Direct arylation of Imidazo[l,2-b]pyridazines: microwave-assisted one-pot Suzuki coupling/Pd-catalysed arylation

Article abstract of DOI:10.1002/ejoc.200900849

Direct intermolecular C-H arylation of 6-chloroimidazo [ 1,2 - b] pyridazine in its 3-position was achieved, and the tolerance to reaction conditions in the presence of chloro groups was investigated. Various 3-(hetero)arylimidazo[l,2-b]pyridazines were synthesized in good to excellent yields. This methodology was successfully applied to the synthesis of 3,6-diand 2,3,6-trisubstituted imidazo[l,2-5]pyridazines by a microwave-assisted, one-pot, two-step Suzuki cross-coupling/ palladium-catalysed arylation process.

Full text of DOI:10.1002/ejoc.200900849

FULL PAPER
DOI: 10.1002/ejoc.200900849
Direct Arylation of Imidazo[1,2-b]pyridazines: Microwave-Assisted One-Pot
Suzuki Coupling/Pd-Catalysed Arylation
Ahmed El Akkaoui,[a,b] Sabine Berteina-Raboin,*[a] Abderrahim Mouaddib,[b] and
Gérald Guillaumet[a]
Keywords: Imidazo[1,2-b]pyridazines / C–H arylation / Microwaves / Multicomponent reactions / Cross-coupling / C–C
coupling
DirectintermolecularC–Harylationof6-chloroimidazo[1,2-b]-
pyridazine in its 3-position was achieved, and the tolerance
to reaction conditions in the presence of chloro groups was
investigated. Various 3-(hetero)arylimidazo[1,2-b]pyridaz-
ines were synthesized in good to excellent yields. This meth-
odology was successfully applied to the synthesis of 3,6-di-
and 2,3,6-trisubstituted imidazo[1,2-b]pyridazines by a mi-
crowave-assisted, one-pot, two-step Suzuki cross-coupling/
palladium-catalysed arylation process.
from imidazo[1,2-b]pyridazines halogenated at the 6-posi-
tion to obtain 2,3,6-trisubstituted imidazo[1,2-b]pyridazine
derivatives.
As far as we know, there is no standard methodology
described in the literature for the synthesis of such com-
pounds.
We have also shown that this procedure can be applied
to quick syntheses of polysubstituted imidazo[1,2-b]pyrid-
azines by a microwave-assisted, one-pot, two-step Suzuki
cross-coupling/palladium-catalysed arylation process.
Introduction
Direct transition-metal-catalysed reactions for the elabo-
ration of C–CAr bonds are widely used in organic synthe-
sis,[1] and the development of powerful catalytic methods
has opened new routes to the synthesis of complex mole-
cules. Usually, heteroaryl–aryl bonds are generated by cou-
pling of two functionalized heteroaromatic carbon atoms,
but that is not always necessary. It is sometimes possible to
introduce an aryl group directly onto an aromatic ring by
replacing a C–H bond with a C–C bond. In the past three
decades, development of transition-metal-catalysed C–H
activation reactions has received considerable attention, and
a wide range of metal catalysts, including Pd,[2] Ru[3] and
Rh[4] catalysts, have been exploited with varying levels of
success.
As a continuation of the research into imidazo[1,2-a]pyr-
idine and imidazo[1,2-b]pyridazine derivatives carried out
in our laboratories,[5] our group has investigated the use of
direct arylation to functionalize imidazo[1,2-a]pyridine at
its 3-position by use of aryl bromides or heteroaryl bro-
mides.[6] Here we report the details of our studies of the
functionalization of imidazo[1,2-b]pyridazines with aryl
bromides. In addition, we demonstrate that various func-
tionalities can be introduced by subsequent palladium-cata-
lysed cross-coupling reactions or aromatic substitutions
Results and Discussion
As a model, we began with the investigation of the direct
cross-coupling arylation reaction between bromobenzene
and 6-chloroimidazo[1,2-b]pyridazine (1a).[7] We first tested
reaction conditions already used in our laboratory for the
(hetero)arylation of imidazo[1,2-a]pyridine by use of palla-
dium(II) acetate (5 mol-%), triphenylphosphane (10 mol-
%), K2CO3 (2 equiv.) and dioxane at 100 °C[6] (Table 1).
Treatment of 6-chloroimidazo[1,2-b]pyridazine (1a) under
these reaction conditions for 24 h thus gave 2, but in only
50% yield (Table 1, Entry 1), with a significant amount of
starting material being recovered.
Increasing the amounts of palladium(II) acetate to
10 mol-% and triphenylphosphane to 20 mol-% under the
same reaction conditions led to compound 2 in 91% yield
(Table 1, Entry 2). The use of DMA as solvent lowered the
yield to 76% (Table 1, Entry 3). The best conditions were
found with toluene as solvent: compound 2 was then ob-
tained in 93% yield with 100% conversion (Table 1, En-
try 4). Other ligands such as AsPh3, (o-tolyl)3P and
Xantphos (Table 1, Entries 5–7) were also tested. A change
in the base afforded product 2 in 80% yield (Table 1, En-
[a] Institut de Chimie Organique et Analytique, Université d’Or-
léans, UMR CNRS 6005,
B. P. 6759, 45067 Orléans Cedex 2, France
Fax: +33-2-38417281
E-mail: sabine.berteina-raboin@univ-orleans.fr
[b] Laboratoire de Chimie Bio-Organique et Analytique, F.S.T. B-
M, Université Sultan Moulay Slimane,
B. P. 523, 23000 Beni-Mellal, Morocco
862
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 862–871

Direct Arylation of Imidazo[1,2-b]pyridazines
Table 1. Optimization of the reaction conditions for the arylation of 1a with bromobenzene.
Entry
Catalyst
Base
Solvent
Conversion (%)
Yield (%)[a]
1
2
3
4
5
6
7
8
9
5% Pd(OAc)2/10% PPh3
10% Pd(OAc)2/20% PPh3
10% Pd(OAc)2/20% PPh3
10% Pd(OAc)2/20% PPh3
10% Pd(OAc)2/20% AsPh3
10% Pd(OAc)2/20% P(o-tolyl)3
10% Pd(OAc)2/20% Xantphos
10% Pd(OAc)2/20% PPh3
10% Pd(OAc)2/20% PPh3
10% Pd(PPh3)4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
K2CO3
dioxane
dioxane
DMA
64
100
85
100
92
98
90
88
17
50
91
76
93
87
92
86
80
10
88
13
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
10
11
95
20
10% PdCl2(PPh3)2
[a] Yields given are for isolated compound 2.
try 8) with caesium carbonate or in 10% yield (Table 1, En- functionalized 2-substituted imidazo[1,2-a]pyridines. We
try 9) with sodium carbonate. We next focused our atten- decided to apply this technique[9] to a reaction mixture con-
tion on the influence of the catalyst system on the cross- sisting of 6-chloroimidazo[1,2-b]pyridazine (1a) and 1-
coupling arylation reaction. The use of Pd(PPh3)4 instead bromo-4-nitrobenzene, which was irradiated under the con-
of Pd(OAc)2/PPh3 gave compound 2 in 88% yield (Table 1, ditions previously optimized with conventional heating
Entry 10). In contrast, Pd(PPh3)2Cl2 afforded compound 2 [Pd(OAc)2 (10 mol-%), PPh3 (20 mol-%)]. Under these con-
in poor yield, and starting material was recovered (Table 1, ditions, at 140 °C for 2 h, compounds 2 and 3 were isolated
Entry 11).
