Copper-catalyzed synthesis of β-haloalkenyl chalcogenides by addition of dichalcogenides to internal alkynes and its application to synthesis of (Z)-tamoxifen

Article abstract of DOI:10.1016/j.tet.2009.01.094

A copper-catalyzed synthesis of β-haloalkenyl sulfides or selenides was carried out by addition of dichalcogenides and tetrabutylammonium halides to internal alkynes. The present reaction anti- and regio-selectively afforded the corresponding alkenyl chal

Full text of DOI:10.1016/j.tet.2009.01.094

Tetrahedron 65 (2009) 2782–2790
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed synthesis of b-haloalkenyl chalcogenides by addition
of dichalcogenides to internal alkynes and its application to synthesis
of (Z)-tamoxifen
*
Nobukazu Taniguchi
Department of Chemistry, Fukushima Medical University, Fukushima 960-1295, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed synthesis of
b-haloalkenyl sulfides or selenides was carried out by addition of
Received 20 November 2008
Received in revised form 27 January 2009
Accepted 28 January 2009
Available online 4 February 2009
dichalcogenides and tetrabutylammonium halides to internal alkynes. The present reaction anti- and
regio-selectively afforded the corresponding alkenyl chalocogenides, and took advantage of both orga-
nochalcogenide-groups on dichalcogenide. Furthermore, the reaction under oxygen atmosphere could
employ thiols. The use of the procedure could easily synthesize (Z)-tamoxifen from diphenyl acetylene in
three steps.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
b-Haloalkenyl chalcogenide
Internal alkyne
Dichalcogenide
Copper catalyst
1. Introduction
a stereoselective procedure to prepare
internal alkynes are desired now.
b-haloalkenyl sulfides from
A transition-metal-catalyzed preparation of alkenyl sulfides
from alkynes was carried out by numerous methods so far.1,2,3
Herein produced compounds have found a widespread utilization
as convenient intermediates in organic synthesis.4
To synthesize b-haloalkenyl sulfides from alkynes, I researched
a reaction using disulfides. These disulfides are stable and useful
compounds, but the utilization is less than that of thiols. In addi-
tion, previously developed procedures using disulfides cannot ef-
ficiently synthesize expected alkenyl sulfides. To solve this
problem, it is required to explore a system producing a sulfenyl
cation and reusing a metal-thiolate complex generated as an in-
termediates.12 From various investigations, I found that a synthesis
As a general rule, to synthesize alkenyl sulfides, disulfidations5
or hydrosulfidations6 of terminal alkynes using disulfides or thiols
have been performed. In these reactions, the use of a palladium or
a rhodium catalyst affords syn-adducts, and a stoichiometric
gallium chloride as a Lewis acid gives anti-adducts.7 However,
a transition-metal-catalyzed preparation of anti-additive products
has been rarely exploited.8 Moreover, an employment of internal
alkyne is very limited though various reactions using terminal
alkynes are reported.6
of
b-haloalkenyl sulfides from disulfides with internal alkynes
could carry out by a copper catalyst in air.13 In this paper, I wish to
describe the methodology.
2. Results and discussion
Although
b-haloalkenyl sulfides are useful intermediates to
prepare various alkenes, an advance of its synthetic method has not
been performed to date. In particular, previous methods can syn-
thesize only simple derivatives. For instance, these are usually
prepared by addition of sulfenyl halides to alkynes9,10 or decar-
To carry out the introduction of halide and sulfide-groups to
alkynes, conditions using 4-octyne 1a with diphenyl disulfide 2a
were initially researched in the presence of copper catalyst
(Table 1). In the selection of various additions, when KBr or
dibromoethane were used, the yield of 4-bromo-5-phenylthio-4-
octene 3a was low yield (entries 1–2). Fortunately, when n-Bu4NBr
boxylative dehydrohalogenation of b-arylmercapto-a,b-dihalopro-
pionic acids.11 Problems in these reactions are the use of chlorine
gas or the separation of stereoisomers, and these methods cannot
construct intricate structures. Therefore, an efficient and
was employed, the corresponding b-bromoalkenyl sulfide 3a could
be obtained in 81% yield without other isomers (entry 3).
This reaction could lead to good results by the use of bpy or 1,10-
phenanthroline (o-Phen) as a ligand (entries 3 and 5), though the
use of TMEDA or Ph3P was unexpected result (entries 6 and 7). In
the investigation of copper catalysts, when Cu(I)I or Cu(I)Br was
* Tel./fax: þ81 24 547 1369.
E-mail address: taniguti@fmu.ac.jp
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.094

N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
2783
Table 1
In this method, not only disulfides but also diselenides can
participate (entries 21–26). The treatment of alkynes with diphenyl
diselenide by CuI catalyst regio- or anti-selectively produced the
Addition of bromide and sulfide-group to 4-octyne
cat.[Cu](5 mol%),
Br
Pr
Pr
Additive
Pr
Pr
(PhS)2
corresponding
b-bromoalkenyl selenides in excellent yields.
+
Solvent, in air
100 °C, 18 h
SPh
3a
As shown in Table 2, the preparation of
b
-chloroalkenyl sulfide
1a
2a
using n-Bu4NCl was unsatisfactory results. To solve this problem, I
examined an introducing condition of chloride (entry 3 in Table 2).
From various experiments, I found that the employment of cesium
Entry
[Cu]–L
Additive
Solvent
3a (%)a
1
2
3
4
5
6
7
8
CuI–bpy
CuI–bpy
CuI–bpy
KBr
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
DMF
38
Trace
81
44
65
21
25
77
5
chloride could form the
b-chloroalkenyl sulfides or selenides in
BrCH2CH2Br
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
good yield (entries 1–8 in Table 3). In addition, the present pro-
cedure could introduce thiocyanide instead of halide by the use of
potassium thiocyanate (entries 9–11 in Table 3).
CuI–none
CuI–Phen
CuI–TMEDA
CuI–Ph3P
CuBr–bpy
CuCl–bpy
CuBr2–bpy
CuCl2–bpy
Cu(OAc)2–bpy
CuI–bpy
CuI–bpy
CuI–bpy
CuI–bpy
Thus,
b-haloalkenyl chalcogenides could anti- and regio-
selectively synthesize from internal alkynes, dichalcogenides and
tetrabutylammonium halides by the copper catalyst.
9
10
11
12
13
14
15
16
15
As an application of the present reaction, I then investigated
Trace
Trace
0
Trace
Trace
0
b-halosulfenylations of alkynes using thiols. From previous exper-
iments, it is evident that although the reaction using thiol can
produce the desired alkenyl sulfide, the yield is very low. Therefore,
to improve the yield, various conditions were researched. By
various examinations, I found that a reaction under oxygen
atmosphere could attain to the best result. When a mixture of 4-
octyne 1a, PhSH 4a, and n-Bu4NBr was treated by CuI–bpy (1:1,
10 mol %) under oxygen atmosphere, (E)-4-bromo-5-phenylthio-4-
octene 3a was obtainedin 60% yield with diphenyldisulfide (entry 1
in Table 4).
DMSO
Dioxane
PhCH3
a
Isolated yields after silica gel chromatography.
used, the present reaction proceeded smoothly. But Cu(II) catalysts
could not promote satisfactorily the reaction (entries 10–12). Other
solvents (DMF, DMSO, dioxane, and PhCH3) could not produce 3a at
all (entries 13–16).
On the basis of the above described condition, numerous addi-
tions of thiols to internal alkynes were carried out (Table 4). The
present procedure could regio- and anti-selectively produce the (E)-
Noteworthily, a combination of alkyne with thiol could afford
b
-bromoalkenyl sulfide 3a in only 24% yield, and disulfide was
b-haloalkenyl sulfides 3, but the yields were decreased slightly.
obtained in 60% yield (Scheme 1). Thus, it has became apparent
that the copper-catalyzed reaction of alkyne with disulfide could
effectively promote the addition of halide and sulfide-groups.
