A General and Efficient Synthesis of 2-Substituted Oxazolopyridines

Abstract

Starting from commercially available halonitropyridines and haloaminopyridines, 2-substituted-oxazolo[5,4-b]pyridines, and 2-aryl-oxazolo[4,5-b]pyridines were synthesized in good yields by using a Cu(I)-mediated cyclization of halopyridylamides as a key step.

Key words

copper-catalyzed cyclization - synthesis - heterocycles - oxazolo[5,4-b]pyridines - oxazolo[4,5-b]pyridines

References and Notes

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8

Typical Procedure for the Synthesis and Purification of 3a
To a mixture of 2a (2.0 mmol), CuI (0.1 mmol), N,N′-dimethylethylenediamine (0.2 mmol), and K₂CO₃ (4.0 mmol) was added dry toluene (5.0 mL) under a nitrogen atmosphere. The reaction was refluxed for 12 h and then allowed to cool to r.t. The crude mixture was added to 10 mL H₂O and then was extracted by CH₂Cl₂ (2 × 20 mL). The organic layer was dried over anhyd Na₂SO₄ and concentrated in vacuo to give the crude product, which was further purified by flash chromatography over silica gel column with PE-EtOAc (5:1) to give the pure product 3a.

9

Selected Spectral Data
Compound 3a: mp 101-102 ˚C. R _f  = 0.55 (EtOAc-PE, 1:2). IR (KBr): 2913, 1617, 1544 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.38 (dd, J = 5.1, 1.5 Hz, 1 H), 8.34 (d, J = 1.5 Hz, 1 H), 8.34 (d, J = 2.1 Hz, 1 H), 8.10 (dd, J = 7.8, 1.5 Hz, 1 H), 7.55-7.62 (m, 3 H), 7.36-7.41 (m, 1 H). MS (EI):
m/z = 196 [M]⁺. Anal. Calcd for C₁₂H₈N₂O: C, 73.46; H, 4.11; N, 14.28. Found: C, 73.46; H, 4.43; N, 14.18.
Compound 3i: mp 79-81 ˚C. R _f  = 0.38 (EtOAc-PE, 1:2). IR (KBr): 2924, 1602, 1523 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.35 (dd, J = 4.2, 1.5 Hz, 1 H), 8.21 (dd, J = 7.8, 1.5 Hz, 1 H), 8.12 (dd, J = 7.8, 1.5 Hz, 1 H), 7.53-7.56 (m, 1 H), 7.32-7.37 (m, 1 H), 7.10-7.16 (m, 2 H), 4.05 (s, 3 H). MS (EI): m/z = 226 [M]⁺. Anal. Calcd for C₁₃H₁₀N₂O₂: C, 69.02; H, 4.46; N, 12.38. Found: C, 68.67; H, 4.34; N, 12.38.
Compound 3k: mp 172-174 ˚C. R _f  = 0.42 (EtOAc-PE, 1:2). IR (KBr): 1496, 1620, 1223 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.34 (dd, J = 4.5, 1.5 Hz, 1 H), 8.05 (dd, J = 7.8, 1.5 Hz, 1 H), 7.54 (s, 2 H), 7.33-7.37 (m, 1 H), 4.04 (s, 9 H). MS (EI): m/z = 286 [M]⁺. Anal. Calcd for C₁₅H₁₄N₂O₄: C, 62.93; H, 4.93; N, 9.79; Found: C, 63.12; H, 4.74; N, 9.78.
Compound 6a: mp 163-164 ˚C. R _f  = 0.38 (EtOAc-PE, 1:2). IR (KBr): 2920, 1670, 1580 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.56 (s, 1 H), 8.46 (dd, J = 1.5, 7.2 Hz, 2 H), 7.81 (s, 1 H), 7.75-7.65 (m, 3 H), 2.65 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 165.1, 154.4, 147.3, 132.3, 130.6, 129.0, 128.0, 126.7, 118.5, 18.9. ESI-MS: m/z = 211 [M⁺ + 1]. Anal. Calcd for C₁₃H₁₀N₂O: C, 74.27; H, 4.79; N, 13.33. Found: C, 74.05; H, 4.77; N, 13.28.
Compound 6b: mp 165-167 ˚C. R _f  = 0.35 (EtOAc-PE, 1:2). IR (KBr): 2918, 1620, 1550 cm^-¹.^¹H NMR (300 MHz, CDCl₃): δ = 8.57 (s, 1 H), 8.32 (d, J = 8.4 Hz, 2 H), 8.01 (d, J = 8.3 Hz, 2 H), 7.84 (s, 1 H), 3.95 (s, 1 H), 2.64 (s, 3 H). ESI-MS: m/z = 241 [M⁺ + 1]. Anal. Calcd for C₁₃H₁₀N₂O: C, 69.99; H, 5.03; N, 11.66. Found: C, 69.78; H, 4.98; N, 11.69.
Compound 6c: mp 193-194 ˚C. R _f  = 0.32 (EtOAc-PE, 1:2). IR (KBr): 2918, 1610, 1560 cm^-¹.^¹H NMR (300 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.16 (d, J = 8.7 Hz, 2 H), 8.04 (d, J = 8.1 Hz, 2 H), 7.84 (s, 1 H), 2.64 (s, 3 H). ^¹³C NMR (75 Hz, CDCl₃): δ = 164.3, 154.2, 147.7, 143.3, 138.4, 130.9, 129.3, 126.2, 118.6, 99.5, 18.9. ESI-MS: m/z = 337 [M⁺ + 1]. Anal. Calcd for C₁₃H₉IN₂O: C, 46.45; H, 2.70, N, 8.33. Found: C, 46.53; H, 2.75; N, 8.40.