Accessing Azetidines from Acyclic Oximes and Alkenes

Science

Visible Light–Mediated Aza Paternò–Büchi Reaction of Acyclic Oximes and Alkenes to Azetidines

E. R. Wearing, Y.-C. Yeh, G. G. Terrones^† , S. G. Parikh^† , I. Kevlishvili, H. J. Kulik* & C. S. Schindler*

Science 2024 (DOI: 10.1126/science.adj6771)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-x76xj) 🔓

The aza Paternò–Büchi reaction is a [2+2]-cycloaddition reaction between imines and alkenes that produces azetidines, four-membered nitrogen-containing heterocycles. Currently, successful examples rely primarily on either intramolecular variants or cyclic imine equivalents. To unlock the full synthetic potential of aza Paternò–Büchi reactions, it is essential to extend the reaction to acyclic imine equivalents. Here, the authors report that matching of the frontier molecular orbital energies of alkenes with those of acyclic oximes enables visible light–mediated aza Paternò–Büchi reactions through triplet energy transfer catalysis. The utility of this reaction is further showcased in the synthesis of epi-penaresidin B. Density functional theory computations reveal that a competition between the desired [2+2]-cycloaddition and alkene dimerization determines the success of the reaction. Frontier orbital energy matching between the reactive components lowers transition-state energy (ΔG^ǂ ) values and ultimately promotes reactivity.

Nature Chemistry

Modular Assembly of Arenes, Ethylene and Heteroarenes for the Synthesis of 1,2-Arylheteroaryl Ethanes

T. Liu, T. Li, Z. Y. Tea, C. Wang, T. Shen, Z. Lei, X. Chen, W. Zhang* & J. Wu*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01560-7)

The 1,2-arylheteroaryl ethane motif stands as a privileged scaffold with promising implications in drug discovery. Conventional de novo syntheses of these molecules have relied heavily on pre-functionalized synthons, entailing harsh conditions and multi-step processes. Here, the authors present a modular approach for the direct synthesis of 1,2-arylheteroaryl ethanes using feedstock chemicals, including ethylene, arenes and heteroarenes. They disclose a photo triplet-energy-transfer-initiated radical cascade process, leveraging homolytic cleavage of C–S bonds in aryl sulfonium salts as the key step to access aryl radicals with excellent regioselectivity. This method allows for rapid structural diversification of bioactive molecules, showcasing excellent functional group tolerance and streamlining the synthesis of bioactive compounds and their derivatives. Furthermore, the approach can be extended to propylene, non-gaseous terminal alkenes and various other electrophilic radical precursors, including heteroaryl radicals, hydroxyl radicals, trifluoromethyl radicals and α-carbonyl alkyl radicals.

Nature Communications

Tandem Dehydrogenation-Olefination-Decarboxylation of Cycloalkyl Carboxylic Acids via Multifold C–H Activation

T. Pal, P. Ghosh, M. Islam, S. Guin, S. Maji, S. Dutta, J. Das, H. Ge* & D. Maiti*

Nat. Commun. 2024, 15, 5370 (DOI: 10.1038/s41467-024-49359-x) 🔓

Dehydrogenation chemistry has long been established as a fundamental aspect of organic synthesis, commonly encountered in carbonyl compounds. Transition metal catalysis revolutionized it, with strategies like transfer-dehydrogenation, single electron transfer and C–H activation. These approaches, extended to multiple dehydrogenations, can lead to aromatization. Dehydrogenative transformations of aliphatic carboxylic acids pose challenges, yet engineered ligands and metal catalysis can initiate dehydrogenation via C–H activation, though outcomes vary based on substrate structures. Herein, the authors have developed a catalytic system enabling cyclohexane carboxylic acids to undergo multifold C–H activation to furnish olefinated arenes, bypassing lactone formation. This showcases unique reactivity in aliphatic carboxylic acids, involving tandem dehydrogenation-olefination-decarboxylation-aromatization sequences, validated by control experiments and key intermediate isolation. For cyclopentane carboxylic acids, reluctant to aromatization, the catalytic system facilitates controlled dehydrogenation, providing difunctionalized cyclopentenes through tandem dehydrogenation-olefination-decarboxylation-allylic acyloxylation sequences.

