Reactivity of 2-substituted imidazo[1,2-b]pyridazines: Preparation of 3-nitro, nitroso and chloro derivatives

Article abstract of DOI:10.1002/jhet.5570390419

The synthesis of 2-substitutedimidazo[1,2-b]pyridazines and their reactivity towards electrophilic substitutions are reported. The nitration was shown to be very dependent on the nature of the 2 substituent. Nitrosation using sodium nitrite in acetic acid media as a general method failed in all cases whereas chlorination was observed in warm hydrochloric acid. In order to ascertain the structure of some chloro derivatives, chlorination using N-chlorosuccinimide was also reported. Depending of the nature of the substituent, the reaction occurred at the C-3 imidazolic position and/or at the substituent on position 2. The 3-nitroso-2-phenyl derivative was finally obtained using an alternative synthetic pathway by direct condensation of 3-amino-6-chloropyridazine to ω-chloro-ω-nitrosoacetophenone. The structural determinations were ascertained using high field ¹H and ¹³C-NMR.

Full text of DOI:10.1002/jhet.5570390419

Reactivity of 2-Substituted Imidazo[1,2-b]pyridazines:
Preparation of 3-Nitro, Nitroso and Chloro Derivatives
Maud Hervet, Christophe Galtier, Cécile Enguehard and Alain Gueiffier*
737
Jul-Aug 2002
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 31 Avenue Monge, 37200 Tours, France
Jean-Claude Debouzy
Unité de Biophysique, Centre de Recherche du Service de Santé des Armées,
24 Avenue des Maquis du Gresivaudan, 38702 La Tronche Cedex, France
Received November 30, 2000
The synthesis of 2-substitutedimidazo[1,2-b]pyridazines and their reactivity towards electrophilic
substitutions are reported. The nitration was shown to be very dependent on the nature of the 2 substituent.
Nitrosation using sodium nitrite in acetic acid media as a general method failed in all cases whereas
chlorination was observed in warm hydrochloric acid. In order to ascertain the structure of some chloro
derivatives, chlorination using N-chlorosuccinimide was also reported. Depending of the nature of the
substituent, the reaction occurred at the C-3 imidazolic position and/or at the substituent on position 2. The
3-nitroso-2-phenyl derivative was finally obtained using an alternative synthetic pathway by direct
condensation of 3-amino-6-chloropyridazine to ω-chloro-ω-nitrosoacetophenone. The structural
1
13
determinations were ascertained using high field H and C-NMR.
J. Heterocyclic Chem., 39, 737 (2002).
Introduction.
In continuation of our studies on the synthesis, the
reactivity and the pharmacological properties of
imidazolic bridgehead nitrogen heterocycles, we have
recently reported the synthesis and the antiviral activity of
substituted 3-aralkylthiomethyl, 3-ureido and 3-thio-
ureidoimidazo[1,2-b]pyridazines [1,2]. To advance our
studies to design a pharmacophore model, we were now
interested in the preparation of 3-amino-2-substituted
derivatives. The usual synthetic pathways use reduction
with tin in hydrobromic acid of the corresponding nitro
compound [3]. Surprisingly, a bibliographic research
showed that electrophilic substitutions in these series were
poorly studied. These works deal with the nitration and
halogenation of unsubstituted derivatives in position 2 [4].
To the best of our knowledge, concerning the 2-substituted
compounds only nitration and bromination of 2-methyl
derivatives [4b,5] and Mannich aminomethylation,
nitration and bromination of 2-aryl compounds [4c,4g]
were described. Thus a general study of nitration, nitro-
sation and chlorination of various 2-aryl or heteroaryl
derivatives was investigated.
When ethyl 6-chloro-7- and 8-methylimidazo[1,2-b]-
pyridazine-2-carboxylate (2, 3) were treated with nitric acid
(d = 1.41), no reaction occurred. Under the same conditions,
the 2-phenyl derivatives (4, 5) led to dinitro compounds
(11, 12) in 90 and 70% yield respectively (Scheme 2). Proof
Results and Discussion.
