Ionic Liquid 4-(3-Methyl-1-imidazolio)-1-butanesulfonic acid hydrogen sulfate-catalyzed synthesis of phthalazinetrione derivatives

Article abstract of DOI:10.5560/ZNB.2012-0090

A simple method for the synthesis of phthalazinetrione derivatives by a one-pot three-component condensation reaction of phthalhydrazide, 1,3-dicarbonyl compounds and aldehydes catalyzed by the ionic liquid 4-(3-methyl-1-imidazolio) -1-butanesulfonic acid

Full text of DOI:10.5560/ZNB.2012-0090

Ionic Liquid 4-(3-Methyl-1-imidazolio)-1-butanesulfonic Acid Hydrogen
Sulfate-catalyzed Synthesis of Phthalazinetrione Derivatives
Shihua Songa, Xiang Dengb, Zhi Guana, and Yanhong Hea
a
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
P. R. China
b
Department of Chemistry and Chemical Engineering, Sichuan University of Arts and Science,
Sichuan Dazhou 635000, P. R. China
Reprint requests to Prof. Zhi Guan and Prof. Yanhong He. Fax: +86-23-68254091.
E-mail: guanzhi@swu.edu.cn (for Zhi Guan); heyh@swu.edu.cn (for Yan-Hong He)
Z. Naturforsch. 2012, 67b, 717 – 724 / DOI: 10.5560/ZNB.2012-0090
Received March 30, 2012
A simple method for the synthesis of phthalazinetrione derivatives by a one-pot three-component
condensation reaction of phthalhydrazide, 1,3-dicarbonyl compounds and aldehydes catalyzed by the
ionic liquid 4-(3-methyl-1-imidazolio)-1-butanesulfonic acid hydrogen sulfate ([BSO3HmIm]HSO4)
is reported. Good to excellent yields were obtained in short reaction times in the solvent PEG 600
(polyethylene glycol 600) at 120 ◦C. The strategy proved to be efficient and environmentally be-
nign. The catalyst/solvent system could easily be recovered and reused for at least 5 times without
noticeable loss of activity.
Key words: Multicomponent Reaction, One-pot, Ionic Liquid, Phthalazinetrione Derivative
Introduction
and dimedone or cyclohexane-1,3-dione catalyzed
by p-TSA [13], H2SO4 [14], H4SiW12O40 [15],
Multicomponent reactions (MCRs), which have H3PW12O40 [16], silica sulfuric acid [17], silica-
emerged as a powerful tool for the construction of supported polyphosphoric acid [18], TMSCl [19],
novel and complex molecules [1], have attracted in- phosphomolybdic acid (PMA)-SiO2 [20], N,N,N0,N0-
creasing attention. These types of reactions have some tetrabromobenzene-1,3-disulfonamide and poly(N-
advantages over conventional linear syntheses, includ- bromo-N-ethylbenzene-1,3-disulfonamide) [21]. Most
ing lower costs, shorter reaction times, higher degrees recently a one-pot four-component reaction for the
of atom economy, the possibility for combinatorial synthesis of phthalazine derivatives was reported
surveying of structural variations, and environmental using Ce(SO4)2 · 4H2O [22] as catalyst. However,
friendliness [2].
these methods have limitations such as the use of
In the past few years, heterocyclic compounds have toxic metals, toxic organic solvents, expensive or
received great interest because they are common in Na- large amounts of catalysts, and tedious work-up
ture and often essential to life. Heterocycles containing procedures. Besides, the recovery of catalysts or
the phthalazine moiety show some pharmacological solvents is difficult for the existing methods. From the
and biological activities [3]. Phthalazine derivatives viewpoint of green chemistry, there is still an urgent
have been reported to possess anticonvulsant [4], need to develop new strategies for the preparation of
cardiotonic [5], vasorelaxant [6], cytotoxic [7], an- heterocycles containing the phthalazine ring fragment.
timicrobial [8], antifungal [9], anticancer [10], and
Ionic liquids have attracted intensive interest re-
anti-inflammatory activities [11]. In addition, these cently. Compared to traditional volatile organic sol-
compounds show good promise as new luminescence vents, they have unique advantages, such as negligible
materials and fluorescence probes [12]. There are vapor pressure, recyclability and solvophobic proper-
several methods to synthesize phthalazine derivatives, ties. By virtue of the incorporated functional groups,
including the reaction of phthalhydrazide, aldehydes ionic liquids can act not only as solvents but also as
c
ꢀ 2012 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

718
S. Song et al. · Synthesis of Phthalazinetrione Derivatives
Scheme 1. The synthesis of phthalazinetrione derivatives catalyzed by [BSO3HmIm]HSO4 (R2 = aryl or alkyl).
catalysts [23]. [BmIm]BF4 has been used as solvent for
Table 1. The effects of different catalysts and catalyst loading
on the three-component reactiona.
the synthesis of phthalazine derivatives [14, 16]. How-
ever, the dosages of [BmIm]BF4 were very large. To
our knowledge, up to now there was no report about
the synthesis of phthalazine derivatives catalyzed by
ionic liquids. As an ionic liquid, [BSO3HmIm]HSO4
is relatively cheap and commercially available or
easily synthesized [24]. For this reason, there have
been some reports about the application [25, 26] of
[BSO3HmIm]HSO4. Polyethylene glycol (PEG) has
been widely used as a medium for organic synthesis in
recent years because it is non-toxic, inexpensive, non-
volatile, thermally stable, biologically acceptable, and
eco-friendly, and allows many useful organic transfor-
mations to occur under mild reaction conditions [27].
