Solvent-free, one-pot, four-component synthesis of 2H-indazolo[2,1-b] phthalazine-triones using sulfuric acid-modified PEG-6000 as a green recyclable and biodegradable polymeric catalyst

Article abstract of DOI:10.1016/j.cattod.2012.05.026

A green practical method for the efficient synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-triones using sulfuric acid-modified polyethylene glycol-6000 (PEG-OSO₃H) as an eco-friendly polymeric catalyst from the four-component condensation reaction of phthalic anhydride, hydrazinium hydroxide, 1,3-cyclohexanedione or 5,5-dimethyl 1,3-cyclohexanedione (dimedone) and aromatic aldehydes under solvent-free conditions at 80 °C is described. This approach allowed the environmental impact factor (E-factor) to be minimized.

Full text of DOI:10.1016/j.cattod.2012.05.026

Catalysis Today 196 (2012) 148–155
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Catalysis Today
journal homepage: www.elsevier.com/locate/cattod
Solvent-free, one-pot, four-component synthesis of
2H-indazolo[2,1-b]phthalazine-triones using sulfuric acid-modified PEG-6000 as
a green recyclable and biodegradable polymeric catalyst
Alireza Hasaninejeda,∗, Maryam Rasekhi Kazeroonia, Abdolkarim Zareb
a Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
b Department of Chemistry, Payame Noor University, PO BOX 19395-4697, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A green practical method for the efficient synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-
triones using sulfuric acid-modified polyethylene glycol-6000 (PEG-OSO3H) as an eco-friendly polymeric
catalyst from the four-component condensation reaction of phthalic anhydride, hydrazinium hydroxide,
1,3-cyclohexanedione or 5,5-dimethyl 1,3-cyclohexanedione (dimedone) and aromatic aldehydes under
solvent-free conditions at 80 ◦C is described. This approach allowed the environmental impact factor
(E-factor) to be minimized.
Received 7 October 2011
Received in revised form 22 April 2012
Accepted 1 May 2012
Available online 30 June 2012
Key words:
© 2012 Elsevier B.V. All rights reserved.
Multi-component synthesis
2H-Indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione
Solvent-free
PEG-OSO3H
Catalyst
E-factor
1. Introduction
friendly catalysts with high-performance [20]. Sulfuric acid-
modified PEG-6000 (PEG-OSO3H) is an example of polyethylene
Multi-component synthesis is an important way for the effi-
cient and rapid synthesis of a wide variety of complex organic
compounds. These reactions have been investigated extensively
in diversely oriented synthesis; primarily due to their ability to
produce complex molecular functionality from simple starting
materials via one-pot reaction [1–4].
glycol supported catalyst that is functionalized by acidic groups
and is a mild, non-volatile and non-corrosive solid organic acid.
Recently we have used this catalyst for the solvent-free synthesis
of poly-substituted quinolones, synthesis of acylals and synthesis
of bis(indolyl)methanes and 4,4ꢀ-(arylmethylene)-bis(3-methyl-1-
phenyl-1H-pyrazol-5-ol)s [21–24].
The best solvent from the green chemistry point of view is no sol-
vent due to minimization of environmental impact factor. Because
of the higher concentration of the reactants, these reactions pro-
ceed with higher yield and often lead to short reaction times and
easier workup [5–8]. The combination of solvent-free conditions
with multi-component reaction has been shown to be a power-
ful strategy to yield complex molecular structures in few synthetic
steps [9,10].
Recent developments for sustainable chemistry are being driven
by a shift from conventional liquid acid catalysts to chemically sta-
ble and biodegradable solid catalysts [11–13]. There is considerable
interest in exploiting biodegradable polymers such as polyethy-
lene glycol-based polymers [14–19], to create environmentally
Sheldon introduced the concept of the E-factor to estimate the
value of environmental impact of manufacturing processes [25].
The E-factor is designated as the weight of waste generated per
weight of product and waste is defined as everything produced in
the process except the desired product.
Aza heterocycles are an important class of compounds and have
many applications in pharmaceutical, agrochemical, and functional
materials [26,27]. Among them, phthalazine derivatives possess
a wide range of biological activities [28–31]. 2H-Indazolo[2,1-
b]phthalazinetriones are a group of phthalazine derivatives that
the development of an efficient method for the synthesis of these
derivatives is an active ongoing research area. There are some
reports on the solution or solid phase synthesis of 2H-indazolo[2,1-
b]phthalazinetriones [32–40]. Most of the mentioned methods
suffer from at least one of the limitations such as; low yield, long
reaction times, effluent pollution, harsh reaction conditions, for-
mation of by-products, the use of toxic organic solvents, the use
∗
Corresponding author. Tel.: +98 771 4541494; fax: +98 771 4541494.
