Tomas Horsten

In this review, an overview is given of chemical oxidants for the radical/electrophilic brominations starting from harmless bromide sources as an alternative for toxic molecular bromine. The characteristics of the active brominating species as well as plausible side reactions have been discussed.

Abstract

Bromination of organic substances is still an important reaction in modern synthetic chemistry. In view of the increasing demand for sustainable synthetic chemistry, oxidative bromination can play an important role to avoid the use of hazardous molecular bromine (Br₂). In this review, a complete overview of the chemical oxidants will be provided which have been used for the electrophilic as well as radical brominations, starting from less hazardous bromide Br(−I); e. g., HBr or a bromide salt, with a focus on the differences caused by the choice of oxidant.

Abstract

An atom and step economy cascade trifluoromethylation/cyclization of unactivated alkene with Langlois reagent as a CF₃ source is described. A variety of polycyclic quinazolinones were successfully synthesized in 52–81% yields under transition metal- and oxidant-free conditions. The Langlois reagent used in this strategy as a CF₃ reagent possesses the advantages of bench-stablity, cost-effectivity and high-efficiency. Additionally, gram-scale reaction, broad substrate scope and good functional group tolerance demonstrated the synthetic usefulness of this protocol.

A new synthetic route towards benzimidazo[2,1-b]quinazolin-12-ones has been developed, which relies on the Pd-catalyzed intramolecular aminocarbonylation of N-(2-bromophenyl)-1H-benzimidazol-2-amines. Using near stoichiometric amounts of ¹³CO, isotopically labelled benzimidazo[2,1-b]quinazolin-12-ones were synthesized.

Abstract

A carbonylative route towards the synthesis of benzimidazo[2,1-b]quinazolin-12-ones was developed. The key step in this strategy consists of an intramolecular carbonylative lactam formation, starting from N-(2-bromophenyl)-1H-benzimidazol-2-amines. These precursor molecules were synthesized by two different methods to introduce a variety of substituents on the aromatic ring systems. Interestingly, only near-stoichiometric amounts of carbon monoxide were required in the ring-closing aminocarbonylation reaction, rendering the developed strategy also suitable for late-stage ¹³C-isotopic labelling.

Nature Catalysis, Published online: 02 December 2021; doi:10.1038/s41929-021-00709-8

Nature Catalysis, Published online: 02 December 2021; doi:10.1038/s41929-021-00710-1

The generation of FSO₂ radicals under electrochemical conditions is reported. Various sulfonyl fluorides and heterocycles, including a novel oxathiazole dioxide heterocycle, can be obtained in good to excellent yields. Some β-keto sulfonyl fluorides and derivatives showed potent activities against Bursaphelenchus xylophilus and Colletotrichum gloeosporioides.

Abstract

Radical fluorosulfonylation is emerging as an appealing approach for the synthesis of sulfonyl fluorides, which have widespread applications in many fields, in particular in the context of chemical biology and drug development. Here, we report the first investigation of FSO₂ radical generation under electrochemical conditions, and the establishment of a new and facile approach for the synthesis of β-keto sulfonyl fluorides via oxo-fluorosulfonylation of alkynes with sulfuryl chlorofluoride as the radical precursor and air as the oxidant. This electrochemical protocol is amenable to access two different products (β-keto sulfonyl fluorides or α-chloro-β-keto sulfonyl fluorides) with the same reactants. The β-keto sulfonyl fluoride products can be utilized as useful building blocks in the synthesis of various derivatives and heterocycles, including the first synthesis of an oxathiazole dioxide compound. Furthermore, some β-keto sulfonyl fluorides and derivatives exhibited notably potent activities against Bursaphelenchus xylophilus and Colletotrichum gloeosporioides.

A series of calix[4]pyrrole-based crosslinked polymer networks was synthesized via Sonogashira–Hagihara polycondensation. One system, C[4]P-BTP, was found to be highly effective for iodine capture from water with an uptake capacity of 3.24 g g⁻¹ and quick kinetics (k _obs=7.814 g g⁻¹ min⁻¹). Flow-through adsorption experiments revealed that C[4]P-BTP was able to remove 93.2 % of iodine from an aqueous phase with a flow rate of 1 mL min⁻¹.

