De-risking Diazonium Chemistry

Science

Nitrate Reduction Enables Safer Aryldiazonium Chemistry

J. Mateos,^‡ T. Schulte,^‡ D. Behera, M. Leutzsch, A. Altun, T. Sato, F. Waldbach, A. Schnegg, F. Neese & T. Ritter*

Science 2024 (DOI: 10.1126/science.adn7006)

Aryldiazonium salts remain a staple in organic synthesis and are still prepared largely in accord with the protocol developed in the 19th century. Because of the favorable reactivity that often cannot be achieved with other aryl(pseudo)halides, diazonium chemistry continues to grow. Facile extrusion of dinitrogen contributes to the desired reactivity but is also reason for safety concerns. Explosions have occurred since the discovery of these reagents and still result in accidents. In this study, the authors report a diazonium chemistry paradigm shift based on nitrate reduction using thiosulfate or dihalocuprates as electron donors that avoids diazonium accumulation. Because nitrate reduction is rate-limiting, aryldiazoniums are produced as fleeting intermediates, which results in a safer and often more efficient deaminative halogenation in a single step from anilines.

Nature Catalysis

A General Strategy for the Amination of Electron-Rich and Electron-Poor Heteroaromatics by Desaturative Catalysis

J. Corpas, H. P. Caldora, E. M. Di Tommaso, A. C. Hernandez-Perez, O. Turner, L. M. Azofra, A. Ruffoni* & D. Leonori*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01152-1)

The introduction of alkylamines onto heteroaromatics is integral to the preparation of high-value molecules. Typical methods rely on heteroaromatic pre-functionalization by halogenation or nitration, followed by metal-catalysed cross-coupling or multi-step manipulation of the nitrogen functionality. This results in often unselective or low-yielding synthetic routes. Here, the authors show an alternative approach in which saturated heterocyclic ketones are used as aryl surrogates for desaturative coupling with amines. The process operates under mild photochemical conditions, is compatible with complex amines and delivers both electron-poor and -rich heteroaromatics that are difficult to access by other methods. As ketones are readily decorated by carbonyl chemistry, this retrosynthetic tactic escapes the rules and limitations of aromatic reactivity and metal-catalysed cross-couplings.

Journal of the American Chemical Society

Engaging Alkenes in Metallaphotoredox: A Triple Catalytic, Radical Sorting Approach to Olefin-Alcohol Cross-Coupling

Q. Cai, I. M. McWhinnie, N. W. Dow, A. Y. Chan & D. W. C. MacMillan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02316)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-f33pj) 🔓

Metallaphotoredox cross-coupling is a well-established strategy for generating clinically privileged aliphatic scaffolds via single-electron reactivity. Correspondingly, expanding metallaphotoredox to encompass new C(sp³ )-coupling partners could provide entry to a novel, medicinally relevant chemical space. In particular, alkenes are abundant, bench-stable, and capable of versatile C(sp³ )-radical reactivity via metal-hydride hydrogen atom transfer (MHAT), although metallaphotoredox methodologies invoking this strategy remain underdeveloped. Importantly, merging MHAT activation with metallaphotoredox could enable the cross-coupling of olefins with feedstock partners such as alcohols, which undergo facile open-shell activation via photocatalysis. Herein, the authors report the first C(sp³ )–C(sp³ ) coupling of MHAT-activated alkenes with alcohols by performing deoxygenative hydroalkylation via triple cocatalysis. Through synergistic Ir photoredox, Mn MHAT, and Ni radical sorting pathways, this branch-selective protocol pairs diverse olefins and methanol or primary alcohols with remarkable functional group tolerance to enable the rapid construction of complex aliphatic frameworks.

Photoredox Nucleophilic (Radio)fluorination of Alkoxyamines

S. Ortalli, J. Ford, A. A. Trabanco, M. Tredwell & V. Gouverneur*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02474) 🔓

The authors report a photoredox nucleophilic (radio)fluorination using TEMPO-derived alkoxyamines, a class of substrates accessible in a single step from a diversity of readily available carboxylic acids, halides, alkenes, alcohols, aldehydes, boron reagents, and C–H bonds. This mild and versatile one-electron pathway affords radiolabeled aliphatic fluorides that are typically inaccessible applying conventional nucleophilic substitution technologies due to insufficient reactivity and competitive elimination. Automation of this photoredox process is also demonstrated with a user-friendly and commercially available photoredox flow reactor and radiosynthetic platform, therefore expediting access to labeled aliphatic fluorides in high molar activity (Am) for (pre)clinical evaluation.

Alkyl Cyclopropyl Ketones in Catalytic Formal [3 + 2] Cycloadditions: The Role of SmI₂ Catalyst Stabilization

J. I. Mansell, S. Yu, M. Li, E. Pye, C. Yin, F. Beltran, J. A. Rossi-Ashton, C. Romano, N. Kaltsoyannis & D. J. Procter*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03073) 🔓

Alkyl cyclopropyl ketones are introduced as versatile substrates for catalytic formal [3 + 2] cycloadditions with alkenes and alkynes and previously unexplored enyne partners, efficiently delivering complex, sp³ -rich products. The key to effectively engaging this relatively unreactive new substrate class is the use of SmI₂ as a catalyst in combination with substoichiometric amounts of Sm⁰ ; the latter likely acting to prevent catalyst deactivation by returning Sm^III to the catalytic cycle. In the absence of Sm⁰ , background degradation of the SmI₂ catalyst can outrun product formation. For the most recalcitrant alkyl cyclopropyl ketones, catalysis is “switched-on” using these new robust conditions, and otherwise unattainable products are delivered.