E-mail address: ahassaninejad@yahoo.com (A. Hasaninejed).
0920-5861/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.cattod.2012.05.026

A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
149
O
n
O
O
O
Ar
CHO
4
O
O
O
O
O
O
O
Ar
O
R
R
O
R
N
N
SO H
O
HO3S
3
Solvent-Free, 80 oC
O
1
3
R
5
2
Scheme 1. The synthesis of 2H-indazolo[1,2-b]phthalazine-triones from phthalic anhydride (1), hydrazinium hydroxide (2), dimedone or 1,3-cyclohexanedione (3), and
arylaldehydes (4) using PEG-OSO3H.
of additional instruments such as ultra sound and tedious workup
procedures. Moreover PEG-based catalysts are very cheaper in
comparison with ionic liquids. In the present study, we report an
efficient, E-factor minimized, one-pot, four-component method for
the preparation of 2H-indazolo[1,2-b]phthalazine-trione deriva-
tives (5) by condensation of phthalic anhydride (1), hydrazinium
hydroxide (2), dimedone or 1,3-cyclohexanedione (3) and aromatic
aldehydes (4) under solvent-free conditions at 80 ◦C (Scheme 1).
2.2.1. Selected spectral data for
2H-indazolo[2,1-b]phthalazine-trione derivatives:
3,4-Dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-trione (3a): M.P. = 207–209 ◦C (lit.
[28] 204–206 ◦C), 1H NMR (CDCl3, 500 MHz) ı: 1.23 (s, 6H), 2.36 (s,
2H), 3.27 (1H, dd, J = 19.03 Hz and 2.07 Hz), 3.44 (d, 1H, J = 19.03 Hz),
6.4 (s, 1H), 7.29–7.37 (m, 5H), 7.44 (d, 2H, J = 7.2 Hz), 7.86–7.87 (m,
2H), 8.28–8.36 (m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 28.9, 29.1,
35.0, 38.4, 51.3, 95.4, 119.0, 127.5, 128.2, 128.4, 129.1, 129.4, 129.5,
133.9, 134.9, 136.8, 151.2, 154.7, 156.4, and 192.5.
2. Experimental
3,4-Dihydro-3,3-dimethyl-13-(4-methylphenyl)-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3b):
All chemicals were purchased from Merck or Fluka Chemical
Companies. The 1H NMR (500 MHz) and 13C NMR (125 MHz) were
run on a BrukerAvance DPX-250, FT-NMR spectrometer (ı in ppm).
Melting points were recorded on a Büchi B-545 apparatus in open
capillary tubes.
M.P. = 225–227 ◦C (lit. [28] 227–229 ◦C), 1H NMR (CDCl3, 500 MHz)
ı: 1.17 (s, 6H), 2.25 (s, 3H), 2.28 (s, 2H), 3.18 and 3.37 (AB system, s,
2H, J = 18.85 Hz), 6.36 (s, 1H), 7.08–7.2 (m, 4H), 7.8 (m, 2H), 8.2–8.3
(m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 21.6, 28.8, 29.1,35.0, 38.4,
51.3, 65.1, 118.9, 127.4, 128.0, 128.3, 129.3, 129.5, 129.7, 133.8,
134.8, 138.8, 151.1, 154.6, 156.3, and 192.5.
3,4-Dihydro-13-(4-isopropylphenyl)-3,3-dimethyl-2-
H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione
2.1. Preparation of PEG-OSO3H
(3c):
M.P. = 226–228 ◦C, 1H NMR (CDCl3, 500 MHz) ı: 1.22–1.25 (m,
12H), 2.37 (s, 2H), 2.9 (m, 1H), 3.26 (AB system, d, 1H, J = 19.0 Hz),
3.42 (AB system, d, 1H, J = 19.0 Hz), 6.47 (s, 1H), 7.19–7.36 (m, 4H),
7.86–7.88 (m, 2H), 8.3–8.4 (m, 2H). 13C NMR (CDCl3, 125 MHz)
ı: 24.2, 28.5, 29.0, 34.1, 35.3, 35.9, 51.9, 64.8, 111.3, 112.0, 114.6,
118.3, 119.2, 121.4, 123.0, 123.9, 127.2, 127.5, 128.3, 128.4, 132.2,
132.3, 135.5, 136.8, 156.4, 158.8, 191.3. m/z (%) = 414 (M+, 63), 349
(23), 295 (100), 239 (15), 104 (23), and 76 (15).
