An efficient synthesis of pyridazinoindazolone

Article abstract of DOI:10.3184/030823409X12506792542701

An efficient synthesis of biologically interesting pyridazinoindazolone derivatives was achieved via a one-pot three-component p-toluenesulfonic acid-catalysed reaction of dimedone, differently substituted aldehydes, and 3,6-dihydroxypyridazine under solv

Full text of DOI:10.3184/030823409X12506792542701

552 RESEARCH PAPER
SEPTEMBER, 552–554
JOURNAL OF CHEMICAL RESEARCH 2009
An efficient synthesis of pyridazinoindazolones
Mohammad Bagher Teimouria*, and Farideh Mansourib
aPetrochemical Department, Iran Polymer and Petrochemical Institute, P.O. Box 14965-115, Tehran, Iran
bFaculty of Chemistry, Firouzabad Branch, Islamic Azad University, Firouzabad, Iran
An efficient synthesis of biologically interesting pyridazinoindazolone derivatives was achieved via a one-pot
three-component p-toluenesulfonic acid-catalysed reaction of dimedone, differently substituted aldehydes,
and 3,6-dihydroxypyridazine under solvent-free conditions. Two plausible mechanisms for the formation of
pyridazinoindazolones are proposed.
Keywords: aldehydes, dimedone, heterocycles, multicomponent reactions
Among a large variety of nitrogen-containing heterocyclic
compounds, heterocycles containing bridgehead hydrazine
have received considerable attention because of their
pharmacological properties and clinical applications.1-13 For
example, benzydamine is the first reported indazole derivative
recognised in the management of pain and inflammation
topically.6 In this direction, many efforts were focused on the
development of new non-steroidal anti-inflammatory drugs
(NSAIDs) with an indazole ring system.2-8 Later, several orally
active indazole derivatives such as triazolo[1,2-a]indazoles,
triazepino[1,2-a]indazoles and pyrazolo[1,2-a]indazole-1,3,9-
trione derivatives were reported to possess 5-lipoxygenase
inhibition with antiinflammatory, analgesic activities.9,10
On the other hand, another fused polycyclic heteroring
system such as diftalone, a phthalazino[2,3-b]phthalazine-
5,12(7H,14H)-dione has been used as a NSAID.11 Recently,
a series of new N2 substituted 1,2-dihydro-3H-indazol-3-ones
as well as their condensed pyrazolo, pyridazino derivatives
such as pyridazino[1,2-a]indazole-6,9,11-triones and 3,9-
dioxo-3H,9H-pyrazolo[1,2-a]indazole were synthesised.12,13
The anti-inflammatory activity of some of these synthesised
compounds was determined by carrageenan-induced rat
paw oedema technique using diclofenac as a reference
drug. The pharmacological data showed that most of the
tested compounds exhibited a significant long lasting anti-
inflammatory activity, which in some cases was superior to
that of diclofenac.
In connection with our recent interest aimed at the
development of efficient protocols for the preparation
of biologically active heterocycles,14-16 we report here
an efficient p-toluenesulfonic acid-catalysed one-pot
condensation reaction of dimedone, differently substituted
aldehydes, and 3,6-dihydroxypyridazine under solvent-free
conditions at 70°C which afforded 2,3,4,11-tetrahydro-1H-
pyridazino[1,2-a]indazole-1,6,9-trione derivatives in good to
moderate isolated yields.
The one-pot three-component condensation reactions of
dimedone 1 with various aldehydes 2 and 3,6-dihydroxy-
OH
O
H3C CH3
CH3
H
O
p-TsOH
CH3
N
N
+
+
H
N
R
H
N
Solvent-Free
70 oC
O
O
O
O
OH
R
1
2
3
4
R
Yield/%
55
-CH3
-CH2CH2CH3
4a
61
4b
4c
80
73
85
Cl
NO2
4d
4e
Cl
91
51
4f
Cl
4g
4h
O2N
O
CH3
63
O
Scheme 1
* Correspondent. E-mail: m.teimouri@ippi.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2009 553
6.87 and 6.93 (AB system, 3JHH = 10.2 Hz, CH=CH) ppm; 13C NMR
(CDCl3, 100.7 MHz): 192.7, 155.0, 153.7, 150.4, 135.8, 134.7,
119.6, 59.5, 51.0, 37.5, 34.5, 28.6, 28.2, 16.9 ppm. Anal. Calcd for
C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.54; H, 6.22;
N, 10.80%.
