Highly efficient two-step synthesis of (Z)-2-halo-1-iodoalkenes from terminal alkynes

Article abstract of DOI:10.1039/c0cc02156c

The easily accessible haloalkynes can be converted to (Z)-2-halo-1- iodoalkenes in high yields with excellent regio- and stereoselectivity. The method shows good functional group compatibility. The resulting products could find broad applications.

Full text of DOI:10.1039/c0cc02156c

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Highly efficient two-step synthesis of (Z)-2-halo-1-iodoalkenes from
terminal alkynesw
Zhengwang Chen, Huanfeng Jiang,* Yibiao Li and Chaorong Qi
Received 28th June 2010, Accepted 8th September 2010
DOI: 10.1039/c0cc02156c
The easily accessible haloalkynes can be converted to (Z)-2-halo-
1-iodoalkenes in high yields with excellent regio- and stereo-
selectivity. The method shows good functional group compatibility.
The resulting products could find broad applications.
yields (entries 16–18), for example, only trace product was
formed when the reaction was conducted at room tempera-
ture (entry 16). It is notable that the reaction can be simplified
in a one-pot style starting from phenylacetylene, which
eventually afforded the corresponding product 2a in 84% yield
(Table 1, entry 19).
Vinyl halides are one of the most important intermediates
in organic synthesis and are often employed for transition-
metal-catalyzed cross-coupling reactions. The dihaloalkenes
are attracting more and more attention as it has been possible
to construct multifunctional and dissymmetrical compounds
in the past decades.1,2 Vicinal hetero-dihaloalkenes, such as
2-chloro-1-iodoalkene and 2-bromo-1-iodoalkene, are one of
the most versatile building blocks, and their preparations are
mainly through the halogenation using iodine monochloride
or iodine monobromide with alkynes. However, the poor
selectivity and difficult separation in the preparation course
prevent them from being widely used in organic synthesis.
Although some methodologies have been developed for the
more efficient and selective halogenation of alkynes,3 there is
still no efficient method to prepare the (Z)-2-halo-1-iodoalkenes.4
Herein, we wish to present the first example of a facile two-step
synthesis of the (Z)-2-halo-1-iodoalkenes from the simple
terminal alkynes in moderate to excellent yields in a highly
regio- and stereoselective manner.5 The reactions proceeded
with haloalkynes,6 which were prepared by reported methods
with high yields (87–99%).7,8
With the success in finding the optimum reaction conditions
(Table 1, entry 5), the scope and the utility of this method
with other haloalkynes in the standard conditions were then
investigated in detail. As summarized in Scheme 1, aromatic
alkynyl bromides with either an electron-donating or electron-
withdrawing group on the benzene ring were able to generate
the corresponding products in good to excellent yields (2a–o).
Substitution at the 2-position of the aromatic ring had a slight
impact and the CF3 substituted substrate required prolonged
reaction time (2g and 2k). The reaction conditions were
compatible with alkyl, methoxy, fluoro, chloro, bromo, nitro,
and trifluoromethyl group (2b–l). Especially, the di-electron-
withdrawing group substituted substrate gave excellent
yield (2l). Furthermore, diyne bromide can be converted into
the corresponding product 2m in good yield as well. In
addition to bromoalkynes, chloroalkynes were also shown to
Table 1 The reaction of KI with bromoalkynea
With the haloalkynes in hand, we then examined the second
step, transforming the haloalkyne 1 into the desired product
1,2-dihaloalkene 2 in detail to tune the reaction conditions. As
summarized in Table 1, bromoalkyne (1a) was used as the
starting material for the model reaction. Initially, we added
different transition metals in the reaction by assuming the
reaction is a catalytic process (Table 1, entries 1–4). However,
the control experiment results showed that the bromoalkyne
(1a) can be effectively converted to the (Z)-2-bromo-1-
iodoalkene (2a) without addition of any transition metals
(entry 5), which implies that it’s a noncatalytic reaction.
Indeed, some transition metals can even prohibit or depress
the reaction (entries 1, 2). The solvent played an important
role and acetic anhydride is the solvent of choice for the
reaction (entries 5–10). Alkaline iodine was the best iodine
source, both KI and NaI can work equally well (entries 5, 12).
Lower temperature and shorter time decreased the reaction
Entry
Solvent
Additive
Iodine source
Yield (%)b
1
2
3
4
5
6
7
8
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
DMF
HOAc
1,4-dioxane
Water
DMSO
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Ac2O
Pd(OAc)2
CuI
AgOAc
FeCl3
—
—
—
—
—
—
—
—
—
—
—
—
—
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
HI
NaI
N(Bu)4I
I2
NIS
KI
n.p.
30
95
96
95
trace
85
trace
trace
20
50
94
56
9
n.p.
trace
55
78
84
9
10
11
12
13
14c
15
16d
17e
18f
19g
KI
KI
KI
—
—
School of Chemistry and Chemical Engineering,
a
Reaction conditions: phenylethynyl bromide (1.0 mmol), KI (1.5 mmol),
b
South China University of Technology, Guangzhou 510640, China.
E-mail: jianghf@scut.edu.cn; Fax: +8620-87112906;
Tel: +8620-87112906
w Electronic supplementary information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
spectra for isolated compounds. See DOI: 10.1039/c0cc02156c
c
solvent (2.0 mL) at 120 1C for 6 h. Isolated yield. The addition
product of I2 was obtained in 88% yield. Room temperature. At
d
e
f
g
60 1C. 3 h. The one-pot method from phenylacetylene to the product,
please see the supporting information.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8049–8051 8049

