An efficient chemo- and regioselective three-component synthesis of pyridazinones and phthalazinones using activated KSF

Article abstract of DOI:10.1016/j.cclet.2009.11.032

The first three-component and regioselective synthesis of pyridazinones and phthalazinones from arenes, anhydrides and ArNHNH₂ in the presence of efficient recyclable heterogeneous catalyst, montmorillonite-KSF, in high yield and short reaction time is reported.

Full text of DOI:10.1016/j.cclet.2009.11.032

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 538–541
www.elsevier.com/locate/cclet
An efficient chemo- and regioselective three-component synthesis
of pyridazinones and phthalazinones using activated KSF
*
L. Zare, N.O. Mahmoodi , A. Yahyazadeh, M. Mamaghani, K. Tabatabaeian
Department of Chemistry, Faculty of Sciences, University of Guilan, Rast 41335-1914, Iran
Received 4 September 2009
Abstract
The first three-component and regioselective synthesis of pyridazinones and phthalazinones from arenes, anhydrides and
ArNHNH2 in the presence of efficient recyclable heterogeneous catalyst, montmorillonite-KSF, in high yield and short reaction
time is reported.
# 2009 N.O. Mahmoodi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Regioselective; Pyridazinones; Phthalazinones; Montmorillonite-KSF
Pyridazinones are useful compounds with a broad array of biologically activities. They have been utilized as
antimicrobial, potent analgesic, anti-inflammatory, antifeedant, herbicidal, antihypertensive and possess antiplatelet
activities, anticancer effects and other anticipated biological and pharmacological properties [1].
Previously, numerous synthetic methods for the preparation of pyridazinones or phthalazinones such as
condensation of Wittig reagents with arylhydrazones or condensation of a-ketoesters with hydrazinocarbonyl acetic
acid esters [2] or catalytic reactions of alkynes with arylhydrazines (hydrohydrazination) [3] is reported. In the other
route the synthesis of 4,5-dihydro-3(2H)-pyridazinones proceeds via reaction of g-ketoacids and their derivatives with
alkylhydrazines or phenylhydrazines to give the pyridazinones [4–9].
Recent development in the pyridazinone chemistry and our continued interest in the development of efficient and
environmentally friendly procedure for the synthesis of pharmaceutical compounds [10–14] prompted us to explore
the synthesis of pyridazinones (1–9) and phthalazinones (10–13) in the first three component procedure from arenes,
anhydrides and ArNHNH2 in the presence of montmorillonite KSF (Scheme 1).
This class of reactions is of particular interest in combinatorial chemistry because it allows the production of vast
arrays of molecules in an efficient mode.
The mechanism of the reaction goes through acylation between arenes and anhydride to prepare keto-carboxylic
acids. Chemo- and regioselective intermolecular hydrazone formation followed by intramolecular cyclization over
an efficient acidic active catalyst [15] led to the formation of pyridazinones (1–9) and phthalazinones (10–13)
(Scheme 2).
* Corresponding author.
E-mail addresses: mahmoodi@guilan.ac.ir, nosmahmoodi@gmail.com (N.O. Mahmoodi).
1001-8417/$ – see front matter # 2009 N.O. Mahmoodi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.11.032

L. Zare et al. / Chinese Chemical Letters 21 (2010) 538–541
539
Scheme 1.
For these reasons, we used KSF because of its environmental compatibility, reusability, operational simplicity, no
toxicity, noncorrosiveness, low cost and ease of isolation [16–21]. High catalytic activity and excellent chemo- and
regioselectivity remained essentially the same even after third reuse of the catalyst. After more than three cycles the
yield of product slightly decreased (ꢀ7–11% yield). The results are summarized in Table 1.
This three-component reaction is applicable to the some of the arenes corresponding pyridazinones and
phthalazinones in varying yields (Table 1) [22,23]. The reaction using the arenes bearing NO2 or CN exhibit no
positive reaction because of the high electron deficiency at the phenyl ring of these arenes limits the Friedel–Crafts
acylation. Overall, the electron-donating group gave the best results. To the best of our knowledge, this is the first
report on the three-component synthesis of pyridazinones and phthalazinones. This multicomponent reaction has
several advantages such as virtue of their convergence, productivity, ease of execution and work-up, the small amount
of waste, short reaction time and chemo- and regioselectivity.
In conclusion we have demonstrated a convenient chemo- and regioselective three-component synthesis of
pyridazinones and phthalazinones from arenes, anhydrides and ArNHNH2 in the presence of active-KSF catalyst in
high yield and short reaction time.
Scheme 2.

