Facile synthesis of 3(2H)-pyridazinones and 2(3H)-furanones of anticipated biological activities

Article abstract of DOI:10.1002/jccs.200800185

3-Aroyl-2-arylpropionic acids 2a-e were utilized to synthesize 3(2H)-pyridazinones 3a-e and 2(3H)-furanones 6 through reaction with hydrazine hydrate and freshly distilled acetic anhydride, respectively, in the hope of obtaining new 3(2H)-pyridazinones wi

Full text of DOI:10.1002/jccs.200800185

Journal of the Chinese Chemical Society, 2008, 55, 1243-1250
1243
Facile Synthesis of 3(2H)-Pyridazinones and 2(3H)-Furanones of
Anticipated Biological Activities
J. M. Morsy
Chemistry Department, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt
3-Aroyl-2-arylpropionic acids 2a-e were utilized to synthesize 3(2H)-pyridazinones 3a-e and 2(3H)-
furanones 6 through reaction with hydrazine hydrate and freshly distilled acetic anhydride, respectively,
in the hope of obtaining new 3(2H)-pyridazinones with no ulcerogenic side effect or with negligible gen-
eral side effects as those currently used NSAIDS as well as biologically active 2(3H)-furanones.
Keywords: 3-Aroyl-2-arylpropionic acids; 4,6-Disubstituted-3(2H)-pyridazinones;
3,5-Disubstituted-2(3H)-furanones; NSAIDS.
INTRODUCTION
RESULTS AND DISCUSSION
3(2H)-Pyridazinones are important scaffolds in the
drug industry, with many of their analogs being utilized in
the treatment of different human pathological states. This
class of heterocyclic compounds have been described as
non-steroidal anti-inflammatory drugs,1 agents for thera-
peutic intervention of renal-urologic,2 cardiovascular,3 re-
spiratory,4 dermatologic diseases.5 They also have platelet
inhibitory activity.6-10 The majority of currently known
non-steroidal anti-inflammatory and analgesic drugs
[NSAIDS], i.e, aspirin and ibuprofen, mainly act peripher-
ally by blocking the production of prostaglandins through
inhibition of cyclooxygenase (COX) enzymes, COX-1
and COX-2.11 These drugs tend to produce side effects
such as gastrointestinal ulceration and suppression of re-
nal function due to inhibition of the constitutive COX-1,
which is responsible for the production of prostaglandins,
which are responsible for gastroprotection and vascular
hemeostasis.12-14 As a result of the previously mentioned
facts, the main trend nowadays in pain therapy focuses on
improved non-steroidal analgesics which are effective as
analgesics but devoid of the side effects which are inherent
to traditional NSAIDS. Moreover, the 2(3H)-furanone frag-
ment is present in a wide variety of biologically active natu-
ral products.15 The importance of 2(3H)-furanones is due to
facile ring cleavage by a variety of nucleophilic species to
afford acyclic derivatives which may undergo ring closure
to produce other synthetically and biologically important
heterocyclic systems.16
Taking into account all the aforementioned facts and
to achieve facile synthetic routes of new 3(2H)-pyrida-
zinones and 2(3H)-furanones, the author decided to carry
out the present study aiming that the new 3(2H)-pyrida-
zinones will be with no ulcerogenic side effects or with
negligible general side effects as those of currently used
NSAIDS. Herein, the author reports a convenient and ver-
satile synthetic approach to novel 3(2H)-pyridazinones
from readily obtainable simple compounds viz 3-aroyl-
prop-2-enoic acids 1.17,18 The methodology adopted by the
author consists of treatment of 3-aroylprop-2-enoic acids 1
by active aromatic hydrocarbons under Friedel-Crafts reac-
tion conditions followed by reaction of the product with
hydrazine hydrate. Thus, when acids 1 were allowed to re-
act with o-xylene, p-xylene, cumene and/or chlorobenzene
in the presence of anhydrous aluminium chloride, it af-
forded 3-aroyl-2-arylpropionic acids 2a-e (cf. Scheme I).
The interesting pharmacological activity displayed
by pyridazinones has been demonstrated in recent years.
They have initially received special attention in the search
of drugs acting on the cardiovascular system,19 but more re-
cent publications have dealt with the wide range of biologi-
cal activities of this class of compounds.20 Despite the use-
fulness of 3(2H)-pyridazinones, few methods for the intro-
duction of a range of substituents into this six-member
heterocyclic system to get good analgesic and anti-inflam-
matory activities have been presented.21-25 For this reason,
new advances in this area continue to be of interest and this
* Corresponding author. E-mail: jmmorsy@yahoo.com

1244 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Morsy
Scheme I
prompted the author to synthesize 4,6-disubstituted-3(2H)-
pyridazinones through interaction of acids 2 with hydra-
zine hydrate in the hope of obtaining new biologically ac-
tive pyridazinones.

Facile Synthesis of 3(2H)-Pyridazinones as NSAIDS
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1245
Thus, when acids 2 reacted with hydrazine hydrate in
boiling ethanol and/or n-butanol, it gave 4,6-diaryl-2,3,4,5-
tetrahydro-3(2H)-pyridazinones 3a-e (cf. Scheme I).
