Synthesis of some heterocyclic systems of anticipated biological activities via 6-aryl-4-pyrazol-1-yl-pyridazin-3-one

Article abstract of DOI:10.1139/v05-045

6-Aryl-4-pyrazol-1-yl-pyridazin-3-one (1) reacted with a PCl ₅-POCl₃ mixture to give the 3-chloropyridazine derivative 3. Reaction of 3 with 2-hydroxybenzoylhydrazide and semicarbazide hydrochloride afforded 4 and 5. Reaction of 1 wi

Full text of DOI:10.1139/v05-045

251
Synthesis of some heterocyclic systems of
anticipated biological activities via 6-aryl-4-
pyrazol-1-yl-pyridazin-3-one
A.S.A. Youssef, M.I. Marzouk, H.M.F. Madkour, A.M.A. El-Soll, and
M.A. El-Hashash
Abstract: 6-Aryl-4-pyrazol-1-yl-pyridazin-3-one (1) reacted with a PCl5–POCl3 mixture to give the 3-chloropyridazine
derivative 3. Reaction of 3 with 2-hydroxybenzoylhydrazide and semicarbazide hydrochloride afforded 4 and 5. Reac-
tion of 1 with ethyl chloroacetate gave 8. Reaction of 8 with hydrazine hydrate yielded the hydrazide 9. The hydrazide
9 condensed with the acetylenic ketones and esters 10a–10d and acetylacetone to give the adducts 11a, 11b, 12, 13,
and 14. Reacting 1 with formaldehyde and piperidine, morpholine, or piperazine, 3-bromopropanoic acid, acetic anhy-
dride, p-toluenesulphonyl chloride, succinyl chloride, oxalyl chloride, ethanolamine, or ethyl chloroacetate gave the
adducts 15–22. The structures of all newly synthesized compounds were evidenced from their spectral and micro-
analytical data.
Key words: 6-aryl-4-pyrazol-1-yl-pyridazinone derivative, 6-aryl-3-chloropyridazine derivative, 3,6-diaryl-1,2,4-
triazino[4,3-b]pyridazine derivative, 6-aryl-3-ethoxycarbonylmethoxypyridazine derivative, 6-aryl-3-(ω-benzoyl-
acetophenone)hydrazinocarbonylmethoxypyridazine.
Résumé : La 6-aryl-4-pyrazol-1-yl-pyridazin-3-one (1) réagit avec un mélange de PCl5–POCl3 pour conduire à la for-
mation du dérivé 3-chloropyridazine 3. La réaction de 3 avec le 2-hydroxybenzoylhydrazide et le chlorhydrate de semi-
carbazide conduit aux dérivés 4 et 5. La réaction de 1 avec le chloroacétate d’éthyle conduit à 8. La réaction de 8 avec
l’hydrate d’hydrazine permet d’obtenir l’hydrazide 9. L’hydrazide 9 se condense avec les cétones acétyléniques, les es-
ters 10a–10d et l’acétylacétone pour fournir les produits 11a, 11b, 12, 13 et 14. La réaction de 1 avec le formaldéhyde
et la pipéridine, la morpholine ou la pipérazine, l’acide 3-bromopropanoïque, l’anhydride acétique, le chlorure de p-to-
luènesulfonyle, le chlorure de succinyle, le chlorure d’oxalyle, éthanolamine ou le chloroacétate d’éthyle conduit aux
adduits 15–22. Les structures de tous les composés nouvellement synthétisés ont été caractérisés par leurs données mi-
croanalytiques et spectroscopiques.
Mots clés : dérivé de la 6-aryl-4-pyrazol-1-yl-pyridazinone, dérivé de la 6-aryl-3-chloropyridazine, dérivé de la 3,6-
diaryl-1,2,4-triazino[4,3-b]pyridazine, dérivé de la 6-aryl-3-éthoxycarbonylméthoxypyridazine, 6-aryl-3-(ω-benzoylacéto-
phénone)hydrazinocarbonylméthoxypyridazine.
[Traduit par la Rédaction] Youssef et al. 259
Introduction
Results and discussion
In a recent previous publication (1) we reported the reac-
tion of β-aroylacrylic acid with some nitrogen nucleophiles
and active methylene reagents and the utility of some of the
reaction products in heterocyclic synthesis. A large number
of pyridazin-3-ones were reported to exhibit insecticidal (2–
6), allergenic (7), antihypertensive (8–12), analgesic (13, 14),
anti-inflammatory, and bactericidal (15, 16) activities. This
prompted us to study the behaviour of 6-(4-chloro-3-methyl)
phenyl-4-(3,5-dimethyl-pyrazol-1-yl)-4,5-dihydropyridazin-3-
one toward various reagents, hoping to get new compounds
of anticipated biological activities.
It has been reported (17, 18) that the reaction of 6-(4-
chloro-3-methyl)phenyl-4-(3,5-dimethylpyrazol-1-yl)-1a or
6-(4-chloro-3-methyl) phenyl-4-(5-isopropyl-2-methyl)phenyl-
1b-2,3,4,5-tetrahydropyridazin-3-one with a phosphorous
pentachloride – phosphorous oxychloride mixture yielded
4,6-diaryl-3-chloro-4,5-dihydropyridazine derivatives 2a and
2b, respectively. In the present investigation, similar treat-
ment of 1a with the same reagent afforded 6-aryl-3-
chloropyridazine derivative 3. The previous reports sug-
gested structure 2 for the products where there was a lack of
spectroscopic data.
Received 8 April 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 30 March 2005.
A.S.A. Youssef,1 M.I. Marzouk, H.M.F. Madkour, and M.A. El-Hashash. Chemistry Department, Faculty of Science, Ain Shams
University, Abbassia, Cairo, Egypt.
A.M.A. El-Soll. Chemistry Department, Faculty of Science, El-Tahdi University, Libya.
1Corresponding author (e-mail: ahmedy93@hotmail.com).
Can. J. Chem. 83: 251–259 (2005)
doi: 10.1139/V05-045
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Can. J. Chem. Vol. 83, 2005
Scheme 1.
