Cu-Catalyzed atom transfer radical addition reactions of alkenes with α-bromoacetonitrile

Article abstract of DOI:10.1039/c9cc01988j

A practical, simple, and efficient copper-catalyzed atom transfer radical addition reaction of alkenes with α-bromoacetonitrile is realized. With this methodology, various γ-bromonitriles and β,γ-unsaturated nitriles were efficiently constructed.

Full text of DOI:10.1039/c9cc01988j

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DOI: 10.1039/C9CC01988J
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Cu-catalyzed atom transfer radical addition reactions of alkenes
with α-bromoacetonitrile
Received 00th January 20xx,
Accepted 00th January 20xx
Weiya Pu,a Dani Sun,a Wanyue Fan,a Wenwen Pan,a Qinghui Chai,a Xiaoxing Wanga and Yunhe
Lva,b
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A practical, simple, and efficient copper-catalyzed atom radical addition of α-iodoalkanenitriles to alkenes in the
transfer radical addition reactions of alkenes with α- absence of solvent initiated by electron transfer from copper
bromoacetonitrile is realized. With this methodology, various metal (Scheme 1, eqn a).7 Unfortunately, this method require
γ-bromonitriles and β,γ-unsaturated nitriles were efficiently high metal-catalyst loading (1.3 equiv of copper powder) and
o
constructed.
high temperature (130 C) to obtain the ATRA product in only
moderate yields. Thus far, it was surprising to find in the
literature only this example involving copper as the radical
initiators in ATRA reactions of alkenes with α-iodoacetonitrile.8
We envisioned that a suitable copper-based catalyst could
generate containing cyano and bromine moieties through
ATRA of α-bromoacetonitrile to olefins. As part of our
continuing interest in Cu-catalyzed difunctionalization of
alkenes and alkynes employing α-haloamides as carbon radical
and cross-coupling of α-haloamides with terminal alkynes,9
herein, we report the Cu-catalyzed ATRA reactions of alkenes
with α-bromoacetonitrile, which leads to the formation of γ-
bromonitriles (Scheme 1, eqn b).
β,γ-Unsaturated nitriles are a useful class of substrates.10
They are also key structural units in bioactive compounds such
as the vitamin D receptor and antifungal agents.11 Many
methodologies for the preparation of β,γ-unsaturated nitriles
have been developed in recent decades.12 The cyanation
process of allyl substrates bearing leaving groups such as
halide, acetate, alcohol, phosphate, carbonate, or esters are
frequently used for the synthesis of β,γ-unsaturated nitriles.12a-
f As an alternative method, Huang, Xu, and Lee independently
Nitriles and organobromides are versatile synthetic
intermediates in organic transformations where nitriles are
easily transformed into a variety of functional groups, such as
aldehydes, amines, amides, acids, or other carboxy
derivatives,1 and organobromides are widely used in
nucleophilic substitution, elimination, cross coupling reactions,
and synthesis of organometallic reagent.2 Because of the
broad applications of nitriles and organobromides, many
methods have been developed to introduce cyano or cyano-
containing moieties and bromine atom in the molecule.3
However, new versatile and reliable methods with high
selectivity and atom economy are still needed. Reported by
Kharasch and coworkers in 1945,4 atom transfer radical
addition (ATRA) has been significant developments in
difunctionalization of alkenes as an atom-economical and
reliable method to introduce two functional groups onto
unsaturated C−C bonds in organic synthesis.5 The majority of
these approaches often require peroxides, organotin reagents,
triethyl boron, metal catalysts (such as ruthenium, iron, nickel,
palladium, and iridium), or expensive photocatalyst as the
radical initiators.4b,6 To date, copper-based catalysts have
emerged as the most cost-effective strategy in above
approaches. However, selective Cu-catalyzed ATRA reactions
of alkenes with α-bromoacetonitrile for the synthesis of
various nitriles and organobromides through simultaneously
forming C-C and C-Br bonds, to the best of our knowledge, are
unexplored. In 1995, Metzger and coworkers reported the first
(a) Previous work
R1
R2
I
Cu (1.3 equiv)
R4
R1
R3
CN
R2
+
inert atmosphere
130 oC, 3-7 h
R4
NC
R3
I
2 examples
(b) This work
X
DBU
CuI / Phen
a. College of Chemistry and Chemical Engineering, Anyang Normal University,
Anyang, 455000, P. R. China. luyh086@nenu.edu.cn; lvyunhe0217@163.com
+
R
NC
X
R
CN
CH3CN, 110 o
C
R
CN
b. Jilin Provincial Key Laboratory of Organic Functional Molecular Design
Synthesis, Northeast Normal University, Changchun 130024, P. R. China.
