Investigation of the chemoselective and enantioselective oxidation of α-thio-β-chloroacrylamides

Article abstract of DOI:10.1016/j.tetasy.2008.04.033

An investigation of the chemoselective and enantioselective oxidation of α-thio-β-chloroacrylamides is described. The α-thio-β-chloroacrylamides can be selectively oxidised to either the racemic sulfoxide or the sulfone very efficiently. The asymmetric su

Full text of DOI:10.1016/j.tetasy.2008.04.033

Tetrahedron: Asymmetry 19 (2008) 1256–1273
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Tetrahedron: Asymmetry
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Investigation of the chemoselective and enantioselective oxidation of
a-thio-b-chloroacrylamides
Marie Kissane a, Denis Lynch a, Jay Chopra a, Simon E. Lawrence a, Anita R. Maguire b,
*
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 April 2008
Accepted 29 April 2008
An investigation of the chemoselective and enantioselective oxidation of a-thio-b-chloroacrylamides is
described. The
a
-thio-b-chloroacrylamides can be selectively oxidised to either the racemic sulfoxide
or the sulfone very efficiently. The asymmetric sulfur oxidation of
a
-thio-b-chloroacrylamides is also dis-
cussed, with sulfoxide enantioselectivities of up to 52% ee achieved using the Kagan oxidation, and up to
71% ee when the Bolm oxidation is employed. While the enantioselectivities achieved are modest, these
are among the most highly functionalised sulfides investigated in catalytic asymmetric oxidation, and the
resulting enantioenriched sulfoxides have significant synthetic potential.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reported using oxaziridines16 and hydroperoxides.17 The most pop-
ular route to asymmetric sulfur oxidation is metal-catalysed oxida-
Sulfoxides and sulfones are widely used in organic synthesis,
particularly in carbon–carbon bond forming reactions.1 These com-
pounds are almost invariably prepared by oxidation of the corre-
sponding thioethers. A variety of oxidants have been employed
for this transformation.2 Among the more common oxidants are
tion. The titanium-based Kagan oxidation method was first
reported in the 1980s and is one of the most widely used oxidation
methods; the amount of water present in these reactions must be
carefully controlled.18 The use of titanium/BINOL complex was la-
ter reported by Uemura et al.19,20 A robust oxidation method based
on vanadium was reported by Bolm and Bienewald.21 This method
involves the in situ formation of a catalyst from vanadyl acetylace-
tonate and a Schiff base. The oxygen source is hydrogen peroxide
and critically the reaction is not moisture sensitive. Due to its ease
of use, this method has recently attracted much attention, includ-
ing an investigation of the nature of the species involved.22,23
Following our recent report24 of the highly efficient and stereo-
m-CBPA,3 CHP,4 NaIO4,5 MMPP,6 OxoneÒ,7 H2O2 and MnO4
.
2
8
ꢀ
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 auxiliary.
Furthermore, many enantiopure sulfoxides are known to have high
biological activity.9 Several methods are currently available for the
preparation of optically active sulfoxides. The most generally used
method is the Andersen method, which involves the nucleophilic
addition of alkyl or aryl ligands to diastereochemically pure chiral
sulfinates.10 Despite the high yields of enantiopure sulfoxides ob-
tained using this method, its scope is limited due to the difficult
preparation and limited availability of suitable chiral precursors.
The development of chiral precursors that possess two leaving
groups11,12 and the use of carbanionic leaving groups13 have ex-
tended the scope of this methodology.
selective transformation of
a-thioamides to the corresponding a-
thio-b-chloroacrylamide derivatives on treatment with NCS, we
herein report the chemoselective and stereoselective oxidation of
the b-chloroacrylamides to the sulfoxide and sulfone levels to ex-
tend the scope of this methodology. While the enantioselectivities
achieved in the oxidation to the sulfoxide derivatives are modest
(up to 71% ee), these are among the most highly functionalised sul-
fides investigated in catalytic asymmetric oxidation, and the
resulting enantioenriched sulfoxides have significant synthetic po-
tential, for example, as Michael acceptors, dienophiles or dipolaro-
philes.25 Asymmetric oxidation of aryl methyl sulfides is readily
achieved with high enantioselectivity using the Kagan and Bolm
methods, among others; however, successful extension to differ-
ently substituted sulfides, or sulfides bearing additional functional-
ity, has been remarkably limited.
An attractive alternative to nucleophilic displacement is asym-
metric sulfur oxidation. Very efficient biological sulfide oxidations
have been reported using both whole cell systems and isolated
enzymes.14,15 Metal-free asymmetric sulfur oxidation has been
* 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.033

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1257
2. Results and discussion
2.1. Oxidation of the b-chloroacrylamides to the racemic
sulfoxide
O
O
PhS
NHEt
The chemoselective oxidation of 1a to the racemic sulfoxide
was investigated using a range of oxidising reagents. The use of
H2O2, KMnO4, peracetic acid and MMPP led to the recovery of
the starting material 1a, while m-CPBA gave a 1:1 mixture of sul-
fide and sulfoxide. Employing 2 equiv of OxoneÒ as oxidant in an
acetone/water mixture led to complete conversion to the sulfoxide
2a, and this reaction has been extended to a series of derivatives as
summarised in Table 1. While most of the compounds explored
had Z-stereochemistry, oxidation of a number of E-isomers was
also undertaken equally efficiently and selectively. Critically, there
was no evidence of sulfone formation in any instance.
Cl
Figure 1. A view of 2d showing the structure and stereochemistry. Anisotropic
displacement parameters are drawn at the 30% probability level.
the phenyl ring of the sulfoxide and the chlorine atom. In all cases,
an upfield shift in the 1H NMR spectrum of the b-hydrogen of
approximately 0.15 ppm occurred on oxidation of the b-chloro-
acrylamides, reflecting a significant impact on the extent of reso-
nance delocalisation in the acrylamide system.
Table 1
Oxidation to the racemic sulfoxide
2.2. Oxidation to the sulfone
O
O
O
R1S
R1S
Cl
An investigation of the oxidation of sulfoxide 2a to sulfone 3a
was undertaken with a range of oxidants, including H2O2, KMnO4,
peracetic acid, MMPP, OxoneÒ and m-CPBA, with m-CPBA the only
oxidant resulting in oxidation to the sulfone. While the crude prod-
ucts were relatively clean by NMR, with sulfoxide oxidation com-
plete, isolation of analytically pure sulfones from the oxidations
is challenging, principally as the labile sulfones, potent Michael
acceptors, are not stable on silica gel. To overcome this issue, mor-
pholine was added to the crude sulfones, triggering a substitution
process to the b-amino derivatives, as illustrated in Table 2. Criti-
cally, the morpholine adducts, which are stabilised by extensive
delocalisation, are readily purified and characterised.
Following this protocol, a series of sulfoxides were treated with
2 equiv of m-CPBA in DCM. Following stirring at room temperature
for 24 h, 4 equiv of morpholine was added. TLC analysis indicated
reaction completion after 15 min and following purification by col-
umn chromatography, the morpholine adduct of the sulfone 4 was
isolated (see Table 2).
NR2R3
NR2R3
2 eq. Oxone
acetone, water
2 h
Cl
R4
R4
R1
R2
R3
R4
E/Z
Product
% Yielda
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Tol
Bn
i-Pr
Et
n-Bu
Allyl
H
4-F–C6H4
Me
4-F–C6H4
n-Bu
Bn
Tol
Ph
Tol
Bn
Et
Tol
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Z
Z
Z
Z
Z
Z
Z
Z
E
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
E
Z
Z
E
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
96
98
98
57
98
98
92
95
98
95
80
80
91
76
84
93
96
84
92
88
92
85
82
69
77
69
72
66
76
46
75
75
83
53
Ph
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
40-MeOC6H4
40-MeOC6H4
In conclusion, the chemoselective oxidation of the b-chloro-
acrylamides to either the sulfoxide or sulfone level is readily
achieved. For ease of characterisation, the sulfones were trapped
as adducts with morpholine.
40-MeOC6H4
40-NO2C6H4
i-Bu
i-Pr
Me
Me
Me
Bn
4-F–C6H4
4-F–C6H4
4-F–C6H4
n-Bu
Bn
2.3. Asymmetric sulfur oxidation of the b-chloroacrylamides
Bn
A number of methods for the enantioselective oxidation of the
b-chloroacrylamides were examined, including Kagan oxidation18
and Bolm oxidation.21
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
4-F–C6H4
n-Bu
Tol
Me
Ph
H
Me
Me
4-F–C6H4
4-F–C6H4
2y
2z
2aa
2ab
2ac
2ad
2ae
2af
2ah
2ag
2.3.1. Kagan oxidation
When the b-chloroacrylamide 1a was oxidised under standard
Kagan conditions employing a ratio of Ti(OiPr)4/(+)-DET/H2O/b-
chloroacrylamide of 1:2:1:2, using cumene hydroperoxide
(2 equiv, i.e., equimolar with the sulfide) as oxidant, the conversion
of the b-chloroacrylamide 1a to the sulfoxide 2a was determined to
be 46% by 1H NMR spectroscopy of the crude reaction product. Fol-
lowing removal of the 2-phenylpropan-2-ol by-product by distilla-
tion, the sulfoxide 2a was isolated in 30% yield after
chromatography on silica gel. However, the enantiomeric ratio of
the product was then determined to be just 12% ee by chiral HPLC.
The standard Kagan oxidation of methyl tolyl sulfide using the
same reagents was undertaken to ensure that the oxidising agent
was correctly formed. Methyl tolyl sulfoxide was isolated in 84%
ee, a value which compares quite favourably with the reported
value of 89% ee.26
Bn
Bn
a
Yields quoted are following purification by column chromatography or
recrystallisation.
Each of the sulfoxides was isolated as a crystalline solid and
purified by column chromatography or recrystallisation. The rela-
tive stereochemistry (E/Z) of the b-chloroacrylamides was retained
on oxidation to the sulfoxides in all cases, as confirmed by single
crystal X-ray crystallography of the N-ethyl derivative 2d (Fig. 1).
Analysis of the dihedral angles and rotation of the crystal struc-
ture illustrate that the sulfoxide moiety is twisted out of the plane
of the acrylamide, presumably due to steric interactions between

1258
M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
Table 2
Oxidation to the sulfone
O
O
O
O
R1O2S
N
R1O2S
Cl
4 eq. morpholine
NHR2
R1S
2 eq. mCPBA
NHR2
NHR2
DCM, R.T.
24 hrs
Cl
O
R1
R2
Sulfone
% Yield
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Tol
Me
Bn
4-F–C6H4
n-Bu
Tol
Me
Ph
H
Bn
Tol
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
42
30
42
43
63
56
38
56
37
38
45
54
Bn
n-Bu
n-Bu
n-Bu
4j
4k
4l
Table 3
Asymmetric oxidation using the Kagan oxidation
O
R1S
O
O
R1S
Cl
NHR2
NHR2
Cl
d
1
R1
R2
Method
Sulfoxide
% Conversiona
% Yieldb
% eec
[a]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Tol
Et
Bn
Tol
Tol
Tol
4-F–C6H4
4-F–C6H4
4-F–C6H4
Tol
4-F–C6H4
4-F–C6H4
Tol
A
A
A
A
A
A
A
A
A
A
A
A
A
B
2a
2d
2l
46
0
0
30
—
—
12
—
—
—
—
—
—
—
n-Bu
4-NO2–C6H4
4-MeO–C6H4
n-Bu
Ph
n-Bu
n-Bu
Me
Me
i-Bu
i-Bu
Ph
2r
20
40
60
60
100
100
100
72
75
73
13
9
4
2o
2m
2h
2j
28
49
40
68
68
66
65
68
65
9
30e
51
25
51
52
39
43
17
7
ꢀ84
—
ꢀ98
+94
ꢀ72
—
2j
2ai
2u
2s
2aj
2a
Tol
15
—
Method A: standard Kagan oxidation using (+)-DET except entry 10, which used (ꢀ)-DET.
Method B: modified Kagan oxidation using 0.1 equiv of the catalyst.
a
As determined by 1H NMR spectroscopy of the crude product mixture
Yield after chromatography on silica gel.
Enantiomeric ratios were determined by chiral HPLC using IPA/hexane as mobile phase on a Chiralcel AS column detected at k 254 nm.
All specific rotations were recorded as solutions in DCM (c 1.3–2.0).
As determined by chiral shift NMR spectroscopy using (+)-Eu(hfc)3 as chiral shift reagent.
b
c
d
e
Extension of the initial work with sulfoxide 2a to the enantiose-
in the electronic properties of the sulfide. In the presence of the 4-
MeO–C6H4 group (Table 3, entry 6), an increase in selectivity to
30% ee resulted, while in the presence of 4-NO2–C6H4 group (Table
3, entry 5) a decrease to 4% ee resulted, cf. 12% ee in the unsubsti-
tuted derivative (Table 3, entry 1).
lective oxidation of a series of b-chloroacrylamides using the Kagan
reagent was next undertaken as summarised in Table 3. In all
cases, with the exception of entry 10, (+)-DET was used and the
(S)-sulfoxide series was formed.
Significantly, oxidation was only observed for N-aryl deriva-
tives, with partial or complete oxidation to the sulfoxides seen un-
der the standard Kagan oxidation conditions, albeit with modest
enantioselectivity.
Investigation of the impact of substitution on the phenylthio
group was first explored. Introduction of p-nitro or methoxy
groups resulted in a decrease in the efficiency of oxidation, but
the enantioselectivity altered significantly, reflecting the variation
Investigation of the alkylthio derivatives proved interesting.
Replacement of the phenylthio moiety with the more electron
donating n-butylthio group resulted in improved conversion and
enantioselectivity (Table 3, entry 7), with 51% ee while using the
N-tolyl group.
The effect of the nature of the amide group was next examined.
It had already been shown that on replacement of N-tolyl amide
with the relatively less electron withdrawing N-benzyl or N-ethyl

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1259
group, no oxidation occurred. Thus we decided to look at incorpo-
rating a more electron withdrawing amide by synthesising the N-
4-fluoroaniline phenylthio and n-butylthio derivatives.
In a 1995 paper, Kagan28 explored the possibility of increasing
the selectivity of the oxidation by varying parameters such as tem-
perature, time, rate of addition and ageing of the catalyst complex.
Up to this point, the optimum conditions as reported in an Organic
Synthesis paper26 had been employed. It was clear that in order to
increase the selectivity of the reaction for the optimum substrate
1j, we needed to further examine the oxidation conditions. To this
end, a number of reactions were conducted, as outlined in Table 4,
where temperature, the number of equivalents of the titanium
complex and the rate of addition of the oxidant were examined.
When the b-chloroacrylamides 1h and 1j were exposed to the
standard Kagan oxidation conditions, an improvement in both
reaction efficiency and selectivity was recorded for both com-
pounds compared to 1a. For 1h (Table 3, entry 8), the increase in
the degree of conversion was moderate, up from 46% for 1a to
60% for 1h, as was the increase in the enantioselectivity, up from
12% ee for 1a to 25% ee for 1h. Some of the sulfoxide (+)-2h isolated
from the oxidation of 1h was recrystallised from ether/hexane and
the mother liquor was found to contain (+)-2h in 32% ee. Subse-
quent analysis of the solid isolated from the recrystallisation
showed that the sulfoxide precipitates as a racemate.
The use of 1j (Table 3, entry 9) gave much better results than
those obtained with any other b-chloroacrylamide. Complete con-
version of the b-chloroacrylamide 1j to the corresponding sulfox-
ide 2j occurred, with 2j isolated in 68% yield after removal of the
2-phenyl-2-propanol and chromatography of the residue on silica
gel. Analysis of the enantiomeric ratio of the material by chiral
HPLC showed almost identical selectivity to that seen with 2m,
with the sulfoxide 2j having 51% ee. The result of this reaction sug-
gests that the amide substituent is important in relation to the ex-
tent of oxidation achieved, while the enantioselectivity of the
reaction is determined by the nature of the sulfide moiety.
Upon scale up of this reaction to 2 mmol of the b-chloroacryl-
amide 1j, the enantioselectivity was virtually identical to that ob-
tained in the smaller scale (0.70 mmol) reactions. When the
opposite (ꢀ)-enantiomer of diethyl tartrate was employed in pre-
paring the catalyst complex, as expected the opposite enantiomer
of the sulfoxide 2j predominated in the product. Analysis of this
material by chiral HPLC showed the material to again have 52%
ee, with the (R)-enantiomer being predominant. As sulfoxide 2j is
an oil, recrystallisation of the product to increase the enantiomer
ratio was not possible.
Table 4
Optimisation of Kagan oxidation of 1j
O
O
Ti(OiPr)4
(+)-DET
BuS
Cl
BuSO
Cl
NHAr
NHAr
CHP
Water
Ar = 4-F-C6H4
Conditions
Conversiona
(%)
eeb
(%)
Standard conditions
>95
53d
1:1:2:2:2 ratio of Ti/water/DET/sulfide/oxidantc
Reagent prepared as describedc, CHP added in one lot at
ꢀ20 °C
CHP added in 6 portions over 1 h
Full equivalent of titanium complex
Full equivalent of Ti complex and CHP added in 6 portions
over 1 h
>95
>95
>95
52
51
52
Reaction conducted at ꢀ50 °C for 18 h
Reaction conducted at 4 °C for 18 h
Reaction conducted at room temperature for 18 h
Standard conditionsc on 2.00 mmol scale
Standard conditionsc using (ꢀ)-DET
30
37
40
32
51
52e
>95
>95
>95
>95
a
As estimated by 1H NMR spectroscopy at 60 MHz in CDCl3 of the crude reaction
mixture.
b
As estimated by chiral HPLC using a Chiralcel AS column at ambient tempera-
The effect of the sulfide substituent of the b-chloroacrylamide
on the outcome of the asymmetric oxidation, using the Kagan pro-
cedure, has been shown above to be quite significant. As replace-
ment of the arylthio substituent with n-butyl thio resulted in a
significantly improved enantioselectivity, further investigation of
N-alkyl thio derivatives was undertaken. The methanethio sulfides
1ai and 1u were investigated, as the optimum results in sulfur oxi-
dation had been achieved with methyl aryl sulfides, while the i-bu-
tyl derivatives 1s and 1aj were explored to determine the impact of
branching in the alkylthio chain on the enantioselective oxidation.
When the methanethio derivatives 1ai and 1u were subjected
to standard Kagan oxidation conditions, a decrease in enantioselec-
tivity was observed in comparison to the n-butylthio derivatives
(Table 3, entries 11 and 12), while Kagan oxidation of the i-butyl
sulfides 1s and 1aj led to recovery of the corresponding (S)-iso bu-
tyl sulfoxides 2s and 2aj with poor enantiomer ratios of 17% ee and
7% ee, respectively (Table 3, entries 13 and 14). Clearly, it can be
seen that branching had a detrimental effect on the enantioselec-
tivity, while the methanethio derivatives did not mimic methyl
aryl sulfides.
In 1996, Kagan published a truly catalytic version of his chiral
titanium derived catalyst for the asymmetric oxidation of sulfides
to sulfoxides.27 The complex employed differed from the original
system in that water was replaced with 4 equiv of isopropanol,
1 equiv of 4 Å molecular sieves was added and the overall ratio
of the catalyst complex to the sulfide was reduced from 2:1 to
0.1:1. Oxidation of 1a and 1m was attempted using this procedure.
Oxidation of 1a using this method resulted in poorer conversion to
the sulfoxide 2a, with a slight increase in the enantioselectivity to
15% ee (Table 3, entry 15). No oxidation occurred when 1m was
employed using this method.
ture in 90:10 hexane/isopropanol, detection at 254 nm.
c
As reported by Kagan et al.26
The specific rotation of this sample was recorded; ½a D20
¼ ꢀ98 (c 1.3, DCM).
ꢁ
d
As expected, the enantioselectivity in the sulfoxide was reversed; ½a D20
ꢁ
¼ þ94
e
(c 1.7, DCM).
The conclusion, which can be drawn from these experiments, is
that none of the modifications resulted in an improved enantiose-
lectivity relative to the standard Kagan conditions. The addition of
the oxidant, CHP, in 6 portions over 1 h, use of a full equivalent of
the titanium complex and a combination of both gave material
with effectively the same enantioselectivity. Only when the reac-
tion was conducted at lower temperature (ꢀ50 °C) was less than
complete conversion obtained and the slower rate of the reaction
was accompanied by a reduction in enantioselectivity. Conducting
the reaction at 4 °C or at room temperature also gave poorer
enantioselectivity, suggesting that ꢀ20 °C is at or near the opti-
mum temperature for the oxidation, as reported by Kagan.26
In conclusion, the optimum enantioselectivity achieved with
the Kagan oxidation was 51% ee with the n-butyl thio derivative
2j. Interestingly, only N-aryl amides undergo the oxidation. Enantio-
selectivity is enhanced by the presence of the N-4-fluoroaniline
substituent.
2.3.2. Bolm oxidation
Asymmetric oxidation of the b-chloroacrylamides using the
Bolm method was also explored. Initially, a number of reactions
were carried out on the (S)-methyl derived b-chloroacrylamides,
where the influences of temperature, scale and ligand were exam-
ined in detail (Table 5).
The initial reaction involved the oxidation of the (S)-methyl b-
chloroacrylamide 1u using the original Bolm conditions {1 mol %

