Photoinduced, Copper-Catalyzed Three-Component Annulation of gem-Dialkylthio Enynes

Article abstract of DOI:10.1021/acs.orglett.0c01645

Photoinduced, copper-catalyzed three-component radical annulation of gem-dialkylthio enynes, cyclobutanone oxime esters, and boronic acids was achieved, forming highly functionalized aryl thienyl sulfides with both good chemo- and diastereoselectivities. The reaction proceeds through a domino sequence involving cyanoalkyl radical-mediated intramolecular annulation of gem-dialkylthio enyne, alkenyl radical-promoted C(sp3)-S bond cleavage, and sulfur-centered radical-trapped Cu(II)-facilitated C-S cross-coupling. The protocol features simultaneous establishment of cyanoalkyl, cyclopentanone, and thiophene moieties and a thioether C-S bond in one pot with broad substrate scopes and versatile functional group tolerance under mild conditions.

Full text of DOI:10.1021/acs.orglett.0c01645

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Letter
Photoinduced, Copper-Catalyzed Three-Component Annulation of
gem-Dialkylthio Enynes
Jiang Lou, Juan Ma, Bao-Hua Xu, Yong-Gui Zhou,* and Zhengkun Yu*
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ABSTRACT: Photoinduced, copper-catalyzed three-component radical
annulation of gem-dialkylthio enynes, cyclobutanone oxime esters, and
boronic acids was achieved, forming highly functionalized aryl thienyl
sulfides with both good chemo- and diastereoselectivities. The reaction
proceeds through a domino sequence involving cyanoalkyl radical-mediated
intramolecular annulation of gem-dialkylthio enyne, alkenyl radical-promoted
C(sp3)−S bond cleavage, and sulfur-centered radical-trapped Cu(II)-
facilitated C−S cross-coupling. The protocol features simultaneous establish-
ment of cyanoalkyl, cyclopentanone, and thiophene moieties and a thioether
C−S bond in one pot with broad substrate scopes and versatile functional group tolerance under mild conditions.
ryl-2-thienyl sulfides are among the important skeletons
conditions can be utilized to couple with unsaturated
compounds to achieve cyanoalkylation.10 However, multi-
component radical cross-couplings involving cyanoalkyl
radicals under mild conditions have received much less
attention. Xiao and Chen et al. disclosed visible-light-driven,
copper-catalyzed three-component radical cross-couplings
between oxime esters, styrenes, and boronic acids or terminal
alkynes to access 1,1-diarylmethane-based alkylnitriles11a and
cyanoalkyl-containing propargylic compounds,11b respectively
(Scheme 1a). Mechanistic studies have suggested that a
radical-Cu(II) rebound process involving the benzylic radical
intermediate generated from addition of a cyanoalkyl radical to
styrene is the key step to execute the radical cross-coupling
reaction. In this context, sulfur-centered radical-Cu(II) re-
bound processes remain unknown due to the intrinsic
instability and catalyst-poisoning of a sulfur radical to interfere
with the catalyst turnover.12
A
in pharmaceutical compounds and functional materials.1
For example, AZD4407 is used as an antiallergic/antiasthmatic
agent for chronic obstructive pulmonary diseases,2
CCT365623 significantly reduces the tumor growth,3 and
bis(arylthio)oligothiophenes exhibit better electronic proper-
ties than unsubstituted oligothiophenes (Figure 1).4 Many
Figure 1. Representative examples of aryl-2-thienyl sulfides used in
pharmaceuticals and functional materials.
During the continuous investigation of transition-metal-
catalyzed annulation of gem-dialkylthio internal alkenes, we
found that they were usually involved in production of O- and
S-heterocycles.7a,13 Wang and Liu et al. reported the
benzannulation of α-alkynyl-α-alkenoyl ketene dithioacetals
with cyanoacetates to form benzo[b]thiophenes.14 Thus, we
envisioned that α-alkynyl-α-oxo ketene dithioacetals, that is,
gem-dialkylthio 1,3-enynes, might be employed for discrete
thiophene ring construction under transition-metal catalysis.
