Copper-Catalyzed C-H Stereoselective Cyanation of Alkenes by Using an α-Iminonitrile as a Cyanating Reagent

Article abstract of DOI:10.1055/s-0037-1610680

The first copper-catalyzed cyanation through alkene C-H bond activation by using an α-iminonitrile as a cyanating agent has been realized. The approach efficiently constructs acrylonitriles in good yields with the advantages of high regioselectivity, cost

Full text of DOI:10.1055/s-0037-1610680

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
C.-B. Chen et al.
Letter
Synlett
Copper-Catalyzed C–H Stereoselective Cyanation of Alkenes by
Using an -Iminonitrile as a Cyanating Reagent
Chen-Bang Chen
Qing-Qing Gao
Kui Liu
R3
N
R1
R1
Cu(TFA)2
N
R2
CN
+
N
THF, air, 120 °C
NC
Yong-Ming Zhu*
H
1
2
3
College of Pharmaceutic Science, Soochow University, Suzhou
215123, P. R. of China
zhuyongming@suda.edu.cn
The first Cu-catalyzed alkenes C–H
bond cyanation
16 Examples; up to 87% yield
High regioselectivity
Cu(II)-promoted C–CN bond cleavage
Operational simplicity
Received: 20.09.2018
Accepted after revision: 18.11.2018
Published online: 13.12.2018
Moreover, acrylonitriles can be easily converted into
other important functionalized compounds. Consequently,
many methods for synthesizing acrylonitrile derivatives
have been developed, including the Peterson olefination,2
the Wittig/Horner−Wadsworth−Emmons reaction,3 acryl-
amide dehydration,4 carbocyanation of alkynes,5 cross-me-
tathesis,6 and oxime dehydration.7 However, these methods
suffer from various drawbacks, such as a limited substrate
scope or poor stereoselectivity. To circumvent such prob-
lems, alternative methods have been developed, including
the transition-metal-catalyzed cyanation of alkenyl ha-
lides8 or alkenyl metal reagents.9 However, this also has
some disadvantages, in that it requires prior functionaliza-
tion of the starting materials, which often leads to poor
compatibility with some functional groups.
In the last decade, direct C–H activation has emerged as
a straightforward and useful tool for organic synthesis.10
The majority of the currently developed C−H activation re-
actions, especially, in the field of alkene C–H bonds activa-
tion, employ precious second-row transition-metals such
as rhodium,11 palladium,12 ruthenium,11a,13 or other met-
als14 as catalysts (Scheme 1, a). For instance, Loh and co-
workers developed palladium-catalyzed12a and rhodi-
um(III)-catalyzed11a direct C−H activations of alkenes. Sub-
sequently, Zhang, Zhong, and co-workers13a developed a ru-
thenium-catalyzed direct C–H activation reaction of elec-
tron-deficient alkenes. In addition, transition-metal-
catalyzed aromatic C–H cyanation reactions have been ex-
tensively studied (Scheme 1, b),15 whereas there are few re-
ports of the direct cyanation of nonactivated alkene C–H
bonds. In 2013, Wang and Falk reported the first example of
an intramolecular C–H cyanation of a styrene through a
rhodium(I)/palladium-catalyzed N–CN bond-cleavage reac-
tion (Scheme 1, c).16 Later, Chaitanya and Anbarasan11b ac-
complished a selective, rhodium-catalyzed, chelation-as-
sisted cyanation of the C−H bonds of alkenes, and in 2015,
Fu and co-co-workers reported a Rh(III)-catalyzed direct vi-
nylic C–H cyanation reaction for the synthesis of alkenyl ni-
triles (Scheme 1, d).11d
DOI: 10.1055/s-0037-1610680; Art ID: st-2018-w0607-l
Abstract The first copper-catalyzed cyanation through alkene C–H
bond activation by using an -iminonitrile as a cyanating agent has
been realized. The approach efficiently constructs acrylonitriles in good
yields with the advantages of high regioselectivity, cost-benefit, and op-
erational simplicity.
Key words copper catalysis, C–H activation, cyanation, iminonitriles,
alkenes, acrylonitriles
,-Unsaturated nitriles (acrylonitriles) are an import-
ant building blocks in organic synthesis, and are often im-
portant constituents of pharmaceutically relevant mole-
cules.1 Some examples of such products that are currently
used in the pharmaceutical industries are shown in Figure 1.