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M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
Table 5
Bolm oxidation of the S-methyl b-chloroacrylamides
O
O
MeS
O
[VO(acac)2]/Ligand
MeS
Cl
NHR
NHR
H2O2, DCM
Cl
R=4-F-C6H4
R=n-Bu
R=Bn
1u
1v
1w
2u
2v
2w
Entry
R
Ligand
Temperature (°C)
% Conversiona
Yieldb (%)
Enantioselectivityc (% ee)
1
2
3
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
4-F–C6H4
Bn
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5c
5d
5d
5e
5e
5f
Ambient
0
72
100
100
100
100
100
100
100
100
60
100
95
60
95
68
51
70
81
73
81
82
85
82
67
41
87
66
41
62
51
71
86
82
85
30
32
37
32
32
30
55
24
88
87
50
85
82
31
72
7
45
71
69
61
71
53
62
63
72
60
23
71
61
66
70
70
71
70
51
36
30
20
71g
24
34
68
22
56
56
30
61
59
35
71
71
—
ꢀ20
4
ꢀ30
5d
6e
ꢀ20
ꢀ20
7e
ꢀ20
8e
ꢀ20
9
Ambient
ꢀ20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35f
36
Ambient
Ambient
ꢀ20
Ambient
ꢀ20
Ambient
ꢀ20
85
5f
100
100
100
47
45
40
51
44
40
80
5g
5g
5h
5h
5h
5h
5i
5i
5i
5i
5j
Ambient
ꢀ10
Ambient
0
ꢀ10
ꢀ20
Ambient
0
ꢀ10
ꢀ20
32
Ambient
ꢀ20
100
100
62
100
100
40
100
20
0
5j
5a
5a
5a
5a
5a
5a
5k
Ambient
ꢀ10
Bn
Bn
n-Bu
n-Bu
n-Bu
n-Bu
ꢀ20
Ambient
ꢀ20
ꢀ20
ꢀ20
—
R=H, X=NO2 5a
NO2
OH
X
R=X=H 5b
R=But, X=NO2 5c
R=Me, X= H 5d
R=H, X=Me 5e
R=H, X=But 5f
R=H, X = Cl 5g
R=X=I 5h
R
OH
N
N
R=X=Br 5i
HO
HO
R=X=But 5k
Estimated from integration of 1H NMR spectra of crude samples.
Yields quoted are following chromatography.
a
5j
b
c
Enantiomer ratios were determined using chiral HPLC using IPA/hexane as mobile phase on a Chiralcel AS column detected at k 254 nm.
This reaction was carried out on a 1 g scale (4 mmol).
This reaction was carried out on a 2.5 g scale. On this scale the enantioselectivity of the product was seen to decrease even when the hydrogen peroxide was added over
d
e
16 h using a syringe pump.
f
This reaction was worked up after 2 h (16 h in all other cases).
>98% ee was achieved on recrystallisation from 1:1 mixture of hexane/chloroform.
g
[VO(acac)2], 1.5 mol % ligand, 1.1 equiv H2O2, rt, DCM} with ligand
5a. Then, 1H NMR spectroscopy of the crude reaction mixture
showed 72% conversion of b-chloroacrylamide 1u to the corre-
sponding sulfoxide 2u. Following chromatography, sulfoxide 2u
was isolated in 51% yield with 45% ee (Table 5, entry 1). Decreasing
the temperature of the reaction increased the conversion (quanti-
tative at ꢀ30 °C or 0 °C) and the ee of the resultant sulfoxide 2u,
with the optimum enantioselectivity obtained at ꢀ20/0 °C (Table

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1261
5, entries 1–4). This transformation was scaled up successfully
from using 1 mmol (0.25 g) to 4 mmol (1.00 g) of b-chloroacryl-
amide 1u, but when increased to 10 mmol, the enantioselectivity
decreased slightly to 62% or 63% ee, even when the oxidant was
added slowly over 16 h. The conversion (100%), yield (81%) and
the enantioselectivity (71% ee) obtained on a 4 mmol scale were
consistent with those obtained on a 1 mmol scale (Table 5, entry
3 vs entry 5).
Since the enantioenriched (S)-methyl sulfoxide 2u is a solid, an
enhancement of the enantiomeric ratio by recrystallisation was at-
tempted. Following slow (ca. 2 weeks) vapour diffusion recrystalli-
sation from chloroform/hexane (1:1), a number of distinct crystals
were obtained. Analysis of the resulting crystals and the mother li-
quor showed that individual enantiopure crystals of 2u could be
obtained but this method was not practical for producing synthet-
ically useful amounts of enantiopure 2u.
The (S)-absolute stereochemistry was determined by single
crystal X-ray diffraction on an enantiopure crystal of 2u (see
Fig. 2). Critically, chiral LC demonstrated that this is the major
enantiomer formed in the Bolm oxidation using the (S)-ligand.
The absolute stereochemistry of the other sulfoxide derivatives
was assigned by analogy on the basis of similar profiles in chiral
LC and direction of specific rotations. The (S)-sulfoxides 2u–w
are formed selectively using the (S)-ligand in the Bolm oxidation.
This is consistent with the stereoselectivity, which has been re-
ported previously.21,23,29
ple, with 5h 71% ee was achieved at ꢀ20 °C (Table 5, entry 23),
while with 5d similar enantioselectivity was achieved at room
temperature (Table 5, entry 12).
Replacement of the t-Bu substituent with i-Pr in 5j resulted in
efficient oxidation but decreased enantioselectivity relative to 5a
(56% ee vs 71% ee), highlighting the importance of a bulky substi-
tuent at this position. The presence of a H, Me or halo substituent
at C-3 of the ligand is readily tolerated, but the introduction of a t-
Bu group at this position results in a dramatic decrease in enanti-
oselectivity (Table 5, entry 11). The presence of a H, Me, t-Bu, NO2
or halo substituent at C-5 can be tolerated. The optimum enanti-
oselectivity with each of the ligands was 70–71% ee.
The impact of the electronic effect of the amide substituent was
next investigated by replacing the N-aryl substituent with N-benz-
yl 1w or N-alkyl 1v using ligands 5a and 5u. In both oxidations
with ligand 5a, the conversions and the ee’s tended to increase
when decreasing the reaction temperature (Table 5, entries 30–
35). Optimum enantioselectivities of 61% ee (2w) and 71% ee
(2v) were achieved. When the oxidation of 1v was repeated and
worked up after 2 h compared to 16 h under standard conditions,
the extent of conversion was significantly decreased, but critically
the enantioselectivity of oxidation to the sulfoxide was unaffected,
indicating that it is not affected by progress of the reaction.
The Bolm oxidation of b-chloroacrylamide 1v was also con-
ducted in the presence of ligand 5k at ꢀ20 °C. Interestingly, the
presence of the bulky t-butyl groups on ligand 5k inhibited the
reaction completely (Table 5, entry 36).
To investigate the impact of substrate structure on the Bolm
oxidation, a study of the Bolm oxidation of b-chloroacrylamides
1s, 1ak and 1t under various reaction conditions was then con-
ducted, and the optimum results of this work are outlined in Table
6. The results obtained are similar to those obtained with the
methanethio derivatives, with 67–71% ee achieved, indicating that
increasing the steric hindrance adjacent to the sulfur does not
noticeably affect the enantioselectivity.
_
O
Ar
O
H
N
+
Me
S
Cl
In conclusion, the outcome of the Bolm oxidation of the b-chlo-
roacrylamides is rather insensitive to variation of the sulfide struc-
ture and the electronic properties of the ligand. The only significant
effect observed during the course of this work was steric, that is,
there was a dramatic fall off in the enantioselectivity of the sulfide
oxidation in all cases when ligands 5c and 5k, both bearing a t-bu-
tyl group on the C-3 position of the aromatic ring, were employed
in the Bolm oxidation of the b-chloroacrylamides (see Fig. 3). Inter-
estingly, this contrasts with Bolm’s results where he described
higher enantioselectivity using ligand 5c bearing the 3-t-butyl
group compared to the less sterically hindered ligand 5a.21 How-
ever, in 2005, Zeng reported that ligands derived from 3,5-di-
tert-butylsalicylaldehyde gave lower enantioselectivities in the
sulfoxidation of thioanisole than those derived from less sterically
Figure 2. A view of 2u showing the structure and absolute stereochemistry. Anis-
otropic displacement parameters are drawn at the 30% probability level.
An investigation on the impact of the nature of the ligand on the
Bolm oxidation of b-chloroacrylamide 1u was then explored. Li-
gands 5a–k were selected for investigation based on the literature
reports by Bolm and others.21,30 For the Bolm oxidation of alkyl
aryl sulfides, 5h has proven to be highly enantioselective, with
97% ee achieved for methyl naphthylsulfoxide.30 Sulfide oxidation
of 1u was achieved with varying efficiency and enantioselectivity
using ligands 5a–k.
In conclusion, the temperature at which optimum selectivity
occurs varies depending on the structure of the ligand. For exam-
Table 6
Bolm oxidation of b-chloroacrylamides 1s, 1ak and 1t
O
O
O
[VO(acac)2]/ 5a
H2O2, DCM, -20 °C
R1S
R1S
NHR
NHR
Cl
Cl
R1
R
Sulfoxide
Eq. H2O2
% Conversiona
% Yieldb
Enantioselectivity (% ee)c
i-Bu
i-Bu
i-Pr
4-F–C6H4
Tol
4-F–C6H4
2s
2ak
2t
2.0
1.1
1.1
73
91
100
59
72
76
67
71
71
a
b
c
Estimated from integration of 1H NMR spectra of crude samples.
Yields quoted are following chromatography.
Enantiomeric ratios were determined by chiral HPLC using IPA/hexane as mobile phase on a Chiralcel AS column detected at k 254 nm.

1262
M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
hindered salicylaldehyde.31 In general, the maximum enantioselec-
tivity obtained for the sulfoxides was ca. 70% ee. However, the tem-
perature at which this maximum occurred varied depending on the
sulfide and ligand employed. Also, the predominant enantiomer in
all cases was identified by X-ray crystallography and chiral HPLC as
the (S)-enantiomer, when the (S)-ligand was employed.
The nature of the catalytically active species has already been
discussed extensively by Bryliakov,29 Zeng,31 Bolm32–34 and Ell-
man.35 It is clear that the presence of a t-Bu group at C-3 hinders
approach of the sulfide to the reacting vanadium complex
(Fig. 4), thereby allowing achiral oxidation to compete with the
enantioselective vanadium catalysed oxidation.
Table 7
Fe(acac)3 catalysed Bolm oxidation
-
O
O
O
[Fe(acac)3], ligand(5mol%)
MeS
Cl
S
NHAr
NHAr
Me
+
1.2eq.H2O2, DCM, RT,16h
Cl
Ar = 4-F-C6H4
Entry Ligand
Temperature
(°C)
%
Yieldb
(%)
Enantioselectivityc
(% ee)
Conversiona
1
2
3
4
5
5h
5i
5i
5g
5a
Ambient
44
41
21
42
46
28
26
19
31
34
23
30
38
14
17
Ambient
ꢀ10
X=NO2, t-Bu, Me,
Ambient
Ambient
H, I, Br, Cl
a
b
c
Estimated from integration of 1H NMR spectra of crude samples.
Yields quoted are following chromatography.
Enantiomeric ratios were determined using chiral HPLC using IPA/hexane as
X
mobile phase on a Chiralcel AS column detected at k 254 nm. As in the vanadium
system, the (S)-enantiomer was obtained when the (S)-ligand was employed.
R
R=Me, H, Br, I
not -Bu
R′=t-Bu not i-Pr
OH
t
N
R′
ever, no conversion to the sulfoxides was observed under these
conditions.
HO
Figure 3.
3. Conclusion
R2
R1
S
Enantioselective oxidation of the b-chloroacrylamides to the
analogous sulfoxides can be achieved using the Kagan oxidation
with titanium catalysis or the Bolm oxidation with vanadium or
iron based systems. Enantioselectivities of up to 71% ee were ob-
tained across a range of derivatives using the vanadium catalyst
with Schiff base ligands. Investigation of the synthetic utility of
the resulting highly functionalised sulfoxides as Michael acceptors,
dienophiles and dipolarophiles is currently underway in our
laboratory.
X
N
O
O
R
O
V
HO
O
Figure 4.
Following the development of the vanadium catalysed process,
Bolm has reported that aryl alkyl sulfides can be rapidly oxidised to
give chiral sulfoxides with enantioselectivities up to 90% ee using
an iron catalyst formed in situ from Fe(acac)3 and Schiff base li-
gands 5g–5i.36 Significantly, Bolm has reported improved stereose-
lectivities in the iron catalysed sulfide oxidation in the presence of
additives such as substituted benzoic acids, although the use of
these additives was not explored in this work.37 Accordingly, the
iron catalysed asymmetric oxidation of sulfide 1u was explored
using ligands 5a, 5g–5i as outlined in Table 7.
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.
1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded
on a Bruker (300 MHz) NMR spectrometer. 1H (270 MHz) and 13C
(67.8 MHz) NMR spectra were recorded on a Jeol GSX (270 MHz)
NMR spectrometer. 1H (60 MHz) NMR spectra were recorded on
a Jeol PMX-60SI spectrometer. All spectra were recorded at room
temperature (ꢂ20 °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).
Elemental analyses were performed by the Microanalysis Labo-
ratory, National University of Ireland, Cork, using a Perkin–Elmer
240 elemental analyser. Melting points were carried out on a
uni-melt Thomas Hoover Capillary melting point apparatus. Mass
spectra were recorded on a Kratos Profile HV-4 double focusing
high resolution mass spectrometer (EI), a Waters/Micromass LCT
Premier Time of Flight spectrometer (ESI) and a Waters/Micromass
Quattro Micro triple quadrupole spectrometer (ESI). Infrared spec-
tra were recorded as potassium bromide (KBr) discs for solids or
thin films on sodium chloride plates for oils on a Perkin–Elmer Par-
agon 1000 FT-IR spectrometer.
The efficiency and the enantioselectivity of the oxidation to
form the methyl sulfoxide 2u are lower than the results obtained
with the vanadium based system. Decreasing the reaction temper-
ature appears to have a positive impact on the enantioselectivity of
sulfoxide 2u, albeit with associated decrease in conversion (Table
7, entry 3).
The Page oxidation38 (with oxaziridines 6a and 6b and sulfides
1a and 1j) and enzymatic oxidation39 (with 1a and chloroperoxi-
dase, CPO from Calsariomyces fumago) were also explored. How-
Cl
Cl
N
O
N
S
S
O
O2
O2
6a
6b

