Protic ionic liquid [TMG][Ac] as an efficient, homogeneous and recyclable catalyst for one-pot four-component synthesis of 2H-indazolo[2,1-b]phthalazine- triones and dihydro-1H-pyrano[2,3-c]pyrazol-6-ones

Article abstract of DOI:10.1039/c4ra03514c

The mildly basic ionic liquid N,N,N,N-tetramethylguanidinium acetate [TMG][Ac] was found to be a very effective basic catalyst for the one-pot, four-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones by condensation of phthalic anhydride, hydrazinium hydroxide, aromatic aldehydes, and dimedone in high yields at 80 °C. [TMG][Ac] catalyzed simple and efficient one-pot four-component reaction of Meldrums acid, ethyl acetoacetate, hydrazine hydrate, and aromatic aldehydes to give dihydro-1H-pyrano[2,3-c] pyrazol-6-ones is reported. The ionic liquid could be recycled several times without loss of efficiency with regards to the reaction times and yields.

Full text of DOI:10.1039/c4ra03514c

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DOI: 10.1039/C4RA03514C
Protic ionic liquid [TMG][Ac] as an efficient, homogeneous and recyclable
catalyst for one-pot four-component synthesis of 2H-indazolo[2,1-
b]phthalazine-triones and dihydro-1H-pyrano[2,3-c]pyrazol-6-ones
Hojat Veisi,a,* Abass Aminimanesh,a,* Narges Khankhani,a Ramin GhorbaniꢀVagheib
aDepartment of Chemistry, Payame Noor University (PNU), 19395-4697 Tehran, Iran
bDepartment of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
E-mails: hojatveisi@yahoo.com
Abstract: The mildly basic ionic liquid N,N,N,Nꢀtetramethylguanidinium acetate [TMG][Ac]
was found to be a very effective basic catalyst for the oneꢀpot, fourꢀcomponent synthesis of
2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones by condensation of phthalic anhydride, hydrazinium
º
hydroxide, aromatic aldehydes, and dimedone in high yields at 80 C. [TMG][Ac] catalyzed
simple and efficient oneꢀpot fourꢀcomponent reaction of Meldrums acid, ethyl acetoacetate,
hydrazine hydrate, and aromatic aldehydes to give dihydroꢀ1Hꢀpyrano[2,3ꢀc]pyrazolꢀ6ꢀones
is reported. The ionic liquid could be recycled several times without loss of efficiency with
regards to the reaction times and yields.
Keywords: Multiꢀcomponent synthesis, Pyranopyrazoleꢀ6ꢀones, Indazolophthalazineꢀtriones,
Ionic liquid.
Multiꢀcomponent reactions (MCRs) have proven to be a valuable asset in organic and
medicinal chemistry.1ꢀ7 Such protocols can be used for drug design, and drug discovery
because of their simplicity, efficiency, and high selectivity.8,9 This environmentally friendly
process can reduce the number of steps and synthesis of bioactive and complex molecules
should be facile, fast, and efficient with minimal workup in this methodology.6,10
Currently, ionic liquids (ILs) have attracted great interest in the area of green chemistry due
to their favorable properties such as negligible vapor pressure, wide liquid range, excellent
salvation ability and feasible design ability.11 While considering ionic liquids as catalyst and
their use in industrial processes, one major concern is cost. The cost of ionic liquid would be
directly dependent on the price of the cations and anions that are used for their production.12
The research on new ILs bearing inert low coordinating and nonꢀfluorinated anions represents
a field of intense investigation in the chemistry of ILs.
Azaꢀcontaining heterocyclic compounds are widespread in nature, and their applications to
pharmaceuticals, agrochemicals, and functional materials are becoming more and more
important.13 Among a large variety of Nꢀcontaining heterocyclic compounds, those
containing hydrazine moiety as ’fusion site’ have received considerable attention because of
their pharmacological properties and clinical applications.14 Moreover, fused phthalazines
and pyranopyrazole derivatives were found to possess multiple biological activities, such as
antimicrobial,15 anticonvulsant,16 antifungal,17 anticancer,18 hypolipidemic,19 and antiꢀ
inflammatory activities.20 Nevertheless the development of new synthetic methods for the
efficient preparation of heterocycles containing phthalazine and pyranopyrazole ring
fragment is an interesting challenge. Recently, several elegant multicomponent strategies for
the synthesis of 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones and pyranopyrazoleꢀ6ꢀones by multi
component reactions utilizing catalysts have been reported.21ꢀ34
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Due to our interest in the synthesis of heterocyclic compounds,35 herein we report a rapid and
efficient oneꢀpot fourꢀcomponent synthesis of some 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones
and
dihydroꢀ1Hꢀpyrano[2,3ꢀc]pyrazolꢀ6ꢀones
in
the
presence
of
N,N,N,Nꢀ
tetramethylguanidinium acetate [TMG][Ac] as mild basic ionic liquid catalyst (Scheme 1).
