Easy synthesis of novel 4-azolylpyridazin-3-ones

Article abstract of DOI:10.1055/s-0031-1290808

Ethyl azol-2-ylglyoxylates react smoothly with acetone in the presence of catalytic amounts of proline and trifluoroacetic acid to give the corresponding azolyl aldols in 93-98% yield. The products are easily transformed into azolyl pyridazinones in 85-98% yield by cyclization with hydrazine hydrate. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290808

PAPER
1263
Easy Synthesis of Novel 4-Azolylpyridazin-3-ones
4
-Azolylpyridazin
l
Pavel K. Mykhailiuk,*a,b Andrey A. Tolmacheva,b
a
Enamine Ltd., Aleksandra Matrosova Street 23, Kyiv 01103, Ukraine
b
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine
Fax +380(44)2351273; E-mail: Geraschenko.Aleksandr@gmail.com; E-mail: Pavel.Mykhailiuk@gmail.com
c
STC, Institute for Single Crystals, National Academy of Science of Ukraine, Lenina Avenue 60, Kharkiv 61001, Ukraine
Received 1 December 2011; revised 25 January 2012
The elaboration of novel synthetic approaches to py-
ridazines, with the aim of at appropriate functionalization
and fine-tuning of the substituents around the pyridazine
core, is therefore of practical importance to modern drug
design and discovery.
Abstract: Ethyl azol-2-ylglyoxylates react smoothly with acetone
in the presence of catalytic amounts of proline and trifluoroacetic
acid to give the corresponding azolyl aldols in 93–98% yield. The
products are easily transformed into azolyl pyridazinones in 85–
98% yield by cyclization with hydrazine hydrate.
Key words: heterocycles, cyclizations, pyridazines, ketones, es-
ters, catalysis
Several basic ways of synthesizing the pyridazinone sys-
tem are known.7 The condensation of 1,4-keto acid deriv-
atives with hydrazine or its derivatives is the most widely
used among these methods and is limited only by the
availability of the 1,4-keto acid starting materials.
The pyridazine nucleus is an interesting heterocyclic ring
that plays the role of a pharmacophore in several classes
of derivatives that show a variety of pharmacological
properties.1 During the last decade, considerable attention
has been devoted to various pyridazin-3(2H)-ones be-
cause of their synthetic versatility, their well-balanced
physicochemical properties, and the presence of possible
binding sites for interaction with various receptors. Some
derivatives are promising drug candidates,2 while others
are already FDA-approved drugs, including the anxiolytic
cetohexazine and the bronchodilator zardaverine
(Figure 1).3 Additionally, pyridazin-3(2H)-ones are use-
ful as starting materials for the synthesis of several biolog-
ically active aminopyridazines,4 including the
antidepressant minaprine5 and the anti-Parkinson’s drug
moxiraprine6 (Figure 1).
Until now, no methods have been reported for the synthe-
sis of 4-azolylpyridazin-3(2H)-ones. Here, we report a
simple two-step procedure that gives novel 4-azolylpy-
ridazin-3(2H)-ones. In the first step, ethyl azol-2-yl-
glyoxylates (1–9), which are easily obtained from the cor-
responding azoles,8 are transformed into aldols (1a–9a)
under mild reaction conditions (Scheme 1). Condensation
of the glyoxylates 1–9 with acetone in the presence of cat-
alytic amounts of proline and trifluoroacetic acid at room
temperature9 gave the corresponding aldols 1a–9a in high
yields (Table 1). Note that under these standard condi-
tions, the formation of product 2a was not observed; how-
ever, this compound was obtained in 97% yield by using
proline as the sole catalyst. In other cases, no reaction oc-
curred in the absence of trifluoroacetic acid. Aldol 7a was
obtained as an inseparable mixture of diastereoisomers
that was used in the next synthesis step. The structure of
product 4a was unambiguously established by X-ray dif-
fraction study (see Supporting Information).
