Palladium-Catalyzed Synthesis of Benzothiophenes via Cross-Dehydrogenative Coupling of 4-Arylthiocoumarins and Pyrones

Article abstract of DOI:10.1002/adsc.201901058

Benzothiophenes represent a pivotal class of sulfur heterocycles and their synthesis has attracted significant attention to generate bioactive scaffolds. Herein, we report a convergent, atom- and step-economic method for the synthesis benzothiophenes by cross-dehydrogenative coupling (CDC) of 4-arylthiocoumarins in good to excellent yields. We further demonstrate cross-dehydrogenative coupling of 4-arylthio-2-pyrones to afford alternative substitution of benzothiophenes. The presence of a labile ester carbonyl moiety provides functional handle for further functionalization by coumarin deconstruction. Most crucially, the manuscript demonstrates that the use of readily accessible templated synthesis has a significant potential for the rapid assembly of sulfur heterocycles by dehydrogenative coupling mechanism.

Full text of DOI:10.1002/adsc.201901058

Title: Palladium-Catalyzed Synthesis of Benzothiophenes via Cross-
Dehydrogenative Coupling of 4-Arylthiocoumarins and Pyrones
Authors: Jin Zhang, Yuyu Zhuang, Yangmin Ma, Xiufang Yang, and
Michal Szostak
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901058
Link to VoR: http://dx.doi.org/10.1002/adsc.201901058

10.1002/adsc.201901058
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Synthesis of Benzothiophenes via Cross-
Dehydrogenative Coupling of 4-Arylthiocoumarins and Pyrones
Jin Zhang,a,* Yuyu Zhuang,a Yangmin Ma,a Xiufang Yang a,* and Michal Szostaka,b,*
a
College of Chemistry and Chemical Engineering, Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi
University of Science and Technology, Xi’an 710021, China
Fax: (+86)- 029-8161-8312; phone: (+86)- 029-8161-8312; e-mail: zhangjin@sust.edu.cn; yangxf@sust.edu.cn
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, United States
b
Fax: (+1)-973-353-1264; phone: (+1)-973-353-5329; e-mail: michal.szostak@rutgers.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
ortho-metallation reported by Snieckus[10a] and
Abstract. Benzothiophenes represent a pivotal class of
sulfur heterocycles and their synthesis has attracted carbonylative cross-coupling using an acetoxy group
as the nucleophile reported by Larock[10b] (Scheme 1
significant attention to generate bioactive scaffolds. Herein,
we report a convergent, atom- and step-economic method
for the synthesis benzothiophenes by cross-
A-B). However, both methods build-up on an existing
benzothiopene ring, and are limited in terms of atom-
and step-economy. The direct templated de novo
synthesis[12,13] of benzothieno[2,3]coumarins by a C–
H functionalization mechanism would enable access
to these important heterocycles avoiding any pre-
functionalization and provide an avenue for the
synthesis of densely functionalized 2-aryl-
benzothiophenes by well-established deconstruction
of the coumarine ring (Scheme 1C).[12]
dehydrogenative coupling (CDC) of 4-arylthiocoumarins in
good to excellent yields. We further demonstrate cross-
dehydrogenative coupling of 4-arylthio-2-pyrones to afford
alternative substitution of benzothiophenes. The presence
of a labile ester carbonyl moiety provides functional handle
for further functionalization by coumarin deconstruction.
Most crucially, the manuscript demonstrates that the use of
readily accessible templated synthesis has a significant
potential for the rapid assembly of sulfur heterocycles by
dehydrogenative coupling mechanism.
We were attracted by the recent progress made in
cross-dehydrogenative
coupling
reaction.[8a,b]
Intramolecular cross-dehydrogenative couplings have
been widely used in the synthesis of heterocycles
beacuse of their advantageous green and sustainable
profile as well as operational-simplicity, step- and
atom-economic nature.[8a-h] However, the synthesis of
benzothiophenes via cross-dehydrogenative coupling
is unknown.[11e,f] The synthesis of benzothiophenes by
cross-dehydrogentive coupling presents major
challenges, such as: (1) catalyst poisoning due to
strong coordination of sulfur atom;[14a] (2) high
stability of aromatic C–H bonds;[14b] (3) the presence
of C-3 and C-5 active sites on the coumarine ring,
which affects regioselectivity of the reaction.[9a,b] As a
result, although syntheses of N- and O-benzofused
heterocycles by CDC have been reported,[11e-g] the
synthesis of benzothiophenes by a CDC pathway is
unknown due to the poisoning effect of the sulfur
atom.
