Kinetic Resolution of dl-Hydrobenzoins Catalyzed by Copper(II) Complexes of C ₂-Symmetric Thiophene-Derived Ligands

Abstract

C ₂-Symmetrical chiral amino alcohol ligands with a central thiophene moiety were shown to be effective in combination with CuCl₂ for the asymmetric acylation of dl-hydrobenzoins. In contrast to previously developed chiral ligands, readily available acetyl chloride and acetic anhydride can be used as reagents, in addition to benzoyl chloride, giving rise to the corresponding monoacylated products in up to 99% ee (S = 532).

Publication History

Received: 28 February 2022

Accepted after revision: 04 April 2022

Accepted Manuscript online:
04 April 2022

Article published online:
09 May 2022

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• 31 Ligands 1a–1l; General Procedure A mixture of the appropriate chiral amino alcohol (1.0 or 2.0 mmol) and aldehyde (1.0 mmol) in EtOH (5 mL) was refluxed for 4 h. The mixture was cooled to 0 °C and NaBH₄ (5.0 mmol) was added. When the amine had been consumed (TLC), the reaction was quenched with 10% aq HCl. The mixture was neutralized with sat. aq NaHCO₃, then concentrated under reduced pressure. The residue was extracted with EtOAc and washed with H₂O. The organic layer was dried (Na₂SO₄) and concentrated to give a crude product that was purified by flash column chromatography (silica gel, PE–EtOAc gradient). (2R,2'R)-2,2'-[Thiene-2,5-diylbis(methyleneimino)]bis(2-phenylethanol) (1g) Prepared according to the general method from thiophene-2,5-dicarbaldehyde (0.140 g, 1.0 mmol) and (R)-phenylglycinol (0.274 g, 2.0 mmol) as a white solid; yield: 0.325 g (85%); mp 103–105 °C; [α]_D ²⁵ = –58.4 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.28 (m, 10 H), 6.66 (s, 2 H), 3.89 and 3.73 (AB, J = 14.0 Hz, 2 × 2 H), 3.85 (ABX, J _BX = 9.0, J _AX = 4.2 Hz, 2 H), 3.69 (ABX, J _AB = 10.9, J _AX = 4.3 Hz, 2 H), 3.57 (ABX, J _AB = 10.9, J _BX = 8.9 Hz, 2 H), 2.72 (br s, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 142.8, 139.9, 128.8, 127.8, 127.4, 124.9, 66.7, 63.3, 45.9. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₂₂H₂₇N₂O₂S: 383.1793; found: 383.1809. Anal. Calcd for C₂₂H₂₆N₂O₂S: C, 69.08; H, 6.85; N, 7.32. Found: C, 69.16; H, 6.86; N, 7.38
• 32 Screening of Catalytic Activities: General Procedure The appropriate chiral ligand (0.025 mmol) and Cu(II) salt (0.025 mmol) were dissolved in CH₂Cl₂ (1.5 mL) and the mixture was stirred at rt for 2 h to afford a green homogeneous solution. The racemic 1,2-diol (0.25 mmol) and DIPEA (42.5 μL, 0.25 mmol) were added, and the mixture was cooled to 0 °C for 1 h. The appropriate acylating agent (0.125 mmol, 0.5 equiv) was added, and the mixture was stirred at 0 °C for 2 h then diluted with H₂O and extracted with CH₂Cl₂ (×3). The combined organic layers were dried (MgSO₄), concentrated under reduced pressure, and purified by chromatography (silica gel, PE–EtOAc). Enantioselectivities were determined by chiral HPLC (Chiralcel OJ-H^® column, heptane–i-PrOH). (1R,2R)-1,2-Bis(4-bromophenyl)-2-hydroxyethyl Acetate (5e) White solid; yield: 44% (99% ee). HPLC [OD-H column, heptane–i-PrOH (9:1), λ = 215 nm, flow rate: 0.5 mL/min]: T _R: 19.3 min (minor isomer); 23.9 min (major isomer). ¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.33 (m, 4 H), 7.00–6.95 (m, 4 H), 5.72 (d, J = 7.5 Hz, 1 H), 4.85 (d, J = 7.5 Hz, 1 H), 2.62 (br s, 1 H), 2.12 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.0, 137.7, 135.5, 131.5, 131.4, 129.0, 128.7, 122.5, 122.3, 79.2, 76.2, 21.1. HRMS (EI-MS): m/z [M⁺] calcd for C₁₆H₁₄Br₂O₃: 411.9310; found: 411.9314