Diastereoselective sulfur oxidation of 2-thio-3-chloroacrylamides

Article abstract of DOI:10.1016/j.tetasy.2010.05.004

Diastereoselective sulfur oxidation in 2-thio-3-chloroacrylamides is described. A range of chiral amine auxiliaries was incorporated in the β-chloroacrylamide, and the efficiency with which the stereochemistry was relayed to the sulfur centre during sulfoxidation was investigated. Diastereomeric ratios of up to 3.3:1 were achieved.

Full text of DOI:10.1016/j.tetasy.2010.05.004

Tetrahedron: Asymmetry 21 (2010) 871–884
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective sulfur oxidation of 2-thio-3-chloroacrylamides
Marie Kissane 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:
Diastereoselective sulfur oxidation in 2-thio-3-chloroacrylamides is described. A range of chiral amine
auxiliaries was incorporated in the b-chloroacrylamide, and the efficiency with which the stereochemis-
try was relayed to the sulfur centre during sulfoxidation was investigated. Diastereomeric ratios of up to
3.3:1 were achieved.
Received 19 April 2010
Accepted 4 May 2010
Available online 2 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the diastereomeric ratios achieved are modest, the resulting sulf-
oxides have significant synthetic potential, for example, as Michael
The asymmetric synthesis of sulfoxides has received particular
attention in recent years as the sulfoxide moiety has been shown
to provide excellent stereochemical control as a chiral auxil-
iary.1–5 Furthermore, many enantiopure sulfoxides are known to
have significant biological activity.6–8 Several methods are cur-
rently available for the preparation of optically active sulfox-
ides.9–16 We have recently described the enantioselective sulfur
oxidation of 2-thio-3-chloroacrylamides, with enantioselectivities
of up to 52% ee achieved using the Kagan oxidation and up to
71% ee when the Bolm oxidation is employed (Scheme 1).17
The diastereoselective oxidation of chiral sulfides using achiral
oxidants has also been described by several research groups.18–25
The basic principle of diastereoselective oxidation is to exploit
the proximity of a defined stereogenic centre to relay stereochem-
istry to the newly formed sulfoxide. Steric interactions or neigh-
bouring group participation accounts for the diastereoselectivity
achieved.26
As the Kagan and Bolm methods led to limited success in the
asymmetric sulfur oxidation of the b-chloroacrylamides,17 the dia-
stereoselective sulfur oxidation of the b-chloroacrylamides was
investigated in detail during the current study. A range of chiral
amine auxiliaries was incorporated in the b-chloroacrylamide,
and the efficiency with which the stereochemistry was relayed to
the sulfur centre during sulfoxidation was investigated. While
acceptors, dienophiles or dipolarophiles.27,28
2. Results and discussion
2.1. Preparation of sulfides
Treatment of a series of
a
-thioamides with N-chlorosuccinimide
resulting in the efficient stereoselective transformation to the anal-
ogous
ety of
a
-thio-b-chloroacrylamides has been described.29–31 A vari-
a-thioamides bearing chiral amide auxiliaries were similarly
transformed to the analogous b-chloroacrylamides by reaction
with NCS (typically 1.95 equiv at 90 °C), with yields following
chromatographic purification ranging from 29% to 76%; Table 1
summarises the results.
The b-chloroacrylamides 11–20 were synthesised in toluene by
reacting the corresponding a-thioamide with 1.95 equiv of NCS at
90 °C. The presence of a hydroxyl group on the amide appears to
have a significant impact on the efficiency of the transformation,
with poor efficiency observed on transformation of the a-thioam-
ides 2–4 and 6–9 relative to derivatives without hydroxyl groups.
In the absence of the hydroxyl group a substantial increase in the
efficiency was observed; for example, sulfides 9 and 10 differ only
in the presence of a primary hydroxyl group, and on reaction with
NCS under identical conditions there is a dramatic difference in the
efficiency of the transformation to the b-chloroacrylamides (28%
with 9 and 96% with 10). The reaction mixtures from the amides
bearing the hydroxyl groups were complex; no other significant
identifiable product was isolated, but all of the starting material
had been consumed.
Information on the conformation of the hydroxylated b-chloro-
acrylamides, and in particular, the hydrogen-bonding patterns, was
of interest as this may aid in explaining the preferred approach of
the oxidant in subsequent diastereoselective oxidations. The con-
formation of 16 in the solid state was determined by single crystal
Kagan Oxidation (up to 52% ee)
or
O
O
O
S
R
NHR1
RS
Cl
NHR1
Bolm Oxidation (up to 71% ee)
Cl
Scheme 1.
* Corresponding author. Tel.: +353 21 4901693; fax: +353 21 4274097.
E-mail address: a.maguire@ucc.ie (A.R. Maguire).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.004

872
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
Table 1
tion with the benzene rings in a T-shaped orientation. The angle
between the benzene ring planes is 87.4°. The edge hydrogen atom
on the benzene ring of the phenylglycinol moiety (labelled H7) is
projected into the face of the phenylthio ring at a close-contact
perpendicular distance of 2.69 Å, with a H7-to-centroid distance
of 2.70 Å and offset by 0.18 Å from the benzene ring centre. These
values are within the range of those normally observed for edge-
to-face interactions.32
Synthesis of b-chloroacrylamides bearing chiral amide auxiliaries
O
SR
RS
Cl
1.95 eq. NCS, 90 °C
Toluene, 0.5-2h
NHAux
NHAux
O
Edge-to-face interactions between aromatic rings were first
reported in 1958 by Cox et al. in single crystals of benzene.33 Influ-
ential work by Burley and Petsko established the importance of
edge-to-face interactions between aromatic rings in determining
the tertiary and quaternary crystalline structures of peptides and
proteins.34,35 Edge-to-face interactions have since been cited as a
structure-determining factor in many examples of molecular
recognition.36–39 Jennings et al. were the first to identify an intra-
molecular edge-to-face interaction in a simple synthetic acyclic
organic molecule in both solution and the solid state.32
The hydrogen-bonding network present in the solid state of 16
is depicted in Figure 1; intramolecular hydrogen bonds exist be-
tween the amide proton and the oxygen of the hydroxyl group
(with a bond length of 2.56 Å) and between the amide proton
and the sulfur atom (with a bond length of 2.74 Å). An intermolec-
ular hydrogen bond between the hydroxyl proton and the carbonyl
group is also evident, with a bond length of 1.91 Å.
Based on this structural analysis, a similar intramolecular
hydrogen bond between the amide proton and the oxygen of the
hydroxyl group can be envisaged in the related hydroxylated b-
chloroacrylamides (Fig. 2), thereby locating the 20-t-butyl, phenyl
or benzyl substituent over one face of the vinyl sulfide and thus
impacting on the diastereofacial approach of the subsequent
oxidation.
½ ꢀ
a 2D0
c
Sulfide
R
Aux
Z/
E
b-Cl
%
%
Efficiencya
Yieldb
Ph
(R)-
11
1d
2d
Bn
Bn
Z
Z
70
61
66.5
(R)-
12
OH
Ph
40
35
32
51
ꢁ54.2
ꢁ30.0
Ph
(S)-
13
3d
Bn
Bn
Z
Z
HO
HO
(S)-
14
4d
36
29
106.0
Ph
CH3
(R)-
15
5e
6d
Ph
Ph
Z
Z
56
41
47
41
6.4
(R)-
16
OH
64.5
Ph
2.2. Diastereoselective oxidation
7d
Ph
Ph
Z
Z
17
26
20
47
34
60.1
84.3
The diastereoselective sulfur oxidation of a range of b-chloro-
acrylamides containing some simple chiral amide auxiliaries was
next investigated, with the results summarised in Table 2. All oxi-
dations were conducted using 2 equiv of OxoneÒ in acetone and
water at room temperature.
HO
Ph
(S)-
18
8d
HO
HO
Oxidation of the a-methylbenzylamide-derived b-chloroacryla-
mide 11 led to a sulfoxide 21 with diastereomeric ratio of 1.3:1,
indicating that simple steric effects do not lead to high diastereo-
selection. The introduction of a hydroxyl group in the phenylgly-
cinol-derived b-chloroacrylamides 12 and 16 allows the potential
for conformational control through hydrogen bonding to the nitro-
gen or carbonyl group, and moderate diastereoselection was
achieved; one of the faces of the b-chloroacrylamide is sterically
protected due to the position of the phenyl group on the auxiliary.
When the phenyl group is moved further away from the stereogen-
ic centre in the phenylalaninol derivatives 13 and 18, the diaste-
reoselection dramatically decreases as the introduction of the
extra CH2 group introduces more conformational flexibility into
the structure and the phenyl group has less impact on the reaction
site. Employment of the aminoindanol-substituted b-chloroacryla-
mide 17, a conformationally constrained analogue of phenylglycin-
ol, resulted in a slight decrease in the selectivity to afford a
diastereomeric ratio of 26 of 1.6:1, but incorporation of the more
sterically demanding t-leucinol as a chiral auxiliary in 14 and 19
led to a significant increase, with a diastereomeric ratio of 3.3:1
achieved for the S-benzyl-derived sulfoxide 27. To confirm that
the hydroxy group is critical, the diastereoselection in the oxida-
tion of 20, in which the t-butyl group was maintained and the hy-
droxy group was removed, was studied and the stereoselectivity
decreased dramatically to just 5% de (Fig. 3). Interestingly, the dia-
stereoselection in the S-benzyl and S-phenyl series is very similar;
(S)-
19
9f
Ph
Ph
Z
Z
28
96
44
76
ꢁ67.7
(R)-
20
10d
92.9
Estimated by integration of the b-H signal in the 1H NMR spectrum of the crude
product. The remaining material is a complex mixture of unidentified material.
Yield after chromatography on silica gel.
For details, see Section 4. An interesting effect was observed for the specific
rotation values; for the auxiliaries bearing a hydroxyl group on the amide, the sign
of the optical rotation measurement was opposite for the benzylthio- and phen-
ylthio-derivatives.
a
b
c
d
Equimolar mixture of diastereomers.
1:1.40 mixture of diastereomers.
1:1.22 mixture of diastereomers.
e
f
X-ray diffraction after recrystallisation from dichloromethane/pen-
tane (Fig. 1).
Examination of the resulting structure revealed some very
interesting features. Firstly, the structure confirms the Z-stereo-
chemistry of the hydroxylated b-chloroacrylamide 16. Notably,
an unexpected intramolecular attractive edge-to-face CH–
matic interaction was also evident, leading to a crowded conforma-
p aro-

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
873
Figure 1. X-ray structure of 16.
comparing entries 2 and 3 and entries 7 and 8 in Table 2, slightly
higher diastereocontrol is observed in the phenylalaninol series
with the S-phenyl substituent, while in the t-leucinol series the
S-benzyl derivative results in slightly higher diastereocontrol.
While there is no structural data confirming the relative stereo-
chemistry in the hydroxylated derivatives, an X-ray crystal struc-
ture has been determined of one of the compounds bearing the
on one of the two diastereotopic lone pairs of the sulfur atom
(Fig. 2). Changing the steric requirements of the auxiliary has a
large impact on the diastereoselection, with the diastereoselectiv-
ity increasing on going from R1 = benzyl to phenyl to t-butyl group
on the auxiliary. As the direction of diastereocontrol in the pres-
ence of the hydroxylated chiral auxiliaries has not been confirmed,
it is not possible to state conclusively that the direction of ap-
proach is controlled by the steric effect of the R1 substituent,
although the evidence suggests this.
An alternative explanation is due to neighbouring group partic-
ipation by the hydroxyl group. As mentioned earlier, it has been re-
ported that suitably positioned hydroxyl substituents have been
used to direct the diastereoselective oxidation of sulfides;40–42
when a percarboxylic acid such as mCPBA is employed as the oxi-
dant, incipient hydrogen bonding between the substrate hydroxyl
group and the percarboxylic acid results in the preferential attack
of the oxidant on the same side of the substrate as the hydroxyl
group. Investigation of the diastereoselective oxidation with
mCPBA is underway to explore in greater detail the impact of the
hydroxylated chiral auxiliary. Investigation of the synthetic poten-
tial of the enantioenriched vinyl sulfoxides will be reported in due
course, including efficient cleavage of the amide chiral auxiliary.
a-methylbenzylamide auxiliary. Thus, the diastereomers 21a and
21b were readily separated by chromatography and the minor dia-
stereomer 21b (diastereomerically pure by 1H NMR spectroscopy)
led to a crystal suitable for diffraction studies after recrystallisation
from ethanol. The resulting crystal structure confirms the Z-stereo-
chemistry of the b-chloroacrylamide and established the configu-
ration at the sulfur centre as (R) (Fig. 4). Also, an intramolecular
hydrogen bond exists from the amide proton to the oxygen atom
of the sulfoxide to form a six-membered ring, with a bond length
of 2.06 Å.
For the b-chloroacrylamides 12–14 and 16–19 with hydroxyl
groups incorporated, as illustrated by the X-ray crystal structure
of 16 (Fig. 1), the hydroxyl group participates in hydrogen bonding
to the amide nitrogen thus holding the b-chloroacrylamide in a
particular conformation, thereby enhancing the diastereocontrol
as sterically there is a preferential attack of the oxidising agent
3. Conclusion
oxidant approach from this
Sulfur oxidation of enantiomerically pure
a-thio-b-chloro-
face envisaged to be hindered
acrylamides affords sulfoxides with reasonable levels of diaste-
reocontrol; diastereomeric ratios of up to 3.3:1 were achieved,
with the highest levels of diastereoselection observed in sys-
tems constrained by intramolecular hydrogen bonding The
conformational freedom of the sulfide precursors is con-
strained by hydrogen bonding and attractive edge-to-face
interactions, as seen in the solid state. The corresponding
H
O
R1
H
R
N
S
Cl
O
R = Bn, Ph
R1 = t-Bu, Bn, Ph
Figure 2. Oxidant approach to b-chloroacrylamides.

