Facile Synthesis of New [1,2,4]Triazolo[4,3-b]pyridazine

Article abstract of DOI:10.1002/jhet.2207

A number of new [1,2,4]triazolo[4,3-b]pyridazines were prepared by either cyclocondesation of substituted hydrazinopyridazines with orthoesters or oxidative cyclization of their hydrazone analogs in nitrobenzene as an oxidizing agent. A host of other new

Full text of DOI:10.1002/jhet.2207

Month 2014
Facile Synthesis of New [1,2,4]Triazolo[4,3-b]pyridazine
*
Z. Arghiani, S. M. Seyedi, M. Bakavoli, and H. Eshghi
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 91775-1436, Iran
*
E-mail: mbakavoli@yahoo.com
Received July 21, 2013
DOI 10.1002/jhet.2207
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A number of new [1,2,4]triazolo[4,3-b]pyridazines were prepared by either cyclocondesation of
substituted hydrazinopyridazines with orthoesters or oxidative cyclization of their hydrazone analogs in
nitrobenzene as an oxidizing agent. A host of other new [1,2,4]triazolo[4,3-b]pyridazine derivatives were
synthesized by sequential treatment of the latter compounds with carbon disulfide and alkyl halides.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
3,6-dicholoro-4-(4-substitutedphenyl)pyridazines 4a–c in
high yields. Compounds 4a–c were subsequently converted
to their hydrazine derivatives 5a–c by selective displacement
of six-chlorine atom [18] with hydrazine hydrate in ethanol
at reflux condition (Scheme 1).
In the last decades, the chemistry of triazolo[4,3-b]
pyridazine derivatives has received considerable attention
owing to their varied biological activities, such as antiviral
[1], antitumor [2,3], sedative/hypnotic [4], anti-anxiety
[5–7], adenine receptor ligand [8,9], hypotensive[10],
herbicidal, pesticidal [11], bactericidal [12] and anti-HAV
activity [13]. In the light of these information and due to
our continuing interest in the synthesis of biologically
important heterocycles [14–16] in this paper, we wish to
report the facile syntheses of some new derivatives of
triazolo[4,3-b]pyridazines.
The 1H nmr spectra of these products showed a chemical
shift displacement of pyridazine hydrogen, from
δ
7.80ppm, of compounds 4a–c to δ 7.20ppm for compounds
5a–c due to resonance electron donation of hydrazine group
to the neighboring atom.
Treatment of these precursors 5a–c with orthoesrters
[RC(OEt)3, R = -H, -CH3, -C2H5] in refluxing acetic acid
gave the new derivatives 6a–i, respectively (Scheme 2).
The structural assignments of these compounds were
based upon spectral and microanalytical data. For example,
the IR spectrum of 6a was devoid of the absorption bands
RESULTS AND DISCUSSION
1
6-Choloro-5-(4-substituted phenyl)-3-pyridazinylhydrazines
5a–c as key compounds were synthesized in four steps.
Initially a set of aryl iodides 1a–c reacted with fumaric acid in
a Heck-type reaction to yield the 2-(4-substituted phenyl)-2-
butenedioic acids 2a–c [17]. Treatment of these compounds
with hydrazine hydrochloride gave the 4-(4-substituted
phenyl)1,2,3,6-tetrahydro-3,6-pyridazinediones 3a–c. Chlo-
rination of the latter compounds with phosphoryl chloride
in the presence of N,N-diethyl aniline afforded the
at 3300–3200/cm (NH–NH2). The H nmr spectrum also
showed the disappearance of two broad signals belonging
to NH2 and NH moieties of compound 5a but the appear-
ance of a sharp signal (1H) at δ 9.5 ppm for triazole ring
of 6a indicates the construction of this heterocyclic ring.
The synthesis of 1,2,4-triazolo derivatives from
hydrazones has remarkably wide scope of applications.
Hydrazones of aromatic aldehydes with both electron-
withdrawing and electron-donating substituents 7a–o were
© 2014 HeteroCorporation

Z. Arghiani, S. M. Seyedi, M. Bakavoli, and H. Eshghi
Vol 000
Scheme 1. General procedure for the synthesis of precursor’s 5a–c.
Scheme 2. General procedure for the synthesis of 6a–i.
oxidized to give the corresponding [1,2,4]triazolo[4,3-b]
pyridazines 8a–o (Scheme 3).
nmr spectra exhibited a sharp signal (1H, N=CH) in
aromatic region and a broad singlet (1H, NH) at δ
11.5 ppm, which was removed on adding D2O.
The IR spectra of compounds 8a–o showed absorption
bands at 1600–1625/cm (N=C), where 1H nmr spectra
showed no signal for NH and N=CH after ring closure. It
is notable that the displacement of chemical shift for 2H
(H-2,6) of the phenylhydrazone moiety to downfield can
be attributed to anisotropic effect of the triazolo ring.
The required hydrazones 7a–o were obtained by treating
the corresponding hydrazine 5a–c with aldehydes in etha-
nol at reflux condition [19]. Heterocyclization was carried
out in nitrobenzene as both oxidant and solvent at reflux
condition [20].
The IR spectra of compounds 7a–o showed absorption
1
bands at 3200 (NH) and 1600–1610/cm (N=CH). The H
Scheme 3. General procedure for the synthesis of 8a–o.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Facile Synthesis of New [1,2,4]Triazolo[4,3-b]pyridazine
Scheme 4. General procedure for the synthesis of 10a–o.
vacuo, the residue washed with EtOAc (26 mL), dried, suspended
in water (15 mL) and treated with concentrated HCl (5mL).
Precipitation might take 3 h at RT to give the crude arylmaleic
acid. The product was dried in air before it crystallizes from ethanol.
The reaction of 5a–c with carbon disulfide in dry pyridine
[13] yielded the corresponding thiones 9a–c (Scheme 4).
The IR spectra showed absorption bands assignable to the
(NH) and (C=S) groups along with their H nmr spectra,
which revealed a signal at aromatic region for the NH proton
(D2O exchangeable).
Finally, The S-alkylated compounds 10a–o were prepared
by reacting thiones 9a–c with appropriate alkyl halides in the
presence of sodium hydroxide [13] (Scheme 4).
The structure of aforementioned compounds was
assigned on the basis of elemental analysis and compatible
spectroscopic data. The 1H nmr spectra showed corre-
sponding alkyl signals, whereas the ir spectra did not
exhibit absorption band at 3200/cm (NH).
1
(Z)-2-phenyl-2-butenedioic acid (2a).
This compound
was obtained as a yellow powder after 22 h in 45% yield,
mp 220–222°C; IR (potassium bromide): (–CO2H) 3434, (=C–H)
3155, (C=O) 1673, 1612 cmÀ1; 1H nmr (DMSO-d6): δ 4.22 (br s,
2H, 2(CO2H), D2O exchangeable), 6.21 (s, 1H, CH-pyridazine),
7.2–7.5 (m, 5H, Ar–H); Anal. Calcd for C10H8O4: C, 62.50; H,
4.20. Found: C, 62.39; H, 4.05.
(Z)-2-(4-methoxyphenyl)-2-butenedioicacid (2b).
This
compound was obtained as a yellow powder after 8:30 AM in
90% yield, mp 240°C (dec); IR (potassium bromide): (–CO2H)
3407, (=C–H) 3077–3002, (–C–H) 2958–2835, (C=O) 1669,
1600 cmÀ1; 1H nmr (DMSO-d6): δ 3.91 (s, 3H, OCH3) 4.10 (br s,
2H, 2(CO2H), D2O exchangeable), 6.11 (s, 1H, CH-pyridazine),
6.82 (d, 2H, Ar–H), 7.30 (d, 2H, Ar–H); Anal. Calcd for
C11H10O5: C, 59.46; H, 4.54. Found: C, 59.29; H, 4.15.
CONCLUSION
(Z)-2-(4-methyphenyl)-2-butenedioic acid (2c).