Then, to clarify the stereochemistry of 4-bromo-5-phenythio-4-
octene 3a, a debromination of 3a was carried out. When 3a was
reduced by cat. Pd(PPh3)4 and MeONa, 4-phenylthio-4-octene 5a
was obtained in 92% yield as a single isomer. The stereochemistry of
5a was Z-isomer.14 This result shows that the addition of bromide
and phenylthio-group to internal alkynes is anti-selectively
reaction.13
Thus, I could also achieve the method using thiol under oxygen
atmosphere.
To investigate the reaction process, we next researched both
a reaction in the absence of oxygen and a reactivity of PhSCu(I).
When the reaction of 4-octyne 1a with diphenyl disulfide 2a
was carried out under nitrogen atmosphere, b-iodoalkenyl sulfide
3b was obtained in only 22% yield with a recovery of disulfide
(Scheme 2).
The reactivity of PhSCu(I) 817 considered as an intermediate was
also examined. The reaction of the complex 8 with 4-octyne 1a in
air could produce the expected alkenyl sulfide 3b in 49% yield, but
the reaction in the absence of oxygen gave in only 10% yield
(Scheme 3). That is to say, the complex 8 cannot carry out sulfe-
nylation of 4-octyne by itself.
On the basis of my developed method, various copper-catalyzed
syntheses of
b-haloalkenyl sulfides using internal alkynes and
disulfides were examined. As shown in Table 2, numerous combi-
nations of diaryl or dialkyl disulfides and symmetrical internal al-
kynes could anti-selectively produced the corresponding b-bromo
Then, I examined changes of PhSCu(I) in various solvents
(Table 5). When PhSCu(I) was treated in acetic acid, diphenyl
disulfide 2a was obtained in 92% yield. On the other hand, in
other solvent such as DMSO or DMF, the formation of disulfide 2a
was inhibited. This fact suggests that PhSCu(I) undergo dispro-
portionation in acetic acid.
From these results, oxygen is necessary for the promotion of the
copper-catalyzed halosulfenylation of alkynes, and it is obvious that
both disulfide and the copper catalyst can be reproduced from
PhSCu(I) under acidic conditions in the presence of oxygen.
Therefore, a reaction mechanism is considered as follows
(Fig. 1). After the Cu(I)-catalyst acted on the disulfide as the oxidant
in air or Lewis acid,13,18,19 a sulfenium ion 9 and PhSCu(I)Ln 11 are
or iodoalkenyl sulfides in excellent yields (entries 1–13).15
Regrettably, the case using n-Bu4NCl or di(4-nitrophenyl)disulfide
showed lower reactivity (entries 3 and 7), and the starting mate-
rials were recovered.
The present procedure could also employ unsymmetrical in-
ternal alkynes, and regio- and anti-selectively produced the corre-
sponding
b
-bromo or iodoalkenyl sulfides (entries 14–18).15,16
Although a reaction using 1-phenyl-1-propyne or 2-butyn-1-ol
afforded good yields, the anti-selectivity decreased slightly (entries
14 and 18).16 On the contrary, a reaction of 2-octyne indicated no
regio-selectivity (entry 19), and the use of terminal alkyne resulted
in lower yield owing to the formation of various products
(entry 20).
CuI-bpy (5 mol%),
Br
Pr
H
Pr
Pr
n-Bu4NBr
Pr
Pr
+ PhSH
+
+
(PhS)2
AcOH, in air,
100 °C, 18 h
SPh
SPh
Pr
1a
4a
3a
5a
2a
24 %
trace
60 %
Scheme 1. Reaction of 4-octyne with benzenethiol.

2784
N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
Table 2
Copper-catalyzed synthesis of
b
-haloalkenyl chalcogenides using dichalcogenides
CuI-bpy (5 mol%),
n-Bu4NX
R2
X
R1
R2
+
1/2(R3Y)2
2
R1
YR3
3
AcOH, in air,
100 °C
1
Y=S or Se
Entry
1
3
Time (h)
18
3 (%)a
Entry
14
3
Time (h)
18
3 (%)a (E/Z)c
Br
Me
Br
Pr
Pr
81
94 (98/2)c,d
Ph
SPh
SPh
3a
3n
I
Me
I
Pr
2
3
4
5
18
18
18
18
80
42
85
87
15
16
18
18
48
36
66
Ph
SPh
Pr
SPh
3b
3o
Cl
Pr
Br
Pr
Et
86
Ph
SPh
SPh
3p
3c
Br
Pr
Br
Pr
CH2OAc
SPh
17f
18g
69
Ph
SC6H44-Me
3q
3d
3e
3f
Br
Pr
Pr
Br
CH2OAc
SPh
85 (87/13)c,d
Me
SC6H44-OMe
3r
R
CH2(CH2)2CH3
R
R=Br or SPh
3s
Br
Pr
Pr
73e
Me
6
18
65
19
40
SC6H44-Br
Br
Pr
Br
SPh
7
24
18
18
18
45
74
77
76
20b
21
18
18
18
40
28 (65/35)c
Pr
SC6H44-NO2
Ph
3t
3g
Br
Pr
Br
Pr
8
94
80
81
Pr
SePh
Pr
SMe
3h
3u
Br
Et
I
Pr
9
22
23
Et
SePh
Pr
SMe
3i
3v
Br
Pr
Pr
Br
Ph
10
Ph
Sn-Bu
SePh
3j
3w
Br
Me
Br
Pr
Pr
11
12
18
18
81
71
24
18
48
80
84
Ph
SePh
SBn
3k
3x
Br
CH2OAc
SePh
Br
Et
Et
25b,f
Ph
SPh
3l
3y
Br
Br
CH2OAc
SePh
Ph
13
42
70
26g
48
87(87/13)c,d
Me
Ph
SC6H44-Me
3m
3z
a
Isolated yields after silica gel chromatography.
CuI was used 10 mol %.
b
c
d
e
f
Determined by 1H NMR.
These isomers can separate by silica gel chromatography.
Regio-isomers were obtained in the ratio of 1:1.
3-Phenyl-2-propyn-1-ol was used as a starting material.
2-Butyn-1-ol was used as a starting material.
g

N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
2785
Table 3
Table 4
Copper-catalyzed introduction of chloride or thiocyanide and chalcogenide-groups
Copper-catalyzed synthesis of
b
-haloalkenyl chalcogenides using thiol
to alkynes
CuI-bpy (10 mol%),
X
CsCl or NH4SCN,
R2
R2
X
CuI-bpy (5 mol%),
n-Bu4NX
+
1/2(R3Y)2
R3SH
R1
R2
R1
R2
+
R1
SR3
3
R1
YR3
AcOH, in air,
100 °C
AcOH, under O2,
100 °C
1
4
1
2 or 6
3c or 7
Entry
1
3
Time 3
(h)
Entry
3
Time 3 (%)a
(h)
X = Cl or SCN
Time (h)
7 (%)a
(%)a
(E/Z)b
Entry
1
7
Br
Pr
Pr
Br
Pr
Cl
Pr
Pr
18
60
6
18
45
Pr
SnBu
SPh
40
42
76
86
3a
3j
Ph
SPh
3c
Br
I
Pr
Cl
Pr
2
4
18
18
24
57
7
8
24
18
77
Ph
SC6H44-Me
Me
Pr
SPh
2
Pr
3b
Pr
SePh
3m
7a
Br
Pr
Br
90
Cl
Et
Et
SC6H44-Me
Ph
(98/2)b,c
SPh
3
4
5
43
40
42
67
75
75
3n
3d
3e
3f
SPh
7b
Br
Br
Pr
CH2OAc
SPh
Pr
52 9d
46
40
74
Cl
Ph
Ph
4
18
18
Ph
SC6H44-OMe
3q
SC6H44-Me
Me
7c
Br
CH2OAc
SPh
Br
Pr
Pr
68
60 10e
Cl
5
(91/9)b,c
Me
SC6H44-Br
3r
Ph
SPh
a
7d
Isolated yields after silica gel chromatography.
Determined by 1H NMR.
These isomers can separate by silica gel chromatography.
3-Phenyl-2-propyn-1-ol was used as a starting material.