Abstract

A series of calix[4]pyrrole-based crosslinked polymer networks designed for iodine capture is reported. These materials were prepared by Sonogashira coupling of α,α,α,α-tetra(4-alkynylphenyl)calix[4]pyrrole with bishalide building blocks with different electronic properties and molecular sizes. Despite their low Brunauer–Emmett–Teller surface areas, iodine vapor adsorption capacities of up to 3.38 g g⁻¹ were seen, a finding ascribed to the presence of a large number of effective sorption sites including macrocyclic π-rich cavities, aryl units, and alkyne groups within the material. One particular system, C[4]P-BTP, was found to be highly effective at iodine capture from water (uptake capacity of 3.24 g g⁻¹ from a concentrated aqueous KI/I₂ solution at ambient temperature). Fast capture kinetics (k_obs=7.814 g g⁻¹ min⁻¹) were seen. Flow-through adsorption experiments revealed that C[4]P-BTP is able to remove 93.2 % of iodine from an aqueous source phase at a flow rate of 1 mL min⁻¹.

A conceptually new trifluoromethoxylation reaction through the combination of readily available trifluoromethylating reagent and oxygen under electrochemical conditions was developed. The synthetic utility of this new protocol is illustrated by the C−H trifluoromethoxylation of (hetero)arenes and biorelevant molecules.

Abstract

Trifluoromethoxylated aromatics (ArOCF₃) are valuable structural motifs in the area of drug discovery due to the enhancement of their desired physicochemical properties upon the introduction of the trifluoromethoxy group (CF₃O). Although significant progress has been made recently in the introduction of CF₃O group into aromatics, current methods either require the use of expensive trifluoromethoxylation reagents or require harsh reaction conditions. We present a conceptually new and operationally simple protocol for the direct C−H trifluoromethoxylation of (hetero)aromatics by the combination of the readily available trifluoromethylating reagent and oxygen under electrochemical reaction conditions. This reaction proceeds through the initial generation of CF₃ radical followed by conversion to CF₃O radical, addition to (hetero)aromatics and rearomatization. The utility of this electrochemical trifluoromethoxylation is illustrated by the direct incorporation of CF₃O group into a variety of (hetero)aromatics as well as bio-relevant molecules.

We report accelerated SuFEx click chemistry utilizing a synergistic BTMG-HMDS catalytic system. The power and versatility of the reaction are showcased by the SuFEx synthesis of >100 unique molecules from diverse SuFExable hubs. Accelerated SuFEx is a next generation click reaction that improves upon existing protocols and expands the scope of accessible products.

Abstract

SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S−O linkages upon exchange of S−F bonds with aryl silyl-ether substrates, and while near-perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs. We demonstrate Barton's hindered guanidine base (2-tert-butyl-1,1,3,3-tetramethylguanidine; BTMG) as a superb SuFEx catalyst that, when used in synergy with silicon additive hexamethyldisilazane (HMDS), yields stable S−O bond linkages in a single step; often within minutes. The powerful combination of BTMG and HMDS reagents allows for catalyst loadings as low as 1.0 mol % and, in congruence with click-principles, provides a scalable method that is safe, efficient, and practical for modular synthesis. ASSC expands the number of accessible SuFEx products and will find significant application in organic synthesis, medicinal chemistry, chemical biology, and materials science.

A commercial heterogeneous catalyst is decorated with iron carbide nanoparticles to produce a multifunctional catalytic system with magnetic heating capabilities. Under magnetic induction, local hot spots are generated at the catalyst surface, unlocking continuous-flow hydrogenation of aromatic ketones under mild conditions. This approach is versatile and potentially transferrable to a wide range of heterogeneous catalysts and transformations.

