Late-stage diversification of indole skeletons through nitrogen atom insertion

Science, Journal Year: 2022, Volume and Issue: 377(6610), P. 1104 - 1109

Published: Sept. 1, 2022

Compared with peripheral late-stage transformations mainly focusing on carbon-hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds still remain scarce despite recent flurry activity in this area. Herein, we report skeletal editing indoles through nitrogen atom insertion, accessing corresponding quinazoline or quinoxaline bioisosteres by trapping an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies strategic use a silyl group as labile protecting that can facilitate subsequent product release. The utility highly functional group-compatible methodology context several commercial drugs is demonstrated.

Language: Английский

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Photocatalytic phosphine-mediated water activation for radical hydrogenation

Nature, Journal Year: 2023, Volume and Issue: 619(7970), P. 506 - 513

Published: June 28, 2023

Abstract The chemical activation of water would allow this earth-abundant resource to be transferred into value-added compounds, and is a topic keen interest in energy research 1,2 . Here, we demonstrate with photocatalytic phosphine-mediated radical process under mild conditions. This reaction generates metal-free PR 3 –H 2 O cation intermediate, which both hydrogen atoms are used the subsequent transformation through sequential heterolytic (H + ) homolytic • cleavage two O–H bonds. –OH intermediate provides an ideal platform that mimics reactivity ‘free’ atom, can directly closed-shell π systems, such as activated alkenes, unactivated naphthalenes quinoline derivatives. resulting H adduct C radicals eventually reduced by thiol co-catalyst, leading overall transfer hydrogenation system, ending up product. thermodynamic driving force strong P=O bond formed phosphine oxide by-product. Experimental mechanistic studies density functional theory calculations support atom key step process.

Language: Английский

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Conversion of Aryl Azides to Aminopyridines

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(39), P. 17797 - 17802

Published: Sept. 22, 2022

A longstanding challenge in fundamental functional group interconversion has been the direct transformation of benzene into pyridine via nitrogen insertion and carbon deletion. Herein, we report a protocol for aryl azides, easily accessible from their corresponding anilines, to 2-aminopyridines using blue light oxygen. Mechanistic studies corroborate that arene conversion is achieved by ring followed oxidative extrusion.

Language: Английский

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Skeletal Editing: Interconversion of Arenes and Heteroarenes

Helvetica Chimica Acta, Journal Year: 2023, Volume and Issue: 106(3)

Published: Jan. 13, 2023

Abstract Skeletal editing involves making specific point‐changes to the core of a molecule through selective insertion, deletion or exchange atoms. It thus represents potentially powerful strategy for step‐economic modification complex substrates and is perfect complement methods such as C−H functionalization that target molecular periphery. Given their ubiquity in biologically active compounds, ability perform skeletal on – therefore interconvert between aromatic heterocycles especially valuable. This review summarizes both recent key historical examples applied interconversion rings; we anticipate it will serve highlight not only innovative enabling nature current methods, but also tremendous opportunities still exist field.

Language: Английский

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Unified Access to Pyrimidines and Quinazolines Enabled by N–N Cleaving Carbon Atom Insertion

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(42), P. 19258 - 19264

Published: Oct. 14, 2022

Given the ubiquity of heterocycles in biologically active molecules, transformations with capacity to modify such molecular skeletons modularity remain highly desirable. Ring expansions that enable interconversion privileged heterocyclic motifs are especially interesting this regard. As such, known mechanisms for ring expansion and contraction determine classes heterocycle amenable skeletal editing. Herein, we report a reaction selectively cleaves N–N bond pyrazole indazole cores afford pyrimidines quinazolines, respectively. This chlorodiazirine-mediated provides unified route related pair otherwise typically prepared by divergent approaches. Mechanistic experiments DFT calculations support pathway involving pyrazolium ylide fragmentation followed cyclization ring-opened diazahexatriene intermediate yield new diazine core. Beyond enabling access valuable heteroarenes from easily starting materials, demonstrate synthetic utility editing synthesis Rosuvastatin analog as well an aryl vector-adjusting direct scaffold hop.

Language: Английский

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Skeletal Editing of Pyrimidines to Pyrazoles by Formal Carbon Deletion

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(48), P. 22309 - 22315

Published: Nov. 28, 2022

A method for the conversion of pyrimidines into pyrazoles by a formal carbon deletion has been achieved guided computational analysis. The pyrimidine heterocycle is most common diazine in FDA-approved drugs, and are diazole. An efficient to convert would therefore be valuable leveraging chemistries unique access diversified pyrazoles. One known, though it proceeds low yields requires harsh conditions. transformation reported here under milder conditions, tolerates wide range functional groups, enables simultaneous regioselective introduction N-substitution on resulting pyrazole. Key success this one-carbon room-temperature triflylation core, followed hydrazine-mediated skeletal remodeling.

Language: Английский

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Photoinduced Oxygen Transfer Using Nitroarenes for the Anaerobic Cleavage of Alkenes

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(34), P. 15437 - 15442

Published: Aug. 5, 2022

Herein we report the anaerobic cleavage of alkenes into carbonyl compounds using nitroarenes as oxygen transfer reagents under visible light. This approach serves a safe and practical alternative to mainstream oxidative protocols, such ozonolysis Lemieux–Johnson reaction. A wide range possessing oxidatively sensitive functionalities underwent generate derivatives with high efficiency regioselectivity. Mechanistic studies support that transformation occurs via direct photoexcitation nitroarene followed by nonstereospecific radical cycloaddition event alkenes. leads 1,3,2- 1,4,2-dioxazolidine intermediates fragment give products. combination clock experiments in situ photoNMR spectroscopy revealed identities key species putative aryl dioxazolidine intermediates, respectively.

Language: Английский

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Aromatic nitrogen scanning by ipso -selective nitrene internalization

Science, Journal Year: 2023, Volume and Issue: 381(6665), P. 1474 - 1479

Published: Sept. 28, 2023

Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis each pyridyl isomer because lack direct carbon-to-nitrogen (C-to-N) replacement reactions. We report site-directable C-to-N reaction allowing unified access to various pyridine isomers through nitrene-internalization process. In two-step, one-pot procedure, azides are first photochemically converted 3

Language: Английский

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Carbon-to-nitrogen single-atom transmutation of azaarenes

Nature, Journal Year: 2023, Volume and Issue: 623(7985), P. 77 - 82

Published: Nov. 1, 2023

Language: Английский

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Cobalt-Catalyzed Nitrogen Atom Insertion in Arylcycloalkenes

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(49), P. 22433 - 22439

Published: Nov. 30, 2022

Developing strategies enabling the modification of underlying molecular frameworks facilitates access to underexplored chemical spaces. Skeletal editing is an emerging technology for late-stage diversification bioactive molecules. However, current state this knowledge remains undeveloped. This work describes a simple protocol that "inserts" nitrogen atom into arylcycloalkenes form corresponding N-heterocycles. The use inexpensive cobalt catalyst under aqueous and open-air conditions makes very practical. Examples compounds pharmaceutical interest complex fused ring further demonstrated potentially broad applicability methodology.

Language: Английский

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