Tomas Horsten

A robust, automated continuous flow system enables safe, high-yield nitration of furfural to key nitrofuran intermediates using in situ acetyl nitrate generation. Demonstrated on representative essential World Health Organization (WHO) active pharmaceutical ingredients (API), this innovative open-source platform ensures rapid synthesis, enhanced safety, and excellent reproducibility, aligning with modern pharmaceutical standards.

Abstract

Nitrofurfural is a key building block for the synthesis of antimicrobial nitrofurans as active pharmaceutical ingredients. Its synthesis involves the nitration of furfural, a substrate derived from biobased resources. However, furfural has a delicate heteroaromatic backbone. Typical nitrations involve harsh reaction conditions, which often compromise this structure, resulting in poor reproducibility and low yields. Although acetyl nitrate, a mild nitrating agent, is suitable for this task, major deterrents remain. First, its conventional preparation method involves conditions that are not compatible with furfural. Second, significant safety concerns are associated with the unstable and explosive nature of acetyl nitrate. These critical issues are addressed herein. A safe and robust continuous flow platform featuring in situ generation of acetyl nitrate for the nitration of furfural to nitrofurfural is reported. The high level of integration and automation enables remote process operation by a single operator. Key furfural-based pharmaceutical intermediates were synthesized with favorable metrics and high reproducibility. The efficiency of this flow platform is demonstrated using a selection of best-selling nitrofuran pharmaceuticals (nifuroxazide, nifurtimox, nitrofurantoin, and nitrofural), which were obtained with excellent isolated yields in under five minutes.

The synthesis of aryl- and silyl-substituted NHCP-plumbylenes is achieved through metathesis reactions. Based on computational studies, the substituent effect and the potential double bond character in these species are discussed. A formal [2+2] cycloaddition at a P−Pb bond demonstrates the synthetic equivalence to double bonds.

Abstract

This work explores the use of plumbylene-phosphinidenes to address the challenge of isolating P=Pb bonds. Herein, we report the synthesis of three N-heterocyclic carbene phosphinidene (NHCP) substituted chlorotetrylene dimers [(IDipp)PECl]₂ (E=Ge, Sn, Pb; IDipp=C([N-(2,6- ⁱ Pr₂-C₆H₃)CH]₂)). Substituent attachment via salt metathesis (E=Sn, Pb) enables the isolation of NHCP-silyl-substituted stannylene (IDipp)PSn(SiTms₂SiTol₃) as well as NHCP-silyl- and NHCP-aryl-substituted plumbylenes (IDipp)PPb(SiTms₂SiTol₃) and (IDipp)PPb( ^m Ter) ( ^m Ter=2,6-Mes₂C₆H₃, Tms=Trimethylsilyl). Access to these structures not only expands this chemistry to the heaviest of group 14 elements but also provides a deeper understanding of the substituent effect on NHCP-tetrylene bonding. Computational studies demonstrate that both silyl- and aryl-substituted species exhibit partial multiple bond character, with the silyl-substituted species showing higher bond orders and reduced polarization. This is further supported by the short P−E bond lengths observed in their solid-state structures. Finally, the formal [2+2] cycloaddition of diphenylketene to (IDipp)PPb( ^m Ter) provides experimental evidence for the ability of NHCP-plumbylenes to serve as synthetic equivalents of P=Pb double bonds.

Nature Communications, Published online: 28 April 2025; doi:10.1038/s41467-025-59358-1

Photocatalysis has greatly advanced in organic synthesis but still confronts challenges, including light attenuation in reaction media and excessive solvent utilization. Here, the authors present a scalable photo-mechanochemical platform that combines visible-light photocatalysis with Resonant Acoustic Mixing, enabling efficient cross-coupling reactions under solvent-minimised conditions.

We report a convenient and scalable strategy for the synthesis of 7-azaindolines and 7-azaindoles using O-vinylhydroxylamines as ring-annulation reagents. These fused nitrogen-containing heterocycles are prominent in numerous biologically active molecules, including FDA-approved pharmaceuticals. Traditional synthetic approaches to these motifs often rely on costly transition metal catalysts and/or high-temperature conditions, such as those employed in the Larock and Fischer indole syntheses. In our approach, O-vinylhydroxylamines undergo N-arylation with aza-arene N-oxides, triggering a rapid [3,3]-sigmatropic rearrangement. This is followed by re-aromatization and cyclization to deliver 7-azaindolines, which can be readily dehydrated to afford the corresponding 7-azaindoles. The method offers a broad substrate scope, enabling access to a diverse array of highly functionalized derivatives. Moreover, the mild reaction conditions facilitate late-stage functionalization of complex molecules, demonstrating their value in both synthetic and medicinal chemistry.

