Preparation of vincinal hetero 1,2-dihalo-olefins by using aqueous hydrohalic acid

Article abstract of DOI:10.1016/j.tetlet.2021.152968

An efficient simple method was developed to prepare hetero E-1,2-dihaloolefins from mono- or disubstituted alkynes, in which, NXS (X = Br, I) was utilized as the electrophilic reagents and aqueous hydrohalic acid as the nucleophile. Moreover, Z-type dihalogenation olefins could be obtained from the terminal silylacetylene.

Full text of DOI:10.1016/j.tetlet.2021.152968

Tetrahedron Letters 70 (2021) 152968
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of vincinal hetero 1,2-dihalo-olefins by using aqueous
hydrohalic acid
⇑
Ya-Ru Lei, Jia-Ying Liang, Yu-Jiang Wang, Zili Chen
Department of Chemistry, Renmin University of China, Beijing 100872, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient simple method was developed to prepare hetero E-1,2-dihaloolefins from mono- or disubsti-
tuted alkynes, in which, NXS (X = Br, I) was utilized as the electrophilic reagents and aqueous hydrohalic
acid as the nucleophile. Moreover, Z-type dihalogenation olefins could be obtained from the terminal
silylacetylene.
Received 11 January 2021
Revised 22 February 2021
Accepted 25 February 2021
Available online 4 March 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
(E) 1,2-Dihalo-olefin
Hetero dihalogenation
Acetylene
NXS
Hydrocholic acid
Introduction
halogen reagents (I2, Br2, ICl, IBr and BrCl) were proposed to be
generated in-situ [5a].
Multisubstituted hetero 1,2-dihaloalkenes are useful intermedi-
ates either in nucleophilic substitutions or in metal catalyzed cross
coupling reactions [1]. One advantage of these compounds, com-
pared with their homo analogues, is that one or two halogen atoms
could be selectively functionalized, based upon different carbon-
halogen bond’s chemical reactivity [2]. To date, three major syn-
thetic methods have been developed for the facile preparation of
these vicinal hetero dihalo-olefin units. As shown in Scheme 1,
the first synthetic route resorted to hydro- [3a–f], carbo- [3g,h]
or heteroatom- [3i] halogenation through either acid-induced or
transition metal assisted transformation from haloalkyne precur-
sors, giving tri- or tetra-substituted E- or Z-type 1,2-dihaloolefines,
which, nevertheless, only works well for terminal acetylene start-
ing materials (Scheme 1, Eq 1) [3]. In route 2, heterogeneous halo-
gen reagents, such as: ICl, IBr, BrCl etc., have ever been employed to
achieve alkyne’s direct bis-halogenation (Scheme 1, Eq 2) [4],
which often produced a mixture of regio- and stereoisomers and
thus should be performed at very low temperature [4a]. Heteroge-
neous halogen reagents are highly toxic, some alternative methods
were then developed in recent years [5]. For example, during the
course of our research, Hammond and Xu reported 1,2-trans-
dihalogenation of alkynes by using a combination of NX1S and
LiX2 in the presence of AcOH, in which, halogen and heterogeneous
In route 3, two types of reagents, including electrophilic I(I), I
(III) or I(V) reagents and nucleophilic organic salts (NEt.3 3HF or
HF/Pyr) or inorganic salts (LiCl, LiBr, Nal) were utilized collabora-
tively to realize alkyne’s double halogenation (Scheme 1, Eq 3)
[6]. For example, He and Zhu group reported ynamide’s double iod-
ofluorination in 2017 by using N-iodosuccinimide (NIS) and NEt.33-
HF [6c]. In 2018 year, Gouverneur group disclosed simple alkyne’s
double halogenation by using a similar reagent system [6d],
including I+ reagent 1,3-diiodo-5,5,-dimethylhydantoin (DIH) and
fluoride reagents (NEt3ꢀ3HF or HF/Pyr). Despite these
achievements, however, there is still no general method for the
synthesis of vicinal hetero 1,2-dihaloalkenes, which could
accommodate a broad range of alkyne substrates and halogen
substitution patterns. In this paper, we will report an efficient
simple method to synthesize hetero E-/Z-1,2-dihaloolefins from
alkynes by using NXS (X = Br, I) as electrophilic reagents and
