HAT Trick

Quick update: We’ve been bringing you weekly highlights in synthetic organic chemistry for 36 weeks straight this year, but now it’s time for a short break! After next week’s issue (Monday 22^nd September) we’ll be on annual leave for two weeks before returning to your inbox on Monday 13^th October.

Nickel-Catalyzed Cross-Dehydrogenative Coupling of Aldehydes and Alkenes toward Skipped Enones

S. Wagulde,^† P. Rai^† & V. Gevorgyan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10306)

The authors report a nickel-catalyzed cross-dehydrogenative coupling (CDC) reaction between aldehydes and alkenes for the synthesis of skipped enones, leveraging aryl radicals as intermolecular HAT agents. The transformation proceeds via the in situ generation of aryl radicals from aryl bromides, which mediates HAT from both the aldehydic and allylic C–H bonds to generate acyl and allylic radicals, respectively. These radicals are then engaged in a nickel-catalyzed radical–radical cross-coupling to deliver the skipped enone products with broad substrate scope, high chemoselectivity, and excellent tolerance to diverse functional groups.

Achieving Mono-Selective Palladium(II)-Catalysed C–H Activation of Arenes with Protein Ligands

H.-J. Xu, Z. Fan, B.-B. Nian, C.-H. Gu, S.-J. Shen, W. Zhang, Y. Hu* & J.-Q. Yu*

Nat. Catal. 2025 (DOI: 10.1038/s41929-025-01407-5)

Achieving mono-selectivity in C–H activation reactions is a considerable challenge when multiple identical C–H bonds coexist. Despite recent rapid advances in site-selective and enantioselective C–H activation, a large number of C–H activation reactions still suffer from poor mono-selectivity. Here, the authors report the use of commercial enzymes as ligands for palladium catalysts, enabling enhanced reactivity and exceptionally high mono-selectivity (up to 99%) in both ortho- and meta-C–H activation of arenes, which originally used bifunctional mono-N-protected amino acid ligands but with poor mono-selectivity. By leveraging these findings, a glycine-containing oligopeptide capable of achieving similarly high mono-selectivity was further developed.

“Cut-and-Sew” Reactions of β-Lactams via C–C Bond Activation

L. Kan,^† R. Zhang,^† S.-L. Lu, Y. Hari & G. Dong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c12770)

The authors report the first “cut-and-sew” transformation between β-lactams and alkenes/alkynes via C–C bond activation. Diverse bridged and fused nitrogen-heterocycles are prepared using this method with good functional group tolerance. The synthetic utility is demonstrated in the unified and streamlined preparation of norbenzomorphan-containing bioactive compounds.

Diversity-Oriented C–H Activation Reactions of the Naphthalene Scaffold

Z. Fan, M. E. Hoque, K. Wu, M. D. Palkowitz, U. Velaparthi, K. W. Gillman, J. X. Qiao & J.-Q. Yu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10482)

Given the pharmacophoric significance of the naphthalene scaffold in clinical drugs, diversity-oriented C–H functionalization reactions on this scaffold would be useful for drug discovery. However, direct C–H activation at the C6 and C7 positions has remained unexplored due to electronic similarity, remote distance from the directing group, and interference from geometrically identical positions (C7 vs. C3, C6 vs. C4). Here, the authors report two types of templates designed to differentiate the C6 and C7 positions on the naphthalene scaffold. The utility of this C–H activation is showcased through the divergent modification of naphthalene-containing complex molecules.

Synthesis of Bicyclo[2.1.0]pentanes and Vinylcyclopropanes Using Palladium Carbenes: Ligand-Controlled Carbene Reactivity

I. K. Eckart-Frank, E. S. Arnold,^‡ L. P. Murphy^‡ & S. M. Wilkerson-Hill*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10617)

The authors report an intramolecular cyclopropanation strategy to obtain functionalized bicyclo[2.1.0]pentanes (colloquially termed housanes) using palladium carbenes (20 substrates, up to 89% yield). Key to the success of this reaction was the insight that the reactivity of Pd(0) carbenes is controlled by the supporting ligand. Strongly donating N-heterocyclic carbene ligands promote cyclopropanation reactivity, while some π-accepting phosphoramidite ligands (e.g., rac-MonoPhos) afford C–H insertion products (8 examples, up to 20:1 selectivity). The housane products were amenable to late-stage cross-coupling reactions and ring-opening reactions to provide cyclopentanes.

