Nickel-Catalyzed Regioselective Cleavage of Csp2-S Bonds: Method for the Synthesis of Tri- and Tetrasubstituted Alkenes

Article abstract of DOI:10.1021/acs.joc.6b00203

We describe here an efficient route for the synthesis of (Z)-vinylic sulfides 3 via the highly regio- and stereoselective coupling of (Z)-1,2-bis(aryl(alkyl)thio)alkenes and Grignard reagents over a Ni catalyst under mild conditions. (Z)-Vinylic sulfides 3 are important intermediates in the synthesis of tri- and tetrasubstituted alkenes that are important construction blocks for drugs and natural products. The directing organosulfur groups (SR) can be converted to diaryl(alkyl) disulfides (RSSR) using H₂O₂ as oxidant, hence avoiding the waste of sulfur resources. The protocol provides a general method that is highly regio- and stereoselective for the synthesis of a diversity of tri- and tetrasubstituted alkenes.

Full text of DOI:10.1021/acs.joc.6b00203

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Article
Nickel-Catalyzed Regio-selective Cleavage of Csp2-S Bonds:
Method for the Synthesis of Tri- and Tetra-Substituted Alkenes
Jinyang Chen, Sihai Chen, Xinhua Xu, Zhi Tang, Chak-Tong Au, and Renhua Qiu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Mar 2016
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The Journal of Organic Chemistry
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NickelꢀCatalyzed Regioꢀselective Cleavage of Csp2ꢀS
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Bonds: Method for the Synthesis of Triꢀ and Tetraꢀ
Substituted Alkenes
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Jinyang Chen, Sihai Chen, Xinhua Xu*, Zhi Tang, ChakꢀTong Au, Renhua Qiu*
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha, 410082, P.R. of China
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xhx1581@hnu.edu.cn, renhuaqiu@hnu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT
We describe here an efficient route for the synthesis of (Z)-vinylic sulfides 3 via the highly regio-
and stereo-selective coupling of (Z)-1,2-diaryl(alkyl)thio alkenes and Grignard Reagents over a
Ni-catalyst under mild conditions. (Z)-Vinylic sulfides 3 are important intermediates in the
synthesis of tri- and tetra-substituted alkenes that are important construction blocks for drugs
and natural products. The directing organosulfur groups (SR) can be converted to diaryl(alkyl)
disulfides (RSSR) using H2O2 as oxidant, hence avoiding the waste of sulfur resource. The
protocol provides a general method that is highly regio- and stereo-selective for the synthesis of a
diversity of tri- and tetra-substituted alkenes.
1
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INTRODUCTION
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Since olefins can be readily obtained from ketone transformation1, they are widely used as building
blocks for the synthesis of pharmaceuticals2 and natural products3 such as (Z)ꢀtamoxifen4a and Nileprost
analogues4b. There are four identical positions in an alkene molecule of which each can be replaced by a
different substituent, meaning that the structural diversity of alkene derivatives can be intrinsically
extraordinary5. However, due to the lack of general methods for programmed synthesis of triꢀ and tetraꢀ
substituted alkenes6, the potential of huge structural diversity has not been fully exploited. For the
preparation of triꢀ and tetraꢀsubstituted alkenes, the carbonmetallation of alkynes (Scheme 1a) is
generally accepted as the most widely used method7, disregard of the problems of poor stereoꢀ
selectivity7a,7b and the lack of structural flexibility7d. Compared to the carbonmetallation approach, the
sequential assembly strategy using configurationꢀfixed heteroatoms (E)8a or halogen substituted8b
alkenes as platforms has the advantages of high regioꢀselectivity and structural flexibility. However,
there are only two pioneering works8 and the studies were on substituents of aryl using hardꢀwon
reagents as starting materials (Scheme 1b). Thus, it is highly desirable to develop a general method for
the synthesis of triꢀ and tetraꢀsubstituted alkenes.
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Scheme 1. General methods for synthesis of tri- and tetra-substituted alkenes.
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Last decade, in the area of transition metalꢀcatalyzed crossꢀcoupling reactions, the C–E (S, Se, or
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2
Te) bond cleaving reactions have attracted considerable attention as they provide a good way to form
new C–C bond with configuration retention9. In the case of C–E bond cleaving reactions, both
stoichiometric10 and catalytic reactions catalyzed by Pd11, Ni12, or other metal13 catalysts have been
established by using organochalcogen compounds as substrates which are easy to construct14. The most
widely used organochalcogen compounds for synthesis of multꢀsubstituted alkenes are vinylic
chalcogenides9aꢀe. However, until now, most of the synthetic applications focus on vinylic
monochalcogenides9 and there are few on vinylic dichalcogenides15. It is because when vinylic
dichalcogenides were treated with nucleophilic reagents, it was hard to control the cleavage of two C–E
bonds regioꢀselectively. In our previous work, we reported simple routes for the synthesis of (Z)ꢀvinylic
disulfides16a and (Z)ꢀvinylic selenosulfides (tellurosulfides)16b via highly regioꢀ and stereoꢀselective
reactions of terminal alkynes and diaryl(alkyl) disulfides (diselenides and ditellurides) catalyzed by
cesium hydroxide under mild conditions. Due to difference in the activity of Csp2–S and Csp2–Se (Te)
bonds, (Z)ꢀvinylic selenossulfides (tellurossulfides) can be used as effective platform molecules for the
stereoselective synthesis of triꢀ and tetraꢀsubstituted alkenes17. However, purification is a problem
because the stereoisomers of (Z)ꢀvinylic selenossulfides (tellurossulfides) are similar in polarity18.
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During our attempt to develop a better way to synthesize triꢀsubstituted alkenes by using (Z)ꢀ1,2ꢀ
aryl(alkyl)thio alkenes as platforms, we observed that the coupling of (Z)ꢀ1,2ꢀaryl(alkyl)thio alkenes
with Grignard Reagents occurs only on C1sp2–S bond of (Z)ꢀ1,2ꢀaryl(alkyl)thio alkenes, and forms (Z)ꢀ1ꢀ
aryl(alkyl)ꢀ2ꢀaryl(alkyl)thio alkenes 3 exclusively in the presence of Niꢀcatalysts (Scheme 1c, key step).
According to previous works, (Z)ꢀvinylic sulfides 3 are important intermediates in the stereoselective
synthesis of triꢀ and tetraꢀsubstituted alkenes via the arylation (alkylation) of C–S19 and C–H20 bonds. To
our knowledge, highly regioꢀselective coupling of (Z)ꢀ1,2ꢀdiaryl(alkyl)thio alkenes with Grignard
Reagents has never been reported before. Herein, we report for the first time the synthesis of (Z)ꢀvinylic
sulfides 3 via the highly regioꢀselective coupling of (Z)ꢀ1,2ꢀdiaryl(alkyl)thio alkenes with Grignard
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Reagents catalyzed by Niꢀcatalysts, and their application in the preparation of triꢀ and tetraꢀsubstituted
alkenes.
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RESULTS AND DISCUSSION
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We initiated our studies with the coupling of (Z)ꢀ1,2ꢀdiphenylthio styrene 1a and
methylmagnesium chloride 2a in the presence of NiCl2 (1.0 equiv.) and PPh3 (1.0 equiv.) under
nitrogen atmosphere at rt for 10 h. The desired product 3a was obtained in 46% yield, and there is no
detection of 4a and the regio isomer of 3a by 1H NMR analysis of the crude products (Table 1, entry 1).
Table 1. Optimization of reaction conditions a
Ph
H
Ph
H
Ph
H
[Ni] , L
N2, rt, Solvent
MeMgCl
+
+
Me
4a: n.d.
PhS
Me
PhS
SPh
Me
1a
2a
3a
[Ni] (equiv.)
L (equiv.)