At 0 ◦C, chlorosulfonic acid (1.16 g, 10 mmol) was added to a
solution of PEG(6000) (6.0 g, 1 mmol) in CH2Cl2 (10 ml). Then the
resulting solution was stirred at room temperature overnight, and
the solution was concentrated under vacuum. Appropriate ether
(50 ml) was added, and the precipitate filtered and washed with
ether (30 ml) three times to afford the PEG-OSO3H [20]. Differ-
ent molecular weights of PEG-OSO3H were prepared according to
above procedure.
3,4-Dihydro-3,3-dimethyl-13-(2-nitrophenyl)-2-H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3d):
M.P. = 238–240 ◦C, 1H NMR (CDCl3, 500 MHz) ı: 1.21 (s, 3H),
1.24 (s, 3H), 2.25 (s, 3H), 2.31–2.39 (m, 2H), 3.28 (AB system, dd,
J = 2.04 Hz and J = 19.1 Hz, 1H), 3.41 (AB system, d, J = 19.1 Hz, 1H),
7.2 (s, 1H), 7.45–7.59 (m, 3H), 7.87–7.96 (m, 3H), 8.27–8.4 (m,
3H), 13C NMR (CDCl3, 125 MHz) ı: 28.9, 29.2, 34.9, 38.4, 51.2, 68.1,
115.3, 128, 128.5, 128.8, 129.5, 129.8, 130.1, 130.2, 133.4, 134.0,
134.9, 137.9, 153.3, 154.5, 156.7, 192.4. m/z (%) = 417 (M+,10), 400
(100), 370 (23), 314 (30), 295 (68), 239 (15), 130 (15), 104 (39),
and 76 (31).
2.2. Typical procedure for the synthesis of
2H-indazolo[2,1-b]phthalazine-trione derivatives
Hydrazinium hydroxide (1.2 mmol), phthalic anhydride
(1 mmol), cyclic 1,3-dicarbonyl compounds (1 mmol), aldehyde
(1 mmol) and PEG-OSO3H (8 mol%) was heated at 80 ◦C. The
completion of reaction is monitored on TLC. The 2-H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-trione derivatives were synthesized.
After satisfactory completion of the reaction, the mixture was
cooled to room temperature and H2O (5 ml) was added to this mix-
ture and was shaken for a few minutes to dissolve PEG-OSO3H. 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 solid
was washed with t-butylmethyl ether, and dried. The recovered
catalyst was reused another time.
3,4-Dihydro-3,3-dimethyl-13-(3-nitrophenyl)-2-H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3e):
M.P. = 269–271 ◦C (lit. [28] 270–272 ◦C); 1H NMR (CDCl3, 500 MHz)
ı: 1.2 (s, 6H), 2.38 (s, 2H), 3.30 (AB system, dd, 1H, J = 19.0 Hz and
J = 2.1 Hz), 3.46 (AB system, d, 1H, J = 19.2 Hz), 6.5 (s, 1H), 7.59 (t,
1H, J = 7.85 Hz), 7.89–7.93 (m, 3H), 8.19 (d, J = 8.7 Hz, 2H), 8.26–8.42
(m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 28.8, 29.1, 35.1, 38.4, 51.2,
64.6, 117.6, 121.9, 124.1, 128.1, 128.7, 129.1, 129.4, 130.1, 134.3,
134.6, 135.2, 139.05, 152.2, and 192.5.

150
A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
3,4-Dihydro-3,3-dimethyl-13-(4-nitrophenyl)-2-H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
d, 1H, J = 19.03 Hz), 3.8 (s, 1H), 6.44 (s, 1H), 6.4 (d, 1H, J = 7.9 Hz),
(3f):
6.9 (s, 1H), 7.03, (d, 1H, J = 7.5 Hz), 7.25–7.22 (m, 1H), 7.87 (t, 2H,
J = 4.2 Hz), 8.2–8.3 (m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 28.9, 29.1,
35.0, 38.4, 51.4, 55.6, 65.2, 110.3, 113.5, 114.2, 118.9, 119.8, 128.1,
128.4, 129.4, 129.5, 130.1, 133.9, 134.9, 138.4, 151.2, 154.7, 156.4,
160.1, 192.5. m/z (%) = 402 (M+, 19), 295 (100), 239 (8), 104 (11),
and 76 (8).
