Selenium Stabilized Carbenium Ions on Organic Synthesis

Organoselenium compounds have been known for a long time as versatile reagents in organic chemistry. In the last years there has been a considerable development of selenium-based methods for organic synthesis. Many of these methods are currrently been used as standard procedures to introduce new functional groups under mild conditions. From the several areas of interest in organoselenium chemistry, selenium stabilized carbocations has emerged as a useful class for interesting transformations and new methods for carbon-carbon bond formation. Aspects related to heterosubstituted carbenium ions, like their formation, structure and stability, has been very well studied and revised by Hevesi in the last years, and will not be the subject of this article. In the following chapter we will detail synthetic aspects of selenium stabilized carbocations as electrophiles.


Introduction
Organoselenium compounds have been known for a long time as versatile reagents in organic chemistry.In the last years there has been a considerable development of selenium-based methods for organic synthesis 1 .Many of these methods are currrently been used as standard procedures to introduce new functional groups under mild conditions.From the several areas of interest in organoselenium chemistry, selenium stabilized carbocations has emerged as a useful class for interesting transformations and new methods for carbon-carbon bond formation.
Aspects related to heterosubstituted carbenium ions, like their formation, structure and stability, has been very well studied and revised by Hevesi in the last years 2 , and will not be the subject of this article.In the following chapter we will detail synthetic aspects of selenium stabilized carbocations as electrophiles.

Synthetic Applications
Several new reactions were developed in the last years using the capability of an organoselenium group to stabilize an adjacent carbenium ion.These carbenium ions were generated from different selenium species and reacted with several nucleophiles, like silyl enol ethers, alkenes, allylsilanes/allylstannanes and aromatic compounds.In the following, we will be presenting these reactions in detail.

Reaction of selenium stabilized carbenium ions with aromatic compounds
The first aplication of this chemistry in order to produce a new carbon-carbon bond, was made by the use of selenoallyl cations in reaction with N-methyl-pyrrole (1) and furan (2) 3 .These carbocations, stabilized by both selenium and allylic resonance, were generated in situ from a mixture of E and Z 1,3-bis(methylseleno)-propene (3) and 1,3bis(phenylseleno)-propene (4) mediated by silver perchlorate and sodium carbonate in nitrometane to give adducts like 5, as depicted in Fig. 1.
The reaction proceed smothly, with relatively good yields and stereospecificity.In the case of N-methyl-pyrrole variable ratios of regioisomers were obtained.After reaction are recovered important quantities of the starting material but one the isomers when are used as Z and E mixture.There have not been detected products derived of a [4 + 3 → 7] cycloaddition.This latter reaction occurs with allyl cations substituted at position 2, especially with 2oxyallyl systems 3 .The same type of reaction have been exploited using other sources of allylic cationic species, like β-bromovinyl selenides 6a-f and electron-rich aromatic compounds as furan, N-methyl-pyrrole, thiophene and 1,3,5-trimethoxybenzene 4 .
Reagents like 6a and 6b have been prepared by addition of benzeneselenenyl chloride or bromide to propargyl bromide in dichloromethane solution at room temperature in 91% and 69%, respectively.In an analogous fashion 6c-f have been prepared by the addition of benzeneselenenyl bromide to the corresponding allenes in quantitative yields 4 .In Fig. 2 below, are presented some of the results obtained on the reaction of selenium stabilized carbenium ions with N-methyl pyrrole, thiphene, furan and 1,3,5trimethoxybenzene.In the case of N-methyl pyrrole or thiophene the products are obtained as a mixture of substituion at 2-and 3-position.
Although 1-selenoallyl cations 7 also undergo Friedel-Crafts reactions with electron rich heterocycles, the nature of the final product is highly dependent on the susbstitution pattern of 8 and 9 as well as on the reaction solvent.This is illustred in Fig. 3 for the case of N-methyl pyrrole 5 .
Unsubstituted 8 and 9 (R1=R2=H) suffers nucleophilic attack by N-methyl pyrrole to give 10 (path a), whereas disubstituted 8 and 9 (R1=R2=alkyl, aryl) follows path b.Compound 11 cannot be isolated most likely because of the high stability of cation 12 which in turn reacts with a second molecule of N-methyl pyrrole to give 13 or 14, depending on the solvent used.Paths a and b also shows some sensitivity to solvent, but the most spectacular effect is seen at the last stage of the reaction, i.e. attack of 12 by N-methyl pyrrole.1,3-dipyrryl propenes 13 are almost exclusively formed in nitromethane, while regioisomers 14 are largely predominant when the reaction is carried out in DMF.The amounts of 15 and/or 14 can in each case be minimized by the use of an excess of N-methyl pyrrole.
One of the most interesting examples is the synthesis of porphyrins by this type of reagents.The high selective access to 1,1-dipyrryl propenes 14, suggest a straightforward synthesis of phorphirins bearing substitited vinyl groups at their meso-positions.Indeed, with the vinylselenoacetal 16 (a-g) like source of electrophile, a series of porphyrins 17 (a-g) have been prepared under the mild conditions 6 using the one pot reaction sequence outlined in Fig. 4. Another synthesis of an interesting class of meso-porphyrins have been developed in the same fashion 7 .In this case, meso-tetraalkynyl porphyrins have been obtained from selenoacetals 18a-b derived from 2-butynal and 3phenylpropynal, with pyrrole and silver perchlorate in DMF.A further treatment with DDQ furnish the porphyrin 19a and 19b albeit in low yield (Fig. 5).
The use of selenocarbenium ions containing an acyl moiety and generated under Friedel-Crafts conditions have proved to be an efficient route to aromatic derivatives of phenyl acetic acids 8 .The interest in this synthetic route is due to that direct introduction of a two carbon unit contain-ing an acyl group with an α-substituent, under these conditions, into an aromatic ring is expected to be difficult, owing to the desactivation of the intermediary electrophilic complex by the electronegative acyl group.The presence of an organoselenium moiety at the α-position of the acyl group could circunvent this problem.
The synthetic procedure involves treatment of aromatic hydrocarbons with a mixture of ethyl α-bromo-α-phenyl- seleno acetate 20a and ethyl α-α-bis-(phenylseleno) acetate 20b and TiCl4 at room temperature, affording the related benzylic selenides 22a-h as shown in Fig. 6.The mixture of ethylacetate derivative 20a and 20b is easily avaiable from reaction of ethyldiazoacetate with phenylselenenyl bromide in THF at 0 °C (Fig. 6).We observed lately that pure ethyl α-bromo-α-phenylseleno acetate can be obtained exclusively if the reaction is made by adding ethyl diazoacetate to a reflux benzene solution of PhSeBr.The chloro derivative may also be prepared by the reaction of PhSeCl and ethyldiazo acetate, as the sole product 9 .Both these reagents gives the Friedel-Crafts reaction under the same conditions described.Also, has been developed an efficient way to remove the phenylseleno group from the alkylation products.By treatment of benzylic selenide 22 with catalytic amounts of thienylditelluride in ethanol and equimolar amounts of sodium borohydride under basic conditions 10 the corresponding deselenate derivative 23 is formed, as depicted in Fig. 6.The result obtained by the Friedel-Crafts reaction are presented in Table 1.

