Marnix van der Kolk

Nature, Published online: 06 August 2025; doi:10.1038/s41586-025-09335-x

Lithium has an essential role in the brain and is deficient early in Alzheimer’s disease, which can be recapitulated in mice and treated with a novel lithium salt that restores the physiological level.

Despite the abundance of oxygen-containing molecules, no unified approach exists that can activate various oxidation states of oxygenated functional groups for deoxygnenative functionalization. Here, we disclose a tandem, one-pot hydrosilylation–electroreduction sequence that enables the conversion of alcohols, aldehydes, ketones, and esters into nucleophilic reagents widely used in cross-coupling chemistry.

Abstract

Oxygen-containing functional groups are prevalent motifs in natural products and feedstock chemicals, but direct methods for their deoxygenative transformation remain rare due to the difficult cleavage of the strong C–O bond. Here, we develop a general activation strategy that employs hydrosilanes as activating reagents for alcohols, carbonyls, and esters to afford a common silyl ether intermediate. Electrochemical reduction of the in situ generated silyl ether results in C–O cleavage to afford a carbanion, which reacts with a number of electrophiles for the construction of C–Si, C–B, C–Ge, and C–Sn bonds.

A milder photoelectrochemical method is presented for obtaining a wide range of α-fluorosulfenyl derivatives from readily available thiol and diazo compounds. Several mechanistic studies reveal the synergistic role of photochemistry and electrochemistry in generating carbene radical anion at the cathode.

α-Fluorosulfenyl compounds are privileged building blocks found in pharmaceuticals and agrochemicals. While the geminal difunctionalization of diazo compounds with two different nucleophiles under mild and sustainable conditions can be envisioned as a versatile method for constructing α-fluorosulfinyl molecules, it remains a significant unmet challenge. Herein, geminal α,α-difunctionalization of diazo compounds by merging sustainable photo- and electrocatalysis is presented. A wide range of α-fluorosulfinyl products are synthesized using commercial ionic liquid as a fluorine source with moderate to good yields and excellent selectivities. Several experiments are performed to detail the reaction mechanism and elucidate the cooperativity of photo- and electrocatalysis in facilitating the reaction under milder, safe, and green conditions.

Acridinium salts are effective organic photoredox catalysts with strong oxidizing properties, but their potential as photoreductants in photocatalysis is underexplored. This study investigates their use for the reductive activation of iodine(III) reagent with monofluoroacetoxy ligands, enabling the synthesis of oxindoles and related N-heterocycles containing monofluoromethyl groups from alkenyl N-arylamides.

Acridinium salts are well-known and highly effective organic photoredox catalysts, particularly recognized for their strong oxidizing properties. While they are widely used as photo-oxidants, their potential as photoreductants, formed easily through interactions with electron donors, has been largely overlooked and underexplored in photocatalysis. In this study, the application of an acridinium salt as a photocatalyst for the reductive activation of iodine(III) reagent containing monofluoroacetoxy ligands is described. This process allows for the synthesis of oxindoles and related N-heterocycles with monofluoromethyl groups, starting from alkenyl N-arylamides. Detailed mechanistic studies are conducted to gain insight into the in situ formation of the active acridine radical species, catalyst species interconversion, and the photocatalytic mechanism underlying the monofluoromethyl radical cascade reaction of alkenyl N-arylamides. A wide range of mechanistic tools is employed, including radical trapping experiments, UV–Vis absorption spectroscopy, time-resolved photoluminescence quenching experiments, electron paramagnetic resonance spectroscopy, and density functional theory calculations. The synthetic utility of this protocol is demonstrated through a substrate scope study, which highlights the efficient access to oxindoles and other polycyclic heterocycles featuring monofluoromethyl units which are widely recognized for their biological significance.