2-Butyn-1-ol was used as a starting material.
b
c
Cl
Me
6
42
72
72
18
18
18
78
52
70
90
63
66
d
e
Ph
SePh
7e
Cl
CH2OAc
SPh
1/2(PhS)2, n-Bu4NX
CuI-bpy (5 mol %)
AcOH, 100 °C, 18 h
under N2
7b
8b
9
X
Pr
Ph
(PhS)2
+
Pr
Pr
7f
Pr
SPh
1a
3
a
2
Cl
CH2OAc
SePh
(1.0 mmol)
X = I (3a) : 22 %
Br (3b): 28 %
60 %
70 %
Ph
7g
Scheme 2. Reaction in the absence of oxygen.
NCS
Pr
Pr
SPh
I
Pr
SPh
7h
n-Bu4NI, bpy
AcOH, 100 °C
18 h
Pr
Pr
+
PhSCu
NCS
Pr
Pr
Pr
,
1a
8
3b
10
SePh
(0.2 mmol)
(0.2 mmol)
7i
(PhS)2 (%)
3b (%)
NCS
Et
Et
in air
under N2
49
10
25
46
11
SPh
7j
a
Scheme 3. Reactivity of PhSCu.
Isolated yields after silica gel chromatography.
3-Phenyl-2-propyn-1-ol was used as a starting material.
b
Table 5
PhSCu(I) in various solvents
bpy
PhSCu
1/2(PhS)2
2a
Solv., 100 °C,
in air, 18 h
7
produced from intermediates 10 with alkyne 1. Sequentially,
b-
haloalkenyl sulfides 3 are formed by a reaction of 9 with Xꢀ.19 On
the other hand, the disproportionation of PhSCu(I)Ln 11 under
acidic conditions gave (PhS)2Cu(II)Ln 12 and Cu(0)Ln. Finally, the
oxidation of the complex 12 produces disulfide 2a and Cu(I)ILn
again in air.12,20
Herein developed method can be carried out on a larger pre-
parative scale. The copper-catalyzed bromosulfenylation of 4-
octyne 1a (1.1 g, 10 mmol) or 1-phenyl-1-propyne 1m (1.2 g,
10 mmol) using (PhS)2 2a (1.1 g, 5 mmol) and n-Bu4NBr (3.5 g,
11 mmol) afforded (E)-4-bromo-5-phenylthio-4-octene 3a (2.3 g)
(0.3 mmol)
Entry
Solvent
AcOH
2a (%)a
1
92
48
57
43
35
2b
3c
4
DMF
DMSO
5
a
Isolated yield after silica gel chromatography.
bpy was not added.
This reaction was carried out at room temperature.
b
c

2786
N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
Ph
dichalcogenide with tetrabutylammonium halide in air. The pres-
ent reaction could prepare the corresponding -haloalkenyl
chalcogenide in anti-selectively, and use both chalcogenide-groups
on dichalcogenide. Herein obtained compounds can take advantage
of preparations of various polysubstituted alkenes.
X
R2
X-
S+
b
R1
R2
R2
R1
R1
SPh
1
9
3
PhS+-SPh
[Cu]
PhS+ or
10
PhSCu(I)Ln
11
4. Experimental section
4.1. General procedure
11
H+
X-, O2
(O2)
(PhS)2
2a
Cu(0)Ln
Cu(I)ILn
Cu(I)XLn
(PhS)2Cu(II)Ln
12
All reactions of dichalcogenides with alkynes were carried out in
air. NMR spectra were recorded on a JEOL EX-270 spectrometer
(270 MHz for 1H, 67.5 MHz for 13C). Chemical shifts are reported in
X-, O2
2a
d
parts per million referenced to an internal tetramethylsilane
Figure 1. Plausible reaction mechanism.
n-Bu4NBr (11 mmol),
standard for 1H NMR and chloroform-d ( 77.0) for 13C NMR. IR
d
spectra were measured by Perkin–Elmer Spectrum One FT-IR spec-
trometer. Melting points were measured on a BUCHI Melting Point
B-540 apparatus. Elemental analysis was performed at the In-
strumental Analysis Center for Chemistry, Tohoku University (Japan).
¨
R2
Br
R1
Cu-L (5 mol %),
R1
R2
+
1/2(PhS)2
AcOH, in air
SPh
3
100 ºC, 24 h
1
2a
(10 mmol)
(5 mmol)
Yield of 3
4.2. Copper-catalyzed synthesis of
(Table 2)
b-bromoalkenyl sulfide
R1 = R2 = n-Pr:
2.3 g (79%)
R
1 = Ph, R2 = Me: 2.4 g (81%)
E/Z = 98/2
To
a mixture of CuI (1.9 mg, 0.01 mmol), bpy (1.6 mg,
0.01 mmol), diphenyl disulfide 2a (21.8 mg, 0.1 mmol), and n-
Bu4NBr (70.9 mg, 0.22 mmol) in AcOH (0.3 mL) was added 4-octyne
1a (22.0 mg, 0.2 mmol), and the mixture was stirred at 100 ꢁC for
18 h in air. After the residue was dissolved in Et2O, the solution was
washed with H2O and saturated sodium chloride and dried over
anhydrous magnesium sulfate. Chromatography on silica gel
(Hexane) gave (E)-4-bromo-5-phenylthio-4-octene 3a (48.7 mg,
Scheme 4. Large scale reaction.
or (E)-1-bromo-2-phenylthio-2-methylstyrene 3n (2.4 g) in 79% or
81% yield, respectively (Scheme 4).
The present procedure can be accessible to the synthesis of
numerous polysubstituted alkenes.21 For example, (Z)-tamoxifen is
known as an estrogen antagonist, and is effective for metastatic
breast cancer.22 Previous syntheses have been carried out by
a classical synthesis using stoichiometric regents or a stereospecific
synthesis by multi-steps.23
However, as shown in Scheme 5, the use of my developed
procedure can synthesized (Z)-tamoxifen from diphenyl acetylene
in three steps.
81%). 1H NMR (270 MHz, CDCl3)
d 7.31–7.16 (m, 5H), 2.90 (t,
J¼7.5 Hz, 2H), 2.38 (t, J¼7.5 Hz, 2H), 1.67–1.51 (m, 4H), 0.92 (t,
J¼7.5 Hz, 3H), 0.86 (t, J¼7.5 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d
135.3, 132.8, 131.5, 129.2, 128.9, 126.2, 41.2, 38.8, 21.9, 21.0, 13.6,
13.1; IR (neat) 2960, 2870, 1582, 1476, 1461 cmꢀ1. Anal. Calcd for
C14H19SBr: C, 56.19; H, 6.40. Found: C, 56.09; H, 6.27.
4.2.1. (E)-4-Iodo-5-phenylthio-4-octene (3b)
Initially, b-bromoalkenyl sulfide 3m was derived in 94% yield
1H NMR (270 MHz, CDCl3)
d
7.31–7.16 (m, 5H), 2.94 (t, J¼7.3 Hz,
from diphenyl acetylene 1m by CuI catalyst. Herein the obtained
3m was converted to the corresponding alkenyl sulfide 13 in 72%
yield by Suzuki–Miyaura coupling. Finally, (Z)-tamoxifen 14 could
be synthesized in 75% yield (Z/E¼93/7) by a nickel-catalyzed cou-
pling of 13 with EtMgBr.
2H), 2.39 (t, J¼7.3 Hz, 2H), 1.66–1.50 (m, 4H), 0.92 (t, J¼7.3 Hz, 3H),
0.87 (t, J¼7.3 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d 135.5, 135.4,
129.3, 128.9, 126.4, 113.0, 45.4, 43.9, 22.9, 21.3, 13.5, 12.9; IR (neat)
2959, 1582, 1476, 1461 cmꢀ1. Anal. Calcd for C14H19SI: C, 48.56; H,
5.53. Found: C, 48.48; H, 5.47.
Thus,
b-haloalkenyl sulfides can use as very convenient in-
termediates for the purpose of preparations of various poly-
substituted alkenes.
