Functionalization of the pyridazin-3(2H)-one ring via palladium-catalysed aminocarbonylation

Article abstract of DOI:10.1016/j.tet.2012.07.030

5-Iodo- and 4,5-dibromo-2-methylpyridazin-3(2H)-ones were aminocarbonylated in the presence of various amines including amino acid methyl esters in a palladium-catalysed reaction. The iodo derivative afforded the corresponding amides with complete conversion and high isolated yields. The dibromo derivative has shown unexpectedly high reactivity in this reaction, resulting in 4,5-dicarboxamides using primary amines as N-nucleophiles. Monoaminocarbonylation has not been observed, i.e., neither 4-bromo-5- carboxamide nor 4-carboxamido-5-bromo derivatives have been formed. However, the use of secondary amines such as piperidine and morpholine resulted in the formations of mixtures of amino-substituted bromopyridazinones. That is, no carbon monoxide insertion took place in these cases. Some mechanistic details of the formation of aminocarbonylation and amination products are also discussed.

Full text of DOI:10.1016/j.tet.2012.07.030

Tetrahedron 68 (2012) 7855e7860
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Functionalization of the pyridazin-3(2H)-one ring via palladium-catalysed
aminocarbonylation
a
b
b
b
a,
*
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Attila Takacs , Andrea Czompa , Gabor Krajsovszky , Peter Matyus , Laszlo Kollar
a
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Department of Inorganic Chemistry, University of Pecs and Janos Szentagothai Science Center, H-7624 Pecs, PO Box 266, Hungary
Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7., H-1092 Budapest, Hungary
b
}
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2012
Received in revised form 15 June 2012
Accepted 10 July 2012
Available online 17 July 2012
5-Iodo- and 4,5-dibromo-2-methylpyridazin-3(2H)-ones were aminocarbonylated in the presence of
various amines including amino acid methyl esters in a palladium-catalysed reaction. The iodo derivative
afforded the corresponding amides with complete conversion and high isolated yields. The dibromo
derivative has shown unexpectedly high reactivity in this reaction, resulting in 4,5-dicarboxamides using
primary amines as N-nucleophiles. Monoaminocarbonylation has not been observed, i.e., neither
4-bromo-5-carboxamide nor 4-carboxamido-5-bromo derivatives have been formed. However, the use
of secondary amines such as piperidine and morpholine resulted in the formations of mixtures of amino-
substituted bromopyridazinones. That is, no carbon monoxide insertion took place in these cases. Some
mechanistic details of the formation of aminocarbonylation and amination products are also discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aminocarbonylation
Carbon monoxide
Palladium
Pyridazin-3(2H)-one
Amino acid
1. Introduction
Recently, a facile synthetic procedure for the synthesis of iodo-
substituted pyridazin-3(2H)-ones from the corresponding chloro
Pyridazin-3(2H)-ones and their fused ring derivatives have
gained much attention recently due to their application as syn-
thetic auxiliaries.1 Their increasing interest is also due to their
pharmacological importance. Pyridazin-3(2H)-one derivatives have
been tested as selective histamine receptor inverse antagonists,2
phosphodiesterase inhibitors (PDE3, PDE4),3,4 agonists for formyl
derivatives was published.13 As a part of our continuing interest in
the systematic investigation of palladium-catalysed carbonylation
reactions, the aminocarbonylation of iodo- and bromopyridazin-
3(2H)-ones to give the corresponding carboxamides is reported,
which was expected to open a direct route to otherwise not easily
accessible oxopyridazinecarboxamides.
peptide receptors5 and some compounds show excellent
a-adre-
noceptor blocking properties, one of which has entered Phase II
clinical studies as a potential drug candidate for the treatment of
benign prostatic hyperplasia.
2. Results and discussion
Among the wide variety of synthetic reactions the application of
organometallic reagents such as Grignard-reagents of different
nucleophilicity,6,7 and especially, that of homogeneous catalysis
play an important role in the functionalization of pyridazinones. As
recent examples, the application of SuzukieMiyaura reaction for
synthesis of 4(5)-mono and 4,5-diarylated pyridazin-3(2H)-ones8
and that of the 4,6-diaryl/heteroarylpyridazinones9 and 5,6-
diarylpyridazinones10 should be mentioned. A Suzuki coupling
was used as a key reaction in a multistep synthesis of azecine ring
systems.11 An intramolecular Heck reaction proved to be very effi-
cient for the synthesis of 5H-pyridazino[4,5-b]indoles and its
benzofurane analogues.12
2.1. Aminocarbonylation of 5-iodo-2-methylpyridazin-3(2H)-
one (1) leading to 5-carboxamido-2-methylpyridazin-3(2H)-
ones (2)
5-Iodo-2-methylpyridazin-3(2H)-one (1) was reacted with N-
nucleophiles such as tert-butylamine (a) and piperidine (b) under
atmospheric carbon monoxide pressure in DMF in the presence
palladium(0) catalysts generated in situ from palladium(II) acetate
catalytic precursor (Scheme 1). It is worth noting that although the
reduction of Pd(II) precursors to Pd(0) species has been proved in
the presence of various phosphines while they have been oxidised
to P(V) derivatives (monophosphine oxides or diphosphine oxide/
hemioxide),14e16 the mechanism of reduction under reductive
conditions (carbon monoxide, primary or secondary amines) is still
not known.
