Synthesis of trisubstituted alkenes by Ni-catalyzed hydroalkylation of internal alkynes with cycloketone oxime esters

Article abstract of DOI:10.1039/d0cc06517j

A method for Ni-catalyzed hydroalkylation of internal alkynes with cycloketone oxime esters was developed. The reaction has a broad substrate scope. This hydroalkylation shows excellent regio-and stereo-selectivity. This method enables readily available starting materials to be used to access a range of cyano-substituted single-configuration trisubstituted alkenes. These are valuable feedstock chemicals and are widely used in synthetic and medicinal chemistry.

Full text of DOI:10.1039/d0cc06517j

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Synthesis of trisubstituted alkenes by Ni-catalyzed
hydroalkylation of internal alkynes with
cycloketone oxime esters†
Cite this:DOI: 10.1039/d0cc06517j
Received 29th September 2020,
Accepted 21st October 2020
ab
a
a
a
a
Xiao-Yu Lu,
*
Chuang-Chuang Liu, Run-Chuang Jiang, Lu-Yu Yan, Qi-Le liu,
a
a
Qing-Qing Wang and Jia-Mei Li
DOI: 10.1039/d0cc06517j
rsc.li/chemcomm
A method for Ni-catalyzed hydroalkylation of internal alkynes with stereo-selectivity. Inspired by this concept, we recently reported
cycloketone oxime esters was developed. The reaction has a broad Ni-catalyzed hydroalkylations of internal alkynes with non-
substrate scope. This hydroalkylation shows excellent regio- and activated alkyl halides (Scheme 1a). This method enables the
stereo-selectivity. This method enables readily available starting efficient synthesis of many single-stereo-configuration trisubsti-
9
materials to be used to access a range of cyano-substituted single- tuted alkenes under mild conditions.
configuration trisubstituted alkenes. These are valuable feedstock
The cyano group is found in a wide range of bioactive
chemicals and are widely used in synthetic and medicinal chemistry. natural products and drug molecules, and a series of novel
1
0
methods have been developed for cyano-group introduction.
Alkenes are important functional moieties in organic synthesis. Recently, the iminyl-radical-triggered C–C bond cleavage of
They are versatile building blocks and are widely used in the cycloketone oxime esters has been reported to be an efficient
1
pharmaceutical, materials, and chemical industries. In recent and straightforward method for accessing diverse valuable
decades, numerous methods have been reported for alkene distally functionalized cyano moieties, with simultaneous con-
2
3
4
11
synthesis, e.g., Wittig, Julia–Kocienski, Heck reactions, and struction of a new C–C/C–X bond. Our interest in Ni-catalyzed
5
alkene metathesis. Single-configuration trisubstituted alkenes alkyne hydroalkylation and trisubstituted alkene synthesis led
are in high demand in synthetic and pharmaceutical chemistry.
6
us to develop a method for Ni-catalyzed hydroalkylation of
The stereoselective synthesis of single-configuration trisubsti- internal alkynes with cycloketone oxime esters (Scheme 1b).
tuted alkenes containing three different carbon-linked groups is This reaction enables efficient cyanide-free synthesis of a range
7
still a considerable challenge in modern organic synthesis. The of cyano-substituted single-configuration trisubstituted
transition-metal-catalyzed cross-coupling reactions of trisubsti- alkenes. The hydroalkylation of cycloketone oxime esters shows
tuted alkenyl metal reagents or trisubstituted alkenyl halides excellent regio- and stereo-selectivity, and provides a method
provide a convenient and straightforward method for the synth- for modifying complex organic molecules.
esis of trisubstituted alkenes. These coupling reactions require
preparation of the corresponding single-stereo-configuration
alkenyl halides or alkenyl metal reagents. However, the stereo-
selective synthesis of these coupling partners is complex and
8
difficult. Recently, intermolecular hydroalkylations of internal
alkynes with electrophilic reagents have been investigated as an
attractive method for synthesizing trisubstituted alkenes.
Such reactions potentially enable the synthesis of a diverse
array of trisubstituted alkenes by controlling the regio- and
a
School of Materials and Chemical Engineering, ChuZhou University, Chu Zhou,
2
39000, China. E-mail: xiaoyulu@mail.ustc.edu.cn
b
School of Chemistry and Chemical Engineering, AnHui University, He Fei, 230601,
China
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Ni-catalyzed hydroalkylation of internal alkynes with cycloketone
d0cc06517j
oxime esters.
