Ligand-Free Copper(I)-Mediated Cross-Coupling Reactions of Organostannanes with Sulfur Electrophiles

Article abstract of DOI:10.1021/acs.joc.0c01399

The synthesis of aryl thioether through the cross-coupling of C-S bond is a highly attractive area of research due to the prevalence of aryl thioether in bioactive natural products, functional materials, agrochemicals, and pharmaceutically active compound

Full text of DOI:10.1021/acs.joc.0c01399

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Ligand-Free Copper(I)-Mediated Cross-Coupling Reactions of
Organostannanes with Sulfur Electrophiles
Feng Zhu,† Zhenhao Chen,† and Maciej A. Walczak*
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ABSTRACT: The synthesis of aryl thioether through the cross-
coupling of C−S bond is a highly attractive area of research due to
the prevalence of aryl thioether in bioactive natural products,
functional materials, agrochemicals, and pharmaceutically active
compounds. Herein, we report a ligand-free Cu(I) mediated
electrophilic thiolation of organostannanes with sulfur electro-
philes. A selective transfer of alkyl groups was achieved in reactions
with alkyl carbastannatranes affording congested thioethers. This
study offers a unified method to access diaryl and aryl alkyl
thioethers and was demonstrated in the context of late-stage
modifications..
hioethers are a common structural motif found in
bioactive natural products, functional materials, agro-
C−S bond formations involving thiols reacting with (hetero)-
aryl halides (Scheme 1C).11 The scope of thiol nucleophiles is
mainly limited to aryl mercaptans, and only selected alkyl thiols
can participate in this process.
T
chemicals, and pharmaceutically active compounds.1 S-Aryl
fragments are becoming privileged architectures in commercial
pharmaceuticals exemplified by montelukast,2a nelfinavir,2b
retapamulin,2c amoxicillin,2d axitinib,2e nolatrexed,2f and
ticagrelor2g (Figure 1). Therefore, the search for methods to
construct a C−S bond beyond direct nucleophilic substitution
is an active research area catering small-molecule and materials
synthesis.3 Among various synthetic approaches described to
date, transition metal catalyzed cross-coupling reactions are a
useful strategy for C−S bond construction because of the
availability of a diverse pool of thiols and aryl halides or
pseudohalides (Scheme 1A).4 Nevertheless, most of the
reported methods require a strong base additive, high catalyst
loadings, and air-sensitive ligands designed for specific
applications. Elevated temperatures are also needed to
promote the reaction owing to strong chelation of the sulfur
atom to transition metal catalysts, which can poison the active
catalytic species and lead to deactivation.5
Expensive photosensitizers required to promote these
reactions are an inherent limitation of these protocols and
introduce challenges in terms of scalability and sustainability.
Collectively, these concerns motivate efforts to search for
brand new methods for C−S formation or to improve existing
catalytic strategies. Compared to the above-mentioned metal
reagents, a direct coupling of electrophilic sulfur sources with
organotin reagents is relatively scarce and limited to unique
substrates such as allyl stannanes activated under radical
conditions.12 A direct coupling of organotin compounds is
potentially appealing because of the following: (a) organotin
compounds are known to be air- and moisture-stable, have
excellent functional group tolerance, and can be introduced in
complex molecules; (b) functionalized (hetero)aryl and alkyl
tin reagents are easily accessible and commercially available;
(c) stannatranes, a class of activated pentavalent tin reagents
with reduced toxicity, can selectively transfer alkyl groups in
the Stille couplings; (d) the byproduct of this coupling,
RSSnBu3, can reduce the concentration of sulfur and suppress
potential catalyst poisoning. We recently reported the synthesis
and reactions of carbohydrate C1-stannanes, a class of
The C−S cross-coupling of organometallic reagents with
sulfur electrophiles is a promising alternative to transition
metal catalyzed reactions (Scheme 1B). Functionalized
reagents such as organolithium,6 Grignard,7 organoboron,8
organosilicon,9 and organoznic10 were employed in reactions
with electrophilic sulfur sources of general formula RS−X (X =
SR, halogen, N-succimidyl, and arylsulfonyl). Complementary
to uncatalyzed processes, the leading catalytic methods require
highly reactive nucleophiles such R−Li and R−MgX and
unstable electrophilic sulfur sources (RS−Cl or RS−Br) to
obtain synthetically useful yields. The nature of these reagents
severely limits the scope and functional group tolerance. More
recently, significant progress has been achieved in photoredox
Received: June 13, 2020
https://dx.doi.org/10.1021/acs.joc.0c01399
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

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Scheme 1. Selected Methods for the Synthesis of Aromatic
Thioethers
Figure 1. Selected pharmaceutical drugs featuring thioethers.
anomeric nucleophiles, as competent partners in the glycosyl
cross-coupling.13 These reactions proceed with high levels of
anomeric stereoselectivity across a broad substrate scope.
Inspired by the prior work on the stereoretentive cross-
coupling reaction of configurationally stable C(sp3) stannanes
to construct a C(sp3)−S bond,13c we wondered if unactivated
C(sp2) or C(sp3) stannanes can also react with sulfur
electrophiles to realize aromatic thioethers synthesis (Scheme
1D). Herein, we report a simple and ligand-free protocol for
the synthesis of aromatic thioethers which can be achieved by
coupling of aryl and alkyl stannanes with disulfides and N-
sulfenylsuccinimide donors promoted by Cu(I).
For the initial optimizations of the reaction conditions, we
selected tributyl(phenyl)stannane 9 and bis(4-methoxyphenyl)
disulfide 10 as the model substrates (Table 1). Cu(I) additives
were first examined on the basis of our recent reports.13b,c We
were pleased to find that the reaction reached completion
furnishing the desired product in 82% isolated yield when 1.5
equiv of CuCl and 2.0 equiv of KF were employed at 120 °C
for 48 h (Table 1, entry 1). We next attempted to reduce the
copper loading to 1.0 equiv and 0.5 equiv, and a marked
decrease in yield was observed (Table 1, entries 2 and 3).
However, the yields did not increase with higher loadings of
CuCl to 3.0 equiv (Table 1, entry 4). Control experiments
showed that CuCl was essential, but KF and a phosphine
ligand (JackiePhos)13c are not necessary for the cross-coupling
reaction (Table 1, entries 5−7). The role of KF is to facilitate
the Sn/Cu transmetalation when the tin group is converted
into insoluble Bu3SnF and improve the efficiency of the
reaction.13b Disulfide 10 was replaced with more active N-(4-
methoxyphenyl)thiosuccinimide resulting in a slightly im-
proved yield, 86% (Table 1, entry 8). It showed that both
disulfides and N-thiosucinimides are good electrophilic sulfur
reagents. When the ratio of 9 and 10 was changed from 1.5:1
to 1:1.5, the reaction yield reduced from 82% to 68% (Table 1,
entry 9). The efficiency of this process was also reduced when
a lower temperature (80 °C) was screened (Table 1, entry 10).
Other common metals such as palladium and nickel salts were
found to give a low yield (<30%) (Table 1, entry 11). Under
the same conditions, a 1 mmol scale of tributyl(phenyl)-
stannane could be completely transformed to afford 76% yield
of the desired product.
