Oxidative Trifluoromethylation Research Articles

On the Existence and Relevance of Copper(III) Fluorides in Oxidative Trifluoromethylation

AbstractNumerous reports invoke CuIII–F intermediates engaging in oxidative cross-couplings mediated by low/mid-valent copper and formal sources of ‘F+’ oxidants. These elusive and typically instable CuIII fluorides have been rarely characterized or spectroscopically identified, making their existence and participation within catalytic cycles somehow questionable. We have authenticated a stable organocopper(III) fluoride that undergoes Csp–CF3 bond formation upon addition of silyl-capped alkynes following a 2 e– CuIII/CuI redox shuttle. This finding strongly supports the intermediacy of CuIII fluorides in C–C coupling. We review herein the state of the art about well-defined CuIII fluorides enabling cross-coupling reactions.1 Introduction2 Brief History of Coupling-Competent CuIII Fluorides3 Design of an Isolable – yet Reactive – Organocopper(III) Fluoride4 Alkyne Trifluoromethylation: Scope and Mechanism5 Extension to Aryl–CF3 and C–Heteroatom Couplings6 Summary and Outlook

Copper‐Catalyzed Oxidative Trifluoromethylation of Aromatic Alkenes for the Synthesis of α‐Trifluoromethylated Ketones

AbstractA copper‐catalyzed oxidative trifluoromethylation of aromatic alkenes has been developed successfully, providing access to a variety of valuable α‐trifluoromethyl‐substituted ketones using Togni's reagent as the trifluoromethyl source. The use of affordable copper catalyst and readily available alkenes as the feedstock, broad substrate scope, mild conditions, and operational simplicity are the attractive features of the method. Preliminary mechanistic studies revealed that both dimethyl sulfoxide (DMSO) and air might function as the oxidant for the transformation.

Ball-milled prepared Fe3O4-FeSAs-NPs@NC catalyst synergistically facilitate the generation of reactive oxygen species for oxidative trifluoromethylation of alkenes

Heterogeneous catalysts have recently regarded as a promising chose for the thermally-driven generation of the reactive oxygen species (ROS) through catalytic reactions with molecular oxygen, which can facilitate this process by specific geometric and electronic structure. However, the oxidative trifluoromethylation of alkenes to α-trifluoromethylated ketones by CF3SO2Na is rarely reported in this system. In this work, we report a one-pot polymerization ball milling strategy to construct precursor, and then pyrolyze it to obtain specific carbon nanotubes matrix with Fe/Fe3O4 nanoparticles and single atoms Fe. Remarkably, the optimized catalyst (Fe3O4-FeSAs-NPs@NC-1) displays excellent catalytic performance, broad substrates and recyclability for this fluorination reaction via radical pathway. Based on characterizations and mechanistic studies, we discover that the coexistence of Fe/Fe3O4 and Fe-Nx not only synergistically facilitates the catalytic efficiency in altering the electronic structure of Fe sites, but also benefits the absorption of O2 and the ability of the thermally-driven generating ROS which can activate CF3SO2Na to CF3 radical. This work offers a method of designing Fe-based catalysts and also opens up a new thermal-heterogeneous catalysis way for the oxidative trifluoromethylation of alkenes.

Photoinduced Synthesis of 2-Trifluoromethylated Indoles through Oxidative Trifluoromethylation Using Langlois’ Reagent in the Absence of External Photocatalyst

AbstractA photoinduced approach for regioselective C-2 trifluoromethylation of indoles was achieved with CF3SO2Na under UV light irradiation (360–365 nm) at ambient conditions without any external photo activator. The key steps involve the in situ conversion of CF3SO2Na reagent to CF3 • radical under oxygen or air and UV irradiation. This proficient method has the advantages of mild reaction conditions, fair substrate tolerability, and gram scalability.

K2S2O8‐Glucose‐Mediated Metal‐Free Oxidative Trifluoromethylation of Indoles with Langlois’ Reagent on the C2 Position

AbstractAn efficient and regioselective trifluoromethylation method of indole at the C2 position with ecologically‐sound Langlois’ reagent (CF3SO2Na) under metal‐free conditions is described. K2S2O8 in presence of glucose at room temperature has been utilized for the generation of CF3 radicals from CF3SO2Na. The desired product can be obtained in good to excellent yields with a wide scope of substrate variability and gram scalability.

General Synthesis of N-Trifluoromethyl Compounds with N-Trifluoromethyl Hydroxylamine Reagents.

