Stabilizing effect of intramolecular lewis base toward racemization of optically active selenoxides

Article abstract of DOI:10.1002/hc.20299

2- (Methylchalcogenomethyl)diphenyl selenoxides 1 and 2-{2′-(N,N- dimethylamino)ethyl}-phenyl alkyl (or aryl) selenoxides 2, which were expected to be stabilized toward racemization by intramolecular coordination, were synthesized and optically resolved i

Full text of DOI:10.1002/hc.20299

Heteroatom Chemistry
Volume 18, Number 3, 2007
Stabilizing Effect of Intramolecular Lewis Base
Toward Racemization of Optically Active
Selenoxides
Takahiro Soma, Toshio Shimizu, Kazunori Hirabayashi,
and Nobumasa Kamigata
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University,
Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan
Received 27 February 2006
INTRODUCTION
ABSTRACT: 2-(Methylchalcogenomethyl)diphenyl
selenoxides 1 and 2-{2ꢀ-(N,N-dimethylamino)ethyl}-
Tricoodinated organosulfur compounds with three
phenyl alkyl (or aryl) selenoxides 2, which were
expected to be stabilized toward racemization by
intramolecular coordination, were synthesized and
optically resolved into their enantiomers on an op-
tically active column using high-performance liquid
chromatography. Relationship between the abso-
lute configurations and the chiroptical properties
of the enantiomers was clarified by compar-
ing with those of sulfur analogues. Stabilities
toward racemization of optically active selenox-
ides 1a and 1b were nearly equal to that
of 2-{(N,N-dimethylamino)methyl}diphenyl selenox-
ide and mesityl phenyl selenoxide. The rates of
different substituents have chirality on the cen-
tral sulfur atom, and the chiral sulfur compounds
have been widely studied. Among tricoodinated
organosulfur compounds, many optically active sul-
foxides were synthesized and isolated, and their
structures and reactions have been studied [1–3].
Moreover, asymmetric reactions utilizing optically
active sulfoxide as a chiral source are becoming a
very important technique in recent asymmetric syn-
thesis [4,5]. The formation of optically active se-
lenoxides is also proposed as a key intermediate
in asymmetric synthesis, e.g. optically active allyl
alcohols were synthesized by [2,3] sigmatropic re-
arrangement via optically active selenoxide by the
enantioselective oxidation of corresponding selenide
[6–8].
For the past two decades, we and other research
groups have succeeded in isolating optically active
selenoxides, which were kinetically stabilized by
bulky substituents [9–12]. We have also succeeded
in isolating optically active selenoxides with 2-(N,N-
dimethylaminomethyl)phenyl group [13], which
were stabilized by intramolecular coordination of
amino group to the selenium atom (thermodynamic
stabilization) [14].
racemization for optically active selenoxides
2
were found to be faster than that of 2-{(N,N-
dimethylamino)methyl}phenyl alkyl (or aryl) selenox-
ꢁ
C
ides.
2007 Wiley Periodicals, Inc. Heteroatom Chem
18:301–311, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20299
Correspondence to: Toshio Shimizu; e-mail: shimizu-toshio@
c.metro-u.ac.jp.
It is of interest to investigate the stabilizing
effect of the other intramolecular Lewis base in-
stead of 2-(N,N-dimethylaminomethyl)phenyl group
Contract grant sponsor: Ministry of Education, Science, Sports,
and Culture, Japan.
c
ꢀ
2007 Wiley Periodicals, Inc.
301

302 Soma et al.
toward racemization of optically active selenox-
ides. We prepared unsymmetric selenoxides with 2-
(methylchalcogenomethyl)phenyl group 1a–c and 2-
{2ꢀ-(N,N-dimethylamino)ethyl}phenyl group 2a–c,
which were expected to retard the racemization by
intramolecular coordination of the Lewis base to the
selenium atom. In this paper, the optical resolution
of selenoxides 1 and 2 by HPLC using a chiral col-
umn and the stabilizing effect of the intramolecular
Lewis base toward racemization of the optically ac-
tive selenoxides will be described.
from corresponding selenide in 80% yield. Treat-
ment of 2-(bromomethyl)diphenyl selenoxide with
methylthiomagnesium chloride or methylseleno-
magnesium chloride gave racemic selenoxides 1b
or 1c in 30 and 35% yields, respectively. Selenides
possessing 2-{2ꢀ-(N,N-dimethylamino)ethyl}phenyl
group [13] were synthesized by reacting aryl
Grignard or lithium reagents with diselenide or se-
lenium atom followed by methyl iodide. Racemic
selenoxides 2a–c were obtained by oxidation of the
corresponding selenides with tert-butyl hypochlorite
or m-chloroperbenzoic acid in 34, 24, and 50% yields,
respectively.
When selenoxide 1a was subjected to an
optically active column packed with amylose
carbamate derivative/silica gel (Daicel Chiralpak
AS; 4.5 × 250 mm) using high-performance liquid
chromatography on an analytical scale with hexane/
ethanol (80/20) as eluent, two peaks corresponding
to enantiomers of 1a were observed on the chro-
matogram, as shown in Fig. 1. Similarly, selenoxides
O
O
1a: Ch = O
1b: Ch = S
1c: Ch = Se
2a: R = Ph
2b: R = Bn
2c: R = Me
Se Ph
Se
R
ChMe
NMe2
RESULTS AND DISCUSSION
2-(Methoxymethyl)diphenyl selenide was obtained
in 69% yield by reacting 2-(methoxymethyl)-
phenylmagnesium bromide with diphenyl diselenide
(Scheme 1). Racemic selenoxide 1a was prepared
by oxidation of 2-(methoxymethyl)diphenyl selenide
with tert-butyl hypochlorite in 51% yield (Scheme 1).
2-(Bromomethyl)diphenyl selenoxide was obtained
1b and 2a–c were also resolved into their enan-
tiomers. However, selenoxide 1c could not be re-
solved under similar conditions. It was considered
as one of the reason why 1c was not resolved that a
rapid intramolecular oxygen transfer from selenox-
ide to the selenium atom of methylseleno group in
the column. However, no change was observed on
the 1H NMR spectrum of the eluate of 1c. Therefore,
it is clarified that no oxygen transfer occurred be-
tween two selenium atoms. At the present time, it is
not clear why the chiral recognition was very weak
by the chiral column in the case of selenoxide 1c.
