylcyclohexane-1,3-dione (3, 1 mmol) at 80 ꢀC, un-
der microwave irradiation in solvent-free conditions were selected
as representative substrates to investigate the reaction conditions.
In the absence of the catalyst, the reaction could be carried out but
the product was obtained in very low yield after prolonged re-
action time. Therefore, our efforts focused on the search for
a suitable catalyst. Initially, TiO2 was chosen as the catalyst to carry
out this reaction. As a result, long reaction times were needed and
low transformation rates were observed. Attempts with different
catalysts at 80 ꢀC, under microwave irradiation in solvent-free
conditions, and the results are listed in Table 2. It was found
that K-10 showed better catalytic activity among these catalysts.
Most excitingly, when K-10 was used, the reaction proceeded very
smoothly and gave the product 4b in 96% yield (Table 2, entry 9).
Moreover, we found that the yields were obviously affected by the
amount of K-10 loaded. When 1 mol %, 3 mol %, 5 mol %, and
10 mol % of K-10 were used, the yields were 30, 75, 96, and 96%,
respectively (Table 2, entries 9e12). Therefore, 5 mol % of K-10 was
sufficient and excessive amount of catalyst did not increase the
yields significantly (Table 2, entries 9). The catalytic activity of the
recycled K-10 was also examined. K-10 could be reused three
times for the reaction without noticeable loss of activity (Table 2,
entry 9).
Scheme 1. Synthesis of 2H-Indazolo[2,1-b]phthalazine-triones catalyzed by K-10 un-
der microwave irradiation in solvent-free condition.
Table 2
Influence of the catalyst on the synthesis of 13-(3-fluorophenyl)-3,4-dihydro-3,3-
dimethyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4b)a
Entry
Catalyst
Catalyst (mol %)
Time (min)
Yieldb (%)
2. Results and discussion
1
2
3
4
5
6
7
8
NO
TiO2
BF3eSiO2
InF3
GaBr3
TiO2eSiO2
Amberlyst 15
Y(OAc)37$H2O
K-10
K-10
K-10
d
5
5
5
5
5
5
5
5
100
60
30
40
30
100
55
100
5
25
40
75
70
60
40
40
35
Initially we have synthesiszed2H-indazolo[2,1-b]phthalazine-
triones by the one-pot condensation of phthalhydrazide, aldehydes
and 5,5-dimethylcyclohexane-1,3-dione in the presence of K-10 as
catalyst by microwave irradiation under solvent-free conditions at
80 ꢀC (Scheme 1). The reactions were carried out in a CEM Discover
Benchmate microwave reactor using an open vessel technique.
First, the optimisation of temperature required for the reaction
of phthalhydrazide(1, 1 mmol), 3-fluorobenzaldehyde (2b, 1 mmol)
and 5,5-dimethylcyclohexane-1,3-dione (3, 1 mmol) in the pres-
ence of K-10 was standardised by carrying out the reaction at dif-
ferent temperatures ranging from 40 to 120 ꢀC for 30 min by
conventional heating (Table 1). It was found that above and below
80 ꢀC and 30 min of time, the yield of the product was low. Only at
80 ꢀC and with 30 min of reaction time, the highest product yield of
75% was observed (Table 1, entry 3). Thus it was proved that 80 ꢀC is
the optimised temperature required for effecting this reaction by
conventional heating. However, when the same reaction was car-
ried out by microwave irradiation at 80 ꢀC, the reaction was com-
plete in 5 min with 96% yield (Table 1, entry 6).
9c
10
11
12
96, 93, 90
1
3
10
20
10
5
30
75
96
K-10
a
Reaction of 3-fluorobenzaldehyde (1 mmol), phthalhydrazide(1 mmol) and 5,5-
dimethylcyclohexane-1,3-dione (1 mmol) under microwave irradiation in solvent-
free conditions at 80 ꢀC.
b
Isolated yield.
Catalyst was reused three times.
c
Then, we examined the effect of solvents over the above re-
action. The results of Table 3 indicate that solvents affected the
efficiency of the reaction. Yields were poor in acetonitrile,
dichloromethane, and tetrahydrofuran (Table 3, entries 1e3). Better

6822
M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
Table 3
Table 4. All of 2 gave the expected products at high yields, either
bearing electron-withdrawing groups or electron-donating groups
under the same reaction condition. The acid-sensitive heterocyclic/
alphatic aldehydes were also obtained in good yields. Various
functional groups were found to be compatible under the reaction
conditions. In general, the reactions were clean and no side prod-
ucts were detected. In all cases, the reactions proceeded efficiently
at 80 ꢀC under microwave irradiation in solvent-free and K-10
(5 mol %) conditions. All of the structures were characterized by 1H
NMR, 13C NMR, IR and HRMS.
