Copper-catalyzed Z-selective semihydrogenation of alkynes with hydrosilane: A convenient approach to cis-alkenes

Article abstract of DOI:10.1016/j.tet.2014.01.053

A copper catalyst generated in situ from widely available copper salt and imidazolium salt in the presence of t-BuOK showed high efficiency for the semihydrogenation of a wide range of internal and terminal alkynes to their corresponding alkenes without obvious over-reduction. Functional groups, such as hydroxyl, nitro, halides, and amino, etc. were tolerated. The Z/E ratios of the obtained alkenes were generally >99%. Finally, semireduction of bulky alkynes also went smoothly.

Full text of DOI:10.1016/j.tet.2014.01.053

Tetrahedron 70 (2014) 2175e2179
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed Z-selective semihydrogenation of alkynes with
hydrosilane: a convenient approach to cis-alkenes
Guang-Hui Wang a, Huai-Yu Bin a, Miao Sun a, Shu-Wei Chen a, Ji-Hong Liu b,
,b,
Chong-Min Zhong a
*
a Department of Applied Chemistry, College of Science, Northwest A&F University, Yangling 712100, PR China
b College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper catalyst generated in situ from widely available copper salt and imidazolium salt in the pres-
ence of t-BuOK showed high efficiency for the semihydrogenation of a wide range of internal and ter-
minal alkynes to their corresponding alkenes without obvious over-reduction. Functional groups, such as
hydroxyl, nitro, halides, and amino, etc. were tolerated. The Z/E ratios of the obtained alkenes were
generally >99%. Finally, semireduction of bulky alkynes also went smoothly.
Received 3 January 2014
Accepted 23 January 2014
Available online 6 February 2014
Keywords:
Copper catalyst
Ó 2014 Elsevier Ltd. All rights reserved.
N-Heterocyclic carbene
Semihydrogenation of alkynes
Hydrosilane
cis-Alkenes
1. Introduction
tolerance for a variety of functional groups. Similar to hetero-
geneous catalyst systems, some trans-alkenes and over-reduction
cis-Olefinic structures exist in many biologically important
molecules.1 The stereoselective semihydrogenation of internal
alkynes is the simplest and most straightforward approach to
achieve cis-alkenes,2 and both heterogeneous and homogeneous
catalytic methods have been developed to obtain the desired
products. The Lindlar catalyst,3 modified Lindlar catalysts,4 pal-
ladium nanoparticals,5 nickel boride on resin,6 dispersed nickel
on graphite,7 nickel nanoparticals,8 and nickel phosphide nano-
particles9 are perhaps the most efficient and well known among
the heterogeneous catalyst systems currently available. However,
partial isomerization of the cis-alkene to the trans-alkene,
double-bond shifts and over-reduction to the alkane are notable
issues, especially with the Lindlar catalyst. Many attempts have
been also made to develop efficient homogeneous catalyst sys-
tems based on rhodium,10 tricarbonylchromium(0),11 hafnium,12
ruthenium,13 nickel,14 iron,15 vanadium,16 and palladium com-
plexes.17 Thus far, however, few palladium catalysts,17c,e,g have
shown good selectivity for the formation of cis-alkenes as well as
to alkanes have also been observed in palladium catalytic
systems.
The reactivity of copper hydride with unsaturated carbon-
ecarbon bonds has been observed in its reaction with terminal
alkynes,18 internal alkynes, 19 and olefins conjugated with aromatic
groups.20 Ryo et al.21 also reported the Cu(II) hydride-mediated
stereoselective reduction of alkynes activated by electron-
attracting sulfonyl groups. All of the copper species that mediate
the semihydrogenation of internal alkynes show nearly perfect cis-
selectivity.19,21 X-ray structures of vinyl copper complexes illustrate
that addition of copper hydride to triple bonds occurs via a cis-
selective manner.22
Recently, significant progress has been made in the copper
catalyzed semihydrogenation of alkynes.23 Tsuji24 and Lalic25 re-
ported a bisphosphine and NHC coordinated copper catalyst, re-
spectively. However, Tsuji’s method utilized different ligands and
reaction conditions for different type substrates, which bring dif-
ficult choice in application. The IPrCuOet-Bu catalyst, reported by
Lalic, is air-unstable, which limits its wide application. Therefore
a more general method is still desired. The present study shows
that a copper catalyst generated in situ from air-stable and widely
available Cu(OAc)2$H2O and IPr$HCl in the presence of t-BuOK is
highly efficient for the semihydrogenation of both internal and
* Corresponding author. E-mail addresses: zhongcm@nwsuaf.edu.cn, zhong_cm@
yahoo.com (C.-M. Zhong).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.053

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G.-H. Wang et al. / Tetrahedron 70 (2014) 2175e2179
Table 2
terminal alkynes and significantly suppress over-reduction to
alkanes.
