Peripheral → Core Heteroatom Transpositions

Welcome to this week’s Organic Synthesis Newsletter.

Monday 20^th January – Sunday 26^th January 2025 | Volume 2, Issue 3

HIGHLIGHTS OF THE WEEK
Exo-to-Endo Nitrogen Transposition in Saturated Rings

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

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

Biologically active molecules are often comprised of ring structures that precisely position functional groups to enable target-specific interactions. The iterative permutation of these structural arrangements is central to modern drug discovery, often necessitating the de novo synthesis of isomeric compounds. Here, the authors report a method for the peripheral-to-core nitrogen internalization of amino cycloalkanols to access N-heterocycles of various oxidation states. This strategy enables the expansion, contraction, and carbon-to-nitrogen substitution of cyclic amino alcohols, providing access to structurally distinct heterocyclic scaffolds.

Oxygen Migration into Carbon–Carbon Single Bonds by Photochemical Oxidation

C. A. MacAllister,^† C. R. Lacker,^† M. F. Maciejewski, F. Wessels, D. M. Bates, S. W. Bagley & T. P. Yoon*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-ssx6g) 🔓

The editing of organic molecules through single-atom modifications is an enabling capability for medicinal chemistry with several examples of single-atom insertions into the carbon–carbon double bonds of unsaturated aromatic ring systems reported. However, heteroatom insertions into chemically inert carbon–carbon single bonds are comparatively rare. The authors report herein a photochemical strategy for formal migration of oxygen atoms into carbon–carbon single bonds. Application of this method to cyclic alcohol substrates results in oxygen-atom insertions into saturated carbocyclic rings, and its extension to linear alcohol substrates enables atomic permutation of hydroxymethyl functionalities into methyl ethers.

NATURE CHEMISTRY
Light-Promoted Aromatic Denitrative Chlorination

T. Liang,^† Z. Lyu,^† Y. Wang, W. Zhao, R. Sang, G.-J. Cheng* & F. Ye*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01728-1)

Nitroarenes are readily accessible bulk chemicals and versatile starting materials; however, due to the inertness of the C_Ar–NO₂ bond, the direct denitrative substitution of unactivated nitroarenes remains challenging with chemists often relying on a reduction/diazotization/Sandmeyer sequence to realize nitro group transformations. Here, the authors develop a general denitrative chlorination reaction under visible-light irradiation in which a chlorine radical replaces the nitro moiety through cleavage of the C_Ar–NO₂ bond. This practical method works with a wide range of unactivated nitro(hetero)arenes and nitroalkenes, is not sensitive to air or moisture and can proceed smoothly on a decagram scale.

NATURE SYNTHESIS
Late-Stage Deuteration and Tritiation through Bioinspired Cooperative Hydrogenolysis

B. Zhang, Z. Zhang, Y. Wang & D. Zhao*

Nat. Synth. 2025 (DOI: 10.1038/s44160-024-00716-0)

Hydrogenolysis has traditionally been performed using heterogeneous catalysis at high temperatures and pressures with limited selectivity. Recent advancements highlight the potential of homogeneous catalysis as a promising alternative, offering improved selectivity under milder conditions. However, the development of a general homogeneous catalysis approach capable of hydrogenolysing carbon–halogen bonds remains unsolved. Here, the authors demonstrate how the interplay of bioinspired carbon–halogen activation and hydrogenation can catalyse the selective hydrogenolysis of unactivated organohalides. The utility of this approach is demonstrated through the deuteration and tritiation of pharmaceutically relevant organohalides.

NATURE CATALYSIS
A Hydrogenative Oxidation Strategy for the Single-Step Synthesis of Lactams from N-Heteroarenes using Water

Y. Liang,^† J. Luo,^† C. You, Y. Diskin-Posner & D. Milstein*

Nat. Catal. 2025 (DOI: 10.1038/s41929-024-01286-2)

Using water as a hydrogen or oxygen source in organic synthesis has enabled various reductive and oxidative transformations but incorporation of both hydrogen and oxygen atoms into the same molecule—representing an atom-economic and environmentally benign process—has scarcely been explored. Here, the authors report a hydrogenative oxidation strategy using water as both a source of H₂ and formal oxidant, enabling the synthesis of lactams from N-heteroarenes and thereby eliminating the need for additional reductants and oxidants, minimizing waste generation.