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Table 1 Optimization of the reaction conditions
With the optimum conditions in hand, we next investigated
the scope of the Ni-catalyzed C–C bond cleavage hydroalkyla-
tion of cycloketone oxime esters (Table 2). Many substituted
internal alkynes coupled with cycloketone oxime esters to give
the products in moderate to good yields. Both electron-rich and
electron-poor alkynes afforded the desired products in moder-
ate to good yields. The alkyne with different chain length did
not affect the reaction (3a–3d). Importantly, many functional
groups were readily tolerated, e.g., methoxy (3e), chlorine (3f),
trifluoromethyl (3h), trifluoromethoxy (3i), cyano (3j), and ester
a
Entry
Ligand Silane
Base
CO
Solvent T (1C) Yield (%)
(3k) groups. Sulfoether (3l), which is incompatible with
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
DEMS
DEMS
DEMS
DEMS
PMHS
K
2
3
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
NMP
r.t.
r.t
r.t
40
12
16
28
21
5
70
46
35
15
43
5
transition-metal-catalyzed cross-coupling reactions, was com-
patible with this C–C bond cleavage hydroalkylation reaction.
Acetylenes disubstituted with aromatic groups were also
suitable substrates (3m, 3n). The naphthyl (3o) group was also
Na
CO
2 3
NaOAc
KF
r.t
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
3
K
3
K
3
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
3
(EtO) SiH
(Me
(Me
(Me
(Me
(Me
(Me
(Me
(Me
(Me
(Me
(Me
(Me
(Me
2
2
2
2
2
2
2
2
2
2
2
2
2
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
SiH)
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
DMF
THF
Table 2 Scope of the hydroalkylation reaction of internal alkynes with
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
ab
cycloketone oxime esters
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
3
Trace
20
78
83
67
0
40
40
50
40
PO
PO
PO
4
4
4
b
a
1
a (2.5 equiv.), 2a (0.25 mmol), base (2.5 equiv.) and silane (3.0 equiv.)
b
in 0.8 mL solvent for 12 h. No catalyst. The yield was determined by GC
using biphenyl as internal standard. PMHS = Poly(methylhydrosiloxane),
DEMS = Diethoxymethylsilane, NMP = 1-Methyl-2-pyrrolidinone. r.t.
about 25 1C.
We began our study by selecting commercially available
1-phenyl-1-propyne (1a) and cycloketone oxime esters (2a) as
model reaction substrates (Table 1). On the basis of our
previous work on Ni-catalyzed hydroalkylations, we first inves-
tigated the use of analogous catalytic conditions for C–C bond
cleavage hydroalkylation. The coupling product was obtained
in 40% yield (entry 1). Next, we screened other bases, namely
Na
increased the reaction yield (entries 2–4). However, the
obtained yields were lower than that achieved with K CO as
the base. We then used other silanes instead of DEMS (entries
–7). The use of (Me SiH) O as the hydrogen source improved
2 3
CO , NaOAc, and KF, to determine whether their use
2
3
5
2
2
the reaction yield (entry 7). We then examined the effects of
other solvents on the reaction yield (entries 8–10). However, the
use of these solvents decreased the reaction yield. The use of
other ligands, namely 1,10-phenanthroline (L3), terpyridine
(
(
L4), and pybox (L5), significantly decreased the reaction yield
entries 11–14). The optimum reaction conditions were
obtained by increasing the reaction temperature to 40 1C, with
K PO as the base (83% GC yield and 80% isolated yield, entry
3
4
1
7, product ratio 4 25 : 1). Further increasing or lowering the
reaction temperature caused the reaction yield to decrease
entries 15 and 18). A control experiment indicated that the
reaction did not occur in the absence of a Ni catalyst (entry 19). unless otherwise noted.
a
Alkynes (2.5 equiv.), cycloketone oxime esters (0.25 mmol), K
SiH) O (3 equiv.) in 0.8 mL solvent at 40 1C for
2 h. Yields of the isolated products. The product ratio 4 25 : 1
3 4
PO
(2.5 equiv.) and (Me
2
2
(
b
c
1
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tolerated in the reaction. Heterocycles such as benzofuran
The scalability of this Ni-catalyzed C–C bond cleavage
(3p) and quinolone (3q) were also compatible with the reaction hydroalkylation of cycloketone oxime esters was investigated
under the standard conditions; the corresponding products by performing the reaction on a gram scale (Scheme 2).
