Tomas Horsten

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well-established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make ‘beyondlinear’ clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

An electrochemical dehydrative reaction of dicarboxylic acids to their cyclic anhydrides is presented. The electrochemically generated anhydrides can be directly employed for amidation reactions. The mechanism of the reaction was investigated by ¹⁸O isotope labeling, revealing the formation of sulfate during electrolysis.

Abstract

An intramolecular electrochemical dehydration reaction of dicarboxylic acids to their cyclic anhydrides is presented. This electrolysis allows dicarboxylic acids as naturally abundant, inexpensive, safe, and readily available starting materials to be transformed into carboxylic anhydrides under mild reaction conditions. No conventional dehydration reagent is required. The obtained cyclic anhydrides are highly valuable reagents in organic synthesis, and in this report, we use them in-situ for acylation reactions of amines to synthesize amides. This work is part of the recent progress in electrochemical dehydration, which – in contrast to electrochemical dehydrogenative reactions for example – is an underexplored field of research. The reaction mechanism was investigated by ¹⁸O isotope labeling, revealing the formation of sulfate by electrochemical oxidation and hydrolysis of the thiocyanate-supporting electrolyte. This transformation is not a classical Kolbe electrolysis, because it is non-decarboxylative, and all carbon atoms of the carboxylic acid starting material are contained in the carboxylic anhydride. In total, 20 examples are shown with NMR yields up to 71 %.

Visible light photocatalysis is an important tool in organic synthesis, enabling the clean and selective generation of reactive intermediates. Current precious metal-based photocatalysts face limitations like cost and toxicity, fueling the search for alternatives like porous organic polymers (POPs). This review examines POPs’ role as photocatalysts in organic synthesis, discussing representative materials, mechanisms, comparisons with other photocatalysts, and future prospects.

Abstract

Concerns about increasing greenhouse gas emissions and their effect on our environment highlight the urgent need for new sustainable technologies. Visible light photocatalysis allows the clean and selective generation of reactive intermediates under mild conditions. The more widespread adoption of the current generation of photocatalysts, particularly those using precious metals, is hampered by drawbacks such as their cost, toxicity, difficult separation, and limited recyclability. This is driving the search for alternatives, such as porous organic polymers (POPs). This new class of materials is made entirely from organic building blocks, can possess high surface area and stability, and has a controllable composition and functionality. This review focuses on the application of POPs as photocatalysts in organic synthesis. For each reaction type, a representative material is discussed, with special attention to the mechanism of the reaction. Additionally, an overview is given, comparing POPs with other classes of photocatalysts, and critical conclusions and future perspectives are provided on this important field.

We illustrate a sustainable and mild reaction process that efficiently transforms biomass-derived furfural directly into GVL. Combining the homogeneous catalyst Ru-MACHO-BH with H₃PO₄(aq) allows to transform furfural to GVL in 84 % yield at 100 °C. This demonstrates the feasibility of transforming a major polysaccharide component in lignocellulose (hemicellulose) to GVL in a one-pot direct approach without intermediate purification and isolation.

Abstract

Herein, we report the direct conversion of biomass-derived furfural to γ-valerolactone (GVL) in a one-pot system, using the combination of Ru-MACHO-BH and a Brønsted acid (H₃PO₄). A GVL yield of 84 % is achieved under mild reaction conditions using 1 mol% of Ru-MACHO-BH and 3.8 M H₃PO₄(aq) at 100 °C for 7 hours.

The synthesis of labile polyoxometalates (POMs) in aqueous solutions has been achieved within the confined cavity of a robust and water-soluble coordination cage. This encapsulation significantly enhances the stability of these POMs in water, rendering them into green catalysts with high reactivity and selectivity. This cavity-directed approach represents the first example of utilizing the coordination cage for synthesizing metallic clusters.

