A. Basilio-Lopes et al. / Tetrahedron Letters 53 (2012) 2583–2587
2587
18. Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64, 5191.
19. Representative example of activation of secondary amide 7 with TiCl4.
Supplementary data
Preparation of ethyl 2-(3,4-dimethoxyphenyl) imidazo[1,2-a]pyridine-3-
carboxylate 12e. TiCl4 (1 M in toluene, 1.35 mL, 1.35 mmol, 1.2 equiv) was
added dropwise to a solution of piperidine (554 lL, 5.61 mmol, 5 equiv) in
Supplementary data associated with this article can be found, in
dioxane (5 mL) under argon. The resulting solution was then heated at 50 °C
and 3,4-dimethoxy-N-pyridin-2-ylbenzamide 7e in dioxane (8 mL) was then
added dropwise. The final solution was stirred at reflux for 15 h. After
evaporation of the volatile, the crude residue was dissolved in ethyl acetate
(40 mL). The solution was washed successively with an aqueous saturated
NaHCO3 solution (2 Â 15 mL) and water (2 Â 15 mL). The organic phase was
then dried (Na2SO4) and evaporated under reduced pressure to give 9. The
resulting product was directly submitted to cyclization. A suspension of 9
(0.20 mmol), the corresponding bromo compound (0.25 mmol) and K2CO3
(0.20 mmol) in DMF (2 mL) was heated at 140 °C for 3 h. The reaction mixture
was then concentrated under reduced pressure, the residue was dissolved in
ethyl acetate (30 mL), washed with water (2 Â 10 mL). The organic phase was
dried (Na2SO4), concentrated to dryness under reduced pressure. The resulting
residue was purified by silica gel column chromatography to afford 12e as a
white solid (97%). mp 102–104 °C TLC Rf = 0.52(AcOEt). 1H NMR (300 MHz,
CDCl3) d: 1.28 (t, 3H, J = 7.3 Hz, CH3), 3.95 (s, 6H, OCH3), 4.29 (q, 2H, J = 7.3 Hz,
OCH2), 6.90–7.07 (m, 2H, ArH), 7.37–7.49 (m, 3H, ArH), 7.74 (d, 1H, J = 9.0 Hz,
ArH), 9.39 (d, 1H, J = 6.8 Hz, ArH). 13C NMR (75 MHz, CDCl3) d: 14.6, 56.3, 60.8,
110.6, 112.1, 113.7, 114.4, 117.7, 123.7, 127.4, 128.3, 128.7, 147.4, 148.5, 150.0,
153.9, 161.6. ESMS m/z: 327.2 (M+H).
References and notes
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20. Representative example of activation of secondary amide 7 with PCl5.
Preparation of ethyl 2-(3-azidopropyl)imidazo[1,2-a]pyridine-3-carboxylate 12k.
PCl5 (1.3 mmol) was added to
a
solution of N-pyridin-2-yl-4-
(azido)butanamide 7k (1.4 mmol) in anhydrous DCM (13 mL). The resulting
reaction mixture was stirred at 40 °C under argon for 1.6 h and then the solvent
and volatiles were removed under reduced pressure at 27 °C. The crude residue
was re-dissolved in anhydrous DCM (13 mL), piperidine (13 mmol) was added
in one portion and the final solution was stirred at room temperature until TLC
showed complete consumption of starting material (40 mn). The solvent was
evaporated under vacuum, the residue taken into diethylether (30 mL), and
washed with water (1 Â 15 mL), brine (1 Â 15 mL). The organic layer was dried
(Na2SO4) filtered and concentrated under reduced pressure to give N-(4-azido-
1-(piperidin-1-yl)butylidene)pyridin-2-amine 9k.
A suspension of 9k (1 mmol), the corresponding bromo compound (1.5 mmol)
and K2CO3 (1.5 mmol) in anhydrous DMF (7 mL) was heated at 130 °C until TLC
showed complete consumption of starting material (15 h). The reaction
mixture was then concentrated under reduced pressure, the residue was
dissolved in ethyl acetate (35 mL) and washed with water (2 Â 15 mL). The
organic phase was dried (Na2SO4), concentrated to dryness under reduced
pressure. The resulting residue was purified by silica gel column
chromatography to afford 12k as a clear oil (61%) TLC Rf = 0.58 (AcOEt/hept
3:1). 1H NMR (300 MHz, CDCl3) d:1.38 (t, 3H, J = 7.2 Hz, CH3), 2.04 (quintet, 2H,
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J = 6.8 Hz, 7.6 Hz, CH2-b), 3.14 (t, 2H, J = 7.6 Hz, CH2-a), 3.32 (t, 2H, J = 6.8 Hz,
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CH2-c), 4.38 (q, 2H, J = 7.2 Hz, OCH2), 6.91–9.94 (m, 1H, ArH), 7.31–7.35 (m, 1H,
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ArH), 7.57 (d, 1H, J = 8.8 Hz, ArH), 9.26 (d, 1H, J = 6.8 Hz, ArH). 13C NMR
(100 MHz, CDCl3) d: 14.5, 27.3, 28.4, 51.2, 60.5, 113.9, 116.9, 127.8, 128.2.
ESMS m/z: 274.2 (M+H).
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23. Supplementary data available: Experimental procedures and spectral data for
compounds 7, 12, 13, 14, 17, 21, 25, 26. This material is available free of charge.
16. Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem. 2006, 71, 3775.
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