Cs2CO3-catalyzed alkylation of indoles with trifluoromethyl ketones

A Cs₂CO₃-catalyzed alkylation reaction of indoles with trifluoromethyl ketones was presented. Both alicyclic and aromatic trifluoromethyl ketones as well as various substituted indoles are compatible with the methodology. Good to excellent yields of the corresponding trifluoromethyl substituted tertiary alcohols 2,2,2-tritrifluoro-1-(1H-indol-3-yl)-ethan-1-ols were acquired as the sole products.     

Exchange reactions between O-nitrosobis(trifluoromethyl)hydroxylamine and M(CF3)3 (M = P,As and Sb)

O-Nitrosobis(trifluoromethyl)hydroxylamine gives novel reactions with tris(trifluoromethyl)-phosphine, -arsine and -stibine to affford mainly the corresponding bis(trifluoromethyl)nitroxol derivatives. Tris(trifluoromethyl) phosphine affords (CF₃)₂NOP(O)(CF₃)₂ and (CF₃)₂NNO. Tris(trifluoromethyl) arsine also gives (CF₃)₂NNO in high yield, together with smaller amounts of (CF₃)₂NOAs(CF₃)₂, CF₃NCF₂, COF₂ and a polymeric white solid. With tris(trifluoromethyl)stibine, no oxidation nor addition reactions occurred. Instead, [(CF₃)₂NO]₃Sb and [(CF₃)NO]₂SbCF₃ were obtained in high yields. The stoichiometry of the reactions suggests that the additional amounts of bis(trifluoromethyl)nitroxyl groups bonded to antimony are derived from the trifluoromethyl groups bonded to antimony. Mechanisms to rationalise these reactions are proposed.     

Conformational studies on heteroleptic trifluoromethyl‐substituted phenylboranes

Organoboranes carrying electron‐withdrawing substituents are commonly used as Lewis acidic catalysts or cocatalysts in a variety of organic processes. These Lewis acids also became popular through their application in `frustrated Lewis pairs', i.e. combinations of Lewis acids and bases that are unable to fully neutralize each other due to steric or electronic effects. We have determined the crystal and molecular structures of four heteroleptic arylboranes carrying 2‐(trifluoromethyl)phenyl, 2,6‐bis(trifluoromethyl)phenyl, 3,5‐bis(trifluoromethyl)phenyl or mesityl substituents. [3,5‐Bis(trifluoromethyl)phenyl]bis[2‐(trifluoromethyl)phenyl]borane, C₂₂H₁₁BF₁₂, (I), crystallizes with two molecules in the asymmetric unit which show very similar geometric parameters. In one of the two molecules, both trifluoromethyl groups of the 3,5‐bis(trifluoromethyl)phenyl substituent are disordered over two positions. In [3,5‐bis(trifluoromethyl)phenyl]bis[2,6‐bis(trifluoromethyl)phenyl]borane, C₂₄H₉BF₁₈, (II), only one of the two meta‐trifluoromethyl groups is disordered. In [2,6‐bis(trifluoromethyl)phenyl]bis[3,5‐bis(trifluoromethyl)phenyl]borane, C₂₄H₉BF₁₈, (III), both meta‐trifluoromethyl groups of only one 3,5‐bis(trifluoromethyl)phenyl ring are disordered. [3,5‐Bis(trifluoromethyl)phenyl]dimesitylborane, C₂₆H₂₅BF₆, (IV), carries only one meta‐trifluoromethyl‐substituted phenyl ring, with one of the two trifluoromethyl groups disordered over two positions. In addition to compounds (I)–(IV), the structure of bis[2,6‐bis(trifluoromethyl)phenyl]fluoroborane, C₁₆H₆BF₁₃, (V), is presented. None of the ortho‐trifluoromethyl groups is disordered in any of the five compounds. In all the structures, the boron centre is in a trigonal planar coordination. Nevertheless, the bond angles around this atom vary according to the bulkiness and mutual repulsion of the substituents of the phenyl rings. Also, the ortho‐trifluoromethyl‐substituted phenyl rings usually show longer B—C bonds and tend to be tilted out of the BC₃ plane by a higher degree than the phenyl rings carrying ortho H atoms. A comparison with related structures corroborates the conclusions regarding the geometric parameters of the boron centre drawn from the five structures in this paper. On the other hand, CF₃ groups in meta positions do not seem to have a marked effect on the geometry involving the boron centre. Furthermore, it has been observed for the structures reported here and those reported previously that for CF₃ groups in ortho positions of the aromatic ring, disorder of the F atoms is less probable than for CF₃ groups in meta or para positions of the ring.     

