Metal-Free Oxidative Trifluoromethylthiolation of Terminal Alkynes with CF(3)SiMe(3) and Elemental Sulfur

A metal-free oxidative trifluoromethyl-thiolation of terminal alkynes using readily available CF(3)SiMe(3) and elemental sulfur at room temperature has been developed. This reaction provides an efficient and convenient method for the preparation of alkynyl trifluoromethyl sulfides bearing a wide range of functional groups. Preliminary investigation revealed that elemental sulfur instead of air acted as the oxidant.     

Synthesis of 2-amino-5-chloro-3-(trifluoromethyl)benzenethiol and conversion into 4H-1,4-benzothiazines and their sulfones

The synthesis of 2-amino-5-chloro-3-(trifluoromethyl)benzenethiol was achieved by hydrolytic cleavage of 2-amino-6-chloro-4-(trifluoromethyl)benzothiazole which was prepared by cyclization of 4-chloro-2-(trifluoromethyl)phenylthiourea by bromine in chloroform, the phenylthiourea was prepared by the reaction of 4-chloro-2-(trifluoromethyl)aniline with ammonium thiocyanate in hydrochloric acid. Condensation and oxidative cyclization of 2-amino-5-chloro-3-(trifluoromethyl)benzenethiol with β-diketones/β-ketoesters provided 4H-1,4-benzothiazines. Fluorinated sulfones were obtained by oxidation of the corresponding benzothiazines with 30% hydrogen peroxide in glacial acetic acid. The structures of the newly synthesized compounds were confirmed by spectral studies.     

2-Aryl-6-Polyfluoroalkyl-4-Pyrones as Promising RF-Building-Blocks: Synthesis and Application for Construction of Fluorinated Azaheterocycles

A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of one-pot oxidative cyclization of (E)-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehydrobromination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were characterized. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of biologically important CF₃-bearing azaheterocycles, such as pyrazoles, pyridones, and triazoles.     

Synthesis of 2-(trifluoromethyl)oxazoles from β-monosubstituted enamines via PhI(OCOCF3)2-mediated trifluoroacetoxylation and cyclization

Treatment of β-monosubstituted enamines with phenyliodine bis(trifluoroacetate) (PIFA) was found to give a variety of 4,5-disubstituted 2-(trifluoromethyl)oxazoles. This approach allows the incorporation of the trifluoromethyl moiety in PIFA into the final products, which presumably takes place via the oxidative β-trifluoroacetoxylation of the enamine substrates followed by subsequent intramolecular cyclization.     

Nickel-Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper- and palladium-mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel-mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF₃). The strategy relies on PMe₃-promoted oxidative addition and transmetalation, and CCl₃CN-induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.     

Pentakis(trifluoromethyl)phenyl, a sterically crowded and electron-withdrawing group: synthesis and acidity of pentakis(trifluoromethyl)benzene, -toluene, -phenol, and -aniline

A general route to functionalized pentakis(trifluoromethyl)phenyl (C6(CF3)5) derivatives, promising building blocks for designing novel stable carbenes, radical species, superacids, weakly coordinating anions and other practically and theoretically useful species, is presented. This pertrifluoromethylation route proceeds via conveniently pregenerated (trifluoromethyl)copper (CF3Cu) species in DMF, stabilized by addition of 1,3-dimethyl-2-imidazolidinone (DMI). These species react with hexaiodobenzene at ambient temperature to give the potassium pentakis(trifluoromethyl)phenoxide along with hexakis(trifluoromethyl)benzene and pentakis(trifluoromethyl)benzene in a combined yield of 80%. A possible reaction pathway explaining the formation of pentakis(trifluoromethyl)phenoxide is proposed. Pentakis(trifluoromethyl)phenol gives rise to easily functionalized pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)aniline. Pertrifluoromethylation of pentaiodochlorobenzene and pentaiodotoluene allows straightforward access to pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)toluene, respectively. XRD structures of several C6(CF3)5 derivatives were determined and compared with the calculated structures. Due to the steric crowding the aromatic rings in all C6(CF3)5 derivatives are significantly distorted. The gas-phase acidities (Delta Gacid) and pKa values in different solvents (acetonitrile (AN), DMSO, water) for the title compounds and a number of related compounds have been measured. The origin of the acidifying effect of the C6(CF3)5 group has been explored using the isodesmic reactions approach.     

Nickel‐Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper‐ and palladium‐mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel‐mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF₃). The strategy relies on PMe₃‐promoted oxidative addition and transmetalation, and CCl₃CN‐induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.     

