Pd/Cu-Catalyzed Vinylation of Terminal Alkynes with (2-Bromoethyl)diphenylsulfonium Triflate

Article abstract of DOI:10.1021/acs.orglett.1c02379

The potential of (2-bromoethyl)diphenylsulfonium triflate to be a powerful vinylation reagent was determined by the Sonogashira cross-coupling reactions with terminal alkynes. The vinylation proceeded smoothly at 25 °C under Pd/Cu catalysis to afford a variety of 1- and 2-unsubstituted 1,3-enynes in moderate to excellent yields. This protocol represents the first application of (2-haloethyl)diphenylsulfonium triflate as a CH═CH2 transfer source in organic synthesis.

Full text of DOI:10.1021/acs.orglett.1c02379

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Letter
Pd/Cu-Catalyzed Vinylation of Terminal Alkynes with
(2‑Bromoethyl)diphenylsulfonium Triflate
Xiao-Xia Ming, Shuai Wu, Ze-Yu Tian, Jia-Wei Song, and Cheng-Pan Zhang*
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ABSTRACT: The potential of (2-bromoethyl)diphenylsulfonium
triflate to be a powerful vinylation reagent was determined by the
Sonogashira cross-coupling reactions with terminal alkynes. The
vinylation proceeded smoothly at 25 °C under Pd/Cu catalysis to
afford a variety of 1- and 2-unsubstituted 1,3-enynes in moderate to
excellent yields. This protocol represents the first application of (2-
haloethyl)diphenylsulfonium triflate as a CHCH2 transfer source in
organic synthesis.
tion-metal-catalyzed Sonogashira couplings of terminal alkynes
with alkenyl (pseudo)halides have been considered as one class
of the most convenient and straightforward strategies to afford
1,3-enyne moieties (Scheme 1b).6 Alkenyl chlorides, bromides,
and iodides and dialkenyl chalcogenides as well as trimethyl-
(3,3,3-trifluoroprop-1-enyl)silane have been successfully used
as the alkenyl sources in the reactions. Despite remarkable
progresses being made, these methods suffered from draw-
backs such as harsh reaction conditions, laborious preparation
of the starting materials, and inconvenient handling of alkene
reagents, especially for the volatile nonsubstituted vinyl halides
as coupling partners. Thus, it remains necessary to develop
mild, general, and more convenient methods for the synthesis
of terminal 1,3-enynes from the easily accessible and tractable
vinyl reagents.
(2-Bromoethyl)diphenylsulfonium triflate has been proven
to be an efficient annulation reagent for a variety of nitrogen-,
sulfur-, oxygen-, and carbon-based nucleophiles, resulting in
the formation of synthetically challenging and pharmaceutically
important 3-, 4-, 5-, 6-, and 7-membered heterocycles in
excellent yields.7,8 It usually serves as a precursor of
diphenyl(vinyl)sulfonim triflate in the reactions and has
exhibited advantages such as good stability, nonvolatility, facile
large-scale preparation, ease of storage and handling, and being
a crystalline solid.7 Diphenyl(vinyl)sulfonim triflate is a less
stable liquid but very reactive electrophile (Michael acceptor)7
undergoing conjugate addition with diverse nucleophiles at the
β-position to form sulfonium ylide intermediates, which further
he 1,3-enynes are prevalent structural motifs in natural
Tproducts, pharmaceutical agents, materials, and other
functionalized molecules.1 The conjugated carbon−carbon
double and triple bonds of 1,3-enynes can be selectively or
concurrently transformed, leading to the construction of very
different chemical scaffolds such as aromatic systems, hetero-
cycles, allenes, and 1,2- or 1,4-addition products.2 Because of
their usefulness and interesting reactivity, significant efforts
have been dedicated to develop efficient methods for the
preparation of 1,3-enynes.3−6 The known synthetic routes
toward 1,3-enynes include Wittig or Horner-Wadsworth-
Emmons (HWE) reactions, carbene-based cross-couplings,
dehydrogenative couplings of 1-alkynes and alkenes, hydro-
alkynylations of allenes, hydrofunctionizations of 1,3-diynes,
enzyme-catalyzed biosynthesis, decarboxylative homodimeriza-
tion of propiolic acids, selective dimerizations of alkynes,
alkynylations of alkenes or organometallic alkenes, and
Sonogashira reactions (Scheme 1).3−6 Notably, the transi-
Scheme 1. Previous Metal-Catalyzed Vinylations Using
Different Alkene Reagents
Received: July 16, 2021
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go through cascade reactions to afford mono- or bicyclic
products.9 Thanks to the convenient synthetic procedures,7−9
both (2-bromoethyl)diphenylsulfonium and diphenyl(vinyl)-
sulfonium triflates have attracted great attention in the realm of
organic chemistry, particularly after the former was successfully
employed instead of the latter in the annulation reactions.8
Nevertheless, the application of (2-bromoethyl)diphenyl- and
diphenyl(vinyl)sulfonium triflates in other reactions has
surprisingly not been exploited so far,10,11 despite various
(alkyl)arylsulfonium salts already being favorably utilized as
excellent arylation reagents for different nuclueophiles.12 In
this article, we presented a Pd/Cu-catalyzed Sonogashira cross-
coupling of terminal alkynes with the readily available (2-
bromoethyl)diphenylsulfonium triflate as the vinylation
reagent, which allowed an efficient and convenient con-
struction of 1- and 2-unsubstituted 1,3-enynes.
