Marnix van der Kolk

We demonstrate a novel electrochemical protocol for the deoxygenative arylation of bench-stable O-alkylisoureas as C(sp³) radical precursors via reductive activation. Combined with nickel catalysis, this methodology enables the deoxygenative cross-coupling of alcohol derivatives with a wide range of aryl electrophiles, offering a mild and efficient electrochemical strategy for C(sp³)–C(sp²) bond formation.

Abstract

The development of efficient methods to employ naturally abundant alcohol derivatives as C(sp³) precursors for deoxygenative carbon–carbon (C–C) cross-coupling holds significant value for expanding sp³-enriched chemical space. While progress has been made in this area, the field lacks readily accessible, bench-stable alkylation reagents capable of undergoing reductive activation to generate alkyl radicals. Herein, we report an electroreductive nickel-catalyzed system for efficient C(sp³)–C(sp²) radical cross-coupling between aryl electrophiles (halides, triflates, tosylates, and boronic acids) and O-alkylisoureas as radical progenitors. This protocol demonstrates broad substrate scope with good functional group compatibility. Its synthetic utility is highlighted through the preparation of beclobrate analogs and bifonazole, as well as late-stage functionalization of bioactive compounds. Mechanistic investigations support a radical cross-coupling pathway for this transformation.

A practical, stereoselective method for synthesizing tri- and tetra-substituted 1,2-fluoro-borylalkenes and alkynes via defluorinative C–C coupling of CF₃–arenes with organodiboron reagents is reported. Enabled by a Lewis base activator, products are formed in up to 94% yield and >98:2 Z/E selectivity. The utility of the method is showcased through several product transformations.

Abstract

A practical method for the stereoselective synthesis of tri- and tetra-substituted 1,2-fluoro-borylalkenes and alkynes by defluoro / C–C coupling of aryl trifluoromethyl groups is disclosed. Transformations convert simple abundant CF₃–arenes and multifunctional organodiboron reagents in the presence of a Lewis base activator into coupled products in up to 94% yield and >98:2 Z/E selectivity. Synthetic utility is highlighted by several product transformations that access an array of diverse scaffolds.

New derivatives of dibenzo-5,10,15-triazaporphyrin (DBTriAP) with substituents on the meso and/or β-pyrrolic carbons were prepared, and their optical and electrochemical properties were revealed. The peripheral substituents were found to exert significant impacts on the fluorescence property and aggregation behavior of the DBTriAP chromophore in solution.

Abstract

In contrast to the great advances of phthalocyanine-based materials, the potential of 5,10,15-triazaporphyrins has not been realized because of the lack of fundamental information about their structure-property relationships. Here, we report new derivatives of dibenzo-5,10,15-triazaporphyrin (DBTriAP) with aryl or alkyl substituents at the meso and/or β positions. Freebases of DBTriAP were prepared by the condensation of two types of 1,9-dibromodipyrrins with 1,3-diiminoisoindoline and subsequent functionalization of the β-pyrrolic carbons. Zinc(II) complexes of DBTriAP were obtained by complexation of the corresponding freebases with zinc(II) acetate. The optical and electrochemical properties of the DBTriAP derivatives were studied by steady-state and transient ultraviolet/visible absorption/emission spectroscopy, magnetic circular dichroism spectroscopy, cyclic voltammetry (CV), and density functional theory (DFT) calculations. Replacing the β-pyrrolic hydrogens of the 5-mesityl-DBTriAP derivatives with aryl groups resulted in substantial red shifts of the low-energy absorption band because of the effective π-delocalization and/or charge-transfer interaction with the DBTriAP chromophore. The 2,3,17,18-tetraethyl-DBTriAP freebase exhibited split redox processes in its cyclic voltammogram, suggesting the rapid formation of a π-stacked dimer radical cation facilitated by the highly planar structure. Most of the DBTriAP derivatives emitted red fluorescence with quantum yields of 0.07–0.31, indicating their potential as luminescent materials.

Use of N-heterocyclic carbenes (NHCs) to activate carbon and heteroatoms in aromatic compounds is reviewed based on key dearomative NHC-bound intermediates, i.e., ortho-quinodimethanes (o-QDMs), ortho-quinone methides (o-QMs) and aza-analogs (aza-o-QMs), aza-fulvene and triaza-diene intermediates. Their formation and reactivity in stereoselective annulation reactions for the synthesis of enantioenriched (hetero)cyclic molecules are discussed.

