Synthesis of pyridazinone-substituted 1,3,4-thiadiazoles, -1,3,4-oxadiazoles and -1,2,4-triazoles

Article abstract of DOI:10.1002/jhet.5570380431

Several 1-(1-aryl-1,4-dihydro-3-carboxy-6-methylpyridazin-4-one)-4-aryl thio-semicarbazides and their corresponding oxadiazole, thiadiazole and triazole derivatives were prepared and characterized by their spectral data. The preliminary biological tests showed that some new compounds exhibit good anti-fungal activity.

Full text of DOI:10.1002/jhet.5570380431

Synthesis of Pyridazinone-substituted 1,3,4-Thiadiazoles,
-1,3,4-Oxadiazoles and -1,2,4-Triazoles
Xiajuan Zou and Guiyu Jin*
993
Jul-Aug 2001
Institute of Elemento-Organic Chemistry, National key laboratory of
Elemento-Organic Chemistry, Nankai University, Tianjin P. R. China 300071
Received September 11, 2000
Several 1-(1-aryl-1,4-dihydro-3-carboxy-6-methylpyridazin-4-one)-4-aryl thio-semicarbazides and their
corresponding oxadiazole, thiadiazole and triazole derivatives were prepared and characterized by their
spectral data. The preliminary biological tests showed that some new compounds exhibit good anti-fungal
activity.
J. Heterocyclic Chem., 38, 993 (2001).
Acylthiosemicarbazides and their related heterocyclic
The starting material, hydrazide of 1-aryl-1,4-dihydro-6-
methylpyridazin-3-carboxy-4-one 1 obtained according to the
literature [5, 6,7], which was reacted with various arylisothio-
cyanates afforded the acylthiosemicarbazides 2a-c [8,9,10].
The treatment of 2a-c with concentrated sulfuric acid yielded
the corresponding 1,3,4-thiadiazoles 3a-c, while the treatment
derivatives are reported to show a broad spectrum of
biological activities. Some of these compounds have been
shown to exhibit bactericide, fungicide and plant growth-
effecting properties [1,2,3]. These observations, and our
interest in 1-aryl-1,4-dihydro-3-carboxy-6-methyl-
pyridazin-4-one chemistry [4], prompted us to undertake
the synthesis of an, as yet unreported series of 1-(1-aryl-
1,4-dihydro-6-methylpyridazin-3-carboxy-4-one)-4-aryl
thiosemicarbazides 2a-c and their corresponding thiadia-
zole 3a-c, oxadiazole 4a-c and triazole 5a-c, 6a-c
derivatives which are novel tri-heterocyclic compounds in
order to studying their biological properties.
of 2a-c with Hg(OAc) resulted in the formation of 1,3,4-
2
oxadiazoles 4a-c. The corresponding substituted 1,2,4-
triazoles 5a-c were obtained by reacting 2a-c with sodium
carbonate. The thioethers 6a-c were prepared by reaction of
thiones 5a-c with iodomethane in sodium hydroxide,
preferably with addition some non-homogeneous catalyst, for
example tetrabutylammonium ion. (Scheme 1)

