Lewis acid free synthesis of 3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-triones promoted by 1,1,1,3,3,3-hexafluoro-2-propanol

Article abstract of DOI:10.1039/c4ra06768a

A convenient, environmentally friendly and efficient procedure for the synthesis 3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione derivatives has been developed via multi-component and one-pot reactions of various aldehydes with cyclic 1,3-

Full text of DOI:10.1039/c4ra06768a

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Lewis acid free synthesis of 3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-triones promoted by 1,1,1,3,3,3-hexafluoro-2-propanol
Behrooz Maleki*, Samaneh Sedigh Ashrafi, Reza Tayebee
Department of Chemistry, Hakim Sabzevari University, Sabzevar, 96179ꢀ76487, Iran
E-mail:b.maleki@hsu.ac.ir, Tel: +98-571-4002643 Fax: +98-571-4410300
Abstract
A convenient, environmentally friendly and efficient procedure for the synthesis 3,4ꢀ
dihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione derivatives have been
developed via multiꢀcomponent and oneꢀpot reactions of various aldehydes with cyclic 1,3ꢀ
diketones and phthalhydrazide 1,1,1,3,3,3ꢀhexafluoroꢀ2ꢀpropanol (HFIP). In simple and mild
reaction conditions, the use of HFIP is explored as an easy workup and a green catalyst for
the oneꢀpot threeꢀcomponent synthesis 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ
1,6,11(2H,13H)ꢀtriones. Thus, this practical method is developed as a notable medium for
these derivatives via a multicomponent reaction.
Key words:
3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtriones, 1,1,1,3,3,3ꢀHexafluoroꢀ
2ꢀpropanol, Cyclic 1,3ꢀdiketones, Phthalhydrazide, Aldehyde
Introduction
Multiꢀcomponent reactions (MCRs) enable multiple reactions1 leading to motivating
heterocyclic framework which are useful for the construction of polyꢀfunctionalized
heterocyclic 'drug like' libraries.2,3 These reactions have been investigated widely in organic
and diversely oriented synthesis. In the past few decades, the synthesis of novel heterocyclic
compounds has been received a great deal of attention, most notably for the construction of
heterocyclic compounds.4,5 Nitrogenꢀcontaining heterocyclic compounds are widespread in
1

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nature, and their applications to pharmaceuticals, agrochemicals, and functional materials are
becoming more and more important.6 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ
1,6,11(2H,13H)ꢀtriones which are important Nꢀheterocycles, comprise a key structural of
numerous natural and synthetic bioactive molecules.7 Moreover, fused Phthalazines were
found to possess multiple pharmacological and biological activities such as antimicrobial,8
antifungal,9 anticancer,10 antiꢀinflammatory,11 anticonvulsant,12 cardiotonic,13 and
vasorelaxant.14 These target molecules also could be promising materials for new
luminescence or fluorescence probes.15
Therefore, a number of methods have been reported for the synthesis of phthalazine
derivatives. Nonetheless the development of new synthetic methods for the proficient
preparation of heterocycles containing phthalazine ring fragment is an interesting challenge.
In recent years, much attention has been directed toward synthesis of 3,4ꢀdihydroꢀ1Hꢀ
indazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione derivatives. Synthesis of these derivatives
have been reported using pꢀTSA,16 Me3SiCl,17 silica sulfuric acid,18 H2SO4,19 Mg(HSO4)2,20
and silica supported poly phosphoric acid,21 montmorillonite Kꢀ10,22 P38 MAP kinase,23 and
N,N,N,N-tetramethylguanidinium acetate [TMG][Ac]24 as catalysts. Since many of these
methods are associated with more disadvantages such as use of expensive catalyst or toxic
organic solvents,17,20 strong acidic conditions,16,19 and harsh reaction conditions,16ꢀ21 synthetic
methods should be designed to use substances that exhibit little or no toxicity to human
health and the environment.
Results and Discussion
In recent years, the fluorous solvents have attracted a grabbing attention and an increasing
interest in the context of green reaction media, as catalyst and coꢀsolvent (additive).