Keywords: benzothiophenes; sulfur heterocycles; sulfur;
cross-dehydrogenative coupling; C–H functionalization
Benzothiophenes are privileged sulfur-containing
scaffolds widely present in natural products,
biologically active molecules and pharmaceuticals
and serve as key building blocks for organic
optoelectronic materials.[1-2] The main driving force
in the emerging strategies for the synthesis of
benzothiophenes is the extraordinary impact of sulfur
on the properties of drugs in medicinal chemistry
(Figure 1).[3,4] It is estimated that more than 25% of
top-selling drugs contain this heteroatom and the
number is rapidly increasing.[5] Because of the
importance of benzothiophenes in diverse fields of
chemistry, it is not surprising that novel methods for
their convergent, atom- and step-economic synthesis
are in high demand.[6]
In order to expand the scope of application of
sulfur heterocycles, we envisioned templated
synthesis enabling efficient double C–H activation.
Herein, we report the successful execution of this
strategy and describe efficient dehydrogenative
coupling of 4-arylthiocoumarins to furnish
benzothiophenes in good to excellent yields.
We proposed that widely available coumarin
would act as a template for the direct synthesis of
benzothiophenes by cross-dehydrogenative coupling
(CDC) (Scheme 1).[7–9] In particular, accessing
benzothieno[2,3]coumarins
has
proven
challenging;[10,11] the classic methods involve directed
1
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10.1002/adsc.201901058
Advanced Synthesis & Catalysis
Notable features of our study include: (1) robust
palladium-catalyzed oxidative cyclization in the
presence of silver as the terminal oxidant, furnishing
functionalization of the fused benzothiophene ring by
coumarin ring deconstruction.
More
broadly,
the
template-directed
dehydrogenative strategy provides an attractive
entryway to the synthesis of sulfur heterocycles in
atom-economic fashion.
We commenced our studies by using 4-(p-
tolylthio)-2H-chromen-2-one (1a) as the model
substrate to evaluate the optimal reaction conditions
(Table 1). Initially, treatment of (1a) with 5 mol% of
Pd(OAc)2 catalyst in the presence of 2.0 equiv of
Ag2O in AcOH at 100 °C for 24 h did not produce
any desired product (entries 1-2). We were pleased to
observe the formation of the benzothiophene product
(2a) using AgOAc as the oxidant (entry 3). Next,
various oxidants, including Cu(OTf)2, Cu(OAc)2,
K2S2O8, BQ (1,4-benzoquinone), DTBP (di-tert-butyl
peroxide) were screened to optimize the reaction
conditions (entries 4-8). AgOAc was found to be the
most effective (entry 3). Other palladium catalysts,
including PdCl2, Pd(dppf)2Cl2 and Pd(PPh3)2Cl2, were
ineffective in the reaction (entries 9-11).
Figure 1 Selected examples of benzothiophenes with
pharmacological activity.
Table 1. Optimization of Reaction Conditions.[a]
Entry
[Pd]
[O]
Solvent Yield (%)
1
2[b]
3
4
5
6
7
8
9
10
11
12
13
14
15
16[c]
17[d]
18[d,e]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag2O
Ag2O
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TFA
HCO2H
EtCO2H
MsOH
EtCO2H
EtCO2H
EtCO2H
<5
<5
35
<5
14
<5
<5
<5
10
16
13
<5
18
64
<5
70
79
82
AgOAc
Cu(OTf)2
Cu(OAc)2
K2S2O8
BQ
DTBP
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
[a]Conditions: 1a (0.20 mmol), [Pd] (5 mol%), oxidant (2.0
equiv), solvent (0.20 M), 100 ℃, 24 h. [b]K2CO3 (2.0 equiv).
[c]120 ℃. [d]140 ℃. [e][Pd] (10 mol%).
