Time for a round-up of this week’s #Reactionoftheday. On offer this time we have a direct hydrodecarboxylation of carboxylic acids, a light-promoted aromatic denitrative chlorination, a direct deoxygenative formylation of ketones, a persistent boryl radical for debrominative borylations and finally a photochemical conversion of indazoles into benzimidazoles.
Direct hydrodecarboxylation of carboxylic acids via N‑hydroxyphthalimide-mediated hydrogen atom transfer
L. Zhang et al, J. Org. Chem. 2025, 90, 7923–7929
https://doi.org/10.1021/acs.joc.5c00898
Hydrodecarboxylation of carboxylic acids has advanced significantly since Barton’s pioneering work in the 1980s. Contemporary methods often rely on stable N-hydroxyphthalimide (NHPI) ester radical precursors. However, these approaches typically require multi-step synthesis.
Recent developments in direct hydrodecarboxylation via single-electron transfer (SET) oxidation offer a pre-activation-free alternative. Nonetheless, these methods suffer from limited substrate scope due to the highly oxidizing nature of the photoredox catalysts employed. Similarly, photoinduced ligand-to-metal charge transfer (LMCT) strategies are promising but remain heavily dependent on transition metals or organophotocatalysts.
A recent publication in JACS by the Zhang group reports a novel, chemoselective hydrodecarboxylation of carboxylic acids that is both transition-metal- and photocatalyst-free. The method employs N-hydroxyphthalimide-mediated hydrogen atom transfer (HAT), using 3,3-bis(diphenylphosphino)propane (DPPP), catalytic diphenyldisulfide, and NaHCO₃ in DMA at 30 °C under 450–455 nm irradiation. The protocol demonstrates broad scope, effectively transforming primary, secondary, and tertiary carboxylic acids—including complex molecules such as chlorambucil and lithocholic acid.
Mechanistically, the phosphine is proposed to generate a phosphoranyl radical, which undergoes fragmentation and facilitates hydrogen atom transfer.
- Nickel-catalyzed Barton decarboxylation and Giese reactions: a practical take on classic transforms: P. Baran et al, Angew. Chem. Int. Ed. 2017, 56, 260−265
- Chemoselective decarboxylative protonation enabled by cooperative Earth-abundant element catalysis: J. West et al, Angew. Chem. Int. Ed. 2023, 62, e202213055
- The design of PINO-like hydrogen-atom-transfer catalysts: C. Stephenson et al, Nat. Rev. Chem. 2023, 7, 653–666
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Light-promoted aromatic denitrative chlorination
F. Ye et al, Nat. Chem. 2025, 17, 598–605
https://doi.org/10.1038/s41557-024-01728-1
Nitro compounds are important feedstock materials in the chemical industry. Functionalisation typically involves reduction and modification of both the activated aryl ring and the aniline nitrogen atom. Conversion of aniline to aryl chloride via a Sandmeyer-type reaction is a well-established two-step process that provides valuable building blocks for pharmaceuticals and agrochemicals.
However, the direct single-step conversion of aryl nitro compounds to aryl chlorides remains challenging due to the inertness of the carbon–nitro bond. The Ye group has recently reported a simple yet powerful direct de-nitrochlorination reaction using visible-light-generated chlorine radicals with concomitant loss of NO₂. This transformation employs FeCl₃ irradiated at 350 nm, with NaCl/Oxone serving as the chlorine source.
The reaction proceeds via ligand-to-metal charge transfer (LMCT) from FeCl₃, and importantly, no nuclear chlorination of the starting materials or products occurs. DFT calculations were used to elucidate the mechanism. This method effectively chlorinates aryl, heteroaryl, and olefinic nitro groups under mild conditions.
- Shining a light on the nitro group: distinct reactivity and selectivity: R. Jana et al, Chem. Commun. 2024, 60, 8806-8823
- Recent progresses in the preparation of chlorinated molecules: electrocatalysis and photoredox catalysis in the spotlight: Reactions 2022, 3, 233-253
- Denitrative iodination of nitroarenes via light-promoted reduction: F. Ye et al, Org. Lett. 2025, 27, 5107–5111
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Direct deoxygenative formylation of ketones with titanium
X. Z. Shu et al, Org. Lett.2025, 27, 6059–6064
https://doi.org/10.1021/acs.orglett.5c01624
Direct introduction of a formyl group, generating high-value synthetically tractable aldehydes, is a valuable process. Traditional methods for aldehyde synthesis—such as reductive formylation of primary alkyl halides with CO (yielding linear aliphatic products) and hydroformylation of alkenes with syngas (yielding linear or branched products)—are powerful but limited in their ability to access highly functionalized, branched aldehydes. To complement these strategies, the Shu group has developed a novel deoxygenative formylation of ketones that enables direct installation of formyl groups at internal aliphatic positions. This method holds promise for synthesizing structurally complex aldehydes, including those found in natural products.
The reaction employs a new titanium-based reagent, (iPrO)₂Ti(bpy)Cl₂, which is readily prepared from TiCl₄, Ti(OiPr)₄, and 2,2′-bipyridine (bpy). Used stoichiometrically (1.8 equiv), this reagent enables formyl transfer from DMF, while suppressing ketone homocoupling and reduction.