1
of the structures was easily found in H-NMR spectroscopy
In order to study the influence of the substituent in position
2 on the reactivity, various 2-substituted-6-chloroimidazo-
[1,2-b]pyridazines (2-10) were prepared by condensation of
3-amino-6-chloropyridazine derivatives (1a-c) with the appro-
priate α-halogenocarbonyl compound in refluxing ethanol
(Scheme 1). The 3-amino-6-chloro-4- and 5-methyl-
pyridazines 1a and 1b were used as a 1:10 mixture.The
separation of the two isomers was performed after the cyclisa-
tion from the obtained mixture of 7- and 8-methyl-6-chloro-
imidazo[1,2-b]pyridazines derivatives.
with the disappearance of the H-3 absorption, whereas the
phenyl ring appeared as a para substituted group. The same
reaction applied to the para-chloro derivatives (6, 7) and
thien-2-yl compound (8) gave a complex mixture which
could not be separated. Under the same conditions, the
fur-2-yl derivative (10) led to total degradation.
We then turned our interest to the nitrosation reaction. It
is well established that in bicyclic fused imidazoles with
bridgehead nitrogen atoms, the reaction occurs in the

738
M. Hervet, C. Galtier, C. Enguehard, A. Gueiffier and J.-C. Debouzy
Vol. 39
submitted to sodium nitrite in acetic acid media, no
reaction occurred. Surprisingly, reaction with the 2-phenyl
derivatives (4, 5) failed as well. These compounds had
poor solubility in acetic acid media so we decided to
perform the reaction in hydrochloric acid in order to
solubilize as the salt. At room temperature no reaction was
found so the reaction mixture was heated at 60 °C for
3 hours. As previously observed the reaction failed with
the ester whereas the phenyl derivative (4) led to the
formation of a single product (13) in 25% yield
1
(Scheme 3). The H-NMR spectrum showed the
13
disappearance of H-3 absorption but in C-NMR, the
absorption of C-3 at δ : 111.2 did not agree with a nitroso
substitution. Furthermore no nitroso band was found in IR
spectrum. Finally, the mass spectrum showed the presence
of two chlorine atoms. These data allowed us to determine
(13) as 3,6-dichloro-7-methyl-2-phenylimidazo[1,2-b]-
pyridazine.
Further confirmation was obtained using the reaction on
the p-chloroderivative (6). The same conditions led to the
3-chloro derivative (14) in 15% yield. When the reaction
was applied to the thienyl compound (8) a mixture of two
derivatives was obtained. The first one was determined as
3-position using sodium nitrite in acetic acid media for the
2-aryl compounds [6] whereas compounds with ester
groups in the same position require the use of nitrosyl
chloride [7]. As expected, when the esters (2, 3) were
1
the 3-chloro derivative (16) from the H-NMR spectrum.
The second compound was identified as the trichloro
derivative (15). The position of the last chlorine was
1
determined from the H-NMR spectrum. The thienyl
group appeared as two doublets with a J-value of 4 Hz
indicative of a 2,5-disubstituted derivative. Finally, the
reaction was applied to the furyl compound (10) to give
only tar materials. Since the halogenation occurred at an
electrophilic position hydrochloric acid might not act as
the reactant. This hypothesis was easily confirmed as no
reaction occurred when (4) was heating at 60 °C for
3 hours in hydrochloric acid. A possible explanation is the
formation of chlorine by oxidation of nitrosyl chloride
formed in the experimental conditions as reported by
Drozin et al. [8].
In order to ascertain the structure of the chloro
derivatives, we decided to study the chlorination reaction.
From the various reaction conditions available, we chose
to use the N-chlorosuccinimide in chloroform media. In
these conditions, the thienyl derivative (8) gave (15,16)
identified by comparison with samples prepared above.
Further confirmation was obtained using an unambiguous
method. Thus the 5-chlorothien-2-yl compound (9) reacted
with NCS in the same conditions to give (15) in 86% yield.
When the reaction was attempted on the furyl derivative
(10), a set of three compounds was obtained (Scheme 4).
The major derivative (45% yield) was determined as the
1
3,6-dichloro derivative (19). The H-NMR spectrum of
(18) showed an H-3 absorption and the furyl group
appeared as two doublets with a J-value of 3.6 Hz indica-
tive of a 2,5-disubstitution. The last one (17) was easily
demonstrated as the 3,6,5'-trichloro compound from the
1
H-NMR spectrum.