This
In summary, we have synthesized a wide variety of
[1,2,4]triazolo[4,3-b]pyridazines by two facile routes,
cyclocondensation of substituted hydrazino pyridazines
with orthoesters and oxidative cyclization of their
hydrazone analogs in nitrobenzene as an oxidizing agent.
compound was obtained as a pale yellow powder after 12 h in
50% yield, mp 213–214°C; IR (potassium bromide): (–CO2H)
3423, (=C–H) 3076, (–C–H) 2913–2847, (C=O) 1672,
1
1604 cmÀ1; H nmr (deuteriochloroform, DMSO-d6): δ 2.06 (s,
3H, CH3), 3.04 (br s, 2H, 2(CO2H), D2O exchangeable), 5.90
(s, 1H, CH-pyridazine), 6.01 (d, 2H, Ar–H), 7.01 (d, 2H, Ar–H);
ms: m/z 187 (M–H2O); Anal. Calcd for C11H10O4: C, 64.07; H,
4.89. Found: C, 64.00; H, 4.65.
EXPERIMENTAL
General procedure for preparation of 4-(4-substituted
Melting points were recorded on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on an
AVATAR 370 FT-IR Thermo Nicolet spectrometer. 1H nmr
spectra were measured at 100 and 400 MHz on Bruker spectrome-
ters with tetramethylsilane (Me4Si) as an internal reference and
deuteriochloroform or DMSO-d6 as solvent. The Mass spectra
were scanned on a Varian Mat CH-7 instrument at 70 eV.
Elemental analysis was performed on a Thermo Finnigan
Flash EA microanalyzer.
General procedure for preparation of (Z)-2-(4-substituted
phenyl)-2-butenedioic acids (2a–c). A mixture of fumaric acid
(1.45 g, 12.5mmol), 4-substituted aryliodides (1a–c), (12.5mmol),
K2CO3 (3.45 g, 25mmol), Ph3P (0.055g, 0.20mmol, 1.6 mol%),
DMF (12 mL), H2O (12 mL) and PdCl2 [0.5 mL of 0.1M
aqueous solution, 0.05mmol, 0.4 mol%] was stirred under argon
at 100–105°C for indicated time. The solvent was evaporated in
phenyl)-1,2,3,6-tetrahydro-3,6-pyridazinedione (3a–c).
A
mixture of 2a–c (10 mmol) and hydrazine hydrochloride
(0.856 gr, 1.2 eq mmol) in 50 mL H2O was refluxed vigorously
for 4 h. After completion, the reaction was allowed to cool to
RT, then the yellow precipitate was filtered, dried and
crystallized from ethanol.
4-Phenyl-1,2,3,6-tetrahydro-3,6-pyridazinedione (3a). This
compound was obtained as a yellow powder in 72% yield, mp
276–278°C; IR (potassium bromide): (NH) 3476, 3411, (C=O)
1654, 1564 cmÀ1 1H nmr (DMSO-d6): δ 7.22 (s, 1H, CH-
;
pyridazine), 7.41 (m, 3H, Ar–H), 7.80 (m, 2H, Ar–H), 11.10 (br
s, 1H, NH, D2O exchangeable), 12.13 (br s, 1H, NH, D2O
exchangeable); Anal. Calcd for C10H8N2O2: C, 63.82; H, 4.28;
N, 14.89. Found: C, 63.58; H, 4.05; N, 14.31. The 1H nmr
spectra data were compared with the authentic sample of ref. [21].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z. Arghiani, S. M. Seyedi, M. Bakavoli, and H. Eshghi
Vol 000
4-(4-Methoxyphenyl)-1,2,3,6-tetrahydro-3,6-pyridazinedione
for C10H9ClN4: C, 54.43; H, 4.11; N, 25.39. Found: C, 54.21;
H, 4.00; N, 25.21. The 1H nmr spectra data were compared
(3b).
This compound was obtained as a yellow powder in
86% yield, mp 260–262°C; IR (potassium bromide): (NH) 3110,
with the authentic sample of ref. [21].
3105, (C=O) 1654, 1609 cmÀ1 1H nmr (deuteriochloroform): δ
;
6-Chloro-5-(4-methoxyphenyl)-3-pyridazinylhydrazine
(5b).
90% yield, mp 201–203°C; IR (potassium bromide): (NHNH2)
3305–3252cmÀ1 1H nmr (DMSO-d6): δ 3.90 (s, 3H, OCH3),
This compound was obtained as a white powder in
3.86 (s, 3H, OCH3), 6.81 (s, 1H, CH-pyridazine), 7.01 (d, 2H,
Ar–H), 8.02 (d, 2H, Ar–H), 11.11 (br s, 1H, NH, D2O
exchangeable), 11.90 (br s, 1H, NH, D2O exchangeable); Anal.
Calcd for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C,
60.15; H, 4.10; N, 12.40.
;
4.20 (br s, 2H, NH2, D2O exchangeable), 7.02 (s, 1H, CH-
pyridazine), 7.10 (d, 2H, Ar–H), 7.53 (d, 2H, Ar–H), 8.37
(br s, 1H, NH, D2O exchangeable); Anal. Calcd for
C11H11ClN4O: C, 52.70; H, 4.42; N, 22.35. Found: C,
4-(4-Methylphenyl)-1,2,3,6-tetrahydro-3,6-pyridazinedione
(3c).
90% yield, mp 269–270°C; IR (potassium bromide): (NH)
3170, (C=O) 1739, 1652 cmÀ1 1H nmr (deuteriochloroform,
This compound was obtained as a yellow powder in
52.65; H, 4.12; N, 22.05.
6-Chloro-5-(4-methylphenyl)-3-pyridazinylhydrazine (5c). This
;
compound was obtained as a white powder in 92% yield, mp
DMSO-d6): δ 2.20 (s, 3H, CH3), 6.87 (s, 1H, CH-pyridazine),
7.05 (d, 2H, Ar–H), 7.48 (d, 2H, Ar–H), 11.05 (br s, 2H,
NH, D2O exchangeable); Anal. Calcd for C11H10N2O2:
C, 65.34; H, 4.98; N, 13.85; Found: C, 65.00; H, 4.69; N,
13.70.
182–183°C; IR (potassium bromide): (NHNH2) 3313, 3249 cmÀ1
;
1H nmr (DMSO-d6): δ 2.36 (s, 3H, CH3), 3.42 (br s, 2H, NH2, D2O
exchangeable), 7.28 (d, 2H, Ar–H), 7.71 (s, 1H, CH-pyridazine),
7.85 (d, 2H, Ar–H,), 13.17 (br s, 1H, NH, D2O exchangeable);
ms: m/z 233 (M+); Anal. Calcd for C11H11ClN4: C, 56.30; H,
4.72; N, 23.87. Found: C, 55.99; H, 4.30; N, 23.66.
General procedure for preparation of 3,6-dichloro-4-(4-
substitutedphenyl)-pyridazine (4a–c).
A mixture of 3a–c
General procedure for preparation of (6a–i).
To a
(10 mM) and phosphoryl chloride (POCl3, 9 mL) in 2 mL N, N-
diethyl aniline was heated under reflux for 2 h. The reaction
mixture was cooled, and then cautiously was poured onto
crushed ice. The crude 3,6 dichloro pyridazine was collected by
filtration, dissolved in 100 mL dry chloroform or petroleum
ether and dried over MgSO4, and filtered. The solvent was
removed under reduced pressure, and the residue was crystallized
from ethanol.
mixture of 5a–c (2 mmol) in acetic acid (4 mL), appropriate
orthoester (20 mmol) was added. The reaction was refluxed for
5 h.the solvent was removed under reduced pressure and the
residue crystallized from methanol.
6-Chloro-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (6a). This
compound was obtained as a white crystal in 40% yield, mp
160–162°C; IR (potassium bromide): (N=CH) 3134 cmÀ1 1H
;
nmr (DMSO-d6): δ 7.41–7.70 (m, 5H, Ar–H), 8.5 (s, 1H, CH-
pyridazine), 9.7 (s, 1H, CH-triazole); ms: m/z 230, 232 (M+);
Anal. Calcd for C11H7ClN4: C, 57.28; H, 3.06; N, 24.29.
Found: C, 57.42; H, 3.30; N, 24.20. The 1H nmr spectra data
3,6-Dichloro-4-phenylpyridazine (4a). This compound was
obtained as a white crystal in 93% yield, mp 90–91°C; IR
(potassium bromide): (=C–H) 3056–3031 cmÀ1
;
1H nmr
(deuteriochloroform): δ 7.41 (s, 1H, CH-pyridazine), 7.52–7.81
(m, 5H, Ar–H); ms: m/z 225, 227 (M+); Anal. Calcd for
C10H6Cl2N2: C, 53.36; H, 2.69; N, 12.45. Found: C, 53.48; H,
2.41; N, 12.22. The 1H nmr spectra data were compared with
the authentic sample of ref. [21].
were compared with the authentic sample of ref. [22].
3-Methyl-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6-ylchloride
(6b).