4.2.2. (E)-4-Chloro-5-phenylthio-4-octene (3c)
1H NMR (270 MHz, CDCl3)
d
7.31–7.15 (m, 5H), 2.79 (t, J¼7.4 Hz,
2H), 2.36 (t, J¼7.4 Hz, 2H), 1.70–1.47 (m, 4H), 0.92 (t, J¼7.4 Hz, 3H),
3. Conclusion
0.86 (t, J¼7.4 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d 139.9, 135.5,
129.5, 128.9, 128.8, 126.1, 39.0, 35.9, 21.3, 21.0, 13.6, 13.2; IR (neat)
2961, 1582, 1477, 1462 cmꢀ1. Anal. Calcd for C14H19SCl: C, 65.99; H,
7.52. Found: C, 65.90; H, 7.15.
In conclusion, I achieved a copper-catalyzed introduction of
halide and sulfide or selenide-groups to internal alkynes using
O(CH2)2NMe2
O(CH2)2NMe2
Me2NCH2CH2OC6H4Bpin
1/2(MeC6H4S)2,
CuI-bpy (8 mol %),
nBu4NBr
AcOH, air, 100 °C,
24 h
cat.Pd(PPh3)4 (8 mol %),
EtMgBr(5eq)
Br
Ph
K2CO3
dioxane-H2O,100 °C,
18 h
NiCl2(dppe) (8 mol%)
Ph
Et
Ph
Ph
Ph
Et2O, reflux, 15 h
Ph
SC6H44-Me
1m
Ph
Ph
SC6H44-Me
3m
13
14
94%
72%
Scheme 5. Synthesis of (Z)-tamoxifen from diphenyl acetylene.
75%(Z/E =93/7)

N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
2787
4.2.3. (E)-4-Bromo-5-(4-tolyl)thio-4-octene (3d)
1H NMR (270 MHz, CDCl3)
4.2.11. (E)-3-Bromo-4-phenylthio-3-hexene (3l)
1H NMR (270 MHz, CDCl3)
7.31–7.15 (m, 5H), 2.91 (q, J¼7.2 Hz,
2H), 2.41 (t, J¼7.2 Hz, 2H), 1.13 (t, J¼7.2 Hz, 3H), 1.05 (t, J¼7.2 Hz,
3H); 13C NMR (67.5 MHz, CDCl3)
135.3, 133.9, 131.8, 129.0, 128.9,
126.2, 33.3, 30.6, 13.5, 12.0; IR (neat) 2970, 2932, 1606, 1582, 1476,
1457, 1438 cmꢀ1. Anal. Calcd for C12H15SBr: C, 53.14; H, 5.57. Found:
C, 52.91; H, 5.56.
d
7.15 (d, J¼8.3 Hz, 2H), 7.09 (d,
d
J¼8.3 Hz, 2H), 2.90 (t, J¼7.4 Hz, 2H), 2.34 (t, J¼7.4 Hz, 2H), 2.32 (s,
3H), 1.49–1.67 (m, 4H), 0.93 (t, J¼7.4 Hz, 3H), 0.86 (t, J¼7.4 Hz, 3H);
d
13C NMR (67.5 MHz, CDCl3)
d
136.5, 132.2, 131.5, 131.4, 130.1, 129.8,
41.2, 38.5, 21.9, 21.0 (2C), 13.6, 13.1; IR (neat) 2960, 2929,1894,1602,
1491 cmꢀ1. Anal. Calcd for C15H21SBr: C, 57.50; H, 6.76. Found: C,
57.21; H, 6.67.
4.2.12. (E)-1-Bromo-1,2-diphenyl-2-(4-tolyl)thioethene (3m)
4.2.4. (E)-4-Bromo-5-(4-methoxyphenyl)thio-4-octene (3e)
Mp 116–117 ꢁC; 1H NMR (270 MHz, CDCl3)
d 7.57–7.53 (m, 2H),
1H NMR (270 MHz, CDCl3)
d
7.24 (d, J¼8.9 Hz, 2H), 6.84 (d,
7.43–7.32 (m, 4H), 7.25–7.16 (m, 4H), 7.00 (d, J¼7.9 Hz, 2H), 6.88 (t,
J¼8.9 Hz, 2H), 3.79 (s, 3H), 2.91 (t, J¼7.3 Hz, 2H), 2.28 (t, J¼7.5 Hz,
J¼7.9 Hz, 2H), 2.18 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d 140.7, 139.6,
2H), 1.48–1.68 (m, 4H), 0.94 (t, J¼7.4 Hz, 3H), 0.85 (t, J¼7.4 Hz, 3H);
137.2,136.3,131.8,130.0,129.7,129.3, 129.2,128.7,128.2, 127.7,127.6,
121.5, 21.0; IR (CHCl3) 3019, 1598, 1492 cmꢀ1. Anal. Calcd for
C21H17SBr: C, 66.14; H, 4.49. Found: C, 66.53; H, 4.53.
13C NMR (67.5 MHz, CDCl3)
d 159.2, 133.3, 132.8, 129.5, 125.1, 114.6,
55.3, 41.1, 38.0, 21.9, 20.9, 13.6, 13.1; IR (neat) 2960, 2930, 1592,
1493 cmꢀ1. Anal. Calcd for C15H21OSBr: C, 54.71; H, 6.43. Found: C,
54.53; H, 6.38.
4.2.13. (E)-1-Bromo-2-phenylthio-2-methylstyrene (3n)
1H NMR (270 MHz, CDCl3) 7.41–7.24 (m, 10H), 2.21 (s, 3H); 13
d C
4.2.5. (E)-4-Bromo-5-(4-bromophenyl)thio-4-octene (3f)
NMR (67.5 MHz, CDCl3) d 140.5, 134.5, 130.5, 130.2, 129.1, 129.0,
1H NMR (270 MHz, CDCl3)
d
7.40 (d, J¼8.6 Hz, 2H), 7.08 (d,
128.5, 128.1, 126.9, 123.3, 24.9; IR (neat) 3057, 1581, 1475,
1439 cmꢀ1. Anal. Calcd for C15H13SBr: C, 59.02; H, 4.29. Found: C,
58.94; H, 4.37.
J¼8.6 Hz, 2H), 2.87 (t, J¼7.2 Hz, 2H), 2.37 (t, J¼7.7 Hz, 2H), 1.67–1.49
(m, 4H), 0.92 (t, J¼7.4 Hz, 3H), 0.87 (t, J¼7.4 Hz, 3H); 13C NMR
(67.5 MHz, CDCl3) d 134.7, 133.7, 132.0, 130.9, 130.2, 120.1, 41.3, 38.8,
21.9, 21.0, 13.6, 13.0; IR (neat) 2960, 2929, 1889, 1603, 1471 cmꢀ1
.
4.2.14. (E)-1-Iodo-2-phenylthio-2-methylstyrene (3o)
Anal. Calcd for C14H18SBr2: C, 44.46; H, 4.80. Found: C, 44.32; H,
4.89.
1H NMR (270 MHz, CDCl3) 7.33–7.22 (m, 10H), 2.27 (s, 3H); 13
d C
NMR (67.5 MHz, CDCl3)
d 144.3, 134.9, 131.0, 129.0, 128.9, 128.7,
128.1, 128.0, 127.2, 99.6, 29.9; IR (neat) 3072, 3056, 1582, 1475,
1439 cmꢀ1. Anal. Calcd for C15H13SI: C, 51.15; H, 3.72. Found: C,
51.10; H, 3.42.
4.2.6. (E)-4-Bromo-5-(4-nitrophenyl)thio-4-octene (3g)
1H NMR (270 MHz, CDCl3)
d
8.14 (d, J¼9.2 Hz, 2H), 7.25 (d,
J¼9.2 Hz, 2H), 2.85 (t, J¼7.2 Hz, 2H), 2.48 (t, J¼7.6 Hz, 2H), 1.67–1.53
(m, 4H), 0.94–0.88 (m, 6H); 13C NMR (67.5 MHz, CDCl3)
146.1,
145.5, 137.5, 128.6, 126.6, 124.2, 41.5, 39.7, 21.9, 21.1, 13.6, 13.0; IR
(neat) 2960, 2930, 1918, 1580, 1515 cmꢀ1
Anal. Calcd for
d
4.2.15. (E)-1-Bromo-1-phenyl-2-phenylthio-1-butene (3p)
1H NMR (270 MHz, CDCl3)
d
7.38–7.18 (m, 10H), 2.56 (q, J¼7.4 Hz,
.
2H), 1.16 (t, J¼7.4 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d 140.7, 136.3,
C14H18NO2SBr: C, 48.84; H, 5.27. Found: C, 48.49; H, 5.20.