Abstract

The artificial microenvironments inside coordination cages have gained significant attention for performing enzyme-like catalytic reactions by facilitating the formation of labile and complex molecules through a “ship-in-a-bottle” approach. Despite many fascinating examples, this approach remains scarcely explored in the context of synthesizing metallic clusters such as polyoxometalates (POMs). The development of innovative approaches to control and influence the speciation of POMs in aqueous solutions would greatly advance their applicability and could ultimately lead to the formation of elusive clusters that cannot be synthesized by using traditional methods. In this study, we employ host–guest stabilization within a coordination cage to enable a novel cavity-directed synthesis of labile POMs in aqueous solutions under mild conditions. The elusive Lindqvist [M₆O₁₉]²⁻ (M=Mo or W) POMs were successfully synthesized at room temperature via the condensation of molybdate or tungstate building blocks within the confined cavity of a robust and water-soluble Pt₆L₄(NO₃)₁₂ coordination cage. Importantly, the encapsulation of these POMs enhances their stability in water, rendering them efficient catalysts for environmentally friendly and selective sulfoxidation reactions using H₂O₂ as a green oxidant in a pure aqueous medium. The approach developed in this paper offers a means to synthesize and stabilize the otherwise unstable metal-oxo clusters in water, which can broaden the scope of their applications.

The copper-catalyzed reaction between azides and alkynes, known as CuAAC, has allowed for the efficient synthesis of 1,2,3-trisubstituted 1,4-triazoles and the formation of a metallocycle intermediate. This intermediate can be used for creating new structures or generating multi-component reactions, collectively referred to as “interrupted click reactions”

Abstract

The particular and unique mechanism of the copper-catalyzed reaction between azides and alkynes (CuAAC) has not only allowed for the efficient synthesis of 1,2,3-trisubstituted 1,4-triazoles in excellent yields and under mild conditions, becoming the quintessential click reaction, but it has also enabled the straightforward formation of a metallocycle intermediate, the copper triazolyl. This, under suitable reaction conditions able to suppress its protonolysis, can be used either for the creation of new bicyclic triazolyl structures or for the generation of novel three or four-component reactions. The aim of this review is to rationalize and unify all these transformations, which are collectively referred to as “interrupted click reactions”.

A first of its kind electrochemical approach for the direct synthesis of alkyl alkenesulfonates using styrenes, SO₂ stock solution and alcohols was developed. The reaction features the in-situ generation of a monoalkylsulfite species with subsequent radical addition to an anodically oxidized styrene substrate. The applicability of the protocol was demonstrated with a broad scope as well as a gram-scale reaction.

Abstract

A novel electrochemical approach to access alkyl alkenesulfonates via a multicomponent reaction was developed. The metal-free method features easy-to-use SO₂ stock solution forming monoalkylsulfites from alcohols with an auxiliary base in-situ. These intermediates serve a dual role as starting materials and as supporting electrolyte enabling conductivity. Anodic oxidation of the substrate styrene, radical addition of these monoalkylsulfites and consecutive second oxidation and deprotonation preserve the double bond and form alkyl β-styrenesulfonates in a highly regio- and stereoselective fashion. The feasibility of this electrosynthetic method is demonstrated in 44 examples with yields up to 81 %, employing various styrenes and related substrates as well as a diverse set of alcohols. A gram-scale experiment underlines the applicability of this process, which uses inexpensive and readily available electrode materials.

Publication date: May 2024

Source: The Journal of Steroid Biochemistry and Molecular Biology, Volume 239

Author(s): Christine Helsen, Konstantina Karypidou, Joice Thomas, Wout De Leger, Tien Nguyen, Steven Joniau, Arnout Voet, Wim Dehaen, Frank Claessens

We report on the design, synthesis, and scanning tunneling microscopy (STM) characterization of physisorbed monolayers of overcrowded alkene photoswitches physisorbed at the solid-liquid interface.

Abstract

Immobilization of stimulus-responsive systems on solid surfaces is beneficial for controlled signal transmission and adaptive behavior while allowing the characterization of the functional interface with high sensitivity and high spatial resolution. Positioning of the stimuli-responsive units with nanometer-scale precision across the adaptive surface remains one of the bottlenecks in the extraction of cooperative function. Nanoscale organization, cooperativity, and amplification remain key challenges in bridging the molecular and the macroscopic worlds. Here we report on the design, synthesis, and scanning tunneling microscopy (STM) characterization of overcrowded alkene photoswitches merged in self-assembled networks physisorbed at the solid-liquid interface. A detailed anchoring strategy that ensures appropriate orientation of the switches with respect to the solid surface through the use of bis-urea groups is presented. We implement a co-assembly strategy that enables the merging of the photoswitches within physisorbed monolayers of structurally similar ‘spacer’ molecules. The self-assembly of the individual components and the co-assemblies was examined in detail using (sub)molecular resolution STM which confirms the robust immobilization and controlled orientation of the photoswitches within the spacer monolayers. The experimental STM data is supported by detailed molecular mechanics (MM) simulations. Different designs of the switches and the spacers were investigated which allowed us to formulate guidelines that enable the precise organization of the photoswitches in crystalline physisorbed self-assembled molecular networks.

