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B2nep2 efficiently cleaves the N–O bond of nitrones through a concerted mechanism to form imines in very high yields via a simple, efficient and scalable protocol. Typical radical traps like DMPO and TEMPO are also deoxygenated by diboron reagents. more...

Carbon-supported catalysts have been considered as macromolecular ligands which modulate the activity of the metallic catalytic center. Understanding the properties and the factors that control the interactions between the metal and support allows a fine tuning of the catalyzed processes. Although huge effort has been devoted to comprehending binding energies and charge transfer for single atom noble metals, the interaction of graphenic surfaces with cheap and versatile Cu(I) salts has been scarcely studied. A methodical experimental and theoretical analysis of different carbon-based Cu(I) materials in the context of the development of an efficient, general, scalable, and sustainable borylation reaction of aliphatic and aromatic halides has been performed. We have also examined the effect of microwave (MW) radiation in the preparation of these type of materials using sustainable graphite nanoplatelets (GNP) as a support. A detailed analysis of all the possible species in solution revealed that the catalysis is mainly due to an interesting synergetic Cu2O/graphene performance, which has been corroborated by an extensive theoretical study. We demonstrated through DFT calculations at a high level of theory that graphene enhances the reactivity of the metal in Cu2O against the halide derivative favoring a radical departure from the halogen. Moreover, this material is able to stabilize radical intermediates providing unexpected pathways not observed using homogeneous Cu(I) catalysed reactions. Finally, we proved that other common carbon-based supports like carbon black, graphene oxide and reduced graphene oxide provided poorer results in the borylation process. more...

We have proven that pyridine–boryl complexes can be used as superelectron donors to promote the coupling of thiols and aromatic halides through a SRN1 mechanism. The reaction is efficient for a broad substrate scope, tolerating heterocycles including pyridines, enolizable or reducible functional groups. The method has been applied to intermediates in drug synthesis as well as interesting functionalized polythioethers through a controlled and consecutive intramolecular electron transfer process. more...

An unusual reaction between GO, DBU and DMF, that typically uses base and solvent, has been thoroughly analyzed providing valuable basic knowledge about the reactivity of GO, which is essential to control functionalization and therefore the properties of graphene derivatives. A combination of characterization techniques, experiments and theoretical calculations allowed us to propose a structure for the materials and a plausible mechanism. The catalytic activity of the new basic materials was also analyzed. more...

The easily available vinyl sulfone 3 showed great potential for new applications in several fields such as organic synthesis and bioconjugate formation. This was demonstrated by performing a systematic assessment of its reactivity in Michael, radical, and cycloaddition reactions. Heteroaryl vinyl sulfone 3 presented excellent output in terms of reactivity and selectivity, proving superior to phenyl vinyl sulfone 1 and with clear advantages over bis-sulfone 2. This behavior might be due to the conformational and orbital control exerted by the tetrazole unit according to DFT calculations. Moreover, some alternative transformations to the Julia-Kocienski olefination on the obtained products are also described. more...

The use of graphene derivatives as supports improves the properties of heterogeneous catalysts, with graphene oxide (GO) being the most frequently employed. To explore greener possibilities as well as to get some insights into the role of the different graphenic supports (GO, rGO, carbon black, and graphite nanoplatelets), we prepared, under the same standard conditions, a variety of heterogeneous Cu catalysts and systematically evaluated their composition and catalytic activity in azide-alkyne cycloadditions as a model reaction. The use of sustainable graphite nanoplatelets (GNPs) afforded a stable CuI catalyst with good recyclability properties, which are compatible with flow conditions, and able to catalyze other reactions such as the regio- and stereoselective sulfonylation of alkynes (addition reaction) and the Meerwein arylation (single electron transfer process). more...

A simple method to transform sulfones into nitrones and therefore into the corresponding carbonyl derivatives has been developed. Some examples demonstrate that it is a new reliable and versatile reaction in the toolbox of sulfones that has great synthetic potential. NMR and computational studies were used to elucidate the mechanism. more...

