Heterogeneously catalyzed direct C-H thiolation of heteroarenes

Article abstract of DOI:10.1002/anie.201411997

The first general methodology for the direct thiolation of electron-rich heteroarenes was developed by employing Pd/Al₂O₃, a recoverable and commercially available heterogeneous catalyst, and CuCl₂. This method represents an operationally simple approach for the synthesis of these valuable compounds. Preliminary mechanistic studies indicate a heterogeneous catalytic system, in which both metals play a complementary role in the formation of the thiolated products. (Hetero)genius: A general method for the direct thiolation of electron-rich heteroarenes was developed by employing Pd/Al₂O₃, a recoverable and commercially available heterogeneous catalyst, and CuCl₂. Preliminary mechanistic studies indicate a heterogeneous active catalytic species, with the two metals playing complementary roles in the formation of the thiolated products.

Full text of DOI:10.1002/anie.201411997

Angewandte
Chemie
DOI: 10.1002/anie.201411997
Catalytic Thiolation
Hot Paper
À
Heterogeneously Catalyzed Direct C H Thiolation of Heteroarenes**
Suhelen Vꢀsquez-Cꢁspedes, Angꢁlique Ferry, Lisa Candish, and Frank Glorius*
Abstract: The first general methodology for the direct
thiolation of electron-rich heteroarenes was developed by
employing Pd/Al2O3, a recoverable and commercially avail-
able heterogeneous catalyst, and CuCl2. This method repre-
sents an operationally simple approach for the synthesis of
these valuable compounds. Preliminary mechanistic studies
indicate a heterogeneous catalytic system, in which both metals
play a complementary role in the formation of the thiolated
products.
poisoning effect on some reagents and transition metals by
sulfur compounds.[6] Pioneering work by the group of
Inamoto in 2008 utilized palladium to synthesize heterocycles
À
through homogeneous C H thiolation in an intramolecular
fashion.[7] Cu, Rh, and Ru catalysts have also proven to be
successful at promoting this transformation.[5t] Nevertheless,
a directing group free[8] general method for the direct C H
À
functionalization of electron-rich heteroarenes, such as thio-
phene, benzo[b]thiophene, or benzofuran, remains elusive.[9]
À
Indeed, only few examples of non-directed C H thiolation
À
T
he formation of C S bonds is important because of their
exist in the literature and they usually require very specific
sulfenylating agents that are not commercially available. In
2001, Kita and co-workers reported the first sulfenylation of
electron-rich (hetero)arenes through the use of a quinone-
derived thiolation reagent (Figure 2).[10] In 2011, Yamaguchi
prevalence in many biologically active compounds and
organic materials.[1] Sulfenylated heteroarenes can be found
in molecules such as AZD4407, a 5-lipoxygenase inhibitor,[2]
and thienoacene-based materials (Figure 1).[3]
Figure 1. Examples of sulfenylated heterocycles used in pharmaceutical
and materials chemistry.
The thiolation of heteroarenes usually involves a transi-
tion-metal-catalyzed cross-coupling reaction between an
organic halide or boronic acid and thiols or disulfides.[4]
These methods have the disadvantage of employing prefunc-
tionalized substrates and usually require ligands and numer-
ous additives for efficient reaction. While numerous
À
À
approaches to C N or C C bond formation through direct
[5]
À
C H functionalization have been reported in recent years,
À
À
reports of analogous C S bond formation through direct C H
thiolation remain scarce. This is presumably due to the
[*] S. Vꢀsquez-Cꢁspedes,[+] Dr. A. Ferry,[+] Dr. L. Candish,
Prof. Dr. F. Glorius
À
À
À
Figure 2. Conversion of heteroarene C H bonds into C S/C Se
bonds. dppe=1,2-bis(diphenylphosphanyl)ethane, Tf=trifluorometh-
anesulfonyl, TMSOTf=trimethylsilyl trifluoromethanesulfonate.
Westfꢂlische Wilhelms-Universitꢂt Mꢃnster
Organisch-Chemisches Institut
Corrensstraße 40, 48149 Mꢃnster (Germany)
E-mail: glorius@uni-muenster.de
[+] These authors contributed equally to this work.
À
and co-workers reported a rhodium-catalyzed C H thiolation
of heteroaromatic compounds that makes use of a-(phenyl-
thio)ketones as the thiol source, however, only single
examples of an electron-poor benzo[b]thiophene and thio-
phene were described.[11] The Prabhu group developed the
direct benzoxazolethiolation of hetero(arenes) by utilizing
a benzoxazolethione under strongly oxidizing conditions.[12]
[**] Generous financial support by the Deutsche Forschungsgemein-
schaft (Leibniz award (F.G.), SFB 858 (S.V.C.)) is gratefully
acknowledged. We thank Theresa Olyschlꢂger, Matthias Freitag, and
Karin Gottschalk for experimental support, Adrian Tlahuext-Aca, Dr.
Karl D. Collins, Roman Honeker and Tobias Gensch for helpful
discussions and Michael Holtskamp and Prof. Dr. Uwe Karst (all
WWU Mꢃnster) for TXRF determination.
