Synthesis of β-Trifluoromethylated Enones: An Unexpected Reactivity of Trifluoromethylated Weinreb Enamides towards Organolithium Species

Abstract

β-Trifluoromethylated enones can be synthesized in four steps from ethyl trifluoroacetoacetate. The key intermediate is a weinreb β-trifluoromethylated enamide.

Key words

trifluoroacetoacetate - enones - fluorine - Weinreb ­enamide - conjugate addition

References and Notes

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15

Typical Experimental Procedure - Synthesis of 1
To a nitrogen-flushed suspension of N,O-dimethylhydroxyl-amine hydrochloride (11.70 g, 120 mmol) in 50 mL of anhyd CH₂Cl₂ was added AlMe₃ (2 M in heptane, 60 mL, 120 mmol) drop by drop at -10 ˚C. The resulting yellow solution was stirred at r.t. for 1 h, cooled to -10 ˚C and a soln of 4 (10.7 g, 58.1 mmol) in 10 mL of anhyd CH₂Cl₂ was slowly added. The reaction mixture was stirred at r.t. overnight, then carefully quenched at -10 ˚C with a sat. aq soln of NH₄Cl. After extraction of the mixture with Et₂O, the organic layers were combined, washed with H₂O, dried over anhyd MgSO₄, filtered, and concentrated in vacuo to give 1 (10.64 g, 91%) as white crystals; mp 63-64 ˚C. ^¹H NMR: δ = 4.91 (br s, 1 H), 4.48 (ddq, J = 9.5, 2.6, 6.9 Hz, 1 H), 3.71 (s, 3 H), 3.20 (s, 3 H) 2.87 (dd, J = 16.8, 9.5 Hz, 1 H), 2.70 (dd, J = 16.8, 2.6 Hz, 1 H). ^¹³C NMR: δ = 171.3, 125.3 (q, J = 281.0 Hz), 67.2 (q, J = 31.8 Hz), 61.7, 32.4 (q, J = 1.8 Hz), 32.3. ^¹9F NMR: δ = -80.02 (d, J = 6.9 Hz). Anal. Calcd for C₆H₁₀F₃NO₃: C, 35.83, H, 5.01. Found: C, 35.98, H, 4.97.
Synthesis of Ketols 6
To a solution of 1 (1 equiv) in anhyd THF (2 mL, 1 mmol) was slowly added at -78 ˚C the organometallic reagent (2 equiv) under inert atmosphere. The reaction mixture was stirred at this temperature for 4 h, then warmed to 0 ˚C and quenched with a sat. aq soln of NH₄Cl. After extraction of the mixture with Et₂O, the organic layers were combined, washed with brine, dried over anhyd MgSO₄, filtered, and concentrated in vacuo to give 6.
Synthesis of Enones 3
To a nitrogen-flushed solution of 6 (1 equiv) in anhyd CH₂Cl₂ (2 mL, 1 mmol) was added Et₃N (1 equiv). The reaction mixture was stirred at r.t. for 30 min, cooled to -78 ˚C and mesyl chloride (1.25 equiv) was slowly added. After stirring at -78 ˚C for 30 min and at r.t. for 3 h, Et₃N (1.5 equiv) was added, and the mixture was stirred overnight. Then, H₂O and n-pentane were added. The organic layer was separated, washed with brine, dried over anhyd MgSO₄, filtered, and concentrated in vacuo to give 3.