Study on the reactions of ethyl 4,4,4-trifluoro-3-oxobutanoate with arylidenemalononitriles

In the presence of a catalytic amount of NEt₃, ethyl 4,4,4-trifluoro-3-oxobutanoate 1 reacted readily with arylidenemalononitriles 2 in ethanol at room temperature. It gave two products 2-trifluoromethyl-3,4-dihydro-2H-pyran derivatives 3 and 2-(trifluoromethyl)piperidine derivatives 4, the ratio of 3 and 4 was depended on the substrates 2 and reaction solvents. Reflux of the ethanol solution of 4 with a catalytic amount of NEt₃ afforded 2-trifluoromethyl-1,4,5,6-tetrahydropyridine derivatives 5 in moderate to good yields. The structures of new compounds 3, 4 and 5 were determined by spectral methods, microanalysis and X-ray diffraction analysis. A possible reaction mechanism for the formation of 3, 4 and 5 was presented.     

Structural studies of lithium 4,4-difluoro- and 4,4,4-trifluoro-3-oxybutenoates

The condensation of ethyl difluoroacetate or ethyl trifluoroacetate with ethyl acetate in the presence of lithium hydride afforded lithium ethyl 4,4-difluoro- and ethyl 4,4,4-trifluoro-3-oxybutenoates, respectively. The structures of the complexes were established by X-ray diffraction.     

Unusual transformations of arylhydrazonoyl chlorides of ethyl oxalate

X-ray diffraction structural analysis, IR,¹³C NMR, and PMR spectroscopy was used to establish that the products of the reactions of arylhydrazonoyl chlorides of ethyl oxalate and sodium ethylate are 1,4-diaryl-3,6-dicarboethoxy-1,4-dihydro-1,2,4,5-tetrazines and 1-aryl-3-carboethoxy-4-arylhydrazono-5-pyrazolones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2635–2637, November, 1990.     

Preparation by yeast reduction and determination of the sense of chirality of enantiomerically pure ethyl (−)-4,4,4-trichloro-3-hydroxy- and (+)-4,4,4-trifluoro-3-hydroxybutanoate

Reduction of ethyl 4,4,4-trichloro- and 4,4,4-trifluoro-3-oxobutanoate by fermenting baker's yeast (Saccharomyces cerevisiae) on a preparative scale (20–50 g in ca. 3 1 of H₂O) gave 70–80% yields of the trichloro- [(?)-(S)- 1a ] and trifluoro-hydroxyesters [(+)-(R) 2a ] of ca. 85 and 45% ee, respectively. Both, (?)- 1a and (+)- 2a could be obtained in > 98% ee by subsequent crystallization (of(?)- 1 , (+)- 2a or the 3,5-dinitrobenzoate (+)- 2b . The absolute configuration of both hydroxyesters was determined (a) by chemical correlation ((?)- 1a ), (b) from the melting diagrams and mixed melting points (differential-scanning calorimetry Fig. 1) of the dinitrobenzoates of the CF₃-derivative (+)- 2a and its CH₃-analogue 8 , and c) by X-ray analysis of the ester 2f from (+)- 2a and (?)-camphanoyl chloride (Fig. 2 and 3).     

Ring-chain isomeric transformations. The cyclohemiketal structure of 4,4,4-trifluoro-1-(2-hydroxyphenyl)-1,3-butanediones

Compounds $\text{4}$-$\text{8}$ exist only in the cyclohemiketal form both in the solid state and in solution, in contrast with earlier assumptions on their enolic structure.     