À
Some reports in the literature refer to the undirected C H
functionalization of electron-rich arenes from disulfides,[13]
however these methods suffer from limited scope and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411997.
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selectivity and have not been applied to electron-rich
heteroarenes.[14] Therefore, the development of general con-
À
ditions for the direct C H thiolation of electron-rich hetero-
arenes with high selectivity, from ubiquitous thiol or disulfide
precursors, is desirable.
Heterogeneous catalysis has potential advantages includ-
ing the easy removal of transition metals from reaction
mixtures and the possibility to recycle the catalyst. Our group
recently reported the Pd/C-catalyzed regioselective arylation
of (hetero)arenes.[15] Following these results, we decided to
focus on the formation of more challenging C–heteroatom
À
bonds through C H functionalization. Indeed, to the best of
our knowledge, no heterogeneously catalyzed methodology
À
exists for direct C H thiolation on electron-rich heteroar-
enes.[16] Herein, we present a general method involving
palladium/copper(II) catalysis for the direct thiolation of
different heteroarenes through the use of disulfides, and the
extension of this method to the synthesis of selenated
compounds through the use of diselenides.
Following our previous results based on the activation of
heteroarenes by heterogeneous catalysts,[15a,b] we expected to
À
be able to perform the more challenging C H thiolation by
Scheme 1. Phenylthiolation of different heteroarenes. Ratios deter-
mined by GC–MS analysis of the crude mixture and yields of isolated
product are given. [a] General procedure A: heteroarene (2.5 equiv),
diphenyldisulfide (0.5 equiv=1 equiv of thiol), Pd/Al2O3 (10 mol%),
and CuCl2 (1 equiv) in 1,2-dichloroethane (DCE) at 808C. [b] 0.5 equiv
of CuCl2. [c] 1008C in DCE. [d] Isolated as a mixture of isomers.
[e] General procedure B: heteroarene (2.5 equiv), diphenyldisulfide
(0.5 equiv), Pd/Al2O3 (10 mol%) and CuCl2 (2 equiv) in toluene at
1308C. Ar=p-OMeC6H4.
using easily available diphenyldisulfide (2a) as the sulfur
source. After extensive screening (see the Supporting Infor-
mation), we successfully realized a highly selective C5-
thiolation of 2-n-butylthiophene (1a) to afford 3a by using
Pd/Al2O3 (Acros Organics: 5 wt% Pd/Al2O3, dry) in the
presence of CuCl2 (Scheme 1).
With the optimized conditions in hand, we explored the
scope of the reaction (Scheme 1). Satisfyingly, we found
a broad range of thiophenes substituted with electron-
donating and electron-withdrawing groups to be suitable
substrates for the reaction, although it was apparent that the
reaction was enhanced by electron-donating substituents on
the thiophene (see 3b versus 3c).
efficient coupling partners, although a preference for elec-
tron-rich disulfides was observed for coupling with 1a (4ab,
4ac, 4ae). Disulfides containing ortho and para substitution
on the arene were well tolerated (4ag), as were aryl disulfides
with electron-withdrawing groups such as Cl and Br (4ad, 4af,
4ch, 4dd).[17] Moreover, the high selectivity for the sulfenyl-
ation of N-methylindole, benzo[b]thiophene, and benzofuran
was not affected when we changed the electronic properties of
the disulfides (Scheme 2). Furthermore, we applied a robust-
ness screen (see the Supporting Information) to further
explore the functional-group tolerance of this reaction.[18]
We extended the scope of the reaction to include the
Pleasingly, the high selectivity was maintained with all of
the 2-substitued thiophenes (3a–3h). High yield and selec-
tivity for monosulfenylation on the 3-position was also
obtained when a 2,5-disubstituted thiophene was employed
(3d). Halogens and a carboxyl ester were also tolerated,
which would allow for further derivatization (3c, 3h, 3p).
Notably, the 3-substituted thiophenes proved to be more
challenging compared to the 2-substituted ones (3b versus 3i).
In the case of bulkier substituents in the 3-position, decreased
selectivity was also observed (3j, 3k). We next explored
different heteroarenes and were pleased to find that N-
methylindole and 5-iodo-N-methylindole reacted with high
selectivity and gave good yields (3l, 3m). The reactivity of
benzo[b]thiophene and benzofuran were also investigated,
however only low yields of the products were obtained under
the optimized reaction conditions. Increasing the amount of
CuCl2 and using toluene as the solvent resulted in the
formation of the thiolated products in modest to good yields
and with high selectivity in the case of benzo[b]thiophenes
(3n–3p). Interestingly, employing a benzofuran substituted at
the 2-position led to the formation of the sulfenylated product
3s in quantitative yield.
À
formation of C Se bonds (Scheme 3). Organoselenium com-
pounds are relevant in medicinal chemistry owing to their
biological activity, specifically their antitumor and anticancer
properties.[19] The selenated heteroarenes (6a–6d) were
obtained in moderate to good yields and with high selectivity.
À
This seems to represent the first C H selenation of the
benzo[b]thiophene core.
