Synthesis and reactivity of α-sulfenyl-β-chloroenones, including oxidation and Stille cross-coupling to form chalcone derivatives

Article abstract of DOI:10.1016/j.tet.2021.132091

The synthesis of a range of novel α-sulfenyl-β-chloroenones from the corresponding α-sulfenylketones, via a NCS mediated chlorination cascade, is described. The scope of the reaction has been investigated and compounds bearing alkyl- and arylthio substituents have been synthesised. In most instances, the Z α-sulfenyl-β-chloroenones were formed as the major products, while variation of the substituent at the β-carbon position led to an alteration in stereoselectivity. Stille cross-coupling with the Z α-sulfenyl-β-chloroenones led to selective formation of Z sulfenyl chalcones, while the E α-sulfenyl-β-chloroenones did not react under the same conditions. Oxidation of the Z α-sulfenyl-β-chloroenones was followed by isomerisation, leading to the E α-sulfinyl-β-chloroenones. Stille cross-coupling with the E α-sulfinyl-β-chloroenones produced the E sulfinyl chalcones. Either the E or Z sulfinyl chalcones can be obtained by altering the sequence of oxidation and Stille cross-coupling.

Full text of DOI:10.1016/j.tet.2021.132091

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and reactivity of a-sulfenyl-b-chloroenones, including
oxidation and Stille cross-coupling to form chalcone derivatives
Aoife M. Kearney a, Linda Murphy a, Chloe C. Murphy a, Kevin S. Eccles a,
,
, *
Simon E. Lawrence b, Stuart G. Collins b **, Anita R. Maguire c
a School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork,
Ireland
c School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre,
University College Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a range of novel a-sulfenyl-b-chloroenones from the corresponding a-sulfenylketones,
via a NCS mediated chlorination cascade, is described. The scope of the reaction has been investigated
and compounds bearing alkyl- and arylthio substituents have been synthesised. In most instances, the Z
Received 1 February 2021
Received in revised form
11 March 2021
Accepted 13 March 2021
Available online xxx
a
b
-sulfenyl-
-carbon position led to an alteration in stereoselectivity. Stille cross-coupling with the Z
-sulfenyl- -chloroenones
-chloroenones was followed by
-chloroenones. Stille cross-coupling with the E -sulfinyl-
b
-chloroenones were formed as the major products, while variation of the substituent at the
a
-sulfenyl-
b-
chloroenones led to selective formation of Z sulfenyl chalcones, while the E
did not react under the same conditions. Oxidation of the Z -sulfenyl-
isomerisation, leading to the E -sulfinyl-
a
b
a
b
Keywords:
Chalcones
Chlorination
Oxidation
a
b
a
b-
chloroenones produced the E sulfinyl chalcones. Either the E or Z sulfinyl chalcones can be obtained by
altering the sequence of oxidation and Stille cross-coupling.
© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Stille cross-coupling
a
-Sulfenyl-b-chloroenones
1. Introduction
[12,13].
The scope of this transformation was investigated and com-
Stereoselective construction of densely functionalised versatile
building blocks which can be employed in organic synthesis re-
mains a key objective [1e3]. Enones have been widely employed as
synthetic intermediates over many decades [4e7]. Indeed, enones
display interesting biological activity in their own right [8].
Our group has previously reported the discovery of a novel class
pounds bearing alkyl- and arylthio substituents were synthesised
as well as the series being extended to the ester, nitrile and Weinreb
amide series [10,14]. The use of the novel
a-sulfenyl-b-chlor-
oacrylamides as Michael acceptors in nucleophilic addition/sub-
stitution reactions, as dienophiles in Diels-Alder cycloadditions, as
well as their use in 1,3-dipolar cycloadditions [15,16] has been re-
ported (Scheme 2). We have also reported the oxidation and sub-
sequent reactivity of sulfoxide and sulfone derivatives of this series
[15].
of compounds, the
[9,10]. The transformation of
ing -sulfenyl- -chloroacrylamides, upon treatment with N-chlor-
a-sulfenyl-b-chloroacrylamides (Scheme 1)
a
-sulfenylamides to the correspond-
a
b
osuccinimide, via a chlorination cascade, is both highly efficient and
also stereoselective, yielding exclusively the Z stereoisomer. The
mechanistic pathway has been explored in detail with the key re-
action intermediates identified, including through use of ReactNMR
[11]. Recently, the synthetic utility of the chlorination cascade has
been enhanced through the use of continuous flow processing
Herein, we report for the first-time, successful application of the
chlorination cascade at the ketone level of oxidation to form the
novel
a-sulfenyl-b-chloroenones; previously, the chlorination
cascade had been implemented with carboxylic acid derivatives
only. The process optimisation and scope of this transformation is
described. These novel compounds, as highly functionalised
enones, offer greater synthetic potential than the previously re-
ported
a-sulfenyl-b-chloroacrylamides. Structurally similar com-
pounds have been described only rarely in the literature, for
** Corresponding author.
* Corresponding author.
example, Iwasaki et al. [17] reported the iron-induced
E-mail addresses: a.maguire@ucc.ie, stuart.collins@ucc.ie (A.R. Maguire).
https://doi.org/10.1016/j.tet.2021.132091
0040-4020/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Please cite this article as: A.M. Kearney, L. Murphy, C.C. Murphy et al., Synthesis and reactivity of
a-sulfenyl-b-chloroenones, including oxidation
and Stille cross-coupling to form chalcone derivatives, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132091

