New and efficient selenium reagents for stereoselective selenenylation reactions

Article abstract of DOI:10.1039/a804264k

The simple substitution of an aryl proton by a methoxy substituent improves the selectivity of the stereoselective selenenylation reaction dramatically, leading to addition products with diastereomeric ratios up to 50:1 in the methoxyselenenylation reacti

Full text of DOI:10.1039/a804264k

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New and efficient selenium reagents for stereoselective selenenylation reactions
Gianfranco Fragale,a Markus Neuburgerb and Thomas Wirth*a†
a Institut für Organische Chemie der Universität Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
b Labor für Kristallographie, Institut für Anorganische Chemie der Universität Basel, Spitalstr. 51, CH-4056 Basel, Switzerland
The simple substitution of an aryl proton by a methoxy
substituent improves the selectivity of the stereoselective
selenenylation reaction dramatically, leading to addition
products with diastereomeric ratios up to 50:1 in the
methoxyselenenylation reaction of styrene.
From diselenide 2a crystals suitable for X-ray analysis were
obtained. The structure of 2a (Fig. 1)§ is substantially different
from other diselenides bearing heteroatom-containing side-
chains. In other structures we found a strong interaction
between the heteroatom of the sidechain and the selenium atom.
In the structure of 2a a strong interaction with the oxygen of the
methoxy group is observed [Se–O (mean): 2.977 Å] while the
distance from the selenium to the oxygen in the side chain
(4.22 Å) is clearly greater than the sum of the van der Waals
radii (3.40 Å).
As a consequence of these interactions the smallest sub-
stituent, namely the hydrogen atom, is placed in the plane of the
benzene ring. Because solid state geometries may not be
adopted in solution, further structural investigations have been
performed.
The structure in solution has been determined through NOE
measurements of diselenide 2a in [2H6]DMSO. Irradiation at
the frequency of the proton in the 5-position (the proton ortho to
the side chain) showed a strong NOE with the protons of the
methyl group and the proton of the hydroxy group. No
interaction could be detected with the benzylic proton. There-
fore, we suggest that the structure is similar to that in the solid
state.
To analyze the substrate efficiency in stereoselective synthe-
sis, we employed these two diselenides in the methoxy-
selenenylation of styrene. The diselenides 2a,b were trans-
formed in situ into the electrophilic triflates 4a,b by
bromination and exchange of the bromine ion with AgOTf
(Scheme 2). The reaction with 4a yielded b-methoxy selenide
5a with a diastereomeric ratio of 50: 1 in 55% yield.¶ By
carrying out the reaction with 4b bearing an ethyl substituent in
the side chain the addition product 5b was obtained with a
diastereomeric ratio of only 11.5: 1 and 60% yield. This is in
Stereoselective reactions using chiral selenium compounds
have been investigated recently by us1 and other research
groups.2 These reagents can be employed in asymmetric
selenenylation reactions or as ligands in metal-catalyzed
transformations. For this purpose we have developed readily
available chiral diselenides of type 1. Diselenide 1a (R' = H),
Et
R
*
OH
Se)2
OH
Se)2
R′
OMe
1
2
which can be synthesized via a two-step procedure, has already
been used in many stereoselective reactions with good results.
We have shown that an oxygen atom in the chiral side chain in
close proximity to the selenium is responsible for the efficient
transfer of chirality.3
C2-Symmetrical chiral diselenides with an additional chiral
side chain at the second ortho-position are also very efficient
reagents in selenenylation reactions, however, they have to be
prepared by multistep synthesis.2a Because an additional simple
substituent in 1 (R' = Me, CF3) does not improve the selectivity
in the selenenylation reaction,4 we decided to prepare com-
pounds 2 with heteroatom-containing substituents such as the
methoxy group.
Diselenides 2a,b were synthesized from the optically active
alcohols 3a,b, respectively (Scheme 1). Alcohol 3a was
obtained by chiral reduction of 3-methoxyacetophenone with
(2)-B-chlorodiisopinocampheylborane in 97% ee.5 Through
diethylzinc addition to 3-methoxybenzaldehyde catalyzed by
(R,R)-bis{2-[1-(pyrrolidin-1-yl)ethyl]phenyl} diselenide,6 al-
cohol 3b was obtained in 97% ee. The alcohols 3a,b were first
deprotonated with BunLi in the presence of TMEDA and then
lithiated in the ortho-position with an excess of PhLi.7
Successive reaction with selenium and oxidative work-up yields
the diselenides 2a,b in 63 and 47% overall yield, re-
spectively.‡
R
R
OH
OH
Se)2
i–iii
OMe
OMe
3a R = Me
b R = Et
2a R = Me
b R = Et
Scheme 1 Reagents and conditions: i, BunLi, TMEDA; ii, PhLi; iii, Se,
Fig. 1 ORTEP plot of the crystal structure of diselenide 2a. Thermal
O2
ellipsoids are at the 30% probability level.
Chem. Commun., 1998
1867