Fluorinated alcohols were reported to possess lower boiling points and higher melting points
than their nonꢀfluorinated counterparts, high polarity, generally selective, without effluents,
2

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strong hydrogen bond donation properties and the ability to solvate water. Reactions in
1,1,1,3,3,3ꢀhexafluoroꢀ2ꢀpropanol (HFIP) have a facile isolation of the product and can be
easily recovered by distillation.25ꢀ27 HFIP has been used in organic synthesis because these
fluorinated alcohols are available on a commercial scale. They can be well dispersed in the
reaction mixtures in solvolysis reaction, where the generated cationic intermediates can be
trapped by nucleophiles. Moreover, HFIP takes part in the reactions as both catalyst and
solvent. The electron withdrawing character of CF3 confers high acidity to the hydrogen of
the hydroxyl group.28 In addition this property, fluorinated alcohols are not nucleophiles or
hydrogen bond acceptors. Thus, the degree of autoꢀassociation of fluorinated alcohols is low.
The chief advantage of fluorinated alcohols, for instance hexafluoroisopropanol (HFIP) and
trifluoroethanol (TFE), is the possibility to carry out, in the absence of promoting agents,
reactions that usually require the aid of Lewis acids or catalysts.29,30
HFIP provides as a dominant hydrogenꢀbond donor, as was indicated not only by the
spectral studies and calorimetric measurements, but also by the isolation of extremely stable
complexes with a number of nucleophilic species.31 Compared to other solvents, HFIP (bp =
58ºC) are unique due to their high ionizing powers, strong hydrogen bond donor abilities,
mild acidic characters (pKa = 12.4 and pKa = 9.3, respectively), and low nucleophilicity.32,33
In recent decades, approaches for the synthesis of biologically interesting products via multiꢀ
component reactions were developed. The challenge in this field was developing efficient and
rapid green methods. Green chemistry approaches are most important due to the reduction in
byproducts, a reduction in produced waste, and reduction of energy cost. In this report, based
on earlier success in the preparation of heterocycles with nucleous nitrogen,34 we present the
results of an extended investigation on the activity this solvent, as an efficient medium for the
synthesis of 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtriones (Scheme 1).
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CHO
R
R
O
O
O
O
O
1
HFIP
Lewic Acid Free
550C
N
N
NH
NH
+
R1
R1
O
O
3
4
R1
R1
R1=CH3,H
2
Scheme 1 Oneꢀpot synthesis of 1HꢀIndazolo[1,2ꢀb]phthalazineꢀtriones.
We decided to explore the possibility of a simple and facile synthesis 3,4ꢀdihydroꢀ1Hꢀ
indazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione derivatives by threeꢀcomponent
a
condensation reaction of cyclic 1,3ꢀdiketones, aromatic aldehydes and phthalhydrazide in the
presence of HFIP as a novel and reusable solvent.
First, we examined the amount of HFIP and the reaction temperature using dimidone (1
mmol), benzaldehyde (1 mmol) and phthalhydrazide (1 mmol) to the consequent 3,3ꢀ
dimethylꢀ13ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione was
studied under reaction conditions in the presence of HFIP at different temperatures and
amount of HFIP. The best results were achieved in 0.3 ml at 55°C. No product was observed
in the absence of HFIP at 55°C after one day.
Based on the optimized reaction conditions, a range of 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀ
b]phthalazineꢀ1,6,11(2H,13H)ꢀtrione derivatives was synthesized by the reaction of cyclic
1,3ꢀdiketones, aldehyde and phthalhydrazide (Table 1). The structures of the products were
established from their spectral properties (1H NMR, 13C NMR and elemental analysis) and
also by comparison with available literature data.
As shown in Table 1, the direct multiꢀcomponent reactions worked fit with a variety of
aldehydes together with those bearing electronꢀwithdrawing and electronꢀdonating groups
4

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such as Me, OMe, Cl, F, Br or NO2, and the target molecules were obtained in high to
excellent yields.