N-CF3 compounds constitute valuable targets in medicinal chemistry. Extensive studies have been reported for the preparation of N-CF3 compounds through fluorination and trifluoromethylation of N-containing compounds. The development of new synthetic methods from abundant and easily available substrates is highly desirable but still challenging. Herein, we report the design and synthesis of novel N-Cbz- and N-Boc-N-trifluoromethyl hydroxylamine reagents by silver-mediated oxidative trifluoromethylation. These reagents have been successfully applied to the direct incorporation of a NCF3 moiety into the commonly used unsaturated substrates under photoredox catalysis. This protocol enables the efficient and regioselective C-H trifluoromethylamination of various (hetero)arenes, including complex bioactive molecules. Furthermore, a variety of alkenes, dienes, and isonitriles undergo tandem trifluoromethylamination/functionalization delivering structurally diverse N-trifluoromethyl aliphatic and heteroaromatic amines. Notably, previously unknown cyclic N-CF3 compounds including N-CF3 oxazolidinones and oxazolones were conveniently prepared with N-Boc-N-trifluoromethyl hydroxylamine reagents. Furthermore, diversification of the resulting α-trifluoromethylamino ketones afforded the largely underexplored N-alkenyl- and N-alkynyl-N-CF3 compounds.

Cross-Coupling through Ag(I)/Ag(III) Redox Manifold.

In ample variety of transformations, the presence of silver as an additive or co-catalyst is believed to be innocuous for the efficiency of the operating metal catalyst. Even though Ag additives are required often as coupling partners, oxidants or halide scavengers, its role as a catalytically competent species is widely neglected in cross-coupling reactions. Most likely, this is due to the erroneously assumed incapacity of Ag to undergo 2e- redox steps. Definite proof is herein provided for the required elementary steps to accomplish the oxidative trifluoromethylation of arenes through AgI /AgIII redox catalysis (i. e. CEL coupling), namely: i) easy AgI /AgIII 2e- oxidation mediated by air; ii) bpy/phen ligation to AgIII ; iii) boron-to-AgIII aryl transfer; and iv) ulterior reductive elimination of benzotrifluorides from an [aryl-AgIII -CF3 ] fragment. More precisely, an ultimate entry and full characterization of organosilver(III) compounds [K]+ [AgIII (CF3 )4 ]- (K-1), [(bpy)AgIII (CF3 )3 ] (2) and [(phen)AgIII (CF3 )3 ] (3), is described. The utility of 3 in cross-coupling has been showcased unambiguously, and a large variety of arylboron compounds was trifluoromethylated via [AgIII (aryl)(CF3 )3 ]- intermediates. This work breaks with old stereotypes and misconceptions regarding the inability of Ag to undergo cross-coupling by itself.

Oxidative Trifluoromethylation of CF3SO2Na with Olefins Mediated by Diacetyl

Oxidative Trifluoromethylation of CF3SO2Na with Olefins Mediated by Diacetyl

Synthesis and Properties ofCF3(OCF3)CH‐SubstitutedArenes and Alkenes†

Summary of main observation and conclusionA silver‐mediated oxidative trifluoromethylation of easily accessible α‐trifluoromethyl alcohols with TMSCF3was developed to access novel CF3(OCF3)CH‐containing compounds. Deprotonation of CF3(OCF3)CH‐substituted arenes afforded synthetically useful CF3O‐substitutedgem‐difluoroalkenes. Furthermore, evaluation of the lipophilicities (logP) indicated that CH(OCF3)CF3is more lipophilic than the common fluorinated motifs such as CF3, OCF3, and SCF3, thus rendering the CH(OCF3)CF3motif appealing in drug discovery.

Copper-Catalyzed Oxidative Trifluoromethylation of Terminal Alkenes Using AgCF3.

A mild and convenient reaction for oxidative trifluoromethylation of terminal alkenes was developed using in situ generated AgCF3 in the presence of a copper catalyst. The reaction proceeded under an air atmosphere to afford trifluoromethylated allylic compounds in moderate to good yield. This reaction, with no need for highly hygroscopic or corrosive reagents, features not only a simple operation but also various functional group tolerances.

Cu(II)-Catalyzed Oxidative Trifluoromethylation of Indoles with KF as the Base

This paper offers an efficient copper-catalyzed oxidative trifluoromethylation of indoles with low-cost CF3SO2Na via C–H activation. Notably, the use of a base is crucial for the trifluoromethylation of indoles. This reaction proceeds efficiently in good to excellent yields and is tolerance of a broad range of functional groups. Furthermore, melatonin, a medicine for sleep disorders, is converted to its 2-CF3 analogue in 68% yield. Studies of possible reaction pathways suggest that this reaction proceeds through a radical process.

