Trifluoroiodomethane Research Articles

Transition‐Metal‐Mediated Fluoroalkylation of Carbon Electrophiles through Cross‐Electrophile Couplings

Comprehensive SummaryOrganofluorine compounds have attracted substantial interest in life and materials sciences due to the unique properties of fluorine atom(s) that often change the physicochemical and biological properties of organic molecules. Transition‐metal‐mediated cross‐electrophile coupling between carbon electrophiles and fluoroalkyl electrophiles has emerged as a straightforward and efficient route for the synthesis of a wide range of fluoroalkylated compounds because of its synthetic convenience without the tedious synthesis of organometallic reagents. Moreover, alkenes or alkynes‐involved three‐component cross‐electrophile couplings provide rapid and effective access to carbonfunctionalized fluoroalkylated alkanes and alkenes. Herein, we comprehensively summarize the transition‐metal‐mediated reductive fluoroalkylation of diverse carbon electrophiles through a historical perspective, including trifluoromethylation, difluoroalkylation, monofluoroalkylation, and so on. Different transition metals (Cu, Ni, etc.) and strategies are discussed, in which nickel‐catalyzed reductive fluoroalkylation reactions represent an attractive and efficient synthetic route to site‐selectively access organofluorine compounds. Key ScientistsAs early as 1965, McLoughlin and Thrower finished the first stoichiometric copper‐mediated fluoroalkylation of aromatic iodides with fluoroalkyl iodides. However, excess aromatic iodides and elevated temperature were used for this method. In 1969, Kobayashi and Kumadaki reported studies on the copper‐mediated trifluoromethylation of aromatic halides with excess trifluoromethyl iodide. After more than four decades, the Zhang group developed a nickel‐catalyzed β‐fluorinated alkylation of (hetero)aryl iodides with fluoroalkylated secondary alkyl bromides in 2015, and a nickel‐catalyzed difluoromethylation of (hetero)aryl chlorides with chlorodifluoromethane ClCF2H in 2017. The Zhang group also developed enantioselective nickel‐catalyzed reductive alkyl‐arylation of 3,3,3‐trifluoropropene with (hetero)aryl and tertiary alkyl iodides. In 2018, the MacMillan group developed a novel copper/photoredox dual catalytic system for the trifluoromethylation of aryl bromides or alkyl bromides with (S)‐(trifluoromethyl) dimesitylsulfonium triflate in the presence of tris‐(trimethylsilyl) silanol. They also developed a nickel/photoredox catalyzed difluoromethylation of aryl bromides in the presence of silane. During this time, the Wang group reported a nickel‐catalyzed monofluoroalkylation of aryl halides with monofluoroalkyl halides. From 2021 to 2023, the same group further developed a series of enantioselective nickel‐catalyzed trifluoroalkylation of aryl, alkenyl, and acyl halides. Moreover, nonfluorinated alkenes or alkynes could also be used in three‐component cross‐electrophile couplings. In 2018, the Chu group reported a nickel‐catalyzed fluoroalkyl‐acylation of alkenes with acyl chlorides and fluoroalkyl iodides. Later, they developed a nickel‐catalyzed enantioselective fluoroalkyl‐arylation of unactivated alkenes tethering with a pendant chelating group. In 2019, the Chaładaj group reported a palladium‐catalyzed reductive perfluoroalkyl‐arylation of alkynes with perfluoroalkyl and aryl iodides.

Visible-light-induced photocatalytic four-component fluoroalkylation-dithiocarbamylation via difunctionalization of styrenes.

Herein we demonstrate that a visible-light-induced photocatalytic four-component fluoroalkylation-dithiocarbamylation is a unified method for the fluoroalkylation of diverse activated fluoroalkyl halides, including monofluoroalkyl bromides, difluoroalkyl bromides, trifluoromethyl iodide, and perfluoroalkyl iodides. The synthetic value of this method has been demonstrated by the transformations of various substrates containing drug/natural product skeletons, gram scale reactions, and further derivatizations of the fluorodithiocarbamate products. This work features an atom economical protocol that is simple to operate, does not require any additives or strong bases, and can be carried out under mild conditions.

Radical‐Mediated Hydroperfluoroalkylation of Unactivated Alkenes

AbstractThe direct hydroperfluoroalkylation of a wide range of unactivated alkenes has been achieved at room temperature with readily available iodoperfluoroalkanes using 4‐tert‐butylcatechol as a source of hydrogen atom and triethylborane. The hydrotrifluoromethylation could also be achieved under these conditions using gaseous trifluoromethyl iodide. An experimentally simple two‐step, one‐pot hydrotrifluoromethylation process using the easy‐to‐use trifluoromethanesulfonyl chloride as the source of trifluoromethyl radicals has also been developed. Using these two approaches, a broad range of substrates, including isoprenoid natural products, were efficiently derivatized.

