Efficient preparation of imidazo[1,2-b]pyridazines under Swern oxidative conditions

Article abstract of DOI:10.1016/S0040-4039(03)00426-X

An efficient synthesis of new imidazo[1,2-b]pyridazine derivatives was effected by treating 3,6-dichloropyridazine with various 2-hydroxyethylamines following by imidazole ring formation under Swern oxidative conditions. Some mechanistic aspects of the cyclization step are discussed.

Full text of DOI:10.1016/S0040-4039(03)00426-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2919–2921
Efficient preparation of imidazo[1,2-b]pyridazines under Swern
oxidative conditions
Pierre Raboisson, Belew Mekonnen* and Norton P. Peet
Department of Lead Optimization, ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 26 November 2002; revised 12 February 2003; accepted 13 February 2003
Abstract—An efficient synthesis of new imidazo[1,2-b]pyridazine derivatives was effected by treating 3,6-dichloropyridazine with
various 2-hydroxyethylamines following by imidazole ring formation under Swern oxidative conditions. Some mechanistic aspects
of the cyclization step are discussed. © 2003 Published by Elsevier Science Ltd.
Derivatives of imidazo[1,2-b]pyridazine are active in a
wide spectrum of biological and therapeutic areas.1–10
The established route for the preparation of imi-
dazo[1,2-b]pyridazines 3 involves the condensation of
3-amino-6-chloropyridazine (1) with substituted a-
halomethylketones in refluxing ethanol (Scheme 1).10
Thus, a-halo-acetaldehydes would be needed for the
synthesis of 3-monosubstituted derivatives. However,
these reagents are generally unstable, leading to dehalo-
genated side products.9 Moreover, the scarce commer-
cial availability of a-haloacetaldehydes associated with
their poor stability limits the scope of this methodol-
ogy. To the best of our knowledge, only two examples
of 3-monosubstituted compounds have been obtained
using a cyclocondensation reaction.9 Recently, direct
electrophilic substitution of imidazopyridazine 3a was
found to be a powerful synthetic tool for the prepara-
tion of N3 functionalized derivatives.11,12 This proce-
dure seemed, however, to be limited to a small number
of electrophiles.
Therefore, a need currently exists for an improved
method that permits easy and rapid access to a large
number of derivatives, especially for applications in
parallel synthesis.
In this communication, we report an efficient two-step
synthesis of imidazo[1,2-b]pyridazines 3a–i starting
from dichloropyridazine 4 and various 2-hydroxyethyl-
amines. The key step in this novel synthetic approach
involved an original one-pot tandem cyclization/oxida-
tion reaction under Swern conditions that allows the
synthesis
of
3-monosubstituted
imidazo[1,2-b]-
pyridazine derivatives which are not available by any
other method.
Condensation of dichloropyridazine 4 with various
ethanolamines led to monoadducts 5a–i in 62–91%
isolated yields (Scheme 2). Attempts to oxidize alcohol
5b to the corresponding ketone 6b using Swern condi-
tions failed and the imidazopyridazine 3b was surpris-
ingly obtained as the major product in this reaction.13
The structure of 3b was unambiguously established
using NMR and mass spectral analyses. Similarly, start-
ing from 3-chloro-6-(2-hydroxyethylamino)pyridazine
5a, imidazopyridazine 3a was obtained, and was identi-
cal in all respects with the product described in the
literature.14 This result could be viewed as the in situ
cyclization of the preformed ketone 6, which can also
be obtained by oxidation of 5 with pyridinium dichro-
mate in dimethylformamide.15
Scheme 1.
However, such a mechanism was unlikely since the
Keywords: imidazo[1,2-b]pyridazine; Swern; oxidation; cyclization;
imidazole.
endocyclic nitrogen of
a heterocyclic amidine is
reported to be a poor nucleophile toward carbonyl
compounds and preferably reacts with alkyl halides or
* Corresponding author. Tel.: (978) 851 7008; fax: (781) 541 6742;
e-mail: bmekonnen@msn.com
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00426-X