134.9, 130.1, 129.1, 128.9, 128.4, 128.0, 126.7, 123.6, 30.3, 12.1; IR
(neat) 3057, 1581, 1475, 1439 cmꢀ1. Anal. Calcd for C16H15SBr: C,
60.19; H, 4.74. Found: C, 59.97; H, 4.70.
4.2.7. (E)-4-Bromo-5-methylthio-4-octene (3h)
1H NMR (270 MHz, CDCl3)
d
2.81 (t, J¼7.2 Hz, 2H), 2.48 (t,
J¼7.7 Hz, 2H), 2.20 (s, 3H), 1.63–1.54 (m, 4H), 0.95 (t, J¼5.3 Hz, 3H),
4.2.16. (E)-1-Bromo-1-phenyl-2-phenylthio-1-propenyl
0.91 (t, J¼5.3 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d
133.4, 127.4,
acetate (3q)
40.8, 37.4, 21.7, 21.0, 16.4, 13.6, 12.9; IR (neat) 2960, 2928, 1602,
1459 cmꢀ1. Anal. Calcd for C9H17SBr: C, 45.57; H, 7.22. Found: C,
45.60; H, 6.93.
1H NMR (270 MHz, CDCl3)
d
7.41–7.20 (m, 10H), 4.96 (s, 2H), 2.00
(s, 3H); 13C NMR (67.5 MHz, CDCl3)
d
170.4, 139.7,133.9,130.8, 130.3,
129.4, 129.3, 129.0, 128.8, 128.1, 127.2, 66.2, 20.6; IR (neat) 3058,
1743, 1581, 1477, 1440 cmꢀ1. Anal. Calcd for C17H15O2SBr: C, 56.21;
H, 4.16. Found: C, 56.32; H, 4.25.
4.2.8. (E)-4-Iodo-5-methylthio-4-octene (3i)
1H NMR (270 MHz, CDCl3)
d
2.85 (t, J¼7.5 Hz, 2H), 2.51 (t,
J¼7.5 Hz, 2H), 2.21 (s, 3H), 1.62–1.51 (m, 4H), 0.97 (t, J¼7.5 Hz, 3H),
4.2.17. (E)-2-Bromo-3-phenylthio-2-butenyl acetate (3r)
0.91 (t, J¼7.5 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d
137.2, 106.8,
1H NMR (270 MHz, CDCl3)
d
7.32–7.21 (m, 5H), 4.87 (d, J¼0.7 Hz,
2H), 2.67 (s, 3H), 1.95 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
170.4,
134.3, 132.3, 129.2, 129.1, 126.8, 126.4, 66.7, 27.9, 20.5; IR (neat)
3058, 1743, 1610, 1581, 1477, 1440 cmꢀ1
Anal. Calcd for
44.8, 42.5, 22.5, 21.2, 16.7, 13.6, 12.8; IR (neat) 2958, 2926, 1455,
1462 cmꢀ1. Anal. Calcd for C9H17SI: C, 38.03; H, 6.03. Found: C,
38.10; H, 6.05.
d
.
C12H13O2SBr: C, 47.85; H, 4.35. Found: C, 47.88; H, 4.59.
4.2.9. (E)-4-Bromo-5-(n-butyl)thio-4-octene (3j)
1H NMR (270 MHz, CDCl3)
d
2.84 (t, J¼7.4 Hz, 2H), 2.61 (t,
J¼7.1 Hz, 2H), 2.45 (t, J¼7.6 Hz, 2H), 1.65–1.51 (m, 6H), 1.48–1.36 (m,
2H), 0.94–0.88 (m, 9H); 13C NMR (67.5 MHz, CDCl3)
132.4, 128.9,
4.2.18. (E)-4-Bromo-5-phenylseleno-4-octene (3u)
1H NMR (270 MHz, CDCl3)
d 7.42–7.36 (m, 2H), 7.28–7.23 (m,
d
3H), 2.89 (t, J¼7.4 Hz, 2H), 2.41 (t, J¼7.4 Hz, 2H), 1.69–1.46 (m,
40.9, 37.8, 32.5, 31.9, 21.9, 21.8, 21.1, 13.6 (2C), 13.0; IR (neat) 2960,
2929, 1601, 1462 cmꢀ1. Anal. Calcd for C12H23SBr: C, 51.61; H, 8.30.
Found: C, 51.36; H, 8.17.
4H), 0.92 (t, J¼7.2 Hz, 3H), 0.86 (t, J¼7.2 Hz, 3H); 13C NMR
(67.5 MHz, CDCl3)
d 132.1, 130.6, 129.5, 129.3, 129.2, 127.1, 43.3,
40.7, 21.9, 21.3, 13.5, 13.0; IR (neat) 2959, 2929, 1608, 1577,
1475 cmꢀ1. Anal. Calcd for C14H19SeBr: C, 48.58; H, 5.53. Found: C,
48.82; H, 5.54.
4.2.10. (E)-4-Bromo-5-benzyllthio-4-octene (3k)
1H NMR (270 MHz, CDCl3)
d 7.31–7.19 (m, 5H), 3.80 (s, 2H), 2.65 (t,
J¼7.2 Hz, 2H), 2.48 (t, J¼7.5 Hz, 2H),1.67–1.53 (m, 2H),1.49–1.36 (m,
4.2.19. (E)-3-Bromo-4-phenylseleno-3-hexene (3v)
2H), 0.94 (t, J¼7.4 Hz, 3H), 0.81 (t, J¼7.4 Hz, 3H); 13C NMR (67.5 MHz,
1H NMR (270 MHz, CDCl3)
d 7.42–7.38 (m, 2H), 7.28–7.23 (m,
CDCl3)
d
137.8, 131.8, 131.5, 128.8, 128.5, 127.0, 40.7, 38.5, 37.9, 21.7,
3H), 2.90 (q, J¼7.4 Hz, 2H), 2.46 (q, J¼7.4 Hz, 2H), 1.12 (t, J¼7.4 Hz,
21.0, 13.6, 12.9; IR (neat) 2960, 2929, 1601, 1494, 1453 cmꢀ1. Anal.
Calcd for C15H21SBr: C, 57.50; H, 6.76. Found: C, 57.15; H, 6.85.
3H), 1.03 (t, J¼7.4 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d 132.1, 131.9,
130.6, 129.8, 129.2, 127.1, 35.4, 32.7, 13.5, 12.3; IR (neat) 2969, 2931,

2788
N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
1610, 1577, 1475, 1456, 1437 cmꢀ1. Anal. Calcd for C12H15SeBr: C,
45.31; H, 4.75. Found: C, 45.02; H, 4.70.
irradiation at 6.70 ppm (]CH–); 13C NMR (67.5 MHz, CDCl3)
d
136.8, 133.6, 132.1, 131.7, 130.9, 129.0, 128.9, 128.0, 127.1, 126.9,
25.6; IR (neat) 3057, 3021, 2915, 1582, 1492, 1475 cmꢀ1. Anal. Calcd
for C15H14S: C, 79.60; H, 6.23. Found: C, 79.34; H, 6.31.
4.2.20. (E)-1-Bromo-1,2-diphenyl-2-phenylselenoethene (3w)
Mp 98–99 ꢁC; 1H NMR (270 MHz, CDCl3)
d
7.55–7.40 (m, 2H),
7.38–7.34 (m, 4H), 7.21–6.97 (m, 9H); 13C NMR (67.5 MHz, CDCl3)
141.2, 140.5, 135.0, 133.3, 129.5, 129.3, 129.1, 128.8, 128.5, 128.3,
127.8, 127.6, 127.4, 117.7; IR (CHCl3) 3019, 1578, 1476, 1443 cmꢀ1
4.4. Copper-catalyzed synthesis of b-chloro or
thiocyanoalkenyl chalcogenides (Table 3)
d
.
Anal. Calcd for C20H15SeBr: C, 58.00; H, 3.65. Found: C, 57.61; H,
3.73.
