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A novel and general approach to six-membered bicyclic benzo fused 1,4-heterocycles is described. The addition–cyclization cascade of benzo 1,2-diols, 1,2-thiols and 2-(benzylamino)phenols with stable and easily available vinyl selenones affords differently substituted 2,3-dihydro-1,4-benzodioxines, benzodithiines and 3,4-dihydro-2H-1,4-benzoxazines in good yields. The same procedure has been extended to the synthesis of 1,2,3,4-tetrahydroquinoxalines. All of these heterocycles are present in a variety of biologically active compounds.

The reactions of readily available vinyl selenones with enantiopure 1,2-diols, N-protected-1,2-aminoalcohols, and diamines gave substituted enantiopure 1,4-dioxanes, morpholines, and piperazines, respectively, in good to excellent yields. The same procedure was extended to the synthesis of thiomorpholine, benzodiazepine, and benzoxazepine. The reactions proceeded in one pot, in the presence of base, through a simple and novel application of the Michael-initiated, ring-closure (MIRC) reactions. The formed heterocycles constitute a framework that is observed in a large number of pharmaceutical compounds.

Variously substituted aziridines were conveniently prepared by an aza-Michael Initiated Ring Closure (aza-MIRC) reaction starting from vinyl selenones and primary amines, aminoalcohols or diamines. The reactions proceed in very high yields at room temperature in toluene or water. A significant rate acceleration was observed under aqueous conditions.

A novel, simple, and flexible approach to α,α-disubstituted γ-lactams via a domino Michael addition/cyclization process involving the phenyl vinyl selenone and β-ketoamides, malonylamides, or β-cyanoamides is reported. The reactions proceed in good to excellent yields under mild reaction conditions.

Aliphatic and aromatic amines are efficiently acylated by acetic, pivalic, benzoic, phthalic, or maleic anhydrides in ethyl acetate at room temperature. Under the same experimental conditions, amino alcohols are chemoselectively acylated at the amino group.

Vinyl selenides can be easily obtained through nucleophilic substitution of the corresponding halides by using PhSeZnCl in THF as well as “on water” conditions. The reaction is stereospecific with retention of the alkene geometry. The only exception has been observed in the reaction conducted on a β-chloro-α,β-unsaturated ketone, which afforded the (Z) product starting from either the (E) or (Z) isomer. DFT calculations have been performed in order to investigate the reaction mechanism, the stereochemistry of the process and the role of the zinc atom. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Enantiomerically pure disubstituted pyrrolidines, recently synthesized from commercially available enantiomerically pure β-aminoalcohol, were used as starting materials to synthesize enantiomerically pure hexahydro-1 H -pyrrolizines and octahydroindolizine through a cyclization reaction promoted by N -(phenylseleno)phthalimide. Similarly, starting from enantiopure 5-(hydroxymethyl)pyrrolidin-2-ones, enantiopure hexahydro-3 H -pyrrolizin-3-ones were obtained.

Under acidic conditions zinc reduces diselenides to afford selenols, which can be either isolated or treated in situ with alkyl halides to produce alkyl selenides or with epoxides to give β-hydroxyselenides.

Here we report the first example in which the phenylseleno group is directly substituted by a hydroxy function. The reaction is promoted by the PhSeOSO 3 H generated “in situ” by oxidation of (PhSe...

Starting from commercially available enantiomerically pure aminoalcohols and using simple conversions promoted by organoselenium reagents, several enantiomerically pure substituted pyrrolidines were prepared. After double protections (R)- or (S)-2-phenylglycinols were converted into the β-amino selenides by displacing the tosyl group with phenyl selenolate anions. The phenylseleno group was then substituted by an allyl group by treatment with allyltributyltin and AIBN. The reaction of these allylic derivatives with electrophilic phenylselenium reagents afforded selenium containing pyrrolidines as the result of a 5-exo-trig cyclization. The pyrrolidine derivatives thus obtained were reductively deselenylated with triphenyltin hydride and AIBN. Moreover, the selenides were converted into the selenones, which easily gave substitution with different nucleophiles. Enantiopure 2,5-pyrrolidines containing azido, methylthio, cyano and iodo groups were thus obtained.

Chiral sulfur-containing electrophilic selenium reagents can be employed to effect efficient asymmetric syntheses. Spectroscopic and chemical evidence demonstrate that the observed high selectivity of the asymmetric reactions is associated with a nonbonding selenium–sulfur interaction that is present in both the crystalline form and in solution. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Alkyl phenyl selenoxides were produced in excellent yields by oxidation of the corresponding selenides with 2-nitrobenzenesulfonyl chloride and potassium superoxide in dry acetonitrile at −15 °C.

