Nitrogen, On Demand

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Scanning Nitrogen in sp³ -Rich Scaffolds Enabled by Carbonyl-to-Nitrogen Atom Swap

Z. Zhang, Z. Liang, R. Ye & G. Dong*

Science 2026, 392, 536–542 (DOI: 10.1126/science.aef0610)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-pj82p) 🔓

The authors report a radical-mediated CO-to-N atom swap that converts cyclic ketones into cyclic amines using N′-alkyl-hydrazonamide (NAHA) reagents. Enabled by a deconstructive pathway, the transformation exhibits broad functional group tolerance. When combined with carbonyl transposition or C–H oxidation, the method enables rapid nitrogen scanning of sp³ -rich scaffolds from common carbocyclic precursors. The strategy further supports late-stage modification and isotopic labelling, providing a streamlined route to functionalized saturated nitrogen heterocycles.

Divergent and Consecutive Skeletal Editing of Saturated Primary Amines

L.-H. Li, S. Su, X. Zheng & L. Zhang*

Science 2026, 392, 528–535 (DOI: 10.1126/science.aee5416)

The authors report a skeletal editing approach that converts saturated primary amines into N-heterocycles with broad functional-group compatibility, high skeletal diversity, and excellent regio- and diastereospecificity. The method relies on hypervalent iodine-mediated oxidation to generate a key imino ether intermediate, which serves as a versatile branching point for reaction with diverse nucleophiles, enabling access to >15 classes of nitrogen heterocycles. The approach enables site-selective carbon-to-nitrogen transmutation and ring contraction of complex natural products through one-pot, consecutive skeletal editing.

Precision Indole Skeletal Editing for Single-Carbon Replacement

L. Zhang,^† Y. Lang,^† Z. Luo,^† X. Han, H. Zeng* & C.-J. Li*

Science 2026, 392, 512–518 (DOI: 10.1126/science.aec3587)

The authors report an intramolecular skeletal editing reaction of tryptamine derivatives that enables regioselective single-carbon replacement and functionalization at the indole C2 position via a photochemically activated pendant amide. The method supports diverse transformations, including deuteration, alkylation, arylation, acylation, and even ¹³ C incorporation at C2. Its utility is demonstrated in a concise four-step total synthesis of quebrachamine.

Decarboxylative Alkylation of Alkenes

T. K. Roy, F. M. Tamborini, R. Petzold, J. Fu, Y. Tang & T. Ritter*

Nature 2026 (DOI: 10.1038/s41586-026-10463-1) 🔓

The authors report a regio- and diastereoselective formal C(sp² )–H alkylation of alkenes using carboxylic acids as alkyl sources. The strategy proceeds via a polar decarboxylative pathway that enables formation of persistent alkylzinc intermediates from redox-active esters, diverging from conventional radical-based approaches. Pd-catalysed cross-coupling with alkenyl thianthrenium salts furnishes substituted alkenes with high diastereoselectivity. The method is applicable across a broad range of alkene classes, including cyclic, acyclic, terminal, and internal systems.

👉️ C&EN write-up, here.

Regio-Orthogonal Single N-Atom Insertion into Indoles via NO Translocation

M. Song, I. Jeong, H. E. Kim, J. Jin, H. Moon, J. K. Im, J. Jung, J. Jo & W.-j. Chung*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01046-z)

Single-atom modifications of indoles typically rely on insertion of reactive nitrene species into the enamine-like C2–C3 bond, enabling functionalization at the 3-position. Here, the authors report an alternative reaction pathway in which an N-nitroso group undergoes sequential intramolecular translocation and deoxygenative rearrangement to yield regiochemically orthogonal 1,4-diazines. This strategy activates the typically inert aromatic C3–C9 bond and is applicable to a range of indoles, including bio-relevant substrates, affording quinoxalines.

Direct Access to Iron Carbenes from Aldehyde, Ketone, and Formamide Feedstocks

P. S. Pedersen,^† K. I. Burton,^† S. H. M. Kaster,^† E. Lin,^† A. L. Pace,^† M. C. Bryan, T. M. Sodano, N. E. Intermaggio, C. B. Kelly & D. W. C. MacMillan*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c21614) 🔓

The authors report photocatalytic and electrochemical strategies for direct carbene formation from unmodified carbonyl compounds using a low-valent iron system. The process involves net oxidative addition of Fe(I) into the carbonyl bond, followed by α-protonation and α-elimination to generate a reactive Fe–carbene intermediate. This platform enables cyclopropanation of diverse alkenes, including complex and drug-like substrates, under mild conditions to afford highly functionalized, sp³ -rich products.

