New Year, New Strategies to Insert Nitrogen-Atoms

Welcome to the first Organic Synthesis Newsletter of 2025!

To start the year, we’ll be looking back to Wednesday 1^st January and highlighting any key papers published within the past 2 weeks.

Wednesday 1^st January – Sunday 12^th January 2025 | Volume 2, Issue 1

HIGHLIGHT OF THE WEEK
Sulfenylnitrene-Mediated Nitrogen-Atom Insertion for Late-Stage Skeletal Editing of N-Heterocycles

B. Ghosh,^† P. Kafle,^† R. Mukherjee,^† R. Welles, D. Herndon, K. M. Nicholas, Y. Shao & I. Sharma*

Science 2025, 387, 102–107 (DOI: 10.1126/science.adp0974)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-f80wf-v2) 🔓

Given the prevalence of nitrogen-containing heterocycles in commercial drugs, selectively incorporating a single nitrogen atom is a promising scaffold hopping approach to enhance chemical diversity in drug discovery libraries. Here, the authors harness the distinct reactivity of sulfenylnitrenes, which insert a single nitrogen atom to transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, and triazines, respectively. This additive-free method employs easily accessible, benchtop-stable sulfenylnitrene precursors, is compatible with diverse functional groups, and has been applied to various natural products and pharmaceuticals.

NATURE
β-C−H Bond Functionalization of Ketones and Esters by Cationic Pd Complexes

Y.-H. Li, N. Chekshin, Y. Lu & J.-Q. Yu*

Nature 2025 (DOI: 10.1038/s41586-024-08281-4)

C–H activation is the most direct way of functionalizing organic molecules; however, many advances in this field still require specific directing groups to achieve the necessary activity and selectivity. Developing C–H activation reactions directed by native functional groups is essential for their broad application in synthesis. Over the past decade, several ligands developed have enabled C(sp³)–H activation reactions of free carboxylic acids, amines, amides and alcohols. However, an effective catalyst for ketones and esters remains to be realized. Here, the authors report diverse methyl β-C−H functionalizations, including intermolecular arylation, hydroxylation and intramolecular C(sp³)–H/C(sp²)–H coupling of ketones and esters with a mono-protected amino neutral amide (MPANA) ligand. The in situ generation of cationic Pd(II) complexes by the combination MPANA ligand and HBF₄ is crucial for achieving the reactivity. The compatibility of these reactions with cyclic ketones and lactams provides a method to access spirocyclic and fused ring system.

NATURE CHEMISTRY
Synthesis of Tertiary Alkyl Amines via Photoinduced Copper-Catalysed Nucleophilic Substitution

H. Cho, X. Tong, G. Zuccarello, R. L. Anderson & G. C. Fu*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01692-w)

In view of the high propensity of tertiary alkyl amines to be bioactive, the development of new methods for their synthesis is an important challenge. Transition-metal catalysis has the potential to greatly expand the scope of nucleophilic substitution reactions of alkyl electrophiles; unfortunately, in the case of alkyl amines as nucleophiles, only one success has been described so far: the selective mono-alkylation of primary amines to form secondary amines. Here, using photoinduced copper catalysis, the authors report the synthesis of tertiary alkyl amines from secondary amines and unactivated alkyl electrophiles, two readily available coupling partners.

Stereoselective Amino Alcohol Synthesis via Chemoselective Electrocatalytic Radical Cross-Couplings

J. Sun, S. Wang, K. C. Harper, Y. Kawamata* & P. S. Baran*

Nat. Chem. 2025 (DOI: 10.1038/s41557-024-01695-7)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-hq8r8) 🔓

Amino alcohols are vital in natural products, pharmaceuticals and as key building blocks for various applications. Traditional synthesis methods often rely on polar bond retrosynthetic analysis, which require extensive protecting group manipulations. Here, the authors show a streamlined approach using a serine-derived chiral carboxylic acid in stereoselective electrocatalytic decarboxylative transformations, enabling access to enantiopure amino alcohols. Unlike conventional strategies, this radical method is both modular and general, offering stereoselective and chemoselective synthesis of diverse substituted amino alcohols. The rapid synthesis of medicinally important compounds, as well as useful building blocks is demonstrated alongside a 72-gram-scale flow reaction.

