Investigation of the reaction of α-thioamides, α-esters and α-nitriles with N-halosuccinimides

Article abstract of DOI:10.1016/j.tet.2008.05.026

Investigation of the reaction of α-thioamides, α-esters and α-nitriles with NBS and NCS is described. The?scope of this stereoselective oxidative transformation to the β-haloacrylamides, β-acrylates and β-acrylonitriles has been determined. A mechanistic

Full text of DOI:10.1016/j.tet.2008.05.026

Tetrahedron 64 (2008) 7639–7649
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Investigation of the reaction of
a-thioamides,
a-esters and
a-nitriles
with N-halosuccinimides
,
Marie Kissane a, Maureen Murphy a, Denis Lynch a, Alan Ford a, Anita R. Maguire b
*
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Investigation of the reaction of
The scope of this stereoselective oxidative transformation to the
b
a
-thioamides,
a
-esters and
a
-nitriles with NBS and NCS is described.
-haloacrylamides, -acrylates and
-acrylonitriles has been determined. A mechanistic rationale to explain the observed differences in
reactivity between the amide, ester and nitrile series is proposed.
Received 21 February 2008
Received in revised form 18 April 2008
Accepted 8 May 2008
b
b
Available online 11 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
dichloride 2 to the
b
-chloroacrylonitriles 4 and 5 did not occur
under these conditions. It was previously shown that treatment of
the analogous dichloride intermediates, formed during the reaction
We have recently reported1 the highly efficient and stereo-
selective transformation of
a
-thioamides to the corresponding
of
b
a-thioamides with NCS, with ZnCl2 gave the corresponding
a
-thio- -chloroacrylamide derivatives on treatment with NCS. As
b
-chloroacrylamides.1 The decomposition of the dichloride 2 was
the highly functionalized acrylamides resulting from this trans-
formation are potentially very useful synthetic intermediates, we
wished to explore the scope of this transformation and, in partic-
ular, to establish if similar reactivity could be achieved with the
analogous esters and nitriles, or by using thioamides with addi-
tional functional groups. In addition, it was decided to examine if
replacement of NCS by NBS was possible leading to formation of the
analogous bromides.
thus attempted using 3 equiv of ZnCl2 in CH2Cl2 under reflux
conditions. After heating for 18 h, the reaction was worked up to
give a mixture of the Z and E
of 6:1. Following chromatographic purification, a mixture of the
E and Z -chloroacrylonitriles was obtained as a yellow oil in the
b-chloroacrylonitriles 4 and 5 in a ratio
b
same ratio.
Table 1
Reaction of NCS with 1
X
EWG
RS
RS
EWG
EWG
RS
X
Cl
H
PhS
Cl
CN
H
PhS
H
CN
H
PhS
Cl
CN
H
PhS
CN
NCS
Toluene
+
+
X
EWG=Ester, Nitrile, Amide,
X=Cl, Br
β-chloroacrylonitrile
acrylonitrile
dichloride
4,5
1
2
3
2. Results and discussion
2.1. Nitrile derivatives
NCS (equiv)
Oil bath
Time (h)
2 (%)a
3 (%)a
4 and 5 (%)a
temperature (ꢀC)
2.1
1.95
2.1
2.1
2.1
130
130
130
130
160b
140
18
18
48
48
18
18
20
40
66
d
80
60
33
>90
Trace
9
d
d
The reaction of the
a
-thiopropionitrile2,3 1 with NCS was
<5
d
examined in detail (Table 1), with optimum conditions for the
formation of the dichloride 2 determined as 1.95 equiv of NCS in
toluene at 140 ꢀC for 18 h. In the amide series investigated earlier,
elimination of HCl occurred during the transformation leading di-
Trace
73
5
d
1.95
18c
85
After ZnCl2 decomposition
10
a
As determined by 1H NMR spectroscopy of the crude reaction product.
This reaction was conducted in xylene, complex mixture of unidentified
rectly to the b
-chloroacrylamides.1 In contrast, elimination from the
b
compounds formed.
c
Two signals were observed corresponding to the E and Z b-chloroacrylonitriles 4
* Corresponding author. Tel.: þ353 21 4901693.
E-mail address: a.maguire@ucc.ie (A.R. Maguire).
and 5. In the crude reaction mixture while 4 and 5 were present in limited amounts,
the ratio of Z/E was 1:1. After treating with ZnCl2, the ratio had changed to 6:1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.026

7640
M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
Table 2
Thus, the methodology for the transformation of the amides to
the corresponding -chloroacrylamides is also applicable to the
transformation of the -thionitrile to the corresponding E and Z
Reaction of 10a and 10c with NCS
b
O
O
a
b-
O
O
Cl
Cl
PhS
PhS
Cl
chloroacrylonitriles although in contrast to the amide series, use of
ZnCl2 is required to effect the final elimination in the nitrile series.
In general, the transformation of the nitriles was found to be less
robust than that of the amides with the outcome very sensitive to
minor changes in the reaction conditions.
PhS
PhS
+
R
R
+
R
R
R=OCH3 10a
R=NHTol 10c
14a
14c
15a
15c
11a
11c
Experimenta
R
14a (%) 15a (%) 11a (%) 14c (%) 15c (%) 11c (%)
2.2. Extension to the ester derivatives
A
B
A
B
OCH3
OCH3
NHTol
NHTol
70b
>90
d
d
d
Trace
2.2.1. Treatment of alkyl 2-(phenylthio)propanoates with NCS
50
d
50
33
d
The reaction of
determine if they could be transformed to the
While -chlorosulfides of esters have been employed in other
work,4 to the best of our knowledge, only one previous report of
sulfenyl- -chloroacrylates has appeared in the literature. A 1985
patent by Viehe et al.5 mentions the ethyl
-chloroacrylate 6b. In
the patent, the use of -thio- -halo- -unsaturated esters and
amides and -haloacrylonitriles for reaction with nucleophiles is
reported, although no experimental details are provided. In 1998,
Hoffman et al.6 reported the preparation of E and Z
-fluoro-
aminoacrylate derivatives 7 and 8 by condensation of methyl car-
a
-thioesters with NCS was investigated next to
66
b
-chloroacrylates.
a
Experiment A¼1.1 equiv NCS, rt, 18 h. Experiment B¼2.2 equiv NCS, rt, 18 h.
The isolated product consisted of 70% 14a and 30% 10a.
a
b
a
-
b
b
was that the
with just a trace of the acrylate seen by 1H NMR spectroscopy (Table
2). Evidently, the -chlorosulfide of the ester 14a is more stable
than that of the amide, with the loss of HCl from the -chlorosulfide
occurring much more readily when the amide functionality is
present.
a-thioester was converted to the a-chlorosulfide 14a
a
b
a,b
b
a
a
b
a-
bamate and the
b
-fluorinated
a
-oxo ester 9.
Further evidence for the increased stability of the ester de-
rivative was seen in the formation of the dichloride when 10a is
treated with 2.2 equiv of NCS in toluene under reflux conditions
(Scheme 1). In the amide series, the dichloride rapidly eliminates
O
O
MeO2CHN
Bn
CO2Et
F
MeO2CHN
F
CO2Et
Bn
PhS
Cl
OEt
Bn
OEt
HCl under these conditions to give the b
-chloroacrylamide.1 Fur-
F
O
thermore, extended storage of the dichloride 11a was possible
without apparent degradation.
6
7
8
9
The rationale for the increased ease of elimination in the amide
series relative to the ester and nitrile series is presumably due to
conformational properties; in the amides the intramolecular hy-
drogen bond holds the compound in a conformation in which loss
The esters 10a and 10b4 were treated with 2.1–2.2 equivalents of
NCS in toluene at 130 ꢀC for 18 h to form the corresponding
dichlorides 11a and 11b (Scheme 1).
Following our experience with the nitrile derivatives, it was
envisaged that Lewis acid catalysed decomposition of the dichlor-
of the chloride from the a-carbon is favoured through captodative
stabilisation7 of the resulting sulfur stabilised carbocation (Fig. 1).
In the ester derivative there is no restriction on the conformation
and presumably the chlorosulfide adopts a different conformation
from which the loss of chloride is less favoured. Another possible
contributor to this is that the increased electron withdrawing effect
of the ester compared to the amide destabilises a carbonium ion at
ides 11a and 11b would produce the
b-chloroacrylates 6a and 6b.
The decomposition of 11a and 11b to the corresponding
b-chloro-
acrylates 6a and 6b was then achieved by reaction with 3 equiv of
ZnCl2 in dichloromethane under reflux for 18 h (Scheme 1). The
formation of 6a and 6b was repeated on a number of occasions in
up to a 24 mmol scale, with the Z isomer of the
b
-chloroacrylates
the
a-carbon therefore stabilising the chlorosulfide and dichloride.
formed exclusively in each instance. Also, the dichlorides can be
carried forward with or without purification by chromatography,
with no effect on the isolated yields of 6a and 6b.
Cl
H
H
+
PhS
NR
O
PhS
NR
O
The
-thioester 10a with NCS in toluene. To this end, 1.1 equiv of NCS
was added to a solution of the -thioester 10a in toluene at room
temperature for 18 h. The isolated product consisted of 70%
chlorosulfide 14a and 30% unreacted -thioester 10a (Table 2).
Significantly, in the amide series under these conditions 50% of the
-chlorosulfide eliminated to form the acrylamide.1 This indicates
that the -chlorosulfide derivative is less prone to elimination of
a-chlorosulfide 14a was also prepared by treatment of the
Figure 1.
a
a
2.2.2. Treatment of methyl 2-(alkylthio)propanoates with NCS
Treatment of the ester 10d with the conditions outlined above
for 10a and 10b resulted in a 1:2 mixture of the dichloride 11d and
b-chloroacrylate 6d (Scheme 2). This was the first time that the
-chloroacrylate had formed to a substantial degree without the
a
-
a
the
b
a
a
need for Lewis acid catalysed decomposition of the dichloride.
