Montmorillonite K-10 clay as reusable heterogeneous catalyst for the microwave-mediated solventless synthesis of phthalazinetetraones

Article abstract of DOI:10.1139/V06-189

Different phthalazino[2,3-b]phthalazine-5,7,12,14-tetraones were synthesized in a simple and environmentally benign method from the reaction of some phthalic anhydrides with semicarbazide or thiosemicarbazide using montmorillonite K-10 clay as solid heterogeneous acidic catalyst and microwaves under solvent-free conditions in good yields and short reaction times. The present method has many obvious advantages compared with those reported in the literature, including high efficiency, higher yield, operational simplicity, environmental benignity, and the possibility of recycling the solid clay. The solid clay catalyst used in the first cycle of the reactions was successfully recovered and reused in the second cycle, showing a gradual decrease in activity.

Full text of DOI:10.1139/V06-189

81
Montmorillonite K-10 clay as reusable
heterogeneous catalyst for the microwave-
mediated solventless synthesis of
phthalazinetetraones
Davood Habibi, Nosratollah Mahmoodi, and Omid Marvi
Abstract: Different phthalazino[2,3-b]phthalazine-5,7,12,14-tetraones were synthesized in a simple and environmentally
benign method from the reaction of some phthalic anhydrides with semicarbazide or thiosemicarbazide using montmo-
rillonite K-10 clay as solid heterogeneous acidic catalyst and microwaves under solvent-free conditions in good yields
and short reaction times. The present method has many obvious advantages compared with those reported in the litera-
ture, including high efficiency, higher yield, operational simplicity, environmental benignity, and the possibility of recy-
cling the solid clay. The solid clay catalyst used in the first cycle of the reactions was successfully recovered and
reused in the second cycle, showing a gradual decrease in activity.
Key words: montmorillonite K-10 clay, microwave, solvent-free condition, phthalazinetetraones, semicarbazide,
thiosemicarbazide.
Résumé : Faisant appel à une méthode simple et environnementalement bénigne, on a réalisé la synthèse de divers
phtalazino[2,3-b]phtalazine-5,7,12,14-tétrones avec de bons rendements en faisant réagir des anhydrides phtaliques avec
de la semicarbazide ou de la thiosemicarbazide, en présence d’argile de montmorillonite K-10 comme catalyseur acide
solide et hétérogène, dans des conditions sans solvant, sous l’influence de microondes et des temps de réaction courts.
Cette méthode présente des avantages évidents par comparaison avec celles rapportées dans la littérature, dont le fait
qu’elle est environnementalement bénigne, sa grande efficacité, son rendement plus élevé, sa simplicité d’opération et
la possibilité de recycler l’argile solide. De plus, de l’argile utilisée dans un premier cycle de réactions a été réutilisée
avec succès dans un second cycle, ce qui démontre que la diminution de son activité n’est que graduelle.
Mots clés : argile de montmorillonite K-10, microonde, condition sans solvant, phtalazinetétrone, semicarbazide, thiose-
micarbazide.
[Traduit par la Rédaction]
Habibi et al. 84
Introduction
druglike libraries in the drug discovery process (3). More-
over, heterocyclic fused phthalazines have been found effec-
tive in the inhibition of p38 MAP kinase (4), the selective
binding of the GABA receptor (5), as antianxiety drugs (6),
as antitumor agents (7), and as high-affinity ligands to the
α2δ-1 subunit of the calcium channel (8). Despite their wide
applicability among the various reported studies on fused ni-
trogen heterocycles (9), only a limited number of phthal-
azinetetraone derivatives have been synthesized (10). Cardia
et al. (11) presented the most recent method for the synthesis
of phthalazino[2,3-b]phthalazine-5,7,12,14-tetraone. Most of
these procedures involve the use of corrosive reagents such
as polyphosphoric and acetic acids and the reported yields
are far from satisfactory. Therefore, the use of inexpensive
and environmentally safe solid acids would extend the scope
of these transformations. Recently, the use of solid acidic
catalysts like clays, zeolites, and ion-exchange resins, has re-
ceived much research interest in different areas of organic
synthesis because of their environmental compatibility, reus-
ability, greater selectivity, noncorrosiveness, low cost, and
ease of handling.
In the past few decades, the synthesis of new heterocyclic
compounds has been a subject of great interest because of
their wide applicability. Heterocyclic compounds occur very
widely in nature and are essential to life. Nitrogen-
containing heterocyclic molecules constitute the largest
portion of chemical entities and are part of many natural
products, fine chemicals, and biologically active pharma-
ceuticals that are vital for enhancing quality of life (1).
Heterocyclic skeletons provide scaffolds on which
pharmacophores can be arranged to yield potent and selec-
tive drugs (2). In this regard, the phthalazine scaffold has
shown its potential as a useful structure for the generation of
Received 6 November 2006. Accepted 13 December 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 7 February 2007.
D. Habibi and O. Marvi.1 Faculty of Chemistry, Bu-Ali
Sina University, Hamedan, Iran.
N. Mahmoodi. Department of Chemistry, Faculty of
Sciences, Guilan University, Rasht, Iran.
In particular, the clay catalysts make the reaction process
more convenient, economical, environmentally benign, and
1Corresponding author (e-mail: marviomid@yahoo.com).
Can. J. Chem. 85: 81–84 (2007)
doi:10.1139/V06-189
© 2007 NRC Canada

