Nano-ferrite supported glutathione as a reusable nano-organocatalyst for the synthesis of phthalazine-trione and dione derivatives under solvent-free conditions

Article abstract of DOI:10.1039/c6ra06376d

Nano-organocatalyzed one-pot four-component reactions for the synthesis of phthalazine-trione/dione derivatives have been devised for the first time from easily accessible starting materials under solvent-free conditions. This methodology showed very good substrate scope and high degree of tolerance for a variety of aldehydes (including aliphatic and heteroaromatic aldehydes) and active methylene compounds. Moreover, the catalyst can be easily separated from the reaction mixture because of its highly paramagnetic nature, by using an external magnet, and can be reused in five more consecutive runs without much decrease in catalytic activities. Other significant advantages of this method are shorter reaction time, good yield, simple work-up procedure, easy catalyst handling etc.

Full text of DOI:10.1039/c6ra06376d

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NANOꢀFERRITE SUPPORTED GLUTATHIONE AS
A
REUSABLE NANOꢀ
ORGANOCATALYST FOR THE SYNTHESIS OF PHTHALAZINEꢀTRIONE AND DIONE
DERIVATIVES UNDER SOLVENT FREE CONDITION
Binoyargha Dam,a Mithu Saha,b Ramen Jamatiaa and Amarta Kumar Pal*a
aDepartment of Chemistry, Centre for Advanced Studies, NorthꢀEastern Hill University,
Shillongꢀ793022, India .bState Key Laboratory of Physical Chemistry for Solid Surfaces, College
of Chemistry and Chemical Engineering, Xiamen university, Chinaꢀ361005.
Abstract:
Nanoꢀorganocatalyzed oneꢀpot four component reaction for the synthesis of phthalazineꢀ
triones/diones derivatives have been devised for the first time from easily accessible starting
materials under solvent free conditions. This methodology showed very good substrate scope and
high degree of tolerance for a variety of aldehydes (including aliphatic and heteroꢀarometic
aldehydes) and active methylene compounds. More over the catalyst can be easily separated
from the reaction mixture because of its highly paramagnetic nature, by using an external magnet
and can be reused in five more consecutive runs without much decrease in catalytic activities.
Other significant advantages of this method are shorter reaction time, good yield, simple workꢀ
up procedure and easy catalyst handling etc.
Keywords: Nanoꢀorganocatalyst, solvent free reaction condition, oneꢀpot MCR, reusability of
catalyst.
Introduction
Organocatalysis, the term which refers to a form of catalysis where the rate of the reaction is
increased by the addition of an organic catalyst is an attractive and productive enterprise in the
modern day chemistry. Fabrication, characterization, modification and application of
organocatalyst is an emerging field which is extensively applied on many name reactions like
Michael reaction,1 Mannich reaction,2 enantioselective CꢀN, CꢀC, CꢀO bond formation etc,3 but
their separation and reusability are the major drawbacks. So, there is a lack of its application
under sustainable circumstances. Nanoparticles are striking candidates as solid supports for
immobilization of homogeneous organocatalyst like glutathione,4 Lꢀproline,5 dopamine,6
sulphonic acids etc.7,8 Out of other solid supports like silica, allumina, metal oxides, polymers etc
1

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nanoparticles are nonꢀarguably most widely investigated because its separation and reusability
are easy. Green chemistry has fascinated substantial attention for overcoming several troubles
relating to environmental pollution. Application of heterogeneous nanoꢀorganocatalyst is
considered as a sustainable approach because: (i) nanoꢀorganocatalysts are well dispersed in
reaction medium thereby providing high surface area for readily access of substrate molecules
and (ii) these can be easily separated from the reaction mixture by filtration, centrifugation or by