ꢀ
* Corresponding author. E-mail address: kollar@ttk.pte.hu (L. Kollar).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.030

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A. Takacs et al. / Tetrahedron 68 (2012) 7855e7860
7856
of aminocarbonylation reactions (Scheme 2, Table 2). The two types
of N-nucleophiles led to completely different products.
O
O
CO, HNR'R"
H3C
H3C
The use of a, e and f resulted in the formation of dicarboxamides
4a, 4e and 4f, respectively (Table 2, entries 1, 2, 6, 9e11). Practically
complete conversion was obtained with a in 24 h, but longer re-
action times were needed to obtain the target compounds in ac-
ceptable yields using amino acid esters (e and f) as N-nucleophiles.
The diamides were isolated in moderate to high yields in all cases.
Diamides were obtained even in those cases where the amine
nucleophiles were used in sub-stoichiometric amounts (entries 7
and 8).
It is worth noting that the pyridazine-based dibromo substrate
(3) has shown much higher reactivity towards palladium-catalysed
aminocarbonylation than bromoarenes or bromoalkenes ever
tested in the same reaction under similar conditions.17,18 The con-
version and isolated yield data closely match those obtained with
the corresponding iodo derivatives (iodoaromatics, iodoalkenes) or
triflates (aryl triflates, enol-triflates). (However, the application of
the less basic primary amine (d) did not lead to the corresponding
diamides or amines in isolable yields, that is, a mixture of some
minor products was obtained.). The high reactivity of 4,5-
dibromopyridazinone we observed in an aminocarbonylation re-
N
N
N
N
Pd(OAc)2 / PPh3
NR'R"
I
O
2
1
R' R"
a
b
H
tBu
-(CH2)5-
d
e
H
H
Ph
CH(CH3)COOCH3
CH2COOCH3
f
H
g
-CH(COOCH3)(CH2)3-
Scheme 1. The synthesis of 5-carboxamido-2-methylpyridazin-3(2H)-one derivatives
via the aminocarbonylation reaction.
Highly selective reactions were observed with all primary and
secondary amines, such as tert-butylamine (a), piperidine (b), an-
iline (d), methyl alaninate (e), methyl glycinate (f) and methyl
prolinate (g) resulting in the exclusive formation of the corre-
sponding 5-carboxamides (2ae2g). Accordingly, all compounds
were isolated in good yields even without further optimization.
Practically complete conversion was achieved both under atmo-
spheric and high (40 bar) carbon monoxide pressures (Table 1,
entries 1e4). Unlike the aminocarbonylation of iodoarenes and aryl
triflates no double carbon monoxide insertion was observed.17 That
is, the corresponding 2-oxocarboxamides were even not detected.
Mild reaction conditions could be used efficiently in the presence of
the less nucleophilic amine (d) (entry 5) and amino acid esters
(eeg) (entries 6e8) as N-nucleophiles. This sharp difference be-
tween the aminocarbonylation of conventional iodoarenes (e.g.,
iodobenzene) and iodopyridazinones can be explained by the dif-
ferent electronic structure of the Pd-acyl intermediates. That is, the
action might be related to its p-deficient nature and the increased
electrophilicity of both its 4- and 5-positions.
Contrary to primary amines, direct amination instead of ami-
nocarbonylation was observed with secondary amines (b and c).
Monoamination took place with both amines either in position-4 or
-5 and accordingly, both 5 and 50 were isolated from the same re-
action mixture (Table 2, entries 3e5). The position of the amino and
bromo substituents on the pyridazinone ring, resulted in
regioisomers of closely related structure, was determined by de-
tailed 2D NMR measurements. Surprisingly, the ‘second’ bromo
substituent was not substituted. The corresponding amide or di-
amide derivatives (4) could not be detected either by GCeMS or
NMR, i.e., no carbon monoxide insertion leading to the expected
carboxamides took place. Comparing the reactivity of the iodo-
pyridazinone and bromopyridazinone, it should be mentioned that
the latter substrate is much sensitive towards the basicity of the N-
nucleophile. Consequently, the most basic secondary amines (b,c)
react directly with the palladium(II)earyl species (see below)
without the insertion of carbon monoxide. The application of the N-
nucleophile with lowest basicity (d) resulted in the formation of no
compounds in an isolable amount.