This compound was obtained as a white crystal in 25%
yield, mp 229–230°C; IR (potassium bromide): (=C–H)
1
2970 cmÀ1; H nmr (DMSO-d6): δ 2.70 (s, 3H, CH3), 7.40–7.66
3,6-Dichloro-4-(4-methoxyphenyl)pyridazine (4b). This
compound was obtained as a yellow crystal in 90% yield,
mp 112–124°C; IR (potassium bromide): (=C–H) 3080–3022,
(m, 5H, Ar–H), 8.41 (s, 1H, CH-pyridazine); ms: m/z 244, 246
(M+); Anal. Calcd for C12H9ClN4: C, 58.90; H, 3.71; N, 22.90.
Found: C, 58.50; H, 3.60; N, 22.82. The 1H nmr spectra data were
(–C–H) 2962–2843 cmÀ1 1H nmr (deuteriochloroform): δ 3.94
;
compared with the authentic sample of ref. [22].
(s, 3H, OCH3), 7.01 (d, 2H, Ar–H), 7.52 (s, 1H, CH-pyridazine),
7.55 (d, 2H, Ar–H); Anal. Calcd for C11H8Cl2N2O: C, 51.79; H,
3.16; N, 10.98. Found: C, 52.58; H, 3.16; N, 9.99.
3,6-Dichloro-4-(4-methylphenyl)pyridazine (4c). This
compound was obtained as a yellow crystal in 92% yield,
mp 95–97°C; IR (potassium bromide): (=C–H) 3027, (–C–H)
2921cmÀ1;1H nmr (deuteriochloroform): δ 2.43 (s, 3H, CH3),
7.8 (s, 1H, CH-pyridazine), 7.50 (m, 4H, Ar–H); Anal. Calcd
for C11H8Cl2N2: C, 55.26; H, 3.37; N, 11.72. Found: C, 54.98;
H, 3.00; N, 11.65.
General procedure for preparation of 6-chloro-5-(4-
substitutedphenyl)-3-pyridazinyl hydrazine (5a–c). A mixture
of 4a–c (10 mmol) in ethanol (15 mL), hydrazine hydrate (4 mL,
99%, and 10 eq mmol) was added. The reaction was refluxed for
4 h after cooling to RT. The precipitate was filtered off, dried and
crystallized from ethanol.
6-Chloro-5-phenyl-3-pyridazinylhydrazine (5a). This
compound was obtained as a white powder in 95% yield, mp
195–196°C; IR (potassium bromide): (NHNH2) 3246–3142 cm
À1;1H nmr (DMSO-d6): δ 3.55 (br s, 2H, NH2), 6.42–8.50
(m, 7H, CH-pyridazine, Ar–H, NH), after D2O exchangeable:
7.10 (s, 1H, CH-pyridazine), 7.52 (m, 5H, Ar–H); Anal. Calcd
3-Ethyl-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-6-ylchloride
(6c). This compound was obtained as a white powder in 50%
yield, mp 176–177°C; IR (potassium bromide): (=C–H)
2989–2848 cmÀ1 1H nmr (deuteriochloroform): δ 1.53 (t, 3H,
;
CH3), 3.22 (q, 2H, CH2), 7.31–7.75 (m, 5H, Ar–H), 8 (s, 1H,
CH-pyridazine); ms: m/z 258, 260 (M+); Anal. Calcd for
C13H11ClN4: C, 60.35; H, 4.29; N, 21.66. Found: C, 60.02; H,
4.00; N, 21.45.
6-Chloro-7-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazine
(6d). This compound was obtained as a white crystal in 38%
yield, mp 206–208°C; IR (potassium bromide): (N=CH)
1
3096cmÀ1; H nmr (DMSO-d6): δ 3.90 (s, 3H, OCH3), 7.11 (d,
2H, Ar–H), 7.54 (d, 2H, Ar–H), 8.20 (s, 1H, CH-pyridazine), 9.4
(s, 1H, CH-triazole); ms: m/z 260, 262 (M+); Anal. Calcd for
C12H9ClN4O: C, 55.29; H, 3.48; N, 21.49. Found: C, 55.19; H,
3.46; N, 21.30.
3-Methyl-7-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazine-
6-ylchloride (6e). This compound was obtained as a white crystal
in 35% yield, mp 225–226°C; IR (potassium bromide): (–C–H)
1
2998–2831 cmÀ1; H nmr (DMSO-d6): δ 2.75 (s, 3H, CH3), 3.90
(s, 3H, OCH3), 7.11 (d, 2H, Ar–H), 7.64 (d, 2H, Ar–H), 8.41 (s,
1H, CH-pyridazine); ms: m/z 274, 276 (M+); Anal. Calcd For
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Facile Synthesis of New [1,2,4]Triazolo[4,3-b]pyridazine
C13H11ClN4O: C, 56.84; H, 4.04; N, 20.40. Found: C, 56.37; H,
4.11; N, 20.65.
3-Ethyl-7-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazine-
3-Chloro-6-(2-(4-methylbenzylidene)hydrazinyl)-4-phenyl-
pyridazine (7c). This compound was obtained as a yellow
powder in 40% yield, mp 276–277°C; IR (potassium bromide):
(NH) 3182, (–C–H) 2974–2834, (N=CH) 1610 cmÀ1 1H nmr
(DMSO-d6): δ 2.30 (s, 3H, CH3), 7.20 (d, 2H, Ar-H), 7.41- 7.65
(m, 5H, Ar-H), 7.73 (d, 2H, Ar-H), 8.10 (s, 1H, N=CH), 8.60 (s,
1H, CH-pyridazine), 11.75 (br s, 1H, NH, D2O exchangeable);
Anal. Calcd for C18H15ClN4: C, 66.98; H, 4.68; N, 17.36 Found:
C, 66.55; H, 4.63; N, 17.02.
3-Chloro-6-(2-(4-nitrobenzylidene)hydrazinyl)-4-phenyl-
pyridazine (7d). This compound was obtained as an orange
powder in 70% yield, mp 270–271°C; IR (potassium bromide):
(NH) 3113, (N=CH) 1617 cmÀ1; 1H nmr (DMSO-d6): δ 7.56–7.85
(m, 5H, Ar–H), 7.92 (s, 1H, N=CH), 8.01 (s, 1H, CH-pyridazine),
8.11–8.55 (m, 4H, Ar–H), 12.16 (br s, 1H, NH, D2O
exchangeable); Anal. Calcd for C17H12ClN5O2: C, 57.72; H, 3.42;
N, 19.80. Found: C, 57.71; H, 3.41; N, 19.78.
6-ylchloride (6f).
crystal in 20% yield, mp 103–104°C; IR (potassium bromide):
(–C–H) 2995–2835 cmÀ1 1H nmr (deuteriochloroform): δ 1.56
This compound was obtained as a white
;
;
(t, 3H, CH3), 3.27 (q, 2H, CH2), 3.91 (s, 3H, OCH3), 7.05 (d,
2H, Ar–H), 7.44 (d, 2H, Ar–H), 8.02 (s, 1H, CH-pyridazine);
13C NMR (400 MHz, deuteriochloroform): δ 160.72, 150.97,
149.68, 143.64, 134.51, 130.73, 126.83, 124.17, 114.21, 55.47,
17.86, 10.94; ms: m/z 288, 290 (M+); Anal. Calcd for
C14H13ClN4O: C, 58.24; H, 4.54; N, 19.40. Found: C, 57.57;
H, 4.35; N, 19.18.
6-Chloro-7-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazine
(6g). This compound was obtained as a white powder in 37%
yield, mp 218–219°C; IR (potassium bromide): (N=CH)
1
3105 cmÀ1; H NMR (deuteriochloroform): δ 2.45 (s, 3H, CH3),
7.45 (m, 4H, Ar–H), 8.10 (s, 1H, CH-pyridazine), 9.12 (s, 1H,
CH-triazole); ms: m/z 244, 246 (M+); Anal. Calcd for
C12H9ClN4: C, 58.90; H, 3.71; N, 22.90. Found: C, 58.38; H,
3.64; N, 22.61.
3-Chloro-6-(2-(4-chlorobenzylidene)hydrazinyl)-4-phenyl-
pyridazine (7e). This compound was obtained as a yellow powder
in 47% yield, mp 280–281°C; IR (potassium bromide): (NH) 3190,
(N=CH) 1609 cmÀ1; 1H nmr (deuteriochloroform, DMSO-d6): δ
7.40–8.01 (m, 9H, Ar–H), 8.10 (s, 1H, N=CH), 8.62 (s, 1H, CH-
pyridazine), 11.66 (br s, 1H, NH, D2O exchangeable); Anal.
Calcd for C17H12Cl2N4: C, 59.49; H, 3.52; N, 16.32 Found: C,
59.51; H, 3.53; N, 16.40.
