5-Phenylpyridazinones-A serendipitous route from coumarins

Article abstract of DOI:10.1016/j.tetlet.2008.05.015

A new route of the ring transformation has been discovered during the reaction of 4-bromomethylcoumarins with hydrazine hydrate leading to the formation of pharmacologically important pyridazinones in a single step with very high yields. These so obtained pyridazinones have the potential for further functional group interconversions.

Full text of DOI:10.1016/j.tetlet.2008.05.015

Tetrahedron Letters 49 (2008) 4394–4396
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Tetrahedron Letters
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5-Phenylpyridazinones-A serendipitous route from coumarins
Manjunath D. Ghate a, Vithal B. Jadhav a, Lokesh A. Shastri a, Manohar V. Kulkarni a,
,
*
Geetha M. Kulkarni b, Chih-Hau Chen c, Chung-Ming Sun c,
*
a Department of Chemistry, Karnatak University, Dharwad 580 003, India
b Department of Chemistry, Karnatak Science College, Dharwad 580 003, India
c Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 December 2007
Revised 1 May 2008
Accepted 5 May 2008
Available online 9 May 2008
A
new route of the ring transformation has been discovered during the reaction of 4-bromo-
methylcoumarins with hydrazine hydrate leading to the formation of pharmacologically important
pyridazinones in a single step with very high yields. These so obtained pyridazinones have the potential
for further functional group interconversions.
Ó 2008 Elsevier Ltd. All rights reserved.
N-containing heterocycles are of biological importance and
design of newer strategies for their synthesis is an important area
of research in organic chemistry.1 Pyridazines are an important
class of nitrogen heterocycles, which are known for a wide range
of biological activities.2,3 Introduction of an aryl moiety on the
pyridazinone skeleton has resulted in a large number of derivatives
exhibiting a plethora of promising pharmacological activities. For
example, 6-phenyl pyridazin-3-ones have been found to be useful
as cardiotonic,4 anti-hypertensive,5 antinociceptive agents,6 as well
as platelet aggregation inhibitors7–9 and their acid–base behaviour
has been analyzed theoretically.10 5-Phenyl pyridazinones are less
common and have been patented11 for their pronounced b-adreno-
receptor antagonist activity. Introduction of a phenyl ring into the
pyridazine scaffold has been achieved by Grignard,12 Sonogosh-
ira,13 Stille14 and by Suzuki15 coupling and palladium16 catalyzed
reactions. In view of the biological importance and the complexity
of the existing methods, it is obvious that a simpler method is
necessary for the synthesis of aryl pyridazinones.
We have been exploring the reactivity of coumarins to construct
biologically active oxygenated bi-heterocycles,17 unsymmetrical
triheterocycles18 and pentacyclic heterocycles19 as well. An at-
tempted reaction of 4-bromomethylcoumarins 1 with hydrazine
hydrate in refluxing ethanol resulted in a product which did not
correspond to the allylic substitution by aromatic amines.20 Inter-
estingly, the product obtained did not show any band around
1700 cmꢀ1 in the IR spectrum, indicating the absence of coumarin
carbonyl. Instead, a band around 1660 cmꢀ1 characteristic of
amides was found. Furthermore, the 1H NMR showed no signals
in the region of 3–6 ppm, which indicated a clear absence of the
H3CO2S
R
O
O
NH
N
N
R2
N
R1
Platelet aggregation inhibitor
COX-2 inhibitor
R3O
O
N
R2
N
R1
β
-Adreno receptor antagonist
Figure 1. Biologically active phenyl pyridazin-3-ones.
C4-methylene protons, observed around 4.6 ppm in 4-bromo-
methyl-coumarins (Fig. 1).
These spectral observations led us to think in terms of a possible
ring opening of the lactone followed by a ring closure involving the
thermodynamically favoured amide bond formation and aromati-
zation leading to pyridazinones 2. When the reaction of hydrazine
hydrate with 1 was carried out in refluxing acetic acid, a different
product was obtained. In the IR spectrum, this compound exhibited
two bands around 1650 cmꢀ1 and 1700 cmꢀ1. In the 1H NMR, an
extra upfield signal around 2.4 ppm was observed corresponding
to acetyl protons. This led us to infer that in acetic acid the product
is N-acetylated pyridazinone 3.
With a view to introduce a phenyl group on the N-2 of pyridaz-
inone, we tried the reaction of phenyl hydrazine with 4-bromo-
methyl coumarins 1. This reaction resulted in the expected
nucleophilic substitution similar to our earlier work on other
* Corresponding authors. Tel.: +886 3 5131511; fax: +886 3 5736007 (C.S).
E-mail address: cmsun@mail.nctu.edu.tw (C.-M. Sun).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.015