Reaction of α-phenylseleno carbenium ions with silyl enol ethers
The use of selenoacetals 24a-f in order to produce synthetically available carbenium ions have been developed succesfully 11 .The reaction of these compounds with silyl enol ethers like 25a mediated by a Lewis acid catalyst, gave the β-seleno carbonyl derivative 26 in good to excellent yields as depicted in Fig. 7.
In Table 2 are reproduced the yields obtained in the former reaction, using 2 eq. of cyclohexanone silyl enol ether, 1 eq. of selenium reagent and 2 eq. of Lewis acid in dichloromethane.
By inspection of values reflected in the previous table, can be observed that the presence of bulkier groups arround the cationic center decrease the yields of the reaction (entries d and e), while the presence of a phenyl group increase the yields by the effect of making the formation of cation easier.
Furthermore the seleno alkylation of 24a with a variety of silyl enol ethers (Fig. 8), in the conditions described previously, gave raise to good yields.
In a similar methodologie, we found that α-halo-α- phenylseleno alkanes 27 reacts with silyl enol ethers in the presence of TiCl4 to give the corresponding aducts 28 in high yields 12 , as described in Fig. 9.
In the Table 3 are presented the results of this study, showing the generality of the method.
Worth of note it is that by this methodology it was posible to obtain the alkylation products of silyl enol ethers with α-bromo-α-(phenylseleno)-methane and 1-bromo-1-(phenylseleno)-ethane, products not formed by the reaction of alkylation of silyl enol ethers with selenoacetals described above 11 .This result suggests that the stability of the carbenium ion it is not the only factor affecting the reaction course.Also, we were able to alkylate the sterically crowded 1-trimethylsilyloxy-2,3-dimethylcyclohexene in good yileds using 1-bromo-1-(phenylseleno)ethane.
In this case the presence of a second selenium atom in the carbenium ion should enhance the stability of the intermediate, facilitating its formation and thus leading to the alkylated product in good yield.The Table 4 presents the results of this study, by reaction with the silyl enol ether from different carbonyl compounds.Similar results were described at the same time by Hevesi and Nsunda 16 , with additional that tris-(methylseleno)-methane could also be employed as the carbenium ion source.
The electrophilic species could be generated from 1,3bis-(methylseleno)-propenes and 3-hydroxy-vinylselenides.With the former, tin tetrachloride showed to be the best catalyst and zinc chloride for the last one.In both cases the reactivity, the efficient and the regiochemistry of the carbenium ions on these reactions were very dependent on the substituents on the selenium reagent.These results are better resumed on Table 5 17 .
In the course of our studies on selenium-stabilized carbenium ions, we observed that α-chloro-α-phenylse- lenoesters 18 33a-b reacted with silyl enol ethers 25 mediated by Lewis acids to give α-phenylseleno-γ-keto esters 34 in fair to high yields, in very clean reactions as depicted in Fig. 12.Thus, the treatment of a dichloromethane solution of 33a-b with 2.0 equivalents of 25a-e and ZnBr2 as Lewis acid, produces the desired adducts 34a-i (Fig. 12; Table 6).
From the results described in Table 6, it can be seen that the presence of an additional methyl group in the halide 33b causes a beneficial effect on the carbocation stabilization.The yields of the reaction of silyl enol ethers with ethyl α-chloro-α-phenylseleno propionate 33b in most cases studied are higher than with 33a, with reaction of silyl enol ether 25b being one exception (product 34d; Table 6).The reactions of 33b were performed at 0 °C, but we observed that for the reaction with ethyl α-chloro-α-phenylseleno acetate, better results could be achieved if the reaction was performed at a somewhat higher temperature (room temperature for cyclic ketones or 42 °C for acyclic ketones) as shown in Table 6.Among the various Lewis acid tried, ZnBr2 gave the best results, although ZnCl2 also reacted efficiently.When AlCl3, TiCl4 and SnCl4 were used, rapid decomposition of the silyl enol ether was observed by TLC and no products were detected.

