Zinc-Mediated Synthesis of Vinyl Selenide and GPx-like activity

Phenyl selenol and the zinc-selenolate PhSeZnCl can be conveniently employed for the stereospecific and stereoselective synthesis of vinyl selenides. These reactions occur with moderate to h igh yields and can be accomplished in eco-compatible conditions using a b iphasic acidic system or directly an aqueous suspension. Introduction Vinyl selenides are intermediates of great syntheti c interest, and their versatility in organic synthesis has been wid ely documented. 1 They combine the functional transformations achieve d by the wellknown reactions of organoselenium compounds (e.g. s elenoxides, syn elimination) with the ability of carbon–carbon bond -forming reactions involving the double bond, associated wit h the ability of selenium to stabilize adjacent positive and negativ e charges. Phenylselenol and selenolate are convenient organos elenium reagent and their role in effecting many synthetic transfor mations is well known. Even if a number of procedures for the in situ generation of these species have been reported, 2 most of them suffer from serious drawbacks such as bad smelling, moisture sensitivit y, strong basic reaction conditions, use of hazardous organic solve nts. In order to overcome these drawback and look for more eco-susta inable strategy to perform organic reaction, recently, we introduced two new procedures using zinc as reducing agent in the preparation of selenols and selenolates 4 starting from diselenides and phenylselenyl halides, respectively. We reported t hat zinc shavings in a 1:1 mixture of 0.18 N HCl/ Et 2O at 20°C reduces diselenides affording the corresponding selenols which can be isolated or directly treated with different nucleophiles. 3 In a different way the ttreatment of commercially available PhSeCl with a s toichiometric amount of zinc powder in refluxing THF leads to the corresponding solid and air-stable zinc selenolate 1 through an oxidative insertion of zinc into the selenium–chlorine bond (Scheme 1). 4 Scheme 1. Zinc-mediated synthesis of selenols and selenolates Results and Discussion We now report that these procedures can be convenie ntly employed to effect the synthesis of vinyl selenides in “on w ater condition” or using a biphasic acidic system, starting from vinyl halides or substituted alkynes (Scheme 2). Scheme 2. Strategies used for the vinyl selenides synthesis The hydroxiselenenylation of alkynes shows high ste reoselectivity affording mainly the Z-isomer. The double bond geom try was determined by H NMR spettroscopy and for the 3e and 4e products by the n.O.e. correlation (Table 1). Table 1. Hydroselenation of alkynes Entry R R1 T(h) Yield % Z/E 2a Ph H 24 68 100:0 2b COOEt H 24 70 100:0 2c p-Br-Ph H 24 60 91:9 2d p-MeO-Ph H 24 48 24:76 2e Ph COOMe 24 70 72:28 2f Tyophen-2-yl H 24 80 85:15 Vinyl selenides have been also achieved by nucleoph ilic substitution on vinyl halides. These reactions were performed bo th in THF solution both in water suspension and in this latte r case the reactions ECSOC-14 (2010) 14 th Electronic Conference of Organic Chemistry


Introduction
Vinyl selenides are intermediates of great synthetic interest, and their versatility in organic synthesis has been widely documented. 1 They combine the functional transformations achieved by the wellknown reactions of organoselenium compounds (e.g. selenoxides, syn elimination) with the ability of carbon-carbon bond-forming reactions involving the double bond, associated with the ability of selenium to stabilize adjacent positive and negative charges. Phenylselenol and selenolate are convenient organoselenium reagent and their role in effecting many synthetic transformations is well known. Even if a number of procedures for the in situ generation of these species have been reported, 2 most of them suffer from serious drawbacks such as bad smelling, moisture sensitivity, strong basic reaction conditions, use of hazardous organic solvents. In order to overcome these drawback and look for more eco-sustainable strategy to perform organic reaction, recently, we introduced two new procedures using zinc as reducing agent in the preparation of selenols 3 and selenolates 4 starting from diselenides and phenylselenyl halides, respectively. We reported that zinc shavings in a 1:1 mixture of 0.18 N HCl/ Et 2 O at 20°C reduces diselenides affording the corresponding selenols which can be isolated or directly treated with different nucleophiles. 3 In a different way the ttreatment of commercially available PhSeCl with a stoichiometric amount of zinc powder in refluxing THF leads to the corresponding solid and air-stable zinc selenolate 1 through an oxidative insertion of zinc into the selenium-chlorine bond (Scheme 1). 4

Results and Discussion
We now report that these procedures can be conveniently employed to effect the synthesis of vinyl selenides in "on water condition" or using a biphasic acidic system, starting from vinyl halides or substituted alkynes (Scheme 2).

Scheme 2. Strategies used for the vinyl selenides synthesis
The hydroxiselenenylation of alkynes shows high stereoselectivity affording mainly the Z-isomer. The double bond geometry was determined by 1 H NMR spettroscopy and for the 3e and 4e products by the n.O.e. correlation (Table 1). Vinyl selenides have been also achieved by nucleophilic substitution on vinyl halides. These reactions were performed both in THF solution both in water suspension and in this latter case the reactions

ECSOC-14 (2010)
14 th Electronic Conference of Organic Chemistry resulted faster (Table 2). Detailed 1 H and 13 C NMR analyses of products 6a-f and of the corresponding crude mixtures indicated the stereospecific (6a, 6b, 6e and 6f) and the stereselective (6c) formation of one stereoisomer depending on the geometry and the substituents on the double bond. In all the cases, except the ketone (E)-6c, derivates from (Z)-5c and (E)-5d, a geometry retention was observed. DFT calculation have been performed on a model system in order to enlighten the reaction mechanism that seems to be influenced by the preservation of a strongly stabilizing Se-Zn interaction. A Michael Type reaction of zinc-selenolate 1 on activated triple bonds represent another usefull strategy for the regio-and stereoselective synthesis of funtionalyzed vinyl selenide ( Table 3). The resulting alkene because of the presence of a -SePh group resulted unable to give a further addition. Also in this case the reactions performed in "on water" conditions proceed faster and the nature of the electron-withdrawing group seems to have no influence on the course of the reaction. In the absence of the catalyst, 66% of DTT red remained unreacted after 15 min. In contrast, the oxidation reaction was completed in 1 min using L-Selenocystine, the actual amino acid located into the active site of the enzyme. Both 6c and 6b showed to be slower catalyst than L-Sec but similar or even faster than the L-Cys. Further vinyl selenides are under investigation.

Conclusion
In conclusion we present here three different and conveniently strategies for the synthesis of vinyl selenides. These procedures offer significant advantages with regards to operation and yields and thus presents an efficient alternative to the existing methods. Finally, the described procedures demonstrate the synthetic utility of the PhSeZnCl as nucleophilic organoselenium reagent.