Finn Moeller

Science, Volume 388, Issue 6744, Page 257-257, April 2025.

A synergistic dual chiral primary amine and naphthalene catalysis was identified through enamine-redox mediator mapping (e-RM²) to enable effective electrochemical singly occupied molecular orbital (SOMO)-type coupling with alkenyl trifluoroborate. Mechanistic studies reveal ion-pair interactions between the protonated aminocatalyst and anionic substrate, leading to exceptional enantioselectivity.

Abstract

External tuning of enamine intermediate has significantly expanded reaction space of typical aminocatalysis. Notwithstanding the progress of chemo- and photo-oxidation of enamine intermediate, electro-oxidation was left as a much less explored area, in stark contrast to the prosperous renaissance of electrochemistry in recent years. Challenges mainly come from the reactivity barrier as a consequence of heterogeneous electron transfer and subtle stereocontrol in ionic electrolyte solution under the influence of electric field. Herein, we report asymmetric α-alkenylation of carbonyl compounds using potassium alkenyl trifluoroborate as a model reaction to demonstrate the capability of primary amine catalysis under electrochemical conditions. By employing enamine redox mediator mapping (e-RM²) strategy, a new organic mediator, dimethoxyl naphthalene, was found to greatly enhance reactivity. Mechanistic studies uncover an ion-pair interaction between protonated aminocatalyst and anionic substrate that accounts for the exceptional enantioselectivity. This catalytic system demonstrates the best level of enantioselectivities in electro-oxidative enamine transformations so far.

A catalytic ortho-arylation method has been developed to convert arylthianthrenium salts into carboxylate-functionalized biaryls, which can be removed in situ or used for further derivatization. This reaction is broadly applicable to (hetero)arenecarboxylic acids, with excellent functional group compatibility and orthogonality to cross-couplings, enhancing the utility of thianthrenium salts in drug discovery.

Abstract

Arylthianthrenium salts have become key intermediates for late-stage functionalizations of drug-like molecules. Ruthenium-phosphine catalysts are now shown to enable their use as aryl sources in high-yielding ortho-C─H arylations of benzoic acids. The arylthianthrenium salts are converted chemo-selectively, leaving aryl halides and boronates untouched. The carboxylate groups are uniquely effective as directing groups, ensuring exclusive ortho-selectivity even in the presence of competing pyridine or amide groups. This makes the reaction orthogonal to cross-couplings and conventional C─H arylations. The carboxylate group can be removed via decarboxylation or serve as an anchor for downstream transformations. Mechanistic studies identify C─H ruthenation as the rate-limiting step and highlight the unique efficiency of P(Cy)₃ ligands.

The reductive hydroformylation of olefins can be catalyzed by Rh which is immobilized on a highly branched amine containing polymer for efficient recycling and a high selectivity and alcohol yield.

Abstract

The reductive hydroformylation of olefins is an important process in the chemical industry to produce alcohols directly without isolating the aldehydes as intermediates. As the hydroformylation is a homogeneously catalyzed reaction, the catalyst recycling and down-stream processing is often complex and energy intensive. A heterogeneous reductive hydroformylation catalyst was developed in this work by immobilizing Rh on polymeric amine macroligands to form solid molecular catalysts (SMCs). An iterative macroligand improvement was carried out by increasing the basicity and number of amine groups at the immobilization sites. With the best performing SMC, olefins were fully converted to >99% alcohols without a hydrogenation of the substrate in a solvent free environment, thus requiring only a separation of the heterogeneous catalyst to yield the pure product. The catalyst was successfully recycled over 12 runs with a perpetual Rh leaching as low as 1.2%, and the metal to macroligand ratio was identified as most important parameter in reducing metal loss.

Nature Communications, Published online: 16 April 2025; doi:10.1038/s41467-025-58990-1

Although Brønsted base-mediated [1,2]- phospha-Brook rearrangements have garnered considerable attention in the development of new methodologies, the strict reliance on pentavalent phosphonates imposes strong limitations on new reaction types. Here, the authors disclose a Lewis acid-mediated trivalent [1,2]- phospha-Brook rearrangement with carbonyl compounds to rapidly access tertiary phosphine oxides.