M. D. Ghate et al. / Tetrahedron Letters 49 (2008) 4394–4396
4395
Table 1
Br
N
H2C
Pyridazinones synthesized from coumarins
OH
NH
R
Entry
R
Compound
Mp (°C)
Yield (%)
(a)
O
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5-CH3
4-CH3
5,6-Benzo
3,4-Benzo
5-Br
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
3e
3f
136–138
140–142
161–163
152–154
147–149
208–210
178–180
168–170
184–186
190–192
170–172
185–187
190–192
184–186
275–277
170–172
78
75
70
68
64
70
75
78
72
68
66
66
71
70
69
65
O
O
1
2
5-Cl
4-Cl
(b)
(c)
H3C
O
O
5-OCH3
5-CH3
4-CH3
5,6-Benzo
3,4-Benzo
5-Br
5-Cl
5-OCH3
4-Cl
O
N
OH
N
CH3
N
H2C
N
H
R
R
3
3h
3g
O
O
4
Acetylation of the initially formed hydrazide.
Scheme 1. Reagents and conditions: (a) NH2–NH2/EtOH, reflux; (b) NH2–NH2/Ac-
OH, reflux; (c) Ph–NH–NH2/AcOH, reflux.
nitrogen nucleophiles20 and was carried out in acetic acid, which
resulted in N-acetylated product 4 (Scheme 1).
attack on the carbonyl group and elimination of acetic acid hydra-
zide would result in a similar intermediate 5a. Dehydrogenation of
the intermediate 5a can lead to the generation of aromatic pyridaz-
inones 3. Intra-molecular expulsion of acetic acid hydrazide has
been proposed in the formation of 3-hydrazinopyridazinones.21
The driving force for this nucleophilic substitution, followed by
ring opening and ring closure (SNRORC) seems to be the stability
of the aromatic pyridazinones.
In conclusion, the present work has demonstrated a novel
transformation that can be used as a new method for the synthesis
of 5-substituted phenyl pyridazin-3-ones.25 Ease of preparing the
starting materials and simple reaction conditions provided a new
route for the introduction of the aryl moiety in pyridazinones.
The functional groups generated in this reaction have the potential
for further transformations, and hence this reaction has a wide
range of applicability.
To the best of our knowledge there are no reports on the trans-
formations of coumarins to pyridazines. Recently, it has been
observed that tricyclic trifluoromethyl dihydro thienosulfonyl cou-
marins obtained in a multistep sequence reacted with hydrazine
hydrate to yield 3-hydrazino-6-o-hydroxy phenyl pyridazines.21
A probable mechanistic pathway for the formation of pyridazines
is given in Scheme 2.
Nucleophilic attack of hydrazine hydrate on the lactone car-
bonyl and the C-4 methylene is equally probable, since excess of
this reagent is employed and would produce a hydrazino hydr-
azide. Hydrazine hydrate and other double nucleophiles like
amidines and thiourea are known to bring about similar ring
opening of coumarins which have resulted in the formation of
o-hydroxyphenyl substituted pyrazoles22 and pyrimidines.23
Further, an intramolecular nucleophilic attack of the hydrazine
on the carbonyl group of the hydrazide followed by the expulsion
of hydrazine results in the intermediates 5 which undergo in situ
dehydrogenation to give pyridazinones 2. In acetic acid medium
the corresponding intermediate can result from the acetylation of
the initially formed hydrazide).
Acknowledgements
The authors are thankful to National Science Council of Taiwan
(NSC) for partial financial assistance and national Center for High-
performance Computing for computer time and facilities and to
University Scientific Instrumentation Centre (USIC), Karnatak
University Dharwad, India, for Spectral and analytical data.
The proposed acetylation of hydrazides is in agreement with the
recent literature reports.24 Further, intramolecular nucleophilic
H
N
N
N
NH
N
NH
Ethanol
-H2
[O]
O
OH
O
R
NH2-NH2
OH
OH
OH
R
R
Br
H2C
5
2
O
O
O
O
O
O
R
H
N
N
1
N
CH3
N
CH3
-H2
[O]
NH2-NH2
R
Acetic acid
OH
OH
5a
3
Scheme 2. Mechanism of formation of pyridazinones.

