Heterocycles Halogenated, Hassles Removed

Practical Ligand-Enabled C–H Halogenation of (Hetero)Benzoic and (Hetero)Aryl Acetic Acids

H. Zhao, Z. Li, X. Zhu & J.-Q. Yu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05774)

Through the discovery and development of three bifunctional bidentate pyridone ligands, the authors have rendered C–H halogenation technology substantially more practical: the reaction conditions require only a ligand-supported Pd(II) catalyst, inexpensive industrial halogenating reagents (NXS), and a commonly used acetonitrile solvent. The utility of this halogenation technology is demonstrated by one-step access to a variety of advanced intermediates for drug molecules that previously involved multistep syntheses.

Thiophenol-Catalyzed Radical Hydroformylation of Unactivated Sterically Hindered Alkenes

Y. Wang,^† P. Bao,^† X. Dong,^† Y. Lan* & Y. Chen*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07415)

The authors report a thiophenol-catalyzed radical hydroformylation that overcomes dual steric and electronic constraints through a synergistic system: bench-stable α-chloro N-methoxyphthalimides (formyl precursors) and a tailored thiophenol HAT catalyst. This metal-free strategy achieves unprecedented hydroformylation of unactivated, tri-, and tetrasubstituted alkenes with high chemo- and regioselectivity. The first hydroformylation of tetrasubstituted styrenes is also demonstrated, delivering β-aryl aldehydes with quaternary centers (up to 74% yield).

Migrating Group Strategy for Remote Functionalization of Seven-Membered Rings

W. Han,^† T. Hwang,^† C. Lian, S. Kolb, M. Yamane, V. Palani & A. E. Wendlandt*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10470)

The authors report a photocatalytic transannular ketone migration strategy that converts 1,1-disubstituted acylcycloheptanes into 1,4-disubstituted products under mild conditions, promoted by sodium decatungstate and thiol cocatalysts under light-emitting diode (LED) irradiation. The process operates via reversible hydrogen atom abstraction and donation at multiple sites within the ring, followed by site-selective migration via radical addition and β-scission at the exocyclic carbonyl group.

Catalytic Asymmetric Ionic Hydrogenation of α-Alkyl Styrenes

W. Leinung, N. Tsuji, M. Merher, M. Leutzsch, R. K. Raut & B. List*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c11514) 🔓

The authors report a highly enantioselective Brønsted acid-catalyzed ionic hydrogenation of α-alkyl styrenes using a hydrosilane in combination with a protic additive. Mechanistic and computational investigations support a pathway proceeding through a carbocation intermediate and a transient silylated catalyst species, with catalyst turnover dependent on the presence of a protic additive.

Bench-Stable Carbamoylzinc Pivalates for Modular Access to Amides, Ureas, and Thiocarbamates

D. Luo, L. Ruan, J. Xue, Z. Jiang, C. Nie, T. Zeng, L. Luo & J. Li*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c12107)

The authors report a new series of salt-stabilized carbamoylzinc pivalates prepared from the corresponding formamides through C–H metalation in the presence of TMP-Li and Zn(OPiv)₂. These carbamoylzinc pivalates are obtained as powders with high air and moisture stability under ambient conditions. They also show excellent reactivity in palladium-catalyzed C–S-selective Negishi carbamoylation and copper-catalyzed electrophilic amination, thiolation, and selenolation.

Enantioselective Total Synthesis of (−)-Novofumigatonin

V. A. P. Ruf,^† L. J. Sprenger,^† K. Volynskiy, V. M. Kandler, N. Nasiri & E. M. Carreira*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c10466)

The authors disclose the first total synthesis of (−)-novofumigatonin, an ortholactone meroterpenoid featuring an unprecedented 7/6/5/6/5/5 hexacyclic skeleton. On a strategic level, this was addressed by a highly convergent strategy that hinges on coupling of a complex neopentylic organolithium reagent and a highly hindered ketone. A unique approach to the ortholactone–acetal was required as it is not peripheral but embedded within the carbocyclic framework. This was addressed by orchestration of a condensation cascade triggered by the selective generation of an oxocarbenium ion.

Enantioselective Total Syntheses of Sannamycins A and B

J. Zhang,^† T. Shimakawa,^† C. N. Ungarean, S. Lee, Q. Zhu, S. Zhong & D. Sarlah*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c11901)

The authors report enantioselective syntheses of 2-deoxyfortamine-type aminoglycosides sannamycins A and B. The described strategy involves an enantioselective dearomative hydroamination, rapid stereo- and chemoselective introduction of heteroatom functionalities, and a unique skeletal rearrangement to forge the aminocyclitol core. The carbohydrate fragment was elaborated from Cyrene, a readily available enantioenriched starting material, and was used in a stereoselective glycosylation reaction to deliver natural products in 14 and 17 steps, respectively, from benzene.

