Trifluoromethylating Reagent Research Articles

ChemInform Abstract: Copper‐Mediated Aerobic Oxidative Trifluoromethylation of Terminal Alkynes with Me3SiCF3.

An efficient copper-mediated trifluoromethylation of terminal alkynes with nucleophilic trifluoromethylating reagent (Me3SiCF3) was developed. Both aromatic alkynes and aliphatic alkynes were effective, and a variety of functionalities such as amino, -OMe, -CO2Et, -Br, and -NO2 were tolerated under the reaction conditions. This reaction provides a general, straightforward, and practically useful method to prepare trifluoromethylated acetylenes.

Electrophilic trifluoromethylation of arenes and N-heteroarenes using hypervalent iodine reagents

The reaction of hypervalent iodine trifluoromethylating reagents with a variety of arenes and N-heteroarenes gives access to the corresponding trifluoromethylated compounds. In comparative studies, 1-trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole ( 2) proved to be the superior to 1-trifluoromethyl-1,2-benziodoxol-3-( 1H)-one ( 1) for the direct aromatic trifluoromethylation. Depending on the individual substrates, additives such as zinc bis(trifluoromethylsulfonyl)imide or tris(trimethylsilyl)silyl chloride proved helpful in promoting the reactions. In the case of nitrogen heterocycles a pronounced tendency for the incorporation of the trifluoromethyl group at the position adjacent to nitrogen was observed.

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

Since the discovery by Yagupolskii and co-workers that S-trifluoromethyl diarylsulfonium salts are effective for the trifluoromethylation of thiophenolates, the design and synthesis of electrophilic trifluoromethylating reagents have been extensively researched in both academia and industry, due to the significant unique features that trifluoromethylated compounds have in pharmaceuticals, agricultural chemicals, and functional materials. Several effective reagents have been developed by the groups of Yagupolskii, Umemoto, Shreeve, Adachi, Magnier, Togni and Shibata. Due to the high stability and reactivity of these reagents, a series of Umemoto reagents, Togni reagent and Shibata reagent are now commercially available. In this review, we wish to briefly provide a historical perspective of the development of so-called “shelf-stable electrophilic trifluoromethylating reagents”, although this field is in constant development.

Copper-Mediated Aerobic Oxidative Trifluoromethylation of Terminal Alkynes with Me3SiCF3

An efficient copper-mediated trifluoromethylation of terminal alkynes with nucleophilic trifluoromethylating reagent (Me(3)SiCF(3)) was developed. Both aromatic alkynes and aliphatic alkynes were effective, and a variety of functionalities such as amino, -OMe, -CO(2)Et, -Br, and -NO(2) were tolerated under the reaction conditions. This reaction provides a general, straightforward, and practically useful method to prepare trifluoromethylated acetylenes.

New hypervalent iodine reagents for electrophilic trifluoromethylation and their precursors: synthesis, structure, and reactivity

Several new five- and a six-membered heterocyclic monochloroiodanes, including two cationic species, were synthesized. Three of which were used for the preparation of corresponding trifluoromethylation reagents. These compounds were characterized by X-ray crystallography for a comparative structural study. A reactivity study on the trifluoromethylation of para-toluenesulfonic acid has been conducted in order to compare initial rates. Compounds having a longer I–O bond display a higher reactivity.

Synthesis of Thiophenium Salts: A Trifluoromethylation Reagent

Synthesis of Thiophenium Salts: A Trifluoromethylation Reagent

Electrophilic Trifluoromethylation of Primary Phosphines: Synthesis of a P-Bis(trifluoromethyl) Derivative of BINAP

The new chiral diphosphine ligand (R)-(2′-(bis(trifluoromethyl)phosphino)-1,1′-binaphthyl-2-yl)diphenylphosphine (2), which contains a bis(trifluoromethyl)phosphine group, was prepared in five steps from (R)-BINOL (5). As a key transformation, the unprecedented electrophilic double trifluoromethylation of the primary phosphine 8 was achieved using the hypervalent iodine trifluoromethylation reagent 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1), derived from o-iodobenzoic acid. The palladium dichloride complex of this ligand (10) shows the P(CF3)2 group with a high degree of pyramidalization at the P atom and a relatively short Pd−P bond (2.2230(4) Å), both features being indicative of the strong s-character of the phosphorus lone pair.

Pd(II)-Catalyzed ortho-Trifluoromethylation of Arenes Using TFA as a Promoter

A Pd(II)-catalyzed C-H activation/trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent using diverse heterocycle directing groups is reported. The presence of trifluoroacetic acid is crucial for this catalytic reaction.