&
N2, 1.0 h
X = Br, I
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Cu-catalyzed ATRA reactions of alkenes with α-
halonitriles
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1 Optimization of the reaction conditionsa
yield when the reaction was performed in absence of K2CO3
View Article Online
(Table 1, entry 2). When the loading of DCOuII: 1w0.a1s03r9e/dCu9CceCd019to882J
mol %, the yield of 3a was dropped to 64%. Other copper salts
such as CuBr and CuCl were also efficient catalyst, affording
product 3a in 82% and 84% yield along with trace amounts of
(E)-4-phenylbut-3-enenitrile 4a, respectively (Table 1, entries 3
and 4). Other ligands such as PPh3, DPPE, TPMA, and Me6tren
did not perform well (Table 1, entries 5–9). An evaluation of
various commonly used solvents revealed that EtOAc and
acetone were also efficient solvents for ATRA reaction (Table 1,
entries 10-12). Further investigation revealed bases have an
important effect for this transformation. To our delight, in the
presence of organic base, the desired ATRA reaction
proceeded to give β,γ-unsaturated nitriles 4a (Table 1, entries
13-16). No desired coupling product was also observed in the
absence of ligand (Table 1, entry 17). In addition, control
experiments demonstrated that the use of the copper as
catalyst was indispensable (entries 18 and 19).
Br
copper salt / L
+
+
Ph
Ph
Br
NC
CN
Ph
CN
base, solvent
1a
2a
3a
4a
yield (%)b
4a
entry metal
ligand
base
solvent
3a
89
91(64)c
82
84
trace
48
47
34
38
45
86
84
65
76
0
1
2
CuI
CuI
CuBr
CuCl
CuI
Phen
Phen
Phen
Phen
none
K2CO3
none
none
none
none
none
none
none
none
none
none
none
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
EtOAc
trace
0
3
trace
trace
0
4
5
6
CuI
PPh3
DPPE
TPMA
trace
trace
6
7
CuI
8
CuI
9
CuI
Me6tren
Phen
Phen
Phen
Phen
Phen
Phen
Phen
none
Phen
Phen
trace
trace
0
10
11
12
13
14
15
16
17
18
19
CuI
CuI
Table 2 Selective synthesis of γ-bromonitriles 3a
CuI
acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
CuI
Na2CO3
K3PO4
Et3N
18
CuI
9
CuI (10 mol%)
X
Phen (20 mol%)
CuI
84
+
R
NC
X
CuI
CuI
DBU
0
90
R
CN
CH3CN, 110 oC, N2
DBU
0
0
X = Br, I
none
none
none
DBU
0
0
1
2
3
0
0
a
Reactions were carried out with 1a (0.3 mmol), 2a (0.6 mmol),
Br
Br
Br
Br
metal (10 mol %), ligand (20 mol %) and base (2.0 equiv) in 1 mL
CN
CN
CN
CN
o
solvent under N2 atmosphere at 110 C for 1.0 h, unless noted
F
Cl
Br
3a, 91%
Br
3b, 91%
3c, 78%b
3d, 81%
b
c
otherwise. Yield of the isolated product. CuI (2 mol %), Phen
(4 mol %). Phen
=
1,10-phenanthroline, DPPE
TPMA
=
1,2-
Br
Br
bis(diphenylphosphino)ethane,
=
tris(2-
CN
CN
CN
pyridylmethyl)amine, Me6tren = tris(2-dimethylaminoethyl)amine,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
O2N
3e, 85%
3f, 66%c
3g, 75%b
Br
Br
Br
Cl
Br
F
employed
azobis(alkylcarbonitriles)
such
as
CN
CN
CN
CN
azobis(isobutyronitrile) (AIBN) and 1,1’-azobis-(cyclohexane-1-
carbonitrile) (ACCN) as a nitrile source for reactions with
cinnamic acids, terminal alkynes or alkynyl carboxylic acids.12g-i
Other methods include hydrocyanation of chiral allenes,
hydrocyanation of butadiene, Ru-catalyzed cross-metathesis
reactions, SmI2-promoted β-elimination reaction, or Wittig
reaction and so on.12j-n However, transition metal catalyzed
ATRA reaction of alkenes with α-bromoacetonitrile for the
preparation of β,γ-unsaturated nitriles are unexplored.