A regioselective insertion of (hetero) aryl groups into the C−C double bond of unactivated internal alkenes by nondirected arene-C(sp²)−H activation has been achieved. The design and development of a new ligand-supported palladium catalysis, enables quick access to trisubstituted alkenes, especially E-1,2-diarylalkenes, from unfunctionalized simple raw materials in moderate to high yields, with excellent regio- and stereocontrol.

Abstract

Regioselective functionalization of internal alkenes has become a highly efficient approach for preparing stereochemically defined multi-substituted olefins. Unlike traditional methods that require directing groups, activating groups, or active chemical bonds (e.g., halide, pseudo halide, organometallic reagent, etc.), there remains a strong demand for nondirected and selective functionalization of unactivated alkenes with simple coupling partners, both in academic research or industrial applications. Herein, we report the development of a pyridone-oxazoline (Pyoox) type ligand that combines the features of both pyridone and pyridine-oxazoline in assisting Pd-catalyzed olefination. This ligand enables the activation of simple (hetero) arenes and internal alkenes within a single reaction system. A nondirected and regioselective arylation from simple raw materials has been achieved, providing a straightforward route to various trisubstituted olefins in moderate to excellent yields, with excellent regio-/stereocontrol. Experimental and computational studies on mechanisms offer insight into the distinctive properties and performance of this ligand-promoted catalysis. The synthetic utility of this method is further demonstrated by the simplified synthesis and late-stage diversification of bioactive molecules.

A reverse regioselective dicarbofunctionalization of acrylamides via anti-Michael-type addition is reported. Various (hetero)arene nucleophiles and carbon electrophiles were incorporated in a manner opposite to conventional regioselectivity. A key feature of this reaction is the formation of an alkylpalladium intermediate, which enables the achievement of the uncommon regioselectivity.

Abstract

Vicinal dicarbofunctionalization of α,β-unsaturated carbonyl compounds is a classical yet versatile method for constructing complex molecular architectures in a single step. However, the regioselectivity is typically governed by the electronic properties of the alkene moiety, leading to the introduction of a nucleophile at the β-position and an electrophile at the α-position. Herein, we report a palladium-catalyzed dicarbofunctionalization of acrylamides via anti-Michael-type addition, achieving reverse regioselectivity relative to traditional approaches. This strategy enables the efficient incorporation of various (hetero)arene nucleophiles at the α-position and carbon electrophiles, including iodoarenes, vinyl iodides, and iodomethane, at the β-position to furnish dicarbofunctionalized amides in good yields. Mechanistic investigations suggest that the reaction proceeds through an alkylpalladium intermediate formed via the α-addition of a nucleophile.

A sequential process combining hydrogenation and a subsequent stereomutation is presented for trans selective hydrogenation of quinolines using water as the hydrogen atom source. Mechanistic studies reveal that the hydrogenation proceeds through a cascade process comprising an initial cis selective photocatalytic hydrogenation of the heteroarene core of the quinoline followed by a trans selective photoisomerization.

Abstract

The design of a sequential process combining hydrogenation and a subsequent stereomutation is an attractive strategy for the stereoselective reduction of cyclic disubstituted π–systems to access the thermodynamically more stable trans isomer, which would be the minor compound considering a kinetically controlled cis hydrogenation process. Herein, we demonstrate stereoselective photocatalytic phosphine-mediated quinoline reductions with water as the hydrogen atom source under mild conditions to afford the corresponding 1,2,3,4-tetrahydroquinolines with complete selectivity towards reduction of the heteroaromatic part. The method shows broad functional group tolerance and provides access to trans-2,3-disubstituted tetrahydroquinolines with moderate to excellent diastereoselectivity. These trans isomers are not readily obtained using established methods, as transition-metal-catalyzed regioselective quinoline hydrogenations provide the corresponding cis-2,3-disubstituted isomers with high selectivity. Mechanistic studies reveal that the hydrogenation of the 2,3-disubstituted quinolines proceeds through a cascade process comprising an initial cis selective photocatalytic hydrogenation of the heteroarene core of the quinoline, followed by a trans selective photoisomerization.

