Design and Synthesis of Enantiopure Tetrakis(pentafluorophenyl) Borate Analogues for Asymmetric Counteranion Directed Catalysis

Published as part of the Cluster Silicon in Synthesis and Catalysis

Abstract

The design and five-step synthesis of chiral tetrakis(pentafluo­rophenyl) borate analogues from commercially available enantiopure BINOL is described. The chiral anions have been tested in a catalytic asymmetric Mukaiyama aldol reaction.

Key words

asymmetric counteranion-directed catalysis (ACDC) - weakly coordinating anion (WCA) - chiral BAr^F - Mukaiyama aldol reaction

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• 9 Synthesis of the Zn-reagent: A flame-dried 50 mL Schlenk flask was charged with 1,2,3,5-tetrafluorobenzene (4.0 mmol, 1.0 equiv) and a magnetic stirring bar. To this Schlenk flask, anhydrous THF (20 mL) was added under an argon atmosphere. The mixture was stirred at r.t. for 5 min and then cooled to –78 °C. After 30 min at –78 °C, n-BuLi (2.5 M in hexane, 1.65 mL, 4.1 mmol, 1.02 equiv) was slowly added through the cold side-wall of the flask under an argon atmosphere (Note: direct addition of n-BuLi to the cold mixture could lead to an explosive reaction). The reaction mixture was stirred at –78 °C for 1 h and freshly dried ZnBr₂ (1.0 M in THF, 4.2 mL, 4.2 mmol, 1.05 equiv) was slowly added to the reaction mixture and stirring was continued for 20 min. The dry-ice bath was removed and the reaction mixture was allowed to warm to r.t. After 20 min at r.t., ca. 15 mL of THF was removed under reduced pressure (Schlenk technique). This Zn-reagent was directly used for the next step.
• 10 General Procedure for Negishi Cross-Coupling: A flame-dried 25 mL Schlenk flask was charged with compound (S)-1 (1.0 mmol, 1.0 equiv) and a magnetic stirring bar. To this flask, the freshly prepared Zn-reagent (4.0 mmol, 4.0 equiv) was transferred under an argon atmosphere. The mixture was degassed (three times) and Pd(PPh₃)₄ (10 mol%, 0.1 mmol, 0.1 equiv) was added. The reaction mixture was heated to 100 °C for 24 h, then cooled to r.t. and treated with saturated aq. NH₄Cl. The crude reaction mixture was extracted with CH₂Cl₂ (3 × 10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Purification was performed by SiO₂ column chromatography using 10% CH₂Cl₂/i-hexanes. (S)-2a: Prepared according to the general procedure as a colorless solid in 72% yield. ¹H NMR (500 MHz, CD₂Cl₂): δ = 8.11 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.85 (d, J = 8.2 Hz, 2 H), 7.60–7.54 (m, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.50–7.45 (m, 1 H), 7.44–7.38 (m, 2 H), 7.36–7.29 (m, 1 H), 7.29–7.21 (m, 3 H), 6.88–6.77 (m, 1 H). (S)-2b: Prepared according to the general procedure as a colorless solid in 81% yield. Compound (S)-2b exists as a 1:1 mixture of rotamers. ¹H NMR (500 MHz, CD₂Cl₂): δ = 8.09 (d, J = 8.5 Hz, 2 H), 8.02 (d, J = 8.2, Hz, 2 H), 7.88–7.80 (m, 4 H), 7.60–7.53 (m, 2 H), 7.53–7.37 (m, 8 H), 7.34–7.28 (m, 2 H), 7.28–7.18 (m, 6 H), 6.67–6.58 (m, 1 H), 6.52–6.39 (m, 1 H).
• 11 General Procedure for Synthesis of 4: A flame-dried 25 mL Schlenk flask was charged with compound (S)-2a (1.0 mmol, 1.0 equiv) and a magnetic stirring bar. To this flask, anhydrous Et₂O (5 mL) was added under an argon atmosphere. The mixture was stirred at r.t. for 5 min to dissolve the substrate and was then cooled to –78 °C. After 30 min at –78 °C, n-BuLi (2.5 M in hexane, 0.42 mL, 1.05 mmol, 1.05 equiv) was slowly added through the cold side-wall of the flask. The reaction mixture was stirred at –78 °C for 4 h. After 4 h, BCl₃ (1.0 M in heptane, 0.2 mL, 0.2 mmol, 0.2 equiv) was slowly added to the reaction mixture and warmed to r.t. over 4 h and the stirring was continued for overnight. Then the mixture was cooled and reaction was subsequently quenched with saturated NaCl (aq.). The crude reaction mixture was extracted with CH₂Cl₂ (3 × 10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Purification was performed by SiO₂ column chromatography using 10% MeOH/CH₂Cl₂. The purified product was dissolved in CH₂Cl₂ and 10 mL saturated NaCl (aq.) solution was added and the reaction mixture was vigorously stirred for 20 min at r.t. It was then extracted with CH₂Cl₂ (3 × 10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. 4a: Prepared according to the general procedure as a white solid in 52% yield. ¹¹B NMR (160 MHz, CD₂Cl₂): δ = –17.12. HRMS (ESI): m/z calcd. for C₁₀₄H₅₂BF₁₆ [M]^–: 1615.39205; found 1615.39121. 4b: Prepared according to the general procedure as a white solid in 41% yield. ¹¹B NMR (160 MHz, CD₂Cl₂): δ = –17.22. HRMS (ESI): m/z calcd. for C₁₀₄H₅₂BF₁₆ [M]^–: 1615.39205; found 1615.39121.
• 12 General Procedure for Mukaiyama Aldol Reaction: An oven-dried 2 mL GC vial was charged with catalyst 4 (4.1 mg, 0.0025 mmol, 0.1 equiv), aldehyde 5 (3.9 mg, 0.025 mmol, 1.0 equiv) and a magnetic stirring bar. To this vial, solvent (0.25 mL) was added and the mixture was stirred at r.t. for 5 min. Then the mixture was cooled to the reaction temperature. Silyl ketene acetal 6 (6.4 μL, 0.031 mmol, 1.25 equiv) was added followed by TMSCl (0.15–0.5 equiv) under an argon atmosphere. After consumption of aldehyde, the reaction was quenched with saturated NaHCO₃ (aq.) solution and the crude mixture was directly purified without further work-up on a SiO₂ preparative TLC using 5–20% EtOAc/i-hexanes (v/v) as eluent.