Synthesis of alkenyl sulfides through the iron-catalyzed cross-coupling reaction of vinyl halides with thiols

Article abstract of DOI:10.1021/jo3008397

We report here the iron-catalyzed cross-coupling reaction of alkyl vinyl halides with thiols. While many works are devoted to the coupling of thiols with alkyl vinyl iodides, interestingly, the known S-vinylation of vinyl bromides and chlorides is limited

Full text of DOI:10.1021/jo3008397

Article
pubs.acs.org/joc
Synthesis of Alkenyl Sulfides Through the Iron-Catalyzed Cross-
Coupling Reaction of Vinyl Halides with Thiols
Yun-Yung Lin, Yu-Jen Wang, Che-Hung Lin, Jun-Hao Cheng, and Chin-Fa Lee*
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, ROC
S
* Supporting Information
ABSTRACT: We report here the iron-catalyzed cross-coupling reaction of alkyl
vinyl halides with thiols. While many works are devoted to the coupling of thiols
with alkyl vinyl iodides, interestingly, the known S-vinylation of vinyl bromides and
chlorides is limited to 1-(2-bromovinyl)benzene and 1-(2-chlorovinyl)benzene.
Investigation on the coupling reaction of challenging alkyl vinyl bromides and
chlorides with thiols is rare. Since the coupling of 1-(2-bromovinyl)benzene and 1-
(2-chlorovinyl)benzene with thiols can be performed in the absence of any catalyst, here we focus on the coupling of thiols with
alkyl vinyl halides. This system is generally reactive for alkyl vinyl iodides and bromides to provide the products in good yields. 1-
(Chloromethylidene)-4-tert-butyl-cyclohexane was also coupled with thiols, giving the targets in moderate yields.
thiols in the absence of any catalyst; an addition−elimination
pathway was proposed.12e Although the alkyl vinyl bromides
can be coupled with thiols in the presence of copper salt with
1,10-phenanthroline as a ligand, this system could not applied
to the challenging alkyl vinyl chlorides.12e Iron is cheap and
nontoxic, and the iron salts have been applied in many useful
chemical transformations.19,20
Herein we report the iron-catalyzed coupling reaction of
thiols with vinyl halides by using xantphos, L1, as a ligand (see
Figure 1). To the best of our knowledge, this is the first iron-
catalyzed coupling of alkyl vinyl chloride with thiols.
INTRODUCTION
■
The transition-metal-catalyzed cross-coupling reaction of aryl
or vinyl halides with thiols1 is a growing area because aryl
thioethers2 and alkenyl sulfides3 are important building blocks
in organic synthesis and nature.1−3 In 1980, Migita et al.
reported the first palladium-catalyzed coupling reaction of
thiols with aryl halides.4 Since this pioneering work, many
systems consisting of palladium with the appropriate ligands
have been reported for the same purpose.5 Other transition
metals including copper,6 nickel,7a,b cobalt,8 gold,9 indium,10
and iron11 are also known to couple aryl halides with thiols.
Surprisingly, the coupling reaction between vinyl halides with
thiols has been less studied.12−19 1-(2-iodovinyl)benzene, 1-(2-
bromovinyl)benzene, and 1-(2-chlorovinyl)benzene are the
most commonly used in the transition-metal-catalyzed S-
vinylation with thiols to give the corresponding styryl
thioethers.12
Other protocols to access alkenyl sulfides from alkyl vinyl
halides using transition metals include the palladium-catalyzed
coupling of thiols with alkyl vinyl iodides,13 bromides,14,12j,k
and chlorides;15 copper-catalyzed coupling of thiols with alkyl
vinyl iodides,12c−g,16 bromides,12e,16,17 and chlorides;17 cobalt-
catalyzed coupling of thiols with alkyl vinyl iodide;8 nickel-
catalyzed coupling of thiols with alkyl vinyl bromides;12i and
ruthenium-catalyzed coupling of thiols with alkyl vinyl
iodides.18 Additionally there are numerous reports of the
coupling of thiols with alkyl vinyl iodides.8,12c−g,13a,b,16,18
The reaction of alkyl vinyl bromides is more demanding than
using alkyl vinyl iodides for S-vinylation; however, this
transformation is known when using palladium,12j,k,14 cop-
per,17,12e,16 and nickel12i catalysts. Moreover, although the
intramolecular copper-catalyzed formation of thiols with alkyl
chlorides is known,17 the general procedure for preparing
alkenyl sulfides from alkyl vinyl chlorides relies on palladium
catalysis.15a,b Recently, we described that 1-(2-bromovinyl)-
benzene and 1-(2-chlorovinyl)benzene can be coupled with
Figure 1. Structures of the ligands L1−L3.
RESULTS AND DISCUSSION
■
Initially, 1-(iodomethylidene)-4-tert-butyl-cyclohexane, and 1-
dodecanethiol were selected as the substrates to screen the
optimized conditions. The results are summarized in Table 1; it
is interesting to note that L1, L2, and L3 have been used as
ligands for metal-catalyzed coupling reaction of thiols with aryl
halides, but we found that L1 is superior to L2 and L3 for this
reaction (Table 1, entries 1−3), providing the target in a 98%
isolated yield. In order to exclude the possibility of metal
impurity (especially copper),21 we have carried out the reaction
by using high purity of FeCl3 (>99.99%) as the iron source.
Received: May 3, 2012
© XXXX American Chemical Society
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a
nitrogen-containing heterocyclo- and chloro-groups can be
tolerated by the reaction conditions employed.