Angewandte Chemie International Edition

Electrochemical Synthesis of C(sp³)-Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds

W.-Q. Liu, B. C. Lee, N. Song, Z. He, Z.-A. Shen, Y. Lu & M. J. Koh*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202402140)

Alkylamines form the backbone of countless nitrogen-containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three-dimensional α-substituted alkylamines bearing complex substitution patterns remain scarce. Here, the authors report the design of a catalyst-free electroreductive manifold that merges amines, carbonyl compounds and carbon-based radical acceptors under ambient conditions without rigorous exclusion of air and moisture. Key to this aminative carbofunctionalization process is the chemoselective generation of nucleophilic α-amino radical intermediates that readily couple with electrophilic partners, providing straightforward access to architecturally intricate alkylamines and drug-like scaffolds which are inaccessible by conventional means.

ChemRxiv

Migratory Aryl Cross-Coupling

Y. Sekiguchi, P. Onnuch, Y. Li & R. Y. Liu*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-z2z04) 🔓

A fundamental property of cross-coupling reactions is regiospecificity, meaning that the site of bond formation is determined by the leaving group’s location on the electrophile. Typically, to achieve a different substitution pattern requires synthesis of a new, corresponding starting-material isomer. As an alternative, the authors proposed the development of cross-coupling variants that afford access to multiple structural isomers from the same coupling partners. Here, they first demonstrate that a bulky palladium catalyst can facilitate efficient, reversible positional transposition of aryl halides by temporarily forming metal aryne species. Despite the nearly thermoneutral equilibrium governing this process, combining it with gradual addition of a suitable nucleophile results in parallel resolution of the isomers and high yields of unconventional product isomers. The method accommodates a range of oxygen- and nitrogen-centered nucleophiles and tolerates numerous common functional groups.

Organic Letters

Evaluation of Retro-Aldol vs Retro-Carbonyl-Ene Mechanistic Pathways in a Complexity-Generating C–C Bond Fragmentation

A. S. Bulger, D. W. Turner, Q. Zhou, K. N. Houk* & N. K. Garg*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01037)

The authors report an experimental and computational investigation of the likely mechanism of a cascade reaction. The reaction involves an intramolecular Diels–Alder reaction, followed by a C–C bond cleavage, to afford a complex bridged bicyclic product. As multiple reaction pathways could be envisioned for the latter step, the mechanism of the C–C bond cleavage step was investigated. Two reasonable reaction pathways were evaluated. Both computations and experiments indicate that the C–C bond cleavage step proceeds by a retro-carbonyl-ene pathway rather than a retro-aldol pathway.

Forging the Tetracyclic Core Framework of Rhodomolleins XIV and XLII: A Ring-Distortion Approach

Z.-N. Yang,^‡ H. Rao,^‡ Y. Yin, S. Mu, Z. Jia & H. Ding*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00885)

A ring distortion approach for the synthesis of an advanced intermediate en route to rhodomolleins XIV and XLII is described, which led to successful construction of the 5/8/5/5 tetracyclic core framework of the kalmane diterpenoids. Key steps of the strategy include an oxidative dearomatization-induced (ODI)-Diels–Alder cycloaddition, a Dowd–Beckwith rearrangement, and a bioinspired Wagner–Meerwein rearrangement.

Deoxy-Arylation of Amides via a Tandem Hydrosilylation/Radical–Radical Coupling Sequence

N. J. Venditto* & J. A. Boerth*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01121)

Vaska’s complex is a prominent catalyst for the hydrosilylation of amides. The O-silyl hemiaminal intermediate formed in these processes has been demonstrated as an electrophile for nucleophilic additions. More recently, these intermediates have been shown to be suitable for single electron reduction to generate α-amino radicals. Leveraging the ability to generate α-amino radicals from these hemiaminals, the authors describe a two-step, one-pot, deoxy-arylation of amides utilizing iridium-catalyzed hydrosilylation and photoredox catalysis. This transformation can be tailored toward the late-stage functionalization of biologically relevant molecules, with drug discovery applications as shown in the streamlined synthesis of an NPY Y2 inhibitor.

Synthesis of Borylated (Aminomethyl)cyclopropanes Using C₁–Bisnucleophiles

T. R. McDonald, J. A. Turner, A. L. Gabbey, P. Balasubramanian & S. A. L. Rousseaux*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00987)

Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, the authors show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes—a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.

Journal of Organic Chemistry

Synthesis of N–H Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids as Aminating Agent

Y. Huang, S.-Y. Zhu, G. He, G. Chen & H. Wang*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00253)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-f33pj) 🔓

The authors present a practical method for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with nonactivated alkenes, and facilitates the transformation of various alkenes substrates, including mono-, di-, tri, and tetra-substituted alkenes, into aziridines with moderate to excellent yield.

That’s all for this issue! Have a great week and we’ll see you next Monday.