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1263
Thin layer chromatography (TLC) was carried out on precoated
silica gel plates (Merck 60 PF254). Column chromatography was
performed using Merck Silica Gel 60. Visualisation was achieved
by UV (254 nm) light detection, iodine staining, vanillin staining
and ceric sulfate staining.
CH), 131.58 (aromatic CH), 137.37 (CHCl@), 138.73 (quaternary
aromatic C or SC@), 140.95 (quaternary aromatic C or SC@),
160.51 (CO); MS m/z 319 (M+, 9%), 284 (4, M+ꢀCl), 194 (17,
M+ꢀSOPh), 134 (97, [PhS@C@CH]+), 91 (100, [PhCH2]+), 77 (65);
isotopic Cl pattern observed; 319, 321 (3:1 ratio 35Cl/37Cl). Found
(HRMS, EI) 319.0438. C16H14N35ClO2S requires 319.0434.
4.1. Single crystal X-ray crystallographic analysis
Note: Two quaternary carbon signals were observed for three
carbons (2 quaternary aromatic carbons and SC@).
Data were collected on a Nonius MACH3 diffractometer using
Mo-Ka
graphite monochromated radiation, k = 0.7107 Å, and cor-
4.4. N-Isopropyl-Z-3-chloro-2-(benzenesulfinyl)propenamide
rected for Lorentz and polarisation effects. The structures were
2c
solved by direct methods and refined by full-matrix least-squares
41
using all F2 data. The SHELXS
,
SHELXL-9740 and PLATON suite of pro-
This was prepared using the procedure described for 2a using
OxoneÒ (9.63 g, 15.66 mmol) in water (50 mL) and N-i-propyl-Z-
3-chloro-2-(phenylthio)propenamide 1c (2.00 g, 7.83 mmol) in
acetone (160 mL) at room temperature. The crude product was
purified by chromatography on silica gel using ethyl acetate/hex-
ane (20:80) as eluent to give the sulfoxide 2c (2.08 g, 98%) as a
white solid; mp 100–102 °C; C12H14NClO2S requires C, 53.03; H,
5.19; N, 5.16; Cl, 13.04; S, 11.80. Found: C, 52.60; H, 5.52; N,
grams were used. All non-hydrogen atoms were refined with
anisotropic displacement factors. The hydrogen atoms were placed
in calculated positions and allowed to ride on the parent atom. The
(S)-enantiomer for 2u was unambiguously confirmed using the
Flack parameter. Full structural data have been deposited at the
Cambridge Crystallographic Data Centre. CCDC reference numbers
676357 and 676358.
5.15; Cl, 13.28; S, 11.39.
m
max/cmꢀ1 (KBr) 3294 (br, NH), 1627
4.2. N-40-Methylphenyl-Z-3-chloro-2-(benzenesulfinyl)-
(CO), 1540, 1082, 1055; dH 1.02 (3H, d, J 6, one of CH(CH3)2), 1.18
(3H, d, J 6, one of CH(CH3)2), 3.89–4.09 (1H, m, NCH), 7.42–7.68
(5H, m, ArH), 7.71 (1H, s, CHCl@), 8.19 (1H, br s, NH); dC 22.29
(both of CH(CH3)2), 41.47 (NCH), 124.03 (aromatic CH), 129.20
(aromatic CH), 131.49 (aromatic CH), 136.83 (CHCl@), 138.90 (qua-
ternary aromatic or SC@), 141.10 (quaternary aromatic or SC@),
159.29 (CO).
propenamide 2a
A solution of OxoneÒ (6.08 g, 9.88 mmol) in water (30 mL) was
added dropwise to a stirred solution of N-40-methylphenyl-Z-3-
chloro-2-(phenylthio)-propenamide 1a (1.50 g, 4.94 mmol) in ace-
tone (120 mL) at room temperature. A colourless precipitate
formed immediately. The reaction mixture was stirred for 2 h
and then checked for completion by TLC. Water (200 mL) was
added and the aqueous solution extracted with DCM (3 ꢃ 75 mL).
The combined extracts were washed with water (2 ꢃ 100 mL)
and brine (100 mL), dried and concentrated to give 2a. The crude
product was purified by chromatography on silica gel using ethyl
acetate/hexane (20:80) as eluent to give the sulfoxide 2a (1.52 g,
96%) as a colourless solid; mp 128–129.5 °C; C16H14NClO2S re-
quires C, 60.09; H, 4.41; N, 4.38; Cl, 11.09; S, 10.03. Found: C,
4.5. N-Ethyl-Z-3-chloro-2-(benzenesulfinyl)propenamide 2d
This was prepared using the procedure described for sulfoxide
2a using N-ethyl-Z-3-chloro-2-(phenylthio)propenamide 1d
(slightly impure) (2.18 g, 9.05 mmol) in acetone (220 mL) and Ox-
oneÒ (16.69 g, 27.15 mmol) in water (96 mL) to give the crude sulf-
oxide. Purification by chromatography on silica gel using ethyl
acetate/hexane (70:30) as eluent gave the sulfoxide 2d (1.32 g,
57%) as a colourless solid; mp 75–78 °C; C11H12NClO2S requires
C, 51.26; H, 4.69; N, 5.44; Cl, 13.75; S, 12.44. Found: C, 51.13; H,
60.40; H, 4.61; N, 4.17; Cl, 11.53; S, 9.80. m
max/cmꢀ1 (KBr) 1671
(CO), 1612, 1555, 1512, 1319, 1034 (SO), 726; dH 2.30 (3H, s, Ar-
CH3), 7.08–7.18 (2H, m, ArH), 7.39–7.56 (5H, m, ArH), 7.67–7.79
(2H, m, ArH), 7.83 (1H, s, CHCl@), 10.37 (1H, br s, NH); dC 20.80
(CH3Ar), 120.69 (aromatic CH), 124.14 (aromatic CH), 129.50 (aro-
matic CH), 129.73 (aromatic CH), 131.84 (aromatic CH), 134.63
(quaternary aromatic or SC@), 134.67 (quaternary aromatic or
SC@), 137.40 (CHCl@), 138.77 (quaternary aromatic C or SC@),
141.07 (quaternary aromatic C or SC@), 158.12 (CO); MS m/z 319
(M+, 84%), 226 (47), 213 (12, M+ꢀNHTol), 134 (73, [PhS@C@CH]+),
125 (100, [SOPh]+), 77 (95); isotopic Cl pattern observed; 319, 321
(3:1 ratio 35Cl/37Cl). Found (HRMS, EI) m/z 319.0377.
C16H14N35ClO2S requires 319.0434.
4.68; N, 5.41; Cl, 14.23; S, 12.55.
m
max/cmꢀ1 (KBr) 3254 (NH),
1664 (CO), 1568, 1541, 1030, 758; dH 1.08 (3H, t, J 7, –CH3),
3.17–3.42 (2H, m, NCH2), 7.48–7.72 (5H, m, ArH), 7.73 (1H, s,
CHCl@), 8.33 (1H, br s, NH); dC 14.37 (–CH3), 34.17 (NCH2),
124.07 (aromatic CH), 129.07 (aromatic CH), 131.59 (aromatic
CH), 136.85 (CHCl@), 138.79, 114.07 (2 signals for 3 carbons: 2
quaternary aromatics and SC@), 160.17 (CO); MS m/z 257 (M+,
80%), 164 (47), 134 (50, [PhS@C@CH]+), 125 (97, [SOPh]+), 77
(93), 44 (100); isotopic Cl pattern observed; 257, 259 (3:1 ratio
35Cl/37Cl); Found (HRMS, EI) m/z 257.0278. C11H12N35ClO2S re-
quires 257.0277.
4.3. N-Benzyl-Z-3-chloro-2-(benzenesulfinyl)propenamide 2b
4.6. N-n-Butyl-Z-3-chloro-2-(benzenesulfinyl)propenamide 2e
This was prepared using the procedure described for 2a using
OxoneÒ (6.09 g, 9.9 mmol) in water (35 mL) to a stirred solution
of b-chloroacrylamide 1b (1.00 g, 3.3 mmol) in acetone (100 mL)
at 0 °C. The crude product was purified by chromatography on sil-
ica gel using ethyl acetate/hexane (20:80) as eluent to give sulfox-
This was prepared using the procedure described for sulfoxide
2a using N-n-butyl-Z-3-chloro-2-(phenylthio)propenamide 1e
(1.50 g, 5.57 mmol) in acetone (120 mL) and OxoneÒ (6.85 g,
11.14 mmol) in water (35 mL) for 2 h to give 2e. The crude product
was purified by chromatography on silica gel using ethyl acetate/
hexane (20:80) as eluent to give the sulfoxide 2e (1.56 g, 98%) as
a clear oil; C13H16NClO2S requires C, 54.63; H, 5.64; N, 4.90; Cl,
12.41; S, 11.22. Found: C, 54.28; H, 5.60; N, 5.00; Cl, 12.62; S,
ide 2b (1.03 g, 98%) as
a colourless solid; mp 80–82 °C;
C16H14NClO2S requires C, 60.09; H, 4.41; N, 4.38; Cl, 11.09; S,
10.03. Found: C, 59.65; H, 4.56; N, 4.32; Cl, 11.89; S, 10.22. mmax
/
cmꢀ1 (KBr) 1659 (CO), 1574, 1028 (SO), 715; dH 4.23–4.37 (1H, A
of ABX, JAX 5, JAB 15, NCH2), 4.55–4.68 (1H, B of ABX, JBX 7, NCH2),
7.02–7.70 (10H, m, ArH), 7.78 (1H, s, CHCl@), 9.73 (1H, br s, NH);
dC 43.27 (CH2Ph), 124.13 (aromatic CH), 127.42 (aromatic CH),
127.64 (aromatic CH), 128.31 (aromatic CH), 128.85 (aromatic
10.78. m
max/cmꢀ1 (film) 3283 (br, NH), 1660 (CO), 1538, 1329,
1160, 1086; dH 0.86 (3H, t, J 7, –CH3), 1.08–1.51 (4H, m, –CH2–
CH2–), 3.08–3.36 (2H, m, NCH2), 7.39–7.66 (5H, m, ArH), 7.74
(1H, s, CHCl@), 8.31 (1H, br s, NH); dC 13.52 (CH3, –CH3), 19.77
(CH2, –CH2-30), 31.14 (CH2, CH2-20), 38.95 (CH2, NCH2–), 124.03

1264
M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
(CH, aromatic CH), 129.20 (CH, aromatic CH), 131.49 (CH, aromatic
CH), 136.90 (CH, CHCl@), 138.81 (quaternary aromatic or SC@),
141.12 (quaternary aromatic or SC@), 160.28 (CO); MS m/z 285
(M+, 36%), 250 (4, M+ꢀCl), 242 (20), 213 (9, M+ꢀNHBun), 155
(100), 125 (65, [SOPh]+), 77 (85); isotopic Cl pattern observed;
285, 287 (3:1 ratio 35Cl/37Cl); Found (HRMS, EI) m/z 285.0583
matic CH), 133.18 (quaternary aromatic), 137.82 (CHCl@), 138.48
(quaternary aromatic or SC@), 140.88 (quaternary aromatic or
SC@), 157.88/161.47 (d, JCF 244, quaternary aromatic, ArC-4),
4
158.30 (CO); MS m/z 323 (M+, 23%), 231 (25), 125 (50, [SPh]+), 43
(100); isotopic Cl pattern observed; 323, 325 (3:1 35Cl/37Cl); Found
(HRMS, EI) m/z 323.0176; C15H11N35ClFO2S requires 323.0154.
Note: The b-chloroacrylamides of the (n-butylthio)propana-
mides are susceptible to over oxidation if exposed to Oxone for
more than 2 h. As with the corresponding b-chloroacrylamides,
these compounds should be stored under nitrogen in the freezer
as they are rather labile. Decomposition of these compounds is evi-
dent by discolouration and the formation of a baseline spot on TLC.
C
13H16N35ClO2S requires M+ 285.0590.
4.7. N-20-Propenyl-Z-3-chloro-2-(benzenesulfinyl)propenamide
2f
This was prepared using the procedure described for sulfoxide
2f using N-20-propenyl-Z-3-chloro-2-(phenylthio)propenamide 1f
(1.50 g, 5.92 mmol) in acetone (120 mL) and OxoneÒ (7.28 g,
11.84 mmol) in water (36 mL) for 2 h to give 2f. The crude product
was purified by chromatography on silica gel using ethyl acetate/
hexane (20:80) as eluent to give the sulfoxide 2f (1.56 g, 98%) as
4.10. Oxidation of E-1i to the sulfoxide 2i
A solution of OxoneÒ (1.02 g, 1.66 mmol) in water (5 mL) was
added dropwise to a stirred solution of b-chloroacrylamide E-1i
(200 mg, 0.83 mmol) in acetone (16 mL) at room temperature.
The reaction mixture was stirred at room temperature for 14 h,
then water (25 mL) was added and the aqueous layer extracted
with DCM (3 ꢃ 20 mL). The combined extracts were washed with
water (2 ꢃ 25 mL) and brine (40 mL), dried and concentrated at re-
duced pressure to give sulfoxide 2i (210 mg, 98%) as a clear oil,
which solidified on standing to give a colourless solid, which
required no further purification; mp 96–98 °C; C11H12NClO2S
requires C, 51.26; H, 4.69; N, 5.44; Cl, 13.75; S, 12.44. Found: C,
a
clear oil, which solidified on standing; mp 87–89 °C;
C12H12NClO2S requires C, 53.43; H, 4.48; N, 5.19; Cl, 13.14; S,
11.89. Found: C, 53.37; H, 4.73; N, 5.21; Cl, 13.50; S, 11.38. mmax
/
cmꢀ1 (film) 3283 (br, NH), 1662 (CO), 1542, 1329, 1167, 1034; dH
3.73–4.00 (2H, m, NCH2), 5.00–5.15 (2H, m, @CH2), 5.63–5.82
(1H, m, CH@), 7.46–7.71 (5H, m, ArH), 7.76 (1H, s, CHCl@), 8.48
(1H, br s, NH); dC 41.68 (CH2, NCH2), 116.46 (CH2, @CH2), 124.14
(CH, aromatic CH), 129.07 (CH, aromatic CH), 129.26 (CH, aromatic
CH), 131.64 (CH, CHCl@ or CH@), 132.83 (CH, CHCl@ or CH@),
138.83 (C, quaternary aromatic or SC@), 141.10 (C, quaternary aro-
matic or SC@), 160.26 (CO).
51.37; H, 4.49; N, 5.36; Cl, 13.29; S, 12.14. m
max/cmꢀ1 (KBr) 1648
(CO), 1560, 1086, 740; dH 2.88 (3H, s, one of N(CH3)2), 3.03 (3H,
s, one of N(CH3)2), 6.74 (1H, s, CHCl@), 7.48–7.60 (3H, m, ArH),
7.74–7.86 (2H, m, ArH); dC 35.19 (one of N(CH3)2), 38.92 (one of
N(CH3)2), 124.86 (aromatic CH), 126.01 (aromatic CH), 128.78 (aro-
matic CH), 131.66 (CHCl@), 141.78 (quaternary aromatic or SC@),
145.45 (quaternary aromatic or SC@), 161.18 (CO); MS m/z 258
(M++1, 49%), 223 (46, 258-Cl), 175 (50), 126 (98), 78 (100), 73 (99).
4.8. Z-3-Chloro-2-(benzenesulfinyl)propenamide 2g
This was prepared using the procedure described for sulfoxide
2a using Z-3-chloro-2-(phenylthio)propenamide 1g (0.50 g,
2.34 mmol) in acetone (40 mL) and OxoneÒ (2.88 g, 4.68 mmol)
in water (14 mL) for 2 h to give 2g. The crude product was purified
by chromatography on silica gel using ethyl acetate/hexane
(20:80) as eluent to give the sulfoxide 2g (0.49 g, 92%) as a colour-
less solid; mp 157–161 °C (with decomposition); C9H8NClO2S re-
quires C, 47.06; H, 3.51; N, 6.10; Cl, 15.43; S, 13.96. Found: C,
4.11. N-40-Fluorophenyl-Z-3-chloro-2-(n-butylsulfinyl)-
propenamide 2j
This was prepared using the procedure described for sulfoxide
2a using N-40-fluorophenyl-Z-3-chloro-2-(n-butylthio)propen-
amide 1j (1.00 g, 3.48 mmol) in acetone (80 mL) and OxoneÒ
(4.28 g, 6.96 mmol) in water (22 mL) for 90 min to give 2j. The
crude product was purified by chromatography on silica gel using
ethyl acetate/hexane (15:85) as eluent to give the sulfoxide 2j
(1.01 g, 95%) as a clear oil; C13H15NClFO2S requires C, 51.39; H,
4.98; N, 4.61; Cl, 11.67; F, 6.25; S, 10.55. Found: C, 51.49; H,
47.19; H, 3.38; N, 6.20; Cl, 15.94; S, 13.48. m
max/cmꢀ1 (KBr) 1678
(CO), 1566, 1031; dH 6.00 (1H, br s, one of NH2), 7.42–7.72 (5H,
m, ArH), 7.80 (1H, s, CHCl@), 8.26 (1H, br s, one of NH2); dC
124.50 (aromatic CH), 129.95 (aromatic CH), 132.02 (aromatic
CH), 138.29 (CHCl@), 139.41 (quaternary aromatic or SC@),
141.32 (quaternary aromatic or SC@), 162.00 (CO); MS m/z 229
(M+, 64%), 194 (3, M+ꢀCl), 125 (100, [SOPh]+), 94 (55), 77 (70),
51 (64); isotopic Cl pattern observed; 229, 231 (3:1 ratio 35Cl/37Cl);
Found (HRMS, EI) m/z 228.9950. C9H8N35ClO2S requires 228.9964.
5.14; N, 4.58; Cl, 11.25; F, 6.44; S, 10.77. m
max/cmꢀ1 (film) 1676
(CO), 1574, 1510, 1224, 1017; dH 1.00 (3H, t, J 7, CH3-40), 1.45–
1.62 (2H, m, CH2-30), 1.72–1.89 (2H, m, CH2-20), 2.90–3.05 (1H,
m, one of SCH2), 3.12–3.25 (1H, m, one of SCH2), 7.02 (2H, overlap-
ping dd, J 8, 8, C-3 ArH), 7.53–7.63 (2H, m, C-2 ArH), 7.80 (1H, s,
CHCl@), 10.67 (1H, br s, NH); dC 13.43 (CH3, CH3-40), 21.66 (CH2,
CH2-30), 24.27 (CH2, CH2-20), 52.93 (CH2, SOCH2), 115.78 (CH, d,
3JCF 22, aromatic CH, ArC-3), 122.38 (CH, aromatic CH, ArC-2),
133.31 (C, quaternary aromatic or SC@), 136.12 (C, quaternary aro-
4.9. N-40-Fluorophenyl-Z-3-chloro-2-(benzenesulfinyl)-
propenamide 2h
This was prepared using the procedure described for sulfoxide
2a using N-40-fluorophenyl-Z-3-chloro-2-(phenylthio)-propena-
mide 1h (1.00 g, 3.25 mmol) in acetone (80 mL) and OxoneÒ
(4.00 g, 6.50 mmol) in water (20 mL) for 4 h to give 2h. The crude
product was purified by chromatography on silica gel using ethyl
acetate/hexane (20:80) as eluent to give the sulfoxide 2h (1.09 g,
95%) as a colourless solid; mp 99–101 °C; C15H11NClFO2S requires
C, 55.64; H, 3.42; N, 4.33; Cl, 10.95; F, 5.87; S, 9.90. Found: C,
4
matic or SC@), 136.30 (CH, CHCl@), 157.79/161.40 (C, d, JCF 245,
quaternary aromatic, ArC-4), 158.61 (CO); 303 (M+, 35%), 268
(12, M+ꢀCl), 247 (40), 164 (20), 149 (10, M+ꢀCONHArꢀO), 136
(58), 111 (80), 57 (100); isotopic Cl pattern observed; 303, 305
(3:1 35Cl/37Cl); Found (HRMS, EI) m/z 303.0463; C13H15N35ClFO2S
requires 303.0496.
56.00; H, 3.69; N, 4.31; Cl, 11.25; F, 5.75; S, 9.65. m
max/cmꢀ1 (KBr)
1675 (CO), 1621, 1574, 1508, 1216, 1029, 721; dH 7.00 (2H, over-
lapping dd, J 9, 9, C-3 ArH), 7.48–7.58 (5H, m, ArH), 7.67–7.73
(2H, m, ArH), 7.83 (1H, s, CHCl@), 10.43 (1H, br s, NH); dC 115.65
4.12. N-n-Butyl-Z-3-chloro-2-(butylsulfinyl)propenamide 2k
3
2
(d, JCF 23, aromatic CH, ArC-3), 122.29 (d, JCF 9, aromatic CH,
This was prepared following the procedure described for sulfox-
ArC-2), 124.11 (aromatic CH), 129.79 (aromatic CH), 131.95 (aro-
ide 2a using N-n-butyl-Z-3-chloro-2-(butylthio)propenamide 1k

