href="#ulink_4bc939b3-c112-5bb8-b4c1-4323266cb676">Scheme 2.35 Metal‐free alkene perfluoroalkylations: (a) carbo‐perfluoroalkylation of aromatic alkenes; (b) bifunctionalization‐type perfluoroalkylations of styrenes.
In addition, alkenes bearing a pendant sulfonamide group efficiently gave a wide variety of intramolecular amino‐perfluoroalkylation products: perfluoroalkyl group‐containing aziridines and pyrrolidines [68b]. In particular, the aziridine product proved to be a good building block; it was derivatized to various amines, including indole alkaloid analogs. Furthermore, their group developed allylic and amino‐chlorodifluoromethylations of alkenes, in which the use of Cu(O2CCF3)2 as the catalyst with pyridine additive was found to improve the yield (Scheme 2.34b) [68c]. The chlorodifluoromethyl group of the products was transformed into difluorodiene, difluoromethyl‐, or trimethylsilyldifluoromethyl groups in order to confirm the utility of these products as synthetic building blocks.
They also performed metal‐free perfluoroalkylations by using perfluorocarboxylic anhydride/urea·H2O2, focusing on the structure of the substrates (Scheme 2.35). When an alkene bearing an aromatic ring at an appropriate position of the carbon side chain was reacted with in situ‐generated diacyl peroxide, intramolecular carbo‐perfluoroalkylation via radical cyclization occurred (Scheme 2.35a) [68a–c].
This method provides simple access to benzo‐fused carbo‐ and heterocyclic products in excellent yields. Notably, switching from amino‐ to carbo‐perfluoroalkylation of the same substrate, e.g. N‐tosyl allylamine, by the removal of copper catalyst remarkably increased the diversity of available perfluoroalkylated molecules. Furthermore, styrene derivatives were found to undergo bifunctionalization‐type perfluoroalkylation, oxy‐ and amino‐perfluoroalkylations, via a carbocation, which is a rare intermediate under metal‐free conditions (Scheme 2.35b) [68d]. Mechanistic studies suggested that the unique redox properties of the peroxide reagent, styrene, and the radical cation formed accounted for the extraordinary carbocation formation under metal‐free conditions.
2.3.2 Photocatalytic Reactions Using Perfluorocarboxylic Anhydride/Pyridine N‐oxide
Stephenson applied photochemistry to perfluoroalkylation using perfluorocarboxylic anhydrides (Scheme 2.36) [68], in which the perfluorocarboxylic anhydride‐pyridine N‐oxide adduct is generated in situ as a reactive intermediate [69]. The reaction was applicable to a diverse array of substrates, such as vinyl, aryl, and heteroaryl compounds, and could be run on a kilogram scale by the use of a flow system. Their conditions are also available for chlorodifluoromethylation of aromatic compounds with chlorodifluoroacetic anhydride. In addition, the reaction of alkyne was found to give gem‐difluoroenones via oxy‐chlorodifluoromethylation and subsequent elimination of chloride (Scheme 2.37).
Scheme 2.36 Photocatalytic reaction using anhydrides/pyridine N‐oxides. a. With pyridine N‐oxide, b. With 4‐Ph‐pyrdine N‐oxide, c. Stirred with MeOH on reaction completion, d. Stirred with DBU on reaction completion.
Schaub and coworkers very recently reported a photocatalytic α‐trifluoromethylation of aromatic ketones by using trifluoroacetic anhydride/pyridine N‐oxide (Scheme 2.38) [70].
The reaction proceeds via oxy‐trifluoromethylation, which installs a CF3 group and trifluoroacetate on in situ‐formed vinyl trifluoroacetate; the resulting trifluoroacetyl‐protected acetal was transformed upon workup to the trifluoromethylated ketone product.
Scheme 2.37 gem‐Difluoroenone synthesis by chlorodifluoromethylation of alkynes.
Scheme 2.38 Photocatalytic α‐trifluoromethylation of aromatic ketones.
2.4 Summary and Prospects
We have reviewed developments in perfluoroalkylation reactions with perfluorocarboxylic acids and anhydrides as perfluoroalkylating reagents. Early work tended to focus on methodologies for the generation of reactive species, such as perfluoroalkyl radicals and perfluoroalkyl metal species, and their reactivities. More recent reports have dealt with precise control of the reactivity of reactive intermediates and efficient production of perfluoroalkylated molecules containing important skeletons as candidate pharmaceuticals and functional materials. Based on the ready availability of the perfluoroalkyl sources and the high synthetic utility of recently reported reactions, we consider that perfluorocarboxylic acids and anhydrides will become the first choice of perfluoroalkylating reagents for practical organic syntheses in the near future.
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