Selenium Radical Mediated Cascade Cyclization: Concise Synthesis of Selenated Benzofurans (Benzothiophenes)

Article abstract of DOI:10.1021/acs.orglett.9b02315

Presented in this work is a novel methodology for the synthesis of selenated benzofurans (or benzothiophenes) via AgNO₂-catalyzed radical cyclization of 2-alkynylanisoles (or 2-alkynylthioanisoles), Se powder, and arylboronic acids. This method

Full text of DOI:10.1021/acs.orglett.9b02315

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selenium Radical Mediated Cascade Cyclization: Concise Synthesis
of Selenated Benzofurans (Benzothiophenes)
Cui An, Chen-Yuan Li, Xiao-Bo Huang, Wen-Xia Gao, Yun-Bing Zhou,* Miao-Chang Liu,*
and Hua-Yue Wu
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s Republic of China
S
* Supporting Information
ABSTRACT: Presented in this work is a novel methodology for
the synthesis of selenated benzofurans (or benzothiophenes) via
AgNO2-catalyzed radical cyclization of 2-alkynylanisoles (or 2-
alkynylthioanisoles), Se powder, and arylboronic acids. This
method enables the construction of a benzofuran (benzothio-
phene) ring, two C−Se bonds, and a C−O(S) bond as well as
the cleavage of a C−O(S) bond in a single step. Preliminary
mechanistic studies imply that the AgNO2-catalyzed cyclization
proceeds via an aryl selenium radical intermediate.
Scheme 1. Diverse Synthetic Routes to
Selenenylbenzofurans or Selenenylbenzothiophenes
rganoselenium compounds represent an important class
Oof molecules with numerous applications in drug,
agricultural chemicals, and catalysis as well as functional
organic materials.1 In this regard, the installation of the
selenium moiety onto organic molecules is of significant
importance in organic synthesis. Much effort has been devoted
to the construction of C−Se bonds, which serves as an
important strategy for the synthesis of organoselenium
compounds.2 In particular, the selenation of heteroarenes
including benzofurans and benzothiophenes has attracted
considerable attention, allowing for diversification of these
privileged scaffolds to further open up promising avenues for
drug discovery. Pioneering work toward the synthesis of
selenated benzofurans or benzothiophenes relied on an
electrophilic cyclization strategy using commercially unavail-
able, toxic, and instable RSeCl as the selenium source (Scheme
1a).3,4 Another method to access selenenylbenzofurans via
electrophilic annulation reactions of 2-alkynylphenol deriva-
tives with diselenides has been developed, yet with the
requirement of precious Pd catalyst or stoichiometric Fe (Cu)
catalysts (Scheme 1b).5 In addition, direct C−H thiolation of
heteroarenes catalyzed by a heterogeneous catalyst Pd/Al2O3
has proven to be a successful strategy to provide
selenenylbenzofurans and selenenylbenzothiophenes, but it
suffered from low yields and moderate selectivities, particularly
for the formation of selenenylbenzofurans (Scheme 1c).6 From
an economic point of view, the use of Se powder7 as the
selenium source is more attractive, yet it is indeed beyond the
scope of current methodologies for the synthesis of
selenenylbenzofurans or selenenylbenzothiophenes. Therefore,
the development of general methods for the preparation of
selenated benzofurans or benzothiophenes from simple and
readily accessible building blocks is still desirable.
due to their high efficiency and powerful functions in the
organic synthesis. Inspired by our previous work,8 we were
interested in the reactivity of aryl selenium radical
intermediates derived from arylboronic acids and Se powder
in the synthesis of organoselenium compounds. On this basis,
we questioned whether in situ generated aryl selenium radicals
could undergo the radical tandem cyclization with 2-
Over the last decades, radical transformations have emerged
as a powerful tool for construction of C−heteroatom bonds
Received: July 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02315
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Organic Letters
Letter
alkynylanisoles (or 2-alkynylthioanisoles) as other radicals
do,9−11 thus providing a direct and facile access to selenated
benzofurans or benzothiophenes.