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
that seen in the amide series (Scheme 4) (See supplementary in-
formation for full details). Interestingly, the a-chlorosulfide B in-
termediate of the NCS cascade was not seen in the preparation of
the aryl ketones, while it was detected in the amide series.
While the scope of the ketone derivatives investigated was
substantially broader than the earlier study with the
a-sulfenyl
amides, for those derivatives which could be compared, the reac-
tion was notably slower with the ketone derivatives than with the
amide series, requiring 16 h at 90 ꢀC for efficient transformation,
while the amide transformation was generally complete within
2e3 h [10]. Although slower than the amide derivatives, the NCS
cascade with the aryl ketone derivatives was seen to be more
efficient than those of the corresponding ester and nitrile de-
rivatives which required Lewis acid catalysis to effect the final
transformation in the cascade [14]. Rapid heating of the reaction
mixture on addition of NCS is critical for efficient transformation
and, in practice, this was achieved by immersing the reaction flask
in a pre-heated oil bath at 90 ꢀC immediately following the NCS
addition. When the reaction mixture was gradually heated to 90 ꢀC,
transformation through the reaction cascade was less efficient with
Scheme 1. Synthesis of a-sulfenyl-b-chloroacrylamides.
Scheme 2. Reactivity of a-sulfenyl-b-chloroacrylamides.
increased amounts of the key intermediates, such as the a,b-un-
saturated ketone and dichloride, evident in the 1H NMR spectra of
the crude product mixtures.
chlorothiolation of internal alkynes with sulfenyl chlorides giving
rise to a compound bearing the
framework.
a
-sulfenyl- -chloroenone core
b
In contrast to the highly selective formation of the Z
-chloroacrylamides, with the ketone series, a mixture of E and Z
sulfenyl- -chloroenones was formed in all cases, and, while in
a-sulfenyl-
b
a-
Selective oxidation to the
a-sulfinyl-b-chloroenones is
b
described. Stille cross-coupling to introduce aryl substituents at the
-carbon was investigated, leading to 2-sulfenyl and 2-sulfinyl
some instances these were separated by chromatography, in many
cases they were isolated as a mixture with the Z isomer the major
isomer formed for the majority of the propenones (4a e 4aa, other
than entries 3, 4, 16 and 23). The assignment of stereochemistry in
b
chalcones, with the stereochemical outcome dependent on the
level of oxidation at sulfur. Chalcones, open chain flavonoids, are of
keen interest due to their diverse biological activities, including
anti-cancer and anti-malarial properties, among others, reported in
the literature [18e20].
the
troscopy utilising NOESY and comparative trends with the spectral
features in the -sulfenyl- -chloroacrylamides, in which case some
derivatives were definitively assigned by crystallography. Typically,
the characteristic -hydrogen singlet was significantly downfield in
a-sulfenyl-b
-chloroenones was undertaken by 1H NMR spec-
a
b
2. Results and discussion
b
the Z isomer relative to the E isomer. There was minor alteration in
E:Z ratios following chromatography, most notably for entries 4, 15,
18, 21 and 22.
2.1. Synthesis of a-chloroketones and a-sulfenylketones
The
a-sulfenylketones (3a e 3ll, Table 1), the majority of which
With the extended chain ketones (entries 28e38, Table 1), for-
were novel, were readily prepared by reaction of known
a
-chlor-
mation of the
a-sulfenyl-b-chloroenones proceeded with similar
oketones with sodium thiolates as summarised in Scheme 3 (Full
details provided in the supplementary information).
All but one of the a-chloroketones were prepared by treating a
range of commercially available ketones with NCS and p-toluene-
sulfonic acid, while one made use of another literature procedure
[21]. The a-sulfenylketones were selected to enable investigation of
the impact of both steric and electronic effects on the outcome of
the chlorination cascade. Use of aryl-, benzyl, alkylthio substituents
efficiency to that seen with the propenones, in contrast to the
decrease in efficiency reported in the amide series [14,15]. This may
be associated with the increased conformational flexibility in the
transition state of the ketone series relative to the amides (Fig. 1).
However, the stereochemical outcome in the formation of the
sulfenyl- -chloroenones was sensitive to the presence of an alkyl
substituent at the -carbon position with increased formation of
a-
b
b
the E isomer evident, and indeed in all cases, the E isomer was the
major product from the reaction, in contrast to the Z isomer which
dominated in the propenones. There was a notable decrease in
and alkyl or aryl ketones were employed. The
were prepared in moderate to excellent yields.
a-sulfenylketones
stereoselectivity for the
fenyl- -chloropentenones with crude E:Z ratios of 1.1e1.4:1
observed in the 1H NMR spectra of the crude products, relative to
that seen with the -sulfenyl- -chloropropenones (typically E:Z
1:2e1:4), indicating that while replacing the terminal hydrogen
with an alkyl group had a significant effect on the stereochemical
a-sulfenyl-b-chlorobutenones and a-sul-
2.2. Synthesis of
a
-sulfenyl-
b
-chloroenones
b
As summarised in Table 1 and Scheme 4, treatment of the
sulfenyl aryl ketones with 1.95 equiv. of NCS in toluene at 90 ꢀC for
16 h resulted in efficient transformation to the corresponding
sulfenyl- -chloroenones, typically in moderate to excellent yields.
a
-
a
b
a-
b
outcome, a change from
b-methyl to b-ethyl had no significant
It appears that a similar mechanistic pathway is followed for the
chlorination cascade with the aryl ketone derivatives (Scheme 5), to
impact on stereoselectivity.
The altered outcome in terms of stereocontrol, relative to the
amide series, may be rationalised as summarised in Fig. 1; as dis-
cussed previously [10], an intramolecular hydrogen bond in the
sulfenylamides holds the intermediate carbocation in a conforma-
tion which leads selectively to the Z sulfenyl -chloroacrylamide. In
that which had been studied in detail with the a-sulfenylamides
[11]. Indeed, in the 1H NMR spectra of the crude reaction mixtures,
characteristic signals could be seen corresponding to the in-
termediates of the chlorination cascade proposed for the ketone
a-
b
series, namely the
a,
b-unsaturated ketones C and the dichlorides D,
the ketones, conformational flexibility is greater in the sulfur sta-
confirming that the mechanistic pathway proceeded similarly to
bilised carbocation, decreasing the steric interaction in the
2