efforts have been devoted to the synthesis of functionalized
aryl-2-thienyl sulfides.5 In this regard, radical cyclization of
unsaturated carbon−carbon bonds with sulfur-centered radi-
cals has been well documented.6 However, use of toxic and
unstable reagents, employing prefunctionalized substrates, and
the poisoning effect on transition metals by sulfur compounds
limit the application of these synthetic methods. In this area,
efficient protocols for the construction of a thiophene ring and
thioether C−S bonds in one pot under mild conditions from
readily available and bench-stable substrates have been seldom
explored.7
Received: May 31, 2020
Transition-metal-catalyzed radical cross-coupling reactions
have recently received much attention for the construction of
complex compounds.8 In this regard, cyanoalkyl radicals9
generated from the nitrogen-centered radicals via β-C−C bond
cleavage of cycloketone oxime esters and analogs under various
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© XXXX American Chemical Society
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A

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Under the optimal conditions, the scope of gem-dialkylthio
enynes (1) was investigated by reacting with 2a and 3a
(Scheme 2). Introduction of an electron-donating group such
Scheme 1. N- and S-Centered Radical Multicomponent
Cross-Couplings
a
Scheme 2. Scope of gem-Dialkylthio Enynes (1)
a
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), 3a (0.4 mmol),
With the following concept in mind, a three-component
annulation process is designed as shown in Scheme 1b. The
cyanoalkyl radical generated in situ from the initially formed N-
centered radical interacts with the gem-dialkylthio 1,3-enyne
substrate to initiate the annulation cascade, forming an alkenyl
radical with construction of the five-membered carbocycle.
Subsequent electrophilic attack of one of the sulfur atoms at
the radical carbon establishes a discrete thiophene ring with
release of ethylene by C(sp3)−S bond cleavage and generation
of the sulfur-centered radical which is then coupled by a
boronic acid, giving the target product under photoinduced
copper catalysis. Herein, we report such a three-component
process for the synthesis of aryl-2-thienyl sulfides.
Initially, the reaction of gem-dialkylthio enyne 1a, cyclobu-
tanone oxime ester (2a), and phenylboronic acid (3a) was
conducted to screen the reaction conditions (see the
Supporting Information for details). After the systematic
work, the optimal reaction conditions were identified. In the
presence of 10 mol % Cu(CH3CN)4BF4, 10 mol % dtbbpy,
and K3PO4 (2 equiv) in CH3CN under the irradiation of a 15
W blue LED at ambient temperature, the reaction gave the
target product 4a in 76% isolated yield and a diastereose-
lectivity of 93/7, and 4a could be obtained in 70% yield on a 2
mmol scale of 1a. Both CuCl2 and CuCl also promoted the
reaction, but the nickel(II) catalyst NiCl2·glyme was not
effective. Use of other ligands such as 2,2′-bpy and 1,10-phen,
bases Na2CO3 and K2CO3, and acetone and EtOAc as the
solvents, diminished the reaction efficiency. The control
experiments revealed that the Cu(CH3CN)4BF4 catalyst,
dtbbpy ligand, and K3PO4 base were crucial for the reaction.
Notably, the reaction only afforded 4a in 50% yield without the
visible-light irradiation.
Cu(CH3CN)4BF4 (10 mol %), dtbbpy (10 mol %), K3PO4 (0.4
mmol), CH3CN (2 mL), rt, 0.1 MPa N2, irradiation using a 15 W
blue LED, 12 h.
as methyl or methoxy to the terminal aryl functionality
attached to the alkynyl backbone of enyne 1 resulted in no
obvious impact on the formation of the target products 4a−4e
(74−77%) with a diastereoselectivity of 90/10 to 20/1, while
electron-withdrawing fluoro and chloro substituents dimin-
ished the yields of products 4f−4h (64−65%). 2-Thienyl also
exhibited a negative effect on the reaction efficiency, leading to
4i in 51% yield. A terminal propyl or cyclopropyl did not affect
the formation of 4j (74%) and 4k (71%). As the steric
hindrance of the terminal alkyl increased, cyclohexyl obviously
deteriorated the formation of 4l (45%), but with a high
diastereoselectivity (>20:1). The steric effect from the alkenoyl
moiety of enynes 1 was remarkable. 2-Methoxyphenyl
inhibited the formation of compound 4m due to the increased
steric hindrance, whereas 3- and 4-methoxyphenyl, 4-
trifluoromethylphenyl, and 2-furyl-functionalized alkenoyl
based enynes reacted well to give the target products 4n−4q
(45−72%) with high diastereoselectivities. These results have
suggested that the reaction is highly dependent on the
electronic and steric effects from the functionalities at the
terminuses of the alkynyl and alkenoyl moieties of substrates 1.
