A General Copper-Catalyzed Vinylic Halogen Exchange Reaction

Article abstract of DOI:10.1021/acs.orglett.6b00678

An efficient and general system for the halogen exchange reaction in alkenyl halides has been developed. Upon reaction with catalytic amounts of copper iodide and trans-N,N′-dimethylcyclohexane-1,2-diamine in the presence of tetramethylammonium chloride or bromide, a wide range of easily accessible alkenyl iodides can be smoothly transformed to their far less available chlorinated and brominated derivatives in excellent yields and with full retention of the double bond geometry. This reaction also enables the chlorination of bromoalkenes and could be extended to the use of gem-dibromoalkenes.

Full text of DOI:10.1021/acs.orglett.6b00678

Letter
pubs.acs.org/OrgLett
A General Copper-Catalyzed Vinylic Halogen Exchange Reaction
Antoine Nitelet and Gwilherm Evano*
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
Libre de Bruxelles (ULB), Avenue F.
S
* Supporting Information
ABSTRACT: An efficient and general system for the halogen exchange
reaction in alkenyl halides has been developed. Upon reaction with
catalytic amounts of copper iodide and trans-N,N′-dimethylcyclo-
hexane-1,2-diamine in the presence of tetramethylammonium chloride
or bromide, a wide range of easily accessible alkenyl iodides can be
smoothly transformed to their far less available chlorinated and
brominated derivatives in excellent yields and with full retention of the double bond geometry. This reaction also enables the
chlorination of bromoalkenes and could be extended to the use of gem-dibromoalkenes.
s a direct consequence of the development of metal-
Acatalyzed cross-coupling reactions, organic halides are now
among the most commonly used building blocks in chemical
synthesis. They are indeed utilized in an impressive and ever
growing number of reactions, notably for the formation of
carbon−carbon and carbon−heteroatom bonds using palladi-
um1 and copper2 catalysis. The efficiency of these reactions
therefore strongly relies on the availability of the starting halides,
and while most aryl halides are either commercially available or
readily prepared regardless of the nature of the halogen atom, the
situation is more complex in the vinyl series.3 Indeed, if alkenyl
iodides are in most cases available through an array of efficient
and selective methods such as iodolysis of vinylmetal species,
Takai4 or Stork-Zhao5 olefinations, hydroiodination of alkynes,6
Figure 1. Alkenyl bromide-/chloride-containing natural and/or bio-
iododesilylation7/destannylation,8 or Hunsdiecker-type reac-
logically active molecules.
tions,9 the synthesis of their brominated and chlorinated
homologues is often much more challenging, mainly due to
problems associated with low-yielding procedures, serious side
reactions, poor stereoselectivity, or limitations to the synthesis of
aryl-substituted derivatives.10
obtained, which should be possible due to the greater stability
of the C−Cl (D°298(C−Cl) = 395 kJ mol−1) and C−Br
(D°298(C−Br) = 318 kJ mol−1) bonds compared to the C−I
bond (D°298(C−I) = 253 kJ mol−1),16 and that the configuration
of the double bond is fully retained during the process, this
vinylic halogen exchange could provide a straightforward and
modular route to brominated and chlorinated alkenes from their
readily available iodinated counterparts. While this halogen
exchange process, commonly named the Finkelstein reaction, has
been extensively studied in the aromatic series, for which a
number of efficient catalytic systems have been reported,17,18 its
use with alkenyl halides has been, for some unknown reasons,
rather underestimated, despite the huge potential and synthetic
utility of such a transformation.18c,19
In addition to being versatile intermediates and building blocks
for chemical synthesis, alkenyl bromides and chlorides are also
commonly found in natural products. Representative examples
include the cytotoxic and antibacterial neomangicols A 1 and B
2,11 laingolide B 3,12 or the costatols 4 and 5 (Figure 1).13 They
are also at the core structure of various biologically active
molecules from the pharmaceutical and agrochemical industries,
the most representative examples being the well-known
bromovinyl-uracil antiviral agent Usevir/Brovavir 6,14 the
sedative Placidy 7,15 or the herbicide Centurion 8.
