An NHC-Catalyzed Cross-Benzoin–Esterification Sequential Reaction for the Synthesis of Trifluoromethyl-Substituted α,β-Unsaturated Esters

Abstract

Efficient preparation of synthetically important CF₃-containing α,β-unsaturated esters is described using an NHC-catalyzed multicomponent reaction. This approach combines sequential NHC-mediated HOMO and LUMO activation to produce a C–C bond and C–O bond in a one-pot operation.

Key words

organocatalytic reaction - multicomponent reaction - NHC catalysis - trifluoromethylated compounds - cross-benzoin - esterification

• References and Notes

• 1 These authors contributed equally.

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• 18 General Procedure for the Synthesis of CF₃-Substituted α,β-Unsaturated Esters The reaction was carried out with aromatic aldehyde 1 (0.5 mmol), CF₃CH(OH)OEt (2, 1.0 mmol), precatalyst A (0.05 mmol, 13.7 mg), and DBU (0.1 mmol, 15 μL) in THF (2.0 mL) at 60 °C under argon to afford the acyloin 3, after which α-bromoenal 4 (0.3 mmol) was added in one-pot. The reaction mixture was stirred at 60 °C for a specified reaction time until the reaction completed. Then the reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (PE–EtOAc = 40:1) to give the final product.
• 19 Analytical Data for Compound 5a Obtained as a white solid in 65% yield (65.3 mg) for two steps after flash chromatography; mp 58–60 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.03–8.01 (m, 2 H), 7.82 (d, J = 16.0 Hz, 2 H), 7.57–7.51 (m, 4 H), 7.44–7.38 (m, 3 H), 6.57 (d, J = 16.0 Hz, 1 H), 6.45 (q, J = 6.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 188.6, 164.8, 148.2, 134.6, 133.7, 131.2, 129.0, 128.9, 128.5, 121.9 (d, J_CF = 280 Hz), 115.2, 70.9 (q, J_CF = 31 Hz) ppm. ESI-HRMS: m/z calcd for C₁₈H₁₃F₃O₃ + Na: 357.0714; found: 357.0717.
• 20 Loner CM, Luzzio FA, Demuth DR. Tetrahedron Lett. 2012; 53: 5641