The formation of nitrones by direct condensation between equimolecular amounts of N-substituted hydroxylamine hydrochlorides and aromatic or aliphatic aldehydes is efficiently promoted by pyrrolidine in a matter of minutes under very mild conditions in almost quantitative yields after a simple filtration through a short pad of silica gel. According to theoretical, spectroscopic, and experimental studies, this success is due to the ability of pyrrolidine to liberate the hydrochloride of the hydroxylamine and catalyze the reaction via iminium activation ion. Moreover, a cooperative pyrrolidine/pyrrolidinium chloride effect facilitates several steps of the catalytic cycle through proton transfer without hampering the nucleophilicity of the hydroxylamine by protonation. more...

A general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds bearing the NH2 group in the presence of pyrrolidine as a catalyst has been developed. These organocatalytic reactions, based on the application of the concept of nucleophilic catalysis, proceed with outstanding yields in the absence of acids and metals under simple conditions and minimum experimental manipulation. The method has been mainly applied to the synthesis of N-sulfinyl and N-sulfonyl imines, but its general validity has been proven with the preparation of representative N-phosphinoyl, N-alkyl, and N-aryl imines. These unprecedented reactions, which presumably occur via iminium activation without requiring acidic conditions, are an interesting and competitive alternative to the classical methods for preparing aldimines. more...

An asymmetric organocatalytic [3 + 3] annulation strategy based on a Michael addition/intramolecular Julia-Kocienski olefination sequence has been developed for the synthesis of 4-substituted-5-nitrocyclohex-1-ene compounds. The strategy is an alternative to the direct reluctant enantioselective Diels-Alder approach. The potential of the methodology has been demonstrated with a concise enantioselective formal synthesis of trandolapril. more...

Although several nucleophiles derived from arylacetic acids have been described in catalysis via iminium activation, none have presented good enantioselectivity and reactivity with both β-alkyl and β-aryl enals. This study on the Michael addition of p-nitrophenylacetic thioesters suggests that this behavior is due to the different reactivity and distinct tendency to reversibility exhibited by these types of enal. Independent optimization of the conditions for β-alkyl and β-aryl enals provide good yields and enantioselectivities with both substrates, affording Michael adducts that are versatile building blocks for the preparation of an interesting variety of arylacetic acid derivatives. more...

The Michael addition of activated methylenes to β-substituted α,β-unsaturated aldehydes (enals) via iminium catalysis takes place following reactivity and enantioselectivity patterns which depend on the electronic nature of the substituent in the β position (β-aryl or β-alkyl). Application of the same reaction conditions to both families of enals may result in erratic levels of asymmetric induction in the reactions of β-aryl enals or low reactivity with β-alkyl enals. A systematic analysis of this behavior using phenylacetic acid derivatives as case studies has led us to find a general trend: the different problems found for β-aryl and β-alkyl enals depend on the acidity of the nucleophile, and the outcome of the reaction for both types of enals can be improved substantially by careful choice of catalyst, solvent, and additive. Furthermore, this study has allowed us to understand subtle aspects of this transformation and has enabled the formulation of a general and reliable protocol to obtain high yields and enantioselectivities consistently, regardless of the acidity of the nucleophile and the nature of the substituent (aromatic or aliphatic) at the β position, We thank CTQ-2009-12168, CAM (AVANCAT CS2009/PPQ-1634), UAM-CAM (CCG10-UAM/PPQ-5769), CTQ-2012-35957, CTQ2015-63997-C2-1-P, CTQ2016-78779-R and FOTOCARBON-CAM S2013/MIT-2841 for financial support. S.D. thanks the Comunidad Autónoma de Madrid (CAM), and E.R. and S.M. thank MICINN, for predoctoral fellowships. P.M. thanks MICINN for a Ramón y Cajal contract and the EU for a Marie Curie grant (CIG: HYPERCAT-304228 more...

Pyrrolidine catalyzes very efficiently, presumably via iminium activation, the formation of acyloximes, acylhydrazones, and thiosemicarbazones derived from aromatic and aliphatic aldehydes using equimolar amounts of reagents and green solvents. Experimental simplicity and excellent yields after a simple filtration are the main advantages of the method, being an alternative to those currently available especially for the acyl derivatives, which do not work under uncatalyzed conditions. Its application to the synthesis of acyloximes by direct condensation between aldehydes and acylhydroxylamines is unprecedented. more...

