MRV

A direct anodic oxidative coupling process for α-heteroarylation using ferrocene-assisted asymmetric nickel electrocatalysis has been developed, enabling the synthesis of a diverse range of chiral heteroaromatic carbonyl compounds with high enantioselectivity and functional group tolerance, which can be applied to the synthesis of valuable frameworks like (−)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

Abstract

Oxidative cross-dehydrogenative C−H/C−H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α-heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2-acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene-assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni-bound α-carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero-compounds. The consequential α-heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (−)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

The novel designed bifunctional chiral electrocatalyst has been presented for the asymmetric electrochemical α-alkylation of aldehydes. The new bifunctional catalyst, which combines a chiral aminocatalyst with a redox mediator, significantly enhances efficiencies and stereoselectivities compared to conventional catalysts. It plays a dual role as a redox mediator for electrooxidation while simultaneously providing remarkable asymmetric induction for the stereoselective α-alkylation of aldehydes.

Abstract

Herein, we describe an innovative approach to the asymmetric electrochemical α-alkylation of aldehydes facilitated by a newly designed bifunctional chiral electrocatalyst. The highly efficient bifunctional chiral electrocatalyst combines a chiral aminocatalyst with a redox mediator. It plays a dual role as a redox mediator for electrooxidation, while simultaneously providing remarkable asymmetric induction for the stereoselective α-alkylation of aldehydes. Additionally, this novel catalyst exhibits enhanced catalytic activity and excellent stereoselective control comparable to conventional catalytic systems. As a result, this strategy provides a new avenue for versatile asymmetric electrochemistry. The electrooxidation of diverse phenols enables the C−H/C−H oxidative α-alkylation of aldehydes in a highly chemo- and stereoselective fashion. Detailed mechanistic studies by control experiments and cyclic voltammetry analysis demonstrate possible reaction pathways and the origin of enantio-induction.

CCS Chemistry, Ahead of Print.

Electrochemistry and photochemistry join forces in the booming field of electrophotocatalysis. Electrophotocatalytic activation is suitable to engage even previously inaccessible compounds in C−H functionalization reactions. Herin we provide an overview of recent developments in this field.

Abstract

Electrophotocatalysis (EPC) has evolved as a new scientific discipline around the boundary of highly active fields: electrochemistry and photocatalysis. EPC allows us to combine the energy of light and electric potential to activate previously inaccessible compounds via single-electron transfer (SET). Herein, we review the most essential applications of EPC to the C−H functionalization of molecules. This work discusses mechanisms that can be encountered when designing such processes and analyzes technical aspects of performing EPC reactions in the laboratory.

This minireview highlights recent advancements and trends in utilizing cobaloxime catalysis within organic synthesis, aiming to inspire further studies in the development of new sustainable transformations and contributing to the advancement of environmentally benign synthetic strategies.

Abstract

Drawing inspiration from nature has long been a cornerstone of chemical innovation, with natural systems offering a wealth of untapped potential for discovery. In this minireview, we delve into the burgeoning field of cobaloxime catalysis in organic synthesis, which mimics the catalytic activity of the natural organometallic alkylcobalamine enzymes. Our focus lies on elucidating the latest advancements in this area, as well as delineating the primary mechanistic pathways at play. By describing, and comparing these mechanisms, we provide a comprehensive overview of the current state-of-the-art, while also shedding light on the key unresolved challenges that await further exploration.

Nature Catalysis, Published online: 07 May 2024; doi:10.1038/s41929-024-01160-1

Photoredox-catalysed coupling of electron-rich aryl electrophiles based on simple nickel salts usually suffers from a slow oxidative addition. Now, it is shown that thianthrenation leads to more favourable redox properties of the substrates, alleviating this problem in carbon–heteroatom bond-forming reactions.

Abstract

Visible-light-induced difunctionalization of alkenes is a powerful strategy for constructing complex molecules. Herein, we disclose a three-component 1,2-alkylpyridylation of alkenes under mild and photosensitizers-free conditions. UV-vis absorption spectroscopy studies and NMR titration experiments indicate that the formation of an EDA complex between 4-alkyl-DHPs and 4-cyanopyridines. Primary, secondary, and tertiary C(sp ³)-centered radicals were formed by homolytic cleavage of 4-alkyl-DHPs. Gram-scale synthesis and late-stage functionalization of medicinally relevant molecules showed the synthetic potential of our methodology.

