Sulfenylnitrene-mediated nitrogen-atom insertion for late-stage skeletal editing of N -heterocycles

Science, Journal Year: 2025, Volume and Issue: 387(6729), P. 102 - 107

Published: Jan. 2, 2025

Given the prevalence of nitrogen-containing heterocycles in commercial drugs, selectively incorporating a single nitrogen atom is promising scaffold hopping approach to enhance chemical diversity drug discovery libraries. We harness distinct reactivity sulfenylnitrenes, which insert transform readily available pyrroles, indoles, and imidazoles into synthetically challenging pyrimidines, quinazolines, triazines, respectively. Our additive-free method for skeletal editing employs easily accessible, benchtop-stable sulfenylnitrene precursors over broad temperature range (−30 150°C). This compatible with diverse functional groups, including oxidation-sensitive functionalities such as phenols thioethers, has been applied various natural products, amino acids, pharmaceuticals. Furthermore, we have conducted mechanistic studies explored regioselectivity outcomes through density theory calculations.

Language: Английский

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Photocatalytic furan-to-pyrrole conversion

Science, Journal Year: 2024, Volume and Issue: 386(6717), P. 99 - 105

Published: Oct. 3, 2024

The identity of a heteroatom within an aromatic ring influences the chemical properties that heterocyclic compound. Systematically evaluating effect single atom, however, poses synthetic challenges, primarily as result thermodynamic mismatches in atomic exchange processes. We present photocatalytic strategy swaps oxygen atom furan with nitrogen group, directly converting into pyrrole analog intermolecular reaction. High compatibility was observed various derivatives and nucleophiles commonly used drug discovery, late-stage functionalization furnished otherwise difficult-to-access pyrroles from naturally occurring furans high molecular complexity. Mechanistic analysis suggested polarity inversion through electron transfer initiates redox-neutral processes at room temperature.

Language: Английский

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Controllable Skeletal and Peripheral Editing of Pyrroles with Vinylcarbenes

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(24)

Published: April 10, 2024

Abstract The skeletal editing of azaarenes through insertion, deletion, or swapping single atoms has recently gained considerable momentum in chemical synthesis. Here, we describe a practical strategy using vinylcarbenes situ generated from trifluoromethyl vinyl N ‐triftosylhydrazones, leading to the first dearomative pyrroles carbon‐atom insertion. Furthermore, depending on used catalyst and substrate, three types peripheral reactions are also disclosed: α‐ γ‐selective C−H [3+2] cycloaddition. These controllable molecular provide powerful platform for accessing medicinally relevant CF 3 ‐containing ‐heterocyclic frameworks, such as 2,5‐dihydropyridines, piperidines, azabicyclo[3.3.0]octadienes, allylated readily available pyrroles. Mechanistic insights experiments density functional theory (DFT) calculations shed light origin substrate‐ catalyst‐controlled chemo‐ regioselectivity well reaction mechanism.

Language: Английский

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Precision single-atom editing: new frontiers in nitrogen insertion and substitution for the generation of N-heterocycles

Organic Chemistry Frontiers, Journal Year: 2024, Volume and Issue: 11(14), P. 4041 - 4053

Published: Jan. 1, 2024

This paper primarily focuses on the editing of nitrogen atoms, encompassing insertion N, substitution C with and utilization 15 N in place 14 for construction N-heterocycles.

Language: Английский

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Skeletal Editing of Cyclic Molecules Using Nitrenes

Chinese Journal of Chemistry, Journal Year: 2024, Volume and Issue: 42(21), P. 2656 - 2667

Published: July 16, 2024

Comprehensive Summary Nitrenes, as neutral monovalent nitrogen‐centered molecular species, can insert into various bond or remove nitrogen atoms from amines. Nitrene assisted single‐atom skeletal editing, discovered decades ago, provides an efficient approach for the precise alteration of cyclic skeletons. In this review, we briefly summarize early studies on editing frameworks involving nitrene and introduce several recent important advances systematically.

Language: Английский

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Skeletal Editing by Hypervalent Iodine Mediated Nitrogen Insertion

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

Hypervalent iodine reagents are versatile and readily accessible that have been extensively applied in contemporary synthesis modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for single-nitrogen-atom insertion reaction, skeletal editing to construct N-heterocycles. Skeletal with components has recently emerged as an exciting approach chemical transformation. These produce biologically relevant heterocycles functionalized molecular architectures. Recently, the of nitrogen-atom into hydrocarbons generate N-heterocyclic compounds using hypervalent significant focus field reactions. In this review, we discuss rapidly emerging nitrene insertion, including nitrogen access nitrogen-containing heterocycles, current mechanistic understanding these processes.

Language: Английский

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Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(41)

Published: July 3, 2024

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) proved robust on scale, while tolerating variety valuable functional groups.

Language: Английский

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Skeletal Editing Through Single Atom Insertion and Transmutation: An Insight into A New Era of Synthetic Organic Chemistry

Synthesis, Journal Year: 2024, Volume and Issue: 56(24), P. 3793 - 3814

Published: Aug. 20, 2024

Abstract Considering the importance of heterocycles, significantly represented in medicinal chemistry and drug development, single-atom insertion technique transmutation strategy provide productive approaches towards complicated molecular structures through heterocycle diversification. It shows a potentially powerful approach for modifying complex substrates concisely chemospecifically. Although skeletal editing applies to cyclic acyclic compounds, this review focuses on diversification carbo- heterocyclic compounds synthesizing various medicinally important molecules via technique. The classification system is based recent critical historical methods as applied aromatic rings. 1 Introduction 2 Skeletal Editing Carbon-Atom Insertion 2.1 Indoles Pyrroles Derivatives: into C=C Bond 2.2 Pyrazole Indazole an N–N 2.3 CF3 Group Heteroarenes 2.4 Imidazole C–N 2.5 Atom-to-Atom Transmutation 3 N-Atom 3.1 Nitrogen-Atom Carbocycles 3.2 Heterocycles 3.3 Carbon Nitrogen Molecular Isotopic 4 Conclusion

Language: Английский

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C-to-N atom swapping and skeletal editing in indoles and benzofurans

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: May 21, 2025

Abstract Skeletal editing comprises the structural reorganization of compounds. Such can be achieved through atom swapping, insertion, deletion or compound’s backbone structure 1,2 . Conducted at a late stage in drug development campaigns, skeletal enables diversification an existing pharmacophore, enhancing efficiency development. Instead constructing heteroarene classically from basic building blocks, variants are readily accessible directly starting lead compound approved pharmacophore. Here we present C to N swapping indoles C2 position give indazoles oxidative cleavage indole core and subsequent ring closure. Reactions proceed ring-opened oximes as intermediates. These deconstructed intermediates also diverted into benzimidazoles resulting overall with concomitant reorganization. The same diverting strategies equally well applicable benzofurans leading either benzisoxazoles benzoxazoles. classes obtained these methods—indazoles 3,4 , 5 6,7 benzoxazoles 8 —are biologically relevant moieties found substructures natural products pharmaceuticals. procedures introduced substantially enlarge methods portfolio emerging field editing.

Language: Английский

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Streamlining the Synthesis of Pyridones through Oxidative Amination of Cyclopentenones

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(38)

Published: June 27, 2024

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

Language: Английский

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