Publication date: 16 February 2024

Source: Polymer, Volume 294

Author(s): Lauren De Grave, Katrien V. Bernaerts, Sandra Van Vlierberghe

Nature Chemistry, Published online: 16 January 2024; doi:10.1038/s41557-023-01404-w

Exploiting the host-guest interaction of 1,4-dihydroxypillar[6]arene (P[HQ]₆) precursor with different alkylammonium or alkali metal cations, the control of the morphology of the pillar[6]quinone (P[Q]₆) crystals can be simply achieved by changing the electrolytic conditions. In addition, the same effect can also be obtained by changing the composition of the solvent.

Abstract

The morphology engineering of porous materials is advantageous for improving their properties and designing the structure of their nanopores. Among the synthetic methods available, electrochemical deposition is one of the most advantageous for shape engineering, because the reaction conditions can be easily controlled and the deposition only occurs at the electrode surface. Herein, we report the manipulation in size and shape of pillar[6]quinone (P[Q]₆) crystal structure by varying the electrolytic conditions during the electrochemical synthesis. Significant morphological change was observed with the use of supporting electrolytes having different alkylammonium cations, presumably due to the host-guest interaction between the cation and the 1,4-dihydroxypillar[6]arene (P[HQ]₆) precursor. However, when alkali metal cations were used, the morphology slightly changed, depending on the size of the alkali metal cation. Powder X-ray diffraction analysis revealed that the electrochemical assembly of P[Q]₆ gives the same crystal structure, while DFT calculations suggested that the change in the crystal morphology was caused by the incorporation of the cation species, which inhibited the crystal growth of P[Q]₆. In addition, it was found that the manipulation in size and shape of the morphologies could also be achieved by changing the composition of the solvent.

Electrocatalytic hydrogenation reactions (ECH) receive growing attention due to their sustainable potential. Our innovative one-step protocol creates carbon-supported silver electrodes, finely tunable for morphology and catalytic activity. Achieving 93 % current efficiency in ECH for the vitamin synthon 2-methyl-3-butyn-2-ol, even at higher current densities and reduced metal loadings, we successfully converted a library of 17 diverse substrates. More information can be found in the Research Article by U.-P. Apfel, D. Siegmund and co-workers (DOI: https://doi.org/10.1002/chem.202303808).

Abstract

Electrocatalytic hydrogenations (ECH) enable the reduction of organic substrates upon usage of electric current and present a sustainable alternative to conventional processes if green electricity is used. Opposed to most current protocols for electrode preparation, this work presents a one-step binder- and additive-free production of silver- and copper-electroplated electrodes. Controlled adjustment of the preparation parameters allows for the tuning of catalyst morphology and its electrochemical properties. Upon optimization of the deposition protocol and carbon support, high faradaic efficiencies of 93 % for the ECH of the Vitamin A- and E-synthon 2-methyl-3-butyn-2-ol (MBY) are achieved that can be maintained at current densities of 240 mA cm⁻² and minimal catalyst loadings of 0.2 mg cm⁻², corresponding to an unmatched production rate of 1.47 kg_MBE g_cat ⁻¹ h⁻¹. For a continuous hydrogenation process, the protocol can be directly transferred into a single-pass operation mode giving a production rate of 1.38 kg_MBE g_cat ⁻¹ h⁻¹. Subsequently, the substrate spectrum was extended to a total of 17 different C−C−, C−O− and N−O−unsaturated compounds revealing the general applicability of the reported process. Our results lay an important groundwork for the development of electrochemical reactors and electrodes able to directly compete with the palladium-based thermocatalytic state of the art.

