Palladium-catalyzed thiocarbonylation of aryl, vinyl, and benzyl bromides

Article abstract of DOI:10.1021/jo5009965

(Chemical Equation Presented) A catalytic protocol for synthesis of thioesters from aryl, vinyl, and benzyl bromides as well as benzyl chlorides was developed using only stoichiometric amounts of carbon monoxide, produced from a solid CO precursor inside a two-chamber system. As a catalytic system, the combination of bis(benzonitrile) palladium(II) chloride and Xantphos furnished the highest yields of the desired compounds, along with the weak base, NaOAc, in anisole at 120°C. The choice of catalytic system as well as solvent turned out to be important in order to ensure a high chemoselectivity in the reaction. Both electron-rich and electron-deficient aryl bromides worked well in this reaction. Addition of 1 equiv of sodium iodide to the reaction improved the chemoselectivity with the electron-deficient aryl bromides. The thiol scope included both aryl and alkyl thiols, including 2-mercaptobenzophenones, whereby a thiocarbonylation followed by a subsequent McMurry coupling yielded differently substituted benzothiophenes. It was demonstrated that the methodology could be applied for ¹³C introduction into the thiophene ring.

Full text of DOI:10.1021/jo5009965

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pubs.acs.org/joc
Palladium-Catalyzed Thiocarbonylation of Aryl, Vinyl, and Benzyl
Bromides
Mia N. Burhardt, Andreas Ahlburg, and Troels Skrydstrup*
Center for Insoluble Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience Center, Aarhus University,
Gustav Wieds vej 14, 8000 Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: A catalytic protocol for synthesis of thioesters
from aryl, vinyl, and benzyl bromides as well as benzyl
chlorides was developed using only stoichiometric amounts of
carbon monoxide, produced from a solid CO precursor inside
a two-chamber system. As a catalytic system, the combination
of bis(benzonitrile) palladium(II) chloride and Xantphos
furnished the highest yields of the desired compounds, along with the weak base, NaOAc, in anisole at 120 °C. The choice
of catalytic system as well as solvent turned out to be important in order to ensure a high chemoselectivity in the reaction. Both
electron-rich and electron-deficient aryl bromides worked well in this reaction. Addition of 1 equiv of sodium iodide to the
reaction improved the chemoselectivity with the electron-deficient aryl bromides. The thiol scope included both aryl and alkyl
thiols, including 2-mercaptobenzophenones, whereby a thiocarbonylation followed by a subsequent McMurry coupling yielded
differently substituted benzothiophenes. It was demonstrated that the methodology could be applied for 13C introduction into
the thiophene ring.
Fukuyama and co-workers developed a chemoselective
protocol for the synthesis of ketones from thioesters using
Pd-catalysis and a zinc aryl or alkyl species.1 Different
procedures have also been developed for the preparation of
acetylene ketones,2 esters,3 amides,4 and acylsilanes5 from
thioesters. Furthermore, it is possible to reduce this carboxylic
acid derivative selectively to either an aldehyde or alcohol
depending on the conditions used while leaving other
functional groups such as esters and amides untouched.6,7
Sekiya and Lawesson demonstrated that the oxygen atom of a
thioester can be replaced by a CCl2 group or sulfur.8,9 The
benzodithioate products can be further exploited for synthesis
of different sulfur-containing heterocycles. Furthermore, it is
possible to synthesize 2-methylthio-1,3-oxazoles from both aryl-
and alkylthioesters using N-(ethoxycarbonylmethyl)-
iminodithiocarbonate.10
INTRODUCTION
■
Thioesters are common intermediates in biochemistry, in many
cases acting as an important class of acyl donors. In organic
chemistry, thioesters represent excellent building blocks for a
number of synthetic transformations. These air-stable acyl
donors are tolerant to column purification on silica gel and
therefore easier to handle than the corresponding acyl halides.
Furthermore, substitution of the sulfur-containing leaving
group with a variety of nucleophiles can be achieved under
relatively mild reaction conditions. Examples of the applications
of thioesters in organic synthesis are illustrated in Scheme 1.
Scheme 1. Examples of the Application of Thioesters as
Building Blocks in Organic Synthesis
Palladium complexes catalyze a number of carbonylation
reactions yielding a large variety of carbonyl-containing
compounds, depending on the applied coupling partners.11
However, Pd-catalyzed thiocarbonylations have not been
explored as intensively as the other carbonylation reactions,
possibly because of the fear for poisoning of the catalyst with
thiol nucleophiles. Nevertheless, Hartwig and co-workers
demonstrated that with the appropriate catalyst composition,
it is possible to overcome this obstacle for Pd-catalyzed
thioarylations.12 Over the last 15 years, the group of Alper has
developed an extensive number of Pd-catalyzed thiocarbony-
Special Issue: Mechanisms in Metal-Based Organic Chemistry
Received: May 7, 2014
© XXXX American Chemical Society
A
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lation reactions with a variety of unsaturations.13 But in 2008,
they reported the first examples of the thiocarbonylation of aryl
iodides employing 5 mol % of a Pd-catalyst in a phosphonium
salt ionic liquid as solvent under a CO pressure of 14 bar.14
Later in 2010, another protocol was published by the Lei group
as part of mechanistic studies for the Pd-catalyzed alkox-
ycarbonylation. They were able to prepare a small range of
thioesters with 2 mol % of a Pd catalyst, with sodium thiolates
as the nucleophiles in a RSH/THF solvent mixture, and in the
presence of 10 bar of CO.15,16 In 2013, we published an
alternative protocol using only 1.5 equiv of carbon monoxide
and 1.0 equiv of thiol. Just 1 mol % of a Pd(OAc)2/DPEphos
mixture was applied as the catalytic system with NaOAc as the
base and dimethoxyethane (DME) or anisole as the solvent
(Scheme 2).17 The choice of solvent for this reaction was
Table 1. Selected Entries from the Optimization Studies for
the Pd-Catalyzed Thiocarbonylation of Aryl Bromides
conv (%)
(yield, %)
A:B
ratio
entry
solvent
ligand
[Pd]
c
1
DME
DPEphos
DPEphos
DPEphos
DPEphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Pd(OAc)2
0
d
2
anisole
diglyme
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
Pd(OAc)2
25 (19)
33
3:1
0:1
3:1
4:1
4:1
9:1
9:1
1:0
1:0
1:0
7:1
5:1
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
55
Scheme 2. Previously Identified Conditions for the Pd-
Pd(OAc)2
65 (46)
>95 (79)
>95 (90)
>95 (87)
58 (58)
25 (25)
65 (65)
80% (64%)
>95 (81%)
Catalyzed Thiocarbonylation of Aryl Iodides17
e
Pd(OAc)2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
f
8
g
9
d
10
h
i
11
12
f
j
13
dependent on the electronic character of the aryl ring
substituents of the electrophilic coupling partner. In order to
avoid the manipulation of carbon monoxide from a cylinder,
this gas was produced from the solid CO-precursor, 9-
methylfluorene-9-carbonyl chloride (COgen), by a Pd-
catalyzed decarbonyation using a two-chamber reactor (CO-
ware) to separate the CO-producing reaction from the CO-
consuming carbonylation reaction.18,19 This technique has been
exploited for a wide variety of Pd-catalyzed carbonylation
protocols;20 as only a slight stoichiometric excess of CO is
applied with this glassware, the methodology is highly adaptable
for 13C- or 14C-isotope labeling.21
Unfortunately, our previously reported conditions for the
thiocarbonylation of aryl iodides were unsuitable for trans-
forming the more attractive aryl bromides into their
corresponding thioesters. Hence, in this paper, we describe
our studies to identify a suitable catalyst and reaction
conditions that include these more interesting substrates to
the scope of Pd-catalyzed thiocarbonylation reactions.
