Preparation of the first bench-stable phenyl selenolate: An interesting "on water" nucleophilic reagent

Article abstract of DOI:10.1002/ejoc.200800869

In this communication we report the synthesis and the characterization of the first solid and air-stable selenolates, starting from commercially available phenylselenenyl halides and elemental zinc. These reagents were efficiently employed in the ring ope

Full text of DOI:10.1002/ejoc.200800869

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800869
Preparation of the First Bench-Stable Phenyl Selenolate: an Interesting
“On Water” Nucleophilic Reagent
Claudio Santi,*[a] Stefano Santoro,[a] Benedetta Battistelli,[a] Lorenzo Testaferri,[a] and
Marcello Tiecco[a]
Keywords: Selenolate / Zinc / “On water” reactions / Epoxides / Nucleophiles
In this communication we report the synthesis and the char- nucleophilic substitution and addition reactions showing an
acterization of the first solid and air-stable selenolates, start-
ing from commercially available phenylselenenyl halides
and elemental zinc. These reagents were efficiently em-
ployed in the ring opening of epoxides as well as in other
unexpected rate acceleration in water suspension at room
temperature.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
selenides or β-hydroxy selenides, respectively.[7] The SN2
ring opening of epoxides by using selenolate ions is a com-
mon method for preparing β-hydroxy selenides. These com-
pounds are valuable intermediates in the synthesis of allylic
alcohols,[8] olefins,[9] bromohydrins[10] and vinyl sele-
nides.[11] Recently, β-hydroxy selenides were also widely
used for the synthesis of some important natural com-
pounds.[12–16] Several selenium anions can be used for this
purpose like (phenylseleno)silanes,[17] aluminium sele-
nolates,[18] selenoboranes,[19] benzeneselenol in the presence
of alumina[20] and selenostannanes.[21] All these reagents are
relatively unstable, and they should be prepared “in situ”
under controlled anhydrous conditions.
Introduction
Selenium-based methods have developed rapidly over the
past few years, and organoselenium chemistry became a
very useful tool in the hands of synthetic chemists. Various
functionalities can be selectively introduced into complex
molecules under very mild reaction conditions by using
electrophilic as well as radical or nucleophilic selenium rea-
gents.[1]
Among the methods for the introduction of a selenium
moiety into organic molecules the use of selenolate anions
is especially convenient and common. These are usually
formed “in situ” from various precursors, for example by
reductive cleavage of diselenides[2] or by insertion of sele-
nium into organometallic reagents.[3] Several reducing
agents, including LiAlH4, NaBH4, Na/NH3, Bu3SnH, have
been reported for the preparation of the corresponding
metal selenolates under basic as well as neutral condi-
tions.[2] A considerable interest in the clarification of the
chemical properties of organoselenium derivatives pos-
sessing selenium–metal bonds stems from their potential
use as precursors for M/Se materials[4] and their relevance
as models for the active sites of selenocysteine-containing
metalloproteins.[5]
Results and Discussion
Here we report that treatment of commercially available
PhSeCl (1) and PhSeBr (2) with a stoichiometric amount
of zinc powder in refluxing THF leads to the corresponding
zinc selenolates 3 and 4 through an oxidative insertion of
zinc into the selenium–halide bond (Scheme 1).
Despite its well-known reducing properties zinc has been
rarely employed in the preparation of selenols or sele-
nolates.[6] We recently reported that zinc in biphasic acidic
systems reduces diselenides to afford selenols, which can be
isolated or directly treated with halides or epoxides to give
Scheme 1. Oxidative zinc insertion.
Compounds 3 and 4 can be isolated in quantitative yields
by precipitation from Et2O as white amorphous solids (m.p.
Ͼ 300 °C), air-stable for several days. These selenolates were
fully characterized by 1H, 13C and 77Se NMR spectroscopy,
and the latter proved particularly diagnostic for the pres-
ence of an Se–Zn bond (δ = –41 ppm for 3 and δ = –28 ppm
for 4).
[a] Dipartimento di Chimica e Tecnologia del Farmaco, Università
degli Studi di Perugia,
Via del Liceo 1, 06123 Perugia, Italy
Fax: +39-075-5855116
E-mail: santi@unipg.it
URL: http://www.metodifisici.net
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 5387–5390
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5387