To demonstrate the utility of our transformation, we
prepared an extended sulfur based heterocycle, a common
motif of organic semiconductors.[1d,3] We subjected the
benzo[b]thiophene thiolated product 4ch to a palladium-
catalyzed intramolecular arylation to obtain BTBT in 79%
yield (Scheme 4).[1d]
Given that the palladium source utilized in the thiolation
reaction was heterogeneous in nature, we were interested to
understand whether the catalytic system was also heteroge-
Next, we explored the scope in terms of the disulfide 2
(Scheme 2). Electronically diverse disulfides were found to be
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filtration and the three-phase test suggested that no active
homogeneous palladium species were formed (see the
Supporting Information).
The presence of metals in the solution was measured by
Total reflection X-Ray Fluorescence (TXRF)[21] for both
catalytic systems (DCE and toluene). Copper was found to be
insoluble and palladium was detected in solution in different
amounts depending on the reaction time (see the Supporting
Information). However, heterogeneity tests (see above)
indicated that this leached Pd is not the active catalytic
species.
These results, along with the observation of the depend-
ence of the reaction on rapid stirring rates, suggest that the
catalytically active system is heterogeneous in nature. The
recycling of Pd/Al2O3 was also investigated, however
a decrease in yield was found for the second (63%) and
third (42%) cycles.
To investigate the role of the metals in the activation of
the heteroarene, a series of experiments were performed. H/
D exchange was observed when the standard substrate 1a was
treated with the catalytic system in presence of an excess of
CD3OD (Scheme 5a). A lesser degree of deuteration was also
Scheme 2. Arylthiolation with different disulfides. Ratios determined by
GC–MS analysis of the crude mixture and yields of isolated product
are given. [a] General procedure A: See Scheme 1. [b] 1:1 ratio of
starting materials. [c] 1008C in DCE. [d] Isolated as a mixture of
isomers. [e] General procedure B: See Scheme 1. [f] Isolated by
preparative HPLC. [g] 5.0 mmol scale.
Scheme 5. Deuteration and scrambling experiments.
observed when using only CuCl2. However, no deuteration of
1a was found when employing only Pd/Al2O3 (Scheme 5a).
No kinetic isotope effect (KIE) was observed when 2-n-
butylthiophene and 2-n-butyl-4-deuterothiophene were
employed under the reaction conditions in parallel and
competition experiments (KIE = 0.95 and 1.2, respectively),
Scheme 3. Phenylselenation of heteroarenes. Ratios determined by
GC–MS analysis of the crude mixture. [a] General procedure A:
heteroarene (2.5 equiv), diphenyldiselenide (0.5 equiv), Pd/Al2O3
(10 mol%), and CuCl2 (1 equiv) in DCE at 808C. [b] General procedure
B: heteroarene (2.5 equiv), diphenyldiselenide (0.5 equiv), Pd/Al2O3
(10 mol%), and CuCl2 (0.5 equiv) in toluene at 1308C. [c] 1:1 ratio of
starting materials. Ar=o-BrC6H4.
À
thus suggesting that C H bond cleavage is not rate determin-
ing.[22] Moreover, a sigmoidal reaction profile indicates the
formation of an active catalytic species from the precursors.
À
The importance of the metals for the activation of the S S
bond was investigated through scrambling and competition
experiments (see the Supporting Information). In the reaction
of two disulfides (2a and 2c), we observed significant
formation of the mixed disulfide 2i when employing either
our catalytic system or only an equivalent amount of Cu
(Scheme 5b). The use of only Pd/Al2O3 did not result in
formation of the mixed disulfide. In a competition experi-
ment, 1a was reacted with an equivalent mixture of two
electronically different disulfides (2c and 1,2-bis(4-bromo-
phenyl)disulfane) under the optimized reaction conditions.
After 2 h, we detected the formation of the sulfenylated
thiophene 4ac and the mixed disulfide as the major product.
In addition, a Hammett plot for the reactionbetween 1a and
different disulfides gave a 1 value of À2.5, thus suggesting the
Scheme 4. Application of the synthetic methodology to the synthesis
of [1]benzothieno[3,2-b][1]benzothiophene (BTBT).
neous. Therefore, we employed two common procedures to
explore the heterogeneity of the reaction.[20] The hot-filtration
test indicated no further increase in product formation after
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À
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À
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À
Keywords: C H functionalization · disulfides · heteroarenes ·
heterogeneous catalysis · thiolation
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[19] a) L. Castla, M. J. Perkins in The Chemistry of Organic Selenium
and Tellurium Compounds (Ed.: S. Patai), Wiley, New York,
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Catalytic Thiolation
S. Vꢁsquez-Cꢂspedes, A. Ferry,
L. Candish, F. Glorius*
&&&& — &&&&
À
Heterogeneously Catalyzed Direct C H
Thiolation of Heteroarenes
(Hetero)genius: A general method for the
direct thiolation of electron-rich hetero-
arenes was developed by employing Pd/
Al2O3, a recoverable and commercially
available heterogeneous catalyst, and
CuCl2. Preliminary mechanistic studies
indicate a heterogeneous active catalytic
species, with the two metals playing
complementary roles in the formation of
the thiolated products.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!