With the optimized conditions in hand, we next evaluated
the scope of the C−S cross-coupling protocol of C(sp2)
stannanes. Aryl and heteroaryl stannanes 12 were found to be
suitable reaction partners in reactions with S(sp2) and S(sp3)
electrophilic sulfur reagents to provide the corresponding
aromatic thioethers shown in Scheme 2. para-Substituted aryl
stannanes bearing benzyloxy and chloro groups engaged in the
cross-couplings to forge C−S bonds in good yields (14a and
14b). It is worth noting that the 2.5 mmol of (4-
benzyloxyphenyl)tributylstannane could be coupled to afford
the desired product without significant reduction of yield. We
were delighted to find that aryl stannanes containing functional
B
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a
products in moderate to good yields (44%−87%). Disulfane
reagents bearing trifluoromethyl and fluoro groups engaged in
the cross-couplings to obtain the desired product in 58% and
60% yield, respectively (14g and 14h). We also tested other
reactions with (4-(benzyloxy)phenyl)tri-n-butylstannane and
alkyl N-sulfenylsuccinimide as alkyl electrophilic sulfur
reagents (14i−14j), because dialkyl disulfide are significantly
less active. It is clear that the cross-coupling yields of alkyl
electrophilic sulfur reagents (41% to 53%) are lower than in
the case of the above-mentioned aryl electrophilic sulfur
reagents. Meanwhile, functional groups such as esters and
carbamates were well tolerated as demonstrated in the
synthesis of S-aryl cysteine 14k.
Table 1. Optimization of Electrophilic Thiolations with 9
Yield
b
Entry
Variation from the standard conditions
(%)
1
2
3
4
5
6
7
8
none
82
52
28
82
45
ND
1.0 equiv of CuCl instead of 1.5 equiv
0.5 equiv of CuCl instead of 1.5 equiv
3.0 equiv of CuCl instead of 1.5 equiv
no KF
no CuCl
JackiePhos (100 mmoll%) added
N-(4-methoxyphenyl)thiosuccinimide instead of
disulfide
The ratio of 9:10 1:1.5
Next, we tested the scope of the C−S cross-coupling
reaction using various alkyl stannanes (Scheme 3). Alkyl
c
38
86
Scheme 3. Scope of C−S Cross-Coupling with Alkyl
Carbastannatranes
d
9
68
10
11
80 °C instead of 120 °C
(50 mmol %) PdCl2 or NiCl2(DME) instead of CuCl
c
<30
a
General conditions: 9 (0.15 mmol), (PMPS)2 (0.10 mmol), CuCl
(1.5 equiv), KF (2.0 equiv), 1,4-dioxane (2.0 mL), 120 °C, 48 h, N2.
b
c
Isolated yield. CuCl (50 mmol %) and JackiePhos (100 mmol %)
d
were used. 9 (0.10 mmol), (PMPS)2 (0.15 mmol). ND = not
detected.
Scheme 2. Scope of C−S Cross-Coupling with Aryl
a b
,
Stannanes 12
a
General conditions: 15 (0.15 mmol), 13a (0.10 mmol), CuCl (1.5
equiv), KF (2.0 equiv), 1,4-dioxane (2.0 mL), 120 °C, 48 h, N2.
b
Isolated yield.
stannanes are considered as poor nucleophiles in the alkyl−aryl
Stille couplings. In addition to a difficult reductive elimination,
the key challenge in the Stille coupling is the selective transfer
of an alkyl group when tetraalkylstannanes are used. A
promising strategy reported in the literatures uses alkyl tin
nucleophiles that bear an activated tin center such as
heteroatoms and/or strongly coordinating substituents,13,14
that have been shown to facilitate transmetalation of the
intrinsically hindered, secondary alkyl centers. Carbastanna-
trane, reported in 1984, are attractive substrates due to their
increased reactivity.15 Compared with their tetraalkylorgano-
stannane counterparts, alkyl carbastannatranes proceed via a
selective alkyl transfer and are known to be air- and moisture-
stable, as well as generally less toxic.16 Inspired by these
findings, we tested selected alkyl carbastannatranes under the
previously optimized conditions (Scheme 3), we found that
primary, secondary, and tertiary stannanes resulted in
moderate to good yields of alkyl thioethers. Cyclic alkyl
thioethers are a challenge to synthesize by traditional
substitution methods,17 and we found that cyclic carbastanna-
tranes of three- to six-membered carbocycles smoothly
underwent coupling to form thioether products 14l−14o.
Other heterocyclic compounds such as tetrahydro-2H-pyran-4-
a
General conditions: 12 (0.15 mmol), 13a or 13b (0.10 mmol), CuCl
(1.5 equiv), KF (2.0 equiv), 1,4-dixoane (2.0 mL), 120 °C, 48 h, N2.
b
Isolated yield.
groups suitable for downstream orthogonal transformations
such as chlorine were coupled with complete chemoselectivity
and good efficiencies to generate the thioether in 70% isolated
yield (14b). A series of heterocyclic substrates such as furan-2-
yl (14c), thiophen-2-yl (14d), 1-methyl-1H-pyrrol-2-yl (14e),
and 1-methyl-1H-pyrazol-5-yl (14f) all proceeded well to give
C
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yl (14p) and 1-methylpiperidin-4-yl (14q) were well
compatible under the standard conditions. Endocyclic
carbastannatrane such as exo-2-norbornyl carbastannatranes
gave 14r in a moderate yield of 67% and exo/endo dr 5:1.
Acyclic carbastannatranes were also employed to test the
generality of this method6-(sec-butyl)-1-aza-6-stannabicyclo-
[4.3.3]dodecane afforded thioether 14s in good yield, but 6-
butyl-1-aza-6-stannabicyclo[4.3.3]dodecane gave a reduced
yield of 14t due to the lower nucleophilicity of the
carbastannatrane substrate. It is noteworthy that sterically
hindered 6-(tert-butyl)-1-aza-6-stannabicyclo[4.3.3]dodecane
also delivered the C−S cross-coupling product 14u in 51%
yield. Taken together, these results indicate the potential
application of the new method in the synthesis of sterically
hindered aromatic thioethers.
first method that allows for direct coupling of aryl and
unactivated alkyl stannanes with electrophilic sulfur reagents.
The ability of the system to operate with high efficiency in the
presence of alkyl carbastannatranes further enhances the
practical utility of this method. We believe our method is a
significant alternative to the current systems and will find
widespread application in organic synthesis and drug discovery.
EXPERIMENTAL SECTION
■
General Information. All chemicals were purchased as reagent
grade and used without further purification unless otherwise noted.
Solvents were filtered through a column of activated alumina prior to
use. All reactions were carried out under anhydrous N2 in oven-dried
glassware. Anhydrous 1,4-dioxane, CuCl, tributylphenylstannane, (4-
(benzyloxy)phenyl)tributylstannane, tributyl(4-chlorophenyl)-
stannane, tributyl(furan-2-yl)stannane, tributyl(thiophen-2-yl)-
stannane, 1-methyl-2-(tributylstannyl)-1H-pyrrole, and 1-methyl-4-
(tributylstannyl)-1H-pyrazole were purchased from Sigma-Aldrich.
