Efficient N-arylation of pyridazin-3(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2004.10.003

A variety of substituted pyridazin-3(2H)-ones are directly N-arylated in good yield using lead tetraacetate/zinc chloride in benzene or in substituted benzenes including chloro- and bromobenzene. A variety of substituted pyridazin-3(2H)-ones are directly N-arylated in good yield using lead tetraacetate/zinc chloride in benzene or in substituted benzenes including chloro- and bromobenzene.

Full text of DOI:10.1016/j.tetlet.2004.10.003

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8781–8784
Efficient N-arylation of pyridazin-3(2H)-ones
Jeum-Jong Kim,a Yong-Dae Park,a Su-Dong Cho,b Ho-Kyun Kim,a Hyun A. Chung,a
Sang-Gyeong Lee,c,* J. R. Falckd and Yong-Jin Yoona,*
aDepartment of Chemistry and Environmental Biotechnology, National Core Research Center, Gyeongsang National University,
Chinju 660-701, Korea
bDepartment of Chemistry and Research Institute of Basic Science, Changwon National University, Changwon 641-773, Korea
cDepartment of Chemistry and Research Institute of Life Science, Gyeongsang National University, Chinju 660-701, Korea
dDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Received 21 August 2004; revised 21 September 2004; accepted 4 October 2004
Abstract—A variety of substituted pyridazin-3(2H)-ones are directly N-arylated in good yield using lead tetraacetate/zinc chloride in
benzene or in substituted benzenes including chloro- and bromobenzene.
ꢀ 2004 Elsevier Ltd. All rights reserved.
There is considerable economic and biological interest in
pyridazinones, many of which are known to possess
copper iodide/haloarene/ligand/base;22,23 (ii) cupric ace-
tate/arylboronic acids,24 arylsiloxanes25 or aryllead tri-
acetate26/base; (iii) catalytic cupric trifluoroacetate/
triphenylbismuth bistrifluoroacetate27 or catalytic cupric
acetate/triphenylbismuth bistrifluoroacetate;28 or (iv) Pd
catalysts/ligand/base.29
1–11
usefulactivities in a variety of appiclations.
For
instance, pyridazin-3(2H)-ones with heteroatoms at
position 5, especially those with aryl substituents at N-
2, show potent herbicidalactivity, for example, Chlorid-
azon,1,5,6,9 BAS 44521,1,9 Norflurazon1,7,9 and Pyridate.9
Typically, 2-phenylpyridazin-3(2H)-ones are synthesized
using phenylhydrazine or the corresponding phenylhy-
drazones,12–18 and phenyldiazonium salts.9,19,20 During
the reaction of hydrazines with maleic anhydrides, how-
ever, N-aminomaleimides are formed as a by-product.20
Also, 2-phenyl-4,5-disubstituted-pyridazin-3(2H)-ones
are often transformed into pyrazoles under the vigorous
conditions required for their preparation.21 The low
yields of 2-phenylpyridazin-3(2H)-ones may be due to
the above-mentioned side reactions during the conden-
sation of phenylhydrazines with mucochloric acids.
The direct N-arylation of heterocycles22 represents an
attractive alternative synthetic strategy that would obvi-
ate the aforementioned problems, although to the best
of our knowledge, this approach has not been applied
to substituted pyridazin-3(2H)-ones.
While all of these methods are useful in their own right,
each suffers from one or more limitations including a
lack of generality, poor yields with halogenated sub-
strates, or incompatibility with base-sensitive com-
pounds. Additionally, the preparation of aryllead
triacetates via metalexchange with aryml ercury or tin
is especially inconvenient.30 Herein, we report the effi-
cient N-arylation of substituted-pyridazin-3(2H)-ones
with benzene or benzene derivatives in the presence of
lead tetraacetate/zinc chloride (Scheme 1).
Firstly, we evaluated the direct N-phenylation of
4,5-dichloropyridazin-3(2H)-one (1a) using varying
amounts of lead tetraacetate in refluxing benzene (Table
1). Treatment of 1a with 0.5equiv of lead tetraacetate
gave 4,5-dichloro-2-phenylpyridazin-3(2H)-one (2a) in
32% yield, whereas 1.0–4.0equiv of lead tetraacetate
boosted the yield of 2a moderately (50–57%).
Most direct N-arylations of NH-containing heteroare-
nes are achieved by one of four methods: (i) catalytic
To further increase the yield, the influence of different
acids and bases on the N-phenylation of 1a using lead
tetraacetate (1.2equiv) in refluxing benzene was studied
(Table 2). Most bases (entries 1–4) interfered or com-
pletely suppressed with the reaction. NaH (entry 5)
Keywords: N-Arylation; Pyridazin-3(2H)-ones; Lead tetraacetate; Zinc
chloride.
*
Corresponding authors. Tel.: +82 055 751 6019; fax: +82 055 761
0244 (Y.-J.Y.); e-mail: yjyoon@nongae.gsnu.ac.kr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.003

