A Copper-Catalyzed Sonogashira Coupling Reaction of Diverse Activated Alkyl Halides with Terminal Alkynes Under Ambient Conditions

Article abstract of DOI:10.1002/adsc.202000189

We describe a copper-catalyzed Sonogashira coupling reaction of alkyl halides with terminal alkynes under ambient conditions, efficiently providing a versatile tool for the construction of substituted alkynes. A new proline-based N,N,P-ligand is utilized to promote the transformation under a mild reaction condition. Diverse alkyl halides, such as primary and secondary (hetero)benzyl chlorides and bromides, secondary and tertiary α-bromo amides and propargylic bromide, are applicable to provide a wide array of alkynes. (Figure presented.).

Full text of DOI:10.1002/adsc.202000189

Title: A Copper-Catalyzed Sonogashira Coupling Reaction of Diverse
Activated Alkyl Halides with Terminal Alkynes Under Ambient
Conditions
Authors: Yu-Xi Cao, Xiao-Yang Dong, Jun Yang, Sheng-Peng Jiang,
Shuangliu Zhou, Zhong-Liang Li, Guo-Qiang Chen, and Xin-
Yuan Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000189
Link to VoR: https://doi.org/10.1002/adsc.202000189

10.1002/adsc.202000189
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Copper-Catalyzed Sonogashira Coupling Reaction of Diverse
Activated Alkyl Halides with Terminal Alkynes Under Ambient
Conditions
Yu-Xi Cao,a Xiao-Yang Dong,b Jun Yang,b,d Sheng-Peng Jiang,b Shuangliu Zhou,d
Zhong-Liang Li,c,* Guo-Qiang Chen,a,* and Xin-Yuan Liub,*
a
College of Chemistry and Environmental Engineering, Shenzhen University, 1066 Xueyuan Road, Shenzhen, China
Fax: +86-755-26536141
E-mail: gqchen@szu.edu.cn
Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalytic
b
Chemistry, Southern University of Science and Technology, Shenzhen, 518055, China
Fax: +86-755-88018314
E-mail: liuxy3@sustech.edu.cn
Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and
c
Technology, Shenzhen, 518055, China
Fax: +86-755-88018314
E-mail: lizl@sustech.edu.cn
College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, China.
d
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
alkynes are less developed. Several challenges are
associated with this transformation, such as the
difficult oxidative addition of alkyl halides and the
easily occurred -hydrogen elimination of metalalkyl
intermediates.[4] Thus, there are only limited reports on
the successful Sonogashira reaction of alkyl halides
which bear a -hydrogen. In this aspect, the groups of
Fu and Glorius have pioneered this field by
demonstrating the coupling reaction of such alkyl
halides using a palladium/copper cocatalyst and a N-
heterocyclic carbene ligand (Scheme 1a).[4a, 5] Later,
Hu[6] and Liu[7] independently introduced the
nickel/copper-cocatalyzed Sonogashira reaction of
such substrates employing pincer and pyridine
bisoxazoline ligand in their strategy, respectively
(Scheme 1a). Notably, these early Sonogashira
reactions require an additional transition metal catalyst
(Pd or Ni) along with the copper catalyst. Therefore,
the utilization of copper as a sole catalyst in
Sonogashira coupling reaction of alkyl halides, a more
appealing and economic strategy, represents an
impress advance in organic synthesis.[8] Unfortunately,
copper also catalyzes the Glaser homocoupling of
terminal alkynes[9] and always leads to lower yields of
the desired cross coupling products, further impeding
the methodology development.
Abstract. We describe a copper-catalyzed Sonogashira
coupling reaction of alkyl halides with terminal alkynes
under ambient conditions, efficiently providing a
versatile tool for the construction of substituted alkynes.
A new proline-based N,N,P-ligand is utilized to promote
the transformation under a mild reaction condition.
Diverse alkyl halides, such as primary and secondary
(hetero)benzyl chlorides and bromides, secondary and
tertiary -bromo amides and propargylic bromide, are
applicable to provide a wide array of alkynes.