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P. Raboisson et al. / Tetrahedron Letters 44 (2003) 2919–2921
Scheme 2. Reagents and conditions: (a) NH2(R1)CH(R2)CHOH, EtOH, reflux; (b) DMSO, (COCl)2, TEA, CH2Cl2, −78°C; (c)
pyridinium dichromate, DMF, rt; (d) EtOH, reflux.
Swern reagent acts as a Lewis acid and generates a
highly reactive electrophilic center with a good leaving
group, which may lead, after nucleophilic displacement,
to imidazolines 8. The second step, which produced the
imidazopyridazines 3, may involve formation of
another N-sulfinium intermediate 9, generated by the
attack of the imidazoline 8 onto a second equivalent of
chlorodimethylsulfinium ion, followed by a subsequent
elimination and deprotonation as shown which leads to
the aromatic imidazopyridazines 3. In support of this
proposed mechanism, pure samples of imidazolines 8a
and 8b, synthesized as previously described,16 gave
under Swern oxidative conditions, the two expected
imidazo[1,2-b]pyridazines 3a and 3b, respectively. In
view of these promising results, the scope of this reac-
tion was expanded to other imidazopyridazine deriva-
tives, using a series of 2-hydroxyethylamines. Results
are summarized in Table 1. When the reaction was
carried out with an activated hydroxyethylamine bear-
ing a heteroatom at position b from the hydroxyl
group, the imidazopyridazines 3b–d were obtained as
the sole products. When an inductively electron-donat-
ing alkyl group was present, only the ketone 6h was
obtained after treatment with the Swern reagent, which
Scheme 3.
suggests that the intermediate 7h is probably not nucle-
ophilic enough to be readily cyclized via the intramolec-
ular electrocyclic process. Finally, 3-chloro-6-
(2–hydroxy - 3 - methyl - 2 - phenylethylamino)pyridazine
(5g) led to a mixture of both ketone and imidazopyri-
dazine (6g and 3g, respectively). Interestingly, the more
geometrically constrained cyclohexylidene derivative 5f
gave only the cyclic imidazole 3f. Thus, the competition
between the two pathways during the oxidation of the
Michael acceptors.9 Moreover, when ketone 6b was
heated in refluxing ethanol, no cyclization product 3b
was obtained. These results suggest that the formation
of the imidazole ring may occur through an intramolec-
ular nucleophilic attack of a pyridazine nitrogen onto
an activated tetrahedral sulfinium intermediate 7 as
depicted in Scheme 3. In this proposed mechanism, the
Table 1. Yields of imidazo[1,2-b]pyridazines 3 and a-aminoketones 613
Compounds 3 and 6
R1
R2
R3
R4
Methoda
Yield ratio 3/6 (%)b
a
b
H
H
H
H
H
H
A
A
B
A
A
A
A
A
A
A
82/0
84/0
0/64
65/0
68/0
81/0
92/0
8/81
0/87
0/81
CH2OPh
CH2OPh
c
d
e
f
g
h
i
H
H
CH2OH
CH2NH-t-BOC
H
H
H
COPh
CHO
CH2NH2
H
c
CHOHPh
-(CH2)4-
-(CH2)4-
CH3
H
H
Ph
CH3
Ph
CH3
H
H
Ph
CH3
Ph
a Method A: DMSO, (COCl)2, triethylamine, CH2Cl2, −78°C“rt; Method B: pyridinium dichromate, DMF, rt.
b Represents the ratio of yields of isolated products 3/6.
c Compound 3c was obtained after treatment with trifluoroacetic acid in dichloromethane.

P. Raboisson et al. / Tetrahedron Letters 44 (2003) 2919–2921
2921
3-chloro-6-(2-hydroxyethylamino) intermediates 5 is
not only dependent on inductive effects, which influence
the electronic character of the hydroxyl group, but is
also highly influenced by geometric parameters.
9. Saturnino, C.; Abarghaz, M.; Schmitt, M.; Wermuth,
C.-G.; Bourguignon, J.-J. Heterocycles 1995, 41, 1491–
1500.
10. Roe, A. M. J. Chem. Soc. 1963, 2195–2200.
11. Palagiano, F.; Arenare, L.; Luraschi, E.; de Caprariis, P.;
Abignente, E.; D’Amico, M.; Filippelli, W.; Rossi, F.
Eur. J. Med. Chem. Chim. Ther. 1995, 30, 901–910.
12. Saldabol, N. O.; Lando, O. E. Zh. Org. Khim. 1977, 13,
2626–2629.
In summary, we have developed a rapid, practical and
efficient procedure for the synthesis of novel 6-
chloroimidazo[1,2-b]pyridazines 3 via substitution reac-
tions of 3,6-dichloropyridazine (4) with various
2-hydroxyethylamines, followed by a tandem cycliza-
tion/oxidation reaction under Swern conditions.13 This
methodology represents an efficient procedure for the
13. Typical procedure: Oxalyl chloride (500 mL, 5.72 mmol)
was slowly added under an argon atmosphere at −78°C
to a stirred solution of DMSO (610 mL, 8.55 mmol) in
dichloromethane (20 mL). After 10 min 3-chloro-6-[(2-
hydroxy-3-phenoxy-propyl)amino]pyridazine (5b) (800
mg, 2.86 mmol in 2.0 mL of DMSO), which was obtained
by condensation of 2-hydroxy-3-phenoxypropylamine
and 3,6-dichloropyridazine (1) as described earlier,17 was
added and stirring was continued for 20 min at −78°C.
Triethylamine (1.7 mL, 12.2 mmol) was added. After 10
min, the reaction mixture was allowed to warm to room
temperature, then quenched with isopropanol (5.0 mL).
The mixture was diluted with ethyl acetate (200 mL),
washed with 2% sodium hypochlorite (200 mL), then with
ice-cold water (200 mL), dried (Na2SO4), and concen-
trated to dryness under reduced pressure. Chromatogra-
phy on silica gel (AcOEt) followed by recrystallization
from diethyl ether yielded compound 3b (622 mg, 84%) as
synthesis
of
3-monosubstituted
imidazo[1,2-b]-
pyridazine derivatives which are not available by any
other method. Moreover, the chloro group in position 6
of imidazopuridazines would permit access to a large
number of 3,6-di- and 2,3,6-tri-substituted derivatives
after palladium cross-coupling reactions or nucleophilic
displacement of the 6-chloro group.8,17,18 Furthermore,
one of the main advantages of this synthesis is its
application to parallel synthesis that permits an easy
and rapid access to a large number of derivatives for
biological evaluation.
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