Furthermore, we report that the methodology is suitable for
the thiocarbonylation of vinyl and benzyl bromides, as well as
benzyl chlorides. Finally, we disclose that this new
thiocarbonylation protocol can be combined with a concom-
itant McMurry coupling for the successful synthesis of
benzothiophenes, including their selective 13C-isotope labeling.
a
Chamber 1: aryl bromide (0.25 mmol), thiol (0.25 mmol), [Pd] (13
μmol), ligand (13 μmol), NaOAc (0.28 mmol), solvent (1.0 mL).
b
Chamber 2: 9-methylfluorene-9-carbonyl chloride (COgen) (0.38
mmol), Pd(dba)2 (13 μmol), P(tBu)3·HBF4 (13 μmol), Cy2NMe
c
(0.63 mmol), solvent (1.5 mL). The reaction was performed at 85 °C.
d
e
f
Reaction performed at 100 °C. Xantphos (25 μmol). Chamber 1:
aryl bromide (0.50 mmol), thiol (0.50 mmol), Pd(PhCN)2Cl2 (25
μmol), Xantphos (25 μmol), NaOAc (0.55 mmol), anisole (2.0 mL).
Chamber 2: 1.5 equiv of 9-methylfluorene-9-carbonyl chloride
(COgen). The reaction was performed at 110 °C. PdCl2(PhCN)2
(5.0 μmol), Xantphos (5.0 μmol). Aryl bromide (2.50 mmol), thiol
(2.50 mmol), [Pd] (25 μmol), Xantphos (25 μmol), NaOAc (2.75
mmol), anisole (10.0 mL). Chamber 2: 9-methylfluorene-9-carbonyl
chloride (COgen) (3.75 mmol), Pd(dba)2 (38 μmol), P(tBu)3·HBF4
(38 μmol), Cy2NMe (5.63 mmol), anisole (15 mL). Reaction set up
without using a glovebox.
g
h
i
j
Information). With anisole as the solvent, we observed a small
reactivity leading to a 25% conversion at 100 °C (entry 2) and a
3:1 selectivity for the thioester A over the direct coupling
product B. After heating to 120 °C, diglyme led to the direct
coupling product, whereas a better selectivity of again 3:1 for
the thioester was observed with anisole as the solvent (entries 3
and 4).
A ligand screening was then undertaken, whereby 12
bidentate and 5 monodentate ligands were examined (see the
Supporting Information). The reaction proved to be partic-
ularly sensitive to the ligand choice, as the only two leading to
any conversion of the starting material were DPEphos and
Xantphos (entries 4 and 5). Notably, the latter led to a slightly
better conversion and selectivity. Xantphos has previously been
shown by Buchwald to be an excellent ligand for the Pd-
catalyzed aminocarbonylations of aryl bromides under low CO
pressure. The exact reasons for the high efficiency for this
reaction with Xantphos as a ligand are still not clear, but it
appears that the Pd complexes bearing this bidentate ligand can
undergo facile interconverion between the cis- and trans-
configurations.22 We have also later observed the usefulness of
RESULTS AND DISCUSSION
■
Our starting point for the optimization of the thiocarbonylation
of aryl bromides began with the conditions identified for the
same transformation with the aryl iodides (Scheme 2), using
equimolar amounts of p-bromoanisole and thiophenol as test
substrates, though with a Pd loading of 5 mol %.
As no conversion of the aryl bromide was observed using
these conditions (entry 1, Table 1), higher boiling solvents
other than DME were tested in order to increase the reaction
temperature. Neither the use of diglyme, toluene, benzotri-
fluoride, nor dioxane led to any conversion of the starting
material at 100 °C over a period of 18 h (see the Supporting
B
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Table 2. Pd-Catalyzed Thiocarbonylation of Electron-Rich Aryl Bromides
a
Chamber 1: aryl bromide (0.50 mmol), thiol (0.50 mmol), Pd(PhCN)2Cl2 (25 μmol), Xantphos (25 μmol), NaOAc (0.55 mmol), anisole (2.0
b
mL). Chamber 2: 9-methylfluorene-9-carbonyl chloride (COgen) (0.75 mmol), Pd(dba)2 (25 μmol), P(tBu)3·HBF4 (25 μmol), Cy2NMe (1.13
mmol), anisole (3 mL).
C
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Table 3. Substrates Requiring Addition of NaI in the Pd-Catalyzed Thiocarbonylation of Aryl Bromides
a
Chamber 1: aryl bromide (0.50 mmol), thiol (0.50 mmol), Pd(PhCN)2Cl2 (25 μmol), Xantphos (25 μmol), NaOAc (0.55 mmol), NaI (0.50
b
mmol), anisole (2.0 mL). Chamber 2: 9-methylfluorene-9-carbonyl chloride (COgen) (0.75 mmol), Pd(dba)2 (25 μmol), P(tBu)3·HBF4 (25
μmol), Cy2NMe (1.13 mmol), anisole (3 mL).
Xantphos in other Pd-catalyzed carbonylation reactions with
aryl bromides.17,20a,b,e
(entry 8). On the other hand, when the reaction temperature
was lowered to 110 and 100 °C, the conversion decreased to
58%, and 25%, respectively (entries 9 and 10). Decreasing the
catalyst loading to 2 mol % also had a dramatic effect on the
yield, which dropped to 65% (entry 11). As these optimization
studies were run on a 0.25 mmol scale, an attempt was made on
a scale 10 times greater in order to see if the catalyst loading
could be decreased without affecting the yield and selectivity, as
previously demonstrated for other carbonylation protocols.20e
Unfortunately, with a catalyst loading of 1 mol % the
conversion was not complete after the same reaction time of
18 h (entry 12). For the optimization studies discussed so far,
By increasing the Xantphos/Pd(OAc)2 ratio to 2:1, the yield
and selectivity could be further improved compared to the test
system, providing full conversion and a 79% yield of thioester A
(entry 6). After testing a number of other palladium complexes
(see the Supporting Information), the use of bis(benzonitrile)-
dichloropalladium proved to be the best precatalyst for the
reaction, leading again to full conversion of the starting material
and a 90% yield of the desired product (entry 7). This yield was
not affected by an increased gas pressure when the same
reaction was run at twice the scale in the same sized glassware
D
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Table 4. Pd-Catalyzed Thiocarbonylation of Vinyl and Benzyl Bromides and Benzyl Chlorides
a
Chamber 1: bromide (0.50 mmol), thiol (0.50 mmol), Pd(PhCN)2Cl2 (25 μmol), Xantphos (25 μmol), NaOAc (0.55 mmol), anisole (2.0 mL).
b
Chamber 2: 9-methylfluorene-9-carbonyl chloride (COgen) (0.75 mmol), Pd(dba)2 (25 μmol), P(tBu)3·HBF4 (25 μmol), Cy2NMe (1.13 mmol),
c
anisole (3 mL). NaI (0.50 mmol) added to chamber 1.
all reactions were set up in a glovebox, whereafter heating was
performed in a standard fumehood. When a similar reaction on
a 0.5 mmol scale as in entry 8 was set up using standard
Schlenk techniques, only a slight drop was observed in the
product yield (81% yield, entry 13).
As illustrated in Table 2, the above protocol proved efficient
for the thiocarbonylation of a series of electron-rich aryl
bromides including substituents in the meta- or para-position
with yields attaining 98%. In contrast to that observed with the
aryl iodides,17 the yield dropped drastically with an aryl
bromide possessing an ortho-substituent as demonstrated with
o-tolyl bromide (entry 5), which only performed in a 20% yield.