Convergent Paired Electrolysis Enables Electrochemical Halogen-Atom Transfer-Mediated Alkyl Radical Cross-Coupling

X. Sun & K. Zheng*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10472)

The authors report a transition-metal-free electrochemical halogen-atom transfer strategy that enables alkyl radical cross-coupling via convergent paired electrolysis. In this system, anodically generated α-aminoalkyl radicals mediate the activation of alkyl iodides, while (hetero)aryl aldehydes or nitriles undergo cathodic reduction to afford persistent ketyl or (hetero)aryl radical anions. The matched redox processes facilitate selective radical–radical anion cross-coupling to furnish diverse alcohols and C(sp³)–C(sp²) coupling products under mild conditions and with broad functional group tolerance. The utility of this strategy is demonstrated in the late-stage modification of natural products, biomolecules, and pharmaceuticals.

Modular Access to N-SF₅ Azetidines

R. Li,^† C. Hu,^† C. Liu,^† T. Lyness, W. Li, C.-Y. Cai, E. Crossley, Y. Kanda, R. R. Merchant, B. S. Matsuura, N. S. Williams & T. Qin*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10954)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-q0c07) 🔓

A general and modular strategy has been developed for the synthesis of N–SF₅ azetidines. This transformation leverages bench-stable and scalable SF₅-transfer reagents to generate the SF₅ radical, which engages azabicyclo[1.1.0]butanes in strain-release difunctionalization reactions. The method proceeds under mild reaction conditions, features broad functional group tolerance, and the resulting N–SF₅ azetidines demonstrate high aqueous stability and increased lipophilicity.

Catalytic Asymmetric (ene–endo)-Carbonyl–Ene Type Cyclizations

L. Shi, N. Tsuji, C. Zhu, M. Leutzsch, J. A. A. Grimm & B. List*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c11553) 🔓

The authors report an efficient regio- and enantioselective catalytic asymmetric (ene–endo)-carbonyl–ene type cyclization of unbiased alkenyl aldehydes using a strong and confined IDPi Brønsted acid catalyst. High enantioselectivities of up to 98:2 e.r. were obtained for a range of homoallylic alcohols.

Ruthenium-Mediated N-Arylation for DNA-Encoded Libraries

S. Kanoo,^† E. de Pedro Beato,^† T. Schulte, L. Vogelsang, L. Torkowski, F. Waldbach, P. Hartmann, R. Kayal, K.-J. Dietz & T. Ritter*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c11842) 🔓

The authors report the development of a new ruthenium reagent that enables the chemoselective N-arylation of amine–DNA conjugates with distinct chemoselectivity when compared to conventional palladium-based C–N bond-forming catalysts. The ruthenium reagent activates commercially available haloarenes in situ via η⁶ π-arene coordination for subsequent S_NAr with the amine. The method is compatible with various commercially available haloarenes and aliphatic amines, and the reaction proceeds under mild conditions.

Bimolecular Homolytic Substitution (S_H2) and Radical Ligand Transfer (RLT): Emerging Paradigms in Radical Transformations

A. J. Fernandes* & D. Katayev*

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c01091) 🔓

The authors present a comprehensive perspective of the evolving landscape of radical ligand transfer (RLT) and bimolecular homolytic substitution (S_H2) chemistry, emphasizing recent advances. Key bioinspired and computationally guided approaches that have enhanced mechanistic understanding and broadened the substrate scope are highlighted, including landmark contributions by Kochi, Groves, Shaik, MacMillan, and others. To complement these studies and encourage further development, DFT-based thermodynamic analyses of radical ligand transfer across first-row transition metal complexes bearing porphyrin and BOX ligands are also reported.

Nickel-Catalyzed Enantioselective Diboration of 1,2-Dihydropyridines: Application and Insight into the Selectivity and Mechanism

M. R. Berwanger, T. K. Kubenik, H. Liang & J. P. Morken*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c04376)

1,2-Dihydropyridine was found to undergo enantioselective nickel-catalyzed 1,4-diboration with exclusive regio- and diastereoselectivity by employing a monodentate chiral phosphine ligand. The products were found to undergo regioselective allylic Suzuki–Miyaura cross-coupling with various electrophiles with high diastereospecificity. Insights into 1,4-diboration regioselectivity as well as putative reaction intermediates were obtained through NMR) experiments and computational studies.

Considerations in Pursuing Reaction Scope Generality

S. B. Zacate,^† J. A. Dantas,^† S. Lin,* A. G. Doyle* & M. S. Sigman*

Angew. Chem. Int. Ed. 2025, Early View (DOI: 10.1002/anie.202511091) 🔓

Synthetic methods that are applicable to a broad range of substrates are sought after, owing to their utility in industrial settings. This minireview describes considerations associated with how chemists define and identify general methods, especially with the emergence of modern analytical, high-throughput, and data science tools in chemistry, and gives the reader an overview of workflows that have been used to expedite this pursuit.

