Copper-catalyzed 1,1-difunctionalization of terminal alkynes: a three-component reaction for the construction of vinyl sulfones

Article abstract of DOI:10.1007/s11426-019-9454-8

A copper-catalyzed 1,1-difunctionalization of terminal alkynes was achieved via a three-component reaction, providing a variety of vinyl sulfones with good yields and excellent chemo- and stereoselectivity. Preliminary mechanistic studies indicated that t

Full text of DOI:10.1007/s11426-019-9454-8

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https://doi.org/10.1007/s11426-019-9454-8
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Copper-catalyzed 1,1-difunctionalization of terminal alkynes: a
three-component reaction for the construction of vinyl sulfones
Qi Sun, Linge Li, Liyan Liu, Yu Yang, Zhenggen Zha & Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Center for Excellence in
Molecular Synthesis of Chinese Academy of Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of
Chemistry and Materials Science in University of Science and Technology of China, Hefei 230026, China
Received January 17, 2019; accepted March 4, 2019; published online April 25, 2019
A copper-catalyzed 1,1-difunctionalization of terminal alkynes was achieved via a three-component reaction, providing a variety
of vinyl sulfones with good yields and excellent chemo- and stereoselectivity. Preliminary mechanistic studies indicated that the
reaction probably underwent a Cu-catalyzed formal C–H insertion to produce an allene intermediate, which was then trapped by
a sulfonyl anion to give the corresponding product.
copper, terminal alkynes, germinal difunctionalization, multicomponent reaction, vinyl sulfones
Citation:
Sun Q, Li L, Liu L, Yang Y, Zha Z, Wang Z. Copper-catalyzed 1,1-difunctionalization of terminal alkynes: a three-component reaction for the
construction of vinyl sulfones. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9454-8
1 Introduction
reaction, in which a carbene chemistry is involved.
As a typical one-pot reaction, multicomponent reactions
(MCRs) were widely investigated and applied in the rapid
construction of complex molecules due to their diversity,
efficiency, and environmental amiability [20]. For instance,
Strecker [21], Biginelli [22] and Ugi [23] reactions are well
employed in the construction of some complex skeletons.
The difunctionalization of the terminal alkynes by using
MCRs is rare, especially for those involving 1,1-difunctio-
nalization. Recently, a copper-catalyzed three-component
reaction for the preparation of β-enamino esters was devel-
oped by Huang’s group [24] (Scheme 2). Another nickel-
catalyzed MCR for the carbosulfonylation of terminal al-
kynes was reported by Nevado’s group [25] (Scheme 2).
These use of MCRs provided a new perspective for the
synthesis of some important molecular skeletons. On the
other hand, due to the particular physiological characteristics
and biological activities of vinyl sulfones [26–32], the sul-
fonylation of the terminal alkyne has attracted attention of
the synthetic chemists over the last decade [33–37]. How-
ever, most of these synthetic strategies involved tedious steps
Difunctionalization of terminal alkynes has been playing a
significant role in many processes for the synthesis of mul-
tisubstituted olefins [1–3]. The most of the previous methods
for difunctionalization of terminal alkynes involved radical
additions or electrophilic additions, and the multi-functio-
nalization of terminal alkynes typically required several
steps under different conditions. Despite the difference in
their synthetic routes, these methods are almost general re-
action patterns of C–C multiple bonds, resulting in 1,2-di-
functionalization [4–15]. By contrast, only a few reports are
related to the 1,1-difunctionalization of terminal alkynes
[16,17]. To the best of our knowledge, the 1,1-difunctiona-
lization of the terminal alkynes by one-step process is still of
great challenge although Sawamura et al. [18] and Chirik et
al. [19] made notable progress in the 1,1-diboration of al-
kynes recently (Scheme 1). Therefore we assumed that we
can overcome this dilemma by virtue of a multicomponent
*Corresponding author (email: zwang3@ustc.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
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Sun et al. Sci China Chem
and 4-methylbenzenesulfonhydrazide 3a as the model sub-
strates (Table 1). Initially, various copper catalysts were
examined in the reaction. To our delight, the reaction cata-
lyzed by CuBr in the presence of TEA could afford the de-
sired product 4a in 10% yield (entry 5). After screening of
the catalysts, it was found that CuI should be the ideal cat-
alyst for this reaction, affording the desired product 4a with a
yield of 88% while other copper salts gave low yields even
no catalytic reactivity for this reaction (entries 1–10).
Scheme 1 Designed strategy for multi-component reaction of terminal
alkynes 1,1-difunctionalization (color online).
On the other hand, the base TEA was necessary for this
reaction, otherwise the reaction did not work. Therefore a
variety of bases were optimized. When DABCO, K2CO3 and
LiOtBu were employed in this reaction, no any desired
product can be observed while the starting materials were
recovered (entries 15–17). After base screening, TEA should
be the best base for this reaction. Subsequently different
kinds of solvent were examined in the reaction. When
acetonitrile was employed as the solvent, the desired product
can be obtained with a yield of 34%, and chloroform was
employed as the solvent, the yield was 78% (entries 11–14).
Moreover, when the reaction was carried out in the DCM, the
desired product can be obtained with a yield of 88% (entry
6). This indicated that DCM was the best solvent for this
Table 1 Reaction condition optimizationa)
Entry
1
Catalyst
Cu(MeCN)4PF6
CuOTf
CuOAc
CuCl
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
Toluene
MeOH
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Base
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
K2CO3
LiOtBu
DABCO
TEA
TEA
TEA
TEA
Yield (%)b)
trace
trace
n.d
Scheme 2 MCRs involving terminal alkynes (color online).
and strict operation condition. In view of the above, we de-
vised a novel and efficient method for both of the sulfony-
lation and the 1,1-difunctionalization of the terminal alkynes
by virtue of a Cu(I)-catalyzed three-component reaction.
Even though any two components of these three reactants
(diazo esters, terminal alkynes and sulfonyl hydrazides) can
react separately [38–40], this reaction can still proceed
smoothly with good chemo- and regioselectivity. By using
this developed reaction, a series of substituted vinyl sulfones
can be obtained rapidly with good functional-group tolerance
and excellent stereoselectivity under mild conditions.
2
3
4
trace
10
5
CuBr
CuI
6
88
7
CuCl2
CuBr2
Pd(OAc)2
AgOAc
CuI
n.d
8
n.d
9
n.d
10
11
12
13
14
15
16
17
18c)
19d)
20e)
21f)
n.d
34
CuI
n.d
CuI
n.d
CuI
78
2 Experimental
CuI
n.d
To a mixture of 1 (0.2 mmol), 2 (2.0 equiv.), 3 (2.0 equiv.),
catalyst (0.02 mmol, 10 mol%), and base (3.0 equiv.), 1.0 mL of
solvent were added. The reaction mixture was stirred at room
temperature until 1 was consumed. Then the reaction mixture
was purified directly by column chromatography (silica gel,
petroleum ether/EtOAc) to afford the desired product.
CuI
n.d
CuI
n.d
CuI
73
CuI
40
CuI
87
CuI
86
a) The reaction was carried out with 1a (0.2 mmol), 2a (2.0 equiv.), 3a
(2.0 equiv.), catalyst (10 mol%), base (3.0 equiv.) in solvent (1 mL) at room
temperature (25 °C) for 14 h. DCM=dichloromethane, TEA=triethylamine,
DABCO=triethylenediamine; b) isolated yields; c) 10 °C; d) 0 °C; e) 50 °C;
f) 100 °C.
3 Results and discussion
We began our studies with phenylacetylene 1a, diazo ester 2a

