Electrophilic Selenium/Tellurium Reagents: Reactivity and their Contribution to Green Chemistry
Organic Selenium and Tellurium (2013)
Published Online: 17 JUN 2013
Copyright © 2009 John Wiley & Sons, Ltd. All rights reserved.
Patai's Chemistry of Functional Groups
How to Cite
Santi, C. and Tidei, C. 2013. Electrophilic Selenium/Tellurium Reagents: Reactivity and their Contribution to Green Chemistry. Patai's Chemistry of Functional Groups. .
- Published Online: 17 JUN 2013
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- Top of page
- Electrophilic Selenium Reagents
- Electrophilic Tellurium Reagents
- References and Notes
Selenium moieties are conveniently introduced into an organic molecule using electrophilic selenenylating reagents and the process is generally highly chemo-, regio and stereoselective requiring mild experimental conditions. In addition, organoselenium derivatives can be directly converted into a number of different functional groups and the organoselenium moiety can be employed for further stereoselective manipulation of the molecule. Several applications are described for the inter- and intramolecular carbon–oxygen, carbon–nitrogen and carbon–carbon bond formation as well as for the α-functionalization of carbonyl derivatives and the nucleophilic aromatic substitution reactions. More recently, the development of simple and efficient procedures for the preparation of chiral selenium reagents allowed their successful application in electrophilic asymmetric synthesis. Nowadays, probably the most recent aspect of this kind of chemistry is correlated with some new reactions that can be effected using organoselenium compounds as catalysts in renewable or alternative non-toxic media (water, glycerol, ionic liquids) bringing this kind of research in line with the concept of ‘Green and Sustainable Chemistry’. During the last half century, the application of tellurium reagents has undergone a notable improvement, overcoming the reluctance of several researchers mainly due to the characteristic persistent smell of many tellurium derivatives. In this chapter some general aspects of the chemistry promoted by electrophilic selenium and tellurium compounds are described exploiting also the differences between these two reagents.
- Top of page
- Electrophilic Selenium Reagents
- Electrophilic Tellurium Reagents
- References and Notes
Starting from suitable substrates, selenium moieties can be introduced into a molecule using electrophilic, nucleophilic or radical reagents, generally combining chemo-, regio- and stereoselectivity with mild experimental conditions. During the last few decades, organoselenium derivatives have emerged as important reagents and/or intermediates in organic synthesis because this functionality can be directly converted into a number of different functional groups or it can be employed for further stereoselective manipulation of the molecule.
The first use of electrophilic selenenylating agents dates to the 1950s when some species of type RSeX were used for the functionalization of alkenes through a stereospecific electrophilic addition reaction1. From this seminal example a number of applications were developed for the inter- and intramolecular carbon–oxygen, carbon–nitrogen and carbon–carbon bond formation as well as for the α-functionalization of carbonyl derivatives and have been collected in a number of books2a and review articles3a.
More recently, the development of simple and efficient procedures for the preparation of chiral selenium reagents allowed their successful application in electrophilic asymmetric synthesis and represented an important topic in the research of several groups during the last twenty years. Nowadays, probably the newest aspect of this kind of chemistry is correlated to some new reactions that can be effected using organoselenium compounds as catalysts in renewable or alternative non-toxic medium (water, glycerol, ionic liquids) bringing this kind of research forward to the concept of ‘Green and Sustainable Chemistry’4.
Following the considerable growth of organoselenium chemistry during the last half century, the application of tellurium reagents experienced a notable improvement, overcoming the reluctance of several researchers mainly due to the characteristic persistent smell of many tellurium derivatives5. In this chapter we will explore some general aspects of the chemistry promoted by electrophilic selenium and tellurium compounds, exploiting also the differences between these two reagents.
2 Electrophilic Selenium Reagents
- Top of page
- Electrophilic Selenium Reagents
- Electrophilic Tellurium Reagents
- References and Notes
2.1 Synthesis of Electrophilic Selenium Reagents
Phenylselenenyl bromide (2), chloride (3) and N-phenylselenophthalimide6 are nowadays commercially available or easily prepared from diselenide 1 and, probably for this reason, they are widely used as sources of electrophilic selenium in synthesis.
In several cases the nucleophilicity of chloride and bromide anions gives rise to undesired side reactions that can be avoided using non-halide counterions.
These new electrophilic species (4, 5, 6) can be prepared in situ starting from the corresponding selenenyl chloride or bromide by treatment with silver salts (e.g. hexafluorophosphate7, hexafluoroantimonate8, tosyl sulfonate9 and triflate10a); see Scheme 1.
When the reaction is effected using a stoichiometric amount of 7, a corresponding stoichiometric amount of trifluoromethansulfonic acid is formed as result of the addition reaction and it could be incompatible with the stability of reactant and products.
A good alternative has been proposed with the use of N-saccharin derivative 8 in which the sulfonamide anion is scarcely nucleophilic and generates, as side product, a molecule of saccharin that is a weak acid species11.
The photoinduced electron transfer dissociation of diphenyl diselenide 1, R = Ph resulted in an efficient strategy for the in situ generation of phenylseleno electrophilic species (PhSe+) that is devoid of any anion12a. Similarly in the presence of a catalytic amount of an electrolyte (tetraethylammonium bromide or calcium chloride), the species PhSe+ can be electrochemically produced by indirect oxidation of an anode (Scheme 2)13.
Starting from a stable diselenide, the oxidation of a selenium–selenium bond is a convenient way to prepare variously substituted and functionalized electrophilic selenium reagents that can be characterized by aromatic as well as aliphatic scaffolds. A number of inorganic oxidants have been reported for this purpose: potassium nitrate14, copper sulfate15, cerium ammonium nitrate (CAN)16, manganese (II) acetate17 and ammonium persulfate18.
The reaction between ammonium persulfate and a diselenide giving 9 (Scheme 3) was suggested to be initiated by an electron transfer or a bimolecular nucleophilic substitution process with the intermediate formation of a radical cation or a selenonium salt, respectively. Both these species can rapidly evolve producing the corresponding selenium cations in the absence of nucleophilic counterions. The oxidation occurred starting from aromatic18 as well as aliphatic19 diselenides and required to be activated by heating (refluxing methanol or acetonitrile) or, alternatively, by the presence of a catalytic amount of trifluoromethansulfonic acid that, reasonably, produces the strong oxidizing and soluble persulfonic acid by protonation of the corresponding ammonium persulfate.
Binary reagents such as PhSeSePh-CuOTf20 and PhSeCN-Cu(OTf)221 were reported as effective sources of electrophilic selenenylating reagents. This latter example is particularly interesting because selenocyanates are widely used as precursors of organoselenium nucleophiles and only few examples have described that these derivatives, in the presence of Lewis acids or metal salts (Cu2+ or Ni2+), can act as electrophiles in synthesis.
Also, some organic oxidizing agents can be used and, usually, the choice of the best reagent mainly depends on the stability of the substrate and the functional groups involved in the reaction with the selenenylating reagent.
1,2-Dicyanonaphthalene22 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)23 promote the oxidation of diphenyl diselenide through a single electron transfer mechanism leading to the formation of phenylselenenyl cation; arenselenenyl trifluoroacetates and triflates can be obtained by reaction of an arenseleninic anhydride with the corresponding diselenide in the presence of trifluoroacetic or triflic anhydride, respectively24.
Some electrophilic selenium reagents were supported on solid resins and are now also commercially available. Polystyrene beads by treatment with strong lithiating reagents in the presence of methyl diselenide were converted into the solid supported selenium resin 10 and this, by exposure to bromine, into the corresponding electrophilic selenenyl bromide 11.
2.2 Electrophilic Functionalization of Carbonyl Compounds
α-Selenenylation of carbonyl compounds (13) followed by the oxidative elimination of the organoselenium moiety via 14 and 15 is a synthetically important strategy for the preparation of the corresponding α,β-unsaturated derivatives (16) (Scheme 5), and it has been used in the synthesis of a number of natural compounds29. Furthermore these compounds can be subjected to oxidation followed by [2,3]-sigmatropic rearrangement with the formation of allylic alcohols30 and amines31.
Sharpless and coworkers first demonstrated that the electrophilic PhSeCl in ethyl acetate at room temperature can be directly used to prepare the α-phenylseleno derivative starting from several ketones and aldehydes32. The subsequent elimination can be promoted by several oxidizing agents (hydrogen peroxide, m-CPBA, peracetic acid, sodium periodate, ozone, TBHP) and leads stereospecifically to the corresponding (E)-isomer, indicating that the elimination of selenoxides takes place through an intramolecular syn-elimination pathway involving a transition state in which the carbon–hydrogen and carbon–selenium bonds are co-planar (Scheme 6).
The use of PhSeBr in similar reactions is unsuitable because of the competitive bromination of the substrate32, 33 a problem that was overcome using a catalytic amount of Dowex resin has been reported in some cases34.
An interesting modification of the procedure can be achieved using supported selenenyl chloride (17) as reported in Scheme 7 for the conversion of 4-methylcyclohexanone (18) via 19 to the corresponding enone 2038.
In order to avoid acidic conditions, especially when the substrates are not stable, an alternative approach has been developed using basic activation. In these cases the ketone is first converted into the corresponding enolate using lithium diisopropylamide (LDA) and then quenched with PhSeCl or PhSeBr39a. Using this procedure it is possible to control kinetically the enolate formation to obtain, starting from unsymmetrical ketones, the selenenylation of the less substituted position (Scheme 8). In a similar way it is possible to obtain the α-selenenylation of esters and lactones for which the direct selenenylation is unavailable39a.
In situ generated enol dibutyl borinates (22), produced from ketones (21) by treatment with dibutyl boron triflate, react with phenylselenyl chloride affording regioselectively the corresponding α-phenylselenoketones (23) in good yield (Scheme 9)40.
Recently, Nazari and Movassagh developed a simple one-pot procedure using as electrophilic selenenylating source diphenyl diselenide in the presence of potassium fluoride loaded on alumina (KF/Al2O3)41.
One of the first asymmetric synthesis promoted by organoselenium reagents was the desymmetrization of 4-substituted cyclohexanones reported by Hiori and Sato using electrophilic chiral selenamides (e.g. 24) (Scheme 10)42.
The reaction of 4-methylcyclohexanone 25 with [N-(S)-1-naphthylethyl]benzenselenamide 24 generated in situ from (S)-1-naphthylethylamine and PhSeCl leads to the corresponding α-selenenyl ketone 26 and, after treatment with hydrogen peroxide, to the (S)(−)-4-methyl-2-cyclohexenone (27) in moderate yield (44%) and moderate enantiomeric excess (26.2%).
Recently, organocatalysis and, in particular, enamine catalysis has gained widespread attention as an efficient tool for the electrophilic α-functionalization of aldehydes and ketones (Scheme 11).
In 2005, Wang and coworkers reported a catalytic procedure for the α-phenylselenenylation of aldehydes and ketones using (S)-pyrrolidine tosyl sulfonamide 30 and the MacMillan second generation imidazolidinone 31 affording 60% and 40% ee, respectively, in the selenenylation of isovaleraldehyde (Scheme 12 and Table 1, entries 3,4)43.
|1||i-Pr||28 (30 mol%)||CH2Cl2, RT, 5′||96||0||43|
|2||i-Pr||29 (30 mol%)||CH2Cl2, RT, 1 h||87||30||43|
|3||i-Pr||30 (30 mol%)||CH2Cl2, RT, 30′||48||60||43|
|4||i-Pr||31 (30 mol%)||CH2Cl2, RT, 12 h||48||40||43|
|5||i-Pr||32 (5 mol%)||Toluene, 0 °C, 40 h||89||99||44|
|6||i-Pr||33 (20 mol%)||Toluene, 0 °C, 30′||93||95||45|
|7||Bu||32 (5 mol%)||Toluene, 0 °C, 40 h||99||98||44|
|8||t-Bu||32 (5 mol%)||Toluene, 0 °C, 40 h||99||99||44|
|9||allyl||32 (5 mol%)||Toluene, 0 °C, 40 h||91||98||44|
|10||CH2SMe||32 (5 mol%)||Toluene, 0 °C, 40 h||94||98||44|
|11||Me||34 (10 mol%)||CH2Cl2, RT, 2 h||82||60||47|
The same authors demonstrated that l-prolinamide (28) and pyrrolidine trifluoromethansulfonamide (29) are efficient organocatalysts for a broad range of aldehydes and ketones even if they produce a very poor level of enantioselectivity affording almost racemic mixtures. Furthermore, it was observed that 28 efficiently catalyzed α-selenenylation of aldehydes whereas 29 resulted in the most effective catalyst for the selenenylation of ketones.