13-Benzoyl-3,3-dimethyl-3,4-dihydro-1-H-indazolo[1,2-
b]phthalazine-1,6,11(2H, 13H)-trione (3o): M.P. = 228–230 ◦C, 1H
NMR (CDCl3, 500 MHz) ı: 1.21 (s, 3H), 1.24 (s, 3H), 2.36 (s, 2H), 3.27
(AB system, d, 1H, J = 19.1 Hz), 3.42 (AB system, d, 1H, J = 19.04 Hz),
6.88 (s, 1H), 7.57 (t, 2H, J = 7.5 Hz), 7.68 (t, 1H, J = 7.5 Hz), 7.8–7.9
(m, 2H), 8.2–8.4 (m, 4H), (d, 1H, J = 7.5 Hz), 7.25–7.22 (m, 1H). 13C
NMR (CDCl3, 125 MHz) ı: 28.6, 29.1, 35.3, 38.5, 51.0, 63.2, 116.5,
128.1, 128.6, 128.8, 129.0, 129.6, 129.7, 134.2, 134.5, 134.9, 136.1,
154.2, 154.7, 156.2, 192.5, 194.6. m/z (%) = 400 (M+, 5), 295 (100),
239 (65), 130 (35), 104 (50), 77 (70), and 51 (20).
M.P. = 225–227 ◦C (lit. [28] 223–225 ◦C), 1H NMR (CDCl3, 500 MHz)
ı: 1.21 (s, 3H), 1.24 (s, 3H), 2.1 (s, 2H), 3.2 (AB system, dd, 1H,
J = 19.1 Hz and J = 2.2 Hz), 3.43 (AB system, d, 1H, J = 19.2 Hz), 6.53
(s, 1H), 7.61–7.64 (m, 2H), 7.90–7.91 (m, 2H), 8.20–8.41 (m, 4H).
13C NMR (CDCl3, 125 MHz) ı: 28.8, 29.1, 31.3, 35.1, 38.4, 51.2, 64.5,
117.7, 128.2, 128.4, 128.6, 129.1, 129.3, 134.3, 135.2, 143.8, 148.3,
152.1, 154.9, 156.3, and 192.4.
3,4-Dihydro-3,3-dimethyl-13-(2-chlorophenyl)-2-
H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3g):
M.P. = 265–267 ◦C (lit. [28] 264–266 ◦C), 1H NMR (CDCl3, 500 MHz)
ı: 1.23 (s, 6H), 2.34 (s, 2H), 3.26 (AB system, d, 1H, J = 18.9 Hz),
3.42 (AB system, d, 1H, J = 19.0 Hz), 6.7 (s, 1H), 7.24–7.50 (m, 4H),
7.87–8.39 (m, 4H). 13C NMR (CDCl3, 125 MHz) ı: 28.8, 29.2, 35.0,
38.4, 51.3, 64.4, 116.7, 127.6, 128.1, 128.4, 129.1, 129.4, 130.2,
130.9, 132.0, 133.0, 133.9, 134.9, 152.2, 154.6, 156.6, and 192.4.
3,4-Dihydro-3,3-dimethyl-13-(3-chlorophenyl)-2-
3,3-Dimethyl-13-(naphthalen-2-yl)-3,4-dihydro-2-
H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3h):
H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione
(3p):
M.P. = 209–211 ◦C (lit. [30] 204–206 ◦C), 1H NMR (CDCl3, 500 MHz)
ı: 1.24 (s, 6H), 2.37 (s, 2H), 3.27 (AB system, d, 1H, J = 19.07 Hz),
3.43 (AB system, d, 1H, J = 19.09 Hz), 6.43 (s, 1H), 7.27–7.40 (m,
4H), 7.88–7.90 (m, 2H), and 8.29–8.40 (m, 2H).
M.P. = 251–253 ◦C, 1H NMR (CDCl3, 500 MHz) ı: 1.16 (s, 6H),
2.27 (s, 2H), 3.22 (d, 1H, J = 19.09 Hz), 3.41 (d, 1H, J = 19.1 Hz), 6.54
(s, 1H), 7.37–7.42 (m, 3H), 7.71–7.89 (m, 6H), 8.16–8.32 (m, 2H).
13C NMR (CDCl3, 125 MHz) ı: 28.7, 29.0, 35.0, 38.4, 51.3, 65.4,
118.8, 124.6, 126.6, 126.7, 127.2, 128.0, 128.0, 128.3, 128.6, 129.0,
129.4, 133.5, 133.7, 133.9, 134.1, 134.9, 151.3, 154.7, 156.4, 192.4.
m/z (%) = 422 (M+, 68), 295 (100), 239 (21), 104 (22), and 76 (17).