Keywords: copper catalysis; Sonogashira coupling
reaction; alkyl halides; proline-based N,N,P-ligand;
ambient conditions
Alkynes are versatile intermediates and precursors in
organic synthesis and structural motifs in many natural
products, bioactive molecules and functional
materials.[1] Therefore, the straightforward assembly
of alkynes has attracted much interest from organic
chemists.[1] Among numerous strategies for the
synthesis of alkynes, transition metal-catalyzed
Sonogashira coupling reaction has evolved into one of
the most prevalent tools during to the wide substrate
scope and broad functional group tolerance.[2] While
the synthesis of aryl/vinyl alkynes from aryl/vinyl
(pseudo)halides and terminal alkynes has been well
documented utilizing the palladium-copper co-
catalysis[2c, 3] or the copper catalysis[2d], the synthesis
of alkyl alkynes from alkyl halides and terminal
In this field, two early reports on copper-catalyzed
Sonogashira coupling of activated - and -
haloamides were disclosed by Shi and Nishikata,
respectively (Scheme 1b).[10] To extend the scope of
alkyl halides, Lalic and co-workers developed a
copper-catalyzed coupling of alkyl iodides, wherein a
1
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10.1002/adsc.202000189
Advanced Synthesis & Catalysis
blue LED had to be used to initiate the reaction
(Scheme 1c).[11] Very recently, Jin and co-workers
accomplished a general copper-catalyzed Sonogashira
coupling of benzyl bromides with terminal alkynes
(Scheme 1c).[12] In Jin’s strategy, only benzyl
bromides were applicable and high temperature
together with a strong base (LiHMDS) was necessary
to reach a good reaction efficiency. Based on these
proline-derived N,N,P-ligand L9 gave rise to the
desired coupling product 3a with the best results at
ambient conditions (entries 8 and 9 in Table 1). Further
screening of the reaction solvent, base and copper salt
(entries 1017 in Table 1) led us to identify the best
reaction conditions as follows: the reaction of 1a and
1.5 equivalents 2a in the presence of 10 mol% CuOAc,
12 mol% L9, 2.0 equivalents of Cs2CO3 in Et2O
delivered 3a in 94% NMR yield under ambient
conditions (entry 16 in Table 1).[15] The control
experiment showed that no product was formed in the
absence of L9.
facts,
a
general and gentle copper-catalyzed
Sonogashira coupling of diverse alkyl halides to forge
the C(sp3)C(sp) bond at ambient conditions is still
desirable. Our group has recently realized a radical
asymmetric Sonogashira reaction of secondary alkyl
halides, during which we found that the use of a chiral
cinchona alkaloid-based N,N,P-ligand is crucial to the
transformation and results in a very mild reaction
condition.[13] As our continuous research interest in
developing novel ligands to promote the copper-
catalyzed radical reactions,[13, 14] we herein report a
copper-catalyzed Sonogashira coupling of alkyl
halides with terminal alkynes. One representative
feature of this strategy is the utilization of a unique
proline-based N,N,P-ligand to promote the reaction
under a very mild condition. Diverse alkyl halides are
applicable to this transformation, such as primary and
secondary benzyl chlorides and bromides, propargylic
bromide and secondary and tertiary -bromo amides
to efficiently provide a wide range of alkynes.
Table 1. Screening of reaction conditions[a,b]
Entry Cu salt Ligand
Base
Solvent Yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuOAc
CuCN
CuOAc
Cs2CO3 dioxane 20%
Cs2CO3 dioxane 15%
Cs2CO3 dioxane 22%
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L9
L9
L9
L9
L9
-
Cs2CO3 dioxane
3%
Cs2CO3 dioxane 37%
Cs2CO3 dioxane
Cs2CO3 dioxane
0
7%
Cs2CO3 dioxane 22%
Cs2CO3 dioxane 81%
Cs2CO3
Cs2CO3 CH2Cl2
THF
78%
0
Cs2CO3
tBuOK
K2CO3
LiOH
Cs2CO3
Cs2CO3
Cs2CO3
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
82%
0
37%
0
94%
41%
0
Scheme 1. Sonogashira coupling of alkyl halides.
