Diazirines, Strain-Release and C–H Functionalisation

Troubleshooting Hyperlinks

All “Open Paper” hyperlinks should take you straight to the desired publication; however, where this is unsuccessful, I would recommend the use of “Chemistry Reference Resolver” to quickly take you to the paper.

I’ve shown an example screenshot for the Google Chrome extension of this below where a reference or DOI can be highlighted, right-clicked and after selecting “Resolve a Reference” the publication is opened in a new tab.

Now that’s out of the way, let’s get into it. 👇

Nature

Copper-Catalyzed Dehydrogenation or Lactonization of C(sp³)−H Bonds

S. Zhou, Z.-J. Zhang & J.-Q. Yu*

Nature 2024 (DOI: 10.1038/s41586-024-07341-z)

Cytochrome P450 enzymes are known to catalyze bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation. Developing analogous catalytic systems for remote C−H functionalization remains a significant challenge. Here, the authors report the development of Cu(I)-catalyzed bimodal dehydrogenation/lactonization reactions of synthetically common N-methoxyamides via radical abstractions of the γ-aliphatic C−H bonds. The feasibility of switching from dehydrogenation to lactonization has also been demonstrated by altering reaction conditions. The use of a readily available amide as both radical precursor and internal oxidant allowed for the development of a redox-neutral C−H functionalization reactions with methanol as the sole side product.

Journal of the American Chemical Society

Aziridination via Nitrogen-Atom Transfer to Olefins from Photoexcited Azoxy-Triazenes

J. K. Mitchell, W. A. Hussain, A. H. Bansode, R. M. O’Connor & M. Parasram*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.3c14713) 🔓

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-kg5g6-v2) - open paper

The authors report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach eliminates the need for external oxidants, precious transition metals, and photocatalysts, marking a departure from conventional methods. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes of varying electronic profiles. Notably, this process avoids the formation of competing C–H insertion products. The described protocol is operationally simple, scalable, and adaptable to photoflow conditions. Mechanistic studies support the idea that the photofragmentation of azoxy-triazenes results in the generation of a free singlet nitrene.

Direct C–H Hydroxylation of N-Heteroarenes and Benzenes via Base-Catalyzed Halogen Transfer

K. I. Bone, T. R. Puleo & J. S. Bandar*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.3c14058)

Hydroxylated (hetero)arenes are valued in many industries as both key constituents of end products and diversifiable synthetic building blocks. Accordingly, the development of reactions that complement and address the limitations of existing methods for the introduction of aromatic hydroxyl groups is an important goal. To this end, the authors apply base-catalyzed halogen transfer (X-transfer) to enable the direct C–H hydroxylation of mildly acidic N-heteroarenes and benzenes. This protocol employs an alkoxide base to catalyze X-transfer from sacrificial 2-halothiophene oxidants to aryl substrates, forming S_NAr-active intermediates that undergo nucleophilic hydroxylation. Key to this process is the use of 2-phenylethanol as an inexpensive hydroxide surrogate that, after aromatic substitution and rapid elimination, provides the hydroxylated arene and styrene byproduct. Use of simple 2-halothiophenes allows for C–H hydroxylation of 6-membered N-heteroarenes and 1,3-azole derivatives, while a rationally designed 2-halobenzothiophene oxidant extends the scope to electron-deficient benzene substrates.

Synthesis of Borylated Carbocycles by [2+2]-Cycloadditions and Photo-Ene Reactions

J. M. Posz, N. Sharma, P. A. Royalty, Y. Liu, C. Salome*, T. C. Fessard & M. K. Brown*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c01557)

Saturated bicyclic compounds make up a valuable class of building blocks in the development of agrochemicals and pharmaceuticals. Here, the authors present the synthesis of borylated bicyclo[2.1.1]hexanes via crossed [2+2]-cycloaddition. Due to the presence of the C–B bond, a variety of structures can be easily prepared that are not accessible by other methods. Moreover, a rare photo-ene reaction is also disclosed, allowing for the diastereoselective synthesis of trisubstituted borylated cyclopentanes.

Total Synthesis of Putative Melognine

Y. Irie & S. Yokoshima*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02086)

Total synthesis of melognine was accomplished. A 10-membered cyclic alkyne was prepared via an intramolecular S_N2 reaction of a nosylamide. Enyne metathesis of the cyclic alkyne under an atmosphere of ethylene afforded a 1,3-diene. Intramolecular cycloaddition of a nitrone and an azomethine ylide with the 1,3-diene moiety constructed the characteristic highly fused skeleton. Further transformation, including ring-closing metathesis, resulted in the synthesis of melognine, whose NMR spectra did not match the reported data. Close inspection of the spectra of melognine in the literature suggested that the structure of melognine might be identical with that of a known alkaloid, melodinine L.