Conditions
Entry
Yield (3a) b (%)
NiCl2 (1.0)
None
PPh3 (1.0)
PPh3 (1.0)
None
THF, rt, 10 h
THF, rt, 10 h
THF, rt, 10 h
THF, rt, 10 h
THF, rt, 10 h
1
2
3
4
5
6
7
8
9
46
0
NiCl2 (1.0)
NiCl2 (1.0)
NiCl2 (1.0)
0
PCy3(1.0)
26
34
42
21
Xantphos (0.5)
PPh3 (1.0)
PPh3 (1.0)
NiBr2 (1.0)
Ni(acac)2 (1.0)
NiF2 (1.0)
THF, rt, 10 h
THF, rt, 10 h
PPh3 (1.0)
THF, rt, 10 h
THF, rt, 10 h
THF, rt, 10 h
88
trace
ddpe (1.0)
PPh3 (1.0)
NiF2 (1.0)
Ni(OAc)2 (1.0)
67
10
THF, rt, 10 h
THF, rt, 10 h
NiF2 (0.5)
NiF2 (0.25)
PPh3 (0.5)
PPh3 (0.25)
75
58
11
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16
PPh3 (0.1)
PPh3 (0.1)
THF, rt, 10 h
THF, rt, 25 h
42
94
NiF2 (0.1)
NiF2 (0.1)
PPh3 (0.1)
THF, rt, 30 h
94
94(91)c
NiF2 (0.1)
NiF2 (0.05)
PPh3 (0.05)
THF, rt, 25 h
NiF2 (0.05)
NiF2 (0.025)
NiF2 (0.025)
NiF2 (0.05)
NiF2 (0.05)
NiF2 (0.05)
NiF2 (0.05)
17
18
19
20
21
THF, rt, 30 h
THF, rt, 35 h
THF,50 oC, 15 h
Toluene, rt, 25 h
DCM, rt, 25 h
THF, rt, 25 h
94
88
80
72
60
PPh3 (0.05)
PPh3 (0.025)
PPh3 (0.025)
PPh3 (0.05)
PPh3 (0.05)
PPh3 (0.05)
PPh3 (0.05)
22d
94
94
23e
THF, rt, 25 h
a Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), solvent (1.0 mL),
N2, rt. b GC yields. c Isolated yields. d 0.50 mmol of 2a was used.
e 0.25 mmol of 2a was used.
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After systematic study on the influence of catalysts and ligands on the reaction, we found that NiF2
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2
is the best catalyst and PPh3 is the best ligand. Together they afford the desired product in 88% yield
(Table 1, entriy 8). Then we examined the minimum amount of NiF2 and PPh3 required to promote the
reaction (Table 1, entries 11ꢀ18), and the rusults show that the use of 0.05 equiv. of NiF2 and 0.05 equiv.
of PPh3 is good enough to effectively promote the reaction, giving the corresponding product in 94%
yield in 25 h (Table 1, entry 16). We also explored solvents such as toluene, DCM and THF (Table 1,
entries 16, 20 and 21), and found that THF is the most suitable. It is noted that when the temperature
was raised to 50 °C, there was reduction of product yield to 80%, and generation of byꢀproduct. Finally,
we examined the influence of the amount of methylmagnesium chloride 2a on the crossꢀcoupling
reaction, and found that 1.25 equiv. of methylmagnesium chloride 2a is enough to promote the reaction
efficiently (Table 1, entries 22 and 23). And after H2O2 oxidation, diphenyl disulfide is obtained as the
major byꢀproduct with a yield of 72%. When excess amount of methylmagnesium chloride 2a was used,
several other byꢀproducts such as biphenyl, toluene and diphenyl disulfide were detected. Thus the
optimized reaction conditions are: 0.05 equiv. of NiF2 and 0.05 equiv. of PPh3, 1.0 equiv. of 1a and 1.25
equiv. of 2a in THF at rt under nitrogen for 25 h.
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Table 2. Reaction Scope of 1,2-diarylthio Aromatic Acetylene a
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a Reaction conditions: 1 (0.2 mmol), 2 (0.25 mmol), NiF2 (0.01 mmol),
PPh3 (0.01 mmol), THF (1.0 mL), N2 , rt, 25 h.
The scope of the coupling reaction was investigated under the optimized conditions. A variety of
(Z)ꢀvinylic disulfides could efficiently undergo crossꢀcoupling to afford the desired products in good to
excellent yields (Table 2). Electronꢀdonating and electronꢀwithdrawing functional groups at the mꢀ and
pꢀpositions of the phenyl ring of aromatic ethylene affect the crossꢀcoupling only slightly, affording the
corresponding products in good to excellent yields (3aꢀ3g, 83%ꢀ93%). The crossꢀcoupling of 1,2ꢀ
diphenylthioꢀ4ꢀ(tꢀbutyl)styrene with methylmagnesium chloride proceeds well with good yield (3d,
93%), suggesting that the steric effect of substituted group present in the aromatic rings of aromatic
ethylene on the reaction is insignificant. The crossꢀcoupling is also suitable for (Z)ꢀ1,2ꢀdiphenylthio
thiophene alkene and (Z)ꢀ1,2ꢀdiphenylthio pentene, affording the corresponding products (3h, 3i) in
83% and 94% yield, respectively. And the electronꢀdonating and electronꢀwithdrawing substituted
functional groups at the phenyl ring bonded to the sulfur atom only slightly affects the crossꢀcoupling
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reaction (3jꢀ3q, 82%ꢀ95%). Good yields also obtained when (Z)ꢀvinylic disulfides were treated with
ethylmagnesium chloride under the optimal conditions (3r and 3s, 93% and 88%, respectively). The
structure of product 3i was determined by examining its NOESY H–H and COSY H–H interactions (SI),
and the results show that the crossꢀcoupling of (Z)ꢀ1,2ꢀdiaryl(alkyl)thio alkenes with Grignard Reagents
occurs stereoselectively to give exclusively Zꢀisomers.
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Table 3. Reaction Scope of Grignard Reagents a
a Reaction conditions: 1 (0.2 mmol), 2 (0.25 mmol), NiF2 (0.05 mmol),
PPh3 (0. 05 mmol), THF (1.0 mL), N2 , rt, 25 h.
Unfortunately, poor yields were obtained when (Z)ꢀvinylic disulfides were treated with other
Grignard Reagents (except for methylmagnesium chloride and ethylmagnesium chloride) under the
above conditions. By increasing the amount of catalyst and ligand to 0.25 equiv., the reactions of (Z)ꢀ
vinylic disulfides with both larger alkylꢀsubstituted and arylꢀsubstituted Grignard Reagents give the
corresponding products in moderate to good yields (Table 3). A closer inspection of the results reveal
that alkylꢀsubstituted (e.g. cyclopentyl and cyclohexyl) Grignard Reagents of large size performed
poorer than those (e.g. Me, Et, allyl) of small size (3tꢀ3w, 72%ꢀ86%). It is noted that the yields of the
crossꢀcoupling with arylꢀsubstituted Grignard Reagents are moderate, mainly due to the steric hindrance
and homocoupling of aryl magnesium bromide (3xꢀ3ab, 61%ꢀ75%). Smaller functional group (propyl)
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bonded to the sulfur atom can accelerate the crossꢀcoupling, giving the corresponding product in 95%
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3
yield (3ac).
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S
cheme 2. Larger-scale synthesis of 3a.
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The method can be carried out on a larger scale, and the yield percentage of the desired products
decrease only slightly comparing with that of the small scale (0.2 mmol). The coupling of (Z)ꢀ1,2ꢀ
diphenylthio styrene 1a (640 mg, 2.0 mmol) and methylmagnesium chloride 2a (1.0 mL, 2.5 mmol)
using NiF2 (9.7 mg, 0.1 mmol) and PPh3 (26.2 mg, 0.1 mmol) affords (Z)ꢀ1ꢀphenylthioꢀ2ꢀmethyl styrene
3a (398 mg) in 88% yield (90% in 20 mmol scale) (Scheme 2).
S
cheme 3. Synthesis of (Z)-tamoxifen using product 3y as starting material.
Recently, a number of methods for stereoselective synthesis of triꢀ and tetraꢀsubstituted alkenes
were reported21, but it is hard to control the chemoꢀ and regioꢀselectivity of products. According to
previous studies19,20, (Z)ꢀVinylic sulfides 3 are important intermediates in the preparation of triꢀ and
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tetraꢀsubstituted alkenes. Here, we use the synthesis of (Z)ꢀtamoxifen as an example to illustrate the
application of (Z)ꢀvinylic sulfides 3 for the production of triꢀ and tetraꢀsubstituted alkenes. First
compound 3y is obtained readily following the method described so far. Then through bromination20a
and Pdꢀcatalyzed coupling20b of compound 3y, there is the formation of alkene 5, which is converted to
(Z)ꢀtamoxifen in high chemoꢀ and regioꢀselectivity using NiCl2(dppe) as catalyst12d (Scheme 3).
