Vinylic substitutions promoted by PhSeZnCl: Synthetic and theoretical investigations

Article abstract of DOI:10.1002/ejoc.200900800

Vinyl selenides can be easily obtained through nucleophilic substitution of the corresponding halides by using PhSeZnCl in THF as well as "on water" conditions. The reaction is stereospecific with retention of the alkene geometry. The only exception has b

Full text of DOI:10.1002/ejoc.200900800

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900800
Vinylic Substitutions Promoted by PhSeZnCl: Synthetic and Theoretical
Investigations
Stefano Santoro,[a] Benedetta Battistelli,[a] Lorenzo Testaferri,[a] Marcello Tiecco,[a] and
Claudio Santi*[a]
Keywords: Selenium / Zinc / Vinylic substitution / Nucleophilic substitution / DFT calculations
Vinyl selenides can be easily obtained through nucleophilic
substitution of the corresponding halides by using PhSeZnCl
in THF as well as “on water” conditions. The reaction is ste-
reospecific with retention of the alkene geometry. The only
exception has been observed in the reaction conducted on a
β-chloro-α,β-unsaturated ketone, which afforded the (Z)
product starting from either the (E) or (Z) isomer. DFT calcu-
lations have been performed in order to investigate the reac-
tion mechanism, the stereochemistry of the process and the
role of the zinc atom.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Here we report that 1 can be used for the synthesis of
vinylic selenides starting from the corresponding halides.
Many vinylic sulfide, selenide and telluride preparations in-
volve the use of expensive catalysts or not readily available
starting materials.[6] Moreover, often the products are ob-
tained as mixtures of regio- or stereoisomers. Vinylic sele-
nides are intermediates of great synthetic interest, and their
versatility in organic synthesis is well documented through
the publication of a number of reviews and books.[6b,7] They
combine the functional transformations achieved by the
well-known reactions of organoselenium compounds (e.g.
selenoxides, syn elimination) with the ability of carbon–car-
bon bond-forming reactions involving the double bond, as-
sociated with the capacity of selenium to stabilize adjacent
positive and negative charges (Scheme 1).
Introduction
Phenyl selenolate is one of the most convenient organo-
selenium reagents, and its role in effecting many synthetic
transformation is known.[1] A number of procedures for the
“in situ” generation of selenolates have been reported,[2] but
most of them suffer from serious drawbacks such as bad
smelling, moisture sensitivity, strong basic reaction condi-
tions, use of hazardous organic solvents. Recently, the use
of zinc as reducing agent for the preparation of selenols was
reported,[3] and we demonstrated that treatment of com-
mercially 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[4] (Fig-
ure 1).
Figure 1. Bench-stable selenolate PhSeZnCl (1).
This reagent has been efficiently employed in the ring
opening of epoxides, and we reported also an unexpected
rate acceleration when these reactions were effected by “on
water” conditions.[5]
[a] Dipartimento di Chimica e Tecnologia del Farmaco, Università
di Perugia,
via Del Liceo 1, 06123 Perugia, Italy
Fax: +39-075-5855116
E-mail: santi@unipg.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900800.
Scheme 1. Vinylic selenides as useful synthetic intermediates.
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4921
Eur. J. Org. Chem. 2009, 4921–4925