The proposed mechanism involves in situ generation of low-valent titanium, which reduces ketones to ketyl radicals. These radicals add to activated DMF to form a titanium-bound intermediate. Subsequent zinc reduction generates an enamine species, which upon aqueous workup is hydrolyzed to the aldehyde. The enamine intermediate has been detected during the reaction, providing mechanistic support.
This reaction proceeds under base-free conditions and is broadly applicable to aromatic, aliphatic, cyclic, and acyclic ketone substrates. The functional group tolerance and ability to access challenging aldehyde motifs make this a valuable tool in synthetic chemistry.
- Recent advances on direct formylation reactions: J. Laha et al, Chem. Rec. 2023, 23, e202300063
- Recent developments in asymmetric hydroformylation: S. Chakrabortty et al, Catal. Sci. Technol., 2021, 11, 5388-5411
- Titanium catalysis for the synthesis of fine chemicals – development and trends: L. Schafer et al, Chem. Soc. Rev., 2020, 49, 6947-6994
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Persistent boryl radicals as highly reducing photoredox catalysts for debrominative borylations
V. Aggarwal & A Noble et al, J. Am. Chem. Soc. 2025, 147, 19450–19457
https://doi.org/10.1021/jacs.5c03864
Radicals are typically short-lived transient intermediates, but with sufficient steric or electronic stabilization, they can persist in the ground state for extended periods. Historically, their low ground-state reactivity has limited synthetic utility. However, the advent of photoredox catalysis has changed this landscape. Visible light excitation enables access to doublet excited states and single-electron transfer (SET) processes, dramatically enhancing radical reactivity. Surprisingly, this potential has not been fully explored in using persistent radicals as photoredox reagents or catalysts.
Aggarwal, Nobel, and colleagues at the University of Bristol have reported a class of persistent boryl–bipyridine radicals, readily generated in situ by combining 2,2′-bipyridines with B₂cat₂. These species are potent excited-state reductants (E* < –3.4 V) and have demonstrated efficacy in a range of transformations, including alkyl bromide borylation, deoxygenation, dechlorination, and N-desulfonylation. For example, borylation proceeds efficiently under mild conditions (alkyl bromide, B₂cat₂ [3 equiv], dimethylamino–bipyridine [20 mol%], DBU [1 equiv], NMP, blue LEDs, 30 °C, 24 h). Given their unique properties, many further applications of these radicals are expected to emerge.
- Persistent and Stable Organic Radicals: Design, Synthesis, and Applications: Y. Li et al, Chem. 2021, 7, 288-332
- Shining fresh light on complex photoredox mechanisms through isolation of intermediate radical anions: D. Scott et al, ACS Catal. 2023, 13, 9392–9403
- Lewis base–boryl radicals enabled borylation reactions and selective activation of carbon–heteroatom bonds: Y. F. Wang et al, Acc. Chem. Res. 2023, 56, 69–186
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Photochemical conversion of indazoles into benzimidazoles
D. Leonori et al, Angew. Chem. Int. Ed. 2025, e202423804
https://doi.org/10.1002/anie.202423804
The interconversion of heteroaromatic cores into alternative heteroaryl systems is an active and valuable area of research. Most efforts in this domain focus on atom swapping, ring-size modification, or ring deconstruction/reconstruction. However, repositioning specific atoms within a ring system remains relatively underexplored.
In drug discovery, modifying the core heterocyclic structure of a privileged heteroaromatic motif—rather than making peripheral changes—typically requires de novo synthesis for each variant. This is time-consuming and often inefficient. Therefore, developing methods to expand heterocycle-based libraries in a single chemical step would be of significant value to medicinal chemists.
A recent study from the Leonori group demonstrates a photochemical strategy for the direct permutation of 1H- and 2H-indazoles into benzimidazoles, capitalizing on the intrinsic photoreactivity of these heterocycles. The transformation proceeds under ambient conditions upon irradiation (λ = 300 nm) without the need for additional reagents.
Mechanistic and computational studies revealed distinct pathways for each isomer. For 1H-indazoles, two sequential photochemical events are required, with hexafluoroisopropanol (HFIP) playing a critical role as a proton donor for excited-state tautomerization (0.05 M HFIP, room temperature). In contrast, the permutation of 2H-indazoles does not require tautomerization, allowing for broader solvent compatibility. Acetonitrile was identified as the preferred solvent for these substrates (0.05 M CH₃CN, room temperature).
This novel concept of photochemical permutation holds considerable promise for future applications in compound library design and heterocyclic diversification.
- Oxygen-, nitrogen-, and sulfur-containing heterocycles: recent advances in de novo synthesis and prospect: C. Qi et al, Org. Process Res. Dev. 2024, 28, 2988–3025
- Single-atom logic for heterocycle editing: R. Sarpong et al, Nat. Synth. 2022, 1, 352–364
- Skeletal editing through single atom insertion and transmutation: an insight into a new era of synthetic organic chemistry: C. Patel et al, Synthesis 2024, 24, 3793-3814