Synthesis of 3,3,3-trifluoropropionic and 4,4,4-trifluoro-2-ketobutyric acids

Trifluoroethyl cyclohexyl ketone ($\text{4}$) is prepared by acylation of difluoroethylene ($\text{2}$) with cyclohexanecarboxylic acid chloride ($\text{1}$), followed by Cl→F exchange with potassium fluoride in the presence of triethylbenzyl- ammonium chloride. Bayer-Villiger oxidation of ketone ($\text{4}$) with trifluoroperacetic acid gives cyclohexyl trifluoropropionate ($\text{5}$). 3,3,3-trifluoropropionic acid ($\text{6}$) is obtained by treatment of ($\text{5}$) with trimethylsilyl iodide. Condensation of 2,2,2-trifluorodiazoethane ($\text{7}$) with ethyl glyoxylate ($\text{8}$) gives mainly ethyl 4,4,4-trifluoro-2-ketobutyric acid ester ($\text{9}$) which leads after hydrolysis to the corresponding acid ($\text{12}$).     

Synthesis of (R)-4,4,4-trifluoro-2-mercaptobutyric acid

Syntheses of (R)-4,4,4-trifluoro-2-mercaptobutyric acid from (S)-malic acid via a Mitsunobu reaction and from (rac)-thiomalic acid on enzymatic resolution, using Pseudomonas cepacia (Amano lipase PS), are described. A new method for direct determination of ees for (R)- and (S)-4,4,4-trifluoro-2-mercaptobutyric acid derivatives by HPLC on a polysaccharide phase is disclosed.     

Addition of thiols to ethyl 4,4,4-trifluorocrotonate

Ethyl 4,4,4-trifluorocrotonate 1 readily adds aliphatic and aromatic thiols and aminothiols at the double bond in the presence of catalytic amounts of alkylamines and ammonia to give 3-thiolation products. Thiolacetic acid reacts with ester 1 in the absence of a catalyst at 100 °C.     

Asymmetric reductions of ethyl 2-(benzamidomethyl)-3-oxobutanoate by yeasts

The stereoselective reduction of ethyl 2-(benzamidomethyl)-3-oxobutanoate 1 using yeasts was investigated among a restricted number (12) of yeasts. Kluyveromyces marxianus var. lactis CL69 diastereoselectively produced (2R,3S)-ethyl 2-(benzamidomethyl)-3-hydroxybutanoate 2, whereas Pichia glucozyma CBS 5766 gave (2S,3S)-2 as the major stereoisomer. The biotransformations were independently optimized for minimizing by-product formation and maximizing the diastereoselectivity. Under optimized conditions, K. marxianus var. lactis CL 69 gave the (2R,3S)-ethyl 2-(benzamidomethyl)-3-hydroxybutanoate 2 with ee > 99% and de = 98%, while P. glucozyma CBS 5766 allowed for the production of (2S,3S)-2 with ee > 99% and de = 86%.     

Synthesis and transformations of 1,1,1-trifluoro-2-benzylthiopropene

Conclusions 1,1,1-Trifluoro-2-benzylthiopropene was synthesized and the reactions of this sulfide with electrophiles and nucleophiles (H₂SO₂, SO₂C₁₂ and NHEt₂) leading 1,1,1-trifluoroacetone, 1,1,1-trifluoro-2,3-dichloro-2-benzylthiopropane and 1-trifluoromethy1-2-(N,N-diethylamino)-ethyl benzyl sulfide, respectively, were studied.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 209–211, January, 1987.     

Unexpected transformation of 3-amino-4,4,4-trifluoro-1-phenylbut-2-en-1-one into 2,6-diphenyl-4-trifluoromethylpyridine

1. Download : Download high-res image (73KB)
2. Download : Download full-size image

     

Preparation of 3-substituted and 2,3-disubstituted-4,4,4-trifluoro-2-butenoic acids—Perkin condensation of activated aromatic ketones

The Perkin reaction of the activated aromatic ketones (2,2,2-trifluoroacetophenone and its 4′-phenyl-derivative) with various condensing agents (acetic anhydride, propionic anhydride, phenylacetic acid/acetic anhydride) gives the title compounds in good or moderate yields, and high E-stereoselectivity. For some derivatives an appreciable amount of the Z isomer was also formed. Several of the resulting butenoic acids and their methyl esters are synthesised and characterised for the first time.     