Scheme 2. Pd/Cu-Catalyzed Vinylation of Various Terminal
Alkynes (1) with 2a
At the beginning, the one-pot reaction of ethynylbenzene
(1a) with (2-bromoethyl)diphenylsulfonium triflate (2a, 1.0
equiv) and K3PO4 (1.0 equiv) in 1,2-dimethoxyethane (DME)
in the presence of Pd(PPh3)4 (5 mol %) and CuI (5 mol %) at
25 °C under a nitrogen atmosphere for 12 h furnished but-3-
en-1-yn-1-ylbenzene (3a) in 35% yield without an observation
of the phenylated product (see the Supporting Information).
This result is in sharp contrast with the Pd/Cu-catalyzed
reaction of 1a with ethyldiphenylsulfonium triflate under
similar conditions, wherein 1,2-diphenylethyne was formed as
the exclusive product in 94% yield.12d A survey of the reaction
conditions showed that Pd(PPh3)4 was a better catalyst and
DME, DCM, acetone, and THF were all suitable solvents for
the vinylation, affording 3a in moderate yields (see the
Supporting Information). Both K3PO4 and K2CO3 were viable
bases among the tested ones for the Pd/Cu-catalyzed
vinylation (see the Supporting Information). The molar ratios
of the reactants had an interesting impact on the formation of
3a, as varying the molar ratios of 1a/2a/K3PO4 from 1:1:1 to
1:1.5:1.5 in the reactions using DME as a solvent led to 74% of
3a (48% isolated yield; see the Supporting Information). A
similar treatment of 1a with 2a (1.5 equiv) and K2CO3 (1.5
equiv) at 25 °C afforded 3a in 70% yield (see the Supporting
Information). Remarkably, if 1a was treated with 2a (1.5
equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (5 mol %), and CuI (5
mol %) in THF at 25 °C for 12 h, 3a was formed in 81% yield
(see the Supporting Information). The reaction time also had
an influence on the yield of 3a as either shortening the reaction
time from 12 to 6 h or extending it from 12 to 24 h in the Pd/
Cu-catalyzed coupling of 1a with 2a (1.5 equiv) and K3PO4
(1.5 equiv) in DME gave a lower yield of 3a (43% or 64%)
(see the Supporting Information). Moreover, the reaction
temperature significantly affected the production of 3a.
Treatment of 1a with 2a (1.5 equiv) and K3PO4 (1.5 equiv)
in DME at 40 °C in the presence of 5 mol % Pd(PPh3)4 and 5
mol % CuI for 12 h supplied 3a in 73% yield, while the same
reaction at 0 °C afforded only a trace amount of 3a (see the
Supporting Information). Furthermore, reactions of 1a, 2a, and
K3PO4 in the absence of Pd(PPh3)4 or CuI yielded 3a in trace
amounts (see the Supporting Information), which suggested
that both Pd and Cu catalysts played a crucial role in the
transformation.
