A simple zinc-mediated preparation of selenols

Article abstract of DOI:10.1055/s-2008-1078408

Under acidic conditions zinc reduces diselenides to afford selenols, which can be either isolated or treated in situ with alkyl halides to produce alkyl selenides or with epoxides to give β-hydroxyselenides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078408

LETTER
1471
A Simple Zinc-Mediated Preparation of Selenols
Z
inc-Mediated Pr
l
eparati
a
on of Selen
u
ols dio Santi,* Stefano Santoro, Lorenzo Testaferri, Marcello Tiecco
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
Received 12 March 2008
In order to investigate different experimental conditions,
preliminary experiments were carried out using as a mod-
el the reduction of diphenyl diselenide 1a followed by in
situ alkylation of the resulting benzeneselenol 2a with
MeI. The yields, reported in Table 1, were calculated on
the basis of the amount of selenides 12a obtained after pu-
rification by flash chromatography on silica gel.
Abstract: Under acidic conditions zinc reduces diselenides to af-
ford selenols, which can be either isolated or treated in situ with
alkyl halides to produce alkyl selenides or with epoxides to give b-
hydroxyselenides.
Key words: zinc, selenium, nucleophilic substitutions, ring open-
ing, reductions
The complete conversion of diselenide into the corre-
sponding selenol is indicated by the discoloration of the
reaction mixture. Even if for all the experimental proce-
dures reported in Table 1 yields are excellent, the reaction
time for the Se–Se bond hydrogenation seems to be corre-
lated to the pH as well as to the nature of the organic sol-
vent. The best results were obtained using strong acidic
conditions in a biphasic system (H2O–Et2O). Surprisingly
the reaction in an almost homogenous system (conditions
I) was slower than in the 1:1 mixture of water and diethyl
ether, and this result can be explained by the lower solu-
bility of diselenide 1a in MeCN than in Et2O. Using the
experimental conditions A and D, the reaction mixture
was filtered and the organic layer separated, dried over
Na2SO4 and evaporated under vacuum affording the col-
orless benzeneselenol 2a in a quantitative yield which was
Over the last thirty years many important chemical trans-
formations were efficiently achieved using organoseleni-
um intermediates.1 Nowadays the majority of these
compounds is no longer considered as toxic and some of
them can even be used as antioxidants, enzyme inhibitors,
cytotoxic agents for tumor cells, and immunomodulators.2
Reductive cleavage of Se–Se bond has attracted consider-
able attention due to the fact that selenols and selenolate
anions can be used to prepare a large variety of com-
pounds. Several reducing agents including LiAlH4,
NaBH4, Na/NH3, Bu3SnH, Zn/NaOH, Zn/AlCl3, Zn/RuCl3
have been reported for the preparation of the correspond-
ing metal selenolates using basic as well as neutral condi-
tions.3,4
Acidification of selenolates produces, usually in moderate
yields, selenols5 which are known to react with metal salts
giving complexes which have been recently studied for
their anticancer activity.6 Synthetically relevant applica-
tion of benzeneselenol has been recently reported for the
desymmetrization of meso epoxides catalyzed by metal–
salen system, a convenient way to prepare precursors for
the synthesis of enantiomerically enriched allylic alco-
hols.7
Table 1 Preliminary Investigation on the Reduction Conditions
Zn
conditions
MeI
r.t.
r.t.
SeH
SeMe
Se)2
1a
2a
12a
Conditions
Time (h)
Yield (%)
99 2aa or 99 12a
99 12a
A: 2.9 N HCl–Et2O (1:1)
B: 0.18 N HCl–Et2O (1:1)
C: 0.09 N HCl–Et2O (1:1)
D: 2.9 N H2SO4–Et2O (1:1)
E: 0.18 N H2SO4–Et2O (1:1)
F: 0.09 N H2SO4–Et2O (1:1)
G: AcOH–Et2O (1:1)
0.17
0.25
1
In this communication we report that zinc, under acidic
conditions, reduces diselenides 1 affording the selenols 2
which can be either isolated or directly treated with elec-
trophiles 3–7 and 8–11 to give selenides 12–16 or b-hy-
droxyselenides 17–21, respectively (Scheme 1).
80 12a
0.17
0.25
1
99 2aa or 99 12a
99 12a
R2X
R1SeR2
Zn
conditions
3–7
12–16
78 12a
R4
(R1Se)2
R1SeH
2
99 12a
R1Se
R3
R4
r.t.
3 O
R
2
1
H: AcOH
1.5
4
99 12a
8–11
OH
17–21
I: 0.18 N HCl–MeCN (1:1)
L: H2 (3 atm), H2O–Et2O (1:1)
99 12a
Scheme 1 Reductive cleavage of Se–Se bond
96
–
SYNLETT 2008, No. 10, pp 1471–1474
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078408; Art ID: G07908ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8
a No inert conditions are required during the workup. After the evap-
oration of the diethyl ether 2a can be stored under argon at room tem-
perature for several days.