The proposed mechanism for the synthesis of 2H-indazolo
[2,1-b]phthalazine-triones is illustrated in Scheme 2. The reaction is
thought to proceed in a stepwise manner. Firstly, we assumed that
the reaction occurs via a Knoevenagel condensation between 1,3-
dicarbonyl compounds 3 and aromatic aldehydes 2 to form the
intermediate 5 on the acidic active surface of K-10, which suffers
immediate Michael addition of phthalhydrazide 1 to the C]C bond
of 5. Intramolecular concerted cyclocondensation of amino and
carbonyl of the Michael adduct 6 was performed to afford the
corresponding products (4aet). During the reaction process, the
hydrogen ion transfers through the surface of K-10. The hydrogen
ion helps in the enolization of 1,3-dicarbonyl compounds to form
the enolate intermediate.
Influence of the solvent on the synthesis of 13-(3-fluorophenyl)-3,4-dihydro-3,3-
dimethyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4b)a
Entry
Solvent (2 mL)
Time (min)
Yieldb (%)
1
2
3
4
5
6
Acetonitrile
Dichloromethane
Tetrahydrofuran
Methanol
Ethanol
Neat
30
30
30
30
30
5
30
40
35
60
65
96
a
Reaction of 3-fluorobenzaldehyde (1 mmol), phthalhydrazide(1 mmol) and 5,5-
dimethylcyclohexane-1,3-dione (1 mmol) catalysed by K-10 under microwave ir-
radiation at 80 ꢀC.
b
Isolated yield.
yields were obtained in more polar solvents like methanol and
ethanol (Table 3, entries 4 and 5). However, the best results were
obtained under solvent free conditions. Recently, organic synthesis
involving multicomponent reactions under solvent-free conditions
has attracted much attention, therefore we explored the possibility
of obtaining the target compounds under solvent-free conditions.
We found that the reaction proceeded smoothly in much shorter
time at mild temperature and resulted in the formation of products
in higher yield. It is desirable to minimize the amount of waste for
each organic transformation.
In order to extend the above reaction (Scheme 1) to a library
system, various kinds of arylaldehydes2 (Table 4) were subjected to
react with 1 and 3 to give the corresponding 2H-indazolo[2,1-b]
phthalazine-triones 4, and representative examples are shown in
3. Conclusion
In conclusion, we have successfully developed a simple, green,
and efficient microwave assisted one-pot multicomponent
Table 4
Microwave-assisted synthesis of 2H-indazolo[2,1-b]phthalazine-trionesa
Entry
Aldehyde
Product
Time (min)
Yieldb (%)
Mp (ꢀC)
Found
Reported
CHO
F
1
5
92
270e272
d
4a
CHO
2
5
96
228e230
d
F
4b
CHO
F
3
8
90
280e282
d
Br
4c

M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
6823
Table 4 (continued )
Entry
Aldehyde
Product
Time (min)
Yieldb (%)
Mp (ꢀC)
Found
Reported
CHO
4
5
96
217e219
(217e219)17
F
4d
CHO
5
5
96
228e230
d
F
4e
CHO
6
6
94
220e222
(218e220)24
OMe
4f
7
12
90
225e227
d
4g
CHO
F
8
7
90
265e267
d
F
4h
CHO
F
9
8
90
266e268
d
F
(continued on next page)
4i

6824
M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
Table 4 (continued )
Entry
Aldehyde
CHO
F
Product
Time (min)
Yieldb (%)
Mp (ꢀC)
Found
Reported
10
7
91
206e208
d
F
4j
CHO
11
6
92
230e232
d
F
F
4k
CHO
12
12
90
233e235
(233e235)23
OMe
MeO
OMe
4l
CHO
13
7
93
178e180
d
OEt
4m
CHO
OH
14
13
92
188e190
d
4n
CHO
N
15
10
90
229e231
(230e232)24
4o

M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
6825
Table 4 (continued )
Entry
Aldehyde
Product
Time (min)
Yieldb (%)
Mp (ꢀC)
Found
Reported
O
O
OHC
16
8
90
254e256
d
4p
OHC
O
O
17
8
91
258e260
d
4q
18
8
90
218e220
(217e219)24
CHO
S
4r
19
15
80
146e148
(145e147)23
CHO
4s
CHO
20
15
81
136e138
(136e138)23
4t
a
Reaction of aldehydes (1 mmol), phthalhydrazide(1 mmol) and 5,5-dimethylcyclohexane-1,3-dione (1 mmol) catalysed by K-10 under solvent-free microwave irradiation
at 80 ꢀC.
b
Isolated yield.
synthesis of 2H-indazolo[2,1-b]phthalazine-triones derivatives
from easily available starting materials using K-10 as a catalyst
under solvent-free conditions. This protocol is attractive in terms
of, atom economy, shortened reaction time, simple and clean re-
action profiles, tolerance of various functional groups, and re-
usability of the catalyst.