Table 1
Synthesis of 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione derivatives
using HFIP
Time (h)
Entry
Product
Yield % ref
O
O
O
N
N
1
8
9217
CH3
CH3
4a
OCH3
O
O
O
2
9
9017
N
N
CH3
CH3
4b
NO2
O
O
O
3
10
9220
N
N
CH3
CH3
4c
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Cl
O
O
O
4
5
6
8
8520
7917
9019
N
N
CH3
CH3
4d
NO2
O
O
O
N
N
11
CH3
CH3
4e
F
O
O
O
15
N
N
CH3
CH3
4f
CH3
O
O
O
O
7
12
8917
N
N
CH3
CH3
4g
S
O
N
N
8
9
8323
CH3
CH3
O
4h
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O
O
O
9
8
8320
N
N
4i
NO2
O
O
O
10
10
8817
N
N
4j
Cl
Cl
O
O
O
11
8
7520
N
N
4k
OH
O
O
O
12
9
8220
N
N
4l
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OMe
O
O
O
13
10
9017
N
N
4m
NO2
O
O
O
14
9
9020
N
N
4n
N(Me)2
O
O
O
15
12
8620
N
N
4o
O
O
O
16
10
9019
N
N
4p
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In continuation of our studies in this field, we decided to synthesize 3,4ꢀdihydroꢀ1Hꢀ
indazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtriones in shorter times and better yields with
HFIP. The reaction between 4ꢀfluorobenzaldehydes (1.0 mmol), dimedone (1.0 mmol) with
phthalhydrazide (1 mmol) was carried out with HFIP (0.5 ml) at 550C. The target molecule
(4f) of this reaction was obtained with 90% of yield in 15h.
Trifluoroethanol (TFE) is a solvent with similar physicochemical properties of
1,1,1,3,3,3ꢀhexafluoroꢀ2ꢀpropanol (HFIP). In order to examine the catalytic activity of TFE in
this reaction, benzaldehyde (1.0 mmol), dimedone (1.0 mmol) with phthalhydrazide (1 mmol)
and TFE (0.3 ml) was selected as the model at 700C. After 8h, only 78% of expected 3,3ꢀ
dimethylꢀ13ꢀphenylꢀ3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione (4a)
was obtained.
The formation of strong hydrogen bonds with C=O groups facilitates all reaction routes.
In this process, HFIP with a strong Hꢀbond donor (α=1.96, pKa=9.3), high ionizing power
(YOTs=3.79), and polarity (Ps=11.08) could activate the C=O groups and play a significant
role in increasing the electrophilic character.25ꢀ27 Therefore, The formation of products 4a-p
can be rationalized by initial formation of heterodiene by standard Knoevenagel condensation
of cyclic 1,3ꢀdiketones and aromatic aldehydes in the presence of a catalytic amount.
Subsequent Michaelꢀtype addition of phthalhydrazide to the heterodienes followed by
cyclization and dehydration afford the corresponding products 4a-p (Scheme 2).
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R1
R1
R1
R1
O
Ar
H
O
O
O
HO
O
O
R1
NH
NH
H
R1
H
O
O
H
Ar
Ar
O
O
O
N
HN
R1
H
O
O
Ar
R1
H
OH
F
F
F
F
F
F
C=O groups were activated through
formation of hydrogen bonding
O
R1
R1
N
N
O
Ar
O
Scheme 2 Proposed mechanism.
To recognize the capability of the present method in comparison with reported methods
for the preparation of 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione
derivatives, the model reaction of dimedone, benzaldehyde and phthalhydrazide was studied
in the literature. Their results clearly demonstrate that HFIP is efficient for this threeꢀ
component reaction (Table 2).
Table 2
Comparison of Methods for the Synthesis of 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀ
b]phthalazineꢀ1,6,11(2H,13H)ꢀtriones
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Entry
Compounds 4
Conditions
Time (h) Yield
(%)a
PMAꢀSiO2/Solventꢀ
Free/80°C17
0.66
0.58
85
[bmim]BF4/H2Oꢀ
EtOH/reflux20
88
O
O
O
1ꢀbutylꢀ3ꢀ
0.25
90
92
N
N
methylimidazolium
bromide/Ultrasound19
CH3
CH3
1
4a
HFIP/55°C
8
NO2
[bmim]BF4/H2Oꢀ
EtOH/reflux20
0.5
92
O
O
O
2
N
N
CH3
CH3
SilicaꢀSO3H/Solventꢀ
free/125°C19a
0.11
0.25
85
90
4c
Sulfuric acidꢀ
modified/Solventꢀ
free/80°C19b
HFIP/55°C
10
92
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OH
PMAꢀSiO2/Solventꢀ
Free/80°C17
0.66
82
Sulfuric acidꢀ
modified/Solventꢀ
free/80°C19
O
O
O
1.16
9
50
82
3
N
N
HFIP/55°C
4l
The reusability of the catalyst was checked by separating HFIP from mixture and reuse in
subsequent reactions. The recovered HFIP can be reused for at least three additional times in
subsequent reactions with 92, 90 and 84% of yields in 8h for 4a without significant loss in
product yield.