F
F
O
O
O
N
NH
N
NH
Me
O
In the second step, aldols 1a–9b were cyclized in the pres-
ence of three equivalents of hydrazine hydrate in acetic
acid with heating9 to give products 1b–9b in 85–98%
yields (Table 1). The structure of product 9b was con-
firmed by X-ray diffraction study (see Supporting Infor-
mation).
cetohexazine
zardaverine
O
O
N
N
NH
NH
Ph
HO
N
N
N
N
minaprine
moxiraprine
Cleavage of the N-benzyl group in 4b by hydrogenation
over 5% palladium/carbon as the catalyst gave imidazole
4c (Scheme 2), the structure of which was also confirmed
by X-ray crystallography (Figure 2).
Figure 1 Some pharmacologically relevant pyridazin-3-ones and
their derivatives: cetohexazine (anxiolytic), zardaverine (bronchodi-
lator), minaprine (antidepressant), and moxiraprine (anti-Parkinson)
In conclusion, a convenient two-step practical synthesis of
novel 4-azol-2-ylpyridazin-3(2H)-ones from easily acces-
sible azolylpyruvates and acetone has been elaborated.
The products have huge potential for use in medicinal
chemistry and drug discovery.
SYNTHESIS 2012, 44, 1263–1267
Advanced online publication: 27.03.2012
DOI: 10.1055/s-0031-1290808; Art ID: Z112411SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
2

1264
O. V. Geraschenko et al.
PAPER
O
O
O
N
N
N
R
O
R
R
N2H4
acetone
93–98%
OEt
NH
N
X
X
X
85–98%
O
O
OH
1–9
1a–9a
1b–9b
Scheme 1 Syntheses of compounds 1a–9a and 1b–9b
Table 1 Syntheses of Aldols 1a–9a and Pyridazinones 1b–9b
Starting material
Aldol
Time (h) Yield (%) Pyridazinone
Yield (%)
90
O
O
O
N
N
N
OEt
NH
1
2
1a
12
24
95
97
1b
2b
OEt
N
N
N
N
O
Me
OH
N
O
N
Me
Me
O
O
N
O
O
OEt
NH
N
2a
3a
4a
5a
95
85
93
90
Cl
OEt
Cl
N
Cl
N
N
O
Me
OH
Me
Me
N
O
O
OH
N
O
O
N
NH
N
N
3
4
5
48
12
12
95
96
93
3b
4b
5b
OEt
Bu
N
OEt
N
Bu
Bu
O
O
O
O
N
OH
OH
N
O
O
N
NH
N
N
OEt
OEt
Bn
N
OEt
N
Bn
Bn
O
N
O
O
O
N
N
O
NH
N
N
N
N
N
OEt
O
O
N
N
N
OH
O
NH
N
OEt
N
6
6a
48
94
6b
95
N
OEt
O
O
O
O
O
N
N
N
OH
O
OEt
NH
N
N
Bn
O
7
8
9
7a
8a
9a
12
12
12
95
98
97
7b
8b
9b
98
96
98
Bn
O
N
N
Bn
O
H
N
H
H
OEt
N
N
O
O
O
O
O
O
N
O
N
OEt
N
NH
OEt
N
N
N
N
O
OH
Me
O
Me
Me
O
O
N
O
N
OEt
N
NH
N
OEt
S
S
S
O
OH
O
Synthesis 2012, 44, 1263–1267
© Thieme Stuttgart · New York

PAPER
4-Azolylpyridazin-3-ones
1265
Ethyl 2-(1-Butyl-1H-imidazol-2-yl)-2-hydroxy-4-oxopen-
tanoate (3a)
Brown liquid; yield: 2.68 g (95%).