Table 2. Substrate Scope for the Reactions of 2-
Alkynylanisoles, Se powder, and Arylboronic Acids
a
Our initial effort focused on identifying the optimal reaction
conditions by selecting 2-alkynylanisole 1a and phenylbonoric
2a as model substrates. A set of optimal reaction conditions
including catalyst, solvent, atmosphere, and temperature were
identified as shown in Table 1. We were pleased to find that
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
AgNO3
AgNO2
AgOAc
AgSbF6
Ag2SO4
Ag2CO3
Ag2O
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
AgNO2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CH3CN
dioxane
toluene
iPrOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
120
120
120
120
120
120
120
130
100
90
77
99
45
trace
trace
trace
trace
20
28
15
0
0
9
10
11
12
13
14
15
16
17
18
19
20
82
99
97
58
67
83
66
trace
a
Reaction conditions: 1 (0.4 mmol), Se powder (0.4 mmol), 2 (0.2
mmol), AgNO2 (0.04 mmol), DMSO (2.0 mL), under O2, 100 °C, 12
b
h, isolated yield. Most of starting materials were recovered.
80
b
100
100
100
100
c
range of arylboronic acids bearing various substituents were
found to be suitable substrates. For example, halogen-
substituted arylboronic acids underwent radical cyclization
with 2-phenylethynylanisole in the presence of Se powder,
delivering the corresponding products in moderate to good
yields (3b−3e, 3j−3l). We noticed that the yields were
generally distinctly lower in the case of ortho-substituted
arylboronic acids. In addition to halogen, substituents
d
e
a
Reaction conditions: 1a (0.4 mmol), Se powder (0.4 mmol), 2a (0.2
mmol), catalyst (0.04 mmol), solvent (2.0 mL), under O2, 12 h,
b
c
isolated yield. 15 mmol % of AgNO2 was used. 1.6 equiv of Se
powder was used. Under air. Under N2.
d
e
t
AgNO3 successfully enabled this transformation in DMSO at
120 °C under O2, furnishing the desired product 3a in 77%
yield (entry 1). Excessive amounts of alkynylanisole 1a are
essential for complete conversion owing to the unavoidable
oxidation of 1a to afford dicarbonyl compound. Screening
several Ag salts revealed that the use of AgNO2 was the best
choice and delivered 3a in 99% yield (entry 2). Further
screening of solvents demonstrated that the solvents such as
DMF, CH3CN, and dioxane were inferior to DMSO (entries
including Bu (1f), CF3 (1g), and methyl groups (1m and
1n) all worked well. For the substrates bearing the substituents
with strong electron effects such as nitro and methoxy, the
reactions led to no formation of the desired products (3h and
3i), while most of the starting materials were converted into
dicarbonyl compounds (3h and 3i). It is worth noting that this
transformation was not sensitive to steric hindrance as
demonstrated by using mesitylboronic acid as a substrate
(1n). Boronic acid bearing an aromatic heterocycle or a fused
ring proved to be a suitable substrate (1o and 1p), whereas
alkylboronic acid (1q) was ineffective under the standard
conditions, probably due to the poorer stability of in situ
generated alkyl selenium radical than aryl selenium radical.
Subsequently, the scope with respect to 2-alkynylanisoles was
also investigated. It was found that halogen and alkyl groups on
the ring B were amenable to the standard reaction conditions
and afforded the desired products in 69−96% yields (3r−3w).
The terminal alkynyl position (ring B) could be functionalized
with a fused ring (1x). When the ring B was installed with a
thiophene ring (1y), no reaction occurred. On the other hand,
ring C could be a halogen-substituted phenyl moiety (1z).
i
8−10). Other solvents including toluene and PrOH shut
down this transformation completely (entries 11 and 12).