Experimental
Chemicals were obtained from Merck and Fluka. IR spectra were recorded on a Shimadzu
1
435ꢀUꢀ04 spectrophotometer (KBr pellets). H NMR spectra were obtained using a Jeol FT
NMR 300 MHz spectrometer in CDCl3 using TMS as an internal reference. Melting points
were determined in open capillary tubes in a Stuart BI Branstead Electrothermal Cat
No:IA92003 apparatus and are uncorrected. Mass spec techniques were conducted in GCMSꢀ
QP1100EX.
General procedure for the synthesis of 3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-triones (4a-p)
To a mixture of various aldehydes (1.0 mmol), dimedone or 1,3 cyclohexadione (1.0 mmol)
with phthalhydrazide (1 mmol) and HFIP (0.3 ml) was stirred magnetically at 55ºC for an
appropriate time as mentioned in Table 1. After completion of the reaction (monitored by
TLC; nꢀhexane/ethylacetate, 4/1), the reaction mixture was diluted with EtOH (96%, 0.1 ml)
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and stirred for 2 min in 55°C. Next, the resulting crude product was poured into crushed ice
and the solid product, which separated was filtered, recrystallized from ethanol (96%, 3 ml)
to get pure 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtriones (4a-p). Then,
the HFIP was separated by distillation and reused in the next run.
3,3-dimethyl-13-phenyl-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-
trione (4a). Yellow powder, mp: 200ꢀ202 °C, (206ꢀ208 °C)17; IR (KBr, cmꢀ1): 2958, 1661,
1575; 1H NMR (300 MHz, CDCl3, ppm) δ 1.23 (6H, s, 2Me), 2.35 (2H, s, CH2CO), 3.26 and
3.44 (2H, AB system, J = 18.6 Hz, CHaHbCO), 6.47 (1H, s, CHN), 7.33ꢀ8.37 (9H, m, Ph);
13C NMR (75 MHz, CDCl3, ppm) δ 28.5, 28.7, 34.7, 38.1, 50.9, 64.9, 118.6, 127.1, 127.7,
127.9, 128.7, 128.9, 129.1, 133.6, 134.5, 136.4, 150.9, 154.3, 156.1, 192.2; MS, m/z (%): 372
(M, 15), 295 (100), 104 (84), 76 (67).
3,3-dimethyl-13-(4-methoxyphenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4b). Yellow powder, mp: 207ꢀ209 °C, (207ꢀ209 °C)17; IR (KBr, cmꢀ
1): 2958, 1663, 1628, 1604, 1513, 1465, 1425, 1361,1312, 1265, 1242, 1172, 1099, 1027,
1
842, 797, 699; H NMR (300 MHz, CDCl3, ppm) δ 8.25ꢀ8.35 (m, 2H), 7.82ꢀ7.85 (m, 2H),
6.84ꢀ7.35 (m, 4H), 6.42 (s, 1H), 3.76 (s, 3H), 3.23 and 3.42 (2H, AB system, J = 19.2 Hz),
2.34 (s, 2H), 1.21 (s, 6H); 13C NMR (75 MHz, CDCl3, ppm) δ 192.23, 159.74, 156.07,
154.28, 150.75, 134.47, 133.47, 129.18, 128.98, 128.51, 128.36, 127.93, 127.71, 118.58,
114.14, 64.59, 55.21, 50.99, 38.07, 34.65, 28.71, 28.51; MS, m/z (%): 402.
