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.     

An effective method for the synthesis of carboxylic esters and lactones using substituted benzoic anhydrides with Lewis acid catalysts

An efficient mixed-anhydride method for the synthesis of carboxylic esters and lactones using benzoic anhydride having electron withdrawing substituent(s) is developed by the promotion of Lewis acid catalysts. In the presence of a catalytic amount of TiCl₂(ClO₄)₂, various carboxylic esters are prepared in high yields through the formation of the corresponding mixed-anhydrides from 3,5-bis(trifluoromethyl)benzoic anhydride and carboxylic acids. The combined catalyst consisting of TiCl₂(ClO₄)₂ together with chlorotrimethylsilane functions as an effective catalyst for the synthesis of carboxylic esters from free carboxylic acids and alcohols with 4-(trifluoromethyl)benzoic anhydride. Various macrolactones are prepared from the free ω-hydroxycarboxylic acids by the combined use of 4-(trifluoromethyl)benzoic anhydride and titanium(IV) catalysts together with chlorotrimethylsilane under mild reaction conditions. The lactonization of trimethylsilyl ω-(trimethylsiloxy)carboxylates using 4-(trifluoromethyl)benzoic anhydride is also promoted at room temperature in the presence of a catalytic amount of TiCl₂(ClO₄)₂. An 8-membered ring lactone, a synthetic intermediate of cephalosporolide D, is successfully synthesized according to this mixed-anhydride method using 4-(trifluoromethyl)benzoic anhydride by the promotion of a catalytic amount of Hf(OTf)₄.     

A simple and convenient synthesis of 3-[5-(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acids from 4-aryl-6-(trifluoromethyl)-2H-pyran-2-ones and sodium azide

4-Aryl-6-(trifluoromethyl)-2H-pyran-2-ones and ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates react with sodium azide to produce highly functionalized CF₃-1,2,3-triazoles: 3-[5-(trifluoromethyl)-1,2,3-triazol-4-yl]cinnamic acids and monoethyl esters of [5-(trifluoromethyl)-1,2,3-triazol-4-yl]arylmethylidene malonic acids.     

Reactions of 5-[3-(trifluoromethyl)-phenyl]furan-2-carbaldehyde

The Knoevenagel condensations of 5-[3-(trifluoromethyl)phenyl]furan-2-carbaldehyde with seven compounds containing an active methyl or methylene group have been studied. The compounds used were: methyl 2-cyanoacetate, malononitrile, 2-furylacetonitrile, acetophenone, 2-thioxo-1,3-thiazolidin-4-one (rhodanine), 5,5-dimethylcyclohexane-1,3-dione (dimedone), and methyl 2-azidoacetate. The effect of microwave irradiation on the condensation reactions was studied and compared with “’classical”’ conditions. Thermolysis of methyl 2-azido-3-{5-[3-(trifluoromethyl)phenyl]-2-furyl}propenoate afforded methyl 2-[3-(trifluoromethyl)phenyl)]-4H-furo[3,2-b]pyrrole-5-carboxylate. (2E)-3-{ 5-[3-(Trifluoromethyl)phenyl]-2-furyl}propenoic acid was converted to the corresponding azide, which was cyclized on heating into 2-[3-(trifluoromethyl)phenyl)]-4,5-dihydrofuro[3,2-c]pyridin-4-one. The latter after successive action of POCl₃ and NH₂NH₂-Pd/C gave 2-[3-(trifluoromethyl)-phenyl]furo[3,2-c]pyridine. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 825–831, June, 2006.     

Remarkable effect of metal fluoride catalyst on reaction of hexafluoropropene, sulfur and vinyl ethers. Convenient synthesis of 2,2-bis(trifluoromethyl)-4-R-thietanes, 3,3-bis(trifluoromethyl)-5-R-1,2-dithiolanes and 2,2-bis(trifluoromethyl)-4-R-1,3-dithiolanes

