E2, Brutus? How Electrochemistry Flipped a Textbook Rule

Out of office: Today’s issue will be the last update for two weeks (no issues will be sent on Monday 29^th September or Monday 6^th October) before we return to your inbox on Monday 13^th October!

Stereo-reversed E2 Unlocks Z-Selective C–H Functionalization

P. J. Verardi, E. A. Ryutov, P. Mukherjee, R. Lalisse, K. Targos, T. Inagaki, M. Kelly, I. A. Guzei, M. Schreier,* O. Gutierrez* & Z. K. Wickens*

Science 2025, 389, 1239–1245 (DOI: 10.1126/science.adv7630)

The authors describe the transformation of alkenes into transient 1,2-bis-sulfonium intermediates found to undergo Z-selective elimination, overturning a textbook E2 stereoselectivity rule through stabilizing interactions. Paired electrolysis was identified as an enabling strategy to both selectively generate the requisite bis-sulfonium intermediate and drive its rapid elimination in situ. The resultant Z-alkenyl sulfonium linchpins provide access to a wide array of Z-alkene targets from inexpensive feedstocks through robust cross-coupling reactions.

Diastereo- and Enantioselective 1,3-Hydrofunctionalization of Trisubstituted Alkenes by a Directing Relay

W. Zhao,^† E.-Z. Lin,^† K.-Z. Chen,^† Y.-W. Sun & B.-J. Li*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01936-3)

The authors report a catalytic 1,3-hydrofunctionalization of unactivated trisubstituted alkenes to generate enantiopure products containing α- and γ-stereocentres. An amide group on the alkene first directs the catalyst to cleave the methylene C–H bond enantioselectively, delivering an allylic stereocentre through C–H transposition. The amide remains bound to the metal centre, subsequently directing the catalyst to hydrofunctionalize the resulting alkene with high regiochemical and stereochemical controls. The separate stereocontrols in this “directing relay” enables stereodivergent access to 1,3-hydroalkynylation products, in which all four possible stereoisomers are obtained with excellent diastereoselectivities and enantioselectivities.

Regiocontrollable [2+2] Benzannulation of γ,δ-C(sp³)–H bonds with Dihaloarenes Using Palladium Catalysis

L. Hu,^† J.-L. Yan,^† Y.-K. Lin, D. A. Strassfeld & J.-Q. Yu*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00883-8)

The authors report a Pd(II)-catalysed method for the γ,δ-methylene C–H activation of aliphatic acids and subsequent coupling with dihaloarenes, which offers an efficient route to diversely functionalized benzocyclobutenes (BCBs). The development of a carboxyl-pyridone ligand was crucial for the remote C(sp³)–H activation.

Iodonitrene-Mediated Nitrogen Transfer to Alkenes for the Direct Synthesis of NH-Aziridines

Y. Gelato,^† L. Marraffa,^† F. Pasca, P. Natho, G. Romanazzi, A. Tota, M. Colella & R. Luisi*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10372) 🔓

This work presents an efficient method for the synthesis of NH-aziridines from a broad range of alkenes under mild conditions. The developed method uses aqueous ammonia and (diacetoxyiodo)benzene (PIDA) at 0 °C, offering a straightforward and atom-economical approach.

A General Metallaphotoredox Platform for N-Alkylated Sulfoximines as Bioisosteric Building Blocks

J. J. Großkopf, D. C. Morgan, A. K. Clarke & D. W. C. MacMillan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c13726)

The authors report a unified, mild, and broadly applicable metallaphotoredox-enabled protocol for the N-alkylation of sulfoximines, which overcomes limitations of previous N-substitution approaches by accommodating diverse alkyl sources, including alcohols, alkyl bromides, and carboxylic acids, under visible-light irradiation. The strategy features high functional group tolerance and its utility was showcased through the late-stage functionalization of pharmacologically active compounds and natural product derivatives. Furthermore, a preliminary drug optimization campaign, exemplified by an atuveciclib analogue, highlighted the platform’s potential for improving key ADME properties such as lipophilicity and cellular permeability.

Synthesis of Diverse Glycosyl Bicyclo[1.1.1]pentanes Enabled by Electrochemical Functionalization of [1.1.1]Propellane

J. Liu, R. Purushothaman, F. Hinrichs, M. Surke, S. Warratz & L. Ackermann*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10732) 🔓

The authors report an electrochemical strategy for the synthesis of BCP–glycosides via the functionalization of [1.1.1]propellane. By leveraging an electrochemical halogen-atom transfer (e-XAT) process, a one-step, three-component reaction of glycosyl bromides, [1.1.1]propellane, and radical acceptors was achieved under mild conditions, enabling the construction of glycosyl BCP–iodides, glycosyl BCP–H, and glycosyl BCP–Bpins with exceptional functional group tolerance and scalability.

A General Copper-Catalyzed Radical Cross-Coupling of Unactivated Alkyl Halides

F.-L. Wang,* Q. Xie, X.-Y. Chen, X.-M. Ye, N.-Y. Yang, J.-L. Deng, S.-H. Zhong, Y.-X. Zhang, J.-J. Chen* & X.-Y. Liu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10285)

The authors report a general copper-catalyzed C(sp³)–C/N cross-coupling of unactivated alkyl halides with diverse nucleophiles under mild thermal conditions. The success of this reaction relies on the use of anionic N,N,N-ligands to enhance the reducing capability of Cu(I) catalysts for the reduction of alkyl halides. This protocol accommodates a wide range of coupling partners with good functional-group compatibility.