The formation of the dicarboxamides and amines from the
dibromopyridazino derivative (3) can be interpreted by a simplified
mechanism depicted in Scheme 3.
The substrate (3) reacts with the coordinatively unsaturated
palladium(0) complex, formed in situ, resulting in arylepalladium
intermediate (A) via oxidative addition. It is followed by carbon
monoxide coordination leading to carbonyl complex (B) and the
insertion of carbon monoxide into the palladium(II)earyl bond. The
formed palladium-acyl derivatives (C) are intercepted by the pri-
2-methylpyridazin-3(2H)-one-5-oyl-palladium(II)
intermediate
(the corresponding Pd-acyl complex) is reluctant to form the acyl-
carbamoyl complex, that might lead to the double carbonylated
derivatives via reductive elimination.
Table 1
Palladium-catalysed aminocarbonylation of 1a,b
Entry
Amine
p(CO) [bar]
Isolated yieldc (amide) [%]
1
2
3
4
5
6
7
8
a
a
b
b
d
e
f
1
40
1
40
1
1
1
1
79 (2a)
67 (2a)
70 (2b)
68 (2b)
54 (2d)
66 (2e)
54 (2f)
66 (2g)
g
a
Reaction conditions: Pd(OAc)2, (0.025 mmol), PPh3 (0.05 mmol), substrate (1)
(1.0 mmol), a (3.0 mmol) (or b (1.5 mmol), d (2.0 mmol), eeg (1.1 mmol)), trie-
thylamine (0.5 mL), DMF (10 mL); temperature: 50 ꢀC, reaction time: 24 h.
mary amines resulting in the formation of
a monobromo-
monocarboxamido intermediate. The abstraction of HBr with trie-
thylamine provides the ‘starting’ palladium(0) complex via re-
ductive elimination. In the ‘second’ cycle (Cycle-II), the oxidative
addition of the monobromo intermediate provides the palla-
diumearyl complex (A0), which reacts further via the palladium
terminal carbonyl (B0) and palladium-acyl (C0) intermediate to
dicarboxamide 4 as described for the analogous ‘first’ cycle (Cycle-I,
AeBeC).
b
Practically complete conversion (>99%) determined by GCeMS was obtained in
all cases.
c
Based on the amount of the substrate (1) used.
2.2. Aminocarbonylation of 4,5-dibromo-2-methylpyridazin-
3(2H)-one (3) leading to 4,5-dicarboxamido-2-
methylpyridazin-3(2H)-ones (4)
However, in case of the secondary amines, the palladiumearyl
intermediates (the oxidative addition products A and A00) might
react directly with the N-nucleophiles resulting in the bromo-
amino products (5 and 50, respectively). That is, unlike the above
two ‘carbonylation cycles’ (Cycle-I and Cycle-II) the carbon
4,5-Dibromo-2-methylpyridazin-3(2H)-one (3) was reacted
with primary amines such as tert-butylamine (a), aniline (d),
methyl alaninate (e), methyl glycinate (f), as well as secondary
amines such as piperidine (b) and morpholine (c) in the next series

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A. Takacs et al. / Tetrahedron 68 (2012) 7855e7860
7857
O
H3C
H3C
Br
N
N
O
O
O
NR'R"
H3C
H3C
Br
Br
5
CO, HNR'R"
N
N
NR'R"
NR'R"
N
N
+
O
Pd(OAc)2 / PPh3
NR'R"
Br
N
O
3
4
N
R'
H
R"
Bu
a
b
c
d
e
t
5'
-(CH2)5-
-(CH2)2O(CH2)2-
H
H
Ph
CH(CH3)COOCH3
CH2COOCH3
f
H
Scheme 2. The synthesis of 4,5-dicarboxamido-2-methylpyridazin-3(2H)-one derivatives via an aminocarbonylation reaction.
Table 2
The appropriate choice of the reaction conditions enabled the
isolation of all above-mentioned compounds including the minor
products.