540
L. Zare et al. / Chinese Chemical Letters 21 (2010) 538–541
Table 1
Synthesis of pyridazinones and phthalazinones by the multicomponent reaction.
Entry
R1
R2
R3
Yielda (%)
Time (h)
mp (8C)
1
2
H
H
H
75
65
63
65
62
60
55
60
67
75
85
82
78
9
9
92–94
Oil
H
H
CH3
OCH3
H
3
H
H
9
Oil
4
H
CH3
CH3
Cl
8
Oil
5
CH3
H
H
8.5
10
8
Oil
6
H
Oil
7
H
OCH3
OCH3
OCH3
H
H
Oil
8
H
CH3
OCH3
H
8
Oil
9
H
8
Oil
10
11
12
13
H
9
161–163
124–126
156–158
164–165
H
CH3
CH3
Cl
H
8
CH3
H
H
8.5
10
H
Identified by spectroscopic analysis (IR, 1H NMR, 13C NMR and elemental analysis) for selected compounds 1,4–6 and 9–13.
a
Isolated yield.
Acknowledgment
The authors are grateful to the Research Committee of University of Guilan for the financial support of this study.
References
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[10] J.L. Belletire, N.O. Mahmoodi, Tetrahedron Lett. 30 (1989) 4363.
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[12] N.O. Mahmoodi, M. Jazayri, Synth. Commun. 31 (2001) 3115.
[13] N.O. Mahmoodi, K. Tabatabaeian, M. Kosari, et al. Chin. Chem. Lett. 12 (2008) 1431.
[14] S. Zarrabi, N.O. Mahmoodi, K. Tabatabaeian, et al. Chin. Chem. Lett. 20 (2009) 1400.
[15] Activation of the catalyst: KSF montomorillonites were purchased from Aldrich. The clays were dried overnight at 398 K prior to use. In some
cases, the clays (10 g) were suspended in a solution of HCl (125 mL, 1 mol/L) and stirred at room temperature for 24 h. The solids were filtered-
off, thoroughly washed with water, dried at 398 K, ground in a mortar and dried again prior to use.
[16] R. Ballini, D. Fiorini, V.M. Gil, et al. Green Chem. 5 (2003) 475.
[17] R.V. Rani, N. Srinivas, R.M. Kishan, et al. Green Chem. 3 (2001) 305.
[18] F. Bigi, R. Maggi, G. Sartori, et al. Chem. Commun. (1998) 513.
[19] L.J. Krstic, S. Sukdolak, S. Solujic, J. Serb. Chem. Soc. 67 (2002) 325.
[20] A. Li, T.S. Li, T.H. Ding, Chem. Commun. (1997) 1389.
[21] J.S. Yadav, S.B.V. Reddy, C. Madan, New J. Chem. 9 (2001) 1114.
[22] Chemicals were purchased from Merck and Fluka and used as purchased. KSF montomorillonites were purchased from Aldrich. The clays
were dried overnight at 398 K prior to use. Melting points were measured on an Electro-thermal 9100 apparatus and are uncorrected. 1H NMR
spectra were obtained on a Bruker DRX 500, 250 and those of 13C NMR spectra on a Bruker DRX 125 Avance spectrometer in CDCl3 as
solvent and with TMS as internal standard. FT-IR spectra were recorded on a Shimadzu FT-IR-8400S spectrometer. Elemental analyses were
done on a Carlo-Erba EA1110CNNO-S analyzer.
[23] Typical procedure: a mixture of anhydride and arenes (10 mmol) each and 0.1 g KSF-H in 96% EtOH (20 mL) was refluxed for the required
reaction time. The progress of the reaction was monitored by TLC (EtOAc:petroleum ether 1:4). After completion of the reaction, PhNHNH2