Herein we wish to report a green and simple strategy
for the synthesis of phthalazinetriones catalyzed by the
ionic liquid [BSO3HmIm]HSO4 in PEG 600 at 120 ◦C
(Scheme 1).
Entry
Catalyst (mol-%)
Time (min) Yield (%)b
1
None
240
240
240
240
60
n. d.
n. d.
n. d.
n. d.
65
2c
3c
4c
5c
6
7
8
9
[BmIm]BF4 (15)
[BmIm]PF6 (15)
[BmIm]Ac (15)
[BmIm]HSO4 (15)
[BSO3HmIm]HSO4 (15)
[BSO3HmIm]HSO4 (10)
[BSO3HmIm]HSO4 (20)
[BSO3HmIm]HSO4 (25)
30
81
30
73
30
81
30
82
a
Experimental conditions: phthalhydrazide (1.0 mmol), dimedone
(1.0 mmol), 4-nitrobenzaldehyde (1.2 mmol) and IL in PEG 600
(1.0 mL) at 120 ◦C; isolated yields; n. d. = not determined;
b
c
[BmIm]: 1-butyl-3-methylimidazolium.
Results and Discussion
In our initial study, the one-pot, three-component alyst was used, the product was obtained only in 73%
condensation reaction of phthalhydrazide, dimedone yield after 30 min (Table 1, entry 7). The catalyst load-
and 4-nitrobenzaldehyde was used as a model reac- ing of 15 mol-% led to a satisfactory yield of 81%
tion. Various ionic liquids (ILs) were tested as cata- (Table 1, entry 6), however no obvious improvement
lysts in PEG 600 (1.0 mL) at 120 ◦C, and the results was observed by further increasing the catalyst load-
are listed in Table 1. No product was detected in the ing to 25 mol-% (Table 1, entries 8 and 9). Therefore,
absence of IL in PEG 600 at 120 ◦C even after 240 min 15 mol-% of [BSO3HmIm]HSO4 was used as the op-
(Table 1, entry 1). Among the tested ILs (15 mol-%), timized catalyst for the following study.
[BSO3HmIm]HSO4 showed the best catalytic activity
In order to find a suitable solvent for the reaction,
for the model reaction, which gave a good yield of water and ethanol were also investigated as solvents
81% after 30 min (Table 1, entry 6). [BmIm]HSO4 also using the model reaction. After refluxing for 30 min,
catalyzed the reaction (Table 1, entry 5), while other a low yield of 38% was obtained in water (Table 2, en-
tested ILs had little effect (Table 1, entries 2–4). Thus, try 1), but only a trace amount of product was observed
[BSO3HmIm]HSO4 was chosen as the catalyst for the in ethanol (Table 2, entry 2). The results indicated that
reaction. Next, we investigated the effect of catalyst PEG 600 was the best choice (Table 2, entry 3). Next,
loading on the model reaction. When 10 mol-% of cat- since the concentration of reactants and catalyst can
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

S. Song et al. · Synthesis of Phthalazinetrione Derivatives
719
Table 2. The effects of solvent and temperature on the three- Table 3. The effects of molar ratio on the three-component
component reactiona.
reactiona.
Entry
T (◦C)
Yield (%)b
1
2a
(mmol)
3
Yield
(%)b
Entry
Solvent (mL)
(mmol)
(mmol)
1
2
3
4
5
6
7
8
9
water (1.0)
100
80
38
trace
81
79
62
45
70
83
84
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.2
1.3
1.4
1.5
1.2
1.3
1.4
1.5
1.6
1.7
81
85
88
93
95
95
ethanol (1.0)
PEG 600 (1.0)
PEG 600 (0.5)
PEG 600 (2.0)
PEG 600 (3.0)
PEG 600 (1.0)
PEG 600 (1.0)
PEG 600 (1.0)
120
120
120
120
100
140
160
a
Experimental conditions: phthalhydrazide (1), dimedone (2a), 4-
nitrobenzaldehyde (3) and [BSO3HmIm]HSO4 (0.15 mmol) in PEG
600 (1.0 mL) at 120 ◦C for 30 min; b isolated yields.
a
Experimental conditions: phthalhydrazide (1.0 mmol), dimedo-
ne (1.0 mmol), 4-nitrobenzaldehyde (1.2 mmol) and [BSO3HmIm]-
HSO4 (0.15 mmol) in a specified solvent at the temperature listed in
Table 2 for 30 min; b isolated yields.
entry 5), which was therefore chosen as the optimized
molar ratio for the three-component reaction.
