Polysubstituted bicyclo-[2.1.1]-hexanes as benzene isosteres for medicinal chemistry

This comprehensive review describes the methodologies reported between 2020 and early 2025 for the synthesis of (hetero)bicyclo[2.1.1]hexane derivatives, organised by mechanisms and the exit vectors achieved.

• Publication year

  2026

• Venue

  Organic Chemistry Frontiers

• Publication date

  Unknown publication date

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  Not labeled

• Identifiers
  DOI 10.1039/d5qo01662b
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  Open on Semantic Scholar

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  Semantic Scholar

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• No concepts are published for this paper.

• Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted benzene bioisosteres with improved biological activity

  2025cited by this paper
• Chemo‐, Diastereo‐, and Enantioselective (3+2) Cycloadditons of Bicyclobutanes with Enals Enabled by Synergistic Palladium and Organocatalysis

  2025cited by this paper
• Controllable divergent transformations of bicyclo[1.1.0]butanes

  2025cited by this paper
• Silver-catalyzed formal [2π+2σ] cycloaddition of bicyclobutanes with naphthols as surrogates for arynes

  2025cited by this paper
• Organocatalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

  2025cited by this paper
• Lewis Acid-Catalyzed Enantioselective (4 + 3)/Thia-(3 + 2) Cycloadditions of Bicyclobutanes and Enaminothiones: Catalyst-Directed Divergent Synthesis of Bridged Sulfur Heterocycles

  2025cited by this paper
• Catalyst-Controlled Regiodivergent Synthesis of Bicyclo[2.1.1]hexanes via Photochemical Strain-Release Cycloadditions.

  2025cited by this paper
• Lewis Acid Catalyzed Divergent Reaction of Bicyclo[1.1.0]butanes with Quinones for the Synthesis of Diverse Polycyclic Molecules.

  2025cited by this paper
• Catalytic Asymmetric Strategies for Bicyclo[1.1.0]butane Transformations: Advances and Applications

  2025cited by this paper
• Catalytic Asymmetric Synthesis of Chiral Caged Hydrocarbons as Arenes Bioisosteres.

  2025cited by this paper
• Substrate-Regulated Divergent Addition of N-Sulfonyl Ketimines to Bicyclo[1.1.0]butanes Enabled by Photoinduced Energy Transfer.

  2025cited by this paper
• Chiral Lewis Acid-Catalyzed Intramolecular [2 + 2] Photocycloaddition: Enantioselective Synthesis of Azaarene-Functionalized Azabicyclo[2.1.1]hexanes and Bicyclo[1.1.1]pentanes.

  2025cited by this paper
• Conditions-Controlled Divergent Annulation of Bicyclo[1.1.0]butanes and Dioxopyrrolidines through Lewis Acid Catalysis

  2025cited by this paper
• Enantioselective Dearomative [2π + 2σ] Photocycloaddition of Naphthalene Derivatives with Bicyclo[1.1.0]butanes Enabled by Gd(III) Catalysis.

  2025cited by this paper
• Late-Stage N-Atom Deletion of Multisubstituted 2-Azabicyclo[2.1.1]Hexanes

  2025cited by this paper
• Direct Access to Functional 2-Azabicyclo[2.1.1]hexanes via Hydrodearomative [2π + 2σ] Cycloaddition of Aza-arenes.

  2025cited by this paper
• Palladium-catalyzed enantioselective [2σ + 2π] cycloadditions of vinyl-carbonyl-bicyclo[1.1.0]butanes with arylidenemalononitriles

  2025cited by this paper
• Sc(OTf)3‐Catalyzed Ring‐Opening Reactions of Donor‐Acceptor Cyclopropanes/Bicyclo[1.1.0]butanes: Access to 3‐Substituted Chromenones, Cyclopenta[b]chromenones and 2‐Aminobicyclo[2.1.1]hexanes

  2025cited by this paper
• Lewis Acid-Catalyzed Asymmetric [2σ + 2π] Cycloaddition Reactions of Bicyclo[1.1.0]butanes and Vinyl Azido/Diazo Compounds

  2025cited by this paper
• σ-Bond insertion reactions of two strained diradicaloids

  2025cited by this paper
• Enantioselective synthesis of 2-substituted bicyclo[1.1.1]pentanes via sequential asymmetric imine addition of bicyclo[1.1.0]butanes and skeletal editing

  2025cited by this paper
• Zinc-Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

  2024cited by this paper
• Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes.

  2024cited by this paper
• 2-Oxabicyclo[2.1.1]hexanes: Synthesis, Properties, and Validation as Bioisosteres of ortho- and meta-Benzenes.