Alkyl lithium reagents, Grignard reagents, and zinc reagents were
purchased from Sigma-Aldrich. Anhydrous KF was purchased from
Strem Chemicals, Inc. Disulfane reagents were synthesized following
the reported method.13c Visualizations were performed with UV light
and/or Hanessian stain and/or sulfuric acid stain (5% H2SO4 in
MeOH). Column chromatography was performed on silica gel (230−
400 mesh). 1H and 13C{1H} NMR spectra were recorded on Bruker/
Varian 300/400/500 MHz instruments and are reported as follows:
chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, br = broad, m = multiplet), coupling constants (Hz), and
integration. The residual solvent reference peaks were used from
published literature. 2D NMR experiments were performed using
standard parameters (200 and More NMR Experiments, S. Berger, S.
Braun, Wiley-VCH, 2004). IR measurements were performed on an
Agilent Cary 630 FT/IR instrument, and optical rotations were
measured on a JASCO P-1030 and are reported as the average of five
data points. High-resolution mass spectra (HR-MS) were recorded on
a Waters Synapt G2 HDMS q-TOF hybrid mass spectrometer.
General Procedure A for Cross-Coupling Reactions. Stannane
reagents (1.50 equiv), sulfide reagents (1.00 equiv), KF (2.00 equiv),
and CuCl (1.50 equiv) were added to a one-dram vial with a screw-
top septum, and the vial was then evacuated and refilled with N2
(3×). Anhydrous 1,4-dioxane (2.00 mL) were added and the reaction
mixture was heated in an oil bath (120 °C) for the indicated period of
time, cooled to rt, filtered through a pad of Celite, and concentrated.
The crude material was purified by column chromatography on SiO2.
General Procedure B for the Preparation of Alkyl Azastanna-
tranes. To a solution of 5-chloro-1-aza-5-stannabicyclo[3.3.3]-
undecane (1.00 equiv) in anhydrous THF (5.00 mL) alkyl lithium/
Grignard reagent solution (2.00−5.00 equiv) was added under N2 at 0
°C. The mixture was allowed to stir for 15 min and then warmed up
to rt. After stirring for 12 h, the reaction was quenched by H2O (10.0
mL). The resulted mixture was then extracted with EtOAc (3 × 50.0
mL). The combined organic layer was dried over Na2SO4,
concentrated, and vacuumed to afford the crude product. The
crude alkyl tin reagents were used without further purification.
1,2-Bis(4-methoxyphenyl)disulfane (10). According to the
reported literature,13c NaBO3·H2O (3.00 g, 30.0 mmol) was added
to a stirring solution of 4-methoxybenzenethiol (1.90 mL, 15.0 mmol)
in AcOH (40.0 mL) and H2O (15.0 mL). The reaction mixture was
stirred for 4 h and concentrated in vacuo. The crude mixture was
purified via flash chromatography on SiO2 (Hexanes/EtOAc, 50:1) to
To gain preliminary mechanistic information about the
electrophilic thiolations of organostannanes, radical trapping
experiments were carried out under the standard conditions.
When coupling of 9 and 10 was attempted with 3 equiv of a
free-radical inhibitor, 1,1-diphenylethylene, the product yield,
was slightly reduced from 82% to 71%. This experiment
indicates that the radical pathway is not operational under the
optimized conditions. Based on the above experimental
observations and the previous work from our group,13c
a
possible Cu(I)/Cu(III) mechanism for the C−S cross-
coupling reaction is outlined in Scheme 4. First, the Cu(I)
Scheme 4. Proposed Mechanism for the C−S Cross-
Coupling
species reacts with electrophilic sulfur reagents RS−X (X = SR,
N-succimidyl) A to generate oxidative addition product
LCu(SR)X B. Base-assisted transmetalation of organostan-
nanes with product LCu(SR)X B occurs to form Cu(III)
intermediate C, which then undergoes reductive elimination to
give the final product D along with regeneration of the
deactivated X−Cu(I)L such as RS−Cu species.13c,18 Because
of the potential coordination of sulfur atoms resulting in
catalyst poisoning, a stoichiometric amount of copper is
required. An alternative nucleophilic substitution mechanism
of organostannanes and electrophilic sulfur reagents cannot be
excluded at this point.13d
1
afford 10 (1.90 g, 87%) as a pale yellow solid: H NMR (300 MHz,
CDCl3) δ 7.50−7.33 (m, 4H), 6.94−6.68 (m, 4H), 3.80 (s, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 160.0, 132.8, 128.6, 114.7, 55.5.
Characterization data matched the literature report.13c
(4-Methoxyphenyl)(phenyl)sulfane (11). According to the general
protocol A, tributylphenylstannane (55.1 mg, 0.150 mmol), 1,2-bis(4-
methoxyphenyl)disulfane (27.8 mg, 0.100 mmol), KF (11.6 mg, 0.200
mmol), and CuCl (14.9 mg, 0.150 mmol) were added to anhydrous
1,4-dioxane (2.00 mL). The reaction mixture was stirred at 120 °C for
In summary, we have developed a simple and ligand-free
method for the cross-coupling of aryl and alkyl stannanes with
electrophilic sulfur reagents mediated by inexpensive Cu(I)
salt. To the best of our knowledge, this study represents the
D
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48 h and afforded after chromatographic purification on SiO2
(Hexanes/EtOAc, 25:1) 11 (17.7 mg, 82%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 7.50−7.38 (m, 2H), 7.28−7.09 (m, 5H),
6.94−6.86 (m, 2H), 3.83 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 160.0, 138.8, 135.5, 129.1, 128.4, 125.9, 124.5, 115.1, 55.5.
Characterization data matched the literature report.19
(55.5 mg, 0.150 mmol), 1,2-bis(4-methoxyphenyl)disulfane (27.8 mg,
0.100 mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150
mmol) were added to anhydrous 1,4-dioxane (2.00 mL). The reaction
mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 10:1) 14e
1
1
(19.1 mg, 87%) as a light yellow oil: H NMR (300 MHz, CDCl3) δ
(4-(Benzyloxy)phenyl)(3,4-dimethoxyphenyl)sulfane (14a). Ac-
cording to the general protocol A, (4-(benzyloxy)phenyl)tributyl-
stannane (71.0 mg, 0.150 mmol), 1,2-bis(3,4-dimethoxyphenyl)-
disulfane (33.8 mg, 0.100 mmol), KF (11.6 mg, 0.200 mmol), and
CuCl (14.9 mg, 0.150 mmol) were added to anhydrous 1,4-dioxane
(2.00 mL). The reaction mixture was stirred at 120 °C for 48 h and
afforded after chromatographic purification on SiO2 (Hexanes/
EtOAc, 10:1) 14a (28.2 mg, 80%) as a light yellow oil: IR (ATR)
ν = 3067, 3033, 3003, 2933, 2840, 1592, 1495, 1465, 1443, 1398,
7.04−6.96 (m, 2H), 6.87−6.83 (m, 1H), 6.82−6.74 (m, 2H), 6.55
(dd, J = 3.7, 1.8 Hz, 1H), 6.24−6.16 (m, 1H), 3.76 (s, 3H), 3.57 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.1, 133.0, 129.3, 128.2,
125.8, 119.1, 114.8, 108.3, 55.5, 34.2. Characterization data matched
the literature report.22
4-((4-Methoxyphenyl)thio)-1-methyl-1H-pyrazole (14f). Accord-
ing to the general protocol A, 1-methyl-4-(tributylstannyl)-1H-
pyrazole (55.7 mg, 0.150 mmol), 1,2-bis(4-methoxyphenyl)disulfane
(27.8 mg, 0.100 mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9
mg, 0.150 mmol) were added to anhydrous 1,4-dioxane (2.00 mL).