4396
M. D. Ghate et al. / Tetrahedron Letters 49 (2008) 4394–4396
18. Khan, I. A.; Kulkarni, M. V.; Sun, C. M. Eur. J. Med. Chem. 2005, 40, 1168–
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25. Typical procedures: Synthesis of 5-(2-hydroxy-5-methyl-phenyl)-2H-pyridazine-
3-one (2a).
A mixture of 6-methyl-4-bromomethylcoumarin (1a, 0.5 g,
0.002 mmol) was refluxed with hydrazine hydrate (99%) (0.5 g, 0.01 mmol)
in ethanol (10 ml) for 2 h. The reaction mixture was cooled and poured on ice-
cold water, and separated solid was filtered off. It was washed several times
with aqueous ethanol, dried and recrystallized from ethanol to give 2a as a
colourless crystalline solid (0.31 g, 78%), mp 138–140 °C; IR (KBr) cmꢀ1 3191
(br), 1661; 1H NMR (CDCl3, 300 MHz, TMS) d 2.41 (s, 3H, CH3), 6.23 (s, (br), 2H,
D2O exchangeable, NH and OH), 6.43 (s, 1H, C4–H of pyridazine), 8.18 (s, 1H,
C6–H of pyridazine), 7.13 (s, 1H, C60–H), 7.20 (d, 1H, C40-H, J = 8.6 Hz), 7.35 (d,
1H, C30–H, J = 8.6 Hz); 13C NMR (CDCl3, 75 MHz, TMS) d 22, 114, 121, 122, 128,
129, 130, 148, 154.3, 154.6, 162; mass (EI) m/z M+ 202 (8%), M–CO 174 (100%);
Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.38; H,
4.95; N, 13.89. Identical procedure was used in all the cases (Table 1). Synthesis
of 2-acetyl-5-(2-hydroxy-5-methyl-phenyl)-2H-pyridazine-3-one (3a). A mixture
of 6-methyl-4-bromomethylcoumarin (0.5 g, 0.002 mmol) was refluxed with
hydrazine hydrate (0.5 g, 0.01 mmol) in glacial acetic acid (10 mL) for 1 h. The
crystalline product separated was filtered off and washed with aqueous
ethanol and recrystallized from ethanol to give colourless solid (0.30 g, 64%),
mp 186–188 °C; IR (KBr) cmꢀ1 3400 (br), 1701, 1654; 1H NMR (CDCl3,
300 MHz, TMS) d 2.43 (s, 3 H, C50–CH3), 2.46 (s, 3H, NCOCH3), 7.49 (d, 1H,
J = 8.0 Hz, C30–H of phenyl), 7.98 (d, 1H, J = 8.0 Hz, C40–H of phenyl), 8.21 (s, 1H,
C6–H of pyridazine), 6.15 (s, 1 H, C4–H of pyridazine), 7.22 (s, 1 H, C6–H of
pyridazine), 7.28 (s (br), 1 H, OH, D2O exchangeable); 13C NMR (CDCl3,75 MHz,
TMS) d 17, 21, 120, 122, 123, 133, 126, 127, 144, 148, 157, 168, 169; mass
m/z M+ 244 (10%), M–CO, 216 (25%), 43 (100%); Anal. Calcd for C13H12N2O3: C,
63.93; H, 4.95; N, 11.47. Found: C, 63.97; H, 4.99; N, 11.44. Similar
procedure was used in all other cases (Table 1). Synthesis of 4-[20-
acetylphenylhydrazino)-methyl]-5,6-benzocoumarin (4). A mixture of 6-methyl-
4-bromomethylcoumarins (0.7 g, 0.002 mmol) and phenyl hydrazine(0.2 ml,
0.002 mmol) was refluxed in glacial acetic acid (10 ml) for 4 h at a temperature
of 120 °C in an oil bath. The reaction mixture was concentrated and poured
over crushed ice (100 ml). The solid separated was filtered, dried and
recrystallized from ethanol to give colourless solid (0.65 g, 65 %); mp 222–
224 °C. IR (KBr) cmꢀ1 3298, 2990, 1696, 1640; 1H NMR (CDCl3, 300 MHz, TMS)
d 2.11 (s, 3H, NCOCH3), 5.31 (s, 2H, CH2–N), 6.57 (s, C3–H of coum), 8.34 (s (br),
1H, NH), 6.75–8.30 (m, 11H, Ar–H).; mass m/z 358 (12%), 315 (10%), 77 (100%).
Anal. Calcd for C22H18N2O3: C, 73.73; H, 5.06; N, 7.82. Found: C, 73.77; H, 5.02;
N, 7.86.
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