Table 1. Optimization of the Reaction Conditions
We then turned our attention to alkyl alkenyl bromides and
chlorides. As shown in Table 3, both alkyl thiols and aryl thiols
are suitable to couple with alkyl vinyl bromides, giving the
alkenyl sulfides in 50−74% isolated yields (Table 3, entries 1−
6). Furthermore, the challenging alkyl chlorides also react with
alkyl and aryl thiols, giving the corresponding alkenyl sulfides in
32−71% combined yields. The alkyl thiol is less reactive in this
reaction, providing the product in 32% yield. The regioisomers
were also detected when (1) bromomethylene cyclopentane
was reacted with 4-chlorobenzenethiol (Table 3, entry 6) and
(2) 1-(chloromethylidene)-4-tert-butyl-cyclohexane was reacted
with aryl thiols including thiophenol (Table 3, entry 8 as the
sole product), 4-methoxybenzenethiol (Table 3, entry 9), and
chlorobenzenethiol (Table 3, entry 10). The regioisomers are
formed in most cases when alkyl vinyl chloride is used; for
instance, the initially formed exocyclic double bond in product
3m could isomerize to the thermodynamically more stable
endocyclic double bond in 3m′ (Table 3, entry 6). The
moderate yields were obtained in the products 3d, 5a, 5b, and
3a (Table 3, entries 2−4 and 7), and the corresponding
disulfides were formed in such cases. It seems that the t-Bu is an
important group in alkyl vinyl chloride. Many alkyl vinyl
chlorides have been studied; however, 1-(chloromethylidene)-
4-tert-butyl-cyclohexane, 4c, is the only successful example for
this transformation. The reason is not clear yet.
entry
[Fe]
ligand
base
solvent
yield (%)
1
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
FeBr2
FeF2
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
NaOt-Bu
Cs2CO3
K3PO4
dioxane
dioxane
dioxane
dioxane
DMSO
NMP
98
84
43
2
3
b
4
92
5
9
20
57
70
83
71
58
40
37
6
7
DME
8
DMF
9
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
10
11
12
13
14
15
16
17
18
19
20
21
K2CO3
c
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
74
51
37
50
22
68
29
Cu2O
FeCl3
d
FeCl3
L1
39
CONCLUSION
a
■
Reaction conditions: iron source (0.05 mmol, 10 mol %), ligand
(0.05 mmol, 10 mol %), 1-(iodomethylidene)-4-tert-butyl-cyclohexane
(0.55 mmol), 1-dodecanethiol (0.5 mmol), base (1.0 mmol) in 0.5 mL
of solvent. 99.99% FeCl3. 120 °C. 1 equiv of TEMPO was added.
In conclusion, we have demonstrated that the catalytic system
comprised of FeCl3 and xantphos is a reactive catalyst toward
the coupling reaction of alkyl vinyl halides with thiols. Both
alkyl vinyl iodides and bromides were shown to be suitable as
the coupling partners, giving the corresponding alkenyl sulfides
in moderate to good yields. So far, 1-(chloromethylidene)-4-
tert-butyl-cyclohexane is the only successful alkyl vinyl chloride
to work with thiols, giving the corresponding alkenyl sulfides.
To the best of our knowledge, this is the first iron-catalyzed S-
vinylation of alkyl vinyl halides.
b
c
d
The product was obtained in 92% yield (Table 1, entry 4); this
result indicates that the FeCl3/L1 is a very reactive system in
this catalytic reaction. Solvents such as DMSO, NMP, DME,
DMF, and toluene could not provide satisfactory results (Table
1, entries 5−9). We also studied the effect of bases (Table 1,
entries 10−13), and the results showed that KOt-Bu is the best
for this transformation. Lower temperature will decrease the
yield of the product (Table 1, entry 14). When the reaction was
carried out using other iron sources such as FeCl2, FeBr2, or
FeF2 to replace FeCl3 (Table 1, entries 15−17), the lower
yields were obtained. A further study using Cu2O as a catalyst,
however, gave the target in only 22% isolated yield. This result
will rule out the participation of copper in this reaction (Table
1, entry 18). Lower yields of 3a were observed when the
reaction was carried out without ligand (Table 1, entry 19) or
without catalyst (Table 1, entry 20). A 39% yield of the product
was obtained when the reaction was carried out in the presence
of TEMPO (Table 1, comparing entry 21 with entry 1). This
result implies the radical mechanism in this reaction; however,
the oxidative addition/reductive elimination steps is also
possible in this transformation.22
EXPERIMENTAL SECTION
■
General Information. All chemicals were purchased from
commercial suppliers and used without further purification. Toluene
was dried over sodium; dioxane, DME, DMSO, and DMF were dried
over CaH2 and stored in the presence of activated molecular sieves. All
reactions were carried out under an inert atmosphere. Flash
chromatography was performed on silica gel 60 (230−400 mesh).
Analysis. NMR spectra were recorded using CDCl3 as solvent.
Chemical shifts are reported in parts per million (ppm) and referenced
to the residual solvent resonance. Coupling constants (J) are reported
in hertz (Hz). Standard abbreviations indicating multiplicity were used
as follows: s = singlet, d = doublet, t = triplet, dd = double doublet, q =
quartet, m = multiplet, b = broad. Melting points (mp) were
determined using an apparatus and are reported uncorrected. High-
resolution mass spectra were performed on an electron ionization mass
spectrometer.
