Carbonyl Out, Sulfur In

Carbonyl-to-Sulfur Swap Enabled by Sequential Double Carbon–Carbon Bond Activation

Z. Zhang & G. Dong*

Science 2025, First Release (DOI: 10.1126/science.adx2723)

The authors report a two-step carbonyl-to-sulfur atom swap enabled by a rationally designed N′-alkyl-hydrazonamide (NAHA) reagent that promotes forming pre-aromatic intermediates twice sequentially by different mechanisms, thereby achieving homolytic cleavage of both α-C−C bonds of the ketone substrates. A Ts-S-Ts (Ts, p-toluenesulfonyl) reagent mediates this process through successive intermolecular and intramolecular alkyl radical trapping by the central sulfur. This method shows a broad substrate scope and excellent chemoselectivity, providing a streamlined route to sulfur-containing scaffolds from readily available ketones.

Modular Alkyl Growth in Amines via the Selective Insertion of Alkynes into C–C Bonds

X.-Y. Zhou, L. Liu, H. Lyu & X.-C. Wang*

Nat. Chem. 2025 (DOI: 10.1038/s41557-025-01849-1)

The authors report a borane-catalysed method for the selective insertion of alkynes into alkyl C–C bonds of amines, resulting in the ring expansion of cyclic amines and chain elongation of acyclic amines. The method is effective with amines lacking an activating or leaving group and is suitable for late-stage functionalization of pharmaceuticals through C–C bond modification. Furthermore, by coupling this reaction with hydrolysis and hydrogenation steps, successive alkyne insertions are achieved, enabling modular and iterative alkyl growth of amines.

Ring Expansions of 1,2-Amino Alcohols to Amine Heterocycles Enabled by Proton-Coupled Electron Transfer

D. Q. Thach & R. R. Knowles*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04694)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-nlj7m) 🔓

The authors report a general method for the peripheral-to-core nitrogen internalization of amino cycloalkanols to access N-heterocycles of various oxidation states. In this process, an excited-state iridium chromophore and weak Brønsted base cooperatively promote the endergonic redox isomerization of cyclic amino alcohols to linear amine-containing products that undergo in situ cyclization. This strategy enables the expansion, contraction, and carbon-to-nitrogen substitution of cyclic amino alcohols, providing access to structurally distinct heterocyclic scaffolds.

Iridium Polypyridyl Carboxylates as Excited-State PCET Catalysts for the Functionalization of Unactivated C–H Bonds

D. A. Granados,^† Y. E. Du,^† S. J. Andersson, A. Cirincione-Lynch, K. Cui, A. Reinhold, P. D. Jeffrey, G. D. Scholes,* S. Hammes-Schiffer* & R. R. Knowles*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04000)

The authors present a novel set of iridium polypyridyl complexes bearing pendent Brønsted basic carboxylates that become potent hydrogen atom abstraction catalysts upon visible light irradiation. Thermochemical and spectroscopic characterization reveal that these excited-state complexes exhibit bond dissociation free energies (BDFEs) of up to 105 kcal mol^–1 with long excited-state lifetimes. These complexes can catalyze C–H alkylation reactions in which the Ir carboxylate mediates both C–H abstraction and formation steps.

Concise Syntheses of Lycojapomine Alkaloids Enabled by Radical Dearomatization of a Pyrrole

B. M. Gross & B. M. Stoltz*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05721)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-d3n5f) 🔓

The authors disclose the first total syntheses of the complex alkaloids Lycojapomine A and B utilizing a dearomatization and stepwise functionalization of a pyrrole starting material enabled by a photoinduced primary radical addition of an N-hydroxy phthalimide ester, and a subsequent silver-catalyzed 5-endo-dig and Aza-silyl-Prins annulation cascade. Divergent control over an aldol reaction yields both Lycojapomines A and B in an efficient manner, without the need for excess protecting groups.

Enantiocontrolled Azetidine Library Synthesis via Strain-Release Functionalization of 1-Azabicyclobutanes

M. Bielecki,^† M. Nassir,^† H. A. Sharma,^† N. J. Truax, N. Raheja, T. M. Thompson, T. El-Hayek Ewing, B. Melillo, B. F. Cravatt* & P. S. Baran*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07227)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-cmvd4) 🔓

A simple, modular, and programmable approach to access complex stereopure azetidines through strain-release functionalization is disclosed. The synthetic methods developed enable the parallel synthesis of stereodefined azetidines that would be otherwise laborious to produce. Given the privileged nature of these structures, a set of stereoprobes for use in activity-based protein profiling was prepared and evaluated, revealing proteins in human cancer cells, which were liganded with clear stereo- and chemo-selectivity.