Jul-Aug 2002
Reactivity of 2-Substituted Imidazo[1,2-b]pyridazines
739
EXPERIMENTAL
General Details
Melting points were determined on a Kofler Hotstage and were
uncorrected. The NMR spectra were recorded on a Bruker DPX
1
200 or Bruker AM 400 WB spectrometers. H-NMR chemical
shifts are expressed in ppm from the residual CHCl at 7.30 ppm
3
13
or DMSO at 2.5 ppm. C-NMR chemical shifts are given from
the central resonance of CDCl at 77.1 ppm or DMSO-d at
3
6
43.5 ppm. Mass spectrum was recorded on a HP 5989A
spectrometer using electronic impact at 70eV. Elemental analysis
were performed by the microanalytical center, ENSCM,
Montpellier, France. The 3-amino-6-chloro-4- and 5-methyl-
pyridazines were synthesized according to previously described
method leading to a 1:10 mixture of unseparable isomers [11].
The bromoketones were commercially available with the
exception of 2-bromoacetylthiophene, 2-bromoacetyl-5-
chlorothiophene and 2-bromoacetylfuran which were prepared
according to previously reported methods [12-14].
In our search for a method to prepare 3-amino
derivatives we then investigated another synthetic
pathway. It was described that the reaction of ω-chloro-ω-
nitrosoacetophenone with an α-aminonitrogen heterocycle
in ethanol at room temperature gave 2-aryl-3-nitroso fused
imidazole compounds [9]. Thus, this reaction was
attempted on 3-amino-6-chloropyridazine (Scheme 5).
Under these conditions, the expected nitroso derivative
(20) was obtained in 68% yield (not optimized). During
the preparation of this article, the use of this reaction was
described by Billi et al., using 3-amino-6-chloropyridazine
and 2-(4-chlorophenyl)-N-hydroxy-2-oxoethaneimidoyl
chloride [10]. Proof of the structure (20) was found in
NMR spectroscopy with the disappearance of the H-3
absorption while C-3 was shifted upfield to 153.0 ppm in
agreement with Billi.
General Procedure for Preparation of Imidazo[1,2-b]pyridazines
(2-10).
A suspension of 0.069 mole of 3-amino-6-chloropyridazine 1c
or of a mixture 1:10 of 3-amino-6-chloro-4- and 5-methyl-
pyridazines 1a-b and 0.084 mole of bromoketone in 100 mL of
ethanol was refluxed for 5 hours and after cooling evaporated to
dryness. The residue was suspended in water, made alkaline with
sodium carbonate and extracted with dichloromethane. After
drying over calcium chloride, the organic layers were evaporated
to dryness.
Ethyl 6-Chloro-7-methylimidazo[1,2-b]pyridazine-2-carboxylate
(2) and Ethyl 6-Chloro-8-methylimidazo[1,2-b]pyridazine-2-
carboxylate (3).
The residue was chromatographed on neutral alumina eluting
with dichloromethane then on neutral alumina eluting with
dichloromethane/petroleum ether (40:60 v/v) to give 0.995 g
1
(6%) of 2, mp 191 °C [Lit [15] 190-192 °C]; H NMR (CDCl ,
3
200 MHz): δ 1.46 (t, 3H, CH , J = 7.2Hz), 2.49 (d, 3H, CH , J =
3
3
1.0Hz), 4.48 (q, 2H, CH , J = 7.2Hz), 7.83 (br. s, 1H, 8-H), 8.41
2
13
(s, 1H, 3-H); C NMR (CDCl , 50 MHz): δ 14.8 (CH ), 20.4
3
3
(CH ), 61.8 (CH ), 120.5 (3-C), 126.7 (8-C), 130.4 (7-C), 137.0
3
2
(2-C), 139.2 (8a-C), 151.0 (6-C), 163.0 (C=O).
Further elution gave 3.55 g (21%) of 3, mp 88 °C [Lit [15]
1
83-85 °C]; H NMR (CDCl , 200 MHz): δ 1.37 (t, 3H, CH , J =
3
3
7.1Hz), 2.65 (d, 3H, CH , J = 1.1Hz), 4.41 (q, 2H, CH , J =
3
2
Conclusions.
13
7.1Hz), 6.92 (d, 1H, 7-H, J = 1.1Hz), 8.33 (s, 1H, 3-H); C NMR
(CDCl , 50 MHz): δ 14.7 (CH ), 17.1 (CH ), 61.7 (CH ), 120.1
3
3
3
2
In this work, we report the synthesis and the reactivity of
some 2-substitutedimidazo[1,2-b]pyridazines. We have
shown that depending upon the nature of the substituent, the
electrophilic reactions occurred at the 3-position and/or on
the 2-aryl or heteroarylsubstituent. In many cases this ring
system was shown to be less reactive than imidazo[1,2-a]-
pyridines. In research directed to the preparation of
3-aminoimidazo[1,2-b]pyridazines we condensed ω-chloro-
ω-nitrosoacetophenone with 6-chloro-3-aminopyridazine
and obtained the desired nitroso compound (20). The scope
and limitation of this method are under investigation.