1H NMR (500 MHz, CDCl3): d = 0.84 (t, J = 7.2 Hz, 3 H), 1.11 (t,
J = 7.1 Hz, 3 H), 1.26 (m, J = 7.3 Hz, 2 H), 1.57 (m, 1 H), 1.66 (m,
1 H), 2.16 (s, 3 H), 3.48 (d, J = 8.1 Hz, 1 H), 3.67 (d, J = 8.1 Hz, 1
H), 3.96 (m, 1 H), 4.07 (m, 2 H), 4.16 (m, 1 H), 4.68 (s, 1 H), 6.81
(s, 1 H), 6.83 (s, 1 H).
O
O
N
N
N
H2, Pd/C
NH
N
NH
N
N
H
EtOH
quant.
Ph
4b
4c
Scheme 2 Synthesis of compound 4c
13C NMR (125 MHz, CDCl3): d = 14.05, 14.29, 19.90, 31.40, 33.14,
46.19, 51.78, 61.48, 74.09, 122.30, 126.62, 145.66, 171.90, 206.22.
MS (APCI): m/z = 283 [M + 1].
Ethyl 2-(1-Benzyl-1H-imidazol-2-yl)-2-hydroxy-4-oxopen-
tanoate (4a)
Brown crystals; yield: 3.04 g (96%); mp 64 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.05 (t, J = 7.1 Hz, 3 H), 2.15
(s, 3 H), 3.44 (d, J = 7.4 Hz, 1 H), 3.65 (d, J = 7.4 Hz, 1 H), 3.84 (m,
1 H), 3.92 (m, 1 H), 5.41 (s, 2 H), 6.39 (s, 1 H), 6.93 (s, 1 H), 7.08
(s, 1 H), 7.12 (d, J = 7.3 Hz, 2 H), 7.29 (d, J = 7.3 Hz, 1 H), 7.34 (t,
J = 7.3 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 14.19, 31.38, 49.75, 51.69,
61.48, 74.14, 123.08, 126.92, 127.48, 127.78, 128.85, 138.23,
146.20, 171.63, 206.09.
Figure 2 X-ray crystal structure of 4c
1H and 13C NMR spectra were recorded on a Bruker Avance 500
spectrometer at 499.9 MHz and 124.9 MHz, respectively. Chemical
shifts (1H and 13C) are reported in ppm downfield from TMS as the
internal standard. Mass spectra were recorded on an Agilent 1100
LCMSD SL instrument in the atmospheric pressure chemical ion-
ization (APCI) mode.
MS (APCI): m/z = 317 [M + 1].
Ethyl 2-Hydroxy-4-oxo-2-(1-vinyl-1H-imidazol-2-yl)pen-
tanoate (5a)
White powder; yield: 2.35 g (93%) mp 93 °C.
1H NMR (500 MHz, CDCl3): d = 1.19 (t, J = 7.1 Hz, 3 H), 2.27 (s,
3 H), 3.56 (d, J = 7.8 Hz, 1 H), 3.68 (d, J = 7.8 Hz, 1 H), 4.16 (m, 1
H), 4.24 (m, 1 H), 4.85 (dd, J = 8.7, 1.4 Hz, 1 H), 5.16 (dd, J = 15.6,
1.4 Hz, 1 H), 6.95 (s, 1 H), 7.21 (s, 1 H), 7.54 (m, 1 H).
Aldols 1a–9a; General Procedure
Hetarylpyruvate 1–9 (10 mmol) was dissolved in acetone (1 mL)
and DMSO (1 mL). Proline (230 mg, 2 mmol) and TFA (228 mg, 2
mmol) were added and the soln was stirred at r.t for 12–48 h (see
Table 1). The mixture was then poured into H2O (50 mL) and ex-
tracted with CH2Cl2 (2  10 mL). The combined organic phase was
washed with H2O (3  10 mL), dried (Na2SO4), and concentrated
under reduced pressure. The products 1a–9a were used in the next
step without further purification. For analysis, aldols 1a–9a were
purified by flash column chromatography [hexane–EtOAc (1:1)].