Efficient Aminations of Aryl Halides by a Cu(II) Catalyst

C. N. Pierson, T. Horak, W. M. Amberg, R. Ray, G. Rao, T. M. Pinkhassik, S. M. Fantasia, S. M. Rummelt, K. Püntener, R. D. Britt & J. F. Hartwig*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05210)

The authors report that the coupling of (hetero)aryl bromides with a range of nitrogen nucleophiles occurs with copper and a simple dianionic, dimethylpyrrole-based oxalohydrazido ligand by a cycle in which Cu(II) complexes of this ligand are the resting state and an active, low-valent, catalytic intermediate. These couplings involving Cu(II) occur in many cases with just 0.1–0.2 mol% catalyst and take place under air, due to the absence of Cu(I) that is less stable to disproportionation and to air.

Consecutive Multiphoton-Mediated Defluorinative Amination of Fluoroarenes

A. Saha,^† M. Roy,^† S. Maji, G. Rana, D. Maiti* & D. Adhikari*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04164)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-j4glq) 🔓

The authors developed a strongly oxidizing photocatalyst, HATCN, which has a large π-delocalized aromatic core that can afford multiple stable redox states upon visible-light excitation and successive reductions under mild potential. This modularity proved instrumental in steering the aromatic defluorinative amination of fluorobenzenes.

Indole Photocatalysts and Secondary Amine Ligands Enable Nickel-Photoredox C(sp²)–Heteroatom Couplings

H. P. Chavda, K. J. Liang, T. J. Megna, O. R. Taylor, G. Kim, A. L. López & A. Bahamonde*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c03251)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-wvhb2) 🔓

The authors introduce a photocatalytic initiation strategy driven by inexpensive indoles and demonstrate the effectiveness of highly tunable secondary amine ligands in facilitating coupling while suppressing side reactions that sequester the Ni catalyst off-cycle. The approach enables a broad range of amination and etherification reactions with good yields and functional group tolerance, providing a scalable platform for C–N and C–O couplings that relies on a readily available photocatalyst and cost-effective, modular ligands.

Strain-Enabled Radical-Polar Crossover Annulation to Access Spiro-, Fused-, and Enantioenriched-Aza/Oxa-Bicyclo[3.1.1]heptanes

B. Ghorai, B. Sahana & D. P. Hari*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202506747)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-px1f3-v2) 🔓

The authors report a unified strategy to access aza- and oxa-bicyclo[3.1.1]heptanes from readily accessible amino- or hydroxy-acid derivatives under photoredox catalysis. The reaction exhibits broad scope to produce previously inaccessible spiro- and fused-hetero-bicyclo[3.1.1]heptanes. Chiral amino- and hydroxy-acids derived redox-active esters could be also used to access enantioenriched hetero-bicyclo[3.1.1]heptanes.

1,2-Boryl/Hydrogen Transposition via Reversible C–H Sampling

L. Xie,^† P. Luo,^† T. Lu,^† W. Zheng,^† Y. Su, J. Wang, X. Qi* & Y. Xu*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-lx3t5) 🔓

The authors report a direct, photocatalytic positional exchange reaction between boronic ester groups and unactivated C–H bonds in alkylboronic esters. The reaction employs a reversible C–H sampling strategy combining distinct hydrogen atom abstraction (HAA) and donation (HAD) catalytic cycles, enabling exclusive 1,2-boryl translocation with no directing groups, stoichiometric reagents or pre-existing functional groups required.

Versatile Positional Editing of Diverse Functional Groups Through Radical 1,2-Boron Shifts

W. Zhang,^† S. Mao,^† M. Peng & Y. Xi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-61whz) 🔓

The authors report a strategy for positional editing of a diverse set of functional groups to access a myriad of corresponding positional isomers by developing a catalytic, direct 1,2-transposition of pinacolboronic esters and harnessing the well-appreciated synthetic versatility of organoboron reagents. Key to the design is the identification of hydrogen atom transfer (HAT) catalysts possessing suitable rate constants, which control the reaction efficiency and selectivities.