C. Santi, S. Santoro, B. Battistelli, L. Testaferri, M. Tiecco
SHORT COMMUNICATION
Some years ago, Xu et al. hypothesized that an
ArSeZnCl compound was formed from the reaction of an
aromatic Grignard salt with ZnCl2 followed by treatment
with grey selenium.[22] The authors described this “in situ”
preparation of selenolates followed by the reaction with
electrophiles to give, in moderate yields, the desired sele-
nides. Nevertheless, our attempts to isolate 3 by using the
above reported procedure starting from PhMgBr failed, and
Figure 1. Competition between electronic (a) and steric (b) effects
controls the regioselectivity of the ring opening reaction.
1
the H NMR spectrum of the reaction mixture showed a
pattern of resonances significantly different from those as-
signed by us to compounds 3 and 4.
a Lewis acid as additive in THF effects negatively the yields
and in some cases also the regioselectivity.
The reaction of a variety of substituted alkyl and aryl
epoxides with PhSeZnCl (3) was then investigated. Table 2
lists the results obtained by treatment of the substrates 5a–
j with selenolate 3 in THF for 24 h and under “on water”
In order to evaluate their nucleophilic properties,
PhSeZnCl (3) and PhSeZnBr (4) were preliminarily em-
ployed in the ring opening of styrene oxide (5a), and the
effects produced by the use of several additives were also
screened (Scheme 2). The results summarized in Table 1
clearly show that in all the cases the selenium attacks re-
gioselectively the benzylic carbon atom to afford mainly 2-
phenyl-2-(phenylselenyl)ethanol (6a) with respect to the
corresponding regioisomer 7a. This is in contrast to the re-
sults obtained with other selenolates,[4d–23] and it probably
indicates that the reaction of styrene oxide with 3 or 4 pro-
ceeds via a partially stabilized carbocation (Figure 1a).
Table 2. SN2 ring opening reaction of epoxides mediated by 3.
Scheme 2. SN2 ring opening mediated by 3 and 4.
Table 1. Preliminary investigation on the best reaction conditions.
Reagent
Solvent
Additive[a]
Time
6a/7a
Yield
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
H2O
ZnBr2
ZnCl2
AlCl3
Yb(OTf)3
Ti(OiPr)4
DMF
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
2 h
60:40
60:40
65:35
70:30
75:25
73:27
60:40
–
80:20
77:23
78:22
–
84%
74%
53%
94%
74%
97%
44%
SnCl2
TiCl4
Al(OTf)3
Zn(OTf)2
Mg(ClO4)2
Cu(OTf)2
Sc(OTf)3
Sm(OTf)3
InBr3
InCl3
In(OTf)3
none
14%
80%
53%
89:11
91:9
25%
87%
34%
34%
30%
100%
20%
100%
79:21
89:11
78:22
88:12
56:44
80:20
none
none
[a] 1.1 equiv.
The best results in terms of regioselectivity and chemical
yields were obtained by using PhSeZnCl (3) at room tem-
perature in THF. When the reaction was carried out in
water suspension a remarkable rate acceleration, similar to
those recently reported by Sharpless et al., was observed.[24]
These preliminary results indicate also that the presence of [a] THF, 20 °C, 24 h. [b] H2O, 20 °C, 2 h. [c] THF, 60 °C, 24 h.
5388 Eur. J. Org. Chem. 2008, 5387–5390
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

