Robert Pollice#RobSelects paper of the week #ACSCentSci: Systematic statistical analysis of 66,000 organic reactions from high-throughput experiments representative of pharmaceutical drug discovery. #orgchem https://doi.org/10.1021/acscentsci.5c02031
#RobSelects preprint of the week #ChemRxiv: Photochemical conversion of aryl azides into pyridines via triplet aryl nitrenes. #orgchem https://doi.org/10.26434/chemrxiv-2026-jn9zb
#RobSelects preprint of the week #ChemRxiv: Photochemical isomerization of N-substituted pyrazoles to imidazoles. #orgchem https://doi.org/10.26434/chemrxiv-2026-68vcj
A photochemical strategy for pyrazole to imidazole conversion
Heteroaromatic scaffolds are central to modern medicinal chemistry. Methods that can reconfigure the core heterocycle of a molecule while preserving its substitution pattern would greatly streamline analogue synthesis and bioisosteric replacement. Yet, direct heterocycle-to-heterocycle interconversions remain rare. Here we report a photochemical strategy that converts pyrazoles into imidazoles in a single step with broad functional-group tolerance and full retention of peripheral substitution. The reaction is effective across densely substituted and annulated systems and extends to pyrazolo[1,5-a]azines, a class of high-value heteroaromatics that have never previously been reconfigured. We show that selective photoexcitation of the pyrazole unit enables clean, predictable rearrangement even in the presence of competing absorption pathways. Mechanistic studies support an N–N bond homolysis pathway in which solvent-dependent conformational changes govern the reactivity of the ensuing biradical intermediates. This photochemical strategy is readily translated to continuous flow, confirming its potential for scalable applications. Overall, this work establishes a practical platform for direct core reconfiguration, providing modular access to imidazole analogues of pyrazoles that are otherwise difficult to prepare or very expensive.
Evan Spotte-Smith (they/them)#RobSelects preprint of the week #ChemRxiv: Intermolecular alkene hydroamination promoted by single electron reduction. #orgchem https://doi.org/10.26434/chemrxiv-2025-fblsl
Solvated Electron-Driven Hydroamination of Olefins
We report a transition metal-free method for the intermolecular hydroamination of olefins using solvated electrons, generated in situ from granulated lithium under sonication in 2-methyltetrahydrofuran (2-MeTHF). This additive-free protocol enables rapid formation of mixed secondary and tertiary amines under ambient conditions with broad substrate scope and functional group tolerance. Mechanistic studies support an SET and HAT pathway, with lithium amide intermediates acting as both reductants and nucleophiles. The method offers excellent atom economy, sustainability, and synthetic utility, exemplified by the selective synthesis of the racemic version of the pharmaceutical benzphetamine in high yield.
#RobSelects preprint of the week #ChemRxiv: E-Selective hydrazine-mediated cross carbonyl-olefine metathesis. #orgchem https://doi.org/10.26434/chemrxiv-2025-hb5l1
Cross Carbonyl-Olefin Metathesis (XCOM) of Unactivated Olefins
A method for the olefination of aryl aldehydes with unactivated alkenes via cross carbonyl-olefin metathesis (XCOM) is described. Reaction of an aldehyde substrate and a cis-1,2-disubstituted or monosubstituted olefin with the HBF4 salt of 2,3-diazabicyclo[2.2.2]octane results in high-yielding olefination with exclusive trans stereoselectivity. The reaction is shown to accommodate a range of substitution patterns on the aryl aldehyde and a diverse set of functional groups, including protic functionality that would complicate traditional olefination methods. We show that product inhibition arising from the aliphatic aldehyde side product limits catalytic turnover, but that distillative removal of this component renders catalysis feasible.
#RobSelects preprint of the week #ChemRxiv: Comprehensive mechanistic study of the oxidative aminative cleavage of alkenes with a hypervalent iodine oxidant and ammonium carbamate. #orgchem https://doi.org/10.26434/chemrxiv-2025-6cdgb
Kinetic, Spectroscopic, and Computational Investigation of Oxidative Aminative Alkene Cleavage Reveals an N-Iodonium-Iminoiodinane Pathway
The combination of hypervalent iodine(III) oxidants and ammonia sources has been applied in various oxidative aminative transformations of high synthetic value. Central to these reactions is the proposed in situ generation of a four-electron oxidizing intermediate, commonly referred to as iodonitrene. However, this species’ mechanism of formation, nature, and relevance to N-atom transfer remains uncertain. Furthermore, evidence for its direct implica-tion as the key reactive intermediate remains elusive. Herein, we present an extensive mechanistic study of a re-cently published oxidative aminative cleavage of alkenes, which allowed us to obtain key insights into these under-studied aspects of hypervalent iodine-mediated nitrogen atom insertion. Through in situ 19F nuclear magnetic reso-nance (NMR), initial rate kinetics, linear free energy relationships (LFER), H/D and 12C/13C kinetic isotope effect (KIE) determination, electrospray ionization mass spectrometry (ESI-MS) and density functional theory (DFT) stud-ies, we show that the formation of an N-iodonium-iminoiodinane is rate-determining in this reaction. This species is highly electrophilic and capable of concerted, asynchronous transfer of a [PhI–N]+ unit to double bonds. These find-ings point towards the N-iodonium-iminoiodinane, not an iodonitrene, being the active N-atom transfer agent gen-erated from the combination of hypervalent iodine(III) oxidants and ammonia. This ultimately deepens our under-standing of this commonly used reagent combination and will help to inform the development of methods and rea-gents for oxidative amination reactions using this reactive manifold.
Ellis CrawfordCheck out the latest Synthesis Workshop video with a presentation from Ann-Sophie Paschke and Stefanie Schiele on their latest work with Bill Morandi group that has been published in Chemical Science.
https://www.youtube.com/watch?v=D513hX1gOTg
The video covers skeletal editing, and the advances made in the latest Chem Sci publication, which involves chemodivergent C-to-N atom swapping reactions.
You can read the full paper (for free) here: https://doi.org/10.1039/D5SC02032H
If you are interested in related developments, do check out our new Editor's Choice collection from Associate Editor Professor Ning Jiao (https://rsc.li/4owdnHw including other work from the Morandi group) and our collection of most popular works in organic chemistry (https://rsc.li/4opmslv.
Thank you too to Matthew Horwitz for the ongoing Synthesis Workshop initiative and Karim Abd El-Latef for hosting this episode!
Visit their YouTube channel at https://lnkd.in/e9wsZPzQ
Chemodivergent C-to-N Atom Swapping Reactions with Ann-Sophie Paschke and Stefanie Schiele
#RobSelects paper of the week #J_A_C_S: Reversible carbon-hydrogen activation of benzene and unactivated arenes with a nickel(0)-silylene complex. #orgchem https://doi.org/10.1021/jacs.5c10922
#RobSelects paper of the week #J_A_C_S: Leveraging a [1,3]-hydride shift in alpha-fluoro-diborylalkanes to synthesize cyclopropyl boronic esters. #orgchem https://doi.org/10.1021/jacs.5c08276