Enhanced Structural Variety of Nonplanar <i>N</i>-Oxyl Radical Catalysts and Their Application to the Aerobic Oxidation of Benzylic C–H Bonds

Abstract

The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation, etherification, and acetoamidation of benzylic C-H bonds are described. The catalytic oxidation of C-H bonds represents a powerful tool to synthesize oxygenated functional molecules from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much attention because of their applications in the oxidation of C-H bonds with high bond dissociation energy (BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF 3 )-substituted sp 3 -carbon, we generated an additional tunable site and a nonplanar backbone, while retaining the desirable electronwithdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of Nhydroxy pre catalysts containing such a CF 3 moiety, and investigated their utility in the aerobic oxidation of benzylic C-H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The introduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF 3 and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy-and 4,5,6,7-tetrafluoro substitution afforded a superior performance. These catalyst systems exhibited high functional group tolerance during the aerobic oxidation of C-H bonds, and benzylic etherification and Ritter-type reactions could be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.

Lipophilic N‐Hydroxyphthalimide Catalysts for the Aerobic Oxidation of Cumene: Towards Solvent‐Free Conditions and Back

“…NHPI catalysis has always been performed in polar solvents to guarantee the complete solubilization of the polar catalyst, especially at room temperature. As a consequence, the reactivity of this derivative in nonpolar mediums is unknown, and, to date, experimentally undetermined; the huge efforts devoted to the synthesis of more active derivatives seem not to consider such a detrimental aspect …”

Chemoselective Oxyfunctionalization of Functionalized Benzylic Compounds with a Manganese Catalyst

“…The presence of a second functionality in the ketone products makes the ketones synthetically much more useful; a number of bioactive molecules can be derived from these products (see Supporting Information, Figure S‐2). As far as we are aware, there appear to be only a few reports on the oxidation of alkylarenes with the alkyl chain functionalized with a nitrile, an acetoxy, or a mesylate moiety, [4d,f,h] and no study is known of those bearing an azide or alkyne group [18] …”

“…Whilst these catalytic systems have advanced selective benzylic oxidation considerably, few of them have been demonstrated to tolerate a wide variety of functionalities on the alkyl side chains in benzylic compounds [4] . Notably, the group of Oisaki and Kanai reported a N ‐oxyl radical‐catalyzed benzylic oxidation of side chains bearing various functional groups, [4d] and Sun and co‐workers reported a manganese catalyst that promotes benzylic oxidation of phenethyl acetate (Figure 1b) [4h] . However, no catalytic systems are known of capable of benzylic oxidation of side chains bearing such important functionalities as alkyne, alkene, azide, amino acid, or free amine moieties.…”

Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N,O-Acetals Derived from l-Tartaric Acid

“…However, the trifluoromethyl group not only strongly stabilizes N , O -acetal functions, and thus renders the formation of the α-trifluoromethyl N -acyliminium ions difficult, but also greatly destabilizes and hinders these ions. A few studies dealing with the addition of nucleophiles on these peculiar species have been reported. ,,, To date, only two studies leading to the functionalization of 5-(trifluoromethyl)-pyrrolidin-2-one derivatives have been described, and none are asymmetric. ,, Fused nitrogen heterocycles carrying the fluorinated group on the bridgehead position were obtained by an intramolecular Friedel–Craft reaction on 5-silyloxy- or 5-hydroxy-5-(trifluoromethyl)-pyrrolidin-2-ones using an excess of a relatively strong Brønsted acid. , The creation of a C–O bond was performed by the addition of methanol in the presence of hydrochloric acid on a α-trifluoromethylated N , F -acetal lactam derivative, because the corresponding N , O -acetal resisted most deoxygenation procedures except for deoxyfluorination . The creation of a tetrasubstituted stereogenic carbon bearing a sterically demanding trifluoromethyl substituent by the addition of a nucleophile on a α-trifluoromethylated N -acyliminium ion is still challenging.…”