3,3-dimethyl-13-(4-nitrophenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4c). Yellow powder, mp: 226ꢀ228 °C, (224ꢀ225 °C)20; IR (KBr, cmꢀ
1
1): 2924, 1695, 1659, 1615; H NMR (300 MHz, CDCl3, ppm) δ 1.21 (3H, s, Me), 1.23 (3H,
s, Me), 2.33 and 2.38 (2H, AB system, J = 16.5 Hz, CHaHbCO), 3.26 and 3.43 (2H, AB
system, J = 19.2 Hz, CHaHbCO), 6.52 (1H, s, CHN), 7.61ꢀ8.41 (8H, m, Ph); 13C NMR (75
MHz, CDCl3, ppm) δ 28.4, 28.7, 34.7, 38.0, 50.8, 64.2, 117.3, 124.1, 127.8, 128.1, 128.3,
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128.6, 128.9, 133.9, 134.9, 143.4, 147.9, 151.7, 154.6, 155.9, 192.1; MS, m/z (%): 417 (M,
5), 295 (100), 104 (48), 76 (75).
3,3-dimethyl-13-(4-chlorophenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4d). White powder, mp: 263ꢀ265 °C, (260ꢀ262 °C)20; IR (KBr, cmꢀ
1): 2957, 1656, 1623; 1H NMR (300 MHz, CDCl3, ppm) δ 1.22 (3H, s, Me), 1.23 (3H, s, Me),
2.35 (2H, s, CH2CO), 3.25 and 3.43 (2H, AB system, J = 19.1 Hz, CHaHbCO), 6.43 (1H, s,
CHN), 7.31ꢀ8.39 (8H, m, Ph); 13C NMR (75 MHz, CDCl3, ppm) δ 28.5, 28.7, 34.7, 38.0,
50.9, 64.3, 118.1, 127.7, 128.1, 128.5, 128.8, 128.9, 129.0, 133.7, 134.5, 134.6, 134.9, 151.1,
154.3, 156.0, 192.2 ppm; MS, m/z (%): 406 (M, 5), 295 (100), 104 (43), 76 (46).
3,3-dimethyl-13-(3-nitrophenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4e). Yellow powder, mp: 270ꢀ272 °C, (270ꢀ272 °C)17; IR (KBr, cmꢀ
1
1): 2926, 1660, 1625; H NMR (300 MHz, CDCl3, ppm) δ 1.12 (6H, s, 2Me), 2.27 (2H, s,
CH2CO), 3.23 (2H, br s, CH2CO), 6.46 (1H, s, CHN), 7.60ꢀ8.37 (8H, m, Ph); 13C NMR (75
MHz, CDCl3, ppm) δ 28.3, 28.9, 34.6, 38.2, 51.5, 64.2, 116.9, 127.3, 127.3, 128.4, 128.7,
129.2, 129.8, 131.5, 132.7, 133.1, 133.6, 134.5, 135.5, 151.8, 154.4, 156.4, 192.2; MS, m/z
(%): 417 (M, 10), 295 (100), 104 (48), 76 (75).
3,3-dimethyl-13-(4-methylphenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4g). Yellow powder, mp: 227ꢀ229 °C, (227ꢀ229 °C)17; IR (KBr, cmꢀ
1
1): 2956, 1663, 1621; H NMR (300 MHz, CDCl3, ppm) δ 1.23 (6H, s, 2Me), 2.30 (3H, s,
CH3), 2.35 (2H, s, CH2CO), 3.24 and 3.43 (2H, AB system, J = 18.5 Hz, CHaHbCO), 6.43
(1H, s, CHN), 7.12ꢀ8.38 (8H, m, Ph); 13C NMR (75 MHz, CDCl3, ppm) δ 21.3, 28.5, 28.8,
34.7, 38.1, 50.9, 64.9, 118.7, 127.1, 127.7, 127.9, 128.9, 129.2, 129.5, 133.4, 133.5, 134.5,
138.5, 150.8, 154.2, 156.1, 192.2; MS, m/z (%): 386 (M, 10), 295 (100), 104 (45), 76 (46).
