MRV

This study presents a synergistic platform merging asymmetric Lewis base catalysis with electrocatalysis for the unprecedented enantioselective radical difunctionalization of alkenes via direct C(sp³)─H activation of simple esters. Covalent Lewis base activation enables precise stereocontrol of radical intermediates under electrochemical conditions, delivering both 1,2-difunctionalized and alkenylated products in good yields (up to 95%) with excellent enantioselectivity (up to 99% ee).

ABSTRACT

Electrochemical asymmetric radical reactions stand at the frontier of sustainable organic synthesis, yet precise enantiocontrol over short-lived radical intermediates under electrochemical conditions remains a formidable challenge. Herein, we report a synergistic integration of electrocatalysis and asymmetric Lewis base catalysis that enables highly enantioselective radical functionalization of alkenes. This strategy centers on the anodic single-electron oxidation of catalytically generated C1-ammonium enolates—derived from simple esters and chiral isothiourea organocatalysts—to furnish chiral catalyst-bound α-acyl ammonium radical intermediates. Confined within the chiral cavity of the Lewis base catalyst, these tethered radicals undergo enantioselective addition to alkenes, and the resulting adduct radical is strategically diverted toward either difunctionalized or alkenylated products with high enantiocontrol (up to 99% ee). This work establishes a versatile platform that merges Lewis base catalysis with electrosynthesis for enantioselective alkene difunctionalization via direct ester C(sp³)─H activation, thereby fundamentally extending the scope of asymmetric Lewis base organocatalysis into the realm of electrocatalytic radical transformations.

This review highlights key contributions of modern nitration chemistry, emphasizing sustainable mechanistic platforms and comparing the performance of both organic and inorganic reagents across aromatic, ipso-, olefin, alkyne, and heteroatom nitration. It provides the community with a clearer, unified perspective on current advances and facilitates the selection of nitrating reagents by establishing a performance score.

ABSTRACT

We highlight recent advances in nitration chemistry with emphasis on the development of sustainable and selective methodologies. A comprehensive overview of nitrating reagents is provided, classified by origin (organic or inorganic) and activation mode (photochemical, electrochemical, thermal, and others). Each reagent is critically analyzed with respect to its performance across different nitration processes, that is, aromatic, ipso-, olefinic, alkyne, and heteroatom nitration. This analysis scrutinizes yield, substrate scope, functional group tolerance, versatility, resource and hazard, key features that comprise an efficiency score. A comparative analysis of activation strategies underscores the evolution of nitration from classical mixed-acid approaches to modern photocatalytic, electrochemical, and cross-coupling methodologies. The insights gathered here provide a practical framework for identifying the most suitable nitrating reagents and highlight future directions toward safer, greener, and more versatile nitration chemistry.

A sustainable electrochemical cascade enables the one-pot synthesis of regioselectively halogenated N-aryl amides from readily available amines and acyl halides under mild conditions. The method merges amidation and C─H halogenation in a single operational step, delivering broad substrate scope, high selectivity, and scalability, and provides an efficient platform for late-stage halogenation of complex molecular scaffolds.

ABSTRACT

The advancement of sustainable synthetic methodologies is a central goal of modern chemistry, given the societal importance of green chemical practices. Amide groups and halogen atoms are prevalent in chemical and biological systems, with major relevance to both organic and medicinal chemistry. Consequently, there is strong demand for efficient methods that enable amide bond formation and selective halogenation under mild, resource-efficient conditions. Conventional approaches typically require separate steps, activating reagents, catalysts, or harsh reaction conditions, which limit scalability and sustainability. To address these challenges, we developed a novel electrochemical cascade methodology that unites amide bond formation and electro-induced C─H halogenation in a single, atom-economical, and environmentally benign process. This strategy provides streamlined access to halogenated N-aryl amides, carbamates, and ureas without additives or co-reagents. The method's generality and robustness are demonstrated across more than 145 examples, encompassing complex, functional group-dense scaffolds and pharmaceutically relevant compounds, including successful scale-up reactions.

ORPCO merges radical reactivity with polar selectivity by converting radical intermediates into carbocations, enabling efficient, enantioselective construction of C–C, C–O, and C–N bonds. This method is particularly valuable for the late stage functionalization of complex molecules and the diversification of medicinal compounds. The article covers recent advances in catalytic systems and mechanisms and outlines future directions focused on novel catalytic strategies and bonding paradigms to broaden the synthetic utility of these reactions.

Radical–polar crossover (RPCO) has emerged as a powerful synthetic strategy, using the complementary properties of both radical and classical polar chemistry. Radical–polar crossover, especially its oxidative radical–polar crossover (ORPCO), facilitates efficient asymmetric synthesis by converting radical intermediates to carbocations, which allow the formation of enantioselective bonds. This ability to form CC, CO, and CN bonds underlines its significant potential for late–stage functionalization of complex molecules and for diversification of medicinal products. This review summarizes the recent developments in the asymmetric ORPCO domain, including catalytic strategies, transformation mechanisms, and current characteristics. Research into new catalytic strategies and asymmetric bonding paradigms is an important frontier of future research, with the potential to significantly increase the scale and usefulness of ORPCO reactions.

This review covers the application of the bifunctional approach to photocatalysis as a means to attain (enhanced) enantioselectivity, and, more in general, as a strategy to enhance the catalytic performance through an effective use of short-lived reaction intermediates.

