Synthesis of difluoromethyl substituted lysophosphatidic acid analogues

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with nuclear hormone receptor PPARγ. We describe a new and efficient route to enantiomerically homogeneous lysophospholipid analogues from (S)-1,2,4-butanetriol to give two 3-difluoromethyl substituted analogues of 2-acyl-sn-glycerol 3-phosphate. These compounds are migration-blocked analogues of the liable sn-2 LPA species. Preliminary studies were conducted on a nuclear reporter assay in which monocytic cells were transfected with a luciferase construct activated by a PPARγ nuclear receptor response element and have shown that the 3-difluoromethyl substituted analogues are fully active as natural LPA.     

Reaction of difluorocarbene with anions from amides and oximes: Synthesis of N-difluoromethyl substituted amides, O-difluoromethylimidates or O-difluoromethyl substituted oximes under phase-transfer catalysis conditions

N-Aryl substituted amides react with chlorodifluoromethane in the presence of concentrated aqueous sodium hydroxide and benzyltriethylammonium chloride (TEBAC) as a catalyst in benzene (phase-transfer catalysis, PTC), affording mixtures of N- and O-difluoromethyl substituted derivatives. Amide anions are involved in this process. The reaction carried out with oximes gives O-difluoromethyl oxime ethers.     

On the enzymatic hydrolysis of methyl 2-fluoro-2-arylpropionates by lipases

The enzymatic hydrolysis of methyl 2-fluoro-2-arylpropionates was performed using lipases from Candida rugosa and Candida cylindracea (OF-360). A careful analysis of the reaction products revealed that racemic 2-hydroxy-2-arylpropionic acid and traces of 2-arylacrylic acid are formed, in addition to the expected 2-aryl-2-fluoropropionic acid. The presence of powerful electron-releasing groups in the aromatic ring of the substrate increase the amount of 2-hydroxypropionic acid. A mechanistic hypothesis has been formulated according to which the enzyme facilitates the elimination of fluoride ion from the hydrolysed acid with the formation of an α-carboxy-stabilized carbocation which provides 2-hydroxypropionic acids by nucleophilic attack of H₂O and 2-arylacrylic acids by a β-elimination process.     

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane as a difluoromethyl building block: A general strategy to α,α-difluoromethyl aryl ketones

The synthetic utility of α,α-difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF₂SiMe₃; 1) as a difluoromethyl building block providing a general strategy to α,α-difluoromethyl aryl ketones was demonstrated. Oxidation, by using m-chloroperoxybenzoic acid, of the readily available 1-aryl-2,2-difluoro-2-phenylsulfanyl-1-trimethylsiloxyethanes obtained from fluoride-catalyzed nucleophilic addition of PhSCF₂SiMe₃ with aromatic aldehydes followed by flash vacuum pyrolytic elimination provided α,α-difluoromethyl aryl ketones in moderate overall yields.     

The stereospecific preparation of two perfluoro-1,3-butadiene synthons; (E)-1-trimethylsilyl-1,2,3,4,4-pentafluoro-1,3-butadiene and (E)-1-tributylstannyl-1,2,3,4,4-pentafluoro-1,3-butadiene

(E)-1-Trimethylsilyl-1,2,3,4,4-pentafluoro-1,3-butadiene (1) can be stereospecifically prepared by Pd(0)/CuI catalyzed cross-coupling of (Z)-1-tributylstannyl-1,2-difluoro-2-trimethylsilylethene with iodotrifluoroethene. The corresponding (E)-1-tributylstannyl-1,2,3,4,4-pentafluoro-1,3-butadiene can be prepared via the stereospecific conversion of 1 with Bu₃SnOSnBu₃/KF (catalysis) to the corresponding vinylstannane.     