Two years later Marini and coworkers44 and Cordova and coworkers45, in two independent papers, reported the optimized conditions for the asymmetric selenenylation of aldehydes, reaching excellent levels of facial selectivity using protected arylprolinols (32 and 33, respectively) as catalysts in toluene at 0 °C. In the first case (Table 1, entry 5) only 5 mol% of catalyst is required to affect the selenenylation of isovaleraldehyde with up to 99% of enantiomeric excess whereas 20 mol% is necessary when the catalyst is 33 (Table 1, entry 6).
Marini and coworkers also demonstrated the broad applicability of the proposed method, reporting very high levels of enantiomeric excess starting from a number of differently functionalized substrates (Table 1, entries 7–10). These conditions combined with Horner–Wadsworth–Emmons olefinations were very recently used for the synthesis of biologically relevant α-alkyl- and α-vinyl amino acids46.
The preparation of the promising polystyrene-supported catalyst 34 has been proposed by Gruttadauria and coworkers and it was used for the α-selenenylation of propanal (Table 1, entry 11), affording the corresponding α-selenoaldehyde in 82% yield and 60% enantiomeric excess47.
The α-selenenylation of β-dicarbonyl derivative 35, effected by treatment with NaH and PhSeCl, has been proposed as the starting point for the synthesis of benzofluorene skeleton. The intermediate 36 cannot be isolated and was treated directly with a Lewis acid, leading to the dihydronaphthalene 37. The authors suggested that the Lewis acid could promote a deselenenylation from 36, producing a new electrophilic species that should be able to activate the double bond leading to a carbocyclization process. (This class of reactions will be taken into consideration in detail later48.) The entire reaction was optimized in one-pot conditions obtaining a strong enhancement of the overall yield (Scheme 13).
2.3 Electrophilic Aromatic Substitution
Diaryl selenides have attracted considerable interest because of their potential as anticancer and antioxidant agents49a. For these reasons a number of methods were reported in literature for their preparation and, among these, the electrophilic aromatic substitution represents a convenient and clean procedure.
The first example was reported in 1959 by Pitombo50, but after that the general attention was mainly focused on other aspects of the electrophilic selenium reagent reactivity. Tiecco and coworkers51 demonstrated that phenylselenenyl sulfate, prepared in situ by oxidation of diphenyl diselenide with ammonium persulfate, can be employed to effect aromatic phenylselenenylation reaction.
Effecting the oxidation of 2,2′-dithienyl diselenide 45 using iodobenzene diacetate in the presence of an excess of thiophene (40), the synthetically interesting polymeric tetramer 4653 was obtained as major reaction product (52% yield), together with a little amount of dimer (8%) and trimer (10%) (Scheme 15a)54.
When the electrophilic acceptor is a furan (47), the reaction is less chemoselective and affords as major isomer the trimer 48 (35% yield, see Scheme 15b).
Thiophene and other activated aromatics () can be selenenylated by the reagent () generated by reaction of dihydroxyarylselenonium p-toluensulfonate (50) (formed from 49 and H2O2) and a further equivalent of 49 affording unsymmetrical diaryl selenides (54) (Scheme 16)55.
The reaction follows a traditional electrophilic aromatic substitution pattern. While anisole and mesitylene were monosubstituted (see structures 55 and 56, respectively), the high reactive thiophene afforded directly the tetraselenenylated derivative (44).
Selenium dichloride can be easily prepared from elemental selenium by treatment with sulfuryl chloride and it is known that in solution it exists in equilibrium with selenium tetrachloride. This inorganic electrophilic selenium reagent is a good source of Se2+ and reacts with anisole (57) in refluxing chloroform, affording regioselectively the selenide 58 (91% yield) in which both molecules of the substrate were specifically selenenylated in the para position (Scheme 17)56.
Very recently, a green procedure for the metal and catalyst free synthesis of diaryl diselenides has been reported using electrophilic selenenyl halides in imidazolium ionic liquids [bmim]PF6 and [bmim]BF4. In the best conditions the reaction occurred between PhSeCl and an arylboronic acid in [bmim]PF6 at room temperature for two hours. Interestingly, the rate of the reaction can be accelerated using microwave irradiation at 50 °C for 15 min.
A large number of cases have been reported using different aryl selenenyl chlorides and arylboronic acids or aryl selenenyl bromides and aryl trifluoroboronates as nucleophiles. In these latter cases it is necessary to change the ionic liquid using [bmim]BF4.
2.4 Electrophilic Addition Reactions
Probably the most studied reactions promoted by electrophilic selenium reagents are the electrophilic additions to double and triple bonds. These latter are largely used for the synthesis of vinyl selenides, an important class of organoselenium compounds already reviewed in Volume 3 of this book and for this reason not included in the present chapter.
We will focus our attention on some representative examples that underline the application of electrophilic selenium reagents in intermolecular functionalization of olefins as well as in the synthesis of heterocyclic skeletons through cyclofunctionalization reactions. Particular attention will be devoted to the application of these reagents in asymmetric synthesis.
2.4.1 Mechanism and Stereocontrol
After 60 years since the first example of stereospecific selenoaddition to a carbon–carbon double bond, some mechanistic aspects of these widely used reactions are still under investigation and not completely clarified and explained in detail.
It is commonly considered that the electrophilic selenium reagents react with olefins on the basis of a stereospecific anti addition mechanism that reasonably involves the formation of a seleniranium ion intermediate () that can be rapidly opened by a nucleophile. Even if the presence of a highly reactive three-member-ring intermediate is the central tenet of this class of reactions, there is no direct evidence of its actual formation during the addition process, and the involvement of a seleniranium ion is usually indirectly assumed to explain the stereochemistry of the observed products.
The regiochemical orientation is usually driven by the thermodynamic stability of the formed Markovnikov adducts but, sometimes, the presence of coordinating heteroatoms (e.g. an hydroxyl group in the allylic position) can modify this orientation, leading to the formation of the anti-Markovnikov regioisomer (Scheme 19).
The net overall result is the trans addition of ‘RSe’ and a nucleophile across the double bond, a procedure that, starting from unsaturated substrates, offers the opportunity to introduce different functionalities (it depends on the nature of the nucleophile) with good chemo-, regio- and trans-stereoselectivity.
Spectroscopic and kinetic studies on the reaction between phenylselenenyl halides (PhSeX) and olefins have shown that, in these cases, a more complicated mechanism is probably involved.
PhSeCl reacts with styrene (Scheme 20) at low temperature via initial formation of a three-member-ring episelenurane ion (60) that rapidly evolves into the corresponding Markovnikov addition product (61). This latter, especially in the presence of polar stabilizing solvents, is in equilibrium with the anti-Markovnikov intermediate through a second three-member-ring intermediate, the seleniranium ion .
At this step of the reaction the introduction of an external oxygen-containing nucleophile (e.g. ROH) moves the equilibrium, leading to the quantitative formation of the Markovnikov β-alkoxyselenide 64 as expected on the basis of the simplified mechanism reported in Scheme 202e, 58a.
When the unsaturated substrate contains, in a suitable position, an internal oxygen-, nitrogen- or carbon-centered nucleophile, the treatment with an electrophilic selenium reagent resulted in the formation, via seleniranium ion, of a functionalized heterocyclic system, usually with excellent control of both stereo- and regioselectivity, depending on the nature of the substrate and on the reaction conditions (Scheme 21),.
During the last twenty years, the use of optically pure electrophilic selenium reagents represents the most attractive development in this field of chemistry, finding interesting applications in several new methodologies for asymmetric synthesis.
When a chiral reagent reacts with an unsymmetrically substituted olefin, the electrophilic attack occurs on both sides of the double bond leading to a couple of diastereomeric seleniranium ions involving two energetically different transition states, a condition that confers a certain facial selectivity on the process.
The preferential formation of or mainly depends on the reaction conditions, but also on some sterical and electronical features of both the selenenylating reagent and the substrate. These two different intermediates, in the presence of an external or internal nucleophile, can be rapidly opened, affording a couple of diastereomers (67 and 68) in a ratio that reflects the facial selectivity of the electrophilic attack to the carbon–carbon double bond (Scheme 22).
Wirth and coworkers demonstrated that the formation of seleniranium ion is a reversible process and, for this reason, a lower temperature will favor the formation of the kinetically controlled intermediate in respect to the thermodynamic one, generally increasing the final diastereomeric ratio60a.
Computational studies on the enthalpy of the activation barrier for direct intramolecular seleniranium ion/olefin transfer61a and more recent crossover experiments reported by Denmark and coworkers62 indicated that the possibility exists of a direct transfer of a seleniranium from one olefin to another and, when this exchange is very rapid, it should be the most likely pathway for racemization of the enantiomerically enriched seleniranium ions.
When the addition reaction occurs on symmetrically (Z) disubstituted olefins, both directions (with respect to the carbon–carbon double-bond plane) produce the same meso-seleniranium ion. In this case, the stereoselection is determined by the attack of the nucleophile that operates a desymmetrization of the meso intermediate () affording a couple of enantiomerically pure diasteroisomers (70 and 71). In these substrates the stereoselection is far away from the chiral scaffold linked to the selenium atom and usually lower diastereomeric ratios are obtained (Scheme 23).
Tomoda and Iwaoka in 1998 reported the first example of an optically pure electrophilic selenium reagent based on a binaphthyl structure63a and from that a number of different structures were proposed and applied in asymmetric intermolecular additions and cyclofunctionalization reactions. Some representative examples (72, 73, 74, 75, 76, 76a, 76b, 76c, 76d, 76e, 76f, 77, 78, 79, 80, 81) of optically pure diselenides that were successfully used as a precursor of electrophilic reagents are reported in Scheme 24 and will be reconsidered later during the discussion of some of their synthetic applications.
It has been observed that the common characteristic of the most selective reagents is the possibility of a non-bonding interaction between positive charged selenium and a suitably positioned heteroatom such as oxygen, nitrogen or sulfur. Evidence of this interaction has been reported by several authors, combining the results of different techniques such as X-ray crystallography, NMR and DFT calculations64.
It has been proposed that this interaction effects the facial selectivity, leading to more rigid transition states and bringing the chiral moiety near to the reactive selenium center during the addition to the double bound. We described the Se–S interactions on a series of selenenyl halides deriving from a diselenide with a structure in which the heteroatom is connected to an adjacent benzylic position (see 76c, X = SMe, R = H summarized in Scheme 24).
X-ray analysis showed a T-shaped geometry around the selenium atom (see structure A in Scheme 25) with a distance between S and Se shorter than the sum of the corresponding van der Waals radii. This distance depends on the nature of the halogenated counterion, indicating a stronger interaction when it is a chlorine. On the basis of some Overhauser NMR experiments we first demonstrated that this interaction exists also in solution and is not a peculiarity of the crystal. Changing the coordinating heteroatom to a methylene group, the stabilizing non-bonding interaction is no longer possible and the complete lost of selectivity proved directly its active participation on the mechanism of the stereoselection65.
Considering conformationally more flexible intermediates (structures B and C, Scheme 25), it has been demonstrated that six-membered intermediate B66 is less effective with respect to the five-membered (A) and seven-membered (C) one67, 68.
Recently theoretical investigations evidenced that in contrast with the corresponding sulfur electrophiles in the case of selenium reagents the regiochemistry as well ad the stereo- and enantioselectivity is effected by α branching to the carbon-carbon double bond.69
2.4.2 Oxyselenenylation Reactions
The term ‘oxyselenenylation’ indicates a group of reactions that produces the stereospecific anti addition of an alkyl- or arylseleno group and an oxygen nucleophile such as OR, OH, OCOR usually deriving from the solvent.
A number of quite old procedures were reported for the alkoxy-, hydroxy- and acetoxyselenenylation of olefins and are today commonly used in consideration of their efficiency associated to the simple experimental conditions required2a.
