Robby Vroemans

• Direct synthesis of useful allylic sulfones.

• Secondary alcohols: feedstock chemicals

• Broad substrate scope

• Excellent selectivity

• Role of water in catalyst regeneration

• Green byproducts: H₂O and H₂

ABSTRACT

Allylic sulfones are valuable structures in bioactive compounds and serve as versatile intermediates in organic synthesis. A selective method for the C–C coupling of aryl sulfones with secondary alcohols has been developed using a Ru-SNS pincer catalyst. This transformation enables efficient access to allylic sulfones under mild conditions with broad functional group tolerance. Sensitive moieties, including olefins and pharmaceutically relevant piperazine-substituted aryl sulfones, are well tolerated. The method demonstrates wide synthetic utility, converting natural product-derived alcohols such as geraniol, nopol, and perillyl alcohol into corresponding sulfone products in high yield. Mechanistic studies suggest the reaction proceeds via initial dehydrogenation of the secondary alcohol to generate a carbonyl intermediate, followed by nucleophilic addition of a sulfone-derived carbanion. A subsequent isomerization step furnishes the allylic sulfone. DFT calculations support this pathway and reveal a key role for the water generated during alcohol oxidation. This in situ formed water facilitates both catalyst regeneration and the final isomerization step, functioning as an essential component in the catalytic cycle. This method provides a practical, atom-economical approach to allylic sulfones with high chemo- and regioselectivity, expanding the toolbox for sulfone chemistry in synthesis and medicinal chemistry applications.

Density functional theory (DFT) calculations elucidate the mechanism of visible-light-driven carboxylation of alkenes with CO₂ mediated by a photoredox catalyst. Spin polarization selectively weakens the C _β C _γ bond, resulting in a significantly lower cleavage barrier compared to the C _α C _β bond, thereby dictating the reaction regioselectivity.

Since cleaving C–C bonds for carboxylation with CO₂ is far more challenging because of their inherent and less favorable orbital directionality for interacting with transition metals, a photocatalytic approach for the deconstructive carboxylation of alkenes with CO₂, is a remarkable methodology for producing carboxylic acids. Density functional theory (DFT) calculations have been carried out to study visible-light-driven photocatalytic deconstructive carboxylation of alkenes with CO₂, which is reported by the Meng's group. The calculation results also confirm the experimental observation that under photoredox catalysis, α-amino radicals can be captured by C=C bonds to form hydroaminoalkylation products.

A protocol for iron octacarboxyphthalocyanine-catalyzed aerobic oxidative dethioacetalization in an aqueous solvent is developed. This method can efficiently convert a broad range of dithioacetals into the corresponding carbonyl compounds. Inspired by enzyme-mediated redox processes, the environmentally friendly catalytic system exhibits remarkable functional group compatibility.

An aerobic oxidative dethioacetalization catalyzed by an iron octacarboxyphthalocyanine complex, which is designed by mimicking enzymatic oxidation, in an aqueous media is developed. The developed method can efficiently convert a broad range of dithioacetals, including those derived from aryl and aliphatic ketones and aldehydes, into the corresponding carbonyl compounds while tolerating various functional groups. This protocol is readily scalable to the gram scale. Mechanistic studies indicate that the iron phthalocyanine complex initiates the reaction by accepting a single electron from the sulfur atom of the dithioacetal, forming a radical cation intermediate. This is followed by unimolecular fragmentation and subsequent degradation of the resulting hemithioacetal to afford the corresponding carbonyl product, along with 1,2-dithiolane and its oxides.

Metal- and cyanide-free aldehyde-to-nitrile synthesis by carbamoylaldoxime intermediates is described. Aldoximes form N,N-dimethylcarbamoyloximes, which undergo clean thermal syn elimination to give nitriles, CO₂, and dimethylamine with broad functional-group tolerance and minimal purification.

Abstract

The development of efficient methods for nitrile syntheses is a challenge due to the current reliance on toxic cyanide sources, metal catalysts and their associated waste products, and harsh conditions that limit functional group compatibility. Here, we show a metal- and complex reagent-free strategy for the conversion of aldehydes to nitriles through carbamoylaldoxime intermediates. Therefore, we synthesize aldoximes from several aldehydes using hydroxylamine, which in turn are reacted with dimethylcarbamoyl chloride (DMCC) to afford N,N-dimethylcarbamoyloximes. Subsequent heating cleanly produces the desired nitriles as well as volatile CO₂ and HNMe₂ through a pericyclic syn elimination. This approach relies on widely available commercial chemicals, proceeds with broad functional group tolerance, and minimizes the need for extensive purification of the nitrile product.

Atropisomeric scaffolds are important building blocks in natural products, organocatalysts, metal ligands, and functional materials. This review introduces current developments for synthesizing atropisomers employing biocatalytic kinetic resolution, dynamic kinetic resolution, and desymmetrization strategies.

