Investigation of the synthetic and mechanistic aspects of the highly stereoselective transformation of α-thioamides to α-thio-β- chloroacrylamides

Article abstract of DOI:10.1039/b618540a

Treatment of a series of α-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous α-thio-β- chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored - aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed. The Royal Society of Chemistry.

Full text of DOI:10.1039/b618540a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Investigation of the synthetic and mechanistic aspects of the highly
stereoselective transformation of a-thioamides to a-thio-b-chloroacrylamides†
Maureen Murphy,a Denis Lynch,a Marcel Schaeffer,a Marie Kissane,a Jay Chopra,a Elisabeth O’Brien,a
Alan Ford,a George Fergusonb and Anita R. Maguire*a
Received 19th December 2006, Accepted 13th February 2007
First published as an Advance Article on the web 8th March 2007
DOI: 10.1039/b618540a
Treatment of a series of a-thioamides with N-chlorosuccinimide results in efficient transformation to
the analogous a-thio-b-chloroacrylamides. The mechanistic pathway has been established through
isolation and characterisation of intermediate compounds. The scope of the transformation has been
explored—aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In
most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with
tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and
Z-stereoisomers is formed.
Pochat5 for the preparation of b-bromo-a-(ethylthio)acrylonitrile
5 whereby a-(ethylthio)acrylonitrile 4was treated with bromine in
carbon tetrachloride or acetonitrile as illustrated in Scheme 2.
Introduction
a-Chlorination of sulfides on treatment with a range of chlorinat-
ing agents such as N-chlorosuccinimide (NCS) is well established.1
As part of an ongoing synthetic programme in our laboratory,
the preparation of the a-chlorosulfide 2 derived from N-tolyl-
a-(phenylthio)propanamide (1) was required. Chlorination of a-
thioesters on treatment with NCS is well precedented2 and, there-
fore, this method was attempted with a-thioamide 1. However,
when 1 was treated with NCS, the reaction pathway was found
to be more complex. The expected a-chlorosufide 2 was formed
initially but, as this was not stable, it was transformed to further
products, notably the a-thio-b-chloroacrylamide 3 (Scheme 1).3 In
this paper, the detailed investigation of the mechanistic pathway
by which this product is formed is described. Furthermore, the
investigation of the scope of this transformation is described,
thereby providing an efficient and stereoselective synthetic route
to a-thio-b-chloroacrylamides.
Scheme 2
Results and discussion
Preliminary observations
Generation of the a-chlorosulfide 2 was observed by NMR when a-
(phenylthio)propanamide 1 was treated with 1 equivalent of NCS
◦
in carbon tetrachloride at 0 C for 3 h and following removal of
the succinimide by filtration (Scheme 3). Further investigations
led to the observation that at room temperature, after 24 h,
the same amount of NCS gave an essentially equimolar mixture
of a-chlorosulfide 2 and acrylamide 6. When the number of
equivalents of NCS was increased to two, under otherwise identical
reaction conditions, the major compound formed was a dichloride
7, although minor amounts of acrylamide 6 were also present.
Treatment of this crude reaction mixture with 1.5 equivalents of
zinc chloride in nitromethane and DCM gave a reaction mixture
containing two major products, which were isolated and identified
as N-4ꢀ-methylphenyl-Z-3-chloro-2-(phenylthio)propenamide (3)
and N-4ꢀ-methylphenyl-Z-2,3-(phenylthio)propenamide (8).
The unexpected highly stereoselective formation of the b-chloro-
a-thioacrylamide 3 caught our attention, providing a potentially
valuable series of highly-functionalised acrylamides which could
be envisioned to act as dienophiles or Michael acceptors, for
example. To explore the scope of this transformation, the synthesis
of a series of thioamides and treatment of each with NCS was
undertaken.
Scheme 1
Some reports of structurally-similar compounds have appeared,
for example Viehe et al. 4 mention a-thio-b-halo-a, b-unsaturated
esters/amides and b-haloacrylonitriles in a patent. No spectro-
scopic details for the amide derivative or details of a synthetic
method for the formation of esters and amides were reported in
this patent. However, Viehe employed a procedure described by
aDepartment of Chemistry, Analytical and Biological Chemistry Research
Facility, University College Cork, Ireland. E-mail: a.maguire@ucc.ie
bSchool of Chemistry, The University of St. Andrews, St. Andrews, Fife,
KY16 9ST, Scotland
† Electronic supplementary information (ESI) available: Full experimental
procedures and spectral data for all compounds described. See DOI:
10.1039/b618540a
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in stability compared to the a-chloro-a-thioesters studied by
McKervey et al.,6 which were found to be stable, as a solution
◦
in carbon tetrachloride at 0 C, for several years. The enhanced
reactivity of 2 relative to the ester derivative is presumably due to
increased sulfide stabilization of the carbocation generated on loss
of chloride, facilitated through conformational factors as a result
of the intramolecular hydrogen bond from the amide hydrogen to
the sulfide group.
On treatment of 1 with 1.1 equivalents of NCS at room
temperature for 24 hours, a 1 : 1 mixture of 2 and 6 was
obtained. When this mixture was passed through a column of
silica gel, complete conversion to 6 occurred. A pure sample of the
acrylamide was readily obtained in this manner.
A second equivalent of NCS was necessary for chlorination of
◦
the acrylamide to occur. At temperatures of 20–45 C in carbon
tetrachloride as solvent, the products resulting from treatment
of 1 with 2.2 equivalents of NCS were 6 and 7. Variation
of reaction times (16–24 h) and temperatures (20–45 ◦C) gave
various ratios of the two products. Despite many attempts at
chromatographic purification, it was not possible to obtain a pure
sample of 7: partial decomposition of 7 on storage or exposure to
silica gel to form the b-chloroacrylamide 3 was observed. However,
when N-benzyl-a-(phenylthio)propanamide (9) was treated with
2.2 equivalents of NCS at 40 ◦C for 17 h, the N-benzyl dichloride
101 formed, which proved considerably more stable than the N-
tolyl analogue (Scheme 4). Purification by chromatography gave
a pure sample of the N-benzyl dichloride 101, which was fully
characterized.
Scheme 3
Determination of the reaction pathway and mechanism
To determine the reaction pathway, the transformation of the a-
thioamide 1 to the b-chloroacrylamide 3 was explored in detail.
Each intermediate was isolated and identified, and the conditions
for the formation of each of the intermediates were determined.
The results of these experiments are outlined in Table 1, below.
It is evident from these results that as the number of equivalents
of NCS, reaction time and temperature increased, the major
products changed from the a-chlorosulfide 2 and acrylamide 6
under mild conditions to the dichloride 7 and b-chloroacrylamide
3 under more forcing conditions.
The a-chlorosulfide 2 was the only product formed when 1 was
treated with 1.1 equivalents of NCS at 0 ◦C for 3 h. Filtration of the
succinimide by-product allowed 1H NMR analysis of the carbon
tetrachloride solution of 2, but partial decomposition occurred
rapidly (ca. 50%in1 h) on concentration ofthe compound, or more
slowly (ca. 50% in 7 days) on storage in solution at temperatures
as low as −20 ◦C.
Scheme 4
Decomposition of 2 leads to 6 by elimination of HCl. The a-
chlorosulfides studied in this work were found to vary considerably
When 1 was treated with 2.1 equivalents of NCS at 40 ◦C, using
toluene as solvent in place of carbon tetrachloride, a mixture of 7
Table 1 Transformation of a-thioamide 1 to b-chloroacrylamide 3
Molar ratio of productsb
NCS/eq.
Temperature/◦C
Time/h
2
6
7
3
1.1
1.1
2.2
2.2
2.1
2.2
2.2
2.2
0
20
20
3
24
48
16–24
22
18–24
18
2
Only
1
—
1
1
—
—
2
—
—
—
—
40–45
Mixtures of 6 and 3, ratio dependant on time & temperature
40a
—
—
—
—
—
—
—
—
3.3
1
—
—
1
10
Only
Only
47–50
Reflux
Refluxa
a Reaction was conducted in toluene, each of the other reactions was conducted in carbon tetrachloride. b Ratios of products were determined by
integration of 1H NMR spectrum of crude reaction mixture.
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and 3 was isolated in a ratio of 3.3 : 1. However, when reactions
were conducted in carbon tetrachloride above 45 ◦C the major
product isolated was 3. When 1 was treated with 2.2 equivalents
of NCS at reflux in either carbon tetrachloride or toluene, 3 was
the only product detected. The difference in reaction time when
the higher boiling solvent, toluene, is used (2 h) in place of carbon
tetrachloride (18 h) is significant.
confirmed that 6 is transformed to 3 under the reaction conditions
(carbon tetrachloride, reflux, 18 h) and is an intermediate in the
reaction pathway. The fact that no dichloride 7 was isolated may
have been due to its lability in refluxing carbon tetrachloride.