It has been found that the heterocyclic ring substitu-
tions at the six-position, and the presence of acetamide side
chain that is linked to the lactam nitrogen of pyridazinone
ring at the two-position, improved the analgesic and anti-
inflammatory activities along with nil or very low ulcer-
ogenicity.26 Accordingly, in the present study, the author
has synthesized the structurally-like amide derivative, i.e,
2-thiocarbamoylaminocarbamoylmethyl pyridazinone de-
rivative (5) through the effect of thiosemicarbazide upon
2-ethoxycarbonylmethyl derivative (4) in pyridine heated
to reflux temperature. Thus, when compounds 3a and/or 3c
were allowed to react with ethyl chloroacetate in dry ace-
tone heated to refluxing temperature in the presence of an-
hydrous potassium carbonate as a basic catalyst, it afforded
2-ethoxycarbonylmethyl-4,6-disubstituted-3(2H)-pyrida-
zinones 4a and 4b respectively.
of anhydrous AlCl3 (40 mmol).
b, heating a mixture of acid 1 (10 mmol), dry aromatic
hydrocarbon (50 mL) and anhydrous AlCl3 (40 mmol) on a
water bath, 10 h.
(ii) 10 mmol of acid 2, EtOH or Bun-OH (30 mL),
N2H4.H2O (10 mL), reflux 3 h.
(iii) 10 mmol of 3, dry acetone (100 mL), ClCH2CO2Et
(20 mmol), anhydrous K2CO3 (40 mmol), reflux 20 h.
(iv) equimolar mixture of 4 and NH2NHCSNH2 (10
mmol), pyridine (30 mL), reflux 5 h.
(v) acid 2 (10 mmol), Ac2O (10 mL), reflux 2 h.
(vi) compound 6 (10 mmol), PhCH2NH2 (10 mmol),
EtOH (40 mL), reflux 4 h.
(vii) a mixture of acid 1 (10 mmol), appropriate amine
(10 mmol), absolute EtOH (50 mL) is left at rt for 5 days or
heated to reflux temperature 6 h in dry benzene (40 mL).
Oxygen containing heterocycles are frequent and im-
portant targets in synthetic organic chemistry due to their
common occurrence in nature as well as that some 2(3H)-
furanones exhibit appreciable photochemical properties.31
Thus, the author intended to extend the present work
through the reaction of 3-(4-bromobenzoyl)-2-(3,4-di-
methylphenyl)propionic acid 2a with freshly distilled ace-
tic anhydride to yield 5-(4-bromophenyl)-3-(3,4-dimethyl-
phenyl)-2(3H)-furanone 6 via an intramolecular cycliza-
tion process. The latter underwent hetero ring cleavage at
C-2 on treatment with a nitrogen nucleophile, namely ben-
zyl amine to afford 3-(4-bromobenzoyl)-2-(3,4-dimethyl-
phenyl)-N-benzoylpropionamide 7.
To the best of my knowledge, the reaction of 4,6-di-
aryl-3(2H)-pyridazinones with ethyl chloroacetate under
the same conditions leads to access of a state of structure-
conflict. In some studies,27-28 it has been reported that the
product is 3-ethoxycarbonylmethoxy pyradizinone deriva-
tive and that means that O-alkylation takes place on the car-
bonyl-oxygen atom. On the other hand, other publications
reported that the product is 2-ethoxycarbonylmethyl pyrid-
azinone derivative which refers to an N-alkylation prod-
uct.29
In the present study, the infra-red spectra of 4a and 4b
showed strong absorption bands at 1672 and 1683 cm-1
(uC=O pyridazine) as well as 1738 and 1741 cm-1 (uC=O es-
ter). The 1H-NMR and IR spectra of 4a and 4b are devoid
of any bands for the NH group. When compound 4a was al-
lowed to react with thiosemicarbazide in pyridine heated to
refluxing temperature, it gave the target compound, 2-thio-
carbamoylaminocarbamoylmethyl derivative (5) through a
tetrahedral mechanism in which the C-N bond formation
precedes the C-O bond breaking and consequently a lot of
energy is accumulated in the reaction medium, and the sys-
tem receives much of its energy payback from the forma-
tion of the newly formed C-N bond before having to return
this energy amount for the C-O bond breaking.30
Recently,32 it has been reported that 3-(4-bromoben-
zoyl)prop-2-enoic acid has antibacterial activity towards
Staphilococus aureus, Escherichia coli and Kllebsiella.
This activity was ascribed to the presence of the highly
conjugated aroylacrylic system which may react with bio-
logically essential –SH groups. Herein, the author sought
the behaviour of this acid towards compounds containing
the -NH groups which might react with the toxophoric sys-
tem in the benzoylacrylic system C=C-C=O. Thus, when
acid 1a was allowed to react with aralkyl and heteroaro-
matic amines, namely benzyl amine and/or 2-aminopyri-
dine, it gave 3-(4-bromobenzoyl)-2-benzylamino-N-ben-
zylpropionamide and 3-(4-bromobenzoyl)-2-(2-pyridyl-
amino)-N-(2-pyridyl)propionamide 8a and 8b, respec-
tively (cf. Scheme I).
Reagents and Reaction Conditions
(i) a, an aromatic hydrocarbon solution of acid 1 (10
mmol/50 mL) is saturated with dry HCl at rt in the presence
EXPERIMENTAL
All melting points are uncorrected and were deter-

1246 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Morsy
mined on a Gallenkamp electric melting point apparatus.
The IR spectra were recorded on a Shimadzu FTIR 8101
PC as KBr discs. The 1H-NMR and 13C-NMR spectra were
measured on a Varian Gemini 200 MHz instrument in
DMSO-d6 as a solvent with chemical shifts (d) expressed in
ppm from downfield to upfield from TMS as internal stan-
dard. TLC was run using TLC aluminium sheets silica gel
F254 (Merck) to check the purity of all synthesized com-
pounds. Mass spectra were recorded on a Shimadzu GC-
MS-QP 1000 Ex instrument operating at 70 eV.