Using methanol as solvent and PhSeCl as electrophile, the formation of β-methoxyselenides is favored in respect to that of the corresponding β-chloro derivatives, which could be observed under kinetically controlled conditions,.
As a general consideration on the regiochemistry of the reaction, it should be observed that terminal olefins gave exclusively the formation of the Markovnikov addition products 8271 whereas the internal one and the conjugated dienes afforded a mixture of regioisomers (83, 84) and the 1,2 addition products with Markovnikov orientation (85), respectively (Scheme 26)72, 73.
Some alternative procedures for the preparation of β-methoxyselenides starting from cyclic and acyclic olefins were later reported: 1) the treatment of the unsaturated substrates with PhSeCN in the presence of Cu(II) or Ni(II) as catalyst and methanol as solvent74a, 2) the use of the electrophilic PhSeOSO3H generated in methanol or in a mixture of dichloromethane and methanol by oxidation of diphenyl diselenide with ammonium persulfate75, 3) the use of strong selenenylating species deriving from the treatment of diphenyl diselenide with different oxidants: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ, iodobenzene diacetate or iodobenzene trifluoroacetate23, 26, 27.
The most recent developments concerning methoxyselenenylation reactions are focused on the use of optically pure electrophilic selenium reagents for the asymmetric functionalization of olefins affording diastereomerically enriched mixtures of β-methoxyselenides. The methoxyselenenylation of styrene 86 to give 87 was usually considered in terms of a comparison of the selectivity produced by different chiral reagents and different reaction conditions.
Selected examples (88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101) of the electrophilic addition are collected in Scheme 27. Terpene-based selenium-centered electrophiles (e.g. 88 and 89), despite the simple preparation of their precursors (72 and 74), usually turned out to be less efficient at promoting asymmetric synthesis in comparison with a number of similar aromatic reagents76, 77.
Among these latter compounds, it is evident that different coordinating heteroatoms produced different diastereomeric excesses and that the sulfur-containing reagents (92, 93)79, 80 are the most effective with respect to the corresponding oxygen (90, 91)78 and nitrogen (94, 95, 96, 97, 98)81-83 analogues, combining the best yields and the best diastereomeric ratios at temperatures nearest to room conditions. A methoxy substituent in ortho position with respect to the selenium atom produced a positive effect on diastereoselectivity and was correlated to a double coordination to the electrophilic center (91, 93)78, 80.
Extensive investigations carried out on nitrogen-containing diselenides demonstrated that for this class of compounds the best counteranion is the sulfate (95, 97, 98) representing a series of selenenylating reagents that could be conveniently and selectively used at 25 °C81-83. Furthermore, the introduction of a second chiral center improved the stereoselectivity (96 and 97)82 but, in the case of 98, probably the reduced diastereomeric ratio is due to the possible formation of a six-membered-ring intermediate with the second nitrogen atom66, 83.
The sulfoxide-containing selenenylating reagent 99 showed only moderate selectivity in the methoxyselenenylation of styrene. The selectivity was better in the case of activated alkenes (e.g. 2-chlorostyrene) even if it was strongly dependent on the solvent (ranging from a de of 60% in THF to a de of 84% in CH2Cl2)84. Several examples have shown that the counteranion can have a strong influence on the selectivity of the selenenylation reactions and it was suggested that a decrease in its nucleophilicity or an increase in the selenium electrophilicity produces an enhancement of the diastereomeric excess85a.
The ester 102 has been converted into the corresponding γ-methoxy-α,β-unsaturated derivative 103 in a 2-step procedure: a methoxyselenenylation reaction promoted by a camphorselenenyl electrophilic reagent followed by an oxidative deselenenylation to afford the conjugated double bond. Interestingly, the nature of the counteranion controls the selectivity of the methoxylation, affording preferentially the enantiomer S when X is a chlorine and R when it is a sulfate (Scheme 28)76. On the basis of this evidence Freudendahl and Wirth investigated stereoselective methoxyselenenylations using some chiral counteranions attaining at least 3% enantiomeric excess86.
In 2004 we reported the first and, at the best of our knowledge, the unique example of a non-enzymatic kinetic resolution using an electrophilic methoxyselenenylation reaction (Scheme 29)87. Racemic allylic alcohols reacted with a half equivalent of 93 and the reaction of the (R)-isomer proved to be kinetically favored with respect to that of the (S)-isomer. Starting from 104, the formation of 105 occurred with very high selectivity (dr 99:1) and the non-reacted alcohol (S)-106 was recovered in quite a quantitative yield and with 92% ee. The addition product 105 can be reconverted into the starting material using CF3SO3H that activates the reverse process in the presence of styrene as trap for the electrophile. The alcohol (R)-106 was recovered in 98% ee. A number of examples investigated obtained in all the cases good level of racemic resolution (from 90% ee to 94% ee measured on the non reacted alcohols). The intermediate 105 can be also deselenenylated by radical reduction affording an interesting class of optically enriched β-methoxy alcohols 107.
It was interesting to observe that starting from the terminal olefin 108, the addition followed an anti-Markovnikov orientation (110) suggesting the presence of an orienting interaction between the positively charged selenium in the seleniranium ion intermediate and the hydroxyl group that is probably responsible also for the observed stereoselectivity. A similar interaction was first reported by Shimitzu and coworkers in order to explain the regiochemistry observed in the selenenylation of allyl ethers and allyl silyl ethers. They also reported that this coordination was less effective in the cases of allyl benzoates, acetates and pivalates88a.
Methoxyselenenylation of α,β-unsaturated aldehydes (111) resulted in a one-pot carbonyl protection as dimethylacetal, and in an electrophilic functionalization of the carbon–carbon double bond. The same reaction effected on the unsaturated dimethylacetal 115 afforded the same product (113 and 114) but in a different diastereomeric ratio. On the basis of this evidence the authors suggested that two different intermediates are involved in the process: a seleniranium ion coordinated to the hydroxyl group of the hemiacetal and the corresponding acetal (Scheme 30)89a.
There are not many examples of alkoxyselenenylation effected using alkyl vinyl ethers as substrates90, and probably the main utility of this reaction was reported by Uchiyama and coworkers91 which demonstrated that a number of enol ethers could be selectively functionalized to afford, after deselenenylation, enantiomerically enriched acetals in which the acetal carbon represented the only stereogenic center. The reactions, summarized in Table 2, with reagent 117 were regiospecific and led to a couple of diastereomers, 118 and 119, in a ratio that reflected the enantiomeric excess of the final acetals 120.
Previously, the asymmetric methoxyselenenylation of silyl enol ethers was proposed for the synthesis of enantiomerically enriched α-selenoketones instead of acetals92.
Several strategies can be used to effect a stereocontrolled reaction, among which the selenenylation of alkenes in the presence of an enantiomerically pure alcohol has been successfully investigated by several authors.
This kind of functionalization is usually preliminary to further stereoselective transformations aimed to obtain more complex structures. The 3,4-dihydro-2H-pyrane 121 reacts with the optically pure diol 122 in the presence of PhSeCl affording two diastereomeric addition adducts in a quite equimolar ratio (1,2:1). After chromatographic separation 123 was subjected to a series of transformations to synthesize the l-arabinose 124 (Scheme 31a). The diastereomer of 123 (not depicted in the scheme) was used to prepare, by the same procedure, the d-arabinose93.
Similarly, cyclohexene 125 reacts with N-(phenylseleno)phthalimide in dichloromethane to afford the oxyselenenylation products, also with a very poor selectivity. The two diastereomers could be separated by chromatography and 126 was used for the synthesis of two biologically important cyclitols (127 and 128, Scheme 31b)94.
More recently, Tiecco and coworkers95a reported that the alkoxyselenenylation of β,γ-unsaturated nitriles and esters promoted by N-(phenylseleno)phthalimide in the presence of enantiomerically pure diols or (R)-phenylglycinol can be employed as key step to prepare enantiomerically pure tetrasubstituted 1,4 dioxanes or 2,3,5-trisubstituted morpholines, respectively95b. A general scheme is reported (Scheme 32).
Chiral periodobenzoxazines 129 were used as good chiral auxiliary for regio- and stereoselective methoxyselenenylation, affording better facial discrimination compared with those obtained with chiral selenenylating electrophiles. The addition products 131 was easily purified by chromatography and the selectivity could be explained by invoking a non-bonding interaction of the oxygen with the selenium of the seleniranium ion intermediate (Scheme 33)96.
Using aqueous organic solvents the electrophilic selenium reagents promote the formation of β-hydroxyselenides, that are valuable intermediates for the preparation of allylic alcohols and epoxides as well as for the formation of the carbon–nitrogen bond97a.
A number of different selenenylating reagents were efficiently employed in different reaction conditions: PhSeCl, N-(phenylseleno)phthalimide or N-(phenylseleno)succinamide in aqueous acetonitrile or methylene chloride98, PhSeBr in water/dimethylformamide or water/CF3CH2OH mixtures99. Selected examples (see 132, 133, 134, 135) are reported in Scheme 34.
The mechanism is identical to that proposed for the methoxyselenenylation reactions, and the electrophilic addition of the formal species PhSeOH is a stereospecific anti addition characterized by high Markovnikov regioselectivity.
The reaction of 2-undecene (136) with PhSeCl in pyridine, after the quenching in water, afforded the corresponding β-hydroxyselenides 137 and 138 in poor yields and without regioselectivity (Scheme 35a). Interestingly, in similar conditions 2-methyl-2-undecene 139 did not give the addition product but the selenide 140 (E:Z = 2:1) (Scheme 35b)100.
This result has been correlated to the competitive nucleophilicity of the chlorine that, in the absence of water or other nucleophilic solvents, attacks a methyl group of the seleniranium intermediate , leading to the exo-alkenyl selenide 142 that rapidly equilibrates to the more thermodynamicallly stable endo-alkenyl allylic selenide 140. A molecule of HCl, produced as side product, could be trapped by the pyridine and, reasonably, it represents the driving force that moves the equilibrium to the formation of 140.
By treatment with hydrogen peroxide 140 afforded a selenoxide intermediate () and, through a [2,3]-sigmatropic rearrangement, the corresponding allylic alcohol 144 (Scheme 36a). The overall result of the sequences is the transformation of trisubstituted olefins 145 into allylic alcohols 146, a method particularly useful to convert the prenyl group into a 3-isopren-2-ol unit, used in some interesting synthetic protocols, like the total synthesis of diversifolin (Scheme 36b)101.
Similarly, the treatment of the trisubstituted olefin 147 with electrophilic PhSeCl and subsequently with hydrogen peroxide to give 148 was successfully used to introduce an allylic alcohol on the side chain of the betulinic acid, affording a promising class of anti-inflammatory drugs (Scheme 36c)102.
In order to avoid the nucleophilic counteranion, PhSeOTf, generated by treatment of PhSeBr with silver triflate, has been conveniently used for the hydroselenenylation of unsaturated terpenes 149, 151 and 153. The regiospecific addition was also stereospecific for the endocyclic double bonds (150, 152) but not for the exocyclic ones (154) (Scheme 37)103.
Tiecco and coworkers described that phenylselenenyl sulfate 9a could be an excellent electrophilic reagent to effect hydroselenenylation reactions. It could be conveniently generated by oxidation of the commercially available diphenyl diselenide with ammonium persulfate in a mixture of acetonitrile and water (5:1). The oxidation occurred at 60 °C in 15–30 minutes or at temperatures ranging from −20 °C to 25 °C in the presence of a catalytic amount of trifluoromethanesulfonic acid18.
Electrophilic selenenyl sulfate derivatives were demonstrated to be the best reagents to effect asymmetric hydroselenenylation reactions. That is probably because they should be conveniently prepared starting from the corresponding optically pure diselenides directly in aqueous media and because they are usually able to produce good selectivity at higher temperatures (−30, +40 °C) compared with those required by the same electrophiles with other counteranions (e.g. Br− or OTf, −100, −78 °C, respectively).
As already reported for the asymmetric methoxyselenenylation reactions, the sulfur-containing 155 is the most selective converting the (E)-β-methylstyrene 156 into the corresponding benzyl alcohol 158 with 96% diastereomeric excess at −30 °C. The same reaction effected using 88 efforded 157 in 30% de79, 80. It is worth mentioning that camphor selenenyl sulfate 88 demonstrated to be particularly efficient in the enantioselective functionalization of (E)-dialkyl substituted olefins, such as 159104. A comparison of the reactivity between reagents 88 and 155 to efford 160 and 161, respectively, is summarized in Scheme 38.