Copper-catalyzed remote C(sp3)\u2013H azidation and oxidative trifluoromethylation of benzohydrazides

The Hofmann-Löffler-Freytag (HLF) reaction is a prototypical example of radical-based remote functionalization of unactivated C(sp3)–H bond. While 1,5-hydrogen atom transfer (1,5-HAT) of the amidyl radical is thermodynamically favorable and is well-established, the method for the subsequent functionalization of the translocated carbon radical is still limited. We report herein two catalytic remote C(sp3)–H functionalization protocols. Cu(MeCN)4PF6-catalyzed reaction of 2-alkyl benzohydrazides 3 with TMSN3 in the presence of MeCO2OtBu affords the γ-azido amides 4, while CuCl-catalyzed reaction of 3 with Togni’s reagent provides 2-(β-trifluoromethylvinyl)benzamides 5 via an oxidative δ-trifluoromethylation of the alkyl group. Mechanistic studies suggest that the γ-azidation of benzohydrazides 3 goes through 1,5-HAT followed by a Cu-mediated azido transfer cascade, while the oxidative δ-trifluoromethylation of 3 proceeds via, after 1,5-HAT process, a radical-polar crossover mechanism.

Photoinduced synthesis of α-trifluoromethylated ketones through the oxidative trifluoromethylation of styrenes using CF3SO2Na as a trifluoromethyl reagent without an external photoredox catalyst

A photoinduced strategy to access α-CF3-substituted ketones by styrenes with sodium trifluoromethanesulfinate (CF3SO2Na) without an external photocatalyst was developed.

Multicomponent Oxidative Trifluoromethylation of Alkynes with Photoredox Catalysis: Synthesis of α-Trifluoromethyl Ketones.

The direct oxidative addition of CF3 and H2O to alkynes was achieved with photoredox catalysis to obtain α-trifluoromethyl ketones via rapid enol-keto tautomerization. The reaction exhibits high functional group tolerance and regioselectivity. Heterocycles of various sizes containing CF3 were synthesized from the α-CF3-substituted diketones obtained through the protocol, thereby demonstrating the versatile applicability of the method. Mechanistic studies of the reaction with isotopes provided insight into the reaction pathway.

Oxidative Trifluoromethylation of Alkynes with Fluoroform-Derived CuCF3

Oxidative Trifluoromethylation of Alkynes with Fluoroform-Derived CuCF3

ChemInform Abstract: Silver‐Mediated Oxidative Trifluoromethylation of Alcohols to Alkyl Trifluoromethyl Ethers.

AbstractThe practical method is efficiently applied to primary, secondary, and tertiary alcohols including natural products such as steroid, amino acid, and glucopyranose derivatives as well as complex pharmacologically relevant compounds.

Oxidative trifluoromethylation and fluoroolefination of unactivated olefins.

Fluorine-containing organic compounds are gaining increasing importance in medicinal chemistry. Described herein is a mild and efficient method for the radical addition of olefins with TMSCF3 and TMSCF2R (R = COOEt or CF3) to deliver various α-trifluoromethylated ketones and α-fluoroolefinated ketones.

ChemInform Abstract: Silver‐Mediated Oxidative Trifluoromethylation of Phenols: Direct Synthesis of Aryl Trifluoromethyl Ethers.

AbstractAg(I)‐mediated conversion of structurally diverse phenols to their CF3‐ethers is achieved using CF3‐SiMe3 as commercially available CF3‐nucleophile.

Silver-Mediated Oxidative Trifluoromethylation ofAlcohols to Alkyl Trifluoromethyl Ethers

Silver-Mediated Oxidative Trifluoromethylation ofAlcohols to Alkyl Trifluoromethyl Ethers

Silver-Mediated Oxidative Trifluoromethylation of Alcohols to Alkyl Trifluoromethyl Ethers.

The development of an efficient and practical method for the preparation of alkyl trifluoromethyl ethers is urgently demanding. The silver-mediated oxidative O-trifluoromethylation of primary, secondary, and tertiary alcohols with TMSCF3 under mild reaction conditions is established to provide a novel approach to a broad range of alkyl trifluoromethyl ethers. Further, this method is applied to the late-stage O-trifluoromethylation of complex natural products and prescribed pharmaceutical agents.