En route to color-stable pyranoflavylium pigments—a systematic study of the reaction between 5-hydroxy-4-methylflavylium salts and aldehydes

The reaction of 5-hydroxy-4-methylflavylium salts with aldehydes, furnishing color-stable pyranoflavylium pigments, has been investigated in terms of scope and limitations. An unexpected chemical reactivity was observed and the origin of this reactivity is discussed.     

New synthetic route to 2,2,6,6-tetraethylpiperidin-4-one: A key-intermediate towards tetraethyl nitroxides

A new synthetic route to 2,2,6,6-tetraethylpiperidin-4-one and derived aminoxyl (nitroxide) radicals is described. In this preliminary work, 2,2,6,6-tetraethylpiperidin-4-one was obtained from ethyl acetoacetate in 3% yield over eight steps, relying only on common reagents and laboratory equipment for organic synthesis.     

On the acetoxylation of 2,3-dihydro-4-pyrones: a concise,fully synthetic route to the glucal stereochemical series

The acetoxylation of the title compounds at C₃ with Mn(OAc)₃ is described.     

Structure-activity relationships of 4-N-substituted ferroquine analogues: Time to re-evaluate the mechanism of action of ferroquine

A series of five new alkyl 4-N-substituted analogues of ferroquine (FQ, SR97193) were designed, synthesized, and characterized. The antimalarial activity of the compounds was measured against twelve strains of Plasmodiumfalciparum. The compounds were more active than chloroquine (CQ) against all the CQ-resistant clones. For a better understanding of their mechanism of action, their physicochemical properties (lipophilicity and basicity) and their action on the inhibition of β-hematin formation were evaluated. The importance of the intramolecular hydrogen bond in neutral FQ in the antimalarial activity was probed, compared to the methyl analogue 1.Results of additional physicochemical measurements suggested new insights into the mechanism of action of FQ in sharp contrast with CQ. We complement here our understanding on the mechanism of action of FQ with the process of catalysis-mediated hemozoin formation at the interface between vacuolar content and membrane lipids.     

A new series of heteroaromatic receptors containing the 1,3-bis(6-oxopyridazin-1-yl)propane unit: their selective transport ability towards NH4 in relation to Na, K and Ca

The synthesis of a new series of heteroaromatic macrocycles 6-9 containing the 1,3-bis(6-oxopyridazin-1-yl)propane and pyridine units is reported. The acyclic compounds 11-15 had to be prepared as the intermediates in the synthetic sequence. Evaluation of the ionophoric properties of 6-9 and 11-15 shows that 8 and 13 behave as good ammonium ion carriers and exhibit a high selectivity for ammonium with respect to spherically symmetric metallic ions like Na⁺, K⁺, and Ca²⁺. Molecular modelling of the ammonium complexes suggests that the host's oxyimino groups play a more relevant part in effective complexation than the pyridine unit, and that the high complexating efficiency of 13 might be related to the formation of a pseudocavity by intramolecular hydrogen bonding.     

Reactivity of the ester group attached isoxazoline, benzisoxazole, and isoxazole: a facial preparation of 3-acyl-substituted these heterocycles

A facile preparation of 3-acyl-substituted isoxazolines, benzisoxazoles, and isoxazoles from the corresponding 3-carboxylate esters is described. The process, involving reaction of the ester derivative of 3-carboxylic acid substituted heterocycles with Grignard or alkynyl lithium reagents, leads to direct generation of the corresponding 3-acyl heterocycle. The presence of α-imino ester moieties in the heterocyclic substrates for the reactions is thought to be a key feature governing the nature of these transformations. The synthetic utility of the new methodology is demonstrated by its application in a two-step route for the preparation of novel linked bis-heterocycles.     

Reaction of lithium eneselenolates derived from selenoamides with ketones: a highly diastereoselective synthetic route to β,β-disubstituted β-hydroxy selenoamides

The reaction of lithium eneselenolates generated from selenoamides with a variety of ketones proceeded smoothly at −78°C to give the corresponding β,β-disubstituted β-hydroxy selenoamides in moderate to good yields. The reaction showed high diastereoselectivity. The products obtained were converted to the corresponding amides by reacting them with cyclohexene oxide.     

Theoretical study of the mechanism of the formation of 3-unsubstituted 4,4-disubstituted beta-lactams by silver-induced ring expansion of alkoxycyclopropylamines: a new synthetic route to 4-alkoxycarbonyl-4-alkyl-2-azetidinones

The mechanisms of formation of 4,4-dialkyl- and 4-alkoxycarbonyl-4-alkyl-2-azetidinones by silver-induced ring expansion of the corresponding 2,2-disubstituted N-chloro-1-hydroxycyclopropylamines were theoretically investigated by means of the B3LYP method and the PCM solvation model. The obtained results indicate that these reactions are facile two-step regioselective processes proceeding through a short-life nitrenium intermediate. The theoretical results thus predict that this synthetic strategy, which has already been used to obtain 4,4-dialkyl-2-azetidinones, could also be a new route to efficiently obtain in a regio- and stereoselective way 4-alkoxycarbonyl-4-alkyl-2-azetidinones, which are precursors of conformationally constrained amino acids.     