Either a free alcohol or an aniline could be tolerated as shown
in entries 2 and 6. The corresponding N,N-dimethyl derivative
provided an increased yield of the thioester (entry 7), whereas
with the N-Boc-protected derivative, we observed a small drop
in efficiency of the carbonylation reaction (entry 8). Longer
reaction times improved the yield for both aniline and its N,N-
dimethyl-protected version, probably due to a slow oxidative
addition into the Ar−Br bond, with these more electron-rich
systems. We never observed any formation of either ester or
amide byproducts, which is undoubtedly related to the superior
E
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nucleophilicity of the thiols. 5-Bromoindole-1-carboxylate was
partially deprotected during the course of the carbonylation
reaction but gave a combined yield of 75% for the protected
and deprotected indole derivative (entry 9). Four additional
thiols were tested with p-bromoanisole and m,p-bromovera-
trole. Both the electron-rich p-methoxybenzenethiol and 2,4-
dimethylbenzenethiol performed well, providing good yields of
the thioesters (entries 10 and 11), while n-octanethiol and the
dipeptide sequence Boc-N-Cys-Ala-OMe provided excellent
yields of 88 and 93% of the desired products, respectively
(entries 12 and 13).
most of these reactions. In order to avoid the thioether
formation, we examined the effect of decreasing the temper-
ature from 120 °C to 80 or even 60 °C for p-tert-butylbenzyl
bromide (entries 6−8). In general, it turned out to be possible
to slow down the rate of the competing side reaction compared
to the carbonylation reaction at the lower reaction temperature,
except in one (entry 3). The coupling between 1-
bromocyclohexene28 and 1-adamentanethiol afforded the
thioester in almost the same yield at 80 and 120 °C (entries
1 and 2), whereas the decrease in the reaction temperature was
more influential for the reaction between β-bromostyrene and
thiophenol, providing a 60% higher yield of the desired product
(entries 4 and 5). Not surprisingly, lowering the reaction
temperature for the benzyl bromides provided more useful
yields of the thioester as illustrated with p-tert-butylbenzyl
bromide (entries 6−8) and 3,4-dichlorobenzyl bromide (entries
9 and 10). At 120 °C, the products from direct coupling were
observed as the major compound, most likely by nucleophilic
substitution, while the conversion of starting material was less
than complete at 60 °C (entry 6). The best carbonylative
couplings with these conditions were observed at 80 °C. Hence,
for the benzyl chlorides, this same reaction temperature was
chosen affording the corresponding thioesters in yields up to
78% (entries 11−15).
In contrast to the electron-rich aryl bromides, applying this
catalytic protocol to the electron-deficient counterparts led to
disappointing yields of the desired thioesters and low selectivity
with respect to the ratio of thioester vs thioether. These
observations may possibly be explained by a mechanism
exhibiting a slow CO-insertion step into the Ar−Pd bond.23
The same effect has been observed in the case of other
carbonylation reactions published by us and others.17,24 To
solve this problem, we explored the effect of addition of iodide
salts in the carbonylative coupling between ethyl 4-
bromobenzoate and thiophenol. These experiments were
undertaken on the basis of literature precedence for the
beneficial effects of added potassium iodide in the carbonylative
Suzuki reaction with aryl bromides.25 After some experimenta-
tion with a few iodide salts, we discovered that the addition of
1.0 equiv of sodium iodide increased the thioester/thioether
ratio from 1:1 to 3:1 (see Supporting Information). The two
products could easily be separated by column chromatography,
and in this way, a 74% yield of the thioester was secured (Table
3, entry 1). We suspect the iodide generates a Pd−I complex
replacing the coordinated bromide, thereby facilitating the CO-
insertion step in the catalytic cycle. Literature precedence
reveals that a Me−Pd−I species performs faster CO insertion
than the corresponding bromide analogue.26 Another possi-
bility could be in situ acid iodide or bromide formation, but
according to the work by Quesnel et al.,27 these species do not
form as readily as the corresponding acid chlorides.
Furthermore, Xantphos proved to be a less efficient ligand
for this transformation. We also attempted to influence the
selectivity and thereby the reaction yield by decreasing the
temperature to 100 °C. This had a slight effect on the yield,
which improved from 50% at 120 °C to 61% at the lower
temperature, but the effect was not as pronounced as the
addition of sodium iodide to the reaction.
Finally, this methodology was applied for the synthesis of
benzothiophenes, whereby the formed thioesters were ring
closed via a McMurry coupling (Scheme 3). There is literature
precedence for the construction of dithienothiophenes from
benzothieno[2,3-b]thiophene structures, but the reaction has to
Scheme 3. Synthesis and 13C-Isotope Labeling of
Benzothiophene via a Sequential Pd-Catalyzed
Thiocarbonylation and Subsequent McMurry Coupling
The improved procedure afforded the thioesters from the
corresponding aryl bromides in yields up to 87% (Table 3);
especially those for the electron-poor aryl bromides could be
improved this way. Para-substituted haloaryl bromides
performed well in the reaction (entry 2 and 3), as did the
free p-bromophenol (entry 9). Not surprisingly, it turned out to
be more difficult to control the selectivity with the aryl
bromides carrying more electron-withdrawing groups such as p-
bromoacetophenone and p-bromobenzonitrile, which led to a
45 and 26% yield, respectively (entries 6 and 7). m,p-
Bromoveratrole led to a slightly better yield when NaI was
applied to the reaction mixture compared to the reaction
without NaI (entry 8, Table 3 compared to entry 1, Table 2).
It was possible to expand the scope of this carbonylation
reaction to include vinyl and benzyl bromides as well as benzyl
chlorides (Table 4) using the same conditions as for the aryl
bromides. However, the yields were in general rather low, and
the corresponding thioethers were seen as the major product in
F
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mmol) were dissolved in anisole (2.0 mL). In case of the thiol being a
solid, thiol (0.5 mmol) was added before sealing of the glassware.
Chamber 2: 1.5 equiv of CO was generated in chamber 2. The
glassware was then removed from the glovebox, and the thiol (0.50
mmol) was injected into chamber 1 before mixing at 120 °C. After 18
or 24 h, the solvent was removed from chamber 1 in vacuo, and the
desired compound was purified by flash chromatography on silica gel
using a pentane/CH2Cl2 eluent system.
our knowledge never before been performed with S-(2-
benzoylphenyl) benzothioates.29 By applying 2- mercaptoben-
zophenones30 as nucleophiles in the thiocarbonylation, it was
possible to generate the S-(2-benzoylphenyl) benzothioate
structures 1−3 in yields from 45 to 70% by refluxing the
prepared thioester with TiCl4 and Zn powder in dry 1,4-
dioxane. As illustrated for the synthesis of compound 2,
selective 13C-isotope labeling proved also feasible. Only in the
case of thioester 4 did the cyclization fail.
Chamber 2. 1.5 equiv of CO: 9-methylfluorene-9-carbonyl chloride
(182 mg, 0.75 mmol), Pd(dba)2 (14.1 mg, 25 μmol), and P(tBu)3·
HBF4 (7.5 mg, 25 μmol) were dissolved in anisole (3.0 mL). Cy2NMe
(241 μL, 1.13 mmol) was added before the glassware was sealed.
S-Phenyl 4-Methoxybenzothioate (A).14 The title compound was
isolated as colorless crystals (106 mg, 0.44 mmol, 87%): mp 92.5−93.6
CONCLUSION
■
In conclusion, we have identified suitable catalytic reaction
conditions for promoting the thiocarbonylation of aryl, vinyl,
and benzyl bromides as well as benzyl chlorides by applying ex
situ generated CO in a two-chamber reactor. Both electron-rich
and electron-poor aryl bromides performed well in the reaction,
including a couple of heterocyclic bromides.