4. Experimental
4.1. General
Chemicals were purchased from Aldrich and Alfaaesar Chemical
Companies. NMR spectra were recorded in parts per million in CDCl3

6826
M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
7.33e7.23 (m, 2H), 7.08 (d, J¼9.5 Hz, 1H), 6.97 (t, J¼8.4 Hz, 1H), 6.42
(s, 1H), 3.40 and 3.23 (AB System, J¼19.0 Hz, 2H), 2.33 (s, 2H), 1.20
(s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
191.9, 161.5, 155.9, 154.3,
d
151.0,138.8, 134.5, 133.6,130.2,128.9, 128.0, 127.6, 122.9, 117.9,115.7,
114.0, 113.8, 64.2, 50.8, 37.9, 34.6, 28.5, 28.4 ppm. HRMS (ESI, m/z):
calcd for C23H19FN2O3 (MþHþ) 390.1380; found: 390.1377.
4.2.3. 13-(4-Bromo-2-fluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4c). Rf value¼0.56
(hexane/ethyl acetate (3:1)); Yield 90%; yellow powder; mp
280e282 ꢀC. IR (KBr):
(400 MHz, CDCl3):
n
¼2956, 2882, 1652, 1349, 1289 cm-1 1H NMR
d 8.37e8.34 (m, 1H), 8.26e8.23 (m, 1H),
7.87e7.85 (m, 2H), 7.38 (t, J¼8.0 Hz, 1H), 7.29 (d, J¼8.4 Hz, 1H), 7.18
(dd, J¼11.7, 1.4 Hz, 1H), 6.48 (s, 1H), 3.40 and 3.21 (AB System,
J¼19.0 Hz, 2H), 2.32 (s, 2H), 1.21 (s, 3H), 1.18 (s, 3H) ppm. 13C NMR
(100 MHz, CDCl3):
d 192.0, 156.0, 154.4, 151.9, 134.5, 133.6, 131.3,
129.2, 128.6, 128.0, 127.8, 123.2, 122.8, 120.1, 119.6, 116.2, 60.8, 50.2,
37.9, 34.6, 28.8, 28.0 ppm. HRMS (ESI, m/z): calcd for C23H18
BrFN2O3 (MþHþ) 468.0485; found: 468.0480.
4.2.4. 13-(4-Fluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-indazolo
[2,1-b]phthalazine-1,6,11(13H)-trione (4d). Rf value¼0.62 (hexane/
ethyl acetate (3:1)); Yield 96%; yellow powder; mp 217e219 ꢀC
Scheme 2. Schematic presentation of the possible mechanism of products 4aet
formation.
(217e219 ꢀC).17 IR (KBr):
NMR (CDCl3, 400 MHz)
n
¼2971, 2850, 1659, 1350, 1312 cm-1 1
H
d
8.30e8.28 (m, 1H), 8.24e8.22 (m, 1H),
7.87e7.84 (m, 2H), 7.42e7.39 (m, 2H), 7.03 (t, J¼8.8 Hz, 2H), 6.43 (s,
1H), 3.42 and 3.25 (AB System, J¼19.1 Hz, 2H), 2.35 (s, 2H), 1.24 (s,
on a Jeol JNM ECP 400 NMR instrument using TMS as internal standard.
Mass spectra were recorded on a Jeol JMS-700 mass spectrometer. All
melting points were determined using open capillaries on an
Electrothermal-9100 (Japan) instrument. Infrared (IR) spectra were
obtained using a ShimadzuIR Prestige-21 FTIR Spectrophotometry.
6H) ppm. 13C NMR (CDCl3, 100 MHz)
d 191.8, 156.4, 154.4, 151.5,
134.6, 133.3, 131.9, 129.2, 128.7, 128.0, 127.5, 117.9, 115.5, 115.0, 60.3,
51.9, 38.2, 34.3, 28.7, 28.4 ppm.
4.2.5. 13-(3-Fluoro-4-methylphenyl)-3,4-dihydro-3,3-dimethyl-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4e). Rf value¼0.60
(hexane/ethyl acetate (3:1)); Yield 96%; yellow powder; mp
4.2. Synthesis of 13-(3-fluorophenyl)-3,4-dihydro-3,
3-dimethyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(4b)
228e230 ꢀC. IR (KBr):
(400 MHz, CDCl3):
n
¼2956, 2865, 1660, 1350, 1312 cm-1 1H NMR
d
8.35e8.33 (m,1H), 8.26e8.24 (m,1H), 7.85e7.83
(m, 2H), 7.15 (dd, J¼12.6, 2.2 Hz, 2H), 7.02, (d, J¼9.2 Hz, 1H), 6.38 (s,
1H), 3.40 and 3.23 (AB System, J¼19.3 Hz, 2H), 2.33 (s, 2H), 2.20 (s,
A
mixture of phthalhydrazide (1, 162 mg, 1 mmol), 3-
3H),1.20 (s, 6H) ppm.13C NMR (100 MHz, CDCl3):
d 192.0,159.9,155.8,
fluorobenzaldehyde (2b, 105 mg, 1 mmol), 5,5-dimethyl-cyclohex-
ane-1,3-dione (3, 140 mg, 1 mmol) and K-10 (5 mol %, 50 mg) was
taken in an open vessel and irradiated at 80 ꢀC in solvent-free con-
dition for 5 min. The reactions were followed by thin layer chroma-
tography(TLC)using hexane/ethylacetate(3:1)asaneluent(Rf¼0.70).