L. Zare et al. / Chinese Chemical Letters 21 (2010) 538–541
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(10 mmol) was added to the mixture and then refluxed for 8–10 h. The progress of the reaction was monitored by TLC (EtOAc:petroleum ether
1:4). Subsequently, the catalyst was removed by filtration and the product (2–9) was purified by column chromatography (petroleum ether/
EtOAc: 4/1) and the product 1 and 10–13 was recrystallized from EtOH to furnish the desired pyridazinones and phthalazinones. The pure
products were collected in 60–85% yields; 2,6-diphenyl-4,5-dihydropyridazin-3(2H)-one (1): off white solid, 1H NMR (CDCl3): d 2.84 (t, 2H,
J = 8.5 Hz), 3.15 (t, 2H, J = 8.5 Hz), 7.30–7.33 (m, 1H), 7.45–7.48 (m, 5H), 7.64 (d, 2H, J = 7.5 Hz), 7.85–7.86 (m, 2H). 13C NMR (CDCl3): d
165.69, 151.93, 141.68, 135.91, 130.42, 129.07, 128.94, 127.00, 126.51, 125.31, 28.47, 23.33. IR (neat): n 1680 (C O), 1600, 1541, 1330,
1490. Anal. Calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.62; H, 5.77; N, 11.10; 6-(4-methylphenyl)-4,5-dihydropyridazin-
3(2H)-one (4): red oil, 1H NMR (CDCl3): d 2.4 (s, 3H), 2.78 (t, 2H, J = 8.5 Hz), 3.06 (t, 2H, J = 8.5 Hz), 7.27 (d, 2H, J = 8.1 Hz), 7.32 (t, 1H,
J = 7.4 Hz), 7.47 (t, 2H, J = 7.6 Hz), 7.67 (d, 2H, J = 8.3 Hz), 7.75 (d, 2H, J = 8.3 Hz). 13C NMR (CDCl3): d 165.87, 152.16, 140.71, 133.12,
129.82, 129.01, 128.97, 126.96, 126.53, 125.33, 28.48, 23.21, 21.86. IR (neat): (nmax/cmÀ1) 1680 (C O), 1595, 1492, 1326. Anal. Calcd. for
C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.26; H, 77.26; N, 10.58; 6-(2,4-dimethylphenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-
one (5): red oil, 1H NMR (CDCl3): d 2.4 (s, 3H), 2.5 (s, 3H), 2.8 (t, 2H, J = 8.5 Hz), 3.0 (t, 2H, J = 8.5 Hz), 7.10 (s, 1H), 7.12 (s, 1H), 7.28–7.33
(m, 2H), 7.45 (t, 2H, J = 8.2 Hz), 7.61 (d, 2H, J = 7.6 Hz). 13C NMR (CDCl3): d 165.75, 155.60, 141.49, 139.66, 136.22, 134.02, 132.51,
128.93, 127.12, 126.93, 125.30, 28.74, 26.95, 21.61, 21.60. IR (KBr): (nmax/cmÀ1) 1677, 1600, 1494, 1326. Anal. Calcd. for C18H18N2O: C,
1
77.67; H, 6.52. N, 10.06; found: C, 77.56; H, 6.23; N, 10.18; 6-(4-chlorophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (6): red oil. H
NMR (CDCl3): d 2.8 (t, 2H, J = 8.5 Hz), 3.08 (t, 2H, J = 8.5 Hz), 7.33 (t, 1H, J = 7.3 Hz), 7.41 (d, 2H, J = 8.6 Hz), 7.48 (t, 2H, J = 8.2 Hz), 7.62
(d, 2H, J = 7.4 Hz), 7.77 (d, 2H, J = 8.62 Hz). 13C NMR (CDCl3): d 165.53, 150.68, 141.59, 136.44, 129.29, 129.00, 127.91, 127.14, 125.39,
125.26, 28.31, 23.17. IR (KBr): (nmax/cmÀ1) 1683, 1595, 1490, 1326, 1012. Anal. Calcd. for C16H13ClN2O: C, 67.49; H, 4.60; N, 9.84. Found:
