Trifluoromethylating Reagent Research Articles

Photocatalytic Regioselective Tandem Cyclization Protocol to Trifluoromethylated Pyrrolidones

A new environmentally friendly and efficient strategy for preparing trifluoromethylated pyrrolidones has been developed. The process involves using visible light to induce radical cyclization of 1,5‐dienes with CF3SO2Na, resulting in excellent regioselectivity. This method uses less expensive and easy‐to‐store trifluoromethylation reagents, making it an attractive option. Additionally, the resulting trifluoromethylated pyrrolidones can be easily modified and preliminary mechanistic studies have been presented.

A General Hydrotrifluoromethylation of Unactivated Olefins Enabled by Voltage-Gated Electrosynthesis.

Here we present the first successful hydrotrifluoromethylation of unactivated olefins under electrochemical conditions. Commercially available trifluoromethyl thianthrenium salt (TT+-CF3BF4-, Ep/2 = -0.85 V vs Fc/Fc+) undergoes electrochemical reduction to generate CF3 radicals which add to olefins with exclusive chemoselectivity. The resulting carbon centered radical undergoes a second cathodic reduction, instead of a classical HAT process, to generate a carbanion that can be terminated by protonation from solvent. The use of MgBr2 (+0.20 V onset oxidation potential) plays a key role as an enabling sacrificial reductant for the reaction to operate in an undivided cell. Guided by cyclic voltammetry (CV) studies, fine-tuning the solvent system, trifluoromethylating reagent's counteranion and careful selection of redox processes, this work led to the development of a voltage-gated electrosynthesis by pairing two redox processes with a narrow potential difference (ΔE ≈ 1.00 V) allowing the reaction to proceed with two important advances: (a) high reactivity and selectivity towards hydrotrifluoromethylation over undesired dibromination, and (b) an unprecedented functional group tolerance, including aniline, phenols, unprotected alcohol, epoxide, trialkyl amine, and several redox sensitive heterocycles.

Synthesis of β‐Trifluoromethylated Ketones by Photocatalyzed Deoxygenative Coupling of Aromatic Acids with α‐CF3‐Substituted Styrenes

Abstractα‐Trifluoromethyl alkenes are versatile CF3‐containing feedstocks. They have been widely used to construct gem‐difluoroalkene scaffolds through β−F elimination. The application of α−CF3 alkenes as trifluoromethylating reagents has been less explored. Herein, we report an efficient route for the synthesis of β‐trifluoromethylated ketones from readily accessed α−CF3 styrenes and aromatic carboxylic acids under photoredox catalysis. The reactions proceed by phosphoranyl radical promoted deoxygenation of aromatic acids, generating acyl radicals for subsequent hydroacylation of α−CF3 styrenes. The valuable trifluoromethyl‐containing compounds could be produced in good yields under mild conditions.

Making Full Use of TMSCF3: Deoxygenative Trifluoromethylation/Silylation of Amides.

As one of the most powerful trifluoromethylation reagents, (trifluoromethyl)trimethylsilane (TMSCF3) has been widely used for the synthesis of fluorine-containing molecules. However, to the best of our knowledge, the simultaneous incorporation of both TMS- and CF3- groups of this reagent onto the same carbon of the products has not been realized. Herein, we report an unprecedented SmI2/Sm promoted deoxygenative difunctionalization of amides with TMSCF3, in which both silyl and trifluoromethyl groups are incorporated into the final product, yielding α-silyl-α-trifluoromethyl amines with high efficiency. Notably, the silyl group could be further transformed into other functional groups, providing a new method for the synthesis of α-quaternary α-CF3-amines.

Efficient Trifluoromethylation of Halogenated Hydrocarbons Using Novel [(bpy)Cu(O2CCF2SO2F)2] Reagent.

This study introduces a novel trifluoromethylating reagent, [(bpy)Cu(O2CCF2SO2F)2], notable for not only its practical synthesis from cost-effective starting materials and scalability but also its nonhygroscopic nature. The reagent demonstrates high efficiency in facilitating trifluoromethylation reactions with various halogenated hydrocarbons, yielding products in good yields and exhibiting broad functional group compatibility. The development of [(bpy)Cu(O2CCF2SO2F)2] represents an advancement in the field of organic synthesis, potentially serving as a valuable addition to the arsenal of existing trifluoromethylating agents.

