Synthesis of 2-Substituted Benzothio(seleno)phenes and Indoles via Ag-Catalyzed Cyclization/Demethylation of 2-Alkynylthio(seleno)anisoles and 2-Alkynyldimethylanilines

Article abstract of DOI:10.1002/ejoc.202001465

An Ag-catalyzed cyclization/demethylation of 2-alkynylthio(seleno)anisoles and 2-alkynyldimethylanilines is described and applied for the construction of valuable benzothio(seleno)phenes as well as indoles. Various 2-substituted benzothio(seleno)phenes and indoles were obtained in good to excellent yields under mild reaction conditions with low catalyst loading. An application of this new method is also exemplified with a concise synthesis of a bioactive molecule precursor. Furthermore, a conceivable reaction mechanism is proposed with supports from isotope-exchange experiments.

Full text of DOI:10.1002/ejoc.202001465

Communications
doi.org/10.1002/ejoc.202001465
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Synthesis of 2-Substituted Benzothio(seleno)phenes and
Indoles via Ag-Catalyzed Cyclization/Demethylation of 2-
Alkynylthio(seleno)anisoles and 2-Alkynyldimethylanilines
Tao Cai,[a] Chengjie Feng,[a] Fangqi Shen,[a] Kejun Bian,[a] Chunlei Wu,[a] Runpu Shen,*[a] and
Yuzhen Gao*[b]
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An Ag-catalyzed cyclization/demethylation of 2-alkynylthio
(seleno)anisoles and 2-alkynyldimethylanilines is described and
applied for the construction of valuable benzothio(seleno)
phenes as well as indoles. Various 2-substituted benzothio
(seleno)phenes and indoles were obtained in good to excellent
yields under mild reaction conditions with low catalyst loading.
An application of this new method is also exemplified with a
concise synthesis of a bioactive molecule precursor. Further-
more, a conceivable reaction mechanism is proposed with
supports from isotope-exchange experiments.
Figure 1. Representative drugs and biologically active molecules with
benzothio(seleno)phene and indole motif.
(Hg(OAc)2, CuCl2, CuBr2, etc.) has been proven to be one of the
Introduction
most efficient and valuable ways[6a–k,8a–e] (Scheme 1). For exam-
ple, by employing this methodology, Flynn’s,[6a] Larock’s,[6b–e,8a–e]
Sanz’s,[6i] Wu’s,[6f] Balova’s[8i] and Kesharwani’s[6j,k] groups re-
ported a series of 2,3-disubstituted benzothio(seleno)phenes or
indoles, respectively. Ingleson and co-workers have described
the preparation of C3-borylated benzofurans and benzothio-
phenes by using BCl3 as an electrophilic partner.[9] Muchalski
and co-workers disclosed the synthesis of 2-substituted benzo-
thiophenes from 2-alkynyl thioanisoles by using 1 mol%
loading of Au(IPr)OH as a catalyst and 100 mol% AcOH as a
protodeauration additive.[10] Generally, these electrophilic cycli-
zation reactions are very efficient and proceed under very mild
reaction conditions with good functional group tolerance.
However, in some cases, these protocols still suffer some
limitations, such as the use of corrosive halogens or toxic
transition-metal salts, the need for a more-than-stoichiometric
amount of electrophilic reagents, or the application of
expensive catalysts. For these reasons, the development of
alternative approaches based on less toxic and cheaper
catalysts, such as silver species, will be highly desirable for
synthetic organic chemists.
Benzothio(seleno)phenes and indoles are important heterocy-
clic scaffolds that have been widely found in many pharmaceut-
icals, natural products, and material science.[1,2] For example,
Zileuton is a market-available drug, which has been widely used
for the treatment of asthma.[3] 2-Butyl-1-(4-carboxybenzyl)-5-[2-
carboxy-3-(benzo[b]selenophen-1-yl)prop-1-enyl]-1H-imidazole
is proved to be an excellent AT1 receptor antagonist.[4]
Ondansetron has been widely used for the suppression of
nausea and vomit caused by cancer chemotherapy and
radiotherapy[5] (Figure 1). Therefore, continuous efforts have
been directed towards the development of efficient methods
for constructing these heterocyclic scaffolds in organic synthesis
and medicinal chemistry.
In the past few decades, a variety of concise and robust
synthetic methods have been established for the synthesis of
substituted benzothio(seleno)phenes[6,7] and indoles.[8] Among
them, the intramolecular 5-endo-dig electrophilic cyclization
and demethylation of 2-alkynylthio(seleno)anisoles or 2-
alkynyldimethylanilines in the presence of electrophilic reagents
(I2, Br2, NBS, PhSeCl, ICl, etc.), as well as transition-metal catalysts
As part of our ongoing interests in the study of new
advantageous silver-catalyzed approaches for the synthesis of
N/S-containing heterocycles starting from 2-alkynylthioanisoles
[a] Dr. T. Cai, C. Feng, F. Shen, K. Bian, C. Wu, Prof. R. Shen
Department College of Chemistry and Chemical Engineering
Shaoxing University,
Shaoxing 312000, P. R. China
E-mail: srunpu@usx.edu.cn
[b] Dr. Y. Gao
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology
Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences,
Fuzhou 350002, P. R. China
E-mail: gyz@fjirsm.ac.cn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001465
Scheme 1. Electrophilic cyclization of 2-alkynylthio(seleno)anisoles.
