Alternative Approach toward the Generation of Benzylic Zinc Reagent: Direct Oxidative Addition of Active Zinc into the Carbon–Oxygen Bond of Benzyl Mesylates

Abstract

The use of highly active zinc, prepared by the Rieke method, for the direct preparation of benzylic zinc mesylate was investigated. The oxidative addition of highly active zinc to benzyl mesylate was easily completed under mild conditions. The resulting benzylic zinc mesylates were employed in subsequent cross-coupling reactions with a broad range of electrophiles, and the formation of the corresponding products was successful.

Key words

benzylic zinc - benzyl meslate - active zinc - oxidative addition - cross-coupling

• References and Notes

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• 11 Representative Procedures Preparation of Benzylic Zinc Mesylate (I) In an oven-dried 250 mL round-bottomed flask equipped with a stir bar was added 4.70 g of active zinc (Zn*, 72.0 mmol) in 100 mL of THF. Benzyl mesylate (11.2 g, 60.0 mmol) was cannulated neat into the flask at r.t. The resulting mixture was stirred for 4.0 h at r.t. The whole mixture was settled down, and then the supernatant was used for the subsequent coupling reactions. Copper-Catalyzed Cross-Coupling Reaction Into a 25 mL round-bottomed flask were placed CuCN (0.02 g, 10 mol%) and LiCl (0.02 g, 20 mol%). Benzylic zinc mesylate (I, 5.0 mL, 0.5 M in THF, 2.5 mmol) was added into the flask under an argon atmosphere. Next, 4-bromobenzoyl chloride (0.44 g, 2.0 mmol) was slowly added via a syringe while being stirred at 0 °C. The resulting mixture was at 0 °C for 2 h, quenched with 3.0 M HCl solution, then extracted with Et₂O (3 × 10 mL), washed with sat. NaHCO₃, Na₂S₂O₃ solution and brine, and then dried over anhydrous MgSO₄. Purification by column chromatography on silica gel (EtOAc–heptane, 2:98) afforded 0.38 g of 1-(4-bromophenyl)-2-phenylethanone (1b) in 70% isolated yield as a white solid (mp 103–104 °C). ¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 8.5 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 2 H), 7.34–7.24 (m, 5 H), 4.25 (s, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 196.65, 135.25, 134.15, 131.99, 131.96, 130.18, 129.40, 128.80, 127.08, 45.55. Palladium-Catalyzed Cross-Coupling Reaction Into a 25 mL round-bottomed flask were added Pd(PPh₃)₂Cl₂ (0.028 g, 2.0 mol%), 2-iodobenzonitrile (0.22 g, 1.0 mmol), and I (4.0 mL, 0.5 M in THF, 2.0 mmol) under an argon atmosphere at r.t. The resulting mixture was stirred at r.t. for 1.0 h, quenched with 3 M HCl solution, then extracted with Et₂O (3 × 10 mL), washed with sat. NaHCO₃, Na₂S₂O₃ solution and brine, and then dried over anhydrous MgSO₄. Purification by column chromatography on silica gel (EtOAc–heptane, 10:90) afforded 0.14 g of 4a in 72% isolated yield as a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.53–7.46 (m, 3 H), 7.43–7.35 (m, 3 H), 7.31–7.29 (m, 1 H), 7.25–7.21 (m, 2 H), 4.04 (s, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 142.71, 139.54, 133.53, 132.40, 129.99, 129.34, 129.01, 128.87, 126.76, 119.03, 112.51, 41.45.