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Scheme 4. Control experiments for mechanism study.
To shed light on the mechanism of the crossꢀcoupling reaction, some control experiments and
NMR experiments were conducted. Comparing the four equations in Scheme 4, one can see that
fluorine plays an important role. As shown in Eqs. 3 and 4, the outcome of the process catalyzed by
NiF2 appears to be different from that catalyzed by NiCl2. Traditionally, the coupling includes steps of
Ni(0) formation, oxidative addition and reductive elimination. To further understand the mechanism, the
coupling of (Z)ꢀ1,2ꢀdiphenylthio styrene and methylmagnesium chloride in THFꢀd8 using NiF2/PPh3 as
catalyst was examined hourly by NMR spectroscopy. From the 31P NMR spectra of Ni(PPh3)4 and those
of the coupling mixture, it is confirmed that there is the absence of Ni0 at the start of the coupling
reaction (see Figure 1 in SI). From the 19F NMR spectra of the reaction mixture, the signal of 19F can be
observed within the first hour but cannot be seen afterward. The phenomenon implies that the fluorine
exists not only as inorganic salt but also as organic intermediate during the coupling reaction, and
finally converted to MgFCl (see Figure 2 in SI). The intensity of the Me signal (1H NMR, δ = 2.07) of
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the desired product increases in the first 8.0 h before reaching constant (see Figure 3 in SI). Analyzing
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2
3
13
the C NMR spectra (see figure 4 in SI), one can see that the peak of the carbon that is bonded to the
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5
6
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8
hydrogen of (Z)ꢀ1,2ꢀdiphenylthio styrene at δ 125.8 shifts highfield to δ 125.3, plausibly due to the
replacement of PhS (an electron drawing group) by Me. The signals at δ ꢀ5.37 and δ ꢀ49.9 (31P NMR)
ascribable to PPh3 and NiII(PPh3)2X2 respectively exist during the whole process. Upon the complete
consumption of (Z)ꢀ1,2ꢀdiphenylthio styrene at the 8th hour, a 31P NMR signal at δ 31.6 consistent with
the Ni0 signal of authentic Ni0(PPh3)4 is observed. Also, with the formation of diphenyl disulfide after
oxidation, it is deduced that PhSMgCl is formed during the coupling process.
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Figure 2. Proposed mechanism of the cross-coupling.
NiF2
MeMgCl
2a
PPh3 = L
Ph
H
MgFCl
L
Ph
H
PhS
SPh
PhS
SPh
NiII
1a
Ph
H
Me NiII
F
PhSMgCl
L
PhS
SPh
PhS
1a
Me
A
F
slow
Ph
H
MeMgCl
MgFCl
F NiII
L
L
2a
Me
PhS
SPh
NiII
PhS NiII
F
PhS NiII Me
2
1
C C
Ph
H
SPh
fast
L
L
PhS
G
F
D
E
Me
B
Ph
H
PhSMgCl
F NiII
Me
L
H
PhS
3a
Ph
Me
2
1
C C
Ph
PhS NiII SPh
H
PhS
3a
MeMgCl
2a
Me
PhS
SPh
L
C
H
Ni(PPh3)4
PhSSPh +
Based on the results described above and those of previous reports22, a mechanism is proposed as
depicted in Figure 2. First Niꢀcomplex A is formed when MeMgCl 2a is treated with NiF2 in the
presence of PPh3. The coordination of compound 1a to the nickel center of A followed by ligand
exchange gives intermediate B. It is worth pointing out that C2 is stabilized by the hyperconjugation of
aryl or electronꢀdonating effect of alkyl. The insertion of nucleophile (Meꢀ) and electrophile (FNi+) into
C1 and C2, respectively, give intermediate C. The steric hindrance of the nucleophiles and electrophiles
obviously affects the addition, in agreement with the results shown in Tables 2 and 3. The elimination of
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PhSNiF from intermediate C furnishes species D and the final coupling product 3a exclusively in the
form of Zꢀisomer. Then species D reacts with MeMgCl to give PhSMgCl and species A (cycle 1, slow)
or MgFCl and species E (cycle 2, fast), and then species E coordinates with 1a to afford intermediate F.
With the insertion of PhSNiF into F, there is the generation of intermediate G that gives product 3a and
species H via elimination. The species H reacts with another portion of MeMgCl to give PhSMgCl and
species E, effectively promoting the coupling reaction as a result.
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CONCLUSIONS
We developed a convenient method for the synthesis of (Z)ꢀvinylic sulfides 3 with high regioꢀ
selectivity via the direct Niꢀcatalyzed crossꢀcoupling of (Z)ꢀ1,2ꢀdiaryl(alkyl)thio alkenes with Grignard
reagents. The method utilizes easily available starting materials, offers operational simplicity, and
enjoys a broad substrate scope as well as functionality tolerance. We also demonstrated that (Z)ꢀ
tamoxifen can be successfully synthesized in high regioꢀ and stereoꢀselectivity using (Z)ꢀvinylic sulfides
3 as starting material. As directing groups, the organosulfur groups can be converted to diaryl(alkyl)
disulfides via the oxidation of the reaction solution in air or with H2O2, hence avoiding the waste of the
sulfur resource.
EXPERIMENTAL SECTION
General information
Unless noted, all reactions were conducted in Schlenk tubes under an atmosphere of nitrogen. Dry
DCM (CH2Cl2), toluene and THF (tetrahydrofuran) and THFꢀd8 were purified according to the standard
methods. Reactions were monitored by thin layer chromatography (TLC) using gel 60 F254 preꢀcoated
plates. Visualization was accomplished with UV lamp or I2 stain. Silica gel 300ꢀ400 mesh size was used
for column chromatography using the combination of ethyl acetate and petroleum ether as eluent.
Preparative thinꢀlayer chromatography (TLC) was performed as described by Anderson23. 1H NMR and
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13C{1H} NMR spectra were recorded on 400 MHz and 100 MHz NMR plus spectrometer using residue
solvent peaks as internal standards, respectively. Mass spectra (MS) were obtained using EI mass
spectrometer. High resolution mass spectra (HRMS) were measured on an electron ionization (EI) mass
spectrometry.
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General procedure for the synthesis of (Z)-1,2-diarl(alkyl)thio alkenes 116a
Terminal alkynes (2.0 mmol), diaryl disulfides (1.0 mmol) were added, under nitrogen, to a solution
of cesium hydroxide monohydrate (0.5 mmol, 25 mol%) in DMF (2 mL). The resulting solution was
stirred at room temperature for 20 hours under nitrogen atmosphere. Then, the reaction mixture was
diluted with water (30 mL), and extracted with ethyl acetate (30 mL ×3). The combined organic phase
was dried over anhydrous Na2SO4, and concentrated in vacuo. The desired products 1 were obtained by
flash chromatography using ethyl acetate/hexane as an eluent.
(Z)-1,2-diphenylthiostyrene (1a) 16a: Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz,
2H), 7.47 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.28ꢀ7.20 (m, 6H), 7.15 (t, J = 8.0 Hz, 1H), 7.05
(t, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.8, 136.6, 135.3, 134.8, 130.7, 129.4, 129.4,
129.0, 128.5, 128.3, 127.7, 127.7, 126.8, 126.0; MS (EI) m/z: 320 (M+, 55), 268 (18), 212 (100), 178
(61), 167 (43), 159 (28), 134 (28), 121 (33), 109 (20), 91 (16), 77 (29), 66 (144).
(Z)-1,2-diphenylthio(4-methylstyrene) (1b): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.50ꢀ7.44
13
(m, 4H), 7.37ꢀ7.23 (m, 6H), 7.20ꢀ7.15 (m, 2H), 7.09ꢀ7.03 (m, 3H), 2.27 (s, 3H); C{1H} NMR (100
MHz, CDCl3) δ 137.6, 136.0, 135.5, 134.9, 130.5, 129.3, 129.2, 128.9, 128.2, 127.5, 126.7, 125.8, 21.1;
MS (EI) m/z: 334 (M+, 100), 225 (72), 210 (64), 192 (13), 167 (16), 147 (11), 115 (15), 109 (8), 91 (5),
65 (5).