Treatment of the crude reaction product with 3 equiv of ZnCl2 with
HCl in the ester series than in the amide series. Furthermore, when
2.2 equiv of NCS was used at room temperature for 18 h with the
a
-thioamide, the acrylamide and the dichloride were formed.1
respect to the remaining dichloride gave the
b-chloroacrylate in
51% yield following chromatographic purification. A trace amount
What was found with the ester under these conditions, however,
O
O
O
O
SPh
O
Cl
Cl
PhS
Cl
PhS
Cl
PhS
PhS
PhS
Cl
3 eq ZnCl2, CH2Cl2
2.1-2.2 eq NCS
toluene, Δ, 18-20h
OR
OR
OR
OR
OR
+
Δ, 16-18h
or
+
Cl
H
RT, 18h
R=Me
R=Et
10a
10b
11a 87%
11b 85%
6a 70%
6b 71%
12a
13a
Minor Products
Scheme 1.

M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
7641
of the bis sulfide 12d was also observed. As with the phenylthio
derivatives of the -chloroacrylates, no evidence for a second
-chloroacrylate was observed (Scheme 2).
Interestingly, the E and Z isomers of 6g are seen to interconvert
in CDCl3 when monitored by 1H NMR spectroscopy over a pro-
longed period (Scheme 5). Compounds E-6g and Z-6g do not
interconvert in the solid state.10
b
isomer of the
b
O
SBu
O
Cl
2.2 eq NCS
toluene, Δ
BuS
Cl
OMe
BuS
Cl
O
O
OMe
OMe
+
PhS
Cl
PhS
Me
CDCl3
rt
NHTol
O
10d
NHTol
11d
6d
Me
Cl
3 eq ZnCl2, DCM
Δ, 18 hours
E-6g
Z-6g
Scheme 5.
O
O
BuS
BuS
Cl
+
OMe
OMe
BuS
H
2.3. Halogenation using NBS
-bromoacrylamide
51%
12d
Scheme 2.
2.3.1. Synthesis of the
To extend the scope of the halogenation process, it was decided
to explore the reaction of N-tolyl- -(phenylthio)propanamide 10c
with NBS. In general -bromosulfides are more reactive but less
stable than -chlorosulfides, and thus have been used less fre-
quently as synthetic intermediates.11 However, most of the
methods used for -chlorosulfide preparation have been applied
with varying degrees of success to the synthesis of -bromo-
sulfides. In the direct -bromination of sulfides, bromine and NBS
have been employed. Benzyl sulfide reacts with NBS to provide
-bromobenzyl benzylsulfide,11 which on distillation resulted in
rapid decomposition to benzylbromide and other unidentified
materials. An interesting example of -bromination was reported
by Caputo et al.;12 the bromosulfonium ion is formed, however, as
b
The preparation of the methanethio-substituted
b-chloro-
a
acrylate 6e has also been attempted. When the
a
-thioester 10e8
a
was reacted with NCS (1.95 equiv) in toluene at 90 ꢀC, the
dichloride 11e was isolated as a colourless oil (Scheme 3). This
compound was identified by the presence of a characteristic AB
quartet at dH 4.85–5.05 with a coupling constant of 13 Hz in the 1H
NMR spectrum.
a
a
a
a
a
O
O
O
Cl
H
MeS
Cl
NCS
ZnCl2
Ether, 36 °C
MeS
Cl
MeS
OMe
OMe
g
OMe
Toluene
90 °C
H
H
there is no
a
-hydrogen atom,
g-bromination occurs.
minor product
N-Tolyl-a-(phenylthio)propanamide 10c was treated with NBS
10e
11e
Scheme 3.
6e
under three sets of reaction conditions, which had been in-
vestigated using NCS,1 to allow comparison of the reactivity of the
a
-thioamide 10c with NCS and NBS (Table 3). The optimum con-
Although treatment of 11e with etheral ZnCl2 affords a small
amount of the desired acrylate (Scheme 3), unidentified de-
composition products predominate in which loss of the meth-
anethio signal was observed.
ditions for reaction with NBS were found to be treatment of 10c
under reflux with 2.2 equiv of NBS in toluene or CCl4 for 3–6 h. A
1:1 mixture of the
acrylamide 17c was isolated.
b
-bromoacrylamide 16c and the
b
,b
-dibromo-
2.2.3. Preparation of extended chain b-chloroacrylates
Table 3
Treatment of
The ester 10f9 was treated under the conditions described pre-
viously for 10a and 10b to give the dichloride 11f as a 3:2 mixture of
diastereomers (Scheme 4).
a
-thioamide 10c with NBS
SPh
O
SPh
SPh
NBS
reflux
NHpTol
NHpTol
Br
NHpTol
Br
The mixed diastereomers of the crude dichloride 11f were
treated with 3 equiv of ZnCl2 in CH2Cl2 under reflux for 18 h, and
+
O
Br
O
the crude
b-chloroacrylate 6f was isolated. Analysis of the crude
10c
16c
17c
material showed predominately one isomer of the
b
-chloroacrylate,
NBS (equiv)
Temperature (ꢀC)
Solvent
Product ratio
tentatively assigned as Z, to have formed although a trace amount
of the other isomer was also observed. After chromatography, 6f
was isolated as a single isomer in 77% yield (Scheme 4). This con-
trasts with what has been previously observed for the butenamides
where mixtures of E and Z isomers were obtained directly from the
NCS reaction, without exposure to ZnCl2.1 It is likely that the ZnCl2
used in the decomposition of the dichloride 11f catalyses the in-
terconversion of the isomers of 6f leading to the thermodynami-
cally favoured isomer.
16c
17c
2.0
2.2
2.2
0–20
Reflux
Reflux
CCl4
CCl4
Toluene
No reaction
1
1
1
1
These preliminary results indicated that extension of this work
to bromo derivatives is possible.
O
O
O
Cl
PhS
Cl
PhS
CH3
2.2 equiv. NCS
Toluene, Δ, 18 hrs
3 eq. ZnCl2
CH2Cl2, Δ, 18 h
PhS
CH3
OMe
CH3
OMe
OMe
Cl
10f
11f
3:2
6f
77%
Scheme 4.

7642
M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
O
O
Br
O
PhS
Br
PhS
Br
3 eq. ZnCl2
OMe
OMe
5-7 eq. NBS, CCl4, Δ
PhS
OMe
CH2Cl2, Δ
10a
18a
16a
87%
99%
Scheme 6.
2.3.2. Synthesis of the
b
-bromoacrylate
X
OH
S
R
NHPh
Methyl 2-(phenylthio)propanoate 10a was treated with NBS and
the solvent, temperature, reaction time, concentration and number
of equivalents of NBS was varied. It was found that use of 5–7 equiv
of NBS, added portionwise, in CCl4 under reflux conditions gave
predominantly the dibromide 18a (Scheme 6). On some occasions,
evidence for methyl 2-bromo-2-(phenylthio)propanoate 16a was
seen in the 1H NMR spectrum of the crude product.
NaS(CH2)2OH
EtOH, rt, 16h
R
NHPh
O
O
R= H, X= Cl or
R= Me, X= Br
R= H 10g 67%
R= Me 10h 92%
Scheme 7.
As with the dichloro compounds, the most significant feature of
the 1H NMR spectrum of the dibromide is the characteristic AB
quartet for the methylene group. Unlike the dichlorides, however,
the range of the AB quartet in the dibromide 18a is quite large, from
dH 3.58 to 4.21 (JAB 11) indicating the alteration in the environment
of the CH2 protons on replacement of chlorine by the larger bro-
mine substituent.
NCS in toluene under reflux conditions for 5 min on a 1–2 mmol
scale. Decomposition to various products occurred on prolonged
heating. Purification by chromatography led to the isolation of the
two isomers of the
b-chloroacrylamide 6g tentatively assigned as
the Z and E isomers in 33% and 13% yields, respectively (Scheme 8).
The decomposition of 18a to the b-bromoacrylate 16a was ach-
S
OH
NHPh
S
OH
NHPh
S
OH
NHPh
2.2 eq NCS
toluene, Δ
+
ieved employing the conditions developed for the decomposition
of dichloride 11a (Scheme 6). Compound 16a was isolated as a pale
yellow oil following chromatography and bulb to bulb distillation at
Cl
Cl
O
O
O
reduced pressure. The characteristic shift of the b
-proton in the 1H
10g
Z-6g
E-6g
13%
33%
NMR spectrum was seen at dH 7.93. Samples of 16a were stored
at room temperature for up to 3 months with no evidence of any
decomposition by 1H NMR spectroscopy.
Scheme 8.
As with the chloro derivative 6a, only one isomer of the
-bromoacrylate 16a was evident on both 1H and 13C NMR
Interestingly, for these substrates the previously observed
Z stereoselectivity is not seen here. Possibly, the hydroxyl group
influences the stereochemistry.
b
spectra. The isolated isomer was assigned Z by analogy to the
-chloroacrylates.
b
Formation of the E and Z
b-chloroacrylamides from a-thio-
butanamide 10h using the conditions optimised for the chlorina-
tion of the propanamide derivative was also possible, albeit in
decreased yields. On a 2 mmol scale the reaction gave the isolated
2.4. Investigation of the transformation of the
bearing additional functional groups
a-thioamides
isomeric b-chloroacrylamides 6h in yields of 34% and 22%, tenta-
In order to broaden the scope of the stereoselective oxidative
chlorination, we investigated the chlorination of functionalized
sulfides such as 10g–i, substrates which are interesting due to their
potential to function as internal nucleophiles in intramolecular
tively assigned as Z and E respectively, following chromatography.
As is usual for extended chain amides, some Z acrylamide 15h was
formed but was isolated together with an unknown compound in
combined 8% yield. The trichloride 13h, which is a product of fur-
substitution reactions of b-chloroacrylamides.
ther reaction of the b-chloroacrylamide with NCS, was also isolated
in 18% yield (Scheme 9).
Ph
On a larger scale, the reaction with NCS is exothermic, so slow
addition is required. Unfortunately, during slow addition, extensive
decomposition occurs and the products are isolated in reduced
yielddZ-b-chloroacrylamide Z-6h (17%), E-b-chloroacrylamide
E-6h (8%) and E and Z acrylamides 15h (12% combined). Again the
assignment of E and Z stereochemistry is tentative.
SPh
O
H
N
OH
OH
S
S
H
NHPh
Me
NHPh
O
O
HO
10i
10g
10h
2.4.1. Use of sulfide substituent bearing a primary hydroxyl group
2.4.2. Use of amide substituent bearing a primary hydroxyl group
Treatment of (S)-phenylalaninol with 2 equiv of 2-chloro-
propionyl chloride resulted in acylation of both the amino and
hydroxyl groups to give a complex mixture of diastereomers.
