A very active Cu-catalytic system for the synthesis of aryl, heteroaryl, and vinyl sulfides

Article abstract of DOI:10.1021/jo1004179

Figure presented cis-1,2-Cyclohexanediol (L3) has been shown to be an efficient and versatile bidentate O-donor ligand that provides a highly active Cu-catalytic system. It was more effective than diols such as trans-1,2-cyclohexanediol or ethylene glycol. This commercially available cis-1,2-cyclohexanediol ligand facilitated the Cu-catalyzed cross-coupling reactions of alkyl, aryl, or heterocyclic thiols with either alkyl, aryl, heterocyclic, or substituted vinyl halides. This new catalytic system promoted the mild and efficient stereo- and regiospecific synthesis of biologically important vinyl sulfides. The yields obtained using electron-rich substituted vinyl sulfides with this catalyst system are generally 75-98%. Most importantly, this singular catalyst system is extremely versatile and provides entry into a wide range of sulfides. This method is particularly noteworthy given its mild reaction conditions, simplicity, generality, and exceptional level of functional group tolerance.

Full text of DOI:10.1021/jo1004179

pubs.acs.org/joc
A Very Active Cu-Catalytic System for the Synthesis of Aryl, Heteroaryl,
and Vinyl Sulfides
M. Shahjahan Kabir, Michael Lorenz, Michael L. Van Linn, Ojas A. Namjoshi,
Shamim Ara, and James M. Cook*
Department of Chemistry and Biochemistry, University of Wisconsin—Milwaukee, Milwaukee,
Wisconsin 53201
capncook@uwm.edu
Received March 5, 2010
cis-1,2-Cyclohexanediol (L3) has been shown to be an efficient and versatile bidentate O-donor
ligand that provides a highly active Cu-catalytic system. It was more effective than diols such as trans-
1,2-cyclohexanediol or ethylene glycol. This commercially available cis-1,2-cyclohexanediol ligand
facilitated the Cu-catalyzed cross-coupling reactions of alkyl, aryl, or heterocyclic thiols with either
alkyl, aryl, heterocyclic, or substituted vinyl halides. This new catalytic system promoted the mild and
efficient stereo- and regiospecific synthesis of biologically important vinyl sulfides. The yields
obtained using electron-rich substituted vinyl sulfides with this catalyst system are generally
75-98%. Most importantly, this singular catalyst system is extremely versatile and provides entry
into a wide range of sulfides. This method is particularly noteworthy given its mild reaction
conditions, simplicity, generality, and exceptional level of functional group tolerance.
1. Introduction
as organic materials and intermediates.1-32 Recent reports
of the activity of aryl sulfides as anti-inflamatory agents and
for the treatment of Alzheimer’s and Parkinson’s disease or
The synthesis of vinyl and aryl sulfides has been an
important objective in organic synthesis since both motifs
are of value as important intermediates in the synthesis of
biologically and pharmaceutically active molecules, as well
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3626 J. Org. Chem. 2010, 75, 3626–3643
Published on Web 04/29/2010
DOI: 10.1021/jo1004179
r
2010 American Chemical Society

Kabir et al.
JOCArticle
as inhibitors for the treatment of human immunodeficiency
virus (HIV), asthma, and obstructive pulmonary disease
have demonstrated the potential of this class of com-
pounds.20-25 Additionally, increased interest in unsymme-
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SCHEME 1. Adverse Effect of Harsh Reaction Conditions on the Thioetherifcation of Electron-Rich (EDG) 3,5-Dimethoxyvinyl Iodides
with Thiols
vinyl sulfides via a cheap copper-catalytic method.82-92
Although a number of methods for the preparation of vinyl
sulfides are available in the literature, many are associated with
limitations.68-81 Among them, the most common is the addi-
tion of a thiol to an alkyne.93-96 This process takes place only
under radical conditions to afford the anti-Markovnikov
product as a mixture of regioisomers. Other methods involve
the use of transition-metal catalysts including Mo, Pd, Pt, Rh,
and Ru. Vinyl sulfides have also been prepared from the cross-
coupling of vinyl halides with Na or Li benzenethiolates or
their Sn analogues.19,97-104 This latter approach often requires
the use of strong bases, and furthermore, the synthesis of this
class of compounds via a Wittig approach can be problematic
because of the synthesis of the appropriate Wittig reagent.105
With the current renaissance in Ullmann coupling pro-
cesses over the past few years, the copper-catalyzed cross-
coupling reactions of thiols and aryl halides have been
shown to be a powerful tool in the formation of aryl C-S
bonds,52-67 while Cu-catalyzed formation of vinyl C-S
bonds has received less attention.
Although a number of methods are available in the litera-
ture, many of the drawbacks of the classical Ullmann coupling,
such as the use of a strong base or stoichiometric amounts
of Cu salts, have recently been overcome, and the resulting
application of Cu-catalyzed methods for the synthesis of
diaryl sulfides has recently appeared in the literature.52-67
However, these newer Cu-catalyzed methods still require
high temperatures, harsh reaction conditions, or longer
reaction times. Therefore, an active Cu-catalytic system
which is effective at milder or at room temperatures had yet
to be reported.68-81 Methods aimed at improving processes
with aryl halides have included Cu-catalytic systems which use
Cs2CO3 as a base, but they often result in significant amounts
of disulfides as side products. Recently, a few methods have
appeared which have shown great improvement in the synth-
esis of diaryl sulfides.52-54,61,90,106
Previous to the use of cis-1,2-cyclohexanediol (L3) as a
ligand, the most important Cu-catalytic method that had
appeared for the preparation of vinyl sulfides was that of
Venkataraman and co-workers, who employed a Cu-cataly-
tic system.19 However, this protocol required the use of an
air- and moisture-sensitive Cu catalyst, which must be
handled in a glovebox. In addition, this process required
harsh reaction conditions (i.e., temperatures of 115 °C and
reaction times of ∼4 h) unsuitable for the electron-rich
arylvinyl sulfides of interest here. In general, harsh reaction
conditions have proven to be inefficient for electron-rich
arylvinyl iodides in coupling reactions. In this regard, the
major side product of the coupling process with electron-rich
arylvinyl iodides is the elimination product, an arylacetylene,
illustrated in Scheme 1. Furthermore, while this method was
compatible with alkylvinyl iodides, it was incompatible with
many substrates, especially with unstable electron-rich vinyl
halides, as mentioned above.
Recently, we have begun to reinvestigate the use of copper
catalysis for the preparation of arylvinyl, alkylvinyl, aryl,
and heterocyclic sulfides employing milder conditions in
order to synthesize vinyl sulfides substituted with electron-
rich aryl rings in order to overcome the aforementioned
elimination illustrated in Scheme 1. Initial success was
obtained with the Cu-cis-1,2-cyclohexanediol system,
which resulted in a mild and efficient Cu-catalyzed stereo-
and regiospecific synthesis of arylvinyl and alkylvinyl sul-
fides from the corresponding vinyl iodides and thiols.105
Advantage of the mild reaction conditions, inexpensive
catalyst, and simple operational features of this method
has now been taken to extend this process to the preparation
of aryl and heterocyclic substituted sulfides, as well as vinyl
sulfides, from their respective iodide and bromide progeni-
tors. Illustrated below is the general, efficient, mild, and
operationally simple Cu-catalyzed formation of arylvinyl,
alkylvinyl, aryl, and heterocyclic substituted C-S bonds.
As mentioned earlier, electron-rich vinyl iodides provided
aryl acetylene side products under either strongly basic
conditions or at higher temperatures. To avoid this elimina-
tion sequence, it was necessary to employ milder reaction
conditions. Moreover, the expensive and less stable vinyl
iodides were also replaced with the cheaper and more stable
vinyl bromides as coupling partners, albeit the temperature
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2009, 131, 78.
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Kabir et al.
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required was higher in the case of the less reactive arylvinyl
bromides. In all cases, broad substrate scope was realized with
good to excellent yields. During the completion of this work,
Chaozhong Li et al. reported an interesting Cu-catalyzed
intramolecular S-vinylation of iodo vinyl thiols.107 A few other
approaches related to the Cu-catalytic process have been re-
ported in the last 2 years while our work was in progress.109-115
TABLE 1. Optimization of Cu-Catalyzed Coupling Reaction of
3,5-Dimethoxyphenylvinyl Iodide with Thiophenol
entry
catalyst
solvent
DMF
toluene
CuI/phena/PPh3 (1:1:2) toluene
base
HPLC yieldb,c (%)
2. Results and Discussion
1
2
CuI
CuI, phena (1:2)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
0
45a
65
63
68
72
63
99
64
72
93
91
94
2.1. Problems Encountered in the Synthesis of Electron-
Rich Vinyl Sulfides. As mentioned in the Introduction,
studies indicated that compounds which contain N-vinyl
heterocycles, arylvinyl ethers, and arylvinyl thioethers were
active against drug-resistant strains of tuberculosis, anthrax,
and many other strains of drug-resistant Gram-positive
bacteria including MRSA and VRE.20-25 Many of these
active agents required at least two or more electron-donating
groups (EDGs) on at least one of the aryl rings of the
molecule.20-25,32 In order to exhibit the most potent activity,
the location of these EDGs on these antibacterial agents
must contain the EDGs on ring A of their structural frame-
work, as illustrated by the two methoxy groups shown in
Scheme 1. This electron-rich substitution pattern is a funda-
mental requirement for the potent activity of this new class of
antibacterials.20-25,32 Furthermore, the most potent agents
contain a 3-hydroxy-5-methoxy pattern (see 5) in ring A
(Scheme 2).32
Initially, electron-rich 3-hydroxy-5-methoxystyryl phenyl
thioethers and a variety of 3,5-dimethoxy analogues (see 3,
Scheme 1) were prepared using the catalytic conditions of
Venkataraman (Table 1).19 These conditions proved to be
inefficient for the corresponding electron-rich arylvinyl iod-
ides since a significant amount of aryl acetylene side products
(approximately 30-35%) were observed in the reaction
mixture due to the elimination process caused by the harsh
reaction conditions.
3
4
CuI, L3 (1:1)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:2)
CuI, L3 (1:1)
toluene
toluene
i-PrOH
DME
5
6
7
8
DMF
DMA
9
10
11
12
13
1,4-dioxane K3PO4
DMF
DMF
DMF
Cs2CO3
K2CO3
K3PO4
aphen =1,10-phenanthroline. bHPLC yields. cThe reactions were
performed at least two times and the yields are the average of at least
two runs.
reaction of electron-rich 3,5-dimethoxyvinyl iodide 1 with
thiophenol 2 (Figure 1) was selected in order to assess the
catalytic activity of the best Cu-catalytic ligand-Cu complex
(i.e., ligand screen). The prototypical reaction conditions
utilized were 10 mol % of Cu(I)I, 20 mol % of the ligand, and
1.5 equiv of K3PO4 in reagent-grade DMF (without drying)
at 30-40 °C. The structures of these ligands (L1-L10) and
their resulting reaction yields are shown in Figure 1. Each
reaction was conducted at 30-40 °C for 4 h with 20 mol % of
ligand and 10 mol % of CuI. The yields of the desired vinyl
sulfides 3 were determined by HPLC. As reported by Buch-
wald et al.,8 the choice of the ligand can alter the selectivity of
the cross-coupling reaction greatly. The coupling of either
oxygen or nitrogen nucleophiles can be reversed by the
choice of the ligand (oxygen- or nitrogen-based). In our
estimation, the bidendate oxygen ligand rendered the copper
softer in the transition state so it would be more prone to
react with sulfur-based (soft nucleophile) substrates, which
turned out to be the case.
In addition to the harsh reaction conditions, it was felt the
use of a nitrogen-based bidentate ligand might also promote
the unwanted elimination due to slightly higher basicity of
the ligand. It had previously been reported that aryl acetyl-
ene formation occurred in the Cu-catalyzed cross-coupling
reactions of unfunctionalized arylvinyl halides when nitro-
gen-based bidentate ligands were employed.10
2.2. Ligand Screening for the Cu-Catalyzed Vinylation of
Thiols. A potential solution was envisioned by the use of
an alternative Cu-catalytic system which would work for
EDG-substituted substrates related to that of ring A in
Scheme 1 under mild conditions. Initially, the coupling
Ligands chosen for screening with CuI included O-based
bidentate ligands L1-L7 and L10 as well as mixed ligands L8
and L9 (Figure 1).52,53,105 The complex from the CuI- and
O-based bidentate ligand L3 clearly generated the most
active catalyst, affording full conversion to the arylvinyl
sulfide in less than 4 h at a temperature of only 40 °C. The
excellent catalytic activity of L3 with CuI was, presumably,
due to the proper geometry of the Cu catalyst itself and the
relatively weak coordination of the Cu-L3 complex. These
factors, coupled with the suitable electron density provided
by the substrate, presumably facilitated oxidative addition of
the vinyl functionality of the substrate, which eventually
resulted in the subsequent reductive elimination. Indeed,
the cis-diol L3 gave better yields than the corresponding
diols L1, L2, or L4, which reinforced the importance of
the aforementioned optimized coordination geometry of the
hydroxyl functions of L3 to the Cu metal cation. The trans-diol
L1 may have formed a tighter complex with Cu, which may
(107) Zhao, Q.; Li, L.; Fang, Y.; Sun, D.; Li, C. J. Org. Chem. 2009, 74,
459.