(Z)-1,2-diphenylthio(3-methylstyrene) (1c): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.45 (t, J =
8.4 Hz, 4H), 7.31 (t, J = 8.0 Hz, 2H), 7.26ꢀ7.22 (m, 3H), 7.19 (s, 1H), 7.14 (t, J = 8.0 Hz, 2H), 7.06ꢀ7.00
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(m, 3H), 2.24 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 137.6, 136.1, 135.53, 135.48, 135.0, 130.6,
129.5, 129.4, 129.3, 129.0, 128.3, 127.6, 126.7, 125.9, 21.2; MS (EI) m/z: 334 (M+, 100), 225 (73), 210
(62), 192 (11), 167 (17), 147 (18), 115 (12), 109 (11), 91 (6), 65 (7).
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(Z)-1,2-diphenylthio(4-(t-butyl)styrene) (1d): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.41 (t, J =
8.0 Hz, 4H), 7.285ꢀ7.27 (m, 2H), 7.21ꢀ7.17 (m, 6H), 7.12 (t, J = 7.6 Hz, 2H), 7.01 (t, J = 7.2 Hz, 1H),
1.19 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 136.4, 136.1, 135.4, 135.1, 130.5, 129.3, 128.9, 127.9,
127.5, 126.3, 125.7, 125.4, 31.3; MS (EI) m/z: 338 (M+, 100), 229 (86), 208 (13), 196 (31), 183 (21),
165 (65), 139 (7), 109 (27), 77 (11), 65 (12).
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(Z)-1,2-diphenylthio(4-(n-propyl)styrene) (1e): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.46ꢀ
7.44 (m, 4H), 7.29 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 6.4 Hz, 4H), 7.13 (d, J = 7.6 Hz, 2H), 7.05ꢀ7.01 (m,
13
3H), 2.48 (t, J = 7.6 Hz, 2H), 1.58ꢀ1.53 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 142.4, 136.4, 135.8, 135.5, 135.1, 130.6, 129.5, 129.4, 129.0, 128. 7, 128.2, 127.6, 126.7,
125.9, 37.7, 24.5, 14.0; MS (EI) m/z: 362 (M+, 100), 334 (16), 239 (61), 224 (45), 210 (11), 195 (16),
148 (5), 123 (4), 91 (3).
(Z)-1,2-diphenylthio(4-methoxystyrene) (1f): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J
= 8.4 Hz, 4H), 7.36ꢀ7.32 (m, 2H), 7.29ꢀ7.23 (m, 3H), 7.17 (t, J = 8.0 Hz, 2H), 7.11ꢀ7.07 (m, 2H), 6.76
(d, J = 8.4 Hz, 2H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.3, 135.5, 134. 9, 134.0, 131.5,
130.4, 129.5, 129.3, 128.9, 128.3, 128.1, 127.4, 125.9, 113.8, 55.3; MS (EI) m/z: 350 (M+, 100), 241
(78), 226 (75), 210 (21), 197 (15), 165 (17), 151 (6), 132 (7), 110 (10), 89 (7), 77 (4), 66 (3).
(Z)-1,2-diphenylthio(4-fluorostyrene) (1g): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.52ꢀ7.49
(m, 4H), 7.36 (t, J = 7.6 Hz, 2H), 7.31ꢀ7.29 (m, 1H), 7.24ꢀ7.14 (m, 5H), 7.09 (t, J = 6.8 Hz, 1H), 6.92 (t,
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J = 7.2 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ 136.0, 135.1, 134.4, 130.7, 128.9, 128.5, 128.4,
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127.7, 126.1, 115.4, 115.2; MS (EI) m/z: 376 (M+, 100), 319 (5), 267 (24), 251 (14), 211 (17), 178 (7),
167 (20), 143 (7), 128 (4), 115 (13), 110 (10), 77 (4), 57 (25).
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(Z)-1,2-di(4-phenylthio)(3-thienylenevinylene) (1h): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.38 (d, J = 7.6 Hz, 2H), 7.25ꢀ7.10 (m, 11H), 7.02 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 140.7, 136.1, 135.2, 135.0, 130.7, 129.4, 129.0, 127.9, 127.6, 126.1, 126.0, 125.4, 124.2, 122.2.
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(Z)-1,2-di(phenylthio) pent-1-ene (1i)24: A mixture of Ph2S2 (1.0 mmol, 218 mg) and PPh3 (0.15 mmol,
47.2 mg) in a tube was heated by a hair dryer until the formation of a homogeneous melt. Then,
Pd(PPh3)4 (0.01 mmol, 12 mg) was added to the melt and the mixture was shaken until complete
dissolution of the salt and formation of a homogeneous dark brown melt. Pentene (1.5 mmol, 102 mg)
was added to the melt and the reaction mixture was stirred at 100 oC overnight. After completion of the
reaction, the no consumed pentene was distilled off on a rotary evaporator. The residue was purified by
flash chromatography with a hexaneꢀchloroform mixture as an eluent to afford (Z)ꢀ1,2ꢀdi(phenylthio)
pentꢀ1ꢀene (1i) (271 mg, 95%).Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.21 (m, 8H), 6.57
(s, 1H), 2.22 (t, J = 7.2 Hz, 2H), 1.56ꢀ1.49 (m, 2H), 0.84 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 135.9, 134.0, 133.9, 130.5, 129.8, 129.5, 129.1, 129.0, 126.9, 126.8, 39.2, 21.8, 13.4.
(Z)-1,2-di(4-methylphenylthio)styrene (1j) 16a: Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J
= 7.6 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.17ꢀ7.14 (m, 6H), 6.98 (d, J = 8.0 Hz,
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2H), 2.35 (s, 3H), 2.23 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 138.9, 137.8, 136.9, 135.8, 131.8,
131.1, 131.0, 130.1, 129.7, 129.2, 128.6, 128.4, 127. 5, 126.8, 21.1, 21.0.
(Z)-1,2-di(4-chlorophenylthio)styrene (1k): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J =
7.2 Hz, 2H), 7.43ꢀ7.40 (m, 2H), 7.34ꢀ7.32 (m, 2H), 7.26ꢀ7.21 (m, 3H), 7.15ꢀ7.13 (m, 4H); 13C{1H}
NMR (100 MHz, CDCl3) δ 138.2, 135.8, 133.9, 133.5, 133.1, 132.0, 131.9, 129.9, 129.5, 129.3, 1129.1,
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128.6, 128.0, 126.8.
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(Z)-1,2-di(4-methoxyphenylthio)styrene (1l): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.50ꢀ7.44
(m, 4H), 7.23ꢀ7.12 (m, 3H), 6.99 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H),
3.69 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 158.5, 138.9, 136.6, 133.3, 131.2, 129.8, 128.3,
127.4, 127.0, 125.8, 125.2, 55.4, 55.3.
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(Z)-1,2-di(n-propylthio) (4-methoxy styrene) (1m)25: Ni(acac)2 (0.18 mmol, 46 mg), (nꢀPr)2S2 (6.0
mmol, 900 mg) and PBu3 (1.8 mmol, 363.6 mg) were placed in a reaction vessel and stirred at room
temperature until homogeneous brown solution was formed. 4ꢀmethoxy phenylacetylene (6.0 mmol,
o
792 mg) was added to the solution and the reaction was carried out at 100 C under stirring until
complete conversion of the nꢀPr2S2. After finish, the residue was purified by flash chromatography to
afford (Z)ꢀ1,2ꢀdi(nꢀpropylthio) (4ꢀmethoxy styrene) (1m) (1.65 g, 72%). Light yellow oil: 1H NMR (400
MHz, CDCl3) δ 7.40 (d, J = 6.8 Hz, 2H), 6.86 (d, J = 7.2 Hz, 2H), 6.41 (s, 1H), 3.82 (s, 3H), 2.77 (t, J =
7.6 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.75ꢀ1.69 (m, 2H), 1.51ꢀ1.46 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H),
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0.91 (t, J = 7.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 159.0, 132.0, 130.7, 130.3, 128.4, 113.8,
55.3, 36.3, 34.6, 27.9, 23.2, 13.2.
