Pd-Catalyzed Allylic Alkylation of CF₃-Containing Esters with Three Electron-Withdrawing Groups

Abstract

Tsuji–Trost reaction (Pd-catalyzed allylic alkylation) of CF₃-containing esters with three electron-withdrawing groups is reported. The reactions with methyl bis(trifluoromethyl)acetate and dimethyl (trifluoromethyl)malonate were carried out with low-loading catalysts of Pd(0) and XPhos at ambient temperature in THF, giving the products in high yields. This method efficiently overcomes the β-defluorination, which is hard to control in the chemical transformation of α-trifluoromethyl carbanions, and provides versatile fluorinated compounds with quaternary carbon centers, which are highly demanded in drug discovery.

Key words

fluorine - carbanions - allylation - palladium - homogeneous catalysis

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• 10 Typical Procedure for the Preparation of Compound 4 To a solution of Pd(dba)₂ (0.04 mmol) and XPhos (0.1 mmol) in THF (2 mL) were added at r.t. under N₂ atmosphere, and the mixture was stirred for 30 min at r.t., then carbonate (0.4 mmol) was added dropwise under N₂ atmosphere. After 10 min, CF₃-containing ester 1 or 2 was added to the mixture dropwise, and the mixture was allowed to react at r.t. for 12 h. Then the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting using a mixture of hexane and CH₂Cl₂ as eluent. (E)-Methyl 5-Phenyl-2,2-bis(trifluoromethyl)pent-4-enoate (4a) ¹H NMR (300 MHz, CDCl₃): δ = 7.35–7.24 (m, 5 H), 6.58 (d, J = 15.9 Hz, 1 H), 6.06 (dt, J = 15.9, 7.2 Hz, 1 H), 3.89 (s, 3 H), 3.08 (d, J = 7.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 162.6, 136.5, 135.9, 128.6, 127.9, 126.5, 122.5 (q, J _CF = 284 Hz), 120.2, 61.5 (m, J _CF = 25 Hz), 53.9, 32.1. ¹⁹F NMR (282 MHz, CDCl₃): δ = –66.5 (s). IR (neat): 282 3085, 3028, 2961, 1760, 1600, 1496, 1297, 1147, 1025 cm^–1. MS (EI): m/z (%) = 326 (13.71) [M⁺]. HRMS (EI): m/z calcd for C₁₄H₁₂O₂F₆ [M⁺]: 326.0741; found: 326.0743.