Treating an equimolar amount of 6-aryl-3-chloro-
pyridazine derivative 3 with 2-hydroxybenzoylhydrazide
in pyridine gave 3-(2-hydroxy) phenyl-6-aryl-1,2,4-tri-
azolo[4,3-b]pyridazine derivative 4. The structure of com-
pound 4 is substantiated from its microanalytical and
1
spectral data. The H NMR spectrum of 4 is in accord with
the proposed structure. The higher δ value of the OH proton
is in accord with the existence of 4 as its chelated form as
shown. Further support for the assigned structure of 4 was
gained from EI-MS that revealed the molecular ion peak.
1
The H NMR spectrum of compound 3 shows the aro-
matic proton resonances and doesn’t exhibit the signals of
the ABX pattern of the CH2-CH- group as well as the sig-
nals of the methyl protons of the dimethylpyrazole ring. This
infers the absence of these moieties. It discloses AB quartet
signals owing to the two protons Ha and Hb of the pyridazine
ring. The appearance of extra signals correlated with methyl
and the aromatic protons is good evidence for the existence
of 3 in the two conformations A and B, as a result of the
limited rotation of the aryl group around the pyridazine ring
as shown. The same phenomenon was observed for strucrures
4, 5, 8, 9, 14, and 22. The structure of 3 gets further support
from mass spectroscopy. Thus, its EI-MS exhibits a molecu-
lar ion peak.
Reacting 3 with semicarbazide hydrochloride in the
presence of triethylamine as a base afforded 3-[6-(4-chloro-
3-methyl)phenylpyridazin-3-yl]amino-6-(4-chloro-3-methyl)-
phenyl-1,2,4-triazolo[4,3-b]pyridazine (5).
The structure of compound 5 is evidenced from its
1
microanalytical and spectral data. The H NMR spectrum
exhibits exchangeable NH as well as two well-separated
singlets consistent with protons of two methyl groups. The
The formation of 3 has been rationalized in terms of the
route mentioned in Scheme 1.
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253
Scheme 2.
hand, the treatment of 8 with hydrazine hydrate afforded the
hydrazides 9.
complexity of signals in the aromatic region suggests the ex-
istence of more than two diastereomers. The EI-MS spec-
trum of 5 doesn’t show the molecular ion peak, but instead
shows the (M+· – Cl) peak. The formation of 5 is outlined in
Scheme 2.
It has been reported (17, 19) that 4,6-diaryl pyridazinone
derivatives 1a and 1c reacted with ethyl chloroacetate in the
presence of potassium carbonate in dry acetone to give the
adducts 6 (17) and 7 (19), respectively. In the present work,
treatment of 1a with ethyl chloroacetate in dioxane instead
of dry acetone yielded the adduct 8 as a mixture of two con-
formers 8A and 8B. Although compounds 6–8 have the
same melting point, the conflict in structure is probably due
to the lack in the spectroscopic evidence used by previous
authors (17, 19) in the assignment of structures.
The structure of compound 8 is evidenced from its
microanalytical and spectral data. Thus, its IR spectrum
1
shows absorptions correlated with the νC=O (ester). The H
NMR spectrum shows absorption signals correlated with the
OCH2 and COOCH2CH3 protons. Moreover, the structure of
8 gets further support from its EI-MS as it shows the molec-
ular ion peak and some of the abundant peaks. On the other
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Can. J. Chem. Vol. 83, 2005
The structure of compound 9 is established from its
microanalytical and spectral data. Thus, its IR spectrum
shows absorptions characteristic for νNH and νC=O (amide).
1
The H NMR spectrum supports the proposed structure as it
is devoid of any signals corresponding to the protons of the
ethyl group, but instead to signals correlated with the
hydrazino group. The suggested structure gets further sup-
port from the EI-MS as it shows the correct molecular ion
peak beside some of the abundant peaks.
The reaction of hydrazide 9 with acetylenic ketones and
ester 10a–10d in refluxing dioxane afforded the adducts
11a, 11b, 12, and 13, respectively. The structures of com-
pounds 11a, 11b, 12, and 13 are deduced from their
microanalytical and spectral data. Thus, their IR spectra re-
veal characteristic bands for νNH and νC=O. The lower ab-
sorption values for the C=O and NH groups in 11 and 13 are
in good agreement with the existence of compounds 11 and
13 in their chelated forms as shown. Further support for the
suggested structure of compounds 11a and 11b was gained
from their 1H NMR spectra, which revealed two ABqs repre-
senting AB systems, one owing to the methylene protons of
the CH2COR group and the other owing to the OCH2CO
protons (20–22). The fact that these methylene protons be-
have as AB systems can be attributed either to the large
anisotropic effect of the C=N or C=O groups and the nitro-
gen lone pair or to the restriction of rotation at the aroyl
group by the weak hydrogen bonding between the NH and
1
carbonyl group. The H NMR spectra of 12 and 13 are in
good agreement with the proposed structures.
Furthermore, the electron impact mass spectra of com-
pounds 11a and 11b don’t show the molecular ion peaks, in-
stead they show the (M+· – ArCOCH2C(Ar′)=N·NH) peak
beside some of the abundant peaks. On the other hand, the
EI-MS spectra of compounds 12 and 13 show molecular ion
peaks beside some of the abundant peaks.
The formation of 11 and 13 seems to proceed by Michael
addition of the hydrazide 9 at the β-carbon of the acetylenic
compounds 10. Similarly, compound 12 is formed, followed
by ring closure.
On the other hand, the reaction of the hydrazide 9 with
acetylacetone in boiling methanol yielded the adduct 14. The
1
structure of 14 is evidenced by microanalytical, H NMR,
and mass spectral data. Thus, its IR spectrum shows bands
characteristic for νC=O, νC=N, and (or) νC=C. Moreover, the as-
signed structure of compound 14 gets further support from
1
the H NMR spectrum.
1
Inspection of the H NMR spectrum revealed the exis-
tence of two closely spaced singlets for the methyl protons
attached at position 5 in the pyrazole ring, probably because
the rate of rotation of the pyrazole ring around the hindered
“partial double bond” is slow (23). This allows the existence
of this methyl group in two different conformations (A and
B) under different magnetic environments as shown in the
following. Furthermore, the mass spectrum of 14 shows the
molecular ion peak in addition to some abundant peaks.