(Z)-1,2-di(4-methoxyphenylthio)(4-methoxystyrene) (1n): Light yellow oil: 1H NMR (400 MHz, CDCl3)
δ 7.45ꢀ7.41 (m, 4H), 7.21 (d, J = 8.8 Hz, 2H), 6.90ꢀ6.86 (m, 3H), 6.73 (d, J = 8.0 Hz, 4H), 3.80 (s, 3H),
3.73 (s, 3H), 3.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 159.0, 158.5, 134.1, 133.1, 134.5,
131.2, 129.8, 128.2, 126.1, 125.3, 114.9, 114.5, 113.7, 55.4, 55.3; MS (EI) m/z: 410 (M+, 56), 271 (100),
256 (44), 240 (28), 227 (29), 165 (7), 139 (56), 125 (18), 95 (13), 89 (7), 77 (6), 63 (5).
(Z)-1,2-di(4-methylphenylthio)(4-methylstyrene) (1o): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.39ꢀ7.33 (m, 4H), 7.19ꢀ7.09 (m, 6H), 6.97 (d, J = 8.0 Hz, 3H), 2.33 (s, 3H), 2.26 (s, 3 H), 2.21 (s, 3H);
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13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 138.0, 137.8, 136.9, 135.8, 131.8, 131.3, 131.1, 130.1, 129.7,
129.3, 128.5, 128.4, 128.3, 127.4, 124.1, 21.5, 21.2, 21.1.
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(Z)-1,2-di(4-methylphenylthio)(4-methoxystyrene) (1p): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.44 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.14ꢀ7.11 (m, 4H), 7.01 (s, 1H), 6.94 (d, J = 8.0 Hz,
2H), 6.72 (d, J = 8.8 Hz, 2H), 3.67 (s, 3H), 2.31 (s, 3H), 2.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.2, 137.6, 135.8, 134.4, 132.1, 131.6, 131.3, 130.9, 130.1, 129.8, 129.4, 128.7, 128.1, 113.8, 55.3,
21.2, 21.1.
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(Z)-1,2-di(4-methylphenylthio)(4-(t-butyl)styrene) (1q): Light yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.48 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.27ꢀ7.25 (m, 3H), 7.19 (s, 1H), 7.17ꢀ7.15 (m, 4H),
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7.00 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 1.27 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ
150.5, 137.6, 136.9, 136.2, 135.5, 131.9, 131.5, 130.9, 130.0, 129.7, 128.6, 128.1, 126.3, 125.3, 34.5,
31.2, 21.1, 21.0.
General procedure for the synthesis of 3a-3s
Methyl (Ethyl) magnesium chloride (0.25 mmol) was added to a mixture of (Z)ꢀvinylic disulfides
(0.2 mmol), NiF2 (0.97 mg, 0.01 mmol), and PPh3 (2.62 mg, 0.01 mmol) in dry THF (1.0 mL) at rt
under N2. The reaction mixture was stirred at rt for 25 h. After completion of reaction, the solution was
quenched with H2O2 (1.0 mL), and stirred at rt for 3 h. The resulting mixture was extracted with
dichloromethane, and the combined organic layers were dried over anhydrous Na2SO4, subject to
filtration, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel
(petroleum ether) to afford the desired products 3a-3s.
General procedure for the synthesis of 3t-3ac
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Grignard Reagents (0.25 mmol) was added to a mixture of (Z)ꢀvinylic disulfides (0.2 mmol), NiF2
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(4.85 mg, 0.05 mmol), and PPh3 (13.1 mg, 0.05 mmol) in dry THF (1.0 mL) at rt under N2. The reaction
mixture was stirred at rt for 25 h. After completion of reaction, the solution was quenched with H2O2
(1.0 mL), and stirred at rt for 3 h. The resulting mixture was extracted with dichloromethane, and the
combined organic layers were dried over anhydrous Na2SO4, subject to filtration, and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether) to afford the
desired products 3t-3ac.
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(Z)-1-phenylthio-2-methyl styrene (3a). Light yellow oil; yield: 91% (41.1 mg). H NMR (400 MHz,
CDCl3) δ 7.54 (d, J = 7.6 Hz, 2H), 7.24ꢀ7.01 (m, 7H), 7.03ꢀ7.00 (m, 1H), 6.51 (q, J = 6.8 Hz, 1H), 2.08
(d, J = 6.8 Hz, 3H); 113C{1H} NMR (100 MHz, CDCl3) δ 104.7, 136.1, 134.7, 134.2, 128.7, 128.2,
127.9, 127.5, 127.4, 125.3, 17.0; MS (m/z): 226 (M+, 100), 211 (14), 117 (86), 110 (17), 91 (23), 77 (7),
65 (7); HRMS calc. for C15H14S 226.0811, found 226.0840.
(Z)-1-phenylthio-2-methyl (4-methylstyrene) (3b). Light yellow oil; yield: 92% (44.1 mg). 1H NMR (400
MHz, CDCl3) δ 7.29ꢀ7.26 (m, 2H), 7.07ꢀ7.04 (m, 5H), 6.96ꢀ6.90 (m, 2H), 6.41 (q, J = 6.8 Hz, 1H), 2.20
(s, 3H), 1.98 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 137.8, 137.2, 136.3, 133.9, 128.9,
128.7, 127.8, 127.2, 125.2, 21.1, 16.9; MS (m/z): 240 (M+, 100), 225 (28), 117 (91), 91 (45), 65 (10);
HRMS calc. for C16H16S 240.0967, found 240.0964.
(Z)-1-phenylthio-2-methyl (3-methylstyrene) (3c). Light yellow oil; yield: 92% (44.1 mg). 1H NMR (400
MHz, CDCl3) δ 7.53, 7.24ꢀ7.21 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.46 (q, J =
13
6.8 Hz, 1H), 2.22 (s, 3H), 2.08 (d, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 104.7, 137.7,
136.3, 134.6, 134.2, 128.7, 128.3, 128.1, 128.0, 127.8, 125.2, 124.6, 21. 5, 16.9; MS (m/z): 240 (M+,
100), 225 (26), 117 (90), 91 (48), 65 (8); HRMS calc. for C16H16S 240.0964, found 240.0963.
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(Z)-1-phenylthio-2-methyl (4-(t-butyl) styrene) (3d). Light yellow oil; yield: 93% (53.4 mg). H NMR
(400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.09ꢀ7.08 (m, 3H), 6.97ꢀ6.96 (m,
1H), 6.49 (q, J = 6.8 Hz, 1H), 1.99 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 150.5, 137.8, 136.6, 134.7, 133.5, 128.7, 127.3, 126.8, 125.1, 125.0, 34.5, 31.3, 16.9; MS (m/z): 282
(M+, 2), 277 (20), 268 (21), 226 (12), 211 (100), 183 (14), 152 (6), 115 (10), 91 (8), 57 (16); HRMS
calc. for C19H22S 282.1437, found 282.1432.
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(Z)-1-phenylthio-2-methyl(4-(n-propyl) styrene) (3e). Yellow oil; yield: 90% (48.2 mg). H NMR (400
MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.14ꢀ7.10 (m, 4H), 7.04ꢀ7.01 (m, 3H), 6.50 (q, J = 6.8 Hz,
1H), 2.50 (t, J = 8.0 Hz, 2H), 2.05 (d, J = 6.8 Hz, 3H), 1.59ꢀ1.56 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 142.1, 138.1, 136.4, 134.1, 133. 9, 128.7, 128.3, 128.1, 127.7,
127.2, 125.1, 37.7, 24.4, 16.9, 13.9; MS (m/z): 268 (M+, 15), 241 (11), 218 (8), 163 (9), 159 (30), 147
(100), 129 (12), 117 (17), 109 (11), 91 (21), 77 (12), 57 (12); HRMS calc. for C18H20S 268.1280, found
268.1273.