Copper-catalyzed semihydrogenation of alkynesa
Entry
Products
PMHS
T
Time Yieldsb [%] (Z/E)c
equiv. (ꢀC) (h)
2. Results and discussion
1d
3.2
25
4
89 (>99/<1)
We first used 4-decyne as a model substrate and poly-
methylhydrosiloxane (PMHS) as a reducing agent to optimize the
reaction condition (Table 1). Quantitative yields of the product
were obtained by using a catalytic system generated in situ from
5 mol % Cu(OAc)2$H2O, 5 mol % 1,3-bis(2,6-diisopropylphenyl)
imidazolium chloride (IPr$HCl), and 10 mol % t-BuOK in toluene
(Table 1, entry 1). The use of CuCl or CuI instead of Cu(OAc)2$H2O
resulted in very low (entry 2, 3%) or moderate (entry 3, 69%)
yields. The NHC ligand generated from commercially available
IPr$HCl was more active than phosphines (entries 4 and 5) and
other NHC ligands (entries 6 and 7). Aside from toluene, hexane
was also a good solvent for the catalytic reaction (entry 8, 68%),
though the reaction in hexane went slower than in toluene. The
reaction using (EtO)3SiH as the reducing agent gave a yield com-
parable with that of the reaction using PMHS. In the absence of
ligand, the reaction resulted in only 9% yield of the desired
product (Table 1, entry 11).
2e
3
2c : R¼n-Pr
3.2
3.2
25
50
10
18
98 (100/0)
95 (>99/<1)
2d : R¼Ph
4
4.0
25
25
92 (>99/<1)
5
6
7
2f : X¼p-CF3
2g : X¼p-Br
2h : X¼p-Cl
4.0
4.0
4.0
25
25
25
25
6
32
88 (>99/<1)
92 (>99/<1)
92 (98/2)
8
4.0
4.0
4.0
4.0
50
80
25
25
20
75
20
30
94 (>99/<1)
97 (>99/<1)
89 (>99/<1)
93 (>99/<1)
9
Table 1
Copper-catalyzed semihydrogenation of 4-decyne: condition optimizationa
10
11
Entry
Ligand
Cu salt
Silane
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
IPr$HCl
IPr$HCl
IPr$HCl
Xantphos
dppb
Mes$HCl
s-IPr$HCl
IPr$HCl
IPr$HCl
IPr$HCl
None
Cu(OAc)2$H2O
CuCl
CuI
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PhSiH3
(EtO)3SiH
PMHS
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Hexane
Toluene
Toluene
Toluene
100
3
69
14
52
25
13
68
62
96
9
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
12f
13
4.0
4.0
4.0
25
25
25
25
25
16
90
9
10
11
80g
a
Reaction conditions: alkyne 1a (0.5 mmol), copper salts (0.05 equiv), ligand
(0.05 equiv), t-BuOK (0.01 equiv), silane (4.0 equiv, as number of SieH unit), t-BuOH
(2.0 equiv), solvent (1.0 ml).
14h
92 (>99/<1)
b
GC yields. No E-alkene and overreduction products were observed by 1H NMR in
2p : R1¼H, R2¼Me
2q : R1¼H, R2¼Ph
2r : R1¼H, R2¼t-Bu
2s : R1¼Me, R2¼i-Pr
4.0
4.0
4.0
4.0
50
80
100
80 124
80 124
10
48
24
92 (>99/<1)
95 (100/0)
90 (>99/<1)
40 (>99/<1)
65 (>99/<1)
any of the cases.