ArCHO
O
O
ArCHO
O
O
O
O
O
O
O
O
OEt
O
NH2NH2.H2O
NH2NH2.H2O
Ar
O
O
O
Ar
O
N
N
N
CH3CO2
N
H
H
O
H
N
N
N
[TMG][Ac]
80 oC
Scheme 1.
First, the four component reaction of hydrazine monohydrate, phthalic anhydride, dimedon,
and 4ꢀchlorobenzaldehyde in the presence of [TMG][Ac] was chosen as model. In order to
establish the optimum conditions for this reaction, initially the influence of the reaction
temperature, the amounts of catalyst and the reaction time were tested and optimized. For this
purpose, a reaction between phthalic anhydride (1 mmol), hydrazinium hydroxide (1.1
mmol), dimedone (1 mmol) and 4ꢀchlorobenzaldehyde (1 mmol) were examined (Table 1).
To evaluate the effect of reaction temperature, system was carried out at different
temperatures. At room temperature, the reaction rate was found to be very slow (Table 1,
º
entries 1 and 15), and it was increased in higher temperatures. At 80 C under solventꢀfree
conditions, the reaction rate was found to be a maximum (Table 1, Entry 9), and further
increases in temperature did not show any enhancement (Table 1, Entry 10). It should be
noted that the optimal catalyst loading in the synthesis of 3,3ꢀdimethylꢀ13ꢀ(4ꢀchlorophenyl)ꢀ
3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀb]phthalazineꢀ1,6,11(2H,13H)ꢀtrione product peaked at a
concentration of 10 mol%. When the amount of catalyst was lower, the yield of the product
decreased (Table 1, Entry 13), whereas raising the catalyst concentration did not lead to a
pronounced increase to the product yield (Table 1, Entry 12). In the absence of catalyst, no
product was observed, even after prolonged reaction time (Table 1, Entry 16). During our
optimization studies, various solvents were examined and solventꢀfree conditions was found
to be the most optimum in terms of reaction rate, and isolated yield, therefore optimized
conditions is shown in Table 1.
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Table 1
Effect of the solvent, temperature, reaction time, amount of catalyst on the synthesis of 2Hꢀ
indazolo[2,1ꢀb]phthalazineꢀtrione.a
Cl
O
O
O
CHO
Cl
O
O
O
N
N
[TMG][Ac]
O
O
NH2NH2.H2O
Entry Solvent
Catalyst (mol %) Temp.
Time (min) Yield (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOHꢀH2O
DMF
CH2Cl2
CH3CN
H2O
toluene
solventꢀfree
solventꢀfree
solventꢀfree
solventꢀfree
solventꢀfree
solventꢀfree
solventꢀfree
solventꢀfree
10
10
10
10
10
10
10
10
10
10
10
20
5
25 ºC
80 ºC
100 ºC
120 ºC
70 ºC
90 ºC
100 ºC
110 ºC
80 ºC
100 ºC
60 ºC
80 ºC
80 ºC
80 ºC
25 ºC
80 ºC
120
120
120
120
120
90
120
120
15
15
15
15
15
25
65
60
60
40
55
60
55
96
90
70
96
70
75
trace
trace
9
10
11
12
13
14
15
16
5
10
0
120
120
120
aphthalic anhydride (1 mmol), hydrazinium hydroxide (1.1 mmol), dimedone (1 mmol) and 4ꢀ
chlorobenzaldehyde (1 mmol).
With a reliable set of conditions in hand (Table 1, entry 9), the scope and generality of the
developed protocol with respect to various aldehydes was investigated in the presence of 10
mol% of ionic liquid at 80 °C under solventꢀfree conditions. The results are summarized in
Table 2.
As shown in Table 2, a series of aliphatic and aromatic aldehydes containing either electronꢀ
withdrawing or electronꢀdonating substituents successfully reacted and afforded good to high
yields of products with high purity, at 80 ºC under solventꢀfree conditions. The nature and
electronic properties of the aldehyde substrates affect the conversion rate and yield. Aromatic
aldehydes (Table 2, entries 1ꢀ9) react faster and in higher yield than the aliphatic aldehydes
(Table 2, entries 10ꢀ12).
