A novel and practical animation of 4,5-dichloropyridazin-3-ones via reduction with hydrazine hydrate

Article abstract of DOI:10.1246/cl.2001.54

A novel and simple protocol: the direct amination of 4,5-dichloropyridazinones can be carried out in hydrazine hydrate under mild conditions. 4-Chloro-5-hydrazinopyridazin-3-ones serves as a key intermediate in this reduction.

Full text of DOI:10.1246/cl.2001.54

54
Chemistry Letters 2001
A Novel and Practical Amination of 4,5-Dichloropyridazin-3-ones
via Reduction with Hydrazine Hydrate
Song Cao,† Xuhong Qian,*††, Gonghua Song †,and Xiayu Huang†
† Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology, Shanghai, 200237, P. R. China
†† State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116102, P. R. China
(Received September 14, 2000; CL-000855)
A novel and simple protocol: the direct amination of 4,5-
dichloropyridazinones can be carried out in hydrazine hydrate
under mild conditions. 4-Chloro-5-hydrazinopyridazin-3-ones
serves as a key intermediate in this reduction.
It is known that hydrazine hydrate is a reducing agent
which can reduce aldehydes and ketones to hydrocarbon requir-
ing relatively harsh conditions,1 aromatic nitro compounds to
aromatic amines2 and alkyl halides to corresponding alkanes in
the presence of metal catalyst, respectively.2,3 In this communi-
cation, we like to report a novel and efficient synthesis of 2-
(un)substituted-4-aminopyridazin-3-ones by reduction of 2-
(un)substituted-4,5-dichloropyridazin-3-ones under mild condi-
tions with hydrazine hydrate. During the course of our studies
on pyridrazinones, treatment of 2-tert-butyl-4-chloro-5-(ethoxy-
carbonylmethoxy)-3(2H)-pyridazin-3-one 1 with hydrazine
hydrate in ethanol under the conditions indicated in Scheme 1,
afforded an unexpected product 4b with good yield, whereas
the anticipated compound namely acetylhydrazine 2, was not
obtained. This reaction is very unusual. Alazawe reported that
methoxy at 6-position of the pyridazinone can be replaced by
the hydrazino group.4 From this point, we assumed that the
first step of this reaction was the formation of intermediate 3b.
hydrazine hydrate in ethanol under reflux 6–8 h.
From the literature, conversion of 2a, 2c into 3a, 3c was
accomplished efficiently5,10 when refluxed in ethanol with
hydrazine for short periods of time (1–2 h). Following the
above procedures, reaction of 2b with hydrazine hydrate under
reflux for 1 h, monitoring the course of the reaction on TLC,
gave just a major product which was identified as 2-tert-butyl-
4-chloro-5-hydrazinopyridazin-3-one 3b. Prolonged reaction
time (8 h), or further reaction of the crude product with fresh
hydrazine hydrate, gave complete conversion of 2b to 4b. The
similar products were observed in the reaction of 2a, 2c with
hydrazine in different reaction stage. Those results confirmed
the assumption that 3a-c is an intermediate in the reaction of
2a-c with hydrazine hydrate. The yields, reaction conditions,
substrates and products of 2 → 3, 3 → 4, 2 → 4 were listed on
Table 1.12,13
Aminopyridazinones have been shown to be useful inter-
mediates for the access to amino agricultural chemicals and
pharmaceutical products. General methods lead to amino pyri-
dazinone involving Raney-Ni cleavage of the hydrazino pyri-
dazinone,5 the direct amination of the pyridazinones6–8 and the
substitution of chloropyridazinone with ammonia at enhanced
pressure, 9 but they were much different from the reaction we
metioned above. On the other hand, the dechlorination of
chloropyridazinone should be performed in the presence of pal-
ladium on charcoal.8 To explore this somewhat unusual reac-
tion, we designed the following synthetic Scheme 2. 2-(Un)sub-
stituted-4,5-dichloropyridazin-3-ones 2a-c gave 2-(un)substitut-
ed-4-aminopyridazin-3-ones 4a-c when allowed to react with
In order to explain the formation of 4a-c,14 we suggested
the following mechanism Scheme 3. 3b can be written as 5 and
undergo another hydrazine incorporation in exchange for Cl-4
to form 6. This intermediate, in turn, may loose NH3 to form 7
and tautomerize to 8 which then further looses dinitrogen. The
product 9 of this homolytic fragmentation would then be just a
tautomer of 4b. Harsh conditions may probably not be needed
