Palladium-catalyzed C-S coupling: Access to thioethers, benzo[b]thiophenes, and thieno[3,2-b]thiophenes

Article abstract of DOI:10.1021/ol2016093

The first C-S bond formation/cross-coupling/cyclization domino reaction using thiourea as a cheap and easy to handle dihydrosulfide surrogate has been developed. Structurally important biarylthioether, benzo[b]thiophenes, and thieno[3,2-b]thiophene scaffolds are provided in high yield.

Full text of DOI:10.1021/ol2016093

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4100–4103
Palladium-Catalyzed CÀS Coupling:
Access to Thioethers, Benzo[b]thiophenes,
and Thieno[3,2-b]thiophenes
Marius Kuhn, Florian C. Falk, and Jan Paradies*
Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6,
D-76131 Karlsruhe, Germany
jan.paradies@kit.edu
Received June 15, 2011
ABSTRACT
The first CÀS bond formation/cross-coupling/cyclization domino reaction using thiourea as a cheap and easy to handle dihydrosulfide surrogate
has been developed. Structurally important biarylthioether, benzo[b]thiophenes, and thieno[3,2-b]thiophene scaffolds are provided in high yield.
Sulfur-containing functional groups and heterocycles
are ubiquitous structural elements in pharmacologically
active compounds and in material sciences.1 In particular
thioethers2 and benzo[b]thiophenes3 have been recognized as
biological and physiological effectors. Novel methodologies
for the synthesis of symmetric4 and unsymmetric5 biar-
ylthioethers have been developed using copper4,5a,6 and
palladium5cÀe catalyzed transformations.7 Benzo-
[b]thiophenes are usually synthesized by the reaction
of metalated arylalkenes with sulfur reagents1a,b,8 or by
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r
10.1021/ol2016093
Published on Web 07/06/2011
2011 American Chemical Society

