CuCl2-catalyzed highly stereoselective and chemoselective reduction of alkynyl amides into α,β-unsaturated amides using silanes as hydrogen donors

Article abstract of DOI:10.1039/d0ob02037k

A CuH-catalyzed Z-selective partial reduction of alkynyl amides to afford α,β-unsaturated amides using silane as the hydrogen donor is developed. This reaction is carried out under mild conditions and able to accommodate a broad scope of alkynyl amides in

Full text of DOI:10.1039/d0ob02037k

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DOI: 10.1039/D0OB02037K
COMMUNICATION
CuCl2-catalyzed highly stereoselective and chemoselective
reduction of alkynyl amides into α, β- unsaturated amides using
silanes as hydrogen donors
Received 00th January 20xx,
Accepted 00th January 20xx
Lingfei Duan,a Kai Jiang,a Hua Zhu*b and Biaolin Yin*a
DOI: 10.1039/x0xx00000x
a) Semihydrogenation of alkynylesters, amides, and ketones
A CuH-catalyzed Z-selective partial reduction of alkynyl amides
to afford α,β- unsaturated amides using silane as the hydrogen
donor is developed. These reactions are carried out under mild
conditions and able to accommodate broad scope of alkynyl
O
H
X
X
PhCOOH
H2O, PPh3
Ph
H
H
H
Ph
COX
THF, 24 h, 65°C
amides including those bearing with
a terminal carbon-
carbon double bond or triple bond, affording alkenyl amides with
high stereoselectivity and excellent yields.
Ph
O
b) Semihydrogenation of internal alkynes, amides and esters
Semi-hydrogenation (partial hydrogenation) of an alkynyl
group to an alkenyl group is an important reaction and used
extensively in synthetic organic chemistry.1 Lindlar’s catalyst, i.
e., calcium carbonate-supported palladium (Pd) modified with
lead (Pb), has been the most frequently used to catalyze semi-
hydrogenation of an alkynyl group with high pressure
hydrogen (1–10 MPa) as hydrogen source.2 Nevertheless, to
reduce the activity of Pd and increase the chemoselectivity of
the product of the alkenyl group, this catalyst system requires
undesirable additives, Pb salts and organic bases. Recently
some other methods for semi-hydrogenation of alkynes have
also been reported and catalyzed by ruthenium3, iridium4,
iron5, aurum6 and nickel7 complexes or nanoparticles. While,
to our best knowledge, copper-catalyzed semi-hydrogenation
of alkynes offers a preferable alternative as copper has higher
earth abundance than precious metals.8
On the other hand, when H2 under high pressure is used as
a hydrogen source for semi-hydrogenation of alkynyl group,
hydrogenation is required to be performed in a pressure-tight
reactor and be monitored to avoid over-hydrogenation to an
alkyl group. Alternatively, transfer hydrogenation has reported
as an encouraging tool to access alkenes from alkynes since it
avoids the use of a flammable gas and complicated
experimental setups.9 Under this circumstance, various H
H
R2
DMF, 80°C
CH3CN, rt
R1
H
H
H
H2O, Mn, [Pd]
R1
R2
R1, R2 = alkyl, aryl
R1
R2
c) This work: partial reduction of alkynyl amide
R1
O
O
[Cu], Ligand, Base
R3SiH, THF, rt
R2
R3
N
H
N
R1
R3
H
R2
R1, R2, R3, = alkyl, aryl
Scheme 1 Semihydrogenation of alkynes.
donors such as formic acid,10 alcohols,11 silanes,12 and others13
have been used in semi-hydrogenation of alkynes. However,
most of the substrates are limited to relative electron-rich
dialkyl, diaryl or alkylaryl alkynes. The semi-hydrogenation of
electron-deficient alkynes such as alkynylesters, amides has
seldom reported. In 2018, Whittaker reported catalytic partial
reduction of alkynylesters, amides, and ketones to form both
(E)- and (Z)- alkenes using H2O as the hydrogen source
(Scheme 1a).14 In 2019, Mei reported semi-hydrogenation of
internal alkynes and alkynoic acid derivatives with H2O as the
hydrogen source (Scheme 1b).15 Nevertheless, highly
stereoselective and regioselective semi-hydrogenation of
alkynyl amide is still scarce. Accordingly,
a transfer
a. Key Laboratory of Functional Molecular Engineering of Guangdong Province,
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China. E-mail: blyin@scut.edu.cn
b. Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University
of Chinese Medicine, Nanning 530200, China.
hydrogenation reaction of alkynyl amide with hydrogen donors
including advantages of safe operations and mild conditions
are required. Herein, we’d like to report a mild steroselective
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
x0xx00000x
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copper catalyzed partial-reduction of alkynyl amide to form ligands were envaluated and dppf was found to be optimal
View Article Online
DOI: 10.1039/D0OB02037K
(entries 18-22). Taken together, the above-described findings
cis-enamide with silane as the hydrogen source.