Regio- and stereoselective selenohydroxylation of 1,2-allenyl sulfoxides 162a giving 163 and phosphine oxides (162b) giving 164 has been achieved using PhSeCl in MeCN/H2O 10:1 and 20:1, respectively105, 106.
In the case of the phosphine oxide derivatives (e.g. 162b), it was demonstrated that the diphenylphosphinyl moiety participates in the ring-opening reaction of the seleniranium intermediate affording 164, as depicted in Scheme 39b.
2.4.3 Intermolecular Formation of CN Bond Promoted by Electrophilic Selenium Reagents
Despite the potentially relevant synthetic utility, especially for the preparation of biologically important molecules, the aminoselenenylation reaction of alkenes has been only poorly explored. This should be mainly correlated to the reduced nucleophilicity of the most used nitrogen-containing reagents that required additional activation strategies. For example, the intermolecular addition of carbamates occurred in the presence of PhSeCl and silver tetrafluoroborate as activating agent or, alternatively, with N-(phenylseleno)phthalimide and HBF4 overcoming the problems originating from the strong hygroscopicity of AgBF4107a.
Using this procedure 5α-cholest-2-ene 165 was transformed in good yield into the β-phenylseleno carbamate derivative 166. The substituents introduced in C-2 and C-3 assumed a trans diaxial position, confirming the intermediate formation of a seleniranium ion that was opened by the nucleophile according to the Furst Plattner rule (Scheme 40)108.
Reductive or oxidative deselenenylation can subsequently lead to the formation of protected aliphatic or allylic amines 167 and 168, respectively. Under kinetic controlled conditions the yields of the aminoselenenylation products decreased and a considerable amount of the corresponding hydroxyselenenylation product was observed. This can be explained considering the ambident nucleophilic nature of the carbamate that can attack the seleniranium ion both with the oxygen and the nitrogen centers.
The kinetically favored O-attack led to an intermediate that was hydrolyzed during the work-up with the formation of the β-hydroxyselenide. On the other hand, the nucleophilic N-attack, and consequently the formation of the β-phenylselenocarbamate, is an irreversible process.
Cyanamide (H2NCN) can also be used efficiently as a nucleophile in selenium-promoted additions to non-activated alkenes. This reaction can be efficiently applied to mono-, di- and trisubstituted alkenes. The tetrasubstituted alkenes do not undergo the cyanamidoselenenylation reaction under different reaction conditions.
Cyclo-octa-1,5-diene (169) reacted with N-(phenylseleno)phthalimide, PTSA and cyanamide affording two regioisomers: 9-azabicyclo[3.3.1]nonane (170) and 9-azabicyclo[4.2.1]nonane (171), as the result of a combined process of inter and intra-molecular electrophilic addition of two phenylseleno groups and of the cyanamide to the diene (Scheme 41).
Electrophilic selenium reagents in acetonitrile and water and in the presence of a strong acid (e.g. trifluoromethanesulfonic acid) activate carbon–carbon double bonds to afford the simultaneous addition of an organoselenium and an acylamino group based on a Ritter-type mechanism (Scheme 42).
The first example of this reaction was reported by Toshimitsu and Uemura109a, who reported that using PhSeCl they obtained low yields starting from styrene and other electron-rich olefins. In these cases better results could be achieved starting from the corresponding β-hydroxy or β-methoxyselenides, as well as by using 2-pyridylselenenyl chloride as the selenenylating reagent110.
A good alternative is represented by PhSeOSO3H. In this case the presence of CF3SO3H activates first the oxidation of diphenyl diselenide (that can be obtained at room temperature) leading to the formation of the electrophilic reagent, and secondly catalyzes the Ritter-type mechanism and the synthesis of the amido group111. Similar reactions could be obtained using other nitriles (propionitrile, butyronitrile, benzonitrile) affording variously substituted β-amidoselenides.
The enantiomerically pure camphorselenenyl sulfate (88) has been used for the asymmetric amidoselenenylation reaction of a number of different olefins112. In Scheme 43 the reaction effected starting from (E)-5-decene 172 is reported as a representative example. Even if the process proceeded with moderate facial selectivity, the two diasteromeric addition products (173 and 174) can be easily separated by chromatography as enantiomerically pure compounds.
The two diastereomers can be treated separately with a second electrophilic reagent (PhSeOTf) in order to activate the camphorseleneyl moiety as a selenonium ion ( and ). These are reasonably unstable intermediates and rapidly evolves through the stereospecific intramolecular displacement of the organoselenium moiety and the formation of the enantiomerically pure oxazoline (4S,5S)-177 and (4R,5R)-177 respectively. Slightly better yields on the cyclization were obtained activating the deselenenylation with SO2Cl2 instead of PhSeOTf.
Further stereospecific transformations were reported by the authors in order to demonstrate the synthetic relevance of the proposed asymmetric amidoselenenylation reaction. Oxazolines (4S,5S)-177 and (4R,5R)-177 can be isomerized to the corresponding (4S, 5R) and (4R, 5S) diasteroisomers by acidic hydrolysis and subsequent cyclization in the presence of SOCl2. These combined strategies accessed the four enantiomerically pure 4,5-disubstituted oxazolines that are suitable precursors on the synthesis of the corresponding enantiopure β-aminoalcohols.
In a different paper it was reported that amido selenides 173 and 174 can be treated with Lawesson's reagent to afford the corresponding thioamido derivatives. These latter underwent deselenenylation by treatment with PhSeCl, affording the formation of the corresponding 2,5-disubstituted thiazolines (4S,5S)-178 and (4R,5R)-178 in enantiomerically pure form113.
The azidoselenenylation of alkenes is probably one of the most interesting electrophilic functionalizations of unsaturated substrates because it combines the reactivity of the organoselenium moiety with the manipulations that can be effected on the azido group. It reacts with both nucleophilic and electrophilic reagents and can be involved in 1,3-dipolar addition reactions.
In 1979, Krief and coworkers described the synthesis of the first β-azido selenide using PhSeBr or MeSeBr as electrophilic reagents and sodium azide in methanol or lithium azide in DMF as nitrogen-centered nucleophile114.
Some years later better results were obtained generating in situ the species phenylselenenyl azide (PhSeN3) by reaction of PhSeCl and sodium azide in DMSO. This new electrophilic reagent adds to double bonds stereospecifically via a common three-membered seleniranium intermediate115. N-(Phenylseleno)phthalimide and azidotrimethyl silane in methylene chloride are alternative methods to prepare PhSe-azide, but they showed generally low regioselectivity116 compared to the couple PhSeOTf and sodium azide that, at 0 °C, afforded regiospecifically the Markovnikov-oriented azido selenenylation of styrene in good yield117. When the reaction is activated by an azido radical (PhSeSePh, NaN3 and PhI(OAc)2) the anti-Markovnikov regioisomer is formed and the stereoselectivity quite completely lost118.
The electrophilic strategies proposed by Tiecco and coworkers are probably the most efficient and of general applicability, showing a good compatibility with a number of other functional groups, leading to the formation of interesting intermediates for the synthesis of more complex molecules. For example, tert-butyl cinnamyl ether 179 reacted with PhSeOTf and sodium azide in MeCN at 0 °C to afford the regio- and stereospecific formation of the selenoazide 180 in 62% yields. This intermediate was employed in a simple five-step synthesis of the taxol side chain (Scheme 44)117.
The use of optically pure arylselenenyl triflate 93 in the presence of sodium azide at −30 °C was reported as the first example of a high enantioselective addition of a nitrogen nucleophile to a carbon–carbon double bond through a process activated by an electrophilic selenium reagent. The azido selenenylation provided good results in terms of yields (up to 90%) as well as in terms of diastereoselectivity (de ranges from 90% to 98%) starting from a series of variously substituted olefins119.
The asymmetric azidoselenenylation of styrene that afforded the adduct 181 in 90% yield and 94% diastereomeric excess is reported in Scheme 45. Using stereospecific transformation this intermediate can be converted in a variety of nitrogen-containing derivatives (182, 183, 184, 185) of very high optical purity.
As already discussed for the hydroselenenylation reaction, also the asymmetric azidoselenenylation of double bonds could be effected under the stereochemical control of the substrate.
When some terpenes were treated with PhSeOTf and sodium azide in order to obtain the corresponding β-azidoselenides, the selectivity mainly depends on the nature of the double bond. The addition to endocyclic double bonds occurred in a stereospecific manner, leading to only one isomer with the geometry controlled by the chirality of the terpenic skeleton. On the other hand, in the case of exocyclic double bonds, such as in the (+)-aromadendrene, the addition showed a lower stereoselectivity and the two possible isomers were obtained in a ratio 4:1. Interestingly, when the olefin is positioned in the side chain of the terpenic unit, both isomers are obtained in a similar amount120.
An interesting example is represented by limonene (186) in which the azidoselenenylation occurred simultaneously on both double bonds, producing only two isomers (187, 188). The addition on the endocyclic double bond produced the same stereochemistry in 187 and 188 whereas the two structures differ on the geometry of the chiral center generated by the addition on the isoprenyl side chain (Scheme 46).
Libraries of 2-pyridones, 1,4-diazepines and 1,4-oxazepines have been realized by using the supported selenium resin 189 obtained from commercially available polystyrene-supported selenenyl bromide 11 by treatment, in one pot, with methyl acrylate and a primary amine as reported on Scheme 47121.
2.4.4 Intermolecular Formation of CC Bond Promoted by Electophilic Selenium Reagents
Intermolecolar addition reactions involving a carbon-centered nucleophile were not extensively studied and only few examples were reported in the literature. In 1996, Toshimitsu and coworkers reported that a seleniranium ion, generated by treatment of a β-hydroxyselenide 190 with a Lewis acid, reacts with some carbon-centered nucleophile such as alkenyl silyl ethers, trimethylsilyl cyanide and allyltrimethylsilane. In order to prevent the nucleophilic attack on the electrophilic selenium atom, a 2,4,6-tri-t-butylphenylselenenyl derivative was used because the bulky environment protects the selenium atom, preventing also the racemization of the seleniranium ion 122a.
When the nucleophile is an aromatic system (e.g. anisole in Scheme 48), the steric protection of the selenium is no longer necessary and phenylselenenyl and 2-pyridinylselenenyl reagents could be efficiently used to obtain 192 in good yield123.
The nature of the nucleophile considerably effected the stereoselectivity of the process; in fact 2,4,6-trimethoxybenzene afforded 194 with a de of 90% whereas N, N-dimethylaniline led to 195 with a de of 80%. No results were obtained using anisole as nucleophile (Scheme 49)124.
2.5 Electrophilic Selenium-Mediated Cyclofunctionalization
Selenium-promoted cyclization of olefins bearing an internal nucleophile is a useful and well-known chemical protocol. The first example dates back to 1960 when Campos and Petragnani reported the selenolactonization of 4-pentenoic acids125.
In some aspects selenocyclofunctionalization can be comparable to the corresponding halo- and thiocyclization, but offers a series of advantages correlated to the chemical characteristics of the selenium that can be variously manipulated and removed using easy and mild conditions: oxidative elimination of selenoxide, radical hydrogenation or nucleophilic substitution of the corresponding selenones.
As extensively discussed for the addition reactions, the cyclofunctionalizations proceed through the formation of a seleniranium ion intermediate and are a stereospecifically anti process. Many factors influence the course of the cyclization such as the substrate, the electrophilic reagent and its counterion, the solvent and the presence of additives126a. Usually, a selenocyclization can generate five- or six-membered rings according to 5-endo-trig, 5-exo-trig or 6-endo-trig mechanism.
The internal nucleophile could be an oxygen or a nitrogen, and when both of these heteroatoms are present an interesting competition can be observed and controlled. Less present in the literature are selenocyclizations involving carbon-centered nucleophiles that lead to the formation of carbocyclic compounds instead of heterocyclic systems.