1
°C; H NMR (400 MHz, CDCl3) δ (ppm) 8.02 (d, J = 9.2 Hz, 2H),
7.54−7.44 (m, 5H), 6.97 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 188.5, 164.0, 135.2, 129.7, 129.4, 129.3,
129.1, 127.6, 113.9, 55.5; HRMS (ESI) m/z calcd for C14H12O2S [M +
H+] 245.0631, found 245.0632.
S-Phenyl 3,4-Dimethoxybenzothioate (Table 2, Entry 1).33 The
title compound was isolated as colorless crystals (111 mg, 0.41 mmol,
A catalytic system consisting of Xantphos/bis(benzonitrile)
dichloropalladium proved to be the most efficient for the
reaction in combination with NaOAc as the base and anisole as
the solvent. Screenings demonstrated that the reaction was very
ligand selective, but also that the choice of solvent proved
highly influential for the efficiency of the coupling.
Finally benzothiophenes could be constructed and selectively
13C-labeled when applying 1-mercaptobenzophenones as
nucleophiles in this carbonylation protocol, followed by a
McMurry coupling for the ring closure. Because of their
versatility as building blocks thioesters are well suited for
parallel synthesis of different carboxylic acid derivatives.
Installation of the carbonyl group can therefore be performed
using the presented procedure, which allows for an easy route
to a number of 13C-isotope labeled compounds.
1
81%): mp 110.9−112.5 °C; H NMR (400 MHz, CDCl3) δ (ppm)
7.75 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.53−7.44 (m, 6H), 6.92 (d, J =
8.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 188.7, 153.7, 149.0, 135.1, 129.5, 129.4, 129.2, 127.6, 122.0,
110.3, 109.7, 56.1, 56.0; HRMS (ESI) m/z calcd for C15H14O3S [M +
Na+] 297.0556, found 297.0554.
S-Phenyl 4-(2-Hydroxyethyl)benzothioate (Table 2, Entry 2). The
reaction time was 24 h for the title compound, which was isolated as
1
colorless crystals (97 mg, 0.38 mmol, 75%): mp 66.2−67.5 °C; H
NMR (400 MHz, CDCl3) δ (ppm) 7.98 (d, J = (7.9 Hz, 2H), 7.53−
7.44 (m, 5H), 7.34 (d, J = 7.2 Hz, 2H), 3.87 (t, J = 6.5 Hz, 2H), 2.92
(t, J = 6.6 Hz, 2H), 1.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 189.9, 145.3, 135.2, 135.0, 129.6, 129.5, 129.3, 127.8, 127.5,
65.2, 39.2; HRMS (ESI) m/z calcd for C15H14O2S [M + H+]
259.0787, found 259.0788.
S-Phenyl 2,3-Dihydrobenzofuran-5-carbothioate (Table 2, Entry
EXPERIMENTAL SECTION
3). The title compound was isolated as colorless crystals (101 mg, 0.40
■
1
mmol, 79%): mp 118.5−120.0 °C; H NMR (400 MHz, CDCl3) δ
General Methods. Dry solvents were prepared according to
standard literature procedures.31 All other chemicals were used as
received from the suppliers unless mentioned otherwise. Starting
materials were made according to literature procedures. Flash column
(ppm) 7.92−7.89 (m, 2H), 7.54−7.44 (m, 5H), 6.84 (d, J = 8.3 Hz,
2H), 4.66 (t, J = 8.7 Hz, 2H), 3.25 (t, J = 8.7, 2H); 13C NMR (100
MHz, CDCl3) δ (ppm) 188.5, 165.0, 135.3, 129.7, 129.5, 129.4, 129.2,
128.0, 127.9, 124.8, 109.4, 72.4, 29.1; HRMS (ESI) m/z calcd for
C15H12O2S [M + H+] 257.0631, found 257.0630.
1
chromatography was performed on silica gel 60 (230−400 mesh). H
and proton-decoupled 13C {1H} NMR spectra were recorded at 400
and 100 MHz. Chemical shifts are reported in ppm downfield to TMS
(δ = 0) and referenced to the solvent residual peak,32 using the
following peak pattern abbreviations: br, broad; s, singlet; d, doublet; t,
triplet; q, quartet; pent, pentet; sext, sextet; sept, septet; m, multiplet;
dd, doublet of doublets; dt, doublet of triplets; ddd, doublet of doublet
of doublets; ddt, doublet of doublet of triplets, and td, triplet of
doublets. HRMS was recorded on a LC TOF (ES).
S-Phenyl 3,4-Dimethylbenzothioate (Table 2, Entry 4). The title
compound was isolated as colorless crystals (119 mg, 0.49 mmol,
1
98%): mp 88.3−89.8 °C; H NMR (400 MHz, CDCl3) δ (ppm)
7.81−7.78 (m, 2H), 7.55−7.51 (m, 2H), 7.49−7.43 (m, 3H), 7.23 (d, J
= 7.8 Hz, 2H), 2.34 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
190.1, 143.6, 137.5, 135.4, 134.8, 130.3, 129.7, 129.5, 128.8, 128.0,
125.5. 20.4, 20.1; HRMS (ESI) m/z calcd for C15H14OS [M + H+]
243.0838, found 243.0838.
Equipment Used for the Thiocarbonylation. The thiocarbo-
nylations were performed in a two-chamber reaction vessel with a total
volume of 20 mL, using 9-methylfluorene-9-carbonyl chloride as the
source of carbon monoxide. The two chambers were loaded in an
argon filled glovebox. Chamber 1 was loaded with the reactants for the
thiocarbonylation, all thiols were injected into chamber 1 outside the
glovebox prior to heating. Chamber 2 was loaded with 1.5 equiv of 9-
methylfluorene-9-carbonyl chloride, Pd(dba)2 (3.3 mol %), P(tBu)3·
HBF4 (3.3 mol %), Anisole and Cy2NMe (1.13 mmol). The chambers
were sealed with a screw cap, 2 mm stabilizing PTFE disc and a 2 mm
thick PTFE-lined silicone disc before taking the two chamber vessel
out of the glovebox and heating at 120 °C. The glass equipment
should be examined for surface damages before use. The equipment
should not be operated above 60 psi, and gas release should only take
place behind a shield.
S-Phenyl 2-Methylbenzothioate (Table 2, Entry 5).17 The title
compound was isolated as colorless crystals (22 mg, 0.098 mmol,
20%): mp 45.0−46.2 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95
(dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.55−7.41 (m, 6H), 7.32 (d, J = 7.6
Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 192.1, 137.4, 136.8, 134.9, 132.0, 131.7, 129.4, 129.2,
128.6, 128.2, 125.8, 20.8; HRMS (ESI) m/z calcd for C14H12OS [M +
H+] 229.0682, found 229.0680.
S-Phenyl 4-Aminobenzothioate (Table 2, Entry 6). The reaction
time was 24 h for the title compound, which was isolated as colorless
1
crystals (76 mg, 0.33 mmol, 66%): mp 157.4−158.5 °C; H NMR
(400 MHz, CDCl3) δ (ppm) 7.87 (d, J = 8.6 Hz, 2H), 7.53−7.50 (m,
2H), 7.46−7.43 (m, 3H), 6.65 (d, J = 8.6 Hz, 2H), 4.17 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 188.4, 152.0, 135.6, 130.3, 129.5,
129.4, 128.4, 126.9, 114.2; HRMS (ESI) m/z calcd C13H12NOS [M +
H+] 230.0634, found 230.0636.