59.55, H 4.37, Br 21.94. 13C-NMR (DMSO-d6): d = 18.81,
19.13, 40.74, 48.88, 126.60, 127.51, 129.82, 130.58,
131.43, 131.50, 132.34, 135.63, 135.73, 137.18, 177.34,
200.10.
2b: Yield: 67%; white crystals, mp 150-52 °C (Ben-
zene), IR (cm-1): 1678 (CO aroyl ketone), 1699 (CO acid),
1
2922 and 2984 (CH aliph) and 3405 (OH). H-NMR,
(DMSO-d6) d: 11.58 (s, 1H, COOH, exchangeable), 7.27-
6.85 (m, 7H, ArH), 4.24 (dd, 1H, CHCH2-), 3.13 (octet,
2H, COCH2-, diastereotropic non-equivalent methylene
protons), 2.17 (s, 6H, 2CH3). MS m/z (%): 296 (M.+, 6.80),
251 (57.00), 119 (100.00), 91 (69.00), 65 (38.00), 45
(41.00). Anal. Calcd. for C19H20O3 (%): C 77.03, H 6.76;
Found: C 76.89, H 6.46. 13C-NMR, (DMSO-d6) d = 18.75,
19.06, 21.26, 40.68, 48.92, 126.63, 128.66, 128.94, 130.64,
131.48, 132.33, 133.72, 135.61, 137.24, 142.81, 177.29,
200.12.
Reaction of 3-aroylprop-2-enoic acids 1a,b with active
aromatic hydrocarbons-Formation of 2a-e
Method (A)
A solution of acid 1a and/or 1b (10 mmol; 2.54 g and
1.90 g, respectively) in aromatic hydracarbon namely, o-
xylene, p-xylene, cumene and/or chlorobenzene (50 mL)
was saturated with dry HCl. Anhydrous AlCl3 (40 mmol;
5.33 g) was then added portionwise with efficient stirring.
A yellow paste was formed with vigorous evolution of HCl
gas. The reaction mixture was stirred for an additional 15 h
at room temperature and left overnight, treated with ice/
HCl. The organic layer was washed with cold water and the
excess solvent was removed by steam distillation. The or-
ganic material was extracted by ether and the ethereal solu-
tion was treated throroughly with Na2CO3 solution (10%).
The alkaline solution was acidified by cold diluted HCl to
afford the crude product which was recrystallized from a
suitable solvent to yield the corresponding propionic acid
derivatives 2a-e.
2c: Yield: 71%; white crystals, mp 164-65 °C (Tolu-
ene). IR (cm-1): 1681 (CO aroyl ketone), 1700 (CO acid),
1
2925 and 2987 (CH aliph) and 3412 (OH). H-NMR,
(DMSO-d6) d: 11.55 (s, 1H, COOH, exchangeable), 7.20-
6.95 (m, 7H, ArH), 4.30 (dd, 1H, CHCH2-), 3.18 (octet,
2H, COCH2-, diastereotropic non-equivalent methylene
protons), 2.12 (s, 6H, 2CH3). Anal. Calcd. for C18H17BrO3
(%): C 59.83, H 4.71, Br 22.16; Found: C 59.65, H 4.43, Br
21.83. 13C-NMR, (DMSO-d6) d = 19.14, 21.58, 41.04,
46.37, 127.48, 127.72, 129.77, 130.55, 131.46, 132.73,
133.68, 135.68, 135.76, 136.37, 177.33, 200.14.
2d: Yield: 53%; white crystals, mp 140-42 °C (Ben-
zene). IR (cm-1): 1683 (CO aroyl ketone), 1702 (CO acid),
2928 and 2990 (CH aliph) and 3418 (OH).1H-NMR,
(DMSO-d6) d: 11.49 (s, 1H, COOH, exchangeable), 7.26-
7.10 (m, 8H, ArH), 4.32 (dd, 1H, CHCH2-), 3.55 (s, 1H,
methine proton of isopropyl group), 3.19 (octet, 2H,
COCH2-, diastereotropic non-equivalent methylene pro-
tons). MS m/z (%): 375 (M.+, 4.90), 330 (49.00), 184
(100.00), 156 (31.00), 76 (29.00), 45 (43.00). Anal. Calcd.
for C19H19BrO3 (%): C 60.80, H 5.07, Br 21.33; Found: C
60.49, H 4.81, Br 21.19. 13C-NMR, (DMSO-d6) d = 23.25,
33.17, 40.73, 48.55, 126.46, 127.53, 129.42, 129.75,
131.46, 135.03, 135.67, 147.24, 177.26, 200.07.
Method (B)
To a solution of acid 1a and/or 1b (10 mmol; 2.54 g
and 1.90, respectively) in aromatic hydrocarbons, namely
o-xylene, p-xylene, cumene and/or chlorobenzene (50
mL), anhydrous AlCl3 (40 mmol; 5.33 g) was added at
room temperature then the reaction mixture was heated on
a boiling water bath for 10 h followed by treatment as de-
scribed in method (A).