82
Can. J. Chem. Vol. 85, 2007
Scheme 1. Synthesis of phthalazino[2,3-b]phthalazine-5,7,12,14-tetraones on montmorillonite K-10 clay using microwave or oil bath.
act as both Bronsted and Lewis acids in their natural and
ion-exchanged forms, enabling them to function as efficient
catalysts for various transformations (12). Montmorillonite
clays have been used as catalysts for a number of organic re-
actions and offer several advantages over classical acids:
strong acidity, noncorrosive properties, recyclability, low
cost, mild reaction conditions, high yields and selectivity,
and the ease of setup and workup (13). Neat reactions, on
the other hand, have their own practical problems such as
overheating and charring of compounds because of ineffec-
tive dissipation of energy.
Also, in the last few years a growing interest has been
shown in the use of microwave irradiation in organic synthe-
sis (14). Microwave-assisted rapid organic reactions consti-
tute an emerging technology that makes experimentally and
industrially important organic syntheses more effective and
more ecofriendly than conventional reactions (15). In addi-
tion, microwave-mediated solvent-free synthesis offers ad-
vantages for reducing hazardous explosions and the need to
to remove solvents with high boiling points from the reac-
tion mixtures. Moreover, coupling solventless synthesis with
microwaves shows benefits of shorter reaction times, uni-
form heating, and higher yields (16, 17).
than the –NH2 group in semicarbazide and hence will pro-
duce better yields. It seems that the nature of the substituents
of phthalic anhydride has some effects on this reaction. It is
of interest to note that the presence of electron-withdrawing
groups like Cl and NO2 gave high product yields and short
reaction times compared with the unsubstituted phthalic an-
hydride. The use of the solid clay as an efficient heteroge-
neous acidic solid catalyst as well as microwave irradiation
offer high product yields compared with conventional proce-
dures. A comparison has been given in the general proce-
dure section. Among the other advantages of our method is
the recyclability of solid clay. The clay catalyst used in the
first cycle was recovered by filtration, washed with metha-
nol, and reused. Recyclability details of the clay have been
explained in the footnote of Table 1. It is notable that all at-
tempts to prepare the products in the absence of montmoril-
lonite K-10 clay failed (despite 15 min irradiation at
180 °C). Therefore, the role of montmorillonite K-10 clay as
a solid catalyst in this reaction is essential. Furthermore, the
use of reusable solid acid makes this method quite simple,
more convenient, and economically viable. Finally, in a sec-
ond series of experiments the reactions were carried out un-
der the conventional heating conditions using an oil bath at
similar temperatures (170–180 °C, solvent-free) without mi-
crowave irradiation. It was observed that under classical
heating the reactions gave the products with relatively lower
yields and longer reaction times. Moreover, the reactions re-
quired continuous stirring to prevent charring. Comparison
of the results clearly shows the preference of microwave ir-
radiation over conventional heating. The results for the ob-
tained products under both conditions are listed in Table 1.
In continuation of our study on microwave-assisted reac-
tion on solid surfaces (18, 19), herein we describe a conve-
nient and simple method to synthesize some of the
phthalazino[2,3-b]phthalazine-5,7,12,14-tetraones
using
montmorillonite clay K-10 as a heterogeneous acidic cata-
lyst and microwave irradiation under solvent-free conditions.
The solid montmorillonite clay was successfully recovered
later and reused in subsequent reactions.
Results and discussion
Experimental
Different substituted phthalic anhydrides and either
semicarbazide or thiosemicarbazide reacted for 3–7 min un-
der solvent-free conditions using microwave irradiation at
180 °C on montmorillonite K-10 clay (Scheme 1). Under
classical heating conditions, the reactions were carried out at
a similar temperature but for longer reaction times (40–
70 min) and lower yields.
The polarity of the carbonyl group of semicarbazide is
greater than its thiocarbonyl analog in thiosemicarbazide, so
the –NH2 group in thiosemicarbazide is a better nucleophile
Melting points were measured on an Electrothermal 9100
apparatus. The IR spectra were obtained on a PerkinElmer
FT IR GX instrument using KBr discs. The H NMR and
1
13C NMR spectra were recorded on a FT-NMR JEOL FX
90Q spectrometer using TMS as internal standard (δ given in
ppm). Mass spectra were measured with a GCMS Agilent
5973N instrument. Elemental analyses were performed using
a Heraeus CHN Rapid analyzer. Chemicals were purchased
from the Sigma-Aldrich and Merck chemical companies and
used without further purification. Montmorillonite K-10 clay
© 2007 NRC Canada