We report stable and isolable difluoromethylene transition metal complexes, synthesized by reaction of free difluorocarbene with organogold(I) precursors. Difluorocarbene insertion reactions occurs with alkyl- or aryl-gold(I) complexes, whereas the difluorocarbene cycloaddition reaction occurs with alkynylgold(I) complex.

Abstract

The gem-difluoromethylene functional group is an important motif in medicinal chemistry, and development of new fluoroalkyl-metal systems has been crucial to enable new syntheses of gem-difluoromethylenes. However, well-defined and isolable examples of either nucleophilic RCF₂M or difluorocyclopropenyl transition metal complexes are rare. The Au(I) platform has been useful for the synthesis of isolable transition-metal complexes bearing reactive ligands. Herein we utilize reactions of difluorocarbene with organogold(I) complexes, analogous to reactions of difluorocarbene with organic substrates, to access novel examples of gem-difluoromethylene organometallics. First, difluorocarbene insertion into the R─Au(I) bond of organogold(I) species with free difluorocarbene was demonstrated for the first time, forming alkyl-CF₂-Au(I) and aryl-CF₂-Au(I) species. Second, via a difluorocarbene cycloaddition reaction we isolate for the first time a κ¹-difluorocyclopropenyl-transition metal complex, formed by reaction of alkynylAu(I) complex with free difluorocarbene. Subsequent study of these reaction systems by density functional theory calculations facilitated study of the difluorocarbene insertion reactions, and a comparison of difluorocarbene insertion and cycloaddition pathways in the reaction of difluorocarbene and alkynylAu(I).

The introduction of diverse functionalities to omnipresent aliphatic C–H bonds is a challenge of notable value in catalysis. Herein, we report a universal platform using readily prepared 9-arylacridine catalysts−a class of neutral, N-centered photocatalysts−that engage aliphatic C–H bonds under mild conditions. This strategy enables the efficient generation of alkyl radicals, allowing various functionalizations of C–H bonds ranging from activated substrates to unativated, gaseous ethane. The platform features broad substrate scope, scalability, and compatibility with transition metal catalysis as well as multicomponent reactions. Its utility is demonstrated in streamlined synthesis of pharmaceutical synthons and late-stage functionalization of bioactive molecules. Detailed mechanistic studies highlight the crucial role of ortho-substituents (e.g. Cl atoms) on the 9-aryl moiety of catalysts, providing a rational basis for current and future catalyst design.

Nature Chemistry, Published online: 04 August 2025; doi:10.1038/s41557-025-01888-8

Primary aliphatic amines are abundant building blocks but underutilized as alkyl sources in C–C bond formation. Now it has been shown that integrating nitrogen-atom deletion into the aza-Michael reaction redirects the classical pathway from (sp3)C–N bond formation to Giese-type (sp3)C–C(sp3) bond construction.

Crowned! Herein we describe a complete series of crown ether coordinated alkali metal phosphides from lithium to cesium, including solid state structures, detailed investigations in solution and extensive quantum chemical investigation of the bonding situation.

Abstract

Herein we present the synthesis and full characterization of the previously unpresented lithium diphenyl phosphides Li(15-crown-5)PPh₂ (1^Li ) and Li(12-crown-4)PPh₂ (2^Li ) as well as the heavy homologues Rb(18-crown-6)PPh₂ (1^Rb ) and Cs(18-crown-6)PPh₂ (1^Cs ). We thus complete the series of crown ether coordinated alkali metal diphenyl phosphides and reveal that the structural diversity increases upon descending the group. Including the previously reported Na and K derivatives, we performed a detailed study of the title compounds in solution that strongly indicated all of them are monomers with an alkali metal phosphide AM–P interaction. We further investigated the influence of the phosphorus-bound substituents on the bond between the Cs(18-crown-6) and the phosphide fragment. For this purpose, we synthesized and characterized two new cesium phosphides, alkyl-aryl Cs(18-crown-6)P ^t BuPh (4^Cs ) and bis-alkyl Cs(18-crown-6)P ^t Bu₂ (5^Cs ). We observed here that the heavy alkali metals Rb and Cs favor coordination via π-arene interactions over the P donor dative interactions. Finally, we used state-of-the-art quantum chemical methods to analyze the bonding situation in the title series of compounds.