13-(2,6-Dichlorophenyl)-3,4-dihydro-3,3-dimethyl-2-H-
indazolo[1,2-b]phthalazine-1,6,11(13H)-trione (3 s): M.P. > 280 ◦C,
1H NMR (CDCl3, 500 MHz) ı: 2.09–2.12 (m, 2H), 2.3 (m, 2H),
3.26–3.30 (m, 2H), 7.04–7.11 (m 3H), 7.29 (s, 1H), 7.73–7.75 (m,
2H), 8.07–8.2 (m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 10.9, 21.4,
33.2, 56.9, 105.9, 122.4, 125.6, 127.5, 127.9, 130.1, 130.5, 131.8,
135.1, 138.4, 142.1, 144.7, 158.8, 159. 1, 193.5. m/z (%) = 412 (M+,
5), 267 (100), 239 (65), 104 (52), 77 (65), and 51 (20).
3,4-Dihydro-3,3-dimethyl-13-(4-chlorophenyl)-2-
H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3i):
M.P. = 260–262 ◦C (lit. [28] 262–264 ◦C), 1H NMR (CDCl3, 500 MHz)
ı: 1.23 (s, 6H), 2.36 (s, 2H), 3.26 (AB system, d, 1H, J = 18.98 Hz),
3.43 (AB system, d, 1H, J = 18.82 Hz), 6.44 (s, 1H), 7.29–7.38 (m,
4H), 7.88–7.90 (m, 2H), and 8.29–8.38 (m, 2H).
3,4-Dihydro-3,3-dimethyl-13-(2,6-chlorophenyl)-2-
H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3j):
M.P. = 260–262 ◦C, 1H NMR (CDCl3, 500 MHz) ı: 1.24 (s, 6H),
2.35 (s, 2H), 3.26 (AB system, d, 1H, J = 19.03 Hz), 3.39 (AB system,
d, 1H, J = 19.13 Hz), 7.47 (s, 1H), 7.19–7.32 (m, 3H), 7.88–7.90 (m,
2H), 8.27–8.36 (m, 2H). MS: m/z (%) = 440 (52), 405 (34), 295 (100),
239 (13), 162 (36), 104 (57), and 76 (34).
4-(2,3,4,6,11,13-Hexahydro-3,3-dimethyl-1,6,11-trioxo-1-H-
indazolo[1,2-b]phthalazin-13-yl)benzonitrile (3t): M.P. > 280 ◦C
1H NMR (CDCl3, 500 MHz) ı: 2.2 (m, 2H), 2.4 (m, 2H), 3.28 (d, 1H,
J = 18.4 Hz), 3.49 (d, 1H, J = 18.5 Hz), 6.39 (s, 1H), 7.51–7.82 (m, 6H),
8.18–8.31 (m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 22.7, 24.9, 32.9,
55.91, 106.0, 114.7, 118.8, 124.3, 127.5, 128.8, 129.2, 133.3, 138.5,
144.4, 152.5, 158.8, 159.4, 193.8. m/z (%) = 369 (M+, 68), 267 (100),
217 (18), 130 (18), 104 (52), and 76 (47).
3-Benzoyl-3,4-dihydro-1-H-indazolo[1,2-b]phthalazine-
1,6,11(2H,13H)-trione (3v): M.P. = 254–256 ◦C 1H NMR (CDCl3,
500 MHz) ı: 2.26 (m, 2H), 2.48 (m, 2H), 3.35–3.57 (m, 2H), 6.8 (s,
1H), 7.56–7.9 (m, 5H), and 8.3–8.4 (m, 3H).
3,4-Dihydro-3,3-dimethyl-13-(4-CN-phenyl)-2-H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3k):
M.P. = 224–226 ◦C, 1H NMR (CDCl3, 500 MHz) ı: 1.22 (s, 3H),
1.24 (s, 3H), 2.36 (s, 2H), 3.29 (AB system, d, 1H, J = 19.1 Hz), 3.42
(AB system, d, 1H, J = 19.1 Hz), 6.48 (s, 1H), 7.61–7.64 (m, 2H), 7.56
(d, 2H, J = 8.05 Hz), 7.6 (d, 2H, 8.04 Hz), 7.90–7.92 (m, 2H), 8.2–8.4
(m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 28.4, 29.1, 35.1, 38.4, 51.2,
64.8, 112.9, 117.8, 118.8, 128.2, 128.3, 128.6, 129.1, 129.3, 133.0,
134.3, 135.2, 141.9, 151.9, 154.9, 156.3, 192.4. m/z (%) = 397 (M+,
63), 295 (100), 239 (15), 130 (10), 104 (44), and 76 (31).
3,4-Dihydro-3,3-dimethyl-13-(4-fluorophenyl)-2-
H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
3,4-Dihydro-13-(naphthalen-2-yl)-2-H-indazolo[1,2-
(3l):
b]phthalazine-1,6,11(13H)-trione (3w): M.P. = 248–250 ◦C 1H
NMR (CDCl3, 500 MHz) ı: 2.29 (m, 2H), 2.49 (m, 2H), 3.41–3.68 (m,
2H), 6.65 (s, 1H), 7.47–7.53 (m, 3H), 7.82–7.94 (m, 6H), 8.27–8.40
(m, 2H). m/z (%) = 394 (M+, 34), 267 (100), 217 (7), 104 (12), 76
(10), and 51 (20).