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Sun et al. Sci China Chem
reaction. Afterwards, the effect of the reaction temperature
was also investigated. The experimental result showed that
the temperature had an influence on the reaction. When we
decreased the temperature from the room temperature to
10 °C, the reaction yield was decreased to 73% (entry 18)
while the reaction yield lessened a lot when the temperature
decreased to 0 °C (entry 19). When the temperature increase
to 50 °C even 100 °C, the reaction yields were reduced a
little (entries 20, 21). After optimization, the room tem-
perature should be the best reaction temperature for this re-
action. Finally, the optimal condition was identified as
below: copper iodide as the catalyst, TEA as the base, DCM
as the solvent.
We then conducted an in-depth study of the scope of the
reaction substrates under the optimal conditions (Table 1,
entry 6). As shown in Figure 1, a variety of sulfonyl hy-
drazines with different functional groups, reacted readily
with phenylacetylene 1a and ethyl diazoacetate 2a to give the
desired products with good yields. Normally, an electron-
donating group (4a–4e) had a positive effect on this con-
version while an electron-withdrawing group negatively af-
fected this transformation (4f–4j). The naphthalenesulfonyl
hydrazide was also tested as a substrate, and the desired
product was obtained with a yield of 85% (4k). Gratifyingly,
phenylmethanesulfonyl hydrazide can also be employed to
give the corresponding product with 70% yield (4l). Next,
the scope of the alkynes and diazo esters was screened. A
variety of terminal alkynes (5a–5i) were used to react with
2a and 3a under the optimized condition. Aromatic alkynes
could afford the desired products in moderate to good yields
regardless of the electron-donating substitution or electron-
withdrawing substitution on the phenyl ring (5a–5k). In
addition, phenylacetylenes with ortho- or meta-substituent
groups reacted smoothly in this reaction and the corre-
sponding products were obtained with good yields (5h–5i).
All aromatic alkynes showed good adaptability in this
transformation to give the desired products. Furthermore, the
positions of the substituents on the phenyl ring had little
influence on the chem- and regioselectivity of the reaction.
Gratifyingly, when the hydrogen of diazo-esters was varied
into methyl group, the reaction could also carried out
smoothly, affording the corresponding products efficiently
(5j–5k).
Figure 1 Reaction scope. The reaction was carried out with 1 (0.2 mmol),
2 (2.0 equiv.), 3 (2.0 equiv.), CuI (10 mol%), TEA (3.0 equiv.) in di-
chloromethane (1 mL) at room temperature for 14 h; isolated yields of all
products; the temperature of the reactions involving 4-chlor-
ophenylacetylene and 4-bromophenylacetylene was 100 °C (color online).
yield of 77% (Scheme 4). This indicates that this developed
method can be applied to the modification of steroid drugs to
change their biological activity [41].
Encouraged by the reaction features, such as high effi-
ciency, simple operation and broad scope, a scaled-up ex-
periment was explored to test the practicality. When
5.0 mmol of phenylacetylene 1a was reacted with 2.0 equiv.
of diazo ester 2a and 2.0 equiv. of 4-methylbenzene-
sulfonhydrazide 3a, the desired product 4a can be obtained
with a yield of 78%, showing a significant potential in or-
ganic synthesis (Scheme 3).
To understand the reaction mechanism, we performed
some control experiments. Firstly, 4 equiv. of different ra-
dical scavengers (TEMPO or BHT) were added respectively
into the reaction mixture, the yield of 4a did not decrease
obviously (Scheme 5(a)). The result almost excluded a ra-
dical process in this reaction. Then, compounds D was
synthesized and reacted with TsNa in the presence of TEA,
affording the desired product 4a with a yield of 52%
Moreover, compound 6 can be synthesized and employed
in this reaction to give a modified natural product with a

