Research and development of new organic high-valent iodine reagents and exploration of new reactivity

In recent years, organic high-valent iodine reagents have attracted wide attention of synthetic chemists because of their rich reactivity, low toxicity, environmental protection, easy availability and stability. In addition to being a general oxidant, organic trivalent iodine reagents are a class of functional group transfer reagents with powerful functions. Since the establishment of the research group, Professor Zhang Chi of Nankai University has been deeply involved in the field of organic high-valent iodine chemistry, and has been committed to the design and synthesis of new organic high-valent iodine reagents for a long time, and has mainly applied them to the synthesis of fluorine-containing organic compounds, the synthesis of heterocyclic compounds, C-H bond functionalization, and the development of a series of new high-valent iodine peptide coupling reagents for the synthesis of oligopeptides and cyclic peptides.



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Figure 1 Representative new organic high-valent iodine reagent developed by Professor Zhang Chi's team



1) Fluorine-containing organic trivalent iodine reagent based on cyclic iodimide skeleton 1) trifluoromethylthio trivalent iodine reagent [1]

In 2020, the first example of organic trivalent iodine reagent TFTI (trifluoromethylthio iodineagent) with trifluoromethylthio as ligand was successfully synthesized by the N-acetyl cyclic iodimide skeleton selected by Zhang Chi's research team. TFTI, white powder in appearance, insensitive to air and water, good thermal stability (decomposition temperature is 137 ℃), and can be stably stored at - 20 ℃ for at least 6 months. TFTI is a highly active and versatile electrophilic trifluoromethylthio transfer reagent, which can realize electrophilic trifluoromethylthiolation of various types of nucleophiles. TFTI and organic alkali can be used in β- Dicarbonyl compounds such as β- Ketate and β- Ketoamide α- Introducing trifluoromethylthio group at the position; TFTI can realize the trifluoromethylthiolation of electron-rich aromatics, heteroaromatics, naphthol and enamine substrates without adding activation reagent, and construct the C (sp2) - S bond; TFTI can also react with nucleophilic compounds such as thiophen, amine and phenylselenol, and efficiently introduce trifluoromethylthio on S, N and Se heteroatoms. Using acetic acid as solvent, TFTI can realize the oxidation of sodium p-phenylsulfite by trifluoromethylthiolation. In addition, TFTI can be used as a source of trifluoromethylthio group and coordinate with CuI catalyst to realize the trifluoromethylthiolation reaction of aryl boric acid and alkenylboric acid compounds.



In the solvent HFIP, TFTI can carry out trifluoromethylthiolation on the sulfhydryl group in bio-related molecules including cysteine, glucose derivatives and the antihypertensive drug captopril. It is worth pointing out that TFTI can also chemically selectively modify the cysteine residues in a series of natural amino acid dipeptides by later trifluoromethylthiolation.



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Fig. 2 Electrophilic trifluoromethylthiolation of various types of nucleophiles by TFTI





2) Monofluorotrivalent iodine reagent [2]

In 2022, Zhang Chi's research team designed and synthesized a new organic monofluorotrivalent iodine reagent AFBI (2-acetyl-1-fluoro-1,2-dihydro-3H-1) based on the N-acetyl cyclic iodimide framework λ 3-benzo [d] [1,2] iodazol-3-one), the existence of intramolecular I... O secondary bond improves the stability of the reagent, and AFBI is not sensitive to air and water, and can be stored at ambient temperature for 6 months without decomposition. AFBI can not only activate the carbon-carbon bond of cyclopropane with high regioselectivity, but also realize the ring-expansion fluorination reaction of cyclopropane, thus realizing a one-step ring-expansion reaction from small ring to fluorinated large ring. In addition, AFBI can also realize the fluorination of 1,3-dicarbonyl compounds, unsaturated carboxylic acids, aromatic diazonium salts, diazonium compounds, etc.



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Fig. 3 Preparation of 4-fluoropiperidine by AFBI-mediated ring expansion fluorination reaction





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Fig. 4 AFBI promoted monofluorination reaction



2 Water-soluble high-valent iodine reagent 1) Water-soluble pentavalent iodine reagent [3]

As a mild and environmentally friendly oxidant, IBX is favored in organic synthesis, but its low solubility in common organic solvents, especially in water, limits its practical application to a certain extent. In 2011, Zhang Chi's research team successfully designed and synthesized the water-soluble pentavalent iodine reagent AIBX (5-trimethyllammonio-1,3-dioxo-1,3-dihydro-1 λ 5-benzo [d] [1,2] iodoxol-1-olanion), compared with IBX, the introduction of trimethyl amino group in the paraposition of the central iodine atom significantly enhances the water solubility of IBX, and the strong electronic pull of trimethyl amino group can enhance the electrophilicity of the iodine center, which is conducive to improving the reaction activity of the reagent. The rich and novel reactivity of AIBX has also been developed successively: (1) dehydrogenation and aromatization of cyclic b-keto ester; (2) Cyclopropanation of C (sp2) - C (sp3) single bond; (3) Epoxidation reaction of C (sp2) - C (sp3) single bond; (4) Dehydrogenation of cyclic b-keto acid ester a, b, - bifunctionalization reaction; (5) Preparation of carbonyl compounds by efficient oxidation of alcohols; (6) The AIBX-H2O2 system efficiently produces singlet oxygen, and has been successfully used in the synthesis of artemisinin, an antimalarial drug.