The reaction mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 3:1) 14f
(12.3 mg, 56%) as a light yellow oil: IR (ATR) ν = 3123, 2936, 2840,
1596, 1577, 1521, 1496, 1465, 1443, 1290, 1246, 1179, 1123, 1033,
1
1253, 1235, 1179, 1141, 1030, 881, 829, 810, 743, 702 cm−1; H
NMR (300 MHz, CDCl3) δ 7.45−7.26 (m, 7H), 6.96−6.86 (m, 4H),
6.80 (d, J = 8.3 Hz, 1H), 5.07−5.03 (m, 2H), 3.86 (s, 3H), 3.81 (d, J
= 0.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.3, 149.5,
148.7, 136.8, 132.7, 128.8, 128.2, 127.7 (2), 127.6, 124.2, 115.9,
114.6, 111.9, 70.3, 56.1, 56.1; HRMS (ESI) m/z: [M + Na]+ calcd for
C21H20O3SNa 375.1025; found 375.1027.
According to the general protocol A, (4-(benzyloxy)phenyl)-
tributylstannane (1.20 g, 2.50 mmol), 1,2-bis(3,4-dimethoxyphenyl)-
disulfane (0.57 g, 1.67 mmol), KF (192 mg, 3.34 mmol), and CuCl
(248 mg, 2.50 mmol) were added to anhydrous 1,4-dioxane (33.0
mL). The reaction mixture was stirred at 120 °C for 48 h and afforded
after chromatographic purification on SiO2 (Hexanes/EtOAc, 10:1)
14a (845 mg, 72%).
1
981, 829, 709, 661 cm−1; H NMR (300 MHz, CDCl3) δ 7.58−7.43
(m, 2H), 7.19−7.12 (m, 2H), 6.84−6.74 (m, 2H), 3.90 (s, 3H), 3.76
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.4, 144.1, 134.5,
129.7, 129.2, 114.7, 55.5, 39.4; HRMS (ESI) m/z: [M + H]+ calcd for
C11H13OSN2 221.0743; found 221.0739.
(4-Trifluoromethyl)phenyl)(phenyl)sulfane (14g). According to
the general protocol A, tributylphenylstannane (55.1 mg, 0.150
mmol), 1,2-bis(4-(trifluoromethyl)phenyl)disulfane (35.4 mg, 0.100
mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol)
were added to anhydrous 1,4-dioxane (2.00 mL). The reaction
mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 30:1) 14g
(4-Chlorophenyl)(4-methoxyphenyl)sulfane (14b). According to
the general protocol A, tributyl(4-chlorophenyl)stannane (60.2 mg,
0.150 mmol), 1,2-bis(4-methoxyphenyl)disulfane (27.8 mg, 0.100
mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol)
were added to anhydrous 1,4-dioxane (2.00 mL). The reaction
mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 10:1) 14b
1
(14.8 mg, 58%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.48−7.38 (m, 4H), 7.38−7.27 (m, 3H), 7.25−7.19 (m, 2H);
13C{1H} NMR (75 MHz, CDCl3) δ 143.0 (J(C−F) = 1.5), 133.7,
132.6, 129.8, 128.8, 128.4, 128.0, 143.0 (J(C−F) = 3.9), 122.4.
Characterization data matched the literature report.23
1
(17.6 mg, 70%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.43−7.37 (m, 2H), 7.22−7.16 (m, 2H), 7.11−7.04 (m, 2H), 6.95−
6.87 (m, 2H), 3.83 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
160.2, 137.5, 135.6, 133.1, 131.8, 129.5, 129.2, 115.3, 55.5.
Characterization data matched the literature report.20
(4-Fluorophenyl)(phenyl)sulfane (14h). According to the general
protocol A, tributylphenylstannane (55.1 mg, 0.150 mmol), 1,2-bis(4-
fluorophenyl)disulfane (25.4 mg, 0.100 mmol), KF (11.6 mg, 0.200
mmol), and CuCl (14.9 mg, 0.150 mmol) were added to anhydrous
1,4-dioxane (2.00 mL). The reaction mixture was stirred at 120 °C for
48 h and afforded after chromatographic purification on SiO2
2-((4-Methoxyphenyl)thio)furan (14c). According to the general
protocol A, tributyl(furan-2-yl)stannane (55.6 mg, 0.150 mmol), 1,2-
bis(4-methoxyphenyl)disulfane (27.8 mg, 0.100 mmol), KF (11.6 mg,
0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were added to
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 20:1) 14c (9.00 mg, 44%) as a colorless oil:
IR (ATR) ν = 2959, 2933, 2840, 1595, 1499, 1465, 1290, 1249, 1179,
1156, 1037, 1011, 911, 829, 750 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.51 (dd, J = 2.0, 0.9 Hz, 1H), 7.28−7.21 (m, 2H), 6.86−6.80 (m,
2H), 6.64 (dd, J = 3.2, 0.9 Hz, 1H), 6.41 (dd, J = 3.3, 2.0 Hz, 1H),
3.77 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.2, 146.1, 133.1,
131.4, 126.1, 117.9, 114.9, 111.8, 55.5; HRMS (ESI) m/z: [M + H]+
calcd for C11H11O2SH 207.0474; found 207.0470.
2-((4-Methoxyphenyl)thio)thiophene (14d). According to the
general protocol A, tributyl(thiophen-2-yl)stannane (56.0 mg, 0.150
mmol), 1,2-bis(4-methoxyphenyl)disulfane (27.8 mg, 0.100 mmol),
KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were
added to anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was
stirred at 120 °C for 48 h and afforded after chromatographic
purification on SiO2 (Hexanes/EtOAc, 20:1) 14d (12.0 mg, 54%) as a
light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.37 (dd, J = 5.4, 1.2
Hz, 1H), 7.30−7.27 (m, 2H), 7.21 (dd, J = 3.6, 1.3 Hz, 1H), 7.00 (dd,
J = 5.3, 3.5 Hz, 1H), 6.87−6.78 (m, 2H), 3.78 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 159.1, 134.0, 133.1, 131.3, 130.2, 128.5,
127.8, 114.8, 55.5. Characterization data matched the literature
report.21
1
(Hexanes/EtOAc, 30:1) 14h (12.1 mg, 60%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 7.37−7.28 (m, 2H), 7.27−7.12 (m, 5H),
7.05−6.90 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 164.2 and
160.9 (J(C−F) = 247.7 Hz), 136.8, 134.3, and 134.2 (J(C−F) = 8.2
Hz), 130.4 and 130.3 (J(C−F) = 3.5 Hz), 130.1, 129.3, 126.9, 116.7,
and 116.4 (J(C−F) = 22.1 Hz). Characterization data matched the
literature report.24
tert-Butyl (2-((4-(Benzyloxy)phenyl)thio)ethyl)carbamate (14i).