Compound 14 is formed through condensation of the hydra-
zide 9 with one of the two carbonyl groups of acetylacetone
followed by ring closure.
Treatment of pyridazinone derivative 1a with piperidine or
morpholine and an excess of 40% formaldehyde solution in
refluxing dioxane afforded 6-aryl-2-piperidin-1-yl-methyl-
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Youssef et al.
255
show molecular ion peaks, whereas that of compound 15a
doesn’t show the molecular ion peak, but does show a peak
corresponding to [M+· – dimethylpyrazole].
The reaction of equimolar amounts of 1a and 3-bromo-
propanoic acid in refluxing dioxane and in the presence of
potassium carbonate as a base gave a mixture of the two iso-
meric products 6-aryl-2-(2-carboxy) ethylpyridazinone de-
rivative 18 and 6-aryl-3-(2-carboxyl)ethoxy pyridazine
derivative 19.
The structures of compounds 18 and 19 are substantiated
from microanalytical and spectral data. Thus, the IR spec-
trum shows absorptions characteristic for νOH(br.), νC=O
1
(acid), and νC=O (amide). Analysis of the H NMR spectrum
inferred that compounds 18 and 19 exist in deuterated
dimethylsulphoxide as a mixture in a ratio of 1:1.2. Exis-
tence of compounds 18 and 19 as a mixture has been evi-
denced from the location of two triplet signals consistent
with the protons of the NCH2 and OCH2 groups for struc-
tures 18 and 19, respectively. The EI-MS spectrum of com-
pounds 18 and 19 doesn’t show the molecular ion peak, but
does show a peak at m/e 220, which corresponds to the
[M+· – CH2=CHCOOH] peak beside some of the abundant
peaks.
Treatment of 1a with acetic anhydride yielded a mixture
of equimolar amounts of 2-acetyl-6-aryl-2,3-dihydropyrida-
zin-3-one derivative 20 and 3-acetoxy-6-arylpyridazine de-
rivative 21.
15a or 6-aryl-2-morpholin-4-yl-methyl-15b-4-(3,5-dimethyl
pyrazol-1-yl)-2,3,4,5-tetrahydropyridazin-3-one. However, sim-
ilar treatment of 1a with piperazine yielded a mixture of
the two isomeric compounds (3-hydroxymethoxy-6-arylpyri-
dazine derivative 16 and 2-hydroxymethyl-6-aryl-2,3-dihy-
dropyridazin-3-one derivative 17, respectively).
The structures of compounds 15–17 are evidenced from
their microanalytical and spectral data. Thus, their IR spec-
tra show absorptions characteristic for νC=O, νC=N, and (or)
νC=C in addition to νOH for structures 16 and 17. The lower
absorption values for the OH and C=O groups for com-
pounds 16 and 17 are in good agreement with their existence
The structures of compounds 20 and 21 are deduced from
microanalytical and spectral data. The IR spectrum shows
1
in the chelated forms shown. The H NMR spectra of com-
absorptions characteristic for νC=O, νC=N, and (or) νC=C.
1
pounds 15a and 15b disclosed ABX patterns consistent with
-CHX-CHAHB-CO moieties in which each of these coupled
protons appears as a doublet of doublet with a geminal cou-
pling constant J ≈ 16.8 Hz and a vicinal coupling constant of
≈13 or 7 Hz. In addition, they show two central peaks of
ABq corresponding to the -CH2-N group. Analysis of the
Moreover, the H NMR spectrum supports the structures of
20 and 21 as it shows two closely spaced singlets at δ 2.75
and 2.78 correlated with the methyl protons of the NCOCH3
and OCOCH3 groups, respectively. The EI-MS spectrum of
the mixture doesn’t show the molecular ion peak, but instead
the [M+· – CH2=C=O] peak as a base peak.
1
observed H NMR spectrum of the mixture containing 16
It has been reported (17) that 6-aryl-4-pyrazolylpyrida-
zinone derivative 1a reacted with benzenesulphonyl chloride
in refluxing acetone and in the presence of potassium car-
bonate as a base to give the N-benzenesulphonyl derivative
23. However, in the present work, treatment of equimolar
amounts of 1 with p-toluenesulphonyl chloride, succinyl
and 17 inferred that they exist in deuterated dimethylsul-
phoxide in a ratio of 2:1, respectively. Moreover, the struc-
tures of compounds 15a and 15b and the mixture containing
16 and 17 get further support from the EI-MS spectra, where
the spectra of compounds 15b and the mixture of 16 and 17
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Can. J. Chem. Vol. 83, 2005
The formation of compounds 16 and 17 (mixture), 18 and
19 (mixture), 20 and 21 (mixture), and 22 upon treating 1
with piperazine–HCHO, 3-bromopropanoic acid – K2CO3,
acetic anhydride, p-toluenesulponyl chloride – pyridine,
succinyl chloride – pyridine, oxalyl chloride – pyridine,
ethanolamine – pyridine, or ethyl chloroacetate – DMF can
be explained on the basis of an acid- or base-catalysed re-
moval of the dimethylpyrazolyl moiety, as in case of 22, fol-
lowed by nucleophilic attacks of the lactam–lactim tautomer
to the reagents used in the other cases.
Experimental
All melting points are uncorrected. The IR spectra were
recorded on FT IR Mattson (infinity series) spectrometers as
1
KBr discs. The H NMR spectra were measured on a Varian
Gemini 200 MHz instrument with chemical shifts (δ) ex-
pressed in ppm downfield from TMS. Mass spectra were
recorded on a Shimadzu GC-MS-QP 1000 Ex instrument op-
erating at 70 eV. TLC was run using TLC aluminum sheets
silica gel F254 (Merck). Note: All attempts to separate all of
the isomeric mixtures mentioned, including column chroma-
tography, failed possibly because of isomerization taking
place during separation.
chloride, oxalyl chloride, or ethanolamine in refluxing pyri-
dine or with ethyl chloroacetate in boiling dimethylforma-
mide afforded 6-aryl-2,3-dihydro pyridazin-3-one (22) as a
mixture of two conformations 22A and 22B. Compounds 22
and 23 have identical melting points although they have dif-
ferent structures, as there is a lack in the spectroscopic evi-
dence used by previous authors (17) in their assignment of
structure 23.