First Bench-Stable Phenyl Selenolate
conditions for 2 h. All the reactions were carried out at nolate that shows an interesting and unexpected nucleo-
room temperature with the only exception of α-methylsty- philic reactivity under “on water” conditions.
rene oxide (5b), β-methylstyrene oxide (5c) and cyclopen-
tene oxide (5g), which reacted in THF at 60 °C.
Experimental Section
As can clearly be seen, the reactions under “on water”
conditions are faster and in all the cases more efficient than
those carried out in THF; they afford in only 2 h almost
quantitative yields for all the analyzed substrates. The re-
gioselectivity of the ring-opening reaction is dependent on
the steric and electronic features of the epoxide system. In
the cases of alkyl-substituted derivatives 5e, 5f and 5i the
nucleophilic attack occurs preferentially on the less hin-
dered carbon atom (Figure 1b) to lead to the stereospecific
formation of 7e, 7f and the regioisomers 6i/7i (9:91), respec-
tively.
(Phenylselenenyl)zinc Chloride (3): Zinc (653.9 mg, 10.0 mmol) was
added to a solution of 1 (1.915 g, 10.0 mmol) in THF (20 mL). The
reaction mixture was refluxed for 30 min, and then diethyl ether
(20 mL) was added. The resulting white solid was filtered, washed
3 times with diethyl ether, and the solvent was removed under re-
duced pressure. Yield 2.569 g (100%). M.p. Ͼ300 °C. 1H NMR
(400 MHz, [D8]THF, 25 °C, TMS): δ = 7.45–7.35 (m, 2 CH, Ar),
3
3
6.78 [t, J(H,H) = 6.5 Hz, 1 CH, Ar], 6.70 [t, J(H,H) = 6.5 Hz, 2
CH, Ar] ppm. 13C NMR (100.62 MHz, [D8]THF, 25 °C, TMS): δ =
133.6, 126.6, 123.4 ppm. 77Se NMR (76.27 MHz, [D8]THF, 25 °C,
Me2Se): δ = –41.6 ppm.
On the other hand in the aryl-substituted epoxides 5a, 5c
and 5j the electronic effects overshadow the steric ones of
the bulky aromatic group (Figure 1a), and the selenium at-
tacks selectively the benzylic carbon atom. Only in the case
of the α-methylstyrene oxide (5b) has a poor regioselectivity
been found.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and characterization data for the new
compounds.
Acknowledgments
To highlight and stress the synthetic versatility of this
new nucleophilic reagent, a series of substitution and nucle-
ophilic addition reactions are presently under investigation
in our laboratory.
In Scheme 3 some representative preliminary examples
are summarized, which were obtained by starting from the
aliphatic halides 8, 9, 10, the vinyl bromide 13, 2,4-dini-
trobromobenzene (14), the tosylate 11 and 2-cylohexenone
(18). All the reaction were carried out in water suspension
at the temperature and with the yields indicated in
Scheme 3.
Financial support from M.I.U.R. (Ministero Italiano Università e
Ricerca), National Projects PRIN2005 (Progetto di Ricerca d’In-
teresse Nazionale), Consorzio CINMPIS, Bari (Consorzio In-
teruniversitario Nazionale di Metodologie e Processi Innovativi di
Sintesi) and University of Perugia is gratefully acknowledged.
[1] a) A. Krief, L. Hevesi, Organoselenium Chemistry, Springer-
Verlag, Berlin, 1988, vol. 1; b) A. Krief, in Comprehensive Orga-
nometallic Chemistry (Ed.: B. M. Trost), Pergamon, Oxford,
1991, p. 85; c) “Organoselenium Chemistry: Modern Develop-
ments in Organic Synthesis”, in Top. Curr. Chem., Springer,
Berlin, 2000, vol. 208 (Ed.: T. Wirth); d) Organoselenium Chem-
istry – A Pratical Approach (Ed.: T. G. Back), Oxford Univer-
sity Press, Oxford, New York, 2000; e) T. Wirth, Angew. Chem.
Int. Ed. 2000, 39, 3742.
[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.
Mingos), Elsevier, Oxford, 2006, vol. 9, p. 457.
[3] D. Liotta, U. Sunay, H. Santiesteban, W. Markievicz, J. Org.
Chem. 1981, 46, 2605.
[4] a) J. G. Brennan, T. Siegrist, P. J. Carroll, S. M. Stuczynski,
L. E. Brus, M. L. Steigerwald, J. Am. Chem. Soc. 1989, 111,
4141; b) J. G. Brennan, T. Siegrist, P. J. Carroll, S. M. Stuczyn-
ski, P. Reynders, L. E. Brus, M. L. Steigerwald, Chem. Mater.
1990, 2, 403; c) M. Bochmann, K. J. Webb, M. B. Hursthouse,
M. Mazid, J. Chem. Soc., Dalton Trans. 1991, 2317; d) M.
Bochmann, K. Webb, M. Harman, M. B. Hursthouse, Angew.
Chem. Int. Ed. Engl. 1990, 29, 638; e) M. G. Kanatzidis, S.
Huang, Coord. Chem. Rev. 1994, 130, 509.
Scheme 3. SN2 ring opening mediated by 3 and 4.
[5] a) T. C. Stadtman, Ann. Rev. Biochem. 1990, 59, 11; b) S.-B.
Yu, G. C. Papaefthymiou, R. H. Holm, Inorg. Chem. 1991, 30,
3476; c) N. Ueyama, T. Sugawara, K. Sasaki, A. Nakamura, S.
Yamashita, Y. Wakatsuki, H. Yamazaki, N. Yasuoka, Inorg.
Chem. 1988, 27, 741; d) M. Bochmann, K. J. Webb, M. B.
Hursthouse, M. Mazid, J. Chem. Soc., Chem. Commun. 1991,
Conclusions
We demonstrated that treatment of readyly available and
inexpensive electrophilic selenium species with zinc causes
umpolung on the selenium atom to lead to a stable sele-
Eur. J. Org. Chem. 2008, 5387–5390
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5389