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1265
n
(0.54 g, 2.2 mmol) in acetone (40 mL) and OxoneÒ (2.68 g,
4.4 mmol) in water (3 mL) for 2 h to give sulfoxide1k. Following
purification by column chromatography on silica gel using hex-
ane/ethyl acetate as eluent (gradient elution 2–5% ethyl acetate),
the pure sulfoxide 1k (0.43 g, 80%) was isolated as a clear oil;
M+ꢀClꢀ Bu), 194 (23, M+ꢀSOnBu), 107 (100), 91 (48), 41 (56); iso-
topic Cl pattern observed; 299, 301 (3:1 ratio 35Cl/37Cl); Found
(HRMS, EI) m/z 299.0736. C14H18N35ClO2S requires 299.0747.
4.15. N-Phenyl-Z-3-chloro-2-(butylsulfinyl)propenamide 2n
m
max/cmꢀ1 (film) 3222 (NH), 1671 (CO), 1574 (NH bend), 1466,
1403 (CN stretch), 1025 (SO); dH (300 MHz) 0.91–1.00 [6H, m,
C(40)H3 and C(400)H3], 1.25–1.77 [8H, m, C(30)H2, C(300)H2, C(20)H2
and C(200)H2], 2.89–2.92 (1H, m, one of SCH2), 3.06–3.11 (1H, m,
one of SCH2), 3.34–3.37 (2H, m, NCH2), 7.67 [1H, s, C(3)HCl@],
8.59 (1H, br s, NH); dC (75.5 MHz) 14.0 [CH3, C(40)H3 or C(400)H3],
14.1 [CH3, C(40)H3 or C(400)H3], 20.6 [CH2, C(30)H2 or C(300)H2], 22.2
[CH2, C(30)H2 or C(300)H2], 24.9 [CH2, C(20)H2 or C(200)H2], 31.6
[CH2, C(20)H2 or C(200)H2], 39.6 [CH2, CH2N], 53.1 (CH2, CH2S),
135.9 [CH, C(3)HCl@], 136.9 [C, C(2)S], 161.3 (C, CO).
This was prepared following the procedure described for sulfox-
ide 2a using N-phenyl-Z-3-chloro-2-(butylthio)propenamide 1n
(2.04 g, 7.1 mmol) in acetone (100 mL) and OxoneÒ (8.77 g,
14.3 mmol) in water (50 mL) for 2 h to give the sulfoxide 2n. Fol-
lowing purification by column chromatography on silica gel using
hexane/ethyl acetate 95:5 as eluent, the pure sulfoxide 2n (1.55 g,
76%) was isolated as a clear oil; m
max/cmꢀ1 (film) 3524 (NH), 3032
(CH), 1680 (CO), 1568 (NH bend), 1495, 1400 (CN stretch), 1019
(SO); dH (300 MHz) 0.97 [3H, t, J 7.4, C(40)H3], 1.41–1.57 [2H, m,
C(30)H2], 1.69–1.92 [2H, m, C(20)H2], 2.90–3.06 (1H, m, one of
SCH2), 3.13–3.27 (1H, m, one of SCH2), 7.09–7.19 (1H, m, ArH),
7.21–7.42 (2H, m, ArH), 7.55–7.68 (2H, m, ArH), 7.80 [1H, s,
C(3)HCl@], 10.66 (1H, br s, NH); dC (75.5 MHz) 13.6 [CH3,
C(40)H3], 21.8 [CH2, C(30)H2], 24.6 [CH2, C(20)H2], 52.9 (CH2, CH2S),
120.8, 125.0, 129.1 (3 ꢃ CH, aromatic CH), 136.2 [C, C(2)S or aro-
matic C], 136.7 [CH, C(3)HCl@], 137.3 [C, C(2)S or aromatic C],
158.8 (C, CO); HRMS (ESI): Exact mass calcd for C13H17NO2SCl
[M+H]+, 286.0669. Found 286.0656; 286 ([M+H]+, 100%).
4.13. N-Benzyl-Z-3-chloro-2-(n-butylsulfinyl)propenamide 2l
This was prepared following the procedure described for sulfox-
ide 2a using N-benzyl-Z-3-chloro-2-(n-butylthio)propenamide 1l
(1.00 g, 3.53 mmol) in acetone (80 mL) and OxoneÒ (4.34 g,
7.06 mmol) in water (22 mL) for 2 h to give crude sulfoxide 2l
(1.06 g, quantitative). Purification by chromatography on silica
gel using ethyl acetate/hexane (gradient elution 10–30% ethyl ace-
tate) as eluent gave N-benzyl-Z-3-chloro-2-(n-butylsulfinyl)pro-
penamide 2l (0.93 g, 80%) as a clear oil; C14H18NClO2S requires C,
56.08; H, 6.05; N, 4.67; Cl, 11.82; S, 10.69. Found: C, 55.87; H,
4.16. N-40-Methylphenyl-Z-3-chloro-2-(40-methoxybenzene-
sulfinyl)propenamide 2o
6.19; N, 4.47; Cl, 11.69; S, 10.88. m
max/cmꢀ1 (film) 3252 (br NH),
1670 (CO), 1573, 1024 (SO), 699; dH 0.93 (3H, t, J 7, –CH3-40),
1.34–1.54 (2H, m, –CH2-30), 1.58–1.84 (2H, m, –CH2-20), 2.80–
2.94 (1H, m, one of SOCH2), 3.00–3.14 (1H, m, one of SOCH2),
4.42–4.64 (2H, sym. m, NCH2Ph), 7.18–7.40 (5H, m, ArH), 7.71
(1H, s, CHCl@), 9.03 (1H, br s, NH); dC 13.41 (CH3, CH3), 21.72
(CH2, CH2-30), 24.16 (CH2, CH2-20), 43.37 (CH2, NCH2Ph), 52.67
(CH2, SOCH2), 127.41 (CH, aromatic CH), 127.74 (CH, aromatic
CH), 128.74 (CH, aromatic CH), 135.75 (CH, CHCl@), 136.70 (C, qua-
ternary aromatic C or SOC@), 137.62 (quaternary aromatic C or
SOC@), 161.00 (CO); MS m/z 299 (M+, 1%), 264 (21, M+ꢀCl), 194
(11, M+ꢀSOBun), 158 (45, M+ꢀSOBunꢀHCl), 91 (100, [PhCH2]+),
77 (36); isotopic Cl pattern observed on expansion; 299, 301 (3:1
ratio 35Cl/37Cl).
This was prepared using the procedure described for sulfoxide
2a using N-40-methylphenyl-Z-3-chloro-2-(40-methoxybenzen-
ethio)propenamide 1o (0.70 g, 2.10 mmol) in acetone (70 mL)
and OxoneÒ (3.88 g, 6.30 mmol) in water (30 mL) overnight to give
the crude sulfoxide 2o (0.71 g, 96%) as a colourless solid. Further
purification was not required although previously samples have
been purified by chromatography on silica gel using ethyl ace-
tate/hexane (70:30) as eluent (84%) or trituration from ether
(80%); mp 128–130 °C; C17H16NClO3S requires C, 58.36; H, 4.61;
N, 4.00; Cl, 10.13; S, 9.16. Found: C, 58.16; H, 4.62; N, 4.07; Cl,
10.27; S, 9.62 (extra combustion required for S analysis). mmax
/
cmꢀ1 (KBr) 3050 (NH), 1670 (CO), 1612, 1495, 1260, 1023, 725;
dH 2.31 (3H, s, Ar CH3), 3.81 (3H, s, OCH3), 6.99 (2H, half of ABq, J
9, ArH), 7.13 (2H, half of ABq, J 8, ArH), 7.47 (2H, half of ABq, J 8,
ArH), 7.63 (2H, half of ABq, J 9, ArH), 7.75 (1H, s, CHCl@), 10.53
(1H, br s, NH); dC 20.92 (Ar CH3), 55.58 (OCH3), 115.37 (aromatic
CH), 120.71 (aromatic CH), 126.32 (aromatic CH), 129.58 (aromatic
CH), 131.82 (quaternary aromatic C or SC@), 134.64 (quaternary
aromatic C or SC@), 134.79 (quaternary aromatic C or SC@),
136.80 (CHCl@), 138.40 (quaternary aromatic C or SC@), 158.39
(C-OMe), 162.69 (CO); MS m/z 349 (M+, 40%), 213 (40), 155 (100,
[SOAr]+), 106 (50), 77 (50); isotopic Cl pattern observed; 349,
351 (3:1 ratio 35Cl/37Cl); Found (HRMS, EI) m/z 349.0536.
4.14. N-40-Methylphenyl-Z-3-chloro-2-(n-butylsulfinyl)-
propenamide 2m
This was prepared following the procedure described for sulfox-
ide 2a using N-40-methylphenyl-Z-3-chloro-2-(n-butylthio) pro-
penamide 1m (1.00 g, 3.53 mmol) in acetone (80 mL) and OxoneÒ
(4.34 g, 7.06 mmol) in water (22 mL) for 2 h to give the crude sulf-
oxide 2m (1.04 g, 98%). Purification by chromatography on silica
gel using ethyl acetate/hexane (10:90) as eluent gave N-40-methyl-
phenyl-Z-3-chloro-2-(n-butylsulfinyl)-propenamide 2m (0.95 g,
91%) as a clear oil, which solidified on standing; mp 67–69 °C;
C
17H16N35ClO3S requires 349.0540.
C14H18NClO2S requires C, 56.08; H, 6.05; N, 4.67; Cl, 11.82; S,
4.17. N-Benzyl-Z-3-chloro-2-(40-methoxybenzene-
10.69. Found: C, 56.39; H, 6.29; N, 4.50; Cl, 11.39; S, 10.24. mmax
/
sulfinyl)propenamide 2p
cmꢀ1 (KBr) 3309 (br NH), 1671 (CO), 1611, 1016 (SO), 819; dH
0.96 (3H, t, J 7, –CH3-40), 1.38–1.63 (2H, m, -CH2-30), 1.64-1.91
(2H, m, –CH2-20), 2.32 (3H, s, Ar CH3), 2.88–3.06 (1H, m, one of
SOCH2), 3.09–3.37 (1H, m, one of SOCH2), 7.14 (2H, d, J 8, ArH),
7.49 (2H, d, J 8, ArH), 7.78 (1H, s, CHCl@), 10.58 (1H, br s, NH); dC
13.43 (CH3, CH3-40), 20.80 (CH3, CH3 Ar), 21.70 (CH2, CH2-30),
24.50 (CH2, CH2-20), 52.93 (CH2, CH2SO), 120.71, (CH, aromatic
CH), 129.81 (CH, aromatic CH), 134.58 (C, quaternary aromatic C
or SC@), 134.78 (C, quaternary aromatic C or SC@), 136.12 (CH,
CHCl@), 136.50 (C, quaternary aromatic C or SC@), 158.48 (CO);
MS m/z 299 (M+, 78%), 264 (2, M+ꢀCl), 243 (33), 207 (52,
This was prepared using the procedure described for sulfoxide
2p using N-benzyl-Z-3-chloro-2-(40-methoxybenzene-thio)pro-
penamide 1p (330 mg, 0.99 mmol) in acetone (10 mL) and OxoneÒ
(1.80 g, 2.97 mmol) in water (9 mL) overnight to give the crude
sulfoxide 2p (320 mg, 93%) as a clear oil. Further purification was
not conducted;
m
max/cmꢀ1 (film) 3280 (NH), 1660 (CO), 1593,
1495, 1085, 1027, 830; dH 3.83 (3H, s, OCH3), 4.28–4.79 (2H, m,
NCH2), 6.88–6.97 (2H, m, ArH), 7.11–7.36 (5H, m, ArH), 7.45–7.53
(2H, m, ArH), 7.72 (1H, s, CHCl@), 8.86 (1H, br s, NH); MS m/z
349 (M+, 18%), 333 (3, M+ꢀO), 155 (94, [SOAr]+), 139 (22), 91

