Catalytic asymmetric oxidation of sulfides to sulfoxides mediated by chiral 3-substituted-1,2-benzisothiazole 1,1-dioxides

Full text of DOI:10.1021/jo0003100

6756
J . Org. Chem. 2000, 65, 6756-6760
Sch em e 1
Ca ta lytic Asym m etr ic Oxid a tion of Su lfid es
to Su lfoxid es Med ia ted by Ch ir a l
3-Su bstitu ted -1,2-ben zisoth ia zole
1,1-Dioxid es
Donald Bethell,† Philip C. Bulman Page,*,‡ and
Hooshang Vahedi‡
Department of Chemistry, University of Liverpool, Liverpool
L69 3BX, England, and Department of Chemistry,
Loughborough University, Loughborough,
Leicestershire LE11 3TU, England
p.c.b.page@lboro.ac.uk
Received March 6, 2000
Optically active sulfoxides are useful chiral synthons1
and auxiliaries2 in asymmetric synthesis. We have
reported the use of a number of mediators for sulfur
oxidation, including several based upon 3-substituted-
1,2-benzisothiazole 1,1-dioxides, using hydrogen peroxide
as the oxidant.3 Study of the 3-n-butyl [1], (()-3-sec-butyl
[2], and 3-tert-butyl [3] compounds in dichloromethane,
in the presence of a 4-fold excess of hydrogen peroxide
and base over the sulfide substrates, showed that oxida-
tion to the sulfoxides occurred in good yield, the tert-butyl
compound being particularly active in promoting oxygen
transfer. In this paper are described the syntheses,
reactions, and enantioselective oxidations mediated by
chiral nonracemic 3-substituted-1,2-benzisothiazole 1,1-
dioxides [4-6] using hydrogen peroxide as the primary
oxidant.
Sch em e 2
1′-menthyl]-1,2-benzisothiazole 1,1-dioxide [4a ] and (+)-
3-[(1′S)-1′-menthyl]-1,2-benzisothiazole 1,1-dioxide [4b],
together with a third compound. The diastereoisomer
ratio 4a :4b, determined by integration of the signals in
the 1H NMR spectrum corresponding to the methine
protons adjacent to the heterocyclic ring, which appear
at 3.1 and 3.7 ppm, respectively, was 3:1. Separation of
these compounds was carried out by column chromatog-
raphy using dichloromethane/hexane (2:1). The structure
of the unknown third compound was shown on the basis
of elemental analysis, NMR spectroscopy and X-ray
crystallography to be 3-menthoxy-1,2-benzisothiazole 1,1-
dioxide [4c]. Single-crystal X-ray structures of imines 4a
and 4b were also determined.
The chiral nonracemic 3-substituted-1,2-benzisothia-
zole 1,1-dioxides [4-6] were synthesized by treatment
of the corresponding chiral organometallic compounds
with ethoxy [7] or chloro [8] saccharin derivatives (Scheme
1). Menthyl chloride, synthesized by the method of Smith
and Wright,4 was converted into menthylmagnesium
chloride using a method previously documented.5 Treat-
ment of the Grignard reagent with 8 in dry THF afforded
a mixture of the diastereoisomeric sulfonylimines [4a /b]
in moderate yield (Scheme 1), consisting of (-)-3-[(1′R)-
An approach similar to that shown in Scheme 1, but
starting with bornyl chloride [9], synthesized in 45% yield
from â-pinene as previously reported,6 was used to
prepare the bornyl pseudosaccharin derivative [5] (Scheme
2). The diastereoisomeric ratio (54:46) of product 5 was
1
determined from the H NMR spectrum by integration
† University of Liverpool.
‡ Loughborough University.
of triplet signals due to the methine groups adjacent to
the heterocyclic ring, which appear at 3.20 and 3.55 ppm,
respectively. All attempts to separate the diastereoiso-
mers by column chromatography or crystallization using
different solvent mixtures proved fruitless.
(1) Page, P. C. B., Ed.. Organosulfur Chemistry, Vol. 2; Academic
Press: London, 1995.
(2) Solladie´, G. Synthesis 1981, 185.
(3) Page, P. C. B.; Bethell, D.; Stocks, P. A.; Heer, J . P.; Graham, A.
E.; Vahedi, H.; Healy, M.; Collington, E. W.; Andrews, D. M. Synlett
1997, 1355.
(4) Smith, J . G.; Wright, G. F. J . Org. Chem. 1952, 17, 1116.
(5) Tanaka, M.; Ogata, I. Bull. Chem. Soc. J pn. 1975, 43, 1094.
(6) Erickson, G. W.; Fry, J . L. J . Org. Chem. 1987, 52, 462.