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J.-J. Kim et al. / Tetrahedron Letters 45 (2004) 8781–8784
Table 3. N-Phenylation of 4-chloropyridazin-3(2H)-ones using lead
tetraacetate (1.2equiv)/ZnCl2 (1equiv)
Y
N
Y
N
Cl
X
Cl
X
R
2 (Yield, %)a
Y
Entry
Pyridazin-3(2H)-
ones
Time (h)
N
N
Pb(OAc)4 /ZnCl2
Cl
X
O
O
Benzene derivatives
+
R'
N
OCH3
Cl
Reflux
O
N
H
1
1b
25
25
21
15
19
2b (68)
N
O
N
H
R
R'
1
2
3
N3
Cl
2
1c
1d
1e
1f
2c (55)
X
H
H
H
H
Y
Cl
OMe
N3
OPh
X
H
Y
Cl
R
H
X
Y
R
1-3
a
2,3
a
R' 2,3
R'
Me
N
O
N
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl Me
Cl NO2
Cl Cl
Cl Br
Cl OMe
h
i
j
k
l
H
H
H
OMe
N3
OPh
H
H
H
H
H
H
H
b
c
d
e
f
b
c
d
e
f
OPh
Cl
3b
2d (37)
N
N
O
H
NO2 Cl
Cl Cl
NO2 Cl
H
Cl
Cl
H
Cl
Cl
H
Me
Cl N(Me)CHO H
m
Cl
NO2
4
2e (71)
g
N
N
O
H
Scheme 1.
Cl
Cl
Cl
5b
2f (59)
N
O
N
H
Table 1. N-Phenylation of 4,5-dichloropyridazin-3(2H)-one (1a) using
varying amounts of lead tetraacetate without ZnCl2
a Isolated yields.
b An unknown product was also detected.
Entry
Pb(OAc)4 (equiv)
Time (h)
2a (Yield, %)a
1
2
3
4
0.5
1.0
2.0
4.0
50
32
33
35
32
50
55
57
4-Chloro-5-methoxypyridazin-3(2H)-one (1b) gave 2b
in 68% yield, 5-azido-4-chloropyridazin-3(2H)-one (1c)
furnished 2c in 55% yield, and the 4,5,6-trisubstituted-
pyridazin-3(2H)-ones 1d, 1e and 1f led to 2d (37%), 2e
(71%) and 2f (59%), respectively.
a Isolated yield.
seemed to have little effect. In contrast, stoichiometric
amounts of ZnCl2 were quite helpful (entries 6–9), with
the maximum benefit occurring with 1equiv. Interest-
ingly, other Lewis acids were detrimental (entries 10–
13).
Encouraged by the preceding results, the combination of
lead tetraacetate/zinc chloride was exploited for the
N-arylation of pyridazinones 1 using various substituted
benzenes to afford 2-phenylpyridazin-3(2H)-ones 2 and
3 (Table 4). As anticipated, toluene gave a regioisomeric
mixture of 2g (32%) and 3g (22%) whereas m-xylene
evolved just 2h (65%).
The applicability of lead tetraacetate/zinc chloride in
refluxing benzene for the N-phenylation of more highly
substituted pyridazin-3(2H)-ones was also investigated
(Table 3).
Even nitrobenzene, which is unreactive towards electro-
philic substitution, yielded 2i (27%) and 3i (34%). Chlo-
robenzene furnished 2j (30%) and 3j (46%) and
bromobenzene analogously gave rise to 2k (24%) and
3k (28%). Methoxybenzene gave 2l (38%) and 3l
(29%). Notably, N-methyl-N-phenylformamide fur-
nished 3m (57%) exclusively.
Table 2. N-Phenylation of 4,5-dichloropyridazin-3(2H)-one (1a) using
lead tetraacetate (1.2equiv) in the presence of a base or an acid
Entry Base or acid Equivalent Time (h) 2a (Yield, %)a
1b
2b
3
K2CO3
Cs2CO3
Et3N
1.0
1.0
1.0
1.0
1.0
0.2
0.5
1.0
2.0
1.0
1.0
1.0
1.0
24
24
48
26
23
48
30
20
20
20
20
30
30
25
14
In view of the results, the C(sp2)–N coupling under our
system occurs between a C–H bond of benzene and the
N–H bond of pyridazin-3(2H)-one.
No reaction
No reaction
4
DMAPc
NaH
5b
6
55
54
70
75
61
In summary, we have developed an efficient, convenient
and direct procedure for the N-arylation of pyridazin-
3(2H)-ones using a wide variety of substituted benzenes.
The catalyst system is compatible with a range of func-
tional groups including phenyl bromides and chlorides.
Further studies involving the application for other nitro-
gen heterocycles containing NH and the detailed mech-
anism are underway in our laboratory.
ZnCl2
ZnCl2
ZnCl2
ZnCl2
AlCl3
7
8
9
d
10
11
12
13
—
d
FeCl3
TiCl4
—
No reaction
No reaction
BF3ÆOEt2
a Isolated yields.
b Starting materialwas recovered.
c 4-(N,N-Dimethylamino)pyridine.
d Unknown products were also detected.
Generalprocedures and data for N-Arylation, 2: A mix-
ture of lead tetraacetate (2.0mmol) in aryl derivatives
was slowly added pyridazine-3(2H)-one (1.82mmol)