Finally, we found that the optimum reaction conditions 2).
were 6-chloroimidazo[1,2-b]pyridazine (1a, 1 equiv.), bro-
in 93% and 96% yields, respectively (Table 3, Entries 1 and
The presence of aryl groups in the 2-positions of 6-chlo-
mobenzene (1.3 equiv.), palladium(II) acetate (10 mol-%), roimidazo[1,2-b]pyridazines 1c–g lowered the yields to 75–
triphenylphosphane (20 mol-%) and K2CO3 (2 equiv.) in 85% (Table 3, Entries 3–7), probably because of steric hin-
toluene at 110 °C (Table 1).
drance.
The halogen substitution on the arylated imidazo[1,2-b]-
The efficiency of the Pd(OAc)2/PPh3 catalyst system for
C-3 arylation of 6-chloroimidazo[1,2-b]pyridazines with de- pyridazines allowed simple functionalization of the hetero-
activated bromobenzene was confirmed. The scope of this cycle through metal-catalysed coupling reactions or aro-
reaction under the optimized conditions (Table 1, Entry 4) matic substitutions. Aryl substituents, for example, were in-
was next investigated with several aryl bromides. The results troduced at the 6-position in imidazo[1,2-b]pyridazine 1a
(Table 2) showed that compound 1a could be efficiently through Suzuki cross-coupling. On the other hand, the re-
functionalized at its 3-position. Under the same reaction action between starting material 1a and p-methoxyphen-
conditions, ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carb- ylboronic acid under the same optimized conditions led to
oxylate (1b) was also arylated in good yield (Table 2, En- incomplete conversion (10% of starting material 1a was re-
try 2). It is noteworthy that this reaction can be applied to covered), and the desired compound 22 (Scheme 2, below)
a wide variety of aryl bromides. Both electron-rich (R = was obtained in only 78% yield (Table 4, Entry 1). How-
Me, OMe) and electron-poor (R = Cl, CN, CO2Me, NO2) ever, complete conversion could be achieved in only 3 h
haloaromatics reacted to give good to excellent yields (78– when the reaction mixture was heated at reflux in a toluene/
98%). Some heterocyclic bromides were also used for direct ethanol mixture (2:1), leading to the desired compound 22
arylation, which led to pyridylimidazo[1,2-b]pyridazines de- in 98% yield. With these results to hand, we speculated that
rivatives 14–16 in good yields (75–95%, Table 2, Entries 13– this methodology might be extendable to the synthesis of
15).
various 3,6-disubstituted imidazo[1,2-b]pyridazine ana-
Our next intent was to determine the effect on our aryl- logues. The starting materials 1a and 8 were thus treated
ation procedure of substitution at the 2-positions of imid- with various arylboronic acids under the optimized condi-
azo[1,2-b]pyridazines. To that end we investigated different tions [80 °C, toluene/ethanol (2:1), 3 h], to provide products
combinations of 2-arylimidazo[1,2-b]pyridazines 1a–g, ob- 23 and 24 in excellent yields (Table 4, Entries 3 and 4). We
tained by standard procedures,[8] with various aryl bromides then decided to try SNAr and palladium-catalysed N-aryl-
(Table 3). We had previously demonstrated the favourable ation reactions. Compound 7 was treated with sodium
influence of microwave irradiation for the preparation of methoxide, affording product 25 in 95% yield (Table 4, En-
Eur. J. Org. Chem. 2010, 862–871
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
863

A. El Akkaoui, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet
Table 2. Arylation and heteroarylation of 6-chloroimidazo[1,2-b]pyridazines.
FULL PAPER
864
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 862–871

Direct Arylation of Imidazo[1,2-b]pyridazines
Table 2. (Continued.)
[a] Isolated yield after purification by chromatography. [b] Reaction carried out with 2 equiv. of aryl bromides. [c] 10% of 1a was recovered.
try 5). Under the palladium-catalysed amination conditions
recently developed in our laboratory,[10] in the presence of
Xantphos,[11] Pd(OAc)2, K2CO3 and p-methoxyaniline at
reflux in dioxane, product 26 was obtained in 90% yield
(Table 4, Entry 6).
One-Pot Suzuki Coupling/Arylation on 6-Chloroimidazo-
[1,2-b]pyridazines
Scheme 1. One-pot Suzuki coupling/arylation on 6-chloroimid-
azo[1,2-b]pyridazine.
We decided to investigate a method based on our pre-
vious work[12] for one-pot double Suzuki coupling/arylation
of 6-chloroimidazo[1,2-b]pyridazines. From our previous
results on monosubstitution of the 6-chloroimidazo[1,2-b]-
pyridazines (Tables 1, 2, and 3), we developed a one-pot
Suzuki coupling/direct arylation sequence for successive in-
troduction of distinct (hetero)aryl groups at the 6-position
and then in the 3-position. This could provide a very inter-
esting and straightforward route to diversely polysubsti-
tuted imidazo[1,2-b]pyridazines (Table 5). As far as we
know, there have been no reports of one-pot Suzuki cou-
pling/direct arylation of 6-chloroimidazo[1,2-b]pyridazines.
Initial efforts were directed towards the application of the
reaction conditions used successfully for Suzuki cross-cou-
pling and direct arylation (Scheme 1).
tions, an alternative strategy was then investigated. This ap-
proach is based on the use of microwave irradiation
(Scheme 2).
Interestingly, although some bis(coupled) product 27 was
isolated, the overall yield was quite modest (30%) and the
mono(coupled) compound 22 (Suzuki coupling) was ob-
Scheme 2. Microwave-assisted Suzuki cross-coupling and arylation
tained in 55% yield (Scheme 1). To overcome these limita- with 6-chloroimidazo[1,2-b]pyridazine (1a).
Eur. J. Org. Chem. 2010, 862–871
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
865

A. El Akkaoui, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet
FULL PAPER
Table 3. Arylation of 2-substituted imidazo[1,2-b]pyridazines with 1-bromo-4-nitrobenzene.
[a] Starting material. [b] Isolated yield after purification by flash chromatography.
