Those of you on LinkedIn may have seen my daily #Reactionoftheday post. The purpose is to highlight reactions that I think are interesting and relevant to the synthetic organic/process chemistry communities. Please feel free to link to me and to Scientific Update (#ScientificUpdate) on the LinkedIn platform and like/re-share my posts. This weekly blog is to summarise each proceeding weeks highlights, and to add a few additional references / review articles here and there.
Iron-mediated nitrate reduction at ambient temperature for deaminative sulfonylation and fluorination of anilines
J. Am. Chem. Soc .2025
https://doi.org/10.1021/jacs.4c17981
The Ritter lab has published several valuable fluorination methodologies over the years. This particular paper is a notable extension of their nitrate reduction–aryl diazonium chemistry, describing a deaminative fluorination and and in addition a chlorosulfonylation process. The method involves in situ generation of aryl diazonium salts via thiosulfate-mediated reduction of iron(III) nitrate to NO₂, followed by diazotization. The aryl diazonium intermediates are then trapped using NaSbF₆ to afford aryl fluorides via a standard Balz–Schiemann mechanism, or with SO₂/CuCl/HCl to yield sulfonyl chlorides.
From a safety standpoint, the nitrate reduction–diazotization approach is appealing, and it’s encouraging to see further synthetic applications emerging from this platform.
- Nitrate reduction enables safer aryldiazonium chemistry: T. Ritter et al, Science 2024, 384, 446-452
- Mr Sandman, Bring Me A Dream: J Studley blog, June 2024, https://www.scientificupdate.com/process-chemistry-articles/mr-sandman-bring-me-a-dream/
- Recent development of aryl diazonium chemistry for the derivatization of aromatic compounds: J. Wanget al, Chem. Rev. 2021, 121, 5741–5829
———————————————————————————————————————————————————
Rapid access to 3-substituted bicyclo[1.1.1]pentanes
Chem 2025, 11, 102537
https://doi.org/10.1016/j.chempr.2025.102537
Bicyclo[1.1.1]pentanes (BCPs) have emerged as prominent “escape-from-flatland” pharmacophores in modern medicinal chemistry. As three-dimensional isosteres of aryl rings, BCPs often confer improved metabolic stability and physicochemical properties. The MacMillan group at Princeton has developed a powerful photoredox methodology to access 3-alkyl and 3-aryl BCPs via a radical linchpin strategy—effectively bypassing the need for organometallic reagents. !! CARE: The Bicyclo[1.1.1]pentane ring is an energetic material!!
- Escape from flatland: increasing saturation as an approach to improving clinical success: J. Med. Chem. 2012, 55, 3414–3424
- The Application of bicyclo[1.1.1]pentane as a bioisostere of the Phenyl Ring in pharmaceutical chemistry: Synthesis 2025, 57, 1171-1179
- Synthesis of bicyclo[1.1.1]pentane bioisosteres of internal alkynes and para-disubstituted benzenes from [1.1.1]propellane:Angew. Chem. Int. Ed. 2017, 56, 12774–12777
———————————————————————————————————————————————————
C-2 Selective palladium-catalyzed C-S cross-coupling of 2,4-dihalopyrimidines
J. Am. Chem. Soc. 2025, 147, 3017–3022
https://doi.org/10.1021/jacs.4c17020
2,4-Dihalopyrimidines are valuable intermediates in the synthesis of screening libraries for drug and agrochemical discovery. Under general Pd-catalyzed cross-coupling conditions, substitution typically occurs at the C4 position, unless steric effects dictate otherwise. In a notable study by Neufeldt et al., a highly selective C2 coupling was achieved using a Pd(II) precatalyst featuring a bulky N-heterocyclic carbene ligand. This atypical reactivity, observed with primary thiols and thiophenols, enables efficient diversity-oriented synthesis.
- Synthesis , reactions, and applications of pyrimidine derivatives: Current Chemistry Letters 2022, 11, 121–138
- Functionalization of 2,4-dichloropyrimidines by 2,2,6,6-tetramethylpiperidyl zinc base enables modular synthesis of antimalarial diaminopyrimidine p218 and analogues: Org. Chem. 2023, 88, 9475–9487
- Unconventional site selectivity in palladium-catalyzed cross-couplings of dichloroheteroarenes under ligand-controlled and ligand-free systems: J. Chem. 2022, 87, 7414–7421
———————————————————————————————————————————————————
Pyridoxal-inspired photo-decarboxylase catalysis: photochemical decarboxylation of unprotected amino acids
Angew. Chem. Int. Ed. C-S, 64, e202424843
https://doi.org/10.1002/anie.202424843
Decarboxylation of amino acids offers a direct route to valuable and structurally diverse amino building blocks. A useful paper by Lipshultz et al. presents a biomimetic, photochemically driven decarboxylative functionalization method, enabled by hydrogen atom transfer (HAT) organocatalysis. This approach operates under mild conditions and accommodates a broad range of natural and unnatural unprotected amino acids. The utility of this methodology is further demonstrated in more complex peptidic systems.
- Going full circle with organocatalysis and biocatalysis: the latent potential of cofactor mimics in asymmetric synthesis: Org. Chem. 2023, 88, 7619–7629
- Organocatalytic decarboxylation of amino acids as a route to bio-based amines and amides: ChemCatChem 2019, 11, 4297-4306
- Radical mediated decarboxylation of amino acids via photochemical carbonyl sulfide (cos) elimination: Molecules 2024, 29, 1464