Interestingly, transformation of 6 to 3 was less efficient than
transformation of 1 to 3 under the same reaction conditions.
(c) When a mixture of 6 and 1 (3 : 1) was stirred with 3
equivalents of NCS in CCl4 at room temperature for 24 h, 1 was
completely transformed to the dichloride, and it appeared that
some transformation of 6 had occurred as the ratio of 6 to 7 was
2 : 1 (estimated by integration of 1H NMR).
Based on these observations, the reaction mechanism in
Scheme 5 can be proposed.
(d) A sample containing a mixture of 7 and 3 (ca. 3 : 1) was
◦
heated at 47 C in CCl4 under nitrogen for 48 h. Partial thermal
decomposition of 7 to 3 was observed. 1H NMR integration data
showed that 50% of the dichloride 7 had decomposed to 3. Also,
a sample of 7 (containing minor amounts of 6 and 3), heated neat
at 80 ◦C under nitrogen, was completely converted to 3 in 2 h.
(e) When a sample of 7 was treated with anhydrous zinc chloride
in DCM and nitromethane at 20 ◦C, 3 was obtained.
Thus, experimental evidence for each step of the proposed
mechanism was secured.
Despite the convincing evidence for the polar reaction mech-
anism, it does not rule out another possible reaction pathway
involving captodative radical intermediates formed by homolytic
7
=
cleavage of the C Cl bond (Scheme 6).
Scheme 6
To establish if the captodative radical compound is a reaction
intermediate, a number of experiments were conducted to trap this
radical if it was formed.
Scheme 5
Sato, Ishibashi and Ikeda8–12 have shown that N-allyl-a-
chloroamide derivatives undergo efficient 5-exo-trig-cyclisation.
Based on their work, N-allyl-a-(phenylthio)propanamide (14) was
prepared and treated with 2.2 equivalents of NCS in CCl4 at reflux
or 1.95 equivalents of NCS in toluene at 90 ◦C (Scheme 7). If
the captodative radical 102 was formed, cyclisation as illustrated
would be expected to form the c-lactam. However, no evidence
for cyclisation was observed. The major product was the N-allyl-
b-chloroacrylamide 56 isolated by chromatography in 84% yield
from reaction in toluene and 56% yield from reaction in CCl4.
Since the N-allyl derivative did not cyclise, the N-cinnamyl-a-
(phenylthio)propanamide (15) was prepared, as the cinnamyl sub-
stituent would be expected to act as a more efficient radical trap.
Again, on treatment of the a-thioamide 15 with 2.2 equivalents of
NCS in CCl4 under reflux conditions, no cyclisation was observed
and the corresponding b-chloroacrylamide 57 was formed in 67%
yield as a white, crystalline solid. These experimental results
suggest that the elimination of HCl from the a-chlorosulfide
occurred by a polar mechanism rather than a radical pathway.
Thus, chlorination of the a-thioamide 1 using the first equivalent
of NCS generates the a-chlorosulfide 2. The mechanism of a-
chlorosulfide 2 formation is believed to involve the formation of a
chlorosulfonium ion. On elimination of HCl, the acrylamide 6 is
formed. A second equivalent of NCS again chlorinates the sulfur
substituent on the acrylamide to generate a chlorosulfonium ion.
This is followed by addition of chloride ion at the b-carbon to
introduce the b-chlorine. Further chloride addition to the resulting
sulfur-stabilized carbonium ion gives the dichloride 7. Subsequent
elimination of HCl, presumably via the carbocation, produces the
b-chloroacrylamide 3. The sulfur-stabilized carbocation generated
by conjugate addition of chloride to the acrylamide 6 may also be
deprotonated to form the b-chloroacrylamide 3 directly.
In order to determine that the proposed mechanism was correct,
the following series of experiments were performed:
(a) The decomposition of 2 to 6 on standing or on passing
through a column of silica gel (as mentioned earlier) confirms the
first step.
(b) When a sample of 6 was heated at 47 ◦C with 1.1 equivalents
of NCS in carbon tetrachloride, no evidence for formation of 7 or
3 was observed. However, when a sample of 6 was treated with 1.1
equivalents of NCS in carbon tetrachloride at reflux for 18 h, the
crude product mixture contained 6 and 3 in a ratio of 1 : 3. This
Synthesis of b-chloroacrylamides
Based on the serendipitous observation of the formation of the
b-chloroacrylamide 3, investigation of the transformation of the
series of a-thioamides 1, 9–50 (see the ESI for synthesis of
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Trichloride
104 R1 = Me, R2 = Me, R3 = Ph
Process optimisation. Since the initial discovery of a-thio-b-
chloroacrylamides, a considerable amount of research has been
carried out to optimize their formation. Toluene has replaced
carbon tetrachloride as the reaction solvent due to significantly
shorter reaction times and for safety reasons. While the succin-
imide by-product is soluble in hot toluene, it was found that, as the
reaction cooled, the by-product precipitated. Hence, almost all of
the succinimide can be removed by cooling the reaction solution at
0 ◦C for 30 minutes followed by filtration. Originally, recrystallised
N-chlorosuccinimide was employed but it was later demonstrated
that there was no significant advantage in using this compared
to unrecrystallised NCS, and commercial NCS is now routinely
used without recrystallisation. The ‘hot plunge’ method has also
proven more beneficial than heating the reaction solution from
room temperature. Using this method, following NCS addition
the reaction vessel is lowered into an oil bath which has been
pre-heated to the desired temperature. The more rapid heating
causes the reaction to cascade more efficiently through from the a-
chlorosulfide to the acrylamide to the dichloride and ultimately to
the b-chloroacrylamide. Heating the reaction solution from room
temperature leads to slower transformation of the intermediates,
which in turn leads to the formation of impurities.
The transformation from a-thioamide to b-chloroacrylamide
was carried out using a range of amide and thiol groups. Initially,
these transformations were carried out using 2.1–2.2 equivalents
of NCS at 130 ◦C for 2 hours. On closer examination, it was found
that impurities resulting from overchlorination were present in
many of the reaction mixtures under these reaction conditions.
These were identified as the trichloride (e.g., 113) and the
dichloroacrylamide (e.g., 114) presumably formed by elimination
of HCl from the trichloride. Having identified these impurities,
prevention of their formation was attempted in two ways: decrease
of the reaction temperature and reduction in the amount of NCS
used in the reaction (Table 3). These optimization experiments
were carried out using N-ethyl-2-(phenylthio)propanamide (10).
By reducing the reaction temperature, it was hoped that the rate
of over-chlorination would be decreased. Reducing the reaction
temperature from 130 to 90 ◦C (approximately the temperature
to which an oil bath would have been heated in order to reflux
carbon tetrachloride in the original experiments described above)
gave promising results. The trichloride 113 comprised 55% of
the product mixture, but it was not being transformed to the
dichloroacrylamide 114. The reaction time was next reduced from
13.5 to 4 hours. While this did not result in an improvement
in product purity, it demonstrated that the reaction could be
conducted over a shorter time period, whilst maintaining 100%
conversion of the starting sulfide.
Scheme 7
a-thioamides†) to the analogous b-chloroacrylamides 3, 51–
100 was undertaken3—the optimised results are summarized in
Table 2, indicating the broad scope of this synthetic transfor-
mation. In most instances, the crude products of the reactions
were sufficiently pure for use in further reactions, but could
be readily obtained in an analytically pure form through chro-
matography, trituration or recrystallisation. The efficiency of the
transformation and the purity of the crude products are readily
determined by integration of the 1H NMR signal for the vinylic b–
H, typically at 7–8 ppm. The synthesis of the b-chloroacrylamides
has been optimised so that synthetically useful amounts of these
materials can be easily prepared from the corresponding sulfides,
for example, the b-chloroacrylamide 51 has been successfully
synthesised on a 39 mmol scale resulting in isolation of over 9.5 g of
material after chromatography, with no evidence of side products
detected. The b-chloroacrylamides proved quite stable and easily
stored, and in many instances are crystalline solids.
Side products. Dichloroacrylamide
103 R1 = Me, R2 = Me, R3 = Ph
105 R1 = Me, R2 = Me, R3 = 4-MeOC6H4
106 R1 = Me, R2 = Me, R3 = Bn
107 R1 = Bn, R2 = H, R3 = Me
109 R1 = Bu, R2 = H, R3 = Me
To date, all of the optimization studies had been conducted
using 2.1–2.2 equivalents of NCS. The reaction mechanism
indicates that just 2 equivalents of NCS are required for complete
transformation. It was decided to reduce the quantity of NCS
employed to a figure closer to this theoretically-required amount.
