Cu-Catalyzed Three-Component Coupling of Aryne, Alkyne, and Benzenesulfonothioate: Modular Synthesis of o-Alkynyl Arylsulfides

Article abstract of DOI:10.1021/acs.orglett.6b02027

A copper-catalyzed three-component coupling reaction of in situ formed arynes, terminal alkynes, and benzenesulfonothioates is described. This reaction provides an efficient modular synthesis of o-alkynyl arylsulfides from easily available starting materials. This process involves one C-S bond and one C-C bond formation in one pot.

Full text of DOI:10.1021/acs.orglett.6b02027

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Three-Component Coupling of Aryne, Alkyne, and
Benzenesulfonothioate: Modular Synthesis of o‑Alkynyl Arylsulfides
Xianglong Peng,† Chen Ma,† Chen-Ho Tung,† and Zhenghu Xu*,†,‡
†Key Lab for Colloid and Interface Chemistry of Education Ministry, School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250100, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed three-component coupling
reaction of in situ formed arynes, terminal alkynes, and
benzenesulfonothioates is described. This reaction provides an
efficient modular synthesis of o-alkynyl arylsulfides from easily
available starting materials. This process involves one C−S
bond and one C−C bond formation in one pot.
ryl sulfides are an important type of structural unit, widely
the reaction of Grignard reagents and Bunte salts (Scheme 1c).5
1
Apresented in bioactive pharmaceuticals and also materials. Very recently, we noticed that benzenesulfonothioates are
excellent electrophilic sulfenylating reagents (RS+) and success-
Aryl sulfides are important synthetic intermediates and chiral
ligands in organic synthesis.2 They could be easily transformed
fully introduced alkyl and aromatic thio groups onto the triazole
ring (Scheme 1d).6 The benzenesulfonothioates are bench-
into different oxidative states, such as sulfoxide and sulfone,
stable, generally have little or no odor, and can be easily prepared.
We believe this type of electrophilic sulfenylation reaction will
find more applications in other important C−S construction
reactions.
which are also important functional groups in medicinal and
organic chemistry.1 Thus, the construction of C−S bonds is of
strategic importance in current synthetic chemistry. Tradition-
ally, the Csp2−S bond formation mainly relies on the transition-
metal-catalyzed coupling reactions of aryl halide and nucleophilic
thiols (RS−), which are air-sensitive and extremely odorous
(Scheme 1a).3 Recently, the Jiang group used Na2S2O3 as the
sulfur source and developed a series of sulfur atom transfer
reactions to construct aryl−sulfur bonds (Scheme 1b).4a−c The
Reeves group developed an elegant C−S construction method by
Aryne chemistry was developed as a powerful platform for 1,2-
difunctionalization of aromatic rings in recent years.7 The in situ
formed arynes are highly reactive electron-deficient intermedi-
ates. Nucleophilic addition to benzyne and subsequent electro-
philic trap cascade reactions are the fundamental reaction mode
in current benzyne chemistry.8 For example, in 2015, the
Greaney group reported a three-component reaction of arynes,
nucleophilic thiol, and electrophilic O-benzoyl N-hydroxylpiper-
idine, giving 1,2-diheterofunctionalized arenes in high yields.8f o-
Alkynyl arylsulfides are important synthetic intermediates that
could be easily transformed into benzothiophene heterocycles
under electrophilic conditions.9 o-Alkynyl arylsulfides were
prepared by stepwise palladium-catalyzed C−S bond and
Sonogashira coupling reactions. In this context, we envisioned
that terminal alkynes nucleophilically attack in situ formed
benzynes, and electrophilically trapping the reaction intermedi-
ate with benzenesulfonothioates (RS+) would rapidly construct
o-alkynyl arylsulfides in one step from easily available starting
materials.
Scheme 1. Methods for Csp2−S Bond Construction
A detailed description of our proposed mechanistic cycle for
the copper-catalyzed three-component coupling reaction is
outlined in Scheme 2. Copper(I) acetylide M1 was formed
from terminal alkyne 1 in the presence of base and copper
catalyst. M1 reacted with electrophilic sulfenylating reagent 3 to
Received: July 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Proposed Mechanism of the Copper-Catalyzed
Table 1. Reaction Condition Optimization
Three-Component Reaction to o-Alkynyl Arylsulfides
form the internal thioalkyne 7. However, when the highly
reactive benzyne was formed in situ, M1 reacted with benzyne,
forming the aryl copper intermediate M2, which was trapped by
the electrophilic reagent 3 to give the final product 4 and
regenerate the copper catalyst. Achieving this catalytic cycle is
challenging because the aryl copper intermediate is easily
protonated to form the internal alkyne 5 and attack another
molecule of the benzyne intermediate to form byproduct 6. To
inhibit the sulfenylation reaction of copper(I) acetylide M1, we
needed to increase the benzyne formation rate; however, this
would also increase the amount of two benzyne addition
byproducts 6. Thus, controlling the benzyne formation rate and
choosing a reactivity-matched electrophile are very crucial for
this reaction.