General Procedures for the Thiocarbonylation. Thiocarbo-
nylation Conditions. Chamber 1. Aryl bromide, allyl bromide, benzyl
bromide, or benzyl chloride (0.50 mmol), Pd(PhCN)2Cl2 (9.6 mg, 25
μmol), Xantphos (14.5 mg, 25 μmol), and NaOAc (45.1 mg, 0.55
S-Phenyl 4-(Dimethylamino)benzothioate (Table 2, Entry 7).34
The reaction time was 24 h for the title compound, which was isolated
G
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as colorless crystals (100 mg, 0.39 mmol, 78%): mp 191.9−193.0 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (d, J = 9.1 Hz, 2H), 7.54−
7.51 (m, 2H), 7.46−7.42 (m, 3H), 6.67 (d, J = 9.1 Hz, 2H), 3.07 (s,
6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 188.0, 154.2, 135.6,
130.0, 129.3, 128.7, 124.3, 111.1, 40.4; HRMS (ESI) m/z calcd
C15H15NOS [M + H+] 258.0947, found 258.0947.
S-Phenyl 4-((tert-Butoxycarbonyl)amino)benzothioate (Table 2,
Entry 8). The title compound was isolated as colorless crystals (81 mg,
0.25 mmol, 49%): mp 198.3−199.6 °C; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.98 (d, J = 8.6 Hz, 2H), 7.53−7.44 (m, 7H), 6.74 (s, 1H),
3.32 (s, 3H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm)
188.9, 152.2, 135.3, 131.1, 129.5, 129.3, 129.1, 127.7, 117.7, 81.6, 28.4;
HRMS (ESI) m/z calcd for C18H19NO3S [M + H+] 330.1158, found
330.1161.
169.9, 169.6, 164.1, 129.7, 129.3, 113.8, 80.4, 55.5, 55.0, 52.4, 48.2,
30.9, 28.2, 18.3; HRMS (ESI) m/z calcd for C20H28N2O7S [M + H+]
441.1690, found 441.1693.
S-(1s,3s)-Adamantan-1-yl Cyclohex-1-enecarbothioate (Table 4,
Entries 1 and 2). The reaction was performed at 80 °C. The title
compound was isolated as a colorless solid (85 mg, 0.31 mmol, 62%):
1
mp 67.2−69.0 °C; H NMR (400 MHz, CDCl3) δ (ppm) 6.91 (s,
1H), 2.27−3.04 (m, 13H), 1.80 (m, 10H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 194.0, 139.6, 137.4, 50.3, 42.2, 36.6, 30.0, 25.9, 24.0,
22.2, 21.7; HRMS (ESI) m/z calcd for C17H24OS [M + H+] 277.1621,
found 277.1621.
(E)-S-Phenyl 3-Phenylprop-2-enethioate (Table 4, Entries 4 and
5).36 The reaction was performed at 80 °C. The title compound was
isolated as a colorless solid (74 mg, 0.31 mmol, 62%): mp 75.5−77.2
°C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.71 (d, J = 15.8 Hz, 1H),
7.59−7.41 (m, 10H), 6.82 (d, J = 15.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 188.0, 141.6, 134.7, 134.1, 130.9, 129.6, 129.3, 129.1,
128.6, 127.8, 124.3; HRMS (ESI) m/z calcd for C15H12OS [M + H+]
241.0687, found 241.0682.
tert-Butyl 5-((Phenylthio)carbonyl)indole-1-carboxylate (Table 2,
Entry 9). The reaction yielded the carbonylation products with and
without the Boc protection group. The title compound was isolated as
colorless solid (48 mg, 0.14 mmol, 27%): mp 97.8−99.8 °C; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.31 (d, J = 1.9 Hz, 1H), 8.24 (d, J = 8.8
Hz, 1H), 8.01 (dd, J = 8.7 Hz, J = 1.9 Hz, 1H), 7.69 (d, J = 3.7 Hz,
1H), 7.57−7.54 (m, 2H), 7.50−7.45 (m, 3H), 6.69 (d, J = 3.7 Hz,
1H), 1.70 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 189.9,
149.4, 135.3, 131.5, 130.6, 129.5, 129.3, 127.9, 127.7, 123.7, 121.3,
115.3, 108.0, 84.7, 28.3; HRMS (ESI) m/z calcd for C20H19NO3S [M
+ H+] 354.1158, found 354.1163. The compound without Boc
protection (S-phenyl indole-5-carbothioate) was isolated as colorless
S-Phenyl 2-(4-tert-Butylphenyl)ethanethioate (Table 4, Entries
6−8). The reaction was performed at 80 °C. The title compound was
1
isolated as a colorless oil (80 mg, 0.28 mmol, 56%): H NMR (400
MHz, CDCl3) δ (ppm) 7.42 (br s, 7H), 7.31 (d, J = 8.0 Hz, 2H), 3.93
(s, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 195.5,
150.5, 134.5, 130.3, 129.44, 129.40, 129.2, 128.0, 125.8, 49.7, 34.6,
31.5; HRMS (ESI) m/z calcd for C18H20OS [M + H+] 285.1308,
found 285.1307.
1
crystals (61 mg, 0.24 mmol, 48%): mp 152.5−154.2 °C; H NMR
S-Phenyl 2-(3,4-Dichlorophenyl)ethanethioate (Table 4, Entries 9
(400 MHz, CDCl3) δ (ppm) 8.57 (br. s, 1H), 8.48 (s, 1H), 7.91 (d, J =
8.9 Hz, 1H), 7.60−7.57 (m, 2H), 7.49−7.40 (m, 4H), 7.26−7.22 (m,
1H), 6.71−6.70 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm)
190.5, 139.0, 135.4, 129.4, 129.3, 129.1, 128.3, 127.6, 126.3, 122.1,
121.6, 111.3, 104.4; HRMS (ESI) m/z calcd for C15H11NOS [M + H+]
254.0635, found 254.0634.
and 10). The reaction was performed at 80 °C. The title compound
1
was isolated as a colorless oil (55 mg, 0.19 mmol, 37%): H NMR
(400 MHz, CDCl3) δ (ppm) 7.43−7.40 (m, 7H), 7.16 (dd, J = 8.2 Hz,
J = 1.7 Hz, 1H), 3.87 (s, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm)
194.4, 134.5, 133.4, 132.8, 132.0, 131.6, 130.7, 129.8, 129.4, 129.1,
127.3, 48.9; HRMS (ESI) m/z calcd for C14H10Cl2OS [M + H+]
296.9902, found 296.9906.
S-(4-Methoxyphenyl) 4-Methoxybenzothioate (Table 2, Entry
10).35 The reaction time was 24 h for the title compound, which was
isolated as colorless crystals (109 mg, 0.40 mmol, 80%): mp 138.0−
138.9 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 8.8 Hz,
2H), 7.41 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8
Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 189.5, 163.9, 160.7, 136.7, 129.7, 129.4, 118.2, 114.9, 113.9,
55.5, 55.4; HRMS (ESI) m/z calcd for C15H14O3S [M + Na+]
297.0556, found 297.0552.
S-Phenyl 2-(4-Methoxyphenyl)ethanethioate (Table 4, Entry 11).
The reaction was performed at 80 °C. The title compound was
1
isolated as a colorless oil (100 mg, 0.39 mmol, 78%): H NMR (400
MHz, CDCl3) δ (ppm) 7.42 (m, 5H), 7.30 (d, J = 8.4 Hz, 2H), 6.94
(d, J = 8.4 Hz, 2H), 3.90 (s, 2H), 3.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 195.9, 159.2, 134.5, 130.9, 129.4, 129.2, 128.0, 55.3,
49.3; HRMS (ESI) m/z calcd for C15H14O2S [M + H+] 259.0787,
found 259.0786.