were obtained in moderate yields. Sterically hindered A vinylsilane product was obtained in 75% yield. This
trimethyl(phenylethynyl)silane (3r) can also be used as the trimethyl(phenylethynyl)silane substrate is incompatible in
hydroalkylation reaction substrate. The reaction with methyl the Ni-catalyzed hydroalkylation of internal alkynes with alkyl
9a
but-2-ynoate (3s) as the substrate also gave the desired alkene halides. Vinylsilanes are important intermediates in synthetic
1
2
with high selectivity. We further examined the substrate scope organic chemistry. They can easily be converted to vinylbro-
of this C–C bond cleavage hydroalkylation by varying the mines, which are key organic synthons and can participate in
cyclobutanone oxime esters structure. Symmetrical cycloketone various coupling reactions. For example, we performed a
oxime esters with a wide array of functional groups, e.g., amide Suzuki cross-coupling reaction of vinylbromine. We confirmed
(3t, 3u, 3x), ester (3v, 4c), phenyl (3w), ether (3y), naph- the configuration of the vinylsilane product on the basis of H–H
thalene (3z), and chlorine (4c), were transformed into the COSY and NOESY spectra.
desired products in 56–77% yields and with high selectivities.
A 2-substituted cyclobutanone oxime ester (4b) was converted (Me
An isotope-labeling experiment was performed with
SiD)2O as the silane. A deuterium-containing trisubsti-
2
to the desired product in 73% yield; selective C–C bond tuted alkene was obtained in moderate yield (Scheme 3). This
cleavage at the more hindered site was achieved because of shows that this Ni-catalyzed hydroalkylation can be used to
generation of a more stable alkyl radical. The conversion of a synthesize single-configuration deuterium-containing trisubsti-
cyclobutanone oxime ester containing internal alkyene (4a) tuted alkenes. This result also confirms that the hydrogen
with an internal alkyne gave the desired product in high yield source is derived from the silane. It is worth noting that
and with an excellent diastereomeric ratio. A less-strained deuterated molecules are important in pharmaceuticals and
1
3
cyclopentanone oxime ester only gave a trace amount of the as tools for understanding metabolic pathways.
desired product under the standard conditions. Alkyl–alkyl
substituted alkynes cannot participate in the reaction.
Various experiments were performed to clarify the reaction
mechanism. The reaction using 0.5 equiv. of the radical-
Next, we investigated the hydroalkylations of cycloketone trapping agent 2,2,6,6-tetramethylpiperidineoxy (TEMPO) was
oxime esters for the late-stage modification of structurally greatly inhibited (Scheme 4, eqn (1)). We performed the reac-
complex biologically active molecules (Table 3). Modification tion with a cycloketone oxime ester carrying an alkene group
of a fructose derivative gave 5a in 72% yield. An indomethacin under the standard reaction conditions (Scheme 4, eqn (2)). In
derivative reacted smoothly with phenyl-1-propyne to afford the this case, only the ring-closure product was isolated. These
desired product 5b in 41% isolated yield with retention of the experiments suggest that a radical intermediate is generated
aryl chloride moiety. Treatment of stigmasterol and cholesterol during this hydroalkylation. A possible catalytic cycle, which is
1
4
derivatives with alkynes afforded the products 5c and 5d in based on these results and those of our previous work, is
good yields. Modification of a vitamin E derivative with phenyl- shown in the Scheme 4.
1
-propyne gave 5e in 75% yield.
In summary, we report here the first example of Ni-catalyzed
C–C bond cleavage hydroalkylation of internal alkynes with
cycloketone oxime esters. A variety of substituted alkynes and
cycloketone oxime esters are suitable reaction substrates. The
hydroalkylation of cycloketone oxime esters shows excellent
regio- and stereo-selectivity. This reaction also provides
ab
Table 3 The modification of complex molecules
a
method for modifying complex organic molecules.
This method provides access to a diverse array of cyano-
substituted single-configuration trisubstituted alkenes. These
are valuable feedstock chemicals and are in high demand in
synthetic and medicinal chemistry.
We are grateful for the support from National Natural
Science Foundation of China (22001029), Natural Science
Foundation of Anhui Province (2008085QB92), and University
Natural Science Research Key Project of Anhui Province.
a
Unless otherwise specified, reactions were performed on a 0.25 mmol
scale of cycloketone oxime esters with 2.5 equiv. alkynes, 10 mol%
NiBr
2
Ádiglyme, 12 mol% ligand, and 3.0 equiv. (Me
2 2
SiH) O in 1 mL of
b
DMAc at 40 1C for 12 h. Yields of the isolated products.
Scheme 2 A Gram-scale reaction and derivatization of product.
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