using an external magnetic field, which is then reused in several more consecutive runs without
much decrease in catalytic activity. Metal nanoparticles attached to enzymes or bioꢀmolecules
are newer class of catalysts with excellent activities in diversity orientated synthesis (DOS) of
small molecules having skeletons found in many important natural products.9,10
Heterocyclic compounds possessing aza group are widely distributed in nature and out of a large
number of Nꢀcontaining compounds, those which possess hydrazine moiety at the fusion site are
of immense importance because of their pharmacological, clinical and agrochemical
applications.11,12 Many of these phthalazine derivatives possess antiꢀfungal,13 antiꢀcancer,14 antiꢀ
tumor15 and many other pharmaceutical activities.16 Because of these biological and medicinal
activities many researchers developed powerful and promising method for synthesizing
phthalazene molecules by using various types of catalysts like inorganic–organic hybrid
materials AlꢀSBAꢀ15ꢀTPI/H6P2W18O62,17 TBBDA,18 Cs2CO3@magnetic nanoparticles,19 SO3Hꢀ
FMSM,20 SBA@BiPy2+2Clꢀ,21 [TMG][Ac],22 RH@[SiPrDABCO@BuSO3H]HSO4,23 CoFe2O4ꢀ
CSꢀSO3H24 etc in by sequential multiꢀcomponent reaction (MCR). These reported methods
possess many advantages but at the same time encounters many disadvantages too. Previously
our group also reported Ni (0) NPs catalyzed synthesis of phthalazine derivatives25 but major
difficulties were agglomerisation of NiꢀNPs and unable to form phthalazine molecules with
aliphatic and heteroaromatic aldehydes. To adress these problems, we applied surface stabilized
magnetic nanoꢀorganocatalyst. By this way we prevented the chance of agglomerisation and
increased the catalytic activity of nanoꢀcomposite. From literature study we have chosen
glutathione as a stabilizer as well as organocatalyst, because it binds to nanoparticles by using –
SH functionality while –NH2 and –COOH groups are free for catalysis.10 Furthermore, for easy
separation we have selected magnetic nanoparticles (Fe3O4) which avoids the involvement of
cumbersome procedure like centrifugation and filtration. Moreover application of nanoꢀFGT also
made the methodology more efficient as compared to the one reported, since the reaction went
2

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smoothly with a diverse range of active methylene compounds and aldehydes including
heteroaromatic and aliphatic aldehydes.
So, the chief purpose behind this presented protocol is to highlight the synergetic effects of
combined nanoꢀorganocatalyst operated synthetic enhancement procedure, MCR and solvent free
reaction condition for development of new ecoꢀcompatible methodology. Therefore, we have
chosen nanoꢀFGT (nanoꢀferrite on glutathione) as a proficient, harmless, mild, magnetically
recyclable, highly stable, powerful solid nanoꢀorganocatalyst and have applied that for the
synthesis of phthalazine derivatives by four components MCR under solvent free conditions.
Results and discussion:
Magnetic nanoꢀFGT, consist of Fe3O4 spheres as the core and glutathione as the outer shell and it
was prepared by a simple, low cost and convenient methods.4 Magnetite nanoparticles were
synthesized by the coꢀprecipitation of Fe2+ and Fe3+ in ammonia solution.26 To improve the
chemical stability of magnetite nanoparticles, their surface modification was successfully
performed by the suitable deposition of glutathione onto nanoparticles surface by ultrasonic
irradiation at room temperature (Schemeꢀ1).
NH2
O
H2N
O
HO
HO
O
O
HN
NH
S
S
O
O
Glutathione (reduced form)
((((, r.t, H2O, 2hrs
NaOH
Fe2+
Fe3+
Fe3O4
NPs
HN
O
NH
Fe3O4
NPs
H2O,
1 h, 60 0
C
O
HO
OH
S
O
H
N
H
O
N
OH
O
NH2
O
O
H
Nano-FGT
Scheme: 1 Synthesis of nanoꢀFGT
Formation of nanoꢀFGT was confirmed by FTꢀIR, TEM, SEM and EDX analysis. Its thermal
stability was analyzed by TGA. Functional group identification was done by FTꢀIR technique.