(108) Fernandez-Rodriguez, M. A.; Hartiwg, J. F. J. Org. Chem. 2009,
74, 1663.
(109) Yong, W.; Yang, B. V. Prog. Heterocycl. Chem. 2009, 21, 261–295.
(110) Reddy, V. P.; Swapna, K. K.; Kumar, A. V.; Rao, K. R. Synlett
2009, 17, 2783.
(111) Jiang, Y.; Quin, Y; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett.
2009, 11, 5250.
(112) Taylor, P. C. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2009,
105, 75.
(113) Luo, P.-S.; Wang, F. L.; Li, J.-H.; Tang, R.-Y.; Zhong, P. Synthesis
2009, 6, 921.
(114) Luo, P.-S.; Yu, M.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Tetrahedron
Lett. 2009, 50, 1066.
(115) Xu, H.-J.; Zhao, X.-Y.; Fu, Y.; Feng, Y.-S. Synlett 2008, 19, 3063.
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have retarded the oxidative addition step. More work is
required to determine why the cis-diol L3 was more efficient
than the trans-diol L1 or ethylene glycol L2. In addition, use of
the sterically hindered, electron-rich ligands L5, L6, and L7
resulted in lower yields. Ligands which have been successfully
employed for C-N (L4, L9, and L10) or C-C (L8) bond
formation by others52,53,105 also proved to be less effective
in the formation of vinylic C-S bonds. These ligands routinely
provided poor yields of the desired sulfides with increased
amounts of aryl acetylene. In these latter cases, the poor
results, presumably, occurred because of the high basicity of
the ligand, unfavorable coordination of the copper cation, or
disadvantageous electron density on the metal cation itself
due to an unfavorable Cu-L geometry.52,53,105 More work is
necessary to determine which plays a greater role.
2.3. Optimization and Establishment of Reaction Condi-
tions. Once the suitable catalytic system with ligand L3 was
established, an optimization study was conducted in order to
determine the most suitable reaction conditions for the afore-
mentioned electron-rich substrates. The experiments were con-
ducted using 10 mol % of Cu(I)I and 20 mol % of L3 with the
mild bases K2CO3, Cs2CO3, or K3PO4 with various solvents at
temperatures of 30-40 °C. These experiments employed the
newly developed Cu-L3 catalyst versus that which was re-
ported with the 1,10-phenanthroline ligand.52,53,105 The percent
formation of the vinyl sulfide was determined after 4 h by HPLC
(Table 1, entries 1-13).
Several reactions were carried out by changing the catalyst
loading and the concentration of the catalyst. The catalytic
conditions with CuI (10 mol %) and L3 (20 mol %) in dry
DMF in the presence of K3PO4 (1.5 equivalent) proved to be
the most efficient in the formation of the desired vinyl
sulfides. Moreover, DME, i-PrOH, and 1,4-dioxane proved
to be inefficient solvent systems at these lower temperatures
because these processes required longer reaction times or
higher temperature and produced a significant amount of
aryl acetylene side product. Since this reaction went, pre-
sumably, through ionic intermediates, we assumed a solvent
with a high dielectric constant would enhance the progress of
the reaction. This was supported by the results presented in
Table 1 (toluene, 2-propanol, DMF, DME, and 1,4-dioxane).
The most common bases employed for Cu catalysis were
screened and K3PO4 gave superior results compared to
Cs2CO3 or K2CO3 (Table 1, entries 8, 11, and 12). Although
the formation of aryl acetylene was observed in most cases, an
optimal system was developed in which the elimination pro-
duct (Table 1, entry 8) was not observed. It was noteworthy;
this catalytic system did not yield any homocoupled product
as well. As a final proof of concept with regard to this new
alternative Cu-L3 catalytic system, a comparison of the
previously reported nitrogen-based bidentate ligand 1,10-phe-
nanthroline was performed using traditional methods; the
yields of the new alternative Cu-L3 catalytic system proved
superior to those requiring the traditional 1,10-phenanthroline
ligand (Table 1, entries 2, 3, and 8).
2.4. Selectivity Issues for the Coupling of Arylvinyl Iodides
with Arylphenols versus Thiophenols. Initially, 3-hydroxy-5-
methoxyphenylvinyl sulfide analogues were of interest
(Scheme 2), since this appears in this series to be a funda-
mental requirement for selective inhibition of Gram-positive
bacteria.32 Therefore, the coupling of the unprotected
3-hydroxy-5-methoxyphenylvinyl iodide 4 with thiophenol
2 with the optimized Cu-catalytic system was carried out
(Scheme 2). The results (Scheme 2) of this key experiment
indicated that no intermolecular coupling with the phenolic
oxygen atom of 3-hydroxy-5-methoxyphenylvinyl iodide 4
had occurred. Instead, with the vinyl iodide 4, the important
chemoselectivity only with S-vinylation was demonstrated.
Although the formation of the desired vinyl sulfide 5 was
poor, a plausible explanation for the low yield of cross-
coupled product can be attributed to the presence of the base
in the reaction mixture which effected the deprotonation of
the phenolic O-H of the vinyl iodide and generated the basic
phenoxide ion. This phenoxide ion could accelerate the
FIGURE 1. Effect of the ligand on the coupling of arylvinyl iodides
with thiols. Reaction condtions: 3,5-dimethoxyphenylvinyl iodide
(1 mmol), PhSH (1.1 mmol), CuI (10 mol %), L3 (20 mol %), and
K3PO4 (1.5 mmol) in DMF (5 mL) at 40 °C for 4 h.
SCHEME 2. Selective Coupling of the Vinyl Iodide with Thiols vs Phenols
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SCHEME 3. Cu-Catalyzed Coupling of Protected 3-Hydroxy-5-methoxyvinyl Iodide with Thiophenol
TABLE 2. Comparison of the Reactivity of Vinyl Iodides vs Vinyl
formation of the elimination side product 3-hydroxy-
5-methoxyphenylacetylene 6 before the coupling reaction
could take place between the requisite 3-hydroxy-5-methoxy-
phenylvinyl iodide 4 and thiophenol 2 (Scheme 2). Therefore,
the side product, 3-hydroxy-5-methoxyphenylacetylene, ap-
peared as a major product because it effectively consumed the
vinyl iodide substrate. As expected, with this new method, the
chemoselectivity of S-vinylation over O-vinylation was readily
apparent; there was no product of intermolecular homocou-
pling obtained when unprotected 3-hydroxy-5-methoxyphe-
nylvinyl iodide 4 was subjected to the coupling process with
thiol 2.
Bromides, Vinyl Chlorides, Vinyl Tosylates, Vinyl Tiflates, and Vinyl
Boron Trifluoride Potassium Salts for the Cu-Catalyzed Cross-Coupling
with 2-Isopropylthiophenol
2.5. Requirement of the Protecting Group for (Phenolic C-3)
the Hydroxy Group of the Arylvinyl Iodide. The important
coupling of the 3-hydroxy-5-methoxyphenylvinyl iodide 4
with thiols by prevention of the unwanted elimination
process was achieved in excellent yield when the phenolic
hydroxyl group was protected as the tert-butyldiphenylsilyl
(TBDPS) function. When the coupling process was carried
out between this protected vinyl iodide 8 and thiophenol 2
using the optimized catalytic system (Cu-L3), as shown in
Scheme 3, a very high yield of the thioether 5 was realized (see
Scheme 3). In addition, upon completion of the coupling
process the silyl group was removed in the same vessel in 30
min when the coupled product was treated with TBAF H2O.
3
The one-pot coupling and deprotection steps occurred to
provide the 3-hydroxy-5-methoxy target 5 in an overall yield
of 95%. Ultimately, these experiments indicated that the
protection of the phenolic hydroxy group of 3-hydroxy-5-
methoxyphenylvinyl iodide 4 and subsequent deprotection
after the coupling process were required in order to accom-
plish successful cross-coupling reactions for the production
ofthese biologically activephenolicvinylsulfidesin highyield.
However, this was not necessary in the case of dimethoxy-
substituted systems which underwent the coupling process
with the Cu-L3 catalytic system in very high yields as well.
2.6.1. Comparison of the Reactivity of Vinyl Iodides, Bro-
mides, Chlorides, Tosylates, Borontrifluoride Salts, and Tri-
flates in the Cu-Catalyzed Synthesis of Vinyl Sulfides. To
compare reactivities, several vinyl halides which contained
either different halogen atoms or other vinyl electrophiles
were studied (Table 2). The coupling of various vinyl halides,
a vinyl tosylate, a vinyl borontrifluoride potassium salt, and
a vinyl triflate, were carried out using 2-isopropylthiophenol
10 as a model substrate. As typically observed in Cu-cata-
lyzed cross-couplings, the phenylvinyl iodides were more
reactive than their corresponding vinyl bromides in the
newly optimized catalytic system (Cu-L3). Full conversion
of phenylvinyl iodide 9 to the thioether 11 was observed in
less than 2 h at 40 °C, while the corresponding bromide 9a
took 15 h at 80 °C for the complete consumption of the
starting material. A slight variation in the yield of 91% from
the vinyl bromide as compared to the arylvinyl iodide (97%)
was observed in this case. It is important to reiterate here
aIsolated yields, the average of at least two runs. bThe starting
arylvinyl iodides contained ∼9-12% Z-isomer; this led to ∼9-12%
c
of the cis-isomer, reflected in the overall yield. The reaction mixture
was heated for 2 h at 40 °C. dThe reaction mixture was heated for 15 h
at 80 °C.
that vinyl bromides required higher temperatures and longer
reaction times when compared to the vinyl iodides. This may
have led to decomposition of some of the reactants in the case
of the bromide, resulted in the 91% yield as compared to the
97% yield in the case of vinyl iodides.
Unfortunately, phenylvinyl chloride, the vinylic tosylate,
and the vinylic boron trifluoride potassium salt did not
provide the desired cross-coupled product. The same result
was observed when a vinyl triflate was employed with the
same thiol (Table 2, entry 6). Analysis of this set of experi-
ments indicated that the catalytic system developed here could
be useful for synthesis of various vinyl sulfides from any
combination of vinyl iodides or bromides with various thiols.
2.6.2. Comparison of the Reactivity of Aryl Iodides, Bro-
mides, Chlorides, Triflates, and Tosylates in the Cu-Catalyzed
Synthesis of Diaryl Sulfides. To extend the scope of the newly
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SCHEME 4. Comparison of the Reactivity of Aryl Iodides vs
Aryl Bromides, Aryl Chlorides, Aryl Triflates, and an Aryl Boron
Trifluride Potassium Salt in the Cu-Catalyzed Cross-Coupling
with 4-tert-Butylthiophenol
TABLE 3. Cu-catalyzed Cross-Coupling of Electron-Rich (E)-3,5-Di-
methoxyvinyl Iodides with Aromatic, Aliphatic, and Heterocyclic Thiols
developed catalytic system (Cu-L3), various aryl halides, an
aryl triflate, and an aryl tosylate were chosen as substrates to
study the reactivity of the coupling process with 4-tert-
butylthiophenol 13 (Scheme 4). The optimized catalytic
system was applied to the above-mentioned system. The aryl
iodide reacted faster (6 h) and under milder conditions
(60 °C) as compared to the corresponding aryl bromide to
provide the desired diaryl sulfide, as expected. The aryl
bromide required an elevated temperature of 90-100 °C
and 15 h for the complete consumption of the starting
material to give the desired cross-coupled product 14. The
aryl chloride, aryl triflate, and aryl boron trifluoride salt did
not yield any cross-coupled product. The trend of reactivity
of this Cu-catalytic system with these different vinyl groups
and aryl groups led to further investigation with regard to the
substrate scope of the thiol moiety itself.
2.7. Scope of the Cu-Catalyzed Vinylation of Thiols. The
cross-coupling of a series of vinyl iodides with aromatic,
heteroaromatic, and aliphatic thiols was carried out using
the aforementioned optimized reaction conditions in combi-
nation with CuI and 1,2-cis-cyclohexanediol ligand L3 as a
catalyst system. The results are summarized in the subse-
quent sections (see Tables 3-7).
2.7.1. Scope of the Cu-Catalyzed Vinylation of Electron-
Rich Vinyl Iodides with Various Thiols. The reactions of
aromatic thiols with electron-rich 3,5-dimethoxyphenylvinyl
iodide 1 were conducted with the optimized catalyst loading
(10 mol % of CuI and 20 mol % of L3) at 30-40 °C for 0.5-
2 h. The coupling processes between 3,5-dimethoxyphenyl-
vinyl iodide and a broad range of aromatic thiols provided
good to excellent yields of the vinyl thioethers (Table 3,
entries 1-5). In all cases, the desired vinyl sulfides were
obtained under mild conditions (30-40 °C) with short
reaction times (0.5-4 h); moreover, no aryl acetylene or
homocoupled byproducts were observed. Analysis of the
data in Table 3 demonstrated the effective use of the newly
developed system to couple electron-rich vinyl iodides with
hindered ortho-substituted aryl thiols (Table 3, entries 4-5).