Stoichiometric and Catalytic Lithium Nickelate-Mediated C–F Bond Alkynylation of Fluoroarenes

A. M. Borys, L. Vedani & E. Hevia*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c02606)

Low-valent nickelates have recently been shown to be key intermediates that facilitate challenging cross-coupling reactions under mild conditions. Expanding the synthetic potential of these heterobimetallic complexes, herein, the authors report the success of trilithium nickelate Li₃(TMEDA)₃Ni(C≡C–Ph)₃ in promoting stoichiometric C–F activation of assorted aryl fluorides furnishing novel mixed Li/Ni(0) or Li/Ni(II) species depending on the substrate and conditions employed. These stoichiometric successes can be upgraded to catalytic regimes to enable the atom-efficient alkynylation of aryl fluorides and polyfluoroarenes with lithium acetylides and precatalyst Ni(COD)₂, which operates without the intervention of external ligands, Cu co-catalysts, or additives.

Angewandte Chemie International Edition

Regio- and Stereo-Selective Isomerization of Borylated 1,3-Dienes Enabled by Selective Energy Transfer Catalysis

B. Kweon, L. Blank, J. Soika, A. Messara, C. Daniliuc & R. Gilmour*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202404233)

Configurationally-defined dienes are pervasive across the bioactive natural product spectrum, where they typically manifest themselves as sorbic acid-based fragments. These C5 motifs reflect the biosynthesis algorithms that facilitate their construction. To complement established biosynthetic paradigms, a chemical platform to facilitate the construction of stereochemically defined, functionalizable dienes by light-enabled isomerization has been devised. Enabled by selective energy transfer catalysis, a variety of substituted β-boryl sorbic acid derivatives can be isomerized in a regio- and stereo-selective manner (up to 99:1). Directionality is guided by a stabilizing nO → pB interaction in the product: this constitutes a formal anti-hydroboration of the starting alkyne. This operationally simple reaction employs low catalyst loadings (1 mol%) and is complete in 1 h.

A Stoichiometric Haloform Coupling for Ester Synthesis with Secondary Alcohols

B. C. Rowett, S. G. Sweeting, D. Heard & A. Lennox*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202400570) 🔓

The haloform reaction from methyl ketones to carboxylic acids is one of the oldest known synthetic organic reactions and has been used in myriad applications over the decades. The corresponding reaction to produce esters is, however, less developed, as the reaction is generally limited to simple, primary alcohols that are used in solvent-level quantities, thereby restricting the complexity of esters that can be directly formed. Herein, the authors detail the development of a general ester‑forming haloform coupling reaction using one equivalent of alcohol.

Lewis Acid-Driven Inverse Hydride Shuttle Catalysis

B. T. Jones & N. Maulide*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202320001)

Inverse hydride shuttle catalysis provides a multicomponent platform for the highly efficient synthesis of alkaloid frameworks with exquisite diastereoselectivity. However, a number of limitations hinder this method, primarily the strict requirement for highly electron-deficient acceptors. Herein, the authors present a general Lewis Acid-driven approach to address this constraint, and have developed two broad strategies enabling the modular synthesis of complex azabicycles that were entirely unattainable using the previous method. The enhanced synthetic flexibility facilitates a streamlined asymmetric cyclization, leading to a concise total synthesis of the alkaloid (–)-tashiromine.

ChemRxiv

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp²)–C(sp³) Couplings via Nickel Catalysis

F. Lukas,^† M. T. Findlay,^† M. Fillols, J. Templ, E. Savino, B. Martin, S. Allmendinger, M. Furegati & T. Noël*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-b7kv6) 🔓

The development of robust and reliable methods for the construction of C(sp² )–C(sp³ ) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, the authors show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (g-C3N4) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners.

Regioselective Hydroamination of Unactivated Olefins with Diazirines as a Diversifiable Nitrogen Source

Q. Xing, P. P. Chandrachud, K. Tillett & J. M. Lopchuk*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-psn1q) 🔓

Nitrogen-containing compounds, such as amines, hydrazines, and heterocycles, play an indispensable role in medicine, agriculture, and materials. Alkylated derivatives of these compounds, especially in sterically congested environments, remain a challenge to prepare. Here, the authors report a versatile method for the regioselective hydroamination of readily available unactivated olefins with diazirines. Over fifty examples are reported, including the protecting group-free amination of fourteen different natural products. A broad functional group tolerance includes alcohols, ketones, aldehydes, and epoxides. The proximate products of these reactions are diaziridines, which, under mild conditions, are converted to primary amines, hydrazines, and heterocycles. Five target- and diversity-oriented syntheses of pharmaceutical compounds are shown, along with the preparation of a bis-¹⁵ N diazirine validated in the late-stage isotopic labeling of an RNA splicing modulator candidate.

Direct Catalytic Photodecarboxylative Amination of Carboxylic Acids with Diazirines: Divergent Access to Amines, Hydrazines, and Nitrogen-Containing Heterocycles

V. Maharaj, P. R. Athawale, P. P. Chandrachud & J. M. Lopchuk*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-4vg2s) 🔓

Amines, hydrazines, and nitrogen-containing heterocycles are pivotal species in medicine, agriculture, fine chemicals, and materials. Diazirines have been recently reported to serve as versatile electrophilic amination reagents for the synthesis of building blocks or late-stage C–N bond formation. Here, the authors report the catalytic photodecarboxylative amination of carboxylic acids with diazirines under mild conditions. The substrate scope includes broad functional group tolerance, such as ketones, esters, olefins, and alcohols, along with the late-stage amination of naproxen, ibuprofen, gemfibrozil, and gibberellic acid. Synthetic applications leverage the versatility of the intermediate diaziridines and include the regioselective preparation of a suite of 1H-indazoles, 2H-indazoles, and fluoroquinolones.