However, the basic conditions used in the sulfenylation of the
diacylated phenylalaninol 19 caused ester cleavage to give the de-
sired propanamide 10i as a mixture of diastereomers (Scheme 10).
Two a-thioamides bearing a hydroxyl group on the sulfur sub-
stituent, N-phenyl-2-[20-(hydroxyethyl)thio]propanamide 10g and
N-phenyl-2-[20-(hydroxyethyl)thio]butanamide 10h, were pre-
pared by treatment of the corresponding
sodium salt of mercaptoethanol (Scheme 7).
Transformation of the -thiopropanamide 10g to the corre-
sponding -chloroacrylamide was possible, but the reaction was
a
-haloamide1 with the
a
b
Treatment of the
under reflux conditions for 15 min gave the Z-
6i in 86% yield following chromatographic purification (Scheme 10).
a
-thioamide 10i with 2.2 equiv of NCS in CCl4
more sensitive than that of the simpler amides. Optimised condi-
tions involved treatment of the propanamide 10g with 2.2 equiv of
b-chloroacrylamide

M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
7643
O
S
OH
NHPh
S
OH
NHPh
S
OH
NHPh
2.2 eq NCS
toluene, Δ
+
Cl
O
NHPh
OH
+
Cl
Cl
Cl
S
O
O
10h
6h
15h
13h
Scheme 9.
O
Ph
SPh
OH
NH2
CH2Cl2, rt, 16h
Ph
Cl
SPh
O
Cl
H
N
H
N
Cl
HN
2.2 eq NCS
CCl4, Δ, 15 min
2.1 eq. NaSPh
EtOH, rt, 16h
Ph
Cl
Cl
O
Ph
O
O
HO
O
HO
19
10i
6i
quantitative
76%
86%
Scheme 10.
2.4.3. Synthesis of the Weinreb amide derivatives
of the -chloroacrylamides
Weinreb amides have been widely used in the literature as ef-
fective acylating reagents.13–15 The Weinreb amide 20 was prepared
as reported, 13 however, triethylamine was used in place of pyridine
product isolated in the ester and nitrile series is the dichloride,
which is then transformed to the acrylate and acrylonitrile on
treatment with ZnCl2. Furthermore, the presence of hydroxyl
groups on the sulfide and amide groups is tolerated. In addition,
use of NBS in place of NCS leads to the corresponding bromide
derivatives.
b
to give the amide as a clear oil in 76% yield. The
then prepared as described previously1 using thiophenol and so-
dium in ethanol for 18 h. The -thioamide 10j was obtained as
a-thioamide was
a
4. Experimental
4.1. General
a colourless oil in 87% yield (Scheme 11).
Cl OCH3
PhSH, Na, EtOH
SPh OCH3
N
Cl
All solvents were distilled prior to use as follows: dichloro-
methane was distilled from phosphorus pentoxide and ethyl ace-
tate was distilled from potassium carbonate, ethanol and methanol
were distilled from magnesium in the presence of iodine. Acetone
was distilled from potassium permanganate and toluene was dis-
tilled from sodium and stored over 4 Å molecular sieves. Dime-
thylformamide was stored overnight over calcium hydride, then
distilled and stored over 4 Å molecular sieves. Organic phases were
dried using anhydrous magnesium sulfate. All commercial re-
agents, including N-chlorosuccinimide, were used without further
purification.
HN(CH3)OCH3
N
Cl
RT, 16 hr
NEt3, CH2Cl2
RT, 4h
O
O
10j
O
20
76%
87%
NCS
toluene,120 °C
O
O
O
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 (w20 ꢀ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
Laboratory, National University of Ireland, Cork, using a Perkin–
Elmer 240 elemental analyzer. 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
PhS
H
OCH3
N
PhS
Cl
OCH3
PhS
OCH3
N
CH3
N
+
+
CH3
CH3
H
Cl
21j
Cl
Z-6j 37%
E-6j 27%
15j
Scheme 11.
The
a-thioamide 10j was treated with 1.95 equiv of NCS in
toluene at 120 ꢀC for 2.5 h. Analysis of the crude reaction mixture
by 1H NMR spectroscopy showed complete conversion of the sul-
fide to a mixture of the isomeric b-chloroacrylamides 6j in a ratio of
2:1 tentatively assigned as Z and E. Some evidence for the acryl-
amide 15j was also observed in this spectrum. The E and Z isomers
are separable by chromatography and were isolated in yields of 27%
and 37%, respectively (E,Z assignment tentative). The dichlor-
oacrylamide 21j was also isolated in 14% yield (Scheme 11).
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 spectra were recorded as potassium bromide (KBr) discs
for solids or thin films on sodium chloride plates for oils on a
Perkin–Elmer Paragon 1000 FT-IR spectrometer.
Thin layer chromatography (TLC) was carried out on 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.
3. Conclusion
The scope of stereoselective oxidative chlorination of thio-
amides to form the chloroacrylamides on treatment with NCS has
been extended to include the analogous ester, nitrile and Weinreb
amide series. Interestingly, chloride elimination is less facile in the
ester and nitrile series than in the amide series, presumably due to
the electronic impact of conformational factors. Thus, the direct

7644
M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
4.2. Nitrile derivatives
4.3.1.1. Methyl 2-chloro-2-(phenylthio)propanoate 14a.4
4.3.1.1.1. Use of 1 equiv of NCS. NCS (75 mg, 0.56 mmol) was
added in one portion to a stirred solution of the sulfide 10a
(100 mg, 0.51 mmol) in toluene (2 mL) at room temperature. The
resulting solution was stirred at room temperature for 18 h before
cooling to 0 ꢀC. The succinimide by-product was removed by fil-
4.2.1. Products of treatment of 2-(phenylthio)propionitrile
1 with NCS
4.2.1.1. 3-Chloro-2-(phenylthio)propenonitriles 4 and 5, 2-(phenyl-
thio)propenonitrile
3
and 2,3-dichloro-2-(phenylthio)propionitrile
tration to give the a-chlorosulfide 14a and approximately 30%
2. NCS (320 mg, 2.40 mmol) was added in one portion to a solution
of the sulfide 1 (200 mg,1.23 mmol) in toluene (4 mL). The flask was
immediately immersed in an oil bath at 140 ꢀC and heating was
maintained for 18 h with stirring. The reaction mixture was cooled to
0 ꢀC and the succinimide by-product was removed by filtration. The
solvent was evaporated at reduced pressure to give the crude prod-
uct mixture of the Z and E 3-chloro-2-(phenylthio)propenonitriles
4 and 5, 2-(phenylthio)propenonitrile 3, 3-dichloro-2-(phenyl-
thio)propionitrile 2 in a ratio of 1:1:1:8 by 1H NMR spectroscopy
unreacted sulfide 10a. No further purification was conducted and
characteristic signals for 14a could be distinguished. dH (270 MHz,
CDCl3) 2.01 (3H, s, CH3-3), 3.72 (3H, s, OCH3), 7.21–7.62 (5H, m,
ArH); m/z (ESI) 230 [(M)þ, 6%], 194 [(MþꢁHCl), 17%].
4.3.1.1.2. Use of 2 equiv of NCS. NCS (150 mg, 1.12 mmol) was
added in one portion to a stirred solution of the sulfide 10a
(100 mg, 0.51 mmol) in toluene (2 mL) at room temperature. The
resulting solution was stirred at room temperature for 18 h before
cooling to 0 ꢀC. The succinimide by-product was removed by
(270 MHz). Evidence for both the E and Z
b-chloroacrylonitriles was
filtration to give the a-chlorosulfide 14a. No further purification
seen, the two compounds being present in equimolar amounts, each
contributing approximately 10% of the reaction mixture. The crude
reaction mixture was dissolved in CH2Cl2 (4 mL) and a solution of
ZnCl2 (2.60 mL of 1.0 M solution in ether, 2.60 mmol) was added. The
reaction solution was heated at reflux for 18 h. After cooling to room
temperature, water (100 mL) was added and the phases separated.
The organic layer was washed with water (100 mL) and brine
(100 mL), dried and concentrated at reduced pressure to give the
crude reaction product. This was then purified by chromatography
on silica gel using ethyl acetate–hexane (5:95) as eluent to give
was conducted and spectral characteristics were as previously
reported. A trace of the acrylate was seen at dH 5.24 and 6.33 as
reported previously.
4.3.2. Ethyl 2,3-dichloro-2-(phenylthio)propanoate 11b
NCS (3.42 g, 25.39 mmol) was added in one portion to a solution
of the sulfide 10b (2.42 g, 11.54 mmol) in toluene (50 mL). The flask
was immediately immersed in an oil bath at 124 ꢀC and heating was
maintained for 20 h with stirring. The reaction mixture was cooled
to 0 ꢀC and the succinimide by-product was removed by filtration.
The crude product was purified by chromatography on silica gel
using ethyl acetate–hexane (30:70) as eluent to give the dichloride
11b (2.74 g, 85%) as a yellow oil. Found: C, 47.70; H, 4.59; Cl, 25.24;
S, 11.35. C11H12Cl2O2S requires C, 47.32; H, 4.33; Cl, 25.40; S, 11.48.
nmax/cmꢁ1 (film) 1747 (CO), 1441, 1256, 1185; dH (270 MHz, CDCl3)
1.29 (3H, t, J 7, CH3), 3.89 (1H, A of ABq, J 11, CClH2), 4.00 (1H, B of
ABq, J 11, CClH2), 4.26 (2H, q, J 7, OCH2), 7.33–7.52 (3H, m, ArH),
7.63–7.72 (2H, m, ArH); dC (270 MHz, CDCl3) 13.8 (CH2CH3), 49.1
(CClH2), 63.5 (OCH2), 78.3 (SCCl), 127.5 (quaternary aromatic), 128.9
(aromatic CH), 131.0 (aromatic CH), 137.3 (aromatic CH), 165.4 (CO);
exact mass (EI) calculated for C11H12Cl2O2S [M]þ 277.9935. Found:
277.9940; 282, 280, 278 (Mþ, 67%), 243 (24, MþꢁCl), 205, 207 (85,
MþꢁCOOEt), 170 (28, MþꢁCOOEtꢁCl), 135 (87, MþꢁCOOEtꢁCl2),
109 (100, [SPh]þ).
a mixture of the Z and E b-chloroacrylonitriles 4 and 5 (126 mg, 52%)
as a yellow oil in a ratio of 6:1 and approximately 10% of the
dichloride 2. nmax/cmꢁ1 (film) 2230 (CN), 1551, 1478, 1442, 1146; dH
(270 MHz, CDCl3) 7.00 (0.86H, s, CHCl] of one diastereomer), 7.14
(0.14H, s, CHCl] of one diastereomer), 7.35–7.59 (5H, m, ArH); dC
(270 MHz, CDCl3) 113.5 (CN of minor diastereomer), 115.9 (CN of
major diastereomer), 128.5 (quaternary aromatic), 129.3 (aromatic
CH),129.8 (aromatic CH),131.8 (CHCl] of minordiastereomer),132.5
(CHCl] of major diastereomer), 134.3 (aromatic CH), 137.5 (SC] of
minor diastereomer), 137.4 (SC] of major diastereomer).
