-

TCI Practical Example: Cross-Coupling Reaction Using the Allylsulfonylpyridine Derivative

We are proud to present the C-C cross-coupling reaction of 2-(allylsulfonyl)-5-methylpyridine and 4-bromoanisole.

Used Chemicals

• 2-(Allylsulfonyl)-5-methylpyridine [A3349]
• 4-Bromoanisole [B0547]
• Palladium(II) Acetate (Purified) [P2161]
• Di-tert-butyl(methyl)phosphonium Tetrafluoroborate (= tBu₂PMe·HBF₄) [D4731]
• Cesium Carbonate [C2160]
• DMF

Procedure

2-(Allylsulfonyl)-5-methylpyridine (592 mg, 3.0 mmol, 1.5 equiv.), palladium(II) acetate (22 mg, 0.1 mmol, 5 mol%), tBu₂PMe·HBF₄ (50 mg, 0.2 mmol, 10 mol%) and cesium carbonate (1.30 g, 4.0 mmol, 2.0 equiv.) were added to a pressure-resistant test tube and the test tube was purged with nitrogen. Then, DMF (10 mL) and 4-bromoanisole (0.25 mL, 2.0 mmol, 1.0 equiv.) were added in one portion at room temperature and the resulting mixture was stirred at 150 °C for 17 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with diethyl ether (100 mL x 3), dried with Na₂SO₄ (20 g) and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 5:95 - 18:82) to afford 2-(4-methoxyphenyl)-5-methylpyridine (1) as a yellow solid (196 mg, 49% yield).

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:5, Rf = 0.37).
DMF was dehydrated by MS4A for 16 h and degassed by bubbling with nitrogen gas for 30 minutes before use.

Analytical Data

2-(4-Methoxyphenyl)-5-methylpyridine (1)

¹H NR (400 MHz, CDCl₃); δ 8.47 (s, 1H), 7.92 (dd, 2H, J = 9.2, 1.8 Hz), 7.50-7.59 (m, 2H), 6.99 (dd, 2H, J = 9.2, 1.8 Hz), 3.86 (s, 3H), 2.35 (s, 3H).

¹³C NMR (101 MHz, CDCl₃); δ 160.1, 154.3, 149.7, 137.4, 131.8, 130.9, 127.9, 119.4, 114.0, 55.3, 18.1.

Lead Reference

• Heterocyclic Allylsulfones as Latent Heteroaryl Nucleophiles in Palladium-Catalyzed Cross-Coupling Reactions
  • T. Markovic, P. R. D. Murray, B. N. Rocke, A. Shavnya, D. C. Blakemore, M. C. Willis, J. Am. Chem. Soc. 2018, 140, 15916.