Reaction of 1a with the PCl5–POCl3 mixture —
Formation of 3
A mixture of 1a (5 mmol), PCl5 (5 mmol), and POCl3
(10 mL) was gently heated for 3 h, cooled, poured into
crushed ice, and the precipitated solid was filtered and
recrystallized from benzene to give 3.
6-(4-Chloro-3-methyl) phenyl-3-chloropyridazine (3)
Yield: 60%; white crystals, mp 175 to 176 °C, lit. value
(17, 18) mp 176 °C. IR (cm–1): 3078 (CHaryl), 2924, 2854
1
(CHalkyl), 1672, 1600 (C=N and (or) C=C), 821 (C-Cl). H
NMR (200 MHz, CDCl3) δ: 2.439, 2.461 (two singlets,
2CH3), 7.37, 7.481 (two doublets, Hd, Jo = 8.2 Hz), 7.559 (d,
Ha, Jab = 9.2 Hz), 7.764 (dd, Hc′, Jo = 8.2 Hz, Jm = 2.2 Hz),
7.806 (d, Hb, Jab = 9.0 Hz), 7.95, 8.041 (two doublets, Hc,
Jm = 2.2 Hz). EI-MS m/z: 238 (M+·, 56), 210 (M+· – N2, 23),
150 (4-Cl-3CH3C6H3CϵCH, base), 115 (89), 90 (6), 89 (29),
64 (10), 63 (44). Anal. calcd. for C11H8N2Cl2 (%): C 55.26,
H 3.37, N 11.72; found: C 55.44, H 3.51, N 11.82.
Reaction of 3 with 2-hydroxybenzoylhdyrazide —
Formation of 4
A mixture of 3 (5 mmol) and 2-hydroxybenzoylhydrazide
(5 mmol) in pyridine (10 mL) was refluxed for 6 h. The re-
action mixture was left to cool then poured into ice-cold wa-
ter. The precipitated solid was filtered off, washed, dried,
and then recrystallized from methanol to give 4.
The structure of compound 22 is deduced spectroscopi-
cally and chemically. Its IR spectrum shows νNH and νC=O
.
1
The H NMR spectrum is in good agreement with the pro-
posed structure considering the existence of the conforma-
tions 22A and 22B. Further support for the proposed
structure was gained from the EI-MS spectrum as it shows
the molecular ion peak beside some of the abundant peaks.
A chemical proof for the structure of compound 22 was
given by comparison (mp, mixed mp, and TLC) with an au-
thentic sample prepared by treating 1a with hydrazine hy-
drate in boiling ethanol. Also, by refluxing compound 1a
with pyridine to give compound 22. This supports the role of
pyridine as a base in the removal of the dimethylpyrazolyl
group.
3-(2-Hydroxyphenyl)-6-(4-chloro-3-methyl) phenyl1,2,4-
triazolo[4,3-b]pyridazine (4)
Yield: 33%; dark brown crystals, mp 249 to 250 °C. IR
(cm–1): 3427 (OH), 3062 (CHaryl), 2924, 2858 (CHalkyl),
1623, 1585 (C=N and (or) C=C). 1H NMR (200 MHz,
CDCl3) δ: 2.506, 2.528 (two singlets, 2 CH3), 7.049–8.932
(m, 9, ArH), 11.92 (br.s, 1, OH exchangeable). EI-MS m/z
(%): 338 (M+· + 2, 22), 337 (M+· + 1, base), 336 (M+·, 60),
184 (49), 183 (58), 157 (16), 156 (16), 127 (34), 126 (15),
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257
125 (20), 102 (14), 101 (15), 89 (50), 77 (35), 76 (18), 65
(18), 64 (34), 63 (52), 52 (22), 51 (59), 50 (28). Anal. calcd.
for C18H13N4OCl (%): C 64.19, H 3.89, N 16.64, Cl 10.53;
found: C 64.26, H 3.92, N 16.76, Cl 10.65.
6-(4-Chloro-3-methyl) phenyl-3-hydrazinocarbonylmeth-
oxypyridazine (9)
Yield: 82%; white crystals, mp 210–212 °C. IR (cm–1):
3409, 3306, 3205 (NH), 3055 (CHaryl), 2953, 2921, 2853
1
(CHalkyl), 1667 (C=O), 1589, 1533 (C=N and (or) C=C). H
NMR (200 MHz, DMSO-d6) δ: 2.393, 2.413 (two singlets,
2CH3), 4.306 (br.s, 2, NH2 exchangeable), 4.742 (s, 2,
OCH2), 7.078, 7.090 (two doublets, Ha, Jab = 9.78 Hz),
7.491, 7.541 (two doublets, Hd, Jo = 8.4 Hz), 7.732, 7.774
(two doublet doublets, Hc, Jo = 8.52 Hz, Jm = 1.86 Hz),
7.885, 7.929 (two doublets, Hc′, Jm = 1.82 Hz), 8.086, 8.110
(two doublets, Hb, Jba = 9.8 Hz), 9.316 (br.s, 1, NH
exchangeable). EI-MS m/z: 292 (M+·, 5), 263 (M+· + 2-NHNH2,
59), 261 (M+· – NHNH2, 17), 235 (M+· + 2-CONHNH2, 29),
231 (M+· – CONHNH2, base), 205 (12), 198 (13), 170 (15),
163 (21), 151 (10), 89 (15), 63 (20). Anal. calcd. for
C13H13N4O2Cl (%): C 53.34, H 4.48, N 19.14, Cl 12.11;
found: C 53.46, H 4.52, N 19.24, Cl 12.35.
Reaction of 3 with semicarbazide hydrochloride —
Formation of 5
A solution of 3 (3 mmol) and semicarbazide hydrochlo-
ride (3.5 mmol) in dry dioxane (20 mL) was refluxed for
12 h in the presence of potassium carbonate (1.0 g). The re-
action mixture was concentrated, cooled, and then poured
into ice-cold water. The solid formed was filtered off,
washed, dried, and then recrystallized from methanol to give
5.
