Nucleophilic substitution of chlorine with hydrazine and methylhydrazine in chlorinated pyridazines and pyridazones

Article abstract of DOI:10.1007/s11167-005-0207-1

The reactions of methylhydrazine and hydrazine hydrate with chlorinated pyridazines and pyridazones were studied.

Full text of DOI:10.1007/s11167-005-0207-1

Russian Journal of Applied Chemistry, Vol. 77, No. 12, 2004, pp. 1997 2000. Translated from Zhurnal Prikladnoi Khimii, Vol. 77, No. 12, 2004,
pp. 2021 2024.
Original Russian Text Copyright
2004 by Baranov, Tsypin, Malin, Laskin.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Nucleophilic Substitution of Chlorine with Hydrazine
and Methylhydrazine in Chlorinated Pyridazines
and Pyridazones
A. B. Baranov, V. G. Tsypin, A. S. Malin, and B. M. Laskin
Prikladnaya Khimiya Russian Scientific Center, St. Petersburg, Russia
Received August 18, 2004
Abstract The reactions of methylhydrazine and hydrazine hydrate with chlorinated pyridazines and
pyridazones were studied.
The reactivity of hydrazine and methylhydrazine
toward aliphatic and aromatic compounds has been
well studied [1, 2]. However, data on reactions of
hydrazine and methylhydrazine with heterocycles and,
in particular, with pyridazines are scarce. The interest
in the chemistry of hydrazine is determined by its
diverse applications in science and technology. In
particular, hydrazine derivatives are widely used in
medicine as physiologically active compounds exhib-
iting antitubercular, anticancer, radiation-protective,
and other effects; in agriculture, as plant growth regu-
lators and stimulants, as insecticides, fungicides, and
hebricides; and in industry, for preparing synthetic
fibers, films, and coatings [3, 4].
with chlorine substitution at the 4-position of the pyr-
idazine ring. This is due to the activating effect of
the keto group on the 4-position in I [10, 12]. How-
ever, it has been reported [13, 14] that the reaction
of I with ammonia yields a mixture of 4-amino-5-
chloro-6-pyridazone VI and 5-amino-4-chloro-6-pyr-
idazone VII.
Our experiments showed that pyridazone I reacts
with methylhydrazine in 2-propanol strictly specifical-
ly to give 4-(1-methylhydrazino)-5-chloro-6-pyrida-
zone VIII in 95% yield. In methylation of VIII with
dimethyl sulfate in methanol in the presence of sodi-
um, the reaction occurs selectively at the 1-posi-
tion of the pyridazine ring, giving 1-methyl-4-(1-
methylhydrazino)-5-chloro-6-pyridazone IX in 37%
yield.
In this study we examined the reactions of hydra-
zine hydrate and methylhydrazine with some chlo-
rinated pyridazines and pyridazones.
It is known [11] that the reaction of I with 95%
hydrazine in methanol yields exclusively 4-hydrazino-
5-chloro-6-pyridazone X. Its structure was determined
by hydrogenation (Pd/C) and independent synthesis of
the dechlorination products. However, under the ex-
perimental conditions, the reaction of I with 100% hy-
drazine hydrate in ethanol yields a mixture of pyrida-
zone X and 5-hydrazino-4-chloro-6-pyridazone XI in
29 and 48% yields, respectively, which is confirmed
In the pyridazine series, available substrates for nu-
cleophilic substitution are 4,5-dichloro-6-pyridazone
I, 1-methyl-4, 5-dichloro-6-pyridazone II, 3, 4, 5-tri-
chloropyridazine III, 3,6-dichloropyridazine IV, and
3-methyl-6-chloropyridazine V [5 8]:
R
Cl
Cl
Cl
Cl
N
N
N
N
N
N
1
by the H NMR and TLC data, and also by depression
R
of the melting point, observed on mixing X and XI.
O
I, II
Cl
III
Cl
IV, V
Then we performed methylation of X with dimeth-
yl sulfate. The reaction was performed in the system
10% aqueous NaOH solution CHCl3 in the presence
of Et4NI. The reaction occurs selectively at the N1
atom of the hydrazine moiety, yielding pyridazone
VIII:
where R = H (I), Me (II, V), Cl (IV).
It is known that pyridazone I reacts with ammonia
[9], alkylamines [10], and hydrazine [11] selectively
1070-4272/04/7712-1997 2004 MAIK Nauka/Interperiodica