FTꢀIR spectrum of nanoꢀFGT (Fig. SI 1) showed broad peaks at 3349 and 3166 cmꢀ1 which
indicated the presence of –OH and –NH2 groups. The peaks at 1643 and 1634 cmꢀ1 corresponds
3

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to the carbonyl stretching of acid and amide groups of glutathione respectively. Peak at 2926 cmꢀ
1 is due to CꢀH stretching. The absorption band at 599 cmꢀ1 corresponds to FeꢀO stretching of
Fe3O4 NPs and absence of SꢀH stretching band at around 2525cmꢀ1 clearly indicated that
glutathione is successfully anchored on to the surface of Fe3O4 NPs via thiol group.27
Morphology and particle size of nanoꢀFGT was determined from TEM images. TEM images
showed the presence of dark spherical nanoparticle core of size 10ꢀ20 nm uniformly coated with
layer of glutathione [Fig. 1(a),(b)]. SAED (Selected Area Electron Diffraction) of freshly
prepared nanoꢀFGT showed spotty diffraction thereby proving its crystalline character [Fig 1
(c)]. EDX analysis was carried out to determine the elemental composition of nanoꢀFGT. This
confirmed the presence of Fe, O, S, N and C (Fig. 2). SEM images were obtained with the help
of JSMꢀ6360 (JEOL) scanning electron microscope. SEM image also confirmed the spherical
morphology of nanoꢀFGT (Fig. 3).
(a)
(b)
(c)
Fig. 1: (a) TEM images of nanoꢀFGT at 0.2 µm, (b) at 5 nm (c) SAED pattern of nanoꢀFGT
Fig. 2 : EDX of nanoꢀFGT
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Fig. 3: SEM of nanoꢀFGT at 200 nm
Prepared nanoꢀFGT was also characterized by powder XRD technique. The XRD diffraction
patterns shows characteristic 2Ɵ peaks at around 30.33, 35.61, 43.19, 57.28, 62.83, 74.30 which
are in good agreement with that reported in literature.4
2800
2600
2400
2200
35.6117
2000
1800
1600
1400
1200
1000
62.8375
57.2808
74.3094
43.1998
30.3338
20
25
30
35
40
45
50
55
60
65
70
75
80
2 theta (Degree)
Fig. 4: Powder XRD pattern of nanoꢀFGT
In order to gain information regarding thermal stability of nanoꢀFGT, we performed TGA
0
(Thermo Gravimetric Analysis). There is degradation at around 53 C in the thermogram which
corresponds to the degradation of solvent molecules trapped in the catalyst. There is another
0
weight loss at 185 C which is due to the degradation of glutathione molecule of nanoꢀFGT.
0
These observations proved that the catalyst is stable below 180 C and therefore can be easily
applied in reactions under that temperature (Fig. 5).
5

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102
100
98
96
94
92
90
88
86
200
400
600
800
Temperature (oC)
Fig. 5: NanoꢀFGT TGA thermogram.
ICPꢀOES analysis was performed in order to know the actual amount of Fe catalyst used in the
nanoꢀferrite heterogeneous catalyst and it was found to be 63.23%.
After successful surface modification and characterization of nanoꢀFGT, we explored its
applicability for the synthesis of phthalazine dione and trione derivatives by four component
condensation reaction of phthalic anhydride (1), hydrazinium hydroxide (2), active methylene
compounds (3, 4 or 5) and aldehydes (6a-q) (Scheme 2). Initially a mixture of phthalic
anhydride (1) (1 mmol), hydrazinium hydroxide (2) (1.2 mmol), dimedone (3) (1 mmol) and 4ꢀ
chlorobenzaldehyde (6a) (1 mmol) was taken as a pilot reaction. Following which the reaction
was allowed to stir at room temperature without any catalyst. It was found that without catalyst
the reaction failed to form the desired product even after 24 h of constant stirring. Only starting
materials were evidenced in the TLC. Then another new set of the reaction was set up with
28
addition of nanoꢀFGT which was stirred according to known procedures, it is important to
mention here that since the reaction is solvent free so, reactants and magnetic nanoꢀ
organocatalyst (nanoꢀFGT) were mixed properly by using a glass rod in to which a magnetic bit
was added in order to maintain proper mixing during reaction period, which in turn increases the
contact between the surface of the catalyst and reactant molecules. Firstly, the reaction was
carried at room temperature, and to our delight it was found that after 12 h of continuous stirring
desired product was forming but the conversion were very poor, most of the starting materials
remained unreacted. This observation prompted us to apply thermal energy to the reaction. A
number of reactions were set up in a preꢀheated oil bath on a temperature controlled magnetic
stirrer at different temperature ranging from 40ꢀ120 0 C and the best result was obtained at 80 0C.