Scheme 1 Previous studies and this work: templated
approach
to
sulfur-containing
heterocycles
by
dehydrogenative coupling.
the corresponding benzothiophenes with broad
substrate generality; (2) facile dehydrogenative
coupling of 4-arylthiopyrones, affording the
alternative substitution of the benzothiophene ring;
(3) the presence of labile ester carbonyl moiety,
which provides functional handle for further
Since in CDC studies we found that an acid solvent
played an indispensable role in promoting the
reaction, we tested the effect of several solvents on
the reaction (entries 12-15). Pleasingly, we found that
CH3CH2COOH was the optimal solvent for the
reaction (entry 15). Although its precise role is
2
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10.1002/adsc.201901058
Advanced Synthesis & Catalysis
unclear, propionic acid is believed to promote the
reaction by higher solubility and/or lower acidity
compared to acetic acid. Further investigations
indicated that the yield could be improved by
conducting the reaction at
10 mol% (entry 18). Under the optimized conditions,
the benzothiophene product (2a) was isolated in 82%
yield. The conditions are as follows: 4-(p-tolylthio)-
2H-chromen-2-one (1.0 equiv), Pd(OAc)2 (10 mol%),
AgOAc (2.0 equiv), CH3CH2COOH (0.20 M), 140 °C.
With the optimized reaction conditions in hand, we
next investigated the substrate scope of the reaction
Table 2. Pd-catalyzed CDC in the templated synthesis of
benzothiophenes using coumarins.[a,b]
Table 3. Pd-catalyzed CDC in the templated synthesis of
benzothiophenes using 2-pyrones.[a,b]
[a]Conditions: 3 (0.20 mmol), Pd(OAc)2 (10 mol%),
AgOAc (2.0 equiv), EtCOOH (0.20 M), 140 °C. [b]Isolated
yields.
(Table 2). As shown, a wide range of 4-
arylthiocoumarins bearing substituents with diverse
electronic properties on either of the aryl rings of the
coumarin
template
provided
the
desired
benzothiophenes in good to excellent yields.
Electron-donating groups at the para-position of the
S-aryl group provided the corresponding products in
80-82% yields (2a-2b). Electron-withdrawing groups
also afforded good yields (2c, 75%). Interestingly, the
reaction is well-compatible with sensitive halide
functional groups, such as F, Cl, Br, including those
located at the ortho-position, furnishing the
corresponding benzothiophene products in 67-73%
yields, and thus providing valuable handles for
further functionalization. Gratifyingly, the reaction is
tolerant of various substituents on the coumarin ring
[a]Conditions: 1 (0.20 mmol), Pd(OAc)2 (10 mol%),
AgOAc (2.0 equiv), EtCOOH (0.20 M), 140 °C. [b]Isolated
yields.
(2g-2l,
70-79%).
These
reactions
furnish
higher temperature (entries 16-17). A further
improvement in the reaction efficiency was observed
upon increasing Pd(OAc)2 loading from 5 mol% to
functionalized benzothieno[2,3]coumarins that could
be readily deconstructed to 2-arylbenzothiophenes by
standard reduction or hydrolysis methods.[12] At this
3
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10.1002/adsc.201901058
Advanced Synthesis & Catalysis
stage, meta-substituted substrates have not been
tested. These substrates are well-known to result in
mixtures of the regioisomeric products.[8f-h]
Next, to expand the generality of the templated
approach to benzothiophenes, we investigated 4-
arylthio-2-pyrones (Table 3). Note that in both cases
(coumarines and pyrones) the sulfur-containing
template is accessed in a single, high yielding step
from the commercial materials, making the
technology
Scheme 2. Proposed mechanism.
On the basis of our results and previous literature
precedents,[8,15,16] we propose a reaction mechanism
shown in Scheme 2. An initial activation of the C–H
bond at the C3 position of the coumarin template
gives intermediate (5).[16] An SEAr-type reaction[17]
affords palladacycle (6). Irreversible deprotonation
and reductive elimination furnish the final product.
The Pd(II) catalyst is regenerated after oxidation. The
key step involves template directed electrophilic C–H
activation to form the benzothiophene ring.