Motivated by the potential of this copper-catalyzed vinylic
halogen−halogen exchange, we therefore decided to study the
feasibility of such a reaction and we report in this manuscript a
general system for the conversion of alkenyl iodides and
bromides to their lighter homologues with high efficiency.
Due to their omnipresence in various areas of sciences, there is
therefore a strong need for general and efficient methods
enabling the selective synthesis of polysubstituted alkenyl
halides, especially in the chlorinated and brominated series.
Capitalizing on the greater availability of alkenyl iodides
compared to their lower homologues, an interesting entry to
these building blocks would rely on a halogen−halogen
exchange. Provided that a complete conversion could be
Received: March 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00678
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Organic Letters
Letter
Table 1. Optimization of the Copper-Catalyzed Iodine/
Chlorine Exchange in Alkenyl Iodides
Scheme 1. Copper-Catalyzed Iodide to Chloride Exchange in
Alkenyl Iodides
a
a
entry
ligand
9a (%) 10a (%)
1
2
3
4
5
6
7
8
9
10
ethylene glycol
97
96
96
40
40
100
93
0
3
4
2-isobutyryl-cyclohexanone
proline
0
1,10-phenanthroline
55
48
0
2,2′-bipyridine
N,N′-dimesitylethane-1,2-diimine
TMEDA
4
N,N′-dimethylethylenediamine
trans-N,N′-dimethylcyclohexane-1,2-diamine
N,N,N′,N″,N″-pentamethyldiethylenetriamine
61
76
41
0
46
a
NMR yields determined using 1.0 equiv of DMF as an internal
standard.
Our first studies focused on the iodide−chloride exchange
starting from alkenyl iodides. The choice of the halogenating
reagent and solvent for this transformation, which is
thermodynamically driven, is crucial since both the starting and
final halide salts have to be soluble in order for the equilibrium to
be shifted toward the formation of the more stable alkenyl
chloride. Tetramethylammonium chloride was therefore chosen
as the source of chloride,18e and ethanol was selected as the
solvent to avoid problems associated with the low boiling points
of some chloroalkenes.
a
b
In DMSO for 24 h. In DMSO using 20 mol % CuI and 40 mol % L.
c
d
NMR yield using DMF as internal standard. In DMSO for 24 h
e
using 20 mol % CuI and 40 mol % L. Using 30 mol % CuI and 60 mol
% L.
10 is almost impossible. A range of β-iodo-styrene derivatives
could be smoothly transformed to their chlorinated analogues
10a−h in good yields, regardless of their electronic properties,
electron-poor 9b−d and electron-rich 9e,h iodo-styrenes
reacting with similar efficiencies, the reaction being best
performed in DMSO in some cases. The configuration of the
double bond was found to have little influence on the outcome of
the copper-catalyzed chlorination since E- and Z-chlorinated
styrenes 9a−f and 9g,h were found to react equally well and no
isomerization could be detected in all cases. In addition, the
absence of a base in the reaction mixture enabled a clean
conversion of Z-β-iodo-styrenes 9g,h without competitive
elimination to the corresponding terminal alkyne. More
challenging β-alkyl-substituted alkenyl iodides 9i−n were also
found to smoothly undergo the iodide to chloride exchange, and
the configuration of the alkene was also completely retained.
