Michael addition of N-sulfinyl metalloenamines to β-trifluoromethyl-α,β-unsaturated ester: an efficient access to chiral 4-trifluoromethyl-2-piperidones

Michael addition of N-sulfinyl metalloenamines to β-trifluoromethyl-α,β-unsaturated ester was investigated. High diastereoselectivities and excellent yields were obtained. The conversion of addition products into 4-trifluoromethyl-2-piperidones asymmetrically, which involved a DIBAL-H reduction and the following cyclization, was illustrated. The absolute configuration of Michael addition products and 4-trifluoromethyl-2-piperidones were determined by X-ray crystallographic analysis and NOESY experiment, respectively. This method affords an efficient and asymmetric approach to a variety of chiral 4-trifluoromethyl-2-piperidones.     

A facile synthesis of 1-trifluoromethyl-β-carboline

The two-step synthesis of the title compound has been achieved by Mannich-type condensation of tryptamine with trifluoroacetaldehyde, followed by dehydrogenation with selenium dioxide; the overall yield was 79.3%.     

Reactions of 3,3-dialkyl-2,3-dihydro-6-trifluoromethyl-4-pyrones with hydroxylamine. Synthesis and structures of 5-(1,1-dialkyl-2-hydroxyethyl)-5-hydroxy-3-trifluoromethyl-Δ2-isoxazolines

The reactions of 3,3-dialkyl-2,3-dihydro-6-trifluoromethyl-4-pyrones with hydroxylamine hydrochloride afforded regioisomeric 3(5)-(1,1-dialkyl-2-hydroxyethyl)-5-hydroxy-5(3)-trifluoromethyl-Δ²-isoxazolines depending on the reaction conditions. The title compounds were also prepared from 2,2-dialkyl-5-amino-1-hydroxy-6,6,6-trifluorohex-4-en-3-ones. The above dihydropyrones reacted with hydroxylamine (base) to yield 3-(1,1-dialkyl-2-hydroxyethyl)-5-hydroxy-5-trifluoromethyl-Δ²-isoxazolines. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1334–1339, July, 1999.     

Stereo-regulated synthesis of peptides containing a β-trifluoromethyl-β-amino acid

For the chemical conversions of a β-trifluoromethyl-β-amino acid ((S)-4,4,4-trifluoro-3-aminobutyric acid, 1), such as the N-terminus protection with benzyloxycarbonyl or tert-butoxycarbonyl group, the C-terminus protection with benzyl or tert-butyl group, and peptide elongation at the both termini, highly practical protocols were established. Through these conversions, the stereochemistry of 1 and/or its condensation counterpart was maintained. Because the protocols developed here are indispensable for the application of 1 in peptide engineering, they would expand the utility of 1 and its derivatives.     

Synthesis of α-trifluoromethyl-β-keto phosphonates by electrophilic trifluoromethylation with Togni reagent

A new synthetic method of trifluoromethylated phosphonates was developed via electrophilic trifluoromethylation with Togni reagent. A variety of β-keto phosphonates were converted into the corresponding α-trifluoromethyl-β-keto phosphonates in moderate to good yields. This protocol could also be extended to other fluoroalkylation reactions, such as pentafluoroethylation.     

Reaction of 1-chloro-1-aryl2,2,2-trifluoroethylisocyanates with the ethyl ester ofβ-N-methylaminocrotonic acid. Synthesis of 2-aryl-2-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-4-ones

1-Chloro-l-aryl-2, 2, 2-trifluoroethylisocyanates react with the ethyl ester of -N-methylaminocrotonic acid with formation of derivatives of 1,2,3,4-tetrahydropyrimidin-4-ones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 30, No. 1, pp. 96–98, January, 1994.     

Reaction of 2-hydroxyethylhydrazine with a trifluoromethyl-β-diketone: Study and structural characterization of a new 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazole intermediate

The reaction of the β-diketone 4,4,4-trifluoro-1-pyridin-2-yl-butane-1,3-dione and the monosubstituted hydrazine 2-hydroxyethylhydrazine has been investigated. Two products have been identified, 2-(2-hydroxyethyl)-3-pyridin-2-yl-5-trifluoromethyl-4,5-dihydropyrazole (P) and 2-(3-pyridin-2-yl-5-trifluoromethylpyrazol-1-yl)ethanol (L) in proportion 2:8, when the reaction was done at room temperature in ethanol for 15 h. The preparation of P as a pure product was performed in ethanol at 0 °C for 7 h. P has been characterized by ¹H, ¹³C{¹H} and ¹⁹F{¹H} NMR spectroscopy and by other techniques as appropriate.     