The base-sensitive ester group contained in the hindered
ortho aryl thiol remained intact and gave thioether 19 in
excellent yield (Table 3, entry 5) without hydrolysis of the
ester group. Examination of these results indicated that the
milder reaction conditions and shorter reaction times ren-
dered this method robust for substrates which contained
acid- or base-sensitive functional groups. The scope of this
coupling reaction to 3,5-dimethoxyphenylvinyl iodide 1 was
then extended to alkyl and heterocyclic substituted thiols. As
expected, alkyl thiols gave the cross-coupled product in
excellent yield but required slightly higher temperatures of
aIsolated yields, the average of at least two runs. bThe starting
arylvinyl iodides contained ∼9-12% of the Z-isomer, which led to
∼9-12% of the cis-isomer, reflected in the overall yield. cThe reaction
mixture was heated for 0.5-2 h at 30-40 °C. dThe reaction mixture was
heated for 8 h at 50-60 °C. eThe reaction mixture was heated for 2-4 h
at 40-50 °C.
40-50 °C and slightly longer reaction times of 2-4 h
(Table 3, entries 6, 8, and 9). Presumably, the nucleophile
generated from the alkyl thiol required a longer reaction time
(2-4 h) and elevated temperatures (40-50 °C) as compared
to aryl thiols (0.5-2 h and 30-40 °C). An exception was
observed in the case of the alkyl thiol, 6-mercapto-1-hexanol,
when reacted with 3,5-dimethoxyphenylvinyl iodide 1 to give
the desired cross-coupled thioether 21 (Table 3, entry 7).
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TABLE 4. Cu-catalyzed Cross-Coupling of Silyl-Protected
Electron-Rich (E)-3-tert-Butyldiphenylsilyloxy-5-methoxy Vinyl Iodides
with Aromatic, Aliphatic, and Heterocyclic Substituted Thiols
TABLE 5. Cu-catalyzed Cross-Coupling of Electron Poor (EWG) (E)-
3-Cyanophenylvinyl Iodides with Aromatic, Aliphatic, and Heterocyclic
Substituted Thiols
aIsolated yields, the average of at least two runs. bThe starting
arylvinyl iodides contained ∼9-12% Z-isomer; this led to ∼9-12%
c
of the cis-isomer, reflected in the overall yield. The reaction mixture
was heated for 0.5-2 h at 30-40 °C. dThe reaction mixture was heated
e
for 2-4 h at 40-50 °C. The reaction mixture was heated for 8 h at
50-60 °C.
material. This process gave 21 in 90% yield. Interestingly,
the same chemoselectivity for S-vinylation was observed for
O-vinylation. The heterocyclic thiols gave the corresponding
cross coupled products 24 and 25, respectively, in excellent
yield when reacted with the electron rich 3,5-dimethoxyaryl-
vinyl iodide 1 (Table 3, entries 10 and 11) as long as the
conditions of elevated temperature and a longer reaction
time (60 °C and 2-8 h) were employed.
2.7.2. Cu-Catalyzed Cross-Coupling of O-Protected Phe-
nolic Vinyl Iodides with Various Thiols. As described in
sections 2.4 and 2.5, the synthesis of the biologically active
3-hydroxy-5-methoxyvinyl sulfides was of interest here. The
difficulties and problems associated with the synthesis of this
class of vinyl sulfides have been described in sections 2.1 and
2.4 using previously reported methods.68-81 Because of these
difficulties, the inexpensive Cu-catalytic system (Cu-L3)
was employed to couple the silyl-protected 3-hydroxy-5-
methoxyphenylvinyl iodide 8 with aryl, alkyl, and heteroaryl
thiols because this Cu-ligand catalyst system required
aIsolated yields, the average of at least two runs. bThe starting
arylvinyl iodides contained ∼9-12% Z-isomer; this led to ∼9-12%
of the cis-isomer, reflected in the overall yield. cTreatment with
TBAF THF provided the desired phenol. dThe reaction mixture was
3
heated for 0.5-2 h at 30-40 °C. eThe reaction mixture was heated for 4 h
at 40-50 °C. fThe reaction mixture was heated for 8 h at 50-60 °C.
This coupling process required a temperature of 60 °C and a
reaction time of 8 h for complete consumption of starting
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TABLE 6. Cu-catalyzed Cross-Coupling of (E)-3-Cyclohexylvinyl
Iodides with Aromatic, Aliphatic, and Heterocyclic Substituted Thiols
TABLE 7. Cu-Catalyzed Cross-Coupling of (Z)-Ethyl-3-iodoacrylate
with Aromatic, Aliphatic, and Heterocyclic Thiols
aIsolated yields, the average of at least two runs. bThe reaction
mixture was heated for 2 h at 30-40 °C. cThe reaction mixture was
heated for 4 h at 40-50 °C.
(Table 4, entry 6). The alkyl thiol, cyclohexylmercaptan, gave
excellent yields of 34 when reacted with the silyl-protected
3-hydroxy-5-methoxyphenylvinyl iodide 8 with the optimized
catalytic system under the conditions of 50 °C for 4 h (Table 4,
entry 9). The scope of the coupling reaction of the silyl-
protected 3-hydroxy-5-methoxyvinyl iodide 8 with heterocyc-
lic thiols was also extended with the same Cu-L3 catalytic
system using the same amount of catalyst loading, as men-
tioned previously. This generated heterocyclic substituted
vinyl sulfides in good to excellent yields (Table 4, entries
10-13). The coupling process of only a few heterocyclic
thiols (Table 4, entries 10 and 11) required elevated tempera-
tures (60 °C) and longer reaction times (8 h). Gratifyingly,
no disulfide side products were observed in any of these
reactions.
The successful extension of this catalytic system, in parti-
cular, to the silyl-protected arylvinyl iodides, provided a
simple process to access the biologically active 3-hydroxy-
5-methoxystyrylthioaryl molecules required for potent anti-
microbial activity against Gram-positive bacteria including
anthrax, MRSA, VRE, and tuberculosis.32
2.7.3. Cu-Catalyzed Vinylation of E-Vinyl Iodides Substi-
tuted with Electron-Withdrawing Groups (EWG) with Thiols.
The efficiency of this Cu-catalytic system prompted evalua-
tion of coupling processes between electron-poor [arylvinyl
iodides which contained an electron-withdrawing group
(EWG)] arylvinyl iodides with various thiols. When the
aromatic A-ring in the arylvinyl iodide was substituted with
a cyano group at the 3-postion, 3-cyanophenylvinyl iodide
39, and subjected to the coupling process with a broad
spectrum of thiols including aryl, alkyl, and heterocyclic
aIsolated yields, the average of at least two runs. bThe starting
arylvinyl iodides contained ∼9-12% Z-isomer; this led to ∼9-12%
of the cis-isomer, reflected in the overall yield.
milder reaction conditions than the more classical meth-
ods.19 It is noteworthy to mention that at higher tempera-
tures (>90 °C) the silyl group was cleaved and the phenolic
group that was generated was responsible for the low yields
of the desired thioether, as mentioned in sections 2.4 and 2.5
(Scheme 2) in part due to the formation of the arylacetylene
side product. Therefore, the separation of the desired vinyl
sulfide from unwanted acetylene 6 side product became
difficult. In addition, the desired vinyl sulfides were obtained
in only poor yields. In the presence of Cu-L3 the silyl-
protected 3-hydroxy-5-methoxyvinyl iodide reacted with
aryl thiols under milder conditions (30-40 °C, 0.5-2 h).
The catalyst loading was typically the same as that used in the
earlier optimized conditions (i.e., 10 mol % of CuI and 20
mol % of L3). The coupled products (Table 4, entries 1-13)
were obtained without cleavage of the silyl protecting group.
Upon completion of the coupling reaction, the deprotection
was carried out in the same reaction vessel by treatment with
tert-butylammonium fluoride hydrate (TBAF H2O) for 30
3
min at room temperature. Ultimately, the desired vinyl
sulfides were obtained in high yields (Table 4, entries 1-8).
Excellent yields of the coupling product were obtained even
when hindered ortho-substituted aryl thiols were employed
(Table 4, entry 5). Base-sensitive ester groups which were
contained in the ortho-hindered thiols also gave good yields
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thiols, this also provided high yields of the corresponding
thioethers. The catalyst loading was kept constant using the
aforementioned optimized reaction conditions. As expected,
the 3-cyanophenylvinyl iodide 39 gave the coupled arylvinyl
sulfides when treated with aryl thiols at 30-40 °C for 0.5-2 h
(Table 5, entries 1-4). The thiols which were ortho-hindered
or carried base sensitive functional groups again gave high
yields of the corresponding vinyl sulfides under the same
reaction conditions (Table 5, entries 5 and 6). Moreover, the
electron poor 3-cyanophenylvinyl iodide 39 was subjected to
coupling with alkyl thiols and heterocyclic thiols. The alkyl
thiol, 2-methylbutanethiol, produced the corresponding
coupled vinyl sulfide 46 in excellent yield at 40-50 °C in
4 h (Table 5, entry 7), while 6-mercapto-1-hexanol gave the
chemoselective S-vinylated product 47 at 60 °C in 8 h
(Table 5, entry 8). Heterocyclic substituted thiols gave the
corresponding vinyl sulfides when subjected to the Cu-
catalyzed coupling reaction with 3-cyanophenylvinyl iodide
39 at 60 °C, albeit a longer reaction time of 4-8 h (Table 5,
entries 9 and 10) was required.
well when the Z-vinyl iodide 60 was subjected to coupling
with aryl-, alkyl-, or heterocyclic-substituted thiols (Table 7,
entries 1-7). Electron-rich, electron-poor, and ortho-sub-
stituted hindered aromatic thiols gave excellent yields with
full retention of double bond geometry when the reaction
was carried out at 30-40 °C over a 2 h period (Table 7,
entries 1-3). As expected from previous results, alkyl and
heterocyclic thiols gave the corresponding vinyl sulfides at
40-50 °C in 4 h (Table 7, entries 4-7). In all cases, the
catalyst loading, base, and solvent were the same as the
optimized conditions previously described.
2.8. The Synthesis of Diaryl Sulfides from the Cu-Catalyzed
Coupling of Aryl Iodides and Thiols. As referenced in the
Introduction, the metal-catalyzed coupling of aryl halides
with thiols was reported in the past few years and has been
noted.53 In addition, the application of the new catalytic
system has been applied to the synthesis of diaryl sulfides and
was described in a previous section (2.6.2, Scheme 3) from
the coupling of aryl halides with thiols. Encouraged by the
earlier results which concerned the coupling of vinyl halides
with thiols using the Cu-L3 catalytic system, attempts were
undertaken to extend the scope of this reaction to include the
synthesis of diaryl sulfides from the corresponding aryl
iodides as well as bromides. Analysis of some reports indi-
cated diaryl sulfides are of significance in the pharmaceutical
industry.108 The classical Ullmann-type Cu-catalyzed ap-
proach has been employed over the past few years for the
synthesis of diaryl sulfides. Many of these approaches usual-
ly require either harsh reaction conditions or substrates with
chelating functional groups in the ortho position. The most
recent reports of the synthesis of diaryl sulfides which are
Cu-catalyzed require either fairly harsh reaction conditions,
a strong base such as NaO-t-Bu at 110 °C as in the case of
Venkataraman,60 or longer reaction times (18-22 h) as in
the case of Buchwald.17 Other routes lack efficiency and
require the use of polyfunctionalized substrates which are
cumbersome.105
To address the aforementioned issues, the new Cu-cataly-
tic system was employed with various functionalized aryl
iodides in combination with a nucleophilic thiol substrate.
These reactions of aryl iodides were conducted between 60
and 80 °C for 2-8 h depending on the requirement of each
substrate (see Table 8). In the cases of functionalized aryl
iodides, the reaction went to completion within 2-4 h, while
for heteroaryl-substituted aryl iodide substrates the coupling
process required 6-8 h to finish. The coupling of a wide
range of functionalized aryl iodides which contained poten-
tially reactive ketones (CO), free anilino (NH2), phenolic
(OH), ester (COOR), ether (C-O-C), or alkyl moieties took
place efficiently to form the corresponding diaryl sulfides in
good to excellent yields (Table 8, entries 1-8). Again, the
base-sensitive ester group (Table 8, entry 4) was maintained
and gave the corresponding coupling product, diaryl sulfide
71, in excellent yield. This process required a relatively
shorter time (4 h) which minimized the hydrolysis of the
ester group in the coupled product. The chemoselectivity of
the S-nucleophile over the O-nucleophile and the relative
reactivity of the iodo- and bromoaryl derivatives was clearly
demonstrated (Table 8, entries 6 and 7). The phenolic aryl
iodide gave the coupled product 73 only with the thiol as the
sole coupling product, instead of any products generated from
the intermolecular coupling at oxygen between two molecules
To date, the coupling process with arylvinyl iodides which
contained either EDG or EWG groups underwent the Cu-
catalyzed coupling reaction with various thiols in high yield.
In general heterocyclic thiols are not as reactive as aryl thiols.