874
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
Table 2
Diastereoselective oxidation of the b-chloroacrylamides
O
O
O
2 eq. Oxone®
acetone/water
RS
Cl
RS
Aux
Aux
Cl
½ ꢀ
a 2D0
c
Entry
1
b-Cl
R
Aux
Sulfoxide
dra
%dea
13
% Yieldb
78d
Ph
CH3
11
Bn
21
1.3:1
1.8:1
2.2:1
ꢁ179.0f and 323.3g
ꢁ67.5f and 122.6g
ꢁ139.5h and ꢁ65.0i
74d
50d
OH
2
3
12
16
Bn
Ph
22
23
29
38
Ph
Ph
OH
Ph
4
5
13
18
Bn
Ph
24
25
1.1:1
1.1:1
5
5
85e
95e
ꢁ1.4j
HO
Ph
ꢁ30.7j
HO
6
7
17
14
Ph
Bn
26
27
1.6:1
3.3:1
23
53
89d
ꢁ66.4j and 99.3i
HO
HO
HO
85d
193.7f and ꢁ123.5g
8
9
19
20
Ph
Ph
28
29
2.8:1
1.1:1
47
5
30d
85e
127.2h and ꢁ109.3i
ꢁ52.1j
a
b
c
d
e
f
Determined by integration of the 1H NMR spectrum of the crude product.
Combined yield after chromatography unless otherwise stated.
For details, see Section 4.
The sulfoxide diastereomers were separable by chromatography on silica gel.
As the 1H NMR spectrum of the crude product was very clean, no further purification was necessary.
Less polar, major diastereomer.
g
h
i
More polar, minor diastereomer.
Less polar, minor diastereomer.
More polar, major diastereomer.
Mixture of diastereomers.
j
enantioselective sulfur oxidation of the b-chloroacrylamides
using the Kagan and Bolm methods of oxidation had previ-
ously led to enantioselectivities of up to 52% ee and up to
71% ee, respectively.17
phases were dried using anhydrous magnesium sulfate. All com-
mercial reagents, including N-chlorosuccinimide, were used with-
out further purification.
1H 300 MHz and 13C (75.5 MHz) NMR spectra were recorded on
a Bruker 300 MHz NMR spectrometer. 1H (400 MHz) NMR spectra
were recorded on a Bruker Avance 400 MHz NMR spectrometer. All
spectra were recorded at room temperature (ꢂ20 °C) in deuterated
chloroform (CDCl3) unless otherwise stated using tetramethylsil-
ane (TMS) as an internal standard. Chemical shifts were expressed
in parts per million (ppm) and coupling constants in hertz (Hz).
Elemental analyses were performed by the Microanalysis Labo-
ratory, National University of Ireland, Cork, using a Perkin–Elmer
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

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
875
move Ph away
from stereocentre
5% de
up to
Ph
38% de
OH
Ph
conformationally
introduce
OH group
HO
constrained
O
O
Ph
CH3
RS
Cl
23% de
Aux
HO
13% de
introduce sterically
demanding t-Bu
HO
remove OH
up to
53% de
5% de
Figure 3. Effect of amide auxiliary on diastereoselective sulfur oxidation.
240 elemental analyzer. Melting points were carried out on a uni-
melt Thomas Hoover Capillary melting point apparatus. Low reso-
lution mass spectra were recorded on a Waters Quattro Micro tri-
ple quadrupole spectrometer in electrospray ionisation (ESI) mode
using 50% water/acetonitrile containing 0.1% formic acid as eluent;
samples were made up in acetonitrile. High resolution mass spec-
tra (HRMS) were recorded on a Waters LCT Premier Time of Flight
spectrometer in electrospray ionisation (ESI) mode using 50%
water/acetonitrile containing 0.1% formic acid as eluent; samples
were made up in acetonitrile. Infrared spectra were recorded as
potassium bromide (KBr) discs for solids or thin films on sodium
chloride plates for oils on a Perkin–Elmer Paragon 1000 FT-IR
spectrometer.
Thin layer chromatography (TLC) was carried out on pre-
coated silica gel plates (Merck 60 PF254). Column chromatogra-
phy was performed using Merck Silica Gel 60. Visualisation
was achieved by UV (254 nm) light detection, iodine staining,
vanillin staining and ceric sulfate staining. Optical rotations were
measured on a Perkin–Elmer 141 polarimeter at 589 nm in a
10 cm cell; concentrations (c) are expressed in g/100 mL. ½a DT
ꢀ
is
the specific rotation of a compound and is expressed in units
of 10ꢁ1 deg cm2 gꢁ1
.
Figure 4. X-ray crystal structure of minor diastereomer 21b.

876
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
Single crystal X-ray analysis was conducted using a Nonius
Mach 3 diffractometer and a Bruker Apex II Duo Diffractometer
with graphite-monochromatised Mo K radiation (k = 0.7107 Å).
Calculations for 16 were made using the APEX2 software,43,44 and
ethyl]propanamide (0.76 g, 3.4 mmol), benzyl mercaptan
(0.60 mL, 5.0 mmol) and sodium hydride (0.20 g of 60% dispersion
in mineral oil, 5.0 mmol) in dry N,N-dimethylformamide (15 mL) to
give the crude sulfide 2 as a clear oil. Following purification by col-
umn chromatography on silica gel using hexane–ethyl acetate as
eluent (gradient elution 40–80% ethyl acetate), the pure sulfide 2
(0.80 g, 76%) was isolated as a white solid and an equimolar mix-
a
45
44
for 21b using PLATON
,
SHELXS and SHELXL
.
Diagrams were prepared
using PLATON
.
42 Full structural data have been deposited at the Cam-
bridge Crystallographic Data Centre. CCDC reference numbers
768983 and 768984.
ture of diastereomers, mp 95–96 °C; ½a D20
¼ ꢁ49:5 (c 0.3 in EtOH);
ꢀ
(C18H21NO2S requires C, 68.54; H, 6.71; N, 4.44; S, 10.17. Found C,
68.40; H, 6.79; N, 4.65; S, 9.93); m
max/cmꢁ1 (KBr) 3396 (OH), 3307
4.1. 2-(Benzylthio)-N-[(R)-1-phenylethyl]propanamide 1
(NH), 3060 (CH), 2929 (CH), 1645 (CO), 1542 (NH bend), 1495; dH
(400 MHz, CDCl3) 1.46 [1.5H, d, J 7.6, C(3)H3 of one diastereomer],
1.50 [1.5H, d, J 7.2, C(3)H3 of one diastereomer], 2.39 (0.5H, t, J 6.0,
OH of one diastereomer), 2.50 (0.5H, t, J 6.0, OH of one diastereo-
mer), 3.31–3.41 [2H, 2 ꢃ overlapping q, J 7.6, 7.2, C(2)H of two dia-
stereomers], 3.69 (1H, SCH2 of one diastereomer), 3.77 (1H, s, SCH2
of one diastereomer), 3.84 (1H, overlapping dd, A of ABM, JAB 5.6,
JAM 5.2, one of CH2OH of two diastereomers), 3.86 (1H, overlapping
dd, B of ABM, JAB 5.6, JBM 5.2, one of CH2OH of two diastereomers),
4.96–5.07 (1H, m, NHCH of two diastereomers), 7.16–7.43 (11H, m,
NH and ArH of two diastereomers); dC (75.5 MHz, CDCl3) 18.4, 18.5
[2 ꢃ CH3, C(3)H3 of two diastereomers], 36.2, 36.3 (2 ꢃ CH2, SCH2
of two diastereomers), 44.2, 44.3 [2 ꢃ CH, C(2)H of two diastereo-
mers], 56.0, 56.1 (2 ꢃ CH, NHCH of two diastereomers), 66.6, 66.7
(2 ꢃ CH2, CH2OH of two diastereomers), 126.6, 126.7, 127.4,
127.97, 128.03, 128.68, 128.71, 128.9, 129.0 (9 ꢃ CH, aromatic CH
of two diastereomers, 9 signals for 12 carbons), 137.2, 137.3,
138.7, 138.9 (4 ꢃ C, aromatic C of two diastereomers), 172.8,
173.0 (2 ꢃ C, CO of two diastereomers); HRMS (ES+): Exact mass
calculated for C18H22NO2S [M+H]+, 316.1371. Found 316.1378; m/
z (ES+) 316.1 {[(C18H21NO2S)+H]+, 100%}.
Sodium hydride (2.84 g of a 60% dispersion in mineral oil,
71.1 mmol) was placed in a three-necked round-bottomed flask
under
a flow of nitrogen. Following washing with hexane
(3 ꢃ 40 mL), dry N,N-dimethylformamide (130 mL) was added
and the resulting suspension was stirred for 10 min. The reaction
mixture was cooled to 0 °C and benzyl mercaptan (8.43 mL,
71.1 mmol) was added slowly via a syringe. After stirring for
20 min, a solution of 2-chloro-N-[(R)-1-phenylethyl]propanamide
(10.02 g, 47.4 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
(150 mL) and dichloromethane (150 mL) and the layers were sep-
arated. The aqueous layer was extracted with dichloromethane
(2 ꢃ 150 mL) and the combined organic layers were washed with
sodium hydroxide (1 M, 150 mL), water (2 ꢃ 150 mL), hydrochloric
acid (2 M, 2 ꢃ 150 mL) and brine (150 mL), dried, filtered and con-
centrated at reduced pressure to give the crude sulfide 1 as a
brown oil. Following purification by column chromatography on
silica gel using hexane–ethyl acetate as eluent (gradient elution
10–40% ethyl acetate), the pure sulfide 1 (10.45 g, 74%)* was iso-
lated as a white solid and an equimolar mixture of diastereomers,
4.3. 2-(Benzylthio)-N-[(S)-1-hydroxy-3-phenylpropan-2-
yl]propanamide 3
mp 75–77 °C; ½a 2D0
¼ þ43:2 (c 0.1, CHCl3); (C18H21NOS requires C,
ꢀ
72.20; H, 7.07; N, 4.68; S, 10.71. Found: C, 72.43; H, 7.02; N,
The title compound was synthesised according to the procedure
described for 1 using 2-chloro-N-[(S)-1-hydroxy-3-phenylpropan-
2-yl]propanamide (0.73 g, 3.0 mmol), benzyl mercaptan (0.53 mL,
4.5 mmol) and sodium hydride (0.18 g of 60% dispersion in mineral
oil, 4.5 mmol) in dry N,N-dimethylformamide (15 mL) to give the
crude sulfide 3 as a clear oil. Following purification by column
chromatography on silica gel using hexane–ethyl acetate as eluent
(gradient elution 20–80% ethyl acetate), the pure sulfide 3 (0.59 g,
61%) was isolated as a white solid and an equimolar mixture of dia-
4.79; S, 11.16);
m
max/cmꢁ1 (KBr) 3360 (NH), 3314 (NH), 3029
(CH), 2973 (CH), 1646 (CO), 1526 (NH bend), 1494, 1371 (CN
stretch); dH (300 MHz, CDCl3) 1.41–1.50 [6H, 3 ꢃ overlapping d, J
7.5, 7.5, 6.9, C(3)H3 and CH(CH3) of two diastereomers], 3.25–
3.35 [1H, 2 ꢃ overlapping q, J 7.5, 7.5, C(2)H of two diastereomers],
3.61 (1H, s, SCH2 of one diastereomer), 3.66 (0.5H, A of AB system,
JAB 13.2, one of SCH2 of one diastereomer), 3.72 (0.5H, B of AB sys-
tem, JAB 13.2, one of SCH2 of one diastereomer), 5.00–5.17 (1H, m,
NHCH of two diastereomers), 6.81 (0.5H, br d, J 7.8, NH of one dia-
stereomer), 6.88 (0.5H, br d, J 7.8, NH of one diastereomer), 7.11–
7.41 (10H, m, ArH of two diastereomers); dC (75.5 MHz, CDCl3)
18.4 [CH3, C(3)H3 of two diastereomers, 1 signal for 2 carbons],
21.6, 21.9 [2 ꢃ CH3, CH(CH3) of two diastereomers], 36.1, 36.2
(2 ꢃ CH2, SCH2 of two diastereomers), 44.1, 44.3, 48.8, 48.9
[4 ꢃ CH, C(2)H of two diastereomers and CHNH of two diastereo-
mers], 126.0, 126.2, 127.32, 127.35, 127.4, 127.5, 128.65, 128.71,
128.72, 128.77, 128.87, 128.88 (12 ꢃ CH, aromatic CH of two dia-
stereomers), 137.1, 137.3, 143.1, 143.2 (4 ꢃ C, aromatic C of two
diastereomers), 171.2, 171.3 (2 ꢃ C, CO of two diastereomers);
stereomers, mp 80–81 °C; ½a D20
¼ ꢁ17:9 (c 0.4, EtOH); (C19H23NO2S
ꢀ
requires C, 69.27; H, 7.04; N, 4.25; S, 9.73. Found C, 68.84; H, 6.83;
N, 4.27; S, 9.95); m
max/cmꢁ1 (KBr) 3341 (OH), 3274 (NH), 3062 (CH),
2925 (CH), 1650 (CO), 1634, 1529 (NH bend), 1495; dH (400 MHz,
CDCl3) 1.29 [1.5H, d, J 7.6, C(3)H3 of one diastereomer], 1.38
[1.5H, d, J 7.2, C(3)H3 of one diastereomer], 2.37 (0.5H, br t, J 5.2,
OH of one diastereomer), 2.67 (0.5H, br t, J 5.2, OH of one diastereo-
mer), 2.74–3.01 (2H, m, CH2Ph of two diastereomers), 3.17 [0.5H, q,
J 7.2, C(2)H of one diastereomer], 3.21–3.28 [1H, m, contains A of
AB system at 3.25, JAB 13.2, one of SCH2 of one diastereomer and
C(2)H of one diastereomer], 3.45 (0.5H, B of AB system, JAB 13.2,
one of SCH2 of one diastereomer), 3.51–3.76 (3H, m, SCH2 of one
diastereomer and CH2OH of two diastereomers; SCH2 could be dis-
tinguished as a singlet at 3.64 ppm), 4.11–4.24 (1H, m, NHCH of
two diastereomers), 6.80–6.94 (1H, m, NH of two diastereomers),
7.08–7.40 (10H, m, ArH of two diastereomers); dC (75.5 MHz,
CDCl3) 18.4, 18.6 [2 ꢃ CH3, C(3)H3 of two diastereomers], 35.9,
36.3, 36.9, 37.0 (4 ꢃ CH2, SCH2 and CH2Ph of two diastereomers),
44.1, 44.4 [2 ꢃ CH, C(2)H of two diastereomers], 52.8, 53.2
(2 ꢃ CH, NHCH of two diastereomers), 64.5, 64.8 (2 ꢃ CH2, CH2OH
of two diastereomers), 126.75, 126.84, 127.29, 127.32, 128.63,
128.65, 128.76, 128.85, 128.90, 129.17, 129.23 (11 ꢃ CH, aromatic
HRMS (ES+): Exact mass calculated for
C
18H22NOS [M+H]+,
300.1422. Found 300.1416; m/z (ES+) 300.1 {[(C18H21NOS)+H]+,
100%}, 104.9 (4%).
*A yield of 91% was obtained for a batch that was synthesised
later.
4.2. 2-(Benzylthio)-N-[(1R)-2-hydroxy-1-
phenylethyl]propanamide 2
The title compound was synthesised according to the procedure
described for
1
using 2-chloro-N-[(R)-2-hydroxy-1-phenyl-