3-Aroyl-2-arylpropionic acids 2a-e
2a: Yield: 72%; white crystals, mp 160-61°C (Tolu-
ene). IR (cm-1): 1675 (CO aroyl ketone), 1697 (CO acid),
2919 and 2980 (CH aliph) and 3395 (OH).1H-NMR,
(DMSO-d6) d: 11.59 (s, 1H, COOH, exchangeable), 7.28-
6.90 (m, 7H, ArH), 4.29 (dd, 1H, CHCH2-), 3.21 (octet,
2H, COCH2-, diastereotropic non-equivalent methylene
protons). MS m/z (%): 361 (M.+, 7.20), 316 (52.00), 184
(100.00), 156 (37.00), 76 (26.00), 45 (36.00). Anal. Calcd.
for C18H17BrO3 (%): C 59.83, H 4.71, Br 22.16; Found: C
2e: Yield: 68%; white crystals, mp 189-90 °C (Etha-
nol). IR (cm-1): 1685 (CO aroyl ketone), 1705 (CO acid),
1
2930 and 2994 (CH aliph) and 3421 (OH). H-NMR,
(DMSO-d6) d: 11.61 (s, 1H, COOH, exchangeable), 7.18-
6.92 (m, 8H, ArH), 4.20 (dd, 1H, CHCH2-), 3.50 (octet,
2H, COCH2-, diastereotropic non-equivalent methylene

Facile Synthesis of 3(2H)-Pyridazinones as NSAIDS
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1247
protons), 2.36 (s, 3H, CH3). MS m/z (%): 302.5 (M.+, 5.20),
257.5 (55.00), 119 (100.00), 91 (62.00), 65 (36.00), 45
(37.0). Anal. Calcd. for C17H15ClO3 (%): C 67.44, H 4.96,
Cl 11.74; Found: C 67.19, H 4.72, Cl 11.34. 13C-NMR,
(DMSO-d6) d = 21.29, 40.67, 48.55, 128.66, 128.85,
129.16, 131.14, 133.13, 133.72, 135.86, 142.78, 177.29,
200.08.
(Ethanol). IR (cm-1): 1670 (CO), 1617 (C=N), 3244 (NH).
1H-NMR (DMSO-d6) d: 11.15 (s, 1H, NH, exchangeable),
7.20-6.90 (m, 7H, ArH), 4.00 (dd, methine proton, C-4 pro-
ton of pyridazinone moiety), 3.10 (octet, 2H, COCH2 dia-
stereotropic non-equivalent methylene protons at C-5 of
pyridazinone moiety), 2.10 (s, 6H, 2CH3). Anal. Calcd. for
C18H17BrN2O (%): C 60.50, H 4.76, N 7.84, Br 22.41;
Found: C 60.28, H 4.39, N 7.65, Br 21.27. 13C-NMR,
(DMSO-d6) d = 19.13, 21.57, 34.16, 50.12, 125.38, 127.77,
128.62, 130.73, 131.65, 132.64, 134.61, 135.43, 135.94,
136.26, 146.48, 177.03.
Reaction of 3-aroyl-2-arylpropionic acids 2a-e with
hydrazine hydrate-Formation of 3a-e
To a solution of acid 2a-e (10 mmol) in absolute etha-
nol and/or dry n-butanol (30 mL), 100% hydrazine hydrate
(10 mmol; 0.5 mL) was added, and the solution was heated
under reflux for 3 h. The solid that separated out after con-
centrating and cooling the reaction solution, was filtered
off by suction and recrystallized from a suitable solvent to
give the pyridazinones 3a-e.
3d: Yield: 62%, pale yellow crystals, mp 170-71 °C
(Dioxan). IR (cm-1): 1674 (CO), 1619 (C=N), 3259 (NH).
1H-NMR (DMSO-d6) d: 11.14 (s, 1H, NH, exchangeable),
7.22-6.93 (m, 8H, ArH), 3.98 (dd, methine proton, C-4 pro-
ton of pyridazinone moiety), 3.60 (m, 1H, methine proton
of isopropyl group), 3.11 (octet, 2H, COCH2, diastereo-
tropic non-equivalent methylene protons at C-5 of pyrida-
zinone moiety), 1.41 (d, 6H, 2CH3 of isopropyl group).
MS m/z (%): 371 (M.+, 2.5), 253 (M-C6H4.C3H7.4]+, 7.5),
215 (M-C6H4Br.4, 2.5), 119 (C6H4.C3H7.4]+, 6.8), 93
(MC6H4.C3H7.4+C6H4.Br.4].+, 86.30), 77 (C6H5.+, 15.60),
61 (100.00), 51 (10.00). Anal. Calcd. for C19H19BrN2O
(%): C 61.46, H 5.12, N 7.55, Br 21.56; Found: C 61.61, H
5.45, N 7.69, Br 21.72. 13C-NMR, (DMSO-d6) d = 23.31,
33.15, 33.87, 52.26, 125.39, 126.61. 128.55, 129.26, 131.66,
133.52, 135.37, 146.58, 147.33, 177.10.
4,6-Disubstituted-3(2H)-pyridazinones 3a-e
3a: Yield: 81%; pale yellow crystals, mp 129-30 °C
(Ethanol). IR (cm-1): 1658 (CO), 1616 (C=N), 3200 (NH).
1H-NMR, (DMSO-d6) d: 11.17 (s, 1H, NH, exchangeable),
7.22-6.92 (m, 7H, ArH), 3.99 (dd, methine C-4 proton of
pyridazinone moiety), 3.07 (octet, 2H, COCH2-, diastereo-
tropic non-equivalent methylene protons of pyridazinone
moiety), 2.15 (s, 6H, 2CH3). MS m/z (%): 357 (M.+, 2.10),
251 (M.+-C6H3(CH3)2-2,5), 201 (M.+-C6H4Br.4, 4.6), 95
(M.+-C6H3(CH3)2-2,5 + C6H4Br.4, 76.50), 76 (C6H4
,
.+
58.00), 50 (100.00). Anal. Calcd. for C18H17BrN2O (%): C
60.50, H 4.76, N 7.84, Br 22.41; Found: C 60.31, H 4.50, N
7.62, Br 22.22. 13C-NMR, (DMSO-d6) d = 18.76, 19.12,
33.86, 52.57, 125.41, 126.53, 128.56, 130.73, 131.38,
131.71, 133.24, 135.42, 135.65, 137.28, 146.53, 177.07.
