Deaminative Suzuki–Miyaura Coupling

Nitrate Reduction for Deaminative Suzuki–Miyaura Coupling of Anilines

C.-C. Li,^† Á. Adorján,^† M. Sofiadis, T. Schulte, J. Mateos, M. Rippegarten & T. Ritter*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202504012) 🔓

The authors present a deaminative Suzuki–Miyaura-type coupling of anilines with nitrate as a diazotization reagent, which integrates transition-metal catalysis with nitrate-based diazonium chemistry for the first time. In comparison to previous diazonium-based Suzuki-Miyaura couplings, the in situ oxidation of anilines by reduction of nitrate allows for broader functional group tolerance.

Synthesis and Reactivity of Nitrogen-Containing Strained Cyclic 1,2,3-Trienes

D. C. Witkowski, D. W. Turner, A. S. Bulger, K. N. Houk & N. K. Garg*

Nat. Synth. 2025 (DOI: 10.1038/s44160-025-00793-9)

Cyclic 1,2,3-trienes are a class of intermediates that confine a functional group with a preferred linear geometry into a ring. When the ring is sufficiently small, the 1,2,3-triene geometry becomes bent, leading to substantial strain and high reactivity. Here, the authors report the fluoride-mediated generation and trapping of six-membered azacyclic 1,2,3-trienes in a host of reactions, including [4+2] and [3+2] cycloadditions and σ-bond insertions, allowing for the synthesis of annulated pyridone.

Asymmetric Hofmann–Löffler–Freytag-type Reaction via a Transient Carbenium Ion Complex Merging Organocatalysis and Photocatalysis

Q. Guo,^† Y. Mao,^† J. Liu,^† L. Zhu, X. Hong* & Z. Lu*

Nat. Catal. 2025 (DOI: 10.1038/s41929-025-01329-2)

The authors detail an asymmetric Hofmann–Löffler–Freytag-type reaction under visible-light irradiation, resulting in chiral Evans auxiliaries with excellent enantioselectivity. This protocol is distinguished by its high efficiency (turnover frequency, 154 h⁻¹) and broad functional group tolerance.

Convergent Total Synthesis of (−)-Calidoustene

W. Yao, Z. Liu, H. Ling, H. Wang, H. Zheng, S.-H. Wang,* D.-Y. Zhu, S.-Y. Zhang & X. Chen*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03983)

The first total synthesis of the sesterterpenoid (−)-calidoustene has been accomplished, featuring a stereoselective Michael/aldol cascade to construct the trans-hydrindane backbone, a tandem Pummerer/Sakurai cyclization to establish the bicyclo[3.2.1]octane framework, a metallaphotoredox enone coupling followed by MHAT-initiated cyclization to forge the congested central C-ring, and late-stage functionalization via Cu-catalyzed desaturation and diimide reduction.

Enantioselective Cobalt(III)-Catalyzed [4+1] Annulation of Benzamides: Cyclopropenes as One-Carbon Synthons

L. K. Verdhi, M. D. Wodrich & N. Cramer*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16953) 🔓

A chiral cyclopentadienyl cobalt(III)-catalyzed enantioselective [4+1] annulation of N-chlorobenzamides with cyclopropenes is reported. The cobalt catalyst engages in the C–H activation as well as promotes the C–C bond cleavage of the cyclopropene, rendering it as a one-carbon unit for the annulation. The reaction efficiently constructs biologically relevant chiral isoindolinones with selectivities of up to 99:1 e.r. and >20:1 E/Z ratios.

Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant S-Methyl and S-Cyclopropyl Sulfoximines

Z. W. Boyer, N. Y. Kwon & J. A. Ellman*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.5c03841)

Sulfoximines are increasingly utilized in pharmaceuticals with all sulfoximine clinical candidates incorporating either an S-methyl or an S-cyclopropyl substituent. Here, the authors report on a general and efficient sequence for the asymmetric synthesis of both of these substitution patterns. The asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.

