Synthesis of 2-substituted-3-nitroimidazo[1,2-b]pyridazines as potential biologically active agents

Article abstract of DOI:10.1002/jhet.5570390125

A new heterocyclic reductive alkylating agent, 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine, was synthesized for the first time. It was shown to react under phase-transfer catalysis conditions with 2-nitropropane anion by an S_RN1 mechanism to give excellent yield of isopropylidene derivative formed from a base-promoted nitrous acid elimination of C-alkylation product. Extension of this S_RN1 reaction to various nitronate anions led to a new class of 3-nitroimidazo[1,2-b]pyridazine derivatives bearing a trisubstituted double bond at the 2-position.

Full text of DOI:10.1002/jhet.5570390125

Jan-Feb 2002
Synthesis of 2-Substituted-3-nitroimidazo[1,2-b]pyridazines as
173
Potential Biologically Active Agents
Thierry Terme [a], Christophe Galtier [b], José Maldonado [a], Michel P. Crozet [a],
Alain Gueiffier [b], Patrice Vanelle* [a]
[a] Laboratoire de Chimie Organique, UMR 6517, Université de la Méditerranée, Faculté de Pharmacie, 27 bd
Jean Moulin, 13385 Marseille Cedex 5, France
[b] Laboratoire de Chimie Thérapeutique, EA 3247, Université de Tours, Faculté de Pharmacie,
31 av Monge, 37200 Tours, France
Received June 27, 2001
A new heterocyclic reductive alkylating agent, 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine,
was synthesized for the first time. It was shown to react under phase-transfer catalysis conditions with
2-nitropropane anion by an S 1 mechanism to give excellent yield of isopropylidene derivative formed
RN
from a base-promoted nitrous acid elimination of C-alkylation product. Extension of this S 1 reaction to
RN
various nitronate anions led to a new class of 3-nitroimidazo[1,2-b]pyridazine derivatives bearing a trisub-
stituted double bond at the 2-position.
J. Heterocyclic Chem., 39, 173 (2002).
In the last decade, numerous pharmacological proper-
The condensation of 3 with dichloroacetone led to
6-chloro-2-chloromethylimidazo[1,2-b]pyridazine (4)
which was converted into 5 by classical nitration using the
ties have been reported for the imidazo[1,2-b]pyridazine
derivatives. These derivatives were shown to possess inter-
esting biological activities such as central nervous system
agents [1], antihistaminics [2] and antiasthmatics [3].
Some derivatives were also patented as herbicides [4].
Furthermore, 3-nitro derivatives have been described as
antibacterial agents particularly against Helicobacter
Pylori [5]. In light of the structure-activity relationships,
reported for numerous derivatives of these compounds, the
effect of substitution at position 6 was well documented.
However, the nature of the substituent in position 2 was
unexplored. In continuation to our studies directed toward
the synthesis of new biologically active compounds [6] via
single electron transfer reactions, we investigated the reac-
tivity of 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]-
pyridazine (5) with various aliphatic, cyclic or heterocyclic
anions in order to prepare original 2-functionalized
3-nitroimidazo[1,2-b]pyridazine derivatives.
nitrating mixture HNO -H SO (Scheme 1). The reaction
3
2
4
of 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyri-
dazine (5) and 3 equivalents of 2-nitropropane anion (6)
under S 1 reaction conditions (inert atmosphere, light
RN
catalysis) gave only the ethylenic compound 8a. This
derivative was obtained via a base-promoted nitrous acid
elimination of the C-alkylation product 7 as shown in
Scheme 2.
Table 1
Entry
[a]
M
Scavenger
Solvent
Yield
8a (%)
1
2
3
4
5
6
7
8
NBu
NBu
NBu
NBu
NBu
NBu
Li
-
CH Cl /H O
83
32
11
46
21
21
73
11
4
4
4
4
4
4
2
2
2
p-dinitrobenzene (1 equiv.) CH Cl /H O
2
2
2
TEMPO (0.1 equiv.)