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R
R
The increased transfer of chirality is due to the forced
interaction of the ortho-oxygen atom with the selenium. An
X-ray diffraction structure and NOE measurements underline
this assumption.
Financial support by the Stipendienfonds der Basler Chemi-
schen Industrie (fellowship for G. F.), the Schweizer Natio-
nalfonds and the Treubel-Fonds (fellowship for T. W.) is
gratefully acknowledged. We thank Professor B. Giese for his
continuing interest and generous support.
OH
i, ii
OH
iii
2
OMe
Ph
Se+
–OTf
Se
OMe
OMe
5a R = Me, 96% de
b R = Et, 84% de
4a R = Me
b R = Et
Scheme 2 Reagents and conditions: i, Br2; ii, AgOTf; iii, styrene, MeOH
Table 1 Results of stereoselective reactions with selenium electrophiles
generated from diselenides 2a and 1
Notes and References
† E-mail: wirth@ubaclu.unibas.ch
Ratio (% yield)
‡ Alcohol 3a (1.37 g, 9 mmol) and TMEDA (1.86 g, 9.6 mmol) were
dissolved in dry pentane (12 ml) under argon, cooled to 0 °C, treated slowly
Entry
Alkene
Product
With 4a With 6
with BunLi (9 mmol, 1.6
min. Then PhLi (27 mmol, 3.0
M
solution in hexane) and allowed to stir for 15
solution in cyclohexane–Et2O) was added
M
OMe
and the mixture was stirred for 14 h. After cooling to 0 °C, selenium powder
(54 mmol, 4.32 g) was added. The mixture was allowed to warm up to room
50:1
(55%)
16:1
(81%)
SeAr*
1
temperature and stirred for an additional 5 h, then 1
M HCl (50 ml) was
OMe
added. After extraction of the resulting mixture with ButOMe (3 3 50 ml)
and drying of the combined organic phases with MgSO4, powdered KOH
(100 mg) was added. The solvent was removed under vacuum and the
residue purified by flash chromatography (silica gel, ButOMe–pentane 1:2)
and recrystallized from EtOH to yield 2a (1.37 g, 66%) as orange crystals:
mp 146–148 °C (Calc. for C18H22O4Se2: C, 46.98; H, 4.82. Found: C, 46.80;
H, 4.90%); [a] +914.5 (c 0.96, CHCl3); dH(CDCl3) 1.26 (t, J 6.5, 6H), 2.22
(br s, 2H), 3.83 (s, 6H), 5.06 (q, 6.5 Hz, 2H), 6.84 (d, J 8.2, 2H), 7.18 (d, J
7.8, 2H), 7.36 (t, J 8.0, 2H); dC(CDCl3) 24.2 (q, 2C), 56.3 (q, 2C), 69.3 (d,
2C), 110.0 (d, 2C), 118.0 (d, 2C), 118.7 (s, 2C), 131.3 (d, 2C), 151.4 (s, 2C),
159.7 (s, 2C); dSe(CDCl3) 365.6; m/z (EI) 462 ([M+], 54%), 230 (60), 214
(100), 214 (100), 198 (28), 182 (16), 134 (35), 107 (22), 91 (26), 77 (21);
n(CHCl3)/cm21 3478, 3376, 3005, 2939, 1568, 1464, 1422, 1136, 1051,
1016.
SeAr*
28:1
5:1
2
3
(45%)
(49%)
F
F
OMe
12:1
(51%)
9:1
(45%)
SeAr*
O
Ph
O
26:1
(54%)
6:1
(41%)
Ph
CO2H
4
5
Ar*Se
O
1.5:1
(42%)
1:1
(60%)
OH
Ar*Se
MeO
MeO
MeO
§ Crystal data for 2a: C18H22O4Se2, M = 460.29, monoclinic, space group
P21, a = 8.1601(5), b = 13.8981(22), c = 16.5883(13) Å, b = 99.903(6)°,
12:1
(66%)
9:1
(66%)
NHBoc
NBoc
SeAr*
6
MeO
U = 1853.2(3) Å3, Z = 4, T = 293 K, l = 1.54180 Å3, Dc = 1.65 g cm23
,
m = 5.28 mm21, for 7767 observed reflections, R1 = 0.0258, wR2
=
0.0313. CCDC 182/957.
¶ The methoxyselenenylations and selenocyclizations were performed as
described in refs. 4 and 8. Selected data for 5a: [a] 21.2 (c 0.55, CHCl3);
dH(CDCl3) 1.48 (d, J 6.5, 3H), 1.65 (br s, 1H), 3.13 (d, J 5.3, 1H), 3.14 (d,
J 8.1, 1H), 3.21 (s, 3H), 3.88 (s, 3H), 4.29 (dd, J 8.1, 5.3, 1H), 5.41 (q, J 5.8,