1266
M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
(100); isotopic Cl pattern observed; 349, 351 (3:1 35Cl/37Cl); Found
1082, dH 1.14 [3H, d, J 6.7 one of CH(CH3)2], 1.17 [3H, d, J 6.7 one
of CH(CH3)2], 2.13–2.39 [1H, m, HX of ABX system, CH(CH3)2],
2.61–2.79 (1H, m, HA of ABX system, SCHA), 3.10–3.23 (1H, m, HB
of ABX system, SCHB), 6.98–7.06 (2H, m, Ar-30-H), 7.49–7.58 (2H,
m, Ar-20-H), 7.76 (1H, s, CHCl@), 10.70 (1H, br s, NH); dC 21.37
[CH3, one of CH(CH3)2], 22.69 [CH3, one of CH(CH3)2], 24.21 [CH,
(HRMS, EI) m/z 349.0523. C17H16N35ClO3S requires 349.0540.
4.18. N-Ethyl-Z-3-chloro-2-(40-methoxybenzene-
sulfinyl)propenamide 2q
3
This was prepared using the procedure described for sulfoxide
2a using N-ethyl-Z-3-chloro-2-(40-methoxybenzene-thio)propen-
amide 1q (0.50 g, 1.84 mmol) in acetone (40 mL) and OxoneÒ
(2.27 g, 3.68 mmol) in water (11 mL) for 1 h to give 2q as a yellow
oil (0.53 g, 100%). The crude product was purified by chromatogra-
phy on silica gel using ethyl acetate/hexane (20:80) as eluent to
give the sulfoxide 2q (0.51 g, 96%) as a colourless solid; mp 53.5–
55 °C; C12H14NClO3S requires C, 50.08; H, 4.90; N, 4.87; Cl, 12.32;
S, 11.14. Found: C, 50.20; H, 5.00; N, 4.54; Cl, 12.34; S, 11.48.
CH(CH3)2], 62.44 (CH2, SOCH2), 115.76 (CH, d, JCF 22.6, aromatic
CH, ArC-30), 122.43 (CH, d, J 7.9, aromatic CH, ArC-20), 133.38 (C,
quaternary aromatic or SC@), 136.24 (2ꢃCH, quaternary aromatic,
4
CHCl@), 158.05/161.29 (C, d, JCF 244.6, quaternary aromatic, ArC-
i
40), 158.65 (CO); MS m/z M+(303,15), M+ꢀClꢀ Bu (211, 12),
111(55), 57 (100); isotopic Cl pattern observed; 303:305 (3:1 ratio
35Cl/37Cl): Found (HRMS, EI) m/z 303.04961 C13H15SNO2 35ClF re-
quires 303.04958.
m
max/cmꢀ1 (KBr) 1662 (CO), 1570, 1496, 1259, 1023, 837; dH 1.16
4.21. N-40-Fluorophenyl-Z-3-chloro-2-(iso-
(3H, t, J 7, –CH3), 3.19–3.43 (2H, m, NCH2), 3.87 (3H, s, OCH3),
7.01–7.62 (4H, ABq, J 5, ArH), 7.71 (1H, s, CHCl@), 8.47 (1H, br s,
NH); dC 14.92 (–CH3), 34.72 (NCH2), 56.02 (OCH3), 115.65 (aromatic
CH), 126.75 (aromatic CH), 132.72 (quaternary aromatic or SC@),
136.41 (CHCl@), 139.60 (quaternary aromatic or SC@), 160.94 (C-
OMe), 163.05 (CO); MS m/z 287 (M+, 7%), 271 (3, M+ꢀO), 199
(35, M+ꢀCONHEtꢀO), 155 (48, [SOAr]+), 72 (100); isotopic Cl pat-
tern observed; 287, 289 (3:1 ratio 35Cl/37Cl); Found (HRMS, EI)
m/z 287.0383. C12H14N35ClO3S requires 287.0383.
propylsulfinyl)propenamide 2t
This was prepared using the procedure described for sulfoxide
2a using N-40-fluorophenyl-Z-3-chloro-2-(methylthio)propen-
amide 1t (1 g, 3.65 mmol), OxoneÒ (4.5 g, 7.31 mmol), acetone
(60 mL) and water (25 mL). Purification by chromatography on
silica gel using ethyl acetate/hexane (80:20) as eluent gave the
sulfoxide 2t (0.97 g, 88%) as
12H13SNO2ClF requires C, 49.74; H, 4.52; N, 4.83; S, 11.07. Found:
C, 49.75; H, 4.48; N, 4.61; S, 11.40.
max/cmꢀ1 (KBr) 3326, 1672,
a white solid; mp 78–80 °C;
C
m
4.19. N-40-Methylphenyl-Z-3-chloro-2-(4-nitrobenzene-
sulfinyl)propenamide 2r
1509, 1212, 832; dH 1.31–1.59 [6H, m, CH(CH3)2], 3.19–3.39 [1H,
m, CH(CH3)2], 7.03–7.09 (2H, m, ArH-3), 7.45 (2H, m, ArH-2),
7.80 (1H, s, @CHCl), 10.90 (1H, br s, NH); dC 15.29 [CH3, CH(CH3)2],
2
This was prepared using the procedure described for sulfoxide
2a using N-40-methylphenyl-Z-3-chloro-2-(4-nitrobenzenesulfi-
nyl)propenamide 1r (0.44 g, 1.26 mmol) in acetone (35 mL) and
OxoneÒ (1.55, 2.53 mmol) in water (8 mL). However, after 2 h,
TLC showed substantial starting material remaining. A further
TLC was run after 6 h and this again showed starting material
remaining. The reaction mixture was stirred for 28 h before
work-up to give 2r as a yellow oil. The crude product was purified
by chromatography on silica gel using ethyl acetate/hexane
(30:70) as eluent to give the sulfoxide 2r (0.39 g, 84%) as a yellow
solid; mp 151–153 °C; C16H13N2ClO4S requires C, 52.68; H, 3.59; N,
7.68; Cl, 9.72; S, 8.79. Found: C, 53.00; H, 3.80; N, 7.52; Cl, 10.13; S,
16.35 [CH3, CH(CH3)2], 53.55 [CH, CH(CH3)2], 115.74 (CH, d, JCF
3
22.57, aromatic CH, ArC-3), 122.33 (CH, d, JCF 7.92, aromatic CH,
ArC-2), 133.37 (C, @SC), 134.86 (C, d, 4JCF 2.88, quaternary aromatic
1
C, ArC-1), 138.11 (CH, @CHCl), 158.00/161.24 (C, d, JCF 248.02,
quaternary aromatic C, ArC-4), 159.28 (CO); MS m/z 289 (M+,
10%), 247 (100%), 239 (40%), 222 (30%).
4.22. N-40-Fluorophenyl-Z-3-chloro-2-
(methylsulfinyl)propenamide 2u
This was prepared using the procedure described for sulfoxide
1a using N-40-fluorophenyl-Z-3-chloro-2-(methylthio)propen-
amide (1.00 g, 4.07 mmol) 2u and OxoneÒ (5.00 g, 8.15 mmol), ace-
tone (60 mL) and water (25 mL) Purification by chromatography on
silica gel using ethyl acetate/hexane (80:20) as eluent gave the
8.98. m
max/cmꢀ1 (KBr) 1673 (CO), 1523, 1346, 1036 (SO), 854; dH
2.32 (3H, s, Ar CH3), 7.14 (2H, d, J 11, ArH), 7.38 (2H, d, J 11,
ArH), 7.88–7.96 (3H, m, ArH, CHCl@), 8.39 (2H, d, J 16, ArH),
10.02 (1H, br s, NH); dC 20.89 (Ar CH3), 120.67 (aromatic CH),
124.89 (aromatic CH), 125.33 (aromatic CH), 129.71 (aromatic
CH), 134.33 (quaternary aromatic), 135.17 (quaternary aromatic),
138.38 (quaternary aromatic), 138.95 (CHCl@), 148.17, 150.10
(quaternary aromatic and SC@), 157.52 (CO); MS m/z 364 (M+,
20), 348 (1, M+ꢀO), 228 (16), 170 (23, [SOAr]+), 106 (50, [NHTol]+),
77 (78), 43 (100); isotopic Cl pattern observed; 364, 366 (3:1
35Cl/37Cl); Found (HRMS, EI) 364.0281. C16H13N235ClO4S requires
364.0285.
sulfoxide 2u (0.98 g, 92%) as
10H9SNO2ClF requires C, 45.89; H, 3.47; N, 5.35; S, 12.25. Found:
C, 45.91; H, 3.44; N, 5.23; S, 12.49.
max/cmꢀ1 (KBr) 1670, 1509,
a white solid; mp 97–99 °C;
C
m
1211; dH 2.94 (3H, s, SCH3), 6.98–7.07 (2H, m, ArH-3), 7.59–7.67
(2H, m, ArH-2), 7.76 (1H, s, @CHCl), 10.67 (1H, br s, NH); dC
2
39.53 (CH3, SCH3), 116.11 (CH, d, JCF 22.49, aromatic CH, ArC-3),
3
4
122.79 (CH, d, JCF 7.92, aromatic CH, ArC-2), 132.72 (C, d, JCF
2.57, quaternary aromatic C, ArC-1), 136.66 (CH, @CHCl), 139.09
1
(C, @SC), 158.36/161.60 (C, d, JCF 244.52, quaternary aromatic C,
ArC-4), 158.61 (CO); MS m/z 261, (M+, 20%), 198 (9%), 164 (10%),
151 (30); isotopic Cl pattern observed; 261:263 (3:1 ratio
35Cl/37Cl).
4.20. N-40-Fluorophenyl-Z-3-chloro-2-(iso-
butylsulfinyl)propenamide 2s
This was prepared using the procedure described for sulfoxide
2a using OxoneÒ (4.71 g, 7.66 mmol) in water (5 mL) and 1s
(1.10 g, 3.83 mmol) in acetone (66 mL) at room temperature. The
crude product was purified by chromatography on silica gel using
ethyl acetate/hexane (20:80) as eluent to give the sulfoxide 2s
(1.14 g, 92%) as a yellow oil, which solidified on standing; mp
65–67 °C; C13H15NClO2SF requires C, 51.40; H, 4.98; N, 4.61; Cl,
11.67; S, 10.56. Found: C, 51.15; H, 5.00; N, 4.61; Cl, 11.76, F,
4.23. N-n-Butyl-Z-3-chloro-2-(methylsulfinyl)propenamide 2v
This was prepared using the procedure described for sulfoxide
2a using N-n-butyl-Z-3-chloro-2-(methylthio)propenamide 1v
(1.24 g, 5.98 mmol), OxoneÒ (7.35 g, 11.96 mmol) in acetone
(74 mL) and water (40 mL). Purification by chromatography on sil-
ica gel using ethyl acetate/hexane (80:20) as eluent gave the sulf-
oxide 2v (1.14g, 85%) as a colourless oil; C8H14SNO2Cl requires C,
43.95; H, 6.31; N, 6.26; S, 14.33. Found: C, 42.62; H, 6.27; N,
6.00; S, 10.90. m
max/cmꢀ1 (KBr) 3294 (br, NH), 1680 (CO), 1540,

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1267
6.18; S, 14.02.
m
max/cmꢀ1 (film) 3278, 1665, 1572; dH 0.94 (3H, t, J
131.0 (CH, aromatic CH), 133.1, 134.8 [C, aromatic C or C(2)S],
1
7.3, CH3-40), 1.31–1.51 (2H, m, CH2-30), 1.52–1.69 (2H, m, CH2-20),
2.85 (3H, s, SCH3), 3.35 (2H, q, J 6.0, NCH2), 7.71 (1H, s, @CHCl),
8.59 (1H, br s, NH); dC 13.71 (CH3, CH3-40), 20.20 (CH3, SCH3),
31.26 (CH2, CH2-30), 38.99 (CH2, CH2-20), 39.27 (CH2, NCH2),
135.08 (C, SC@), 137.65 (CH, @CHCl), 160.48 (CO); MS m/z 223
(M+, 1%), 222 (10%), 205 (100%).
137.5 [CH, C(3)HCl@], 159.6 [C, d, JCF 245, aromatic C, ArC(40)],
158.4 (C, CO); m/z (ESI) 360 ([M+Na]+, 6%), 91 (C7H7þ, 100%).
4.27. N-n-Butyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2z
This was prepared following the procedure described for 2a
using
N-n-butyl-Z-3-chloro-2-(benzylthio)propenamide
1z
4.24. N-Benzyl-Z-3-chloro-2-(methylsulfinyl)propenamide 2w
(0.32 g, 1.1 mmol) in acetone (20 mL) and OxoneÒ (1.39 g,
2.3 mmol) in water (10 mL) for 2 h to give 2z. Following purifica-
tion by column chromatography on silica gel using hexane/ethyl
acetate as eluent (gradient elution 2–10% ethyl acetate), 2z
This was prepared using the procedure described for sulfoxide
2a using N-benzyl-Z-3-chloro-2-(methylthio)propenamide 1w
(0.35 g, 1.69 mmol), OxoneÒ (2.07 g, 1.69 mmol) in acetone
(21 mL) and water (11 mL). Purification by chromatography on sil-
ica gel using ethyl acetate/hexane (80:20) as eluent gave the sulf-
oxide 2w (0.31 g, 82%) as a colourless oil; C11H12SNO2Cl requires C,
51.36; H, 4.66; N, 5.44; S, 12.45. Found: C, 51.32; H, 4.60; N, 5.31; S,
(0.23 g, 69%) was isolated as a clear oil; m
max/cmꢀ1 (film) 3400
(NH), 1646 (CO), 1560 (NH bend), 1457, 1402 (CN stretch), 1045
(SO); dH (300 MHz, CDCl3) 0.91 [3H, t, J 7.1, C(40)H3], 1.23–1.46
[4H, m, C(30)H2 and C(20)H2], 2.99–3.27 (2H, m, CH2NH), 4.19 (1H,
A of ABq, J 12.8, one of SCH2), 4.25 (1H, B of ABq, J 12.8, one of
SCH2), 7.23–7.41 (5H, m, ArH), 7.61 [1H, s, C(3)HCl@], 8.19 (1H,
br s, NH); dC (75.5 MHz, CDCl3) 14.1 [CH3, C(40)H3], 20.6 [CH2,
C(30)H2], 31.5 [CH2, C(20)H2], 39.5 (CH2, CH2N), 58.8 (CH2, SCH2),
128.6 (C, aromatic C), 129.2, 129.4, 131.0 (3 ꢃ CH, aromatic CH),
135.8, [C, C(2)S], 136.4 [C, C(3)HCl@], 161.0 (C, CO); HRMS (ESI):
Exact mass calcd for C14H19NO2SCl [M+H]+, 300.0825. Found
300.0826; 322 ([M+Na])+, 8%, 91 (C7H7þ, 100%).
12.15. m
max/cmꢀ1 (film) 3290, 1644, 1519; dH 2.86 (3H, s, SCH3),
4.42–4.68 (2H, m, CH2Ph), 7.12–7.41 (5H, m, ArH), 7.71 (1H, s,
@CHCl); 8.99 (1H, br s, NH); dC 38.93 (CH3, SCH3), 43.98 (CH2,
CH2Ph), 127.50 (2 ꢃ CH, ArCH), 127.60 (2 ꢃ CH, ArCH), 128.72 (C,
@SC), 135.55 (CH, @CHCl), 137.51 (C, quaternary aromatic C),
160.59 (CO); MS m/z No M+, 240 (30%), 158 (45%), 135 (32%).
4.25. N-Benzyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2x
4.28. N-40-Methylphenyl-Z-3-chloro-2-(benzylsulfinyl)-
This was prepared using the procedure described for sulfoxide
2a using a solution of OxoneÒ (7.74 g, 12.6 mmol) in water
(40 mL) and N-40-benzyl-Z-3-chloro-2-(benzylthio)propenamide
1x (2.00 g, 6.3 mmol) in acetone (150 mL) at room temperature.
Following purification by column chromatography on silica gel
using hexane/ethyl acetate as eluent (gradient elution 2–10% ethyl
propenamide 2aa
This was synthesised according to the procedure outlined for 2a
using N-40-methylphenyl-Z-3-chloro-2-(benzylthio)propenamide
1aa (0.50 g, 1.6 mmol) in acetone (50 mL) and OxoneÒ (1.93 g,
3.2 mmol) in water (15 mL). The reaction mixture was stirred at
room temperature for 2 h and following the work-up, 2aa was ob-
tained as an off-white solid. This was then purified by column
chromatography on silica gel using hexane/ethyl acetate as eluent
(gradient elution 2–5% ethyl acetate) to give 2aa (0.38 g, 72%) as a
white solid, mp 116–118 °C; (C17H16ClNO2S requires C, 61.61; H,
4.83; N, 4.20; S, 9.61; Cl, 10.62. Found: C, 61.05; H, 4.62; N, 4.32;
acetate), 2x (1.44 g, 69%) was isolated as a clear oil; m
max/cmꢀ1
(film) 3258 (NH), 3061 (CH), 1661 (CO), 1572 (NH bend), 1496,
1454 (CN stretch), 1023 (SO); dH (300 MHz, CDCl3) 4.23 (1H, A of
ABq, J 12.8, one of SCH2), 4.31 (1H, B of ABq, J 12.8, one of SCH2),
4.27–4.33 (1H, A of ABX, JAB 14.9, JAX 5.6, CH2NH), 4.45–4.52 (1H,
B of ABX, JAB 14.9, JBX 5.6, CH2NH), 7.18–7.38 (10H, m, ArH), 7.79
[1H, s, C(3)HCl@], 8.63 (1H, br s, NH); dC (75.5, CDCl3) 43.8 (CH2,
CH2NH), 58.8 (CH2, SCH2), 127.9, 128.1, 129.1, 129.2, 129.4, 131.0
(CH, aromatic CH), 135.8 [C, aromatic C or C(2)S], 137.0 [CH,
C(3)HCl@], 137.8 [C, aromatic C or C(2)S], 161.1 (C, CO); HRMS
(ESI): Exact mass calcd for C17H16NO2SClNa [M+Na]+, 356.0488.
Found 356.0490; 334 ([M+H]+, 100%), 91 (C7H7þ, 70%); isotopic Cl
pattern observed; 334, 336 (3:1 35Cl/37Cl).
S, 9.48; Cl, 10.63.); m
max/cmꢀ1 (KBr) 3056 (NH), 1673 (CO), 1560
(NH bend), 1513, 1408 (CN stretch), 1023 (SO); dH (300 MHz,
CDCl3) 2.36 (3H, s, Ar-CH3), 4.25 (1H, A of ABq, J 13.0, one of
SCH2), 4.30 (1H, B of ABq, J 13.0, one of SCH2), 7.00–7.41 (9H, m,
ArH), 7.79 [1H, s, C(3)HCl@], 10.10 (1H, br s, NH); dC (75.5 MHz,
CDCl3) 21.4 (CH3, Ar-CH3), 58.9 (CH2, SCH2), 121.1 (CH, aromatic
CH), 128.2 [C, aromatic C or C(2)S], 129.3, 129.5, 129.7, 131.0
(CH, aromatic CH), 134.9, 135.0, 135.6 [C, aromatic C or C(2)S],
137.3 [CH, C(3)HCl@], 158.6 (C, CO); m/z (ESI) 334 ([M+H]+,
100%), 91 (C7H7þ, 48%); isotopic Cl pattern observed; 334, 336
(3:1 35Cl/37Cl).
4.26. N-40-Fluorophenyl-Z-3-chloro-2-
(benzylsulfinyl)propenamide 2y
The title compound was synthesised following the procedure
outlined for 2a using N-40-fluorophenyl-Z-3-chloro-2-(benzyl-
thio)propenamide 1y (1.05 g, 3.3 mmol) in acetone (80 mL) and
OxoneÒ (4.00 g, 6.5 mmol) in water (15 mL). Following stirring at
room temperature for 2 h, the crude 2y was obtained as an off-
white solid. This was then purified by column chromatography
on silica gel using hexane/ethyl acetate as eluent (gradient elution
2–5% ethyl acetate) to give the pure product (0.84 g, 77%) as a
white solid, mp 121–122 °C; (C16H13NClFO2S requires C, 56.89; H,
3.88; N, 4.15; S, 9.49; Cl, 10.50; F, 5.62. Found: C, 56.76; H, 3.81;
4.29. N-Methyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2ab
The title compound was synthesised following the procedure
outlined for 2a using N-methyl-Z-3-chloro-2-(benzylthio)propen-
amide 1ab (2.00 g, 8.0 mmol) in acetone (150 mL) and OxoneÒ
(10.14 g, 16.5 mmol) in water (40 mL). The crude sulfoxide was ob-
tained as a pale yellow oil and following purification by column
chromatography on silica gel using hexane/ethyl acetate as eluent
(gradient elution 20–40% ethyl acetate), 2ab (1.36 g, 66%) was iso-
N, 4.05; S, 9.67; Cl, 10.68; F, 5.89.);
m
max/cmꢀ1 (KBr) 3201 (NH),
lated as a clear oil; m
max/cmꢀ1 (film) 3240 (NH), 3061 (CH), 1667
3060 (CH), 1670 (CO), 1573 (NH bend), 1508, 1409 (CN stretch),
1025 (SO); dH (300 MHz, CDCl3) 4.27 (2H, s, SCH2), 6.96 [2H, over-
lapping dd (appears as a triplet), J 8.6, 8.6, C(30)H], 7.19–7.40 (8H,
m, ArH), 7.81 [1H, s, C(3)HCl@], 10.08 (1H, br s, NH); dC
(CO), 1567 (NH bend), 1496, 1411 (CN stretch), 1030 (SO); dH
(300 MHz, CDCl3) 2.65 (3H, d, J 4.8, CH3NH), 4.21 (2H, s, SCH2),
7.19–7.37 (5H, m, ArH), 7.70 [1H, s, C(3)HCl@], 8.06 (1H, br s,
NH); dC (75.5 MHz, CDCl3) 25.9 (CH3, CH3NH), 58.4 (CH2, SCH2),
128.1 [C, aromatic C or C(2)S], 128.8, 129.0, 130.7 (CH, aromatic
CH), 135.4 [C, aromatic C or C(2)S], 136.1 [CH, C(3)HCl@], 161.3
2
(75.5 MHz, CDCl3) 58.7 (CH2, SCH2), 115.9 [CH, d, JCF 22, aromatic
CH, ArC(30)], 122.6 [CH, d, 3JCF 8, aromatic CH, ArC(20)], 129.3, 129.6,

