To a 500 mL round bottom flask equipped with a stir bar was added CsF¹ (1.670 g, 10.99 mmol, 0.2 equiv). Toluene (138 mL, ≈ 0.4 M in the Weinreb amide) was rapidly added² to the flask, followed by N-methoxy-3-(4-methoxyphenyl)-N-methylpropanamide³ (12.27 g, 54.96 mmol, 1 equiv). The flask was sealed with a septum equipped with two inlet needles as an exit valve. The flask was cooled to 0 ^oC for 10 minutes⁴.   TMS-CF₃ (15.61 g, 109.91 mmol, 2 equiv) was added to the reaction mixture dropwise over a period of ≈ 10 minutes. After completion of addition, the reaction mixture was allowed to stir for 10 minutes at 0 ^oC. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature. CAUTION: Upon reaching room temperature, the reaction occurs and is mildly exothermic and gas is evolved.⁵ After completion of addition, the reaction mixture was allowed to stir at room temperature. Reaction progress was monitored by ¹H NMR.^6,7

Once complete conversion to the silylated intermediate was confirmed, the toluene was removed in vacuo by rotary evaporation. Hexanes (40 mL), followed by deionized water (55 mL) followed by 1M solution of TBAF in THF (55 mL, 55 mmol, 1 equiv⁸) were added to the reaction flask. The flask was equipped with a reflux condenser, open to air. The reaction mixture was then heated to 60 ^oC in an oil bath and allowed to stir 2-3 hours. Once cooled to room temperature, the reaction mixture were diluted with Et₂O (≈ 120 mL), and transferred to a separatory funnel. The organic layer was washed with deionized water (2 X 60 mL each), followed with a brine solution (1 X 120 mL). The organic layer was dried with Na₂SO₄ and the solvent was removed in vacuo by rotary evaporation to yield the crude trifluoromethylketone. Further purification was accomplished vacuum distillation (b.p. 68-71 ^oC @ 0.2 mmHg) affording the pure CF₃ ketone (9.28 g, 73%)  as a clear colorless oil.

1. We have found since publishing the lead reference that the use of oven dried CsF leads to slightly improved reaction times and yields

2. A cushion of toluene prevents hydration of the CsF as this fluoride salt is highly hydroscopic. While the reaction does not require extensive removal of water, minimizing the amount of water in the reaction vessel improves yields and reactions times.

3. Prepared via the procedure outlined in Synthetic Page 571 from (4-methoxy)hydrocinnamic acid

4. The flask must be cooled for this period of time. If this time is not observed an exotherm will likely occur upon warming to room temperature

5. In most cases this is not an issue (especially with the procedure outlined here which uses more dilute conditions than previously reported). However, the septa with two vent needles prevents loss of most of the product.

6. Note: Over this time period the solution became dark yellow to dark brown in color.

7. Typically reactions were completed in four hours but NMR should be used to confirm complete conversion. There is a dramatic shift of one of the Weinreb singlets and the appearance of a silane peak that integrates with the Weinreb peaks.

8. In an effort to reduce the amount of TBAF required, we have found that using 0.5 equiv rather than 1 equiv will lead to successful cleavage. However, the cleavage step must be left for an addition 4 hours to ensure complete cleavage. This process can also be conducted overnight. 

¹H NMR (CDCl₃, 500 MHz) δ ppm 2.94 (apparent triplet, J=6.80 Hz, 2 H) 3.02 (apparent triplet, J=6.60 Hz, 2 H) 3.79 (s, 3 H) 6.85 (d, J=8.56 Hz, 2 H) 7.12 (d, J=8.56 Hz, 2 H)

¹³C NMR (CDCl₃, 100 MHz) δ ppm 27.73 (CH₂) 38.61 (CH₂) 55.49 (CH₃) 115.77 (q, J_C-F =292.00 Hz, CF₃) 114.36 (CH) 129.51 (CH) 131.53 (C) 158.62 (C) 191.00 (q, J_C-C-F =35.90 Hz, C)

¹⁹F  NMR (CDCl₃, 377 MHz, Reference: Hexafluorobenzene (–164.9 ppm))  δ ppm -82.34 δ ppm

GC-MS (EI) 232 ([M]⁺, 19%), 121(100%), 91 (13%), 77 (10%), 69 (4%), 65 (5%).

Rudzinski, D. M.; Kelly, C. B.; Leadbeater, N. E. Chem. Commun., 2012, 48, 9610. DOI: 10.1039/c2cc35037h