13C NMR (125 MHz, CDCl3): d = 14.01, 30.91, 49.57, 62.64, 74.67,
102.54, 118.04, 127.96, 130.53, 143.80, 171.03, 208.90.
MS (APCI): m/z = 253 [M + 1].
Ethyl 2-(1-Allyl-1H-imidazol-2-yl)-2-hydroxy-4-oxopentanoate
(6a)
Brown liquid; yield: 2.50 g (94%).
1H NMR (500 MHz, DMSO-d6): d = 1.12 (t, J = 7.1 Hz, 3 H), 2.15
(s, 3 H), 3.36 (d, J = 17.1 Hz, 1 H), 3.60 (d, J = 17.1 Hz, 1 H), 4.02
(m, 1 H), 4.09 (m, 1 H), 4.74 (m, 1 H), 5.03 (d, J = 17.1 Hz, 1 H),
5.15 (d, J = 10.3 Hz, 1 H), 5.91 (m, 1 H), 6.14 (s, 1 H), 6.82 (s, 1 H),
7.06 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.98, 30.88, 49.40, 49.92,
62.52, 74.56, 117.24, 122.30, 127.15, 133.68, 143.91, 171.35,
208.94.
Ethyl 2-Hydroxy-2-(1-methyl-1H-imidazol-2-yl)-4-oxopen-
tanoate (1a)
Brown liquid; yield: 2.28 g (95%).
1H NMR (500 MHz, DMSO-d6): d = 1.13 (t, J = 7.1 Hz, 3 H), 2.15
(s, 3 H), 3.33 (d, J = 17 Hz, 1 H), 3.55 (d, J = 17 Hz, 1 H), 3.65 (s,
3 H), 4.11 (m, 2 H), 6.1 (s, 1 H), 6.76 (s, 1 H), 7.1 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.32, 31.32, 34.23, 51.42,
61.49, 74.06, 124.21, 126.14, 145.90, 171.62, 206.04.
MS (APCI): m/z = 267 [M + 1].
MS (APCI): m/z = 241 [M + 1].
Ethyl 2-[1-(2-{[(Benzyloxy)carbonyl]amino}propyl)-1H-imida-
zol-2-yl]-2-hydroxy-4-oxopentanoate (7a)
Brown liquid; yield: 3.97 g (95%).
Ethyl 2-(5-Chloro-1-methyl-1H-imidazol-2-yl)-2-hydroxy-
4-oxopentanoate (2a)
Brown liquid; yield: 2.66 g (97%).
1H NMR (500 MHz, DMSO-d6): d = 1.05–1.16 (m, 6 H), 2.14 (s, 3
H), 3.39 (d, J = 17.4 Hz, 1 H), 3.62 (dd, J = 17.4, 6.1 Hz, 1 H), 3.80
(m, 1 H), 3.96 (m, 1 H), 4.05 (m, 1 H), 4.13 (m, 1 H), 4.25 (m, 1 H),
4.98 (s, 1 H), 6.20 (s, 1 H), 6.77 (s, 1 H), 7.11 (s, 1 H), 7.32–7.37
(m, 6 H).
13C NMR (125 MHz, DMSO-d6): d = 14.26, 19.11, 30.09, 31.27,
47.89, 50.49, 51.73, 61.56, 65.64, 74.03, 123.01, 126.50, 128.07,
128.80, 137.62, 145.63, 155.95, 171.98, 206.13.
1H NMR (500 MHz, DMSO-d6): d = 1.15 (t, J = 7.1 Hz, 3 H), 2.16
(s, 3 H), 3.33 (d, J = 16.9 Hz, 1 H), 3.54 (d, J = 16.9 Hz, 1 H), 3.61
(s, 3 H), 4.13 (m, 2 H), 6.32 (s, 1 H), 6.91 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.21, 31.27, 31.85, 50.96,
61.67, 74.37, 119.05, 123.45, 146.21, 171.15, 205.63.
MS (APCI): m/z = 275 [M + 1].
MS (APCI): m/z = 418 [M + 1].