It is noteworthy that the molecular structure of compound 4a
was further confirmed by the X-ray single crystal crystallo-
graphic determination (see the Supporting Information for
details).
Next, the protocol generality was explored by performing the
reaction of 1a and 3a with a variety of cycloketone oxime
esters (2) under the standard conditions (Scheme 3). 3-Phenyl
B
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a
a
Scheme 3. Scope of Cycloketone Oxime Esters (2)
Scheme 4. Scope of Boronic Acids (3)
a
Conditions: 1a (0.2 mmol), 2 (0.4 mmol), 3a (0.4 mmol),
Cu(CH3CN)4BF4 (10 mol %), dtbbpy (10 mol %), K3PO4 (0.4
mmol), CH3CN (2 mL), rt, 0.1 MPa N2, irradiation using a 15 W
blue LED, 12 h.
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3 (0.4 mmol),
Cu(CH3CN)4BF4 (10 mol %), dtbbpy (10 mol %), K3PO4 (0.4
mmol), CH3CN (2 mL), rt, 0.1 MPa N2, irradiation using a 15 W
blue LED, 12 h.
substituted cyclobutanone oxime ester (2b) underwent the
reaction smoothly to give the target product 5a in 56% yield
with d.r. = 56/44. 3-(4-tert-Butyl) and 3-(4-chloro)-substituted
phenyl, 3-benzyl, and 3-alkyl-bearing cyclobutanone oxime
esters reacted similarly to form 5b−5e (50−58%), respectively.
Increased steric hindrance led to lowered yields for 5b (50%)
and 5e (50%). 3-Methyl-3-phenyl disubstituted oxime ester
(2g) further increased the steric hindrance to execute the
formation of 5f in a moderate yield (45%). However, 2-alkyl
substituents such as methyl, ethyl, and butyl in 2 enhanced the
yields of products 5g−5i to 62−68% in comparison to the 3-
substituent-bearing cases, which is attributed to the stabiliza-
tion of 2-alkyls to the in situ generated cyanoalkyl radicals that
initiate the annulation process. 2-Benzyl exhibited a negative
steric effect on the formation of 5j (56%). It should be noted
that cyclopentanone- and cyclohexanone-derived oxime esters
2l and 2m and the corresponding acyclic oxime ester of 5-
methyl-2-hexanone (2n) could not undergo the same type of
radical cross-coupling reactions under the stated conditions,
and the desired products 5k−5m were not produced.
Finally, the scope of boronic acids (3) was extended by
treating them with 1a and 2a (Scheme 4). Obvious steric and
electronic effects were observed from arylboronic acids. The
electron-donating substituents such as methoxy, methyl,
benzyloxy, and tert-butyl facilitated the reaction to form the
target products 6a−6g (60−77%) with diastereoselectivity
from 93/7 to 95/5, while the phenyl group and electron-
withdrawing substituents acetyl, fluoro, and chloro reduced the
yields of products 6h−6k (40−62%). The steric effect was
obvious in the cases of using 2- methoxy and 3,5-
dimethylphenylboronic acids and 2-naphthyl boronic acid,
leading to 6a (60%), 6l (60%), and 6m (63%), respectively, as
compared with the formation of 6b (70%)/6d (77%), 6c
(70%), and 4a (76%). It is noteworthy that vinylboronic acids
such as 1-pentenyl and 2-cyclohexylvinyl boronic acids also
effectively participated in the reaction, affording products 6n
and 6o in moderate yields (43−50%) with tolerance of a
carbon−carbon double bond under the stated conditions.
