Trifluoromethanesulfonamide vs. Non-Fluorinated Sulfonamides in Oxidative Sulfamidation of the C=C Bond: An In Silico Study.

A theoretical analysis of the reaction of oxidative sulfamidation of several alkenes was performed in order to explain the various experimental observations and different reactivity of triflamide and non-fluorinated sulfonamides. Transformations occurring in the system alkene-sulfonamide in the presence of oxidative system (ButOCl + NaI) were analyzed at the MP2/DGDZVP//B3LYP/DGDZVP level of theory using the IEF-PCM method for taking into account the solvent acetonitrile (MeCN) effect. As the model substrates, styrene, trimethyl(vinyl)silane, dimethyl(divinyl)silane and diphenyl(divinyl)silane were chosen and mesylamide, triflamide, tosylamide and p-nosylamide were taken as the reagents. ButOI generated from ButOCl and NaI reacts with sulfonamides to give N-iodinated sulfonamides RSO2NHI and RSO2NI2 as active intermediates, the iodinating activity of the latter being notably higher. The analysis allowed to answer such challenging questions as different reactivity of nonfluorinated sulfonamides leading to aziridination and of triflamide resulting in the formation the main products of bis-triflamidation, or different regioselectivity of halogenation of styrene and trimethyl(vinyl)silane caused by a linear intermediate iodonium cation in the former case and a cyclic one in the latter.

Rapid Syntheses of [11C]Arylvinyltrifluoromethanes through Treatment of (E)-Arylvinyl(phenyl)iodonium Tosylates with [11C]Trifluoromethylcopper(I).

We report a method for labeling arylvinyltrifluoromethanes with carbon-11 (t1/2 = 20.4 min) as representatives of a new radiolabeled chemotype that has potential for developing radiotracers for biomedical imaging with positron emission tomography. Treatment of (E)-arylvinyl(phenyl)iodonium tosylates (1a-1k) with [11C[CuCF3 gave the corresponding [11C]arylvinyltrifluoromethanes ([11C]2a-[11C]2k) in high radiochemical yields (90-97%) under rapid (2 min) and mild (60 °C) conditions.

18F-Trifluoromethanesulfinate Enables Direct C-H 18F-Trifluoromethylation of Native Aromatic Residues in Peptides.

18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride and its application to direct [18F]CF3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF218F)] enables in vivo positron emission tomography imaging.

Negative-ion/positive-ion coincidence spectroscopy as a tool to identify anionic fragments: The case of core-excited CHF3.

We have studied the dissociation of the trifluoromethane molecule, CHF3 , into negative ionic fragments at the C 1s and F 1s edges. The measurements were performed by detecting coincidences between negative and positive ions. We observed five different negative ions: F- , H- , C- , CF- , and F2 - . Their production was confirmed by the analysis of triple coincidence events (negative-ion/positive-ion/positive-ion or NIPIPI coincidences) that were recorded with cleaner signals than those of the negative-ion/positive-ion coincidences. The intensities of the most intense NIPIPI coincidence channels were recorded as a function of photon energy across the C 1s and F 1s excitations and ionization thresholds. We also observed dissociation channels involving the formation of one negative ion and three positive ions. Our results demonstrate that negative-ion/positive-ion coincidence spectroscopy is a very sensitive method to observe anions, which at inner-shell edges are up to three orders of magnitude less probable dissociation products than cations.

A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a Z-Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole.

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, Z-chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F3C-substituted alkene can also be prepared with similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, generating mycothiazole in 14.5% overall yield.

A Gas Phase Route to [18F]fluoroform with Limited Molar Activity Dilution.

Positron emission tomography (PET) is an important imaging modality for biomedical research and drug development. PET requires biochemically selective radiotracers to realize full potential. Fluorine-18 (t1/2 = 109.8 min) is a major radionuclide for labeling such radiotracers but is only readily available in high activities from cyclotrons as [18F]fluoride ion. [18F]fluoroform has emerged for labeling tracers in trifluoromethyl groups. Prior methods of [18F]fluoroform synthesis used difluoro precursors in solution and led to high dilution with carrier and low molar activity (Am). We explored a new approach for the synthesis of [18F]fluoroform based on the radiosynthesis of [18F]fluoromethane from [18F]fluoride ion and then cobaltIII fluoride mediated gas phase fluorination. We estimate that carrier dilution in this process is limited to about 3-fold and find that moderate to high Am values can be achieved. We show that [18F]fluoroform so produced is highly versatile for rapidly and efficiently labeling various chemotypes that carry trifluoromethyl groups, thereby expanding prospects for developing new PET radiotracers.

Feasibility of trifluoromethyl TROSY NMR at high magnetic fields.