  2024cited by this paper
• Enantioselective [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis.

  2024cited by this paper
• Synthesis of Borylated Carbocycles by [2 + 2]-Cycloadditions and Photo-Ene Reactions.

  2024cited by this paper
• Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

  2024cited by this paper
• Titanium catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres

  2024cited by this paper
• Lewis Acid Catalyzed Cycloaddition of Bicyclobutanes with Ynamides for the Synthesis of Polysubstituted 2-Amino-bicyclo[2.1.1]hexenes.

  2024cited by this paper
• Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions

  2024cited by this paper
• C(sp3)–C(sp3) bond formation through nitrogen deletion of secondary amines using O-diphenylphosphinylhydroxylamine

  2024cited by this paper
• Lewis Acid-Catalyzed Formal [2π+2σ] Cycloaddition of Bicyclobutanes with Quinoxalin-2(1H)-ones: Access to Quinoxaline-Fused Aza-Bicyclo[2.1.1]hexanes.

  2024cited by this paper
• Synthesis of Azabicyclo[3.1.1]heptenes Enabled by Catalyst-Controlled Annulations of Bicyclo[1.1.0]butanes with Vinyl Azides.

  2024cited by this paper
• Intramolecular [2+2] Cycloadditions of α‐Heteroatom Substituted γ,δ‐Unsaturated Ketenes

  2024cited by this paper
• Three-dimensional saturated C(sp3)-rich bioisosteres for benzene

  2024cited by this paper
• [2 + 2] Photocycloadditions to Form Cyclobutanes and Bicyclo[2.1.1]hexanes Employing Copper-Based Photocatalysis

  2024cited by this paper
• Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes

  2024cited by this paper
• Intermolecular Formal [2π + 2σ] Cycloaddition of Enol Silyl Ethers with Bicyclo[1.1.0]butanes Promoted by Lewis Acids.

  2024cited by this paper
• Synthesis of 1-azabicyclo[2.1.1]hexanes via formal single electron reduction of azabicyclo[1.1.0]butanes under photochemical conditions.

  2024cited by this paper
• Synthesis of 2‐Substituted Bicyclo[2.1.1]hexan‐1‐ols via SmI2‐Mediated Reductive Cyclization Reactions

  2024cited by this paper
• A general synthesis of gem-difluorobicyclo[2.1.1]hexanes

  2024cited by this paper
• Recent Progress in (3+3) Cycloadditions of Bicyclobutanes to Access Bicyclo[3.1.1]heptane Derivatives

  2024cited by this paper
• Photocatalytic Oxidative Activation of Bicyclo[1.1.0]butanes for Formal [2σ+2π] Cycloadditions

  2024cited by this paper
• Modular Synthesis of Azidobicyclo[2.1.1]hexanes via (3 + 2) Annulation of α-Substituted Vinyl Azides and Bicyclo[1.1.0]butanes.

  2024cited by this paper
• Palladium-catalysed [2σ + 2π] cycloaddition reactions of bicyclo[1.1.0]butanes with aldehydes

  2024cited by this paper
• Divergent Enantioselective Access to Diverse Chiral Compounds from Bicyclo[1.1.0]butanes and α,β-Unsaturated Ketones under Catalyst Control.

  2024cited by this paper
• Bicyclo[2.1.1]hexanes via Intramolecular Formal (3+2)-Cycloaddition.

  2024cited by this paper
• Catalyst-free, visible-light-induced [2π + 2σ] cycloaddition towards azabicyclohexanes

  2024cited by this paper
• Access to 2-Oxabicyclo[2.1.1]hexanes and their use in Scaffold Hopping.

  2024cited by this paper
• Synthesis of 1-Substituted Bicyclo[2.1.1]hexan-2-ones via a Sequential SmI2-Mediated Pinacol Coupling and Acid-Catalyzed Pinacol Rearrangement Reaction

  2024cited by this paper
• Enantioselective [2π + 2σ] Photocycloaddition Enabled by Brønsted Acid Catalyzed Chromophore Activation.

  2024cited by this paper
• gem-Difluorobicyclo[2.1.1]hexanes via Photochemical [2π + 2σ] Cycloaddition Initiated by Oxidative Activation of gem-Difluorodienes.

  2024cited by this paper
• Catalytic Intermolecular Asymmetric [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes.

  2024cited by this paper
• Structure-Dependent, Switchable Alder-Ene/[2π + 2σ] Cycloadditions of Vinyl Bicyclo[1.1.0]butanes with α-Ketoesters Enabled by Palladium Catalysis.