N-Benzyloxycarbonyl-2,2,2-trifluoroacetimidoyl chloride—A convenient reagent for the synthesis of 2-trifluoromethyl-4H-pyrido[1,2-a][1,3,5]triazin-4-one

N-Benzyloxycarbonyl-2,2,2-trifluoroacetimidoyl chloride reacted with pyridin-2-amine derivatives to form substituted 2-trifluoromethyl-4H-pyrido[1,2-a][1,3,5]triazin-4-ones.     

Synthesis of α-trifluoromethyl-α-amino-β-sulfone hydroxamates: novel nanomolar inhibitors of matrix metalloproteinases

The racemic α-trifluoromethyl-α-amino-β-sulfone hydroxamates 1 were synthesized by means of a nucleophilic addition of sulfur-stabilized carbanions to a N-Cbz imine of trifluoropyruvate (4). The free amino derivative 1a was the most potent inhibitor of both MMP-3 (stromelysin-1) and MMP-9 (gelatinase-B), showing an IC₅₀ = 14 nM and 1 nM, respectively, and excellent selectivity versus MMP-1 (>5000-fold difference in inhibitory capacity). The N-Me derivative 1b was the most selective for MMP-3 with respect to MMP-9 (62-fold difference).     

Diastereoselective synthesis of trans-trifluoromethyl-β-lactams and α-alkyl-β-trifluoromethyl-β-amino esters

The diastereoselective synthesis of β-lactams was examined from N-tosyl-1-chloro-2,2,2-trifluoroethylamine 3 and various nonactivated aliphatic acid chlorides in the presence of a Brønsted base. The mild reaction conditions allowed to get trifluoromethyl-β-lactams in good yields with high trans-diastereo selectivity. In addition, we also demonstrated that ring-opening of β-lactams easily provided α-alkyl-β-trifluoromethyl-β-amino esters.     

The thermodynamics of dissolution of low-molecular-mass compounds in polymethyl[2′-(3-trifluoromethyl-2,2,3-trifluorocyclobutyl)ethyl]siloxane studied via inverse gas chromatography

The effect of the 2′-(3-trifluoromethyl-2,2,3-trifluorocyclobutyl)ethyl radical in fluorosiloxane on the thermodynamics of dissolution of various low-molecular-mass compounds in this polymer is studied via inverse gas chromatography. The activity coefficients at infinite dilution, Ω ₁ ^∞ , in the temperature range 20–100°C are determined for C₆–C₈ n-alkanes, cyclohexane, benzene, toluene, tetrachloromethane, trichloromethane, 2-butanone, and ethyl acetate. Flory-Huggins interaction parameters χ ₁₂ ^∞ are calculated. It is shown that hydrocarbons are poor solvents (Ω ₁ ^∞ > 6, χ ₁₂ ^∞ > 0.5) and that the studied fluorosiloxane is not inferior to commercial polymethyl(3,3,3-trifluoropropyl)siloxane with respect to stability in nonpolar liquid media in the range 20–70°C. Trichloromethane (above 50°C) and compounds containing a carbonyl group are found to be good solvents. The dispersion component of the solubility of the polymer, δ ₂, is determined to be 14.0 (J/cm³)^1/2 at 20°C and slightly lower, 13.5 (J/cm³)^1/2, at 100°C. Possible causes of these low values of δ₂ are discussed.     

Synthesis of β-amino-α-trifluoromethyl-α-amino acids exhibiting intramolecular interaction of CF3 with NHβ

We prepared β-amino-α-trifluoromethyl-α-amino acids through ring-opening reaction of N-tosyl-2-trifluoromethyl-2-ethoxycarbonylaziridine with aromatic and benzylic amines, and investigated the intramolecular interaction between the trifluoromethyl (CF₃) group at the α-position and the NH group at the β-position (NH_β). NMR, UV/vis, and circular dichroism measurements indicated that the conformation of these compounds is fixed by intramolecular interaction of CF₃ with NH_β to form a six-membered ring.     

