Synthesis and stereoselective oxidation of α-thio-β- chloropropenyloxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2010.10.007

The investigation of the stereoselective reaction of α- thiopropanoyloxazolidin-2-ones with NCS to yield α-thio-β- chloropropenyloxazolidin-2-ones is described. Diastereoselective sulfur oxidation of the resulting α-thio-β-chloropropenyloxazolidin-2-ones

Full text of DOI:10.1016/j.tetasy.2010.10.007

Tetrahedron: Asymmetry 21 (2010) 2550–2558
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and stereoselective oxidation of
a-thio-b-chloropropenyloxazolidin-2-ones
Marie Kissane a, Maureen Murphy a, Simon E. Lawrence a, Anita R. Maguire b,
⇑
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The investigation of the stereoselective reaction of a-thiopropanoyloxazolidin-2-ones with NCS to yield
Received 27 September 2010
Accepted 12 October 2010
Available online 8 November 2010
a
-thio-b-chloropropenyloxazolidin-2-ones is described. Diastereoselective sulfur oxidation of the result-
ing a-thio-b-chloropropenyloxazolidin-2-ones shows modest diastereocontrol. However, via a combina-
tion of diastereoselective oxidation and subsequent kinetic resolution in the sulfoxide oxidation,
diastereoselectivities of up to 94% de have been achieved.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
O
RS
O
O
O
RS
Cl
RS
[O]
NCS
We have recently reported the highly efficient and stereoselec-
tive transformation of
to the corresponding
N
N
O
O
N
O
a
a
-thioamides,
-thio-b-chloroacrylamide,
a
-thioesters and
a-thionitriles
Cl
a
-thio-b-chloro-
Ph
Ph
Ph
acrylate and
ment with NCS,1–3 with the novel transformation proving
particularly effective for the -thioamide derivatives. While amides
a-thio-b-chloroacrylonitrile derivatives upon treat-
Scheme 1.
a
have been employed as chiral auxiliaries in asymmetric synthesis
with some success,4 the use of oxazolidinones as chiral auxiliaries
has in many instances led to excellent relay of stereochemistry.5–10
Chiral 2-oxazolidinones, first reported by Evans in 1981,5 have pro-
ven to be highly versatile chiral auxiliaries, with high asymmetric
induction achieved in alkylations, aminations, azidations, bromina-
tions, hydroxylations, aldol additions, Diels–Alder cycloadditions
and conjugate addition reactions.6–9 Therefore, we wished to
the resulting
discussed.
a
-thio-b-chloropropenyloxazolidin-2-ones is also
2. Results and discussion
2.1. Preparation of b-chloropropenyloxazolidin-2-ones
extend this chlorination chemistry to
2-ones, and explore asymmetric induction in reactions of the
resulting -thio-b-chloropropenyloxazolidin-2-ones, focussing
a-thiopropanoyloxazolidin-
The
steps; the
scribed by Evans and Gage in 80% yield as an equimolar mixture
of diastereomers.12 The
-phenylthiopropanoyloxazolidin-2-one
a
-thiopropanoyloxazolidin-2-ones were synthesised in two
a
a-chloroamide 1 was first prepared by the method de-
specifically on diastereoselective oxidation (Scheme 1). We have re-
cently shown that with simple chiral amide auxiliaries, some, albeit
modest, diastereocontrol is possible.11 The diastereoselective sulfur
oxidation of chiral N-arylthio and N-(alkylthio)oxazolidinones has
been investigated by Evans using a range of achiral oxidising re-
agents.10 Although the diastereoselectivity was poor, the diastereo-
mers could be easily separated by fractional crystallisation or
chromatography and reacted readily with a variety of Grignard
reagents to afford chiral sulfoxides.
a
2 was prepared by sulfenylation of 1 by reaction in ethanol with
1.1 equiv of the freshly prepared salt of benzenethiol to produce
2 as an equimolar mixture of diastereomers in 90% yield. The syn-
thesis of
a-benzylthiopropanoyloxazolidin-2-one 3 was initially
attempted in a similar manner; however, in addition to the nucle-
ophilic displacement of the chloride group by the benzylthiolate
anion, displacement of the oxazolidinone group by ethoxide also
Herein, the reactivity of
a-thiopropanoyloxazolidin-2-ones
occurred. The
a-benzylthiopropanoyloxazolidin-2-one 3 was sub-
with NCS is described. The diastereoselective sulfur oxidation of
sequently prepared in 77% yield by reaction of 1 with 1.05 equiv
of sodium hydride and 1.05 equiv of benzyl thiol in anhydrous
DMF. The
a-benzylthiopropanoyloxazolidin-2-one 3 was isolated
⇑
Corresponding author. Tel.: +353 21 4901693; fax: +353 21 4274097.
E-mail address: a.maguire@ucc.ie (A.R. Maguire).
as a 1:1.24 mixture of diastereomers (Scheme 2).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.007

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
2551
O
N
O
O
SR
Cl
O
Cl
O
N
HN
O
n-BuLi, THF
Cl
RSH
+
NaOEt/EtOH
O
°
-78 C, 30 min, 80%
O
O
or NaH/DMF
Ph
Ph
Ph
1
2
3
R = Ph (90%), d.r. 1:1
R = Bn (77%), d.r. 1:1.24
Scheme 2.
An investigation of the reaction of the
din-2-ones 2 and 3 with NCS was then undertaken, with the results
summarised in Table 1.
a
-thiopropanoyloxazoli-
results obtained with amides throughout this research programme
and therefore is mechanistically significant.3 The presence of the
oxazolidinone moiety results in the sulfur-stabilised intermediate
carbocation adopting a very different conformation to that of the
primary and secondary propanamides, and it appears that deproto-
nation from the sulfur-stabilised carbocation through conforma-
tion B to form the corresponding E-isomer is energetically more
favourable than elimination through conformation A (Scheme 3).
An alternative explanation involves E–Z isomerisation in the b-
chloropropenyloxazolidin-2-one 6; earlier results with tertiary
amides had suggested the possibility of interconversion in the ben-
zylthio series.2
The treatment of
a-phenylthiopropanoyloxazolidin-2-one 2
with 2.2 equiv of NCS in toluene at 130 °C resulted in a complex
mixture of products, from which the E- and Z-b-chloropropenylox-
azolidin-2-ones E-4 and Z-5 were isolated following chromato-
graphic purification in yields of 29% and 22%, respectively. The
stereochemistry of the E- and Z-isomers was assigned by X-ray
analysis on the sulfoxide derivative 8a (see below). While chlorina-
tion of the primary and secondary
a-thioamides with NCS pro-
ceeds in highly stereoselective manner, with exclusive
a
formation of the b-chloroacrylamides as the Z-stereoisomer, the
absence of an amide hydrogen in tertiary amides for intramolecu-
lar hydrogen bonding to sulfur results in a change in conformation
of the intermediate carbocation, and deprotonation to form either
the E- or the Z-isomer is possible.3 Thus, the current work is consis-
tent with this earlier observation, as the lack of a hydrogen for
intramolecular bonding to sulfur in 2 leads to the subsequent for-
In the 1H NMR spectrum of the crude product from the reaction
of the a-benzylthiopropanoyloxazolidin-2-one 3 with 2.2 equiv of
NCS, there was evidence for the presence of another compound
(ꢀ30 mol %), a minor amount (9%) of which was recovered after
chromatography. Elemental analysis indicated a molecular formula
of C20H18Cl3NO3S and the spectroscopic evidence suggested that
the oxazolidinone was no longer intact; in particular, the CH2O
signal at dC 66 ppm in the 13C NMR spectrum of 3 now appeared
at dC 42 ppm. Furthermore, in the IR spectrum two carbonyl
stretches were evident, with one of these carbonyl stretches at a
much higher frequency than that normally seen for the oxazolidi-
none derived b-chloroacrylamides (1827 and 1754 cmꢁ1 vs 1773
and 1674 cmꢁ1 for E-6). The structure was eventually confirmed
as the oxazolidine-2,4-dione 7 by single crystal X-ray diffraction
on a sample recrystallised from ethanol (Scheme 4 and Fig. 1).
