Asymmetric methoxyselenenylations with chiral selenium electrophiles

Article abstract of DOI:10.1002/ejoc.201101373

Very simple, chiral, non-racemic diselenides were prepared and their corresponding selenium electrophiles were used for the stereoselective functionalization of alkenes. The influence of different alkenes on the outcome of the selenenylation reaction was

Full text of DOI:10.1002/ejoc.201101373

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101373
Asymmetric Methoxyselenenylations with Chiral Selenium Electrophiles
Liwei Zhao,[a,b] Zhong Li,[a] and Thomas Wirth*[b]
Keywords: Electrophilic addition / Alkenes / Selenium / Diastereoselectivity
Very simple, chiral, non-racemic diselenides were prepared
and their corresponding selenium electrophiles were used for
the stereoselective functionalization of alkenes. The influ-
ence of different alkenes on the outcome of the selenenyl-
ation reaction was investigated.
able, cheap starting materials in a very short synthesis and
the addition reactions of their corresponding selenium elec-
trophiles to alkenes.
Introduction
The functionalization of alkenes with selenium com-
pounds offers attractive possibilities for synthetic organic
chemistry. Selenium electrophiles are quite powerful and
can easily react with double bonds to generate the corre-
sponding addition products after reaction with a nucleo-
phile.[1] The general reaction is illustrated in Scheme 1. A
variety of nucleophiles have been used to open seleniranium
intermediates 1, and addition products 2 can be used for
many subsequent reactions (Scheme 1). The reaction exhib-
its anti stereoselectivity with the nucleophile attacking usu-
ally at the more highly substituted carbon atom. In a stereo-
selective approach to this reaction, other research groups
and we have investigated stereoselective reactions of alkenes
with chiral selenium electrophiles,[2,3] and also several com-
putational approaches have been made on these reactions.[4]
However, the syntheses of chiral diselenides can be com-
plex, involving many steps or expensive reagents with often
low overall yields.
Results and Discussion
Non-bonding interactions between selenium and hetero-
atoms play a remarkable role in methoxyselenylation, espe-
cially Se···O, Se···N, and Se···S non-bonding interactions.[6]
In many cases the heteroatom is connected to an adjacent
benzylic position, and intermediate species such as 3 are
generated (Figure 1). We have proven such interactions by
various experiments and also by calculations.[4a–4c,7] The
success of larger ring intermediates in related iodine-based
reagents[8] prompted us to investigate similar structures that
can form seven-membered intermediates of type 4, as
shown in Figure 1, by increasing the distance between the
heteroatom and the selenium.
Scheme 1. Selenenylation of alkenes.
Figure 1. Interaction of heteroatoms with selenium electrophiles.
The starting material for the one-step synthesis is bis(2-
hydroxyphenyl) diselenide (6), which is easily prepared from
2-bromophenol (5).[9] A subsequent Mitsunobu reaction
can be successfully used with different chiral alcohols 7 un-
der very mild conditions to generate the required diselen-
ides 8 in high yields (Scheme 2). This reaction proceeds with
clean inversion of the stereocenter, as no diastereomeric di-
selenide was detected by NMR spectroscopy. Unfortu-
nately, mandelic acid ester derivatives 7 (R1 = Ph, R2 = Me)
were found to be oxidized under the reaction conditions
and did not lead to reaction products 8.[10]
Recently, we have reported optically active diselenides
with sulfoxides or ethers as chiral moieties.[5] Herein, we
describe new chiral diselenides prepared from readily avail-
[a] School of Pharmacy,
East China University of Science and Technology,
Shanghai, China
[b] School of Chemistry, Cardiff University,
Park Place, Cardiff, CF10 3AT, UK
Fax: +44-29-20876968
E-mail: wirth@cf.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101373.
7080
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7080–7082

