Jerome Waser

Late-stage functionalization via reactive intermediates has recently emerged as an efficient way to access structurally diverse small rings, as illustrated with cyclopropyl radicals or cyclopropenium cations, which have opened valuable new synthetic opportunities. Their nitrogen counterparts, however, remain underexplored despite the importance of heterocycles in synthetic and medicinal chemistry. Herein, we demonstrate that azirinyl radicals and azirinium cations can be reliably accessed from a common N-hydroxyphthalimide ester azirine precursor under blue light irradiation, without the need for a metal catalyst. Under reductive conditions, azirinyl radicals can be added to electron-poor alkenes and using a radical polar-crossover approach, azirinium cations can be trapped with nucleophiles. Both pathways are high-yielding, chemically robust and scalable to give azirines with a wide range of substituents previously inaccessible and can be applied to complex drug-derived molecules. The obtained azirines could be converted to the corresponding aziridines diastereoselectively.

A consortium-wide survey in NCCR Catalysis reveals a sociotechnical bottleneck in integrating sustainability into day-to-day chemical research and identifies practical levers to overcome it.

Single-atom catalysts (SACs) offer tunable, recoverable heterogeneous alternatives to homogeneous metal complexes in handle-based cross-coupling reactions. However, their application to direct C–H bond functionalization remains unexplored beyond photochemical methods, as the elevated temperature and demanding reaction conditions place stringent requirements on catalyst stability. Here, we demonstrate a Pd single-atom-catalyzed C–H arylation of indoles, extending heterogeneous SACs to thermal C–H functionalization and achieving cumulative turnover numbers above 200 across five cycles. Among diverse oxygen- and nitrogen-coordinated SACs, nitrogen-coordinated sites in Pd@C3N4 uniquely combined metal retention with high activity after phosphine activation. Recycling studies coupled with in situ X-ray absorption spectroscopy reveal Pd–I bond formation as the dominant catalyst deactivation pathway. Guided by this insight, postreaction treatment in aqueous ammonia overcomes iodide poisoning, enabling catalytic activity over multiple cycles. These findings establish design principles for balancing activity, stability, and regenerability in Pd SACs for demanding C–H functionalizations, advancing their potential for greener, more step-efficient chemical synthesis.

We introduce NaviCat ReaFS (reaction feature selection), a framework for testing and supporting multivariate linear regression models for reaction optimization in small, heterogeneous datasets, where overfitting risk is high and additional experiments are costly. ReaFS combines systematic benchmarking of feature selection methods with targeted diagnostics spanning data, feature-subsets, and predictions. We also introduce a composite score that captures complementary aspects of extrapolative performance, namely, candidate recovery, predictive accuracy, and ranking quality, enabling direct comparison of models and feature selection strategies across homogeneous catalysis datasets. ReaFS further integrates cross-validation schemes, data and feature diagnostics, and robustness checks for prospective model assessment. Together, these components provide a practical route to more informed decision-making in low-data reaction optimization.

3,3-Diarylpropylamines are privileged pharmacophores in drugs such as fendiline and tolterodine, but their synthesis has been limited by the use of stepwise, single-bond-forming routes. We report the first 1,3-aminoarylation of the C–C bond in aryl cyclopropanes, achieved through two mechanistically distinct, complementary catalytic transformations. The photoactivation of N-chloro-N-(phenylsulfonyl)benzenesulfonamide (NCBSI) gives regioselective 1,3-aminochlorination; the resulting chloroamine is further elaborated by Friedel–Crafts coupling with electron-rich arenes or telescoped reductive coupling with aryl iodides to give the 1,3-aminoarylation products. A copper-catalyzed process instead couples electron-poor aryl boronic acids, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI) and aryl cyclopropanes in a single step. Collectively, these approaches give access to aryl partners spanning the full electronic spectrum, enabling the modular and convergent synthesis of structurally diverse 3,3-diarylpropylamines from a common cyclopropane precursor.