Acrylamide
108 R1 = Bn, R2 = H, R3 = Me
110 R1 = Bu, R2 = H, R3 = Me
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Table 2 Synthesis of the b-chloroacrylamides
Entry
Sulfide
R1
R2
R3
R4
E/Z
Methoda
Product
Yield (%)b
1
2
3
4
5
6
7
8
1
p-Tol
Bn
Et
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
E
Z
E
Z
Z
Z
Z
Z
Z
Z
Z
Z
E
Z
Z
Z
Z
Z
Z
Z
Z
Z
A
A
A
A
A
A
A
B
3
91
81
81
89
81
69
84c
67
95
46
41d
36e
40f
20
65
67
84
84
96
88
64
59
73g
21
71h
65
64
70
70
79
84
58n
42i
17
70
83n
78
51
61
68j
63k
60
60
27l
19
13
17
27
13
14m
9
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
10
11
12
13
14
15
16
17
18
i-Pr
n-Bu
Me
Allyl
Cinnamyl
4-FC6H4
H
9
10
11
A
A
C
Ph
12
19
Me
Me
Ph
H
A
13
14
15
16
17
18
19
20
21
20
21
22
23
24
25
26
27
28
(
)-CH(CH3)Ph
H
H
H
H
H
H
H
H
Me
Ph
Ph
H
H
H
H
H
H
H
H
H
B
B
(S)-CH(CH3)Ph
Bn
p-Tol
4-FC6H4
p-Tol
Bn
n-Bu
D
D
D
A
E
A
A
n-Bu
n-Bu
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Et
Me
22
23
24
25
26
27
28
29
30
29
30
31
32
33
34
35
36
37
p-Tol
p-Tol
4-FC6H4
Et
4-FC6H4
Bn
4-FC6H4
n-Bu
Me
H
H
H
H
H
H
H
H
Me
4-NO2C6H4
i-Bu
i-Bu
i-Bu
i-Pr
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
E
A
A
A
A
A
A
A
A
E
A
A
A
A
F
F
F
F
F
B
E
B
E
B
E
B
E
31
32
33
34
35
36
37
38
39
40
38
39
40
41
42
43
44
45
46
47
p-Tol
Me
Ph
H
H
H
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
H
H
H
Me
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
H
4-FC6H4
Bn
n-Bu
i-Pr
p-Tol
p-Tol
41
42
43
48
49
50
p-Tol
H
H
H
Ph
Ph
Ph
Et
Et
Ph
Z
Z
Z
(S)-CHCH3Ph
p-Tol
a Method A: 1.95 equivalents NCS, toluene, 90 ◦C, 2–4 hours. Method B: 2.20 equivalents NCS, CCl4, reflux, 18 hours. Method C: 2.10 equivalents NCS,
toluene, 130 ◦C, 1.5 hours. Method D: 2.10 equivalents NCS, toluene, 120 ◦C, 2–3 hours. Method E: 2.20 equivalents NCS, toluene, reflux, 2.5 hours.
Method F: 1.80 equivalents NCS, toluene, 90 ◦C, 2 hours. b Unless indicated otherwise, the yields quoted are after chromatography on silica gel. c A
yield of 56% was obtained when the reaction was conducted in CCl4. d The crude product was isolated as an equimolar mixture. The Z isomer contained
∼10% of the E-isomer. e The E-isomer was isolated as a mixture (3 : 2) with the Z-isomer. f The Z-b-chloroacrylamide 62 was isolated as a 50 : 50
mixture with the dichloroacrylamide 103. A sample of the trichloride 104 was also isolated from this reaction. This was also conducted in CCl4—see
Scheme 8. g The Z-b-chloroacrylamide 72 was contaminated with the chloroacrylamide 105 (6%). h 74 was purified by trituration with 5% diethyl ether
in hexane. i The Z-b-chloroacrylamide 82 was contaminated with the dichloroacrylamide 106 (10%). j The crude product was composed of 75% 89, 15%
dichloroacrylamide 107 and 5% acrylamide 108. k The crude product contained 76% 90, 23% dichloroacrylamide 109 and 1% acrylamide 110. l The
acrylamide 111 and the trichloride 112 were also isolated from this reaction—see Table 7. m 99 and 100 were isolated as an equimolar mixture—see
Scheme 10. n For the two benzylthio N-alkyl derivatives 81 and 85 ∼20% of the E-isomer was detected in the product.
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Table 3 Optimisation of transformation of a-thioamide 10 to b-chloroacrylamide 52
Crude product ratiosa
NCS/eq.
Solvent
Temperature/◦C
Time/h
52 (%)
113 (%)
114 (%)
2.2
2.2
2.2
2.05
1.95
CCl4
D
16
13.5
4
2
2
53
45
59
81
>98
27
55
35
19
7
Toluene
Toluene
Toluene
Toluene
90
90
90
90
N.d.b
6
N.d.
N.d.
N.d.
a Crude product ratios as determined by 1H NMR spectroscopy. b N.d. = not detected by 1H NMR spectroscopy.
Table 4 Optimisation of transformation of a-thioamide 22 to b-
chloroacrylamide 66
Based on the previous temperature optimization experiments, the
reaction was attempted using 2.05 equivalents of NCS at 90 ◦C for
2 hours. At this stage the b-chloroacrylamide 52 was formed in a
4 : 1 ratio with the trichloride 113, the best result obtained at this
stage.
Although lowering the reaction temperature had improved the
selectivity, it now seemed that the selective formation of the b-
chloroacrylamide was more dependant on the amount of NCS
used in the reaction than on any other factor. It was therefore
decided to attempt the reaction using a slightly lower amount
of NCS than is theoretically required. The transformation was
thus attempted using 1.95 equivalents of NCS at 90 ◦C for
2 hours. When these reaction conditions were employed, the H
NMR spectrum of the crude product showed no evidence of any
impurities.
It has since been demonstrated that, for the transforma-
tion of phenylthioamides, isobutylthioamides, 4-methoxybenzene-
thioamides and benzylthioamides to their corresponding b-
chloroacrylamides, 1.95 equivalents of NCS in toluene at 90 ◦C for
2 hours results in the most efficient conversion. Table 2 summarises
these results.
Crude product ratiosa
NCS/eq.
Temperature/◦C
106 (%)
150 (%)
1
1.95
2.1
1.95
2.1
90
90
120
120
95
93
94
97
5
7
6
3
a Crude product ratios as determined by 1H NMR spectroscopy.
corresponding b-chloroacrylamides using 1.95 equivalents of NCS
in toluene at 90 ◦C for 2 hours led to the formation of a significant
amount of the dichloroacrylamide (Table 5).
a-Butanethio-derived b-chloroacrylamides. When the prepa-
ration of the b-chloroacrylamides of the n-butanethiol-derived
sulfides was attempted using the conditions described above, a
small, but appreciable, amount of the corresponding trichlorides
formed in each case, and therefore these transformations required
further optimization (Table 4).
As the dichloroacrylamide is a product which results from
overchlorination, the optimization of this transformation was
attempted by reducing the number of equivalents of NCS. For
the N-4-FC6H4 derivative 42, reducing the amount of NCS to
1.8 equivalents produced 74% of the b-chloroacrylamide 88, 20%
of the dichloroacrylamide 117 and 5% of the acrylamide 116,
an under-chlorination product. On decreasing the amount of
NCS further to 1.7 equivalents, 20% of the acrylamide 116 as
well as 13% of the dichloroacrylamide 117 were produced. The
dichloride 118 was not detected in these experiments. On the basis
of these results, the optimum conditions for the formation of the
b-chloroacrylamides of the S-methyl derivatives are the use of 1.8
equivalents of NCS in toluene at 90 ◦C for 2 hours.
Four reactions were conducted in toluene with the N-benzyl
derivative 22, two using 1.95 equivalents of NCS and two using
2.1 equivalents of NCS. One of each was lowered into an oil bath
at 90 ◦C and one into an oil bath at 120 ◦C, and each reaction was
heated for 2 hours. It was found that the harsher conditions gave
◦
the better results. Increasing the reaction temperature to 120 C
resulted in a decrease in the amount of trichloride 115 formed only
when 2.1 equivalents of NCS were employed. Thus, 2.1 equivalents
of NCS in toluene at 120 ◦C for 2 hours are the conditions
routinely employed for conversion of the butylthioamides to the
corresponding b-chloroacrylamide.
Tertiary b-chloroacrylamides. In earlier work, the preparation
of the b-chloroacrylamides of the tertiary amides, in which 2.1
equivalents of NCS in CCl4 at reflux were the conditions employed,
generally resulted in the formation of both the E- and Z- b-
chloroacrylamides and the dichloroacrylamide. For example, for
the N,N-dimethylphenylthio derivative (entry 12, Table 2), typical
a-Methanethio-derived- b-chloroacrylamides. The transforma-
tion of the methylthioamide derivatives 42 and 46 to their
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Table 5 Transformation of methylthioamides 42 and 46 to b-chloroacrylamides 88 and 92
Crude product ratiosb
Ra
NCS/eq.
