Pd(0)-catalyzed Cu(I)-thiophene-2-carboxylate-mediated cross-coupling of heteroaromatic thioethers and boronic acids - First Liebeskind-Srogl reaction in water

Article abstract of DOI:10.1002/jhet.2005

The first example of a Liebeskind-Srogl cross-coupling reaction in water as sole reaction solvent is reported. 2-(Methylthio)pyridine and 2-(methylthio)benzothiazole were reacted in the presence of a Pd(0) catalyst and copper(I) thiophene-2-carboxylate with a series of arylboronic acids. These cross coupling reactions in water proceeded well with electron-rich boronic acids and gave comparable yields to literature examples using organic solvents. Electron-poor boronic acids gave somewhat lower yields in aqueous medium.

Full text of DOI:10.1002/jhet.2005

Month 2013 Pd(0)-Catalyzed Cu(I)-Thiophene-2-carboxylate-mediated Cross-Coupling
of Heteroaromatic Thioethers and Boronic Acids—First Liebeskind–Srogl
Reaction in Water
a
a
a
a
Moumita Koley, Laurin Wimmer, Michael Schnürch, * and Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna,
Austria
*
E-mail: michael.schnuerch@tuwien.ac.at
Received December 19, 2012
DOI 10.1002/jhet.2005
Published online 00 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
The first example of a Liebeskind–Srogl cross-coupling reaction in water as sole reaction solvent is
reported. 2-(Methylthio)pyridine and 2-(methylthio)benzothiazole were reacted in the presence of a Pd(0)
catalyst and copper(I) thiophene-2-carboxylate with a series of arylboronic acids. These cross coupling
reactions in water proceeded well with electron-rich boronic acids and gave comparable yields to literature
examples using organic solvents. Electron-poor boronic acids gave somewhat lower yields in aqueous
medium.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
thioester, and thiamide) are employed as leaving groups
in this transformation. Originally, thioesters were reacted
with a series of boronic acids to give ketones in good
yields [8]. These functionalities are inert under the reac-
tion conditions of the aforementioned coupling proto-
cols, and hence, the selectivity problems previously
mentioned can be overcome. Only upon addition of a
copper salt the S–R groups undergo cross-coupling
reactions. The copper salt, very often copper(I) thiophene-
2-carboxylate (CuTC), is required in stoichiometric amounts
as thiophilic cofactor. When the copper(I) carboxylate was
replaced with a copper(I) halide or CuCN, no coupling prod-
uct was obtained [8]. All these features make the method
well suited for being included in sequences where multiple
cross-coupling reactions have to be carried out consecutively
with high selectivity [10].
It is noteworthy that the Liebeskind–Srogl reaction can
be carried out under neutral conditions without any base
present (often required for other cross-coupling protocols);
in fact, a base is even not tolerated and completely shuts
down the reaction. This can be problematic if sufficiently
basic groups are present in the substrate; however, it can
also be exploited for obtaining high selectivity in cross-
coupling events.
Transition metal-catalyzed cross-coupling reactions had
an enormous impact on C–C bond formation strategies in
organic synthesis that was also recognized in 2010 by
awarding the noble prize in this area of chemistry [1]. More
specific, the cross-coupling of heteroaromatics is a process
of significant synthetic potential because heterocyclic
scaffolds are incorporated in many target molecules
displaying biological activity or material science proper-
ties [2]. Amongst others, methods such as the Suzuki–
Miyaura, Heck, or Negishi reaction were applied in a vast
variety of synthetic sequences involving heterocyclic
scaffolds with great success [3–5]. However, these methods
have certain limitations: first of all, they follow in principal
the same reaction mechanism, which requires on the one
hand an organic (pseudo)halide and on the other hand
an organometallic component. Consequently, selectivity
becomes an issue in reaction sequences where more
than one (pseudo)halide is present in one reaction partner.
The aspects of regioselectivity and chemoselectivity are
increasingly relevant in modular synthetic strategies,
because the trend in cross-coupling reactions aims at carry-
ing out multiple cross-coupling steps in a one-pot fashion
avoiding purification of intermediates [6,7].
