Marnix van der Kolk

The remodeling of arenes is a critical frontier in molecular design, with far-reaching implications for drug discovery, late-stage functionalization, and chemical space exploration. This holds particularly true for N-heteroarenes, which are key units of many bioactive molecules. However, their inherent stability severely limits the convenience and the generality of chemical remodeling methods. Here, we introduce Molecular Reprogramming as a general and divergent strategy for the one-pot conversion of pyridines into diverse N-heterocycles, either homopyrroles, pyrroles, pyrrolidines or tropanes. The key step of the sequence is a photocatalytic di-π-methane rearrangement, which was unlocked thanks to the rational installation of a π- handle onto 1,2-dihydropyridine intermediates. This original activation avoids the limitations of UV- and thermal protocols, which are incompatible with present reactivity, and provides multipotent chemical entities, namely syn-π-homopyrroles, that could easily undergo divergent core modification. The logic offers a versatile foundation for skeletal contraction/expansion strategies and suggests new opportunities for visible-light-driven molecular editing. Highly decorated products become readily accessible, and challenging species, including several organometallic reagents, are smoothly tolerated. The one-pot approach targets a broad chemical space, which includes the late- stage derivatization of FDA-approved drugs, minimizing time consumption and wastes. The sequential process affords privileged three-dimensional N-heterocycles, including many bioactive compounds, from a ubiquitous family of aromatic precursors.

In a recent manuscript, Imam Mahdi in World Religions: A Universal Saviour from the Lineage of Fatima, I revisit this eschatological figure through a comparative and analytically grounded framework.

We report the convenient synthesis of Ni(DQ)2 (DQ=duroquinone) from readily available Ni(II) and Ni(0) precursors, guided by DFT calculations. By virtue of its π-accepting homoleptic ligand environment, Ni(DQ)2 undergoes facile ligand exchange with phosphine, bis-nitrogen, and diene ligands and thus represents a convenient Ni(0) source in synthetic organometallic chemistry. As a precatalyst, Ni(DQ)2 is found be a competent air-stable precursor for emerging methodology where Ni(COD)(DQ) is ineffective (COD=1,5-cyclooctadiene).

Publication date: November 2025

Source: Journal of Fluorine Chemistry, Volume 288

Author(s): Martin Möbs, Jan Moritz, Thomas Schwarze, Michael Pittroff, Florian Kraus

The bread and butter of drug discovery in the pharmaceutical industry is the synthesis of complex scaffolds, including chiral heterocyclic motifs. However, general access remains a long-standing goal and challenge. Despite the high demand, the synthesis of some entities is limited by step-intensive and costly routes. To address these challenges, we herein present the development of a highly selective ruthenium-NHC catalyst that enables direct access to a broad range of chiral 6,5-heterocycles from readily available arenes.

The nature of ‘improper’ hydrogen bonds is explored in FnC─H⋯X systems, such as RCF₂H interaction with chloride and water. It is noted that increased fluorination decreases the positive charge density on H but increases it on C, thus these interactions are dominated by electrostatic attraction to C over H. Such interactions map experimental blue and red shift IR phenomenon.

Abstract

The RCH₂F and RCHF₂ groups are substituents of interest in medicinal and agrochemicals products. They have a polar aspect relative to the methyl (RCH₃) or trifluoromethyl (RCF₃) groups which results in a lowering of Log P's (water affinity). Here we use a computational approach to explore the nature of the interaction between RCH₂F and RCHF₂ in methanes and ethanes with chloride ion (and water), as a hydrogen bonding acceptor. A key observation is that the hydrogen atoms geminal to the fluorine(s) become less positively charged with increasing fluorination, a trend anticipated to weaken, not strengthen, their hydrogen bonding interactions. However this study demonstrates a dominating role for the electrostatic interaction of the acceptor with the CF carbons and profiles a shift in negative charge density from hydrogen to the carbon and fluorine(s) as chloride ion (or water) approach. The common occurrence of blue shifts (shortening C─H length) in these ‘improper’ or ‘non-classical’ hydrogen bonds is also explored and is correlated with the electrostatic interactions between the acceptor and the carbon atoms. These observations are extended to C₃─C₆ alicyclic rings containing these motifs and predict particularly strong interactions energies between chloride ion and specifically designed organo-fluoro alicycles.

A rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropenyl esters or ketones has been achieved, affording the disubstituted cis-gem-difluorocyclopropanes with high enantio- and diastereoselectivities (up to 99% ee and >20:1 dr). Furthermore, the hydrogenation proceeds smoothly at gram scale without erosion of activity and enantioselectivity. The chiral gem-difluorocyclopropane products could be transformed into chiral building blocks and bioactive molecule.

A rhodium-catalyzed asymmetric hydrogenation of gem-difluorocyclopropenyl esters or ketones has been achieved, affording the disubstituted cis-gem-difluorocyclopropanes with high enantio- and diastereoselectivities (up to 99% ee and >20:1 dr). Furthermore, the hydrogenation proceeds smoothly at gram scale without erosion of activity and enantioselectivity. The chiral gem-difluorocyclopropane products could be transformed into chiral building blocks and bioactive molecule.

A practical and scalable protocol for the deoxyfluorination of hydroxyalkyl-substituted aryl- and alkenylboronates was developed. The optimized conditions (combining Deoxo-Fluor with TEA·3HF as the reagents and substrate pre-conversion to trifluoroborate salts) enabled efficient transformation across a wide range of (homo)benzylic and allylic alcohols, while tolerating protected carboxyl and amino groups. The resulting fluorinated boronates performed well as versatile building blocks in oxidation and Suzuki cross-coupling reactions. Furthermore, a telescoped one-pot strategy allowed direct utiliza-tion of crude fluorinated intermediates, enabling access to complex molecular frameworks containing alcohol, carbonyl, and ester functionalities, typically intolerant to the late-stage fluorination conditions. This methodology offers a general and efficient route for the incorporation of monofluorinated aliphatic fragments into structures of relevance for medicinal chem-istry and material science.

This review highlights recent synthetic strategies for introducing fluorine groups (mono-, di-, and trifluoromethylation) into 11 major azole classes, identifying research gaps to inform future innovations in materials science, medicinal chemistry, and biomedical research.

Incorporating fluorine into azoles is not only a common practice but also an essential tactic in medicinal chemistry, due to their ability to fine-tune a molecule's physicochemical, pharmacokinetic, and pharmacodynamic profiles. The strategic introduction of fluorine into nitrogen-containing five-membered heterocycles can significantly enhance metabolic stability, membrane permeability, and binding affinity—key factors in modern drug development. This review provides an up-to-date overview of key synthetic strategies for monofluorination, difluoromethylation, and trifluoromethylation across 11 prominent azoles: 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles, pyrazoles, imidazoles, pyrroles, isoxazoles, oxazoles, thiazoles, thiadiazoles, and isothiazoles. This review aims to identify current limitations in the field and delineate existing research gaps that present further opportunities for innovation in these domains, which are essential for propelling pharmaceutical and biomedical research. By integrating new synthetic advancements and diverse strategies to access them, this review aims to serve as both a practical guide and a source of inspiration for chemists exploring the next generation of fluorinated azole pharmaceuticals.

A synthetic protocol for polypeptides 6–58 residue long, using recyclable greener solvent mixture (Anisole/DMSO) was developed and compared to traditional SPPS methods and to state-of-the-art synthesizers.

Abstract

The high cost and the large amount of toxic waste generated during peptide production overshadow the current technology, requiring the reduction of excess reagents and the replacement of the solvents used. Advances have been made to replace N,N-Dimethylformamide with moderate success. By exploring the solvent parameter space, we have selected several mixtures, tested their swelling ability, amino acid solubility, coupling efficiency, and Fmoc-cleaving capacity, and found the Anisole/DMSO (17:3) mixture to be ideal for coupling. By adjusting the flow parameters, racemization was reduced to < 2% in the case of His, and < 1% for Cys. Several mixtures were screened for optimal Fmoc-cleavage, selected to cover the solvent parameter space uniformly. To test the selected solvent mixtures for aspartimide formation, and Fmoc-cleavage efficiency, both Scorpion Toxin II (VKDGYI) and JR10-mer (WFTTLISTIM) challenging sequences were synthesized. Fmoc-cleavage parameter optimization was performed using a machine learning algorithm (Bayesian Optimization) to reduce aspartimide formation and maximize Fmoc-deprotection. With the final parameters obtained, the Aib-ACP (10-mer), the glucagon like peptide 1 (GLP-1, 30-mer) and bovine pancreatic trypsin inhibitor (BPTI, 58-mer) polypeptides were synthesized with high efficiency and synthetic speed (12 min/cycle). The method is ideal for high temperature synthetic approaches and outperforms current state-of-the-art synthesizers.