After completion of the reaction, the mixture was washed with ethyl
acetate and filtered to recover the catalyst. The filtratewasevaporated,
and the crude product was recrystallized from ethanol to afford pure
13-(3-fluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-indazolo-[2,1-b]
phthalazine-1,6,11(13H)-trione (4b) in excellent yield (380 mg).
154.2,150.9,136.0,134.4,133.5, 131.6, 128.8,127.9, 127.6, 125.4,122.7,
118.0,113.6, 64.2, 50.8, 37.9, 34.5, 28.5, 28.3,14.3 ppm. HRMS (ESI, m/
z): calcd for C24H21FN2O3 (MþHþ) 404.1536; found: 404.1534.
4.2.6. 3,4-Dihydro-13-(4-methoxyphenyl)-3,3-dimethyl-2H-indazolo
[2,1-b]phthalazine-1,6,11(13H)-trione (4f). Rf value¼0.58 (hexane/
ethyl acetate (3:1)); Yield 94%; yellow powder; mp 220e222 ꢀC
(218e220 ꢀC).24 1H NMR (CDCl3, 400 MHz)
d 8.36e8.33 (m, 1H),
8.26e8.23 (m, 1H), 7.86e7.83 (m, 2H), 7.30 (d, J¼8.8 Hz, 2H), 6.86 (d,
J¼8.4 Hz, 2H), 6.42 (s, 1H), 3.78 (s, 3H), 3.40 and 3.24 (AB System,
J¼19.1 Hz, 2H), 2.35(s, 2H),1.22(s, 6H)ppm.13CNMR(CDCl3,100MHz)
4.2.1. 13-(2-Fluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-indazolo
[2,1-b]phthalazine-1,6,11(13H)-trione (4a). Rf value¼0.56 (hexane/
ethyl acetate (3:1)); Yield 92%; yellow powder; mp 270e272 ꢀC. IR
d
192.2,159.9,156.0,154.6,150.1,134.4,133.3,129.1,128.8,128.5,128.3,
127.9, 127.7, 118.5, 114.1, 60.6, 55.2, 51.0, 38.5, 34.0, 28.7, 28.1 ppm.
(KBr):
CDCl3):
n
¼2956, 2865, 1660, 1357, 1312 cm-1 1H NMR (400 MHz,
4.2.7. 13-(4-Fluoro-3-nitrophenyl)-3,4-dihydro-3,3-dimethyl-2H-in-
dazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4g). Rf value¼0.60
(hexane/ethyl acetate (3:1)); Yield 90%; yellow powder; mp
d
8.35e8.33 (m, 1H), 8.21e8.19 (m, 1H), 7.89e7.87 (m, 2H),
7.44 (t, J¼7.3 Hz, 1H), 7.31e7.26 (q, 1H), 7.14 (t, J¼7.6 Hz, 1H), 7.01 (t,
J¼10.2 Hz, 1H), 6.54 (s, 1H), 3.41 and 3.22 (AB System, J¼19.1 Hz,
2H), 2.31 (s. 2H), 1.22 (s, 3H), 1.18 (s, 3H) ppm. 13C NMR (100 MHz,
225e227 ꢀC. IR (KBr):
(400 MHz, CDCl3):
n
¼2958, 2874, 1652, 1319, 1274 cm-1 1H NMR
d
8.38e8.36 (m,1H), 8.26e8.23 (m, 1H), 8.02 (dd,
CDCl3):
d 191.1, 159.2, 155.0, 153.3, 150.8, 133.7, 132.8, 129.5, 1294.5,
J¼9.2, 2.0 Hz, 1H), 7.90e7.87 (m, 3H), 7.30 (d, J¼8.5 Hz, 1H), 6.46 (s,
128.2, 127.9, 127.2, 126.5, 123.5, 115.9, 114.9, 59.7, 50.0, 37.1, 33.8,
28.0, 27.2 ppm. HRMS (ESI, m/z): calcd for C23H19FN2O3 (MþHþ)
390.1380; found: 390.1378.
1H), 3.42 and 3.26 (AB System, J¼19.2 Hz, 2H), 2.35 (s, 2H), 1.22 (s,
6H) ppm. 13C NMR (100 MHz, CDCl3):
d 192.1, 155.9, 154.7, 151.9,
135.2, 134.8, 133.9, 133.6, 128.9, 128.5, 127.6, 124.3, 118.8, 118.6,
116.7, 63.5, 50.7, 37.9, 34.7, 28.7, 28.4 ppm. HRMS (ESI, m/z): calcd
for C23H18FN3O5 (MþHþ) 435.1230; found: 435.1230.
