Transformations thermiques des photooxydes méso des acènes—V: Influence des phényles en méso en série naphtacénique

The influence of meso-phenyisubstituents on the thermal behaviour of naphthacenic endoperoxides is illustrated by the disparity of isomerizations which undergo, under thermolysis at reflux temperatures in various solvents, the two isomeric photooxides, 1d (5–12) and 1e (6–11), afforded by 5,12-diphenylnaphthacene 2d. Whereas 1d, which dissociates also to an appreciable extent, gives only the cyclobutenic diether 4d, 1e leads to a bicyclic acetal, 12, accompanied by a dimer, 18. The primary intermediates of these transformations are unstable diepoxides apt to open more or less easily into o-quinodimethanic diethers, as is shown by the trapping of 6d, 11 and also 16, as adducts 9d, 13 and 14, when one carries out the thermolysis in the presence of N-methylmaleimide The established discrepancies are explained by the effect of phenyl groups on the successive steps of this isomerization process, which has been described before for anthracenic and unsubstituted naphthacenic photooxides. Chemical degradations along with spectral data, which prove the structures of the new compounds, are presented.     

Reactions of N,N-diisopropyl-2-aminoethylp-fluorobenzene thiosulfonate with oxidising agents

The behaviour of N,N-diisopropyl-2-aminoethyl p-fluorobenzene thiosulfonate 3, which may be considered as a weakly toxic chemical analogue of VX agent, was investigated against oxidising agents. As VX 1, this compound exhibits the same tendency to give S–S bond cleavage. Its degradation by Curox® shows the formation of the N-oxide 6 which subsequently gives the sulfonate 7 by hydrolysis. The action of hydrogen peroxide, with or without boric acid, leads to the sulfinate 4 by S-S bond cleavage. Its oxidation gives sulfonate 7. Finally, reactions of MMPP and m-CPBA afford sulfonate 7 but no intermediates are highlighted with these reagents.     

The expedient access to bromo-pyridine carbaldehyde scaffolds using gem-dibromomethyl intermediates

A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds is described. This direct route involves sequential reactions employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of calcium carbonate. Bromo-pyridine carbaldehyde scaffolds 1-7 were obtained in good overall yield. Bromo-dibromomethyl-pyridine intermediates have been isolated and characterized.     

Addition nucleophile des anions d'esters α-cyanoacetiques sur les cations succinimidosulfonium: Fragmentation ionique ou radicalaire des′ σ-sulfuranes intermediaires

Reactions of substituted cyanoacetate anions 4 with S,S-dialayklsuccinimidosulfonium salts resulted generally in the formation of N-alkylthiomethylketenimines and α-alkylthiomethylesters. Coupling products were also obtained with anion 4d and only observed in the case of methyl phenylcyanoacetate anion 4b. The results were interpreted by the formation of instable σ-sulfurane intermediates. Homolytic cleavage of these intermediates gave radical pairs, then the coupling products. Heterocyclic clevage gave new sulfonium salts which rearranged via sulfonium ylides.     

Thiosulfonic s-esters - 5. Mechanistic aspects of the reaction with chlorotrimethylsilane and sodium iodide

Thiosulfonic S-esters (1) are readily converted to disulfides (2) by chlorotrimethylsilane and sodium iodide. The reaction is shown to proceed through a complex mechanism, and more than one conversion pathway to disulfides must be considered. Evidence is presented for several S-S bond cleavage and reformation reactions involved in the conversion. In view of these results, the mechanistic interpretations proposed for already known reactions of various sulfur compounds with either chlorotrimethylsilane-iodide or iodotrimethylsilane should probably be revised. The behaviour of other reducing agents of thiosulfonates (1) to disulfides (2) was also checked.     

An efficient enzyme-catalyzed kinetic resolution: large-scale preparation of an enantiomerically pure indole-ethyl ester derivative,a key component for the synthesis of a prostaglandin D2 receptor antagonist,an anti-allergic rhinitis drug candidate

Three racemic esters including indole-ethyl ester 1 as well as its related derivatives 3 and 4 in Scheme 1, all synthetic intermediates for the preparation of chiral compound 5, were used as substrates to evaluate the catalytic potentials of a panel of commercial enzymes for asymmetric hydrolysis. After an extensive evaluation of the conversion rates (C), enantiomeric excesses (ee) and enantioselectivity determination (E), lipase from Pseudomonas fluorescens was identified. This lipase catalyzed the asymmetric hydrolysis of racemic indole-ethyl ester 1 affording the desired enantiomerically pure intermediate 1 with 97% ee and an E value of 425. Indole-ethyl ester 1, with the following attributes: being early in the synthetic scheme, showing resistance to racemization in the later chemical reactions as well as the possibility of the recycling of the unwanted enantiomer, was therefore selected for optimization and establishment of an enzyme-catalyzed reaction for the industrial-scale synthesis of the compound 5, a drug candidate for the treatment of allergic rhinitis.     

