An Approach to Highly Hindered BINOL Phosphates

Abstract

The synthesis of 3-3′-substituted BINOL-derived chiral phosphoric acid catalysts is still largely limited by the limitations of current cross-coupling methodologies. For this reason, despite the importance of sterically demanding catalysts in Brønsted acid catalysis, highly hindered congeners are still unprecedented. Exploiting the aryne addition reaction as key step, we report herein the development of a novel synthetic route to access this unexplored class of catalysts.

Key words

phosphoric acids - confined catalysts - asymmetric organocatalysis - biaryl synthesis - aryne coupling reaction

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See also:
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• 22 Key Experimental Procedures (±)-2,2′-Diiodo-3,3′-bis(2,4,6-tri-tert-butylphenyl)-1,1′-binaphthalene (7) A flame-dried, two-neck round-bottom flask was charged with a solution of 2,4,6-tri(tert-butyl)bromobenzene (2 g, 6.15 mmol, 5 equiv) in dry THF (10.5 mL) under an argon atmosphere. The solution was cooled down to –78 °C and BuLi (2.5 M in hexane, 2.45 mmol, 5.1 equiv) was added dropwise. The solution was then stirred at 0 °C for 1 h. Next the reaction was cooled at –78 °C, and a solution of 5 in THF (814 mg, 1.23 mmol, 1 equiv) was added dropwise. The temperature was raised to r.t., and the reaction was vigorously stirred for 12 h. CH₂Cl₂ was added, and the organic phase washed three times with H₂O. After anhydrification over Na₂SO₄, the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (eluent: hexane–CH₂Cl₂, 10:1) gave the desired compound in 39% yield. ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.99 (s, 2 H), 7.83 (d, 2 H), 7.52–7.40 (m, 6 H), 7.18 (t, 2 H), 7.05 (d, 2 H), 1.29 (s, 18 H), 1.14 (s, 36 H). ¹³C NMR (125 MHz, CD₂Cl₂): δ = 149.5, 147.8, 147.5, 146.1, 145.8, 140.2, 132.6, 132.3, 131.8, 128.7, 127.2, 127.1, 127.0, 124.1, 123.9, 114.5, 38.9, 38.8, 35.2, 35.0, 34.1, 31.6. HRMS: m/z calcd for C₅₆H₆₈I₂ [M]: 994.3410; found: 994.3405. (±)-3,3′-Bis(2,4,6-tri-tert-butylphenyl)-[1,1′-binaphthalene]-2,2′-diol (8) In a flame-dried, two-neck round-bottom flask, a 0.007 M solution of 7 in dry Et₂O was added under an argon atmosphere. The stirred solution was cooled down to –78 °C, BuLi (2.5 M in hexanes, 4 equiv) was added dropwise, and the reaction was left at –78 °C for 1 h before being cooled down to –95 °C. Next a 2.8 M solution of nitrobenzene in Et₂O was added dropwise. After 30 min MeOH was added (1:1 with the reaction solvent), and the temperature was raised to r.t. and stirred for 2 additional hours. CH₂Cl₂ was added, and the organic phase was washed with H₂O. After anhydrification over Na₂SO₄, the solvent was evaporated in vacuo. Purification by column chromatography on silica gel (eluent: mixtures hexane–CH₂Cl₂) gave the desired compound in 43% yield. ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.82–7.75 (m, 4 H), 7.58–7.48 (m, 4 H), 7.29 (t, 2 H), 7.20 (t, 2 H), 7.10 (d, 2 H), 4.89 (s, 2 H), 1.29 (s, 18 H), 1.14 (s, 18 H), 1.05 (s, 18 H). ¹³C NMR (125 MHz, CDCl₃): δ = 152.8, 149.5, 149.5, 134.1, 133.5, 132.4, 130.4, 128.3, 127.8, 126.6, 124.7, 123.7, 123.3, 123.3, 113.1, 38.1, 38.0, 35.1, 33.1, 33.0, 31.4. HRMS: m/z calcd for C₅₆H₇₀O₂ [M + Na]: 797.5268; found: 797.5269. 3,3′-Bis(2,4,6-tri-tert-butylphenyl)-1,1′-binaphthyl-2,2′-diyl Hydrogenphosphate (2) In a flame-dried, two-neck round-bottom flask, equipped with a reflux condenser, a 0.025 M solution of 8 in dry pyridine was added under Ar atmosphere. Then the stirred solution was cooled down to 0 °C, and 10 equiv of POCl₃ were added. The reaction mixture was then heated up to 95 °C, and 10 additional equivalents of POCl₃ were added after 24 h. After 4 d full consumption of starting material was observed (TLC eluent: hexane–CH₂Cl₂, 1:1). Then the reaction was cooled to 0 °C, and H₂O (2.5 mL) were added dropwise [careful: exothermic reaction] before raising the temperature to 100 °C. After 4 h the reaction was cooled down to r.t., CH₂Cl₂ was added, and the organic phase was sequentially washed with a 3 M HCl (aq) solution, H₂O, and brine. Then the organic phase was dried over anhydrous Na₂SO₄, and the solvent was evaporated in vacuo. Purification was accomplished by column chromatography (eluent: mixtures hexane–EtOAc). The isolated compound was subjected to preparative HPLC on chiral stationary phase [Chiralpak QN-AX, 5 μm, 150 × 29 mm; eluent: MeOH–NH₄OAc (0.1 M, aq), 80:20] to achieve separation of the enantiomers. Both enantiomers were eventually dissolved in CH₂Cl₂ and subjected to an acidic wash with 6 M HCl (aq) solution (2: 36% yield; ent-2: 36% yield). ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.83 (s, 2 H), 7.74 (d, J = 8.2 Hz, 2 H), 7.40–7.33 (m, 6 H), 7.09 (t, J = 8.2 Hz, 2 H), 6.87 (d, J = 8.2 Hz, 2 H), 6.32 (br s, 1 H), 1.21 (s, 18 H), 0.97 (s, 18 H), 0.88 (s, 18 H). ¹³C NMR (125 MHz, CD₂Cl₂) [overlapping signals]: δ = 149.3, 149.0, 148.7, 148.5, 148.4, 135.7, 135.7, 135.3, 133.2, 130.4, 130.3, 128.4, 127.6, 126.4, 125.9, 124.3, 123.5, 121.5, 38.9, 38.5, 35.1, 34.3, 33.6, 31.6. ³¹P NMR (202 MHz, CD₂Cl_2­): δ = –0.02 (s). HRMS: m/z calcd for C₅₆H₆₉O₄P [M – H]: 835.4861; found: 835.4861.