4.2.2. 13-(3-Fluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-indazolo
[2,1-b]phthalazine-1,6,11(13H)-trione (4b). Rf value¼0.70 (hexane/
ethyl acetate (3:1)); Yield 96%; yellow powder; mp 228e230 ꢀC. IR
(KBr):
CDCl3):
n
¼2971, 2865, 1660, 1365, 1304 cm-1 1H NMR (400 MHz,
4.2.8. 13-(2,3-Difluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-in-
dazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4h). Rf value¼0.56
d
8.36e8.34 (m, 1H), 8.27e8.25 (m, 1H), 7.86e7.84 (m, 2H),

M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
6827
(hexane/ethyl acetate (3:1)); Yield 90%; yellow powder; mp
127.4, 126.6, 117.3, 113.9, 63.8, 62.9, 50.2, 37.2, 34.2, 28.0, 27.8,
14.6 ppm. HRMS (ESI, m/z): calcd for C25H24F2N2O4 (MþHþ)
416.1736; found: 416.1730.
265e267 ꢀC. IR (KBr):
n
¼2956, 2863, 1652, 1350, 1312 cm-1 1H NMR
(400 MHz, CDCl3):
d 8.37e8.34 (m, 1H), 8.26e8.20 (m, 1H),
7.80e7.88 (m, 2H), 7.22e7.19 (m, 1H), 7.13e7.10 (m, 2H), 6.57 (s, 1H),
3.41 and 3.23 (AB System, J¼19.4 Hz, 2H), 2.34 (s, 2H), 1.22 (s, 3H),
4.2.14. 3,4-Dihydro-13-(2-hydroxyphenyl)-3,3-dimethyl-2H-in-
dazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4n). Rf value¼0.56
(hexane/ethyl acetate (3:1)); Yield 92%; yellow powder; mp
1.19 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 191.3, 155.4, 153.8,
134.0, 133.2, 131.9, 128.4, 128.0, 127.5, 126.8, 125.8, 125.2, 123.8,
116.9, 116.4, 115.7, 59.3, 50.1, 37.3, 34.0, 28.2, 27.5. HRMS (ESI, m/z):
calcd for C23H18F2N2O3 (MþHþ) 408.1285; found: 408.1282.
188e190 ꢀC. IR (KBr):
(400 MHz, CDCl3):
n
¼2971, 2865, 1644, 1365, 1229 cm-1 1H NMR
d
11.5 (s, 1H), 8.03e8.01 (m, 2H), 7.85e7.81 (m,
2H), 7.06e7.02 (m, 1H), 6.95e6.89 (m, 3H), 3.42 and 3.22 (AB Sys-
tem, J¼19.1 Hz, 2H), 2.30 (s, 2H), 1.28 (t, J¼6.8 Hz, 3H), 1.17 (s, 6H)
4.2.9. 13-(2,4-Difluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-in-
dazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4i). Rf value¼0.59
(hexane/ethyl acetate (3:1)); Yield 90%; yellow powder; mp
ppm. 13C NMR (100 MHz, CDCl3):
d 195.7, 155.1, 154.0, 149.6, 132.5,
128.3, 126.8, 125.6, 125.1, 124.1, 120.3, 115.2, 111.2, 62.3, 50.4, 38.8,
31.5, 28.1, 27.5 ppm. HRMS (ESI, m/z): calcd for C23H20F2N2O4
(MþHþ) 388.1423; found: 388.1420.
266e268 ꢀC. IR (KBr):
(400 MHz, CDCl3):
n
¼2956, 2865, 1660, 1357, 1304 cm-1 1H NMR
d 8.37e8.34 (m, 1H), 8.26e8.24 (m, 1H),
7.87e7.84 (m, 2H), 7.50e7.45 (m, 1H), 6.91e6.88 (m, 1H), 6.77e6.74
(m, 1H), 6.50 (s, 1H), 3.41 and 3.21 (AB System, J¼19.0 Hz, 2H), 2.33
(s, 2H), 1.21 (s, 3H), 1.19 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
4.2.15. 3,4-Dihydro-3,3-dimethyl-13-(pyridin-2-yl)-2H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-trione (4o). Rf value¼0.56 (hexane/ethyl
acetate (3:1)); Yield 90%; yellow powder; mp 229e231 ꢀC
d
193.3, 156.1, 154.4, 151.7, 134.5, 133.6, 131.7, 130.2, 129.1, 128.9,
(230e232 ꢀC).24 1H NMR (400 MHz, CDCl3):
d 8.36e8.30 (m, 2H),
128.0, 127.6, 121.0, 116.6, 112.1, 111.8, 104.7, 60.8, 50.8, 37.9, 34.6,
28.8, 28.0 ppm. HRMS (ESI, m/z): calcd for C23H18F2N2O3 (MþHþ)
408.1285; found: 408.1285.
8.04 (d, J¼8.4 Hz, 1H), 7.87e7.84 (m, 2H), 7.66e7.50 (m, 3H), 6.40 (s,
1H), 3.40 and 3.21 (AB System, J¼19.1 Hz, 2H), 2.30 (s, 2H), 1.19 (s,
6H) ppm. 13C NMR (100 MHz, CDCl3):
d 192.1, 156.2, 154.3, 151.6,
148.6, 138.6, 134.4, 133.4, 129.3, 128.2, 127.8, 123.8, 119.4, 115.4, 60.0,
50.9, 38.4, 31.2, 28.8, 28.4 ppm.