Reactivity of Electrophilic Trifluoromethylating Reagents

AbstractKinetics of the reactions of colored carbanions (reference nucleophiles) with S‐(trifluoromethyl)dibenzothiophenium ions (Umemoto's reagents) and hypervalent trifluoromethyl‐substituted iodine compounds (Togni's reagents) have been determined photometrically using stopped‐flow techniques. The second‐order rate constants k2(20 °C) for the reactions of Umemoto's sulfonium ions (generation I and II) with the reference nucleophiles in DMSO follow the correlation lg k2(20 °C)=sN(N+E) and can be used to determine the electrophilicity parameters E of these trifluoromethylating reagents. It is shown that the conditions reported for the reactions of Umemoto's generation I reagents with a variety of C‐nucleophiles are in line with the electrophilicity parameter E≈−13 determined for these reagents. Though Togni's hypervalent iodine‐based trifluoromethylation reagents do not follow this linear free energy relationship, the kinetics of their reactions with carbanions indicate that they cover the same reactivity range as Umemoto's generation I and II reagents.

Introducing Weakly Ligated Tris(trifluoromethyl)copper(III)

AbstractTris(trifluoromethyl)copper(III), Cu(CF3)3, was prepared for the first time and fully characterized in the form of weakly coordinated highly reactive solvent neutral adducts (DMF)2Cu(CF3)3 and (MeCN)Cu(CF3)3. Free Cu(CF3)3 is an elusive molecule of distorted T‐shaped geometry with Lewis acid properties, which is stabilized by solvation. Substitution of solvent molecules with monoanionic ligands in mild conditions afforded the first Cu(III)(CF3)3 carboxylates [Cu(CF3)3(OAc)]− and [Cu(CF3)3(OBz)]− and Cu(III) nitrito complex [Cu(CF3)3(ONO)]−. An improved synthesis of valuable Grushin's trifluoromethylation reagents via the intermediacy of (MeCN)Cu(CF3)3 was developed. (DMF)2Cu(CF3)3 demonstrated promising properties in photoinduced radical C‐H trifluoromethylation. Oxidation state theoretical studies showed the Cu(CF3)3 compounds to be borderline between classical Cu(III) and inverted ligand field Cu(I) assignment.

Photocatalytic Keto- and Amino-Trifluoromethylation of Alkenes.

Efforts to develop alternatives to triflic anhydride (Tf2O) as a trifluoromethylation reagent continue due to its limitations, including volatility, corrosiveness, and moisture sensitivity. Described herein is the use of a trifluoromethylsulfonylpyridinium salt (TFSP), easily obtained by a one-step reaction of Tf2O with 4-dimethylaminopyridine, as a reagent for the trifluoromethylative difunctionalization of alkenes by photoredox catalysis. DMSO and CH3CN are suitable solvents for achieving keto- and amino-trifluoromethylation of alkenes, respectively, with good functional group tolerance.

Photoredox Catalyzed Radical Fluoroalkylation with Non-Classical Fluorinated Reagents.

The emergence of photocatalysis has greatly advanced radical fluoroalkylation reactions. Central to this advancement is the introduction and refinement of radical reagents, which play a pivotal role in driving these reactions forward. Intriguingly, some of these reagents, previously not recognized for their radical properties, have emerged as key players in this area. In this Perspective, we provide an overview of four representative reagents pioneered by our laboratory, which have subsequently garnered extensive application in broader research contexts, including difluorocarbene precursors bromodifluoromethylphosphonium bromide, electrophilic sulfonylation reagent triflic anhydride, and nucleophilic trifluoromethylation reagent methyl fluorosulfonyldifluoroacetate (Chen's reagent). The integration of phosphonium reagents, triflic anhydride, and methyl fluorosulfonyldifluoroacetate into photocatalysis has enabled some unexpected reactivities and now notably expanded the capabilities in radical difluoromethylation, trifluoromethylation, and difluoroalkylation. Our discussion highlights how these atypical reagents have enriched the toolkit available for radical fluoroalkylations, offering insights that could inspire future research and application in this area.

Synthesis and Applications of Trifluoromethylphosphines

AbstractTrifluoromethylphosphines (TFMPhos) represent a rare kind of phosphine with unique electronic properties that result in unusual reactivities, such as the ability to promote a reductive elimination step or as a trifluoromethylation reagent. This concept article summarizes current developments in methods for synthesizing this tertiary phosphine, as well as their practical applications.