(7-C), 121.6 (3-C), 136.4 (2-C), 139.5 (8a-C), 141.0 (8-C), 148.9
(6-C), 162.8 (C=O).
6-Chloro-7-methyl-2-phenylimidazo[1,2-b]pyridazine (4) and
6-Chloro-8-methyl-2-phenylimidazo[1,2-b]pyridazine (5).
These compounds were separated as above to give 5.26 g
1
(31%) of 4, mp 193 °C; H NMR (CDCl , 200 MHz): δ 2.45
3
(d, 3H, CH , J = 1.1Hz), 7.42 (m, 3H, 3',4',5'-H), 7.75 (q, 1H,
3
13
8-H, J = 1.1Hz), 7.95 (m, 2H, 2',6'-H), 8.15 (s, 1H, 3-H);
C
NMR (CDCl , 50 MHz): δ 20.2 (CH ), 112.4 (3-C), 125.3 (8-C),
3
3
126.4 (2',6'-C), 128.1 (7-C), 128.9 (4'-C), 129.2 (3',5'-C), 133.4
(1'-C), 139.5 (8a-C), 146.4 (2-C), 148.5 (6-C).

740
M. Hervet, C. Galtier, C. Enguehard, A. Gueiffier and J.-C. Debouzy
Vol. 39
Anal. Calcd. for C
H
N Cl: C, 64.06; H, 4.11; N, 17.25.
J = 3.4Hz, J
= 0.8Hz), 7.09 (d, 1H, 7-H, J = 9.4Hz), 7.55
3',5' 7,8
13 10
3
Found: C, 64.15; H, 4.09; N, 17.10.
Further elution give 1.90 g (11%) of 5, mp 160 °C; H NMR
(CDCl , 200 MHz): δ 2.73 (s, 3H, CH ), 6.90 (s, 1H, 7-H), 7.46
(dd, 1H, 5'-H, J = 1.8 Hz, J = 0.8 Hz), 7.90 (d, 1H, 8-H, J =
1
13
9.4Hz), 8.16 (s, 1H, 3-H); C NMR (CDCl , 50 MHz): δ 108.2
3
(3'-C), 112.2 (4'-C), 113.1 (3-C), 119.6 (7-C), 126.5 (8-C), 138.4
(8a-C), 139.2 (2-C), 143.3 (5'-C), 147.1 (6-C), 149.0 (2'-C).
Anal. Calcd. for C H N OCl: C, 54.67; H, 2.73; N, 19.13.
3
3
13
(m, 3H, 3',4',5'-H), 8.00 (m, 2H, 2',6'-H), 8.19 (s, 1H, 3-H) ;
C
NMR (CDCl , 50 MHz): δ 17.0 (CH ), 113.5 (3-C), 118.3 (7-C),
3
3
10
6 3
126.4 (2',6'-C), 128.9 (4'-C), 129.2 (3', 5'-C), 133.5 (1'-C), 139.1
(8-C), 139.6 (8a-C), 146.0 (2-C), 146.7 (6-C).
Found: C, 54.82; H, 2.95; N, 19.30.
General Procedure for Nitration.
Anal. Calcd. for C
H N Cl: C, 64.06; H, 4.11; N, 17.25.
13 10 3
Found: C, 63.86; H, 4.01; N, 17.32.
To concentrated sulfuric acid (15 mL) cooled to –10 °C was
added portionwise 6.16 mmoles of the imidazopyridazine
derivative (2-10) without the temperature rising above –5 °C.
After complete dissolution, nitric acid (d = 1.41, 1.5 mL) was
added keeping the temperature below –5 °C. The resulting
mixture was stirred for further 1 hour at –10 °C then was poured
on ice. The precipitate that was formed was filtered off, dried in a
dessicator to give the nitro derivatives.
6-Chloro-2-(4-chlorophenyl)-7-methylimidazo[1,2-b]pyridazine
(6) and 6-Chloro-2-(4-chlorophenyl)-8-methylimidazo[1,2-b]-
pyridazine (7).