Efficient syntheses of fluorescent, highly functionalized 4-amino-1,3′-bipyrazoles from pyrazolyldiazonium salts via 2-(2-(pyrazol-3-yl)hydrazine-ylidene)acetates, which were subsequently subjected to Thorpe-Ziegler type cyclisation reactions, are described.

Abstract

An efficient protocol for the synthesis of fluorescent 4-amino-1,3′-bipyrazoles, which are substituted at the positions N-1′, C-4′, C-3 and C-5, is described. By a two-step synthetic strategy, an initial azo coupling of ethyl cyanoacetate and various 1-alkylpyrazolyldiazonium chlorides gave substituted ethyl 2-cyano-2-(2-(pyrazol-3-yl)hydrazine-ylidene)acetates, which were subsequently subjected to Thorpe-Ziegler type cyclisation reactions to yield the title compounds.

Abstract

The catalytic deoxygenative reduction of hydrazides to the corresponding alkyl hydrazine with PhSiH₃ via B(C₆F₅)₃-catalyzed hydrosilylation is reported. This metal-free protocol is compatible with various acylhydrazides and diacylhydrazides, giving rise to a variety of structurally diverse alkyl hydrazine products in 63–95% yields. The proper selection of borane catalyst and hydrosilane reductant is essential for catalysis. Mechanistic investigations reveal that the reaction involves a hydrazone intermediate.

The three-component “CN-free” reactions of 2,2,2-trifluoroethyl ketones, aryl azides and aqueous ammonia for the synthesis of fully substituted 4-cyano-1,2,3-triazoles has been disclosed.

Abstract

A new method for the synthesis of 4-cyano-1,2,3-triazoles is developed using a three-component strategy. The cyano group is generated in situ by the reaction of 2,2,2-trifluoroethyl ketone and aqueous ammonia. The one-pot protocol allows the synthesis of 4-cyano-1,2,3-triazoles under mild reaction conditions.

No metal, just POP: A range of porous organic polymers (POPs) was synthesized using readily available building blocks. These materials were applied as efficient metal-free photocatalysts, enabling the aromatization of a wide range of N-heterocycles under extremely mild conditions.

Abstract

Porous organic polymers (POPs), and especially covalent triazine frameworks (CTFs), are being developed as the next generation of metal-free heterogeneous photocatalysts. However, many of the current synthetic routes to obtain these photoactive POPs require expensive monomers and rely on precious metal catalysts, thus hindering their widespread implementation. In this work, a range of POPs was synthesized from simple unfunctionalized aromatic building blocks, through Lewis acid-catalyzed polymerization. The obtained materials were applied, for the first time, as heterogeneous photocatalysts for the aromatization of N-heterocycles. With the use of the most active material, denoted as CTF-Pyr, which consists of photoactive pyrene and triazine moieties, a wide range of pyridines, dihydroquinoline-5-ones, tetrahydroacridine-1,8-diones and pyrazoles were obtained in excellent yields (70–99 %). Moreover, these reactions were carried out under very mild conditions using air and at room temperature, highlighting the potential of these materials as catalysts for green transformations.

A mechanochemical nitrene transfer reaction towards N-acyl sulfonimidamides from sulfinamides and dioxazolones with the catalysis of iron(II) chloride is presented. This one-step solvent-free procedure shows better conversions rate and chemoselectivity compared to its solution-phase counterpart, providing a wide range of N-acyl sulfonimidamides in up to 87 % yield. Mechanistically, crucial nitrene iron complex intermediates are suggested by ESI-MS.

Abstract

A mechanochemical synthesis of sulfonimidamides by iron(II)-catalyzed exogenous ligand-free N-acyl nitrene transfer to sulfinamides is reported. The one-step method tolerates a wide range of sulfinamides with various substituents under solvent-free ambient conditions. Compared to its solution-phase counterpart, this mechanochemical approach shows better conversion and chemoselectivity. Mechanistic investigations by ESI-MS revealed the generation of crucial nitrene iron intermediates.

An electrocatalytic hypervalent iodine(III)-mediated in-cell synthesis of 3,4-dihydroquinolin-2-ones by C−N coupling is established, applying catalytic amounts of reagents, inexpensive electrode materials and a simple galvanostatic set-up. With this method 23 examples in yields up to 96 % could be synthesized, exhibiting various functional groups. Furthermore, a 10-fold scale-up was performed and a reaction mechanism was proposed.