Journal of the American Chemical Society

Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols

M. J. Strauss, K. X. Liu, M. E. Greaves, J. C. Dahl, S.-T. Kim, Y.-J. Wu, M. A. Schmidt, P. M. Scola & S. L. Buchwald*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05246)

The authors report a general and functional-group-tolerant method for the Cu-catalyzed amination of base-sensitive aryl bromides including substrates possessing acidic functional groups and small five-membered heteroarenes. The results presented substantially expand the scope of Cu-catalyzed C–N coupling reactions. The combination of L8, an anionic N¹ ,N² -diarylbenzene-1,2-diamine ligand, along with the mild base NaOTMS leads to the formation of a stable yet reactive catalyst that resists deactivation from coordination to heterocycles or charged intermediates. This system enables the use of low catalyst and ligand loadings. Exploiting the differences in nucleophile deprotonation in C–O and C–N coupling reactions catalyzed by Cu·L8 the authors developed a method to chemoselectively N- and O-arylate a variety of amino alcohol substrates. Employing NaOt-Bu as the base resulted exclusively in C–O coupling when the amino alcohols featured primary alcohols and more hindered amines or aniline groups. Utilizing NaOTMS enabled the ability to override the steric-based selectivity of these reactions completely and exclusively promoted C–N coupling regardless of the structure of the amino alcohol.

Vinyltriarylbismuthonium Salts: Powerful Vehicles for α-Vinylation of Carbonyl Compounds

L. Li, L. Hu, J. Sae-Jew & V. H. Rawal*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05709)

α-Vinyl-carbonyl compounds are a class of orthogonally functionalized molecules, wherein the intrinsic C═O and C═C bonds can be used to unlock distinctly different reactivities. In this report, the authors present a simple method for the direct α-vinylation of carbonyl compounds utilizing vinyltriarylbismuthonium (“Vinyl-Bis”) salts, which are stable and readily preparable on a decagram scale. This transformation is accomplished efficiently through the reaction of an in situ generated Li-enolate intermediate with a Vinyl-Bis reagent, leading to the formation of α-vinylated carbonyl compounds in good to excellent yields and with a remarkably broad substrate scope. Critically, this vinylation method is effective for enolates generated via numerous methods, enabling the sequencing of reactions that generate enolates with the vinylation step and the ready synthesis of diversely functionalized compounds, thereby underscoring the versatility and practicality of this method.

General Regio- and Diastereoselective Allylic C–H Oxygenation of Internal Alkenes

K. Yamada, K. P. S. Cheung & V. Gevorgyan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06421)

Branched allylic esters and carboxylates are fundamental motifs prevalent in natural products and drug molecules. The direct allylic C–H oxygenation of internal alkenes represents one of the most straightforward approaches, bypassing the requirement for an allylic leaving group as in the classical Tsuji–Trost reaction. However, current methods suffer from limited scope—often accompanied by selectivity issues—thus hampering further development. Here, the authors report a photocatalytic platform as a general solution to these problems, enabling the coupling of diverse internal alkenes with carboxylic acids, alcohols, and other O-nucleophiles, typically in a highly regio- and diastereoselective manner.

A Unified Synthetic Approach to the Pleurotin Natural Products

Y. Gao, Q. Xia, A. Zhu, W. Mao, Y. Mo, H. Ding* & J. Xuan*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06746)

The asymmetric total syntheses of four pleurotin natural products, namely, (−)-pleurotin, (+)-leucopleurotin, (+)-leucopleurotinic acid, and (+)-dihydropleurotinic acid, are described in a concise manner. Key transformations feature a Johnson–Claisen rearrangement, a diastereo-controlled sequential hydroboration-oxidation, a SOMO/photoredox activated aldehyde α-alkylation, and oxidative cyclizations.