Pd-catalyzed coupling of aryl iodides with triarylbismuths as atom-economic multi-coupling organometallic nucleophiles under mild conditions

The facile cross-coupling reactivity of triarylbismuth compounds with aryl iodides was achieved under mild heating conditions. The established catalytic protocol using Pd(OAc)₂(Cy₂NH)₂ system exhibited high coupling reactivity with a variety of triarylbismuth and aryl iodide compounds under mild conditions. These coupling reactions were completed in short reaction time affording good to high yields of functionalized biaryl products. The studies of multi-coupling reactions with tris(4-iodophenyl)amine, 8 also furnished moderate to good yields of coupled products, 8a-8f.     

Synthesis of polyfluoroalkylated glycerol and crown ether

Perfluoroalkylated glycerol (5, 9) and crown ethers (22, 23, 24) were synthesized starting from glycerol. 5 was synthesized by allylation of glycerol 1,2-acetonide followed by perflu-oroalkylation initiated with sodium dithionite, reduction of iodide and hydrolysis in good overall yield and was shown to poccess good surface activities. Glycerol bis-ether (9) was synthesized in a similar way. Allyloxymethyl crown ethers (15, 16, 18) were prepared as key intermediates through multi-step reactions, which were then perfluoroalkylated to give the title crown ethers 22, 23 ,24.     

The chemistry of fulminic acid revised

The availability of a new synthesis of fulminic acid by hydrolysis of trimcthylsilanecarbonitrile oxide allowed a reinvestigation of the chemistry of the title compound. Thus, cycloadditions to olefinic and acetylenic dipolarophiles are improved with respect to previous results and the oligomerisation is proved to occur via the reactive species hydroxyiminoacetonitrile oxide 7 and hydroxyiminomethyl-hydroxyiminoacetonitrile oxide 8. The Z-configuration, found for the oxime groups in these intermediates, is maintained in their derivatives, under kinetic controls.     

Efficient synthesis of functionalized 6-substituted-thiosalicylates via microwave-promoted Suzuki cross-coupling reaction

Functionalized 6-substituted-thiosalicylates are key intermediates for the synthesis of pyrimidinyl(thio)salicylic acids, a group of important herbicides targeting plant acetohydroxyacid synthase. Therefore, it is of great interest to develop an efficient method for the syntheses of 6-substituted-thiosalicylates. Herein, we have developed a direct and efficient method for the synthesis of functionalized 6-substituted-thiosalicylates (4) from aryl iodide (1) by using an improved microwave-assisted Suzuki cross-coupling reaction. Almost all the reactions proceeded smoothly and afforded moderate to excellent yields of products. Moreover, this protocol is obviously superior to the traditional available methods and could be utilized to synthesize pyrimidinyl(thio)salicylic acid and its derivatives.     

Transposition homoallenylique—X : Interpretation des resultats en serie acyclique

Hydrolysis of the cyclopropylvinyl chloride 6 occurs with ring enlargement, involving principally the most substituted bond. A comparison of the hydrolysis products of 6 with those from the β-allenic tosylates, 9 and 11, shows that the cyclopropylvinyl cations, 27 and 28, cannot be the sole carbonium ions involved in the homoallenic participation, and that it is necessary to postulate a cation of the methylenebicyclobutonium type, which may capture water to give a methylenencyclobutanol before it isomerises to a cyclopropylvinyl cation.     

Synthese und reaktionen neuartiger n-vinylaziridine

The ketene S,S-acetals 1 readily react with aziridine to give the corresponding 3-(1-aziridinyl)-3-methylthio-acrylnitriles 2 and 3,3-bis-(1-aziridinyl)-acrylnitriles 3. Ketene S,N-acetals 4 yield 3-anilino-3-(1-aziridinyl)-acrylnitriles 5. Reaction of 5 with potassium iodide in acetone at room temperature leads to imidazolidines 8. The isomerisation is explained in terms of a two-step mechanism. The iodide ion-catalysed rearrangement was not successful when applied to 2a. Cyclisation of 5b in the presence of sodium hydride and following hydrolysis form the tautomeric quinolone 10. On contrary to 1 and 4 mercapto ethylenes 11 and 13 with aziridine give the thiazolidine 15.     

3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: aza-Michael addition reactions and the preparation of poly-HOPO chelators

The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10 were easily prepared by short synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of 3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide 10 with 1,4,7-triazacyclononane gave the tris-adduct 17 which was deprotected to give the desired tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by the solvent but also by the nature of the amine and the solubility of the reaction intermediates.     

A four step synthesis of violaceic acid

The total synthesis of the biaryl ether natural product violaceic acid (1) in four steps is described. The steps included a S_NAr reaction between phenol 7 and flouroarene 12 to afford the biaryl ether 13, selective reduction of a nitro group to an amine in the presence of an aldehyde, a Cu mediated Sandmeyer reaction and final hydrolysis to afford the target compound 1. The amine 14 was also converted into the known iodide 18 which gave impure 1 on Pd mediated hydroxide cross coupling.     

Aminyloxide—XVIII : ESR-spektroskopische untersuchung der tautomerie beim “hydrolyseprodukt des porphyrexids”

The hydrolysis of porphyrexine 2a yields 3a not 1a, as was shown by means of the ¹⁵N-labelled compound 2c. Analysis of the ESR spectra of radicals 4 derived from 3 shows that in dimethylsulfoxide these radicals exist in the tautomeric form B whereas in dioxan they exist in form A. The stabilization of form B in dimethylsulfoxide is shown to be due to a specific effect of the solvent.     

Trifluoromethylated cyclopropanes and epoxides from CuI-mediated transformations of α-trifluoromethyl-diazophosphonate

An efficient method for the preparation of α-(trifluoromethyl)-cyclopropylphosphonates and α-(trifluoromethyl)-1,2-epoxyphosphonates has been developed. The method is based on metal-catalyzed reaction of diethyl 1-diazo-2,2,2-trifluoroethylphosphonate (1) with alkenes or carbonyl compounds, respectively. It established an essential advantage of CuI-catalysis over Rh₂(OAc)₄ in cyclopropanation reactions. An inexpensive copper iodide has also exhibited a good catalytic activity in the synthesis of epoxyphosphonates (3).     

Synthesis of a chiral phosphonium salt for the preparation of α-substituted alaninol derivatives

We herein report the synthesis of a chiral phosphonium salt, {[(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]methyl}(triphenyl)phosphonium iodide 13 to provide a new Wittig reagent for the general method of synthesizing α-substituted alaninol derivatives. Our method described here is widely applicable to reactions with various types of aldehyde to afford olefin products with high E-selectivity, enabling us to provide a new approach to the synthesis of chiral S1P₁ agonists including our key intermediates, and of the trace amine-associated receptor 1 (TAAR1) agonist.     

Synthesis of spirocyclic azacycles from the cyclization of furan tethered N-acyliminium ions

The protic and Lewis acid promoted cyclization reactions of tethered furan-4,5-dihydroxypiperid-2-ones, furan-4,5-diacetoxypiperid-2-ones and furan-3,4-diacetoxypyrrolid-2-ones, via their corresponding N-acyliminium ion intermediates, have been studied. In the case of the furan-4,5-dihydroxypiperid-2-one 2a and its diacetate derivative 2b, macrocyclic products were formed from an initial intermolecular reaction between 2a or 2b, via the nucleophilic C5 furan carbon, and their corresponding N-acyliminium ion intermediates. When the furan C5 position of 2b was blocked by substitution with bromine then TFA or Sc(OTf)₃ catalysed cyclization reactions gave a spirotricyclic product (a 5-6-6-tricycle) in a highly diastereoselective manner. Cyclization of the analogous C5-Br-furan-pyrrolidone 29 with TFA resulted in a related spirotricyclic (a 5-6-5 tricycle) product. Attempts to prepare an analogous azepine system, a 5-7-5 tricycle, were not successful. Cyclization reactions of the C5-PhS-furan- or C5-phenylsulfonyl-pyrrolidone analogues of 29 with TFA were also not successful.     

New Insights into the Chemistry of Lithium Carbamoyls: Characterization of an Adduct (R(2)NC(O)CLi(OLi)NR(2))

Studies of the reaction of lithium dicyclohexylamide with N,N-dibutylformamide, 1-formylpiperidine, and 4-formylmorpholine indicate that the equilibria resulting from these compounds are shifted toward the formation of an adduct, which quickly collapses to dicyclohexylamine and the lithiated carbamoyl anion derived from the initial disubstituted formamide. Further reactions of the lithium carbamoyl lead to a new adduct where a lithiated carbon is bounded to N, O, and a carbonyl functionality. The (13)C NMR analysis of the reaction mixtures showed the presence of similar intermediates in all cases: adducts of this type have not been reported before. These dilithiated intermediates were trapped with methyl iodide giving the corresponding doubly methylated derivatives. Isolation of substituted glyoxylamides and quantitative determination of the products yields constitute further evidence of the whole reaction scheme proposed.     

Stereochime de reactions au niveau des liaisons silicium (ou germanium)— phosphore dans le systeme dimethyl-1,2 sila (ou germa)) cyclopentanique

The stereochemistry of nucleophilic displacement of diethylphosphino leaving group from geometrical isomers of 1,2-dimethy -1-diethylphosphino-1-sila (or germa) cyclopentane 1 (or 2 has been studied. Retention of configuration at Si (or Ge) atom was found in reduction with LiAlH₄(Et₂OorTHF), and inversion with bdLiBH₄. With reagents like n-butyllithium, allyllithium or allylmagnesium bromide, 1 (or 2) gives retention of configuration. Alcohols and acidic reagents react far more rapidly, but reactions are not (or weakly) stereospecific. PR₂; is a poor leaving group, neighbouring hydrogen atom in the Sommer-Corriu's scale.The stereochemistry of addition reactions of 1 (or 2) with various unsaturated derivatives (carbonyl and dissymetric ethylenic derivatives, ambident nucleophiles) has been also investigated. It was shown that these reactions are both regiospecitic and stercospecific, and proceed with retention at the silicon (or germanium) centre.The stereochemical results are consistent with recent conclusions that S_N-Si retention reactions involve frontier orbital interactions.Relative configurations of these geometrical isomers, and the stereochemistry of their reactions, were assigned by pmr and cmr spectroscopy.