The optical resolution of racemic selenoxide 1a
was carried out at a preparative scale using larger
column (10 × 250 mm) of the same type with the
same eluent. The enantiomer of selenoxide 1a, which
was eluted first, showed a negative specific rotation
{(−)-1a: ee 100%; [α]D –59.8 (c 0.21, CHCl3)}, and the
second-eluted enantiomer of 1a showed a positive
specific rotation {(+)-1a: ee 60%; [α]D + 30.0 (c 0.28,
CHCl3)}. The optical purities were determined by the
HPLC analysis using chiral column. Selenoxide (+)-
1a could not be obtained as an optically pure form
in spite of repeated chromatography, perhaps due to
tailing of the first enantiomer on a preparative scale.
Similarly, selenoxides (−)-1b and (−)-2a–c were
ii
i
1a
Se Ph
OMe
Br
OMe
1b
1c
2a
O
iii
ii
Se Ph
Br
Se Ph
Br
iv
viii
Se Ph
v
NMe2
ix
vi
2b
2c
Se Bn
Br
vii
NMe2
NMe2
viii
Se Me
NMe2
SCHEME 1 i: Mg, THF then PhSeSePh; ii: t-BuOCl, MeOH
then NaOHaq; iii: MeSMgCl, THF; iv: MeSeMgCl, THF; v:
BuLi, THF then PhSeSePh; vi: Mg, THF then BnSeSeBn; vii:
BuLi, THF then Se powder, Mel; viii: t-BuOCl, MeOH then
NaOHaq; ix: m-CPBA, CH2Cl2.
Heteroatom Chemistry DOI 10.1002/hc

Stabilizing Effect of Intramolecular Lewis Base Toward Racemization of Optically Active Selenoxides 303
FIGURE 1 Optical resolution of selenoxides 1a–c and 2a–c on an optically active column packed with amylose carba-
mate derivative/silica gel (Daicel Chiralpak AS; 4.6 × 250 mm) by HPLC on an analytical scale at 25◦C. (a) hexane/ethanol
(80/20), (b) hexane/ethanol (85/15), (c) hexane/ethanol (90/10), (d) hexane/ethanol (75/25), (e) hexane/ethanol (85/15),
and (f) hexane/ethanol (75/25).
obtained from the first eluate, and (+)-1b and (+)-
2a–c from the second eluate. Among those selenox-
ides, (−)-2a–c were isolated in pure form. These
results are summarized in Table 1.
be S-form and (+)-1a was R-form. Similarly, the
absolute configuration of selenoxide (−)-1b was
S-form and (+)-1b was R-form. In cyclohexane, CD
spectra of optically active selenoxides 1a and 1b
were quite similar to those in acetonitrile, respec-
tively, while difference was observed in the case of
sulfoxide 3.
The circular dichroism spectra of selenoxides
(−)-2a–c showed a negative first Cotton effects at
260–280 nm, as shown in Fig. 3. These Cotton ef-
fects corresponded with those of (S)-(−)-4a–c [14].
Therefore, the absolute configurations of selenoxides
(−)-2a–c were assigned to be S-form and those of
(+)-2a–c were R-form.
The absolute configuration of optically pure se-
lenoxide (−)-1a or (−)-2a–c could not be determined
by X-ray analysis, because suitable crystal for X-
ray analysis was not obtained. Therefore, the ab-
solute configuration of selenoxide (−)-1a was as-
signed by comparing the specific rotation and cir-
cular dichroism spectra with those of optically ac-
tive sulfoxide (S)-(−)-3 synthesized by Andersen’s
method [1]. The circular dichroism spectrum of se-
lenoxide (−)-1a showed a negative first Cotton ef-
fect at 266 nm in acetonitrile, as shown in Fig.
2. On the other hand, selenoxide (+)-1a showed
a positive first Cotton effect at the correspond-
ing regions. Sulfoxide (S)-(−)-3 showed a negative
first Cotton effect at 270 nm (Fig. 2), which cor-
responded with well that of selenoxide (−)-1a. In
addition, sulfoxide (S)-(−)-3 was also eluted faster
than (R)-(+)-3 on the optically active column in
the HPLC analysis. Therefore, the absolute con-
figuration of selenoxide (−)-1a was assigned to
O
S
tol-p
OMe
(S)-(−)-3
Stabilities toward racemization of selenoxides
(S)-(−)-1a and (S)-(−)-1b were examined. Selenox-
ides (S)-(−)-1a and (S)-(−)-1b did not racemize
TABLE 1 Optical Resolution and Specific Rotation of Selenoxides 1a, 1b, and 2a–ca
First Eluted Enantiomer
Second Eluted Enantiomer
Compound
Ethanol/%b
[α]D (c)2
ee/%
[α]D (c)2
ee/%
1a
1b
2a
2b
2c
20
15
25
15
25
−59.8 (0.21)
−31.1 (0.11)
−34.2 (0.27)
−20.9 (0.33)
−117.4 (0.10)
100
75
100
100
100
+30.0 (0.28)
+10.8 (0.24)
+21.6 (0.57)
+13.6 (0.22)
+87.7 (0.10)
60
25
60
75
75
aOptical resolution was carried out on an optically active column packed with amylose carbamate derivative/silica gel (Daicel Chiralpak AS;
10 × 250 mm) by HPLC on a preparative scale at 25◦C.
bVolume percentage of ethanol in hexane used as mobile phase.
cSpecific rotations were taken in chloroform at 25◦C.