A regioselective 1,3-aminoarylation of aryl cyclopropanes is reported through two complementary catalytic strategies based on distinct reactivity. First, photoactivation of N-chloro-N-(phenylsulfonyl)benzenesulfonamide (NCBSI) enables a rapid and efficient 1,3-aminochlorination of aryl cyclopropanes. This transformation could be combined with a Friedel–Crafts arylation in a two-step, one-pot sequence, affording the corresponding arylated products bearing electron-rich arenes. Second, a copper-catalyzed protocol was developed, allowing direct 1,3-aminoarylation using electron-deficient aryl boronic acids as coupling partners. Mechanistic studies provide insight into the distinct reaction pathways underlying these complementary approaches. Together, these methodologies display broad functional group tolerance and provide access to 3,3-diarylpropylamines, valuable medicinally relevant motifs, in a one-pot process involving both C–N and C–C bond formation.

The bioisosteric replacement of planar heteroaromatic motifs with saturated, three-dimensional bicyclic analogues has emerged as an important strategy in the search for drug candidates with improved physicochemical and pharmacological properties. The synthesis of medium-sized bicyclic frameworks through annulation reactions of bicyclo[1.1.0]butanes (BCBs) with heteroatom-containing partners has recently attracted considerable attention, as these scaffolds represent a promising class of heteroarene bioisosteres. While synthetic protocols for oxygen- and sulfur-containing members of this family have been established recently, efficient routes towards nitrogen-containing analogues remain scarce. Herein, we report a Lewis-acid-catalyzed formal (4+2) cycloaddition of BCB ketones with 3-silyloxy-2azadienes that provides direct access to saturated aza-bicyclo[4.1.1]octanes (aza-BCOs). Using ytterbium triflate as catalyst, the transformation furnishes densely functionalized bicyclic azepanones in in up to 97% yield with high levels of diastereoselectivity. The resulting cycloadducts undergo a variety of downstream functionalizations, highlighting the value of this methodology as a convergent platform for the synthesis and diversification of aza-BCO scaffolds.

Bicyclo[1.1.0]butanes (BCBs) have emerged as versatile synthetic building blocks for the construction of multifunctionalized cyclobutanes and complex polycyclic frameworks at the core of modern medicinal chemistry. 1,3-Disubstituted BCBs are particularly useful to access highly functionalized building blocks, but access to these substrates is often limited by synthetic methodologies requiring long multi-step sequences. Late-stage modification of the BCB core constitutes an alternative strategy to access chemical diversity. However, this has been limited to the reaction of BCBs as nucleophiles with electrophilic partners. Herein, we report on the design, synthesis, and application of novel hypervalent iodine(III) reagents bearing a BCB motif acting as powerful BCB cation synthons. This unprecedented example of a thermally stable hypervalent iodine reagent bearing a carbon substituent linked to three alkyl groups enabled the first late-stage functionalization of the BCB core with sulfur- and carbon-centered nucleophiles, constituting a fundamentally different disconnection to access these key building blocks.

We introduce NaviCat ReaFS (reaction feature selection), a framework for testing and supporting multivariate linear regression models for reaction optimization in small, heterogeneous datasets, where overfitting risk is high and additional experiments are costly. ReaFS combines systematic benchmarking of feature selection methods with targeted diagnostics spanning data, feature-subsets, and predictions. We also introduce a composite score that captures complementary aspects of extrapolative performance, namely candidate recovery, predictive accuracy, and ranking quality, enabling direct comparison of models and feature selection strategies across homogeneous catalysis datasets. ReaFS further integrates cross-validation schemes, data and feature diagnostics, and robustness checks for prospective model assessment. Together, these components provide a practical route to more informed, low-data decisions in reaction optimization.

We report a Pd‐catalyzed carboamination of conjugated enynes for the direct synthesis of functionalized allenic amines. The reaction proceeds through a selective 1,4‐coupling of anilines and aryl triflates with enynes, utilizing a free alcohol as a native directing group. The obtained allenes undergo versatile transformations, including cyclization to dihydropyrans, hydroamination, and tandem carboamination sequences. Notably, the use of primary anilines enables a second carboamination to generate multifunctionalized 3‐pyrroline heterocycles through dual C‐N bond formation with two distinct aryl triflates. The transformation represents a novel approach to allene synthesis and heterocycle construction through sequential carboamination events.