According to the general protocol A, (4-(benzyloxy)phenyl)tributyl-
stannane (71.0 mg, 0.150 mmol), tert-butyl (2-((2,5-dioxopyrrolidin-
1-yl)thio)ethyl)carbamate (27.4 mg, 0.100 mmol), KF (11.6 mg,
0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were added to
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 10:1) 14i (14.7 mg, 41%) as a colorless oil:
IR (ATR) ν = 3424, 3362, 2977, 2929, 1704, 1596, 1495, 1458, 1395,
1
1369, 1246, 1171, 1026, 952, 829, 739, 702 cm−1; H NMR (300
MHz, CDCl3) δ 7.44−7.31 (m, 7H), 6.97−6.87 (m, 2H), 5.05 (s,
2H), 1.43 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 158.6, 155.9,
136.8, 133.8, 128.8, 128.2, 127.6, 125.6, 115.8, 79.6, 70.3, 39.6, 36.3,
28.5; HRMS (ESI) m/z: [M + Na]+ calcd for C20H25O3SNNa
382.1447; found 382.1450.
2-Ethylhexyl 3-((4-(Benzyloxy)phenyl)thio)propanoate (14j). Ac-
cording to the general protocol A, (4-(benzyloxy)phenyl)tributyl-
stannane (71.0 mg, 0.150 mmol), 2-ethylhexyl 3-((2,5-dioxo-
pyrrolidin-1-yl)thio)propanoate (31.5 mg, 0.100 mmol), KF (11.6
mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were added to
2-((4-Methoxyphenyl)thio)-1-methyl-1H-pyrrole (14e). According
to the general protocol A, 1-methyl-2-(tributylstannyl)-1H-pyrrole
E
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Note
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 25:1) 14j (18.8 mg, 47%) as a colorless oil:
IR (ATR) ν = 3342, 2987, 2945, 1710, 1596, 1490, 1458, 1403, 1365,
(20.0 mg, 85%) as a light yellow oil: IR (ATR) ν = 3294, 3249, 3175,
3108, 3052, 2929, 2854, 1666, 1599, 1544, 1495, 1451, 1398, 1324,
1261, 1182, 1097, 1019, 836, 747 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.55−7.38 (m, 3H), 7.36−7.28 (m, 2H), 3.51 (dq, J = 13.3, 7.1, 6.3
Hz, 1H), 2.15 (s, 3H), 2.07−1.92 (m, 2H), 1.88−1.46 (m, 6H);
13C{1H} NMR (75 MHz, CDCl3) δ 168.5, 136.5, 132.2, 131.8, 120.4,
46.9, 33.6, 24.8, 24.7; HRMS (ESI) m/z calcd for C13H17OSNNa [M
+ Na]+ 258.0929; found 258.0930. HRMS (ESI) m/z: [M + Na]+
calcd for C13H17OSNNa 258.0923; found 258.0926.
1
1243, 1168, 1020, 957, 819, 734, 690 cm−1; H NMR (300 MHz,
CDCl3) δ 7.46−7.30 (m, 7H), 6.96−6.88 (m, 2H), 5.05 (s, 2H), 3.99
(dd, J = 5.8, 1.2 Hz, 2H), 3.05 (t, J = 7.4 Hz, 2H), 2.57 (t, J = 7.4 Hz,
2H), 1.32−1.22 (m, 8H), 0.95−0.82 (m, 7H); 13C{1H} NMR (75
MHz, CDCl3) δ 172.2, 158.6, 136.8, 134.2, 128.8, 128.2, 127.6, 125.8,
115.7, 70.3, 67.3, 38.9, 34.8, 31.2, 30.5, 29.1, 23.9, 23.1, 14.2, 11.1;
HRMS (ESI) m/z: [M + Na]+ calcd for C24H32O3SNa 423.1964;
found 423.1971.
Cyclobutyl(4-methoxyphenyl)sulfane (14n). According to the
general protocol B, to a solution of 5-chloro-1-aza-5-stannabicyclo-
[3.3.3]undecane (150 mg, 0.510 mmol) in anhydrous THF (5.00
mL) was added cyclobutylmagnesium bromide solution (3.10 mL,
1.55 mmol, 0.5 M in methyltetrahydrofuran) under N2 at 0 °C. The
mixture was allowed to stir for 15 min and then warmed up to rt. After
stirring for 12 h, the reaction was quenched by H2O (10.0 mL). The
resulted mixture was then extracted with EtOAc (3 × 50.0 mL). The
combined organic layer was dried over Na2SO4, concentrated, and
vacuumed to afford the crude product (151 mg, 91%) as a yellow oil.
The crude alkyl tin reagents were used without further purification.
According to the general protocol A, the above crude 5-cyclobutyl-1-
aza-5-stannabicyclo[3.3.3]undecane (47.1 mg, 0.150 mmol), 1,2-
bis(4-methoxyphenyl)disulfane (27.8 mg, 0.100 mmol), KF (11.6 mg,
0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were added to
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 100:1) 14n (15.7 mg, 82%) as a colorless oil:
IR (ATR) ν = 2940, 2858, 2836, 1596, 1573, 1495, 1465, 1443, 1287,
1246, 1179, 1104, 1033, 829, 713 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.34−7.26 (m, 2H), 6.90−6.79 (m, 2H), 3.79 (s, 3H), 3.78−3.66
(m, 1H), 2.39−2.25 (m, 2H), 2.10−1.81 (m, 4H); 13C{1H} NMR
(75 MHz, CDCl3) δ 159.0, 133.6, 126.3, 114.5, 55.4, 42.1, 30.6, 18.5;
HRMS (ESI) m/z: [M + H]+ calcd for C11H15OS 195.0838; found
195.0844.
tert-Butyl S-(4-(Benzyloxy)phenyl)-N-(tert-butoxycarbonyl)-L-cys-
teinate (14k). According to the general protocol A, (4-(benzyloxy)-
phenyl)tributylstannane (71.0 mg, 0.150 mmol), tert-butyl N-(tert-
butoxycarbonyl)-S-(2,5-dioxopyrrolidin-1-yl)-L-cysteinate (37.4 mg,
0.100 mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg,
0.150 mmol) were added to anhydrous 1,4-dioxane (2.00 mL). The
reaction mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 8:1) 14k
(24.4 mg, 53%) as a colorless oil: IR (ATR) ν = 3442, 3350, 2982,
2955, 1710, 1594, 1496, 1458, 1400, 1368, 1247, 1165, 1024, 957,
1
823, 736, 698 cm−1; H NMR (300 MHz, CDCl3) δ 7.44−7.29 (m,
7H), 6.93−6.84 (m, 2H), 5.29−5.16 (m, 1H), 5.04 (s, 2H), 4.39 (d, J
= 6.6 Hz, 1H), 3.39−3.02 (m, 2H), 1.46−1.39 (m, 18H); 13C{1H}
NMR (75 MHz, CDCl3) δ 169.9, 158.6, 155.1, 136.8, 135.0, 132.8,
128.8, 128.2, 127.6, 115.8, 82.6, 70.3, 54.3, 39.0, 28.4, 28.1; HRMS
(ESI) m/z: [M + Na]+ calcd for C25H33O5SNNa 482.1972; found
482.1978.
