Vitamin B1 supported on alumina as an efficient heterogeneous catalyst for synthesis of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione derivatives

Article abstract of DOI:10.1007/s13738-015-0623-y

The efficient synthesis of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione derivatives via four-component reaction of hydrazine hydrate, phthalic anhydride, aromatic aldehydes and barbituric acid using vitamin B₁ supported on alumina (VB₁-Al₂O₃) as a heterogeneous catalyst under thermal solvent-free conditions in excellent yields is described.

Full text of DOI:10.1007/s13738-015-0623-y

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0623-y
ORIGINAL PAPER
Vitamin B1 supported on alumina as an efficient heterogeneous
catalyst for synthesis of tetrahydro‑2,6‑dioxopyrimidin‑4‑yl)‑2,3‑
dihydrophthalazine‑1,4‑dione derivatives
Asiyeh Biabangard · Hamid Reza Shaterian
Received: 14 December 2014 / Accepted: 27 February 2015
© Iranian Chemical Society 2015
Abstract The efficient synthesis of tetrahydro-2,6-diox-
opyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione deriva-
tives via four-component reaction of hydrazine hydrate,
phthalic anhydride, aromatic aldehydes and barbituric acid
using vitamin B1 supported on alumina (VB1-Al2O3) as a
heterogeneous catalyst under thermal solvent-free condi-
tions in excellent yields is described.
barbituric acid, and arylaldehydes using FeCl3 as catalyst
was reported on the basis of central core of phthalazine
[8]. In continuation of our researches in applications of
reusable and green catalysts in organic reactions [9, 10],
herein, we report a new and simple method for the syn-
thesis of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihy-
drophthalazine-1,4-dione derivatives via four-component
reaction of hydrazine hydrate, phthalic anhydride, alde-
hydes and barbituric acid in the presence of VB1-Al2O3 as
highly efficient and recyclable catalyst under solvent-free
conditions (Scheme 1).
Keywords Hydrazine hydrate · Phthalic anhydride ·
Barbituric acid · Aldehyde · VB1-Al2O3 · Catalyst
Introduction
Experimental
Multicomponent reactions (MCRs) have been consid-
ered as a superior synthetic strategy for preparation of
libraries of drug-like advanced compounds [1]. MCRs
provide environmentally friendly processes by reduc-
ing the number of steps, energy consumption, and waste
production [2].
Phthalazine derivatives have been shown to have
many important biological properties such as vasorelax-
ant [3], anticonvulsant [4], cardiotonic [5], and many
other pharmacological applications. Literature survey
showed that three-component condensation reaction of
phthalhydrazide, 1,3-diketone, and aldehydes to produce
2H-indazolo[1,2-b]phthalazine-triones [6, 7] but the only
one synthetic method for preparation of tetrahydro-2,6-di-
oxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-diones
via three-component condensation from phthalhydrazide,
All reagents were purchased from Merck or Aldrich and
used without further purification. All yields refer to iso-
lated products after purification. Vitamin B1 supported
on alumina (VB1-Al2O3) as a heterogeneous catalyst was
prepared according to the literature [11]. Nuclear mag-
netic resonance (NMR) spectra were recorded using a
Bruker Advance DPX 500 MHz instrument. The spectra
were measured in DMSO‐d6 relative to tetramethylsi-
lane. Infrared (IR) spectra were recorded using a JASCO
FTIR 460 Plus spectrophotometer. Melting points were
determined in open capillaries using a BUCHI 510 melt-
ing point apparatus. Thin-layer chromatography (TLC)
was performed on silica‐gel Poly Gram SIL G/UV 254
plates.