1268
M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
(C, CO); Exact mass calcd for C11H12NO2SClNa [M+Na]+, 280.0175.
Found 280.0175; 258 ([M+H]+, 80%), 91 (C7H7þ, 100%); isotopic Cl
pattern observed; 258, 260 (3:1 35Cl/37Cl).
4.33. N,N-Dimethyl-Z-3-chloro-2-(benzylsulfinyl)propenamide
2af
The title compound was prepared following the procedure de-
scribed for 2a using N,N-dimethyl-Z-3-chloro-2-(benzylthio)pro-
penamide 1af (1.00 g, 3.9 mmol) in acetone (100 mL) and OxoneÒ
(4.81 g, 7.8 mmol) in water (30 mL) for 2 h to give the crude sulfox-
ide 2af as a yellow oil. Following purification by column chroma-
tography on silica gel using hexane/ethyl acetate as eluent
(gradient elution 0–20% ethyl acetate), the pure sulfoxide 2af
4.30. N-Phenyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2ac
This was prepared following the procedure described for 2a
using
N-phenyl-Z-3-chloro-2-(benzylthio)propenamide
1ac
(1.49 g, 4.9 mmol) in acetone (120 mL) and OxoneÒ (6.04 g,
9.8 mmol) in water (30 mL). The crude sulfoxide 2ac (1.19 g, 76%)
was isolated as a white solid, which was carried forward without
further purification, mp 105–107 °C; (C16H14NO2SCl requires C,
60.09; H,4.41; Cl, 11.09; S, 10.03. Found: C, 59.49; H, 4.30; Cl,
(0.80 g, 75%) was isolated as a yellow oil; m
max/cmꢀ1 (film) 3032
(CH), 1645 (CO), 1496, 1052 (SO); dH (300 MHz, CDCl3) 3.10 [6H,
d, J 1.7, N(CH3)2], 4.46 (1H, A of ABq, J 12.2, one of SOCH2), 4.58
(1H, B of ABq, J 12.2, one of SOCH2), 6.59 [1H, s, C(3)HCl@], 7.31–
7.38 (3H, m, ArH), 7.43–7.51 (2H, m, ArH); dC (75.5 MHz, CDCl3)
35.2 [CH3, one of N(CH3)2], 39.0 [CH3, one of N(CH3)2], 60.1 (CH2,
SCH2), 125.3, 128.5, 128.8 (CH, aromatic CH), 129.1 (C, aromatic C
or C(2)S), 130.9 [CH, C(3)HCl@], 142.0 [C, aromatic C or C(2)S],
162.0 (C, CO); HRMS (ESI): Exact mass calcd for C12H15NO2SCl
[M+H]+, 272.00512. Found 272.0500; 272 ([M+H]+, 100%); isotopic
Cl pattern observed; 272, 274 (3:1 35Cl/37Cl).
11.16; N, 4.39; S, 9.99.); m
max/cmꢀ1 (KBr) 3435 (NH), 3061 (CH),
1672 (CO), 1609, 1564 (NH bend), 1494, 1409 (CN stretch), 1024
(SO); dH (300 MHz, CDCl3) 4.29 (2H, s, SCH2), 7.04–7.50 (10H, m,
ArH), 7.81 [1H, s, C(3)HCl@], 10.08 (1H, br s, NH); dC (75.5 MHz,
CDCl3) 58.5 (CH2, SCH2), 120.7, 124.8 (CH, aromatic CH), 127.7 [C,
C(2)S or aromatic C], 128.8, 128.9, 129.1, 130.5 (CH, aromatic
CH), 135.1, 137.1 [C, C(2)S or aromatic C], 137.2 [CH, C(3)HCl@],
158.4 (C, CO); Exact mass calcd for C16H14NO2SClNa [M+Na]+,
342.0331. Found 342.0331; 320 ([M+H]+, 100%), 91 (C7H7þ, 66%);
isotopic Cl pattern observed; 320, 322 (3:1 35Cl/37Cl).
4.34. N-40-Fluorophenyl-Z-3-chloro-2-(benzylsulfinyl)-2-
butenamide 2ag
4.31. Z-3-Chloro-2-(benzylsulfinyl)propenamide 2ad
The title compound was synthesised following the procedure
outlined for sulfoxide 2a using N-40-fluorophenyl-Z-3-chloro-2-
(benzylthio)-2-butenamide 1ag (1.35 g, 4.0 mmol) in acetone
(110 mL) and OxoneÒ (4.95 g, 8.0 mmol) in water (25 mL). Following
stirring at room temperature for 2 h, the crude sulfoxide 2ag was ob-
tained as a yellow oil. This was then purified by column chromatog-
raphy on silica gel using hexane/ethyl acetate (98:2)as eluentto give
the pure product (1.17 g, 83%) as a white solid, mp 152–153 °C;
(C17H15NClFO2S requires C, 58.04; H, 4.30; N, 3.98; S, 9.11; Cl,
10.08; F, 5.40. Found: C, 57.83; H, 4.26; N, 3.71; S, 9.53; Cl, 10.50;
The title compound was synthesised according to the proce-
dure outlined for 2a using Z-3-chloro-2-(benzylthio)propenamide
1ad (0.24 g, 1.1 mmol) in acetone (20 mL) and OxoneÒ (1.29 g,
2.1 mmol) in water (5 mL), to give the crude sulfoxide as an off-
white solid. Following purification by column chromatography
on silica gel using hexane/ethyl acetate as eluent (gradient elution
5–40% ethyl acetate), the pure sulfoxide 2ad (0.12 g, 46%) was iso-
lated as a white solid, mp 115–117 °C; (C10H10NO2SCl requires C,
49.28; H, 4.14; Cl, 14.55; N, 5.75; S, 13.16. Found: C, 49.33; H,
4.15; Cl, 14.99; N, 5.75; S, 12.94.);
m
max/cmꢀ1 (KBr) 3433 (NH),
F, 5.40.); m
max/cmꢀ1 (KBr) 3251 (NH), 3062 (CH), 1671 (CO), 1612
1646 (CO), 1026 (SO); dH (300 MHz, CDCl3) 4.22 (1H, A of ABq, J
12.8, one of SCH2), 4.31 (1H, B of ABq, J 12.8, one of SCH2), 5.65
(1H, br s, one of NH2), 7.17–7.48 (5H, m, ArH), 7.73 [1H, s,
C(3)HCl@], 8.19 (1H, br s, one of NH2); dC (75.5 MHz, CDCl3)
58.6 (CH2, SCH2), 128.1 [C, aromatic C or C(2)S], 128.9, 129.0,
130.6 (CH, aromatic CH), 135.8 [C, aromatic C or C(2)S], 137.9
(NH bend), 1514, 1407 (CN stretch), 1034 (SO); dH (300 MHz, CDCl3)
2.59 (3H, s, CH3CCl@), 4.18 (1H, A of ABq, JAB 13.4, one of SCH2), 4.26
(1H, B of ABq, JAB 13.4, one of SCH2), 7.00 [2H, overlapping dd (ap-
pears as a triplet), J 8.5, 8.5, C(30)H], 7.26–7.59 (7H, m, ArH), 9.86
(1H, br s, NH); dC (75.5 MHz, CDCl3) 27.2 (CH3, CH3CCl@), 58.7
(CH2, SCH2), 116.0 [CH, d, 2JCF 22, aromatic CH, ArC(30)], 122.5 [CH,
3
[CH, C(3)HCl@], 161.8 (C, CO); m/z (ESI) 244 ([M+H]+, 100%), 91
d, JCF 8, aromatic CH, ArC(20)], 129.2, 129.3, 130.9, (3 ꢃ CH, 3 ꢃ
þ
(C7H7
,
62%); isotopic Cl pattern observed; 244, 246 (3:1
aromatic CH), 128.6, 131.3, 133.9, 152.5 [4 ꢃ C, aromatic C, C(2)S
35Cl/37Cl).
or C(3)Cl], 159.7 [C, d, JCF 245, aromatic C, ArC(40)], 160.4 (C, CO);
1
m/z (ESI) 352 ([M+H]+, 100%), 91 (C7H7þ, 18%).
4.32. N,N-Dimethyl-E-3-chloro-2-(benzylsulfinyl)propenamide
2ae
4.35. N-40-Fluorophenyl-E-3-chloro-2-(benzylsulfinyl)-2-
butenamide 2ah
The title compound was prepared following the procedure
described for 2a using N,N-dimethyl-E-3-chloro-2-(benzylthio)-
propenamide 1ae (1.00 g, 3.9 mmol) in acetone (100 mL) and
OxoneÒ (4.81 g, 7.8 mmol) in water (30 mL) for 2 h to give the
crude sulfoxide 2ae as a white solid. Following purification by col-
umn chromatography on silica gel using hexane/ethyl acetate as
eluent (gradient elution 0–20% ethyl acetate), the pure sulfoxide
2ae (0.80 g, 75%) was isolated as a white solid, mp 111–113 °C;
The title compound was synthesised following the procedure
outlined for sulfoxide 2a using N-40-fluorophenyl-E-3-chloro-2-
(benzylthio)-2-butenamide 1ah (0.42 g, 1.2 mmol) in acetone
(40 mL) and OxoneÒ (1.53 g, 2.5 mmol) in water (10 mL). Following
stirring at room temperature for 2 h, the crude sulfoxide 2ah was
obtained as a yellow solid. This was then purified by column chro-
matography on silica gel using hexane/ethyl acetate as eluent (gra-
dient elution 20–40% EtOAc) to give the pure product (0.22 g, 53%)
m
max/cmꢀ1 (KBr) 3069 (CH stretch), 1643 (CO), 1495, 1403 (CN
stretch), 1078 (SO); dH (300 MHz, CDCl3) 3.10 [3H, s, one of
N(CH3)2], 3.13 [3H, s, one of N(CH3)2], 4.36 (1H, A of ABq, J 13.9,
one of SOCH2), 4.74 (1H, B of ABq, J 13.9, one of SOCH2), 6.82
[1H, s, C(3)HCl@], 7.35–7.42 (3H, m, ArH), 7.47–7.55 (2H, m,
ArH); dC (75.5 MHz, CDCl3) 35.3 [CH3, one of N(CH3)2], 37.9 [CH3,
one of N(CH3)2], 61.4 (CH2, SCH2), 127.9 [C, aromatic C or C(2)S],
129.1, 129.5, 131.8 (CH, aromatic CH), 135.2 [CH, C(3)HCl@],
137.2 [C, aromatic C or C(2)S], 161.4 (C, CO).
as a colourless oil; m
max/cmꢀ1 (NaCl) 3250 (NH), 3068 (CH), 1672
(CO), 1618 (NH bend), 1508, 1408 (CN stretch), 1034 (SO); dH
(300 MHz, CDCl3) 1.93 (3H, s, CH3CCl@), 4.30 (1H, A of ABq, JAB
12.2, one of SCH2), 4.41 (1H, B of ABq, JAB 12.2, one of SCH2), 7.05
[2H, overlapping dd (appears as a triplet), J 9.0, 9.0, C(30)H], 7.34–
7.39 (5H, m, ArH), 7.60–7.64 (2H, m, ArH), 8.76 (1H, br s, NH); dC
(75.5 MHz, CDCl3) 23.7 (CH3, CH3CCl@), 58.8 (CH2, SCH2), 115.6
2
3
[CH, d, JCF 23, aromatic CH, ArC(30)], 122.0 [CH, d, JCF 8, aromatic

