Synthesis and applications of ?-trifluoromethylated alkylboron compounds.
ABSTRACT: RBF3 K is a chemist's BFF: A metal-free synthetic route to unprecedented organoboron compounds bearing an ?-trifluoromethyl substituent, employing a variety of trifluoroborate (RBF3 K) starting materials, is reported. These substrates represent the first isolated ?-trifluoromethylated alkylboron building blocks, and these reagents lead to a variety of useful bench-stable, synthetic intermediates. Pin=pinacol.
Project description:Isoxazolidines have proven to be important substrates in synthetic organic chemistry. Limited examples in the literature that provide trifluoromethylated versions of these compounds have prompted us to investigate a 1,3-dipolar cycloaddition route providing access to N-functionalized isoxazolidines containing a trifluoromethyl group. Thus, a 1,3-dipolar cycloaddition of nitrosoarenes, (trifluoromethyl)diazomethane, and alkenes was developed. The starting materials can be synthesized from easy to handle and accessible reagents. The reaction proved to be tolerant of a variety of electron-deficient alkenes and nitrosoarenes.
Project description:Enabled by the discovery of new cinchonium salts and coadditives, a direct and efficient asymmetric access to trifluoromethylated ?-amino esters/lactones has been realized through the enantioselective and diastereoselective umpolung reaction of trifluoromethyl imines with acrylates or ?,?-unsaturated lactones as carbon electrophiles. At 0.5-5.0 mol % catalyst loadings, the newly developed catalytic system activates a variety of imine substrates as unconventional nucleophiles to mediate highly chemo-, regio-, diastereo-, and enantioselective C-C bond forming reactions. The developed synthetic protocol represents an excellent strategy to target a series of versatile and enantiomerically enriched ?-amino esters/lactones in good to excellent yields from the readily available starting materials. Additionally, we found that the epi-vinyl catalysts based on cinchonidine and quinine promote a similarly high enantioselective reaction generating the opposite configuration of chiral products in a highly efficient manner, which allows convenient access to either the R- or S-enantiomer of the chiral amine products in high yields and excellent enantioselectivities.
Project description:An efficient palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides has been developed. The reaction proceeds under mild reaction conditions with high efficiency and excellent functional group tolerance, even towards formyl and hydroxy groups. Preliminary mechanistic studies reveal that a secondary trifluoromethylated alkyl radical is involved in the reaction.
Project description:A new approach toward the asymmetric synthesis of optically active trifluoromethylated amines was enabled by an unprecedented, highly enantioselective catalytic isomerization of trifluoromethyl imines with a new chiral organic catalyst. Not only aryl but also alkyl trifluoromethylated amines could be obtained in high enantioselectivities.
Project description:The reaction of enamine compounds with the Togni reagent in the presence of CuI afforded ?-trifluoromethylated enamine intermediates, which were converted directly to biologically interesting trifluoromethylated 2H-azirines by an iodosobenzene (PhIO)-mediated intramolecular azirination in a one-pot process.
Project description:We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable <i>a priori</i>. The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling.
Project description:Addition of nitrosobenzene to pinacol allylboronates leads to oxidation of the organoboron with concomitant rearrangement of the substrate alkene. This reaction appears to proceed by allylboration of the nitroso group in analogy to carbonyl and imine allylation reactions. Remarkably, the N-O bond is cleaved during the reaction such that simple alcohols are the final reaction product.
Project description:Protected guanosine and adenosine ribonucleosides and guanine nucleotides are readily functionalized with CF3 substituents within the nucleobase. Protected guanosine is trifluoromethylated at the C8 position under radical-generating conditions in up to 95% yield and guanosine 5'-oligophosphates in up to 35% yield. In the case of adenosine, the selectivity of trifluoromethylation depends heavily on the functional group protection strategy and leads to a set of CF3-modified nucleosides with different substitution patterns (C8, C2, or both) in up to 37% yield. Further transformations based on phosphorimidazolide chemistry afford various CF3-substituted mono- and dinucleoside oligophosphates in good yields. The utility of the trifluoromethylated nucleotides as probes for 19F NMR-based real-time enzymatic reaction monitoring is demonstrated with three different human nucleotide hydrolases (Fhit, DcpS, and cNIIIB). Substrate and product(s) resonances were sufficiently separated to enable effective tracking of each enzymatic activity of interest.
Project description:A series of trifluoromethylated pyrazole thiosemicarbazone, trifluromethylated pyrazole isothiosemicarbazone, and trifluoromethylated pyrazole 2-amino-1,3,4-thiadiazole hybrids were synthesized and evaluated in vitro against the promastigote form of Leishmania amazonensis and the epimastigote form of Trypanosoma cruzi, the pathogens causing the neglected tropical diseases leishmaniasis and Chagas disease, respectively. The results show the potential of these compounds regarding their antiparasitic properties. Studies on the structure-activity relationship demonstrated that compounds containing a bulky group at the para position of the phenyl ring attached to the 5-position of the pyrazole core had better antiparasitic effects. Among the substituents attached at the 3-position of the pyrazole ring, the insertion of the 2-amino-1,3,4-thiadiazole nucleus led to the most potent compounds compared to the thiosemicarbazone derivative.
Project description:The prenyl group is an important component in bioactive compounds. Herein, we report the assembly of prenylated heteroarenes through a cascade Minisci reaction and acid-promoted dehydration sequence. The use of potassium (3-hydroxy-3-methylbut-1-yl)trifluoroborate as a new coupling reagent allows the direct introduction of prenyl and 3-hydroxy-3-methylbutyl groups to a wide variety of electron-deficient heteroarenes. Synthetic application is also demonstrated.