PhI(OAc)2‐Mediated Radical Trifluoromethylation of Vinyl Azides with Me3SiCF3

The fluorine‐containing organic motif is becoming privileged in pharmaceuticals, agrochemicals, and functional materials, owing to its unique properties such as electron‐withdrawing character, metabolic stability, and lipophilicity. Described herein is the PhI(OAc)₂‐mediated radical trifluoromethylation of vinyl azides with Me₃SiCF₃ to efficiently generate α‐trifluoromethyl azines. The resulting α‐trifluoromethyl azines were successfully transformed to valuable fluorine‐containing molecules such as α‐trifluoromethyl ketones, β‐trifluoromethyl amines, 5‐fluoropyrazoles, and trifluoroethyl isoquinolines.     

An unexpected reaction between perfluoroisobutylene,caesium fluoride and haloforms

(CF₃)₂ CCF₂ reacts with CHCl, CHBr₃ and CHI₃ in the presence of CsF in diglyme, giving 3,3 - difluoro - 2 - halogeno - 4,4,5,5 - tetrakis(trifluoromethyl)cyclopent - 1 - enes. In the case of CHCl₃ the intermediate is shown to be 1,1 - dichloro - 3,3 - bis - (trifluoromethyl)allene (identified as an adduct with furan). 3,3 - Difluoro - 2 - chloro - 4,4,5,5 - tetrakis(trifluoromethyl)cyclopent - 1 - ene eliminates HCI under the action of CsF, giving a trimer of 3,3 - difluoro - 4,4,5,5 - tetrakis(trifluoromethyl)cyclopent - 1 - yne, namely, perfluorocarbon C₂₇F₄₂ (a Dewar benzene derivative).     

From C1 to C3: Copper-Catalyzed gem-Bis(trifluoromethyl)olefination of α-Diazo Esters with TMSCF3

A Cu-catalyzed gem-bis(trifluoromethyl)olefination of α-diazo esters, using TMSCF₃ as the only fluorocarbon source, has been developed and provides an exquisite method to access gem-bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into “CuCF₃” to generate the α-CF₃-substituted organocopper species, which then undergoes β-fluoride elimination and two consecutive addition-elimination processes to give the desired products. The key to this efficient one-pot C₁-to-C₃ synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem-difluoroalkene intermediates.     

From C1 to C3: Copper‐Catalyzed gem‐Bis(trifluoromethyl)olefination of α‐Diazo Esters with TMSCF3

A Cu‐catalyzed gem‐bis(trifluoromethyl)olefination of α‐diazo esters, using TMSCF₃ as the only fluorocarbon source, has been developed and provides an exquisite method to access gem‐bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into “CuCF₃” to generate the α‐CF₃‐substituted organocopper species, which then undergoes β‐fluoride elimination and two consecutive addition‐elimination processes to give the desired products. The key to this efficient one‐pot C₁‐to‐C₃ synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem‐difluoroalkene intermediates.     

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.     

POCl3-mediated synthesis of hydrolysis-prone 2-trifluoroethylbenzimidazoles

Loss of a trifluoromethyl group has been observed as an unproductive side reaction in the formation of 2-trifluoroethylbenzimidazoles. A hydrolytic mechanism for this transformation is proposed that is consistent with evidence for the identity of reaction intermediates. Cyclodehydration with POCl₃ suppresses hydrolysis of the trifluoromethyl group and provides 2-trifluoroethylbenzimidazoles in good yields.     

Fluor(trifluormethyl)disulfan

Fluoro(trifluoromethyl)disulfane Fluoro(trifluoromethyl)disulfane results from the reaction of gaseous chloro(trifluoromethyl)disulfane with active potassium fluoride. The new compound could be characterized by NMR, IR and mass spectra and by its volatility. A new synthesis for CF₃SSCl is reported.     