The first example of a kinetic resolution process promoted by an electrophilic selenium reagent is reported. Racemic allylic alcohols react with half equivalents of a selenenylating agent in methanol leading to the regiospecific formation of the corresponding addition products with a very high level of facial selectivity (98% de). The unreacted alcohol can be recovered in a optically enriched form (92% ee).

Titanium enolates derived from methyl phenylselenoacetate and other acetates bearing a selenium containing chiral auxiliary have been employed to bring about 1,4-addition reactions to enones. These reactions generate δ-oxo-α-seleno esters in good yields and with excellent regio- and diastereoselectivities. The results obtained clearly indicate that the Lewis acids, employed to activate the starting enones towards addition, greatly influence reactivity as well as the stereochemical outcomes of these reactions. TiCl4 complexation resulted in particularly efficient promotion of the 1,4-addition. Simple manipulations of the organoselenium moiety allowed some enantiomerically pure δ-oxo-α-camphorseleno esters to be transformed into the corresponding δ-oxo-α-hydroxy or δ-oxo-α-allyl esters or into trisubstituted tetrahydrofurans. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

A simple and stereospecific synthesis of both (R)- and (S)-GABOB has been developed. The synthetic approach involves the conversion, through organoselenium intermediates, of commercially available ethyl (R)- and (S)-4-chloro-3-hydroxybutyrate into a protected 1,2-amino alcohol with retention of the original configuration.

Se-Phenyl selenocarboxylates have been conveniently prepared from (phenylseleno)acetylenes by treatment with p-toluenesulfonic acid monohydrate in dichloromethane. This easy conversion is compatible with a broad range of oxygen- and nitrogen-containing functional groups. The Se-phenyl selenocarboxylates were easily converted into the corresponding esters and amides. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Starting from commercially available enantiomerically pure epoxides, enantiomerically pure substituted tetrahydrofurans were prepared using simple conversions promoted by organoselenium reagents. The first step consisted in the opening of the epoxides with phenylselenolate anions to afford hydroxyalkyl phenyl selenides. The PhSe group was then substituted by an allyl group by treatment with allyltributyltin and AIBN. The reaction of these allylic derivatives with electrophilic phenylselenium reagents afforded selenium containing tetrahydrofurans as the result of a stereospecific 5-exo-trig cyclization. The tetrahydrofuran derivatives thus obtained were finally deselenenylated with triphenyltin hydride and AIBN.

An alkene can be converted into two enantiomerically pure diastereomeric selenoethers through a regio- and stereospecific anti addition reaction mediated by N -(phenylseleno)phthalimide in the presence of an enantiomerically pure 1,2-diol. This alkoxyselenylation reaction can be employed as the key step to allow the synthesis of several isomeric tetrasubstituted 1,4-dioxanes in enantiomerically pure form.

The mixtures of two enantiomerically pure diastereoisomeric amido selenides, obtained from the reactions of alkenes with camphorselenyl sulfate in a mixture of water and a nitrile, were treated with Lawesson's reagent to afford a mixture of the two corresponding thioamido derivatives. The two diastereoisomeric thioamido selenides could be easily separated by flash chromatography. The thioamido selenides, after activation with PhSeCl, underwent deselenylation by a stereospecific intramolecular substitution. Thus both enantiomeric thiazolines could be obtained in enantiomerically pure form.

A novel, simple, and flexible approach to α,α-disubstituted γ-lactams via a domino Michael addition/cyclization process involving the phenyl vinyl selenone and β-ketoamides, malonylamides, or β-cyanoamides is reported. The reactions proceed in good to excellent yields under mild reaction conditions.

Treatment of the di-2-[(1 S )-1-(methylthio)ethyl]phenyl diselenide or of the di-2-methoxy-6-[(1 S )-1-methylthio)ethyl]phenyl diselenide with bromine and silver triflate afforded the corresponding electrophilic selenylating triflates which were used in situ to promote the asymmetric selenocyclization of γ-alkenyl oximes and δ-phenyl-γ-alkenyl oximes. The course of these reactions and hence the structures of the cyclization products were dictated by the ( E )- or ( Z )-geometry of the starting oximes. The two types of cyclization products were either the cyclic nitrones or the 1,2-oxazines; in both cases the reactions proceeded with excellent yields, complete regioselectivity and good diastereoselectivity.

The substitution reactions of thiophene and 2-methylthiophene with the electrophilic selenenylating agent produced from the 2,2′-dithienyl diselenide by oxidation with iodobenzene diacetate involve only the α-positions and give rise to the formation of oligo(seleno-2,5-thienylenes). Products deriving from the attack at the α-positions of thiophene and 2-methylthiophene were also observed starting from the 5,5′-dimethyl-2,2′-dithienyl diselenide. The same electrophilic reagents reacted with furan and 2-methylfuran to afford a mixture of the mono- and di-substituted compounds.

