Silver-catalyzed synthesis of 1-chloroalkynes directly from terminal alkynes

Article abstract of DOI:10.1002/cctc.201500243

An efficient method to prepare 1-chloroalkynes was investigated. The method involved the use of readily available terminal alkynes and a catalytic amount of a silver salt with N-chlorosuccinimide as the chlorinating agent under mild conditions. Compared with the existing process, this method has a broad substrate scope: 19 examples were explored, and the products were obtained in excellent yields and were easily isolated by vacuum distillation. Moreover, recycling of the catalyst was achieved by simple filtration and desiccation, which made the method more economic and environmentally benign.

Full text of DOI:10.1002/cctc.201500243

DOI: 10.1002/cctc.201500243
Communications
Silver-Catalyzed Synthesis of 1-Chloroalkynes Directly
from Terminal Alkynes
Dunfa Shi, Zhiwen Liu, Ziyu Zhang, Wei Shi,* and Hao Chen*[a]
An efficient method to prepare 1-chloroalkynes was investigat-
ed. The method involved the use of readily available terminal
alkynes and a catalytic amount of a silver salt with N-chloro-
succinimide as the chlorinating agent under mild conditions.
Compared with the existing process, this method has a broad
substrate scope: 19 examples were explored, and the products
were obtained in excellent yields and were easily isolated by
vacuum distillation. Moreover, recycling of the catalyst was
achieved by simple filtration and desiccation, which made the
method more economic and environmentally benign.
transfer catalysts.[11] Recently, Liang and Jin et al. reported the
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-accelerated chlorina-
tion of terminal alkynes by using N-chlorophthalimide (NCP),[12]
but only aryl alkynes were formed, and the authors proved
that NCS did not work in this process. Waser et al. have used
the AgOAc/NCS system to obtain 1-chloroalkynes,[13] but only
one example (1-chlorooct-1-yne) was presented, and aryl al-
kynes were not included in this method.
Despite all of these methods mentioned above, there is still
a lack of a versatile method for the easy preparation of various
types of 1-chloroalkynes directly from terminal alkynes. Herein,
we wish to report a simple and efficient method to prepare 1-
chloroalkynes with a broad substrate scope.
1-Haloalkynes are important building blocks in organic chemis-
try.[1] Owing to their CꢀC bonds and CÀX bonds, they show
both nucleophilic and electrophilic properties and undergo
a series of reactions including coupling reactions,[2] nucleophil-
ic addition reactions,[3] and cycloadditions.[4] According to the
different halogen atoms, there are three types of haloalkynes:
chloroalkynes, bromoalkynes, and iodoalkynes. Bromoalkynes
and iodoalkynes have better reactivity in most cross-coupling
reactions, but their relative instability[5] has restricted their ap-
plications. Chloroalkynes, however, exhibit the best stability
with the least potential cost and toxicity.[5] Although the prepa-
rations of 1-iodoalkynes and 1-bromoalkynes are well known,
methods for the synthesis of 1-chloroalkynes are still far from
perfect.
The initial step of the chlorination is the activation of the
terminal alkynes. Common activating reagents include strong
bases such as organolithium and Grignard reagents or transi-
tion-metal salts such as CuI or AgI complexes. One challenge in
the chlorination of terminal alkynes is the formation of 1,3-
diyne byproducts from the homocoupling of the terminal al-
kynes under the oxidative atmosphere.[14] According to Lei’s
report, the use of silver carbonate in reactions involving termi-
nal alkynes could avoid the generation of diynes.[15] This indi-
cated to us that silver carbonate may be a good catalyst in the
chlorination of terminal alkynes, and thus we performed our
preliminary explorations with the use of silver carbonate.