10.1021/jo0003100 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/06/2000

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6757
Ta ble 1. Oxid a tion of Su lfid es to Su lfoxid es Usin g
Sch em e 3
Im in es 4-6a
confign
temp, time, yield, ee,
at
no. imine
sulfide
°C
h
%
%
sulfur
1
2
3
5
5
4
tert-butyl methyl -10
14
24
40
63
44
48
15
21
35
p-tolyl methyl
2-phenyl-
-10
S
R
0
1,3-dithiane
4
5
6
4
4
6
tert-butyl methyl -15
23
23
14
29
28
2
16
benzyl methyl
2-phenyl-
-15
-5
S
S
99b 20
100b 34
31b 31
50b 38
1,3-dithiane
2-phenyl-
1,3-dithiane
2-phenyl-
1,3-dithiane
2-phenyl-
7
8
9
6
6
6
-15
-15
-25
14
2
S
S
S
R
14
1,3-dithiane
p-tolyl methyl
tert-butyl methyl
10
11
6
6
-15
-5
14
14
61
100
25
8
a
The enantiomeric excesses of sulfoxide products were deter-
mined by NMR spectroscopy using (R)-(-)-2,2,2-trifluoro-1-(9-
anthryl)ethanol,12 and the absolute configurations were estab-
b
lished by comparison with those of authentic samples.8-10 Anti.
Sch em e 4
TLC. The results of the oxidation reactions are shown in
Table 1. The imine could be recovered by column chro-
matography and reused; in all of the oxidation reactions
in Table 1 the imine was recovered in >90% yield.
As expected, the tertiary alkyl derivative [6] is more
efficient for the oxidation of sulfides to sulfoxides than
are 4 or 5 (Table 1), in agreement with our previous
reports.3 For example, using imine 6, 2-phenyl-1,3-
dithiane was oxidized to give the corresponding sulfoxide
in quantitative yield at -15 °C after 14 h (Table 1, entry
7); using imine 4, with the same substrate at higher
temperature and longer reaction time (0 °C, 40 h), the
sulfoxide was isolated in only 48% yield (Table 1, entry
3). Lower temperature resulted in improved enantio-
selectivity (compare entries 6, 8, and 9). Although the
conversions in sulfoxidation reactions are high using
imine 6, enantioselectivities are low under our reaction
conditions. We excluded the possibility that racemization
of the chiral sulfoxide might be occurring under the
reaction conditions in reactions carried out over long time
periods by showing that, in the oxidation of 2-phenyl-
1,3-dithiane, the enantioselectivity after completion of the
reaction, 14 h, was almost the same as that in the product
of a reaction stopped after just 2 h (Table 1, entries 7
and 8). The implication is that the enantioselectivity is
determined kinetically in the O-transfer process.
Our earlier work3 had shown that 3-tert-alkyl pseu-
dosaccharins are more efficient mediators of sulfur oxida-
tion than are the 3-n- and 3-sec-alkyl derivatives, prob-
ably because of the absence of acidic protons at the
R-position in the side chain. Accordingly, a tert-alkyl
pseudosaccharin derivative [6] was prepared: (1R,4R)-
1-chloro-3,3-dimethyl-3-methylenebicyclo[2.2.1]heptane
(1-chlorocamphene) [10a ] was prepared in 80% yield from
D-camphor as a 96:4 mixture with its isomer [10b]
(Scheme 3).7 By heating the mixture of alkyl halides with
lithium powder in dry cyclohexane under an argon
atmosphere, the organolithium reagents were prepared
and these were then treated with the ethoxy pseuodosac-
charin derivative [7] at -78 °C, allowed to reach room
temperature, and stirred overnight (Scheme 3). After
column chromatography, 3-[(1′R,4′R)-1′-(2′,2′-dimethyl-
3′-methylenebicyclo[2.2.1]heptane)]-1,2-benzisothiazole 1,1-
dioxide [6] was obtained as a single, pure compound in
46% yield.
All new sulfonylimines gave a satisfactory elemental
analyses, exhibited a signal in the 13C NMR spectrum at
175-180 ppm for the imino carbon, and showed absorp-
tion at 1602 cm-1 (CdN stretch) in the infrared spectrum.
Asymmetric sulfoxidation reactions mediated by chiral
sulfonylimines 4-6 were carried out using the method
developed by Bulman Page and Bethell by addition of a
solution of hydrogen peroxide (30% w/v aqueous solution;
4.0 equiv) to a cooled, stirred dichloromethane solution
of DBU (4.0 equiv), followed by the sulfonylimine (1.0
equiv) (Scheme 4).8 The sulfide substrate (1.0 equiv) was
then added, and the reaction progress was monitored by
Ta ble 2. Ca ta lytic Su lfoxid a tion a t Room Tem p er a tu r e
Usin g Im in e [6]
mol %
confign
sulfide
of imine time, h yield, % ee, % at sulfur
p-tolyl methyl
phenyl methyl
10
20
48
24
100 (16)a
95 (9)a
14
14
R
R
a
Sulfoxide yield in the absence of the imine.
