A. El Akkaoui et al. / Tetrahedron Letters 49 (2008) 2472–2475
2475
Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Synlett 2006, 3237; (e) Koubachi, J.; El Kazzouli, S.;
Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. J. Org. Chem.
2007, 72, 7650.
was treated with an excess of amine in refluxing THF
(Table 5, entry 1). Unfortunately, no reaction was
observed. We then turned our attention to palladium-
catalyzed amination recently developed in our laboratory21
using XANTPHOS22 (0.2 equiv), Pd(OAc)2 (0.1 equiv),
and K2CO3 (20 equiv) in the presence of 1.2 equiv of
various amines in refluxing dioxane. This method gave
the desired product in good yields (70–86%, Table 5).
In conclusion, we have applied short, efficient, and ver-
satile palladium-assisted synthetic approaches (Stille and
Sonogashira cross-coupling) to achieve structural diversifi-
cation at the 3-position of the imidazo[1,2-b]pyridazine
system. Then, 6-substituted analogs were prepared in good
yield using either nucleophilic aromatic substitution with
primary alcohols or palladium-mediated N-arylation.
15. Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.; Delagrange, P.;
Caignard, D.-H. PCT, Int. Appl. WO 027474, 2006; Chem. Abstr.,
2006, 144, 254132.
16. Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.;
Vance, L. J. Med. Chem. 1999, 42, 50.
17. (a) Sonogashira, K.; Tohda, Y.; Hagihra, N. Tetrahedron Lett. 1975,
16, 4467; (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46; (c)
Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34,
6403; (d) Neghishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979; (e)
Sakomoto, T.; Shiga, F.; Yasuhara, A.; Yamanaka, H. Synthesis
´
1992, 746; (f) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
18. (a) Collot, V.; Varlet, D.; Rault, S. Tetrahedron lett. 2000, 41, 4363;
(b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (c) Farina,
V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction; Wiley-
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References and notes
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21. (a) El Kazzouli, S.; Lavecchia, G.; Berteina-Raboin, S.; Mouaddib,
A.; Guillaumet, G. Tetrahedron Lett. 2006, 47, 4437; (b) Garnier, E.;
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22. XANTPHOS = 9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene.
23. 6-Chloro-3-(3-methoxy-prop-1-ynyl)-2-phenyl-imidazo [1,2-b]pyrida-
zine (3). Under argon, a mixture of 6-chloro-3-iodoimidazo[1,2-b]-
pyridazine (0.2 g, 0.56 mmol), methyl propargyl ether (0.086 mL,
1.2 mmol), Pd2(dba)3 (0.051 g, 0.056 mmol), and AsPh3 (0.034 g,
0.0113 mmol) dissolved in a mixture of Et3N/DMF (1:1, v/v) was
heated to 50 °C and stirred for 12 h. The mixture was then cooled to
room temperature and extracted with CH2Cl2 (3Â). The combined
organic layer was dried over MgSO4 and concentrated under vacuum.
The residue was purified by column chromatography on a silica gel
(EtOAc/PE) to give 6-chloro-3-(3-methoxy-prop-1-ynyl)-2-phenyl-
imidazo[1,2-b]pyridazine 3 (0.140 g, 84%) as a yellow solid. NMR
1H (CDCl3): d 3.50 (s, 3H), 4.52 (s, 2H), 7.07 (d, 1H, J = 9.3 Hz),
7.40–7.45 (m, 3H), 7.84 (d, 1H, J = 9.3 Hz), 8.25 (d, 2H). NMR 13C
(CDCl3): d 58.0, 60.8, 74.3, 98.3, 109.5, 120.3, 126.4, 127.3, 128.7,
129.3, 132.6, 137.8, 147.4, 148.5.
24. (4-Methoxy-phenyl)-[3-(3-methoxy-prop-1-ynyl)-2-phenyl-imidazo[1,2-
b]pyridazin-6-yl]-amine (21): A three-necked flask was flushed with
argon and charged with XANTPHOS (0.065 g, 0.113 mmol) and dry
dioxane (1 mL). After degassing, Pd(OAc)2 (0.013 g, 0.28 mmol) was
added, and the mixture was stirred under argon for 10 min. In another
three-necked round-bottom flask, 6-chloro-3-(3-methoxy-prop-
1-ynyl)-2-phenyl-imidazo[1,2-b]pyridazine 3 (0.2 g, 0.56 mmol), 4-
methoxyphenylamine (0.083 g, 0.68 mmol), and K2CO3 (1.55 g,
11.3 mmol) were poured into dry dioxane (2 mL). Then, the
Pd(OAc)2/ XANTPHOS solution was added with double syringe.
The resulting mixture was subsequently heated to reflux. After
cooling, the reaction mixture was extracted with CH2Cl2 (3Â). The
combined organic layer was dried over MgSO4 and concentrated
under vacuum. The residue was purified by column chromatography
`
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Willis, A. C. Aust. J. Chem. 1996, 49, 451; (d) Barlin, G. B.; Davies, L.
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Kuwahara, M.; Kawano, K.; Shimazu, H.; Ashida, Y.; Miyake, A.
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14. (a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet,
G. Tetrahedron Lett. 2002, 44, 6265; (b) El Kazzouli, S.; Berteina-
Raboin, S.; Mouaddib, A.; Guillaumet, G. Tetrahedron Lett. 2003,
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on
a silica gel (MeOH/CH2Cl2) to give (4-methoxy-phenyl)-[3-
(3-methoxy-prop-1-ynyl)-2-phenyl-imidazo[1,2-b]pyridazin-6-yl]-amine
21 (0.227 g, 88%) as a yellow solid. NMR 1H (CDCl3. 250,131 Hz):
d = 3.54 (s, 3H), 3.80 (s, 3H), 4.56 (s, 2H), 6.65 (d, 1H, J = 9.3 Hz),
6.83 (s, 1H), 6.88 (d, 2H, J = 9.3 Hz), 7.32–7.48 (m, 6H), 7.64 (d, 1H,
J = 9.3 Hz), 8.25 (d, 2H). NMR 13C (CDCl3): d 56.1, 58.3, 61.4, 97.2,
109.3, 113.5, 115.1, 123.3, 126.2, 126.5, 127.3, 128.9, 129.1, 133.0,
134.0, 137.3, 146.6, 152.5, 156.8.