It was demonstrated that the outcome of the reaction of hexafluoropropene, sulfur and vinyl ether strongly depends on the catalyst and reaction conditions. The reaction of HFP and S_x leading to the formation of 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane (1) when it is catalyzed by CsF, proceeds under milder conditions and is easier to control compared to KF catalyzed process. The order of addition of reagents plays a crucial role on the outcome of the reaction. For example, the addition of vinyl ether to pregenerated solution of 1 in DMF solvent results in slow reaction, leading to the corresponding 2,2-bis(trifluoromethyl)-4-R-thietanes in 8-91% yield, and it is catalyzed by either by KF or CsF. The addition of second mole of sulfur to the solution of 2,2-bis(trifluoromethyl)-4-R-thietanes in the presence MF catalyst leads to insertion of sulfur into thietane ring with the formation of the corresponding cyclic disulfides—3,3-bis(trifluoromethyl)-5-R-1,2-dithietanes. On the other hand, the addition of second mole of sulfur to the solution of 1 in DMF in the presence of CsF catalyst, followed by addition of vinyl ether results in exothermic reaction, and it produces the corresponding 2,2-bis(trifluoromethyl)-4-alkoxy-1,3-dithiolanes in good yield.It was also demonstrated that 2,2-bis(trifluoromethyl)-4-R-thietanes can undergo disproportionation under action of fluoride anion, producing a mixture of the corresponding 1,2-dithiolane and CF₂C(CF₃)CH₂CFHOR. The nucleophilic attack of fluoride anion in this case proceeds selectively on the carbon of the thietane ring, bearing alkoxy group.The structure of 2,2-bis(trifluoromethyl)-4-R-thietanes forming as the result of 2 + 2 cycloaddition reaction between hexafluorothioacetone generated “in situ” from dimer 1 and vinyl ether was firmly supported by single crystal X-ray diffraction data, obtained for thietane bearing t-BuO-group.     

Synthesis of 4-(trifluoromethyl)pyrido[4,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidine derivatives

Earlier unknown 4-alkoxy-and 4-hydroxy-5-methyl-4-trifluoromethyl-1,4-dihydropyri-do[4,3-d]pyrimidines were obtained by the reaction of 5-acetyl-4-dimethylaminovinyl-6-(trifluoromethyl)pyrimidine with alcoholic (aqueous) solutions of NH₃. The former eliminate alcohol (water) on sublimation in vacuo to be converted to 5-methyl-4-(trifluoromethyl)-pyrido[4,3-d]pyrimidine. The latter upon the action of alcohols (water) under mild conditions were reverted to the corresponding 4-alkoxy-and 4-hydroxydihydropyrido[4,3-d]pyrimidines.     

Bis(trifluoromethyl)-containing 1-azatricycloheptanes

6-Substituted 7-halo-3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were synthesized by the addition of water, alcohols, and acetic acid to 3-halo-7,7-bis(trifluoromethyl)-1-azatricyclo[2.2.1.0^2,6]heptanes in the presence of H₂SO₄. 5,6-Disubstituted 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were prepared by oxymercuration of 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene.     

Fluorinated pyridine derivatives: Part 1. The synthesis of some mono- and bis-quaternary pyridine salts of potential use in the treatment of nerve agent poisoning

Experiments were performed to determine whether F- and CF₃-substituted pyridines undergo quaternization with iodomethane (1:1 molar ratio in THF) and 1,3-diiodopropane (2:1 molar ratio in MeCN). 2-Fluoropyridine and 2-(trifluoromethyl)pyridine did not react with MeI even under prolonged reflux, while 3-fluoropyridine, 3,5-difluoropyridine, 3-(trifluoromethyl)pyridine and 4-(trifluoromethyl)pyridine gave methiodide salts in 28-72% yield. 2-Fluoropyridine did not react with I(CH₂)₃I, 3-fluoropyridine gave the bis-quaternary salt and 3,5-difluoropyridine yielded a mono-quaternary derivative. Both 3- and 4-(trifluoromethyl)pyridine furnished the bis-quaternary products in 53 and 55% yield, respectively. The bis-quaternary salts are potentially useful in the treatment of organophosphorus nerve agent poisoning.     

In situ synthesis,crystal structures,and luminescence of two new tetrazole complexes

The synthesis, crystal structures, and luminescent properties of two new complexes containing tetrazolyl ligands are described. Refluxing a mixture of fipronil (fipronil = (±)-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile), sodium azide, and CuCl₂ in ethanol and water gives complex 1, [M(L)₂](H₂O)₂] ? 2H₂O (HL = (±)-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-tetrazole, M = Cu). Hydrothermal reaction of fipronil, sodium azide, and Cd(ClO₄)₂ in the presence of water and ethanol (Demko–Sharpless tetrazole synthesis) yields 2, [M(L)₂](H₂O)₂] ? 2H₂O (M = Cd). The metals in both complexes are six coordinate from two water molecules, two nitrogens from different tetrazolyl groups, and two nitrogens from pyrazolyl groups. Photoluminescence studies reveal that 2 exhibits strong blue fluorescent emission at λ _max = 451 nm in solid state at room temperature.     

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.     