J.-J. Kim et al. / Tetrahedron Letters 45 (2004) 8781–8784
Table 4. N-Arylation of 4,5-dichloropyridazin-3(2H)-one (1a) using
8783
Supplementary data
lead tetraacetate (1.2equiv)/ZnCl2 (1equiv) in refluxing substituted
benzene
Supplementary data associated with this article can
found, in the online version, at doi:10.1016/j.tetlet.
2004.10.003.
Entry Substituted benzene Time (h) Products Yield (%)a
1
2
3
4
5
6
7
Toluene
m-Xylene
20
25
11
40
39
20
10
2g (32)
2h (65)
2i (27)
2j (30)
2k (24)
2l (38)
—
3g (22)
—
Nitrobenzene
Chlorobenzene
Bromobenzene
Methoxybenzene
N-Methyl-N-
phenylformamide
3i (34)
3j (46)
3k (28)
3l (29)
3m (57)
References and notes
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4,5-Dichloro-2-phenylpyridazin-3(2H)-one (2a): White
solid; mp 161–162ꢁC; Rf (CH2Cl2) = 0.67; IR (KBr)
3272, 3050, 2922, 1652, 1544, 1408, 1296, 1084, 1072,
1
660cmÀ1; H NMR (CDCl3) d 7.91 (s, 1H), 7.59–7.56
(m, Aro–2H), 7.50–7.47 (m, Aro–2H), 7.44–7.42 (m,
Aro–1H); 13C NMR (CDCl3) d 125.18, 128.89, 128.95,
135.36, 136.11, 136.37, 140.90, 176.63. Anal. Calcd for
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4-Chloro-5-methoxy-2-phenylpyridazin-3(2H)-one (2b):
White solid; mp 153–154 ꢁC; Rf (CH2Cl2) = 0.28; IR
(KBr) 3070, 2970, 2880, 1645, 1610, 1480, 1460, 1400,
1300, 1240, 1150, 1100, 950, 830, 760, 680cmÀ1 1H
;
NMR (CDCl3) d 7.95 (s, 1H), 7.58–7.54 (m, Aro–2H),
7.50–7.39 (m, Aro–3H), 4.09 (s, 3H); 13C NMR (CDCl3)
d 57.82, 117.29, 125.36, 127.13, 128.51, 128.80, 141.29,
154.70, 158.30. Anal. Calcd for C11H9ClN2O2: C, 55.83;
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5-Azido-4-chloro-2-phenylpyridazin-3(2H)-one
(2c):
White solid; mp. 99–100ꢁC; Rf (CH2Cl2) = 0.38; IR
(KBr) 3070, 2980, 2950, 2890, 2150, 1660, 1600, 1500,
1
1380, 1330, 1310, 1150, 840, 780, 700 cmÀ1; H NMR
(CDCl3) d 7.76 (s, 1H), 7.58–7.55 (m, Aro–2H), 7.51–
7.41 (m, Aro–3H); 13C NMR (CDCl3) d 123.35,
125.17, 128.70, 128.86, 130.27, 139.11, 140.96, 156.81.
Anal. Calcd for C10H6ClN5O: C, 48.50; H, 2.44; N,
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Acknowledgements
This work was supported by a grant from the Korea Sci-
ence and Engineering Foundation (KOSEF) to the
EnvironmentalBiotechnool gy NationalCore Research
Center (grant #: R15-2003-012-02001-0).

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