Any combination of an arylvinyl iodide with an alkyl or
heterocyclic substituted thiol required slightly higher tem-
peratures and slightly longer reaction times, albeit the yields
were still very good.
2.7.4. The Cu-Catalyzed Vinylation of E-Alkylvinyl Iodides
with Thiols. Since the earlier focus had concerned only
coupling of aromatic vinyl iodides, it was now decided to
extend this process to the coupling of alkylvinyl iodides with
thiols. The goal remained to broaden the substrate scope and
the application of this Cu-catalytic system; hence the cou-
pling between alkylvinyl iodides and various thiols was
explored to prepare the corresponding alkylvinyl sulfides.
The readily available alkylvinyl iodide, cyclohexylvinyl io-
dide 50, was chosen as a standard alkylvinyl iodide for the
coupling with various thiols. The ability to couple such an
alkylvinyl iodide with thiols was investigated using aryl,
alkyl and heterocyclic substituted thiols under the following
reaction conditions: optimized catalyst loading [CuI 10 mol
% and L3 20 mol %, temperature of 40-50 °C for 2-4 h].
Electron rich, electron poor, and ortho-hindered aryl thiols,
alkyl thiols, as well as heterocyclic substituted thiols all gave
alkylvinyl thioethers in good to excellent yields ranging from
88 to 98% (Table 6, entries 1-9). To the best of our knowl-
edge, no Cu-catalytic systems have been published to date,
with regard to vinylations of thiols which operate under such
mild reaction conditions and work for both arylvinyl iodides
and alkylvinyl iodides, which employ nearly the same sub-
strate profile with such a wide variety of functionalized
thiols.
2.7.5. Cu-Catalyzed Vinylation of Z-Alkylvinyl Iodides
with Thiols. The retention of regio- and stereochemistry in
all products was observed in the cases of E-arylvinyl iodides.
To ensure the coupling reaction proceeded in a regio- and
stereospecific fashion, the coupling reaction was investigated
using an electron-poor Z-vinyl iodide 60 which contained a
base-sensitive group (ethyl cis-3-iodoacrylate) with various
thiols. The results are summarized in Table 7. Analysis of
the results indicated that the Cu-L3 catalytic system worked
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TABLE 8. Copper-Catalyzed Cross-Coupling of Various Aryl and Heterocyclic Substituted Iodides with Aromatic, Aliphatic, and Heterocyclic Thiols
aIsolated yields, the average of at least two runs. bThe reaction mixture was heated for 2-4 h at 60-70 °C. cThe reaction mixture was heated for 4-6 h
at 60-70 °C. dThe reaction mixture was heated for 8 h at 80 °C.
of the phenolic aryl iodide (Table 8, entry 6). This result clearly
demonstated the chemoselective nature again of this reaction
for the coupling of thiols and phenolic aryl iodides. A coupling
reaction between a bromo-substituted aryl iodide and aryl thiol
also gave only the intended coupling product with no homo-
coupling regardless of the respective iodo and thiol progenitors.
In essence, no unintended side products were observed despite
the presence of the competing bromo functionality and thiols
(Table 8, entry 7). Analysis of these results clearly differentiated
the relative reactivity of bromo versus iodo groups and under-
scores the strong iodo selectivity of the reaction.
The next extension of this Cu-L3 mediated process in-
volved application of this protocol for the coupling of ortho-
substituted aryl iodides and aryl thiols. As indicated in
Table 8 (entires 9-12), the presence of functional groups in
the ortho position of both aryl iodides and thiols was well
tolerated. Substrates which contained o-hydroxymethyl,
o-methyl, o-isopropyl, and o-carboxymethyl groups gave
the corresponding diaryl sulfides 76-79, respectively, in
good to excellent yield (Table 8, entries 9-12). This demon-
strated, this catalytic method could be applied to both
electron-rich and electron-deficient substrates in the case of
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TABLE 9. Cu-Catalyzed Cross-Coupling of Phenylvinyl Bromide with
Various Aromatic Thiols
TABLE 10. Copper-Catalyzed Cross-Coupling of Aryl Bromides with
Various Aromatic Thiols
aIsolated yields, the average of at least two runs.
aIsolated yields, the average of at least two runs. bThe starting
arylvinyl iodides contained ∼9-12% Z-isomer, which led to ∼9-12%
of the cis-isomer, reflected in the overall yield.
tion of the experimental results indicated this catalytic system
could be applied to more stable and less expensive arylvinyl
bromides as well as aryl bromides compared to their iodo
counterparts. The results of these studies are summarized in
Tables 9 and 10.
either aryl iodides or thiols. The process was also extremely
tolerant in terms of steric hindrance, although the reaction
was, in some cases, slightly more demanding and required a
little longer time or an elevated temperature. For example, the
coupling of 2-isopropylthiophenol with 2-iodotoluene (Table 8,
entry 11, 78) required 4 h to go to completion (96% yield). In
comparison, the reaction of p-methoxythiophenol with 2-hy-
doxymethyliodobenzene took 8 h to finish but still gave the
desired diaryl sulfide 79 in 93% yield (Table 8, entry 12).
Alkanethiols were also found to be effective nucleophiles
with the optimized reaction conditions (Table 8, entries
13-15). tert-Butyl thiol and benzylmercpatan gave the
S-arylated products in excellent yields (Table 8, entries 14
and 15). In addition, the selective S-arylation was observed
when 6-mercapto-1-hexanol was used as a nucleophile
(Table 8, entry 13). Once again, the chemoselectivity of soft
sulfur nucleophiles over the hard oxygen nucleophiles was
clearly demonstrated. As seen in Table 8, entries 16 and 17,
heterocyclic-substituted thiols gave the corresponding cou-
pling product of the desired sulfides when reacted with aryl
iodides in good to excellent yields, although as typically
expected by now, these reactions required a longer reaction
time (8 h) and a slightly elevated temperature of 80 °C.
Studies on the scope of the coupling of heterocyclic aryl
iodides with electron-rich, electron-deficient, and ortho-
hindered aryl thiols as well as alkyl thiols were conducted
using the optimized reaction conditions (Table 8, entries
18-22). Again, very high yields were obtained in these cases
using a relatively short reaction time without formation of
any side products. All the reactions with heterocyclic-sub-
stituted aryl iodides were conducted at 80 °C for 6-8 h with
the same amount of catalyst loading (CuI, 10 mol % and L3,
20 mol %).
The studies were carried out using the Cu-L3 system and
indicated arylvinyl bromides coupled well with the electron-
rich, electron-poor, and ortho-hindered thiols when used
in combination with 10 mol % of CuI, 20 mol % of L3,
and a base K3PO4 (1.5 equiv). The results from these studies
provided arylvinyl sulfides in good to excellent yields
(Table 9). It is noteworthy to mention that the reaction with
arylvinyl bromides required elevated temperatures (70-
80 °C) as compared to those with arylvinyl iodides (40-
60 °C). Furthermore, as expected, the completion of the
reaction required a longer reaction time (15 h) for arylvinyl
bromides as compared to arylvinyl iodides (0.5-2) h. In
order to extend the scope of this catalytic system, the
synthesis of diaryl sulfides from the corresponding aryl
bromides was attempted as well. Again, the optimized
catalytic conditions proved to be very effective when using
aryl bromides to synthesize diaryl sulfides but again required
slightly elevated reaction temperatures and longer reaction
times (100-110 °C, 15 h), as compared to the corresponding
aryl iodides (60-80 °C, 2-8 h). The results of the coupling
reaction of aryl bromides with thiols are summarized in
Table 10. Once again, the yields of each reaction were
good to excellent with various thiols including electron-rich,
electron-poor, and ortho-hindered thiophenols.
2.10. AWorkingHypothesis of the Cu-Catalyzed Mechanistic
Cycle for the Synthesis of Sulfides. To date, a pathway for
palladium catalysis is better understood than the mechanism of
the corresponding copper catalytic systems. According to
recent mechanistic studies,52,53,106 two possible mechanistic
pathways may operate for the synthesis of these arylvinyl
sulfides and diaryl sulfides. Both pathways begin with chela-
tion of the CuI species by the 1,2-cis-cyclohexanediol ligand L3
and solvent (Figure 2) to form a CuI tetrahedral species. The
reactive CuI tetrahedral species is considered most likely in the
case of this reaction. Nucleophilic substitution of the halide by
the deprotonated thiol leads to a CuI tetrahedral complex
ligated with solvent, as illustrated in path 1. The subsequent
complexation followed by oxidative addition of an arylvinyl or
aryl halide generates a square planar CuIII complex (Figure 2).
2.9. The Synthesis of Diaryl Sulfides and Arylvinyl Sulfides
from the Cu-Catalyzed Coupling of Their Respective Bromides
and Thiols. As described in sections 2.6.1 (Table 1) and 2.6.2
(Scheme 3), the reactivity pattern of different vinyl halides and
other pseudo halides indicated that diaryl sulfides and arylvinyl
sulfides could also be synthesized from their respective bromo
derivatives. Therefore, processes with aryl bromides and aryl-
vinyl bromides were explored with this catalytic system for the
synthesis of the corresponding sulfides from thiols. Examina-
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FIGURE 2. Working hypothesis of the mechanistic cycle for the synthesis of vinyl sulfides.
After this oxidative addition, the delivery of the cross-coupled
product via reductive elimination occurs, which subsequently
regenerates the Cu(I) species to take part in a new catalytic
cycle. An alternative pathway (path 2, Figure 2) begins with the
ligation of the nucleophile by substitution of the solvent and
generation again of a CuI tetrahedral species. This is followed
by the deprotonation of the cationic thiol-CuI complex to
generate a neutral solvent-ligated CuI complex. This neutral
solvent-ligated CuI complex then, in turn, undergoes an
oxidative addition step, followed by a reductive elimination
similar to path 1. This second pathway (i.e., path 2) can
effectively be ruled out by following the recent mechanistic
studies of Buchwald, Liu, Hartwig, and others.52,53 It is
important to note that both mechanistic possibilities proceed
via Cu(I) and Cu(III).
tolerance in this system, in part, is due to these milder
reaction conditions. The relative reactivity for both vinyl
and aryl halides followed the conventional trend of: vinyl
iodide > vinyl bromide and aryl iodide > aryl bromide. The
use of less reactive vinyl or aryl chlorides and pseudo halides
did not prove to be effective for coupling with thiols when
subjected to the newly developed catalytic system. In the case
of electron-rich unstable vinyl iodides, the method gave
exclusively the desired arylvinyl sulfides in high yield without
any aryl acetylene side product or any other side product.
The same results were observed with aryl and alkylvinyl
halides.
4. Experimental Section
General Considerations. Copper(I) iodide (99.99% purity), lig-
ands L1-L10, and N,N-dimethylformamide (DMF) (anhydrous,
99.8% purity) were purchased from commercial sources. All thiols
were used as received from major laboratory chemical and biochemi-
cal supply firms without further purification. Cesium carbonate,
potassium phosphate, and potassium carbonate were purchased
from commercial suppliers and used as is. Silica gel (230-400 mesh)
chromatography was utilized for purification of products. 1H and
13C NMR data were obtained on a 300 or 500 MHz NMR
instrument with chemical shifts reported relative to TMS. Melting
points were recorded on a electrothermal melting point apparatus
and are uncorrected. Mass spectra and high-resolution mass spectra
were performed by the mass spectroscopic laboratory from three
different laboratories. The HRMS was performed by ESI on a PE
SCIEX QSTAR, by APCI on a LCQ-DECA, and by EI on a
GC-MS.
General Procedure A for the Synthesis of Aryl, Alkyl, and Vinyl
Sulfides (Tables 3 and 5-10). An oven-dried round-bottom flask
containing a magnetic stir bar was sealed with a rubber septum
and then evacuated and backfilled with argon (the sequence was
repeated three times) with cooling to rt. The round-bottom flask
was then charged with anhydrous potassium phosphate (1.5
equiv), copper(I) iodide (10 mol %), cis-1,2-cyclohexanediol
(20 mol %), and dry DMF (2 mL). The solution which resulted
was stirred for 5-10 min at rt. The reaction mixture turned a
light green color within 3-5 min. The reaction vessel was
evacuated and backfilled with argon one more time before
3. Conclusion
In summary, it has been shown that CuI-L3 complexes
generated from 1,2-cis-cyclohexanediol are highly efficient
catalysts for the coupling of vinyl, aryl, heteroaryl, and alkyl
halides with thiols. Most importantly, this singular catalyst
system is extremely versatile for the synthesis of a wide range
of sulfides including arylvinyl sulfides, diaryl sulfides, hete-
roaryl sulfides, and alkyl sulfides. This method is particularly
noteworthy given its mild reaction conditions, simplicity,
generality, and exceptional level of functional group tole-
rance. The catalyst can be handled in open air, although it
should be noted that all of the reaction vessels were evac-
uated and degassed when conducting the coupling reactions
in order to prevent the formation of disulfides due to
oxidation of starting thiols from the presence of air oxygen.
This might well be achieved by addition of an inhibitor such
as BHT to the reaction mixture. To the best of our knowl-
edge, none of the Cu-catalytic methods which have been
reported to date can operate under such mild conditions with
such broad substrate scope. In the case of vinyl iodides, the
regio- and stereochemistry of the vinyl sulfides was retained
as in the starting vinyl halides. The broad functional group
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Kabir et al.
