Strain-Release [2π + 2σ] Cycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated by Energy Transfer

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(18), P. 7988 - 7994

Published: April 27, 2022

Saturated bicycles are becoming ever more important in the design and development of new pharmaceuticals. Here a strategy for synthesis bicyclo[2.1.1]hexanes is described. These significant because they have defined exit vectors, yet many substitution patterns underexplored as building blocks. The process involves sensitization bicyclo[1.1.0]butane followed by cycloaddition with an alkene. scope mechanistic details method discussed.

Language: Английский

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A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(4), P. 535 - 541

Published: Feb. 13, 2023

Language: Английский

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Bicyclobutanes: from curiosities to versatile reagents and covalent warheads

Chemical Science, Journal Year: 2022, Volume and Issue: 13(40), P. 11721 - 11737

Published: Jan. 1, 2022

A flurry of reports for preparing, functionalizing, and using bicyclo[1.1.0]butanes (BCBs) have positioned them to be powerful synthons with numerous applications. This review discusses the recent developments regarding this strained carbocycle.

Language: Английский

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Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Nature, Journal Year: 2022, Volume and Issue: 611(7937), P. 721 - 726

Published: Sept. 15, 2022

Language: Английский

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Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(51), P. 23685 - 23690

Published: Dec. 16, 2022

The development of synthetic strategies for the preparation bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous have been developed synthesis bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not previously explored. Herein, we disclose first photoinduced [3σ + 2σ] cycloaddition trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes cyclopropylamines. This transformation only uses mild operationally simple conditions but also provides unique bioisosteres. applicability this method showcased by derivatization reactions.

Language: Английский

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Strain-Release Photocatalysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(38), P. 20716 - 20732

Published: Sept. 15, 2023

The concept of strain in organic compounds is as old modern chemistry and was initially introduced to justify the synthetic setbacks along synthesis small ring systems (pars construens strain). In last decades, chemists have developed an arsenal strain-release reactions destruens strain) which can generate─with significant driving force─rigid aliphatic that act three-dimensional alternatives (hetero)arenes. Photocatalysis added additional dimension processes by leveraging energy photons create chemical complexity under mild conditions. This perspective presents latest advancements photocatalysis─with emphases on mechanisms, catalytic cycles, current limitations─the unique architectures be produced, possible future directions.

Language: Английский

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Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(44), P. 20207 - 20213

Published: Oct. 27, 2022

Synthesis of bicyclic scaffolds has attracted growing interest because they are high importance in modern pharmaceutical development. Here we report a strategy to access polysubstituted 2-oxabicyclo[2.1.1]hexanes single operation from readily accessible benzoylformate esters and bicyclo[1.1.0]butanes via visible-light-induced triplet energy transfer catalysis. The process is proposed involve formal [2π + 2σ] photocycloaddition/backbone C-H abstraction/aryl group migration sequence. A diverse range (hetero)aryl groups successfully underwent the backbone (C2) position provide previously inaccessible molecules, ester product can serve as handle for downstream manipulation, thus offering opportunities rapidly build up molecular complexity new sp3-rich chemical space.

Language: Английский

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ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(22), P. 12324 - 12332

Published: May 26, 2023

Dearomative photocycloadditions are valuable chemical transformations, serving as an efficient platform to create three-dimensional molecular complexity. However, the photolability of original addition product especially within context ortho cycloadditions often causes undesired consecutive rearrangements, rendering these cycloadducts elusive. Herein, we report ortho-selective intermolecular photocycloaddition bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach. With bicyclo[1.1.0]butanes coupling partners, this dearomative [2π + 2σ] cycloaddition enables straightforward construction C(sp3)-rich bicyclo[2.1.1]hexanes directly connected N-heteroarenes. Photophysical experiments DFT calculations revealed origin selectivity indicate that, in originally proposed energy transfer or direct excitation pathways, chain reaction mechanism is operative depending on conditions.

Language: Английский

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Lewis Acid Catalyzed Formal (3+2)‐Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(34)

Published: May 11, 2023

Design, synthesis and application of benzene bioisosteres have attracted a lot attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes emerged as highly attractive for ortho- meta-substituted benzenes. Herein we report mild, scalable transition-metal-free protocol construction substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance documented by successful preparation various 3-alkyl-3-aryl well 3,3-bisalkyl (26 examples, up to 89 % yield). Postfunctionalization exocyclic ketone moiety is also demonstrated.

Language: Английский

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Pyridine-Boryl Radical-Catalyzed [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Alkenes

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(7), P. 5096 - 5103

Published: March 30, 2023

Bicyclo[2.1.1]hexanes (BCHs) represent an intriguing class of structurally rigid hydrocarbons that can serve as the bioisosteres benzenoids in medicinal chemistry. Methods for synthesis BCHs are, however, limiting. Reported herein is a facile via strain-release-driven [2π + 2σ] cycloaddition bicyclo[1.1.0]butanes (BCBs) with alkenes facilitated by pyridine-boryl radical catalyst. The mild reaction conditions, broad substrate scope, and decent functional group tolerance this protocol render it appealing relevant fields drug design synthesis. Theoretical mechanistic studies reveal relay mechanism involved. Synthetic applications products are performed.

Language: Английский

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