Iodine-mediated facile dehydrogenation of dihydropyridazin-3(2H)one

Article abstract of DOI:10.1016/j.cclet.2011.07.019

A new protocol for the dehydrogenation of dihydropyridazin-3(2H)-one has been carried out by catalytic amount of iodine in dimethyl sulphoxide in good yield with easy workup.

Full text of DOI:10.1016/j.cclet.2011.07.019

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1435–1438
www.elsevier.com/locate/cclet
Iodine-mediated facile dehydrogenation
of dihydropyridazin-3(2H)one
*
Vivek T. Humne, Shankaraiah G. Konda, Kamal Hasanzadeh, Pradeep D. Lokhande
Center for Advance Studies, Department of Chemistry, University of Pune, Pune 411007, India
Received 16 May 2011
Available online 10 October 2011
Abstract
A new protocol for the dehydrogenation of dihydropyridazin-3(2H)-one has been carried out by catalytic amount of iodine in
dimethyl sulphoxide in good yield with easy workup.
# 2011 Pradeep D. Lokhande. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Dehydrogenation; Iodine; Dihydropyridazin-3(2H)-one; Pyridazin-3(2H)-one
The design of newer methods for the synthesis of N-containing heterocyclic moiety is essential in organic chemistry
owing to its biological and pharmacologically point of view. The pyridazin-3(2H)-ones and their dihydro derivatives
show wide biological activity; they constitute the pyridazinone class of herbicides, which are carotenoid biosynthesis
inhibitors [1], and also act as fungicide and insecticides [2]. Even more important, the pyridazin-3(2H)-one ring is
present in many compounds that posses a variety of pharmacological properties, and therefore play the role of a
pharmacophore viz. cardiotonic [3], anti-hypertensive [4], antinociceptive agents [5], antifungal [6], and antiulcer [7].
Additionally, some of pyridazinone derivatives have been found to be formyl peptide receptor [8], a1, a2-adrenoceptor
[9] and inhibited aggregation of platelet [10]. The presence of N-substituent like acetamide chain in 6-phenyl
pyridazin-3(2H)-one derivative show potent analgesic activity [11].
Several methods are reported for the synthesis of pyridazin-3(2H)-ones. Janecki et al. [12] reported the
disubstituted pyridazin-3(2H)-ones by Horner–Wadsworth–Emmons olefination of aldehyde and diethoxy-
phosphorylpyridazinones. Ghate et al. [13] prepared the series of 4-phenyl pyridazin-3(2H)-ones from coumarins.
4,6-Diaryl-4,5-dihydro pyridazin-3(2H)-ones have been synthesized from b-aroyl-a-arylpropionic acids obtained
either from b-aroyl acrylic acids [14a] or from chalcones [14b]. The classical method involved condensation of 4-
oxoalkanoic acid with hydrazine and its derivatives to produce 4,5-dihydropyridazinones, which may be
dehydrogenated to the corresponding pyridazinones. Therefore dehydrogenation is an significant step in the
transformation of 4,5-dihydropyridazin-3(2H)-one to the corresponding pyridazin-3(2H)-ones. Often, dehydrogena-
tion of 4,5-dihydropyridazin-3(2H)-one has been carried out by Br2/AcOH [15], SeO2/microwave [16], CuCl2 [17]
and need of favorable precursors which can rearranged into aromatic compound[12]. But these synthetic approaches
so far have some limitations such as requirement of higher molar ratio, use of expensive catalyst as well as convoluted
* Corresponding author.
E-mail address: vivekhumne@rediffmail.com (P.D. Lokhande).
1001-8417/$ – see front matter # 2011 Pradeep D. Lokhande. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.07.019

