Selective Ruthenium-Catalyzed Hydrochlorination of Alkynes: One-Step Synthesis of Vinylchlorides

Article abstract of DOI:10.1002/anie.201505144

An unprecedented ruthenium-catalyzed direct and selective alkyne hydrochlorination is reported and leads to vinylchlorides in excellent yields with atom economy. The reaction proceeds at room temperature from terminal alkynes and provides a variety of chloroalkenes. Only the regioisomer resulting from the formal Markovnikov addition is selectively formed. Mechanistic studies show the stereoselective syn addition of HCl to alkynes at room temperature and suggest a chloro hydrido Ru^IV species as a key intermediate of the reaction.

Full text of DOI:10.1002/anie.201505144

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International Edition: DOI: 10.1002/anie.201505144
German Edition: DOI: 10.1002/ange.201505144
Halogenation
Selective Ruthenium-Catalyzed Hydrochlorination of Alkynes:
One-Step Synthesis of Vinylchlorides
Sylvie DØrien,* Hubert Klein, and Christian Bruneau
Abstract: An unprecedented ruthenium-catalyzed direct and
selective alkyne hydrochlorination is reported and leads to
vinylchlorides in excellent yields with atom economy. The
reaction proceeds at room temperature from terminal alkynes
and provides a variety of chloroalkenes. Only the regioisomer
resulting from the formal Markovnikov addition is selectively
formed. Mechanistic studies show the stereoselective syn
addition of HCl to alkynes at room temperature and suggest
a chloro hydrido RuIV species as a key intermediate of the
reaction.
hydrochlorination of alkynes by gaseous HCl was also
realized on immobilized metal chloride catalysts, but good
yields were limited to the reaction of acetylene.[15] Finally,
a hydrochlorination reaction can proceed with a source of
proton along with metal chlorides such as ZnCl2, MgCl2,
FeCl3, or LiCl but the requirement of a stoichiometric amount
of metallic salt hampers its applicability.[16] To the best of our
knowledge, Zhu and co-workers described the unique palla-
dium-catalyzed hydrochlorination of haloalkynes using
a LiCl/HOAc system.[16f] Thus, the efficient, ecofriendly, and
general formation of vinylchlorides in a stereoselective fash-
ion by a direct hydrochlorination of alkynes still constitutes
a challenging objective.
In the course of our studies on the catalytic activity of the
complex [Cp*RuCl(cod)] (cod = 1,5-cyclooctadiene, Cp* =
C5Me5) towards alkynes,[17] we developed a catalytic hydro-
halogenative dimerization of alkynes in one step under mild
reaction conditions[18] and we observed the formation of
alkenylchlorides as side products [Eq. (1); DCE = 1,2-
dichloroethane]. Herein we report on a new efficient and
productive ruthenium-based catalytic system, which provides
selective alkyne hydrochlorination, thus giving access to
vinylchlorides in good yields under mild reaction conditions.
T
he development of straightforward and selective method-
ology to produce vinylhalides is an important continuing goal.
These versatile and reactive substrates constitute valuable
intermediates in many organic transformations either in
industry or on a bench scale.[1] In the last decade, thanks to
the emergence of new ligands, vinylchlorides are becoming
increasingly interesting partners in catalyzed cross-coupling
À
À
processes, notably for C N and C C bond formation in
palladium-catalyzed amination[2] or Suzuki–Miyaura reac-
tions.[3] This class of compounds also exhibits broad biological
activities and many natural or synthetic products contain
a vinylchloride moiety.[4–7] Therefore, the straightforward
regio- and stereoselective synthesis of vinylchlorides is highly
desirable. Vinylchlorides mainly arise from carbonyl com-
pounds,[6,8] by a halogenation reaction with harmful, tradi-
tional phosphorous reagents or acid chlorides, or from
alkynes.[9] The stoichiometric formation of a boron or metal