A nickel-catalyzed group-exchange strategy has been developed for the direct conversion of aromatic lactones into cyclic hemiboronic acid bioisosteres. Scope evaluation and product derivatization experiments demonstrate broad functional-group compatibility and the synthetic value of this strategy. Furthermore, the application of this methodology to the rapid modification of lactone cores in bioactive molecules underscores its practical utility.

Abstract

Bioisosteric replacement is an important strategy in drug discovery and is commonly practiced in medicinal chemistry; however, the incorporation of bioisosteres typically requires laborious multistep de novo synthesis. The direct conversion of a functional group into its corresponding bioisostere is of particular significance in evaluating structure-property relationships. Herein, we report a functional-group-exchange strategy that enables the direct conversion of aromatic lactones, a prevalent motif in bioactive molecules, into their corresponding cyclic hemiboronic acid bioisosteres. Scope evaluation and product derivatization experiments demonstrate the synthetic value and broad functional-group compatibility of this strategy, while the application of this methodology to the rapid remodeling of chromenone cores in bioactive molecules highlights its utility.

By employing complex arylthianthrenium salts and readily available (hetero)aryl (pseudo)halides as starting materials, in conjunction with hypoboric acid as a reductant, structurally diverse (hetero)biaryl motifs can be rapidly synthesized via palladium-catalyzed cross-coupling reaction. Key to this advance is the selective and mild borylation of arylthianthrenium salts, followed by a conventional SMC (Suzuki–Miyaura cross-coupling) reaction with aryl halides.

Abstract

Herein, we present a cross-coupling reaction of arylthianthrenium salts at a late stage with diverse (hetero)aryl (pseudo)halides under reductive conditions, in which a palladium(0) catalyst differentiates between two aryl electrophiles based on the different rates of oxidative addition of arylthianthrenium salts and aryl halides for selective umpolung. A measured near-zero Hammett rho value is consistent with oxidative addition of the arylthianthrenium salts to palladium(0) being insensitive to substituent effects, which enables reaction with structurally and electronically diverse arylthianthrenium salts. In addition, we show the robustness of this method by coupling of two complex fragments that would otherwise be difficult to access in a single step.

We report the first bis(pinacolato)diboron-enabled Ni-catalyzed regio- and enantioselective reductive [3 + 2] annulation of β-bromoenones with alkynes, providing convenient access to synthetically valuable chiral five-membered cyclic tertiary alcohols via axial chirality transfer to central chirality. A broad substrate scope, late-stage functionalization of complex molecules, and diverse transformations highlight the utility of this reaction.

Abstract

Chiral five-membered cyclic tertiary alcohols are important structural motifs in functional materials, pharmaceuticals, and bioactive molecules. Hence, developing efficient methodologies for synthesizing compounds featuring these privileged scaffolds represents a crucial pursuit within synthetic chemistry. Herein, we present a regio- and enantioselective Ni-catalyzed strategy for the reductive [3 + 2] annulation of β-bromoenones with alkynes, providing convenient access to chiral five-membered cyclic tertiary alcohols with high levels of regio-, and enantioselectivity via axial chirality transfer to central chirality. The utilization of an environmentally sustainable bis(pinacolato)diboron (B₂pin₂) is crucial for the success of this asymmetric reductive cyclization reaction. Simultaneously, the mild reaction environment greatly enhances functional group compatibility. This has been demonstrated by the broad substrate scope, late-stage functionalizations of bioactive compounds or drug molecules, and subsequent transformations. Amongst, it is worth emphasizing that these functionally enriched chiral five-membered cyclic tertiary alcohols can efficiently participate in Diels–Alder reactions to synthesize enantioenriched polycyclic and heterocyclic molecules, thereby further validating the significance of introducing a cyclopentadiene skeleton. The preliminary mechanistic studies revealed the mode of action of B₂pin₂ in mononuclear Ni-catalyzed asymmetric reductive [3 + 2] annulation reactions and density functional theory (DFT) calculations clarified the origin of the experimentally observed regio- and enantioselectivity.