C. Santi, S. Santoro, B. Battistelli, L. Testaferri, M. Tiecco
SHORT COMMUNICATION
1735; e) N. Baidya, B. C. Noll, M. M. Olmstead, P. K. Masch-
arak, Inorg. Chem. 1992, 31, 2999.
[14]
[15]
E. M. Treadwell, J. D. Neighbors, D. F. Wiemer, Org. Lett.
2002, 4, 3639.
T. D. Bagul, G. Lakshmaiah, T. Kawabata, K. Fuji, Org. Lett.
2002, 4, 249.
[6] 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.
[16]
[17]
S. Knapp, D. L. Zhao, Org. Lett. 2000, 2, 4037.
a) M. Tiecco, L. Testaferri, F. Marini, S. Sternativo, F.
Del Verme, C. Santi, L. Bagnoli, A. Temperini, Tetrahedron
2008, 64, 3337; b) M. R. Detty, Tetrahedron Lett. 1978, 19,
5087.
[7] C. Santi, S. Santoro, L. Testaferri, M. Tiecco, Synlett 2008,
1471.
[18]
[19]
[8] K. B. Sharpless, R. F. Lauer, J. Am. Chem. Soc. 1973, 95, 2697.
[9] J. H. Reich, F. Chow, J. Chem. Soc., Chem. Commun. 1975,
1135.
[10] a) M. Sevring, W. Dumont, L. Hevesi, A. Krief, Tetrahedron
Lett. 1976, 17, 2647; b) G. Holzle, W. Jenny, Helv. Chim. Acta
1958, 41, 712.
[11] a) D. Van Ende, W. Dumont, L. Hevesi, A. Krief, Angew.
Chem. Int. Ed. Engl. 1975, 14, 700; b) D. Van Ende, A. Krief,
Tetrahedron Lett. 1976, 17, 457; c) W. Dumont, A. Krief, An-
gew. Chem. Int. Ed. Engl. 1975, 14, 350.
[12] H. Azuma, S. Tamagaki, K. Ogino, J. Org. Chem. 2000, 65,
3538.
a) A. P. Kozikowski, A. Ames, Tetrahedron 1985, 41, 4821; b)
P. A. Bartlett, L. A. McQuaid, J. Am. Chem. Soc. 1984, 106,
7854.
A. Cravador, A. Krief, Tetrahedron Lett. 1981, 22, 2491.
[20] G. H. Posner, D. Z. Rogers, J. Am. Chem. Soc. 1977, 99, 8208.
[21] N. Yutaka, O. Hironori, I. Kazujoshy, S. Noboru, Chem. Lett.
1998, 2, 159.
[22] X. H. Xu, W. Q. Liu, Chin. Chem. Lett. 2002, 13, 283.
[23] Y. Nishiyama, N. Somoda, Mini-Rev. Org. Chem. 2005, 2, 147.
[24] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb,
K. B. Sharpless, Angew. Chem. Int. Ed. 2005, 44, 3275.
Received: September 8, 2008
[13] J. H. Rigby, U. S. M. Maharoof, M. E. Mateo, J. Am. Chem.
Soc. 2000, 122, 6624.
Published Online: October 1, 2008
5390
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5387–5390