Stereoselective Suzuki Coupling Reaction of an α-Bromo-α-fluoro-β-lactam
Received: 22 September 2014
Accepted after revision: 09 November 2014
28 November 2014 (online)
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.
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.