Based on the examination of reaction temperature (entries
14−16), we chose 100 °C as the optimal reaction temperature.
Reducing the amount of either AgNO2 or Se powder decreased
the yield of 3a (entries 17 and 18). It was found that air
atmosphere resulted in a low yield (entry 19), while N2
atmosphere led to trace amount of 3a (entry 20). Therefore,
the reaction conditions of entry 14 proved to be optimal.
With the optimal reaction conditions in hand, we sought to
assess the scope of the three-component reactions of 2-
alkynylanisoles, Se powder, and arylboronic acids (Table 2). A
B
DOI: 10.1021/acs.orglett.9b02315
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Organic Letters
Letter
t
Next, the strategy was expanded toward the synthesis of
selenated benzothiophenes (Table 3). To our delight, the
When ring D was replaced by Bu group the reaction failed
to deliver the desired product 5s but with most of starting
material being recovered, and same result was observed by
using substrate 4y in which ring E carried a strong electron-
donor substituent.
Table 3. Substrate Scope for the Reactions of 2-
a
Alkynylthioanisoles, Se Powder, and Arylboronic Acids
Finally, we investigated whether this methodology could be
used to intramolecular radical cyclization (Scheme 2). Gladly,
a
Scheme 2. Ag-Catalyzed Intramolecular Cyclization
a
Standard conditions: 6 (0.2 mmol), Se powder (0.4 mmol), AgNO2
(0.04 mmol), DMSO (2.0 mL), under O2, 100 °C, 12 h, isolated
yields.
the arylboronic acids bearing methylthio group successfully
underwent intramolecular radical cyclization with Se powder,
enabling one-pot synthesis of benzo[b]benzo[4,5]-
selenopheno[2,3-d]thiophene (7a) albeit in 22% yield (eq
1). In a similar manner, the arylboronic acids bearing methoxy
group delivered the corresponding product (7b) in 25% yield
(eq 2).
Further control experiments were designed to gain a deeper
understanding of the catalytic process (Scheme 3). Preliminary
investigation on the substituents on the S atom showed that in
addition to the methyl group, the reaction was shown to
a
Reaction conditions: 4 (0.2 mmol), Se powder (0.4 mmol), 2 (0.4
mmol), AgNO2 (0.04 mmol), DMSO (2.0 mL), under O2, 100 °C, 12
a
b
Scheme 3. Some Control Experiments
h, isolated yield. The reaction was conducted on a 10 mmol scale.
c
Most of the starting material was recovered.
three-component reaction of 2-alkynylanisoles, Se powder, and
arylboronic acids could be successfully achieved under the
same reaction conditions, and no conversion of 2-alkynylth-
ioanisoles to dicarbonyl compounds was observed.
As a result, a mixture containing alkynylthioanisoles, Se
powder, and boronic acids with a ratio of 1:2:2 was submitted
to standard reaction conditions. Arylboronic acids with
substitutions such as halogen, TMS, and alkyl reacted well
with 2-phenylethynylanisole to provide the desired products
(5b−5k) under the standard conditions. The reaction of 4a, Se
powder, and phenylboronic acid was run on a 10 mmol scale,
affording 60% yield of 5a with 35% of 4a being recovered.
Hindered arylboronic acid also underwent radical cyclization
with 2-phenylethynylanisole as well as Se powder, yielding the
desired product (5l) in good yield. Boronic acid bearing a
naphthalene or thiophene ring was effective as well under the
standard reaction conditions, giving the desired products in
47% and 41% yields, respectively (5m and 5n). On the other
hand, the scope with respect to 2-alkynylanisoles was also
tested. This radical cyclization strategy displayed high
efficiency toward 2-alkynylanisoles bearing methyl and halogen
on the ring D or E (4o−4q and 4t−4x). Furthermore, ring D
could be a fused ring, with 41% yield of 5r being obtained.
a
Standard conditions: 1 or 4 (0.2 mmol), Se powder (0.4 mmol), 2a
(0.4 mmol), AgNO2 (0.04 mmol), DMSO (2.0 mL), under O2, 100
°C, 12 h, isolated yields.