Multicomponent Hantzsch cyclocondensation as a route to highly functionalized 2- and 4-dihydropyridylalanines, 2- and 4-pyridylalanines, and their N-oxides: preparation via a polymer-assisted solution-phase approach

An improved and efficient entry to highly functionalized β-(2-pyridyl)- and β-(4-pyridyl)alanines and the corresponding 1,4-dihydro and N-oxide derivatives has been developed by one-pot thermal Hantzsch-type cyclocondensation of aldehyde-ketoester-enamine systems in which one of the reagents (aldehyde or ketoester) was carrying the unmasked but protected chiral glycinyl moiety. Thus coupling N-Boc-O-benzyl aspartate β-aldehyde, acetoacetate and aminocrotonate esters afforded tetrasubstituted β-(4-dihydropyridyl)alanines (75% yield). One of these products was almost quantitatively transformed into the β-(4-pyridyl)alanine derivative which in turn was oxidized to the corresponding N-oxide. Each of these enantiomerically pure (Mosher's amide analysis) heterocyclic α-amino acids was incorporated into a tripeptide by coupling with (S)-phenylalanine. In a similar way tetrasubstituted β-(2-dihydropyridyl)alanine, β-(2-pyridyl)alanine and β-(1-oxido-2-pyridyl)alanine were prepared via Hantzsch cyclocondensation reaction using benzaldehyde, aminocrotonate, and acetoacetate carrying the N-Boc-O-benzyl glycinate moiety. It was shown that the work up of the reaction mixtures derived from the cyclocondensation and oxidation reactions can be carried out by the use of polymer supported reagents and sequestrants thus allowing the isolation of the products in high purity without any chromatography.     

Pd(0) catalyzed intramolecular Heck reaction: a versatile route for the synthesis of 2-aryl substituted 5-, 6-, and 7-membered O-containing heterocycles

An efficient and convenient method for the synthesis of 2-aryl substituted tetrahydropyran, tetrahydrofuran, and oxepine derivatives via intramolecular palladium catalyzed cyclization is developed. The two exo-cyclic double bonds at adjacent carbon atoms in these ring systems could serve as potential dienes for cycloaddition reactions.     

Base-free amination of BH acetates of 2-chloroquinolinyl-3-carboxaldehydes: a facile route to the synthesis of N-substituted-1,2-dihydrobenzo[b][1,8]naphthyridines

An efficient base-free one-pot synthesis of 1,2-dihydrobenzo[b][1,8]naphthyridines from BH acetates of 2-chloro-3-formylquinolines and activated alkenes followed by their acetylation, with different amines have been reported. These reactions are completed in very short time and provided the products in good to excellent yields. We further explored the scope of BH acetate with carbon nucleophile providing a new route to the synthesis of acridine derivative in excellent yield under mild condition.     

Evaluation and optimization of synthetic routes from dihydroartemisinin to the alkylamino-artemisinins artemiside and artemisone: A test of N-glycosylation methodologies on a lipophilic peroxide

10-Alkylamino-artemisinins including artemiside and artemisone display enhanced activities against malaria. Earlier, dihydroartemisinin (DHA) TMS ether was converted by trimethylsilyl bromide into the 10-β-bromide that with amine nucleophiles provided the amino-artemisinins. In an attempt to develop more economic approaches, direct N-glycosylation of DHA was examined but 2-deoxyartemisinin was invariably obtained. However, hydroxyl group activation by conversion into the 10β-halide in non-polar solvents with anhydrous HCl and Group I and II metal halides, oxalyl chloride or thionyl chloride with catalytic DMSO, and oxalyl bromide did succeed. The β-halides were converted in situ by thiomorpholine into artemiside, and by thiomorpholine-1,1-dioxide into artemisone respectively in scalable reactions. Hydrogen peroxide-acetonitrile or the urea-hydrogen peroxide complex efficiently oxidized the sulfide artemiside to the sulfone artemisone. Overall, a generalized approach to 10-alkylamino-artemisinins is now available.     