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(Z)-1-(phenylthio)-2-methyl(4-methoxystryrene) (3f). Yellow oil; yield: 83% (42.3 mg). H NMR (400
MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.15ꢀ7.14 (m, 4H), 7.06ꢀ7.03 (m, 1H), 6.77 (d, J = 8.8 Hz,
2H), 6.43 (q, J = 6.8 Hz, 1H), 3.76 (s, 3H), 2.07 (d, J = 6.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.0, 136.2, 133.5, 133.2, 132.9, 128.7, 128.5, 127.8, 125.2, 113.5, 55.2, 16.8; MS (m/z): 256 (M+,
36), 156 (6), 147 (100), 132 (12), 115 (18), 103 (11), 91 (24), 77 (8), 51 (4); HRMS calc. for C16H16OS
256.0916, found 256.0916.
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1-(phenylthio)-2-methyl-4-fluorostryrene (3g). Yellow oil; yield: 92% (44.9 mg). H NMR (400 MHz,
CDCl3) δ 7.51ꢀ7.47 (m, 2H), 7.14ꢀ7.13 (m, 4H), 7.05ꢀ7.02 (m, 1H), 6.93ꢀ6.87 (m, 2H), 6.43 (d, J = 6.8
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Hz, 1H), 2.08 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.2 (d, JCꢀF = 245.2 Hz),
136.7, 135.6, 134.2, 133.4, 129.0, 128.9, 128.8, 128.7, 128.2, 125.5, 115.1, 114.9, 16.9; MS (m/z): 244
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(M+, 63), 229 (7), 196 (4), 154 (18), 139 (47), 135 (100), 123 (40), 109 (54), 95 (17), 75 (7), 69 (13);
HRMS calc. for C15H13FS 244.0717, found 244.0709.
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(Z)-1-phenylthio-2-methyl(3-thienylenevinylene) (3h). Yellow oil; yield: 83% (35.6 mg). 1H NMR (400
MHz, CDCl3) δ 7.35 (s, 1H), 7.25ꢀ7.23 (m, 1H), 7.18ꢀ7.17 (m, 5H), 7.09ꢀ7.04 (m, 1H), 6.64 (q, J = 6.8
Hz, 1H), 2.05 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.3, 136.3, 133.8, 128.8,
128.4, 127.4, 125.9, 125.6, 125.2, 122.4, 16.4; MS (m/z): 232 (M+, 74), 217 (11), 199 (13), 184 (5), 160
(7), 127 (27), 123 (100), 110 (10), 97 (8), 79 (25), 51 (7); HRMS calc. for C13H12S2 232.0375, found
232.0370.
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(Z)-4-propylthio-3-heptene (3i). Yellow oil; yield: 94% (40.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.26ꢀ
7.25 (m, 4H), 7.17ꢀ7.14 (m, 1H), 5.90 (t, J = 6.8 Hz, 1H), 2.37ꢀ2.30 (m, 2H), 1.52ꢀ1.46 (m, 2H), 1.00 (t,
J = 7.6 Hz, 3H), 0.82 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.5, 135.8, 132.2,
129.1, 128.7, 125.6, 39.6, 23.3, 21.6, 14.0, 13.3; MS (m/z): 206 (M+, 65), 191 (35), 177 (15), 161 (34),
136 (64), 97 (100), 77 (35), 51 (14); HRMS calc. for C13H18S 206.1152, found 206.1154.
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(Z)ꢀ1ꢀ(4ꢀmethylphenylthio)ꢀ2ꢀmethyl stryrene (3j). Yellow oil; yield: 92% (44.1 mg). H NMR (400
MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 2H), 7.26ꢀ7.17 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0
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Hz, 2H), 6.46 (q, J = 6.8 Hz, 1H), 2.22 (s, 3H), 2.08 (d, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 140.8, 135.2, 134.8, 134.0, 132.4, 129.6, 128.4, 128.2, 127.5, 127.4, 21.0, 16.9; MS (m/z):
240 (M+, 100), 225 (27), 121 (41), 147 (88), 91 (47), 65 (7); HRMS calc. for C16H16S 240.0967, found
240.0963.
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(Z)-1-(4-chlorophenylthio)-2-methylstryrene (3k). Yellow oil; yield: 91% (47.3 mg). H NMR (400
MHz, CDCl3) δ 7.51 (d, J = 7.2 Hz, 2H), 7.25ꢀ7.19 (m, 3H), 7.09ꢀ7.08 (m, 4H), 6.51 (q, J = 6.8 Hz,
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1H), 2.08 (d, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 140.2, 134.9, 134.0, 131.2, 129.5,
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129.3, 128.8, 128.3, 127.6, 127.3, 16.9; MS (m/z): 260 (M+, 40), 225 (7), 144 (8), 121 (17), 117 (100),
108 (4), 91 (28), 65 (5); HRMS calc. for C15H13ClS 260.0421, found 260.0413.
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(Z)-1-(4-methoxyphenylthio)-2-methylstryrene (3l). Yellow oil; yield: 82% (41.7 mg). H NMR (400
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Hz, 2H), 6.35 (q, J = 6.8 Hz, 1H), 3.70 (s, 3H), 2.09 (d, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 158.1, 140.7, 135.8, 132.6, 130.9, 128.0, 127.6, 127.3, 126.2, 114.4, 55.2, 16.7; MS (m/z):
256 (M+, 26), 207 (4), 147 (100), 135 (96), 132 (10), 115 (21), 103 (15), 91 (36), 77 (28), 65 (13);
HRMS calc. for C16H16OS 256.0924, found 256.0926.
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(Z)-1-propylthio-2-ethyl(4-methoxystryrene) (3m). Yellow oil; yield: 95% (41.8 mg). H NMR (400
MHz, CDCl3) δ 7.36 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 5.83 (t, J = 7.2 Hz, 1H), 3.74 (s, 3H),
2.42ꢀ2.35 (m, 2H), 2.27 (t, J = 7.2 Hz, 2H), 1.37ꢀ1.32 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H), 0.80 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.0, 136.2, 134.7, 133.2, 129.0, 113.6, 55.3, 34.0, 23.9,
23.1, 14.0, 13.1; MS (m/z): 236 (M+, 67), 207 (12), 194 (35), 161 (100), 128 (28), 107 (42), 75 (28);
HRMS calc. for C14H20OS 236.1278, found 236.1276.
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(Z)-1-(4-methoxyphenylthio)-2-methyl(4-methoxystryrene) (3n). Yellow oil; yield: 84% (47.9 mg). H
NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.2 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.76ꢀ6.68 (m, 4H), 6.26
(q, J = 6.8 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 2.07 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 135.5, 133.4, 129.8, 129.5, 129.1, 129.0, 128. 7, 128.6, 115.0, 114.8, 21.1, 20.9, 16.8; MS
(m/z): 286 (M+, 26), 147 (100), 115 (13), 103 (6), 91 (15), 77 (5); HRMS calc. for C17H18O2S 286.1037,
found 286.1032.
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(Z)-1-(4-methylphenylthio)-2-methyl(4-methylstryrene) (3o). Light yellow oil; yield: 87% (44.2 mg). H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.15ꢀ7.13 (m, 1H), 7.06ꢀ7.02 (m, 4H), 6.95 (d, J =
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8.4 Hz, 2H), 6.44 (q, J = 6.8 Hz, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.08 (d, J = 6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 137.9, 137.1, 135.0, 134.4, 133.3, 132.5, 129.5, 128.8, 128.1, 127.2, 60.4, 21.0,
14.2; MS (m/z): 254 (M+, 98), 240 (17), 135 (32), 131 (100), 115 (34), 105 (5), 91 (34), 77 (6), 65 (5);
HRMS calc. for C17H18S 254.1124, found 254.1116.
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(Z)-1-(4-methylphenylthio)-2-methyl(4-methoxystryrene) (3p). Yellow oil; yield: 88% (47.4 mg). H
NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H),
6.67 (d, J = 8.8 Hz, 2H), 6.28 (q, J = 6.8 Hz, 1H), 3.65 (s, 3H), 2.13 (s, 3H), 1.97 (d, J = 6.8 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.0, 135.1, 133.7, 133.3, 132.3, 129.5, 128.5, 128.2, 113.5, 55.2,
20.9, 16.8; MS (m/z): 270 (M+, 45), 255 (12), 224 (52), 175 (37), 163 (35), 148 (17), 123 (26), 107
(100), 72 (18); HRMS calc. for C17H18OS 270.1127, found 270.1124.