General Procedure for the Synthesis of Vinyl Halides.
Anhydrous CrCl2 (5.92 g, 48.0 mmol) was suspended in THF (60
mL) under an argon atmosphere. A solution of ketone (12.0 mmol)
and haloform (24.0 mmol) in THF (30 mL) was added dropwise to
the suspension at 25 °C. After stirring at this temperature for 24 h, the
reaction mixture was poured into water (25 mL) and extracted with
ether. The combined extracts are dried over MgSO4 and concentrated
to give the crude material, which was then purified by column
chromatography (SiO2, hexane) to provide vinyl halide.
In order to extend the scope of this catalytic system, we
explored alkenyl iodides with many thiols. The results are
summarized in Table 2, The alkyl and aryl thiols are all coupled
with alkenyl iodides, giving the alkenyl sulfides in moderate to
good yields. Compound 3m was formed when the reaction was
carried out by reacting iodomethylene cyclopentane with 4-
chlorobenzenethiol; interestingly, the regioisomer 3m′ was
detected in this reaction (Table 2, entry 12). Remarkably, the
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a
Table 2. Iron-Catalyzed Coupling Reaction of Vinyl Iodides with Thiols
a
Reaction conditions: FeCl3 (0.05 mmol, 10 mol %), L1 (0.05 mmol, 10 mol %), vinyl iodide (0.55 mmol), thiol (0.5 mmol), KOt-Bu (1.0 mmol) in
b
dioxane (0.5 mL). DMF as solvent.
1-(Iodomethylidene)-4-tert-butyl-cyclohexane 1a.23 Follow-
ing the general procedure for the synthesis of vinyl halide, using 4-tert-
butylcyclohexanone (1.84 g, 12.0 mmol) and iodoform (9.48 g, 24.0
mmol), and then purification by column chromatography (SiO2,
purification by column chromatography (SiO2, hexane) provided 1c as
a colorless oil (2.33 g, 70%): 1H NMR (400 MHz, CDCl3) δ = 1.72−
1.82(m, 4 H), 2.22−2.26(m, 2 H), 2.31−2.35(m, 2 H), 5.88(m, 1 H);
13C NMR (100 MHz, CDCl3) δ = 25.7, 28.2, 35.1, 37.2, 68.1., 156.6.
1-(Iodomethylidene)-4-tert-butyl-cyclohexane 4c.25 Follow-
ing the general procedure for the synthesis of vinyl halide, using 4-tert-
butylcyclohexanone (1.84 g, 12.0 mmol) and chloroform (1.92 mL,
24.0 mmol), and then purification by column chromatography (SiO2,
1
hexane) provided 1a as a colorless oil (2.33 g, 70%): H NMR (400
MHz, CDCl3) δ = 0.86 (s, 9 H), 1.01−1.22 (m, 3 H), 1.77−1.90 (m, 3
H), 2.04−2.11(m, 1 H), 2.12−2.58(m, 1 H), 2.78−2.83 (m, 1 H),
5.76(s, 1 H); 13C NMR (100 MHz, CDCl3) δ = 27.6, 27.7, 28.7, 32.3,
35.8, 37.0, 70.7, 151.3.
1
hexane) to give 4c as a colorless oil (1.76 g, 76%): H NMR (400
(Iodomethylene)cyclohexane 1b.23 Following the general
procedure for the synthesis of vinyl halide, using cyclohexanone
(1.24 mL, 12.0 mmol) and iodoform (9.48 g, 24.0 mmol), and then
purification by column chromatography (SiO2, hexane) provided 1b as
MHz, CDCl3) δ = 0.87 (s, 9 H), 1.02−1.08 (m, 2 H), 1.14−1.20 (m, 1
H), 1.71−1.72(m, 1 H), 1.75−1.99(m, 3 H), 2.29−2.35 (m, 1 H),
2.94−2.99 (m, 2 H), 5.73−5.74 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ = 27.4, 27.6, 28.4, 28.6, 32.4, 34.0, 48.0, 108.1, 142.0.
General Procedure for Table 1. A 4 mL vial, sealed and
equipped with a magnetic stirrer bar, was charged with base (1.0
mmol), FeCl3 (0.008 g, 0.05 mmol), and ligand (0.05 mmol) under a
nitrogen atmosphere. The vial was covered with a rubber septum, and
1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a, 0.153 g, 0.55
mmol), 1-dodecanethiol (2a, 0.120 mL, 0.5 mmol), and solvent (0.5
1
a colorless oil (1.66 g, 75%): H NMR (400 MHz, CDCl3) δ =1.51−
1.59 (m, 6 H), 2.26−2.30 (m, 4 H), 5.77 (s, 1 H); 13C NMR (100
MHz, CDCl3) δ = 26.1, 17.0, 18.0, 35.9, 37.3, 71.0, 151.3.
(Iodomethylene)cyclopentane 1c.24 Following the general
procedure for the synthesis of vinyl halide, using cyclopentanone
(1.06 mL, 12.0 mmol) and iodoform (9.48 g, 24.0 mmol), and then
C
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a
Table 3. Iron-Catalyzed Coupling Reaction of Alkyl Vinyl Bromides and Chlorides with Thiols
a
Reaction conditions: FeCl3 (0.05 mmol, 10 mol %), L1 (0.05 mmol, 10 mol %), alkyl vinyl bromide or chloride (0.55 mmol), thiol (0.5 mmol),
b
KOt-Bu (1.0 mmol) in 0.5 mL of DMF for 24 h. 30 h.
mL) were added by syringe under a nitrogen atmosphere. The septum
was then replaced by a screw cap containing a Teflon-coated septum,
and the reaction vessel was heated at 135 °C. After stirring at this
temperature for 24 h, the heterogeneous mixture was cooled to room
temperature and diluted with ethyl acetate (20 mL). The resulting
solution was filtered through a pad of silica gel and then washed with
ethyl acetate (20 mL) and concentrated to give the crude material,
which was then purified by column chromatography (SiO2, hexane) to
give 3a.