Heteroatom Chemistry DOI 10.1002/hc

304 Soma et al.
FIGURE 2 Circular dichroism spectra of optically active selenoxides 1a, 1b, and sulfoxide (S)-(−)-3 in acetonitrile or
cyclohexane.
under solvent-free condition for 1 week or in freshly
distilled chloroform solution for 3 days. However,
selenoxides (S)-(−)-1a and (S)-(−)-1b racemized in
methanol containing 20 vol% of water. The de-
crease in the optical purity showed a good lin-
ear relationship with the first-order rate plots. The
first-order rate constants for racemization of se-
lenoxides (S)-(−)-1a and (S)-(−)-1b were 6.10 × 10−5
and 1.70 × 10−4 s−1, respectively. These rate con-
stants were nearly equal to those of selenox-
ides (S)-(−)-4a and (S)-(−)-5 (k1 = 5.13 × 10−5 and
3.34 × 10−5 s−1, respectively) under similar condi-
tions [14,15] (Table 2). These results show that
methoxymethyl and methylthiomethyl groups in se-
lenoxides 1 have similar stabilizing effect toward
racemization by intramolecular coordination with
N,N-dimethylaminomethyl group of selenoxide 4a.
Stabilities toward racemization of selenoxides
(S)-(−)-2a–c were also examined under similar con-
ditions. Selenoxides (S)-(−)-2a–c did not racem-
ize for 1 week under solvent-free conditions. No
racemization of selenoxides (S)-(−)-2a and (S)-(−)-
2b was also observed in freshly distilled chloroform
solution for 3 days. On the other hand, selenox-
ide (S)-(−)-2c racemized in freshly distilled chloro-
form, and the first-order rate constant was deter-
mined to be 2.10 × 10−5 s−1 (Table 3). Selenoxides
(S)-(−)-2a and (S)-(−)-2b racemized in methanol
containing 20 vol% of water. The rate constants for
racemization of selenoxides (S)-(−)-2a and (S)-(−)-
2b were 1.70 × 10−3 and 5.29 × 10−3 s−1, respectively.
On the other hand, selenoxide (S)-(−)-2c racemized
within 1 min under these conditions. Previously,
we reported that the rate constants for racemiza-
tion of selenoxides (S)-(−)-4a–c were 5.13 × 10−5,
3.03 × 10−4, and 1.23 × 10−3 s−1, respectively, in aque-
ous methanol solution [14]. It was found that the
racemization of selenoxides (S)-(−)-2a–c was faster
than selenoxides (S)-(−)-4a–c. In order to under-
stand the experimental results, the structures of se-
lenoxides 2c and 4c were optimized by theoretical
calculations (B3LYP/LANL2DZ). Distances between
O
O
Se
Se
R
Ph
NMe2
(S)-(−)-5
(S)-(−)-4a: R = Ph
(S)-(−)-4b: R = Bn
(S)-(−)-4c: R = Me
Heteroatom Chemistry DOI 10.1002/hc

Stabilizing Effect of Intramolecular Lewis Base Toward Racemization of Optically Active Selenoxides 305
FIGURE 3 Circular dichroism spectra of optically active selenoxides 2a–c and 4a–c in cyclohexane.
selenium and nitrogen atoms of the optimized struc-
tures of selenoxides 2c and 4c were 3.4 and 3.0 A,
CONCLUSION
˚
Selenoxides 1a, 1b, and 2a–c could be optically
resolved into their enantiomers using an optically
active column. The absolute configurations of (−)-
isomers were assigned to be S-form by comparing
their specific rotation, circular dichroism spectra,
and behavior in optical resolution with those of the
sulfur analogues. Selenoxides 1a and 1b were found
to be stabilized toward racemization by intramolec-
ular coordination of the chalcogen atoms to sele-
nium atom and also found to be more stable than se-
lenoxides 2a–c. Thermodynamic stabilization effect
toward racemization by coordination of Lewis bases
to selenium atom forming five-membered ring in 1
and 4a is larger than those forming six-membered
ring in 2.
respectively. The sum of van der Waals radii of ni-
trogen and selenium atoms is 3.4 A. This result in-
dicates that the interaction between selenium and
nitrogen atoms of selenoxide 2c is weaker than that
of selenoxide 4c, and hence thermodynamic stabi-
lization effect by coordination in selenoxide 2c is
less than selenoxide 4c.
˚
TABLE 2 First-Order Rate Constants and Half-Lives for
Racemization of Optically Active Selenoxides (S)-(−)-1a, (S)-
(−)-1b, (S)-(−)-4a, and (S)-(−)-5 in the Solutiona
k (s−1)(t1/2(h))
Solvent (S)-(−)-1a (S)-(−)-1b (S)-(−)-4ab (S)-(−)-5c
CHCl3
Ad
A
A
A
MeOH/ 6.10 × 10−5 1.70 × 10−4 5.13 × 10−5 3.34 × 10−5
EXPERIMENTAL
H2O
Tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl before use. Cyclohexane,
chloroform, dichloromethane, and hexane were
distilled from calcium hydride before use. Methanol
and ethanol were distilled from magnesium cake.
(4/1)
(3.15)
(1.10)
(3.76)
(5.76)
aIn ca. 7 mM solution at 28 1◦C.
bFrom [14].
cFrom [15].
dA, No racemization was observed even after 3 days.
Heteroatom Chemistry DOI 10.1002/hc

306 Soma et al.
TABLE 3 First-Order Rate Constants and Half-Lives for Racemization of Optically Active Selenoxides (S)-(−)-2a–c and
(S)-(−)-4a–c in the Solutiona
k (s−1)(t1/2(h))
Solvent
CHCl3
(S)-(−)-2a
(S)-(−)-2b
(S)-(−)-2c
(S)-(−)-4ab
(S)-(−)-4bb
(S)-(−)-4cb
Ac
A
2.10 × 10−5
A
A
A
(9.41)
MeOH/H2O
(4/1)
1.70 × 10−3
5.29 × 10−3
Bd
5.13 × 10−5
3.03 × 10−4
1.23 × 10−3
(0.11)
(0.037)
(3.76)
(0.63)
(0.16)
aIn ca. 7 mM solution at 28 1◦C.
bFrom [14].
cA, No racemization was observed even after 3 days.
dB, Racemization was completed within 1 min.
