Catalyst-free hydrochlorination protocol for terminal arylalkynes with hydrogen chloride

Article abstract of DOI:10.1016/j.cclet.2016.04.019

We present a simple and straightforward protocol for hydrochlorination of terminal arylalkynes to vinyl chlorides using hydrogen chloride under mild reaction conditions. This protocol does not involve any metal catalysts or additives. It is simple, inexpensive, and easy to prepare, and exhibits good reaction activity. The hydrochlorination proceeds smoothly to yield unique regioselective products via the Markovnikov addition rule.

Full text of DOI:10.1016/j.cclet.2016.04.019

G Model
CCLET 3683 1–3
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Catalyst-free hydrochlorination protocol for terminal arylalkynes with
hydrogen chloride
*
Q1 Cai-Xia Xu, Cun-Hua Ma, Fu-Rong Xiao, Hong-Wei Chen, Bin Dai
5
6
7
School of Chemistry and Chemical Engineering, Shihezi University/Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi,
832003, China
A R T I C L E I N F O
A B S T R A C T
Article history:
We present a simple and straightforward protocol for hydrochlorination of terminal arylalkynes to vinyl
chlorides using hydrogen chloride under mild reaction conditions. This protocol does not involve any
metal catalysts or additives. It is simple, inexpensive, and easy to prepare, and exhibits good reaction
activity. The hydrochlorination proceeds smoothly to yield unique regioselective products via the
Markovnikov addition rule.
Received 18 February 2016
Received in revised form 19 April 2016
Accepted 27 April 2016
Available online xxx
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Hydrochlorination
Arylalkynes
Vinyl chlorides
Catalyst-free
Markovnikov addition
8
9
1. Introduction
hydrochlorination in excellent yields, which presented a powerful 31
tool for producing vinyl chlorides [21]. However, most reported 32
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Vinyl chlorides are one of the most important intermediates in
organic synthesis, which have been extensively used as important
building blocks for natural and synthetic products with biological
activities [1,2] and also to construct carbon–carbon and carbon–
heteroatom bonds through cross-coupling reactions [3–7]. Over
the past decades, tremendous efforts have been devoted to the
synthesis of vinyl chlorides, commonly from ketones [8–11] and/
or alkynes [12–14]. However, stoichiometric phosphorous
reagents [8,9] or acyl chlorides [10,11] are required to react with
ketones to produce vinyl chlorides. Alkynes react with reagents
that contain chlorine [13–16], such as acyl chlorides, LiCl, TMSCl,
and MgCl2, to form vinyl chlorides in one step or with boron
reagents [17,18] and Al reagent [19] to form vinyl chlorides in two
or three steps. In addition, these protocols have disadvantages
such as significant waste generation and less efficient multi-step
sequences. Based on our continuous interest in the field of
alkyne chemistry [20], we recently developed interest in alkyne
hydrochlorination, which involves simply adding HCl to the
alkyne with 100% atom efficiency and is regarded as a direct and
efficient method for producing vinyl chlorides. Very recently,
Derien reported the Ru-catalyzed direct and selective alkyne
hydrochlorinations of alkynes have focused on acetylene [22,23] 33
and hydrochlorination of arylalkynes has received very little 34
attention [21,24–30]. Several methods require catalysts [21,25] or 35
additives [29,30] (e.g. PtCl2 or Al2O3) to promote the hydro- 36
chlorination. Others focus more on the kinetics and mechanism 37
and have not achieved products in synthetically useful yields 38
because of poor selectivity or low conversion [26–28]. Hence, 39
hydrochlorination of terminal arylalkynes in the absence of any 40
additives or catalysts has not been studied well. Herein, we report 41
a mild, straightforward, highly regioselective, and catalyst-free 42
method for the synthesis of vinyl chlorides through hydrochlor- 43
ination of arylalkynes with HCl.
44
2. Experimental
45
The melting points were determined using a WRS-2 apparatus. 46
The IR spectra were recorded on an Avatar 360 FT-IR spectrometer. 47
The 1H (400 MHz) and 13C (100 MHz) NMR spectra of the samples 48
were recorded on an AVANCE III HD 400 spectrometer and 49
calibrated to the residual solvent signals or the internal standard 50
signal. MS (EI, 70 eV) experiments were performed on an Agilent 51
5973 N or GCT spectrometer. HRMS (EI) experiments were 52
performed on a Waters Micromass GCT spectrometer. Synthesis 53
of arylalkynes 1i–1k and the spectral data and spectra of all 54
*
Corresponding author.
compounds are given in Supporting information.
55
E-mail address: db_tea@shzu.edu.cn (B. Dai).
http://dx.doi.org/10.1016/j.cclet.2016.04.019
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: C.-X. Xu, et al., Catalyst-free hydrochlorination protocol for terminal arylalkynes with hydrogen
chloride, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.019