These compounds were purified as for 2 and 3 to give 8.1 g
1
(42%) of 6, mp 181-182 °C; H-NMR (CDCl , 200 MHz): δ
3
2.49 (s, 3H, CH ), 7.44 (m, 2H, 3',5'-H), 7.77 (s, 1H, 8-H), 7.89
3
13
(m, 2H, 2',6'-H), 8.14 (s, 1H, 3-H); C NMR (CDCl , 50 MHz):
3
6-Chloro-7-methyl-3-nitro-2-(4-nitrophenyl)imidazo[1,2-b]pyri-
dazine (11).
δ 20.3 (CH ), 112.4 (3-C), 125.3 (8-C), 127.6 (2',6'-C), 128.4
3
(7-C), 129.4 (3',5'-C), 132.0 (4'-C), 134.7 (1'-C), 139.6 (8a-C),
145.3 (2-C), 148.7 (6-C).
Compound 11 was obtained in 91% yield (1.88 g), mp
Anal. Calcd. for C H N Cl : C, 56.11; H, 3.24; N, 15.11.
1
13
9
3
2
186 °C; H NMR (CDCl , 200 MHz): δ 2.64 (d, 3H, CH , J =
3
3
Found: C, 56.20; H, 3.25; N, 15.06.
Further elution gave 8.6 g (44%) of 7, mp 180 °C; H NMR
(CDCl , 200 MHz): δ 2.71 (d, 3H, CH , J = 1.1Hz), 6.90 (q, 1H,
1.1Hz), 7.99 (q, 1H, 8-H, J = 1.1Hz), 8.13 (m, 2H, 2',6'-H),
1
13
8.40 (m, 2H, 3',5'-H); C NMR (CDCl , 100 MHz): δ 20.2
3
3
3
(CH ), 123.4 (3',5'-C), 125.7 (8-C), 130.8 (2',6'-C), 134.3
3
7-H, J = 1.1Hz), 7.44 (m, 2H, 3',5'-H), 7.91 (m, 2H, 2',6'-H), 8.14
(7-C), 137.0 (1'-C), 138.3 (8a-C), 139.4 (3-C), 143.6 (2-C),
148.6 (4'-C), 151.6 (6-C).
13
(s, 1H, 3-H); C NMR (CDCl , 50 MHz): δ 17.0 (CH ), 113.6
3
3
(3-C), 118.5 (7-C), 127.7 (2',6'-C), 129.4 (3',5'-C), 132.0 (4'-C),
134.6 (1'-C), 139.1 (8-C), 139.6 (8a-C), 144.8 (2-C), 146.9 (6-C).
Anal. Calcd. for C H N O Cl: C, 46.78; H, 2.40; N, 20.99.
13
8 5 4
Found: C, 46.82; H, 2.38; N, 20.96.
Anal. Calcd. for C H N Cl : C, 56.11; H, 3.24; N, 15.11.
13
9
3
2
Found: C, 55.97; H, 3.36; N, 15.27.
6-Chloro-8-methyl-3-nitro-2-(4-nitrophenyl)imidazo[1,2-b]-
pyridazine (12).
6-Chloro-2-(thien-2-yl)imidazo[1,2-b]pyridazine (8).
Compound 12 was obtained in 70% yield (1.88 g), mp
The residue was chromatographed on neutral alumina eluting
with dichloromethane to give 2.25 g (25%) of 8 mp 222-224 °C;
1
252 °C; H NMR (CDCl , 200 MHz): δ 2.82 (d, 3H, CH , J =
3
3
1.1Hz), 7.35 (q, 1H, 7-H, J = 1.1Hz), 8.14 (m, 2H, 2',6'-H),
1
H NMR (CDCl , 200 MHz): δ 7.08 (d, 1H, 7-H, J = 9.4Hz),
3
7,8
13
8.40 (m, 2H, 3',5'-H); C NMR (CDCl , 100 MHz): δ 16.8
3
7.16 (dd, 1H, 4'-H, J = 5Hz, J = 3.6Hz), 7.41 (dd, 1H, 5'-H,
4',5'
4',3'
(CH ), 123.6 (7-C), 124.0 (3',5'-C), 131.2 (2',6'-C), 137.6
3
J = 5Hz, J = 1.1Hz), 7.54 (dd, 1H, 3'-H, J = 3.6 Hz, J = 1.1Hz),
5',3'
(1'-C), 138.8 (8-C), 138.9 (8a-C), 140.8 (3-C), 143.0 (2-C),
149.1 (4'-C), 150.3 (6-C).