Habibi et al.
83
Table 1. The yields and reaction times of compounds a–j.
Yield (%)a
Time
(min)
Fresh
clay
Recovered
clay
No.
Anhydride
Reagent
Compoundb
1
2
3
4
5
6
7
8
9
Phthalic anhydride
Semicarbazide
Semicarbazide
Semicarbazide
Semicarbazide
a
b
c
d
e
f
g
h
i
7.0 (70)
3.5 (45)
5.5 (60)
5.0 (55)
6.0 (65)
5.0 (55)
3.0 (40)
4.0 (50)
3.5 (45)
4.0 (50)
61 (43)
73 (56)
69 (52)
67 (48)
65 (45)
67 (48)
82 (61)
74 (53)
73 (55)
70 (54)
54 (32)
64 (38)
60 (35)
57 (34)
58 (30)
61 (35)
77 (43)
58 (34)
56 (39)
64 (36)
Tetrachloro-phthalic anhydride
3-Nitro-phthalic anhydride
4-Nitro-phthalic anhydride
3-Fluoro-phthalic anhydride
Phthalic anhydride
Tetrachloro-phthalic anhydride
3-Nitro-phthalic anhydride
4-Nitro-phthalic anhydride
3-Fluoro-phthalic anhydride
Semicarbazide
Thiosemicabazide
Thiosemicabazide
Thiosemicabazide
Thiosemicabazide
Thiosemicabazide
10
j
Note: The results given in parentheses correspond to those reactions that were carried out under classical heating conditions (solvent-free, 170–180 °C,
oil bath, without microwave irradiation).
aIsolated yields after recrystallization. The solid clay portion used in the first cycle was filtered off, washed with methanol (2 × 20 mL) under stirring
for 1 h, and dried at 120 °C for 5 h under reduced pressure, to be reused in the subsequent reaction, which showed a gradual decrease in activity.
b(a, f) Phthalazino[2,3-b]phthalazine-5,7,12,14-tetraone; (b, g) octachlorophthalazino[2,3-b]phthalazine-5,7,12,14-tetraone; (c, h) 1,11-dinitro-
phthalazino[2,3-b]phthalazine-5,7,12,14-tetraone; (d, i) 2,10-dinitro-phthalazino[2,3-b]phthalazine-5,7,12,14-tetraone; (e, j) 1,11-difluorophthalazino[2,3-
b]phthalazine-5,7,12,14-tetraone.
was purchased from Fluka chemical company [surface area:
200 m2/g; pH 2.5–3.5; chemical composition (average
value): SiO2 (73.0%), Al2O3 (14.0%), Fe2O3 (2.7%), CaO
(0.2%), MgO (1.1%), Na2O (0.6%), K2O (1.9%)].
MS m/z: 292 (M+). Anal. calcd. for C16H8N2O4: C 65.76, H
2.76, N 9.58; found: C 65.12, H 2.60, N 9.48.
Octachlorophthalazino[2,3-b]phthalazine-5,7,12,14-
tetraone (b, g)
Melting point 317–321 °C. ΙR (KBr, cm–1) ν: 1846.7,
1835.4, 1775.7, 1757.76, 1373.9, 1299.3, 1233.8, 923.3. 13C
NMR (DMSO-d6) δ: 170.24, 139.92, 135.46, 127.41. MS
m/z: 568 (M+). Anal. calcd. for C16Cl8N2O4: C 33.80, N
4.92; found: C 33.67, N 4.53.
Typical procedure for microwave-mediated synthesis of
phthalazino[2,3-b]phthalazine-5,7,12,14- tetraones
In a typical experiment, phthalic anhydride (2.2 mmol,
0.330 g), thiosemicarbazide (1 mmol, 0.091 g), and mont-
morillonite K-10 clay (1 g) were mixed in a mortar and the
mixture was placed in a pyrex tube and introduced into a
Synthewave 402® (Prolabo, France) single mode focused mi-
crowave reactor for 5 min at 180 °C (monitored temperature
(20)) with continuous rotation. The reaction mixture was