Harnessing Strain-Release Driven Reactivity of a Chiral SuFEx Reagent: Stereocontrolled Access to Sulfinamides, Sulfonimidamides, and Sulfoximines

P. R. Athawale,^‡ Z. P. Shultz^‡ , A. Saputo, Y. D. Hall, J. M. Lopchuk*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-m92kq) 🔓

Efforts aimed at enriching the chemical and structural diversity of small molecules have invigorated synthetic exploration in the last two decades. Spatially defined molecular functionality serves as the foundation to construct unique chemical space to further advance discovery science. The chiral SuFEx reagent t-BuSF provides a modular platform for the stereocontrolled bifunctionalization of sulfur. Here, the authors report a third functional feature of t-BuSF enabled by carbamoyl torsional strain-release that further expands the S(IV) and S(VI) chemical space accessible as showcased in over seventy examples, multiple applications in medicinal chemistry, organocatalysis, and diversity-oriented synthesis.

Direct Benzylic C–H Etherification Enabled by Base-Promoted Halogen Transfer

K. I. Bone^† , T. R. Puleo^† , M. D. Delost, Y. Shimizu & J. S. Bandar*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-fvrc1) 🔓

The authors disclose a benzylic C–H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence. The combination of tert-butoxide bases with 2-halothiophene halogen oxidants enables the first general protocol for generating and using benzyl halides through a deprotonative pathway. In contrast to existing radical-based pathways for C–H functionalization, this process is guided by C–H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision regioselectivity for polyalkylarenes and use of a double C–H etherification process to controllably oxidize methylarenes to benzaldehydes.

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π+2σ] Cycloaddition Reactions

J. L. Tyler, F. Schäfer, H. Shao, C. Stein, A. Wong, C. G. Daniliuc, K. N. Houk* & F. Glorius*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-p2pvb) 🔓

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, the authors report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π+2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including non-activated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations.

Photoredox Catalyzed Strain-Release Driven Synthesis of Functionalized Spirocyclobutyl Oxindoles

T. Singha,^† N. A. Bapat,^† S. K. Mishra^† & D. P. Hari*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-9ggdm) 🔓

Spirocyclobutyl oxindoles have garnered substantial attention in drug discovery and pharmaceuticals owing to their wide range of biological activities. Strain-release in small-ring compounds is a powerful strategy to enable efficient access to complex molecules. In this study, the authors have successfully realized a photoredox-catalyzed strain-release radical spirocyclization approach to attain functionalized spirocyclobutyl oxindoles. A diverse array of radicals, such as sulfonyl, phosphonyl, and trifluoromethyl, were added efficiently to the strained C–C bond of bicyclobutanes (BCBs) to afford a library of spirocyclobutyl oxindoles.

Organic Letters

Climbing the Oxidase Phase Ladder by Using Dioxygen as the Sole Oxidant: The Case Study of Costunolide

K. Gennaiou, A. Kelesidis & A. L. Zografos*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00406)

Natural sesquiterpenoid lactones are prominent scaffolds in drug discovery. Despite the progress made in their synthesis, their extensive oxidative decoration makes their chemo- and stereoselective syntheses highly challenging. Herein, the authors report their effort to mimic part of the oxidase phase used in the costunolide pathway to achieve the protecting-group-free total synthesis of santamarine, dehydrocostus lactone, estafiatin, and nine more related natural sesquiterpenoid lactones by using dioxygen as the sole oxidant.

Gold-Catalyzed C(sp³)–C(sp²) Suzuki–Miyaura Coupling Reaction

W. Du, F. Zhao, R. Yang & Z. Xia*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c00755)

A gold-catalyzed C(sp³ )–C(sp² ) Suzuki–Miyaura coupling reaction facilitated by ligand-enabled Au(I)/Au(III) redox catalysis was developed. The cross-coupling of alkyl organometallics was first realized in the redox catalytic cycle in gold chemistry, without the use of external oxidants. This gold-catalyzed C(sp³ )–C(sp² ) coupling reaction allows a variety of alkyl chain and useful methyl trifluoroborates to react with aryl and vinyl iodides under very mild conditions, which provides a new reactivity pattern for challenging couplings with alkyl organometallics.

Journal of Organic Chemistry

General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp³)-Rich Benzene Bioisosteres

X. Ma*, A. M. Beard, S. A. Burgess, M. Darlak, J. A. Newman, L. M. Nogle, M. J. Pietrafitta, D. A. Smith, X. Wang & L. Yue

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c00225)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-9k7kc) - open paper

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists’ toolkits. Herein, the authors report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp³ )-rich benzene bioisosteres. They have also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

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