G Model
CCLET 3683 1–3
2
C.-X. Xu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Table 1
56
57
58
59
60
61
62
63
64
General procedure for hydrochlorination: The arylalkyne 1,
acetic anhydride (Ac2O), and an anhydrous solvent were added to a
dried three-necked flask under argon atmosphere and the mixture
was stirred for 30 min at room temperature. Further, HCl(g)
prepared using H2SO4 and NaCl at 160 8C was added to the mixture
through the rubber tube until the starting material conversed
completely, monitored by TLC, and the unreacted HCl(g) was
absorbed by aqueous NaOH. The solvent was removed and the
residue was purified using flash chromatography on a silica gel.
Optimization of the reaction conditions.a
Entry
Temperature
Solvent
Time (h)
Yield (%) of 2ab
1
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0 8C
60 8C
r.t.
r.t.
Ethyl acetate
CH2Cl2
DMF
5.3
10
2
–
2
–
3
Complicated
4
CH3OH
Benzene
THF
2.3
2.4
5
5
5
40
65
3. Results and discussion
6
40
7
AcOH
1.6
1.8
1.3
2.5
2
70
8
CH3CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
70
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
According to the literatures [26,27], hydrochlorination was
accompanied by hydration of alkynes with H2O. Thus, we used
HCl(g) instead of aqueous HCl and Ac2O as the drier. To optimize
the reaction conditions, 4-methoxy phenylacetylene 1a was
chosen as the model substrate for hydrochlorination of arylalkynes
with HCl in the presence of Ac2O. We observed that no reaction
occurred when ethyl acetate and CH2Cl2 were used as the solvents,
while a complicated mixture was produced when DMF was used
(Table 1, entries 1–3). The 1-(1-chlorovinyl)-4-methoxybenzene
2a was isolated in a 5% yield when the reaction was conducted in
CH3OH (Table 1, entry 4). To improve the reaction efficiency, we
further screened benzene, THF, AcOH, CH3CN, and
CH3NO2. CH3NO2 was found to be the best solvent, and using
the other solvents resulted in lower yields of 2a in 40–70% (Table 1,
entries 5–9). To determine the optimized reaction temperature,
the model reaction was carried out at different temperatures. It
was observed that room temperature was best and lower and
higher temperatures did not improve the yield of 2a (Table 1,
entries 9–11). The control experiment showed that the addition of
Ac2O is necessary, which can inhibit the formation of ketone
through hydration of 1a; however, the amount of Ac2O has a
marginal influence on the reaction because water was little bit in
the reaction system (Table 1, entries 12–13).
9
89
10
11
12
13
86
86
83c
91 (37:1)d
0.5
1
a
Reaction conditions: 1a (0.2 mmol), HCl(g), Ac2O (0.5 mL), solvent (3 mL), under
argon, unless otherwise noted.
b
Isolated yield.
c
No Ac2O.
d
Ac2O (0.1 mL), ratio of 2a:3a in parenthesis based on 1H NMR analysis of the
crude reaction mixture.
initially explored the electronic effect of the substituents on the
phenyl ring. Arylalkynes with strong electron-donating groups,
such as 4-alkoxy, 4-dimethylamino, 4-acetamido, 4-benzamido,
and 2-benzamido, were easily converted to their corresponding
vinyl chlorides in good to excellent yields (75–99%) (Table 2,
entries 1, 6–12). While reactions of arylalkynes substituted by
weak electron-donating groups such as 4-alkyl (Table 2, entries