Visible-light mediated carbonyl trifluoromethylative amination as a practical method for the synthesis of β-trifluoromethyl tertiary alkylamines.

We report the development of an operationally straigtforward, visible-light-mediated multicomponent strategy for the construction of β-trifluoromethylated tertiary alkylamines from feedstock aldehydes, secondary amines and a convenient source of trifluoromethyl iodide. The new process does not require a photocatalyst, is metal-free, displays a broad functional group tolerance and offers rapid, one-pot access to trifluoromethylated drug-like compounds that will be of interest in medicinal chemistry.

Hydrogen Atom Transfer Induced Boron Retaining Coupling of Organoboronic Esters and Organolithium Reagents.

α-Functionalization of alkyl boronic esters and homologation of aryl boronic esters by regioselective radical C(sp3)–H activation in boron-ate complexes is reported. Reaction of commercial or readily accessed aryl boronic acid pinacol esters with alkyl lithium reagents provides boron-ate complexes. Selective α-C–H abstraction by in situ generated trifluoromethyl radicals leads to radical anions that undergo electron transfer oxidation followed by 1,2-aryl/alkyl migration from boron to carbon to give the α-arylated/alkylated alkyl boronic esters. The valuable boronic ester functionality remains in the products and the cheap trifluoromethyl iodide acts as the oxidant in these C–C couplings. The 1,2-alkyl migration from boron to carbon is highly stereospecific allowing access to stereoisomerically pure boronic esters.

Trifluoroethoxy-Coated Subphthalocyanine affects Trifluoromethylation of Alkenes and Alkynes even under Low-Energy Red-Light Irradiation.

Photoredox chemical reactions induced by visible light have undergone a renaissance in recent years. Polypyridyl dyes such as Ir(ppy)3 and Ru(bpy)3 are key catalysts in this event, and blue‐ or white‐light irradiation is required for the chemical transformations. However, it remains a challenge to achieve reactions under the lower energy of red light. We disclose, herein, that trifluoroethoxy‐coated subphthalocyanine realizes the red‐light‐driven trifluoromethylation of alkenes and alkynes with trifluoromethyl iodide in good‐to‐high yields. Perfluoroalkylations were also achieved under red light. The reaction mechanism is discussed with the support of UV/Vis spectroscopy and cyclic voltammetry of trifluoroethoxy‐coated subphthalocyanine. Light irradiation/dark study also supports the proposed mechanism.

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide.

The trifluoromethylation of aryl iodides catalyzed by copper(I) salt with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide and Zn dust was accomplished. The catalytic reactions proceeded under mild reaction conditions, providing the corresponding aromatic trifluoromethylated products in moderate to high yields. The advantage of this method is that additives such as metal fluoride (MF), which are indispensable to activate silyl groups for transmetallation in the corresponding reactions catalyzed by copper salt by using the Ruppert–Prakash reagents (CF3SiR3), are not required.

ChemInform Abstract: Direct Preparation of Trifluoromethylindium Reagents from Trifluoromethyl Iodide: Effective Trifluoromethylation and Perfluoroalkylation Reagents.

The direct synthesis of trifluoromethylindium reagents prepared from trifluoromethyl iodide by using just one equivalent each of indium, lithium chloride or sodium iodide, and ferrocene is reported. The weak In···F interaction is suitable to prepare stable but nucleophilic perfluoroalkyl reagents, which were successfully employed in the perfluoroalkylation of aldehydes. Notably, the nucleophilic trifluoromethylation of various aldehydes took place with trifluoromethyl iodide by utilizing just one equivalent each of indium, lithium chloride, and ferrocene.

Direct Preparation of Trifluoromethylindium Reagents from Trifluoromethyl Iodide: Effective Trifluoromethylation and Perfluoroalkylation Reagents

AbstractThe direct synthesis of trifluoromethylindium reagents prepared from trifluoromethyl iodide by using just one equivalent each of indium, lithium chloride or sodium iodide, and ferrocene is reported. The weak In···F interaction is suitable to prepare stable but nucleophilic perfluoroalkyl reagents, which were successfully employed in the perfluoroalkylation of aldehydes. Notably, the nucleophilic trifluoromethylation of various aldehydes took place with trifluoromethyl iodide by utilizing just one equivalent each of indium, lithium chloride, and ferrocene.