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
877
CH of two diastereomers, 11 signals for 12 carbons), 137.2, 137.4,
137.5 (3 ꢃ C, aromatic C of two diastereomers), 173.0, 173.2
(2 ꢃ C, CO of two diastereomers); HRMS (ES+): Exact mass calcu-
lated for C19H24NO2S [M+H]+ 330.1528. Found 330.1516; 330.1
{[(C19H23NO2S)+H]+, 100%}, 147.0 (88%).
1374 (CN stretch); dH (400 MHz, CDCl3) 1.32 [1.2H, d, J 7.2, CH(CH3)
of one diastereomer], 1.43 [1.8H, d, J 6.8, CH(CH3) of one diastereo-
mer], 1.54 [1.2H, d, J 7.6, C(3)H3 of one diastereomer], 1.58 [1.8H, d,
J 7.2, C(3)H3 of one diastereomer], 3.84 [0.6H, q, J 7.6, C(2)H of one
diastereomer], 3.85 [0.4H, q, J 7.2, C(2)H of one diastereomer],
4.98–5.08 (1H, m, NHCH of two diastereomers), 6.77–6.89 (1H, br
d, NH of two diastereomers), 7.00–7.07 (1H, m, ArH of two diaste-
reomers), 7.17–7.37 (8H, m, ArH of two diastereomers).
4.4. 2-(Benzylthio)-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-
yl]propanamide 4
Benzyl mercaptan (1.08 mL, 9.1 mmol) was added to a solution
of freshly prepared sodium ethoxide [prepared from sodium
(0.21 g, 9.1 mmol) in dry ethanol (30 mL) at 0 °C] while stirring un-
der nitrogen. After stirring for 20 min under nitrogen, a solution of
2-chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]propanamide
(1.58 g, 7.6 mmol) in ethanol (20 mL) was added gradually over
15 min to the reaction mixture. Following stirring for 16 h at room
temperature, the reaction was quenched by addition of water
(40 mL) and dichloromethane (30 mL). The phases were separated
and the aqueous layer was extracted with dichloromethane
(2 ꢃ 30 mL). The combined organic layers were washed with aque-
ous sodium hydroxide (1 M, 2 ꢃ 30 mL), water (30 mL) and brine
(30 mL), dried and concentrated under reduced pressure to give
the crude sulfide 4 as a clear oil. Following purification by column
chromatography on silica gel using hexane–ethyl acetate (40:60)
as eluent, the pure sulfide 4 (1.77 g, 79%) was isolated as a white
solid and an equimolar mixture of diastereomers, mp 54–55 °C;
4.6. N-[(1R)-2-Hydroxy-1-phenylethyl]-2-
(phenylthio)propanamide 6
The title compound was synthesised according to the procedure
described for
1
using 2-chloro-N-[(R)-2-hydroxy-1-phenyl-
ethyl]propanamide (0.76 g, 3.4 mmol), benzenethiol (0.53 mL,
5.0 mmol) and sodium hydride (0.20 g of 60% dispersion in mineral
oil, 5.0 mmol) in dry N,N-dimethylformamide (15 mL) to give the
crude sulfide 6 as a clear oil. Following purification by column
chromatography on silica gel using hexane–ethyl acetate as eluent
(gradient elution 40–80% ethyl acetate), the pure sulfide 6 (0.80 g,
76%) was isolated as a white solid and an equimolar mixture of dia-
stereomers, mp 69–70 °C; ½a D20
¼ ꢁ49:9 (c 0.1, EtOH); (C17H19NO2S
ꢀ
requires C, 67.74; H, 6.35; N, 4.65; S, 10.51. Found C, 68.25; H, 6.65;
N, 4.36; S, 10.51); m
max/cmꢁ1 (KBr) 3385 (OH), 3284 (NH), 3060
(CH), 2927 (CH), 1647 (CO), 1541 (NH bend); dH (400 MHz, CDCl3)
1.57 [1.5H, d, J 7.6, C(3)H3 of one diastereomer], 1.61 [1.5H, d, J 7.2,
C(3)H3 of one diastereomer], 2.07–2.19 (1H, m, OH of two diaste-
reomers), 3.66–3.86 (2H, m, CH2OH of two diastereomers), 3.87–
3.96 [1H, 2 ꢃ overlapping q, J 7.6, 7.2, C(2)H of two diastereomers],
4.94–5.02 (1H, m, NHCH of two diastereomers), 6.96–7.03 (1H, m,
NH of two diastereomers), 7.15–7.40 (10H, m, ArH of two diaste-
reomers); dC (75.5 MHz, CDCl3) 18.1, 18.2 [2 ꢃ CH3, C(3)H3 of two
diastereomers], 47.0, 47.1 [2 ꢃ CH, C(2)H of two diastereomers],
55.8, 55.9 (2 ꢃ CH, NHCH of two diastereomers), 66.34, 66.36
(2 ꢃ CH2, CH2OH of two diastereomers), 126.55, 126.61, 127.4,
127.5, 127.8, 127.9, 128.8, 128.9, 129.3, 130.5, 130.6 (11 ꢃ CH, aro-
matic CH of two diastereomers, 11 signals for 12 carbons), 133.80,
133.83, 138.5, 138.6 (4 ꢃ C, aromatic C of two diastereomers),
172.1, 172.3 (2 ꢃ C, CO of two diastereomers); HRMS (ES+): Exact
½
a 2D0
ꢀ
¼ þ6:0 (c 0.5, CHCl3); (C16H25NO2S requires C, 65.05; H,
8.53; N, 4.74. Found C, 64.36; H, 8.36; N, 4.79);
m
max/cmꢁ1 (KBr)
3249 (NH), 3085 (CH), 2963 (CH), 1646 (CO), 1567 (NH bend),
1495, 1370 (CN stretch); dH (400 MHz, CDCl3) 0.97 [4.5H, s,
C(CH3)3 of one diastereomer], 0.98 [4.5H, s, C(CH3)3 of one diaste-
reomer], 1.46 [1.5H, d, J 7.6, C(3)H3 of one diastereomer], 1.48
[1.5H, d, J 7.2, C(3)H3 of one diastereomer], 2.32 (0.5H, br t, J 5.6,
OH of one diastereomer), 2.49 (0.5H, br t, J 5.6, OH of one diastereo-
mer), 3.35 [0.5H, q, J 7.2, C(2)H of one diastereomer], 3.37 [0.5H, q, J
7.6, C(2)H of one diastereomer], 3.49 (0.5H, ddd, J 11.0, 8.4, 5.6,
NHCH of one diastereomer), 3.54 (0.5H, ddd, J 11.0, 8.0, 5.2, NHCH
of one diastereomer), 3.71–3.94 (4H, m, SCH2 and CH2OH of two
diastereomers), 6.86 (0.5H, br d, J 8.4, NH of one diastereomer),
6.99 (0.5H, br d, J 8.8, NH of one diastereomer), 7.21–7.37 (5H,
m, ArH); dC (75.5 MHz, CDCl3) 18.7, 18.8 [2 ꢃ CH3, C(3)H3 of two
diastereomers], 26.9, 27.0 [2 ꢃ CH3, C(CH3)3 of two diastereomers],
33.45, 33.54 [2 ꢃ C, C(CH3)3 of two diastereomers], 36.1, 36.4
(2 ꢃ CH2, SCH2 of two diastereomers), 44.3, 44.8 [2 ꢃ CH, C(2)H
of two diastereomers], 59.8, 60.1 (2 ꢃ CH, NHCH of two diastereo-
mers), 63.2, 63.4 (2 ꢃ CH2, CH2OH of two diastereomers), 127.39,
127.44, 128.7, 128.8, 128.92, 128.93 (6 ꢃ CH, aromatic CH of two
diastereomers), 137.1, 137.3 (2 ꢃ C, aromatic C of two diastereo-
mers), 173.7, 173.8 (2 ꢃ C, CO of two diastereomers); HRMS
(ES+): Exact mass calculated for C16H26NO2S [M+H]+ 296.1684.
Found 296.1685; m/z (ES+) 296.1 {[(C16H25NO2S)+H]+, 100%}, 79.8
(6%).
mass calculated for
C
17H20NO2S [M+H]+, 302.1215. Found
302.1221; m/z (ES+) 302.1 {[(C17H19NO2S)+H]+, 100%}.
4.7. N-[(1R,2S)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]-2-
(phenylthio)propanamide 7
The title compound was synthesised according to the procedure
described for 4 using 2-chloro-N-[(1R,2S)-2,3-dihydro-2-hydroxy-
1H-inden-1-yl]propanamide (0.69 g, 2.9 mmol), benzenethiol
(0.36 mL, 3.5 mmol) and sodium (0.08 g, 3.5 mmol) in dry ethanol
(20 mL) to give the crude sulfide 7 as a white solid. Following puri-
fication by column chromatography on silica gel using hexane–
ethyl acetate as eluent (gradient elution 40–60% ethyl acetate),
the pure sulfide 7 (0.65 g, 73%) was isolated as a white solid and
an equimolar mixture of diastereomers, mp 138–140 °C;
4.5. N-[(R)-1-Phenylethyl]-2-(phenylthio)propanamide 5
½
a 2D0
ꢀ
¼ þ19:1 (c 0.2, CHCl3);
m
max/cmꢁ1 (KBr) 3429 (OH), 3320
The title compound was synthesised according to the procedure
described for 1 using 2-chloro-N-[(R)-1-phenylethyl]propanamide
(2.45 g, 11.6 mmol), benzenethiol (1.83 mL, 17.4 mmol) and so-
dium hydride (0.69 g of 60% dispersion in mineral oil, 17.4 mmol)
in dry N,N-dimethylformamide (70 mL) to give the crude sulfide
5 as a pale yellow oil. Following purification by column chromatog-
raphy on silica gel using hexane–ethyl acetate as eluent (gradient
elution 10–20% ethyl acetate), the pure sulfide 5 (2.35 g, 71%) was
isolated as a white solid (as a 1:1.37 mixture of diastereomers),
(NH), 3071 (CH), 2954 (CH), 1642 (CO), 1541 (NH bend), 1477,
1368 (CN stretch); dH (400 MHz, CDCl3) 1.65 [1.5H, d, J 7.2,
C(3)H3 of one diastereomer], 1.68 [1.5H, d, J 7.2, C(3)H3 of one dia-
stereomer], 2.83–2.95, 3.08–3.18 (2 ꢃ 1H, 2 ꢃ m, ArCH2 of two dia-
stereomers), 3.97–4.05 [1H, 2 ꢃ overlapping q, J 7.2, 7.2, C(2)H of
two diastereomers], 4.44–4.48 (0.5H, ddd, J 5.0, 4.8, 1.6, CHOH of
one diastereomer), 4.54–4.59 (0.5H, ddd, J 5.0, 4.8, 2.0, CHOH of
one diastereomer), 5.28–5.34 (1H, m, NHCH of two diastereomers),
7.00–7.42 (10H, m, NH and ArH of two diastereomers); dC
(75.5 MHz, CDCl3) 18.3, 18.4 [2 ꢃ CH3, C(3)H3 of two diastereo-
mers], 39.6, 39.7 (2 ꢃ CH2, ArCH2 of two diastereomers), 47.0,
mp 98–99 °C; ½a 2D0
ꢀ
¼ þ58:1 (c 0.2, CHCl3);
m
max/cmꢁ1 (KBr) 3267
(NH), 3059 (CH), 2973 (CH), 1660 (CO), 1553 (NH bend), 1494,