1998
BARANOV et al.
NH2
MeN
NH2
MeN
R
MeNHNH2
N
N
Me2SO4
MeOH
MeNHNH2
N
NH
N
N
IV, V
I
i-PrOH
Cl
Cl
Me
MeN NH2
XIII, XIV
O
VIII
O
IX
NH2NH2,
EtOH
Me2SO4
where R = Cl (XIII), Me (XIV).
H2NHN
Cl
Cl
N
NH
N
NH
+
EXPERIMENTAL
H2NHN
1
O
X
O
XI
The H NMR spectra were measured on a DPX-300
spectrometer (300 MHz), solvent DMSO-d6, internal
reference TMS. The elemental analysis was performed
on a Hewlett Packard automatic C, H,N analyzer.
The melting points were determined on a PTP device.
The TLC analysis was performed on Silufol UV-254
plates (eluent 90 vol % CHCl3 10 vol % MeOH), de-
velopment with UV light and iodine vapor.
It is known that the reaction of pyridazone II with
various amines occurs selectively with the substitution
of chlorine at the 4-position of the pyridazine ring
[10]. We also studied the reactions of pyridazone II
with methylhydrazine and hydrazine hydrate. Pyrida-
zone II does not react with methylhydrazine in reflux-
ing alcohols (methanol, 56 C, 30 h; ethanol, 78 C,
30 h; 2-propanol, 86 C, 30 C; 1-butanol, 110 C,
30 h) and is recovered unchanged from the reaction
mixture. The attempted reaction of II with 100% hy-
drazine hydrate in ethanol and 2-propanol results in
tarring.
4,5-Dichloro-6-pyridazone I and 1-methyl-4,5-di-
chloro-6-pyridazone II were prepared by the proce-
dure described in [5].
3,4,5-Trichloropyridazine III. To 10 ml of POCl3
we added with stirring 3 g of I. The mixture was
stirred at 70 C for 6 h, after which excess POCl3 was
distilled off. The residue was cooled to 0 2 C and
carefully neutralized with 5% aqueous NaOH. The pre-
cipitate of III was filtered off and dried in air; yield
1.45 g (43%), mp 56 58 C.
It is known that pyridazine III is synthesized by
the reaction of I with POCl3 [6]; acidolysis of III in
glacial acetic acid eliminates chlorine from the 3-posi-
tion of the pyridazine ring to give tion of I.
Our experiments showed that pyridazine III reacts
with methylhydrazine in 2-propanol at 45 C selective-
ly with substitution of the 5-Cl atom to give 5-(1-
methylhydrazino)-3,4-dichloropyridazine XII in 40%
yield. Acidolysis of XII in glacial acetic acid at 60 C
gives pyridazone VIII in 10% yield:
Found, %: C 26.10, H 0.01, N 15.20.
C4HCl3N2.
Calculated, %: C 26.16, H 0.01, N 15.26.
4-(1-Methylhydrazino)-5-chloro-6-pyridazone
VIII. (a) A 5-g portion of I was dissolved in 85 ml of
2-propanol, and a solution of 2.9 g of methylhydra-
zine in 15 ml of 2-propanol was added. The mixture
was refluxed with stirring for 2 h, after which it was
cooled and kept for 12 h at 0 C. The precipitate of
VIII was filtered off and dried in air; yield 5.04 g
NH2
MeN
MeNHNH2
N
AcOH
III
VIII
i-PrOH
NH
Cl
Cl
XII
1
(95%), mp 144 146 C (dec.). H NMR spectrum, ,
ppm: 12.40 s (1H, NH in heterocycle), 8.19 d (1H,
CH), 4.77 s (2H, NH2), 3.40 s (3H, Me).
The starting substrates IV and V were prepared
by the procedures described in [7, 8, 15]. We found
that pyridazine IV in ethanol at 78 C reacts with
methylhydrazine selectively with substitution of one
chlorine atom to give 3-(1-methylhydrazino)-6-chlo-
ropyridazine XIII in 55% yield. The reaction of V
with methylhydrazine in 1-butanol at 110 C gives
3-methyl-6-(1-methylhydrazino)pyridazine XIV in
32% yield:
Found, %: C 34.31, H 0.04, N 32.05.
C5H7ClN4O.
Calculated, %: C 34.38, H 0.04, N 32.09.
(b) A 2-g portion of X was dissolved in 20 ml of
10% aqueous NaOH, and 3.25 g of Et4NI was added.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 77 No. 12 2004