The route to the structure determination of amorphous solids: a case study of the ceramic Si(3)B(3)N(7)

Si(3)B(3)N(7) is the parent compound of a new class of amorphous ceramics containing silicon, boron, nitrogen, and carbon that display a unique spectrum of properties. It consists of a random network in which the constituent elements are linked by predominantly covalent bonds. Similarly to quartz glass, the composition of amorphous Si(3)B(3)N(7) is virtually stoichiometric. As all three of its constituent elements can serve as the objects of various structural probes, Si(3)B(3)N(7) was selected as the basis of a systematic structural investigation, in which methods for the structure determination of solids without translational symmetry could be validated and improved. However, as the complete amorphous structure cannot be deduced from experimental data, these results must be complemented by computer simulations. Thus, five classes of structure models were generated and compared to experimental results. Only the models generated by following the actual synthesis route as closely as possible agreed well with the experimental data.     

Anion effect on the coordination behavior of N,O-hybrid pyrazole ligand towards Pd(II): synthesis,characterization, and supramolecular properties

Four new Pd(II) coordination complexes using 2-(3-methyl-5-phenyl-1H-pyrazol-1-yl)ethanol (L) with different counter-anions have been prepared to examine their effect on the coordination mode of the ligand as well as on the self-assembly of the supramolecular structure. Reaction of trans-[PdCl₂(L)₂] (R) with AgCF₃SO₃ gives the ionic complex [Pd(L)₂](CF₃SO₃)₂ (1). When AgNO₃ is used, [Pd(NO₃)(L)₂](NO₃) (2) and [Pd(L)₂](NO₃)₂ (3) are obtained in the ratio 70?:?30, respectively, where the nitrate ion is present in- and/or outside the coordination sphere. Reaction of R with Ag₂SO₄ in the presence of (NH₄)₂C₂O₄ yields [Pd(C₂O₄)(L)₂] (4). These new complexes have been characterized by elemental analyzes, conductivity measurements, mass spectrometry, IR, ¹H and ¹³C{¹H} NMR spectroscopies, and X-ray diffraction, whenever possible. The denticity varies from N-monodentate to NO-bidentate, depending on the conditions, showing the versatility of L. Finally, the results of X-ray diffraction analyzes of 1 reveal that CF₃SO₃^? plays a fundamental role in self-assembly, generating a 2-D supramolecular layer with different inter- and intra-molecular interactions. The easy preparation and the high efficiency of this ligand make it a promising alternative to improve established systems.     

Pseudopolymorphism of aliphatic amine/4-tert-butylcalix[4]arene inclusion compounds: supramolecular stabilization as a route to polar clusters and layers

4-tert-Butylcalix[4]arene (4tBC4A) is a versatile host capable of forming a variety of 1:1 and 2:1 inclusion compounds typically stabilized through van der Waals interactions. Preliminary studies in our group have demonstrated that inclusion of n-butylamine in 4tBC4A results in a series of pseudopolymorphic inclusion compounds, including a new 3:1 inclusion motif. Using a combination of SCXRD, TGA, solid state NMR, and PXRD, we now elaborate upon the relationship between these pseudopolymorphs. We also demonstrate that larger amines demonstrate a similar degree of pseudopolymorphism, allowing for the production of customized materials using self-assembly guided by competing weak forces. Finally, we comment on the structural implications of the relative dominance such forces in the formation of calixarene-based supramolecular frameworks.     

Photochemical reaction of N,N-dimethyl-4-chloroaniline with dienes: new synthetic paths via a phenyl cation

The irradiation of N,N-dimethyl-4-chloroaniline in the presence of open-chain dienes in acetonitrile leads to addition of the aminophenyl and chloro groups across one of the double bonds; transannular cyclization takes place with cyclic dienes, leading to an arylnortricyclene from norbornadiene and to 1-arylbicyclo[3.3.0]octanes from 1,5-cyclooctadiene. The reaction proceeds by photoheterolysis of the chloroaniline to yield the 4-aminophenyl cation and addition to a CdoublebondC . The chemistry of the adduct cation depends on structure and medium, involving ion pairs in MeCN and solvated ions in CF(3)CH(2)OH. In the latter solvent, formation of ethers from open-chain alkenes is accompanied by Wagner-Meerwein hydride shift. In acetonitrile, the cation from cyclooctadiene partitions between deprotonation and Ritter addition, while the one from norbornadiene is reduced; both cations undergo nucleophilic addition in trifluoroethanol. The relevance of these cationic reactions under unusually mild conditions is discussed.     