2-p−Tolylsulfinyl benzyltributyltin undergoes smooth coupling conditions with allyl and alkynyl derivatives in the presence of Cu(I) salts. It demonstrates that the sluggish benzyl transfer in Stille coupling reactions mediated by copper can be significantly improved by the presence of a sulfinyl group at the ortho position. more...

Background: In the field of asymmetric aminocatalysis, chiral catalysts derived from azoles (five-membered heterocycles containing exclusively N atoms) play an important role. Surprisingly, all the catalysts used for enamine and/or iminium ion activation derive from pyrrole or imidazole. We decided to test if other reduced azole derivatives could be used as organocatalysts and particularly in aminocatalysis via iminium ion activation. The azole derivatives that came naturally to mind are the 3,5-disubstituted 2-pyrazolines (also called 4,5-dihydro-1H-pyrazoles). Methods: We synthesized racemic 3,5-diphenyl-2-pyrazoline, separated both enantiomers by chiral-HPLC on a Lux-Cellulose-4 column (heptane/ethanol 70:30 as mobile phase), determined the absolute configuration of their hydrochloride salts (pyrazolinium) by the combined use of experimental rotatory power and B3LYP/6-311++G(d,p) theoretical calculations and use one the enantiomers, the R, as the catalyst. Results: We have demonstrated that the enantiopure (R)-3,5-diphenyl-2-pyrazoline is able to catalyze the Michael addition of 1-(4-nitrophenyl)propan-2-one to cinnamaldehyde and crotonaldehyde via iminium activation. Conclusion: This is the first example of activation of both types of enals, aliphatic and aromatic, via pyrazolinium salts and opens new possibilities to the design of other type of chiral organocatalysts than the traditional pyrrole and imidazole derivatives. more...

The cinchona alkaloid quinine promotes the enantioselective nitroso-aldol reaction between alpha-aryl-alpha-cyanoacetates and nitrosobenzene to give the hydroxyamination products with total chemoselectivity. Treatment of the reaction mixture with Zn/AcOH affords the corresponding amines in high yield and moderate enantioselectivity. An unusual effect on the enantioselectivity was observed with the catalyst loading and solvent. A reductive protocol allows the construction of an optically active 1,2-diamine moiety bearing a quaternary center. more...

N-Sulfinylimines derived from aromatic and aliphatic aldehydes react with nitroethane and NaOH, yielding mainly two diastereoisomeric β-nitroamines as the result of a highly diastereoselective reaction and further epimerization of the carbon linked to the nitro group. The resulting β-nitroamines are used as precursors of N-sulfonyl α-amino methyl ketones and β-amino hydroxylamines. more...

The glycosylation of 1,2-trans-diequatorial diols derived from tetrabenzoylated and tetrabenzylated D- and L-chiro-inositol with several glycosyl donors has been investigated. An unprecedented dependence of the regioselectivity on the absolute configuration of the acceptor has been found. However this trend is also modulated by the nature of the protecting groups on both the donor and acceptor, with benzoylated acceptors affording higher levels of regioselectivity. Most of the results have been rationalized by DFT calculations which indicate that stereoelectronic factors and hydrogen bonding between the donor and acceptor govern their relative orientation and determine the regiochemical outcome of the process. These studies also highlight the role of the acyl group adjacent to the OH to be glycosylated in facilitating the glycosylation reaction. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) more...

Optically pure 2-(l-hydroxybenzyl)piperidine and pyrrolidine were prepared by reaction of oxygenated 2-(p-tolylsulfinyl)benzyl carbanions with the appropriate chlorinated N-sulfinylimines followed by subsequent elimination of the sulfinyl groups. The main reaction is a tandem process involving nucleophilic addition of the sulfinylbenzyl carbanion to the C=N bond followed by intramolecular elimination of the chlorine by the resulting amide. The matched pair of the reagents (exhibiting the same configuration at their respective sulfinyl moieties) evolves with a complete control of the stereoselectivity at the two newly created chiral carbons. more...