3-[6-(4-Chloro-3-methyl)phenylpyridazin-3-yl]amino-6-(4-
chloro-3-methyl)phenyl-1,2,4-triazolo[4,3-b]pyridazine (5)
Yield: 54%; violet crystals, mp 194–196 °C. IR (cm–1):
3447 (NH), 3057 (CHaryl), 2983, 2900, 2859 (CHalkyl), 1687,
1603, 1573 (C=N and (or) C=C). 1H NMR (200 MHz,
CDCl3) δ: 2.423, 2.491 (two singlets, 2CH3), 7.146–8.184
(m, 11, ArH + NH). EI-MS m/z: 426 (M+· – Cl, 11), 390
(40), 360 (14), 297 (14), 244 (24), 216 (25), 164 (77), 151
(37), 150 (15), 125 (25), 115 (40), 89 (82), 63 (80). Anal.
calcd. for C23H17N7Cl2 (%): C 59.75, H 3.71, N 21.21, Cl
15.34; found: C 60.01, H 3.79, N 21.36, Cl 15.41.
Reactions of 9 with acetylenic ketones, esters 10a–10d,
and with acetylacetone
General procedure
A mixture of 9 (3 mmol) and 10a–10d (3 mmol) in
dioxane (15 mL) or acetylacetone (3 mmol) in methanol
(20 mL) was refluxed for 10 h. The reaction mixture was
concentrated, left to stand at room temperature. The solid
formed was recrystallized from a suitable solvent to give
11a, 11b, 12, 13, and 14.
Reaction of 1a with ethyl chloroacetate — Formation of
8
6-(4-Chloro-3-methyl)phenyl-3-[␻-(4-chlorobenzoyl)aceto-
phenone]hydrazonocarbonylmethoxypyridazine (11a)
Yield: 62%; white crystals, mp 198–200 °C (from metha-
nol). IR (cm–1): 3391 (NH), 3039 (CHaryl), 2954, 2906, 2843
(CHalkyl), 1662 (C=O). 1H NMR (200 MHz, CDCl3) δ: 2.421
(s, 3, CH3), 3.371, 3.752 (ABq, 2, CH2CO, J = 18.5 Hz),
4.848 (br.s, 1, NH), 5.355, 5.688 (ABq, 2, OCH2CO, J =
16.4 Hz), 7.005–7.756 (m, 14, Ar-H). EI-MS m/z: 533 (M+·,
missed), 272 (3.5), 263 (8.4), 261 (24.5), 256 (38.5), 254
(base), 235 (5.3), 233 (15), 170 (56.4), 153 (10.1), 151 (27),
115 (12.9), 113 (6.1), 111 (9.1), 103 (3.8), 89 (27.7), 82
(4.2), 63 (24.1). Anal. calcd. for C28H22N4O3Cl2 (%): C
63.30, H 4.16, N 10.50; found: C 63.54, H 4.23, N 10.67.
A solution of 1a (5 mmol) in dry dioxane (20 mL) was
heated with ethyl chloroacetate (5 mmol) for 24 h in the
presence of potassium carbonate (3 g). The reaction mixture
was concentrated, cooled then poured into ice-cold water.
The precipitated solid was filtered off, dried, and then
recrystallized from petroleum ether 80–100 °C.
6-(4-Chloro-3-methyl)phenyl-3-ethoxycarbonylmethoxy-
pyridazine (8)
Yield: 70%; pale yellow crystals, mp 100 °C, lit. value
(17, 19) mp 96 °C, 89 °C. IR (cm–1): 3071 (CHaryl), 2987,
2911 (CHalkyl), 1749 (C=O), 1672, 1596 (C=N and (or) C=C).
1H NMR (200 MHz, CDCl3) δ : 1.292 (t, 3, CH3CH2O, J =
7.2 Hz), 2.403, 2.421 (two singlets, 2CH3), 4.255 (q, 2,
CH3CH2O, J = 7.2 Hz), 4.956 (s, 2, OCH2CO), 7.041, 7.646
(two doublets, Ha, Jab = 9.8 Hz), 7.292, 7.399 (two doublets,
Hd, Jo = 8.4 Hz), 7.551, 7.501 (two doublet doublets, Hc,
Jo = 8.6 Hz, Jm = 1.8 Hz), 7.557, 7.771 (two doublets, Hc′,
Jm = 1.8 Hz), 7.676, 7.682 (two doublets, Hb, Jba = 9.6 Hz).
6-(4-Chloro-3-methyl)phenyl-3-(␻-benzoylaceto-
phenone)hydrazonocarbonylmethoxypyridazine (11b)
Yield: 21%; pale yellow crystals, mp 118–120 °C (from
benzene). IR (cm–1): 3435 (NH), 3063, 3032 (CHaryl), 2960,
2920, 2859 (CHalkyl), 1668 (C=O). 1H NMR (200 MHz,
CDCl3) δ: 2.418 (s, 3, CH3), 3.409, 3.756 (ABq, 2, CH2CO,
J = 18.3 Hz), 4.905 (br.s, 1, NH exchangeable), 5.410, 5.590
(ABq, 2, OCH2CO, J = 16.6 Hz), 6.988–7.755 (m, 15, Ar-
H). EI-MS m/z: 498 (M+·, missed), 240 (8.2), 238 (24.2),
263 (41.2), 261 (base), 235 (23.5), 233 (79.1), 220 (40.9),
170 (27.8), 153 (5.1), 151 (14.5), 118 (2), 115 (12.4), 77
(61.2), 103 (9.3), 89 (17.9), 87 (3.1), 63 (22.3). Anal. calcd.
for C28H23N4O3Cl (%): C 67.40, H 4.65, N 11.23; found: C
67.65, H 4.81, N 11.44.