a
Isolated yields from one-pot reactions (see the Supporting
b
Information). Isolated yields from stepwise reactions (see the
Supporting Information). THF. 24 h. The reaction was run on a
1.0 mmol scale. 40 °C. K3PO4 (0.2 mmol).
c
d
e
f
g
arylacetylenes bearing either electron-withdrawing groups
(e.g., chloro (1b), bromo (1c), iodo (1d), fluoro (1k),
trifluoromethyl (1e), nitro (1f), cyano (1g), keto (1h), amide
(1i), phenyl (1j), and ester (1l)) or electron-donating groups
(such as ethoxy (1m), methoxy (1n−o), and ethyl (1p)
functionalities) on the aryl rings were smoothly converted
under the standard condition to form the corresponding
vinylated products (2b−2p) in good to excellent yields. The
sensitive halo groups (1b−d), ketone (1h), amide (1i), and
ester (1l) were well tolerated in the reactions. In some cases,
prolonging the reaction time from 12 to 24 h (and elevating
the temperature from 25 to 40 °C) was beneficial for the full
consumption of starting alkynes (e.g., 1d, 1e, 1h, 1i, 1j, 1m,
1o, and 1p), furnishing the respective desired products in
satisfactory yields (59−94%). The position of substituents on
phenyl moieties of arylacetylenes might have an effect on the
reaction. Treatment of 1-ethynyl-3-methoxybenzene (1n) with
2a, K3PO4, Pd(PPh3)4, and CuI at 25 °C for 12 h gave 3n in
93% yield, whereas the same reactions of 1-ethynyl-2-
methoxybenzene (1o) and 1-ethoxy-4-ethynylbenzene (1m)
required a longer time and higher temperature to finish the
vinylation. In addition, the Sonogashira coupling was also
applicable to heteroarylacetylenes and alkylalkynes. When 3-
ethynylthiophene (1q), 6-ethynyl-4,4-dimethylthiochromane
(1r), and 3-ethynyl-1-tosyl-1H-indole (1s) reacted with 2a
under the standard condition, the expected vinylation products
(3q−s) were formed in 78−95% yields. Similar treatment of
(prop-2-yn-1-yloxy)benzene (1t), prop-2-yn-1-yl benzoate
(1u), and 4-(but-3-yn-1-yl)benzonitrile (1v) with 2a and
K3PO4 in the presence of Pd(PPh3)4 and CuI at 25 or 40 °C
for 12 or 24 h afforded 50% of 3t, 57% of 3u, and 61% of 3v,
respectively. It should be noted that N-benzyl-N-methylprop-
2-yn-1-amine (Pargyline, 1w), an irreversible monoamine
Next, an assembly of 1 (0.2 mmol), 2a (0.3 mmol), K3PO4
(0.3 mmol), Pd(PPh3)4 (5 mol %), CuI (5 mol %), DME or
THF (2 mL), 25 °C, N2, and 12 h was chosen as one of the
optimal reaction conditions to probe the substrate scope of the
vinylation (Scheme 2). To our delight, a variety of
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oxidase (MAO) inhibitor with antihypertensive and anticancer
activities, reacted with 2a under the standard condition to form
3w in 49% yield. The combination of all these results
demonstrated the high efficiency, good compatibility, and
ready availability of this method in the production of 1- and 2-
unsubstituted 1,3-enynes.
out that the yields of 1,3-enynes in the reactions using 2b were
comparable to those using 2a as the vinylation reagent. These
results supported again that the diphenyl(vinyl)sulfonium salt
was the key intermediate in the reactions. Since diphenyl-
(vinyl)sulfonium triflate had relatively poor stability during
preparation and storage,7 the direct use of 2a as an effective
and crystalline stable CHCH2 reagent was very preferable in
the Pd/Cu-catalyzed preparation of unsubstituted 1,3-enynes.