[reaction: see text] N-Sulfinylimines derived from aromatic or aliphatic aldehydes and ketones react with nitromethane and NaOH in a highly diastereoselective manner under mild conditions. In the presence of TBAF, the reaction rates are strongly increased and the stereoselectivity is inverted. This method provides enantiomerically pure beta-nitroamines derived from enolizable aldimines and ketimines, which so far are hardly accessible by aza-Henry reactions. more...

The intramolecular glycosylation of thiomannoside donors linked through C6' by a phthaloyl group to C3 of a diol mannoside acceptor is described. The unexpected results led us to undertake a systematic analysis of the factors affecting the regioselectivity of the intermolecular process. The substituents on the diol mannoside acceptor have been found to play an important role. more...

[Reaction: see text] A simple procedure to obtain N-sulfonyl imines involving the condensation of carbonyl compounds with p-tolyl or tert-butyl sulfinamides followed by oxidation with m-CPBA of the resulting N-sulfinylimines is reported. The method is applicable to aldehydes (aliphatics and aromatics) and ketones (diaryl, dialkyl, and aryl alkyl), even those containing enolizable protons. It also does not affect C=N or C=C double bonds and does not epimerize alpha-stereogenic centers. more...

Reduced graphene oxide (rGO) has been used as a support for piperazine to provide a heterogeneous bifunctional organocatalyst (rGO-NH) that is able to efficiently promote vintage organic transformations such as Knoevenagel, Michael and aldol reactions. The obtained results suggest a significant role of the support in the course of these reactions. more...

A general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds bearing the NH2 group in the presence of pyrrolidine as a catalyst has been developed. These organocatalytic reactions, based on the application of the concept of nucleophilic catalysis, proceed with outstanding yields in the absence of acids and metals under simple conditions and minimum experimental manipulation. The method has been mainly applied to the synthesis of N-sulfinyl and N-sulfonyl imines, but its general validity has been proven with the preparation of representative N-phosphinoyl, N-alkyl, and N-aryl imines. These unprecedented reactions, which presumably occur via iminium activation without requiring acidic conditions, are an interesting and competitive alternative to the classical methods for preparing aldimines. more...

Reduced graphene oxide (rGO) has been used as a support for piperazine to provide a heterogeneous bifunctional organocatalyst (rGO-NH) that is able to efficiently promote vintage organic transformations such as Knoevenagel, Michael and aldol reactions. The obtained results suggest a significant role of the support in the course of these reactions., We thank the Spanish Government (CTQ-2012-35957) and CAM (AVANCAT CS2009/PPQ-1634) for financial support. E.R. thanks the Spanish Ministry for a predoctoral fellowship (FPU/AP-2010-0807). R.S. thanks the Spanish Ministry of Science for a postdoctoral contract (PTQ-11-04601). more...

A synthetic approach towards the cytotoxic polyene polyol macrolide amphidinolide B (1), based on elaboration of the C1C13 carboxylic acid 4 and the C14C25 alcohol 3 units, their esterification to the iodostannyl ester 2, and an intramolecular Stille sp2–sp2 coupling reaction, is described. In spite of adequate precedent and model experiments, circumstances conspired and the aforementioned coupling reaction was not realised in this case. more...