With the optimized reaction conditions in hand, the
affect the yield and rate of a reaction, it was neces- scope and limitations of the one-pot three-component
sary to confirm the optimum solvent volume. Thus, we reaction for the synthesis of phthalazinetriones cat-
screened the volume of PEG 600 from 0.5 to 3.0 mL alyzed by [BSO3HmIm]HSO4 in PEG 600 were
for 1 : 1 : 1.2 mmol of reactants (Table 2, entries 3–6), explored using phthalhydrazide, dimedone or
and the best yield of 81% was obtained in 1.0 mL of cyclohexane-1,3-dione and a variety of aldehydes.
PEG 600 (Table 2, entry 3). A relatively low yield of The results are summarized in Table 4. In general,
79% was received in 0.5 mL of solvent probably due to aromatic aldehydes bearing electron-withdrawing
the low solubility of phthalhydrazide and product (Ta- or electron-donating functional groups at different
ble 2, entry 4). However, the reaction in 2.0 or 3.0 mL positions reacted with the other two components in
of solvent was too dilute to proceed effectively, and the presence of catalyst to generate the correspond-
only gave the product in low yields of 62 and 45%, re- ing products in good to excellent yields. The nature
spectively (Table 2, entries 5 and 6). Hence, we chose and electronic properties of the aldehydes did affect
1.0 mL of PEG 600 as the optimized solvent volume. the reaction yields. Aromatic aldehydes containing
Then, we further investigated the effects of tempera- electron-withdrawing groups gave superior yields.
ture on the reaction. When the reaction was performed For instance, when reacting with phthalhydrazide and
at 100 ◦C, it provided the product in a yield of 70% af- dimedone, 4-nitrobenzaldehyde gave an excellent
ter 30 min (Table 2, entry 7). Raising the temperature yield of 95% after 30 min (Table 4, entry 1), however
to 120 ◦C led to a good yield of 81% (Table 2, entry 4-methoxybenzaldehyde only provided the product in
3), but further increase of the temperature to 160 ◦C 70% yield after 60 min, and prolonging the reaction
hardly improved the yield (Table 2, entries 8 and 9). time to 120 min did not give a better yield (Table 4,
So we chose 120 ◦C as the optimum temperature for entry 9). The procedure was also applicable to aliphatic
the three-component reaction.
aldehydes, which gave satisfactory yields although
To further optimize the reaction conditions for the longer reaction times were required in comparison with
three-component reaction, the effects of molar ra- aromatic aldehydes (Table 4, entries 10 and 11). In ad-
tio of phthalhydrazide (1), dimedone (2a) and 4- dition, the three-component reactions using dimedone
nitrobenzaldehyde (3) on the yield of phthalazinetrione (Table 4, entries 1–9) generally gave better yields than
4a1 were studied, and the results are listed in Table 3. cyclohexane-1,3-dione (Table 4, entries 12–19).
In consideration of the potential oxidation of aldehy-
Finally, we investigated the reusability of the cata-
des, the amount of 4-nitrobenzaldehyde (3) was used lyst/solvent system using the model reaction. That both
in 0.2 molar excess over 2a. It was obvious that the the ionic liquid and PEG 600 have little vapor pressure
yields could be improved by increasing the molar ra- and high boiling points made it possible to recycle and
tio of reactants. The best yield of 95% was obtained reuse the catalyst/solvent system by distillation. Af-
with the molar ratio of 1 : 2a : 3 = 1 : 1.4 : 1.6 (Table 3, ter the completion of the reaction, water was added to
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

720
S. Song et al. · Synthesis of Phthalazinetrione Derivatives
Table 4. [BSO3HmIm]HSO4-
catalyzed synthesis of phtha-
lazinetrione derivativesa.
Entry R2
R1 Product
Time
(min)
Yield
(%)b
M. p. (◦C)
found/reported [Ref.]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4-NO2C6H4
3-NO2C6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
2,3-Cl2C6H3
C6H5
4-CH3C6H4
CH3CH2
CH3CH2CH2 Me
4-NO2C6H4
3-NO2C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4a1
4a2
4a3
4a4
4a5
4a6
4a7
4a8
4a9
4a10
4a11
4b1
4b2
4b3
4b4
4b5
4b6
4b7
4b8
30
40
40
30
40
30
40
40
95
95
87
93
92
96
94
82
223–225/223–225 [13]
269–271/270–272 [13]
219–222/217–219 [13]
261–262/262–264 [13]
264–266/264–266 [13]
263–266/265–267 [13]
252–254/251–253 [21]
204–206/204–206 [13]
225–228/227–229 [14]
144–146/145–147 [21]
135–138/136–138 [21]
251–253/252–254 [20]
228–230/228–230 [14]
257–260/258–260 [14]
270–272/272–273 [19]
278–281/280–281 [19]
275–277/274–275 [19]
223–225/222–224 [14]
245–248/244–246 [14]
60 (120)c
120
120
30
70 (71)c
73
70
94
84
86
86
88
83
80
H
H
H
H
H
H
H
H
30
40
30
30
30
40
40
4-CH3C6H4
82
a
Experimental conditions: phthalhydrazide (1.0 mmol), dimedone or cyclohexane-1,3-dione
(1.4 mmol), aldehyde (1.6 mmol), [BSO3HmIm]HSO4 (0.15 mmol) in PEG 600 (1.0 mL) at
120 ◦C; b isolated yields; c when the reaction time was 120 min, the yield was 71%.