EI-MS m/z: 308 (M+· + 2, 20), 306 (M+·, 55), 263 (M+·
+
2-OC2H5, 9), 261 (M+· – OC2H5, 4), 233 (M+· + 2-COOC2H5,
base), 231 (M+· – COOC2H5, 41), 205 (19), 198 (13), 170
(17), 163 (51), 128 (23), 115 (15), 89 (17), 63 (73). Anal.
calcd. for C15H15N2O3Cl (%): C 58.73, H 4.93, N 9.13, Cl
11.56; found: C 58.81, H 5.00, N 9.22, Cl 11.63.
Reaction of 8 with hydrazine hydrate
A solution of 8 (3 mmol) in ethanol (20 mL) was refluxed
with hydrazine hydrate (5 mmol) for 4 h. The reaction mix-
ture was cooled. The precipitated solid was filtered off and
recrystallized from methanol.
6-[4-Chloro-3-methyl)phenyl-3-[3-(4-chlorophenyl-5-oxo-
2,5-dihydro-pyrazol-1-yl)carbonylmethoxypyridazine (12)
Yield: 19%; white crystals, mp > 300 °C (from methanol).
© 2005 NRC Canada

258
Can. J. Chem. Vol. 83, 2005
IR (cm–1): 3154 (NH), 3032 (CHaryl), 2958, 2920, 2850
(CHalkyl), 1673 (C=O), 1628, 1586 (C=N and (or) C=C). H
Hy, Jo = 8.4 Hz), 7.599 (dd, Hx, Jo = 8.4 Hz, Jm = 2 Hz),
1
7.64 (d, Hx′, Jm = 2 Hz). EI-MS m/z: 317 (M+·
–
NMR (200 MHz, DMSO-d6) δ: 2.478 (s, 3, CH3), 4.855 (s,
2, OCH2), 7.090–8.135 (m, 10, ArH + CH=), 10.469 (br.s, 1,
NH exchangeable). EI-MS m/z: 454 (M+·, 6), 234 (18), 208
(10), 163 (base), 64 (10). Anal. calcd. for C22H16N4O3Cl2
(%): C 58.04, H 3.54, N 12.31, Cl 15.57; found: C 58.22, H
3.62, N 12.44, Cl 15.68.
dimethylpyrazole, 1), 221 (3), 220 (2), 163 (2), 109 (3), 99
(7), 98 (base), 97 (12). Anal. calcd. for C22H28N5OCl (%): C
63.83, H 6.82, N 16.92; found: C 63.94, H 6.97, N 17.02.
6-(4-Chloro-3-methyl)phenyl-2-morpholin-4-yl)methyl-4-
(3,5-dimethyl-pyrazol-1-yl)-2,3,4,5-tetrahydropyridazin-3-
one (15b)
6-(4-Chloro-3-methyl) phenyl-3-(1,2-diethoxycarbonyl
acetaldehyde hydrazonocarbonyl)methoxypyridazine (13)
Yield: 36%; white crystals, mp 179 to 180 °C (from meth-
anol). IR (cm–1): 3233, 3150 (NH), 3090 (CHaryl), 2920,
2851 (CHalkyl), 1736, 1711 (C=O ester), 1661 (C=O amide),
1626, 1592 (C=N and (or) C=C). 1H NMR (200 MHz, DCl3)
δ: 1.287 (t, 3, CH3(a), J = 7.02 Hz), 1.346 (t, 3, CH3(b), J =
7.05 Hz), 2.409, 2.426 (two singlets, CH3(Ar)), 3.662 (s, 2,
Yield: 44%; white crystals, mp 186 to 187 °C (from petro-
leum ether 80–100 °C). IR (cm–1): 1672 (C=O), 1597, 1557
1
(C=N and (or) C=C). H NMR (200 MHz, CDCl3) δ: 2.219,
2.555 (two sinlgets, 2CH3 of pyrazol ring), 2.409 (s, 3,
CH3), 2.715 (m, 4, N (CH2)2), 3.442 (dd, Hb, Jbc = 16.7 Hz,
Jba = 7.0 Hz), 3.675 (m, 4, O(CH2)2), 3.892 (dd, Hc, Jcb
=
15.3 Hz, Jca = 14.4 Hz), 4.691, 4.869 (ABq, CH2-N, J =
13.1 Hz), 4.858 (m, 1, Ha), 5.895 (s, 1, Hd), 7.383 (d, Hy,
Jo = 8.2 Hz), 7.554 (dd, Hx, Jo = 8.4 Hz, Jm = 2 Hz), 7.628
CH2(d)), 4.129 (q, 2, CH2(e), J = 7.08 Hz), 4.311 (q, 2, CH2(f)
,
J = 7.08 Hz), 5.468 (s, 2, CH2(g)), 7.051–7.731 (m, 5, ArH),
10.099 (br.s, 1, NH exchangeable). EI-MS m/z: 462 (M+·, 3),
391 (M+· + 2-CO2C2H5, 12), 289 (M+· – CO2C2H5, 36), 261
(64), 233 (84), 205 (10), 170 (57), 115 (13), 89 (20), 63
(23), 54 (base). Anal. calcd. for C21H23N4O6Cl (%): C 54.49,
H 5.01, N 12.01; found: C 54.61, H 5.28, N 12.31.
(d, Hx′, Jm = 1.8 Hz). EI-MS m/z: 415 (M+·, 1), 397 (M+·
–
H2O, 1), 319 (M+· – dimethylpyrazole, 1), 221 (4), 220 (4),
100 (base), 99 (4), 97 (15), 96 (4), 56 (19), 54 (4). Anal.
calcd. for C21H26N5O2Cl (%): C 60.64, H 6.30, N 16.84, Cl
8.52; found: C 60.75, H 6.44, N 16.96, Cl 8.68.