A computational study of lithium enolate mixed aggregates

Ab initio calculations were performed to examine the formation of mixed dimer and trimer aggregates between the lithium enolate of acetaldehyde (lithium vinyloxide, LiOV) and lithium chloride, lithium bromide, and lithium amides. Gas-phase calculations showed that in the absence of solvation effects, the mixed trimer 2LiOV.LiX is the most favored species. Solvation in ethereal solvents was modeled by a combination of specific coordination of dimethyl ether ligands on each lithium and "dielectric solvation" (DSE, dielectric solvation energies), immersion of each molecule in a cavity within a continuous dielectric having the dielectric constant of THF at room temperature. DSE is less important for aggregates (reduced dipoles or quadrupoles) than monomers (dipoles) and is also reduced for the coordinatively solvated species. Both solvation terms reduce the exothermicity of aggregation. In many cases, lithium salts that are three- rather than four-coordinate have significant populations at room temperature. The strongly basic lithium amides prefer mixed aggregates with weaker bases than homoaggregates. The computational results are consistent with the limited experimental data available.     

Synthesis of ethyl 3-oxo-2-(3,4,5-trifluoro-2,6-dimethoxybenzoyl)butyrate

Ethyl acetoacetate was acylated with 3,4,5-trifluoro-2,6-dimethoxybenzoyl chloride to give, for the first time, ethyl 3-oxo-2-(3,4,5-trifluoro-2,6-dimethoxybenzoyl)butyrate and its copper chelate. The title compound was used for the synthesis of 6,7,8-trifluoro-5-hydroxy-2-methylchromone, 1-(3,4,5-trifluoro-2,6-dimethoxyphenyl)butane-1,3-dione, and its copper chelate.     

Molecular and crystal structure of 4,4,4-trifluoro-3,3-dihydroxy-1-thiophene-2-yl-butane-1-one

An X-ray diffraction analysis and quantum chemical calculations of hydrated 2-thenoyltrifluoroacetone show that the planar diketone, form of TTA found in its metal complexes, does not occur in the free ligand. Hydrated TTA with two geminal hydroxo groups has a non-planar structure stabilized by an intramolecular hydrogen bond.     

Indium-mediated diastereoselective allylation of D- and L-glyceraldimines with 4-bromo-1,1,1-trifluoro-2-butene: highly stereoselective synthesis of 4,4,4-trifluoroisoleucines and 4,4,4-trifluorovaline

A practical and efficient route for the stereoselective synthesis of (2R,3S)- and (2S,3R)-4,4,4-trifluoroisoleucines and (2R,3S)-4,4,4-trifluorovaline was developed. Indium-mediated allylation of (R)-N-benzyl-2,3-O-isopropylideneglyceraldimine 7 with 4-bromo-1,1,1-trifluoro-2-butene 4 gave the desired homoallylic amine 8 in high diastereoselectivity (>95% de) with moderate yield. The Cbz-protected (2R,3S)-4,4,4-trifluoroisoleucine 14 and Boc-protected (2R,3S)-4,4,4-trifluorovaline 21 were then readily prepared from 8. In addition, following the same procedure, Cbz-protected (2S,3R)-4,4,4-trifluoroisoleucine 28, the enantiomer of 14, was prepared starting from (S)-N-benzyl-2,3-O-isopropylideneglyceraldimine 24.     

Synthesis of chiral tetronic acid derivatives via organocatalytic conjugate addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes

Asymmetric conjugate addition of ethyl 4-chloro-3-oxobutanoate to nitroalkenes and subsequent intramolecular cyclization had been developed. This one-pot reaction provided tetronic acid derivatives in good yields and with excellent enantioselectivities. 6′-Demethyl quinine was found to be the best catalyst for the conjugate addition and AcOLi was identified as the best base for the intramolecular cyclization. Various β-aryl, heteroaryl, and alkyl nitroalkenes are generally applicable in the reaction.