Reactivity of a Hypervalent Iodine Trifluoromethylating Reagent toward THF: Ring Opening and Formation of Trifluoromethyl Ethers

1-Trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1) is able to transfer the electrophilic CF(3) group to the oxygen atom of THF in the presence of a Lewis or Bronsted acid. This results in a new ring-opening reaction of THF yielding trifluoromethyl ethers. Details of this reaction and the insight gained into the mechanism of action of reagent 1 are reported.

ChemInform Abstract: Zinc‐Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Concise Synthesis of ortho-Iodobenzyl Alcohols via Addition of ortho-Iodophenyl Grignard Reagent to Aldehydes and Ketones

A wide range of both secondary and tertiary ortho-iodobenzyl alcohols was synthesized via addition of ortho-iodophenyl Grignard reagents to aldehydes and ketones. Significant improvements in terms of yields were observed with ketones upon addition of CeCl 3 . The potential application of the target compounds as precursors for novel electrophilic trifluoromethylating reagents based on hypervalent iodine derivatives was demonstrated.

Sulfilimines and Sulfoximines by Reaction of Nitriles with Perfluoroalkyl Sulfoxides

AbstractThe species obtained by activation of perfluoroalkylated sulfoxides with trifluoromethanesulfonic anhydride behaves as highly electrophilic entities. Their reaction with nitriles allows a Ritter‐like process leading to the new fluorinated acylsulfilimines 1–21 after hydrolysis. This flexible methodology allows some variation of both the sulfoxide and nitrile components. Derived acylsulfoximines 22–25 or free sulfoximines 26–28 could be selectively obtained, as needed, by further controlled oxidation with the cheap and nontoxic potassium permanganate. This oxidation may be performed either after isolation of the intermediate sulfilimine, or more conveniently in a one‐pot process directly from fluorinated sulfoxides. This versatile, solvent and metal free, reaction is thus an opening way through the synthesis of new ligands or electrophilic trifluoromethylating reagents.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Zinc‐Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents

AbstractSchieb mal rüber: Der Transfer einer intakten Trifluormethylgruppe von einem hypervalenten Iodreagens zu einem aliphatischen Alkohol verläuft glatt bei einer Aktivierung durch Zinkbis(triflimid). Dies ist eine einfache Methode zur Synthese von Trifluormethoxyalkyl‐Derivaten, die sonst nur schwer zugänglich sind.magnified image

Zinc‐Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents

A (fluor)ry of activity: The transfer of an intact trifluoromethyl group from a hypervalent iodine reagent to an aliphatic alcohol occurs smoothly upon activation by zinc bis(triflimide). This constitutes a straightforward method for the preparation of trifluoromethoxy alkyl derivatives, compounds otherwise difficult to access.

Benchmark and Solvent‐Free Preparation of Sulfonium Salt Based Electrophilic Trifluoromethylating Reagents

AbstractHere we describe work devoted to the one‐pot preparation of electrophilic trifluoromethylating reagents. The first part describes a reappraisal of our earlier experimental conditions and leads to an improved protocol that avoids the use of solvent and allows better yields. The second part carefully studies the behavior of biaryl substrates, whose structures can drive the reaction through the formation of original noncyclic or tricyclic dibenzothiophenium salts. New compounds were tested, in a standard reaction with aniline, for their trifluoromethylating power and revealed equivalent or improved reactivity relative to that of existing reagents. Furthermore, contrary to common knowledge, the presence of electron‐donating methyl groups gave reagents with very high activity.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

ChemInform Abstract: Reactivity of a 10‐I‐3 Hypervalent Iodine Trifluoromethylation Reagent with Phenols.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reactivity of a 10-I-3 Hypervalent Iodine Trifluoromethylation Reagent With Phenols

The reaction of the 10-I-3 hypervalent iodine electrophilic trifluoromethylation reagent 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (2) with 2,4,6-trimethylphenol, after deprotonation with NaH and in the presence of 18-crown-6 in a polar, nonprotic solvent, affords 1,3,5-trimethyl-2-(trifluoromethoxy)benzene (4) only as a byproduct. Trifluoromethylation occurs preferentially at the ortho- and para-positions of the aromatic core, giving the corresponding trifluoromethylcyclohexadienones 5 and 6. In case the ortho- and/or para-positions are not substituted, the corresponding products of an aromatic, electrophilic substitution are obtained in moderate yield, for example, 2-trifluoromethyl-4-tert-butylphenol (10a) from 4-tert-butylphenol (10).