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(Z)-1-(4-methylphenylthio)-2-methyl(4-(t-butyl)stryrene) (3q). Yellow oil; yield: 87% (50.7 mg). H
NMR (400 MHz, CDCl3) δ 7.26ꢀ7.23 (m, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.51
(q, J = 6.8 Hz, 1H), 2.22 (s, 3H), 2.05 (d, J = 6.8 Hz, 3H), 1.27 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 150.4, 138.0, 134.9, 134.1, 134.0, 132.9, 129.5, 129.1, 127.7, 126.9, 125.1, 34.5, 31.3, 20.9,
16.9; MS (m/z): 296 (M+, 13), 175 (100), 161 (64), 147 (18), 123 (12), 115 (14), 91 (27), 77 (8), 57
(23); HRMS calc. for C20H24S 296.1641, found 296.1645.
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(Z)-1-phenylthio-2-ethylstryrene (3r). Yellow oil; yield: 93% (44.6 mg). H NMR (400 MHz, CDCl3) δ
7.55 (d, J = 8.4 Hz, 2H), 7.23ꢀ7.09 (m, 7H), 7.02ꢀ6.99 (m, 1H), 6.42 (t, J = 7.2 Hz, 1H), 2.57ꢀ2.50 (m,
2H), 1.09 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 141.7, 140.5, 132.7, 128.7, 128.2,
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128.1, 127.5, 125.3, 24.5, 13.9; MS (m/z): 240 (M+, 17), 211 (7), 133 (37), 115 (18), 110 (23), 105 (15),
91 (100), 77 (17), 57 (13), 79 (25), 51 (7); HRMS calc. for C16H16S 240.0967, found 240.0962.
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(Z)-1-phenylthio-2-ethyl(4-methoxystryrene) (3s). Light yellow oil; yield: 88% (47.5 mg). 1H NMR (400
MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2H), 7.07ꢀ7.01 (m, 4H), 6.94ꢀ6.91 (m, 1H), 6.66 (d, J = 8.4 Hz,
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(100 MHz, CDCl3) δ 159.1, 140.1, 136.4, 133.0, 132.1, 128.7, 128.6, 128.0, 125.2, 113.6, 55.2, 24.5,
14.0; MS (m/z): 270 (M+, 8), 185 (4), 161 (100), 128 (44), 117 (38), 107 (15), 91 (36), 66 (14); HRMS
calc. for C17H18OS 270.1175, found 270.1173.
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(Z)-1-phenylthio-2-allylstryrene (3t). Yellow oil; yield: 82% (41.3 mg). H NMR (400 MHz, CDCl3) δ
7.55 (d, J = 7.6 Hz, 2H), 7.35ꢀ 7.27 (m, 1H), 7.24 (s, 1H), 7.20ꢀ7.13 (m, 5H), 7.03 (t, J = 6.8 Hz, 1H),
6.40 (t, J = 7.2 Hz, 1H), 5.92ꢀ5.86 (m, 1H), 5.15ꢀ5.04 (m, 2H), 3.31 (t, J = 6.4 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 140.2, 136.5, 135.70, 134.69, 131.1, 129.2, 128.7, 128.4, 128.2, 127.7, 127.6,
125.5, 115.8, 35.2; MS (m/z): 252 (M+, 10), 239 (16), 199 (15), 175 (8), 157 (13), 128 (19), 105 (100),
77 (53), 51 (19); HRMS calc. for C17H16S 252.1045, found 252.1047.
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(Z)-1-phenylthio-2-cyclopentylstryrene (3u). Yellow oil; yield: 86% (48.1 mg). H NMR (400 MHz,
CDCl3) δ 7.55 (d, J = 7.2 Hz, 2H), 7.24ꢀ7.20 (m, 2H), 7.16ꢀ7.10 (m, 5H), 7.02 (d, J = 6.8 Hz, 1H), 6.37
(d, J = 9.2 Hz, 1H), 3.34ꢀ3.28 (m, 1H), 1.91ꢀ1.88 (m, 2H), 1.74ꢀ1.59 (m, 4H), 1.43ꢀ1.37 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 140.4, 136.4, 131.7, 128.7, 128.1, 127.9, 127.43, 127.38,
125.2, 42.0, 33.6, 25.6; MS (m/z): 280 (M+, 100), 212 (17), 203 (18), 184 (5), 171 (45), 141 (46), 129
(60), 121 (37), 91 (38), 77 (8), 67 (7); HRMS calc. for C19H20S 280.1280, found 280.1275.
(Z)-1-phenylthio-2-cyclohexylstryrene (3v). Light yellow oil; yield: 85% (50.0 mg). 1H NMR (400 MHz,
CDCl3) δ 7.54 (d, J = 7.2 Hz, 2H), 7.22ꢀ7.09 (m, 5H), 7.01 (t, J = 7.2 Hz, 1H), 6.25 (d, J = 9.2 Hz, 1H),
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2.94ꢀ2.86 (m, 1H), 1.77ꢀ1.70 (m, 4H), 1.34ꢀ1.19 (m, 6H); C{1H} NMR (100 MHz, CDCl3) δ 145.7,
140.3, 136.2, 131.3, 128.6, 128.1, 128.1, 127.5, 127.4, 125.3, 39.9, 32.8, 26.0, 25.7; MS (m/z): 294 (M+,
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100), 217 (26), 212 (28), 185 (21), 161 (14), 141 (34), 128 (36), 117 (28), 115 (23), 103 (15), 91 (24),
71 (14); HRMS calc. for C20H22S 294.1416, found 294.1418.
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8.8 Hz, 2H), 6.29 (d, J = 9.2 Hz, 1H), 3.75 (s, 3H), 3.34ꢀ3.28 (m, 1H), 1.94ꢀ1.88 (m, 2H), 1.86ꢀ1.58 (m,
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4H), 1.44ꢀ1.37 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 159.0, 144.1, 136.6, 132.9, 130.8, 128.6,
128.5, 127.9, 125.2, 113.5, 55.2, 41.9, 33.7, 25.6; MS (m/z): 310 (M+, 77), 279 (8), 242 (11), 201 (89),
159 (36), 145 (16), 133 (35), 121 (100), 115 (25), 110 (45), 91 (17), 77 (18), 67 (15); HRMS calc. for
C20H22OS 310.1452, found 310.1450.
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(Z)-1-phenylthio-2-phenylstryrene (3x)26. Light yellow oil; yield: 72% (41.5 mg). H NMR (400 MHz,
CDCl3) δ 7.32ꢀ7.29 (m, 8H), 7.22ꢀ7.20 (m, 2H), 7.13ꢀ7.10 (m, 3H), 7.04ꢀ7.02 (m, 2H), 6.97 (s, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 143.4, 142.6, 140.4, 137.4, 130.4, 129.6, 128.6, 128.2, 128.2,
128.0, 127.6, 127.5, 127.4, 136.7; MS (m/z): 288 (M+, 48), 211 (28), 198 (38), 178 (100), 109 (54), 102
(15), 77 (26); HRMS calc. for C20H16S 288.1052, found 288.1050.
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(Z)-1-(4-methylphenylthio)-2-phenylstryrene (3y). Light yellow oil; yield: 75% (45.3 mg). H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.37ꢀ7.33 (2, 4H), 7.25ꢀ7.23 (m,
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4H), 7.13 (s, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 2.17 (s, 3H); C{1H} NMR (100
MHz, CDCl3) δ 141.1, 136.9, 135.8, 135.4, 135.1, 131.5, 129.6, 129.5, 128.18, 128.17, 128.15, 128.0,
127.84, 127.77, 21.0; MS (m/z): 302 (M+, 35), 256 (23), 246 (12), 178 (100), 152 (14), 123 (20), 105
(18), 91 (13), 77 (22), 63 (5), 51 (9); HRMS calc. for C21H18S 302.1125, found 302.1127.
(Z)-1-phenylthio-2-(4-methoxyphenyl)stryrene (3z). Light yellow oil; yield: 65% (41.3 mg). 1H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.27ꢀ7.23 (m, 2H), 7.20ꢀ7.19
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(m, 4H), 7.11 (t, J = 8.0 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 159.3, 141.4, 135.9, 135.6, 131.8, 131.1, 129.4, 128.7, 128.2, 127.8, 127.6,
125.6, 113.6, 55.3; MS (m/z): 318 (M+, 100), 209 (43), 197 (31), 194 (17), 165 (29), 139 (5), 91 (6);
HRMS calc. for C21H18OS 318.1073, found 318.1080.