Synthesis and antimicrobial activity of some novel 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines

The synthesis of several 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines (2a-t) was carried out by base-catalyzed cyclization of corresponding 1-(fluorobenzoyl)-3-(fluorophenyl)thioureas (1a-t) with 2-bromoacetone in aqueous medium. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa). The minimum inhibitory concentration (MIC) was determined for the most active compounds. In vitro antifungal activity was also determined against the five fungal species (Rhizopus oryzae, Fusarium oxysporum, Aspergillus terreus, A. niger and A. fumigatus).     

p-TsOH promoted Fischer indole synthesis of multi-substituted 2-trifluoromethyl indole derivatives

A p-TsOH promoted one-pot synthesis of multi-substituted 2-trifluoromethyl indole derivatives, for instance, 2-trifluoromethyl-3-phenylindoles, 2-trifluoromethyl-indole-3-propanoates, and 2-trifluoromethyl-indole-3-butanoates from reactions of 1,1,1-trifluoro-3-phenylacetone and simply prepared ω-trifluoromethyl substituted δ and ?-ketoesters with arylhydrazines via Fischer indole synthesis has been developed.     

Reaction of RF-palmitic acid-F13 with dicyclohexylcarbodiimide

The 1,3-dicyclohexylcarbodiimide (DCC) adduct of R_F-palmitic acid-F₁₃1 has been synthesized and characterized. The X-ray crystal structure shows that the product arises from an O- to N-acyl migration of an initially formed N,N′-dicyclohexyl-O-R_F-palmitoyl-F₁₃-isourea 2 to give 1-R_F-palmitoyl-F₁₃-1,3-dicyclohexylurea 3. X-ray data for an R_F-palmitic acid-F₁₃ unit are reported for the first time. The product of the reaction of DCC with palmitic acid is also the urea derivative which has been characterized by IR and NMR methods.     

Reactions of trimethylsilyl fluorosulfonyldifluoroacetate with purine and pyrimidine nucleosides

Difluorocarbene, generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), reacts with the uridine and adenosine substrates preferentially at the enolizable amide moiety of the uracil ring and the 6-amino group of the purine ring. 2′,3′-Di-O-benzoyl-3′-deoxy-3′-methyleneuridine reacts with TFDA to produce 4-O-difluoromethyl product derived from an insertion of difluorocarbene into the 4-hydroxyl group of the enolizable uracil ring. Reaction of the difluorocarbene with the adenosine substrates having the unprotected 6-amino group in the purine ring produced the 6-N-difluoromethyl derivative, while reaction with 6-N-benzoyl protected adenosine analogues gave the difluoromethyl ether product derived from the insertion of difluorocarbene into the enol form of the 6-benzamido group. Treatment of the 6-N-phthaloyl protected adenosine analogues with TFDA resulted in the unexpected one-pot conversion of the imidazole ring of the purine into the corresponding N-difluoromethylthiourea derivatives. Treatment of the suitably protected pyrimidine and purine nucleosides bearing an exomethylene group at carbons 2′, 3′ or 4′ of the sugar rings with TFDA afforded the corresponding spirodifluorocyclopropyl analogues but in low yields.     

Palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-bromophenylboronic acid: Synthesis of 6-fluoroalkyl-phenanthridines

An efficient method has been developed to synthesize 6-fluoroalkyl-phenanthridines via the palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-bromophenylboronic acid. This methodology facilitates the rapid synthesis of 6-fluoroalkyl-phenanthridines through dual C–C bond formation in an oxidant-free one-pot manner.     

Syntheses of 6-fluoro-meta-tyrosine and of its metabolites

6-Fluoro-meta-tyrosine (1) was prepared from 2-fluoro-5-hydroxybenzaldehyde (6) based on an Erlenmeyer-Plöchl azlactone strategy. Products of expected metabolism of the amino acid, including 6-fluoro-meta-tyramine (2) and its O-sulfate conjugate (3), (2-fluoro-5-hydrxoyphenyl)acetic acid (4), and 6-fluoro-meta-octopamine (5) also were prepared from 1. The use of a recently reported ultrasound-catalyzed Henry reaction facilitated the preparation of the tyramine derivative 2. The compounds synthesized are available for high performance liquid chromatography (HPLC) standards in positron emission tomography (PET) studies employing 6-[¹⁸F]fluoro-meta-tyrosine and as reference samples for metabolic studies of the amino acid.     