994
X. Zou and G. Jin
Vol. 38
Table 1
Physical Data of New Compounds
No.
R
R
M.p
(°C)
Yield
(%)
Formula
Analysis % Calcd./Found
H
1
2
C
N
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
p-Cl
p-Cl
o-Cl
p-Cl
p-Cl
o-Cl
p-Cl
p-Cl
o-Cl
p-Cl
p-Cl
o-Cl
p-Cl
p-Cl
o-Cl
o-F
m-CF
m-CF
o-F
231-2
234-5
227-8
298-30
>300
94
95
94
95
95
C
H
ClFN O S
52.84/52.94
49.84/49.61
49.84/49.75
55.10/55.37
51.77/51.55
51.77/51.60
57.33/57.12
53.62/53.52
53.62/53.56
55.10/54.99
51.77/51.79
51.77/51.69
56.12/56.07
52.72/52.42
52.72/52.55
3.48/3.60
3.16/3.13
3.16/3.11
3.16/3.11
2.80/2.81
2.80/2.84
3.27/3.47
2.90/3.25
2.90/2.85
3.16/3.11
2.80/3.00
2.80/2.80
3.50/3.44
3.14/3.11
3.14/3.12
16.22/16.36
14.54/14.40
14.54/14.49
16.98/16.98
15.16/15.25
15.16/15.15
17.28/17.49
15.70/15.78
15.70/15.62
16.93/16.70
15.16/15.15
15.16/15.15
16.44/16.45
14.72/14.83
14.72/14.72
19 15
5 2
C
C
H ClF N O S
3
3
20 15 3 5 2
H ClF N O S
20 15 3 5 2
C H ClFN OS
C H ClF N OS
20 13 3 5
C H ClF N OS
C H ClFN O
19 13 5 2
C
C
C H ClFN OS
C
C
C H ClFN OS
C
C
19 13 5
m-CF
m-CF
o-F
3
3
>300
90
20 13 3 5
257-8
278-80
142-4
>250
>250
>240
110-2
171-3
198-20
86.3
85.6
88
89.7
96
95
85
84
88
m-CF
m-CF
o-F
H ClF N O
3
3
20 13 3 5
2
H
ClF N O
3 5
20 13
2
19 13 5
H ClF N OS
20 13 3 5
m-CF
m-CF
o-F
3
3
H ClF N OS
20 13 3 5
20 15 5
H ClF N OS
21 15 3 5
m-CF
m-CF
3
3
H ClF N OS
21 15 3 5
Table 2
Spectral Analyses of New Compounds
-1
1
No
IR(ν/cm )
H-NMR(Solvent/δ)
2a
3266.5 (NH), 1670.0,
1639.5 (C=O), 1347 (C=S).
3263.5 (NH), 1670.5, 1622.
0 (C=O), 1349.4 (C=S)
3232.0 (NH), 1700.7,
(DMSOd ): 2.20 (s, 3H, CH ), 6.80 (s, 1H, pyridazinone),
6 3
7.20-7.84 (m, 8H, 2C H ), 9.76(bs), 12.20 (bs).
6
4
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
(DMSOd ): 2.20 (s, 3H, CH ), 6.96 (s, 1H, pyridazinone),
6 3
7.44-8.24 (m, 8H, 2C H ), 10.28 (bs), 12.20 (bs).
6
4
1626.0 (C=O),1329.2 (C=S)
(DMSOd ): 2.20 (s, 3H, CH ), 7.12 (s, 1H, pyridazinone),
6 3
7.44-8.32 (m, 8H, 2C H ), 10.40 (bs).
6
4
3235.5 (NH), 1619.1 (C=O)
3255.0 (NH), 1605.1 (C=O)
3261.0 (NH), 1604.7 (C=O)
1631.1 (C=O).
(DMSOd ): 2.20 (s, 3H, CH ), 6.64 (s, 1H, pyridazinone),
6 3
7.15-8.44 (m, 8H, 2C H ).
6
4
(DMSOd ): 2.20 (s, 3H, CH ), 6.88 (s, 1H, pyridazinone),
6
3
7.36-8.32 (m, 8H, 2C H ), 10.96 (bs).
6
4
(DMSOd ): 2.20 (s, 3H, CH ), 6.80 (s, 1H, pyridazinone),
6
3
7.36-8.40 (m, 8H, 2C H ), 11.04 (bs).
6
4
(DMSOd ): 2.20 (s, 3H, CH ), 6.80 (s, 1H, pyridazinone),
6
3
7.12-8.32 (m, 8H, 2C H ), 10.64 (bs).
6
4
3151.0 (NH), 1655.6 (C=O)
3250.0 (NH), 1627.1 (C=O)
2709.5, 1619.1 (C=O)
2730.0, 1618.2 (C=O)
2726.5, 1615.8 (C=O)
1631.1 (C=O)
(DMSOd ): 2.20 (s, 3H, CH ), 6.80 (s, 1H, pyridazinone),
6 3
7.36-8.08 (m, m, 2C H ), 11.28 (bs).
6
4
(DMSOd ): 2.00 (s, 3H, CH ), 6.80 (s, 1H, pyridazinone),
6
3
7.28-8.00 (m, 8H, 2C H ), 11.12 (bs).
6
4
(DMSOd ): 2.10 (s, 3H, CH ), 6.60 (s, 1H, pyridazinone),
6
3
7.20-7.80 (m, 9H, 2C H ,triazole-H).
6
4
(DMSOd ): 2.10 (s, 3H, CH ), 6.41 (s, 1H, pyridazinone),
6
3
7.10-7.64 (m, 8H, 2C H ), 8.18 (s, 1H).
6
4
(DMSOd ): 2.00 (s, 3H, CH ), 6.41 (s, 1H, pyridazinone),
6
3
7.44-7.80 (m, 9H, 2C H ,triazole-H).
6
4
(CDCl ): 2.20 (s, 3H, CH ), 2.78 (s, 3H, CH ), 6.60 (s, 1H,
3
3
3
pyridazinone), 7.20-7.70 (m, 8H, 2C H ).
6
4
1632.1(C=O)
(CDCl +DMSOd ): 2.20 (s, 3H, CH ), 2.70 (s, 3H, CH ), 6.40
3 6 3 3
(s, 1H, pyridazinone), 7.00-7.80 (m, 8H, 2C H ).
6
4
1635.6 (C=O)
(CDCl ): 2.20 (s, 3H, CH ), 2.78 (s, 3H, CH ), 6.60 (s, 1H,
3 3 3
pyridazinone), 7.32-7.90 (m, 8H, 2C H ).
6
4
The infrared spectra of 3a-c, 4a-c, 5a-c and 6a-c show
absorption bands in the region between 3151.0-3261.0
-1
-1
C=C/C=N absorption bands between 1593.6-1400.0 cm
cm . The absorption bands due to the C=O group were
-1
-1
and show a broad band at 1314.5-1398.9 cm . The
observed in the range of 1604.7-1655.6 cm . In the
compounds 3a-c and 4a-c exhibited N-H stretching
nuclear magnetic resonance spectra, compounds 3a-c and