4.2.10. 13-(3,4-Difluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-in-
dazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4j). Rf value¼0.65
(hexane/ethyl acetate (3:1)); Yield 91%; yellow powder; mp
206e208 ꢀC. IR (KBr):
n
¼2956, 2855, 1667, 1357, 1266 cm-1 1H NMR
4.2.16. 3,4-Dihydro-13-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3,3-
dimethyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4p). Rf
value¼0.62 (hexane/ethyl acetate (3:1)); Yield 90%; yellow powder;
(400 MHz, CDCl3):
d 8.36e8.34 (m, 1H), 8.27e8.25 (m, 1H),
7.87e7.85 (m, 2H), 7.23e7.11 (m, 3H), 6.39 (s, 1H), 3.39 and 3.23 (AB
mp 254e256 ꢀC. IR (KBr):
n
¼2956, 2880, 1660, 1349, 1289 cm-1 1
H
System, J¼19.1 Hz, 2H), 2.34 (s, 2H), 1.20 (s, 6H) ppm. 13C NMR
NMR (400 MHz, CDCl3):
d 8.34e8.32 (m, 1H), 8.28e8.26 (m, 1H),
(100 MHz, CDCl3):
d 192.0, 155.9, 154.5, 151.2, 134.7, 133.7, 133.4,
7.84e7.82 (m, 2H), 6.95 (d, J¼8.2 Hz,1H), 6.82 (d, J¼9.2 Hz, 2H), 6.34
(s, 1H), 4.19 (s, 4H), 3.39 and 3.22 (AB System, J¼19.1 Hz, 2H), 2.33
(s, 2H), 1.22 (s, 3H), 1.19 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
128.9, 128.8, 128.1, 127.7, 123.8, 117.6, 117.4, 116.3, 63.9, 50.8, 38.0,
34.6, 28.6, 28.4 ppm. HRMS (ESI, m/z): calcd for C23H18F2N2O3
(MþHþ) 408.1285; found: 408.1285.
d
192.1, 155.9, 154.2, 150.6, 143.8, 134.4, 133.4, 129.5, 129.1, 128.9,
127.9, 127.6, 120.7, 118.4, 117.4, 115.7, 64.4, 64.1, 50.9, 37.9, 34.6,
28.5 ppm. HRMS (ESI, m/z): calcd for C25H22N2O5 (MþHþ)
430.1529; found: 430.1528.
4.2.11. 13-(3,5-Difluorophenyl)-3,4-dihydro-3,3-dimethyl-2H-in-
dazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4k). Rf value¼0.58
(hexane/ethyl acetate (3:1)); Yield 92%; yellow powder; mp
230e232 ꢀC. IR (KBr):
n
¼2971, 2865, 1652, 1357, 1305 cm-1 1H NMR
4.2.17. 13-(Benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-3,3-dimethyl-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4q). Rf value¼0.61
(hexane/ethyl acetate (3:1)); Yield 91%; yellow powder; mp
(400 MHz, CDCl3):
d 8.37e8.35 (m, 1H), 8.28e8.26 (m, 1H),
7.88e7.86 (m, 2H), 6.95 (d, J¼7.2 Hz, 2H), 6.74e6.69 (m, 1H), 6.39 (s,
1H), 3.38 and 3.23 (AB System, J¼19.1 Hz, 2H), 2.34 (s, 2H), 1.20 (s,
258e260 ꢀC. IR (KBr):
(400 MHz, CDCl3):
n
¼2956, 2880, 1660, 1364, 1312 cm-1 1H NMR
6H) ppm. 13C NMR (100 MHz, CDCl3):
d 191.9, 164.2, 155.9, 154.5,
d 8.36e8.33 (m, 1H), 8.26e8.23 (m, 1H),
151.4, 140.3, 134.7, 133.8, 128.9, 128.1, 127.7, 117.4, 110.4, 104.4, 103.9,
63.9, 50.8, 38.0, 34.6, 28.6, 28.4 ppm. HRMS (ESI, m/z): calcd for
C23H18F2N2O3 (MþHþ) 408.1285; found: 408.1284.
7.88e7.84 (m, 2H), 6.88e6.75 (m, 3H), 6.32 (s, 1H), 5.93 (s, 2H), 3.40
and 3.22 (AB System, J¼19.2 Hz, 2H), 2.32 (s, 2H), 1.21 (s, 6H) ppm.
13C NMR (100 MHz, CDCl3):
d 193.0, 156.9, 152.0, 148.4, 145.3, 137.5,
135.6, 133.5, 129.6, 128.9, 128.1, 121.6, 115.6, 114.5, 106.7, 102.3, 65.0,
51.3, 35.4, 33.9, 28.0, 27.8 ppm. HRMS (ESI, m/z): calcd for
C24H20N2O5 (MþHþ) 416.1372; found: 416.1374.