However, no desired product was forming without addition of catalyst even at 80 0C after 24 h of
stirring. All these observations proved the efficient role of catalyst in carrying out the reaction.
The structure of the compound was identified by elemental and spectral analysis. IR spectrum of
compound 15a showed absorption bands at 1453 and 1109 cmꢀ1 which are due to CꢀN and NꢀN
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1
band stretching, band at 1666 cmꢀ1 corresponds to carbonyl group of dimedone. In H NMR of
compound 15a showed eight aromatic protons appear at δ 8.29ꢀ7.24. The methine proton was
observed as a singlet at δ 6.34. The four methylene protons of the dimedone residue appeared as
a AB system in δ 3.35ꢀ3.13 and singlet at δ 2.26. The two methyl groups were observed as two
singlets at δ 1.137 and δ 1.132. Next, the reaction conditions were optimized and, for this,
various reaction parameters were examined.
O
Z
O
R
O
O
O
Z
3 or 4
N
N
Z
O
NanoꢀFGT,
10 mg
[11.31 mol% of Fe]
Z
O + NH2NH2.H2O +
15a-p, 16a
RCHO
2
6
Solvent free, 80 0
C
1
R
O
O
X
20ꢀ35 min
N
N
X
CN
H2N
5aor 5b
O
If Z= ꢀCH3, 3;If Z= ꢀH,4
17a, 18a
If X= ꢀCOOEt, 5a;
If X= ꢀCN, 5b;
R= Various aromatic, alliphatic and heteroaromatic aldehydes.
Scheme 2: Synthesis of Phthalazine derivatives by using nano-FGT
Firstly we focused on the optimization of amount of catalyst required to catalyze the reaction. It
was discovered that 10 mg [6.32 mg of Fe, 11.31 mol%] of the catalyst was sufficient enough to
furnish maximum yield within very short period of time. Application of higher amount of
catalyst viz. 12 mg showed no increase in the yield of desired product, neither decreased reaction
time. On the other hand, reduction in the amount of catalyst below 10 mg produced lower yield
within same amount of time frame. The optimization plot of the reaction time and the catalyst is
shown in Fig. 6.
Encouraged by the above success, we investigated the effect of various solvents on the pilot
reaction at 80 0C using 10 mg nanoꢀFGT as a catalyst. In presence of solvents like water, ethanol,
acetonitrile and THF, bisꢀadduct 15a′, 2,2′ꢀ(4ꢀchlorophenylmethylene)ꢀ bis(3 hydroxyꢀ5,5ꢀ
dimethylcyclohexꢀ2ꢀenone), (see SI) was the major product instead of phthalazine derivative
15a. But under solvent free condition, reaction proceeded very smoothly and offered phthalazine
derivative 15a as major product within very short period of time (Fig. 7).
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100
80
60
40
20
0
5 min
10 min
15 min
20 min
25 min
0
2
4
6
8
10
12
Amount of catalyst (g)
Fig. 6: Optimization of catalyst loading with respect to yield and time
Fig. 7: Solvent standardization
Now in order to render the catalytic activity of nanoꢀFGT in the above reaction as the best, we
compared its catalytic activity with other homogeneous and heterogeneous catalysts. The cases
where FeCl3, Fe2SO4 and Fe3O4 NPs were used as catalyst witnessed very less conversion
thereby leading to the poor yield of the desired product (Table 1). The fourth case where
glutathione was used as the catalyst showed very good improvement in result but the time
required for the completion of the reaction was high and in this case glutathione being soluble in
water could not be recycled back. Application of nanoꢀFGT however solved this problem of
recyclability and since it is attached to nanoparticles which have higher surface/ volume ratios
and it leads to better catalytic activity,9 which in turn reduced the time and increase the product
yield.
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Table 1: Standardization of catalyst a
Cl
O
O
O
CHO
O
O
N
N
catalyst ( 10g )
+ NH NH .H O +
+
O
O
2
2
2
Solvent free, 80 0C
O
Cl
6a
1
2
3
15a
Scheme 3: Catalyst Screening
Sl.No.