Characteristic peaks for the acrylamide 3 and the dichloride 2
were observed and were as reported below.
4.3. Ester derivatives
4.3.1. Methyl 2,3-dichloro-2-(phenylthio)propanoate 11a, methyl 2-
(phenylthio)propenoate 15a and methyl 2-chloro-
4.3.3. Methyl Z-3-chloro-2-(phenylthio)propenoate 6a from the
sulfide 10a
2(phenylthio)propanoate 14a4
NCS (23.00 g, 22.44 mmol) was added to a solution of the sulfide
10a (2.00 g, 10.20 mmol) in toluene (40 mL). The reaction flask was
immediately lowered into a pre-heated oil bath at 128 ꢀC and the
reaction solution refluxed for 16 h. After cooling to 0 ꢀC, the suc-
cinimide by-product was removed by filtration and the toluene
evaporated at reduced pressure. 1H NMR spectroscopy (60 MHz) of
this material showed complete conversion of the sulfide 10a to the
corresponding dichloride 11a. The crude dichloride 11a was dis-
solved in CH2Cl2 (40 mL) and a solution of ZnCl2 in ether (31.00 mL
of 1 M soln, 31.00 mmol) was added. The resulting solution was
then heated at reflux for 16 h when, after cooling to room tem-
perature, water (100 mL) was added and the phases separated. The
organic layer was washed with water (100 mL) and brine (100 mL),
dried and concentrated at reduced pressure to give the crude
product mixture, which appeared to be of good quality by NMR.
The crude product was purified by chromatography on silica gel
NCS (1.86 g, 13.93 mmol) was added in one portion to a stirred
solution of the sulfide 10a (1.30 g, 6.63 mmol) in toluene (26 mL).
The flask was immediately lowered into a pre-heated oil bath at
130 ꢀC. Heating was maintained for 4 h. The reaction solution was
cooled to 0 ꢀC and the succinimide by-product was removed by
filtration. The toluene was evaporated at reduced pressure to give
the crude dichloride 11a as a yellow oil. The crude product was
purified by chromatography on silica gel using ethyl acetate–hex-
ane (gradient elution 10–20% ethyl acetate) to give the dichloride
11a (1.53 g, 87%) as a clear oil. nmax/cmꢁ1 (film) 1753 (CO), 1440,
1286, 1258; dH (270 MHz, CDCl3) 3.79 (3H, s, OCH3), 3.90–4.05 (2H,
ABq, J 12, CH2Cl), 7.39–7.51 (3H, m, ArH), 7.65–7.71 (2H, m, ArH); dC
(270 MHz, CDCl3) 49.3 (CH2Cl), 53.9 (OCH3), 78.3 (SCCl), 128.0
(quaternary aromatic), 129.2 (aromatic CH), 131.2 (aromatic CH),
137.3 (aromatic CH), 166.0 (CO); exact mass (EI) calculated for
C
10H10Cl2O2S [M]þ 263.9779. Found: 263.9793; 264 [(M)þ, 34%].
using ethyl acetate–hexane (10:90) as eluent to give the b-chloro-
Evidence for the acrylate 15a was seen in some crude NMR spectra
at dH 3.82 (s, OCH3), 5.24 (s, one of CH2) and 6.33 (s, one of CH2).
The NMR spectra of some crude reaction mixtures also showed
acrylate 6a (1.53 g, 66% from sulphide) as a yellow oil. A portion
of this material was purified by bulb to bulb distillation (100 ꢀC
at 0.02 mmHg). Found: C, 52.83; H, 4.09; Cl, 15.62; S, 13.90.
evidence of the
a
-chlorosulfide 14a at dH 2.01 (s, CH3-3) and 3.72
C
10H9ClO2S requires C, 52.52; H, 3.97; Cl, 15.50; S, 14.02. nmax/cmꢁ1
(s, OCH3).
(film) 1732 (CO), 1557, 1271, 1242, 741; dH (270 MHz, CDCl3) 3.67

M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
7645
(3H, s, OCH3), 7.18–7.38 (5H, m, ArH), 7.71 (1H, s, ClHC]); dC
(270 MHz, CDCl3) 52.8 (OCH3), 127.7 (aromatic CH), 129.3 (aromatic
CH), 129.9 (aromatic CH), 133.3 (quaternary aromatic or SC], one
signal observed for two quaternary carbons), 138.0 (ClHC]), 163.7
(CO); MS m/z (EI) 228, 230 (Mþ, 100%), 192 (18, MþꢁHCl), 161 (35),
149 (42), 134 (100, [PhS–C]CH]þ), 110 (48), 109 (42, [SPh]þ); iso-
topic Cl pattern observed: 228, 230 (3:1 35Cl/37Cl).
product, a 2: 1 mixture of the
b
-chloroacrylate 6d/dichloride 11d.
Characteristic signals for the dichloride 11d were seen at 4.01–4.20
(ABq, J 10). The crude reaction product was dissolved in CH2Cl2
(3 mL) and ZnCl2 (1.80 mL of 1 M soln in ether) added. The resulting
solution was heated at reflux for 16 h, then water (5 mL) was added
and the phases separated. The organic layer was washed with water
(5 mL) and brine (5 mL), dried and concentrated at reduced pres-
A mixed fraction (least polar, 90 mg) consisting of the
b
-chloro-
sure to give the crude
by chromatography on silica gel using ethyl acetate–hexane (5:95)
as eluent to give the -chloroacrylate 6d (238 mg, 51%) as a col-
b-chloroacrylate 6d, which was purified
acrylate 6a and the trichloride 13a was also isolated in a ratio of
6a/13a of 1:2. Characteristic signals for the trichloride were seen at
dH (270 MHz, CDCl3) 3.72 (3H, s, OCH3) and 6.76 (1H, s, CHCl2–).
A further fraction (most polar, 25 mg) was also isolated and was
shown to be the bis sulfide 12a with characteristic signals seen at dH
(270 MHz, CDCl3) 3.73 (3H, s, OCH3), 7.18–7.58 (10H, m, ArH), 8.43
(1H, s, CHSPh]); exact mass (EI) calculated for C16H14O2S2 [M]þ
302.0435. Found: 302.0430; 302 (Mþ, 100%), 193 (16, MþꢁSPh), 161
(16), 134 (38, [PhS–C]CH]þ), 109 (17, [SPh]þ), 51 (12).
b
ourless oil. Found: C, 46.48; H, 6.49; Cl, 16.70; S, 15.33. C8H13ClO2S
requires C, 46.04; H, 6.28; Cl, 16.99; S, 15.36. nmax/cmꢁ1 (film) 1729
(CO), 1556, 1239; dH (270 MHz, CDCl3) 0.90 (3H, t, J 7, CH3-40), 1.35–
1.63 (4H, m, CH2-30, CH2-20), 2.86 (2H, t, J 7, SCH2), 3.83 (3H, s,
OCH3), 7.53 (1H, s, CHCl]); dC (270 MHz, CDCl3) 13.8 (CH3-40), 21.9
(CH2-30), 32.2 (CH2-20), 33.2 (SCH2), 53.1 (OCH3), 136.2 (CHCl]).
Quaternary carbons (SC] and CO) not observed; exact mass (EI)
calculated for C8H13ClO2S [M]þ 208.0325. Found: 208.0310; 208,
210 (Mþ, 7%), 173 (11, MþꢁCl), 157 (100), 143 (74), 135 (54), 57 (58);
isotopic Cl pattern observed: 208, 210 (3:1 35Cl/37Cl).
4.3.4. Methyl Z-3-chloro-2-(phenylthio)propenoate 6a from the
dichloride 11a
A signal corresponding to the bis sulfide compound 12d (trace
amount) was also seen at dH 8.08. The molecular ion of this com-
pound was also seen in the mass spectrum at 262 (6%).
A solution of ZnCl2 in ether (71.00 mL of 1 M soln, 71.00 mmol)
was added to a stirred solution of the dichloride 11a (6.27 g,
23.70 mmol) in CH2Cl2 (120 mL). The reaction solution was then
heated at reflux for 18 h, then water (100 mL) was added and the
phases separated. The organic layer was washed with water
(100 mL) and brine (100 mL), dried and concentrated at reduced
pressure to give the crude product, which was purified by chroma-
tography on silica gel using ethyl acetate–hexane (gradient elution
4.3.7. Attempted synthesis of methyl Z-3-chloro-2-
(methylthio)acrylate 6e
Treatment of methyl 2-(methylthio)propionate 10e (2.0 g,
14.9 mmol) with NCS (3.88 g, 29.1 mmol) in toluene (40 mL) at
90 ꢀC for 2 h afforded a material assumed to be the vic-dichloride,
methyl 2,3-dichloro-2-(methylthio)propionate 11e, on the basis of
the 1H NMR spectrum. Yield 2.65 g (87%). dH (300 MHz, CDCl3)
5.07–4.95 (m, 2H, CH2), 3.87 (s, 3H, OCH3), 2.12 (s, 3H, SCH3).