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adding the thiol and the aryl, alkyl, or vinyl iodide. This
operation was done to prevent the formation of disulfides in
the presence of oxygen inside the reaction vessel. The appro-
priate thiol (1.2 equiv) was added to the reaction mixture
through a rubber septum and the mixture stirred for another
5 min at rt. The aryl or alkyl or vinyl iodide or bromide (1.0
equiv) of choice was dissolved in a minimum amount of dry
DMF and was added to the resulting reaction mixture through a
rubber septum. The contents of the reaction mixture were
allowed to stir at 30-110 °C for 0.5-15 h depending on the
substrate. The reaction mixture was then cooled to rt and
filtered through a pad of silica gel to remove insoluble residues.
The pad of silica gel was washed ethyl acetate (100 mL). The
combined filtrate was washed with brine (4 ꢀ 50 mL), dried
(Na2SO4), and concentrated in vacuo on a rotatory evaporator.
The concentrated crude oil was purified by flash column chro-
matography on silica gel using the eluent (2-10%) ethyl acetate
and hexane (depending on the substrate) to obtain the pure
product (75-98% yields).
cis-cyclohexanediol (8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52
mmol), and DMF (2.0 mL) were stirred at 30-40 °C to obtain
the thioether 16 (108 mg, 97% yield) as a colorless oil. Column
chromatography solvent (2-3% EtOAc in hexane) provided
pure 16. 1H NMR (300 MHz, CDCl3): δ 7.46-7.37 (4H, m), δ
6.90 (1H, d, J=15.4 Hz), δ 6.63 (1H, d, J=15.4 Hz), δ 6.51 (2H,
d, J=2.2 Hz), δ 6.39 (1H, t, J=2.3 Hz), δ 3.81 (6H, s), δ 1.35 (9H,
s). 13C NMR (75 MHz, CDCl3): δ 160.9, 150.5, 138.5, 131.2,
130.3, 127.7, 126.2, 125.1, 106.6, 103.9, 99.7, 55.3, 31.2. HRMS
(ESI) (M þ H)þ: calcd for C20H25O2S 329.1575, found 329.1580.
(E)-3-[2-(4-Chlorophenylsulfanyl)vinyl]-3,5-dimethoxyben-
zene (17) (Table 3, Entry 3). General procedure A was followed (30
min). Vinyl iodide 1 (100 mg, 0.34 mmol), 4-chlorobenzenethiol
(59.3 mg, 0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-cis-cyclohex-
anediol (8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52 mmol), and
DMF (2.0 mL) were stirred at 30-40 °C to obtain the thioether 17
(99 mg, 95% yield) as an off-white semisolid. Column chromatog-
raphy solvent (2-3% EtOAc in hexane) provided pure 17.1HNMR
(300 MHz, CDCl3):δ 7.35 (4H, d, J=2.8 Hz), δ6.83 (1H, d, J=15.4
Hz), δ 6.67 (1H, d, J=15.6 Hz), δ 6.51 (2H, d, J=2.2 Hz), δ 6.40
(1H, t, J=2.2 Hz), δ 3.82 (6H, s). 13C NMR (75 MHz, CDCl3): δ
160.9, 138.1, 133.0, 132.2, 131.1, 126.0, 123.3, 106.7, 104.1, 100.0,
55.3. HRMS (ESI) (M þ H)þ: calcd for C16H16ClO2S 306.0481,
found 306.0484
(E)-3-[2-(2-Isoproplyphenylsulfanyl)vinyl]-3,5-dimethoxyben-
zene (18) (Table 3, Entry 4). General procedure A was followed
(30 min). Vinyl iodide 1 (100 mg, 0.34 mmol), 2-isopropylben-
zenethiol (62.4 mg, 0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-
cis-cyclohexanediol (8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52
mmol), and DMF (2.0 mL) were stirred at 30-40 °C to obtain
the thioether 18 (104 mg, 97% yield) as a colorless oil. Column
chromatography solvent (2-3% EtOAc in hexane) provided
pure 18. 1H NMR (300 MHz, CDCl3): δ 7.46 (1H, d, J=7.8 Hz),
δ 7.38-7.28 (2H, m), δ 7.24-7.20 (1H, m), δ 6.85 (1H, d, J=15.4
Hz), δ 6.53-6.49 (3H, m), δ 6.38 (1H, t, J=2.2 Hz), δ 3.80 (6H,
s), δ 3.54-3.49 (1H, m), δ 1.28 (6H, d, J=6.8 Hz). 13C NMR (75
MHz, CDCl3): δ 160.9, 149.3, 138.6, 132.3, 131.9, 130.1, 128.0,
126.5, 125.8, 125.2, 103.9, 99.6, 55.2, 30.5, 23.4. HRMS (ESI)
(M þ H)þ: calcd for C19H23O2S 315.1419, found 315.1420.
(E)-2-[2-(3,5-Dimethoxyphenyl)vinylsulfanyl]benzoic Acid
Methyl Ester (19) (Table 3, Entry 5). General procedure A was
followed (2 h). Vinyl iodide 1 (100 mg, 0.34 mmol), 2-mercapto-
benzoic acid methyl ester (69 mg, 0.41 mmol), CuI (6.5 mg, 0.034
mmol), 1,2-cis-cyclohexanediol (8.0 mg, 0.069 mmol), K3PO4
(109 mg, 0.52 mmol), and DMF (2.0 mL) were stirred at 30-
40 °C to obtain the thioether 19 (94 mg, 84% yield) as a colorless
semisolid. Column chromatography solvent (2-3% EtOAc in
hexane) provided pure 19. 1H NMR (300 MHz, CDCl3): δ 8.08
(1H, d, J=7.8 Hz), δ 7.46-7.40 (2H, m), δ 7.28-7.22 (2H, m), δ
6.94 (2H, dd, J=15.2 Hz, J=23.8 Hz), δ 6.60 (1H, d, J=2.2 Hz),
δ 6.44 (1H, t, J=2.3 Hz), δ 4.01 (6H, s), δ 3.83 (3H, s). 13C NMR
(75 MHz, CDCl3): δ 166.8, 160.9, 140.3, 137.7, 136.4, 133.0,
131.4, 127.6, 125.8, 124.9, 122.1, 104.5, 100.3, 55.3, 52.3. HRMS
(ESI) (M þ Li)þ: calcd for C18H18O4SLi 337.1086, found
337.1082.
General Procedure B for the Synthesis of Vinyl Sulfides
(Table 4). An oven-dried round-bottom flask containing a
magnetic stir bar was sealed with a rubber septum and then
evacuated and backfilled with argon (the sequence was repeated
three times) while cooling to rt. The round-bottom flask was
then charged with anhydrous potassium phosphate (1.5 equiv),
copper(I) iodide (10 mol %), cis-1,2-cyclohexanediol (20 mol
%), and dry DMF (2 mL). The solution which resulted was
stirred for 5-10 min at rt.The reaction mixture turned a light
green color within 3-5 min. The reaction vessel was evacuated
and backfilled with argon one more time before addition of the
thiol and the vinyl iodide. This operation was done to prevent
the formation of disulfides in the presence of oxygen or moisture
inside the reaction vessel. The appropriate thiol (1.2 equiv) was
added to the reaction mixture through a rubber septum and the
mixture stirred for another 5 min at rt. The vinyl iodide (1.0
equiv) of choice in a minimum amount of dry DMF was added
to the resulting reaction mixture through a rubber septum. The
contents of the reaction mixture were heated to 30-60 °C for
0.5-8 h depending on the substrate. The reaction mixture was
then cooled to rt, and TBAF H2O (1.5 equiv) was added to the
3
reaction mixture. After being stirred at rt, the reaction mix-
ture was filtered through a pad of silica gel to remove insolu-
ble residues. The pad of silica gel was washed ethyl acetate
(100 mL). The combined filtrate was washed with brine (4 ꢀ
50 mL) and dried (Na2SO4) after which it was concentrated in
vacuo on a rotatory evaporator. The concentrated crude oil was
purified by flash column chromatography on silica gel using the
eluent (2-3%) ethyl acetate and hexane to obtain the pure
product (83-97% yields).
Characterization Data for Products Shown in Table 3.
(E)-3-[2-(Phenylsulfanyl)vinyl]-3,5-dimethoxybenzene (3) (Table 3,
Entry 1). General procedure A was followed (1 h). Vinyl iodide
1 (50 mg, 0.17 mmol), benzenethiol (22.5 mg, 0.2 mmol), CuI
(3.3 mg, 0.017 mmol), 1,2-cis-cyclohexanediol (4.0 mg, 0.034
mmol), K3PO4 (32 mg, 0.39 mmol), and DMF (2.0 mL) were
stirred at 30-40 °C to obtain the thioether 3 (44.4 mg, 96%
yield) as a colorless oil. Column chromatography solvent
(2-3% EtOAc in hexane) provided pure 3. 1H NMR (300
MHz, CDCl3): δ 7.47-7.28 (5H, m), δ 6.90 (1H, d, J = 15.4
Hz), δ 6.67 (1H, d, J=15.4 Hz), δ 6.52 (2H, d, J=2.2 Hz), δ 6.40
(1H, t, J=2.2 Hz), δ 3.82 (6H, s). 13C NMR (75 MHz, CDCl3): δ
161.0, 138.4, 131.3, 130.0, 129.1, 126.9, 124.2, 106.6, 104.0, 99.8,
55.3. HRMS (ESI) (M þ H)þ: calcd for C16H17O2S 273.0949,
found 273.0947.
(3,5-Dimethoxystyryl)(benzyl)sulfane (20) (Table 3, Entry 6).
General procedure A was followed (2 h). Vinyl iodide 1 (100 mg,
0.34 mmol), benzylthiol (51 mg, 0.41 mmol), CuI (6.5 mg, 0.034
mmol), 1,2-cis-cyclohexanediol (7.9 mg, 0.068 mmol), K3PO4
(108 mg, 0.51 mmol), and DMF (2.0 mL) were stirred at 40-
50 °C to obtain the thioether 20 (87 mg, 88% yield) as a colorless
oil. Column chromatography solvent (2-3% EtOAc in hexane)
1
provided pure 20. H NMR (300 MHz, CDCl3): δ 7.42-7.28
(5H, m), δ 6.75 (1H, d, J=15.4 Hz), δ 6.50-6.44 (3H, m), δ 6.35
(1H, t, J=2.3 Hz), δ 4.04 (2H, s), δ 3.81 (6H, s). 13C NMR (75
MHz, CDCl3): δ 160.9, 138.9, 137.0, 128.7, 128.6, 127.6, 127.3,
125.1, 103.7, 99.2, 55.2, 37.2. HRMS (ESI) (M þ H)þ: calcd for
C17H19O2S 287.1106, found 287.1112.
(E)-3-[2-(4-tert-Butylphenylsulfanyl)vinyl]-3,5-dimethoxyben-
zene (16) (Table 3, Entry 2). General procedure A was followed
(30 min). Vinyl iodide 1 (100 mg, 0.34 mmol), 4-tert-butylben-
zenethiol (68.2 mg, 0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-
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(E)-6-[2-(3,5-Dimethoxyphenyl)vinylsulfanyl]hexan-1-ol (21)
(Table 3, Entry 7). General procedure A was followed (8 h).
Vinyl iodide 1 (100 mg, 0.34 mmol), 6-mercaptohexan-1-ol (55
mg, 0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-cis-cyclohex-
anediol (8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52 mmol), and
DMF (2.0 mL) were stirred at 50-60 °C to obtain the thioether
21 (91 mg, 90% yield) as a colorless oil. Column chromatogra-
8.2 Hz), δ 7.80 (1H, d, J=8.0 Hz), δ 7.46 (1H, t, J=7.6 Hz) δ
7.37-7.26 (3H, m), δ 6.99 (1H, d, J=15.6 Hz), δ 6.63 (2H, d, J=
2.2 Hz), δ 6.47 (1H, t, J=2.2 Hz), δ 3.85 (6H, s). 13C NMR (75
MHz, CDCl3): δ 160.9, 153.5, 137.4, 136.6, 135.3, 126.2, 124.4,
121.9, 120.9, 118.0, 106.7, 104.8, 100.7, 55.4. HRMS (ESI)
(M þ H)þ: calcd for C17H16NO2S2 330.0622, found 330.0624.
Characterization Data for Products Shown in Table 4.