Jul-Aug 2001
995
Synthesis of Pyridazinone-substituted 1,3,4-Thiadiazoles
Table 3
Mass Spectra of some New Compounds
No.
m/e ( Relative Intensity )
3a
413(41), 394(52), 354(3), 263(3), 246(21), 229(12), 201(18), 193(34), 178(78), 168(61), 164(45), 152(89), 136(21), 111(100), 95(19),
75(95), 51(18).
3c
5a
463(43), 444(2), 274(12), 263(1), 246(34), 218(63), 203(24), 193(43), 178(83), 152(100), 145(40), 125(18), 111(52), 95(12), 75(53).
413(54), 394(16), 380(1), 340(11), 302(8), 246(10), 219(10), 201(38), 193(30), 178(71), 164(49), 152(62), 150(45), 123(22),
111(100), 95(49), 75(91).
5c
463(85), 444(4), 430(3), 404(2), 341(8), 298(7), 269(31), 246(29), 218(18), 203(3), 193(36), 178(94), 152(100), 145(46), 130(15),
111(59), 95(9), 75(48).
4a-c exhibited broad singlet between 10.64-11.28 ppm due
to the phenylamino N-H protons. These peaks disappear
upon addition of deuterium oxide.
The preliminary biological tests showed that new
compounds 2 exhibit antiviral activity against TMV.
Compounds 3a-c and 4c gave mortality levels of 100%
against Puccinia recondita and compound 5c gave
mortality levels of 80% at 500 ppm in vivo. A further study
of their biological activity is underway.
The 5-[1-aryl-1,4-dihydro-6-methylpyridazin-4-one-3-
yl]-4-aryl-1,2,4-triazole-3-thiol 5a-c exhibited a
-1
characteristic band between 2709.5-2726.5 cm due to the
S-H group because there are large ortho-space block.
These absorption bands disappear after compounds 5a-c
were reacted with iodomethane in sodium hydroxide to
produce thioether 6a-c. The previous reference mentioned
that substituted 1,2,4-triazole thiols exist in a tautomeric
form [2,11]. We found that compound 5a-c exist mainly as
the thiol form. Addition of silver nitrate solution dropwise
to the solution of compounds 5a-c in DMF, causes a white
solid to appear immediately. The absorption bands due to
the C=O group were observed in the ranged of
EXPERIMENTAL
Melting points were measured on a Yanaco melting point
apparatus and are uncorrected. Infrared spectra (ir) (potassium
bromide) were recorded in a Shimadzu IR-435. H NMR spectra
on a JEOL FX-90Q spectrometer were used TMS as internal
standard (chemical shift are in δ values). A HP 5988 A
spectrometer operating at 70 ev was used to obtain the mass
spectra. Elemental (C, H, and N) analyses were carried out on
MT-3 analyzer.
1
-1
1615.0-1619.1 cm . In the nuclear magnetic resonance
(1-Aryl-1,4-dihydro-3-carboxy-6-methylpyridazin-4-one)-4-aryl
Thiosemicarbazides (2a-c).
spectra of 5a-c, the S-H protons showed a singlet between
7.53-8.18 ppm. These peaks disappear upon addition of
deuterium oxide.
Equimolar quantities of hydrazide of 1-aryl-1,4-dihydro-3-
carboxy-6-methylpyridazin-4-one 1 and appropriate aryliso-
thiocyanates (1 mmol) were refluxed in 30 mL of absolute
ethanol for 3 hours. The excess of solvent was removed under
reduced pressure. The solid mass thus obtained was washed with
ethanol, dried and recrystallized from ethanol. The physical
constants and spectral analyses of these substituted thio-
semicarbazides are recorded in Table 1 and Table 2.
The mass spectra of 3a, 3c, 5a and 5c were studied
(scheme II). The molecular ion peak was found to be
present in all the compounds. The intensity of the peaks
varied from 1-100%. The cleavage of S-C2 and N4-C5
bonds gave ion with m/e 263 in 5-[1-aryl-1,4-dihydro-6-
methylpyridazin-4-one-3-yl]-2-arylamino-1,3,4-thiadia-
zoles 3a and 3c. The cleavage of N1-C5 and N4-C3 in
5-[1-aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-4-
aryl-1,2,4-triazole-3-thiols 5a and 5c yield ion of m/e 390
and 340, respectively. In triazole 5a and 5c, the molecular
ion lost HS• to give ions of m/e 380 and 430. This
observation is accordant with our inference.
5-[1-Aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-2-aryl-
amino-1,3,4-thiadiazole (3a-c).
Substituted thiosemicarbazides 2a-c 0.5 mmol was added in
portion to concentrated sulfuric acid (5 mL) at 0 °C and stirred
for 1 hour maintaining the temperature at 0 °C. The reaction