Even the sensitive and readily isomerized Z-β-iodo-acrylate 9o, a
compound for which it should be noted that no reaction occurred
in the absence of the copper catalyst, could be smoothly
chlorinated to 10o in 70% yield without isomerization. The
presence of an additional substituent such as in 10p did not slow
down the reaction, since a clean chlorination could still be
performed. Moving to the chlorination of α-substituted
iodoalkenes such as 9q−t required a slight modification of the
reaction conditions which was found to be best performed, in this
case, using a shorter reaction time (24 h vs 48 h) and a higher
catalyst loading in DMSO, conditions that allowed for a full
conversion without noticeable degradation of both the starting
materials and products. Using these modified conditions, the
corresponding α-substituted chloroalkenes 10q−t could be
obtained in synthetically useful yields (60−77%). Finally, the
presence of two substituents close to the C−I bond was found to
slow down the reaction and required the halogen exchange
reaction to be performed for 48 h with a higher amount of both
With these parameters set, a screening of the efficiency of
various representative ligands commonly used in copper catalysis
was performed using copper iodide as the source of copper(I)
and β-iodo-styrene 9a as a model substrate. Results from these
studies are shown in Table 1 and demonstrate a dramatic effect of
the ligand used for this halogen−halogen exchange reaction.
Indeed, while bidentate O,O- and N,O- ligands such as ethylene
glycol, 2-isobutyrylcyclohexanone, and L-proline were found to
be totally ineffective to promote the chlorination of 9a, bidentate
N,N-ligands were found to be much more efficient in most cases.
Among these ligands, which include a set of representative
phenanthroline, bipyridine, bis-imine, and diamine derivatives,
only secondary 1,2-diamines such as N,N′-dimethylethylene-
diamine and trans-N,N′-dimethylcyclohexane-1,2-diamine en-
abled a full conversion. The latter was more effective, allowing
the smooth transformation of alkenyl iodide 9a to the
corresponding chloride 10a in 76% NMR yield and with full
conservation of the double bond geometry since no traces of the
Z-isomer could be detected in the crude reaction mixture. Of
note, decreasing the reaction temperature to 80 °C resulted in a
slightly lower yield of 72% and other solvents such as butanol and
DMSO, which avoids performing the reaction above the boiling
point of the solvent, were also found to be suitable solvents.
This optimized catalytic system was next applied to the
chlorination of a set of iodoalkenes 9 possessing representative
substitution patterns and electronic properties. As evidenced by
results shown in Scheme 1, the copper catalyzed halogen
exchange was found to be general and allowed us to unite a rather
large collection of alkenyl chlorides 10 that could efficiently be
obtained in fair to good yields from their readily available
iodinated derivatives 9. Importantly, complete conversions could
be obtained in all cases, a key point for this iodine/chlorine
exchange to be of synthetic value since the separation of 9 from
B
DOI: 10.1021/acs.orglett.6b00678
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Scheme 2. Copper-Catalyzed Iodide to Bromide Exchange in
Alkenyl Iodides
Scheme 3. Copper-Catalyzed Bromide to Chloride Exchange
in Alkenyl Bromides
a
In DMSO for 24 h using 20 mol % CuI and 40 mol % L.
brominated olefins 11 using 2 equiv of tetramethylammonium
chloride. As in previous cases, the reaction was found to be rather
general, regardless of the substitution pattern, the configuration,
or the electronic properties of the starting materials, and the
chloroalkenes 10 could be readily obtained as single isomers by
simple concentration of the crude mixtures followed by filtration
over a plug of silica gel. The yields obtained, in the 74−85%
range, highlight the synthetic potential of this copper-catalyzed
bromide to chloride exchange.
To further demonstrate the applicability of our procedure, we
next decided to study the possibility of performing a double
vinylic Finkelstein reaction from gem-dibromoalkenes 12.
Besides expending the scope of our reaction, the feasibility of
this reaction would allow conversion of these readily available
dibromides to the corresponding dichlorides 13 whose synthesis
is much more difficult and low-yielding20 besides a synthetic
usefulness that does not have to be demonstrated anymore.20
Preliminary studies showed that if the first substitution of the less
hindered bromide was quite simple, the second one was much
more sluggish and the standard conditions used for the bromide
to chloride exchange starting from bromoalkenes only gave
inseparable mixtures of dibromo-, dichloro-, and bromo,chloro
alkenes. A brief reoptimization revealed that the reaction could
be driven to completion by increasing the amount of the catalytic
system together with increasing the reaction time to 96 h: using
these conditions, we were glad to note that various
dibromoalkenes 12 could be converted to their dichlorinated
derivatives 13 in fair to good yields (Scheme 4).