Coupling with 6-chloroimidazo[1,2-b]pyridazine (1a)
The one-pot cross-coupling between 1a, p-methoxyphen-
rapidly afforded either product 2 (regioselective arylation) ylboronic acid and bromobenzene under the optimized
or product 22 (Suzuki coupling) in excellent yields with use arylation and Suzuki reaction conditions assisted by micro-
either of regioselective arylation conditions D [Pd(OAc)2/ wave irradiation [Pd(OAc)2/PPh3 as catalyst in a toluene/
PPh3 as catalyst in a toluene/EtOH mixture at 140 °C, PhBr EtOH mixture at 140 °C, M.W.] (Table 5) afforded the ex-
(1.5 equiv.), 2 h, M.W., 95%] or of Suzuki coupling condi- pected 3,6-disubstituted imidazo[1,2-b]pyridazine 27 in
tions E [Pd(OAc)2/PPh3 as catalyst in a toluene/EtOH mix- 71% yield without any traces of the monosubstituted prod-
ture at 140 °C, p-methoxyphenylboronic acid (1.1 equiv.), uct 22 (Suzuki coupling). With a suitable protocol to hand,
15 min, M.W., 98%], respectively (Scheme 2).
the scope of the one-pot tandem Suzuki/arylation coupling
866
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 862–871

Direct Arylation of Imidazo[1,2-b]pyridazines
Table 4. Further functionalization of arylated 6-chloroimidazo[1,2-b]pyridazines.
Entry
R1
R2
Conditions
Product, yield (%)
1
2
3
4
5
6
H
H
p-MeOC6H4
p-MeOC6H4
m-NCC6H4
p-F3CC6H4
MeO
(A), toluene
(A), toluene/ethanol (2:1)
(A), toluene/ethanol (2:1)
(A), toluene/ethanol (2:1)
(B)
22, 78%
22, 98%
23, 92%
24, 96%
25, 95%
26, 90%
3-pyridyl
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-MeOC6H4NH
(C)
Table 5. Results of one-pot Suzuki coupling/Pd-catalysed arylation under microwave irradiation conditions.
[a] Isolated yield (after purification by flash chromatography).
Eur. J. Org. Chem. 2010, 862–871
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
867

A. El Akkaoui, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet
FULL PAPER
The combined organic layers were dried with MgSO4 and concen-
trated under vacuum. The residue was purified by column
chromatography on silica gel (EtOAc/petroleum ether). Products 2,
4 and 8 are known compounds, which were identified by spectral
comparison with literature data. The NMR and elemental analysis
data for the other products are as follows.
was extended to the synthesis of various polysubstituted im-
idazo[1,2-b]pyridazine analogues. Thus, under microwave
irradiation conditions, 6-chloroimidazo[1,2-b]pyridazine
was treated successively in one-pot fashion without workup
with palladium acetate, triphenylphosphane and one of a
number of boronic acids (1.1 equiv.), and the reaction mix-
ture was then irradiated for 15 min (Suzuki coupling). After
the system had cooled to room temperature, one of a
number of aryl bromides (1.5 equiv.) was added, and the
reaction mixture was irradiated again for 2 h (direct aryl-
ation). These sequences afforded the desired polysubstituted
imidazo[1,2-b]pyridazines in nearly quantitative conver-
sions. Compounds 27–32 were isolated in good overall
yields (69–78%, Table 5, Entries 1–6).
Ethyl 6-Chloro-3-phenylimidazo[1,2-b]pyridazine-2-carboxylate (3):
Yield: 178 mg, 91%; yellow solid; m.p. 194 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H, CH2CH3), 4.39
(q, J = 7.1 Hz, 2 H, CH2CH3), 7.15 (d, J = 9.5 Hz, 1 H, 7-H),
7.49–7.57 (m, 3 H, HAr), 7.62–7.69 (m, 2 H, HAr), 8.02 (d, J =
9.5 Hz, 1 H, 8-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3,
61.5, 121.2, 126.4, 128.2, 128.5, 129.7, 130.9, 133.3, 133.6, 136.9,
148.7, 162.8 ppm. HRMS: calcd. for C15H12ClN3O2 [M]+ 302.0696;
found 302.0711.
6-Chloro-3-(4-nitrophenyl)imidazo[1,2-b]pyridazine
(5):
Yield:
166 mg, 93%; yellow solid; m.p. 216 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.52 (d, J = 9.4 Hz, 1 H, 7-H), 8.33 (d, J = 9.4 Hz, 1
H, 8-H), 8.36–8.40 (m, 4 H, HAr), 8.53 (s, 1 H, 2-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 119.9, 124.0, 125.7, 126.3, 128.3,
134.1, 135.9, 139.8, 146.1, 146.7 ppm. HRMS: calcd. for
C12H7ClN4O2 [M]+ 275.0336; found 275.0333.
Conclusions
We initially developed a short and efficient approach for
the Pd0-mediated arylation of imidazo[1,2-b]pyridazines at
the C-3 position with aryl bromides. The efficiency and
scope of this procedure was established by the synthesis of
a library of various 3-substituted and 2,3-disubstituted 6-
chloroimidazo[1,2-b]pyridazines. We established optimal
conditions with the use of the Pd(OAc)2/PPh3 system as
catalyst in toluene at 110 °C. We have also demonstrated
that this procedure could be applied to the synthesis of
Ethyl 6-Chloro-3-(4-nitrophenyl)imidazo[1,2-b]pyridazine-2-carbox-
1
ylate (6): Yield: 218 mg, 97%; yellow solid; m.p. 205 °C. H NMR
(400 MHz, CDCl3): δ = 1.38 (t, J = 7.1 Hz, 1 H, CH2CH3), 4.42
(q, J = 7.1 Hz, 2 H, CH2CH3), 7.24 (d, J = 9.4 Hz, 1 H, 7-H),
7.88–7.90 (m, 1 H, HAr), 7.90–7.92 (m, 1 H, HAr), 8.08 (d, J =
9.4 Hz, 1 H, 8-H), 8.37–8.39 (m, 1 H, HAr), 8.39–8.41 (m, 1 H,
2,3,6-trisubstituted imidazo[1,2-b]pyridazines by a micro- HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3, 61.9, 122.1,
123.3, 128.8, 130.6, 132.1, 132.9, 134.4, 137.4, 148.3, 149.3,
162.5 ppm. HRMS: calcd. for C15H11ClN4O4 [M]+ 347.0547; found
347.0555.
wave-assisted, one-pot, two-step Suzuki cross-coupling/pal-
ladium-catalysed arylation sequence. This approach has the
potential to be of great benefit in an easy and convergent
synthesis of polysubstituted imidazo[1,2-b]pyridazines.
4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile (7): Yield:
144 mg, 87%; yellow solid; m.p. 214 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.18 (d, J = 9.4 Hz, 1 H, 7-H), 7.78 (m, 2 H, HAr),
8.01 (d, J = 9.4 Hz, 1 H, HAr), 8.17 (s, 1 H, HAr), 8.21 (m, 2 H, 8-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 111.5, 118.8, 119.4,
126.7, 127.2, 127.7, 132.3, 132.7, 134.8, 139.6, 147.4 ppm. HRMS:
calcd. for C13H7ClN4 [M]+ 255.0437; found 255.0435.