The synthesis of a new chiral non-racemic sulfur containing diselenide is described. The electrophilic selenium reagent, produced from this diselenide by treatment with bromine and silver triflate, has been used to effect the selenomethoxylation and the selenohydroxylation of alkenes. These addition reactions occurred with good chemical yield and with high diastereoselectivities. © 2000 Elsevier Science Ltd. All rights reserved.

(R)-3-Aminotetradecanoic acid (iturinic acid) has been synthesized starting from dodecanoyl chloride. This new synthetic approach involved the enantioselective reduction of an ynone to the corresponding propargylic alcohol and then into a protected propargylic amine. The iturinic acid was obtained by the transformation of a (phenylseleno)acetylene intermediate into a carboxylic group followed by N-deprotection.

The reaction of β,γ-unsaturated esters and nitriles with camphor diselenide and ammonium persulfate in methanol, ethylene glycol or water affords enantiomerically enriched γ-alkoxy or γ-hydroxy α,β-unsaturated derivatives, respectively, in good chemical yields and with moderate to good enantioselectivity.

A simple substrate-controlled asymmetric synthesis of ( R )-3-aminooctanoic acid ( D -BAOA) is described. The present method involves the conversion of commercially available ( S )-1-octyn-3-ol into the protected propargylic amine, with complete inversion of configuration, and the successive transformation of the (phenylseleno)acetylene intermediate into the Se-phenyl selenocarboxylate, which is then easily converted into the carboxylic group. The phthalimido group was eventually removed by treatment with hydrazine hydrate.

By reaction with ammonium persulfate the easily available diselenide derived from (1 R )-(+)-camphor was converted into the camphorselenenyl sulfate. This chiral electrophilic selenium reagent reacted at room temperature with alkenes in the presence of methanol to afford selenomethoxylated adducts in good yields and with moderate to good facial selectivity. The two diastereomeric addition products could be separated in most cases.

4-Pentenyl hydrazines, CH 2 CHCH 2 CH 2 CH 2 NHNHR, react with phenylselenenyl sulfate, produced by diphenyl diselenide, ammonium persulfate and trifluoromethanesulfonic acid, to afford phenylseleno-substituted hexahydropyridazine or pyrrolidinamine derivatives depending on the nature of the substituent R.

Upon treatment with phenylselenenyl bromide, alkenyl phenylhydrazones give rise to cyclization reactions affording, after reduction with sodium borohydride, either pyrrolidinamine and piperidinamine or tetrahydropyridazine derivatives depending on the geometrical structure of the starting substrates.

A novel and general approach to six-membered bicyclic benzo fused 1,4-heterocycles is described. The addition–cyclization cascade of benzo 1,2-diols, 1,2-thiols and 2-(benzylamino)phenols with stable and easily available vinyl selenones affords differently substituted 2,3-dihydro-1,4-benzodioxines, benzodithiines and 3,4-dihydro-2H-1,4-benzoxazines in good yields. The same procedure has been extended to the synthesis of 1,2,3,4-tetrahydroquinoxalines. All of these heterocycles are present in a variety of biologically active compounds.

Quinidine-catalyzed reaction of indanone carboxylates with vinyl selenone followed by azidation, cyclization, and reduction allows a highly diastereo- and enantioselective access to indenopyrrolidines like (VI) and (IX).

The synthesis of a new bench-stable and odorless zinc thiolate is here reported. The thiolysis of epoxides effected using this reagent showed a considerable rate acceleration of the reaction when effected in “on-water” conditions. In addition, the reactions evidenced a good regioselectivity combining the advantage of the procedures effected in organic solvent with those effected using Lewis acid catalysis.

Alkenyl nitrones reacted with phenyselenenyl bromide to afford ring closure reaction products deriving by the intramolecular capture of the seleniranium intermediates by the oxygen atom. Owing to the relative positions of the oxygen atom and of the carbon-carbon double bond in the nitrones employed, six-membered cyclic iminium salts were thus formed. These have ben directly treated with nucleophilic reagents and afforded 1,2-oxazine derivatives in good yield. It has been observed that, under the experimental conditions employed, the iminium salts in which the carbon-nitrogen double bond is exocyclic, depending on the nucleophile employed, gave the N-alkyl 1,2-oxazines and/or the N-unsubstituted 1,2-oxazines. On the contrary, with iminium salts in which the carbon-nitrogen double bond is endocyclic only N-alkyl 1,2-oxazines were obtained.