Thin-layer chromatography (TLC) was performed
with Merck Art. 5554 DC-Alfolie Kieselgel 60
4.57 (s, 2H), 7.15 (ddd, 1H, J = 7.6, 7.4, 0.9 Hz), 7.25–
7.28 (m, 4H), 7.33–7.35 (m, 1H), 7.42–7.45 (m, 3H);
IR (neat) 3057, 2820, 1578, 1476, 1437, 1380, 1193,
1099, 739, 691 cm−1. MS (EI, 70 ev) m/z: 277 (M+ − 1,
80Se), 275 (M+ − 1, 78Se), 244, 242, 184, 182.
F254
. Column chromatography was performed
with Merck 7734 Kieselgel 60. Gel permeation
chromatography (GPC) was performed using JAI
LC-908 liquid chromatograph with two JAIGEL-1H
columns (20 mm × 600 mm), and the products
were eluted with chloroform. All reactions were
2-(Methoxymethyl)diphenyl Selenoxide (1a)
1
carried out under nitrogen. H, 13C, and 77Se NMR
To a stirred solution of 2-(methoxymethyl)diphenyl
selenide (1.44 g, 5.2 mmol) in methanol (5 mL)
and dichloromethane (30 mL) was added dropwise
tert-butyl hypochlorite (0.60 mL, 5.4 mmol) at
−50◦C. After additional stirring for 40 min at −50◦C,
NaOHaq (2.0 M, 5.0 mL) was added to the reaction
mixture. The solvent was removed in vacuo, and
water was added to the residue. The product was
extracted with dichloromethane, washed with brine,
and dried over magnesium sulfate. After removal
of the solvent in vacuo, purification of the remain-
ing residue by silica gel column chromatography
(dichloromethane/methanol = 10/1) gave selenoxide
1a in 51% yield (753 mg): 1H NMR (500 MHz, CDCl3)
δ 3.36 (s, 3H), 4.39 (d, 1H, J = 12.5 Hz), 4.62 (d, 1H,
J = 12.5 Hz), 7.21 (d, 1H, J = 7.4 Hz), 7.39–7.42 (m,
4H), 7.53 (dd, 1H, J = 7.8, 7.6 Hz), 7.70–7.72 (m,
2H), 8.24 (d, 1H, J = 7.8 Hz); 13C NMR (125 MHz,
CDCl3) δ 57.7, 73.5, 126.0, 127.0, 127.7, 129.2, 129.3,
130.6, 130.7, 136.8, 142.1, 143.4; 77Se NMR (95 MHz,
CDCl3) δ 853; IR (KBr) 3052, 2924, 1629, 1474, 1442,
1385, 1206, 1093, 800, 753, 688 cm−1; UV (cyclohex-
ane) λmax 234 (ε 8.4 × 103), 262 (sh, ε 1.7 × 103); MS
(EI, 30 ev) m/z 277 (M+−O−1, 80Se), 275 (M+−O−1,
78Se), 244, 242, 184, 182; Anal. Calcd for C16H19NOSe:
C, 57.35; H, 4.81; N. Found C, 57.15; H, 4.68.
spectra were measured on a JEOL JNM-LA-500
with Me4Si, Me4Si, and MeSeMe as internal or
external standard, respectively. Elemental analysis
was performed by a Perkin-Elmer 240-C. Melting
points were determined on a Yamato MP-21 melting
point apparatus. UV–VIS spectra were measured on
a UV-3100PC UV–VIS–NIR scanning spectrometer.
IR spectra were measured on a Perkin-Elmer spec-
trum GX FT-IR system. Mass spectra (MS) were
determined on a Jeol JMS-GCMATE system. Cir-
cular dichroism spectra were measured on a Jasco
J-725 spectropolarimeter. Specific rotations were
measured on a Jasco DIP-140 digital polarimeter.
2-(Methoxymethyl)diphenyl Selenide
To a stirred solution of diphenyl diselenide (3.12 g,
10.0 mmol) in THF (20 mL) was added 2-
(methoxymethyl)phenylmagnesium bromide, pre-
pared from 2-(methoxymethyl)bromobenzene (1.85 g,
10.0 mmol) and magnesium (240 mg, 10.0 mmol),
dropwise at 0◦C. After additional stirring for 18 h
at room temperature, the solution was poured into
HClaq (1.0 M, 10 mL) and the product was ex-
tracted with ether. The ether solution was washed
with brine and dried over magnesium sulfate. Af-
ter removal of the solvent in vacuo, purification
of the remaining residue by silica gel column
chromatography (hexane/chloroform = 3/1) gave 2-
(methoxymethyl)diphenyl selenide in 69% yield
2-(Bromomethyl)diphenyl Selenoxide
To a stirred solution of 2-(bromomethyl)diphenyl
selenide (3.31 g, 10.2 mmol) in methanol
(2 mL) and dichloromethane (20 mL) was added
1
(1.94 g); H NMR (500 MHz, CDCl3) δ 3.40 (s, 3H),
Heteroatom Chemistry DOI 10.1002/hc

Stabilizing Effect of Intramolecular Lewis Base Toward Racemization of Optically Active Selenoxides 307
dropwise tert-butyl hypochlorite (1.20 mL, 10.6
solution, 0.50 mL, 1.3 mmol). After additional
stirring for 1 h at room temperature, the solu-
tion was added 2-(bromomethyl)diphenyl selenoxide
(340 mg, 1.0 mmol). After additional stirring for 11
h at room temperature, the solution was poured into
HClaq (1.0 M, 10 mL) and the product was extracted
with dichloromethane. The solution was washed
with brine and dried over magnesium sulfate. After
removal of the solvent in vacuo, purification of the
remaining residue by silica gel column chromatog-
raphy (dichloromethane/methanol = 10/1) gave se-
lenoxide 1c in 35% yield (120 mg):1H NMR
(500 MHz, CDCl3) δ 1.94 (s, 3H), 3.81 (d, 1H,
J = 12.5 Hz), 4.01 (d, 1H, J = 12.5 Hz), 7.35–7.48
(m, 6H), 7.76–7.80 (m, 2H), 7.89 (t, 1H, J = 7.4,
7.4 Hz); 13C NMR (125 MHz, CDCl3) δ 8.6, 36.3,
127.2, 127.5, 127.9, 128.3, 130.4, 130.7, 131.9, 136.4,
141.6, 143.6; 77Se NMR (95 MHz, CDCl3) δ 822, 210;
IR (neat) 3040, 2926, 1573, 1468, 1432, 1012, 810,
743, 679 cm−1; UV (cyclohexane) λmax 230 (ε 7.8 ×
103), 273 (sh, ε 2.0 × 103); MS (EI, 30 ev) m/z 341
(M+−O−1, 80Se 80Se), 339 (M+–O –1, 80Se 78Se), 337
(M+−O−1, 78Se 78Se), 326, 324, 322; Anal. Calcd for
C16H19NOSe: C, 47.23; H, 3.96; N. Found C, 46.98; H,
4.24.