M.P. = 216–218 ◦C (lit. [29] 218–220 ◦C), 1H NMR (CDCl3, 500 MHz)
ı: 1.24 (s, 6H), 2.36 (s, 2H), 3.26 (AB system, dd, 1H, J = 19.06 Hz
and J = 2.2 Hz), 3.43 (AB system, dd, 1H, J = 19.4 Hz and J = 1.15 Hz),
6.46 (s, 1H), 7.02–7.06 (m, 2H), 7.40–7.44 (m, 2H), 7.86–7.89 (m,
2H), 8.27–8.39 (m, 2H). 13C NMR (CDCl3, 125 MHz) ı: 28.8, 29.1,
1
35.1, 38.4, 51.3, 64.7, 116.0, 116.2 (d, JC–F = 275 Hz), 118.6, 128.1,
128.4, 129.3, 129.4, 132.6, 134.0, 135.0, 151.4, 154.8, 156.4, 162.1,
164.1, and 192.5.
3. Results and discussion
3,4-Dihydro-3,3-dimethyl-13-(4-bromophenyl)-
2-H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3 m): M.P. = 262–264 ◦C (lit. [29] 266–268 ◦C), 1H NMR (CDCl3,
500 MHz) ı: 1.23 (s, 6H), 2.36 (s, 2H), 3.26 (AB system, d, 1H,
J = 19.02 Hz), 3.42 (AB system, d, 1H, J = 18.9 Hz), 6.42 (s, 1H),
7.29–7.4 (m, 4H), 7.8–8.3 (m, 4H).
In order to establish the optimum conditions for this reac-
tion, initially the influence of the reaction temperature, the
amounts of catalyst and the reaction time were tested and opti-
mized. For this purpose, a reaction between phthalic anhydride
(1 mmol), hydrazinium hydroxide (1.2 mmol), 5,5-dimethyl-1,3-
cyclohexanedione (1 mmol) and benzaldehyde (1 mmol) were
examined as the model reaction in the presence of PEG-OSO3H.
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, and it was increased in higher
3,4-Dihydro-3,3-dimethyl-13-(3-methoxyphenyl)-2-
H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
(3n):
M.P. = 210–212 ◦C, 1H NMR (CDCl3, 500 MHz) ı: 1.23 (s, 6H),
2.36 (s, 2H), 3.26 (AB system, d, 1H, J = 19.07 Hz), 3.42 (AB system,

A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
151
Table 1
the synthesis of 2H-indazolo[1,2-b]phthalazine-triones under the
optimum conditions were examined and the desired products were
obtained in high yields (Table 1, entries 3s–3w).
The reaction of phthalic anhydride (1 mmol), hydrazinium hydroxide (1.2 mmol),
5,5-dimethyl-1,3-cyclohexanedione (1 mmol) and benzaldehyde (1 mmol) in the
presence of different catalysts (8 mol%) at 80 ◦C.
To assess the feasibility application of this method on a
preparative scale, the model reaction for the synthesis of 2H-
indazolo[1,2-b]phthalazine-trione was performed on a 20-mmol
scale. As expected, the reaction preceded similarly to the smaller
scale, providing the desired product in high yield.
We also determined the E-factor of our method to evaluate that
this method minimizes environmental impacts. For the case stud-
ied, data involved for the E-factor calculation, such as the amount
of reactants and the volume of solvents used in the synthesis step
and in the workup. The E-factor was calculated from the equation
described by Sheldon [25]. For example; the E-factor calcula-
tion for the condensation of hydrazinium hydroxide (1.2 mmol),
phthalic anhydride (1 mmol), dimedone (1 mmol) and benzalde-
hyde (1 mmol) in the presence of PEG-OSO3H as catalyst has given
as bellow:
Entry
Catalyst
Time (min)
Yield (%)a
1
2
3
4
5
6
7
10
10
92
92
85
70
–
10
10
180
180
180
180
–
E-factor = {{0.14 g (phthalic anhydride) + 0.06 g (hydrazinium
–
hydroxide) + 0.14 g
(dimedone) + 0.106 g
(benzaldehyde) + 5 g
(water) + 7.8 g
uct} = 40.4.