To validate the efficiency of 2a in this Sonogashira cross-
coupling, the reactions of 1f with different (2-haloethyl)-
diphenylsulfonium salts (2c−g) were compared under the
standard conditions (Scheme 4). Pd/Cu-catalyzed vinylation
Since (2-bromoethyl)diphenylsulfonium cation could be
rapidly transformed to diphenyl(vinyl)sulfonium cation under
basic conditions,7,8 we wondered whether this Pd/Cu-
catalyzed Sonogashira cross-coupling of terminal alkynes with
2a in the presence of K3PO4 might involve an in situ formed
diphenyl(vinyl)sulfonium salt as the intermediate. To verify
this hypothesis, we changed the charging sequence of reactants
under the standard condition (stepwise reactions, Scheme 2):
(2-bromoethyl)diphenylsulfonium triflate (1.5 equiv) was first
treated with K3PO4 (1.0 or 1.5 equiv) in DME or THF at 25
°C under N2 for 20 min, from which the diphenyl(vinyl)-
sulfonium cation was identified according to the NMR analysis
of the reaction mixtures (see the Supporting Information);
then, Pd(PPh3)4 (5 mol %), CuI (5 mol %), alkyne, and DME
or THF were added, and the mixture was kept at 25 °C for
another 12 h. The outcomes revealed that the substrates suited
for the one-pot reactions were all amenable to the stepwise
reactions, and the yields from the latter were comparable or
even better than those from the former. These data suggested
that diphenyl(vinyl)sulfonium might be a key intermediate in
the vinylation.
Scheme 4. Comparison of the Pd/Cu-Catalyzed Vinylation
of 1f with Different (2-(Pseudo)haloethyl)sulfonium Salts
(2)
Furthermore, the Pd/Cu-catalyzed Sonogashira cross-
coupling of terminal alkyne with the isolated diphenyl(vinyl)-
sulfonium triflate (2b) was implemented (Scheme 3).
a
b
Scheme 3. Pd/Cu-Catalyzed Vinylation of Terminal Alkynes
(1) with 2b
HPLC yields from one-pot reactions. HPLC yields from stepwise
a
c
reactions. 5-Vinyl-5H-thianthren-5-ium triflate (2k) was used instead
of 2i. K3PO4 (1.0 equiv). 1-Vinyltetrahydro-1H-thiophen-1-ium
triflate (2l) was used instead of 2j.
d
e
of 1f with (2-fluoroethyl)diphenylsulfonium triflate (2c) by the
one-pot or stepwise method gave 3f in 43% or 22% yield,
suggesting that 2c was a less effective vinylation reagent than
2a. This phenomenon might be caused by the faster in situ
generation of the unstable diphenyl(vinyl)sulfonium inter-
mediate from 2c (see the Supporting Information). Surpris-
ingly, if 1f was treated with (2-chloroethyl)diphenylsulfonium
triflate (2d) or tetrafluoroborate (2e) under the same
conditions, 3f was obtained in trace amounts and most of 1f
was recovered. Similar results were obtained when using (2-
iodoethyl)diphenylsulfonium triflate (2f) or tetrafluoroborate
(2g) as the reagent. It was found that 2d−g were unstable
sulfonium salts and tended to decompose during the NMR
measurement (see the Supporting Information). Additionally,
the treatment of 2d and 2f with KHCO3 or K3PO4 in THF/
H2O or THF-d8 at room temperature for 20−25 min provided
complicated mixtures according to the NMR experiments (see
the Supporting Information). These data suggested that (2-
chloroethyl)- and (2-iodoethyl)diphenylsulfonium salts were
not suitable CHCH2 reagents in the reactions and the use of
different counteranions could not improve the transformation.
Moreover, if 1f was mixed with diphenyl(2-(tosyloxy)ethyl)-
sulfonium triflate (2h) under the standard conditions, 26% or
29% of 3f was formed. Taking 5-(2-bromoethyl)-5H-
thianthren-5-ium triflate (2i) instead of 2h in the same
reactions provided 3f in 48% or 45% yield. Unfortunately,
when 1-(2-bromoethyl)tetrahydro-1H-thiophen-1-ium triflate
a
Reaction conditions: 1 (0.2 mmol), 2b (0.24 mmol), K3PO4 (1.0
equiv), Pd(PPh3)4 (5 mol %), CuI (5 mol %), DME (2 mL), 25 °C,
12 h, N2. Isolated yields. 24 h. The reaction was run with 1.0 mmol.
b
c
Treatment of 1a with 2b (1.2 equiv), K3PO4 (1.0 equiv),
Pd(PPh3)4 (5 mol %), and CuI (5 mol %) in DME (2 mL) at
25 °C under N2 for 12 h afforded 3a in 59% yield. When
arylacetylenes 1b−c, 1f, and 1h−o (as examples) were mixed
with 2b under the same condition, the respective vinylation
products 3b−c, 3f, and 3h−o were obtained in 75−99% yields.