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Synthesis of aryl a-sulfenyl-b-chloroenones.
Entry
Thioketone
R1
R3
R2
b-Chloroenone
Crude
% Yield
% Yield
%
Purified
Z:Ea
Zb
Eb
Yield (overall)b
Z:Ec
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
Ph
Ph
Ph
Ph
Bn
n-Bu
Ph
Bn
n-Bu
Ph
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
2:1
1:1
1:1.8
1:1.75
3:1
e
e
68
86
75
88
57
89
65
56
53
50
51
61
32
53
48
66
36
39
62
46
63
76
73
66
40
64
62
67
74
54
65
63
50
67
69
65
63
72
2.2:1
1.1:1
1:1.5
1.6:1
4.3:1
2.3:1
1.7:1
e
e
e
e
e
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
Ph
e
e
e
e
2.1:1
1.5:1
2.5:1
1.3:1
2.8:1
2.6:1
2.7:1
2.7:1
1.7:1
1.7:1
1:2
2.7:1
2.3:1
2.2:1
2.5:1
1.3:1
1.4:1
1:1.2
2.2:1
2.6:1
2.6:1
2.3:1
1:1.7
1:1.3
1:1.2
1:1.4
1:1.4
1:1.4
1:1.4
1:1.4
1:1.2
1:1.1
1:1.4
e
e
e
e
40
e
16
e
9
n-Bu
1.3:1
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
4-ClC6H4CH2
4-MeOC6H4CH2
4-FC6H4CH2
4-MeC6H4CH2
Ph
32
39
46
23
e
18
12
15
9
e
e
e
e
2.1:1
2.4:1
1:1.3
e
Bn
n-Bu
e
e
e
e
4-ClC6H4CH2
4-MeOC6H4CH2
4-FC6H4CH2
4-MeC6H4CH2
Ph
20
e
16
e
9:1
2.5:1
e
e
e
33
e
13
e
3.8:1
2:1
1:1.1
2.2:1
2.8:1
3:1
Bn
n-Bu
e
e
e
e
4-ClC6H4CH2
4-MeOC6H4CH2
4-FC6H4CH2
4-MeC6H4CH2
Bn
4-ClC6H4CH2
4-MeOC6H4CH2
4-FC6H4CH2
4-MeC6H4CH2
Ph
e
e
3y
3z
H
H
H
4y
4z
e
e
e
e
3aa
3bb
3cc
3dd
3ee
3ff
3gg
3hh
3ii
3jj
3kk
3ll
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
4ii
4jj
4kk
4ll
45
e
17
e
e
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
1:1.6
1:1.4
e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
e
e
29
e
25
e
1:1.4
1:1.8
1:1.2
1:1.4
1:1.2
1:1.3
1:1.1
1:1.4
e
e
e
e
Bn
e
e
4-ClC6H4CH2
4-MeOC6H4CH2
4-FC6H4CH2
4-MeC6H4CH2
e
e
e
e
Ph
Ph
e
e
e
e
a
Ratio of Z:E determined from the 1H NMR spectrum of the crude product.
Isolated yield after column chromatography.
Z and E isomers could not be separated following column chromatography and were isolated as a mixture.
b
c
characterisation, showed partial conversion to the opposite isomer,
with the pure Z isomer seen to have interconverted to a larger
degree than the corresponding pure E isomer (Fig. 2). Similar
interconversion was seen with compound 4r as detailed in the
Supplementary Information.
As summarised in Fig. 3, characteristic trends are evident in the
Scheme 3. Synthesis of a-chloroketones and a-sulfenylketones.
1H NMR spectra of the Z and E isomers of the
a-sulfenyl-b-chlor-
oenones with the stereochemistry confirmed through NOESY
studies.
transition state, relative to the amide series, resulting in the for-
mation of both Z and E sulfenyl -chloroenones.
Building on the success of the chlorination cascade in the a-
b
sulfenyl aryl ketones, our attention next focussed on the corre-
sponding alkyl ketones as summarised in Table 2 and Schemes 6
and 7.
Interconversion of Z and E alkene isomers has been reported,
especially in the presence of UV light [22], although this has not
been observed in the a-sulfenyl-b-chloroacrylamides studied over
the past decade. In contrast, some evidence of interconversion was
seen with the ketone series. 1H NMR spectra of samples of pure Z-
4h and pure E-4h, taken after neat, bench-top storage at room
temperature without protection from light, 4 months after initial
To investigate the pathway and intermediates in the chlorina-
tion
cascade
with
the
alkyl
a
-sulfenylketones,
3-
phenylthiobutanone 5a was selected for investigation as the in-
termediates derived from this ketone were anticipated to have
3

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
Scheme 4. Characteristic components detected in the reaction mixtures of the chlo-
rination cascade.
Fig. 2. Interconversion of Z and E
a
-sulfenyl-b-chloroenone 4h.
Fig. 3. Characteristic 1H NMR signals of
b-substituent signal in a-sulfenyl-b-
chloroenones.
Table 2
Initial reactions of 5a with N-chlorosuccinimide.
Scheme 5. Proposed mechanistic pathway for the formation of
a-sulfenyl-b-
chloroenones.
NCS (equiv.) Time (h) Temp (ꢀC)
Entry
Solvent
CCl4
Toluene 33
Toluene 14
Toluene
Toluene 31
Toluene 20
Toluene N.D
Toluene 30
crude product
ratiosa
6a
%
7a
%
8a
%
1
2
3
4
5
6
7
8
9
10
1.10
1.90
1.90
2.05
2.10
2.15
2.20
2.00
2.60
2.60
3
2
1
2
2
2
2
1
0
56
N.D. N.D.
25
90
90
90
90
90
25
50
9
17
77
83
7
10
N.D. 69
N.D. 70
N.D. 75
27
N.D. 92
120 (MW) Toluene N.D. N.D. 98
43
0.5
1
120 (MW) Toluene
8
N.D. ¼ not detected by 1H NMR spectroscopy. MW ¼ microwave heating at 200 W.
a
% conversion to each product was estimated by integration of the 1H NMR
spectrum of the crude product mixture.
Fig. 1. Stereochemical control in the formation of
-sulfenyl- -chloroenones.
a-sulfenyl-b-chloroacrylamides and
a
b
4

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
ketone with a methyl ketone results in stabilisation of the
dichloride, presumably associated with the decreased conjugation
which destabilises the sulfur stabilised carbocation. The conditions
subsequently employed for the formation of the dichloride 8a were
2 equivalents of NCS in toluene at 90 ꢀC for 2 h. Subsequent reaction
of 8a with zinc chloride as the Lewis acid furnishes the desired
sulfenyl- -chloroenone 9a.
As summarised in Scheme 6, transformation of the
sulfenyl ketone 5c to the -sulfenyl- -chloroenone 9c can be con-
a-
b
a-benzyl-
a
b
ducted directly by effecting the chlorination cascade under
microwave heating or alternatively, in a two-step sequence forming
initially the dichloride 8c in toluene at 90 ꢀC for 2 h, followed by
exposure to zinc chloride to effect elimination of HCl to provide the
a
-sulfenyl-
Furthermore, as summarised in Scheme 7, when the
ketones 5a, b, d, and e were subjected to the chlorination cascade
under microwave conditions, both the dichlorides A and the
sulfenyl- -chloroenones B were seen in the crude product mix-
b-chloroenone 9c.
Scheme 6. Reaction of 5c under both microwave and thermal conditions.
a
-sulfenyl
a-
b
tures, with the HCl elimination completed on exposure to zinc
chloride. While the ease of the final HCl elimination leading to the
a
-sulfenyl-b-chloroenones is sensitive to the substituents, from a
synthetic perspective, exposure to zinc chloride effectively com-
pletes the process leading to the products in good yields following
chromatographic purification. Formation of the Z isomer pre-
dominated throughout the series, in agreement with the observa-
tions with the aryl ketones, but to an even greater extent (relative
to Table 1). Interestingly, the stereochemical outcome is compara-
ble to that seen with the ester and nitrile derivatives [14].
In contrast to the secondary amide series [9,10,14,15], where the
efficiency of the reaction cascade was relatively insensitive to
substituent alteration, it is interesting to see increased sensitivity to
differences in substitution in the ketone series, with aryl ketones
leading efficiently to the
a-sulfenyl-b-chloroenones while alkyl
ketones require more forcing conditions to complete the reaction
cascade in some instances. However, from a synthetic perspective,
it is clear that access to the Z a-sulfenyl-b-chloroenones is readily
achieved, albeit in some cases requiring the use of a Lewis acid to
complete the final elimination step.
Investigation of the chlorination cascade was undertaken with
4-phenyl ketone 10a to establish the impact of an aryl substituent
at the b-position on both the efficiency and stereoselectivity of the
chlorination sequence (Scheme 8). Under the standard reaction
conditions, characteristic signals were seen in the 1H NMR spectra
of the crude product mixture confirming the presence of the enone
11a, the dichloride 12a and the
indicating that the efficiency of the transformation through the
a-sulfenyl-b-chloroenone 13a,
Scheme 7. Synthesis of alkyl a-sulfenyl-b-chloroenones using optimised conditions.
clearly distinguishable methyl singlets in the 1H NMR spectra of the
crude product mixtures.
As summarised in Table 2, the a-sulfenylketone 5a was exposed
to increasing amounts of NCS and increasing temperatures in
toluene under both thermal and microwave conditions, or in car-
bon tetrachloride at 0 ꢀC. At low temperatures and low equivalents
of NCS, the
action as seen from Entry 1. Increasing the temperature from 0 ꢀC to
25 ꢀC led to a mixture of the
-chlorosulfide 6a, the -unsaturated
a-chlorosulfide 6a was the major product from the re-
a
a,b
ketone 7a and the dichloride 8a. Entries 4 to 7 in Table 2 show that
increasing the reaction temperature to 90 ꢀC and using 2 equiva-
lents of NCS led to the dichloride 8a being the major product from
the reaction. The reaction was also investigated under microwave
conditions, proving the dichloride could be successfully formed
using this method. In contrast to the results with the aryl ketones
(Table 1), there was no evidence for the formation of the
a-sulfenyl-
b
-chloroenone 9a during this study. Clearly, replacing the aryl
Scheme 8. Reaction of a-sulfenylketone 10a with NCS.
5