Palladium-catalysed aminocarbonylation of 3a
Entry
Amine
3/amine
p(CO)
R. time
[h]
Conversionb,c
[%]
Isolated
molar ratio
[bar]
yieldd [%]
1
2
3
a
a
b
1:6
1:6
1:3
1
40
1
24
24
24
>98 (4a)
73 (4a)
62 (4a)
52 (5b);
17 (50b)
50 (5b);
19 (50b)
68 (5c);
17 (50c)
45 (4e)
n.d.
>98 (4a)
4. Experimental
>98 (5b, 50b)
4.1. General procedures
4
5
b
c
1:3
1:3
40
1
24
24
>98(5b, 50b)
>98 (5c, 50c)
1H and 13C NMR spectra were recorded in CDCl3 on a Varian
Inova 400 spectrometer at 400.13 MHz and 100.62 MHz, re-
spectively. Chemical shifts
6
7
8
9
10
11
e
e
e
e
f
1:2.2
1:1.1
1:1.1
1:2.2
1:2.2
1:2.2
1
40
40
40
40
40
168
24
69
24
24
69
88 (4e)
50 (4e)
52 (4e)
90 (4e)
83 (4f)
>98 (4f)
d are reported in parts per million rela-
tive to CHCl3 (7.26 and 77.00 ppm for 1H and 13C, respectively).
Elemental analyses were measured on an 1108 Carlo Erba appara-
tus. Samples of the catalytic reactions were analysed with a Hewlett
Packard 5830A gas chromatograph fitted with a capillary column
coated with OV-1. The FTIR spectra were taken in KBr pellets using
an IMPACT 400 spectrometer (Nicolet) applying a DTGS detector in
the region of 400e4000 cmꢁ1, the resolution was 4 cmꢁ1. The
amount of the samples was ca. 0.5 mg.
15 (4e)
65 (4e)
n.d.
f
52 (4f)
a
Reaction conditions: Pd(OAc)2 (0.025 mmol), PPh3 (0.05 mmol), substrate (3)
(1.0 mmol), triethylamine (0.5 mL), DMF (10 mL); temperature: 50 ꢀC.
b
The products (including minor products) are indicated in brackets.
Determined by GC and GCeMS.
Based on the amount of the substrate (3) used.
c
d
The substrates 112 and 320,21 were synthesised as described
previously. Amines (aed) and amino acid esters (e, f, g) were
purchased from SigmaeAldrich. Silica gel 60 (Merck,
0.063e0.200 mm) was used for column chromatography.
monoxide insertion is not operative. A base (NEt3) is also needed in
these ‘amination catalytic cycles’ (Cycle-III and Cycle-IV) as a hy-
drogen bromide acceptor in order to re-form the coordinatively
unsaturated palladium(0) species. It has to be added that the amino
products, including the two regioisomers (5 and 50) could also be
formed by a direct nucleophilic substitution reaction without the
formation of Pd-intermediates.19
4.2. Aminocarbonylation of 5-iodo-2-methylpyridazin-3(2H)-
one (1) under atmospheric carbon monoxide pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3
(13.1 mg, 0.050 mmol), 5-iodo-2-methylpyridazin-3(2H)-one
(236 mg, 1.0 mmol), 3 mmol of a (or the amount of amine given in
Table 1) and triethylamine (0.5 mL) were dissolved in DMF (10 mL)
under argon in a 100 mL three-necked flask equipped with a gas
inlet and a reflux condenser with a balloon at the top. The at-
mosphere was changed to carbon monoxide. The reaction was
conducted for the given reaction time upon stirring at 50 ꢀC and
analysed by GCeMS. The mixture was then concentrated and
evaporated to dryness. The residue was dissolved in chloroform
(20 mL) and washed with water (2ꢂ20 mL). The organic phase
was dried over Na2SO4 and evaporated to a solid material or to
a waxy residue. All compounds were subjected to column chro-
matography using the solvent mixture indicated for the Rf values
in Section 4.6.
3. Conclusions
It has been shown that both iodo- and bromopyridazinones can
be efficiently transformed into the corresponding carboxamides via
a
palladium-catalysed aminocarbonylation. Especially the un-
expectedly high reactivity of the dibromopyridazinone derivative
compared to conventional bromoarene test substrates should be
emphasised. This method provides simple and efficient way to
obtain new pyridazinecarboxamides. It is worth noting that under
same conditions, the dibromopyridazinone substrate reacts directly
with secondary amines resulting in the formation of the bromo-
amino isomers instead of carboxamides, which perhaps might
also be utilized for amination of such substrates, as a mild alter-
native to classical nucleophilic substitution.

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A. Takacs et al. / Tetrahedron 68 (2012) 7855e7860
Scheme 3. The simplified mechanism for the palladium-catalysed transformations of 3.