A Ring-Deconstructive Carbon-Deletion Approach to the Enantioselective Total Synthesis of [5]-Ladderanoic Acid

S. Ray,* S. Das,^‡ D. Behera,^‡ P. Biswas, P. K. Tarafdar & S. Mukherjee*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c09164)

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

In 2022, the authors reported an enantioselective total synthesis of [3]-ladderanol using an alkylative desymmetrization reaction. This strategy has now been adapted for the enantioselective synthesis of [5]-ladderanoic acid, utilizing the symmetry of its pentacyclododecane skeleton. The strategy also enabled the synthesis of inverse-[3]-ladderanol, an unnatural isomer, and a hypothesis for the biosynthetic conversion of (−)-[5]-ladderanoic acid to (+)-[3]-ladderanol is proposed. Preliminary biophysical studies hinted at a possible evolutionary exclusion of inverse-[3]-ladderanol by nature.

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*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c04085)

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

The authors describe the development of titanocene photocatalysis for the carbon–carbon bond cleavage functionalization of alcohol substrates. A variety of alcohols, including pharmaceutical compounds, can be effectively cleaved, and the catalytic manifold can also be employed in cyanation and chlorination reactions.

Photoredox-Catalyzed Nitroarene C–H Alkylation Using Carboxylic Acids

K. Das & B. König*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-2tgc9) 🔓

The authors report a photocatalytic strategy for the direct C–H alkylation of nitroarenes using readily available carboxylic acids as alkyl radical precursors. This transformation proceeds under mild, visible-light irradiation conditions, exhibits broad functional group tolerance, and is compatible with both aromatic and aliphatic carboxylic acids. This method enables late-stage functionalization of complex molecules and provides a modular platform for sequential C–H diversification.

Catalytic C-Demethylation of Phenols and Anilines Enabled by a Removable Mono-Directing Group

C. Yu,^† Y. Xue,^† L. Kan,^† L. Yiu & G. Dong*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-r0r7n) 🔓

The authors report a ruthenium-catalyzed activation of aryl–methyl (Ar–Me) bonds enabled by a removable mono-directing group, phosphinite, which is easily installed and cleaved. This approach offers broad substrate scope, tolerating various functional groups including halides, ethers, boronates, and heterocycles. The method demonstrates remarkable selectivity for Ar–Me bonds over other aryl–alkyl linkages and is applicable to both phenol and aniline derivatives.

Photoinduced N-Center Radical Catalyzed Direct Hydrogen Atom Transfer Platform for Aliphatic C–H Functionalization

B. Feng, M. Lepori, M. Domański, P. C. Tiwari, G. Zhang, T. Noel & J. P. Barham*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-r2760) 🔓

The authors demonstrate that 9-arylacridine catalysts—neutral, N-centered photocatalysts—can engage aliphatic C–H bonds under mild conditions to enable the efficient generation of alkyl radicals, allowing various functionalizations of C–H bonds. The platform features broad substrate scope, scalability, compatibility with transition metal catalysis, and its utility was demonstrated in the synthesis of pharmaceutical synthons and late-stage functionalization of bioactive molecules.

Modular Enantioselective Photocatalysts from Privileged Pybox Scaffolds

R. M. Kelch, L. Hämmerling, E. Zysman-Colman* & T. P. Yoon*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-x7lc6) 🔓

The authors have designed a new family of enantioselective photocatalysts by modifying the structures of privileged pyridine bis(oxazoline) (pybox) complexes with electron-donating carbazole units. The chiral ligands are accessible via a three-step synthetic sequence starting from commercially available chiral pool materials, and their charge-transfer photochemistry can be rationally tuned to optimize photocatalytic activity. The generality of these new chiral photocatalyst structures was demonstrated in a series of three model asymmetric reactions that include both photoredox and excited-state photoreactions.

General Access to Chiral Piperidines via Enantioselective Catalytic C(sp³)–H Oxidation using Manganese Catalysts

S. Muthuramalingam, A. Call,* Q. Lefebvre, M. S. Sigman* & M. Costas*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-3l55k) 🔓

The authors describe a catalytic method for the enantioselective synthesis of chiral piperidines via direct site-selective α-C(sp³)–H bond oxidation using hydrogen peroxide and an evolved manganese catalyst in trifluoroethanol media. The reaction enables the desymmetrization of piperidines, yielding chiral N,O-acetal products in good yields (up to 86%) with excellent enantioselectivity (up to 98% e.e.).

