Stereoselective Suzuki Coupling Reaction of an α-Bromo-α-fluoro-β-lactam

Abstract

A new strategy has been developed for the synthesis of α-aryl-α-fluoro-β-lactams via the Suzuki cross-coupling of α-bromo-α-fluoro-β-lactam with a range of different aryl-(9-BBN) reagents. This method provides facile access to multisubstituted α-fluoro-β-lactams in a diastereoselective manner. The synthetic utility of α-bromo-α-fluoro-β-lactam has been demonstrated by the arylation of α-bromo-α-fluoro-β-lactam.

Key words

fluorine - β-lactam - cross-coupling - nickel - 9-BBN

• References and Notes

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• 13 Typical Experimental Procedure for the Ni-Catalyzed Suzuki Coupling Reaction of α-Bromo-α-fluoro-β-lactam: 4,4′-Di-tert-butylbipyridine (29.5 mg, 0.11 mmol) and NiBr₂·diglyme (35 mg, 0.10 mmol) were added to a flask equipped with a magnetic stirrer bar. To the flask was added anhyd benzene (7.5 mL) and the resulting mixture was stirred vigorously for 2 h (a light-green slurry formed). The solution of the activated Ph-(9-BBN) solution (1.25 mmol) was added to the slurry, and the whole mixture was stirred for 20 min at same temperature. Then, 1 (0.5 mmol) was added to the slurry and the resulting mixture was stirred for 1 h under reflux. The reaction was quenched by brine and the mixture was extracted with EtOAc, and then the extract was dried over MgSO₄. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (hexane–EtOAc) to give the desired product 3.(3S,4R/3R,4S)-1-Benzyl-3-fluoro-3,4-diphenylazetidin-2-one (3a): colorless solid (145 mg, 87%); mp 78.0–79.0 °C (uncorrected). ¹H NMR (400 MHz, CDCl₃): δ = 3.98 (dd, J = 14.8, 2.4 Hz, 1 H), 4.66 (d, J = 3.5 Hz, 1 H), 5.03 (d, J = 14.8 Hz, 1 H), 7.16–7.18 (m, 2 H), 7.29–7.33 (m, 5 H), 7.38 (m, 5 H), 7.42–7.44 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 44.4 (d, J = 2 Hz), 68.6 (d, J = 25 Hz), 102.2 (d, J = 225 Hz), 125.2 (d, J = 7 Hz), 128.0, 128.2 (d, J = 2 Hz), 128.5, 128.6, 128.7, 128.8, 129.0, 129.2 (d, J = 2 Hz), 132.1, 134.2 (d, J = 24 Hz), 134.4, 164.8 (d, J = 25 Hz). ¹⁹F NMR (84 MHz, CDCl₃): δ = –102.5 (s, 1 F). MS: m/z = 331 [M⁺]. HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₈FNO: 331.1372; found: 331.1378.
• 14 See supporting information for the determination of the relative configuration and the diastereoselective formation of coupling products.
• 15 The ee value was determined to be 92% by HPLC analysis [Daicel CHIRALPAK AD-H, hexane–EtOH = 98:2, flow rate = 2.0 mL/min, λ = 254 nm, t _R (major) = 10.0 min and t _R (minor) = 8.9 min]. [α]_D ²⁵ +63.4 (c = 1.05, CHCl₃). See the Supporting Information for enantiopurity of 3a.