S. Santoro, B. Battistelli, L. Testaferri, M. Tiecco, C. Santi
SHORT COMMUNICATION
A serious drawback that prevents the preparation on a Table 1. Vinylic substitution by using selenolate 1.
large scale and the use in organic synthesis of vinylic sele-
nides is the lack of simple and efficient methods for their
preparation. We considered vinylic halides as easy and inex-
pensive starting materials, since many methods are available
for their diastereoselective preparation.[8]
Results and Discussion
The starting vinylic halides 2a,g used in the present inves-
tigation are commercially available or were prepared ac-
cording to literature procedures.[9] With these compounds
in hand we started the study by treating the halide 2a with
PhSeZnCl (1) at 25 °C in THF as well as under “on water”
conditions at the same temperature. As already observed
for the ring opening of epoxides, a rate acceleration under
“on water” conditions has also been observed in this case.
Under the latter conditions the starting material was almost
quantitatively consumed after 2 h, whereas in THF solution
the reaction was stopped after 24 h. After determining the
best experimental conditions for the vinylic substitution re-
action, a more detailed study was performed by treating a
[a] (Z)/(E) ratio = 95:5. [b] (Z)/(E) ratio = 91:9. [c] (Z)/(E) ratio =
81:19.
series of functionalized halides 2a–f with 1 (Scheme 2,
1
Table 1). Detailed H and 13C NMR analyses of products
3a–f and of the corresponding crude mixtures indicated the
stereospecific (3a, 3b, 3e, 3f) or stereoselective (3c) forma-
tion of one stereoisomer depending on the geometry and
the substituents on the double bond.
Scheme 3. Chemoselectivity investigation.
leaving group, the solvent and the substituents on the olefin
(particularly the presence and the nature of electron-with-
drawing groups). For this reason we believe that any general
argumentation on this topic can be oversimplifying and
misleading. Since nucleophilic vinylic substitutions with se-
lenium nucleophiles have never been studied by computa-
tional methods and by considering the singularities of our
system, i.e. the presence of zinc, we decided to undertake a
mechanistic study by means of DFT calculations (see Sup-
porting Information for details). In particular, we consid-
ered that in our case the reaction can be significantly influ-
enced by the presence of Zn–O and Zn–Se interactions.
We focused our attention on the substitution of the two
isomers of 3-chloro-1-phenylprop-2-en-1-one (2c,d), the
only example in which both the isomers lead to the (Z)-1-
phenyl-3-(phenylseleno)prop-2-en-1-one (3c). However, due
to limitations in computational resources we decided to use
a model system in which both the phenyl rings of substrate
and nucleophile are replaced by methyl groups (Scheme 4).
Scheme 2. Vinylic substitution of halides.
In all the cases, with the only exception of ketone (E)-
2d that leads mainly to the formation of selenide (Z)-3c, a
geometry retention was observed. Interestingly the reaction
performed starting from the dibromide 2g affords quantita-
tively the product deriving from the nucleophilic substitu-
tion only at the aliphatic carbon atom, even in the presence
of 2.2 equiv. of PhSeZnCl (1; Scheme 3). This clearly indi-
cates that non-activated vinylic halides are almost unreac-
tive toward substitution both in water and THF.
The mechanism of vinylic nucleophilic substitutions has
received considerable attention in the last 40 years.[10] Many
mechanistic variants have been found for this reaction,
ranging from a single-step in-plane substitution, affording
the products stereospecifically with inversion of the config-
uration, to a multi-step process in which the nucleophile
attacks the alkene on the π* orbital giving a tetrahedral
intermediate. The fate of the latter depends especially on
the nature of the leaving group: if it is a poor nucleofuge a
rotation about the Cα–Cβ bond can occur leading to stereo-
convergence. The course of the transformation, however,
depends on several factors such as the nucleophile and the Scheme 4. Model system for computational study.
4922 Eur. J. Org. Chem. 2009, 4921–4925
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Vinylic Substitutions Promoted by PhSeZnCl
Figure 2. Free-energy profile for the vinylic substitution on (Z)-A. The black lines represent the gas-phase reaction, the grey lines include
the solvation contributions in tetrahydrofuran (see Supporting Information for details).
First, we focused our attention on the reaction on (Z)-A (E)-C has an activation energy significantly higher than the
(Figure 2). After the exergonic formation of a substrate– virtual no barrier found for the elimination leading to (Z)-
nucleophile complex, the attack of the nucleophilic sele- C (TS2) (Ea = 15.5 vs. 1.4 kcal/mol in the gas phase and
nium atom occurs perpendicular to the olefin plane leading 15.4 vs. 1.0 kcal/mol in THF). The transition state for the
to tetrahedral intermediate E.
SNVσ mechanism has a prohibitively high activation energy
An early transition state (TS2) allows the elimination of (Ea = 42.4 kcal/mol in the gas phase and 41.5 kcal/mol in
the chlorine atom and the formation of the product (Z)-C. THF), and thus this mechanism can be reasonably ex-
Two possible mechanisms can be envisioned for the forma- cluded. The mechanism of the reaction on the substrate (E)-
tion of the (E) product: (a) the elimination of the chlorine A is similar (Figure 3). The nucleophile attacks the substrate
atom occurs after a rotation of the Cα–Cβ bond; (b) a sin- at the π* orbital to afford a tetrahedral intermediate F. This
gle-step SNVσ reaction in which the nucleophile attacks at can then turn in the intermediate E, passing through low-
the σ* orbital of the C–Cl bond. Transition states have been activation-energy transition states TS6 and TS7 and inter-
found for both possibilities. The transition state for the ro- mediate G. This process seems to be energetically favored by
tation (TS3) leading to a possible formation of the product the preservation of a strongly stabilizing Se–Zn interaction.
Figure 3. Free-energy profile for the vinylic substitution on (E)-A. The black lines represent the gas-phase reaction, the grey lines include
the solvation contributions in tetrahydrofuran (see Supporting Information for details).
Eur. J. Org. Chem. 2009, 4921–4925
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4923