To optimize the reaction conditions for partial-reduction of indicate that the optimal reaction conditions for 2a was
alkynes, N, N-dimethyl-3-phenylpropiolamide (1a) was chosen determined to involve using CuCl2 as the catalyst, dppf as the
as a model substrate (Table 1). In the presence of CuI as the ligand, Me(EtO)2SiH as the hydrogen source, LiOMe as the
catalyst, dppf as the ligand, Me(EtO)2SiH as the hydrogen base.
source, LiOMe as the base, the reaction in THF at room
temperature gave the hydrogenated product 2a in 86% yield
(entry 1). When Co(OAc)2, FeCl2, CuBr, Cu(OAc)2, CuC2O4 and
Table 2 Substrate scopea
CuF2 were used as the catalyst, 2a was formed lower yields
than CuI (entries 2-7). Notably, no reaction occurred when
NiCl2 served as the catalyst (entry 8). To our pleasure, CuCl2 as
the catalyst led to a higher yield of 96% than CuI (entry 9).
With CuCl2 as the catalyst, a range of silanes of Ph3SiH, Et3SiH,
(SiMe3O)2MeSiH, (EtO)3SiH, (MeO)3SiH and (Ph)2SiH2 were
screened, but all of them afforded 2a in lower yields than
Me(EtO)2SiH (entries 10-15). t-BuOLi as the base led to a
complex reaction mixture, and no 2a was detected (entry 16).
2a was produced in a very low yield of 25% when KOAc was
used as the base (entry 17). Finally, several diphosphine
H
H
O
Me(EtO)2SiH (250 mol %)
R2
R3
R1
CuCl2 (10 mol %), dppf (10 mol %)
LiOMe (250 mol %),THF, N2, rt, 8 h
R1
N
N
R2
O
1
R3
2
H
H
O
H
H
H
H
N
Me
O
N
Et
N
O
2a
2b
2c
, 92%
, 96%
, 91%
H
H
H
O
MeO
H
H
N
Me
H
N
O
N
MeO
O
OMe
2f
2d
2e
, 93%
H
, 98%
H
, 95%
H
Table 1 Optimization of reaction conditionsa
H
N
H
N
H
Catalyst (10 mol %)
H
Ligand (10 mol %)
[Si-H] (250 mol %)
O
H
N
Cl
O
Ph
Ph
Br
O
F
O
N
N
base (250 mol %)
THF, N2, rt, 8 h
2g
2h
2i
, 96%
, 90%
, 98%
H
O
1a
2a
H
F
H
F
H
H
N
H
Entry
1
2
3
4
5
6
7
8
Catalyst
CuI
Co(OAc)2
FeCl2
L
[Si-H]
Base
Yieldb (%)
86
82
70
62
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Ph3SiH
Et3SiH
(SiMe3O)2Me
SiH
(EtO)3SiH
(MeO)3SiH
(Ph)2SiH2
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
Me(EtO)2SiH
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
O
N
O
O
N
H
2j
2k
2l,
99%
, 99%
, 93%
CuBr
H
O
H
Cu(OAc)2
CuC2O4
CuF2
NiCl2
CuCl2
41
37
H
H
H
N
66
S
O
N
N
NRc
96
N
O
2m
, 87%
2n
, 92%
9
2o
, 42%
10
11
12
CuCl2
CuCl2
NR
NR
H
H
H
H
N
H
H
CuCl2
dppf
LiOMe
79
Bn
Et
Ph
O
O
N
O
N
H
13
14
15
16
17
18
19
20
21
22
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
dppf
dppf
dppf
dppf
dppf
L1
dppe
L2
dppp
L3
LiOMe
LiOMe
LiOMe
t-BuOLi
KOAc
LiOMe
LiOMe
LiOMe
LiOMe
LiOMe
68
29
Bn
Et
2p
, 91%
H
2q
, 94%
H
2r
, 99%
71
H
NDd
25
H
N
H
N
56
30
ND
89
95
Ph
OMe
O
O
N
H
O
Ph
b
2t
, 99%
H
2u
, 99%
2s
, 16%(98% )
H
H
H
OBn
PPh2
PPh2
O
N
O
N
O
O
PPh2
PPh2
PPh2
PPh2
Bn
Et
2v
2w
, 83%
, 98%
L1
L2
L3
a Reaction conditions, unless otherwise noted: 1 (0.5 mmol), CuCl2
(0.05 mmol, 10 mol %), dppf (0.05 mmol, 10 mol %), Me(EtO)2SiH
(1.5 mmol, 250 mol%), LiOMe (1.5 mmol, 250 mol %), N2, THF (2
mL), 25°C, 8 h. Isolated yields are given. b CuCl2 (0.5 mmol, 100
mol %), dppf (0.5 mmol, 100 mol %).