CH Cl /H O
2 2 2
O bubbling
CH Cl /H O
2 2 2
2
Dark
CH Cl /H O
Starting with 3,6-dihydroxypyridazine (1), com-
pound 5 could be easily prepared in four-steps. Thus, 1
was first converted into the corresponding dichloro deriv-
2 2 2
Dark, O bubbling
CH Cl /H O
2 2 2
2
-
DMF
DMF
Li
CuCl (0.1 equiv.)
2
ative 2 using POCl , followed by an amination reaction
3
[a] All reactions were performed during 6 hours under argon and irradia-
tion with a 300 W fluorescent lamp using one equivalent of imidazopyri-
dazine (5) and three equivalents of 2-nitropropane anion (6).
with NH OH to form 3-amino-6-chloropyridazine (3) [7].
4
The best C-alkylation yield was obtained under phase-
transfer conditions [8] (40% tetrabutylammonium hydrox-
ide in water and dichloromethane) with 3 equivalents of 2-
nitropropane anion (6) during 6 hours.
The S 1 mechanism was confirmed by inhibition
RN
studies [9] under optimum conditions (Table 1): addition
of p-dinitrobenzene as radical anion scavenger, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) as radical trap,
CuCl or bubbling dioxygen through the solution in the
2
dark strongly decreased the ethylenic yield. Moreover, the

174
T. Terme, C. Galtier, J. Maldonado, M. P. Crozet, A. Gueiffier, P. Vanelle
Vol. 39
importance of the nitro group has been demonstrated by
the reaction of 6-chloro-2-chloromethylimidazo[1,2-b]-
pyridazine (4) with 2-nitropropane anion (6), leading to the
O-alkylation product 9 in a low yield and unidentifiable
tarry matters (Scheme 3).
double bond has been determinated by nmr (NOESY), where
the E isomer was found to be the only isolated product.
In order to obtain new more soluble nitroimidazo[1,2-b]-
pyridazines, we have applied this S 1 reactivity with a het-
RN
erocyclic nitronate anion. The 2,2-dimethyl-5-nitro-1,3-
dioxane salt was prepared from the previously described
(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)methanol after treat-
ment with lithium methoxide, which induced a formalde-
hyde elimination [12]. The reaction of this heterocyclic
nitronate anion with 5 was carried out in dimethylfor-
mamide using 3 equivalents of dioxane salt during 30 min-
utes to give 53% of the corresponding ethylenic compound
10. Ring opening of derivative 10 was easily effected in
methanol reflux with ion exchange resin (Dowex 50x8-50)
during 24 hours to give the corresponding diol 11 in 86%
yield [13]. Finally, we obtained an original bis-alkylating
agent 12 by treating the diol 11 with 6 equivalents of thionyl
chloride during 24 hours in 79% yield (Scheme 5).
All these experimental data provide good evidence for
assigning the S 1 mechanism to the reaction of 6-chloro-
RN
2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine (5) and
2-nitropropane anion (6).
The understanding of the relationship between the
nucleophile and the substrate in single electron transfer
reaction is useful in order to increase the selectivity and the
yield of the reaction [10], thus we have investigated the
reactivity of 5 with other nitronate anions (aliphatic,
cyclic, heterocyclic). The precursors of the nitronate
anions were commercially available or obtained by oxida-
tion of the corresponding amines with m-chloroperbenzoic
acid [11]. By reacting 5 with 3 equivalents of nitronate
anion under phase-transfer conditions (40% tetrabutylam-
monium hydroxide in water and dichloromethane), new 3-
nitroimidazo[1,2-b]pyridazines bearing a trisubstituted
ethylenic double bond at the 2-position (8a-i) have been
prepared in moderate to good yields (Scheme 4).
These alkenes have been classically formed by electron-
transfer C-alkylation and base-promoted nitrous acid elimi-
nation from the C-alkylation product. When the ethylenic
derivative was unsymmetrical, the stereochemistry of the
In conclusion, we have demonstrated in this paper that
this methodology, based on electron transfer reactions, is a
valuable and general method for the preparation of new
nitroimidazo[1,2-b]pyridazines, of potential biological
activity, under mild operating conditions.