(E)-3-Methoxy-5-[2-(3-methoxyphenylsulfanyl)vinyl]phenol (26)
(Table 4, Entry 1). General procedure B was followed (1 h).Vinyl
iodide 8 (140 mg, 0.27 mmol), 3-methoxybenzenethiol (44.9 mg,
0.32 mmol), CuI (5.2 mg, 0.027 mmol), 1,2-cis-cyclohexanediol
(6.3 mg, 0.054 mmol), K3PO4 (86 mg, 0.41 mmol), and DMF
(2.0 mL) were stirred at 30-40 °C to obtain the thioether 26 (65 mg,
84% yield) as a colorless oil. Column chromatography solvent
(2-3% EtOAc in hexane) provided pure 26. 1H NMR (300
MHz, CDCl3): δ 7.30-7.25 (2H, m), δ 7.03-6.96 (2H, m), δ 6.88
(1H, d, J=15.4 Hz), δ 6.64 (1H, d, J=15.4 Hz), δ 6.49 (1H, t, J=
1.6 Hz), δ 6.45 (1H, t, J=13.6 Hz), δ 6.33 (1H, t, J=2.2 Hz), δ 4.90
(1H, s), δ 3.83 (3H, s), δ 3.80 (3H, s). 13C NMR (75 MHz, CDCl3):
δ 156.7, 138.7, 131.1, 129.9, 126.6, 124.1, 122.0, 115.0, 113.2, 112.8,
105.4, 104.4, 100.8, 55.3. HRMS (ESI) (M þ H)þ: calcd for
C16H17O3S 289.0898, found 289.0895.
(E)-3-Methoxy-5-[2-(4-methoxyphenylsulfanyl)vinyl]phenol (27)
(Table 4, Entry 2). General procedure B was followed (30 min to
1 h). Vinyl iodide 8 (100 mg, 0.27 mmol), 4-methoxybenzenethiol
(44.9 mg, 0.32 mmol), CuI (5.2 mg, 0.027 mmol), 1,2-cis-cyclohex-
anediol (6.3 mg, 0.054 mmol), K3PO4 (86 mg, 0.41 mmol), and
DMF (2.0 mL) were stirred at 30-40 °C to obtain the thioether 27
(74 mg, 95% yield) as a colorless oil. Column chromatography
solvent (2-3% EtOAc in hexane) provided pure 27. 1H NMR(300
MHz, CDCl3): δ 7.42 (2H, d, J=8.8 Hz), δ 6.93 (2H, d, J=8.8 Hz),
δ 6.81 (1H, d, J=15.4 Hz), δ 6.43 (1H, t, J=1.5 Hz), δ 6.38 (1H, d,
J=15.4 Hz), δ 6.38 (1H, t, J = 1.9 Hz), δ 6.29 (1H, t, J=2.2 Hz), δ
4.84 (1H, s), δ 3.85 (3H, s), δ 3. 78 (3H, s). 13C NMR (75 MHz,
CDCl3): δ 161.0, 159.6, 156.7, 138.9, 133.6, 129.3, 128.0, 126.8,
114.8, 105.2, 104.1, 100.4, 55.3. HRMS (ESI) (M þ H)þ, Calcd. for
C16H17O3S 289.0898; Found 289.0894.
1
phy solvent (3-5% EtOAc in hexane) provided pure 21. H
NMR (300 MHz, CDCl3): δ 6.73 (1H, m), δ 6.46 (2H, d, J=2.2
Hz), δ 6.42-6.36 (1H, m), δ 6.34 (1H, t, J=2.2 Hz), δ 3.81 (6H,
s), δ 3.70-3.64 (2H, m, J=7.3 Hz), δ 2.82 (2H, t, J=7.3 Hz), δ
1.75-1.36 (8H, m). 13C NMR (75 MHz, CDCl3): δ 160.9, 139.0,
126.4, 125.9, 103.5, 99.0, 62.7, 55.2, 32.5, 32.4, 29.2, 28.4, 25.2.
HRMS (ESI) (MþLi)þ: calcd for C16H24O3SLi 303.1606, found
303.1608.
(E)-1-(2-Cyclohexylsulfanylvinyl)-3,5-dimethoxybenzene (22)
(Table 3, Entry 8). General procedure A was followed (2 h).
Vinyl iodide 1 (100 mg, 0.34 mmol), cyclohexyl thiol (48 mg, 0.41
mmol), CuI (6.5 mg, 0.034 mmol), 1,2-cis-cyclohexanediol
(7.9 mg, 0.068 mmol), K3PO4 (108 mg, 0.51 mmol), and DMF
(2.0 mL) were stirred at 40-50 °C to obtain the thioether 22
(90 mg, 95% yield) as a colorless oil. Column chromatography
solvent (2-3% EtOAc in hexane) provided pure 22. 1H NMR
(300 MHz, CDCl3): δ 6.78 (1H, d, J=15.5 Hz), δ 6.53-6.43 (3H,
m), δ 6.37-6.34 (1H, m), δ 3.81 (6H, s), δ 3.04-2.97 (1H, m), δ
2.09-1.58 (5H, m) δ 1.53-1.28 (5H, m). 13C NMR (75 MHz,
CDCl3): δ 160.9, 139.1, 128.2, 124.8, 103.7, 99.1, 55.2, 45.2, 33.5,
25.9, 25.6. HRMS (ESI) (M þ H)þ: calcd for C16H23O2S
279.1419, found 279.1421.
(E)-1,3-Dimethoxy-5-[2-(2-methylbutylsulfanyl)vinyl]benzene
(23) (Table 3, Entry 9). General procedure A was followed (4 h).
Vinyl iodide 1 (100 mg, 0.34 mmol), 2-methylbutane-1-thiol
(42.7 mg, 0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-cis-
cyclohexanediol (8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52
mmol), and DMF (2.0 mL) were stirred at 40-50 °C to obtain
the thioether 23 (84 mg, 93% yield) as a colorless oil. Column
chromatography solvent (3-5% EtOAc in hexane) provided
pure 23. 1H NMR (300 MHz, CDCl3): δ 6.74 (1H, d, J=15.6
Hz), δ 6.46 (2H, m), δ 6.42-6.37 (1H, m), δ 6.35-6.33 (1H, m), δ
3.81 (6H, s), δ 2.75 (2H, m), δ 1.80-1.63 (1H, m), δ 1.35-1.25
(2H, m), δ 1.05 (3H, d, J=6.6 Hz), δ 0.95 (3H, t, J=7.4 Hz). 13C
NMR (75 MHz, CDCl3): δ 160.6, 144.8, 139.1, 126.7, 103.5,
98.9, 55.2, 39.7, 34.7, 28.6, 18.8, 11.2. HRMS (ESI) (M þ H)þ:
calcd for C15H23O2S 267.1419, found 267.1415.
(E)-3-[2-(4-Chlorophenylsulfanyl)vinyl]-5-methoxyphenol (28)
(Table 4, Entry 3). General procedure B was followed (2 h).
Vinyl iodide 8 (100 mg, 0.19 mmol), 4-chlorobenzenethiol (33
mg, 0.23 mmol), CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohex-
anediol (4.4 mg, 0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and
DMF (2.0 mL) were stirred at 30-40 °C to obtain the thioether
28 (53 mg, 96% yield) as a colorless oil. Column chromatogra-
1
phy solvent (2-3% EtOAc in hexane) provided pure 28. H
(E)-2-[2-(3,5-Dimethoxyphenyl)vinylsulfanyl]pyridine (24)
(Table 3, Entry 10). General procedure A was followed (8 h).
Vinyl iodide 1 (100 mg, 0.34 mmol), pyridine-2-thiol (45.6 mg,
0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-cis-cyclohexanediol
(8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52 mmol), and DMF
(2.0 mL) were stirred at 50-60 °C to obtain the thioether 24
(90 mg, 97% yield) as a colorless oil. Column chromatography
NMR (300 MHz, CDCl3): δ 7.39-7.28 (3H, m), δ 6.83 (1H, d,
J=14.8 Hz), δ 6.49-6.44 (2H, m), δ 6.39-6.36 (2H, m), δ 6.35
(1H, t, J=2.2 Hz), 4.91 (1H, s), δ 3.80 (3H, s). 13C NMR (75
MHz, CDCl3): δ 160.9, 156.6, 144.5, 139.7, 134.1, 131.6, 131.1,
129.3, 123.7, 108.1, 105.4, 101.5, 55.3. HRMS (ESI) (M þ H)þ:
calcd for C15H14ClO2S 293.0403, found 293.0402.
1
solvent (10% EtOAc in hexane) provided pure 24. H NMR
(E)-3-[2-(4-tert-Butylphenylsulfanyl)vinyl]-5-methoxyphenol (29)
(Table 4, Entry 4). General procedure B was followed (30 min).
Vinyl iodide 8 (100 mg, 0.19 mmol), 4-tert-butylbenzenethiol
(38 mg, 0.23 mmol), CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohex-
anediol (4.4 mg, 0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and
DMF (2.0 mL) were stirred at 30-40 °C to obtain the thioether 29
(58 mg, 97% yield) as a colorless oil. Column chromatography
solvent (2-3% EtOAc in hexane) provided pure 29. 1H NMR (300
MHz, CDCl3): δ 7.41-7.36 (2H, m), δ 7.30 (1H, d, J=9.2 Hz), δ
6.85 (1H, dd, J=15.0, J=2.2 Hz), δ 6.57 (1H, d, J=15.4 Hz), δ
6.47-6.36 (3H, m), δ 6. 37 (1H, t, J=2.2 Hz), δ 5.11 (1H, s), δ 3.80
(3H, s), δ 1.35 (9H, s); 13C NMR (75 MHz, CDCl3): δ 161.0, 156.7,
144.5, 138.9, 130.2, 129.8, 126.2, 125.4, 105.4, 104.4, 104.3, 101.5,
100.6, 55.3, 31.2. HRMS (ESI) (M þ H)þ: calcd for C19H23O2S
315.1419, found 315.1421.
(300 MHz, CDCl3): δ 8.52-8.49 (1H, m), δ 7.57 (1H, t, J=7.9
Hz), δ 7.50 (1H, d, J=15.8 Hz), δ 7.29-7.24 (1H, m), δ 7.07 (1H,
dd, J=6.8 Hz, J=7.8 Hz), δ 6.82 (1H, d, J=15.8 Hz), δ 6.60 (2H,
d, J=2.2 Hz), δ 6.41 (1H, t, J=2.2 Hz), δ3.83 (6H, s). 13C NMR
(75 MHz, CDCl3): δ 160.9, 157.8, 149.7, 138.4, 136.4, 131.6,
122.0, 120.4, 120.2, 104.3, 99.9, 55.3. HRMS (ESI) (M þ H)þ:
calcd for C15H16NO2S 274.0902, found 274.0904.
(E)-2-[2-(3,5-Dimethoxyphenyl)vinylsulfanyl]benzothiazole
(25) (Table 3, Entry 11). General procedure A was followed (8 h).
Vinyl iodide 1 (100 mg, 0.34 mmol), benzothiazole-2-thiol (68.5
mg, 0.41 mmol), CuI (6.5 mg, 0.034 mmol), 1,2-cis-cyclohex-
anediol (8.0 mg, 0.069 mmol), K3PO4 (109 mg, 0.52 mmol), and
DMF (2.0 mL) were stirred at 50-60 °C to obtain the thioether
25 (104 mg, 93% yield) as an off-white solid. Column chroma-
tography solvent (10% EtOAc in hexane) provided pure 25. Mp:
77.2-78.0 °C. 1H NMR (300 MHz, CDCl3): δ 7.95 (1H, d, J=
(E)-3-[2-(2-Isopropylphenylsulfanyl)vinyl]-5-methoxyphenol (30)
(Table 4, Entry 5). General procedure B was followed (1 h).Vinyl
3640 J. Org. Chem. Vol. 75, No. 11, 2010

Kabir et al.
JOCArticle
iodide 8 (140 mg, 0.27 mmol), 2-isopropylbenzenethiol (48.7 mg,
0.32 mmol), CuI (5.2 mg, 0.027 mmol), 1,2-cis-cyclohexanediol
(6.3 mg, 0.054 mmol), K3PO4 (86 mg, 0.41 mmol), and DMF
(2.0 mL) were stirred at 30-40 °C to obtain the thioether 30 (78 mg,
96% yield) as a colorless oil. Column chromatography solvent
(2-3% EtOAc in hexane) provided pure 30. 1H NMR (300 MHz,
CDCl3): δ 7.45-7.21 (3H, m), δ 6.82 (1H, d, J = 14.8 Hz), δ
6.47-6.37 (4H, m), δ 6.31 (1H, t, J=2.1 Hz), δ 5.05 (1H, br s), δ
(300 MHz, CDCl3): δ 6.76 (1H, d, J=15.6 Hz), δ 6.49-6.40 (3H,
m), δ 6.29 (1H, t, J=2.1 Hz), δ 4.84 (1H, s), δ 3.80 (3H, s), δ
3.06-2.92 (1H, m), δ 2.08-1.65 (5H, m), δ 1.48-128 (5H, m).
13C NMR (75 MHz, CDCl3): δ 156.6, 139.4, 127.7, 125.1, 105.0,
104.1, 101.5, 100.1, 55.3, 45.2, 33.5, 25.9, 25.5. HRMS (ESI)
(M þ H)þ: calcd for C15H21O2S 265.1262, found 265.1265.