ChemInform Abstract: Activation of C—F Bonds in Preference to C—I Bonds: Difluoromethylation of Lithium Enolates with Trifluoromethyl Iodide.

AbstractThe reaction represents an unprecedented construction of the all‐carbon quarternary centers using lithium enolates and gaseous CF3I without any metal catalysts.

ChemInform Abstract: Synthesis of 1,3-Dioxin-4-ones Having a Trifluoromethyl Group at the 5- Position: Versatile Building Blocks for Trifluoromethylated Compounds.

The reaction of 5-iodo-1,3-dioxin-4-ones with trifluoromethyl iodide in the presence of copper powder in hexamethylphosphoric triamide affords the title compounds, which can be converted either to α-trifluoromethylated β-keto acid derivatives or to uracil or oxazine derivatives bearing a trifluoromethyl group.

ChemInform Abstract: A Simple, Novel Method for the Preparation of Trifluoromethyl Iodide and Diiododifluoromethane.

CF3l was synthesized in high yields by treatment of XCF2CO2Me(X = Cl or Br) with iodine in the presence of potassium fluoride and copper iodide; if Kl was used instead of KF under similar conditions, CF2l2 was obtained in moderate yields.

A Convenient and Efficient Synthesis of Trifluoromethyl Vinyl Sulfoxide and Its Reactivity in Addition Reactions

We report a novel high-yielding approach to trifluoro­methyl vinyl sulfoxide from 2-mercaptoethanol and trifluoromethyl iodide. Additionally, the principal ability of this compound to react with N-, O-, and S-nucleophiles is demonstrated.

Activation of CF Bonds in Preference to CI Bonds: Difluoromethylation of Lithium Enolates with Trifluoromethyl Iodide

Activation of CF Bonds in Preference to CI Bonds: Difluoromethylation of Lithium Enolates with Trifluoromethyl Iodide

Activation of CF Bonds in Preference to CI Bonds: Difluoromethylation of Lithium Enolates with Trifluoromethyl Iodide

Activation of CF Bonds in Preference to CI Bonds: Difluoromethylation of Lithium Enolates with Trifluoromethyl Iodide

Trifluoromethylation of Organic Compounds and Related Reactions

This review concentrates on trifluoromethylation and related reactions from the authors’ group. Mainly, our new rhodium complex catalyzed synthesis of trifluoromethyl and other fluorine compounds will be discussed. However, initially we would like to discuss the origins and development of this reaction. Thus, trifluoromethylation of aromatic and aliphatic halides with trifluoromethyl iodide in the presence copper powder will be discussed first, and then the application of this copper-mediated reaction to ethyl bromodifluoroacetate for the synthesis of difluoromethylene compounds will be presented. The investigation of the mechanism of this reaction led us to the Michael addition of the (ethoxycarbonyl)difluoromethyl group to α,β-unsaturated carbonyl compounds. To improve this reaction, we examined the rhodium-catalyzed Michael reaction, and found that the fluorine substituent was introduced surprisingly not to the β-position but to the α-position. This reaction could be used to introduce other fluoroalkyl groups, including­ the trifluoromethyl group, to the α-position of almost all Michael acceptors. Furthermore, this reaction was developed for the introduction of the trifluoromethyl or other fluoroalkyl groups into the α-position of ketones or carboxylic acid derivatives through silyl­ enol ethers or ketene silyl acetals.

Crystal and molecular structures of trifluoromethyl derivatives of fullerene C86, C86(CF3)16 and C86(CF3)18

Trifluoromethyl derivatives of C86 were obtained by the reaction of a mixture of higher fullerenes with trifluoromethyl iodide, followed by the HPLC separation of the products. The crystal and molecular structures of C86(CF3)16 (two isomers) and C86(CF3)18 were determined by single-crystal X-ray diffraction using synchrotron radiation. All compounds studied are derivatives of the cage isomer of C86 no. 17 (C2).

Radical‐Mediated Hydroxytrifluoromethylation of α,β‐Unsaturated Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Radical-mediated hydroxytrifluoromethylation of α,β-unsaturated esters

Treatment of α,β-unsaturated esters with trifluoromethyl iodide and triethylborane in the presence of KF and H 2O gave the corresponding hydroxytrifluoromethylated esters.

Novel Nucleophilic Trifluoromethylation of Vicinal Diol Cyclic Sulfates.

[reaction: see text] A novel method for highly regioselective and stereospecific nucleophilic trifluoromethylation of vicinal diol cyclic sulfates, using the reagent derived from reduction of trifluoromethyl iodide by tetrakis(dimethylamino)ethylene (TDAE), is presented.