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V.T. Humne et al. / Chinese Chemical Letters 22 (2011) 1435–1438
workup. Bromine is, however, a toxic and corrosive reagent. Therefore development of easy, efficient, general and
conventional method for the dehydrogenation of dihydropyridazinone is highly desirable.
The molecular iodine is favorable to pharmaceutical synthesis owing to its inexpensive, non-toxic, and
environmental benign characteristics [18]. Besides, iodine can be easily removed from reaction system. Moreover,
molecular iodine is insensitive to air and moisture. We have reported several iodine-catalyzed organic transformations
[19]. As part of a continuing effort in our laboratory to study the iodine mediated transformations, we became
interested in the possibility of developing a novel and efficient method to construct the pyridiazin-3(2H)-one scaffold.
Herein we expose the dehydrogenation of dihydropyridazin-3(2H)-ones by catalytic amount of iodine (25 mol%).
1. Experimental
1.1. General procedure for the synthesis of N-substituted 3,4-dihydropyridazin-3(2H)-one (3a–e)
To a mixture of 3,4-dihydropyridazin-3(2H)-one (0.98 mmol) and sodium hydride (2 mmol) was added alkyl halide
(0.99 mmol) in DMF portionwise in ice cold condition. The resulting reaction mixture was stirred at 0 8C to r.t. for 8–
10 h. The completion of reaction was monitored by TLC (acetone:hexane = 30:70). The reaction mixture was poured
into crushed ice. The separated solid product was filtered and dried.
1
Compound 3a: White colour; IR (KBr) cmÀ1: 3066, 1685, 1600; H NMR (300 MHz, CDCl3): d 7.65 (d, 2H,
J = 8.7 Hz), 7.40 (d, 2H, J = 7.5 Hz), 7.22–7.305 (multiplet, 3H), 6.88 (d, 2H, J = 8.8 Hz), 5.14 (s, 2H), 3.82 (s, 3H),
2.86 (t, 2H, J = 7.6 Hz), 2.69(t, 2H, J = 7.5 Hz).
1.2. General procedure for the dehydrogenation of 3,4-dihydropyridazin-3(2H)-one (2a–j) and (4a–e)
A mixture of 3,4-dihydropyridazin-3(2H)-one 3a (0.98 mmol) and iodine (25 mol%) in DMSO was stirred for 8 h
at 100 8C. The completion of reaction was monitored by TLC (acetone:hexane = 30:70). The brown-red coloured
reaction mixture was poured into saturated solution of sodium thiosulphate. The separated solid product was filtered,
dried and recrystallized from methanol.
1
Compound 4a: White colour; IR (KBr) cmÀ1: 3064, 1668, 1605; H NMR (300 MHz, CDCl3): d 7.71 (d, 2H,
J = 8.7 Hz), 7.61 (d, 1H, J = 9.9 Hz), 7.49 (d, 2H, J = 6.9 Hz), 7.26–7.36 (multiplet, 3H), 6.99 (d, 1H, J = 9.3 Hz), 6.96
(d, 2H, J = 8.7 Hz), 5.39 (s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3): d 160.4, 159.3, 144, 136.1, 130, 129.7,
128.5, 128.3, 127.6, 127.0, 114, 55.2, 55.2.
2. Results and discussion
Our initial endeavor was to synthesis pyridazinones scaffold from phenyloxobutenoic acids. The phenyloxobutyric
acids were conveniently prepared by Friedel Craft‘s acylation of substituted anisoles with succinic anhydride. When
phenyloxobutyric acids or its corresponding esters were subjected to iodine in dimethyl sulphoxide, no further changes
have been seen in the reaction system. Conventionally, the dihydropyridazin-3(2H)-ones (1a–j) were conveniently
prepared by substituted phenyl-4-oxobutyric acids and phenyl hydrazine in acetic acid followed by dehydrogenation
using iodine (25 mol%) to afford titled compounds (Scheme 1 and Table 1). Among the solvents examined, dimethyl
sulphoxide was found efficient solvent for dehydrogenation system. The reaction did not proceed in methanol,
dichloromethane, diethyl ether and acetonitrile. Thereafter system was studied at different temperature (room
temperature to 140 8C); the better result was found at 100 8C, whereas reaction was incommoded above 120 8C. We
next, investigated the amount of iodine required to catalyze the transformation.
R
R
1
R
R
R
4
1
1
4
N
N
N N
O
O
a
b
O
O
R
R
2
OH
2
R
2
R
R
3
3
R
3
1a- j
2a - j
Scheme 1. Reagents and conditions: (a) R4NHNH2, AcOH, reflux, (b) I2 (25 mol%), DMSO, 100 8C.