CDCl3) δ = 14.2, 22.7, 27.6, 27.8, 28.7, 28.9, 29.3, 29.4, 29.6, 29.6,
29.7, 29.7, 30.2, 30.2, 31.9, 32.5, 34.1, 36.3, 48.0, 114.6, 141.8.
General Procedure for Table 2. A 4 mL vial, sealed and
equipped with a magnetic stirrer bar, was charged with KOt-Bu (112
mg, 1.0 mmol), FeCl3 (0.008 g, 0.05 mmol), and L1 (0.029 g, 0.05
mmol) under a nitrogen atmosphere. The vial was covered with a
rubber septum, and vinyl iodide (1, 0.55 mmol), alkyl or aryl thiol (2,
0.5 mmol), and 1,4-dioxane (0.5 mL) were added by syringe under a
nitrogen atmosphere. The septum was then replaced by a screw cap
containing a Teflon-coated septum, and the reaction vessel was heated
at 135 °C. After stirring at this temperature for 24 h, the
heterogeneous mixture was cooled to room temperature and diluted
with ethyl acetate (20 mL). The resulting solution was filtered through
a pad of silica gel and then washed with ethyl acetate (20 mL) and
concentrated to give the crude material, which was then purified by
column chromatography on silica gel to yield 3.
Representative Example Of Table 1. ((4-tert-
Butylcyclohexylidene)methyl)(dodecyl)sulfane 3a (Entry
1).12e Following the general procedure for Table 1, using KOt-Bu
(0.112 g, 1.0 mmol) and L1 (0.029 g, 0.05 mmol) in 1,4-dioxane (0.5
mL), and then purification by column chromatography (SiO2, hexane)
1
provided 3a as a colorless oil (0.172 g, 98% yield): H NMR (400
MHz, CDCl3) δ = 0.81−0.89 (m, 12 H), 0.95−1.18 (m, 3 H), 1.25−
1.38 (m, 18 H), 1.57−1.63 (m, 2 H), 1.70−1.78 (m, 1 H), 1.80−1.87
(m, 2 H), 1.99−2.06 (m, 1 H), 2.28−2.33 (m, 1 H), 2.62 (t, J = 7.6
Hz, 2 H), 2.76−2.82 (m, 1 H), 5.56 (s, 1 H); 13C NMR (100 MHz,
((4-tert-Butylcyclohexylidene)methyl)(2-methylbutyl)-
sulfane 3b (Table 2, Entry 1).12e Following the general procedure
for Table 2, using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a,
D
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0.153 g, 0.55 mmol) and 2-methylbutane-1-thiol (0.0625 mL, 0.5
27.6, 28.1, 29.0, 30.2, 32.4, 36.5, 48.0, 110.9, 128.75, 128.84, 131.2,
136.3, 149.1.
mmol), and then purification by column chromatography (SiO2,
1
2-((4-tert-Butylcyclohexylidene)methylthio)-1-methyl-1H-
imidazole 3i (Table 2, Entry 8). Following the general procedure for
Table 2, using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a,
0.153 g, 0.55 mmol) and 1-methyl-1H-imidazole-2-thiol (0.057 g,
0.5 mmol), and then purification by column chromatography (SiO2,
hexane/EA = 9:1) provided 3i as a yellow oil (0.070 g, 53% yield): 1H
NMR (400 MHz, CDCl3) δ = 0.78 (s, 9 H), 0.97−1.12 (m, 3 H),
1.75−1.85 (m, 3 H), 1.99−2.00 (m, 1 H), 2.31−2.35 (m, 1 H), 2.80−
2.83 (m, 1 H), 3.55 (s, 3 H), 5.86 (s, 1H), 6.868−6.871(d, J = 1.2 Hz,
1H), 6.98−6.99(d, J = 1.2 Hz, 1H).; 13C NMR (100 MHz, CDCl3) δ =
27.4, 27.6, 28.5, 30.2, 32.3, 33.2, 35.9, 47.7, 109.7, 122.3, 129.0, 140.8,
144.9; HRMS (EI) (m/z) calcd. for C15H24N2S 264.1660, found
264.1662. Elemental analysis calcd for C15H24N2S: C 68.13; H 9.15; N
10.59; S 12.13. Found: C 68.13; H 9.15; N 10.59; S 12.13.
hexane) provided 3b as a colorless oil (0.093 g, 73% yield): H NMR
(400 MHz, CDCl3) δ = 0.83−0.91 (m, 12 H), 0.95−1.25 (m, 7 H),
1.46−1.61 (m, 2 H), 1.70−1.88 (m, 3 H), 1.98−2.05 (m, 1 H), 2.27−
2.33 (m, 1 H), 2.43−2.49 (m, 1 H), 2.59−2.65 (m, 1 H), 2.79−2.83
(m, 1 H), 5.54 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ = 11.3, 18.7,
27.6, 27.7, 28.5, 28.9, 30.1, 32.4, 35.2, 36.3, 41.4, 48.0, 115.3, 141.3.