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1269
CH, ArC(20)], 128.8, 129.0, 130.9, (3 ꢃ CH, 3 ꢃ aromatic CH), 128.0,
132.8, 133.4, 145.7 [4 ꢃ C, aromatic C, C(2)S or C(3)Cl], 159.1 (C,
(0.20 g, 0.6 mmol) in dichloromethane (15 mL) and m-CPBA
(0.32 g of 65% pure material, 1.2 mmol) in dichloromethane
(5 mL). Following stirring at room temperature for 24 h, morpho-
line (0.21 mL, 2.4 mmol) was added and TLC analysis showed that
the reaction was complete after 10 min and the crude sulfone 4d
was obtained as an off-white solid. Following purification by col-
umn chromatography on silica gel using hexane/ethyl acetate as
eluent (gradient elution 5–40% ethyl acetate), the sulfone 4d
(0.10 g, 43%) was isolated as a white solid, mp 179–182 °C;
(C20H21FN2O4S requires C, 59.39; H, 5.23; N, 6.93; S, 7.93; F, 4.70.
1
CO), 159.7 [C, d, JCF 245, aromatic C, ArC(40)],; Exact mass calcd
for
C
17H16NO2SClF [M+H]+, 352.0574. Found 352.0584; 352
([M+H]+, 100%), 91 (C7H7þ, 4%).
4.36. N-Benzyl-3-morpholino-2-(benzylsulfonyl)propenamide
4c
A solution of m-CPBA (0.51 g of 65% pure material, 1.9 mmol) in
dichloromethane (5 mL) was added dropwise to a stirred solution
of the sulfoxide N-benzyl-Z-3-chloro-2-(benzylsulfinyl)propen-
amide 2c (0.32 g, 1.0 mmol) in dichloromethane (15 mL). Following
stirring at room temperature for 24 h, TLC analysis showed that all
the sulfoxide starting material had been consumed and morpholine
(0.33 mL, 3.8 mmol) was added directly to the reaction mixture. The
reaction progress was monitored by TLC, which indicated that the
reaction was complete after 5 min and the work-up involved wash-
ing with water (3 ꢃ 10 mL) and brine (10 mL). Following drying
using anhydrous magnesium sulfate and evaporation of the solvent
at reduced pressure, the crude sulfone 4c was obtained as a brown
oil. This was purified by column chromatography on silica gel using
hexane/ethyl acetate as eluent (gradient elution 20–50% ethyl ace-
tate) and the pure sulfone 4c (0.16 g, 42%) was isolated as a white so-
lid, mp 177–180 °C; (C21H24N2O4S requires C, 62.98; H, 6.04; N, 6.99;
Found: C, 59.45; H, 5.38; N, 6.57; S, 7.56; F, 4.69.);
m
max/cmꢀ1
(KBr) 3335 (NH), 2929 (CH), 1652 (CO), 1615, 1534 (NH bend),
1508, 1407 (CN stretch), 1362 (asymmetric SO2 stretch), 1114
(symmetric SO2 stretch); dH (300 MHz, CDCl3) 3.22–3.44 [4H, m,
NC(20)H2 and NC(60)H2], 3.54–3.76 [4H, m, OC(30)H2 and OC(50)H2],
4.37 (2H, s, SCH2), 6.85 [1H, s, C(3)HN@], 6.95 [2H, overlapping dd
(appears as a triplet), J 8.7, 8.7, ArC(30)H], 7.20–7.55 (7H, m, ArH),
9.22 (1H, br s, NH); dC (75.5 MHz, CDCl3) 52.4 [CH2, br, NC(20)H2
and NC(60)H2], 62.5 (CH2, SCH2), 66.8 [CH2, OC(30)H2 and OC(50)H2],
2
98.1 [C, C(2)S], 115.8 [CH, d, JCF 22, aromatic CH, ArC(30)], 121.7
3
[CH, d, JCF 8, aromatic CH, ArC(20)], 128.9, 129.0, (CH, aromatic
CH), 129.5 (C, aromatic C), 131.5 (CH, aromatic CH), 134.3 (C, aro-
matic C), 153.5 [CH, C(3)HN@], 158.0/161.3 [C, d, 1JCF 243, aromatic
C, ArC(40)], 161.1 (C, CO); m/z (ESI) 427 ([M+Na]+, 100%), 91 (C7H7
,
þ
99%).
S, 8.01. Found: C, 62.67; H, 5.96; N, 6.72; S, 8.20.); m
max/cmꢀ1 (KBr)
3378 (NH), 3028 (CH), 2968 (CH), 1640 (CO), 1595 (NH bend),
1508, 1439 (CN stretch), 1352 (asymmetric SO2 stretch), 1120 (sym-
metric SO2 stretch); dH (300 MHz, CDCl3) 3.29–3.36 [4H, m, NC(20)H2
and NC(60)H2], 3.64–3.70 [4H, m, OC(30)H2 and OC(50)H2], 4.14 (2H, s,
SCH2), 4.44 (2H, d, J 6.0, CH2NH), 6.83 [1H, s, C(3)HN@], 7.22–7.37
(10H, m, ArH), 7.59 (1H, br s, NH); dC (75.5 MHz, CDCl3) 42.7 (CH2,
CH2NH), 51.1 [CH2, br, NC(20)H2 and NC(60)H2], 60.2 (CH2, SCH2),
65.5 [CH2, OC(30)H2 and OC(50)H2], 96.8 [C, C(2)S], 126.5, 126.8,
127.4, 127.5, 127.7, 130.1 (CH, aromatic CH), 137.3 (C, aromatic C),
151.5 [CH, C(3)HN@], 161.3 (C, CO); m/z (ESI) 401 ([M+H]+, 100%).
4.39. N-n-Butyl-3-morpholino-2-(benzylsulfonyl)propenamide
4e
This was synthesised as described for 4c using N-n-butyl-Z-3-
chloro-2-(benzylsulfinyl)propenamide 2e (0.10 g, 0.3 mmol) in
dichloromethane (15 mL) and m-CPBA (0.18 g of 65% pure mate-
rial, 0.7 mmol) in dichloromethane (5 mL). Morpholine (0.12 mL,
1.3 mmol) was added to the reaction mixture after stirring at room
temperature for 24 h. TLC analysis indicated that the reaction was
complete after 10 min and following the work-up, the crude sul-
fone was obtained as a yellow solid. Following purification by col-
umn chromatography on silica gel using hexane/ethyl acetate
(60:40) as eluent, the sulfone 4e (0.08 g, 63%) was isolated as a
4.37. N-Benzyl-3-morpholino-2-(benzylsulfonyl)propenamide
4a
white solid, mp 116–119 °C;
m
max/cmꢀ1 (KBr) 3347 (NH), 2922
This was prepared following the procedure outlined for 4c using
m-CPBA (0.51 g of 65% pure material, 1.9 mmol) in dichlorometh-
ane (5 mL) and N-40-methylphenyl-Z-3-chloro-2-(phenylsulfi-
nyl)propenamide (0.32 g, 1.0 mmol) in dichloromethane (15 mL)
to give the crude sulfone as a brown oil. This was purified by col-
umn chromatography on silica gel using hexane/ethyl acetate as
eluent (gradient elution 20–50% ethyl acetate) and the pure sulfone
(CH), 1635 (CO), 1594 (NH bend), 1514, 1436 (CN stretch), 1351
(asymmetric SO2 stretch), 1120 (symmetric SO2 stretch); dH
(300 MHz, CDCl3) 0.94 [3H, t, J 7.3, C(40)H3], 1.32–1.46 [4H, m,
C(30)H2 and C(20)H2], 3.24 (2H, m, CH2NH), 3.28–3.37 [4H, m,
NC(200)H2 and NC(600)H2], 3.65–3.71 [4H, m, OC(300)H2 and
OC(500)H2], 4.24 (2H, s, SCH2), 6.80 [1H, s, C(3)HN@], 7.18 (1H, br
s, NH), 7.21–7.38 (5H, m, ArH); dC (75.5 MHz, CDCl3) 14.2 [CH3,
C(40)H3], 20.6 [CH2, C(30)H2], 32.0 [CH2, C(20)H2], 39.9 (CH2, CH2NH),
52.5 [CH2, br, NC(200)H2 and NC(600)H2], 61.6 (CH2, SCH2), 66.9 [CH2,
OC(300)H2 and OC(500)H2], 98.4 [C, C(2)S], 128.8, 128.9 (CH, aromatic
CH), 129.6 (C, aromatic C), 131.6 (CH, aromatic CH), 152.6 [CH,
C(3)HN@], 162.8 (C, CO); Exact mass calcd for C18H26N2O4SNa
[M+Na]+, 389.1511. Found 389.1506; 389 ([M+Na]+, 100%), 91
(C7H7þ, 89%).
(0.16 g, 42%) was isolated as a white solid; m
max/cmꢀ1 (KBr) 3346
(NH), 2964 (CH), 2920 (CH), 1661 (CO), 1597 (NH bend), 1515,
1445 (CN stretch), 1354 (asymmetric SO2 stretch), 1136 (symmetric
SO2 stretch); dH (300 MHz, CDCl3) 2.29 (3H, s, Ar-CH3), 3.46–3.56
[4H, m, NC(200)H2 and NC(600)H2], 3.71–3.81 [4H, m, OC(300)H2 and
OC(500)H2], 7.04–7.13 (2H, m, ArH), 7.22–7.30 (2H, m, ArH), 7.37–
7.54 (3H, m, ArH), 7.65 [1H, s, C(3)HN@], 7.78–7.85 (2H, m, ArH),
8.98 (1H, br s, NH); dC (75.5 MHz, CDCl3) 20.9 (CH3, Ar-CH3), 52.4
[CH2, br, NC(200)H2 and NC(600)H2], 66.4 [CH2, OC(300)H2 and
OC(500)H2], 101.6 [C, C(2)S], 120.3, 126.6, 129.1, 129.5, 132.6 (CH,
aromatic CH), 134.0, 135.0, 142.1 (C, aromatic C), 151.7 [CH,
C(3)HN@], 159.9 (C, CO); Exact mass calcd for C20H23N2O4S
[M+H]+, 387.1379. Found 387.1384; 387 ([M+H]+, 100%).
4.40. N-40-Methylphenyl-3-morpholino-2-
(benzylsulfonyl)propenamide 4f
This was prepared following the procedure outlined for 4c using
N-40-methylphenyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2f
(0.20 g, 0.6 mmol) in dichloromethane (15 mL) and m-CPBA
(0.32 g of 65% pure material, 1.2 mmol) in dichloromethane
(5 mL). Following stirring at room temperature for 24 h, morpho-
line (0.21 mL, 2.4 mmol) was added to the reaction mixture and
TLC analysis showed that the reaction was complete 5 min after
the addition. The crude sulfone was obtained as a brown solid after
4.38. N-40-Fluorophenyl-3-morpholino-2-
(benzylsulfonyl)propenamide 4d
This was prepared following the procedure outlined for 4c using
N-40-fluorophenyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2d

1270
M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
the work-up and this was then purified by column chromatogra-
phy on silica gel using hexane/ethyl acetate as eluent (gradient elu-
tion 20–50% ethyl acetate) to give the pure sulfone 4f (0.14 g, 56%)
3303 (NH), 2960 (CH), 1655 (CO), 1607, 1531 (NH bend), 1499,
1407 (CN stretch), 1314 (asymmetric SO2 stretch), 1111 (symmet-
ric SO2 stretch); dH (300 MHz, CDCl3) 3.23–3.45 [4H, m, NC(20)H2
and NC(60)H2]. 3.55–3.94 [4H, m, OC(30)H2 and OC(50)H2], 4.31
(2H, s, SCH2), 6.94 [1H, s, C(3)HN@], 7.05–7.64 (10H, m, ArH),
9.10 (1H, br s, NH); dC (75.5 MHz, CDCl3) 52.7 [CH2, br, NC(20)H2
and NC(60)H2], 62.2 (CH2, SCH2), 66.9 [CH2, OC(30)H2 and OC(50)H2],
98.4 [C, C(2)S], 120.2, 124.7, 128.5, 128.9 (CH, aromatic CH), 129.2
(C, aromatic C), 129.3, 131.5 (CH, aromatic CH), 138.3 (C, aromatic
C), 153.7 [CH, C(3)HN@], 160.8 (C, CO). Exact mass calcd for
as a white solid, mp 154–156 °C; m
max/cmꢀ1 (KBr) 3337 (NH), 3032
(CH), 1651 (CO), 1613, 1526, 1406, 1359 (asymmetric SO2 stretch),
1120 (symmetric SO2 stretch); dH (300 MHz, CDCl3) 2.33 (3H, s, Ar-
CH3), 3.32–3.44 [4H, m, NC(200)H2 and NC(600)H2], 3.63–3.75 [4H, m,
OC(300)H2 and OC(500)H2], 4.30 (2H, s, SCH2), 6.88 [1H, s, C(3)HN@],
7.14 (2H, m, ArH), 7.24–7.50 (7H, m, ArH), 9.02 (1H, br s, NH); dC
(75.5 MHz, CDCl3) 20.9 (CH3, Ar-CH3), 52.6 [CH2, br, NC(200)H2 and
NC(600)H2], 61.7 (CH2, SCH2), 66.5 [CH2, OC(300)H2 and OC(500)H2],
98.0 [CH, C(2)S], 119.9, 128.5, 128.6 (CH, aromatic CH), 129.1 (C,
aromatic C), 129.4, 131.1 (CH, aromatic CH), 134.0, 135.3 (C, aro-
matic C), 153.1 [CH, C(3)HN@], 160.3 (C, CO); Exact mass calcd
for C21H24N2O4SNa [M+Na]+, 423.1354. Found 423.1346; 401
([M+H]+, 100%), 91 (C7H7þ, 18%).
C
20H23N2O4S [M+H]+, 387.1379. Found 387.1379; 387.2 ([M+H]+,
100%).
4.43. 3-Morpholino-2-(benzylsulfonyl)propenamide 4i
This was synthesised according to the procedure outlined for 4c
using Z-3-chloro-2-(benzylsulfinyl)propenamide 2i (0.08 g,
0.4 mmol) in dichloromethane (10 mL) and m-CPBA (0.18 g of
65% pure material, 0.7 mmol) in dichloromethane (5 mL). Follow-
ing stirring at room temperature for 24 h, TLC analysis indicated
that there was some starting material still present and so a further
2 equiv of m-CPBA (0.18 g of 65% pure material, 0.7 mmol) was
added to the reaction mixture. After stirring for a further 24 h all
traces of the starting material had disappeared and morpholine
(0.12 mL, 1.4 mmol) was added. TLC analysis indicated that this
reaction was complete after 5 min and following the work-up
the crude sulfone was obtained as an orange solid. This was then
purified by column chromatography on silica gel using hexane/
ethyl acetate as eluent (gradient elution 20–100% ethyl acetate)
to give the pure sulfone 4i (0.04 g, 37%) as a white solid, mp
4.41. N-Methyl-3-morpholino-2-(benzylsulfonyl)propenamide
4g
This was synthesised according to the procedure outlined for 4c
using N-methyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2g
(0.21 g, 0.80 mmol) in dichloromethane (10 mL) and m-CPBA
(0.43 g of 95% pure material, 2.4 mmol) in dichloromethane
(5 mL). Morpholine (0.42 mL, 4.8 mmol) was added to the reaction
solution following stirring at room temperature for 48 h. TLC anal-
ysis indicated that the reaction was complete after 5 min and the
crude sulfone 4g was obtained as an orange oil after the work-
up. This was then purified by column chromatography on silica
gel using hexane/ethyl acetate as eluent (gradient elution 40–60%
ethyl acetate) to give the pure sulfone 4g (0.10 g, 38%) as a white
solid, mp 130–132 °C; (C15H20N2O4S requires C, 55.54; H, 6.21; N,
178–179 °C; m
max/cmꢀ1 (KBr) 3440 (NH), 3168 (NH), 2981 (CH),
1646 (CO), 1579 (NH bend), 1495, 1410 (CN stretch), 1324 (asym-
metric SO2 stretch), 1116 (symmetric SO2 stretch); dH (300 MHz,
CDCl3) 3.21–3.46 [4H, m, NC(20)H2 and NC(60)H2], 3.55–3.80 [4H,
m, OC(30)H2 and OC(50)H2], 4.32 (2H, s, SCH2), 5.59 (1H, br s, one
of NH2), 6.83 [1H, s, C(3)HN@], 7.19 (1H, br s, one of NH2), 7.26–
7.46 (5H, m, ArH); dC (75.5 MHz, CDCl3) 53.0 [CH2, br signal,
NC(20)H2 and NC(60)H2], 61.3 (CH2, SCH2), 61.9 [CH2, OC(30)H2
and OC(50)H2], 97.2 [C, C(2)S], 128.9, 129.0 (CH, aromatic CH),
129.6 (C, aromatic C), 131.5 (CH, aromatic CH), 154.4 [CH,
C(3)HN@], 164.5 (C, CO); Exact mass calcd for C14H19N2O4S
[M+H]+, 311.1066. Found 311.1070; 311 ([M+H]+, 50%), 91
(C7H7þ, 26%).
8.64; S, 9.88. Found: C, 55.40; H, 6.25; N, 8.64; S, 9.75.); mmax
/
cmꢀ1 (film) 3323 (NH), 2996 (CH), 1652 (CO), 1548 (NH bend),
1495, 1410 (CN stretch), 1310 (asymmetric SO2 stretch), 1110
(symmetric SO2 stretch); dH (300 MHz, CDCl3) 2.77 (3H, d, J 4.8,
CH3NH), 3.30-3.42 [4H, m, NC(20)H2 and NC(60)H2], 3.64–3.73
[4H, m, OC(30)H2 and OC(50)H2], 4.25 (2H, s, SCH2), 6.82 [1H, s,
C(3)HN@], 7.14 (1H, br s, NH), 7.31–7.39 (5H, m, ArH); dC
(75.5 MHz, CDCl3) 26.9 (CH3, CH3NH), 52.4 [CH2, br, NC(20)H2 and
NC(60)H2], 61.7 (CH2, SCH2), 66.9 [CH2, OC(30)H2 and OC(50)H2],
98.3 [C, C(2)S], 128.9, 129.0 (CH, aromatic CH), 129.6 (C, aromatic
C), 131.6 (CH, aromatic CH), 152.8 [CH, C(3)HN@], 163.5 (C, CO);
Exact mass calcd for
C
15H21N2O4S [M+H]+, 325.1222. Found
325.1213; 325.3 ([M+H]+, 100%).
4.44. N-Benzyl-3-morpholino-2-(butylsulfonyl)propenamide 4j
4.42. N-Phenyl-3-morpholino-2-(benzylsulfonyl)propenamide
4h
This was prepared following the procedure outlined for 4c using
N-benzyl-Z-3-chloro-2-(butylsulfinyl)propenamide 2j (0.25 g,
0.85 mmol) in dichloromethane (15 mL) and m-CPBA (0.90 g of
65% pure material, 3.38 mmol) in dichloromethane (5 mL). Follow-
ing stirring at room temperature for 24 h, morpholine (0.60 mL,
6.80 mmol) was added and TLC analysis showed that the reaction
was complete after 10 min and the crude sulfone was obtained
as an orange oil. Following purification by column chromatography
on silica gel using hexane/ethyl acetate as eluent (gradient elution
10–60% ethyl acetate), the sulfone 4j (0.10 g, 38%) was isolated as a
white solid, mp 139–141 °C; (C18H26N2O4S requires C, 58.99; H,
7.15; N, 7.64; S, 8.75. Found: C, 58.72; H, 7.07; N, 7.59; S, 8.49.);
This was prepared following the procedure described for 4c
using N-phenyl-Z-3-chloro-2-(benzylsulfinyl)propenamide 2h
(0.30 g, 0.9 mmol) in dichloromethane (20 mL) and m-CPBA
(0.50 g of 65% pure material, 1.9 mmol) in dichloromethane
(15 mL). Following stirring at room temperature for 24 h, TLC anal-
ysis indicated that there was some starting material still present
and so a further 2 equiv of m-CPBA (0.50 g of 65% pure material,
1.9 mmol) was added to the reaction mixture. After stirring for a
further 24 h all traces of the starting material had disappeared
and morpholine (0.50 mL, 5.6 mmol) was added. TLC analysis indi-
cated that this reaction was complete after 5 min and following the
work-up the crude sulfone was obtained as an orange solid. This
was then purified by column chromatography on silica gel using
hexane/ethyl acetate as eluent (gradient elution 20–60% ethyl ace-
tate) to give the pure sulfone 4h (0.19 g, 56%) as a white solid, mp
129–132 °C; (C20H22N2O4S requires C, 62.16; H, 5.74; N, 7.25; S,
m
max/cmꢀ1 (KBr) 3379 (NH), 2971 (CH), 1642 (CO), 1593 (NH bend),
1505, 1351 (asymmetric SO2 stretch), 1119 (symmetric SO2
stretch); dH (300 MHz, CDCl3) 0.86 [3H, t, J 7.4, C(40)H3], 1.24–
1.34 [2H, m, C(30)H2], 1.49–1.69 [2H, m, C(20)H2], 2.85–2.90 (2H,
m, SCH2), 3.44–3.47 [4H, m, NC(20)H2 and NC(60)H2], 3.73–3.76
[4H, m, OC(30)H2 and OC(50)H2], 4.48 (2H, d, J 6.1, CH2NH), 7.22–
7.55 [6H, m, ArH and C(3)HN@], 7.62 (1H, br s, NH); dC
(75.5 MHz, CDCl3) 13.9 [CH3, C(40)H3], 21.8 [CH2, C(30)H2], 25.3
8.30. Found: C, 62.23; H, 5.76; N, 7.08; S, 7.98.); m
max/cmꢀ1 (KBr)

