Marnix van der Kolk

Given the significant prevalence of N-heterocycles in small-molecule pharmaceuticals, the selective incorporation of a difluoromethyl (−CF2H) motif and the creation of a new functional group within the same molecular framework are of paramount importance in drug discovery and development. However, such integrated approaches remain underexplored, presumably due to the lack of efficient synthetic methods. In the present research, we introduce a new platform and broadly applicable technique for the difluoromethylation of various N-heterocyclic substrates using low-cost and commercially available bromo(difluoro)acetic acid in the presence of K2CO3 at room temperature to produce >70 desired complex Het−NCF2H products featuring either imine and/or ketone functional group, which were hitherto impossible to produce. Depending on the type of N-heterocycle, this advance also permits the inclusion of two CF2H units. Crucial to success is the more nucleophilicity and less steric hindrance on the nitrogen atom of the heteroarene ring that enables N-difluoromethylative dearomatization of N-heterocycles. Overall, this unique transformation was transition metal-free, practical, scalable (>50 grams), tolerant to diverse reactive functional groups with excellent chemoselectivity, adaptable to diversities of challenging N-heteroaromatic ring systems, and could be used for the late-stage diversification of 18 commercial drug molecules. Mechanistic investigation revealed the formation of N-difluoromethylquinolinium salt as a key intermediate, which occurs via nucleophilic substitution followed by decarboxylation with bromo(difluoro)acetic acid. Ultimately, we have also unveiled a prominent synthetic application for rapid hydrodefluorinative reduction in a single step to access complex N-methylated Fsp3-enriched motif. This cost-effective strategy encompasses a full package of medicinally important functionalities (heterocycle, −NCF2H, and imine/keto), making them highly valuable in the preparation of chemical libraries and effective drugs.

Nature Chemistry, Published online: 20 February 2025; doi:10.1038/s41557-024-01730-7

Catalytic methods to introduce fluorine into the backbone of small-ring heterocycles are challenging due to the problems of strain-induced ring cleavage and defluorination. Now, a copper catalyst mediates insertion of an in situ-generated difluorocarbene into oxygen heterocycles, affording ring-expanded fluorinated pharmacophores. Experimental and computational studies provide insights into the mechanism.

Nature Chemistry, Published online: 20 February 2025; doi:10.1038/s41557-025-01748-5

On-surface synthesis of two-dimensional polymers is a useful strategy for designing the lattice, orbital and spin symmetries of materials, but controlling their layer stacking remains challenging. Now, a method to synthesize bilayer two-dimensional covalent organic frameworks at a liquid–substrate interface through monomer condensation has been developed; large-area moiré superlattices emerge from the twisted bilayer stacking.

Nature, Published online: 18 February 2025; doi:10.1038/d41586-025-00454-z

Interest in psychedelic substances as medicines is rising. Identifying the neural circuits that mediate the benefits of psychedelics could pave the way for long-lasting anxiety treatments without the short-term sensory disturbances.

A mechanochemical Horner-Wadsworth-Emmons reaction enabled the formation of monofluoroalkenes with yields up to 99 %. The solid-state reaction condition allowed the formation of a broad scope of trisubstituted and tetrasubstituted fluorinated alkenes (48 examples) with the use of a weak base and a short reaction time from aldehydes of ketones. Moreover, the reaction conditions proved to be broadly applicable to various fluorophosphonoacetates, providing access to valuable fluorinated compounds.

Abstract

A solvent-free synthesis of valuable monofluoroalkenes was developed under ball-milling agitation. The use of 1.0 equivalent of carbonyl substrates and 1.1 equivalent of fluorophosphonoacetate derivatives with a weak inorganic base enabled the formation of the desired products after 30 min of reaction under sustainable conditions with minimized synthetic waste. No sequential addition of base, fluorophosphonate, and carbonyl substrates was needed, and the desired products were obtained with high purity only after a simple filtration. The protocol showed general efficiency and tolerance to a large panel of carbonyl substrates including aldehydes and ketones, as well as fluorophosphonoacetate derivatives with moderate stereoselectivities and yields ranging from 21 % to 99 % (48 examples).

Publication date: February 2025

Source: Journal of Fluorine Chemistry, Volume 282

Author(s): Karolina Paszek, Henryk Koroniak, Katarzyna Koroniak–Szejn

Carbon dioxide, a primary driver of global warming, offers a promising feedstock for valuable chemical synthesis. Nonetheless, the reliance on highly pressurized canisters and specialized equipment limits its practical application in fine chemical synthesis. This study explores the innovative use of sodium bicarbonate (NaHCO3) as a safe, solid on-demand source of CO2 under mechanochemical conditions to perform carboxylation reactions. In one example, we report the mechanochemical synthesis of cyclic carbamate, enabling more practical and sustainable conditions for the synthesis of these compounds respect to solution-based precedents. In a second application, we disclose the synthesis of organic carbonates from bicarbonate, which has no precedents in solution. We further showcase the potential of our approach in the pharmaceutical industry by demonstrating the solvent-minimized synthesis of pharmaceutically relevant molecules and introducing a novel 13C-labeling strategy utilizing NaH13CO3.

Recent progress in electrochemical alkene difunctionalization is covered, which is organized according to the alkene difunctionalization types and the radical category, as well as is divided to three sections, including (1) dicarbofunctionalization, (2) hetero-carbofunctionalization and (3) diheterofunctionalization. Selected impressive examples showcase the importance of the electrochemical difunctionalization in academia and industry.

Abstract

Owing to their wide utilizations in synthesis and their products prevalence in numerous natural products, pharmaceuticals and functional materials, the alkene difunctionalization methods for the selective transformations of the olefins are important and have attracted much attention form the synthetic chemists. Among them, the electrochemical alkene difunctionalization reaction is particularly promising and has becoming a potent and sustainable tool for the selective transformations of alkenes into vicinal difunctionalized structures in organic synthesis through simultaneous incorporation of two functional groups. Herein, we summarize recent progress in the electrochemical alkene difunctionalization reactions according to the alkene difunctionalization types as well as the category of the radicals over the past five years. By selecting the remarkable synthetic examples, we have elaborately discussed the substrate scope and the mechanisms for the electrochemical olefin difunctionalization reaction.

Nature, Published online: 03 February 2025; doi:10.1038/d41586-025-00355-1

The anti-ageing effect was even greater when combined with vitamin D and exercise.

Red light driven catalysis presents a promising alternative to conventional blue light photocatalysis, offeringenhanced light penetration, functional group tolerance, and energy efficiency. However, its widespread application remains underdeveloped, partly due to the lack of readily accessible photocatalysts. [Ru(bpy)3]2+ is one of the most frequently used blue light photocatalysts. Here, we demonstrate the application of [Ru(bpy)₃]²⁺ in various red light-induced transformations and investigate the underlying photophysical properties, revealing a direct singlet-to-triplet excitation under red light irradiation. Our findings suggest that red light driven photocatalysis could be possible with many other photocatalysts not considered for this purpose until now.

Nature, Published online: 27 January 2025; doi:10.1038/d41586-025-00223-y

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