To assess the efficiency as a catalyst for sulfoxidation
of imine 6 using substoichiometric quantities, a series of
reactions was carried out at room temperature (Table 2)
(7) J oshi, G. C.; Warnhoff, E. W. J . Org. Chem. 1972, 37, 2383.
(8) (a) Page P. C. B.; Graham, A. E.; Bethell, D.; Park, B. K. Synth.
Commun. 1993, 23, 1507. (b) Page P. C. B.; Heer, J . P.; Bethell, D.;
Collington, E. W.; Andrews, D. M. Tetrahedron: Asymmetry 1995, 6,
2911. (c) Page P. C. B.; Heer, J . P.; Bethell, D.; Collington, E. W.;
Andrews, D. M. Tetrahedron Lett. 1994, 35, 9629. (d) Page P. C. B.;
Heer, J . P.; Bethell, D.; Collington, E. W.; Andrews, D. M. Synlett 1995,
773.
(9) Page P. C. B.; Wilkes, R. D.; Namwindwa, E. S.; Witty, M. J .
Tetrahedron 1996, 52, 2125; Davis, F. A.; Reddy, R. T.; Han, W.;
Carroll, P. J . J . Am. Chem. Soc. 1992, 114, 1428.
(10) Page P. C. B.; Gareh, M. T.; Porter, R. A. Tetrahedron:
Asymmetry 1993, 4, 2139.

6758 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
Ta ble 3. Oxid a tion of Su lfid es to Su lfoxid es Usin g
Oxa zir id in es [11] a n d [12]
Sch em e 5
confign
at
sulfur
oxazir-
no. idine
temp, time, yield, ee,
min
sulfide
2-phenyl-
1,3-dithiane
2-phenyl-
1,3-dithiane
2-phenyl-
1,3-dithiane
2-phenyl-
1,3-dithiane
2-phenyl-
1,3-dithiane
2-phenyl-
1,3-dithiane
tert-butyl methyl -20
p-tolyl methyl -20
C
%
%
1
2
3
4
5
6
11
11
11
12
12
12
20
60 100a 44
R
R
R
S
S
S
-14
-25
0
60
99a 54
80 100a 62
45 100a 82
80 100a 83
30 100a 60
-20
0
in which the primary oxidant was potassium percarbon-
ate. Control reactions under similar reaction conditions
but in the absence of 6 suggested that direct oxidation
can occur for alkyl aryl sulfides, but only very slowly.
We were thus able to confirm catalytic turnover in
sulfoxidations catalyzed by imine 6, although the enan-
tiomeric excesses were low.
7
8
12
12
80 100
120 100
18
19
-
R
a
b
Anti. Dichloromethane was used as solvent. c Carbon tetra-
chloride was used as solvent.
We have previously argued8d that in imine-mediated
S-oxidation using hydrogen peroxide there are two path-
ways for O-transfer to sulfur: (i) via the hydroper-
oxyamine obtained by addition of the oxidant to the Cd
N bond of the imine; (ii) via the oxaziridine produced by
cyclodehydration of the hydroperoxyamine. To determine
the nature of the chiral oxidizing species involved in the
present process, we examined the stereochemistry of
O-transfer to prochiral sulfides from the oxaziridines
derived from imines 4 and 6 (Scheme 5). To oxidize these
imines to the corresponding oxaziridines, the procedure
used was that previously reported by Davis et al.11 In
each case the reaction afforded the oxaziridine in high
yield as a colorless crystalline solid. The CdN bond in
imines 4 and 6 possesses diastereotopic faces, so that two
diastereoisomeric oxaziridines can in principle be formed
in the reactions, each as a single enantiomer. The
oxaziridines formed in each case, however, appear to be
single enantiomers of single diastereoisomers 11 and 12,
as indicated by their clean 13C and 1H NMR spectra, even,
in the case of 12, in the presence of a chiral shift reagent.
Using the known absolute configuration of the menthyl
moiety in 11, and the expected absolute configuration of
the 1-camphenyl group in 12, based on the absolute
configuration of the camphor from which it was gener-
ated, X-ray crystallography on 11 and 12 permitted
assignment of the absolute configurations of the oxaziri-
dine rings as (2R,3S) and (2S,3R), respectively, intrigu-
ingly having opposite configuration at the oxaziridine
carbon atom.
2-phenyl-1,3-dithiane; (iii) the major enantiomer in the
product obtained using 12 was of opposite configuration
to that from reactions using 11; (iv) the predominant
enantiomers were the same as those obtained using
hydrogen peroxide and the corresponding imine mediator;
(v) enantioselectivities were surprisingly low in the
oxidations of tert-butyl methyl and p-tolyl methyl sul-
fides.