since carbons 3,4,5 constitute also a 1,3-dicarbonyl system and
C-5 is doubly activated.
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
55
The position of amino was identified on the basis of cou-
pling constants of the 1H NMR spectrum of 4a-c. The coupling
constant of 4a was in complete agreement with the literature
value for the 4-aminopyridazin-3-one ortho coupling constant,8
whereas the meta coupling constant of pyridazinone is small (J
= 3.0 Hz).11 The coupling constants of 4b, 4c were analogous
to that of 4a (J = 4.7 Hz). Homonuclear (1H–1H) correlation
5
W. M. Osner and R. N. Castle, J. Pharm. Sci., 52, 539
(1963).
B. Singh, Heterocycles, 22, 1801 (1984).
W. J. Coates and A. McKillop, Heterocycles, 29, 1077
(1989).
W. J. Coates and A. McKillop, Heterocycles, 35, 1313
(1993).
V. Konecny, S. Kovac, and S. Varkonda, Collect. Czech.
Chem. Commun., 50, 493 (1985).
6
7
8
9
1
further confirmed the conclusions drawn from the H NMR,
and clearly showed the interaction within two ortho protons.
The determination of the position of amino should be helpful to
understand the mechanism of the reduction reaction.
10 F. Reicheneder, K. Dury, and A. Fisher. U.S. Patent
3157646 (1964); Chem. Abstr., 62, 14691c (1965).
11 T. Yamasaki, M. Oda, Y. Okamoto, T. Okawara, and M.
Furukawa, Heterocycles, 43, 1863 (1996).
12 Typical procedure for aminopyidazinones 4: A stirred mix-
ture of the dichloropyridazinone 2 (2.26 mmol), hydrazine
hydrate (22.6 mmol) and ethanol (15 mL) was heated at 85
°C for 8 h, then concentrated to dryness in vacuo and sepa-
rated by chromatography using silica gel with petroleum
ether/ethyl acetate (4/1). (4a was purified by recrystalliza-
tion in H2O).
13 Selected data for 3b: Yield 75%, mp 133–134 °C; IR
1
(cm–1) 3380, 3328, 3170, 1640, 1610, 1420, 1360; H
NMR (500 MHz, CDCl3): δ 1.58 (9H, s, (CH3)3C), 5.76
(2H, br, NH2), 6.68(1H, br, s, NH), 8.17(1H, s, H-6); 13C
NMR(125 MHz, CDCl3): δ 28.8(C-2'), 66.1(C-1'),
107.2(C-4), 125.9(C-5), 146.1(C-6), 158.8(C-3); EI-
MS(70eV): m/z(%): 216(5), 160(52), 125(25), 97(48),
56(74), 41(100), 29(84); Anal. Found: C, 44.24; H, 6.15;
N, 26.17%. Calcd for C8H13ClN4O: C, 44.33; H, 6.05; N,
25.85%. Selected data for 4b: Yield 70%, mp 109–110 °C;
The influence of polar solvents on the yield of the reduc-
tion reactions was also observed. When we used benzene
instead of ethanol as the solvent, the yield of 4b reduced to
40%. Furthermore 4b was formed in only 20% yield by using
anhydrous hydrazine in anhydrous benzene. Those results
showed that polar solvents are favourable to the reaction.
In conclusion, a novel and convenient route has been
developed. Thus this method provides a simple, operationally
easy way for the preparation of these useful intermediates,
which are of potential importance in the pharmaceutical indus-
try and are not easily accessible by previous methods. Studies
are underway to extend the reaction to other heterocycles, as
well as to study in detail the mechanistic features of the new
method.
1
IR (cm–1) 3480, 3400, 3340, 1640, 1600, 1540, 1360; H
NMR (500 MHz, CDCl3): δ 1.69 (9H, s, (CH3)3C), 5.29
(2H, br, NH2), 6.33(1H, d, J = 4.7 Hz, H-5), 7.59(1H, d, J
= 4.7 Hz, H-6); 13C NMR (125 MHz, CDCl3): δ 28.4(C-2'),
65.0(C-1'), 101.6(C-5), 136.7(C-4), 145.4(C-6), 157.7(C-
3); EI-MS(70eV): m/z(%): 167(62), 111(100), 83(30),
57(20), 55(35), 41(47); Anal. Found: C, 57.42; H, 7.93; N,
25.30%. Calcd for C8H13N3O: C, 57.46; H, 7.84; N,
25.13%.
14 According to reference 8, 4a was synthesized by the reac-
tion of 4-amino-6-chloro-3(2H)-pyridazinone, sodium
hydroxide with 10% Pd-C and water, shaked under hydro-
gen at atmospheric pressure, the data of 1H NMR is as fol-
low: 6.18(d, J = 4.7 Hz, 1H, H-5); 6.33( br s, 2H, NH2);
7.47(d, J = 4.7 Hz, 1H, H-6); 12.50(br s, 1H, H-2). The
References and Notes
1
2
M. Huang, J. Am. Chem. Soc., 68, 2487 (1946).
M. D. Bell and H. D. Strutz, EP 621259 (1994); Chem.
Abstr., 122, 9653k (1995).
1
3
4
F. H. Wu, B. N. Huang, and W. Y. Huang, J. Fluorine
Chem., 73,159 (1995).
S. Alazawe and J. A. Elvidge, J. Chem. Soc., Perkin Trans.
1, 1974, 696.
data of H NMR of 4a which was synthesized by our
method IS as follows: 6.17(d, J = 4.7 Hz, 1H, H-5); 6.28(br
s, 2H, NH2); 7.46(d, J = 4.7 Hz, 1H, H-6); 12.50(br s, 1H,
H-2).