15
16i
17
18
19
The scope of the catalytic system was examined using various
alkynes (Table 2). Semihydrogenation occurred much faster in al-
kynes conjugated with one phenyl group (Table 2, entries 1 and 2)
than in substrates conjugated with two phenyl groups (entry 3).
Several functional groups on the conjugated phenyl ring were
tolerated (entries 4e13). Product 2q was contaminated by 8% over-
reduced by-product due to the higher temperature and longer
reaction time. For substrates bearing NH2 and OH groups, higher
temperatures were necessary for the reaction to proceed (entries 8
and 9). The low reactivity of these substrates presumably was due
to the deactivation by the strong electron-donating groups or to the
coordination of the groups to metals.
However, the substrates bearing electron-withdrawing groups
(EWG) that have direct resonance effect with triple bonds were over-
reduced completely (Table 2, entry 12) or to a large extent (entry 13).
The over-reductionwas considered to be resulted from the activation
of the double bonds in the desired products and further hydroge-
nation (Eq. 1). In contrast to the strong activation effect of the con-
jugated electron-withdrawing groups (NO2 and CN) on the desired
2t : R1¼Me, R2¼PhCH2CH2 4.0
20d
21
3.2
50
50
10
20
55 (>99/<1)
90 (>99/<1)
4.0
4.0
3.2
22
100 100
46 (>99/<1)
23d
25
3
70

G.-H. Wang et al. / Tetrahedron 70 (2014) 2175e2179
2177
Table 2 (continued )
(entry 24, 7 h, alkane yield 17%; entry 25, 9 h, alkane yield 15%).
Propargyl acetate was reduced to its corresponding allyl acetate
with no formation of the allene.19,27 The reaction scale could be
increased to 10 mmol without any lowering of the yield and Z/E
selectivity (Table 2, entry 28).
Having established the wide scope of our methodology, we tried
its application in the synthesis of cis-combretastatin A-4 (CA-4).
CA-4 is a natural product first isolated from the bark of the South
African tree Combretum caffrum in 1989.28 CA-4 is a powerful in-
hibitor of tubulin polymerization by binding to the colchicine site. It
also can induce vascular damage within tumors at doses less than
one-tenth of the maximum tolerated dose.29 Two prodrugs of CA-4
are now in clinical trials: fosbretabulin disodium in phase II and
Ombrabulin in phase III. Several methods have been reported for
the synthesis of CA-4.30
Entry
Products
PMHS
T
Time Yieldsb [%] (Z/E)c
equiv. (ꢀC) (h)
24d
25
3.0
3.0
24
24
3
3
99j
98
26
27
4.0
4.0
25
50
10
10
60
98
Our rout to CA-4 is shown in Scheme 1, starting from com-
mercially available 3,4,5-trimethoxybenzaldehyde (3) and o-
methoxyphenol (4). Compounds 1z and 6 were prepared according
to reported procedure from 331 in a yield of 70% and from 432 in
a total yield of 83%, respectively. Palladium-catalyzed coupling of 1z
and 6 afforded CA-4 precursor 7 in a good yield (70%). Under
standard reaction conditions, semihydrogenation of 7 elicited
combretastatin A-4 with a yield of 70%.
28k
4.0
50
20
91 (>99/<1)
a
Reaction conditions: alkynes (0.5 mmol), Cu(OAc)2$H2O (0.05 equiv), IPr$HCl
(0.05 equiv), t-BuOK (0.1 equiv), t-BuOH (2.0 equiv), PMHS (3.2e4.0 equiv), toluene
(0.5 M).
b
Isolated yields after flash chromatography. For substrates with a hydroxyl
group, the products were isolated after hydrolysis by addition of 1.0 M TBAF in
THF.26
Determined by 1H NMR.
Hexane was used as solvent for the purpose of easy separation.
6.0 mmol alkyne was used.
The alkyne was completely over-reduced.
The product is composed of 80% over-reduced product and 20% cis-alkene.
4.0 mmol alkyne was used.
The product contains 8% over-reduction by-product.