Total Synthesis of Annotinolide B via Sequential Quinoline Dearomatization

B. Duvvuru & M. W. Smith*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-z0nt2) 🔓

The authors report the first total synthesis of the complex cyclobutane-containing Lycopodium alkaloid annotinolide B, leveraging a sequential quinoline dearomatization strategy that enabled the transformation of this heteroaromatic precursor to a tricyclic N-acyl dihydropyridone intermediate. Extensive studies aimed at forging the signature cyclobutane revealed a β-silyl acrylate to be essential for the success of a key [2+2] photocycloaddition reaction. Further transformations and a one-pot methylation/lactonization sequence furnish annotinolide B in 20 steps.

Manganese Low-Energy Photocatalysis for Remodeling Nitrogenation of Alkenes

W. Yang, Y. Lan,* Y. Bai, Z. Zhao, Y. Song, R. Chang, X. Shang, S. Li, S. Jia, S. Liu, S.-J. Li* & L. Niu*

Chem 2025, Online Now (DOI: 10.1016/j.chempr.2025.102702)

The authors describe a manganese low-energy photoredox catalytic platform generated by the modular in situ assembly of manganese(II) salt, bidentate N ligand, nucleophilic azide reagent, and alcohol, which can enable the generation of azido radicals under 850 nm light irradiation and facilitate the oxidative remodeling nitrogenation of alkenes via carbon-carbon double-bond cleavage to afford ketonitriles, ketones, or nitriles.

Selective endo-Cyclic α-Functionalization of Saturated N-Alkyl Piperidines

R. C. Phillips, J. C. K. Chu, A. A. Rafaniello & M. J. Gaunt*

J. Org. Chem. 2025, ASAP (DOI: 10.1021/acs.joc.5c01742) 🔓

The authors report the late-stage α-functionalization of N-alkyl piperidines through a sequential process involving iminium ion formation followed by nucleophilic functionalization. Key to this strategy is the selective formation of endo-iminium ions from six-membered N-heterocycles, achieved via α-C–H elimination of cyclic tertiary alkylamine N-oxides. The method allows for the in situ addition of diverse carbon-based nucleophiles to the iminium intermediates, enabling alkylation, azinylation and trifluoromethylation. Furthermore, the formal C–H functionalization sequence has been successfully applied to the late-stage modification of complex bioactive molecules.

Skeletal Editing Based on Nitrogen-Atom Manipulation

L. Ding,^† Y. Fan^† & H. Lu*

Chem. Soc. Rev. 2025, Tutorial Review (DOI: 10.1039/D4CS00974F) 🔓

This tutorial review provides a structured and in-depth overview of nitrogen-atom editing, tracing its historical development and highlighting recent breakthroughs. Mechanistic insights are discussed and applications of these methodologies in synthesizing and modifying bioactive molecules, natural products, pharmaceuticals, and functional materials are illustrated through representative examples.

Heavy Metal, Light Evidence

💉 Heavy metal, light evidence. In a move that has shocked absolutely nobody, US Health Secretary Robert F. Kennedy Jr. has demanded the retraction of a landmark Danish study that found no link between aluminium adjuvants in vaccines and childhood disorders. His reason? That the paper doesn’t fit his narrative is “a deceitful propaganda stunt by the pharmaceutical industry” (the study was, in fact, carried out by Statens Serum Institut—a public health institute funded by the Danish government—but who cares about facts anyway?).

Annals of Internal Medicine, which published the work, isn’t budging. The journal stands firmly by the publication: no misconduct, no errors, no retraction. The study tracked 1.2 million Danish children over two decades and found no evidence that aluminium exposure increased the risk of autoimmune, allergic, or neurodevelopmental conditions. In the first six months of life, babies will ingest more aluminium from breast milk or formula than they’ll ever receive from vaccines anyway.

A recent blistering editorial in The Lancet also marked the week of August 4^th as Kennedy’s “most dangerous and tragic” yet: cancelling $500 million in mRNA research, demanding the retraction noted above, and the fatal CDC shooting in Atlanta. That attack, in which a deranged gunman who believed that the COVID-19 vaccine made him depressed and suicidal, fired nearly 500 rounds at the CDC headquarters, underscores how anti-vaccine rhetoric can metastasize into violence. Millions have received vaccines safely, yet anti-vaccine propaganda offers endless validation just one social media search away for anyone who decides the jab must be to blame for every ailment. Now that rhetoric is echoed from the very top of the US healthcare system.