This minireview is aimed at giving an overview of recent advances in olefin functionalisation reactions involving aryl radicals generated from arenediazonium salts. Based on the well-known Meerwein arylation, in which an aryl and a halogen substituent are coupled to an olefinic substrate, new reaction types have been developed that allow the introduction of a broad spectrum of other atoms and functional groups at the place of the original halogen atom and that are applicable to an extended range of olefinic substrates.

SignificanceThe development of selective antagonists for muscarinic acetylcholine receptors is challenging due to high homology in orthosteric binding sites among subtypes. Starting from a single amino acid difference in the orthosteric pockets in M2 muscarinic acetylcholine receptor (M2R) and M3R, we developed an M3R-selective antagonist using molecular docking and structure-based design. The resulting M3R antagonist showed up to 100-fold selectivity over the M2R in affinity and 1,000-fold selectivity in vivo. The docking-predicted geometry was further confirmed by a 3.1 Å crystal structure of M3R in complex with the selective antagonist. The potential of structure-based design to develop selective drugs with reduced off-target effects is supported by this study.

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Introduction of [(18) F]fluoride ion into the aromatic core of phenylazocarboxylic esters was achieved in only 30 seconds, with radiochemical yields of up to 95 % (85(±10) %). For labeling purposes, the resulting (18) F-substituted azoester can be further converted in radical-arylation reactions to give biaryls, or in substitutions at its carbonyl unit to produce azocarboxamides.

The radical carbohydroxylation of styrenes with aryldiazonium salts has been achieved under mild thermal conditions. A broad range of aryldiazonium salts was tolerated, and the reaction principle based on a radical–polar crossover mechanism could be extended to carboetherification as well as to a two‐step, metal‐free variant of the Meerwein arylation leading to stilbenes.

About 12% of all de novo acute myeloid leukemias are characterized by the translocation t(8;21), which generates the oncogenic fusion protein RUNX1/ETO. RUNX1/ETO has a modular structure and contains several docking sites for heterologous proteins, including transcriptional corepressors like N-CoR, SMART, and mSIN3A. RUNX1/ETO is found in high molecular weight complexes, which are crucial for the block in myeloid differentiation observed in RUNX1/ETO-transformed cells. Essential for high molecular weight complex formation is the nervy homology region 2 (NHR2) within ETO, which serves as interacting surface for oligomerization as well as association with members of the ETO protein family. Here, we show that the expression of a fusion peptide consisting of 128 amino acids (NC128), including the entire NHR2 domain of ETO, disrupts the stability of the RUNX1/ETO high molecular weight complexes, restores transcription of RUNX1/ETO target genes, and reverts the differentiation block induced by RUNX1/ETO in myeloid cells. In the presence of NC128, RUNX1/ETO-transformed cells lose their progenitor cell characteristics, are arrested in cell cycle progression, and undergo cell death. Our results indicate that selective interference with the oligomerization domain of ETO could provide a promising strategy to inhibit the oncogenic properties of the leukemia-associated fusion protein RUNX1/ ETO. [Cancer Res 2007;67(5):2280-9]

Radical arylations of para-substituted phenols and phenyl ethers proceeded with good regioselectivity at the ortho position with respect to the hydroxy or alkoxy group. The reactions were conducted with arenediazonium salts as the aryl radical source, titanium(III) chloride as the reductant, and diluted hydrochloric acid as the solvent. Substituted biaryls were obtained from hydroxy- and alkoxy-substituted benzylamines, phenethylamines, and aromatic amino acids. The methodology described offers a fast, efficient, and cost-effective new access to diversely functionalized biphenyl alcohols and ethers. Free phenolic hydroxy groups, aromatic and aliphatic amines, as well as amino acid substructures, are well tolerated. Two examples for the applicability of the methodology are the partial synthesis of a beta-secretase inhibitor and the synthesis of a calcium-channel modulator.

Radically shortened: In the propagation step of the title reaction, the cyclohexadienyl radical intermediate is oxidized by an arenediazonium ion to give the biaryl product (see scheme) while simultaneously a new aryl radical and nitrogen are formed.