(E)-3-[2-(Benzothiazol-2-ylsulfanyl)vinyl]-5-methoxyphenol (35)
(Table 4, Entry 10). General procedure B was followed (8 h). Vinyl
iodide 8 (140 mg, 0.27 mmol), benzothiazole-2-thiol (53.5 mg,
0.32 mmol), CuI (5.1 mg, 0.027 mmol), 1,2-cis-cyclohexanediol
(6.3 mg, 0.054 mmol), K3PO4 (86 mg, 0.41 mmol) and DMF
(2.0 mL) were stirred at 50-60 °C to obtain the thioether 35
(78 mg, 92% yield) as a light yellow solid. Column chromatogra-
phy solvent (10% EtOAc in hexane) provided pure 35. Mp:
137.6-142.2 °C. 1H NMR (300 MHz, CD3OD): δ 7.93-7.86
(2H, m), δ7.50 (1H, t, J=7.2 Hz), δ7.41-7.28 (2H, m), δ7.05 (1H,
d, J=15.4 Hz), δ6.60 (2 H, d, J=6.1 Hz), δ6.38 (1H, d, J=2.2 Hz),
3.80 (3H, s). 13C NMR (75 MHz, CDCl3): δ 166.5, 160.2, 157.7,
152.1, 137.4, 136.2, 133.9, 125.1, 123.3, 119.9, 115.1, 104.8, 102.4,
100.7, 100.0, 53.2. HRMS (ESI) (M þ H)þ: calcd for C16H14-
NO2S2 316.0466, found 316.0465.
3.80 (3H, s), δ 3.52-3.48 (1H, m), δ 1.27 (6H, d, J=6.8 Hz). 13
C
NMR (75 MHz, CDCl3): δ 160.9, 156.7, 148.8, 144.5, 138.9, 131.9,
129.6, 128.0, 126.5, 125.8, 125.5, 105.3, 104.2, 100.6, 55.3, 30.5, 23.4.
HRMS (ESI) (M þ H)þ: calcd for C18H21O2S 301.1262, found
301.1260.
(E)-2-[2-(3-Hydroxy-5-methoxyphenyl)vinylsulfanyl]benzoic
Acid Methyl Ester (31) (Table 4, Entry 6). General procedure B
was followed (30 min). Vinyl iodide 8 (100 mg, 0.19 mmol),
benzenethiol-2-carboxylic acid methyl ester (38 mg, 0.23 mmol),
CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohexanediol (4.4 mg,
0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF (2.0 mL)
were stirred at 30-40 °C to obtain the thioether 31 (50 mg, 83%
yield) as a colorless oil. Column chromatography solvent
(2-3% EtOAc in hexane) provided pure 31. 1H NMR (300
MHz, CDCl3): δ 8.01 (1H, d, J=7.8 Hz), δ 7.46-7.38 (2H, m), δ
7.28-7.22 (1H, m), δ 6.97 (1H, d, J=15.4 Hz), δ 6.88 (1H, d, J=
15.4 Hz), δ 6.60-6.57 (2H, m), δ 6.40 (1H, t, J=2.2 Hz) δ 4.01
(1H, s), δ 3.97 (3H, s), δ 3.82 (3H, s); 13C NMR (75 MHz,
CDCl3): δ 161.1, 157.0, 140.9, 138.4, 136.1, 132.5, 131.2, 127.5,
125.8, 124.9, 122.1, 108.3, 105.9, 104.8, 101.3, 55.3, 52.3. HRMS
(ESI) (M þ H): calcd for C17H17O4S 317.0848, found 317.0850.
(E)-3-Methoxy-5-[2-(naphthalen-2-ylsulfanyl)vinyl]phenol (32)
(Table 4, Entry 7). General procedure B was followed (1-2 h).
Vinyl iodide 8 (100 mg, 0.19 mmol), 2-naphthylthiol (37 mg, 0.23
mmol), CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohexanediol (4.4
mg, 0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF (2.0 mL)
were stirred at 30-40 °C to obtain the thioether 32 (54 mg, 92%
yield) as a colorless oil. Column chromatography solvent (2-3%
EtOAc in hexane) provided pure 32. 1H NMR (300 MHz,
CDCl3): δ 7.89-7.79 (4H, m), δ 7.53-7.49 (3H, m), δ 6.97 (1H,
d, J=15.4 Hz), δ 6.67 (1H, d, J=15.4 Hz), δ 6.51 (1H, t, J=1.6
Hz), δ 6.46 (1H, t, J=1.9 Hz), δ 6.34 (1H, t, J=2.2 Hz), δ 4.90
(1H, s, b), δ 3.80 (3H, s); 13C NMR (75 MHz, CDCl3): δ 161.1,
156.8, 138.7, 133.7, 132.2, 131.1, 128.7, 128.4, 127.7, 127.2, 126.6,
126.1. 124.3, 105.4, 104.4, 100.9, 55.3. HRMS (EI): calcd for
C19H16O2S 308.0871, found 308.0851.
(E)-3-Methoxy-5-[2-(pyrimidin-2-ylsulfanyl)vinyl]phenol (36)
(Table 4, Entry 11). General procedure B was followed (8 h).
Vinyl iodide 8 (140 mg, 0.27 mmol), pyrimidine-2-thiol (35.9 mg,
0.32 mmol), CuI (5.1 mg, 0.027 mmol), 1,2-cis-cyclohexanediol
(6.3 mg, 0.054 mmol), K3PO4 (86 mg, 0.41 mmol), and DMF
(2.0 mL) were stirred at 50-60 °C to obtain the thioether 36 (61
mg, 87% yield) as an yellow solid. Column chromatography
solvent (10% EtOAc in hexane) provided pure 36. Mp:
1
107.1-110.2 °C. H NMR (300 MHz, CDCl3): δ 8.59 (2H, d,
J=4.8 Hz), δ 7.56 (1H, d, J=16.0 Hz), δ 7.06 (1H, t, J=4.9 Hz),
δ 6.75 (1H, d, J=16.0 Hz), δ 6.55 (2H, d, J=1.6 Hz), δ 6.35 (1H,
t, J=2.2 Hz) δ 6.09 (1H, s), δ 3.81 (3H, s). 13C NMR (75 MHz,
CDCl3): δ 160.9, 157.5, 157.0 138.4, 131.1, 119.9, 117.2, 106.7,
105.8, 104.6, 101.2, 55.3. HRMS (ESI) (M þ H)þ: calcd for
C13H13N2O2S 261.0698, found 261.0696.
(E)- 3-Methoxy-5-[2-(pyridin-2-ylsulfanyl)vinyl]phenol (37)
(Table 4, Entry 12). General procedure was B followed (4 h).
Vinyl iodide 8 (100 mg, 0.19 mmol), pyridine-2-thiol (25 mg,
0.23 mmol), CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohexanediol
(4.4 mg, 0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF
(2.0 mL) were stirred at 40-50 °C to obtain the thioether 37 (45
mg, 92% yield) as a colorless solid. Column chromatography
1
solvent (10% EtOAc in hexane) provided pure 37. H NMR
(E)- 3-Methoxy-5-[2-(naphthalen-1-ylsulfanyl)vinyl]phenol (33)
(Table 4, Entry 8). General procedure B was followed (1-2 h).
Vinyl iodide 8 (100 mg, 0.19 mmol), 1-naphthylthiol (37 mg, 0.23
mmol), CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohexanediol (4.4
mg, 0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF (2.0 mL)
were stirred at 30-40 °C to obtain the thioether 33 (53 mg, 91%
yield) as a colorless oil. Column chromatography solvent (2-3%
EtOAc in hexane) provided pure 33. 1H NMR (300 MHz,
CDCl3): δ 8.38 (1H, d, J=8.3 Hz), δ 7.93-7.85 (2H, m), δ 7.72
(1H, d, J=7.2 Hz), δ 7.60-7.56 (2H, m), δ 7.51-7.45 (1H, m), δ
6.87 (1H, t, J=15.4 Hz), δ 6.49 (1H, d, J=15.4 Hz), δ 6.43 (1H, s),
δ 6.37 (1H, s), δ 6.30 (1H, t, J=2.2 Hz), δ 5.16 (1H, s) δ 3.76 (3H,
s); 13C NMR (75 MHz, CDCl3): δ 161.0, 156.7, 138.8, 134.0,
130.4, 129.9, 128.9, 128.7, 128.5, 128.2, 126.8, 126.4, 125.7, 125.2,
125.1, 105.3, 104.3, 100.7, 55.3. HRMS (ESI) (M þ H)þ: calcd for
C19H17O2S 309.0949, found 309.0952.
(E)- 3-(2-Cyclohexylsulfanylvinyl)-5-methoxyphenol (34)
(Table 4, Entry 9). General procedure B was followed (4 h).
Vinyl iodide 8 (140 mg, 0.27 mmol), cyclohexanethiol (37.2 mg,
0.32 mmol), CuI (5.1 mg, 0.027 mmol), 1,2-cis-cyclohexanediol
(6.3 mg, 0.054 mmol), K3PO4 (86 mg, 0.41 mmol), and DMF
(2.0 mL) were stirred at 40-50 °C to obtain the thioether 34 (69
mg, 96% yield) as a colorless oil. Column chromatography
solvent (3-5% EtOAc in hexane) provided pure 34. 1H NMR
(300 MHz, CDCl3): δ 8.50 (1H, d, J=5.0 Hz), δ 7.59 (1H, t, J=
7.8 Hz), δ 7.38 (1H, d, J=15.8 Hz), δ 7.29-7.27 (1H, m), δ
7.12-7.08 (1H, m), δ 6.77 (1H, d, J=15.8 Hz) δ 6.51 (2H,d, J=
2.1 Hz), δ 6.34 (1H, t, J=2.1 Hz), δ 6.14 (1H, br s), δ 3.79 (3H, s);
13C NMR (75 MHz, CDCl3): δ 160.9, 157.9, 157.0, 149.6, 138.5,
136.6, 132.3, 122.3, 120.4, 120.0, 105.8, 104.5, 101.2, 55.2.
HRMS (ESI) (M þ H)þ: calcd for C14H14NO2S 260.0745, found
260.0744.
(E)- 3-Methoxy-5-[2-(thiophene-2-ylsulfanyl)vinyl]phenol (38)
(Table 4, Entry 13). General procedure B was followed (4 h).
Vinyl iodide 8 (100 mg, 0.19 mmol), 2-thiothiophene (27 mg,
0.23 mmol), CuI (3.7 mg, 0.019 mmol), 1,2-cis-cyclohexanediol
(4.4 mg, 0.038 mmol), K3PO4 (60 mg, 0.28 mmol), and DMF
(2.0 mL) were stirred at 40-50 °C to obtain the thioether 38 (43
mg, 86% yield) as a colorless solid. Column chromatography
1
solvent (10% EtOAc in hexane) provided pure 38. H NMR
(300 MHz, CDCl3): δ 7.47 (1H, m), δ 7.25 (1H, dd, J=3.6, 1.3
Hz), δ 7.08 (1H, dd, J=5.3, J=3.6 Hz), δ 6.75 (1H, d, J=15.4
Hz), δ 6.43-6.35 (3H, m), δ 6.30 (1H, t, J=2.2 Hz), δ 5.21 (1H,
s), δ 3.78 (3H, s). 13C NMR (75 MHz, CDCl3): δ 160.9, 156.7,
138.5, 134.1, 130.3, 127.9, 127.8, 127.0, 125.3, 105.4, 104.3,
100.7, 55.3. HRMS (ESI) (M þ H)þ: calcd for C13H13O2S2
265.0357, found 265.0363.
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Characterization Data for Products Shown in Table 5.
(E)-N-[4-[2-(3-Cyanophenyl)vinylsulfanyl]phenyl]acetamide (40)
(Table 5, Entry 1). General procedure A was followed (2 h). Vinyl
iodide 39 (90 mg, 0.35 mmol), N-(4-mercaptophenyl)acetamide
(70.2 mg, 0.42 mmol), CuI (6.7 mg, 0.035 mmol), 1,2-cis-cyclo-
hexanediol (8.2 mg, 0.071 mmol), K3PO4 (112 mg, 0.53 mmol), and
DMF (2.0 mL) were stirred at 30-40 °C to obtain the thioether 40
(90 mg, 87% yield) as a light yellow solid. Column chromato-
graphy solvent (2-3% EtOAc in hexane) provided pure 40. Mp:
89.4-91.1 °C. 1H NMR (300 MHz, CDCl3): δ 7.80 (1H, s),
δ 7.59-7.52 (3H, m), δ 7.49-7.37 (4H, m), δ 6.95 (1H, d, J=
15.4 Hz), δ 6.50-6.42 (1H, m), δ 2.21 (3H, s). 13C NMR (75 MHz,
CDCl3): δ 168.6, 138.1, 137.7, 132.5, 131.5, 130.2, 129.7, 129.4,
129.1, 128.7, 126.1, 123.9, 120.6, 118.6, 24.5. HRMS (ESI) (M þ
Li)þ: calcd for C17H14N2OSLi 301.0987, found 301.0988.
7.42-7.35 (3H, m), δ 7.28-7.22 (1H, m), δ 6.97 (1H, d, J=15.4
Hz), δ 6.38 (1H, d, J=15.4 Hz), δ 3.56-3.48 (1H, m), δ 1.28 (6H,
d, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3): δ 150.2, 137.9,
133.1, 130.1, 129.6, 129.3, 129.0, 128.9, 128.8, 126.7, 126.1,
125.8, 123.9, 118.6, 112.8, 30.7, 23.5. HRMS (EI) (M)þ: calcd
for C18H17NS 279.1082, found 279.1079.