pyridazine 3 in the presence of a catalytic amount (30 mol%)
of p-toluenesulfonic acid (p-TsOH) proceeded spontaneously
at 70°C under solvent-free conditions and were complete after
10 minutes to afford 2,3,4,11-tetrahydro-1H-pyridazino[1,2-a]
indazole-1,6,9-triones 4a–h in moderate to good yields
(Scheme 1). The 1H and 13C NMR spectra of the crude products
clearly indicated the formation of fused pyridazinoindazolone
4. Any product other than 4 could not be detected by NMR
spectroscopy. All the products were characterised by FT-IR,
1H and 13C NMR spectra, and elemental analysis.
3,3-Dimethyl-11-propyl-2,3,4,11-tetrahydro-1H-pyridazino[1,2-a]-
indazole-1,6,9-trione (4b): Yellow powder (0.176 g, 61%).
M.p. 168–170°C (dec.); IR (KBr): n = 1688, 1654, 1648 (C=O),
1
3
1582 (C=C) cm-1; H NMR (CDCl3, 400.1 MHz): dH 0.87 (t, JHH
= 7.0 Hz, CH2CH2CH3), 1.16 and 1.17 (2 s, 2 C(CH3)2), 2.01–2.04
(m, CH2CH2CH3), 2.26 and 2.27 (AB system, 2JHH = 16.4 Hz, CH2),
2
3.06 and 3.15 (AB system, JHH = 19.0 Hz, CH2), 3.75-3.77 (m,
The elucidation of the structure of 4 using 1H and 13C
NMR spectroscopic data is discussed with 4a as an example.
The central pyrazole moiety in compound 4a has an
asymmetric carbon atom bearing a hydrogen atom. In fact,
these products 4a–h are chiral molecules. The 1H NMR
spectrum of 4a consisted of two singlet signals for the geminal
methyl protons (dH 1.15 and 1.16 ppm) and a doublet for the
methyl group directly attached to the central pyrazole ring
(dH 1.64 ppm). Two AB-quartet resonances (dH 2.33–2.34
and 3.05–3.13 ppm) were observed for the two methylene
groups. The methine group of the pyrazole moiety (N-CH-
C=) resonated as a quartet (dH 5.44 ppm). An AB-system
was observed for two vicinal vinylic protons (dH 6.87 and
6.93 ppm).
CH2CH2CH3), 5.52 (t, 3JHH = 6.0 Hz, CH), 6.87 and 6.93 (AB system,
3JHH = 10.2 Hz, CH=CH) ppm; 13C NMR (CDCl3, 100.7 MHz):
197.1, 163.8, 154.1, 150.7, 135.8, 134.6, 118.8, 63.5, 51.0, 40.9,
37.5, 28.7, 28.3, 25.5, 18.6, 14.2 ppm. Anal. Calcd for C16H20N2O3:
C, 66.65; H, 6.99; N, 9.72. Found: C, 66.73; H, 7.02; N, 9.70%.
3,3-Dimethyl-11-phenyl-2,3,4,11-tetrahydro-1H-pyridazino[1,2-a]
-indazole-1,6,9-trione (4c): Yellow powder (0.258 g, 80%). M.p.
203–205°C (dec.); IR (KBr): n = 1690, 1661, 1650 (C=O), 1580
(C=C) cm-1; 1H NMR (CDCl3, 400.1 MHz): dH 1.16 and 1.17 (2 s, 2
C(CH3)2), 2.29 (s, CH2), 3.13 and 3.25 (AB system, 2JHH = 19.2 Hz,
CH2), 6.27 (s, CH), 6.89 (s, CH=CH), 7.27–7.33 (m, C6H5) ppm;
13C NMR (CDCl3, 100.7 MHz): 192.0., 154.9, 153.2, 150.3, 136.0,
135.1, 134.8, 128.9, 128.8, 127.1, 119.0, 65.4, 51.0, 37.5, 34.7, 28.7,
28.3 ppm. Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69.