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1263–1267

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O. V. Geraschenko et al.
PAPER
Ethyl 2-hydroxy-2-(1-methyl-1H-benzimidazol-2-yl)-4-oxopen-
tanoate (8a)
White powder; yield: 2.84 g (98%); mp 117 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.24 (s, 3 H), 5.35 (s, 2 H), 7.04
(d, J = 7.1 Hz, 2 H), 7.09 (s, 1 H), 7.23–7.29 (m, 3 H), 7.37 (s, 1 H),
7.46 (s, 1 H), 13.14 (s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 1.14 (t, J = 7.3 Hz, 3 H), 2.23
(s, 3 H), 3.52 (d, J = 16.9 Hz, 1 H), 3.74 (d, J = 16.9 Hz, 1 H), 3.88
(s, 3 H), 4.12 (m, 1 H), 4.18 (m, 1 H), 6.57 (s, 1 H), 7.23 (t, J = 7.3
Hz, 1 H), 7.30 (t, J = 7.3 Hz, 1 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.64 (d,
J = 7.3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 20.45, 50.71, 124.07, 127.75,
128.06, 129.03, 129.58, 131.99, 135.19, 137.94, 142.00, 145.06,
159.20.
MS (APCI): m/z = 267 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 14.32, 31.52, 51.53, 61.79,
74.71, 110.62, 119.72, 122.23, 123.17, 137.22, 141.36, 152.76,
171.21, 205.76.
4-(1H-Imidazol-2-yl)-6-methylpyridazin-3(2H)-one (4c)
5% Pd/C (0.1 g) was added to a soln of pyridazinone 4b (1 mmol)
in EtOH (10 mL) and the mixture was hydrogenated at atmospheric
pressure for 5 h. The catalyst was then filtered off and discarded.
The solvent was evaporated in vacuum to give white crystals; yield:
174 mg (99%); mp >250 °C.
MS (APCI): m/z = 291 [M + 1].
Ethyl 2-Hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-4-oxopen-
tanoate (9a)
White powder; yield: 2.50 g (97%); mp 82 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.33 (s, 3 H), 7.16 (s, 1 H), 7.26
(s, 1 H), 7.93 (s, 1 H), 12.43 (s, 1 H), 13.23 (s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 1.13 (t, J = 7.1 Hz, 3 H), 2.11
(s, 3 H), 2.33 (s, 3 H), 3.19 (d, J = 17.4 Hz, 1 H), 3.63 (d, J = 17.4
Hz, 1 H), 4.10 (m, 1 H), 6.53 (s, 1 H), 7.24 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.28, 17.36, 30.90, 52.13,
61.68, 76.40, 116.04, 152.26, 171.14, 172.17, 205.18.
13C NMR (125 MHz, DMSO-d6): d = 20.76, 119.96, 127.02,
127.61, 130.41, 140.30, 145.81, 159.52.
MS (APCI): m/z = 177 [M + 1].
6-Methyl-4-(1-vinyl-1H-imidazol-2-yl)pyridazin-3(2H)-one
(5b)
White powder; yield: 1.82 g (90%); mp 216 °C.
MS (APCI): m/z = 258 [M + 1].
Pyridazine-3(2H)-ones (1b–9b); General Procedure
N2H4·H2O (30 mmol) was added to a soln of aldol 1a–9a (10 mmol)
in HOAc (5 mL) and the mixture was refluxed for 1 h then cooled
to r.t. The solvent was evaporated under vacuum and the residue
was triturated with aq NaHCO3.
1H NMR (500 MHz, DMSO-d6): d = 2.31 (s, 3 H), 4.86 (s, 1 H), 5.45
(d, J = 14.4 Hz, 1 H), 6.98 (s, 1 H), 7.16 (s, 1 H), 7.58 (s, 1 H), 7.85
(s, 1 H), 13.15 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 20.53, 102.52, 118.83,
130.57, 130.85, 131.05, 135.99, 141.58, 145.09, 159.09.