(ethylaetate) − 0.32 g
product}/0.32 g
prod-
8
–
To assess the capability and efficiency of our catalyst, from the
green chemistry point of view, with respect to the reported cat-
alysts for the synthesis of 2H-indazolo[1,2-b]phthalazine-triones,
E-factor values for application of these catalysts are tabulated in
Table 3. As is clear from Table 3, better E-factor value was obtained
for products 3a in the presence of PEG-OSO3H.
a
Isolated yield.
temperatures. At 80 ◦C, the reaction rate was found to be a max-
imum, and further increases in temperature did not show any
enhancement. It should be noted that the optimal catalyst load-
ing in the synthesis of 2,2-dimethyl-13-phenyl-2,3-dihydro-1H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione product peaked at
a concentration of 8 mol%. When the amount of catalyst was lower,
the yield of the product decreased, whereas raising the catalyst
concentration did not lead to a pronounced increase to the prod-
uct yield. During our optimization studies, various solvents were
examined and solvent-free conditions was found to be the most
optimum in terms of reaction rate, and isolated yield, therefore
optimized conditions is shown in Scheme 1.
For further study on different catalyst of the some nature, the
model reaction was examined in the presence of different molec-
ular weight of PEG and PEG-OSO3H (Table 1). As it can be seen
from Table 1, the reaction did not proceed at all in the presence of
PEG alone with different molecular weights. To recognize the role
of poly(ethylene glycol) skeleton in PEG-OSO3H, the reaction was
examined in the presence of different molecular weight of PEG-
OSO3H. As it is clear from Table 1, entry 2 PEG(6000)-OSO3H is the
best catalyst and the yield of product in the presence of this catalyst
is high.
The generality and functional group tolerance of this procedure
in the direct synthesis of 2H-indazolo[1,2-b]phthalazine-trione
derivatives was examined using a number of substituted aromatic
aldehydes in the presence of PEG(6000)-OSO3H as catalyst under the
optimized conditions (Scheme 1 and Table 2). In all cases, the reac-
tions gave the corresponding products in good to excellent yields
(Table 2) and in very short reaction times. This method offers signif-
icant improvements with regard to the scope of the transformation,
simplicity, and green aspects by avoiding expensive or corrosive
catalysts.
As shown in Table 2, aromatic aldehydes bearing electron-
donating or -withdrawing substituents gave the desired 2H-
indazolo[1,2-b]phthalazine-trione in high yields. The method
tolerates key functional groups such as halides, alkyl, nitro,
methoxy, thiomethoxy and nitrile and besides the para and meta
positions on the aromatic ring of aldehyde, different functional
groups were also introduced to ortho position indicating the
method is not sensitive to steric or electronic ortho variation of sub-
stituents. In the same way, the reaction of 1,3-cyclohexanedione for
To explore the mechanism of the reaction, in model com-
pound for the synthesis of 2H-indazolo[1,2-b]phthalazine-trione,
the phthalhydrazide is formed within the first 2 min of the
beginning of reaction. So, it is not necessary to prepare the
phthalhydrazide in advance. The rate-determining step was found
to be the dehydrative cyclization step. We can directly use
phthalic anhydride, hydrazinium hydroxide, 5,5-dimethyl-1,3-
cyclohexanedione or 1,3-cyclohexandione and benzaldehyde as
starting materials in the presence of PEG-OSO3H, which should
be synthetically useful and practical. A plausible pathway for the
formation of 2H-indazolo[1,2-b]phthalazine-trione involves initial
nucleophilic addition of hydrazinium hydroxide (2) to phthalic
anhydride (1), followed by dehydration to form phthalhydrazide
A. In the next step, via a PEG-OSO3H catalyzed Knoevenagel con-
densation of 1,3-dione (3) with aromatic aldehyde (4) intermediate
B was formed. Subsequent Michael addition of A to intermediate
B was occurred in the catalytic media, followed cyclization affords
the corresponding product (5) in the catalytic cycle (Scheme 2).
Acidic PEG-based catalysts have been shown a dual role in
organic reactions: as a catalyst to activate the substrate molecules
and as a solvent to soluble organic reactants due to their low melt-
ing points [15–17]. As a matter of fact, in the presented reaction, we
propose that not only the substrate molecules are activated by the
catalyst, but also PEG-OSO3H as a solvent increases the collapse of
organic reactants and they are also accompanied by inherent Bron-
sted acidity of SO3H groups, which are capable of bonding with
carbonyl oxygen of the substrates assisting in generation of ionic
intermediates through activation of reactants. In other words, these
intermediates are generated inside the crown-shape moiety by suf-
ficient energy released during the collapse and strong polarity of the
SO3H groups. By using PEG-OSO3H, the reaction rates and yields
under the reaction condition are enhanced, whereas in the absence
of mentioned Bronsted acid no product is obtained. Regarding the
solvent effect in the synthesis of 2H-indazolo[1,2-b]phthalazine-
trione it should be noted that since by cyclization of intermediate B,
the nucleophilic nitrogen is already incorporated to the skeleton of
this intermediate, because of the proper spatial orientation caused
by simple rotation of the carbon-carbon and carbon–oxygen bonds

152
A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
Table 2
PEG-OSO3H-catalyzed synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives via a one-pot, four-component reaction.