Directed Hydrogen Atom Transfer for Selective Reactions of Polyenols

D. E. Essayan, M. J. Schubach, J. M. Smoot, T. Puri & S. V. Pronin*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06601)

Directed hydrogen atom transfer to alkenes is described. The process is catalyzed by iron complexes and allows for the site-selective hydrofunctionalization of polyenols. Experimental data suggest that coordination of the hydroxy group to the iron hydride intermediate plays an important role in preferential engagement of the allylic alcohol motif and provides a new basis for selectivity in radical hydrofunctionalization events. As a proof of concept, β- and γ-amino alcohols are prepared from the corresponding polyenols in a selective manner.

Asymmetric 2,3-Addition of Sulfinylamines with Arylboronic Acids Enabled by Nickel Catalysis

L. Xi,^† X. Fang,^† M. Wang* & Z. Shi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04050)

Sulfinamides have been widely used in organic synthesis, with research on their preparation spanning more than a century. Despite advancements in catalytic methodologies, creating sulfur stereocenters within these molecules remains a significant challenge. In this study, the authors present an effective and versatile method for synthesizing a diverse range of S-chirogenic sulfinamides through catalytic asymmetric aryl addition to sulfinylamines. By utilizing a nickel complex as a catalyst, this process exhibits impressive enantioselectivity and can incorporate various arylboronic acids at the sulfur position. The resulting synthetic sulfinamides are stable and highly adaptable, allowing for their conversion to a variety of sulfur-containing compounds.

Synthesis of Azabicyclo[3.1.1]heptenes Enabled by Catalyst-Controlled Annulations of Bicyclo[1.1.0]butanes with Vinyl Azides

Z. Lin, H. Ren, X. Lin, X. Yu & J. Zheng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04485)

Bridged bicyclic scaffolds are emerging bioisosteres of planar aromatic rings under the concept of “escape from flatland”. However, adopting this concept into the exploration of bioisosteres of pyridines remains elusive due to the challenge of incorporating an N-atom into such bridged bicyclic structures. Herein, the authors report practical routes for the divergent synthesis of 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes) as potential bioisosteres of pyridines from the readily accessible vinyl azides and bicyclo[1.1.0]butanes (BCBs) via two distinct catalytic annulations. The reactivity of vinyl azides tailored with BCBs is the key to achieving divergent transformations. Ti^III -catalyzed single-electron reductive generation of C-radicals from BCBs allows a concise (3 + 3) annulation with vinyl azides, affording novel 2-aza-BCHepe scaffolds. In contrast, scandium catalysis enables an efficient dipolar (3 + 2) annulation with vinyl azides to generate 2-azidobicyclo[2.1.1]hexanes, which subsequently undergo a chemoselective rearrangement to construct 3-aza-BCHepes. In addition, the related sp² -hybridized nitrogen atom and the similar geometric property between pyridines and corresponding aza-BCHepes indicate that they are promising bioisosteres of pyridines.

Switchable and Chemoselective Arene Hydrogenation for Efficient Late Stage Applications

F. Zhang, H. S. Sasmal, D. Rana & F. Glorius*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05883)

The incorporation of three-dimensional structures into drug molecules has demonstrated significant improvements in clinical success. Late-stage saturation of drug molecules provides a direct pathway for this transformation. However, achieving selective and controllable reduction of aromatic rings remains challenging, particularly when multiple aromatic rings coexist. Herein, the authors present the switchable and chemoselective hydrogenation of benzene and pyridine rings. The utility of the protocol has been comprehensively investigated in diversified substrates with the assistance of a fragment-screening technique. This approach provides convenient access to a diverse array of cyclohexane and piperidine compounds, prevalent in various bioactive molecules and drugs. Furthermore, it discloses promising avenues for applications in the late-stage switchable saturation of drugs, facilitating an increase in the fraction of sp³ -carbons which holds the potential to enhance the medicinal properties of drugs.