Table 5. Reuse of the catalyst/solvent system.
the cooled reaction mixture to dissolve the catalyst and
solvent, and the residue (product and some unreacted
reactants) precipitated during the process and could be
separated from the solution by filtration. The residue
was then washed with ethanol to get NMR-pure prod-
ucts, and unreacted reactants could be washed into the
filtrate. The filtrate was then distilled to remove wa-
ter and ethanol, and the [BSO3HmIm]HSO4/PEG 600
system containing some unreacted reactants was eas-
ily recovered and could be reused for the next cycle
by loading new reactants without adding any new cat-
alyst and solvent. The molar ratio of reactants 1 : 2 :
3 = 1.0 : 1.4 : 1.6 was used for the first cycle, but
1 : 2 : 3 = 1 : 1 : 1 was used for the next cycles because
Cycle
Time
(min)
Yield
(%)a
1b
2c
3c
4c
5c
30
30
30
30
30
95
94
94
92
87
a
b
Isolated yields;
experimental conditions: phthalhydrazide
(1.0 mmol), dimedone (1.4 mmol), 4-nitrobenzaldehyde (1.6 mmol),
and [BSO3HmIm]HSO4 (0.15 mmol) in PEG 600 (1.0 mL) at
c
120 ◦C;
experimental conditions: phthalhydrazide (1.0 mmol),
dimedone (1.0 mmol) and 4-nitrobenzaldehyde (1.0 mmol) in the
catalyst/solvent system recovered from the previous cycle at 120 ◦C.
there were already excess 2 and 3 (or Knoevenagel in- cles 1–4). The fifth cycle still provided a good yield of
termediates generated by them) left in the recovered 87% (Table 5, cycle 5).
system. The model reaction was performed five times
using the same catalyst/solvent system (Table 5). No Conclusion
obvious decrease in the isolated yield was observed for
the first four cycles, and an excellent yield of 92% was
In summary, we have developed a simple and ef-
obtained at the fourth cycle after 30 min (Table 5, cy- ficient green method to synthesize phthalazinetrione
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

S. Song et al. · Synthesis of Phthalazinetrione Derivatives
721
derivatives through a one-pot three-component reac- the specified time. The reaction was monitored by TLC. Af-
ter the reaction was complete, the reaction mixture was al-
lowed to cool to r. t. Then saturated brine (10 mL) was added
to the cooled reaction mixture which was stirred for 5 min.
The mixture was extracted twice with dichloromethane (2×
10 mL), and the solvent was removed under reduced pressure
to give the crude product which was purified by flash chro-
matography using petroleum ether-ethyl acetate (3 : 1, v/v)
as eluent to afford the pure product.
tion using phthalhydrazide, dimedone or cyclohexane-
1,3-dione and a variety of aromatic or aliphatic alde-
hydes. [BSO3HmIm]HSO4 was employed as an inex-
pensive, non-toxic, non-metallic, readily available, and
environmentally benign catalyst. The chosen solvent
of this reaction was PEG 600, which is non-toxic, in-
expensive, non-volatile, thermally stable, biologically
acceptable, and eco-friendly. In most cases, NMR-pure
products could be readily obtained in good to excellent
yields just through filtration and washing with ethanol.
The catalyst/solvent system can be easily recovered
by distillation. The attractive features of this proce-
dure are the efficiency, clean reaction profiles, inexpen-
sive starting materials, and an environmentally friendly
reusable catalyst/solvent system.
Procedure for the recovery of the catalyst/solvent system
(4a1)
A
mixture of phthalhydrazide (1.0 mmol), dime-
done (1.4 mmol), 4-nitrobenzaldehyde (1.6 mmol), and
[BSO3HmIm]HSO4 (0.15 mmol) in PEG 600 (1.0 mL) was
stirred at 120 ◦C for 30 min. After the reaction was complete,
the reaction mixture was allowed to cool to r. t. Then water
(5 mL) was added and the mixture stirred for 5 min. The
residue precipitated during the process was separated by
filtration and was washed with ethanol to give product 4a1.
The filtrate was then distilled to remove water and ethanol
which gave the residue containing [BSO3HmIm]HSO4 and
Experimental Section
General
All solvents and chemicals were obtained commercially PEG 600 as the recovered catalyst/solvent system. This
1
and were used as received. H and 13C NMR spectra were system was then used for the second cycle by loading new
recorded at a 300 and 75 MHz spectrometer. Chemical reactants (molar ratio was 1 : 1 : 1) without adding any new
shifts (δ) are expressed in ppm with TMS as internal stan- [BSO3HmIm]HSO4 and PEG 600.
dard, and coupling constants (J) are reported in Hz. Rou-
tine monitoring of reactions was performed by TLC using
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a1)
precoated Haiyang GF254 silica gel TLC plates. Column
chromatography separations were done by using silica gel
(200 – 300 mesh) at increased pressure. Melting points were
determined on an X-4 digital display micro melting point ap-
paratus and are uncorrected.