Abstract

Electrochemically generated hypervalent iodine(III) species are powerful reagents for oxidative C−N coupling reactions, providing access to valuable N-heterocycles. A new electrocatalytic hypervalent iodine(III)-mediated in-cell synthesis of 1H-N-aryl-3,4-dihydroquinolin-2-ones by dehydrogenative C−N bond formation is presented. Catalytic amounts of the redox mediator, a low supporting electrolyte concentration and recycling of the solvent used make this method a sustainable alternative to electrochemical ex-cell or conventional approaches. Furthermore, inexpensive, readily available electrode materials and a simple galvanostatic set-up are applied. The broad functional group tolerance could be demonstrated by synthesizing 23 examples in yields up to 96 %, with one reaction being performed on a 10-fold higher scale. Based on the obtained results a sound reaction mechanism could be proposed.

A mild electrocatalytic system is reported for the reductive alkylation of primary, secondary, or tertiary alkyl chlorides with conjugated alkenes.

Abstract

Reactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt-catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes. Co-catalyzed activation of alkyl chlorides is performed under electroreductive conditions, and the resulting reactions constitute formal alkyl-alkyl bond formation. In addition to developing an operationally simple methodology, detailed mechanistic studies provide insights into the elementary steps of a proposed catalytic cycle. In particular, we propose a switch in the mechanism of C−Cl bond activation from nucleophilic substitution to halogen atom abstraction, which is critical for efficiently generating alkyl radicals. These mechanistic insights were leveraged in designing ligands that enable couplings of primary, secondary, and tertiary alkyl chlorides.

The Front Cover illustrates the electroenzymatic regeneration of ATP. The electrons of an enzymatically catalyzed redox reaction necessary for the ATP regeneration cascade are transferred to an electrode mediated by ferrocenyl-methanol. Regenerative and green energy can therefore be used to drive the reaction. Cover design by Tobias Prenzel and Finn Moeller. More information can be found in the Research Article by R. Siedentop et al.

Nature Communications, Published online: 09 November 2023; doi:10.1038/s41467-023-43136-y

Electrochemical synthesis of isoxazoles is enabled via direct anodic oxidation of readily available oximes. The easiest galvanostatic set-up in combination with inexpensive electrode materials and the recyclability of the solvent system allow for a facile synthetic strategy on up to multi-gram scale.

Abstract

Isoxazol(in)es are widely featured structural motifs in natural products, agrochemicals, and pharmaceuticals. The first intermolecular approach for a direct electrochemical synthesis from readily available aldoximes is reported. Isoxazoles and isoxazolines were obtained in yields up to 81 %. The synthesis is carried out in an undivided cell as the simplest electrochemical set-up and requires only the use of electric current as traceless oxidizing agent. The application of inexpensive and widely available electrode materials in combination with recyclable supporting electrolytes and solvents paves the path for translation of the presented reaction onto preparative scale. This is underlined by successful scale-up to multi-gram runs.

A scalable electrochemical synthesis of sulfonamides in single-pass flow in an undivided cell at room temperature has been developed. Stock solutions of sulfur dioxide are utilized as atom-economic source of SO₂, which omits the need for expensive SO₂ surrogates.

Abstract

An electrochemical multicomponent synthesis of sulfonamides at room temperature in single-pass flow is presented. In contrast to batch-type electrolysis, an undivided flow cell setup with a stainless-steel cathode and either a boron-doped diamond (BDD) anode or a glassy carbon anode can be employed. Simply by using SO₂ stock solutions, less atom-economic sulfur dioxide surrogates can be avoided. Moreover, no additional supporting electrolytes are required due to the in-situ generation of amidosulfinates, which also serve as intermediate for this transformation. This protocol allows sulfonamides to be synthesized directly from non-prefunctionalized electron-rich arenes with amines and SO₂. In total, 10 examples are demonstrated with isolated yields up to 92 %. The robust scalability of this electrosynthesis with an easy downstream processing was also proven.

Nature Communications, Published online: 26 October 2023; doi:10.1038/s41467-023-42566-y