The structures of 1,4‐diaryl‐5‐trifluoromethyl‐1H‐1,2,3‐triazoles related to J147, a drug for treating Alzheimer's disease

J147 [N‐(2,4‐dimethylphenyl)‐2,2,2‐trifluoro‐N′‐(3‐methoxybenzylidene)acetohydrazide] has recently been reported as a promising new drug for the treatment of Alzheimer's disease. The X‐ray structures of seven new 1,4‐diaryl‐5‐trifluoromethyl‐1H‐1,2,3‐triazoles, namely 1‐(3,4‐dimethylphenyl)‐4‐phenyl‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₇H₁₄F₃N₃, 1 ), 1‐(3,4‐dimethylphenyl)‐4‐(3‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 2 ), 1‐(3,4‐dimethylphenyl)‐4‐(4‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 3 ), 1‐(2,4‐dimethylphenyl)‐4‐(4‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 4 ), 1‐[2,4‐bis(trifluoromethyl)phenyl]‐4‐(3‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₀F₉N₃O, 5 ), 1‐(3,4‐dimethoxyphenyl)‐4‐(3,4‐dimethoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₉H₁₈F₃N₃O₄, 6 ) and 3‐[4‐(3,4‐dimethoxyphenyl)‐5‐(trifluoromethyl)‐1H‐1,2,3‐triazol‐1‐yl]phenol (C₁₇H₁₄F₃N₃O₃, 7 ), have been determined and compared to that of J147 . B3LYP/6‐311++G(d,p) calculations have been performed to determine the potential surface and molecular electrostatic potential (MEP) of J147 , and to examine the correlation between hydrazone J147 and the 1,2,3‐triazoles, both bearing a CF₃ substituent. Using MEPs, it was found that the minimum‐energy conformation of 4 , which is nearly identical to its X‐ray structure, is closely related to one of the J147 seven minima.     

Synthese und Kristallstrukturen von monomeren bis(thiophenolato)metall(II)-Komplexen

Preparation and Structures of Monomeric Bis(thiophenolato)metal(II) Complexes Sodium-2,4,6-tris(trifluoromethyl)thiophenolate (NaSR_f) reacts with MCl₂ (M = Zn, Pb) in the molar ratio of 2:1 to form the bis(thiophenolato)metal(II)complexes bis[2,4,6-tris(trifluoromethyl)thiophenolato]zinc 1 and bis[2,4,6-tris(trifluoromethyl)thiophenolato]lead 2 . Reaction of Mn[N(SiMe₃)₂]₂· THF with two equivalents of 2,4,6-tris(trifluoromethyl)thiophenol (R_fSH) forms Mn(SR_f)₂ · THF 3 . All compounds crystallize as THF adducts. The structures of Zn(SR_f)₂ · 2THF 1a , Pb(SR_f)₂ · THF 2a and Mn(SR_f)₂ · 2THF 3a are discussed.     

Stereoselective Access to Fluorinated and Non‐fluorinated Quaternary Piperidines: Synthesis of Pipecolic Acid and Iminosugar Derivatives

The preparation of optically pure quaternary piperidines, both fluorinated and non‐fluorinated, has been achieved from a chiral imino lactone derived from (R)‐phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF₃) followed by iodoamination and migration of the CF₃ group allowed access to four derivatives of α‐(trifluoromethyl)pipecolic acid. A theoretical study of the CF₃‐group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl‐substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable synthetic intermediates. Conversely, alkylation of the starting substrate and subsequent cross‐metathesis and aza‐Michael reactions led to α‐alkyl derivatives of the target compounds.     

Novel route of the reaction of trifluoromethyl-containing N-methyl(4-ethoxyphenyl)imidazolidin-2-ones with urea

The reactions of perfluorobiacetyl with N-(4-ethoxyphenyl)- and N-methylurea afforded cis- and trans-isomers of 1-methyl-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one and 1-(4-ethoxyphenyl)-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one in a yield of ～60—75%. N-Alkyl(aryl)bis(trifluoromethyl)imidazooxazoles were obtained as unexpected products in the reaction of 1-alkyl(aryl)-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-ones with urea in dimethylacetamide. The reaction is accompanied by the rearrangement of imidazolidin-2-ones to N-alkyl(aryl)-5,5-bis(trifluoromethyl)hydantoins with CF₃ group migration from position 5 to position 4 of the starting heterocycle. A similar rearrangement is observed on boiling of the studied imidazolidin-2-ones in dimethylacetamide. The molecular structures of 3-(4-ethoxyphenyl)-5,5-bis(trifluoromethyl)imidazolidine-2,4-dione and 6-(4-ethoxyphenyl)-3a,6a-bis(trifluoromethyl)tetrahydroimidazo[4,5-d]oxazole-2,5-dione were studied by X-ray diffraction analysis.     