vinyl intermediate from alkynes, followed by addition of
a chloride, is a classical process to provide chloroalkenes.[10]
Although the direct addition of HCl to alkynes seems to be
one of the most straightforward synthetic methods to produce
chloroalkenes, this reaction does not take place in a prepara-
tively useful manner. Historically, first attempts to add
a solution of HCl to a triple bond provided mixtures of
compounds with low selectivity and/or low yields.[11] Some
improvements were obtained in the presence of a Lewis acid
catalyst such as ZnCl2 or FeCl3,[12] or by the use of appropriate
silica gel or alumina surfaces.[13] Unfortunately, the scope of
these reactions is quite narrow. Recently, a preparation of a-
chlorovinylethers was also reported and involved the in situ
generation of HCl from TMSCl and MeOH.[14] Vapor-phase
The [Cp*RuCl(cod)] catalyst (A) was found to be active
in the direct addition of HCl with alkynes to give vinyl-
chlorides. However, a modest yield of 2a was obtained during
our initial attempts [Eq. (1)]. Reaction temperature and
concentration had only limited impact, so we investigated the
influence of the catalyst (Table 1). The presence of the Cp*
ligand seems to be necessary to provide 2a, whereas half-
sandwich (p-cymene)ruthenium complexes inhibit the reac-
tion (entries 1 and 2). Gratifyingly, the addition of one
equivalent of a phosphine ligand to the [Cp*RuCl(cod)]
complex prevented the side formation of a bis(carbene)
ruthenium complex intermediate, which leads to dienylchlor-
ides,[18] and afforded 2a in 98% yield after 10 minutes at room
temperature. Only the regioisomer resulting from formal
Markovnikov addition was selectively formed. This reaction
did not proceed with the sole presence of PPh3. A lower
amount of catalyst (2.5mol%) still led to a good yield of 2a
(entries 3 and 4). The isolated [Cp*RuCl(PPh3)2] complex
was then used as the catalyst precursor to produce similar
[*] Dr. S. DØrien, Dr. H. Klein, Dr. C. Bruneau
Institut des Sciences Chimiques de Rennes—UMR 6226
CNRS-UniversitØ de Rennes 1
Campus de Beaulieu 35042 Rennes (France)
E-mail: sylvie.derien@univ-rennes1.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505144.
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Table 1: Development of the catalytic reaction.[a]
the chlorodecenes 5a, in a 85:15 ratio for the two
stereoisomers. NMR spectroscopic analyses seem
consistent with a syn addition of HCl to the triple
bond for the major isomer, thus leading to the
E stereoisomer. When the reaction was carried out at
908C the second stereoisomer, arising from a formal
anti addition of HCl, became the major one. Similar
results were produced from hex-3-yne (4b), whereas
the more bulky diphenylacetylene (4c) was less
reactive and afforded only 30% conversion after
3 hours. The conversion and the yield of 5c increased
to 60% after 20 hours with 5 mol% of catalyst, but in
a lower E/Z ratio of 65:35.
During our studies on the dimerization of
alkynes, we described an efficient hydrohalogenative
system consisting of separate proton and halide
sources. The best results were obtained by using
a combination of camphorsulfonic acid (CSA)/
BnEt3NX.[18] Adjustment of this protocol, through
Entry Cat (mol%)
[1a][b] HCl/1a
t
Conv. Yield
1a[%] 2a[%][c]
1
2
3
4
5
6
7
8
9
[Cp*RuCl(cod)] (5)
0.25 2.0
0.25 2.0
0.25 2.0
0.25 2.0
0.25 2.0
0.25 2.0
20 h
20 h
10 min 100
10 min 100
10 min 100
75
0
25
–
[{(p-cymene)RuCl2}2] (5)
[Cp*RuCl(cod)]/PPh3 (5)
[Cp*RuCl(cod)]/PPh3 (2.5)
[Cp*RuCl(PPh3)2] (2.5)
[CpRuCl(PPh3)2] (2.5)
[Cp*Ru(CH3CN)3]PF6/PPh3 (2.5) 0.25 2.0
[Cp*RuCl(cod)]/PPh3 (2.5)
[Cp*RuCl(cod)]/PPh3 (2.5)
98
97
97
58
95
97
99
4 h
100
10 min 100
10 min 100
10 min 100
1.0
2.0
2.0
1.1
[a] Reaction conditions: 1a (1.0 mmol), HCl (2n in Et2O), DCE, RT. [b] Molar
concentration. [c] Determined by H NMR analysis of the reaction mixture using
naphthalene as an internal standard.