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doi.org/10.1002/ejoc.202001465
or 2-alkynylaniline derivatives,[11] herein we were pleased to
report our results on the Ag2O-mediated synthesis of 2-
disubstituted benzothio(seleno)phenes and indoles via electro-
philic cyclization/demethylation of 2-alkynylthio(seleno)anisoles
and 2-alkynyldimethylanilines.
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Results and Discussion
Table 1. Optimization of reaction conditions.[a]
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In the beginning, methyl(2-(phenylethynyl)phenyl)sulfane (1a)
was chosen as the model substrate to optimize the reaction
conditions (Table 1). Initially, HOAc was employed as the
solvent, and 1.0 equiv. of Ag2O was used as the catalyst, 2a was
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°
obtained in 79% yield after being heated at 70 C in an oil bath
Entry
Catalyst
[mol %]
Solvent
T
Yield
[%][b]
°
for 4 h under air (Table 1, entry 1). Subsequently, various
solvents were evaluated, and TFA was found to be the best
(entries 2–6). The Ag2O loading optimization showed 10 mol%
of Ag2O also could give a competitive yield of 2a (entries 7–9).
By screening other silver catalysts, such as AgOTf, AgNO3, AgCl,
AgBr, and AgOAc, Ag2O turned out be the most effective one
(entries 10À 14). Further temperature and Ag2O loading opti-
mization showed that in the presence of 5 mol% of Ag2O, 2a
was obtained in 90% yield after stirring for 1.5 h in TFA at room
temperature (entries 13–15).
[ C]
1
2
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8
Ag2O (100)
Ag2O (100)
Ag2O (100)
Ag2O (100)
Ag2O (100)
Ag2O (100)
Ag2O (10)
Ag2O (5)
Ag2O (2.5)
AgOTf (10)
AgNO3 (10)
AgOAc (10)
AgCl (10)
AgBr (10)
Ag2O (5)
HOAc
TFA
CHCl3
DMF
1,4-Dioxane
DCE
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
70
70
70
70
70
70
70
70
70
70
70
70
25
25
25
25
25
79
92
Trace
N.R
N.R
N.R
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90
81
70
75
85
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In order to investigate the generality of this Ag-mediated
cyclization process, a series of substrates possessing diverse
substituents were tested under the optimized reaction con-
ditions (Table 2). Initially, substrates with variation at the S
substituents were first examined. When the methyl group at the
S atom was changed to ethyl or phenyl group, 2a was also
obtained in 76% and 40% yields, respectively. Afterwards,
various substituents on the benzene ring A were examined.
Substrates with electron-donating groups such as methyl, ethyl,
and methoxyl groups, as well as electron-withdrawing groups
such as fluoro, choloro, bromo, nitryl, and formyl groups were
tolerated in this reaction without much difference in reactivity,
and all delivered the corresponding targeted products (2b–2k)
in good to excellent yields. Compounds bearing functional
groups such as OMe and halogen atoms on the benzene ring B
were also examined and afforded the corresponding products
2l–2n in excellent yields. Terminal alkyne was also examined,
unfortunately, no desired product (2o) was detected, which
might be attributed to the formation of acetylene silver
intermediate to suppress the reaction. Remarkably, this reaction
also proceeded efficiently with aliphatic and carboxyl alkynes to
give the desired products (2p, 2q, 2u) in excellent yields. In
addition, compounds with naphthyl or thienyl were also viable
in this reaction (2r, 2s). However, no desired product (2t) was
afforded when a pyridyl-based compound was employed,
which might be due to the formation of ammonium salt in the
strong acid TFA. Moreover, this Ag-mediated cyclization process
was also suitable for the preparation of benzoselenophenes
stemming from 2-alkynylselenoanisoles 3, as exampled by 4a–
4c. It should be noted that this cyclization process was not
suitable for the synthesis of benzofurans by employing 1-
methoxy-2-(phenylethynyl)benzene as the substrate, which
might due to the high energy of C(sp3)À O bond.
80
91
Ag2O (5)
Ag2O (1)
90[c]
82[c]
[a] Reaction conditions: 1a (0.2 mmol), solvent (2.0 mL), stirred under air.
[b] Isolated yield. [c] Reaction time (1.5 h). DCE=1,2-dichloroethane,
DMF=N,N-dimethylformamide, TFA=trifluoroacetic acid.
Table 2. Scope for the formation of benzothio(seleno)phenes.[a]
Furthermore, product 2l, a key intermediate of polymer-
ization inhibitor[6a] and Reloxifene,[12] was obtained in 79% yield
in 10 mmol scale through this Ag-mediated cyclization protocol
[a] Reaction conditions: 1 or 3 (0.2 mmol), Ag2O (0.01 mmol), in TFA (2 mL)
stirring under air at room temperature (25 C) for 1.5 h. [b] Two mmol scale.
