MRV

Electrochemical benzylic C(sp³)H functionalization (since 2021) enables efficient CC, CN, and CO bond formations. This review summarizes mechanistic insights and applications in bioactive molecule synthesis, highlighting recent advances in this powerful strategy.

Direct benzylic C(sp³)H functionalization has emerged as a topic in organic synthesis due to its critical role in constructing complex and valuable molecules. Among the various methodologies employed, electroorganic synthesis has garnered considerable attention in diversifying benzylic C(sp³)H functionalization. In recent years, substantial progress has been made in electrochemical benzylic C(sp³)H functionalization. However, a comprehensive review summarizing recent advancements in this area is still lacking. This review provides an overview of the latest developments (2021–2025) in electrochemical benzylic C(sp³)H functionalization, with a particular emphasis on mechanistic insights and practical applications in the synthesis of biologically active molecules. Additionally, current challenges and future perspectives in this field are discussed.

The synthesis and catalytic properties of Ni(II) complexes, with the general formula Ni(NHC)[P(OR)₃](Ar)Cl, are described. These air-stable complexes are effective under mild conditions and low catalytic loading for the Suzuki-Miyaura cross-coupling for a range of electronically and sterically differentiated coupling partners. This paper also highlights experimental and spectroscopic methods, alongside DFT calculations, to support an operating mechanism of these precatalysts.

Abstract

The synthesis and catalytic properties of Ni(II) complexes with the general formula Ni(NHC)[P(OR)₃](Ar)Cl are described. These complexes are air-stable and extremely effective precatalysts in the Suzuki-Miyaura cross-coupling reaction. The reaction protocols described allow for the cross-coupling of aryl chlorides and arylboronic acids, employing low catalytic loading, to deliver a large variety of functionalized biaryl compounds. For the coupling of aryl chlorides with N-heterocyclic boronic acids, TBAF was used as an additive to afford nitrogen-containing biaryl products. Overall, these reaction protocols operate at room or mild temperatures and can be applied to a variety of electronically and sterically differentiated coupling partners. Fundamental insights into the mechanism of this reaction, including the proposed formation of the catalytically active Ni(NHC)[P(Oi-Pr)₃] and resting state species, are also reported.

Abstract

This article presents a method for asymmetric formal cross-dehydrogenative coupling of benzylic alcohols with ketones through combined electrooxidation and organocatalysis. Employing inexpensive and environmentally friendly proline as a chiral organocatalyst, various benzylic alcohols and simple ketones serve as substrates to directly obtain diverse chiral β-hydroxycarbonyl compounds with moderate to good yields (up to 85%) and excellent stereoselectivity (up to 99% ee and 99:1 dr). The reaction proceeds under mild conditions at room temperature in air, without oxidants or additives, demonstrating robust functional group tolerance and atom efficiency. Hydrogen gas released at the cathode is the sole byproduct. Using L- or D-proline allows straightforward access to both chiral configurations of β-hydroxycarbonyl compounds.

Cyclopropanes are prevalent in natural products, pharmaceuticals, and bioactive compounds, functioning as a significant structural motif. Although a series of methods have been developed for the construction of the cyclopropane skeleton, the development of a direct and efficient strategy for the rapid synthesis of cyclopropanes from bench-stable starting materials with a broad substrate scope and functional group tolerance remains challenging and highly desirable. Herein, we present an electrochemical method for the direct cyclopropanation of unactivated alkenes using active methylene compounds. The strategy shows a broad substrate scope with a high level of functional group compatibility, as well as potential application as demonstrated by late-stage cyclopropanation of complex molecules and drug derivatives. Further mechanistic investigations suggest that Cp2Fe (Fc) plays an essential role as an oxidative mediator in generating radicals from active methylene compounds.

The photoredox activation of D−A cyclopropanes is unlocked, leading to distonic radical cations for a traditionally polarity-mismatched [3+2] cycloaddition with unactivated olefins. Further extension leads to facile access of cyclopentenes as well as bicyclo[3.1.1]heptanes by [σ+π] and [σ+σ] cycloaddition respectively.

