The stabilization of thiepin by substitution

Resonance energies of 430 substituted thiepins have been calculated using a simple Hückel method described before. The results predict that thiepins substituted with electron-withdrawing groups (methoxycarbonyl and fluorine) will be less antiaromatic than the parent thiepin. Thus the calculated REPE of the only known type of monocyclic thiepin viz. 3,4 - bis(methoxycarbonyl) - 5 pyrrolidinothiepin (-0.007β) is less negative than that of the parent thiepin.     

Rapid access to structured triacylglycerols acylated with n-3 polyunsaturated fatty acids for nutritional applications

In order to better understand the metabolic fate of n-3 polyunsaturated fatty acids (PUFAs), an efficient access to symmetrical and unsymmetrical triacylglycerols (TGs), esterified with PUFAs, with known high purity, is required. In this context, we optimized the esterification of a mixture of glycerols protected as dioxane and dioxolane with PUFAs. The kinetics of this reaction depends on various factors, such as the fatty acid chain length and the stereochemistry of the dioxane. Then, one-pot acetal hydrolysis and esterification of hydroxyl groups led to the desired structured TGs without either double bond isomerization or acyl migration (except when symmetrical TGs are acylated with long-chain saturated fatty acids in external positions). PUFAs location on the glycerol backbone was assayed by NMR, HPLC and pancreatic lipase hydrolysis.     

A novel route for the synthesis of benzo[b]thiepins

3,4 - Di(methoxycarbonyl) - 5 - pyrrolidinobenzo[b]thiepin 5 is synthesized by a [2+2]cycloaddition of 3 - pyrrolidinobenzo[b]thiephene 3 to dimethyl acetylenedicarboxylate, with subsequent ring opening of the cyclobutene moiety in the intermediate 6,7-di(methoxycarbonyl)-5-pyrrolidino - 2 - thiabenzo[b]bicyclo[3.2.0]hepta - 3,6 - diene 4 (detectable by PMR spectroscopy at ?30°C). Hydrolysis of the pyrrolidino group in 5 affords 3,4 - di(methoxycarbonyl) - 5 - hydroxybenzo[b]thiepin 8. Peracid oxidation of 5 yields the corresponding 1,1-dioxide. The benzo[b]thiepins are thermally unstable and (depending on the substituents) either extrude sulphur or rearrange to a 4-mercapto-1-naphthol, probably via the thianorcaradiene as the intermediate. The kinetics of the latter reaction are discussed. On being irradiated, the benzo[b]thiepins isomerize to 2-thiabenzo[b]bicyclo[3.2.0]hepta-3,6-dienes.     

Copper-catalyzed formation of C-O bonds by direct α-C-H bond activation of ethers using stoichiometric amounts of peroxide in batch and continuous-flow formats

Peroxides and ethers in flow: 2-Carbonyl-substituted phenols and β-ketoesters react safely with ethers in a microreactor environment using a copper catalyst and an organic peroxide (TBHP). This protocol results in unsymmetrical acetal scaffolds not easily available otherwise (see scheme).     

Diverging pathways to topologically complex polycyclic bis-acetals and their ring system interchange

Carbinol-tethered octalin-diols (1), which differ only by the C11 configuration at the angular position, were transformed selectively to three types of structurally unrelated original scaffolds such as unsymmetrical octahydroanthracenes (5/7), furofuranes (6), or spirans (8/9) via a two-step protocol. The 11S* configuration ensures a C13-C4 Friedel-Crafts type C-C bonding (through an unprecedented oxidative cleavage-triggered domino process) while the 11R* configuration allows for a C13-C2 Marson-type Friedel-Crafts C-C bonding (through a nucleophilic acetal opening).     

A feature of reaction of 1,1′-diacetylferrocene with dimethylformamide dimethyl acetal leading to a new strategy of the synthesis of asymmetrical 1,1′-disubstituted ferrocene

The reaction of 1,1′-diacetylferrocene with the dimethylformamide dimethyl acetal proceeds regioselectively to afford [1-acetyl-1′-(1-dimethylamino-3-oxoprop-1-en-3-yl)]ferrocene, based on which new approaches to the synthesis of 1,1′-disubstituted unsymmetrical ferrocene derivatives via the reaction with nucleophilic reagents hydrazine hydrate, hydroxylamine, and amidines were developed.     

Thermal epimerization of inositol 1,3-benzylidene acetals in the molten state

1,3-O-Benzylidene-2,4,5,6-tetra-O-substituted-myo-inositol derivatives obtained by the DIBAL-H reduction of the corresponding myo-inositol 1,3,5-orthobenzoate derivatives undergo epimerization at the acetal carbon on heating, in the molten state, just above their melting point. The same epimerization reaction does not proceed either in the crystalline state or in solution. DFT calculations suggest that the epimeric acetal obtained by this thermal process is relatively more stable than the starting acetal. Either of these acetals could not be obtained by the reaction of the corresponding inositol derived diol with benzaldehyde. These observations constitute a novel reaction solely in the molten state, which are rarely encountered in the literature. X-ray crystal structures of the epimeric acetals as well as their radical deoxygenation reaction are also reported.     

Chemoselective Heck arylation of acrolein diethyl acetal catalyzed by an oxime-derived palladacycle

A dimeric 4-hydroxyacetophenone oxime-derived palladacycle has been used as a very efficient precatalyst for the chemoselective arylation of acrolein diethyl acetal to give either cinnamaldehyde derivatives or 3-arylpropanoate esters by proper choice of the reaction conditions. The synthesis of cinnamaldehyde derivatives can be performed by Heck reaction of acrolein diethyl acetal with iodo-, bromo- or chloroarenes in N,N-dimethylacetamide (DMA) using K₂CO₃ as base at 120 °C and tetra-n-butylammonium acetate (TBAA) and KCl as additives, followed by acid workup. In the case of 3-arylpropanoate esters the corresponding arylation of acrolein diethyl acetal with iodoarenes can be performed at 90 °C in aqueous DMA using (dicylohexyl)methylamine as base, whereas for bromoarenes the reaction has to be performed at 120 °C using tetra-n-butylammonium bromide (TBAB) as additive. Alternatively, this process can be performed under microwave irradiation. These couplings take place in good yields and with lower catalyst loading than with palladium(II) acetate as well as in shorter reaction times and with lower excess of acrolein diethyl acetal.     

Tetrabutylammonium tribromide (TBATB) as an efficient generator of HBr for an efficient chemoselective reagent for acetalization of carbonyl compounds

Acyclic and cyclic acetals of various carbonyl compounds were obtained in excellent yields under a mild reaction condition in the presence of trialkyl orthoformate and a catalytic amount of tetrabutylammonium tribromide (TBATB) in absolute alcohol. Chemoselective acetalization of an aldehyde in the presence of ketone, unsymmetrical acetal formation, shorter reaction times, mild reaction conditions, the stability of acid-sensitive protecting groups, high efficiencies, facile isolation of the desired products, and the catalytic nature of the reagent make the present methodology a practical alternative.     

An efficient route to unsymmetrical bis(azolium) salts: CCC-NHC pincer ligand complex precursors

The coupling of N-heterocyclic azoles (imidazoles, benzimidazoles, triazoles) to bromobenzenes (1,2-; 1,3-; or 1,4) in a step-wise, sequential manner was accomplished by manipulation of reaction time and stoichiometry, which provided straight-forward access to unsymmetrical bis(azolium) salts in only three isolation steps from commercially-available starting materials. Eight mono(azole) substituted bromobenzenes, four mono(azolium)bromobenzene salts, twelve unsymmetrical bis(azole)benzenes, and fourteen unsymmetrical bis(azolium) salts, which are precursors for pincer ligand complexes, are reported.     

A concise approach to CF3-containing furan-3-ones, (bis)pyrazoles from novel fluorinated building blocks based on 2,3-butanedione

1,1,1-Trifluoro-4,5,5-trimethoxyhex-3-en-2-one and lithium (2Z)-1,1,1-trifluoro-5,5-dialkoxy-4-oxohex-2-en-2-olate were synthesized for the first time via direct trifluoroacetylation of 2,3-butanedione acetal derivatives. A simple and effective approach to acetal or acyl substituted CF₃-pyrazoles, 5,5′-bis(trifluoromethyl)-3,3′-bipyrazole, and, to 5-trifluoromethylfuran-3-ones is presented.     

Effective strategy for the preparation of indolocarbazole aglycons and glycosides: total synthesis of tjipanazoles B, D, E, and I

[reaction: see text] An effective strategy has been developed for the rapid and efficient preparation of ortho-nitrostyrenes, which can be converted to unsymmetrical 2,2'-biindoles. A unique condensation of these 2,2'-biindoles with (dimethylamino)-acetaldehyde diethyl acetal affords the indolocarbazole ring system of the tjipanazole aglycon alkaloids in three synthetic steps and good to excellent overall yield. The first total synthesis of the tjipanazole glycoside alkaloids B and E is also discussed.     

Selective mono-fluorination of diols via a cyclic acetal of N,N-diethyl-4-methoxybenzamide

Selective mono-fluorination of 1,2- and 1,3-diols was achieved using N,N-diethyl-4-methoxybenzamide diethyl acetal and Et₃N-3HF. The reaction proceeds through a cyclic acetal of the benzamide, and only one hydroxy group was fluorinated and another one was acylated.     

Probing of PSE acetal protection for nucleoside chemistry

The use of phenylsulfonylethylidene (PSE) acetal as a new 3′,5′-bridged protecting group in nucleoside chemistry is reported. The PSE acetal demonstrates to be compatible with Lewis acids used in standard glycosylation reactions. In addition, a selective 2′-O-deacylation from a 3′,5′-O-(phenylsulfonyl)-2′-O-acetyl nucleoside can be achieved, giving access to subsequent chemical modifications in 2′ position. However, the PSE acetal cleavage surprisingly appeared to be purine/pyrimidine base dependent.     

Direct synthesis of 3-arylpropionic acids by tetraphosphine/palladium catalysed Heck reactions of aryl halides with acrolein ethylene acetal

Through the use of [PdCl(C₃H₅)]₂/Cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst, a range of aryl bromides undergoes Heck reaction with acrolein ethylene acetal. With this acetal, the selective formation of 3-arylpropionic acids/esters was observed. The functional group tolerance on the aryl halide is remarkable; substituents such as fluoro, methyl, methoxy, acetyl, formyl, benzoyl, nitro or nitrile are tolerated. Furthermore, this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides.     

Controlling chemoselectivity—application of DMF di-t-butyl acetal in the regioselective synthesis of 3-monosubstituted indolizines

Among a number of DMF dialkyl acetals investigated for the regioselective synthesis of 3-acylindolizines, the di-t-butyl acetal, via its iminium intermediate readily formed in situ, provides the highest chemoselectivity for the intermolecular cyclization of picolinium salts. DMF di-t-butyl acetal was applied to the syntheses of a variety of 3-acylated indolizines including alkyl, aryl, and heteroaryl substituents.     

The first asymmetric total syntheses of both enantiomers of cryptocaryone

The first asymmetric total syntheses of the (+)- and (−)-cryptocaryones are described. Removal of the acetal unit of the enone acetal 5, which was obtained in our previous study from the cyclohexadiene acetal 3, afforded the enone acetal 8 in a one-pot procedure. The acylation of 8 with cinnamoyl chloride and subsequent hydrolysis of the resulting acetal gave the lactol 11. Its oxidation with NIS and tetra-n-butylammonium iodide (TBAI) finally furnished the natural (+)-cryptocaryone 2. The same procedure from ent-3 afforded the unnatural one 1.     

Anodic cyclization reactions: probing the chemistry of N,O-ketene acetal derived radical cations

The chemical reactivity of radical cations derived from N,O-ketene acetals has been examined and compared with the reactivity of radical cations derived from both ketene dithioacetals and enol ethers. Synthetically, the N,O-ketene acetal radical cations lead to more efficient cyclization reactions than either the ketene dithioacetal or enol ether derived radical cations. Cyclic voltammetry experiments using allylsilane trapping groups show that the efficiency of these cyclizations is not due to the N,O-ketene acetal radical cations being more reactive but rather more stable to decomposition. Finally, cyclizations using chiral oxizolidinones were examined.     

Conformations privilegiees de dithieno[c,e]dihydro azepines,oxepinnes et thiepinnes: Etude par spectroscopie d'absorption electronique

The comparative study of the electronic absorption spectra (uv) of dithieno[c,e]dihydro azepins, oxepins and thiepins and of the corresponding bithiophens shows that “twist” forms are privileged for the cyclic compounds. This conclusion is confirmed by a theoretical analysis (CNDO/S) and by a study of sterically hindered compounds.     

Reactions of 2-alkylimidazoles and 2-methylbenzimidazoles with 1,3-diacid chlorides. Synthesis of highly functionalized hetero-cycles under mild conditions

Highly functionalized heterocycles were synthesized in one-pot reactions of 2-alkylimidazoles or 2-methylbenzimidazoles with 1,3-diacid chlorides. Some of the cyclizations proceed through cyclic-N,N′-ketene acetal intermediates.