Experimental Section
General Remarks: All reagents were purchased from Sigma–
Aldrich, Acros Organics or Alfa Aesar and were used without fur-
ther purification. Melting points were determined with a Büchi
SMP-20 melting point apparatus and are uncorrected. 1H NMR
and 13C NMR spectra were recorded with a Bruker Avance II 400
spectrometer (1H: 400 MHz; 13C: 100 MHz) with tetramethylsilane
as the internal standard; multiplicities were determined by use of
the DEPT 135 sequence. Chemical shifts (δ) are reported in ppm.
Coupling constants are reported in Hz. Splitting patterns are desig-
nated as s = singlet, d = doublet, t = triplet, m = multiplet. High-
resolution mass spectra (HRMS) were recorded with a TOF spec-
trometer in the electrospray ionization (ESI) mode or with a Finni-
gan MAT 95 XL spectrometer in the chemical ionization (CI) mode
at the Regional Center of Physical Measurement, Blaise Pascal
University, Clermont Ferrand. All commercial solvents were used
without further purification. Column chromatography was carried
out with silica gel 60N (spherical, neutral, 40–63 mm, Merck).
4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)benzaldehyde (9): Yield:
164 mg, 98%; yellow solid; m.p. 148 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.15 (d, J = 9.4 Hz, 1 H, 7-H), 7.94–8.05 (m, 3 H,
HAr), 8.18 (s, 1 H, 2-H), 8.25 (m, 2 H, HAr, 8-H), 10.05 (s, 1 H,
CHO) ppm. 13C NMR (100 MHz, CDCl3): δ = 119.2, 126.7, 127.6,
130.2, 133.6, 134.9, 135.6, 139.6, 147.3, 191.5 ppm. HRMS: calcd.
for C13H8ClN3O [M]+ 258.0434; found 258.0428.
6-Chloro-3-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)imidazo[1,2-b]pyr-
idazine (10): Yield: 167 mg, 83%; yellow solid; m.p. 235 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 9.4 Hz, 1 H, 7-H), 7.75–
7.82 (m, 2 H, HAr), 8.06 (d, J = 9.4 Hz, 1 H, 8-H), 8.09–8.16 (m,
1 H, HAr), 8.16–8.22 (m, 1 H, HAr), 8.37 (s, 1 H, HAr), 8.88 (s, 1
H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.5, 121.1,
126.1, 127.2, 127.6, 131.2, 132.0, 132.5, 133.9, 134.2, 134.5, 140.8,
142.1, 147.5, 183.5, 185.3 ppm. HRMS: calcd. for C16H8ClN3O2
[M]+ 310.0383; found 310.0383.
General Procedure for the Palladium-Catalysed C-3 Arylation of 6-
Chloroimidazo[1,2-b]pyridazine with Aryl and Heteroaryl Bromides:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (0.1 g, 0.65 mmol),
an aryl or heteroaryl bromide (0.85 mmol, 1.3 equiv.), K2CO3
(1.3 mmol, 2 equiv.), PPh3 (0.13 mmol, 0.2 equiv.) and Pd(OAc)2
(0.065 mmol, 0.1 equiv.) in toluene (2 mL) was heated to 110 °C.
The reaction mixture was stirred for 24 h, and the mixture was then
allowed to cool to room temp. and extracted with CH2Cl2 (3ϫ).
6-Chloro-3-(3-tolyl)imidazo[1,2-b]pyridazine (11): Yield: 141 mg,
1
89%; yellow solid; m.p. 60 °C. H NMR (400 MHz, CDCl3): δ =
2.43 (s, 3 H, CH3) 7.01 (d, J = 9.3 Hz, 1 H, 7-H), 7.16–7.18 (m, 1
H, HAr), 7.36 (dd, J = 9.7, 5.6 Hz, 1 H, HAr), 7.77 (m, 1 H, HAr),
7.82 (d, J = 7.8 Hz, 1 H, HAr), 7.90 (d, J = 9.3 Hz, 1 H, 8-H), 8.01
(s, 1 H, 2-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5, 117.9,
868
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 862–871

Direct Arylation of Imidazo[1,2-b]pyridazines
123.8, 126.7, 127.1, 127.3, 127.6, 128.6, 129.1, 133.4, 138.3, 138.3,
146.7 ppm. HRMS: calcd. for C13H10ClN3 [M]+ 244.0642; found
244.0631.
(400 MHz, CDCl3): δ = 3.77 (s, 3 H, OCH3), 6.92 (dd, J = 8.2,
2.5 Hz, 1 H, HAr), 7.12 (d, J = 7.6 Hz, 1 H, HAr), 7.16 (d, J =
9.4 Hz, 1 H, 7-H), 7.19–7.23 (m, 1 H, HAr), 7.26 (m, 1 H, HAr),
7.82 (d, J = 8.9 Hz, 2 H, HAr), 8.00 (d, J = 9.4 Hz, 1 H, 8-H), 8.30
(d, J = 8.9 Hz, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ =
55.4, 113.9, 115.0, 120.1, 121.2, 123.5, 123.9, 127.1, 129.9, 131.1,
134.3, 134.7, 138.1, 145.6, 147.1, 147.5, 160.0 ppm. HRMS: calcd.
for C19H13ClN4O3 [M]+ 381.0754; found 381.0750.
6-Chloro-3-(2,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine
(12):
Yield: 147 mg, 78%; yellow solid; m.p. 116 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
6.60–6.62 (m, 2 H, HAr), 6.66 (dd, J = 8.5, 2.3 Hz, 1 H, HAr), 7.02
(d, J = 9.3 Hz, 1 H, 7-H, 7-H), 7.86 (d, J = 8.5 Hz, 1 H, HAr), 7.92
(d, J = 9.3 Hz, 1 H, 8-H), 8.04 (s, 1 H, 2-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 55.6, 55.7, 99.2, 104.7, 109.6, 117.6, 126.0,
127.0, 130.0, 135.6, 137.7, 146.3, 158.5, 161.4 ppm. HRMS: calcd.
for C14H12ClN3O2 [M]+ 290.0696; found 290.0702.
6-Chloro-2-(4-methoxyphenyl)-3-(4-nitrophenyl)imidazo[1,2-b]pyrid-
azine (19): Yield: 198 mg, 80%; yellow solid; m.p. 194 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 6.90 (d, J = 8.8 Hz,
2 H, HAr), 7.15 (d, J = 9.3 Hz, 1 H, 7-H), 7.55 (d, J = 8.8 Hz, 2
H, HAr), 7.83 (d, J = 8.9 Hz, 2 H, HAr), 7.97 (d, J = 9.3 Hz, 1 H,
8-H), 8.30 (d, J = 8.9 Hz, 2 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 55.4, 114.3, 119.7, 122.6, 123.9, 125.4, 126.7, 130.0,
130.9, 134.9, 138.1, 145.7, 146.7, 147.4,160.3 ppm. HRMS: calcd.
for C19H13ClN4O3 [M]+ 381.0754; found 381.0771.