Table 1 lists our initial investigations and proves the advantage
of using silver carbonate. Copper(I) salts led to the formation
One method to prepare 1-chloroalkynes involves the use of
alkynylsilanes with electron-withdrawing substituents, as Niel-
sen[5,6] and Szafert[7] reported. However, alkynylsilanes are ex-
pensive and the low atom efficiency of this process has limited
its application. The direct chlorination of terminal alkynes
would be the best choice. Verboom et al. treated terminal al-
kynes with n-butyllithium (nBuLi) to form lithium acetylenides,
which were then treated with N-chlorosuccinimide (NCS) to
form 1-chloroalkynes.[8] This represents the classical method to
prepare 1-chloroalkynes: deprotonation of a terminal alkyne
with a strong base such as nBuLi, followed by treatment with
an appropriate chlorinating agent. The use of nBuLi has limited
the application of this method. Other protocols include the
chlorination of terminal alkynes by using hypochlorites,[9] CCl4/
K2CO3/tetrabutylammonium fluoride (TBAF),[10] or other phase-
Table 1. Screening of the reaction conditions.[a]
Entry
Cat. (equiv.)
K2CO3 [equiv.]
T [8C]
Yield[b] [%]
2a
3a
1
2
3
4
5
6
7
8
none
CuCl (1.0)
AgNO3 (1.0)
AgBr (1.0)
Ag2CO3 (0.5)
Ag2CO3 (0.3)
Ag2CO3 (0.1)
Ag2CO3 (0.1)
Ag2CO3 (0.05)
Ag2CO3 (0.1)
Ag2CO3 (0.1)
Ag2CO3 (0.1)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
–
50
50
50
50
50
50
50
50
50
50
RT
60
0
64
83
70
92
94
77
95
70
39
87
78
0
33
0
0
0
0
0
0
0
9
[a] D. Shi, Z. Liu, Z. Zhang, Dr. W. Shi, Prof. H. Chen
College of Science
10
11
12
0
0
0
0.5
0.5
Huazhong Agricultural University
Wuhan (P.R. China)
[a] Reaction conditions: 1a (1 mmol), NCS (2.0 mmol), K2CO3, PrOH (2 mL),
Ar. For entries 1–7, the reaction time was 2.5 h; for entries 8–12, the reac-
tion time was 4 h. [b] Determined by GC by using 1,1’-biphenyl as the in-
ternal standard.
E-mail: shiwei@mail.hzau.edu.cn
hchenhao@mail.hzau.edu.cn
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500243.
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Communications
of a considerable amount of diyne (33%; Table 1, entry 2). The
use of silver carbonate, however, significantly improved the ef-
ficiency of the chlorination and the homocoupled diynes were
not formed (Table 1, entries 5–12). A temperature of 508C was
high enough to effect the chlorination, whereas any increase
in the temperature caused a slight decrease in the product
yield (Table 1, entry 12). The base was also crucial to this reac-
tion (Table 1, entry 10), and potassium carbonate performed
well in this transformation.
Scheme 1. Cross-coupling of 1-chloroalkynes with terminal alkynes.
ered by simple filtration, which made our process more eco-
nomic and environmentally benign.
We then applied this method towards the synthesis of vari-
ous 1-chloroalkynes. The results are shown in Table 2. Alkynes
substituted with either electron-donating or electron-with-
drawing groups were good substrates for this method. Satis-
Furthermore, we also tested the reactivity of 1-chloroalkynes
in Pd-catalyzed cross-coupling reactions with terminal al-
kynes.[16] Details of this reaction are illustrated in Scheme 1. By
using Pd2(dba)3 (dba=dibenzylideneacetone) as the catalyst
and CuI as the co-catalyst, 2a underwent cross-coupling
with 2-methyl-3-butyn-2-ol smoothly to give diyne prod-
uct 3a in excellent yield. This discovery shows that 1-
chloroalkynes may also be good substrates in Pd-cata-
lyzed coupling reactions.
Table 2. Substrate scope of various alkynes.[a]
In conclusion, an efficient and simple method for the
synthesis of 1-chloroalkynes directly from terminal alkynes
was explored. High yields were achieved for various types
of alkynes with a catalytic amount of silver carbonate as
the catalyst. The catalyst was easily recovered and reused,
which made the method more attractive.