Catalyst b
Time
24 h
Yield c (%)
1
2
3
4
5
No catalyst
FeCl3
0
180 min
180 min
180 min
120 min
20 min
21
25
53
78
97
Fe2SO4
Fe3O4 NPs
Glutathione
NanoꢀFGT
6
a
Reaction Condition : phthalic anhydride (1 mmol), hydrazinium hydroxide (1.2 mmol), dimedone (1 mmol) and 4ꢀ
chlorobenzaldehyde (1 mmol), 80 0C, SFRC. b amount of catalyst: 10 mg. c isolated yield.
To explore generality of the reaction, we extended the scope of the present protocol for the
synthesis of various phthalazine derivatives. The results of this study are shown in Table 2. As
shown in the Table 2, aromatic aldehydes carrying either electron donating or withdrawing
substituent worked well, giving excellent yield of products (87ꢀ97 %) with high purity. The
reaction went smoothly with various active methylene compounds like dimedone (3), 1,3ꢀ
cyclohexanedione (4), ethyl cyanoacetate (5a), and malononitrile (5b). To analyze the ability of
our methodology, the said synthesis was also performed with different heteroaromatic and
aliphatic aldehydes (15o, 15p and 18a) under similar conditions and we were delighted to see the
formation of our desired product in good yields within similar time duration. As per as literature
survey very less reported procedure for the synthesis of phthalazine derivatives showed good
results with aliphatic and heteroaromatic aldehydes, but our methodology provides excellent
results with both kinds of aldehydes (Table 2). Reaction was also tried with ethyl acetoacetate as
active methylene compound but no desired product formed after 6 h of constant stirring only
starting materials were recovered. All the syntheized products were characterized from their
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analytical and spectroscopic data. Structure of compound 17a was again confirmed by single Xꢀ
ray crystallography (Fig. 8).
Fig.8: Molecular structure of compound 17a CCDC 1438715.
Table 2: Synthesis of various phthalazine derivatives by using nano-FGT.
O
R
O
N
N
O
Z
Z
O
O
Z
15a-p, 16a
NanoꢀFGT,
10 mg
Solvent free, 80 0
O
Z
O +
NH2NH2.H2O+
RCHO
+
R
O
3 or 4
or
C
X
2
6
1
N
N
O
X
CN
20ꢀ35 min
5a or 5b
H2N
O
17a, 18a
If Z= ꢀCH3, 3;If Z= ꢀH,4
If X= ꢀCOOEt, 5a;
If X= ꢀCN, 5b;
R= Various aromatic, alliphatic and heteroaromatic aldehydes.
Scheme 4: Synthesis of Phthalazine derivatives
Sl.
Aldehydes
Active
Product
Time Yield (%) b M.P. (0 C)
(min)
No.
methylene
compounds
1
2
3
4
5
6
7
4ꢀClC6H5 (6a)
4ꢀCNC6H5 (6b)
4ꢀNO2C6H5(6c)
4ꢀBrC6H5(6d)
4ꢀFC6H5(6e)
3
3
3
3
3
3
3
15a
15b
15c
15d
15e
15f
15g
20
20
20
25
20
20
23
97
96
97
96
95
92
91
261ꢀ26217
271ꢀ27325
224ꢀ22617
265ꢀ26717
219ꢀ22017
205ꢀ20725
266ꢀ26817
3ꢀClC6H5(6f)
2ꢀClC6H5 (6g)
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8
3ꢀ NO2C6H5 (6h)
3ꢀBrC6H5 (6i)
3ꢀFC6H5 (6j)
2ꢀBrC6H5 (6k)
C6H5 (6l)
3
3
15h
15i
24
21
21
22
25
25
20
30
30
20
20
92
92
90
91
93
87
89
88
87
94
97
269ꢀ27025
9
266ꢀ26825
271ꢀ27325
262ꢀ26525
205ꢀ20717
228ꢀ23017
220ꢀ22225
227ꢀ23024
133ꢀ13622
237ꢀ239
10
11
12
13
14
15
16
17
18
3
15j
3
15k
15l
3
4ꢀMeC6H5 (6m)
4ꢀMeOC6H5 (6n)
2ꢀC5NH4 (6o)
C4H8 (6p)
3
15m
15n
15o
15p
16a
17aa
3
3
3
4ꢀNO2C6H5(6c)
4ꢀCl,3ꢀNO2C6H5
(6q)
4
5a
212ꢀ214
19
C4H8 (6p)
5b
18a
25
92
220ꢀ223
a Reaction Condition : phthalic anhydride (1 mmol), hydrazinium hydroxide (1.2 mmol), active methylene compounds (1 mmol)
and aldehydes (1 mmol), 80 0C, SFRC,10 mg of nanoꢀFGT. b isolated yield.