NATURE COMMUNICATIONS
Deoxygenative Photochemical Alkylation of Secondary Amides Enables a Streamlined Synthesis of Substituted Amines

A. Pulcinella,^† S. Bonciolini,^† R. Stuhr, D. Diprima, M. T. Tran, M. Johansson, A. J. von Wangelin & T. Noël

Nat. Commun. 2025, 16, 948 (DOI: 10.1038/s41467-025-56234-w) 🔓

The authors present a streamlined deoxygenative photochemical alkylation of secondary amides enabling the synthesis of α-branched secondary amines. The method leverages triflic anhydride-mediated semi-reduction of amides to imines followed by a photochemical radical alkylation step. This approach broadens the synthetic utility of amides, facilitating late-stage modifications of drug-like molecules and the synthesis of saturated N-substituted heterocycles. The pivotal role of flow technology in developing a scalable and robust process underscores the practicality of this method.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Standardized Approach for Diversification of Complex Small Molecules via Aryl Thianthrenium Salts

D. Ahmadli, S. Müller, Y. Xie, T. Smejkal, S. Jaeckh, A. V. Iosub, S. R. Williams & T. Ritter*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14391) 🔓

Thianthrenation is a useful strategy for the late-stage diversification of complex small molecules owing to the positional selectivity and the synthetic versatility of thianthrenium salts as electrophilic linchpins. However, substrate-dependent identification of suitable reaction conditions for thianthrenation can be difficult. Reported reaction conditions for the functionalization of thianthrenium salts vary significantly and, in some instances, lack robustness and practicality. Herein, the authors report a generalized approach for the preparation of thianthrenium salts and two reaction manifolds for practical, robust, and parallel diversification of thianthrenium salts.

ACS CENTRAL SCIENCE
Single Dose of a Small Molecule Leads to Complete Regressions of Large Breast Tumors in Mice

M. P. Mulligan, M. W. Boudreau, B. A. Bouwens, Y. Lee, H. W. Carrell, J. Zhu, S. Mousses, D. J. Shapiro, E. R. Nelson, T. M. Fan & P. J. Hergenrother*

ACS Cent. Sci. 2025, ASAP (DOI: 10.1021/acscentsci.4c01628) 🔓

Patients with estrogen receptor α positive (ERα+) breast cancer typically undergo surgical resection, followed by 5–10 years of treatment with adjuvant endocrine therapy. This prolonged intervention is associated with a host of undesired side effects that reduce patient compliance, and ultimately therapeutic resistance and disease relapse/progression are common. An ideal anticancer therapy would be effective against recurrent and refractory disease with minimal dosing; however, there is little precedent for marked tumor regression with a single dose of a small molecule therapeutic. Herein, the authors report ErSO-TFPy as a small molecule that induces quantitative or near-quantitative regression of tumors in multiple mouse models of breast cancer with a single dose. Importantly, this effect is robust and independent of tumor size with eradication of even very large tumors (500−1500 mm³) observed.

ACS CATALYSIS
Data Science-Driven Discovery of Optimal Conditions and a Condition-Selection Model for the Chan–Lam Coupling of Primary Sulfonamides

S. S. Gandhi, G. Z. Brown, S. Aikonen, J. S. Compton, P. Neves, J. I. M. Alvarado, I. I. Strambeanu,* K. A. Leonard* & A. G. Doyle*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.4c07972)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-22jrq) 🔓

Secondary N-arylsulfonamides are common in pharmaceutical compounds owing to their valuable physicochemical properties. Direct N-arylation of primary sulfonamides presents a modular approach to this scaffold but remains a challenging disconnection for transition metal-catalyzed cross coupling broadly, including the Chan–Lam (CL) coupling of nucleophiles with (hetero)aryl boronic acids. Although the CL coupling reaction typically operates under mild conditions, it is also highly substrate-dependent and prone to overarylation, limiting its generality and predictivity. To address these gaps, the authors employed data science tools in tandem with high-throughput experimentation to study and model the CL N-arylation of primary sulfonamides. This enabled the identification of broadly applicable, highly selective conditions for the CL coupling of aliphatic and (hetero)aromatic primary sulfonamides with complex organoboron coupling partners.

CHEMRXIV
Synergistic Photoenzymatic Anti-Markovnikov Hydroarylation of Olefins via Heteroaryl Radical Intermediates

P. Mukherjee, Z. Alassad & T. K. Hyster*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-xp59w) 🔓

The anti-Markovnikov hydroarylation of olefins using heteroaryl halides furnishes the product as a single regioisomer, however, catalytic variants are ineffective in controlling the stereochemical outcome of these reactions. Here, the authors report a synergistic photoenzymatic hydroarylation of olefins using flavin-dependent ‘ene’-reductases with ruthenium photoredox catalysts. Enzyme homologs were identified, which provide access to both product enantiomers in high yield (>80% yield) and excellent enantioselectivities (up to 99:1 e.r.).

👉️ For recent, complementary methodology, see: here.