Overriding Norrish Type II to Access Cyclopropanols

J. W. Pearson, S. L. Dudra, A. F. Palermo, B. S. Y. Chiu, J. Dang, A. L. Gabbey, B. A. B. Henson, T. R. Hou, N. Nabavi & S. A. L. Rousseaux*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-cdqzk) 🔓

Since its discovery in 1958, the Norrish-Yang photocyclization has become a prominent method to access cyclobutanols under mild photoirradiative conditions. However, access to medicinally relevant 3-membered rings remains limited due to the strong kinetic preference for 1,5-HAT over 1,4-HAT. Here, the authors demonstrate the first photocyclization of β-boryl aryl ketones to cyclopropanols. The strategy relies on solvent controlled selective population of the π,π* triplet state over the n,π* triplet state, with the former preferentially undergoing 1,4-boryl group transfer over 1,5-HAT.

Degradative Alcohol Functionalization by Titanocene Photocatalysis

J. A. Shah, A. E. Lojko, Z. Tang, Y. Lin, E. H. Scher, C. A. Barefoot & J. M. Lipshultz*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-vg021) 🔓

The authors describe the development of titanocene photocatalysis for the carbon-carbon bond cleavage functionalization of alcohol substrates. Mechanistic studies are consistent with in situ generation of a photoactive titanium alkoxide followed by subsequent photogeneration of alkoxyl radical and β-scission to carbon-centered radical, which is quenched through hydrogen atom transfer from an aryl thiol co-catalyst. A variety of alcohols can be effectively cleaved and the catalytic manifold has also been employed in cyanation and chlorination reactions.

Downsizing Lactams via Rh-Catalyzed C–C Activation

R. Zhang, K. Wen & G. Dong*

Chem 2025, Online Now (DOI: 10.1016/j.chempr.2025.102622)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-rqq9s) 🔓

The authors report an unprecedented lactam downsizing strategy by taking advantage of removable directing groups (DGs) and Rh-catalyzed C–C activation. The ring-contraction exhibits a broad substrate scope, excellent functional-group tolerance and high selectivity for γ-lactams, facilitating “6-to-5,” “7-to-5,” and “8-to-5” ring contractions.

Vaccine Confidence Falls, Misinformation Rises.

💉 Vaccine confidence falls, misinformation rises. Public attitude towards vaccinations have shifted significantly since the pandemic. A UNICEF global study has found a sharp decline in public confidence in the importance of childhood vaccinations—despite reports that COVID-19 vaccines saved an estimated 14.4 million lives worldwide in 2021 alone. To combat this increase in vaccine hesitancy, Nature have written an article on “how to speak to a vaccine sceptic”.

The UNICEF study found a substantial drop in vaccine confidence in 52 of the 55 countries studied. In Japan, confidence levels fell nearly 35% and in the United States, 21% are now vaccine-hesitant, a worrying figure that is reflected in the nearly 1,200 measles cases reported so far this year. Appointing vaccine skeptic Robert F. Kennedy Jr. as US Secretary of Health and Human Services certainly hasn’t helped. He’s recently fired every member of the CDC vaccine advisory committee and to those who will say Kennedy will just install his own team of yes men and ideologues, well…you’d be right—at least half of his new appointees have been characterized as “COVID-19 deniers, skeptics and outright anti-vaccine individuals.” Collectively, the new committee have published about 78% fewer vaccine-related papers than their predecessors with some having published no scientific papers at all. One member even claimed that the COVID vaccines caused 17 million excess deaths.

This mass overhaul comes shortly after Kennedy’s suggestion that the government might prevent federally-funded scientists from publishing in leading medical journals, proposing that the NIH might establish its own journals and publish in-house. All of this from the same guy whose recent report contained major citation errors and a strong suggestion that AI was involved—truly “gold standard” science. It is the advisory committee that makes recommendations about which vaccines to recommend and when, ultimately dictating insurance coverage that provides vaccines to children of low-income households for free. This move will seemingly do little other than further the spread of vaccine-preventable illnesses.

NB: Japan had an anti-vaccine movement as early as the mid-1970s in response to the death of two infants from adverse reactions to the whole-cell pertussis vaccine. However, following temporary suspension of these vaccines by the Japanese government, a pertussis (whooping cough) outbreak occurred, causing 41 deaths in 1979 and revealing to the public the beneficial effects of the vaccine. Since then, Japan proceeded to develop safer pertussis vaccines and now has the most experience worldwide with acellular pertussis vaccines.