Cyclohexyl(4-acetylaminophenyl)sulfane (14l). According to the
general protocol B, to a solution of 5-chloro-1-aza-5-stannabicyclo-
[3.3.3]undecane (150 mg, 0.510 mmol) in anhydrous THF (5.00
mL) was added cyclohexylmagnesium chloride solution (1.53 mL,
1.53 mmol, 1.0 M in methyltetrahydrofuran) under N2 at 0 °C. The
mixture was allowed to stir for 15 min and then warmed up to rt. After
stirring for 12 h, the reaction was quenched by H2O (10.0 mL). The
resulted mixture was then extracted with EtOAc (3 × 50.0 mL). The
combined organic layer was dried over Na2SO4, concentrated, and
vacuumed to afford the crude product (147 mg, 84%) as a light-yellow
oil. The crude alkyl tin reagents were used without further
purification. According to the general protocol A, 5-cyclohexyl-1-
aza-5-stannabicyclo[3.3.3]undecane25 (51.3 mg, 0.150 mmol), 1,2-
bis(4-acetylaminophenyl)disulfane (33.2 mg, 0.100 mmol), KF (11.6
mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were added to
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 100:1) 14l (16.0 mg, 64%) as a white foam:
1H NMR (300 MHz, CDCl3) δ 7.51−7.29 (m, 5H), 2.99 (td, J = 10.3,
3.6 Hz, 1H), 2.16 (s, 3H), 2.02−1.84 (m, 2H), 1.81−1.75 (m, 2H),
1.44−1.13 (m, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.5, 137.1,
133.8, 130.1, 120.3, 47.5, 33.5, 26.2, 25.9, 24.7. Characterization data
matched the literature report.26
N-(4-(Cyclopentylthio)phenyl)acetamide (14m). According to the
general protocol B, to a solution of 5-chloro-1-aza-5-stannabicyclo-
[3.3.3]undecane (200 mg, 0.680 mmol) in anhydrous THF (5.00
mL) was added cyclopentylmagnesium bromidee solution (2.00 mL,
2.00 mmol, 1.0 M in tetrahydrofuran) under N2 at 0 °C. The mixture
was allowed to stir for 15 min and then warmed up to rt. After stirring
for 12 h, the reaction was quenched by H2O (10.0 mL). The resulted
mixture was then extracted with EtOAc (3 × 50.0 mL). The
combined organic layer was dried over Na2SO4, concentrated, and
vacuumed to afford the crude product (159 mg, 74%) as light-yellow
oil. The crude alkyl tin reagents were used without further
purification. According to the general protocol A, the above crude
5-cyclopentyl-1-aza-5-stannabicyclo[3.3.3]undecane (49.2 mg, 0.150
mmol), N,N′-(disulfanediylbis(4,1-phenylene))diacetamide (33.2 mg,
0.100 mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150
mmol) were added to anhydrous 1,4-dioxane (2.00 mL). The reaction
mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 2:1) 14m
Cyclopropyl(4-methoxyphenyl)sulfane (14o). According to the
general protocol B, to a solution of 5-chloro-1-aza-5-stannabicyclo-
[3.3.3]undecane (100 mg, 0.340 mmol) in anhydrous THF (5.00
mL) was added cyclobutylmagnesium bromide solution (2.80 mL,
1.68 mmol, 0.6 M in THF) under N2 at 0 °C. The mixture was
allowed to stir for 15 min and then warmed up to rt. After stirring for
12 h, the reaction was quenched by H2O (10.0 mL). The resulted
mixture was then extracted with EtOAc (3 × 50.0 mL). The
combined organic layer was dried over Na2SO4, concentrated, and
vacuumed to afford the crude product (81.6 mg, 80%) as a light-
yellow oil. The crude alkyl tin reagents were used without further
purification. According to the general protocol A, the above crude 5-
cyclopropyl-1-aza-5-stannabicyclo[3.3.3]undecane (45.0 mg, 0.150
mmol), 1,2-bis(4-methoxyphenyl)disulfane (27.8 mg, 0.100 mmol),
KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were
added to anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was
stirred at 120 °C for 48 h and afforded after chromatographic
purification on SiO2 (Hexanes/EtOAc, 100:1) 14o (15.0 mg, 83%) as
1
a colorless oil: H NMR (300 MHz, CDCl3) δ 7.45−7.31 (m, 2H),
6.89−6.74 (m, 2H), 3.80 (s, 3H), 2.18 (tt, J = 7.4, 4.4 Hz, 1H), 1.04−
0.93 (m, 2H), 0.74−0.59 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3)
δ 158.3, 130.1, 128.9, 114.6, 55.5, 14.2, 8.6. Characterization data
matched the literature report.27
4-((4-Methoxyphenyl)thio)tetrahydro-2H-pyran (14p). According
to the general protocol B, to a solution of 5-chloro-1-aza-5-
stannabicyclo[3.3.3]undecane (100 mg, 0.340 mmol) in anhydrous
THF (5.00 mL) was added (tetrahydro-2H-pyran-4-yl)magnesium
chloride solution (3.36 mL, 1.68 mmol, 0.5 M in THF) under N2 at 0
°C. The mixture was allowed to stir for 15 min and then warmed up
to rt. After stirring for 12 h, the reaction was quenched by H2O (10.0
mL). The resulted mixture was then extracted with EtOAc (3 × 50.0
mL). The combined organic layer was dried over Na2SO4,
concentrated, and vacuumed to afford the crude product (103.3
mg, 88%) as a yellow solid. The crude alkyl tin reagents were used
without further purification. According to the general protocol A, the
above crude 5-(tetrahydro-2H-pyran-4-yl)-1-aza-5-stannabicyclo-
F
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Note
[3.3.3]undecane28(51.6 mg, 0.150 mmol), 1,2-bis(4-methoxyphenyl)-
disulfane (22.8 mg, 0.100 mmol), KF (11.6 mg, 0.200 mmol), and
CuCl (14.9 mg, 0.150 mmol) were added to anhydrous 1,4-dioxane
(2.00 mL). The reaction mixture was stirred at 120 °C for 48 h and
afforded after chromatographic purification on SiO2 (Hexanes/
EtOAc, 40:1) 14p (17.5 mg, 78%) as a colorless oil: IR (ATR) ν =
2948, 2840, 1596, 1495, 1465, 1447, 1387, 1290, 1249, 1179, 1134,
1089, 1033, 1011, 985, 888, 832 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.50−7.34 (m, 2H), 6.92−6.71 (m, 2H), 4.03−3.90 (m, 2H), 3.80
(s, 3H), 3.38 (ddd, J = 11.6, 10.8, 2.4 Hz, 2H), 3.07 (tt, J = 10.8, 4.1
Hz, 1H), 1.95−1.79 (m, 2H), 1.70−1.49 (m, 2H); 13C{1H} NMR
(75 MHz, CDCl3) δ 159.8, 136.3, 123.7, 114.6, 67.5, 55.4, 44.7, 33.3;
HRMS (ESI) m/z: [M + H]+ calcd for C12H17O2S 225.0944; found
225.0941.
