Trifluoromethyl ketones (TFMKs) are exceedingly valuable synthetic targets in their own right and as synthons in the construction of fluorinated pharmacons. This Feature Article provides an overview of the properties of TFMKs, an in-depth discussion of the methods available for their synthesis, and two illustrative examples of their application as key intermediates in medicinal chemistry.

We describe the synthesis of the lesser-known stoichiometric oxidation reagent 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1, Bobbitt's salt), as well as of 4-acetamido-(2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (2, AcNH-TEMPO). Several representative oxidation reactions are also presented to demonstrate the salt's oxidative capabilities. Bobbitt's salt has a range of applications, from the oxidation of various alcohols to their corresponding carbonyl derivatives to the oxidative cleavage of benzyl ethers, whereas 2 has been shown to serve as a catalytic or stoichiometric oxidant. The oxyl radical can be obtained in 85% yield over two steps on a 1-mole scale from commercially available 4-amino-2,2,6,6-tetramethylpiperidine (5), and is far more cost-effective to prepare in-house than purchase commercially. An additional step converts the oxyl radical into the oxoammonium salt (1, Bobbitt's salt) in 88% yield, with an overall yield of 75%. The synthesis of the salt takes ∼5 d to complete. Oxoammonium salts are metal-free, nontoxic and environmentally friendly oxidants. Preparation of 1 is also inherently 'green', as water can be used as the solvent and the use of environmentally unfriendly materials is minimal. Moreover, after it has been used, the spent oxidant can be recovered and used to regenerate 1, thereby making the process recyclable.

A simple, mild method for the oxidation of α-trifluoromethyl alcohols to trifluoromethyl ketones (TFMKs) using the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) is described. Under basic conditions, oxidation proceeds rapidly and affords good to excellent yields of TFMKs, without concomitant formation of the hydrate. The byproduct of the oxidation, 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (1c), is easily recovered and can be conveniently reoxidized to regenerate the oxoammonium salt.

A scalable, high yielding, rapid route to access an array of nitriles from aldehydes mediated by an oxoammonium salt (4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and hexamethyldisilazane (HMDS) as an ammonia surrogate has been developed. The reaction likely involves two distinct chemical transformations: reversible silyl-imine formation between HMDS and an aldehyde, followed by oxidation mediated by the oxoammonium salt and desilylation to furnish a nitrile. The spent oxidant can be easily recovered and used to regenerate the oxoammonium salt oxidant.

A simple, high yielding, rapid route for the oxidative esterification of a wide range aldehydes to hexafluoroisopropyl (HFIP) esters using the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1a) is reported. These esters can be readily transformed into a variety of other functional groups. The spent oxidant (1b) can be recovered and conveniently reoxidized to regenerate the oxoammonium salt, 1a.

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (-)-crispine A and (-)-harmicine.

A continuous-flow approach to the hydrogenation of alkenes utilizing Wilkinson's catalyst is reported. The approach relies on a newly developed coil design in which it is possible to load gas and heat the reaction mixture simultaneously. The hydrogenation of various substrates has been performed successfully on small scale and can be scaled up substantially.

Here we describe the oxidation of 1,3-cyclohexanediones with 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (Bobbitt’s salt) to generate 5-ene-1,2,4-triones in moderate-to-good (40–80%) yields. This inexpensive oxidant facilitated an unprecedented cascade of oxidation and elimination to yield novel ene-triketones. The reactivity of these products was explored in the Diels-Alder reaction and provided moderate-to-good yields of cycloaddition products. The products described in this study represent unique, densely functionalized, and versatile building blocks for the synthesis of more complex molecules.