Treatment of this material with ZnCl2 under a range of condi-
tions (10 equiv ZnCl2, 36 ꢀC, 18 h; 10 equiv, rt, 18 h; 10 equiv, rt, 4 h;
2 equiv, rt, 18 h) afforded only traces of the desired chloroacrylate
6e accompanied by a complex mixture of decomposition products
with no SCH3 signal in the 1H NMR. On a 1.5 g scale, under the first
conditions described above, a 4% isolated yield of the desired
material was obtained in an impure state, which was characterised
only by 1H NMR. dH (300 MHz, CDCl3) 3.83 (s, 3H, OCH3), 2.39 (s, 3H,
SCH3).
0–5% ethyl acetate) as eluent to give the
70%) as a yellow oil. Spectral details were as previously reported. A
mixed fraction (0.34 g) consisting of a mixture of the -chloro-
b-chloroacrylate 6a (3.65 g,
b
acrylate 6a and the bis sulfide 12a was also isolated with a ratio of
6a/12a of 2:3. Again, spectral details were as previously reported.
4.3.5. Ethyl Z-3-chloro-2-(phenylthio)propenoate 6b
A solution of ZnCl2 in ether (18.00 mL of 1 M soln, 18.00 mmol)
was added to a stirred solution of the dichloride 11b (2.00 g,
7.20 mmol) in CH2Cl2 (40 mL) at room temperature. The reaction
solution was stirred for 18 h, then water (50 mL) was added and the
phases separated. The organic layer was washed with water
(50 mL) and brine (50 mL), dried and concentrated at reduced
pressure to give the crude
was purified by chromatography on silica gel using ethyl acetate–
hexane as eluent to give the -chloroacrylate 6b (1.25 g, 71%) as
b-chloroacrylate 6b. The crude product
4.3.8. Methyl 2,3-dichloro-2-(phenylthio)butanoate 11f
b
NCS (668 mg, 5.00 mmol) was added in one portion to a solution
of methyl 2-(phenylthio)butanoate 10f (500 mg, 2.38 mmol) in
toluene (10 mL). The reaction solution was immediately lowered
into a pre-heated oil bath at 130 ꢀC. After 18 h heating under reflux,
the reaction solution was cooled to 0 ꢀC and the succinimide was
removed by filtration. The toluene was removed by evaporation at
reduced pressure to give the crude dichloride 11f (546 mg, 83%) as
a 3:2 mixture of diastereomers, which was used without further
purification. dH (270 MHz, CDCl3) 1.60 (1.8H, d, J 6, CH3 of major
diastereomer), 1.84 (1.2H, d, J 6, CH3 of minor diastereomer), 3.58
(1.8H, s, OCH3 of major diastereomer), 3.60 (1.2H, s, OCH3 of minor
diastereomer), 4.78–4.90 (1H, two overlapping q, CHCl–).
a clear oil. Found: C, 54.56; H, 4.50; Cl, 14.90; S, 13.02. C11H11ClO2S
requires C, 54.43; H, 4.57; Cl, 14.61; S, 13.21. nmax/cmꢁ1 (film) 1728
(CO),1560,1267,1242; dH (270 MHz, CDCl3) 1.09 (3H, t, J 7, CH3), 4.10
(2H, q, J 7, OCH2), 7.20–7.51 (5H, m, ArH), 7.64 (1H, s, CHCl]); dC
(270 MHz, CDCl3) 13.7 (CH2CH3), 62.0 (OCH2), 127.2 (aromatic CH),
128.7 (aromatic CH), 129.2 (aromatic CH), 130.1 (quaternary aro-
matic or SC]), 131.7 (quaternary aromatic or SC]), 136.9 (CHCl]),
163.2 (CO); MS m/z (EI) 242, 244 (Mþ, 86%), 207 (34, MþꢁCl), 206
(41, MþꢁHCl), 178 (44), 161 (62, MþꢁHClꢁOEt), 135 (100), 134 (99,
[PhS–C]CH]þ), 109 (81, [SPh]þ), 77 (70); isotopic Cl pattern ob-
served: 242, 244 (3:1 35Cl/37Cl).
4.3.6. Methyl 2,3-dichloro-2-(n-butylthio)propanoate 11d, methyl
Z-3-chloro-2-(n-butylthio)propenoate 6d and methyl 2,3-di-
(n-butylthio)propanoate 12d
NCS (636 mg, 4.77 mmol) was added to a solution of the sulfide
10d (400 mg, 2.27 mmol) in toluene (8 mL). The reaction solution
was immediately lowered into a pre-heated oil bath at 130 ꢀC. After
18 h heating under reflux, the reaction solution was cooled to 0 ꢀC
and the succinimide was removed by filtration. The toluene was
removed by evaporation at reduced pressure to give the crude
4.3.9. Methyl 3-chloro-2-(phenylthio)butenoate 6f
A solution of ZnCl2 (4.6 mL of 1.0 M soln in ether, 4.60 mmol)
was added to a solution of the dichloride 11f (107 mg, 0.39 mmol)
in CH2Cl2 (2 mL). The reaction solution was heated at reflux for 18 h
before work-up as outlined for 6a to give the crude
b-chloro-
acrylate, which was purified by chromatography on silica gel using
ethyl acetate–hexane (5:95) as eluent to give methyl 3-chloro-2-
(phenylthio)butenoate 6f, tentatively assigned as Z, (73 mg, 77%) as
a yellow oil. Found: C, 54.18; H, 4.66; Cl, 14.27; S, 13.46. C11H11ClO2S

7646
M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
requires C, 54.43; H, 4.57; Cl, 14.61; S, 13.21. dH (270 MHz, CDCl3)
2.43 (3H, s,¼CCH3), 3.49 (3H, s, OCH3), 7.20–7.39 (5H, m, ArH); dC
(270 MHz, CDCl3) 25.4 (CH3), 52.4 (OCH3), 127.5 (aromatic CH),
129.2 (aromatic CH), 130.8 (aromatic CH), 133.3 (quaternary
aromatic or SC] or CCl]), 136.7 (quaternary aromatic or SC] or
CCl]), 143.5 (quaternary aromatic or SC] or CCl]), 165.2 (CO); MS
m/z (EI) 242, 244 (Mþ, 20), 226 (30), 155 (43), 91 (46), 77 (100);
isotopic Cl pattern observed: 242, 244 (3:1 35Cl/37Cl).
129.0 (aromatic CH), 130.9 (aromatic CH), 137.0 (aromatic CH), 166.2
(CO); exact mass (EI) calculated for C10H10Br2O2S [M]þ 353.8748.
Found: 353.8747; 354 (Mþ, 1%), 273, 275 (19, MþꢁBr), 194 (45,
MþꢁBr2), 163 (5, MþꢁBr2ꢁOCH3), 135 (100, [PhS–C]CH2]þ), 109
(20, [SPh]þ), 91 (55).
When this reaction was repeated using 3.00 g (15.31 mmol) of
10a, the dibromide 18a was isolated in 99% yield. No further puri-
fication of this material was required.
A second compound was also seen in the NMR, possibly the E
A
characteristic signal for methyl 2-bromo-2-(phenyl-
isomer of the
b
-chloroacrylate, at dH (270 MHz, CDCl3) 2.45 (3H, s,
thio)propanoate 16a was seen in some crude NMR spectra at
dH 2.83 (s).
¼CCH3), 3.65 (3H, s, OCH3) and at dC 24.5, 126.2, 129.6 and 167.7.
4.4.3. Methyl Z-3-bromo-2-(phenylthio)propenoate 16a from 18a
A solution of ZnCl2 in ether (45.60 mL of 1 M soln, 45.60 mmol)
was added to a stirred solution of the dibromide 18a (5.38 g,
15.20 mmol) in CH2Cl2 (110 mL). The reaction solution was then
heated under reflux for 18 h, thenwater (100 mL) was added and the
phases separated. The organic layer was washed with water
(100 mL) and brine (100 mL), dried and concentrated at reduced
pressure to give the crude product, which was purified by chroma-
tography on silica gel using ethyl acetate–hexane (gradient elution
4.4. Halogenation using NBS
4.4.1. Treatment of N-40-methylphenyl-2-(phenylthio)-
propanamide 10c with NBS
NBS (0.41 g, 2.3 mmol) was added to a solution of N-40-methyl-
phenyl-2-(phenylthio)propanamide 10c (0.30 g, 1.1 mmol) in tolu-
ene (7 mL) and the reaction flask was immersed in an oil bath at
130 ꢀC. After stirring for 6 h, the reaction mixture was cooled to 0 ꢀC
and the succinimide by-product was removed by filtration. The fil-
trate was evaporated to give a complex mixture of products (0.39 g).
Purification by chromatography using ethyl acetate–hexane (15:85)
as eluent followed by preparative TLC using ethyl acetate–hexane
(15:85) as eluent gave two major fractions, which contained com-
pounds which were tentatively assigned as N-40-methylphenyl-3-
bromo-2-(phenylthio)propenamide 16c (10 mg) as a colourless oil.
0–5% ethyl acetate) as eluent to give the
b-bromoacrylate 16a
(3.61 g, 87%) as a yellowoil. A portion of this material was purified by
bulb to bulb distillation (110 ꢀC at 0.02 mmHg); Found: C, 43.95; H,
3.36; S, 11.70. C10H9BrO2S requires C, 43.97; H, 3.32; S, 11.74. nmax
/
cmꢁ1 (film) 1732 (CO), 1554, 1434, 1258, 741; dH (270 MHz, CDCl3)
3.62 (3H, s, OCH3), 7.19–7.38 (5H, m, ArH), 7.93 (1H, s, ClHC]); dC
(270 MHz, CDCl3) 52.7 (OCH3), 127.3 (aromatic CH or SC]), 128.2
(aromatic CH or SC]), 129.4 (aromatic CH), 130.1 (aromatic CH),
133.2 (quaternary aromatic or SC]), 134.7 (quaternary aromatic or
SC]), 163.5 (CO); exact mass (EI) calculated for C10H9BrO2S [M]þ
271.9507. Found: 271.9508; 274 (Mþ Br81, 24%), 272 (Mþ Br79, 26),
149 (23), 134 (100, MþꢁBrꢁCOOMe), 109 (32, [SPh]þ), 59 (26).
nmax/cmꢁ1 (neat) 3318 (br, NH),1676 (CO
a,b-unsaturated amide); dH
(270 MHz, CDCl3) 2.31 (3H, s, ArCH3), 7.07–7.47 (9H, m, ArH), 8.31
(1H, s, BrHC]); MS m/z (EI) 347 (Mþ, 40%), 239 (57, MþꢁPhSꢁH), 212
(20, [PhS]C]CBr]þ), 134 (67, [PhS]C]CH]þ), isotopic bromine
pattern observed 347, 349 (1:1 ratio 79Br/81Br). N-40-Methylphenyl-
3,3-dibromo-2-(phenylthio)propenamide 17c (10 mg) was also re-
covered as a colourless oil. nmax/cmꢁ1 (neat) 3298 (br, NH), 1659,
1604 (CO amide); dH (270 MHz, CDCl3) 2.27 (3H, s, ArCH3), 7.03–7.65
(9H, m, ArH), 8.31 (1H, s, BrHC]); MS m/z (EI) 425 (Mþ, 22%), 212
(100, [PhS]C]CBr]þ), 91 (48, [Tol]þ); isotopic bromine pattern
observed 425, 427, 429 (79Br/81Br), 212, 214 (1:1 ratio 79Br/81Br).
