Jean Pierre Bazureau

Catalysed esterifications in room temperature ionic liquids with acidic counteranion as recyclable reaction media

Esterification reactions of acetic acid, methoxyacetic acid and methylmalonic acid with neo-pentanol, hexanol, heptanol and decanol have been investigated in three ionic liquids with hydrogen sulphate, dihydrogen phosphate as counteranions and also two ionic liquids modified with HPF6 as catalyst. The nature of both the counteranion and cation influence the behavior of the catalyst. Good yields and high selectivities were obtained and all the produced esters could be easily recovered due to their immiscibility with the ionic liquid as green reaction medium. 2002 Elsevier Science B.V. All rights reserved.

Rate accelerations of 1,3-dipolar cycloaddition reactions in ionic liquids

The 1,3-dipolar cycloaddition reactions between imidate 1 derived from diethyl aminomalonate and 2-ethoxybenzaldehyde 2 as dipolarophile has been investigated in various air and moisture stable ionic liquids. Significant rate enhancements and improved yields at 70°C have been observed with [emim][BF4] and [emim][NfO] ionic liquids. The reactivity of dipolarophiles covalently grafted on the ionic liquids were also evaluated.

Grafted ionic liquid-phase-supported synthesis of small organic molecules

Abstract The preparation and applications in the Knoevenagel and 1,3-dipolar cycloaddition reactions of new grafted soluble liquid phases derived from imidazolium ionic liquids are described. Good yields and high regioselectivity are the features observed with these unconventional liquid phases.

Efficient combination of task-specific ionic liquid and microwave dielectric heating applied to one-pot three component synthesis of a small library of 4-thiazolidinones

Abstract The first report of the use of task-specific ionic liquid as synthetic equivalent of ionic liquid-phase matrice for the preparation of a small library of 4-thiazolidinones is reported in this paper. The starting (ethyleneglycol)ionic liquid-phase is functionalized in good yields with 4-(formylphenoxy)butyric acid by using usual esterification reaction conditions (DCC/DMAP as catalyst). The synthesis of the ionic liquid-phase bound 4-thiazolidinones was performed by a one-pot three-component condensation under microwave dielectric heating. The final cleavage under microwave/catalysis strategy provides the expected 4-thiazolidinones in high purity after flash-chromatography purification. According to the ionic liquid-phase organic synthesis (IoLiPOS) methodology, it was found that optimized reaction conditions were performed by standard analytical methods (NMR, TLC). The 1H, 13C NMR spectrum of some representative 4-thiazolidinones and ionic liquid-phase bound benzaldehyde are also reported.

Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B

DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimers disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimers disease.

Leucettines, a Class of Potent Inhibitors of cdc2-Like Kinases and Dual Specificity, Tyrosine Phosphorylation Regulated Kinases Derived from the Marine Sponge Leucettamine B: Modulation of Alternative Pre-RNA Splicing

We here report on the synthesis, optimization, and biological characterization of leucettines, a family of kinase inhibitors derived from the marine sponge leucettamine B. Stepwise synthesis of analogues starting from the natural structure, guided by activity testing on eight purified kinases, led to highly potent inhibitors of CLKs and DYRKs, two families of kinases involved in alternative pre-mRNA splicing and Alzheimers disease/Down syndrome. Leucettine L41 was cocrystallized with CLK3. It interacts with key residues located within the ATP-binding pocket of the kinase. Leucettine L41 inhibits the phosphorylation of serine/arginine-rich proteins (SRp), a family of proteins regulating pre-RNA splicing. Indeed leucettine L41 was demonstrated to modulate alternative pre-mRNA splicing, in a cell-based reporting system. Leucettines should be further explored as pharmacological tools to study and modulate pre-RNA splicing. Leucettines may also be investigated as potential therapeutic drugs in Alzheimers disease (AD) and in diseases involving abnormal pre-mRNA splicing.

1,3-DIPOLAR CYCLOADDITION OF IMIDATE YLIDES ON IMINO-ALCOHOLS : SYNTHESIS OF NEW IMIDAZOLONES USING SOLVENT FREE CONDITIONS

Abstract Imidates derived from α-amino esters as potential azomethine ylides, undergo 1,3-dipolar cycloaddition with imino-alcohols, in tautomeric equilibrium with 1,3-oxazolidines, without solvent at 70°C or under microwave irradiation. This reaction leads to a wide range of novel polyfunctionalized 4-yliden-2-imidazolin-5-ones in good yields with short reaction times. The reactivity of these imidates derived from α-amino esters with imino-alcohols is rationalized from the energy of the Frontier Molecular Orbitals (FMO) determined by semi-empirical PM3 calculations: the reaction is controlled by the interaction HOMO (1,3-dipole) - LUMO (dipolarophile) and the second order pertubation energy calculations are in agreement with the experimental reaction orientation.

A new route to 2-oxazolines, bis-oxazolines, and 2-imidazoline-5-ones from imidates using solvent-free cycloadditions: Synthesis, chemical properties, and PM3 MO calculations

Abstract The 1,3-dipolar cycloadditions between imidate 1, derived from dimethylaminomalonate and aldehydes 2(a-f), phthalaldehyde 2g, isophthalaldehyde 2h. 4-chlorophenylisocyanate 9a, ethoxycarbonylisothiocyanate 9d as dipolarophiles proceeds regioselectively in good yield using solvent-free conditions. Synthesis of ortho- and meta-bis-(2′-oxazoline-5′-yl)benzenes 6g, 6h are also reported. The regiochemistry and the reactivity in these cycloaddition reactions are rationalized by PM3 MO calculations. The stereoselective demethoxycarbonylation of dimethyl 2-oxazoline-4,4-dicarboxylate 4a is described. The mild hydrolysis of 5-(2-formylphenyl)-2-oxazoline 4g leads to the formation of a new 3,4-dihydroisoquinoline 8h in quantitative yield.

Acidic task-specific ionic liquid as catalyst of microwave-assisted solvent-free Biginelli reaction

A simple and effective synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidine-2(1H)-thione derivatives has been developed on the basis of three-component condensation of substituted aromatic and heterocyclic aldehydes, methyl acetoacetate, and urea or thiourea in the presence of 10% of an acidic task-specific ionic liquid ([C4mim][HSO4]) as catalyst under microwave irradiation in the absence of a solvent. The proposed procedure ensures short reaction times (4.4–8 min) and good yields after purification by recrystallization.

Cycloaddition with stabilized imidates as potential azomethines ylides : A new route to 2-imidazoline and 4-yliden-s-imidazolinone

Abstract Imidates derived from α-amino esters, undergo cycloaddition reactions as stabilized ylides, with imines in good yields.