Open research questions in Catalytic C–H Functionalization Methods
89 unresolved questions extracted from the limitations and future-work sections of 768 Catalytic C–H Functionalization Methods papers in our library. Each links back to the study that raised it.
What the literature leaves open
To date, numerous synthetic methods have been successfully developed however, most of them are limited to a narrow subset of cyclic amines, with variations in ring size often requiring different substrates and distinct synthetic strategies.
Radical‐Polar Crossover Bicyclization Enables a Modular Synthesis of Saturated Bicyclic Amines · 2025 · DOIIn contrast, for the more sterically hindered catalyst, the Sc···Ph interactions in cis -insertion are insufficient to overcome the steric effects, leading to a preference for the trans -insertion mode, which minimizes steric hindrance.
Theoretical Insights into Rare-Earth-Catalyst-Controlled Diastereo- and Enantioselective [3 + 2] Annulation of Aromatic Aldimines with Styrenes · 2025 · DOIHowever, the mechanisms underlying these reactions remain poorly understood, limiting the rational design of related catalytic systems.
Theoretical Insights into Rare-Earth-Catalyst-Controlled Diastereo- and Enantioselective [3 + 2] Annulation of Aromatic Aldimines with Styrenes · 2025 · DOIHowever, a significant limitation is the need for stepwise optimization of reaction conditions for different carbonyl types due to the inherent reactivity differences among coupling partners.
Streamlined Carbonylation of Csp3–H Bonds: Divergent Synthesis of Diverse Carbonyl Compounds · 2025 · DOImeta -Selective arene C–H activations typically rely on rather costly palladium or rhodium catalysts, elaborate template auxiliaries, or elevated temperatures, and meta -glycosylations are scarce.
Photochemical activation, though, has only been scarcely explored despite the fact that it represents a comparably environmentally benign protocol using light as a renewable energy source.
Photoredox catalysis has led to a diverse array of enabling C(sp 3 )–H activation strategies; however, a general platform for the direct functionalization of C(sp 3 )–H to carboxylic acid derivatives remains elusive.
However, combining both peripheral and skeletal editing of pyrrolidines for the diversity-oriented synthesis of azepinoindoles remains underexplored yet challenging.
Diversity-Oriented Synthesis of Azepinoindoles through sp 3 C–H Functionalization and Skeletal Remodeling · 2025 · DOIThe photocatalytic decarboxylative functionalization of carboxylic acids was mostly limited to alkyl carboxylic acids.
Iron Photocatalysis Enabling Decarboxylative Bromination of (Hetero)Aryl Carboxylic Acids · 2025 · DOIAnd, the synthesis of 2,5-diamino acid derivatives via a mild photocatalytic approach has not been reported yet.
Photoexcited Copper-Catalyzed Difunctionalization of Alkenes for the Synthesis of 2,5-Diamino Acid Derivatives via Uncommon 1,2-Hydrogen Atom Transfer of Amidyl Radicals · 2025 · DOINotably, due to the intimidating challenges in the stereocontrol for the intramolecular amidation, the asymmetric cascade carboamidation of the C═C bond to access structurally diverse chiral γ-lactams from readily available 2-bromoamides remains unexplored.
Photoinduced, Pd-Catalyzed Enantioselective Cascade Carboamidation of Dienes to Access γ-Lactams · 2025 · DOIDespite extensive research, the cycloaddition of aldehydes with cyclopropenones catalyzed by metal complexes has not been documented.
Rh-Catalyzed Formal [3 + 2] Cycloaddition Reactions with Cyclopropenones via Sequential C–H/C–C Bond Activation · 2025 · DOIN–N linked dimeric indolosesquiterpene alkaloids represent an underexplored class of natural products, and strategies for direct dehydrogenative N–N bond formation are limited.
Total Synthesis of Dixiamycins A and B via a Late-Stage N–N Bond Formation under Visible Light Photoredox Catalysis · 2025 · DOIWhile considerable progress has been made in meta -C–H functionalization strategies, including olefination, cyanation, acetoxylation, and arylation, regioselective meta -C–H homo-biaryl coupling remains unexplored.
An Oxidative Palladium-Catalyzed Remote meta -Selective Homo-Biaryl Coupling Assisted by Nitrile Directing Templates · 2025 · DOIDespite the impressive advances, enantioselective photoinduced strong arene C–H activations by cobalt catalysis remain unexplored.
However, sustainable and selective approaches remain scarce, and the majority of the existing conditions still hinge on hazardous oxidants or costly metal catalysts.
Although remarkably powerful, existing dearomatization processes have been limited to the hydrogenation or addition of carbon-based nucleophiles to activated pyridiniums.
However, direct observation and detailed investigation of these fundamental steps remain elusive owing largely to the typically slow oxidative addition rate of copper(I) complexes and the instability of the copper(III) species.