(Cyclohexylidenemethyl)(dodecyl)sulfane 3c (Table 2, Entry
2).12e Following the general procedure for Table 2, using
iodomethylenecyclohexane (0.122 g, 0.55 mmol) and 1-dodecanethiol
(0.120 mL, 0.5 mmol), and then purification by column chromatog-
raphy (SiO2, hexane) provided 3c as a colorless oil (0.133 g, 90%
1
yield): H NMR (400 MHz, CDCl3) δ = 0.88 (t, J = 6.8 Hz, 3 H),
1.26−1.51 (m, 24 H), 1.53−1.62 (m, 2 H), 2.13−2.14 (m, 2 H), 2.24−
2.26 (m, 2 H), 2.60 (t, J = 7.6 Hz, 2 H), 5.57 (s, 1 H); 13C NMR (100
MHz, CDCl3) δ = 14.1, 22.7, 26.4, 27.0, 28.2, 28.6, 29.2, 29.3, 29.5,
29.61, 29.63, 30.1, 30.3, 31.9, 34.0, 36.4, 115.0, 141.9.
Benzyl((4-tert-butylcyclohexylidene)methyl)sulfane 3j
(Table 2, Entry 9).12e Following the general procedure for Table 2,
using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a, 0.153 g, 0.55
mmol) and phenylmethanethiol (0.059 mL, 0.5 mmol), and then
purification by column chromatography (SiO2, hexane) provided 3j as
Phenylthiomethylenecyclohexane 3d (Table 2, Entry 2).7b
Following the general procedure for Table 2, using iodomethylene-
cyclohexane (0.122 g, 0.55 mmol) and thiophenol (0.05 mL, 0.5
mmol), and then purification by column chromatography (SiO2,
1
a pink oil (0.051 g, 37% yield): H NMR (400 MHz, CDCl3) δ =
0.80−1.27 (m, 12 H), 1.62−1.81 (m, 3 H), 1.98−2.03 (m, 1 H), 2.23−
2.27 (m, 1 H), 2.74−2.76 (m, 1 H), 3.78 (s, 2 H) 5.57 (s, 1 H), 7.20−
7.30 (m, 5 H); 13C NMR (100 MHz, CDCl3) δ = 27.5, 27.7, 28.8,
30.2, 32.4, 36.3, 38.4, 47.9, 113.0, 126.8, 128.3, 128.8, 138.5, 144.4.
((4-tert-Butylcyclohexylidene)methyl)(cyclohexyl)sulfane 3k
(Table 2, Entry 10).12e Following the general procedure for Table 2,
using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a, 0.153 g, 0.55
mmol) and cyclohexanethiol (0.062 mL, 0.5 mmol), and then
purification by column chromatography (SiO2, hexane) provided 3k
as a white solid (0.076 g, 57% yield): mp 44−45 °C (lit.12e 44−45
°C); 1H NMR (400 MHz, CDCl3) δ = 0.83−0.90 (s, 9 H), 0.98−1.18
(m, 3 H), 1.23−1.41 (m, 5 H), 1.60−1.87 (m, 6 H), 1.97−2.07 (m, 3
H), 2.30−2.34 (m, 1 H), 2.68−2.74 (m, 1 H), 2.81−2.85 (m, 1 H),
5.64 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ = 25.7, 26.1, 27.6, 27.8,
28.9, 30.2, 32.4, 33.7, 36.4, 45.6, 48.0, 112.7, 142.7.
(Cyclopentylidenemethyl)(dodecyl)sulfane 3l (Table 2, Entry
11). Following the general procedure for Table 2, using
(iodomethylene)cyclopentane (0.114 g, 0.55 mmol) and 1-dodeca-
nethiol (0.12 mL, 0.5 mmol), and then purification by column
chromatography (SiO2, hexane) provided 3k as a colorless oil (0.104 g,
74% yield): 1H NMR (400 MHz, CDCl3) δ = 0.88 (t, J = 6.8 Hz, 3 H),
1.25−1.39 (m, 24 H), 2.19−2.21 (m, 2 H), 2.23−2.31 (m, 2 H), 2.61−
2.64 (m, 2 H), 5.72 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ = 14.1,
22.7, 26.3, 26.8, 28.7, 29.2, 29.3, 29.5, 29.58, 29.61, 29.64, 30.4, 30.7,
31.9, 34.05, 34.07, 113.3, 144.5; HRMS (EI) (m/z) calcd. for
C12H13ClS 282.2381, found 282.2377.
(Cyclopentylidenemethyl)(dodecyl)sulfane 3m (Table 2,
Entry 12). Following the general procedure for Table 2, using
(iodomethylene)cyclopentane (0.114 g, 0.55 mmol) and 4-chlor-
obenzenethiol (0.072 g, 0.5 mmol), and then purification by column
chromatography (SiO2, hexane) provided 3m as a colorless oil (0.050
g, 45% yield): 1H NMR (400 MHz, CDCl3) δ = 1.56−1.76 (m, 4 H),
2.35−2.36 (m, 2 H), 2.41−2.42 (m, 2 H), 5.97 (s, 1 H), 7.19−7.26
(m, 4 H); 13C NMR (100 MHz, CDCl3) δ = 26.1, 26.7, 31.1, 34.3,
109.7, 128.8, 128.9, 131.3, 136.1, 152.3; HRMS (EI) (m/z) calcd. for
C12H13ClS 224.0427, found 224.0424.