ABSTRACT

The bifunctional approach has often been employed in catalysis to obtain more effective and enantioselective transformations. In the sub-area of photocatalysis, bifunctional systems have been designed (i) to introduce chirality in the system and thus gain stereocontrol, and (ii) to more effectively exploit the short-lived catalytic intermediates (e.g., photoexcited species and radicals). In some cases, instead of two distinct catalytic units, a single photoactive group displaying also other types of activity can be employed (“bivalent photocatalysts”). This review aims to cover the most recent examples in this field, establishing—when possible—a comparison with the corresponding dual catalytic systems.

We here reported an iridium-catalyzed enantioselective allylation reaction with allylic electrophiles and alkynyl boronates, resulting in various 1,4-dienes with excellent Z/E ratios and enantioselectivity. The reaction proceeds through a concerted mechanism that involves an allylation-induced 1,2-migration of the alkynyl boronate, followed by a syn-addition of the migrating group and Ir(π-allyl) complex across the alkynyl fragment.

ABSTRACT

Skipped dienes, particularly 1,4-dienes, play significant roles in pharmaceuticals and organic synthesis as they serve as key intermediates for the construction of complex structures and also bioactive molecules. However, the catalytic assembly of this motif with high stereoselectivity from readily available starting materials remains a substantial synthetic challenge. Herein, we reported a direct iridium-catalyzed enantioselective allylation reaction with allylic electrophiles and alkynyl boronates, resulting in various 1,4-dienes with excellent Z/E ratios and enantioselectivity. The reaction proceeds through a concerted mechanism that involves an allylation-induced 1,2-migration of the alkynyl boronate, followed by a syn-addition of the migrating group and Ir(π-allyl) complex across the alkynyl fragment to selectively deliver the more challenging Z-alkenes. DFT calculations clarify the origins of the observed high chemo- and stereoselectivity. Furthermore, this method demonstrates a broad substrate scope, and the resulting enantiomerically enriched 1,4-diene products can be readily derivatized.

CCS Chemistry, Ahead of Print.
Electrochemical synthesis offers an effective platform for reductive cross-coupling reactions without stoichiometric reagents. Here, we show a cobalt-catalyzed electroreductive reaction that enables defluorination–olefination coupling between aldehydes/ketones and α-trifluoromethyl alkenes, accessing 2,2-difluorohomoallylic alcohols under mild conditions. The reaction shows broad substrate scope with aldehydes, ketones, and substituted α-trifluoromethyl alkenes that can be extended to allylic alcohols. Its successful implementation in a continuous-flow system further highlights its scalability and potential for practical applications.

CCS Chemistry, Ahead of Print.
The saturation of planar pyridines through concurrent introduction of multiple substituents to access complex piperidines represents a highly attractive strategy in modern drug discovery. Capitalizing on the exceptional selectivity and unique capability of synthetic electrochemistry in generating diverse reactive intermediates, we herein develop an electrocatalytic saturation strategy for pyridines. It enables the chemo-, regio-, and stereoselective dearomative multifunctionalization of pyridines, yielding structurally complex piperidines decorated with four synthetically versatile functional groups. Preliminary mechanistic studies suggest that electrochemically generated cyanogen bromide promotes dearomatization of pyridines to form dihydropyridines, which subsequently undergo stereoselective electrochemical vicinal difunctionalization to afford the target multifunctionalized piperidines.

Staged diversity-constrained modeling enables efficient navigation of high-dimensional reaction spaces, validated on cross-coupling HTE data and applied to ruthenium-catalyzed meta-C─H functionalization.

ABSTRACT

Optimizing reaction conditions in high-dimensional chemical spaces remains a central challenge in modern synthesis. In this context, we developed and evaluated a staged diversity-constrained machine learning framework that efficiently balances exploration and exploitation during condition optimization. At each stage, a within-batch diversity constraint promotes broad chemical coverage, while the constraint is progressively relaxed to focus on promising subspaces. Systematic evaluation across large-scale palladium-catalyzed C─C and C─N coupling datasets revealed that the number of stages, rather than the exploration portion, was the dominant factor governing optimization efficiency. A comparison with Bayesian optimization (BO) methods shows a dimension-dependent performance trend. Here, the staged diversity-constrained strategy was shown to be more advantageous in higher-dimensional reaction spaces, whereas BO performed better in lower-dimensional settings. Moreover, we developed a user-friendly software tool making the herein developed framework readily accessible for experimental chemists. Our strategy was further applied to challenging ruthenium-catalyzed meta-C─H functionalization involving 11,880 possible conditions, only 44 experiments were required to identify the optimal setup (91% yield). This work provides a validated and practical framework for accelerating high-dimensional reaction condition optimization, bridging data-driven modeling with experimental synthesis.

Nature, Published online: 11 February 2026; doi:10.1038/s41586-025-09941-9

Aluminium redox catalysis is achieved with a low-valent aluminium species, carbazolylaluminylene, enabling cyclotrimerization of alkynes and producing diverse benzene derivatives.

Enabling late-stage transformations and skeletal editing, anomeric amides have recently emerged as powerful synthetic tools. Due to their unique properties, anomeric amides have been employed in reactions ranging from amination to halogenation. This minireview provides an overview of recent progress in using anomeric amides across a variety of synthetic transformations.

ABSTRACT

The quest for synthetic tools to achieve molecular complexity is of paramount importance. In recent years, strategies have been developed for the late-stage functionalization of molecules. Anomeric amides have emerged as valuable reagents in this active research area due to their broad range of synthetic applications, and they continue to draw growing interest from the scientific community. This minireview aims to discuss and highlight recent progress in using anomeric amides across a variety of synthetic transformations.