4.3. Aminocarbonylation of 5-iodo-2-methylpyridazin-3(2H)-
4.6. Characterization of the products
one (1) under high carbon monoxide pressure
4.6.1. 5-(N-tert-Butylcarboxamido)-2-methylpyridazin-3(2H)-one
(2a). Yield: 166 mg (79%); white solid, mp 152e153 ꢀC. Found: C,
57.20; H, 7.41; N, 19.89. C10H15N3O2 requires C, 57.40; H, 7.23; N,
20.08%. Rf (50% EtOH/CHCl3) 0.34; dH (400 MHz, CDCl3) 8.13 (1H, d,
1.5 Hz, AreH), 7.25 (1H, d,1.5 Hz, AreH), 6.1 (1H, br s, NH), 3.77 (3H,
s, NeCH3), 1.45 (9H, s, C(CH3)3); dC (100.6 MHz, CDCl3) 162.0, 160.3,
The above amounts of catalyst, substrate and amines were dis-
solved in DMF (10 mL) under argon in a 100 mL autoclave. The at-
mosphere was changed to carbon monoxide and the autoclave was
pressurized to 40 bar with carbon monoxide. The reaction was
conducted for the given reaction time upon stirring at 50 ꢀC and
analysed by GCeMS. The work-up procedure was identical to that
described in Section 4.2.
138.2, 135.1, 125.4, 52.4, 40.2, 28.5; IR (KBr,
n
(cmꢁ1)): 3300 (v br,
NH), 1669 (CH3NCO), 1653 (CON). MS m/z (rel int.): 209 (43, Mþ),
194 (55), 154 (57), 137 (100), 109 (25), 57 (16).
4.4. Aminocarbonylation of 4,5-dibromo-2-methylpyridazin-
3(2H)-one (3) under atmospheric carbon monoxide pressure
4.6.2. 5-(N,N-Pentan-1,5-diylcarboxamido)-2-methylpyridazin-
3(2H)-one (2b). Yield: 155 mg (70%); beige solid, mp 119e120 ꢀC.
Found: C, 59.60; H, 7.01; N, 18.80. C11H15N3O2 requires C, 59.71; H,
6.83; N, 18.99%. Rf (50% EtOAc/CHCl3) 0.27; dH (400 MHz, CDCl3)
7.72 (1H, d, 1.5 Hz, AreH), 6.79 (1H, d, 1.5 Hz, AreH), 3.77 (3H, s,
NeCH3), 3.68e3.63 (2H, m, NeCH2), 3.37e3.33 (2H, m, NeCH2),1.67
(4H, br s, 2CH2), 1.57e1.53 (2H, m, CH2); dC (100.6 MHz, CDCl3)
163.5, 159.8, 139.2, 134.2, 125.5, 48.3, 42.9, 40.2, 26.5, 25.3, 24.1; IR
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3
(13.1 mg, 0.05 mmol), 4,5-dibromo-2-methylpyridazin-3(2H)-one
(268 mg,1.0 mmol), tert-butylamine (a) (6 mmol) (or the amount of
amine given in Table 2) and triethylamine (0.5 mL) were dissolved
in DMF (10 mL) under argon in a 100 mL three-necked flask
equipped with a gas inlet, reflux condenser with a balloon at the
top. The atmosphere was changed to carbon monoxide. The re-
action was conducted for the given reaction time upon stirring at
50 ꢀC and analysed by GCeMS. The work-up procedure was iden-
tical to that described in Section 4.2.
(KBr
n
(cmꢁ1)): 1667 (CH3NCO), 1630 (CON); MS m/z (rel int.): 221
(83, Mþ), 193 (7), 178 (27), 150 (100), 137 (31), 109 (46), 84 (49).
4.6.3. 5-(N-Phenylcarboxamido)-2-methylpyridazin-3(2H)-one
(2d). Yield: 124 mg (54%), off-white solid, mp 218e219 ꢀC. Found:
C, 62.66; H, 4.97; N, 18.22. C12H11N3O2 requires C, 62.84; H, 4.84; N,
18.33%. Rf (50% EtOAc/CHCl3) 0.38; dH (400 MHz, CDCl3) 9.50 (1H, br
s, NH), 8.36 (1H, s, AreH), 7.86 (2H, d, 7.4 Hz, Ph(ortho)), 7.66 (1H, s,
AreH), 7.41 (2H, t, 7.4 Hz, Ph(meta)), 7.20 (1H, t, 7.4 Hz, Ph(para)),
3.86 (3H, s, NeCH3); dC (100.6 MHz, CDCl3) 160.9, 160.7, 138.0, 137.6,
4.5. Aminocarbonylation of 4,5-dibromo-2-methylpyridazin-
3(2H)-one (3) under high carbon monoxide pressure
The above amounts of catalyst, substrate and amines were dis-
solved in DMF (10 mL) under argon in a 100 mL autoclave. The at-
mosphere was changed to carbon monoxide and the autoclave was
pressurized to 40 bar with carbon monoxide. The reaction was
conducted for the given reaction time upon stirring at 50 ꢀC and
analysed by GCeMS. The work-up procedure was identical with
those described in Section 4.2.