Asymmetric Methoxyselenenylations with Chiral Selenium Electrophiles
The reaction of the selenium electrophile generated from
diselenide 8a showed the highest selectivity of 93:7 (Table 1,
Entry 1), which could be enriched to 95:5 after flash
chromatography.
Then the reactivity towards other alkene substrates was
investigated by using diselenide 8a (Scheme 4). Yields of the
methoxyselenenylation reaction and the diastereomeric ra-
tios of the products are presented in Table 2. In contrast to
other recent results,[5a] 2-chlorostyrene produced a low yield
of the methoxyselenenylated product. 3-Methylstyrene and
β-methylstyrene gave good yields and diastereomeric ratios.
The result using β-methylstyrene is important, because this
means that, unlike other recently investigated com-
pounds,[5b] the electrophile generated from diselenide 8a
will react with disubstituted alkenes and can be used in the
future for selenium-mediated cyclizations.
Scheme 2. Synthesis of diselenides 8.
A typical methoxyselenenylation with the use of disele-
nides 8 proceeds through the generation of the corresponding
selenenyl bromides by addition of bromine to the diselenide,
followed by treatment with silver triflate in methanol. Then
the alkene (styrene) is added to yield the methoxyselenenyl-
ated products, as shown in Scheme 3. Typically, these reac-
tions are performed at –78 °C in dry dichloromethane and
are complete after a reaction time of 2 h. The mixtures of
diastereomers can usually not be separated, and sometimes
they are enriched during flash chromatography. The dia-
stereomeric ratio (dr) was therefore determined by integra-
1
tion of the H NMR signals in the crude reaction mixture.
All chiral diselenides 8 were converted into the addition
products 9 in reasonable yields and with high selectivities,
as shown in Table 1.
Scheme 4. Methoxyselenenylation of alkenes with diselenide 8a.
Table 2. Methoxyselenenylation of alkenes with diselenide 8a.
Entry
Alkene
10, % yield
dr[a]
Ar
R
1
2
3
2-ClC6H4
3-MeC6H4
Ph
H
H
Me
10a, 25
10b, 59
10c, 56
89:11
91:9
92:8
1
[a] The diastereomeric ratios were determined from the H NMR
spectra of the crude reaction mixtures and confirmed after purifica-
tion by column chromatography.
Scheme 3. Methoxyselenenylation of styrene with diselenides 8.
The selectivities observed in the asymmetric methoxy-
selenenylations mentioned above prove the existence of
non-bonding interactions between the selenium electrophile
and the oxygen in the ester moieties in the chiral selenium
electrophiles.
Table 1. Methoxyselenenylation of styrene with thee use of diselen-
ides 8.
Entry
Diselenide
Yield 9 [%]
dr[a]
1
2
3
4
8a
8b
8c
8d
62
55
46
78
93:7[b]
92:8
80:20
83:17
Conclusions
1
[a] The diastereomeric ratios were determined from the H NMR
spectra of the crude reaction mixtures and confirmed after purifica-
tion by column chromatography. [b] 95:5 after flash column
chromatography.
Four new diselenides have been synthesized in only very
few steps from cheap commercial compounds with ester
moieties as substituents of a stereogenic center. The sele-
nium electrophiles, generated from these diselenides, have
been successfully applied in methoxyselenenylation reac-
tions with good yields and diastereomeric ratios. Further
experiments to improve the stereoselectivity of these reac-
tions and related processes and to gain additional insight
into the observed selectivities are in progress.
Diselenide 8c with an isopropyl substituent at the ste-
reogenic carbon atom (R1 = iPr) gave methoxyselenenylated
product 9c with the lowest diastereomeric ratio. The in-
creased size of the isopropyl substituent over that of a
methyl substituent (i.e., 8a and 8b) slightly disturbs the sele-
nium–oxygen interaction. Also, the change of the R2 sub-
stituent from isopropyl (8c) to methyl (8d) does not lead to
a large increase in selectivity. A similar behavior has already
been observed with the size of the R substituent in electro-
philes of type 3.[11] Comparing the reaction products by
using diselenides 8a and 8b revealed that the nature of the
Experimental Section
General Procedure for the Addition of Selenium Electrophiles to
Alkenes: Diselenide 8 (0.1 mmol) was dissolved in dry dichloro-
ester (R2 = Et vs. iPr) does not influence the selectivity. methane (2.5 mL) under an atmosphere of argon, cooled to –78 °C,
Eur. J. Org. Chem. 2011, 7080–7082
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7081

L. Zhao, Z. Li, T. Wirth
SHORT COMMUNICATION
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at –78 °C. The alkene derivative (0.4 mmol) was added. After the
mixture had been stirred for 2 h at –78 °C, saturated NaHCO3
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organic phases were dried with MgSO4 and the solvent was re-
moved under reduced pressure. The residue was purified by column
chromatography on silica gel, yielding the addition products as col-
orless oils. The diastereomers could not be separated by column
chromatography (ethyl acetate/hexane, 5:1).
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Acknowledgments
We thank the China Scholarship Council (CSC) (L.Z.) and the
School of Chemistry, Cardiff University, for support and the
EPSRC National Mass Spectrometry Service Centre, Swansea, for
mass spectrometric data.
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Received: September 20, 2011
Published Online: November 4, 2011
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