Reinvestigation of the reaction of ethyl 4,4,4-trifluoroacetoacetate with aldehydes and ammonia

Reaction of ethyl 4,4,4-trifluoroacetoacetate with aromatic aldehydes and ammonia gives diethyl 4-aryl-2,6-dihydroxy-2,6-bis(trifluoromethyl)-3,5-piperidinedicarboxylates ( 4 ) instead of diethyl 4-aryl-1,4-dihydro-2,6-bis(trifluoromethyl)-3,5-pyridinedicarboxylates ( 3 ) as reported previously (1).     

A Convenient Synthesis of 3,5-bis(Trifluoromethyl)Salicylic Acid

A convenient method is reported for the synthesis of the biologically important intermediate, 3,5-bis(trifluoromethyl)-salicylic acid, by a sequence involving diazotization/iodination of 2-bromo-3,5-bis(trifluoromethyl)aniline, displacement of the bromide with sodium methoxide, and carboxylation of the anion generated by lithium-iodine exchange with carbon dioxide. Alternatively, the anion could be carbonylated with dimethylformamide and the resulting aldehyde oxidized with Jones reagent. Demethylation of 3,5-bis(trifluoromethyl)anisic acid with boron tribromide gave the title compound.     

Simple and convenient synthesis of 3,5-bis-(trifluoromethyl)benzylamine via biomimetic 1,3-proton shift reaction

This paper describes an efficient, practical synthesis of 3,5-bis(trifluoromethyl)benzylamine via biomimetic transamination of 3,5-bis(trifluoromethyl)benzaldehyde with benzylamine. From a synthetic standpoint the reported procedure is highly operationally convenient and scalable as it does not require any chromatographic purification of the intermediate products.     

Reaction of 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole with primary amines. Synthesis of 4-substituted-3,5-bis(trifluoromethyl)-4H-1,2,4-triazoles

Reaction of 3,5-bis(trifluoromethyl)-1,3,4-oxadiazole ( 1a ) with primary amines under a variety of conditions conveniently produced 4-substituted-3,5-bis(trifluoromethyl)-4H-1.2,4-triazoles 4a in 26-85% yield. Alkyl amines reacted with 1a in methanol at ?42° to provide hydrogen-bonded monoadduct-methanol complexes 5a , as determined by X-ray. The reaction of 1a with sterically hindered or strongly electron deficient anilines required high temperatures in the absence of solvent.     

Synthesis and characterization of new soluble fluorinated seco-porphyrazines

Magnesium porphyrazinate substituted with eight 3,5-bis(trifluoromethyl)phenyl groups on the peripheral positions has been synthesized by the cyclotetramerization of 3,4-[3,5-bis(trifluoromethyl)phenyl]pyrroline-2,5-diimine in the presence of magnesium butanolate. Acid-mediated demetallation of the magnesium porphyrazine resulted in peripheral oxidation of one pyrrole ring to reveal the seco-porphyrazine, octakis[3,5-bis(trifluoromethyl)phenyl]-2-seco-porphyrazine-2,3-dione. Further reaction of this product with copper (II) acetate, zinc (II) acetate and cobalt (II) acetate has led to the metallo-derivatives, {octakis[3,5-bis(trifluoromethyl)phenyl]-2-seco-2,3-dioxoporphyrazinato} M(II) [M = Cu(II), Zn(II), Co(II)]. These new soluble complexes were characterized by elemental analysis, together with FT-IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, UV-Vis and mass spectral data.     

Et3N-Catalyzed Cycloaddition Reactions ofα-(Trifluoromethyl)styrenes with 2,2,2-Trifluorodiazoethane to Access Bis(trifluoromethyl)-Substituted Pyrazolines

A novel and practical method for the synthesis of 3,5-bis(trifluoromethyl)-4,5-dihydro-1H-pyrazoles by [3+2] cycloaddition reactions of α-(trifluoromethyl)styrenes with 2,2,2-trifluorodiazoethane (CF3CHN2) has been developed. The cyclization reaction proceeds smoothly in the presence of a catalytic amount of Et₃N, affording a variety of bis(trifluoromethyl)-substituted 2-pyrazolines in good to excellent yields. This method also exhibits a broad substrate scope and tolerates various functional groups.     