Stable Isotope Labeling of Pyrimidines Using a Deconstruction–Reconstruction Strategy

B. J. H. Uhlenbruck & A. McNally*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c09719)

The authors present an isotope exchange method for synthesizing isotopically enriched pyrimidines. By deconstructing pyrimidines into vinamidinium salts and reconstructing them with deuterium, ¹³C, and ¹⁵N-enriched amidines, high isotopic enrichment was achieved across various substitution patterns, including complex drug-like pyrimidine derivatives.

Development of a Heteroleptic Palladium Catalyst for the Fluorination of Arylboronic Acids using Data Science Tools

S. Deolka,^† D. Dalmau,^† A. G. Roca,^† S. Vasylevskyi, M. H. Samha & M. S. Sigman*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c11929)

The authors report the development of a rare example of metal-catalyzed arylboronic acid fluorination that utilizes heteroleptic palladium complexes—catalysts that utilize two distinct ligands to achieve effective catalysis. Reaction optimization was achieved using high-throughput experimentation (HTE) for data collection, accelerated using multiobjective Bayesian optimization (EDBO+) for selection of experiments. Substrate scope was selected employing data science tools, and evaluation of these substrates revealed excellent functional group tolerance. Extensive mechanistic studies suggest that the two ligand types play unique roles in promoting the reaction.

Decoding the Nested, Multi-Cycle Mechanism of Ni-Catalyzed Redox Neutral Cross-Coupling Through Temperature Scanning Reaction Calorimetry

D. A. Cagan,^† Á. Péter,^† B. P. Vokits, M. Chan, P. S. Baran* & D. G. Blackmond*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-8hghl) 🔓

Catalytic reactions involving multiple cycles are common in many key organic transformations. Here, the authors report a detailed mechanistic analysis of one such network of “nested” cycles, the Ni-catalyzed cross-coupling of alkyl sulfonyl hydrazides with (hetero)aryl halides, employing temperature scanning reaction (TSR) calorimetry coupled with Reaction Progress Kinetic Analysis (RPKA), quantitative NMR time-course analysis, kinetic modeling, and density functional theory (DFT) quantum chemical calculations. Expanding the analysis to the coupling of an array of electron-poor and electron-rich sulfonyl hydrazides with a range of (hetero)aryl halide coupling partners introduces the concept of “kinetic matching,” and demonstrates that optimal yields may be obtained when the reactivities of the separate cycles are tuned to work in unison.

Photochemical Thiocarbonyl Difluoride Generation Enables Azetidine Synthesis

R. I. Rodríguez, J. Paut, G. Armellin, S. Visentini, G. Cormier, M. Bortolus, G. Pelosi, F. Droghetti, M. Natali & L. Dell’Amico*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-6dfrf) 🔓

The authors report a mild, photochemical method for in situ generation of thiocarbonyl difluoride from N-trifluoromethylthiophthalimide using visible light and organic reductants. This strategy was applied to the synthesis of structurally complex azetidines from strained azabicyclo[1.1.0]butanes. Thiocarbonyl difluoride-mediated ring opening followed by semipinacol rearrangement or nucleophilic additions enabled direct access to spiro- and fluorinated azetidines in a single step.

Celebrating Silliness

🎉 Celebrating silliness. The 35^th annual Ig Nobel Prizes were handed out last week at Boston University, celebrating research that “first makes people laugh, then think”, and this year was no exception. Amid a hail of paper airplanes and “a gaggle of bemused Nobel laureates” (if that is the proper collective noun), the winners each had one minute to explain their research ranging from the Physics prize for “discoveries about the physics of pasta sauce” to the Peace prize for showing that “drinking alcohol sometimes improves a person’s ability to speak in a foreign language”.

For Chemistry, that prize went to a team who tested whether or not Teflon—polytetrafluoroethylene (PTFE)—could act as a zero-calorie food additive to promote weight loss. That’s right, forget Mounjaro and Ozempic, the non-stick coating on your frying pan might as well be eaten with those fried eggs and bacon too. Inspired by a DuPont study from the 1960s, the researchers revisited old data showing that rats could ingest PTFE without apparent toxicity, losing weight when 25% of their diet was replaced with the polymer. A patent was even granted to the team for the use of PTFE as a satiety enhancer, though human trials never materialised. Given what we now know about microplastics, perhaps that was for the best.

Other notable winners worth a shout out:

• Biology Prize: Painting cows with zebra stripes reduces fly bites.

• Aviation Prize: Drunk bats fly slower and echolocate less accurately.

• Psychology Prize: Telling narcissists (or anyone) they’re intelligent reliably boosts their self-regard.

Ig Nobel founder Marc Abrahams insists these aren’t just jokes: “It’s not all about groundbreaking discoveries, but also about carefully examining everyday assumptions”. In a year marked by global tensions and misinformation, the Ig Nobels remind us that curiosity, humour, and critical thinking are cornerstones of good science.

💻️ Oral BTK Degrader Breakthrough. Be sure to catch the German Chemical Society’s next Medicinal Chemistry webinar on Thursday 25^th September from Dr. Barbara Czako of Nurix Therapeutics on the “Discovery of Bexobrutideg (NX-5948), an Oral Targeted Degrader of Bruton's Tyrosine Kinase (BTK) for the Treatment of B-cell Malignancies”.