However, heteroaryl boronic acids such as 2-thienyl and 2-furyl
boronic acids only reacted to afford trace amounts of the target
products, and 2-alkylboronic acids could not react under the
same conditions.
To demonstrate the applicability of the synthetic protocol,
various transformations of product 4a were performed
(Scheme 5). With m-chloroperoxybenzoic acid (m-CPBA) as
a
Scheme 5. Derivatizations of Thiophene Product 4a
a
Conditions: (a) 4a (0.2 mmol), m-CPBA (0.6 mmol), CH2Cl2 (2
mL), rt, 1.5 h; (b) 4a (0.2 mmol), NaBH4 (0.2 mmol), MeOH (2
mL), rt, 10 h.
the oxidant 4a was readily converted to the corresponding
sulfone 7 (91%) through oxidation of the phenylthio group.
The ketone carbonyl of 4a was selectively reduced to hydroxyl
(85%) by means of NaBH4 as the reductant with the tolerance
of a cyano group.
Control experiments were conducted to probe into the
reaction mechanism. Addition of 2 equiv of a radical scavenger,
that is, 2,6-di-tert-butyl-4-methylphenol (BHT), into the
reaction system of 1a, 2a, and 3a under the standard
conditions obviously diminished the yield of 4a to 32%,
while use of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
completely inhibited the reaction. The radical-trapping product
TEMPO-(CH2)3CN (9) was detected in the reaction mixture
C
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by HRMS analysis (see the Supporting Information for
details). These results have implicated that the reaction may
proceed through a radical pathway. To identify the possible
redox states of the copper catalyst that might be involved in the
process, EPR spectroscopy was employed to investigate the
redox process between Cu(CH3CN)4BF4/dtbbpy or Cu-
(CH3CN)4BF4/dtbbpy/1a with cyclobutanone oxime ester
(2a). Addition of 2a to the solution of Cu(CH3CN)4BF6/
dtbbpy or Cu(CH3CN)4BF4/dtbbpy/1a in CH3CN resulted in
obvious EPR signals of a Cu(II) species (see the Supporting
Information for details).11,15 These results suggest a single-
electron transfer (SET) process between the Cu(I) complex
and substrate 2a. To validate that the C(sp3)−S bond cleavage
was facilitated by the in situ generated alkenyl radical and the
resultant Cu(II) species was trapped by the in situ generated S-
centered radical, six-membered gem-dialkylthio enyne 10 was
reacted with 2a and 3a under the standard conditions (eq 1).
molecule of ethylene to form sulfur-centered radical F.
Subsequently, radical F is intercepted by the LCuIIPh complex
generated in situ from the transmetalation between LCuII
species and boronic acid PhB(OH)2 (3a), yielding high-valent
CuIII species H, which undergoes reductive elimination to give
the target product 4a and regenerate the LCuI species.
In summary, a photoinduced, copper-catalyzed three-
component radical cross-coupling of gem-dialkylthio 1,3-
enynes, cycloketone oxime esters, and boronic acids was
developed to access highly functionalized aryl-2-thienyl sulfides
with good chemo- and diastereoselectivities. The synthetic
protocol features simultaneous formation of four new C−C
and C−S bonds and construction of a carbocycle and a
thiophene ring in one pot. This work provides a direct route to
highly functionalized thiophene derivatives.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01645.
Experimental materials and procedures, NMR of
compounds, and X-ray crystallographic analysis for
compound 4a (CCDC 1949838) (PDF)
The three-component radical cross-coupling reaction
occurred to afford product 11 (65%) with retention of the
(CH2)3 group of the dialkylthio moiety of 10, suggesting
involvement of a carbon-centered radical-Cu(II) rebound
process without β-H elimination.
Accession Codes
CCDC 1949838 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of these results and the known reports,9−12
a
plausible mechanism is proposed in Scheme 6. Initially,
Scheme 6. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Authors
Zhengkun Yu − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; Innovation
Academy for Green Manufacture, Chinese Academy of Sciences,
Beijing 100190, P. R. China; State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.
