Compound data: NMR
Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.
General Procedure A: tert-Butyl lithium (in pentane, 0.31 mmol, 1.30 equiv)A was added dropwiseB to a solution of BCB-sulfoxide 5 (60 mg, 0.31 mmol, 1.30 equiv) and the boronic ester (0.24 mmol, 1.0 equiv) in anhydrous 2-methyl tetrahydrofuran (2.1 mL) at ‒78 °C (dry ice/acetone) and allowed to stir for 5 min. After removing the cooling bath a solution of Pd(dba)2 (4.1 mg, 7.2 μmol, 3.0 mol%) and dippf (3.6 mg, 8.6 μmol, 3.6 mol%) in 2-methyl tetrahydrofuran (0.5 mL) (pre-mixed under argon for 20 min) was then added followed by the triflate (0.29 mmol, 1.20 equiv)C. The flask was sealed and heated at 40 °C (oil bath) for 14 h. After cooling to ambient temperature, the solution was transferred to a 28 mL vial and the flask was washed with pentaneD (15 mL). H2O (5 mL) and NH4Cl or NaHCO3 (saturated aqueous solution, 5 mL) were then added, and the flask was sealed and shaken vigorously. The layers were allowed to separate, and the top organic phase was carefully collected using a pipette. The aqueous phase was subsequently washed with pentaneD (2× 7 mL) and then the combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. At this stage, the crude residue was analysed by 1H NMR spectroscopy to assess the diastereomeric ratio of the product. The crude residue was purifiedE by flash column chromatography (SiO2) to yield the desired cyclobutanes. Notes: (A) tert-Butyl lithium should be carefully titrated prior to use. (B) On this scale this dropwise addition takes approximately 30 sec. (C) Oils were added via syringe, and solids were added directly into the top of the flask. On the rare occasions when the triflate was insufficiently fluid to syringe, it was added as a solution in 2-methyl tetrahydrofuran (0.5 mL). (D) Pentane was most commonly used, however if there was large quantities of undissolved solid then either Et2O or EtOAc was used instead. (E). Typically, the only impurities of concern are the excess triflate and any unreacted boronic ester starting material. According to General Procedure A outlined above, cyclohexyl pinacol boronic ester (50 mg, 0.24 mmol, 1.0 equiv) and phenyl triflate (0.05 mL, 0.29 mmol, 1.2 equiv) were coupled to give a crude residue (>98:2 d.r. by crude NMR) that was purified by flash column chromatography (SiO2; 60:20:20 hexane:DCM:PhMe) to afford the corresponding cyclobutane 6 (62 mg, 77 %, >98:2 d.r.) as a colorless oil that crystallised slowly to a white solid. m.p.: 50 – 54 °C (pentane). TLC: Rf = 0.36 (60:20:20 hexane:DCM:PhMe). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.25 (m, 2H, 2× ArH), 7.23 – 7.18 (m, 2H, 2× ArH), 7.17 – 7.13 (m, 1H, ArH), 3.34 – 3.25 (m, 1H, ArCH), 2.59 – 2.53 (m, 2H, ArCH(CHaHb)2), 1.90 – 1.83 (m, 2H, ArCH(CHaHb)2), 1.76 – 1.62 (m, 5H, 2× CH2, CHaHb), 1.35 – 0.93 (m, 6H, 2× CH2, CH, CHaHb), 1.31 (s, 12H, Bpin) ppm. 13C NMR (101 MHz, CDCl3) δ 146.8 (ArC), 128.2 (ArCH), 126.5 (ArCH), 125.6 (ArCH), 83.2 (OC(CH3)2), 49.2 (CH), 37.6 (ArCCH(CH2)2), 35.9 (ArCCH), 29.2 (CH2), 27.0 (CH2), 26.9 (CH2), 24.9 (OC(CH3)2) ppm. HRMS (m/z): (ESI) calc’d for C22H34BO2 [M+H]+: 341.2650, found: 341.2658. IR (thin film) νmax: 2976, 2923, 2850, 1384, 1142, 966, 862, 748 and 698 cm−1