Preparation of vitamin B1 supported on alumina [11]
A. Biabangard · H. R. Shaterian (*)
VB1-Al2O3 was prepared by mixing aluminum oxide (9 g,
90 active acidic, 0.063–0.200 mm) with a solution of VB1
(1 g) in distilled water (15 mL). The suspension was stirred
Department of Chemistry, Faculty of Sciences, University
of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
e-mail: hrshaterian@chem.usb.ac.ir
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J IRAN CHEM SOC
Scheme 1 Preparation of
tetrahydro-2,6-dioxopyrimidin-
4-yl)-2,3-dihydrophthalazine-
1,4-diones
Ar
O
N
O
O
NH
O
O
Catalyst
N
NH
O
HN
NH
+
O
NH2NH2.H2O +
+
ArCHO
Solvent-free,60oC
O
O
O
Catalyst:
VB1-Al2O3
Scheme2 Preparation of VB1-
Al2O3
CH3
N
H N
3
Cl
N
N
Cl
H3C
S
HO
O
CH3
Cl
Al2O3
active
acidic
H2O
NH3 Cl
N
N
Al2O3
OH
S
room temperature
N
O
CH3
CH3
N
VB1
S
NH3 Cl
VB1
=
Cl
N
N
CH3
VB1-Al2O3
Fig. 1 preparation of tetrahy-
dro-2,6-dioxopyrimidin-4-yl)-
2,3-dihydrophthalazine-1,4-
dione
for 1 h at room temperature, followed by removal of water
in a rotary evaporator, and the solid powder was dried at
100 °C for 3 h in an oven and then cooled in a desiccators
[11] (Scheme 2). Back titration analysis showed that 0.8 g
of the catalyst is equivalent to 0.05 mmol H+ per grams
[11].
Typical procedure for the preparation
of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-
dihydrophthalazine-1,4-dione
Hydrazine hydrate (1.2 mmol) and phthalic anhy-
dride (1 mmol) were mixed at 70 °C until a white solid
1 3

J IRAN CHEM SOC
phthalhydrazide was formed (10 min). Then, barbituric acid
(1 mmol), benzaldehyde (1 mmol) and VB1-Al2O3 (0.8 g,
5 mol %) was added to this solid-state mixture. The completion
of reaction is monitored on TLC. After completion of reaction,
the mixture cooled to room temperature. Then, EtOAc (30 mL)
was added and the catalyst was recovered by simple filtration.
The catalyst was washed with EtOAc and dried at 100 °C for
3 h, which could be reused without loss of its activity. The
filtrate solution was concentrated and the solid product was
recrystallized in EtOH to give pure products (Fig. 1).
(Table 1, entry 1): yellow solid; Mp: 230–232 °C. IR (KBr,
υ, cm−1): 3390, 3017, 2853, 1761, 1657, 1639, 1596, 713,
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.41 (s, 1H),
11.25 (s, 1H), 8.27 (s, 1H), 8.09–8.05 (m, 4H), 7.88–7.85
(m, 2H), 7.51–7.49 (m, 1H), 7.45–7.43 (m, 2H).
2-((13Z)-5-(4-Methylbenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3 dihydrophthalazine-1,4-dione
(Table 1, entry 2): yellow solid; Mp: 258–260 °C. IR (KBr,
υ, cm−1): 3290, 3096, 2840,1749, 1665, 1621, 1581, 712,
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.38 (s, 1H),
11.23 (s, 1H), 8.23 (s, 1H), 8.08–8.05 (m, 4H),7.88–7.85
(m, 2H), 7.26 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H).
Selected spectroscopic data for one known compounds are
given below
2-((13Z)-5-(4-Nitrobenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3 dihydrophthalazine-1,4-dione
(Table 1, entry 3): yellow solid; Mp: 274–276 °C. IR (KBr,
υ, cm−1): 3350, 3017, 2853, 1740, 1657, 1634, 1596, 717,
2-((13Z)-5-Benzylidene-1,2,5,6-tetrahydro-2,6-
dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione
Table 1 Preparation of
tetrahydro-2,6-dioxopyrimidin-
4-yl)-2,3-dihydrophthalazine-
Found m.p (oC) / L M.P (oC)b
230/230-232
Entry
Substrate
Time (min) / yield (%) a
12 / 91
1,4-dione derivatives via the
four-component condensation
reaction from hydrazine
hydrate, phthalic anhydride,
barbituric acid, and aromatic
aldehydes using VB1-Al2O3 as
catalyst under thermal solvent-
free conditions
CHO
1
2
3
CHO
10 / 92
13 / 89
259/258-261
274/274-276
H3C
O2N
CHO
11 / 90
10 / 92
255/256-258
231/232-234
4
5
CHO
6
7
11 / 91
14 / 88
256/255-257
280/280-282
MeO
CHO
NO2
CHO
8
10 / 91
12 / 91
262/ 262-264
271/270-272
Cl
9
a
10
Yields refer to the isolated
10 / 92
270/268-270
pure products
b
Melting point of products was
compared with literature [8]
1 3

J IRAN CHEM SOC
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.52 (s, 1H),
11.34 (s, 1H), 8.31 (s, 1H), 8.27–8.20 (m, 2H), 8.07–8.04
(m, 2H), 8.00 (d, J = 7.2 Hz, 2H), 7.87–7.83 (m, 2H).