Acrylamide (%)
b-Chloroacrylamide (%)
Dichloroacrylamide (%)
Tol
1.95
1.95
1.8
0
0
5
71
52
74
67
29
48
20
13
4-FC6H4
4-FC6H4
4-FC6H4
1.7
20
a R = Tol for 46, 92 and 119. R = 4-FC6H4 for 42, 88, 116, 117 and 118. b Crude product ratios as determined by 1H NMR spectroscopy.
Scheme 8
ratios of 62 : 63 : 103 were on the order of 4.6 : 2 : 1 (Scheme 8).
While separation of the b-chloroacrylamides is possible by chro-
matography on silica gel, the dichloroacrylamide 103 elutes with
the major Z-b-chloroacrylamide 62. In view of the results of
the optimization experiments on the other b-chloroacrylamides,
the possibility of reducing the amount of dichloroacry-
lamide contaminant by adjusting the reaction parameters was
explored.
The best results were obtained using 1.95 equivalents of NCS at
90 ◦C. On repeating this experiment on a 12 mmol scale, a small
amount (6%) of the dichloroacrylamide 105 was present in the Z-
chloroacrylamide 72 following chromatography. Regardless of the
conditions employed, the minor E-b-chloroacrylamide formed in
approximately 20% yield, suggesting that the dichloroacrylamide
is formed selectively from the Z-chloroacrylamide 72.
The transformation of N,N-dimethyl-2-(4ꢀ-methoxyben-
zenethio)propanamide 28 to the corresponding Z- and E-b-
chloroacrylamides 72 and 73 (entry 21, Table 2) was conducted
under a variety of conditions as shown in Table 6. The reactions
were carried out in toluene for 2 hours, the amount of NCS was
varied from 1.95 to 2.2 equivalents and the temperature varied
from 90 to 120 ◦C.
Extended chain b-chloroacrylamides. Treatment of the butana-
mide 47 and the pentamide 48 with 2.1 equivalents of NCS in
carbon tetrachloride at reflux resulted in the formation of the
E- and Z-isomers of the b-chloroacrylamides and their corres-
ponding acrylamides (Table 7 & entries 40 and 41, Table 2). On
replacing carbon tetrachloride with toluene at reflux, the b-chloro-
acrylamides were formed in elevated yields and transformation
Table 6 Optimisation of transformation of a-thioamide 28 to b-chloroacrylamides 72 and 73
Crude product ratiosa
NCS/eq.
Temperature/◦C
Time/h
72 (%)
73 (%)
105 (%)
Ratio of b-Clsa
2.2
1.95
2.2
90
90
120
120
2
2
2
2
60
78
61
74
20
22
21
18
20
N.d.
18
8
3.0 : 1
3.5 : 1
2.6 : 1
4.0 : 1
1.95
a As estimated from the 1H NMR spectra of the crude reaction products.
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Table 7 Treatment of 47 and 48 with NCS
Crude product ratiosa
Acrylamide (%)
R
Solventb
b-Chloroacrylamides E : Z (%)
Trichloride (%)
Me
Me
Et
CCl4
Toluene
CCl4
20
—
54
10
19 : 27
41 : 23
17 : 13
20 : 47
—
9
—
10
Et
Toluene
a Crude product ratios as determined by 1H NMR spectroscopy. b All reactions were conducted under reflux conditions.
of the acrylamides was improved—for the butanamide 47 no
butenamide was detected in the product mixture and for the
pentamide 48 the amount of pentenamide in the product mix-
ture decreased significantly from 54 to 10%. However, products
resulting from overchlorination, trichlorobutanamide 112 and
trichloropentanamide 121 were isolated from both reactions in
toluene. It is interesting to note that the major isomer isolated
changed when carbon tetrachloride or toluene was used as solvent.
During the chromatographic purification of a reaction mix-
ture, obtained from the treatment of pentanamide 48 with 2.1
equivalents of NCS in carbon tetrachloride, interesting gelation
properties were observed with the Z-isomer 95—the test tubes in
which 95 was collected from the column in ethyl acetate–hexane
contained gels, so that the test tubes could be turned upside down
without loss, and indeed, DCM had to be added to get the gels
out of the test tubes as they were not mobile. To illustrate this, the
amount of 95 in one test tube was quantified—a sample of just
86 mg of 95 in 9.5 ml of ethyl acetate–hexane formed a firm gel.
There has been considerable interest in the literature in gelation of
organic solvents by small molecules.13,14
Table 2). There was no evidence by 1H NMR spectroscopy of the
acrylamide derivative in the crude product mixture.
Treatment of 50 with 2.1 equivalents of NCS in carbon
tetrachloride at reflux led to a mixture of four products (Scheme 10
and entry 43, Table 2).
Complete separation of the four products by chromatographic
purification was not possible, 99 and 100 were isolated as an
inseparable mixture in a combined yield of 14%. The intermediate
acrylamide 123 formed as a single (Z)-isomer in 49% yield.
A fourth compound tentatively assigned as N-tolyl-a-chloro-b-
phenylpropenamide 113 was isolated as a low melting solid in 8%
yield. The formation of this acrylamide is believed to occur by
elimination of thiophenol from the intermediate a-chlorosulfide.
The diastereomeric propanamides 20-R*R*/R*S* were sepa-
rated chromatographically and treated individually with 2.2 equiv-
alents of NCS in carbon tetrachloride under reflux conditions, in
both cases the same b-chloroacrylamide 64 formed in addition to
the acrylamide 124. The reaction with 20-R*R* gave 64 in higher
yield (65%) than the corresponding reaction with 20-R*S*, which
produced 64 in 19% yield (Table 8).
Treatment of (S)-pentanamide 49 (as an equimolar mixture of
diastereomers) with NCS for 18 hours in carbon tetrachloride
led to isolation of the Z- and E-b-chloroacrylamides 97 and 98
in yields of 27 and 13%, respectively (Scheme 9 and entry 42,
The reaction of 21, which was an equimolar mixture of
diastereomers, with 2.2 equivalents of NCS in carbon tetrachloride
under reflux conditions was also carried out. The enantioenriched
b-chloroacrylamide 65 and acrylamide 125 were isolated in yields
of 67 and 15%, respectively (Table 8). As racemisation was not
envisaged, no attempt was made to establish the enantiopurity.
The relative stereochemistry of the diastereomeric
propanamides 20-R*R*/R*S*, as observed from the X-ray
crystal structure (Fig. 1), allows some insight into the differences
in efficiency of transformation of the diastereomeric sulfides. In
20-R*R*, the aromatic rings of the sulfide and amide groups are
staggered and therefore the initial chlorination of the sulfur is
Scheme 9
Scheme 10
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Table 8 Treatment of 20 and 21 with NCS
a-Thioamide
R
Acrylamide (%)a
b-Chloroacrylamide (%)a
20-R*R*
20-R*S*
21b
(
(
)-CH(CH3)Ph
)-CH(CH3)Ph
24
20
15
65
19
67
(S)-CH(CH3)Ph
a Isolated yields following purification by column chromatography. b This compound exists as a mixture of diasteromers at C-2; the enantiopure amine
was employed.
in Scheme 11 by the intramolecular hydrogen bond between
the amide and the sulfide. Loss of the b-proton must occur
coplanar with the vacant orbital, i.e., through either of the two
conformations A and B, shown in Scheme 11. Steric repulsion
between the amide carbonyl and the chloro substituent disfavour
conformation B and, therefore, elimination occurs exclusively
through conformation A, providing the Z-stereoisomer of the b-
chloroacrylamides.
Fig. 1
easier than in the case of 20-R*S* where the substituents are
closer together.
Stereochemistry
The b-chloroacrylamides are formed, in most cases exclusively, as
the Z-stereoisomers (Table 2). Single crystal X-ray crystallography
confirmed the Z-stereochemistry of the N-benzyl derivative 513
Scheme 11
and the stereochemistry of the other derivatives is assigned by
comparison. Notably, the signal for the b-H in the NMR spectra
of the chloroacrylamides is very distinctive; in cases where both
With the tertiary amides and the extended chain derivatives,
formation of both E- and Z-stereoisomers (60–63, 72–73, 82–
the E- and Z- isomers are formed this signal differs significantly as
83, 93–94, 95–96, 97–100) is observed. For the tertiary amides,
illustrated in Fig. 2. Exceptionally, for the two benzylthio N-alkyl
the conformation of the intermediate carbocation is different, as
intramolecular hydrogen bonding is not possible and, therefore,
deprotonation to form either the E- or Z-isomer is possible. In
derivatives 81 and 85 ∼20% of the E-isomer was detected in the
product.
the case of the extended-chain derivatives, the energetic difference
between the two conformations A and B is less, as the steric
demands of an alkyl group and a chloro substitutent are rather
similar, and therefore elimination through both conformations can
occur.
