Synlett 2009(8): 1241-1244  
DOI: 10.1055/s-0029-1216748
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Olivier Marrec, Julien Borrini, Thierry Billard*, Bernard R. Langlois
Université de Lyon, Université Lyon 1, CNRS, ICBMS, Laboratoire SERCOF, Bat Chevreul, 43 Boulevard du 11 Novembre 1918,69622 Lyon, France
Fax: +33(4)72431323; e-Mail: billard@univ-lyon1.fr;
Further Information

Publication History

Received 7 January 2009
Publication Date:
07 May 2009 (online)

Abstract

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

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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.