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
cascade was somewhat less efficient than with the other de-
rivatives, possibly due to the stability associated with the extended
conjugation in the enone 11a [23].
instances, extending the reaction time and/or increasing the tem-
perature increased the efficiency of transformations (Entries 8,
10e15, 17e21).
Notably, an interesting observation was made on the relative
stability of the two diastereomers of the dichloride 12a. On
extended storage at room temperature (40 months), one of the two
diastereomers was seen to convert completely to a mixture of Z and
As anticipated, while Reddy [24] had reported the synthesis and
biological evaluation of related E sulfenyl chalcones, formation of
the Z sulfenyl chalcones as the major product provides access to the
complementary series for evaluation. Extending this work to
generate the 2-sulfinyl chalcones was next explored with particular
interest in establishing the impact of increasing the oxidation level
at sulfur on both the efficiency and the stereochemical outcome of
the Stille cross-coupling. Reddy [24] noted the impact of sulfur
oxidation on the biological activity of chalcones and, accordingly, it
was of interest to determine whether similar results would be seen
with these derivatives.
E
a-sulfenyl-b-chloroenones 13a (E:Z, 1:2), indicating that, for
stereoelectronic reasons, the HCl elimination is favoured in one
diastereomer over the other, presumably due to the relative sta-
bility of the trans co-planar orientation leading to the
chloroenones.
a-sulfenyl-b-
Having established that the chlorination cascade successfully
leads to -sulfenyl- -chloroenones, attention focussed on the po-
a
b
tential synthetic utility of these highly functionalised enones.
While 2-sulfenyl chalcones are rare in the literature, Reddy and co-
workers [24] have reported the synthesis and biological evaluation
in cytotoxicity screens of a series of E 2-sulfenyl chalcones, noting in
particular the importance of a nitro substituent on the styryl ring.
Oxidation of the a-sulfenyl-b-chloroenones to the correspond-
ing sulfoxides was readily achieved using Oxone® as summarised
in Table 4. Chemoselective oxidation to the sulfoxide level was very
efficient with only minor amounts of the sulfone by-product pre-
sent (less than 10%) in the 1H NMR spectra of the crude product
mixtures (Entries 1e3, 6). Interestingly, while exclusively the Z
Accordingly, we envisaged that transformation of the novel
a-sul-
fenyl- -chloroenones to the Z 2-sulfenyl chalcones, by palladium-
b
sulfenyl b-chloroenones 4 were employed for the oxidation in most
mediated cross-coupling, would provide access to these com-
pounds for further biological evaluation and in particular, to
establish the impact of the stereochemistry.
cases (Entries 1e5) or as the major component (Entry 6), 1H NMR
spectroscopy of the crude product mixtures indicated the presence
of both Z and E isomers of the
following either chromatography or recrystallisation, the products
were isolated as exclusively sulfinyl -chloroenones E-38.
a-sulfinyl-b-chloroenones 38, and,
As summarised in Table 3, Stille cross-coupling of the
a-sulfenyl-
b
-chloroenones with a number of aryl stannanes [25e27] proved
E
b
effective in forming a range of novel 2-sulfenyl chalcones with
yields of up to 92%, using reaction conditions described by Aguilar-
Evidently, the E sulfoxides are more stable, with the position of
thermodynamic equilibrium altered on sulfur oxidation and, in
addition, interconversion of the E-38 and Z-38 isomers is relatively
facile, notably faster than at the sulfide level of oxidation. In some
instances, a minor amount of a by-product (39) can be seen in the
1H NMR spectra (less than 6%, Entries 3, 5, 6), presumably formed
~
Aguilar and Pena-Cabrera [28]. Interestingly, the efficiency of the
cross-coupling was impacted by the nature of the substituent on
the aryl stannane, with better yields obtained when using
substituted aryl stannanes [25e27] (36be36f) compared to the
unsubstituted phenyl stannane 36a (Table 3, Entries 3 and 24). Use
of the 4-nitro phenyl stannane 36f [27] in the cross-couplings was
of particular interest as Reddy has highlighted the significance of
the nitro substituent in the bioactivity profile of related E sulfenyl
chalcones, and notably, the efficiencies of the couplings were very
effective with this stannane. Alteration of the substituent of the aryl
ketone (R1) did not notably affect the efficiency of the cross-
coupling, while alteration of the substituent on the thio benzyl
group (R3) had more of an impact with no cross-coupling evident in
the crude product mixture for the 2-(p-methoxybenzyl)sulfenyl-3-
by over oxidation to the
hydrolysis and retro-Claisen condensation (Fig. 4). It is clear that
the rate of addition of water to the -sulfonyl- -chloroenone is
a-sulfonyl-b-chloroenone followed by
a
b
enhanced by oxidation from the sulfide to sulfone level of
oxidation.
As summarised in Table 5, the Stille couplings with the E sulfinyl
b
-chloroenones E-38 proved effective leading to the E sulfinyl
chalcones E-40 as the principal product in all cases, with the Z
sulfinyl chalcones Z-40 isolated as a minor product in some in-
stances (Entries 1 and 7) and detected in the 1H NMR spectra of the
crude product mixtures. With a halogenated substituent on the
benzyl sulfinyl moiety, extended reaction times were required for
reaction completion but in all cases, reactions were conducted at
chloroenones (Entry 11 and 19). Interestingly, while the Z
fenyl- -chloroenones undergo efficient cross-coupling with the
aryl stannanes, it appears that the E -sulfenyl- -chloroenones do
a-sul-
b
a
b
not react under the same conditions. In entry 9, where the starting
room temperature. Notably, the stereochemistry of the E sulfinyl b-
enone 4h was predominantly E, there was no evidence of cross-
coupling while in many of the other entries, the E a-sulfenyl-b-
chloroenones E-38 was retained to a very large extent during the
Stille cross-coupling and there was no evidence of isomerisation of
the E sulfinyl chalcones E-40 following storage over a prolonged
period, consistent with these being the thermodynamically
preferred isomers. It appears that at the sulfoxide level of oxidation,
chloroenone was present as a minor component in the starting
material and in most instances was recovered unchanged following
the cross-coupling reaction. In most instances, the Z chalcone
predominated in the reaction product and for many of the com-
pounds was isolated as a single stereoisomer following chroma-
tography (Entries 1e7, 10, 16e18, 20e27). On prolonged storage,
there is some evidence of isomerisation to form minor amounts of
the reactivity of the E sulfinyl
b-chloroenones E-40 towards Stille
cross-coupling is greater than that seen at the sulfide level of
oxidation, where the E sulfenyl b-chloroenones E-4 did not react
under these conditions.
the E isomer. From a synthetic perspective, the fact that the E
sulfenyl- -chloroenones did not undergo cross-coupling but were
recovered from the reaction mixtures enabled isolation and char-
acterisation of the pure E -sulfenyl- -chloroenones. While the
a
-
As the sequence involving sulfur oxidation followed by Stille
cross-coupling of E-sulfinyl- -chloroenones led to the E sulfinyl
b
b
chalcones, access to the complimentary Z sulfinyl chalcones was
investigated using the alternative approach of conducting the Stille
cross-coupling to form the Z sulfenyl chalcones prior to sulfur
oxidation; the key question to be addressed was whether the Z
stereochemistry in the chalcone would be retained on sulfur
oxidation.
a
b
efficiencies of the cross-couplings as evidenced by the 1H NMR
spectra of the crude product mixtures was typically greater than
70%, the isolated yields in some cases were negatively impacted by
the challenge of separation from bi-aryl side product 37 [29]
formed from the stannane 36f [27]. The cross-couplings were
initially conducted at room temperature for 2 h but in some
As summarised in Table 6, the Z sulfenyl chalcones 20e24 and
26e29 were oxidised to the corresponding sulfinyl chalcones 40
6