2.5.1 Internal Oxygen Nucleophile
Selenocyclizations of alkenes having an internal oxygen nucleophile in a suitable position are the most widely investigated selenium-promoted cyclofunctionalizations. When the nucleophilic group is an alcohol or a carboxylic acid, the reaction is named selenoetherification and selenolactonization and affords cyclic ethers or lactones, respectively. The synthesis of substituted tetrahydrofurans by the electrophilic 5-exo-trig cyclization has been well documented127 and, similarly, the 5-endo-trig process is frequently described even if it should be unfavorable in accordance with the Baldwin rule128.
These reactions are generally characterized by a pronounced stereoselectivity. Mihelic and Hite129 first and Lipshutz and Gross130 later demonstrated that, in the case of homoallylic alcohols , it is mainly dependent on the thermodynamic stability of the final tetrahydrofurans 198, 199, 200, 201, 202, 203, 204, 205, combining the steric requirements of the substituents on the ring with the geometry of the double bond. Using N-phenylselenophthalimide the cyclization is selective in the cases of substituted Z-alkenols but not in the cases of the corresponding E-isomers. In contrast, using as electrophilic reagent the (2,4,6-triisopropylphenyl)selenium bromide 196 the selectivity can be recovered also for this latter substrates (Scheme 50).
This enhanced selectivity can be explained on the basis of increased steric demands in the approach of the electrophile to the carbon–carbon double bond occurring preferentially away from the allylic group.
Phenylselenenyl sulfate has been used for the cyclization of a series of 2 carbomethoxy-3 alkenols structurally similar to . The reaction is stereoselective for both the erythro and threo isomers, affording as major product the tetrahydrofurans in which the electrophilic attack on the double bond occurred away from the carbomethoxy group.
Interestingly, the phenylseleno tetrahydrofurans 207 and 210 can be deselenenylated by oxidation giving the 2,5-dihydrofurans 211 and 212. The formation of a double bond conjugated with the electron-withdrawing group has been proposed as the driving force of the process.
Using PhSeCl or PhSeBr to promote cycloetherifications, the yield as well as the chemo- and stereoselectivity are usually unsatisfactory and some additives were necessary to obtain good results, especially starting from secondary and tertiary alcohols. For this purpose pyridine was first investigated by Mojslovic and Bugarcic in 2001, and later the same group reported that a stoichiometric amount of SnCl2 promotes the selenoetherification of (Z)- and (E)-hex-4-en-1-ols (213 and 216) rapidly and in almost quantitative yield132a. As reported in Table 3, they demonstrated that the stereoselectivity of the synthesis of the isomers 214/215 and 217/218 is also positively effected by the SnCl2 used in the stoichiometric as well as in the catalytic amount. Reasonably, the additive acts by minimizing the competitive side reactions deriving from the presence of a nucleophilic anion (Cl− or Br−).
Recently, the mechanism of phenylselenoetherification of alkenols in the presence of a catalytic amount of bases, such as pyridine, triethylamine, quinoline and 2,2′-bipyridine, has been studied on the basis of kinetic and spectroscopic evidence. It was demonstrated that after the formation of a seleniranium ion intermediate, the intramolecular cyclization is favored by the hydrogen bond between the base and the hydroxyl group of alkenol, and it was reported that the triethylamine is the most active catalyst, in accordance with a number of experimental yields133.
The stereochemistry of the carbon bearing the hydroxyl group is unable to control the geometry of the seleniranium intermediate. Starting from the optically pure alkenol 220, prepared in two steps from the commercially available (S)-styrene oxide 219, a mixture of two diastereomers was obtained by reaction with phenylselenenyl sulfate. Nevertheless, compounds 221 and 222 can be separated by chromatography and the process can be used to prepare the optically pure 2-methyl-5-phenyltetrahydrofurans 223 and 224 (Scheme 52).
Similarly, (1R, 2R)-1-phenylpropylene oxide and its S, S isomer can be used to prepare the eight possible isomers of 2,5-dimethyl-3-phenyltetrahydrofurans in enantiomerically pure form134.
A multistep procedure involving two selenocycloetherification reactions was reported for the synthesis of perhydrofuro[3,4-b]pyrans and perhydrofuro[3,4-b]furans135.
A mixture of cis and trans alkenols 225 and 226 can be easily obtained from the d-glyceraldheyde acetonide after chromatographic separation. As depicted in Scheme 53, the PhSeOTf-promoted selenoetherification afforded from 225 the tetrahydrofurans 227 and 228, and from 226 the tetrahydrofurans 229 and 230. In each of these compounds the phenylselenenyl group can be replaced by the allyl group reacting with tributyl allyltin in the presence of AIBN as activator of the radical process. Compounds 227 and 230 as well as the couple 228 and 229 produced the same radical intermediates, affording consequently the same allyl derivatives: the couple of isomeric tetrahydrofurans 231 and 232 and the compound 233, respectively. In this latter case the reaction was stereospecific, giving the less bulky compound as a unique product.
A second equivalent of PhSeOTf-promoted cyclofunctionalization providing the perhydrofuro[3,4-b]pyrans 234 and 236 when the nucleophile and the allylic moiety are trans (231 and 233) and a couple of isomeric perhydrofuro[3,4-b]furans (235) when the nucleophile and the allylic moiety are cis (232) gives 236.
A number of examples were reported in which an in situ generated hydroxyl group participates in selenocyclization reactions. The addition of an alcohol to the aldehyde 237 generated a hemiacetal intermediate undergoing the 6-endo-trig-cyclization depicted in Scheme 54a and affording the formation of 238136. This strategy has been successfully applied to the synthesis of polycyclic compounds. For example bis alkenyl ketone 239, treated with PhSeCl in a mixture of acetonitrile and water, suffered a hydroxyselenenylation reaction that activated the carbonyl group in a tandem double cyclization affording perhydrofuro[2,3-b]furan 240 (Scheme 54b). Using camphorselenyl sulfate as electrophilic reagent, these heterocycles can be obtained in enantiomerically pure form137.
Similarly, 1-hydroxyoct-7-en-4-one 241 reacts with camphorselenenyl tetrafluoroborate to afford a mixture of four isomeric 2-(camphorseleno)methyl-1,6-dioxaspiro[4,4]nonanes 242 (Scheme 54c). These were separated by chromatography and deselenenylated, affording the corresponding enantiomerically pure 1,6-dioxaspiro[4,4]nonanes138.
Another possibility for the in situ generation of the nucleophile arises from the tautomerization of the β-dicarbonyl systems that produces a vinylic oxygen leading to the formation of cyclic vinyl ethers. An example is the conversion of 243 into 244 (Scheme 54d)139.
(E)-2-(Arylmethylene)cyclopropylaldehyde 245 reacts with PhSeBr in an acetonitrile/water mixture and in the presence of K2CO3 producing stereospecifically the 3-oxabicyclo[3.1.0]hexan-2-ol (), an important structural motif frequently present in pharmacologically active structures140.
The mechanism involves the intermediate formation of the seleniranium ion () and the simultaneous hydration of the carbonyl group with the in situ formation of a hydroxyl group that attacks the seleniranium ion to afford the cyclization in good yields and very high stereoselectivity, that proved to be not particularly effected by the nature of the substituent on the aryl group (Scheme 55). Using as selenenylating agent the N-phenylselenophthalimide in the presence of ammonium persulfate in DMSO at 70 °C, the mechanism is not electrophilic and probably the reaction is promoted by a phenylselenenyl radical producing the 1-naphthaldeyde 248 in a completely different way.
Selenolactonization reactions are important steps present in the synthesis of several natural products141 and a number of electrophilic reagents have been employed to convert unsaturated carboxylic acids into the corresponding lactones.
When the conversion proceeds via a 5-endo cyclization, the obtained product is suitable for a subsequent elimination via selenoxide with the formation of a butenolide. The conversion of 3-alkene-carboxylic acids (249) into the corresponding butenolide (251) was realized for the first time by Tiecco and coworkers using diphenyl diselenide and ammonium persulfate in a two-step procedure. The electrophile PhSeOSO3H promotes the cyclofunctionalization to afford in good yields the lactone 250, which further reacts with the oxidizing reagent affording 251 via selenoxide elimination (Scheme 56)142.
Recently, the reaction of polystyrene-supported selenium bromide 11 with γ,δ-unsaturated acids 252 has been reported. The reaction proceeds regioselectively on the basis of a 5-exo-trig cyclization leading to a polystyrene-linked selenolactone 253. The cleavage from the polymer has been obtained by treatment with methyl iodide and sodium iodide, affording the 5-iodomethyldihydrofuran-2-ones 254 in excellent yields, ranging from 90 to 96% (Scheme 57). The reaction showed also an appreciable stereoselectivity when the carbon-bearing substituents R1 and R2 are chiral. For example, when R1 = H, R2 = Me, Et or PhCH2 and R3 = H, the syn lactones were obtained as major products in a diastereomeric ratio of 6:1, 6:1 and 5:1, respectively. The polymeric reagent can be recovered in the form of methylselenenyl derivative and can be regenerated by treatment with bromine and reused several times, increasing the greenness of the entire process143.
β-Phenylselenobutenolides (258) can be obtained in moderate yields by the electrophilic cyclization of 2,3-allenoic esters (255) with PhSeCl in acetonitrile (Scheme 58)144. Some years later, the same authors demonstrated that, starting from the corresponding ethyl 2,3-allenoates, the same butenolides can be obtained in good yields using aqueous acetonitrile as solvent and the best results were obtained for a H2O/MeCN ratio of 10:1145.
The electrophile PhSeCl reacted with the more electron-rich CC double bond of the ethyl 2,3-allenoates 255 forming the seleniranium intermediate 256, which is opened by the intramolecular attack of the carbonyl oxygen to form the cyclic intermediate 257. Subsequent attack of a molecule of water would be followed by intramolecular proton transfer and the elimination of ethanol, producing the butenolide 258. In the case of unsubstituted allenoates the seleniranium intermediate suffered nucleophilic attack of the chloride ion instead of the cyclization reaction. It was later demonstrated that in the absence of water and in the presence of Li2CO3 as a base, the corresponding 3-phenylseleno-4-oxo-2(E)-alkenoates were obtained as the result of a decomposition of a selenato ester intermediate146.
Other oxygen-containing functional groups were used in cyclofunctionalization reactions promoted by electrophilic selenium reagents. As an example, alkenyl nitrones generate reactive imminium salt intermediates that can be reduced in situ by treatment with NaBH4 or subjected to methanolysis, affording 1,2-oxazines147.
An elegant application of the selenium-promoted electrophilic oxacyclization reactions has been reported for the asymmetric total synthesis of trilobacin, an annonaceous acetogenin with strong anticancer activity. Starting from 259, PhSeCl promotes a first phenylselenoetherification affording the bicyclic derivative 260. At this point the exposure to a second equivalent of PhSeCl transforms the organoselenium moiety to a good leaving group activating a transannular attack of the etheric oxygen and affording the formation of the oxonium intermediate . The nucleophilic attack of chloride anion on carbon 22 produces a bis 2,2′-tetrahydrofuran 262 that is the core structure of the final product (Scheme 59)148.
As previously described for some intermolecular addition reactions, asymmetric electrophilic selenium reagents can be used to effect enantioselective selenolactonizations and selenoetherifications and the strategy represents an intriguing route to interesting enantioenriched heterocycles. Some representative examples, involving 264, 266, 268, 269 and 271 from 263, 265, 267, 163 and 270, respectively, are reported in Scheme 60. Also, in this case the electrophilic reagents bearing a coordinating sulfur atom are among the most efficient reagents combining selectivity to mild reaction conditions. In particular, the selenenyl triflate 93 at −30 °C showed a comparable stereoselectivity and, in such cases, higher than those obtained using analogous sulfurated reagents at −78 °C or a similar oxygen- and nitrogen-containing electrophile at −100 °C79, 80.
Denmark and Collins reported that selenolactonization promoted by weak electrophilic selenium reagents can be efficiently catalyzed by some Lewis bases149.
The hypothetical mechanism depicted in Scheme 61 involves the initial reaction of the Lewis base with the electrophilic selenium reagent, affording an activated species that combines with the olefin to produce the seleniranium intermediate and, subsequently, the cyclization reaction. Unfortunately, even if in theory the selenium reagent, combined with a chiral base, could discriminate the enantiotopic faces of a prochiral olefin, a variety of enantioenriched Lewis bases produced only racemic lactones in the cyclization of a number of alkenoic acids.