Deoxygenative Olefin Insertion of Cyclic Alcohols Promoted by Sulfoxide Cation Radicals

J. C. Genova, K. Cheng & D. A. Nicewicz*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c23176)

The authors report a strategy for ring expansion of aliphatic cyclic alcohols via deoxygenative olefin insertion. Acridinium-catalyzed generation of sulfoxide radicals converts unfunctionalized alcohols to alkoxy radicals, which undergo β-scission of the weakest adjacent C–C bond. The resulting alkyl radicals engage in Giese addition to vinyl phosphonates, and subsequent Horner–Wadsworth–Emmons olefination furnishes two-carbon-expanded products bearing internal alkenes. The method does not require pre-activated substrates, enables access to 5–7-membered cycloalkenes, and exhibits broad functional group tolerance with moderate to excellent yields.

Asymmetric Synthesis of Tertiary Alkyl Boronates via Ligand-Controlled Enantioconvergent Homologation

M. Chen,^† A. Z. Xu,^† C. Liu & G. Dong*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c04941)

A ligand-controlled strategy for the synthesis of chiral tertiary alkyl boronates via enantioconvergent homologation with racemic tertiary α-thio lithium carbenoids is described. Enantioselectivity is governed by chiral hydrobenzoin-derived diether ligands, affording aryl and alkyl boronates in high yields and excellent enantioselectivities (up to >99:1 e.r.) with broad functional group tolerance. Mechanistic studies support an unusual pathway involving ligand-mediated dynamic thermodynamic resolution of racemic carbenoids, followed by rapid ate-complex formation and indium-mediated stereospecific 1,2-migration. This strategy enables efficient construction of fully substituted stereocenters and concise modular syntheses of precursors to muscarinic M3 receptor antagonists.

Enantioselective Contrathermodynamic Olefin Isomerization

B. L. Imbriaco,^† S. Lee,^† E. Y. Xu,^† K. Zhao & R. R. Knowles*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c04825) 🔓

A light-driven, enantioselective contrathermodynamic positional isomerization of enol ethers is achieved via dual photoredox and chromium catalysis. Sequential oxidation and deprotonation of a tetrasubstituted enol ether generate an allylic radical, which is captured by a Cr(II) cocatalyst bearing a chiral bioxazoline (BiOX) ligand. Regio- and enantioselective protodemetalation of the resulting Cr(III) allyl complex by methanol affords terminal olefins in up to 95:5 e.r.

Asymmetric Synthesis of S-Trifluoromethyl Sulfoxide and Sulfoximine Pharmacophores

N. Y. Kwon,* J. Ye & J. A. Ellman*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c03062) 🔓

Chiral sulfoxides and sulfoximines are prevalent in pharmaceuticals, yet S-trifluoromethyl variants remain underexplored due to the lack of asymmetric synthetic routes. Here, the authors report a general approach to their asymmetric synthesis via enantioenriched S-trifluoromethyl sulfilimines, prepared through Cu(II)-BOX-catalyzed enantioselective S-trifluoromethylation of diverse sulfenamides, including complex drug and natural product derivatives. These intermediates are efficiently converted to sulfoximines by stereoretentive oxidation and to sulfoxides by hydrolysis with inversion.

Enantioselective Pyrazole Alkylation via Iridium and Squaramide Catalyzed N–H Insertion

K. J. Ruud, A. J. Antonucci, V. Lukovic, A. Vennemeyer & V. M. Dong*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c00508)

The authors report an iridium and squaramide-catalyzed N–H insertion that enables site- and enantioselective synthesis of α-pyrazole esters, overcoming challenges in regio- and enantioselective pyrazole alkylation arising from tautomerization and Lewis basicity. An iridium catalyst promotes selective insertion at the less hindered N_β position, while the squaramide catalyst enables asymmetric protonation with high enantiocontrol. The concept extends to indazole functionalization and enables the first reported asymmetric synthesis of a PARP7 inhibitor.

Divergent Asymmetric Total Synthesis of the cis-Clerodane Diterpenoids

H.-X. Zhao & T. Gaich*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c05761)

The authors report the first asymmetric total synthesis of five cis-clerodane diterpenoids (scaparvins B–D and parvitexins B–C). The strategy features a TEMPO⁺ BF₄⁻ -mediated lactonization, discovered in this work, to construct the cis-5/6-fused bicyclic ring system, followed by a stereoselective intramolecular nitrile oxide–alkene [3+2] cycloaddition to establish the cis-decalin core. Subsequent Stille coupling and ketalization enabled assembly of the complete carbon skeleton. Reductive ring opening of the isoxazoline moiety led to unexpected C6 epimerization, enabling a divergent synthetic approach.