4.2.12. 3,4-Dihydro-13-(3,4,5-trimethoxyphenyl)-3,3-dimethyl-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4l). Rf value¼0.60
(hexane/ethyl acetate (3:1)); Yield 90%; yellow powder; mp
235e237 ꢀC (233e235 ꢀC).231H NMR (CDCl3, 400 MHz)
d 8.30e8.22
4.2.18. 3,4-Dihydro-3,3-dimethyl-13-(thiophen-3-yl)-2H-indazolo
[2,1-b]phthalazine-1,6,11(13H)-trione (4r). Rf value¼0.59 (hexane/
ethyl acetate (3:1)); Yield 90%; yellow powder; mp 218e220 ꢀC
(m, 2H), 7.89e7.87 (m, 2H), 6.60 (s, 2H), 6.45 (s, 1H), 3.83 (s, 9H),
3.42 and 3.21 (AB System, J¼19.1 Hz, 2H), 2.33 (s, 2H), 1.24 (s, 6H)
ppm. 13C NMR(CDCl3, 100 MHz)
d 192.0, 156.3, 154.6, 153.0, 150.8,
(217e219 ꢀC).24 1H NMR (CDCl3, 400 MHz):
d 8.30e8.25 (m, 2H),
138.6, 134.3, 133.3, 131.3, 129.0, 128.4, 128.0, 127.5, 118.3, 104.3, 65.6,
60.3, 56.9, 50.9, 38.0, 34.6, 28.9, 28.1 ppm.
7.85e7.82 (m, 2H), 7.30 (s, 1H), 7.23e7.22 (m, 1H), 6.95e6.93 (m,
1H), 6.52 (s, 1H), 3.41 and 3.22 (AB System, J¼19.1 Hz, 2H), 2.31 (s,
2H), 1.22 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d 192.0, 154.2,
4.2.13. 13-(4-Ethoxyphenyl)-3,4-dihydro-3,3-dimethyl-2H-indazolo
[2,1-b]phthalazine-1,6,11(13H)-trione (4m). Rf value¼0.60 (hexane/
ethyl acetate (3:1)); Yield 93%; yellow powder; mp 178e180 ꢀC. IR
150.5, 138.6, 134.3, 133.5, 129.0, 128.8, 128.1, 127.9, 127.2, 125.8,
117.3, 60.2, 50.2, 37.8, 34.3, 28.9, 28.0 ppm.
(KBr):
CDCl3):
n
¼2971, 2850, 1652, 1349, 1312 cm-1 1H NMR (400 MHz,
4.2.19. 13-Ethyl-3,4-dihydro-3,3-dimethyl-2H-indazolo[2,1-b]phtha-
lazine-1,6,11(13H)-trione (4s). Rf value¼0.61 (hexane/ethyl acetate
(3:1)); Yield 80%; yellow powder; mp 146e148 ꢀC (145e147 ꢀC).23
d
8.24e8.22 (m, 1H), 8.09e8.09 (m, 1H), 7.95e7.92 (m, 2H),
7.32 (d, J¼8.8 Hz, 2H), 6.83 (d, J¼8.5 Hz, 2H), 6.22 (s, 1H), 4.00e3.94
(m, 2H), 3.32 and 3.15 (AB System, J¼19.2 Hz, 2H), 2.25 (s, 2H), 1.28
(t, J¼6.8 Hz, 3H), 1.19 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d
8.30e8.33 (m, 1H), 8.26e8.23 (m,
1H), 7.88e7.84 (m, 2H), 5.70e5.68 (m, 1H), 3.40 and 3.22 (AB
d
191.8, 158.2, 155.3, 154.0, 151.0, 134.4, 133.6, 129.2, 128.9, 128.7,

6828
M. Veeranarayana Reddy et al. / Tetrahedron 68 (2012) 6820e6828
9. Rostamizadeh, S.; Ghaieni, H. R.; Aryan, R.; Amani, A. M. Tetrahedron 2010, 66,
494.
10. Litvinov, V. P. Russ. Chem. Rev. 2003, 72, 69.
System, J¼19.2 Hz, 2H), 2.32 (s, 2H), 1.65e1.61 (m, 2H), 1.21 (s, 6H),
0.96 (t, J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 192.1,
155.3, 151.6, 134.5, 133.2, 129.3, 128.6, 127.8, 117.6, 62.0, 51.3, 38.4,
33.9, 28.0, 27.8, 22.3, 8.2 ppm.
11. Clement, R. A. J. Org. Chem. 1960, 25, 1724.
12. El-Saka, S. S.; Soliman, A. H.; Imam, A. M. Afinidad 2009, 66, 167.
13. Zhang, L.; Guan, L. P.; Sun, X. Y.; Wei, C. X.; Chai, K. Y.; Quan, Z. S. Chem. Biol.
Drug Des. 2009, 73, 313.
