Marnix van der Kolk

The norbornane-2,6-dione framework can accommodate a carbon-carbon ylide with a zwitterionic σ-bond.

Abstract

Here, we have reported the computational design of a new class of ylides, elusive carbon–carbon ylides featuring zwitterionic σ-bonds, derived from the norbornane-2,6-dione framework. Utilizing the state-of-the-art computational methods, we have demonstrated that appropriate substitutions on this scaffold can stabilize a carbanion at C1 and a carbocation at C7 without orbital overlap, ensuring a zwitterionic electronic structure akin to a CC-ylide. Large singlet–triplet energy gaps guarantee that these species do not adopt a diradical ground state. Time-dependent DFT computations further have revealed small T1–S1 energy gaps, suggesting potential applications of similar scaffolds in thermally activated delayed fluorescence (TADF) materials. Our analyses have identified the cation on C7 as the most reactive site on the molecule toward unwanted reactions, leading to the degradation of the ylides. With their unique electronic structure, CC-ylides present new opportunities for unexplored chemical reactivity and functional material design.

We have unlocked commercial DAST-type reagents as versatile sulfur precursors for the modular synthesis of multi-heteroatom-substituted S(IV)/S(VI) centers, expanding their utility beyond classical fluorination. This practical strategy, operating under ambient and mild conditions, enables late-stage functionalization of bioactive molecules and gram-scale synthesis. A highly reactive S(IV)–F species is identified as the key intermediate.

Abstract

Multi-heteroatom-substituted sulfur centers are increasingly significant in drug discovery, yet their modular synthesis remains challenging. Current strategies employing sulfinylamines, sulfurdiimides, or SOF₄ suffer from inherent limitations. To address this, a general and practical strategy for constructing diverse sulfur centers bearing multiple oxygen or nitrogen substituents is urgently needed. Herein, we report a modular synthesis of such motifs using commercially available DAST-type reagents as underexplored sulfur precursors. This methodology expands the utility of classical fluorination agents as sulfur sources, operates under ambient and mild conditions, and enables rapid access to diverse S(IV) and S(VI) architectures through sequential substitution and further flexible transformations. The practicality of this approach is highlighted by late-stage functionalization of bioactive molecules and gram-scale synthesis. Mechanistic studies support the proposed highly reactive S(IV)-F intermediate.

Increasing the bond dissociation enthalpy (BDE) of potential hydrogen atom transfer (HAT) catalysts has the potential to un-lock a greater substrate scope for radical C-H functionalization reactions. For the archetype N-oxyl catalyst phthalimide-N-oxyl (PINO), tuning the BDEO-H of its precursor N-hydroxyphthalimide (NHPI) by substitution of the the aryl ring has minimal effects, limiting meaningful advances in catalyst development by modifications of PINO. Herein, we demonstrate that inserting a heteroatom between one of the carbonyl groups of PINO and the aryl ring significantly increases the BDEO-H. For example, an N-phenyl moiety, O-atom or S-atom raises the BDEO-H by 6.5, 6.9 and 8.1 kcal/mol, respectively, relative to NHPI – which translates to an increased kHAT of 4, 36.3 and 24.3, respectively. Our studies of these compounds and a panel of analogs thereof highlight three advantages of this strategy: 1) high synthetic accessibility of catalyst candidates; 2) simultaneous optimization across multiple parameters; and 3) effective activity tuning. These new scaffolds are promising for the development of next-generation HAT catalysts and C-H functionalization reactions.

Thanks to chelating ligands and enhanced backdonation, genuine gold(I) difluorocarbenes persistent for hours at −30 °C or even 0 °C have been obtained. In addition to classical Fisher-type electrophilic behavior, these complexes display unprecedented reactivity toward alkenes and 1,3-dienes. Most noticeable is the formation of Au(III) metallacycles as a general, productive, and divergent route to [1+2] and [1+4] cycloadducts.

Abstract

Difluorocarbene is a very powerful synthon in organic chemistry, but its reactivity is very challenging to tame. While a few recent studies have pinpointed the potential of transition metals such as Pd and Cu to stabilize and harness difluorocarbene, known examples are confined to relatively classical transformations. Here we report gold(I) difluorocarbenes persisting for hours at 0 °C thanks to ligand-enhanced backdonation. These complexes exhibit unforeseen reactivity with alkenes and 1,3-dienes. The key intermediates, gold(III) metallacycles, have been spectroscopically and crystallographically characterized. Choosing the ligand at gold and operating conditions (thermal or photochemical) enable to direct C─C coupling to the desired product. This novel gold-mediated two-electron redox pathway was leveraged to prepare difluorocyclopentenes, overcoming the intrinsic challenge of [1+4] cycloaddition between carbenes and 1,3-dienes.