Treatment of a b-disubstituted propanamide with NCS
Having investigated the reaction of a-thio-n-alkanamides with
NCS in detail, we were interested to determine the effect of b-
branching on the transformation. The reaction of the b-methyl-
butanamide 126 with NCS was thus conducted under a variety
of conditions. The reactions were carried out using either toluene
Fig. 2
The stereochemical outcome of the transformation is deter-
mined in the final deprotonation step. The planar sulfur-stabilised
carbocation intermediate is held in the conformation illustrated
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Table 9 Treatment of 126 with NCS
Table 10 Synthesis of dichlorides
R
Dichloride
Yield (%)
Crude ratio of
productsa
Tol
Bn
i-Pr
Allyl
7
75
46a
50
45
101
130
131
NCS/eq. Solvent
Temperature/◦C Time/h 156
157 158
1
1
CCl4
CCl4
0
20
20
20
20
4
4
4
24
24
1
—
2
4
—
1
3
—
1
2
1
1
a Isolated yield following purification by column chromatography.
1
Toluene
Toluene
CCl4
2.1
2.1
2.1
Trace
—
—
2
—
—
at 40 ◦C for 16 hours (Table 10). These dichlorides were each
formed as mixtures with the respective b-chloroacrylamide and/or
acrylamide, and purification by column chromatography was not
possible as decomposition to the b-chloroacrylamide occurred
on exposure to silica gel. As mentioned earlier, the N-benzyl
derivative 101 could be purified chromatographically, but this was
an exception. The dichlorides were very easily characterised due
to a distinctive AB quartet in the 1H NMR spectra at 3.5–4.5 ppm
for the methylene protons.
Toluene 130
1
a Crude product ratios as determined by 1H NMR spectroscopy.
or carb◦on tetrachloride as solvent, the temperature varied from 0
to 130 C, the reaction time from 1 to 24 hours and the number
of equivalents of NCS from 1 to 2.1. The results are summarised
in Table 9. Evidently, elimination to form a b-chloroacrylamide is
not possible in this instance due to the b-branching.
Investigation of Lewis acid-catalysed decomposition of 130
& 131 was undertaken. In particular, we wished to establish if
elimination of HCl would be highly stereoselective producing
only the Z-isomer or, if a mixture of E/Z-b-chloroacrylamides
would be obtained. Treatment of 130 & 131 (crude products
containing ca. 50% of 130 or 131 in addition to the respective
b-chloroacrylamide and/or acrylamide) with zinc chloride, either
anhydrous or as a dichloromethane solution of the etherate, led to
elimination to the analogous b-chloroacrylamide 53, 56—in each
case stereospecifically Z (Scheme 12). 1.5 Equivalents of either
solid zinc chloride or zinc chloride etherate were used. However,
in practice, use of the zinc chloride etherate was more convenient.
Analysis of these results show interesting comparisons to those
obtained on treatment of N-tolyl-a-(phenylthio)propenamide 1
with NCS as illustrated in Table 1.
◦
At 0 C using 1 equivalent of NCS, chlorination of 1 to form
2 readily occurred whereas chlorination of sulfide 126 occurred
at room temperature only. In contrast to the reaction of 1 with
1 equivalent of NCS at 20 ◦C, where only acrylamide 6 and a-
chlorosulfide 2 were formed, some dichloride 129 was also detected
in addition to 127 and 128 in the reaction of 126 under the same
conditions.
It can be seen from the results in Table 9 that the use of
carbon tetrachloride results in more efficient transformation of
126 than the use of toluene. Under identical conditions, with the
exception of solvent, incomplete transformation to the dichloride
129 was observed in toluene at room temperature in 24 h, while
use of carbon tetrachloride led to 129, essentially exclusively.
Furthermore, use of 1 equivalent of NCS in toluene gave a lower
ratio of dichloride 129 to acrylamide 128. However, in refluxing
toluene and at room temperature in carbon tetrachloride, the
transformation to 129 was essentially quantitative, 80% (following
purification by chromatography) in toluene and 90% in carbon
tetrachloride as estimated by 1H NMR spectroscopy.
Scheme 12
Treatment of the dichloride 7 with a range of reagents was
briefly explored: 7 (∼90% pure) was treated with 1.5 equivalents
triethylamine, methylaluminium chloride, p-toluenesulfonic acid
and 1 equivalent hydrochloric acid (0.1 M) individually at room
temperature for 20–24 h in DCM (Table 11). None of these
reagents brought about any significant transformation of the
dichloride 7 which was recovered in 70–80% yield as estimated
by 1H NMR integration.
Zinc chloride catalysed transformation of dichlorides
As mentioned earlier, during studies to establish the reaction mech-
anism, the dichloride 7 was treated with anhydrous zinc chloride
◦
in DCM and nitromethane at 20 C. Two products resulted: the
b-chloroacrylamide 3 and N-tolyl-2,3-di(phenylthio)propenamide
8 (which is presumably formed by nucleophilic substitution of
the chloride of 3 by thiophenol formed by decomposition of the
dichloride, Scheme 3).
A brief study on the formation of a number of dichlorides
was conducted. This involved the preparation of dichlorides 130
and 131 by treatment of 11 and 14 with 2.2 equivalents of NCS
Conclusion
The b-chloro-a-thioacrylamides (3, 51–100) prepared in this work
are novel compounds and offer interesting synthetic potential,
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Table 11
Reagents
X-Ray crystal determination of 20-R*R* and 20-R*S*
The structures were determined using data collected with an Enraf
Equivalents
7 (% yield)
6 (% yield)
Nonius CAD4 diffractometer (graphite monochromator, Mo Ka
ZnCl2 (s)
ZnCl2·Et2O
MeAlCl2
TsOH
1.5
1.5
1.5
1.5
1.0
28
22
5
4
˚
radiation k = 0.71073 A). Crystal data for 20-R*R*: C17H19NOS,
crystal dimensions 0.40 × 0.15 × 0.15 mm, orthorhombic, space
No reaction
No reaction
No reaction
group Pca21 chosen and confirmed by the successful refinement,
HCl
˚
−3
a = 8.1168(11), b = 18.618(5), c = 10.168(2) A, V = 1536.5(6)
3
˚
A , Mr = 285.40, Z = 4, Dc = 1.234 g cm , l (Mo Ka) =
0.20 mm−1, F (000) = 608, S = 1.009, R1=0.0827 (for 973 observed
reflections), wR2 = 0.2278 for all 1771 unique reflections. Crystal
data for 20-R*S*: C17H19NOS, crystal dimension 0.40 × 0.40 ×
0.20 mm, monoclinic, space group Cc chosen and confirmed by
the successful refinement, a = 12.848(3), b = 13.3462(13), c =
for example as Michael acceptors or dienophiles. The ease and
stereoselectivity of the transformation on exposure to NCS, broad
scope in terms of the nature of the substituents, and amenability
to production of multigram quantities of the highly-functionalised
b-chloro-a-thioacrylamides are particularly significant.
◦
3
˚
˚
18.932(4) A, b = 103.94(2) , V = 3175.5(11) A , Mr = 285.40,
Z = 4, Dc = 1.194 g cm−3, l (Mo Ka) = 0.19 mm−1, F (000) =
1216, S = 1.004, R1 = 0.0399 (for 1969 observed reflections), wR2 =
0.0891 for all 3597 unique reflections.‡
Experimental
The crystals were of rather poor quality and, although some
diffraction peaks were not well defined, the reflection/parameter
ratios were still greater than 9 and the analyses established the
relative stereochemistries unequivocally.
All solvents were distilled prior to use as follows: dichloromethane
was distilled from phosphorus pentoxide and ethyl acetate 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
Intermediates in the synthesis of N-4ꢀ-methylphenyl-3-
chloro-2-phenylthiopropenamide (6)
˚
distilled from sodium and stored over 4 A molecular sieves.
N-4ꢀ-Methylphenyl-2-chloro-2-(phenylthio)propanamide (2).
A
1
Dimethylformamide was stored overnight over calcium hydride,
˚
solution of N-4ꢀ-methylphenyl-2-(phenylthio)propanamide
then distilled and stored over 4 A molecular sieves. Organic phases
◦
were dried using anhydrous magnesium sulfate. All commercial
reagents, including N-chlorosuccinimide, were used without fur-
ther purification.
(100 mg, 0.37 mmol) in carbon tetrachloride (2 ml) at 0 C was
stirred. NCS (54 mg, 0.41 mmol) was added and the stirring
was continued for a further 3 h at 0 ◦C. Filtration to remove
the succinimide by-product gave a solution of a-chlorosulfide 2
in carbon tetrachloride. The transformation was quantitative, dH
(CCl4) (60 MHz) 2.11 [3 H, s, C(3)H3], 2.37 (3 H, s, ArCH3), 6.83–
7.83 (9 H, m, ArH). This compound is very labile (see below).