An efficient direct deoxygenation coupling strategy for the deoxygenation cross-coupling of alkyl alcohols with various aryl electrophiles has been developed. The substrate alcohols require no preliminary activation, and the reaction occurs in a single step, representing the first direct deoxygenation arylation of non-activated alkyl alcohols. The reaction is catalyzed under mild conditions, and all reagents utilized are commercially available, inexpensive, and readily accessible.

Abstract

The formation of carbon–carbon bonds constitutes the most critical fundamental reaction in organic synthesis. Although synthetic chemists have achieved significant advancements in the cross-coupling of stable C(sp³) substrates, such as aliphatic carboxylic acids and alkyl halides, cost-effective, accessible, and versatile sources of alkyl groups, specifically alcohols, remain underutilized. The direct deoxygenation of alcohols under mild circumstances presents a significant challenge in organic synthesis, primarily due to the absence of an efficient mechanism for the direct activation of C─O bonds. Consequently, there is an imperative necessity for chemists to devise a multifaceted approach for the cross-coupling of alcohols. This study aims to utilize neutral diphenylboron radicals as hydroxyl activation agents to directly activate the carbon–oxygen bonds of prevalent alcohols, thereby generating alkyl radicals, which are subsequently involved in nickel-catalyzed arylation processes. Both free alcohols and aryl bromides, which are easily accessible compounds, can serve as coupling partners directly without requiring pre-functionalization. The direct arylation process of alcohols exhibits a broad substrate scope, as demonstrated by the subsequent arylation of several structurally intricate natural compounds and pharmaceuticals.

β-hydroxy ketones represent a class of compounds with broad applications in pharmaceuticals and bioactive molecules. However, the synthesis of these compounds often encounters various challenges. Herein, an electrochemical method is reported that utilizes methanol as a C1 source, enabling the α-hydroxymethylation of a series of aryl ketones under oxidant-free conditions. This approach achieves high yields and exhibits broad substrate compatibility.

β-hydroxy ketones represent a class of compounds with broad applications in pharmaceuticals and bioactive molecules. However, the synthesis of these compounds often encounters various challenges. Herein, an electrochemical method is reported that utilizes methanol as a C1 source, enabling the α-hydroxymethylation of a series of aryl ketones under oxidant-free conditions for constructing β-hydroxy ketones. This approach achieves high yields and exhibits broad substrate compatibility. Mechanistic investigations indicate that the reaction proceeds via a radical pathway, rather than through conventional methanol oxidation to formaldehyde.

We report a safe and scalable flow-based strategy for the on-demand generation of NCF₂R anions using a packed-bed microreactor containing CsF. This protocol enables the late-stage installation of the CF₂ group under mild conditions leveraging three points of diversification, allowing efficient access to a broad range of NCF₂R scaffolds.

Abstract

The α,α-difluoromethylene amine (NCF₂R) motif represents a useful functionality in medicinal chemistry, yet practical and modular methods to access this class of compounds are lacking. Here, we report a safe and scalable flow-based strategy for the on-demand generation of NCF₂R anions using a packed-bed microreactor containing caesium fluoride. This protocol enables the late-stage installation of the CF₂ group under mild conditions, avoiding the use of hazardous fluorinating agents and minimizing fluorinated waste. This fully modular strategy features three points of diversification (carboxylic acid, sulfonamide, and electrophile), allowing efficient access to a broad range of α,α-difluoromethylene amines. The method tolerates a variety of functional groups, supports late-stage functionalization of pharmaceutically relevant scaffolds, and is compatible with downstream cross-coupling reactions, demonstrating the robustness of the reaction protocol. This work provides a versatile platform for the streamlined incorporation of NCF₂ motifs, expanding the range of synthetic strategies available in medicinal and fluorine chemistry.