We report the enantiodivergent syntheses of cycloaurenones and dysiherbols via a common cyclohexadienone intermediate, that is, a local desymmetric Giese–Baran-type cyclization and a copper-catalyzed enantioselective conjugate addition reaction. This cyclohexadienone was obtained by a bidirectional synthesis from a chiral bis-Weinreb amide, with stereocenters set by a novel Rh-catalyzed hydrogenation (>99:1 chiral/meso ratio, >99% e.e.).

Abstract

Cycloaurenones and dysiherbols are naturally occurring sesquiterpene quinones/quinols that share a 6/6/5/6 tetracyclic carbon skeleton with either a cis- or trans-decalin system containing four contiguous stereocenters, including three contiguous all-carbon quaternary stereocenters. Total syntheses of cycloaurenones have not been reported. Herein, we present the first enantiodivergent syntheses of cycloaurenones and dysiherbols based on manipulation of a common cyclohexadienone intermediate: namely, a local desymmetric Giese–Baran-type cyclization for cycloaurenones and a copper-catalyzed enantioselective conjugate addition for dysiherbols. Moreover, the key cyclohexadienone intermediate was readily accessible by a bidirectional approach from a chiral bis-Weinreb amide. The 1,4-nonadjacent stereocenters were installed by an unprecedented enantioselective hydrogenation of the corresponding bis-α,β-unsaturated Weinreb amide (>99:1 chiral/meso ratio, >99% enantiomeric excess).

Efficient electrophotochemical C─H fluoroalkylation of complex bioactive substrates with abundant fluoroalkyl carboxylic acids employing an inexpensive iron(III) catalyst accompanied by hydrogen evolution reaction has been developed.

Abstract

Chemo- and site-selective functionalization of complex molecules poses a fundamental challenge. Herein, we introduce a resource-economic photoelectrocatalysis strategy to enable versatile direct fluoroalkylations catalyzed by Earth-abundant iron and paired with the hydrogen evolution reaction (HER). Notably, the devised approach proved amenable to versatile late-stage C─H fluoroalkylations of bio-relevant heterocycles, such as xanthines, nucleobases, and nucleosides. Mechanistic studies supported a ligand-to-metal charge transfer-induced formation of the fluoroalkyl radical.

The merger of deprotonation and halogenation into compatible processes provides a new strategy for functionalizing traditionally unstable carbanionic intermediates, including α,α-difluorobenzylic carbanions. This capability is leveraged toward the first general method for oxidative coupling of α,α-difluoromethylarenes with common pronucleophiles to produce valuable α,α-difluorobenzylic (thio)ethers.

Abstract

We describe how the merger of deprotonation, halogenation, and substitution into compatible processes enables the productive functionalization of traditionally unstable carbanionic intermediates. This strategy enables the first oxidative coupling protocol of α,α-difluorobenzylic C─H bonds with heteronucleophiles. Here, transiently generated α,α-difluorobenzylic carbanionic intermediates undergo halogen transfer from 2-bromothiophenes to form electrophilic ArCF₂Br compounds for in situ nucleophilic substitution, thereby avoiding α-fluoride elimination pathways that typically plague α-fluorocarbanions. This method streamlines the modular synthesis of α,α-difluorobenzyl(thio)ethers and led to the broader realization that halogen transfer to unstable carbanions is an enabling principle across diverse C(sp²)─H and C(sp³)─H systems.

ChemElectroChem, Volume 12, Issue 19, October 3, 2025.