Oxidant-Free Amidation of Aldehydes Enabled by Electrophotocatalysis

D. I. Ioannou, E. Bombonato, J. Sanramat, J. N. H. Reek* & T. Noël*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-v1jd8) 🔓

Electrophotocatalysis (EPC) is emerging as a powerful tool in organic synthesis offering unique redox transformations without the need for sacrificial oxidants or reductants. Building on this, the authors developed an electrophotocatalytic method for the direct amidation of aldehydes using electricity as the sole oxidant, and light to generate chlorine radicals for hydrogen atom transfer. This approach is compatible with a wide range of aldehydes and nitrogen-based nucleophiles, performing efficiently under batch conditions and demonstrating scalability with flow technology.

Difluoroenol Phosphinates as Versatile Difluoroenolate Surrogates: Synthesis and Applications in Defluorination and Deoxygenative Coupling

M. B. Kurosawa,^† S. Shimoyama,^† H. Tanaka, K. Kato & J. Yamaguchi*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-1rklr) 🔓

The authors report the defluorinative and deoxygenative functionalization of trifluoromethyl ketones mediated by a phospha-Brook rearrangement, offering a streamlined approach to selectively modifying fluorinated compounds. Trifluoromethyl ketones react with phosphine oxides to undergo a phospha-Brook rearrangement followed by β-fluoride elimination providing difluoromethyl ketones. By tuning the reaction conditions, the selective one-pot synthesis of monofluoromethyl ketones and methyl ketones was achieved. Finally, a range of deoxygenative transformations of key intermediates, such as difluoroenol phosphinates was demonstrated.

ORGANIC LETTERS
One-Pot Chlorination and Cross-Electrophile Coupling of Alcohols with Aryl Chlorides

B. N. Ahern & D. J. Weix*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.4c04676)

Although alkyl alcohols and aryl chlorides are the two most abundant substrate pools for cross-electrophile coupling, methods to couple them remain limited. Here, the authors demonstrate a simple procedure for the in situ deoxychlorination of alcohols followed by XEC with aryl chlorides. A broad substrate scope can be achieved by tuning the rate of reaction via halide exchange. Key to success is the identification of 1-chloro-N,N,2-trimethyl-1-propenylamine as a mild, non-interfering halogenation reagent.

PREVIOUSLY IN CHEMRXIV

• Directed Evolution and Unusual Protonation Mechanism of Pyridoxal Radical C–C Coupling Enzymes for the Enantiodivergent Photobiocatalytic Synthesis of Noncanonical Amino Acids, L. Cheng, Z. Bo, B. Krohn-Hansen & Y. Yang,* J. Am. Chem. Soc. 2025, DOI: 10.1021/jacs.4c16716.

  👉️ Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-32vjk; highlighted last week in Deaminative Cross-Coupling).

• Diastereo- and Enantioselective Chemoenzymatic Synthesis of Chiral Tricyclic Intermediate of Anti-HIV Drug Lenacapavir, W. Fu, A. Liu & Y. Yang,* ACS Catal. 2025, DOI: 10.1021/acscatal.4c07464.

  👉️ Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-w7q5k; highlighted last week in Deaminative Cross-Coupling).

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Microplastics in Motion

🔬 Microplastics in motion. Microplastics have been found everywhere, from the top of Mount Everest to the bottom of the Mariana trench, and when combined with “forever chemicals” such as per- and polyfluorinated alkyl substances (PFAS) they can pose a serious risk to the environment with research suggesting that 8–10 million tonnes of plastic ends up in the ocean every year, which by 2050 will outweigh all the fish in the ocean.

I’ve written about the latter here before (see: Lighting the Way to C–F Bond Activation) and how widespread the issue is with these compounds turning up in almost every part of the human body. We’re only really just starting to understand the effects of microplastics on human health but so far, the outlook isn’t good with evidence indicating them as a potential risk factor for cardiovascular disease.

Now, for the first time, researchers have been able to track the movement of microplastics through the bloodstream of mice using a fluorescence imaging technique called miniature two-photon microscopy. Following the ingestion of fluorescent polystyrene spheres, fluorescent cells—specifically, immune cells that had ingested the fluorescent plastic—were observed travelling through the bloodstream and into the brain where they obstructed blood vessels in the brain cortex, reducing blood flow and causing neurological abnormalities such as decreased mobility.

💻️ A potential new treatment for heart failure. The German Chemical Society’s online Medicinal Chemistry webinar series starts back up for 2025 on Tuesday 4^th February with “Augmenting Parasympathetic Activity in Heart Failure Patients: Discovery of a Novel Class of Naphthyridine Carboxamides as Highly Selective Positive Allosteric Modulators of the M2 Receptor”.