Most probable mechanism of the said conversion is shown in Scheme 5. In the initial step nanoꢀ
FGT facilitates the nucleophilic attack of hydrazinium hydroxide (2) to phthalic anhydride (1)
leading to the formation of phthalhydrazide (7). On the other hand, aldehydes reacts with nanoꢀ
FGT forming imminium intermediate (8).9 Then cyclic 1,3ꢀdiketones (3 and 4) forms 9 which
reacts with 8 and afforded knoevenagel product 11 (path a)9 where acyclic active methylene
compounds (5a or 5b) generates knoevenagel product 12 through carbanion formation (path b).
29
Phthalhydrazide (7) attacks these intermediates (11 and 12) under Michael fashion leading to
the formation of other intermediates 13 and 14 which eventually undergoes cyclization followed
by dehydration to furnish our desired product.
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NH2
Fe3O4
NPs
O
Fe3O4
NPs
H
O
O
O
H
H
OOC
N
NH
O
NH2NH2.H2O
6
R
H
nanoꢀFGT
NH
2
1
R
8
O
NH2
O
O
Fe3O4
NPs
7
H
O
O
Path (a)
Path (b)
O
O
Fe3O4
NPs
nanoꢀFGT
X
H
C
H
N
Fe3O4
NPs
X
CN
O
N
H2N
H
5
10
3 or 4
9
H
N
H
R
H
N
H
R
COO
O
O
COO
8
R
CN
X
8
or
R
12
O
11
NH
NH
R
O
7
O
O
R
O
O
O
O
X
NH2
R
N
N
H
O
O
N
N
H
N
N
N
N
X
O
13
N
H2O
H
H2O
O
H
H
O
O
H
O
R
O
H2N
H2N
14
O
15 or 16
O
17 or 18
H
O
Fe3O4
NPs
H2N
H2N
Fe3O4
NPs
O
O
Fe3O4
NPs
Fe3O4
NPs
Scheme 5: Plausible mechanism for the synthesis of 2Hꢀindazolo[1,2ꢀb]phthalazineꢀtriones and
1Hꢀpyrazolo[1,2ꢀb]phthalazineꢀdiones.
Following this, the possibility of recovery and reusability of the catalyst was investigated. After
completion of the reaction, the catalyst was recovered from the reaction mixture simply by using
an external magnet and washed with ethylacetate, acetone and dried. The recovered catalyst was
reused under same reaction condition and it was found that the catalyst could be reused for five
times without any significant loss of the product yield. The reproducibility of the reaction was
then investigated by performing five sets of reaction under same condition. Each set was
repeated five times and mean of yield was calculated (95.6, 94.8, 94.2, 93.2 and 92.6 %) by
standard deviation method, the error bars were also reported (Fig. 9). After carrying out 5th set of
reaction, again ICPꢀOES analysis was performed and amount of Fe found was 60.04%, this
observation confirmed there is 3.19% leaching of the catalyst. Then in order to confirm the
structure of the reused (after 5 consecutive runs) catalyst we performed powder XRD (Fig. 10a),
SEM (Fig. 10b), TEM (Fig. 10c), FTꢀIR (Fig. SI 1b) and TGA (Fig. 10d) analysis which were
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very similar to that of freshly synthesized catalyst and it also remained well dispersed and
retained the size (10ꢀ20 nm).