Abstract

Copper chromite is decorated with iron carbide nanoparticles, producing a magnetically activatable multifunctional catalytic system. This system (ICNPs@Cu₂Cr₂O₅) can reduce aromatic ketones to aromatic alcohols when exposed to magnetic induction. Under magnetic excitation, the ICNPs generate locally confined hot spots, selectively activating the Cu₂Cr₂O₅ surface while the global temperature remains low (≈80 °C). The catalyst selectively hydrogenates a scope of benzylic and non-benzylic ketones under mild conditions (3 bar H₂, heptane), while ICNPs@Cu₂Cr₂O₅ or Cu₂Cr₂O₅ are inactive when the same global temperature is adjusted by conventional heating. A flow reactor is presented that allows the use of magnetic induction for continuous-flow hydrogenation at elevated pressure. The excellent catalytic properties of ICNPs@Cu₂Cr₂O₅ for the hydrogenation of biomass-derived furfuralacetone are conserved for at least 17 h on stream, demonstrating for the first time the application of a magnetically heated catalyst to a continuously operated hydrogenation reaction in the liquid phase.

Except for a single example, sydnone methides have been unknown to date. Syntheses are described here, leading to 10 stable and intensely colorful, slightly fluorescent sydnone methides with Z=CN, COOMe, and SO₂Me, respectively. On deprotonation, unique anionic π-electron-rich N-heterocyclic carbenes are formed which react to thioethers and selenoethers, mercury, gold and rhodium complexes, and 4-acylsydnone methide on treatment with acyl chlorides.

Abstract

Sydnone methides are described from which only one single example has been mentioned in the literature so far. Their deprotonation gave anions which can be formulated as π-electron rich anionic N-heterocyclic carbenes. Sulfur and selenium adducts were stabilized as their methyl ethers, and mercury, gold as well as rhodium complexes of the sydnone methide carbenes were prepared. Sydnone methide anions also undergo C−C coupling reactions with 1-fluoro-4-iodobenzene under Pd(PPh₃)₄ and CuBr catalysis. ⁷⁷Se NMR resonance frequencies and ¹ J _C4-Se as well as ¹ J _C4-H coupling constants have been determined to gain knowledge about the electronic properties of the anionic N-heterocyclic carbenes. The carbene carbon atom of the sydnone methide anion 3 j resonates at δ=155.2 ppm in ¹³C NMR spectroscopy at −40 °C which is extremely shifted upfield in comparison to classical N-heterocyclic carbenes.

“3 D” drug development: The deuterated “magic methyl” group is attracting increased interest in pharmaceutical industry. In this review, we discuss the currently available methods for C−CD₃ bond forming reactions and classify them according to the trideuteromethylation reagent. The mechanisms, scope and limitations of each method are considered in order to provide a guide for targeted trideutermethylation.

Abstract

In the field of medicinal chemistry, the precise installation of a trideuteromethyl group is gaining ever-increasing attention. Site-selective incorporation of the deuterated “magic methyl” group can provide profound pharmacological benefits and can be considered an important tool for drug optimization and development. This review provides a structured overview, according to trideuteromethylation reagent, of currently established methods for site-selective trideuteromethylation of carbon atoms. In addition to CD₃, the selective introduction of CD₂H and CDH₂ groups is also considered. For all methods, the corresponding mechanism and scope are discussed whenever reported. As such, this review can be a starting point for synthetic chemists to further advance trideuteromethylation methodologies. At the same time, this review aims to be a guide for medicinal chemists, offering them the available C−CD₃ formation strategies for the preparation of new or modified drugs.

Abstract

Transition-metal-catalyzed reactions of N-tosylhydrazones provide a convenient access to various molecules by novel carbon-carbon or carbon-heteroatom bond formations via carbene-type intermediates. The present review highlights recent developments in the field emphasize of the employment of different transition metals as catalysts, synthetic applications, mechanistic studies and use in domino and multicomponent reactions.

Abstract

Several new heterocyclic systems based on a hydroxybenzofuro[2,3-b]pyridine building block were prepared. This benzofuropyridine is easily available from the Meerwein reaction of benzoquinone and a heterocyclic diazonium salt, followed by reduction and cyclization. Electrophilic substitution and further condensations give polycyclic systems, including oxazolo- and chromeno-fused analogues.

Beilstein J. Org. Chem. 2021, 17, 977–982. doi:10.3762/bjoc.17.79