HFIP-Promoted Bischler Indole Synthesis under Microwave Irradiation.
ABSTRACT: 1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP) was found to be effective for the Bischler indole synthesis under microwave irradiation in the absence of a metal catalyst. Under the catalysis of HFIP, a wide range of ?-amino arylacetones were successfully transformed into indole derivatives with moderate to good yields.
Project description:In the present work, the employment of fluorinated alcohols, specifically 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), as solvent and promoter of the catalyst-free synthesis of substituted tetrahydrofuranes through the addition of electron-rich alkenes to epoxydes is described. The unique properties of this fluorinated alcohol, which is very different from their non-fluorinated analogs, allows carrying out this new straightforward protocol under smooth reaction conditions affording the corresponding adducts in moderate yields in the majority of cases. Remarkably, this methodology has allowed the synthesis of new tetrahydrofuran-based spiro compounds as well as tetrahydrofurobenzofuran derivatives. The scope and limitations of the process are also discussed. Mechanistic studies were also performed pointing towards a purely ionic or a SN2-type process depending on the nucleophilicity of the alkene employed.
Project description:An efficient synthesis of novel 2,3-dihydro-4H-pyrido[1,2-a]pyrimidin-4-ones has been reported. Inexpensive and readily available substrates, environmentally benign reaction condition, and product formation up to quantitative yield are the key features of this methodology. Products are formed by the aza-Michael addition followed by intramolecular acyl substitution in a domino process. The polar nature and strong hydrogen bond donor capability of 1,1,1,3,3,3-hexafluoropropan-2-ol is pivotal in this cascade protocol.
Project description:Mechanistic insight into the pathway of the Bischler-Mohlau indole formation reaction is provided by isotopic labeling utilizing judicious incorporation of a (13)C atom within the ?-bromoacetophenone analogue reactant. The resulting rearranged 2-aryl indole, isolated as the major product, located the (13)C isotope label at the methine carbon of the fused five-membered heterocyclic ring, which suggested that the mechanistic pathway of cyclization, in this specific example, required two equivalents of the aniline analogue reactant partner and proceeded through an imine intermediate rather than by direct formation of the corresponding 3-aryl indole accompanied by a concomitant 1,2-aryl shift rearrangement.
Project description:Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and profiling technology have become the easiest methods for quickly accessing the protein composition of a tissue area. Unfortunately, the demand for the identification of these proteins remains unmet. To overcome this bottleneck, we combined several strategies to identify the proteins detected via MALDI profiling including on-tissue protein extraction using hexafluoroIsopropanol (1,1,1,3,3,3-hexafluoro-2-propanol, HFIP) coupled with two-dimensional cetyl trimethylammonium bromide/sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2D CTAB/SDS-PAGE) for separation followed by trypsin digestion and MALDI-MS analyses for identification. This strategy was compared with an on-tissue bottom-up strategy that we previously developed. The data reflect the complementarity of the approaches. An increase in the number of specific proteins identified has been established. This approach demonstrates the potential of adapted extraction procedures and the combination of parallel identification approaches for personalized medicine applications. The anatomical context provides important insight into identifying biomarkers and may be considered a first step for tissue-based biomarker research, as well as the extemporaneous examination of biopsies during surgery.
Project description:In strong Brønsted acids (CF3SO3H, FSO3H, D2SO4), (arysulfonyl)allenes (ArSO2-CR1=C=CR2R3) and (arylsulfinyl)allenes (ArSO-CR1=C=CR2R3) undergo cyclization into the corresponding stable 1,2-oxathiolium ions, which were studied by means of NMR and DFT calculations. Quenching of solutions of these cations with low nucleophilic media, aqueous HCl, leads to their deprotonation with a stereoselective formation of (arysulfonyl)butadienes (for instance, ArSO2-CR1=C-C(Me)=CH2, for R2 = R3 = Me, yields of 87-98%). Reactions of (arysulfonyl)allenes in the system TfOH (0.1 equiv)-HFIP (hexafluoropropan-2-ol) followed by hydrolysis give rise to allyl alcohols (ArSO2-CR1=CH-C(OH)R2R3, yields of 78-99%). Reflux of solutions of (arysulfonyl)allenes in the presence of TfOH (1 equiv) in 1,2-dichlorobenzene leads to the cyclization into thiochromene 1,1-dioxides in high yields. Under the action of TfOH or AlX3 (X = Cl, Br) followed by hydrolysis of reaction mixtures, (arylsulfinyl)allenes give allyl alcohols (ArSO2-CR1=CH-C(OH)R2R3). Plausible reaction mechanisms have been proposed for all studied reactions.
