Fluoroalkylations and Fluoroalkenylations with Iodonium Salts.

Synthesis and applications of fluoroalkyl and fluoroalkenyliodonium salts are summarized in this account article, focusing preferably to the reagents designed in our laboratory in the last decade. Among these reagents trifluoroethyl(aryl)iodonium salts have been used most frequently to build carbon-carbon and carbon-heteroatom bonds in simple nucleophilic substitutions and through transition metal catalyzed coupling reactions. Iodonium salts equipped with unsaturated fluorinated function showed diverse reactivity due to their electron deficient character, and these molecular motifs enable cycloadditions and nucleophilic additions to prepare fluorinated carbo- and heterocyclic molecules. Beyond the overview of existing transformations, with the presented collection, we aim to inspire future developments of iodonium reagents and their application in organic synthesis.

Synthesis of Hydrofluoroolefin-Based Iodonium Reagent via Dyotropic Rearrangement and Its Utilization in Fluoroalkylation.

[1,2]-shift of atoms in alkyl fragments belongs to the class of dyotropic rearrangements. Various atoms, including halogens can be involved in the migration, however participation of iodine is unprecedented. Herein, we report our experimental and DFT studies on the oxidation triggered dyotropic rearrangement of iodo and chloro functions via butterfly-type transition state to demonstrate the migrating ability of λ3 -iodane centre. With the exploitation of dyotropic rearrangement we designed and synthesized a novel fluoroalkyl iodonium reagent from industrial feedstock gas HFO-1234yf. We demonstrated that the hypervalent reagent serves as an excellent fluoroalkylation agent for various amines and nitrogen heterocycles.

Synthesis and Photochemical Application of Hydrofluoroolefin (HFO) Based Fluoroalkyl Building Block.

A novel fluoroalkyl iodide was synthesized on multigram scale from refrigerant gas HFO-1234yf as cheap industrial starting material in a simple, solvent-free, and easily scalable process. We demonstrated its applicability in a metal-free photocatalytic ATRA reaction to synthesize valuable fluoroalkylated vinyl iodides and proved the straightforward transformability of the products in cross-coupling chemistry to obtain conjugated systems.

Vicinal difunctionalization of carbon-carbon double bond for the platform synthesis of trifluoroalkyl amines.

Regioselective vicinal diamination of carbon-carbon double bonds with two different amines is a synthetic challenge under transition metal-free conditions, especially for the synthesis of trifluoromethylated amines. However, the synthesis of ethylene diamines and fluorinated amine compounds is demanded, especially in the pharmaceutical sector. Herein, we demonstrate that the controllable double nucleophilic functionalization of an activated alkene synthon, originated from a trifluoropropenyliodonium salt with two distinct nucleophiles, enables the selective synthesis of trifluoromethylated ethylene amines and diamines on broad scale with high efficiency under mild reaction conditions. Considering the chemical nature of the reactants, our synthetic approach brings forth an efficient methodology and provides versatile access to highly fluorinated amines.

Glycogen phosphorylase inhibitor, 2,3-bis[(2E)-3-(4-hydroxyphenyl)prop-2-enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells.

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of ß cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of ß cells. The purpose of this study was to assess whether an analogue of FR258900 can influence ß cell function. BF142 (Meso-Dimethyl 2,3-bis[(E)-3-(4-acetoxyphenyl)prop-2-enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence ß cell function and can support the insulin producing ability of ß cells.

Synthesis of Multifunctional Aryl(trifloxyalkenyl)iodonium Triflate Salts.

A convenient procedure for the synthesis of aryl(trifloxyalkenyl)iodonium triflate salts from commercially available (diacetoxyiodo)benzene, trimethylsilyl trifluoromethanesulfonate, and acetylenes under mild conditions was developed. The obtained multifunctional hypervalent vinyliodonium salts equipped with electrophilic and nucleophilic functions could serve as novel C2 synthons for organic transformations. The structure of the iodonium salts was identified by multidimensional NMR spectroscopy and X-ray crystallography.