3,3-dimethyl-13-(thiophen-2-yl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4h). Yellow powder, mp: 219ꢀ222 °C, (218ꢀ220 °C)23; IR (KBr, cmꢀ
14

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1): 2958, 1661, 1575; 1H NMR (300 MHz, CDCl3, ppm) δ 1.22 (6H, s, 2Me), 2.31 (2H, s,
CH2CO), 3.19 and 3.35 (2H, AB system, J = 18.6 Hz, CHaHbCO), 6.48 (1H, s, CHN), 7.29ꢀ
8.35 (7H, m, Ar); 13C NMR (75 MHz, CDCl3, ppm) δ 28.6, 28.7, 34.7, 38.0, 50.9, 64.9,
118.6, 127.1, 127.7, 127.9, 128.7, 128.9, 129.1, 133.6, 134.5, 136.4, 150.9, 154.3, 156.0,
192.1; MS, m/z (%): 372 (M, 15), 295 (100).
13-(phenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione
Yellow powder, mp: 223–225 °C, (223ꢀ225 °C)20; IR (KBr, cmꢀ1): 2954, 1659, 1623, 1366,
1304, 1267, 702; 1H NMR (300 MHz, CDCl3, ppm) δ 8.24ꢀ8.36 (m, 2H), 7.82–7.85 (m, 2H),
7.31ꢀ7.43 (m, 5H), 6.44 (s, 1H), 3.29ꢀ3.60 (m, 2H), 2.44ꢀ2.62 (m, 2H), 2.23ꢀ2.27 (m, 2H);
13C NMR (75 MHz, CDCl3 ppm) δ 192.50, 156.01, 154.21, 152.29, 144.35, 136.33, 134.51,
133.52, 129.04, 128.65, 128.07, 127.95, 127.69, 119.64, 64.94, 36.89, 24.47, 22.26; MS, m/z
(%): 344.
(4i).
13-(4-hydroxyphenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-
trione (4l). White powder, mp: 267ꢀ269 °C, (265ꢀ266 °C)20; IR (KBr, cmꢀ1): 3424, 2899,
1642, 1612, 1371, 1310, 1279,703; 1H NMR (300 MHz, CDCl3, ppm) δ 8.83 (s, 1H), 8.23ꢀ
8.35 (m, 2H), 7.83ꢀ7.86 (m, 2H), 7.23 (d, 2H, J = 8.7 Hz), 6.78 (d, 2H, J = 8.4 Hz), 6.37 (s,
1H), 3.35ꢀ3.60 (m, 2H), 2.46ꢀ2.47 (m, 2H), 2.24ꢀ2.28 (m,2H); 13C NMR (75 MHz, CDCl3,
ppm) δ 197.29, 162.42, 160.57, 158.79, 157.08, 139.25, 138.28, 137.07, 133.73, 133.38,
132.66, 132.09, 131.80, 130.27, 124.18, 120.28, 69.25, 41.68, 29.16, 27.02; MS, m/z (%):
360.
13-(4-methoxyphenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-
trione (4m). Yellow powder, mp: 245–247 °C, (242ꢀ244 °C)17; IR (KBr, cmꢀ1): 2950, 1657,
1
1624, 1365, 1306, 1246, 703; H NMR (300 MHz, CDCl3, ppm) δ 8.25ꢀ8.35 (m, 2H), 7.82ꢀ
7.86 (m,2H), 7.32ꢀ7.37 (m, 2H), 6.83ꢀ6.87 (m, 2H), 6.42 (s, 1H), 3.75 (s, 3H), 3.28ꢀ3.60 (m,
2H), 2.44ꢀ2.49 (m, 2H), 2.23–2.30 (m, 2H); 13C NMR (75 MHz, CDCl3, ppm) δ 192.60,
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159.73, 156.05, 154.22, 152.19,134.48, 133.47, 129.16, 128.94, 128.55, 128.30, 127.93,
127.69,119.65, 114.09, 64.58, 55.23, 36.96, 24.51, 22.34; MS, m/z (%): 374.
13-(3-nitrophenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione
(4n). Yellow powder, mp: 232ꢀ234 °C, (228ꢀ230 °C)20; IR (KBr, cmꢀ1): 2926, 1662, 1624,
1369, 1305, 1285, 697; 1H NMR (300 MHz, CDCl3, ppm) δ 8.22ꢀ8.40 (m, 2H), 8.14ꢀ8.17 (m,
2H), 7.52ꢀ7.92 (m, 4H), 6.52 (s, 1H), 3.31ꢀ3.65 (m, 2H), 2.46ꢀ2.50(m, 2H), 2.23ꢀ2.38 (m,
2H); 13C NMR (75 MHz, CDCl3, ppm) δ 192.46, 164.62, 155.99, 154.65, 153.21, 148.53,
138.60, 134.78, 129.62, 128.27, 127.76, 123.69, 121.70, 118.26, 64.25, 36.79, 24.54, 22.23;
MS, m/z (%): 389.