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Table 2
[TMG][Ac]ꢀCatalyzed synthesis of 3,3ꢀdimethylꢀ13ꢀarylꢀ3,4ꢀdihydroꢀ1Hꢀindazolo[1,2ꢀ
b]phthalazineꢀ1,6,11(2H,13H)ꢀtrione derivatives via a fourꢀcomponent reaction
Entry Ar/ R
Time (min)
Yield (%)a Mp (ºC)
1
C6H5
15
20
15
15
10
12
10
12
15
30
30
30
92
96
90
96
96
95
98
93
90
65
60
55
202ꢀ20433
226ꢀ22833
217ꢀ21927
263ꢀ26533
218ꢀ22033
224ꢀ22627
269ꢀ27127
280ꢀ28233
250ꢀ25227
146ꢀ14827
136ꢀ13827
80ꢀ8227
2
3
4
5
6
7
8
9
4ꢀMeꢀC6H4
4ꢀMeOꢀC6H4
4ꢀClꢀC6H4
2,4ꢀCl2ꢀC6H3
4ꢀNO2ꢀC6H4
3ꢀNO2ꢀC6H4
4ꢀBrꢀC6H4
2ꢀNaphthyl
Propanal
10
11
12
Butanal
Heptanal
aYield refers to isolated product.
A possible mechanism for the formation of 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones in the
presence of [TMG][Ac] is proposed in Scheme 2. The reaction occurs via initial formation of
the phthalhydrazide 3 by nucleophilic addition of hydrazinium hydroxide 2 to phthalic
anhydride 1 followed by dehydration. The second step involves initial formation of
heterodiene 6 by standard Knoevenagel condensation of dimedone 5 and aldehyde 4.
Subsequent Michaelꢀtype addition of the phthalhydrazide 3-6 followed by cyclization affords
the corresponding product 7 (Scheme 2).
N
N
CH3CO2
N
H
H
O
O
H
O
CH3CO2
H
N
Ar
H
O
6
N
N
NH
O
NH2NH2.H2O
NH
2
1
O
H
Ar
4
3
O
O
H
N
O
H
CH3CO2
O
N
CH3CO2
H
H
N
Ar
O
N
N
H
O
N
N
5
NH
O
[TMG][Ac]
O
H
H
N
CH3CO2
O
O
Ar
N
N
O
N
N
7
Scheme 2.
The ionic liquid, [TMG][Ac], could be recovered from the aqueous extracts of the reaction
mixtures by evaporation of water under reduced pressure. It retains almost all the initial
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activity after recovery, when reused in the next successive cycles. For instance running the
model reaction of phthalic anhydride, hydrazinium hydroxide, dimedone and 4ꢀ
chlorobenzaldehyde in 10 mol% of fresh, first recycled, and second recycled [TMG][Ac] at
80 ºC under solventꢀfree conditions has given, respectively, 96%, 94%, and 90% yield of the
product.
In continuation of work, we also report a rapid and efficient oneꢀpot fourꢀcomponent
synthesis of some 3ꢀmethylꢀ4ꢀarylꢀ4,5ꢀdihydroꢀ1Hꢀpyrano[2,3ꢀc]pyrazolꢀ6ꢀones by the
reaction of aromatic aldehydes, Meldrums acid, hydrazine hydrate, and ethyl acetoacetate in
the presence of N,N,N,Nꢀtetramethylguanidinium acetate [TMG][Ac] as green and mild basic
ionic liquid medium (Scheme 1).
To find the best conditions, we carried out the reaction between 3,4,5ꢀ
trimethoxybenzaldehyde, ethyl acetoacetate, Meldrums acid, and hydrazine hydrate in the
presence of 10 mol % of [TMG][Ac] at 80 ºC under solventꢀfree conditions. We found that,
the product was obtained in very high yield (98%) within 0.5 h (Table 3, entry 6). After
optimization of the conditions for the model reaction, a range of different aldehydes were
screened to explore the scope of this protocol. As shown in Table 3, the reaction is
compatible with an array of arylaldehydes bearing either electronꢀwithdrawing or electronꢀ
donating substituents.