EXPERIMENTAL
Melting points were determined on a Buchi capillary melting
point apparatus and are uncorrected. Elemental analyses were per-
formed by the Centre de Microanalyses of the University of Aix-
1
Marseille 3 and of the INP-ENSCT (Toulouse, France). Both H

Jan-Feb 2002
Synthesis of 2-Substituted-3-nitroimidazo[1,2-b]pyridazines
175
13
for 6 hours at room temperature under nitrogen and irradiation
with a 300 W fluorescent lamp. The organic layer was separated
and the aqueous layer was extracted with dichloromethane (3 x
10 ml). The combined organic layers were washed twice with
water (30 ml), dried over anhydrous magnesium sulfate and
removed under reduced pressure. Purification by chromatogra-
phy on silica column eluting with dichloromethane and recrystal-
lization from ethanol gave the required products (8a-i).
and C nmr spectra were determined on a Bruker ARX 200 spec-
1
trometer. The H chemical shifts are reported as parts per million
downfield from tetramethylsilane (Me Si), and the C chemical
shifts were referenced to the solvents peaks: deuteriochloroform
(76.9 ppm) or dimethylsulfoxide-d (39.6 ppm). Absorptions are
reported with the following notations: s, singlet; d, doublet; t, triplet;
q, quartet; m, a more complex multiplet or overlapping multiplets.
Flash column chromatography was performed on silica gel 60
(Merck, particle size 0.063-0.200 mm, 70-230 mesh ASTM) and
aluminium oxide (Fluka, type 507 C neutral, 100-125 mesh). Thin
layer chromatography was performed on 5 x 10 cm aluminium plates
coated with silica gel 60 F-254 (Merck) in an appropriate solvent.
13
4
6
6-Chloro-2-(2-methylpropenyl)-3-nitroimidazo[1,2-b]pyridazine
(8a).
This compound was obtained as an orange solid in 83% yield;
1
mp 202 °C. H nmr (deuteriochloroform, 200 MHz): δ 2.09 (s,
3-Amino-6-chloropyridazine (3).
3H), 2.32 (s, 3H), 6.97 (s, 1H), 7.35 (d, 1H, J = 9.5 Hz), 7.94 (d,
13
This compound was obtained from reaction of 3,6-dichloropyri-
1H, J = 9.5 Hz). C nmr (deuteriochloroform, 50 MHz): δ 21.0
dazine (2) with ammonium hydroxide in 71% yield, mp 201°C [7].
(CH ), 28.3 (CH ), 114.2 (CH), 123.7 (CH), 126.9 (CH), 137.3
3
3
(C), 146.3 (C), 148.5 (C), 150.8 (C).
6-Chloro-2-chloromethylimidazo[1,2-b]pyridazine (4).
Anal. Calcd for C H ClN O : C, 47.54; H, 3.59; N, 22.18.
10
9
4 2
A mixture of 3-amino-6-chloropyridazine (3) (5 g, 38.6
mmoles) and 1,3-dichloroacetone (4.86 g, 38.6 mmoles) in
ethanol (80 ml) was heated at reflux with stirring for 4 hours.
After evaporation of solvent in vacuo, the residue was dissolved
in water (30 ml), basified with 2 N sodium hydroxide solution
and then extracted with methylene chloride (2 x 30 ml). The
organic layer was dried over anhydrous magnesium sulfate and
removed under reduced pressure. The 6-chloro-2-chloromethyl-
imidazo[1,2-b]pyridazine (4) was purified by column chromatog-
raphy on aluminium oxide eluting with methylene chloride and
recrystallized from ethanol to give 2.5 g (32%) as a pale yellow
Found: C, 47.59; H, 3.51; N, 22.16.
6-Chloro-2-cyclopentylidenemethyl-3-nitroimidazo[1,2-b]pyri-
dazine (8b).