NUCLEOPHILIC SUBSTITUTION OF CHLORINE WITH HYDRAZINE AND METHYLHYDRAZINE
1999
The mixture was heated with stirring to 30 C, and
2.1 ml of dimethyl sulfate in 20 ml of chloroform
was added. The resulting mixture was stirred at 40 C
for 10 h, cooled, and settled. The aqueous layer was
treated with a 20-ml portion of chloroform. The ex-
tract was combined with the organic phase, the sol-
vent was distilled off, and the precipitate of VIII was
dried in air and recrystallized from ethanol; yield
0.21 g (10%).
For 5-hydrazino-4-chloro-6-pyridazone XI: yield
1.55 g (48%), mp 189 C. H NMR spectrum, , ppm:
12.29 s (1H, CH), 8.07 s (1H, NH in heterocycle),
7.60 s (1H, NH), 4.50 s (2H, NH2).
1
Found, %: C 29.90, H 3.10, N 34.85.
C4H5ClN4O.
Calculated, %: C 29.91, H 3.11, N 34.89.
Mixing of X (Rf 0.11) and XI (Rf 0.35) showed
20 C depression of the melting point.
(c) A 2-g portion of XII was dissolved in 50 ml of
glacial acetic acid. The mixture was stirred at 60 C
for 12 h, cooled, and kept at 0 5 C for 12 h. The pre-
cipitate of VIII was filtered off, dried in air, and
recrystallized from ethanol; yield 0.19 g (10%).
5-(1-Methylhydrazino)-3,4-dichloropyridazine
XII. A 3-g portion of III was dissolved in 30 ml of
2-propanol. The solution was heated with stirring to
40 C, a solution of 1.87 g of methylhydrazine in 5 ml
of 2-propanol was added, and the mixture was stirred
at 45 C for 10 h, cooled, and kept at 0 2 C for 12 h.
The precipitate of XII was filtered off and dried in air;
1-Methyl-4-(1-methylhydrazino)-5-chloro-6-pyr-
idazone IX. A 2-g portion of Na was dissolved in
30 ml of methanol, 3 g of VIII was added, the mix-
ture was heated to 35 40 C, and a solution of 3 ml
of dimethyl sulfate in 5 ml of methanol was slowly
added with stirring. The mixture was stirred at 35
40 C for an additional 14 h and cooled; excess meth-
anol was distilled off. The residue was mixed with
20 ml of 10% aqueous NaOH and treated with 50 ml
of chloroform. Excess chloroform was distilled off,
and the precipitate of IX was filtered off and dried
1
yield 1.27 g (40%), mp 116 117 C. H NMR spec-
trum, , ppm: 9.11 s (1H, CH), 4.99 s (2H, NH2),
3.40 s (3H, Me).
Found, %: C 30.98, H 3.10, N 28.95.
C5H6Cl2N4.
Calculated, %: C 31.09, H 3.11, N 29.01.
1
in air; yield 1.22 g (38%), mp 136 137 C. H NMR
spectrum, , ppm: 8.19 s (1H, CH), 4.82 s (2H, NH2),
3.57 s (3H, CH3 in heterocycle), 3.38 s (3H, Me).
3-(1-Methylhydrazino)-6-chloropyridazine XIII.
A 30-g portion of IV was dissolved with stirring in
200 ml of ethanol, a solution of 19.4 g of methyl-
hydrazine in 40 ml of ethanol was added, the mixture
was stirred at 70 80 C for 1 h, and the solvent was
distilled off. The residue was stirred with 200 ml
of water at 50 60 C until it completely dissolved.
The resulting mixture was cooled, and the precipitate
of XIII was filtered off, dried in air, and crystallized
from water or benzene; yield 17.5 g (55%), mp 110
Found, %: C 38.15, H 4.72, N 29.68.
C6H9ClN4O.
Calculated, %: C 38.19, H 4.77, N 29.71.
4-Hydrazino-5-chloro-6-pyridazone X and 5-hy-
drazino-4-chloro-6-pyridazone XI. A 3.3-g portion
of I was dissolved in 60 ml of ethanol. This solution
was heated to 70 75 C, and 3 g of 100% hydrazine
hydrate in 10 ml of ethanol was added. The mixture
was stirred at 70 75 C for 4 h and cooled; the pre-
cipitate containing a mixture of X and XI was filtered
off and dried in air. To separate X and XI, the mixture
was boiled in 50 ml of water and filtered while hot to
separate difficultly soluble pyridazone XI. The mother
liquor was cooled, and the precipitate of X was fil-
tered off and dried; yield 0.95 g (30%), mp 195 C.
1H NMR spectrum, , ppm: 12.30 s (1H, CH), 8.07 s
(1H, NH in heterocycle), 7.63 s (1H, NH), 4.62 s (2H,
NH2).
1
111 C. H NMR spectrum, , ppm: 3.33 s (3H, Me),
4.61 s (2H, NH2), 7.23 d (1H, CH in heterocycle),
7.53 d (1H, CH in heterocycle).
Found, %: C 37.3, H 4.3, N 34.9.
C5H7ClN4.
Calculated, %: C 37.9, H 4.4, N 35.1.
3-Methyl-6-(1-methylhydrazino)pyridazine XIV.
A solution of 2.24 g of methylhydrazine in 10 ml of
1-butanol was added with stirring to a solution of
2.5 g of V in 25 ml of 1-butanol. The mixture was
stirred at 108 111 C for 1 h, and excess solvent was
distilled off. The residue was dissolved in 25 ml of
water and treated with 50 ml of chloroform. Excess
chloroform was distilled off, and the precipitate of
Found, %: C 29.83, H 3.09, N 34.80.
C4H5ClN4O.
Calculated, %: C 29.91, H 3.11, N 34.89.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 77 No. 12 2004

