One-pot synthesis of novel 2-(Thiazol-2-yl)-4,5-dihydropyridazin-3(2 H)-one derivatives catalyzed by activated KSF

Article abstract of DOI:10.1080/00397911.2013.801077

A series of 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were synthesized by one-pot multicomponent cyclocondensation of ketoacid, thiosemicarbazide, and phenacyl bromide using catalytical amount of KSF in EtOH under reflux. The straightforward synthesis, presence of two important class of heterocyclic rings in the individual molecule, easy workup of the products, rapid reaction, mild conditions, and good to excellent yields are notable features of this protocol. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.801077

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One-Pot Synthesis of Novel 2-(Thiazol-2-yl)-4,5-
dihydropyridazin-3(2H)-one Derivatives Catalyzed by
Activated KSF
Nosrat O. Mahmoodi a , Niloufar Safari a & Bahman Sharifzadeh a
a Department of Chemistry , Faculty of Sciences, University of Guilan , Iran
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): One-Pot Synthesis of Novel 2-(Thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-
one Derivatives Catalyzed by Activated KSF, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.801077
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One-pot synthesis of novel 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one
derivatives catalyzed by activated KSF
Nosrat O. Mahmoodi1,, Niloufar Safari1, Bahman Sharifzadeh1
1Department of Chemistry, Faculty of Sciences, University of Guilan, Iran
, E-mail: mahmoodi@guilan.ac.ir
Abstract
A series of 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were synthesized
by one-pot multicomponent cyclocondensation of ketoacid, thiosemicarbazide and
phenacyl bromide using catalytical amount of KSF in EtOH under reflux. The
straightforward synthesis, presence of two important class of heterocyclic rings in
individual molecule, easy work-up of the products, rapid reaction, mild conditions and
providing the title compounds in good to high yields are notable features of this protocol.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: 2-(Thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one, Pyridazinone,
Thiazole, Regioselective, KSF, Multicomponent
INTRODUCTION
Properties of pyridazinone derivatives have been extensively studied and many of them
display important pharmacological properties, including antihypertensive, antidepressant,
antibacterial, anti HIV and anticancer [1-5]. Recently some drugs containing pyridazinone
derivatives like levosimendan, [6] azanrinone, [7] emorfazone, [8] primobendan, [9]
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minaprine, [10] indolidan [11] and bemoradan [12] is employing widely in the medical
market.
One of the other most important moieties are thiazole derivatives that have effective
function in treatment of allergies, [13] hypertension, [14] inflammation, [15] schizophrenia,
[16] bacterial, [17] HIV infections [18] and hypnotics [19]
.
Literature survey shows that one pot synthesized of compounds with two rings containing
thiazole and pyridazinone has not yet been reported. Recently, we report the synthesis of
pyridazinone derivatives in the presence of montmorillonite KSF and via one pot
multicomponent reaction [20] and have been announced new methods for synthesis of
novel heterocyclic ring as pioneer in drug compounds [21-26]
.
RESULTS AND DISCUSSION
In this protocol, we explain an efficient method for the regioselective synthesis of new
thiazolyl-pyridazinone derivatives 4a–l via a one-pot three-component reaction. Using an
equimolar mixture of ketoacid 1, thiosemicarbazide 2 and phenacyl bromide 3 in
anhydrous EtOH in the presence of catalytic amounts of activated KSF leads to 4.
Intermolecular preparation of thiohydrazone was achieved via nucleophilic attack of
thiosemicarbazide 2 to activated ketoacid by KSF and subsequently addition of phenacyl
bromide 3 led to 4.
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Here, we used montmorillonite KSF as a catalyst due to its environmental compatibility,
reusability, simple preparation, no toxicity, non corrosiveness, low cost and ease of
isolation [27–30]. 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 7–11% was decreased.
This type of reactions is of exacting significance in combinatorial chemistry because it
allows the production of infinite array of molecules in an efficient mode.
All of the compounds described in Scheme 1 were characterized by spectroscopic
methods (IR, 1H NMR, 13C NMR) and elemental analysis. The IR spectra of 2-(thiazol-2-
yl)-4,5-dihydropyridazin-3(2H)-one 4a-l reveals the presence of thiocarboxamide amino
stretching vibration bands at 3482–3123 cm-1, absorption bands in the 1509–1610 cm-1
region corresponding to endocyclic C=N stretching bands, and peaks in the regions