This compound was obtained as brown solid in 80% yield; mp
1
172 °C. H nmr (deuteriochloroform, 200 MHz): δ 1.80 (m, 4H),
2.65 (t, 2H, J = 6 Hz), 2.95 (t, 2H, J = 6 Hz), 7.23 (s, 1H), 7.36 (d,
1H, J = 9.5 Hz), 7.95 (d, 1H, J = 9.5 Hz). C nmr (deuteriochlo-
13
roform, 50 MHz): δ 25.7 (CH ), 26.8 (CH ), 33.6 (CH ), 37.0
2
2
2
(CH ), 109.8 (CH), 123.7 (CH), 126.8 (CH), 137.6 (C), 146.8
2
(C), 148.1 (C), 164.2 (C).
1
solid; mp 154 °C. H nmr (deuteriochloroform, 200 MHz): δ 4.78
Anal. Calcd for C H ClN O : C, 51.72; H, 3.98; N, 20.10.
12 11
4 2
(s, 2H), 7.10 (d, 1H, J = 9.4 Hz), 7.89 (d, 1H, J = 9.4 Hz), 7.98 (s,
Found: C, 51.71; H, 3.93; N, 20.05.
13
1H). C nmr (deuteriochloroform, 50 MHz): δ 36.5 (CH ), 115.1
2
6-Chloro-2-cyclohexylidenemethyl-3-nitroimidazo[1,2-b]pyri-
dazine (8c).
(CH), 118.3 (CH), 125.3 (CH), 136.9 (C), 144.7 (C), 146.1 (C).
Anal. Calcd for C H Cl N : C, 41.61; H, 2.49; N, 20.80.
7
5
2 3
Found: C, 41.59; H, 2.53; N, 20.82.
This compound was obtained as a brown solid in 62% yield;
mp 150 °C. H nmr (deuteriochloroform, 200 MHz): δ 1.67 (m,
1
6-Chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine (5).
6H), 2.41 (t, 2H, J = 5.5 Hz), 2.98 (t, 2H, J = 5.5 Hz), 6.91 (s,
13
To a solution of 6-chloro-2-chloromethylimidazo[1,2-b]pyri-
dazine (4) (2.5 g, 12.4 mmoles) in concentrated sulfuric acid (25
ml) cooled to – 10 °C was added dropwise nitric acid (d = 1.38,
2.5 ml) without allowing the temperature to rise above –5 °C.
The reaction mixture was stirred at the same temperature for 2
hours, warmed to room temperature and poured into cooled
water. The yellow precipitate obtained was filtered, washed with
water, dried and recrystallized from ethanol to give 2.6 g (87%)
of 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine (5);
1H), 7.37 (d, 1H, J = 9.5 Hz), 7.96 (d, 1H, J = 9.5 Hz). C nmr
(deuteriochloroform, 50 MHz): δ 26.3 (CH ), 27.9 (CH ), 28.8
2
2
(CH ), 30.6 (CH ), 38.8 (CH ), 111.2 (CH), 123.7 (CH), 126.8
2
2
2
(CH), 137.3 (C), 146.2 (C), 148.4 (C), 158.2 (C).
Anal. Calcd for C ClN O : C, 53.34; H, 4.48; N, 19.14.
H
13 13
4 2
Found: C, 53.28; H, 4.52; N, 19.13.
6-Chloro-2-cycloheptylidenemethyl-3-nitroimidazo[1,2-b]pyri-
dazine (8d).
1
mp 196 °C. H nmr (deuteriochloroform, 200 MHz): δ 5.14 (s,
This compound was obtained as a brown solid in 54% yield;
13
1
2H), 7.52 (d, 1H, J = 9.5 Hz), 8.14 (d, 1H, J = 9.5 Hz). C nmr
(deuteriochloroform, 50 MHz): δ 38.3 (CH ), 124.5 (CH), 127.8
(CH), 137.3 (C), 145.1 (C), 150.3 (C).
mp 152 °C. H nmr (deuteriochloroform, 200 MHz): δ 1.57 (m,
8H), 2.54 (t, 2H, J = 5.6 Hz), 3.03 (t, 2H, J = 5.6 Hz), 7.11 (s, 1H),
2
13
7.36 (d, 1H, J = 9.5 Hz), 7.95 (d, 1H, J = 9.5 Hz). C nmr (deu-
Anal. Calcd for C H Cl N O : C, 34.03; H, 1.63; N, 22.68.
teriochloroform, 50 MHz): δ 26.6 (CH ), 28.6 (CH ), 29.2
7
4
2 4 2
2
2
Found: C, 34.08; H, 1.66; N, 22.64.