Therefore, we further report the efficient synthesis of β,γ-
unsaturated nitriles though Cu-catalyzed ATRA reaction of
alkenes with α-bromoacetonitrile (Scheme 1, eqn b).
During the investigation of the copper-catalyzed cross-
coupling of secondary α-haloamides with terminal alkynes9c
and intermolecular oxyalkylation of styrenes,9d we observed
that using styrene (1a) and α-bromoacetonitrile (2a) as the
substrates afforded γ-bromonitriles 3a under similar reaction
conditions (Table 1, entry 1). We started our investigation by
applying 1a and 2a in a model reaction to identify the
optimum reaction conditions. Product 3a was obtained in 91%
3h, 90%
3i, 87%
3j, 84%
Br
Br
Br
CN
CN
Br
N
Cl
Br
3k, 81%
3l, 80%
3m, 82%
Br
O
O
MeO
MeO
Br
Br
CN
CN
CN
CN
3n, 76%
3o, 52%
3p, 46%
I
I
I
CN
CN
Cl
Cl
3q, 83%d
3r, 78%d
3s, 80%d
a
Reactions were carried out with 1 (0.3 mmol), 2 (0.60 mmol),
CuI (10 mol %), and Phen (20 mol %) in CH3CN (1 mL) under N2
o
b
atmosphere at 110 C for 1.0 h. Yield of the isolated product.
CuI (2 mol %), Phen (4 mol %). c CuI (2 mol %), Phen (4 mol %),
80 oC. d 80 oC.
2 | J. Name., 2012, 00, 1-3
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standard conditions
(Table 1, entry 2)
Table 3 Selective synthesis of β,γ-unsaturated nitriles 4a
Br
View Article Online
DOI: 10.1039/C9CC01988J
(1)
+
+
NC
NC
Br
Br
Ph
1a
NC
Ph
TEMPO (2.0 equiv)
or BHT (2.0 equiv)
CuI (10 mol%)
2a
2a
3a
Phen (20 mol%)
TEMPO, 0%
BHT, 10%
+
R
NC
Br
R
CN
standard conditions
(Table 1, entry 16)
DBU (2.0 equiv)
CH3CN, 110 oC, N2
1
2a
4
(2)
Ph
Ph
CN
TEMPO (2.0 equiv)
or BHT (2.0 equiv)
1a
4a
TEMPO, 0%
BHT, 16%
CN
Br
CN
CN
CN
Cl
F
Ph
standard conditions
(Table 1, entry 2)
4a, 90%
4b, 92%
4c, 86%
4d, 80%
4h, 81%
(3)
CN
+
+
Br
NC
Br
NC
Ph
CN
CN
CN
CN
CN
5
2a
6
7
O2N
Ph
6 : 7 = 6.5 : 1, and total yield 83%
4e, 77%
4i, 76%
4f, 85%
4g, 87%
CN
O
CN
NC
NC
Br
MeO
EtO
O
4j, 70%
4k, 76%
LCuI
LCuII Br
Ph
F
Br
Cl
CN
CN
CN
CN
CN
Br
DBU
F
Ph
CN
Ph
CN
4l, 91%
4m, 79%
CN
4n, 76%
4o, 91%
Ph
CN
4a
H
3a
Ph
Ph
CN
CN
Cl
Br
4q, 76%
CN
Scheme 2 Proposed mechanism
4p, 81%
4r, 69%
4s, 75%
functional groups, such as F, Cl, Br, nitryl, methyl, tert-butyl,
phenyl and alkoxy, undergo the desired reactions. 1,1-
Diphenylethylene and 1H-indene were also effective to
provide 4s and 4t in 75% and 71% yields, respectively.
Remarkably, the reaction also worked well with 9-vinyl-9H-
carbazole 1u. For 1-chloro-4-(prop-1-en-2-yl)benzene 1v, the
regio-isomers 4v and 4v’ were obtained in 45% and 30% yields,
respectively.