Scheme 5 summarises a proposed mechanistic pathway for the
formation of the side-product 7; as 2.2 equiv of NCS are used in the
reaction of 3, overchlorination is possible. Thus, the formation of
the chlorosulfonium ion 9 is followed by the nucleophilic addi-
tion of chloride to give the sulfur-stabilised carbocation 10. The
key step in the formation of the side-product 7 then involves
intramolecular nucleophilic addition of oxazolidinone to the
mation of the
mixture of E- and Z-isomers.
The -benzylthiopropanoyloxazolidin-2-one 3 was then reacted
a-phenylthio-b-chloroacryloyloxazolidin-2-ones as a
a
under identical conditions (2.2 equiv NCS, toluene, 130 °C), and
again a complex mixture of products was obtained from which
the E-b-chloropropenyloxazolidin-2-one 6 was isolated in 41%
yield. There was no evidence for the formation of the Z-isomer in
the 1H NMR spectrum of the crude product. The reaction of 3
was also conducted using 1.95 equiv of NCS in toluene at 90 °C
for 1 h, and again the Z-isomer was not detected. When using these
conditions, the 1H NMR spectrum of the crude product contained a
number of unassigned signals and lower yields were obtained for
E-6 (32–36%) than with the higher temperature (see Scheme 4).
The absence of the Z-isomer in the reaction of the a-benzylthio-
propanoyloxazolidin-2-one 3 with NCS is in direct contrast to the
Table 1
Synthesis of b-chloroacrylamides bearing (4S)-benzyloxazolidin-2-one auxiliary
Ph
O
O
RS
Cl
SR
N
O
2.2 eq. NCS, 130 °C
O
N
Toluene, 0.5-1h
O
O
Ph
Sulfide
R
Z/E
b-Cl
% Yielda
2b
Ph
E
Z
E-4c
Z-5c
29d
22d
3e
Bn
E
E-6f
41
a
b
c
d
e
f
Yield after chromatography on silica gel.
Equimolar mixture of diastereomers.
Stereochemistry tentatively assigned.
Crude ratio of E-5:Z-6 1:1.05.
1:1.24 mixture of diastereomers.
Oxazolidine-2,4-dione 7 was also isolated in 9% yield.

2552
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
facial approach to the carbocation in 10. Oxazolidine-2,4-diones
O
O
O
O
are biologically active compounds, which have anticonvulsant
S
S
Bn
Bn
Cl
properties.13–15
N
N
O
O
H
Cl
H
H
A
H
B
Bn
Bn
2.2. Diastereoselective oxidation of b-
chloropropenyloxazolidin-2-ones
Having formed the b-chloropropenyloxazolidin-2-ones E-4, Z-5
and E-6, the role of the oxazolidinone moiety in controlling the ste-
reochemistry of oxidation at sulfur was next explored. We have re-
cently shown that with simple chiral amide auxiliaries, some,
albeit modest, diastereocontrol is possible.11 The reaction of E-4
with 2 equiv of OxoneÒ led to a diastereomeric ratio of 1:0.9 of
the resulting sulfoxides 15a and 15b, indicating that efficient
asymmetric induction from the more remote oxazolidinone auxil-
iary was not feasible (in contrast to Evans’ work where the oxazo-
lidinone was bonded directly to the sulfide).10 The diastereomers
15a and 15b were easily separated by chromatography on silica
gel (Scheme 6).
O
O
O
O
BnS
H
BnS
Cl
N
N
O
O
H
Cl
Bn
Bn
E
Z
Scheme 3.
sulfur-stabilised carbocation 10 to form initially the intermediate
cation 11, followed by ring-opening through nucleophilic addition
of chloride to form the oxazolidine-2,4-dione 7 (Scheme 5). Only a
single isomer was detected, indicating selectivity in the diastereo-
Oxidation of Z-5 with 1.4 equiv of mCPBA led to a 1:0.7:0.5
mixture of 16a:16b:17 sulfoxide diastereomers/sulfone (as
O
O
O
O
SBn
O
CH2Cl
H
BnS
O
N
O
N
NCS
N
BnS
Cl2HC
+
toluene
Bn
Cl
O
1 h
O
Ph
Ph
3
6
7
Crude Product Ratios (2.2 eq., NCS, toluene, 130 °C)
Yields (2.2 eq., NCS, toluene, 130 °C)
Yields (1.95 eq. NCS, toluene, 90 °C)
Scheme 4.
1
0.43
9%
41%
32-36%
N.D.
Figure 1. ORTEP of 7 (anisotropic displacement parameters are drawn at the 30% probability level).

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
2553
Cl+
O
O
O
PhS
O
O
O
O
2 eq. Oxone ,
acetone/H2O
O
Cl
BnS
O
O
O
PhS
BnS
N
N
O
O
BnS
Cl
5% de
N
O
N
N
O
O
rt, 40 h
Cl
Cl
Cl
Cl
Cl
Cl-
Ph
Ph
d.r. 1 : 0.9
Ph
10
Ph
Ph
6
9
E-4
15a and 15b
Scheme 6.
O
N
Cl-
Bn
O
CH2Cl
H
O
Substituting the S-phenyl group in E-4 and Z-5 with the S-ben-
zyl group in E-6 resulted in improved diastereoselectivities. As
indicated in Schemes 6 and 7, enhanced diastereoselectivity was
observed starting from the E-isomer, although the extent of this
is very modest. The employment of mCPBA as an oxidant afforded
a 1:0.5:0.03 mixture of 8a:8b:18 sulfoxide diastereomers/sulfone,
and an increase in the diastereoselectivity to 48% de was observed
when sodium periodate was used. OxoneÒ proved to be the most
expedient oxidant, with a diastereomeric excess of up to 94%
achieved when 2 equiv of OxoneÒ were employed. On closer exam-
ination of the OxoneÒ oxidation, it was clear that the initial diaste-
reoselective oxidation was followed by selective oxidation of the
minor sulfoxide 8b to the sulfone 18, leading to an enhancement
of the diastereomeric excess of the sulfoxide (Scheme 8); kinetic
resolution has been shown to enhance the enantioselectivity in
sulfur oxidation.17–19 The sulfoxide 8a was easily separated from
the less polar sulfone 18 by chromatography on silica gel. From
the product ratios summarised in Table 2, it is clear that oxidation
of the minor diastereomer 8b occurs selectively, but not exclu-
sively, as the extent of sulfone formation clearly indicates that
8a also undergoes oxidation. Through appropriate choice of reac-
tion conditions, the combination of diastereoselective oxidation
and selective oxidation can lead to a very high diastereomeric
purity in the sulfoxide 8a, albeit in modest yield. Following
O
BnS
Cl
N
BnS
Cl2HC
Bn
O
Cl
O
7
11
Scheme 5.
determined by 1H NMR spectroscopy) (Scheme 7). Chromatographic
purification on silica gel led to the separation of sulfoxides 16a and
16b, and a minor fraction (ꢀ7%) containing a 4.7:1 mixture of
sulfone 17; the minor sulfoxide 16b was also isolated. Evidently,
the control of the sulfide oxidation of the oxazolidinone derivatives
is more challenging than in the corresponding amide derivatives,
where chemoselective oxidation to the sulfoxide is easily achieved.
Again, the diastereofacial discrimination is very small.