(E)-2-[2-(3-Cyanophenyl)vinylsulfanyl]benzoic Acid Methyl
Ester (45) (Table 5, Entry 6). General procedure A was followed
(30 min). Vinyl iodide 39 (100 mg, 0.39 mmol), benzenethiol-2-
carboxylic acid methyl ester (79 mg, 0.47 mmol), CuI (7.4 mg,
0.039 mmol), 1,2-cis-cyclohexanediol (9.1 mg, 0.078 mmol),
K3PO4 (124 mg, 0.59 mmol), and DMF (2.0 mL) were stirred
at 30-40 °C to obtain the thioether 45 (100 mg, 87% yield) as a
colorless oil. Column chromatography solvent (2-3% EtOAc
1
in hexane) provided pure 45. H NMR (300 MHz, CDCl3): δ
(E)-3-(2-m-Tolylsulfanylvinyl)benzonitrile (41) (Table 5, Entry
2). General procedure A was followed (1 h).Vinyl iodide 39
(90 mg, 0.35 mmol), 3-methylbenzenethiol (50.2 mg, 0.42 mmol),
CuI (6.7 mg, 0.035 mmol), 1,2-cis-cyclohexanediol (8.2 mg, 0.071
mmol), K3PO4 (112 mg, 0.53 mmol), and DMF (2.0 mL) were
stirred at 30-40 °C to obtain the thioether 41 (74 mg, 84% yield) as
a colorless oil. Column chromatography solvent (2-3% EtOAc in
8.02 (1H, d, J=7.8 Hz), δ 7.71 (1H, s), δ 7.65-7.62 (1H, m), δ
7.58-7.47 (3H, m), δ 6.43-6.40 (1H, m), δ 7.32-7.28 (1H, m), δ
7.07-6.93 (2H, m), δ 3.96 (3H, s). 13C NMR (75 MHz, CDCl3):
δ 166.5, 139.6, 137.5, 132.5, 132.3, 131.2, 131.0, 130.3, 129.5,
129.2, 128.0, 126.0, 125.7, 125.5, 118.4, 113.0, 52.2. HRMS
(ESI) (M þ Li)þ: calcd for C17H13NO2SLi 302.0827, found
302.0821.
1
hexane) provided pure 41. H NMR (300 MHz, CDCl3): δ 7.58
(E)-3-[2-(2-Methylbutylsulfanyl)vinyl]benzonitrile (46) (Table 5,
Entry 7). General procedure A was followed (4 h). Vinyl iodide 39
(90 mg, 0.35 mmol), 2-methylbutane-1-thiol (43.8 mg, 0.42 mmol),
CuI (55.0 mg, 0.035 mmol), 1,2-cis-cyclohexanediol (8.2 mg, 0.071
mmol), K3PO4 (112 mg, 0.53 mmol), and DMF (2.0 mL) were
stirred at 40-50 °C to obtain the thioether 46 (75 mg, 93% yield) as
a colorless oil. Column chromatography solvent (3-5% EtOAc in
(1H, s), δ7.55-7.48 (2H, m), δ7.43 (1H, q, J=7.8 Hz, J=2.7 Hz), δ
7.31-7.28 (3H, m), δ 7.17-7.14 (1H, m), δ 7.01 (1H, d, J=15.6
Hz), δ 6.57 (1H, d, J=15.6 Hz), δ 2.39 (3H, s). 13C NMR (75 MHz,
CDCl3): δ 142.6, 139.3, 137.8, 132.6, 131.4, 130.2, 129.7, 129.4,
129.1, 128.6, 127.9, 126.7, 124.1, 118.6, 112.8, 21.2. HRMS (EI)
(M)þ: calcd for C16H13NS 251.0769, found 251.0767.
1
(E)-3-[2-(3-Methoxyphenylsulfanyl)vinyl]benzonitrile (42)
(Table 5, Entry 3). General procedure A was followed (2 h).
Vinyl iodide 39 (100 mg, 0.39 mmol), 3-methoxybenzenethiol
(66 mg, 0.47 mmol), CuI (7.4 mg, 0.039 mmol), 1,2-cis-cyclo-
hexanediol (9.1 mg, 0.078 mmol), K3PO4 (124 mg, 0.59 mmol),
and DMF (2.0 mL) were stirred at 30-40 °C to obtain the
thioether 42 (88 mg, 84% yield) as a colorless oil. Column
chromatography solvent (2-3% EtOAc in hexane) provided
pure 42. 1H NMR (300 MHz, CDCl3): δ 7.59 (1H, s), δ
7.56-7.49 (2H, m), δ 7.44-7.39 (1H, m), δ 7.31 (1H, t, J=8.1
Hz), δ 7.06-7.00 (3H, m), δ 7.02 (1H, d, J = 15.4 Hz), δ
6.61 (1H, d, J=15.5 Hz), δ 3.84 (3H, s). 13C NMR (75 MHz,
CDCl3): δ 160.1, 137.7, 134.8, 132.7, 131.9, 130.4, 130.1, 129.8,
129.4, 129.1, 127.7, 127.3, 122.8, 116.1, 113.4, 55.3. HRMS
(ESI) (M þ Li)þ: calcd for C16H13NOSLi 274.0878, found
274.0883.
(E)- 3-[2-(4-Methoxyphenylsulfanyl)vinyl]benzonitrile (43)
(Table 5, Entry 4). General procedure A was followed (1 h).
Vinyl iodide 39 (100 mg, 0.39 mmol), 4-methoxybenzenethiol
(66 mg, 0.47 mmol), CuI (7.4 mg, 0.039 mmol), 1,2-cis-cyclo-
hexanediol (9.1 mg, 0.078 mmol), K3PO4 (124 mg, 0.59 mmol),
and DMF (2.0 mL) were stirred at 30-40 °C to obtain the
thioether 43 (90 mg, 86% yield) as a colorless oil. Column
chromatography solvent (2-3% EtOAc in hexane) provided
pure 43. 1H NMR (300 MHz, CDCl3): δ 7.52 (1H, s), δ
7.49-7.43 (4H, m), δ 7.37 (1H, d, J = 7.6 Hz), δ 6.98-6.92
(3H, m), δ 6.33 (1H, d, J=15.5 Hz), δ 3.86 (3H, s). 13C NMR (75
MHz, CDCl3): δ 160.1, 137.9, 134.4, 133.1, 132.0, 130.1, 129.9,
129.5, 129.3, 128.9, 124.6, 123.0, 115.0, 55.3. HRMS (ESI) (M þ
Li)þ: calcd for C16H13NOSLi 274.0878, found 274.0881.
(E)-3-[2-(2-Isopropylphenylsulfanyl)vinyl]benzonitrile (44)
(Table 5, Entry 5). General procedure A was followed (1 h).
Vinyl iodide 39 (90 mg, 0.35 mmol), 2-isopropylbenzenethiol
(64 mg, 0.42 mmol), CuI (6.7 mg, 0.035 mmol), 1,2-cis-cyclo-
hexanediol (8.2 mg, 0.071 mmol), K3PO4 (112 mg, 0.53 mmol),
and DMF (2.0 mL) were stirred at 30-40 °C to obtain the
thioether 44 (96 mg, 98% yield) as a colorless oil. Column
chromatography solvent (2-3% EtOAc in hexane) provided
pure 44. 1H NMR (300 MHz, CDCl3): δ 7.55-7.46 (4H, m), δ
hexane) provided pure 46. H NMR (300 MHz, CDCl3): δ 7.55
(1H, s), δ7.51-7.36 (3H, m), δ6.86 (1H, d, J=15.6 Hz), δ6.39 (1H,
d, J=15.4 Hz), δ 2.77 (2H, m), δ 1.77-1.70 (1H, m), 1.59-1.52
(1H, m), δ 1.36-1.26 (2H, m), δ 1.06-1.03 (3H m), δ 0.97-0.91
(3H m). 13C NMR (75 MHz, CDCl3): δ 138.3, 132.5, 129.8,
129.6, 129.3, 128.6, 123.0, 118.7, 112.7, 39.6, 34.7, 28.6, 18.8, 11.2.
HRMS (ESI) (M þ Li)þ: calcd for C14H17NSLi 238.1242, found
238.1241.
(E)-3-[2-(6-Hydroxyhexylsulfanyl)vinyl]benzonitrile (47) (Table 5,
Entry 8). General procedure A was followed (8 h).Vinyl iodide 39
(90 mg, 0.35 mmol), 6-mercaptohexan-1-ol (56.4 mg, 0.42 mmol),
CuI (55.0 mg, 0.035 mmol), 1,2-cis-cyclohexanediol (8.2 mg, 0.071
mmol), K3PO4 (112 mg, 0.53 mmol), and DMF (2.0 mL) were
stirred at 50-60 °C to obtain the thioether 47 (82 mg, 90% yield) as
a colorless oil. Column chromatography solvent (3-5% EtOAc in
hexane) provided pure 47.1H NMR (300 MHz, CDCl3):δ7.56 (1H,
s), δ7.51-7.37(3H,m),δ6.86 (1H, d, J=15.6 Hz), δ6.39 (1H, d, J=
15.6 Hz), δ 3.67 (2H, t, J=6.4 Hz), δ 2.85 (2H, t, J=7.2 Hz), δ
1.79-1.27 (8H, m). 13C NMR (75 MHz, CDCl3): δ 137.8, 129.7,
129.3, 129.1, 128.6, 123.4, 118.2, 113.1, 62.7, 32.5, 32.3, 29.2, 28.4,
25.2. HRMS (ESI) (M þ Li)þ: calcd for C15H19NOSLi 268.1347,
found 268.1344.
(E)-3-[2-(Pyrimidin-2-ylsulfanyl)vinyl]benzonitrile (48) (Table 5,
Entry 9). General procedure A was followed (8 h). Vinyl iodide 39
(90 mg, 0.35 mmol), pyrimidine-2-thiol (47.1 mg, 0.42 mmol),
CuI (6.7 mg, 0.035 mmol), 1,2-cis-cyclohexanediol (8.2 mg,
0.071 mmol), K3PO4 (112 mg, 0.53 mmol), and DMF (2.0 mL)
were stirred at 50-60 °C to obtain the thioether 48 (72 mg, 86%
yield) as an off-white solid. Column chromatography solvent
(10% EtOAc in hexane) provided pure 48. Mp: 85.0-87.9 °C. 1H
NMR (300 MHz, CDCl3): δ 8.62 (2H, d, J=4.8 Hz), δ 7.84 (1H, d,
J=16.2 Hz), δ 7.75 (1H, s), δ 7.70-7.64 (1H, m), δ 7.56-7.53
(1H, m), δ 7.7 (1H, t, J=7.7 Hz), δ 7.10 (1H, t, J=4.8 Hz), δ 6.82
(1H, d, J=16.2 Hz). 13C NMR (75 MHz, CDCl3): δ 169.7, 157.6,
137.6, 130.7, 130.3, 129.4, 129.3, 127.4, 123.5, 118.6, 117.4, 112.9.
HRMS (ESI) (M þ H)þ: calcd for C13H10N3S 240.0595, found
240.0598.
(E)-3-[2-(4,5-Dihydrothiazol-2-ylsulfanyl)vinyl]benzonitrile (49)
(Table 5, Entry 10). General procedure A was followed (4 h). Vinyl
3642 J. Org. Chem. Vol. 75, No. 11, 2010

Kabir et al.
JOCArticle
iodide 39 (90 mg, 0.35 mmol), 4,5-dihydrothiazole-2-thiol (50.1
mg, 0.42 mmol), CuI (6.7 mg, 0.035 mmol), 1,2-cis-cyclohexane-
diol (8.2mg, 0.071 mmol), K3PO4 (112 mg, 0.53 mmol), and DMF
(2.0 mL) were stirred at 40-50 °C to obtain the thioether 49 (78
mg, 90% yield) as a pale yellow solid. Column chromatography
solvent (10% EtOAc in hexane) provided pure 49. Mp: 72.0-74.0
°C. 1H NMR (300 MHz, CDCl3): δ 7.66 (1H, s), δ 7.62-7.53 (2H,
m), δ7.48 (1H, d, J=3.0Hz), δ7.44(1H, d, J=5.2 Hz), δ6.77 (1H,
d, J=16.0 Hz), δ 4.30 (2H, t, J=8.1 Hz), δ 3.47 (2H, t, J=8.1 Hz).
13C NMR (75 MHz, CDCl3): δ 137.0, 131.1, 130.3, 129.6, 129.5,
129.4, 122.3, 118.4, 112.9, 64.3, 35.5, 29.6. HRMS (ESI) (M þ
H)þ: calcd for C12H11N2S2 247.0364, found 247.0362.
Acknowledgment. We thank Dr. Steven H. Bertz, Complex-
ity Study Center, Mendham, NJ, for helpful discussions,
Dr. M. E. Dudley, Marquette University, for technical advice,
and The Research Growth Initiative of the University of
Wisconsin—Milwaukee as well as The UW-System Applied
Research Grants Program for financial support.
Supporting Information Available: Detailed experimental
and characterization data for the compounds in Tables 6-10
including copies of the 1H and 13C for each (new and reported)
compound. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 11, 2010 3643