°
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in one step (Scheme 2), demonstrating the synthetic applic-
ability of this method.
1
2
Importantly, with modification on the reaction conditions
(see supporting information), this Ag-mediated cyclization proc-
ess was successfully applied to the synthesis of indole
derivatives. It was found that the reactions in TFA gave no
desired products under the typical conditions by using 2-
alkynyldimethylanilines instead of 2-alkynylthioanisoles. How-
ever, when a DMF solution of the N,N-dimethyl-2-(arylethynyl)
aniline substrates 5, 1.0 equiv. of p-toluenesulfonic acid mono-
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hydrate (p-TSA·H2O) and 5 mol% of Ag2O were heated at 60 C
in an oil bath for 12 h, the corresponding 2-aryl substituted
indoles 6 could be obtained in good to excellent yields (Table 3,
6a–6g, 86%–96%).
In order to investigate the reaction mechanism, an isotope-
labeling experiment was performed by using deuterated TFA
(d-TFA) as the solvent under the optimized reaction conditions
(Scheme 3a). Gladly, a significant deuterium-labeling product d-
2a was obtained, and the byproduct methyl 2,2,2-trifluoroace-
tate was detected by gas chromatography-mass spectrometry
(GC-MS) from the reaction mixtures (see supporting information
Scheme 3. Mechanism study.
for detail). This result illustrated that TFA is likely to act as an
electrophilic reagent. Therefore, a tentative mechanism for the
reaction was proposed for the Ag-mediated cyclization process
(Scheme 3b). Initially, the coordination of silver catalyst with the
alkyne that is followed by an anti-attack from sulfur gives the
cationic intermediate II. Subsequently, the methyl group is
released and captured by 2,2,2-trifluoroacetate (CF3COOÀ ), to
form methyl 2,2,2-trifluoroacetate (CF3COOMe) along with the
desired product 2a, and a silver species is released and re-
enters the catalytic cycle.
Conclusion
Scheme 2. Synthetic applications.
In summary, we have successfully developed an efficient
protocol for the construction of valuable benzothio(seleno)
phenes as well as indoles through an Ag-catalyzed cyclization/
demethylation process. Various 2-substituted benzothio(seleno)
phenes and indoles were obtained in good to excellent yields
under mild reaction conditions with low catalyst loading.
Furthermore, the current protocol was successfully applied to
the synthesis of a raloxifene precursor and a polymerization
inhibitor. A conceivable reaction mechanism is proposed and
supported by isotope-exchange experiments.
Table 3. Scope for the formation of indoles.[a]
Experimental Section
General Procedures for the Preparation of Benzothio(seleno)
phenes
A
mixture of Ag2O (2.3 mg, 0.01 mmol), 2-Alkynylthioanisole
derivatives 1[6c] or 2-alkynylselenoanisole derivatives 3[6c] (0.2 mmol)
and CF3COOH (2.0 mL) in a Schlenk tube was stirred at room
temperature for 1.5 hours. Upon completion, the reaction mixture
was quenched with NaOH (1 M, 10 mL) aqueous solution, and then
extracted by DCM (2×10 mL). The organic layer was dried over
[a] Reaction conditions: 5 (0.2 mmol), Ag2O (0.01 mmol) and p-TSA·H2O
°
(0.2 mmol) in DMF (2 mL) stirring under air at 60 C in an oil bath for 12 h.
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by silica gel column chromatography using a petroleum ether/
AcOEt (100:1~50:1, v/v) as the eluent to give the corresponding
products.
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General Procedures for the Preparation of Indoles
A mixture of Ag2O (2.3 mg, 0.01 mmol), N,N-dimethyl-2-(1-alkynyl)
anilines derivatives 5[13] (0.2 mmol), 4-methylbenzenesulfonic acid
hydrate (38.1 mg, 0.2 mmol) and DMF (2.0 mL) in a Schlenk tube
°
was stirred 60 C in an oil bath for 12 hours. Upon completion, the
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reaction mixture was quenched with H2O (50 mL) and then
extracted by AcOEt (2×5 mL). The organic layer was washed with
brine (20 mL) and then dried over Na2SO4. The residue was purified
by silica gel column chromatography using a petroleum ether/
AcOEt (100:1, v/v) as the eluent to give the corresponding
products.
Acknowledgements
We gratefully thank the financial support from NSFC (Grant No.
21801240), the Youth Foud of Shaoxing University (No. 20185019),
the Zhejiang Provincial Natural Science Foundation of China (No.
LQ21B020005), as well as the Public Projects of Zhejiang Province
of China (No. LGG19B020002).
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Benzothiophenes
·
Cyclization
·
Indoles
·
Heterocycles · Homogeneous catalysis · Synthetic methods
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Manuscript received: November 8, 2020
Revised manuscript received: December 1, 2020
Accepted manuscript online: December 3, 2020
Eur. J. Org. Chem. 2021, 653–656
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656
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