Trifluoromethyl Arenes Research Articles

Deoxytrifluoromethylation/aromatization of cyclohexan(en)ones to access highly substituted trifluoromethyl arenes

Trifluoromethyl arenes (Ar–CF3) are amongst the commonly encountered fluorinated substructures in pharmaceutical, agrochemical, and material sciences. However, predominant methods to access Ar–CF3 possess several limitations, including harsh conditions, lack of availability of substrates, and poor regioselectivity, which combined restrict access to desirable highly functionalized Ar–CF3-containing compounds. To expand the scope of accessible Ar–CF3-based molecules, we present an orthogonal deoxyfluoroalkylation/aromatization approach that exploits readily accessible and programable cyclohexan(en)one substrates, which undergo a reliable 1,2-addition reaction with the Ruppert-Prakash reagent (TMSCF3) followed by aromatization to deliver highly functionalized Ar–CF3 compounds in a one/two-pot sequence. This general strategy enables access to highly substituted Ar–CF3-containing molecules that are difficult, expensive, and/or impossible to access by current synthetic methods.

Mechanochemical Synthesis of Trifluoromethyl Arenes: Nanocellulose-Supported Deaminative Trifluoromethylation of Aromatic Amines

Mechanochemical Synthesis of Trifluoromethyl Arenes: Nanocellulose-Supported Deaminative Trifluoromethylation of Aromatic Amines

Selective Mono-Defluorinative Cross-Coupling of Trifluoromethyl arenes via Multiphoton Photoredox Catalysis.

A new cross-coupling of trifluoromethyl arenes has been realized via multiphoton photoredox catalysis. Trifluoromethyl arenes were demonstrated to undergo selective mono-defluorinative alkylation under mild reaction conditions providing access to a series of valuable α,α-difluorobenzylic compounds. The reaction shows broad substrate scope and general functional group tolerance. In addition to the electron-deficient trifluoromethyl arenes that are easily reduced to the corresponding radical anion, more challenging electron-rich substrates were also successfully applied. Steady-State Stern-Volmer quenching studies indicated that the trifluoromethyl arenes were reduced by the multiphoton excited Ir-based photocatalyst.

Domino Reactions with Dicyanoalkenes and Fluorinated Conjugated Sulfinyl Imines. A Convenient Strategy for the Generation of Structural Diversity

AbstractDicyanoalkenes are versatile reagents in organic synthesis and they have been extensively used in a wide variety of organic transformations. However, their reactivity towards fluorinated imines remained almost unnoticed. The divergent reactivity of fluorinated conjugated sulfinyl imines with dicyanoalkenes is described herein. On the one hand, when tert‐butyl sulfinyl imines were employed, a cycloaromatization cascade process took place preferentially, rendering valuable trifluoromethyl arenes. On the other hand, the reaction with p‐tolyl sulfinyl imines mainly led to a complex tetracyclic skeleton, involving an azetidinimine rearrangement of a reaction intermediate. Finally, when 1‐indanone‐derived dicyanoalkenes were employed, the aromatization process was interrupted, rendering a new family of diene derivatives. Theoretical calculations were performed in order to shed light on the mechanistic outcome of this transformation.

Nickel-Catalyzed Exhaustive Hydrodefluorination of Perfluoroalkyl Arenes

Perfluoroalkyl compounds are persistent environmental pollutants due to their strong C(sp3)-F bonds. Hydrodefluorination has emerged as a potential alternative disposal method for perfluoroalkyl compounds. Although the transformation of trifluoromethyl arenes into the corresponding methyl arenes has been studied by several research groups, hydrodefluorination reactions of longer perfluoroalkyl chains remain rare. Herein, we report exhaustive hydrodefluorination reactions of pentafluoroethyl arenes and longer-chain analogues using molecular nickel catalysis. Despite the cleavage of multiple C(sp3)-F bonds, the reaction already proceeds upon gentle heating (60 °C). A mechanistic investigation indicated that the reaction proceeds via benzylic hydrodefluorination reactions followed by homobenzylic ones. We reveal the multiple roles of the Ni catalyst, which include C-F bond cleavage, promotion of HF elimination, and hydrosilylation.

Electrochemical C-F bond activation of trifluoromethylarenes using silylium ions.

We report a mild, electrochemical trihydrodefluorination (e-THDF) for breaking highly stable C-F bonds in trifluoromethyl arenes to form the corresponding methyl arene products. Uniquely, this "green" approach relies on the in situ generation of Lewis acidic silyl cations that mediate fluoride abstraction. Overall, e-THDF has significantly improved functional group tolerance over current methods and should inspire the continued development of defluorinative processes.

Recent Advances in C-F Bond Cleavage Enabled by Visible Light Photoredox Catalysis.

The creation of new bonds via C-F bond cleavage of readily available per- or oligofluorinated compounds has received growing interest. Using such a strategy, a myriad of valuable partially fluorinated products can be prepared, which otherwise are difficult to make by the conventional C-F bond formation methods. Visible light photoredox catalysis has been proven as an important and powerful tool for defluorinative reactions due to its mild, easy to handle, and environmentally benign characteristics. Compared to the classical C-F activation that proceeds via two-electron processes, radicals are the key intermediates using visible light photoredox catalysis, providing new modes for the cleavage of C-F bonds. In this review, a summary of the visible light-promoted C-F bond cleavage since 2018 was presented. The contents were classified by the fluorosubstrates, including polyfluorinated arenes, gem-difluoroalkenes, trifluoromethyl arenes, and trifluoromethyl alkenes. An emphasis is placed on the discussion of the mechanisms and limitations of these reactions. Finally, my personal perspective on the future development of this rapidly emerging field was provided.