Ethyl 6-Chloro-3-(2,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine-2-
carboxylate (13): Yield: 188 mg, 80%; yellow solid; m.p. 155 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H, CH2CH3),
3.73 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.36 (q, J = 7.1 Hz, 2
H, CH2CH3), 6.60 (d, J = 2.3 Hz, 1 H, HAr), 6.64 (dd, J = 8.4,
2.3 Hz, 1 H, HAr), 7.11 (d, J = 9.4 Hz, 1 H, 7-H), 7.37 (d, J =
8.4 Hz, 1 H, HAr), 7.97 (d, J = 9.4 Hz, 1 H, 8-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.3, 55.5, 55.6, 61.1, 98.9, 104.7, 108.4,
120.6, 128.2, 130.6, 133.1, 134.3, 136.9, 148.1, 159.1, 162.5,
162.9 ppm. HRMS: calcd. for C17H16ClN3O4 [M]+ 262.0908; found
262.0919.
6-Chloro-2-(4-chlorophenyl)-3-(4-nitrophenyl)imidazo[1,2-b]pyridaz-
1
ine (20): Yield: 205 mg, 82%; yellow solid; m.p. 209 °C. H NMR
(400 MHz, CDCl3): δ = 7.18 (d, J = 9.4 Hz, 1 H, 7-H), 7.34 (d, J
= 8.5 Hz, 1 H, HAr), 7.55 (d, J = 8.5 Hz, 1 H, HAr), 7.80 (d, J =
8.9 Hz, 1 H, HAr), 7.99 (d, J = 9.4 Hz, 1 H, 8-H), 8.32 (d, J =
8.9 Hz, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.3,
123.4, 124.1, 127.1, 129.2, 129.9, 131.0, 131.5, 134.4, 135.1, 138.2,
144.4, 147.3, 147.7 ppm. HRMS: calcd. for C18H10Cl2N4O2 [M +
H]+ 385.0259; found 385.0271.
6-Chloro-3-(pyridin-3-yl)imidazo[1,2-b]pyridazine
(14):
Yield:
142 mg, 95%; yellow solid; m.p. 145 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.14 (d, J = 9.4 Hz, 1 H, 7-H), 7.43–7.46 (dd, J = 8.0,
3.9 Hz, 1 H, HPyr), 7.99 (d, J = 9.4 Hz, 1 H, 8-H), 8.01 (s, 1 H, 2-
H), 8.42 (td, J = 1.9, 8.0 Hz, 1 H, HPyr), 8.63 (dd, J = 1.5, 4.8 Hz,
1 H, HPyr), 9.23 (d, J = 2.0 Hz, 1 H, HPyr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 119.0, 121.6, 123.6, 124.3, 126.2, 127.5,
133.6, 139.1, 147.3, 147.8, 149.3 ppm. HRMS: calcd. for
C11H7ClN4 [M]+ 231.0437; found 231.0432.
6-Chloro-2-(4-fluorophenyl)-3-(4-nitrophenyl)imidazo[1,2-b]pyridaz-
1
ine (21): Yield: 192 mg, 80%; yellow solid; m.p. 206 °C. H NMR
(400 MHz, CDCl3): δ = 7.03–7.11 (m, 2 H, HAr), 7.18 (d, J =
9.4 Hz, 1 H, 7-H), 7.56–7.63 (m, 2 H, HAr), 7.81 (d, J = 8.9 Hz, 2
H, HAr), 7.99 (d, J = 9.4 Hz, 1 H, 8-H), 8.31 (d, J = 8.9 Hz, 2 H,
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 115.9, 116.1, 120.2,
123.1, 124.0, 127.0, 129.1, 129.2, 130.5, 130.5, 130.9, 134.5, 138.1,
144.7, 147.1, 147.5,161.9, 164.4 ppm. HRMS: calcd. for
C18H10ClFN4O2 [M]+ 369.0555; found 369.0546.
6-Chloro-3-(5-methoxypyridin-3-yl)imidazo[1,2-b]pyridazine
(15):
Yield: 127 mg, 75%; yellow solid; m.p. 195 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.96 (s, 3 H, OCH3), 7.14 (d, J = 9.4 Hz,
1 H, 7-H), 8.01 (d, J = 9.4 Hz, 1 H, 8-H), 8.02–8.04 (m, 1 H, 2-
H), 8.15 (s, 1 H, HPyr), 8.34 (d, J = 2.7 Hz, 1 H, HPyr), 8.83 (d, J
= 1.6 Hz, 1 H, HPyr) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.8,
118.1, 119.0, 124.8, 126.0, 127.6, 133.9, 137.0, 139.2, 140.1, 147.2,
155.6 ppm. HRMS: calcd. for C12H9ClN4O [M]+ 261.0543; found
261.0545.
3-[3-(Pyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl]benzonitrile (23):
Yield: 178 mg, 92 %; yellow solid; m.p. 226 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.47 (ddd, J = 8.0, 4.8, 0.6 Hz, 1 H, HAr),
7.54 (d, J = 9.5 Hz, 1 H, 7-H), 7.63 (td, J = 7.6, 0.9 Hz, 1 H, HAr),
7.79 (td, J = 7.7, 1.3 Hz, 1 H, HAr), 8.15 (d, J = 9.5 Hz, 1 H, 8-
H), 8.16 (s, 1 H, 2-H), 8.20–8.28 (m, 2 H, HAr), 8.37–8.45 (m, 1 H,
HPyr), 8.64 (dd, J = 4.8, 1.5 Hz, 1 H, HPyr), 9.33 (d, J = 1.6 Hz, 1
H, HPyr) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.7, 115.5,
118.3, 123.7, 124.9, 127.0, 130.2, 130.6, 131.4, 133.5, 133.8, 134.2,
135.3, 136.9, 139.9, 144.6, 147.9, 149.1, 150.0 ppm. HRMS: calcd.
for C18H11N5 [M]+ 298.1093; found 298.1102.
Ethyl 6-Chloro-3-(5-methoxypyridin-3-yl)imidazo[1,2-b]pyridazine-
2-carboxylate (16): Yield: 192 mg, 89%; yellow solid; m.p. 164 °C.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.1 Hz, 3 H,
CH2CH3), 3.93 (s, 3 H, OCH3), 4.41 (q, J = 7.1 Hz, 2 H, CH2CH3),
7.21 (d, J = 9.5 Hz, 1 H, 7-H), 7.55 (s, 1 H, HAr), 8.05 (d, J =
9.5 Hz, 1 H, 8-H), 8.40–8.54 (m, 2 H, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.3, 55.8, 61.6, 121.7, 122.9, 128.6, 129.6,
134.3, 137.3, 138.1, 143.5, 149.0, 162.5 ppm. HRMS: calcd. for
C15H13ClN4O4 [M]+ 333.0754; found 333.0762.