(CH ), 29.8 (CH ), 33.0 (CH ), 40.0 (CH ), 113.7 (CH), 123.6
2 2 2 2
(CH), 126.9 (CH), 137.3 (C), 146.3 (C), 148.3 (C), 161.3 (C).
Anal. Calcd for C ClN O : C, 54.82; H, 4.93; N, 18.26.
Found: C, 54.80; H, 4.90; N, 18.20.
General Procedure for S 1 Reactions with Aliphatic and Cyclic
Nitronate Anions.
RN
H
14 15
4 2
Under nitrogen atmosphere, a solution of tetrabutylammonium
hydroxide (40% in water, 1.62 ml, 2.4 mmoles) was treated with
nitroalkane (2.4 mmoles) or ethyl-2-nitropropionate (0.354 g, 2.4
mmoles) for 1 hour. A solution of 6-chloro-2-chloromethyl-3-
nitroimidazo[1,2-b]pyridazine (5) (0.2 g, 0.8 mmoles) in
dichloromethane (20 ml) was added and the mixture was stirred
6-Chloro-2-cyclooctylidenemethyl-3-nitroimidazo[1,2-b]pyri-
dazine (8e).
This compound was obtained as a brown solid in 43% yield;
1
mp 172 °C. H nmr (deuteriochloroform, 200 MHz): δ 1.50 (m,
6H), 1.84 (m, 4H), 2.51 (t, 2H, J = 6 Hz), 2.97 (t, 2H, J = 6 Hz),

176
T. Terme, C. Galtier, J. Maldonado, M. P. Crozet, A. Gueiffier, P. Vanelle
Vol. 39
7.09 (s, 1H), 7.36 (d, 1H, J = 9.5 Hz), 7.95 (d, 1H, J = 9.5 Hz).
and 2-nitropropane (0.215 g, 2.4 mmoles). After work up and
13
C nmr (deuteriochloroform, 50 MHz): δ 25.8 (CH ), 26.5
purification, the 6-chloro-2-formylimidazo[1,2-b]pyridazine (9)
2
1
(CH ), 26.8 (CH ), 27.1 (CH ), 27.4 (CH ), 31.3 (CH ), 39.5
was obtained as a yellow solid in 5% yield; mp 120 °C. H nmr
2
2
2
2
2
(CH ), 113.7 (CH), 123.6 (CH), 126.8 (CH), 137.4 (C), 146.2
(deuteriochloroform, 200 MHz): δ 7.19 (d, 1H, J = 9.5 Hz), 8.00
2
(C), 148.2 (C), 162.9 (C).
(d, 1H, J = 9.5 Hz), 8.44 (s, 1H), 10.15 (s, 1H).
Anal. Calcd for C
H
ClN O : C, 56.16; H, 5.34; N, 17.47.
Anal. Calcd for C H ClN O: C, 46.30; H, 2.22; N, 23.14.
15 17
4
2
7 4 3
Found: C, 56.11; H, 5.39; N, 17.44.
Found: C, 46.22; H, 2.18; N, 23.11.
6-Chloro-2-cyclododecylidenemethyl-3-nitroimidazo[1,2-b]-
pyridazine (8f).
Inhibited Reaction of 5 with 2-Nitropropane (6) (Table 1).
The procedure was similar to that of the general procedure except
that the inhibitor was added to the reaction mixture immediately
prior to the chloride 5. The study in the dark was obtained by wrap-
ping the flask in aluminium foil. The inhibition study with molecu-
lar oxygen was carried out by replacing nitrogen with oxygen.