The identity of the oxidizing species using imines 4 and
6, hydrogen peroxide, and DBU remains uncertain. The
observation that ee values are all lower than those found
in reactions in which the related oxaziridines 11 and 12
were the oxidants clearly indicates that the oxaziridines
cannot be the sole O-transfer agent in imine-mediated
oxidations. Oxygen transfer from the oxaziridine to sulfur
is not stereospecific, but it shows higher enantioselec-
tivity than the corresponding imine-mediated reaction.
Because 11 and 12 have opposite absolute absolute
configurations at their oxaziridine carbon atoms, it is
tempting to conclude from the outcome of the oxaziridine
reactions that the stereochemistry of O-transfer from the
three-membered ring to sulfur is determined largely by
the absolute configuration at the oxaziridine carbon atom,
the nature of the chiral side chain being of secondary
importance, provided that the orientation of the sulfide
substrate with respect to the oxaziridine unit is similar
for both catalysts.
In the imine-mediated reactions, the O-transfer inter-
mediate could be the R-hydroperoxyamine, from which
sulfonylimine is regenerated by elimination of water after
oxygen transfer to sulfur. Although we have observed
cyclization of R-hydroperoxyamines to yield oxaziridines
under certain conditions, such a transformation is un-
likely on the time scale of the present experiments in
dichloromethane/DBU for the following reasons: (i)
hydroxide ion is a poorer leaving group than sulfate or
carboxylate, which arise from Oxone- or peracid-mediated
oxidations; (ii) even the hindered oxaziridine derived from
3-tert-butyl-1,2-benzisothiazole 1,1-dioxide [13] reacts
completely with DBU after only half an hour at room
temperature to regenerate the corresponding imine,
making it unlikely that it would transfer oxygen ef-
ficiently to the less nucleophilic sulfide in the presence
of DBU if formed in the imine-catalyzed process.
The absolute sense of stereochemical induction is the
same in imine-mediated oxidations as in the oxaziridine
The evaluation of the enantioselective efficiencies of
these chiral N-sulfonyloxaziridines, 11 and 12, in the
asymmetric oxidation of sulfides to sulfoxides is shown
in Table 3. These oxidations were carried out by treating
the sulfide with an equivalent amount of the oxaziridine
in the absence of base in dichloromethane or carbon
tetrachloride solution over a range of temperatures from
room temperature to as low as -25 °C. The following
points should be noted: (i) sulfoxide yields were es-
sentially quantitative in all cases; (ii) 12 gave substan-
tially higher ee values than 11 in the oxidation of
(11) Davis, F. A.; Reddy, R. E.; Kasu, P. V. N.; Portonovo, P. S.;
Carroll, P. J . J . Org. Chem. 1997, 62, 3625; Davis, F. A.; Reddy, R. T.;
McCauley, J . P., J r.; Przeslawski, R. M.; Harakal, M. E.; Carroll, P. J .
J . Org. Chem. 1991, 56, 809.
(12) Pirkle, W. H.; Rinaldi, P. L. J . Org. Chem. 1977, 42, 3217.

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6759
D
dioxide 4a (1.24 g, 38%): mp 148-149 °C (from EtOH); [R]20
reactions for every example in this study (Tables 1, 2,
and 3). Although this might seem to be expected since
the hydroperoxyamine should have the same configura-
tion at the peroxyaminal carbon atom as the correspond-
ing carbon atom in the related oxaziridine, it would only
be so if the formation of the R-hydroperoxyamine were
stereospecific and if the mechanism and transition state
of O-transfer from the R-hydroperoxyamines and oxaziri-
dines were essentially the same, a situation which would
require the oxygen atom attached to the peroxyaminal/
oxaziridine carbon atom to be transferred in both cases.
We have already shown that, in sulfoxidations mediated
by camphorsulfonylimine, the major sense of asymmetric
induction is opposite to that found in oxidations brought
about by the derived oxaziridine.8d This difference in
behavior between the camphor-derived systems and those
based on pseudosaccharin is a continuing puzzle that will
require further investigation.
-71.4 (c 1.12 in CHCl3) (Found: C, 67.14; H, 7.63; N, 4.56;
C
17H23NO2S requires C, 66.85; H, 7.60; N, 4.59%); νmax (Nujol)/
cm-1 1606 and 1175; δH (300 MHz; CDCl3) 0.75 (3 H, d, J ) 7),
0.91 (3 H, d, J ) 7), 0.95 (3 H, d, J ) 6), 1.1-1.4 (3 H, m), 1.4-
1.6 (2 H, s), 1.65-2.1 (5 H, m), 3.1 (1 H, m, J ) 5), and 7.6-8.0
(4 H, m); δC (75 MHz; CDCl3) 16.3, 21.3, 22.1, 24.3, 28.5, 32.8,
34,4, 40.7, 45.1, 122.8, 123.8, 133.6, 133.8 and 179.8; m/z (EI)
306 (M+, 0.78%).