1355–1365 cm-1 and 1055–1096 cm-1 indicate the presence of C–S and C–N groups.
The 1H NMR spectra of 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one 4a-l showed a
sharp singlet at 7-7.30 ppm due to the thiazole ring proton. The vicinal protons of the
adjacent carbon atom in the dihydropyridazinone ring of compounds 4a-l appear in the
regions of 1.90-4.2 and 2.45-3.05 ppm with J = 8.4 Hz. Protons belonging to the aromatic
ring were observed within the expected chemical shift regions along with their integral
values.
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The 13C NMR spectra of 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one 4a-l showed
signals at 172.11-173.09 and 107.31-107.91 ppm assigned ordonnance to C2 and C5 of
thiazol ring. Also C3 (C=O) and C6 (C=N) of pyridazinone ring appeared in the region of
167.11- 168.12 and 146.03-147.12 ppm. The signals due to the aromatic and aliphatic
carbon groups resonate at their usual positions (see the Section on Experimental and
Supporting Information).
CONCLUSION
In conclusion we have verified a convenient simple, efficient and versatile one-pot three-
component protocol for the chemo- and regioselective synthesis of novel derivatives of
functionalized 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one by the reaction of keto
acid, thiosemicarbazide and phenacyl bromide in the presence of active-KSF catalyst in
moderate to high yields and short reaction time. The simplicity, high atom economy,
effortless carrying out, easy workup, and good yields, together with the use an
environmentally friendly procedure, are features of this procedure.
EXPERIMENTAL
General Procedure For The Synthesis Of 2-(Thiazol-2-Yl)-4,5-Dihydropyridazin-3(2h)-
One
To a 100 ml round bottom flask equipped with condenser and magnetic stir bar were
added absolute EtOH (20 mL), ketoacid (10 mmol), 0.2 g activated KSF and
thiosemicarbazide (10 mmol). The reaction mixture was refluxed for required reaction
time (about 7 hours). The progress of reaction was monitored by TLC (EtOAc:petroleum
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ether 2:1). After completion of the reaction, phenacyl bromide (10 mmol) was added and
refluxed for required reaction time (about 2 hours). The progress of the reaction was
monitored by TLC (EtOAc: petroleum ether 1:2). The catalyst was removed by
filtration. The reaction solution was cooled to r.t. The product was isolated by filtration
and purified by washing with EtOH.
2-(4-(4-Hydroxyphenyl)Thiazol-2-Yl)-6-(P-Tolyl)-4,5-Dihydropyridazin-3(2H)-One
(4a)
Yield 78%; mp 243-245 °C; yellow; IR (KBr, υmax, cm-1): 3350, 3080, 2980, 1667,
1587, 1560, 1500, 1300, 1260, 1187; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 2.39 (s,
3H), 2.62 (t, 2H, J = 8.4 Hz), 3.03 (t, 2H, J = 8.4 Hz), 5.48 (s, 1H), 6.81-6.83 (d, 2H, J =
7.6 Hz), 7.16 (s, 1H), 7.27-7.29 (d, 2H, J = 8.0 Hz), 7.49-7.51 (d, 2H, J = 7.6 Hz), 7.74-
7.76 (d, 2H, J = 8.0 Hz); 13C-NMR (100 MHz, DMSO-d6, ppm): δ 21.42, 24.45, 32.56,
107.66, 117.25, 125.81, 126.92, 128.23, 129.36, 132.86, 139.21, 146.56, 150.41, 157.23,
167.72, 172.91. Anal. calcd. for C20H17N3O2S: C, 66.10; H, 4.72; N, 11.56, Found: C,
66.08; H, 4.73; N, 11.54%.
6-(2,4-Dimethylphenyl)-2-(4-(4-Hydroxyphenyl)Thiazol-2-Yl)-4,5-
Dihydropyridazin-3(2H)-One (4b)
Yield 75%; mp 231-232 °C; yellow; IR (KBr, υmax, cm-1): 3350, 3075, 2925, 1665,
1587, 1560, 1500, 1300, 1260, 1187; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 2.38 (s,
3H), 2.43 (s, 3H), 2.63 (t, 2H, J = 8.4 Hz), 3.03 (t, 2H, J = 8.4 Hz), 5.36 (s, 1H), 6.80-
6.82 (d, 2H, J = 7.6 Hz), 7.07 (s, 1H), 7.10-7.12 (d, 1H, J = 8.0Hz), 7.17 (s, 1H), 7.49-
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7.51 (d, 2H, J = 7.6 Hz), 7.62-7.64 (d, 1H, J = 8.0 Hz). 13C-NMR (100 MHz, DMSO-d6,
ppm): δ 19.52, 21.63, 26.91, 33.11, 107.91, 117.31, 122.02, 122.91, 124.04, 126.42,
128.36, 129.24, 135.31, 136.21, 146.12, 150.88, 157.41, 168.12, 173.08. Anal. calcd. for
C21H19N3O2S: C, 66.82; H, 5.07; N, 11.13, Found: C, 66.80; H, 5.09; N, 11.12%.
Full experimental detail, 1H and 13C NMR spectra, can be found via the “Supplementary
Content” section of this article’s webpage.
ACKNOWLEDGMENTS
The authors are grateful to the Research Council of University of Guilan for the financial
support of this research work.
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Scheme 1. One-pot synthesis of 2-(thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one. 4a: R1
= 4-MeC6H4, R2 = OH; 4b: R1 = 2,4-(Me)2C6H4 , R2 = OH; 4c: R1 = 4-ClC6H4 , R2 = OH;
4d: R1 = 4-BrC6H4 , R2 = OH; 4e: R1 = Me, R2 = OH; 4f: R1 = 4-MeC6H4 , R2 = OMe; 4g:
R1 = 2,4-(Me)2C6H4 , R2 = OMe; 4h: R1 = 4-ClC6H4 , R2 = OMe; 4i: R1 = 4-BrC6H4 , R2 =
OMe; 4l: R1 = Me, R2 = OMe
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