A new efficient route to chiral 1,3-disubstituted ferrocenes: application to the syntheses of (R(p))- and (S(p))-17alpha-[(3'-formylferrocenyl)ethynyl]estradiol

Starting from (2S,4S)-2-ferrocenyl-4-(methoxymethyl)-1,3-dioxane (4), use of the stereogenic ortho-directing menthyl para-tolyl sulfoxide group, which occupies the 2' position in the ferrocenyl ring and redirects subsequent lithiation to the 3' position, allowed the synthesis of optically pure (S(p))-1-formyl-3-iodoferrocene (8), that was characterized by single-crystal X-ray diffraction. Combination of this method with a protection-deprotection strategy, using trimethylsilyl as a temporary blocking group, yielded (R(p))-1-formyl-3-iodoferrocene (13). Separate Sonogashira coupling of each of the enantiomeric iodoformylferrocenes 8 and 13 with 17alpha-ethynyl-estradiol produced (R(p))-17alpha-[(3'-formylferrocenyl)ethynyl]estradiol (14) and (S(p))-17alpha-[(3'-formylferrocenyl)ethynyl]estradiol (15), respectively.     

PtII Coordination to N1 of 9‐Methylguanine: Why it Facilitates Binding of Additional Metal Ions to the Purine Ring

The preparation and X‐ray crystal structure analysis of {trans‐[Pt(MeNH₂)₂(9‐MeG‐N1)₂]} ? {3 K₂[Pt(CN)₄]} ? 6 H₂O ( 3 a ) (with 9‐MeG being the anion of 9‐methylguanine, 9‐MeGH) are reported. The title compound was obtained by treating [Pt(dien)(9‐MeGH‐N7)]²⁺ ( 1 ; dien=diethylenetriamine) with trans‐[Pt(MeNH₂)₂(H₂O)₂]²⁺ at pH 9.6, 60 °C, and subsequent removal of the [(dien)Pt^II] entities by treatment with an excess amount of KCN, which converts the latter to [Pt(CN)₄]^2?. Cocrystallization of K₂[Pt(CN)₄] with trans‐[Pt(MeNH₂)₂(9‐MeG‐N1)₂] is a consequence of the increase in basicity of the guanine ligand following its deprotonation and Pt coordination at N1. This increase in basicity is reflected in the pK_a values of trans‐[Pt(MeNH₂)₂(9‐MeGH‐N1)₂]²⁺ (4.4±0.1 and 3.3±0.4). The crystal structure of 3 a reveals rare (N7,O6 chelate) and unconventional (N2,C2,N3) binding patterns of K⁺ to the guaninato ligands. DFT calculations confirm that K⁺ binding to the sugar edge of guanine for a N1‐platinated guanine anion is a realistic option, thus ruling against a simple packing effect in the solid‐state structure of 3 a . The linkage isomer of 3 a , trans‐[Pt(MeNH₂)₂(9‐MeG‐N7)₂] ( 6 a ) has likewise been isolated, and its acid–base properties determined. Compound 6 a is more basic than 3 a by more than 4 log units. Binding of metal entities to the N7 positions of 9‐MeG in 3 a has been studied in detail for [(NH₃)₃Pt^II], trans‐[(NH₃)₂Pt^II], and [(en)Pd^II] (en=ethylenediamine) by using ¹H NMR spectroscopy. Without exception, binding of the second metal takes place at N7, but formation of a molecular guanine square with trans‐[(Me₂NH₂)Pt^II] cross‐linking N1 positions and trans‐[(NH₃)₂Pt^II] cross‐linking N7 positions could not be confirmed unambiguously, despite the fact that calculations are fully consistent with its existence.     

Synthesis and characterization of a new chloro-di-phenyltin(IV) complex with 2-mercapto-nicotinic acid: Study of its influence upon the catalytic oxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase

The complex [(C₆H₅)₂SnCl(HMNA)] (1) where H₂MNA is thioamide 2-mercapto-nicotinic acid has been synthesized by reacting a methanolic solution of di-chloro-di-phenyltin(IV) Ph₂SnCl₂ with an aqueous solution of 2-mercapto-nicotinic acid, containing twofold amount of potassium hydroxide. The Sn/ligand molar ratio is 2:1. The complex was characterized by elemental analysis, FT-IR and Mössbauer spectroscopic techniques. In addition the crystal structure of the molecule was determined by an X-ray diffraction at 293(2) K. C₁₈H₁₄ClNO₂SSn is monoclinic, space group P2₁/n, a = 15.089(3) Å, b = 15.846(3) Å, c = 16.691(3) Å, β = 105.57(3)°, Z = 8. The ligand coordinates to the metal center through the exocyclic sulfur and the heterocyclic nitrogen atoms, forming a four membered ring. The coordination sphere around the tin(IV) ion is completed with two carbon atoms from the two phenyl groups and one chlorine atom. The geometry around the tin atom can be described either as trigonal bipyramidal or tetragonal pyramidal. Finally, the influence of the complex [(C₆H₅)₂SnCl(HMNA)] (1) upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was also kinetically and theoretically studied and the results compared with the ones of the corresponding binuclear complex [(C₆H₅)₃Sn(MNA)Sn(C₆H₅)₃ · (acetone)] (2) reported in the literature.