Fluoroalkyl substituted (Z)-dehydro α-amino ester as a building block for the fluorine-containing cyclopropyl α-amino esters and dihydrooxazole

Multi-functionalized β-trifluoromethyl and β-difluoromethyl substituted (Z)-α,β-dehydro α-amino esters have been successfully prepared from N-protected fluorinated threonine ester. Applications of this new fluorine-containing building block to the synthesis of biologically important fluorinated cylcopropyl α-amino esters and dihydrooxazole ester have also been reported.     

Cycloadditions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and various tosylacetamides: Synthesis of trifluoromethylated pyroglutamates and 2-pyridones derivatives

Cycloaddition reactions between methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate and various 2-tosylacetamides are described. Various 2-tosylacetamides react with methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate in the presence of NaH at room temperature in one step to form trifluoromethylated pyroglutamates as single diastereomers. However, employing the same reactants using t-BuOK as base at ?78?°C results in the formation of trifluoromethylated 2-pyridones. A ring-closure mechanism is proposed for the reaction.     

Fluorinated acrylates via alkoxycarbonylation of 1-alkynes with fluorinated alcohols

The system formed by combining in situ Pd(OAc)₂ with (2-pyridyl)diphenylphosphine (PyPPh₂) and CH₃SO₃H catalyzes efficiently the carbonylation of terminal alkynes (phenylacetylene or 1-hexyne) with alcohols having perfluorinated segments of the type CF₃(CF₂)_m(CH₂)_n–OH (m=1 or 3, n=1, 2 or 3) or with pentafluorophenol. Good carbonylation rates accompanied by high regioselectivity towards acrylate ester formation are obtained under mild reaction conditions (T=60–80 °C, P(CO)=30 atm). The influence of the CO pressure, the catalyst composition, the temperature and the number (n) of protonated methylene groups on the catalysis has been studied.     

Thermomorphic metal scavengers: A synthetic and multinuclear NMR study of highly fluorinated ketones and their application in heavy metal removal

The preparation of a ketone with two long chain perfluoroalkyl groups is reported via the coupling reaction of a perfluorinated alkylzinc reagent and a perfluoro-acid chloride. This ketone has been investigated in the heterogeneous removal of heavy metals M²⁺ (M = Sn, Cd, Pb, Hg) and As⁵⁺ from aqueous solutions and removal of these metals from organic solvents using the unique thermomorphic properties of the fluorous ketone. In addition, a comprehensive ¹³C NMR study of one of the intermediates in the synthesis, 2H,2H,3H,3H-perfluoronanoic acid, has allowed the determination of all ¹J_C-F and ²J_C-F coupling constants. Also reported is the crystal structure of the acid CF₃(CF₂)₅CH₂CH₂CO₂H.     

Synthesis of 2-aryl-3-hydroxymethyl-5,5-difluoropiperidines

A strategy toward the synthesis of functionalized 5,5-difluoropiperidines, a class of compounds with potential as building block in medicinal chemistry, was developed. In a three-step procedure 2,2-difluoroglutaric anhydride was synthesized starting from ethyl bromodifluoroacetate. This key intermediate reacts fluently with various imines to yield 5,5-difluoropiperidinone carboxylic acids. Subsequent esterification of the obtained carboxylic acids enabled the isolation of trans-substituted 5,5-difluoro-2-arylpiperidinone-3-carboxylates as the major isomers. Reduction of the difluorinated piperidinonecarboxylates using borane gave rise to new trans-2-aryl-1-benzyl-5,5-difluoro-3-hydroxymethylpiperidines in excellent yields.     