Diversity Oriented Preparation of Pillar[5]arene-Containing [2]Rotaxanes by a Stopper Exchange Strategy

Rotaxane building blocks bearing 3,5-bis(trifluoromethyl) benzenesulfonate (BTBS) stoppers have been efficiently prepared from a pillar[5]arene derivative, 3,5-bis(trifluoromethyl) benzenesulfonyl chloride (BTBSCl) and different diols, namely 1,10-decanediol and 1,12-dodecanediol. The BTBS moieties of these compounds are good leaving groups and stopper exchange reactions could be achieved by treatment with different nucleophiles thus affording rotaxanes with ester, thioether or ether stoppers.     

Process development and large-scale synthesis of NK1 antagonist

A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)(1) antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluoromethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3). Treatment of 15 with 1,8-diazabicyclo[5,4,0]undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is amenable to large scale synthesis.     

An improved preparation of 3,5-bis(trifluoromethyl)acetophenone and safety considerations in the preparation of 3,5-bis(trifluoromethyl)phenyl Grignard reagent

An improved and efficient bromination of 3,5-bis(trifluoromethyl)benzene was developed. A safe and reliable preparation of the potentially explosive 3,5-bis(trifluoromethyl)phenyl Grignard and 3-trifluoromethylphenyl Grignard reagents, from the precursor bromides, is described. Reaction System Screening Tool (RSST) and Differential Thermal Analysis (DTA) studies suggest these trifluoromethylphenyl Grignard reagents can detonate on loss of solvent contact or upon moderate heating. When prepared and handled according to the methods described herein, these Grignard reagents can be safely prepared and carried on to advanced intermediates.     

Production,Partial Purification,and Biochemical Characterization of a Thermotolerant Alkaline Metallo-protease from Staphylococcus sciuri

Applied Biochemistry and Biotechnology - (R)-[3,5-bis(trifluoromethyl) phenyl] ethanol [(R)-3,5-BTPE] is a crucial chiral intermediate for the synthesis of the NK-1 receptor antagonists aprepitant,...     

A green approach to the preparation of triangular silver(I) 3,5-bis(trifluoromethyl)pyrazolate: crystal structures of two adducts with triethylammonium nitrate or benzoic acid

Transition Metal Chemistry - An improved procedure is described herein for the synthesis of triangular Ag(I) 3,5-bis(trifluoromethyl)pyrazolate ({[3,5-(CF3)2Pz]Ag}3), which involves initial...     

Development of perfluoroarene-arene interactions for macrocyclic en-yne metathesis and the total synthesis of macrocyclic natural products

Efficient direct en-yne metathesis of strained macrocyclic systems is possible using highly active Grubbs-Hoveyda second-generation catalyst and when exploiting fluoroarene-arene gearing interactions. These interactions are effective even under high reaction temperatures and in the presence of a competitive pi-rich solvent such as toluene. These results suggest that efficient pi-pi stacking or pi-lp interactions between auxiliaries containing pentafluorophenyl and 3,5-bis(trifluoromethyl)phenyl groups are responsible for the good yields of macrocyclization products. The 3,5-bis(trifluoromethyl)benzyl gearing elements provide higher yields and greater E-selectivity in the macrocyclic en-yne metathesis to form model paracyclophanes that could be applied toward the preparation of members of the longithorone family of natural products.     

Asymmetric conjugate additions of α-substituted-α-cyanoacetates to acetylenic ketones by chiral phase transfer catalysis

Asymmetric conjugate addition of α-substituted-α-cyanoacetates to acetylenic ketones has been achieved with high enantioselectivity and moderate E/Z selectivity under the influence of our recently designed, binaphthyl-modified 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl substituted phase transfer catalyst.     