  2024cited by this paper
• Zwitterionic π-Allyl-Pd Species Enabled [2σ+2π] Cycloaddition Reactions of Vinylbicyclo[1.1.0]butanes (VBCBs) with Alkenes, Carbonyls, and Imines

  2024cited by this paper
• Diverse Synthesis of Arene-Fused [n.1.1]-Bridged Molecules via Catalytic Cycloaddition and Rearrangement Reactions.

  2024cited by this paper
• Palladium-Catalyzed Strain-Enabled [2π + 2σ] Cycloadditions of Vinyl Bicyclo[1.1.0]butanes with Methyleneindolinones.

  2024cited by this paper
• Mechanistic Insight into Lewis Acid-Catalyzed Cycloaddition of Bicyclo[1.1.0]butanes with Ketene: Bicyclo[1.1.0]butanes Serving as an Electrophile.

  2024cited by this paper
• Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols.

  2024cited by this paper
• Double Strain-Release [2π+2σ]-Photocycloaddition.

  2024cited by this paper
• Ti-Catalyzed Formal [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with 2-Azadienes to Access Aminobicyclo[2.1.1]hexanes.

  2024cited by this paper
• Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

  2023cited by this paper
• A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres

  2023cited by this paper
• Lewis Acid Catalyzed Formal (3+2)-Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes.

  2023cited by this paper
• Pyridine-Boryl Radical-Catalyzed [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Alkenes

  2023cited by this paper
• ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes.

  2023cited by this paper
• 2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring

  2023cited by this paper
• Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2-Oxabicyclo[2.1.1]hexanes.

  2023cited by this paper
• Synthesis of Bicyclo[2.1.1]hexan‐5‐ones via a Sequential Simmons–Smith Cyclopropanation and an Acid‐Catalyzed Pinacol Rearrangement of α‐Hydroxy Silyl Enol Ethers

  2023cited by this paper
• Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis.

  2023cited by this paper
• Strain-Release Photocatalysis.

  2023cited by this paper
• Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes.

  2023cited by this paper
• Enantioselective, Intermolecular [π2+σ2] Photocycloaddition Reactions of 2(1H)-Quinolones and Bicyclo[1.1.0]butanes.

  2023cited by this paper
• Hantzsch Esters Enabled [2π+2σ] Cycloadditions of Bicyclo [1.1.0] butanes and Alkenes under Photo Conditions.

  2023cited by this paper
• Stereospecific Transformations of Alkylboronic Esters Enabled by Direct Boron-to-Zinc Transmetalation.

  2023cited by this paper
• Diboron(4)-Catalyzed Remote [3+2] Cycloaddition of Cyclopropanes via Dearomative/Rearomative Radical Transmission through Pyridine.

  2022cited by this paper
• Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer.

  2022cited by this paper
• Strain-Release [2π + 2σ] Cycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated by Energy Transfer.

  2022cited by this paper
• Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes.

  2022cited by this paper
• Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer

  2022cited by this paper
• Bicyclo[2.1.1]hexanes by Visible Light-Driven Intramolecular Crossed [2 + 2] Photocycloadditions.

  2022cited by this paper
• Skeletal editing through direct nitrogen deletion of secondary amines

  2021cited by this paper
• Strain‐Release‐Driven Friedel–Crafts Spirocyclization of Azabicyclo[1.1.0]butanes

  2021cited by this paper
• Visible Light-Mediated Photochemical Reactions of 2-(2′-Alkenyloxy)cycloalk-2-enones

  2020cited by this paper
• Saturated mimetics for ortho-substituted benzenes.

  2020cited by this paper
• Water-soluble non-classical benzene mimics.

  2020cited by this paper
• Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients.

  2019cited by this paper
• Nonconjugated Hydrocarbons as Rigid-Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry.

  2019cited by this paper
• A Survey of the Structures of US FDA Approved Combination Drugs.

  2018cited by this paper
• Improving Nonspecific Binding and Solubility: Bicycloalkyl Groups and Cubanes as para‐Phenyl Bioisosteres

  2017cited by this paper
• Ring-strain-enabled reaction discovery: new heterocycles from bicyclo[1.1.0]butanes.

  2015cited by this paper
• Rings in drugs.

  2014cited by this paper
• Escape from flatland: increasing saturation as an approach to improving clinical success.

  2009cited by this paper
• The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design?

  2009cited by this paper
• Enantioselective Friedel-Crafts alkylations of alpha,beta-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes.

  2005cited by this paper
• Bicyclo[1.1.1]pentanes, [n]Staffanes, [1.1.1]Propellanes, and Tricyclo[2.1.0.0(2,5)]pentanes.

  2000cited by this paper

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