13
7.91 (d, 1H, 8-H, J = 9.4Hz), 8.15 (s, 1H, 3-H); C NMR
(CDCl , 50 MHz): δ 112.7 (3-C), 119.5 (7-C), 125.1 (5'-C),
3
Anal. Calcd. for C H N O Cl: C, 46.78; H, 2.40; N, 20.99.
13
8 5 4
126.4 (8-C), 126.6 (3'-C), 128.4 (4'-C), 136.9 (2'-C), 138.2
(8a-C), 142.3 (2-C), 147.1 (6-C).
Found: C, 46.59; H, 2.37; N, 20.75.
Anal. Calcd. for C H N SCl: C, 50.96; H, 2.55; N, 17.83.
Found: C, 50.80; H, 2.54; N, 17.70.
10
6
3
3,6-Dichloro-7-methyl-2-phenylimidazo[1,2-b]pyridazine (13).
To a solution of 500 mg (2.05 mmoles) of 6-chloro-7-methyl-
2-phenylimidazo[1,2-b]pyridazine (4) dissolved in hydrochloric
acid (16 mL) was slowly added 1.4 g of sodium nitrite
(20.5 mmoles) in water (1.5 mL). The mixture was heated at 60
°C for 3 hours. After cooling the solution was basified with
sodium carbonate and extracted with dichloromethane. The
organic layers were dried over calcium chloride then evaporated
to dryness. The residue was chromatographed on silica gel
eluting with dichloromethane to give 0.71 g (25%) of 13 as white
6-Chloro-2-(5-chlorothien-2-yl)imidazo[1,2-b]pyridazine (9).
A chromatography on neutral alumina eluting with
dichloromethane gave 2.1 g (15%) of 9, mp 221-223 °C;
1
H
NMR (CDCl , 200 MHz): δ 6.96 (d, 1H, 4'-H, J = 4Hz), 7.09
3
3',4'
(d, 1H, 7-H, J = 9.4Hz), 7.28 (d, 1H, 3'-H, J = 4Hz), 7.89
7,8
13
(d, 1H, 8-H, J = 9.4Hz), 8.08 (s, 1H, 3-H); C NMR (CDCl ,
3
50 MHz): δ 112.6 (3-C), 119.7 (7-C), 124.1 (3'-C), 126.5 (8-C),
127.4 (4'-C), 131.3 (5'-C), 135.6 (2'-C), 138.2 (8a-C), 141.5
(2-C), 147.3 (6-C).
1
plates, mp 234-236 °C; H NMR (CDCl , 200 MHz): δ 2.52
3
(s, 3H, CH ), 7.49 (m, 3H, 3',4',5'-H), 7.80 (s, 1H, 8-H), 8.17
Anal. Calcd. for C H N SCl : C, 44.44; H, 1.85; N, 15.56.
3
10
5
3
2
13
(m, 2H, 2',6'-H); C NMR (CDCl , 50 MHz): δ 20.2 (CH ),
Found: C, 44.32; H, 1.78; N, 15.50.
3
3
111.2 (3-C), 125.5 (8-C), 127.8 (2',6'-C), 128.5 (7-C), 129.0
(3',5'-C), 129.1 (4'-C), 132.4 (1'-C), 137.9 (8a-C), 140.8 (2-C),
149.5 (6-C).
6-Chloro-2-(fur-2-yl)imidazo[1,2-b]pyridazine (10).
This derivative was purified as above to give 6.2 g (40%) of
1
Anal. Calcd. for C H N Cl : C, 56.12; H, 3.24; N, 25.54.
10, mp 200-202 °C; H NMR (CDCl , 200 MHz): δ 6.57
13
9
3
2
3
Found: C, 56.10; H, 3.21; N, 25.52.
(dd, 1H, 4'-H, J
= 3.4Hz, J
= 1.8Hz), 6.96 (dd, 1H, 3'-H,
4',3'
4',5'

Jul-Aug 2002
Reactivity of 2-Substituted Imidazo[1,2-b]pyridazines
741
2-(4-Chlorophenyl)-3,6-dichloro-7-methylimidazo[1,2-b]pyri-
dazine (14).