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 (∼20 ◦C) in deuterated chloroform (CDCl3) unless
otherwise stated, using tetramethylsilane (TMS) as an internal
standard. Chemical shifts were expressed in parts per million
(ppm) and coupling constants in Hertz (Hz).
N-4ꢀ-Methylphenyl-2-(phenylthio)propenamide (6). A solution
of the a-thioamide 1 (100 mg, 0.37 mmol) in carbon tetrachloride
(2 ml) was stirred at room temperature, NCS (54 mg, 0.41 mmol)
was added in one portion and stirring was continued for 24 h.
Filtration and evaporation of the solvent gave the crude product
which was an equimolar mixture of 2 and 6. After 24 h standing
neat at room temperature the a-chlorosulfide 2 had almost entirely
decomposed to 6. Purification by chromatography using ethyl
acetate–hexane (5 : 95) as eluent gave the acrylamide 6 (39 mg,
39%) as a white, crystalline solid, mp 137–139 ◦C; (found C, 71.02;
H, 5.66; N, 5.27. C16H15NOS requires C, 71.34; H, 5.61; N, 5.20%);
mmax/cm−1 (KBr) 3344 (br, NH), 1665 (CO), 1592; dH (270 MHz)
Elemental analyses were performed by the Microanalysis Labo-
ratory, 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 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.
=
2.28 (3 H, s, ArCH3), 6.08, 6.83 (2 × 1 H, 2 × br s, CH2 ), 7.02–
7.61 (9 H, m, ArH), 8.52 (1 H, br s, NH); dC (67.8 MHz) 20.87
(ArCH3), 119.92, 127.60, 129.19, 129.63 (aromatic CH), 132.6
=
(CH2 ), 133.52, 134.81, 135.06, 136.25 (quaternary aromatic C
and [C(2)S], 161.49 (CO); m/z 269 (M+, 100%), 160 (37), 135 (68),
120 (51), 91(56).
N-4ꢀ-Methylphenyl-2,3-dichloro-2-(phenylthio)propanamide (7).
A solution of the sulfide 1 (0.40 g, 1.46 mmol) in carbon
tetrachloride was stirred under nitrogen at room temperature. NCS
Selected experimental data, including representatives of each
of the synthetic methods, are given below—full experimental
procedures and spectral data for all compounds described in the
paper are given in the ESI.†
‡ CCDC reference numbers 630666 and 630667. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b618540a
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(0.43 g, 3.2 mmol) was added in one portion and the mixture was
stirred for 10 min at room temperature then heated to 40 ◦C and
stirred at this temperature for 17 h. Filtration and evaporation of
Preparation of b-chloroacrylamides
N-4ꢀ-Methylphenyl-Z-3-chloro-2-(phenylthio)propenamide (3).
1
the solvent from the filtrate gave the crude product which by H
Method A. Unrecrystallised NCS (5.57 g, 41.73 mmol) was
added in one portion to a solution of the sulfide 1 (5.80 g,
21.40 mmol) in toluene (116 ml). The flask was immediately
immersed in an oil bath at 90 ◦C and heating was maintained
NMR was at least 75% dichloride 7 containing a minor amount
of 3. Slow decomposition to 3 was observed on standing (35%
of 7 had been transformed to 3 after 10 days at −20 ◦C) or on
stirring in DCM with silica (36% of 7 had been transformed to 3
after 22 h). The dichloride 7 was characterised as a mixture with
3: dH (270 MHz) 2.32 (3 H, s, ArCH3), 3.94–4.48 (2 H, ABq, J 11,
CH2), 7.03–7.69 (9H, m, ArH), 8.08 (1 H, br s, NH). Characteristic
signals for the b-chloroacrylamide 3 were also present.
◦
for 3.5 h with stirring. The reaction mixture was cooled to 0 C
and the succinimide by-product removed by filtration. The solvent
was evaporated at reduced pressure to give the b-chloroacrylamide
3 as an off-white solid. The crude product was purified by
chromatography on silica gel using ethyl acetate–hexane (20 : 80)
as eluent to give the b-chloroacrylamide 3 as a colourless solid
(5.93 g, 91%), mp 110–111 ◦C; (found C, 63.34, H, 4.69; Cl, 11.98;
N, 4.34; S, 10.24. C16H14ClNOS requires C, 63.26; H, 4.64; Cl,
11.67; N, 4.61; S, 10.55%); mmax/cm−1 (KBr) 3336 (b, NH), 1653
(CO), 1523, 817; dH (270 MHz) 2.28 (3H, s, ArCH3), 7.04–7.45 (9
N-Benzyl-2,3-dichloro-2-phenylthiopropanamide
was prepared following the procedure described for the
preparation of dichloride using N-benzyl-2-(phenylthio)-
(101). This
7
propanamide 9 (0.15 g, 0.55 mmol), NCS (0.16 g, 1.22 mmol)
and carbon tetrachloride (4 ml) and a reaction time of 16 h to
give a reaction mixture containing dichloride 101 (0.12 g) as
an off-white solid. Purification by chromatography using ethyl
acetate–hexane (5 : 95) as eluent gave the dichloride 101 (86 mg,
46%) as a white, crystalline solid, mp 93–94 ◦C; (found C, 56.32;
H, 4.39; N, 4.50; S, 9.71. C16H15Cl2NOS requires C, 56.48; H,
4.44; N, 4.12; S, 9.42%); mmax/cm−1 (KBr) 3368 (br NH), 1667
(CO amide); dH (270 MHz) 3.88–4.45 (2 H, ABq, J 12, CH2Cl),
7.13–7.63 (11 H, m, ArH and NH); dC (67.8 MHz) 44.63 (NCH2),
50.52 (CH2Cl), 81.50 [C(2)Cl], 127.76, 128.02, 128.64, 129.18,
130.85 (aromatic CH), 136.84 (quaternary aromatic C), 137.39
(aromatic CH), 139.63 (quaternary aromatic C), 164.88 (CO);
m/z 339 (M+, 18%), 269 (100, M+-2Cl).
=
H, m, ArH), 8.05 [1H, s, C(3)HCl ], 8.63 (1H, b s, NH); dC (67.8
MHz) 20.8 (ArCH3), 120.3, 127.4, 128.3, 129.5, 129.6 (aromatic
CH), 130.9, 132.6, 134.5, 134.7 [quaternary aromatic C or C(2)S],
+
+
=
140.3 [C(3)HCl ], 160.3 (CO). m/z 303 (M , 42%), 267 (30, M
+
= =
−Cl), 159 (23), 134 (100, [PhS C CH] ), 106 (21), 77 (18, Ph).
N-3ꢀ-Phenylpropenyl-Z-3-chloro-2-(phenylthio)propanamide
(57).
Method B. A solution of the sulfide 15 (0.51 g, 1.7 mmol) in
carbon tetrachloride (10 ml) was stirred at room temperature
under nitrogen, NCS (0.50 g, 3.7 mmol) was added in one
portion. The reaction mixture was stirred at room temperature
for 10 min then heated to reflux for 18 h. The reaction mixture was
cooled, filtered and concentrated to give the b-chloroacrylamide
57. Purification by chromatography using ethyl acetate–hexane
(10 : 90) as eluent gave 57 (0.37 g, 67%) as a colourless oil,
mmax/cm−1 (neat) 3384 (br NH), 1651 (CO a, b-unsaturated amide);
dH (270 MHz) 3.97–4.03 [2H, m, C(1ꢀ)H2], 5.86–5.97 [1H, dt, J
16, 6, C(2ꢀ)H], 6.27 [1H, dd, J 16, < 1, C(3ꢀ)H], 6.98 (1H, br s,
Lewis acid mediated decomposition of dichloride 7
ZnCl2 treatment of N-4ꢀ-methylphenyl-2,3-dichloro-2-(phenyl-
thio)propanamide (7).