In this regard, palladium(0)-catalyzed, copper(I)-
mediated desulfitative Liebeskind–Srogl cross-coupling
reactions offer a unique advantage [8,9]. Rather than
halides, organosulfur groups (e.g., S-alkyl, S-aryl,
Besides thioesters, heteroaryl thioethers can also be applied
in Liebeskind–Srogl couplings which in turn can be easily
prepared from readily available starting materials and
©
2013 HeteroCorporation

M. Koley, L. Wimmer, M. Schnürch, and M. D. Mihovilovic
Vol 000
generally represent stable chemical entities. Simple homo-
arylthioethers do not react efficiently within Liebeskind–Srogl
coupling reactions, which represents a limitation of this proto-
col [11]. On the other hand, the reactions proceed usually
successfully and with synthetically useful yields when
employing heteroaryl thioethers and various boronic
acids [11]. The enhanced reactivity of heteroaryl thioethers
can be rationalized in terms of the electron deficiency at the
carbon center attached to the leaving group (usually SMe)
of the heteroaromatic core, which incorporates an electro-
negative atom (N or S) in the a-position to the sulfide group
out in water as solvent, the conversion was below ~15%
according to GC–MS. By switching to the most frequently
used and cheapest Pd catalyst Pd(PPh ) , which is also the
3
4
most commonly used system in Liebeskind–Srogl reac-
tions, significantly improved results were obtained as
compared with using Pd dba /TFP system (15% conver-
2
3
sion with Pd dba /TFP vs 63% with Pd(PPh ) ). We
2
3
3 4
screened a number of other catalytic systems, some of
them common in LS-coupling reactions and some of them
so far not applied in this type of reaction, but unfortu-
nately, the conversion could not be improved further.
One reason for that could be the fact that the products
(and also the pyridine substrate) might act as ligand for
the catalyst inhibiting the reaction. Hence, it was finally
decided to stick with Pd(PPh ) as catalyst for further
[9c]. The use of heterocyclic thioethers and aryl, heteroaryl,
and alkenyl stannanes as coupling partners in C–C coupling
reactions led to a variety of substituted heterocycles in good
overall yields [12]. In addition to that, the C–C coupling of
thioethers was applied in the synthesis of protected aryl
and heteroaryl amidines [13], the functionalization of chi-
ral oxazolines with organoborane and organostannane re-
agents [14], the synthesis of diketopyrrolo[3,4-c]pyrrole
fluorophores [15], and the formation of differently
substituted triazines [16] and tetrazines [17]. Various het-
erocyclic methylthioethers have already been used in
Sonogashira-type cross-coupling [18]. We have success-
fully investigated the scope of 2-methylthio-3-iodo pyri-
dine in Liebeskind–Srogl coupling reactions recently [10].
To the best of our knowledge, one feature of all
Liebeskind–Srogl cross-couplings reported so far have in
common is that they are carried out in organic solvents
3
4
transformations. The reaction conditions applied were as
follows: phenylboronic acid (1.1equiv), heteroaryl
thioethers (1 equiv), CuTC (1.2 equiv), and Pd(PPh ) (5 mol
3
4
%). Initially, 2-(methylthio)pyridine was used as the
heteroaryl compound, which was synthesized according to a
literature protocol in quantitative yield [22].
The reactions proceeded very slowly in water and after
3 days, there was generally about 50% conversion
(Scheme 1). Even after prolonging the reaction time up to
7 days, there was no further improvement. When monitor-
ing the reaction over time, it was observed that the reaction
was very slow within the first 24 h (11% conversion
according to GC–MS), but the reaction rate increased
afterwards (61% conversion after 3 days, according to
GC–MS). It was hypothesized that CuTC was partially
converted to thiophene-2-carboxylic acid under aqueous
conditions, which then might help to increase the reaction
rate (e.g., by protonating the pyridine substrate and hence
increasing the positive charge). Therefore, adding an exter-
nal acid should have a beneficial effect on the rate of the
reaction. Hence, a few drops of AcOH were added to the
reaction mixture at the beginning, and indeed, product for-
mation could be significantly accelerated to about 50%
conversion within 24 h. However, also under these con-
ditions, full conversion could never be achieved, again
suggesting an inhibition at a certain product concentration;
in all cases, the reaction stopped at about 50–60% conver-
sion. Even the addition of stoichiometric amounts of acid
did not improve the conversion. A variety of acids was
investigated for any beneficial effect. Using diluted HCl,
(often THF or dioxane). This is a shortcoming that cannot
be neglected in view of green and sustainable chemistry es-
pecially because competitive protocols such as the Suzuki–
Miyaura reaction are frequently carried out in aqueous me-
dia [1f,3f]. Of course to make a Liebeskind–Srogl reaction
a “green” reaction, other issues (e.g., the use of stoichio-
metric amounts of copper) have to be addressed as well.