C
DOI: 10.1021/acs.orglett.9b02315
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tolerate the sterically bulkier substituents such as ethyl and
isopropyl groups, whereas a phenyl group resulted in no
product (eq 1). When the reaction of 1a′, Se powder, and
PhB(OH)2 was performed in the 18O2 atmosphere, we
detected 18O-labeled benzaldehyde (eq 2). The reaction was
completely inhibited upon the addition of TEMPO under the
standard conditions, supporting a radical process (eq 3). When
a mixture of ethene-1,1-diyldibenzene, PhB(OH)2, and Se
powder was subjected to the standard conditions, product 3aa
was detected by GC−MS (eq 4), providing experimental
evidence for the formation of aryl selenium radical.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02315.
■
S
Experimental procedures, GC−MS data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
According to these results and relevant literature,9−11
a
*E-mail: zyb@wzu.edu.cn.
*E-mail: mcl@wzu.edu.cn.
possible pathway for the radical cascade cyclization is
described in Scheme 4. At the beginning, ArB(OH)2 is
ORCID
Scheme 4. Possible Pathway for the Cascade Cyclization
Wen-Xia Gao: 0000-0002-3373-9827
Miao-Chang Liu: 0000-0002-4603-3022
Hua-Yue Wu: 0000-0003-3431-561X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21472140 and 21372177), the
Wenzhou Science & Technology Bureau Program (No.
G20170021), and Xinmiao Talent Planning Foundation of
Zhejiang Province (No. 2018R429058).
REFERENCES
■
(1) (a) Mugesh, G.; du Mont, W.; Sies, H. Chemistry of Biologically
Important Synthetic Organoselenium Compounds. Chem. Rev. 2001,
101, 2125. (b) Mugesh, G.; Singh, H. B. Heteroatom-Directed
Aromatic Lithiation: A Versatile Route to the Synthesis of
Organochalcogen (Se, Te) Compounds. Acc. Chem. Res. 2002, 35,
226. (c) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Organoselenium
and Organotellurium Compounds: Toxicology and Pharmacology.
Chem. Rev. 2004, 104, 6255. (d) Manjare, S. T.; Kim, Y.; Churchill, D.
G. Selenium- and Tellurium-Containing Fluorescent Molecular
Probes for the Detection of Biologically Important Analytes. Acc.
Chem. Res. 2014, 47, 2985. (e) Xu, H.; Cao, W.; Zhang, X. Selenium-
Containing Polymers: Promising Biomaterials for Controlled Release
and Enzyme Mimics. Acc. Chem. Res. 2013, 46, 1647. (f) Shao, L.; Li,
Y.; Lu, J.-M.; Jiang, X. Recent Progress in Selenium-Catalyzed
Organic Reactions. Org. Chem. Front. 2019, 6, 2999.
(2) (a) Beletskaya, I. P.; Ananikov, V. P. Transition-Metal-Catalyzed
C−S, C−Se, and C−Te Bond Formation via Cross-Coupling and
Atom-Economic Addition Reactions. Chem. Rev. 2011, 111, 1596.
(b) Ranu, B. C.; Dey, R.; Chatterjee, T.; Ahammed, S. Copper
Nanoparticle-Catalyzed Carbon-Carbon and Carbon-Heteroatom
Bond Formation with a Greener Perspective. ChemSusChem 2012,
5, 22.