A sample of dichloride 7 (2.70 g,
8.0 mmol) was freshly prepared by stirring N-4ꢀ-methylphenyl-2-
(phenylthio)propanamide 1 (1.89 g, 7.0 mmol) with NCS (1.95 g,
14.6 mmol) in toluene (40 ml) at 40 ◦C for 22 h followed by filtration
of the succinimide by-product and evaporation of the filtrate. This
sample, which was 90% pure by 1H NMR, was dissolved in DCM
(13 ml) and nitromethane (9 ml). Zinc chloride (oven dried) (3.25 g,
23.9 mmol) was added and the solution was stirred at RT for
20 h. Water (20 ml) and DCM (20 ml) were added and the phases
were separated. The aqueous phase was extracted with DCM (2 ×
10 ml) and the combined organic layers were washed with brine
(3 × 10 ml), dried and evaporated. Purification by chromatography
using ethyl acetate–hexane (5 : 95) as eluent gave the Z-b-
chloroacrylamide 3 (0.59 g, 28%) as a white, crystalline solid (spec-
tral characteristics were identical to those described earlier) and N-
4ꢀ-methylphenyl-2,3-di(phenylthio)propenamide (8, 138 mg, 5%)
as a white, crystalline solid, mp 109–110 ◦C; (found C, 70.03; H,
5.06; N, 3.78; S, 16.54. C22H19NOS2 requires C, 70.00; H, 5.07; N,
3.76; S, 16.99%); mmax/cm−1 (KBr) 3255 (br NH), 1640 (CO), 1592;
dH (270 MHz) 2.28 (3H, s, ArCH3), 7.07–7.55 (14H, m, ArH),
=
NH), 7.18–7.42 (10H, m, ArH), 7.96 [1H, s, C(3)HCl ]; dC (67.8
MHz) 41.9 [C(1ꢀ)H2], 124.6, 126.46, 127.1, 127.4, 128.18, 128.5,
=
129.5 (aromatic CH or CH CH), 130.4 [quaternary aromatic C or
=
C(2)S], 132.1 (aromatic CH or CH CH), 132.9, 136.4 [quaternary
=
aromatic C or C(2)S], 139.6 [C(3)HCl ], 162.2 (CO); m/z 329
(M , 28%), 294 (52, M −Cl), 184 (69), 134 (100, [PhS C CH] ).
+
+
+
= =
N,N-Diphenyl-Z-3-chloro-2-(phenylthio)propenamide (60) and
N,N-diphenyl-E-3-chloro-2-(phenylthio)propenamide (61).
Method C. NCS (1.69 g, 12.0 mmol) was added in one portion
to a solution of sulfide 18 (2.00 g, 6 mmol) in toluene (40 ml).
The flask was immediately immersed in an oil bath at 130 ◦C
and heating at reflux was maintained for 1.5 h while stirring.
The reaction mixture was cooled to 0 ◦C, the succinimide by-
product was removed by filtration and the solvent was evaporated
under reduced pressure to give a crude reaction mixture (close
to quantitative) of E- and Z-b-chloroacrylamides (equimolar
mixture). Purification by repeated chromatography was possible
using DCM–hexane (50 : 50) to elute the less-polar N,N-diphenyl-
E-3-chloro-2-(phenylthio)propenamide (61, tentatively assigned)
(Rf 0.4 ethyl acetate–hexane (25 : 75) as eluent) (0.77 g, 36%
characterised as a mixture (3 : 2) with the Z-isomer) as a low-
melting solid, (found 69.29; H, 4.56; N, 3.53; S, 9.00; Cl, 9.69.
=
8.69 [1H, s, C(3)H ], 8.74 (1H, br s, NH); dC (67.8 MHz) 20.85
(ArCH3), 115.00 [C(2)S], 119.94, 126.55, 127.25, 129.05, 129.45,
131.05 (aromatic CH), 133.28, 133.30, 134.13, 135.17 (quaternary
+
=
aromatic C), 156.00 [C(3)H ], 160.86 (CO); m/z 378 (M , 100%),
+
+
= =
268 (45, M -PhSH), 165 (75), 134 (84, [PhS C CH] .
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C21H16ClNOS requires C, 68.94; H, 4.41; N, 3.83; S, 8.76; Cl,
76–77 ◦C; (found C, 61.03; H, 5.11; N, 4.19; Cl, 10.94; S, 9.51.
C17H16NClO2S requires C, 61.16; H, 4.83; N, 4.20; Cl, 10.62;
S, 9.60%); mmax/cm−1 (KBr) 3323 (br, NH), 1636 (CO), 1494,
1029, 820; dH (270 MHz) 3.83 (3H, s, OCH3), 4.42 (2H, d, J 6,
CH2Ar), 6.80–7.46 (10H, m, ArH, NH seen as bs at dH 7.09), 7.81
=
9.69%); dH (270 MHz) 6.24 [1H, s, C(3)HCl ], 6.94–7.63 (15H, m,
ArH); dC (67.8 MHz) signal seen in 13C NMR of mixture at 122.6
[quaternary aromatic C or C(2)S], other signals present in complex
series of peaks between 127 and 143 ppm), 165.3 (CO); m/z 365
+
+
+
= =
=
(M , 22%), 330 (25, M –Cl), 167 (55), 134 (95, [PhS C CH] );
and ethyl acetate–DCM–hexane (20 : 40 : 40) to elute the more
polar N,N-diphenyl-Z-3-chloro-2-(phenylthio)propenamide (60,
tentatively assigned) (Rf 0.35) (0.89 g, 41% contains < 10% of E-
isomer) as a light green, crystalline solid, mp 125–130 ◦C; (found
68.60; H, 4.50; N, 3.59; Cl, 9.80; S, 8.42. C21H16ClNOS requires
C, 68.94; H, 4.41; N, 3.83; Cl, 9.69; S, 8.76%); mmax/cm−1 (KBr)
1644, 1586 (CO a, b-unsaturated amide); dH (270 MHz) 6.76 (3H,
[1H, s, C(3)HCl ]; dC (67.8 MHz) 44.1 (CH2Ar), 55.4 (OCH3),
115.0, 115.3 (aromatic CH), 123.1 (S-C), 127.7, 128.3, 131.3
(aromatic CH), 133.7, 135.6 [quaternary aromatic C or C(2)S],
=
137.5 [C(3)HCl ], 159.6 (COMe), 162.5 (CO); m/z (EI) 333.0584
(M+, C17H16N35ClO2S requires 333.0590). 333 (M+, 50%), 298
(7, M+–Cl), 164 (25, M+–CONHBn–Cl), 158 (75, M+–SAr–HCl),
149 (23, [SAr]+), 91 (100).
A signal corresponding to the analogous dichloroacrylamide
was also seen at dH 4.21.
=
br m, ArH), 7.07 [1H, s, C(3)HCl ], 7.23–9.67 (12H, m, ArH); dC
(67.8 MHz) 127.2, 127.6 (aromatic CH), 128.6, 128.7 [quaternary
N-4ꢀ-Fluorophenyl-Z-3-chloro-2-(methylthio)propenamide (88).
aromatic C or C(2)S], 129.0, 129.2, 129.3, 131.7 (aromatic CH),
=
133.9, 136.8 [quaternary aromatic C or C(2)S], 142.5 (C(3)HCl ),
Method F. Unrecrystallised NCS (5.64 g, 42.50 mmol) was
added in one portion to a solution of the sulfide 42 (5.00 g,
23.50 mmol) in toluene (100 ml). The flask was immediately
immersed in an oil bath at 90 ◦C and heating was maintained
for 2 hours with stirring. The reaction mixture was cooled to 0 ◦C
and the succinimide by-product removed by filtration. The solvent
was evaporated at reduced pressure to give the b-chloroacrylamide
88 as a brown solid. The 1H NMR of the crude product showed the
composition of the mixture to be 70% 88, 20% dichloroacrylamide
117 (evidence for presence at dH 2.34) and 10% dichloride 118
(dH 4.07, 4.12, ABq, J 11, CH2Cl). The product was purified by
chromatography on silica gel using ethyl acetate–hexane (5 : 95)
as eluent to give the b-chloroacrylamide 88 as a white solid (61%),
mp 89–91 ◦C; (found C, 48.55; H, 3.69; N, 5.84; Cl, 14.04; F,
7.73; S, 13.28. C10H9NClFOS requires C, 48.88; H, 3.69; N, 5.70;
Cl, 14.43; F, 7.73; S, 13.05%); mmax/cm−1 (KBr) 3339, 1652 (CO),
1507, 1211; dH (300 MHz) 2.31 (3H, s, SCH3), 7.02–7.09 [2H, m,
165.4 (CO); m/z 365 (M+, 13%), 330 (22, M+- Cl), 169 (45,
+
+
= =
[NPh2 + H] ), 134 (100, [PhS C CH] ).
N-Benzyl-Z-3-chloro-2-(n-butylthio)propenamide (66).
Method D. Unrecrystallised NCS (4.47 g, 33.47 mmol) was
added in one portion to a solution of the sulfide 22 (4.00 g,
15.94 mmol) in toluene (80 ml). The flask was immediately
immersed in an oil bath at 120 ◦C and heating was maintained
for 3 hours with stirring. The reaction mixture was cooled to
0
◦C and the succinimide by-product removed by filtration.