Substrate-Photocatalyst Reactivity Matching Enables Broad Aryl Halide Scope in Light-Driven, Reductive Cross-Electrophile Coupling Using ¹³C NMR as a Predictor

C. H. Chrisman, W. Z. Elder, G. C. Haug, R. Pérez-Soto, A. K. Bains, C. Jepsen, T. K. Stewart, T. C. Sherwood, M. Kudisch, D. J. Boston, C.-H. Lim,* E. M. Simmons,* S. Kim,* R. S. Paton* & G. M. Miyake*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c02019)

This work expands photoredox catalyzed cross-electrophile couplings with a focus on the use of organic photocatalysts and an inexpensive, readily available sacrificial electron source (triethanolamine). To overcome limitations in substrate scope arising from redox incompatibilities between photocatalyst and substrate, two sets of conditions were introduced that minimize unwanted substrate-specific side reactivity. The propensity of aryl halide reagents to undergo side reactions was found to correlate with electronic parameters: the C–Br ¹³C chemical shift of aryl bromides is a robust predictor for this reactivity and enables reaction condition selection.

Development of Robust, Efficient and Scalable Transition Metal Catalyzed Transformations: Translation of Reactions from Micromole to Multi-Kilogram Scale Processes

J. M. Ganley, C. L. Joe & E. M. Simmons*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.5c00836) 🔓

This Perspective highlights various factors that can impact both the scalability as well as the robustness and efficiency of transition metal catalyzed transformations, with selected examples to illustrate specific challenges that were identified and the solutions that have been devised to overcome them.

Access to N-Monofluoromethylated (Thio)Carbamates, Formamides, Alkynamides and Related Derivatives

F. G. Zivkovic,^† F. Bahns,^† C.-M. Hsu & F. Schoenebeck*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202505478)

This work presents the first general synthetic access to N-CH₂F and N-CHRF carbamates, thiocarbamates, formamides, alkynamides, and related compounds. The synthetic approach employs N-CH₂F and N-CHRF carbamoyl fluorides as versatile strategic building blocks, which can be efficiently synthesized in a single step directly from readily available amines or imines.

Direct N–SF₅ and N–SF₄CF₃ Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0]Azabicyclobutanes

Y. Kraemer,^† S. Park,^† W.-Y. Kong, Y. Chen, A. J. Witt, J. A. Buldt, A. N. Ragan, L. M. Holder, D. J. Tantillo* & C. R. Pitts*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-68s1q) 🔓

The authors report that direct N–SF₅ bond formation can be accomplished through strain-release pentafluorosulfanylation of 3-aryl [1.1.0]azabicyclobutanes (ABBs), using an easy-to-access solution of SF₅Cl. Surprisingly, the resultant N–SF₅ azetidines proved remarkably stable and amenable to peripheral synthetic modifications (e.g. amination, cross-coupling, oxidation etc.). The methodology also extended to direct N–SF₄CF₃ bond formation and the dynamic, spectroscopic, and crystallographic features of both motifs, as well as computed properties (e.g. BDE and pK_b values) were obtained. Finally, an N–SF₅ derivative of a spleen tyrosine kinase inhibitor was synthesized and profiled vs. its parent N–SO₂Me azetidine.

👉️ The group of A. Tlili has recently published complementary work on both the “Strain-Release-Driven Synthesis of Pentafluorosulfanylated Four-Membered Rings under Energy Transfer Photocatalysis” and “A Shelf-Stable Reagent for Photocatalytic Radical Pentafluorosulfanylation of Styrene Derivatives”.

Iridium(III)-Catalyzed Ionic Hydrogenation of Pyridines to Multi-Substituted Piperidines

A. Despois & N. Cramer*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-78q6b) 🔓

The authors report a robust and selective iridium(III)-catalyzed ionic hydrogenation of pyridines to the corresponding piperidines. Importantly, highly reduction-sensitive groups including nitro-, azido-, bromo-, alkenyl- and alkynyl are inert, enabling access to a broad range of multi-substituted piperidines in high yields. The method requires low catalyst loadings, is scalable to decagrams, delivers the products as easily isolable piperidinium salts, and can be applied in complex late-stage settings with the pyridine motif in several FDA-approved drugs successfully and selectively hydrogenated.

Blue-Light-Promoted Sulfenylnitrenes for Late-Stage Skeletal Editing of N-Heterocycles: Application to Tethered C-Glycosides and N-Nucleosides

P. Kafle, P. Kharel, D. Nilson, S. Yasuda & I. Sharma*

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

This report presents a class of bench-stable sulfenylnitrene precursors that yield sulfenylnitrenes without photosensitizers or additives upon exposure to blue-light irradiation. The operationally mild protocol facilitates late-stage, single nitrogen-atom insertion into N-heterocycles, including pyrroles, indoles, and imidazoles, culminating in the generation of valuable heterocyclic scaffolds, such as pyrimidines, quinazolines, and triazines. The transformation occurs efficiently in aqueous media, accommodates a broad range of functional groups, and enables the selective modification of amino acids, protecting-group-free C-glycosides, tethered N-nucleosides, and pharmaceuticals.