Later, on the basis of a deep mechanistic investigation, the same authors found that the critical step was the suppression of the racemization of seleniranium ion intermediates. N-2-Nitrophenylselenosuccinimide 272 was the reagent of choice and, in association with BINAM-derived thiophosphoramides 273 as catalysts, selenoetherification reactions can be effected with appreciable enantioselectivity. Two selected examples (274 275 and 276 277) are reported in Scheme 62; even if the results in terms of selectivity are still not comparable with those obtained using enantiomerically pure diselenides, it represents a pioneering attempt to effect an organocatalytic seleno-cyclofunctionalization and a considerable improvement for the simplicity and greenness of the reaction150.
2.5.2 Internal Nitrogen Nucleophile
In recent years the electrophilic activated cyclofunctionalizations of unsatured substrates bearing a suitable positioned internal nitrogen nucleophile have been the object of much attention when considering the synthetic relevance of the nitrogen-containing heterocycles, especially for the total synthesis of alkaloids. Primary amines were found to be scarcely reactive in the presence of electrophilic reagents whereas secondary amines or amines functionalized with an electron-withdrawing group, such as carbamates, afforded efficiently the corresponding heterocycles151a.
Usually, these reactions are characterized by good regio- and stereoselectivity; carbamate 278 reacts with PhSeCl to give the cis-2,6-disubstituted pyrrolidine 279 as a unique product (Scheme 63a) and in a similar way the optically pure pentenyl amide 280 is transformed into the pyrrolidine 281 with a considerable loss of enantiomeric excess (25%) (Scheme 63b).
Homoallylic secondary amines 282, as a consequence of competition between a 5-endo-trig and a 4-exo-trig process, afforded a mixture of azetidine 283 and pyrrolidine 284, and the regioselectivity depends strongly on the nature of the substituents R1 and R2. For unsubstituted substrates (R1 = R2 = H), the pyrrolidine was the major product (283/284 = 18:82) while when R1 = R2 = Me, a larger amount of azetidine was obtained (283/284 = 83:17) (Scheme 63c). Using an excess of PhSeCl a deselenenylation could be observed, and the process is reasonably promoted by the attack of the electrophilic selenium on the selenium atom of the formed phenylselenide 284 followed by a nucleophilic substitution and the formation of the corresponding halopyrrolidine from a substrate in which R1 = H and R2 = Me152a.
More recently, the same authors, using as electrophilic reagent PhSeBr, investigated the influence on the regio- and stereoselectivity of the substituents present on the double bond at γ and δ positions, respectively (Scheme 64). In the first case, the homoallylic amine 285 afforded azetidine 286 as the only regioisomer in a mixture of cis/trans isomers with a large prevalence of the cis isomer. When the substituent is a phenyl group in the δ-position (287), only the pyrrolidine 288 was obtained in a good yield and the 2,4-cis isomer was largely the major isomer also in this case.
Concerning the substituent R1, it was observed that as a consequence of an increased steric demand, a Thorpe Ingold effect is very important in enhancing the yield, but the effect on the stereoselectivity is not substantial153.
The selenium-induced electrophilic cyclization of 4-hydroxy-5-pentenylamines 289 and 5-hydroxy-6-hexenylamines 291 proceeds regioselectively to give the exo adducts with a diastereoselectivity governed by the interaction with the hydroxyl group. cis-3-Hydroxy-2-phenylselenomethylpyrrolidines 290 were found to be the major isomers from the cyclization of 289 whereas trans-3-hydroxy-2-phenylselenomethylpiperidines 292 were the isomers predominantly obtained from the cyclization of 291154.
Isoxazolines 294 can be prepared by the cyclization of O-allylhydroxylamines 293 promoted by the phenylselenenyl sulfate155. The same heterocyclic system can be obtained starting from O-allyl oximes (295) in a one-pot procedure that involves first the electrophilic cyclization promoted by PhSeBr and subsequently the reduction of the imminium salts intermediate by treatment with NaBH4. If the imminium salt was hydrolyzed, the corresponding NH oxazoline could be obtained (Scheme 65)156a.
In a similar way some different imines can be also cyclized. The CN double bond can be either internal or external to the forming cycle, and in both cases the reaction leads to the formation of an imminium intermediate that can be easily reduced by NaBH4 with the formation of a stable nitrogen-containing heterocycle157.
Some interesting substrates in which the nitrogen is incorporated in a functional group containing other nucleophilic atoms can produce competitive cyclization reactions leading to different heterocycles.
Examples in which a chemoselective synthesis could be obtained depending on the experimental conditions as well as on the structural properties of the starting material have been reported.
Alkenyl hydroxamic acids (296) can be cyclized using as electrophilic reagent phenylselenenyl sulfate. Tiecco and coworkers, using the electrophilic reagent phenylselenenyl sulfate, demonstrated that in this case the seleniranium ion intermediate can be trapped by the oxygen, affording a cyclic N-hydroxy imidate (299), or by the nitrogen affording an N-hydroxy γ-lactam (298) (Scheme 66). The attack of the more nucleophilic oxygen is faster than that of the nitrogen atom and the process can be controlled using kinetic or thermodynamic reaction conditions, respectively158. In contrast, taking into consideration O-allyl hydroxamic acids the cyclization is governed by the structure of the starting material which is taking place with Markovnikov addition159.
A different kind of chemoselection was encountered in the cyclization of alkenyl oximes and alkenyl phenylhydrazones. Depending on the geometry of the functional group a 5-exo-trig or a 6-exo-trig could be the preferred process. Starting from the oximes 300 and 301, the 1,2-oxazine 302 or alternatively the cyclic nitrone 303 should be obtained as a consequence of an O-mediated or an N-mediated cyclofunctionalization (Scheme 67)160. The authors demonstrated that the formation of 1,2-oxazones is a reversible process and that, on the basis of an isomerization between 300 and 301 for a long reaction time with the electrophilic phenylselenenyl sulfate, the cyclic nitrone 303 is formed (Scheme 67).
Optically pure electrophilic selenium reagents 92 and 93 were employed for the stereoselective synthesis of 1,2-oxazones as well as cyclic nitrones with a diastereomeric excess ranging from 50% to 92% depending on the nature of the substrates161.
In the case of phenylhydrazones 304 and 305, both the amino and the imino nitrogen acts as internal nucleophile after activation with PhSeBr and, depending on the syn/anti geometry of the hydrazone, the process lead to the tetrahydropyrazine 306 or to an imminum salt that was reduced in situ by treatment with NaBH4, affording 307 (Scheme 67)162.
The tertiary N-p-toluenesulfonamides 308 and 310 reacted with PhSeSbF6, leading to the N-aryl pyrrolidine 309 and the N-aryl piperidine 311, respectively, on the basis of an electrophilic promoted detosylative cyclization (Scheme 68). The reaction is required to be conducted at low temperature in order to afford good yield and good chemoselectivity163.
Selenium-promoted carbocyclization reactions occurred when a nucleophilic carbon (olefins, enols, aromatics) attacks a seleniranium ion leading to a cyclization through the formation of a carbon–carbon bond. Some of the earliest successful carbocyclizations are reported in Scheme 69. In the first two examples (a, b) the seleniranium ion intermediate, generated starting from a diene (312, 314), is attacked by the second double bond, producing a carbocation that can be quenched by the solvent (AcOH or MeCN), leading to acetoxy- (313) or acetamido- (315) bicyclic derivatives, respectively164.
Also, olefinic enolic bonds can act as nucleophiles in selenium-activated carbocyclizations of systems such as β-dicarbonyl compound 316. It reacts with N-phenylselenophthalimide in the presence of a Lewis acid (ZnI2, AlCl3, or SnCl4). The formation of 317 (Scheme 69c) is the result of a thermodynamic cyclization that passes through equilibrium with a kinetic selenoether intermediate165a.
The first example of Friedel–Crafts-like carbocyclization was reported by Deziel and coworkers in 1998 using the optically pure selenenyl triflate 318 (Scheme 69d)166. The reaction of 319 requires the presence of methanol as a co-solvent and for this reason it is not possible to avoid the formation of the methoxyselenenylated adduct as side product. A long reaction time and a final treatment with a protic Lewis acid afforded the bicyclic 320 in 70% yield and up to 98% enantioselectivity.
The main limitations of this procedure are represented by the impossibility to effect the reaction in the absence of the alcohol and starting from non-activated aromatic systems.
Some years later Lim and RajanBabu reported that these limitations could be overcome by changing the electrophilic reagent. PhSeBr, in the presence of AgSbF6 in aqueous dichloromethane at −80/−90 °C, converted 321 into the expected product 322 in 85% yield and the reaction proceeded also on non-activated aromatic carbon-centered nucleophile (97% yield) without competition with the hydroxyselenenylation (Scheme 70).
In Scheme 70 two examples of 6-endo-trig carbocyclizations are reported. The first example is 323 324. In the second case of Boc-protected N-allylaniline 325, the strong electrophilic condition promotes also the loss of the Boc-protecting group leading to 326 in 74% yield163.
More recently, Wirth and coworkers reported the cyclization of some β-ketoester substituted stilbenes 327 using PhSeCl and FeCl3 as Lewis acid. Functionalized naphth-1-ols 333 are the results of a carbocyclization of the enol 328 via 329 and followed by a 1,2-rearrangment (, ) of an aryl (or alkyl) group after an electrophilic ‘selenium up to selenium’ activated deselenenylation () that leads to the formation of a carbocation intermediate (Scheme 71)167.
2.6 Recent Acquisitions Toward Green Chemistry
The mythology surrounding the ‘high toxicity’ of selenium and organoselenium derivatives, which can be traced to the voyager Marco Polo, is nowadays largely dispelled and many selenium-containing molecules are accepted as potentially useful drugs. Also concerning the chemistry of organoselenium reagents, a number of modern research projects have explored new eco-friendly methodologies and conditions to effect selenium-mediated reactions.
In 2009, for the first time, the use of some electrophilic selenium reagents as catalysts in Green Chemistry were highlighted168. Three main aspects of modern selenium chemistry should be stressed as strategies toward ‘Green Chemistry’ and ‘Eco-Friendly’ applications:
Use of supported and reusable reagents.
Use of organoselenium catalysts.
Use of non-conventional reaction media (water, glycerol, ionic liquids, biphasic systems).
Same examples of resin-supported electrophilic reagents have already been reported and discussed in this chapter, here some additional examples of electrophilic selenium-centered catalysts as well as some reactions effected in water, in ‘on water conditions’ or in an aqueous medium will now be reported.
A number of examples were reported in which diphenyl diselenide in the presence of ammonium persufate promotes one-pot selenenylation–deselenenylation reactions in which the organoselenium reagent acts formally as a catalyst2c, 2d.
As depicted in Scheme 3, the oxidation of diphenyl diselenide in the presence of a slight excess of ammonium persulfate produces the strong electrophilic specie, PhSeOSO3H, which is able to promote electrophilic additions as well as cyclofunctionalizations. The resulting phenyl selenides can be further oxidized by an excess of ammonium persulfate, transforming the selenium moiety as a good leaving group that can evolve by elimination or by substitution, depending on the nature of the substrate and on the reaction conditions.
In both cases the deselenenylation regenerates the electrophilic selenenylating reagent, allowing the continuation of the catalytic cycle summarized in Scheme 72.
For example, the cyclofunctionalization of 2-carbomethoxy-3-alkenols (206), already described in Scheme 50, can be effected using a catalytic amount of diselenide and 3 equivalents of ammonium persulfate at 70 °C in acetonitrile, affording stereospecifically the syn 2,5-dihydrofuran (214) from the erythro alkenol and the anti isomer (212) from the threo alkenol131.
We recently reported the first example of a one-pot catalytic hydroselenenylation–deselenenylation in which the phenylselenium moiety, introduced during the hydroselenenylation, is directly removed by a molecule of water, leading to the formation of 1,2-diols103.