(+)-3-[(1′S)-1′-Men th yl]-1,2-ben zisoth ia zole 1,1-d ioxid e
4b (0.41 g, 13%) was also isolated as a colorless crystalline solid
from the product mixture by flash column chromatography using
n-hexane-dichloromethane (1:2) as eluent: mp 202-204 °C
D
(from EtOH), [R]20 +63.29 (c 0.79 in CHCl3) (Found: C, 66.65;
H, 7.61; N; 4.55. C17H23NO2S requires C, 66.85; H, 7.59; N,
4.59%); δH (300 MHz; CDCl3) 0.18-0.78 (9 H, m), 1.08-2.04 (9
H, m), 3.70 (1 H, s), and 7.60-8.00 (4 H, m); δC (75 MHz; CDCl3)
16.8, 20.6, 21.9, 23.7, 26.7, 31.4, 34.0, 39.9, 47.4, 83.6, 121.9,
123.3, 133.4, 134.0 and 176.8; m/z (EI) 305 (M+, 0.2%).
Compound 4c was isolated from the above reaction mixture
by flash column chromatography using n-hexane-dichlo-
romethane (1:2) as eluent and shown to be 3-[(1′R)-menthoxy]-
1,2-benzisothiazole 1,1-dioxide (0.51 g, 15%). Crystallization gave
Exp er im en ta l Section
D
colorless needles: mp 121-122 °C (from EtOH), [R]20 -92.9 (c
3.11 in CHCl3) (Found: C, 63.47; H, 7.23; N, 4.34. C17H23NO3S
requires C, 63.52; H, 7.22; N, 4.36%); νmax (Nujol)/cm-1 1614 and
1173; δH (300 MHz; CDCl3) 0.8-1.4 (12 H, m), 1.4-2.2 (5 H, m),
2.2-2.6 (1 H, m), 5.0-5.2 (1 H, m) and 7.6-8.0 (4 H, m); δC (75
MHz; CDCl3) 16.8, 20.5, 21.8, 23.7, 26.7, 31.4, 34.0, 39.9, 47.4,
83.6, 121.8, 123.3, 133.3, 133.9 and 168.6; m/z (EI) 321 (M+,
0.04%).
Gen er a l. All moisture-sensitive reactions were carried out
in round-bottomed flasks, which were baked at 150 °C for a
minimum of 2 h. The flasks were allowed to cool in a desiccator
and were purged with nitrogen prior to being sealed with septum
caps. Other apparatus such as syringes, needles, cannulas, and
magnetic stirrer bars were dried under similar conditions and
allowed to cool in a desiccator. Tetrahydrofuran and cyclohexane
were freshly distilled under an atmosphere of nitrogen from the
sodium benzophenone ketyl radical, and chloroform was distilled
from CaH2 prior to use. Aqueous hydrogen peroxide (30% w/v
aqueous solution) and other reagents were used as supplied.
Saccharin derivatives, chloro, ethoxy, and t-Bu, were synthesized
as reported previously.3
Flash column chromatography was performed using Merck
9385 Kieselgel 60 silica gel (230-400 mesh); compressed air was
used to supply any necessary pressure to the column. Thin-layer
chromatography was carried out on aluminum plates coated with
a 0.25 mm layer of silica gel containing fluorescence indicator
(Merck). UV-inactive compounds were visualized by exposure
to iodine mixed with silica gel or by spraying with aqueous
potassium permanganate (10 g in 1 L of water containing 5 g of
Na2CO3) followed by heating.
3-(2-Bor n yl)-1,2-ben zisoth ia zole 1,1-Dioxid e [5]. 3-(2-
Bornyl)-1,2-benzisothiazole 1,1-dioxide 5 was prepared using the
same procedure as described for (-)-3-[(1′R)-1′-menthyl]-1,2-
benzisothiazole 1,1-dioxide 4a above using (-)-bornyl chloride
9 (2.0 g, 11.5 mmol, 1.0 equiv), magnesium (1.0 g, 41.1 mmol),
ethyl bromide (0.05 mL), and 3-chloro-1,2-benzisothiazole 1,1-
dioxide 8 (2.3 g, 11.4 mmol). Bornyl chloride was purified before
use by sublimation under reduced pressure, followed by recrys-
tallization from methanol and vacuum-drying for several hours.
3-(2-Bornyl)-1,2-benzisothiazole 1,1-dioxide 5 was isolated from
the reaction mixture by flash column chromatography using
petroleum ether-dichloromethane (1:1) as eluent (0.9 g, 26%).