878
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
47.1 [2 ꢃ CH, C(2)H of two diastereomers], 57.66, 57.70 (2 ꢃ CH,
NHCH of two diastereomers), 73.6, 73.7 (2 ꢃ CH, CHOH of two dia-
stereomers), 124.3, 124.4, 125.3, 125.4, 127.1, 127.2, 127.35,
127.39, 128.2, 128.3, 129.28, 129.32, 130.2, 130.7 (14 ꢃ CH, aro-
matic CH of two diastereomers), 134.1, 134.2, 139.8, 140.0, 140.1,
140.2 (6 ꢃ C, aromatic C of two diastereomers), 172.50, 172.53
(2 ꢃ C, CO of two diastereomers); HRMS (ES+): Exact mass calcu-
lated for C18H20NO2S [M+H]+ 314.1215. Found 314.1223; m/z
(ES+) 314.0 {[(C18H19NO2S)+H]+, 100%}.
mer), 3.50 (0.55H, ddd, J 13.2, 8.0, 5.2, NHCH of one diastereomer),
3.64–3.85 (2H, m, CH2OH of two diastereomers), 3.97 [0.55H, q, J
7.6, C(2)H of one diastereomer], 3.99 [0.45H, q, J 7.2, C(2)H of
one diastereomer], 6.85 (0.55H, br d, NH of one diastereomer),
6.88 (0.45H, br d, NH of one diastereomer), 7.18–7.39 (5H, m,
ArH of two diastereomers); dC (75.5 MHz, CDCl3) 18.4*, 18.5
[2 ꢃ CH3, C(3)H3 of two diastereomers], 26.7*, 26.8 [2 ꢃ CH3,
C(CH3)3 of two diastereomers], 33.3*, 33.6 [2 ꢃ C, C(CH3)3 of two
diastereomers], 46.6, 47.2* [2 ꢃ CH, C(2)H of two diastereomers],
59.9, 60.0* (2 ꢃ CH, NHCH of two diastereomers), 63.0, 63.4
*
4.8. N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-2-
(phenylthio)propanamide 8
(2 ꢃ CH2, CH2OH of two diastereomers), 127.0*, 127.2, 129.1 ,
129.3*, 129.36, 129.40 (6 ꢃ CH, aromatic CH), 134.1*, 134.3
(2 ꢃ C, aromatic C), 172.7, 173.2* (2 ꢃ C, CO); HRMS (ES+): Exact
The title compound was synthesised according to the procedure
described for 1 using 2-chloro-N-[(S)-1-hydroxy-3-phenylpropan-
2-yl]propanamide (0.73 g, 3.0 mmol), benzenethiol (0.47 mL,
4.5 mmol) and sodium hydride (0.18 g of a 60% dispersion in min-
eral oil, 4.5 mmol) in dry N,N-dimethylformamide (15 mL) to give
the crude sulfide 8 as a pale yellow oil. Following purification by
column chromatography on silica gel using hexane–ethyl acetate
60:40 as eluent, the pure sulfide 8 (0.43 g, 45%) was isolated as a
white solid and as an equimolar mixture of diastereomers, mp
mass calculated for
C
15H24NO2S [M+H]+ 282.1528. Found
282.1527; m/z (ES+) 282.1 {[(C15H23NO2S)+H]+, 100%}, 208.1 (4%),
172.1 (2%), 118.0 (2%).
*Major diastereomer.
4.10. N-[(R)-3,3-Dimethylbutan-2-yl]-2-
(phenylthio)propanamide 10
The title compound was synthesised according to the procedure
described for 1 using 2-chloro-N-[(S)-3,3-dimethylbutan-2-yl]pro-
panamide (2.02 g, 10.5 mmol), benzenethiol (1.17 mL, 11.1 mmol)
and sodium hydride (0.44 g of 60% dispersion in mineral oil,
11.1 mmol) in dry N,N-dimethylformamide (50 mL) to give the
crude sulfide 10 as a yellow oil. Following purification by column
chromatography on silica gel using hexane–ethyl acetate as eluent
(gradient elution 10–40%), the pure sulfide 10 (2.19 g, 79%) was iso-
lated as a white solid and an equimolar mixture of diastereomers,
90–92 °C; ½a 2D0
¼ þ27:0 (c 0.1, EtOH); (C18H21NO2S requires C,
ꢀ
68.54; H, 6.71; N, 4.44; S, 10.17. Found C, 68.51; H, 6.65; N, 4.67;
S, 10.50);
m
max/cmꢁ1 (KBr) 3379 (OH), 3282 (NH), 3060 (CH),
2927 (CH), 1655 (CO), 1638 (CO), 1536 (NH bend); dH (400 MHz,
CDCl3) 1.42 [1.5H, d, J 7.2, C(3)H3 of one diastereomer], 1.53
[1.5H, d, J 7.6, C(3)H3 of one diastereomer], 1.90 (0.5H, br s, OH
of one diastereomer), 2.38 (0.5H, br s, OH of one diastereomer),
2.67–2.91 (2H, m, CH2Ph of two diastereomers), 3.37–3.65 (2H,
m, CH2OH of two diastereomers), 3.73–3.85 [1H, 2 ꢃ q, J 7.6, 7.2,
C(2)H of two diastereomers], 4.02–4.18 (1H, m, NHCH of two dia-
stereomers), 6.72–6.87 (1H, br d, NH of two diastereomers),
7.05–7.13 (1H, m, ArH), 7.14–7.36 (9H, m, ArH); dC (75.5 MHz,
CDCl3) 18.0, 18.4 [2 ꢃ CH3, C(3)H3 of two diastereomers], 36.8,
36.9 (2 ꢃ CH2, CH2Ph of two diastereomers), 47.1, 47.2 [2 ꢃ CH,
C(2)H of two diastereomers], 52.7, 53.2 (2 ꢃ CH, NHCH of two dia-
stereomers), 64.0, 64.1 (2 ꢃ CH2, CH2OH of two diastereomers),
126.68, 126.71, 127.28, 127.34, 128.6, 129.15, 129.22, 130.2,
130.3 (9 ꢃ CH, aromatic CH of two diastereomers, 9 signals for 12
carbons), 134.0, 137.3, 137.4 (3 ꢃ C, aromatic C of two diastereo-
mers, 3 signals for 4 carbons), 172.1, 172.6 (2 ꢃ C, CO of two diaste-
reomers); HRMS (ES+): Exact mass calculated for C18H22NO2S
[M+H]+ 316.1371. Found 316.1374; m/z (ES+) 316.1
{[(C18H21NO2S)+H]+, 100%}.
mp 109–110 °C; ½a D20
¼ þ20:4 (c 0.14, CHCl3); (C15H23NOS requires
ꢀ
C, 67.88; H, 8.73; N, 5.28; S, 12.08. Found C, 68.03; H, 8.70; N, 5.35;
S, 12.22); m
max/cmꢁ1 (KBr) 3286 (NH), 3059 (CH), 2970 (CH), 1638
(CO), 1553 (NH bend), 1446, 1374 (CN stretch); dH (400 MHz,
CDCl3) 0.67 [4.5H, s, C(CH3)3 of one diastereomer], 0.83 (1.5H, d, J
6.8, NHCHCH3 of one diastereomer), 0.86 [4.5H, s, C(CH3)3 of one
diastereomer], 1.00 (1.5H, d, J 6.8, NHCHCH3 of one diastereomer),
1.56 [1.5H, d, J 7.2, C(3)H3], 1.58 [1.5H, d, J 7.6, C(3)H3], 3.70–3.79
(1H, m, NHCH of two diastereomers), 3.89 [0.5H, q, J 7.6, C(2)H of
one diastereomer], 3.93 [0.5H, q, J 7.2, C(2)H of one diastereomer],
6.52–6.67 (1H, 2 ꢃ overlapping br d, NH of two diastereomers),
7.16–7.36 (5H, m, ArH); dC (75.5 MHz, CDCl3) 15.6, 16.0 (2 ꢃ CH3,
NHCHCH3 of two diastereomers), 18.3, 18.6 [2 ꢃ CH3, C(3)H3 of
two diastereomers], 33.9, 34.1 [2 ꢃ C, C(CH3)3 of two diastereo-
mers], 46.5, 47.4, 52.9, 53.1 [4 ꢃ CH, C(2)H and NHCH of two dia-
stereomers], 126.8, 127.0, 129.1, 129.2, 129.5 (5 ꢃ CH, aromatic
CH of two diastereomers, 5 signals for 6 carbons), 134.3 (C, aro-
matic C of two diastereomers, 1 signal for 2 carbons), 170.77,
170.83 (2 ꢃ C, CO of two diastereomers); HRMS (ES+): Exact mass
calculated for C15H24NOS [M+H]+ 266.1579. Found 266.1580; m/z
(ES+) 266.1 {[(C15H23NOS)+H]+, 100%}, 104.9 (6%).
4.9. N-[(S)-1-Hydroxy-3,3-dimethylbutan-2-yl]-2-
(phenylthio)propanamide 9
The title compound was synthesised according to the procedure
described for 4 using 2-chloro-N-[(S)-1-hydroxy-3,3-dimethylb-
utan-2-yl]propanamide
(1.94 g,
9.4 mmol),
benzenethiol
(1.18 mL, 11.2 mmol) and sodium (0.26 g, 11.2 mmol) in dry etha-
nol (60 mL) to give the crude sulfide 9 as a clear oil. Following puri-
fication by column chromatography on silica gel using hexane–
ethyl acetate as eluent (gradient elution 40–80%), the pure sulfide
9 (1.98 g, 75%) was isolated as a white solid and a 1:1.22 mixture
of diastereomers (material contained ꢂ14% starting material), mp
4.11. (Z)-2-(Benzylthio)-3-chloro-N-[(R)-1-
phenylethyl]acrylamide 11
Unrecrystallised NCS (2.80 g, 20.6 mmol) was added in one
portion to a solution of the sulfide 2-(benzothio)-N-[(R)-1-phenyl-
ethyl]propanamide 1 in toluene (60 mL). The flask was immedi-
ately immersed in an oil bath and heated at 90 °C for 2 h.
Following filtration and evaporation of the solvent at reduced pres-
sure, the crude product was obtained as a yellow oil, containing
70% b-chloroacrylamide by 1H NMR spectroscopy. This was puri-
fied by column chromatography on silica gel using hexane–ethyl
acetate 95:5 as eluent to give the pure product 11 (2.14 g, 61%)
64–66 °C; ½a 2D0
ꢀ
¼ þ1:8 (c 0.5, CHCl3);
m
max/cmꢁ1 (KBr) 3369 (OH),
3280 (NH), 3082 (CH), 2961 (CH), 1654 (CO), 1642 (CO), 1547
(NH bend), 1470, 1370 (CN stretch); dH (400 MHz, CDCl3) 0.76
[4.95H, s, C(CH3)3 of one diastereomer], 0.91 [4.05H, s, C(CH3)3 of
one diastereomer], 1.60 [1.35H, d, J 7.2, C(3)H3 of one diastereo-
mer], 1.61 [1.65H, J 7.6, C(3)H3 of one diastereomer], 1.77 (0.45H,
t, J 5.6, OH of one diastereomer), 2.20 (0.55H, br t, J 5.6, OH of
one diastereomer), 3.31–3.40 (0.45H, m, NHCH of one diastereo-
as a white solid, mp 77–78 °C; ½a D20
¼ þ66:5 (c 0.5, CHCl3);
ꢀ
(C18H18ClNOS requires C, 65.15; H, 5.47; Cl, 10.68; N, 4.22; S,