3,3-Dimethyl-13-(4-nitrophenyl)-3,4-dihydro-1H-
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.37–
8.19 (4H, m, Ph), 7.89, 7.62–7.59 (4H, m, Ph), 6.51
(1H, s, CHN), 3.44–3.22 (2H, AB system, J = 18.99 Hz,
CHaHbCO), 2.34 (2H, s, CH2C), 1.22, 1.19 (6H, s, 2-Me).
–
13C NMR (75 MHz, CDCl3): δ = 191.98, 155.87, 154.50,
General procedure for the preparation of 4 (4a1–4a9,
4b1–4b8)
151.66, 147.80, 143.43, 134.73, 133.89, 128.89, 128.66,
128.54, 128.15, 128.03, 127.66, 123.94, 123.80, 117.20,
64.09, 50.74, 37.96, 34.65, 28.61, 28.29.
A mixture of phthalhydrazide (1.0 mmol), dimedone
or cyclohexane-1,3-dione (1.4 mmol), aldehyde (1.6 mmol), 3,3-Dimethyl-13-(3-nitrophenyl)-3,4-dihydro-1H-
and [BSO3HmIm]HSO4 (0.15 mmol) in PEG 600 (1.0 mL) indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a2)
was stirred at 120 ◦C for the specified time. The reaction was
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.39–
monitored by TLC. After the reaction was complete, the re-
8.18 (4H, m, Ph), 7.89 (3H, m, Ph), 7.59–7.53 (1H, m, Ph),
action mixture was allowed to cool to r. t. Then water (5 mL)
6.52 (1H, s, CHN), 3.47–3.24 (2H, AB system, J = 19.22 Hz,
was added to the cooled reaction mixture, and the mixture
CHaHbCO), 2.35 (2H, s, CH2C), 1.22 (6H, s, 2Me).
was stirred for 5 min. The residue precipitated during the pro-
cess was separated from the solution by filtration, and the
13-(4-Fluorophenyl)-3,3-dimethyl-3,4-dihydro-1H-
filter cake was washed with ethanol to yield NMR-pure 4.
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a3)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.34–
General procedure for the preparation of 4a10 and 4a11
8.27 (2H, m, Ph), 7.85 (2H, m, Ph), 7.40 (2H, m, Ph), 7.02
A mixture of phthalhydrazide (1.0 mmol), dimedone (2H, m, Ph), 6.43 (1H, s, CHN), 3.38–3.27 (2H, AB sys-
(1.4 mmol), aldehyde (1.6 mmol), and [BSO3HmIm]HSO4 tem), 2.34 (2H, s, CH2C), 1.21 (6H, s, 2-Me). – 13C NMR
(0.15 mmol) in PEG 600 (1.0 mL) was stirred at 120 ◦C for (75 MHz, CDCl3): δ = 192.10, 155.96, 154.33, 150.97,
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

722
S. Song et al. · Synthesis of Phthalazinetrione Derivatives
134.53, 133.57, 132.21, 132.17, 128.99, 128.93, 128.88, 3,3-Dimethyl-13-phenyl-3,4-dihydro-1H-indazolo[1,2-
127.97, 127.65, 118.15, 115.80, 115.51, 64.23, 50.86, 37.98, b]phthalazine-1,6,11(2H,13H)-trione (4a8)
34.60, 28.62, 28.40.
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
8.27 (2H, m, Ph), 7.85 (2H, m, Ph), 7.40–7.27 (5H, m, Ph),
6.45 (1H, s, CHN), 3.45–3.21 (2H, AB system, J = 19.06 Hz,
13-(4-Chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a4)
CHaHbCO), 2.33 (2H, s, CH2C), 1.21 (6H, s, 2-Me). –
13C NMR (75 MHz, CDCl3): δ = 192.02, 155.98, 154.23,
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.34–
8.25 (2H, m, Ph), 7.85 (2H, m, Ph), 7.37–7.28 (4H, m, Ph),
6.40 (1H, s, CHN), 3.43–3.20 (2H, AB system, J = 19.10 Hz,
CHaHbCO), 2.33 (2H, s, CH2C), 1.20 (6H, s, 2-Me). –
13C NMR (75 MHz, CDCl3): δ = 192.06, 155.96, 154.34,
150.95, 134.52, 133.56, 132.22, 132.17, 128.99, 128.95,
128.91, 128.87, 127.97, 127.65, 118.16, 115.80, 115.50,
64.23, 50.88, 37.99, 34.59, 28.62, 28.40.
150.79, 136.36, 134.43, 133.45, 129.05, 128.94, 128.64,
128.61, 127.90, 127.67, 127.07, 118.55, 64.91, 50.91, 38.00,
34.58, 28.63, 28.40.