Entry
1
1
2
t [h] Yield[b] [%]
1a
2a
4
93
2
3
4
5
6
7
8
9
10
11
12
13
14
1b R’=2-F
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
4
6
4
4
8
8
6
6
8
4
6
6
6
86
93
91
94
91
80
90
88
88
96
92
92
92
1c R’=4-nBu
1d R’=4-Et
1e R’=4-Me
1 f R’=4-OMe
1g R’=4-OEt
1h R’=4-Br
1i R’=4-F
1j R’=4-CN
1k R’=4-(4-EtC6H4)
1l R’=3-Br
1m R’=3-Cl
1n R’=3-Me
Experimental Section
General procedure for the synthesis of chlorinated al-
kynes
A dry reaction tube was charged with K2CO3 (1 mmol), NCS
(4 mmol), and Ag2CO3 (0.2 mmol). The tube was sealed, evacu-
ated, and backfilled with argon (3”). Then n-propanol (4 mL)
and the terminal alkyne (2 mmol) were added to the system,
and the mixture was stirred at 508C for a period of time. The
mixture was allowed to cool to room temperature, and brine
was then added at 08C. The resulting mixture was extracted
with ethyl ether (3”), and the combined organic phase was
washed with a large amount of water and dried with sodium
sulfate. The solvent was removed under reduced pressure and
purified by column chromatography on silica gel to give the
product.
15
16
17
1o R’’=H
1p R’’=OEt
1q R’’=F
2o
2p
2q
4
4
4
95
87
93
18
1r
2r 20 86
19
1s
2s 20 74
Acknowledgements
[a] Reactions were performed with 2 mmol of 1. [b] Yield of the isolated prod-
uct.
This work was supported by the National Natural Science
Foundation of China (NSFC) (21202050) and the Natural Sci-
ence Foundation of Hubei Province of China (2014CFB930).
factory results were achieved from both aliphatic alkynes and
aromatic alkynes. Notably, terminal 1,3-diynes were also good
substrates, and the products were isolated in 87–95% yield
(Table 2, entries 15–17).
Keywords: alkynes · 1-chloroalkynes · chlorination · silver ·
sustainable chemistry
Notably, the silver catalyst could be recycled just by simple
filtration under reduced pressure. The recycled catalyst was
then washed with water, dried under vacuum, and then reused
for the next chlorination, although with a slight loss in catalytic
activity (62% yield for the generation of 2a). During our inves-
tigation, more than 95% of the silver catalyst could be recov-
[1] a) Z. Lu, H. Liang, X. Pan, Guangdong Huagong 2010, 37, 76–77; b) W.
Wu, H. Jiang, Acc. Chem. Res. 2014, 47, 2483–2504; c) J. P. Brand, J.
Waser, Chem. Soc. Rev. 2012, 41, 4165–4179.
[2] a) L. Cornelissen, M. Lefrancq, O. Riant, Org. Lett. 2014, 16, 3024–3027;
b) M. A. Christensen, M. Rimmen, M. B. Nielsen, Synlett 2013, 24, 2715–
2719; c) Y. Wen, H. Jiang, Huaxue Xuebao 2012, 70, 1716–1720; d) X.
Chen, D. Chen, Z. Lu, L. Kong, G. Zhu, J. Org. Chem. 2011, 76, 6338–
ChemCatChem 2015, 7, 1424 – 1426
www.chemcatchem.org
1425
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
6343; e) D. Chen, Y. Cao, Z. Yuan, H. Cai, R. Zheng, L. Kong, G. Zhu, J.
Org. Chem. 2011, 76, 4071–4074; f) Z. Chen, H. Jiang, A. Wang, S. Yang,
J. Org. Chem. 2010, 75, 6700–6703; g) C. Laroche, J. Li, M. W. Freyer,
S. M. Kerwin, J. Org. Chem. 2008, 73, 6462–6465.
[10] a) Y. Sasson, O. W. Webster, J. Chem. Soc. Chem. Commun. 1992, 1200–
1201; b) Y. Taniguchi, T. Sakaguchi, M. Shiotsuki, F. Sanda, T. Masuda,
Macromolecules 2006, 39, 243–248.
