1-n-Butyl-2,3-dimethylimidazolium (BMMI) ionic liquids (ILs) associated with different anions undergo H/D exchange preferentially at 2-Me group of the imidazolium in deuterated solvents. This process is mainly related to the existence of ion pairs rather than the anion basicity. The H/D exchange occurs in solvents (CDCl3 and MeCN for instance) in which intimate contact ion pairs are present and the anion possesses a labile H in its structure, such as hydrogen carbonate and prolinate. In D2 O, separated ion pairs are formed and the H/D exchange does not occur. A plausible catalytic cycle is that the IL behaves as a neutral base in the course of all H/D exchange processes. NMR experiments, density functional calculations, and molecular dynamics simulations corroborate these hypotheses.
It is well known that the macroscopic physico-chemical properties of ionic liquids (ILs) are influenced by the presence of water that strongly interferes with the supramolecular organization of these fluids. However, little is known about the function of water traces within this confined space and restricted ionic environments, i.e. between cations and anions. Using specially designed ILs namely 1,2,3-trimethyl-1H-imidazol-3-ium imidazol-1-ide (MMMI·Im) and 3-n-butyl-1,2-dimethyl-1H-imidazol-3-ium imidazol-1-ide (BMMI·Im), the structure and function of water have been determined in condensed, solution and gas phases by X-ray diffraction studies, NMR, molecular dynamics simulations (MDS) and DFT calculations. In the solid state the water molecule is trapped inside the ionic network (constituted of contact ion pairs formed by π(+)-π(-) interaction) through strong H-bonds involving the water hydrogens and the nitrogens of two imidazolate anions forming a guest@host supramolecular structure. A similar structural arrangement was corroborated by DFT calculations and MDS. The presence of a guest@host species (H2O@ILpair) is maintained to a great extent even in solution as detected by (1)H-(1)H NOESY-experiments of the ILs dissolved in solvents with low and high dielectric constants. This confined water catalyses the H/D exchange with other substrates containing acidic-H such as chloroform.
A series of functionalized N-alkylimidazolium based ionic liquids (ImILs) were designed, through anion (carboxylates and halogenated) and cation (N-alkyl side chains) structural modifications, and studied as potential sorbents for CO . The sorption capacities of as prepared bare ImILs could be enhanced from 0.20 to 0.60 molar fraction by variation of cation-anion-CO and IL-CO -water interaction. By combining NMR spectroscopy with molecular dynamics simulations, a good description of interactions between ImIL and CO can be obtained. Three types of CO sorption modes have been evidenced depending on the structure of the ImIL ion pair: Physisorption, formation of bicarbonate, and covalent interaction through the nucleophilic addition of CO to the cation or anion. The highest CO sorption capacity was observed with the ImIL containing the 1-n-butyl-3-methylimidazolium cation associated with the carboxylate anions (succinate and malonate). This study provides helpful clues for better understanding the structure-activity relationship of this class of materials and the ion pair influence on CO capture.
Activating germline fibroblast growth factor receptor 3 (FGFR3) mutations cause achondroplasia (ACH), the most common form of human dwarfism and a spectrum of skeletal dysplasias. FGFR3 is a tyrosine kinase receptor and constitutive FGFR3 activation impairs endochondral ossification and triggers severe disorganization of the cartilage with shortening of long bones. To decipher the role of FGFR3 in endochondral ossification, we analyzed the impact of a novel tyrosine kinase inhibitor (TKI), A31, on both human and mouse mutant FGFR3-expressing cells and on the skeleton of Fgfr3(Y367C/+) dwarf mice. We found that A31 inhibited constitutive FGFR3 phosphorylation and restored the size of embryonic dwarf femurs using an ex vivo culture system. The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. Premature cell cycle exit and defective chondrocyte differentiation were observed in the Fgfr3(Y367C/+) growth plate. A31 restored normal expression of cell cycle regulators (proliferating cell nuclear antigen, KI67, cyclin D1 and p57) and allowed pre-hypertrophic chondrocytes to properly differentiate into hypertrophic chondocytes. Our data reveal a specific role for FGFR3 in the cell cycle and chondrocyte differentiation and support the development of TKIs for the treatment of FGFR3-related chondrodysplasias.
As a convenient and direct synthesis of 1,2-dihydroisoquinolines, the gold(I)-catalyzed intramolecular hydroamination of (2-alkynyl)benzyl carbamates has been developed. The reaction with cationic gold(I) complex [AuCl(PPh(3))/AgNTf(2)] proceeded at room temperature, giving the desired 6-endo adducts. The addition of alcohol efficiently promoted the reaction, and the amount of the catalyst could be reduced to 1 mol %. However, the alkynes bearing either an electron-deficient aryl group or an alkyl group resulted in predominant production of 5-exo adducts. In such cases, use of a bulky gold catalyst, AuCl[(o-biPh)((t)Bu)(2)P]Cl/AgNTf(2), improved the regioselectivity, giving the 6-endo adducts in better yields. Furthermore, the hydroamination of alkynyl carbamates bearing an acetal or enone was successfully applied to the concise synthesis of tetracyclic heterocycles such as nitidine via the single catalyst-mediated tandem cyclization which consists of a condensation or a Michael addition of the resulting enecarbamates.
A library of pyrido[2,3-d]pyrimidines was designed as inhibitors of FGFR3 tyrosine kinase allowing possible interactions with an unexploited region of the ATP binding-site. This library was built-up with an efficient step of click-chemistry giving easy access to triazole-based compounds bearing a large panel of substituents. Among the 27 analogues synthesized, more than half exhibited 55-89% inhibition of in vitro FGFR3 kinase activity at 2 microM and one (19g) was able to inhibit auto-phosphorylation of mutant FGFR3-K650M in transfected HEK cells.
The intramolecular carbolithiation of a series of propargylic ethers has been performed to evaluate the influence of the terminal substituent on the efficiency and the stereochemical outcome of the cyclization. Our results show that only 5‐exo‐dig cyclizations are observed, and dihydrobenzofurans are obtained exclusively. Depending on the nature of the terminal substituent, two cases can be considered. If the terminal substituent carried by the acetylenic carbon atom is itself a carbon atom, the cyclization can occur provided the terminal propargylic position bears a coordinating element and is at least disubstituted. When the cyclization occurs, it follows an anti‐carbolithiation pathway and thus leads to the E isomer of the exocyclic double bond. Only in one case (Ph) was a mixture of the E and Z isomers of the resulting olefin recovered. The cyclization can also take place if the alkyne is directly substituted by S or Si, provided the cyclization conditions are tuned. In the case of the trimethylsilyl substituent, a syn‐carbolithiation was observed. If the double bond is recovered, in most cases, in the exocyclic position, the products can aromatize directly for SPh‐substituted substrate 24. Furthermore, in the two latter cases, when alkylation of the vinyllithium intermediate is performed, isomerization of the double bond seems instantaneous.
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