Entry
R
Ar
Product
Time (min)
Yield (%)a
O
O
N
N
O
3a
Me
C6H5
13
87
Me
O
O
O
N
N
3b
Me
4-Me C6H4
15
90
O
O
O
N
N
3c
3d
3e
Me
Me
Me
4-isopropyl-C6H4
17
15
10
83
90
92
O
NO2
O
N
N
O
O
2-NO2 C6H4
NO2
O
N
N
O
O
3-NO2 C6H4
NO2
O
N
N
O
O
3f
Me
Me
Me
4-NO2 C6H4
2-Cl C6H4
3-Cl C6H4
15
10
15
90
87
91
Cl
O
N
N
O
O
3g
3h
Cl
O
N
N
O
Cl
O
O
O
N
N
3i
Me
4-Cl C6H4
10
92

A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
153
Table 2 (Continued)
Entry
R
Ar
Product
Time (min)
Yield (%)a
O
O
Cl
Cl
O
N
N
3j
Me
2,6 di-Cl C6H3
20
80
93
85
CN
O
O
N
N
O
3k
Me
Me
4-CN C6H4
15
10
F
O
O
O
N
N
3l
4-F C6H4
Br
O
O
N
N
O
O
3m
3n
Me
Me
4-Br C6H4
15
18
87
86
OMe
O
N
N
O
3-MeO C6H4
O
O
O
N
N
O
3o
Me
C6H5 CO
10
92
O
O
N
N
O
O
3p
3q
Me
Me
2-Naphthyl
1-Naphthyl
10
15
91
89
O
N
N
O
Cl
O
O
N
N
O
O
3r
3s
H
H
3-Cl C6H4
10
20
90
80
Cl
Cl
O
N
N
O
2,6-di Cl C6H3

154
A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
Table 2 (Continued)
Entry
R
Ar
Product
Time (min)
Yield (%)a
CN
O
O
N
N
O
3t
H
H
4-CN C6H4
15
10
92
85
SMe
O
O
O
N
N
3u
4-MeS C6H4
O
O
O
N
N
O
3v
H
H
C6H5 CO
10
10
90
90
O
O
N
N
O
3w
2-Naphthyl
a
Isolated yield.
Table 3
(“symphoria”) between this aza group and the carbonyl group, an
intramolecular cyclization occurs without the assist of solvent.
The reusability of the catalyst in the reaction of 4-
chlorobenzaldehyde, dimedone, phthalic anhydride, and
hydrazinium hydroxide under solvent-free conditions at 80 ◦C
was studied. In this procedure, after completion of each reaction,
H2O was added to the reaction mixture and was shaken for a few
minutes to dissolve PEG-OSO3H. The crude product (insoluble in
water) was filtered and recrystallized from hot ethanol for more
purification. In order to recover the catalyst, H2O was evaporated
under reduced pressure, and the resulting solid was washed with
t-butylmethyl ether, and dried. The recovered catalyst was reused
Comparison of the E-factor for the synthesis of 2H-indazolo[1,2-b]phthalazine-
trione 3a using the reported catalysts versus PEG-OSO3H.
Entry
E-factor
Ref.
1
2
3
4
5
>73a
[32]
[40]
[33]
This work
[39]
>85.2a
>98.4a
40.4
>72a
a
E-factor for the preparation of phthalhydrazide has not added.
Scheme 2. Proposed mechanism for the PEG-OSO3H-catalyzed synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione.

A. Hasaninejed et al. / Catalysis Today 196 (2012) 148–155
155
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In summary, an efficient protocol for the one-pot synthesis of
2-H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives by
a four-component condensation reaction of phthalic anhydride,
hydrazinium hydroxide, 1,3-cyclohexanedione or 5,5-dimethyl
1,3-cyclohexanedione (dimedone) and aromatic aldehydes has
been described under thermal solvent-free conditions using PEG-
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reaction conditions, operational simplicity, enhanced rates and
high isolated yields of pure products are significant advantages of
the protocol described here. This easy removal and reusability of
the catalyst makes this method a better choice for chemical indus-
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The authors thank Persian Gulf University and Payame Noor Uni-
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