NATURE SYNTHESIS
Anti-Markovnikov Hydro- and Deuterochlorination of Unsaturated Hydrocarbons Using Iron Photocatalysis

K.-J. Bian, D. Nemoto Jr, Y. Chen, Y.-C. Lu, S.-C. Kao, X.-W. Chen, A. A. Martí & J. G. West*

Nat. Synth. 2025 (DOI: 10.1038/s44160-024-00698-z)

The hydrochlorination of unsaturated hydrocarbons is a fundamental reaction in organic synthesis. Traditional acid-mediated approaches proceed with Markovnikov selectivity but direct access to anti-Markovnikov hydrochlorination products is still a longstanding pursuit. Previous methods are restricted by the need for multiple synthetic steps, stoichiometric chlorine and hydride sources, and/or highly oxidative photocatalysis. So, the development of redox-neutral hydrochlorination with high anti-Markovnikov regioselectivity remains important. Here, the authors report a photocatalytic anti-Markovnikov hydro- and deuterochlorination of unsaturated hydrocarbons enabling access to diverse alkyl and alkenyl chlorides regio- and stereoselectively. Broad scope (125 examples), mild conditions and regio- and isotopo-divergent syntheses are demonstrated.

NATURE CATALYSIS
Site- and Enantioselective Allylic and Propargylic C–H Oxidation Enabled by Copper-Based Biomimetic Catalysis

H. Zhang,^† Y. Zhou,^† T. Yang,^† J. Wu, P. Chen, Z. Lin* & G. Liu*

Nat. Catal. 2025 (DOI: 10.1038/s41929-024-01276-4)

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

Enzymatic catalysis, which uses key metal-oxo species to facilitate efficient hydrogen atom abstraction, has evolved as a highly selective approach for C–H oxidation in biological systems. Despite its effectiveness, reproducing this function and achieving high stereoselectivity in biomimetic catalysts has proven to be a daunting task. Here, the authors present a copper-based biomimetic catalytic system that achieves highly efficient asymmetric sp³ C–H oxidation with C–H substrates as the limiting reagent. A Cu(II)-bound tert-butoxy radical is responsible for site-selective C–H bond cleavage, resembling the active site of copper-based enzymes for C–H oxidation. The method has good functional group compatibility alongside high site- and enantioselectivity.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Aminoalkylation of Alkenes Enabled by Triple Radical Sorting

W. L. Lyon, J. Z. Wang, J. Alcázar & D. W. C. MacMillan*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14965)

C(sp³)-rich scaffolds can impart beneficial properties onto drug molecules, correlating with greater clinical success. Consequently, there is a strong impetus to develop new methods to access sp³-rich molecules from commercial feedstocks, such as alkenes. Herein, the authors report a three-component aminoalkylation reaction that utilizes the principles of triple radical sorting to regioselectively add N-centered and C-centered radicals across alkenes. This process relies upon photoredox catalysis to transform alkyl bromides and reductively activated N-centered radical precursors into high-energy radical species in a redox-neutral fashion. A broad scope of coupling partners is demonstrated, with multiple synthetic applications, including facile syntheses of pharmacophoric substituted N-heterocycles.

Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles

S. F. Kim,^† J. P. Liles,^† M. C. Lux, H. Park, J. Jurczyk, Y. Soda, C. S. Yeung,* M. S. Sigman* & R. Sarpong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c13999)

The authors recently reported a chiral phosphoric acid (CPA) catalyzed enantioselective photomediated ring contraction of piperidines and other saturated heterocycles. By extruding a single heteroatom from a ring, this transformation builds desirable C(sp³)–C(sp³) bonds in the ring contracted products; however, the origins of enantioselectivity remain poorly understood. In this work, enantioselectivity of the ring contraction has been explored across an expanded structurally diverse substrate scope, revealing a wide range of enantioselectivities (0–99%) using two distinct CPA catalysts. Mechanistic investigations support rate-determining excitation that generates short-lived achiral intermediates that are intercepted by the CPA in an enantiodetermining ring closure. Statistical models were built, which suggested distinct factors that influence the enantioselectivity response for each catalyst and enabled rational modification of a pharmaceutically relevant target molecule to improve enantioselectivity.

Site-Selective Copper(I)-Catalyzed Hydrogenation of Amides

D.-I. Tzaras, M. Gorai, T. Jacquemin, T. Arndt, B. M. Zimmermann, M. Breugst & J. F. Teichert*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14174) 🔓

The authors present a bifunctional catalyst consisting of a copper(I)/N-heterocyclic carbene and an organocatalytic guanidine moiety that enables, for the first time, a copper(I)-catalyzed reduction of amides with H₂ as the terminal reducing agent. The guanidine allows for reactivity tuning of the originally weakly nucleophilic copper(I) hydrides—formed in situ—to be able to react with difficult-to-reduce amides. Additionally, the guanidine moiety is key for the selective recognition of “privileged” amides in the presence of other amides, giving rise to hitherto unknown site-selective catalytic amide hydrogenation.