Clearly, retention of stereochemistry in the acrylamide is ob-
served during the sulfur oxidation, with no evidence of E/Z isom-
erisation in the 1H NMR spectra. This is consistent with the
simpler b-chloroacrylamides.16
The diastereoselective sulfur oxidation of the S-benzyl substi-
tuted oxazolidinone derivative E-6 was investigated under a vari-
ety of conditions, with the results summarised in Table 2.
O
O
O
O
PhS
O
O
O
O
O
1.4 eq. mCPBA,
S
PhS
Cl
+
Ph
N
N
O
O
N
CH2Cl2
O
rt, 1h
Cl
Cl
19% de
Ph
Ph
Ph
Z-5
16a and 16b
16a:16b:17 1 : 0.7 : 0.5
17
crude ratios
Scheme 7.
Table 2
Diastereoselective oxidation of E-6 with subsequent kinetic resolution
O
O
O
BnS
O
O
BnS
O
O
O
[O]
S
BnS
Bn
Aux
Aux
+
Aux
+
Aux
O
Aux =
Cl
Cl
Cl
Cl
O
N
Bn
E-6
8b
8a
18
Conditions
8a:8b:18a
% dea
1.1 equiv mCPBA, CH2Cl2, rt, 16 h
3 equiv NaIO4, MeOH/H2O, rt, 5 d
1 equiv OxoneÒ, acetone/H2O, rt, 16 h
1.5 equiv OxoneÒ, acetone/H2O, rt, 16 h
2 equiv OxoneÒ, acetone/H2O, rt, 16 h
1:0.5:0.03
1:0.4:NDb
1:0.2:0.2
1:0.1:0.6
1:0.03:0.7
36
48
72
90
94
a
Estimated by integration of the 1H NMR spectrum of the crude product.
ND = not detected.
b

2554
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
O
O
O
O
O
O
O
BnS
O
BnS
diastereoselective BnS
O
O
N
N
+
O
N
oxidation
Cl
Cl
Cl
8b
8a
Ph
Ph
Ph
6
E-
selective oxidation
O
O
O
O
S
O
Bn
N
up to 94% de
Cl
8
18
Ph
Scheme 8.
Figure 2.
[O]
S
O
S
O
O
N
O
O
O
O
O
O
Bn
N
O
S
Bn
Bn
N
O
on
Cl
Cl
Bn
rotation
Cl
Bn
Bn
Figure 3.
chromatographic purification it is possible to obtain 8a in diaste-
reomerically pure form in 17% yield as the diastereomers 8a and
8b and the sulfone 18 are separable.
conformation is the same in the sulfide. This is consistent with
the work conducted by Evans on the diastereoselective sulfur oxi-
dation of chiral N-aryl and N-(alkylthio)oxazolidinones.10 Investi-
gation of the synthetic potential of the enantioenriched vinyl
sulfoxides will be reported in due course, including efficient cleav-
age of the oxazolidinone moiety.
The stereochemical assignment of 8a, establishing the configu-
ration at the sulfur centre as (R), was determined by single crystal
X-ray diffraction of a diastereomerically pure sample, recrystal-
lised from dichloromethane and hexane (Fig. 2). The X-ray
crystallography also confirmed the E-stereochemistry of the
b-chloroacrylamide 8a and hence of the sulfide precursor 6.
Examination of the crystal structure reveals that the electro-
philic oxygen is delivered to the face opposite the benzyl group
of the oxazolidinone as illustrated in Figure 3, assuming that the
3. Conclusion
In summary, the formation of b-chloro-a,b-unsaturated deriva-
tives of oxazolidinones is feasible, albeit with lower yields and re-
duced selectivity compared to studies with simple primary and

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
2555
secondary amides, and comparable in many ways to reactions with
tertiary amides. Thus, we can access compounds which enable
investigation of the efficiency of the transfer of stereoselectivity
from the oxazolidinone auxiliary in reactions of the highly func-
169.5, 169.6 (2 ꢃ C, CO of 2 diastereomers); HRMS (ES+): Exact
mass Calcd for C13H15NO3Cl [M+H]+, 268.0740. Found 268.0731;
m/z (ES+) 268.0 {[(C13H14NO3Cl)+H+], 12%]}, 219.1 (100%).
tionalised
a,b-unsaturated system. While the diastereofacial dis-
4.2. (4S)-4-Benzyl-3-[2-(phenylthio)propanoyl]oxazolidin-2-one 2
crimination is very small in the subsequent sulfur oxidations,
selective oxidation of the minor sulfoxide 8b to the sulfone 18
led to an enhancement of the diastereomeric excess of the sulfox-
ide, with diastereoselectivities of up to 94% de being achieved.
Benzenethiol (1.67 mL, 16.4 mmol) was added to a solution of
freshly prepared sodium ethoxide [prepared from sodium (0.38 g,
16.4 mmol) in dry ethanol (40 mL) at 0 °C] while stirring under
nitrogen. After stirring for 20 min, a solution of (4S)-4-benzyl-3-
(2-chloropropanoyl)oxazolidin-2-one 1 (3.99 g, 14.9 mmol) in eth-
anol (150 mL) was added gradually to the reaction mixture over
15 min. After stirring at room temperature for 2 h, the reaction
was quenched by the addition of water (150 mL) and dichloro-
methane (150 mL). The combined organic layers were washed with
aqueous sodium hydroxide (1 M, 2 ꢃ 150 mL), water (150 mL) and
brine (150 mL), dried and concentrated under reduced pressure to
give the crude sulfide as a clear oil. This was purified by column
chromatography on silica gel using hexane–ethyl acetate as eluent
(gradient elution 5–10% ethyl acetate) to give the sulfide 2 (4.58 g,
90%) as a clear oil and an equimolar mixture of diastereomers;
4. Experimental
All solvents were distilled prior to use as follows: dichlorometh-
ane was distilled from phosphorous pentoxide and ethyl acetate
was distilled from potassium carbonate, ethanol and methanol
were distilled from magnesium in the presence of iodine. Organic
phases were dried using anhydrous magnesium sulfate. All com-
mercial reagents, including N-chlorosuccinimide, were used with-
out further purification. All spectra were recorded at room
temperature (ꢀ20 °C) in deuterated chloroform (CDCl3) unless
otherwise stated using tetramethylsilane (TMS) as an internal
standard. Chemical shifts were expressed in parts per million
(ppm) and coupling constants in Hertz (Hz).