In this scientific perspective, we intend to provide a coherent framework for the field of magnetocatalysis by highlighting opportunities associated with the use of magnetic fields to activate catalysts. A particular focus will be placed on magnetically induced catalysis , providing an overview on current advances and identifying scientific and technical challenges on the path toward a widespread use of this technology in research and industry.

Abstract

The rapidly growing importance of electrification in the chemical industry opens room for disruptive innovations regarding energy input into catalytic processes. Energy efficiency and dynamics of renewable energy supplies represent important challenges, but the design of catalytic systems to cope with such new frameworks may also stimulate the discovery of new catalyst materials and reaction pathways. In this context, many opportunities arise when catalysts are activated in a rapid, localized, and energy-efficient manner. Among the various concepts to achieve adaptivity in catalysis, magnetic induction heating applied directly at the catalyst or in vicinity of the active site has gained increasing attention recently. In this Scientific Perspective, we provide a coherent framework to the emerging field of catalysis using magnetic fields—and in particular alternating current magnetic fields—to activate catalytic materials and define it as magnetically induced catalysis . Promising approaches and selected examples are described to illustrate the scientific concept and to highlight its broad potential for innovation in catalysis from laboratory to industrial scale.

In this work, we present our efforts to develop a Grignard reagent free, low valent cobalt-catalysed C-H arylation, using high-throughput experimentation (HTE). Although we did not succeed to obtain a protocol with synthetically relevant yields, we believe that this data will be valuable for researchers working in the same domain. Additionally, these data will be useful considering the current trend to develop machine learning methods for predicting or optimizing new transformations. Such efforts frequently face the challenge, that data for training sets mainly consist of positive results. However, a good training set needs to include a significant number of negative results as well. Sharing such data can reduce bias in machine learning models and help expand our understanding of chemical space through more complete and realistic datasets.

Alternating polarity (AP) is a powerful tool for controlling selectivity in olefin hydrofunctionalization, but this use is underdeveloped. Using electrochemical olefin hydrocarboxylation as a model, we highlight how AP controls product selectivity, yield, and material decomposition. It hinders overreduction, limiting dicarboxylation and electrode passivation, and facilitates a unique electrochemical–chemical–chemical (ECC) mechanism.

Abstract

The electrochemical generation of radical anions from feedstock olefins offers a selective and efficient route for synthesizing commodity chemicals and pharmaceutical precursors via hydrofunctionalization. Traditional methods for electrochemical olefin hydrofunctionalization, for example, hydrocarboxylation, rely on anion intermediates and follow an electrochemical–chemical–electrochemical–chemical (ECEC) mechanism involving olefin reduction, carboxylation, further reduction, and protonation. Enhancing terminal carboxylate selectivity often requires a proton source, reducing functional group tolerance and favoring proton reduction over olefin reduction. Alternating polarity, a nascent technique in organic electrochemistry, can improve product selectivity by influencing electron transfer rates and electrode surface species. Herein, we report the use of alternating polarity to selectively generate radical anions from styrene derivatives, using electrochemical hydrocarboxylation as a model. This approach shifts the mechanism to an electrochemical–chemical–chemical (ECC) pathway, where the final step involves hydrogen atom transfer. We showcase how alternating polarity modulates product selectivity, yield, and material decomposition, offering new insights into how alternating polarity can advance olefin functionalization by enabling more controlled and selective reaction pathways.

A scalable electrochemical strategy for reduction of various aryl alkenes/alkynes to saturated carbon was achieved. The protocol was also applied to dehalogenation of structural versatile aryl/alkyl halides. This strategy shows good functional group compatibility to gain the desired products in good yields under mild reaction condition and air atmosphere with simple undivided electrolysis cell.

Abstract

A facile and efficient electrochemical strategy for reduction of various aryl alkenes/alkynes to aryl alkyl derivatives was achieved. The protocol was also suitable to dehalogenation of structural versatile aryl/alkyl halides. This strategy has good functional group compatibility to gain the desired products in good yields under mild reaction condition and air atmosphere with simple undivided electrolysis cell. The preliminary study of the reaction mechanism was carried out. Gram-scale experiment exhibited the potential application of this method in practical synthesis.