1472
C. Santi et al.
LETTER
characterized by 1H NMR, 13C NMR, and 77Se NMR spec-
tra.
RSe-SeR
yellow
RSeH ZnCl2
colorless
Et2O
H2O
Zn
Diselenide 1a was not reduced by hydrogen (3 atm) in a
mixture 1:1 H2O–Et2O (conditions L) dispelling all
doubts about the possible role of H2 produced as side
product by the reaction of zinc with acid.
ZnCl2
RSe-Zn-SeR
2 HCl
To show the applicability of this simple procedure for the
in situ preparation of selenols, a variety of diselenides 1a–
f were treated with an excess of zinc shavings in a 1:1
mixture of 0.18 N HCl–Et2O (conditions B) at 20 °C. Af-
ter the discoloration of the organic layer, three equivalents
of MeI were added to obtain the corresponding methyl se-
lenides 12a–f. Chemical yields and reaction times, sum-
marized in Table 2, clearly show that this procedure is
compatible with aromatic as well as aliphatic diselenides
Scheme 2 Proposed mechanism for the zinc-mediated diselenide
reduction in a biphasic system
Encouraged by this findings an extensive study of nucleo-
philic substitutions and ring-opening reactions promoted
by the in situ prepared selenol 2a was realized. The results
obtained with a series of different electrophiles are sum-
marized in Table 3.
in the presence of other functional groups, affording in all All the reactions were carried out at room temperature
cases almost quantitative conversion into the correspond- adding an excess of electrophile directly to the reaction
ing selenols.
mixture used to generate selenol 2a. Nucleophilic substi-
tutions on alkyl halides 3–7 proceed in moderate to good
yields depending on the nature of the leaving group and on
the steric hindrance of the carbon in which the substitution
occurs. The results obtained with the primary iodine (3
and 4) and bromine (5 and 6) derivatives were better than
those observed with the secondary bromide 7, suggesting
a plausible SN2 mechanism.
Table 2 Reduction and Alkylation of Diselenides 1a–f
1. Zn, 0.18 N HCl
Et2O, r.t.
(RSe)2
RSeMe
2. MeI, r.t.
1
12a–f
R
Time (h)
0.17
Yield (%)
When selenol 2a, prepared using conditions B and E, was
allowed to react with a series of epoxides (8–11) the ring-
opening reaction to afford b-hydroxyselenides proceeds
generally with very high regioselectivity. The reaction of
styrene oxide 8 with phenylselenolate has already been
described but only few examples of regioselective ring
opening are reported.4d,13 Furthermore in our case the se-
lenium attacks regiospecifically the benzylic carbon af-
fording the 2-phenyl-2-(phenylselenyl)ethanol 17 in a
ratio of 19:1 in respect to the other regioisomer 18. This is
probably due to the acidic conditions, which are responsi-
ble for the initial formation of a stabilized carbocation
which is rapidly attacked by the selenium atom. In the oth-
er cases (9 and 10) the ring opening occurs regiospecifi-
cally on the less-substituted carbon affording derivatives
19 and 20.
1a
12a 99
1b8
0.5
0.5
0.5
12b 99
12c9 95
12d 88
SMe
1c
Br
1d10
N
Ph
The reaction with 1,2-epoxycyclohexane 11 is stereospe-
cific and gives trans-2-(phenylseleno)cyclohexanol 21
using 0.18 N H2SO4. In the case in which 0.18 N HCl was
employed, the formation of trans-2-chlorocyclohexanol,
in a 10% yield, was also observed.
1e11
0.5
0.5
12e 98
12f 89
As an additional example conditions B were used to re-
duce the cyclic diselenide 229 to afford a diselenol (23),
which was alkylated with MeI, CH2Cl2, or MeCHI2 af-
fording, respectively, the bisselenide 24 (94% yield) and
the heterocyclic compounds 25 (57% yield), 26 and 27
(dr = 1:1, 72% yield, Scheme 3).
1f12
O
On the basis of the proposed mechanism, reported on
Scheme 2, the reaction reasonably proceeds through the
initial formation of a water-soluble zinc selenolate which
is rapidly protonated by the acid to give the selenol and the
corresponding zinc salt.
In conclusion, even if zinc, after sodium, is the most com-
monly used reducing metal only few examples describe its
use in the reduction of diselenides. To the best of our
knowledge the results here described represent the first
Synlett 2008, No. 10, 1471–1474 © Thieme Stuttgart · New York

LETTER
Zinc-Mediated Preparation of Selenols
1473
Table 3 Reaction of in situ Generated Selenols 2a with Electrophiles 3–11
Entry
1
Electrophiles
Products
Conditions
B
Time (h)
2
Yield (%)
CH3I
3
PhSeCH3
12a
99
99
78
85
CH3CH2I
PhSeCH2CH3
2
3
4
B
B
B
2
4
13
CH3(CH2)9Br
PhSe(CH2)9CH3
48
72
5
14
CH3(CH2)5Br
Me(CH2)5CH3
6
15
Br
SePh
( )7
5
B
B
72
4
48
78
( )7
7
16
SePh
OH
O
6
7
8
OH
SePh
8
17
19:1
OH
18
O
B
E
4
4
90
99
SePh
9
19
20
21
OH
O
45
72
O
O
SePh
B
E
4
4
10
11
OH
O
SePh
B
E
4
4
60
76
9
fect the reaction with a series of electrophiles thus repre-
senting a convenient way to prepare selenides as well as
b-hydroxyselenides.
i
SeH
SeH
ii
SeMe
SeMe
Se
Se
Further investigation on other kind of reactions and on the
application of these procedures in asymmetric synthesis
are actually on going in our laboratories.
24
23
22
iii
iv
Se
Se
Se
Acknowledgment
Se
Se
Se
Financial support from MIUR, National Projects PRIN2005,
Consorzio CINMPIS, Bari, and University of Perugia is gratefully
acknowledged.
27
25
26
Scheme 3 Synthesis of heterocyclic selenium containing com-
pounds starting from the cyclic diselenide 22. Reagents and conditi-
ons: (i) Zn, 0.18 N HCl–Et2O, 20 °C; (ii) MeI, 20 °C; (iii) CH2Cl2,
Et3N, 20 °C; (iv) CHI2Me, Et3N, 20 °C.
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