2000
BARANOV et al.
XIV was filtered off, dried in air, and recrystallized
from CCl4; yield 0.91 g (32%), mp 73 75 C. H
(Chemistry of Organic Hydrazine Derivatives), Le-
ningrad: Khimiya, 1979.
1
NMR spectrum, , ppm: 3.30 s (3H, Me), 4.38 s (2H,
NH2), 7.06 d (1H, CH in heterocycle), 7.39 d (1H,
CH in heterocycle).
2. Audrieth, L.F. and Ogg, B.A., The Chemistry of Hy-
drazine, New York: Wiley, 1951.
3. Soldatenkov, A.T., Kolyadina, N.M., and Shendrik, I.V.,
Osnovy organicheskoi khimii lekarstvennykh ve-
shchestv (Fundamentals of the Organic Chemistry of
Drugs), Moscow: Khimiya, 2001.
4. Mel’nikov, N.N., Khimiya i tekhnologiya pestitsidov
(Chemistry and Technology of Pesticides), Moscow:
Khimiya, 1974.
Found, %: C 52.3, H 7.1, N 40.4.
C6H10N4.
Calculated, %: C 52.2, H 7.2, N 40.6.
5. Mowry, D.T., J. Am. Chem. Soc., 1953, vol. 75, no. 8,
CONCLUSIONS
pp. 1909 1910.
(1) In the reaction of 4,5-dichloro-6-pyridazone
with methylhydrazine, the nucleophilic substitution of
chlorine occurs selectively at the 4-position of the ring
to give 4-(1-methylhydrazino)-5-chloro-6-pyridazone
(yield 95%), whereas the reaction of 4,5-dichloro-6-
pyridazone with hydrazine hydrate gives a mixture of
products of chlorine substitution at the 4-and 5-posi-
tions (yield 30 and 48%, respectively).
6. Kuraishi, T., Chem. Pharm. Bull., 1957, vol. 5, no. 4,
pp. 376 378.
7. Mizzoni, R.H. and Spoerri, P.E., J. Am. Chem. Soc.,
1951, vol. 73, no. 4, pp. 1873 1874.
8. Overend, W.G. and Wiggins, L.F., J. Chem. Soc.,
1947, no. 2, pp. 239 244.
9. Kuraishi, T., Chem. Pharm. Bull., 1958, vol. 6, no. 4,
pp. 331 333.
10. Bourdais, J., Bull. Soc. Chim. Fr., 1964, no. 9,
pp. 2124 2132.
11. Osner, W.M., Castle, R.N., and Alduns, D.L.,
J. Pharm. Sci., 1963, vol. 52, no. 6, pp. 539 540.
12. Shepherd, R.G. and Fedrick, J.L., Adv. Heterocyclic
Chem., 1965, vol. 4, pp. 145 423.
(2) 3,4,5-Trichloropyridazine reacts with methyl-
hydrazine in 2-propanol selectively with substitution
of the 5-Cl atom to give 5-(1-methylhydrazino)-3,4-
dichloropyridazine in 40% yield. Acidolysis of 5-(1-
methylhydrazino)-3,4-dichloropyridazione in glacial
acetic acid gives 4-(1-methylhydrazino)-5-chloro-6-
pyridazone (yield 10%).
13. Castle, R.N. and Seese, W.S., J. Org. Chem., 1958,
vol. 23, no. 10, pp. 1534 1538.
14. Landguist, J.K. and Thornber, C.W., J. Chem. Soc.,
Perkin Trans. 1, 1973, no. 10, pp. 1114 1117.
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 77 No. 12 2004