4.5. Use of sulfide bearing a primary hydroxyl group
4.5.1. N-Phenyl-2-[20-(hydroxyethyl)thio]propanamide 10g
Mercaptoethanol (2.3 mL, 32.8 mmol) was added to a freshly
prepared solution of sodium ethoxide [made from sodium (1.38 g,
49.3 mmol) in dry ethanol (100 mL) at 0 ꢀC] while stirring under
nitrogen. The resulting solution was stirred for 20 min when
N-phenyl-2-chloropropanamide 22g (4.10 g, 22.4 mmol) was added
gradually over 15 min. Following stirring for 16 h, the reaction was
quenched by addition of water (50 mL) and CH2Cl2 (30 mL). The
phases were separated and the aqueous layer was extracted with
CH2Cl2 (2ꢂ30 mL). The combined organic layers were washed with
NaOH (1 M, 2ꢂ50 mL), water (100 mL) and brine (100 mL), dried and
concentrated to give a yellow solid (4.93 g, 98% crude). Recrystalli-
sation from ether–hexane (20:80) gave the sulfide 10g (3.47 g, 67%)
as awhite, crystalline solid. Mp 70–72 ꢀC. Found: C, 58.81; H, 6.77; N,
6.22; S,14.43. C11H15NO2S requires C, 58.64; H, 6.71; N, 6.22; S,14.23.
nmax/cmꢁ1 (KBr) 3248, 1664, 1601; dH (270 MHz, CDCl3) 1.52 (3H, d,
J 7, CH3-3), 2.69–2.96 (3H, m, CH2S, OH), 3.63 (1H, q, J 7, CH-2), 3.79–
3.88 (2H, m, CH2O), 7.09–7.56 (5H, m, ArH), 8.80 (1H, br s, NH); dC
(270 MHz, CDCl3) 18.4 (CH3-3), 34.4 (CH2S), 44.9 (CH-2), 61.8 (CH2O),
120.0,124.6,129.1 (aromatic CH),137.7 (quaternaryaromatic C),171.1
(CO); MS m/z (EI) 225 (Mþ, 2%), 207 (5), 149 (20), 135 (3).
4.4.2. Methyl 2,3-dibromo-2-(phenylthio)propanoate 18a and
methyl 2-bromo-2-(phenylthio)propanoate 16a
NBS (454 mg, 2.55 mmol) was added to a solution of the sulfide
10a (200 mg, 1.02 mmol) in CCl4 (4 mL). The reaction flask was
immediately lowered into a pre-heated oil bath at 90 ꢀC. After
heating under reflux for 3 h, the flask was removed from the oil bath
and a sample (1 mL) was removed. A 1H NMR spectrum (60 MHz)
was recorded (in CCl4), which showed the reaction to be approxi-
mately 78% complete. The NMR sample was returned to the reaction
flask and a further addition of NBS (454 mg, 2.55 mmol) was made.
The reaction vessel was again lowered into the pre-heated oil bath
and reflux was maintained for a further 18 h. 1H NMR spectroscopy
(60 MHz in CCl4) showed 95% conversion to the dibromide 18a. A
final addition of NBS (200 mg, 1.10 mmol) was made and after
refluxing for a further 6 h, the reaction was complete as determined
by 1H NMR spectroscopy (60 MHz). The reaction mixture was fil-
tered to remove the succinimide by-product and the CCl4 was
evaporated at reduced pressure to give the crude dibromide 18a as
a yellow oil. The crude product was purified by chromatography on
silica gel to give the dibromide 18a (274 mg, 76%) as clear oil. Found:
C, 34.00; H, 2.81; Br, 45.26; S, 9.22. C10H10Br2O2S requires C, 33.92;
H, 2.85; Br, 45.14; S, 9.06. nmax/cmꢁ1 (film) 1747 (CO), 1439, 1269,
1165, 753; dH (270 MHz, CDCl3) 3.61 (1H, HA of ABq, J 11, one of
CH2Br), 3.90 (3H, s, OCH3), 4.19 (1H, HB of ABq, J 11, one of CH2Br),
7.39–7.58 (3H, m, ArH), 7.74–7.82 (2H, m, ArH); dC (270 MHz, CDCl3)
36.7 (CH2Br), 54.1 (OCH3), 69.3 (SCBr), 128.2 (quaternary aromatic),
4.5.2. N-Phenyl-2-[20-(hydroxyethyl)thio]butanamide 10h
This was prepared following the procedure described for sulfide
10g using N-phenyl-2-bromobutanamide 22h (7.90 g, 32.6 mmol),
mercaptoethanol (2.5 mL, 35.9 mmol), sodium (1.58 g, 68.5 mmol)
and dry ethanol (100 mL) to give the sulfide (7.81 g, 100% crude).
Trituration from cold hexane gave the sulfide 10h (7.22 g, 92%) as an
off-white, crystalline solid. Mp 71–73 ꢀC. Found: C, 59.83; H, 7.23;

M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
7647
N, 6.06; S, 13.14. C12H17NO2S requires C, 60.22; H, 7.16; N, 5.85; S,
13.40. nmax/cmꢁ1 (KBr) 3388, 1670, 1604; dH (270 MHz, CDCl3) 1.06
(3H, t, J 7, CH3-4), 1.70–1.84 (1H ,m, CHAHB-3), 1.92–2.08 (1H, m,
CHAHB-3), 2.68–2.88 (2H, m, CH2S), 2.92–2.97 (1H, br t, OH), 3.45
(1H, t, J 7, SCH-2), 3.78–3.81 (2H, m, CH2O), 7.08–7.58 (5H, m, ArH),
8.81 (1H, br s, NH); dC (270 MHz, CDCl3) 12.0 (CH3-4), 26.0 (CH2-3),
34.5 (CH2S), 52.3 (CH-2), 61.8 (CH2O), 120.0, 124.6, 129.0 (aromatic
CH), 137.7 (quaternary aromatic C), 170.2 (CO); MS m/z (EI) 239 (Mþ,
1%), 179 (45), 166 (55), 151 (70), 124 (100).
J 8, H-40), 7.30 (2H, t, J 8, H-30 and H-50), 7.57 (2H, d, J 8, H-20 and H-60),
8.33 (1H, br s, NH); dC (270 MHz, CDCl3) 24.2 (CH3-4), 37.0 (CH2S),
62.0 (CH2O),120.1, 124.5 (aromatic CH), 126.4 (probably SC]), 129.0
(aromatic CH), 136.3, 137.3 (quaternary aromatic C and CCl]), 164.4
(CO); exact mass (EI) calculated for C12H14ClNO2S [M]þ 271.04338.
Found: 271.04269; 271 (Mþ, 9%), 235 (15, MþꢁHCl), 220 (28), 151
(40, MþꢁCONHPh), 123 (52); isotopic Cl pattern observed: 271, 273
(3:1 ratio 35Cl/37Cl); N-phenyl-Z-2-[20-(hydroxyethyl)thio]-2-bute-
namide 15h (tentatively assigned as Z) (Rf 0.45) as a mixture with an
unknown compound (ca. 70:30) (40 mg, 8% of total product mix-
ture, estimated by 1H NMR integration) as a yellow oil. dH (270 MHz,
CDCl3) 2.15 (3H, d, J 8, CH3-4), 3.00 (2H, dd, J 7, 7, CH2S), 3.64 (2H, dd,
J 7, 7, CH2O), 7.11–7.73 (6H, m, ArH and CH]), 9.14 (1H, br s, NH);
signals observed for the unknown compound at 2.44 (s), 3.09 (dd,
J 7,7), 3.70 (dd, J 7, 7), 7.11–7.73 (m, ArH); N-phenyl-2-[20-(hydroxy-
ethyl)thio]-2,3,3-trichlorobutanamide 13h (43 mg, 6%) (Rf 0.35)
as a yellow oil. nmax/cmꢁ1 (neat) 3394, 1686, 1599; dH (270 MHz,
CDCl3) 2.57 (3H, s, CH3-4), 3.09, 3.11 (2H, 2ꢂdd, J 6, 6, CHAHBS),
3.83 (2H, dd, J 6, 6, CH2O), 7.19 (1H, t, J 8, H-40), 7.36 (2H, dd,
J 8, 8, H-30 and H-50), 7.54 (2H, d, J 8 H-20 and H-60), 9.10
(1H, br s NH); dC (270 MHz, CDCl3) 35.4, 36.5 (CH3-4 and CH2S),
60.0 (CH2O), 92.1, 92.5 (CCl2-3 and CCl-2), 120.5, 126.1, 129.2
(aromatic CH), 136.6 (quaternary aromatic C), 161.9 (CO); exact
mass (EI) calculated for C12H14Cl3NO2S [M]þ 340.98108. Found:
340.98099; 341 (Mþ, 1%), 271 (1, Mþꢁ2Cl), 120 (45), 93 (45), 77
(30, [SCH2CH2OH]þ); isotopic Cl pattern observed: 341, 343, 345,
347 (35Cl/37Cl); 271, 273 (3:1 ratio 35Cl/37Cl).