A new fluorinated anion for room-temperature ionic liquids

A new room-temperature ionic liquid (RTIL) consisting of the fluorinated anion bis(trifluoromethyl)-phosphinate((CF₃)₂PO₂⁻) coupled with the 1-butyl-3-methyl-imidazoliuim (BMIM) cation has been synthesized and characterized by physicochemical and electrochemical means including differential scanning calorimetry (DSC), thermogravimetric analysis, viscosity, conductivity and cyclic voltammetry measurements. Properties are compared with those of the known RTIL consisting of BMIM coupled with the bis(trifluoromethyl)-sulfonylimide (TFSI) anion.     

Proton-ligand stability constants of halo-N-arylhydroxamic acids

In sealed tube reactions bis(trifluoromethyl)mercury has been shown to exchange ligands with halogenated compounds such as GeBr₄ and SnBr₄ to produce a series of trifluoromethyl containing germanium and tin compounds including Ge(CF₃)₄ and Sn(CF₃)₂Br₂. These exchange reactions are shown to be synthically useful provided the desired products are stable at the required reaction temperatures.     

Reactions of polyfluorinated thietanes: Selective synthesis of 4-R-2,2-bis(trifluoromethyl)thietane-1-S-oxides and 2-substituted 5-fluoro-4-(trifluoromethyl)-2,3-dihydrothiophenes

Oxidation of 4-substituted 2,2-bis(trifluoromethyl)thietanes by m-chloroperoxybenzoic acid results in selective formation of the corresponding S-oxides in 65-86% yield. Oxidation of 4-C₂H₅S-2,2-bis(trifluoromethyl)thietane under mild conditions led to selective formation of 4-C₂H₅SO₂-2,2-bis(trifluoromethyl)thietane, which under more rigorous conditions was selectively converted into trans-4-C₂H₅SO₂-2,2-bis(trifluoromethyl)thietane-1-S-oxide. Reaction of 4-substituted 2,2-bis(trifluoromethyl)thietanes with activated aluminum powder results in a highly selective ring expansion process, producing the corresponding 5-fluoro-4-(trifluoromethyl)-2,3-dihydro-2-alkoxythiophenes in 58-93% yield. These compounds were also prepared in 61-85% yield using a “one-pot” procedure, starting from sulfur, hexafluoropropene and the corresponding vinyl ether without isolation of any intermediates. Both 2-i-C₃H₇O- and 2-t-C₄H₉O- 5-fluoro-4-(trifluoromethyl)-2,3-dihydrothiophenes were converted into 2-fluoro-3-trifluormethylthiophene by reaction with P₂O₅.     

The Reactivity of Hexafluorothioacetone and Hexafluoroacetone versus Phosphites

Abstract

The dimer of hexafluorothioacetone reacted with various phosphites to form thiophosphates and bis(trifluoromethyl)methylenphosphoranes, being unstable in the case of (Me₃SiO) P(OMe)_3-n, (n=1?3), where phosphonates (Me₃SiO)_n-1(MeO)_3-nP(O)[C(CF₃)=CF₂] (n=1-3) and Me₃SiF were observed. In general, cyclic phosphites behaved similar to acyclic ones. The resulting bis(trifluoromethyl)methylenphosphoranes were thermally stable except compound A, because of a new intramolecular fluorine transfer to phosphorus forming fluorophosphorane B.     

Photochemically induced reaction between perfluoroacetone and ethane

The gas-phase photolysis of perfluoroacetone in the presence of ethane has been shown to result in the production of significant amounts of 1, 1-bis(trifluoromethyl)propanol-1, (CF₃)₂(C₂H₅)COH, and 1, 1, 4, 4-tetrakis(trifluoromethyl)butane-1, 4-diol, (CF₃)₂C(OH)-CH₂CH₂C(OH)(CF₃)₂. A mechanism is presented which accounts for the relative rates of formation of these products at room temperature.