The synthesis of (±)-( E )-1-( p -tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 1 and ( S S )-2-( p -tolylsulfinyl)-3-trimethylsilyloxybuta-1,3-diene 2 and their reactions with cyclic dienophiles are described. Cycloaddition of diene 1 with N -methylmaleimide 10 was performed under pressure affording a complex reaction mixture from which two epimers at C-3′, (±)- 11a and (±)- 11b [2,3,3a,4,5,7a-hexahydro-2-methyl-7a-(1-methylsuccinimide-3-yl)-1 H -isoindole-1,3,5-triones], were isolated in equal amounts. Diene (±)- 1 cycloadded to the more reactive 4-methyl-1,2,4-triazoline-3,5-dione 14 at atmospheric pressure and room temperature. However, nothing can be said about the stereochemical outcome of this addition since the loss of the chiral auxiliary via the sulfoxide–sulfenate rearrangement gave the bicyclic α,β-unsaturated ketone 17 (2-methyl-2,3,5,6-tetrahydro-1 H -[1,2,4]triazolo[1,2- a ]pyridazine-1,3,6-trione). Diels–Alder cycloaddition of enantiopure diene 2 with 10 occurred under pressure leading to a diastereomeric mixture of adducts where the trimethylsilyl enol ether moiety spontaneously evolved to the ketone function. The major enantiopure product 18a [(3a S ,6 S ,7a R , R S )-2-methyl-6-( p -tolylsulfinyl)perhydroisoindole-1,3,5-trione] was isolated and characterized. Cycloadditions of both dienes to dienophile 10 appear highly stereoselective. more...

Enantiomerically pure hydroxy substituted triazolopyridazine 5a was obtained in one pot under mild conditions by reaction of (+)-( R )-(1 E ,3 E )-1-( p -tolylsulfinyl)-1,3-pentadiene and 4-methyl-1,2,4-triazoline-3,5-dione in the presence of P(OMe) 3 . The process involved a tandem Diels-Alder cycloaddition/sulfoxide-sulfenate rearrangement and trapping of the intermediate sulfenate. more...

Application of this method is demonstrated by the formal total synthesis of Trandolapril (VIII).

The differences in the reactivity of the thioesters (I) with β-alkyl and β-aryl-substituted enals (II) are overcome by optimization allowing the synthesis of diastereomeric mixtures of Michael adducts (III) and (IV). more...

Diels-Alder reactions of [(S)R]-(1E,3E)-1-p-tolylsulfinyl-1,3-pentadiene with 1-pyrrolidinyl-1-cyclohexene and methyl acrylate evidenced: i) low reactivity of the diene regardless of the electronic character of the dienophile (high pressures were always required); ii) a complete regio- and endo-selectivity (both controlled by the sulfoxide), but a low π-facial diastereoselectivity in the cycloaddition with enamine; iii) diastereoselectivity (facial and endo exo ) for the reaction with methyl acrylate is dependent on the regiochemistry (mainly controlled by the methyl substituent). more...

The Diels-Alder adducts resulting in the reaction of enantiomerically pure [(S)R]-(1E,3E)-1-p-tolylsulfinyl-1,3-pentadiene with maleic anhydride evolved stereoselectively in situ through several intramolecular tandem reactions, involving [2,3]-sigmatropic sulfoxide-sulfenate rearrangement, acylation of the sulfinyl oxygen, and elimination of the sulfur function through a SN2′ process yielding lactones 3 and 4. more...

[(S) R ,1 E ,3 E ]-4- p -Tolylsulfinyl-1-X-1,3-butadienes 1 (X = CO 2 Me, CN, PO(OEt) 2 , SO 2 Ph, SEt) are synthesized from a common starting material, [(S) R ]-3- p -tolylsulfinyl-2-propenal 2 , through a Hormer-Wadsworth-Emmons reaction with the phosphonate (XCH 2 PO(OEt) 2 ). The synthesis of 2 is also described. more...

The ammonium salt supports the formation and stabilization of the iminium intermediate and, additionally, activates the nucleophile as an enolate.

We report herein the efficiency of quaternary ammonium salts as co-catalysts in organocatalytic Michael reactions involving iminium activation of α,β-unsaturated aldehydes. The enantioselective formal benzylation of these substrates has been optimized and used to rationalize the role of the ammonium salts in these processes. more...

α,β-Disubstituted cyclohexenones are easily obtained by simple organocatalytic Michael addition of commercially available ketone (I) to α,β-unsaturated aldehydes, followed by aldol reaction and a dehydration sequence. more...