1
results, whereas the [CpRuCl(PPh3)2] precursor showed
a lower reactivity, thus providing 2a in only 58% yield
(entries 5 and 6). The use of the cationic [Cp*Ru-
(CH3CN)3]PF6/PPh3 system also led to good yield and
selectivity in 2a (entry 7). Interestingly, increasing the con-
centration of 1a led to the best results and allowed a decrease
in the HCl/1a ratio from 2.0 to 1.1 (entries 8 and 9). Further
optimization of solvents revealed that the reaction took place
in various polar and nonpolar solvents, however the best
results were obtained in DCE and in DMC (dimethyl
carbonate).
addition of extra PPh3, resulted in an efficient catalytic system
to produce 2a (for X = Cl) in 97% yield (Scheme 3).
Modification of the counteranion of the ammonium salt
provided a straightforward methodology to selectively pro-
duce the corresponding halides and led to a-bromostyrene
(6a) and a-iodostyrene (7a) in 95 and 88% yield, respec-
tively.
With our optimized reaction conditions, we then exam-
ined the scope of the preparation of vinylchlorides from
various terminal alkynes (Scheme 1). The reaction proceeded
smoothly and appeared to be quite general with various
functional groups. Excellent yields of the vinylchlorides 2b–h
(90–99%) were obtained from arylacetylenes containing
either electron-withdrawing or electron-donating groups.
The reaction of 2 equivalents of HCl with 1,4-diethynylben-
zene afforded 1,4-di(chloroethenyl)benzene (2h) in 90%
yield. Hetero-arylacetylene derivatives also reacted with HCl
to give vinylchlorides. Thus, 2-ethynylthiophene led to the
volatile compound 2i in 75% yield and 3-ethynylpyridine
produced vinylchlorides 2j in 95% yield. In this latter case,
10% of a regioisomer, 3-(E-2-chlorovinyl)pyridine, was
formed. Alkylacetylenes containing either an ester, cyano,
chloro, or a second alkynyl functional group gave, quantita-
tively, the corresponding vinylchlorides 2k–m, as well as 2,7-
dichloroocta-1-7-diene (2n) by addition of 2 equivalents of
HCl to 1,7-octadiyne. The non-activated alkynes 1o–q also
led to good yields of the compounds 2o–q, as only one
regioisomer, but required slight modifications of the reaction
conditions.
Internal alkynes showed lower reactivity but because of
the impossible formation of the bis(carbene) species, the
addition of PPh3 was not required. At 308C, only a 10%
conversion of dec-5-yne (4a) was observed after 3 hours
(Scheme 2). Two stereoisomers for 5a were produced in
a 93:7 ratio. Gratifyingly, at 608C, complete conversion of 4a
could be obtained after 3 hours, thus leading to a 96% yield in
Scheme 1. Ruthenium-catalyzed reaction of terminal alkynes (1a–q)
with HCl. Reaction conditions: 1 (1.0 mmol), HCl (2n in Et2O,
1.1 equiv/triple bond), DCE (0.5 mL), RT, cat A/PPh3 system (1/[Ru] in
1:0.025 molar ratio). Yields are for products isolated after purification
by silica gel chromatography. [a] 3 equiv of HCl in DCE (4 mL).
[b] 1/[Ru] in 1:0.05 molar ratio. [c] 2 equiv of HCl in DCE (4 mL).
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Scheme 2. Ruthenium-catalyzed reaction of internal alkynes with HCl.
Scheme 5. Proposed catalytic cycle.
Scheme 3. Ruthenium-catalyzed hydrohalogenation of phenylacetylene
with the CSA/BnEt3NX system.
first mechanistic pathway may be then advocated for terminal
alkynes.
A possible catalytic cycle for the formation of the
vinylchlorides 2 is presented in Scheme 5. In the presence of
PPh3, the complex [Cp*RuCl(cod)] (A) can lose its cod ligand
to produce the complex [Cp*RuCl(PPh3)2] (B). Indeed, when
one equivalent of PPh3 was added to a solution of A in CD2Cl2
under Ar, 1H and 31P NMR signals corresponding to B
appeared. In acidic medium, by adding one equivalent of
HCl, B probably ionizes, thus leading to the cationic complex
[Cp*RuHCl(PPh3)2]+ (C).[20] Indeed, when we followed the
reaction of 1a with one equivalent of the system CSA/
BnEt3NBr in the presence of 10% of [Cp*RuCl(cod)]/PPh3,
we observed the almost exclusive formation of bromide
derivative at the beginning of the reaction, thus showing the
dissociation of the complex B and the oxidative addition of
HX reagent. In addition, the ruthenium(IV) chloro hydrido
complexes [Cp*RuHCl(PEt3)2]BAr4 and [Cp*RuHCl-
(PMeiPr2)2]BAr4 were isolated and characterized by Valerga
and co-workers after oxidative addition of HCl to the cationic
16eÀ complexes [Cp*Ru(PEt3)2]BAr4 and [Cp*Ru-
Scheme 4. Key steps of the formation of the vinylchlorides 2.