MS (APCI): m/z = 203 [M + 1].
6-Methyl-4-(1-methyl-1H-imidazol-2-yl)pyridazin-3(2H)-one
(1b)
4-(1-Allyl-1H-imidazol-2-yl)-6-methylpyridazin-3(2H)-one (6b)
White powder; yield: 2.05 g (95%); mp 209 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.30 (s, 3 H), 4.73 (s, 2 H), 4.93
(d, J = 17.1 Hz, 1 H), 5.09 (d, J = 10.3 Hz, 1 H), 5.88 (m, 1 H), 7.08
(s, 1 H), 7.31 (s, 1 H), 7.53 (s, 1 H), 13.10 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 20.50, 49.81, 117.74, 123.59,
129.44, 132.04, 134.79, 135.11, 141.86, 145.11, 159.19.
Beige powder; yield: 1.71 g (90%); mp 226 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.31 (s, 3 H), 3.63 (s, 3 H), 7.02
(s, 1 H), 7.32 (s, 1 H), 7.53 (s, 1 H), 13.08 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 20.52, 34.43, 124.66, 129.07,
131.79, 135.19, 142.35, 145.03, 159.13.
MS (APCI): m/z = 191 [M + 1].
MS (APCI): m/z = 217 [M + 1].
4-(5-Chloro-1-methyl-1H-imidazol-2-yl)-6-methylpyridazin-
3(2H)-one (2b)
Benzyl {1-Methyl-2-[2-(6-methyl-3-oxo-2,3-dihydropyridazin-
4-yl)-1H-imidazol-1-yl]ethyl}carbamate (7b)
Beige powder; yield: 3.60 g (98%); mp 103 °C.
1H NMR (500 MHz, DMSO-d6): d = 0.96 (d, J = 6.6 Hz, 3 H), 2.24
(s, 3 H), 3.76 (m, 1 H), 3.98–4.02 (m, 1 H), 4.14 (dd, J = 14.0, 4.2
Hz, 1 H), 4.89 (dd, J = 31.1, 12.5 Hz, 2 H), 7.04 (s, 1 H), 7.22–7.38
(m, 7 H), 7.44 (s, 1 H), 13.10 (s, 1 H).
White powder; yield: 2.13 g (95%); mp 228 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.32 (s, 3 H), 3.53 (s, 3 H), 7.17
(s, 1 H), 7.56 (s, 1 H), 13.17 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 20.54, 32.47, 119.81, 126.18,
131.16, 135.49, 142.37, 145.09, 158.92.
MS (APCI): m/z = 225 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 18.58, 20.51, 47.98, 51.75,
65.59, 123.88, 128.12, 128.23, 128.82, 129.33, 132.06, 135.35,
137.53, 142.24, 145.00, 155.68, 159.30.
4-(1-Butyl-1H-imidazol-2-yl)-6-methylpyridazin-3(2H)-one
(3b)
White powder; yield: 1.97 g (85%); mp 194 °C.
1H NMR (500 MHz, CDl3): d = 0.89 (t, J = 7.2 Hz, 3 H), 1.25 (m,
J = 7.2 Hz, 2 H), 1.70 (m, J = 7.2 Hz, 2 H), 2.39 (s, 3 H), 4.15 (t,
J = 7.2 Hz, 2 H), 7.09 (s, 1 H), 7.17 (s, 1 H), 7.60 (s, 1 H), 11.42 (s,
1 H).
MS (APCI): m/z = 368 [M + 1].
6-Methyl-4-(1-methyl-1H-benzimidazol-2-yl)pyridazin-3(2H)-
one (8b)
White powder; yield: 2.30 g (96%); mp >250 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.36 (s, 3 H), 3.76 (s, 3 H), 7.26
(t, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.63 (d, J = 7.8 Hz,
1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.76 (s, 1 H), 13.27 (s, 1 H).