α-Trifluoromethylated Carbanion Synthons

Trifluomethylated organic compounds often have properties that make them suitable for diverse applications, including materials science, agrochemistry, and pharmaceutical industry. But of all the therapeutic drugs currently available, about 10% of them have a partially fluorinated moiety. Thus, a great deal of attention is being paid to the development of reliable methodologies for trifluoromethylation. Introduction of a trifluoromethyl group into the target molecules mostly relies on either trifluoromethylating reagents or trifluoromethylated synthetic blocks. The chemistry of trifluoromethyl carbanions, nucleophilic trifluoromethylating agents such as the Ruppert-Prakash reagent, and organometallic species has been intensively developed for their important synthetic applications. But the chemistry of beta,beta,beta-trifluoroethyl carbanions (alpha-trifluoromethyl carbanions) and organometallic species has remained undeveloped despite their potential usefulness in organic synthesis. The issue needs to be addressed. This Account outlines successful alkylations and useful synthetic applications of alpha-trifluoromethyl carbanions, such as alpha-substituted beta,beta,beta-trifluoroethyl, alpha-trifluoromethylethenyl, trifluoroacetimidoyl, alpha-trifluoromethyloxiranyl, and related alpha-trifluoromethylated carbanions. The strong electron-withdrawing effect of the alpha-trifluoromethyl group may stabilize the carbanion species electronically. But alpha-trifluoromethyl carbanions and their corresponding organometallic species mostly release fluoride spontaneously to produce difluoroalkenes. This notorious decomposition of alpha-trifluoromethylated carbanions and anionoids has hindered the development of these species for organic synthesis. A well-designed device for the generation, stabilization, and acceleration for alkylation of the alpha-trifluoromethylated carbanions is needed for their synthetic application, as well as stabilization by the electron-withdrawing alpha-substituent. The reported alpha-substituted alpha-trifluoromethyl carbanions can be roughly categorized into three classes based on their structures. The first category, A, is pi-conjugation-stabilized carbanions, which are stabilized by ester, nitro, sulfone, carbonyl, or phenyl groups. alpha-Substituents of these carbanions can delocalize the negative charges on their pi-system with large sigma R electron-withdrawing effects; this prevents accumulation of negative charge on the fluorine atoms. The second category, B, consists of carbanions with sp(3) orbitals either of highly halogenated carbanionsexamples include pentafluoroethyl(trimethyl)fluorosilicate, pentafluoroethyllithium, and alpha,alpha-dichloro-beta,beta,beta-trifluoroethylzinc speciesor of cyclic structures such as oxiranyl- and aziridinyllithiums. Both of these carbanions are also stabilized since they reduce molecular orbital (MO) overlapping of the carbanion orbital to C-F bond orbitals. The third category, C, has carbanions with their anion center at the sp(2) orbital, such as alpha-trifluoromethylated alkenyl carbanions and imidoyl carbanions. These sp(2) orbitals of the carbanion center usually have a small overlap with the C-F bonds of trifluoromethyl groups. The small overlap is able to suppress the E2-type eliminations. alpha-Trifluoromethylated carbanions are, in general, unstable. Their stability is largely affected by factors like hybridization of the orbital that accommodates lone pair electrons, the electronic nature of the alpha-substituents, the degree of covalency in a bond between the carbon and metal, the class of countercation, stabilization by chelation of a metal cation, and so on. The stability, therefore, can be sometimes controlled by tuning these factors adequately so that they can be used for organic synthesis. The chemistry of alpha-trifluoromethylated carbanions for organic synthesis has been progressing steadily. However, the simplest trifluoroethyl and trifluoroacetyl carbanions have never been successfully produced and employed for organic synthesis. Elegant generation and synthetic application of these metal species are one of the most attractive and challenging subjects for active investigation in the future.

A new method for the synthesis of trifluoromethylating agents—Diaryltrifluoromethylsulfonium salts

A new synthetic method has been developed to prepare diaryltrifluoromethylsulfonium salts from diaryldifluorosulfuranes by the action of Me 3SiCF 3/F −. This reaction is the transformation of nucleophilic trifluoro-methylating reagent into electrophilic one.

Mild Electrophilic Trifluoromethylation of Carbon‐ and Sulfur‐Centered Nucleophiles by a Hypervalent Iodine(III)–CF3 Reagent

Inexpensive, recyclable, and activable: these are the features of a new mild electrophilic trifluoromethylation reagent that can be used to transfer a CF3 group to C-centered nucleophiles, such as β-keto esters and α-nitro esters, and to S-centered nucleophiles (see scheme).