R. China; orcid.org/0000-0002-9908-0017; Email: zkyu@
dicp.ac.cn
Yong-Gui Zhou − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China;
orcid.org/0000-0002-3321-5521; Email: ygzhou@
dicp.ac.cn
Authors
Jiang Lou − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; University of
Chinese Academy of Sciences, Beijing 100049, P. R. China;
orcid.org/0000-0002-5653-1359
Juan Ma − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; University of
Chinese Academy of Sciences, Beijing 100049, P. R. China
Bao-Hua Xu − Innovation Academy for Green Manufacture,
Chinese Academy of Sciences, Beijing 100190, P. R. China;
orcid.org/0000-0002-7222-4383
interaction of cyclobutanone oxime ester 2a with photoexcited
complex LCuI* (path a) or the ground state complex LCuI
(path b) via a SET process generated iminyl (N-centered)
radical A and the oxidized LCuII species. Iminyl radical A
undergoes homolytic α,β-C−C cleavage to form γ-cyanoalkyl
radical B, which is captured by gem-dialkylthio 1,3-enyne 1a to
yield a relatively stable alkyl radical C, followed by intra-
molecular cyclization to form alkenyl radical species D. The
alkenyl radical facilitates the homolytic C(sp3)−S bond
cleavage to produce alkyl radical species E, which releases a
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01645
D
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(9) (a) Yu, X.-H.; Zhao, Q.-Q.; Chem, J.; Xiao, W.-J.; Chen, J.-R.
When Light Meets Nitrogen-Centered Radicals: From Reagents to
Catalysts. Acc. Chem. Res. 2020, 53, 1066−1083. (b) Zard, S. Z.
Recent Progress in the Generation and Use of Nitrogen-Centred
Radicals. Chem. Soc. Rev. 2008, 37, 1603−1618.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of
China (21672209 and 21871253).
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(10) (a) Li, Z.; Torres-Ochoa, R. O.; Wang, Q.; Zhu, J.
Functionalization of Remote C(sp3)−H Bonds Enabled by Copper-
Catalyzed Coupling of O-acyloximes with Terminal Alkynes. Nat.
Commun. 2020, 11, 403. (b) Zhao, B.; Wu, Y.; Yuan, Y.; Shi, Z.
Copper-Catalysed Csp3−Csp Cross-Couplings Between Cyclobuta-
none Oxime Esters and Terminal Alkynes Induced by Visible Light.
Chem. Commun. 2020, 56, 4676−4679. (c) Wang, T.; Wang, Y.-N.;
Wang, R.; Zhang, B.-C.; Yang, C.; Li, Y.-L.; Wang, X.-S.
Enantioselective Cyanation via Radical-Mediated C−C Single Bond
Cleavage for Synthesis of Chiral Dinitriles. Nat. Commun. 2019, 10,
5373. (d) Chen, J.; Wang, P.-Z.; Lu, B.; Liang, D.; Yu, X.-H.; Xiao,
W.-J.; Chen, J.-R. Enantioselective Radical Ring-Opening Cyanation
of Oxime Esters by Dual Photoredox and Copper Catalysis. Org. Lett.
2019, 21, 9763−9768. (e) Lu, B.; Cheng, Y.; Chen, L.-Y.; Chen, J.-R.;
Xiao, W.-J. Photoinduced Copper-Catalyzed Radical Aminocarbony-
lation of Cycloketone Oxime Esters. ACS Catal. 2019, 9, 8159−8164.
(f) Dauncey, E. M.; Dighe, S. U.; Douglas, J. J.; Leonori, D. A Dual
Photoredox-Nickel Strategy for Remote Functionalization via Iminyl
Radicals: Radical Ring-Opening-Arylation, -Vinylation and -Alkylation
Cascades. Chem. Sci. 2019, 10, 7728−7733. (g) Zhang, J.-J.; Duan, X.-
H.; Wu, Y.; Yang, J.-C.; Guo, L.-N. Transition-Metal Free C−C Bond
Cleavage/Borylation of Cycloketone Oxime Esters. Chem. Sci. 2019,
10, 161−166. (h) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.;
Sheikh, N. S.; Leonori, D. Photoinduced Remote Functionalisations
by Iminyl Radical Promoted C−C and C−H Bond Cleavage
Cascades. Angew. Chem., Int. Ed. 2018, 57, 744−748. (i) Yu, X.-Y.;
Chen, J.-R.; Wang, P.-Z.; Yang, M.-N.; Liang, D.; Xiao, W.-J. A
Visible-Light-Driven Iminyl Radical-Mediated C−C Single Bond
Cleavage/Radical Addition Cascade of Oxime Esters. Angew. Chem.,
Int. Ed. 2018, 57, 738−743.