Synthesis of 3-(trifluoromethyl)indeno[2,1-c]pyran-1,9-diones from 4-aryl-3-carbethoxy-6-(trifluoromethyl)-2-pyrones and their reaction with sodium azide leading to new carbostyril derivatives

Treatment of ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates, prepared from 4,4,4-trifluorobutane-1,3-diones, PCl₅ and sodium diethyl malonate, with sulfuric acid afforded the intramolecular Friedel–Crafts acylation products, 3-(trifluoromethyl)indeno[2,1-c]pyran-1,9-diones, from which 2-(trifluoromethyl)-6H-pyrano[3,4-c]quinoline-4,5-diones were obtained via the Schmidt reaction in moderate yields. The latter reacted with sodium azide to give 2-oxo-4-(5-trifluoromethyl-1,2,3-triazol-4-yl)-1,2-dihydroquinoline-3-carboxylic acids in good yields.     

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).     

Sodium dithionite initiated addition of CF2Br2, CF3I and (CF3)2CFI to allylaromatics: Synthesis and the reactivity of 4-aryl-1,1-difluorodienes and 4-aryl-1,1-bis(trifluoromethyl)dienes

Sodium dithionite initiated addition of CF₂Br₂, CF₃I and (CF₃)₂CFI to the terminal double bond of allylbenzenes and of (CF₃)₂CFI to allylpyridines in a MeCN/H₂O system were investigated. The reactions of CF₂Br₂ with allylbenzenes gave comparable amounts of adducts, 1-(2,4-dibromo-4,4-difluorobutyl)benzenes, debrominated products,1-(4-bromo-4,4-difluorobutyl)benzenes, and dimeric compounds in total yields 40-66%. Treatment of the adducts with DBU resulted in double dehydrohalogenation affording 4-aryl-1,1-difluorobutadienes which undergo Diels-Alder condensation with nitrogen dienophiles to give N-heterocycles with difluoromethylene group in the ring. The reactions of CF₃I and (CF₃)₂CFI with allylbenzenes gave the respective adducts, (4,4,4-trifluoro-2-iodobutyl)benzenes and 1-(4,5,5,5-tetrafluoro-4-(trifluoromethyl)-2-iodopentyl)benzenes as the main products. Dehydrohalogenation of these adducts resulted, respectively, in (4,4,4-trifluoro-but-1-enyl)benzenes and 4-aryl-1,1-bis(trifluoromethyl)butadienes in high yields. (CF₃)₂CFI reacted rapidly with allylpyridines to give mixtures from which, after treatment with DBU, 4-pyridyl-1,1-bis(trifluoromethyl)butadienes were isolated in a ca. 60% yield.     

Syntheses of 2-(trifluoromethyl)-1,3-dicarbonyl compounds through direct trifluoromethylation with CF3I and their application to fluorinated pyrazoles syntheses

Direct trifluoromethylation of 1,3-dicarbonyl compounds with CF₃I in the presence of a Fenton reagent in dimethylsulfoxide was investigated. 1,3-Diketones, 3-oxocarboxylates and 3-oxocarboxamides were readily trifluoromethylated at the methylene carbon between two oxo groups. Cycloaddition of hydrazine derivatives to the obtained 2-(trifluoromethyl)-1,3-dicarbonyl compounds provided fluorinated pyrazoles. 4-(Trifluoromethyl)pyrazole derivatives were formed from 2-(trifluoromethyl)-1,3-diketones, while 3-oxo-2-(trifluoromethyl)carboxylates or carboxamides gave 5-fluoropyrazole-4-carboxylates or carboxamides, respectively, via 3-hydrazono-2-(trifluoromethyl)carboxylates or carboxamides as an intermediate.     

Oxidative transformations of 6-trifluoromethyl-2H-thiopyran as a route to fluoro-containing thiopyranosides

The synthesis of cis- and trans-6-(trifluoromethyl)-3,4-dihydro-2H-thiopyran-3,4-diols from 6-(trifluoromethyl)-2H-thiopyran via an OsO₄-catalysed dihydroxylation and bromohydroxylation-alkaline hydrolysis sequence is described. Acetylation of the diols followed by S-oxidation affords the corresponding cis- and trans-3,4-diacetoxy-6-(trifluoromethyl)-3,4-dihydro-2H-thiopyran S-oxides which reacted with acetic anhydride and boron trifluoride diethyl ether complex by an additive Pummerer pathway giving tetraacetyl derivatives of trifluoromethyl-containing thiopyranoses.     

Diels-Alder reactions of trifluoromethyl alkenes with 5-ethoxyoxazoles: synthesis of trifluoromethylated pyridine derivatives

Cycloaddition reactions between 5-ethoxyoxazole derivatives [2,4-dimethyl 5-ethoxyoxazole and 4-methyl 5-ethoxyoxazole] and various trifluoromethyl alkenes [ethyl 4,4,4-trifluorocrotonate CF₃CHCHCO₂Et, 3,3,3-trifluoro 1-(phenylsulfonyl)-1-propene CF₃CHCHSO₂Ph and 2-(trifluoromethyl) propenoic acid CF₃(HO₂C)CCH₂] gave several trifluoromethyl-substituted pyridine systems in moderate yield (20-56%). Their structures were determined by multinuclear NMR techniques including ¹H-¹³C HETCOR spectroscopy.     