½
a 2D0
ꢂ
¼ þ95:2 (c 0.5, EtOH);
m
max/cmꢁ1 (film) 3061 (CH), 2929
(CH), 1779 (CO oxazolidinone), 1697 (CO); dH (300 MHz, CDCl3)
1.46 [1.5H, d, J 6.9, C(3)H3 of 1 diastereomer], 1.49 [1.5H, d, J 6.9,
C(3)H3 of 1 diastereomer], 2.66 (0.5H, dd, A of ABM, JAB 13.2, JAM
9.9, CHAHBPh of 1 diastereomer), 2.75 (0.5H, dd, A of ABM, JAB
13.2, JAM 9.6, CHAHBPh of 1 diastereomer), 3.26–3.33 (1H, 2 over-
lapping dd, B of ABM, JAB 13.2, JBM 6.6, CHAHBPh of 1 diastereomer
and B of ABM, JAB 13.2, JBM 3.3, CHAHBPh of 1 diastereomer), 4.00–
4.25 (2H, m, CH2O of 2 diastereomers), 4.49–4.61 (0.5H, m, CHN of
1 diastereomer), 4.64–4.77 (0.5H, m, CHN of 1 diastereomer), 5.15–
5.23 [1H, 2 ꢃ overlapping q, J 6.9, 6.9, C(2)H of 2 diastereomers],
7.15–7.39 (8H, m, ArH of 2 diastereomers), 7.43–7.57 (2H, m,
ArH of 2 diastereomers); dC (150 MHz, CDCl3) 16.7, 16.8 [2 ꢃ CH3,
C(3)H3 of 2 diastereomers], 37.7, 37.9 (2 ꢃ CH2, CH2Ph of 2 diaste-
reomers), 42.3, 42.6, 55.3, 55.8 [4 ꢃ CH, C(2)H and CHN of 2 diaste-
reomers], 66.1, 66.2 (2 ꢃ CH2, OCH2 of 2 diastereomers), 127.38,
127.41, 128.7, 128.8, 128.92, 128.94, 128.98, 129.02, 129.4
(9 ꢃ CH, 9 ꢃ aromatic CH), 131.5, 131.6 (2 ꢃ C, 2 ꢃ aromatic C),
134.76, 134.79 (2 ꢃ CH, 2 ꢃ aromatic CH), 135.2 (C, aromatic C),
152.9, 153.0 (2 ꢃ C, CO of 2 diastereomers), 172.1, 172.2 (2 ꢃ C,
For specific rotations, concentrations (c) are expressed in g/
100 mL. ½a T
ꢂ
D is the specific rotation of a compound and is expressed
in units of 10ꢁ1 deg cm2 gꢁ1. Single crystal X-ray analysis calcula-
tions for 7 were made using the APEX2 software,20 SHELXS
, SHELXL
21
22
23
21
22
and PLATON and for 8a using CRYSALIS
,
SHELXS
,
SHELXL and PLATON.
22
Diagrams were prepared using PLATON
.
Full structural data have
been deposited at the Cambridge Crystallographic Data Centre.
CCDC reference numbers 782119 and 782120.
4.1. (4S)-4-Benzyl-3-(2-chloropropanoyl)oxazolidin-2-one 1
Anhydrous tetrahydrofuran (30 mL) was added to a 3-necked
round-bottomed flask containing (S)-4-benzyl-2-oxazolidinone
(1.62 g, 9.0 mmol) under a nitrogen atmosphere. The resulting
solution was cooled to ꢁ78 °C. n-Butyllithium (2.3 M in hexanes,
3.97 mL, 9.1 mmol) was then added to the reaction flask over
10 min. On completion of this addition, 2-chloropropionyl chloride
(1.00 mL, 9.9 mmol) was added in one portion via syringe. The
resulting solution was stirred for 30 min at ꢁ78 °C, and then al-
lowed to warm slowly to room temperature over 30 min. The ex-
cess 2-chloropropionyl chloride was quenched by the addition of
aqueous saturated ammonium chloride (10 mL). Most of the tetra-
hydrofuran and hexane were removed by concentration at reduced
pressure (bath temperature 25–30 °C) and the resulting slurry was
extracted with dichloromethane (2 ꢃ 10 mL). The combined organ-
ic extracts were washed with sodium hydroxide (1 M, 10 mL) and
brine (10 mL), dried and concentrated under reduced pressure to
give 1 as a white solid and an equimolar mixture of diastereomers
CO of
2 diastereomers); HRMS (ES+): Exact mass Calcd for
C
19H20NO3S [M+H]+, 342.1164. Found 342.1148; m/z (ES+) 342.0
{[(C19H20NO3S)+H+], 100%]}, 104.9 (28%).
4.3. (4S)-4-Benzyl-3-[2-(benzylthio)propanoyl]oxazolidin-2-one 3
Sodium hydride (0.50 g of a 60% dispersion in mineral oil,
12.5 mmol) was placed in a three-necked round-bottomed flask un-
der a flow of nitrogen. After washing with hexane (3 ꢃ 10 mL), dry
N,N-dimethylformamide (60 mL) was added and the resulting sus-
pension was stirred for 10 min. The reaction mixture was cooled to
0 °C and benzyl thiol (1.47 mL, 12.5 mmol) was added slowly via
syringe. After stirring for 20 min, a solution of (4S)-4-benzyl-3-(2-
chloropropanoyl)oxazolidin-2-one (3.14 g, 11.7 mmol) in dry
N,N-dimethylformamide (20 mL) was added. On completion of
the addition, the ice bath was removed and the reaction mixture
was stirred at room temperature for 4 h. The reaction was quenched
by the addition of water (60 mL) and dichloromethane (60 mL) and
the layers were separated. The aqueous layer was extracted with
dichloromethane (2 ꢃ 60 mL), and the combined organic layers
were washed with sodium hydroxide (1 M, 60 mL), water
(2 ꢃ 60 mL), hydrochloric acid (2 M, 2 ꢃ 60 mL) and brine
(60 mL), dried, filtered and concentrated at reduced pressure to give
the crude sulfide 3 as a pale yellow oil and a 1:1.24 mixture of dia-
stereomers. This was purified by column chromatography on silica
(1.95 g, 80%), mp 80–82 °C; ½a D20
ꢂ
¼ þ109:0 (c 1, EtOH);
m
max/cmꢁ1
(KBr) 3028 (CH), 1786 (CO oxazolidinone), 1708 (CO); dH
(300 MHz, CDCl3) 1.72, 1.74 [3H, contains 2 overlapping d, J 6.6,
6.6, C(3)H3 of 2 diastereomers], 2.76–2.89 (1H, m, CHAHBPh of 2
diastereomers), 3.26–3.35 (1H, m, CHAHBPh of 2 diastereomers),
4.20–4.33 (2H, m, CH2O of 2 diastereomers), 4.65–4.77 (1H, m,
CHN of 2 diastereomers), 5.63–5.74 [1H, contains 2 overlapping
q, J 6.9, 6.9, C(2)H of 2 diastereomers], 7.15–7.41 (5H, m, ArH of
2 diastereomers); dC (150 MHz, CDCl3) 20.4, 20.8 [2 ꢃ CH3, C(3)H3
of 2 diastereomers], 37.3, 37.8 (2 ꢃ CH2, CH2Ph of 2 diastereomers),
50.5, 50.8, 55.3, 55.7 [4 ꢃ CH, C(2)H and CHN of 2 diastereomers],
66.4, 66.6 (2 ꢃ CH2, OCH2 of 2 diastereomers), 127.5, 127.6,
129.1, 129.4, 129.5 (5 ꢃ CH, 5 ꢃ aromatic CH), 134.77, 134.83
(2 ꢃ C, 2 ꢃ aromatic C), 152.5, 152.6 (2 ꢃ C, CO of 2 diastereomers),

2556
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
gel using hexane–ethyl acetate as eluent (gradient elution 10–20%
ethyl acetate) to give the less polar minor diastereomer as a clear
oil (1.42 g, 34%) and the more polar major diastereomer as a clear
H, 4.31; N, 3.75; S, 8.58; Cl, 9.48. Found: C, 61.21; H, 4.70; N,
3.65; S, 8.54; Cl, 9.70);
max/cmꢁ1 (KBr) 2919 (CH), 1788 (CO oxa-
m
zolidinone), 1678 (CO); dH (300 MHz, CDCl3) 2.26 (1H, dd, J 13.4,
10.0, CHAHBPh), 3.00 (1H, overlapping dd, J 13.5, 3.6, CHAHBPh),
3.84–3.93 (1H, m, one of CH2O), 3.98 (1H, dd, J 9.0, 3.9, one of
CH2O), 4.21–4.30 (1H, br m, CHN), 6.80 [1H, s, ClHC(3)@], 7.04–
7.11 (2H, m, ArH), 7.22–7.37 (6H, m, ArH), 7.44–7.52 (2H, m,
ArH); dC (125 MHz, CDCl3) 37.1 (CH2, CH2Ph), 55.5 (CH, CHN),
66.6 (CH2, OCH2), 126.4, 127.4, 128.5, 129.0, 129.3, 129.4 [6 ꢃ CH,
aromatic CH or ClHC(3)@], 131.2 [C, aromatic C or C(2)S], 132.5
[CH, aromatic CH or ClHC(3)@], 134.7, 134.8 [2 ꢃ C, aromatic C or
C(2)S], 151.8 (C, CO), 164.1 (C, CO); HRMS (ES+): Exact mass Calcd
oil (1.75 g, 43%); Minor diastereomer: ½a D20
¼ þ138:5 (c 0.04,
ꢂ
CHCl3); m
max/cmꢁ1 (film) 1778 (CO oxazolidinone), 1694 (CO); dH
(300 MHz, CDCl3) 1.52 [3H, d, J 7.2, C(3)H3], 2.71 (1H, dd, A of
ABM, JAB 13.5, JAM 9.9, CHAHBPh), 3.23 (1H, dd, B of ABM, JAB 13.5,
JAM 3.3, CHAHBPh), 3.81 (1H, A of AB system, J 13.5, one of SCH2),
3.87 (1H, B of AB system, J 13.5, one of SCH2), 3.97–4.12 (2H, m,
CH2O), 4.24–4.34 (1H, m, CHN), 4.83 [1H, q, J 7.2, C(2)H], 7.12–
7.39 (10H, m, ArH); dC (75.5 MHz, CDCl3) 17.2 [CH3, C(3)H3], 34.6
(CH2, CH2Ph), 37.9 (CH2, SCH2), 39.3, 55.6 [2 ꢃ CH, C(2)H and
CHN], 66.1 (CH2, OCH2), 127.1, 127.4, 128.4, 129.0, 129.1, 129.4
(6 ꢃ CH, 6 ꢃ aromatic CH), 135.2, 137.9 (2 ꢃ C, 2 ꢃ aromatic C),
153.0 (C, CO), 172.4 (C, CO); HRMS (ES+): Exact mass Calcd for
for
C
19H17NO3SCl [M+H]+, 374.0618. Found 374.0602; 374.0
([C19H16NO3SCl+H)+, 50%).