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
879
9.66. Found C, 65.50; H, 5.30; Cl, 10.30; N, 4.16; S, 9.90);
m
max/cmꢁ1
CH), 130.8, 137.1, 137.2 [3 ꢃ C, 2 ꢃ aromatic C and C(2)S], 139.9
[CH, ClHC(3)@], 163.3 (C, CO); HRMS (ES+): Exact mass calculated
for C19H21NO2S35Cl [M+H]+ 362.0982. Found 362.0968; m/z (ES+)
364.0 {[(C19H20NO2S37Cl)+H+], 42%}, 362.0 {[(C19H20NO2S35Cl)+H+],
100%}.
(KBr) 3309 (NH), 2977 (CH), 1630 (CO), 1529 (NH bend), 1451 (CN
stretch); dH (400 MHz, CDCl3) 1.34 [3H, d, J 6.8, CH(CH3)], 3.90 (2H,
s, SCH2), 4.95 (1H, overlapping dq, J 7.2, 6.8, NHCH), 7.07–7.39
(11H, m, NH and ArH), 7.83 [1H, s, ClHC(3)@]; dC (75.5 MHz, CDCl3)
21.7 [CH3, CH(CH3)], 38.2 (CH2, SCH2), 49.6 (CH, NHCH), 126.0,
127.5, 127.69, 128.74, 128.77, 128.80 (6 ꢃ CH, 6 ꢃ aromatic CH),
130.9, 137.2 [2 ꢃ C, aromatic C or C(2)S], 139.4 [C, ClHC(3)@],
142.6 [C, aromatic C or C(2)S], 161.9 (C, CO); HRMS (ES+): Exact
4.14. (Z)-2-(Benzylthio)-3-chloro-N-[(S)-1-hydroxy-3,3-
dimethylbutan-2-yl]acrylamide 14
mass calculated for
C
18H19NOS35Cl [M+H]+ 332.0876. Found
This was prepared following the procedure described above for
11 using 2-(benzylthio)-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-
332.0891; m/z (ES+) 334.0 {[(C18H18NOS37Cl)+H+], 44%}, 332.0
{[(C18H18NOS35Cl)+H+], 100%}.
yl]propanamide
4
(1.66 g, 5.6 mmol), N-chlorosuccinimide
(1.50 g, 11.0 mmol) and toluene (50 mL). The reaction mixture
was heated at 90 °C for 1 h. Following filtration and evaporation
of the solvent at reduced pressure, the crude product was obtained
as a brown oil, containing 36% b-chloroacrylamide by 1H NMR
spectroscopy. This was purified by column chromatography on sil-
ica gel using hexane–ethyl acetate (gradient elution 20–40% ethyl
acetate) as eluent to give the pure product 14 (0.54 g, 29%) as an
4.12. (Z)-2-(Benzylthio)-3-chloro-N-[(R)-2-hydroxy-1-
phenylethyl]acrylamide 12
This was prepared following the procedure described above for
11 using 2-(benzylthio)-N-[(1R)-2-hydroxy-1-phenylethyl]propan-
amide
2
(2.46 g, 7.8 mmol), N-chlorosuccinimide (2.08 g,
15.2 mmol) and toluene (50 mL). The reaction mixture was heated
at 90 °C for 2 h. Following filtration and evaporation of the solvent
at reduced pressure, the crude product was obtained as a brown
oil, containing 40% b-chloroacrylamide by 1H NMR spectroscopy.
This was purified by column chromatography on silica gel using
hexane–ethyl acetate (gradient elution 10–40% ethyl acetate) as
eluent to give the pure product 12 (0.86 g, 32%) as a pale brown so-
orange oil; ½a 2D0
ꢀ
¼ þ106:0 (c 0.1, CHCl3);
m
max/cmꢁ1 (film) 3440
(OH), 3367 (NH), 3062 (CH), 2963 (CH), 1645 (CO), 1515 (NH
bend), 1455 (CN stretch); dH (400 MHz, CDCl3) 0.88 [9H, s,
C(CH3)3], 1.97 (1H, br s, OH), 3.33 (1H, br dd, J 7.9, 7.0, NHCH),
3.64–3.76 (2H, m, CH2OH), 3.95 (1H, A of AB system, JAB 12.9, one
of SCH2), 4.00 (1H, B of AB system, JAB 12.9, one of SCH2), 7.12 (1H,
br d, J 7.0, NH), 7.18–7.40 (5H, m, ArH), 7.90 [1H, s, ClHC(3)@]; dc
(75.5 MHz, CDCl3) 26.8 [CH3, C(CH3)3], 33.5 [C, C(CH3)3], 38.1
(CH2, SCH2), 60.6 (CH, NHCH), 63.1 (CH2, CH2OH), 127.8, 129.1 (sig-
nal for 2 ꢃ CH) (2 ꢃ CH, 2 ꢃ aromatic CH), 130.8, 137.4 [2 ꢃ C, aro-
matic C and C(2)S], 140.0 [CH, ClHC(3)@], 164.0 (C, CO); HRMS
lid, mp 95–96 °C; ½a D20
ꢀ
¼ ꢁ54:2 (c 0.1, CHCl3);
m
max/cmꢁ1 (KBr)
3379 (OH), 3304 (NH), 3029 (CH), 2928 (CH), 1625 (CO), 1524
(NH bend), 1453 (CN stretch); dH (400 MHz, CDCl3) 2.14 (1H, dd,
J 6.8, 5.6, OH), 3.70–3.75 (2H, m, CH2OH), 3.95 (2H, s, SCH2),
4.87–4.94 (2H, overlapping ddd, J 7.2, 5.2, 5.0, NHCH), 7.10–7.15
(2H, m, ArH), 7.18–7.39 (8H, m, ArH), 7.54 (1H, br d, J 6.8, NH),
7.89 [1H, s, ClHC(3)@]; dC (75.5 MHz, CDCl3) 38.2 (CH2, SCH2),
56.5 (CH, NHCH), 66.5 (CH2, CH2OH), 126.6, 127.7, 128.0, 128.78,
128.86, 128.93 (6 ꢃ CH, 6 ꢃ aromatic CH), 130.7, 137.2, 138.3 [3
ꢃ C, 2 ꢃ aromatic C and C(2)S], 140.0 [CH, ClHC(3)@], 163.3 (C,
(ES+): Exact mass calculated for
C
16H23NO2S35Cl [M+H]+
m/z (ES+) 330.0
328.1138.
Found
328.1148;
{[(C16H22NO2S37Cl)+H+], 44%}, 328.0 {[(C16H22NO2S35Cl)+H+],
100%}.
4.15. (Z)-2-(Phenylthio)-3-chloro-N-[(R)-1-
phenylethyl]acrylamide 15
CO); HRMS (ES+): Exact mass calculated for
C
18H19NO2S35Cl
[M+H]+ 348.0825. Found 348.0834; m/z (ES+) 349.9
{[(C18H18NO2S37Cl)+H+], 44%}, 348.0 {[(C18H18NO2S35Cl)+H+],
100%}.
This was prepared following the procedure described above for
11 using N-[(R)-1-phenylethyl]-2-(phenylthio)propanamide
5
(2.51 g, 8.8 mmol), N-chlorosuccinimide (2.33 g, 17.1 mmol) and
toluene (60 mL). The reaction mixture was heated at 90 °C for
2 h. Following filtration and evaporation of the solvent at reduced
pressure, the crude product was obtained as a yellow oil, contain-
ing 56% b-chloroacrylamide by 1H NMR spectroscopy. This was
purified by column chromatography on silica gel using hexane–
ethyl acetate 95:5 as eluent to give the pure product 11 (1.30 g,
4.13. (Z)-2-(Benzylthio)-3-chloro-N-[(S)-1-hydroxy-3-
phenylpropan-2-yl]acrylamide 13
This was prepared following the procedure described above for
11 using 2-(benzylthio)-N-[(S)-1-hydroxy-3-phenylpropan-2-
yl]propanamide
3
(1.76 g, 5.4 mmol), N-chlorosuccinimide
(1.42 g, 10.5 mmol) and toluene (50 mL). The reaction mixture
was heated at 90 °C for 1 h. Following filtration and evaporation
of the solvent at reduced pressure, the crude product was obtained
as a brown oil, containing 35% b-chloroacrylamide by 1H NMR
spectroscopy. This was purified by column chromatography on sil-
ica gel using hexane–ethyl acetate (gradient elution 20–40% ethyl
acetate) as eluent to give the pure product 13 (1.00 g, 51%) as a pale
47%) as a white solid, mp 51–53 °C; ½a D20
¼ þ6:4 (c 0.5, EtOH);
ꢀ
m
max/cmꢁ1 (KBr) 3302 (NH), 2918 (CH), 1643 (CO), 1514 (NH bend);
dH (400 MHz, CDCl3) 1.30 [3H, d, J 6.8, CH(CH3)], 4.99 (1H, overlap-
ping dq, J 7.6, 6.8, NHCH), 6.89–7.05 (3H, m, ArH and NH), 7.17–
7.38 (8H, m, ArH), 7.87 [1H, s, ClHC(3)@].
4.16. (Z)-3-Chloro-N-[(R)-2-hydroxy-1-phenylethyl]-2-
(phenylthio)acrylamide 16
brown solid, mp 77–78 °C;
(C19H20ClNO2S requires C, 63.06; H, 5.57; Cl, 9.80; N, 3.87; S,
8.86. Found C, 62.72; H, 5.73; Cl, 10.00; N, 4.01; S, 9.09); mmax
½
a 2D0
ꢀ
¼ ꢁ30:0 (c 0.1, CHCl3);
/
This was prepared following the procedure described above for
cmꢁ1 (KBr) 3363 (NH), 3062 (CH), 2929 (CH), 1644 (CO), 1515
(NH bend), 1454 (CN stretch); dH (400 MHz, CDCl3) 2.20 (1H, dd,
J 5.6, 5.6, OH), 2.72 (1H, dd, A of ABX, JAX 13.8, JAB 7.2, one of CH2Ph),
2.83 (1H, dd, B of ABX, JBX 14.0, JAB 7.2, one of CH2Ph), 3.41–3.48
(1H, m, one of CH2OH), 3.51–3.57 (1H, m, one of CH2OH), 3.74
(2H, s, SCH2), 4.03–4.14 (1H, m, NHCH), 7.04–7.39 (11H, m, NH
and ArH), 7.80 [1H, s, ClHC(3)@]; dC (75.5 MHz, CDCl3) 36.7, 38.1
(2 ꢃ CH2, SCH2 and CH2Ph), 53.4 (CH, NHCH), 64.1 (CH2, CH2OH),
126.9, 127.6, 128.7, 128.8, 128.9, 129.2 (6 ꢃ CH, 6 ꢃ aromatic
11 using N-[(1R)-2-hydroxy-1-phenylethyl]-2-(phenylthio)pro-
panamide
6 (2.04 g, 6.8 mmol), N-chlorosuccinimide (1.80 g,
13.2 mmol) and toluene (40 mL). The reaction mixture was heated
at 90 °C for 2 h. Following filtration and evaporation of the solvent
at reduced pressure, the crude product was obtained as a yellow
oil, containing 41% b-chloroacrylamide by 1H NMR spectroscopy.
This was purified by column chromatography on silica gel using
hexane–ethyl acetate (gradient elution 20–40% ethyl acetate) as
eluent to give the pure product 16 (0.92 g, 41%) as a white solid,

880
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
mp 102–103 °C; ½a D20
ꢀ
¼ þ64:5 (c 0.5, CHCl3); (C17H16ClNO2S re-
(1.50 g, 11.0 mmol) and toluene (50 mL). The reaction mixture
was heated at 90 °C for 1 h. Following filtration and evaporation
of the solvent at reduced pressure, the crude product was obtained
as a yellow oil, containing 20% b-chloroacrylamide by 1H NMR
spectroscopy. This was purified by column chromatography on sil-
ica gel using hexane–ethyl acetate (gradient elution 20–40% ethyl
acetate) as eluent to give the pure product 18 (0.67 g, 34%) as a
quires C, 61.07; H, 4.92; Cl, 10.95; N, 4.22; S, 9.60. Found C,
61.16; H, 4.83; Cl, 10.62; N, 4.20; S, 9.61); m
max/cmꢁ1 (KBr) 3400
(OH), 3361 (NH), 3047 (CH), 2929 (CH), 1643 (CO), 1518 (NH
bend), 1452 (CN stretch); dH (400 MHz, CDCl3) 1.82 (1H, dd, J 7.2,
5.2, OH), 3.66–3.78 (2H, m, CH2OH), 4.94–4.98 (2H, overlapping
ddd, J 7.2, 4.8, 4.4, NHCH), 6.88–6.96 (2H, m, ArH), 7.18–7.37 (8H,
m, ArH), 7.46 (1H, br d, J 6.8, NH), 7.89 [1H, s, ClHC(3)@]; dC
(75.5 MHz, CDCl3) 56.0 (CH, NHCH), 66.1 (CH2, CH2OH), 126.4,
127.4, 127.8, 128.7, 128.8, 129.7 (6 ꢃ CH, 6 ꢃ aromatic CH),
130.7, 133.0, 138.2 [3 ꢃ C, 2 ꢃ aromatic C and C(2)S], 139.2 [CH,
ClHC(3)@], 162.4 (C, CO); HRMS (ES+): Exact mass calculated for
white solid, mp 80–81 °C;
(C18H18ClNO2S requires C, 62.15; H, 5.22; Cl, 10.19; N, 4.03; S,
9.22. Found C, 61.83; H, 5.21; Cl, 10.40; N, 4.08; S, 8.90); mmax
½
a 2D0
ꢀ
¼ þ84:3 (c 0.1, EtOH);
/
cmꢁ1 (KBr) 3423 (OH), 3368 (NH), 3061 (CH), 2928 (CH), 1640
(CO), 1518 (NH bend), 1439 (CN stretch); dH (400 MHz, CDCl3)
1.81 (1H, br t, J 5.0, OH), 2.68 (1H, dd, A of ABX, JAB 13.9, JAX 7.4,
one of CH2Ph), 2.74 (1H, dd, B of ABX, JAB 13.9, JBX 7.4, one of
CH2Ph), 3.38–3.48 (2H, m, CH2OH), 4.07–4.13 (1H, symm, NHCH),
6.97–7.11 [3H, m, NH (br d) and ArH], 7.14–7.34 (8H, m, ArH),
7.86 [1H, s, ClHC(3)@]; dc (75.5 MHz, CDCl3) 36.7 (CH2, CH2Ph),
53.2 (CH, NHCH), 63.6 (CH2, CH2OH), 126.8, 127.3, 128.4, 128.7,
129.2, 129.5 (6 ꢃ CH, 6 ꢃ aromatic CH), 130.8, 133.0, 137.1
[3 ꢃ C, 2 ꢃ aromatic C and C(2)S], 139.2 [CH, ClHC(3)@], 162.6 (C,
C
17H17NO2S35Cl [M+H]+ 334.0669. Found 334.0672; m/z (ES+)
336.0 {[(C17H16NO2S37Cl)+H+], 40%}, 334.0 {[(C17H16NO2S35Cl)+H+],
100%}.
The structure of 16 was determined by single crystal X-ray dif-
fraction on a crystalline sample of 16 recrystallised from dichloro-
methane/pentane. Crystals of 16 are monoclinic, space group C2,
formula
6.0525(4) Å, c = 15.0786(11) Å, b = 121.914(3)°, U = 1638.3(2) Å3,
F(0 0 0) = 696, (Mo K
) = 0.366 mmꢁ1, R(Fo) = 0.0282, for 2862 ob-
served reflections with I > 2
(I), wR2(F2) = 0.0596 for all 3105 un-
ique reflections. Data in the h range 1.59–26.02° were collected at
100 K on a Bruker Apex II Duo diffractometer using Mo K radia-
C17H16ClNO2S, M = 333.82, a = 21.1484(15) Å, b =
l
a
CO); HRMS (ES+): Exact mass calculated for C
18H19NO2S35Cl
r
[M+H]+ 348.0825. Found 348.0831; m/z (ES+) 350.0
{[(C18H18NO2S37Cl)+H+], 40%}, 348.0 {[(C18H18NO2S35Cl)+H+],
100%}.
a
tion, k = 0.7107 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.
4.19. (Z)-3-Chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]-2-
(phenylthio)acrylamide 19
This was prepared following the procedure described above for
4.17. (Z)-3-Chloro-N-[(1R,2S)-2,3-dihydro-2-hydroxy-1H-inden-
11 using 2-(phenylthio)-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-
1-yl]-2-(phenylthio)acrylamide 17
yl]propanamide
9
(1.93 g, 6.9 mmol), N-chlorosuccinimide
(1.83 g, 13.4 mmol) and toluene (50 mL). The reaction mixture
was heated at 90 °C for 1 h. Following filtration and evaporation
of the solvent at reduced pressure, the crude product was obtained
as a pale yellow oil, containing 28% b-chloroacrylamide by 1H NMR
spectroscopy. This was purified by column chromatography on sil-
ica gel using hexane–ethyl acetate (gradient elution 20–40% ethyl
acetate) as eluent to give the pure product 19 (0.95 g, 44%) as pale
This was prepared following the procedure described above for
11 using N-[(1R,2S)-2,3-dihydro-2-hydroxy-1H-inden-1-yl]-2-
(phenylthio)propanamide 7 (0.63 g, 2.0 mmol), N-chlorosuccini-
mide (0.53 g, 3.9 mmol) and toluene (20 mL). The reaction mixture
was heated at 90 °C for 30 min. Following filtration and evapora-
tion of the solvent at reduced pressure, the crude product was ob-
tained as a brown oil, containing 26% b-chloroacrylamide by 1H
NMR spectroscopy. This was purified by column chromatography
on silica gel using hexane–ethyl acetate (gradient elution 10–20%
ethyl acetate) as eluent to give the pure product 17 as a white solid
yellow solid, mp 37–39 °C; ½a D20
ꢀ
¼ ꢁ67:7 (c 0.5, CHCl3);
m
max/cmꢁ1
(KBr) 3401 (OH), 3264 (NH), 3062 (CH), 2964 (CH), 1657 (CO),
1635, 1526 (NH bend), 1476 (CN stretch); dH (400 MHz, CDCl3)
0.74 [9H, s, C(CH3)3], 1.82 (1H, br s, OH), 3.39 (1H, dd, J 7.9, 7.4,
NHCH), 3.64–3.76 (2H, m, CH2OH), 7.00 (1H, br d, J 8.0, NH),
7.20–7.36 (5H, m, ArH), 7.97 [1H, s, ClHC(3)@]; dC (75.5 MHz,
CDCl3) 26.6 [CH3, C(CH3)3], 33.4 [C, C(CH3)3], 60.4 (CH, NHCH),
63.0 (CH2, CH2OH), 127.3, 128.0, 129.6 (3 ꢃ CH, 3 ꢃ aromatic CH),
130.5, 133.1 [2 ꢃ C, aromatic C and C(2)S], 140.0 [CH, ClHC(3)@],
163.2 (C, CO); HRMS (ES+): Exact mass calculated for
(0.33 g, 47%), mp 124–125 °C;
(C18H16ClNO2S requires C, 62.51; H, 4.66; Cl, 10.25; N, 4.05; S,
9.27. Found C, 62.15; H, 4.46; Cl, 10.69; N, 4.09; S, 8.96); mmax
½
a 2D0
ꢀ
¼ þ60:1 (c 0.5, CHCl3);
/
cmꢁ1 (KBr) 3388 (OH), 3290 (NH), 3036 (CH), 2916 (CH), 1630
(CO), 1514 (NH bend), 1457 (CN stretch); dH (400 MHz, CDCl3)
2.86 (1H, dd, A of ABX, JAB 16.6, JAX 1.6, one of ArCH2), 3.10 (1H,
B of ABX, JAB 16.6, JAX 4.8, one of ArCH2), 4.43–4.50 (1H, m, CHOH),
5.29–5.35 (1H, m, NHCH), 6.69 (1H, d, J 7.2, ArH), 7.05–7.13 (1H, m,
ArH), 7.25–7.36 (8H, m, NH and ArH), 7.96 [1H, s, ClHC(3)@]; dC
(75.5 MHz, CDCl3) 39.6 (CH2, ArCH2), 58.2 (CH, NHCH), 73.6 (CH,
CHOH), 124.2, 125.3, 127.2, 127.3, 128.3, 128.6, 129.6 (7 ꢃ CH,
7 ꢃ aromatic CH), 131.0, 133.2 [2 ꢃ C, C(2)S or aromatic C], 139.0
[CH, ClHC(3)@], 139.78, 139.82 [2 ꢃ C, C(2)S or aromatic C], 162.9
(C, CO); HRMS (ES+): Exact mass calculated for C18H17NO2S35Cl
[M+H]+ 346.0669. Found 346.0681; m/z (ES+) 348.0
{[(C18H17NO2S37Cl)+H+], 38%}, 345.9 {[(C18H17NO2S35Cl)+H+],
100%}.
C
15H21NO2S35Cl [M+H]+ 314.0982. Found 314.0979; m/z (ES+)
316.0 {[(C15H20NO2S37Cl)+H+], 46%}, 314.0 {[(C15H20NO2S35Cl)+H+],
100%}.
4.20. (Z)-3-Chloro-N-[(R)-3,3-dimethylbutan-2-yl]-2-
(phenylthio)acrylamide 20
This was prepared following the procedure described above for
11 using N-[(R)-3,3-dimethylbutan-2-yl]-2-(phenylthio)propana-
mide 10 (1.10 g, 4.1 mmol), N-chlorosuccinimide (1.10 g,
8.1 mmol) and toluene (40 mL). The reaction mixture was heated
at 90 °C for 1 h. Following filtration and evaporation of the solvent
at reduced pressure, the crude product was obtained as an off-
white solid, containing 96% b-chloroacrylamide by 1H NMR spec-
troscopy. This was purified by column chromatography on silica
gel using hexane–ethyl acetate 95:5 as eluent to give the pure
4.18. (Z)-3-Chloro-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-2-
(phenylthio)acrylamide 18
This was prepared following the procedure described above for
11
using
N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-2-(phenyl-
(1.78 g, 5.6 mmol), N-chlorosuccinimide
product 20 (0.94 g, 76%) as
a white solid, mp 85–86 °C;
thio)propanamide
8
½ ꢀ
a 2D0
¼ þ92:9 (c 0.1, CHCl3); (C15H20ClNOS requires C, 60.49; H,