The synthesis of (R)- and (S)-α-trifluoromethyl-α-hydroxycarboxylic acids via enzymatic resolutions

Kinetic resolution of 1,1,1-trifluoro-2-alkanone cyanohydrin acyl derivatives with Candida rugosa lipase afforded the remaining (R)-enantiomer in high selectivity (E from 30 to >200). Candida rugosa lipases from several suppliers were compared and found to differ remarkably in their selectivity. The (R)-enantiomer was hydrolyzed in one step to yield optically pure (R)-α-trifluoromethyl-α-hydroxycarboxylic acids in excellent yield. The (S)-acids were obtained in good e.e. by subtilisin-catalyzed resolution of the corresponding racemic esters followed by chemical hydrolysis of the remaining (S)-esters.     

A novel synthesis of γ-nitro ketones via detrifluoroacetylative Michael addition of 1-trifluoromethyl-1,3-diketones to conjugated nitroalkenes

A novel synthesis of γ-nitro ketones via detrifluoroacetylative Michael addition of 1-trifluoromethyl-1,3-diketones to conjugated nitroalkenes in the presence of sodium acetate in ethanol at room temperature is developed. A series of trifluoromethylated 1,3-diones and nitroalkenes are surveyed to determine the scope of this high-yielding reaction.     

Asymmetric synthesis of β-aryl-β-trifluoromethyl-β-aminoarones via Mannich-type reactions of ketone enolates with chiral aryl CF3-substituted N-tert-butanesulfinyl ketimines

A method for the preparation of chiral β-aryl-β-trifluoromethyl-β-aminoarones has been developed involving the Mannich-type reactions of ketone-derivative enolates with chiral aryl CF₃-substituted N-tert-butanesulfinyl ketimines. This method tolerates a wide of aromatic ketones, giving the products in moderate to excellent yields (up to 91%) with good diastereoselectiveties (up to 93:7 dr). Acidic cleavage of the tert-butanesulfinyl group gave optically pure β-aryl-β-trifluoromethyl-β-aminoarones in excellent yields (up to 98%), which can be further transformed into CF₃-substituted aziridine derivatives.     

Efficient synthesis of an α-trifluoromethyl-α-tosyloxymethyl epoxide enabling stepwise double functionalisation to afford CF3-substituted tertiary alcohols

The efficient synthesis of an α-trifluoromethyl-α-tosyloxymethyl epoxide is reported. This highly versatile building block may be reacted sequentially with two different nucleophiles to furnish α-trifluoromethyl tertiary alcohols. Furthermore, the two enantiomers of this key intermediate have been separated using chiral HPLC and the stereochemistry shown to be conserved during subsequent chemical manipulations. Finally, an enzyme-driven desymmetrisation approach has been successfully employed to confer chirality on an intermediate in the sequence.     

Reaction of (S)-(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-ones with α-chlorobenzyl isocyanates. Synthesis of (S)-(+)-4-aryl-6-(2-arylethenyl)-4-trifluoromethyl-3,4-dihydro-pyrimidin-2(1H)-ones

(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-ones reacted with 6h-chlorobenzyl isocyanates with formation of (S)-(+)-4-aryl-6-(2-arylethenyl)-4-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-ones.     

Synthesis,Crystal Structure,and Antitumor Activity of 1-（4-Methoxybenzylidene）-2-（1-phenyl-6-trifluoromethyl- 1H-pyrazolo [3,4-d] pyrimidin-4-yl）hydrazine Monohydrate

The novel title compound 1-(4-methoxybenzylidene)-2-(1-phenyl-6-trifluoromethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hydrazine monohydrate(C20H15F3N6O·H2O, Mr = 430.40) has been synthesized by a four-step procedure including the cyclization, chlorination, hydrazinolysis and condensation reaction, and its crystal structure was determined by single-crystal X-ray diffraction. The crystal belongs to orthorhombic, space group Pbca with a = 8.3779(13), b = 17.607(3), c = 26.774(4) , V = 3949.2(11) 3, Z = 8, Dc = 1.448 g/cm3, μ = 0.117 mm–1, F(000) = 1776, the final R = 0.0553 and wR = 0.1516 for 2354 observed reflections with I 2■(I). X-ray diffraction analysis reveals that the title compound is almost coplanar except for the trifluoromethyl and phenyl moieties. In the crystal packing, the molecules are linked by intermolecular O(1W)–H(1WA)···N(2), O(1W)–H(1WA)···N(4) and N(5)–H(5A)···O(1W) hydrogen bonds via water molecules and stacked through π-π stacking interactions. The preliminary bioassay suggested that the title compound exhibits relatively good antitumor activity against HepG2 and BCG-823.