However, within this contribution, we report the first
Liebeskind–Srogl reaction in water as sole solvent, which
is one step in the right direction.
RESULTS AND DISCUSSION
In our continuing quest to efficiently and selectively
arylate heteroaryl systems such as thiazole [19], oxazole
[20], and pyridine [21], we investigated the possibility to
carry out Liebeskind–Srogl reactions in water to make
the overall process more environmentally benign.
Initially, reaction conditions successfully implemented
in Liebeskind–Srogl couplings of heteroaryl thioethers in
organic solvents were adopted for conversions in aqueous
environment. According to previous literature reports, the
best results in such reactions were obtained when the
precatalyst Pd dba and the ligand tris(2-furyl)phos-
Scheme 1. Coupling of 2-methylthiopyridine with boronic acids.
2
3
phine (TFP) were used as catalytic system in THF as
solvent [11]. However, when the reaction was carried
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Liebeskind–Srogl Coupling in Water as Sole Solvent
Scheme 2. Coupling of 2-methylthiobenzothiazole with boronic acids.
the reaction did not proceed as well as with AcOH (45%
conversion versus 55% after 24 h according to GC–MS).
Even increasing the amount of catalyst (up to 10 mol%)
or boronic acid (up to 3 equiv) and CuTC (up to 3 equiv)
did not show any improvement. An adverse effect by aerial
oxidation of the catalyst within the prolonged reaction
times could be ruled out, as results were comparable with
conversions under argon. Also, adding the catalyst in
portions to the reaction mixture (2.5 mol% at the begin-
ning, 2.5% after 6–8 h) under argon atmosphere did not
improve the conversion. Consequently, the presence of an
inert atmosphere was not necessary, and future experiments
were conducted under ambient conditions.
When phenylboronic acid was used as coupling partner
with 2-methylthio pyridine, it gave an isolated yield of
product 3a of 47% in the presence of AcOH and 1 day
reaction time, whereas 54% were isolated within 3 days
in the absence of AcOH (Entry 1). When electron-rich
p-methoxy-phenylboronic, p-tolyl-phenylboronic, and
p-t-butyl-phenylboronic acids were used as coupling
partners, isolated yields of products were 49 (3b), 57
(3d), and 52% (3e), respectively (entries 2, 4, and 5).
Sterically hindered o-tolyl boronic acid gave a lower
isolated yield of 42% (3c, entry 3). Prolongation of
reaction time did not show any improvement in this
case. In case of 3-nitro boronic acid as coupling partner,
even after 3 days, the conversion was below 50%, and
the isolated yield of product 3h was 22% (entry 8, the re-
action was carried out in the absence of AcOH). Even in
the presence of AcOH, there was no improvement in the
reaction rate, and conversion was still below 50% (product
not isolated in this experiment). The lower yield in this
case is probably because m-nitrophenylboronic acid has
Because poor solubility of the substrates in water could
be a reason for slow and incomplete conversion, one exper-
iment was carried out where the aqueous reaction mixture
ꢀ
was sonnicated for 24 h at 50 C. Also in this case, no
improvement was observed. All further experiments were
carried out using arylboronic acid (1.1 equiv), CuTC
(1.2 equiv), and Pd(PPh3)4 (5 mol%) as catalyst with
addition of catalytic amounts of AcOH. The catalyst was
added in portions, at the beginning 2.5 mol% and after
6
–8 h another 2.5 mol%.