Figure 2. X-ray structure of (4c). Selected bond lenghts
(Å) and angles (deg): S1–C1, 1736(3); S1–C9, 1.726(3);
C9–C8, 1.370(4); O2–C7, 1.399(3). C2–C1–S1–C9, -
178.8(3); C11–C10–C9–S1, -176.5(3); C8–C7–O2–C11,
1.6(5).[15]
In conclusion, we have developed a general, mild
and operationally-convenient method for the
synthesis of benzothiophenes by Pd-catalyzed
dehydrogenative coupling. The key features involve
convergent, atom- and step-economic benzothiophene
synthesis and the use of template to facilitate double
C–H activation. The reaction demonstrates good
functional group tolerance and broad substrate scope,
appealing for benzothiophene synthesis. Furthermore,
this approach allows one to rapidly introduce
structural diversity by convergent de novo
benzothiophene assembly. We found that although 4-
arylthio-2-pyrones proved more challenging in the
dehydrogenative coupling, the developed conditions
were amenable to a broad range of benzothiophenes
(Table 3). As shown, electron-donating and electron-
withdrawing groups at the para-position of the S-aryl
moiety gave the benzothiophene products in good
yields (4a-4d, 61-68%). Furthermore, halide
functional handles (Cl, Br) located at the ortho-
position were well-compatible, and the corresponding
products (4e-4f) were isolated in 61-64% yields. Note
that the reaction is compatible with sensitive halides
that would be problematic in previous approaches to
thieno[2,3]pyrones using either strong metal bases or
low valent metals, showcasing the advantage of the
present methodology.
providing
rapid
access
to
functionalized
benzothiophenes from simple starting materials. Most
crucially, the use of readily accessible templated
synthesis has a significant potential to facilitate the
assembly of sulfur heterocycles by C–H
functionalization.
Experimental Section
General procedure for synthesis of thieno[3,2-
c]coumarins. An oven-dried sealed tube equipped with a
stir bar was charged with 4-arylsulfanylcoumarin substrate
(neat, typically, 0.20 mmol, 1.0 equiv), Pd(OAc)2
(typically, 10 mol%) and AgOAc (typically, 2.0 equiv).
CH3CH2COOH (0.20 M) were added with vigorous
stirring at room temperature, and the reaction mixture was
stirred for 24 h at 140 °C. After the indicated time, the
reaction mixture was neutralized with saturated sodium
hydrogen carbonate (1.0 N, 1.0 mL) and extracted with
ethyl acetate, then the organic layer was dried and
concentrated. A sample was analyzed by 1H NMR (CDCl3,
400 MHz) and/or GC-MS to obtain conversion, yield and
selectivity using internal standard and comparison with
authentic samples. Purification by chromatography on
silica gel (EtOAc/hexanes) afforded the title product.
Benzothiophene (4c) was crystalline and we were
able to confirm its structure by X-ray crystallography
(Figure 2). The heterocyclic ring is planar and the
S1–C1 bond length (1.736 Å) is comparable to those
found in fused benzothiophenes.[1,2]
4
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10.1002/adsc.201901058
Advanced Synthesis & Catalysis
General procedure for synthesis of 4-arylthio-2-pyrones. [6] For recent selected examples, see: a) D. P. Hari, T.
An oven-dried sealed tube equipped with a stir bar was
charged with 4-arylsulfanyl-6-methyl-2-pyrone substrate
(neat, typically, 0.20 mmol, 1.0 equiv), Pd(OAc)2
(typically, 10 mol%) and AgOAc (typically, 2.0 equiv).
CH3CH2COOH (0.20 M) were added with vigorous
stirring at room temperature, and the reaction mixture was
stirred for 24 h at 140 °C. After the indicated time, the
reaction mixture was neutralized with saturated sodium
hydrogen carbonate (1.0 N, 1.0 mL) and extracted with
ethyl acetate, then the organic layer was dried and
concentrated. A sample was analyzed by 1H NMR (CDCl3,
400 MHz) and/or GC-MS to obtain conversion, yield and
selectivity using internal standard and comparison with
authentic samples. Purification by chromatography on
silica gel (EtOAc/hexanes) afforded the title product.
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Acknowledgements
J.Z. thanks the China Scholarship Council (No. 201808610096).
Financial support was provided by the Foundation for Young
Scholars of Shaanxi University of Science and Technology (No.
BJ12-26). M.S. thanks Rutgers University and the NSF (CAREER
CHE-1650766).
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10.1002/adsc.201901058
Advanced Synthesis & Catalysis
UPDATE
Palladium-Catalyzed Synthesis of Benzothiophenes
via Cross-Dehydrogenative Coupling of 4-
Arylthiocoumarins and Pyrones
Adv. Synth. Catal. 2019, Volume, Page – Page
Jin Zhang,* Yuyu Zhuang, Yangmin Ma, Xiufang
Yang* and Michal Szostak*
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