4.4.1. (E)-4-Chloro-5-phenylseleno-4-octene (7a)
1H NMR (270 MHz, CDCl3)
d 7.41–7.36 (m, 2H), 7.29–7.24 (m,
3H), 2.79 (t, J¼7.4 Hz, 2H), 2.41 (t, J¼7.4 Hz, 2H), 1.69–1.57 (m, 2H),
4.2.21. (E)-1-Bromo-2-phenylseleno-2-methylstyrene (3x)
1.57–1.46 (m, 2H), 0.92 (t, J¼7.4 Hz, 3H), 0.86 (t, J¼7.4 Hz, 3H); 13C
1H NMR (270 MHz, CDCl3)
d
7.48–7.43 (m, 2H), 7.39–7.12 (m,
NMR (67.5 MHz, CDCl3) d 136.9, 131.9, 130.6, 129.2, 127.9, 126.9, 41.0,
8H), 2.22 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d
141.4, 134.3, 133.5,
37.7, 21.4, 21.3, 13.5, 13.2; IR (neat) 3057, 1746, 1576, 1488,
1476 cmꢀ1. Anal. Calcd for C14H19SeCl: C, 55.73; H, 6.35. Found: C,
55.56; H, 6.21.
129.1, 129.0, 128.6, 128.2, 127.9, 127.7, 118.4, 26.3; IR (neat) 3055,
1576, 1475, 1438 cmꢀ1. Anal. Calcd for C15H13SeBr: C, 51.16; H, 3.72.
Found: C, 51.00; H, 3.82.
4.4.2. (E)-3-Chloro-4-phenylthio-3-hexene (7b)
4.2.22. (E)-1-Bromo-1-phenyl-2-phenylseleno-1-propenyl
1H NMR (270 MHz, CDCl3)
d
7.30–7.15 (m, 5H), 2.79 (q, J¼7.4 Hz,
2H), 2.39 (q, J¼7.4 Hz, 2H), 1.14 (t, J¼7.4 Hz, 3H), 1.05 (t, J¼7.4 Hz,
3H); 13C NMR (67.5 MHz, CDCl3)
140.9, 135.5, 129.9, 128.9, 128.7,
acetate (3y)
1H NMR (270 MHz, CDCl3)
d
7.41–7.34 (m, 6H), 7.26–7.23 (m,
d
4H), 4.97 (s, 2H), 1.98 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d
170.4,
126.1, 30.9, 27.8, 12.8, 12.1; IR (neat) 2971, 2934, 1582, 1477, 1457,
1439 cmꢀ1. Anal. Calcd for C12H15SCl: C, 63.56; H, 6.67. Found: C,
63.58; H, 6.60.
138.9, 135.4, 133.7, 129.2, 129.1, 128.8, 128.1, 128.0, 124.7, 77.2, 64.8,
20.6; IR (neat) 3057, 1741, 1577, 1476, 1438 cmꢀ1. Anal. Calcd for
C17H15O2SeBr: C, 49.78; H, 3.69. Found: C, 49.78; H, 3.79.
4.4.3. (E)-1-Chloro-1,2-diphenyl-2-(4-tolyl)thioethene (7c)
4.2.23. (E)-2-Bromo-3-phenylseleno-2-butenyl acetate (3z)
1H NMR (270 MHz, CDCl3)
d
7.62–7.58 (m, 2H), 7.46–7.36 (m,
4H), 7.35–7.20 (m, 4H), 7.18 (d, J¼6.0 Hz, 2H), 7.01 (t, J¼6.0 Hz, 2H),
2.20 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
139.1, 138.1, 136.9, 133.7,
1H NMR (270 MHz, CDCl3)
d
7.49–7.40 (m, 2H), 7.32–7.26 (m,
3H), 4.91 (s, 2H), 2.66 (s, 3H), 1.95 (s, 3H); 13C NMR (67.5 MHz,
d
CDCl3)
d
170.4, 132.1, 129.9, 129.4, 129.3, 127.5, 123.6, 68.4, 29.9,
132.7, 131.3, 130.3, 129.8, 129.4, 128.8, 128.1, 127.8, 127.7, 127.6, 20.9;
IR (CHCl3) 3018, 1583, 1491, 1443 cmꢀ1. Anal. Calcd for C21H17SCl: C,
74.87; H, 5.09. Found: C, 74.49; H, 5.19.
20.6; IR (neat) 3057, 1739, 1615, 1577, 1476, 1437 cmꢀ1. Anal. Calcd
for C12H13O2SeBr: C, 41.40; H, 3.76. Found: C, 41.46; H, 3.80.
4.3. Debromination of
b-bromoalkenyl sulfides
4.4.4. (E)-1-Chloro-2-phenylthio-2-methylstyrene (7d)
1H NMR (270 MHz, CDCl3) 7.46–7.21 (m, 10H), 2.19 (s, 3H); 13
d C
To a mixture of Pd(PPh3)4 (17.3 mg, 0.015 mmol) and MeONa
(16.2 mg, 0.3 mmol) in DMF (0.5 mL) was added (E)-4-bromo-5-
phenylthio-4-octene 3a (44.9 mg, 0.15 mmol) under nitrogen at-
mosphere, and the mixture was stirred at 100 ꢁC for 18 h. After the
residue was dissolved in Et2O, the solution was washed with H2O
and saturated sodium chloride and dried over anhydrous magne-
sium sulfate. Chromatography on silica gel (Hexane) gave (Z)-4-
phenylthio-4-octene 5a (30.3 mg, 92%).6b 1H NMR (270 MHz,
NMR (67.5 MHz, CDCl3) d 138.7, 134.6, 132.8, 130.2, 129.1, 129.0,
128.6, 128.0, 127.9, 126.8, 22.0; IR (CHCl3) 3019, 2157, 1475,
1441 cmꢀ1. Anal. Calcd for C15H13SCl: C, 69.08; H, 5.02. Found: C,
68.72; H, 5.15.
4.4.5. (E)-1-Chloro-2-phenylseleno-2-methylstyrene (7e)
1H NMR (270 MHz, CDCl3) 7.46–7.24 (m, 10H), 2.21 (s, 3H); 13
d C
NMR (67.5 MHz, CDCl3)
d 139.7, 133.9, 131.5, 129.7, 129.1, 129.0,
CDCl3)
d
7.29–7.11 (m, 5H), 5.90 (t, J¼7.1 Hz, 1H), 2.31 (q, J¼7.2 Hz,
128.7, 128.1, 127.8, 125.7, 23.4; IR (neat) 3056, 1577, 1475, 1438 cmꢀ1
.
2H), 2.14 (t, J¼7.2 Hz, 2H), 1.56–1.36 (m, 4H), 0.92 (t, J¼7.2 Hz, 3H),
0.82 (t, J¼7.2 Hz, 3H). The NOE was observed at two allyl positions
(–CH2–CH], 15%) and (]C(SPh)CH2–, 11%) on irradiation at
Anal. Calcd for C15H13SeCl: C, 58.56; H, 4.26. Found: C, 58.28; H,
4.34.
5.90 ppm (]CH–); 13C NMR (67.5 MHz, CDCl3)
d
136.7, 135.8, 133.0,
4.4.6. (E)-1-Chloro-1-phenyl-2-phenylthio-1-propenyl acetate (7f)
129.2, 128.7, 125.6, 39.6, 31.9, 22.7, 21.6, 13.8, 13.3; IR (neat) 2958,
1583, 1476 cmꢀ1. Anal. Calcd for C14H20S: C, 76.30; H, 9.15. Found: C,
76.03; H, 8.92.
1H NMR (270 MHz, CDCl3)
d
7.47–7.44 (m, 2H), 7.37–7.22 (m,
8H), 4.96 (s, 2H), 1.99 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
d
170.5,
138.9, 137.8, 134.0, 130.1, 129.3, 129.1, 128.9, 128.1, 127.1, 127.0, 63.9,
20.6; IR (neat) 3058, 3020, 1743, 1583, 1477, 1441 cmꢀ1. Anal. Calcd
for C17H15O2SCl: C, 64.04; H, 4.74. Found: C, 63.90; H, 4.79.