3b: Yield: 59%; pale yellow crystals, mp 125-26 °C
(Ethanol). IR (cm-1): 1662 (CO), 1618 (C=N), 3235 (NH).
1H-NMR, (DMSO-d6) d: 11.16 (s, 1H, NH, exchangeable),
7.14-688 (m, 7H, ArH), 3.96 (dd, methine C-4 proton of
pyridazinone moiety), 3.08 (octet, 2H, COCH2-, diastereo-
tropic non-equivalent methylene protons of pyridazinone
moiety), 2.34 (s, 3H, CH3), 2.15 (s, 6H, 2CH3). MS m/z
(%): 292 (M.+, 4.60), 201 (M.+-C6H4.CH3.4, 3.8), 187
(54.00), 186 (M.+-C6H3(CH3)2-3,4, 42.00), 92 (66.00), 91
3e: Yield: 64%, pale yellow crystals, mp 204-06 °C
(Ethanol). IR (cm-1): 1679 (CO), 1621 (C=N), 3255 (NH).
1H-NMR (DMSO-d6) d: 11.16 (s, 1H, NH, exchangeable),
7.15-6.86 (m, 8H, ArH), 4.11 (dd, methine proton, C-4 pro-
ton of pyridazinone moiety), 3.14 (octet, 2H, COCH2, dia-
stereotropic non-equivalent methylene protons at C-5 of
pyridazinone moiety), 2.39 (s, 3H, CH3). MS m/z (%):
298.5 (M.+, 3.89), 207.5 (M.+-C6H4.CH3.4,-2,9), 187 (M.+-
C6H4Cl.4, 7.20), 111.5 (C6H4Cl.+, 8.4), 96 (MC6H4Cl.4 +
C6H4CH3.4, 3.5), 91 (tropylium ion, 84.00), 77 (23.00), 76
(18.50). Anal. Calcd. for C17H15ClN2O (%): C 68.34, H
5.03, N 9.38, Cl 11.89.41; Found: C 68.66, H 5.19, N 9.53,
Cl 12.19. 13C-NMR, (DMSO-d6) d = 21.34, 33.92, 52.27,
127.04, 129.13, 129.34, 131.03, 133.22, 133.38, 134.42,
140.66, 146.48, 177.06.
+
(tropylium ion, 86.00), 65 (C5H5 , 100.00). Anal. Calcd.
for C19H20N2O (%): C 78.80, H 6.85, N 9.59; Found: C
77.91, H 6.60, N 9.28. 13C-NMR, (DMSO-d6) d = 18.77,
19.11, 21.27, 33.86, 52.55, 126.49, 127.03, 129.06,
130.71, 131.43, 133.17, 133.42, 135.66, 137.31, 140.72,
146.48, 177.02.
Reaction of 6-(4-bromophenyl)-4-(3,4- and/or 2,5-
dimethylphenyl)-3(2H)-pyridazinone 3a and/or 3c
with ethyl chloroacetate-Formation of 4a and 4b
To a solution of 3a and/or 3c (10 mmol; 3.57 g), ethyl
cloroacetate (10 mmol; 1.1 mL) in dry acetone (60 mL), an-
3c: Yield: 74%, pale yellow crystals, mp 180-82 °C

1248 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Morsy
hydrous potassium carbonate (40 mmol; 5.52 g) was added,
then the reaction mixture was heated to refluxing tempera-
ture on a boiling water bath for 24 h. Most of the solvent
was distilled off and the residue was left to cool and then
poured, with stirring, onto ice-cold water after being cold.
The solid that separated out was collected by suction filtra-
tion, dried and recrystallized from light petroleum (80-100
°C) to afford 4a and 4b, respectively.
and recrystallized from ethanol to give 5.
6-(4-Bromophenyl)-4-(3,4-dimethylphenyl)-2-thiocar-
bamoylaminocarbamoylmethyl-2,3,4,5-tetrahydropyr-
idazin-3(2H)-one 5
Yield: 55%; yellow crystals, mp 178-79 °C (Ethanol).
IR (cm-1): 3409, 3306, 3205 (NH) 1674 (CO pyridazinone),
1
1665 (CO). H-NMR (DMSO-d6): d: 7.21-6.90 (m, 7H,
ArH), 6.48 (s, 2H, 2NH, exchangeable), 5.00 (s, 2H, NH2,
exchangeable), 4.68 (s, 2H, CH2CO), 3.98 (dd, methine
C-4 proton of pyridazinone moiety), 3.15 (octet, 2H,
COCH2-, diastereotropic non-equivalent methylene pro-
tons of pyridazinone moiety), 2.18 (s, 6H, 2CH3), MS m/z
(%): 488 (M.+, 5.00), 398 (17.50), 370 (100.00), 156 (14.50),
105 (12.20), 104 (16.50), 91 (88.00), 65 (53.00). Anal.
Calcd. for C21H22BrN2O5S (%): C 51.64, H 4.51, N 14.34,
Br 16.39, S 6.56; Found: C 51.36, H 4 .36, N 14.20, Br
16.18, S 6.41. 13C-NMR, (DMSO-d6) d = 18.76, 19.13,
34.16, 50.13, 55.44, 125.37, 126.52, 128.63, 130.71,
131.42, 131.65, 133.23, 135.42, 135.68, 137.27, 146.54,
170.27, 176.04, 182.53.