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
Table 3
Synthesis of Chalcone derivatives from a-sulfenyl-b-chloroenone precursors.
Entry
b
-Chloroenone Z:E
R1
R3
R4
Temp.
Time (h)
Relative Ratiosa
% Yieldb
Purified Z:Ec
4 Z:E
Chalcone Z:E
1
4e
4:1
4e
4:1
4e
4:1
4e
4:1
4e
4:1
4e
4:1
4h
5.2:1
4h
14:1
4h
1:18
4j
4.5:1
4k
68:1
4l
3.4:1
4l
3.4:1
4o
2.4:1
4q
1.7:1
4r
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
Cl
H
4-Me
rt
2
2
9%
E only
18%
1:3
39%
2:1
9%
E only
10%
E only
9%
E only
24%
1.8:1
4%
E only
1:11
14 (91%)
Z only
15 (82%)
Z only
16 (59%)
Z only
17 (91%)
Z only
18 (90%)
Z only
19 (90%)
Z only
20 (76%)
Z only
20 (79%)
Z only
86
66
59
70
83
87
18
38
e
Z only
Z only
Z onlyd
Z only
Z only
Z only
Z only
10.6:1
e
2
H
4-F
rt
3
H
H
rt
2
4
H
4-OMe
3-OMe
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
rt
2
5
H
rt
2
6
H
rt
2
7
H
rt
2
8
H
rt
24
2
9
H
rt
-
10
11
12
13
14
15
16
17
18
19
20
Cl
OMe
F
rt
5
6%
E only
24:1
21 (94%)
Z only
e
43e
e
Z only
e
reflux
rt
3
5
77%
3.2:1
26%
1:1.4
7%
E only
11%
E only
55%
5.4:1
17%
1.2:1
26%
1:3.7
2.7:1
22 (23%)
9.6:1
22 (74%)
6.3:1
23 (93%)
8.4:1
24 (89%)
8.3:1
25 (45%)
Z only
26 (83%)
Z only
27 (74%)
8.8:1
4
4.9:1
3.2:1
4.6:1
31:1
F
reflux
rt
5
28
64
47
9f
H
5
Cl
Cl
OMe
F
reflux
rt
5
Cl
2
Z only
Z only
Z only
e
9:1
4s
2.5:1
4x
2.2:1
4y
2.8:1
4z
Cl
rt
5
18
20
e
F
Cl
OMe
F
reflux
reflux
rt
5
F
13
6
e
F
10%
E only
28 (90%)
Z only
24
Z only
3:1
14:1
4aa
21
22
23
24
25
26
27
F
F
F
F
F
F
F
Me
H
4-NO2
4-Me
4-F
rt
rt
rt
rt
rt
rt
rt
24
2
7%
E only
e
29 (93%)
Z only
30 (100%)
Z only
31 (78%)
Z only
32 (37%)
Z only
33 (88%)
Z only
34 (70%)
Z only
35 (80%)
Z only
51
92
75
35
77
65
78
Z only
Z only
Z only
Z only
Z only
Z only
Z only
4v
2.2:1
4v
2.2:1
4v
2.2:1
4v
2.2:1
4v
2.2:1
4v
H
2
22%
1:1.2
63%
2.5:1
12%
E only
30%
1:2
H
H
2
H
4-OMe
3-OMe
4-NO2
2
H
2
H
2
14%
1:4
2.2:1
a
Determined by integration of key signals in 1H NMR spectrum of crude product mixtures.
b
c
d
e
f
% yield after purification by column chromatography on silica gel.
Ratio of Z:E chalcone products determined by integration of key signals in 1H NMR spectrum of product mixtures.
14% Z b-chloroenone starting material remaining in sample.
Approximately 90% pure by 1H NMR spectroscopy.
Contains approx. 22% bi-aryl 37.
7

