Photochemical Skeletal Editing of Pyridines to Bicyclic Pyrazolines and Pyrazoles

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(31), P. 21389 - 21400

Published: June 14, 2024

We present an efficient one-pot photochemical skeletal editing protocol for the transformation of pyridines into diverse bicyclic pyrazolines and pyrazoles under mild conditions. The method requires no metals, photocatalysts, or additives allows selective removal specific carbon atoms from pyridines, allowing unprecedented versatility. Our approach offers a convenient means late-stage modification complex drug molecules by replacing core pyridine skeleton. Moreover, we have successfully scaled up this procedure in stop-flow flow-chemistry systems, showcasing its applicability to intricate transformations such as Diels–Alder reaction, hydrogenation, [3 + 2] cycloaddition, Heck reaction. Through control experiments DFT calculations, provide insights mechanistic underpinnings protocol.

Language: Английский

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Photochemical dearomative skeletal modifications of heteroaromatics

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(12), P. 6600 - 6624

Published: Jan. 1, 2024

Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance photocatalysis expansion activation mode, last few years have witnessed impressive developments in innovative photochemical methodologies, enabling skeletal modifications dearomatized structures. They offer truly efficient useful tools facile highly complex structures, which are viable natural product synthesis drug discovery. In this review, we aim to provide mechanistically insightful overview on these innovations based degree alteration, categorized into dearomative functionalization editing, highlight their utilities.

Language: Английский

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Synthesis of benzenes from pyridines via N to C switch

Chem, Journal Year: 2024, Volume and Issue: 10(6), P. 1940 - 1949

Published: June 1, 2024

The skeletal editing of heteroarenes introduces new disconnections to the chemistry lexicon, enabling interconversion ring systems via selective breaking/re-making carbon framework. We describe one-pot transformation pyridines into benzene derivatives, using a nucleophilic addition ring-opening/ring-closing (ANRORC) process with soft nucleophiles such as malonate. Triflic anhydride activates pyridine ANRORC synthesis an isolable amine intermediate, which aromatizes on simple heating. reaction has been exemplified room temperature protocol, along direct syntheses drug-like, tertiary-alkylated, and isotopically labeled benzoates.

Language: Английский

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Synthesis of Collidine from Dinitrogen via a Tungsten Nitride

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(12), P. 7979 - 7984

Published: March 15, 2024

The synthesis of pyridines from dinitrogen in homogeneous solution is known to be challenging considering that an N2 cleavage step needs combined with two N–C coupling steps. Herein, a tungsten complex bearing tailor-made 2,2′-(tBu2As)2-substituted tolane ligand scaffold was shown split afford the corresponding nitride, which not case for (iPr2As)2-substituted derivative. former nitride then reacted 2,4,6-trimethylpyrylium triflate, led formation oxo complex, along collidine. Over course this reaction, O atom pyrylium starting material replaced N via hitherto unprecedented skeletal editing process.

Language: Английский

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Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes

Nature Catalysis, Journal Year: 2024, Volume and Issue: 7(11), P. 1232 - 1242

Published: Oct. 22, 2024

Abstract Replacing planar aromatic rings in drug molecules with C( sp 3 )-rich isosteric mimetics, such as bicyclo[ n .1.1]alkanes, can significantly alter their physicochemical and pharmacokinetic properties, often leading to higher clinical success rates. However, unlike a benzene ring, the structurally rigid mimetics of heteroaromatic are rare. Heterobicyclo[ .1.1]alkanes promising this regard, but lack modular synthetic methods has currently hindered exploration. We envisioned that strategic selective insertion different heteroatomic units bicyclo[1.1.0]butanes could offer highly platform access diverse heterobicyclo[ .1.1]alkanes. Herein we report photoredox-catalysed regioselective chemoselective amidyl radicals bicyclo[1.1.0]butanes, providing direct 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. The exit vector analysis shows geometric resemblance these heterobicyclic motifs pyridine pyrimidine derivatives, suggesting potential medicinally important heterocycles. Additionally, various downstream transformations demonstrate utility versatile building blocks chemistry.