2-((13Z)-5-(2-Methylbenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-
dione (Table 1, entry 4): yellow solid; Mp: 256–258 °C.
IR (KBr, υ, cm−1): 3452, 3314, 3070, 2959, 2872, 1691,
1615, 1569, 1226, 746, 1H NMR (500 MHz, DMSO-d6) (δ,
ppm): 11.42 (s, 1H), 11.19 (s, 1H), 8.40 (s, 1H), 8.09–8.06
(m, 2H), 7.89–7.86 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H),
7.31 (t, J = 7.3 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.17 (t,
J = 7.6 Hz, 1H), 2.27 (s, 3H).
2-((13Z)-5-(3-Methylbenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione
(Table 1, entry 5): yellow solid; Mp: 232–234 °C. IR (KBr,
υ, cm−1): 3352, 3086, 2857, 1751, 1678, 1639, 1588, 709,
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.40 (s, 1H),
Fig. 2 FT-IR spectra of a Al2O3, b vitamin B1, and c VB1-Al2O3
Scheme 3 The proposed
mechanism for the synthesis of
tetrahydro-2,6-dioxopyrimidin-
4-yl)-2,3-dihydrophthalazine-
1,4-dione derivatives
CH3
N
H N
Cl
3
N
N
Cl
H3C
O
S
O
O
HN
NH
Ar
H
Al2O3
OH
O
O
5
4
O
CH3
N
S
NH3 Cl
VB1
=
Cl
N
N
CHAr
CH3
O
O
VB1-Al2O3 (Catalyst)
H
N
HN
NH
O
O
6
O
N
Ar
H
N
8
O
N
O
N
HO
O
NH
N
VB1-Al2O3
Ar
H2O
H
HO
O
N
O
7
NH
NH
O
3
O
H O
-
2
O
NH2NH2.H2O
1
O
2
O
1 3

J IRAN CHEM SOC
11.24 (s, 1H), 8.23 (s, 1H), 8.08–8.05 (m, 3H), 7.88–7.85
(m, 3H), 7.33 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H).
2-((13Z)-5-(4-Bromobenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione
(Table 1, entry 9): yellow solid; Mp: 270–272 °C. IR (KBr,
υ, cm−1): 3203, 3092, 2850, 1726, 1660, 1654, 1598, 711,
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.42 (s, 1H),
11.28 (s, 1H), 8.21 (s, 1H), 8.07–8.04 (m, 2H), 7.97 (d,
J = 8.8 Hz, 2H), 7.86 (dd, J = 2.1, 10.2 Hz, 2H), 7.66–7.62
(m, 2H).
2-((13Z)-5-(3,4,5-Trimethoxybenzylidene)-1,2,5,6-
tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthala-
zine-1,4-dione (Table 1, entry 10):yellow solid; Mp: 268–
270 °C. IR (KBr, υ, cm−1): 3370, 3042, 2847, 1744, 1690,
1646, 1578, 716,1H NMR (500 MHz, DMSO-d6) (δ, ppm):
11.37 (s, 1H), 11.24 (s, 1H), 8.25 (s, 1H), 8.07–8.05 (m,
2H), 7.89–7.86 (m, 2H), 7.83 (s, 2H), 3.81 (s, 6H), 3.78 (s,
3H).