Silver‐Promoted Oxidative Benzylic C−H Trifluoromethoxylation

A silver‐promoted oxidative benzylic C?H trifluoromethoxylation has been reported for the first time. With trifluoromethyl arylsulfonate as the trifluoromethoxylation reagent, various arenes, having diverse functional groups, undergo trifluoromethoxylation of their benzylic C?H bonds to form trifluoromethyl ethers under mild reaction conditions. In addition, the trifluoromethoxylation and the fluorination of methyl groups of electron‐rich arenes have been achieved to prepare α‐fluorobenzyl trifluoromethyl ethers in one step.     

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

Aryl trifluoromethyl ethers (ArOCF₃) are prevalent in pharmaceuticals, agrochemicals, and materials. However, methods for the general and efficient synthesis of these compounds are extremely underdeveloped and limited. Herein, we describe a highly efficient and general procedure for the direct O‐trifluoromethylation of unprotected phenols through a silver‐mediated cross‐coupling reaction using CF₃SiMe₃ as the CF₃ source and exogenous oxidants. This novel oxidative trifluoromethylation provides access to a wide range of aryl trifluoromethyl ethers from simple phenols. The mild process was also applied to the late‐stage trifluoromethylation of a medicinally relevant compound.     

How trimethyl(trifluoromethyl)silane reacts with itself in the presence of naked fluoride--a one-pot synthesis of bis([15]crown-5)cesium 1,1,1,3,5,5,5-heptafluoro-2,4-bis(trifluoromethyl)pentenide

Reactions of trimethyl(trifluoromethyl)silane in the presence of "naked" fluoride proceed up to a temperature of +5 degrees C mainly with formation of [Me3Si(CF3)2]-. A further rise of temperature up to about 20 degrees C gives evidence for the formation of a salt with the 1,1,1,2,3,6,6,6-octafluoro-2,4,4,5,5-pentakis(trifluoromethyl)hexan-3-ide anion. This intermediate decomposes at room temperature into the 1,1,1,3,5,5,5-heptafluoro-2,4-bis(trifluoromethyl)pentenide anion. The bis([15]crown-5)cesium salt, [Cs([15]crown-5)2][(CF3)2CCFC(CF3)2] has been characterized unambiguously as the stable final product of this reaction sequence. Thermal decomposition of this salt opens a convenient nontoxic route to obtain 1,1,3,3-tetrakis(trifluoromethyl)allene, (F3C)2C=C=C(CF3)2.     

Iron(II)‐Catalyzed Direct Cyanation of Arenes with Aryl(cyano)iodonium Triflates

A direct oxidative cyanation of arenes under Fe^II catalysis with 3,5‐di(trifluoromethyl)phenyl(cyano)iodonium triflate (DFCT) as the cyanating agent has been developed. The reaction is applicable to wide range of aromatic substrates, including polycyclic structures and heteroaromatic compounds.     

Me3SiCF3/AgF/Cu—A new reagents combination for selective trifluoromethylation of various organic halides by trifluoromethylcopper,CuCF3

An alternative copper halide-free route to obtain highly reactive trifluoromethylcopper species has been developed via the reaction of silver fluoride and trimethyl(trifluoromethyl)silane followed by a redox transmetallation with elemental copper. The composition of the reactive intermediate was investigated by means of UV/Vis/NIR, ESR, ¹⁹F NMR spectroscopy and ESI mass spectrometry. “Trifluoromethylcopper” prepared by the oxidative transmetallation route exhibits excellent reactivity and selectivity in substitutions of iodine or bromine bond to aromatic or heterocyclic compounds for trifluoromethyl groups without any additional catalyst.     

Oxidative addition of substituted arsines and stibines with bis(trifluoromethyl)nitroxyl

Reactions of bis(trifluoromethyl)nitroxyl with a number of methyl- and trifluoromethyl- substituted arsines and stibines at room temperature lead to the formation of pentavalent arsenic and antimony derivatives, namely (CH₃)_3?n(CF₃)_nM[ON(CF₃)₂]₂ (M = As, n = 0, 1, 2; M = Sb, n = 0, 1). The derivatives yield bis(trifluoromethyl)- hydroxylamine and the corresponding dichlorides on treatment with hydrogen chloride. A free radical mechanism is proposed for the oxidative addition reactions.     

Ruthenium-catalyzed regio- and stereoselective addition of carboxylic acids to aryl and trifluoromethyl group substituted unsymmetrical internal alkynes

The regio- and stereoselective addition of carboxylic acids to aryl and trifluoromethyl group substituted unsymmetrical internal alkynes has been accomplished: the Ru(3)(CO)(12)/3PPh(3) catalyst system has effectively catalyzed the reaction to afford the trifluoromethyl group substituted (E)-enol esters with high regio- and stereoselectivities.     

An efficient method to access 2-fluoroalkylbenzimidazoles by PIDA oxidation of amidines

A mild and practical strategy for the synthesis of 2-bromodifluoromethyl (or trifluoromethyl)-1H-benzimidazoles via PIDA-mediated oxidative intramolecular cyclization of the fluorinated amidines is described. The approach has the advantages of superior yields, excellent functional groups tolerance and mild reaction conditions.     