a
Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), 3a (0.2 mmol),
[Cu] (10 mol %), F− (0.6 mmol), base (0.6 mmol), 4 Å MS (100 mg),
and solvent (2 mL) were stirred under N2 atmosphere for 5 h. Isolated
b
yields of 4a were reported. 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4
c
mmol), CuI (10 mol %), F− (0.6 mmol), base (0.4 mmol). BnBr (0.4
mmol) was added. 18-C-6 = 18-crown-6.
Initially, alkyne 1a, benzyne precursor 2a, and electrophilic
sulfenylating reagents 3a (PhS+) were chosen as the model
substrates to optimize the reaction conditions (Table 1; for
details, see Supporting Information). When TBAF was selected
as the fluoride source, K2CO3 as the base, and 10 mol % of CuI as
the catalyst, the target three-component coupling product 4a
could be isolated in 25% yield (entry 1). Two major byproducts,
5 and 6, were observed in the reaction system. Varying different
bases did not give better results (entries 2 and 3). When we
increased the reaction temperature from room temperature to 40
°C, the isolated yield increased to 50% (entry 4). Other fluorides,
such as CsF, led to lower yields under this condition (entries 5
and 6). When we tuned the ratios of the three reactants and
increased the amounts of electrophile 3, the yield increased to
64% (entry 7). Under these conditions, sulfonyldibenzene 10
became the major byproduct, which was formed between the
addition reaction of released PhSO2− with benzyne.10 To inhibit
this undesired side reaction, 2 equiv of BnBr was added into the
a
Scheme 3. Scope of the Terminal Alkynes
−
reaction system as a scavenger to trap the PhSO2 , and formation
of PhSO2Bn was isolated and also confirmed by GC-MS. When
CsF and 18-crown-6 were used as the fluoride source, the target
product 4a was isolated in 87% yield, which is the optimal
reaction conditions (entry 9). Other electrophilic sulfenylating
reagents (8 and 9) were also tested. The expected 4a was not
observed, but only product 5 and 6 were (entries 10 and 11).
The scope of the three-component reaction with a variety of
terminal acetylenes was explored (Scheme 3). A variety of
electronically varied aryl acetylenes were compatible with the
system, providing expected α-alkynylated aryl sulfides 4a−4e in
excellent yields. Heterocycles, including thiophenes and
ferrocene-substituted alkynes, were also efficient coupling
partners, giving corresponding aryl sulfides 4f−4h in 75−85%
yields. Moreover, alkyl acetylenes were also suitable substrates
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol),
CuI (10 mol %), F− (0.6 mmol), 18-crown-6 (0.6 mmol), K2CO3 (0.4
mmol), BnBr (0.4 mmol), 4 Å MS (100 mg), and solvent (2 mL) were
stirred under N2 atmosphere for 5 h.
for this reaction, and commonly encountered functional groups
such as cyclopropyl (4j) and sterically hindered alcohol (4k)
were well-tolerated. Additionally, electron-deficient methyl
B
DOI: 10.1021/acs.orglett.6b02027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
propiolate could also react efficiently in this three-component
reaction (4l).
The scope of benzenesulfonothioates was examined (Scheme
4). Various aromatic thio and aliphatic thio groups could be easily
presence of 2 mol % of AuCl.11 Interestingly, iodine-mediated
electrophilic cyclization of methyl selenide 4s gave benzosele-
nophene 12 in 90% yield.12
In conclusion, a copper-catalyzed three-component coupling
reaction of alkynes, arynes, and benzenesulfonothioates was
described. This nucleophilic attack and electrophilic trap reaction
involves efficient C−C and Csp2−S bond formation in one pot. A
wide variety of o-alkynyl aryl sulfides were modularly constructed
from readily available starting materials, and various functional
groups were tolerated under these mild conditions. We envision
that the reaction mode outlined here will have potential
applications in other significant synthetic transformations.
Scheme 4. Substrate Scope of Benzenesulfonothioates and
a
Arynes
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02027.