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
Table 4
Oxidation of a-sulfenyl-b-chloroenones to sulfoxides.
Entry
b
-Chloroenone
Z:E ratio
R1
R3
Sulfoxideb
Crude
% Yield
S.M.a
Z:Ec
Ed
1
2
3
4
5
6
4h
4m
4t
Z only
Z only
Z only
Z only
Z only
4.3:1
Me
Me
Me
Me
Cl
H
38h
96%
38m
89%
38t
88%
38aa
98%
38q
90%
38z
88%
1:15
53e
Me
Cl
F
E only
2.8:1
1:1.03
2.4:1
1.5:1
37e
76f
77f
39f
54f
4aa
4q
4z
Cl
F
F
a
Z:E ratio of
a
-sulfenyl-
b
-chloroenone starting material used.
b
c
d
e
f
% of sulfoxide product estimated from 1H NMR spectrum of the crude product mixture.
Z:E ratio of the sulfoxide products estimated from 1H NMR spectrum of the crude product mixture.
Yield of E sulfoxide following purification.
Purified by recrystallisation from methanol.
Purified by column chromatography on silica gel.
using Oxone® to enable comparison with the stereochemical
outcome when the Stille coupling was conducted at the sulfoxide
level of oxidation (Table 6). In most cases (other than Entry 8) the
oxidation was efficient with little or none of the sulfone formed, as
evidenced by the 1H NMR spectra of the crude product mixtures.
However, for the para-halo aryl ketones 23, 24, 26e29, it was
necessary to increase the temperature of the reaction mixtures to
30e35 ꢀC (Entries 5e7) or the reaction time (Entries 4e9) to ach-
ieve efficient oxidation. It is clear that the oxidation of the Z sulfenyl
chalcones is considerably slower than that of the corresponding Z
chloroenones 4 are subjected to Stille cross-coupling, the Z sulfenyl
chalcones 14e35 are formed, which on oxidation, produce selec-
tively the Z sulfinyl chalcones 40. In contrast, oxidation of the Z
sulfenyl b-chloroenones 4 forms the E sulfinyl b-chloroenones 38,
which form selectively the E sulfinyl chalcones 40 on Stille cross-
coupling.
Finally, Stille cross-couplings were undertaken using the
b-
chloroacrylate 41 [14], and -chloroacrylamides 42 [10] and 43 [30],
b
with the first two compounds at the sulfide level of oxidation, while
43 [30] was at the sulfoxide level of oxidation (Table 7). It is clear
that the extent of conversion within 2 h is substantially less than
sulfenyl b
-chloroenones 4 (Table 4). Examination of the 1H NMR
spectra of the crude product mixtures showed that the principal
isomer of the sulfoxides formed was the Z isomer, although there
were minor amounts of the E isomer detectable in the crude
product mixtures. On purification and storage, there was evidence
of further isomerisation to the E sulfinyl chalcones 40, the ther-
modynamically more stable isomer. In most instances, the Z and E
stereoisomers were inseparable, however, both isomers of 40s were
recovered as pure components.
that seen in the a-sulfenyl-b-chloroenone series, although, the
sulfoxide 43 [30] was more reactive than the sulfides 41 [14] and 42
[10]. Once again, the Z stereochemistry was retained in the Stille
cross-coupling with the Z chalcones 44e46 formed with no evi-
dence of the E isomer detected in contrast to the outcome of the
cross-couplings with the
a-sulfenyl-b-chloroenones. The relative
stereochemistry was confirmed by single crystal X-ray crystallog-
raphy of 46 as illustrated in Fig. 5 revealing a strong intramolecular
hydrogen bond (1.88 Å) between the amide proton and the oxygen
of the sulfoxide group. The carbonyl group is distorted somewhat
from planarity presumably due to the conformational constraints of
As summarised in Scheme 9, complementary stereochemical
outcomes can be achieved by altering the sequence of sulfur
oxidation and Stille cross-coupling. Thus, when the Z sulfenyl b-
this intramolecular hydrogen bond. The aryl ring at the b-position
lies in the same plane as the acrylamide, indicating effective
conjugation.
Preliminary one-dose (10 mM) screening of the Z sulfenyl and E
sulfinyl chalcones against a range of cancer cell lines was under-
taken (NCI, see SI for details); a number of the compounds dis-
played significant activity in terms of inhibiting cell growth, with
cytotoxicity evident in some instances, with nine compounds
progressed for five-dose screening. In the case of the Z sulfenyl
chalcones, the substituent at both the R1 and R3 positions had a
notable impact on the inhibition of cell growth with the greatest
inhibition seen for compound 27 with fluoro (R1) and chloro (R3)
substituents, with a mean growth of 49.6% seen across all 60 cancer
cell lines. The most significant level of inhibition with 27 was seen
against the colon cell line HCT-116, with a cell growth of ꢁ59.9%.
Fig. 4. Formation of retro-Claisen impurity from sulfone by-product.
8

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
Table 5
Synthesis of Chalcones using sulfoxide derivatives of a-sulfinyl-b-chloroenones.
Entry
b
Z:E
-Chloroenone
R1
R3
Time (h)
Relative Ratiosa
% Yield
% Yield
Eb
Zb
14
Chalcone
Z:E
Z:E
1
2
3
4
5
6
7
38h
Me
Me
Me
Cl
H
2
8%
E only
e
40h (92%)
1:4.5
40m (90%)
E only
40aa (99%)
1:31
40q (78%)
1:5.7
40z (92%)
1:35
40t (96%)
E only
47
70
74
45
69
46
22
8
E only
38m
E only
38aa
E only
38q
E only
38z
E only
38t
Me
F
5
e
e
e
e
e
10
24
21
21
26
21
e
Cl
F
22%
E only
e
F
Me
Me
Cl
Cl
e
E only
38t
39%
1:1
40t (56%)
5:1c
2.5:1d
1:2.7e
a
Determined by integration of key signals in 1H NMR spectrum of crude product mixtures.
% yield after purification by column chromatography on silica gel.
b
c
Reaction was carried out immediately after sulfur oxidation to minimise conversion of Z-14t to E-14t.
d
e
Z:E ratio estimated from 1H NMR spectrum of crude product. Z isomer is the major product.
Z:E ratio estimated from 1H NMR spectrum of major impure fraction following initial column chromatography.
Interestingly, the E sulfinyl chalcones displayed enhanced biological
activity compared with their sulfenyl counterparts, with the impact
of altered substitution patterns evident once again. Notably, com-
pound 40h displayed a mean growth of just 6.7% across all 60
cancer cell lines. The E sulfinyl chalcones were most active against
renal, colon and melanoma cell lines, while the Z sulfenyl chalcones
were most effective against a number of leukaemia and colon
cancer cell lines. Although a direct comparison of biological activity
cannot be made due to the opposite stereochemistry of the Z sul-
fenyl and E sulfinyl chalcones, the E sulfinyl chalcones were notably
more active than the Z sulfenyl derivatives, presumably due to the
impact of sulfur oxidation on their ability to act as Michael accep-
previously explored only at the carboxylic acid level of oxidation.
Interestingly, on oxidation of the Z sulfenyl -chloroenones,
while the Z sulfinyl -chloroenones were the initial direct products,
these rapidly isomerised to the thermodynamically more stable E
sulfinyl -chloroenones. The Stille cross-coupling with the novel
sulfenyl or sulfinyl -chloroenones 4/38 provided an efficient route
to the Z sulfenyl 14e35 or E/Z sulfinyl 40 chalcones; at the sulfide
level of oxidation, the Z stereochemistry is retained in the Stille
cross-coupling while at the sulfoxide level, the stereochemical
outcome is determined by the sequence of oxidation and Stille
cross-coupling, providing access to either the E or the Z sulfinyl
chalcone isomer as the major product. This sequence illustrates the
synthetic potential of combining the chlorination cascade with
subsequent transformations, leading to stereoselective bond for-
mation at the previously unactivated methyl substituent.
b
b
b
b
tors. Interestingly, Reddy [24] reported a loss of activity in the E a-
benzylthiochalcones when oxidised to either the sulfoxide or sul-
fone level of oxidation.
3. Conclusion
4. Experimental
The chlorination cascade with
with NCS follows a similar mechanistic pathway to that seen with
the -sulfenylamides, leading to novel -sulfenyl- -chloroenones
in a synthetically useful manner with modest stereocontrol, typi-
cally with the Z-propenones as the major product from the trans-
formation. The influence of the substituents on the ketone
impacted on the efficiency of the chlorination cascade, but in all
a
-sulfenylketones on heating
4.1. General procedures
a
a
b
All commercial reagents were used without further purification.
Proton (300 MHz) and carbon (75 MHz) NMR spectra were
recorded on a Bruker Avance 300 MHz NMR spectrometer. All
spectra were recorded at 300 K (27 ꢀC) in deuterated chloroform
(CDCl3) using tetramethylsilane (TMS) as an internal standard.
Chemical shifts (dH and dC) are reported in parts per million (ppm)
relative to TMS and coupling constants (J) are expressed in Hertz
(Hz). Splitting patterns in 1H NMR spectra are designated as s
(singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublets), qd (quartet of doublets), and m (multiplet).
13C NMR spectra were assigned with the aid of DEPT experiments.
instances, the
a-sulfenyl-b-chloroenones were readily isolated
either directly from the chlorination cascade (for aryl ketones) or
on exposure to the Lewis acid zinc chloride which effects the final
HCl elimination (alkyl ketones). Access to the synthetically versatile
a
-sulfenyl-b-chloroenones broadens substantially the synthetic
potential of application of this chlorination methodology,
9

