Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols by Vinylogous Aldol Reaction of 3-Methylcyclohex-2-en-1-one with (Het)aryl Trifluoromethyl Ketones

^◊ These authors contributed equally to this work.

Abstract

A direct enantioselective vinylogous aldol reaction of trifluoromethyl ketones with 3-methylcyclohex-2-en-1-one through hydrogen-bond-directing dienamine catalysis by a diamine–sulfonamide catalyst has been demonstrated. A range of trifluoromethylated tertiary alcohols were efficiently produced in yields of up to 86% and with 93% enantioselectivity.

Key words

organocatalysis - enantioselectivity - vinylogous aldol reaction - asymmetric catalysis - trifluorohydroxypropylcyclohexenones - aryl trifluoromethyl ketones

• References and Notes

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• 24 3-[(2R)-3,3,3-Trifluoro-2-hydroxy-2-phenylpropyl]cyclohex-2-en-1-one (3a); Typical Procedure Catalyst 12 (0.02 mmol, 20 mol%) was added to a stirred solution of PhCOCF₃ (2a; 0.3 mmol, 3.0 equiv), 3-methylcyclohex-2-en-1-one (1a; 0.1 mmol, 1.0 equiv), and BzOH (0.05 mmol, 0.5 equiv) in Et₂O (1 mL), and the resulting mixture was stirred at r.t. until the starting material disappeared (TLC). The mixture was then directly purified by column chromatography [silica gel, hexane–EtOAc (15:1 to 10:1)] to give a white solid; yield: 22.4 mg (79%, 73% ee); mp 151.3–152.1 °C;[α]_D ²⁰ –8.22 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.55 (d, J = 7.4 Hz, 2 H), 7.43–7.33 (m, 3 H), 5.83 (s, 1 H), 3.40 (s, 1 H), 3.07–2.97 (m, 2 H), 2.25–2.17 (m, 2 H), 2.15 –2.09 (m, 1 H), 1.90–1.84 (m, 1 H), 1.79–1.72 (m, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 199.7, 159.1, 136.0, 130.7, 128.9, 128.5, 126.1, 125.3 (q, J = 286.4 Hz), 76.8 (q, J = 28.1 Hz), 43.8, 37.0, 30.9, 22.6. ¹⁹F NMR (470 MHz, CDCl₃): δ = –79.6. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₆F₃O₂ = 285.1097; found = 285.1102. HPLC (Chiralpak AD-H; λ = 254 nm; 20% i-PrOH–hexanes, flow rate = 1.0 mL/min): t_R (major) = 4.55 min, t _R (minor) = 9.96 min.