Reaction with allylsilanes and allylstannanes
The first reaction studied of an organo-selenium stabilized carbenium ion with allylsilanes was the reaction described by Hermans and Hevesi 20 .They described the reaction of allyltrimethylsilane with selenoacetals mediated by tin tetrachloride to produce the corresponding   homoallylselenides 40 in moderate to good yields, in accordance with Fig. 14.
By the results described on Table 7, one can observe that the yields of the products are very dependent on the substitution pattern of the selenoacetal.The ones derived from cyclohexanone or methylketones gives better yields than derived from aldehydes or internal ketones which could be accounted from electronic effects (stabilization of the intermediate carbenium ion for selenoacetals derived from aldehydes) or steric crowding around the electrophilic center (in the case of more substituted ketones).Table 8 presents the results obtained in this study.
Similar reactions of selenoacetals with allyltrimethylstannane were studied, and was observed that they occured at room temperature and in presence of zinc chloride or boron trifluoride etherate as catalyst.Compared to the above described reaction with allylsilane, the reactions with allyltributylstannane, as depicted by Fig. 15, gave yields in the same range and some selenoacetals that fails to react with allylsilanes [like 1,1-bis-(phenylseleno)-4-(tbutyl)-cyclohexene] do react with allyltributylstannanes.Besides, the reactions showed good stereoselectivity in some examples depending on the substituion pattern and reaction conditions, as can be seen on Table 9, where are reproduced some examples of interest 20 .
Soon after was studied the coupling of mixed (O, Se) acetals with allyltrimethylsilane and allyltributylstannane mediated by a Lewis acid catalyst 21 .The methodology is illustred in Fig. 16.
In this study was expected that could be possible selectively produce homoallylethers or homoallyl selenides by carefull choice of the Lewis acid.Unfortunatelly this was not the case, since in almost all cases the homoallyl ethers were produced with different Lewis acid (for selected examples see Table 10).The main reason for this result

