Photochemical and Electrochemical Strategies towards Benzylic C−H Functionalization: A Recent Update

Abstract

Transition metal-catalysed processes have been widely used for the functionalization of inert CÀ H bonds. Strategies for the functionalization of the benzylic CÀ H position having a relatively weak CÀ H bond (bond dissociation energy~80-90 kcal/mol) differ from the inert aliphatic and aromatic CÀ H positions with stronger CÀ H bonds. The recent advances in the direct activation of the benzylic position through the generation of C(sp 3) radicals have demonstrated the potential of electrochemistry and photochemistry as a means for constructing new chemical bonds. This review will cover the recent progress of benzylic CÀ H functionalization through organic radical strategies employing photochemistry and electrochemistry as sustainable tools. In addition, the mechanistic details of the typical reactions have been included which, in turn, will help the researchers to look at this promising area from a different perspective towards new discoveries and often hidden opportunities. 2.1. C(sp 3)À C Bond Formation 2.2. C(sp 2)À O and C(sp 3)À O Bond Formation 2.3. C(sp 3)À N Bond Formation 2.4. C(sp 3)À S Bond Formation 2.5. C(sp 3)À Halogen Bond Formation 3. Electrochemical Benzylic C(sp 3)À H Functionalization 3.1. C(sp 3)À C Bond Formation 3.2. C(sp 3)À O Bond Formation 3.3. C(sp 3)À N Bond Formation 3.4. C(sp 3)À P Bond Formation 3.5. C(sp 3)À Halogen Bond Formation 4. Benzylic C(sp 3)À H Functionalization via Synthetic Photoelectrochemistry 5. Conclusions and Outlook

Unlocking the Accessibility of Alkyl Radicals from Boronic Acids through Solvent-Assisted Organophotoredox Activation

“…It is worth mentioning that in the case of benzyl acrylate (42), flow conditions were found to be particularly beneficial, with a lower formation of byproducts probably derived from the labile benzylic scaffold. 26 We next turned our attention to the functionalization of dehydroalanine (Dha), an amino acidic residue whose unsaturated backbone can serve as a radical acceptor. Indeed, in recent years, the seminal work by Davis' group on "post-translational mutagenesis" using the dehydroalanine residue as free-radical trapping has inspired many researchers to install side chains on peptides and proteins, employing several radical sources to engage in this transformation.…”

Unlocking the Accessibility of Alkyl Radicals from Boronic Acids through Hydrogen-bond Assisted Organophotoredox Activation

“…2-(1-Phenylvinyl)pyridine successfully reacted with cyclobutyl, cyclopentyl, cyclohexyl BA to give the desired products in 50%, 62%, and 65% yield, respectively (21)(22)(23). Chloro-substituted vinyl pyridines smoothly underwent this Giese-type addition as well to deliver the desired products in good yields (24)(25)(26)(27). N-Boc protected pyrrolidine boronic acid was also employed to form the antihistamine pheniramine analogue 28 in 75% yield.…”

“…It is worth mentioning that, in the case of benzyl acrylate (39), flow conditions were found to be particularly beneficial, with a lower formation of byproducts probably derived from the labile benzylic scaffold. 26 We next turned our attention to the functionalization of dehydroalanine (Dha), an aminoacidic residue whose unsaturated backbone can serve as radical acceptor. Indeed, in recent years, the seminal work by Davis' group on 'post-translational mutagenesis' using dehydroalanine residue as free-radical trapping, has inspired many researchers to install side chains on peptides and proteins, employing several radical sources to engage in this transformation.…”

Electrochemical Benzylic C-H Functionalization with Isocyanides

“…1 In this field, photoredox catalysis and electrochemistry have emerged as proficient strategies, with which the use of stoichiometric quantities of strong oxidants and the generation of a substantial amounts of waste can be avoided. 2 Notably, organic electrochemistry has been employed for the formation of valuable C-N, 3 C-O 4 or C-halogen 5 bonds at benzylic positions (1 to 2, Scheme 1). 2 Nonetheless, the formation of a C-C bond by anodic oxidation stands challenging, and mainly relies on the use of activated substrates such as tetrahydroisoquinolines, xanthenes or parasubstituted phenols.…”

“…2 Notably, organic electrochemistry has been employed for the formation of valuable C-N, 3 C-O 4 or C-halogen 5 bonds at benzylic positions (1 to 2, Scheme 1). 2 Nonetheless, the formation of a C-C bond by anodic oxidation stands challenging, and mainly relies on the use of activated substrates such as tetrahydroisoquinolines, xanthenes or parasubstituted phenols. 6 Indeed, inactivated substrates entail them to be used in large excess, which severely impacts the synthetic potential of such benzylic functionalization processes.…”