135.8, 129.0, 125.7, 125.2, 120.4, 40.5; IR (KBr
n
(cmꢁ1)): 3336 (v,
NH), 1681.5 (CH3NCO), 1649 (CON); MS m/z (rel int.): 229(100, Mþ),
212 (5), 200 (11), 171 (5), 137 (9), 120 (5), 109 (18), 92 (5), 77 (13).
4.6.4. 5-(N-(1-(Methoxycarbonyl)ethyl)carboxamido)-2-
methylpyridazin-3(2H)-one (2e). Yield: 158 mg (66%), beige solid,

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A. Takacs et al. / Tetrahedron 68 (2012) 7855e7860
7859
mp 138e139 ꢀC. Found: C, 50.03; H, 5.52; N, 17.69. C10H13N3O4 re-
quires C, 50.21; H, 5.48; N, 17.56%. Rf (50% EtOAc/CHCl3) 0.36; dH
(400 MHz, CDCl3) 8.19 (1H, d, 2.0 Hz, AreH), 7.68 (1H, d, 6.9 Hz,
NH), 7.42 (1H, d, 2.0 Hz, AreH), 4.73 (1H, dq, 7.3 Hz, 6.9 Hz, NeCH),
3.81 (3H, s, OeCH3), 3.79 (3H, s, NeCH3), 1.56 (3H, d, 7.3 Hz,
CHeCH3); dC (100.6 MHz, CDCl3) 172.8, 162.4, 160.3, 136.6, 134.9,
requires C, 45.88; H, 4.74; N, 16.46%. Rf (EtOAc) 0.29; dH (400 MHz,
CDCl3) 9.86 (1H, s, NH), 7.9 (1H, s, AreH), 6.86 (1H, s, NH), 4.23 (2H,
d, 5.2 Hz, NeCH2), 4.16 (2H, d, 5.2 Hz, N-CH2), 3.88 (3H, s, OeCH3),
3.78 (3H, s, NeCH3), 3.76 (3H, s, NeCH3); dC (100.6 MHz, CDCl3)
169.7, 169.3, 164.9, 161.3, 159.8, 140.7, 135.6, 124.2, 52.4 (double
intensity), 41.6, 41.4, 41.3; IR (KBr
n
(cmꢁ1)): 3324 (v br, NH), 1755
126.3, 52.6, 48.7, 40.3, 17.7; IR (KBr
n
(cmꢁ1)): 3299 (v br, NH), 1747
(COO), 1674 (CH3NCO), 1670 (CON); MS m/z (rel int.): 340 (1.8, Mþ),
309 (1.8), 281 (3.5), 252 (74),192 (100),164 (7),136 (12),110 (19), 93
(12), 59(17).
(COO), 1677.5 (CH3NCO), 1655 (CON); MS m/z (rel int.): 239 (23,
Mþ), 208 (2), 180 (85), 137 (100), 124 (6), 109 (19), 66 (8).
4.6.5. 5-(N-(Methoxycarbonylmethyl)carboxamido)-2-
methylpyridazin-3(2H)-one (2f). Yield: 121 mg (54%), brown solid,
mp 172e173 ꢀC. Found: C, 47.78; H, 4.80; N, 18.51. C9H11N3O4 re-
quires C, 48.00; H, 4.92; N, 18.66%. Rf (50% EtOAc/CHCl3) 0.19; dH
(400 MHz, CDCl3) 8.19 (1H, d, 1.9 Hz, AreH), 7.78e7.63 (1H, m, NH),
7.34 (1H, d, 1.9 Hz, AreH), 4.21 (2H, d, 5.1 Hz, NeCH2), 3.81 (3H, s,
OeCH3), 3.8 (3H, s, NeCH3); dC (100.6 MHz, CDCl3) 169.7, 163.0,
4.6.10. 4-Bromo-5-(N,N-pentan-1,5-diylamino)-2-methylpyridazin-
3(2H)-one (5b). Yield: 142 mg (52%), yellow viscous material.