13C NMR (125 MHz, CDl3): d = 13.27, 19.20, 19.59, 32.06, 46.65,
122.56, 125.92, 126.56, 138.28, 140.35, 157.90, 159.92.
MS (APCI): m/z = 233 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 20.56, 31.71, 111.00, 119.78,
122.55, 123.47, 131.48, 136.73, 136.86, 143.05, 145.07, 148.76,
158.99.
4-(1-Benzyl-1H-imidazol-2-yl)-6-methylpyridazin-3(2H)-one
(4b)
White powder; yield: 2.48 g (93%); mp 210 °C.
MS (APCI): m/z = 241 [M + 1].
Synthesis 2012, 44, 1263–1267
© Thieme Stuttgart · New York

PAPER
4-Azolylpyridazin-3-ones
1267
6-Methyl-4-(4-methyl-1,3-thiazol-2-yl)pyridazin-3(2H)-one
(9b)
Yellow crystals; yield: 2.03 g (98%); mp >250 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.37 (s, 3 H), 2.47 (s, 3 H), 7.55
(s, 1 H), 8.10 (s, 1 H), 11.38 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 17.27, 20.77, 120.45, 127.61,
130.13, 145.51, 153.36, 156.48, 158.82.
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references therein.
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MS (APCI): m/z = 208 [M + 1].
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S.; Gordon, R.; Guay, J.; Guiral, S.; Huang, Z.; Robichaud,
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X-ray Diffraction Studies
X-ray diffraction studies were performed on an automatic Xcalibur
3 diffractometer (graphite-monochromated MoKa radiation, CCD
detector, w-scanning). The structures were solved by a direct meth-
od using the SHELXTL package.11 A restriction on the bond length
in the ethyl group (1.54 Å) in compound 4a was applied. Positions
of hydrogen atoms were located from electron-density difference
maps and refined by using a riding model with Uiso = nUeq (n = 1.5
for methyl groups and 1.2 for other hydrogen atoms) for the carrier
atom. The hydrogen atoms participating in the formation of hydro-
gen bonds were refined within the isotropic approximation. The
crystallographic data and experimental parameters are listed in Ta-
ble S1 of the Supporting Information. Final atomic coordinates,
geometrical parameters and crystallographic data for compounds
4a, 4c, and 9b have been deposited with accession numbers CCDC
854559, CCDC 854560, and CCDC 854561, respectively, and can
be obtained free of charge from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk; Web site:
www.ccdc.cam.ac.uk/conts/retrieving.html.
(5) Laborit, H. Agressologie 1969, 10, 469.
(6) Worms, P.; Kan, J.; Wermuth, C.; Biziere, K. Naunyn-
Schmiedeberg’s Arch. Pharmacol. 1986, 334, 246.
(7) Mason, J. W.; Aldous, D. L. In The Chemistry of
Heterocyclic Compounds, Vol. 28; Weissberger, A.; Taylor,
E. C., Eds.; Wiley-Interscience: New York, 1973, 24.
(8) Geraschenko, O. V.; Khodakovskiy, P.; Shishkin, O.;
Mykhailiuk, P.; Zaporozhets, O.; Tolmachev, A. Synthesis
2011, 1633.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(9) (a) Osamu, T.; Taichi, K.; Wei-Guo, G.; Tetsuya, I.; Keiji,
M. Org. Lett. 2005, 7, 22–5103. (b) Nobuyuki, M.; Fujie,
T.; Carlos, F. Angew. Chem. Int. Ed. 2004, 43, 2420.
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Z.; Da-Bin, Q. Tetrahedron Lett. 2008, 49, 7434.
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1907.
References
(1) Conteras, J. M.; Rival, Y. M.; Chayer, S.; Borguignon, J. J.;
Wermuth, C. G. J. Med. Chem. 1999, 42, 730.
(11) SHELXTL, Version 5.10; Bruker AXS Inc.: Madison, 1997.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1263–1267