Experimental details and spectral data for new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xuzh@sdu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Natural Science
Foundation of China and Shandong province (Nos. 21572118,
JQ201505) and the fundamental research and subject con-
struction funds of Shandong University (Nos. 2014JC008,
104.205.2.5).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol),
CuI (10 mol %), F− (0.6 mmol), 18-crown-6 (0.6 mmol), K2CO3 (0.4
mmol), BnBr (0.4 mmol), 4 Å MS (100 mg), and solvent (2 mL) were
stirred under N2 atmosphere for 5 h.
REFERENCES
■
introduced onto the adjacent position of an alkyne moiety in
good yields (4m−4r). When the reaction was extended to the
selenylation, the methylselenyl and phenylselenyl products 4s
and 4t were obtained in 63 and 67% yields. The scope of various
functionalized arynes was also examined. All arynes tested were
compatible with the standard conditions, and the corresponding
aryl sulfides could be isolated in reasonable yields. When the
unsymmetrical 2v was used, mixtures of 4v and 4v′ were isolated
in 71% yields (4v/4v′ = 1.4:1). The reaction of methoxyl-
substituted aryne 2x was regioselective and led to arylsulfide 4x as
the major product (4x/4x′ = 9:1).
(1) (a) Nakazawa, T.; Xu, J.; Nishikawa, T.; Oda, T.; Fujita, A.; Ukai,
K.; Mangindaan, R. E. P.; Rotinsulu, H.; Kobayashi, H.; Namikoshi, M. J.
J. Nat. Prod. 2007, 70, 439. (b) Mishra, A.; Ma, C. Q.; Bauerle, P. Chem.
Rev. 2009, 109, 1141. (c) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med.
Chem. 2014, 57, 2832. (d) Nair, D. P.; Podgorski, M.; Chatani, S.; Gong,
T.; Xi, W. X.; Fenoli, C. R.; Bowman, C. N. Chem. Mater. 2014, 26, 724.
(2) (a) Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am.
Chem. Soc. 2003, 125, 3534. (b) Mellah, M.; Voituriez, A.; Schulz, E.
Chem. Rev. 2007, 107, 5133. (c) Wei, Y.; Lu, L.-Q.; Li, T.-R.; Feng, B.;
Wang, Q.; Xiao, W.-J.; Alper, H. Angew. Chem., Int. Ed. 2016, 55, 2200.
(d) Wang, B.; Lin, C.; Liu, Y.; Fan, Z.; Liu, Z.; Zhang, Y. Org. Chem.
Front. 2015, 2, 973. (e) Bao, D.-H.; Wu, H.-L.; Liu, C.-L.; Xie, J.-H.;
Zhou, Q.-L. Angew. Chem., Int. Ed. 2015, 54, 8791.
(3) (a) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002,
4, 2803. (b) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (c) Kwong,
F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (d) Fernandez-Rodriguez,
M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180.
(e) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47,
2880. (f) Arisawa, M.; Suzuki, T.; Ishikawa, T.; Yamaguchi, M. J. Am.
Chem. Soc. 2008, 130, 12214. (g) Larsson, P. F.; Correa, A.; Carril, M.;
Norrby, P. O.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691.
(h) Arisawa, M.; Ichikawa, T.; Yamaguchi, M. Org. Lett. 2012, 14, 5318.
(i) Wang, H.; Wang, L.; Shang, J.; Li, X.; Wang, H.; Gui, J.; Lei, A. Chem.
Commun. 2012, 48, 76.
Further transformations of the generated o-alkynyl aryl sulfides
were investigated. As shown in Scheme 5, allylic sulfide 4r could
isomerize into 3-allyl benzothiophene 11 in 81% yield in the
Scheme 5. Further Transformations of o-Alkynyl Aryl Sulfides
(4) (a) Qiao, Z.; Wei, J.; Jiang, X. Org. Lett. 2014, 16, 1212. (b) Li, Y.;
Pu, J.; Jiang, X. Org. Lett. 2014, 16, 2692. (c) Zhang, Y.; Li, Y.; Zhang, X.;
Jiang, X. Chem. Commun. 2015, 51, 941.
(5) Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca, C. A.;
Senanayake, C. H. Org. Lett. 2014, 16, 1196.
C
DOI: 10.1021/acs.orglett.6b02027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) Wang, W.; Peng, X.; Wei, F.; Tung, C.-H.; Xu, Z. Angew. Chem.
2016, 128, 659.
(7) For recent reviews on arynes, see: (a) Bronner, S. M.; Goetz, A. E.;
Garg, N. K. Synlett 2011, 2011, 2599. (b) Gampe, C. M.; Carreira, E. M.