This compound was obtained as a brown solid in 29% yield; mp
1
182 °C. H nmr (deuteriochloroform, 200 MHz): δ 1.41 (m, 14H),
1.65 (m, 4H), 2.39 (t, 2H, J = 6.8 Hz), 2.89 (t, 2H, J = 6.8 Hz), 7.02
13
(s, 1H), 7.36 (d, 1H, J = 9.5 Hz), 7.95 (d, 1H, J = 9.5 Hz). C nmr
(deuteriochloroform, 50 MHz): δ 22.2 (CH ), 23.0 (CH ), 23.7
2
2
6-Chloro-2-(2,2-dimethyl[1,3]dioxan-5-ylidenemethyl)-3-
nitroimidazo[1,2-b]pyridazine (10).
(CH ), 24.1 (CH ), 24.2 (CH ), 24.3 (CH ), 24.4 (CH ), 24.6
2
2
2
2
2
(CH ), 24.8 (CH ), 29.8 (CH ), 33.6 (CH ), 114.6 (CH), 123.6
2
2
2
2
(CH), 126.9 (CH), 137.2 (C), 146.5 (C), 148.4 (C), 157.5 (C).
2,2-Dimethyl-5-nitro-1,3-dioxane salt (0.405 g, 2.42 mmoles)
was added to a solution of 6-chloro-2-chloromethyl-3-nitroimi-
dazo[1,2-b]pyridazine (5) (0.2 g, 0.8 mmoles) in dry dimethylfor-
mamide (30 ml). The reaction was allowed to proceed for 6 hours
at room temperature under nitrogen and in the presence of light
(300 W fluorescent lamp). After stirring, the reaction mixture was
removed under reduced pressure. The residue was dissolved in
dichloromethane (40 ml), washed with water (2 x 30 ml), dried
over anhydrous magnesium sulfate and removed under reduced
pressure. Purification by chromatography on silica gel eluting
with dichloromethane and recrystallization from ethanol gave 6-
chloro-2-(2,2-dimethyl[1,3]dioxan-5-ylidenemethyl)-3-nitroimi-
dazo[1,2-b]pyridazine (10) as a brown solid in 53% yield; mp 176
Anal. Calcd for C ClN O : C, 60.55; H, 6.69; N, 14.87.
H
19 25
4 2
Found: C, 60.38; H, 6.57; N, 14.70.
6-Chloro-2-(2,6-dimethylhepten-1-yl)-3-nitroimidazo[1,2-b]-
pyridazine (8g).
This compound was obtained as a brown solid in 58% yield;
1
mp 102 °C. H nmr (deuteriochloroform, 200 MHz): δ 0.89 (d,
6H, J = 3 Hz), 1.25 (m, 3H), 1.60 (m, 4H), 2.31 (m, 3H, J = 6 Hz),
6.98 (s, 1H), 7.37 (d, 1H, J = 9.5 Hz), 7.95 (d, 1H, J = 9.5 Hz).
13
C nmr (deuteriochloroform, 50 MHz): δ 19.4 (CH ), 22.5
3
(CH ), 22.6 (CH ), 25.7 (CH ), 27.8 (CH), 38.5 (CH ), 42.1
3
3
2
2
(CH ), 113.7 (CH), 123.7 (CH), 126.9 (CH), 137.1 (C), 146.4
2
1
(C), 148.4 (C), 155.8 (C).
°C. H nmr (deuteriochloroform, 200 MHz): δ 1.45 (s, 6H), 4.48
(s, 2H), 5.07 (s, 2H), 7.04 (s, 1H), 7.40 (d, 1H, J = 9.5 Hz), 7.98 (d,
1H, J = 9.5 Hz). C nmr (deuteriochloroform, 50 MHz): δ 24.0
Anal. Calcd for C
Found: C, 55.72; H, 5.95; N, 17.32.
H ClN O : C, 55.81; H, 5.93; N, 17.36.
15 19 4 2
13
(2xCH ), 62.4 (CH ), 64.0 (CH ), 99.9 (C), 110.4 (CH), 124.1
(CH), 127.1 (CH), 137.4 (C), 144.3 (C), 148.9 (C), 152.0 (C).
3
2
2
6-Chloro-3-nitro-2-(2-phenylpropenyl)imidazo[1,2-b]pyridazine
(8h).