(3) (a) Mehta, S.; Waldo, J. P.; Larock, R. C. Competition Studies in
Alkyne Electrophilic Cyclization Reactions. J. Org. Chem. 2009, 74,
1141. (b) Yue, D.; Larock, R. C. Synthesis of 2,3-Disubstituted
Benzo[b]thiophenes via Palladium-Catalyzed Coupling and Electro-
philic Cyclization of Terminal Acetylenes. J. Org. Chem. 2002, 67,
1905. (c) Yue, D.; Yao, T.; Larock, R. C. Synthesis of 2,3-
Disubstituted Benzo[b]furans by the Palladium-Catalyzed Coupling
of o-Iodoanisoles and Terminal Alkynes, Followed by Electrophilic
Cyclization. J. Org. Chem. 2005, 70, 10292. (d) Sanz, R.; Guilarte, V.;
oxidized into an aryl radical species in the presence of an
catalytic system of AgNO2/O2. The resulting aryl radical is
then trapped by Se powder to generate an aryl selenium radical
B which undergoes radical addition with 2-alkynylanisole (or
2-alkynylthioanisole) to afford intermediate C. Finally,
intermediate C undergoes cyclization to give the desired
product, along with methyl radical being converted into
formaldehyde. It could be inferred from the propose
mechanism that the butyl group is difficult to stabilize alkenyl
radical intermediate in contrast to aryl group, which could be
responsible for the failure in the synthesis of 5s.
In conclusion, we disclosed a novel methodology for the
preparation of selenated benzofurans (or benzothiophenes) via
AgNO2-catalyzed radical cyclization of 2-alkynylanisoles (or 2-
alkynylthioanisoles), Se powder, and arylboronic acids. It is
worth noting that the method enables the formation of a
benzofuran (benzothiophene) ring, two C−Se bonds, and C−
O(S) bond as well as the cleavage of C−O(S) bond in one
step. It also proved to be available for intramolecular radical
cyclization to provide polycyclic selenium-containing hetero-
aromatics. Preliminary mechanistic studies imply that the
three-component cyclization involved an aryl selenium radical
intermediate in situ generated from arylboronic acids and Se
powder, thus in turn demonstrating a novel strategy of
activating Se powder by in situ generated aryl radical. Selenium
radical mediated cyclization has heavy development potential-
ity to construct complex Se-containing compounds, and more
efforts are underway to expand the selenium radical
intermediates for the preparation of other selenated hetero-
arenes.
́
Hernando, E.; Sanjuan, A. M. Synthesis of Regioselectively Function-
alized Benzo[b]thiophenes by Combined ortho-Lithiation−Halocyc-
lization Strategies. J. Org. Chem. 2010, 75, 7443.
(4) (a) Neto, J. S. S.; Iglesias, B. A.; Back, D. F.; Zeni, G. Iron-
Promoted Tandem Cyclization of 1,3-Diynyl Chalcogen Derivatives
D
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with Diorganyl Dichalcogenides for the Synthesis of Benzo[b]furan-
fused Selenophenes. Adv. Synth. Catal. 2016, 358, 3572. (b) Kaz-
mierczak, J. C.; Recchi, A. M. S.; Gritzenco, F.; Balbom, E. B.;
Barcellos, T.; Speranca̧ , A.; Godoi, B. Copper-Iodide- and Diorganyl-
Diselenide-Promoted Cyclization of 2-Alkynylphenols: Alternative
Approach to 3-Organoselanylbenzo[b]furans. Eur. J. Org. Chem. 2017,
2017, 6382. (c) Gay, R. M.; Manarin, F.; Schneider, C. C.; Barancelli,
D. A.; Costa, M. D.; Zeni, G. FeCl3-Diorganyl Dichalcogenides
Promoted Cyclization of 2-Alkynylanisoles to 3-Chalcogen Benzo-
[b]furans. J. Org. Chem. 2010, 75, 5701.
(5) Du, H.-A.; Zhang, X.-G.; Tang, R.-Y.; Li, J.-H. PdCl2-Promoted
Electrophilic Annulation of 2-Alkynylphenol Derivatives with
Disulfides or Diselenides in the Presence of Iodine. J. Org. Chem.
2009, 74, 7844.
́
́
(6) Vasquez-Cespedes, S.; Ferry, A.; Candish, L.; Glorius, F.
