E. Mosaddegh, A. Hassankhani / Tetrahedron Letters 52 (2011) 488–490
489
Table 1
The enhanced reactivity of cerium(IV) sulfate has led to its
emergence as a promising Lewis acid catalyst. Ce(SO4)2Á4H2O is a
moisture-stable compound, easy to handle, and easily available.20
To develop optimum conditions, first, the effect of temperature
on the rate of the reaction was studied for the preparation of 2,2-
dimethyl-13-phenyl-2,3-dihydro-1H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione. At 125 °C, the reactions proceeded to completion
very rapidly. A decrease in temperature leads to decreasing prod-
uct yields and rate of the reaction. It was observed that the reaction
did not proceed at room temperature.
Next, the optimum amount of Ce(SO4)2Á4H2O was evaluated.
The highest yield was obtained with 0.01 g (2.5 mol %) of the cata-
lyst. A further increase in the amount of cerium(IV) sulfate up to
10 mol % did not have any significant effect on the product yield
or reaction time.
Ce(SO4)2Á4H2O-catalyzed synthesis of 2,2-dimethyl-13-phenyl-2,3-dihydro-1H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives via
a
four-component
reaction
Entry
Ar
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
C6H5
6
7
5
6
10
5
5
5
5
8
78
93
80
82
76
84
95
87
71
80
4-Br–C6H4
4-Cl–C6H4
4-CH3O–C6H4
2,4-Cl2–C6H3
3-O2N–C6H4
3-HO–C6H4
3-CH3O–C6H4
3-H3C–C6H4
2-Cl–C6H4
10
a
Yield refers to isolated pure product.
The generality of this reaction was examined using different
aldehydes. In all cases, the reactions gave the corresponding prod-
ucts in good to excellent yields (Table 1) and in very short reaction
times. This method offers significant improvements with regard to
the scope of the transformation, simplicity, and green aspects by
avoiding expensive or corrosive catalysts.
NH2NH2.H20
2
O
Ce(IV)
+
NHNH2
OH
O
The reusability of the catalyst was examined in the synthesis
of 2,2-dimethyl-13-(4-chlorophenyl)-2,3-dihydro-1H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-trione. The catalyst was recovered after
each run, washed three times with CH2Cl2, dried in an oven at 60 °C,
and tested for its activity in subsequent runs. It was found that the
catalyst could be reused four times without the loss of activity.
A possible mechanism for the formation of the products is shown
in Scheme 2. The reaction occurs via initial formation of the
phthalhydrazide 3 by nucleophilic addition of hydrazinium hydrox-
ide 2 to phthalic anhydride 1 followed by dehydration. The second
step involves initial formation of heterodiene 6 by standard Knoeve-
nagel condensation of dimedone 5 and aldehyde 4. Subsequent Mi-
chael-type addition of the phthalhydrazide 3–6 followed by
cyclization affords the corresponding product 7 (Scheme 2).
In summary, an efficient protocol for the one-pot synthesis of
2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives has
been described under thermal solvent-free conditions using inex-
pensive starting materials. To the best of our knowledge, this
new procedure represents the first example of an efficient syn-
thetic method for these derivatives via a four-component reaction.
O
O
Ce(IV)
H2O
O
O
O
O
O
1
NH
NH
Ce(SO4)2.4H2O
3
O
Ce(IV)
Ce(IV)
O
O
OH
5
O
HN
HN
O
CHAr
O
Ce(IV)
O
6
H
4
R
Acknowledgment
O
H
The authors thank the Khoramshahr Marine Science and Tech-
nology University, for partial financial support of this investigation.
O
Ar
O
N
R
HN
Ce(SO4)2.4H2O
References and notes
O
O
Ce(IV)
1. (a) Anastas, P. T.; Warner, J. C. In Green Chemistry: Theory and Practice; Oxford
University Press: Oxford, UK, 1998; (b) Anastas, P. T.; Williamson, T. In Green
Chemistry: Frontiers in Benign Chemical Synthesis and Process; Oxford University
Press: Oxford, UK, 1998.
2. McDonald, E.; Jones, K.; Brough, P. A.; Drysdale, M. J.; Workman, P. Curr. Top.
Med. Chem. 2006, 6, 1193.
3. Elguero, J.. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5,.
4. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Targets Heterocycl. Syst. 2002, 6,
52.
O
Ar
O
N
N
7
O
5. Quiroga, J.; Mejia, D.; Insuasty, B.; Abonia, R.; Nogueras, M.; Sanchez, A.; Cobo,
J.; Low, J. N. Tetrahedron 2001, 57, 6947.
Scheme 2.
6. Quiroga, J.; Hormaza, A.; Insuasty, B.; Ortiz, A. J.; Sanchez, A.; Nogueras, M. J.
Heterocycl. Chem. 1998, 35, 231.
7. Tu, S.; Fang, F.; Li, T.; Zhu, S.; Zhang, X. J. Heterocycl. Chem. 2005, 42, 707.
8. Quiroga, J.; Insuasty, B.; Hormaza, A.; Saitz, C.; Jullian, C. J. Heterocycl. Chem.
1998, 35, 575.
9. Shaabani, A.; Rahmati, A.; Naderi, S. Bioorg. Med. Chem. Lett. 2005, 15, 5553.
10. (a) Franklin, E. C. Chem. Rev. 1935, 16, 305; (b) Bergstrom, F. W. Chem. Rev. 1944,
35, 77; (c) Lichtenthaler, F. W. Acc. Chem. Res. 2002, 35, 728; (d) Litvinov, V. P.
Russ. Chem. Rev. 2003, 72, 69; (e) Xu, Y.; Guo, Q. X. Heterocycles 2004, 63, 903.
neous-catalyzed organic reactions,18 we decided to explore the
possibility of synthesizing 2H-indazolo[2,1-b]phthalazine-trione
derivatives via a novel, one-pot, four-component condensation of
phthalic anhydride, hydrazinium hydroxide, aromatic aldehydes,
and dimedone under solvent-free conditions using Ce(SO4)2Á4H2O
as a recyclable catalyst (Scheme 1).19