3-Methyl-7-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazine-
6-ylchloride (6h).
crystal in 30% yield, mp 193–194°C; IR (potassium bromide):
(–C–H) 2999–2856 cmÀ1 1H nmr (deuteriochloroform): δ 2.40
This compound was obtained as a white
;
(s, 3H, CH3), 2.85 (s, 3H, CH3), 7.45 (m, 4H, Ar–H), 8.01 (s,
1H, CH-pyridazine); ms: m/z 258, 260 (M+); Anal. Calcd for
C13H11ClN4: C, 60.35; H, 4.29; N, 21.66. Found: C, 59.81;
H, 4.17; N, 22.29.
6-(2-Benzylidenehydrazinyl)-3-chloro-4-(4-methoxyphenyl)
pyridazine (7f). This compound was obtained as a light yellow
powder in 30% yield, mp 300°C (dec); IR (potassium bromide):
1
(NH) 3297, (N=CH) 1608cmÀ1; H nmr (DMSO-d6): δ 3.9 (s,
3-Ethyl-7-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazine-
3H, OCH3), 7.14 (d, 2H, Ar–H), 7.32–7.85 (m, 8H, Ar–H,
N=CH), 8.20 (s, 1H, CH-pyridazine), 11.86 (br s, 1H, NH, D2O
exchangeable); Anal. Calcd for C18H15ClN4O: C, 63.81; H, 4.46;
N, 16.54. Found: C, 63.45; H, 4.09; N, 16.50.
6-ylchloride (6i).
This compound was obtained as a white
powder in 60% yield, mp 171–172°C; IR (potassium bromide):
1
(–C–H) 2989–2913 cmÀ1; H nmr (deuteriochloroform): δ 1.50
3-Chloro-6-(2-(4-methoxybenzylidene)hydrazinyl)-4-(4-
methoxyphenyl)pyridazine (7g). This compound was obtained
as a yellow powder in 50% yield, mp 173–174°C; IR (potassium
(t, 3H, CH3), 2.43 (s, 3H, CH3), 3.25 (q, 2H, CH2), 7.4 (m,
4H, Ar–H), 8.04 (s, 1H, CH-pyridazine); ms: m/z 272, 274
(M+); Anal. Calcd for C14H13ClN4: C, 61.65; H, 4.80; N,
20.54. Found: C, 61.45; H, 4.47; N, 20.39.
General procedure for preparation of (7a–o). A mixture
of 5a–c (3 mmol) and appropriate aromatic aldehyde (3 mmol)
in ethanol (15 mL) and 5 drops of acetic acid was heated
under reflux for 3 h and cooled. The product was separated,
filtered and washed with saturated sodium carbonate solution
before washing with water, then dried and recrystallized
from ethanol.
bromide): (NH) 3191, (–C–H) 2974–2835, (N=CH) 1603 cmÀ1
;
1H nmr (deuteriochloroform): δ 3.92 (s, 6H, 2(OCH3)), 6.93–7.26
(m, 4H, Ar–H), 7.62–7.97 (m, 4H, Ar–H), 8.10 (s, 1H, CH-
pyridazine), 8.60 (s, 1H, N=CH), 10.49 (br s, 1H, NH, D2O
exchangeable); Anal. Calcd for C19H17ClN4O2: C, 61.87; H,
4.65; N, 15.19. Found: C, 61.65; H, 4.43; N, 14.89.
3-Chloro-4-(4-methoxyphenyl)-6-(2-(4-methylbenzylidene)
hydrazinyl)pyridazine (7h). This compound was obtained as
a yellow powder in 40% yield, mp 183–184°C; IR (potassium
6-(2-Benzylidenehydrazinyl)-3-chloro-4-phenylpyridazine
(7a). This compound was obtained as a light yellow powder
in 55% yield, mp 350°C (dec); IR (potassium bromide): (NH)
bromide): (NH) 3187, (–C–H) 2997–2831, (N=CH) 1608 cmÀ1
;
1H nmr (deuteriochloroform): δ 2.50 (s, 3H, CH3), 3.92 (s, 3H,
OCH3), 7.15 (d, 2H, Ar–H), 7.12–7.76 (m, 4H, Ar–H), 7.70 (d,
2H, Ar–H), 8.22 (s, 1H, CH-pyridazine), 8.70 (s, 1H, N=CH),
11.05 (br s, 1H, NH, D2O exchangeable); Anal. Calcd for
C19H17ClN4O: C, 64.68; H, 4.86; N, 15.88. Found: C, 64.78; H,
4.90; N, 15.89.
3215, (N=CH) 1610 cmÀ1 1H nmr (DMOS-d6): δ 7.31–7.81
;
(m, 11H, N=CH, Ar–H), 8.20 (s, 1H, CH-pyridazine), 11.85 (br s,
1H, NH, D2O exchangeable); Anal. Calcd for C17H13ClN4: C,
66.13; H, 4.24; N, 18.15. Found: C, 65.88; H, 4.01; N, 17.89. The
1H nmr spectra data were compared with the authentic sample of
ref. [21].
3-Chloro-4-(4-methoxyphenyl)-6-(2-(4-nitrobenzylidene)
hydrazinyl)pyridazine (7i).
as an orange powder in 20% yield, mp 286- 287°C; ir
(Potassium bromide): (NH) 3203, (N=CH) 1594 cmÀ1 1H
This compound was obtained
3-Chloro-6-(2-(4-methoxybenzylidene)hydrazinyl)-4-phenyl-
pyridazine (7b).
powder in 35% yield, mp 170–171°C; IR (potassium bromide):
(NH) 3203, (–C–H) 2966–2839, (N=CH) 1604 cmÀ1 1H nmr
This compound was obtained as a yellow
;
nmr (DMSO-d6): δ 3.90 (s, 3H, OCH3) 7.14 (d, 2H, Ar–H),
7.53 (d, 2H, Ar–H), 7.91 (s, 1H, N=CH), 8.10 (s, 1H, CH-
pyridazine), 8.15–8.52 (m, 4H, Ar–H), 12.17 (br s, 1H, NH,
D2O exchangeable); ms: m/z 383(M+); Anal. Calcd for
C18H14ClN5O3: C, 56.33; H, 3.68; N, 18.25. Found: C, 56.00; H,
3.66; N, 18.02.
;
(DMSO-d6): δ 3.90 (s, 3H, OCH3), 7.02 (d, 2H, Ar–H), 7.51–7.72
(m, 5H, Ar–H), 7.73 (d, 2H, Ar–H), 8.10 (s, 1H, CH-pyridazine),
8.60 (s, 1H, N=CH), 11.6 (br s, 1H, NH, D2O exchangeable);
Anal. Calcd for C18H15ClN4O: C, 63.81; H, 4.46; N, 16.54.
Found: C, 63.55; H, 4.45; N, 16.19.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z. Arghiani, S. M. Seyedi, M. Bakavoli, and H. Eshghi
Vol 000
3-Chloro-6-(2-(4-chlorobenzylidene)hydrazinyl)-4-(4-methoxy-
phenyl)pyridazine (7j). This compound was obtained as a yellow
powder in 38% yield, mp 208–209°C; IR (potassium bromide):
3052–3020cmÀ1 1H nmr (DMSO-d6): δ 7.52–7.84 (m, 8H,
;
Ar–H), 8.30–8.56 (m, 2H, Ar–H), 8.61 (s, 1H, CH-pyridazine);
ms: m/z 306, 308 (M+); Anal. Cald for C17H11ClN4: C, 66.56;
H, 3.61; N, 18.26. Found: C, 66.65; H, 3.42; N, 17.71. The
1H nmr spectra data were compared with the authentic sample
of ref. [21,22].
(NH) 3191, (N=CH) 1609 cmÀ1 1H nmr (DMSO-d6): δ 3.90
;
(s, 3H, OCH3), 7.13 (d, 2H, Ar–H), 7.44–7.76 (m, 4H, Ar–H),
7.96 (d, 2H, Ar–H), 8.10 (s, 1H, CH-pyridazine), 8.72 (s, 1H,
N=CH), 11.95 (br s, 1H, NH, D2O exchangeable); Anal. Calcd
for C18H14Cl2N4O: C, 57.92; H, 3.78; N, 15.01. Found: C,
57.70; H, 3.55; N, 14.78.