1
201-203 °C; H NMR (CDCl , 200 MHz): δ 6.40 (d, 1H, 4'-H,
3
J
J
= 3.6Hz), 7.09 (d, 1H, 3'-H, J = 3.6Hz), 7.18 (d, 1H, 7-H,
= 9.4Hz), 7.94 (d, 1H, 8-H, J = 9.4Hz); C NMR (CDCl ,
50 MHz): δ 108.9 (4'-C), 111.5 (3-C), 112.4 (3'-C), 120.2 (7-C),
127.0 (8-C), 133.6 (2-C), 137.2 (8a-C), 138.5 (5'-C), 146.3 (6-C),
148.4 (2'-C).
Anal. Calcd. for C H N OCl : C, 41.59; H, 1.39; N, 14.56.
Found: C, 41.65; H, 1.50; N, 14.71.
Further elution gave 75.2 mg (13%) of 18, mp 207-209 °C; H
4',3'
13
7,8
3
This compound was obtained from 500 mg (1.80 mmoles) of
6-chloro-2-(4-chlorophenyl)-7-methylimidazo[1,2-b]pyridazine
(6) according to the above procedure as white plates in 15% yield
1
(92.2 mg); mp 228-230 °C; H NMR (CDCl , 200 MHz): δ 2.53
3
10
4
3
3
(d, 3H, CH , J = 1.1Hz), 7.50 (m, 2H, 3',5'-H), 7.79 (q, 1H, 8-H,
3
13
J = 1.1Hz), 8.13 (m, 2H, 2',6'-H); C NMR (CDCl , 50 MHz): δ
3
1
20.3 (CH ), 111.2 (3-C), 125.5 (8-C), 128.9 (2',6'-C), 129.3
3
NMR (CDCl , 200 MHz): δ 6.34 (d, 1H, 4'-H, J
= 3.4Hz),
= 9.4Hz),
3
4',3'
(3',5'-C), 130.9 (7-C), 134.3 (4'-C), 135.1 (1'-C), 137.9 (8a-C),
139.7 (2-C), 149.8 (6-C).
6.94 (d, 1H, 3'-H, J = 3.4Hz), 7.11 (d, 1H, 7-H, J
7.89 (d, 1H, 8-H, J = 9.4Hz), 8.14 (s, 1H, 3-H); C NMR
(CDCl , 50 MHz): δ 108.9 (4'-C), 110.1 (3'-C), 113.2 (3-C),
120.0 (7-C), 126.6 (8-C), 137.4 (2-C), 138.1 (5'-C), 138.4 (8a-C),
147.3 (6-C), 148.5 (2'-C).
7 ,8
13
Anal. Calcd. for C H N Cl : C, 49.92; H, 2.56; N, 13.44.
13
8
3
3
3
Found: C, 50.04; H, 2.68; N, 13.52.
3,6-Dichloro-2-(5-chlorothien-2-yl)imidazo[1,2-b]pyridazine (15)
and 3,6-Dichloro-2-(thien-2-yl)imidazo[1,2-b]pyridazine (16).
Anal. Calcd. for C H N OCl : C, 47.24; H, 1.97; N, 16.55.
10
5
3
2
Found: C, 47.22; H, 1.96; N, 16.54.
Further elution gave 260.3 mg (45%) of 19, mp 193-195°; H
NMR (CDCl , 200 MHz): δ 6.62 (dd, 1H, 4'-H, J = 3.4Hz,
Method A.
1
These compounds were obtained according to the above
procedure. Separation of the crude products was made on a silica
gel column eluting with dichloromethane and the derivatives
were purified on silica gel using chloroform as the mobile phase.
3
4',3'
J
= 1.8Hz), 7.12 (dd, 1H, 3'-H, J = 3.4Hz, J = 0.8Hz), 7.16
4',5'
3',5'
(d, 1H, 7-H, J = 9.4Hz), 7.65 (dd, 1H, 5'-H, J = 1.8Hz, J =
7,8
13
0.8Hz), 7.92 (d, 1H, 8-H, J = 9.4Hz); C-NMR (CDCl ,
3
50 MHz): δ 110.4 (3'-C), 111.4 (3-C), 112.2 (4'-C), 119.8 (7-C),
126.9 (8-C), 134.5 (2-C), 137.1 (8a-C), 143.9 (5'-C), 146.7 (6-C),
148.1 (2'-C).
Method B.
To a solution of 500 mg (2.12 mmoles) of 8 dissolved in
chloroform (12.5 mL) was added 283 mg (2.12 mmoles) of
N-chlorosuccinimide. The mixture was heated on a steam bath
(55 °C) for 2 hours. The solvent was evaporated and the residue
treated according to method A was chromatographed on neutral
alumina eluting with dichloromethane then on silica gel eluting
Anal. Calcd. for C H N OCl : C, 47.24; H, 1.97; N, 16.55.