Unexpected metal-free synthesis of trifluoromethyl arenes via tandem coupling of dicyanoalkenes and conjugated fluorinated sulfinyl imines.

A novel strategy for the synthesis of policyclic trifluoromethyl arenes has been devised. It involves a DBU-promoted tandem cycloaromatization reaction of dicyanoalkenes and fluorinated conjugated sulfinyl imines. This unprecedented transformation is a metal-free and air-tolerant process that takes place from readily available starting materials under mild reaction conditions.

Palladium‐Catalyzed Decarbonylative Trifluoromethylation of Acid Fluorides

AbstractWhile acid fluorides can readily be made from widely available or biomass‐feedstock‐derived carboxylic acids, their use as functional groups in metal‐catalyzed cross‐coupling reactions is rare. This report presents the first demonstration of Pd‐catalyzed decarbonylative functionalization of acid fluorides to yield trifluoromethyl arenes (ArCF3). The strategy relies on a Pd/Xantphos catalytic system and the supply of fluoride for transmetalation through intramolecular redistribution to the the Pd center. This strategy eliminated the need for exogenous and detrimental fluoride additives and allows Xantphos to be used in catalytic trifluoromethylations for the first time. Our experimental and computational mechanistic data support a sequence in which transmetalation by R3SiCF3 occurs prior to decarbonylation.

Palladium-Catalyzed Decarbonylative Trifluoromethylation of Acid Fluorides.

While acid fluorides can readily be made from widely available or biomass‐feedstock‐derived carboxylic acids, their use as functional groups in metal‐catalyzed cross‐coupling reactions is rare. This report presents the first demonstration of Pd‐catalyzed decarbonylative functionalization of acid fluorides to yield trifluoromethyl arenes (ArCF3). The strategy relies on a Pd/Xantphos catalytic system and the supply of fluoride for transmetalation through intramolecular redistribution to the the Pd center. This strategy eliminated the need for exogenous and detrimental fluoride additives and allows Xantphos to be used in catalytic trifluoromethylations for the first time. Our experimental and computational mechanistic data support a sequence in which transmetalation by R3SiCF3 occurs prior to decarbonylation.

Selective Late‐Stage Hydrodefluorination of Trifluoromethylarenes: A Facile Access to Difluoromethylarenes

A selective reductive monodefluorination reaction of trifluoromethyl arenes was developed. Mediated by magnesium metal, various difluoromethylated aromatics were accessed at room temperature in the presence of acetic acid. This protocol shows tolerance to a wide range of functional groups and it was applicable in late‐stage hydrodefluorination of complex pharmaceutical compounds, affording the corresponding CF2H analogues and their deuterated (CF2D) counterparts.

4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions.

In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation.

ChemInform Abstract: Catalytic Activation of a Single C—F Bond in Trifluoromethyl Arenes.

AbstractAn optimized combination of a Pd and a Cu catalyst allows the selective monodefluorination of the title compounds under mild conditions.

Catalytic activation of a single C-F bond in trifluoromethyl arenes.

Synthetic methods for the direct transformation of ArCF3 to ArCF2R would enable efficient diversification of trifluoromethyl arenes and would be of great utility in medicinal chemistry. Unfortunately, the development of such methods has been hampered by the fundamental properties of C-F bonds, which are exceptionally strong and become stronger with increased fluorination of the carbon atom. Here, we describe a method for the catalytic reduction of ArCF3 to ArCF2H through a highly selective activation of a single C-F bond. Mechanistic studies reveal separate reaction pathways for the formation of ArCF2H and ArCH3 products and point to the formation of an unexpected intermediate as the source of the unusual selectivity for the mono-reduction.

Direct Aromatic C-H Trifluoromethylation via an Electron-Donor-Acceptor Complex.

A novel electron-donor-acceptor (EDA) complex-mediated direct C-H trifluoromethylation of arenes with Umemoto's reagent has been developed. This transformation has been enabled by an unprecedented EDA complex formed by Umemoto's reagent and an amine, which was supported by experiments and theoretical calculations. The radical-based methodology presented here allows to access highly-functionalized trifluoromethyl arenes in up to 81 % chemical yield.

Cu(I)-mediated (18)F-trifluoromethylation of arenes: rapid synthesis of (18)F-labeled trifluoromethyl arenes.

This report is concerned with an efficient, Cu(I)-mediated method for the radiosynthesis of [(18)F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Three (18)F-labelled radiotracer candidates were synthesised from [(18)F]fluoride ions as proof of principle. The new protocol is widely applicable for the synthesis of novel radiotracers in high radiochemical yields.

Copper-mediated trifluoromethylation of aryl-, heteroaryl-, and vinyltrifluoroborates with Langlois' reagent

An effortless and realistic procedure for the copper-mediated trifluoromethylation of aryl-, heteroaryl- and vinyltrifluoroborates with CF3 radicals generated from NaSO2CF3 and tert-butyl hydroperoxide (TBHP) is presented. The developed method produces trifluoromethyl arenes and -alkenes in good to excellent yields and a wide range of electronically and structurally diverse substrates are tolerated.