a
b
In DMSO for 48 h. NMR yield using DMF as internal standard,
c
contaminated with 13% of the starting iodide. In DMSO using 20 mol
% CuI and 40 mol % L.
copper iodide and the ligand, affording the corresponding alkenyl
chloride 10u in 72% yield. It ought to be mentioned that the
reaction, which is performed under neutral conditions, was found
to be compatible with a range of functional groups including
benzyl groups, esters, phthalimide, acetals, or silyl ethers, and
even a labile allylic PMP ether such as that in 10l was well
tolerated under the reaction conditions; no competitive
nucleophilic substitution by the halides present in the reaction
mixture could be observed.
Given the efficiency of the copper-catalyzed iodide to chloride
exchange in alkenyl iodides, we next decided to investigate its
extension to the less favorable synthesis of bromoalkenes,
building blocks of great interest and whose synthesis can also be
problematic in some cases. As expected, the lower difference in
carbon−halogen bond energies for the copper-catalyzed iodide
to bromide exchange in alkenyl iodides compared to the iodide to
chloride exchange resulted in a more sluggish reaction and in
incomplete conversion when the exact same conditions were
applied to the bromination of 9a using tetramethylammonium
bromide instead of tetramethylammonium chloride. Doubling
the amount of tetramethylammonium bromide however allowed
the reaction to completely shift to the exclusive formation of the
corresponding brominated derivative 11a which could be
gratefully obtained in 85% yield. A scope and limitations study
using similar substrates as those used in the previous one
demonstrated both the generality and broad substrate scope of
this second halogen/halogen exchange which could be applied to
the preparation of a wide range of polysubstituted bromoalkenes
11 from their iodinated counterparts 9 (Scheme 2).
Scheme 4. Copper-Catalyzed Bromide to Chloride Exchange
in gem-Dibromo-alkenes
a
b
Contaminated with 10% of the monochlorinated alkene. For 48 h
using 20 mol % CuI and 40 mol % L.
Having demonstrated the generality of our copper-catalyzed
vinylic halogen exchange reaction and its rather broad
applicability, we next decided to try to push our procedures to
their limits and to test them in more complex situations. With
this goal in mind, their compatibility with more complex
substrates was then evaluated starting first from cholic acid and
peracetyl-glucose derivatives embedded with an appending
alkenyl iodide 14 and 16 (Scheme 5). We were pleased to see
that their chlorination proceeded well, the corresponding alkenyl
chlorides 15 and 17 being obtained in moderate to good yields
Having suitable conditions in hands for the conversion of
alkenyl iodides to their chlorinated and brominated counterparts,
we next briefly evaluated a last halogen−halogen exchange in the
vinylic series: the copper-catalyzed chlorination of alkenyl
bromides. Results from these studies are collected in Scheme 3
and show that the same catalytic system optimized for the
chlorination of alkenyl iodides can also be efficiently used for the
synthesis of chlorinated alkenes 10 from the corresponding
C
DOI: 10.1021/acs.orglett.6b00678
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Scheme 5. Copper-Catalyzed Vinylic Finkelstein Reaction
with Complex/Sensitive Substrates
ACKNOWLEDGMENTS
Our work was supported by the Universite
■
́
libre de Bruxelles
(ULB), the FNRS (Incentive Grant for Scientific Research No.
F.4530.13), and the Federation Wallonie-Bruxelles (ARC
Consolidator 2014-2019). A.N. acknowledges the Fonds pour
la formation a la Recherche dans l’Industrie et dans l’Agriculture
́
́
̀
(F.R.I.A.) for a graduate fellowship.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00678.
̀
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Detailed experimental procedures and full characterization
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gevano@ulb.ac.be.
Notes
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The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b00678
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