We initiated our hypothesis by examining the cross
coupling reaction of (1-bromoethyl)benzene (1a) with
phenylacetylene (2a) in 1,4-dioxane in the presence of
10 mol% CuI and 2 equivalents of Cs2CO3 (Table 1).
We systematically screened various types of
commercially available mono-, bi- and tri-dentate
ligands (L1-L9). The results showed that mono- and
di-phos ligands provided the desired product in very
low yields (entries 1 and 2 in Table 1). The widely used
bi-and tri-pyridine ligands were also not ideal ligands
to enhance the reactivity (entries 37 in Table 1).
Screening of the N,N,P-ligands revealed that the
[a] All the reactions were conducted on a 0.05 mmol scale. [b]
Yields were determined by H NMR using CH2Br2 as an
1
internal standard.
Having established the optimal condition, we next
investigated the substrate scope of alkyl halides. As
shown in Table 2a, a variety of secondary benzyl
bromides can be successfully coupled with
2
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10.1002/adsc.202000189
Advanced Synthesis & Catalysis
[a]
phenylacetylene 2a under the standard conditions to
afford the coupling products 3a3j in 5190% yields.
Substrates with electron-withdrawing groups, such as
the CF3 group at para-, meta-, and ortho-positions all
participated in the cross coupling reaction to provide
3b3d in good yields, though the ortho-substituted
substrates provided a relatively lower yield of product.
The cyano group can also be tolerated under the
coupling conditions to give rise to 3e in 73% yield. The
halogen (F, Cl, I)-substituted benzyl bromides reacted
smoothly to provide the desired products 3f3i in good
yields. The electron-donating group on the phenyl ring
is also compatible with the standard conditions to
deliver 3j in 83% yield. In addition, the 1- and 2-
naphthyl bromides both underwent the cross coupling
reaction smoothly to afford 3k and 3l in 65% and 78%
yield, respectively. The aliphatic chain of benzyl
bromides is not limited to methyl group, as can be
viewed by the formation of 3m and 3n. The alkyl
Reaction conditions: 1 (0.50 mmol), 2a (0.75 mmol),
CuOAc (10 mol%), L9 (12 mol%), and Cs2CO3 (1.0 mmol)
in Et2O (2.0 mL). The yield is isolated.
Encouraged by the above results, we then switched
our attention to the terminal alkynes (Table 3). As such,
substrates bearing diverse substituents on the phenyl
ring of alkynes reacted well to give the products 3t3w
in good yields. Besides, heteroaryl alkynes were also
applicable to the standard coupling conditions, which
can be proved by the formation of 3x from the reaction
of thiophene-type alkynes. Notably, aliphatic alkynes
were also tolerable to generate 3y and 3z, albeit with
relatively low yields.
Table 3. Scope of terminal alkynes.[a]
bromide containing
a
heterocycle, such as
benzo[b]furan, worked well to provide 3o in 60% yield.
Moreover, the primary and tertiary bromides were also
suitable to deliver the coupling products 3p and 3q.
More significantly, the coupling reaction is also
applicable to other type of alkyl bromides. As such, the
-bromo amide coupled successfully with
phenylacetylene under the standard conditions to
generate the -alkynylated amide 3r in 56% yield. The
propargylic bromide underwent the coupling reaction
smoothly to afford the target product 3s in 64% yield.
Moreover, the benzyl chloride was also amenable to
the reaction to afford 3a in a comparable yield with the
bromide counterpart (Table 2b).
[a]
Reaction conditions: 1a (0.50 mmol), 2 (0.75 mmol),
CuOAc (10 mol%), L9 (12 mol%), and Cs2CO3 (1.0 mmol)
in Et2O (2.0 mL). The yield is isolated.
Table 2. Substrate scope of alkyl halides.[a]
To gain some insight into the reaction mechanism,
we carried out the control experiments (Scheme 2a).