Trifluoromethylated cyclopropanes and epoxides from CuI-mediated transformations of α-trifluoromethyl-diazophosphonate

An efficient method for the preparation of α-(trifluoromethyl)-cyclopropylphosphonates and α-(trifluoromethyl)-1,2-epoxyphosphonates has been developed. The method is based on metal-catalyzed reaction of diethyl 1-diazo-2,2,2-trifluoroethylphosphonate (1) with alkenes or carbonyl compounds, respectively. It established an essential advantage of CuI-catalysis over Rh₂(OAc)₄ in cyclopropanation reactions. An inexpensive copper iodide has also exhibited a good catalytic activity in the synthesis of epoxyphosphonates (3).     

A facile synthetic route to 2-trifluoromethyl-substituted polyfunctionalized chromenes and chromones

A method for the preparation of methyl 4-hydroxy-2-(trifluoromethyl)-4H-chromenes-3-carboxylate derivatives 3a–j from readily available trifluoromethylated building block methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate 1 was described. Treatment of 3a–j with Sarrett reagent in CH₂Cl₂ generated methyl 4-oxo-2-(trifluoromethyl)-chromene-3-carboxylate derivatives 4a–h with moderate to good yields, which can be converted to 2-trifluoromethyl-substituted multifunctional benzoxepins through cyclopropanation and Lewis acid-catalyzed ring opening.     

Unprecedented and Effective Synthesis of Thiazolines from Perfluoro-3-isothiocyanato-2-methyl-2-pentene and Certain P-Nucleofuges

The reactions of perfluoro-3-isothiocyanato-2-methyl-2-pentene with PPh₃ and P(NEt₂)₃ in the presence of NaBF₄, KI, and NaBPh4 form phosphonium salts with the heterocyclic substituent (4E)-5,5-bis(trifluoromethyl)-4-(tetrafluoroethylidene)-4,5-dihydro-1,3-thiazol-2-yl, instead of involving desulfurization and formation of P-F-containing products. The reaction with tris(pentafluorophenyl)phosphine fails. The reactions with P(OEt)₃ in the presence of ClSiMe₃ or (CH₃O)₂POSiMe₃ yield diethyl or dimethyl [(4E)-5,5-bis(trifluoromethyl)-4-(tetrafluoroethylidene)-4,5-dihydro-1,3-thiazol-2-yl]phosphonates and no intramolecular alkylation products. The ¹H, ¹³C, ¹⁹F, and ³¹P spectra are presented, and the reaction pathways are discussed. Potential mechanisms of the biological and catalytic activity of the reaction products are considered.     

Synthesis and investigation of spectroelectrochemical properties of peripherally tetra-substituted phthalocyanine bearing 3-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)propan-1-ol and its metallo compounds

In this study, the new compounds; 3-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)propan-1-ol 3 was prepared by the reaction of 4-(3-hydroxypropyl)phenol 1 with 1-(bromomethyl)-3-(trifluoromethyl)benzene 2 and 4-[3-(4-{[3 (trifluoromethyl)benzyl]oxy}phenyl)propoxy] phthalonitrile 5 was synthesized by the reaction of 4-nitrophthalonitrile 4 with 3-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)propan-1-ol 3. Novel peripherally tetra substituted H₂Pc 6, Co(II) 7, Cu(II) 8, Ni(II) 9 and Fe(II) 10 phthalocyanines, which have peripheral positions with 4-[3-(4-{[3 (trifluoromethyl)benzyl]oxy}phenyl)propoxy] groups, were synthesized and all of the new compounds characterized by IR, ¹H NMR, ¹³C NMR, UV–Vis, mass spectroscopies and elemental analysis. The electrochemical and spectroelectrochemical investigation of the phthalocyanines carrying 4-[3-(4-{[3 (trifluoromethyl)benzyl]oxy}phenyl)propoxy] groups were studied using various electrochemical techniques in DMF on a glassy carbon electrode. Cyclic voltammetry and square wave voltammetry studies show that the complexes have either metal based or ligand-based diffusion controlled electron transfer properties. To shed more light on the electron-transfer steps of the complexes and assignments of the redox couples were carried out by spectroelectrochemical measurements. The color changes during spectral changes of redox species were recorded with in situ electrocolorimetric measurements. The electrochemical and in situ UV–Vis spectral change of complexes indicated their applicability in the fields of the electrochemical technologies.