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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Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 19, 2024

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than century research, Ciamician-Dennstedt (C-D) rearrangement limited to halocarbene precursors. Herein, we report general methodology reaction using α-halogen-free carbenes generated situ from N-triftosylhydrazones. This one-pot, two-step protocol enables various carbenes, including those previously unexplored C-D chemistry, indoles/pyrroles scaffolds access 3-functionalized quinolines/pyridines. Mechanistic studies reveal pathway involving intermediacy 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative form different carbon-atom products. Ciamician–Dennstedt authors

Language: Английский

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Synthesis of naphthalene derivatives via nitrogen-to-carbon transmutation of isoquinolines

Science Advances, Journal Year: 2025, Volume and Issue: 11(5)

Published: Jan. 29, 2025

Heteroarene skeletal editing is gaining popularity in synthetic chemistry. Transmuting single atoms generates molecules that have distinctly varied properties, thereby fostering potent molecular exchanges can be extensively used to synthesize functional molecules. Herein, we present a convenient protocol for nitrogen-carbon single-atom transmutations isoquinolines, which inspired by the Wittig reaction and enables easy access substituted naphthalene derivatives. The uses an inexpensive commercially available phosphonium ylide as carbon source furnish wide range of naphthalenes. key success this transformation formation triene intermediate through ring opening, undergoes 6π-electrocyclization elimination processes afford product. Furthermore, strategy facile synthesis 13 C-labeled naphthalenes using CH 3 PPh I commercial C facilitates modifying directing group C─H functionalization.

Language: Английский

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Transition Metal-Catalyzed Nitrogen Atom Insertion into Carbocycles

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

ConspectusN-Heterocycles are essential in pharmaceutical engineering, materials science, and synthetic chemistry. Recently, skeletal editing, which involves making specific point changes to the core of a molecule through single-atom insertion, deletion, or transmutation, has gained attention for its potential modify complex substrates. In this context, insertion nitrogen atoms into carbocycles form N-heterocycles emerged as significant research focus modern chemistry owing novel logic. This distinctive retrosynthetic approach enables late-stage modification molecular skeletons provides different pathway synthesizing multiply substituted N-heterocycles. Nevertheless, atom proven challenging because inherent inertness carbon-based difficulty cleaving C-C bonds. Therefore, selective editing remains growing field Account primarily highlights contributions our laboratory active acknowledges key from other researchers. It is organized two sections based on type carbocycle. The first section explores cycloalkenes. Recent Co-catalyzed oxidative azidation strategies have enabled cyclobutenes, cyclopentenes, cyclohexenes, facilitating synthesis polysubstituted pyridines, been conventionally pyridine cross-coupling. subsequent discovery realm arenes. site-selective stable arenes We developed method intramolecular benzene rings 2-amino biaryls by suppressing competing C-H process using paddlewheel dirhodium catalyst. addition, address issues we employed arenols substrates, could act controlling elements editing. reported Cu-catalyzed arenols, proceeds dearomative azidation/aryl migration process, enabling incorporation Inspired result, recently extended reaction model Fe-catalyst facilitate ring contraction nitrogen-inserted product, achieving carbon-to-nitrogen transmutation arenols. Various polyaromatic effectively undergo desired atom's presenting considerable various applications Account, present an overview achievements reactions, with scopes, mechanistic features, applications. anticipate that will provide valuable insights propel development innovative methodologies both N-heterocycle synthesis.

Language: Английский

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Cascade ring expansion reactions for the synthesis of medium-sized rings and macrocycles

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(38), P. 4999 - 5009

Published: Jan. 1, 2024

This Feature Article discusses recent advances in the development of cascade ring expansion reactions for synthesis medium-sized rings and macrocycles. Cascade have much potential use biologically important macrocycles, most notably as they don't require high dilution conditions, which are commonly used established end-to-end macrocyclisation methods. Operation by method can allow large products to be accessed

Language: Английский

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