a Reaction conditions, unless otherwise noted: 1a (0.25 mmol), THF
(2 mL), N2 atmosphere, room temperature (rt), dppe = 1,2-
bis(diphenylphosphino)ethane, dppf = 1,1'-bis(diphenylphosphino)
ferrocene. b Yields were determined by 1H NMR using CH2Br2 as the
internal standard. c NR = no reaction. d ND = not detected.
2 | J. Name., 2012, 00, 1-3
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With the optimal reaction conditions in hand, the substrate Table 3 Unsuccessful products
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O
scope was explored with 1 bearing various substituents (R1–R3,
Table 2). For the substrates with R2 = R3 = Me, when R1 was a
phenyl group or a phenyl group substituted with an electron-
donating substituent group (Me, Et, MeO) (1a−1e) or two (1f)
or with an electron-withdrawing substituent group (Cl, Br, F)
(1g−1k), the corresponding products were yielded in excellent
yields (90%−99%) which revealed that the electron density of
the benzene ring has little influence on the yields of this
transformation. What’s more, it was demonstrated that the
position of the substituent group on benzene ring did not
influence much on the yields (93%−99%, 2e, 2j and 2k), either.
When R1 was 2-naphthyl or styryl, the reactions also
proceeded well, giving 2l and 2m in 99% and 87% yield,
respectively. When R1 was 2-thienyl or 3-pyridinyl, products 2n
and 2o were obtained in yields of 92% and 42%. 52% recovery
of the reactant 1m indicates the coordination of pyridine ring
with the catalyst may place restrictions on this reaction.
With R1 = Ph, substrates carrying various R2 and R3 groups
were also screened. When R2 and R3 were alkyl groups or aryl
groups, desired products (2p−2r) were obtained in 91−99%
yields. Notably, for 1r bearing two Bn groups, its desired
product 2r was afforded in 99% yield without the reductive
deprotonation of Bn group observed. Product 2s bearing an
allyl group was given in only 16% yield. While increasing the
amount of CuCl2 and dppf to 100 mol %, the yield was raised to
98%. The larger catalyst loading for a much higher yield may
result from consumption of the most copper catalyst
coordinating with the alkene and alkyl functionalities. When R2
= Ph and R3 = H or R2 = MeO and R3 = Me, the corresponding
product 2t and 2u were produced in excellent yields of 99%.
Product 2v bearing a terminal alkyne group was afforded in a
yield of 83%, which indicated that the more electron-rich
alkyne group was tolerated under such conditions. When R2
was Et and R3 was hydroxyethyl protected by Bn, the desired
product 2w was observed in 98% yield.
Some unsuccessful cases were demonstrated in Table 3.
For 1x, in which R2 was a hydroxyethyl and R3 was Et, a
complex reaction mixture was obtained, and product 2x was
not detected. We inferred that the hydroxyl group might
interrupt the transformation. 1y with methyl group of R1 led to
no detection of the product 2y. Phenylpropargylate as the
substrate gave a complex reaction mixture and no 2z was
detected, indicating that very electron-deficient carbon carbon
triple bond was not suitable for this transformation. Finally,
the examination of two relative electron-deficient TMS
phenylethynyl and diphenylethyne were carried out, no
reaction occurred without the formation of 2aa and 2ab.
Clearly, above outcome indicates that the electron-nature of
the alkynes is an important factor for this reaction and alkynyl
amides with moderate electron-density of carbon carbon triple
bond are suitable for this reaction.