2-((13Z)-5-(4-Methoxybenzylidene)-1,2,5,6-tetrahy-
dro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-
1,4-dione (Table 1, entry 6): yellow solid; Mp: 255–257 °C.
IR (KBr, υ, cm−1): 3370, 3042, 2847, 1745, 1693, 1646,
1545, 710, 1H NMR (500 MHz, DMSO-d6) (δ, ppm):11.31
(s, 1H), 11.18 (s, 1H), 8.36 (d, J = 9.1 Hz, 2H), 8.24 (s,
1H), 8.07–8.05 (m, 2H), 7.88–7.86 (m, 2H), 7.04 (d,
J = 8.8 Hz, 2H), 3.86 (s, 3H).
2-((13Z)-5-(3-Nitrobenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione
(Table 1, entry 7): yellow solid; Mp: 280–282 °C. IR (KBr,
υ, cm−1): 3300, 3056, 2831, 1726, 1670, 1689, 1598, 715,
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.50 (s, 1H),
11.35 (s, 1H), 8.90 (s, 1H), 8.31–8.29 (m, 1H), 8.21 (d,
J = 7.6 Hz, 1H), 8.07–8.05 (m, 2H), 7.89–7.85 (m, 3H),
7.72 (t, J = 8.0 Hz, 1H).
2-((13Z)-5-(4-Chlorobenzylidene)-1,2,5,6-tetrahydro-
2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione
(Table 1, entry 8): yellow solid; Mp: 262–264 °C. IR (KBr,
υ, cm−1): 3309, 3012, 2850, 1761, 1662, 1644, 1559, 718,
1H NMR (500 MHz, DMSO-d6) (δ, ppm): 11.42 (s, 1H),
11.21 (s, 1H), 8.24 (s, 1H), 8.07 (d, J = 8.8 Hz, 3H), 7.89–
7.85 (m, 2H), 7.51 (d, J = 8.4 Hz, 3H).
Results and discussions
FT-IR analysis of VB1-Al2O3
FT-IR spectra of Al2O3, vitamin B1, and VB1-Al2O3 are
depicted in Fig. 2. The FT-IR spectrum of Al2O3 is well
known, and its principal feature is a broad band between
950 and 500 cm−1, ascribed to Al–O stretching. The sur-
face of Al2O3 is covered by OH groups that cause water
adsorption, and the band due to these species is between
3800 and 3000 cm−1, centered at 3460 cm−1 [12]. In addi-
tion, this band is ascribed to OH stretching of the adsorbed
water, the bridged hydroxyl group with molecular water,
other OH groups, and isolated OH groups [13].The spec-
trum of supported VB1-Al2O3 (c) also shows small bands
around 2900 cm−1 that are related to asymmetric and sym-
metric C–H stretching. The peaks located at 3440 cm−1 can
be attributed to the N–H stretching and confirmed that vita-
min B1 (b) was tethered on an alumina surface through its
hydroxyl group. In the spectrum (c), the peak at 1626 cm−1
can be ascribed to the C=N or C=C bands stretching fre-
quency of vitamin B1 supported on alumina.