CN
4u, 50%
CN
CN
+
N
Cl
+
Cl
4t, 71%
4v, 45%
4v', 30%
a
Reactions were carried out with 1 (0.3 mmol), 2a (0.6 mmol),
CuI (10 mol %), Phen (20 mol %) and DBU (2.0 equiv) in CH3CN
o
(1 mL) under N2 atmosphere at 110 C for 1.0 h. Yield of the
isolated product.
To investigate the mechanism, some control experiments
were carried out. The reaction between 1a and 2a was
inhibited by adding 2.0 equiv of radical scavenger such as
2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) or 2,6-di-tert-
butyl-4-methylphenol (BHT) [Eq. (1) and (2)]. Furthermore, the
reaction of (1-cyclopropylvinyl)benzene was carried out under
the standard reaction conditions. Interestingly, the ring-
opening product 6 and ring-expanded product 7 was obtained
in 83% total yield [Eq. (3)]. These results revealed that a radical
mechanism may be involved.
On the basis of the above-mentioned experiments results, a
possible radical mechanism was proposed in Scheme 2. Initially,
the Phen-ligated [Cu(Phen)2]+ catalyst reacts with α-
bromoacetonitrile to generate a cyanomethyl radical species3f
and a CuII species by a single electron transfer (SET) process.7,13
Then, addition of cyanomethyl radical to styrene takes place to
give benzyl radical, which reacts with the Cu(II) species to
produce the product 3a and regenerate Cu(I) species to
complete the catalytic cycle. 3a undergoes elimination to give
the desired product 4a in the presence of DBU.
With the optimized conditions in hand, the Cu-catalyzed
ATRA reaction was investigated using different functionalized
styrenes 1 (Table 2). Halo-substituted styrene substrates (1b-
1d, 1h-3l) were tolerated in the ATRA reaction, allowing for
further functionalization through a cross-coupling manifold. In
addition, the para-, meta-, and ortho-chloro, bromo styrene
afforded the corresponding 3c, 3d, 3i-3l in similar yields. The
steric hindrance on the aryl ring played little role in the
reaction. Heteroaromatic alkenes such as 2-vinylpyridine (1m)
was also effective and provided 3m in 82% yield. Starting from
eugenol methyl ether 1n, 3n was obtained in 76% yield.
Aliphatic olefins, such as but-3-en-1-yl benzoate and 4-
bromobut-1-ene were also effective, providing 3o and 3p in 52%
and 46% yields, respectively. Remarkably, in the case of α-
iodoacetonitrile 2b, corresponding alkenes smoothly
underwent ATRA to yield γ-iodonitriles 3q-3s in 78-83% yield.
In all cases, the regioselectivity of the ATRA reaction was
excellent, since radical polymerization were not observed.
We then evaluated the generality of Cu-catalyzed ATRA
reaction for the synthesis of β,γ-unsaturated nitriles using
various alkenes under the optimized reaction conditions (Table
1, entry 16). As described in Table 3, styrenes with different
In conclusion, a novel copper-catalyzed ATRA reaction of
alkenes with α-bromoacetonitrile has been described. This
work provided an atom-economical and efficient route to
synthesize γ-bromonitriles. Moreover, we have also
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6
(a) D. P. Curran, M.-H. Chen, E. Spletzer, C. M. Seong and C.-T.
successfully developed a facile method for the preparation of a
broad spectrum of β,γ-unsaturated nitriles via though Cu-
catalyzed ATRA reaction of alkenes with bromoacetonitrile.
Considering the importance of the Br, alkene and CN
functional groups, this protocol has potential application in
organic synthesis and medicinal chemistry. Further
mechanistic investigations are underway in our lab.
We gratefully acknowledge the National Natural Science
Foundation of China (21801008), the Science& Technology
Foundation of Henan Province (162300410208), the
Foundation of Henan Educational Committee (18A150001),
the Henan Key Laboratory of New Opto-electronic Functional
Materials and Jilin Provincial Key Laboratory of Organic
Functional Molecular Design & Synthesis (130028833) for
financial support.
View Article Online
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Conflicts of interest
The authors declare no conflict of interest.
9
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DOI: 10.1039/C9CC01988J
Table of contents entry
X
CuI / Phen
DBU
+
R
NC
X
R
CN
one-step
CH3CN, 110 o
N2, 1.0 h
C
R
CN
X = Br, I
A novel copper-catalyzed ATRA reaction of alkenes with α-bromoacetonitrile for the synthesis of
γ-bromonitriles and β,γ-unsaturated nitriles was developed.