10
5
3
2
Found: C, 47.21; H, 2.02; N, 16.63.
6-Chloro-3-nitroso-2-phenylimidazo[1,2-b]pyridazine (20).
A mixture of 5 g (21.8 mmoles) of (Z,E)-1-chloro-2-oxo-2-
phenylethanaloxime [16] and 5.6 g (43.6 mmoles) of 3-amino-6-
chloropyridazine in ethanol (400 mL) was stirred for 3 hours at
room temperature. The green precipitate that formed was isolated
with dichloromethane to give 129 mg (20%) of 15, mp 218 °C;
1
H NMR (CDCl , 200 MHz): δ 7.01 (d, 1H, 4'-H, J
= 4Hz),
3
4',3'
7.15 (d, 1H, 7-H, J = 9.4Hz), 7.63 (d, 1H, 3'-H, J = 4Hz), 7.89
(d, 1H, 8-H, J = 9.4Hz); C NMR (CDCl , 50 MHz): δ 111.7
(3-C), 120.0 (7-C), 125.8 (3'-C), 126.7 (8-C), 127.6 (4'-C), 132.3
(5'-C), 133.9 (2'-C), 136.8 (2-C), 137.0 (8a-C), 148.2 (6-C); ms
(EI): m/z (%): 309 (5), 307 (36), 305 (100), 303 (99).
Anal. Calcd. for C H N SCl : C, 40.75; H, 1.36; N, 14.26.
Found: C, 40.70; H, 1.40; N, 14.24.
Further elution gave 326 mg (57%) of 16, mp 190-191 °C; H
NMR (CDCl , 200 MHz): δ 7.14 (d, 1H, 7-H, J = 9.4Hz), 7.22
(dd, 1H, 4'-H, J
7,8
by filtration, washed with ethanol and dried in an oven to give
13
3
1
3.85 g (68%) of 20 as green plates, mp 244 °C; H NMR (CDCl ,
3
200 MHz): δ 7.60 (d, 1H, 7-H, J = 9.4Hz), 7.63 (m, 3H,
7,8
1
3',4',5'-H), 8.18 (d, 1H, 8-H, J = 9.4Hz), 8.66 (m, 2H, 2',6'-H); H
NMR (DMSO-d , 400 MHz, 320 K): δ 7.66 (m, 3H, 3',4',5'-H),
6
10
4
3
3
8.02 (d, 1H, 7-H, J = 9.4Hz), 8.53 (m, 2H, 2',6'-H), 8.59 (d, 1H,
7,8
13
8-H, J = 9.4Hz); C NMR (DMSO-d , 100 MHz, 320 K): δ
1
6
127.2 (8-C), 127.3 (3',5'-C), 127.4 (7-C), 128.5 (2',6'-C), 129.8
(4'-C), 133.6 (1'-C), 136.6 (8a-C), 147.7 (6-C), 153.0 (3-C),
157.6 (2-C).
3
7,8
= 5Hz, J
= 3.7Hz), 7.49 (dd, 1H, 5'-H, J =
4',5'
4',3'
5Hz, J
= 0.8Hz), 7.89 (dd, 1H, 3'-H, J = 3.7Hz, J = 0.8Hz),
5',3'
Anal. Calcd. for C H N OCl: C, 55.71; H, 2.71; N, 21.66.
12
7 4
13
7.91 (d, 1H, 8-H, J = 9.4Hz); C NMR (CDCl , 50 MHz): δ
3
Found: C, 55.58; H, 2.79; N, 21.75.
111.2 (3-C), 119.8 (7-C), 126.6 (8-C), 126.7 (3'-C), 127.4 (5'-C),
128.5 (4'-C), 135.2 (2'-C), 137.0 (8a-C), 137.7 (2-C), 148.0
(6-C).
REFERENCES AND NOTES
Anal. Calcd. for C H N SCl : C, 44.44; H, 1.85; N, 15.55.
Found: C, 44.45; H, 1.80; N, 15.52.
10
5
3
2
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6-Chloro-2-(5-chlorofur-2-yl)imidazo[1,2-b]pyridazine (18) and
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for 3 hours. After a chromatography on silica gel eluting with
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alumina gel eluting with dichloromethane: petroleum ether
(70: 30 v/v then 50: 50 v/v) to give 98.5 mg (15%) of 17, mp
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