(11) (a) Yu, X.-Y.; Zhao, Q.-Q.; Chen, J.; Chen, J.-R.; Xiao, W.-J.
Copper-Catalyzed Radical Cross-Coupling of Redox-Active Oxime
Esters, Styrenes, and Boronic Acids. Angew. Chem., Int. Ed. 2018, 57,
15505−15509. (b) Chen, J.; He, B.-Q.; Wang, P.-Z.; Yu, X.-Y.; Zhao,
Q.-Q.; Chen, J.-R.; Xiao, W.-J. Photoinduced, Copper-Catalyzed
Radical Cross-Coupling of Cycloketone Oxime Esters, Alkenes, and
Terminal Alkynes. Org. Lett. 2019, 21, 4359−4364.
(12) (a) Gu, Q.-S.; Li, Z.-L.; Liu, X.-Y. Copper(I)-Catalyzed
Asymmetric Reactions Involving Radicals. Acc. Chem. Res. 2020, 53,
170−181. (b) Kaiser, D.; Klose, I.; Oost, R.; Neuhaus, J.; Maulide, N.
Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides,
Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts. Chem. Rev. 2019,
119, 8701−8780. (c) Wang, F.; Chen, P.; Liu, G. Copper-Catalyzed
Radical Relay for Asymmetric Radical Transformations. Acc. Chem.
Res. 2018, 51, 2036−2046.
(13) (a) Wang, Q. N.; Liu, Z. Q.; Lou, J.; Yu, Z. K. Palladium-
Catalyzed C−S Bond Cleavage with Allenoates: Synthesis of
Tetrasubstituted 2-Alkenylfuran Derivatives. Org. Lett. 2018, 20,
6007−6011. (b) Lou, J.; Wang, Q. N.; Wu, K. K.; Wu, P.; Yu, Z. K.
Iron-Catalyzed Oxidative C−H Functionalization of Internal Olefins
for the Synthesis of Tetrasubstituted Furans. Org. Lett. 2017, 19,
3287−3290.
(14) Ming, W.; Liu, X.; Wang, L.; Liu, J.; Wang, M. Tandem Thien-
and Benzannulations of α-Alkenoyl-α-alkynyl Ketene Dithioacetals
with Cyanoacetates: Synthesis of Functionalized Benzo[b]thiophenes.
Org. Lett. 2015, 17, 1746−1749.
(15) (a) Tang, S.; Liu, Y.; Gao, X.; Wang, P.; Huang, P.; Lei, A.
Multi-Metal-Catalyzed Oxidative Radical Alkynylation with Terminal
Alkynes: A New Strategy for C(sp3)−C(sp) Bond Formation. J. Am.
Chem. Soc. 2018, 140, 6006−6013. (b) Lu, Q.; Zhang, J.; Peng, P.;
Zhang, G.; Huang, Z.; Yi, H.; Miller, J. T.; Lei, A. Operando X-ray
Absorption and EPR Evidence for a Single Electron Redox Process in
Copper Catalysis. Chem. Sci. 2015, 6, 4851−4854.
REFERENCES
■
(1) (a) Wang, N.; Saidhareddy, P.; Jiang, X. Construction of Sulfur-
Containing Moieties in the Total Synthesis of Natural Products. Nat.
Prod. Rep. 2020, 37, 246−275. (b) Scott, K. A.; Njardarson, J. T.
Analysis of US FDA-Approved Drugs Containing Sulfur Atoms. Top.
Curr. Chem. (Z) 2018, 376, 5.
(2) Alcaraz, M.-L.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D.
M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon,
R. A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.;
Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.; Woodland, I. A.
Efficient Syntheses of AZD4407 via Thioether Formation by
Nucleophilic Attack of Organometallic Species on Sulphur. Org.