The reaction of 1a and 2a was completely inhibited by
the addition of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or p-benzoquinone. Furthermore, the
enantioenriched 1a delivered the alkyne 3a with very
low ee under the standard conditions (Table 2b). These
results suggested that radical intermediates might be
involved in the process. Based on the experimental
16]
results and previous reports,[13
we proposed a
,
plausible mechanism as depicted in Scheme 2c. A
single electron transfer process occurred between the
in situ generated copper(I) acetylide complex and alkyl
halides 1 to generate the copper(II) complex II and the
alkyl radical intermediates III. The subsequent
coupling of the complex II and III provided the
coupling products 3 and regenerated the CuIL complex
for next catalytic cycle.
3
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10.1002/adsc.202000189
Advanced Synthesis & Catalysis
Education of Guangdong, China (2017KQNCX174), Shenzhen
Special Funds for the Development of Biomedicine, Internet, New
Energy, and New Material Industries (JCYJ20170412152435366,
JCYJ20180302180235837), Research Start-Up Funding of SZU
(8530300000137 and 860000002110230), Shenzhen Nobel Prize
Scientists Laboratory Project (C17783101), SUSTech Special
Fund for the Construction of High-Level Universities
(G02216303).
References
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Scheme 2. Mechanistic investigation and plausible
mechanism.
In conclusion, we have developed a mild copper-
catalyzed Sonogashira reaction of alkyl halides and
terminal alkynes. Owing to the utilization of a novel
proline-based N,N,P-ligand, the cross coupling
reaction is accomplished under ambient conditions. A
wide range of alkyl halides, such as primary and
secondary (hetero)benzyl chlorides and bromides,
secondary and tertiary -bromo amides and
propargylic bromide were suitable to the strategy, thus
providing diverse alkynes in good efficiency.
Mechanistic study revealed that the reaction might
proceed via a free radical process.
[5] G. Altenhoff, S. Würtz, F. Glorius, Tetrahedron Lett.
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Experimental Section
General Procedure for Sonogashira coupling of all
substrates: To a 10-mL Schlenk tube was added CuOAc
(6.0 mg, 0.05 mmol), L9 (23 mg, 0.06 mmol), Cs2CO3 (325
mg, 1.0 mmol), and anhydrous Et2O (2.0 mL). Aryl bromide
1 (0.50 mmol) and alkyne 2 (0.75 mmol) were sequentially
added into the mixture. The reaction mixture was stirred at
room temperature for 20 h. After completion of the reaction,
the precipitate was filtered off and concentrated in vacuo.
The residue was purified by flash column chromatography
on silica gel with petro ether to afford 3.
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Y. Fu, H.-J. Xu, Org. Lett. 2015, 17, 3682-3685.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21722203, 21831002, and 21801116),
Guangdong Provincial Key Laboratory of Catalysis (No.
2020B121201002),
Guangdong
Innovative
Program
(2019BT02Y335), Guangdong Natural Science Foundation
(2018A030310083), Distinguished Young Talents in Higher
4
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10.1002/adsc.202000189
Advanced Synthesis & Catalysis
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[15] A preliminary trial with (S)-L9 as the ligand under
otherwise identical conditions gave 3a in less than 5%
ee, indicating that the proline-based N,N,P-ligand might
not be a potent chiral ligand for the asymmetric
Sonogashira reaction at the current stage. See details in
the Supporting Information.
[16] F. Wang, P. Chen, G. Liu, Acc. Chem. Res. 2018, 51,
2036-2046.
5
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10.1002/adsc.202000189
Advanced Synthesis & Catalysis
UPDATE
A
Copper-Catalyzed Sonogashira Coupling
Reaction of Diverse Activated Alkyl Halides with
Terminal Alkynes Under Ambient Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Yu-Xi Cao, Xiao-Yang Dong, Jun Yang, Sheng-
Peng Jiang, Shuangliu Zhou, Zhong-Liang Li*,
Guo-Qiang Chen,* and Xin-Yuan Liu*
6
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