C
20H21NO3S23Na [M+Na]+, 378.1140. Found 378.1138; m/z (ES+)
4.5. 5-(Benzylthio)-3-(1-chloro-3-phenylpropan-2-yl)-5-(dichloro-
methyl)oxazolidine-2,4-dione-one 7 and (S)-4-benzyl-3-[(E)-2-
(benzylthio)-3-chloroacryloyl]oxazolidin-2-one 6
356.2 {[(C20H21NO3S)+H+], 100%]}, 213.2 (4%), 104.9 (12%).
Major diastereomer: ½a D20
ꢂ
¼ ꢁ27:4 (c 0.04, CHCl3);
m
max/cmꢁ1
(film) 1777 (CO oxazolidinone), 1693 (CO); dH (300 MHz, CDCl3)
1.50 [3H, d, J 6.9, C(3)H3], 2.67 (1H, dd, A of ABM, JAB 13.5, JAM
9.9, CHAHBPh), 3.21 (1H, dd, B of ABM, JAB 13.5, JAM 3.3, CHAHBPh),
3.85 (1H, A of AB system, JAB 12.6, one of SCH2), 3.90 (1H, B of AB
system, JAB 12.6, one of SCH2), 4.10–4.23 (2H, m, CH2O), 4.64–
4.75 (1H, m, CHN), 4.87 (1H, q, J 6.9, C(2)H), 7.18–7.39 (10H, m,
ArH); dC (75.5 MHz, CDCl3) 16.9 [CH3, C(3)H3], 34.3 (CH2, CH2Ph),
37.5 (CH2, SCH2), 39.2, 55.2 [CH, C(2)H and CHN], 66.0 (CH2,
OCH2), 127.2, 127.4, 128.6, 129.0, 129.2, 129.5 (6 ꢃ CH, 6 ꢃ aro-
matic CH), 135.2, 137.5 (2 ꢃ C, 2 ꢃ aromatic C), 153.0 [C, CO],
172.0 [C, CO]; HRMS (ES+): Exact mass Calcd for C20H21NO3S23Na
[M+Na]+, 378.1140. Found 378.1134; m/z (ES+) 356.2
{[(C20H21NO3S)+H+], 100%]}.
Unrecrystallised N-chlorosuccinimide (2.63 g, 19.3 mmol) was
added in one portion to a solution of the sulfide (4S)-4-benzyl-3-
[2-(benzylthio)propanoyl]oxazolidin-2-one 3 (3.12 g, 8.8 mmol)
in toluene (60 mL). The flask was immediately immersed in an
oil bath at 130 °C and heating was maintained for 30 min with stir-
ring. The reaction mixture was cooled to 0 °C and the succinimide
by-product was removed by filtration. The solvent was evaporated
at reduced pressure to give the crude product as an orange oil, ratio
of 7:6 0.43:1. Following purification by column chromatography
on silica gel using hexane–ethyl acetate as eluent (gradient elution
5–40% ethyl acetate), 7 was isolated as a white solid (0.45 g, 9%);
(C20H18Cl3NO3S requires C, 52.36; H, 3.95; N, 3.05. Found: C,
For subsequent reactions, the 2 diastereomers were combined
(ratio of diastereomers 1:1.24) and the specific rotation of the mix-
52.48; H, 4.03; N, 3.00); m
max/cmꢁ1 (KBr) 3028 (CH), 2924 (CH),
1827 (CO), 1754 (CO); dH (300 MHz, CDCl3) 3.19 (1H, dd, A of
ABX, JAB 14.3, JAX 6.9, one of NCHCH2), 3.27 (1H, dd, B of ABX, JAB
14.3, JBX 9.6, one of NCHCH2), 3.73 (1H, dd, A of ABX, JAB 11.9, JAX
4.5, one of CH2Cl), 3.78 (1H, d, A of AB system, JAB 11.4, one of
SCH2), 3.83 (1H, d, B of AB system, JAB 11.4, one of SCH2), 4.08
(1H, dd, B of ABX, JAB 11.9, JBX 10.2, one of CH2Cl), 4.64–4.75
(1H, br m, CHN), 5.82 (1H, s, CHCl2), 7.14–7.36 (10H, m, ArH);
dC (75.5 MHz, CDCl3) 34.6, 35.5 (2 x CH2, NCHCH2 and SCH2), 42.4
(CH2, CH2Cl), 56.9 (CH, CHN), 70.6 (CH, CHCl2), 92.9 [C, C(5)],
127.6, 128.2, 128.9, 129.0, 129.1, 129.3 (6 ꢃ CH, 6 ꢃ aromatic
CH), 133.9, 135.0 (2 ꢃ C, 2 ꢃ aromatic C), 151.9 (C, CO), 167.8
(C, CO).
ture was recorded; ½a D20
¼ þ34:6 (c 0.5, CHCl3) (of the mixture of
ꢂ
diastereomers).
4.4. (S)-4-Benzyl-3-[(E)-3-chloro-2-(phenylthio)acryloyl] oxazoli-
din-2-one 4 and (S)-4-benzyl-3-[(Z)-3-chloro-2-(phenylthio)-
acryloyl]oxazolidin-2-one 5
Unrecrystallised N-chlorosuccinimide (4.00 g, 29.4 mmol) was
added in one portion to a solution of the sulfide (4S)-3-[2-(phenyl-
thio)propanoyl]-4-benzyloxazolidin-2-one 2 (4.56 g, 13.4 mmol) in
toluene (80 mL). The flask was immediately immersed in an oil
bath at 130 °C and heating was maintained for 15 min with stir-
ring. The reaction mixture was cooled to 0 °C and the succinimide
by-product was removed by filtration. The solvent was evaporated
at reduced pressure to give the crude product as a clear oil, ratio of
4:5 1:1.05. Following purification by column chromatography on
silica gel using hexane–ethyl acetate as eluent (gradient elution
5–40% ethyl acetate), 4 (1.42 g, 29%) was isolated as a low melting
The structure of 7 was determined by single crystal X-ray dif-
fraction on a crystalline sample of 7 recrystallised from ethanol.