ABSTRACT

The asymmetric synthesis of atropisomers has garnered extensive attention in recent years. Atropisomers constitute a key structural motif in natural products, chiral ligands, organocatalysts, and functional materials. Despite progress driven by transition-metal and organocatalysis, inherent limitations in enantioselectivity and sustainability have hampered further development in this field. Alternatively, biocatalysis offers a promising solution employing strategies including (dynamic) kinetic resolution, desymmetrization, and other strategies. These biocatalytic processes operate under mild, environmentally friendly conditions, achieving high stereoselectivity that is often difficult to attain with traditional methods. This review highlights recent advances in the biocatalytic synthesis of atropisomers and offer insights in the development of the relevant field.

Catalysts generated from the halogen-bridged methylnaphthyl-palladium dimer [Pd(1-MeNAP)Br]₂ and biarylphosphine ligands in combination with the base LiHMDS promote Buchwald-Hartwig type aminations and para-C─H arylations of non-activated aryl fluorides already at 60 °C. Their enabling performance is attributed to the efficient generation of monoligated Pd(0)-species.

Abstract

The C─F bond is among the strongest in organic molecules and can be cleaved only by few transition metal catalysts under harsh conditions or with highly reactive nucleophiles. We herein report that a methyl naphthyl (MeNAP) palladium bromide / BrettPhos catalyst with lithium bis(trimethylsilyl)amide (LiHMDS) as the base promotes aminations of non-activated aryl fluorides already at 40–60 °C to give primary, secondary, and tertiary anilines. A related catalyst system further enables para-C─H arylations of tritylated anilines with aryl fluorides, yielding biarylamines.

Synthesis
DOI: 10.1055/a-2722-9900

An efficient, facile, and one-pot four-component methodology for the cyclization of readily available benzyl alcohols, acetophenones, Meldrum’s acid, and NH4OAc to access dihydropyridinones (valuable scaffolds in medicinal and synthetic organic chemistry) was established. This four-component cyclization reaction supports the straightforward manufacture of several dihydropyridinones. Several C–C and C–N bonds were constructs to synthesize the desired product. Readily available starting materials, operational simplicity, good to excellent reaction yields, and tolerance of various functional groups are the interesting features of this protocol.
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Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

A Pd(II)-catalyzed atroposelective C–H olefination and desymmetrization strategy has been developed, enabling the efficient synthesis of axially chiral BODIPYs with exceptional stereocontrol and broad functional group tolerance.

Abstract

Enantioenriched BODIPYs have emerged as a class of exceptionally valuable fluorophores, distinguished by their remarkable chiroptical properties and versatile applications in bioimaging, molecular sensing, and optoelectronic materials. The development of asymmetric catalytic methodologies for their synthesis represents a significant advancement in this field. Herein, we present a robust and efficient strategy for the Pd(II)-catalyzed atroposelective C–H olefination and desymmetrization at the γ-position of BODIPYs, facilitated by a thioether directing group and a chiral amino acid-derived ligand. This oxidative Heck-type reaction enables the direct synthesis of a wide array of axially chiral BODIPY derivatives with exceptional E-selectivity and outstanding enantioselectivities. The resultant chiral fluorophores exhibit tunable photophysical properties, including near-infrared emission and robust circularly polarized luminescence, and demonstrate excellent biocompatibility in live-cell imaging. This method establishes a comprehensive platform for the streamlined synthesis of axially chiral BODIPYs, thereby advancing their potential applications in cutting-edge photonic, biological, and optoelectronic technologies.

A mechanochemical strategy has been developed for the nickel-catalyzed Suzuki–Miyaura cross-coupling of cyano esters derived from phenol, as electrophilic substrates using arylboronic acids via C_sp ²O bond cleavage.

A mechanochemical strategy has been developed for the nickel-catalyzed Suzuki–Miyaura cross-coupling of cyano esters derived from phenols, as electrophilic substrates using arylboronic acids via C_sp ²O bond cleavage. This approach capitalizes on the abundance of phenols, using cyano-functionalized derivatives to enable high reactivity and functional group compatibility without halogenated reagents. The reaction is carried out under solvent-free, temperature-trace conditions, significantly reducing environmental impact. The methodology offers a sustainable and scalable alternative for biaryl synthesis, with implications for pharmaceutical and material sciences.

Synthesis
DOI: 10.1055/a-2705-6850

This short review describes recent advances in π–π stacking interaction-enabled catalysis for selective transformations. Owing to their charge-independent and spatially accessible nature, π–π interactions have been utilized to control chemo-, regio-, and stereoselectivity in a range of transformations. Selected examples are presented to illustrate how these noncovalent forces modulate transition-state geometry or stabilize key intermediates in C–C, C–O, and C–N bond formations, as well as in reductions and hydrogenation reactions.
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Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Inherently chiral calix[4]arenes (ICCs) were synthesized via asymmetric lower-rim functionalization. In this approach, chiral phosphoric acid (CPA) organocatalysis, with vinylidene ortho-quinone methides (VQMs) serving as pivotal intermediates, enables stepwise asymmetric halo-cyclization. A diverse library of inherently chiral calix[4]arenes featuring multiple C─C axial stereogenic axes with excellent enantio- and diastereoselectivities is obtained.