Electrolysis-Assisted Reduction of Dimethylformamide for Unactivated Alkene Functionalizations

Y. Xi,^† S. Sharma,^† C. O. Kappe & G. Laudadio*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-526dj) 🔓

The electrolysis-assisted generation of N,N-dimethylformamide distonic radical anion is presented and its synthetic applicability was demonstrated via functionalization of unactivated alkenes. The transformation was validated across several mono- and disubstituted olefins, generating the corresponding hydroformylated and hydroaminomethylated products.

Stereodivergent Construction of Decalin-Based Terpenoids

S. L. Barlock,^† A. S. Shved,^† K. D. Landers, B. K. Mai, S. Fujiki, W. Y. Lo, P. C. Ryffel, A. G. Feng, V. D. Nguyen, D. A. Petrone,* S. E. Denmark* & D. Sarlah*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-8r6bx) 🔓

The authors report an expedient route to a versatile terpenoid building block primed for elaboration into numerous complex natural products. This intermediate is provided from (R)-carvone in three steps through a diastereodivergent intramolecular carboborylation reaction. Notably, this method uniquely provides either equatorial or axial functionalization products from a single, common precursor. The synthetic utility of this method was demonstrated in the total synthesis of several diterpenoid natural products.

Safety Letter: Evaluation of the Popular Oxidant 2-Iodoxybenzoic Acid (IBX)

L. McDermott,^† D. Aljovic,^† Z. G. Walters, F. Peng, R. Zhao,* K. R. Campos & N. K. Garg*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c02282)

2-Iodoxybenzoic acid (IBX) is a versatile oxidant used in chemical synthesis. It has been employed as a reagent in more than 1400 publications since its initial use as an oxidant described in 1994. Here, the authors report a thorough assessment of IBX’s safety profile, including differential scanning calorimetry (DSC) experiments, a model for its self-accelerated decomposition temperature (SADT), assessment of IBX’s shock sensitivity through impact-sensitivity experiments, and calorimetry measurements with an advanced reactive system screening tool (ARSST). These studies confirm the explosive nature of the oxidant and provide insight into how IBX should be handled to maximize safety in a laboratory setting.

“Not Internationally Competitive”

🔬 “Not Internationally Competitive”. In a major blow to the UK’s life science sector, Merck & Co. (known as MSD outside the US and Canada) has scrapped plans for a £1 billion Discovery Centre in London’s King’s Cross—a facility already under construction that was due to open in just two years. The company will also lay off around 125 highly skilled scientists in the capital and relocate research to existing sites, most likely in the US amid pressure from the Trump administration to invest domestically. That’s 125 of our peers and for some of us, myself included, former colleagues. These are among the most talented organic chemists you could meet: the next generation of drug hunters who may well leave the UK for new horizons overseas.

MSD, which has operated in the UK for nearly a century, was blunt and lambasted the UK as “not internationally competitive”. The decision amplifies growing concern among global pharma leaders that Britain’s operating environment undervalues innovation and fails to provide a stable, attractive base for long-term investment. Industry sources also point to soaring rebate rates under the Voluntary Pricing and Access Scheme—23.5% compared with just 5–7% in France and Germany, as a key deterrent (that’s the amount of UK revenue that companies agree to pay back to the NHS from sales of branded drugs).

Foreign direct investment in UK life sciences has fallen nearly 60% since 2017, from £1.9 billion to £795 million. AstraZeneca also recently paused a £200 million investment into their UK headquarters and previously scaled back a £450 million vaccine manufacturing expansion in northern England after government support faltered. The loss of MSD’s centre, which intended to focus on neuroscience, inflammation and immunology, will be felt for a long time. London was poised to attract highly educated scientists that could strengthen the UK’s drug discovery pipeline. Instead, those scientists, opportunities and the economic benefit, are now heading elsewhere.

To avoid slipping further behind Europe and the US, the UK must urgently re-evaluate how it incentivises and rewards innovation. Biotech hubs like Basel thrive because of stable politics, supportive tax incentives and excellent infrastructure, conditions that have allowed pharma companies, start-ups, and top universities to cluster together and draw in talent worldwide. Switzerland has capitalized on this for years: Swiss biotech start-ups secured nearly £700 million from investors in 2024, up 50% on the previous year.

The UK government has rightly flagged life sciences as a “growth-driving sector” in its industrial strategy, but strategies alone will not retain companies like MSD. Without bold policy changes to restore competitiveness, Britain risks surrendering its position as a global leader in drug discovery and innovation.

NB: The Trump administration’s goal to lower US drug prices is one of those “even a stopped clock is right twice a day” moments but it’s happening at the expense of other countries. Eli Lilly’s ~170% hike on Mounjaro’s UK price is a clear example of costs being shifted abroad instead of addressing the real problem: a fragmented US healthcare system that prioritises profits over patients. Without meaningful price controls, centralised negotiation, removal of unnecessary middlemen and reform of private insurers who inflate costs, life-saving medications will remain unnecessarily expensive.