(4-Chlorophenyl)(cyclopentenylmethyl)sulfane 3m′ (Table
2, Entry 12). Following the general procedure for Table 2, using
(iodomethylene)cyclopentane (0.114 g, 0.55 mmol) and 4-chlor-
obenzenethiol (0.072 g, 0.5 mmol), and then purification by column
chromatography (SiO2, hexane) provided 3m′ as a colorless oil (0.056
g, 50% yield): 1H NMR (400 MHz, CDCl3) δ = 1.86−1.91 (m, 2 H),
2.27−2.30 (m, 2 H), 2.34−2.38 (m, 2 H), 3.59(s, 2 H), 5.97 (t, J = 2.0
Hz, 1 H), 7.23−7.25 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ =
23.5, 32.5, 34.0, 35.3, 128.7, 128.8, 130.9, 131.9, 135.3, 139.2; HRMS
(EI) (m/z) calcd. for C12H13ClS 224.0427, found 224.0420.
1
hexane) provided 3d as a yellow oil (0.076 g, 58% yield): H NMR
(400 MHz, CDCl3) δ = 1.58 (s, 6 H), 2.25−2.28 (m, 2 H), 2.36−2.39
(m, 2 H), 5.88 (s, 1 H), 7.13−7.17 (m, 1 H), 7.26−7.32 (m, 4 H); 13C
NMR (100 MHz, CDCl3) δ = 26.4, 27.3, 28.3, 30.3, 36.6, 111.8, 125.4,
127.6, 128.8, 137.6, 148.2.
tert-Butyl((4-tert-butylcyclohexylidene)methyl)sulfane 3e
(Table 2, Entry 4).12e Following the general procedure for Table 2,
using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a, 0.153 g, 0.55
mmol) and 2-methylpropane-2-thiol (0.0587 mL, 0.5 mmol), and then
purification by column chromatography (SiO2, hexane) provided 3e as
a colorless oil (0.080 g, 67% yield): 1H NMR (400 MHz, CDCl3) δ =
0.85 (s, 9 H), 0.97−1.18 (m, 3 H), 1.33 (s, 9 H), 1.68−1.88 (m, 3 H),
2.05−2.13 (m, 1 H), 2.34−2.39 (m, 1 H), 2.93−2.99 (m, 1 H), 5.77
(s, 1 H); 13C NMR (100 MHz, CDCl3) δ = 27.6, 28.0, 29.1, 30.2, 30.8,
32.4, 36.8, 43.6, 48.1, 110.7, 146.3.
((4-tert-Butylcyclohexylidene)methyl)(phenyl)sulfane 3f
(Table 2, Entry 5).12e Following the general procedure for Table 2,
using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a, 0.153 g, 0.55
mmol) and thiophenol (0.051 mL, 0.5 mmol), and then purification by
column chromatography (SiO2, hexane) provided 3f white solid
(0.091 g, 70% yield): mp 54−55 °C (lit.12e 54−55 °C); 1H NMR (400
MHz, CDCl3) δ = 0.87 (s, 9 H), 1.02−1.24 (m, 3 H), 1.79−1.92 (m, 3
H), 2.12−2.18 (m, 1 H), 2.42−2.47 (m, 1 H), 2.97−3.02 (m, 1 H),
5.87 (s, 1 H), 7.12−7.17 (m, 1 H), 7.25−7.32 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ = 27.6, 28.0, 29.0, 30.2, 32.4, 36.5, 48.0, 111.5,
125.4, 127.7, 128.8, 137.6, 147.9.
((4-tert-Butylcyclohexylidene)methyl)(4-methoxyphenyl)-
sulfane 3g (Table 2, Entry 6).12e Following the general procedure
for Table 2, using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a,
0.153 g, 0.55 mmol) and 4-methoxybenzenethiol (0.062 mL, 0.5
mmol), and then purification by column chromatography (SiO2,
hexane/EA = 15:1) provided 3g as a white solid (0.091 g, 63% yield):
mp 39−40 °C (lit.12e 39−40 °C); H NMR (400 MHz, CDCl3) δ =
1
0.86 (s, 9 H), 1.01−1.26 (m, 3 H), 1.76−1.91 (m, 3 H), 2.05−2.12
(m, 1 H), 2.34−2.39 (m, 1 H), 2.93−2.98 (m, 1 H), 3.75 (s, 3 H), 5.78
(s, 1 H), 6.82 (d, J = 9.2 Hz, 2 H), 7.26 (d, J = 9.2 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ = 27.5, 27.9, 28.9, 30.1, 32.4, 36.3, 48.0, 55.2,
113.9, 114.5, 127.7, 130.7, 144.8, 158.3.
