Enantioselective Addition of Thiols to ortho-Quinone Methides Catalyzed by Chiral Phosphoric Acids

Abstract

The first Brønsted acid catalyzed enantioselective addition of thiols to the in situ generated ortho-quinone methides (o-QMs) is described. Complementary to the chiral amine catalyzed approach, the present reaction employs a chiral phosphoric acid as the catalyst. The readily available o-hydroxybenzyl alcohols serve as the atom-economical precursors of o-QMs to react with tritylthiol with moderate to good efficiency and enantioselectivity under mild conditions.

Key words

asymmetric catalysis - quinone methide - organocatalysis - nucleophilic addition - Brønsted acid

• References and Notes


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• 7 General Procedure: At −20 °C (or otherwise noted), to an oven-dried 5-mL flask charged with a mixture of the substrate 1 (0.15 mmol), the thiol (0.165 mmol), and 3 Å MS (30 mg) in CHCl₃ (0.75 mL) was added the catalyst (R)-B3 (10 mg, 15 μmol, 10 mol%). The reaction mixture was stirred for 4 d at the same temperature. The reaction mixture was then treated with solid Na₂CO₃ (30 mg) and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford the pure product 2. (R)-4-Methyl-2-[phenyl(tritylthio)methyl]phenol (2b): Prepared as a colorless oil according to the general procedure (purification by flash column chromatography: hexanes–EtOAc, 10:1): 32.3 mg, 46% yield, 89:11 er); [α]_D ²⁵ −57.6 (c = 1.0, CHCl₃). HPLC analysis of the product (Daicel CHIRALPAK AD-H column; 10% i-PrOH in hexanes; flow rate = 1.0 mL/min): t _R = 5.6 min (major), 7.6 min (minor). ¹H NMR (400 MHz, CDCl₃): δ = 7.43 (d, J = 7.7 Hz, 6 H), 7.13–7.33 (m, 14 H), 6.83 (d, J = 8.1 Hz, 1 H), 6.75 (s, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 5.63 (s, 1 H), 4.83 (s, 1 H), 2.17 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.7, 143.9, 141.5, 130.3, 129.7, 129.6, 128.5, 128.4, 128.1, 127.7, 127.3, 126.8, 126.7, 116.6, 69.6, 50.4, 20.4. IR (neat): 3688, 3056, 1593, 1495, 1262, 1083, 740 cm^–1. HRMS (EI): m/z [M − H] calcd for C₃₃H₂₇OS: 471.1783; found: 471.1767.