Process Res. Dev. 2005, 9, 555−569.
(3) Tang, H.; Leung, L.; Saturno, G.; Viros, A.; Smith, D.; Di Leva,
G.; Morrison, E.; Niculescu-Duvaz, D.; Lopes, F.; Johnson, L.;
Dhomen, N.; Springer, C.; Marais, R. Lysyl Oxidase Drives Tumour
Progression by Trapping EGF Receptors at the Cell Surface. Nat.
Commun. 2017, 8, 14909.
(4) Hicks, R. G.; Nodwell, M. B. Synthesis and Electronic Structure
Investigations of α,ω-Bis(arylthio)oligothiophenes: Toward Under-
standing Wire-Linker Interactions in Molecular-Scale Electronic
Materials. J. Am. Chem. Soc. 2000, 122, 6746−6753.
(5) (a) Hosseinian, A.; Arshadi, A.; Sarhandi, S.; Monfared, A.;
Vessally, E. Direct C−H Bond Sulfenylation of (Het)arenes Using
Sulfonyl Hydrazides as Thiol Surrogate: A Review. J. Sulfur Chem.
2019, 40, 289−311. (b) Li, L.; Ding, Y. Recent Advances in the
Synthesis of Thioether. Mini-Rev. Org. Chem. 2017, 14, 407−431.
(6) (a) Capella, L.; Montevecchi, P. C.; Navacchia, M. L. Radical
Sequential Processes Promoted by 1,5-Radical Translocation
Reaction: Formation and [3 + 2] Anulation of Alkenesulfanyl
Radicals. J. Org. Chem. 1996, 61, 6783−6789. (b) 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, 1156−1160. (c) Wan, D.;
Yang, Y.; Liu, X.; Li, M.; Zhao, S.; You, J. Radical Cyclization of
Arenesulfonyl Chlorides and Alkynes: A Rapid Access to π-
Conjugated Benzothiophenes. Eur. J. Org. Chem. 2016, 2016, 55−
59. (d) Zhang, G.; Yi, H.; Chen, H.; Bian, C.; Liu, C.; Lei, A. Trisulfur
Radical Anion as the Key Intermediate for the Synthesis of Thiophene
via the Interaction between Elemental Sulfur and NaOtBu. Org. Lett.
2014, 16, 6156−6159. (e) Agrawal, A. R.; Kumar, N. R.; Debnath, S.;
Das, S.; Kumar, C.; Zade, S. S. Radical-Cascade Avenue for 3,4-Fused-
Ring-Substituted Thiophenes. Org. Lett. 2018, 20, 4728−4731.
(7) (a) He, Y.; Lou, J.; Wu, P.; Zhou, Y.-G.; Yu, Z. K. Copper-
Catalyzed Annulative Coupling of S,S-Disubstituted Enones with
Diazo Compounds to Access Highly Functionalized Thiophene
Derivatives. J. Org. Chem. 2020, 85, 1044−1053. (b) Garg, P.; Singh,
A. Unmasking Dipole Character of Acyl Ketene Dithioacetals via a
Cascade Reaction with Arynes: Synthesis of Benzo[b]thiophenes. Org.
Lett. 2018, 20, 1320−1323. (c) Fang, G.; Li, J.; Wang, Y.; Gou, M.;
Liu, Q.; Li, X.; Bi, X. An Atom-Economic Route to Thiophenes and
2,2′-Bithiophenes by Intramolecular Transannulation of gem-Dia-
lkylthio Enynes. Org. Lett. 2013, 15, 4126−4129.
(8) (a) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A.
K.; Lei, A. Recent Advances in Radical C−H Activation/Radical
Cross-Coupling. Chem. Rev. 2017, 117, 9016−9085. (b) Xie, J.; Jin,
H.; Hashmi, A. S. K. The Recent Achievements of Redox-Neutral
Radical C−C Cross-Coupling Enabled by Visible-Light. Chem. Soc.
Rev. 2017, 46, 5193−5203. (c) Studer, A.; Curran, D. P. Catalysis of
Radical Reactions: A Radical Chemistry Perspective. Angew. Chem.,
Int. Ed. 2016, 55, 58−102.
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