3-Hydroxymethoxy-6-(4-chloro-3-methyl)phenylpyridazine
(16) and 2-hydroxymethyl-6-(4-chloro-3-methyl)phenyl-
2,3-dihydropyridazin-3-one (17)
6-(4-Chloro-3-methyl)phenyl-3-[(3,5-dimethylpyrazole-1-
yl)carbonylmethoxypyridazine (14)
Yield: 38%; white crystals, mp 164–166 °C (from petro-
leum ether 60–80 °C – benzene). IR (cm–1): 3047, 3011
(CHaryl), 2968, 2925, 2854 (CHalkyl), 1739 (C=O), 1668,
Yield: 30%; white crystals, mp 152 to 153 °C (from aque-
ous ethanol). IR (cm–1): 3335 (OHbr.), 3072 (CHaryl), 2958,
2918, 2852 (CHalkyl), 1652 (C=O), 1601, 1515 (C=N and
1
1
1591 (C=N and (or) C=C). H NMR (200 MHz, CDCl3) δ:
(or) C=C). For 16: H NMR (200 MHz, DMSO-d6) δ: 2.421
2.257, 2.274 (two singlets, CH3a′, CH3a), 2.407, 2.421 (two
singlets, CH3 (aryl)), 2.529 (s, 3, CH3b), 5.765 (s, 2, OCH2),
6.001 (s, 1, CH=), 7.057–7.734 (m, 5, ArH). EI-MS m/z: 356
(M+·, 2), 260 (base), 261 (26), 233 (40), 170 (79), 151 (20),
116 (24), 89 (13), 63 (14). Anal. calcd. for C18H17N4O2Cl
(%): C 60.59, H 4.80, N 15.70, Cl 9.94; found: C 60.67, H
4.91, N 15.89, Cl 10.02.
(s, 3, CH3), 5.418 (d, 2, OCH2), 6.802 (t, 1, OH, exchange-
able), 7.061 (d, 1, Ha, Jab = 10.1 Hz), 7.529 (d, 1, Hd, Jo =
8.48 Hz), 7.742 (dd, 1, Hc′, Jo = 8.4 Hz, Jm = 2.8 Hz), 7.862
(d, 1, Hc, Jm = 2.9 Hz), 8.042 (d, 1, Hb, Jba = 9.7 Hz). For
1
17: H NMR (200 MHz, DMSO-d6) δ: 2.400 (s, 3, CH3),
4.464 (d, 2, NCH2), 6.802 (t, 1, OH, exchangeable), 7.061
(d, 1, Ha, Jab = 10.1 Hz), 7.529 (d, 1, Hd, Jo = 8.48 Hz),
7.742 (dd, 1, Hc′, Jo = 8.4 Hz, Jm = 2.8 Hz), 7.862 (d, 1, Hc,
Jm = 2.9 Hz), 8.042 (d, 1, Hb, Jba = 9.7 Hz). EI-MS m/z: 252
(M+· + 2, 4), 250 (M+·, 12), 185 (M+· – CH2O-Cl, 19), 163
(61), 128 (37), 89 (12), 63 (39). Anal. calcd. for
C12H11N2O2Cl (%): C 57.49, H 4.42, N 11.17, Cl 14.14;
found: C 57.58, H 4.57, N 11.01, Cl 14.20.
Reactions of 1a with piperidine, morpholine, or
piperazine and 40% formaldehyde
A mixture of 1a (5 mmol), formaldehyde (15 mL) and
piperidine (5 mmol), morpholine (5 mmol), or piperazine
(5 mmol) in dioxane (20 mL) was refluxed for 20 h. The re-
action mixture was concentrated, cooled, and poured into
ice-cold water. The precipitated solid was filtered off, then
recrystallized from a suitable solvent to give 15a, 15b and
16, 17 as a mixture.
Reaction of 1a with 3-bromopropanoic acid
A mixture of 1a (5 mmol) and 3-bromopropanoic acid
(5 mmol) in dry dioxane (20 mL), in the presence of potas-
sium carbonate (3 g), was refluxed for 10 h. The reaction
mixture was concentrated, cooled, and poured into ice-cold
water. The precipitated solid was filtered off, washed, dried,
and recrystallized from methanol to give a mixture of 18 and
19.
6-(4-Chloro-3-methyl)phenyl-2-piperidin-1-yl-methyl-4-
(3,5-dimethyl-pyrazol-1-yl)-2,3,4,5-tetrahydropyridazin-3-
one (15a)
Yield: 42%; white crystals, mp 188–190 °C (from petro-
leum ether 80–100 °C). IR (cm–1): 1672 (C=O), 1596, 1557
1
6-(4-Chloro-3-methyl)phenyl-2-(2-carboxy)ethyl-2,3-
dihydropyridazin-3-one (18) and 6-(4-chloro-3-methyl)
phenyl-3-(2-carboxy)ethoxypyridazine (19)
Yield: 68%; yellowish white crystals, mp > 300 °C. IR
(cm–1): 3197 (OHbr.), 1710, 1668 (C=O). 1H NMR (200 MHz,
DMSO-d6) δ: 2.095 (t, 2, CH2COOH, J = 6.8 Hz), 2.408
(two singlets, 2CH3), 3.496 (t, 2, NCH2CH2, J = 6.8 Hz),
(C=N and (or) C=C). H NMR (200 MHz, CDCl3) δ: 1.391
(m, 2, CH2CH2CH2), 1.523 (m, 4, CH2CH2CH2), 2.229,
2.257 (two singlets, 2CH3 of pyrazol ring), 2.413 (s, 3,
CH3), 2.570 (m, 4, N(CH2)2), 3.444 (dd, Hb, Jbc = 16.9 Hz,
Jba = 7 Hz), 3.881 (dd, Hc, Jcb = 16.8 Hz, Jca = 13.8 Hz),
4.682, 4.925 (ABq, -CH2-N, J = 13 Hz), 4.842 (q, Ha,
JHaHb = 6.4 Hz, JHaHc = 13.8 Hz), 5.897 (s, 1, Hd), 7.385 (d,
© 2005 NRC Canada

Youssef et al.
259
7.017 (d, Ha, Jab = 9.6 Hz), 7.528 (d, Hd, Jo = 8.6), 7.761
220 (M+·, 88), 206 (15), 192 (M+· – CO, 10), 185 (17), 166
(20), 165 (19), 163 (55), 157 (12), 129 (44), 128 (30), 127
(23), 78 (18), 77 (27), 75 (15), 64 (23), 63 (45), 50 (20).
Anal. calcd. for C11H9N2OCl (%): C 59.87, H 4.09, N 12.69,
Cl 16.07; found: C 59.96, H 4.27, N 12.76, Cl 16.25.