GC yield.
c
d
e
f
g
h
i
ð2Þ
j
k
10.0 mmol alkyne was used.
products, EWG group CF3 only has inductive effect and did not acti-
vate the product (2f) obviously. This is a reasoned result considering
that
p electrons involved in the reaction were polarized more
strongly by conjugated EWG groups than by inductive EWG ones.
ð1Þ
Allylic alcohols with aryl groups at the
g position are an im-
portant type of synthetic intermediates.26 We studied the reduction
of this type of substrate with different substitution groups at the
a
position (Table 2, entries 14e19). Substrates with larger sub-
stituents at the position required higher reaction temperatures
a
(entries 16 and 17) than those with smaller substituents. 8% over-
reduction product was observed in the reduction of alkyne 1p
(entry 16). For tertiary allylic alcohols (entries 18 and 19), low to
moderate yields were obtained. Internal alkynes with no conjuga-
tion (Table 2, entries 20e22) necessitated higher temperatures
than those conjugated with one phenyl group (entries 1 and 2).
Semihydrogenation was retarded by bulky substituents (entry 22)
and terminal alkynes were reduced much faster than internal al-
kynes (Table 2, entries 23e26). For terminal aryl alkynes (entries 24
and 25), longer reaction times resulted in significant over-reaction
Scheme 1. Synthesis of combretasatin A-4.

2178
G.-H. Wang et al. / Tetrahedron 70 (2014) 2175e2179
A possible reaction mechanism is shown in Scheme 2. Active
values are given in Hertz. Gas chromatographic analyses were
conducted on a Shimadzu GC-2014C equipped with a flame ioni-
zation detector. 1,3,5-Trimethylbenzene was used as internal stan-
dard. High-resolution mass spectra (HRMS) were recorded on
a Micromass GCT GCeMS (Waters Corporation) or a maXis UHR-
TOF HPLC-MS (Bruker Corporation) spectrometers.
catalytic species A was generated in situ from IPr$HCl, t-BuOK,
Cu(OAc)2$H2O, and PMHS. Alkenyl copper B is the key intermediate,
which was formed from the cis-addition of copper hydride A to
alkyne substrates. B was protonated by the alcohol to form species
C and the desired product. The protonation step was supported by
the fact that in the absence of t-BuOH, product 2b was obtained
only in a yield of 5% (GC). Hydrosilylation step (from B to D) could
be excluded based on two experimental facts in the transformation
from 1b to 2b: (1) under the standard reaction conditions, 2b was
obtained quantitatively without addition of the alkaline aqueous to
hydrolyze the reaction mixture;33 (2) In the absence of the alcohol,
92% (GC) of alkyne 1b was recovered.34
4.2. General procedure for the copper-catalyzed semi-
hydrogenation of alkynes: for liquid substrates (1a, b, c, e, k, o,
p, q, t, u, v, x, y, aa, ab, ac)
In air, Cu(OAc)2$H2O (5.0 mg, 5 mol %) and IPr$HCl (10.6 mg,
5 mol %) were placed in a screw-capped reaction vial. The vial was
moved in to a glove box and t-BuOK (5.6 mg, 10 mol %) and solvent
(1.0 ml) were added. The vial was moved out of the glove box and
connected to an argon line through a needle. The mixture was
raised to 50 ꢀC and stirred for 1 h. PMHS (131 mg, 4.0 equiv)
was then added dropwise with a microsyringe and the solution was
stirred for an additional 30 min. After the mixture was changed to
the specified reaction temperature, liquid alkyne (0.5 mmol) and t-
BuOH (74 mg, 2.0 equiv) was added dropwise. The mixture was
stirred for a specified period of time. The reaction mixture was
subsequently hydrolyzed by adding 1 M NaOH aqueous (2 ml) (for
substrates with no hydroxyl group) or 1 M TBAF in THF (2 ml) at
0
ꢀC (for substrates with a hydroxyl group) for several hours. The
mixture was extracted with ether (2 mlꢁ3). Crude products
were obtained after evaporation and purified by silica gel
chromatography.
4.3. General procedure for the copper-catalyzed semi-
hydrogenation of alkynes: for solid substrates (1d, f, g, h, i, j, l,
m, q, r, w, z, and CA-4)
Scheme 2. Proposed mechanism.