Angewandte Chemie International Edition

Streamlining the Synthesis of Pyridones through Oxidative Amination of Cyclopentenones

B. B. Botlik, M. Weber, F. Ruepp, K. Kawanaka, P. Finkelstein & B. Morandi*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408230)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-xrtr3) 🔓

The authors report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of ¹⁵ N-labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way.

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

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

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408750)

Previously: ChemRxiv (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 site-selectivity for polyalkylarenes and use of a double C–H etherification process to controllably oxidize methylarenes to benzaldehydes.

Site-Selective Activation and Stereospecific Functionalization of Bis(boronic esters) Derived from 2-Alkenes: Construction of Propionates and Other 1,2-Difunctional Motifs

N. Xu, J. L. Holmgren III & J. P. Morken*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408436)

Non-directed regioselective activation of diboronic esters, followed by functionalization, is reported. A bulky activator is shown to selectively activate the less hindered boronic ester enabling it to undergo stereospecific cross-coupling to a variety of electrophiles. This steric-based regioselectivity provides a simple and efficient method to prepare highly functionalized, enantiomerically enriched products starting from simple alkenes.

Regio- and Diaseteroselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition

Z. Ding, Z. Wang, Y. Wang, X. Wang, Y. Xue, M. Xu, H. Zhang, L. Xu & P. Li*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202406612)

The authors present a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations.

ChemRxiv

Enantioselective Total Synthesis of Lycoposerramine W through Late-Stage Nitrogen Deletion

K. Yokoi & H. Renata*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-pp1wv) 🔓

A concise total synthesis of lycoposerramine W was accomplished in 10 steps (longest linear sequence) through the union of two fully elaborated piperidine and tetrahydroquinoline fragments, which were prepared by remote biocatalytic C–H oxidation and metal-catalyzed oxidative annulation, respectively. Several C–C bond forming reactions were surveyed for the key fragment coupling, which ultimately identified a nitrogen deletion strategy as the only feasible solution to the problem. This work highlights the benefits of incorporating modern synthetic methodologies in streamlining access to complex molecules.

Electroinduced Reductive and Dearomative Alkene-Aldehyde Coupling

L. J. Franov, T. L. Wilsdon, M. L. Czyz & A. Polyzos*

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

The direct coupling of alkene feedstocks with aldehydes represents an expedient approach to the generation of new and structurally diverse C(sp³ )-hybridized alcohols that are primed for elaboration into privileged architectures. Despite their abundance, current disconnection strategies enabling the direct coupling of carbon-carbon π-bonds and aldehydes remains challenging because contemporary methods are often limited by substrate or functional group tolerance, and compatibility in complex molecular environments. Here, the authors report a coupling between simple alkenes, heteroarenes and unactivated aliphatic aldehydes via an electrochemically induced reductive activation of C–C π-bonds. The cornerstone of this approach is the discovery of a rapid alternating polarity (rAP) electrolysis to access and direct, highly reactive radical anion intermediates derived from conjugated alkenes and heterocyclic compounds. The developed catalyst-free protocol enables direct access to new, and structurally diverse C(sp³ )-hybridized alcohol products. This is achieved by the controlled reduction of conjugated alkenes and the C2–C3 π-bond in heteroarenes via an unprecedented reductive dearomative functionalization for heterocyclic compounds.

Organic Letters

Ni-Catalyzed Reductive 1,2-Alkylarylation of Alkenes for the Synthesis of Spirocyclic γ-Lactams

J. W. Pearson, T. R. Hou, J. Golijanin, P. I. Stewart, E. S. Choi, A. L. Gabbey, M. S. West & S. A. L. Rousseaux*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01981)

An intermolecular nickel-catalyzed reductive 1,2-alkylarylation of acrylates with cyclopropylamine NHP esters and aryl iodides is reported. This operationally simple protocol provides direct access to 1-alkylcyclopropylamine scaffolds. The mild conditions are compatible with four-membered α-amino strained rings as well as five- and six-membered ring systems. The products undergo cyclization to access α-arylated spirocyclic γ-lactams─a motif present in several pharmaceuticals.

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