nucleophilic aromatic substitution9 with sodium hy-
drosulfide and subsequent cyclization at high tempera-
tures (160À190 °C). Only few catalytic processes have
been reported in the literature to circumvent these
strong basic and harsh reaction conditions. Typical
promotors or catalysts are strong electrophiles, such
as AuCl,10 stoichiometric cupric halides,11 halonium
ions,3b,12 and strong acids (p-toluene sulfonic acid).13
The cyclization requires the preformation of the corre-
sponding alkynyl arylthioether, which subsequently
undergoes endo-dig cyclization onto the alkyne moiety.
Still, these reactions require the prerequisite formation
of the aryl-thiols prior to cyclization. Efficient meth-
odologies have been reported for the coupling of aryl
iodides and bromides with dihydrosulfide surrogates,
e.g. xanthate5a and tris(isopropyl)silylthiol,5c to furnish
unsymmetric biarylthioether according to a consecu-
tive additionÀdeprotectionÀaddition protocol. How-
ever, the use of thiourea (1) as a surrogate4,5a,5b,14 in the
coupling of arylbromides seems appealingsince itiseasyto
handle and not affected by air or moisture. Yet, a palla-
dium-catalyzed transformation has not been reported so
far. This report concentrates on the application of 1 as a
dihydrosulfide surrogate in a domino reaction15 to access
Scheme 1. Domino CÀS Bond Formation Cross-Coupling/Cy-
clization Reaction
symmetrical biarylthioether, benzo[b]thiophenes, and
thieno[3,2-b]thiophenes in one step (Scheme 1).16
First, the aryl thiol5d,6e,17 is generated in situ. Subsequent
coupling with an aryl halide results in thioethers (Scheme 1a).
Alternatively, in the presence of an alkyne an 5-endo-
dig cyclization of the thiolate yields benzo[b]phiophene
or thieno[3,2-b]thiophene derivatives (Scheme 1b). This in
situ cross-coupling/cyclization sequence12a,18 represents
the first palladium-catalyzed one-pot synthesis of sulfur-
heterocycles3b,10À13 making these valuable structures
readily available.
The catalyst system was optimized for the synthesis of
symmetrical biarylthioether ensuring efficient CÀS bond
formation (see Supporting Information for details). The
optimal catalyst system for the coupling of thiourea (1) with
aryl halides (2) to form the symmetrical thioethers (3)
consisted of the tridentate ligand Triphos (L), tris-
(dibenzylideneacetone)dipalladium(0) ([Pd2dba3]), ceasium
carbonate as base, and 1,4-dioxane as solvent (Table 1). In
general, the reaction can be applied to aryl iodides and
bromides, while aryl chlorides proved unreactive (entry 1,
2ac). Diphenylsulfide (3a) was obtained from the coupling
of iodo- (2aa) or bromobenzene (2ab) with 1 in 80% and
74% yield respectively (entry 1).
Interestingly, sterically encumbered aryl bromides (2b
and 2c) were converted into the thioethers 3b and 3c in
excellent yields (93% and 98% yield, entries 2 and 3). The
coupling of polyaromatic naphthyl derivatives (2d and 2e)
underwent thioether formation in good to excellent yields
(77% and 92% yield, entries 4 and 5). The coupling of
electron-rich thiophene 2f (entry 6) proceeded in 44% yield
indicating that the electronic nature of the aryl halide is
crucial for efficient coupling. Indeed, electron-rich aryl iodides
and bromides (2ga, 2gb, entry 7) furnished the thioether 3g
in 18% yield. Interestingly only the free amino functionality
(6) (a) Shu, Q.; Kun, X.; Junsheng, Q. Chin. J. Chem. 2010, 28, 1441–
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Org. Lett., Vol. 13, No. 15, 2011
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was tolerated in the coupling in comparison to the hydroxy
functionality (entry 9 versus 8). However, electron-withdraw-
ing groups are well tolerated (entries 10À16, 67À98% yield).
Scheme 2. Benzo[b]thiophene Synthesis Applying Thiourea (1)
as Dihydrosulfide SurrogateaÀc
Table 1. Domino Reaction for the Synthesis of Biarylthioether
Using Thiourea (1) as Dihydrosulfide Surrogatea
entry
1
aryl halide 2
product 3
yield/%b
C6H5-X; X = I (2aa),
Br (2ab), Cl (2ac)
3a
X = I (80),
Br (74), Cl (0)
2
3
4
5
6
7
2-CH3-C6H4-Br (2b)
1,4-(CH3)2-C6H3-Br (2c)
2-naphthylbromide (2d)
1-naphthylbromide (2e)
2-bromothiophene (2f)
4-OCH3-C6H4-X;
3b
3c
3d
3e
3f
93
98
77
92
44
a 0.2À0.7 mmol 4, 0.3À0.9 mmol 1, 5 mol % Pd2dba3/L (Pd/L; 1/3),
100 °C, 18 h. bThe yield was determined after column chromatography.
cThe reaction was performed with 2 mol % Pd2dba3/L.
3g
X = I (18),
X = I (2ga), Br (2gb)
4-OH-C6H4-Br (2h)
2-bromoaniline (2i)
4-chlorobromobenzene (2j)
3,4-dichlorobromobenzene
(2k)
Br (18)
8
3h
3i
0
9
24
78
67
10
11
3j
3k
groups, such as nitrile (5h), ketone (5i), or nitro (5j), were
well tolerated. The thiolation/cyclization reaction proved
very efficient for the thiophene derivative 4k. 2-Thio-
phenylbenzo[b]thiophene (5k) was obtained in excellent
yield (92%) making the presented domino-reaction process
a valuable methodology for efficient benzo[b]thiophene
syntheses. Furthermore, the described domino thiolation/
cyclization reaction can be applied for the synthesis of
thieno[3,2-b]thiophenes.
12
13
14
4-CF3-C6H4-Br (2l)
4-acetyliodobenzene (2m)
4-CO2Et-C6H4-X;
3l
67
3m
3n
80
X = I (95),
Br (98)
75
X = I (2na), Br (2nb)
4-nitrobromobenzene (2o)
4-bromobenzonitrile (2p)
15
16
3o
3p
98
a 0.5 mmol of 2, 0.33mmolof1, 2mol%Pd2dba3/L(Pd/L;1/3), 100°C,
18 h. b The yield was determined after column chromatography.
Scheme 3. Palladium-Catalyzed Thieno[3,2-b]thiophene
Having the efficient thiolation of aryl bromides estab-
lished employing thiourea (1) as a dihydrosulfide surrogate
we turned our attention to the intramolecular trapping of
the formed arylthiolate with alkynes accessing benzo-
[b]thiophenes in good to excellent yields in a single process.19
When 1-bromo-2-(phenylethynyl)benzene (4a, Scheme 2)
was reacted with 1.2 equiv of 1 under the same reaction
conditions as developed for the thioethers 3 the heteroaro-
matic product 5a was obtained in 54% yield (Scheme 2). An
increase of catalyst loading from 2 to 5 mol % resulted in an
improved yield of 60%.20 The substrate scope of this first
domino thiolation/cyclization reaction was investigated
(Scheme 2). The reaction proceeded in high yield for ortho
and para substituted aryl groups (5b and 5c). The reaction is
relatively independent of the electronic nature of the aryl
substituent. Electron-rich (5dÀe) and electron-poor aro-
matic systems (5fÀj) underwent cyclization in good to high
yields irrespective of the substitution pattern. Functional
Synthesisa,b
a 0.5 mmol of 6, 0.6 mmol of 1, 5 mol % Pd2dba3/L (Pd/L; 1/3), 100 °C,
18 h. bThe yield was determined after column chromatography.
In fact, when 6a was subjected to the reaction with 1
under palladium catalysis the thieno[3,2-b]thiophene 7a
was obtained in 70% yield (Scheme 3).
The cyclization is more susceptible to the electronic nature
of the aryl substituent than the cyclizations with the benzo
(21) 7b was isolated in 80% yield. However, the isolated material was
contaminated with 30% debrominated starting material (6b), which was
impossible to separate from the product by all techniques applied. The
yield was calculated from the integration of the OMe resonances in the
1H NMR spectrum.
(19) Malte, A. M.; Castro, C. E. J. Am. Chem. Soc. 1967, 89, 6770–
6770.
(20) 5 mol % catalyst loading improved the yield for the other
substrates 4 from 30 to 34% to 56À89% yield.
4102
Org. Lett., Vol. 13, No. 15, 2011

derivatives 4 since the electron-rich 3-bromothiophene 6b
underwent annelation in lower yield (50%)21 compared to its
electron-deficient analogue 6c, which was generated in ex-
cellent yield (80%).
cyclization reaction provides straightforward access
to valuable structures for drug discovery and material
sciences.
In summary, an efficient methodology for the CÀS
coupling of aryl bromides and iodides applying thiourea
as a cheap and easy to handle dihydrosulfide surrogate was
developed. The new methodology was used to synthesize
symmetrical biarylthioethers in high to excellent yields.
The reaction conditions were successfully transferred
to the domino thiolation/cyclization reaction furnish-
ing benzo[b]thiophenes and thieno[3,2-b]thiophenes
in high yield. This unprecedented domino coupling/
Acknowledgment. We thank the Fonds der Chemischen
Industrie for a Fonds-fellowship to F.C.F. and a Liebig-
€
Grant to J.P. and Prof. Dr. Stefan Brase for his kind
support.
Supporting Information Available. Experimental pro-
1
cedures, product characterization data, and H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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