All attempts to prepare diastereoisomerically pure 3-(2-bornyl)-
1,2-benzisothiazole 1,1-dioxide by column chromatography or
crystallization using different mixtures of solvents proved dis-
appointing. The 1H NMR spectrum indicated the presence of a
54:46 ratio of 3-[(2′S)-2′-bornyl)-1,2-benzisothiazole 1,1-dioxide
5a and 3-[(2′R)-2′-bornyl)]-1,2-benzisothiazole 1,1-dioxide 5b,
determined by integration of the triplets for the methine proton
adjacent to the heterocyclic ring and appearing at 3.20 and 3.55
ppm. The isomeric mixture had mp 158-160 °C (from EtOH):
The chiral shift reagent used to determine enantiomeric
excesses from nuclear magnetic resonance (1H, 13C) spectra was
(R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol.12
P r oced u r es. (-)-3-[(1′R)-1′-Men th yl]-1,2-ben zisoth ia zole
1,1-Dioxid e [4a ], (+)-3-[(1′S)-1′-Men t h yl]-1,2-b en zisot h ia -
zole 1,1-Dioxid e [4b ], a n d 3-[(1′R)-Men t h oxy]-1,2-b en z-
isoth ia zole 1,1-Dioxid e [4c]. In a 100 mL three-necked round-
bottomed flask equipped with a magnetic stirrer bar, argon inlet,
rubber septum, condenser, and dropping funnel was placed
magnesium (340 mg, 13 mmol) and dry tetrahydrofuran (4 mL).
The mixture was treated with ethyl bromide (0.4 mL), and after
the reaction had progressed for a few minutes, a solution of (-)-
menthyl chloride (2.0 mL, 1.87 g, 10 mmol) in tetrahydrofuran
(4 mL) was added, portionwise, over a period of 4 h at 50 °C,
followed by reflux for 30 min. This solution was added via
syringe to a separate 250 mL round-bottom flask equipped with
an argon inlet and rubber septum and containing 3-chloro-1,2-
benzisothiazole 1,1-dioxide 8 (2.01 g, 10 mmol), in dry tetrahy-
drofuran (60 mL) cooled to 0 °C. The resulting mixture was
stirred overnight and quenched by adding water (50 mL). The
solution was diluted with ether (45 mL), and the organic layer
was washed with 10% aqueous HCl (35 mL), water (3 × 45 mL),
and dried over MgSO4. Removal of the solvent in vacuo gave a
mixture of (-)-3-[(1′R)-1′-menthyl]-1,2-benzisothiazole 1,1-
dioxide 4a and (+)-3-[(1′S)-1′-menthyl]-1,2-benzisothiazole 1,1-
dioxide 4b (3:1) determined by integration from the NMR
spectrum, together with a third, unknown compound, 4c. The
crude material was separated by flash column chromatography
using n-hexane-dichloromethane (1:2) as eluent to give as a
colorless solid (-)-3-[(1′R)-1′-menthyl]-1,2-benzisothiazole 1,1-
D
[R]20 +49.4 (c 0.89 in CH2Cl2) (Found: C, 67.05; H, 7.01; N,
4.53. C17H21NO2S requires C, 67.30; H, 6.98; N, 4.62%); νmax
(Nujol)/cm-1 1602 and 1171; δH (300 MHz; CDCl3) 0.85-1.17 (6
H, m) 1.20-2.08 (9 H, m), 2.10-2.60 (1 H, m), 3.20 (1 H, t, J )
9), 3.55 (1 H, m, J ) 5) and 7.45-8.60 (4 H, m); δC (75 MHz;
CDCl3) 14.4, 18.8, 20.1, 27.5, 29.2, 34.0, 40.3, 45.3, 48.5, 51.6,
122.4, 124.7, 133.3 and 133.6; m/z (EI) 305 (M+, 0.45%).
(1R,4R)-1-Ch lor o-3,3-d im eth yl-2-m eth ylen ebicyclo[2.2.1]-
h eptan e [10]. (1R,4R)-1-Chloro-3,3-dimethyl-2-methylenebicyclo-
[2.2.1]heptane, 10, was prepared as previously described.7 In a
dry 250 mL round-bottomed flask equipped with a magnetic
stirrer was placed D-camphor (15.2 g, 0.10 mol) in dichlomethane
(25 mL). The flask was chilled in an ice bath, and phosphorus
trichloride (12.8 g) and phosphorus pentachloride (22.2 g) were
added in small portions. After 2 h the reaction mixture was
allowed to reach room temperature for 10 h. The reaction
mixture was poured onto ice and extracted with petroleum ether
(2 × 40 mL). The extract was washed with water (2 × 30 mL)
and evaporated to leave a clear, colorless liquid (15 g) which
was refluxed for 12 h with potassium acetate (20 g) in ethanol-
water (100 mL, 75:25). The solution was then poured into water
(100 mL) and extracted with petroleum ether (2 × 40 mL). The
combined organic extracts were washed with water (2 × 40 mL),
dried over MgSO4, and evaporated in vacuo. Distillation of the
residue under reduced pressure (72-78 °C, 1 mmHg) gave a

6760 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
colorless oil which partially solidified on standing. This product
was further purified by flash column chromatography using
petroleum ether as eluent to give a colorless oil (14 g, 82%). H
to a separating funnel and washed with saturated aqueous
sodium sulfite (15 mL) to quench any hydrogen peroxide
remaining. The organic layer was washed with brine (2 × 15
mL), dried over MgSO4, and evaporated in vacuo. Separation of
the imine and sulfoxide was achieved by column chromatography
on silica gel using successively dichloromethane and ethyl
acetate as eluents.