The obtained results are listed in Table 1. Several
different boronic acids were used for cross-coupling and
either 2-(methylthio)pyridine (Scheme 1) or 2-(methythio)
benzothiazole (Scheme 2) as S-containing coupling partner.
Table 1
Liebeskind–Srogl coupling results in water.
Entry
1
Ar-SMe
Boronic acid
Product
Yield (%)
47
a
54
3a [23]
2
49
3b [24]
3
4
42
57
3c [25]
3d [24]
(Continued)
Journal of Heterocyclic Chemistry
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M. Koley, L. Wimmer, M. Schnürch, and M. D. Mihovilovic
Vol 000
Table 1
(Continued)
Entry
5
Ar-SMe
Boronic acid
Product
Yield (%)
52
a
34
3e [26]
6
7
43
53
3f [27]
3g [28]
a
8
9
22
3
h [29]
52
54
47
39
4
a [30]
1
1
1
0
4
b [31]
1
2
4
c [29]
4d [32]
1
3
4
42
49
4e [33]
1
4f [32]
Reaction conditions: Ar-B(OH)
2
(1.1 equiv), CuTC (1.2 equiv), Pd(PPh
3
)
4
(5 mol%, 2.5 mol% at the beginning and after 6–8 h another 2.5 mol%), glacial
ꢀ
AcOH (0.25 equiv) with stirring for 24 h in a screw cap vial in a heating block at 50 C.
a
ꢀ
Without AcOH and the whole portion of catalyst (5 mol%) was added at the beginning and stirring for 3 days at 50 C.
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Liebeskind–Srogl Coupling in Water as Sole Solvent
a limited stability in water. In case of p-chlorophenylboronic
and m-chlorophenylboronic acid as coupling partner, the
isolated yields of products were 43 (3f, entry 6) and 53%
was limited to 2-(methylthio)pyridine and 2-(methylthio)
benzothiazole, where conversions usually around 50–60%
were observed. It is noteworthy that no electron-
withdrawing substituents on pyridine were necessary to
achieve good results, which is different from reported
Liebeskind–Srogl couplings so far. Additionally, our
protocol does not require inert atmosphere but can be
carried out under air. The use of different catalytic systems
or longer reaction time could not improve the conversion.
Usually electron-rich boronic acids gave better yields.
Isolated yields were within 40–50%, which is slightly lower
compared with organic solvents. Still, the reactions are
important as these are the first examples of Liebeskind–
Srogl reactions performed in water as solvent, and we are
trying to broaden the substrate scope and further improve
the conversion in ongoing work, especially aimed at the
reaction of thioesters in water. Additionally, the developed
protocol is interesting for application in sequential
Liebeskind–Srogl–Suzuki–Miyaura reactions because the
two different leaving groups applied in the two protocols are
inert under the conditions of the respective other protocol,
and both reactions can be carried out in water. To make a
Liebeskind–Srogl reaction environmentally benign, future
efforts will need to be undertaken, for example, addressing
the stoichiometric usage of Cu salt.
(3g, entry 7), respectively.