Synthesis of Organofluorine Compounds with Acylsilanes†

Comprehensive SummaryOrganofluorine compounds are central in synthetic chemistry, medicinal chemistry and material chemistry. In this review, we summarize the investigations on the synthesis of organofluorine compounds with acylsilanes. For the non‐fluorinated acylsilanes, the in situ generation of difluoroenoxysilanes from the reactions of the acylsilanes with trifluoromethylation reagents is the major pathway, leading to the facile preparation of various α,α‐difluoroketones. For the fluoroalkylacylsilanes, apart from the in situ generation of difluoroenoxysilanes through anion Brook rearrangement, radical Brook rearrangement of the photoexcited acylsilanes and the selective control of reactivities of the biradicals pave the way for the synthesis of a variety of organofluorine compounds. In general, most of these reactions gave racemic products, and the asymmetric synthesis of organofluorine compounds with acylsilanes is still rare, which would be a future direction of this field. Key ScientistsIn 1957, the first acylsilane compound, triphenylsilyl phenyl ketone was reported by Brook group. In 1991, Portella and coworkers reported the reaction of non‐fluorinated acylsilanes and perfluoroorganometallic reagents without Brook rearrangement, resulting in the formation of alcohols as the products. In 1992, Xu and coworkers carried out the first investigation on fluoroalkylacylsilanes for the preparation of difluoroenoxysilanes through anion Brook rearrangement. In 1994, Portella group reported the synthesis of difluoroenoxysilanes with non‐fluorinated acylsilanes and Ruppert‐Prakash reagent. In 2009, Otaka and coworkers reported a NHC‐mediated intramolecular redox reaction to prepare (Z)‐fluoroalkene dipeptide isosteres (FADIs) from γ,γ‐difluoro‐α,β‐ enoylsilane. Until 2022, the application of radical Brook rearrangement of fluoroalkylacylsilanes for the generation of fluoroalkylsiloxycarbenes was achieved by Shen group, enabling the synthesis of fluoroalkylated cyclopropenols. In 2022, Shen and coworkers successfully achieved the trapping of biradical intermediates generated from fluorine‐containing acylsilanes, leading to the facile preparation of fused gem‐difluorooxetanes. In the same year, Shen group reported the first asymetric reactions of fluoroalkylacylsilanes to prepare enantiomerically enriched fluoroalkyl alcohols and difluoroenoxysilanes.

Cobalt(II)-Catalyzed Selective Three-Component Oxyalkylation of N-Aryl Glycinates: A Route to CF3-Labeled Threonine Analogues.

Glycinates, protected enols, and an electrophilic trifluoromethylating reagent were employed to assemble CF3-labeled threonine analogues through a radical addition cascade. To suppress the competing oxidation of the oxyalkyl radical intermediate, various redox catalysts were evaluated and Co(II) exhibited supreme selectivity control with a proper counterion. A series of glycinate and related peptides were thus successfully modified under Co-catalysis. Mechanistic studies revealed that a N-aryl glycinate could be preferentially oxidized by cobalt over the oxyalkyl radical to generate an imine intermediate, and the key to this selectivity could be ascribed to the prechelation of glycinate, as well as a weakly basic carboxylate counterion.

Cooperative Photoredox and N-Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α-Trifluoromethyl-Substituted Ketones.

α-Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α-CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem-difluoroalkenes through cooperative photoredox and N-heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre-functionalization, thus enabling an efficient and general synthetic method to access α-CF3 -substituted ketones. A wide variety of gem-difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono- or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

Cooperative Photoredox and N‐Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α‐Trifluoromethyl‐Substituted Ketones

Abstractα‐Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α‐CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem‐difluoroalkenes through cooperative photoredox and N‐heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre‐functionalization, thus enabling an efficient and general synthetic method to access α‐CF3‐substituted ketones. A wide variety of gem‐difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono‐ or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

Catalytic C-H Trifluoromethylation of Arenes and Heteroarenes via Visible Light Photoexcitation of a Co(III)-CF3 Complex.