Previous reports on accessing trifluoromethoxylated compounds have been limited by utilizing toxic/volatile/expensive precursors that required multistep preparation of trifluoromethylating reagents. Herein, this study proposes an efficient nucleophilic trifluoromethoxylation protocol via commercially available, inexpensive, bench-stable and solid reagent, carbonyl diimidazole and AgF as the fluoride source through a novel mechanism not involving AgOCF₃ as an intermediate.

An operationally simple nucleophilic trifluoromethoxylation protocol via an inexpensive, commercially available and bench stable reagent, carbonyl diimidazole and AgF is presented. Mechanistic studies are performed to reveal that this method does not proceed through the conventional trifluoromethoxide anion pathway that generates toxic difluorophosgene as an intermediate.

This manuscript describes a synthetic approach to a wide range of unsymmetrical alkylphosphorus(V) compounds using imidazolium phosphonites as bifunctional reagents. This protocol allows the introduction of primary, secondary and tertiary alkyl substituents and various heteroatom substituents onto the P(V) scaffold. In addition, a phosphorus radical species generated by the single electron reduction of alkyl imidazolium-P(V) enabled P─C bond formation by radical addition to alkenes.

Abstract

Here, we report a synthetic approach for a wide range of unsymmetrical alkylphosphorus(V) compounds, alkyl-P(O)XY (X ≠ Y) using imidazolium phosphonites as bifunctional reagents. This protocol consists of two sequences, C(sp³)─P bond formation via an organic photoredox-catalyzed decarboxylative alkylation of imidazolium phosphonites with aliphatic carboxylic acid derivatives and P─X (X═O, N, F, and S) bond formation via the S_NP(V) reaction. In this process, the imidazolium group facilitates 1) radical addition to the phosphonite reagent by stabilizing the resulting phosphoranyl radical intermediate and 2) the S_NP(V) reaction as a good leaving group. This protocol allows the introduction of primary, secondary and tertiary alkyl substituents and various heteroatom substituents onto P(V) scaffolds.

Cooperative N-heterocyclic carbene and photoredox catalysis for C─H benzoylation and esterification of allenes is presented. This reaction proceeds through the cross-coupling of in situ generated ketyl and allyl radicals.

Abstract

This study demonstrates the use of cooperative photoredox and N-heterocyclic carbene (NHC) catalysis for sp² C─H acylation of allenes. The cascade comprises oxidative generation of an allene radical cation from an allene, its nucleophilic trapping to the corresponding allyl radical and highly regioselective cross coupling by a concomitantly reductively generated NHC-derived ketyl type radical. Ionic fragmentation of both the NHC and nucleophile ultimately yields the desired substituted allene. The organic photocatalyst, 4CzIPN, is highly effective in promoting both oxidative and reductive electron transfer steps. Tri- and tetra-substituted allenes can be obtained in good yields through such a cascade. Mechanistic studies—including radical trapping, acylazolium reactions, and Stern–Volmer quenching—support the proposed mechanism. Moreover, follow-up chemistry is conducted to demonstrate the synthetic value of the cascade products.

Synthesis
DOI: 10.1055/a-2637-3568

Emerging as the basic structural units in a variety of bioactive molecules, developing straightforward and efficient methods for synthesizing benzylic fluorinated compounds is of considerable significance. Herein, an electrocatalytic strategy utilizing sulfur hexafluoride (SF6) as a fluorinating reagent to transform benzylic alcohols into benzyl fluorides has been developed under mild conditions. This reaction is compatible with several substrate backbones and avoids the excessive usage of chemical reductants, which provides new routes for the efficient utilization and degradation of SF6, the potent greenhouse gas.
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