6-(4-Bromophenyl)-4-(3,4- and/or 2,5-dimethylphen-
yl)-2-ethoxycarbonylmethyl-2,3,4,5-tetrahydropyrida-
zin-3(2H)-one 4a and 4b
4a: Yield: 66%; pale yellow crystals, mp 109-10 °C
(Light petrol). IR (cm-1): 1672 (CO pyridazinone) and 1738
(CO ester). The spectrum is devoid of any band for NH.
1H-NMR (DMSO-d6) d: 7.20-6.94 (m, 7H, ArH), 3.96 (dd,
methine C-4 proton of pyridazinone moiety), 3.92 (s, 2H,
CH2COO-), 3.28 (q, 2H, CH2CH3, J = 6.98 Hz), 3.08 (octet,
2H, COCH2-2CH3), 1.25 (t, 3H, CH2CH3, J = 6.98 Hz). MS
m/z (%): 443 (M.+, 3.70), 417 (6.20), 373 (29.00), 370
(100.00), 287 (23,30), 156 (18.60), 105 (9.80), 104 (11.40),
92 (28.20), 91 (71.00), 65 (34.00). Anal. Calcd. for
C22H23BrN2O3 (%): C 59.59, H 5.19, N 6.32, Br 18.06;
Found: C 59.88, H 5.41, N 6.64, Br 18.29. 13C-NMR,
(DMSO-d6) d = 14.14, 18.76, 19.13, 34.24, 50.06, 61.03,
125.37, 126.52, 128.55, 130.68, 131.41, 131.73, 133.24,
135.38, 135.73, 137.28, 146.51, 169.52, 176.04.
Reaction of 3-(4-bromobenzoyl)-2-(3,4-dimethylphen-
yl)propionic acid 2a with acetic anhydride-Formation
of 6
Propionic acid derivative 2a (10 mmol; 3.61 g) was
added to freshly distilled acetic anhydride (10 mL) and the
reaction mixture was heated under reflux on a boiling water
bath for 1 h and then left to cool. The solid that deposited
down was filtered off, washed with cold ethanol and re-
crystallized from n-butanol to give 6.
4b: Yield: 69%; pale yellow crystals, mp 118-19 °C
(Light petrol). IR (cm-1): 1683 (CO pyridazinone) and 1741
(CO ester). The spectrum is devoid of any band for NH.
1H-NMR (DMSO-d6) d: 7.27-6.90 (m, 7H, ArH), 3.99 (dd,
methine C-4 proton of pyridazinone moiety), 3.90 (s, 2H,
CH2COO-), 3.16 (q, 2H, CH2CH3, J = 7.10 Hz), 3.09 (octet,
2H, COCH2-, diastereotropic non-equivalent methylene
protons of pyridazinone moiety), 2.12 (s, 6H, 2CH3), 1.29
(t, 3H, CH2CH3, J = 7.10 Hz). Anal. Calcd. for C22H23BrN2O3
(%): C 59.59, H 5.19, N 6.32, Br 18.06; Found: C 59.79, H
5.38, N 6.59, Br 18.31.
5-(4-Bromophenyl)-3-(3,4-dimethylphenyl)-2(3H)-
furanone 6
Yield: 60%; pale yellow crystals, mp 260-62 °C
(Butanol). IR (cm-1): exhibits a strong absorption band at
1789 attributable to lactonic CO. 1H-NMR (DMSO-d6): d:
7.60-7.40 (m, 7H, ArH), 6.00 (s, 1H, olefinic), 3.15 (s, 1H,
methine proton), 2.10 (s, 6H, 2CH3). MS m/z (%): 284
(M.+[CO2+CH3], 15.40), 224 (68.00), 223 (100.00), 144
(75.00), 92 (11.00), 91 (12.00), 89 (74.00). Anal. Calcd. for
C18H15BrO2 (%): C 62.97, H 4.37, Br 23.32; Found: C
63.23, H 4.61, Br 23.69. 13C-NMR, (DMSO-d6) d = 18.76,
19.13, 50.02, 95.04, 122.31, 126.55, 128.62, 129.33, 130.57,
131.46, 135.57, 136.39, 137.22, 147.23, 169.04.
Reaction of 5-(4-bromophenyl)-2-(3,4-dimethylphen-
yl)-2(3H)-furanone 6 with benzylamine-Formation of
7
Reaction of 6-(4-bromophenyl)-4-(3,4-dimethylphen-
yl)-2-ethoxycarbonylmethyl-2,3,4,5-tetrahydropyrida-
zin-3(2H)-one 4a with thiosemicarbazide-Formation
of 5
A solution of 4a (10 mmol; 4.42 g) in pyridine (30
mL) thiosemicarbazide (10 mmol; 0.91 g) was added and
the mixture was heated under reflux for 5 h. The reaction
solution was concentrated, left to cool, poured onto ice/
HCl with stirring. The solid that deposited was collected by
suction filtration, washed thoroughly with cold water, dried
Equimolar amounts of 6 (10 mmol; 3.43 g) and ben-
zylamine (10 mmol; 1.1 mL) are added to ethanol (50 mL)

Facile Synthesis of 3(2H)-Pyridazinones as NSAIDS
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1249
and the reaction mixture was heated under reflux for 4 h,
concentrated and left to cool at room temperature. The
solid that separated out was filtered off and recrystallized
from ethanol to yield 7.