Alkoxy-Directed Dienamine Catalysis in [4+2]-Cycloaddition: Enantioselective Synthesis of Benzo-[3]-ladderanol

S. Ray, D. Behera, M. S. Harariya, S. Das, P. K. Tarafdar & S. Mukherjee*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c13713)

Despite the tremendous progress made in dienamine catalysis, certain limitations, especially with respect to regioselectivity in the dienamine generation step, continue to persist. To overcome these shortcomings, the authors introduce the concept of alkoxy-directed dienamine catalysis and apply it to enantioselective de novo arene construction by desymmetrizing meso-enediones through [4+2]-cycloaddition. The utility of this strategy is demonstrated in the concise enantioselective synthesis of a benzo-analogue of the natural ladderane phospholipid component (+)-[3]-ladderanol. This unnatural benzo-[3]-ladderanol was found to impart lower proton permeability and higher stability to the membrane vs. its natural counterpart.

Divergent Total Syntheses of Phragmalin and Khayanolide-Type Limonoids: A Torquoselective Interrupted Nazarov Approach

P. Rao, D. Tang, Q. Xia, J. Hu, X. Lin, J. Xuan* & H. Ding*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c16265)

The asymmetric and divergent total syntheses of two phragmalin (moluccensins G and H) and two khayanolide-type (krishnolide F and khayseneganin F) limonoids are disclosed, which employed a torquoselective interrupted Nazarov cyclization as the key step. Taken together with a Liebeskind–Srogl coupling, a benzoin condensation and bidirectional acyloin rearrangements, the strategy simplifies the synthesis of both phragmalin and khayanolide-type limonoids. The described approach also provides additional insights into the biosynthetic relationships between these two distinct skeletons.

A General Three-Component Nozaki–Hiyama–Kishi-Type Reaction Enabled by Delayed Radical-Polar Crossover

Y.-B. Li,^† M. Xu,^† L. A. Kellermann, J. E. Erchinger, S. Dutta, C. G. Daniliuc, X. Qi* & F. Glorius*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14913)

Nozaki–Hiyama–Kishi (NHK) reactions offer a mild approach for the formation of alcohol motifs through radical-polar crossover-based pathways from various radical precursors. However, the application of multicomponent NHK-type reactions, which form multiple bonds in a single step, have been largely restricted to bulky alkyl radical precursors—limiting their utilization. Here, the authors disclose a general three-component NHK-type reaction enabled by delayed radical-polar crossover, which efficiently tolerates a plethora of radical precursors. This method enables the modular assembly of versatile homoallylic alcohols from feedstock chemicals with excellent chemo-, regio-, diastereo- and enantioselectivities in a single step.

Deacylative Homolysis of Ketone C(sp³)–C(sp²) Bonds: Streamlining Natural Product Transformations

M. Šimek, S. Mahato, B. W. Dehnert & O. Kwon*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15045) 🔓

The homolytic cleavage of C–C bonds adjacent to specific functional groups has emerged as a versatile approach for molecular diversification. Despite the ubiquity and synthetic utility of ketones, radical fragmentation of their α-C–C bonds has proven to be a formidable challenge. Here, the authors present a deacylative strategy to homolytically cleave aliphatic ketones into carboxylic acids and C-centered free radicals that can engage in diverse radical-based processes. The method involves ketone activation with hydrogen peroxide, yielding gem-dihydroperoxides, followed by single-electron-transfer reduction to generate alkyl radicals that can be captured with a radicophile of choice. This deacylative functionalization is exemplified in the total synthesis of 14 natural products, 1 analogue, and 2 drugs.

Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Triflates with Alkyl Halides: Mechanism-Informed Design of More General Conditions

S. Kim, M. J. Goldfogel, B. N. Ahern, D. C. Salgueiro, I. A. Guzei & D. J. Weix*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c14769)

Despite the known reactivity of nickel complexes for aryl C–O bond activation of phenol derivatives, nickel-catalyzed cross-electrophile coupling using aryl triflates has proven challenging. Here, the authors report a method to form C(sp²)–C(sp³) bonds by coupling aryl triflates with alkyl bromides and chlorides using phenanthroline (phen) or pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCam^CN)-ligated nickel catalysts. The scope of the reaction is demonstrated with 38 examples (61 ± 14% average yield). Mechanistic studies provide a rationale for the conditions used and a roadmap for further applications of cross-electrophile coupling.

Photoinduced Regiodivergent and Enantioselective Cross-Coupling of Glycine Derivatives with Hydrocarbon Feedstocks

F. Yang, L. Chi, Z. Ye & L. Gong*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c13321)

Regiodivergent asymmetric synthesis represents a transformative strategy for the generation of structurally diverse chiral products from a single set of starting materials. However, the design of radical-mediated regiodivergent and enantioselective reactions has posed significant challenges. Here, the authors have developed a catalytic system that integrates photoinduced hydrogen atom transfer (HAT) and chiral copper catalysis to facilitate the regiodivergent and enantioselective cross-coupling between N-aryl glycine ester/amide derivatives and abundant hydrocarbon feedstocks. This approach allows for the controlled and stereoselective formation of C(sp³)–C(sp³) and C(sp³)–N bonds, yielding a variety of C- or N-alkylated glycine esters and amides with high yields (up to 92% yield), exclusive regioselectivities (typically >20:1 r.r.), and high enantioselectivities (up to 96% e.e.).