Anal. Calcd for C ClN O : C, 48.08; H, 4.04; N, 17.25.
H
13 13
4 4
This compound was obtained as a brown solid in 65% yield;
mp 234 °C. H nmr (deuteriochloroform, 200 MHz): δ 2.71 (s,
Found: C, 48.01; H, 4.09; N, 17.18.
1
2-(6-Chloro-3-nitroimidazo[1,2-b]pyridazin-2-ylmethylene)-
propane-1,3-diol (11).
3H), 7.39 (m, 5H), 7.50 (s, 1H), 7.62 (d, 1H, J = 9.5 Hz), 8.01 (d,
13
1H, J = 9.5 Hz). C nmr (deuteriochloroform, 50 MHz): δ 18.6
(CH ), 115.6 (CH), 123.9 (CH), 126.5 (2xCH), 127.0 (CH),
128.5 (2xCH), 128.7 (CH), 137.4 (C), 143.1 (C), 148.8 (C), 150.0
(C), 186.2 (C).
A stirred mixture of 6-chloro-2-(2,2-dimethyl-[1,3]dioxan-5-
ylidenemethyl)-3-nitroimidazo[1,2-b]pyridazine (10) (1.5 g, 4.6
mmoles) and 0.32 g of ion-exchange resin (Dowex 50x8-50,
Aldrich) in methanol (75 ml) was refluxed for 24 hours. After fil-
tration of the resin and evaporation under reduced pressure, the
residue was purified by recrystallization from ethanol to give
1.13 g (86% yield) of 2-(6-chloro-3-nitroimidazo[1,2-b]-
pyridazin-2-ylmethylene)propane-1,3-diol (11) as an orange
3
Anal. Calcd for C H ClN O : C, 57.24; H, 3.52; N, 17.80.
15 11
4 2
Found: C, 57.18; H, 3.55; N, 17.75.
3-(6-Chloro-3-nitroimidazo[1,2-b]pyridazin-2-yl)-2-methyl
Acrylic Acid Ethyl Ester (8i).
1
solid; mp 166 °C. H nmr (dimethylsulfoxide-d , 200 MHz): δ
This compound was obtained as a dark pink solid in 59% yield;
6
1
3.15-3.55 (br, 2H, OH), 4.34 (s, 2H, CH ), 4.68 (s, 2H, CH ),
mp 178 °C. H nmr (deuteriochloroform, 200 MHz): δ 1.21 (t,
2
2
3H, J = 7.1 Hz), 2.31 (s, 3H), 4.18 (q, 2H, J = 7.1 Hz), 7.31 (d,
1H, J = 9.5 Hz), 7.92 (d, 1H, J = 9.5 Hz), 8.02 (s, 1H). C nmr
7.25 (s, 1H, CH), 7.85 (d, 1H, J = 9.1 Hz), 8.46 (d, 1H, J = 9.1
13
13
Hz). C nmr (dimethylsulfoxide-d , 50 MHz): δ 59.6 (CH ),
6
2
(deuteriochloroform, 50 MHz): δ 14.2 (CH ), 15.0 (CH ), 61.5
62.5 (CH ), 110.8 (CH), 125.3 (CH), 128.4 (CH), 138.3 (C),
3
3
2
(CH ), 124.3 (CH), 124.8 (CH), 127.6 (CH), 137.3 (C), 138.7
144.9 (C), 148.3 (C), 157.1 (C).
2
(C), 143.2 (C), 149.6 (C), 167.7 (C).
Anal. Calcd for C H ClN O : C, 42.19; H, 3.19; N, 19.68.
10
9
4 4
Anal. Calcd for C H ClN O : C, 46.39; H, 3.57; N, 18.03.
Found: C, 42.08; H, 3.26; N, 19.63.
12 11
4 4
Found: C, 46.34; H, 3.59; N, 18.01.
6-Chloro-2-(3-chloro-2-chloromethylpropenyl)-3-nitroimi-
Influence of Electron-withdrawing Group.
dazo[1,2-b]pyridazine (12).