aqueous hydrohalic acid [7,8] as the nucleophile with the addition
of small amount of pyridine additive.
We chose 1-propynyl benzene (1a)’s iodofluorination as the
model system for our initial investigation. As shown in table 1,
when 1a (0.2 mmol) was treated with N-iodosuccinimide (NIS,
1.2 eq) and aqueous HF (40%, 1.5 eq) in dichloromethane (DCM)
with the addition of small amount of pyridine (0.5 eq) at rt., the
desired E-type iodofluorination product 2a were readily obtained
in 44% yield (Table 1, entry 1), together with the formation of
two side products, including 1,2-diiodination product 5 (20% yield)
⇑
Corresponding author.
E-mail address: zilichen@ruc.edu.cn (Z. Chen).
https://doi.org/10.1016/j.tetlet.2021.152968
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Ya-Ru Lei, Jia-Ying Liang, Yu-Jiang Wang et al.
Tetrahedron Letters 70 (2021) 152968
Table 2
Preparation of Hetero (E) 1,2-Dihalo-olefins by using NIS as electrophile in the
condition various aqueous hydrohalic acid.a,b,c
Scheme 1. Different synthetic routes to prepare hetero 1,2-dihalo olefin.
and 2,2-diiodo-1-phenylpropanone 6 (8% yield). Although the
major component of the aqueous HF is water, the H2O-trapping
product 60s yield is very low. Increasing HF’s amount to 3 eq. could
not enhance 2a’s yield (Table 1, entry 2). It was found that additive
pyridine’s amount could affect the reaction yield (Table 1, entry 3–
6). When 0.1 equivalent of pyridine was added, 2a’s yield could be
improved to 70% (Table 1, entry 5). In the control experiment, 2a’s
yield was reduced to 25% without the addition of pyridine (Table 1,
entry 7). Further optimization upon the solvent (Table 1, entry 8–
9) and reaction temperature (Table 1, entry 10–12) were per-
formed, in which, the highest reaction yield was obtained in
DCM at 35 °C (Table 1, entry 12), which providing 2a in 84% yield.
With the optimized conditions in hand (Table 1, entry 12), we
turned to extending the substrate scope. Various acetylene sub-
strates, including phenyl and alkyl acetylenes, were explored by
using NIS as the electrophile and aqueous hydrohalic acid HX (in-
cluding HF, HCl, HBr) as the nucleophiles. As shown in Table 2,
when aqueous HF solution (40% m/m) was utilized as the nucle-
ophile, a series of E-configuration iodofluorination olefin products
a
Unless noted, all reactions were carried out on 0.2 mmol scale in 3 mL anhy-
drous CH2Cl2 at rt for 12 h.
b
When HF aqueous solution was utilized, the reaction was performed in a plastic
tube.
c
Isolated yields.
were obtained in moderate to good yields (2a-m, Table 2), in
which, the phenylpropyne substrates with electro-rich sub-
stituents on the phenyl ring (Table 2, 2b-c) worked better than
their electro-poor analogues (Table 2, 2d-e). p-Trifluo-
romethylphenyl substituted olefin product 2f’s yield was obtained
in 27% yield. The reactions of the bulky acetylene substrates, in
which, a naphthalenyl group or two phenyl group were contained,
went smoothly to provide the desired (E)-1-fluoro-2-iodo olefins 2f
and 2g. Nevertheless, 2g’s yield was only 35%. A long alkyl chain
didn’t affect the reaction yield, while the yields of the terminal
acetylene and dialkyl substituted acetylene were relatively low
(Table 2, 2h-j). Although the hydroxyl group was tolerated in
Table 1
NIS mediated 1-propynyl benzene’s iodofluorination reactiona,b,c
Eq(HF)/Eq(Py)
Sol/Temp
Conver. rate
Yield of 2a
Yield of 5/6
1
2
3
4
5
6
7
8
1.5/0.5
3/0.5
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCM/rt
DCE/rt
CHCl3/rt
DCM/0°C
DCM/35 °C
DCM/50 °C
73
79
75
95
100
96
88
100
90
98
44%
37%
35%
63%
70%
62%
25%
60%
39%
50%
84%
83%
20%/8%
18%/13%
16%/7%
13%/9%
10%/9%
11%/8%
25%/19%
7%/10%
11%/14%
23%/14%
2%/5%
1.5/0.8
1.5/0.2
1.5/0.1
1.5/0.05
1.5/0
1.5/0.1
1.5/0.1
1.5/0.1
1.5/0.1
1.5/0.1
9
10
11
12
100
100
2%/5%
a
b
c
Unless noted, all reactions were carried out on 0.2 mmol scale in 3 mL anhydrous solvent at rt for 12 h.
The reaction was performed in plastic tube.
2a/5/60s yield were determined by 1H NMR spectral data.
2

