Acceptor-substituted ferrocenium salts as strong, single-electron oxidants: synthesis, electrochemistry, theoretical investigations, and initial synthetic application

A series of mono- and 1,1'-diheteroatom-substituted ferrocene derivatives as well as acylated ferrocenes was prepared efficiently by a unified strategy that consists of selective mono- and 1,1'-dilithiation reactions and subsequent coupling with carbon, phosphorus, sulfur and halogen electrophiles. Chemical oxidation of the ferrocene derivatives by benzoquinone, 2,3-dichloro-5,6-dicyanobenzoquinone, AgPF(6) , or 2,2,6,6-tetramethyl-1-oxopiperidinium hexafluorophosphate provided the corresponding ferrocenium salts. The redox potentials of the synthesized ferrocenes were determined by cyclic voltammetry, and it was observed that all new ferrocenium salts have stronger oxidizing properties than standard ferrocenium hexafluorophosphate. An initial application of selected derivatives in an oxidative bicyclization revealed that they mediate the transformation under considerably milder conditions than ferrocenium hexafluorophosphate. Quantum chemical calculations of the reduction potentials of the substituted ferrocenium ions were carried out by using a standard thermodynamic cycle that involved the gas-phase energetics and solvation energies of the contributing species. A remarkable agreement between theory and experiment was found: the mean average deviation amounted to only 0.030?V and the maximum deviation to 0.1?V. This enabled the analysis of various physical contributions to the computed reduction potentials of these ferrocene derivatives, thereby providing insight into their electronic structure and physicochemical properties.     

A ferrocene-based reagent for the conjugation and quantification of reactive metabolites

In the present study, a method for the analysis of reactive metabolites via liquid chromatography (LC) with inductively coupled plasma–mass spectrometry (MS) was developed. A ferrocenyl-modified glutathione (GSH) reagent, consisting of GSH and succinimidyl-3-ferrocenylpropionate, was synthesized. Derivatization of the tripeptide was performed at the N-terminus, leaving the nucleophilic thiol group vacant for the attack of electrophilic compounds. The potential of ferrocenylpropionate (FP)-GSH as a trapping agent for reactive metabolites was investigated using an electrochemical flow-through cell for metabolism simulation coupled online to a LC system with electrospray ionization mass spectrometric detection. The pharmaceuticals amodiaquine, an antimalarial agent, and clozapine, an antipsychotic compound, served as model substances. By proving the successful adduct formation between the reactive metabolite and ferrocene-labeled GSH, it could be shown that FP-GSH is an effective trapping agent which eases routine reversed-phase LC analyses. In contrast to GSH, which is usually used for the conjugation of reactive metabolites and where the resulting adducts often show no or only very little retention, FP-GSH facilitates the detection of the corresponding metabolite adducts due to higher retention times.     

4-(1-Haloalkyl)-3-nitrotetrahydrofurans as versatile scaffolds for the synthesis of diversely functionalized tetrahydrofurans

4-(1-Haloalkyl)-3-nitrotetrahydrofurans, which are accessible by tandem oxidative oxa-Michael addition/radical cyclization/ligand transfer reactions, can be processed to diversely substituted tetrahydrofuran derivatives. Selective epimerization at the nitro function provides tetrahydrofuran diastereomers, which cannot be prepared by the tandem process. Intramolecular alkylations furnish interesting bridgehead nitro oxabicyclo[3.1.0]hexane derivatives in high yields. Intermolecular substitution reactions of the halide functions succeed only with nucleophiles, which are not basic enough to trigger intramolecular alkylations. The aryl substituent in 2-aryl-3-nitrotetrahydrofurans can be selectively oxidatively transformed to carboxylic acid derivatives using catalytic Ru(III) and NaIO₄ without affecting the nitro group. Reduction and hydrogenation reactions provide differently substituted 3-aminotetrahydrofuran derivatives depending on the conditions with moderate to good chemoselectivity.