Another heterocyclic methylthio compound that could
successfully be coupled in water as solvent was 2-
(
methylthio)benzothiazole. Also in this case, similar conver-
sion of the starting material was observed as in the case of
-methylthiopyridine. The reaction conditions and yield of
2
these coupling reactions are also displayed in Table 1. Using
the benzothiazole, starting material led to isolation problems
because starting material and products could not be separated
in many case via column chromatography. To separate the
product from the starting material, the reaction mixture was
first extracted in CH Cl from water, and then after drying
2
2
the organic layer over brine and Na SO , one equivalent
2
4
(calculated according to the starting material used) of 55%
m-CPBA was added and stirred at room temperature for 2 h
to oxidize the starting material, 2-(methylthio)benzothiazole,
mainly to the corresponding sulfone and minor amounts of
sulfoxide (as detected by GC–MS). This significantly
changed the polarity and greatly facilitated the isolation of
the products. Excess m-CPBA was then removed by
extraction with a saturated solution of Na CO , and the de-
2
3
sired product was isolated by column chromatography. Cou-
pling with phenylboronic acid gave 52% isolated yield of
product 4a (entry 9). In cases of p-methoxyphenylboronic
acid (entry 10) and p-chlorophenylboronic acid (entry 13)
EXPERIMENTAL
as aryl donors, the difference of R values between the
f
resulting products 4b and 4e and starting material was suffi-
cient for separation by column chromatography. The corre-
sponding products were isolated in 54 (4b) and 42% (4e),
respectively. However, for the products resulting from
cross-coupling with p-tolylphenylboronic and p-t-
butylphenylboronic acid (4c and 4d, entries 11 and 12),
oxidation of the starting material to the sulfone prior to
column chromatography was necessary. The product 4c in
entry 11 was isolated in 47% yield. A lower yield was ob-
served in the coupling reaction with p-t-butylphenylboronic
acid, although the boronic acid is electron rich (4d, entry
General notes.
Unless otherwise noted, chemicals were
purchased from commercial suppliers (Sigma-Aldrich, Vienna,
Austria; STREM Chemicals Inc., Bischheim, France; Apollo
Scientific, Cheshire, UK) and used without further purification.
Flash column chromatography was performed on silica gel 60
from Merck (40–63 mm), and separations were carried out using
a Büchi Sepacore MPLC system using a 45 g column. For TLC,
aluminium-backed silica gel was used. NMR spectra were
recorded mostly in CDCl with TMS as internal standard or in
3
DMSO-d or CD OD on a Bruker AC 200 (200 MHz)
6 3
spectrometer (Rheinstetten, Germany), and analytical data of the
prepared compounds are in agreement with previously published
data. GC–MS runs were performed on a Thermo Finnigan Focus
GC/DSQ II (Vienna, Austria) using a standard capillary column
BGB 5 (30 m  0.32 mm ID).
1
2). Here, the isolated yield was 39%, and the more elaborate
isolation procedure might be responsible for the lower yield.
In the reaction of 3-nitrophenyl boronic acid, very low con-
version was detected, and products had not been isolated.
Again, 3-chlorophenylboronic acid gave better conversion
with isolated yield of product of 46% (4f, entry 14),
although elaborate purification was necessary.
General procedure A.
2-(Methylthio)pyridine or 2-
(
methylthio)benzothiazole (1 equiv), boronic acid (1.1 equiv),
CuTC (1.2 equiv), Pd(PPh3)4 (5 mol%), and glacial AcOH
(0.25 equiv) were charged into a screw cap vial, and water
(2 mL) was added. The vial was closed, and the reaction
ꢀ
mixture was stirred in a heating block at 50 C for 24 h. After
cooling to RT, a 2 N solution of NaOH (3 mL) was added to the
reaction mixture and then extracted with EtOAc (5 mL) three
times. The combined organic layers were then washed with
brine and dried over Na SO . The solid material was filtered off
2 4
and washed with 5 mL of EtOAc. The solvent was evaporated,
CONCLUSION
In summary, the palladium-catalyzed CuTC-mediated
Liebeskind–Srogl cross-coupling reaction of S-methylheteroaryls
in water gave reasonable yields in most examples. The
substrate scope regarding the methylthio-heterocycles
and the resulting crude product was purified by flash column
chromatography. Because the R values of the starting material
f
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Koley, L. Wimmer, M. Schnürch, and M. D. Mihovilovic
Vol 000
and products were very similar, purification by column
2
117. (c) Negishi, E.; King, A. O.; Okukado, N. J Org Chem 1977,
chromatography was only successful in case of products 3a–3h
and 4b and 4d. In all other cases, work-up was carried out
according to general procedure B.
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Na SO . After filtration, 1 equiv (calculated according to the
2 2
Cl (5 mL,
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8
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Substances prepared within this contribution are all known to
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Austrian Wirtschaftsservice (Uni:Invent Project Z090391). M.K.
would like to thank the Afro-Asiatisches Institut for providing a
fellowship under the One-World Scholarship program.
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