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(Z)-1-phenylthio-2-phenyl(4-methoxystryrene) (3aa)27. Light yellow oil; yield: 61% (38.8 mg). 1H NMR
(400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.36ꢀ7.32 (m, 2H), 7.26ꢀ7.23
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(m, 1H), 7.19ꢀ7.09 (m, 5H), 7.03ꢀ7.00 (m, 1H), 7.78 (t, J = 8.4 Hz, 2H), 3.74 (s, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 159.5, 137.0, 135.6, 134.4, 134.1, 133.4, 129.5, 129.2, 128.9, 128.7, 128.2, 127.6,
125.7, 113.6, 55.3; MS (m/z): 318 (M+, 55), 209 (100), 194 (18), 165 (34), 151 (20), 139 (5), 110 (4), 84
(33), 77 (5); HRMS calc. for C21H18OS 318.1154, found 318.1156.
(Z)-1-phenylthio-2-(4-methylphenyl) (4-methoxystryrene) (3ab). Light yellow oil; yield: 72% (47.8 mg).
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.17ꢀ7.09 (m, 7H),
7.04ꢀ7.02 (m, 1H), 6.78 (t, J = 8.8 Hz, 2H), 3.76 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 159.4, 137.6, 135.8, 134.7, 134.1, 133.6, 132.9, 129.4, 129.1, 128.84, 128.75, 128.6, 125.6,
113.6, 55.2, 21.3; MS (m/z): 332 (M+, 56), 223 (100), 208 (20), 193 (7), 178 (13), 165 (18), 151 (24),
115 (6); HRMS calc. for C22H20OS 332.1235, found 332.1236.
(Z)-1-propylthio-2-phenyl(4-methoxystyrene) (3ac). Light yellow oil; yield: 95% (54.1 mg). 1H NMR
(400 MHz, CDCl3) δ 7.72 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.25ꢀ
7.24 (m, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.47ꢀ1.42 (m,
2H), 0.82 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 137.43, 137.35, 133.7, 129.54,
129.48, 128.0, 126.9, 113.7, 55.4, 34.9, 23.2, 13.3; MS (m/z): 284 (M+, 100), 241 (45), 226 (26), 216
(77), 197 (16), 116 (83), 151 (72), 135 (11), 115 (8), 91 (8), 63 (6); HRMS calc. for C18H20OS
284.1272, found 284.1275.
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The experimental procedure for larger-scale synthesis of 3a
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Methyl magnesium chloride (1.0 mL, 2.5 mmol) was added to a mixture of (Z)ꢀ1,2ꢀdiphenylthio
styrene (640 mg, 2.0 mmol), NiF2 (9.7 mg, 0.1 mmol), and PPh3 (26.2 mg, 0.1 mmol) in dry THF (6.0
mL) at rt under N2. The reaction mixture was stirred at rt for 25 h. Upon completion, the reaction was
quenched by H2O2 (5.0 mL), and the resulting mixture was extracted with dichloromethane. The organic
layer was washed with water (30 mL×3) and brine (30 mL×1), and the separated aqueous phase was
extracted with CH2Cl2 (30 mL × 2). The combined organic layers were dried over anhydrous Na2SO4,
subject to filtration, and concentrated in vacuo. The residue was purified by flash chromatography on
silica gel (petroleum ether) to afford (Z)ꢀ1ꢀphenylthioꢀ2ꢀmethyl styrene 3a as light yellow oil (88%, 398
mg).
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Experimental procedure for the synthesis of (Z)-tamoxifen
Procedure for the synthesis of compound 5: A mixture of Br2 (2.0 mmol) and glacial acetic acid
(2.0 mL) was added to a solution of (Z)ꢀ1ꢀ(4ꢀmethylphenylthio)ꢀ2ꢀphenylstryrene (2.0 mmol) and
glacial acetic acid (4.0 mL), and the reaction mixture was stirred at rt for 2 h. Upon completion of
reaction, the product was filtered out and recrystallized from 95% ethanol to give (E)ꢀ1ꢀphenylthioꢀ2ꢀ
bromo toluylene in 75% yield. Then Pd(PPh3)4 (5.0 mmol%) was added to a solution of (E)ꢀ1ꢀ
phenylthioꢀ2ꢀbromo toluylene (1.0 mmol), 4ꢀ(N,Nꢀdimethylethoxy) phenylboronic acid (2.0 mmol),
Na2CO3 (2.0 mmol) and dry THF (3.0 mL) under nitrogen amosphere. The reaction solution was stirred
o
at 150 C for 16 h. Upon completion of reaction, the desired product (compound 5) was obtained by
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column chromatography in 87% yield. H NMR (400 MHz, CDCl3) δ 7.34ꢀ7.27 (m, 7H), 7.06ꢀ6.99 (m,
5H), 6.90ꢀ6.84 (m, 4H), 6.58 (d, J = 8.8 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 2.75 (t, J = 5.6 Hz, 2H), 2.35
(s, 6H), 2.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.4, 145.7, 144.1, 139. 6, 135.5, 135.1,
132.9, 132.2, 132.1, 131.1, 129.61, 129.56, 129.2, 128.1, 127.6, 127.2, 126.8, 113.6, 65.5, 58.0, 45.6,
21.0; MS (m/z): 465 (M+, 91), 406 (7), 394 (8), 329 (7), 283 (8), 252 (23), 239 (13), 178 (8), 126 (6), 72
(88), 58 (100).
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Procedure for the synthesis of (Z)-tamoxifen: EtMgCl (5.0 mL, 0.2 M in diethyl ether) was
added to a mixture of compound 5 (100 mg, 0.1 mmol) and NiCl2(dppe) (9.0 mg, 0.017 mmol) in
diethyl ether (2.0 mL) under nitrogen atmosphere, and the mixture was refluxed with stirring for 15 h.
After addition of H2O to the mixture, the residue was dissolved in Et2O, and 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 (Z)ꢀtamoxifen (58.5 mg, 73% Z/E=96/4). 1H NMR
(400 MHz, CDCl3) δ 7.33–7.12 (m, 10H), 6.77 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 3.91 (t, J =
5.6 Hz, 2H), 2.63 (t, J = 5.6 Hz, 2H), 2.45 (q, J = 7.2 Hz, 2H), 2.27 (s, 6H), 0.92 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.8, 143.9, 142.5, 141.3, 138.3, 135.6, 131.9, 129.7,
129.5, 128.1, 127.9, 126.5, 126.0, 113.4, 65.7, 58.3, 45.9, 29.0, 13.6; MS (m/z): 371 (M+, 18), 312 (4),
252 (24), 191 (6), 178 (5), 152 (3), 115 (3), 91 (5), 72 (33), 58 (100).
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The procedure for the NMR experiment
Methyl magnesium chloride (0.3 mmol, 2.5 mol/L in THF) was added to a dry Schlenk tube under
nitrogen. The solvent (THF) was removed in vacuo, and dry THFꢀd8 (0.5 ml) was injected into the
Schlenk tube under nitrogen. Then fresh methyl magnesium chloride (THFꢀd8) was added to a Low
Pressure/Vacuum Valve (PLV) NMR sample tube containing a mixture of (Z)ꢀ1,2ꢀdiphenylthio styrene
(32 mg, 0.1 mmol), NiF2 (0.5 mg, 0.005 mmol), and PPh3 (1.3 mg, 0.005 mmol) in dry THFꢀd8 (0.5 mL)
at rt under N2. The reaction mixture was examined in hourly intervals by NMR spectroscopy.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (Nos. 21273068 and
21373003, J1210040), and the Fundamental Research Funds for the Central University, Hunan
University. All authors thank Prof. Nobuaki Kambe and Dr. Takanori Iwasaki of Osaka University for
helpful discussion. C.T. Au thanks HNU for an adjunct professorship.
Supporting Information:
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1H NMR and 13C{1H} NMR spectra of compounds 1aꢀ1q, 3a–3ac, compound 5 and (Z)ꢀtamoxifen.
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This material is available free of charge via the Internet at http://pubs.acs.org.
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