Abstract

We report herein an efficient approach for the enantioselective synthesis of inherently chiral calix[4]arenes (ICCs) via chiral phosphoric acid (CPA)-catalyzed lower-rim asymmetric functionalization. With vinylidene ortho-quinone methides (VQMs) as the key intermediates, a stepwise asymmetric halo-cyclization strategy was applied to construct diverse inherently chiral calix[4]arenes bearing multiple C─C axially stereogenic elements with high enantio- and diastereoselectivities (up to 96% ee, all d.r. > 20:1). The obtained lower-rim functionalized products underwent further photocatalytic transformations to access novel inherently chiral naphthofuran-based calix[4]arene architectures. Further synthetic modifications and analysis of their photophysical/chiroptical properties demonstrated their potential in optoelectronic materials and related fields. Mechanistic studies reveal that the reaction proceeds via a stepwise process, with the stereoselectivity-determining step occurring in the first VQMs-mediated cyclization, and the second step constituting a chiral transfer process.

We demonstrate a sustainable strategy for pharmaceutical manufacturing by combining hydrogen, heterogeneous catalysis, and continuous flow synthesis. The development of novel catalysts and their application in a multi-step synthesis of donepezil enabled a highly productive process with no intermediate purification. This work establishes a new, greener pathway for a hydrogen-powered, carbon-neutral future.

Abstract

Conventional pharmaceutical manufacturing relies on fossil fuels and inefficient batch processes, creating significant waste. This review presents a strategy using hydrogen, heterogeneous catalysts, and continuous-flow synthesis for a more sustainable and efficient approach to pharmaceutical manufacturing. We detail two key innovations: first, highly efficient catalysts (Pt/C and polysilane-modified Pd) for atom-economical C─N bond formation. Our flow systems offered superior performance and broad functional group tolerance. Second, we developed a robust polysilane-immobilized Rh-Pt bimetallic catalyst for selective arene hydrogenation under mild conditions. We successfully integrated these technologies into a seamless, multi-step continuous-flow synthesis of donepezil. By successfully integrating these technologies and overcoming challenges like catalyst inhibition, this work demonstrates a highly productive and sustainable process. This approach represents a significant step toward a greener, hydrogen-powered future for chemical manufacturing.

Acetylation of alcohols with vinyl acetate! Environmentally amenable method for acetylation of alcohols with vinyl acetate using anhydrous potassium carbonate as a readily available, environmentally benign, recyclable catalyst is reported. The method is purification-free and gives excellent yields. Multigram scale reaction gave near quantitative yield and excellent green matrices to establish its possible sustainable application in industry.

Abstract

Despite acetylation being the go-to protecting group for alcohols, regulatory restrictions on the use of acetic anhydride as the acetylating agent has forced to look for other alternatives. Recently, ethyl acetate and vinyl acetate have found applications as acetyl surrogate for protection of alcohols, but the reported methods are a few. Given the recent emphasis on development of green and sustainable methodology, here, we present one of the most efficient, user friendly, and environmentally benign methods for acetylation of alcohols via irreversible trans-esterification of alcohols with vinyl acetate under sonication in the presence of a catalytic amount of anhydrous potassium carbonate as reusable heterogeneous catalyst. The reaction gives quantitative yields, uses recyclable vinyl acetate as solvent, needs no work up, and reuses the catalyst up to five times without needing any processing after use. The method demonstrated excellent green matrices as evident from low E-factor (2.31) and PMI (3.62), and high RME (73.43%) at multigram scale.

This review focuses on the frontier field of catalytically transforming lignin and its depolymerization products into high-value natural bioactive compounds. It systematically summarizes recent research advances in the efficient conversion of lignin-derived aromatic monomers into various important natural products.

Lignin, as the most abundant renewable aromatic polymer in nature, holds significant potential for the sustainable synthesis of high-value natural bioactive compounds (NBCs). However, current research exhibits a disjointed approach, in which upstream lignin depolymerization processes remain disconnected from downstream catalytic synthesis of these medicinally and nutritionally valuable chemicals. Consequently, most studies are limited to using lignin model derivatives as substrates. Furthermore, existing literature on synthesizing natural active components from lignin and its derivatives is fragmented and lacks comprehensive reviews. To address this gap, this review first outlines lignin depolymerization methods and their resulting primary aromatic monomers. Subsequently, following the classification framework of NBCs, it systematically evaluates recent advances in synthesizing high-value natural products (e.g., flavonoids, curcumin analogs, and tetrahydroisoquinolines) from lignin and its derived feedstocks using chemo-catalytic, biocatalytic, and chemo-bio cascade strategies. This integrated analysis aim is to bridge upstream depolymerization with downstream conversion processes, providing theoretical guidance and technical references for enhancing lignin valorization and enabling accelerated synthesis of NBCs from lignin.