Likewise, the standard reactions of 1i−j with 2b and K3PO4 at
25 °C for 24 h provided 3i−j in 88% yields. Hetero-
arylacetylenes like 1q and 1s underwent smooth vinylation
with 2b to afford 3q in 96% yield and 3s in 81% yield.
Alkylalkynes such as 1t and 1u reacted similarly with 2b to give
3t in 69% yield and 3u in 55% yield. It was effortless to point
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Authors
(2j) reacted with 1f in a one-pot procedure, only a trace
amount of 3f was observed. The reactions afforded similar
yields (40% or trace) when 2i and 2j were replaced by 5-vinyl-
5H-thianthren-5-ium triflate (2k) and 1-vinyltetrahydro-1H-
thiophen-1-ium triflate (2l), respectively, under similar
conditions. The inferior production of 3f from 2d−j was
probably attributed to their poor stability, the frustrated
formation or cross-coupling of vinylsulfonium intermediates,
and the in situ generation of harmful halides (see the
Supporting Information), which implied that these (2-
(pseudo)haloethyl)sulfonium salts were much poorer CH
CH2 transfer sources than 2a in the vinylation reactions.
Tentatively, a plausible reaction mechanism including
successive elimination of 2a to 2b and Pd/Cu-catalyzed
coupling of 2b with terminal alkynes was suggested for the
preparation of unsubstituted 1,3-enynes from 2a.
Xiao-Xia Ming − School of Chemistry, Chemical Engineering
and Life Science, Wuhan University of Technology, Wuhan,
Hubei 430070, China
Shuai Wu − School of Chemistry, Chemical Engineering and
Life Science, Wuhan University of Technology, Wuhan,
Hubei 430070, China
Ze-Yu Tian − School of Chemistry, Chemical Engineering and
Life Science, Wuhan University of Technology, Wuhan,
Hubei 430070, China
Jia-Wei Song − School of Chemistry, Chemical Engineering
and Life Science, Wuhan University of Technology, Wuhan,
Hubei 430070, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02379
In summary, we have developed an efficient Sonogashira
cross-coupling of terminal alkynes with (2-bromoethyl)-
diphenylsulfonium triflate (2a) under Pd/Cu catalysis, which
enabled conversion of a variety of aryl- and alkylacetylenes to
the corresponding 1,3-enynes in moderate to high yields. 2a is
successfully used as a precursor of diphenyl(vinyl)sulfonium
triflate (2b) and a powerful vinylation reagent for terminal
alkynes. This study expands the uses of 2a and 2b in organic
synthesis beyond their applications in the preparation of cyclic
compounds. The advantages of the method include conven-
ience, high efficiency, specific CVinyl−S bond cleavage rather
than CAr−S bond breakage, mild reaction conditions, ease of
handling, good functional group tolerance, ready accessibility
and stable starting materials, and lacking the use of sensitive or
toxic organometallic reagents or volatile CHCH2 sources.
The selective CVinyl−S bond over CAr−S bond fragmentation of
2b might be attributed to the much more favorable oxidative
addition of the former than the latter to Pd(0) species in the
reactions, which was analogous to the case reported for (E)-(β-
trifluoromethyl)vinyldiphenylsulfonium triflate toward arylbor-
onic acid in the literature.10c When compared with other (2-
(pseudo)haloethyl) sulfonium salts, 2a has been verified to be
the most effective CHCH2 reagent in the Pd/Cu-catalyzed
vinylations. Further application of 2a as a promising vinylation
reagent in other reactions is currently underway in our
laboratory.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Wuhan University of Technology and the “Hundred
Talent” Program of Hubei Province (China) for financial
support.
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AUTHOR INFORMATION
■
Corresponding Author
Cheng-Pan Zhang − School of Chemistry, Chemical
Engineering and Life Science, Wuhan University of
Technology, Wuhan, Hubei 430070, China; orcid.org/
0000-0002-2803-4611; Email: cpzhang@whut.edu.cn,
zhangchengpan1982@hotmail.com
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