4-{6-[4-(Trifluoromethyl)phenyl]imidazo[1,2-b]pyridazin-3-yl}benzo-
nitrile (24): Yield: 227 mg, 96 %; yellow solid; m.p. 218 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 9.4 Hz, 1 H, 7-H), 7.80
(d, J = 8.4 Hz, 2 H, HAr), 7.83 (d, J = 8.3 Hz, 2 H, HAr), 8.12 (d,
J = 8.3 Hz, 2 H, HAr), 8.17 (d, J = 9.4 Hz, 1 H, 8-H), 8.23 (s, 1 H,
2-H), 8.29 (d, J = 8.4 Hz, 2 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 111.1, 116.3, 118.8, 122.5, 125.2, 126.2, 126.3, 126.3,
126.3, 126.6, 126.8, 127.6, 132.1, 132.6, 133.0, 135.2, 138.8,
150.9 ppm. HRMS: calcd. for C20H11F3N4 [M]+ 365.1014; found
365.1016.
6-Chloro-3-(4-nitrophenyl)-2-phenylimidazo[1,2-b]pyridazine
(17):
Yield: 194 mg, 85%; yellow solid; m.p. 232 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.16 (d, J = 9.4 Hz, 1 H, 7-H), 7.34–7.40
(m, 3 H, HAr), 7.57–7.64 (m, 2 H, HAr), 7.82 (d, J = 8.9 Hz, 1 H,
HAr), 7.99 (d, J = 9.4 Hz, 1 H, 8-H), 8.31 (d, J = 8.9 Hz, 1 H, HAr
)
ppm. 13C NMR (100 MHz, CDCl3): δ = 120.0, 123.4, 124.0, 127.1,
128.8, 128.9, 129.0, 131.0, 133.1, 134.7, 138.2, 145.8, 147.1,
147.5 ppm. HRMS: calcd. for C18H11ClN4O2 [M]+ 351.0649; found
351.0661.
4-(6-Methoxyimidazo[1,2-b]pyridazin-3-yl)benzonitrile (25): Yield:
154 mg, 95 %; yellow solid; m.p. 186 °C. 1H NMR (400 MHz,
CDCl3): δ = 4.07 (s, 3 H, OCH3), 6.80 (d, J = 9.6 Hz, 1 H, 7-H),
7.74 (d, J = 8.4 Hz, 2 H, HAr), 7.88 (d, J = 9.6 Hz, 1 H, 8-H), 8.02
6-Chloro-2-(3-methoxyphenyl)-3-(4-nitrophenyl)imidazo[1,2-b]pyrid-
azine (18): Yield: 186 mg, 75%; yellow solid; m.p. 227 °C. 1H NMR (s, 1 H, 2-H), 8.24 (d, J = 8.4 Hz, 2 H, HAr) ppm. 13C NMR
Eur. J. Org. Chem. 2010, 862–871
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
869

A. El Akkaoui, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet
FULL PAPER
(100 MHz, CDCl3): δ = 54.9, 110.6, 112.4, 118.9, 128.0, 132.0,
132.1, 132.5, 132.9, 133.1, 133.4, 160.1 ppm. HRMS: calcd. for
C14H10N4O [M + H]+ 251.0933; found 251.0925.
3-Phenyl-6-(3-tolyl)imidazo[1,2-b]pyridazine (30): Yield: 128 mg,
69%; yellow solid; m.p. 169 °C. H NMR (400 MHz, CDCl3): δ =
1
2.45 (s, 3 H, CH3), 7.29 (d, J = 7.5 Hz, 1 H, HAr), 7.35–7.42 (m, 2
H, HAr), 7.48–7.53 (m, 3 H, HAr), 7.76–7.79 (m, 2 H, HAr), 8.03
(d, J = 9.4 Hz, 1 H, 8-H), 8.06 (s, 1 H, 2-H), 8.16 (d, J = 7.4 Hz,
2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7, 115.7,
124.3, 125.9, 126.9, 127.8, 127.9, 128.7, 128.8, 128.9, 129.0, 130.8,
133.1, 135.8, 138.8, 139.5, 151.7 ppm. HRMS: calcd. for C19H15N3
[M]+ 286.1344; found 286.1354.
4-{6-[(4-Methoxyphenyl)amino]imidazo[1,2-b]pyridazin-3-yl}benzo-
nitrile (26): Yield: 200 mg, 90 %; yellow solid; m.p. 245 °C. 1H
NMR (400 MHz, DMSO): δ = 3.78 (s, 3 H, OCH3), 6.99–7.00 (m,
3 H, 7-H, HAr), 7.61 (d, J = 9.0 Hz, 2 H, HAr), 7.93 (d, J = 9.7 Hz,
1 H, 8-H), 7.95 (d, J = 8.5 Hz, 2 H, HAr), 8.11 (s, 1 H, 2-H), 8.35
(d, J = 8.5 Hz, 2 H, HAr), 9.48 (s, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 55.4, 109.0, 114.0, 114.2, 119.1, 120.8,
125.7, 126.0, 126.4, 132.4, 132.6, 133.2, 133.6, 138.3, 151.2,
154.7 ppm. HRMS: calcd. for C20H15N5O [M]+ 342.1355; found
342.1371.
3-(Pyridin-3-yl)-6-(3-tolyl)imidazo[1,2-b]pyridazine (31): Yield:
138 mg, 74 %; yellow solid; m.p. 167 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.46 (s, 3 H, CH3), 7.32 (d, J = 7.5 Hz, 1 H, HAr),
7.42 (d, J = 7.4 Hz, 1 H, HAr), 7.45 (dd, J = 7.9, 4.7 Hz, 1 H, HAr),
7.55 (d, J = 9.5 Hz, 1 H, 8-H), 7.75–7.81 (m, 2 H, HAr), 8.06 (d, J
= 9.5 Hz, 1 H, 8-H), 8.11 (s, 1 H, 2-H), 8.48 (td, J = 8.0, 1.8 Hz,
1 H, HPyr), 8.62 (dd, J = 4.7, 1.4 Hz, 1 H, HPyr), 9.40 (d, J =
1.9 Hz, 1 H, HPyr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7,
116.5, 123.6, 124.4, 125.3, 125.8, 126.1, 127.8, 129.1, 131.1, 133.3,
133.7, 135.4, 138.9, 139.9, 147.7, 148.6, 152.2 ppm. HRMS: calcd.
for C18H14N4 [M]+ 287.1297; found 287.1303.