mmol) at 0◦C. After additional stirring for 12 h
at −50◦C, NaOHaq (2.0 M, 10.0 mL) was added to
the reaction mixture. The solvent was removed in
vacuo, and water was added to the residue. The prod-
uct was extracted with dichloromethane, washed
with brine, and dried over magnesium sulfate. After
removal of solvent in vacuo, purification of the
remaining residue by silica gel column chromatog-
raphy (dichloromethane/methanol = 10/1) gave 2-
(bromomethyl)diphenyl selenoxide in 80% yield
1
(2.75 g): H NMR (500 MHz, CDCl3) δ 4.69 (d, 1H,
J = 12.5 Hz), 4.87 (d, 1H, J = 12.5 Hz), 7.21 (d,
1H, J = 7.4 Hz), 7.39–7.42 (m, 4H), 7.53 (dd, 1H,
J = 7.8, 7.6 Hz), 7.70–7.72 (m, 2H), 8.24 (d, 1H,
J = 7.8 Hz); 13C NMR (125 MHz, CDCl3) δ 68.5, 126.2,
127.2, 127.6, 129.1, 129.4, 130.0, 131.7, 136.8, 141.1,
143.4.
2-(Methylthiomethyl)diphenyl Selenoxide (1b)
To a stirred solution of sulfur (32 mg, 1.0 mmol) in
THF (3 mL) was added methylmagnesium chloride
solution (2.60 M diethylether solution, 0.50 mL,
1.3 mmol). After additional stirring for 1 h at room
temperature, the solution was added 2-(bromo-
methyl)diphenyl selenoxide (340 mg, 1.0 mmol). Af-
ter additional stirring for 13 h at room tempera-
ture, the solution was poured into HClaq (1.0 M,
10 mL), and the product was extracted with
dichloromethane. The solution was washed with
brine and dried over magnesium sulfate. After re-
moval of the solvent in vacuo, purification of the
remaining residue by silica gel column chromatog-
raphy (dichloromethane/methanol = 10/1) gave se-
lenoxide 1b in 30% yield (87 mg): 1H NMR (500 MHz,
CDCl3) δ 1.96 (s, 3H), 3.69 (d, 1H, J = 13.8 Hz), 3.81
(d, 1H, J = 13.8 Hz), 7.24 (dd, 1H, J = 7.8, 1.0 Hz),
7.38 (ddd, 1H, J = 7.8, 7.3, 1.0 Hz), 7.41–7.45 (m,
4H), 7.76–7.78 (m, 2H), 7.98 (dd, 1H, J = 7.8, 1.2
Hz); 13C NMR (125 MHz, CDCl3) δ 14.6, 36.3, 127.0,
127.4, 128.9, 129.3, 130.0, 130.7, 130.9, 137.4, 142.6,
142.8; 77Se NMR (95 MHz, CDCl3) δ 838; IR (neat)
3053, 2906, 1573, 1473, 1439, 1022, 813, 734, 689
cm−1; UV (cyclohexane) λmax 237 (ε 8.2. × 103), 267
(sh, ε 1.8 × 103); MS (EI, 30 ev) m/z 293 (M+−O−1,
80Se), 291 (M+−O−1, 78Se), 278, 276, 244, 242; Anal.
Calcd for C16H19NOSe: C, 54.37; H, 4.56; N. Found
C, 54.41; H, 4.54.
2-{2ꢀ-(N,N-Dimethylamino)ethyl}diphenyl
Selenide
To a stirred solution of 2-{2ꢀ-(N,N-dimethylamino)-
ethyl}bromobenzene (1.14 g, 5.0 mmol) in THF
(20 mL) was added dropwise butyllithium solution
(1.6 M hexane solution, 3.3 mL, 5.3 mmol) at −50◦C.
After the solution was stirred for 30 min at −50◦C,
a stirred solution of diphenyl diselenide (1.56 g,
5.0 mmol) in THF (20 mL) was added dropwise
to the solution at −30◦C, and stirring was contin-
ued for an additional 17 h at room temperature.
The solution was poured into water, and the prod-
uct was extracted with ether. The ether solution
was washed with brine and dried over magnesium
sulfate. After removal of the solvent in vacuo, pu-
rification of the remaining residue by silica gel col-
umn chromatography (chloroform) gave 2-{2ꢀ-(N,N-
dimethylamino)ethyl}diphenyl selenide in 68% yield
1
(1.04 g): H NMR (500 MHz, CDCl3) δ 2.27 (s, 6H),
2.48–2.51 (m, 2H), 2.95–2.98 (m, 2H), 7.08 (ddd, 1H,
J = 7.5 Hz, 7.3 Hz, 1.6 Hz), 7.21–7.28 (m, 5H), 7.37–
7.39 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 4.2, 45.2,
60.6, 127.0, 127.1, 128.1, 129.3, 129.9, 131.3, 131.5,
132.4, 134.8, 142.2; IR (neat) 2939, 2816, 2766, 1577,
1435, 1438, 1052, 1021, 737, 690 cm−1; MS (EI, 70
ev) m/z 304 (M+−1, 80Se), 302 (M+−1, 78Se), 257, 255,
244, 242.