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Scheme 2 The Sonogashira reaction of 2a and 3a.
reaction in a 10 mmol scale; the product could be formed in
84% yield (2a).
With a viable route to the (Z)-2-halo-1-iodoalkenes, we then
worked on exploring their potential applications as building
blocks for the synthesis of highly substituted alkenes. For
example, by elaborately designing, the (Z)-2-bromo-1-
iodoalkene 2a can be selectively cross-coupled with two different
alkynes in order in good yields through the Sonogashira
reaction, as iodine and bromine atoms in the molecule have
quite different reaction activities (Scheme 2). The (Z)-bromo-
enyne 3a, with the bromine functional group on the terminal
CQC double bond, is a very useful intermediate in organic
synthesis;9 and the dissymmetric enediyne 4a is a key frame-
work for the preparation of a variety of target compounds
with applications ranging from natural products and pharma-
ceuticals to molecular organic materials.10,11
In conclusion, a convenient and practical route to syntheti-
cally useful (Z)-2-halo-1-iodoalkenes from the simple terminal
alkynes in high yields with excellent regio- and stereoselectivity
was described. The method shows excellent functional group com-
patibility. Moreover, the useful intermediate was briefly trans-
formed to the conjugated (Z)-haloenyne and (Z)-dissymmetric
enediyne in good yields. The use of these precursors for
multifunctional synthesis and further applications is in progress
and will be reported in due course.
This work was supported by the National Natural Science
Foundation of China (Nos. 20625205, 20772034, and 20932002),
National Basic Research Program of China (973 Program)
(No. 2011CB808603) and the Doctoral Fund of the Ministry
of Education of China (20090172110014).
a
Scheme 1 The scope of halogenation of haloalkynesa,b
.
Reaction
Notes and references
conditions: haloalkyne (1 mmol), KI (1.5 mmol), acetic anhydride
(2.0 mL) at 120 1C for 6 h. b Isolation yield and the ratio of Z/E isomers
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c
was above 99: 1 determined by GC. 10 mmol scale of the reaction.
d 24 h. e The substrate was 1-bromo-5-chloropent-1-yne. f The substrate
was 4-bromo-2-methylbut-3-yn-2-ol. g The substrate was 5-bromopent-
4-yn-2-ol.
be highly effective substrates for the transformation; the
corresponding products (Z)-2-chloro-1-iodoalkenes can be
obtained in excellent yields as well (2n and 2o). Except for
the aryl haloalkynes, the alkyl haloalkynes were also found to
be suitable substrates for the standard conditions (2p–w).
When the aliphatic alkynes bearing cyclohexyl, cyano, chloro,
hydroxyl and ester group were employed, the reaction proceeded
in moderate to excellent yields (2q–v). In the case of the
aliphatic alkyne bearing chloro and hydroxyl groups, the
functionalization proceeded simultaneously at both the alkyne
and hydroxyl, chloro moieties (2s, 2t and 2v). Furthermore,
diene formation was performed in excellent yield (2w). To
further explore its potential application, we scaled up the
c
8050 Chem. Commun., 2010, 46, 8049–8051
This journal is The Royal Society of Chemistry 2010

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5 The regio- and stereochemistry of (Z)-2-halo-1-iodoalkenes were
1
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c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8049–8051 8051