General Procedure for the One-Pot Suzuki Coupling/Arylation with
6-Chloroimidazo[1,2-b]pyridazines (Table 5): An arylboronic acid
(0.72 mmol, 1.1 equiv.), potassium carbonate (1.3 mmol, 2 equiv.),
triphenylphosphane (0.13 mmol, 0.2 equiv.), and palladium(II) ace-
tate (0.065 mmol, 0.1 equiv.) were added under argon to a solution
of 6-chloroimidazo[1,2-b]pyridazine (0.1 g, 0.65 mmol) in a tolu-
ene/EtOH mixture [2:1, (v/v), 2 mL] in a microwave tube. The reac-
tion vessel was sealed with a silicon septum and subjected to micro-
wave irradiation at 140 °C with stirring for 15 min. After the mix-
ture had been allowed to cool to room temperature, the aryl or
heteroaryl bromide (1.5 equiv.) was injected into the tube by sy-
ringe, and the reaction mixture was again subjected to microwave
irradiation at 140 °C for 2 h. The reaction vessel was allowed to
cool to room temperature, the mixture diluted with dichlorometh-
ane (20 mL) and extracted (3ϫ). The combined organic layers were
dried with MgSO4 and concentrated under vacuum. The crude ma-
terial thus obtained was purified by column chromatography on
silica gel (EtOAc/petroleum ether) to give the polysubstituted imid-
azo[1,2-b]pyridazine derivative (27–32).
3-(Pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridaz-
1
ine (32): Yield: 172 mg, 78%; yellow solid; m.p. 115 °C. H NMR
(400 MHz, CDCl3): δ = 7.47 (dd, J = 7.7, 4.8 Hz, 1 H, HAr), 7.59
(d, J = 9.4 Hz, 1 H, 7-H), 7.80 (d, J = 8.2 Hz, 2 H, HAr), 8.12 (d,
J = 8.1 Hz, 2 H, HAr), 8.15 (d, J = 9.4 Hz, 1 H, 8-H), 8.18 (s, 1 H,
2-H), 8.45 (td, J = 8.0, 1.5 Hz, 1 H, HPyr), 8.66 (m, 1 H, HPyr),
9.40 (m, 1 H, HPyr) ppm. 13C NMR (100 MHz, CDCl3): δ = 115.9,
122.5, 123.7, 123.7, 125.3, 126.1, 126.2, 126.2, 126.2, 126.7, 127.5,
133.7, 134.0, 138.8, 147.7, 148.9, 150.7 ppm. HRMS: calcd. for
C18H11F3N4 [M]+ 341.1014; found 341.1007.
[1] For recent reviews on direct arylation, see: a) D. Alberico,
M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238; b)
L. C. Campeau, D. Stuart, K. Fagnou, Aldrichim. Acta 2007,
40, 35–41; c) L. C. Campeau, K. Fagnou, Chem. Commun.
2006, 1253–1264; d) T. Satoh, M. Miura, Chem. Lett. 2007, 36,
200–205; e) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007,
36, 1173–1193; f) B. J. Li, S. D. Yang, Z. J. Shi, Synlett 2008,
949–957; g) O. Daugulis, V. G. Zaitsev, D. Shabashov, Q. N.
Pham, A. Lazareva, Synlett 2006, 3382–3388; h) S. Pascual, P.
De Mendoza, A. M. Echavarren, Org. Biomol. Chem. 2007, 5,
2727–2734; i) M. Catellani, E. Motti, N. Della Ca’, R. Ferrac-
cioli, Eur. J. Org. Chem. 2007, 4153–4165; j) J. C. Lewis, R. C.
Bergman, J. A. Ellman, Acc. Chem. Res. 2008, 41, 1013–1025.
[2] For recent examples of direct arylation processes with Pd0, see:
a) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173–
1193; b) L. Ackermann, A. Althammer, Angew. Chem. Int. Ed.
2007, 46, 1627–1629; c) R. J. Phipps, N. P. Grimster, M. J.
Gaunt, J. Am. Chem. Soc. 2008, 130, 8172–8174; d) B. Laleu,
M. Lautens, J. Org. Chem. 2008, 73, 9164–9167; e) L. Ackerm-
ann, R. Vicente, R. Born, Adv. Synth. Catal. 2008, 350, 741–
748; f) S. H. Hwang, S. H. Cho, S. Chang, J. Am. Chem. Soc.
2008, 130, 16158–16159; g) F. Bellina, F. Benelli, R. Rossi, J.
Org. Chem. 2008, 73, 5529–5535; h) E. F. Flegeau, M. E. Pop-
kin, M. F. Greaney, Org. Lett. 2008, 10, 2717–2720; i) T. Mar-
tin, C. Verrier, C. Hoarau, F. Marsais, Org. Lett. 2008, 10,
2909–2912; j) X. Wang, D. V. Gribkov, D. Sames, J. Org. Chem.
2007, 72, 1476–1479; k) D. H. Wang, T. S. Mei, J. Q. Yu, J.
Am. Chem. Soc. 2008, 130, 17676–17677; l) J. X. Wang, J. A.
McCubbin, M. Jin, R. S. Laufer, Y. Mao, A. P. Crew, M. J.
Mulvihilland, V. Snieckus, Org. Lett. 2008, 10, 2923–2926; m)
S. D. Yang, C. L. Sun, Z. Fang, B. J. Li, Y. Z. Li, Z. J. Shi,
Angew. Chem. Int. Ed. 2008, 47, 1473–1476; n) L. Ackermann,
A. Althammer, S. Fenner, Angew. Chem. Int. Ed. 2009, 48, 201–
204; o) J. Kim, M. Jo, W. So, Z. No, Tetrahedron Lett. 2009,
50, 1229–1235; p) P. Li, Z. Chai, G. Zhao, S. Zhu, Tetrahedron
6-(4-Methoxyphenyl)-3-phenylimidazo[1,2-b]pyridazine (27): Yield:
141 mg, 72 %; yellow solid; m.p. 186 °C. 1H NMR (400 MHz,
CDCl3): δ = 3.86 (s, 3 H, OCH3), 7.01 (d, J = 8.7 Hz, 2 H, HAr),
7.37 (t, J = 7.3 Hz, 1 H, HAr), 7.44 (d, J = 9.4 Hz, 1 H, 7-H), 7.50–
7.51 (m, 2 H, HAr), 7.93 (d, J = 8.7 Hz, 2 H, HAr), 7.98 (d, J =
9.4 Hz, 1 H, 8-H), 8.03 (s, 1 H, 2-H), 8.14 (d, J = 7.3 Hz, 2 H,
H
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.4, 114.5, 115.2,
125.8, 126.8, 127.8, 128.2, 128.4, 128.7, 133.0, 139.4, 151.1,
161.2 ppm. HRMS: calcd. for C19H15N3O [M]+ 302.1293; found
302.1298.
Ethyl 6-(4-Methoxyphenyl)-3-(4-nitrophenyl)imidazo[1,2-b]pyridaz-
ine-2-carboxylate (28): Yield: 206 mg, 76 %; yellow solid; m.p.