V.T. Humne et al. / Chinese Chemical Letters 22 (2011) 1435–1438
1437
Table 1
Iodine-catalyzed dehydrogenation of 4,5-dihydropyridazin-3(2H)-ones.
Entry
Product
R1
R2
R3
R4
Time (h)
Yields %
m.p. (8C)
1
2
2a
2b
2c
2d
2e
2f
H
H
H
H
8
7
87
91
85
87
80
93
79
75
74
73
152–153
99–101
H
H
H
Ph
H
3
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
H
8
173–175
118–120
176–177
131–132
182–185
176–177
183–185
114–115
4
H
H
Ph
H
8.5
7.5
8
5
OMe
OMe
OMe
Cl
H
6
H
Ph
Ph
Ph
Ph
Ph
7
2g
2h
2i
NO2
H
12
10
8
8
9
CH3
H
H
10
2j
H
8
Table 2
Study of iodine on 4,5-dihydropyridazin-3(2H)-one (1d) at 100 8C.
Entry
mol%
Time (h)
Yields (%)
1
2
3
4
5
10
20
8.5
52
87
85
87
86
25
75
8.5
8
1 equiv.
2 equiv.
8
First, we investigated the synthesis by using one equivalent of iodine. The reaction was completed after 8 h with
87% yield. As less as 10 mol% of iodine afforded the product in 52% yield, after 20 h. By means of 25 mol% of iodine
though product yield was improved to 87%, but the reaction time was almost same as that of one proportion of iodine
(Table 2, entry 2). Apparently almost same yield and reaction time was found by using two equivalent of iodine without
formation of side products.
To make the generality of this new method and check the versatility of iodine catalyzed dehydrogenation, various
substitution of dihydropyridazin-3(2H)-ones were successful employed. The remarkable influence of electron
withdrawing and donating groups has been seen on the rate of reaction. The time required for the completion of
reaction was longer in compound 2g and 2h (Table 1).
Next, to explore the utility of iodine mediated dehydrogenation, we sought to extend this methodology to spectrum
of N-substituents of pyridazin-3(2H)-one (Scheme 2). We synthesized N-alkyl dihydropyridazin-3(2H)-ones from 4,5-
dihydro-6-(4-methoxyphenyl)pyridazin-3(2H)-one (2c) with alkyl halides such as benzyl chloride, allyl bromide,
ethyl bromide by strong base treatment (sodium hydride). Dehydrogenation of 3a–e (Table 3) under the optimized
R
R
N
N
N N
N
NH
a
b
O
O
O
MeO
MeO
MeO
3a-e
2c
4a -e
Scheme 2. Reagents and conditions: (a) R-X, NaH (2 equiv.), DMF, rt (b) I2 (25 mol%), DMSO, 100 8C.
Table 3
Dehydrogenation of various N-substituted 4,5-dihydropyridazin-3(2H)-ones.
Entry
R-X
Yields%
m.p. (8C)
4a
4b
4c
4d
4e
PhCH2Cl
87
41
81
79
85
94–97
CH2 = CH-CH2Br
CH3CH2Br
111–4
71–73
CH3(CH2)2CH2Br
CH3I
Viscous oil
95–97

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V.T. Humne et al. / Chinese Chemical Letters 22 (2011) 1435–1438
condition preceded smoothly, afforded products 4a–e in moderate to good yield. The reaction was neat and clean. It
was observed that these N-substituents remain unchanged and no significant influence on reaction time and yields have
been seen during dehydrogenation process.
In conclusion, we have successfully developed a facile and convenient pathway for the dehydrogenation of 3,4-
dihydropyridazin-3(2H)-ones by catalytic use of iodine in good yield with easy workup. The attractiveness of the
current methodology is to tolerant different N-substituents of pyridazin-3(2H)-one. The operational simplicity and
economic viability of this method definitely broaden the preview of further study in this area. Furthermore, the
application of this methodology for dehydrogenation of pyridazin-3(2H)-one is ongoing and will be reported due
course.
Acknowledgments
V.T.H. is thanks to CSIR, New Delhi, India for the award of Senior Research Fellowship. S.G.K. is also thankful to
UGC, New Delhi for D.S. Kothari Post Doctoral Fellowship [F.4-2/2006(BSR)/13-301/2008(BSR)].
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