Two types of reaction mechanism may explain this
ruthenium-catalyzed hydrochlorination of alkynes, thus
affording the vinylchlorides 2 by incorporation of the chloride
at the more substituted carbon atom of the alkyne
(Scheme 4): 1) an intramolecular pathway involving the
À
insertion of the triple bond into the Ru Cl bond can
occur.[19] Because of the steric hindrance of the R substituent,
a regioselective chlororuthenation could lead to the syn
addition product. 2) an external nucleophilic attack of
a chloride on the coordinated triple bond results in the anti
addition of HCl.
(PMeiPr2)2]BAr4.[20] The compounds [Cp*RuHCl(PMe3)2]X
[21]
(X = PF6
or CF3SO3[22]) were also obtained from the
To discriminate between these postulated pathways, we
performed an experiment using a deuterated alkyne. When
the reaction of [D1]-1e was carried out in the presence of HCl
under the optimized reaction conditions, [D1]-2e was
obtained in 94% yield with an E/Z ratio of 95:5, as
determined by 1H NMR spectroscopy [Eq. (2)]. The observed
deuterium labelling showed that the major stereoisomer
corresponds to a syn addition of HCl to the triple bond. The
complex [Cp*RuCl(PMe3)2] by addition of NH4PF6 or
CF3SO3H. For all these chloro hydrido complexes, the
1H NMR spectra display one triplet resonance in the hydride
region, and it results from the coupling with the two
equivalent phosphorus atoms. To evaluate the possible
formation of a cationic [Cp*RuHCl(PPh3)2]+ intermediate,
we performed the addition of one equivalent of HCl (2n in
Et2O) to a solution of [Cp*RuCl(cod)]/PPh3 in CD2Cl2 at
1
room temperature. The H and 31P NMR spectra, obtained
after 2 hours, revealed the presence of both free cod ligand
1
and B, as well as new resonances. The H NMR spectrum
exhibited the methyl resonance of a Cp* ligand as a broad
singlet at d = 1.26 ppm and one triplet resonance in the
hydride region, at d = À7.73 ppm (2JPH = 33 Hz), whereas the
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31P{1H} NMR spectrum displayed a new singlet arising at d =
32.3 ppm. These observations are consistent with the forma-
tion of a cationic RuIV hydrido intermediate. Thus, we
postulate the formation of the complex C as catalytic species
which can coordinate one molecule of alkyne, after displace-
ment of one PPh3 ligand, thus leading to species E by insertion
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of the triple bond into the Ru Cl bond.[19] The regioselective
À
chlororuthenation favors the addition of the chloride at the
more substituted carbon atom. However, if the alkyne
possesses a substituent which can coordinate to the ruthenium
center [e.g. the 3-ethynylpyridine (1i)], the product resulting
from the opposite regioselectivity can be obtained (E’). These
species E are subject to reductive elimination to give the
vinylchlorides 2, syn addition products, and to regenerate the
catalyst C. In the case of internal alkynes, and in the absence
of PPh3 ligand, another mechanistic pathway cannot be ruled
out.
In summary, we have successfully developed an unprece-
dented, efficient, and selective alkyne hydrochlorination by
a ruthenium-catalyzed process. This straightforward access to
aliphatic and aromatic vinylchlorides proceeds in excellent
yields and constitutes a good example of an atom-economic
transformation. A sole regioisomer is selectively formed and
mechanistic studies show a stereoselective syn addition of
HCl to alkynes at room temperature.
Acknowledgements
The authors are grateful to the CNRS and the Minist›re de la
recherche for support, the latter for a PhD grant to H.K. They
thank Dr Mathieu Achard for helpful discussions.
Keywords: alkenes · alkynes · hydrohalogenation · ruthenium ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12112–12115
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Received: June 5, 2015
Published online: August 24, 2015
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