Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

Communications Chemistry, Journal Year: 2023, Volume and Issue: 6(1)

Published: Jan. 12, 2023

Abstract Bicyclobutanes are among the most highly strained isolable organic compounds and their associated low activation barriers to reactivity make them intriguing building-blocks in chemistry. In recent years, numerous creative synthetic strategies exploiting heightened have been presented these discoveries often gone hand-in-hand with development of more practical routes for synthesis. Their proclivity as strain-release reagents through weak central C–C bond has harnessed a variety addition, rearrangement insertion reactions, providing rapid access rich tapestry complex molecular scaffolds. This review will provide an overview different options available bicyclobutane synthesis, main classes that can be prepared from bicyclobutanes, modes used.

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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Energy transfer photocatalysis: exciting modes of reactivity

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(3), P. 1068 - 1089

Published: Jan. 1, 2024

Leveraging light energy to expose the ‘dark’ reactive states describes whole essence of triplet–triplet transfer. This offers an impressive opportunity conduct a multitude diverse reactions and access sought-after molecular motifs.

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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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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Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2‐Oxabicyclo[2.1.1]hexanes

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

Published: June 12, 2023

Synthesis of bicyclic scaffolds has attracted tremendous attention because they are playing an important role as saturated bioisosteres benzenoids in modern drug discovery. Here, we report a BF3 -catalyzed [2π+2σ] cycloaddition aldehydes with bicyclo[1.1.0]butanes (BCBs) to access polysubstituted 2-oxabicyclo[2.1.1]hexanes. A new kind BCB containing acyl pyrazole group was invented, which not only significantly facilitates the reactions, but can also serve handle for diverse downstream transformations. Furthermore, aryl and vinyl epoxides be utilized substrates undergo BCBs after situ rearrangement aldehydes. We anticipate that our results will promote challenging sp3 -rich frameworks exploration BCB-based chemistry.

Language: Английский

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Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(46), P. 25411 - 25421

Published: Nov. 7, 2023

We report the use of photocatalysis for homolytic ring-opening carbonyl cyclopropanes. In contrast to previous studies, our approach does not require a metal cocatalyst or strong reductant. The cyclopropanes can be employed both [2σ + 2σ] and 2π] annulation with either alkenes/alkynes bicyclo[1.1.0]butanes, yielding cyclopent-anes/-enes bicyclo[3.1.1]heptanes (BCHs), respectively. BCHs are promising bioisosteres 1,2,4,5 tetra-substituted aromatic rings. Mechanistic including density functional theory computation trapping experiment DMPO, support 1,3-biradical generated from cyclopropane as key intermediate these transformations.

Language: Английский

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Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(48)

Published: Oct. 12, 2023

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles bicyclobutane precursors is described. The strain-release operates under mild conditions, tolerating wide range functional groups. It capable forming with up four contiguous quaternary carbon centers, achieving yields 99 %. In addition, scale-up experiment synthetic transformations cycloadducts further highlighted utility.

Language: Английский

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