Insights into the structure and dynamics of large biological systems has been greatly improved by two concurrent NMR approaches: the application of transverse relaxation-optimized spectroscopy (TROSY) techniques in multi-dimensional NMR, especially the methyl-TROSY, and the resurgence of 19F NMR using trifluoromethyl (CF3) probes. Herein we investigate the feasibility of combining these approaches into a trifluoromethyl-TROSY experiment. Using a CF3-labelled parvalbumin, we have evaluated the natural abundance 13C-19F correlation spectra and find no indication of a CF3 TROSY at high magnetic fields.

Catalytic Performance of Nitrogen-Doped Activated Carbon Supported Pd Catalyst for Hydrodechlorination of 2,4-Dichlorophenol or Chloropentafluoroethane.

Nitrogen-doped activated carbon (N-AC) obtained through the thermal treatment of a mixture of HNO3-pretreated activated carbon (AC) and urea under N2 atmosphere at 600 °C was used as the carrier of Pd catalyst for both liquid-phase hydrodechlorination of 2,4-dichlorophenol (2,4-DCP) and gas-phase hydrodechlorination of chloropentafluoroethane (R-115). The effects of nitrogen doping on the dispersion and stability of Pd, atomic ratio of Pd/Pd2+ on the surface of the catalyzer, the catalyst's hydrodechlorination activity, as well as the stability of N species in two different reaction systems were investigated. Our results suggest that, despite no improvement in the dispersion of Pd, nitrogen doping may significantly raise the atomic ratio of Pd/Pd2+ on the catalyst surface, with a value of 1.2 on Pd/AC but 2.2 on Pd/N-AC. Three types of N species, namely graphitic, pyridinic, and pyrrolic nitrogen, were observed on the surface of Pd/N-AC, and graphitic nitrogen was stable in both liquid-phase hydrodechlorination of 2,4-DCP and gas-phase hydrodechlorination of R-115, with pyridinic and pyrrolic nitrogen being unstable during gas-phase hydrodechlorination of R-115. As a result, the average size of Pd nanocrystals on Pd/N-AC was almost kept unchanged after liquid-phase hydrodechlorination of 2,4-DCP, whereas crystal growth of Pd was clearly observed on Pd/N-AC after gas-phase hydrodechlorination of R-115. The activity test revealed that Pd/N-AC exhibited a much better performance than Pd/AC in liquid-phase hydrodechlorination of 2,4-DCP, probably due to the enhanced stability of Pd exposed to the environment resulting from nitrogen doping as suggested by the higher atomic ratio of Pd/Pd2+ on the catalyst surface. In the gas-phase hydrodechlorination of R-115, however, a more rapid deactivation phenomenon occurred on Pd/N-AC than on Pd/AC despite a higher activity initially observed on Pd/N-AC, hinting that the stability of pyridinic and pyrrolic nitrogen plays an important role in the determination of catalytic performance of Pd/N-AC.

Redox-Active Reagents for Photocatalytic Generation of the OCF3 Radical and (Hetero)Aryl C-H Trifluoromethoxylation.

The trifluoromethoxy (OCF3 ) radical is of great importance in organic chemistry. Yet, the catalytic and selective generation of this radical at room temperature and pressure remains a longstanding challenge. Herein, the design and development of a redox-active cationic reagent (1) that enables the formation of the OCF3 radical in a controllable, selective, and catalytic fashion under visible-light photocatalytic conditions is reported. More importantly, the reagent allows catalytic, intermolecular C-H trifluoromethoxylation of a broad array of (hetero)arenes and biorelevant compounds. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1 resulting in exclusive liberation of the OCF3 radical. Addition of this radical to (hetero)arenes gives trifluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of trifluoromethoxylation.

Metallaphotoredox Difluoromethylation of Aryl Bromides.

Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl-radical-mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late-stage functionalization of several drug analogues.

Unexpected, Latent Radical Reaction of Methane Propagated by Trifluoromethyl Radicals.

Thorough mechanistic studies and DFT calculations revealed a background radical pathway latent in metal-catalyzed oxidation reactions of methane at low temperatures. Use of hydrogen peroxide with TFAA generated a trifluoromethyl radical (•CF3), which in turn reacted with methane gas to selectively yield acetic acid. It was found that the methyl carbon of the product was derived from methane, while the carbonyl carbon was derived from TFAA. Computational studies also support these findings, revealing the reaction cycle to be energetically favorable.

Simple and Clean Photoinduced Aromatic Trifluoromethylation Reaction.

We describe a simple, metal- and oxidant-free photochemical strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes under either ultraviolet or visible light irradiation. We demonstrated that photoexcited aliphatic ketones, such as acetone and diacetyl, can be used as promising low-cost radical initiators to generate CF3 radicals from sodium triflinate efficiently. The broad utility of this strategy and its benefit to medicinal chemistry are demonstrated by the direct trifluoromethylation of unprotected bidentate chelating ligand, xanthine alkaloids, nucleosides, and related antiviral drug molecules.

Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars: synthesis and glycosidase inhibition.

Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars have been synthesized from cyclic nitrones 12, 13, 18, ent-18 or 23 and nitrone-derived aldehydes 20 or ent-20. The fluorinated iminosugars were assayed against various glycosidases, and ent-8 showed moderate but selective α-l-rhamnosidase inhibition. Difluoro or trifluoro units influenced the inhibitory activities of iminosugars in a more complex manner than single fluoro substitution. This may be correlated with their highly hydrophobic character and strong electron-withdrawing effect.

Ultraviolet light triggers the conversion of Cu2+-bound Aß42 aggregates into cytotoxic species in a copper chelation-independent manner.

Increasing evidence indicates that abnormal Cu2+ binding to Aß peptides are responsible for the formation of soluble Aß oligomers and ROS that play essential roles in AD pathogenesis. During studying the Cu2+-chelating treatment of Cu2+-bound Aß42 aggregates, we found that UV light exposure pronouncedly enhances cytotoxicity of the chelator-treated and -untreated Cu2+-bound Aß42 aggregates. This stimulated us to thoroughly investigate (1) either the chelation treatment or UV light exposure leads to the increased cytotoxicity of the aggregates, and (2) why the chelator-treated and -untreated Cu2+-bound Aß42 aggregates exhibit the increased cytotoxicity following UV light exposure if the latter is the case. The data indicated that the controlled UV exposure induced the dissociation of Cu2+-free and -bound Aß42 aggregates into SDS-stable soluble oligomers and the production of ROS including H2O2 in an UV light intensity- and time-dependent, but Cu2+ chelation-independent manner. Although we can't fully understand the meaning of this finding at the current stage, the fact that the UV illuminated Aß42 aggregates can efficiently kill HeLa cells implies that the aggregates after UV light exposure could be used to decrease the viability of skin cancer cells through skin administration.

Addition of CFCl3 to Aromatic Aldehydes via in Situ Grignard Reaction.

Synthetic modification of trichlorofluoromethane (CFCl3) to non-volatile and useful fluorinated precursors is a cost-effective and an environmentally benign strategy for the safe consumption/destruction of the ozone depleting potential of the reagent. In this report, we present a novel method for in situ Grignard reaction using magnesium powder and CFCl3 for synthesis of dichlorofluoromethyl aromatic alcohols.

Copper-Promoted Trifluoromethanesulfonylation and Trifluoromethylation of Arenediazonium Tetrafluoroborates with NaSO2CF3.

A tunable chemoselective trifluoromethanesulfonylation and trifluoromethylation of arenediazonium tetrafluoroborates with Langlois' reagent (NaSO2CF3) was developed. The Cu2O-catalyzed reaction in DMSO gave aryl trifluoromethanesulfones as the major products. On the other hand, the trifluoromethylated arenes were produced in the presence of oxidant tert-butyl hydroperoxide, CuBF4(MeCN)4, and 2,2';6',2″-terpyridine (tpy). Both of these transformations proceed under mild conditions and tolerate functional groups.

Copper-Catalyzed Trifluoromethylazidation of Alkynes: Efficient Access to CF3-Substituted Azirines and Aziridines.

A novel method for convenient access to CF3-containing azirines has been developed, and involves a copper-catalyzed trifluoromethylazidation of alkynes and a photocatalyzed rearrangement. Both terminal and internal alkynes are compatible with the mild reaction conditions, thus delivering the CF3-containing azirines in moderate to good yields. The azirines can be converted into various CF3-substituted aziridines.

Copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols.

An efficient copper-catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni's reagent has been developed. This strategy, accompanied by a double-bond migration, leads to various branched CF3-substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which ß-H elimination is prohibited, CF3-containing oxetanes are isolated as the sole product.

Trifluoromethylation-initiated remote cross-coupling of carbonyl compounds to form carbon-heteroatom/carbon bonds.

By involving the reversal of conventional reactivity expectations without external oxidants, we describe a novel and convenient protocol of remote cross-coupling of carbonyl compounds with a series of common and simple nucleophiles. This cross-coupling is triggered by radical trifluoromethylation of alkenes, thereby achieving highly selective remote difunctionalization of alkenes and α-position of the carbonyl group for facile access to trifluoromethyl α-halo- and α-cyanocarbonyl compounds. The reaction exhibits a broad substrate scope with excellent functionality tolerance and many different types of nucleophiles; further synthetic applicability of the obtained compounds proved to be suitable, thus showing great potential for synthetic utility.

General synthesis of trifluoromethyl selenides utilizing selenocyanates and fluoroform.

Trifluoromethylated selenoethers are quite rare despite their potential and the interest that they generate. A series of trifluoromethylseleno derivatives, either primary and secondary aliphatic or aromatic and heterocyclic, is described herein by the reaction of easily prepared organic selenocyanates and CuCF3. Another beneficial feature of this reaction is the use of fluoroform as a source for the CF3 group, a compound whose chemistry is currently being intensively researched because it is a potent greenhouse gas that should not be released into the atmosphere.