13–15), proceeded slower and afforded the desired products in
lower yields (60–65%) than those with strong electron-donating
groups. However, hydrochlorination of arylalkynes bearing strong
electron-withdrawing groups, such as 4-cyano and 4-acetyl, did
not proceed at all even after 38 h (Table 2, entries 18 and 19). These
results indicate that the electronic effect of the substituents on the
phenyl ring plays significant role in hydrochlorination of alkynes
92
93
94
95
96
97
98
99
100
101
102
103
104
105
With the optimized reaction conditions in hand, we then
investigated the scope of the hydrochlorination reaction of
arylalkynes, and the results are summarized in Table 2. We
Table 2
Hydrochlorination of arylalkynes with HCl.a
Entry
1
R
Time (h)
2
2:3b
Yield (%) of 2c
1
1a
1b
1c
1d
1e
1f
4-MeO
3-MeO
2-MeO
2,6-diMeO
2-MeO-5-Me
4-EtO
1
2a
2b
2c
2d
2e
2f
37:1
2.6:1
35:1
68:1
38:1
25:1
68:1
86:1
50:1
>99:1
15:1
19:1
11:1
9:1
91
35
85
95
90
86
75
91
76
99
80
80
61
65
60
35d
22d
86e
83e
2
72
5
3
4
3
5
4
6
5
7
1 g
1 h
1i
4-BunO
4-BnO
2.5
3
2 g
2 h
2i
8
9
4-Me2N
4-AcNH
4-PhCONH
2-PhCONH
4-Et
4-But
4-Pentyln
H
3.5
5
10
11
12
13
14
15
16
17
18
19
1j
2j
1k
1l
5
2k
2l
8
1 m
1n
1o
1p
1q
1r
23
23
23
24
22
48
38
2 m
2n
2o
2p
2q
–
6:1
10:1
18:1
–
4-F
4-CN
1s
4-Ac
–
–
a
Reaction conditions: 1 (0.2 mmol), HCl (g), CH3NO2 (3 mL), Ac2O (0.1 mL), r.t., under argon.
Based on 1H NMR analysis of the crude reaction mixture.
Isolated yield.
b
c
d
e
The low yield resulted from extracting partly by pump during removing the eluent before recording of NMR.
Recovery yield of 1.
Please cite this article in press as: C.-X. Xu, et al., Catalyst-free hydrochlorination protocol for terminal arylalkynes with hydrogen
chloride, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.019

G Model
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C.-X. Xu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
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and the hydrochlorination mechanism has an electrophilic nature
[31]. Furthermore, the relative position effect of the substituents
on the phenyl ring was investigated. Arylalkynes possessing a
methoxy at the 4-, 3-, or 2-position of the phenyl ring yielded the
desired vinyl chlorides in 91, 35, and 85% yields (Table 2, entries
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yield (35%) owing to bad chemoselectivity. These results show that
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We presented a simple and straightforward method for the
synthesis of vinyl chlorides that exhibit unique regioselectivity
through hydrochlorination of arylalkynes using HCl(g) under mild
conditions. The advantage of this protocol is that the hydrochlor-
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We greatly acknowledge financial support from the National
Basic Research Program of China (973 Program, No.
2012CB720300), the Applied Basic Research Program of Bingtuan
(No. 2015AG001), and the High-level Talent Scientific Research
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Please cite this article in press as: C.-X. Xu, et al., Catalyst-free hydrochlorination protocol for terminal arylalkynes with hydrogen
chloride, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.019