S-(2,4-Dimethylphenyl) 3,4-Dimethoxybenzothioate (Table 2,
S-Phenyl 2-(2-Methoxyphenyl)ethanethioate (Table 4, Entry 12).
The reaction was performed at 80 °C. The title compound was
Entry 11). The title compound was isolated as a colorless solid (116
1
mg, 0.38 mmol, 76%): mp 113.2−115.0 °C; H NMR (400 MHz,
1
isolated as a colorless oil (85 mg, 0.33 mmol, 66%): H NMR (400
CDCl3) δ (ppm) 7.77 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 7.52 (d, J = 2.1
Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.20−7.15 (m, 1H), 7.10−7.03 (m,
1H), 6.91 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.36 (s, 6H);
13C NMR (100 MHz, CDCl3) δ (ppm) 188.6, 153.6, 149.0, 142.4,
MHz, CDCl3) δ (ppm) 7.43−7.27 (m, 7H), 7.00 (t, J = 7.4 Hz, 1H),
6.95 (d, J = 8.2 Hz, 1H), 3.99 (s, 2H), 3.90 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 196.0, 157.9, 134.6, 131.6, 129.3, 129.2, 129.1,
128.4, 122.3, 120.7, 110.7, 55.6, 44.9; HRMS (ESI) m/z calcd for
C15H14O2S [M + H+] 259.0787, found 259.0787.
Methyl 4-(2-Oxo-2-(phenylthio)ethyl)benzoate (Table 4, Entry
13). The reaction was performed at 80 °C. The title compound was
isolated as a colorless solid (102 mg, 0.36 mmol, 71%): mp 100.0−
101.8 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.03 (d, J = 8.2 Hz,
2H), 7.42−7.39 (m, 7H), 3.97 (s, 2H), 3.92 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 194.5, 166.8, 138.4, 134.5, 130.1, 129.75,
129.66, 129.5, 129.3, 127.5, 52.2, 50.0; HRMS (ESI) m/z calcd for
C16H14O3S [M + H+] 287.0736, found 287.0737.
140.3, 136.3, 131.7, 129.8, 127.5, 123.6, 122.0, 110.3, 109.7, 56.1, 56.0,
21.3, 20.8; HRMS (ESI) m/z calcd for C17H18O3S [M + H+]
303.1050, found 303.1052.
S-Octyl 3,4-Dimethoxybenzothioate (Table 2, Entry 12). The title
compound was isolated as a colorless solid (137 mg, 0.44 mmol, 88%):
mp 27.8−28.3 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.61 (dd, J
= 8.4 Hz, J = 2.1 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 8.5 Hz,
1H), 3.89 (s, 6H), 3.01 (t, J = 7.4 Hz, 2H), 1.62 (pent, J = 7.0 Hz 1H),
1.45−1.17 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 190.7, 153.3, 148.9, 130.3, 121.6, 110.2, 109.4, 56.0,
31.8, 29.7, 29.20, 29.17, 29.1, 29.0, 22.7, 14.1; HRMS (ESI) m/z calcd
for C17H26O3S [M + H+] 311.1675, found 311.1677.
(S)-Methyl 2-((R)-2-((tert-Butoxycarbonyl)amino)-3-((4-
methoxybenzoyl)thio)propanamido)propanoate (Table 2, Entry
13).17 The title compound was isolated as a colorless solid (205 mg,
0.47 mmol, 93%): mp 113.3−115.9 °C;; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.93(d, J = 9.2 Hz, 2H), 7.05 (br s, 1H), 6.90 (d, J = 9.2 Hz,
2H), 5.45 (br. d, J = 7.2 Hz, 1H), 4.55 (pent, J = 7.2 Hz, 1H), 4.38 (br.
s, 1H), 3.85 (s, 3H), 3.70 (s, 3H), 3.52 (dd, J = 14.4 Hz, J = 4.4 Hz,
1H), 3.36 (dd, J = 14.4 Hz, J = 8.0 Hz, 1H), 1.42 (d, J = 11.6 Hz, 3H),
1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 190.7, 172.9,
S-Phenyl 2-(4-Nitrophenyl)ethanethioate (Table 4, Entry 14). The
reaction was performed at 80 °C. The title compound was isolated as a
1
yellow solid (58 mg, 0.21 mmol, 42%): mp 63.4−64.6 °C; H NMR
(400 MHz, CDCl3) δ (ppm) 8.21 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.4
Hz, 2H), 7.43−7.38 (m, 5H), 4.03 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 193.9, 147.5, 140.6, 134.5, 130.6, 129.9, 129.4, 127.1,
124.0, 49.5; HRMS (ESI) m/z calcd for C14H11NO3S [M + Na+]
296.0352, found 296.0354.
S-Phenyl 2-(3-Bromophenyl)ethanethioate (Table 4, Entry 15).
The reaction was performed at 80 °C. The title compound was
1
isolated as a colorless oil (75 mg, 0.25 mmol, 49%): H NMR (400
H
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MHz, CDCl3) δ (ppm) 7.40−7.30 (m, 7H), 7.18−7.10 (m, 2H), 3.79
(s, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 194.7, 135.5, 134.5,
132.7, 130.8, 130.3, 129.7, 129.3, 128.4, 127.5, 122.8, 49.5; HRMS
(ESI) m/z calcd for C14H11BrOS [M + H+] 306.9787, found 306.9788.
General Procedure for the Thiocarbonylation with NaI as
Additive. Thiocarbonyation Conditions. Chamber 1. Aryl bromide
or allyl bromide (0.50 mmol), Pd(PhCN)2Cl2 (9.6 mg, 25 μmol),
Xantphos (14.5 mg, 25 μmol), NaI (74.9 mg, 0.50 mmol), and NaOAc
(45.1 mg, 0.55 mmol) were dissolved in anisole (2.0 mL). In case of
the thiol being a solid, thiol (0.5 mmol) was added before sealing of
the glassware. Chamber 2: 1.5 equiv of CO were generated in chamber
2. The glassware was then removed from the glovebox, and the thiol
(0.50 mmol) was injected into chamber 1 before mixing at 120 °C.
After 18 or 24 h, the solvent was removed from chamber 1 in vacuo,
and the desired compound was purified by flash chromatography on
silica gel using a pentane/CH2Cl2 eluent system.
Chamber 2. 1.5 equiv of CO: 9-methylfluorene-9-carbonyl chloride
(182 mg, 0.75 mmol), Pd(dba)2 (14.1 mg, 25 μmol), and P(tBu)3·
HBF4 (7.5 mg, 25 μmol) were dissolved in anisole (3.0 mL). Cy2NMe
(241 μL, 1.13 mmol) was added before the glassware was sealed.
Ethyl 4-((Phenylthio)carbonyl)benzoate (Table 3, Entry 1).17 The
title compound was isolated as colorless crystals (106 mg, 0.37 mmol,
74%): mp 65.3−66.1 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.16
(d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 7.54−7.46 (m, 5H), 4.42
(q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 189.7, 165.6, 139.8, 135.0, 134.8, 129.9, 129.8, 129.4,
127.4, 126.8, 61.5, 14.3; HRMS (ESI) m/z calcd for C16H14O3S [M +
H+] 287.0736, found 287.0737.
(400 MHz, CDCl3) δ (ppm) 8.11 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6
Hz, 2H), 7.54−7.47 (m, 5H); 13C NMR (100 MHz, CDCl3) δ (ppm)
189.4, 140.1, 135.2, 133.0, 130.4, 129.8, 126.6, 118.1, 117.2; HRMS
(ESI) m/z calcd for C14H9NOS [M + H+] 240.0478, found 240.0473.