14. Ryu, C. K.; Park, R. E.; Ma, M. Y.; Nho, J. H. Bioorg. Med. Chem. Lett. 2007, 17, 2577.
15. Li, J.; Zhao, Y. F.; Yuan, X. Y.; Xu, J. X.; Gong, P. Molecules 2006, 11, 574.
16. Sinkkonen, J.; Ovcharenko, V.; Zelenin, K. N.; Bezhan, I. P.; Chakchir, B. A.; Al-
Assar, F.; Pihlaja, K. Eur. J. Org. Chem. 2002, 2046.
4.2.20. 3,4-Dihydro-3,3-dimethyl-13-propyl-2H-indazolo[2,1-b]
phthalazine-1,6,11(13H)-trione (4t). Rf value¼0.65 (hexane/ethyl
acetate (3:1)s); Yield 81%; yellow powder; mp 136e138 ꢀC
(136e138 ꢀC).23 1H NMR (400 MHz, CDCl3):
d 8.30e8.22 (m, 2H),
17. Sayyafi, M.; Seyyedhamzeh, M.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64,
7.88e7.85 (m, 2H), 5.72e5.69 (m, 1H), 3.40 and 3.21 (AB System,
J¼19.1 Hz, 2H), 2.32 (s, 2H), 2.20e1.68 (m, 4H), 1.21 (s, 6H), 0.92 (t,
2375.
18. Khurana, J. M.; Devanshi, M. Tetrahedron Lett. 2009, 50, 7300.
19. Shaterian, H. R.; Ghashang, M.; Feyzi, M. Appl. Catal. A: Gen. 2008, 345, 128.
20. Mosaddegh, E.; Hassankhani, A. Tetrahedron Lett. 2011, 52, 488.
21. Fazaeli, R.; Aliyan, H.; Fazaeli, N. Open Catal. J. 2010, 3, 14.
22. Sabitha, G.; Srinivas, C.; Raghavendar, A.; Yadav, J. S. Helv. Chim. Acta 2010, 93,
1375.
J¼7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 192.0, 154.3, 151.6,
134.4, 133.4, 129.3, 128.2, 127.8, 119.4, 60.0, 50.9, 38.0, 33.2, 31.5,
28.8, 28.4, 20.3, 14.6 ppm.
23. Ghorbani-Vaghei, R.; Karimi-Nami, R.; Toghraei-Semiromi, Z.; Amiri, M.; Gha-
Acknowledgements
videl, M. Tetrahedron 2011, 67, 1930.
24. Gaurav, S.; Rajiv, K. V.; Girijesh, K. V.; Shankar Singh, M. Tetrahedron Lett. 2011,
52, 7195.
This research work was supported by the second stage of BK21
Program.
25. Xiao, W.; Wei-Wei, M.; Li-Qiang, W.; Fu-Lin, Y. J. Chin. Chem. Soc. 2010, 57, 1341.
26. Agarwal, A.; Prem, M. S. C. Tetrahedron Lett. 2005, 46, 1345.
27. Ali Reza, K.; Zahra, A.; Mostafa, M. A. Mol. Diversity 2010, 14, 635.
28. Mohammadpoor-, B.; Tangestaninejad, S.; Moghadam, M.; Mirkhani, V.; Anvar,
S.; Mirjafari, A. Synlett 2010, 3104.
References and notes
29. Dıaz-Ortiz, A.; delaHoz, A.; Moreno, A.; Sanchez-Migallon, A.; Valiente, G.
1. Arif, D.; Aditya, K.; Bela, T. Green. Chem. 2012, 14, 17.
2. Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
3. Leitner, W. Green. Chem. 2009, 11, 603.
4. Adriano, C.; Arianna, R.; Paolo, S. Tetrahedron 2010, 66, 7169.
5. Bing, L.; Xitian, W.; Jin-Xian, W.; Zhengyin, D. Tetrahedron 2007, 63, 1981.
6. Kumkum, K.; Dushyant Singh, R.; Viatcheslav, J.; Krishna, N. S. Tetrahedron Lett.
2012, 53, 1130.
7. Shainaz, M. L.; Allison, S.; Verona, O.; Bela, T. Synlett 2007, 1600.
8. Chtchigrovsky, M.; Primo, A.; Gonzalez, P.; Molvinger, K.; Robitzer, M.;
Quignard, F.; Taran, F. Angew. Chem., Int. Ed. 2009, 48, 5916.
Green. Chem. 2002, 4, 339.
30. Omar De, P.; Liliana, T.; Bela, T. Tetrahedron Lett. 2009, 50, 2939.
31. Aditya, K.; Bela, T. Green. Chem. 2010, 12, 875.
32. Aditya, K.; Phong, Q.; Bela, T. Synthesis 2009, 4010.
33. Verona, M.; Outerbridge, S. M.; Landge, H. T.; Bela, T. Synthesis 2009, 1801.
34. Veeranarayana Reddy, M.; Dindulkar, S. D.; Jeong, Y. T. Tetrahedron Lett. 2011, 52,
4764.
35. Veeranarayana Reddy, M.; Jongsik, K.; Jeong, Y. T. J. Fluorine Chem. 2012,
135, 155.