2-(Methylselenomethyl)diphenyl Selenoxide (1c)
To a stirred solution of selenium powder (78 mg,
1.0 mmol) in THF (3 mL) was added dropwise
methylmagnesium chloride solution (2.60 M ether
Heteroatom Chemistry DOI 10.1002/hc

308 Soma et al.
70 ev) m/z: 318 (M+−1, 80Se), 316 (M+−1, 78Se), 275,
2-{2ꢀ-(N,N-Dimethylamino)ethyl}diphenyl
Selenoxide (2a)
273, 245, 243.
To a stirred solution of 2-{2ꢀ-(N,N-dimethylamino)-
ethyl}diphenyl selenide (1.04 g, 4.5 mmol) in
methanol (60 mL), dropwise tert-butyl hypochlorite
(0.50 mL, 4.5 mmol) at −50◦C was added. After
additional stirring for 40 min at −50◦C, NaOHaq
(2.0 M, 4.5 mL) was added to the reaction mix-
ture. The solvent was removed in vacuo, and water
was added to the residue. The product was extracted
with dichloromethane, washed with brine, and dried
over magnesium sulfate. After removal of the sol-
vent in vacuo, purification of the remaining residue
by silica gel column chromatography (methanol)
Benzyl 2-{2ꢀ-(N,N-dimethylamino)ethyl}phenyl
Selenoxide (2b)
To a stirred solution of benzyl 2-{2ꢀ’-(N,N-dimethyl-
amino)ethyl}phenyl selenide (381 mg, 1.2 mmol) in
dichloromethane (5 mL) was added by portions m-
chloroperbenzoic acid (290 mg, 1.8 mmol) at 0◦C.
After additional stirring for 5 h at room temperature,
the reaction mixture was poured into sat. NaHCO3aq
.
The product was extracted with dichloromethane,
washed with brine, and dried over magnesium sul-
fate. After removal of the solvent in vacuo, purifi-
cation of the remaining residue by gel permeation
chromatography gave selenoxide 2b in 24% yield (85
1
gave selenoxide 2a in 50% yield (517 mg): H NMR
(500 MHz, CDCl3) δ 2.23 (s, 6H), 2.34–2.39 (m, 1H),
2.50–2.55 (m, 1H), 2.87–2.98 (m, 2H), 7.25–7.26 (m,
1H), 7.41–7.45 (m, 5H), 7.66–7.67 (m, 2H), 7.96–7.98
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 32.0, 45.4,
60.6, 126.2, 127.1, 128.0, 129.5, 129.8, 131.0, 131.3,
139.5, 142.0, 143.1; 77Se NMR (95 MHz, CDCl3) δ
840; IR (neat) 3053, 2945, 2821, 2780, 1469, 1441,
1052, 825, 747, 689 cm−1; UV (cyclohexane) λmax
223 (ε 7.4 × 103), 251 (sh, ε 1.5 × 103); MS (EI, 30
ev) m/z 303 (M+−O−2, 80Se), 301 (M+−O−2, 78Se),
257, 255, 244, 242 ; Anal. Calcd for C16H19NOSe: C,
60.00; H, 5.98; N, 4.37. Found C, 60.34; H, 6.22; N,
4.59.
1
mg); mp 130–132◦C, H NMR (500 MHz, CDCl3) δ
2.20 (s, 6H), 2.20–2.29 (m, 1H), 2.40–2.51 (m, 3H),
3.99 (d, 1H, J = 11.3 Hz), 4.20 (d, 1H, J = 11.3 Hz),
6.95–6.97 (m, 2H), 7.17–7.27 (m, 4H), 7.39–7.42 (m,
2H), 7.79–7.82 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 31.7, 45.5, 59.1, 60.7, 125.7, 127.8, 128.1, 128.5,
129.2, 129.7, 130.1, 131.2, 139.8, 139.8; 77Se NMR
(95 MHz, CDCl3) δ 866; IR (neat) 2978, 2946, 2778,
1653, 1467, 1454, 1264, 1052, 811, 765, 696 cm−1;
UV (cyclohexane) λmax 238 (ε 7.7 × 103), 273 (sh, ε
4.0 × 103); MS (EI, 30 eV) m/z: 318 (M+−O−1, 80Se),
316 (M+−O−1, 78Se), 275, 273, 245, 243; Anal. Calcd
for C17H21NOSe: C, 61.17; H, 6.33; N, 4.19. Found: C,
61.09; H, 6.49; N, 4.59.
Benzyl 2-{2ꢀ-(N,N-dimethylamino)ethyl}phenyl
Selenide
2-{2ꢀ-(N,N-Dimethylamino)ethyl}phenyl Methyl
Selenide
To a stirred solution of dibenzyl diselenide (1.71 g,
5.0 mmol) in THF (30 mL) was added 2-{2ꢀ-(N,N-
dimethylamino)ethyl}phenylmagnesium bromide,
prepared from 2-{2ꢀ-(N,N-dimethylamino)ethyl}-
bromobenzene (1.14 g, 5.0 mmol) and magnesium
(115 mg, 5.0 mmol), dropwise at 0◦C. After addi-
tional stirring for 16 h at room temperature, the so-
lution was poured into HClaq (1.0 M, 10 mL). Aque-
ous layer was washed with ether. NaOHaq (2.0 M, 10
mL) was added to aqueous layer, and the product
was extracted with dichloromethane, washed with
brine and dried over magnesium sulfate. After re-
moval of the solvent in vacuo, purification of the re-
maining residue by gel permeation chromatography
gave benzyl 2-{2ꢀ-(N,N-dimethylamino)ethyl}phenyl
selenide in 24% yield (381 mg): 1H NMR (500 MHz,
CDCl3) δ 2.27 (s, 6H), 2.37–2.40 (m, 2H), 2.83–2.86
(m, 2H), 4.06 (s, 2H), 7.09–7.25 (m, 8H), 7.49 (d, 1H,