(dd, Hc, Jo = 8.6 Hz, Jm = 1.8 Hz), 7.904 (d, Hc ′, Jm
=
1.9 Hz), 8.043 (d, Hb, Jba = 9.6 Hz), 11.5 (br.s, 1, OH ex-
changeable). EI-MS m/z: 222 (M+· + 2-CH2=CHCOOH, 38),
220 (M+· – CH2=CH-COOH, base), 192 (M+· – CH2=CHCOOH-
CO, 19), 185 (M+· – CH2=CHCOOH-Cl, 20), 165 (34), 163
(76), 157 (14), 128 (36), 102 (16), 89 (18), 72 (50), 63 (46),
55 (61). Anal. calcd. for C14H13N2O3Cl (%): C 57.44, H
4.48, N 9.57; found: C 57.62, H 4.53, N 9.74.
References
1. A.S.A. Youssef, H.M.F. Madkour, M.I. Marzouk, A.M.A. El-
Soll, and M.A. El-Hashash. Afinidad, 61, 304, (2003).
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(Bratislava), 9, 129 (1969).
Acetylation of 1a with acetic anhydride
A solution of 1a (5 mmol) in acetic anhydride (15 mL)
was heated for 3 h. The reaction mixture was cooled and
then poured into ice-cold water. The precipitated solid was
filtered off, washed, dried, and then recrytallized from ben-
zene to give a mixture of 20 and 21.
3. V. Koneꢀnv. Pestic. Sci. 4, 775 (1973).
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2-Acetyl-6-(4-chloro-3-methyl)phenyl-2,3-dihydropyrida-
zin-3-one (20) and 3-acetoxy-6-(4-chloro-3-methyl)phenyl-
pyridazine (21)
Yield: 72%; white crystals, mp 167 to 168 °C. IR (cm–1):
1
1764, 1674 (C=O), 1616, 1595 (C=N and (or) C=C). H
NMR (200 MHz, CDCl3) δ: 2.424, 2.442 (two singlets,
2CH3), 2.75 (s, 3, NCOCH3), 7.044 (d, Ha, Jab = 9.8 Hz),
7.437 (d, Hd, Jo = 8.4 Hz), 7.547–7.601 (m, 2, Hc, Hc ′), 7.65
(d, Hb, Jba = 9.8 Hz). EI-MS m/z: 222 (M+· + 2-CH2=C=O,
36), 220 (M+· – CH2=C=O, base), 185 (M+· – CH2=C=O-Cl,
17), 163 (88), 157 (14), 128 (49), 89 (14), 63 (75). Anal.
calcd. for C13H11N2O2Cl (%): C 59.44, H 4.22, N 10.66;
found: C 59.61, H 4.35, N 10.81.
Reaction of 1a with p-toluenesulphonyl chloride,
succinyl chloride, oxalyl chloride, ethanolamine, or
ethyl chloroacetate
13. R. Jaunin. Chim. Ther. 2, 317 (1967).
14. C. Rubat, P. Coudert, P. Tronche, J. Bastide, and A.M. Privat.
Chem. Pharm. Bull. 37, 2832 (1989).
15. S. Kamiya, A. Nakamira, T. Itai, K. Koshinuma, and G. Okusa.
Yakugaku Zasshi, 86, 1099 (1966).
A mixture of 1a (5 mmol) and ethyl chloroacetate
(5 mmol) in DMF (10 mL) or p-toluene sulphonyl chloride
(5 mmol), succinyl chloride (5 mmol), oxaylchloride (5 mmol),
or ethanolamine (5 mmol) in pyridine (10 mL) was heated
for 12 h. The reaction mixture was cooled then poured into
ice-cold water in the former case or ice-cold HCl in the lat-
ter cases. The precipitated solid was filtered, washed, dried,
and then recrystallized from ethanol to give 22.
16. G.H. Sayed, A.A. Ismail, S. El-Nagdy, and S.M. Mohamed.
Egypt. J. Chem. 29, 433 (1986).
17. G.H. Sayed, A.A. Ismail, M. El-Mobayed, and S.M. Mohamed.
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18. M.A. El-Hashash, M.M. Mohamed, A.A. Sayed, and O.A. Abo-
Baker. Pak. J. Sci. Ind. Res. 28, 229 (1985).
19. M.A. El-Hashash and S.I. El-Nagdy. J. Chem. Eng. Data, 29,
361 (1983).
20. Y.A. Al-Farkh, F.H. Al-Hajjar, N.R. El-Rayyes, and H.S. Hamoud.
6-(4-Chloro-3-methyl)phenyl-2,3-dihydropyridazin-3-one (22)
Yield: 50%; white crystals, mp 232 to 233 °C, lit. value
(17) mp 238 °C. IR (cm–1): 3189, 3146 (NH), 3041 (CHaryl),
2929, 2836 (CHalkyl), 1679 (C=O), 1592, 1548 (C=N and
J. Heterocycl. Chem. 15, 759 (1978).
21. F.G. Baddar, F.H. Al-Hajjar, and N.R. El-Rayyes. J. Hetero-
cycl. Chem. 15, 385 (1978).
1
(or) C=C). H NMR (200 MHz, DMSO-d6) δ: 2.358, 2.380
(two singlets, 2CH3), 6.998, 7.009 (two doublets, Ha, Jab
=
22. F.G. Baddar, F.H. Al-Hajjar, and N.R. El-Rayyes. J. Hetero-
9.8 Hz), 7.446, 7.496 (two doublets, Hd, Jo = 8.4 Hz), 7.696,
7.736 (two doublet doublets, Hc, Jo = 8.2 Hz, Jm = 2.0 Hz),
7.847, 7.879 (two doublets, Hc ′, Jm = 1.8 Hz), 8.034, 8.059
(two doublets, Hb, Jba = 9.8), 13.271 (br.s, 1, NH exchange-
able). EI-MS m/z: 222 (M+· + 2, 28), 221 (M+· + 1, base),
cycl. Chem. 13, 257 (1976).
23. R.M. Silverestin. Spectrometric identification of organic com-
pounds. 6th ed. John Wiley and Sons, Inc., New York. 1997.
Chap. 4. p. 173.
© 2005 NRC Canada