Abstract

N-Heterocyclic carbene (NHC) organocatalysis has long been recognized as a powerful and versatile method for the implementation of (asymmetric) transformations enabling the formation of C─C and C–heteroatom bonds. A number of NHC-bound active ionic species have been classically established for activation of carbon atoms as either nucleophiles or electrophiles at diverse positions, such as (aza)Breslow intermediates, homoenolate equivalents, azolium (di)enolates, simple acyl (imidoyl) azoliums, and α,β-unsaturated/alkynyl acyl azoliums. Within this realm, the past decade has witnessed a blossoming interest in the deployment of NHC-tethered dearomative intermediates for the activation of both carbon atoms and heteroatoms in aromatic compounds. Accordingly, functionalization of benzylic carbon atoms was made possible through catalyst-bound o-quinodimethanes (o-QDMs), while remote activation of oxygen and nitrogen atoms was effectively achieved through NHC-bound o-quinone methides (o-QMs) and aza-analogs (aza-o-QMs), along with aza-fulvene type intermediates and triaza-diene species. Aim of this review is to provide an overview of the most relevant literature on the development of NHC-bound dearomative intermediates for carbon and heteroatom activation since 2013, with emphasis on their applications for stereoselective annulation reactions.

Methods to access 1,3-functionalized patterns from alkenes remain limited. Recently, Silvi and co-workers reported a strategy to add the methyl thianthrenium radical across alkenes to rapidly produce 1,3-dielectrophiles. The 1,3-dielectrophiles can be diversified through sequential nucleophilic substitution reactions, delivering a wide array of 1,3-functionalized products.

Abstract

Despite tremendous progress in alkene 1,2-difunctionalization, analogous methods to generate 1,3-patterns from alkenes remain limited. Recently, Silvi and co-workers reported a homologative strategy to transform alkenes into 1,3-dielectrophiles (DOI: https://doi.org/10.1002/anov.70005). They introduce a novel iodomethyl thianthrenium salt as a precursor to methyl thianthrenium radical, which adds across unactivated alkenes. Substitution of the 1,3-dielectrophiles delivers a general homologative alkene difunctionalization platform.

A difluorinative rearrangement of substituted cyclopropenes is disclosed using I(I)/I(III) catalysis. This platform enables di-, tri-, and tetra-substituted allyl difluorides to be generated with high levels of stereoselectivity, with the I(III) center serving as a traceless directing group. X-ray crystal structural analysis is described together with facile post-reaction modifications that include expedient access to fluorinated indenes.

Abstract

Allyl difluorides are pervasive in the pharmaceutical arena, but synthetic challenges in the construction of highly substituted derivatives impede chemical space exploration. Consequently, efforts to develop general approaches that display high levels of regio- and stereo-selectivity continue to be intensively pursued. To contribute to this vibrant area of contemporary organofluorine chemistry, a highly efficient difluorinative rearrangement of densely substituted cyclopropenes is disclosed under the auspices of I(I)/I(III) catalysis. This platform leverages a highly intuitive ring opening model that enables di-, tri-, and tetra-substituted allyl difluorides to be generated with high levels of stereoselectivity where the transient I(III) center serves as a traceless directing group. X-ray crystal structural analysis is described together with facile post-reaction modifications that include expedient access to fluorinated indenes. Given the ubiquity of the allyl difluoride chemotype in drug discovery, it is envisaged that this operationally simple, organocatalytic platform will expedite bioisostere design.

An additive-free photochemical atom-transfer radical addition of fluoroiodomethyl sulfoxide to [1.1.1]propellane provides fluoromethyl-bicyclopentane sulfonium reagents, enabling nucleophilic substitution under mild conditions.

Fluoroalkyl-substituted bicyclo[1.1.1]pentanes (BCPs) have emerged as an attractive scaffold in drug discovery. Herein, the modular construction of fluoromethyl-linked BCPs is reported. Fluoroiodomethyl phenyl sulfoxide is found to be a synthetic equivalent of a formal fluoromethylene radical cation synthon, which, under metal-free conditions and violet light irradiation (400 nm), enables an atom-transfer radical addition reaction to [1.1.1]propellane. This straightforward approach provides access to novel bicyclo[1.1.1]pentane-substituted fluoromethyl sulfonium reagents. The electrophilic properties of these sulfonium salts allow nucleophilic displacement under mild conditions, enabling the introduction of the fluoromethyl bicyclopentyl group into diverse natural products and drug molecules with good functional group tolerance.