1
NMR spectroscopy indicated the presence of a 96:4 ratio of
(1R,4R)-1-ch lor o-3,3-dim et h yl-2-m et h ylen ebicyclo[2.2.1]-
heptane 10a and (1R,4R)-1-chloro-2,2-dimethyl-3-methylenebi-
cyclo[2.2.1]heptane 10b as determined by integration of the
D
olefinic protons, [R]20 -9.4 (c 2.1 in CH2Cl2): νmax (neat)/cm-1
(+)-(2R,3S)-3-[(1′R)-1′-Men th yl]-1,2-ben zisoth ia zole 1,1-
Dioxid e Oxid e [11] a n d (+)-(2S,3R)-3-[(1′R,4′R)-1′-(3′,-
3′-D im e t h y l-2′-m e t h y le n e b ic y c lo [2.2.1]h e p t a n e )]-1,2-
ben zisoth ia zole 1,1-Dioxid e Oxid e [12]. In a 250 mL, two-
necked round-bottomed flask equipped with a magnetic stirrer
were placed imines 4 or 6 (3.32 mmol) in dichloromethane (50
mL) and saturated aqueous potassium carbonate (54 mL). The
reaction mixture was vigorously stirred while a solution of 85%
mCPBA (11.4 mmol) in dichloromethane (33 mL) was added
dropwise over 30 min. The reaction mixture was stirred over-
night. Saturated aqueous sodium sulfite (20 mL) was added, and
the reaction mixture was diluted with dichloromethane (25 mL)
and water (25 mL). The aqueous layer was extracted with
dichloromethane (2 × 20 mL), and the combined organic phases
were washed with a saturated sodium hydrogen carbonate
solution (20 mL) and brine (2 × 30 mL), and dried over MgSO4.
Removal of the solvent in vacuo gave the crude oxaziridines.
Recrystallization from absolute ethanol afforded the pure ox-
aziridines.
1664; δH (300 MHz; CDCl3) 1.07-1.14 (6 H, s), 1.64-2.18 (7 H,
m), and 4.95 (2 H, s); m/z (EI) 171.09378 (M+, C10H16Cl requires
171.09405).
(+)-3-[(1′R,4′R)-1′-(3′,3′-Dim et h yl-2′-m et h ylen eb icyclo-
[2.2.1]h ep ta n e)]-1,2-ben zisoth ia zole 1,1-Dioxid e [6]. In a
100 mL, oven-dried, three-necked, round-bottomed flask equipped
with a magnetic stirrer, dropping funnel, reflux condenser, and
rubber septum, under argon, was placed lithium powder (0.6 g,
86 mmol), the equipment was purged with dry argon for 2 min,
and the atmosphere maintained using an argon-filled balloon.
Cyclohexane (12 mL), freshly distilled from sodium and ben-
zophenone, was added to the flask via a cannula, followed
dropwise by (1R,4R)-1-chloro-3,3-dimethyl-2-methylenebicyclo-
[2.2.1] heptane 10a (4.0 g, 23 mmol) in dry cyclohexane (6 mL).
The reaction mixture was stirred for 30 min and then held at
reflux for 2 h. As the reaction progressed, the initially clear
mixture acquired a brown coloration and the lithium took on a
black coating and sank to the bottom of the flask. At this point
the stirring was stopped and the solids were allowed to settle
to the bottom of the flask.