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Sun et al. Sci China Chem
Scheme 3 Gram-scale synthesis (color online).
Scheme 6 Proposed mechanism (color online).
sertion of alkynyl group. After protonation of C, the
compound D is formed and the catalyst Cu(I) can be gen-
erated for the next catalytic round. In the presence of TEA, D
can be converted into the intermediate E, which reacts with
the sulfonyl anion generated from 3a, affording the desired
product 4a. It is noted that the excellent stereoselectivity of
the vinyl sulfones can be obtained in the reaction perhaps due
to the steric effect between the sulfonyl group and the phenyl
group of the alkyne, which was also supported by the NOE
spectrum of 5f, as shown in Supporting Information online.
In order to confirm this advantage, methyl 2-diazopropano-
ate and benzyl 2-diazopropanoate were employed in the re-
action. Both 5j and 5k can be obtained with E-configuration.
This stereoselctivity only was dependent to the structures of
the sulfonyl hydrazide and the alkyne regardless of the re-
action conditions.
Scheme 4 Product modifcation. The reaction was carried out with 1a
(0.2 mmol), 6 (2.0 equiv.), 3a (2.0 equiv.), CuI (10 mol%), TEA (3.0
equiv.) in DCM (1 mL) under room temperature (color online).
4 Conclusions
Scheme 5 Control experiments. TsNa=sodium p-toluenesulfinate; TEM-
PO=2,2,6,6-tetramethylpiperidine-1-oxyl; BHT=tert-butylhydroxy-toluene.
In summary, a copper-catalyzed three-component reaction
was developed to realize 1,1-difunctionalization of the
terminal alkynes under mild condition. A series of α, β-dis-
ubstituted vinyl sulfones can be obtained with good yields
and excellent chem- and stereoselectivity. This developed
method features the tolerance of various functional groups,
mild conditions and gram-scale operation. The investigation
of the mechanism revealed that the reaction involved the
copper carbene migration insertion to the terminal alkynes
and the sulfonyl anion addition to the allenyl compound E.
Moreover, the modification of steroidal drugs presents a
great potential in pharmaceutical industry. Further in-
vestigation on mechanistic details and synthetic applications
is ongoing in our laboratory.
(Scheme 5(b)) while compound E gave 4a with a yield of
57% under the same condition (Scheme 5(e)). In the absence
of TEA, however, the reaction did not work (Scheme 5(c)).
In order to detect the possible intermediate in this reaction,
we employed D to react with TEA for 2 h, and then TsNa was
added to this mixture. It was found that the product 4a can be
obtained with a yield of 48% (Scheme 5(d)). This implied
that D should be converted to E instantly in the presence of
TEA. Subsequently E was consumed with the time going to
afford the desired product. Finally, E was identified as the
real intermediate in the reaction based on the above experi-
ment results.
According to the above-mentioned and previous reports
[24, 41–48], a possible mechanism was proposed and de-
picted in Scheme 6. First, copper iodide reacts with pheny-
lacetylene 1a to form the copper acetylide A. Then diazo 2a
reacts with A to afford the copper carbenoid B, and the in-
termediate C is formed from the subsequent migration in-
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21432009, 21672200, 21472177, 21772185,
21801233), and the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000). Thanks for the assistance of the
product characterization from the Chemistry Experiment Teaching Center of
University of Science and Technology of China.

5
Sun et al. Sci China Chem
Conflict of interest The authors declare that they have no conflict of
interest.
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