Crystals of 7 are orthorhombic, space group P212121, formula
C
20H18Cl3NO3S, M = 458.76, a = 9.4675(9) Å, b = 10.1086(9) Å,
c = 21.340(2) Å, = 90.00°, b = 90.00°,
= 90.00°, U = 2042.3(3) Å3,
F(0 0 0) = 944, (Mo K
) = 0.573 mmꢁ1, R(Fo) = 0.0574, for 4406
observed reflections with I > 2
(I), wR2(F2) = 0.1525 for all 5951
unique reflections. Data in the h range 1.91–30.00° were collected
at 100 K on a Bruker Apex II Duo diffractometer using Mo K radi-
a
c
l
a
r
white solid; ½a 2D0
ꢂ
¼ þ11:1 (c 2.5, EtOH);
m
max/cmꢁ1 (film) 3063
(CH), 2922 (CH), 1790 (CO oxazolidinone), 1688 (CO); dH
(300 MHz, CDCl3) (the spectrum of this compound is very poorly
resolved in the oxazolidinone region of dH 2–5) 2.59–2.82 (1H, br
m, CHAHBPh), 3.20–3.39 (1H, br m, CHAHBPh), 4.07–4.20 (2H, m,
CH2O), 4.49–4.73 (1H, br m, CHN), 6.73 [1H, s, ClHC(3)@], 7.13–
7.64 (10H, m, ArH); dC (67.8 MHz, CDCl3) 37.5 (CH2, CH2Ph), 55.0
(CH, CHN), 66.4 (CH2, CH2O), 124.8 (C, aromatic C), 127.4, 128.1,
128.99, 129.01, 129.1, 129.26, 129.29, 129.4, 129.8, 130.9, 131.2,
134.9 [aromatic CH, aromatic C, ClHC(3) and C(2)S], 151.6 (C, CO),
161.8, 163.3 (2 ꢃ C, CO); HRMS (ES+): Exact mass Calcd for
a
ation, k = 0.71073 Å, and corrected for Lorentz and polarisation ef-
fects. The structure was solved by direct methods and refined by
full-matrix least-squares using all F2 data. The hydrogen atoms
were placed in calculated positions and allowed to ride on the par-
ent atom.
Compound 6 (1.41 g, 41%) was isolated as a white solid, mp 97–
99 °C; ½a 2D0
¼ þ63:2 (c 0.5, CHCl3); (C20H18ClNO3S requires C,
ꢂ
61.93; H, 4.68; N, 3.61; S, 8.27; Cl, 9.14. Found: C, 61.61; H, 4.58;
N, 3.62; S, 8.27; Cl, 9.38); m
max/cmꢁ1 (KBr) 3074 (CH), 2917 (CH),
C
19H17NO3SCl [M+H]+, 374.0618. Found 374.0604; 374.0
1773 (CO oxazolidinone), 1674 (CO); dH (300 MHz, CDCl3) (The
spectrum of this compound was very poorly resolved in the region
of dH 3–5) 2.77 (1H, dd, A of ABX, JAB 13.5, JAX 9.9, CHAHBPh), 3.32–
3.45 (1H, br m, CHAHBPh), 3.93 (2H, s, SCH2), 4.14–4.22 (2H, br m,
([C19H16NO3SCl+H)+, 28%).
Compound 5 (1.11 g, 22%) was isolated as a white solid, mp 97–
99 °C; ½a 2D0
¼ þ5:5 (c 2.5, DCM); (C19H16ClNO3S requires C, 61.04;
ꢂ

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
2557
CH2O), 4.53–4.73 (1H, br m, CHN), 6.33 [1H, s, ClHC(3)@], 7.20–
7.41 (10H, m, ArH); dC (75.5 MHz, CDCl3) 37.7, 39.0 (2 ꢃ CH2,
SCH2 and CH2Ph), 55.0 (CH, CHN), 66.4 (CH2, OCH2), 125.5, 127.5,
128.5, [3 ꢃ CH, aromatic CH or ClHC(3)@], 128.6 [C, aromatic C or
C(2)S], 129.1, 129.3, 129.4, 129.5 [4 ꢃ CH, aromatic CH or
ClHC(3)@], 135.0, 137.0 [2 ꢃ C, aromatic C or C(2)S], 151.6 (C, CO),
164.1 (C, CO); HRMS (ES+): Exact mass Calcd for C20H19NO3SCl
[M+H]+, 388.0774. Found 388.0789; 388 ([M+H)+, 54%).
reomers. After purification by column chromatography on silica gel
using hexane–ethyl acetate as eluent (gradient elution 10–20%
ethyl acetate), the less polar minor sulfoxide diastereomer 16b
was isolated as a low melting white solid (0.006 g, 5%); dH
(300 MHz, CDCl3) 2.81 (1H, dd, A of ABX, JAB 13.8, JAX 10.5,
CHAHBPh), 3.53 (1H, dd, B of ABX, JAB 13.8, JBX 3.6, CHAHBPh),
4.09–4.16 (1H, m, CHAHBOH), 4.19 (1H, dd, B of ABX, JAB 9.0, JBX
3.3, CHAHBOH), 4.57–4.68 (1H, br m, CHN), 6.72 [1H, s, ClHC(3)@],
7.19–7.41 (5H, m, ArH), 7.48–7.63 (3H, m, ArH), 7.80–7.92 (2H, m,
ArH); m/z (ES+) 392.1 {[(C19H16NO4S37Cl)+H+], 42%}, 390.1
{[(C19H16NO4S35Cl)+H+], 100%}.
An X-ray crystal structure of the sulfoxide derivative 8 was ob-
tained, which confirmed the relative stereochemistry as E. The rel-
ative stereochemistry of 6 was assigned by analogy.
A second fraction containing a mixture of the less polar sulfoxide
diastereomer 16b and the sulfone 17 in a ratio of 1:4.7, respectively,
was isolated (0.009 g, 7%) as a white solid. The sulfone 17 was seen
at dH (300 MHz, CDCl3) 2.89 (1H, dd, A of ABX, JAB 13.5, JAX 9.9,
CHAHBPh), 3.45 (1H, dd, B of ABX, JAB 13.5, JBX 3.6, CHAHBPh), 4.27
(1H, dd, A of ABX, JAB 9.0, JAX 3.3, CHAHBOH), 4.35 (1H, dd, B of
ABX, JAB 9.0, JBX 7.8, CHAHBOH), 4.72–4.84 (1H, br m, CHN), 6.87
[1H, s, ClHC(3)@], 7.19–7.42 (5H, m, ArH), 7.49–7.75 (3H, m, ArH),
8.03–8.13 (2H, m, ArH); m/z (ES+) 408.1 {[(C19H16NO5S37Cl)+H+],
26%}, 406.1 {[(C19H16NO5S35Cl)+H+], 58%}, 392.1 {[(C19H16
NO4S37Cl)+H+], 22%}, 390.1 {[(C19H16NO4S35Cl)+H+], 54%}.
4.6. (S)-4-Benzyl-3-[(E)-3-chloro-2-(Ss/Rs)-(benzenesulfinyl)
acryloyl]oxazolidin-2-one 15
A solution of OxoneÒ (0.85 g, 1.4 mmol) in water (5 mL) was
added to a stirring solution of (S)-4-benzyl-3-[(E)-3-chloro-2-
(phenylthio)acryloyl]oxazolidin-2-one 4 (0.26 g, 0.7 mmol) in ace-
tone (20 mL) at room temperature. A colourless precipitate formed
immediately. The reaction mixture was stirred for 40 h. Water
(20 mL) was added and the aqueous solution was extracted with
dichloromethane (3 ꢃ 20 mL). The combined extracts were washed
with water (2 ꢃ 20 mL) and brine (20 mL), dried, filtered and con-
centrated at reduced pressure to give the crude sulfoxides 15a and
15b as a white sticky solid and a 1:0.91 mixture of diastereomers.