Treatment of 2-aryloxy-1,1-difluorocyclopropanes with Me₂AlCl promotes fluoride abstraction, followed by cyclopropane ring opening, to generate α,β-unsaturated oxocarbenium ions. These cations are trapped with nucleophiles such as arenes and silyl enol ethers to provide functionalized 2-fluoro-1-alkenes. The instability of vinyl cations prevents further fluoride abstraction, resulting in completely selective CF bond activation.

Functionalized monofluoroalkenes (3-arylated and 5-oxygenated 1-aryloxy-2-fluoro-1-alkenes) are synthesized via selective activation of the CF bonds in 2-aryloxy-1,1-difluorocyclopropanes that are readily prepared from aryl vinyl ethers. Treatment of these difluorocyclopropanes with Me₂AlCl promotes fluoride abstraction followed by cyclopropane ring opening to generate α,β-unsaturated oxocarbenium ions. These cations are subsequently trapped with nucleophiles, such as arenes and silyl enol ethers (Friedel–Crafts- and aldol-type reactions), to provide functionalized 2-fluoro-1-alkenes. Because of the instability of vinyl cations, further fluoride abstraction is suppressed, resulting in completely selective CF bond activation.

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A novel reductive approach towards symmetric biaryls has been developed based on Ni/photo-redox catalysis. Employing NEt3 as a cheap and energetically favorable, weak reducing agent in the homo-coupling of conveniently accessible (pseu-do)halides, highly functionalized biaryls were obtained in general high yields. Highlighting the synthetic value of our herein reported method, different potentially interesting compounds and the hepatitis C drug daclatasvir were synthesized.

Synthetic methods that are applicable to a broad range of substrates are sought after, owing to their utility in industrial settings. This minireview describes considerations associated with how chemists define and identify general methods, especially with the emergence of modern analytical, high-throughput, and data science tools in chemistry, and gives the reader an overview of workflows that have been used to expedite this pursuit.

Abstract

The term “generality” has recently been popularized in synthetic chemistry, owing largely to the increasing use of high-throughput technology for producing vast quantities of data and the emergence of data science tools to plan and interpret these experiments. Despite this, the term has not been clearly defined, and there is no standardized approach toward developing a method with a diverse (general) scope. This minireview will examine different emerging strategies toward achieving generality using selected examples and aims to give the reader an overview of modern workflows that have been used to expedite this pursuit.

A modular electrochemical platform is developed to access alkyl functionalization utilizing decarboxylative radical generation. This platform enables the mild late-stage modification of privileged saturated fragments which have seen interest in drug discovery. The conditions are translated to a radiochemical workflow to achieve the synthesis of an ¹⁸F-labeled PARP1 inhibitor with subsequent biodistribution imaging to showcase broad applicability toward radiochemistry.

The incorporation of privileged saturated fragments into pharmaceutically relevant scaffolds has seen increased prevalence in drug discovery. Electrochemistry, a single-electron enabling platform, has demonstrated remarkable synthetic potential, particularly in alkyl functionalizations. However, these two concepts have not yet been fully considered in ¹⁸F-radiochemistry workflows. This work presents the development of a practical late-stage electrochemical platform that utilizes mild conditions, low voltages, and applications toward the installation of rigid alkyl bioisosteres onto relevant drug scaffolds. The utility of this platform is further demonstrated in the electrochemical synthesis of a PARP1 radiotracer and its application in subsequent biodistribution studies.

This review comprehensively illuminates the latest advancements in stabilizing persistent organic radicals using N-heterocyclic carbenes. Understanding the chemical reactivity of these systems is framed by a detailed examination of how their distinct electronic and steric attributes enable radical stabilization and control spin delocalization. The profound implications for redox-active materials, photocatalysis, and electronic devices are highlighted, offering critical insights into advanced material design and fundamental chemical reactivity.

Publication date: October 2025

Source: Journal of Fluorine Chemistry, Volume 287

Author(s): Ahmed Aldulaimi, Shakir Mahmood Saeed, Soumya V Menon, Waam Mohammed Taher, Ruya yilmaz saber, Subhashree Ray, Karthikeyan Jayabalan, Aashna Sinha, Mariem Alwan, Renu Sharma

The synthesis of molecules with emerging fluorinated substituents associating fluoroalkyl group, selenium and another chalcogen (R_F–Se–E–R) has been described. These molecules were easily obtained by using electrophilic fluoroalkylselenolating reagents and thiols, selenols, disulfides, diselenides or ditellurides.

