Copper-Catalyzed Oxidative Coupling of AIBN and Ketone-Derived Enoxysilanes to γ-Ketonitriles

Article abstract of DOI:10.1021/acs.orglett.8b02154

A new and efficient oxidative coupling reaction between enoxysilane and alkylnitrile radicals derived from readily available AIBN and its analogues has been developed by using redox-active metal as a catalyst in which the redox-active copper is used for enhancing the electrophilicity of a free radical via coordination and bringing the radical and nucleophilic enol ether closer to facilitate the single-electron transfer. The present catalytic protocol afforded a variety of γ-ketonitriles in good to excellent yields with good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b02154

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Oxidative Coupling of AIBN and Ketone-Derived
Enoxysilanes to γ‑Ketonitriles
†
,†,‡
Xuexia Zhang and Hanmin Huang*
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in
Molecular Synthesis, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, 230026, P. R. China
‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, P. R. China
*
S Supporting Information
ABSTRACT: A new and efficient oxidative coupling reaction
between enoxysilane and alkylnitrile radicals derived from readily
available AIBN and its analogues has been developed by using
redox-active metal as a catalyst in which the redox-active copper is
used for enhancing the electrophilicity of a free radical via coordination and bringing the radical and nucleophilic enol ether
closer to facilitate the single-electron transfer. The present catalytic protocol afforded a variety of γ-ketonitriles in good to
excellent yields with good functional group tolerance.
9
itriles are prevalent functional groups in biologically
isobutyronitrile radical derived from AIBN. Recently, we
developed an efficient strategy for directing and accelerating
the single electron transfer between a free radical and a
nucleophile via bridging them with a metal complex (Scheme
N
active molecules and important synthetic intermediates
1
for fine chemicals and materials. In particular, ketonitriles are
important building blocks for the synthesis of various
pharmaceuticals and bioactive compounds, such as pyridi-
11
1, eq 1). This strategy has been successfully applied to
2
3
4
nones, α-hydroxy ketones, and thiophenes. The direct
installation of a CN functional group into an enone via
nucleophilic addition is one attractive route to γ-ketonitriles.
However, a long-standing challenge that plagues these
reactions is to find an active and less toxic CN source. In
this context, a series of less toxic CN sources such as TMSCN
and cyanohydrin have been explored and employed in these
Scheme 1. Background of the Method Development
5
reactions. However, a tedious procedure was generally
required for preparation of these CN sources, which reduced
the appeal of these processes and hindered large-scale
applications. On the other hand, alkyl nitriles could also be
utilized as nitrile sources through the direct C−H function-
alization, which represents one of the most efficient and low-
6
toxic strategies for the synthesis of substituted nitriles. In this
context, a radical involved process toward γ-ketonitriles from
alkyl nitriles and simple alkenes has been developed by Wang
and co-workers, in which the C−H bond of the alkyl nitriles
was cleaved via a radical process in the presence of a
7
superstoichiometric amount of strong oxidants. However, this
harness the reactivity of the isobutyronitrile radical derived
from AIBN and has enabled a novel cascade reaction with
AIBN and cinnamic acids (Scheme 1, eq 2). Mechanistic
studies have been conducted and have disclosed that the
energy of the SOMO of the isobutyronitrile radical was
reduced via coordination of its nitrile group with the copper,
enabling the radical species to be more electrophilic to be
attacked by the MBH-enolate, furnishing an oxidative coupling
reaction in the presence of oxidant. Naturally, we have been
interested in determining whether this strategy is general and
system suffered from lower yields, limited substrate scope.
Therefore, it is desirable and challenging to explore simple and
nontoxic nitrile sources as well as an efficient method to
prepare γ-ketonitriles.
Azobis(isobutyronitrile) (AIBN) is a commercially available
radical precursor and is one of the most widely used radical
initiators in polymer chemistry and radical-mediated synthetic
organic chemistry. In general, AIBN usually does not get
involved as a reactant in radical reactions or polar reactions,
although it might be used as a good “CN” source from the
8
viewpoint of utility in organic synthesis. This is largely due to
Received: July 10, 2018
the inherently lower nucleophilicity and electrophilicity of the
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02154
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
can be employed for reaction partners other than MBH-
enolates. For example, we were intrigued by the possibility of
synthesizing γ-ketonitriles via the treatment of AIBN with
ketone-derived enoxysilanes through the above strategy.