Second Comes First: Switching Elementary Steps in Palladium-Catalyzed Cross-Coupling Reactions

The electron-poor palladium(0) complex L₃Pd (L=tris[3,5-bis(trifluoromethyl)phenyl]phosphine) reacts with Grignard reagents RMgX and organolithium compounds RLi via transmetalation to furnish the anionic organopalladates [L₂PdR]⁻, as shown by negative-ion mode electrospray-ionization mass spectrometry. These palladates undergo oxidative additions of organyl halides R′X (or related S_N2-type reactions) followed by further transmetalation. Gas-phase fragmentation of the resulting heteroleptic palladate(II) complexes results in the reductive elimination of the cross-coupling products RR′. This reaction sequence corresponds to a catalytic cycle, in which the order of the elementary steps of transmetalation and oxidative addition is switched relative to that of palladium-catalyzed cross-coupling reactions proceeding via neutral intermediates. An attractive feature of the palladate-based catalytic system is its ability to mediate challenging alkyl–alkyl coupling reactions. However, the poor stability of the phosphine ligand L against decomposition reactions has so far prevented its successful use in practical applications.     

Regioselective synthesis and characterization of new 3‐aryl‐7‐trifluoromethyl‐[1,2,4]triazolo[4,3–a]pyrimidines

The regioselective synthesis and characterization of a new series of 3‐aryl‐7‐trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines from the oxidative heterocyclization of 2‐(N′‐benzylidenehydrazino)‐4‐trifluoromethylpyrimidines with copper dichloride is described. J. Heterocyclic Chem., (2011).     

Fluorocarbon polymers with alternating oxyalkylene and oxysilylene units

Linear polymers were prepared by the condensation of bis(dimethylamino)dimethylsilane and 1,4-bis(dimethylaminodimethylsily)benzene with fluorocarbon diols. 1,5-Dihydroxy-3-methyl-1,1,5,5-tetrakis(trifluoromethyl)-2-pentene, the cis addition product of hexafluoroacetone and isobutylene, with the silylbenzene monomer gave a polymer that cured at room temperature to a rubber exhibiting a glass transition temperature of 0°C, low swelling in hydrocarbons, and excellent resistance to hydrolytic, oxidative, and thermal degradation, retaining its flexibility after exposure to air for 3 hr at 305°C. The polymers obtained by condensing 1,5-dihydroxy-1,1,5,5-tetrakis(trifluoromethyl)-2-pentene, the trans addition product of hexafluoroacetone and propylene, with the silylbenzene and the silane monomers had glass transition temperatures of ?12 and ?50°C respectively, and greater resistance to swelling in hydrocarbons.     

Synthesis of fluorinated cyclic s-trans vinylogous acid and amide ester derivatives

A two-step procedure for the preparation of ethyl 4-amino-2-oxo-6-(trifluoromethyl)cyclohex-3-ene-1-carboxylate (enaminone) and methyl 4-hydroxy-2-oxo-6-(trifluoromethyl)cyclohex-3-ene-1-carboxylate (vinylogous acid) has been accomplished, using reactive Michael acceptors under basic condition. In addition, acyclic trifluoromethylated ester derivatives were isolated as competing by-products. The above compounds represent novel synthetically useful trifluoromethyl building blocks.     

Low dielectric constant polyimide nanomats by electrospinning

The proper combination of material (i.e. fluorinated polyimides) and processing technique (electrospinning) could lead to the formation of polyimides with low dielectric constant, high thermo‐oxidative stability and glass transition temperature, and high hydrophobicity. The polyimides in this work were based on 4, 4‐bis [3′‐trifluoromethyl‐4′ (4′‐amino benzoxy) benzyl] biphenyl (Q) and various fluorinated and non‐fluorinated dianhydrides namely benzene‐1,2,4,5‐tetracarboxylic dianhydride, 3,3′,4,4′‐biphenyltetracarboxylic dianhydride, benzophenone‐3,3′,4,4′‐tetracarboxylic dianhydride, and 4,4′‐(hexafluoroisopropylidene)diphthalic anhydride (6FDA). Processing of the polyimides was carried out in poly(amic acid) stage by two different methods—electrospinning and solution casting for comparison purposes. The processing of polyimides by electrospinning led to enhancement in mechanical properties (dianhydride‐structure dependent) and hydrophobicity without sacrificing thermo‐oxidative stability and glass transition temperatures significantly. Also, low dielectric constants (as low as 1.43) could be attained by suitable combination of dianhydride (6FDA) with 4, 4‐bis [3′‐trifluoromethyl‐4′ (4′‐amino benzoxy) benzyl] biphenyl diamine. Copyright © 2011 John Wiley & Sons, Ltd.