3,3-Dimethyl-13-p-tolyl-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4a9)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
8.27 (2H, m, Ph), 7.84 (2H, m, Ph), 7.31–7.29 (2H, m,
Ph), 7.15–7.12 (2H, m, Ph), 6.42 (1H, s, CHN), 3.45–3.20
(2H, AB system, J = 19.02 Hz, CHaHbCO), 2.33 (2H, s,
CH2C), 2.29 (3H, s, Me), 1.21 (6H, s, 2-Me). – 13C NMR
(75 MHz, CDCl3): δ = 192.08, 155.99, 154.19, 150.68,
138.42, 134.38, 133.39, 129.39, 129.12, 128.94, 127.86,
127.66, 127.01, 118.64, 64.79, 50.92, 38.01, 34.58, 28.64,
28.40, 21.15.
13-(2-Chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a5)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.37–
8.24 (2H, m, Ph), 7.85–7.84 (2H, m, Ph), 7.49–7.47 (1H, m,
Ph), 7.33–7.29 (2H, m, Ph), 7.23–7.21 (1H, m, Ph), 6.68
(1H, s, CHN), 3.44–3.20 (2H, AB system, J = 19.09 Hz,
CHaHbCO), 2.32 (2H, s, CH2C) 1.21 (6H, s, 2-Me). –
13C NMR (75 MHz, CDCl3): δ = 192.05, 156.11, 154.17,
151.80, 134.47, 133.53, 132.96, 132.51, 130.47, 129.82,
128.98, 128.65, 127.97, 127.61, 127.16, 125.65, 116.60,
64.01, 50.80, 37.96, 34.54, 28.74, 28.34.
13-Ethyl-3,3-dimethyl-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4a10)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.38–
8.33 (2H, m, Ph), 7.93–7.84 (2H, m, Ph), 5.72 (1H, s, CHN),
3.38–3.11 (2H, AB system, J = 19.15 Hz, CHaHbCO), 2.59–
2.50 (1H, m, CH), 2.39 (2H, s, CH2C), 2.19–2.10 (1H, m,
CH), 1.23–1.20 (6H, s, 2-Me), 0.77–0.72 (3H, t, Me). –
13C NMR (75 MHz, CDCl3): δ = 193.01, 156.02, 154.66,
151.84, 134.41, 133.37, 128.94, 128.83, 127.83, 127.45,
116.64, 63.43, 50.93, 38.02, 34.43, 28.79, 28.32, 22.05, 7.21.
13-(4-Bromophenyl)-3,3-dimethyl-3,4-dihydro-1H-
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a6)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
8.27, 7.86 (4H, m, Ph), 7.47–7.28 (4H, m, Ph), 6.40
(1H, s, CHN), 3.43–3.20 (2H, AB system, J = 19.09 Hz,
CHaHbCO), 2.33 (2H, s, CH2C), 1.20 (6H, s, 2-Me). –
13C NMR (75 MHz, CDCl3): δ = 192.04, 155.93, 154.33,
151.09, 135.44, 134.57, 133.63, 131.84, 128.88, 128.84,
128.77, 128.00, 127.66, 122.69, 117.92, 64.33, 50.83, 37.97,
34.61, 28.64, 28.36.
13-Butyl-3,3-dimethyl-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4a11)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.38–
8.32 (2H, m, Ph), 7.92–7.83 (2H, m, Ph), 5.70 (1H, s, CHN),
3.36–3.10 (2H, AB system, J = 19.25 Hz, CHaHbCO), 2.44–
2.38 (3H, m), 2.12–2.03 (1H, m), 1.22–1.10 (8H, m), 0.89–
0.84 (3H, t, Me). – 13C NMR (75 MHz, CDCl3): δ = 193.00,
156.02, 154.66, 151.56, 134.39, 133.34, 128.95, 128.82,
127.80, 127.45, 117.22, 62.77, 50.93, 37.98, 34.40, 31.46,
28.69, 28.39, 16.69, 13.67.
13-(2,3-Dichlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-
indazolo[1,2-b]phthalazine-1,6,11(2H,13H)-trione (4a7)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.37–
13-(4-Nitrophenyl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4b1)
7.26 (7H, m, Ph), 6.70 (1H, s, CHN), 3.43–3.21 (2H, AB
system, J = 17.98 Hz, CHaHbCO), 2.33 (2H, s, CH2C), 1.21
(6H, s, 2-Me). – 13C NMR (75 MHz, CDCl3): δ = 192.05,
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.39–
156.07, 154.24, 152.13, 135.30, 134.58, 134.10, 133.67, 8.19 (4H, m, Ph), 7.90–7.89 (2H, m, Ph), 7.63–7.60 (2H,
130.85, 130.68, 130.18, 128.94, 128.49, 128.05, 127.62, m, Ph), 6.51(1H, s, CHN), 3.60–3.32 (2H, AB system, J =
127.50, 116.11, 64.43, 50.77, 37.95, 34.56, 28.70, 28.40.