Project description:A mixture of hexafluoroisopropanol (HFIP) and water was used as a new and unknown monophasic reaction solvent for fructose dehydration in order to produce HMF. HFIP is a low-boiling fluorous alcohol (b.p. 58 °C). Hence, HFIP can be recovered cost efficiently by distillation. Different ion-exchange resins were screened for the HFIP/water system in batch experiments. The best results were obtained for acidic macroporous ion-exchange resins, and high HMF yields up to 70% were achieved. The effects of various reaction conditions like initial fructose concentration, catalyst concentration, water content in HFIP, temperature and influence of the catalyst particle size were evaluated. Up to 76% HMF yield was attained at optimized reaction conditions for high initial fructose concentration of 0.5 M (90 g/L). The ion-exchange resin can simply be recovered by filtration and reused several times. This reaction system with HFIP/water as solvent and the ion-exchange resin Lewatit K2420 as catalyst shows excellent performance for HMF synthesis.
Project description:Hexafluoroisopropanol (HFIP) has been widely used as an acidic modifier for mobile phases for liquid chromatography-mass spectrometry (LC-MS) analysis of oligonucleotides ever since the first report of its use for this purpose. This is not surprising, considering the exceptional performance of HFIP compared with carboxylic acids, which cause significant MS signal suppression in electrospray ionization. However, we have found that other fluorinated alcohols can also be utilized for mobile phase preparation and the choice of optimal fluorinated alcohol is determined by the ion-pairing (IP) agent. Although HFIP is a very good choice to be used alongside less hydrophobic IP agents, other fluorinated alcohols such as 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol (HFMIP) can significantly outperform HFIP when used with more hydrophobic IP agents. We also found that more acidic fluorinated alcohols assist with the transfer of oligonucleotides with secondary structure (e.g., folded strands and hairpins) into the gas phase. Graphical Abstract ?.
Project description:Although amyloid fibrils deposit with various proteins, the comprehensive mechanism by which they form remains unclear. We studied the formation of fibrils of human islet amyloid polypeptide associated with type II diabetes in the presence of various concentrations of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) under acidic and neutral pH conditions using CD, amyloid-specific thioflavin T fluorescence, fluorescence imaging with thioflavin T, and atomic force microscopy. At low pH, the formation of fibrils was promoted by HFIP with an optimum at 5% (v/v). At neutral pH in the absence of HFIP, significant amounts of amorphous aggregates formed in addition to the fibrils. The addition of HFIP suppressed the formation of amorphous aggregates, leading to a predominance of fibrils with an optimum effect at 25% (v/v). Under both conditions, higher concentrations of HFIP dissolved the fibrils and stabilized the α-helical structure. The results indicate that fibrils and amorphous aggregates are different types of precipitates formed by exclusion from water-HFIP mixtures. The exclusion occurs through the combined effects of hydrophobic interactions and electrostatic interactions, both of which are strengthened by low concentrations of HFIP, and a subtle balance between the two types of interactions determines whether the fibrils or amorphous aggregates dominate. We suggest a general view of how the structure of precipitates varies dramatically from single crystals to amyloid fibrils and amorphous aggregates.
Project description:A novel approach towards the activation of different arenes and purines including caffeine and theophylline is presented. The simple, safe and scalable electrochemical synthesis of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) aryl ethers was conducted using an easy electrolysis setup with boron-doped diamond (BDD) electrodes. Good yields up to 59?% were achieved. Triethylamine was used as a base as it forms a highly conductive media with HFIP, making additional supporting electrolytes superfluous. The synthesis was optimized using Design of Experiment (DoE) techniques giving a detailed insight to the significance of the reaction parameters. The mechanism was investigated by cyclic voltammetry (CV). Subsequent transition metal-catalyzed as well as metal-free functionalization led to interesting motifs in excellent yields up to 94?%.
Project description:A mild and efficient amination of arenes with azodicarboxylates using potassium bisulfate (KHSO4) as the catalyst in 1,1,1,3,3,3-hexafluoro-2-propanol has been developed. This protocol allowed the amination of a broad range of arenes leading to corresponding hydrazides in good to excellent yields.