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
Table 6
Oxidation of chalcone derivatives.
Entry
Starting Material
R1
R3
Time (h)
Temp (ᵒC)
Relative Ratiosa
% Yieldb
Purified Z:Ec
Z:E
S.M.
Z:E
Sulfoxide
Z:E
Sulfone
8%
1
2
3
4
5
6
7
8d
9
20
Z only
Me
Me
Me
F
H
Cl
F
2
rt
6%
Z only
40h
86%
11:1
40j
75%
4.5:1
40l
94%
16:1
40aa
71%
6.3:1
40x
91%
10.4:1
40z
92.5%
7:1
40o
87%
4:1
40q
52%
Z only
40s
47
59
53
33
76
70
73
56
51
4:1
21
Z only
2
rt
25
Z only
e
8:1
22
Z only
2
rt
6%
Z only
e
11.5:1
1:1.3
7:1
29
Z only
Me
Cl
F
6
rt
29%
Z only
e
27
Z only
F
7.5
7.5
9.5
4
35
35
30
rt
7.5%
Z only
1.5%
6%
e
28
Z only
F
1.5%
Z only
6:1
23
Z only
Cl
Cl
Cl
H
Cl
F
13%
Z only
1:1.6
Z only
24
Z only
e
48%
e
26
23
rt
18%
39% Ze
12% E
Z only
Z only
82%
5:1
a
Determined by integration of key signals in 1H NMR spectrum of crude product mixtures.
b
c
% yield after purification by column chromatography on silica gel.
Products isolated as a mixture after column chromatography. Ratios determined by integration of key signals in 1H NMR spectrum of purified material.
d
After initial stirring at room temperature for 2 h, 28% conversion of starting material was observed. 1 Eq. of mCPBA in dichloromethane was subsequently added and the
reaction was stirred at room temperature for 1 h.
e
Isomers were separated following column chromatography on silica gel.
Scheme 9. The impact of alternating the sequence of sulfur oxidation and Stille cross-coupling on the stereochemical outcome.
10