J = 7.7 Hz); 13C NMR (125 MHz, CDCl3) δ 31.7, 45.4,
49.1, 60.7, 125.8, 127.9, 128.2, 128.6, 129.1, 129.3,
129.8, 130.2, 131.3, 140.0; IR (neat) 3060, 2937, 2856,
2779, 1494, 1263, 1038, 910, 751, 696 cm−1. MS (EI,
To a stirred solution of 2-{2ꢀ-(N,N-dimethylamino)-
ethyl}bromobenzene (1.47 g, 6.4 mmol) in THF
(30 mL) was added dropwise butyllithium solu-
tion (1.60 M hexane solution, 8.2 mL, 13 mmol) at
−60◦C. After the solution was stirred for an addi-
tional 30 min, selenium powder (505 mg, 6.4 mmol)
was added by portions to the solution at −40◦C. Af-
ter disappearance of selenium powder, iodomethane
(0.40 mL, 6.4 mmol) was added to the solution,
and stirring was continued for an additional 4 h
at room temperature. The solution was poured
into water, and the product was extracted with
ether. The ether solution was washed with brine
and dried over magnesium sulfate. After removal
of the solvent in vacuo, purification of the re-
maining residue by silica gel column chromatogra-
phy (ethyl acetate/methanol = 3/1) gave 2-{2ꢀ-(N,N-
dimethylamino)ethyl}phenyl methyl selenide in 34%
yield (531 mg): 1H NMR (500 MHz, CDCl3) δ 2.29 (s,
3H), 2.32 (s, 6H), 2.21–2.54 (m, 2H), 2.89–2.93 (m,
Heteroatom Chemistry DOI 10.1002/hc

Stabilizing Effect of Intramolecular Lewis Base Toward Racemization of Optically Active Selenoxides 309
2H) 7.11–7.20 (m, 3H), 7.32–7.35 (m, 1H); 13C NMR
−6.9 × 103), 249 ([θ] +9.8 × 103), 221 ([θ] −3.6 ×
104) nm; CD (acetonitrile): λmax 270 ([θ] −4.0 × 103),
220 ([θ] −1.2 × 104) nm; [α]D −78.9 (c 0.12, CHCl3),
(125 MHz, CDCl3) δ 7.0, 33.9, 45.4, 60.4, 126.2, 127.0,
128.3, 129.3, 129.8, 140.3; IR (neat) 2941, 2766, 1567,
1535, 1463, 1372, 1266, 1144, 1053, 908, 747 cm−1;
MS (EI, 70 eV) m/z: 242 (M+−1, 80Se), 240 (M+−1,
78Se), 198, 196, 168, 166, 105, 91, 77.
1
[α]435−123.3 (c 0.12, CHCl3); H NMR (500 MHz,
CDCl3) δ 2.36 (s, 3H), 3.34 (s, 3H), 4.47 (d, 1H,
J = 13.6 Hz), 4.63 (d, 1H, J = 13.6 Hz), 7.24 (d, 2H,
J = 8.0 Hz), 7.40 (dd, 1H, 7.5 Hz, 1.5 Hz), 7.44 (td,
1H, J = 7.5 Hz, 1.5 Hz), 7.49 (td, 1H, J = 7.5 Hz,
1.5 Hz), 7.53 (d, 2H, J = 8.0 Hz), 7.75 (dd, 1H,
J = 7.5 Hz, 1.5 Hz); 13C NMR (125 MHz, CDCl3) δ
21.3, 43.3, 64.1, 125.6, 128.1, 128.2, 129.5, 130.1,
137.1, 139.2, 142.5; 77Se NMR (95 MHz, CDCl3) δ
812; IR(neat) 2930, 1468, 1441, 1250, 1143, 1051,
820 cm−1; UV (cyclohexane) λmax 206 (ε 4.5 × 104),
240 (sh, ε 1.2 × 104); MS (EI, 30eV) m/z: 260
(M+), 244, 229, 213, 199, 123, 91; Anal. Calcd for
C15H16O2S: C, 69.20; H, 6.19. Found: C, 69.31; H,
6.35.
2-{2ꢀ-(N,N-Dimethylamino)ethyl}phenyl methyl
selenoxide (2c)
To a stirred solution of 2-{2ꢀ-(N,N-dimethylamino)-
ethyl}phenyl methyl selenide (531 mg, 2.2 mmol) in
a methanol (50 mL) was added dropwise tert-butyl
hypochlorite (0.35 mL, 2.2 mmol) at −40◦C. After
additional stirring for 40 min at −40◦C, NaOHaq
(2.0 M, 3.0 mL) was added to the reaction mix-
ture. The solvent was removed in vacuo, and water
was added to the residue. The organic component
was extracted with dichloromethane, washed with
brine, and dried over magnesium sulfate. After the
solvent was removed in vacuo, purification of the
remaining residue by silica gel column chromatog-
raphy (methanol) gave selenoxide 2c in 34% yield
(193 mg): 1H NMR (500 MHz, CDCl3) δ 2.24 (s, 6H),
2.44–2.48 (m, 1H), 2.58–2.62 (m, 1H), 2.62 (s, 3H),
2.75–2.78 (m, 1H), 2.88–2.92 (m, 1H), 7.25 (dd, 1H,
J = 7.3 Hz, 1.2 Hz), 7.43 (ddd, 1H, 8.2 Hz, 6.9 Hz,
1.2 Hz), 7.48 (ddd, 1H, J = 8.2 Hz, 7.3 Hz, 1.2 Hz),
8.00 (dd, 1H, J = 6.9 Hz, 1.2 Hz); 13C NMR (125 MHz,
CDCl3) δ 32.3, 37.3, 45.7, 64.1, 125.3, 128.0, 129.5,
131.1, 139.2, 142.5; 77Se NMR (95 MHz, CDCl3) δ 812;
IR(neat) 2930, 2786, 1650, 1468, 1441, 1261, 1144,
1051, 803, 762 cm−1; UV (cyclohexane) λmax 214 (ε
1.3 × 104), 260 (sh, ε 5.2 × 103); MS (EI, 30eV) m/z:
242 (M+−O−1, 80Se), 240 (M+−O−1, 78Se), 199, 197,
169, 167; Anal. Calcd for C11H17NOSe: C, 51.17; H,
6.64; N, 5.42. Found: C, 51.09; H, 6.49; N, 5.59.