Total syntheses of the meroterpenoid quinones dactyloquinone A and spiroetherone A were achieved from a common intermediate through the following original key steps: a metal-hydride hydrogen atom transfer (MHAT) process with a quinone monoacetal in the case of dactyloquinone A, and a quinol–enedione rearrangement in the case of spiroetherone A.

Abstract

We report the total synthesis of dactyloquinone A and spiroetherone A from a meroterpenoid scaffold obtained by the deconjugative alkylation of a Wieland–Miescher type ketone. For dactyloquinone A, we employed an intramolecular hydrofunctionalisation of the internal trisubstituted alkene with a quinone monoacetal via a metal-hydride hydrogen atom transfer (MHAT) process to form the key C─O bond. For spiroetherone A, we relied on a stereospecific quinol–spiroenedione rearrangement. The initially postulated structure of spiroetherone A was first synthesized, but was found to be different from the natural product. Finally, spiroetherone A was shown to be epimeric at the spirocyclic carbon. This finding was confirmed by total synthesis involving epimerization of the spirocycle via a late-stage singlet oxygen [4+2] cycloaddition to a cyclohexadiene derived from the initial enedione.

“I am most proud of my research group when multifunctional materials are achieved by facile one-step processes… My favorite time of day is evening time when I like to summarize the day and make plans for tomorrow…”

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A General and Efficient Method for the Direct Synthesis of Primary Arylamines Through Electrochemical Amination of Aryl Halides With NH₃ Has Been Developed. The Weak Nucleophilic Reagent NH₃ Acted as an Ammonia Surrogate. This Approach Shows Good Functional Group Tolerance and a Broad Scope of Functionalized Primary Arylamines That Can be Further Late-stage Modification of Drug Molecules and Gram-scale Reaction Demonstrate Its Synthetic Utility.

Abstract

Primary arylamines are the most pivotal class of organic motifs in pharmaceuticals, agrochemicals, ligands and natural products. Ammonia (NH₃) is an ideal nitrogen source in terms of reactivity, atom economy, and environmental compatibility. Despite significant progress in the synthesis of primary arylamines, the development of a general method for rapid access to diversely functionalized primary arylamines is still urgent and necessary. Herein, we developed a method for the direct synthesis of primary arylamines through electrochemical amination of aryl halides with NH₃. Notably, the weak nucleophilic reagent NH₃ was directly used as an ammonia surrogate, allowing for efficient conversion of carbon-halogen bonds to diverse primary arylamines with good functional group tolerance. A broad scope of functionalized primary arylamines has been achieved in moderate to excellent yields.

We present a practical method for synthesizing aromatic allylamines via iron-catalyzed reductive allylic amination. This approach eliminates the need for noble metals and complements existing oxidative allylic amination by tolerating oxidizable and nucleophilic functionalities.

Abstract

Aromatic allylamines are essential in the synthesis of diverse pharmaceutical building blocks. While oxidative allylic C─H amination using anilines has advanced significantly, achieving intermolecular reductive allylic C─H amination of olefins with readily available nitroarenes remains a considerable challenge. Here, we demonstrate that replacing silanes with a combination of protons and electrons enables selective reductive allylic C─H amination, avoiding the competing hydroamination pathway. The key to this transformation is the use of 2,2,2-trifluoroethanol (TFE) as the solvent. This process complements previous oxidative allylic C─H amination by eliminating the need for noble metal catalysts while tolerating oxidizable or nucleophilic functional groups. Notably, this method facilitates the functionalization of bioactive compounds, underscoring its potential in medicinal chemistry. Furthermore, by leveraging its reactivity with trisubstituted olefins, this approach, when combined with metal hydride atom transfer (MHAT) reactions, offers a unique strategy for regioselective and modular difunctionalization of aliphatic olefins. Experimental and computational mechanistic studies highlight the crucial roles of TFE in stabilizing the nitrosoarene intermediate and promoting the key nitroso-ene step.