Piecewise Stereoselective Assembly of Multi-Substituted Alkenes

E. Jones,^† R. T. Martin^† & D. W. C. MacMillan*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002635/v1) 🔓

A nickel metallaphotoredox-enabled deoxygenative cross-coupling of alcohols with vinyl bromides and gem-dibromoolefins provides a modular route to multi-substituted alkenes and stereodefined vinyl bromides, respectively. The platform exhibits broad scope and functional group tolerance, with high stereoselectivity for tri-substituted alkenes and vinyl bromides. This enables iterative, piecewise assembly of complex alkenes through sequential coupling or stereoretentive Suzuki–Miyaura reactions, as demonstrated in the synthesis of (+)-sponalisolide B.

Regiocontrolled Minisci Alkylations Guided by Phosphonium Ions

A. K. Abesingha,^† N. Amire,^† S. Pal,^† D. J. Babcock & E. D. Nacsa*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002473/v1) 🔓

Minisci alkylation is a widely used method for the C–H functionalization of N-heteroarenes, but its utility is often limited by poor regioselectivity. Here, the authors address this limitation by employing N-heteroaryl phosphonium salts as transient blocking groups to control the site of radical addition. Site-selective installation of the phosphonium group enables on-demand, complementary regioselectivity: C4-phosphonium pyridines and quinolines undergo C2-alkylation, while C2-phosphonium N-heteroarenes undergo C4-alkylation. Following alkylation, the phosphonium group can be removed under mild conditions or leveraged in subsequent transformations, enabling regiospecific C–H/C–H difunctionalization.

👉️ For recent complementary work by McNally and co-workers on the use of phosphonium ions as activating groups in regioselective Minisci alkylations, see here.

Enantioselective anti-Michael Hydroarylation of Unsaturated Carbonyl Compounds

S. Yang, A. M. Vasquez, B. K. Mai, T. M. Alturaifi, Y. Hu, Y. Gao, S. Sun, J. E. Smith, J. B. Bailey, M. Gembicky, J. A. Gurak Jr., C. J. Joe, M. A. Schmidt, P. Liu* and K. M. Engle*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002500/v1) 🔓

The authors report a palladium-catalyzed synthesis of chiral α-arylated amides and esters via enantioselective α-hydroarylation of acrylamides and acrylates, addressing the limited development of catalytic α-selective functionalization of α,β-unsaturated carbonyl compounds. Ligand screening identified the trans-bisphosphine (S,S)-(R,R)-PhTRAP as uniquely effective. A broad range of aryl and azaheteroaryl iodides couple under mild conditions to afford products in high yields with excellent enantioselectivity.

Deoxycyanation of Alkyl Alcohols Using Photoredox Catalysis

C. Hümpel,^† W. L. Lyon, R. E. McNamee, D. W. C. MacMillan & J. Chen*^†

Org. Lett. 2026, ASAP (DOI: 10.1021/acs.orglett.6c00711) 🔓

Cyano groups represent an important class of functional motifs in medicinal chemistry; however, the synthesis of sterically hindered alkyl nitriles remains challenging and conventional methods often rely on toxic cyanide sources. Here, a photoredox-catalyzed, metal-free deoxycyanation of alkyl alcohols is described, enabling rapid access to a broad range of primary, secondary, and tertiary cyanides using a readily handled, low-toxicity tosyl cyanide reagent.

Gone Fishin’

🐟️ Gone Fishin’. If Hollywood has taught us anything, it’s that giving powerful drugs to apex predators rarely ends well—whether it’s cocaine bears, meth gators, or even crabs from outer space. But what happens when cocaine ends up in rivers instead? That’s the question behind a new field study exploring how cocaine pollution affects aquatic life. Its residues, particularly the breakdown product benzoylecgonine, are now widely detected in rivers and lakes, and evidence is beginning to show they can alter animal behaviour in the wild.

In the first experiment of its kind outside the lab, researchers tracked juvenile Atlantic salmon released into a Swedish lake after exposure to environmentally relevant levels of cocaine or its metabolite via slow-release implants. Interestingly, the metabolite had a stronger effect than cocaine itself, and over two months, fish exposed to benzoylecgonine swam up to ~1.9× farther per week than controls and dispersed much further from the release site (~32 km vs ~20 km).

What this means at the ecosystem level is still uncertain but even modest shifts in how far salmon disperse could affect where they feed, how they encounter predators, and how nutrients are transported. These small changes are subtle but could scale into potentially significant consequences as chemical pollution continues to accumulate in aquatic environments.