C, 67.21; H, 4.58; N, 9.81; 2,6-bis(4-methoxyphenyl)-4,5-dihydropyridazin-3(2H)-one (9): red oil; 1H NMR (CDCl3): d 2.73 (t, 2H,
J = 8.5 Hz), 3.02 (t, 2H, J = 7.64 Hz), 3.81 (s, 3H), 3.83 (s, 3H), 6.90–6.94 (m, 4H), 7.47 (d, 2H, J = 8.9 Hz), 7.73 (d, 2H, J = 8.86 Hz). 13C
NMR (CDCl3): d 165.86, 161.53, 158.50, 151.61, 134.95, 128.42, 128.07, 126.83, 114.40, 114.24, 55.92, 55.81, 28.37, 23.23. IR (neat): (nmax
/
cmÀ1) 1683, 1595, 1490, 1326; Anal. Calcd. for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.51; H, 5.69; N, 9.45; 2,4-
diphenylphthalazin-1(2H)-one (10): light brown solid. 1H NMR (CDCl3): d 7.41 (t, 1H, J = 7.3 Hz), 7.51–7.57 (m, 5H), 7.69 (d, 2H,
J = 5.5 Hz), 7.78 (d, 2H, J = 7.6 Hz), 7.84–7.87 (m, 3H), 8.66 (d, 1H, J = 7.4 Hz). 13C NMR (CDCl3): d 159.37, 148.05, 142.43, 135.47,
133.59, 132.18, 131.98, 130.06, 129.87, 129.40, 129.11, 128.20, 128.08, 127.18, 126.18. IR (KBr): (nmax/cmÀ1) 1656, 1580, 1487, 1325. Anal.
Calcd. for C20H14N2O: C, 80.52; H, 4.73; N, 9.39. Found: C, 80.25; H, 4.51; N, 9.27; 2-phenyl-4-o-tolyl-2H phthalazin-1-one (11): brown
solid.1H NMR (CDCl3): d 2.5 (s, 3H), 7.37–7.42 (m, 3H), 7.52 (t, 2H, J = 8.0 Hz), 7.59 (d, 2H, J = 7.9 Hz), 7.79 (d, 2H, J = 7.7 Hz), 7.82–7.86
(m, 3H), 8.66 (d, 1H, J = 7.6 Hz). 13C NMR (CDCl3): d 159.37, 148.07, 142.50, 139.67, 133.51, 132.62, 131.99, 129.88, 129.74, 129.65,
129.41, 129.11, 128.15, 128.00, 127.35, 126.26, 21.80. IR (KBr): (nmax/cmÀ1): 1662, 1595, 1490, 1330. Anal. Calcd. for C21H16N2O: C, 80.75;
H, 5.16; N, 8.97. Found: C, 80.35; H, 5.87; N, 8.43; 4-(2,4-dimethylphenyl)-2-phenyl-2H phthalazin-1-one (12): light brown solid, 1H NMR
(CDCl3,): d 2.25 (s, 3H), 2.45 (s, 3H), 7.17 (d, 1H, J = 7.6 Hz), 7.21 (s, 1H), 7.30 (d, 1H, J = 7.5 Hz), 7.38–7.43 (m, 2H), 7.50 (t, 2H,
J = 7.7 Hz), 7.76 (d, 3H, J = 7.8 Hz), 7.83 (t, 1H, J = 7.3 Hz), 8.63 (d, 1H, J = 7.8 Hz). 13C NMR (CDCl3): d 159.48, 148.42, 142.41, 139.54,
137.30, 133.74, 133.54, 131.98, 131.78, 130.30, 129.14, 127.98, 127.28, 127.07, 126.35, 126.17, 21.70, 20.28. IR (KBr): (nmax/cmÀ1) 1662
(C O), 1583, 1492, 1330. Anal. Calcd. for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.80; H, 5.57; N, 8.39; 4-(2-chlorophenyl)-2-
phenyl-2H phthalazin-1-one (13): light brown solid, 1H NMR (CDCl3): d 7.40 (t, 1H, J = 7.4 Hz), 7.51–7.59 (m, 5H), 7.68 (d, 2H, J = 7.2 Hz),
7.78 (d, 2H, J = 7.6 Hz), 7.83–7.88 (m, 2H), 8.66 (d, 1H, J = 7.5 Hz). 13C NMR (CDCl3): d 159.37, 148.04, 142.44, 135.48, 133.59, 132.08,
129.98, 129.66, 129.55, 129.40, 129.15, 129.07, 128.18, 128.08, 127.30, 126.27, 126.27. IR (KBr): (nmax/cmÀ1) 1662 (C O), 1593, 1569,
1490, 1323, 1139. Anal. Calcd. for C20H13ClN2O: C, 72.18; H, 3.94; N, 8.42. Found: C, 72.52; H, 3.57; N, 8.27.