Typical Procedure for Optical Resolution of
Racemic Selenoxides by Means of
High-Performance Liquid Chromatography
Using an Optically Active Column
Racemic selenoxide (20 mg) in eluent (0.3 mL)
was applied to an optically active column packed
with amylose carbamate derivative/silica gel (Daicel
Chiralpak AS; 10 × 250 mm) and eluted with hexane
containing 20 (for 1a), 15 (for 1b), 25 (for 2a), 15
(for 2b), and 25 (for 2c) vol% ethanol at a flow rate
of 1.0 mL min−1. About 5 mg of each optically active
selenoxide was collected from the first- and second
elutes, respectively. Their optical purities were deter-
mined by the HPLC analysis using the same type of
chiral column (4.6 × 250 mm) at an analytical scale.
(S)-(−)-2-(Methoxymethyl)diphenyl Selenoxide
{(S)-(−)-1a}. Pale yellow oil; 100% ee; CD (cyclo-
hexane): λmax 266 ([θ] −7.8 × 103), 227 ([θ]
−3.6 × 105) nm; CD (acetonitrile): λmax 260 ([θ]
−8.1 × 103), 229 ([θ] −3.4 × 105) nm; [α]D −59.8 (c
(S)-(−)-2-(Methoxymethyl)-4ꢀ-methyldiphenyl
Sulfoxide ((S)-(−)-3)
To a stirred solution of 2-(S)s-(−)-menthyl-(−)-p-
toluenesufinate (100% ee; 178 mg, 0.60 mmol) in
THF (3 mL) was added 2-(methoxymethyl)phenyl-
magnesium bromide, prepared from 2-(methoxy-
methyl)bromobenzene (114 mg, 0.72 mmol) and
magnesium (16 mg, 0.70 mmol), dropwise at 0◦C.
After additional stirring for 3 h at room tempera-
ture, the mixture was poured into brine. The prod-
uct was extracted with ether, washed with brine,
and dried over magnesium sulfate. After the sol-
vent was removed in vacuo, purification of the re-
maining residue by gel permeation chromatography
gave sulfoxide (S)-(−)-3 in 57% yield (90 mg): col-
orless oil; 96% ee; CD (cyclohexane): λmax 278 ([θ]
1
0.21, CHCl3), [α]435−159.8 (c 0.21, CHCl3). H NMR
and UV spectra were similar to that of the racemic
one.
(R)-(+)-2-(Methoxymethyl)diphenyl Selenoxide
{(R)-(+)-1a}. Pale yellow oil; 60% ee; CD (cyclo-
hexane): λmax 265 ([θ] +3.0 × 103), 227 ([θ] +
3.0 × 105) nm; CD (acetonitrile): λmax 261 ([θ] +
2.8 × 103), 228 ([θ] + 2.8 × 105) nm; [α]D + 30.0 (c
0.28, CHCl3), [α]435 + 119.8 (c 0.28, CHCl3). 1H NMR
and UV spectra were similar to that of the racemic
one.
Heteroatom Chemistry DOI 10.1002/hc

310 Soma et al.
ee; CD (cyclohexane): λmax 260 ([θ] +6.3 × 103), 229
([θ] −7.0 × 103) nm; [α]D +87.7 (c 0.10, CHCl3),
[α]435+201.6 (c 0.10, CHCl3). 1H NMR and UV
spectra were similar to that of the racemic one.
(S)-(−)-2-(Methylthiomethyl)diphenyl Selenoxide
{(S)-(−)-1b}. Pale yellow oil; 75% ee; CD (cyclo-
hexane): λmax 227 ([θ] −1.4 × 104) nm; CD (acetoni-
trile): λmax 262 ([θ] − 3.0 × 103), 230 ([θ] −1.1 × 104)
nm; [α]D − 31.1 (c 0.11, CHCl3), [α]435 − 86.2 (c 0.11,
CHCl3). 1H NMR and UV spectra were similar to that
of the racemic one.
Kinetic Studies for Racemization of Optically
Active Selenoxides
(R)-(+)-2-(Methylthiomethyl)diphenyl Selenoxide
{(R)-(+)-1b}. Pale yellow oil; 25% ee; CD (cyclo-
hexane): λmax 228 ([θ] + 4.6 × 103) nm; CD (acetoni-
trile): λmax 228 ([θ] + 3.2 × 103) nm; [α]D + 10.8 (c
Kinetic studies on the racemization of optically
active selenoxides (S)-(−)-1a, (S)-(−)-1b,(S)-(−)-2a,
(S)-(−)-2b, and (S)-(−)-2c were examined in chloro-
form and in methanol/water = 4/1 (ca. 7 mM) at 28◦C.
The rates of the racemization were calculated based
on their specific rotation and plotted according to
the first-order rate equation.
1
0.24, CHCl3), [α]435 + 28.8 (c 0.24, CHCl3). H NMR
and UV spectra were similar to that of the racemic
one.
(S)-(−)-2-{2ꢀ-(N,N-Dimethylamino)ethyl}diphenyl
Selenoxide {(S)-(−)-2a}. Pale yellow oil; 100% ee;
CD (cyclohexane): λmax 275 ([θ] − 3.8 × 103), 231
([θ] − 1.1 × 104) nm; [α]D − 34.2 (c 0.27, CHCl3),
[α]435 − 73.5 (c 0.27, CHCl3). 1H NMR and UV
spectra were similar to that of the racemic one.
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−20.9 (c 0.33, CHCl3), [α]435 −56.0 (c 0.33, CHCl3).
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([θ] +2.8 × 103), 239 ([θ] −2.6 × 104) nm; [α]D +13.6
(c 0.22, CHCl3), [α]435 +45.1 (c 0.22, CHCl3). 1H NMR
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(S)-(−)-2-{2ꢀ-(N,N-Dimethylamino)ethyl}phenyl
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229 ([θ] +5.2 × 103) nm; [α]D −117.4 (c 0.10, CHCl3),
[α]435 −264.8 (c 0.10, CHCl3). 1H NMR and UV spec-
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Heteroatom Chemistry DOI 10.1002/hc

Stabilizing Effect of Intramolecular Lewis Base Toward Racemization of Optically Active Selenoxides 311
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Heteroatom Chemistry DOI 10.1002/hc