3.20 (octet, 2H, COCH2 diastereotropic non-equivalent
methylene protons at C-5 of pyridazinone). MS m/z (%):
299 (M-[benzylamine+isocyanic acid+H2], 16.20), 184
(BrC6H4CO]+, 100.00), 156 (C6H4Br]+, 49.00), 107 (ben-
zylamine]+, 87.00), 91 (tropyliumion, 29.00), 76 (C6H4]+,
81.00), 65 (C5H5]+, 31.00), 50 (79.00). Anal. Calcd. for
C24H23BrN2O2 (%): C 63.86, H 5.10, N 6.21, Br 17.74;
Found: C 63.65, H 4.87, N 6.52, Br 17.56. 13C-NMR,
(DMSO-d6) d = 43.55, 46.57, 50.85, 56.13, 126.65, 126.94,
127.03, 127.46, 127.88, 128.52, 129.75, 131.47, 135.71,
137.86, 140.23, 172.04, 197.37.
3-(4-Bromobenzoyl)-2-(3,4-dimethylphenyl)-N-benzyl-
propionamide 7
Yield: 52%; pale yellow crystals, mp 190-91 °C (Eth-
anol). IR (cm-1): 3400 (NH), 1622 (CONH), 1693 (CO ke-
tone). 1H-NMR (DMSO-d6): d: 7.57-7.36 (m, 12H, ArH),
6.36 (s, 1H, NH, exchangeable), 4.53 (dd, methine proton,
C-4 proton of pyridazinone moiety), 4.53 (s, 2H, CH2Ph),
3.22 (octet, 2H, COCH2-, diastereotropic non-equivalent
methylene protons of pyridazinone), 2.14 (s, 6H, 2CH3).
MS m/z (%): 343 (M.+-C6H5CH2NH2, 29.00), 184
(Br.C6H4.CO]+, 100.00), 156 (46.00), 134 (59.00), 107
(61.00), 91 (92.00), 65 (74.00), 50 (69.00). Anal. Calcd.
for C25H24BrNO2 (%): C 66.67, H 5.33, N 3.11, Br 17.78;
Found: C 66.39, H 5.12, N 3.33, Br 17.38. 13C-NMR,
(DMSO-d6) d = 18.75, 19.13, 40.76, 41.63, 43.86. 126.46,
126.66, 126.85, 127.51, 128.49, 129.78, 130.72, 131.36,
131.54, 133.23, 135.68, 137.34, 137.92, 171.39, 200.14.
Reaction of 3-(4-bromobenzoyl)prop-2-enoic acid 1a
with benzylamine and/or 2-aminopyridine-Formation
of 8a and 8b
8b: Yield: 75%, pale yellow crystals, mp 183-84 °C
(Ethanol). IR (cm-1): 1682 (CO ketonic), 1656 (CO carbox-
amide). 1H-NMR (DMSO-d6) d: 8.55-7.72 (m, 12H, ArH),
6.46 (s, 1H, NH, exchangeable), 6.28 (s, 1H, NH, ex-
changeable), 4.62 (dd, methine proton, C-4 proton of pyr-
idazinone moiety), 3.24 (octet, 2H, COCH2 diastereotropic
non-equivalent methylene protons at C-5 of pyridazinone).
MS m/z (%): 286 (M-[2-aminopyridine + isocyanicacid +
H2], 12.00), 184 (BrC6H4CO]+, 100.00), 156 (C6H4Br]+,
45.0) 94 (2-aminopyridine].+, 82.00), 93 (diazatropyliumion,
20.00), 76 (C6H4]+, 85.00), 50 (80.00). Anal. Calcd. for
C20H17BrN4O2 (%): C 56.47, H 4.00, N 13.18, Br 18.82;
Found: C 56.22, H 3.92, N 12.96, Br 18.74. 13C-NMR,
(DMSO-d6) d = 46.24, 58.15, 106.48, 115.76, 117.86,
124.35, 127.53, 129.75, 131.46, 135.67, 138.26, 138.65,
146.72, 148.13, 151.77, 154.18, 172.65, 197.27.
Method (A)
An equimolar mixture of acid 1a (10 mmol; 2.54 g)
and benzylamine (10 mmol; 1.1 mL) and/or 2-aminopyri-
dine (10 mmol; 0.94 g) was kept at room temperature for 5
days with occasional shaking. The reaction mixture was fil-
tered off, washed with light petrol and recrystallized from
ethanol to afford 8a and/or 8b, respectively.
CONCLUSION
The present research aims to synthesize some new
3(2H)-pyridazinones of anticipated biological activity as
non-steroidal anti-infalmmatory and analgesic drugs
[NSAIDs] devoid of the undesired side effects which are
inherent to traditional NSAIDs like aspirin and ibuprofen.
Method (B)
7.80-7.30 (m, 14H, ArH), an equimolar mixture of
acid 1a (10 mmol; 2.54 g) and benzylamine (10 mmol; 1.1
mL) and/or 2-aminopyridine (10 mmol ; 0.94 g) was heated
under reflux in dry benzene (40 mL) for 6 h. The reaction
solution was concentrated, left to cool, and the solid that
deposited was filtered off and recrystallized from ethanol
to yield 8a and/or 8b, respectively.
Received January 30, 2008.
REFERENCES
1. Piaz, V. D.; Vergelli, C.; Giovannoni, M. P.; Scheideler, M.
A.; Petrone, G.; Zaratin P. Farmaco 2003, 58, 1063.
2. Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.;
Kinoshita, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida, K.;
Shikawa, Y. J. Med. Chem. 1999, 42, 779.