996
X. Zou and G. Jin
Vol. 38
mixture was then allowed to stand for 20 hours at room
temperature, poured over crushed ice with stirring and the
separated solid was washed with water and recrystallized from
ethanol/DMF. The physical constants and spectral analyses of
these substituted 1,3,4-thiadiazoles are recorded in Table 1,
Table 2 and Table 3.
formed was stirred at room temperature for 2 days and 4 mL of
water was added. The mixture was stirred at room temperature
for 1 hour. The dichloromethane was isolated and concentrated
under pressure. The residue was purified by silica gel column
chromatography, eluted with ethyl acetate/acetone. The physical
constants and spectral analyses of these substituted 1,2,4-
triazole-3-methylthioes are recorded in Table 1 and Table 2.
5-[1-Aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-2-aryl-
amino-1,3,4-oxadiazole (4a-c).
Acknowledgements.
Financial support of this work by the National Nature Science
Foundation of China (projects number 29832050) is gratefully
acknowledged.
To a solution of compound 2a-c 0.5 mmol in ethanol (20 mL)
was added 0.5 mmol Hg(OAc) . The reaction mixture was
2
refluxed for 3 hours and concentrated under reduced pressure.
The solid was dissolved in hot N,N-dimethylformamide and
filtered. The filtrate was concentrated under reduced pressure and
recrystallized from ethanol/DMF. The physical constants and
spectral analyses of these substituted 1,2,4-oxadiazoles are
recorded in Table 1 and Table 2.
REFERENCES AND NOTES
[1] H. V. Patel and P. S. Fernandes, J. Indian Chem. Soc., 67, 401
(1990).
[2] P. J. Kothari, M. A. Mehlhoff, S. P. Singh, S. S. Parmar, and
V. I. Stenberg, J. Heterocyclic Chem., 17, 1369 (1980).
[3] P. F. Juby and T. W. Hudyma, J. Med. Chem., 12, 396 (1969).
[4] Z. M. Li, X. J. Zou , E. Y. Yao and S. H. Wang, Chinese
Journal Apply Chemistry, 10(6), 86-88. (1993)
[5] T. T. Fujimoto, US 4,345,934; Chem. Abstr., 97, p194594
(1982).
[6] T. T. Fujimoto, Ger Offen. 2,808,795; Chem. Abstr., 90, p1691
(1978).
[7] E. Haddock, W. J. Hopwood, EP 0037133; Chem. Abstr., 96,
p69011 (1981).
5-[1-Aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-4-aryl-
1,2,4-triazole-3-thiol (5a-c).
Compound 2a-c (1 mmol) was refluxed in 30 mL of 5%
aqueous sodium carbonate solution for 5 hours. The reaction
mixture was filtered, cooled and acidified to pH 2 with
2 N hydrochloric acid. The precipitate of the crude product was
filtered, washed several times with cold water, dried and purified
by silica gel column chromatography, eluted with ethyl acetate.
The physical constants and spectral analyses of these substituted
1,2,4-triazole-3-thiols are recorded in Table 1, Table 2 and
Table 3.
[8] B. Rigo, J. Heterocyclic chem.., 26, 1723 (1989).
[9] B. K. Paul and U. P. Basu, J. Indian Chem. Soc., 46, 1121
(1969).
5-[1-Aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-4-aryl-
1,2,4-triazole-3-methylthio (6a-c).
[10] Z. Y. Zhang and. H. Yang, Chinese Journal of Organic
Chemistry, 3, 184 (1986).
[11] A. K. S. Gupta and H. K. Misra, J. Indian Chem. Soc., Vol.
LVIII, 508 (1981).
A mixture of compound 5a-c (0.5 mmol) and 0.1ml of 20%
sodium hydroxide and 2.5 X 10 mmol tetrabutylammonium in
15 mL dichloromethane was stirred for 10 minutes, then
iodomethane (0.5 mmol) was added at 5 °C .The suspension
-3