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
881
6.77; N, 4.70; S, 10.77; Cl, 11.90. Found C, 60.41; H, 6.70; N, 4.66; S,
11.17; Cl, 11.99);
max/cmꢁ1 (KBr) 3276 (NH), 3064 (CH), 2965
Crystals of 21b are monoclinic, space group P21, formula
C18H18ClNO2S, M = 347.84, a = 5.8018(6) Å, b = 18.291(3) Å,
m
(CH), 1636 (CO), 1533 (NH bend), 1475 (CN stretch); dH
(400 MHz, CDCl3) 0.68 [9H, s, C(CH3)3], 0.86 (3H, d, J 6.8, CHCH3),
3.71–3.78 (1H, dq, J 9.6, 6.8, NHCH), 6.69 (1H, br d, J 9.6, NH),
7.19–7.33 (5H, m, ArH), 7.93 [1H, s, ClHC(3)@]; dC (75.5 MHz,
CDCl3) 15.6 (CH3, CHCH3), 25.9 [CH3, C(CH3)3], 33.9 [C, C(CH3)3],
53.7 (CH, NHCH), 127.1, 128.1, 129.6 (3 ꢃ CH, 3 ꢃ aromatic CH),
130.8, 133.1 [2 ꢃ C, aromatic C and C(2)S], 139.2 [CH, ClHC(3)@],
161.4 (C, CO); HRMS (ES+): Exact mass calculated for
c = 8.1019(13) Å, b = 93.218(11)°, U = 858.4(2) Å3, F(0 0 0) = 364,
l
(Mo K
tions with I > 2
tions. Data in the h range 2.23–25.51° were collected at 293 K on
a Nonius MACH3 diffractometer using Mo K graphite-monochro-
a
) = 0.352 mmꢁ1, R(Fo) = 0.0611, for 1827 observed reflec-
(I), wR2(F2) = 0.1539 for all 3195 unique reflec-
r
a
mated radiation, k = 0.7107 Å and corrected for Lorentz and polar-
isation effects. 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 parent atom.
A fraction containing a mixture of the two diastereomers 21a
and 21b in a ratio of 1:2.8 was also isolated from the column as
a white solid (0.34 g, 31%).
C
15H21NOS35Cl [M+H]+ 298.1032. Found 298.1038; m/z (ES+)
300.0 {[(C15H20NOS37Cl)+H+], 44%}, 298.0 {[(C15H20NOS35Cl)+H+],
100%}.
4.21. (Z)-2-(Ss)-(Benzylsulfinyl)-3-chloro-N-[(R)-1-
phenylethyl]acrylamide 21a and (Z)-2-(Rs)-(benzylsulfinyl)-3-
chloro-N-[(R)-1-phenylethyl]acrylamide 21b
4.22. (Z)-2-(Ss/Rs)-(Benzylsulfinyl)-3-chloro-N-[(R)-2-hydroxy-
1-phenylethyl]acrylamide 22
A solution of OxoneÒ (3.93 g, 6.4 mmol) in water (20 mL) was
added to a stirring solution of (Z)-2-(benzylthio)-3-chloro-N-[(R)-
1-phenylethyl]acrylamide 11 (1.06 g, 3.2 mmol) in acetone
(60 mL) at room temperature. A colourless precipitate formed
immediately. The reaction mixture was stirred for 2 h. Water
(80 mL) was added and the aqueous solution was extracted with
dichloromethane (3 ꢃ 50 mL). The combined extracts were washed
with water (2 ꢃ 50 mL) and brine (50 mL), dried, filtered and con-
centrated at reduced pressure to give the crude sulfoxides 21a and
21b as a white solid and a 1.3:1 mixture of diastereomers. The 1H
NMR spectrum of the crude product was very clean, with no evi-
dence of sulfone formation. Following purification by column chro-
matography using hexane–ethyl acetate (gradient elution 5–20%
ethyl acetate) as eluent, the less polar and major diastereomer
This was prepared following the procedure described above for
21 by addition of (Z)-2-(benzylthio)-3-chloro-N-[(R)-2-hydroxy-1-
phenylethyl]acrylamide 12 (0.16 g, 0.5 mmol) in acetone (15 mL)
to OxoneÒ (0.57 g, 0.9 mmol) in water (5 mL). Following stirring
at room temperature for 16 h, the crude sulfoxides 22a and 22b
were obtained as a yellow oil and a 1.8:1 mixture of diastereomers.
Following purification using hexane–ethyl acetate (gradient elu-
tion 10–40% ethyl acetate) as eluent, the less polar major diaste-
reomer 22a was isolated as a clear oil (0.09 g, 50%); ½a D20
¼ ꢁ67:5
ꢀ
(c 0.1, CHCl3); m
max/cmꢁ1 (film) 3396 (OH), 3247 (NH), 2926 (CH),
1656 (CO), 1534 (NH bend), 1454 (CN stretch), 1028 (SO); dH
(400 MHz, CDCl3) 2.08 (1H, t, J 6.0, OH), 3.56–3.71 (2H, m, CH2OH),
4.31 (1H, d, A of AB system, JAB 13.2, one of SCH2), 4.38 (1H, d, B of
AB system, JAB 13.2, one of SCH2), 4.87–4.94 (1H, overlapping dt, J
6.8, 7.2, NHCH), 7.18–7.47 (10H, m, ArH), 7.68 [1H, s, ClHC(3)@],
8.98 (1H, br d, J 7.2, NH); dC (75.5 MHz, CDCl3) 56.1 (CH, NHCH),
58.1 (CH2, SCH2), 66.7 (CH2, CH2OH), 126.7, 127.9 (2 ꢃ CH, 2 ꢃ aro-
matic CH), 128.3 (C, aromatic C), 128.89, 128.92, 129.1, 130.9
(4 ꢃ CH, 4 ꢃ aromatic CH), 135.6 [C, C(2)S or aromatic C], 136.6
[CH, ClHC(3)@], 138.1 [C, C(2)S or aromatic C], 161.0 (C, CO); HRMS
(ES+): Exact mass calculated for C18H19NO3S35Cl [M+H]+ 364.0774.
Found 364.0770; m/z (ES+) 366.0 {[(C18H18NO3S37Cl)+H+], 42%},
364.0 {[(C18H18NO3S35Cl)+H+], 100%}.
21a was isolated as a clear oil (0.31 g, 28%); ½a D20
¼ ꢁ179:0 (c 0.4,
ꢀ
CHCl3); m
max/cmꢁ1 (KBr) 3237 (NH), 3071 (CH), 2925 (CH), 1667
(CO), 1571, 1455 (CN stretch), 1030 (SO); dH (400 MHz, CDCl3)
1.48 [3H, d, J 6.8, CH(CH3)], 4.05 (1H, d, A of AB system, JAB 12.4,
one of SCH2), 4.23 (1H, d, B of AB system, JAB 12.8, one of SCH2),
5.09 (1H, overlapping dq, J 7.2, 6.8, NHCH), 7.05–7.15 (2H, m,
ArH), 7.17–7.46 (8H, m, ArH), 7.67 [1H, s, ClHC(3)@], 8.86 (1H, br
d, J 6.8, NH); dC (75.5 MHz, CDCl3) 22.4 [CH3, CH(CH3)], 49.5 (CH,
NHCH), 58.6 (CH2, SCH2), 126.3, 127.4 (2 ꢃ CH, 2 ꢃ aromatic CH),
128.2 (C, aromatic C), 128.75, 128.83, 128.9, 130.4 (4 ꢃ CH,
4 ꢃ aromatic CH), 135.5 [C, aromatic
C
or C(2)S], 136.6 [C,
The more polar minor diastereomer 22b was isolated as a clear
oil, containing ꢂ18% of the major diastereomer 22a (0.04 g, 24%);
ClHC(3)@], 143.0 [C, aromatic C or C(2)S], 159.8 (C, CO); HRMS
(ES+): Exact mass calculated for
C
18H19NO2S35Cl [M+H]+
½
a 2D0
ꢀ
¼ þ122:6 (c 0.08, CHCl3);
m
max/cmꢁ1 (film) 3401 (OH), 3203
348.0825. Found 348.0822; m/z (ES+) 350.0 {[(C18H18NO2S37Cl)+
(NH), 2923 (CH), 1651 (CO), 1529 (NH bend), 1455 (CN stretch),
1029 (SO); dH (400 MHz, CDCl3) 2.49 (1H, t, J 6.0, OH), 3.78 (2H,
overlapping dd, J 6.0, 5.6, CH2OH), 4.12 (1H, d, A of AB system, JAB
13.2, one of SCH2), 4.23 (1H, d, B of AB system, JAB 13.2, one of
SCH2), 4.97 (1H, overlapping dt, J 7.2, 5.6, NHCH), 7.08–7.50 (10H,
m, ArH), 7.73 [1H, s, ClHC(3)@], 9.04 (1H, br d, J 7.2, NH); dC
(75.5 MHz, CDCl3) 56.6 (CH, NHCH), 58.2 (CH2, SCH2), 67.1 (CH2,
CH2OH), 127.0 (CH, aromatic CH), 127.9 (C, aromatic C), 128.0,
128.79, 128.89, 128.93, 130.5 (5 ꢃ CH, 5 ꢃ aromatic CH), 135.1 [C,
C(2)S or aromatic C], 137.0 [CH, ClHC(3)@], 138.1 [C, C(2)S or aro-
matic C], 161.2 (C, CO); HRMS (ES+): Exact mass calculated for
H+], 42%}, 348.0 {[(C18H18NO2S35Cl)+H+], 100%}.
The more polar minor diastereomer 21b was isolated as a white
solid (0.22 g, 19%), mp 137–138 °C; ½a D20
¼ þ323:3 (c 0.5, CHCl3);
ꢀ
(C18H18ClNO2S requires C, 62.15; H, 5.22; N, 4.03; S, 9.22; Cl, 10.19.
Found C, 61.90; H, 4.96; N, 3.98; S, 8.79; Cl, 10.27);
m
max/cmꢁ1
(KBr) 3247 (NH), 3030 (CH), 2973 (CH), 1655 (CO), 1572, 1454 (CN
stretch), 1035 (SO); dH (400 MHz, CDCl3) 1.27 [3H, d, J 6.8, CH(CH3)],
4.24 (1H, d, A of AB system, JAB 12.8, one of SCH2), 4.29 (1H, d, B of AB
system, JAB 13.2, one of SCH2), 4.91 (1H, overlapping dq, J 7.2, 7.2,
NHCH), 7.16–7.35 (7H, m, ArH), 7.37–7.46 (3H, m, ArH), 7.67 [1H,
s, ClHC(3)@], 8.64 (1H, br d, J 7.2, NH); dC (75.5 MHz, CDCl3) 22.6
[CH3, CH(CH3)], 49.3 (CH, NHCH), 58.2 (CH2, SCH2), 125.9, 127.3
(2 ꢃ CH, 2 ꢃ aromatic CH), 128.2 (C, aromatic C), 128.7, 128.9,
129.0, 130.8 (4 ꢃ CH, 4 ꢃ aromatic CH), 135.4 [C, aromatic C or
C(2)S], 136.0 [C, ClHC(3)@], 142.9 [C, aromatic C or C(2)S], 159.6 (C,
C
18H19NO3S35Cl [M+H]+ 364.0774. Found 364.0774; m/z (ES+)
366.0 {[(C18H18NO3S37Cl)+H+], 44%}, 364.0 {[(C18H18NO3S35Cl)+H+],
100%}.
4.23. (Z)-3-Chloro-N-[(R)-2-hydroxy-1-phenylethyl]-2-(Ss/Rs)-
(benzenesulfinyl)acrylamide 23
CO); HRMS (ES+): Exact mass calculated for
C
18H19NO2S35Cl
[M+H]+ 348.0825. Found 348.0814; m/z (ES+) 350.0
{[(C18H18NO2S37Cl)+H+], 42%}, 348.0 {[(C18H18NO2S35Cl)+H+], 100%}.
The stereochemistry was determined by single crystal X-ray dif-
fraction on a crystalline sample of 21b recrystallised from ethanol.
This was prepared following the procedure described above for
21 by addition of (Z)-3-chloro-N-[(R)-2-hydroxy-1-phenylethyl]-2-
(phenylthio)acrylamide 16 (0.10 g, 0.3 mmol) in acetone (10 mL) to