Dearomative Addition-Hydrogen Autotransfer for Branch-Selective N-Heteroaryl C–H Functionalization via Ruthenium-Catalyzed C–C Couplings of Diene Pronucleophiles

J. Z. Shezaf, S. Lee,^‡ Y. S. Teoh,^‡ Z. H. Strong,^‡ P.-P. Xie,^‡ J. Wu, P. Liu* & M. J. Krische*

J. Am. Chem. Soc. 2025, ASAP (DOI: 10.1021/jacs.4c15157)

A novel mechanism for N-heteroaryl C–H functionalization via dearomative addition-hydrogen autotransfer is described. Upon exposure to the catalyst derived from RuHCl(CO)(PPh₃)₃ and Xantphos, a selection of dienes undergo hydroruthenation to form allylruthenium nucleophiles that engage in N-heteroaryl addition-β-hydride elimination to furnish branched products of C–C coupling. Oxidative cleavage of isoprene adducts followed by ruthenium-catalyzed dynamic kinetic asymmetric ketone reduction provides enantiomerically enriched N-heteroarylethyl alcohols and, therefrom, N-heteroarylethyl amines.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Late-Stage Diazoester Installation via Arylthianthrenium Salts

L. Li, S. Müller, R. Petzold & T. Ritter*

Angew. Chem. Int. Ed. 2025, Accepted (DOI: 10.1002/anie.202419931) 🔓

By leveraging the fast oxidative addition of arylthianthrenium salts (aryl–TT⁺) to palladium(0), a regioselective diazoester installation has been developed. This approach enables the introduction of a diazo moiety to densely functionalized arenes at a late stage. The installed diazo group is amenable to facile further derivatization.

CHEMRXIV
A Four-Step Synthesis of (±)-Nanolobatolide via Site-Specific Olefin Functionalization

A. Panigrahi & K. K. Pulukuri*

ChemRxiv 2025 (DOI: 10.26434/chemrxiv-2025-k27df) 🔓

For the first time, guaiazulene has been utilized as a starting material, employing a novel dearomative approach to construct the guaiane core. This strategy facilitated the concise, four-step total synthesis of (±)-nanolobatolide, a complex tetracyclic diterpenoid (5/5/5/7 system). The synthesis features a selective Diels–Alder reaction targeting a specific diene within a polyene framework, a site-specific epoxidation coupled with an in situ lactonization, and a late-stage face- and site-selective hydrogenation mediated by cooperative hydrogen atom transfer catalysis.

Enantioselective Ring Opening of Azetidines via Charge Recognition in Hydrogen-Bond-Donor Catalysis

J. J. Gair,^† M. Isomura,^† C. C. Wagen, D. A. Strassfeld & E. N. Jacobsen*

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

The authors report the highly enantioselective ring-opening of 3-substituted azetidines by alkyl and acyl halides promoted by a chiral squaramide H-bond donor catalyst. Broad scope is achieved across a variety of substrate combinations possessing disparate steric features. The same catalyst had been identified previously to promote enantioselective opening of oxetanes via both Lewis and Bronsted acid mechanisms. This remarkable generality is interpreted to arise from catalyst recognition of the conserved electrostatic features of the dipolar enantioselectivity-determining transition states in the ring- opening S_N2 mechanisms with simultaneous tolerance of variation of the specific functional group and steric features of the reactions.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
A Retraction Watch for Preprints

🔎 A Retraction Watch for Preprints. Believe it or not, ArXiv, the open-access preprint server is 33 years old—born out of necessity to cope with sharing physics preprints to an ever-expanding email list of string theorists, Joanne Cohn and Paul Ginsparg launched the repository on 14^th August 1991. In the three decades since, the site has grown exponentially with 24,000 articles submitted each month, a long way from the 17 years it took to get the first 500,000 articles.

Now, a team of researchers have created “WithdrarXiv”, a large-scale dataset of withdrawn papers from arXiv consisting of over 14,000 papers and their retraction comments since the repository's launch. Crucial errors (factual, methodological or other important errors) make up the bulk of these retractions, coming at just over 6000. Given that preprints often make headlines, this figure raises concerns as much of the general public don’t understand the difference between a preprint and a peer reviewed journal article. While the creators of WithdrarXiv hope it will help develop automated tools to flag potential errors in manuscripts, this should also be coupled with a greater push to better communicate the peer review process to the general public. Although as it turns out, only around 50% of news articles about COVID-19 preprints from early 2020 noted that the manuscripts were unreviewed anyway…