A novel class of organosoluble and light-colored fluorinated polyamides derived from 2,2-bis(4-amino-2-trifluoromethylphenoxy)biphenyl or 2,2-bis(4-amino-2-trifluoromethylphenoxy)-1,1-binaphthyl

Two series of novel fluorinated aromatic polyamides were prepared from 2,2^′-bis(4-amino-2-trifluoromethylphenoxy)biphenyl (2) and 2,2^′-bis(4-amino-2-trifluoromethylphenoxy)-1,1^′-binaphthyl (4) with various aromatic dicarboxylic acids using the phosphorylation polycondensation technique. The polyamides had inherent viscosities ranging from 0.43 to 0.62 dl/g and 0.36 to 0.74 dl/g, respectively. All the fluorinated polyamides were soluble in many polar organic solvents such as N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidinone, and afforded transparent, light-colored, and flexible films upon casting from DMAc solvent. These polyamides showed glass-transition temperatures in the ranges of 190-240 °C (for the 6 series from diamine 2) and 247-255 °C (for the 7 series from diamine 4) by differential scanning calorimetry, softening temperatures in the ranges of 196-230 °C (6 series) and 241-291 °C (7 series) by thermomechanical analysis, and decomposition temperatures for 10% weight loss above 420 °C in both nitrogen and air atmospheres.     

Synthesis and characterization of a new class of polyfluorinated alkanes: tetrakis(perfluoroalkyl)alkane

The synthesis and physico-chemical characterization of 1,1,2,2-tetrakis(perfluoroalkyl-methylene)ethane {[F(CF₂)_nCH₂]₂CH}₂ (n=6, TK6; n=8, TK8) are reported. The synthesis consists of four steps: (1) addition of allyl alcohol to a perfluoroalkyl iodide, F(CF₂)_nI (n=6,8) to give the corresponding iodo-adduct; (2) dehalogenation of the adduct by treatment with zinc in aqueous acetic acid, yielding 3-perfluoro-n-alkyl-1-propene; (3) addition of 3-perfluoro-n-alkyl-l-propene to perfluoroalkyl iodide, F(CF₂)_nI (n=6,8) to give 1,3-perfluoro-n-alkyl-2-iodo-propane; (4) coupling of 1,3-perfluoro-n-alkyl-2-iodo-propane by zinc in acetic anhydride giving the final products. TK6 and TK8 are characterized by very low surface tension values and exhibit very good properties as potential ski-waxes.     

A convenient one-pot synthesis of 2-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one derivatives and their further transformations

The trifluoromethyl containing heterocycles, 2-hydroxy-4-aryl-3-(thien-2-oyl)-2-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one derivatives 4, were synthesized via a one-pot three-component reaction of aldehyde 1 with 1,3-cyclohexanedione 2 and 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione 3 in the presence of a catalytic amount of Et₃N. The effect of bases and solvents on the reaction efficiency and yield was briefly investigated. Treatment of 4 with an excess amount of NH₄OAc in ethanol afforded 2-trifluoromethyl-1H-quinolin-5-one derivatives 5. Refluxing of 4 with TsOH in CHCl₃ gave the corresponding dehydrated products 8.     

Synthesis and characterization of partially fluorinated stearolic acid analogs: Effect of their fluorine content on the monolayer at the air-water interface

Novel stearolic acid analogs (i.e., 9-octadecynoic acid analogs: 1a-d) containing the shorter perfluoroalkyl groups, CF₃, C₂F₅, n-C₃F₇ or n-C₄F₉ group were synthesized. Equilibrium spreading pressures (π_es) of their monolayers at the air-water interface were measured in order to demonstrate how the fluorine content has an effect on the stability of the fatty acid monolayers. As the fluorine content in stearolic acid molecule increased, its melting points was lowered indicating the solid bulk phase of stearolic acid became thermally unstable, while its monolayer stability evaluated by π_e at 25 °C, dramatically increased and subsequently leveled off above a certain fluorine content. Under this condition, the replacement of at least five hydrogen atoms at the terminal hydrophobic segment in stearolic acid molecule by fluorine atoms (CF₃CF₂ group) was required to alter the bulk property of stearolic acid and exhibit the stabilization of monolayers, whereas further fluorination of stearolic acid had a minor effect on the monolayer stability. This behavior suggests the terminal fluorinated hydrophobic segment exclusively controls the interfacial stability of fatty acid monolayers.