4.3.1. (Z)-3-Phenylthio-3-hexene (5b)
1H NMR (270 MHz, CDCl3)
d
7.27–7.12 (m, 5H), 5.91 (dt, J¼7.3
and 1.0 Hz, 1H), 2.33 (dq, J¼7.4 and 7.3 Hz, 2H), 2.18 (dq, J¼7.4 and
1.0 Hz, 2H), 1.04 (t, J¼7.4 Hz, 3H), 1.01 (t, J¼7.4 Hz, 3H). The NOE was
observed at two allyl positions (–CH2–CH], 5%) and (]C(SPh)CH2–,
6%) on irradiation at 5.91 ppm (]CH–); 13C NMR (67.5 MHz,
4.4.7. (E)-1-Chloro-1-phenyl-2-phenylthio-1-propenyl acetate (7g)
1H NMR (270 MHz, CDCl3)
d
7.42–7.34 (m, 6H), 7.28–7.23 (m,
4H), 4.95 (s, 2H), 1.99 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
170.3,
138.9, 135.4, 133.7, 129.2, 129.1, 128.9, 128.8, 128.1, 128.0, 124.8,
64.9, 20.6; IR (neat) 2959, 1610, 1578, 1476, 1462, 1437 cmꢀ1
d
CDCl3)
d
137.2, 135.8, 134.1, 129.1, 128.7, 125.6, 30.8, 23.3, 13.9, 13.5;
.
IR (neat) 3072, 2965, 2930,1583,1476 cmꢀ1. Anal. Calcd for C12H16S:
C, 74.94; H, 8.39. Found: C, 74.98; H, 8.24.
Anal. Calcd for C17H15O2SeCl: C, 55.83; H, 4.13. Found: C, 55.49;
H, 4.20.
4.3.2. (Z)-2-Phenylthio-2-methylstyrene (5c)6b
4.4.8. (E)-4-Phenylthio-5-thiocyanato-4-octene (7h)
1H NMR (270 MHz, CDCl3)
d
7.54 (d, J¼7.6 Hz, 2H), 7.42–7.21 (m,
1H NMR (270 MHz, CDCl3)
d
7.34–7.26 (m, 5H), 2.89 (t, J¼7.4 Hz,
8H), 6.70 (s, 1H), 2.02 (d, J¼1.3 Hz, 3H). The NOE was observed at
the phenyl (14%) and allyl positions (]C(SPh)CH2–, 15%) on
2H), 2.33 (t, J¼7.4 Hz, 2H), 1.74–1.66 (m, 2H), 1.53–1.44 (m, 2H), 0.99
(t, J¼7.4 Hz, 3H), 0.81 (t, J¼7.4 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)

N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
2789
d
142.1, 133.0, 131.6, 129.2, 127.7, 126.2, 110.2, 37.2, 36.1, 21.8, 21.7,
(t, J¼5.4 Hz, 2H), 2.45 (q, J¼8.1 Hz, 2H), 2.28 (s, 6H), 0.92
13.4, 13.3; IR (neat) 2960, 2154, 1582, 1475, 1462, 1439 cmꢀ1. Anal.
Calcd for C15H19S2NCl: C, 57.58; H, 6.12; N, 4.48. Found: C, 57.52; H,
5.96; N, 4.36.
(t, J¼8.1 Hz, 3H); 13C NMR (67.5 MHz, CDCl3)
d 150.7, 143.8, 142.4,
141.3, 138.2, 135.5, 131.8, 129.7, 129.4, 128.1, 126.4, 125.9, 113.4, 65.7,
58.3, 45.9, 28.9, 13.6; IR (CHCl3) 2971, 2823, 1606, 1508 cmꢀ1. Anal.
Calcd for C26H29NO: C, 84.06; H, 7.87; N, 3.77. Found: C, 83.60; H,
7.89; N, 3.62.
4.4.9. (E)-4-Phenylseleno-5-thiocyanato-4-octene (7i)
1H NMR (270 MHz, CDCl3)
d 7.50–7.46 (m, 2H), 7.34–7.26 (m,
3H), 2.84 (t, J¼7.4 Hz, 2H), 2.36 (t, J¼7.4 Hz, 2H), 1.73–1.62 (m, 2H),
1.56–1.39 (m, 2H), 0.99 (t, J¼7.4 Hz, 3H), 0.78 (t, J¼7.4 Hz, 3H); 13C
Acknowledgements
NMR (67.5 MHz, CDCl3)
d 141.7, 134.4, 129.4, 128.5, 128.3, 123.6,
This work was financially supported by a Grant-in-Aid for Young
Scientists (B) (No. 19750081) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
110.4, 39.2, 37.8, 22.1, 21.6, 13.3 (2C); IR (neat) 2960, 2152, 1577,
1476,1462,1438 cmꢀ1. Anal. Calcd for C15H19SeSN: C, 55.55; H, 5.90;
N, 4.32. Found: C, 55.52; H, 5.96; N, 4.36.
4.4.10. (E)-3-Phenylthio-4-thiocyanato-3-hexene (7j)
References and notes
1H NMR (270 MHz, CDCl3)
d
7.31–7.24 (m, 5H), 2.90 (q, J¼7.4 Hz,
2H), 2.36 (q, J¼7.4 Hz, 2H), 1.23 (t, J¼7.4 Hz, 3H), 1.02 (t, J¼7.4 Hz,
3H); 13C NMR (67.5 MHz, CDCl3)
142.9, 132.9, 131.5, 129.2, 127.7,
1. For selected reviews: (a) Beletskaya, I.; Moberg, C. Chem. Rev. 2006, 106, 2320–
2354; (b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43,
3368–3398; (c) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205–3220;
(d) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079–3159;
(e) Beletskaya, I.; Moberg, C. Chem. Rev. 1999, 99, 3435–3461; (f) Han, L.-B.;
Tanaka, M. Chem. Commun. 1999, 395–402.
d
127.0, 110.2, 29.1, 27.9, 13.0(2C); IR (neat) 2971, 2933, 2154, 1581,
1475, 1457, 1439 cmꢀ1. Anal. Calcd for C13H15S2N: C, 62.61; H, 6.06;
N, 5.62. Found: C, 62.24; H, 6.07; N, 5.64.
2. For selected paper for the metal-catalyzed synthesis of alkenyl sulfides: (a)
Yamashita, F.; Kuniyasu, H.; Terao, J.; Kambe, N. Org. Lett. 2008, 10, 101–104; (b)
Huang, X.; Xu, X.-H.; Zheng, W.-X. Synth. Commun. 1999, 29, 2399–2404; (c)
Murahashi, S.-I.; Yamamura, M.; Yanagisawa, K.-i.; Mita, N.; Kondo, K. J. Org.
Chem. 1979, 44, 2408–2417; (d) Gridnev, I. D.; Miyaura, N.; Suzuki, A. J. Org.
Chem. 1993, 58, 5351–5354; (e) Nebois, P.; Kann, N.; Greene, A. E. J. Org. Chem.
1995, 60, 7690–7692.
3. For selected recent paper for no metal-catalyzed synthesis of alkenyl sulfides:
(a) Sridhar, R.; Surendra, K.; Srilakshmi, N.; Srinivas, B.; Rao, K. R. Synlett
2006, 3495–3497; (b) Manarin, F.; Roehrs, J. A.; Prigol, M.; Alves, D.; Nogueira,
C. W.; Zeni, G. Tetrahedron Lett. 2007, 48, 4805–4808; (c) Kanemura, S.;
Kondoh, A.; Yasui, H.; Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81,
506–514.
4. (a) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 43–46; (b) Ma-
griotis, P. A.; Doyle, T. J.; Kim, K. D. Tetrahedron Lett. 1990, 31, 2541–2544; (c)
Takeda, T.; Kanamori, F.; Matsusita, H.; Fujiwara, T. Tetrahedron Lett. 1991, 32,
6563–6566; (d) Block, E.; Guo, C.; Thiruvazhi, M.; Toscano, P. J. J. Am. Chem. Soc.
1994, 116, 9403–9404; (e) Su, M.; Yu, W.; Jin, Z. Tetrahedron Lett. 2001, 42, 3771–
3774; (f) Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J.-i. Org. Lett. 2005, 7, 1219–
1222.