Enantioselective hydrogenation of acyclic aromatic N-aryl imines catalyzed by an iridium complex of (S,S)-1,2-bis(tert-butylmethylphosphino)ethane

[reaction: see text] An iridium(I) complex of (S,S)-1,2-bis(tert-butylmethylphosphino)ethane with tetrakis(3,5-bis(trifluoromethyl)phenyl)borate as the counterion catalyzes the hydrogenation of acyclic aromatic N-aryl imines under 1 atm of hydrogen pressure at room temperature to give the corresponding optically active secondary amines with up to 99% ee.     

Reactions of tri- and hexafluoroacetylacetones and 4-ethoxy-1,1,1-trifluorobut-3-en-2-one with 2-aminobenzohydrazide

Reactions of 1,1,1-trifluoropentane-2,4-dione and 1,1,1,5,5,5-hexafluoropentane-2,4-dione with 2-aminobenzohydrazide afforded (2-aminophenyl)[5-hydroxy-3-methyl-5-(trifluoromethyl)- and (2-aminophenyl)[ 5-hydroxy-3,5-bis(trifluoromethyl)-4,5-dihydropyrazol-1-yl]methanones, respectively. 4-Ethoxy-1,1,1- trifluorobut-3-en-2-one reacted with 2-aminobenzhydrazide to give 2-(trifluoromethyl)-3a,4-dihydropyrazolo-[5,1-{ptb}]quinazolin-9(3{ptH})-one.     

Deprotonation of pyrazole and its analogs by aqueous copper acetate in the presence of triethylamine

Deprotonation reactions of pyrazole and its analogs by aqueous copper acetate in benzene at room temperature in the presence of triethylamine were studied. Unlike 3,5-dimethylpyrazole, more acidic pyrazole, 5-methyl-3-trifluoromethylpyrazole, and 3,5-bis(trifluoromethyl)pyrazoles are deprotonated to give pyrazolate bridges. The structural features of the obtained compounds are discussed based on X-ray diffraction data.     

Enantio- and diastereoselective hydrogenation via dynamic kinetic resolution by a cationic iridium complex in the synthesis of beta-hydroxy-alpha-amino acid esters

Anti-selective asymmetric hydrogenation of alpha-amino-beta-keto esters via dynamic kinetic resolution under low hydrogen pressure has been achieved by an easily-handled cationic iridium complex with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF) as a counterion.     

Thiourea catalyzed aminolysis of epoxides under solvent free conditions. Electronic control of regioselective ring opening

A reactant economizing process for the regioselective aminolysis of epoxides using equimolar quantities of reactants catalyzed by the double hydrogen bond donor N,N′-bis[3,5-bis(trifluoromethyl)phenyl]thiourea is reported. Regioselectivity of the reaction is controlled by the electronic nature of the substituent on the styrene oxide, which has been substantiated on the basis of ¹³C NMR data and DFT calculations.     

Synthesis,Molecular Structure,Biological Activity,and Sensor Properties of (E)-2-[(3,5-Bis(trifluoromethyl)phenylimino)methyl]-4,6-dichlorophenol

Russian Journal of General Chemistry - In the present study, a Schiff base (E)-2-[(3,5-bis(trifluoromethyl)phenylimino)methyl]-4,6-dichlorophenol has been synthesized. Its spectroscopic and X-ray...     

Boron-based rotaxanes by multicomponent self-assembly

The multicomponent reaction of 1,2-di(4-pyridyl)ethylene, catechol, 3,5-bis(trifluoromethyl)phenylboronic acid and 1,5-dinaphtho-38-crown-10 or bis-para-phenylene-34-crown-10, respectively, resulted in the formation of rotaxanes, which were characterized by X-ray crystallography.