100
80
60
40
Yield (%)
20
0
1st Set 2nd Set 3rd Set 4th Set 5th Set
Number of runs
Fig. 9: Reproducibility chart
3200
35.6515
3000
2800
2600
62.957
2400
2200
2000
1800
1600
1400
30.2342
57.241
43.2198
2
74.409
57.7986
30
35
40
45
50
55
60
65
70
75
80
2 theta (Degree)
(a)
(b)
100
95
90
85
80
200
400
600
800
1000
Temperature (0 C)
(c)
(d)
13

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Page 14 of 17
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DOI: 10.1039/C6RA06376D
Fig. 10: (a) powder XRD, (b)TEM image of nanoꢀFGT at 50 nm, (C) SEM image of nanoꢀFGT
at 500 nm and (d) TGA curve of nanoꢀFGT after 5th run.
Conclusion:
In conclusion, herein we report a stable nanoꢀorganocatalyst mediated solvent free oneꢀpot
synthesis of 2Hꢀindazolo[2,1ꢀb] phthalazineꢀtrione derivatives and 1Hꢀpyrazolo[1,2ꢀb]
phthalazineꢀdione derivatives within short period of time. The reaction went smoothly with
various active methylene compounds and also with diverse range of aldehydes (aromatic,
aliphatic and heteroaromatic) showing the versatility of the methodology. After completion of
the reaction NanoꢀFGT was easily recovered from the reaction mixture by a simple and
convenient magnetic separation using an external magnet. This methodology also overcomes the
formation of by product, low yields, use of toxic catalyst and hazardous organic solvent.
Moreover, catalyst can be recycled and reused up to five consecutive run without much decrease
in catalytic activity.
Experimental:
Phthalic anhydride (1 mmol) (1), hydrazinium hydroxide (1.2 mmol) (2), active methylene
compounds (1 mmol) (3/4/5), aryl aldehydes (1 mmol) (6a-q) and nanoꢀFGT (10 mg) were
added to a round bottom flask and since the reaction is under solvent free condition so it was
mixed properly by using a glass rod. Following this, a magnetic bit was added and the reaction
0
mixture was set on a preꢀheated oil bath at 80 C accompanied with magnetic stirrer (model no:
IKA CꢀMAG, HS4 Digital) and stirring was started and continued for the time mentioned in the
Table 2. During stirring a centrifugal force was generated, which mixed the reactants nicely
thereby making a reasonable contact between the surface of the catalyst and the reactants. This
fact was clearly explained from the observation that when no catalyst was added to the reaction
mixture, no desired product was formed even after 24 h of stirring. After completion of the
reaction (monitored by TLC), the reaction mixture was cooled to room temperature. 10 mL of
ethyl acetate was added to the reaction mixture and nanoꢀFGT attached to magnetic bit was
separated by another external magnet. After that, in order to reuse the catalyst, it was washed
several times with ethyl acetate, acetone to remove presence of any residual product and dried.
The catalyst was then applied in subsequent reactions. The organic extract was then washed with
water (3x10 ml), followed by brine and dried with anhydrous Na2SO4. The solvent was removed
14

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DOI: 10.1039/C6RA06376D
under vacuum and the crude reaction mixture was purified by column chromatography using
ethyl acetate: hexane (4:6) to afford the pure products (15a-p, 16a, 17a, 18a).
Acknowledgement:
We thank the Department of Chemistry, NorthꢀEastern Hill University, Sophisticated Analytical
and Instrumentation Facility (SAIF) of NorthꢀEastern Hill University, Indian Association for the
cultivation of ScienceꢀKolkata, IASSTꢀGuwahati, IITꢀBombay and UGC for supporting this
work under Special Assistance Programme (SAP). We will also like to thank DST for financial
support (sanctioned no: SERC/F/0293/2012ꢀ13) and DSTꢀPurse. I am also thankful to NEHUꢀ
NON NET fellowship for their constant financial support.
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DOI: 10.1039/C6RA06376D
O
O
R
O
O
N
N
Z
Recyclable
Z
O
Z
NH2NH2.H2O
3 or 4
Z
O
2
Nano-FGT
15a-p, 16a
O
Paramagnetic
R
O
1
O
RCHO
X
X
CN
N
N
6
SFRC
5a or 5b
H2N
O
17a, 18a