In order to obtain new molecules with specific properties, the design of new fluorinated emerging group is an interesting approach. Herein, the development of new fluorinated motifs is described by associating fluoroalkyl groups with selenium and another chalcogen. Such compounds are obtained by efficient electrophilic fluoralkylselenolations of chalcogen substrates by using two previously described reagents. Thus, molecules bearing R_FSeS, R_FSeSe and R_FSeTe motifs have been obtained with good yields.

The potential of fluorinated mono- and diketones as electrophilic warheads for reversible covalent drugs is described by studying their equilibria reactions with the protected nucleophilic amino acids serine, cysteine and lysine.

Fluorinated diketones (FDKs) are electrophilic moieties holding unique molecular properties that make them potential reversible and multifaceted covalent warheads for drug design. To further explore this potential, the multicomponent equilibrium systems of various fluorinated monoketones (FMKs) and FDKs in the presence of the relevant nucleophilic amino acids serine, cysteine, and lysine are studied. These equilibrium systems are investigated using ¹⁹ F- and ¹³C- NMR spectroscopy, and reveal that for both cysteine and lysine most of the FMKs and FDKs studied may potentially serve as electrophilic warheads for reversible covalent drugs.

Aldehydes are the key building block in organic synthesis due to their high availability and diverse reactivity. However, their intrinsic reducing ability remains underutilized. Herein, we report a ruthenium-catalyzed reductive alkylation of ketones and other nucleophiles using aldehydes as both alkylating agents and reductants. This operationally simple protocol proceeds under neat conditions without external hydrogen sources or stoichiometric reductants. The reaction exhibits broad substrate scope, tolerating both aromatic and aliphatic aldehydes and ketones, as well as functional groups sensitive to conventional reductive conditions (alkenes, esters, halides, benzyloxy groups). The protocol was applied to the synthesis of pharmaceutically relevant scaffolds, including Nabumetone and a derivative of pregnenolone acetate. Mechanistic experiments along with DFT-calculations were conducted to investigate mechanism of this transformation. This study highlights the overlooked potential of aldehydes as dual-purpose reagents in redox transformations.

This work reveals a detailed mechanistic study of the oxidative addition of aryl bromides to a Pd(I) center to generate an isolable Pd(III) species. UV–vis and cryo stopped-flow kinetic studies, including Eyring and Hammett analyses, reveal a rapid oxidative addition step occurring at a Pd(I) center, and a zero-order dependence on the substrate.

Abstract

Herein, we report the first systematic study of the oxidative addition of aryl bromides to a Pd^I center to generate organometallic Pd^III complexes. These isolable Pd^III complexes stabilized by tetradentate macrocyclic pyridinophane ligands exhibit distinct UV–vis and EPR spectroscopic signatures that allowed for the monitoring of their generation in situ. These ligand scaffolds were sterically and electronically tuned using a modular synthetic approach to probe the kinetic properties and activation parameters of the oxidative addition reaction, and a combination of UV–vis and cryo stopped-flow spectroscopic studies reveal a rapid oxidative addition step occurring at a Pd^I center. In addition, these results are in strong agreement with our recent reactivity studies, which demonstrated that mononuclear Pd^I systems are competent catalysts in Kumada cross-coupling reactions, and thus set the stage for an improved understanding of potential catalytic applications for odd-electron Pd systems.

Multicomponent reactions are robust synthetic tools to assamble complex polyheterocycles and other interesting molecular architectures with potential application in medicinal chemistry, including their fluorine-containing analogues. Fluorine atoms placed strategically into bioactive molecules often enhance essential pharmacokinetic parameters like bioavailability, lipophilicity and metabolic resistance. Indeed, various marketed drugs contain fluorine atoms in their structures.

It is well known that fluorine atoms placed strategically into bioactive molecules often enhance essential pharmacokinetic parameters like bioavailability, lipophilicity, and metabolic resistance. In the same way, a relatively broad spectrum of marketed drugs contains one or more fluorine atoms in their structures, usually in the form of fluorine-, difluoromethyl-, trifluoromethyl-, or perfluoroalkyl aromatic moieties, being essential parts of their corresponding pharmacophores. Besides, multicomponent reactions (MCR) are highly convergent one-pot processes in which three or more smartly substituted/functionalized reagents are combined simultaneously, sequentially or consecutively, in the same reactor to assemble complex products (including polyheterocycles) containing most or all atoms from the reagents. Thus, the scope of the present review is to discuss selected MCR-based works since 2009 for the synthesis of bioactive compounds and drugs that contain at least one fluorine atom in their structures, as well as relevant results from in silico, in vitro, and/or in vivo studies against a variety of important target biomolecules, highlighting the role of fluorine-containing moieties.