192 °C. 1H NMR (400 MHz, CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H,
CH2CH3), 3.87 (s, 3 H, OCH3), 4.44 (q, J = 7.1 Hz, 2 H, CH2CH3),
7.01 (d, J = 8.8 Hz, 2 H, HAr), 7.66 (d, J = 9.6 Hz, 1 H, 7-H), 7.85
(d, J = 8.8 Hz, 2 H, HAr), 8.01 (d, J = 8.8 Hz, 2 H, HAr), 8.10 (d,
J = 9.6 Hz, 1 H, 8-H), 8.39 (d, J = 8.8 Hz, 2 H, HAr) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.4, 55.5, 61.6, 114.7, 118.7, 123.0,
126.9, 127.1, 128.6, 130.4, 132.1, 133.8, 134.0, 138.2, 147.9, 153.0,
161.9, 162.9 ppm. HRMS: calcd. for C22H18N4O5 [M]+ 419.1355;
found 419.1351.
1-[4-(3-Phenylimidazo[1,2-b]pyridazin-6-yl)phenyl]ethanone (29):
Yield: 155 mg, 76 %; yellow solid; m.p. 162 °C. 1H NMR
(400 MHz, CDCl3): δ = 2.66 (s, 3 H, COCH3), 7.41 (t, J = 7.4 Hz,
1 H, HAr), 7.50–7.56 (m, 3 H, HAr), 8.05–8.11 (m, 6 H, HAr), 8.13
(d, J = 7.5 Hz, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ =
26.8, 115.1, 126.2, 126.8, 127.2, 128.1, 128.6, 128.8, 128.9, 129.0,
133.7, 137.9, 139.9, 150.2, 197.4 ppm. HRMS: calcd. for
C20H15N3O [M]+ 314.1293; found 314.1299.
870
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 862–871

Direct Arylation of Imidazo[1,2-b]pyridazines
2009, 65, 1673–1678; q) B. Mariampillai, J. Alliot, M. Li, M.
Lautens, J. Am. Chem. Soc. 2007, 129, 15372–15379.
[3] For selected direct arylation processes with Ru, see: a) L. Ack-
ermann, A. Althammer, R. Born, Angew. Chem. Int. Ed. 2006,
45, 2619–2622; b) I. Ozdemir, S. Demir, B. Cetinkaya, C. Gour-
laouen, F. Maseras, C. Bruneau, P. H. Dixneuf, J. Am. Chem.
Soc. 2008, 130, 1156–1157.
6267; c) S. El Kazzouli, A. Berthault, S. Berteina-Raboin, A.
Mouaddib, G. Guillaumet, Lett. Org. Chem. 2005, 2, 184–187;
d) A. El Akkaoui, J. Koubachi, S. El Kazzouli, S. Berteina-
Raboin, A. Mouaddib, G. Guillaumet, Tetrahedron Lett. 2008,
49, 2472–2475; e) J. Koubachi, S. El Kazzouli, S. Berteina-Ra-
boin, A. Mouaddib, G. Guillaumet, Synthesis 2008, 2537–2542;
f) J. Koubachi, S. Berteina-Raboin, A. Mouaddib, G. Guil-
laumet, Synthesis 2009, 2, 271–276.
J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib,
G. Guillaumet, Synlett 2006, 3237–3242.
a) B. Stanovnik, M. Tisler, Tetrahedron 1967, 23, 2739–2746;
b) B. Stanovnik, M. Tisler, Tetrahedron 1967, 23, 387–395; c)
E. Abignente, F. Arena, P. De Capriis, L. Parente, Farmaco, Ed.
Sci. 1977, 32, 430–437.
[4] For selected direct arylation processes with Rh, see: a) S. Oi,
S. Fukita, Y. Inoue, Chem. Commun. 1998, 2439–2440; b) R. B.
Bedford, S. J. Coles, M. B. Hursthouse, M. E. Limmert, Angew.
Chem. Int. Ed. 2003, 42, 112–114; c) R. B. Bedford, M. E. Lim-
mert, J. Org. Chem. 2003, 68, 8669–8682; d) X. Wang, B. S.
Lane, D. Sames, J. Am. Chem. Soc. 2005, 127, 4996–4997; e)
S. Proch, R. Kempe, Angew. Chem. Int. Ed. 2007, 46, 3135–
3138; f) R. B. Bedford, M. Betham, A. J. M. Caffyn, J. P. H.
Charmant, L. C. L. Alleyne, P. D. Long, D. P. Ceron, S. Pra-
shar, Chem. Commun. 2008, 990–992; g) J. C. Lewis, A. M.
Berman, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2008,
130, 2493–2500; h) J. C. Lewis, J. Y. Wu, J. A. Ellman, R. G.
Bergman, Angew. Chem. Int. Ed. 2006, 45, 1589–1591; i) J. C.
Lewis, S. H. Wiedemann, R. G. Bergman, J. A. Ellman, Org.
Lett. 2004, 6, 35–38; j) K. L. Tan, A. Vasudevan, R. G.
Bergman, J. A. Ellman, A. J. Souers, Org. Lett. 2003, 5, 2131–
2134; k) K. L. Tan, R. G. Bergman, J. A. Ellman, J. Am. Chem.
Soc. 2002, 124, 3202–3203; l) S. Yanagisawa, T. Sudo, R.
Noyori, K. Itami, Tetrahedron 2008, 64, 6073–6081.
[6]
[7]
[8]
[9]
A. M. Roe, J. Chem. Soc. 1963, 2195–2200.
a) A. Hallberg, Tetrahedron Lett. 1996, 37, 8219–8220; b) A.
Hallberg, J. Org. Chem. 1996, 61, 9582–9584; c) P. Nilsson, Top.
Curr. Chem. 2006, 266, 103–144; d) C. O. Kappe, Chem. Soc.
Rev. 2008, 37, 1127–1140.
[10] a) S. El Kazzouli, G. Lavecchia, S. Berteina-Raboin, A. Mou-
addib, G. Guillaumet, Tetrahedron Lett. 2006, 47, 4437–4440;
b) E. Garnier, J. Audoux, E. Pasquinet, F. Suzenet, D. Poullain,
B. Lebret, G. Guillaumet, J. Org. Chem. 2004, 69, 7809–7815.
[11] Xantphos
thene.
=
9,9-dimethyl-4,5-bis(diphenylphosphanyl)xan-
[12] J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib,
G. Guillaumet, J. Org. Chem. 2007, 72, 7650–7655.
Received: July 27, 2009
[5] a) G. Guillaumet, S. Berteina-Raboin, S. El Kazzouli, P. Delag-
range, D. H. Caignard, WO 2006,027,474, 2006; Chem. Abstr.
2006, 144, 254132; b) S. El Kazzouli, S. Berteina-Raboin, A.
Mouaddib, G. Guillaumet, Tetrahedron Lett. 2003, 44, 6265–
Published Online: January 5, 2010
Eur. J. Org. Chem. 2010, 862–871
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
871