Herein, we report a novel copper-catalyzed oxidative coupling
reaction between AIBN and enoxysilanes. The present reaction
provides a new route to γ-ketonitriles with good to excellent
yields from simple starting materials (Scheme 1, eq 3).
14). The yield diminished slightly when the temperature was
changed from 100 to 80 °C or 120 °C (Table 1, entries 15 and
16). The desired product could be obtained in relatively lower
yield when the reaction was carried out in the absence of
copper catalyst under otherwise identical reaction conditions
(
Table 1, entry 17). Only 38% yield of the target product 3aa
was obtained when a stoichiometric amount of Cu-
CH COCHCO C H ) was utilized in the absence of
(
3
2
2
5 2
We initiated our studies by implementation of the reaction
of trimethyl((1-phenylvinyl)oxy)silane (1a) with AIBN (2a) in
the presence of a catalytic amount of CuCl and a
stoichiometric amount of Ag CO . To our delight, the desired
Ag CO (Table 1, entry 18). Increasing the loading of
2
3
Ag CO to 2.0 equiv did not improve the yield of the desired
2
3
product (Table 1, entry 19). Notably, no desired product 3aa
was observed in the absence of copper and silver salts. All
together, these results strongly indicate that the combination of
a suitable oxidant and copper source is critical for the present
transformation.
2
3
product 3aa was obtained in 45% yield together with 4aa was
obtained as byproduct when the reaction was conducted at 100
°C in anisole (Table 1, entry 1). Solvent screening revealed
a
To explore the synthetic utility of this process, we have
investigated the generality of the present process. A series of
enoxysilanes derived from different ketones were subjected to
this process under the catalysis of Cu(CH COCHCO C H ) .
Table 1. Optimization of Reaction Conditions
3
2
2
5 2
As shown in Scheme 2, substituted acetophenone-derived
yield (%)
solvent temp (°C) 3aa 4aa
a
Scheme 2. Substrate Scope of Enoxysilanes
entry
[Cu]
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl
CuCl
CuBr
CuCN
anisole
DCE
xylene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
45
41
35
60
66
61
50
52
72
85
77
69
44
84
78
75
66
38
74
28
47
32
20
24
25
8
30
<5
<5
<5
<5
<5
<5
13
<5
<5
15
<5
Cu(CH CN) PF
3
4
6
Cu (PO )
4 2
3
Cu(CF COCH COCF )
3 2
3
2
1
1
1
1
1
1
1
1
1
1
0
Cu(CH COCHCO C H )
3 2 2 5
2
2
2
2
2
2
2
b
1
2
3
4
5
6
7
8
9
Cu(CH COCHCO C H )
3 2 2 5
c
Cu(CH COCHCO C H )
Cu(CH COCHCO C H )
Cu(CH COCHCO C H )
Cu(CH COCHCO C H )
3
2
2
5
d
e
3
2
2
5
3
2
2
5
3
2
2
5
Cu(CH COCHCO C H )
120
100
100
100
3
2
2
5
f
Cu(CH COCHCO C H )
Cu(CH COCHCO C H )
3
2
2
5
2
2
g
3
2
2
5
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [Cu] (0.05
mmol, 10 mol %), Ag CO (0.5 mmol), solvent (2.0 mL), 100 °C, 12
2
3
b
c
d
e
h, isolated yield. 2a (1.5 mmol). 2a (2.0 mmol). 100 °C, 6 h. 100
f
°
C, 24 h. Ag CO3 (0 mmol), Cu(CH COCHCO C H ) (0.5
2 3 2 2 5 2
g
mmol). Ag CO (1.0 mmol).