4.5.3. N-Phenyl-Z-3-chloro-2-[20-(hydroxyethyl)-
thio]propenamide Z-6g and N-phenyl-E-3-chloro-2-[20-
(hydroxyethyl)thio]propenamide E-6g
NCS (3.65 g, 27.3 mmol) was added in one portion to a solution of
10g (3.00 g, 13.3 mmol) in toluene (60 mL) at 130 ꢀC. Reaction was
complete after 5 min (by TLC analysis) to give a crude mixture of
acrylamides (4.23 g) (ca. 60% of mixture) and several unidentified
components. Purification by chromatography using ethyl acetate–
hexane (7:93–30:70) as eluent gave b-chloroacrylamide 6g (tenta-
tively assigned as E) (0.45 g, 13%) (Rf 0.5 using ethyl acetate–hexane
(25:75) as eluent) as a yellow oil (which seems to bind a molecule
of water, see MS). Found: C, 50.93; H, 4.34; N, 5.46. C11H12ClNO2S
requires C, 51.26; H, 4.69; N, 5.43. nmax/cmꢁ1 (neat) 3336,1668,1598;
dH (270 MHz, CDCl3) H2O peak seen at 1.70–1.90 (br s), 2.56 (1H, s,
OH), 3.15 (2H, t, J 7, CH2S), 3.67 (2H, t, J 7, CH2O), 7.14–7.66 (5H, m,
ArH), 7.97 (1H, s, ClHC]), 9.08 (1H, br s, NH); dC (270 MHz, CDCl3)
36.7 (CH2S), 42.7 (CH2O), 120.2, 125.1, 129.2 (aromatic CH and SC]),
130.9, 137.2 (quaternary aromatic C), 140.7 (ClHC]), 160.6 (CO);
MS m/z 275 (MþþH2O, 8%), 240 (10, MþþH2OꢁCl), 163 (100,
MþþH2Oꢁ[S(CH2)2OH]þ); isotopic Cl pattern observed: 275, 277
4.6. Use of amide substituent bearing a primary hydroxyl
group
(3:1 ratio 35Cl/37Cl) and
b-chloroacrylamide 6g (tentatively assigned
4.6.1. N-20-[30-Phenyl-10-(200-chloropropoxylate)]propyl-2-
chloropropanamide 19
as Z) (1.14 g, 33%) (Rf 0.1) as a colourless oil. dH (270 MHz, CDCl3) 2.56
(1H, br s, OH), 2.99 (2H, t, J 6, CH2S), 3.79 (2H, t, J 6, CH2O), 7.12–7.64
(5H, m, ArH), 7.85 (1H, s, ClHC]), 9.33 (1H, br s, NH); dC (270 MHz,
CDCl3) 37.2 (CH2S), 60.4 (CH2O), 120.2, 125.0, 129.0 (aromatic CH),
131.7, 137.3 (quaternary aromatic C and SC]), 139.6 (ClHC]), 161.4
(CO); exact mass (EI) calculated for C11H12ClNO2S [M]þ 257.02773.
Found: 257.02451; 257 (Mþ, 18%), 239 (18, MþꢁCl), 204 (58), 178
(43), 93 (100, [NH2Ph]þ), isotopic Cl pattern observed: 257, 259 (3:1
ratio 35Cl/37Cl).
A solution of 2-chloropropanoyl chloride (3.45 g, 27.2 mmol) in
CH2Cl2 (20 mL) was added dropwise to a solution of (S)-phenyl-
alaninol (2.01 g, 13.3 mmol) in CH2Cl2 (50 mL) while stirring at
room temperature. Stirring was continued for 16 h, then saturated
sodium bicarbonate (30 mL) was added. The phases were separated
and the aqueous layer was extracted with CH2Cl2 (2ꢂ10 mL). The
combined organic layers were washed with water (2ꢂ10 mL), brine
(2ꢂ10 mL), dried and evaporated to give the amide ester 19 (4.59 g,
quantitative) as a white, crystalline solid, which was used without
further purification. Mp 109–111 ꢀC. nmax/cmꢁ1 (KBr) 3281, 1734,
1654, 1560; dH (270 MHz, CDCl3) 1.59 (3H, d, J 7, CH3CHCl), 1.65–1.70
(3H, m, CH3CHCl), 2.89 (2H, br d, J 7, CH2Ph), 4.10–4.47 (5H, m,
OCH2CHN, 2ꢂCHCl), 6.77 (1H, br m, NH), 6.82–7.33 (5H, m, ArH); dC
(270 MHz, CDCl3) 21.6, 22.6 (CH3CHCl), 37.0 (CH2Ph), 49.5, 52.3,
55.3 (3ꢂCH), 65.6 (CH2O), 127.0, 128.4, 128.7 (ArCH), 136.2 (qua-
ternary aromatic C), 169.4, 169.8 (CO ester and CO amide); MS m/z
(EI) 331 (Mþ, 2%), 296 (1, MþꢁCl), 224 (75, MþꢁCH3CHClCO2), 132
(100, [CH3CHClCO2CH2CH]þ), isotopic Cl pattern observed: 331,
335, 337 (35Cl/37Cl), 132, 134 (3:1 ratio 35Cl/37Cl).
4.5.4. Treatment of N-phenyl-2-[20-(hydroxyethyl)-
thio]butanamide 10h with NCS
This was prepared following the procedure described for 6g
using N-phenyl-2-[20-(hydroxyethyl)thio]butanamide 10h (0.50 g,
2.09 mmol), NCS (0.65 g, 4.83 mmol) and toluene (15 mL) at 130 ꢀC.
After stirring for 5 min, the reaction was complete (by TLC analysis)
giving a crude mixture of products. Purification by chromatography
using ethyl acetate–hexane (30:70) as eluent gave N-phenyl-
E-3-chloro-2-[20-(hydroxyethyl)thio]butanamide 6h (tentatively
assigned as E) (Rf 0.6 using ethyl acetate–hexane (25:75) as eluent)
(128 mg, 22%) as a colourless oil. nmax/cmꢁ1 (neat) 3278, 1651, 1598;
dH (270 MHz, CDCl3) 2.48 (3H, s, CH3-4), 2.94 (2H, dd, J 5, 5, CH2S),
3.80 (2H, dd, J 5, 5, CH2O), 7.15 (1H, t, J 8, H-40), 7.35 (2H, dd, J 8, 8, H-
30 and H-50), 7.57 (2H, d, J 8, H-20 and H-60), 8.74 (1H, br s, NH); dC
(270 MHz, CDCl3) 25.5 (CH3-4), 36.6 (CH2S), 61.1 (CH2O), 119.9,
124.9 (aromatic CH), 126.7 (probably SC]), 129.1 (aromatic CH),
137.5 (quaternary aromatic C), 144.5 (CCl]), 163.6 (CO); exact mass
(EI) calculated for C12H14ClNO2S [M]þ 271.04338. Found: 271.04357;
271 (Mþ, 1%), 235 (2, MþꢁHCl), 151 (85, MþꢁCONHPh), 124 (100);
isotopic Cl pattern observed: 271, 273 (3:1 ratio 35Cl/37Cl); and
N-phenyl-Z-3-chloro-2-(20-hydroxy)ethylthiobutanamide 6h (ten-
tatively assigned as Z) (191 mg, 34%) (Rf 0.5) as a brown solid. Mp
91–93 ꢀC. dH (270 MHz, CDCl3) 2.42 (3H, s, CH3-4), 2.91 (2H, dd, J 5, 5,
CH2S), 3.10–3.50 (1H, br s, OH), 3.84 (2H, dd, J 5, 5, CH2O), 7.11 (1H, t,
4.6.2. (2R/S,20S)-N-20-[(10-Hydroxy-30-phenyl)propyl]-2-
phenylthiopropanamide 10i
This was prepared following the procedure described for sul-
fide 10g using 10i (2.00 g, 6.04 mmol), thiophenol (1.3 mL,
12.7 mmol), sodium (0.57 g, 24.8 mmol) and dry ethanol (30 mL)
to give the crude sulfide 10i (1.90 g, 99%). Ester hydrolysis took
place during the washing of the organic phase with NaOH (5 M).
Purification by recrystallisation from dry ethanol gave the sulfide
10i (as an equimolar mixture of two diastereomers) (1.45 g, 76%),
as a white, crystalline solid. Mp 115–118 ꢀC. Found: C, 68.42; H,
6.89; N, 4.31; S, 10.15. C18H21NO2S requires C, 68.54; H, 6.71; N,
4.44; S, 10.17. nmax/cmꢁ1 (KBr) 3285, 1655; dH (270 MHz, CDCl3)

7648
M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
1.41, 1.51 (3H, 2ꢂd, J 7, CH3-3), 2.43 (1H, br s, OH), 2.74–2.86 (2H,
m, CH2Ph), 3.42–3.56 (2H, m, CH2O), 3.74, 3.79 (1H, 2ꢂq, J 7, CHS),
4.02–4.18 (1H, br m, CHN), 6.85 (1H, br d, J 8, NH), 7.08–7.31 (10H,
m, ArH); dC (270 MHz, CDCl3) 18.2, 18.4 (CH3-3), 36.8, 36.9 (CH2Ph),
47.1, 47.3 (CHS), 52.7, 53.2 (CHN), 63.9, 64.0 (CH2O), 126.7, 127.6,
128.6, 129.3, 130.4 (aromatic CH), 134.1, 137.4 (quaternary aromatic
C), 172.2, 172.6 (CO); MS m/z (EI) 315 (Mþ, 30%), 284 (10,
MþꢁCH2OH), 224 (80, MþꢁCH2Ph), 137 (100, [PhSCHCH3]þ), 91
(75, [CH2Ph]þ).
4.7.3. N-Methoxy-N-methyl-Z-3-chloro-2-phenylthio-
propenamide Z-6j, N-methoxy-N-methyl-E-3-chloro-
2-phenylthiopropenamide E-6j, N-methoxy-N-methyl-2,3-
dichloro-2-phenylthiopropenamide 21j and N-methoxy-
N-methyl-2-phenylthiopropenamide 15j
Note: rotation about the C–N bond results in broadening of the
1H NMR spectra of both isomers of the
b-chloroacrylamides at
270 MHz. This broadening is not seen when the 1H NMR spectra are
recorded at 60 MHz.