( R )-(1 E ,3 E )-2-Cyclohexenyl-1-vinyl- p -tolylsulfoxide 1a and ( R )-(1 E ,3 E )-N-methyl-3-[2-( p -tolylsulfinyl) vinyl]-1H-in 1b reacted with N-methylmaleimide to give Diels-Alder adducts whose in situ evolution through a tandem sulfoxide-sulfenate rearrangement/dehydration/[4+2]-cycloaddition sequence afforded the all- cis substituted bicyclo [2,2,2] octene 7 in a highly stereoselective manner. more...

The asymmetric Diels-Alder reactions of (R)-1-(p-tolylsulfinyl)-1,3-bu- tadienes (3a-c) with N-methylmaleimide (NMM) have been explored. The cycloadditions are stereospecific: only one endo adduct is formed, the π-facial diastereoselectivity being controlled by the sulfoxide both in thermal and catalytic conditions. The in situ cycloaddition/sulfoxide sulfenate [2,3]-sigmatropic rearrangement starting from chiral (3a-c) in the presence of an excess of NMM, which acts as thiophilic agent, provides a convenient one-step access to enantiomerically pure and all- cis functionalized cyclohexenols (-)-5a-c more...

The title nitriles (I) and (VII) smoothly undergo Michael addition to α,β-unsaturated aldehydes to afford the adducts in high yields, moderate diastereoselectivity, and good enantioselectivity.

Arylacetonitriles are able to participate in organocatalytic Michael additions to alpha,beta-unsaturated aldehydes by incorporating a nitro group at the phenyl ring, which acts as a temporary activating group in a remote position and allows further transformations. The sequential protocol Michael addition/NaBH(4) reduction/lactonization allows the synthesis of diastereomerically pure disubstituted lactones in high yield and optical purity. more...

11 páginas, 9 figuras, 2 tablas, 1 esquema., The assistance of neighboring protecting groups with different orientations in 1,2-diol acceptors and the reactivity of both reaction partners, the donor and the acceptor, have been evaluated as factors that determine the regioselectivity of glycosylation reactions. It has been established, by experimental and theoretical studies, that the regioselectivity for the glycosylation of a given OHgroup can be considerably increased by the presence of groups able to form a hydrogen bond with that OHgroup. Moreover higher regioselectivities are observed when armed donor/activated acceptor combinations are avoided., This research was supported by the Dirección General de Investigación Científica y Técnica (Grant BQU2002–03734). more...

Enantiomerically pure 2-p-tolylsulfinylmaleates 1, 2 and 3 have been readily prepared by Knoevenagel reaction between (S)-menthyl p-toluenesulfinate and glyoxylic acid. Their asymmetric Diels-Alder reactions with cyclopentadiene have been studied under a wide range of uncatalyzed and catalyzed conditions and the stereochemical results have been explained by assuming a steric control approach, in term of S-cis or S-trans favoured conformations. Uncatalyzed Diels-Alder reactions of 1 and some Lewis acid catalyzed Diels-Alder reactions of 2 show high facial and endo selectivities. The facial selectivity of dienophile 2 highly depends on the Lewis acid, whereas reactivity of 1 and 3 is very sensitive to the solvent. These sulfinylmaleates 1, 2 and 3 act as synthetic equivalents of chiral acetylenedicarboxylates in Diels-Alder reactions after basic elimination of the sulfinylic moiety in the resulting adducts. more...

Optically pure cyano tert-alkyl sulfones have been obtained by organocatalytic enantioselective Michael addition of alpha-substituted cyanosulfones to vinyl ketones using cinchona alkaloids as catalysts. The best results were obtained for p-trifluorophenylsulfones by using VIII as catalyst in toluene at -40 degrees C. Reactions proved to be applicable for a variety of alpha,beta-unsaturated ketones, affording alpha,alpha-disubstituted cyanosulfones in excellent yields with er's up to 90:10. more...

A three step efficient strategy for the synthesis of substituted 5-nitropiperidones in high de, employing Michael addition of N-p-tolylsulfinyl β-nitroamines to α,β-unsaturated esters, hydrolysis of the sulfinyl group, and cyclization of the resulting free amines, has been developed. A very simple experimental procedure involving mild conditions and only one chromatographic purification are the main features of the process. more...