Found: C, 44.02; H, 5.40; N, 15.19. C10H14N3OBr requires C, 44.13; H,
5.19; N,15.44%. Rf (20% EtOAc/CHCl3) 0.62; dH (400 MHz, CDCl3) 7.42
(1H, s, AreH), 3.66 (3H, s, NeCH3), 3.26e3.21 (4H, m, 2NeCH2),
1.63e1.56 (6H, m, 3CH2); dC (100.6 MHz, CDCl3) 158.9, 151.2, 130.8,
109.2, 50.6, 40.5, 25.8, 23.8; IR (KBr
n
(cmꢁ1)): 1636 (CH3NCO); MS
160.3, 136.6, 134.7, 126.4, 52.6, 41.6, 40.4; IR (KBr
n
(cmꢁ1)): 3348 (v
m/z (rel int.): 271/273 (80, Mþ), 230(11), 192 (100), 164 (9), 146 (13),
br, NH), 1748 (COO), 1653 (vs, CH3NCOþCON); MS m/z (rel int.): 225
124 (11), 84 (9), 55 (16).
(100, Mþ), 194 (3), 166 (33), 137 (95), 109 (41), 88 (15), 66 (15).
4.6.11. 5-Bromo-4-(N,N-pentan-1,5-diylamino)-2-methylpyridazin-
3(2H)-one (50b). Yield: 52 mg (19%), yellow viscous material.
Found: C, 44.22; H, 5.33; N, 15.24. C10H14N3OBr requires C, 44.13; H,
5.19; N,15.44%. Rf (20% EtOAc/CHCl3) 0.86; dH (400 MHz, CDCl3) 7.66
(1H, s, AreH), 3.68 (3H, s, NeCH3), 3.42e3.35 (4H, m, NeCH2),
1.75e1.60 (6H, m, 3CH2); dC (100.6 MHz, CDCl3) 159.2, 146.6, 140.3,
4.6.6. 5-(N,N-(1-Methoxycarbonyl-butan-1,4-diyl)-carboxamido)-2-
methylpyridazin-3(2H)-one (2g), (ca. 5:1 mixture of two C(O)N ro-
tamers). Yield: 176 mg (66%), orange viscous material. Found: C,
54.21; H, 5.81; N, 15.68. C12H15N3O4 requires C, 54.33; H, 5.70; N,
15.84%. Rf (50% EtOAc/CHCl3) 0.19; dH (400 MHz, CDCl3) 7.81/7.68
(major/minor), (1H, d, 1.9 Hz, AreH), 6.92/6.70 (major/minor) (1H,
d, 1.9 Hz, AreH), 4.57e4.54/4.35e4.32 (major/minor) (1H, m,
NeCH), 3.73 (3H, s, NeCH3), 3.70/3.59 (major/minor) (3H, s,
OeCH3), 3.61e3.57 (1H, m, NeCHaHb), 3.47e3.43 (1H, m,
NeCHaHb), 2.06e1.80 (4H, m, 2CH2); dC (100.6 MHz, CDCl3) 171.7/
171.6 (minor/major), 164.1/163.4 (minor/major), 159.7/159.6 (ma-
jor/minor), 139.6/138.6 (minor/major), 134.2, 126.3/125.1 (major/
minor), 60.7/59.1 (minor/major), 52.8/52.4 (minor/major), 49.3/
46.5 (major/minor), 40.2, 31.2/29.0 (minor/major), 25.0/22.4 (ma-
110.8, 51.3, 40.0, 26.6, 24.2; IR (KBr
n
(cmꢁ1)): 1636 (CH3NCO); MS
m/z (rel int.): 271/273 (36, Mþ), 242/244 (10), 216/218 (14), 192 (41),
162 (10), 109 (28), 84 (100), 52 (21).
4.6.12. 4-Bromo-5-(N,N-3-oxapentan-1,5-diylamino)-2-
methylpyridazin-3(2H)-one (5c). Yield: 187 mg (68%), yellow solid,
mp 134e135 ꢀC. Found: C, 39.29; H, 4.60; N, 15.08; C9H12N3O2Br
requires C, 39.44; H, 4.41; N, 15.33%. Rf (30% EtOAc/CHCl3) 0.31; dH
(400 MHz, CDCl3) 7.41 (1H, s, AreH), 3.75e3.68 (4H, m, 2OeCH2),
3.65 (3H, s, NeCH3), 3.30e3.23 (4H, m, 2NeCH2); dC (100.6 MHz,
jor/minor); IR (KBr
n
(cmꢁ1)): 1747 (COO), 1669 (CH3NCO), 1655
(CON); MS m/z (rel int.): 265 (13, Mþ), 234 (2), 222 (9), 206 (100),
CDCl3) 158.5, 150.2, 130.1, 110.8, 66.4, 49.4, 40.5; IR (KBr n
(cmꢁ1)):
150 (4), 137 (79), 109 (16), 66 (5).
