Direct C–H Alkylation of Simple Arenes via Visible-Light Induced Palladium Catalysis

We successfully realized the catalytic C–H alkylation of benzene with readily available alkyl bromides without any rearrangement enabled by photoinduced Pd catalysis.

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Alkylarenes are essential scaffolds in a wide range of commodity chemicals, including surfactants and detergents, and some biologically active molecules. Despite the fundamental importance of efficient and selective synthesis of widely utilized alkylarenes, the direct catalytic C(sp2)–H alkylation of unactivated arenes with a readily available alkyl halide remained elusive. The traditional Friedel-Crafts alkylation approach has a number of drawbacks including the requirement for a strong acid catalyst, harsh reaction conditions, and the generation of complex isomeric mixtures. Hence, the majority of the reported transition metal-catalyzed C(sp2)–H alkylation reactions using alkyl electrophiles require directing groups, or have a limited applicability to heteroarenes, activated electron-deficient arenes, and intramolecular alkylation systems. This significantly limited scope is due to the challenging oxidative addition to the alkyl electrophile and the high C–H activation barrier of the unactivated arenes. Such high reaction barriers inevitably lead to a requirement for harsh reaction conditions, which are often accompanied by undesirable side reactions, such as β–hydride elimination. 

     With these challenges in mind, we envisioned that a controlled radical-mediated reaction could afford a high activity and selectivity because the rearrangement of reactive carbon-centered radicals is much slower than that of their cationic counterparts. However, the insertion of nucleophilic alkyl radicals to the electron-rich arenes is more sluggish and the alkyl radicals are prone to undergo side reactions, such as homodimerization and hydrogen atom transfer. To control the reaction pathways, the recently reported photoinduced Pd catalysis approach was identified as an attractive activation mode to generate alkyl radicals from alkyl halides, since it operates under mild conditions while controlling the concentration of free radical species to suppress undesired side reactions.

     We successfully realized the catalytic C(sp2)–H alkylation of benzene with readily available alkyl bromides without any rearrangement enabled by photoinduced Pd catalysis. Exclusive chemoselectivity and excellent functional group tolerance were demonstrated by synthesizing various linear and branched alkylbenzenes including the late-stage phenylation of bioactive molecule derivatives and an orthogonal one-pot sequential Pd-catalyzed C–C bond formation reaction. Comprehensive mechanistic investigations were conducted with a combination of experimental and computational studies to construct the complete catalytic cycle. Consequently, it clarified the catalytic turnover mechanism involving a Pd(0)/Pd(I) redox cycle through the reciprocal exchange of a bromine atom between the Pd catalyst and the alkylating species. It also accounted for the distinctive reactivity of alkyl bromides compared to other halides by disclosing the unexpected role of the formate base which reduces the off-cycle Pd(II) dibromide complex Pd(PPh3)2Br2 to an active Pd(0) species. We anticipate that the developed method will streamline the synthesis of industrially useful alkylbenzenes and the disclosed mechanistic information can help to design new reactions. More details of this work can be found here: “Direct C(sp2)–H Alkylation of Unactivated Arenes Enabled by Photoinduced Pd Catalysis” in Nature Communications,

Daeun Kim

Graduate student, Seoul National University