S. Santoro, B. Battistelli, L. Testaferri, M. Tiecco, C. Santi
SHORT COMMUNICATION
Figure 4. Transition states and structures of intermediates. Distances are in Å, relative free energies in kcal/mol. Values in parentheses
include the solvation contributions in tetrahydrofuran.
Intermediate E, as already found in the mechanism of water” conditions. The reaction mechanisms of a β-chloro-
the substitution of the (Z) substrate, can afford the experi- α,β-unsaturated ketone has been computationally investi-
mentally most abundant product (Z)-C by passing through gated on a model system. The preferential formation of the
TS2. Also in this case a transition state (TS9) for an SNVσ (Z) product both when the reaction is performed on the (Z)
mechanism, leading to the same product, has been found, and on the (E) substrate has been explained in terms of
but the extremely high activation energy (Ea = 47.0 kcal/ relative activation energies. The contribution of the solvent
mol in the gas phase and 46.0 kcal/mol in THF) discards has been considered but it has been found to be irrelevant.
any possibility of this mechanism to occur. The formation Finally, these results suggest that the outcome of the reac-
of a small amount of (E)-C can be explained by rotation tion is strongly influenced by the presence of zinc.
about the Cα–Cβ bond leading to a structure with the sele-
nium moiety in a trans relationship to the carbonyl group.
A transition state (TS8) relative to this rotation has been
Experimental Section
found, but again the activation energy is considerably
higher than the one relative to the rotation leading to (Z)-
C (∆Ea = 11.5 kcal/mol in the gas phase and 12.2 kcal/mol
in THF) (Figure 4).
General Procedure for the Reactions Effected in THF: To a solution
of 1 (1.0 mmol) in THF (3 mL), under anhydrous conditions,
1.0 mmol of the vinylic halide 2a–g dissolved in THF (2 mL) was
added. The resulting mixture was stirred at room temperature for
24 h, and the reaction progress was monitored by TLC and GC-
MS. The reaction mixture was then poured into water and ex-
tracted three times with CH2Cl2. The combined organic layers were
Conclusions
We reported the first study of nucleophilic vinylic substi-
tution of a zinc selenolate on vinylic halides by using “on dried with Na2SO4, filtered, and the solvent was removed under
4924
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4921–4925