1629 (CH3NCO); MS m/z (rel int.): 273/275 (76, Mþ), 215/217 (17),
194 (100), 166 (19), 146 (17), 108 (14), 86 (2), 65 (16).
4.6.7. 4,5-Bis(N-tert-butylcarboxamido)-2-methylpyridazin-3(2H)-
one (4a). Yield: 226 mg (73%), white solid, mp 194e195 ꢀC. Found:
C, 58.49; H, 7.94; N, 18.03. C15H24N4O3 requires C, 58.42; H, 7.84; N,
18.17%. Rf (50% EtOAc/CHCl3) 0.50; dH (400 MHz, CDCl3) 7.93 (1H, br s,
NH), 7.89 (1H, s, AreH), 6.72 (1H, br s, NH), 3.78 (3H, s, N-CH3); 1.41
(18H, s, C(CH3)3); dC (100.6 MHz, CDCl3) 163.3, 161.2, 159.3, 138.6,
4.6.13. 5-Bromo-4-(N,N-3-oxapentan-1,5-diylamino)-2-methylpyr-
idazin-3(2H)-one (50c). Yield: 47 mg (17%), pale yellow solid, mp
121e123 ꢀC. Found: C, 39.26; H, 4.55; N, 15.19. C9H12N3O2Br re-
quires C, 39.44; H, 4.41; N, 15.33%. Rf (30% EtOAc/CHCl3) 0.43; dH
(400 MHz, CDCl3) 7.68 (1H, s, AreH), 3.82e3.75 (4H, m, 2OeCH2),
3.68 (3H, s, NeCH3), 3.51e3.44 (4H, m, 2NeCH2); dC (100.6 MHz,
136.4, 128.2, 52.3, 52.1, 40.8, 28.4, 28.3; IR (KBr n
(cmꢁ1)): 3272 (v br,
NH), 1673 (CH3NCO), 1643 (CON); MS m/z (rel int.): 308 (8, Mþ), 293
(3), 251 (11), 236 (22), 209 (7), 180 (100), 162 (8), 58 (30).
CDCl3) 158.7, 145.2, 140.0, 111.5, 67.4, 50.1, 40.0; IR (KBr n
(cmꢁ1)):
1629 (CH3NCO); MS m/z (rel int.): 273/275 (9, Mþ), 255/257 (36),
188/190 (100), 162 (11), 136 (15), 109 (73), 86 (15), 52 (69).
4.6.8. 4,5-Bis(N-(1-(methoxycarbonyl)ethyl)carboxamido)-2-
methylpyridazin-3(2H)-one (4e). Yield: 230 mg (65%), beige solid,
mp 105e106 ꢀC. Found: C, 48.70; H, 5.31; N, 15.02. C15H20N4O7 re-
quires C, 48.91; H, 5.47; N, 15.21%. Rf (EtOAc) 0.55; dH (400 MHz,
CDCl3) 9.76 (1H, d, 6.9 Hz, NH), 7.86 (1H, s, AreH), 6.75 (1H, d,
6.9 Hz, NH), 4.74 (1H, dq, 7.2 Hz, NeCH), 4.65 (1H, dq, 7.2 Hz, 6.9 Hz,
NeCH), 3.85 (3H, s, OeCH3), 3.75 (3H, s, NeCH3), 3.73 (3H, s,
NeCH3),1.5 (3H, d, 7.2 Hz, CHeCH3),1.46 (3H, d, 7.2 Hz, CHeCH3); dC
(100.6 MHz, CDCl3) 172.9, 172.6, 164.4, 160.5, 160.0, 140.8, 135.9,
Acknowledgements
The authors thank the Hungarian Research Fund (CK78553 and
K73389) and Developing Competitiveness of Universities in the
South Transdanubian Region (SROP-4.2.1.B-10/2/KONV-2010-0002
and SROP-4.2.2./B-16 10/1-2010-0029) for the financial support and
Johnson Matthey for the generous gift of palladium(II) acetate.
124.6, 52.6, 52.5, 48.6, 48.5, 41.3, 18.1, 17.8; IR (KBr
n
(cmꢁ1)): 3299
(v br, NH), 1747 (COO), 1685 (CH3NCO), 1651 (CON); MS m/z (rel
int.): 368 (1, Mþ), 309 (34), 266 (100), 206 (81),179 (10),162 (5), 136
(10), 110 (8), 93 (5), 59(5).
References and notes
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