6-Chloro-3-(4-methoxyphenyl)-7-phenyl-[1,2,4]triazolo[4,3-
b]pyridazine (8b). This compound was obtained as a yellow
powder in 20% yield, mp 140–142°C; IR (potassium bromide):
(=C–H) 3060–3039, (–C–H) 2917–2848 cmÀ1
;
1H nmr
6-(2-Benzylidenehydrazinyl)-3-chloro-4-(p-tolyl)pyridazine
(7k). This compound was obtained as a light yellow powder in
60% yield, mp 295–297°C; IR (potassium bromide): (NH)
(deuteriochloroform): δ 3.95 (s, 3H, OCH3), 7.10 (d, 2H,
Ar–H), 7.45–7.67 (m, 5H, Ar–H), 8.10 (s, 1H, CH-pyridazine),
8.55 (d, 2H, Ar–H); ms: m/z 336, 338 (M+); Anal. Cald for
C18H13ClN4O: C, 64.19; H, 3.89; N, 16.64. Found: C, 63.87; H,
1
3199, (N=CH) 1608 cmÀ1; H nmr (DMSO-d6): δ 2.35 (s, 3H,
CH3), 7.34–7.86 (m, 10H, Ar–H, N=CH), 8.20 (s, 1H, CH-
pyridazine), 11.88 (br s, 1H, NH, D2O exchangeable); Anal.
Calcd for C18H15ClN4: C, 66.98; H, 4.68; N, 17.36. Found:
C, 66.90; H, 4.60; N, 17.23.
3-Chloro-6-(2-(4-methoxybenzylidene)hydrazinyl)-4-(p-tolyl)
4.60; N, 16.45.
6-Chloro-7-phenyl-3-(p-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine
(8c). This compound was obtained as a pale yellow powder in
45% yield, mp 161–162°C; IR (potassium bromide): (=C–H)
3051–3018, (–C–H) 2912–2855 cmÀ1 1H nmr (DMSO-d6): δ
;
pyridazine (7l).
powder in 35% yield, mp 206–208°C; IR (potassium bromide):
(NH) 3182, (–C–H) 2970–2835, (N=CH) 1603 cmÀ1 1H nmr
This compound was obtained as a yellow
2.40 (s, 3H, CH3), 7.45 (d, 2H, Ar–H), 7.54–7.89 (m, 5H, Ar–H),
8.39 (d, 2H, Ar–H), 8.50 (s, 1H, CH-pyridazine); ms: m/z 321,
323 (M+); Anal. Cald for C18H13ClN4: C, 67.40; H, 4.08; N,
;
(deuteriochloroform): δ 2.45 (s, 3H, CH3), 3.90 (s, 3H, OCH3),
6.93 (d, 2H, Ar–H), 7.30–7.76 (m, 4H, Ar–H), 7.85 (d, 2H,
Ar–H), 8.23 (s, 1H, CH-pyridazine), 8.70 (s, 1H, N=CH), 11.17
(br s, 1H, NH, D2O exchangeable); Anal. Calcd for
C19H17ClN4O: C, 64.68; H, 4.86; N, 15.88. Found: C, 64.50;
H, 4.60; N, 15.87.
17.47. Found: C, 67.20; H, 4.00; N, 17.31.
6-Chloro-3-(4-nithrophenyl)-7-phenyl-[1,2,4]triazolo[4,3-b]
pyridazine (8d).
This compound was obtained as a light
brown powder in 68% yield, mp 220–221°C; IR (potassium
1
bromide): (=C–H) 3068 cmÀ1; H nmr (DMSO-d6): δ 7.50–7.75
3-Chloro-6-(2-(4-methylbenzylidene)hydrazinyl-4-(p-tolyl)
(m, 5H, Ar–H), 8.44–8.77 (m, 5H, CH-pyridazine, Ar–H); ms: m/z
351 (M+); Anal. Cald for C17H10ClN5O2: C, 58.05; H, 2.84; N,
pyridazine (7m).
powder in 30% yield, mp 232–234°C; IR (potassium bromide):
(NH) 3178, (–C–H) 2945–2847, (N=CH) 1609 cmÀ1 1H nmr
This compound was obtained as a yellow
19.91. Found: C, 58.00; H, 2.63; N, 19.81.
6-Chloro-3-(4-chlorophenyl)-7-phenyl-[1,2,4]triazolo[4,3-b]
;
pyridazine (8e). This compound was obtained as a pale yellow
powder in 50% yield, mp 180–181°C; IR (potassium bromide):
(deuteriochloroform): δ 2.30 (s, 3H, CH3), 2.42 (s, 3H, CH3),
7.15–7.75 (m, 6H, Ar–H), 7.86 (d, 2H, Ar–H), 8.20 (s, 1H, CH-
pyridazine), 8.74 (s, 1H, N=CH), 11.77 (br s, 1H, NH, D2O
exchangeable); Anal. Calcd for C19H17ClN4: C, 67.75; H, 5.09;
N, 16.63. Found: C, 67.80; H, 4.76; N, 16.54.
3-Chloro-6-(2-(4-nitrobenzylidene)hydrazinyl-4-(p-tolyl)
(=C–H) 3051–3018 cmÀ1 1H nmr (DMSO-d6): δ 7.50–7.91
;
(m, 7H, Ar–H), 8.39–8.65 (m, 3H, Ar–H, CH-pyridazine); ms:
m/z 341, 343 (M+); Anal. Cald for C17H10Cl N4: C, 59.84; H,
2
2.95; N, 16.42. Found: C, 59.77; H, 2.94; N, 16.40.
6-Chloro-7-(4-methoxyphenyl)-3-phenyl-[1,2,4]triazolo[4,3-b]
pyridazine (7n).
powder in 80% yield, mp 300–302°C; IR (potassium bromide):
(NH) 3207, (N=CH) 1609 cmÀ1 1H nmr (DMSO-d6): δ 2.35
This compound was obtained as an orange
pyridazine (8f).
powder in 48% yield, mp 158–159°C; IR (potassium bromide):
(=C–H) 3072–3007 cmÀ1 1H nmr (deuteriochloroform): δ 3.90
This compound was obtained as a yellow
;
;
(s, 3H, CH3) 7.38–7.56 (m, 6H, Ar–H), 7.92 (s, 1H,
N=CH), 8.01 (s, 1H, CH-pyridazine), 8.30 (d, 2H, Ar–H),
12.27 (br s, 1H, NH, D2O exchangeable); Anal. Calcd for
C18H14ClN5O2: C, 58.78; H, 3.84; N, 19.04. Found: C,
(s, 3H, OCH3), 7.11 (d, 2H, Ar–H), 7.40–7.84 (m, 5H, Ar–H),
8.11 (s, 1H, CH-pyridazine), 8.54 (d, 2H, Ar–H); ms: m/z 336,
338 (M+); Anal. Cald for C18H13ClN4O: C, 64.19; H, 3.89; N,
58.66; H, 3.80; N, 19.14.
3-Chloro-6-(2-(4-chlorobenzylidene)hydrazinyl)-4-(p-tolyl)
16.64. Found: C, 64.18; H, 3.59; N, 16.50.
6-Chloro-3, 7-bis (4-methoxyphenyl)-[1,2,4]triazolo[4,3-b]
pyridazine (8g).
powder in 35% yield, mp 198–199°C; IR (potassium
bromide): (=C–H) 3068, (–C–H) 2957–2839 cmÀ1 1H nmr
This compound was obtained as a yellow
pyridazine (7o).
This compound was obtained as a yellow
powder in 40% yield, mp 201–202°C; IR (potassium bromide):
(NH) 3190, (N=CH) 1608 cmÀ1; H nmr (deuteriochloroform):
1
;
(deuteriochloroform): δ 3.90 (s, 6H, 2(OCH3)), 6.94–7.27 (m,
4H, Ar–H), 7.53 (d, 2H, Ar–H), 8.13 (s, 1H, CH-pyridazine),
8.50 (d, 2H, Ar–H); ms: m/z 366, 368 (M+); Anal. Cald for
C19H15ClN4O2: C, 62.21; H, 4.12; N, 15.25. Found: C,
δ 2.44 (s, 3H, CH3), 7.32 (d, 2H, Ar–H), 7.34 (d, 2H, Ar–H),
7.39 (s, 1H, N=CH), 7.49 (d, 2H, Ar–H), 7.78 (d, 2H, Ar–H),
8.13 (s, 1H, CH-pyridazine), 11.87 (br s, 1H, NH, D2O
exchangeable); ms: m/z 219 (M–N=CHC6H4Cl); Anal. Calcd
for C18H14Cl2N4: C, 60.52; H, 3.95; N, 15.68. Found: C,
60.22; H, 3.86; N, 15.70.
General procedure for preparation of 8a–o. A mixture of
appropriate hydrazones 7a–o (1.2 mmol) and nitrobenzene (7 mL)
was refluxed in an oil bath at 216°C for 20 h. Nitrobenzene was
removed under reduced pressure and the residue recrystallized
61.71; H, 4.19; N, 14.86.
