Direct Trifluoromethylation Research Articles

An electron donor-acceptor complex-initiated C-H trifluoromethylation and perfluoroalkylation of enamides and quinoxalinones.

Facilitated by an electron donor-acceptor (EDA) complex, an efficient β-trifluoromethylation and perfluoroalkylation of enamides with Togni reagent or perfluoroalkyl iodides is presented under transition-metal-free, photocatalyst-free and mild reaction conditions. Notably, using this photocatalyst-free strategy, direct trifluoromethylation and perfluoroalkylation of quinoxalin-2(1H)-one derivatives was also achieved via a photoactive electron donor-acceptor complex.

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.

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.

Using fluoroform in trifluoromethylation reactions

Fluoroform (CF3H), a large-volume industrial by-product and potent greenhouse gas, has emerged as an attractive CF3 source for the development of trifluoromethylation reagents and reactions. This article highlights the recent reports since 2017 on the use of fluoroform in organic synthesis. Topics include direct trifluoromethylation facilitated by organic and inorganic bases, preparation of trifluoromethylation reagents based on transition metals and borazine, and radiolabelled fluoroform.

Visible-Light-Promoted Direct Trifluoromethylation of Tryptophan-Containing Oligapeptides with YlideFluor

Visible-Light-Promoted Direct Trifluoromethylation of Tryptophan-Containing Oligapeptides with YlideFluor

A straightforward access to trifluoromethylated natural products through late-stage functionalization.

Covering: 2011 to 2021Trifluoromethyl (CF3)-modified natural products have attracted increasing interest due to their magical effect in binding affinity and/or drug metabolism and pharmacokinetic properties. However, the chemo and regioselective construction of natural products (NPs) bearing a CF3 group still remains a long-standing challenge due to the complex chemical scaffolds and diverse reactive sites of NPs. In recent years, the development of late-stage functionalization strategies, including metal catalysis, organocatalysis, light-driven reactions, and electrochemical synthesis, has paved the way for direct trifluoromethylation process. In this review, we summarize the applications of these strategies in the late-stage trifluoromethylation of natural products in the past ten years with particular emphasis on the reaction model of each method. We also discuss the challenges, limitations, and future prospects of this approach.

Electrolyte-free electrochemical C–H trifluoromethylation of 2-pyridones under batch and flow conditions

An environmentally friendly electrochemical process for the direct trifluoromethylation of 2-pyridones with a broad substrate scope has been developed.

Recent Advances in Direct C−H Trifluoromethylation of N‐Heterocycles

AbstractFluorine chemistry executes a vital role in the agricultural, pharmaceutical, and materials industries. Moreover, introducing fluorine atom and fluorine‐containing groups onto organic compounds can enhance the chemical and physical properties of the parent molecules. Because of this reason, researchers have been putting continuous efforts into developing newer and practical methodologies to incorporate fluorinated groups into organic molecules. Mainly, molecules bearing the trifluoromethyl (−CF3) group show various pharmacological and biological properties. The current review provides comprehensive coverage of the recent development on the direct trifluoromethylation of some essential N‐heterocycles involving CF3 radicals.

Microwave Assisted Cu-Mediated Trifluoromethylation of Pyrimidine Nucleosides.

Trifluoromethylated nucleosides, such as trifluridine, have widespread applications in pharmaceuticals as anticancer and antiviral agents. However, site-selective addition of a trifluoromethyl group onto a nucleobase typically requires either inconvenient multi-step synthesis or expensive trifluoromethylation reagents, or results in low yield. This article describes a simple, scalable, and high-yielding protocol for late-stage direct trifluoromethylation of pyrimidine nucleosides via a microwave-irradiated pathway. First, 5-iodo pyrimidine nucleosides undergo complete benzoylation to obtain N3 -benzoyl-3',5'-di-O-benzoyl-5-iodo-pyrimidine nucleosides as key precursors. Next, trifluoromethylation is carried out under both conventional and microwave heating using an inexpensive and commercially accessible Chen's reagent, i.e., methyl fluorosulfonyldifluoroacetate, to produce N3 -benzoyl-3',5'-di-Obenzoyl-5-trifluoromethyl-pyrimidine nucleosides. The microwave-assisted transformation accentuates its simplicity, mild reaction conditions, and dominance, providing a facile route to access trifluoromethylation. Finally, the envisioned 5-trifluoromethyl pyrimidine nucleosides are obtained by a routine debenzoylation procedure. This concludes a convenient three-step synthesis to obtain trifluridine and its 2'-modified analogs on a gram scale with consistently high yields, starting from their respective iodo-precursors, and requires only one chromatographic purification at the trifluoromethylation step. Furthermore, this operationally simple protocol can be utilized as a definitive methodology to produce various other trifluoromethylated therapeutics. © 2021 Wiley Periodicals LLC. Basic Protocol: Synthesis of 5-trifluoromethyl pyrimidine nucleosides 4a-c Alternate Protocol: Conventional trifluoromethylation: Synthesis of N3-benzoyl-3',5'-di-O-benzoyl-5-trifluoromethyl pyrimidine nucleosides (3a-c).