4.5. Copper-catalyzed synthesis of
thiol (Table 4)
b-haloalkenyl sulfide using
To
a mixture of CuI (3.8 mg, 0.02 mmol), bpy (3.1 mg,
0.02 mmol), PhSH 4a (26.4 mg, 0.24 mmol), and n-Bu4NBr
(70.9 mg, 0.22 mmol) in AcOH (0.3 mL) was added 4-octyne 1a
(22.0 mg, 0.2 mmol), and the mixture was stirred at 100 ꢁC for 18 h
under oxygen atomosphere using a balloon. After the residue was
dissolved in Et2O, the solution was washed with H2O and saturated
sodium chloride and dried over anhydrous magnesium sulfate.
Chromatography on silica gel (Hexane) gave (E)-4-bromo-5-phe-
nylthio-4-octene 3a (35.9 mg, 60%).
4.6. Synthesis of (Z)-tamoxifen
5. (a) Kuniyasu, H.; Ogawa, A.; Miyazaki, S.-I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1991, 113, 9796–9803; (b) Arisawa, M.; Yamaguchi, M. Org. Lett. 2001,
3, 763–764; (c) Ananikov, V. P.; Kabeshov, M. A.; Beletskaya, I. P.; Khrustalev,
V. N.; Antipin, M. Y. Organometallics 2005, 24, 1275–1283; (d) Ananikov, V. P.;
Gayduk, K. A.; Beletskaya, I. P.; Khrustalev, V. N.; Antipin, M. Y. Chem.dEur. J.
2008, 14, 2420–2434.
To
a mixture of (E)-1-bromo-1,2-diphenyl-2-(4-tolyl)thio-
ethene 3m (178.3 mg, 0.47 mmol), Me2N(CH2)2OC6H4B(pin)
(151.4 mg, 0.52 mmol), Pd(PPh3)4 (46.2 mg, 0.04 mmol), and K2CO3
(194.9 mg, 1.41 mmol) in dioxane (4 mL), and H2O (0.4 mL) was
poured under nitrogen atmosphere, and the mixture was stirred at
100 ꢁC for 24 h. After the residue was dissolved in Et2O, the
solution was washed with H2O and saturated sodium chloride
and dried over anhydrous magnesium sulfate. Chromatography
on silica gel (5% methanol in ethyl acetate) gave (E)-1-(4-
dimethylaminoethoxyphenyl)-1,2-diphenyl-2-(4-tolyl)thioethene
6. (a) Kuniyasu, H.; Ogawa, A.; Sato, K.-I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1992, 114, 5902–5903; (b) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T.
J. Am. Chem. Soc. 1999, 121, 5108–5114; (c) Backvall, J.-E.; Ericsson, A. J. Org.
Chem. 1994, 59, 5850–5851; (d) Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc.
2005, 127, 17614–17615.
¨
7. Usugi, S.-i.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 601–603.
8. (a) Kondoh, A.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1383–1385; (b)
Wang, Z.-L.; Tang, R.-Y.; Luo, P.-S.; Deng, C.-L.; Zhong, P.; Li, J.-H. Tetrahedron
2008, 64, 10670–10675.
13 (156.4 mg, 72%). 1H NMR (270 MHz, CDCl3)
d 7.30–7.29 (m, 7H),
9.
b-Haloalkenyl sulfide synthesis using sulfenyl chloride: (a) Okuyama, T.; Izawa,
7.07–7.00 (m, 5H), 6.89–6.83 (m, 4H), 6.59 (d, J¼8.1 Hz, 2H), 3.94 (t,
K.; Fueno, T. J. Org. Chem. 1974, 39, 351–354; (b) Busi, E.; Capozzi, G.; Menichetti,
S.; Nativi, C. Synthesis 1992, 643–645.
J¼5.4 Hz, 2H), 2.65 (t, J¼5.4 Hz, 2H), 2.28 (s, 6H), 2.17 (s, 3H); 13C
10.
b
-Haloalkenyl sulfoxide synthesis using sulfonyl halide: (a) Amiel, Y. J. Org.
NMR (67.5 MHz, CDCl3)
d 157.4, 145.7, 144.1, 139.5, 135.4, 134.9,
Chem. 1974, 39, 3867–3870; (b) Amiel, Y. J. Org. Chem. 1971, 36, 3691–3696.
132.9, 132.2, 132.0, 131.0, 129.6, 129.5, 129.2, 128.0, 127.6, 127.1,
126.7, 113.6, 65.7, 58.2, 45.8, 20.9; IR (CHCl3) 2977, 2779, 1605,
1507 cmꢀ1. Anal. Calcd for C31H31NOS: C, 79.96; H, 6.71, N, 3.01.
Found: C, 79.91; H, 6.85, N, 2.92.
11. (a) Angeletti, E.; Montanari, F.; Negrni, A. Gazz. Chim. Ital. 1957, 87, 1086–1101;
Chem. Abstr. 1958, 52, 9989f–9992a; (b) Angeletti, E.; Montanari, F.; Negrni, A.
Gazz. Chim. Ital. 1957, 87, 1115–1124; Chem. Abstr. 1958, 52, 9985g–9986d.
12. Taniguchi, N. J. Org. Chem. 2006, 71, 7874–7876.
13. Taniguchi, N. Synlett 2008, 849–852.
14. Organometallics in Organic Synthesis; Negishi, E., Ed.; Wiley: New York, NY,
1980.
15. The stereochemistry of compounds of entries 1, 2, 12, 14 and 15 in Table 2 was
determined by NOE after the debromination.
16. These E,Z isomers of entries 14, 18 and 26 can separate by silica gel
chromatography.
17. For the preparation of PhSCu: Adams, R.; Reifschneider, W.; Ferretti, A. Organic
Syntheses; John Wiley & Sons: New York, NY, 1973; Collect. Vol. V, pp 107–110.
18. Kadooka, M. M.; Warner, L. G.; Seff, K. J. Am. Chem. Soc. 1976, 98, 7569–7578.
19. Takeuchi, H.; Hiyama, T.; Kamai, N.; Oya, H. J. Chem. Soc., Perkin Trans. 2 1997,
2301–2305.
To
a mixture of (E)-1-(4-dimethylaminoethoxyphenyl)-1,2-
diphenyl-2-(4-tolyl)thioethene 13 (100 mg, 0.21 mmol), NiCl2(dppe)
(9.0 mg, 0.017 mmol) in diethyl ether (2.0 mL) was added EtMgBr
(2.0 mL, 0.5 M in diethyl ether) under nitrogen atmosphere, and the
mixture was refluxed with stirring for 15 h. After H2O was added to
the mixture, the residue was dissolved in Et2O, the solution was
washed with H2O and saturated sodium chloride and dried over
anhydrous magnesium sulfate. Chromatography on silica gel (5%
methanol in ethyl acetate) gave tamoxifen 14 (60.1 mg, 75%
20. In the present reaction, iodonium or bromium ion is necessary. Because the
Z/E¼93/7). 1H NMR (270 MHz, CDCl3)
d 7.34–7.10 (m, 10H), 6.77
reaction using CuOAc or Cu(OAc)2 could not afford the corresponding
alkenyl sulfide.
b-halo-
(d, J¼10.8 Hz, 2H), 6.55 (d, J¼10.8 Hz, 2H), 3.92 (t, J¼5.4 Hz, 2H), 2.64

2790
N. Taniguchi / Tetrahedron 65 (2009) 2782–2790
21. (a) Ishiyama, T.; Miyaura, N.; Suzuki, A. Chem. Lett. 1987, 25–28; (b) Hoshi, Y.;
Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1988, 29, 3983–3986; (c)
Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L. J. Chem. Soc., Chem. Commun.
1982, 647–649; (d) Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L. J. Chem.
Soc., Perkin Trans. 1 1985, 1115–1119.
22. (a) Bedford, G. R.; Richardson, D. N. Nature 1966, 211, 733–734; (b) Jaiyesimi, I.
A.; Buzdar, A. U.; Decker, D. A.; Hortobagyi, G. N. J. Clin. Oncol. 1995, 13, 513–
529; (c) Osborne, C. K. N. Engl. J. Med. 1998, 339, 1609–1618.
23. (a) Miller, R. B.; Al-Hassan, M. I. J. Org. Chem. 1985, 50, 2121–2123; (b) Itami, K.;
Kamei, T.; Yoshida, J.-i. J. Am. Chem. Soc. 2003, 125, 14670–14671.