The treatment of methylcyclohexene 334 with a catalytic amount of diphenyl diselenide and 3 equivalents of ammonium persulfate afforded a mixture of syn/anti isomers 335 and 336, respectively. The stereochemistry can be explained assuming the intermediate formation of a carbocation during the deselenenylation. The yield can be enhanced using a stoichiometric amount of selenenylating reagent, producing also a positive effect on the stereoselectivity. At the end of the reaction diphenyl diselenide can be quantitatively recovered, confirming its formal role as catalyst (Scheme 73).
It was demonstrated that, in order to obtain a greener procedure for the selenium-mediated dihydroxylation of olefins, hydrogen peroxide can be used in place of ammonium persulfate. In this case, the proposed mechanism is different and involves the formation of an epoxide intermediate 338 by reaction of 337 with a perselenenic specie that is the actual catalyst of the process. The epoxide was not isolated and is regio- and stereoselectively opened by a molecule of water to afford 339 and 340 with the anti-1,2-diol as the main product.
Diphenyl diselenide169 and l-selenocystine170 were used as precatalysts. In the first case, 10% of catalyst in a 3:1 mixture of acetonitrile and water were necessary to obtain good yields in a reasonable reaction time. On the contrary, when the reaction was effected using the dimer of the naturally occurring amino acid, good results could be obtained in ‘on water’ conditions and with only 1% of the catalyst. In this case an additional advantage was correlated with the stereoselectivity of the process. Starting from some cyclic olefins only the anti adducts were obtained as enantiomerically enriched mixtures (Table 4). At the end of the reaction the organic components can be extracted with ethyl acetate and the aqueous layer, containing the actual catalyst, could be reused five times without appreciable loss of yields.
By changing the solvent to methanol, the corresponding methoxyhydroxylation products were obtained in good yields on the basis of a similar mechanism. The enantiomeric excess of the isolated methoxyalcohols were considerably reduced owing to the presence of a non-catalyzed side epoxidation reaction occurring in methanol.
The catalytic system diphenyl diselenide/ammonium persulfate has been used in water to effect the one-pot conversion of alkynes 341 into the corresponding 1,2-dicarbonyl derivatives 346171.
The first step of the reaction consists in the selenohydroxylation of the carbon–carbon triple bond affording the enol in tautomeric equilibrium with the ketone . The excess of ammonium persulfate activates the deselenenylation occurring with a nucleophilic substitution of a molecule of water on a selenonium salt 344 and the formation of 345 that undergoes a further oxidation, producing the final dicarbonyl compound 346 (Scheme 74).
Very recently, Wirth and coworkers described the use of in situ prepared PhSeI to effect catalytic carboxyselenenylation of alkenes using styrene and styrene derivatives as nucleophiles. This new carboaddition reaction, promoted by an electrophilic selenium reagent, has been effected also using water as solvent and afforded the desired product (Ar = Ph) in 31% yield, not far from the best results obtained in 1,2-dichloroethane (55%)172. As depicted in Scheme 75, the reaction requires only a catalytic amount of iodine to generate the electrophilic reagent, interesting progress toward the optimization of the atom economy for this kind of reaction.
Starting from commercially available PhSeCl and PhSeBr, the umpolung of the selenium atom has been obtained by an oxidative insertion of a zinc atom. The resulting PhSeZnCl and PhSeZnBr resulted in an efficient nucleophilic reagent in on-water conditions for a number of different synthetic applications173a.
3 Electrophilic Tellurium Reagents
- Top of page
- Electrophilic Selenium Reagents
- Electrophilic Tellurium Reagents
- References and Notes
3.1 Preparation of Electrophilic Tellurium Reagents
Tellurium tetrachloride (TeCl4) can be prepared by passing a stream of chlorine over elemental tellurium or by refluxing it in sulfuryl chloride for 12 h174a. It represent a good starting material for the preparation of tellurium trihalides (RTeCl3) by the reaction with an appropriate organic nucleophile.
For example, two useful conversions are reported in Scheme 76 involving activated aromatics175 or alkyne176; 350 and 352 (formed from 349 and 351, respectively) are useful intermediates for the synthesis of a number of organotellurium derivatives.
Alternatively, aryltelluro trihalides including tribromides (RTeBr3) and triiodides (RTeI3) can be accessed by halogenations of the corresponding ditellurides, as summarized in Scheme 77. Tellurium monohalides (RTeX) are difficult to be prepared and isolated because of a general instability associated with the high reactivity. In the case of bromine, it was demonstrated that the initially formed monohalide rapidly gives rise to trimerization, affording a molecule of tribromides and the corresponding ditelluride (Scheme 77)177.
For synthetic purposes, monohalo tellurides can be prepared in situ and immediately trapped by a nucleophile, such as a Grignard reagent (Scheme 78) affording, e.g., the corresponding diorgano telluride 354 from 353178.
A restricted number of examples were reported in which monohalo tellurides can be isolated as a consequence of kinetic or thermodynamic stabilization by the presence of bulky substituents or a suitably positioned coordinating heteroatom, respectively179.
The reaction of the ditelluride 355 with 1 equivalent of SO2Cl2, Br2 or I2 afforded in high yield the corresponding monohalotellurides (, 356b, 356c356a) as stable crystalline compounds. The use of larger amounts of halogenating reagents produced, in the cases of chlorine and bromine, the corresponding trihalides 357a and 357b whereas iodine, probably for steric reasons, led to the monohalo reagent (Scheme 79).
Triiodo derivatives were obtained starting from (2,3,4,6-tetramethylphenyl) ditelluride 358. It reacts with 1 equivalent of iodine to give the sterically stabilized arentellurenyl iodide 359 that, with a further 2 equivalents of iodine, is quantitatively transformed into the triiodotelluride 360 (Scheme 80)180.
Aryltellurenyl halides 356b and 356c were recently used to prepare the corresponding tellurenyl triflate and tellurenyl tetrafluoroborate by treatment with AgOTf and AgBF4, respectively. These new electrophilic species were used for the trapping and characterization of a tellurenyl cation as a diene or a triphenylphosphane complex181.
Contrary to what we reported for the selenium derivatives, only few examples exist concerning the synthesis of optically active organotellurium reagents stabilized by intramolecular interaction for the application in asymmetric synthesis.
(R)-[2-(4-Ethyl-2-oxazolidinyl)phenyl]tellurium(IV)trihalides 362 (trichloride), 363 (tribromide) and 364 (triiodide) were prepared starting from the corresponding ditelluride 361 by treatment with an overstoichiometric amount of halogenating agents (Scheme 81). The chemoselective synthesis of monohalides resulted in being unsuccessful on the basis of the simple stoichiometric control, but (R)-[2-(4-ethyl-2-oxazolidinyl)phenyl]tellurium(II)bromide 365 can be easily prepared by reduction of 363 with hydrazine in ethanol182.
3.2 Telluration Reactions of Nucleophilic Carbons
The electrophilicity of reagents containing tellurium(II) and tellurium(IV) can be used to effect substitution reactions with carbon-centered nucleophiles such as enols or carbanions.
As reported in Scheme 82, treatment of the bis(2,6-dimethoxyphenyl) ditelluride 366 with an excess of bromine produced in good yield the tribromotellurenylaryl derivative 367 that, dissolved in acetone, underwent a nucleophilic substitution to afford the corresponding α-chalcogenation product 368 as yellow crystals183. In a similar way, when trichlorotellurides 369 and 372 were reacted with thiophenyl methyl ketone the corresponding α-telluroketones 370 and 373 were obtained. These latter can be reduced by treatment with aqueous bisulfate to afford the diorganotellurides 371 and 374 in moderate yields184.
Ortho-mercurated Schiff bases 375 were used to prepare organotellurium compounds containing azomethine groups. The reaction was performed in chloroform using tetrachlorotelluride as electrophile. A half equivalent of TeBr4 afforded the dibromo derivative 376, and one equivalent the tribromo derivative 377. This compound can be easily reduced to afford good yields, respectively, of the telluride 378 and the ditelluride 379 (Scheme 83)185.
Diethyl methylphosphonate 380, after deprotonation with LDA, reacts with PhTeBr (preparated in situ by bromination of diphenyl ditelluride), leading to diethyl[(phenyltellanyl)methyl]phosphonate 381 in 85% yield. An excess of base produces the phosphonate anion 382 that reacts with a number of aldehydes, providing the ketene Te,Te-acetals 383 in 41–94% yields (Scheme 84)186.
Interestingly, a one-pot procedure was demonstrated to be less effective than the multi-step one, affording the desired product in a very poor yield of <16%.
3.3 Addition Reactions to Olefins Promoted by Electrophilic Tellurium Reagents
Intermolecular addition reactions to olefins promoted by electrophilic tellurium reagents were first reported in 1959 by Campos and Petragnani, who described the reaction of cyclohexene with TeCl4 and with p-ethoxyphenyl tellurium trichloride (384)187. In the first case the reaction was described as ‘violent’ and afforded the 2-chlorocyclohexyl tellurium trichloride 385188, whereas with the aryltellurium trihalides it was necessary to perform the reaction in boiling cyclohexene in order to isolate the p-ethoxyphenyl-2-chlorocyclohexyl tellurium dichloride 386 (Scheme 85). The same authors later reported that the addition of TeCl4 to cyclohexene can be easily obtained in 66% yield, also preparing TeCl4 in situ from elemental tellurium in boiling SO2Cl2174b.
It should be noted that, concerning the reaction of cyclohexene with TeCl4, there is some confusion regarding the background literature that we will try to reorganize in this chapter following its historical development.
The mechanism of this reaction was initially proposed to be similar to those previously described for the electrophilic selenium reagents, passing via a cyclic telluronium ion intermediate which undergoes nucleophilic attack by the chloride ion, leading to a stereospecific trans addition188. In the papers of Campos and Petragnani this reaction was described as not general, because other simple olefins such as styrene did not react with 384 under similar conditions and were almost quantitatively recovered at the end of the workup. Using TeCl4 in boiling carbon tetrachloride the reduction of the reagent with the formation of elemental tellurium was reported as the main process.
Later, Ogawa and Ishioki proposed as product of the reaction between cyclohexene and TeCl4 the formation of a mixture of mono adduct (385) and bis adduct TeCl2(C6H10Cl2). This latter product arises from the reaction in which the monoadduct 385 acts as electrophile and suffers the attack of the carbon–carbon double bond. They also reported a similar addition reaction starting from 1-propene, observing a regiospecific Markovnikov addition with the formation of a mixture of mono and bis adducts (387 and 388) in a ratio that depends on the dielectric constant of the solvent: more polar solvents showing higher solvating power accelerated the addition of 387 to the olefin, favoring the formation of the bis adduct 388 (Scheme 86)189a.
For the first time, some years later Engman and coworkers studied by means of 1H NMR the stereochemistry of the addition of 2-naphthyltellurium trichloride and TeCl4 to a number of linear and cyclic olefins190. They demonstrated that the addition of 2-naphthyltellurium trichloride (389) is in all cases an anti-addition stereospecific process consistent with the formation of the cyclic telluronium ion intermediate () postulated by Campos and Petragnani and depicted in Scheme 87.
A different, and more complex, situation has been described when the electrophile was tellurium tetrachloride. The previously described mechanism via telluronium ion cannot explain the formation of syn addition products and, in general, the poor stereospecificity that was observed in numerous examples.
This behavior was first attributed to a side radical reaction. However, bearing in mind that in the presence of benzoquinone as radical inhibitor, with the only exception of cyclohexene, all the other olefins afforded quite exclusively the syn isomer, it is more reasonable to suppose the presence of a concerted syn-addition in competition with the radical reaction.
The mechanism of this concerted addition was supposed to be similar to a [2 + 2] cycloaddition reaction that is notably disfavored in the case of cyclohexene. In this case, probably, the stereoselective anti-addition could be the result of a stereospecific radical pathway or an anti-addition mechanism.
In Scheme 88, a plausible radical mechanism and the concerted syn-addition reaction are summarized considering cyclopentene as a starting material.
The syn addition of TeCl4 in the presence of a radical inhibitor followed by an anti elimination induced by aqueous Na2S has been proposed as a mild procedure for the inversion of olefin geometry191a. Achampong and Parkins192 employed X-ray analysis to investigate the structure of the diadducts obtained by reacting cyclohexene and TeCl4 in the condition reported by Ogawa189a. Changing the reaction temperature, in order to obtain better yields in the preparation of the crystals, they discovered that under refluxing conditions a mixture of racemate 392 and meso diaducts 391 is formed whereas mixing the reactants at low temperature (0 °C to −5 °C) and then warming them at room temperature give rise to the stereoselective formation of the pure racemate 392 (Scheme 89)192.