92
87
100
80
60
40
20
0
91
85
90
85
88
82
1
2
3
4
Run Number
Catalyst Yield(%)
Product Yield (%)
The acidity of VB1-Al2O3 was also confirmed by the
back-titration method. Thus, triplicate of 1 g sample was
added to 5 mL of 0.1 N NaOH solution. To ensure that
Fig. 3 Reusability of the catalyst in the reaction of 4-methylbenza-
ldehyde, barbituric acid and phthalic anhydride, hydrazine hydrate
under solvent-free conditions (Table 1, Entry 2)
Table 2 Comparison results of VB1-Al2O3 in the four-component synthe-
sis with FeCl3 in the three-component synthesis of tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthalazine-1,4-dione derivatives
Entry
Catalyst (mol %)
Conditions
Time (min)
Yield (%) [References]
1
2
FeCl3 (15 mol %)
Solvent-free, 60 °C three-component reactions
Solvent-free, 60 °C four-component reactions
16–25
10–14
89–94 [8]a
(88–92)b (present work)
VB1-Al2O3 (5 mol %)
a
Three-component condensation from phthalhydrazide, barbituric acid, and arylaldehydes using FeCl3 as catalyst was studied [8]
Four-component reaction of hydrazine hydrate, phthalic anhydride, aldehydes and barbituric acid in the presence of VB1-Al2O3 was studied
b
1 3

J IRAN CHEM SOC
all of the VB1-Al2O3 was reacted with NaOH, the mix-
ture was sonicated for 10 min. To each vessel, two drops
of phenolphthalein pH-indicator was added. Back-titration
was accomplished by titrating the unreacted base in solu-
tion with standardized 0.1 N HCl solutions to the first per-
manent cloudy pink color. This was subtracted from the
primary amount of base to find the amount of base that
actually reacted with the VB1-Al2O3 as an acid. The acid-
ity value of VB1-Al2O3 was obtained as 0.06 mmol g−1 by
adding 4.4 mL of HCl. Our result was confirmed by the lit-
erature [8].
was reused for at least four runs without any loss of its
activity (Fig. 3).
To show the accessibility of the four-component reac-
tion of the present work in comparison results with only
one catalyst (FeCl3) which reported in the literature [8],
we summarized some of the results for the preparation of
tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthala-
zine-1,4-dione derivatives in Table 2. Table 2 shows that
VB1-Al2O3 is an efficient catalyst with respect to the reac-
tion time and obtained yields relative to FeCl3 as catalyst.
Total number of moles of NaOH added to the sam-
ple: 0.5 mmol, total volume of HCl added to each vessel:
4.4 mL (0.44 mmol), number of moles of NaOH that neu-
tralize VB1-Al2O3: 0.06 mmol (0.5–0.44 mmol).
Conclusions
We have developed a practical and green strategy for the
synthesis of tetrahydro-2,6- dioxopyrimidin-4-yl)-2,3-di-
hydrophthalazine-1,4-diones using VB1-Al2O3 as environ-
mentally bingeing catalyst under solvent-free conditions.
Clean reactions, short reaction times, high yields, reusabil-
ity of the catalyst and easy workup are advantages of this
protocol.
To choose optimum conditions, first we tried to prepare
tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydrophthala-
zine-1,4-dione from the reaction of phthalic anhydride
(1 mmol) and hydrazine hydrate (1.2 mmol), barbituric
acid (1 mmol), benzaldehyde (1 mmol) as a model reac-
tion in the presence of different catalytic amount of catalyst
(1, 3, 5, 8, 10 mol %) at different temperatures (25, 40, 60,
70, 80 °C) under solvent-free conditions. The best results
were obtained with 5 mol % of VB1-Al2O3 at 60 °C. Using
these optimized conditions, the scope and efficiency of
these procedures were explored for the synthesis of a wide
variety of substituted tetrahydro-2,6-dioxopyrimidin-4-yl)-
2,3-dihydrophthalazine-1,4-dione. Interestingly, a variety
of aldehydes including ortho-, meta-, and para-substituted
aryl aldehydes participated well in this reaction and gave
Acknowledgments We are thankful to the University of Sistan and
Baluchestan Research Council for the partial support of this research.
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tetrahydro-2,6-dioxopyrimidin-4-yl)-2,3-dihydroph-
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electron-withdrawing and electron-donating substituent act
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shown in Scheme 3. First, the reaction occurs via initial
nucleophilic addition of hydrazine hydrate (1) to phthalic
anhydride (2), followed by dehydration to obtain phthalhy-
drazide (3). The second step stared by Knoevenagel con-
densation of barbituric acid (4) and aldehyde (5) in the
presence of catalyst follow to get the compound (6). After
Michael addition of phthalhydrazide (3) at C=O bond of 6,
cause to formation intermediate (7). Finally, the products
(8) obtained by elimination of water molecule.
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Recovery of the green catalyst is more important in a
synthetic methodology. Thus, we investigated the reusabil-
ity of VB1-Al2O3 in the reaction. The recovered catalyst
1 3