19.23 Hz, CHaHbCO), 2.48–2.36 (2H, m), 2.33–2.27 (2H,
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

S. Song et al. · Synthesis of Phthalazinetrione Derivatives
723
m). – 13C NMR (75 MHz, CDCl3): δ = 192.28, 155.91, (2H, AB system, J = 19.29 Hz, CHaHbCO), 2.46–2.44 (2H,
154.48, 153.00, 147.85, 143.28, 134.77, 134.76, 133.88, m), 2.26–2.24 (2H, m). – 13C NMR (75 MHz, CDCl3):
128.87, 128.59, 128.56, 128.19, 128.06, 127.74, 123.94, δ = 192.40, 155.94, 154.29, 152.51, 135.35, 135.15, 134.58,
118.34, 64.15, 36.72, 24.47, 22.16.
133.63, 131.80, 128.85, 128.82, 128.01, 127.67, 122.70,
119.02, 64.35, 36.81, 24.44, 22.22.
13-(3-Nitrophenyl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4b2)
13-(2,4-Dichlorophenyl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4b6)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.39–
1
8.25 (2H, m, Ph), 8.17(2H, m, Ph), 7.89 (3H, m, Ph), 7.56
(1H, Ph), 6.52 (1H, s, CHN), 3.63–3.33 (2H, AB system,
J = 18.76 Hz, CHaHbCO), 2.48 (2H, m), 2.28 (2H, m). –
13C NMR (75 MHz, CDCl3): δ = 192.42, 155.91, 154.57,
153.17, 138.54, 135.78, 134.70, 134.18, 133.86, 129.54,
128.90, 128.58, 128.19, 127.66, 123.60, 121.55, 118.17,
64.17, 36.71, 24.46, 22.16.
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.37–
8.25 (2H, m, Ph), 7.87 (2H, m, Ph), 7.42–7.27 (3H, m, Ph),
6.62 (1H, s, CHN), 3.54–3.25 (2H, AB system,), 2.46–2.26
(4H, m). – 13C NMR (75 MHz, CDCl3): δ = 192.34, 156.05,
154.25, 153.43, 135.06, 134.57, 133.65, 133.33, 131.63,
130.28, 128.92, 128.54, 128.06, 127.62, 127.54, 117.18,
111.41, 63.62, 36.74, 24.42, 22.20.
13-(4-Fluorophenyl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4b3)
13-Phenyl-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4b7)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
8.27 (2H, m, Ph), 7.85 (2H, m, Ph), 7.41–7.39 (2H, m,
Ph), 7.04–6.99 (2H, m, Ph), 6.44 (1H, s, CHN), 3.60–3.29,
2H, AB system, J = 19.24 Hz, CHaHbCO), 2.47–2.45 (2H,
m), 2.28–2.24 (2H, m). – 13C NMR (75 MHz, CDCl3):
δ = 192.43, 155.98, 154.29, 152.37, 134.53, 133.56, 132.13,
132.09, 129.04, 128.95, 128.92, 128.87, 127.98, 127.66,
119.25, 115.75, 115.46, 64.24, 36.84, 24.43, 22.23.
8.25 (2H, m, Ph), 7.84 (2H, m, Ph), 7.43–7.31(5H, m, Ph),
6.45 (1H, s, CHN), 3.60–3.29 (2H, AB system, J = 19.27 Hz,
CHaHbCO), 2.47–2.45 (2H, m), 2.27–2.23 (2H, m). –
13C NMR (75 MHz, CDCl3): δ = 192.47, 155.97, 154.18,
152.27, 136.29, 134.47, 133.48, 129.00, 128.88, 128.60,
127.90, 127.65, 127.11, 119.60, 111.41, 64.90, 36.85, 24.43,
22.22.
13-(4-Chlorophenyl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4b4)
13-p-Tolyl-3,4-dihydro-1H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (4b8)
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.36–
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
8.27 (2H, m, Ph), 7.86 (2H, m, Ph), 7.36–7.31(4H, m, Ph),
6.42 (1H, s, CHN), 3.59–3.29 (2H, AB system, J = 18.30 Hz,
CHaHbCO), 2.47 (2H, m), 2.25 (2H, m). – 13C NMR
(75 MHz, CDCl3): δ = 192.39, 155.95, 154.29, 152.47,
134.82, 134.57, 134.51, 134.45, 133.61, 128.86, 128.52,
128.00, 127.67, 119.08, 64.29, 36.81, 24.43, 22.21.
8.26 (2H, m, Ph), 7.84 (2H, m, Ph), 7.32–7.26 (2H, m, Ph),
7.15–7.12 (2H, m, Ph), 6.42 (1H, s, CHN), 3.60–3.29 (2H,
AB system, J = 19.09 Hz, CHaHbCO), 2.46 (2H, m), 2.29
(3H, s, Me), 2.25 (2H, m). – 13C NMR (75 MHz, CDCl3):
δ = 192.50, 155.91, 154.08, 152.18, 138.37, 134.41, 133.42,
133.34, 129.33, 129.03, 128.86, 127.82, 127.59, 127.07,
119.64, 64.77, 36.87, 24.43, 22.24, 21.19.
13-(4-Bromophenyl)-3,4-dihydro-1H-indazolo[1,2-
b]phthalazine-1,6,11(2H,13H)-trione (4b5)
Acknowledgement
1
Yellow solid. – H NMR (300 MHz, CDCl3): δ = 8.35–
8.25 (2H, m, Ph), 7.85 (2H, m, Ph), 7.46–7.44 (2H, m,
The Natural Science Foundation Project of CQ CSTC
Ph), 7.32–7.29 (2H, m, Ph), 6.39 (1H, s, CHN), 3.58–3.28 (2009BA5051) is gratefully acknowledged.