The merger of hydrogen atom transfer and Sulfinyl-Smiles rearrangement enables the asymmetric arylation of C(sp³)−H bonds in remote position to the double bond under photoredox conditions. Various chiral α-arylated amides are obtained with up to >99 : 1 er where the sulfinamido groups dictates the stereochemical outcome.

Abstract

An efficient asymmetric remote arylation of C(sp³)−H bonds under photoredox conditions is described here. The reaction features the addition radicals to a double bond followed by a site-selective radical translocation (1,n-hydrogen atom transfer) as well as a stereocontrolled aryl migration via sulfinyl-Smiles rearrangement furnishing a wide range of chiral α-arylated amides with up to >99 : 1 er. Mechanistic studies indicate that the sulfinamide group governs the stereochemistry of the product with the aryl migration being the rate determining step preceded by a kinetically favored 1,n-HAT process.

We have developed a Pd-catalyzed Z-retentive allylic substitution reaction for the first time. The utilization of a sterically bulky phosphoramidite ligand enables the nucleophilic attack step to proceed prior to the π-σ-π isomerization process of the π-allyl-Pd intermediate. This synthetic protocol displays a general scope for both nucleophiles and Z-allyl electrophilic precursors. In addition, an enantioselective variant has been demonstrated for the synthesis of highly diastereo- and enantioenriched cyclic ketones possessing a Z-alkene moiety starting from Z-allyl carbonates.

Nature Chemistry, Published online: 01 March 2024; doi:10.1038/s41557-024-01472-6

Although generally perceived as an old-fashioned and unselective tool to build molecules, the photochemistry community is now re-discovering the power of UV light and is using key mechanistic information to develop new catalytic processes driven by visible light. This Perspective discusses the progress and impact of UV light in organic synthesis.

Photocatalytic reactions with a reductive radical-polar crossover (RRPCO) involve intermediates with carbanionic reactivity. These are best described as free carbanions. Reactions with such carbanions depend on the balance between their nucleophilicity and basicity. Deprotonation of reaction partners and common organic solvents such as acetonitrile, dimethylformamide, and dimethylsulfoxide is the main competing reaction to nucleophilic addition.

Abstract

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

Nature Catalysis, Published online: 23 February 2024; doi:10.1038/s41929-024-01118-3

Electrochemical cross-electrophile coupling with alkyl halides for the construction of C(sp3)–C(sp3) bonds is generally limited to activated alkyl halides. Now this approach is extended to coupling of unactivated alkyl halides using a nickel catalyst under mild conditions.

Phenols and naphthols are dearomatized to methoxycyclohexadienones under simple and robust electrochemical conditions, in a green way without chemical oxidants. The mechanism of the reaction is established using density functional theory calculations, which also explain the chemo- and regioselectivity for differently-substituted substrates.

Abstract

The electrochemical oxidative dearomatizing methoxylation of phenols and naphthols was developed. It provides an alternative route for the preparation of methoxycyclohexadienones, important and versatile synthetic intermediates, that eliminates the need for stoichiometric high-energy chemical oxidants and generates hydrogen as a sole by-product. The reaction proceeds in a simple constant current mode, in an undivided cell, and it employs standardized instrumentation. A collection of methoxycyclohexadienones derived from various 2,4,6-tri-substituted phenols and 1-substituted-2-naphthols was obtained in moderate to excellent yields. These include a complex derivative of estrone, as well as methoxylated dearomatized 1,1′-bi-2-naphthols (BINOLs). The mechanism of the reaction was subject to profound investigations using density functional theory calculations. In particular, the reactivity of two key intermediates, phenoxyl radical and phenoxenium ion, was carefully examined. The obtained results shed light on the pathway leading to the desired product and rationalize experimentally observed selectivities regarding a side benzylic methoxylation and the preference for the functionalization at the para over the ortho position. They also uncover the structure-selectivity relationship, inversely correlating the steric bulk of the substrate with its propensity to undergo the side-reaction. Moreover, the loss of stereochemical information from enantiopure BINOL substrates during the reaction is rationalized by the computations.