Found: C, 70.85; H, 5.66; N, 8.73%.
11-(4-Chlorophenyl)-3,3-dimethyl-2,3,4,11-tetrahydro-1H-
pyridazino[1,2-a]-indazole-1,6,9-trione(4d):Yellowpowder(0.260g,
73%). M.p. 201–203°C (dec.); IR (KBr): n = 1720, 1659, 1622
The 1H decoupled 13C NMR spectrum of 4a showed
14 distinct resonances in agreement with the suggested
structure. The structural assignments made on the basis of
the 1H and 13C NMR spectra of compound 4a were supported
by measurement of its IR spectra. The IR spectrum of 4a
showed strong absorptions at 1700, 1662 and 1658 cm-1 due
to the carbonyls and the C=C bond at 1579 cm-1 as a weak
1
(C=O), 1588 (C=C) cm-1; H NMR (CDCl3, 400.1 MHz): dH 1.13
and 1.17 (2 s, 2 C(CH3)2), 2.28 and 2.30 (AB system, 2JHH = 16.4 Hz,
CH2), 3.12 and 3.24 (AB system, 2JHH = 19.2 Hz, CH2), 6.24 (s, CH),
6.89 (s, CH=CH), 7.28 and 7.31 (AA'BB' system, C6H4NO2) ppm;
13C NMR (CDCl3, 100.7 MHz): 191.9, 154.8, 153.2, 150.6, 135.9,
135.0, 134.8 133.7, 129.0, 128.5, 118.5, 64.8, 50.9, 37.5, 34.7, 28.7,
28.3 ppm. Anal. Calcd for C19H17ClN2O3: C, 63.96; H, 4.08; N, 7.85.
Found: C, 64.03; H, 4.77; N, 7.80%.
1
broad band. The H decoupled 13C NMR spectra of 4b-h are
similar to those of 4a except for the R groups, which exhibit
characteristic signals with appropriate chemical shifts.
The scope and limitations of this simple process with respect
to the aldehyde component was examined and it was found
that aliphatic aldehydes, substituted aromatic aldehydes and
a,b-unsaturated aldehydes all tolerate the reaction conditions
with moderate to good yields. Although the mechanism of
the reaction has not yet been established experimentally, two
possible pathways are by reaction of dimedone first with either
3,6-dihydroxypyridazine or with an aldehyde. In conclusion,
some merits of this method are its generalisation with respect
to aldehydes, shorter reaction times, easy work-up and no
need for toxic organic solvents.
3,3-Dimethyl-11-(4-nitrophenyl)-2,3,4,11-tetrahydro-1H-
pyridazino[1,2-a]-indazole-1,6,9-trione (4e): Yellow powder (0.312
g, 85%). M.p. 209–211°C (dec.); IR (KBr): n = 1680, 1658, 1623
1
(C=O), 1589 (C=C) cm-1; H NMR (CDCl3, 400.1 MHz): dH 1.13
and 1.18 (2 s, 2 C(CH3)2), 2.28 and 2.30 (AB system, 2JHH = 16.4 Hz,
CH2), 3.14 and 3.24 (AB system, 2JHH = 19.2 Hz, CH2), 6.33 (s, CH),
6.91 and 6.95 (AB system, 3JHH = 10.3 Hz, CH=CH), 8.51 and 8.18
(2 d, 3JHH = 8.7 Hz, C6H4NO2) ppm; 13C NMR (CDCl3, 100.7 MHz):
191.9, 154.7, 153.3, 151.1, 148.0, 142.2, 135.7, 135.3, 128.1,
124.1, 117.7, 64.5, 50.8, 37.5, 34.7, 28.9, 28.3 ppm. Anal. Calcd for
C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 62.06; H, 4.61;
N, 11.50%.