((4-tert-Butylcyclohexylidene)methyl)(4-chlorophenyl)-
sulfane 3h (Table 2, Entry 7).12e Following the general procedure
for Table 2, using 1-(iodomethylidene)-4-tert-butyl-cyclohexane (1a,
0.153 g, 0.55 mmol) and 4-chlorobenzenethiol (0.072 g, 0.5 mmol),
and then purification by column chromatography (SiO2, hexane)
1
provided 3h as a colorless oil (0.132 g, 90% yield): H NMR (400
MHz, CDCl3) δ = 0.86 (s, 9 H), 1.01−1.21 (m, 3 H), 1.81−1.92 (m, 3
H), 2.10−2.17 (m, 1 H), 2.41−2.47 (m, 1 H), 2.95−2.99 (m, 1 H),
5.81 (s, 1 H), 7.18−7.24 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ =
General Procedure for Table 3, Entries 1−6 (Method A). A 4
mL vial, sealed and equipped with a magnetic stirrer bar, was charged
E
dx.doi.org/10.1021/jo3008397 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
with KOt-Bu (0.112 g, 1.0 mmol), FeCl3 (0.008 g, 0.05 mmol), and L1
(0.029 g, 0.05 mmol) under a nitrogen atmosphere. The vial was
covered with a rubber septum, and alkenyl bromide (0.55 mmol), alkyl
or aryl thiol (2, 0.5 mmol), and DMF (0.5 mL) were added by syringe
under a nitrogen atmosphere. The septum was then replaced by a
screw cap containing a Teflon-coated septum, and the reaction vessel
was heated at 135 °C. After stirring at this temperature for 24 h, the
heterogeneous mixture was cooled to room temperature and diluted
with ethyl acetate (20 mL). The resulting solution was filtered through
a pad of silica gel and then washed with ethyl acetate (20 mL) and
concentrated to give the crude material, which was then purified by
column chromatography on silica gel to yield product 5.
(chloromethylidene)-4-tert-butyl-cyclohexane (0.103 g, 0.55 mmol)
and 1-dodecanethiol (0.120 mL, 0.5 mmol), and then purification by
column chromatography (SiO2, hexane) provided 3a as a colorless oil
(0.056 g, 32% yield).
((4-tert-Butylcyclohex-1-enyl)methyl)(phenyl)sulfane 3f′
(Table 3, Entry 8).7c Following the method B, using 1-
(chloromethylidene)-4-tert-butyl-cyclohexane (0.103 g, 0.55 mmol)
and thiophenol (0.05 mL, 0.5 mmol), and then purification by column
chromatography (SiO2, hexane) provided 5d as a colorless oil (0.081
g, 62% yield): 1H NMR (400 MHz, CDCl3) δ = 0.87 (s, 9 H), 1.11−
1.28 (m, 2 H), 1.71−1.88 (m, 2 H), 1.98−2.09 (m, 1 H), 2.13−2.26
(m, 2 H), 3.50 (s, 2 H), 5.59 (s, 1 H), 7.27−7.35(m, 5H); 13C NMR
(100 MHz, CDCl3) δ = 24.0, 26.9, 27.2, 28.7, 32.1, 41.7, 43.8, 125.8,
125.9, 128.6, 129.8, 132.8, 137.0.
(Cyclohexylidenemethyl)(dodecyl)sulfane 3c (Table 3, Entry
1).14 Following the method A, using bromomethylenecyclohexane
(0.073 mL, 0.55 mmol) and 1-dodecanethiol (0.120 mL, 0.5 mmol),
and then purification by column chromatography (SiO2, hexane)
provided 3c as a colorless oil (0.109 g, 74% yield).
((4-tert-Butylcyclohexylidene)methyl)(4-methoxyphenyl)-
sulfane 3g and 3g′ (Table 3, Entry 9).14 Following the method B,
using 1-(chloromethylidene)-4-tert-butyl-cyclohexane (1a, 0.103 g,
0.55 mmol) and 4-methoxybenzenethiol (0.062 mL, 0.5 mmol), and
then purification by column chromatography (SiO2, hexane/EA =
15:1) provided 3g and 3g′ isomer as a white solid (0.093 g, 64%
Phenylthiomethylenecyclohexane 3d (Table 3, Entry 2).7b
Following the method A, using bromomethylenecyclohexane (0.073
mL, 0.55 mmol) and thiophenol (0.05 mL, 0.5 mmol), and then
purification by column chromatography (SiO2, hexane) provided 3d as
a yellow oil (59 mg, 58% yield).
1
combined yield): H NMR (400 MHz, CDCl3) δ = 0.86 (s, 18 H, 3g
and 3g′ isomer), 1.01−1.25 (m, 6 H, 3g and 3g′ isomer), 1.58−2.44
(m, 10 H, 3g and 3g′ isomer), 2.92−2.98 (m, 1 H, 3g), 3.31−3.39 (m,
2 H, 3g′), 3.80 (s, 6 H, 3g and 3g′ isomer), 5.34 (m, 1 H, 3g′), 5.78 (s,
1 H, 3g), 6.80−6.87 (m, 4 H, 3g and 3g′ isomer), 7.26−7.33 (m, 4 H,
3g and 3g′ isomer); 13C NMR (100 MHz, CDCl3) δ = 24.1, 26.7, 27.1,
27.6, 27.9, 28.5, 28.9, 30.1, 32.1, 32.5, 36.3, 43.8, 43.9, 48.0, 113.8,
114.1, 114.5, 125.7, 130.8, 133.1, 134.0, 145.0, 158.9; HRMS (EI) (m/
z) calcd. for C18H26OS 290.1704, found 290.1707. Elemental analysis
calcd for C18H26OS: C 74.43; H 9.02; O 5.51; S 11.04. Found: C
74.33; H 8.89; O 5.39; S 10.74.
((4-tert-Butylcyclohexylidene)methyl)(4-chlorophenyl)-
sulfane 3h (Table 3, Entry 10).14 Following the method B, using 1-
(cholormethylidene)-4-tert-butyl-cyclohexane (1a, 0.103 g, 0.55
mmol) and 4-chlorobenzenethiol (0.072 g, 0.5 mmol), and then
purification by column chromatography (SiO2, hexane) provided 3h as
a colorless oil (0.054 g, 37% yield).