THF (5.00 mL) was added s-butyllithum solution (3.60 mL, 5.10
mmol, 1.40 M in hexane) under N2 at 0 °C. The mixture was allowed
to stir for 15 min and then warmed up to rt. After stirring for 12 h, the
reaction was quenched by H2O (10.0 mL). The resulted mixture was
then extracted with EtOAc (3 × 50.0 mL). The combined organic
layer was dried over Na2SO4, concentrated, and vacuumed to afford
the crude product (290 mg, 92%) as a yellow oil. The crude alkyl tin
reagents were used without further purification. According to the
general protocol A, the above crude 5-(1-methylpropyl)-1-aza-5-
stannabicyclo[3.3.3]undecane25 (63.2 mg, 0.200 mmol), 1,2-bis(4-
acetylaminophenyl)disulfane (33.2 mg, 0.100 mmol), KF (11.6 mg,
0.200 mmol), and CuCl (19.8 mg, 0.200 mmol) were added to
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 100:1) 14s (18.3 mg, 82%) as a yellow oil: IR
(ATR) ν = 3301, 3178, 3104, 3048, 2966, 2925, 2877, 1670, 1596,
1532, 1499, 1462, 1398, 1376, 1316, 1294, 1261, 1019, 832 cm−1; 1H
NMR (300 MHz, CDCl3) δ 7.51−7.27 (m, 4H), 3.06 (h, J = 6.7 Hz,
1H), 2.17 (s, 3H), 1.67−1.56 (m, 1H), 1.49 (dt, J = 14.1, 7.1 Hz,
1H), 1.24 (d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 168.4, 137.1, 133.8, 130.4, 120.2, 45.8,
29.5, 24.8, 20.6, 11.6; HRMS (ESI) m/z: [M + Na]+ calcd for
C12H17ONSNa 246.0923; found 249.0926.
n-Butyl(4-acetylaminophenyl)sulfane (14t). According to the
general protocol B, to a solution of 5-chloro-1-aza-5-stannabicyclo-
[3.3.3]undecane (150 mg, 0.510 mmol) in anhydrous THF (5.00
mL) was added n-BuLi (0.410 mL, 1.02 mmol, 2.5 M in hexane)
under N2 at 0 °C. The mixture was allowed to stir for 15 min and then
warmed up to rt. After stirring for 12 h, the reaction was quenched by
H2O (10.0 mL). The resulted mixture was then extracted with EtOAc
(3 × 50.0 mL). The combined organic layer was dried over Na2SO4,
concentrated, and vacuumed to afford the crude product (147 mg,
91%) as a dark yellow oil. The crude alkyl tin reagents were used
without further purification. According to the general protocol B, the
above crude 5-butyl-1-aza-5-stannabicyclo[3.3.3]undecane (47.6 mg,
0.150 mmol), 1,2-bis(4-acetylaminophenyl)disulfane (33.2 mg, 0.100
mmol), KF (11.6 mg, 0.200 mmol), and CuCl (14.9 mg, 0.150 mmol)
were added to anhydrous 1,4-dioxane (2.00 mL). The reaction
mixture was stirred at 120 °C for 48 h and afforded after
chromatographic purification on SiO2 (Hexanes/EtOAc, 100:1) 14t
(10.0 mg, 45%) as a white foam: IR (ATR) ν = 3309, 3108, 3056,
2959, 2929, 2873, 1670, 1599, 1536, 1499, 1397, 1376, 1320, 1261,
1097, 1019, 825 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.52−7.39 (m,
2H), 7.30 (td, J = 6.7, 3.2 Hz, 3H), 2.93−2.80 (m, 2H), 2.16 (s, 3H),
1.65−1.50 (m, 2H), 1.48−1.33 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 168.4, 136.3, 132.1, 130.7, 120.5,
34.3, 31.4, 24.7, 22.0, 13.8; HRMS (ESI) m/z: [M + Na]+ calcd for
C12H17ONSNa 246.0923; found 249.0922.
4-((4-Methoxyphenyl)thio)-1-methylpiperidine (14q). According
to the general protocol B, to a solution of 5-chloro-1-aza-5-
stannabicyclo[3.3.3]undecane (100 mg, 0.340 mmol) in anhydrous
THF (5.00 mL) was added (tetrahydro-2H-pyran-4-yl)magnesium
chloride solution (2.80 mL, 1.68 mmol, 0.6 M in THF) under N2 at 0
°C. The mixture was allowed to stir for 15 min and then warmed up
to rt. After stirring for 12 h, the reaction was quenched by H2O (10.0
mL). The resulted mixture was then extracted with EtOAc (3 × 50.0
mL). The combined organic layer was dried over Na2SO4,
concentrated, and vacuumed to afford the crude product (102 mg,
84%) as a yellow solid. The crude alkyl tin reagents were used without
further purification. According to the general protocol A, the above
crude 5-(1-methylpiperidin-4-yl)-1-aza-5-stannabicyclo[3.3.3]-
undecane24(53.6 mg, 0.150 mmol), 1,2-bis(4-methoxyphenyl)-
disulfane (22.8 mg, 0.100 mmol), KF (11.6 mg, 0.200 mmol), and
CuCl (14.9 mg, 0.150 mmol) were added to anhydrous 1,4-dioxane
(2.00 mL). The reaction mixture was stirred at 120 °C for 48 h and
afforded after chromatographic purification on SiO2 (DCM:MeOH,
15:1) 14q (19.9 mg, 84%) as a colorless oil: IR (ATR) ν = 3417,
2940, 2840, 2784, 2735, 2672, 2471, 1596, 1495, 1469, 1380, 1287,
1
1249, 1179, 1130, 1108, 1033, 1000, 978, 832 cm−1; H NMR (300
MHz, CDCl3 δ 7.44−7.34 (m, 2H), 6.91−6.75 (m, 2H), 3.79 (s, 3H),
2.91−2.84 (m, 3H), 2.31 (s, 3H), 2.23−2.08 (m, 2H), 2.04−1.92 (m,
2H), 1.68 (dtd, J = 13.7, 10.0, 3.7 Hz, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 159.8, 136.1, 124.0, 114.6, 55.5, 54.7, 45.9, 44.6, 31.8;
HRMS (ESI) m/z: [M + H]+ calcd for C13H20ONS 238.1260; found
238.1259.