Abstract

Altering the reactivity model of a molecule can potentially eliminate limitations existing in its current paradigm. When it comes to the activation of Donor-Acceptor Cyclopropanes (DACs), Lewis acids have been the state-of-the-art. Although a variety of polarized 2π components have been successfully coupled with DACs for [3+2] cycloaddition, unpolarized alkenes prove to be a roadblock due to an inherent polarity mismatch with the Lewis acid-mediated 1,3-zwitterionic intermediate. Hereby, harnessing the distonic radical cation mode of cleavage by photoredox catalysis overcomes this mismatched reactivity of the zwitterionic intermediate, providing a unique route to highly substituted cyclopentanes and cyclopentenes. Expansion of this strategy to bicyclo[1.1.0]butanes enables access to bicyclo[3.1.1]heptanes (BCHs) through a facile [3σ+2σ] cycloaddition. Detailed mechanistic insights are also provided using dispersion-corrected density functional theory.

We present a groundbreaking electrochemical ring-opening protocol for the direct synthesis of remote amino alcohols via copper-catalyzed sequential paired electrolysis under mild, biocompatible conditions. This method enables rapid access to a wide variety of remote amino alcohols with diverse functional groups, utilizing an electro-redox ring-opening approach for efficient peptide alcohol modification and assembly. Mechanistic studies and DFT calculations confirm that water serves as both the solvent and hydrogen source, generating CuH to reduce aldehydes to alcohols.

Abstract

Amino alcohols, particularly remote amino alcohols and peptide alcohols, are valuable due to their functional diversity in biologically active compounds. However, traditional synthesis methods face significant challenges, making electrochemistry an attractive alternative. We have developed a mild and biocompatible sequential paired electrolysis strategy, leveraging copper-electrocatalysis to synthesize diverse remote amino alcohols, including unnatural peptide alcohols. Both experimental results and density functional theory (DFT) calculations demonstrated that water serves as both the hydroxyl source and the solvent, facilitating the generation of CuH with Cu(I) at the cathode, which in turn reduces the aldehyde intermediates formed during the reaction.

An α-nucleophilic addition reaction to α,β-unsaturated carbonyl compounds was developed via α-carbonyl carbocations that are generated in situ through the photocatalytic oxidation of α-carbonyl radicals by the organic super-photoreductant CBZ6. The α-carbonyl radicals are formed by the β-addition of alkyl radicals generated in situ by the photocatalytic fragmentation of N-hydroxyphthalimide esters to the α,β-unsaturated amides and esters.

Abstract

We report the photocatalytic oxidation of α-carbonyl radicals of amides or esters to the corresponding α-carbonyl carbocations through super photoreductant CBZ6 induced redox-neutral photocatalysis. The α-carbonyl radicals are formed by the β-addition of alkyl radicals generated in situ by the photocatalytic fragmentation of N-hydroxyphthalimide esters to the α,β-unsaturated amides and esters. This method enables the α-nucleophilic addition of hydroxyl or alkoxyl radicals to amides and esters without any prefunctionalization.

The recent development of photoredox and energy transfer catalysis has led to a significant expansion of visible light-driven chemical transformations. These methods have demonstrated exceptional efficiency in converting a wide range of substrates into radical intermediates and generating open-shell catalytic species. However, the simplification of catalytic systems and the direct generation of highly reactive radical organocatalysts through direct visible light irradiation from stable precatalysts remains largely an unrealized goal. This challenge is mainly due to the limited availability of precatalysts that are responsive to visible light. Herein, we introduce a new class of bench-stable dicationic disulfuranes, which release highly reactive thiyl radicals upon blue light excitation. Spectroscopic and computational studies reveal that this reactivity arises from a combination of structural features and intermolecular interactions. This family of molecules has been employed to catalyze radical cascades previously incompatible with photoredox conditions, enabling the efficient formation of 1,2-dioxolanes and 1,3-hydroxyketones in excellent yields and short reaction times.