Following purification by column chromatography on silica gel
using dichloromethane–methanol as eluent (gradient elution
0–0.5% methanol), the less polar minor diastereomer 15b was iso-
A fraction containing the more polar major sulfoxide diastereo-
mer 16a was also isolated as a white solid (0.009 g, 7%); dH
(300 MHz, CDCl3) 2.72 (1H, dd, A of ABX, JAB 13.5, JAX 9.9, CHAHBPh),
3.25 (1H, dd, B of ABX, JAB 13.5, JBX 3.6, CHAHBPh), 4.19 (1H, dd, A of
ABX, JAB 9.0, JAX 3.0, CHAHBOH), 4.33 (1H, overlapping dd, B of ABX,
JAB 9.0, JBX 8.1, CHAHBOH), 4.67–4.79 (1H, br m, CHN), 6.75 [1H, s,
ClHC(3)@], 7.12–7.40 (5H, m, ArH), 7.48–7.63 (3H, m, ArH), 7.80–
7.91 (2H, m, ArH); m/z (ES+) 392.1 {[(C19H16NO4S37Cl)+H+], 42%},
390.1 {[(C19H16NO4S35Cl)+H+], 100%}.
lated as a low melting white solid (0.13 g, 48%); m
max/cmꢁ1 (film)
3066 (CH), 2919 (CH), 1795 (CO oxazolidinone), 1687 (CO), 1085
(SO); dH (300 MHz, CDCl3) 2.71 (1H, dd, A of ABX, JAB 13.5, JAX
10.5, CHAHBPh), 3.32–3.47 (1H, br m, CHAHBPh), 4.15–4.27 (2H,
m, CH2O), 4.64–4.85 (1H, br m, CHN), 7.15–7.42 (5H, m, ArH),
7.50–7.77 [4H, m, ArH and ClHC(3)@], 7.92 (2H, d, J 7.5, ArH); m/
z (ES+) 392.0 {[(C19H16NO4S37Cl)+H+], 16%}, 390.0 {[(C19H16NO4
S35Cl)+H+], 36%}.
The 13C NMR spectrum was recorded on a 1.65:1:1.19 mixture
of 16a:16b:17: dC (67.8 MHz, CDCl3) 37.7, 37.8*, 38.2À (3 ꢃ CH2,
À
À
*
*
CH2Ph), 55.66 , 55.72, 55.8 (3 ꢃ CH, CHN), 66.9 , 67.16, 67.20
(3 ꢃ CH2, CH2O), 126.2, 126.3, 126.4, 126.8, 127.0, 127.9, 129.2,
129.36, 129.41, 129.6, 129.7, 129.8, 132.5, 133.1, 134.7 [15 ꢃ CH,
aromatic CH and ClHC(3)@], 135.5, 140.3, 142.0, 142.9, 143.1,
145.6, 145.7, 152.9, 153.1, 160.6À, 160.7, 160.9 [12 ꢃ C, CO, aro-
A second fraction containing the more polar major diastereomer
15a was also isolated (0.06 g, 27%) as a white solid;
m
max/cmꢁ1
(KBr) 3061 (CH), 2923 (CH), 1789 (CO oxazolidinone), 1685 (CO),
1081 (SO); dH (300 MHz, CDCl3) 2.79 (1H, dd, J 13.5, 9.3, CHAHBPh),
3.41 (1H, dd, J 13.5, 3.6, CHAHBPh), 4.22 (1H, dd, J 9.0, 3.0, one of
CH2O), 4.34 (1H, dd, J 9.0, 8.1, one of CH2O), 4.69–4.86 (1H, br m,
CHN), 7.02–7.99 [11H, m, ArH and ClHC(3)@]; m/z (ES+) 392.0
{[(C19H16NO4S37Cl)+H+], 12%}, 390.0 {[(C19H16NO4S35Cl)+H+], 26%}.
The 13C NMR spectrum was recorded on a 3:1 mixture of 15a
matic C and C(2)S]; HRMS (ES+): Exact mass Calcd for
C
19H17NO5SCl 17 [M+H]+, 406.0516. Found 406.0510; Exact mass
Calcd for C19H17NO4SCl (16a and 16b) [M+H]+, 390.0567. Found
390.0558; 406.1 (8%), 390.1 (100%).
*Minor diastereomer.
ÀMajor diasteromer.
*
*
and 15b: dC (67.8 MHz, CDCl3) 37.3, 37.8 (CH2Ph), 55.1 , 55.6
(CHN), 66.5*, 66.8 (CH2O), 125.7, 126.0, 127.1, 127.9, 129.3,
129.4, 132.5, 132.6, 134.3, 134.7, 139.2, 151.0 [aromatic CH, aro-
matic C, C(2)S and ClHC(3)@].
4.8. (S)-4-Benzyl-3-[(E)-2-(Ss/Rs)-(benzylsulfinyl)-3-chloro-
acryloyl]oxazolidin-2-one 8 and (S)-4-benzyl-3-[(E)-2-
(benzylsulfonyl)-3-chloroacryloyl]oxazolidin-2-one 18
*Minor diastereomer.
A solution of OxoneÒ (0.60 g, 1.0 mmol) in water (5 mL) was
added to a stirring solution of (S)-4-benzyl-3-[(E)-2-(benzylthio)-
3-chloroacryloyl]oxazolidin-2-one 6 (0.19 g, 0.5 mmol) in acetone
(20 mL) at room temperature. A colourless precipitate formed
immediately. The reaction mixture was stirred for 16 h. Water
(20 mL) was added and the aqueous solution was extracted with
dichloromethane (3 ꢃ 20 mL). The combined extracts were washed
with water (2 ꢃ 20 mL) and brine (20 mL), dried, filtered and con-
centrated at reduced pressure to give the crude product as a white
4.7. (S)-4-Benzyl-3-[(Z)-3-chloro-2-(Ss/Rs)-(benzenesulfinyl)
acryloyl]oxazolidin-2-one 16 and (S)-4-benzyl-3-[(Z)-3-chloro-
2-(benzenesulfonyl)acryloyl]oxazolidin-2-one 17
A solution of mCPBA (0.08 g of 77% pure material, 0.4 mmol) in
dichloromethane (4 mL) was added to a stirring solution of (S)-4-
benzyl-3-[(Z)-3-chloro-2-(phenylthio)acryloyl]oxazolidin-2-one 5
(0.12 g, 0.3 mmol) in dichloromethane (4 mL) at room tempera-
ture. After stirring at room temperature for 1 h, the reaction was
quenched by the addition of saturated sodium bicarbonate
(10 mL). The layers were separated and the aqueous layer was
washed with dichloromethane (2 ꢃ 10 mL). The combined organic
layers were washed with water (2 ꢃ 10 mL) and brine (10 mL),
dried and concentrated to give the product as a white sticky solid
and a 1:0.68:0.53 mixture of 16a:16b:17 sulfone/sulfoxide diaste-
*
solid and a mixture of 8a, 8b and 18 in a ratio of 1:0.03:0.7,
respectively (by 1H NMR spectroscopy). Following purification by
column chromatography on silica gel using hexane–ethyl acetate
as eluent (gradient elution 10–20% ethyl acetate), 18 was isolated
as a white solid (0.03 g, 16%), mp 162–164 °C; (C20H18ClNO5S re-
quires C, 57.21; H, 4.32; N, 3.34; S, 7.64; Cl, 8.44. Found: C,
56.94; H, 4.34; N, 3.25; S, 7.84; Cl, 8.30);
(CH), 2921 (CH), 1784 (CO), 1671 (CO), 1390 (asymmetric SO2
m
max/cmꢁ1 (KBr) 3072

2558
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 2550–2558
stretch), 1116 (symmetric SO2 stretch); dH (300 MHz, CDCl3) (This
spectrum was very poorly resolved) 2.72–2.99 (1H, br m,
CHAHBPh), 3.36–3.59 (1H, br m, CHAHBPh), 4.18–4.65 (4H, br m,
SCH2 and CH2OH), 4.73–4.90 (1H, br m, CHN), 6.70 [0.42H, s,
ClHC(3)@], 6.78 [0.58H, s, ClHC(3)@], 7.19–7.58 (10H, m, ArH); dC
(75.5 MHz, CDCl3) 37.2/37.9* (2 ꢃ CH2, CH2Ph), 55.3*/55.5
diffractometer using Cu Ka graphite monochromated radiation,
k = 1.54184 Å, and corrected for Lorentz and polarisation effects.