6-Chloro-7-(4-methoxyphenyl)-3-(p-tolyl)-[1,2,4]triazolo[4,3-
b]pyridazine (8h). This compound was obtained as a yellow
powder in 57% yield, mp 187–188°C; IR (potassium bromide):
(=C–H) 3060–3025, (–C–H) 2994–2823 cmÀ1
;
1H nmr
(deuteriochloroform): δ 2.50 (s, 3H, CH3), 3.90 (s, 3H, OCH3),
7.11 (d, 2H, Ar–H), 7.40 (d, 2H, Ar–H), 7.63 (d, 2H, Ar–H),
8.1 (s, 1H, CH-pyridazine), 8.40 (d, 2H, Ar–H); ms: m/z 351,
353 (M+); Anal. Cald for C19H15ClN4O: C, 65.05; H, 4.31; N,
15.97. Found: C, 64.77; H, 4.12; N, 15.81.
in ethanol and methanol-ethyl acetate, respectively.
3,7-Diphenyl-[1,2,4]triazolo[4,3-b]pyridazine-6-ylchloro
(8a). This compound was obtained as a pale yellow powder in
90% yield, mp 155–156°C; IR (potassium bromide): (=C–H)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Facile Synthesis of New [1,2,4]Triazolo[4,3-b]pyridazine
6-Chloro-7-(4-methoxyphenyl)-3-(4-nitrophenyl)-[1,2,4]triazolo
[4,3-b]pyridazine (8i). This compound was obtained as a yellow
powder in 80% yield, mp 225–226°C; IR (potassium bromide):
6-Chloro-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-3(2H)
thione (9a). This compound was obtained as an orange
powder in 90% yield, mp 246–248°C; IR (potassium
1
bromide): 3121 (NH), 1271 (C=S) cmÀ1; H nmr (DMSO-d6)
(=C–H) 3045–3040 cmÀ1 1H nmr (DMSO-d6): δ 3.90 (s, 3H,
;
δ: 7.40–8.15 (m, 6H, Ar–H, CH-pyridazine), 8.29 (br s, 1H,
NH, D2O exchangeable); ms: m/z 262 (M+1); Anal. Cald for
C11H7ClN4S: C, 50.29; H, 2.69; N, 21.33; S, 12.21. Found:
C, 50.10; H, 2.49; N, 21.55, S, 12.00.
OCH3), 7.11 (d, 2H, Ar–H), 7.56 (d, 2H, Ar–H), 8.1 (s, 1H,
CH-pyridazine), 8.40 (d, 2H, Ar–H), 8.82 (d, 2H, Ar–H); ms:
m/z 381, 383 (M+); Anal. Cald for C18H12ClN5O3: C, 56.63; H,
3.17; N, 18.34. Found: C, 56.59; H, 3.09; N, 18.11.
6-Chloro-7-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-b]pyridazine-
6-Chloro-3-(4-chlorophenyl)-7-(4-methoxyphenyl)-[1,2,4]
triazolo[4,3-b]pyridazine (8j). This compound was obtained
as a light yellow powder in 75% yield, mp 203–205°C; IR
3(2H)thione (9b).
powder in 85% yield, mp 200–201°C; IR (KBr disk): (NH) 3215,
(C=S) 1253 cmÀ1 1H nmr (DMSO-d6) δ: 3.90 (s, 3H, OCH3),
This compound was obtained as a yellow
(potassium bromide): (=C–H) 3064–3032 cmÀ1
;
1H nmr
,
7.02 (d, 2H, Ar–H), 7.21–8.65 (m, 4H, Ar–H, CH-pyridazine, NH,
D2O exchangeable); ms: m/z 278 (M–CH3); Anal. Cald for
C12H9ClN4OS: C, 49.23; H, 3.10; N, 19.14; S, 10.95. Found: C,
49.01; H, 2.89; N, 19.34, S, 11.35.
(deuteriochloroform): δ 3.93 (s, 3H, OCH3), 7.16 (d, 2H, Ar–H),
7.44 (d, 2H, Ar–H), 7.63 (d, 2H, Ar–H), 8.13 (s, 1H, CH-
pyridazine), 8.50 (d, 2H, Ar–H); ms: m/z 371, 373 (M+); Anal.
Cald for C18H12Cl N4O: C, 58.24; H, 3.26; N, 19.10. Found: C,
2
6-Chloro-7-(4-methyphenyl)-[1,2,4]triazolo[4,3-b]pyridazine-
57.99; H, 3.11; N, 19.12.
6-Chloro-3-phenyl-7-(p-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine
(8k). This compound was obtained as a pale brown powder in
45% yield, mp 283–284°C; IR (potassium bromide): (=C–H)
3(2H)thione (9c).
powder in 87% yield, mp 272–271°C; IR (potassium bromide):
(NH) 3125, (C=S) 1271 cmÀ1 1H nmr (DMSO-d6) δ: 2.35 (s,
3H, CH3), 7.39–7.95 (m, 6H, Ar–H, CH-pyridazine, NH, D2O
exchangeable); ms: m/z 276 (M+1); Anal. Cald for C12H9ClN4S:
C, 52.08; H, 3.28; N, 20.24; S, 11.59. Found: C, 52.00; H,
3.43; N, 19.99, S, 11.23.
General procedure for preparation of 10a–o. A solution
of compound 9a–c (1 mM) and sodium hydroxide (0.04 g,
1 mmol) in ethanol (50 mL) was treated with appropriate alkylation
reagent (2 mmol), and the reaction mixture was warmed on a steam
bath at 70°C for 6–8 h. The solvent was removed under reduced
pressure and residue washed with water and recrystallized from
ethanol, ethyl acetate and 1,4-dioxan, respectively.
This compound was obtained as a yellow
,
3068–3040 cmÀ1
;
1H nmr (deuteriochloroform): δ 2.53 (s, 3H,
CH3), 7.36–7.75 (m, 7H, Ar–H), 8.22 (s, 1H, CH-pyridazine),
8.5 (m, 2H, Ar–H); ms: m/z 320, 322 (M+); Anal. Cald for
C18H13ClN4: C, 67.40; H, 4.08; N, 17.47. Found: C, 67.09; H,
4.07; N, 17.21.
6-Chloro-3-(4-methoxyphenyl)-7-(p-tolyl)-[1,2,4]triazolo[4,3-b]
pyridazine (8l). This compound was obtained as a light yellow
powder in 15% yield, mp 163–164°C; IR (potassium bromide):
(=C–H) 3039–3019, (–C–H) 2966–2843 cmÀ1
;
1H nmr
(deuteriochloroform): δ 2.50 (s, 3H, CH3), 3.95 (s, 3H, OCH3),
7.14 (d, 2H, Ar–H), 7.47 (m, 4H, Ar–H), 8.11 (s, 1H, CH-
pyridazine), 8.52 (d, 2H, Ar–H); ms: m/z 350, 352 (M+); Anal.
Cald for C19H15ClN4O: C, 65.05; H, 4.31; N, 15.97. Found: C,
64.77; H, 4.19; N, 15.69.
6-Chloro-3-(methylthio)-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine
(10a). This compound was obtained as a light yellow powder
in 25% yield, mp 275–277°C; IR (potassium bromide): (–C–H)
2927 cmÀ1
;
1H nmr (deuteriochloroform) δ: 2.70 (s, 3H,
6-Chloro-3,7-di-p-tolyl-[1,2,4]triazolo[4,3-b]pyridazine
(8m). This compound was obtained as a yellow powder in 60%
yield, mp 195–196°C; IR (potassium bromide): (=C–H) 3027,
SCH3), 7.55–7.77 (m, 5H, Ar–H), 7.93 (s, 1H, CH-pyridazine);
ms: m/z 274 (MÀ2); Anal. Cald for C12H9ClN4S: C, 52.08; H,
3.28; N, 20.24; S, 11.59. Found: C, 52.01; H, 3.04; N, 20.21;
S, 11.39.
(–C–H) 2917–2847 cmÀ1 1H nmr (deuteriochloroform): δ 2.44
;
(s, 6H, 2CH3), 7.31–7.54 (m, 6H, Ar–H), 8.11 (s, 1H, CH-
pyridazine), 8.41 (d, 2H, Ar–H); ms: m/z 334, 336 (M+); Anal.
Cald for C19H15ClN4: C, 68.16; H, 4.52; N, 16.73. Found: C,
68.00; H, 4.51; N, 16.70.
6-Chloro-3-(ethylthio)-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine
(10b).