(+)-(2R,3S)-3-[(1′R)-1′-Menthyl]-1,2-benzisothiazole 1,1-diox-
ide oxide, 11, colorless solid (0.601 g, 95%): mp 133-135 °C
D
In a separate 250 mL reaction flask was placed pseudosac-
charin ethyl ether (3-ethoxy-1,2-benzisothiazole 1,1-dioxide) 7
(1.8 g, 8.52 mmol) in tetrahydrofuran (50 mL), cooled to -78
°C. The 1-lithio-3,3-dimethyl-2-methylenebicyclo[2.2.1]heptane
solution, prepared above, was added to the cooled reaction flask
containing pseudosaccharin ethyl ether, via a cannula, at -78
°C. The flask containing organolithium compound was washed
with cyclohexane (3 × 6 mL), and the contents were transferred
to the reaction mixture. The reaction mixture was stirred
overnight and was quenched by slow addition of water (40 mL)
and diluted with ether (2 × 30 mL). The combined organic phase
was washed with water (2 × 40 mL) and dried over MgSO4. The
solvent was removed in vacuo and the residue purified by flash
column chromatography using dichloromethane-petroleum ether
(1:1) as eluent to give (+)-3-[(1′R,4′R)-1′-(3′,3′-dimethyl-2′-
methylenebicyclo[2.2.1]heptane)]-1,2-benzisothiazole 1,1-dioxide
(from EtOH); [R]20 +75 (c 2.14 in CHCl3) (Found: C, 63.57; H,
7.19; N, 4.34. C17H23NO3S requires C, 63.52; H, 7.19; N, 4.35%);
ν
max(CHCl3)/cm-1 1184; δH (300 MHz; CDCl3) 0.73 (3 H, d, J )
7), 0.82-0.94 (3 H, m), 1.17 (3 H, d, J ) 7), 1.45-1.22 (1 H, m),
1.22-1.70 (5 H, m), 1.70-1.94 (3 H, m), 1.94-2.30 (1 H, m) and
7.60-8.00 (4 H, m); δC (75 MHz; CDCl3) 15.4, 21.3, 22.1, 24.5,
28.4, 32.3, 34.5, 37.4, 45.4, 88.0, 124.4, 126.6, 132.4 and 133.9;
m/z (EI) 321 (M+, 0.36%).
(+)-(2S,3R)-3-[(1′R,4′R)-1′-(3′,3′-Dimethyl-2′-methylenebicyclo-
[2.2.1] heptane)]-1,2-benzisothiazole 1,1-dioxide oxide, 12, color-
D
less crystals (0.92 g, 87%): mp 152-153 °C (from EtOH); [R]20
+67 (c 0.1 in CHCl3) (Found: C, 64.15; H, 6.7; N, 4.34. C17H19
-
NSO3 requires C, 64.33; H, 6.03; N, 4.41%); νmax (CHCl3)/cm-1
1186; δH (300 MHz; CDCl3) 1.56 (6 H, s), 1.44-1.74 (3 H, m),
1.76-1.88 (2 H, m), 2.28 (1 H, s), 2.20-2.34 (1 H, m), 4.70 (2 H,
d, J ) 5) and 7.50-8.00 (4 H, m); δC (75 MHz; CDCl3) 23.4, 25.7,
29.4, 30.7, 40.2, 43.6, 47.7, 55.0, 86.6, 103.9, 124.0, 128.3, 132.2,
133.4, 135.1 and 162.1; m/z (EI) 317 (M+, 0.76%).
D
6 (3.25 g, 46%): mp 162-164 °C (from EtOH); [R]20 +61 (c 1.0
in CHCl3) (Found: C, 67.61; H, 6.37; N, 4.66. C17H19NO2S
requires C, 67.75; H, 6.35; N, 4.65%); νmax (Nujol)/cm-1 1602,
1175, and 1647; δH (300 MHz; CDCl3) 1.23 (3 H, s), 1.33 (3 H,
s), 1.50-1.84 (5 H, m), 1.85-1.98 (1 H, m), 2.22 (1 H, s), 2.32-
2.56 (2 H, m), 4.50 (1 H, s), 4.80 (1 H, s), and 7.50-8.10 (4 H, m;
δC (75 MHz; CDCl3) 23.8, 25.9, 29.7, 32.7, 43.1, 44.1, 48.8, 59.2,
104.1, 122.4, 127.1, 130.7, 133.0, 133.3, 140.6, 164.2 and 177.4;
m/z (EI) 301 (M+, 35%).
Gen er a l P r oced u r e for Oxid a tion of Su lfid es to Su lfox-
id es Usin g Oxa zir id in es 11 a n d 12. Typically, oxaziridine 11
or 12 (0.311 mmol) was added to a precooled solution of sulfide
(1.0 equiv) in dichloromethane or carbon tetrachloride (5 mL).
The progress of the reaction was monitored by TLC (using ethyl
acetate as eluent) until complete sulfoxidation had occurred.
Sulfoxide was isolated by column chromatography using ethyl
acetate as eluent.
Gen er a l P r oced u r e for Asym m etr ic Oxid a tion Med ia ted
by Im in es [4-6]. Aqueous hydrogen peroxide (0.15 mL, 4.0
equiv., 30% w/v) was added to a stirred dichloromethane (7 mL)
solution of DBU (202 mg, 4.0 equiv), and this was followed by
imines 4-6 (1.0 equiv). The sulfide substrate (1.0 equiv) was
then added and the mixture stirred at the appropriate temper-
ature. The reaction progress was monitored by TLC. Dichlo-
romethane (15 mL) was then added and the mixture transferred
Ack n ow led gm en t. We are indebted to the Govern-
ment of the Islamic Republic of Iran for financial
support (H.V.).
J O0003100