882
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
OxoneÒ (0.35 g, 0.6 mmol) in water (5 mL). Following stirring at
room temperature for 16 h, the crude sulfoxides 23a and 23b were
obtained as a clear oil and 2.2:1 mixture of diastereomers. The 1H
NMR spectrum of the crude product was very broad. The crude
product was purified by column chromatography on silica gel
using hexane–ethyl acetate 60:40 as eluent to give the less polar
minor diastereomer 23b as a clear oil (0.01 g, 14%), containing
mers], 160.9*, 161.0 (2 ꢃ C, CO of two diastereomers); HRMS (ES+):
Exact mass calculated for C18H17NO3S35Cl [M+H]+ 362.0618. Found
362.0609; m/z (ES+) 364.0 {[(C18H17NO3S37Cl)+H+], 40%}, 362.0
{[(C18H17NO3S35Cl)+H+], 100%}.
*Signals for 26a.
A second fraction containing the more polar major diastereo-
mer 26a was also isolated (0.03 g, 43%) and contained ꢂ4% of
ꢂ4% of 23a; ½a 2D0
ꢀ
¼ ꢁ139:5 (c 0.1, CHCl3);
m
max/cmꢁ1 (film) 3391
26b; ½a 2D0
ꢀ
¼ 99:3 (c 0.1, CHCl3);
m
max/cmꢁ1 (KBr) 3414 (OH),
(OH), 3253 (NH), 3055 (CH), 2923 (CH), 1656 (CO), 1536 (NH
bend), 1446 (CN stretch), 1026 (SO); dH (400 MHz, CDCl3) 1.87
(1H, overlapping dd, J 7.2, 6.0, OH), 3.65–3.77 (2H, m, CH2OH),
4.96 (1H, overlapping dt, J 7.6, 5.2, NHCH), 7.23–7.43 (5H, m,
ArH), 7.53–7.63 (3H, m, ArH), 7.72 [1H, s, ClHC(3)@], 7.74–7.81
(2H, m, ArH), 9.17 (1H, br d, J 7.6, NH); dC (75.5 MHz, CDCl3) 55.7
(CH, NHCH), 66.3 (CH2, CH2OH), 124.2, 126.7, 128.0, 128.9, 129.7,
131.9 (6 ꢃ CH, 6 ꢃ aromatic CH), 137.7 [CH, ClHC(3)@], 138.1,
138.6, 141.0 [3 ꢃ C, C(2)S and 2 ꢃ aromatic C], 160.4 (C, CO); HRMS
(ES+): Exact mass calculated for C17H17NO3S35Cl [M+H]+ 350.0618.
Found 350.0611; m/z (ES+) 352.0 {[(C17H16NO3S37Cl)+H+], 40%},
350.0 {[(C17H16NO3S35Cl)+H+], 100%}.
3247 (NH), 3051 (CH), 2922 (CH), 1654 (CO), 1527 (NH bend),
1475 (CN stretch), 1034 (SO); dH (300 MHz, CDCl3) 2.24 (1H, d,
J 5.4, OH), 2.97 (1H, dd, A of ABX, JAB 16.5, JAX 2.1, one of ArCH2),
3.06–3.23 (1H, dd, B of ABX, JAB 16.5, JAX 5.1, one of ArCH2), 4.65
(1H, ddd, J 10.2, 5.1, 2.1, CHOH), 5.36 (1H, dd, J 8.1, 5,1, NHCH),
6.59 (1H, d, J 7.5, ArH), 7.03–7.34 (4H, m, ArH), 7.43–7.63 (5H,
m, ArH), 7.83 [1H, s, ClHC(3)@], 8.90 (1H, br d, J 8.1, NH); dC
(75.5 MHz, CDCl3) 39.8 (CH2, ArCH2), 57.6 (CH, NHCH), 73.6
(CH, CHOH), 124.2, 124.5, 125.3, 126.9, 128.2, 129.7, 131.6
(7 ꢃ CH, 7 ꢃ aromatic CH), 138.1 [CH, ClHC(3)@], 138.9, 139.9,
140.9 [3 ꢃ C, C(2)S and aromatic C], 160.9 (C, CO); HRMS
(ES+): Exact mass calculated for
C
18H17NO3S35Cl [M+H]+
m/z (ES+) 364.0
The more polar major diastereomer 23a was isolated as a white
solid (0.04 g, 36%) and contained ꢂ4% of 23b, mp 105–107 °C;
362.0618.
Found
362.0605;
{[(C18H17NO3S37Cl)+H+], 40%}, 362.0 {[(C18H17NO3S35Cl)+H+],
100%}.
½
a 2D0
ꢀ
¼ ꢁ65:0 (c 0.1, CHCl3);
m
max/cmꢁ1 (KBr) 3401 (OH), 3293
(NH), 3042 (CH), 2919 (CH), 1629 (CO), 1538 (NH bend), 1444
(CN stretch), 1056 (SO); dH (400 MHz, CDCl3) 2.35 (1H, t, J 6.0,
OH), 3.81–3.98 (2H, m, CH2OH), 5.02 (1H, overlapping dt, J 6.4,
6.0, NHCH), 6.99–7.13 (2H, m, ArH), 7.24–7.60 (8H, m, ArH), 7.79
[1H, s, ClHC(3)@], 9.03 (1H, br d, J 6.8, NH); dC (75.5 MHz, CDCl3)
56.1 (CH, NHCH), 66.2 (CH2, CH2OH), 124.1, 126.8, 127.8, 128.7,
128.9, 129.6 (6 ꢃ CH, 6 ꢃ aromatic CH), 138.1 [C, aromatic C or
C(2)S], 138.2 [CH, ClHC(3)@], 138.4, 140.7 [2 ꢃ C, C(2)S or aromatic
C], 160.6 (C, CO); HRMS (ES+): Exact mass calculated for
4.25. (Z)-2-(Ss/Rs)-(Benzylsulfinyl)-3-chloro-N-[(S)-1-hydroxy-
3-phenylpropan-2-yl]acrylamide 24
This was prepared following the procedure described above for
21 by addition of (Z)-2-(benzylthio)-3-chloro-N-[(S)-1-hydroxy-3-
phenylpropan-2-yl]acrylamide 13 (0.13 g, 0.4 mmol) in acetone
(8 mL) to OxoneÒ (0.44 g, 0.7 mmol) in water (5 mL). Following
stirring at room temperature for 16 h, the crude sulfoxides 24a
and 24b were obtained as a clear oil (0.11 g, 85%) and a 1.1:1 mix-
ture of diastereomers. As the 1H NMR spectrum of the crude prod-
C
17H17NO3S35Cl [M+H]+ 350.0618. Found 350.0617; m/z (ES+)
352.0 {[(C17H16NO3S37Cl)+H+], 52%}, 350.0 {[(C17H16NO3S35Cl)+H+],
100%}.
uct was very clean, no purification was necessary; ½a D20
¼ ꢁ1:4 (c
ꢀ
0.3, CHCl3); m
max/cmꢁ1 (film) 3412 (OH), 3253 (NH), 3061 (CH),
4.24. (Z)-3-Chloro-N-[(1R,2S)-2,3-dihydro-2-hydroxy-1H-inden-
1-yl]-2-(Ss/Rs)-(benzenesulfinyl)acrylamide 26
2926 (CH), 1655 (CO), 1571, 1455 (CN stretch), 1031; dH
(300 MHz, CDCl3) 2.44 (1H, br s, OH of 24a and 24b), 2.73
(0.48H, dd, A of ABX, JAX 14.1, JAB 9.3, one of CH2Ph of 24b), 2.82
(1.04H, d, J 7.2, CH2Ph of 24a), 2.96 (0.48H, dd, B of ABX, JAX 14.1,
JAB 9.3, one of CH2Ph of 24b), 3.43 (0.48H, dd, A of ABX, JBX 11.4,
JAB 5.7, one of CH2OH of 24b), 3.52 (0.48H, dd, B of ABX, JBX 11.4,
JAB 3.9, one of CH2OH of 24b), 3.62 (0.52H, dd, A of ABX, JBX 11.1,
JAB 5.4, one of CH2OH of 24a), 3.66 (0.48H, d, A of AB system, JAB
12.9, one of SCH2 of 24b), 3.72 (0.52H, dd, B of ABX, JBX 11.1, JAB
3.9, one of CH2OH of 24a), 3.99 (0.48H, d, B of AB system, JAB
12.9, one of SCH2 of 24b), 4.07–4.16 (0.48H, m, NHCH of 24b),
4.18 (0.52H, d, A of AB system, JAB 12.9, one of SCH2 of 24a), 4.26
(0.52H, d, B of AB system, JAB 12.9, one of SCH2 of 24a), 4.32–4.46
(0.52H, m, NHCH of 24a), 6.99–7.46 (10H, m, ArH of 24a and
24b), 7.58 [0.52H, s, ClHC(3)@ of 24a], 7.60 [0.48H, s, ClHC(3)@
of 24b], 8.47 (0.48H, br d, J 7.5, NH of 24b), 8.61 (0.52H, br d, J
7.5, NH of 24a); dC (75.5 MHz, CDCl3) 36.8, 37.0* (2 ꢃ CH2, CH2Ph
of two diastereomers), 53.1*, 53.7 (2 ꢃ CH, NHCH of two diastereo-
mers), 58.1, 58.5* (2 ꢃ CH2, SCH2 of two diastereomers), 63.9, 64.6
(2 ꢃ CH2, CH2OH of two diastereomers), 126.7*, 126.8 (2 ꢃ CH, aro-
matic CH), 128.1, 128.3 (2 ꢃ C, aromatic C), 128.6, 128.7, 128.8,
128.9, 129.0, 129.3, 130.5, 130.8 (8 ꢃ CH, aromatic CH), 134.8,
135.3 [2 ꢃ C, aromatic C or C(2)S], 136.5 (CH, aromatic CH), 137.5
(C, aromatic C), 137.79*, 137.81 [2 ꢃ CH, ClHC(3)@ of two diaste-
reomers], 161.1, 161.3* (2 ꢃ C, CO of two diastereomers)—all of
the aromatic signals were not resolved; HRMS (ES+): Exact mass
calculated for C19H21NO3S35Cl [M+H]+ 378.0931. Found 378.0917;
This was prepared following the procedure described above for
21 by addition of (Z)-3-chloro-N-[(1R,2S)-2,3-dihydro-2-hydroxy-
1H-inden-1-yl]-2-(phenylthio)acrylamide 17 (0.07 g, 0.2 mmol) in
acetone (8 mL) to OxoneÒ (0.26 g, 0.4 mmol) in water (4 mL). Fol-
lowing stirring at room temperature for 16 h, the crude sulfoxides
26a and 26b were obtained as a clear oil and a 1.6:1 mixture of dia-
stereomers. This was purified by column chromatography on silica
gel using hexane–ethyl acetate 60:40 as eluent to give a 1.1:1 mix-
ture of the two diastereomers 26a and 26b as a clear oil (0.04 g,
46%); ½a 2D0
ꢀ
¼ ꢁ66:4 (c 0.2, CHCl3);
m
max/cmꢁ1 (KBr) 3436 (OH),
3231 (NH), 3055 (CH), 2924 (CH), 1650 (CO), 1534 (NH bend),
1474 (CN stretch), 1033 (SO); dH (300 MHz, CDCl3) 1.83 (1H, br s,
OH of 26a and 26b), 2.93 (0.52H, dd, A of ABX, JAB 16.5, JAX 1.8,
one of ArCH2 of 26b), 2.96 (0.48H, dd, A of ABX, JAB 16.5, JAX 2.1,
one of ArCH2 of 26a), 3.06–3.23 (1H, m, one of ArCH2 of 26a and
26b), 4.49 (0.52H, dt, J 8.1, 1.8, CHOH of 26b), 4.63 (0.48H, dt, J
7.8, 2.1, CHOH of 26a), 5.26–5.47 (1H, m, NHCH of 26a and 26b),
6.59 (0.48H, d, J 7.5, ArH of 26a), 7.02–7.77 (10H, m, ArH of 26a
and 26b), 7.81 [0.52H, s, ClHC(3)@ of 26b], 7.82 [0.48H, s, ClHC(3)@
of 26a], 8.78–9.06 (1H, br m, NH of 26a and 26b); dC (75.5 MHz,
CDCl3) 39.7, 39.8* (2 ꢃ CH2, ArCH2 of two diastereomers), 57.6*,
58.3 (2 ꢃ CH, NHCH of two diastereomers), 73.6*, 73.7 (2 ꢃ CH,
CHOH of two diastereomers), 124.2*, 124.3, 124.5*, 124.6, 125.3*,
125.4, 126.9*, 127.4, 128.2*, 128.4, 129.67*, 129.70, 131.6*, 131.8
(14 ꢃ CH, aromatic CH of two diastereomers), 137.5, 138.0*
[2 ꢃ CH, ClHC(3)@ of two diastereomers], 139.0*, 139.7, 139.8,
139.9*, 140.9*, 141.1 [6 ꢃ C, C(2)S and aromatic C of two diastereo-
m/z
(ES+)
380.0
{[(C19H20NO3S37Cl)+H+],
42%},
378.0
{[(C19H20NO3S35Cl)+H+], 100%}.
*Signals for 24a (major).