Synthesis of α-trifluoromethyl piperidine derivatives from tetrahydropyridines via nucleophilic trifluoromethylation of pyridinium cations

The synthesis of α-trifluoromethyl piperidines from tetrahydropyridine derivatives in three steps (the oxidation into the corresponding pyridinium, the nucleophilic trifluoromethylation and then, the hydrogenation) is described. The trifluoromethylation step occurs at the less hindered side of the pyridinium intermediate, with moderate-to-high regioselectivity. The method was also successfully applied to the direct trifluoromethylation of one piperidine derivative.

Direct Trifluoromethylation of Alcohols Using a Hypervalent Iodosulfoximine Reagent.

The direct trifluoromethylation of a variety of aliphatic alcohols using a hypervalent iodosulfoximine reagent afforded the corresponding ethers in moderate to good yields (14-72 %). Primary, secondary, and even tertiary alcohols, including examples derived from natural products, underwent this transformation in the presence of catalytic amounts of zinc bis(triflimide). Typical reaction conditions involved a neat mixture of 6.0 equivalents of the alcohol with 1.0 equivalent of the reagent, with the majority of reactions complete within 2 h with 2.5 mol % of the Lewis acid catalyst. Furthermore, experimental evidence was provided that the C-O bond-forming process occurred via the coordination of the alcohol to the iodine atom and subsequent reductive elimination.

Visible-light-promoted direct C3-trifluoromethylation and perfluoroalkylation of imidazopyridines.

An efficient method for direct trifluoromethylation and perfluoroalkylation at C3 of imidazopyridines through visible light-promoted C-H bond functionalization was developed. Under the irradiation of a blue LED, a series of C3-perfluoroalkyl-substituted imidazopyridines were synthesized from the corresponding imidazopyridines and perfluoroalkyl iodides in moderate to good yields at room temperature. It should be mentioned that this reaction proceeded in the absence of any transition-metal catalyst, oxidant and photocatalyst.

Metal-free electrochemical oxidative trifluoromethylation/C(sp2)[sbnd]H functionalization of quinolinones

Electrochemical direct trifluoromethylation of quinolinones was described under metal-free catalysis and oxidant-free conditions. A series of 2-aryl-3-trifluoromethylquinoline-4(1H)-ones were obtained in medium to good yield by using the method. By using butylated hydroxytoluene (BHT) as free radical blocker, adduct of BHT-CF3 was originally captured, which confirmed that the reaction was a free radical mechanism. Based on the results of capturing radical and cyclic voltammetry (CV), a reaction mechanism was proposed.

Mechanistic study of visible light-driven CdS or g-C3N4-catalyzed C[sbnd]H direct trifluoromethylation of (hetero)arenes using CF3SO2Na as the trifluoromethyl source

The mild and sustainable methods for CH direct trifluoromethylation of (hetero)arenes without any base or strong oxidants are in extremely high demand. Here, we report that the photo-generated electron-hole pairs of classical semiconductors (CdS or g-C3N4) under visible light excitation are effective to drive CH trifluoromethylation of (hetero)arenes with stable and inexpensive CF3SO2Na as the trifluoromethyl (TFM) source via radical pathway. Either CdS or g-C3N4 propagated reaction can efficiently transform CF3SO2Na to CF3 radical and further afford the desired benzotrifluoride derivatives in moderate to good yields. After visible light initiated photocatalytic process, the key elements (such as F, S and C) derived from the starting TFM source of CF3SO2Na exhibited differential chemical forms as compared to those in other oxidative reactions. The photogenerated electron was trapped by chemisorbed O2 on photocatalysts to form superoxide radical anion (O2−) which will further attack CF3 radical with the generation of inorganic product F− and CO2. This resulted in a low utilization efficiency of CF3 (<50%). When nitro aromatic compounds and CF3SO2Na served as the starting materials in inert atmosphere, the photoexcited electrons can be directed to reduce the nitro group to amino group rather than being trapped by O2. Meanwhile, the photogenerated holes oxidize SO2CF3− into CF3. Both the photogenerated electrons and holes were engaged in reductive and oxidative paths, respectively. The desired product, trifluoromethylated aniline, was obtained successfully via one-pot free-radical synthesis.