The procedure was similar to that for using 6-chloro-2-
Thionyl chloride (0.8 ml, 10.5 mmoles) was added dropwise to a
chloromethylimidazo[1,2-b]pyridazine (4) (0.145 g, 0.8 mmoles)
solution of (11) (0.5 g, 1.75 mmoles) in dry dichloromethane (10

Jan-Feb 2002
Synthesis of 2-Substituted-3-nitroimidazo[1,2-b]pyridazines
177
[3a] M. Kuwahara, K. Kawano, H. Shimazu, H. Yamamoto, Y.
Ashida and A. Miyake, Chem. Pharm. Bull., 43(9), 1517 (1995); [b]
M. Kuwahara, K. Kawano, H. Shimazu, Y. Ashida and A. Miyake,
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Abstr., 127, 318972z (1997).
[4] T. Fusaka, O. Ujikawa, T. Kajiwara and Y. Tanaka, PCT
Int. Appl. WO 97 11,075 (1997); Chem. Abstr., 126, 293354p (1997).
[5a] H. Yukimasa and M. Nakao, Eur. Pat. Appl. EP 632,040
(1995); Chem. Abstr., 122, 214110x (1995); [b] H. Yukimasa and M.
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[d] Y. Akiyama, M. Nakao, N. Nagahara and E. Nara, Jpn Kokai
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ml) in a round-bottomed flask equipped with a reflux condenser
surmounted by a calcium chloride drying tube. After stirring at
room temperature for 24 hours, the reaction mixture was evapo-
rated under reduced pressure. The residue was dissolved in water
(20 ml), the aqueous solution was then basified with saturated
sodium bicarbonate solution. Extraction with dichloromethane (2 x
20 ml), drying of the extracts over anhydrous magnesium sulfate,
removal of the solvent under reduced pressure and recrystallization
of the product from ethanol gave 0.44 g (79% yield) of 6-chloro-2-
(3-chloro-2-chloromethylpropenyl)-3-nitroimidazo[1,2-b]pyri-
1
dazine (12) as a brown solid; mp 144 °C. H nmr (deuteriochloro-
form, 200 MHz): δ 4.48 (s, 2H), 5.14 (s, 2H), 7.43 (s, 1H), 7.46 (d,
13
1H, J = 9.5 Hz), 8.06 (d, 1H, J = 9.5 Hz). C nmr (deuteriochloro-
form, 50 MHz): δ 39.4 (CH ), 47.1 (CH ), 120.4 (CH), 124.6
2
2
(CH), 127.6 (CH), 137.3 (C), 142.0 (C), 143.8 (C), 149.8 (C).
Anal. Calcd for C H Cl N O : C, 37.35; H, 2.19; N, 17.42.
10
7
3 4 2
Found: C, 37.27; H, 2.24; N, 17.35.
[6a] P. Vanelle, J. Maldonado, N. Madadi, A. Gueiffier, J. C.
Teulade, J. P. Chapat and M. P. Crozet, Tetrahedron Letters, 31, 3013
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P. Crozet, Tetrahedron, 47, 5173 (1991); [c] P. Vanelle, S. Ghezali, J.
Maldonado, O. Chavignon, A. Gueiffier, J. C. Teulade and M. P.
Crozet, Heterocycles, 36, 1541 (1993); [d] P. Vanelle and M. P.
Crozet, Recent Res. Devel. Organic Chem., 2, 547 (1998); [e] P.
Vanelle, K. Benakli, L. Giraud and M. P. Crozet, Synlett, 801 (1999);
[f] P. Vanelle, T. Terme, L. Giraud and M. P. Crozet, Recent Res.
Devel. Organic Chem., 4, 1 (2000).
Acknowledgements.
This work has been supported by the Centre National de la
Recherche Scientifique and the Universities of Aix-Marseille and
1
13
Tours. We express our thanks to M. Noailly for H and C nmr
spectra recording. T. Terme thanks the President of the Université
de la Méditerranée for his appointement as ATER at Université
de la Méditerranée. Moreover, we thank Jérôme Grassi for tech-
nical assistance.
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Randles, Tetrahedron Letters, 13, 3063 (1972).
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