then allowed to cool to room temperature. The resulting
product was extracted into dichloromethane (2 × 25 mL), fil-
tered off, and the solvent was removed by rotary evapora-
tion. The obtained product, phthalazino[2,3-b]phthalazine-
5,7,12,14-tetraone (f), was very thoroughly washed with dis-
tilled water, dried in an oven, and recrystallized from acetic
acid. Melting point 332–336 °C. Yield with the fresh K-10
clay, 67% and 0.195 g; yield with the recovered K-10 clay,
61% and 0.178 g (lit. values (11) mp 343 to 344 °C, yield
55%, reaction time 1.5 h using polyphosphoric acid). The
solid clay portion was washed with methanol and dried at
120 °C under reduced pressure to be reused in the subse-
quent reactions, which showed a gradual decrease in activity
(Table 1). With this procedure compounds, a–j were synthe-
sized. The physical data (mp, IR, NMR, and MS) of known
compounds a and f were found to be identical with those of
authentic samples. Unknown compounds were characterized
by mp, spectra (IR, NMR, and MS), and elemental analyses.
1,11-Dinitrophthalazino[2,3-b]phthalazine-5,7,12,14-
tetraone (c, h)
Melting point 271–274 °C. ΙR (KBr, cm–1): 3172.9,
3026.24, 2922.0, 1669.9, 1603.3, 1578.1, 1560.8, 1491.6,
1
1336.5, 1298.2, 825.6. H NMR (DMSO-d6) δ: 7.92–8.63
(6H, m, Ar). 13C NMR (DMSO-d6) δ: 167.71, 167.43,
148.45, 136.85, 133.39, 132.70, 132.52, 129.61. MS m/z:
382 (M+). Anal. calcd. for C16H6N4O8: C 50.26, H 1.57, N
14.56; found: C 50.14, H 1.38, N 14.33.
2,10-Dinitrophthalazino[2,3-b]phthalazine-5,7,12,14-
tetraone (d, i)
Melting point 263–267 °C. ΙR (KBr, cm–1) ν: 3106.3,
3006.5, 1641.8, 1626.7, 1598.7, 1539.9, 1466.6, 1355.1,
1
1188.4, 1061.3, 791.9. H NMR (DMSO-d6) δ: 8.36–8.94
(6H, m, Ar). 13C NMR (DMSO-d6) δ: 162.52, 162.43,
154.81, 137.78, 134.66, 133.19, 129.26, 122.34. MS m/z:
382 (M+). Anal. calcd. for C16H6N4O8: C 50.26, H 1.57, N
14.56; found: C 50.09, H 1.29, N 14.25.
1,11-Difluorophthalazino[2,3-b]phthalazine-5,7,12,14-
tetraone (e, j)
Melting point 298–302 °C. ΙR (KBr, cm–1): 3021.9,
2921.0, 1671.2, 1603.1, 1577.8, 1560.2, 1491.3, 1336.6,
Phthalazino[2,3-b]phthalazine-5,7,12,14-tetraone (a, f)
Melting point 332–336 °C. ΙR (KBr, cm–1) ν: 3092.7,
1853.5, 1792.6, 1763.5, 1686.4, 1597.4, 1471.3, 1258.7,
1
1299.7, 825.8. H NMR (DMSO-d6) δ: 7.82–8.27 (6H, m,
1
Ar). 13C NMR (DMSO-d6) δ: 175.27, 163.66, 163.32, 163.08,
136.42, 136.27, 130.52. MS m/z: 328 (M+). Anal. calcd. for
1109.8, 907.2. H NMR (DMSO-d6) δ: 7.81–7.98 (8H, m,
Ar). 13C NMR (DMSO-d6) δ: 123.0, 129.3, 134.8, 168.9.
© 2007 NRC Canada

84
Can. J. Chem. Vol. 85, 2007
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Acknowledgement
Financial support from the Department of Chemistry, Fac-
ulty of Sciences, Bu-Ali Sina University, Hamedan,
6517838683, Iran is gratefully appreciated.
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