M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
883
4.26. (Z)-3-Chloro-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-2-
(Ss/Rs)-(benzenesulfinyl)acrylamide 25
The more polar minor diastereomer 27b was isolated as a white
solid (0.03 g, 21%), containing ꢂ21% of 27a; ½a D20
¼ ꢁ123:5 (c 0.12,
ꢀ
CHCl3); m
max/cmꢁ1 (KBr) 3434 (OH), 3271 (NH), 3060 (CH), 2966
This was prepared following the procedure described above for
21 by addition of (Z)-3-chloro-N-[(S)-1-hydroxy-3-phenylpropan-
2-yl]-2-(phenylthio)acrylamide 18 (0.22 g, 0.6 mmol) in acetone
(15 mL) to OxoneÒ (0.78 g, 1.3 mmol) in water (5 mL). Following
stirring at room temperature for 16 h, the crude sulfoxides 25a
and 25b were obtained as a white solid (0.22 g, 95%) and a 1.1:1
mixture of diastereomers. As the 1H NMR spectrum of the crude
product was very clean, purification was not required;
(CH), 1665 (CO), 1574, 1445 (CN stretch), 1032 (SO); dH
(400 MHz, CDCl3) 0.99 [9H, s, C(CH3)3], 2.75 (1H, br t, OH), 3.51–
3.65 (1H, m, NHCH), 3.84–3.98 (2H, m, CH2OH), 4.21 (1H, d, A of
AB system, JAB 12.4, one of SCH2), 4.39 (1H, d, B of AB system, JAB
12.8, one of SCH2), 7.22–7.47 (5H, m, ArH), 7.72 [1H, s, ClHC(3)@],
8.78 (1H, br d, J 7.6, NH); dC (75.5 MHz, CDCl3) 27.1 [CH3, C(CH3)3],
33.5 [C, C(CH3)3], 59.1 (CH2, SCH2), 61.4 (CH, NHCH), 63.7 (CH2,
CH2OH), 129.1, 130.5 [2 ꢃ CH (2 signals for 3 ꢃ CH), 2 ꢃ aromatic
CH], 135.3, 136.4 [2 ꢃ C, C(2)S and aromatic C], 137.2 [CH,
ClHC(3)@], 162.4 (C, CO); HRMS (ES+): Exact mass calculated for
½
a 2D0
ꢀ
¼ ꢁ30:7 (c 0.1, CHCl3);
m
max/cmꢁ1 (KBr) 3401 (OH), 3231
(NH), 3045 (CH), 2922 (CH), 1643 (CO), 1541 (NH bend), 1444
(CN stretch), 1032 (SO); dH (300 MHz, CDCl3) 1.74 (0.52H, br s,
OH of 25a), 2.45 (0.48H, br s, OH of 25b), 2.69 (0.48H, dd, A of
ABX, JAB 14.1, JAX 8.1, one of CH2Ph of 25b), 2.82–2.94 (1.52H, m,
CH2Ph of 25a and one of CH2Ph of 25b), 3.42 (0.48H, dd, A of
ABX, JAB 11.1, JAX 4.8, one of CH2OH of 25b), 3.47 (0.48H, dd, B of
ABX, JAB 11.1, JBX 4.8, one of CH2OH of 25b), 3.62 (0.52H, dd, A of
ABX, JAB 11.1, JAX 4.8, one of CH2OH of 25a), 3.70 (0.52H, dd, A of
ABX, JAB 11.1, JAX 3.6, one of CH2OH of 25a), 4.09–4.31 (1H, m,
NHCH of 25a and 25b), 7.11–7.56 (9H, m, ArH of 25a and 25b),
7.59–7.66 (1H, m, ArH of 25a and 25b), 7.68 [0.48H, s, ClHC(3)@
of 25b], 7.71 [0.52H, s, ClHC(3)@ of 25a], 8.58 (0.48H, br d, J 7.2,
NH of 25b), 8.73 (0.52H, br d, J 7.8, NH of 25a); dC (75.5 MHz,
CDCl3) 36.9, 37.0* (2 ꢃ CH2, CH2Ph of two diastereomers), 53.2*,
53.5 (2 ꢃ CH, NHCH of two diastereomers), 63.5, 64.3* (2 ꢃ CH2,
CH2OH of two diastereomers), 124.2, 124.3*, 126.65*, 126.71,
128.60, 128.62, 129.1, 129.3, 129.7, 131.76, 131.80 [11 ꢃ CH (11
signals for 12 carbons), aromatic CH of two diastereomers],
137.32 [C, aromatic C or C(2)S of one diastereomer], 137.3*, 137.4
[2 ꢃ CH, ClHC(3)@ of two diastereomers], 137.5, 138.3*, 138.7,
140.9*, 141.1 [5 ꢃ C, C(2)S and aromatic C of two diastereomers],
160.6, 161.0* (2 ꢃ C, CO of two diastereomers); HRMS (ES+): Exact
C
16H23NO3S35Cl [M+H]+ 344.1087. Found 344.1071; m/z (ES+)
346.0 {[(C16H22NO3S37Cl)+H+], 44%}, 344.0 {[(C16H22NO3S35Cl)+H+],
100%}.
4.28. (Z)-3-Chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]-2-
(Ss/Rs)-(benzenesulfinyl)acrylamide 28
This was prepared following the procedure described above for
21 by addition of (Z)-3-chloro-N-[(S)-1-hydroxy-3,3-dimethylb-
utan-2-yl]-2-(phenylthio)acrylamide 19 (0.25 g, 0.8 mmol) in ace-
tone (20 mL) to OxoneÒ (0.96 g, 1.6 mmol) in water (5 mL).
Followingstirringat roomtemperature for16 h, thecrudesulfoxides
28a and 28b were obtained as a clear oil and a 2.8:1 mixture of dia-
stereomers. This was purified by column chromatography on silica
gel using hexane–ethyl acetate 60:40 as eluent to give the less polar
minor diastereomer 28b as a clear oil (0.02 g, 10%); ½a D20
¼ þ127:2 (c
ꢀ
0.1, CHCl3); m
max/cmꢁ1 (KBr) 3428 (OH), 3264 (NH), 3060 (CH), 2963
(CH), 1667(CO), 1573, 1547(NHbend), 1476(CNstretch), 1032(SO);
dH (400 MHz, CDCl3) 0.98 [9H, s, C(CH3)3], 1.66 (1H, dd, J 7.2, 4.8, OH),
3.36 (1H, ddd, J 11.4, 8.4, 4.8, NHCH), 3.68–3.84 (2H, m, CH2OH),
7.48–7.60 (3H, m, ArH), 7.67–7.74 (2H, m, ArH), 7.78 [1H, s,
ClHC(3)@], 8.58 (1H, br d, J 8.4, NH); dC (75.5 MHz, CDCl3) 26.9
[C(CH3)3], 33.5 [C(CH3)3], 60.8 (NHCH), 63.3 (CH2OH), 124.5, 129.8,
131.9 (3 ꢃ aromatic CH), 137.5 [ClHC(3)@], 138.6, 141.3 [C(2)S and
aromatic C], 161.6 (CO); HRMS (ES+): Exact mass calculated for
mass calculated for
C
18H19NO3S35Cl [M+H]+ 364.0774. Found
364.0757; m/z (ES+) 366.0 {[(C18H18NO3S37Cl)+H+], 38%}, 364.0
{[(C18H18NO3S35Cl)+H+], 100%}.
*Signals for 25a (major).
C
15H21NO3S35Cl [M+H]+ 330.0931. Found 330.0935; m/z (ES+)
4.27. (Z)-2-(Ss/Rs)-(Benzylsulfinyl)-3-chloro-N-[(S)-1-hydroxy-
3,3-dimethylbutan-2-yl]acrylamide 27
332.0 {[(C15H20NO3S37Cl)+H+], 46%}, 330.0 {[(C15H20NO3S35Cl)+H+],
100%}.
The more polar major diastereomer 28a was isolated as a clear oil
This was prepared following the procedure described above for
21 by addition of (Z)-2-(benzylthio)-3-chloro-N-[(S)-1-hydroxy-
3,3-dimethylbutan-2-yl]acrylamide 14 (0.12 g, 0.4 mmol) in
acetone (10 mL) to OxoneÒ (0.44 g, 0.7 mmol) in water (5 mL).
Following stirring at room temperature for 16 h, the crude sulfox-
ides 27a and 27b were obtained as a clear oil and a 3.3:1 mixture of
diastereomers. Following purification by column chromatography
on silica gel using hexane–ethyl acetate 60:40 as eluent, the less
polar major diastereomer 27a was isolated as a clear oil (0.08 g,
(0.05 g, 20%); ½a D20
ꢀ
¼ ꢁ109:3 (c 0.2, CHCl3);
m
max/cmꢁ1 (KBr) 3412
(OH), 3277 (NH), 3060 (CH), 2962 (CH), 1663 (CO), 1545 (NH bend),
1476 (CN stretch), 1052 (SO); dH (400 MHz, CDCl3) 0.75 [9H, s,
C(CH3)3], 2.49 (1H, t, J 4.8, OH), 3.51–3.62 (1H, m, NHCH), 3.78–
3.89 (2H, m, CH2OH), 7.47–7.60 (3H, m, ArH), 7.62–7.75 (2H, m,
ArH), 7.90 [1H, s, ClHC(3)@], 8.39 (1H, br d, J 8.4, NH); dC
(75.5 MHz, CDCl3) 26.7 [CH3, C(CH3)3], 33.4 [C, C(CH3)3], 60.4 (CH,
NHCH), 62.9 (CH2, CH2OH), 124.4, 129.7, 131.6 (3 ꢃ CH, 3 ꢃ aro-
matic CH), 138.3 [C, C(2)S or aromatic C], 138.7 [CH, ClHC(3)@],
141.0 [C, C(2)S or aromatic C], 161.8 (C, CO); HRMS (ES+): Exact mass
calculated for C15H21NO3S35Cl [M+H]+ 330.0931. Found 330.0935;
64%), containing ꢂ6% of 27b; ½a D20
ꢀ
¼ 193:7 (c 0.2 in CHCl3); mmax
/
cmꢁ1 (film) 3429 (OH), 3247 (NH), 3064 (CH), 2924 (CH), 1668
(CO), 1650, 1580, 1456 (CN stretch), 1021 (SO); dH (400 MHz,
CDCl3) 0.92 [9H, s, C(CH3)3], 2.24 (1H, t, J 6.0, OH), 3.23–3.35 (1H,
m, NHCH), 3.73–3.92 (2H, m, CH2OH), 4.32 (1H, d, A of AB system,
JAB 12.8, one of SCH2), 4.39 (1H, d, B of AB system, JAB 12.8, one of
SCH2), 7.21–7.50 (5H, m, ArH), 7.68 [1H, s, ClHC(3)@], 8.49 (1H, br
d, J 8.0, NH); dC (75.5 MHz, CDCl3) 26.9 [CH3, C(CH3)3], 33.3 [C,
C(CH3)3], 58.0 (CH2, SCH2), 61.0 (CH, NHCH), 63.4 (CH2, CH2OH),
128.4 [C, C(2)S or aromatic C], 128.9, 129.0, 130.8 (3 ꢃ CH, 3 ꢃ aro-
matic CH), 135.3 [C, C(2)S or aromatic C], 136.4 [CH, ClHC(3)@],
162.2 (C, CO); HRMS (ES+): Exact mass calculated for
m/z
(ES+)
332.0
{[(C15H20NO3S37Cl)+H+],
62%},
330.0
{[(C15H20NO3S35Cl)+H+], 100%}.
4.29. (Z)-3-Chloro-N-[(R)-3,3-dimethylbutan-2-yl]-2-(Ss/Rs)-
(benzenesulfinyl)acrylamide 29
This was prepared following the procedure described above for
21 by addition of (Z)-3-chloro-N-[(R)-3,3-dimethylbutan-2-yl]-2-
(phenylthio)acrylamide 20 (0.18 g, 0.6 mmol) in acetone (10 mL)
to OxoneÒ (0.75 g, 1.2 mmol) in water (5 mL). Following stirring
at room temperature for 16 h, the crude sulfoxides 29a and 29b
were obtained as a clear oil (0.16 g, 85%) and a 1.1:1 mixture of dia-
stereomers. As the 1H NMR spectrum of the crude product was
C
16H23NO3S35Cl [M+H]+ 344.1087. Found 344.1088; m/z (ES+)
346.0 {[(C16H22NO3S37Cl)+H+], 48%}, 344.0 {[(C16H22NO3S35Cl)+H+],
100%}.

884
M. Kissane et al. / Tetrahedron: Asymmetry 21 (2010) 871–884
very clean, no purification was necessary; ½a D20
¼ ꢁ52:1 (c 0.1,
ꢀ
10. Holland, H. L. Nat. Prod. Rep. 2001, 18, 171–181.
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CHCl3); m
max/cmꢁ1 (KBr) 3269 (NH), 3060 (CH), 2966 (CH), 1669
(CO), 1549 (NH bend), 1476 (CN stretch), 1032 (SO); dH
(400 MHz, CDCl3) 0.68 [4.68H, s, C(CH3)3 of 29a], 0.86 (1.56H, d, J
6.8, CHCH3 of 29b), 0.93 [5.32H, s, C(CH3)3 of 29b], 1.07 (1.44H,
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C(CH3)3 of two diastereomers], 34.0*, 34.1 [2 ꢃ C, C(CH3)3 of two
diastereomers], 53.4*, 53.6 (2 ꢃ CH, NHCH of two diastereomers),
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[M+H]+ 314.0982. Found 314.0974; m/z (ES+) 316.0
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100%}.
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edged for funding this work.
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