13-(4-N,N-dimethylphenyl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-
trione (4o). White powder, mp: 257ꢀ259 °C, (256ꢀ258 °C)20; IR (KBr, cmꢀ1): 2923, 1661,
1
1616, 1364, 1305,1280, 699; H NMR (300 MHz, CDCl3, ppm) δ 8.25ꢀ8.34 (m, 2H), 7.80ꢀ
7.83 (m, 2H), 7.26ꢀ7.29 (m, 2H), 6.63ꢀ6.66 (m, 2H), 6.40 (s, 1H), 3.35ꢀ3.61 (m, 2H), 2.89 (s,
6H), 2.46ꢀ2.48 (m, 2H), 2.24ꢀ2.28 (m, 2H); 13C NMR (75 MHz, CDCl3, ppm) δ 192.59,
156.12, 154.12, 151.89, 150.64, 134.34, 133.28, 129.39, 128.98, 128.92, 128.21, 127.84,
127.70, 123.41, 119.95, 112.40, 112.26, 64.83, 40.64, 40.36, 37.02, 24.53, 22.39; MS, m/z
(%): 387.
13-(naphthalen-2-yl)-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione
(4p). Yellow powder, mp: 248ꢀ250 °C, (248ꢀ250 °C)19b; IR (KBr, cmꢀ1): 2961, 1655, 1626;
1H NMR (300 MHz, CDCl3, ppm) δ 1.22 (6H, s, 2Me), 2.33 (2H, s, CH2C), 3.24ꢀ3.50 (2H,
AB system, J =18.6 Hz, CHaHbCO), 6.62 (1H, s, CHN), 7.45ꢀ8.38 (11H, m, Ph); 13C NMR
(75 MHz, CDCl3, ppm); δ 28.4, 28.7, 34.6, 38.1, 50.9, 65.1, 118.6, 124.2, 126.2, 126.3,
126.8, 127.6, 127.7, 127.9, 128.2, 128.7, 129.0, 129.6, 133.2, 133.4, 133.5, 133.6, 134.5,
150.8, 154.2, 156.1, 192.1; MS, m/z (%): 422 (M, 5), 295 (100), 104 (40), 76 (56).
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Conclusion
In summary, a novel and highly efficient methodology for the synthesis of 3,4ꢀdihydroꢀ1Hꢀ
indazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtriones by a threeꢀcomponent condensation
reaction of cyclic 1,3ꢀdiketones, aromatic aldehydes and phthalhydrazide in the presence of
HFIP was reported. In contrast to the existing methods using potentially hazardous
catalysts/additives, this new method offers the following competitive advantages such as
avoiding the use of any base, metal, or Lewis acid catalysts. To the best of our knowledge,
this method represents the first example of the synthesis 3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀ
b]phthalazineꢀ1,6,11(2H,13H)ꢀtriones in the absence of catalyst.
Acknowledgements
This research work was supported by the the University of Hakim Sabzevari. Authors wish to
thank the University of Hakim Sabzevari for financial support to carry out this research.
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Graphical Abstract
Lewis acid free synthesis of 3,4-dihydro-1H-
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-
triones promoted by 1,1,1,3,3,3-hexafluoro-2-
propanol
CHO
R
R
O
O
O
O
O
Behrooz Maleki*, Samaneh Sedigh Ashrafi,
Reza Tayebee
1
HFIP
Lewic Acid Free
550C
N
N
NH
NH
+
R1
R1
O
O
ꢀ
For the first time a Lewis acid catalyst
free is proposed for the synthesis of 3,4-
dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-triones derivatives
Avoiding of any base, metal, or Lewis
acid catalysts
3
4
R1
R1
R1=CH3,H
ꢀ
ꢀ
2
Reusability of the catalyst