41-syn 41-anti
SeR  relies on the much stronger C-O bond as compared to the C-Se bond, giving rise to homoallyl ethers as main products 21 .
Recently we have described the reaction of allylsilanes with tris-(phenylchalcogeno)-methane (S,Se), mediated by tin tetrachloride in the case of selenium derivatives and zinc  dibromide on sulphur derivatives, Fig. 17.The reaction was studied in detail with several different allylsilanes, as described on the Table 11 22 .
All reactions of allylsilanes and tris-(phenylseleno)methane were observed to be completed in one hour or less, while the phenylthio derivative 45 reacts slower (4.5 h to 24 h) than the corresponding phenylseleno derivative as indicated in Table 11.In all cases studied on the reaction of allylsilanes with tris-(phenylseleno)-methane, SnCl4 was the most effective catalyst and CH2Cl2 was used as solvent.On the other hand, for the sulfur analogue 45, ZnBr2 was the best catalyst and the use of nitromethane as a co-solvent was more effective.
Along with homoallylselenoacetals, small amounts of the corresponding allylmonoselenides were formed, which were easily separated by column chromatography.The formation of these compounds occurs probably by reaction of the allylsilane with a phenylselanyl species formed in the reaction media.This is in accordance with previous 23 reports that allylsilanes react with C6H5SeCl to give allylselenides.In reactions of 44a-f with 45 the formation of allylsulfides was not observed.
Homoallylselenides have been prepared by the reaction of selenosulphones with allyltrimethylsilane mediated by a Lewis acid 24 .The best results were obtained with EtAlCl2, as can be seen on the Fig. 18.Similar results were also described for the thio analogs.

Reaction with alkenes
Recently was described the reaction of mixed Se,O-heteroacetals with alkenes in a intramolecular pathway to produce cyclohexane derivatives, promoted by TiCl4 at low  temperature 25 .In Fig. 19 are presented the results of this study.
A slightly different type of olefin and acetylenic Se,Oheteroacetals gives the corresponding Se-heteroacetals in good yields, as described on Fig. 20 26 .
Intramolecular version have been developed emploing cationic cyclizations in the 6-endo fashion, by way of selenonium ion generated from selenoacetals 27 .
The reaction of 33a with alkenes 60a-d was promoted by several Lewis acids like TiCl4, SnCl4, ZnCl2, ZnBr2 and AlCl3.Among these Lewis acids TiCl4 was found to give the best yields.Dichloromethane was found to be the best solvent (Method A).The use of the 1-alkene as solvent did not improve yields significantly, but reaction times are reduced (Method B; Table 12).
Since the reaction of 33a with 1-alkenes furnished α-phenyl seleno-γ,δ-unsaturated esters, we continued our studies to the conversion of these species to α-phenylse- leno-γ-butyrolactones.The γ,δ unsaturated α-phenylseleno substituted ester 60a derived from the reaction with 1hexene were subjected to hydrolysis with an aqueous KOH solution and afforded the corresponding carboxylic acid 61a in nearly quantitative yield.The acid was submitted to lactonization with some of the more commom electrophiles 29 such as iodine, phenylselenenyl chloride, or phenylsulfenyl chloride, to give the highly functionalized lactones of type 62 (Fig. 24).During the seleno and sulfurlactonizations reactions, we observed that the use of tributylamine gives a better yield than triethylamine.In view of the formation of α-phenylseleno γ,δ-unsaturated esters when 1-alkenes were employed which need further transformations to give rise to γ-butyrolactones, we decided to explore the use of more substituted alkenes, which would produce γ-butyrolactones directly (Fig. 25, Table 12).
The treatment of a dichloromethane solution of di and tri-substituted alkenes 63a-g with 33a in the presence of SnCl4 yields α-phenylseleno-γ-butyrolactones in variable yields, with the corresponding γ,δ-unsaturated ester 65 being formed as by-product.The ratio between lactone and ester was observed to be dependent of the substitution pattern of the alkene.For example, the reaction of 33a with 1-methyl-cyclohexene gives the corresponding lactone 64f in 52% yield and the γ,δ-unsatured ester 65f in 32% yield; in the same way, 2-methyl-2-butene gives the lactone in 64% yield and a 23% yield of the ester.With less substituted alkenes, like cyclohexene, the corresponding lactone 64e is formed in 44% yield plus a 43% yield of γ,δ-unsatu- rated ester 65e (Fig. 26).

Miscellaneous
Kataoka and co-workers 30 described recently the reaction of γ-chalcogen substituted prop-2-ynyl cations, generated from γ-chalcogen-substituted propynal diethylacetals with several nucleophiles.The starting material 68 were prepared by reaction of propynal diethyl acetal with ethylmagnesium bromide followed by treatment with ben-zenesulfenyl or benzeneselenenyl chloride (Fig. 27).The reaction of these reagents with nucleophiles are shown in Table 13.

Table 5 .
a) 51% of 31a (E+Z) recovered unreacted; b) 31b is a[1,3]sigmatropic mixture of the acetal and the related vinyl selenide; c) 31c is in fact the pure acetal.

Table 6 .
a) Isolated yields; b) Lower yields were observed at 42 °C.