2
3
that THF was the best choice for giving the desired product in
6
0% yield (Table 1, entries 1−4). Afterward, we began to
optimize the reaction conditions by screening different copper
catalysts. As shown in Table 1, both Cu(I) and Cu(II) can
catalyze the present reaction, and Cu(CH COCHCO C H )
5 2
3
2
2
was found to be the most efficient catalyst, affording the
desired product in 85% yield with excellent chemoselectivity
(
Table 1, entries 4−10). With Cu(CH COCHCO C H ) as
3
2
2
5 2
the catalyst, other reaction parameters were screened to
maximize the efficiency of this coupling reaction. This study
led to the finding that increasing the amount of AIBN
decreased the yield of the desired product (Table 1, entries 11
and 12). Further shortening or prolonging of the reaction time
showed a negative effect on the yield (Table 1, entries 13 and
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), Cu-
(CH COCHCO C H ) (10 mol %), Ag CO (0.5 mmol), THF
3
2
2
5
2
2
3
(2.0 mL), 100 °C, 12 h, isolated yield.
B
DOI: 10.1021/acs.orglett.8b02154
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
enoxysilanes, which bear substituted groups such as methyl,
methoxyl, chloro, bromo, fluoro, iodine, and trifluoromethyl at
the para or meta positions, all reacted smoothly to afford the
desired corresponding products in good to excellent yields,
except in the case of reaction with sterically hindered ortho-
substituted substrates. These results indicate that there is no
major electronic effect on the substitution pattern of the
substrates. In addition, the reaction performed well with
naphthyl-substituted enoxysilane to afford the desired product
in 85% yield (3ma). Meanwhile, heteroaromatic ketone-
derived enoxysilanes were also suitable for this coupling
reaction. When 2-acetalfuran-, 2-acetylthiophene-, and 2-
acetylpyridine-derived enoxysilanes were used as substrates,
the corresponding γ-ketonitriles were obtained in good yields
Scheme 4. Reaction Scale-up and Functional Group
Transformation
eq 1). In addition, the product 3aa could be easily transformed
into amino alcohol (Scheme 4, eq 2) via treatment of the
product 3aa with LiAlH , which could find some applications
(
(
3na−pa). However, only 22% yield was obtained when the 1-
4
in synthetic organic chemistry.
pyridin-4-yl)ethan-1-one derived enoxysilane was subjected to
Based on the present experimental data and our precedent
the reaction conditions. In addition to the coupling reactions
with aromatic ketone-derived enoxysilanes, we also examined
the coupling reaction with enone-derived enoxysilane. Utilizing
the optimized reaction conditions, benzalacetone-derived
enoxysilane can be converted to the corresponding product
in 40% yield (3ra). Unfortunately, cyclic ketone and simple
aliphatic ketone derived enoxysilanes could not afford the
desired products under the current reaction conditions. The
lower activity observed here might be rationalized in terms of
the stronger Si−O bond of the enoxysilanes derived from
10
results, a plausible reaction pathway for the present Cu-
catalyzed oxidative cross-coupling reaction is proposed in
Scheme 5. In this scenario, the active copper catalyst initially
Scheme 5. Plausible Reaction Mechanism
1
1
aliphatic ketones. Further experiments demonstrated that
other nitrile-containing radicals, derived from 2,2′-azobis(2-
methylbutyronitrile) (2b), 1,1′-azobis(cyclohexane-1-carbon-
itrile) (2c), and 2,2′-azobis(2,4-dimethylvaleronitrile) (2d),
were successfully incorporated into enoxysilane 1a to afford
the corresponding products (3ab−ad) in 53−74% yields.
To gain insight into the reaction mechanism, several control
experiments were conducted (Scheme 3). Radical trapping by
Scheme 3. Control Experiments
coordinates with the free isobutyronitrile radical, which was
generated from AIBN on heating, to form intermediate A. The
coordination of the nitrile group to Cu(II) makes the radical
species more electrophilic to be attacked by the nucleophilic
enoxysilane through the intermediate B, which is formed via
transmetalation. The resulting Cu-bridge brings the radical and
the enolate closer, which is beneficial to direct and accelerate
the single-electron transfer between the radical and the enolate
confined in the assembly to construct a new C−C bond, giving
the desired product together with Cu(I). Finally, the Cu(I)
species was oxidized to Cu(II) by Ag CO to complete the
catalytic cycle.
introducing TEMPO into the standard reaction was carried
out, and the result shows that the reaction was completely
inhibited. The radical-trapping product 2-((2,2,6,6-tetrame-
thylpiperidin-1-yl)oxy)propanenitrile was observed (Scheme 3,
eq 1), which indicated that a free-radical process was indeed
involved. Upon treatment of 3aa with AIBN under the
standard reaction conditions, no 4aa was detected, and the 3aa
was fully recovered (Scheme 3, eq 2). This result suggests that
the byproduct 4aa is most likely produced from the
noncatalytic background reaction of free-radical addition
process between 1a and 2a.