3-(4-Bromobenzoyl)-2-benzylamino-N-benzylpropion-
amide 8a and 3-(4-bromobenzoyl)-2-(2-pyridylamino)-
N-(2-pyridyl)propionamide 8b
8a: Yield: 85%, pale yellow crystals, mp 162-63 °C
(Ethanol). IR (cm-1): 1677 (CO ketonic), 1650 (CO carbox-
amide). 1H-NMR (DMSO-d6) d: 7.80-7.30 (m, 14H, ArH),
6.40 (s, 2H, 2NH, exchangeable), 4.60 (dd, methine proton,
C-4 proton of pyridazinone moiety), 4.00 (s, 4H, 2 CH2Ph),
3. Horino, H.; Mimura, T.; Kagechika, K.; Ohta, M.; Kubo, H.;
Kitagawa, M. Chem. Pharm. Bull. 1998, 46, 602.
4. Yamamoto, A.; Iwama, T.; Takeda, H.; Nagai, H. J. Phar-
mcol. 1995, 68, 47.
5. Tsubaki, K.; Taniguchi, K.; Tabuchi, S.; Okitsu, O.; Hattori,

1250 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Morsy
K.; Seki, J. ; Sakane, K.; Tanaka, H. Bioorg. Med. Chem.
Lett. 2000, 10, 2787.
idazines, Part 2, Progress in Medicinal Chemistry; Ellis, G.
P.; Luss Combe, D. K., Eds.; Elsevier: Amsterdam, 1992;
Vol. 29, p 141.
6. Sotelo, E.; Centeno, N. B.; Rodrigo, J.; Ravina, E. Tetrahe-
dron 2002, 58, 2389.
20. Murineddu, G.; Cignarella, G.; Chelucci, G.; Lorgia, G.;
Pinna, G. A. Chem. Pharm. Bull. 2002, 50, 754.
21. Banoglu, E.; Akoylu, C.; Unlu, S.; Kupeli, E.; Yesilada, E.;
Sahin, M. F. Arch. Pharm. 2004, 337, 7.
7. Laguna, R.; Rodriguez-Linares, B.; Cano, E.; Estevez, I.;
Ravina, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151.
8. Sotelo, E.; Ravina, E.; Estevez, I. J. Heterocycl. Chem.
1999, 36, 985.
22. Gokce, M.; Dogruer, D.; Sahin, M. F. Farmaco 2001, 56,
233.
9. Estevez, I.; Ravina, E.; Sotelo, E. J. Heterocycl. Chem.
1998, 35, 1421.
23. Okcelik, B.; Unlu, S.; Banoglu, E.; Kupeli, E.; Yesilada, E.;
Sahin, M. F. Arch. Pharm. 2003, 336, 406.
10. Ravina, E.; Teran, C.; Santana, L.; Garcia, N.; Estevez, I.
Heterocycles 1990, 31, 1967.
24. Dogruer, D. S.; Sahin, M. F.; Unlu, S.; Shigru, I. Arch.
Pharm. 2000, 333, 79.
11. Meade, E. A.; Smith, W. L.; DeWitt, D. L. J. Biol. Chem.
1993, 268, 6610.
25. Gokce, M.; Sahin, M. F.; Kupeli, E.; Yesilada, E. Arzneim.
Forsch. 2004, 54, 396.
12. Brooks, P.; Emery, P.; Evans, J. F.; Fener, H.; Hawkey, C. J.;
Patrono, C.; Smolen, J.; Breedveld, F.; Day, R.; Dougados,
M.; Ehrich, E.W.; Gijon-Banos, J.; Kvien, T. K.; Van
Rijswijk, M. H.; Wamer, T.; Zeidler, H. Rheumatology 1999,
38, 779.
26. Sukuroglu, M.; Ergun, B. C.; Unlu, S.; Sahin, M. F.; Kupel,
E.; Yesilada, E.; Banoglu, E. Arch. Pharm. Res. 2005, 28,
509.
27. Youssef, A. S. A.; Marzouk, M. I.; Madkour, H. M. F.;
El-Soll, A. M. A.; El-Hashash, M. A. Can. J. Chem. 2005,
83, 251.
13. Clinch, D.; Banerjee, A. K.; Ostick, G.; Levy, D. W. J. R.
Coll. Physicians Lond. 1983, 17, 228.
14. Patrono, C.; Dunn, M. J. Kidney Int. 1987, 32, 1.
15. Katritzky, A. R. Comprehensive Heterocyclic Chemistry;
Pergamon Press: New York, 1984; Vol. 4, p 694.
16. Hashem, A.; Senning, A. Adv. Heterocycl. Chem. 1999, 73,
275.
28. El-Hashash, M. A.; El-Nagdy, S. I.; Saleh, R. M. J. Chem.
Eng. Data 1983, 29, 361.
29. Sayed, G. H.; Ismail, A. A.; El-Mobayed, M.; Mohamed, S.
M.; Commun. Fac. Sci. Univ. Ankra Ser. B; Chem. Chem.
Eng. 1990, 36, 53; Chem. Abstr. 1995, 123, 256625.
30. Morsy, J. M. Bulg. Chem. Commun. 2007, 39, 146.
31. Ambily, M. J.; Thumpakkara, R.; Prathapan, S.; Josy, B. Tet-
rahedron 2005, 61, 4601.
17. Amine, M. S.; El-Hashash, M. A.; Soliman, F. M. A.;
Salman, A. S. Ind. J. Chem. 1996, 35(B), 1097.
18. Domenik, P.; Erwin, S.; Frank, V.; Erwin, K. J. Am. Chem.
Soc. 1948, 70, 3356.
32. Juranic, Z.; Stevovic, L. J.; Drakulic, B.; Stanojkovic, T.;
Radulovic, S.; Juranic, I. J. Serb. Chem. Soc. 1999, 67, 505.
19. Frank, H.; Heinisch, G. In Pharmacologically Active Pyr-