Catalytically Relevant Organocopper(III) Complexes Formed through Aryl-Radical-Enabled Oxidative Addition · 2024 · DOI)-H lactonization of free carboxylic acids provides the most straightforward means to prepare biologically important lactone scaffolds from abundant and inexpensive carboxylic acids; however, a versatile catalyst for this transformation with a broad substrate scope remains elusive.
However, this strategy is currently focused on the 1,2-difunctionalization of olefins or alkynes, and the 1,4-alkylcarbonylation of 1,3-enynes remains unexplored.
Nickel-Catalyzed Modular Four-Component 1,4-Alkylcarbonylation of 1,3-Enynes to Tetra-Substituted CF3–Allenyl Ketones · 2024 · DOIAtomic carbon and its corresponding masked analogues are exceedingly underexplored intermediates in synthesis.
Atomic Carbon Equivalent: Design and Application to Diversity-Generating Skeletal Editing from Indoles to 3-Functionalized Quinolines · 2024 · DOISelective functionalization of a specific C(sp 3 )–H bond remains an open challenge in synthetic chemistry.
Advances in Palladium-Catalyzed C(sp3)–H Functionalization: The Role of Traceless Directing Groups · 2024 · DOIAsymmetric reductive three-component arylalkylation of alkenes via the radical relay method has been well established, while asymmetric arylalkylation via the migratory insertion strategy remains unexplored.
Enantioselective Directed Nickel-Catalyzed Three-Component Reductive Arylalkylation of Alkenes via the Carbometalation/Radical Cross-Coupling Sequence · 2024 · DOIHowever, previous reports are limited to the enantioselective functionalization of C(sp 2 )–H bonds of aryl phosphine derivatives.
Pd(II)-Catalyzed Enantioselective C(sp3)–H Arylation toward P-Stereogenic Dialkylphosphinamides · 2024 · DOIMeanwhile, the asymmetric Wacker-type cyclization and carbonylation reactions are plagued by narrow substrate scope and low enantioselectivity and remain underexplored.
Synthesis of Chiral Polycyclic Indoles via Pd(II)-Catalyzed Sequential Cyclization and Carbonylation · 2024 · DOI
Most-cited papers in Catalytic C–H Functionalization Methods
- The Atom Economy—A Search for Synthetic Efficiency · Science · 1991 · 4,586 citations
- Copper-catalyzed radical relay in C(sp 3 )–H functionalization · Chemical Society Reviews · 2022 · 369 citations
- A Perspective on Late-Stage Aromatic C–H Bond Functionalization · Journal of the American Chemical Society · 2022 · 305 citations
- Enantioselective electrochemical cobalt-catalyzed aryl C–H activation reactions · Science · 2023 · 293 citations
- Organothianthrenium salts: synthesis and utilization · Chemical Science · 2022 · 261 citations
- Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines · Nature · 2023 · 172 citations
- Skeletal editing of pyridines through atom-pair swap from CN to CC · Nature Chemistry · 2024 · 159 citations
- Nickel-Catalyzed Ligand-Controlled Selective Reductive Cyclization/Cross-Couplings · Accounts of Chemical Research · 2023 · 157 citations
- The chemistry of heterocycles in the 21st century · Russian Chemical Reviews · 2024 · 155 citations
- Synthesis, characterization and evaluation of urethane derivatives of Bis-GMA · Dental Materials · 2003 · 145 citations
Most recent work
- Modular Synthesis of Densely Functionalized Azetidines: Ni-Catalyzed 1,4-Alkylarylation of 1,3-Enynes with 1-Azabicyclo[1.1.0]butanes through Polar–Radical Relay · Organic Letters · 2026
- Nickel-Catalyzed Regioselective Hydroalkynylation of Nitrogen Heterocycle-Tethered Unactivated Alkenes · Organic Letters · 2026
- Cross- and branched-selective hydroalkenylation by metal hydride selection · Science · 2026
- Chiral Carboxylic Acid Assisted Ir(III)-Catalyzed Asymmetric C–H Activation/Desymmetrization of Sulfoximines · Organic Letters · 2026
- Copper(I)-Catalyzed Amide Oxazoline-Directed, Atom-Economic C–H Selenylation of (Hetero)Arenes under External Oxidant-Free Conditions · Organic Letters · 2026
- Direct Catalytic Decarboxylative C1-Alkylation of Unprotected Tetrahydroisoquinolines via Photoredox Catalysis · Organic Letters · 2026
- CuCl-Promoted β-Acylation of Cyclopropanols with Thioesters · Organic Letters · 2026
- Regioselective Reductive Coupling of o -Haloaromatic Ketones with Terminal Alkynes via Photoredox/Cobalt Dual Catalysis · Organic Letters · 2026
- Hypervalent Iodine Diazo Esters as C1 Synthons in [3+2+1] Cascade Cyclization: Access to Fully Substituted Pyridines · Organic Letters · 2026
- Carbene-Catalyzed C–H Arylation of Aldehyde-Hydrazone via Radical Cross-Coupling with Iodobenzene · Organic Letters · 2026
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