The carbocations generated through electrochemical Hofer-Moest pathways can be trapped by diverse nucleophiles or undergo elimination to form alkenes, significantly expanding synthetic versatility. This review systematically surveys advances in electrochemical Hofer-Moest reactions since 2019, categorizing transformations by bond-forming events. The review concludes by highlighting key challenges and proposing strategic research directions in this rapidly evolving field.

In contrast to radical-mediated electrochemical decarboxylative couplings, electrochemical decarboxylative functionalizations proceeding through carbocation intermediates (Hofer-Moest pathway) unlock unique reactivity and selectivity. These in situ-generated carbocations can be trapped by diverse nucleophiles or undergo elimination to form alkenes, significantly expanding synthetic versatility. This review systematically surveys advances in electrochemical Hofer-Moest-type reactions since 2019, categorizing transformations by bond-forming events (CN, CO, CP, CF, CC, and CC). Beyond summarizing key breakthroughs, it also provide balanced evaluation of current limitations to delineate the scope and applicability of these methods. Finally, persistent challenges are outlined and future research directions in this emerging field is proposed.

A new synthetic approach to anionic N-heterocyclic olefins (NHOs) via ligand exchange of metalated ylides/diazomethanes with free carbenes is reported. The anionic NHOs adopt bent structures with delocalized anionic charge, which enables versatile reactivity, including the formation of highly functionalized NHOs, thermal rearrangement to N-heterocyclic imines and generation of carbo(phosphino)carbene ligands.

Abstract

N-Heterocyclic olefins (NHOs) have emerged as powerful bases and nucleophiles with broad applications in synthesis and catalysis. Here, we report a new synthetic approach to accessing their anionic derivatives through a formal ligand exchange reaction of metalated ylides or diazomethanes with free carbenes. The reaction was found to depend on the nature of the carbene, with more electrophilic carbenes reacting more readily via N₂ and PPh₃ extrusion, respectively. Spectroscopic and crystallographic analyses, combined with computational studies revealed that the anionic NHOs exhibit bent structures. In these structures, the anionic charge at the central carbon atom is partly delocalized into the carbene and the second substituent (Z). These stabilizing effects confer versatile reactivity at the central carbon atom, the nitrogen atom of the N-heterocyclic carbene (NHC) or at the Z substituent. While the predominant reactivity occurs at the central carbon atom—enabling the convenient synthesis of functionalized NHOs—anionic NHOs also undergo a thermally induced rearrangement to N-heterocyclic imines via a skeletal rearrangement involving ring-opening of the N-heterocyclic carbene.

Carbon dioxide, a renewable and eco-friendly carbon source, has garnered significant research interest in recent years for its application as a methyl source in synthesizing bioactive methylated compounds. This review systematically summarizes recent advances in reductive methylation of various nucleophiles with carbon dioxide as a C1 synthon for constructing carbon–carbon and carbon-nitrogen bonds through various catalytic systems.

Methylation reactions have extraordinary value in organic chemistry, ranging from the assembly of structurally diverse organic functional chemicals to the introduction of methyl groups into pharmaceutical and agrochemical intermediates. In the context of sustainable chemistry, carbon dioxide (CO₂) has emerged as an idea and alternative greener C1 source. As a result, reductive methylation strategies utilizing CO₂ as a methylating agent have garnered substantial research interest in recent decades, particularly for synthesizing methylated derivatives, compounds with broad applications in drug discovery and agrochemical development. In this review, reductive methylations using CO₂ as C1 synthon have been summarized and discussed in detail with focus on metal-catalyzed C/N-methylation reactions, base catalyzed C/N-methylation reactions, ionic liquids catalyzed C/N-methylation reactions, and catalyst-free C/N-methylation reactions based on various reductants. We also elucidate substrate compatibility in these reductive methylations, competing side reactions, and representative reaction mechanisms. Furthermore, conclusions and future trends are depicted finally in this review.

