One-Carbon Deletion

Carbon-Atom Scavengers Enable Divergent, Selective Carbon Deletion of Azaarenes

J. Woo, T. Zeqiri, A. H. Christian, M. C. Ryan & M. D. Levin*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c06577)

The authors report the serendipitous discovery of reagent-controlled selective deletion of C3 or C2 carbon atoms of quinolines, affording indoles. An initial observation that an impurity in commercial samples of DBU promoted cyclization of a benzoxazepine-derived imidate led to the identification of indoline and aminoethanol as C3- and C2-selective carbon-atom scavengers, respectively. These two methods successfully convert a broad scope of quinolines and related azaarenes to the corresponding indoles and azaindoles, enabling divergent carbon deletion.

Persistent Boryl Radicals as Highly Reducing Photoredox Catalysts for Debrominative Borylations

J. Wu,^† H. Wang,^† H. Fang, K. C. Wang, D. Ghosh, V. Fasano, A. Noble* & V. K. Aggarwal*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03864) 🔓

The authors report the identification of persistent boryl-bipyridine radicals that function as highly reducing photoredox catalysts, enabling the borylation of alkyl bromides. These radicals, which are generated by simply mixing a bipyridine with a diboron reagent, were found to possess excited state reduction potentials that rival the most powerful photoreductants reported to date.

Enantioselective β-C(sp³)–H Nucleophilic Tosylation of Native Amides: A Synthetic Platform for Chiral Methyl Stereocenters

Y. Ouyang,^† D. Q. Phan,^† N. Chekshin, Y.-H. Li, J. X. Qiao, M. D. Eastgate & J.-Q. Yu*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c17267) 🔓

The authors report the development of a Pd-catalyzed, enantioselective C(sp³)–H tosylation of native amides with NaOTs as the nucleophile, representing a rare example of enantioselective C–H functionalization with a nucleophilic coupling partner. Through desymmetrization of the readily available isopropyl moiety, structurally diverse β-tosylated amides bearing an α-methyl stereocenter were obtained with high yield and enantioselectivity.

Mechanism-Guided Development of Directed C–H Functionalization of Bicyclo[1.1.1]pentanes

A. Bunnell, M. W. Milbauer, J. V. Bento, S. M. Taimoory, P. M. Zimmerman, D. Kalyani,* T. Piou* & M. S. Sanford*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c07190)

This report describes a detailed study of the palladium-mediated directed C(2)–H functionalization of bicyclo[1.1.1]pentanes (BCPs). This approach was leveraged to access derivatives of a key intermediate in the synthesis of bioisosteric analogues of the angiotensin II receptor blocker telmisartan. A four-step sequence from commercially available BCP carboxylic acids, involving directing group installation, cyclopalladation, C(2) arylation, and directing group cleavage, afforded a comparable or improved overall yield, step-count, and functional group compatibility relative to state-of-the-art synthetic approaches.

Photo- and Copper-Catalyzed Enantioselective Oxidation of Benzylic C(sp³)–H Bonds

F. Li, X.-M. Liu, J.-B. Pan, L. Dai, Y. Yang, L.-J. Xiao, C. Fan & Q.-L. Zhou*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c04142)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-6k7n9) 🔓

The authors report a photo- and copper-catalyzed enantioselective oxidation of benzylic C(sp³)–H bonds using N-hydroxyphthalimide as the oxygenating reagent. The reaction proceeds under mild conditions, does not require excess substrates or oxidants, and the products can be readily transformed into chiral benzylic alcohols or hydroxylamines.

Formally Stereoretentive S_N1 Reactions of Homoallylic Tertiary Alcohols via Nonclassical Carbocation

K. Patel, L. Wilczek, F. Calogero & I. Marek*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c05680) 🔓

The authors present a stereoretentive nucleophilic substitution of homoallylic tertiary alcohols via the formation of a nonclassical cyclopropyl carbinyl (CPC) carbocation intermediate. This strategy enables the creation of highly congested tertiary centers with preserved stereocontrol, addressing the typical challenges of carbocation instability and reactivity in S_N1 mechanisms.

Atom-by-Atom Iterative Synthetic Logic: Laying the Foundation for Programmable Automated Construction of Small Organic Molecules

M. Chen & G. Dong*

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.5c00526) 🔓

The authors propose atom-by-atom iterative synthesis (AIS) as a new synthetic logic to construct molecular skeletons through iterative coupling of simple atomic-scale building blocks (BBs) by a unified type of reaction─boron homologations. This Outlook describes the AIS concept, recent progress, current limitations, and future opportunities in the field.

Synergistic Cobaloxime Catalysis for Photo-Dehydrogenative Transformations

A. Mandal, M. Lim, L. Zhang, K.-W. Huang & S. U. Dighe*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c00343)

This review highlights recent advancements in the application of cobaloxime within metallaphotoredox catalysis, with a focus on its effectiveness in dehydrogenation processes that drive the formation of sp²-hybridized C–C bonds via hydrogen atom transfer (HAT) and related pathways.