(Bicyclo[2.2.1]heptan-2-yl)(4-methoxyphenyl)sulfane (14r). Ac-
cording to the general protocol B, to a solution of 5-chloro-1-aza-5-
stannabicyclo[3.3.3]undecane (100 mg, 0.340 mmol) in anhydrous
THF (5.00 mL) was added exo-2-norbornylzinc bromide solution
(3.36 mL, 1.68 mmol, 0.5 M in THF) under N2 at 0 °C. The mixture
was allowed to stir for 15 min and then heated at 80 °C. After stirring
for 12 h, the reaction was quenched by H2O (10.0 mL). The resulted
mixture was then extracted with EtOAc (3 × 50.0 mL). The
combined organic layer was dried over Na2SO4, concentrated, and
vacuumed to afford the crude product (118 mg, 98%) as a light-yellow
oil. The crude alkyl tin reagents were used without further
purification. According to the general protocol A, the above crude
5-(exo-2-norbornyl)-1-aza-5-stannabicyclo[3.3.3]undecane (53.1 mg,
0.150 mmol), N,N′-(disulfanediylbis(4,1-phenylene))diacetamide
(33.2 mg, 0.100 mmol), KF (11.6 mg, 0.200 mmol), and CuCl
(14.9 mg, 0.150 mmol) were added to anhydrous 1,4-dioxane (2.00
mL). The reaction mixture was stirred at 120 °C for 48 h and afforded
after chromatographic purification on SiO2 (Hexanes/EtOAc, 3:1)
14r (17.5 mg, 67%) as a colorless oil: IR (ATR) ν = 3298, 3178,
3104, 3048, 2951, 2869, 1666, 1596, 1536, 1495, 1454, 1398, 1376,
tert-Butyl(3,4-dimethoxyphenyl)sulfane (14u). According to the
general protocol A, to a solution of 5-chloro-1-aza-5-stannabicyclo-
[3.3.3]undecane (200 mg, 0.680 mmol) in anhydrous THF (5.00
mL) was added tert-butylmagnesium chloride (1.70 mL, 3.40 mmol,
2.0 M in diethyl ether) under N2 at 0 °C. The mixture was allowed to
stir for 15 min and then warmed up to rt. After stirring for 12 h, the
reaction was quenched by H2O (10 mL). The resulted mixture was
then extracted with EtOAc (3 × 50.0 mL). The combined organic
layer was dried over Na2SO4, concentrated, and vacuumed to afford
the crude product (159 mg, 74%) as white foam. The crude alkyl tin
reagents were used without further purification. According to the
general protocol B, the above crude 5-(tert-butyl)-1-aza-5-stanna-
bicyclo[3.3.3]undecane (47.7 mg, 0.150 mmol), 1,2-bis(3,4-
dimethoxyphenyl)disulfane (33.8 mg, 0.100 mmol), KF (11.6 mg,
0.200 mmol), and CuCl (14.9 mg, 0.150 mmol) were added to
anhydrous 1,4-dioxane (2.00 mL). The reaction mixture was stirred at
120 °C for 48 h and afforded after chromatographic purification on
SiO2 (Hexanes/EtOAc, 100:1) 14u (11.5 mg, 51%) as a colorless oil:
IR (ATR) ν = 2962, 2933, 2862, 1737, 1588, 1506, 1462, 1395, 1320,
1
1320, 1261, 1182, 1097, 1019, 970, 832, 736 cm−1; H NMR (300
MHz, CDCl3 δ 7.57−7.26 (m, 5H), 3.11 (ddd, J = 8.3, 4.5, 1.7 Hz,
1H), 2.34−2.19 (m, 2H), 2.16 (s, 3H), 1.84−1.09 (m, 10H);
13C{1H} NMR (75 MHz, CDCl3) δ 168.4, 136.2, 132.8, 130.9, 120.5,
77.2, 49.3, 42.4, 38.6, 36.7, 35.6, 29.0, 28.8, 24.7; HRMS (ESI) m/z:
[M + Na]+ calcd for C15H19ONSNa 284.1080; found 284.1075.
1-Methylpropyl(4-acetylaminophenyl)sulfane (14s). According
to the general protocol B, to a solution of 5-chloro-1-aza-5-
stannabicyclo[3.3.3]undecane(300 mg, 1.02 mmol) in anhydrous
1
1257, 1235, 1179, 1141, 1030, 862, 814, 769, 702 cm−1; H NMR
(300 MHz, CDCl3) δ 7.11 (dd, J = 8.2, 2.1 Hz, 1H), 7.03 (d, J = 2.0
Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.28 (s,
G
https://dx.doi.org/10.1021/acs.joc.0c01399
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
9H); 13C{1H} NMR (75 MHz, CDCl3) δ 150.0, 148.5, 130.6, 124.0,
120.5, 111.0, 56.1, 56.0, 45.9, 31.0; HRMS (ESI) m/z: [M + Na]+
calcd for C12H18O2SNa 249.0925; found 249.0923.
Newell, D. R.; Calvete, J. A.; Clendeninn, N.; Boddy, A. V. Phase I
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01399.
■
sı
Experimental procedures, characterization data of all
new compound, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(4) (a) Kwong, F. Y.; Buchwald, S. L. A General, Efficient, and
Inexpensive Catalyst System for the Coupling of Aryl Iodides and
Thiols. Org. Lett. 2002, 4, 3517−3520. (b) Murata, M.; Buchwald, S.
L. A General and Efficient Method for the Palladium-Catalyzed
Cross-Coupling of Thiols and Secondary Phosphines. Tetrahedron
Maciej A. Walczak − Department of Chemistry, University of
Colorado, Boulder, Colorado 80309, United States;
orcid.org/0000-0002-8049-0817; Email: maciej.walczak@
colorado.edu
́
2004, 60, 7397−7403. (c) Fernandez-Rodríguez, M. A.; Shen, Q.;
Authors
Hartwig, J. F. A General and Long-Lived Catalyst for the Palladium-
Catalyzed Coupling of Aryl Halides with Thiols. J. Am. Chem. Soc.
2006, 128, 2180−2181. (d) Alvaro, E.; Hartwig, J. F. Resting State
and Elementary Steps of the Coupling of Aryl Halides with Thiols
Catalyzed by Alkylbisphosphine Complexes of Palladium. J. Am.
Chem. Soc. 2009, 131, 7858−7868. (e) Sayah, M.; Organ, M. G.
Carbon−Sulfur Bond Formation of Challenging Substrates at Low
Temperature by Using Pd-PEPPSI-IPent. Chem. - Eur. J. 2011, 17,
11719−11722. (f) Gogoi, P.; Hazarika, S.; Sarma, M. J.; Sarma, K.;
Barman, P. Nickel−Schiff Base Complex Catalyzed C-S Cross-
Coupling of Thiols with Organic Chlorides. Tetrahedron 2014, 70,
7484−7489. (g) Xu, J.; Liu, R. Y.; Yeung, C. S.; Buchwald, S. L.
Monophosphine Ligands Promote Pd-Catalyzed C−S Cross-Cou-
pling Reactions at Room Temperature with Soluble Bases. ACS Catal.
2019, 9, 6461−6466.
(5) (a) Murray, S. G.; Hartley, F. R. Coordination Chemistry of
Thioethers, Selenoethers, and Telluroethers in Transition-Metal
Complexes. Chem. Rev. 1981, 81, 365−414. (b) Lee, C.-F.; Liu, Y.-
C.; Badsara, S. S. Transition-Metal-Catalyzed C−S Bond Coupling
Reaction. Chem. - Asian J. 2014, 9, 706−722. (c) Oderinde, M. S.;
Frenette, M.; Robbins, D. W.; Aquila, B.; Johannes, J. W. Photoredox
Mediated Nickel Catalyzed Cross-Coupling of Thiols with Aryl and
Heteroaryl Iodides via Thiyl Radicals. J. Am. Chem. Soc. 2016, 138,
1760−1763. (d) Scattolin, T.; Senol, E.; Yin, G.; Guo, Q.;
Schoenebeck, F. Site-Selective C−S Bond Formation at C−Br over
C−OTf and C−Cl Enabled by An Air-Stable, Easily Recoverable, and
Recyclable Palladium (I) Catalyst. Angew. Chem., Int. Ed. 2018, 57,
12425−12429.
Feng Zhu − Department of Chemistry, University of Colorado,
Boulder, Colorado 80309, United States
Zhenhao Chen − Department of Chemistry, University of
Colorado, Boulder, Colorado 80309, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01399
Author Contributions
†F.Z. and Z.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of Colorado
Boulder, National Science Foundation (CAREER Award No.
CHE-1753225). Mass spectral analyses were recorded at the
University of Colorado Boulder Central Analytical Laboratory
Mass Spectrometry Core Facility (partially funded by the NIH,
RR026641).
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