NO2
NC
NH
N
HO
HO
N
Et
N
NH
NC
Et
NC
O
Entacapone
treatment of Parkinson's disease
Rilpivirine
treatment of HIV infection
Cl
Cl
N
N
N
N
Chlorpheniramine
antihistamine drug
Triprolidine
anticholinergic drug
Figure 1 Examples of pharmaceutically important acrylonitriles
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
C.-B. Chen et al.
Letter
Synlett
peared to be the most effective (entries 8–13). We also tried
reducing the amount of Cu(II) in the catalyst system (en-
tries 15 and 16), but obtained a lower yield, suggesting that
the copper serves not only as a catalyst, but also as an oxi-
dant.
a, Alkene C–H bond activation reactions
R1
R2
DG
R1
DG
Allyl
or
[M]
+
NR3
[M] = [Pd], [Rh], [Ru], [Co]
R2
X
2
X/Allyl
X = Br, I
Table 1 Optimization of the Reaction Conditionsa
b, Transition-metal-catalyzed aromatic C–H cyanation reactions
DG
DG
transition-metal-catalyzed
+
''CN''
R
H
t-Bu
R
additives (2.0 equiv)
N
C–H activation
CN
+
N
N
solvent, 24 h
Ph
CN
c, Intramolecular C–H cyanation of styrenes
R2
NC
R2
1a
2
3a
[Rh]/[Pd]
R1
R1
CN
N
Entry
Additive
Solvent
Temp (°C)
Yieldb (%)
CN
NH
Ts
Ts
1
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
CuCl2
THF
100
100
100
100
100
80
71
d, Rhodium-catalyzed cyanation of alkene C–H bonds
2
toluene
1,4-dioxane
DCE
33
DG
DG
3
65
cat. [Rh]
NCTS
+
H
CN
4
40
R
R
DG = CONiPr2, MeC=NOMe, Py
5
DMF
THF
37
6
55
e, This work
7
THF
120
120
120
120
120
120
120
120
120
120
120
120
73
R
Cu(TFA)2
R
8
THF
<10
trace
<10
0
+
α-iminonitrile
N
N
THF, air, 120 °C
9
CuBr2
THF
NC
10
11
12
13
14
15
16
17
18
Cu(OAc)2
THF
Scheme 1 Transition-metal-catalyzed alkene C–H bond-activation and
cyanation reactions
Cu(OTf)2
THF
CuSO4
THF
trace
0
CuI
THF
Noble metals are used as catalysts in almost all the
above cases, which adds to the cost of the reactions and is
not conducive to industrial manufacture. With the advan-
tages of greater abundance, lower price, ready availability,
and lower toxicity, a number of first-row transition metals
have recently been used increasingly as catalysts for C−H
activation reactions.17 Inspired by these pioneering works,
and as a continuation of our interest in developing simpler
and more-efficient methods for cyanation,4,18 we describe a
C–H cyanation reaction of alkenes in which copper is used
as a catalyst (Scheme 1, e).
Initially, we found the cyanation of aromatic C–H bonds
with an -iminonitrile as a nitrile source proceeded in good
yield in the absence of palladium.18b Encouraged by this re-
sult, we attempted to using copper to catalyze the cyana-
tion of alkene C–H bonds. We started our investigations by
using 2-(1-phenylvinyl)pyridine as a model substrate with
1.5 equivalents of (2E)-(tert-butylimino)(phenyl)acetoni-
trile (2) and 2.0 equivalents of Cu(TFA)2·xH2O in tetrahydro-
furan (THF) under air at 100 °C for 24 hours.19 To our sur-
prise, the acrylonitrile 3a was obtained in 71% yield (Table
1, entry 1). Subsequently, various solvents were screened
(entries 2–5); however, none of these was superior to THF.
Raising the temperature increased the yield of product (entries
6 and 7). Catalyst screening showed that Cu(TFA)2·xH2O ap-
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
–
THF
58c
40d
66e
0
THF
THF
THF
Cu(TFA)2·xH2O
THF
70f
a Reaction conditions: 1a (0.5 mmol), 2 (1.5 equiv), additive (2.0 equiv),
solvent (2 mL), 24 h, under air in a sealed tube.
b Isolated yield.
c 12 h.
d Additive (1.2 equiv).
e Additive (1.5 equiv).
f H2O (10.0 equiv).
Because the cyanation of 1a does not take place in the
absence of a copper salt (Table 1, entry 17), we consider
that the copper(II) cation plays a key role in the process of
C–CN bond cleavage to provide cyanide anions. Therefore, a
possible catalytic mechanism for the cyanation reaction is
depicted in Scheme 2. First, 2 undergoes copper-promoted
C–CN bond cleavage to generate intermediate A, which is
hydrolyzed to form the copper cyanide species B and N-
tert-butylbenzamide. Complex B then participates in the
copper-catalyzed cyanation cycle, which is initiated by oxi-
dative addition of alkene 1a to form intermediate C. Subse-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
C.-B. Chen et al.