The structure was solved by direct methods and refined by full-ma-
trix least-squares using all F2 data. The hydrogen atoms were placed
in calculated positions and allowed to ride on the parent atom.
*Characteristic signals for 8b were evident in the 1H NMR of the
crude product from the mCPBA reaction at dH (300 MHz, CDCl3)
3.56 (1H, dd, J 13.5, 3.3, one of CH2Ph), 4.79–4.87 (1H, m, CHN),
6.36 [1H, s, ClHC(3)@].
*
(2 ꢃ CH, CHN), 61.6 /61.8, 66.6 (major and minor) (3 ꢃ CH2, OCH2
and SCH2), 127.6, 128.8*, 129.0, 129.2, 129.4, 131.3 (6 ꢃ CH,
6 ꢃ aromatic CH), 134.6, 135.3, 135.8 [3 ꢃ C, 2 ꢃ aromatic C and
C(2)S], 136.6/137.5* [2 ꢃ CH, ClHC(3)@], 151.1 (major and minor)
(C, CO), 160.1 (major and minor) (C, CO); HRMS (ES+): Exact mass
Calcd for C20H19NO5S35Cl [M+H]+ 420.0672. Found 420.0655; m/z
(ES+) 422.2 {[(C20H18NO5S37Cl)+H+], 42%}, 420.0 {[(C20H18NO5
S35Cl)+H+], 100%}.
Acknowledgements
IRCSET and University College Cork are gratefully acknowl-
edged for funding of this work. We thank Oxford diffraction for
data collection and structural analysis of compound 8a.
*Signals for major diastereomer.
The more polar fraction contained 8a (0.03 g, 17%) which was
isolated as a white solid, mp 133–135 °C; ½a D20
¼ ꢁ10:8 (c 0.5,
ꢂ
References
CHCl3); (C20H18ClNO4S requires C, 59.48; H, 4.49; N, 3.47; S, 7.94;
Cl, 8.78. Found: C, 59.18; H, 4.48; N, 3.38; S, 7.84; Cl, 8.80);
1. Maguire, A. R.; Murphy, M. E.; Schaeffer, M.; Ferguson, G. Tetrahedron Lett.
1995, 36, 467–470.
m
max/cmꢁ1 (KBr) 3060 (CH), 2917 (CH), 1787 (CO oxazolidinone),
2. Kissane, M.; Murphy, M.; Lynch, D.; Ford, A.; Maguire, A. R. Tetrahedron 2008,
64, 7639–7649.
1667 (CO), 1061 (SO); dH (300 MHz, CDCl3) 2.80 (1H, dd, A of
ABX, JAB 13.5, JAX 9.9, CHAHBPh), 3.41 (1H, dd, B of ABX, JAB 13.5,
JAX 3.6, CHAHBPh), 4.18–4.46 (4H, m, SCH2 and CH2O), 4.66–4.81
(1H, m, CHN), 6.33 [1H, s, ClHC(3)@], 7.18–7.50 (10H, m, ArH); dC
(75.5 MHz, CDCl3) 37.9 (CH2, CH2Ph), 55.3 (CH, CHN), 60.4, 66.7
(2 ꢃ CH2, OCH2 and SCH2), 126.5, 127.6 (2 ꢃ CH, aromatic CH),
128.2 (C, aromatic C or SC@), 128.7, 129.1, 129.4, 131.0 [4 ꢃ CH
(for 5 carbons), aromatic CH and ClHC(3)@], 134.7, 139.1 (2 ꢃ C,
aromatic C or SC@), 151.6 (C, CO), 160.7 (C, CO); HRMS (ES+): Exact
mass Calcd for C20H19NO4S35Cl [M+H]+ 404.0723. Found 404.0715;
3. Murphy, M.; Lynch, D.; Schaeffer, M.; Kissane, M.; Chopra, J.; O’Brien, E.; Ford,
A.; Ferguson, G.; Maguire, A. R. Org. Biomol. Chem. 2007, 5, 1228–1241.
4. Kissane, M.; Maguire, A. R. Chem. Soc. Rev. 2010, 39, 845–883.
5. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129.
6. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–875.
7. Evans, D. A.; Shaw, J. T. Actual. Chim. 2003, 35–38.
8. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30, 3–12.
9. Evans, D. A. Aldrichim. Acta 1982, 15, 23–32.
10. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. J. Am.
Chem. Soc. 1992, 114, 5977–5985.
11. Kissane, M.; Lawrence, S. E.; Maguire, A. R. Tetrahedron: Asymmetry 2010, 21,
871–884.
12. Gage, J. R.; Evans, D. A. Org. Synth. 1993, Coll. Vol. 8, 83.
13. Clark-Lewis, J. W. Chem. Rev. 1958, 58, 63–99.
m/z
(ES+)
406.2
{[(C20H18NO4S37Cl)+H+],
40%},
404.2
{[(C20H18NO4S35Cl)+H+], 100%}.
The stereochemistry of 8a was determined by single crystal X-
ray diffraction on a crystalline sample of 8a recrystallised from
dichloromethane and hexane.
14. Bao, J. U.S. Pat. Appl. Publ. US 2007078177.
15. Cesa, S.; Mucciante, V.; Rossi, L. Tetrahedron 1999, 55, 193–200.
16. Kissane, M.; Lynch, D.; Chopra, J.; Lawrence, S. E.; Maguire, A. R. Tetrahedron:
Asymmetry 2008, 19, 1256–1273.
17. Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58,
4529–4533.
18. Kelly, P.; Lawrence, S. E.; Maguire, A. R. Synlett 2006, 1569–1573.
19. Kelly, P.; Lawrence, S. E.; Maguire, A. R. Eur. J. Org. Chem. 2006, 4500–4509.
20. APEX2 v2010.1-2, Bruker AXS, 2010.
21. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112–122.
22. Spek, A. L. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 148–155.
23. CRYSALIS RED, Oxford Diffraction Ltd, 2008.
Crystals of 8a are monoclinic, space group P21, formula
C
20H18ClNO4S, M = 403.86, a = 6.3053(7) Å, b = 23.418(4) Å,
c = 12.9820(13) Å, = 90.00°, b = 90.715(10)°, = 90.00°, U =
1916.8(4) Å3, F(0 0 0) = 840, ) = 3.007 mmꢁ1
(Cu R(Fo) =
(I),
a
c
l
Ka
,
0.1125, for 4041 observed reflections with I > 2
r
wR2(F2) = 0.3225 for all 4887 unique reflections. Data in the h range
3.40–67.42° were collected at 293 K on an Oxford Gemini R Ultra