Table 3
[TMG][Ac]ꢀCatalyzed synthesis of 3ꢀmethylꢀ4ꢀarylꢀ4,5ꢀdihydroꢀ1Hꢀpyrano[2,3ꢀc]pyrazolꢀ6ꢀ
ones derivatives via a fourꢀcomponent reaction
ArCHO
Ar
O
O
O
O
O
O
O
[TMG][Ac]
N
OEt
N
O
H
NH2NH2.H2O
Entry Ar/ R
Time (h) Yield (%)a Mp (ºC)
1
2
3
4
5
6
7
4ꢀMeOꢀC6H4
4ꢀFꢀC6H4
0.5
1
96
92
90
95
95
98
0
158ꢀ16030
180ꢀ18230
142ꢀ14430
234ꢀ23630
212ꢀ21430
204ꢀ20630
ꢀ
2ꢀClꢀC6H4
2ꢀOHꢀC6H4
3ꢀNO2ꢀC6H4
3,4,5ꢀ(MeO)3ꢀC6H2
Butanal
1
1
1.2
0.5
24
aYield refers to isolated product.
A possible pathway is proposed in Scheme 3. The synthesis is likely initiated by [TMG][Ac],
which upon removing a proton from Meldrum’s acid 11 promotes a Knoevenagel
condensation with the aldehyde 12, resulting in formation of the intermediate 13. This
intermediate subsequently undergoes a Michael type addition with pyrazolone 10 (the
pyrazolone 10 is produced by the reaction between 8 and 9) to produce the adduct 13.
Cyclization of 13 via a translactonization reaction leads to liberation of an acetone molecule
leaving the initial product 14 bearing a carboxyl group at the 3ꢀposition. Spontaneous
decarboxylation of the product 14 affords the corresponding product 15.
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N
N
H
CH3CO2
N
O
O
H
H
O
O
CH3CO2
H
O
O
N
5
Ar
H
9
8
OEt
NH2NH2.H2O
N
N
H
O
Ar
12
NH
N
O
10
H
CH3CO2
O
H
H
N
O
O
N
H
O
O
N
N
N
N
O
H
11
CH3CO2
HO
HN
N
[TMG][Ac]
H
Ar
13
Ar
N
O
O
N
O
O
H
CO2H
Ar
O
15
HN
N
CO2
14
Scheme 3.
We also investigated the recycling of the ionic liquid under solventꢀfree conditions using a
model reaction of hydrazine monohydrate, 3,4,5ꢀtrimethoxybenzaldehyde, ethyl acetoacetate
and Meldrums acid for the preparation of 3ꢀmethylꢀ4ꢀ(3',4',5'ꢀtrimethoxyphenyl)ꢀ4,5ꢀdihydroꢀ
1Hꢀpyrano[2,3ꢀc]pyrazolꢀ6ꢀone in the presence of [TMG][Ac] at 80 ºC. After completion of
the reaction, water was added and the precipitated mixture was filtered off for separation of
crude products. After washing the solid products with water completely, the water containing
ionic liquid (IL is soluble in water) was evaporated under reduced pressure and ionic liquid
was recovered and reused (Fig. 1). The recovered catalysts were reused four runs without any
loss of their activities.
Fig. 1. The recycling of [TMG][Ac] as catalyst under solventꢀfree conditions.
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In summary, we have demonstrated a simple, efficient, and a oneꢀpot fourꢀcomponent
protocol for the synthesis of 2Hꢀindazolo[2,1ꢀb]phthalazineꢀtriones and dihydroꢀ1Hꢀ
pyrano[2,3ꢀc]pyrazolꢀ6ꢀones in the presence of N,N,N,Nꢀtetramethylguanidinium acetate
[TMG][Ac] as mild basic ionic liquid catalyst at 80 ºC. The attractive features of this protocol
are simple procedure, cleaner reaction, use of inexpensive and reusable ionic liquid as
catalyst. Satisfactory yields of products, as well as a simple reactions, isolation, and
purification of the products make it a useful protocol for the synthesis of these classes of
compounds.
Preparation of [TMG][Ac]
Protic ILs were synthesized simply by neutralization of N,N,N,Nꢀtetramethylguanidin with
corresponding acetic acid. In a typical reaction, 0.1 mol N,N,N,Nꢀtetramethylguanidin
dissolved in 10 ml methanol was put into a 100 ml flask, and 0.1 mol acetic acid was slowly
added under stirring. The solution was stirred at room temperature for 24 h to complete the
º
reaction, and then the methanol was removed at 50 C under reduced pressure to give a
colorless viscous liquid.