33% yield, mp 250–251°C. IR (potassium bromide): (–C–H)
2967–2864 cmÀ1 1H nmr (deuteriochloroform) δ: 1.38 (t, 3H,
This compound was obtained as a pale yellow powder
6-Chloro-3-(4-nitrophenyl)-7-(p-tolyl)-[1,2,4]triazolo[4,3-b]
;
pyridazine (8n).
yellow powder in 60% yield, mp 270–271°C; IR (potassium
bromide): (=C–H) 3031 cmÀ1 1H nmr (DMSO-d6): δ 2.40 (s,
This compound was obtained as a pale
CH3), 3.36 (q, 2H, SCH2), 7.55–7.87 (m, 5H, Ar–H), 7.93 (s,
1H, CH-pyridazine); ms: m/z 289 (MÀ1); Anal. Cald for
C13H11ClN4S: C, 53.70; H, 3.81; N, 19.27; S, 11.03. Found: C,
53.66; H, 3.75; N, 19.23; S, 10.01.
6-Chloro-7-phenyl-3-(propylthio)-[1,2,4]triazolo[4,3-b]pyridazine
(10c). This compound was obtained as a pale yellow powder 33%
yield, mp 213°C (dec); IR (potassium bromide): (–C–H)
2963–2868 cmÀ1; 1H nmr (deuteriochloroform) δ: 0.93 (t, 3H, CH3),
1.76 (m, 2H, CH2), 3.23 (t, 2H, SCH2), 7.57–7.88 (m, 5H, Ar–H),
7.95 (s, 1H, CH-pyridazine); ms: m/z 301 (MÀ3); Anal. Cald for
C14H13ClN4S: C, 55.17; H, 4.30; N, 18.38; S, 10.52. Found: C,
55.16; H, 4.29; N, 18.30; S, 10.22.
;
3H, CH3) 7.30–7.63 (m, 4H, Ar–H), 8.59–8.85 (m, 5H, Ar–H,
CH-pyridazine); ms: m/z 363 (MÀ2); Anal. Cald for
C18H12ClN5O2: C, 59.11; H, 3.31; N, 19.15. Found: C, 59.01;
H, 3.19; N, 19.19.
6-Chloro-3-(4-chlorophenyl)-7-(p-tolyl)-[1,2,4]triazolo[4,3-b]
pyridazine (8o).
This compound was obtained as a yellow
powder in 45% yield, mp 183–184°C; IR (potassium bromide):
1
(=C–H) 3052–3027 cmÀ1; H nmr (deuteriochloroform): δ 2.40
(s, 3H, CH3), 7.27 (d, 2H, Ar–H), 7.33 (d, 2H, Ar–H), 7.50 (d,
2H, Ar–H), 8.02 (s, 1H, CH-pyridazine), 8.42 (d, 2H, Ar–H);
ms: m/z 355, 357 (M+); Anal. Cald for C18H12Cl2N4: C, 60.86;
H, 3.40; N, 15.77. Found: C, 60.55; H, 3.39; N, 15.45.
General procedure for preparation of 9a–c. A mixture of
compound 5a–c (10 mM) and carbon disulfide (10mL) in dry
pyridine (15mL) was refluxed for 10h. The solvent was removed
under reduced pressure and residue washed with water, dried and
recrystallized from ethanol and acetonitrile, respectively.
3-(Butylthio)-6-chloro-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine
(10d).
25% yield, mp 210–212°C; IR (potassium bromide): (–C–H)
2969–2955 cmÀ1 1H nmr (deuteriochloroform) δ: 0.92 (t, 3H,
This compound was obtained as a light yellow powder
;
CH3), 1.29–1.77 (m, 4H, CH2CH2), 3.24 (t, 2H, SCH2), 7.49–7.75
(m, 5H, Ar–H), 7.81 (s, 1H, CH-pyridazine); ms: m/z 315 (MÀ3);
Anal. Cald for C15H15ClN4S: C, 56.51; H, 4.74; N, 17.57; S,
10.06. Found: C, 56.23; H, 4.35; N, 17.52; S, 10.00.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z. Arghiani, S. M. Seyedi, M. Bakavoli, and H. Eshghi
Vol 000
3-(Benzylthio)-6-chloro-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazine
(–C–H) 2917–2729 cmÀ1
;
1H nmr (deuteriochloroform) δ:
(10e). This compound was obtained as a pale yellow powder 35%
1.10 (t, 3H, CH3), 2.40 (s, 3H, CH3), 3.25 (q, 2H, SCH2),
7.36–7.58 (m, 4H, Ar–H), 7.92 (s, 1H, CH-pyridazine); ms:
m/z 298 (MÀ6); Anal. Cald for C14H13ClN4S: C, 55.17; H,
4.30; N, 18.38; S, 10.52. Found: C, 55.01; H, 4.23; N,
18.23; S, 10.47.
6-Chloro-7-(4-methylphenyl)-3-(propylthio)-[1,2,4]triazolo
[4,3-b]pyridazine (10m). This compound was obtained as a
yellow powder 40% yield, mp 197–198°C; IR (potassium
bromide): (–C–H) 2949–2880cmÀ1; 1H nmr (deuteriochloroform)
δ: 0.91 (t, 3H, CH3), 1.64 (q, 2H, CH2), 2.35 (s, 3H, CH3), 3.34
(t, 2H, SCH2), 7.34–7.55 (m, 4H, Ar–H), 7.93 (s, 1H, CH-
pyridazine); ms: m/z 217 (M–N=CSC3H7); Anal. Cald for
C15H15ClN4S: C, 56.51; H, 4.74; N, 17.57; S, 10.06. Found: C,
56.30; H, 4.53; N, 17.48; S, 10.08.
3-(Butylthio)-6-chloro-7-(4-methylphenyl)-[1,2,4]triazolo
[4,3-b]pyridazine (10n). This compound was obtained as a
pale yellow powder 20% yield, mp 232°C (dec); IR (potassium
bromide): (–C–H) 2953–2859cmÀ1; 1H nmr (deuteriochloroform)
δ: 0.92 (t, 3H, CH3), 1.15–1.86 (m, 4H, CH2CH2), 2.43 (s, 3H,
CH3), 3.24 (t, 2H, SCH2), 7.43–7.64 (m, 4H, Ar–H), 7.85 (s, 1H,
CH-pyridazine); ms: m/z 330 (MÀ2); Anal. Cald for
C16H17ClN4S: C, 57.73; H, 5.15; N, 16.83; S, 9.63. Found: C,
57.61; H, 5.05; N, 16.73; S, 9.54.
3-(Benzylthio)-6-chloro-7-(4-methylphenyl)-[1,2,4]triazolo
[4,3-b]pyridazine (10o). This compound was obtained as a
pale yellow powder 47% yield, mp 262–263°C; IR (potassium
bromide): (–C–H) 2921–2733cmÀ1; 1H nmr (deuteriochloroform)
δ: 2.44 (s, 3H, CH3), 4.45 (s, 2H, SCH2), 7.03–7.65 (m, 9H,
Ar–H), 7.71 (s, 1H, CH-pyridazine); ms: m/z 363 (MÀ3); Anal.
Cald for C19H15ClN4S: C, 62.20; H, 4.12; N, 15.27; S, 8.74.
Found: C, 62.15; H, 4.05; N, 15.23; S, 8.67.
yield, mp 242–243°C; IR (potassium bromide): (–C–H) 2980 cmÀ1
;
1H nmr (deuteriochloroform) δ: 4.50 (s, 2H, SCH2), 7.16–7.37
(m, 5H, Ar–H), 7.44–7.76 (m, 5H, Ar–H), 7.84 (s, 1H, CH-
pyridazine); ms: m/z 352 (M+1); Anal. Cald for C18H13ClN4S: C,
61.27; H, 3.71; N, 15.88; S, 9.09. Found: C, 61.05; H, 3.60; N,
15.66; S, 9.02.
6-Chloro-7-(4-methoxyphenyl)-3-(methylthio)-[1,2,4]triazolo
[4,3-b]pyridazine (10f).
This compound was obtained as a
yellow powder 29% yield, mp 267–268°C IR (potassium
bromide): (–C–H) 2925–2737 cmÀ1; 1H nmr (deuteriochloroform)
δ: 2.75 (s, 3H, SCH3), 3.93 (s, 3H, OCH3), 7.10 (d, 2H, Ar–H),
7.58 (d, 2H, Ar–H), 7.81 (s, 1H, CH-pyridazine); ms: m/z 306
(M+1); Anal. Cald for C13H11ClN4OS: C, 50.90; H, 3.61; N,
18.26; S, 10.45. Found: C, 50.88; H, 3.55; N, 18.21; S, 10.12.