Electrochemical Self-Optimization for the Synthesis of Densely Functionalized Molecules

E. Rial-Rodríguez, F. L. Wagner, T. Fuchß, A. Sommer, J. Krieger, H.-M. Eggenweiler,* C. O. Kappe & G. Laudadio*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-d1z1f) 🔓

The implementation of closed-loop automation in electrochemistry has been limited by engineering and chemical difficulties, especially when applied to the synthesis of densely functionalized molecules. To overcome these issues, the authors developed a modular autonomous platform integrating Bayesian optimization and on-line analysis. This flow electrochemical system leveraged a slug-based approach to minimize the material consumption while ensuring a fast workflow. The versatility of the platform was demonstrated in three different case studies: (i) a nickel-catalyzed C–N cross-coupling, (ii) an anodic modification of an amino acid, and (iii) a decarboxylative alkylation of a natural product, with the isolation of the desired products achieved by translating the slug conditions into continuous flow.

Borane-Catalyzed Stereoselective Synthesis of Cyclic Ethers via Reductive Cycloetherification of Diketones

N. V. Shcherbakov, N. Potin & J. Mas-Roselló*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-sx0m4) 🔓

The authors report a direct, catalytic approach to cis-2,5- and cis-2,6-disubstituted THFs and THPs via reductive cycloetherification of 1,4- and 1,5-diketones. This metal-free transformation is enabled by a simple triarylborane catalyst and employs molecular hydrogen as the reductant, producing water as the sole by-product. A broad range of products were obtained in high yields (up to 94%) and cis-selectivity (up to >20:1 d.r.). The method was applied to the concise synthesis of pharmaceutically relevant THFs, offering shorter routes with improved yields, and was scalable to gram quantities.

Synthesis of Bicyclo[3.2.0]heptane Lactones via a Ligand-Enabled Pd-Catalyzed C(sp³)–H Activation Cascade

Z. Fan, X. Cai, T. Sheng & J.-Q. Yu*

Chem. Sci. 2025, Accepted (DOI: 10.1039/D5SC00711A) 🔓

The authors report the diastereoselective synthesis of bicyclo[3.2.0]heptane lactones from bicyclo[1.1.1]pentane carboxylic acids, which proceeds through palladium-catalyzed C–H activation and C–C cleavage processes. By using two different classes of ligands, either all-syn arylated bicyclo[3.2.0]heptane lactones or non-arylated ones can be obtained. The bicyclo[3.2.0]heptane lactone products were converted into substituted cyclobutane, γ-lactone and oxobicyclo[3.2.0]heptane derivatives.

Quinol–Enedione Rearrangement

T. Vieira de Castro, F. Richard,^‡ S. H. Bennett,^‡ C. S. Lamborelle, G. S. Nichol, R. Szabla* & A. L. Lawrence*

Org. Lett. 2025, ASAP (DOI: 10.1021/acs.orglett.5c01266) 🔓

The quinol–enedione rearrangement enables the synthesis of 2-cyclohexene-1,4-diones from readily available para-quinol substrates. Building on sporadic early reports of this transformation, the authors have optimized the reaction conditions and systematically investigated its substrate scope. The utility of Brønsted acid-mediated reaction conditions for a variety of quinol derivatives, including those with substituted and unsubstituted migrating termini, is highlighted. Notably, kinetic selectivity between quinol–enedione and dienone–phenol rearrangements is demonstrated. The synthetic potential of the enedione products is showcased through a range of transformations, leading to the formation of complex polycyclic structures.

Green Glow

🛰️ Green glow. Nature have just released their selection of the best science images in April, featuring footage of a green aurora captured by NASA astronaut Don Pettit aboard the International Space Station. The aurora is caused by charged particles from the Sun that are carried to Earth by the solar wind and enter the upper atmosphere near the magnetic poles, exciting gases such as nitrogen and oxygen, which emit light as they return to their ground state. This particular green colour is primarily the result of oxygen excitation at an altitude of ~100 km above the Earth.

💻️ Regenerator. Be sure to catch the German Chemical Society’s next Medicinal Chemistry webinar on Thursday 15^th May from Prof. Dr. Stefan Laufer on the “Discovery and Development of a First in Class MKK-4 Inhibitor HRX-215 to Increase Liver Regeneration”.