Nature, Published online: 30 September 2025; doi:10.1038/d41586-025-03148-8

Nature Chemistry, Published online: 25 September 2025; doi:10.1038/s41557-025-01956-z

A modular approach for construction of multi-substituted β-fluoropyrrole is established via a Lewis acid mediated defluorinative fluoro-aza-Nazarov cyclization. With this method, a wide range of tetra-/penta-substituted fluoropyrroles are synthesized in a highly efficient manner. A Pd-catalyzed protocol is also developed as an alternative for access to tri-substituted fluoropyrrole through an allyl-Pd involved cycloisomerization.

Abstract

A highly efficient approach toward polysubstituted β-fluoropyrroles is described herein. Starting from α,α-difluoro-β,γ-unsaturated ketone, which is easily available from corresponding difluorinated silyl enol ether, an unprecedented defluorinative fluoro-aza-Nazarov cyclization mediated by TiCl₄ is successfully developed, which enables expedient construction of fluorine-containing tetra-/penta-substituted pyrroles in moderate to excellent yields. The protocol features the use of inexpensive Lewis acid, insensitivity to steric hindrance and compatibility with substrates of different substitution patterns. Furthermore, a two-step sequence and also a one-pot protocol were established for synthesizing tri-substituted pyrroles bearing a 3-fluorine substituent, utilizing a Pd-catalyzed defluorinative fluoro-aza-Nazarov cyclization. This methodology provides a modular solution for the rapid assembly of structurally complex β-fluoropyrrole scaffolds, which are notoriously difficult targets using previous methods. Mechanistic studies indicated a Ti-mediated allylic C─F bond activation pathway, triggering the unprecedented defluorinative Nazarov-type cyclization.

The use of N-heterocyclic carbenes (NHC) in organocatalytic reactions is of paramount interest and has been the subject of numerous studies over the years. Indeed, this hot and vast topic has been covered and often updated in many excellent articles. In this review, this subject is approached by highlighting thiazolium salts from an evolutionary perspective over time. Indeed, the idea is to retrace the origins of thiazolium-based NHC by featuring the crucial role played by thiazolium salts as precatalysts: In other words, to provide an account from the umpolung-concept beginnings through thiamine biocatalytic crucial transformations to cutting-edge thiazolylidene organocatalysts.

In this comprehensive review, the history of thiazolium salts as N-Heterocyclic Carbenes (NHC) in organocatalytic reactions is intended to be presented. Although the subject (i.e., NHC in organocatalysis) has been covered in several reviews in past years, the idea here stands on the exclusive use of thiazolium salts in such transformations. Indeed, thiazoliums and their related NHCs are the first identified as efficient mediators for the CC bond formation through its peculiar ability to reverse the classical reactivity (umpolung) of carbonyl groups. However, they are relatively quickly overtaken by other classes of NHCs generated from imidazolium and triazolium salts. Even though, thiazolylidenes are still better catalysts in some particular reactions affording outstanding results in terms of conversion and selectivity. Owing to the remarkably high number of reactions that are made possible thanks to the very characteristic properties of such NHCs, the aim of this review is to provide a full account on the discovery and evolution of thiazolium salts and thiazolylidenes in NHC organocatalysis. Information is first provided on their synthesis, structural evolution, physicochemical and electronic properties, and then reactivity and application in various organocatalytic methodologies.

We present a synergistic strategy combining photocatalytic direct C─F borylation of polyfluoroarenes with Suzuki–Miyaura cross-coupling. The high nucleophilicity of amine-ligated boryl radicals enables efficient homolytic aromatic substitution of polyfluoroarenes, forming stable amine–borane adducts that resist protodeboronation and can be directly used in cross-coupling to access functionalized polyfluoroarenes.

Abstract

Polyfluoroarenes are privileged scaffolds in pharmaceutical and materials science, yet their synthesis remains challenging. Aromatic borylation offers a modular entry point for derivatization via Suzuki–Miyaura cross-coupling, but progress is hindered by two persistent issues: the difficulty of direct borylation on electron-deficient polyfluoroarenes, and the pronounced susceptibility of the resulting boron species to rapid protodeboronation under standard cross-coupling conditions. Here, we present an orthogonal strategy that addresses both limitations. Amine-ligated boryl radicals enable direct radical C─F borylation of polyfluoroarenes under visible-light photoredox catalysis. The resulting amine–borane adducts are crystalline, bench-stable, and resistant to protodeboronation, allowing their direct use in Pd-catalyzed Suzuki–Miyaura cross-couplings. This platform provides scalable and broadly applicable access to functionalized polyfluoroarenes and overcomes some of the synthetic constraints associated with these valuable motifs.