S-Phenyl 3,4-Dimethoxybenzothioate (Table 3, Entry 8).33 The
title compound was isolated as colorless crystals (119 mg, 0.43 mmol,
1
87%): mp 110.9−112.5 °C; H NMR (400 MHz, CDCl3) δ (ppm)
7.75 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.53−7.44 (m, 6H), 6.92 (d, J =
8.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 188.7, 153.7, 149.0, 135.1, 129.5, 129.4, 129.2, 127.6, 122.0,
110.3, 109.7, 56.1, 56.0; HRMS (ESI) m/z calcd for C15H14O3S [M +
Na+] 297.0556, found 297.0554.
S-Phenyl 4-Hydroxybenzothioate (Table 3, Entry 9). The reaction
time was 24 h for the title compound, which was isolated as colorless
1
crystals (92 mg, 0.40 mmol, 80%): mp 172.8−174.4 °C; H NMR
(400 MHz, CDCl3) δ (ppm) 7.96 (d, J = 8.7 Hz, 2H), 7.53−7.44 (m,
5H), 6.87 (d, J = 8.7 Hz, 2H), 5.58 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 189.3, 160.7, 135.4, 130.2, 129.7, 129.6, 129.4, 127.6,
115.7; HRMS (ESI) m/z calcd for C13H10O2S [M + H+] 231.0474,
found 231.0474.
S-Phenyl Thiophene-2-carbothioate (Table 3, Entry 10).14 The
title compound was isolated as yellow crystals (83 mg, 0.37 mmol,
75%): mp 59.4−60.2 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.92
(dd, J = 4.0 Hz, J = 1.2 Hz, 1H), 7.67 (dd, J = 5.2 Hz, J = 1.2 Hz, 1H),
7.56−7.43 (m, 5H), 7.16 (dd, J = 4.8 Hz, J = 3.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 182.0, 141.4, 135.0, 133.2, 131.6, 129.6,
129.2, 128.0, 126.9; HRMS (ESI) m/z calcd for C11H8OS2 [M + Na+]
242.9909, found 242.9906.
S-phenyl Cyclohex-1-enecarbothioate (Table 4 entry 3).38 The
title compound was isolated as a colorless oil (41 mg, 0.19 mmol,
S-Phenyl 4-Fluorobenzothioate (Table 3, Entry 2). The title
compound was isolated as colorless crystals (93 mg, 0.40 mmol, 80%):
mp 59.2−60.0 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.07 (dd, J
= 8.5 Hz, J = 5.3 Hz, 2H), 7.62−7.37 (m, 5H), 7.17 (t, J = 8.5 Hz,
1
38%): H NMR (400 MHz, CDCl3) δ (ppm) 7.45−7.39 (m, 5H),
7.13 (s, 1H), 2.37−2.25 (m, 4H), 1.73−1.62 (m, 4H); 13C NMR (100
MHz, CDCl3) δ (ppm) 190.9, 139.4, 138.4, 135.2, 129.3, 129.2, 128.1,
26.1, 24.3, 22.1, 21.7; HRMS (ESI) m/z calcd for C13H14OS [M + H+]
219.0844, found 219.0839.
2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 188.8, 166.2, (d, JC−F
=
255 Hz), 135.2, 133.1 (d, JC−F = 3.0 Hz), 130.2 (d, JC−F = 9.4 Hz)
129.7, 129.4, 127.2, 116.0 (d, JC−F = 22.1 Hz); 19F NMR (377 MHz,
CDCl3) δ (ppm) −104.09; HRMS (ESI) m/z calcd for C13H9FOS [M
+ H+] 233.0431, found 233.0430.
2-(4-Methoxyphenyl)-3-phenylbenzo[b]thiophene (1). The thio-
carbonylation procedure was followed to make S-(2-benzoylphenyl) 4-
methoxybenzothioate, which was isolated as colorless crystals (120 mg,
S-Phenyl 4-Chlorobenzothioate (Table 3, Entry 3).14 The title
compound was isolated as colorless crystals (93 mg, 0.37 mmol, 75%):
mp 81.2−82.3 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J =
8.8 Hz, 2H), 7.53−7.46 (m, 7H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 189.0, 140.1, 135.04, 134.96, 129.7, 129.3, 129.1, 128.8, 126.9;
HRMS (ESI) m/z calcd for C13H9ClOS [M + H+] 249.0135, found
249.0141.
1
0.35 mmol, 69%): H NMR (400 MHz, CDCl3) δ (ppm) 7.82−7.79
(m, 4H), 7.66 (d, J = 7.6 Hz, 1H), 7.59−7.47 (m, 4H), 7.38 (t, J = 7.6
Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 196.4, 187.6, 164.1, 144.1, 137.6, 137.1, 133.4, 130.6,
130.3, 129.8, 129.2, 129.1, 128.9, 128.4, 126.2, 113.9, 55.6; HRMS
(ESI) m/z calcd for C21H16O3S [M + Na+] 371.0712, found 371.0715.
S-(2-Benzoylphenyl) 4-methoxybenzothioate (116 mg, 0.33 mmol)
was dissolved in dry dioxane (35 mL) and cooled to 0 °C, and TiCl4
(110 μL, 1.0 mmol) was added dropwise under an argon atmosphere.
After the mixture was stirred at 8 °C for 0.5 h, Zn powder (131 mg, 2.0
mmol) was added, and the reaction mixture was refluxed overnight.
The reaction was quenched with water and the product extracted with
Et2O (3 × 20 mL) and dried with Na2SO4. The organic solvent was
removed under vacuum, and the desired compound was purified by
flash chromatography on silica gel using pentane/CH2Cl2 as eluent
system. The title compound was isolated as yellow crystals (78 mg,
0.25 mmol, 75%): mp 119.4−121.1 °C; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.88 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.45−7.29
(m, 7H), 7.28 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.80 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 159.3, 141.2, 139.6,
138.7, 135.9, 132.5, 130.9, 130.6, 128.8, 127.4, 126.8, 124.5, 124.4,
123.3, 122.1, 114.0, 55.3; HRMS (ESI) m/z calcd for C21H16OS [M +
H+] 317.1000, found 317.1003.
S-Phenyl 3-Cyano-4-methoxybenzothioate (Table 3, Entry 4).
The title compound was isolated as colorless crystals (94 mg, 0.35
1
mmol, 70%): mp 113.9−115.1 °C; H NMR (400 MHz, CDCl3) δ
(ppm) 8.24 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.8 Hz, J = 2.3 Hz, 1H),
7.51−7.44 (m, 5H), 7.06 (d, J = 8.9 Hz, 1H), 4.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 187.3, 164.7, 135.1, 133.9, 133.5, 129.8,
129.6, 129.4, 126.6, 115.3, 111.5, 102.5, 56.8; HRMS (ESI) m/z calcd
for C15H11NO2S [M + H+] 270.0583, found 270.0585.
S-Phenyl Naphthalene-1-carbothioate (Table 3, Entry 5).14 The
title compound was isolated as colorless crystals (83 mg, 0.31 mmol,
63%): mp 58.8−59.6 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.55
(d, J = 8.4 Hz, 1H), 8.23 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H),
7.90 (d, J = 7.6 Hz, 1H), 7.63−7.50 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 192.2, 134.9, 134.7, 133.8, 133.3, 129.6, 129.4, 129.3,
128.4, 128.3, 128.1, 128.0, 126.7, 125.3, 124.5; HRMS (ESI) m/z calcd
for C17H12OS [M + Na+] 287.0501, found 287.0501.