11-(2,6-Dichlorophenyl)-3,3-dimethyl-2,3,4,11-tetrahydro-1H-
pyridazino[1,2-a]-indazole-1,6,9-trione (4f): Yellow powder (0.356
g, 91%). M.p. 280–282°C (dec.); IR (KBr): n = 1715, 1658, 1624
1
(C=O), 1588 (C=C) cm-1; H NMR (CDCl3, 400.1 MHz): dH 1.17
and 1.18 (2 s, 2 C(CH3)2), 2.28 and 2.31 (AB system, 2JHH = 16.4 Hz,
Experimental
2
CH2), 3.13 and 3.22 (AB system, JHH = 19.2 Hz, CH2), 6.86 and
Melting points were measured on a Büchi 535 apparatus. Elemental
analyses (C, H, N) were conducted using an elementar vario EL III
instrument. FT-IR Spectra were recorded on a Bruker Equinox-55
3
6.91 (AB system, JHH = 10.3 Hz, CH=CH), 7.15 (s, CH), 7.16-
7.18 and 7.40–7.43 (2 m, C6H3Cl2) ppm; 13C NMR (CDCl3, 100.7
MHz): 191.8, 155.2, 152.9, 152.3, 135.1, 135.0, 132.7, 130.0, 129.7,
129.2, 115.4, 61.8, 50.9, 37.5, 34.5, 28.8, 28.4 ppm. Anal. Calcd for
C19H16Cl2N2O3: C, 58.33; H, 4.12; N, 7.16. Found: C, 58.40; H, 4.10;
N, 7.19%.
1
spectrometer. H and 13C NMR spectra were recorded on a Bruker
DRX-400 Avance spectrometer at 400.13 and 100.77 MHz, with
CDCl3 as solvent. The solvents and reagents used in this work were
purchased from Merck. All reagents were used without further
purification.
3,3-Dimethyl-11-[2-(2-nitrophenyl)-1-ethenyl]-2,3,4,11-tetrahydro-
1H-pyridazino[1,2-a]-indazole-1,6,9-trione (4g): Yellow powder
(0.200 g, 51%). M.p. 175–177°C (dec.); IR (KBr): n = 1720, 1683,
Typical procedure for the preparation of 4a
1
1641 (C=O), 1580 (C=C) cm-1; H NMR (CDCl3, 400.1 MHz): dH
In a 20-mL screw-capped vial, a mixture of dimedone (0.140 g,
1.0mmol),3,6-dihydroxypyridazine(0.112g,1.0mmol),acetaldehyde
(0.066 g, 1.5 mmol) and p-TSA (0.05 g, 0.3 mmol) was heated at
70°C for 10 min and the completion of reaction was confirmed
by TLC (EtOAc–hexane 1:2). After cooling, the reaction mixture
was washed with water (10 mL) and the residue recrystallised
from CH2Cl2:n-hexane (1:6) to afford pure 4a as yellow crystals
(0.143 g, 55%).
2
1.08 and 1.10 (2 s, 2 C(CH3)2), 2.28 and 2.31 (AB system, JHH
=
2
16.4 Hz, CH2), 2.43 and 2.47 (AB system, JHH = 19.2 Hz, CH2),
3
4
6.63 (dd, JHH = 6.3 Hz, JHH = 1.0 Hz, CH), 7.15 (s, CH), 7.24 (s,
CH=CH), 7.28–7.8.11 (m, CH=CH-C6H4NO2 and CH=CH) ppm;
13C NMR (CDCl3, 100.7 MHz): 192.6, 152.1, 149.3, 145.8, 133.4,
132.7, 131.1, 130.4, 129.6, 129.2, 128.8, 125.2, 125.0, 124.4, 117.3,
54.2, 52.4, 50.8, 40.9, 29.1, 28.6 ppm. Anal. Calcd for C21H19N3O5:
C, 64.12; H, 4.87; N, 10.68. Found: C, 64.04; H, 4.81; N, 10.73%.