Letter
Synlett
quently, intermediate C undergoes copper-catalyzed oxida-
tive C–H activation to form intermediate D, which under-
goes reductive elimination to give product 3a.
R1
R2
N
1
Cull
t-Bu
Cu(TFA)2 (2.0 equiv)
THF, 120 °C, 24 h
N
R2
R1
+
2
t-Bu
N
N
Ph
CuCN
H2O
A
NC
Ph
CN
O
3
2
Ph
NHtBu
1a
TFA CullCN
N
N
N
B
NC
NC
3a, 73%
NC
air
3b, 45%
3c, 52%
Cl
F
TFA Cul
N
CuII
N
N
N
TFA
CN
NC
3d, 85%
NC
N
NC
3f, 48%
3e, 54%
C
O
CF3
Ph
3a
Cull
N
CuIII
N
N
N
N
TFA
CN
NC
NC
NC
Cul
3i, 53%
3g, 60%
3h, 37%
D
air
S
O
Bn
Scheme 2 Proposed mechanism
N
N
With the optimized conditions in hand, we then investi-
gated the substrate scope of this reaction by changing the
substitution on the arene and the directing group (Scheme
3). Cyanation of 2-(1-phenylvinyl)pyridine derivatives with
para-, meta-, or ortho-groups on the phenyl ring proceeded
smoothly and showed excellent monoselectivity. Substrates
bearing either electron-rich or electron-deficient substitu-
ents at the para-position of the phenyl ring all worked well.
Trisubstituted alkenes were compatible with our condi-
tions, giving the corresponding cyanated products in mod-
erate to good yields. In addition, 5-methyl-2-(1-phenylvi-
nyl)pyridine underwent a smooth reaction to give the de-
sired product 3p in 67% yield. It is necessary to mention
that the electronic effect of the pyridine ring has a marked
effect on the reaction, because when compounds contain-
ing a fluoro-substituted pyridine, or other directing groups
such as quinoline, were tested under our conditions, none
of the desired products were obtained.
NC
NC
NC
NC
3l, 50%
3j, 19%
3k, 49%
N
N
N
NC
3n, 51%
NC
NC
3m, 66%
3o, 87%
3p, 67%
Scheme 3 Cyanation of alkene substrates. Reaction conditions: 1a (0.5
mmol), 2 (1.5 equiv), Cu(TFA)2 (2.0 equiv), THF (2 mL), 120 °C, 24 h,
sealed tube. Isolated yields are reported.
Funding Information
This work was supported by the PAPD (A project funded by the Priori-
ty Academic Program Development of Jiangsu Higher Education Insti-
tutions).()
In conclusion, we have developed the first example of a
copper-catalyzed cyanation of nonactivated C–H bonds of
alkenes by using an -iminonitrile as a cyanating reagent.
This approach provides an alternative route for the synthe-
sis of acrylonitriles with high regioselectivity and good
cost-effectiveness. Further investigations on the synthetic
applications of the present method are currently underway
in our laboratory.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610680.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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C.-B. Chen et al.
Letter
Synlett
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(19) 3-Phenyl-3-pyridin-2-ylacrylonitrile; Typical Procedure
A solution of 1a (0.50 mmol), -iminonitrile 2a (139.5 mg, 0.75
mmol), and Cu(TFA)2 (1.0 mmol) in THF (2.0 mL) was stirred at
120 °C for 24 h, then cooled to r.t. The solvent was then evapo-
rated in vacuo, and the residue was purified by column chroma-
tography [silica gel, PE–EtOAc (9:1)] to give a brown oil; yield:
75 mg (73%).1H NMR (400 MHz, CDCl3):  = 8.7 (d, J = 3.6 Hz, 1
H), 7.8 (t, J = 7.3 Hz, 1 H), 7.5 (d, J = 7.8 Hz, 1 H), 7.4–7.3 (m, 4 H),
7.3 (d, J = 7.2 Hz, 2 H), 5.8 (s, 1 H). 13C NMR (151 MHz, CDCl3):
 = 161.2 (s), 155.1 (s), 150.0 (s), 137.7 (s), 136.8 (s), 130.5 (s),
128.8 (s), 128.4 (s), 125.0 (s), 124.4 (s), 117.4 (s), 97.3.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D