[1] D. J. Ramon, M. Yus, Angew. Chem. Int. Ed. 2005, 44,
1602 – 1634.
[2] H. J. Wang, L. P. Mo, Z. H. Zhang, ACS Comb. Sci.
[4] S. Grasso, G. De Sarro, N. Micale, M. Zappala`, G. Puia,
M. Baraldi, C. De Micheli, J. Med. Chem. 2000, 43,
2851 – 2859.
2011, 13, 181 – 185.
[3] R. P. Jain, J. C. Vederas, Bioorg. Med. Chem. Lett.
2004, 14, 3655 – 3658.
[5] Y. Nomoto, H. Obase, H. Takai, M. Teranishi, J. Naka-
mura, K. Kubo, Chem. Pharm. Bull. 1990, 38,
2179 – 2183.
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM

724
S. Song et al. · Synthesis of Phthalazinetrione Derivatives
[6] N. Watanabe, Y. Kabasawa, Y. Takase, M. Matsukura, [17] H. R. Shaterian, M. Ghashang, M. Feyzi, Appl. Catal.
K. Miyazaki, H. Ishihara, K. Kodama, H. Adachi, J.
Med. Chem. 1998, 41, 3367 – 3372.
A 2008, 345, 128 – 133.
[18] H. R. Shaterian, A. Hosseinian, M. Ghashang, Arkivoc
[7] J. S. Kim, H.-K. Rhee, H. J. Park, S. K. Lee, C.-O. Lee,
2009, ii, 59 – 67.
H-Y. Park Choo, Bioorg. Med. Chem. 2008, 16, [19] L. Nagarapu, R. Bantu, H. B. Mereyala, J. Heterocycl.
4545 – 4550. Chem. 2009, 46, 728 – 731.
[8] S. S. El-Sakka, A. H. Soliman, A. M. Imam, Afinidad [20] G. Sabitha, C. Srinivas, A. Raghavendar, J. S. Yadav,
2009, 66, TN540 – 167. Helv. Chim. Acta 2010, 93, 1375 – 1380.
[9] C.-K. Ryu, R.-E. Park, M.-Y. Ma, J.-H. Nho, Bioorg. [21] R. Ghorbani-Vaghei, R. Karimi-Nami, Z. Toghraei-
Med. Chem. Lett. 2007, 17, 2577 – 2580.
[10] J. Li, Y.-F. Zhao, X.-Y. Yuan, J.-X. Xu, P. Gong,
Molecules 2006, 11, 574 – 582.
Semiromi, M. Amiri, M. Ghavidel, Tetrahedron 2011,
67, 1930 – 1937.
[22] E. Mosaddegh, A. Hassankhani, Tetrahedron. Lett.
[11] J. Sinkkonen, V. Ovcharenko, K. N. Zelenin, I. P.
2011, 52, 488 – 490.
Bezhan, B. A. Chakchir, F. Al-Assar, K. Pihlaja, Eur. [23] N. Isambert, M. del Mar Sanchez Duque, J.-C. Plaque-
J. Org. Chem. 2002, 13, 2046 – 2053.
vent, Y. Ge´nisson, J. Rodriguez, T. Constantieux,
[12] H. Wu, X.-M. Chen, Y. Wan, H.-Q. Xin, H.-H. Xu,
Chem. Soc. Rev. 2011, 40, 1347 – 1357.
R. Ma, C.-H. Yue, L.-L. Pang, Lett. Org. Chem. 2009, [24] W. J. Wang, L. L. Shao, W. P. Cheng, J. G. Yang, M. Y.
6, 219 – 223. He, Catal. Commun. 2008, 9, 337 – 341.
[13] M. Sayyafi, M. Seyyedhamze, H. R. Khavasi, A. Baz- [25] A. Davoodnia, M. M. Heravi, L. Rezaei-Daghigh,
gir, Tetrahedron 2008, 64, 2375 – 2378.
[14] J. M. Khurana, D. Magoo, Tetrahedron Lett. 2009, 50,
7300 – 7303.
N. Tavakoli-Hoseini, Monatsh. Chem. 2009, 140,
1499 – 1502.
[26] N. Karimi, H. Oskooi, M. Heravi, M. Saeedi, M. Za-
keri, N. Tavakoli, Chin. J. Chem. 2011, 29, 321 – 323.
[27] T. Deligeorgiev, N. Gadjev, A. Vasilev, S. Kaloyanova,
J. J. Vaquero, A. J. Builla, Mini-Rev. Org. Chem. 2010,
7, 44 – 53.
[15] H.-J. Wang, X.-N. Zhang, Z.-H. Zhang, Monatsh.
Chem. 2011, 141, 425 – 430.
[16] R. Fazaeli, H. Aliyan, N. Fazaeli, Open. Catal. J. 2010,
3, 14 – 18.
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 11/19/15 8:38 AM