3,3-Dimethyl-11-(6-methyl-4-oxo-4H-chromen-3-yl)-2,3,4,11-
tetrahydro-1H-pyridazino[1,2-a]-indazole-1,6,9-trione (4h): Yellow
powder (0.255 g, 63%). M.p. 271–273°C (dec.); IR (KBr): n = 1715,
1710, 1681, 1644 (C=O), 1581 (C=C) cm-1; 1H NMR (CDCl3, 400.1
MHz): dH 1.15 and 1.16 (2 s, 2 C(CH3)2), 2.26 and 2.28 (AB system,
3,3,11-Trimethyl-2,3,4,11-tetrahydro-1H-pyridazino[1,2-a]-
indazole-1,6,9-trione(4a):M.p.166–168°C(dec.);IR(KBr):n=1700,
1662, 1658 (C=O), 1579 (C=C) cm-1; 1H NMR (CDCl3, 400.1 MHz):
d
H 1.15 and 1.16 (2 s, 2 C(CH3)2), 1.64 (d, 3JHH = 6.2 Hz, CH–CH3),
2.33 and 2.34 (AB system, 2JHH = 16.4 Hz, CH2), 3.05 and 3.13 (AB
2
3
system, JHH = 19.2 Hz, CH2), 5.44 (q, JHH = 6.2 Hz, CH–CH3),

554 JOURNAL OF CHEMICAL RESEARCH 2009
2JHH = 16.4 Hz, CH2), 2.36 (s, CH3), 3.11 and 3.29 (AB system, 2JHH
=
4
5
L. Mosti, G. Menozzi, P. Fossa, W. Filippelli, S. Gessi, B. Rinaldi and
G. Falcone, Arzneimittelforschung, 2000, 50, 963.
U. Wrzeciono, E. Linkowska, K. Majewska, A. Gzella and K. Stochla,
Pharmazie, 1993, 48, 582.
E. Tse, L. Butner, Y. Huang and I.H. Hall, Arch. Pharm., 1996, 329, 35.
E.A.M. Badawey and I.M. El-Ashmawey, Eur. J. Med. Chem. Chim.
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19.2 Hz, CH2), 5.97 (s, CH), 6.81 and 6.89 (AB system, 2JHH = 10.2 Hz,
CH=CH), 7.33–7.84 (m, arom. H) ppm; 13C NMR (CDCl3, 100.7
MHz): 193.1, 177.2 164.4, 156.9, 154.7, 152.8, 135.5, 135.4, 135.1,
135.0, 134.7, 124.8, 124.5, 118.0, 117.2, 116.9, 61.1, 50.9, 37.5, 34.7,
28.7, 28.3, 20.9 ppm. Anal. Calcd for C23H20N2O5: C, 68.31; H, 4.98;
N, 6.93. Found: C, 68.40; H, 5.02; N, 6.94%.
6
7
8
9
R. Schindler, N. Hoefgen, K. Heinecke, H. Poppe and I. Szelenyi,
Pharmazie, 2000 55, 857.
M.M. Badran, M.A. Ismail, K.A. Youssef and M. Abdel-Hakeem, Alex.
J. Pharm. Sci., 1999, 13, 68.
We would like to thank the Iran Polymer and Petrochemical
Institute (IPPI) Research Council for the financial support.
10 M.M. Badran, M.A. Ismail, K.A. Youssef and M. Abdel-Hakeem, Alex.
J. Pharm. Sci., 1999, 13, 73.
11 P. Schiatti, D. Selva, E. Arrigoni-Martelli, L.J. Lerner, A. Diena and
M.G. Sard, Arzneimittelforschung, 1974, 24, 2003.
Received 16 July 2009; accepted 10 August 2009
Paper 09/0685 doi: 10.3184/030823409X12506792542701
Published online: 8 September 2009
12 K.A.M. Abouzid and H.S. El-Abhar, Arch. Pharm. Res., 2003, 26, 1.
13 M. Sayyafi, M. Seyyedhamzeh, H.R. Khavasi and A. Bazgir, Tetrahedron,
2008, 64, 2375.
14 M.B. Teimouri and R. Bazhrang, Monatsh. Chem., 2008, 139, 957.
15 M.B. Teimouri and F. Mansouri, J. Comb. Chem., 2008, 10, 507.
16 M.B. Teimouri, T. Abbasi and H. Mivehchi, Tetrahedron, 2008, 64,
10425.
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