Carbonylative Ring Expansion of Cyclic Carboxylic Acids through Spin-Center Shift

H. Shimono,^† M. Kusakabe,^† K. Nagao* & H. Ohmiya*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-0856k) 🔓

The authors utilize spin-center shift (SCS) as a radical-mediated ring-opening process towards the photochemical or electrochemical carbonylative ring expansion of cyclic carboxylic acids into lactams, lactones, and ketones, by incorporating the exocyclic carbonyl group into the cyclic framework. When combined with α-amino C–H carboxylation of cyclic aliphatic amines, the process enables the carbonylative ring expansion of ticlopidine and a streamlined synthesis of an ivabradine fragment.

Breaking the “Rule-of-Five” to Access Bridged Bicyclic Heteroaromatic Bioisosteres

Z.-X. Zhang, K. Shu, M. J. Tilby, M. J. P. Mandigma, Y. Guo, A. Noble* & V. K. Aggarwal*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-285mh) 🔓

Intramolecular [2+2] cycloadditions of unconjugated dienes provide an efficient route to bridged bicyclic hydrocarbons but are governed by the “rule-of-five”, which dictates that five-membered rings are preferentially formed. To challenge this paradigm, the authors introduce a visible light-mediated intramolecular [2+2] cycloaddition of aza-1,6-dienes that leverages radical stabilisation strategies to enable the selective formation of previously elusive 6-azabicyclo[3.1.1]heptanes (6-N-BCHeps). Exit vector analysis and comparison of physicochemical and pharmacological properties of a 6-N-BCHep analogue of a piperazine-based drug demonstrate the potential of this scaffold in medicinal chemistry.

Separation of Redox Events Unlocks Electrocatalytic C–N Bond Formation with Inert Fluoroarenes

B. D. Akana-Schneider, J. S. Genova & J. Derosa*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-jl8jt) 🔓

Nucleophilic aromatic substitution (S_NAr) reactions are a critical method for forming C–N bonds but limitations in electrophile electronics restrict access to a large portion of chemical space. Photochemical oxidation of fluoroarenes offers limited success due to back-electron transfer to solution-phase reduced photocatalysts. Here, the authors describe an electrochemical strategy to overcome this by spatially separating redox events at electrode surfaces, extending the lifetime of the activated electrophile.

Chemodivergent C-to-N Atom Swap from Benzofurans to Benzisoxazoles and Benzoxazoles

A.-S. K. Paschke,^† S. Schiele,^† C. Pinard, F. Sandrini & B. Morandi*

Chem. Sci. 2025, Accepted (DOI: 10.1039/D5SC02032H) 🔓

The authors describe a convenient, chemodivergent protocol to perform a net C-to-N atom swap in benzofurans, affording benzoxazoles or benzisoxazoles via a cascade of oxidative cleavage, oxime formation, and cyclization using commercially available reagents.

Synthesis and Nucleophilic Ring-Opening of 1,1-Dicyanocyclopropanes: Accessing β-Aminocarbonyl Derivatives from Olefins

S. Govaerts,^†* J. L. Mayer-Figge,^† M. Chotia, S. F. Kirsch & A. Gómez-Suárez*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c00395)

The authors report an atom-transfer radical addition-ring closure sequence for the preparation of 1,1-dicyanocyclopropane electrophiles and demonstrate their nucleophilic ring-opening with alkyl amines under mild conditions. The resulting aminomalononitrile products were converted to complex β-aminocarbonyl derivatives in one pot under aerobic conditions.

Publish or Perish

📰 Publish or perish. What do the Wacker oxidation, osmium tetroxide-catalyzed dihydroxylations, and proline-catalyzed aldol reactions have in common? All were discovered in industry by chemists at Wacker Chemie, The Upjohn Company, and Hoffmann-La Roche and Schering, respectively. These reactions have since become staples of organic chemistry—taught at the undergraduate level and, in the case of the latter two, forming the basis of Nobel Prize-winning research in 2001 and 2021.

It doesn’t end there either. Not content with their cornerstone contribution to methodology, the Upjohn company also published the first total synthesis of thromboxane B₂ (TxB₂)—the natural metabolite of the potent vasoconstrictor and platelet aggregator, TxA₂—only one year after its structure had been elucidated. However, that was in 1976. Nearly 50 years later, the number of publications from chemists in industry has declined substantially, prompting Dean Brown of Jnana Therapeutics to pen an editorial in the Journal of Medicinal Chemistry on the topic, which was later picked up by C&EN.

Since 1993, industrial-affiliated authorships have declined 78%, while academic and government-affiliated authorships have increased 137%, resulting in nearly 9× as many academic chemists publishing compared to their industrial counterparts in 2023. Many factors may have played a role in this steep decline but one possible cause may be the shift from in-house chemistry to contract research organizations (CROs) that may not receive permission to publish from the parent company. This can be due to legitimate concerns such as the disclosure of potentially patentable information but with over 90% of drugs failing to reach the market, a lot of valuable synthetic information from unsuccessful projects can be left by the wayside as researchers may be unwilling or unincentivized to share their work.

Looking ahead, it’s worrying how many new reactions or enabling technologies that may only ever exist as proprietary knowledge when they could be potentially transformative in other companies’ drug discovery programs. Greater transparency and communication could help the medicinal chemistry community to develop new drugs quicker and more effectively.

NB: In 1976, only one year after the structure of both TxA₂ and TxB₂ had been elucidated, Nelson and Kelly of the Upjohn company reported the first two total syntheses of TxB₂. Both authors collaborated, submitted, and published two independent routes on the same date.