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
max/cmꢁ1 (film) 3058 (CH), 2934 (CH), 1659 (CO), 1598
Table 7
1.6:1;
(aromatic), 1253.
n
Synthesis of chalcones from b-chloroacrylates and b-chloroacrylamides.
Z-4d (more polar): dH (300 MHz, CDCl3) 7.73 (2H, d, J 9.0, ArH),
7.20e7.29 (2H, m, ArH), 7.10e7.16 (3H, m, ArH), 6.83 (2H, d, J 9.0,
ArH), 6.79 (1H, s, CHCl), 3.83 (3H, s, OCH3); dC (75.5 MHz, CDCl3)
189.2 (C), 163.8, 140.4 (2 x C), 132.6, 131.9 (2 x CH), 130.9, 129.1 (2 x
C), 129.0, 128.1 (2 x CH), 126.0 (CH), 113.6 (CH), 55.5 (CH3).
E-4d (less polar): dH (300 MHz, CDCl3) 7.84 (2H, d, J 9.0, ArH),
7.38e7.44 (3H, m, ArH), 7.20e7.29 (2H, m, ArH), 6.90 (2H, d, J 9.0,
ArH), 6.64 (1H, s, CHCl), 3.85 (3H, s, OCH3); dC (75.5 MHz, CDCl3)
189.6 (C), 164.3 (C), 135.4 (C), 132.4, 132.1 (2 x CH), 131.2 (C), 129.3,
128.5 (2 x CH), 127.5 (C), 121.0 (CH), 114.0 (CH), 55.6 (CH3).
HRMS (ESþ): Exact mass calculated for C16H14O2S35Cl[MþH]þ
305.0403. Found 305.0390; m/z (ESþ) 305.1 [(C16H13O2S35Cl)þHþ],
100%, 307.0 [(C16H13O2S37Cl)þHþ], 40%.
Entry Starting Material
X
R3
n
Relative Ratiosa
S.M. Chalcone
% Yield
Z:E
Zb
1
2
3
41 Z only
42 Z only
43 Z only
OMe
NHBn Bn
NHTol Ph
Ph
0
0
1
55% 44 (45%) Z only 45
89% 45 (11%) Z only 10
38% 46 (62%) Z only 59
a
Determined by integration of key signals in 1H NMR spectrum of crude product
4.3. Procedure for synthesis of compound 31
mixtures.
b
% yield after purification by column chromatography on silica gel.
The
b-chloroenones Z-4v and E-4v (ratio 2.2:1) (150 mg,
0.5 mmol) and the arylstannane, tributyl(4-fluorophenyl)stannane
36c (227 mg, 0.6 mmol) were dissolved in anhydrous acetonitrile
(5 mL) under nitrogen. The mixture was then purged with nitrogen
for 5 min whereupon the palladium catalyst, (CH3CN)2PdCl2 (5%)
was added and the reaction mixture was stirred at room temper-
ature for 2 h. The mixture was then washed with hexane
(3 ꢂ 20 mL) to remove the tin by-products and the remaining
acetonitrile phase was evaporated under reduced pressure to give
the crude chalcone as a yellow oil. 1H NMR analysis showed the
crude product to contain 22% b-chloroenone starting material as a
mixture of Z and E isomers Z-4v and E-4v in a ratio of 1:1.2 and 78%
Z chalcone 31. This was purified by column chromatography on
silica gel using hexane-ethyl acetate (98:2) as eluent to give the Z
Fig. 5. Single crystal X-ray data of 46.
chalcone 31 (137 mg, 75%) as a yellow oil; n
max/cmꢁ1 (film) 3032
Compounds which were assigned with the aid of DEPT experiments
were assigned by identifying the carbon type (CH3, CH2, CH or C).
Infrared spectra were measured using universal ATR sampling
accessories on a PerkinElmer Spectrum Two spectrometer. Flash
chromatography was performed using Kieselgel silica gel 60,
0.040e0.063 mm (Merck). Thin layer chromatography (TLC) was
carried out on pre-coated silica gel plates (Merck 60 PF254). Visu-
alisation was achieved by UV (254 nm) light detection and vanillin
staining.
(CH), 1657 (CO), 1598 (aromatic), 1505, 1236, 846; dH (400 MHz,
CDCl3) 7.53e7.72 (4H, m, ArH), 7.15 (5H, s, ArH), 7.02e7.09 (4H, m,
ArH), 6.94 [1H, s, C(3)H], 4.00 (2H, s, SCH2); dC (75.5 MHz, CDCl3)
192.4 (C), 165.5 (C),162.8 (C), 138.6 (CH), 137.2, 135.2 [2 x C], 133.5
(C), 132.5 (CH), 132.4 (CH), 130.8 (C), 129.4, 128.5, 127.3 (3 x CH),
115.5 (CH), 115.4 (CH), 36.7 (CH2); HRMS (ESþ): Exact mass calcu-
lated for C22H17SOF2 [M þ Hþ] 367.0968. Found 367.0960; m/z
(ESþ) 367.3 [(C22H16SOF2)þHþ], 100%.
Nominal mass spectra were recorded on a Waters Quattro Micro
triple quadrupole spectrometer in electrospray ionisation (ESI)
mode using 50% water/acetonitrile containing 0.1% formic acid as
eluent; samples were made up in acetonitrile. High resolution mass
spectra (HRMS) were recorded on a Waters LCT Premier Time of
Flight spectrometer in electrospray ionisation (ESI) mode using 50%
water/acetonitrile containing 0.1% formic acid as eluent; samples
were made up in acetonitrile.
4.4. Procedure for synthesis of compound 38h
A solution of Oxone® (824 mg, 1.3 mmol) in water (5 mL) was
added dropwise to a stirring solution of the sulfide Z-4h (203 mg,
0.6 mmol) in acetone (10 mL) at room temperature. A white pre-
cipitate formed immediately. After stirring for 2 h, water (15 mL)
was added and the aqueous solution was extracted with dichloro-
methane (3 ꢂ 15 mL). The organic layers were washed with water
(2 ꢂ 10 mL) and brine (10 mL), dried, and concentrated under
reduced pressure to give a yellow solid. 1H NMR spectroscopy
showed this product to contain 90% of the E sulfoxide E-38h with
approx. 6% of the Z sulfoxide Z-38h. The product was recrystallised
from methanol to give the sulfoxide E-38h (112 mg, 53%) as an off-
4.2. Procedure for synthesis of compound 4d
N-Chlorosuccinimide (0.248 g, 1.9 mmol, 1.95 eq) was added in
one portion to a solution of the sulfide 1-(4-methoxyphenyl)-2-
(phenylthio)propan-1-one 3d (0.232 g, 0.9 mmol) in toluene
(10 mL). The flask was immediately immersed in an oil bath at 90 ꢀC
and heating was maintained for 16 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 product as an orange oil and a mixture of
E and Z isomers in a ratio of 1:1.7. Following purification by column
chromatography on silica gel using hexane-ethyl acetate (98:2) as
white solid (mp 86e88 ꢀC); max/cmꢁ1 (neat) 3048, 1654 (C]O),
n
1599, 1284, 1225, 1175, 1061 (SeO), 704; dH (400 MHz, CDCl3): 7.85
(2H, d, J 8.1, ArH), 7.27e7.38 (7H, m, ArH), 6.57 (1H, s, CHCl), 4.36
(1H, B of AB system, JAB 13.0, one of SCH 2),4.14 (1H, A of AB system,
JAB 13.0, one of SCH 2), 2.45 (3H, s, ArCH3); dC (100 MHz, CDCl3):
189.6 (C), 146.2, 142.8, 133.0 (3 ꢂ C), 131.1, 130.0, 129.8 (3 ꢂ CH),
128.6 (CH), 128.4 (CH), 128.1 (C), 127.9 (CH), 59.8 (CH2), 21.9 (CH3);
HRMS (ESþ): Exact mass calculated for C17H16O2S35Cl [M þ Hþ]
319.0560. Found 319.0550; m/z (ESþ) 319.2 [(C17H15O2S35Cl)þHþ],
11%.
eluent, the
b-chloroenone 4d (0.241 g, 88%) was isolated as a yellow
oil and a mixture of Z and E isomers Z-4d and E-4d in a ratio of
11

A.M. Kearney, L. Murphy, C.C. Murphy et al.
Tetrahedron xxx (xxxx) xxx
pp. 215e266.
CCDC 2050621 (Compound 46) contains the supplementary
crystallographic data for this paper. This data can be obtained free
of charge from The Cambridge Crystallographic Data Centre.
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Declaration of competing interest
[10] M. Murphy, D. Lynch, M. Schaeffer, M. Kissane, J. Chopra, E. O’Brien, A. Ford,
G. Ferguson, A.R. Maguire, Org. Biomol. Chem. 5 (2007) 1228e1241.
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Res. Dev. 24 (2020) 1978e1987.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
[14] M. Kissane, M. Murphy, D. Lynch, A. Ford, A.R. Maguire, Tetrahedron 64 (2008)
7639e7649.
[15] M. Kissane, A.R. Maguire, Synlett 9 (2011) 1212e1232.
[16] A.J. Flynn, A. Ford, U.B.R. Khandavilli, S.E. Lawrence, A.R. Maguire, Eur. J. Org
Chem. 18 (2019) 5368e5384.
The authors would like to acknowledge the Irish Research
Council (formerly IRCSET) (L.M., C.C.M., A.M.K. - GOIPG/2018/112),
MSD (L.M.) and The Department of Education (C.C.M.) for funding.
Dr. Lorraine Bateman and Dr. Denis Lynch (supported by Science
Foundation Ireland 12/RC/2275_P2) are gratefully acknowledged
for their help in acquiring NOESY NMR spectra during this project.
The authors would also like to gratefully acknowledge the NCI
(Maryland, USA) for biological testing.
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Appendix A. Supplementary data
€
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
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