[11] E. Abele, M. Fleisher, K. Rubina, R. Abele, E. Lukevics, J. Mol. Catal. A
2001, 165, 121–126.
[12] M. Li, Y. Li, B. Zhao, F. Liang, L.-Y. Jin, RSC Adv. 2014, 4, 30046–30049.
[13] S. Nicolai, R. Sedigh-Zadeh, J. Waser, J. Org. Chem. 2013, 78, 3783–
3801.
[14] W. Shi, A. Lei, Tetrahedron Lett. 2014, 55, 2763–2772.
[15] a) T. Wang, S. Chen, A. Shao, M. Gao, Y. Huang, A. Lei, Org. Lett. 2015,
17, 118–121; b) J. Ke, C. He, H. Liu, M. Li, A. Lei, Chem. Commun. 2013,
49, 7549–7551; c) C. He, J. Hao, H. Xu, Y. Mo, H. Liu, J. Han, A. Lei,
Chem. Commun. 2012, 48, 11073–11075; d) C. He, S. Guo, J. Ke, J. Hao,
H. Xu, H. Chen, A. Lei, J. Am. Chem. Soc. 2012, 134, 5766–5769; e) M.
Gao, C. He, H. Chen, R. Bai, B. Cheng, A. Lei, Angew. Chem. Int. Ed. 2013,
52, 6958–6961; Angew. Chem. 2013, 125, 7096–7099.
[16] a) Y. Weng, B. Cheng, C. He, A. Lei, Angew. Chem. Int. Ed. 2012, 51,
9547–9551; Angew. Chem. 2012, 124, 9685–9689; b) W. Shi, Y. D. Luo,
X. C. Luo, L. Chao, H. Zhang, J. Wang, A. W. Lei, J. Am. Chem. Soc. 2008,
130, 14713–14720.
[3] a) W. Zeng, W. Wu, H. Jiang, Y. Sun, Z. Chen, Tetrahedron Lett. 2013, 54,
4605–4609; b) M. Yamagishi, J. Okazaki, K. Nishigai, T. Hata, H. Urabe,
Org. Lett. 2012, 14, 34–37; c) Y. Li, X. Liu, H. Jiang, Z. Feng, Angew.
Chem. Int. Ed. 2010, 49, 3338–3341; Angew. Chem. 2010, 122, 3410–
3413.
[4] a) E. Rasolofonjatovo, S. Theeramunkong, A. Bouriaud, S. Kolodych, M.
Chaumontet, F. Taran, Org. Lett. 2013, 15, 4698–4701; b) T. Ohmura, A.
Kijima, Y. Komori, M. Suginome, Org. Lett. 2013, 15, 3510–3513; c) T. De-
launay, P. Genix, M. Es-Sayed, J.-P. Vors, N. Monteiro, G. Balme, Org. Lett.
2010, 12, 3328–3331.
[5] M. H. Vilhelmsen, A. S. Andersson, M. B. Nielsen, Synthesis 2009, 1469–
1472.
[6] M. H. Vilhelmsen, A. S. Andersson, M. B. Nielsen, Synthesis 2012, 44, 158.
[7] N. Gulia, B. Pigulski, M. Charewicz, S. Szafert, Chem. Eur. J. 2014, 20,
2746–2749.
[8] W. Verboom, H. Westmijze, L. J. De Noten, P. Vermeer, H. J. T. Bos, Syn-
thesis 1979, 296–297.
[9] T. B. Poulsen, L. Bernardi, J. Aleman, J. Overgaard, K. A. Jorgensen, J.
Am. Chem. Soc. 2007, 129, 441–449.
Received: March 6, 2015
Revised: March 14, 2015
Published online on April 15, 2015
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