A cobalt photocatalyst for direct trifluoromethylation of (hetero)arene C(sp2)-H bonds is described and shown to operate via visible light activation of a Co-CF3 intermediate, which functions as a combined chromophore and organometallic reaction center. Chemical oxidations of previously reported (OCO)Co complexes containing a redox-active [OCO] pincer ligand afford a Co-CF3 complex two oxidation states above Co(II). Computational and spectroscopic studies are consistent with formulation of the product as [(OCO•)CoIII(CF3)(THF)(OTf)] (II) containing an open-shell [OCO•]1- radical ligand bound to a S = 0 Co(III) center. II is thermodynamically stable, but exposure to blue (440 nm) light induces Co-CF3 bond homolysis and release of •CF3, which is trapped by radical acceptors including TEMPO•, (hetero)arenes, or the radical [OCO•] ligand in II. The latter comprises a competitive degradation pathway, which is overcome under catalytic conditions by using excess substrate. Accordingly, generation of II from the reaction of [(OCO)CoIIL] (III) (L = THF, MeCN) with Umemoto's dibenzothiophenium trifluoromethylating reagent (1) followed by photolytic Co-CF3 bond activation completes a photoredox catalytic cycle for C-H (hetero)arene trifluoromethylation utilizing visible light. Electronic structure and photophysical studies, including time-dependent density functional theory (TDDFT) calculations, suggest that Co-CF3 bond homolysis at II occurs via an ligand-to-metal charge-transfer (LMCT) (OCO0)CoII(CF3) state, revealing ligand redox activity as a critical design feature and establishing design principles for the use of base metal chromophores for selectivity in photoredox bond activations occurring via free radical intermediates.

Current State of Microflow Trifluoromethylation Reactions.

The trifluoromethyl group is a powerful structural motif in drugs and polymers; thus, developing trifluoromethylation reactions is an important area of research in organic chemistry. Over the past few decades, significant progress has been made in developing new methods for the trifluoromethylation of organic molecules, ranging from nucleophilic and electrophilic approaches to transition-metal catalysis, photocatalysis, and electrolytic reactions. While these reactions were initially developed in batch systems, more recent microflow versions are highly attractive for industrial applications owing to their scalability, safety, and time efficiency. In this review, we discuss the current state of microflow trifluoromethylation. Approaches for microflow trifluoromethylation based on different trifluoromethylation reagents are described, including continuous flow, flow photochemical, microfluidic electrochemical reactions, and large-scale microflow reactions.

Ex-situ generation and synthetic utilization of bare trifluoromethyl anion in flow via rapid biphasic mixing

Fluoroform (CF3H) is the simplest reagent for nucleophilic trifluoromethylation intermediated by trifluoromethyl anion (CF3–). However, it has been well-known that CF3– should be generated in presence of a stabilizer or reaction partner (in-situ method) due to its short lifetime, which results in the fundamental limitation on its synthetic utilization. We herein report a bare CF3– can be ex-situ generated and directly used for the synthesis of diverse trifluoromethylated compounds in a devised flow dissolver for rapid biphasic mixing of gaseous CF3H and liquid reagents that was designed and structurally optimized by computational fluid dynamics (CFD). In flow, various substrates including multi-functional compounds were chemoselectively reacted with CF3–, extending to the multi-gram-scale synthesis of valuable compounds by 1-hour operation of the integrated flow system.

N-Trifluoromethyl Succinimide as a New Reagent for Direct C-H Trifluoromethylation of Free Anilines.

N-trifluoromethylsuccinimide (NTFS) as a new trifluoromethylation reagent was designed and prepared via Ag-CF3 , and applied to the direct trifluoromethylation of free aniline, and a series of trifluoromethyl products were obtained with good yields. The practicability of the protocol was verified by a gram-level experiment and the synthesis of the antiasthmatic drug Mabuterol. In addition, a possible radical mechanism was proposed and verified by related experiments. The protocol provided a new solution for C-H trifluoromethylation of free anilines.

Visible-Light-Mediated Deacylated Alkynylation of Unstrained Ketone.

Deconstructive alkynylation of an unstrained ketone catalyzed by an organic photocatalyst under blue light irradiation is reported for the first time. A broad substrate scope with up to 63 examples, excellent functional group tolerance, and gram scale reaction demonstrated the practicality of this novel alkynylation method. The dihydroquinazolinone derivative of trifluoroacetophenone had been proved to have potential as a novel trifluoromethylation reagent after working well for the trifluoromethylation reaction with various alkynyl bromides.

Catalyst-free direct C[sbnd]H trifluoromethylation of indoles with Togni’s reagent

In the present study, we report the catalyst-free direct CH trifluoromethylation of electron-rich indoles in MeOH at 50 °C using Togni’s reagent II as a trifluoromethylation reagent, affording the desired trifluoromethylated compounds in good yields. Furthermore, this new method is demonstrated to be useful for the trifluoromethylation of bioactive molecules melatonin and zolmitriptan, indicating its application in late-stage trifluoromethylation.