O
DOI: 10.1039/D0OB02037K
OMe
Si
(NR)
H
Ph
N
Ph
Et
N
Ph
Ph
Ph
O
OH
a
b
2y
2z
2ab
(ND)
(ND)
(NR)
2x
2aa
(ND)
a ND = not detected. b NR = no reaction.
CuCl2 (10 mol %), dppf (10 mol %)
Li
N
Me(EtO)2SiH (250 mol %)
1a
LiOMe (250 mol %),THF, N2, rt, 2 h
O
B
detected by ESI-HRMS
Scheme 2 Control experiment
Schlenk flask under nitrogen atmosphere. After being stirred at
room temperature for 2 h, the reaction mixture was detected
by ESI-HRMS. Discovery of B indicated that this reaction may
undergo the protodecupration of this intermediate.
On the basis of the above experiments and previous
reports on CuH structure,16 a plausible mechanism was
described in Scheme 3. The reaction of the Cu pre-catalyst
with R3SiH and LiOMe forms the catalytically active species
LCuH. It undergoes cis insertion of alkynyl amides 1 to
generate alkenyl copper intermediate A. Subsequently, with
the σ-bond metathesis of A and LiOMe, LCuOMe and
intermediate B was formed. Protodecupration of B with H2O
would extrude 2. Finally, the metathesis reaction of B and
R3SiH regenerates LCuH.
Conclusions
In summary, we have developed an efficient copper-
catalytic protocol for partial-reduction of alkynyl amides. With
silane as hydrogen donor, Z-α, β-unsaturated amides can be
produced in high yields and high stereoselectivity at room
temperature. This protocol is expected to provide an
L = dppf
LCuCl2 + R3SiH + LiOMe
O
N
LCuH
R3SiOMe
R3SiH
Ph
1
H
CuL
N
Ph
LCuOMe
O
A
H
LiOMe
H
O
Li
N
H
N
To probe the possible mechanism of this partial- reduction,
a control experiment was implemented (Scheme 2). CuCl2 (6.7
mg, 0.05 mmol) and dppf (27.8 mg, 0.05 mmol) were dissolved
in THF. Subsequently, 1 (0.5 mmol), Me(EtO)2SiH (167.8 mg,
1.25 mmol,) and LiOMe (47.5 mg, 1.25 mmol) were added in a
Ph
Ph
H2O
O
B
2
Scheme 3 Proposed reaction mechanism
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J. Name., 2013, 00, 1-3 | 3
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alternative method for the partial-reduction of alkynyl amides
instead of Lindlar’s catalysts.
Angew. Chem. Int. Ed., 2013, 52, 14131; (c) M.VTie.wSAertricrlaenOon,linJe.
R. C. Antonino, V. M. Ruiz, M. L. Haro, J. C. H. Garrido, J. J.
DOI: 10.1039/D0OB02037K
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgments
This work was supported by grants from the National Program
on Key Research Project (No. 2016YFA0602900), the National
Natural Science Foundation of China (No. 21871094),
Guangdong
Natural
Science
Foundation
(No.
2017A030312005), and the Science and Technology Planning
Project of Guangdong Province, China (No. 2017A020216021),
and Guangxi Key Laboratory of Zhuang and Yao Ethnic
Medicine [(2014) No. 32].
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB02037K
Graphical Abstract
CuCl2-catalyzed highly stereoselective and chemoselective reduction of
alkynyl amides into α, β- unsaturated amides using silanes as hydrogen
donors
Linfei Duana, Kai Jiang a, Hua Zhub and Biaolin Yina*
a Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou, P. R. China, 510640
E-mail: blyin@scut.edu.cn
b Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi University of Chinese Medicine，Nanning 530200,
China.
H
O
H
H
CuCl2, dppf, LiOMe
THF, N2, rt, 8 h
R2
R3
R3
R1
N
N
R2
Si
+
O
O
R1
O
Z stereoselective, 20 examples, up to 99% yield
Herein, we describe
a
CuH-catalyzed semi-hydrogenation of alkynyl amides to afford
Z-α,β-unsaturated amides using silane as the hydrogen donor. These reactions are carried out under
mild conditions and able to accommodate broad scope of alkynyl amides including terminal double
bonds and triple bonds, affording alkenyl amides with high stereoselectivity and excellent yields.