[reaction: see text] The first example of a kinetic resolution process promoted by electrophilic selenium reagents is reported. Racemic allylic alcohols react with half equivalents of a selenenylating agent in methanol leading to the regiospecific formation of the corresponding addition products with a very high level of facial selectivity (from 95:5 to 98:2 dr). The unreacted alcohols can be recovered in an optically enriched form (from 90 to 94% ee).

Phenylselenenyl bromide easily reacts with O-allyl oximes to afford cyclic iminium bromides which can be reduced in situ with sodium borohydride to produce substituted N-alkyl isoxazolidines in good yield.

The reaction of O-allyl hydroxylamines with phenylselenenyl sulfate, generated from the oxidation of diphenyl diselenide with ammonium persulfate, easily affords N-alkyl isoxazolidines as the result of a cyclization reaction through the formation of a carbon-nitrogen bond.

A variety of selenoesters (III) is readily prepared by reaction of acid chlorides (I) with zinc selenolate (II).

The reaction of a variety of tert-butyl β-ketoesters with vinyl selenone in the presence of CIE generates a Michael intermediate which is cyclized by treatment with silica gel to give spirolactams with high levels of enantioselectivity.

A Michael addition of racemic indanone carboxylates to vinyl selenone catalyzed by C6′hydroxyl cinchona derivatives is the key step of a synthetic sequence for a practical access to highly enantioenriched (up to 98% ee) polycyclic pyrrolidines bearing contiguous tertiary and quaternary stereocenters.

PhSeZn-halides react under “on water” mild conditions with acid chlorides to provide a high yield route to a variety of aromatic and aliphatic phenylselenoesters.

The phenylselenenyl sulfate, generated from the oxidation of diphenyl diselenide with ammonium persulfate, easily effects electrophilic aromatic substitution reactions on thiophene, 2- and 3-methylthiophenes and on 3-bromothiophene. The phenylseleno group activates the substrate to further substitution. Under controlled experimental conditions, it is thus possible to introduce the desired number of phenylseleno groups into the thiophene ring.

Selenium-based reagents bear a high potential for the improvement of known reactions not only from an environmental and pharmaceutical point of view, but also as interesting reagents for the development of, completely new synthetic transformations and as potential ligands in catalytic reactions. A variety of organoselenium compounds have been proven to be useful for organic synthesis over several decades. Organoselenium species can be introduced as either nucleophiles or electrophiles to other organic molecules, producing useful intermediates for organic synthesis. Optically active organoselenium derivatives and their application to highly selective asymmetric synthesis are also of current interest. Probably the most interesting aspect, which emerged in recent years, concerns the possibility of effecting some functional group conversions using catalytic amounts of the selenium reagent or using selenium containing compounds as chiral ligands in metal catalyzed reactions. The developments of all these catalytic processes represent the most important results which have been reported recently in this field and their conceptual and synthetic relevance considerably increases the use of some organoselenium derivatives as Green Catalysts. [1] In consideration that in Nature, the main biological function of selenium is associated with its incorporation in the form of selenocysteine (Sec) into certain proteins having redox motifs different selenium containing compounds can be investigated as bio-inspired catalysts in the carbon-carbon multiple bond oxidation mediated by H2O2 in water. These catalysts resulted to be also interesting good GPx-mimetics. Acknowledgement: Financial support from M.I.U.R.-PRIN2007, Consorzio CINMPIS, Bari, University of Perugia, the grant "British-Italian Partnership" from the British Council/CRUI. References [1] a) D. M. Freudendahl, S. Santoro, S. A. Shahzad, C. Santi, T. Wirth Angew. Chem. Int. Ed.2009, 8, 8409.b) C. Santi, M. Tiecco, L. Testaferri, C. Tomassini, S. Santoro, G. Bizzoca Phosphorus Sulfur Silicon Relat. Elem. 2008,183, 956. c) S. Santoro, C. Santi, M. Sabatini, L. Testaferri, M. Tiecco Adv.Synth. Catal. 2008, 350, 2881. d) S. Santoro, B. Battistelli, B. Gjoka, C-w.S.Si, L.Testaferri, M. Tiecco, C. Santi Synlett, 2010, 1402.

A simple activation of MOM-, MEM- and SEM-phenyl selenides by iodonium or copper(I) ions in the presence of alcohols to give the corresponding alkoxymethyl ethers is described.

The reaction of a variety of tert-butyl β-ketoesters with vinyl selenone in the presence of CIE generates a Michael intermediate which is cyclized by treatment with silica gel to give spirolactams with high levels of enantioselectivity.

The reaction of enantiopure diols, amino alcohols, or diamines with vinyl selenones in the presence of NaH represents a novel route to the title compounds.

A simple activation of MOM-, MEM- and SEM-phenyl selenides by iodonium or copper(I) ions in the presence of alcohols to give the corresponding alkoxymethyl ethers is described.