S-Phenyl 4-Acetylbenzothioate (Table 3, Entry 6).17 The title
compound was isolated as colorless crystals (58 mg, 0.23 mmol, 45%):
mp 113.2−114.8 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.10 (d, J
= 8.7 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 7.53−7.46 (m, 5H), 2.65 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 197.2, 189.6, 140.6,
139.9, 135.0, 129.8 129.4, 128.6, 127.7, 126.8, 26.9; HRMS (ESI) m/z
calcd for C15H12O2S [M + H+] 257.0631, found 257.0633.
[13C]-2-(4-Methoxyphenyl)-3-phenylbenzo[b]thiophene (2). The
thiocarbonylation procedure was followed to make [13C]-S-(2-
benzoylphenyl)4-methoxybenzothioate, which was isolated as colorless
1
crystals (123 mg, 0.35 mmol, 70%): H NMR (400 MHz, CDCl3) δ
(ppm) 7.84−7.79 (m, 4H), 7.66 (d, J = 7.6 Hz, 1H), 7.61−7.48 (m,
4H), 7.39 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 196.3, 187.5 (13C), 164.0 (d,
S-Phenyl 4-Cyanobenzothioate (Table 3, Entry 7).37 The reaction
time for the title compound was 24 h, which was isolated as colorless
J
C−C = 1 Hz), 144.1 (d, JC−C = 1 Hz), 137.6, 137.0, 133.3, 130.5, 130.2,
1
crystals (31 mg, 0.13 mmol, 26%): mp 134.2−135.7 °C; H NMR
129.8 (d, JC−C = 4 Hz), 129.2, 129.0 (d, JC−C = 65 Hz), 128.9, 128.4,
I
dx.doi.org/10.1021/jo5009965 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
126.2 (d, JC−C = 1 Hz), 113.8 (d, JC−C = 5 Hz), 55.5; HRMS (ESI) m/
z calcd for C2013CH16O3S [M + H+] 350.0926, found 350.0929. [13C]-
S-(2-Benzoylphenyl)4-methoxybenzothioate (123 mg, 0.35 mmol)
was subjected to the same conditions as in the previous McMurry
coupling. The title compound was isolated as yellow crystals (79 mg,
0.26 mmol, 75%): mp 119.9−121.7 °C; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.88 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.44−7.33
(m, 7H), 7.28 (dd, J = 4.1 Hz, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz,
2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 159.3,
141.2 (d, JC−C = 4 Hz), 139.6 (13C), 138.7 (d, JC−C = 4 Hz), 135.9 (d,
JC−C = 3 Hz), 132.4 (d, JC−C = 71 Hz), 130.9 (d, JC−C = 2 Hz), 130.6
(d, JC−C = 3 Hz), 128.8, 127.4, 126.8 (d, JC−C = 63 Hz), 124.5, 124.4
(d, JC−C = 1 Hz), 123.3 (d, JC−C = 6 Hz), 122.1 (d, JC−C = 2 Hz), 114.0
(d, JC−C = 5 Hz), 55.3; HRMS (ESI) m/z calcd for C2013CH16OS [M +
H+] 318.1028, found 318.1025.
2-(4-Methoxyphenyl)-3-phenylbenzo[b]thiophene (3). The thio-
carbonylation procedure was followed to make S-(2-benzoylphenyl) 4-
methoxybenzothioate, which was isolated as colorless crystals (85 mg,
0.25 mmol, 49%): 1H NMR (400 MHz, CDCl3) δ (ppm) 7.82 (d, J =
7.4 Hz, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.61−7.47 (m, 6H), 7.39 (t, J =
7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 1H), 2.27 (s, 3H), 2.25 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 196.9, 188.9, 144.1, 143.4, 137.6,
137.2, 137.1, 134.2, 133.4, 130.6, 130.3, 129.9, 129.3, 129.0, 128.6,
128.4, 126.3, 125.3, 20.1, 19.7; HRMS (ESI) m/z calcd for C22H18O2S
[M + H+] 347.1100, found 347.1102. S-(2-Benzoylphenyl) 4-
methoxybenzothioate (85 mg, 0.25 mmol) was subjected to the
same conditions as in the previous McMurry coupling. The title
compound was isolated as yellow crystals (55 mg, 0.18 mmol, 75%):
mp 108.2−109.3 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.89 (d, J
= 8.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.42−7.33 (m, 7H), 7.18 (s,
1H), 7.03 (q, J = 7.9 Hz, 2H), 2.25 (s, 3H), 2.20 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 141.2, 140.0, 138.8, 136.7, 136.5, 136.0,
132.8, 131.8, 130.9, 130.6, 129.8, 128.7, 127.4, 127.1, 124.48, 124.45,
123.3, 122.2, 19.9, 19.6; HRMS (ESI) m/z calcd for C22H18S [M +
H+] 315.1202, found 315.1204.
ACKNOWLEDGMENTS
■
We are deeply appreciative of generous financial support from
the Danish National Research Foundation (Grant No.
DNRF59), the Villum Foundation, the Danish Council for
Independent Research: Technology and Production Sciences,
the Carlsberg Foundation, and Aarhus University.
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S-(2-(2,3-Dimethoxybenzoyl)phenyl) 4-(Dimethylamino)-
benzothioate (4). 4-Bromo-N,N-dimethylaniline (80 mg, 0.40
mmol), (2,3-dimethoxyphenyl)(2-mercaptophenyl)methanone (110
mg, 0.40 mmol), Pd(PhCN)2Cl2 (7.7 mg, 20 μmol), Xantphos (11.6
mg, 20 μmol), and NaOAc (36.1 mg, 0.44 mmol) were dissolved in
anisole (2.0 mL). Chamber 2: 1.5 equiv of CO was generated in
chamber 2. The glassware was then removed from the glovebox, and
the contents were mixed at 120 °C. After 18 h, the solvent was
removed from chamber 1 in vacuo, and the desired compound was
purified by flash chromatography on silica gel using a gradient starting
from pentane to CH2Cl2 as eluent system. The title compound was
1
isolated a yellow oil (mg, 0.23 mmol, 45%): H NMR (400 MHz,
CDCl3) δ (ppm) 7.80 (d, J = 9.1 Hz, 2H), 7.65 (dd, J = 9.2 Hz, J = 2.9
Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.43 (dt, J = 6.7 Hz, J = 1.9 Hz, 1H),
7.10 (dd, J = 6.9 Hz, J = 2.4 Hz, 1H), 7.03−6.97 (m, 2H), 6.58 (d, J =
9.1 Hz), 3.82 (s, 3H) 3.58 (s, 3H), 3.03 (s, 3H); 13C NMR (100 MHz,
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130.6, 129.8, 129.5, 128.6, 127.2, 123.9, 123.7, 122.3, 115.8, 110.6,
61.4, 56.1, 40.1; HRMS (ESI) m/z calcd for C24H23NO4S [M + H+]
422.1421, found 422.1423.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and copies of 1H NMR, 13C NMR, and 19F
NMR spectra for all coupling products. This material is
available free of charge via the Internet at http://pubs.acs.org
(18) COgen is commercially available at: www.sigmaaldrich.com and
www.sytracks.com.
(19) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
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Andersen, B.; Skrydstrup, T. Org. Lett. 2014, 16, 2216. (b) Nielsen, D.
U.; Lescot, C.; Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T.
Chem.Eur. J. 2013, 19, 17926. (c) Korsager, S.; Nielsen, D. U.;
Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. Chem.Eur. J. 2013,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ts@chem.au.dk.
Notes
The authors declare no competing financial interest.
J
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K
dx.doi.org/10.1021/jo5009965 | J. Org. Chem. XXXX, XXX, XXX−XXX