1H), 6.79 (d, J 8.0, 1H), 7.14 (dd, J 7.8, 0.8, 1H), 7.22–7.35 (m, 6H);
dC(CDCl3) 24.1 (q), 34.9 (t), 56.1 (q), 56.8 (q), 69.8 (d), 83.4 (d), 109.9 (d),
117.1 (s), 118.2 (d), 126.6 (d, 2C), 128.0 (d), 128.5 (d, 2C), 129.7 (d), 141.0
(s), 150.0 (s), 162.8 (s). MS(EI): m/z (%) 366 (18) [M+], 230 (37), 184 (30),
151 (27), 135 (21), 121 (100), 103 (14), 91 (18), 77 (15); n(CHCl3)/cm21
3666, 3382, 3005, 2937, 2838, 1570, 1464, 1431, 1136, 1103, 1052, 1016
(HRMS found: 366.0747. Calc. for C18H22O3Se: 366.0734).
contrast to our previous observations where diselenides bearing
ethyl substituents gave better selectivities than those with
methyl substituents. Comparison of these results with those
obtained using the arylselenenyl triflate 6 generated from
diselenide 1a (16 : 1) showed that selenenyl triflate 4a repre-
sents a more efficient reagent for stereoselective selenenylation
reactions (Table 1).
Encouraged by these results, we carried out further investiga-
tions with the electrophilic selenenyl triflate 4a generated from
diselenide 2a. The methoxyselenenylation reaction of 4-fluoro-
styrene as well as b-methylstyrene showed increased facial
selectivity compared to the reaction with the selenenyl triflate 6
derived from diselenide 1a (entries 2 and 3). The selenolactoni-
zation of the unsaturated carboxylic acid (entry 4) was
improved to a ratio of 26: 1 by using the electrophile 4a. The
product of the cyclization of (E)-hex-3-enol and electrophile 6
(entry 5) was isolated as a racemate.8 Cyclization with 4a
showed a modest facial selectivity of 1.5: 1 in the resulting
product. The stereochemistry of the major diastereomer could
not be assigned in this case. The product of the cyclization of a
carbamate (entry 6) is obtained with a diastereomeric ratio of
12 : 1. After radical removal of the selenium moiety and
deprotection, (S)-salsolidine is obtained.9 The absolute ster-
eochemistry is in all cases the same as that observed with
diselenide 1a.
1 Review: T. Wirth, Liebigs Ann./Recueil, 1997, 2189 and references cited
therein.
2 (a) R. Déziel, E. Malenfant, C. Thibault, S. Fréchette and M. Gravel,
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H. Takada, S.-I. Fukuzawa and S. Uemura, J. Chem. Soc., Chem.
Commun., 1995, 2321; (c) K.-I. Fujita, K. Murata, M. Iwaoka and S.
Tomoda, Tetrahedron, 1997, 53, 2029; (d) T. G. Back and B. P. Dyck,
Chem. Commun., 1996, 2567; (e) S.-I. Fukuzawa, K. Takahashi, H. Kato
and H. Yamazaki, J. Org. Chem., 1997, 62, 7711.
3 T. Wirth, G. Fragale and M. Spichty, J. Am. Chem. Soc., 1998, 120,
3376.
4 T. Wirth and G. Fragale, Chem. Eur. J., 1997, 3, 1894.
5 H. C. Brown, J. Chandrasekharan and P. V. Ramachandran, J. Am. Chem.
Soc., 1988, 110, 1539.
6 T. Wirth, K. J. Kulicke and G. Fragale, Helv. Chim. Acta, 1996, 79,
1957.
7 D. L. Comins and J. D. Brown, J. Org. Chem., 1989, 54, 3730.
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9 T. Wirth and G. Fragale, Synthesis, 1998, 162.
In summary, we present herein a new, readily available
organoselenium reagent bearing a methoxy substituent ortho to
the selenium. The electrophilic methoxyselenenylation of
styrene was performed with a diastereomeric excess of 96%.
Received in Cambridge, UK, 5th June 1998; 8/04264K
1868
Chem. Commun., 1998