3. Conclusions
In air, Cu(OAc)2$H2O (5.0 mg, 5 mol %), IPr$HCl (10.6 mg,
5 mol %), and solid substrates (0.5 mmol) were placed in a screw-
capped reaction vial. The vial was moved into a glove box and t-
BuOK (5.6 mg, 10 mol %) and solvent (1.0 ml) were added. The vial
was moved out of the glove box and connected to an argon line
through a needle. The mixture was raised to 50 ꢀC and stirred for
1 h. The mixture was then treated in two different manners: (1) if
reaction temperature ꢂ50 ꢀC (1d, i, j, q, r, w and CA-4), PMHS
(131 mg, 4.0 equiv) was then added dropwise with a microsyringe
at 50 ꢀC and the solution was stirred for an additional 30 min. After
t-BuOH (74 mg, 2.0 equiv) was added, the mixture was raised to
required reaction temperature and stirred for a specified period of
time; (2) if reaction temperature <50 ꢀC (1f, g, h, l, m, z), the
mixture was first cooled to the required temperature and PMHS
(131 mg, 4.0 equiv) was then added and the solution was stirred for
an additional 30 min. After t-BuOH (74 mg, 2.0 equiv) was added,
the mixture was stirred for a specified period of time. The reaction
mixture was subsequently hydrolyzed by adding 1 M NaOH aque-
ous (2 ml) (for substrates with no hydroxyl group) or 1 M TBAF in
THF (2 ml) at 0 ꢀC (for substrates with a hydroxyl group) for several
hours. The mixture was extracted with ether (2 mlꢁ3). Crude
products were obtained after evaporation and purified by silica gel
chromatography.
A convenient catalyst generated in situ from commercially
available Cu(OAc)2$H2O, IPr$HCl, and t-BuOK, efficiently catalyzed
the semihydrogenation of various internal and terminal alkynes to
their corresponding alkenes with excellent Z-alkene selectivity for
internal alkynes. Over-reduction was significantly suppressed in
most cases, except for terminal aromatic alkynes and alkynes ac-
tivated by strong electron-withdrawing groups. The catalytic re-
actions were carried out under mild conditions, and several
functional groups were tolerated. The semireduction went
smoothly even for bulky alkynes. Our catalyst can serve as a prac-
tical alternative to Lindlar catalyst in the semireduction of both
internal and terminal alkynes.
4. Experimental section
4.1. Materials and analysis
Materials were obtained from commercial suppliers and puri-
fied by the standard procedure unless otherwise noted.
Cu(OAc)2$H2O (98þ%, extra pure) and Polymethylhydrosiloxane
(PMHS) were purchased from Acros and degassed before used. 1,3-
Bis(2,6-diisopropylphenyl)imidazolium chloride (IPr$HCl) was
prepared according to reported procedures.35 t-BuOK was pur-
chased from Acros and purified by sublimation. Toluene was pur-
chased from Sinopharm Chemical Reagent Co, Ltd. (SCRC), distilled
from sodium metal and degassed via three freezeepumpethaw
cycles before use.
Acknowledgements
This work was supported by the Foundation of Northwest A&F
University (No. Z111021007), the Natural Science Foundation of
Heilongjiang Province of China (No. B200604), the Scientific
Research Foundation for Returned Scholars, Ministry of Education
of China, the Science and Technology Innovation Program of Harbin
Science and Technology Bureau for Returned Scholars (No.
NMR spectra were recorded on Advance Bruker 400M (1H:
399 MHz; 13C: 100 MHz) or Bruker Avance III 500M (1H: 500 MHz;
13C: 126 MHz) spectrometer. Tetramethylsilane (1H) and CDCl3 (13C)
were employed as internal and external standards, respectively. J

G.-H. Wang et al. / Tetrahedron 70 (2014) 2175e2179
2179
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Supplementary data
Supplementary data associated with this article can be found.
These data include additional reaction condition screening, spectra
data for the main products described in this article. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.01.053. These data include MOL files and InChiKeys of the
most important compounds described in this article.
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