Angew. Chem., Int. Ed. 2012, 51, 3766. (c) Bhojgude, S. S.; Biju, A. T.
Angew. Chem., Int. Ed. 2012, 51, 1520. (d) Tadross, P. M.; Stoltz, B. M.
Chem. Rev. 2012, 112, 3550. (e) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem.
Soc. Rev. 2012, 41, 3140. (f) Dubrovskiy, A. V.; Markina, N. A.; Larock,
R. C. Org. Biomol. Chem. 2013, 11, 191. (g) Pellissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701. (h) Wenk, H. H.; Winkler, M.; Sander, W.
Angew. Chem., Int. Ed. 2003, 42, 502. (i) Sanz, R. Org. Prep. Proced. Int.
2008, 40, 215. (j) Yoshida, H.; Takaki, K. Synlett 2012, 23, 1725. (k) Wu,
C.; Shi, F. Asian J. Org. Chem. 2013, 2, 116. (l) Hoffmann, R. W.; Suzuki,
K. Angew. Chem., Int. Ed. 2013, 52, 2655. (m) Goetz, A. E.; Garg, N. K. J.
Org. Chem. 2014, 79, 846. (n) Goetz, A. E.; Shah, T. K.; Garg, N. K.
Chem. Commun. 2015, 51, 34.
(8) (a) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem.
Soc. 2006, 128, 7426. (b) Chakrabarty, S.; Chatterjee, I.; Tebben, L.;
Studer, A. Angew. Chem., Int. Ed. 2013, 52, 2968. (c) Bhunia, A.; Roy, T.;
Pachfule, P.; Rajamohanan, P. R.; Biju, A. T. Angew. Chem., Int. Ed. 2013,
52, 10040. (d) Goetz, A. E.; Garg, N. K. Nat. Chem. 2013, 5, 54.
(e) Bhunia, A.; Porwal, D.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013,
15, 4620. (f) Garcia-Lopez, J.-A.; Cetin, M.; Greaney, M. F. Angew.
Chem., Int. Ed. 2015, 54, 2156. (g) Liu, Z.; Larock, R. C. J. Org. Chem.
2006, 71, 3198. (h) Xie, C.; Liu, L.; Zhang, Y.; Xu, P. Org. Lett. 2008, 10,
2393. (i) Jayanth, T. T.; Cheng, C.-H. Angew. Chem., Int. Ed. 2007, 46,
5921. (j) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2009, 48, 391. (k) Qiu, Z.; Xie, Z. Angew. Chem., Int. Ed.
2009, 48, 5729. (l) Peng, X.; Wang, W.; Jiang, C.; Sun, D.; Xu, Z.; Tung,
C.-H. Org. Lett. 2014, 16, 5354. (m) Wang, W.; Peng, X.; Qin, X.; Zhao,
X.; Ma, C.; Tung, C.-H.; Xu, Z. J. Org. Chem. 2015, 80, 2835.
(n) Yoshida, S.; Yano, T.; Misawa, Y.; Sugimura, Y.; Igawa, K.; Shimizu,
S.; Tomooka, K.; Hosoya, T. J. Am. Chem. Soc. 2015, 137, 14071.
(o) Garve, L. K. B.; Werz, D. B. Org. Lett. 2015, 17, 596. (p) Chen, Q.;
Zhang, C.; Chen, L.; Wen, C.; Du, Z.; Chen, H.; Zhang, K. Tetrahedron
Lett. 2015, 56, 2094. (q) Liu, F.; Yang, H.; Hu, X.; Jiang, G. Org. Lett.
2014, 16, 6408. (r) Rao, B.; Tang, J.; Zeng, X. Org. Lett. 2016, 18, 1678.
(s) Yoo, W.-J.; Nguyen, T. V. Q.; Kobayashi, S. Angew. Chem., Int. Ed.
2014, 53, 10213. (t) Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. J. Am. Chem.
Soc. 2015, 137, 5670. (u) Holden, C. M.; Sohel, S. M. A.; Greaney, M. F.
Angew. Chem., Int. Ed. 2016, 55, 2450. (v) Medina, J. M.; Mackey, J. L.;
Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 15798.
(w) Cheong, P. H.-Y.; Paton, R. S.; Bronner, S. M.; Im, G-Y. J.; Garg, N.
K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267.
(9) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
(10) Pandya, V. G.; Mhaske, S. B. Org. Lett. 2014, 16, 3836.
(11) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006,
45, 4473.
(12) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006,
71, 2307.
D
DOI: 10.1021/acs.orglett.6b02027
Org. Lett. XXXX, XXX, XXX−XXX