Selective Photoredox Trifluoromethylation of Tryptophan‐Containing Peptides

For application in drug discovery and biomedicine, it is crucial to develop new biocompatible methods to modify polypeptides. Herein, a visible‐light‐induced photoredox trifluoromethylation of tryptophan‐containing peptides is reported. Under a mild, biocompatible, and straightforward condition, this strategy could incorporate the trifluoromethyl group into tryptophan residue with excellent chemo‐ and site‐selectivity. The use of lower photocatalyst loading in 2 mol‐% and cheap CF3SO2Na salt represents a great catalytic activity and economic CF3 source. This direct trifluoromethylation strategy allows the ready study of fluorinated peptides exploiting 19F‐NMR. Additionally, the development of this protocol enables the study of biochemical systems and potentially modulates the function of biomolecules. Careful mechanistic studies (Stern‐Volmer fluorescence quenching, EPR, and radical inhibition/trapping experiments) indicate that the reaction would proceed with a radical–radical cross‐coupling procedure.

Phenyliodonium Diacetate Mediated Carbotrifluoromethylation of Quinoxalin‐2(1H)‐ones

AbstractAn efficient method for the synthesis of 3‐trifluoromethylquinoxalin‐2(1H)‐ones by a direct trifluoromethylation of quinoxalin‐2(1H)‐one derivatives has been developed under transition‐metal‐free conditions. The strategy uses cheap and commercially available PhI(OAc)2 as a promoter, TMSCF3 as a trifluoromethylation reagent in the presence of catalytic amount of benzoquinone to give the products in good yields.

Copper-Catalyzed Late-Stage Benzylic C(sp3)–H Trifluoromethylation

Summary Direct trifluoromethylation of C(sp3)–H bonds, especially in late stages, remains a formidable challenge. Herein, we describe the copper-catalyzed benzylic C(sp3)–H trifluoromethylation. With Cu(I) or Cu(II) as the catalyst, (bpy)Zn(CF3)2 (bpy = 2,2′-bipyridine) as the CF3 source, and NFSI (or Selectfluor) as the oxidant, site-selective benzylic C(sp3)–H trifluoromethylation is successfully implemented in high efficiency under mild conditions. The protocol not only exhibits broad substrate scope and wide functional-group compatibility but also allows efficient late-stage C(sp3)–H trifluoromethylation of natural products or drug derivatives.

Transition‐Metal‐Free Direct Trifluoromethylation and Perfluoroalkylation of Imidazopyridines under Mild Conditions

AbstractThe first transition‐metal‐free method for direct C−H trifluoromethylation of imidazo[1,2‐a]pyridine derivatives with readily available Ruppert‐Prakash reagent TMSCF3 under mild conditions was described. Moreover, this method could be applied to direct C−H perfluoroalkylation of imidazopyridines, affording a series of novel perfluoroalkylated products in moderate to good yields. Notable advantages of this protocol include easy operation, high‐efficiency and wide substrate scope.magnified image

Recent advances in direct trifluoromethylation of olefinic C-H bonds.

The aim of this review is to provide a comprehensive overview of the direct trifluoromethylation of olefinic C–H bonds with special attention on the mechanistic aspects of the reactions. The review is divided into two major sections. The first focuses exclusively on trifluoromethylation of terminal alkenes, while the second will cover trifluoromethylation of internal alkenes. Literature has been surveyed until the end of April 2019.

Metal‐free, Visible‐Light‐Mediated Direct Csp2−H Radical Mono‐ and Bis‐trifluoromethylation of Coumarins and Bioactivity Evaluation

AbstractA clean, transition metal‐ and oxidant‐free photochemical protocol was described for the direct trifluoromethylation of coumarins with Togni reagent. The reaction proceeded smoothly under mild condition to afford regioselective 3‐trifluoromethyl coumarins, moreover novel bis‐trifluoromethylated coumarins were formed. Preliminary bioactivity evaluation on some products showed potential antifungal activities.