Ya-Ru Lei, Jia-Ying Liang, Yu-Jiang Wang et al.
Tetrahedron Letters 70 (2021) 152968
reaction (Table 2, 2k), no desired product was obtained in the iod-
ofluorination reaction of ynone 1m. Heterocycle substituted
acetylenes were also explored. 2-Ethynylpyridine’s dihalogenation
gave a complex mixture, while only small amount of iodofluorina-
tion product was obtained from 3-(prop-1-yn-1-yl)furan [9].
Acetylene’s iodochlorination (3a-m, Table 2) and iodobromina-
tion (4a-m, Table 2) reactions were then explored. As shown in
Table 2, the yields of the latter two reactions were generally higher
than that of iodofluorination reaction (Table 2), due to chloro and
bromo anion’s higher nucleophilicity [10]. Similar reaction trend,
including the favored reactivity exhibited by electro-rich sub-
strates, could be observed in the latter two types of reactions. Espe-
cially, among the iodochlorination of the electron-rich acetylenes,
excellent to quantitative yields could be obtained (3a-c, 3f-3k,
Table 2). Among the iodobromination reactions, most of the sub-
strates worked very well, providing E-configuration 1-bromo-2-
iodo olefins in moderate to good yields. Nevertheless, ynone
1m’s iodobromination gave only an inseparable mixture.
Next, various acetylene substrates were evaluated by using NBS
as the electrophile and aqueous hydrohalic acid HX (including HF,
HCl) as the nucleophiles. As shown in Table 3, a series of bromoflu-
orination and bromochlorination products were readily prepared.
Unlike the NIS mediated reactions shown in Table 2, the yields of
bromofluorination were higher than that of the bromochlorination
reaction, due to the higher tendency to form the dibromination
products in the latter reactions. In addition, the phenylpropyne
substrates with electro-poor substituents (Table 3, 7c-d and 8c-
d) worked better than their electro-rich analogues (Table 3, 7b
and 8b). Nevertheless, p-trifluoromethylphenyl substituted olefin
products 7e and 8e have very poor performance, in which, 8e
was obtained as an inseparable mixture. The hydroxyl group was
also tolerated in NBS mediated reactions (Table 3, 7g and 8g), while
dialkyl substituted acetylene’s reaction yields were relatively low
(Table 3, 7h and 8h).
Scheme 2. Acetylene’s bisfunctionalization by using NCS as electrophile.
Then, terminal silylacetylene 120s dihalogenation reaction was
examined [12]. Two Z-configuration dihalogenation products 13a
and 13b were prepared in good yields (Scheme 3, Eq 5) [13,14].
In addition, a gram-scale synthesis of 3a was performed with
10 mmol of 1a. Under standard reaction conditions, 3a was
obtained in 91% yield (2.52 g) (Scheme 3, Eq 6).
In order to elucidate the reaction mechanism, 1a’s iodochlorina-
tion was monitored by ESI-HRMS and 1H NMR spectroscopy [15].
In ESI-HRMS monitoring, two possible intermediates, including I+.
Py (intermediate I) and 1a-I+.Py (intermediate II) could be
detected. {HRMS (ESI) for [C5H5IN]+, calcd: 205.9461; found:
205.9461, corresponding to [I+.Pyridine]; HRMS (ESI) for
[C14H13IN]+, calcd: 322.0093; found: 322.0090, corresponding to
[1a-I+.Pyridine]} [15]. However, these intermediates could not be
detected in 1H NMR monitoring experiments.
A plausible simple mechanism was then proposed. A fast equi-
librium existed between insoluble I+.Pyridine intermediate I and
[1a-I+.Pyridine] intermediate II. The latter one might be short-lived
and could not be detected by 1H NMR monitoring. When aqueous
HF was added, intermediate II was trapped by HF to provide hetero
(E)-1,2-dihalo-olefin 2a (Route A, Scheme 4). According to Table 1’s
result (entry 7), the competitive H2O-trapping process, which
Acetylene’s bisfunctionalization by using NCS as the elec-
trophile were also performed. As shown in Scheme 2, dichlorina-
tion product 9 could be obtained in 54% yield, with the addition
of 0.5 equivalent of 2-fluoro pyridine [11]. While the chlorotosyla-
tion product 10 was obtained in 32% yield. When 40% aquous HF
was utilized as the nucleophile, the chlorofluorination product
110s yield was less than 5%.
Table 3
Preparation of Hetero (E) 1,2-Dihalo-olefins by using NBS as electrophile by using
aqueous HF and HCl as nucleophile.a,b,c
Scheme 3. Further exploration to prepare (Z) 1,2-Dihalo-olefin 13a/b from Termi-
nal silyl acetylene 12 and 1a’s scale-up reaction.
a
Unless noted, all reactions were carried out on 0.2 mmol scale in 6.5 mL
anhydrous DCM/CH3CN (12/1) at rt for 12 h, in which, a solution of NBS was added
dropwise within 30 min.
b
When HF aqueous solution was utilized, the reaction was performed in a plastic
tube.
c
Isolated yields.
Scheme 4. A plausible simple mechanism for acetylene’s hetereo-dihalogenation.
3

Ya-Ru Lei, Jia-Ying Liang, Yu-Jiang Wang et al.
Tetrahedron Letters 70 (2021) 152968
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would give side product 6 after further iodination by NIS (Route B,
Scheme 4), might be inhibited by I+. Pyridine’s formation. We
assumed that another side product 5 would be derived from small
amount of I2, which could be in-situ generated from NIS.
In summary, an efficient simple method was developed to pre-
pare hetero E-1,2-dihaloolefins from alkynes, in which, NXS (X = Br,
I) was utilized as the electrophilic reagents and aqueous hydrohalic
acid as the nucleophile [16]. Furthermore, Z-configuration
dihalogenation olefins could be obtained from the terminal
silylacetylene.
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Declaration of Competing Interest
(g) J. Tendil, M. Verney, R. Vessiere, Tetrahedron. 30 (1974) 579–584;
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The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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Acknowledgement
Financial Support for this work with the grant from the National
Natural Science Foundation of China (Nos. 21871294) is gratefully
acknowledged.
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Appendix A. Supplementary data
Supplementary data (a brief experimental details, and spectral
data for all new products) to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152968.
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4