The solvent was evaporated at reduced pressure to give the
crude b-chloroacrylamide 66 (4.42 g, 98%) as an oil which was
purified by chromatography on silica gel using ethyl acetate–
hexane (gradient elution 5 to 30% ethyl acetate) as eluent to give the
b-chloroacrylamide 66 as a clear oil (3.76 g, 84%) which solidified
on storing in the freezer overnight, (found C, 58.75; H, 6.31; N,
5.06; S, 11.70. C14H18ClNOS requires C, 59.25; H, 6.39; N, 4.94;
S, 11.30%); mmax/cm−1 (film) 3304 (br NH), 1648 (CO), 1560; dH
(270 MHz) 0.87 (3H, t, J 7, CH3), 1.28–1.62 [4H, m, C(3ꢀ)H2,
C(2ꢀ)H2], 2.67 (2H, d, J 7, SCH2), 4.54 (2H, d, J 6, NCH2), 7.24–
ꢀ
ꢀ
=
ArC(3 )H], 7.54–7.60 [2H, m, ArC(2 )H], 7.84 [1H, s, C(3)HCl ],
9.01 (1H, b s, NH); dC (75.5 MHz) 17.35 (SCH3), 115.9 [d, 2JCF 22,
3
aromatic CH, ArC(3ꢀ)], 121.8 [d, JCF 8, aromatic CH, ArC(2ꢀ)],
4
133.2 [d, JCF 3, quaternary aromatic C, ArC(1ꢀ)], 134.0 [C(2)S],
=
7.39 (5H, m, ArH), 7.50 (1H, b s, NH), 7.78 [1H, s, C(3)HCl ];
1
dC (67.8 MHz) 13.9 [C(4ꢀ)H3], 22.1 [C(3ꢀ)H2], 32.2 [C(2ꢀ)H2], 34.5
(SCH2), 44.5 (NCH2), 128.1, 128.2, 129.2 (aromatic CH), 132.2
=
139.1 [C(3)HCl ], 159.7 [d, JCF 245, quaternary aromatic C,
ArC(4ꢀ)], 160.7 (CO); m/z (EI) 245 (M+, 20%), 210 (30), 135 (22),
107 (100).
=
(quaternary aromatic C), 137.9 [C(3)HCl ], 138.2 [C(2)S], 163.5
(CO); m/z (EI) 283 (M+, 8%), 248 (12, M+–Cl), 158 (22), 106 (11),
91 (68).
During optimization studies, characteristic signals for the
=
acrylamide 116 were seen at dH 6.45 (s, one of CH2 ) and 5.58 (s,
=
one of CH2 ).
A trace amount (2%) of the corresponding trichloride was
evident in the NMR spectra of both the crude and the purified
material as a singlet at dH 6.56.
Products obtained from treatment of N-4ꢀ-methylphenyl-3-
methyl-2-(phenylthio)butanamide (126) with NCS
N-Benzyl-Z-3-chloro-2-(4ꢀ-methoxybenzenethio)propenamide
(70).
N-4ꢀ-Methylphenyl-2,3-dichloro-3-methyl-2-(phenylthio)butana-
mide (129). N-4ꢀ-Methylphenyl-3-methyl-2-(phenylthio)butana-
mide (126, 0.99 g, 3.3 mmol) and NCS (1.05 g, 7.0 mmol)
were heated in toluene (30 ml) at 130 ◦C. After 1 h TLC
analysis indicated that the reaction was complete. Purification
by chromatography using ethyl acetate–hexane (7 : 93) as eluent
gave 129 (0.94 g, 80%) as a yellow, crystalline solid, mp 75–80 ◦C;
(found C, 58.82; H, 5.14; N, 3.74; S, 19.31. C18H19Cl2OS requires
C, 58.68; H, 5.20; N, 3.80; S, 19.26%); mmax/cm−1 (KBr) 3405
(br NH), 1688 (CO amide); dH (270 MHz) 2.08 [3H, s, C(3)H3],
2.14 [3H, s, C(3)H3], 2.33 (3H, s, ArCH3), 7.08–7.65 (9H, m,
ArH), 8.45 (1H, br s, NH); dC (67.8 MHz) 20.9 (ArCH3), 30.8,
Method E. Unrecrystallised NCS (0.96 g, 7.14 mmol) was
added in one portion to a solution of the N-benzyl-2-(4ꢀ-
methoxybenzenethio)propanamide (26, 1.04 g, 3.40 mmol) in
toluene (21 ml). The flask was immediately immersed in an oil bath
◦
at 130 C and heating was maintained for 2 hours with stirring.
The reaction mixture was cooled to 0 ◦C and the succinimide
by-product removed by filtration. The solvent was evaporated
at reduced pressure to give the crude b-chloroacrylamide 70.
The crude product was purified by chromatography on silica
gel using ethyl acetate–hexane (20 : 80) as eluent to give the b-
chloroacrylamide 70 as a colourless solid (720 mg, 64%), mp
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mixture with the b-chloroacrylamide 56: dH (270 MHz) 3.60–3.95
[2H, m, C(1ꢀ)H2], 3.72–4.30 [2H, ABq, J 11, C(3)H2], 4.72–5.98
31.5 {[C(3)H3]2}, 74.6 [C(3)Cl], 94.1 (CClS), 119.9, 128.1, 129.1
(aromatic CH), 129.5 (quaternary aromatic C), 130.4 (aromatic
CH), 134.1, 135.0 (quaternary aromatic C), 137.1 (aromatic CH),
=
(3H, m, CH CH2), 6.57 (1H, br s, NH), 7.10–7.83 (5H, m, ArH).
162.9 (CO); MS m/z 367 (M+, 28%), 297 (16, M+-2Cl), 198 (98),
(Characteristic signals for the b-chloroacrylamide 56 were also
+
= =
present.)
163 (29, [PhS C C(CH3)2] ).
N-4ꢀ-Methylphenyl-3-methyl-2-(phenylthio)-2-butenamide (128)
and N-4ꢀ-methylphenyl-2-chloro-3-methyl-2-(phenylthio)butana-
mide (127). NCS (44 mg, 0.33 mmol) was added to a
stirred solution of N-4ꢀ-methylphenyl-3-methyl-2-(phenylthio)-
butanamide 126 (100 mg, 0.33 mmol) in carbon tetrachloride
(2 ml) at RT. An aliquot was removed which contained 127
dH (60 MHz, CCl4) 1.10 (3H, d, J 8), 1.35 (3H, d, J 8), 2.28
(3H, s, ArCH3), 2.90–3.12 [1H, m, C(3)H], 6.89–7.67 (9H,
m, ArH). After stirring at RT for 4 h the reaction mixture
was cooled to 0 ◦C, the succinimide by-product was removed
by filtration and the filtrate was evaporated to dryness. The
product mixture containing acrylamide 128 was allowed to stand,
neat at RT, for 48 h to promote elimination of HCl from the
a-chlorosulfide 127, and purified by column chromatography
using ethyl acetate–hexane (10 : 90) as eluent to give 128 (49 mg,
50%) as an off-white solid, mp 88–90 ◦C; (found C, 72.34; H,
6.19; N, 4.82; S, 10.43. C18H19NOS requires C, 72.69; H, 6.44;
N, 4.71; S, 10.78%); mmax/cm−1 (KBr) 3281 (br NH), 1648, 1597
(CO a, b-unsaturated amide); dH (270 MHz) 2.14, 2.17 [2 × 3H, 2
× s, (CH3)2], 2.30 (3H, s, ArCH3), 7.04–7.38 (9H, m, ArH), 8.33
(1H, br s, NH); dC (67.8 MHz) 20.8 (ArCH3), 23.8, 25.4 [(CH3)2],
120.1, 126.3, 127.5, 129.3, 129.5 (aromatic CH), 133.9, 135.2,
Acknowledgements
Enterprise Ireland, IRCSET, Eli Lilly, BioResearch Ireland, For-
bairt and University College Cork are gratefully acknowledged for
funding of this work. The authors wish to thank final year project
students F. McSweeney, M. Groarke, S. Mullane, and P. Lyne for
input on some aspects of this work.
References
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Formation of dichlorides for decomposition using Lewis acids
N-i-Propyl-2,3-dichloro-2-(phenylthio)propanamide
(130).
This was prepared following the procedure described for
dichloride 7 using sulfide 11 (0.26 g, 1.17 mmol), NCS (0.33 g,
2.45 mmol) in carbon tetrachloride (5 ml) at 40 ◦C with a reaction
time of 16 h. The dichloride 130 was present in ca. 45% with the
b-chloroacrylamide 53. The 1H NMR spectrum was complex,
however a signal was observed at dH (270 MHz) 3.70–4.50 [2H,
ABq, J 11, C(3)H2] for the b-hydrogens.
N-2ꢀ-Propenyl-2,3-dichloro-2-(phenylthio)propanamide (131).
This was prepared following the procedure described for
dichloride 7 using sulfide 14 (0.30 g, 1.36 mmol), NCS (0.38 g,
2.86 mmol) in carbon tetrachloride (6 ml) at 40 ◦C with a reaction
time of 16 h. The dichloride 131 was characterised as a ca. 1 : 1
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1228–1241 | 1241
©