Typical procedure for the synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives
Hydrazinium hydroxide (1.1 mmol), phthalic anhydride (1 mmol), dimedone (1 mmol),
º
aldehyde (1 mmol) and [TMG][Ac] (10 mol%) was heated at 80 C. The completion of
reaction is monitored on TLC. The 2ꢀHꢀindazolo[2,1ꢀb]phthalazineꢀ1,6,11(13H)ꢀtrione
derivatives were synthesized. After satisfactory completion of the reaction, the mixture was
cooled to room temperature and H2O (10 ml) was added to this mixture and was shaken for a
few minutes to dissolve [TMG][Ac]. The crude product (insoluble in water) was filtered and
recrystallized from hot ethanol for more purification. The desired pure products were
characterized by comparison of their physical data with those of known compounds. In order
to recover the catalyst, H2O was evaporated under reduced pressure, and the resulting ionic
liquid was washed with diꢀethyl ether, and dried. The recovered catalyst was reused 5 times.
Typical procedure for the synthesis of dihydro-1H-pyrano[2,3-c]pyrazol-6-ones derivatives
In a 50 mL round bottom flask, a mixture of hydrazine hydrate (1.2 mmol), ethyl
acetoacetate (1 mmol), and [TMG][Ac] (10 mol %) were taken, the mixture was stirred in an
º
oil bath and heated for 15 min at 80 C; aromatic aldehyde (1 mmol) and Meldrums acid (1
mmol) were then added and heating was continued for the remaining time (Table 4). After
completion of the reaction, the mixture was cooled to room temperature and H2O (10 ml) was
added to this mixture and was shaken for a few minutes to dissolve [TMG][Ac]. The crude
product (insoluble in water) was filtered and recrystallized from hot ethanol 80% for more
purification. In order to recover the catalyst, H2O was evaporated under reduced pressure, and
the resulting ionic liquid was washed with diꢀethyl ether, and dried. The recovered catalyst
was reused next times.
Analytical data for selected products
3,3-Dimethyl-13-(3-nitrophenyl)-3,4-dihydro-2H-indazolo [1,2-b]phthalazine-1,6,11(13H)-
trione (Table 2, entry 7):
1
Yellow powder (98%); mp 269ꢀ271 ºC; IR (KBr): νmax (cmꢀ1) 2975, 1682, 1660, 1625; H
NMR (300 MHz, CDCl3): δ 1.24 (6H, s, 2Me), 2.36 (2H, s, CH2C), 3.24ꢀ3.47 (2H, CH2CO),
6.53 (1H, s, CHN), 7.53ꢀ8.4 (8H, m, Ph); 13C NMR (300 MHz, CDCl3): δ 28.4, 28.7, 34.7,
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38.0, 50.8, 64.1, 117.1, 121.5, 123.7, 127.7, 128.2, 128.6, 128.9, 129.6, 133.9, 134.2, 134.7,
138.4, 148.5, 150.8, 154.3, 155.9, 192.1.
3',4',5'ꢀtrimethoxyphenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrano[2,3ꢀc]pyrazolꢀ6ꢀone (Table 3, entry 6):
Yellow solid (98%); mp 204ꢀ206 ºC: IR (KBr): νmax (cmꢀ1) 3372, 2972, 1735, 1691, 1620,
1
1569, 1498, 1448, 1375, 1235, 1173; H NMR (400 MHz, DMSOꢀd6): δ 2.87 (d, 2H, CH2),
3.42 (s, 3H, Me), 3.59 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.81 (t, 1H,
CH), 6.61 (s, 2H, Ph), 10.84 (s, 1H, NH); 13C NMR (100 MHz, DMSOꢀd6): d 169.8, 154.6,
147.3, 132.8, 128.8, 114.8, 108.1, 145.0, 136.8, 117.8, 60.1, 56.5, 54.7, 29.7, 14.7.
Acknowledgments. We are thankful to Payame Noor University (PNU) for partial support of
this work.
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DOI: 10.1039/C4RA03514C
Graphical Abstract
Protic ionic liquid [TMG][Ac] as an efficient, homogeneous and recyclable catalyst for
one-pot four-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones and
dihydro-1H-pyrano[2,3-c]pyrazol-6-ones
Hojat Veisi, Abass Aminimanesh, Narges Khanjani, Ramin GhorbaniꢀVaghei
ArCHO
O
O
ArCHO
O
O
O
O
O
O
O
O
OEt
O
NH2NH2.H2O
NH2NH2.H2O
Ar
O
O
O
Ar
O
N
N
N
CH3CO2
N
H
H
O
H
N
N
N
[TMG][Ac]
80 oC
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