((4-tert-Butylcyclohex-1-enyl)methyl)(4-chlorophenyl)-
sulfane 3h′ (Table 3, Entry 10). Following the method B, using 1-
(cholormethylidene)-4-tert-butyl-cyclohexane (1a, 0.103 g, 0.55
mmol) and 4-chlorobenzenethiol (0.072 g, 0.5 mmol), and then
purification by column chromatography (SiO2, hexane) provided 3h′
as a colorless oil (0.049 g, 34% yield): 1H NMR (400 MHz, CDCl3) δ
=0.85 (s, 9 H), 1.12−1.24 (m, 2 H), 1.57−1.86 (m, 2 H), 1.97−2.23
(m, 3 H), 3.46 (s, 2 H), 5.53 (s, 1 H), 7.13−7.33 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ = 24.0, 26.9, 27.2, 28.6, 32.1, 42.0, 43.8, 126.2,
128.7, 131.4, 132.0, 132.6, 135.4; HRMS (EI) (m/z) calcd. for
C17H23ClS 294.1209, found 294.1203. Elemental analysis calcd for
C17H23ClS: C 69.24; H 7.86; S 10.87. Found: C 68.90; H 8.00; S
10.58.
tert-Butyl(cyclohexylidenemethyl)sulfane 5a (Table 3, Entry
3).14 Following the method A, using bromomethylenecyclohexane
(0.073 mL, 0.55 mmol) and 2-methylpropane-2-thiol (0.059 mL, 0.5
mmol), and then purification by column chromatography (SiO2,
1
hexane) provided 5a as a colorless oil (0.052 g, 57% yield): H NMR
(400 MHz, CDCl3) δ = 1.32 (s, 9 H), 1.48−1.54 (m, 6 H), 2.19−2.33
(m, 4 H), 5.78 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ = 26.5, 27.3,
28.4, 30.3, 30.8, 37.0, 43.6, 110.9, 146.7.
4-Chlorophenylthiomethylenecyclohexane 5b (Table 3,
Entry 4).14 Following the method A, using bromomethylenecyclohex-
ane (0.073 mL, 0.55 mmol) and 4-chlorothiophenol (0.087 g, 0.5
mmol), and then purification by column chromatography (SiO2,
1
hexane) provided 5b as a yellow oil (0.060 g, 50% yield): H NMR
(400 MHz, CDCl3) δ = 1.59 (br s, 6 H), 2.25−2.28 (m, 2 H), 2.36−
2.39 (m, 2 H), 5.82 (s, 1 H), 7.19−7.25 (m, 4 H); 13C NMR (100
MHz, CDCl3) δ = 26.3, 27.3, 28.3, 30.4, 36.6, 111.2, 128.7, 128.8,
131.2, 136.3, 149.4.
(Cyclopentylidenemethyl)(dodecyl)sulfane 3l (Table 3, Entry
5). Following the method A, using (bromomethylene)cyclopentane
(0.044 g, 0.55 mmol) and 1-dodecanethiol (0.120 mL, 0.5 mmol), and
then purification by column chromatography (SiO2, hexane) provided
3l as a colorless oil (0.093 g, 66% yield).
(Cyclopentylidenemethyl)(dodecyl)sulfane 3m (Table 3,
Entry 6). Following the method A, using (bromomethylene)-
cyclopentane (0.044 g, 0.55 mmol) and 4-chlorobenzenethiol (0.072
g, 0.5 mmol), and then purification by column chromatography (SiO2,
hexane) provided 3m as a colorless oil (0.037 g, 33% yield).
(4-Chlorophenyl)(cyclopentenylmethyl)sulfane 3m′ (Table
3, Entry 6). Following the method A, using (iodomethylene)-
cyclopentane (0.114 g, 0.55 mmol) and 4-chlorobenzenethiol (0.072 g,
0.5 mmol), and then purification by column chromatography (SiO2,
hexane) provided 3m′ as a colorless oil (0.044 g, 39% yield).
General Procedure for Table 3, Entries 7−10 (Method B). A 4
mL vial, sealed and equipped with a magnetic stirrer bar, was charged
with KOt-Bu (0.112 g, 1.0 mmol), FeCl3 (0.008 g, 0.05 mmol), and L1
(0.029 g, 0.05 mmol) under a nitrogen atmosphere. The vial was
covered with a rubber septum, and alkenyl chloride (0.55 mmol), alkyl
or aryl thiol (2, 0.5 mmol), and DMF (0.5 mL) were added by syringe
under a nitrogen atmosphere. The septum was then replaced by a
screw cap containing a Teflon-coated septum, and the reaction vessel
was heated at 135 °C. After stirring at this temperature for 30 h, the
heterogeneous mixture was cooled to room temperature and diluted
with ethyl acetate (20 mL). The resulting solution was filtered through
a pad of silica gel and then washed with ethyl acetate (20 mL) and
concentrated to give the crude material, which was then purified by
column chromatography on silica gel to yield product 5.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra for 1a−1c, 4c, and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cfalee@dragon.nchu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Science Council, Taiwan (NSC 99-2113-M-005-
004-MY2) and the National Chung Hsing University are
gratefully acknowledged for financial support. We also thank
Prof. Fung-E Hong (NCHU) for sharing his GC−MS
((4-tert-Butylcyclohexylidene)methyl)(dodecyl)sulfane 3a
(Table 3, Entry 7).14 Following the method B, using 1-
F
dx.doi.org/10.1021/jo3008397 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
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