Vinylic Substitutions Promoted by PhSeZnCl
Mingos), Elsevier, Oxford, 2006, vol. 9, p. 457; g) D. Liotta, U.
Sunay, H. Santiesteban, W. Markievicz, J. Org. Chem. 1981,
46, 2605.
vacuum. The product was purified by flash chromatography. The
yields reported in Table 1 refer to isolated products.
General Procedure for the Reactions Effected under “On Water”
Conditions: 1.0 mmol of 1 and 1.0 mmol of the vinylic halide 2a–g
were poured into 6 mL of water and vigorously stirred at room
temperature for 2 h. Then the water was extracted three times with
CH2Cl2. The combined organic layers were dried with Na2SO4, fil-
tered, and the solvent was removed under vacuum. The product
was purified by flash chromatography. The yields reported in
Table 1 refer to isolated products.
[3] a) L. W. Bieber, F. A. C. P. de Sà, P. H. Menezes, S. M. C. Gon-
calves, Tetrahedron Lett. 2001, 42, 4597; b) B. Movassagh, M.
Shamsipoor, Synlett 2005, 121; c) A. Krief, M. Derock, D. Lac-
roix, Synlett 2005, 2832; d) B. Movassagh, M. Shamsipoor,
Synlett 2005, 1316; e) B. Movassagh, A. Tatar, Synlett 2007,
1954; f) C. Santi, S. Santoro, L. Testaferri, M. Tiecco, Synlett
2008, 1471.
[4] C. Santi, S. Santoro, B. Battistelli, L. Testaferri, M. Tiecco,
Eur. J. Org. Chem. 2008, 5387.
[5] For the first example of rate acceleration under “on water con-
dition”, see: S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin,
H. C. Kolb, K. B. Sharpless, Angew. Chem. Int. Ed. 2005, 44,
3275.
[6] a) G. Perin, E. J. Lenardão, R. G. Jacob, R. B. Panatieri, Chem.
Rev. 2009, 109, 1277 and references cited therein; b) J. V. Com-
asseto, L. W. Ling, N. Petrignani, H. A. Stefani, Synthesis
1997, 373 and references cited therein.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, spectroscopic data of new
compounds, computational details and cartesian coordinates for all
optimized stationary points and transition states.
Acknowledgments
[7] a) “Organoselenium Chemistry: Modern Developments in Or-
ganic Synthesis”, in Top. Curr. Chem. (Ed.: T. Wirth), Springer,
Berlin, 2000, vol. 208; b) Organoselenium Chemistry – A Prat-
ical Approach (Ed.: T. G. Back), Oxford University Press, Ox-
ford, New York, 2000.
[8] a) C. Kuang, H. Senboku, M. Tokuda, Tetrahedron Lett. 2001,
42, 3893; b) N. Kamiya, Y. Chikami, Y. Ishii, Synlett 1990, 675.
[9] a) S. Ma, X. Lu, Z. Li, J. Org. Chem. 1992, 57, 709; b) C.
Kuang, Q. Yang, H. Senboku, M. Tokuda, Tetrahedron 2005,
61, 4043–4052.
Financial support from M.I.U.R. (Ministero Italiano Università e
Ricerca), National Projects PRIN2007 (Progetto di Ricerca d’In-
teresse Nazionale), Consorzio CINMPIS (Consorzio Interuni-
versitario Nazionale di Metodologie e Processi Innovativi di Sin-
tesi), Bari and University of Perugia is gratefully acknowledged.
Prof. A. Macchiarulo and Dr. A. Carotti are acknowledged for
computational resources.
[1] a) R. J. Heffner, J. Jiang, M. M. Joullié, J. Am. Chem. Soc.
1992, 114, 10181; b) B. M. Trost, W. Tang, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 14785; c) M. Tiecco, L. Testaferri, F.
Marini, S. Sternativo, F. Del Verme, C. Santi, L. Bagnoli, A.
Temperini, Tetrahedron 2008, 64, 3337; d) M. R. Detty, Tetra-
hedron Lett. 1978, 19, 5087.
[2] a) K. K. Bashin, N. Singh, R. Kumar, D. G. Deepali, S. K. Me-
tha, T. M. Klapoetke, M.-J. Crawford, J. Organomet. Chem.
2004, 689, 3327; b) M. Yoshimatsu, T. Sato, H. Shimizu, M.
Hori, T. Kataoka, J. Org. Chem. 1994, 59, 1011; c) D. Crich,
D. Grant, J. Org. Chem. 2005, 70, 2384; d) I. Andreadou,
W. M. P. B. Menge, J. N. M. Commandeur, E. A. Worthington,
N. P. E. Vermeulen, J. Med. Chem. 1996, 39, 2040; e) M.
Sakakibara, K. Katsumata, Y. Watanabe, T. Toru, Y. Ueno,
Synthesis 1992, 377; f) T. Wirth, “Selenium”, in Comprehensive
Organometallic Chemistry III (Eds.: R. H. Crabtree, D. M. P.
[10] a) C. F. Bernasconi, Z. Rappoport, Acc. Chem. Res., DOI:
10.1021/ar900048q; b) M.-Y. Lei, K. Fukamizu, Y.-J. Xiao, W.-
M. Liu, S. Twiddy, S. Chiba, K. Ando, K. Narasaka, Tetrahe-
dron Lett. 2008, 49, 4125; c) K. Ando, J. Org. Chem. 2004, 69,
4203; d) K. Ando, M. Kitamura, K. Miura, K. Narasaka, Org.
Lett. 2004, 6, 2461; e) C. Galli, Z. Rappoport, Acc. Chem. Res.
2003, 36, 580; f) R. D. Bach, A. G. Baboul, H. B. Schlegel, J.
Am. Chem. Soc. 2001, 123, 5787; g) C. K. Kim, K. H. Hyun,
C. K. Kim, I. Lee, J. Am. Chem. Soc. 2000, 122, 2294; h) V.
Lucchini, G. Modena, L. Pasquato, J. Am. Chem. Soc. 1995,
117, 2297; i) M. N. Glukhovtsev, A. Pross, L. Radom, J. Am.
Chem. Soc. 1994, 116, 5961; j) Z. Rappoport, Acc. Chem. Res.
1992, 25, 474; k) Z. Rappoport, Acc. Chem. Res. 1981, 14, 7;
l) G. Modena, Acc. Chem. Res. 1971, 4, 73.
Received: July 16, 2009
Published Online: September 1, 2009
Eur. J. Org. Chem. 2009, 4921–4925
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4925