To further demonstrate the synthetic utility, we tested the
synthesis of γ-ketonitriles on gram scale. When 10 mmol of
enoxysilane 1a was reacted with 20 mmol of AIBN 2a in the
presence of 5 mol % of copper catalyst, the corresponding
product 3aa was obtained in 83% isolated (1.55 g, Scheme 4,
2
3
In summary, we have developed a novel and simple copper-
catalyzed oxidative coupling reaction between AIBN and
enoxysilanes. This method delivers a set of γ-ketonitriles with
good functional-group compatibility. A free-radical process was
involved in this method, in which the redox-active copper is
used for enhancing the electrophilicity of free radical via
coordination and bringing the radical and nucleophilic enol
ether closer to facilitate the single electron transfer. This
method provides a novel approach to C−C bond formation,
which can potentially employ to a range of transition-metal-
catalyzed radical involved oxidative coupling reactions. Further
studies on expanding the scope of this copper-catalyzed radical
activation strategy are in progress.
C
DOI: 10.1021/acs.orglett.8b02154
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Z.; Xiao, Y.; Liu, Z.-Q. Chem. Commun. 2015, 51, 9969−9971.
ASSOCIATED CONTENT
Supporting Information
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(i) Chu, X.-Q.; Meng, H.; Zi, Y.; Xu, X.-P.; Ji, S.-J. Org. Chem. Front.
*
S
2
015, 2, 216−220. (j) Chu, X.-Q.; Xing, Z.-H.; Meng, H.; Xu, X.-P.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02154.
Ji, S.-J. Org. Chem. Front. 2016, 3, 165−169. (k) Liu, Z.-Q.; Li, Z.
Chem. Commun. 2016, 52, 14278−14281. (l) Chu, X.-Q.; Ge, D.;
Shen, Z.-L.; Loh, T.-P. ACS Catal. 2018, 8, 258−271.
(
7) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Lan, C.-L.; Zhang, T.; Chen,
Experimental details and full spectroscopic data for all
new compounds (PDF)
S.-L.; Xing, Y. Org. Lett. 2016, 18, 5986−5989.
8) (a) Zhang, M.; Sheng, W.; Ji, P.; Liu, Y.; Guo, C. RSC Adv. 2015,
, 56438−56443. (b) Zhou, D.; Li, Z.-H.; Li, J.; Li, S.-H.; Wang, M.-
(
5
AUTHOR INFORMATION
Corresponding Author
W.; Luo, X.-L.; Ding, G.-L.; Sheng, R.-L.; Fu, M.-J.; Tang, S. Eur. J.
Org. Chem. 2015, 2015, 1606−1612. (c) Tang, S.; Deng, Y.-J.; Li, J.;
Wang, W.-X.; Wang, Y.-C.; Li, Z.-Z.; Yuan, L.; Chen, S.-L.; Sheng, R.-
L. Chem. Commun. 2016, 52, 4470−4473.
■
*
hanmin@ustc.edu.cn
ORCID
(
9) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.;
Geerlings, P.; De Proft, F. Org. Lett. 2007, 9, 2721−2724.
10) Xie, Y.; Guo, S.; Wu, L.; Xia, C. Angew. Chem., Int. Ed. 2015, 54,
5900−5904.
11) (a) Song, J. J.; Tan, Z.; Reeves, J. T.; Yee, N. K.; Senanayake, C.
Hanmin Huang: 0000-0002-0108-6542
Notes
(
(
The authors declare no competing financial interest.
H. Org. Lett. 2007, 9, 1013−1016. (b) Omoto, K.; Fujimoto, H. J. Am.
Chem. Soc. 1997, 119, 5366−5372.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (21672199, 21702197, and 21790333),
the CAS Interdisciplinary Innovation Team, and the Anhui
Provincial Natural Science Foundation (1708085MB28).
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DOI: 10.1021/acs.orglett.8b02154
Org. Lett. XXXX, XXX, XXX−XXX