M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
1271
[CH2, C(20)H2], 44.1 (CH2, CH2NH), 52.5 [CH2, br, NC(20)H2 and
NC(60)H2], 55.0 (CH2, SCH2), 66.8 [CH2, OC(30)H2 and OC(50)H2],
99.7 [C, C(2)S], 127.9, 128.3, 129.1 (3 ꢃ CH, 3 ꢃ aromatic CH),
138.6 (C, aromatic C), 151.9 [CH, C(3)HN@], 162.8 (C, CO); m/z
(ESI) 367 ([M+H]+, 100%).
dichloroethane (Aldrich reagent grade, 3 mL) in a round-bot-
tomed flask under a nitrogen atmosphere. The reaction solution
was cooled to ꢀ20 °C by careful addition of dry ice to an acetone
bath. Cumene hydroperoxide (0.12 mL, 0.66 mmol) was added be-
fore the b-chloroacrylamide 1a (100 mg, 0.33 mmol) was added
as a solution in 1,2-dichloroethane (1 mL). The reaction solution
was maintained at ꢀ20 °C for 1 h before it was transferred to
the freezer for 18 h when it was washed with a 5% aqueous solu-
tion of sodium sulfite (3 ꢃ 5 mL), water (10 mL) and brine
(10 mL), dried and concentrated at reduced pressure to give the
crude product mixture. 1H NMR spectroscopy (60 MHz) of this
material showed no conversion of the b-chloroacrylamide 1a to
the sulfoxide 2a.
4.45. N-40-Methylphenyl-3-morpholino-2-
(butylsulfonyl)propenamide 4k
This was prepared following the procedure outlined for 4c using
N-40-methylphenyl-Z-3-chloro-2-(butylsulfinyl)propenamide 2k
(0.23 g, 0.75 mmol) in dichloromethane (15 mL) and m-CPBA
(0.68 g of 65% pure material, 3.01 mmol) in dichloromethane
(5 mL). Following stirring at room temperature for 24 h, morpho-
line (0.53 mL, 6.02 mmol) was added to the reaction mixture and
TLC analysis showed that the reaction was complete 5 min after
the addition. The crude sulfone was obtained as an orange oil after
the work-up and this was then purified by column chromatogra-
phy on silica gel using hexane/ethyl acetate as eluent (gradient elu-
tion 10–40% ethyl acetate) to give the pure sulfone 4k (0.11 g, 45%)
4.48. Attempted asymmetric oxidation of 1a to 2a: Modena
procedure, toluene as solvent
Freshly distilled titanium isopropoxide (0.10 mL, 0.33 mmol)
was added to a solution of (+)-DET (0.22 mL, 1.32 mmol) in
freshly distilled toluene (3 mL) in a round-bottomed flask under
a nitrogen atmosphere. The reaction solution was cooled to
ꢀ20 °C by careful addition of dry ice to an acetone bath. Cumene
hydroperoxide (0.12 mL, 0.66 mmol) was added before the
b-chloroacrylamide 1a (100 mg, 0.33 mmol) was added as a solu-
tion in toluene (1 mL). The reaction solution was maintained at
ꢀ20 °C for 1 h before it was transferred to the freezer for 18 h
when it was washed with a 5% aqueous solution of sodium
sulfite (3 ꢃ 5 mL), water (10 mL) and brine (10 mL), dried and
concentrated at reduced pressure to give the crude product
mixture. 1H NMR spectroscopy (60 MHz) of this material showed
no conversion of the b-chloroacrylamide 1a to the sulfoxide
2a.
as a pale orange oil; m
max/cmꢀ1 (NaCl) 3295 (NH), 2963 (CH), 1658
(CO), 1614, 1529, 1406, 1358 (asymmetric SO2 stretch), 1120 (sym-
metric SO2 stretch); dH (300 MHz, CDCl3) 0.88 [3H, t, J 7.1, C(40)H3],
1.33–1.49 [2H, m, C(30)H2], 1.67–1.82 [2H, m, C(20)H2], 2.32 (3H, s,
Ar-CH3), 3.08 (2H, t, J 8.1, SCH2), 3.43–3.57 [4H, m, NC(20)H2 and
NC(60)H2], 3.69–3.84 [4H, m, OC(30)H2 and OC(50)H2], 7.14 (2H, d,
J 8.4, ArH), 7.38 [1H, s, C(3)HN@], 7.42 (2H, d, J 8.4, ArH), 9.02
(1H, br s, NH); dC (75.5 MHz, CDCl3) 13.9 [CH3, C(40)H3], 21.3
(CH3, Ar-CH3), 21.9 [CH2, C(30)H2], 25.4 [CH2, C(20)H2], 52.7 [CH2,
br, NC(200)H2 and NC(600)H2], 55.4 (CH2, SCH2), 66.8 [CH2, OC(300)H2
and OC(500)H2], 100.0 [CH, C(2)S], 120.4, 129.9 (2 ꢃ CH, 2 ꢃ aro-
matic CH), 134.5, 135.6 (2 ꢃ C, 2 ꢃ aromatic C), 152.5 [CH,
C(3)HN@], 160.8 (C, CO).
4.49. Oxidations using in situ generation of oxaziridines
4.46. N-Phenyl-3-morpholino-2-(benzylsulfonyl)propenamide
4l
4.49.1. Attempted oxidation of N-40-methylphenyl-Z-3-chloro-
2-(phenylthio)propenamide 1a with (+)-[(7,7-dichlorocamphoryl)-
sulfonyl]imine 6b
This was prepared following the procedure described for 4c
using
N-phenyl-Z-3-chloro-2-(butylsulfinyl)propenamide
2l
The b-chloroacrylamide 1a (50 mg, 0.17 mmol) was treated
with (+)-[(7,7-dichlorocamphoryl)sulfonyl]imine 6b (46 mg,
0.17 mmol) and hydrogen peroxide (0.08 mL of 30% aqueous
solution, 0.66 mmol) in DCM (3 mL) as outlined by Page
et al.42 for 9 days at room temperature. Following work-up, 1H
NMR spectroscopy (270 MHz) showed that no oxidation had
occurred.
(0.30 g, 1.07 mmol) in dichloromethane (15 mL) and m-CPBA
(0.96 g of 65% pure material, 4.26 mmol) in dichloromethane
(5 mL). Following stirring at room temperature for 48 h, morpho-
line (0.75 mL, 8.56 mmol) was added. TLC analysis indicated that
this reaction was complete after 5 min and following the work-
up the crude sulfone was obtained as an orange solid. This was
then purified by column chromatography on silica gel using hex-
ane/ethyl acetate as eluent (gradient elution 10–40% ethyl acetate)
4.49.2. Attempted oxidation of N-40-fluorophenyl-Z-3-chloro-2-
(n-butylthio)propenamide 1j with (+)-[(7,7-dichlorocamphoryl)-
sulfonyl]imine 6b
The b-chloroacrylamide 1j (50 mg, 0.17 mmol) was treated with
(+)-[(7,7-dichlorocamphoryl)sulfonyl]imine 6b (49 mg, 0.17 mmol)
and hydrogen peroxide (0.09 mL of 30% aqueous solution,
0.70 mmol) in DCM (3 mL) as outlined by Page et al.42 for 9 days
at room temperature. Following work-up, 1H NMR spectroscopy
(270 MHz) showed that no oxidation had occurred.
to give the pure sulfone 4l (0.18 g, 54%) as a colourless oil; mmax
/
cmꢀ1 (NaCl) 3297 (NH), 2962 (CH), 1656 (CO), 1614, 1536, 1443,
1357 (asymmetric SO2 stretch), 1119 (symmetric SO2 stretch); dH
(300 MHz, CDCl3) 0.91 [3H, t, J 7.4, C(40)H3], 1.33–1.51 [2H, m,
C(30)H2], 1.64–1.83 [2H, m, C(20)H2], 3.03–3.18 (2H, m, SCH2),
3.41–3.59 [4H, m, NC(20)H2 and NC(60)H2], 3.66–3.86 [4H, m,
OC(30)H2 and OC(50)H2], 7.00–7.14 (1H, m, ArH), 7.22–7.43 [3H,
m, ArH and C(3)HN@], 7.45–7.63 (2H, m, ArH), 9.12 (1H, br s,
NH); dC (75.5 MHz, CDCl3) 14.0 [CH3, C(40)H3], 21.9 [CH2, C(30)H2],
25.4 [CH2, C(20)H2], 52.6 [CH2, br, NC(200)H2 and NC(600)H2], 55.6
(CH2, SCH2), 66.8 [CH2, OC(300)H2 and OC(500)H2], 100.0 [CH,
C(2)S], 120.2, 124.8, 129.4 (3 ꢃ CH, 3 ꢃ aromatic CH), 138.2, (C,
aromatic C), 152.4 [CH, C(3)HN@], 161.1 (C, CO).
4.50. Oxidations using pre-prepared oxaziridines
4.50.1. Attempted oxidation of N-40-methylphenyl-Z-3-chloro-
2-(phenylthio)propenamide 1a with (+)-(2R,8aS)-10-camphor-
ylsulfonyloxaziridine 6a
4.47. Attempted asymmetric oxidation of 1a to 2a: Modena
procedure, 1,2-dichloroethane as solvent
The b-chloroacrylamide 1a (100 mg, 0.33 mmol) was treated
with (+)-(2R,8aS)-10-camphorylsulfonyloxaziridine 6a (76 mg,
0.33 mmol) in CCl4 (1.60 mL) as outlined by Page et al.42 for 5 days
at room temperature. Following work-up, 1H NMR spectroscopy
(270 MHz) showed that no oxidation had occurred.
Freshly distilled titanium isopropoxide (0.10 mL, 0.33 mmol)
was added to a solution of (+)-DET (0.22 mL, 1.32 mmol) in 1,2-

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M. Kissane et al. / Tetrahedron: Asymmetry 19 (2008) 1256–1273
4.50.2. Attempted oxidation of N-40-methylphenyl-Z-3-chloro-
2-(n-butylthio)propenamide 1j with (+)-(2R,8aS)-10-
camphorylsulfonyloxaziridine 6a
The b-chloroacrylamide 1j (100 mg, 0.35 mmol) was treated
with (+)-(2R,8aS)-10-camphorylsulfonyloxaziridine 6a (80 mg,
0.35 mmol) in CCl4 (1.60 mL) as outlined by Page et al.42 for 5 days
at room temperature. Following work-up, 1H NMR spectroscopy
(270 MHz) showed that no oxidation had occurred.
plete recovery of the product (the total volume of DCM after wash-
ing was 100 mL). Aqueous NaOH (2 mL of 2 M solution) and brine
(1 mL) were added and the reaction mixture was stirred for 90 min.
At this point, more brine (50 mL) was added and the phases sepa-
rated. The organic layer was washed with brine (50 mL), dried and
evaporated at reduced pressure to give a mixture of the sulfoxide
2a [46% conversion by 1H NMR spectroscopy (60 MHz)], the b-chlo-
roacrylamide 1a (54%) and 2-phenylpropan-2-ol. The 2-phenylpro-
pan-2-ol was removed by bulb-to-bulb distillation at reduced
pressure (100 °C at 2 mm Hg). Following chromatography on silica
gel using ethyl acetate/hexane (gradient elution 5–30% ethyl ace-
tate) as eluent, the sulfoxide (ꢀ)-2a was recovered (62 mg, 30%)
as a colourless solid with 12% ee (enantiomeric excess determined
by HPLC on a chiral AS column using hexane/IPA 90:10 as mobile
phase detected at k 254 nm). The major enantiomer eluted before
the minor. Spectral characteristics were as reported previously.
4.50.3. Attempted oxidation of N-40-methylphenyl-Z-3-chloro-
2-(phenylthio)propenamide 1a with (+)-(2R,8aR*)-[(8,8-
dichlorocamphoryl)sulfonyl]oxaziridine 6b
The b-chloroacrylamide 1a (100 mg, 0.33 mmol) was treated
with (+)-(2R,8aR*)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine
OxDiCl (98 mg, 0.33 mmol) in CCl4 (2 mL) as outlined by Page
et al.42 for 5 days at room temperature. Following work-up, 1H
NMR spectroscopy (270 MHz) showed that no oxidation had
occurred.
4.52. General Bolm procedure—room temperature
4.50.4. Attempted oxidation of N-40-methylphenyl-Z-3-chloro-
2-(n-butylthio)propenamide 1j with (+)-(2R,8aR*)-[(8,8-
dichlorocamphoryl)sulfonyl]oxaziridine 6b
VO(acac)2 (2.6 mg, 0.01 mmol) was added to a round-bottomed
flask containing the ligand (0.015 mmol) in DCM (2 mL). The
resulting solution was stirred at room temperature for 5 min, then
a solution of the appropriate b-chloroacylamide (1 mmol) in DCM
(2.00 mL) was added. Then H2O2 (0.13 mL, 30%, 1.1 mmol) was
added to the resulting solution. The reaction mixture was then stir-
red at room temperature for a further 16 h. Water (5 mL) was
added and the phases separated; the organic layer was washed
with water (2 ꢃ 5 mL) and brine (5 mL), dried and concentrated
at reduced pressure to the crude product. Following chromatogra-
phy on silica gel using ethyl acetate and hexane (20:80), the sulf-
oxide was recovered. The enantiomeric excess was determined
by chiral HPLC.
The b-chloroacrylamide 1j (100 mg, 0.35 mmol) was treated
with (+)-(2R,8aR*)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine
6b (105 mg, 0.35 mmol) in CCl4 (2 mL) as outlined by Page
et al.42 for 5 days at room temperature. Following work-up, 1H
NMR spectroscopy (270 MHz) showed some oxidation had oc-
curred. Chromatography on silica gel using ethyl acetate/hexane
(10:90) as eluent gave the b-chloroacrylamide 1j (55 mg) and the
sulfoxide (ꢀ)-2j (22 mg, 21%) as a colourless solid with 29% ee.
Spectral characteristics were as reported previously.
4.50.5. Attempted asymmetric oxidation of 1a using
chloroperoxidase
4.53. General Bolm procedure—low temperature
The b-chloroacrylamide 1a (127 mg, 0.42 mmol) was treated
with hydrogen peroxide (0.07 mL of 30% aqueous solution,
0.63 mmol) in citrate buffer solution (45 mL, pH 4.8) in the pres-
ence of chloroperoxidase (250 units) as outlined by Colonna et al.
After 24 h, the reaction was worked up as described by Colonna
VO(acac)2 (2.6 mg, 0.01 mmol) was added to a round-bottomed
flask containing the appropriate ligand (0.015 mmol) in DCM
(2 mL). The resulting solution was stirred at room temperature
for 5 min, then a solution of the appropriate b-chloroacylamide
(1 mmol) in DCM (2.00 mL) was added. The temperature was then
lowered to the required value. H2O2 (0.13 mL, 30%, 1.1 mmol) was
added to the resulting solution at this temperature. The reaction
mixture was then stirred at this temperature for a further 16 h.
Water (5 mL) was added and the phases separated; the organic
layer was washed with water (2 ꢃ 5 mL) and brine (5 mL), dried
and concentrated at reduced pressure to give the crude product.
Following chromatography on silica gel using ethyl acetate and
hexane, the sulfoxide was recovered. The enantiomeric excess
was determined by chiral HPLC.
et al.39 1H NMR spectroscopy (60 MHz) of the reaction product
;
showed that no oxidation had occurred.
4.51. Asymmetric oxidation of 1a to (ꢀ)-2a using the Kagan
procedure
Freshly distilled titanium isopropoxide (bp 43–45 °C at
0.04 mm Hg) (0.10 mL, 0.33 mmol) was added to a solution of
(+)-diethyl tartrate (bp 100 °C at 0.1 mm Hg) (0.11 mL, 0.66 mmol)
in freshly double distilled (P2O5 and CaH2) DCM (2.75 mL) in a
round-bottomed flask under a nitrogen atmosphere. On addition
Note: a similar procedure was employed for reactions carried
out at elevated temperatures, except in these experiments the
H2O2 was added before heating commenced.
Details of the outcome of the Kagan and Bolm oxidations are
summarised in Tables 3–6.
of the Ti(OiPr)4, the reaction solution turned yellow. Water (6
lL,
0.33 mmol) was then added from a micro syringe as slowly as pos-
sible. On completion of the water addition, the reaction solution
was stirred at room temperature for 25 min. A solution of the b-
chloroacrylamide 1a (200 mg, 0.66 mmol) in freshly double dis-
tilled DCM (1 mL) was added and the reaction solution cooled to
ꢀ30 °C by careful addition of dry ice to an acetone bath. The reac-
tion solution was maintained at ꢀ30 °C for 40 min, then cumene
hydroperoxide (0.12 mL, 0.66 mmol) was added dropwise from a
micro syringe. The reaction solution was stirred at ꢀ30 °C for
5 min, then the reaction flask was transferred to a freezer at
ꢀ21 °C. After 18 h, the flask was removed from the freezer and
the contents were allowed to warm to room temperature. Water
(0.1 mL) was added and the solution stirred for 2 h, during which
time a gel formed. The gel was removed by filtration through a
bed of Celite, which was then washed with DCM to ensure com-
Acknowledgements
IRCSET, Enterprise Ireland, BioResearch Ireland, Forbairt and
University College Cork are gratefully acknowledged for funding
of this work. The authors wish to thank final year project students
M. Brennan and D. Foley for input on some aspects of this work.
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