Similarly to the alkoxyselenenylation, the alkoxytelluration of olefins can be obtained by electrophilic activation of a carbon–carbon double bond with phenyltellurium (II) or (IV) in the presence of an alcohol. At room temperature the conversion required a long reaction time, but the process can be accelerated by heating at reflux temperature. The electrophilic reagent can be conveniently prepared in situ by reacting diphenyl ditelluride and bromine and the addition reaction produced the corresponding α-methoxyphenyltellurium dibromide derivatives (393, 397, 399, 401)193.
From these initially formed compounds the corresponding phenyl tellurides 394, 398, 400 and 402 can be obtained by reduction with hydrazine as well as with other reducing agents such as Na2S2O3 or Na2S. Phenyltellurium dibromide moiety can be also eliminated in order to introduce a double bond into the structure. Treatment of 393 with NaOH produced the telluroxide 395, which was thermally decomposed at 200 °C leading to 3-methoxycyclohexene 396 (Scheme 90b).
When the reaction was performed starting from terminal olefins, it was regiospecific with the formation of the Markovnikov addition product 397 (Scheme 90c) and stereospecific affording the adducts deriving from an anti-addition mechanism. As an example we reported the methoxytelluration of cis- and trans-2-butene (Schemes 90d and 90e), which occurred in a trans fashion with the formation of the threo-399 and erythro-401 isomers, respectively.
When terminal olefins were heated with tellurium dioxide in the presence of an alcoholic solution of hydrochloric acid and the crude product, without any purification, was reduced with sodium bisulfate the bis(β-alkoxyalkyl) ditellurides (405) could be obtained in moderate to good yields194.
Tellurium dioxide by reaction with hydrochloric acid forms the species hexachlorotellurate (H2TeCl6), which is able to promote electrophilic telluration with the formation of tellurium trihalides derivatives195.
When the reaction is effected starting from a terminal olefin (see the example reported in Scheme 91) using an alcohol as a solvent, an alkoxytelluration occurred via telluroniun ion intermediate () leading to regiospecific formation of a trihalotelluride(IV) . This compound, by reduction with Na2S2O8, is rapidly converted into the corresponding ditelluride 405 and the process represents a convenient and versatile strategy to access an interesting class of functionalized compounds.
Benzenetellurinyl acetate 407, prepared by the reaction of benzenetellurinic anhydride 406 and acetic acid or anhydride, has been used to promote the acetoxytellurinylation of an olefin196.
More interestingly, it was reported that 407 reacts with styrene 408a in the presence of an excess of ethyl carbamate and a Lewis acid in refluxing chloroform to afford the aminotellurinylation products (5 and 5), which was reduced to the more easily isolable telluride 411a197a.
The aminotellurinylation of terminal olefins proceeds with prevalent Markovnikov regioselectivity even if, as reported in Table 5, the isomeric ratios strongly depend on the steric and electronic features of the substituents. It has been observed for the olefins 408b, 408c and 408d that the anti Markovnikov orientation is favored by the steric demand of the substituents, and with allyl phenyl ether 408e the electronic effect of the phenoxy group produced the inversion of the ratio.
Regioselective functionalization of substituted allylic systems represents a relevant goal in organic synthesis. While simple terminal olefins react with TeCl4 according to a Markovnikov addition pathway, the presence of a substituent on the allylic position showed in several cases a strong influence on controlling the course of the reaction. For example, allyl bromide and chloride afforded a mixture of Markovnikov and anti-Markovnikov products, ether and alcohols added TeCl4 regiospecifically with Markovnikov orientation, ester and amides gave a 1,3-addition with concomitant 1,2-migration of the functional group and, when a trichloroacetate is at the allylic position, the reaction did not occur198.
When a trimethylsilane group is present at the allylic position (see 413), the reaction with TeCl4 at −40 °C afforded the synthesis of a diallyltellurium dichloride 414 in 93% yield (Scheme 92).
The reaction reported in Scheme 92 proceeds reasonably through a regioselective Markovnikov chlorotellurinylation with the concomitant elimination of Me3SiCl199. Under similar conditions, the diallyldimethylsilane 415 also afforded prevalently the diallyl dichloro telluride 414 after reaction with the electrophilic TeCl4. The mechanism reported in Scheme 93 suggests a double 1,3-substitution of the silyl group (, ) promoted first by TeCl4 and subsequently by RTeCl3 (417) that reacts with the double bond of the intermediate 200.
3.4 Cyclofunctionalizations Promoted by Electrophilic Tellurium Reagents
The first examples of cyclofunctionalization promoted by electrophilic tellurium reagents are older than the similar selenium-promoted reactions and were reported by Campos and Petragnani's pioneering papers starting from 1959187, 188, 201a.
Treatment of 2,2-diphenylpent-4-oic acid (420) with aryl tellurotrichloro reagents yielded a cyclolactonization reaction affording the corresponding aryl tellurodichloro derivative 421. When the electrophilic reagent is TeCl4 in a stoichiometric ratio of 1:2 with respect to the carboxylic acid 420, the initially formed (but not isolable) tellurotrichloro lactone reacts with the excess of unsaturated substrate to produce the dichloride 422.
Aryl tellurodichlorolactone 421 can be dehalogenated by treatment with one equivalent of NaBH4; an excess of reducing agent reverses the reaction, leading back to the carboxylic acid and the formation of the corresponding diaryl ditelluride 424. The cleavage of the carbon–tellurium bond (423) could be efficiently obtained via a radical mechanism in the presence of tin hydride reagents in refluxing toluene (Scheme 94)201b.
Considering a series of γ,δ-unsaturated acids containing a geminal disubstituted olefins, it was noted that the tellurolactonization was negatively affected by the side addition reaction of a molecule of HCl to the carbon–carbon double bond of the starting material. From these acids good results were achieved, effecting the tellurolactonization starting from the corresponding benzyl ester202.
Similarly, aryltellurium trihalides can be used to promote cycloetherifications of unsaturated alcohols (425, 427) and phenols (429). The reactions were carried out in refluxing chloroform affording cyclic ethers bearing an aryltelluro group in the β-positions, as reported for some selected examples in Scheme 95.
All the reactions proceeded via a 5-exo (425, 429) or a 6-exo (427) mechanism producing tetrahydrofuranyl (426, 430) and tetrahydropyranyl (428) skeletons, respectively. The exo-cyclization appeared to be the only mechanism allowed with these reagents. Starting from 3-buten-1-ol (431), a 4-exo process is probably disfavored on the basis of the ring strain of the final heterocycle and, instead of the cyclic ether deriving from a 5-endo cyclization, the product of intermolecular chlorotelluration (432) has been quantitatively obtained203.
Ogura and coworkers reported similar conversions using benzenetellurinic anhydride in refluxing acetic acid. Under these conditions the electrophilic species is the benzene tellurinyl acetate 408, 408a, 408b, 408c, 408d, 408e [PhTe(O)OAc] and the reactions were found to be limited by the severe required conditions (110 °C for 15 h). In addition, the processes are slower and less efficient in comparison to those previously reported by Petragnani and coworkers while the products (, ) are hygroscopic and difficult to handle and could be isolated only after reduction with hydrazine in ethanol (Scheme 96)204.
In order to overcome these limitations, boron trifluoride etherate or tin(IV) chloride can be used to activate the process on the basis of a Lewis acid-mediated catalysis. This allowed one to reduce the reaction time from 15 hours to 30 minutes, to effect the reaction at room temperature and to increase the overall yields in the synthesis of 435205.
Diphenyl ditelluride has been used to generate in situ the electrophilic species benzenetellurenyl p-nitrobenzenesulfonate (PhTeOSO2Ar) by reaction with p-nitrobenzenesulfonyl peroxide (NBSP). This electrophilic reagent has the weakly nucleophilic nitrobenzenesulfonate as a counteranion and has been used to effect tellurolactonization and tellurocycloetherification in appreciable yield and very good regio- and stereoselectivity206. The reaction has been assumed to involve a telluronium intermediate or, alternatively, the product of a chlorotelluration on the carbon–carbon double bond. Both supposed intermediates rapidly undergo an intramolecular nucleophilic attack of the hydroxy group leading to the formation of the heterocyclic ring.
Tellurium dioxide in acetic acid and in the presence of LiCl reacts with two equivalents of alkenols (425) or allylphenols (429) to afford the dialkyl tellurium dichlorides 436 and 437, respectively, through a bis cyclofunctionalization of the unsaturated alcohols or phenols (Scheme 97)207.
All the methodologies reported here for the tellurium-mediated cyclofunctionalizations generally present common drawbacks correlated to the use of acidic conditions or the formation of hydrochloric acid during the cyclization reaction. A strategy to overcome this problem has been proposed by Comasseto and Grazini, realizing that the cyclization of olefinic benzyl ethers is promoted by aryltellurium trichlorides under neutral conditions208. The authors stressed that these reactions occurred in high yields at reaction times very close to those necessary for the cyclization of the corresponding alcohols (see Table 6).
|R||Ar||T (°C)||cis/trans||Yield (%)||Time (min)|
The stereoselectivity was investigated starting from the alcohol 438 and the corresponding benzyl ether. The cis/trans ratio of 6 was not affected by the nature of the internal nucleophile when the electrophilic reagent is the p-phenoxybenzenetellurium trichloride and only slightly reduced in the case of the benzyl ether when the p-methoxy tellurating analogue has been used.
Cyclic enol ethers such as 441 and 443 can be accessed by cyclization of β-dicarbonyl compounds (440, 442) through the enolic form of the substrates after the activation with an electrophilic reagent (Scheme 98). While the selenium-mediated cyclization is of general application for this class of substrates, the p-methoxyphenyltellurium trichloride has been proved to be efficient only in the case of β-keto esters bearing a monosubstituted double bond (e.g. 440). Starting from these substrates it produced higher yields compared to those obtained with PhSeBr (for example, in the case of 441, 84% vs 66% of the corresponding selenide). However, for similar substrates bearing a disubstituted double bond lower yield or complex reaction mixtures (from 444) were obtained (Scheme 98b and 98c)209.
α-Allenoic acids 445 and in situ generated aryl tellurenyl halides were used to synthesize β-organotellurobutenolides 448 via electrophilic tellurolactonization. The attack of the aryltelluro cation on the central carbon of the allenyl moiety affords an allyl cation intermediate or, alternatively, a telluronium cation . Both intermediates can undergo nucleophilic attack of the oxygen, leading to the formation of the butenolide. It was observed that the reaction proceeds in excellent yields when the halide is chlorine or bromine whereas iodine produced generally unsatisfactory results (Scheme 99)210.
Phenyltellurium bromide is the reagent of choice for the tellurocyclization of the 1,2-allenic phosphonate 449. In this case the participation of the phosphonate group facilitates the formation of a cyclic cation intermediate () that undergoes a Arbuzov-like SN2 demethoxylation mediated by the bromide ion, affording the final product (Scheme 100). The attack of the bromide occurs stereoselectively on the methoxyl group cis to the more bulky substituent, leading to the preferential formation of the E-isomer211.
Only a few examples in which the internal nucleophile is a nitrogen have been reported. Olefinic carbamates (452, 454, 456) react with PhTe(O)COOCF3, giving aminotellurinylation reaction with the formation of nitrogen-containing heterocycles bearing a (phenyltelluro)methyl group (453, 455, 457). The reaction is required to be activated by a Lewis acid and proceeds in refluxing chloroform controlled by a Markovnikov-type regioselectivity for the addition (Scheme 101)197a.
- Top of page
- Electrophilic Selenium Reagents
- Electrophilic Tellurium Reagents
- References and Notes
This chapter is dedicated to the memory of Prof. Marcello Tiecco, the reference and source of inspiration for us and for a large part of the new generation of organic chemists and specialists in organoselenium chemistry. We are pleased to thank our colleagues, coworkers and students cited in the references for their contributions to our own work described here.
References and Notes
- Top of page
- Electrophilic Selenium Reagents
- Electrophilic Tellurium Reagents
- References and Notes
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