6-Chloro-3-(ethylthio)-7-(4-methoxyphenyl)-[1,2,4]triazolo
[4,3-b]pyridazine (10g). This compound was obtained as a
yellow powder 60% yield, mp 258°C (dec); IR (potassium
bromide): (–C–H) 2962–2839 cmÀ1; 1H nmr (deuteriochloroform)
δ: 1.20 (t, 3H, CH3), 3.12 (q, 2H, SCH2), 3.84 (s, 3H, OCH3), 7.01
(d, 2H, Ar–H), 7.49 (d, 2H, Ar–H), 7.73 (s, 1H, CH-pyridazine);
ms: m/z 316 (MÀ4); Anal. Cald for C14H13ClN4OS: C, 52.42; H,
4.08; N, 17.46; S, 10.00. Found: C, 52.39; H, 3.98; N, 17.11; S, 9.01.
6-Chloro-7-(4-methoxyphenyl)-3-(propylthio)-[1,2,4]triazolo
[4,3-b]pyridazine (10h).
This compound was obtained as a
yellow powder 52% yield, mp 270–272°C; IR (potassium
bromide): (–C–H) 2960–2838 cmÀ1; 1H nmr (deuteriochloroform)
δ: 0.92 (t, 3H, CH3), 1.64 (q, 2H, CH2), 3.21 (t, 2H, SCH2), 3.90
(s, 3H, OCH3), 7.12 (d, 2H, Ar–H), 7.63 (d, 2H, Ar–H), 7.81 (s,
1H, CH-pyridazine); ms: m/z 331 (MÀ3); Anal. Cald for
C15H15ClN4OS: C, 53.81; H, 4.52; N, 16.73; S, 9.58. Found: C,
53.72; H, 4.52; N, 16.70; S, 9.31.
3-(Butylthio)-6-chloro-7-(4-methoxyphenyl)-[1,2,4]triazolo
CHEMOTHERAPEUTIC ACTIVITIES
[4,3-b]pyridazine (10i).
This compound was obtained as a
pale yellow powder 15% yield, mp 145–146°C; IR (potassium
bromide): (–C–H) 2954–2835 cmÀ1; 1H nmr (deuteriochloroform)
δ: 0.91 (t, 3H, CH3), 1.11–1.86 (m, 4H, CH2CH2), 3.28 (t, 2H,
SCH2), 3.91 (s, 3H, OCH3), 7.16 (d, 2H, Ar–H), 7.65 (d, 2H,
Ar–H), 7.83 (s, 1H, CH-pyridazine); ms: m/z 346 (MÀ2); Anal.
Cald for C16H17ClN4OS: C, 55.09; H, 4.91; N, 16.06; S, 9.19.
Found: C, 55.03; H, 4.77; N, 15.99; S, 9.01.
The screening of all the synthesized compounds for their
antibacterial activity (Gram positive and Gram negative
bacteria) and also inhibitory activity against soybean
15-lipoxygenase (15-LO) enzyme is underway, and the
results will be published elsewhere.
3-(Benzylthio)-6-chloro-7-(4-methoxyphenyl)-[1,2,4]triazolo
[4,3-b]pyridazine (10j).
This compound was obtained as a
Acknowledgments. We are grateful to Ferdowsi University of
Mashhad for financial support of this work.
pale yellow powder 50% yield, mp 280°C (dec); IR (potassium
bromide): (–C–H) 2995–2835 cmÀ1; H nmr (deuteriochloroform,
1
DMSO-d6) δ: 3.81 (s, 3H, OCH3), 4.44 (s, 2H, SCH2), 7.05
(d, 2H, Ar-H), 7.17–7.36 (m, 5H, Ar–H), 7.55 (d, 2H, Ar–H),
7.7 (s, 1H, CH-pyridazine); ms: m/z 382 (M+1); Anal. Cald for
C19H15ClN4OS: C, 59.60; H, 3.95; N, 14.63; S, 8.37. Found:
C, 59.55; H, 3.85; N, 14.53; S, 8.27.
REFERENCES AND NOTES
[1] Rashad, A. E.; Shamroukh, A. H.; Ali, M. A.; Abdel Motti,
F. M. Heteroatom Chem 2007, 18, 274.
[2] Rakib, E. M.; Abouricha, S.; Hannioui, A.; Benchat, N. J Iran
Chem Soc 2006, 3, 272.
6-Chloro-7-(4-methylphenyl)-3-(methylthio)-[1,2,4]triazolo
[4,3-b]pyridazine (10k).
This compound was obtained as a
yellow powder 31% yield, mp 249–250°C; IR (potassium
bromide): (–C–H) 2925–2851 cmÀ1; 1H nmr (deuteriochloroform)
δ: 2.55 (s, 3H, CH3), 2.75 (s, 3H, SCH3), 7.29–7.56 (m, 4H,
Ar–H), 7.85 (s, 1H, CH-pyridazine); ms: m/z 290 (MÀ2); Anal.
Cald for C13H11ClN4S: C, 53.70; H, 3.81; N, 19.27; S, 11.03.
Found: C, 53.55; H, 3.80; N, 19.01; S, 11.92.
[3] Barnett, S. F.; Defeo-Jones, D.; Haskell, K. M.; Huber,
H. E.; Nahas, D. D. PCT Int Appl WO 02 83,064 (Cl. A61K) 24
Oct. 2002, US Appl. Pv 282, 783, 10 Apr. 2001. Chem Abstr 2002,
137, P333127c.
[4] Noguchi, H.; Kitazumi, K.; Mori, M.; Shiba, T. Eur J
Pharmacol 2002, 434, 21.
[5] Polsky–Fisher, S. L.; Vickers, S.; Cui, D.; Subramanian, R.
Drug Metab Dispos 2006, 34, 1004.
[6] McMahon, L. R.; France, C. P. Br J Pharmacol 2006,
147, 260.
6-Chloro-3-(ethylthio)-7-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]
pyridazine (10l).
This compound was obtained as a yellow
powder 56% yield, mp 284–285°C; IR (potassium bromide):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Facile Synthesis of New [1,2,4]Triazolo[4,3-b]pyridazine
[7] Carling, R. W.; Madin, A.; Guibin, A.; Russell, M. G. N. J
[14] Bakavoli, M.; Nikpour, M.; Rahimizadeh, M.; Saberi, M. R.;
Med Chem 2005, 48, 7089.
Sadeghian, H. Bioorg Med Chem 2007, 15, 2120.
[8] Albright, J. D.; Moran, D. P.; Wright, W. B.; Collins, J. P. J
Med Chem 1981, 24, 592.
[9] Biziere, K.; Bourguignon, J. J.; Chambon, J. P.; Heaulme,
M. Br J Pharmacol 1987, 90, 183.
[15] Bakavoli, M.; Sadeghian, H.; Tabatabaei, Z.; Rezaei, E.;
Rahimizadeh, M.; Nikpour, M. J Mol Model 2008, 14, 471.
[16] Bakavoli, M.; Seyedi, S. M.; Shiri, A.; Saberi, S.; Gholami,
M.; Sadeghian, H. J Chem Res 2013, 37, 48.
[10] Katrusiak, A.; Melzer, E.; Baloniak, S.; Bobkiewicz, T.;
Polcyn, P. Acta Pol Pharm 2001, 58, 217. (Chem. Abstr. 2002, 136,
350111q).
[11] Alig, B.; Marhold, A.; Mueller, P.; Wolfrum, P. PCT Int Appl
WO 02 12,236 (Cl. CO7D 471/04) 14 Feb. 2002, DE Appl. 10,038,019, 4
Aug. 2000. (Chem Abstr 2000, 136, P183832s).
[12] Mohamed, M. I.; Zaky, H. T.; Mohamed, H. M.; Kandile, N.
G. Afinidad 2005, 62, 48. (Chem Abstr 2006, 144, 254075a).
[13] Shamroukh, A. H.; Ali, M. A. Arch Pharm Chem Life Sci
2008, 341, 223.
[17] Roshchin, A. I. Tetrahedron Lett 2010, 51, 3633.
[18] Yassin, F. A. Chem Heterocycl Comp 2009, 45, 8, 997.
[19] Deeb, A.; Hassaneen, M.; Kotb, M. Heteroatom Chem 2005,
16, 4, 278.
[20] Razvi, M.; Ramalingam, T.; Sattur, P. B.; Indian J Chem 1989,
28B, 987.
[21] Carling, R. W.; Madin, A.; Guiblin, A.; et al., J Med Chem
2005, 48, 23,7089.
[22] Fluran, A.; Fluran, M.; Stanovink, B.; Tisler, M.; Monatsh
Chem 1974, 105, 834.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet