Electronic Effects in a Green Protocol for (Hetero)Aryl-S Coupling.

Aryl and heteroaryl iodides have been efficiently converted into the corresponding thioacetates in cyclopentyl methyl ether (CPME), a green solvent, under Cu catalysis. The chemoselectivity of the reaction is mainly controlled by electronic factors, enabling the conversion of both electron-rich and electron-deficient substrates into the corresponding thioacetates in good to excellent yields. The products can be easily deprotected to the corresponding thiolates to carry out additional synthetic transformations in situ. Surprisingly, despite CPME's relatively low dielectric constant, the reaction rate significantly increased when conducted under microwave irradiation conditions. This synthetic methodology exhibits a remarkable tolerance to functional groups, mild reaction conditions, and a wide substrate scope, utilizing a safe and inexpensive CuI pre-catalyst in the green solvent CPME. A non-aqueous workup allowing for the complete recovery of both catalyst and solvent makes this approach an environmentally sustainable protocol for C(sp2) sulfur functionalization. Additionally, the reaction shows selective cross-coupling with iodides in competition with chlorides and bromides, allowing its use in multistep syntheses. To demonstrate the potential of this methodology, it was applied to the high-yield synthesis of a photochromic dithienylethene, where a selective synthesis had not been reported before.

Visible Light-Promoted Oxidative Cross-Coupling of Alcohols to Esters.

Ester is one of the most significant functional groups in organic chemistry and is enclosed in several valued molecules. Usually, esters are prepared through the acid-catalyzed esterification reaction of carboxylic acids with alcohols, transesterification of esters with alcohols, or via activation of carboxylic acids followed by the addition of alcohols. However, these procedures typically imply the excess use of reactants and harsh reaction conditions. Visible light-mediated photoreactions have been disclosed to display a safe, sustainable, and accessible alternative to traditional methods, and to lead new reactivity modes in organic procedures. In this context, we propose a transition metal-based and organic-based photocatalyst-free synthesis of esters from alcohols induced by visible light. The methodology can be carried out using sunlight or artificial visible light as a solar simulator or a blue LED source.

Aquivion perfluorosulfonic superacid as an effective catalyst for selective epoxidation of vegetable oils.

The acid-promoted epoxidation of vegetable oils was studied using a variety of acidic ion exchange resins as heterogeneous acid catalysts. Quantitative and selective epoxidation of a series of vegetable oils with different composition of saturated, mono-, di- and tri-unsaturated fatty acids was obtained upon identification of the more efficient catalyst and experimental conditions. Furthermore, optimized reaction conditions were successfully applied to the epoxidation of a waste cooking oil, thus extending our procedure to the valorization of a biowaste, an area of increasing importance within a more sustainable society. The use of quantitative 1HNMR besides making accurate evaluation of the amounts of reagents to be employed and of the selectivity, allowed facile and rapid quantification of mono-, di- and tri-epoxides, thus providing an indirect indication on the fatty acid composition of the vegetable oils, even in the presence of very low quantities of linolenic acid.

Visible-Light Photoredox-Catalyzed Amidation of Benzylic Alcohols.

A new photocatalyzed route to amides from alcohols and amines mediated by visible light is presented. The reaction is carried out in ethyl acetate as a solvent. Ethyl acetate can be defined a green and bio-based solvent. The starting materials such as the energy source are easily available, stable, and inexpensive. The reaction has shown to be general and high yielding.

Synthesis of glycosyl sulfoximines by a highly chemo- and stereoselective NH- and O-transfer to thioglycosides.

A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several ß-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucose, mannose and galactose as glycosyl units. The process has been extended to a lactose derived thioglycoside and to a glucose derived sulfenamide. The process was chemo- and stereoselective, and X-ray analysis confirmed the structure and provided stereochemical information on the configuration at the sulfur atom. A model for the stereochemical outcome is proposed based on the steric environment of the sulfide.

Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines.

A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines.

Cyclopentyl Methyl Ether: An Elective Ecofriendly Ethereal Solvent in Classical and Modern Organic Chemistry.

Solvents represent one of the major contributions to the environmental impact of fine-chemical synthesis. As a result, the use of environmentally friendly solvents in widely employed reactions is a challenge of vast real interest in contemporary organic chemistry. Within this Review, a great variety of examples showing how cyclopentyl methyl ether has been established as particularly useful for this purpose are reported. Indeed, its low toxicity, high boiling point, low melting point, hydrophobicity, chemical stability towards a wide range of conditions, exceptional stability towards the abstraction of hydrogen atoms, relatively low latent heat of vaporization, and the ease with which it can be recovered and recycled enable its successful employment as a solvent in a wide range of synthetic applications, including organometallic chemistry, catalysis, biphasic reactions, oxidations, and radical reactions.

Heterogeneous acidic catalysts for the tetrahydropyranylation of alcohols and phenols in green ethereal solvents.

The application of heterogeneous catalysis and green solvents to the set up of widely employed reactions is a challenge in contemporary organic chemistry. We applied such an approach to the synthesis and further conversion of tetrahydropyranyl ethers, an important class of compounds widely employed in multistep syntheses. Several alcohols and phenols were almost quantitatively converted into the corresponding tetrahydropyranyl ethers in cyclopentyl methyl ether or 2-methyltetrahydrofuran employing NH4HSO4 supported on SiO2 as a recyclable acidic catalyst. Easy work up of the reaction mixtures and the versatility of the solvents allowed further conversion of the reaction products under one-pot reaction conditions.

Regio- and Stereoselective Synthesis of Sulfur-Bearing Four-Membered Heterocycles: Direct Access to 2,4-Disubstituted Thietane 1-Oxides.

Starting from readily available C2-substituted thietane 1-oxides, a straightforward synthesis of new C2,C4-disubstituted thietane 1-oxides has been developed by using a lithiation/electrophilic trapping sequence. The chemical and configurational stability of lithiated C2-substituted thietane 1-oxides has been investigated as well as the stereochemical implications for this process. The results demonstrate that a stereoselective functionalization at the C2, C4 positions of a thietane is feasible, leaving intact the four-membered ring.

Behavior of the potential antitumor V(IV)O complexes formed by flavonoid ligands. 2. Characterization of sulfonate derivatives of quercetin and morin, interaction with the bioligands of the plasma and preliminary biotransformation studies.

The biotransformation in the plasma and red blood cells of two potential antitumor V(IV)O complexes formed by flavonoid ligands (quercetin or que and morin or mor) and their sulfonic derivatives (quercetin-5'-sulfonic acid or que(S) and morin-5'-sulfonic acid or mor(S)) was studied by spectroscopic (EPR, Electron Paramagnetic Resonance) and computational (DFT, Density Functional Theory) methods. Que and que(S) form with V(IV)O stable complexes, and in the systems with apo-transferrin (apo-hTf) and albumin (HSA) VO(que)2 and VO(que(S))2 remain unchanged. VO(mor)2 and VO(mor(S))2 undergo displacement reactions to give the partial formation of (VO)x(HSA) and (VO)(apo-hTf)/(VO)2(apo-hTf); moreover, mor(S) forms with apo-transferrin and albumin mixed species VO-mor(S)-apo-hTf and VO-mor(S)-HSA. In the systems with apo-hTf and HSA anisotropic EPR spectra at room temperature are detected in which the protein is not directly coordinated to V(IV)O(2+) ion. This is explained assuming that the bis-chelated complexes interact strongly with the proteins through a network of hydrogen bonds with the polar groups present on the protein surface. It is suggested that this "indirect" transport of V(IV)O species could be common to all the species containing ligands which can interact with the blood proteins. Uptake experiments by red blood cells were also carried out, using vanadium concentration of 5.0×10(-4)M and incubation time in the range 0-160min. VO(que)2/VO(que(S))2 and VO(mor)2/VO(mor(S))2 cross the erythrocytes membrane and in the cytosol VO(que)2/VO(que(S))2 do not transform, whereas VO(mor)2/VO(mor(S))2 give the partial formation of mixed species with hemoglobin (Hb) and other V(IV)O complexes.

Nitrogen Stereodynamics and Complexation Phenomena as Key Factors in the Deprotonative Dynamic Resolution of Alkylideneaziridines: A Spectroscopic and Computational Study.

The present work is aimed at shedding light on the origin of the stereoselectivity observed in the reactions of chiral heterosubstituted organolithiums, generated by lithiation of alkylideneaziridines. Factors such as the nitrogen inversion barrier, the stereochemistry at the nitrogen atom, the substitution pattern of the alkylideneaziridines, and the reaction conditions are taken into consideration. The interplay between nitrogen stereodynamics and complexation phenomena seems to be crucial in determining the stereochemical outcome of the lithiation/trapping sequence. The findings were rationalized by a synergistic use of NMR experiments, run on the lithiated intermediates, alongside computational data. It has been demonstrated that, in such systems, the stereochemistry-determining step is the deprotonation reaction, and a model based on a deprotonative dynamic resolution has been proposed. Such findings could find application in dynamic systems other than aziridines.

Harnessing the ortho-directing ability of the azetidine ring for the regioselective and exhaustive functionalization of arenes.

This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.

Straightforward access to 4-membered sulfurated heterocycles: introducing a strategy for the single and double functionalization of thietane 1-oxide.

A strategy for the stereoselective functionalization of thietane 1-oxide has been developed. Mono (C2 substituted) and doubly (C2, C4 disubstituted) functionalized thietanes have been obtained from the readily available thietane 1-oxide by using the corresponding organometallic intermediates that reacted with electrophiles leaving intact the 4-membered ring.

V(IV)O versus V(IV) complex formation by tridentate (O, N(arom), O) ligands: prediction of geometry, EPR 51V hyperfine coupling constants, and UV-Vis spectra.

Systems formed using the V(IV)O(2+) ion with tridentate ligands containing a (O, N(arom), O) donor set were described. Examined ligands were 3,5-bis(2-hydroxyphenyl)-1-phenyl-1H-1,2,4-triazole (H2hyph(Ph)), 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (H3hyph(C)), 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzenesulfonic acid (H3hyph(S)), and 2,6-bis(2-hydroxyphenyl)pyridine (H2bhpp), with H3hyph(C) being an orally active iron chelator that is commercially available under the name Exjade (Novartis) for treatment of chronic iron overload arising from blood transfusions. The systems were studied using EPR, UV-Vis, and IR spectroscopies, pH potentiometry, and DFT methods. The ligands bind vanadium with the two terminal deprotonated phenol groups and the central aromatic nitrogen to give six-membered chelate rings. In aqueous solution the main species were the mono- and bis-chelated V(IV)O complexes, whereas in the solid state neutral non-oxido V(IV) compounds were formed. [V(hyph(Ph))2] and [V(bhpp)2] are hexacoordinated, with a geometry close to the octahedral and a meridional arrangement of the ligands. DFT calculations allow distinguishing V(IV)O and V(IV) species and predicting their structure, the (51)V hyperfine coupling constant tensor A, and the electronic absorption spectra. Finally, EPR spectra of several non-oxido V(IV) species were compared using relevant geometrical parameters to demonstrate that in the case of tridentate ligands the (51)V hyperfine coupling constant is related to the geometric isomerism (meridional or facial) rather than the twist angle Φ, which measures the distortion of the hexacoordinated structure toward a trigonal prism.

BH3-promoted stereoselective ß-lithiation of N-alkyl-2-phenylaziridines.

BH(3) complexes of N-alkyl-2-phenylaziridines have been synthesized and their structure and stereochemistry proved with DFT calculations and NMR experiments. It has been demonstrated that the Lewis acid complexation is able to promote a regioselective ß-lithiation in 2-phenylaziridino-borane complexes. The lithiated intermediates were configurationally stable, allowing an enantioselective preparation of cis-2,3-disubstituted aziridines.

Tuning the reducing properties of 1,2-diaryl-1,2-disodiumethanes.

We investigated the reducing properties of a series of 1,2-diaryl-1,2-disodiumethanes by means of equilibration reactions. The electron-donor power of these vic-diorganometals is strongly affected by the nature of substituents present either on the aromatic ring(s) or on the carbanionic centers, and it can be correlated with their ability to delocalize the arylmethyl carbanions. These findings are supported by electrochemical analysis of the reduction behavior of the parent 1,2-diarylalkene. Applications of these results to the reduction of selected substrates are described.

Thermodynamics, kinetics, and dynamics of the two alternative aniomesolytic fragmentations of C-O bonds: an electrochemical and theoretical study.

Fragmentation reactions of radical anions (mesolytic cleavages) of cyanobenzyl alkyl ethers (intramolecular dissociative electron transfer, heterolytic cleavages) have been studied electrochemically. The intrinsic barriers for the processes have been established from the experimental thermodynamic and kinetic parameters. These values are more than 3 kcal/mol lower as an average than the related homolytic mesolytic fragmentations of radical anions of 4-cyanophenyl ethers. In the particular case of isomers 4-cyanobenzyl phenyl ether and 4-cyanophenyl benzyl ether, the difference in intrinsic barriers amounts to 5.5 kcal/mol, and this produces an energetic crossing where the thermodynamically more favorable process (homolytic) is the kinetically slower one. The fundamental reasons for this behavior have been established by means of theoretical calculations within the density functional theory framework, showing that, in this case, the factors that determine the kinetics are clearly different (mainly present in the transition state) from those that determine the thermodynamics and they are not related to the regioconservation of the spin density ("spin regioconservation principle"). Our theoretical results reproduce quite well the experimental energetic difference of barriers and demonstrate the main structural origin of the difference.