NCS (3.20 g, 23.99 mmol) was added to a solution of the sulfide
10j (3.00 g, 13.33 mmol) in toluene (60 mL). The reaction solution
was immediately lowered to a pre-heated oil bath at 120 ꢀC. After
heating for 2.5 h, the reaction solution was cooled to 0 ꢀC and
the succinimide by-product was removed by filtration. The toluene
was removed by distillation at reduced pressure to give the crude
4.6.3. (20S)-20-N-[10-(Hydroxy)-30-(phenyl)]propyl-Z-3-chloro-2-
(phenylthio)propenamide 6i
A solution of 10i (0.46 g, 1.46 mmol) in carbon tetrachloride
(10 mL) was stirred at room temperature under nitrogen and NCS
(0.40 g, 2.99 mmol) was added in one portion. The reaction mix-
ture was then heated at reflux for 15 min. The reaction was cooled,
filtered and concentrated to give 6i. Purification by chromatogra-
phy using ethyl acetate–methanol–hexane (30:5:65) as eluent gave
b-chloroacrylamides in a ratio of 2:1. The crude reaction product
was chromatographed on silica gel using ethyl acetate–hexane
(20:80) as eluent to give the two
clear oils.
b-chloroacrylamides, both as
b
-chloroacrylamide 6i (0.44 g, 86%) as a white, crystalline solid. Mp
Major (less polar)
b-chloroacrylamide 6j (1.27 g, 37%), tenta-
20
86–88 ꢀC. [
a
]
95.9 (c 0.06, EtOH). Found: C, 62.23; H, 5.13; N,
D
tively assigned as Z. Found: C, 51.57; H, 4.71; N, 5.43; Cl,
13.80. C11H12NClO2S requires C, 51.26; H, 4.69; N, 5.44; Cl, 13.75.
nmax/cmꢁ1 (film) 1661, 1581, 1475, 1440, 1382; dH (500 MHz, 193 K)
2.82 (1H, s, part of NCH3 or NOCH3), 3.08 (0.5H, s, part of NCH3 or
NOCH3), 3.12 (0.5H, s, part of NCH3 or NOCH3), 3.19 (1.5H, s, part of
NCH3), 3.49 (0.5H, s, part of NOCH3), 3.70 (2H, s, part of NOCH3)
6.42 (0.28H, s, one rotamer of ClHC]), 6.58 (0.72H, s, one rotamer
of ClHC]), 7.30–7.62 (5H, m, ArH); dC (500 MHz, 233 K) 32.6 (part
of NCH3), 36.0 (part of NCH3), 36.2 (part of NCH3), 60.6 (part
of NOCH3), 61.1 (part of NOCH3), 63.0 (part of NOCH3), 119.9
(ClHC] of minor rotamer), 124.0 (ClHC] of major rotamer), 127–
133 (aromatic signals for all rotamers), 135.2 (aromatic carbon),
135.5 (aromatic carbon), 158.2 (quaternary aromatic or C]O),
160.7 (quaternary aromatic or C]O), 163.6 (quaternary aromatic
or C]O), 165.2 (quaternary aromatic or C]O); exact mass (EI)
calculated for C11H12NClO2S [M]þ 257.0277. Found: 257.0278. MS
m/z 257, 259 (Mþ, 22), 222 (2, MþꢁCl), 197, 199 (17, MþꢁNR1R2),
169, 171 (33, MþꢁCONR1R2), 134 (100, [PhS–C]CH]þ), 109 (12,
[SPh]þ); isotopic Cl pattern observed: 257, 259 (3:1 ratio of
35Cl/37Cl).
3.80; S, 8.94. C18H18ClNO2S requires C, 62.15; H, 5.22; N, 4.03; S,
9.22. nmax/cmꢁ1 (KBr) 3368, 1639, 1561; dH (270 MHz, CDCl3) 2.23
(1H, br s, OH), 2.69–2.84 (2H, m, CH2Ph), 3.34–3.55 (2H, m, CH2O),
4.05–4.18 (1H, m, CHN), 7.05–7.41 (10H, m, ArH), 7.85 (1H, s,
ClHC]); dC (270 MHz, CDCl3) 37.6 (CH2Ph), 54.1 (CHN), 64.3
(CH2O), 127.6, 128.2, 129.4, 129.6, 130.1, 130.4 (aromatic CH), 131.8,
133.9, 138.0 (quaternary aromatic C and SC]), 140.0 (ClHC]),
163.5 (CO); MS m/z (EI) 347 (Mþ, 8%), 316 (6, MþꢁCH2OH), 256 (10,
MþꢁCH2Ph), 166 (100), 134 (30, [PhS]C]CH]þ), 91 (70,
[CH2Ph]þ); isotopic Cl pattern observed: 347, 349 (3:1 ratio
35Cl/37Cl).
4.7. Synthesis of the Weinreb amide derivatives
4.7.1. N-Methoxy-N-methyl-2-chloropropanamide 20
The title compound was prepared as described previously1 using
N,O-dimethylhydroxylamine hydrochloride (5.00 g, 51.23 mmol), 2-
chloropropionyl chloride (5.02 mL, 51.74 mmol) and triethylamine
(15.60 mL, 112.71 mmol) in CH2Cl2 (200 mL) for 4 h. Following the
work-up the amide 20 was isolated (7.30 g, 76%) as a yellow oil,
which was used without further purification. dH (270 MHz, CDCl3)
1.65 (3H, d, J 7, CH3-3), 3.24 (3H, s, NCH3), 3.79 (3H, s, OCH3), 4.85–
4.97 (1H, br q, CHCl); dC (270 MHz, CDCl3) 21.2 (CH3-3), 32.9 (br,
NCH3), 49.0 (OCH3), 62.1 (CHCl), 170.2 (CO).
NMR spectra of this compound (1H and 13C) were also recor-
ded in acetone-d6. dH 3.16 (3H, s, NCH3), 3.73 (3H, br s, OCH3),
6.77 (1H, br s, ClHC]), 7.28–7.62 (5H, m, ArH); dC 32.4 (br, NCH3),
62.2 (br, OCH3), 123.3 (br, aromatic CH), 130.1 (br), 131.8 (br),
133.8 (br).
When the operating temperature of the 1H NMR experiment
was elevated (in CDCl3), some sharpening of the signals was ob-
served. This sharpening was at the optimum at 50 ꢀC.
4.7.2. N-Methoxy-N-methyl-2-phenylthiopropanamide 10j
The title compound was prepared as outlined for 10i using N-
methoxy-N-methyl-2-chloropropanamide 20 (5.00 g, 33.00 mmol)
and thiophenol (4.10 mL, 39.60 mmol) in freshly prepared sodium
ethoxide [made from sodium (0.91 g, 39.60 mmol) and ethanol
(80 mL) at 0 ꢀC] for 18 h at room temperature. Following work-up
as described previously, the sulfide 10j was isolated (6.61 g, 89%) as
a clear oil, which was used without further purification. A sample
(300 mg) was prepared for analysis by chromatography on silica gel
using ethyl acetate–hexane (40:60) as eluent to give the sulfide
(260 mg, 87% recovery) as a clear oil. Found: C, 58.55; H, 6.90; N,
6.50; S, 14.47. C11H15NO2S requires C, 58.67; H, 6.67; N, 6.22; S,
14.22. dH (270 MHz, CDCl3) 1.46 (3H, d, J 7, CH3-3), 3.19 (3H, s, NCH3),
3.64 (3H, s, OCH3), 4.23–4.36 (1H, br q, CHS), 7.27–7.38 (3H, s, ArH),
7.45–7.54 (2H, m, ArH); dC (270 MHz, CDCl3) 17.7 (CH3-3), 32.5 (br,
NCH3), 41.7 (OCH3), 61.4 (CHS), 127.9 (aromatic CH), 128.5 (aromatic
CH), 133.2 (quaternary aromatic), 133.5 (aromatic CH), 173.0 (CO);
exact mass (EI) calculated for C11H15NO2S [M]þ 225.0824. Found:
225.0810; 225 (Mþ, 34%), 218 (18), 137 (100, MþꢁCONCH3OCH3),
109 (45, [SPh]þ), 65 (15).
Minor (more polar) b-chloroacrylamide 6j (0.93 g, 27%), tenta-
tively assigned as E. Found: C, 51.13; H, 4.86; N, 5.60; Cl, 13.64; S,
12.86. C11H12NClO2S requires C, 51.26; H, 4.69; N, 5.44; Cl, 13.75; S,
12.44. nmax/cmꢁ1 (film) 1659, 1474, 1440, 1378; dH (60 MHz) 2.82
(3H, s NCH3), 3.46 (3H, s, OCH3), 6.70 (1H, s, ClHC]), 7.20–7.78 (5H,
m, ArH); exact mass (EI) calculated for C11H12NClO2S [M]þ 257.0277.
Found: 257.0270. MS m/z 257, 259 (Mþ, 34), 222 (2, MþꢁCl), 197,
199 (30, MþꢁNR1R2), 169, 171 (29, MþꢁCONR1R2), 134 (100, [PhS–
C]CH]þ), 109 (13, [SPh]þ); isotopic Cl pattern observed: 257, 259
(3:1 ratio of 35Cl/37Cl).
The 1H NMR spectrum of this compound was also recorded in
acetone-d6. dH 2.92 (3H, br s, NCH3), 3.52 (3H, br s, OCH3), 6.74 (1H,
s, ClHC]), 7.21–7.57 (5H, m, ArH).
A fraction (500 mg) believed to be the dichloroacrylamide 21j
was also isolated. dH (60 MHz) 3.27 (3H, s, NCH3), 3.80 (3H, s, OCH3),
7.28–7.80 (5H, m, ArH).
Evidence for the acrylamide 15j was also seen in the crude NMR
spectrum at dH 5.36 (s) and 5.71 (s).

M. Kissane et al. / Tetrahedron 64 (2008) 7639–7649
7649
8. Bernardi, A.; Cardani, S.; Colombo, L.; Poli, G.; Schimperna, G.; Scolastico, C.
J. Org. Chem. 1987, 52, 888–891.
Acknowledgements
9. Stoit, A. R.; Pandit, U. K. Tetrahedron 1985, 41, 3345–3354.
10. A similar effect has been observed for the benzylsulfinyl derivative N-n-butyl-
Z-3-chloro-2-(benzylsulfinyl)propenamide, which is an oil at room tempera-
ture. When left at room temperature for a period of time, the Z isomer was seen
to interconvert to the E isomer.
IRCSET, BioResearch Ireland, Forbairt and University College
Cork are gratefully acknowledged for funding of this work.
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O
O
O
O
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