Abstract

A photoinduced energy transfer strategy has been developed for the direct 1,2-thiocyanato-imination of alkenes using N-SCN reagents. The methodology facilitates the synthesis of β-aminothiocyanates through N−S bond cleavage, with over 30 examples exhibiting yields up to 88%. Mechanistic studies reveal a radical pathway involving the generation of thiocyanate and iminyl radical species. The resulting β-aminothiocyanate serves as valuable building blocks for diverse transformations, particularly in the construction of SCN-containing bioactive molecules with potential pharmaceutical applications.

Triphenylphosphine-free Rh catalysts are the preferred catalyst type for the regioselective hydroformylation of methyl 4-chlorocinnamate to the pharmaceutically interesting racemic β-aldehyde. High regioselectivities of 88–93 % to the β-aldehyde were obtained with various phosphine ligand-free rhodium complexes. In contrast, adding triphenylphosphine as common phosphine ligand shifts the regioselectivity to the undesired α-aldehyde.

Abstract

Hydroformylation of α,β-unsaturated esters is an atom-economical route towards aldehydes as precursors for pharmaceuticals. In this work, regioselective hydroformylation of an α,β-unsaturated ester to the β-aldehyde was initially re-evaluated using a commercial Rh catalyst sample named “[HRh(PPh₃)₄]” due to reported high selectivity for the β-aldehyde with this type of catalyst. However, while such high selectivity was achieved, subsequent investigation of this sample by high-pressure NMR and in situ IR spectroscopy under process conditions revealed a behavior like a phosphine-free system, indicating that the sample is decomposed and may be present as rhodium carbonyl clusters. This hypothesis has been supported by hydroformylation experiments with and without phosphine ligands. While a strong decrease in regioselectivity to the β-aldehyde was observed in the presence of triphenylphosphine as added ligand, phosphine-free rhodium complexes led to high regioselectivities. In detail, the hydroformylation showed high regioselectivity (91 %) and overall selectivity to the β-aldehyde (70–77 %) with [Rh₆(CO)₁₆] as well as [Rh(acac)(CO)₂] as ligand-free rhodium complexes. With further unmodified, phosphine-free rhodium compounds as catalysts, again high regioselectivities (90–93 %) towards the β-aldehyde were obtained. Thus, our results indicate that non-modified triphenylphosphine-free Rh catalysts are efficient catalysts for regioselective hydroformylation of β-aryl-substituted α,β-unsaturated carboxylates to the β-aldehyde.

An electrochemical three-component synthesis of alkyl alkenesulfonates from cinnamic acids, SO₂, and alkyl alcohols is reported. This metal-free process employs inexpensive and readily available graphite electrodes in combination with easy-to-use stock solutions of SO₂ and enables a straightforward decarboxylative preparation of styrene sulfonates via a pseudo-Kolbe type pathway.

A novel, electrochemical three-component reaction for the synthesis of alkyl alkenesulfonates from cinnamic acids, SO₂, and alkyl alcohols is reported. This metal-free process employs inexpensive and readily available graphite electrodes in combination with easy-to-use stock solutions of SO₂ and enables a straightforward construction of the styrene sulfonate scaffold via a decarboxylative transformation. Mechanistic studies indicate a pseudo-Kolbe type reaction. This novel reaction pathway enables a regioselective synthesis of alkenesulfonates from substituted cinnamic acids without double-bond translocation. Gram-scale and anolyte reusability experiments demonstrate the applicability of this process for the construction of alkenesulfonates from cinnamic acids as potential biogenic feedstock.

Science, Volume 387, Issue 6738, Page 1108-1114, March 2025.

A seminal example of aryl silicon nucleophiles in Bi catalysis is reported, in the context of the synthesis of aromatic fluorinated thiosulfones. The protocol is compatible with a wide range of anionic and neutral Ar-Si compounds, including heterocycles. Stoichiometric investigations of individual organometallic steps provide strong evidence supporting a Bi-redox-neutral catalytic cycle.

Abstract

We present a catalytic protocol utilizing bismuth for the synthesis of aromatic fluorinated thiosulfones, showcasing a seminal example of aryl silicon nucleophiles in Bi catalysis. This catalytic process is enabled by a series of Bi-based organometallic transformations, including an unprecedented transmetalation of aryl silicates to Bi(III) complexes and the formal migratory insertion of sulfur dioxide (SO₂) into the Bi-C bond. The protocol is compatible with a wide range of anionic and neutral Ar-Si compounds, including heterocycles. Stoichiometric investigations of individual organometallic steps provide strong evidence supporting a Bi-redox-neutral catalytic cycle.