Heterogeneously Catalyzed Direct C-H Thiolation of Heteroarenes.
Angew. Chem., Int. Ed. 2015, 54, 5772.
(7) (a) Taniguchi, N. Mono- or Dichalcogenation of Aryl Iodide
with Sulfur or Selenium by Copper Catalyst and Aluminum. Synlett
2005, 11, 1687. (b) Singh, D.; Deobald, A. M.; Camargo, L. R. S.;
Tabarelli, G.; Rodrigues, O. E. D.; Braga, A. L. An Efficient One-Pot
Synthesis of Symmetrical Diselenides or Ditellurides from Halides
with CuO Nanopowder/Se0 or Te0/Base. Org. Lett. 2010, 12, 3288.
(c) Wu, B.; Yoshikai, N. Versatile Synthesis of Benzothiophenes and
Benzoselenophenes by Rapid Assembly of Arylzinc Reagents, Alkynes,
and Elemental Chalcogens. Angew. Chem., Int. Ed. 2013, 52, 10496.
(d) Luo, D.; Wu, G.; Yang, H.; Liu, M.; Gao, W.; Huang, X.; Chen, J.;
Wu, H. Copper-Catalyzed Three-Component Reaction for Regiose-
lective Aryl- and Heteroarylselenation of Indoles using Selenium
Powder. J. Org. Chem. 2016, 81, 4485. (e) Gao, C.; Wu, G.; Min, L.;
Liu, M.; Gao, W.; Ding, J.; Chen, J.; Huang, X.; Wu, H. Copper-
Catalyzed Three-Component Coupling Reaction of Azoles, Se
Powder, and Aryl Iodides. J. Org. Chem. 2017, 82, 250. (f) Hu, D.;
Liu, M.; Wu, H.; Gao, W.; Wu, G. Copper-catalyzed diarylation of Se
with aryl iodides and heterocycles. Org. Chem. Front. 2018, 5, 1352.
(8) Leng, T.; Wu, G.; Zhou, Y.-B.; Gao, W.-X.; Ding, J.; Huang, X.;
Liu, M.; Wu, H. Silver-Catalyzed One-Pot Three-Component
Selective Synthesis of β-Hydroxy Selenides. Adv. Synth. Catal. 2018,
360, 4336.
(9) (a) Yan, J.; Xu, J.; Zhou, Y.; Chen, J.; Song, Q. Photoredox-
catalyzed Cascade Annulation of Methyl(2-(phenylethynyl)phenyl)-
sulfanes and Methyl(2-(phenylethynyl)phenyl)selanes with Sulfonyl
Chlorides: Synthesis of Benzothiophenes and Benzoselenophenes.
Org. Chem. Front. 2018, 5, 1483. (b) Xu, J.; Yu, X.; Yan, J.; Song, Q.
Synthesis of 3-(Arylsulfonyl)benzothiophenes and Benzoseleno-
phenes via TBHP-Initiated Radical Cyclization of 2-Alkynylthioani-
soles or -Selenoanisoles with Sulfinic Acids. Org. Lett. 2017, 19, 6292.
(10) Gong, X.; Wang, M.; Ye, S.; Wu, J. Synthesis of 3-
(Methylsulfonyl)benzo[b]thiophenes from Methyl(2-alkynylphenyl)-
sulfanes and Sodium Metabisulfite via a Radical Relay Strategy. Org.
Lett. 2019, 21, 1156.
(11) Liu, W.; Hu, Y.-Q.; Hong, X.-Y.; Li, G.-X.; Huang, X.-B.; Gao,
W.-X.; Liu, M.-C.; Xia, Y.-Z.; Zhou, Y.-B.; Wu, H.-Y. Direct Synthesis
of 3-Acylbenzothiophenes via the Radical Cyclization of 2-
Alkynylthioanisoles with α-Oxocarboxylic Acids. Chem. Commun.
2018, 54, 14148.
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